C O MMU N I C A T I O N S
Table 2. Asymmetric R-Prenylation of Various Aldehydes
Scheme 2. Stereoselectivity Studya
a
The condition CH2Cl2/ In(OTf)3 was chosen other than hexane/ TfOH
for the concern of the solubility of steroidal aldehyde.
racemization can be overcome by carrying out the reaction in
hexane. Studies using chiral aldehyde have shown that the stere-
ochemistry of the product was solely dependent on the stereochem-
istry of the prenyl source. Further application of this chemistry for
natural product synthesis is in progress.
Acknowledgment. We are grateful to NUS and ICES for their
generous financial support.
a
Isolated yield. b The absolute configuration was assigned as R by
Supporting Information Available: Spectroscopic and analytical
data for all compounds and the representative procedure (PDF). This
material is available free of charge via the Internet at http:// pubs.acs.org.
comparing the optical rotation with that of the known product.8
Scheme 1. Monitoring Enantiomeric Excess of 3h with HPLC
References
(
1) (a) Thomasar, A. F.; Bessiere, Y. In The Total Synthesis of Natural
Products; ApSimon, J. W., Ed.; Wiley: New York, 1988; Vol. 7, pp 275-
4
54. (b) For reviews, see: (b) Papageorgiou, V. P.; Assimopoulou, A.
N.; Couladouros, E. A.; Hepworth, D. H.; Nicolaou, K. C. Angew. Chem.,
Int. Ed. Engl. 1999, 38, 270.
(
2) (a) Yamamoto, H.; Yanagisawa, A.; Habaue, S.; Yasue, K. J. Am. Chem.
Soc. 1994, 116, 6130-6141. (b) Yanagisawa, A.; Yamada, Y.; Yamamoto,
H. Synlett 1997, 1090-1092. (c) Hong, B. C.; Hong, J. H.; Tsai, Y. C.
Angew. Chem., Int. Ed. 1998, 37, 468-470. (d) Depew, K. M.;
Danishefsky, S. J.; Rosen, N.; Sepp-Lorenzino, L. J. Am. Chem. Soc. 1996,
alcohols were obtained in moderate to high yields. It is also worth
noting that this reaction is highly chemoselective, reacting selec-
9
tively with the aldehyde without affecting the enone and the R,â-
118, 12463-12464.
unsaturated ester functionalities.
Surprisingly, when the reaction was performed in dichlo-
romethane in the presence of In(OTf) , the aromatic aldehydes
3
(
3) For reviews, see: (a) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93,
2207-2293. (b) Roush, W. R. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 2, pp 1-53.
(4) a) Loh, T. P.; Hu. Q. Y.; Tan, K. T.; Cheng, H. S. Org. Lett. 2001, 3,
afforded a much lower enantiomeric excess (entries 1-2), in sharp
contrast to the aliphatic counterparts (entries 3-4). On the other
hand, the enantioselectivities were surprisingly high for both
aromatic and aliphatic aldehydes in reactions using TfOH in hexane
2
669-2672. (b) Loh, T. P.; Hu. Q. Y.; Ma. L. T. J. Am. Chem. Soc.
2
001, 123, 2450-2451. For review, see: (c) Mikami, K.; Shimizu, M.
Chem. Rev. 1992, 92, 1021.
(
5) For review, see: (a) Overman, L. E. Acc. Chem. Res. 1992, 25, 352. For
examples, see: (b) Nokami, J.; Yoshizane, K.; Matsuura, H.; Sumida, S.
J. Am. Chem. Soc. 1998, 120, 6609-6610. (c) Sumida, S.; Ohga, M.;
Mitani, J.; Nokami, J.; J. Am. Chem. Soc. 2000, 122, 1310-1313. (d)
Nokami, J.; Anthony, L.; Sumida, S.; ChemsEur. J. 2000, 16, 2909-
(entries 5-12).
To investigate this discrepancy, optically active aromatic 3h was
injected into two parallel reactions using In(OTf) in hexane and
3
2
913. (e) Loh, T. P.; Tan, K. T.; Hu, Q. Y. Angew. Chem., Int. Ed. 2001,
4
0, 2921. (f) Loh, T. P.; Tan, K. T.; Yang, J. Y.; Xiang, C. L. Tetrahedron
dichloromethane respectively, and the optical purity was monitored
with HPLC over time (Scheme 1). It was found that the optical
purity decreased much more dramatically in dichloromethane than
in hexane.1
Lett. 2001, 42, 8701.
(6) The γ-prenyl can be easily obtained in 75% yield from a one-pot synthesis
by generating lactol in situ from DHP in acidic aqueous media, followed
by zinc-mediated prenylation of the corresponding lactol.
(7) It was done by chiral resolution with (S)-O-acetylmandelic acid. Whitesell,
J. K.; Reynolds, D. J. Org. Chem. 1983, 48, 3548. Enantiomeric excess
0,11
To study the diastereoselectivity of the substrate, both enanti-
omers of 2 were used in the prenylation of steroidal aldehyde, 1i
for both R-2 and S-2 was 99%. (R)-Mosser acid di-protection of R-2 and
S-2 give 19F NMR at 4.73, 3.89 and 4.84, 3.89, respectively.
(
Scheme 2). We found that the absolute stereochemistry depends
(8) [R]
D
) +53.3 (c )0.15 in C
6 6 D
H ); literature value: R isomer, [R] ) +50.2
(
c )1.16 in C H
6 6
). Ishihara, K.; Mouri, M.; Gao, Q.; Muruyama, T.;
solely upon the stereochemistry of 2 (entries 1 and 2), and that the
anti-Cram product was the major product when racemic 2 was
employed (entry 3). The reasons for these observations are currently
being investigated.
Furuta, K.; Yamamoto, H. J. Am. Chem. Soc. 1993, 115, 11490-11495.
(9) Refer to Scheme 2 for the steroidal enone moiety.
(
10) To validate this observation, naphthalene-2-carbaldehyde, 1h, was reacted
with In(OTf)
yield, 93% enantiomeric excess.
3
in hexane. Indeed, the product, 3h, was obtained in 61%
In summary, the study of the mechanism of the intramolecular
oxonium-ene cyclization has led to the establishment of a general
R-regioselective and highly enantioselective prenylation of alde-
hydes. Further studies disclosed the facile racemization of aromatic
(11) For racemization under other conditions, see: (a) Crosby, S. R.; Harding,
J. R.; King, C. D.; Parker, G. D.; Willis, C. L. Org. Lett. 2001, 4, 3407-
3
410. (b) Rychnovsky, S. D.; Marumoto, S.; Jaber, J. J. Org. Lett. 2001,
3, 3815-3818. (c) Marumoto, S.; Jaber, J. J.; Vitale, J. P.; Rychnovsky,
S. D. Org. Lett. 2002, 4, 3919-3922.
alcohols in dichloromethane in the presence of In(OTf)
3
. This
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