Highly stereoselective oxy-Michael additions to β,γ-unsaturated α-Keto Esters: Rapid enantioselective synthesis of 3-hydroxybutenolides

Article abstract of DOI:10.1021/ol702693m

The highly diastereoselective oxy-Michael addition of the "naked" anion of (6S)-methyl δ-lactol to γ-substituted β,γ- unsaturated α-keto esters leading to the direct formation of THP*-protected γ-hydroxy α-keto ester derivatives is described. Subsequent a

Full text of DOI:10.1021/ol702693m

ORGANIC
LETTERS
2008
Vol. 10, No. 4
565-567
Highly Stereoselective Oxy-Michael
Additions to -Unsaturated -Keto
Esters: Rapid Enantioselective
â
,
γ
r
Synthesis of 3-Hydroxybutenolides
Xin Xiong, Caroline Ovens, Adam W. Pilling, John W. Ward, and Darren J. Dixon*
School of Chemistry, The UniVersity of Manchester, Oxford Road,
Manchester M13 9PL, U.K.
darren.dixon@man.ac.uk
Received November 6, 2007
ABSTRACT
The highly diastereoselective oxy-Michael addition of the “naked” anion of (6S)-methyl
δ
-lactol to
γ-substituted â,γ-unsaturated r-keto esters
leading to the direct formation of THP*-protected
affords the 3-hydroxybutenolides in high yields.
γ-hydroxy r-keto ester derivatives is described. Subsequent acid-mediated deprotection
The stereoselective addition of oxygen-centered nucleophiles
is an emerging area in the Michael addition field.1 Our group2
and others3 have been involved with the development of
chiral water equivalents for the addition to reactive nitro
olefin-4 and malonate-derived acceptors.5 Although useful
for the asymmetric synthesis of 1,2-amino alcohols and
protected â-hydroxy esters, we believed an extension of this
chemistry to incorporate other types of Michael acceptors,
while maintaining reaction efficiency and diastereoselectivity,
would expand significantly the utility and scope of the
reaction.
(1) For reviews, see: (a) Misra, M.; Luthra, R.; Singh, K. L.; Sushil, K.
ComprehensiVe Natural Products Chemistry; Barton, D. H. R., Nakunisha,
K., Meth-Chon, O., Eds.; Pergamon Press: Oxford, UK, 1999; Vol. 4, p
25. (b) Berkessel, A. In Houben-Weyl Methods of Organic Synthesis, Vol.
E21e; Helmchen, G., Hoffman, R. W., Mulzer, J., Schaumann, E., Eds.;
Thieme: Stuttgart, 1996; pp 4818-4856. For recent catalytic asymmetric
examples, see: (c) Dine´r, P.; Nielsen, M.; Bertelsen, S.; Niess, B.; Jørgensen
K. A. Chem. Commun. 2007, 3646-3648. (d) Kano, T.; Tanaka, Y.;
Maruola, K. Tetrahedron 2007, 63, 8658-8664. (e) Li, H.; Wang, J.;
E-Nunu, T.; Zu, L.; Jiang, W.; Wei, S.; Wang, W. Chem. Commun. 2007,
507-509. (f) Sunde´n, H.; Ibrahem, I.; Zhao, G.-L.; Eriksson, L.; Co´rdova,
A. Chem. Eur. J. 2007, 13, 574-581. (g) Vanderwal, C. D.; Jacobsen, E.
N. J. Am. Chem. Soc. 2004, 126, 14724-14725. (h) Govender, T.; Hojabri,
L.; Moghaddam, F. M.; Arvidsson, P. I. Tetrahedron: Asymmetry 2006,
17, 1763-1767. For a phosphine-catalyzed example, see: (i) Stewart, I.
C.; Bergman, R. G.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 8696-
8697.
(2) (a) Adderley, N. J.; Buchanan, D. J.; Dixon, D. J.; Laine´, D. I. Angew.
Chem., Int. Ed. 2003, 35, 4241-4244. (b) Buchanan, D. J.; Dixon, D. J.;
Scott, M. S.; Laine´, D. I. Tetrahedron: Asymmetry 2004, 15, 195-197.
(c) Buchanan, D. J.; Dixon, D. J.; Hernandez-Juan, F. Org. Lett. 2004, 6,
1357-1360. (d) Buchanan, D. J.; Dixon, D. J.; Hernandez-Juan, F. Org.
Biomol. Chem. 2004, 2, 2932-2934. (e) Buchanan, D. J.; Dixon, D. J.;
Looker, B. E. Synlett 2005, 1948-1950. (f) Hernandez-Juan, F. A.; Xiong,
X.; Brewer, S. E.; Buchanan, D. J.; Dixon, D. J. Synthesis 2005, 3283-
3286. (g) Hernandez-Juan, F. A.; Richardson, R. D.; Dixon, D. J. Synlett
2006, 2673-2675.
(3) (a) Enders, D.; Haertwig, A.; Raabe, G.; Runsink, J. Angew. Chem.,
Int. Ed. 1996, 35, 2388-2390. (b) Enders, D.; Haertwig, A.; Raabe, G.;
Runsink, J. Eur. J. Org. Chem. 1998, 1771-1792. (c) Enders, D.; Haertwig,
A.; Runsink, J. Eur. J. Org. Chem. 1998, 1793-1801.
(4) For diastereoselective/non-enantioselective additions to nitro olefin
acceptors, see: (a) Dumez, E.; Faure, R.; Dulce`re, J.-P. Eur. J. Org. Chem.
2001, 2577-2588. (b) Yakura, T.; Tsuda, T.; Matsumura, Y.; Yamada, S.;
Ikeda, M. Synlett 1996, 985-986.
(5) For non-enantioselective additions of oxygen-centred nucleophiles
to benzylidene-(or alkylidene-)malonates and related Michael acceptors
see: (a) Cavicchioli, M.; Marat, X.; Monteiro, N.; Hartmann, B.; Balme,
G. Tetrahedron Lett. 2002, 43, 2609-2611. (b) Marat, X.; Monteiro, N.;
Balme, G. Synlett 1997, 845-847. (c) Monteiro, N.; Balme, G. J. Org.
Chem. 2000, 65, 3223-3226. For an asymmetric diastereoselective substrate
controlled addition of achiral oxygen-centred nucleophiles, see, for ex-
ample: (d) Paquette, L. A.; Tae, J.; Arrington, M. P.; Sadoun, A. H. J. Am.
Chem. Soc. 2000, 122, 2742-2748. For an interesting (non-enantioselective)
synthesis of tetrahydrofurans using an oxy-Michael/Michael cyclization
strategy, see: (e) Greatrex, B. W.; Kimber, M. C.; Taylor, D. K.; Tiekink,
R. T. J. Org. Chem. 2003, 68, 4239-4246.
10.1021/ol702693m CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/23/2008

To provide an initial proof of principle study, γ-phenyl-
substituted acceptor 2a was chosen as a test substrate. The
initial conditions adopted were identical to those previously
established for the addition to â-substituted nitro olefin
acceptors.2 Thus, deprotonation of the diastereomeric mixture
of (6S)-methyl δ-lactol 1 with KHMDS in THF at -78 °C
and addition of 18-crown-6 (1.0 equiv) generated the “naked”
chiral lactol alkoxide nucleophile (Table 1). Addition of 2a
(0.67 equiv) to this mixture, stirring for 2 h, and quenching
with acetic acid (2.0 equiv) at -78 °C afforded, after aqueous
workup, the crude oxy-Michael adduct 3a in a pleasing
>95% de and, after purification by flash column chroma-
tography, in 76% yield. The necessity for 18-crown-6 in the
reaction was confirmed by repeating the above protocol in
its absence; 3a was formed in a much diminished 33% de.
The stereochemistry was assigned by analogy with previous
oxy-Michael reactions using the naked anion of (6S)-methyl
δ-lactol.2
Table 1. Stereoselective Oxy-Michael Addition of the “Naked”
Anion of 1 to a Range of â,γ-Unsaturated R-Keto Ester
Acceptors
Having identified 2a as a suitably reactive substrate, the
scope of the oxy-Michael addition to a range of γ-substituted
â,γ-unsaturated R-keto esters was probed. Acceptors were
chosen to contain simple esters and the γ-substituent varied
between both aromatic and aliphatic groups (Table 1), the
oxy-Michael addition products (3a-i) were obtained with
consistently excellent diastereoselectivities (>95% de) and
good yields (60-81%).
As well as inducing excellent levels of stereocontrol on
addition to the electron poor alkenes, the tetrahydropyranyl
ether moiety (THP*) is easily removed to reveal the parent
alcohol functionality. To demonstrate the readiness of this
removal, a range of adducts were subjected to methanol
containing Amberlyst-15 resin (Table 2).
a Adducts are prone to retro-Michael decomposition during chromatog-
raphy; elution with chilled solvents is necessary (see the Supporting
Information). b The minor diastereomer cannot be detected by analysis of
the 300 or 500 MHz 1H NMR spectra of the crude reaction product.
c Isolated as a mixture of keto/enol isomers.
Table 2. Acid-Mediated Deprotection, Cyclization, and
Enolization of Oxy-Michael Adducts
Herein, we wish to describe a highly diastereoselective
oxy-Michael reaction of a chiral water equivalent to γ-sub-
stituted â,γ-unsaturated R-keto esters.6 â,γ-Unsaturated
R-keto esters are readily prepared by the condensation of
pyruvate esters with aldehydes7 and have been identified as
reactive substrates in diastereo- and enantioselective Michael
addition reactions.6,8 We believed a stereoselective addition
of a chiral water equivalent to such acceptors would
constitute a powerful extension to the field as the adducts
would have considerable synthetic utility; the high density
and placement of functional groups and the abundance of
â-hydroxy ketones in natural products9 all supported the
underlying need for the development of such methodology.10
(6) For a catalytic asymmetric addition of phenol nucleophiles to such
acceptors, see: van Lingen, H. L.; Zhuang, W.; Hansen, T.; Rutjes, F. P.
J. T.; Jørgensen, K. A. Org. Biomol. Chem. 2003, 1, 1953-1958.
(7) (a) Sugimura, H.; Shigekawa, Y.; Uematsu, M. Synlett. 1991, 153-
154. (b) Sugimura, H.; Yoshida, K. Bull. Chem. Soc. Jpn. 1992, 3209-
3211. (c) Keum, Y. S.; Seo, J. S.; Qing, X. L. Synth. Comm. 2005, 2685-
2693.
a Eantiomeric excesses were determined by chiral HPLC using a Chiralcel
a
AS column eluting with hexane/IPA 98:2, 254 nm, 1 mL/min; bhexane/
c
IPA 90:10, 220 nm, 1 mL/min; hexane/IPA 97:3, 220 nm, 1 mL/min.
(8) (a) Jensen, K. B.; Thorhauge, J.; Hazell, R. G.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2001, 160-163. (b) Halland, N.; Velgaard, T.;
Jørgensen, K. A. J. Org. Chem. 2003, 68, 5067-5074. (c) U¨ naleroglu, C.;
Temelli, B.; Demir, A. S. Synthesis 2004, 2574-2578. (d) Lyle, M. P. A.;
Draper, N. D.; Wilson, P. D. Org. Lett. 2005, 7, 901-904.
In all reactions, the hydroxybutenolide products 4 were
isolated from the reaction mixture in excellent yields. Thus,
the acid facilitated a smooth three step process; THP*
566
Org. Lett., Vol. 10, No. 4, 2008

removal, lactonization, and enolization. The enantiomeric
excesses of 4a-d were measured as >95% ee by chiral
HPLC analysis and confirmed that no racemization was
occurring in the sequence.
In summary, the naked anion of enantiopure 6-methyl
δ-lactol undergoes highly diastereoselective oxy-Michael
additions to a range of γ-substituted â,γ-unsaturated R-keto
esters. The reactions provide a new approach to γ-hydroxy
R-keto ester compounds complimentary to aldol strategies.
The products may be converted efficiently to butenolide
compounds using a polymer-supported acid in methanol.
Owing to the abundance of the butenolide motif in natural
products, this chemistry should provide a solid synthetic basis
for their asymmetric synthesis, and applications toward these
goals will be reported in due course.
Acknowledgment. We gratefully acknowledge the EPSRC
(to X.X.).
(9) For a review, see: Schetter, B.; Mahrwald, R. Angew. Chem., Int.
Ed. 2006, 45, 7506-7525.
(10) For examples of the complimentary stereoselective aldol reaction
leading to similar product types, see: (a) Metternich, R.; Lu¨di, W.
Tetrahedron Lett. 1988, 29, 3923-3926. (b) Enders, D.; Dyker, H.; Raabe,
G. Angew. Chem., Int. Ed. 1993, 32, 421-423. (c) Enders, D.; Dyker, H.;
Leusink, F. R. Chem. Eur. J. 1998, 4, 311-320. (d) Gathergood, N.; Juhl,
K.; Poulsen, T. B.; Thordrup, K.; Jørgensen, K. A. Org. Biomol. Chem.
2004, 2, 1077-1085. (e) Dambruoso, P.; Massi, A.; Dondoni, A. Org. Lett.
2005, 7, 4657-4660. (f) Vincent, J.-M.; Margottin, C.; Berlande, M.;
Cavagnat, D.; Buffeteau, T.; Landais, Y. Chem. Commun. 2007, 4782-
4784.
Supporting Information Available: Experimental pro-
cedures, NMR spectra (3a-i and 4a-d), and HPLC traces.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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