Homoallylic sterol/indium(III) Lewis acid: A novel enantioselective allylation system exhibiting α-regioselectivity

Article abstract of DOI:10.1016/S0040-4039(01)02011-1

A homoallylic sterol/indium(III) Lewis acid reagent system was utilized for the enantioselective and α-regioselective allylation of various aldehydes.

Full text of DOI:10.1016/S0040-4039(01)02011-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 9277–9280
Homoallylic sterol/indium(III) Lewis acid: a novel
enantioselective allylation system exhibiting a-regioselectivity†
Teck-Peng Loh,* Qi-Ying Hu, Yew-Keong Chok and Kui-Thong Tan
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543
Received 3 September 2001; revised 5 October 2001; accepted 19 October 2001
Abstract—A homoallylic sterol/indium(III) Lewis acid reagent system was utilized for the enantioselective and a-regioselective
allylation of various aldehydes. © 2001 Elsevier Science Ltd. All rights reserved.
The development of new highly enantioselective CꢀC
bond formation methods is an enduring task for
organic chemists.2 In this respect, extensive efforts have
been devoted to the exploration of chiral reagents and
catalysts for the carbonyl–allylation and carbonyl–ene
reactions, since the resulting homoallylic alcohols are
versatile building blocks for the synthesis of many
natural products and pharmaceuticals.3 Although
prominent progress in this area has been achieved
during the last two decades, the situation that almost
all existing allylation methods exhibit g-regioselectivity,
except in a few special cases,4 limits access to optically
active a-adduct homoallylic alcohols. This greatly
decreases the efficiency of many synthetic routes. For
instance, preparation of the C15ꢀC22 homoallylic alco-
hol fragment in Williams and Meyer’s synthesis of
(+)-amphidinolide K (1, Fig. 1) involved tedious multi-
step transformations.5 Recently, the emergence of
nucleophile-transfer reactions6 offers opportunities for
the development of new enantioselective CꢀC bond
formation methods. Herein we report a novel chiral
allylation system, homoallylic sterol (2)/indium(III)
Lewis acid, for enantioselective allyl-transfer to various
aldehydes exhibiting exclusive a-regioselectivity.
H
H
O
Recently, our efforts in the exploration of indium(III)
Lewis acids7 led to the discovery of an a-regioselective
allyl-transfer reaction catalyzed by indium(III) Lewis
acid in this laboratory.6e,8 It is interesting to note that
transfer of the allyl fragment and chirality from g-
adduct homoallylic sterol (2)9 to its parent aldehyde
afforded the corresponding a-adduct with inversion of
stereochemistry (Scheme 1). This was accounted for by
H
O
15
18
OH
O
22
O
Figure 1. (+)-Amphidinolide K (1).
O
Std
H
OH
OH
3
Std =
R
β
In(OTf)3 (10 mol%)
CH2Cl2
α
Std
R = Me 2a
R = Ph
R
Std
O
4
2b
Scheme 1. Indium(III) Lewis acid-catalyzed allyl-transfer reaction.
* Corresponding author. Tel.: 65-874-7851; fax: 65-779-1691; e-mail: chmlohtp@nus.edu.sg
† See Ref. 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02011-1

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T.-P. Loh et al. / Tetrahedron Letters 42 (2001) 9277–9280
invoking a 2-oxonia[3,3]-sigmatropic rearrangement
mechanism proposed by Samoshin6f and Nokami6d
(Scheme 2). Thus, the utilization of g-adduct homoal-
lylic sterol as an allylation reagent for the transfer of its
allyl fragment to other aldehydes appears to be a
promising method for an enantioselective a-regioselec-
tive allylation.
respectively) afforded the a-adducts 6c and 6d in much
higher yields than in the case of the analogous crotyl-
transfer. This could be because the release of steric
strain is greater in the case of 2b than in 2a. Also, the
conjugated internal cinnamyl motif in the resulting
a-adducts is thermodynamically more stable than the
isolated terminal double bond in 2b, providing for
greater driving force toward the direction of the desired
a-adducts 6.
In our initial studies, a solution of 2a10 (0.4 mmol, 1
equiv.) and 3-phenylpropanal (0.48 mmol, 1.2 equiv.) in
dichloromethane was stirred at room temperature, in
the presence of a catalytic amount of In(OTf)3 (10
mol%), overnight. The desired a-homoallylic alcohol 6a
was isolated in 54% yield, and in at least 98% ee as
determined by chiral stationary phase HPLC employing
a Daicel Chiralcel OD column (entry 1). The double
bond was also found to be exclusively of the E geome-
try. Nonetheless, a small amount of the self-transfer
side-product 4a was observed and thus, subsequent
reactions were conducted at −30°C instead. The allyl-
transfer from 2a to benzaldehyde (entry 2) gave a
slightly lower yield of the a-adduct 6b, though with
identical excellent enantio- and E/Z selectivity. In addi-
tion, no self-transfer was observed in this case (Table
1).
With the success in crotylation and cinnamylation, we
explored the allyl-transfer from sterol 2c to hydrocin-
namaldehyde. It is interesting to note however that the
reaction exhibited significantly lower enantioselectivity.
In addition, prolonged reaction times led to lower
enantioselectivities as well (62% ee at 2 h, 56% ee at 4
h, 50% ee at 8 h and 46% ee at 20 h).11 This observation
can be explained by the involvement of a second com-
peting [3,3]-sigmatropic rearrangement leading to allyl-
transfer from 6e to hydrocinnamaldehyde (Scheme 3).12
Ph(CH2)2CHO,
OH
OH
OH
In(OTf)3
+
Ph
Ph
Std
2c
6e
6e'
Ph(CH2)2CHO
Allyl-transfer
Upon changing to the cinnamyl bromide derivative 2b
as the chiral allyl donor, similar stereoselectivities were
obtained. Again, no self-transfer product 4b was
obtained in both instances. More importantly, both
3-phenyl-propanal and benzaldehyde (entries 3 and 4,
Scheme 3.
RCHO
OH
R
– "OH–"
E
+ "OH–"
R
O
R'
R'
R
R
Sn(OTf)2 or
In(OTf)3
OH
R'
anti
H
Scheme 2. Reaction pathway of the allyl-transfer reaction.
Table 1. Allyl-transfer from g-adduct 22b-sterol 2 to various aldehydes 5a
O
R"
H
OH
OH
*
5 (0.48 mmol)
Std =
β
R
R"
In(OTf)3 (10 mol%)
CH2Cl2 (2 mL)
Std
R
6
O
R = Me 2a (0.4 mmol)
R = Ph
2b (0.4 mmol)
Entry
g-Adduct
5 R%%
T (°C)
a-Adduct 6
Yieldb (%)
R:Sc (E/Z)d
1
2
3
4
2a
2a
2b
2b
PhCH2CH2
Ph
PhCH2CH2
Ph
25
−30
−30
−30
6a, 54e
6b, 49
6c, 72
6d, 73
1:99 (E)
99:1 (E)
1:99 (E)
99:1 (E)
a Reactions were performed with 2 (0.4 mmol, 1 equiv.), 5 (0.48 mmol, 1.2 equiv.) and In(OTf)3 (10 mol%) in CH2Cl2 (2 mL).
b Isolated yield with respect to the limiting reagent, g-adduct 2.
c Determined by HPLC analysis employing a Daicel Chiralcel OD column.
d Determined from 1H NMR (300 MHz).
e A small amount of self-transfer a-adduct 4a was observed.

T.-P. Loh et al. / Tetrahedron Letters 42 (2001) 9277–9280
9279
lide K, where the desired enantioselectivity, regioselec-
tivity and geometry of the double bond were obtained
in a single step as predicted, in moderate yield. Last but
not least, the improvement of this reagent with respect
to recycling of the chiral source was explored and InBr3
has shown promising results in the preliminary trials.
Further studies along this line are in progress.
This observation suggests that a Lewis acid-catalyzed
allyl-transfer pathway might be an important side reac-
tion in many enantioselective allylation reactions, which
will substantially undermine the enantioselectivity.
Application of this new method to organic synthesis
proved successful in the asymmetric allylation of alde-
hyde 9 derived from butane-1,4-diol (7), to give the
secondary carbinol 10 in 98% ee and 65% yield (Scheme
4). Subsequent manipulations could lead to 11, an
intermediate employed in a recent total synthesis of the
antitumor macrolide, (+)-amphidinolide K (1), in which
the original route necessitated six steps in 56% yield,
commencing from a known chiral homoallylic alcohol.
Acknowledgements
We gratefully acknowledge the National University of
Singapore for generous financial support.
In addition, attempts were made to recover the regener-
ated steroidal aldehyde. Unfortunately, all efforts
proved futile with the recovery of a mixture of both
C20-epimers, which could be traced to the rather strong
Lewis acidity of In(OTf)3. To overcome this problem, a
weaker indium(III) Lewis acid, InBr3, was employed in
this reaction instead of In(OTf)3. In our studies, a
solution of 2a, benzaldehyde (0.6 mmol, 1.5 equiv.) and
References
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3. For reviews, see: (a) Yamamoto, Y.; Asao, N. Chem.
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C. H., Eds.; Pergamon: Oxford, 1991; Vol. 2, p. 1; (c)
Mikami, K.; Shimizu, M. Chem. Rev. 1992, 92, 1021. For
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Yanagisawa, A.; Habaue, S.; Yamamoto, H. J. Am.
Chem. Soc. 1991, 113, 8955 and references cited therein;
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a
catalytic amount of InBr3 (0.1 equiv.) in
dichloromethane was stirred for 16 h at −30°C. Upon
purification by means of column chromatography, the
desired a-homoallylic alcohol was isolated in 60% yield
and 82% ee, together with the regenerated steroidal
aldehyde without epimerization in 69% yield and 7% of
recovered sterol.
In conclusion, the method was applied to the allylation
of various aldehydes, and afforded a-adduct homoal-
lylic alcohols in excellent enantioselectivity (98% ee). It
was also found in the case of allyl bromide derived
sterol 2c, that absence of the allylic substituent under-
mines the inherent enantiospecificity of the allyl-trans-
fer, which degrades with prolonged reaction times. This
suggested that such Lewis acid-catalyzed allyl-transfers
could be important side reactions in many enantioselec-
tive allylations, which will substantially erode the enan-
tioselectivity. Studies on some known systems to verify
this postulate are currently being carried out in this
laboratory. In addition, the efficiency of the chiral
allylation reagent 2b has been demonstrated in the
assembly of the C15–C22 fragment of (+)-amphidino-
5. William, D. R.; Meyer, K. G. J. Am. Chem. Soc. 2001,
123, 765.
TBDPSCl, Et3N
OH
OTBDPS
HO
HO
6. Alkynyl-tranfer reactions: (a) Ooi, T.; Miura, T.;
Maruoka, K. J. Am. Chem. Soc. 1998, 120, 10790; (b)
Ooi, T.; Takahashi, M.; Maruoka, K. Angew. Chem., Int.
Ed. Engl. 1998, 37, 835. Allyl-transfer reactions: (c)
Nokami, J.; Yoshizane, K.; Matsuura, H.; Sumida, S. I.
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Ohga, M.; Mitani, J.; Nokami, J. J. Am. Chem. Soc.
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3422. Cyano-transfer reaction: (h) Mori, A.; Kinoshita,
K.; Osaka, M.; Inoue, S. Chem. Lett. 1990, 7, 1171.
DMAP, CH2Cl2
7
8
95%
2a, In(OTf)3
(COCl)2, DMSO
O
OTBDPS
HO
CH2Cl2, –30 ºC
H
Et3N, CH2Cl2, –78 ºC
65%
9
80%
OH
OTBDMS
E
E
TBDPSO
S
S
10
98% ee
11
(+)-amphidinolide K (1)
Scheme 4. Application to the synthesis of intermediate 10.

9280
T.-P. Loh et al. / Tetrahedron Letters 42 (2001) 9277–9280
point to account for the low initial ee observed in this
7. (a) Li, X.-R.; Loh, T.-P. Tetrahedron: Asymmetry 1996, 7,
case. Due to the absence of the allylic substituent in 2c,
the transition state for the allyl transfer (vide infra) no
longer suffers from as much 1,3-allylic strain if it now
adopts the alternative chair-like transition state, leading
to the formation of product 6e%.
1535; (b) Loh, T.-P.; Chua, G.-L.; Vittal, J. J.; Wong,
M.-W. Chem. Commun. 1998, 861.
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10. Prepared according to the typical procedure for indium-
mediated allylation in DMF (Ref. 9), by reaction of
crotyl bromide with 3, in 56% yield (22b:22a=99:1) and
anti:syn (C22:C23) selectivity of 78:22.
11. During the course of this manuscript preparation, a
similar observation was described in: Nokami, J.; Ohga,
M.; Nakamoto, H.; Matsubara, T.; Hussain, I.; Kataoka,
K. J. Am. Chem. Soc. 2001, 123, 9168.
Std
OH
O
R
RCHO,
R
R
OH
6e
H
In(OTf)3
– "OH–"
Std
Std
OH
H
2c
O
R
6e'
12. The referee suggested an equally viable alternative view-