Catalytic and asymmetric vinylogous mukaiyama reactions on aliphatic ketones: Formal asymmetric synthesis of taurospongin A

Article abstract of DOI:10.1021/ja051573k

Catalytic asymmetric vinylogous Mukaiyama reactions on ketones, leading to the formation of α,β-unsaturated lactones with tertiary alcohols, have been described (11 examples, up to 93% ee). This methodology has been applied in a formal enantioselective sy

Full text of DOI:10.1021/ja051573k

Published on Web 04/28/2005
Catalytic and Asymmetric Vinylogous Mukaiyama Reactions on Aliphatic
Ketones: Formal Asymmetric Synthesis of Taurospongin A
Xavier Moreau, Belen Baza´n-Tejeda, and Jean-Marc Campagne*
Institut de Chimie des Substances Naturelles, CNRS, AVenue de la Terrasse F-91190 Gif-sur-YVette France
Received March 11, 2005; E-mail: campagne@icsn.cnrs-gif.fr
Scheme 1
The asymmetric construction of tertiary alcohols is a continuing
stimulating task.1 In particular, catalytic and asymmetric C-C bond
reactions on ketones are difficult due to their lower reactivity and
lesser steric dissimilarity compared to that of aldehydes.2,3 Un-
branched aliphatic ketones are particularly challenging substrates
where the catalyst needs to discriminate between a methyl and a
Chart 1
methylene group. Recently, efficient enantioselective addition of
organometallics (mainly zinc alkylation,4 zinc arylation,5 zinc
vinylation,6 zinc alkynylation,7 tin8 and boron9 allylations10) to
ketones to form tertiary alcohols has been described. However,
catalytic and asymmetric aldol reactions on ketones are rather rare,
to the notable exception of the enantioselective chiral Lewis base
promoted aldol reactions developed by Denmark11 and copper-
bisoxazoline catalyzed aldol reactions on R-diketones and pyruvate
esters developed by Evans.12 Shibasaki has also reported one
example of an asymmetric aldol reaction to a ketone using a CuF
catalyst.13 We previously reported catalytic and asymmetric
vinylogous Mukaiyama reactions with aldehydes leading to the
formation R,â-unsaturated lactones in good enantioselectivities.14
These results prompt us to investigate this reaction with ketones
(Scheme 1).
Initial studies carried out in the presence of silyl dienolate 1 and
acetophenone 2a in the presence of CuF-(S)-tolBinap15 were quite
encouraging, leading to the isolation of lactone 3a in 71% yield
and 80% ee.16 The “linear” product 4a could also be detected in
the crude mixture, albeit in a relatively small amount (<10% yield
and <10% ee). The scope of the reaction has then been surveyed
using various aromatic, olefinic, and aliphatic (branched and linear)
ketones (Chart 1). Results obtained in these reactions are sum-
marized in Table 1.
Reactions on aromatic ketones (entries 1-4) gave the corre-
sponding lactones 2a-2d in 19-71% yield and 59-81% ee. These
reactions are sensitive to electronic effects with lower selectivities/
yields for electron-poor and electron-rich ketones (entries 2-4).
In the presence of the p-nitroacetophenone 2d, the major product
is the linear product 4d, isolated in 39% yield with a very low
enantioselectivity (<10% ee). The more impressive results have
been obtained with aliphatic ketones (entries 5-8), leading to the
lactones in high enantioselectivities (87-93%). In the presence of
branched aliphatic ketones, such as isobutylmethyl ketone 2g and
tertbutylmethyl ketone 2h (entries 7 and 8), yields are somewhat
lower due to steric hindrance, with however no marked difference
in enantioselectivity.
Table 1. Catalyzed Additions of 1 to Ketones 2
isolated
entry
ketone
lactone
yield (%)a
eeb
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
3a
3b
3c
3d
3e
3f
3g
3h
3i
71
39
58
19
70
81
40
39
17
73
72
80
59
81
75
87
90
93
92
24
10
11
2j
2k
3j
3k
39 (60%)c
88
a Yields of analytically pure materials. b Determined by chiral HPLC.
c In the presence of Binap.
Chart 2
deeper understanding of the reaction mechanism and ligand effects
will now be necessary to further improve the scope and results in
this methodology. Mechanistic investigation and ligand screening
are in progress.
As previously observed (in a lesser extent) for R,â-unsaturated
aldehydes,17 limits of this methodology have been found in the
presence of R,â-unsaturated ketone 2i (entry 9), where the lactone
has been isolated in a modest 17% yield and 24% ee. In the presence
of propiophenone 2j (entry 10), enantioselectivity was disappoint-
ingly low (39% ee). Nevertheless, the enantioselectivity could be
increased up to 60% by simply changing tolBinap to Binap. A
The strategic potential offered by these reactions led us to target
taurospongin A (Chart 2), a natural product isolated from the marine
sponge Hippospongia sp. in 1997, which is a potent inhibitor of
DNA polymerase and HIV reverse transcriptase.18
Two total syntheses of taurospongin A have been reported by
Jacobsen19 and Ley20 as well as a formal synthesis by Ghosh21 and
a synthesis of the central fragment by Lu.22 In our retrosynthetic
9
7288
J. AM. CHEM. SOC. 2005, 127, 7288-7289
10.1021/ja051573k CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Formal Enantioselective Synthesis of Taurospongin A
in 12 steps from ketone 2k and with 6% overall yield. This work
illustrates for the first time the use of catalytic and asymmetric
vinylogous Mukaiyama reactions on aliphatic ketones to create
enantiomerically enriched lactones with tertiary alcohols. Further
developments and optimization of this methodology will be
published in due course.
Acknowledgment. We are grateful to the CNRS for financial
support, MENRT-France (X.M.), and CONACYT-Mexico (B.B.T.)
for grants.
Supporting Information Available: Experimental details and
characterization for all new compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Denissova, I.; Barriault, L. Tetrahedron 2003, 59, 10105. (b)
Christoffers, J.; Baro, A. Angew. Chem., Int. Ed. 2003, 42, 1688. (c) Corey,
E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388.
(2) For an excellent highlight on this topic, see: Ramon, D. J.; Yus, M. Angew.
Chem., Int. Ed. 2004, 43, 284.
(3) Betancort, J. M.; Garcia, C.; Walsh, P. J. Synlett 2004, 749.
(4) (a) Ramon, D. J.; Yus, M. Tetrahedron 1998, 54, 5651. (b) Ramon, D. J.;
Yus, M. Tetrahedron Lett. 1998, 39, 1239. (c) Yus, M.; Ramon, D. J.;
Prieto, O. Tetrahedron: Asymmetry 2002, 13, 2291. (d) Yus, M.; Ramon,
D. J.; Prieto, O. Tetrahedron: Asymmetry 2003, 14, 1103. (e) Garcia, C.;
LaRochelle, L. K.; Walsh, P. J. J. Am. Chem. Soc. 2002, 124, 10970. (f)
Jeon, S.-J.; Walsh, P. J. J. Am. Chem. Soc. 2003, 125, 9544.
(5) (a) Dosa, P. I.; Fu, G. C. J. Am. Chem. Soc. 1998, 120, 445. (b) Garcia,
C.; Walsh, P. J. Org. Lett. 2003, 5, 3641. (c) Prieto, O.; Ramon, D. J.;
Yus, M. Tetrahedron: Asymmetry 2003, 14, 1955.
(6) Li, H.; Walsh, P. J. J. Am. Chem. Soc. 2004, 126, 6538.
(7) (a) Cozzi, P. G. Angew. Chem., Int. Ed. 2003, 42, 2895. (b) Lu, G.; Li,
X.; Jia, X.; Chan, W. L.; Chan, A. S. C. Angew. Chem., Int. Ed. 2003,
42, 5057.
(8) (a) Casolari, S.; D’Addario, D.; Tagliavini, E. Org. Lett. 1999, 1, 1061.
(b) Waltz, K. M.; Gavenonis, J.; Walsh, P. J. Angew. Chem., Int. Ed.
2002, 41, 3697. (c) Kim, J. G.; Waltz, K. M.; Garcia, I. F.; Kwiatkowski,
D.; Walsh, P. J. J. Am. Chem. Soc. 2004, 126, 12580. (d) Kii, S.; Maruoka,
K. Chirality 2003, 15, 68. (e) Cunningham, A.; Woodward, S. Synlett
2002, 43. (f) Cunningham, A.; Mokal-Parekh, V.; Wilson, C.; Woodward,
S. Org. Biomol. Chem 2004, 2, 741.
analysis, we anticipated that the tertiary alcohol could be created
using a catalytic and asymmetric vinylogous Mukaiyama reaction
on ketone 2k (Scheme 2 and Table 1, entry 11).
Indeed, in the presence of (R)-tolBinap, the corresponding lactone
3k was obtained in 72% yield and 88% ee. After hydrogenation of
the double bond, the lactone 5 was opened-up in the presence of
the Weinreb amine, and the tertiary alcohol was protected as a TES
silyl ether in 64% yield (two steps). After reduction to the
corresponding aldehyde using Dibal-H, an asymmetric Keck
allylation23 afforded the corresponding homoallylic alcohol 7 in
81% yield (and 91% ee, determined using the Mosher ester method).
Compound 7 was then transformed into the corresponding epoxide
9 using a diastereoselective three-step Smith’s methodology.24 After
Boc protection (81% yield) followed by treatment with IBr and
K2CO3/MeOH, epoxide 9 was thus obtained in 51% yield in a 9:1
diastereoselectivity. After acetylation, diastereomerically pure
epoxide 10 was obtained (after flash chromatography) and selec-
tively hydrogenated25 in the presence of palladium ethylenediamine
(Pd/C(en)) to the expected secondary alcohol in 50% yield (92%
based on recovered starting material). As previously observed by
Jacobsen,19 this compound is quite unstable, and to prevent acetyl
migration, the secondary alcohol was rapidly protected as a TBS
silyl ether using TBSOTf (65% yield). The conversion of 11 to
taurospongin A (Chart 2) has been demonstrated by Jacobsen. In
conclusion, we have completed a formal synthesis of taurospongin
(9) Wada, R.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2004,
126, 8910.
(10) Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103, 2763.
(11) Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2002, 124, 4233.
(12) Evans, D. A.; Johnson, J. Acc. Chem. Res. 2000, 33, 325.
(13) Oisaki, K.; Suto, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2003,
125, 5644.
(14) (a) Bluet, G.; Campagne, J.-M. Tetrahedron Lett. 1999, 40, 5507. (b) Bluet,
G.; Campagne, J.-M. J. Org. Chem. 2001, 66, 4293. (c) Bluet, G.; Baza´n-
Tejeda, B.; Campagne, J.-M. Org. Lett. 2001, 3, 3807.
(15) (a) Pagenkopf, B. L.; Kruger, J.; Stojanovic, A.; Carreira, E. M. Angew.
Chem., Int. Ed. 1998, 37, 3124. (b) Kruger, J.; Carreira, E. M. J. Am.
Chem. Soc. 1998, 120, 837.
(16) Absolute configurations have been attributed by correlation after hydro-
genation of lactone 3a to the known reduced (R)-lactone. Date, M.; Tamai,
Y.; Hattori, T.; Takayama, H.; Kamikubo, Y.; Miyano, S. J. Chem. Soc.,
Perkin Trans. 1 2001, 645 (see Supporting Information).
(17) Unpublished work from this laboratory.
(18) Ishiyama, H.; Ishibashi, M.; Ogawa, A.; Yoshida, S.; Kobayashi, J.-i. J.
Org. Chem. 1997, 62, 3831.
(19) Lebel, H.; Jacobsen, E. N. J. Org. Chem. 1998, 63, 9624.
(20) (a) Hollowood, C. J.; Ley, S. V.; Yamanoi, S. Chem. Commun. 2002,
1624. (b) Hollowood, C. J.; Yamanoi, S.; Ley, S. V. Org. Biomol. Chem.
2003, 1, 1664.
(21) Ghosh, A. K.; Lei, H. Tetrahedron: Asymmetry 2003, 14, 629.
(22) Zheng, G. R.; Lu, W.; Cai, J. C. Chin. Chem. Lett. 2001, 12, 961.
(23) Keck, G. E.; Krishnamurthy, D. Org. Synth. 1998, 75, 12.
(24) Duan, J. J. W.; Smith, A. B., III. J. Org. Chem. 1993, 58, 3703.
(25) Sajiki, H.; Hattori, K.; Hirota, K. Chem. Commun. 1999, 1041.
JA051573K
9
J. AM. CHEM. SOC. VOL. 127, NO. 20, 2005 7289