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DOI: 10.1002/ajoc.201200038
Enantiomerically Enriched (4 + 3) Cycloadducts from Optically Active
Epoxy Enolsilanes
Sarah Lam,[a] Brian Lo,[a] Wing-Tak Wong,[a] and Pauline Chiu*[a, b]
The (4 + 3) cycloaddition of oxyallyl cations and dienes is
a classical method for the assembly of seven-membered car-
bocycles.[1] Asymmetric versions of these cycloadditions
provide access to optically enriched cycloheptanoids, which
are prevalent substructures in natural products.[2] The strat-
egies that have been used for asymmetric (4 + 3) cycloaddi-
tions include employing chiral dienes and/or cations in the
cycloadditions,[3] and catalysis by chiral Lewis acids[4] or or-
ganocatalysts.[5] Some of these cycloadditions have been ap-
plied as key steps in the asymmetric total synthesis of natu-
ral products, including dactylol and colchicine.[6]
We reported our studies on the use of epoxy enolsilanes
as the three-carbon component in intramolecular (4 + 3) cy-
cloadditions to directly afford hydroxylated cycloheptenone
fused ring systems.[7] The intramolecular (4 + 3) cycloaddi-
tion was found to generate carbobicycloACHTUNGRE[5.4.0] systems with
high diastereoselectivity. Furthermore, enantiomerically en-
riched epoxy enolsilanes reacted to give cycloadducts with
correspondingly high enantiomeric excess (ee). This intra-
molecular cycloaddition was the key step in our recent
asymmetric synthesis of the pentacyclic core of cortistatin J,
which is a potent anti-angiogenic natural product.[8]
Without the constraints of a tether between the epoxy
enolsilane 1 (Figure 1) and the diene, the intermolecular
version of this cycloaddition has high stereospecificity for
the E- or Z-enol ether, by reacting through endo- and exo-
cycloaddition modes to yield two out of a possible four dia-
Figure 1. Epoxy enolsilanes in the intermolecular (4 + 3) cycloaddition.
[a] S. Lam, B. Lo, Prof. W.-T. Wong, Prof. P. Chiu
Department of Chemistry, The University of Hong Kong
Pokfulam Road, Hong Kong (P. R. China)
Fax: (+ 852) 28571586
E-mail: pchiu@hku.hk
[b] Prof. P. Chiu
State Key Laboratory of Synthetic Chemistry
The University of Hong Kong, Pokfulam Road
Hong Kong (P. R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/ajoc.201200038.
30  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
stereomeric cycloadducts.[9] Herein, as an extension of this
method we further examine the scope of this intermolecular
reaction and demonstrate that the use of optically enriched
epoxy enolsilanes, such as 2 in which R2 ¼6 H, affords (4 + 3)
cycloadducts with essentially complete conservation of
enantiomeric purity. This reaction is a general method for
producing optically active bicyclic intermediates for further
synthesis.
To obtain optically enriched epoxyketones from a series
of enones 3 a–f, we carried out catalytic asymmetric epoxi-
dation according to the conditions reported by Deng et al.,
to afford epoxyketones 4 a–f in 93-99 % ee (Scheme 1).[10, 11]
Deprotonation and silylation of 4 a–f generated enantiomer-
ically enriched epoxy enolsilanes 2 a–f.
Scheme 1. Synthesis of enantiomerically enriched epoxy enolsilanes 2.
LHMDS = lithium hexamethyldisilazide; TES = triethylsilyl; TBDPS =
tert-butyldiphenylsilyl.
ACHTUNGRE(4+3) Cycloadditions of enantiomerically enriched 2
were executed under conditions similar to those previously
reported,[9] that is, by using a catalytic amount of triethylsil-
yl trifluoromethanesulfonate (TESOTf) at low tempera-
tures, and then treating the mixture with triethylamine tri-
hydrofluoride. The results are shown in Table 1. Overall,
relative to 1 (Figure 1),[9] epoxy enolsilanes 2 are more hin-
dered, and consequently their cycloadditions proceeded
with lower reaction rates than those with 1. Reactions of
2 a–e in the presence of an excess of cyclopentadiene yield-
ed endo and exo cycloadducts a-5 and b-5 (X = CH2), re-
spectively (Table 1, entries 1–5; Scheme 2). These cycload-
ducts were obtained out of a possible four diastereomeric
products, which demonstrates facial and diastereoselectivity
as obtained in previous examples of this (4 + 3) cycloaddi-
tion. The reaction of the very hindered enolsilane 2 e gave
a particularly diminished yield (Table 1, entry 5). Neverthe-
Asian J. Org. Chem. 2012, 1, 30 – 33
Table 1. ACHTUNGRE(4+3) Cycloadditions of 2 a–e with dienes. which are diastereomers of a-5 and b-5, were also generat-
ed from endo and exo cycloadditions that are not facially
selective, respectively.
In all cases, the ee values of the furan cycloadducts were
completely conserved from those of 2 a–d. The relative ste-
reochemistry of a-5 db, b-5 db, and b-6 db were confirmed
by X-ray crystallography.[13] Furthermore, as the stereo-
chemistry at the C4 position is unperturbed from epoxy
enolsilane to cycloadduct (Figure 1), the absolute configura-
Entry 2 (ee [%]) X Yield [%] a-5 (ee [%]), b-5 (ee [%]) tions of these cycloadducts have been deduced to be the
(dr a-5/b-5)[c] structures shown.
1 2 a (94) CH2 89 (1:1) a-5 aa (92), b-5 aa (93) The cycloaddition of enantiomerically pure 2 f, in which
2 2 b (97) CH2 68 (1.4:1) a-5 ba (97), b-5 ba (97)
R1, R2 ¼6 H, was also explored (Scheme 4). Cycloaddition
3 2 c (98) CH2 75 (1.4:1) a-5 ca (97), b-5 ca (97)
4[a] 2 d (97) CH2 84 (1.5:1) a-5 da (97), b-5 da (97) with cyclopentadiene proceeded by endo and exo modes in
5 2 e (96) CH2 41 (1.2:1) a-5 ea (96), b-5 ea (97)
6 2 a (93) O 43[b,c] (1.8:1) a-5 ab (94), b-5 ab (90)
7[a] 2 b (97) O 48[b,d] (1:1.2) a-5 bb (97), b-5 bb (97)
8[a] 2 c (98) O 36[b,c,d] (1:1.1) a-5 cb (97), b-5 cb (97)
9[a] 2 d (97) O 37[c,d,e] (1.1:1) a-5 db (97), b-5 db (97)
[a] Reaction in neat diene. [b] a/b-6 obtained in < 5 % yield. [c] 7 ob-
tained in 18–28 % yield. [d] 8 was obtained. [e] a/b-6 obtained in 11 %
yield.
Scheme 4. ACHTUNGRE(4+3) Cycloaddition of 2 f with cyclopentadiene (CpH).

78 % yield to generate two major diastereomers a-5 fa and

b-5 fa, each of which has five stereocentres, with complete
conservation of enantiomeric purity in 99 % ee.[14]
The (4 + 3) cycloaddition of enantiomerically enriched
epoxy enolsilanes was explored with other dienes. Scheme 5
shows the cycloaddition between 2 a and 3,4-dimethylfuran
to generate a-9 and b-9 in 97 % ee.
Scheme 2. Endo and exo (4 + 3) cycloadditions of 2 generate a/b-5.

less, complete conservation of the ee value from 2 a–e was

obtained for all cycloadducts.[12] These results show that the
configuration of the epoxide controls the stereochemical
outcome of the three newly established stereocentres in the
cycloaddition.
Epoxy enolsilanes 2 reacted even more sluggishly with
the less reactive furan as the diene, but acceptable yields of
cycloadducts were obtained when the cycloaddition was
conducted in neat furan (Table 1, entries 7–9). Side reac-
tions that produced bisfurans 7 and alkylated furans 8 from
arrested cycloaddition, as well as 4 from desilylation of 2,
also contributed to the lower yields of cycloadducts.
Whereas a-5 and b-5 (X = O) remained as the major
endo and exo products in the cycloadditions with furan,
minor cycloadducts a-6 and b-6 (X = O, R1 = H, Scheme 3),
Scheme 3. Other products from the (4 + 3) cycloaddition.
Scheme 5. ACHTUNGRE(4+3) Cycloaddition of 2 a with 3,4-dimethylfuran.
Whereas many cycloadditions were not endo or exo se-
lective, the use of sterically hindered substrates magnifies
the steric preferences of the reaction and results in im-
proved diastereoselectivity. Therefore, the cycloaddition of
sterically demanding spiroACHTUNGRE[2.4]hepta-4,6-diene proceeded
with 2 a exclusively in the endo mode, to generate a-10 as
the sole cycloadduct in 97 % ee (Scheme 6). Cycloadduct a-
10 could be reduced to afford optically-enriched gem-dime-
thylated ()-12.
The generation of both endo and exo cycloadducts in this
reaction can be advantageously exploited for synthesis. For
example, the diastereomers a-5 da and b-5 da were obtained
from the same epoxyketone ()-4 d, and were converted
and converged to enantiomeric ketones (+)-13 da and ()-
13 da, respectively, by dehydration and reduction in greater

Asian J. Org. Chem. 2012, 1, 30 – 33  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.AsianJOC.org 31

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Scheme 6. ACHTUNGRE(4+3) Cycloaddition of 2 a and reduction of a-10. a) MsCl,
Et3N, CH2Cl2 ; b) 1,8-diazabicycloACHTUNGRE[5.4.0]undec-7-ene, THF; c) H2, Pd/C,
EtOAc, RT.
Scheme 7. Conversion of ()-4 d to (+)-13 da and ()-13 da via a/b-5 da.
than 95 % overall yield (Scheme 7). Therefore, in general,
for all epoxy ketones 4 each enantiomer could be parlayed
into both antipodes of bicyclic ketones 13 or similar deriva-
tives via the separable, diastereomeric cycloadducts a-5 and
b-5. This protocol could find applications in asymmetric
synthesis and catalysis.
In conclusion, the (4 + 3) cycloadditions of enantiomeri-
cally enriched epoxy enolsilanes 2 with dienes proceeded
with near complete conservation of ee values to yield cyclo-
adducts 5, which have up to five stereocentres, in up to
99 % ee. This reaction provides access to versatile hydroxy-
lated carba- and oxabicycloACHTUNGRE[3.2.1]oct-6-en-3-ones in enan-
tiomerically pure forms, and we are further investigating
their applications in asymmetric epoxidation[15] and in syn-
thesis.
Experimental Section
Typical procedure for (4 + 3) cycloaddition
TESOTf (0.2 m in CH2Cl2, 0.280 mL, 0.06 mmol) was added to a solution
of 2 c (0.2721 g, 0.5636 mmol), and freshly cracked cyclopentadiene
(1.4 mL, 17 mmol) in CH2Cl2 (1.4 mL) at 78 8C. The reaction mixture
was stirred at 78 8C for 1 h. Triethylamine trihydrofluoride (0.50 mL,
3.1 mmol) was added and the mixture was stirred at room temperature
for 45 min. Aqueous NaHCO3 was added until the effervescence ceased.
The mixture was extracted with EtOAc (10 mL x 3), separated, and the
organic phase was dried over anhydrous MgSO4. The volatiles were re-
moved in vacuo. The residue was purified by chromatography on a silica
32 www.AsianJOC.org  2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Pauline Chiu et al.
gel column (1 % acetone in CH2Cl2) to afford cycloadducts a-5 ca and b-
5 ca (0.1832 g, 75 % yield, 1.4:1).
(1 R,2 R,5 R)-2-((R)-3-(Tert-butyldiphenylsiloxy)-1-
hydroxypropyl)bicycloACHTUNGRE[3.2.1]oct-6-en-3-one (a-5 ca)
Colourless oil; Rf = 0.46 (20 % EtOAc/hexane); [a]20 D = + 20.48 (c = 5.36
in CH2Cl2); 1H NMR (500 MHz, CDCl3): d = 7.71–7.69 (m, 4 H), 7.45–
7.37 (m, 6 H), 6.06 (dd, J = 5.8, 2.9 Hz, 1 H), 5.95 (dd, J = 5.8, 2.7 Hz,
1 H), 4.13 (br s, 1 H), 3.99 (dddd, J = 6.2, 6.2, 2.4, 2.4 Hz, 1 H), 3.94–3.86
(m, 2 H), 2.98 (ddd, J = 5.8, 2.9, 2.7 Hz, 1 H), 2.91–2.89 (m, 1 H), 2.52
(dd, J = 8.0, 3.2 Hz, 1 H), 2.45 (dd, J = 16.1, 3.3 Hz, 1 H), 2.34 (ddd, J =
16.4, 3.0, 2.7 Hz, 1 H), 2.16–2.11 (m, 1 H), 1.92–1.86 (m, 1 H), 1.82 (d, J =
11.2 Hz, 1 H), 1.69–1.63 (m, 1 H), 1.07 ppm (s, 9 H); 13C NMR (125 MHz,
CDCl3): d = 214.6, 136.7, 135.6, 135.5, 133.8, 133.7, 133.6, 129.6, 129.6,
127.6, 127.6, 68.6, 61.8, 60.8, 46.4, 43.3, 41.3, 39.1, 36.0, 26.9, 19.2 ppm;
IR (CH2Cl2): ñ = 3495 (OH), 3071, 2955, 2862, 1690 (C=O), 1427, 1196,
1111 cm1; LRMS (EI, 20 eV): m/z: 377 [M + -C4H9] (1), 359 (11), 329
(4), 299 (7), 281 (5), 255 (24), 225 (27), 199 (100), 183 (33), 177 (19), 117
(19), 77 (14); HRMS (EI, 20 eV): calcd for C23H25O3Si [M + -C4H9]:
377.1573; found: 377.1564. Enantiomeric excess was determined by
HPLC analysis (Daicel Chiralpak IC-3, 0.5 mL min1, l = 210 nm, 2 %
isopropanol in hexane); tR (major) = 34.26 min, tR (minor) = 32.31 min.
(1S,2 R,5S)-2-((R)-3-(Tert-butyldiphenylsiloxy) 1-
hydroxypropyl)bicycloACHTUNGRE[3.2.1]oct-6-en-3-one (b-5 ca)
Colourless oil; Rf = 0.37 (20 % EtOAc/hexane); [a]20 D = + 47.78 (c = 2.71
in CH2Cl2); 1H NMR (500 MHz, CDCl3): d = 7.69–7.67 (m, 4 H), 7.46–
7.38 (m, 6 H), 6.11 (dd, J = 5.6, 2.8 Hz, 1 H), 6.01 (dd, J = 5.7, 3.0 Hz,
1 H), 4.16 (dddd, J = 6.2, 6.2, 3.2, 2.7 Hz, 1 H), 3.94–3.84 (m, 2 H), 3.28
(d, J = 2.6 Hz, 1 H), 2.88–2.85 (m, 1 H), 2.81 (ddd, J = 5.3, 2.3, 2.2 Hz,
1 H), 2.54 (dd, J = 17.0, 3.8 Hz, 1 H), 2.36 (ddd, J = 17.0, 4.0, 2.4 Hz, 1 H),
2.25 (d, J = 6.2 Hz, 1 H), 2.22 (d, J = 11.0 Hz, 1 H), 1.90–1.86 (m, 1 H),
1.84–1.80 (m, 2 H), 1.06 ppm (s, 9 H); 13C NMR (125 MHz, CDCl3): d =
212.6, 137.4, 135.9, 135.5, 135.5, 133.2, 133.0, 129.8, 129.8, 127.8, 127.8,
71.9, 62.4, 60.1, 46.2, 41.8, 38.4, 37.5, 36.8, 26.8, 19.0 ppm; IR (CH2Cl2):
ñ = 3495 (OH), 3055, 2955, 2862, 1697 (C=O), 1643, 1466, 1427, 1350,
1265, 1196, 1111, 1003 cm1; LRMS (EI, 20 eV): m/z: 377 [M + -C4H9]
(1), 359 (3), 299 (5), 255 (32), 225 (36), 199 (100), 183 (48), 177 (28), 117
(27), 77 (21); HRMS (EI, 20 eV): calcd for C23H25O3Si [M + -C4H9]:
377.1573; found: 377.1569. Enantiomeric excess was determined by
HPLC analysis (Daicel Chiralpak IC-3, 0.5 mL min1, l = 210 nm, 2 %
IPA in hexane); tR (major) = 46.98 min, tR (minor) = 57.36 min.
Acknowledgements
We thank the University of Hong Kong, the Research Grants Council of
Hong Kong SAR, P. R. China (GRF 7015/10P), and UGC Special
Equipment Grant (Grant no: SEG_HKU02) for research support and
conference travel funding.
Keywords: asymmetric synthesis · bicyclic compounds ·
cycloaddition · cycloheptanoids · enantioselectivity
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[14] In this reaction, minor diastereomers ( 10 % yield) a-6 fa and b-
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Received: May 25, 2012
Published online: July 2, 2012
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