Tandem Reaction Sequences

Chris Borths
MacMillan Group Meeting
November 21, 2000

I. Cationic Transformations
II. Anionic Transformations
III. Pericyclic Transformations
IV. Metal-catalyzed Transformations

Reviews: Ho, T.L. Tandem Organic Reactions; Wiley: New York, 1992.
Tietze, L.F.; Beifuss, U. Angew. Chem. Int. Ed. Engl. 1993, 32, 131.
Tietze, L.F. CHem. Rev. 1996, 96, 115.

Why Tandem Reactions?

Practical Considerations

! Reduction of waste

! Avoids isolation of intermediates

! Reduces labor, time to effect given transformation

Academic Considerations

! Builds a large degree of complexity in one transformation

! Novel avenues of research, new reaction development

A Definition:

! A tandem reaction is a reaction in which several bonds are formed in sequence without
isolating intermediates, changing reaction conditions, or adding reagents.
 Polyene Cationic Cyclization

O
Me
O + O
O O Me O Me
Me
O H2O
Me Me H Me H
HO CF3CO2H 65% yield
CH3CHF2 H H H H
-30 ºC
H H

Me O ! Acetals and allylic alcohols are good initiators

Me O
Me
+ O ! Only one out of 32 possible diastereomers formed
H2O
! Double bond geometry controls stereochemistry of
product

! Vinyl fluorides can increase yield by stabilizing

O
+ intermediate carbcations
Me
Me O
O

Johnson, W.S. Angew. Chem. Int. Ed. Engl. 1976, 15, 9.

Fish, P.V.; Johnson, W.S. J. Org. Chem. 1994, 59, 2324.

Mannich-Cation Olefin Cyclization

CH2O H
NH N 6 steps N
N 40 ºC N N
H H
SO2Ar 63% yield
H H

O
TMS
(±)-Yohimbone

! Allylsilanes are common

terminators of cationic olefin
+ + cyclizations
N N
N N
! This is the first example of an
SO2Ar SO2Ar
iminium ion as the initiator

TMS TMS

Grieco, P.A.; Fobare, W.F. J. Chem. Soc. Chem. Commun. 1987, 185.
 Cascade Polyether Cyclization

Me
OBz O Me Me O O
O Me
Me O
HCl R
O
Me O
O O Me 30% yield
OMe H O
Me DEIPS R3Si Me O H
BnO OPMB
+

DEIPS = diethylisopropylsilyl OPMB

OBz O
OBz O Me Me
Me Me PPTS
(MeO)3CH Me
O O
Me MeOH OMe H H O
O O Me
OH H O 51% yield BnO Me
Me
BnO Me
O
O Me
Me HO OPMB
HO OPMB
C1 - C22 of Etheromycin

! Stereochemistry of epoxide determines the stereochemistry of the polyether

Paterson, I.; Tillyer, R.D.; Smaill, J.B. Tet. Lett. 1993, 34, 7137.
Review: Koert, U. Synthesis 1995, 115.

Diastereoselective Ugi Reaction

C
N
O O
ZnCl2, THF, -78 °C, 3 d H+
OTBS + RCHO R R
OPiv N O
PivO H
N NH3Cl
O TBSO Sug* CHO NH3Cl
+ HCO2H NH2
PivO
OPiv
31-99% yield

O
Ugi Coupling R
HO

R d.r. yield NH3Cl

Ph 90 : 10 61%

CH2CH(CH3)2 97 : 3 80%
! The opposite enantiomer can be accessed by using
(CH2)4CO2CH3 98 : 2 80% a different sugar auxiliary. Diastereoselectivities are
similar (90:10 - 96:4); yields are lower (48 - 76%).
Bn 98 : 2 85%

(CH2)2CF=CHC6H5 98 : 2 65%

Linderman, R.J.; Binet, S.; Petrich, S.R. J. Org. Chem. 1999, 64, 336.
 Ugi Reaction Mechanism
C
N
O
ZnCl2, THF, -78 °C, 3 d
OTBS + RCHO R
OPiv N
+ HCO2H PivO H
N
O TBSO Sug* CHO
PivO NH2

PivO

Sug* Cl2Zn Sug*

O N ZnCl2 N C N Ar
+ H2N Sug*
R H R H R H +H+

Sug* Sug* R H
HN R
HCO2- HN Ar Sug* N
H N Ar
R
N O O N
O
Ar
O

H R Sug* R O
Sug* N Ar N Ar R
~H+ N
O N O NH H
H O H O N
TBSO Sug* CHO

Linderman, R.J.; Binet, S.; Petrich, S.R. J. Org. Chem. 1999, 64, 336.
Ugi, I. Angew. Chem. Int. Ed. Engl. 1962, 1, 8.

Tandem Knoevenagel Diels-Alder Reaction

Me

O
Me O
CHO [4+2]
100 °C
+ Knoevenagel Me Me O C5H11
O C5H11

Me Me

Me Me
C5H11 i) LDA, PhSeBr
O OH
H ii) MCPBA H
O O
Me
Me 65% yield H
46% yield
H
Me Me O C5H11 Me O C5H11
Me Me

(+)-Hexahydrocannabol

! The Diels-Alder reaction is controlled by the chiral center in citronellal.

! The product is a 2:1 (!:") mixture of diastereomers at the alkyl chain.

Tietze, L.F.; Kiedrowski, G.; Berger, B. Angew. Chem. Int. Ed. Engl. 1982, 21, 221.
 Tethered Biginelli Condensation
O
H H Ptilomycalin A
H2N NH Me i) O3, Me2S CO2R1
R N OTBS Crambescidin 657
R Me
ii) morpholine-HOAc (1:1.1) Neofoliispates 2
Na2SO4, 70 °C O N Crambescidin 800
H
O OTBS
R1O2C
Me

O3, Me2S
! Both cis and trans product can be accessed
based on rxn conditions and guanidine
O
equivalent
H2N NH uncharacterized
complex mixture ! R When X=NH2+, trans product is formed
O NH
R
H When X=O, cis product is formed
X NH2

Knoevenagel

CO2R1
H H H H
alkyl CO2R1 -H2O CO2R1
~H+ R N R N
O alkyl
R NH O
NH2 O O N alkyl
H
O NH2

McDonald, A.I.; Overman, L.E. J. Org. Chem. 1999, 64, 1520.

Coffey, D.S.; McDonald, A.I.; Overman, L.E.; Rabinowitz, M.H.; Renhowe, P.A. J. Am. Chem. Soc. 2000, 122, 4893.

Tandem Radical Cyclization

O O
Me H
O O 1) H3O+ Me H
Bu3SnH 2) NH2NH2
Me
Me
Me 66 - 80% yield?
Me Me
Me
Me
(±)-Siliphiperfol-6-ene
Br
2.5 : 1 d.r.
65% yield

! The stereochemistry of the

vinyl bromide does not affect
reaction outcome
O O
O O Bu3Sn H H
O O ! Direct cyclization of the !,"-
unsaturated ketone is possible,
Me
but favors the !-methyl
Me Me
diastereomer 3:1. The cyclic
Me Me acetal shields the endo face of the
Me
bicyclic system and favors the "-
Me Me Me
methyl diastereomer.

Curran, D.P.; Kuo, S.C. J. Am. Chem. Soc. 1986, 108, 1106.
 A Biomimetic Cyclization
BnO
OBn
i) Swern
H ii) NH3
HO H
iii) HOAc, 70 ºC
Me
HO 82% yield Me
HN

Me

Me

Me
Isolated intermediates

Swern 70 ºC
Imino-ene reaction

BnO BnO
OBn

H H HOAc
O
NH3 H
r.t Me
O N Diels-Alder Me
Me N

Me Me

Me Me

Me Me

Heatchcock, C.H. Angew. Chem. Int. Ed. Engl. 1992, 31, 665.

Tandem Michael Reaction

CO2Et Formal
r.t. O2N
Synthesis HO2C Me
+ O2N EtO2C Me
Me quant. yield
HO HO HO2C N
NHBn N H
Bn
(-)-!-Kainic Acid

+H+

-
CO2Et -O EtO2C O ! Nitro group used as a
- +
+ O N removable electron-withdrawing
N -H+ Me group
O Me
HO Bn
N N
H
Bn

Barco, A.; Benetti, S.; Pollini, G.P.; Spalluto, G.; Zanirato, V. J. Chem. Soc. Chem. Comm. 1991, 390.
 Tandem Alkylation, Oxy-Cope, Cyclization

Me
O
O O O O O
2
BrMg Me O OMOM
Me OMOM Me
CO2Me 5 5
53% yield
O
OPMB
PMB

Grignard addition Dieckmann cyclization

MeO O Me MeO O Me
R R

5 Oxy-Cope 5

BrMgO BrMgO
OPMB OPMB

! Grignard addition sets up an anion-accelerated oxy-Cope which rearranges through a chair transition state

! The enolate resulting from the oxy-Cope spontaneously cyclizes onto the methyl ester

Chen, C.; Layton, M.E.; Sheehan, S.M.; Shair, M.D. J. Am. Chem. Soc. 2000, 122, 7424.

Tandem Fries rearrangement, Cyclization, Deprotection

Me Me
O O
O O
2 O O Fries-like
2
O OMOM TMSOTf O rearrangement
OMOM
Me Me
5 (MeO)3CH
MeO2C MeO2C 5

O OMOM OMOM
O O
O
MeO OMe TMS

MeO
TMS
O O O O
O O O O O
Me O Me
MeO 2
2
O O
Me Me
5 MeO2C 5
MeO2C

O OH
TMS O OMe O

! This intermediate was elaborated iinto (+)-CP-263,114.

Chen, C.; Layton, M.E.; Sheehan, S.M.; Shair, M.D. J. Am. Chem. Soc. 2000, 122, 7424.
 Tandem Diels-Alder Retro Diels-Alder

Me Me
O Me
N
Me N O
136 °C Me
MeO
O 136 °C O
Me
MeO - CH3CN
Me OMe
Me O Me O
Me
Me

poor formal
synthesis

! Intramolecular Diels-Alder reaction assures regiocontrol over

Me
product
OH Me
! The rest of the synthesis involves several oxidation-reduction
and deprotonation-reprotonation sequences.
O O
Me O

(±)-Paniculide-A

Jacobi, P.A.; Kaczmarek, C.S.R.; Udodong, U.E. Tet. Lett. 1984, 25, 4859.

Oxy-Cope, Diels-Alder, Retro Diels-Alder

O Me
O H
H O O
O O 160 ºC O O [3,3] Diels-Alder
O
Me Me Me O
N N O
Me
OH
Me
Me N Me
Me

Me Me Me
H H H
Retro
O O O
O Diels-Alder O hydrolysis
Me O
O - HCN O Me Me
O
Me Me O Me O
N

!-Me 45% yield of Gnididione

"-Me 57% yield of Isognididone

! Note: Each olefin geometry (E and Z) was prepared selectively and subjected to the reaction conditions

! Oxy-Cope rearrangement proceeds through a chair transition state, possibly stabilized by intramolecular hydrogen bonding.
Analysis of crude reaction mixtures indicated that less than 2% of material rearranged through the boat conformation.

! Regiocontrol over the Diels-Alder reaction was established by geometrical constraints, and the retro Diels-Alder was
entropically favored.

Jacobi, P.A.; Selnick, H.G. J. Am. Chem. Soc. 1984, 106, 3041.
 Tandem Oxy-Cope Claisen

Me
Me
Me
O OTIPS [3,3]
Me
O OTIPS Me
Me 200 ºC O
Me Me
Me OTIPS

Me
Me Me
1) KF-2H2O
[3,3] Me 2) CH2N2
Me Me Me 7 steps
O O
30% yield Me
OTIPS OMe O H
Me
O

(+)-dihydrocostunolide

! Rearrangement shows no evidence of silyl migration. When TBS is the silyl group, the rearrangement is complicated
by silyl migration.

! Both [3,3] rearrangements occur through chair transition states.

Raucher, S.; Chi, K.W.; Hwang, K.J.; Burks, J.E. J. Org. Chem. 1986, 51, 5503.

Aza-Cope Mannich Reaction

O
Me CSA HO
Me 3 steps
O CF3CH2OH
Bn C9H19 61 - 68% yield Bn C9H19
N Bn C9H19 N
Me N Me
Me
80% ee (+)-Preussin

O
HO Me
Bn Me
Me N Mannich
Bn N C9H19
C9H19 Me
C-C
O
rotation
OH Me
OH
Me [3,3] Me
Mannich
Me Me
H+ Me Bn N C9H19 Bn C9H19
Bn N C9H19 N
O Me
favored favored
Bn C9H19 O
N OH OH
Me [3,3] Me Me
Me Mannich
Me Me
Bn N Bn N
H+
Bn C9H19
C9H19 N
C9H19 Me
C-C
disfavored
rotation O
HO Me
Bn Me Mannich
Me N
C9H19
Bn N C9H19
favored Me
Deng, W.; Overman, L.E. J. Am. Chem. Soc. 1994, 116, 11241.
 Tandem Claisen-Ene Reaction

PO CHO CO2Me
Me
Me OMe O
HO 180 ºC H
Me Me Me 14
60 h
P = Si 8 H
+
Me Me Me
MeO

CO2Me
76% yield
after hydrolysis

PO
CO2Me
! Claisen rearrangement proceeds through a chair transition state-- Me
evidinced by high 8,14 syn selectivity and the 14S configuration O
H
! Ene rearrangement proceeds through the bicyclic transition state with
the A,B ring at a pseudo-equatorial position H

PO
Me
PO CO2Me CO2Me
Me Me
O O
Me PO H
PO O
R H

MeO H
H

MeO2C
Mikami, K.; Takahashi, K.; Nakai, T. J. Am. Chem. Soc. 1990, 112, 4035.
Mikami, K.; Takahashi, K.; Nakai, T.; Uchimaru, T. J. Am. Chem. Soc. 1994, 116, 10948.

Cascade Aromatic Annulation

OTIPS
OMe OMe
O OH O
h! O2, TBAF
N2 +
MeO 54% yield 67% yield
9 nBu O nBu
9 9
OTIPS OH
nBu
Maesanin
photochemical Wolff
6 electron ring closure
rearrangement
and tautomerization
OMe
O O

MeO H R
OTIPS

[2+2] 4 electron electrocyclic

O R ring opening

MeO OTIPS

Danheiser, R.L.; Cha, D.D. Tet. Lett. 1990, 31, 1527.

 Tandem [2,3] Rearrangement, Diels-Alder

OH Ph
O
Me PhSCl S H
O Ph S
Me Et3N H [2,3]
Me Me
r.t. Me Me Me
38 h
Me

Me

Ph O
O S
1) MeMgBr, Ni(dppp)Cl2 H
Ph S
[4+2] 2) Na, NH3, tBuOH Me
Me Me
Me Me
Me Me 43% yield
Me H Me H
H
70% yield (+)-Sterpurene

! Chirality of secondary alcohol is effectively transferred to the axial chirality of the allene intermediate

! The intramolecular Diels-Alder sets two stereocenters enatio- and diastereoselectively from the allene intermediate

Gibbs, R.A.; Okamura, W.H. J. Am. Chem. Soc. 1988, 110, 4062.

Pericyclic Domino Reaction

! [2,3]-allyl sulfenate and [2,3]-allyl sulfoxide shifts are reversible. The [1,5] sigmatropic hydride migration is the
stereodifferentiating step in this reaction sequence.

Me

Me R Me Me
PhSCl
Me Et3N S(O)Ph
OTBS
=R
R 61% yield
Me Me
OH

A OTBS

Me
Me Me
Me
OTBS Me O Me
OTBS OTBS
R PhS
R
O
S S(O)Ph
R
Ph

Me
Me
Me
OTBS
R H A
Me
S(O)Ph
O
R S
Ph
OTBS

Iglesias, B.; Torrado, A.; de Lera, A.R. J. Org. Chem. 2000, 65, 2696.
 Cobalt-Mediated [2+2+2] Cycloaddition
NHAc
N
CpCo(C2H4)2
NHAc
C2H4, THF, 0 °C 8 steps H
47% yield N
N N CoCp H
H
O O
O H

Strychnine
NHAc
NHAc CpCo(CO)2 TMS

TMS OMe OMe

N
46% yield
N CoCp
O H
O
! Cyclization tolerates a wide range of
functionality as olefin equivalents

Bn C C C N C C
N
Bn
N C O N C O
CpCo(CO)2
N 40% yield
N CoCp
H
O
O

1:1 syn:anti

Eichberg, M.J.; Dorta, R.L.; Lamottke, K.; Vollhardt, K.P.C. Org. Lett. 2000, 2, 2479.

Nickel-Catalyzed [2+2+2] Cyclizations

O 10 mol% Ni(COD)2 O
tBuLi, ZnCl2
Ph
52% yield Ph H

Me
O O 20 mol% Ni(COD)2 O
100 mol% PPh3 O
Me + Ph Ph Ph
75% yield Ph H

Me Me O
Ln
O Ph Ln Ph O
O L
Ni Ph
Ni Ni L
Ph O
H Ph
Ph H

Ph Ln ! Radical mechanism eliminated as a

O possibility due to high stereoselectivities of
Ni
products in model systems.
Ph
H ! E and Z enones yield same product
stereochemistry.

Montgomery, J.; Seo, J. Tetrahedron 1998, 54, 1131.

Seo, J.; Chui, H.M.; Heeg, M.J.; Mongomery, J. J. Am. Chem. Soc. 1999, 121, 476.
 Nickel-Catalyzed Cyclization

OTBS
O X O Me OTBS Me
O HO2C
10 mol% Ni(COD)2
300 mol% AlMe3 X
O N =X 4 steps
73% yield HO2C
N
Me N N H
Me >97:3 d.r.
O O
O O
(+)-!-allokainic acid

Ni(COD)2

O Ln Me
Ni Me2AlO LnNi OTBS
H COX X OTBS
NiLn AlMe3 X
O
N
O OTBS N N
O O
O O

! Metallocycle formation proceeds through a transitions state with all substituents in a pseudo-equatorial configuration

! Unsaturated acyl oxazolidinones show greater reactivity and selectivity than unsaturated esters.

Chevliakov, M.V.; Montgomery, J. J. Am. Chem. Soc. 1999, 121, 11139.

Seo, J.; Fain, H.; Blanc, J.B.; Mongomery, J. J. Org. Chem. 1999, 64, 6060.

Palladium Polyene Cyclization

OMe
OMe 2.5 mol% (dba)3Pd2CHCl3
10 mol% HOAc
PhO2S
10 mol% SbPh3
PhO2S
65 °C
6 77% yield PhO2S
PhO2S

HPd(OAc)(SbPh3)2
OMe
OMe
OMe
H
PhO2S PdLn H PdLn
PdHLn PhO2S
PhO2S PdLn
PhO2S R
PhO2S
R PhO2S
R

! The geometry of the double bonds controls the ring-fusion geometry. 1,1-disubstituted olfins form spiro ring systems - 1,2-
disubstituted olefins form fused ring systems.

! The two new bonds formed with the "-system are cis to one another due to the syn addition of the Pd species.

! This tandem cyclization process can be initiated by an alkyne in the presence of HOAc or by a vinyl halide.

Trost, B.M.; Shi, Y. J. Am. Chem. Soc 1993, 115, 9421.

Review: Overman, L.E.; Abelman, M.M.; Kucera, D.J.; Tran, V.D.; Ricca, D.J. Pure Appl. Chem. 1992, 64, 1813.
 Enantioselective Heck-Anion Addition

2.5 mol% [Pd(allyl)Cl]2 CO2Et

EtO2C Me
OTf 6 mol% (S)-BINAP OTBDPS
Me H H
H 8 steps
200 mol% NaBr

Na+ H
Me
TBDPSO - CO2Et Me
Me

CO2Et 77% yield (-)-Capnellene

87% ee

! Heck reaction is
Na+ enantiodifferentiating
R R
- ! Nucleophile adds to less hindered
carbon
H PdLn*
H
* P
P ! Wide range of soft nucleophiles will
Pd
add to the !-allyl Pd species
PdLn*
Me Me Me

Oshima, T.; Kagechika, K.; Adachi, M.; Sodeoka, M.; Shibasaki, M. J. Am .Chem. Soc. 1996, 118, 7108.

Enantioselective Michael Aldol

O O O OH
H
CO2Me 5 mol% catalyst CO2Me
H
5 4.5 mol% NaOtBu 5 O O
Al
O O
CMe(CO2Bn)2 Li
BnO2C CO2Bn
84% yield
Me 92% ee
6 : 1 - 17 : 1 d.r catalyst

Nu
Nu
O Na
O Na
O O O O
Al Al
O O O O
Li Li

! Enantioselectivity is determined in the Michael addition.

! When simple malonates were used as nucleophiles, low yields resulted.

Yamada, K.; Arai, T.; Sasai, H.; Shibasaki, M. J. Org. Chem. 1998, 63, 3666.
 Enantioselective Tandem Mukaiyama Aldol Reaction

10 mol% TiCl2(OiPr)2 HCl

OH OTBS OH OH O OH
OTBS O 10 mol% (R)-BINOL MeOH
+ 2
CH2Cl2 MeO2C CO2Me MeO2C CO2Me
Me H CO2Me
0 ºC, 3 h 1:4 E:Z 77% yield
>99% de
>99% ee

OH O OH
kR,R = 3.4
MeO2C CO2Me
OH OTBS (R,R)
! ee of major product of
kR = 129 MeO2C
first reaction amplified
(R) kR,S = 0.1 OH O OH
OTBS
! minor product of first
Me MeO2C CO2Me aldol converted into
kS,R = 17
meso meso product
OH OTBS
kS = 1 preferentially
MeO2C
(S) OH O OH
kS,S = 1
MeO2C CO2Me
(S,S)

Mikami, K.; Matsukawa, S.; Nagashima, M.; Funabashi, H.; Morisima, H. Tet. Lett. 1997, 38, 579.

Tandem Sakurai Ene Reaction

! High diastereoselectivity of the tandem sequence was observed when a mixture of all four olefin isomers was
submitted to the reaction conditions.

OtBu H
Me H
Me Me
TMSOTf TMS O TMS
Sakurai O
Me TMS Me Me
Me TMS
Me
OtBu OtBu
O Me
TMS

d.r. 1:1:1:0.1

H
Me Me
TMS TMS
O ~H+ O
Me Ene
Me H
Me OtBu
OtBu

Me OtBu
Me
TMS H
O Me
Me
H 52% yield
OtBu H H
HO

Tietze, L.F.; Rischer, M. Angew. Chem. Int. Ed. Engl. 1992, 31, 1221.
 Prins-Pinacol Reaction
Me Me
Me Me
CHO Me Me
p-TsOH•H2O
HO O
MgSO4 10 mol% SnCl4
+ OH
76% yield O 88% yield

TIPSO

TMS
TMS TIPSO

Me Me Me
Me
Cl4Sn O Cl4Sn O
OHC H Me
O Prins Pinacol Me
O
Me CHMe2 Me CHMe2 O
H H

TMS TMS
OTIPS OTIPS TMS OTIPS

Me

H H Me
H H ! Diastereomeric mixture yielded only one diastereomer of the product under
reaction conditions.
O
Me
Me O ! no olefin isomerization was observed

HO
alleged structure of
Overman, L.E.; Pennington, L.D. Org. Lett., 2000, 2, 2683.
Sclerophytin A for a previous example: MacMillan, D.W.C.; Overman, L.E. J. Am. Chem. Soc. 1995, 117, 10391.

Tandem Acyl-Claisen Rearrangement

! The tandem acyl claisen tolerates a wide range of functionality with excellent yields and diastereocontrol.

O O R1 O
N O
O 10 mol% Yb(OTf)3 N N
+ R2
N Cl i-Pr2EtN, CH2Cl2 O R2 R2 O
excess
R1

R1 R2 yield d.r.

Me Me 97% 97:3

Cl Me 96% >95:5

CN Me 81% >95:5

SPh Me 70% 93:7

OBz Me 86% 91:9

Me NPhth 98% 95:5

Me OPv 97% 97:3

Me Bn 100% 94:6

Dong, V.M.; MacMillan, D.W.C. unpublished results.

 Tandem Acyl–Claisen Rearrangement: Stereocontrol
! Rearrangment via the trans morpholine is favored in the first rearrangement

O
O
N O + NR2
O 10 mol% Yb(OTf)3 N [3,3]
+ Me
N Cl Me
i-Pr2EtN, CH2Cl2 LAO Me

Me

! A1,2 strain controls the second rearrangement

O O NR2
Me
2nd equiv. Cl H H O Me O
O
Me Me
N + N N
O Me Me O
Me OLA
O Me
syn-syn isomer
disfavored
N N
O Me O

syn O
H O Me O
favored O Me
NR2
intermediate +
N N N
Me
O Me Me O
LAO Me

favored syn-anti isomer

Amino-Thio Tandem Acyl-Claisen

Me
O
O
Me S R Me SiPr
iPr Cl N
N 20 mol% TiCl4, iPr2EtN Me
Cl4TiO R
-30 °C, 1 d
O

O
O Me TBDPSO OTBDPS
OTBDPS OLA LAO
Cl S iPr iPr S
N SiPr Me H Me H Me Me
5 eq. Me2AlCl, iPr2EtN
O R
Me -50 °C, 4 d R(iPr) R(iPr)

favored disfavored

O Me Me O R yield d.r. (syn, anti, anti):(syn, syn, anti)

Me 83% 12 : 1
N SiPr
OTBDPS 80% 9:1
O R OTBDPS
OBn 80% 7:1

! Stereochemistry of first rearrangement is controlled by a chair transition state

! Stereochemistry of second rearrangement is dictated by "Felkin-Anh" type control

! When the OTBDPS group on the second acid chloride is substituted with a smaller substituent, the
diastereoselectivity decreases
Seo, J.; MacMillan, D.W.C. unpublished results.
"Felkin-Anh" control in a [3,3] rearrangement: Hatakeyama, S.; Saijo, K.; Takano, S. Tet. Lett. 1985, 26, 865.
 The Conclusion Slide

! There are many tandem reaction sequences, grouping together almost any pair of reactions with compatable reaction
conditions.

! Tandem reactions are typically calssified by the mechanism of each step.

! Tandem reaction sequences can quickly build significant complexity into a molecule.

! There are few enantioselective tandem reactions.