An unusual approach to the synthesis of enantiomerically cis linear homoallylic alcohols based on the steric interaction mechanism of camphor scaffold

Article abstract of DOI:10.1021/ol049633z

Camphor is used as the chiral auxiliary for the enantioselective synthesis of cis linear homoallylic alcohols. A range of catalysts, aldehydes, and solvents were investigated to obtain the optimum yield, enantioselectivity, and cis olefinic geometry.

Full text of DOI:10.1021/ol049633z

ORGANIC
LETTERS
2004
Vol. 6, No. 8
1281-1283
An Unusual Approach to the Synthesis
of Enantiomerically Cis Linear
Homoallylic Alcohols Based on the
Steric Interaction Mechanism of
Camphor Scaffold
Chi-Lik Ken Lee, Cheng-Hsia Angeline Lee, Kui-Thong Tan, and Teck-Peng Loh*
Department of Chemistry, National UniVersity of Singapore, 3 Science DriVe 3,
Singapore 117543
chmlohtp@nus.edu.sg
Received February 29, 2004
ABSTRACT
Camphor is used as the chiral auxiliary for the enantioselective synthesis of cis linear homoallylic alcohols. A range of catalysts, aldehydes,
and solvents were investigated to obtain the optimum yield, enantioselectivity, and cis olefinic geometry.
Over the last few decades, homoallylic alcohols have become
indispensable moieties for the construction of complex
organic molecules, securing their widespread involvement
in the synthesis of both natural products and medicinal
agents.1 Even though extensive efforts have been devoted
to the exploration of chiral reagents and catalysts for the
carbonyl-allylation and carbonyl-ene reactions to produce
homoallylic alcohols, almost all current methods produce
branched homoallylic alcohols 1 exclusively,2 except a few
special cases, hence limiting access to the linear homoallylic
alcohols E-2 and Z-23 (Figure 1).
While the enantioselective crotyl transfer reactions devel-
oped by Nokami3a,4 and our group5 have been shown to be
useful for the synthesis of trans linear homoallylic alcohols
E-2, there are no reported examples for a one-pot synthesis
(1) (a) Nicolaou, K. C.; Kim, D. W.; Baati. R. Angew. Chem., Int. Ed.
2002, 41, 3701. (b) Hornberger, K. R.; Hamblet, C. L.; Leighton, J. L. J.
Am. Chem. Soc. 2000, 122, 12894. (c) Felpin, F. X.; Lebreton. J. J. Org.
Chem. 2002, 67, 9192.
(2) For reviews, see: (a) Yamamoto, Y.; Asao, N. Chem. ReV. 1993,
93, 2207. (b) Helmchen, G., Hoffmann, R., Mulzer, J., Schaumann, E., Eds.
In StereoselectiVe Synthesis, Methods of Organic Chemistry (Houben-Weyl),
21st ed.; Thieme Stuttgart: New York, 1996; Vol. 3, pp 1357-1602. (c)
Denmark, S. E.; Fu, J. P. Chem. ReV. 2003, 103, 2763.
(3) For some examples, see: (a) Nokami, J.; Yoshizane, K.; Matsuura,
H.; Sumida, S. J. Am. Chem. Soc. 1998, 120, 6609. (b) Tan, K. T.; Cheng,
H. S.; Chng, S. S.; Loh, T. P. J. Am. Chem. Soc. 2003, 125, 2958. (c) Loh,
T. P.; Lee, C. L. K.; Tan, K. T. Org. Lett. 2002. 17, 2985. (d) Cheng, H.
S.; Loh, T. P. J. Am. Chem. Soc. 2003, 125, 4990. (e) Hirashita, T.;
Yamamura, H.; Kawai, M.; Araki, A. Chem. Commun. 2001, 387. (f)
Okuma, K.; Tanaka, Y.; Ohta, H.; Matsuyama, H. Heterocycles, 1993, 1,
37.
(4) Nokami, J.; Nomiyana, K.; Matsuda, S.; Imai, N.; Kataoka, K. Angew.
Chem., Int. Ed. 2003, 42, 1273.
(5) Loh, T. P.; Hu, Q. Y.; Chok, Y. K.; Tan, K. T. Tetrahedron Lett.
2001, 42, 9277.
Figure 1. Various regioisomers of homoallylic alcohols.
10.1021/ol049633z CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/19/2004

tion level (6.0 M solution), with 3 equiv of the branched
homoallylic alcohol 1a being added slowly to a stirred
solution of 1 equiv of 3-phenylpropanal and 0.1 equiv of
CSA for 120 h (Table 1, entry 8). This superior catalytic
efficiency exhibited by CSA prompted us to select this
Bro¨nsted acid for further explorations.
Scheme 1. Crotyl Transfer Reactions Furnishing Trans Linear
Homoallylic Alcohol
With these optimized conditions, we carried out crotyl
transfer reactions on various aldehydes. While the slightly
bulkier substrate3c (Table 2, entry 4) gave a moderate yield,
the linear ones offered excellent yields (Table 2, entries 2
and 3). Reactions of the dioxygenated substrates (Table 2,
entries 5-7) afforded the desired products with ee up to 99%
displaying the cis olefinic geometries almost predominantly.
This reaction can also be tolerated on other functional
groups. Using cis-hept-4-enal afforded fine yields with
comparable ee and cis olefinic geometry (>99% ee, 84% Z)
(Table 2, entry 8), while the R,â-unsaturated ethyl ester-
of enantiomerically cis linear homoallylic alcohols Z-2
(Scheme 1).
We recognized that if another chiral auxiliary6 can be
judiciously chosen to effectively present a steric environment,
in which the formation of the branched homoallylic alcohols
precursor is highly diastereometrically selective, stereo-
selective access to the linear homoallylic alcohols would be
achieved. It is hence predictable that this crotyl transfer
reaction can provide a valuable platform for the development
of a new highly stereoselective homoallylic alcohol protocol.
This plan was probed by allowing the diastereomic mixture
(syn/anti ) 70/30) of camphor7 branched homoallylic
alcohol, prepared from the addition of crotylmagnesium
bromide to (1R)-(+)-camphor,8 to react with 3-phenyl-
propanal under the catalysis of a series of Bro¨nsted and Lewis
acids. In accordance with the recent surge in interest in metal
triflates, indium(III) triflate has emerged as a promising
choice particularly in our research group.9 However, no
desired product was obtained for this crotyl transfer reaction
when In(OTf)3 was employed as the acid catalyst (Table 1,
entry 1).
Table 2. Catalyzed Allyl Transfer Reaction from 1a to Various
Aldehydes 3a,b
time yieldc
entry
3
(h)
(%)
% ee (% Z)
1
2
3
4
5
6
7
8
9
PhCH2CH2CHO
n-C5H11CHO
n-C8H17CHO
120 88
144 68
144 95
144 40
120 74
96 94
96 80
96 83
240 66
240 trace
240 trace
94 (99)d,g,h
97 (>99)f
90 (94)f
Optimal results were obtained when the reaction was
carried out at ambient temperature and at a higher concentra-
c-C6H11CHO
92 (96)e
BnO(CH2)2CHO
BnO(CH2)3CHO
BnO(CH2)4CHO
CH3CH2CHdCH(CH2)2CHO
EtO2CCHdCH(CH2)3CHO
PhCHO
97 (>99)d
99 (>99)d
98 (98)d
>99 (84)f
98 (99)f
Table 1. Allyl Transfera from 1ab to 3-Phenylpropanal with
Various Acids
10
11
2-NO2PhCHO
a Reactions were performed with branched homoallylic alcohol 1a (0.913
mmol), 2 (0.304 mmol), and CSA (0.03 mmol) in CH2Cl2 (0.1 mL), unless
otherwise stated. b Branched homoallylic alcohol used has a syn/anti ratio
of 70/30. c Combined yield based on 2. d Determined by chiral HPLC.
e Determined by HPLC of the 2,4-dinitrobenzoyl derivative. f Determined
by HPLC of the Mosher derivative. g Absolute stereochemistry was
determined by comparison with literature values. h Reactions of the (1S)-
(-)-camphor branched homoallylic alcohol with 2 furnished the other
enantiomer (60% yield; 93% ee; 99% Z).
entry
acid
T (°C)
time (h)
yield (%)
% ee (Z:E)
1c
2
3
4
5
6
7
8d
In(OTf)3
pTSA
TFA
CSA
CSA
CSA
Br-CSA
CSA
25
25
25
25
0
-78
25
25
18
18
18
18
18
10
120
120
<7
<7
25
20
15
77
88
96 (95:5)
94 (94:6)
93 (94:6)
93 (97:3)
93 (97:3)
95 (99:1)
94 (99:1)
type aldehyde needed a longer time to be depleted before
moderate yields were achieved with admirable ee and cis
olefinic geometry (>99% ee, 97% Z) (Table 2, entry 9). On
a Reactions were performed with branched homoallylic alcohol 1a (0.5
mmol), aldehyde (0.75 mmol), and acid (0.05 mmol) in CH2Cl2 (2 mL),
unless otherwise stated. b Branched homoallylic alcohol is synthesized by
Grignard reaction with a yield of 87% (syn:anti ) 70:30). c Desired product
not formed. d Reactions were performed with branched homoallylic alcohol
1a (0.913 mmol), aldehyde (0.304 mmol), and acid (0.03 mmol) in CH2Cl2
(0.1 mL).
(6) For an extensive list of chiral auxiliaries, see: (a) Rahmen, A. U.;
Shah, A. StereoselectiVe Synthesis in Organic Cheimstry; Springer: Berlin,
1993. (b) Seyden-Penne, I. Chiral Auxiliaries and Ligands in Asymmetric
Synthesis; Wiley: New York, 1995. (c) Ager, D. J.; Prakash, J.; Schaad,
D. R. Chem. ReV. 1996, 96, 835.
(7) For a review on camphor-based chiral auxiliaries, see: Oppolzer,
W. Tetrahedron 1987, 43, 1969.
(8) Dimitrov, V.; Simova, S.; Kostova, K. Tetrahedron 1996, 52, 1699.
1282
Org. Lett., Vol. 6, No. 8, 2004

the basis of the sluggish reactivity of aromatic aldehydes
(Table 2, entries 10 and 11), a chemoselective study revealed
that the transfer selectively will go to the aliphatic substrate
even in the presence of a more reactive aldehyde (Scheme
2).
Scheme 3. Proposed Transition State of Crotyl Transfer Using
the Camphor Scaffold
Scheme 2. Chemoselective Study
Of mechanistic interest is the recovery of the excess chiral
camphor homoallylic alcohol 1a, which is enriched with the
anti isomer (syn/anti ) 40/60) from a diastereomeric ratio
of syn/anti ) 70/30. From the molecular model for the
transition state of the corresponding camphor branched
homoallylic alcohol depicted in Scheme 3, we realized that
only one isomer, the syn branched homoallylic alcohol, was
allowed to transfer using this camphor auxiliary.10
The branched homoallylic alcohol 1a probably formed
oxonium-type ions with the aldehyde catalyzed by an acid
catalyst, revealing two possible transition states. The anti
branched homoallylic alcohol would most likely adopt a
transition state similar to that of A. On the basis of a six-
membered transition state,11 it is evident that this anti isomer
of the branched homoallylic alcohols will have a severe steric
repulsion with the C-6 of the camphor scaffold, which
explained why the trans linear isomer 2c was not observed
at all. On the contrary, the transition state C shows that the
syn isomer’s methyl groups are fixed in a manner that avoids
any close contacts with the camphor’s methylene protons
before undergoing the rearrangement to furnish the thermo-
dynamically preferred linear regioisomer 2d.
With that, a conceptually different strategy to access to
cis linear homoallylic alcohols, with moderate to high yields,
has been demonstrated. To the best of our knowledge, this
is the first efficient method that controls, in situ, both the
enantioselectivity (up to 99% ee) and the olefinic geometry
(up to 99% Z) of cis linear homoallylic alcohols. Our
investigations have also shown that this chemoselective crotyl
transfer is highly feasible for aliphatic substrates. Moreover,
excess chiral camphor-derived branched homoallylic alcohol
(89%) and the camphor (83%) generated from the reaction
can be recovered and reused, thus, making this method
attractive for scale-up preparation of cis linear homoallylic
alcohols with high enantioselectivities. We anticipate that
this new Bro¨nsted acid-catalyzed allyl transfer reaction will
be an indispensable tool in the synthesis of complex natural
products, thereby allowing this methodology to undergo an
exciting renaissance as a synthetic method.
Acknowledgment. We thank the National University of
Singapore and Biomedical Research Council (BMRC) for
generous financial support. Chi-Lik Ken Lee is grateful to
Agency for Science Technology and Research (ASTAR) for
a doctorate scholarship.
(9) (a) Loh, T. P.; Hu, Q. Y.; Ma, L. T. J. Am Chem. Soc. 2001, 123,
2450. (b) Loh, T. P.; Hu, Q. Y.; Tan, K. T.; Cheng, H. S. Org. Lett. 2001,
3, 2669. (c) Loh, T. P.; Tan, K. T.; Hu, Q. Y. Angew. Chem., Int. Ed.
2001, 40, 2921.
(10) Another reaction, performed with only the pure syn branched
homoallylic alcohol 1a (0.36 mmol; 1.2 equiv), 3-phenylpropanal (0.3 mmol;
1 equiv), and CSA (0.03 mmol; 0.1 equiv) in CH2Cl2 (0.1 mL.; 3.0 M),
furnished the desired linear homoallylic alcohol (81% yield, 98% ee, and
99% Z).
(11) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79,
1920.
Supporting Information Available: Experimental details
and characterization data for the products. This material is
available free of charge via the Internet at http://pubs.acs.org.
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