Review 83

Tetrahedron: Asymmetry 24 (2013) 11491188
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Tetrahedron: Asymmetry Report Number 144
Oxazolidinones as chiral auxiliaries in asymmetric aldol reactions

applied to total synthesis
Majid M. Heravi , Vahideh Zadsirjan
Department of Chemistry, School of Science, Alzahra University, Vanak, Tehran, Iran
a r t i c l e
i n f o
Article history:
Received 17 June 2013
Accepted 14 August 2013
a b s t r a c t
Asymmetric aldol reactions of oxazolidinones as chiral auxiliaries have been achieved and attracted
signicant consideration as one of the most powerful synthetic tools for the carboncarbon bond-forming
reactions. The methodology has been highly successful in the stereoselective construction of a number of
natural products, antibiotics, and other medicinally important compounds. The present review is focused
on the utility and versatility of oxazolidinones (Evans chiral auxiliaries) in the asymmetric aldol condensations for the total synthesis of natural products and complex targets.
2013 Elsevier Ltd. All rights reserved.
Contents
1.
2.
3.
4.
5.
6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Asymmetric catalyzed aldol reactions of oxazolidinones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.
Generation of boron enolates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.
Applications in total synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Asymmetric aldol reaction of oxazolidinones. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.
Generation of titanium enolates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.
Asymmetric aldol reaction of oxazolidinones. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.
Generation of magnesium enolates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.
Removal of the oxazolidinone auxiliary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusions and future prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
Oxazolidin-2-ones, were disclosed in 1981 by Evans et al.1 to
have numerous applications and since then a great number of structural modications of these auxiliaries have been reported.210
A chiral auxiliary is an optically active chemical compound that is
added temporarily to an organic reaction and it can convey chirality
with an expected stereochemistry in newly formed stereocenters.
The 2-oxo-1,3-oxazolidine ring is a cyclic carbamate framework
which is fairly rare in natural products but extremely popular and
useful in the asymmetric synthesis of organic compounds. Evans
reported on the use of enantiomerically pure 4-substituted
Corresponding author. Tel.: +98 129121329147; fax: +98 2188041344.
E-mail address: mmh1331@yahoo.com (M.M. Heravi).
0957-4166/$ - see front matter 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.08.011
1149
1151
1151
1153
1180
1180
1181
1183
1183
1184
1185
1186
1187
oxazolidin-2-ones as chiral auxiliaries in asymmetric synthesis.

Oxazolidinones also have various applications as protective groups
in the 1,2-aminoalcohol system. Linzolid has recently introduced
an oxazolidin-2-one as an antibacterial drug, in the pharmaceutical
market.11 Some oxazolidinones (generally called Evans auxiliaries)
such as Evans oxazolidinone, mono substituted oxazolidinones 1
and 2, the more highly substituted oxazolidinones 3 and 4, and
Super Quats 5 are extremely popular and useful in asymmetric
synthesis (Fig. 1).212
Evans oxazolidinones are among the most important and
broadly used chiral auxiliaries for stoichiometric asymmetric
methods in total synthesis.
Although Evans chiral oxazolidinones have been extensively
employed in many highly diastereoselective reactions such as
alkylations, aldol reactions, cycloadditions, Michael additions,
1150
M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 24 (2013) 11491188
O
O
NH
NH
NH
NH
NH
R
R
Ph
R = i-Pr, t-Bu, Ph, Bn
SuperQuat
R1 = i-Pr, Ph, Bn
R2 = Me, Ph
R = Ph, Bn
R1
R2
Me
Figure 1.
aminations, azidations, brominations, hydroxylations, Diels Alder,

and conjugate additions,1317 their most common applications
are in asymmetric aldol reactions.
N-Acyl oxazolidinones can be prepared from the reaction of
these auxiliaries with acyl chloride in the presence of n-butyl lithium.1,18,19 N-Acylimides20,21 have been produced with the lithiated
oxazolidinones and mixed anhydrides.
Bu
Bu
n-Bu2BOTf, i-Pr2NEt
Me
Bu
R1CHO 8
R1
O
H
B
Bu
O
R1
10, Evans syn
OH
Useful reviews on the applications of oxazolidin-2-ones as the

chiral auxiliaries have been published.2226 We have also recently
published a review concerning asymmetric aldol reactions.27
Armed with this experience, in recent years and its importance,
we decided to make them classied, up to date, and to show the
applications of these chiral auxiliaries in aldol reactions for the total synthesis of various biologically active natural products. It is
9, favored
R1CHO 8
OH
N
R1
Bu
Bu
O
12, non-Evans
11, unfavored
Scheme 1.
OBn
CH2Cl2, - 78 oC
16
15
14
O
O
BnO
MeONHMeHCl, Me3Al
MeO
N
CH2Cl2, - 15 oC to 0 oC
96%
Me
O
OBn
Me
17
89%
OH
Me
Ph
- 78 oC
Me
Ph
CSA, ClCH2CH2Cl, 80 oC
CH2
BnO
CHO
Ph
n-Bu2BOTf, Et3N
18
OH
O
OCH2OBn
O
OH
CO2H
13, X-206
19
Scheme 2.
OH
O
OH
O
OH
OH
O
Et
1151
worthwhile noting that in this short review along with the

introduction of the natural products, only the key steps involving
the attachment and removal of the chiral auxiliaries have been described and illustrated.
enantioselection should be the main concern. The Z-enolates of

chiral N-acyl imides undergo an aldol reaction with aldehydes in
a highly stereoselective process, providing a-substituted-b-hydroxy
imides in high yields. Various aldehydes were successfully used in
this reaction.
The diversity of oxazolidinone auxiliaries is illustrated by their
extensive applications in aldol reactions.26,28,29 Suitable reagents
and appropriate reaction conditions provide access to all four
possible diastereomers. The generation of boron enolates is very
prevalent and established. Due to the short BC and BO bonds,
they manage to form tighter transition states, frequently leading
to higher selectivity. Accordingly, the reaction of Z-boron
enolates of acyl oxazolidinones with an aldehyde frequently leads
2. Asymmetric catalyzed aldol reactions of oxazolidinones

2.1. Generation of boron enolates
Chiral oxazolidinone auxiliaries offer an entrance for the synthesis and creation of chiral enolates that are used in highly stereoregulated aldol reactions. It has been a challenging and stimulating
task, because the control of both the diastereoselection and
HO
O
N
n-Bu2BOTF, Et3N,
H2O2, CH2Cl2,
1) MeNHOMe, Me3Al
CH2Cl2, 0 oC, 91%
2) TBSOTf, Et3N,
CH2Cl2, -78 oC, 96%
TBSO
TBSO
Bn
Bn
CHO
21
70%
22
TBSO
23
TBSO
Me
N
TBSO
OMe
OH
24
25
O
O
OH
OAc
HO2C
HO2C
O
CO2H
HO
20, Zaragozic Acid C
L-697,350
Scheme 3.
OH
n-Bu2BOTf, Et3N, CH2Cl2, - 78 oC

N
TBDPSCl, imidazole, DMF

N
BnO
81%
CHO
BnO
27
OR
28
O
N
BnO
88%
OR
O
LiBH4, MeOH, THF, 0 oC
BnO
OH
62%
29
30
R = TBDPS
R = TBDPS
O
OR
S
OH
OAc
HO2C
R = TBDPS
HO2C
O
CO2H
HO
31
26: Zaragozic acid D
Scheme 4.
1152

O
Zn, NH4Cl, MeOH, 96%

O
OH
n-Bu2BOTf, i-PrNEt2
Cl
OH
or Bu3SnH, AIBN, , 67%
Br
Br
Br
Cl
, H2O2
CHO
71%
33
35
34
36
EtO2C
O
OH
OH
LiOOH
HO
82%
Br
OTBDMS
TBDMSO
A
HO
37
OH
38
32: (+)-Calcitrol
Scheme 5.
OH
n-Bu2BOTf, Et3N
N
Bn
N
H
42
41
OH
LiOOH
40
OH
OH
76%
Bn
43
39: Serricornin
Scheme 6.
OH
O
Br
n-Bu2BOTf, Et3N, Et2O
O
NaN3, DMSO
N
Br
H3C(H2C)9
Bn
H3C(H2C)9
72%
Bn
H
45
46
47
S
58%
OH
H3C(H2C)9
S
OH
MeOMgBr, MeOH
H3C(H2C)9
N
O
N3
LiAlH4, Et2O
S
65%
Bn
49
48
OH
H3C(CH2)9
OH
S
+
NH3X -
44a: 4-yl X = (-)-maleate

44b: 4-yl X = (-)- HCl
44c: 4-yl X = acetate
Scheme 7.
O
OMe
N3
45%
1153
to the selective formation of syn products (also known as Evans

syn-aldol products).30 The most appropriate method for the formation of boron enolates involves the use of dialkyl boron triates (R2BOSO2CF3) and a weak hindered base.
In a classic aldol reaction, ketones 6 (Scheme 1) give Z-enolate 7
under kinetic conditions (n-Bu2BOTf, i-Pr2NEt). Further reaction
with aldehyde 8 provides syn-aldol 10 (commonly known as Evans
syn) with high diastereofacial selectivity. The reaction is assumed
to advance via a ZimmermanTraxler-type cyclic transition state
9, in which the si-face of the enol ether is hindered by the chiral
auxiliary directing the attack from the re-face of the enol ether
yielding Evans syn product 10.31
Despite the establishment of the ZimmermannTraxler model,
it is by no means clear and apparent that the aldol transition state
is generally chair-like. In certain cases, boat like or open transition
state models have better relevance.3235
O
Evans suggested that boron enolates undergo aldol reactions via

a chiral-like cyclohexane transition state: the R group is at a distance from the enolate p-face to minimize dipoledipole interaction within the imides; the R1 group is in a pseudo-equatorial
position to avoid the steric interaction with the butyl ligand on
boron (Scheme 6).36
The most common reactions in boron enolates are in the total
synthesis of many natural products. These provide well-ordered
transition states that result in high levels of stereoselection.37
2.2. Applications in total synthesis
Evans et al. have reported on a highly asymmetric approach
using aldol reactions for the synthesis of keto-aldehyde 19, which
contains the structural features of the C17C26 section of the
polyether X-206 13.38 Aldol coupling occurs between the
O
OH
TBSO
n-Bu2BOTf, Et3N
N
C7H15
C7H15CHO 51
C7H15
Bn
21
TBSOTf, 2,6-lutidine
97%
74%
Bn
Bn
53
52
O
TBSO
COOH
C7H15
97%
LiOH, H2O2
N
O
Me
HO
50: Hapalosin
54
Scheme 8.
O
n-Bu2BOTf, Et3N, CH2Cl2, -78 oC
OH
OMPM
(i-PrOOC-N=)2, PPh3,
p-NO2C6H4COOH
OMPM
OHC
Me
Ph
Ph
benzene, 23 oC
67%
Me
59
57
58
98%
NO2
LiOH, 30% H2O2,

THF, H2O, 23 oC
O
OTBS
OMPM
HOOC
OMPM
61
60
Me
Ph
OMe
OMe
Me
N
O
Me
N
O
O
O
OH
Me
N
O Me
Me
O Me
O
N
Me
Me
OMe
56: Nordolastatin G
55: Dolastatin G
Scheme 9.
N
O
OH
1154
dibutylboron enolate of imide 14 and 4-methyl-4-pentenal 15 to

create compound 16 with >98% diastereomeric purity. The C22
and C23 stereocenters in X-206 were formed, after cyclization in
the presence of acid, tetrahydrofuran 17 was transformed into
amide 18 with an aluminum amide reagent derived from MeONHMeHCl and Me3Al (Scheme 2).39
The asymmetric synthesis of the Cl side chain of the zaragozic
acid C 20, a class of potent squalene synthase inhibitors,40 which
are used as cholesterol-lowering drugs and as inhibitors of enzymes in the anti-cancer area (enzyme ras-farnesyl protein transferase), was based on the aldol reaction. Aldol product 23 was
prepared from 1,4-butanal ether 22 and the boron enolate of the
chiral (S)-oxazolidinone 21 with good yield and >98% de. Compound 23 with MeNHOMeHCl and double protection was converted into diol 24 in 87% overall yield, and then deprotected to
give 25. Compound 25 was then converted into the desired natural
product in several steps (Scheme 3).41
In a similar manner, as depicted in Scheme 4, the C1-side chain
31 of zaragozic acid D 2642 can be prepared by Evans aldol reaction
of aldehyde 27 and the valine derived oxazolidinone 6 (an enolate
bearing an oxazolidinone auxiliary) as the key step in controlling
the syn-stereochemistry. Aldol product 28 was produced with
88% yield and as a single diastereomer, after protection of the free
secondary alcohol in 28 as the TBDPS ether. The chiral auxiliary
was removed from 29 to give the primary alcohol 30.43
The synthesis of the A-ring in (+)-1a-25-dihydroxyvitamin D3
((+)-calcitrol 32) has attracted much attention not only for the
Me
n-Bu2BOTf, Et3N
complexity and sensitivity of the A-ring but also for the biological
activities.44 It has been synthesized by the use of Evans type
syn-selective asymmetric aldol reaction followed by ring closure
via a Heck type reaction as key steps. For the synthesis of intermediate 38, an aldol reaction was carried out between L-valine derived
chloroacetyl oxazolidinone 33 with a-bromoacrolein 34 in the
presence of dibutylboron triate and Hunigs base resulting in the
isolation of a single crystalline adduct 35 in 71% yield. The relative
and absolute stereochemistry of the two new stereocenters in 35
were assigned according to the standard Evans model for the aldol
reactions of Z-boron enolates of propionyl oxazolidinones.11 Aldol
35 was reacted with zinc powder and ammonium chloride to give
product 36 in 96% isolated yield, then saponication of 36 with
lithium hydroperoxide afforded 37 in 82% yield, which was then
converted into the intermediate diene ester 38 (Scheme 5).45
As illustrated in Scheme 6, the sex attractant of the female cigarette beetle, which is identied as serricornin [(4S,6S,7S)-7-hydroxy4,6-dimethyl-3-nonanon] 3946 can be prepared in 8 steps via the
key step Evans aldol reaction with an overall yield of 35%. In this
route for installing the key C6 and C7 streocenters, the boron
enolate of oxazolidinone 40 with propanal 41 was reacted to construct aldol adduct 42 with excellent diastereoselectivity, which
was then hydrolyzed with LiOH to give acid 43 in high yield and
was tolerable for the recovery of oxazolidinone (84% after recrystallization) by acidbase extraction.47
The analogue of sphingosine, a type of natural product, D-(+)erythro-1,3-dihydroxy-2-amino-4-trans-octadecane, inhibitor of
Me
CH2Cl2, - 78 oC - 0 oC
N
Ph
CHO
O
64
57
O
OH
92%
O
OTBDMS
65
66
O
O
N
H
NaBH4, EtOH,
- 20 oC, CSA
Me
CHO
O
n-Bu2BOTf, Et3N
OTBDMS
TBDMSO
67
Me
CH2Cl2, - 78 oC- 0 oC
91%
68
Ph
MeO
MeO
Ph
57
89%
MeO
O
Me
Ph
Ph
OMe
H
H
N
O
OH
OTBDMS
1) MeONMeHHCl, Me3Al
CH2Cl2, 0 oC
Me
O
O
2) TIPSOTf, 2,6-lutidine
CH2Cl2, 0 oC
69
TIPSO
OTBDMS
70
90%
CO2Me
MeO
H
MeO
O
OMe
TIPSO
OTBDMS
O
MeO
NH
71
O
62: Macbecin I
Scheme 10.
CONH2
1155
PKC in vitro (protein kinase C is a family of phospholipid-dependent proteins with anti-inammatory activity in human neutrophils and a reducer of phorbol ester-induced inammation and
epidermal hyperplasia in vivo48) was prepared using an asymmetric aldol reaction. For the synthesis of the enantiomers of thiophene analogue 44ac, thiophene carboxaldehyde 46 was reacted
with the boron enolate derived from (S)-bromoacetyl-oxazolidinone 45 to provide diastereomerically pure bromohydrin 47 (58%
yield), which was then reacted with sodium azide to give hydroxylazide 48 in 72% yield. This was followed by reductive removal of
the chiral oxazolidinone using methoxy magnesium bromide and
nally, reduction of the resulting azide ester 49 with lithium aluminum hydride gave the desired targets 44ac (Scheme 7).49
O
O
MeO
Ph
1) MeONMeHHCl, Me3Al
CH2Cl2, 0 oC
H
N
O
MeO
Ph
Me
Me
OMe
MeO
n-Bu2BOTf, Et3N
CH2Cl2, - 78 oC- 0 oC
Application of the Evans aldol reaction in the total synthesis of

hapalosin 50,50,51 a 12-membered cyclic depsipeptide, with mild
cytotoxic and better multidrug resistance agents than verapamil
especially in promoting taxol accumulation in SKVLB1 cells was
described by Zhu et al. in 1996.52 For the synthesis of the intermediate b-hydroxy acid 54 starting from L-valine, the aldol reaction
occurred between n-octanaldehyde 51 and chiral imide 21 to yield
syn-aldol 52 in excellent yield and diastereoselectivity. After introducing the TBS protecting group, the chiral auxiliary was cleaved
by LiOH from 53 (Scheme 8). It is notable that the synthesis of
hapalosin and its analogues were followed further using the Evans
aldol reaction as one of the key steps by Zhu and Maier et al. in
199953 and 2000.54
OH
2) TIPSOTf, 2,6-lutidine
CH2Cl2, 0 oC
90%
OTBDMS
CHO
64
72
O
OTBDMS
91%
68
OMe
MeO
MeO
OMe OMe
H
MeO
N
O
TIPSO
OMe
H
Me
CO2Me
CONH2
O
OMe
O
O
TIPSO
OTBDMS
MeO
NH
OTBDMS
O
73
74
63: Herbimycin A
Scheme 11.
P(Cy)3
Cl
Ru
O
OH
O
N
77
Ph
78
OH
Cl
P(Cy)3
n-Bu2BOTf, Et3N,CH2Cl2
O
CH2Cl2
CH2=CHCHO , -78C
H
Ph
82%
97%
Ph
Ph
80
79
N
O
N
HO
NH
NH2
LiBH4, THF, MeOH
>99.6% ee, 78%
HO
75: Carbovir
HO
81
H
N
N
HO
NH2
76: 1592U89
Scheme 12.
1156

O
O
n-Bu2BOTf, Et3N,
OBn
CH2Cl2, -78 to 0 oC,
TfOH, Et2O r.t.,
BzO
OBn
86%
O
OMe
CHO
BzO
83
Cl3CC(NH)OPMB,
OH
OMe
85
84
OBn
90%
OR
OBn
N
BzO
LiOOH, THF-H2O (3:1)
OH
BzO
0 oC to r.t.
OMe
OMe
O
86
R = PMB
OBn
OR
OR
R=PMB
87
HO
OMe
R= PMB
88
Scheme 13.
O
O
OH
n-Bu2BOTf, Et3N,
CH2Cl2, -78 oC to 0 oC
PMBO
MeNHOMeHCl, Me3Al
CHO
THF, -30 oC to r.t.
PMBO
O
83
90
89
OH
PMBO
OTES
N
OMe
CHO
PMBO
Me
91
OBn
OR
92
O
OTES
HO
CHO
PMBO
OMe
R= PMB
92
88
OH
OH
OH
H
O
O
H
OMe
82: Tautomycin
Scheme 14.
Dolastatin G 55 and nordolastatin G 56, cytotoxic 35-membered

cyclopeptides of marine origin, isolated from the Japanese sea hare
Dolabella auricularia55 have been prepared via an enantioselective
route by Yamada et al.56 Aldehyde 58 was reacted with (4R,5S)4-methyl-5-phenyl-3-propionyl-2-oxazolidinone 57 via an Evans
aldol reaction to yield the key intermediate 59 in 89% yield. Under

basic conditions, both the p-nitrobenzoyl group and the chiral auxiliary group were cleaved from 60 with LiOH and 30% H2O2 to yield
a b-hydroxy acid, which in turn, was transformed into the protected dihydroxy acid 61 (88% yield) (Scheme 9).56
1157
The intermediates 71 and 74, which constitute the C3C15

segment of the stereochemically complex ansa chain of (+)macbecin I 6257 and herbimycin A 63,58 respectively, are representative ansamycin antibiotics with a broad range of biological
activities such as antibacterial, antifungal, antiprotozoal, herbicidal, antiangiogenic, antiviral, and antitumor. They were synthesized by Martin et al. using an asymmetric aldol strategy. In the
synthesis of macbecin I and herbimycin A, in the rst step, the
stereochemistry at C10 and C11 of the ansa chain was induced
by the Evans asymmetric aldol reaction of oxazolidinone 57 and
furaldehyde 64 to yield 65 in 92% yield. After two steps, treatment of 66 with NaBH4 proceeded stereoselectively along with
cyclization and release of the chiral auxiliary to yield c-lactone
67, which is an intermediate in this route. After several steps,
the latter was converted into aldehyde 68, which is a common
advanced intermediate for the synthesis of both macbecin I and
herbimycin. For the synthesis of macbecin I 62, aldehyde 68
was rst reacted via an Evans aldol reaction with a suitable
propionate equivalent to yield adduct 69 in 91% yield. Reductive
removal of the chiral auxiliary and protection of the secondary
alcohol at C7 afforded the protected hydroxamide 70 in 90% overall yield. After stereoselective Z-olenation of the intermediate,
afforded 71, which contains the C3C15 segment of the ansa
chain of macbecin I 62 (Scheme 10).59
In a similar process for conversion of 68 into 74, the required
methoxy group at C6 in 72 was introduced by a diastereoselective
aldol addition in which a 2-methoxyacetate equivalent was considered as a nucleophilic partner. The chiral auxiliary was replaced
with an N-methyl amide group, and the C4C5 Z-double bond
was created by a stereoselective HornerEmmons reaction on the
protected aldehyde derived from 73 (Scheme 11).
An efcient synthesis of carbovir 75 and 1592U89 76, carbocyclic nucleosides60 with signicant in vitro activity and inhibitors of
HIV reverse transcriptase was accomplished via an Evans aldol

condensation with a ring closing metathesis reaction, as illustrated
in Scheme 12, to obtain the required diol 81 in 78% yield (>99.6%
ee). The reaction of the lithiated (S)-4-benzyl-2-oxazolidinone with
the pentenoic pivalic mixed anhydride afforded pentenoyloxazolidinone 77 in near-quantitative yield, in which the latter was treated with acrolein 78 by the Evans dialkylboron triate method to
yield the syn-aldol product 79 in 82% yield (>99% de). After ring
closing metathesis of diene 79, the chiral auxiliary was reductively
cleaved from cyclopentenol 80 in the presence of lithium
borohydride.61
The total synthesis of (+)-tautomycin 82,62 an antifungal antibiotic and an inhibitor of protein serine/threonine phosphatase (PPs)
1 and 2A,63 was reported by Shibasaki et al. in a highly selective
manner,64 in which the Evans aldol reaction was used for the construction of C12C16 and C17C26 fragments from the 2-deoxyglucose derivative. The C19 and C20 stereogenic centers were
constructed by the Evans aldol reaction between aldehyde 84
and oxazolidinone 83, to give the C18C26 unit 85 as a single diastereomer, after protection of alcohol 86. The chiral auxiliary was
removed without cleavage of the Bz ester by selective hydrolysis
in the presence of LiOH to yield carboxylic acid 87 and then converted into hydroxyketone 88, the C17C26 fragment of 82
(Schemes 13 and 14).
On the other hand, for the construction of three consecutive stereogenic centers C13C15 in the C12C16 fragment 92, the Evans
aldol reaction was employed as the most important step to induce
high diastereoselctivity. Aldehyde 89 prepared from Swern oxidation was reacted with oxazolidinone 83 via the Evans aldol reaction to give 90 as an inseparable mixture of diastereomers, which
was converted directly into amide 91 by treatment with Me3Al
and MeONHMeHCl. Finally (+)-tautomycin 82 was obtained
(Scheme 14).64
Bn
Bn
n-Bu2BOTF, Et3N
O
CH2Cl2, - 78 C- 0 C
SMe
N
OBn
OMe
SMe
OMe
o
OH
Cl
, - 78 C-0 C
94
OHC
OBn
96
Cl
95%
95
Bn
O
OMe
OMe
LiOH, H2O2, THF: MeOH: H2O (3:1:1),
N
OH
O
OR
97
R = TES
0 oC, 3h, 81%,
Cl
HO
OMe
O
H
HN
Me
Cl
OMe
OH
Me
N
H
Me
OH
OH
OH
O
O
93: Maduropetin chromophore
Scheme 15.
HO
OH
O
OR
98
R = TES
Cl
1158
The development of the Evans aldol reaction for direct access to

aryl fragment (building block) 98 for the total synthesis of maduropetin chromophore 93 was performed by Nicolaou et al.65 Benzyl
ether 95 was reacted with the boron enolate obtained from Evans
oxazolidinone 94 and n-Bu2BOTf to give 96 (95% yield), after two
steps. Hydrolysis of the amide group in 97 was accomplished using
LiOH and H2O2 in THF: MeOH:H2O, which led to the desired carboxylic acid 98 in 81% yield (Scheme 15).
A signicant reaction in the production of A.B.C. [6.6.6] trans
syncis tricycle 104, a key intermediate in the total synthesis of
quassine 99 and bruceantine 100, two members of the quassinoid

family66,67 is an Evans aldol reaction between aldehyde 101 and
(R)-3-(1-oxopropyl)-4-benzyl-2-oxazolidinone 40 to give aldol
adduct 102. Using Weinrebs technique, the chiral auxiliary was
removed to yield 103 (Scheme 16).68
The production of 110, a precursor to the C1C7 segment of halichomycin 10569 has been achieved by Wood et al. via the Evans
aldol reaction of acylated oxazolidinone 21 and aldehyde 106 to
afford aldol adduct 107, which was converted into chiral tri-substituted olen 108 in high yield (87% yield, >95% de). Standard
O
O
O
n-Bu2BOTf, CH2Cl2,
OH
0 C to -78 C
O
MeO
N
N
87%
Me
Bn
Bn
OH
MeNHOMe. HCl,Me3Al,
CH2Cl2, 0 oC,
103
102
40
CHO
66%
OMe
101
O
O
MeO
H
E
O
H
E
H
99: Quassine
OH
104
HO
OMe
O
O
H
O
HO
O
H
100: Bruceantine
Scheme 16.
O
n-Et2BOTf, Et3N
OH
O
OEt
87-95%
O
OEt
N
Bn
21
Bn
Bn
O
CHO
1M HCl
107
106
108
O
O
PhH
O
CO2Et
OMe
O
PPh3
Bn
O
OEt
109
NH
94%
O
110
105: Halichomycin
Scheme 17.
1159
homologation of 108 completed the two step (82% yield) preparation from 110 (Scheme 17).70
Taxol 111, which has a complex and highly functionalized
structure,71 shows potent antitumor activity but has limited natural abundance and is an attractive target for total synthesis. The
C-ring of taxol can be obtained enantiomerically pure by using
two asymmetric Evans aldol reactions to create the C5 and C7 stereocenters. In the rst step, chloroacetyl oxazolidinone 112, in the
presence of Z-dibutyl enolborinate, was coupled with a-bromoacrolein 34 to give the syn-aldol 113 as a single diastereomer in 77%
yield. After two more steps, the chiral auxiliary was removed by
LiBH4 from 114 to create alcohol 115 in 92% yield. This was
O
O
Cl
n-Bu2BOTf, i-Pr2NEt
re-oxidized with the DessMartin reagent to yield 98% of aldehyde

116.72 Aldehyde 116 was then reacted with the enolborinate
derived from propionyl oxazolidinone 57 to afford aldol 117 in
75% yield (major isomer). Finally in the presence of lithium
hydroxide and hydrogen peroxide in THF, the latter was transformed into the desired acid 118 in 71% yield (Scheme 18).
Concanamycin A 119, a family of structurally related polyketide
macrolide antibiotics that are potent and specic inhibitors of vacuolar H+-ATPase,73 was rst isolated by Kinashi et al. in 1981.74
Toshima et al. reported the application of the Evans aldol protocol
for the preparation of the key intermediate C5C13 123 in the total
synthesis of concanamycin A. Aldol product 121 was obtained in
Br
Me
Ph
Me
Ph
N
Br
Br
Cl
, H2O2
OTBS
Me
Ph
OH
CHO
112
34
113
77%
OH
OTBS
Dess-Martin
92%
98%
Me
Ph
OTBS
O
N
LiBH4
114
57
OH
Br
Br
Br
115
Me
Ph
116
117
AcO
O
OH
OTBS
OH
PhCO
NH
LiOH, H2O2/THF
OTBS
HO
Ph
Br
O
H
OH OBz OAc
HO
118
111: Taxol
Scheme 18.
O
O
O
N
n-Bu2BOTf, Et3N,
CH2Cl2, 0 oC
MP
LiBH4, EtOH, Et2O,

- 10 oC
O
OH
Bn
MP
O
O
100%
Bn
MP
O
CHO
21
122
121
O
120
MP = p-methoxybenzylidene
81%
OH
I
OMe
OH
ODEIPS
DEIPSO
OPv
OH
O
OH
HO
O
OMe
DEIPS = diethylisopropylsily
Pv = Pivaloyl
119: Concanamycin A
123
Scheme 19.
OCONH2
O
O
OH
OH
1160
81% overall yield by the aldol reaction of aldehyde 120 and N-propionyl-(4S)-benzyl-2-oxazolidinone 21 under the inuence of
n-Bu2BOTf and Et3N in CH2Cl2. Subsequently LiBH4 and EtOH in
Et2O at 10 C reduced 121 to give diol 122 in quantitative yield
(Scheme 19).75
Amphidinolides have potent toxicity against various tumor cell
lines and activity toward rabbit skeletal muscle actomyosin ATPase. They are also the most potent of all substances examined in
the NCI screen, and potential cancer drugs isolated from marine
dinoagellates of the genus amphidinium.76,77 Due to the cytotoxic activities of some structurally similar members of this family
such as amphidinolides B, D, G, H and L, their preparation with nine
stereogenic centers (except for amphidinolide L which contains
one extra stereogenic center) and the 26,27-membered polyene
macrolide skeleton have attracted signicant attention. In a stereoselective route, the (16S,18S,21R,22S,23R,25R)-C15C16 segment
131 of the entire top half of amphidinolides H 124 and G 125
was synthesized from two smaller units using the aldol reaction
as one of the key steps. For the synthesis of the intermediate
130, distereoselective aldol coupling of aldehyde 127 and chiral
oxazolidinone 126 gave exclusively the all-syn-aldol product 128
in 84% yield. After protection of the hydroxyl function as a TBSether, reductive removal of the chiral auxiliary and oxidation, aldehyde 129 (85% yield) was obtained (Scheme 20).78
Using a similar strategy, the diastereoselective synthesis of the
macrolactone core of amphidinolide W 132 was successfully
achieved using an Evans asymmetric aldol reaction as one of the
key reactions. Amphidinolide W 132 contains a 12-membered core
with potent cytotoxicity against murine lymphoma L1210 cells
in vitro and isolated by Kobayashi et al. in 2002.79 For the preparation of intermediate 136, the Evans syn-aldol reaction of aldehyde
133 and oxazolidinone 21 using n-Bu2BOTf gave the required
Evans syn-isomer 134 with high yield and excellent diastereoselectivity (19:1). After protection of the secondary hydroxyl as a TBS
ether and removal of the oxazolidinone in the presence of LiBH4,
alcohol 135 was obtained in good yield (Scheme 21).80
As shown in Scheme 22, the 6-epi analogue of amphidinolide W
has been obtained via a exible and efcient asymmetric route
from achiral, inexpensive and commercially available 4-pentenoic
acid, in which the successful preparation of stereocenters was
accomplished using an Evans chiral auxiliary-based alkylation
and aldol reaction. For the construction of the C5 and C6 centers
Bn
O
Bn
n-Bu2BOTf, Et3N,
toluene, - 50 oC
OR
O
OR
O
O
126
R = BMP
, -40 oC
OHC
2) LiBH4, H2O, Et2O, 0 oC-25 oC

(COCl)2, DMSO, Et3N, CH2Cl2,
- 78 oC-0 oC
OH
128
127
1) TBSOTf, 2,6-lutidine,
CH2Cl2, 0 oC, 1h,
R = BMP
OR1
OR1
OR1
H
O
OR
R1 = BMP
R2 = TBS
OR2
130
O
O
Me
O
129
O
O
OR2
TBDPSO
OR2
R1 = BMP
R2 = TBS
131
OH
O
OH
HO
OH
O
O
O
124: Amphidinolide H
OH
O
OH
HO
OH
O
O
O
125: Amphidinolide G
Scheme 20.
R1 = BMP
R2 = TBS
1161
of macrolactone 141, aldehyde 133 was exposed to oxazolidinone

138 generated from (4S)-4-benzyloxazolidin-2-one, with a mixed
anhydride (prepared from a mixture of 5-hexenoic acid and pivaloyl chloride) in the presence of n-Bu2BOTf, i-Pr2EtN in CH2Cl2 at
78 C to yield the syn-aldol adduct 139 in 72% yield and high diastereoselectivity (>97%). The auxiliary was reductively removed
using sodium borohydride in an aqueous THF medium at room
temperature to provide diol 140 in 87% yield.81
Evans aldol addition was used as one of the key reactions in the
asymmetric synthesis of functionalized dihydrobenzo[b] furan segment of the ephedradine C 142. Ephedradine C has been utilized as
an antiperspirant in oriental medicine.82,83 The structure of poly
n-Bu2BOTf, DIPEA,
CH2Cl2, 0 oC
O
O
substituted dihydrobenzofuran nucleus was established. It has a

17-member lactam ring bearing a spermine unit, with an absolute
conguration of (2R,3R,17S) at the three stereogenic centers assigned. In an enantioselective route with high yield and de, oxazolidinone 143 (prepared in ve steps from 4-bromophenol) was
reacted with 3,4-demethoxybenzaldehyde 144 in the presence of
boron triuoride-ether to give the aldol product 145. Next, the chiral oxazolidinone 146 was transformed into methyl ester 147
(Scheme 23).84
The two building blocks of aldehyde 153 and b,c-unsaturated
methyl ketone 157, correspond to the C5C21 segment 158 of tedanolide 148 and 13-deoxtedanolide 149, a highly cytotoxic
OH
1) TBDSOTf, 2,6-lutidine,
CH2Cl2, 0 oC-r.t., 0.5 h, 95%
OBn
2) LiBH4, EtOH/THF,
0 oC-r.t., 6h, 83%
CH2Cl2, -78 0 oC
Bn
Bn
CHO
BnO
134
21
75%
133
OBn
OTBDMS
H
HO
OBn
TBSO
135
O
O
136
OH
O
TBSO
O
132: Amphidinolide W
revised structure
Scheme 21.
O
O
n-Bu2BOTf, i-Pr2NEt,
CH2Cl2,-78 oC,
OH
OBn
NaBH4, THF-H2O, r.t.,

87%
OHC
138
Bn
OBn
Bn
133
139
72%
OBn
OH
O
OBn
HO
MEMO
140
141
HO
O
H
O
137: Amphidinolide W
Scheme 22.
1162
dermolide.91,92 It was synthesized from methacrolein by Day et al.93

(+)-Discodermolide 168 is a C24:4 fatty acid lactone with three
Z-double bonds, four hydroxy groups, eight methyl substituents,
a carbamate moiety, and 13 stereogenic centers, with potential
immunosuppressant activity. The key step in the synthesis of the
latter is the Evans aldol reaction of the boron enolate generated
from the acylated oxazolidinone derivative of (1S, 2R)-norephedrine with inexpensive methacrolein 170 to generate the desired
aldol product 171 in 85% yield as the sole diastereomer. To obtain
the desired product, the chiral oxazolidinone was cleaved using
Me3Al and Me(OMe)NHHCl to yield the Weinreb amide 172
(Scheme 27).
A successful method for the asymmetric synthesis of the C13
C22 fragment of the marine sponge polyketide callystatin A with
extraordinarily activity against KB tumor cells94 reported via an
efcient Evans syn-aldol reaction by Dias et al.95 The addition of
the boron enolate derived from oxazolidinone 21 (produced by
acylation of the corresponding (S)-oxazolidinone) to 2-(S)-methylbutanal 175 has generated the syn-aldol product 176 as a crystalline solid with high 89% yield and excellent diastereoselectivity
(>95:5). Afterward 176 was reacted with N,O-dimethylhydroxylamine to afford the Weinreb amide 177 in 83% yield. The latter
can be transformed into the natural product in several steps
(Scheme 28).
The total synthesis of the natural product ( )-FR182877 178
isolated from Streptomyces sp.96 was achieved by Evans et al.97 It
has a microtubule stabilizing activity similar to the mode of action
of paclitaxel and has potent cytotoxicity toward multiple tumor
cell lines. In this route, the aldol reaction of (R)-4-benzyl-N-propionyl-2-oxazolidinone 40 with aldehyde 179 in the presence of dibutylboron triate was achieved to give the syn-aldol adduct 180 in
88% yield. Subsequently, compound 180 is converted into Weinreb
amide 181 in 96% yield (Schemes 29 and 30).
In a similar way, for the synthesis of intermediate 187, aldehyde 183 and boron-enolate afforded syn-aldol adduct 185 in
89% yield, which was then converted into Weinreb amide 186
(Scheme 30).
Pectenotoxins (PTXs) are a family of polyether macrolides, with
hepatotoxic properties, and selective nanomolar cytotoxicity
against several human cancer cell lines with an impressive
capacity for site-specic interaction.98,99 The C29C40 fragment
of pectenotoxin has been prepared in an enantioselective route
macrolide against KB and PS tumor cell lines in vivo, isolated in

198485 from the Caribbean sponge Tedania ignis. It was prepared
by using an Evans aldol reaction as a key step by Roush et al.86
The intermediate 153 was prepared by starting from a chiral aldehyde via an aldol reaction of epoxyaldehyde 151 and the chiral
crotonyl imide 150. After protection, the chiral auxiliary was
removed by using LiBH4 in THF to generate homoallylic alcohol
152.
On the other hand, similar to the construction of the chiral b,cunsaturated methyl ketone 157, the diastereoselective aldol reaction of enal 154 with D-valine derived from acyl oxazolidinone
83 afforded 155 with high selectivity (89% yield). After protection
of the hydroxyl group as a TBS ether (96%), reduction of the acyl
unit (62%) and protection of the primary hydroxyl group as a TES
ether, 156 was obtained in 95% yield (Scheme 24).
Attachment of the desired aldehyde generated from the oxidation of allylic alcohol 160 to a boron enolate prepared from the carboximide 40 was attempted by the application of the Evans aldol
reaction to prepare a key intermediate syn-aldol adduct 161 in high
yield for the total synthesis of an ichthyotoxic cyclic lipopeptide
isolated from the marine cyanobacterium Lyngbya and majuscule,
antillatoxin 159.87 The chiral auxiliary was then cleaved from 161
by using alkaline hydrogen peroxide followed by methylation of
the resulting carboxylic acid to afford methyl ester 162 in 60% yield
(Scheme 25) 88.
( )-Amphidinolide P 163 is a member of a family of cytotoxic
marine natural products bearing diverse structural features with
biological activities such as anticancer activity when exposed
against various tumor cell lines.89 A formal total synthesis of
( )-amphidinolide P 163 was proposed by Chakraborty et al. in
2001.90 In order to generate two stereogenic centers in the C1C6
allylsilane segment 167, oxazolidinone 21 and aldehyde 164 (generated from mono-PMB-protected propane-1,3-diol by oxidation)
were coupled via the Evans aldol reaction to yield the synaldol adduct 165. The latter was then transformed into the methyl
ester intermediate 166 (in three steps in 70% overall yield) with
DDQ to convert the PMB-ether into the PMP-acetal. Oxidative
removal of the chiral auxiliary and conversion of the acid into an
ester by CH2N2 completed the reaction sequence (Scheme 26).
(2R,3S,4R)-3-(tert-Butyldimethylsilanyloxy)-2,4-dimethyl-5oxopentanoic acid methoxy-methylamide 173 is an important
intermediate for the synthesis of the natural product (+)-disco-
Ph
Ph
O
Br
O
OH
9-BBN triflate, i-Pr2NEt,

CH2Cl2, 0 oC, 1h,
O
O
OMe
Br
Me3SiI, CH2Cl2, r.t., 1h

71%
CHO
N
OMe
O
- 78 oC to r.t.
MeO
143
OMe
144
145
87%
OMe
OMe
O
OMe
OMe
NaOMe, MeOH,
0 oC, 2h
O
OMe
OMe
78%
O
Br
O
Br
H
N
HN
CO2Me
N
O
O
147
146
N
H
142: Ephedradine C
Scheme 23.
1163

O
O
N
OH
1) n- Bu2BOTf, Et3N
CH2Cl2, -78 C
OAc
PMBO
PMBO
O
150
OTES
CHO
151
CHO
OTBS
PMBO
TBS
153
152
2) TBSOTf, lutidine
3) LiBH4, THF, H2O
62%
O
O
N
n-Bu2BOTf, Et3N
CH2Cl2, -78 oC
1) TBSOTf, lutidine
2) LiBH4, THF, H2O
OH
BOMO
CHO
83
3) TESOTf, lutidine
56%
155
89%
154
OTES
BOMO
BOMO
OTES
OTBS
OTBS
156
157
AcO
PMBO
CHO
O
O
OTES
OTES
TBS
OTBS
153
157
OH
TESO
OTBS
OH
OAc
O
OMe O
PMBO
O
O
TBS
OH
OH
TES
158
148: tedanolide, R = OH
149: 13-deoxytedanolide, R = H
Scheme 24.
via aldol condensation of the Z-enolate of chiral oxazolidinone 40

in the presence of Lewis acid dibutylboron triate with crotonaldehyde 189 to yield anti-aldol adduct 190 as a single diastereomer.
After protection as a MOM derivative, the chiral auxiliary was removed with sodium borohydride in aqueous tetrahydrofuran to
give alcohol 191 (Scheme 31).100
The total synthesis of the 19-epi-C18C25 segment 197 of ( )lasonolide A, a polyketide isolated from extracts of the Caribbean
marine sponge Forcepia sp.,101 an inhibitor of the proliferation of
the A-549 human lung carcinoma cell as well as cell adhesion
in vitro was described by Shishido et al. In a diastereoselective
synthesis, the aldol reaction of 192, which was generated from
(S)-malic acid, reacted with (S)-3-(1-oxopropyl)-4-benzyl-2-oxazolidinone 21 in the presence of dibutylboron triate to produce
aldol adduct 194 in 95% yield. After two more steps, the chiral auxiliary was removed hydrolytically from 195, and the unmasked
compound was treated with EDC, HOBT and triethylamine to yield
lactone 196 in 59% yield (Scheme 32).102
Eunicellins, such as sclerophytin A 198, are marine natural

products with a wide range of biological activity containing an
oxygenated 2,11-cyclized cembranoid structure.103 It is notable
that an unusual oxatricylic ring system is the key structural feature
of the eunicellins in which is embedded an ocathydroisobenzofuran core. The stereoselective synthesis of exo-methylene octahydroisobenzofuran core of the sclerophytin was achieved in 16
steps from the deconjugative aldol reaction of (E)-crotonyl oxazolidinone 199 with 3-phenylpropanal 200 to give the syn-aldol
product 201 as a single diastereoisomer. Later in the presence of
NaBH4, the chiral auxiliary was removed from compound 202 to
produce 203 (Scheme 33).104
A highly convergent total synthesis of 12,13-desoxyepothilone
B 205 (Epothilone D), a macrolide natural product with potent
antitumor activity against a wide spectrum of human tumor cell
lines including multi-drug resistant cells105 was reported by
Broadrup et al. They applied the Evans aldol methodology to create
C6C7 with high diastereoselectivity as one of the key steps. For
1164
1) chemical manganese
dioxide (CMD), CH2Cl2
OH
2)
OH
Bn
160
1) LiOH, aq. THF

2) MeI, KHCO3, DMF
60% (2steps)
Bn
40
161
n-Bu2BOTf, Et 3N, CH2Cl2

80%
CO 2Me
N
H
O
H
N
OH
162
159: (4S,5R)-Antillatoxin
Scheme 25.
n-Bu2BOTf, Et3N, CH2Cl2
HO
PMBO
1) DDQ, 4 MS, CH2Cl2

2) LiOH, H2O2, THF.H2O
3) CH2N2, Et2O
PMBO
CHO
Bn
164
21
Bn
70%
165
92%
PMP
PMP
O
O
H
Me3Si
MeO2C
H
O
H
O
OH
167
166
163: (-)-amphidinolide P
Scheme 26.
O
O
Me
OB(n-Bu)2
CHO
170
Ph
84%
Me
Ph
N
N
OH
Me3Al, - 20 oC, 95%
Me
OH
O
172
171
169
OMe
Me(OMe)NH.HCl
OMe
O
N
Me
H
173
OR
R = TBS
OH
HO
OH
OH
168: (+)-Discodermolide
Scheme 27.
O
H 2N
1165

O
n-Bu2BOTf, Et3N,
CH2Cl2, - 78 oC
OH
1) MeONHMe.HCl
Me3Al, THF, 0 oC
2) TBSOTf, 2,6-lutidine
CH2Cl2, - 25 oC
Bn
Bn
H
21
de > 95: 5
175
O
83% (over 2 steps)
176
89%
OTBS
OH
MeO
N
Me
177
O
O
174: Callystatin A
Scheme 28.
O
O
O
O
OH
1) MeNHOMe.HCl
Me3Al, THF, 96%,
n-Bu2BOTf, TEA,
O
N
2) TBSCl imidazole, 96%

OTBS 3) TsOH:n-Bu4NHSO4 (1:4)
MeOH, 89%
O
Bn
H
Bn
179
40
OTBS
180
88%
O
O
OTBS
OTBS
MeO
N
MeO
N
Me
Me
OH
Br
181
Br
182
Scheme 29.
the synthesis of the olen segment 209, aldehyde 206 was coupled
with (S)-4-benzyl-3-propionyloxazolidinone 21 in the presence of
dibutylboron triuoromethanesulfonate to afford aldol adduct
207 in 95% yield as an inseparable mixture of diastereomers, which
was then converted into the corresponding Weinreb amide 208 via
transamidation [AlMe3, MeO(Me)NHHCl] to separate the diastereomers, after purication by ash chromatography on silica gel.
The major diastereomer 208 was obtained in 80% yield
(Scheme 34).106
The preparation of monocyclic, disubstituted a-methylene-cbutyrolactones in many structurally complex natural products
such as ( )-methylenolactocin, trans-nephrosterinic acid, and
( )-protolichesterinic acid have attracted much attention because of their biological activities.107 They are antibacterial,
antifungal, antitumor, and, in certain cases, growth regulating
agents. The total synthesis of ( )-methylenolactocin 210 was
performed by Hon et al. in 8 steps and 29% overall yield using
the aldol reaction of N-acyl oxazolidinone 211 and n-hexanal
212 to give syn-aldol 213 in 73% yield (de >95:5). The corresponding 1,3-diol 214 was produced by reduction with NaBH4
(Scheme 35).108
Epoxyquinols A 215 and B 216 with unique pentaketide dimeric

structures and potent antiangeogenic activity (angiogenesis plays a
critical role in many physiological processes for instance wound
healing)109,110 can be prepared by oxidative dimerization of a
monomeric pentaketide precursor obtained by the Evans asymmetric aldol reaction as the source of induction of chirality. Oxazolidinone derivative 77 in combination with senecialdehyde 217
afforded syn-aldol 218 in 87% isolated yield. The chiral auxiliary
was removed by LiBH4 to obtain diol 219 (Scheme 36).111
Evans et al. have applied the aldol reaction during the stereoselective total synthesis of clavolonine 220112, which was rst isolated in Jamaica from the club moss lycopodium clavatum (a
family of alkaloids with 16 carbon atoms and a variety of polycyclic
ring sizes).113,114 For the preparation of the lycopodium skeleton, in
the rst step, the boron-mediated aldol addition of (R)-3-propionyl-4-benzyloxazolidinone 40 to cinnamaldehyde 221 afforded a
crystalline 222 as a single diastreomer, which was reduced to the
diol and trapped as the derived benzylidine acetal. After that,
reductive cleavage with DIBAl-H gave the corresponding primary
alcohol, which was converted into nitrile 223 via the intermediate
tosylate (Scheme 37).112
1166

Bn
OB(Bu)2
N
O
O
OTBDPS
OTBDPS
N
H
89%
183
O
MeNHOMe.HCl,
Bn
185
OH
OR
MeO
OTBDPS
OR
HO
Me3Al, THF, 97%,
OH
184
Me
OH
OTBDPS
186
187
R = TBS
HO
O
OTBS
OR
MeO
N
OR
HO
OH
Me
OH
OTBDPS
Br
187
Br
R = TBS
182
178: FR182877
Scheme 30.
O
O
O
n-Bu2BOTF, i-Pr2NEt,
OH
1) MOMCl, i-Pr2NEt, CH2Cl2, 92%
Et2O, - 78 C
Bn
2) NaBH4, THF/H2O (3:1), 87%
Bn
190
40
189
62%
O
O
O
OMOM
OH
O
HO
OH
HO
O
O
191
188: Pectenotoxin
Scheme 31.
As shown in Scheme 38, the C9C15 fragment of the ansamycin

antibiotic geldanamycin 224,115 which has signicant antitumor
activity116 was synthesized by Bach et al. from L-leucine in ve
steps with 31% overall yield. The aldol addition product 226 was
prepared from the well-established Evans methodology of
N-propionyl-(S)-4-benzyl-2-oxazolidinone 40 to give a-methoxycarbaldehyde 225. The latter then reduced with NaBH4 to give
the synsyn-diol 227.117
A cyclic depsipeptide with particularly potent cytotoxic activity
against KB cells, arenastatin A, was isolated from Okinawan marine
organisms.118,119 For increasing metabolic stability and water solubility and considering an SAR study, the synthesis of 15,20-triamide and analogues 228ac with a polar substituent on the
phenyl ring, was reported by Kobayashi et al. It was mentioned

that 15,20-triamide analogues with a polar substituent 228ac
showed increased solubility in MeOH and stronger cytotoxicity
against KB cells. In the rst step, an established strategy based
on an Evans syn-selective asymmetric aldol reaction between
chiral N-crotonyl oxazolidinone 229 and aldehyde 230 was used
to produce (2R,3S)-aldol product 231 in high yield. The chiral
auxiliary was removed by LiBH4, deoxygenated to allow the
stereoselective synthesis of segment 233 (Scheme 39).120
In 2006, Park et al. purposed a strategy based on an Evans
asymmetric aldol condensation to generate the core skeleton of
furofuran rings in (+)-eudesmin, (+)-yangambin, ( )-eudesmin,
and ( )-yangambin121 with a wide range of attractive biological
1167

Et
O
N
n-Bu2OTF, i-Pr2NEt,
CH2Cl2, 0 oC, 1h,
Et
Bn
Et
21
Bn
193
RO
194
95%
OH
OH
1) LiOH.H2O, 35% H2O2,

H2O, THF, 0 oC
2) EDC, HOBT, Et3N,
CH2Cl2, r.t.
Me
Bn
RO
O
68% for the two steps

195
CHO
OH
OH
Et
196
R =TBDPS
R =TBDPS
HO
O
OH
CN
OH
OH
O
O
197
192: (-)-Iasonolide A
Scheme 32.
O
O
O
O
n-Bu2BOTf, Et3N, CH2Cl2,
OH
CH2Bn
N
O
CH2Bn
Bn
CHO
Bn
Bn
200
199
CH2Bn
202
201
- 78 to 0 oC
85%
CH2Bn
CH2Bn
NaBH4, THF/H2O, r.t.
HO
OH
HO
89%
CH2Bn
CH2Bn
203
204
OH
198: Sclerophytin A
Scheme 33.
activities such as antitumor, antimitomic, antiviral, antioxidant,

and antihypertensive.122,123 In order to obtain (+)-eudesmin 234a
and (+)-yangambin 235a, the stereoselective aldol reaction of
1,4-bis[4-(S)-benzyl-2-oxazolidin-3-yl]butane-1,4-dione 236 prepared from (S)-( )-4-benzyl-2-oxazolidinone and succinyl chloride, with the aldehydes (3,4-dimethoxybenzaldehyde 144 or
2,3,4-trimethoxybenzaldehyde 237) was carried out using dibutylboron triate at 78 C to give aldol products 238 and 239,
which were subjected to intramolecular ring cyclization to create
dilactone 240 and 241. After two steps, (+)-eudesmin 234a and
(+)-yangambin 235a were obtained (Scheme 40).
The key step in this synthesis, involved the stereoselective
aldol condensation of enolizable substrates 236 with aldehydes
144 and 237 with different enolating agents such as Et2BOTf/CH2Cl2, Bu2BOTf/CH2Cl2, n-BuLi, ZnCl2/THF, LDA/THF, TiCl4/CH2Cl2,
TiCl(OiPr)3/CH2Cl2, and SnOTf/CH2Cl2 under customary conditions.
The best results were obtained by using Bu2BOTf/CH2Cl2 at
78 C to 0 C for 1 h, with regard to the diastereoselectivity
and yields. In the same process, aldol coupling of oxazolidinone
242 with aldehydes (3,4-dimethoxybenzaldehyde 144 or 2,3,4-trimethoxybenzaldehyde 237) using n-Bu2BOTf in dry dichloromethane afforded diastereomeric boron complex mixtures. After
intramolecular ring cyclization, dilactones were created in 80%
and 83% yields, with 19:1 diastereomeric selectivity, respectively.
Finally ( )-eudesmin 234b and ( )-yangambin 235b were prepared (Scheme 41).121
1168

O
O
HO
n-Bu2BOTf, Et3N, CH2Cl2,
BnO
MeONHMe.HCl,
Me3Al, THF, - 5 oC to r.t.,
CHO
BnO
Bn
80%
Bn
21
206
- 78 oC to 0 oC, 95%,
96 : 4 mixture of diasteromers
OH
207
TBSO
OTBS
OMe
BnO
CO2Me
N
Me
208
209
Me
S
OH
N
O
O
OH
205: Epothilone D
Scheme 34.
OH
O
N
n-Bu2BOTf, Et3N,
n-C5H11CHO 212
O
N
- 78 oC, CH2Cl2
NaBH4, THF/H2O (4:1)

93%
Bn
Bn
211
213
OH
R = C5H11
OH
CO2H
C5H11
214
R = C5H11
210: (-)-Methyleneolactocin
Scheme 35.
The total synthesis of microcarpalide 243, a 10-membered lactone, with a weak cytotoxicity to mammalian cells and disruption
of action microlaments,124 was reported by Cherukupalli et al.125
One of the key steps in the synthesis of microcarpalide 243 was an
asymmetric aldol reaction which provides the chiral precursor for
the synthesis of olenic acid 248 starting from commercially available 1,4-butanediol. For the construction of the two adjacent stereocenters with the required absolute (R)-conguration in a threo
fashion, aldehyde 245 was reacted with oxazolidinone 244 using
dibutylboron triate in the presence of N-ethyldiisopropyl amine
in an Evans aldol reaction to yield aldol adduct 246. The reduction
of the latter by DIBAl-H gave compound 247 (Scheme 42).
Ulongamide A, the rst member of the marine cyanobacterium
Lyngbya sp. with an attractive biological activity against some
types of cancer was isolated in 2002 by Luesch et al.126 The structure of ulongamide A 249, a cyclic depsipeptide, contained ve
structural units, four of which are amino acids, with the fth being
L-lactic
acid. The unusual b-amino acid 254 prepared from N-propionyl derivative 57 (generated from a (4R,5S)-oxazolidinone
derivative) was exposed to low temperature for aldolization with
n-butanal 250 and propionyl chloride. The required pure (2R,3S)aldol 251, was transformed into azide 252 (43% yield). Removal
of the chiral auxiliary from 252 with alkaline hydrogen peroxide,
and then catalytic reduction of the azido acid 253 afforded b-amino
acid 254 (Scheme 43).127
The 6,6-spiroketal core of CP-61,405 (routiennocin) 255,128 a
member of the family of pyrrolylcarbonyl spiroketal ionophore
antibiotics has an effect on protoncation exchange across biological membranes as they have the ability to form lipophilic complexes with divalent cations such as Ca2+ and Mg2+ as well as
with monovalent cations such as Li+, Na+, K+, and Rb+.129,130 It
was prepared via an efcient and stereoselective route from N-propionylnoxazolidinone 21 in 10 steps and 36% overall yield. In the
rst step, Evans aldol reaction of boron enolate derived from
1169

O
O
O
n-Bu2BOTf, i-Pr2NEt
OH
LiBH4, THF-MeOH,
0 oC to r.t.
Me2C=CHCHO 217
CH2Cl2, - 78 oC
Bn
Bn
218
77
O
HO
OH
O
OH
OH
O
H
O
215: epoxyquinol A
219
O
HO
OH
O
O
O
H
O
216: epoxyquinol B
Scheme 36.
Bn
1) LiBH4, Et2O, H2O, 0 oC,

PhCH(OMe)2, TsOH, 93%
Bn
n- Bu2BOTf, Et3N
N
O
Ph
OH
CHO
2) DIBAl-H, CH2Cl2, - 35 oC, 76%

3) TsCl Et3N, DMAP, KCN,
DMSO, 50 oC, 94%
4) NaH, allyl bromide, DMF,
- 20 oC-10 oC, 55%
Ph
221
222
40
H
Ph
CN
OBn
OH
223
220: clavolonine
Scheme 37.
oxazolidinone 21 reacted with chiral aldehyde 89 to form aldol adduct 256 in 87% yield and excellent diastereoselectivity (ds >95:5)
followed by an exchange of the oxazolidinone auxiliary in the synaldol 256 with N,O-dimethylhydroxyamine that gave Weinreb
amide 257. After purication, the chiral auxiliary was recycled
from the reaction mixture which is nearly quantitative
(Scheme 44).131
In 1996, Minale et al. isolated very small quantities of callipeltoside A 258 from the lithistid sponge Callipelta sp. This macrolide
was characterized by numerous distinctive structural features
and is a member of a new class of marine natural products. Analysis of the sponge extracts showed the presence of two further
members of this family: callipeltosides B and C.132 The enantioselective total synthesis of callipeltoside A 258 has been described
and along with this the synthesis of the macrolactone subunit
was also reported on. In this route, an Ireland Claisen rearrange-
ment was implemented to create the trisubstituted olen geometry. The enantioselective total synthesis of callipeltoside A 258
has been successfully completed in 25 steps (longest linear sequence) in 4% overall yield. The synthesis began with the antiselective aldol addition of the (E)-boron enolate of b-ketoimide
259 to cinnamaldehyde 221 (Scheme 45). This reaction was used
for the formation of aldol adduct 260 with excellent diastereoselectivity (de: 95: 5), which followed the construction of aldehyde
261. In the reaction sequences the chiral auxiliary was removed
with DIBAl-H.133
The synthesis of paraconic acids 263270 were completed by
Park et al. They are a family of chiral c-butyrolactones containing
a carboxylic acid at the b-position, with important biological activities, such as antitumor, antibiotic, antifungal, and antibacterial,
and isolated from various species of mosses, lichens, and fungus.134
Eight enantiopure (2S,3S)-2-aryl-5-oxotetrahydrofuran-3-carbox-
1170

OH
n-Bu2BOTf, i-Pr2NEt, CH2Cl2

N
NaBH4, (aq).THF
60%
OMe
CHO
Bn
, CH2Cl2
Bn
OMe
225
40
226
43%
O
MeO
OH
OH
N
H
O
OMe
OH
MeO
O
MeO
227
NH2
224: Geldanamycin
Scheme 38.
Ph
O
Me
N
n-Bu2BOTf, Et3N,
CH2Cl2, - 78 oC,
OTBS
OHC
91%
230
Ph
O
OH
1) Bu3B, AcOH,
LiBH4, THF, 88%
Me
O
O
OTBS
2) TsCl, pyridine, 90%

OH
O
OTBS
232
OH
229
231
OTBS
O
R
OH
233
HN
NH HN
OMe
O
15,20-triamide analogue
228a: R = NEt2
228b: R = NEt3+
228c: R =
NH
N
Scheme 39.
ylic acids were prepared using stereoselective aldol reactions

between N-acyloxazolidinone 271 and the corresponding aldehydes as the key step (Table 1). Aldol condensation occurred between the boron Z-enolate, which was prepared by the treatment
of N-acyl oxazolidinone 271 with dibutylboron triate and DIPEA,
and the corresponding aldehydes 272 to give aldol product 273
as an unstable key intermediate, which was not isolated but exposed to intramolecular ring cyclization to construct c-lactone
274 with 95:5 diastereoselectivity. As illustrated in Scheme 46,
using lithium peroxide, the chiral auxiliary was removed from
274 to give (2S,3S)-2-aryl-5-oxotetrahydrofuran-3-carboxylic acid
and its analogues 263270.135
Due to its considerable cytotoxicity against the human carcinoma cell line HCT-116 and antifungal activity against Candida
albicans and the poor availability of the marine natural products
such as the microsclerodermins FI 275278,136 asymmetric synthesis of the key amino acid of microsclerodermins FI was
achieved in seven steps using an Evans glycolate aldol reaction
as the key step. In order to prepare the core of AMPTD, a transa,b-unsaturated ester, the key amino acid in microsclerodermins
FI, Evans chiral oxazolidinone 279 was reacted with aldehyde
280 to yield adduct 281. Although the reaction was not spotless
at room temperature, it gave a single diastereomer of 281 at 0 C
(Scheme 47). Subsequently oxazolidinone 281 was transformed
into Weinreb amide 282.137
A stereoselective total synthesis of polyketide lactone,
(3R,4S,5S,9S)-3,5,9-trihydroxy-4-methyl undecanoic acid d-lactone
284138 which has been completed by Sabitha et al.,139 is based on
the use of the Evans syn-aldol reaction as one of the crucial steps.
Aldol product 286 was obtained in high yield and diastereoselectivity (78%, de: 98%) from aldehyde 285 and the enolate of chiral
N-propionyl oxazolidinone 40, in which the chiral auxiliary was
replaced with the methoxy group using a Grignard reagent to yield
287 (Scheme 48).
d-Lactone ( )- and (+)-dihydrokawain-5-ol 288a,b (6-alkyl-5hydroxy-5, 6-dihydropyran-2-one), which show biological
1171
Bn
O
N
O
n-Bu2BOTf, DIPEA/CH2Cl2, - 78 oC
CHO
KH2PO4(aq),
H2O2 (28%)/MeOH, 25 oC
N
O
Ar
HO
O
CHO
238: 84%
239 : 81%
OMe
Bn
OH
Ar
or
OMe
236
238 Ar =3,4-di-OMe-C6H3,
R = (-)-Benzoxazolidinyl
239: Ar = 2,3,4-tri-OMe-C6H2,
R = (-)-Benzoxazolidinyl
OMe
OMe
OMe
144
237
R3
O
Ar
Ar
R2
O
R1
R1
O
240: Ar = 3,4-di-OMe-C6H3
241: Ar = 2,3,4-tri-OMe-C6H2
R3
R1= H, R2 = R3= -OMe
234a: (+)-Eudesmin
R1 = R2 =R3 = -OMe
235a: (+)-Yangambin
Scheme 40.
R3
Bn
O
R2
N
N
O
R1
R1
Bn
242
O
R2
R3
R1= H, R2 = R3= OMe
234b (-)-Eudesmin
R1= R2 = R3 = OMe
235b (-)-Yangambin
Scheme 41.
activities, and can be isolated from the methanol extracts of the

kava plant (piper mythisticum), a polynesian shrub of the paper
family,140 have been synthesized via the Evans aldol reaction as
one of the key steps for the construction of the six-membered ring.
For the synthesis of 288a, (4S)-4-benzyl-3-[2-(benzyloxy)acetyl]1,3-oxazolan-2-one 289 (90% yield) was prepared using Hos protocol141 from coupling the 2-(benzyloxy) acetic acid derivative
with oxazolidinone and then reacted with hydrocinnamaldehyde
200 in the presence of dibutylboron triate and triethylamine to
afford syn-aldol product 290 in good yield (81%) as a single diastereomer. The chiral auxiliary was removed by transamidation to
give Weinreb amide 291 in 84% yield (Scheme 49).142
In a similar manner, the synthesis of (+)-dihydrokawain-5-ol
288b has been completed from the reaction of (4R)-4-benzyl-3[2-(benzyloxy) acetyl]-1,3-oxazolan-2-one 279 as the starting
material (Scheme 50).142
A fast and straightforward path for the synthesis of the core
structure of dichlorolissoclimide 292 including a chiral succini-
mide subunit and an exocyclic double bond,143 has been proposed

by Chai et al. in 2010.144 Compound 292 is the rst member of the
lissoclimide family with highly potent cytotoxic activity against
P388 leukemia cell lines and KB human carcinoma cell lines bearing three rings. The core structure 297, consisting of the entire carboskeleton of the lissoclimide alkaloids, was produced using an
asymmetric boron-mediated aldol addition to establish the stereogenic centers of the succinimide as the key step, without the use of
any protecting groups for the alcohol at C-12. Oxazolidinone 293
was generated by acylation of the corresponding oxazolidinone
via its lithium amide, and subsequent O-methylation (89% yield).
The latter reacted with aldehyde 294 prepared from commercially
available (3aR)-(+)-sclareolide (60% yield) over three steps in the
presence of n-Bu2BOTf/DIPEA in CH2Cl2 to yield syn-selective aldol
product 295. This compound after a work-up in a pH = 7 phosphate
buffer and 30% H2O2 in MeOH was isolated as a single diastereoisomer in 30% yield. Compound 297 was then synthesized in several
steps from 295 (Scheme 51).
1172

O
O
N
n-Bu2BOTF, i-Pr2NEt
OPMB
CH2Cl2, 0 oC- 78 oC, 5 h
OH
OBn
BnO
73%
Bn
245
244
- 78 oC, 2h
OPMB
CHO
Bn
DIBAl-H, CH2Cl2,
246
66%
OH
OH
OH
OBn
OHC
O
OPMB
O
O
HOOC
OH
248
247
243: Microcarpalide
Scheme 42.
OH
Me
Me
1) DBBT, EDIPA, CH2Cl2, 0 oC

2) CH3CH2CH2CHO 250 - 78 oC
Ph
43%
Ph
O
251
57
N3
DEAD, PPh3, HN3, Toluene,
Me
N
N3
H2O2, LiOH, H2O
OH
O
NH
Ph
OH
252
253
254
HN
N
N
HN
N
O
249: Ulongamide A
Scheme 43.
O
O
O
N
n-Bu2BOTf, Et3N
CH2Cl2, -78 oC
OH
OH
MeONHMe. HCl, Me3Al

N
PMBO
OMe
PMBO
Bn
HCl, THF, 0 C
CHO
PMBO
Bn
256
21
89
257
87%
O
N
H
O
O
OH
N
CO2H
255: CP-61,405 (routiennocin)
Scheme 44.
1173

O
O
O
Cy2BCl, EtNMe2,
- 78 oC to - 20 oC
OH
O
O
Bn
Bn
259
Ph
260
Ph
221
Ph
261
78%
O
O
NH
MeO
OTBS
O
H
O
H
MeO
O
MeO
O
H
SEt
OH
MeO
O
262
Cl
258: Callipeltoside A
Scheme 45.
Table 1
Entry
263
264
265
HO2C
HO2C
MeO
Product
Entry
67
268
270
HO2C
HO2C
MeO
Yeild (%)
69
60
52
Bn
n- Bu2BOTf, DIPEA/CH2Cl2,
- 78 oC,
N
OMe
Ar CHO 272
1
46
Bn
O
H
O
Ar1
N
O
271
OBR
O
273
Bn
H
O
N
O
274
57
260
HO2C
HO2C
Product
OMe
48
267
MeO
OMe
65
HO2C
MeO
O
Yeild (%)
266
HO2C
HO2C
O
Ar1
Ar1
263- 270: Paraconic acids
Scheme 46.
LiOH, H2O2/THF: H2O

0 oC to r.t., 3h
1174

O
n-Bu2BOTf, DIPEA, CH2Cl2,

- 78 oC-0 oC
OBn
OH
MeOMeNH.HCl, Me3Al
THF, 83%
OHC
OBn
Bn
OTBDPS
Bn
53%
OTBDPS
279
281
280
HO2C
O
OH
OH
MeO
H 2N
N
Me
OBn
OH
Ph
OTBDPS
OH
3
282
283
H
N
O
O
HN
H
N
N
Me
HO
O
O
HN
NH
OH
O
OH
H
N
N
H
OH
Ph
OH
R
275: R =H, Microsclerodermin F

276: R = Me, Microsclerodermin H
H
N
O
O
HN
H
N
N
Me
HO
HN
O
O
NH
OH
O
OH
H
N
N
H
OH
Ph
OH
R
277: R = H, Microsclerodermin G
278: R = Me, Microsclerodermin I
Scheme 47.
O
N
n-Bu2BOTf, Et3N,
O
OMOM
OH
O
n-BuLi, i-Pr2NH, anhydrous THF,
anhydrous CH2Cl2,
- 80
Bn
oC
0 oC, 1h,
t-BuOAc, - 78 oC to - 15 oC, 1.45 h
Bn
OMOM
O
40
285
82%
286
78%
OH
OMOM
OH
OH
OMe
287
284: Undecanoic acid-lactone
Scheme 48.
1175

O
O
OBn
OH
n-Bu2BOTf, Et3N, CH2Cl2
MeNHOMe.HCl, Me3Al
O
Ph
THF, 0 oC- r.t., 1 h, 84%
OBn
Ph
Bn
Bn
200 - 78 oC, 881%
289
290
O
O
OH
MeO
Ph
Ph
OBn
Me
OH
291
288a: (-)- dihydrokawain-5-ol
Scheme 49.
O
O
crocacin C 298 was achieved in 10 linear steps starting from commercially available Evans chiral propionimide in the Evans aldol
reaction. Ketoimide 299 was prepared by aldol reaction of oxazolidinone 40 and propionaldehyde 41 (dr > 20:1), after oxidation
by the ParikhDoering reaction in 71% overall yield. Aldol product
300 (dr > 20:1, 75% yield) was formed via enolization of 299 in the
presence of TiCl4 and i-Pr2NEt and trans-cinnamaldehyde 221. As
depicted in Scheme 52, the chiral auxiliary was removed from
302 with LiBH4 (66% yield) and after oxidation with DessMartin
periodinane provided aldehyde 303 in 59% yield over two steps.147
Analogues of the precursors of natural product simplactone 304
(Fig. 2) with the ability to inhibit IjB kinase and NF-jB148 were
synthesized by Khan et al.149 The NF-jB family of transcription factors has a signicant role in determining the cell survival during
immune, inammatory, and stress responses. Due to the importance and attractive therapeutics for treating a variety of diseases,
much attention has been focused on the synthesis of new compounds that are analogues of precursors of the natural product
O
OBn
Ph
OH
Bn
279
288b: (+)-Dihydrokawain-5-ol
Scheme 50.
Cytotoxic polyketide natural product (+)-crocacin C 298, an

inhibitor of Gram-positive bacterial growth and possessing moderate inhibition of Gram-positive bacterial growth, as well as antifungal activities,145 was prepared by Chakraborty and
Jayaprakash in 2001.146 Crocacin C 298 is composed of a polyketide
fragment with antiantisyn stereotetrad, C16-C19, and a conjugated (E,E)-dienamide system C11-C15. The total synthesis of (+)-
O
OMe
N
O
N
2) pH 7 phosphate buffer,
30% H2O2, MeOH
p-TsOH (cat.), CH2Cl2,

reflux, 2h
OH
Bn
CHO
OMe
O O O
1) n-Bu2BOTf, DIPEA,
CH2Cl2, -78 oC
58%
(2 steps)
Bn
293
295
294
O O
O
O
N
H
N
H
N
Bn
OH
OH
Cl
Cl
OH
296
297
Scheme 51.
292: Dichlorolissoclimide
1176

O
HO
O
N
n-Bu2BOTf, Et3N
CH3CH2CHO 41
N
Bn
95%
40
42
HO
299
OH
TiCl4, i-Pr2NEt,
CH2Cl2, - 78 oC
DMSO/CH2Cl2, 0 oC
Bn
CH2Cl2, -78 oC
Bn
SO3Pyr, Et3N
OH
NMe4BH(OAc)3
O
N
MeCN/AcOH, - 40 oC
CHO
Bn
Bn
Ph
300
221
88%
dr > 20 :1
301
75%, dr > 20 : 1
OMe OMe
CHO
N
CHCl3, 0 oC
OMe OMe
MeOTf
2, 6-di-t-Bu-4-Me-Pyr
1) LiBH4, THF/MeOH
2) Dess-Martin
periodinane
Bn
303
302
49%
OMe OMe
59%
Me
O
NH2
298: (+)-Crocacin C
Scheme 52.
simplactone. Among them compound SK2009 was the most effective of these in suppressing NF-jB activation in KBM-5 leukemic
cells. The asymmetric Evans aldol reaction was the fundamental
step for the construction of these new compounds, and to set up
the stereochemistry of the two contiguous stereogenic centers in
the total synthesis. Acyloxazolidinone was prepared from (S)-4benzyl-2-oxazolidinone 307 and pivaloyl chloride in the presence
of triethylamine. Compound 307 in the presence of n-Bu2BOTf
was then reacted with aldehyde 245 to provide aldol product
308 in 91% yield. After removal of the oxazolidinone auxiliary with
aqueous NaBH4, diol 309 was obtained. Diol 309 then underwent
acetonide protection with 2,2-dimethoxypropane (2,2-DMP) gave
compound 306 (Scheme 53). In a similar manner, SK2009 305
was synthesized using the appropriate acid.149
The stereoselective asymmetric synthesis of the C1C9 and C9
C17 fragments, of (+)-13-deoxytedanolide 310, isolated from Mycale adhaerens by Fusetani et al. in 1991150 with high cytotoxicity
against the P388 murine Leukemia cells and the rst macrolide
inhibitor that binds to the eukaryotic ribosome151 has been the focus of notable efforts. For the synthesis of C9C17 fragment 314,
the Evans aldol reaction between aldehdyde 311 and N-acylated
oxazolidinone 83 was used to create aldol adduct 312 with the desired chirality; the stereochemical outcome is a key step. The aldol
OH
OH
OH
O
C7H15
304: Simplactone A
305: SK2009
Figure 2.
adduct was then reduced with NaBH4 in EtOH to give 313

(Scheme 54).152
Due to the important biological activities as well as structural
diversity present in macrolides, neomethynolide derivative 315,
which contains a 12-membered macrolactone153 was synthesized
by Kang et al. for the rst time.154 Starting from the commercially
available methyl D-(+)-lactone. Asymmetric aldol condensation of
aldehyde 316 with acyloxazolidinone 21 gave aldol adduct 317
as one of the key steps. As depicted in Scheme 55, the chiral auxiliary was removed by reduction in the presence of LiBH4 from
318, to produce compound 319.154
( )-Chicanine 320 is a unique structure that includes a densely
functionalized tetrahydrofuran core with four contiguous stereogenic centers and is interesting for its neurotrophic activities such
as considerable neurite-outgrowth promotion and protective
effects against cell death induced by several mistreatments in primary cultured rat cortical neurons and NGF-mediated PC12
cells.155 For the rst time, ( )-chicanine 320 was prepared in 14
steps by a syn-selective Evans aldol addition of 3-benzyloxy-4methoxybenzaldehyde 321 with the boron enolate derived from
(+)-(S)-4-benzyl-3-propionyl-2-oxazolidinone 21 to supply the aldol adduct 322 in 80% yield (98% de), which was one of the key
steps. Subsequent protecion and reduction with NaBH4 (along with
removal of the oxazolidinone auxiliary) gave 324 in 98% yield over
two steps (Scheme 56).156
The C1C11 framework of a peloruside A-lauulimalide analogue, a microtubule stabilizing agent with high potency was
completed by Teesdale-Spittle et al.157 from a monoprotected
2,2-dimethylpropane-1,3-diol.158 Synthesis of the C1C2 fragment
was achieved by a boron-mediated Evans aldol reaction to set the
1,2-syn stereochemistry at C2 and C3. Aldehyde 327 was treated
with Evans oxazolidinone 326 obtained from acylation of the
1177

O
O
O
n-Bu2BOTf, Et3N,
OH
Aq NaBH4, THF
C8H17
CHO
BnO
307
OH
245
308
OH
O
2,2-DMP, CH2Cl2, PTSA
C8H17
C8H17
309
306
Scheme 53.
n- Bu2BOTf, DIPEA, CH2Cl2,

- 78 0 oC- r.t.,
N
OTBDPS
N
OH
NaBH4, EtOH,
0 oC, 15 min
OTBDPS
85%
OH
OH
CHO
83
313
312
OTBDPS
311
OH
O
OH
OTES
OH
O
OMe O
OPMB
OH
314
310: (+)-13-Deoxytedanolide
Scheme 54.
Bn
Bn
O
n-Bu2BOTf, Et3N,
CH2Cl2, - 78 oC
OSiEt3
N
O
OPMB
O
21
Et3SiOTf, 2,6-lutidine,
CH2Cl2, 0 oC, 97%
O
O
Bn
OH
N
O
OPMB
O
317
318
OPMB
75%
316
OH
LiBH4, H2O, ether, 73%
OSiEt3
HO
O
OH
OPMB
319
315: Neomethynolide
Scheme 55.
lithium salt of benzyl oxazolidinone to afford the 1,2-syn-adduct

328 in high yield and with a diastereomeric ratio of 10:1. Finally
the C1C11 segment 329 was obtained to furnish peloruside A
325 (Scheme 57).
An advantage of the Evans aldol condensation was applied to

the synthesis of cyclic diaminopropane inhibitors 159 for the treatment Alzheimer by Thompson et al. The aldol reaction of the
Z-boron enolate of acyl oxazolidinone 331 with aldehydes 332
1178
TBSO
OH
MeO
N
MeO
n-Bu2BOTf, i-Pr2NEt
21
CHO
BnO
TBSCl, DMF,r.t., 13h

99%
MeO
Bn
BnO
Bn
Bn
323
322
BnO
321
CH2Cl2, -78 oC, 11h,
de: 98%
80%
TBSO
NaBH4,THF,
MeO
OH
HO
MeOH, r.t., 3h
O
O
OMe
BnO
99%
320: (-)-Chicanine
324
Scheme 56.
O
O
OH
O
N
n-Bu2BOTf, Et3N
OPMB
H
H
H
PMBO O
H
TBSO
326
OMe
MeO
PMBO O
H
Bn
O
Bn
328
329
TBSO
327
OH
OMe
O
OH
HO
O
HO
MeO
OMe
OH
325: peloruside A
Scheme 57.
produced aldol adduct 333 in high yield. The chiral auxiliary was
cleaved under the action of LiOOH, THF to yield 334
(Scheme 58).160
One of the key transformations in the total synthesis of the
dihydrotetrabenazine 335 (DTBZ), a vesicular monoamine transporter (VMAT2) inhibitor,161,162 is the Evans aldol reaction.
The total synthesis of ( )-dihydrotetrabenazine 335 was
achieved via the allylation of an (R)-tert-butanesulnamide as a
chiral source. (R)-Acyloxazolidinone 336 was obtained by acylation
of the corresponding (R)-oxazolidinone with 4-methyl-pentanoic
acid. The asymmetric aldol condensation occurred between the
boron enolate derived from acyloxazolidinone 336 with aldehyde
337 to give the syn-aldol adduct 338 in 80% yield. Ester 339
(63%) was formed after removal of the chiral auxiliary using sodium methoxide in methanol, as shown in Scheme 59, and can
be successfully converted into ( )-dihydrotetrabenazine 335.163
Natural products spirangiens A 340 and B 341, two structurally
related polyketide metabolites were separated from the epothilone
producing myxobacterium Sorangium cellulosum. Spirangien A 340

is active against selected yeasts and fungi and is highly cytotoxic
against the L929 mouse broblast cell line, as well as being an
effective inhibitor of IL-8 expression.164,165 It is notable that both
have a core structure bearing a heavily functionalized 6,6-spiroacetal, 14 stereocentres, a complex pentaene side-chain and a terminal carboxyl group. However, the two compounds differ in
structure only by an additional CH2 group present in spirangien
B (Scheme 60).
The synthetic route to aldehydes 345 and 346 take advantage of
the high diastereoselectivity identied in the boron mediated aldol
reactions of Evans benzyl oxazolidinone auxiliary and prots from
the opportunity for differential protection of the 1,3-diol. Aldehyde
342 was synthesized in four steps from Evans auxiliary (R)-40
(76% yield) via a double stereo-differentiating aldol reaction with
(S)-21 to afford the required C2427 stereotetrad 343 (65% yield,
>98% ds), a common intermediate for aldehydes to synthesize
345 and 346.166 Silyl protection of the new hydroxyl group
1179
O
O
OH
n-Bu2BOTf, DIEA, THF, - 78 oC,
Boc
LiOOH, THF/water,
Bn
Bn
0 oC-r.t.
N
H
331
Boc
F
333
332
O
OH
R = H, OMe
R = H, OMe
Boc
N
HO
F
R
O
OH
H
N
F
O
334
N
H
H
N
OMe
O
R = H, OMe
F
330
Scheme 58.
Bn
MeO
n-Bu2BOTf, Et3N, CH2Cl2, - 78 oC,
NaOMe, MeOH
CH2Cl2, -25 oC, 1h,
NBoc
MeO
MeO
Bn
336
MeO
OH
Boc
H
337
63%
O
N
338
MeO
MeO
NBoc
MeO
MeO
OMe
OH
O
OH
339
335: (-)-Dihydrotetrabenazine
Scheme 59.
(TESOTf/2,6-lutidine), followed by reductive cleavage of the auxiliary (LiBH4/EtOH) and Swern oxidation gave silyl protected aldehyde 346 (56% yield, three steps). For the preparation of the
acetonide protected aldehyde 345, the C27 hydroxyl in TBS-ether
343 was deprotected under mild conditions (HF/pyr/pyr) and the
resulting anti-1,3-diol 344 protected as the acetonide with 2,2dimethoxypropane/PPTS. Reductive removal of the auxiliary, followed by Swern oxidation gave the acetonide protected aldehyde
345 (79% yield, four steps).166
Asymmetric synthesis of 7-hydroxydibenzylbutyrolactone
lignans such as (7S)-hydroxymatairesinol (plant lignan) 347167
and (7S)-hydroxyarctigenin (non-natural compound) 348,168 an
important subclass of the lignan family, with a wide range of biological activities such as immune regulatory, neuroprotective, anticancer, antitumor, and anti-HIV properties, was achieved in six
steps from N-succinyl-2-oxazolidinone in which the diastereoselective aldol reaction was one of the key steps. For the synthesis
of target molecules 347 and 348, (cy-Hex)2 BOTf catalyzed synaldol reactions of N-succinyl-2-oxazolidinone 349, imposed on
350a and 350b aldehydes to provide the corresponding syn-aldol
products 351a,b with 92:8 and >95:5 diastereoselectivities, respectively. After protection with TBSOTf, O-silyl aldols 352a and 352b
were obtained respectively as a single diastereomer with 68%
and 75% yields over two steps. The corresponding acids 353a,b
were formed after removal of the chiral auxiliary via LiOHH2O2
mediated hydrolysis in THFH2O (5:1) in 83% and 88% yields,
respectively (Scheme 61).169
Functionalized succinic acid derivatives are structural motifs
that are usually found in biologically active molecules of natural
and non-natural origin, such as the matrix metalloproteinase
1180
inhibitor BB-1101. The synthesis of the antifungal and antibacterial

agent dihydroprotolichesterenic acid, the glaucoma drug pilocarpine and the anti-inammatory and antiviral agent antrodin D
has been reported.170 The total synthesis of ( )- and dihydroprotolichesterinic acid 354 was achieved by Evans aldol reaction as
the key step, in which oxazolidinone 355 was reacted with myristyl aldehyde 356 to give aldol adduct 357, followed by lactone formation, and removal of the chiral auxiliary. An aldol reaction of a
substrate similar to 355 has been demonstrated,170 using a higher
concentration of n-Bu2BOTf in the presence of Hnigs base, with
myristyl aldehyde which eventually gives lactone 357 in higher
yield (95% based upon recovered starting material) and >95:5 dr.
Hydrolysis of the oxazolidinone ring 357 gave ( )-dihydroprotolichesterenic acid 354 in 85% yield, thereby completing a four step,
enantioselective synthesis of 354 that proceeded in 31% overall
yield (56% based upon recovered starting material) (Scheme 62).171
In some cases, the use of a bulkier Lewis acid, such as Et2AlCl,
led to the formation of the anti-products.172 A cyclic depsipeptide
with antiviral and antifungal properties and selective powerful
inhibition of the cardiac sodium/calcium exchanger isolated from
marine natural products is callipeltin A.173 Its total synthesis was
reported by Guerlavais et al. A silyl derivative of the (2R,3R,4S)3-hydroxy-2,4,6-trimethylheptanoic acid segment 362 in the cyclic
depsipeptide callipeltin A 358, was generated in nine steps based
on an Evans aldol reaction starting from L-valine. Aldol reaction
of aldehyde 359 with Et2AlCl in CH2Cl2 at 78 C, with the boron
enolate of carboximide 6, generated the anti aldol product 360 in
21% yield over two steps. The latter was protected to give 361. In
the presence of lithium hydroxide and hydrogen peroxide in
THF/H2O (3/1), the removal of the chiral auxiliary occurred to afford 362 in 76% yield. The latter can be transformed into the natural product 358 (Scheme 63).174
3. Asymmetric aldol reaction of oxazolidinones
3.1. Generation of titanium enolates
Titanium enolates have been shown to be highly selective under
chelationcontrolled aldol reactions. The rst reports of asymmetric aldol reactions in the presence of boron and titanium afforded
the Evans syn-aldol product 365 with excellent diastereoselectivity. It was reported that chelate-controlled methods usually result
Bn
Bn
N
O
1) i. Bu2BOTf, 0 oC, 30 min

ii. Et3N, 0 oC, 30 min
iii. methacrolein, -78 oC,
30 min to 0 oC, 4h
2) 2,6-lutidine, TBSOTf,
CH2Cl2, -78 oC, 5h
TBS
- 78 oC, 30 min to 0 oC, 4h
342
4) i. DMSO, CH2Cl2, -78 oC

ii. (COCl)2, -78 oC, 30 min
iii. alcohol from 3), -78 0 oC, 45min
iv. Et3N, - 78oC, 30 min to 0 oC, 30 min
21
Et3N, 0 oC, 30 min,
3) EtOH, LiBH4, Et2O, -10 oC, 4h
40
n-Bu2BOTf, 0 oC, 30 min
65%
76%
Bn
HF/pyr/pyr, THF,
H2O (cat), r.t., 5 days
94%
OH
Bn
O
N
O
OH
TBS
OH
343
O
H
O
344
1) 2, 6-lutidine, TESOTf,
CH2Cl2, - 78 oC, 7h
2) EtOH, LiBH4, Et2O, - 10 oC, 4h
345
3) i. DMSO, CH2Cl2, - 78 oC,

ii. (COCl)2, - 78 oC, 30 min,
iii. alcohol from 2), - 78 oC, 45 min
iv. Et3N, - 78 oC, 30 min to 0 oC, 30 min
O
O
TBS TES
56%
346
MeO
CO2H
H
OP1
OP2
HO
H
345: P = P =C(CH3)2
346: P1 =TBS, P2 = TES
1
H
O
MeO
OH
HO
340: Spirangien A: R = Me
341: Spirangien B: R = CH2CH3
Scheme 60.
1181

OR'
O
MeO
N
MeO
CHO
RO
O
RO
OR'
TBSOTf, lutidine, DMAP,

CH2Cl2, 5 oC, 16 h,
MeO2C
TBSO
MeO
N
RO
351a: R =TBS, R' = H, dr: 92: 8

351b: R =Me, R' = H, dr > 95: 5
350a: R= TBS
350b: R = Me
349
MeO
(cy-Hex)2BOTf, i-Pr2NEt,
MeO
OH
LiOH, H2O2, THF-H2O, 0 oC - r.t.
MeO2C
RO
CO2Me
353a: R =TBS, 83%
353b: R =Me, 88%
352a: R = R' = TBS, dr > 92: 5; 68%

352b: R =Me, R' = TBS, dr > 95: 05, 75%
OH
H
MeO
O
RO
H
OMe
OH
347: R = H
(7'S)-hydroxymatairesinol
348: R = Me
(7'S)-hydroxyyarctigenin
Scheme 61.
in the formation of non-Evans product 367. The use of titanium

enolates (also Li, Zn or Sn) gives rise to non-Evans syn products
(Scheme 64).175
strong antibacterial and anticancer activities was described by

Mohapatra et al.179 The 3,4-disubstituted pyrrolidine ring system
in 378 was prepared via aldol reaction of (R)-oxazolidinone derivative 40 and (R)-Garners aldehyde 375 in the presence of TiCl4 and
DIPEA at 0 C to provide syn-376 as the sole product in 82% yield.
The primary alcohol 377 was then obtained by hydrolysis with
lithium borohydride (Scheme 66).
An aldol-CurtiusRCM sequence can be used to construct the
key azepane moiety in SB-462795 379,180a highly potent cathepsin
K inhibitor with signicant therapeutic potential in the treatment
of osteoporosis and osteoarthritis. An efcient aldol reaction was
carried out between aldehyde 381 and crotonate imide 380 to afford aldol adduct 382. The oxazolidinone moiety in aldol adduct
382 can be removed using hydrazine to construct hydrazide 383
(Scheme 67).181
Alkaloid tyroscherin 384,182 which is a hybrid between tyrosine
and a polyketide fragment, bearing a vicinal anti-amino alcohol
subunit, which is an inhibitor of the growth of cancer cells and
dependent on the insulin-like growth factor (IGF) was developed
by Maier et al. (Scheme 68).183 For the synthesis of tyroscherin
384, the aldol reaction between acylated oxazolidinone 385

An Evans aldol reaction was used to synthesize an intermediate
373, which is needed for the production of ( )-isolaurallene 368. It
has signicant biological activity containing the core of a nine
membered ether fused with a bromoallene substituted tetrahydrofuran and ve stereogenic tetrahedral carbons and a stereogenic
allene.176 For the synthesis of diene 373, N-acyloxazolidinone
369 prepared from lithio (S)-4-benzyl-2-oxazolidinone and pivalic
anhydride rst reacted with 3-butanal 370 via an aldol condensation in the presence of TiCl4 diisopropylethyl amine to give 371 in
58% yield. The chiral auxiliary was then removed using lithium
borohydride to afford 372. The latter can be transformed into the
desired natural product 368 (Scheme 65).177
Application of the Evans aldol reaction is in the synthesis of the
spiro fused b-lactonec-lactam segment 378 in oxazolomycin 374
isolated from the Streptomyces sp.178 KBFP-2025, which possesses
n-Bu2BOTf, DIPEA,
C13H27CHO 356
O
MeO
N
O
Ph
oC,
C13H27
15 h, CH2Cl2,
53%
LiOH, H2O2
THF/H2O (4: 1)
85%
N
Ph
C13H27
HO
O
355
357
Scheme 62.
354: (-)-Dihyroprotolichesterein acid
1182
1) n-Bu2BOTf,Et3N, CH2Cl2, 0 oC
TBDMSTf
2,6-lutidine, CH2Cl2
2) Et2AlCl, CH2Cl2, -78 oC

N
N
HO
360
65%
359
LiOH, H2O2
OH
THF, H2O (3:1) 76%
TBDMSO
TBDMSO
361
362
CONH2
OH
H2N
OH
NH
H
N
OH
NH
O
NH
N
H
N
H
N
H
HN
N
H
O
NH
O
HN
NH2
O
O
MeO
N
N
H
OH
OH
358: Callipeltin A
Scheme 63.
Lx
Ti
O
N
TiCl4
R CHO 8
1
OH
Bn
LxTi
Bn
R1
Bn
Bn
''Evans'' syn
O
21
363
365
364
- Cl-
OH
Bn
Cl
O
N
R
Ti
366
R1
Cl
O
O
Cl
Bn
''non-Evans'' syn
367
Scheme 64.
derived from L-phenylalanine in the presence of TiCl4 and sparteine

with ent-386 gave the hydroxy acid derivative 387 in 70% yield.
With the classical boron enolate (Bu2BOTf, Et3N, CH2Cl2) only a
low yield could be obtained for this aldol reaction. After protection
of the alcohol to MOM ether 388, the chiral auxiliary was removed
with LiOH/H2O2 to yield acid 389.
The unique fragment in some bioactive marine cyanobacterial
metabolites such as peloruside A, mycalamide A, and epothil-
ones184 is the a,a-dimethyl-b-hydroxy carbonyl functionality.

Lately several marine cyanobacterial natural products with an
a,a-dimethyl-b-hydroxy carbonyl functionality in the form of 3hydroxy-2,2-dimethyloctynoic acid (DHOYA, 396) unit have been
identied. Fragment 396 in mantillamide A 390, a secondary
metabolite, can be prepared in three steps, enantioselectively via
a aldol reaction of an acylated Evans chiral auxiliary and an
aldehyde containing an unprotected terminal alkyne to afford the
1183
Bn
Bn
OH
BnO
N
O
H
LiBH4, Et2O
TiCl4, DIEA
BnO
CH2=CHCH2CHO 370
O
H
CH2Cl2, - 78 oC
369
Br
OH
371
OH
H
O
OTBS
TIPSO
CH3OH, 0 oC
61%
58%
BnO
H
C
H
372
OTBS
H
Br
373
368: Isolaurallene
Scheme 65.
TiCl4, DIPEA,
CH2Cl2, 0 oC
OHC
N
+
Boc
OH
O
N
82%
Bn
Boc
Bn
75%
376
375
40
LiCl, NaBH4,
EtOH: THF(2:1), r.t.
OH
OBz
HO
O
N
Boc
N
Boc
377
378
N
O
O
O
HO
OMe
N
H
HO
OH
O
N Me
O
374: Oxazolomycin
Scheme 66.
desired stereochemistry at the b-hydroxyl carbon. Since the terminal alkyne of fragment 396 is unstable to acid hydrolysis, saturated
3-hydroxy-2,2-dimethyloctanoic acid 393 (DHOAA) was chosen for
chiral GCMS analysis. For the synthesis of 393, the aldol reaction
was carried out with hexanal and both (4S)- and (4R)-391 to give
yields of 98% and 82%, of (3R,4R)-392 and (3S,4S)-392, respectively. Hydrolysis of (3R,4R)-392 and (3S,4S)-392 with LiOH and
H2O2 afforded the desired products with 68% yield for (3R)-393
and 87% yield for (3S)-393, resulting in an overall yield of 52% for
the (R)-enantiomer and 83% for the (S)-enantiomer (Scheme 69).
On the other hand, for the synthesis of 396, aldol reaction between
5-hexyn-1-al 394 and both (4S)- and (4R)-391 gave yields of 58%
and 74%, of (3S,4S)-392 (3R,4R)-392 respectively. Hydrolysis of
the aldol products containing a terminal alkyne gave (3S)-396 with

a yield of 84% (47% overall yield) and (3R)-396 with a yield of 81%
(56% overall yield).185
4. Asymmetric aldol reaction of oxazolidinones
4.1. Generation of magnesium enolates
The magnesium-catalyzed aldol reaction was found to display
an extraordinarily high asymmetric induction when acyl oxazolidinones were used as chiral auxiliaries. The synthesis of non-Evans
anti products has been reported by Evans et al. employing MgCl2catalyzed aldol reaction (Scheme 70).186
1184

O
TiCl4, Hunig's base, NMP
O
S
OH
N2H4, quant.
91%
Ph
Ph
O
380
381
O
382
OH
O
H2NHN
O
H
N
N
H
N
S
N
O
O
383
379, SB-462795
Scheme 67.
In addition, the reaction produces anti-aldol products, which

were previously problematic to access from aldol reactions of this
group of substrates. The reaction is restricted to non-enolizable
aldehydes, since self-condensation of the aldehydes in those circumstances competes with the preferred aldol process. Mechanistic studies have disclosed that the aldol reaction of oxazolidinone
21 is reversible, but can be motivated to completion by adding
chlorotrimethylsilane and triethylamine. If the aldolate intermediate is silylated and the metal, (MgCl2 in this case) is generated and
to catalyze further reaction cycles, the Non-Evans anti stereochemistry is expected 397. The result of a boat-like transition state
is 398 (Scheme 70).186
The asymmetric total synthesis of (+)-prelactone B 399, a biologically important natural b-hydroxy-d-lactone derivative bear-
ing a 2,3-trans-dialkylpyran ring system separated from

balomycin producing Streptomyces griseus by Zeek and Bindseil in 1993,187was performed by Dias, from oxazolidinone 21 in
seven steps and with 33% overall yield. An efcient anti-aldol
reaction occurred between oxazolidinone 21 and methacrolein
170 to yield aldol product 400 in 77% yield and 15:1 diastereoselectivity. After two steps, primary alcohol 402 was obtained
in 79% yield by the reductive removal of the chiral auxiliary with
LiBH4 and water in Et2O. It is noteworthy that the recovery of
the oxazolidinone auxiliary was nearly quantitative in this reaction (Scheme 71).188
( )-Talaumidin 403189 with signicant neurite outgrowth promoting and neuroprotective activities in the primary cultured rat
cortical and in the hippocampal neurons, belongs to a diaryl tetrahydrofuran-type lignin. It was prepared using an Evans aldol reaction in 16 steps from 4-benzyloxy-3-methoxybenzaldehyde in ca.
10.7% overall yield for the rst time. As shown in Scheme 72,
OAllyl
OAllyl
Bn
O
TiCl4, sparteine
+
N
CH2Cl2, - 80 oC
386
70%
N
O
OH
387
Bn
385
OAllyl
MOMCl, Et3N
CH2Cl2
, 90%
CO2H
AllylO
Bn
O
LiOH, H2O2
THF/H2O 85%
N
O
OMOM
389
388
HO
OMOM
Me
N
OH
384: revised structure of tyroscherin
Scheme 68.
1185

O
O
1) LDA, THF, - 78 oC
2) Ti(o-i-Pr)3Cl
3) Hexanal 212
OH
O
1) H2O2
2) LiOH
OH
HO
THF : H2O, 4 : 1
THF, -40 oC -0 oC
(3S)-393; 87%, 83% overall

(3S,4'S)-392; 98%
(4'S)-391
O
O
OH
3) Hexynal 394
1) H2O2
2) LiOH
THF,-40 oC-0 oC
OH
HO
THF : H2O, 4 : 1
3-Hydroxy-2,2-dimethyloctynoic acid (DHOYA)
(4'R)-391
(3R,4'R)-395: 74%
(3R)-396: 81% , 56% overall
O
O
N
H
O
O
HN
O
O
N
O
O
N
N
H
390: Mantillamide A
Scheme 69.
two stereogenic centers C2C5 of ( )-(2S,3S,4S,5S)-talaumidin 403

were created by the asymmetric aldol reaction of 4-benzyloxy-3methoxybenzaldehyde 321 with (S)-4-benzyl-3-propionyl-2-oxazolidinone 21 in the presence of TMSCl, Et3N, and 10 mol % of
MgCl2 to form the (2S,3S)-aldol adduct 404 in medium yield with
excellent diastereoselectivity (de = 98%). The hydroxy group was

then protected as a TBS ether, and the reaction was continued by
the reductive removal of the oxazolidinone in the presence of
LiBH4 to provide the primary alcohol 405 in excellent yield.190
5. Removal of the oxazolidinone auxiliary
1) R CHO 8
MgCl2, Et3N, TMSCl
1
OH
R1
2) TFA, MeOH
Bn
Bn
397
21
"Non-Evans" anti
H
Me
Ph
H2O
Cl
Mg
H2O
Bn
O
398
Scheme 70.
After the stereospecic reaction with an oxazolidinone, the chiral auxiliary should be separated from the product and preferably
recycled. Two types of cleavage of oxazolidinones have been observed: exocyclic and endocyclic cleavages.6 The exocyclic cleavage
is usually more desirable but endocyclic cleavage occurs even
when the oxazolidinone derived carboximides 406 bear a bulky
R1 group (Scheme 73).
Numerous reagents such as central strategic steps in the total
synthesis of a wide variety KOH, LiOH, LiBH4, LiOR, N2H4/n-amylONO/NH4Cl, Cp2TiCl2, and Cp2ZrCl2 MeONHMe HCl/AlMe have
been used to cleave N-acyloxazolidinones.6,17 Lithium hydroxide
is the common reagent for the transformation of 406 into 407
and 408, However sometimes undesired endocyclic cleavage
occurs. The undesired endocyclic oxazolidinone cleavage can be
sidestepped by the use of lithium hydroperoxide in place of the
hydroxide.191,192 Thus, regioselective exocyclic cleavage is observed for all classes of oxazolidinone-derived carboximides, even
those with bulky R1 groups, when the peroxide reagent is
employed. The cleavage by using lithium boron (or aluminum) hydride reductively removes the auxiliary to form alcohol 409.193
These two methods are among the most common routes used to
1186

O
1) MgCl2, NaSbF6
21
CHO
O +
OH
Et3N, TMSCI, rt
N
H2, Pd/C, EtOAc
99%
2) MeOH, CF3CO2H,
Bn
170
400 Bn
dr 15:1
77%
O
O
OH
O
N
TBSO
1) TBSOTf, THF
2,6-lutidine, 0oC
O
OH
O
2) LiBH4, H2O, Et 2O,
OH
79% (2 steps)
Bn
401
402
399: Prelactone B
Scheme 71.
OH
O
N
MeO
O
CHO
+
BnO
Bn
21
1) MgCl2, TMSCl,
Et3N, EtOAC, rt, 16 h
MeO
2) HF/py/MeCN (1:3:5),
0 oC, overnight
BnO
321
N
Bn
68%
404
TBSO
1) TBSOTf, 2,6-lutidine,
CH2Cl2, r.t., 5 min
2) LiBH4, MeOH, Et2O, r.t., 1 h
91% (2 steps)
MeO
OH
MeO
O
BnO
HO
405
403: (-)-talaumidin
Scheme 72.
O
OH-
exocyclic
NH
R
407
R1
HO
408
O
HO
O
O
N
NH
R1
406
R1
409
407
R
HO
endocyclic
HO
OH- or H-
R1
HN
R
410
Scheme 73.
remove the oxazolidinone 407 with no racemization or epimerization (Scheme 73).17

6. Conclusions and future prospects
In this review, we have presented some highlights of the asymmetric aldol reaction using chiral oxazolidinones for the total
synthesis of natural products and complex molecular targets. In
these reactions, auxiliary controlled processes are essential tools
to generate the desired stereocenters. The availability of the starting materials, ease of cleavage and submission to a wide variety of
steroselective reactions indicate that the oxazolidinone auxiliary is

an ideal intermediary for asymmetric synthesis. Since the rst realization that small chiral organic molecules such as oxazolidinones
could induce considerably high stereoselectivities during CC bond
forming reactions, such as aldol condensation, the use of these processes has become a vibrant area of study, and they have found
applications as central strategic steps in the total synthesis of a
wide variety of natural products. Inspiring and sophisticated CC
bond stereoselective formations have been recognized and showcased in this review. These precedents, which reveal the asymmetric and efcient CC bond formation, should continue to stimulate
and motivate the interests of synthetic chemists to use oxazolidinones as a chiral auxiliary in their future endeavors in the total
synthesis of natural products.
Acknowledgments
The authors are thankful to Alzahra Research Council for
support.
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Tetrahedron: Asymmetry 24 (2013) 11491188

Contents lists available at ScienceDirect

Tetrahedron: Asymmetry Report Number 144

Oxazolidinones as chiral auxiliaries in asymmetric aldol reactions

oxazolidin-2-ones as chiral auxiliaries in asymmetric synthesis.

M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 24 (2013) 11491188

R = i-Pr, t-Bu, Ph, Bn

aminations, azidations, brominations, hydroxylations, Diels Alder,

10, Evans syn

Useful reviews on the applications of oxazolidin-2-ones as the

M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 24 (2013) 11491188

worthwhile noting that in this short review along with the

enantioselection should be the main concern. The Z-enolates of

2. Asymmetric catalyzed aldol reactions of oxazolidinones

n-Bu2BOTf, Et3N, CH2Cl2, - 78 oC

TBDPSCl, imidazole, DMF

LiBH4, MeOH, THF, 0 oC

26: Zaragozic acid D

M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 24 (2013) 11491188

Zn, NH4Cl, MeOH, 96%

or Bu3SnH, AIBN, , 67%

n-Bu2BOTf, Et3N, Et2O

44a: 4-yl X = (-)-maleate

M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 24 (2013) 11491188

to the selective formation of syn products (also known as Evans

Evans suggested that boron enolates undergo aldol reactions via

LiOH, 30% H2O2,

M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 24 (2013) 11491188

dibutylboron enolate of imide 14 and 4-methyl-4-pentenal 15 to

M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 24 (2013) 11491188

Application of the Evans aldol reaction in the total synthesis of

M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 24 (2013) 11491188

CH2Cl2, -78 to 0 oC,

TfOH, Et2O r.t.,

LiOOH, THF-H2O (3:1)

THF, -30 oC to r.t.

Dolastatin G 55 and nordolastatin G 56, cytotoxic 35-membered

aldol reaction to yield the key intermediate 59 in 89% yield. Under

M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 24 (2013) 11491188

The intermediates 71 and 74, which constitute the C3C15

HIV reverse transcriptase was accomplished via an Evans aldol

0 oC, 3h, 81%,

93: Maduropetin chromophore

M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 24 (2013) 11491188

The development of the Evans aldol reaction for direct access to

quassine 99 and bruceantine 100, two members of the quassinoid

M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 24 (2013) 11491188

re-oxidized with the DessMartin reagent to yield 98% of aldehyde

LiBH4, EtOH, Et2O,

M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 24 (2013) 11491188

2) LiBH4, H2O, Et2O, 0 oC-25 oC

M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 24 (2013) 11491188

of macrolactone 141, aldehyde 133 was exposed to oxazolidinone

substituted dihydrobenzofuran nucleus was established. It has a

NaBH4, THF-H2O, r.t.,

M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 24 (2013) 11491188

dermolide.91,92 It was synthesized from methacrolein by Day et al.93

macrolide against KB and PS tumor cell lines in vivo, isolated in

9-BBN triflate, i-Pr2NEt,

Me3SiI, CH2Cl2, r.t., 1h

M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 24 (2013) 11491188

via aldol condensation of the Z-enolate of chiral oxazolidinone 40