Catalytic asymmetric access to α,β unsaturated δ-lactones through a vinylogous aldol reaction: Application to the total synthesis of the Prelog-Djerassi lactone

Article abstract of DOI:10.1021/ol0168317

Figure presented A one-step catalytic asymmetric access to α,β unsaturated δ-lactones is described, using a vinylogous Mukaiyama-aldol reaction between a γ-substituted dienolate and various aldehydes in the presence of Carreira catalyst CuF·(S)-tolBinap.

Full text of DOI:10.1021/ol0168317

ORGANIC
LETTERS
2001
Vol. 3, No. 23
3807-3810
Catalytic Asymmetric Access to r,â
Unsaturated δ-Lactones through a
Vinylogous Aldol Reaction: Application
to the Total Synthesis of the
Prelog-Djerassi Lactone
Guillaume Bluet, Bele´n Baza´n-Tejeda, and Jean-Marc Campagne*
Institut de Chimie des Substances Naturelles 91198 Gif sur YVette, France
jean-marc.campagne@icsn.cnrs-gif.fr
Received September 28, 2001
ABSTRACT
A one-step catalytic asymmetric access to r,â unsaturated δ-lactones is described, using a vinylogous Mukaiyama-aldol reaction between a
γ-substituted dienolate and various aldehydes in the presence of Carreira catalyst CuF‚(S)-tolBinap. This methodology has been further
applied to a straightforward access to the Prelog-Djerassi lactone.
The R,â unsaturated and saturated δ-lactones are found in
an impressive number of natural and unnatural products
possessing interesting biological activities.1-9 These com-
pounds are also useful chiral building blocks, such as for
example the Prelog-Djerassi lactone.10,11 Efficient asymmetric
syntheses of such lactones have been described but required
the use of a stoichiometric amount of chiral auxiliary and/
or a multiple-step sequence.12-18
(1) (a) Davis-Coleman, M. T.; Rivett, D. E. A. In Progress in the
Chemistry of Organic Natural Products; Herz, W., Grisebach, H., Kirby,
G. W., Tamm, Ch., Eds.; Springer: New York, 1989; 55, pp 1-35. (b)
Collet, L. A.; Davis-Coleman, M. T.; Rivett, D. E. A. In Progress in the
Chemistry of Organic Natural Products; Herz, W., Falk, H., Kirby, G. W.,
Moore, E., Tamm, Ch., Eds.; Springer: New York, 1998; 75, pp 182-
209.
(2) Leptomycin B and callystatin A: (a) Kobayashi, M.; Wang, W.;
Tsutsui, Y.; Sugimoto, M.; Murakami, N. Tetrahedron Lett. 1998, 39, 8291.
(b) Smith, A. B., III; Brandt, B. M. Org. Lett. 2001, 3, 1685. (c) Murakami,
N.; Sugimoto, M.; Kobayashi, M. Bioorg. Med. Chem. 2001, 9, 57.
(3) Boronolide: Ghosh, A. K.; Bilcer, G. Tetrahedron Lett. 2000, 41,
1003 and references therein.
(9) Spicigerolide: Pereda-Miranda, R.; Fragoso-Serrano, M.; Cerda-
Garcia-Rojas, C. M. Tetrahedron 2001, 57, 47.
(10) For a review, see: Martin, S. F.; Guinn, D. E. Synthesis 1991, 245.
(11) For more recent approaches: (a) Oppolzer, W.; Walther, E.; Pe´rez
Balado, C.; De Brabander, J. Tetrahedron Lett. 1997, 38, 809. (b) Hiscock,
S. D.; Hitchcock, P. B.; Parsons, P. J. Tetrahedron 1998, 54, 11567. (c)
Chow, H.; Fleming, I. J. Chem. Soc., Perkin Trans. 1 1998, 2651. (d) Cossy,
J.; Bauer, D.; Bellosta, V. Tetrahedron Lett. 1999, 40, 4187. (e) Pilli, R.
A.; Kleber, C.; Souto, C. R. O.; de Meijere, A. J. Org. Chem. 1998, 63,
7811.
(4) Ratjadone: Christmann, M.; Bhatt, U.; Quitschalle, M.; Claus, E.;
Kalesse, M. Angew. Chem., Int. Ed. 2000, 39, 4364.
(5) Gonodiol: Surivet, J. P.; Vate`le, J. M. Tetrahedron 1999, 55, 13011
and references therein.
(12) For asymmetric reactions using vinylogous urethane chemistry,
leading to syn unsaturated lactones, see: (a) Schlessinger, R. H.; Li, Y. J.;
Von Langen, D. J. J. Org. Chem. 1996, 61, 3226. (b) Dankwardt, S. M.;
Dankwardt, J. W. Tetrahedron Lett. 1998, 39, 4971.
(6) Pironetin: Watanabe, H.; Watanabe, H.; Bando, M.; Kido, M.;
Kitahara, T. Tetrahedron 1999, 55, 9755.
(7) δ-Lactones isolated from Cryptocarya latifolia: Jorgensen, K. B.;
Suenaga, T.; Nakata, T. Tetrahedron Lett. 1999, 40, 8855.
(8) Umuravumbolide: Reddy, M. V. R.; Rearick, J. P.; Hoch, N.;
Ramachandran, P. V. Org. Lett. 2001, 3, 19.
(13) For RCM strategies, see: (a) Ghosh, A. K.; Cappiello, J.; Shin, D.
Tetrahedron Lett. 1998, 39, 4651. (b) Cossy, J.; Bauer, D.; Bellosta, V.
Tetrahedron Lett. 1999, 40, 4187. (c) Dirat, O.; Kouklovsky, C.; Langlois,
Y.; Lesot, P.; Courtieu, J. Tetrahedron: Asymmetry 1999, 10, 3197. (d)
Fuerstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H. J.; Nolan, S. P. J.
Org. Chem. 2000, 65, 2204.
10.1021/ol0168317 CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/16/2001

We wish to report herein an efficient catalytic asymmetric
one-step protocol to access R,â unsaturated δ-lactones using
a vinylogous aldol reaction.19
Scheme 2a
Recently, we have described the efficient formation of
vinylogous aldol product using silyl dienolate 1 in good
yields, excellent γ: R regioselectivity, and moderate to good
enantioselectivity (Scheme 1).20
Scheme 1. Vinylogous Mukaiyama-Aldol Reactions
a (a) TBAT 10%, THF, rt, 60%; (b) N-benzyl cinchodinium
fluoride 10%, THF, rt, 60%; (c) CuF‚(S)-tolBinap, 10%, rt, 85%
(3a/5a 16/84).
To observe the influence of a γ substituent on the course
(R/γ and syn/anti ratio) of the reaction, we envisioned the
reaction of γ-substituted silyl-dienolate 221 with benzalde-
hyde. Unexpected results were observed depending on the
nature of the dienolate activation (Scheme 2).
lactone 5a was isolated in 85% yield (Table 1). The
vinylogous aldol product 3a was obtained with no syn/anti
diastereoselectivity and very poor enantioselectivities (<5%
ee for both syn and anti products). On the other hand, the
R,â unsaturated lactone 5a was found to be highly anti
selective (syn/anti > 2:98) in 87% ee, suggesting that a more
organized transition state had occurred.
Using 10% of tetrabutylammonium triphenyldifluorosili-
cate TBAT as a racemic nonhygroscopic source of fluoride,22
the expected vinylogous aldol product 3a was isolated in
45% yield in a disappointing 1:1 syn/anti ratio. Changing
the fluoride source to a chiral nonracemic ammonium
fluoride,20c we were surprised to isolate only the R aldol
product in 68% yield, in a 1:1 syn/anti mixture.
Moving to the Carreira catalyst CuF‚(S)-tolBinap,23
a
Table 1. Vinylogous Mukaiyama Reactions of Dienolate 2
with Various Aldehydes in the Presence of 10% of
CuF‚(S)-tolBinap
14:86 mixture of the vinylogous aldol product 3a and the
(14) For a palladium-catalyzed rearrangement of vinyl-oxiranes, see:
Marion, F.; Le Fol, R.; Courillon, C.; Malacria, M. Synlett 2001, 138.
(15) For an hydrozirconation-carbonylation strategy, see: Dupont, J.;
Dupont, A. J. Tetrahedron: Asymmetry 1998, 9, 949.
(16) For (Z)-selective olefination strategies, see: (a) Nicoll-Griffith, D.
A.; Weiler, L. Tetrahedron 1991, 47, 2733. (b) Yokokawa, F.; Fujiwara,
H.; Shiori, T. Tetrahedron Lett. 1999, 40, 1915.
(17) For cis-alkyne reduction strategies, see: (a) Surivet, J. P.; Vate`le,
J. M. Tetrahedron 1999, 55, 13011. (b) Watanabe, H.; Watanabe, H.; Bando,
M.; Kido, M.; Kitahara, T. Tetrahedron 1999, 55, 9755. (c) Marshall, J.
A.; Adams, N. D. J. Org. Chem. 1999, 64, 5201.
(18) For an elimination strategy, see: Jorgensen, K. B.; Suenaga, T.;
Nakata, T. Tetrahedron Lett. 1999, 40, 8855.
(19) For a general review on vinylogous Mukaiyama-aldol reaction,
see: Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. ReV. 2000,
100, 1929.
(20) (a) Bluet, G.; Campagne, J. M. Tetrahedron Lett. 1999, 40, 5507.
(b) Bluet, G.; Campagne, J. M. Synlett 2000, 221. (c) Bluet, G.; Campagne,
J. M. J. Org. Chem. 2001, 66, 4293.
yield % ratioa
lactones 5
entry
aldehyde
(4 + 5)
5/4
no. anti/syna
ee
1
2
3
benzaldehyde
2-naphthaldehyde
2,3-dimethoxy
benzaldehyde
2-furaldehyde
(E)-cinnamal-
dehyde
85
95
87
86/14 5a
80/20 5b
81/19 5c
>98/2
>98/2
>98/2
87b, 98c
85d
91e, 98c
4
5
60
60
50/50 5d
70/30 5e
>98/2
>98/2
86f
82g
6
isobutyraldehyde
95
64/36 5f
>98/2
91h
a Determined by 1H NMR on the crude product. b HPLC DAICEL-OD,
hexane/2-propanol 95/5. c After recrystallization (heptane). d HPLC DA-
ICEL-OJ, hexane/2-propanol 82/18. e HPLC DAICEL-OJ, hexane/2-pro-
panol 95/5. f HPLC DAICEL-OJ, hexane/2-propanol 95/5. g HPLC DAICEL-
OJ, hexane/2-propanol 90/10. h HPLC ChiralPAK AD, hexanes/ethanol 99/
1.
(21) Botha, M. E.; Giles, R. G. F.; Yorke, S. C. J. Chem. Soc., Perkin
Trans. 1 1991, 85.
(22) (a) Pilcher, A. S.; Ammon, H. L.; Deshong, P. J. Am. Chem. Soc.
1995, 117, 5166. (b) Handy, C. J.; Lam, Y.-F.; Deshong, P. J. Org. Chem.
2000, 65, 3542.
(23) (a) Kruger, J.; Carreira, E. M. J. Am. Chem. Soc. 1998, 120, 837.
(b) Pagenkopf, B. L.; Kruger, J.; Stojanovic, A.; Carreira, E. M. Angew.
Chem., Int. Ed. 1998, 37, 3124.
The reaction with other aromatic aldehydes (Table 1,
entries 2-4) was also efficient, leading to lactones with
excellent diastereoselectivities (>2:98 syn/anti) and high
enantioselectivities (85-91% ee and even 98% ee for the
3808
Org. Lett., Vol. 3, No. 23, 2001

recrystallized lactones 5a and 5c). Reaction with 2-furalde-
hyde proved to be less selective, leading to the lactone with
a high ee (86%) but generally in a 1:1 ratio of linear and
lactone products. The reactions with unsaturated (entry 5)
and aliphatic (entry 6) aldehydes were also efficient in terms
of anti/syn ratio (>98/2) and ee (respectively, 82%, 91%),
but the lactone/linear product ratios were somewhat lower
(respectively, 70/30, 64/36) compared to aromatic aldehydes.
To determine the absolute configuration of the lactones,
lactone 5a was oxidized to the previously described enan-
tiomerically pure compound 6.24 A rotation of -13.9 (for
87% ee) was found, in agreement with the reported rotation
of -17.5 described for the enantiomerically pure anti (2R,3S)
compound.
products were found to be less than 10% of the mixture.
After flash chromatography, lactone 9a was isolated in a
gratifying 60% yield. Using the (R)-tolBinap ligand with
aldehyde 8 (mismatched pair), an inversion of the diaste-
reoselectivity could be observed: a 9/1 mixture of lactones
9b27 and 9a was obtained (the amount of linear products
was again found to be less than 10%). After purification by
flash chromatography, the mixture of lactones was isolated
in 55% yield.
Scheme 5a
Scheme 3a
a (a) RuCl3 6%, NaIO4 4.2 equiv, CH3CN/CCl4/H2O (1/1/1.5),
50 °C, 24 h, 35%.
a (a) CuF‚(S)-tolBinap, 10%, rt, 60%; (b) CuF‚(R)-tolBinap, 10%,
rt, 55%.
Consequently, asolute configurations of lactones 5, ob-
tained with CuF‚(S)-tolBinap, were tentatively assigned as
shown in Scheme 4.
According to the procedures described by Cossy,11d the
lactone 9a was further transformed in three steps to the
Prelog-Djerassi lactone 10. This procedure constitutes a
straightforward (four steps from aldehyde 8) catalytic asym-
metric access to the Prelog-Djerassi lactone (Scheme 6).
Scheme 4
Scheme 6
This methodology was then applied to chiral aldehyde 8.25
The reaction of chiral aldehyde 8 with the (S)-tolBinap ligand
(matched pair) led predominantly to the syn/anti lactone
9a.11d,26 The other anti/anti lactone 9b26 could not be
1
In conclusion, the catalytic asymmetric vinylogous aldol
of γ-substituted dienolate constitutes a valuable one-step
route to R,â unsaturated lactones, as illustrated by the
synthesis of the Prelog-Djerassi lactone. Further optimization
observed by H NMR of the crude product, and linear
(24) Van Draanen, N. A.; Arseniyadis, S.; Crimmins, M. T.; Heathcock,
C. H. J. Org. Chem. 1991, 56, 2499.
(25) Ley, S. V.; Anthony, N. J.; Armstrong, A.; Brasca, M. G.; Clarke,
T.; Culshaw, D.; Greck, C.; Grice, P.; Jones, A. B.; Lygo, B.; Madin, A.;
Sheppard, R. N.; Slawin, A. M. Z.; Williams, D. J. Tetrahedron 1989, 45,
7161.
(27) Diez-Martin, D.; Kotecha, N. R.; Ley, S. V.; Mantegani, S.;
Menendez, J. C.; Organ, H. M.; White, A. D. Tetrahedron 1992, 48, 7899-
7938.
(26) Marshall, J. A.; Adams, N. D. J. Org. Chem. 1999, 64, 5201.
Org. Lett., Vol. 3, No. 23, 2001
3809

and applications of this reaction to the synthesis of natural
products are currently under investigation.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank Prof. J. Cossy for kindly
providing us the spectra of compounds 9a and 10 and Dr. J.
Dudash for the revision of the manuscript.
OL0168317
3810
Org. Lett., Vol. 3, No. 23, 2001