Efficient asymmetrie synthesis of chiral hydroxy-y-butyrolactones

Article abstract of DOI:10.1021/ol9008365

Treatment of β-vinyl-β-hydroxy-N-acyloxazolidin-2-ones with VO(acac)₂ and tert-butyl hydroperoxide results In formation of unstable epoxides that are ring-opened by intramolecular nucleophilic attack of their exocyclic carbonyl fragments to aff

Full text of DOI:10.1021/ol9008365

ORGANIC
LETTERS
2009
Vol. 11, No. 13
2896-2899
Efficient Asymmetric Synthesis of Chiral
Hydroxy-γ-butyrolactones
Iwan R. Davies,† Matt Cheeseman,† Rachel Green,† Mary F. Mahon,‡
Andrew Merritt,§ and Steven D. Bull*,†
Department of Chemistry, UniVersity of Bath, BA2 7AY, U.K., Department of Chemical
Crystallography, UniVersity of Bath, BA2 7AY, U.K., and GlaxoSmithKline Research
and DeVelopment, Medicines Research Centre, Gunnels Wood Road, SteVenage,
Hertfordshire SG1 2NY, U.K.
s.d.bull@bath.ac.uk
Received April 23, 2009
ABSTRACT
Treatment of ꢀ-vinyl-ꢀ-hydroxy-N-acyloxazolidin-2-ones with VO(acac)2 and tert-butyl hydroperoxide results in formation of unstable epoxides
that are ring-opened by intramolecular nucleophilic attack of their exocyclic carbonyl fragments to afford highly functionalized trisubstituted
hydroxy-γ-butyrolactones in >95% de, with a polymer-supported oxazolidin-2-one having been used to transfer this methodology to the solid
phase.
A large number of natural products containing chiral trisub-
stituted γ-butyrolactone fragments have been isolated that
exhibit a broad range of activity against different biological
targets.1 Enantiopure trisubstituted γ-butyrolactones have also
been used as chiral building blocks for natural product
syntheses,2 with a wide range of methodology having been
developed for their asymmetric synthesis.3 Given this interest,
we now report that hydroxyl-directed epoxidation of ꢀ-hy-
droxy-ꢀ-vinyl-N-acyloxazolidin-2-ones results in a highly
efficient methodology for the stereoselective synthesis of
trisubstituted hydroxy-γ-butyrolactones.4
We have recently reported the development of novel
synthetic strategies to reversibly generate “temporary ste-
reocenters” for the asymmetric synthesis of chiral aldehydes.5
This methodology relies on the use of highly diastereose-
lective substrate directable cyclopropanation and hydrogena-
tion reactions of ꢀ-hydroxy-ꢀ-vinyloxazolidin-2-ones 2 for
(3) (a) Yamauchi, C.; Kuriyama, M.; Shimazawa, R.; Morimoto, T.;
Kakiuchi, K.; Shirai, R. Tetrahedron 2008, 64, 3133. (b) Fillion, E.; Carret,
S.; Mercier, L. G.; Trepanier, V. E. Org. Lett. 2008, 10, 437. (c) Cailleau,
T.; Cooke, J. W. B.; Davies, S. G.; Ling, K. B.; Naylor, A.; Nicholson,
R. L.; Price, P. D.; Roberts, P. M.; Russell, A. J.; Smith, A. D.; Thomson,
J. E. Org. Biomol. Chem. 2007, 5, 3922. (d) Ghosh, M. Tetrahedron 2007,
63, 11710. (e) Garnier, J. M.; Robin, S.; Guillot, R.; Rousseau, G.
Tetrahedron: Asymmetry 2007, 18, 1434.
† Department of Chemistry, University of Bath.
‡ Department of Chemical Crystallography, University of Bath.
§ GlaxoSmithKline Research and Development.
(4) (a) Chamberlin, A. R.; Dezube, M. Tetrahedron Lett. 1982, 23, 3055.
(b) Chamberlin, A. R.; Dezube, M.; Reich, S. H.; Sall, D. J. J. Am. Chem.
Soc. 1989, 111, 6247. (c) Honda, T.; Satoh, A.; Yamada, T.; Hayakawa,
T.; Kanai, K. J. Chem. Soc., Perkin Trans. 1 1998, 397. (d) Dias, L. C.; de
Castro, I. B. D.; Steil, L. J.; Augusto, T. Tetrahedron Lett. 2006, 47, 213.
(e) Shiina, I.; Takasuna, Y.; Suzuki, R.; Oshiumi, H.; Komiyama, Y.; Hitomi,
S.; Fukui, H. Org. Lett. 2006, 8, 5279.
(1) (a) Anticancer: Popsavin, V.; Benedekovic, G.; Sreco, B.; Popsavin,
M.; Francuz, J.; Kojic, V.; Bogdanovic, G. Org. Lett. 2007, 9, 4235. (b)
Antibiotic: Matsumoto, N.; Tsuchida, T.; Maruyama, M.; Kinoshita, N.;
Homma, Y.; Iinuma, H.; Sawa, T.; Hamada, M.; Takeuchi, T.; Heida, N.;
Yoshioka, T. J. Antibiot. 1999, 52, 269. (c) Antifungal: Larrosa, I.; Da Silva,
M. I.; Gomez, P. M.; Hannen, P.; Ko, E.; Lenger, S. R.; Linke, S. R.; White,
A. J. P.; Wilton, D.; Barrett, A. G. M. J. Am. Chem. Soc. 2006, 128, 14042.
(2) (a) Evans, D. A.; Burch, J. D.; Hu, E.; Jaeschke, G. Tetrahedron
2008, 64, 4671. (b) Li, Y.; Hale, K. J. Org. Lett. 2007, 9, 1267. (d) Nicolaou,
K. C.; Harrison, S. T. J. Am. Chem. Soc. 2007, 129, 429.
(5) (a) Cheeseman, M.; Feuillet, F. J. P.; Johnson, A. L.; Bull, S. D.
Chem. Commun. 2005, 2372. (b) Green, R.; Cheeseman, M.; Duffill, S.;
Merritt, A.; Bull, S. D. Tetrahedron Lett. 2005, 46, 7931. (c) Cheeseman,
M.; Bull, S. D. Synlett 2006, 1119. (d) Niyadurupola, D. G.; Davies, I. R.;
Wisedale, R.; Bull, S. D. Eur. J. Org. Chem. 2007, 5487.
10.1021/ol9008365 CCC: $40.75
Published on Web 06/10/2009
 2009 American Chemical Society

stereocontrol. Consequently, it was decided to explore
whether carrying out hydroxyl-directed epoxidation reactions
on these types of substrates could be used to develop a
“temporary stereocenter” methodology for the asymmetric
synthesis of chiral R,ꢀ-epoxy-aldehydes 3 (see Scheme 1).
Scheme 2
.
Stereoselective Epoxidation of ꢀ-Vinyl-syn-aldol 2a
Affords Lactone (S,S,S)-8a
Scheme 1. Proposed “Temporary Stereocenter” Approach for
the Asymmetric Synthesis of Chiral R,ꢀ-Epoxy
Carboxaldehydes 3
with lactone 8a being isolated in good yield once more. This
implies that intramolecular 5-exo-tet ring-opening of epoxide
4a occurs very rapidly under these conditions. It was also
shown that N-acyloxazolidin-2-one 1 was stable under these
epoxidation conditions, with no oxazolidin-2-one 7 being
formed, suggesting that hydrolysis of the oxazolidin-2-one
fragment of aldol 2a does not occur prior to epoxidation.
Finally, we note that the ability of an N-acyloxazolidin-2-
one fragment to participate as an intramolecular nucleophile
in this manner has been invoked previously to explain the
stereochemical outcome of related iodolactonization reactions
of ꢀ-vinyl-N-acyloxazolidin-2-ones.12
In order to investigate the scope and limitation of this
epoxidation/lactonization methodology, we prepared a series
of ꢀ-vinyl-syn-aldols 2b-i containing alkene fragments with
different substitution patterns.7 syn-Aldols 2b-h were then
treated with 10 mol % of VO(acac)2 and 1 equiv of tert-
butyl hydroperoxide in benzene to afford seven hydroxylated
lactones 8b-h in >90% de and 74-84% isolated yield
(Table 1).13 The diastereoselectivity observed in directed
epoxidation reactions of these types of allylic alcohols is well
established14 and known to be highly dependent on the
substitution pattern of their alkene functionality.15 Therefore,
A1,2 strain is known to dominate for 1-substitued alkenes
Epoxidation of the 1,1-disubstituted alkene functionalities
of secondary allylic alcohols using VO(acac)2 and tert-butyl
hydroperoxide has been shown to proceed with high levels
of erythro diastereoselectivity.6 However, we found that
treatment of ꢀ-vinyl-syn-aldol 2a7 with 10 mol % of
VO(acac)2 and 1 equiv of tert-butyl hydroperoxide in
benzene at room temperature did not result in the expected
erythro-epoxide 4a,8,9 but instead gave a 1:1 mixture of 5,5-
dimethyloxazolidin-2-one 7 and lactone 8a whose configu-
ration was confirmed as (S,S,S) by X-ray crystallographic
analysis.
This outcome is consistent with the reaction mechanism
outlined in Scheme 2,10 where hydroxyl-directed epoxidation
of 2a is predicted to afford an erythro-epoxide 4a. This
unstable epoxide is then ring-opened by intramolecular
nucleophilic attack of the exocyclic carbonyl of its N-acyl
fragment with inversion of configuration at C4 to afford an
unstable iminium species 5 (that may be stabilized via
reversible formation of N,O,O-orthoester 6) which is hydro-
lyzed on workup.11 Attempts to intercept the intermediate
-
epoxide 4a via addition of a good nucleophile (EtSH, N3 )
(11) An alternative mechanism involving intramolecular 6-endo-tet ring-
opening of erythro-epoxide 4a with retention of configuration at C4 was
discounted because rearrangement of the resultant δ-lactone would have
afforded a diastereoisomeric (2S,3S,4R)-γ-lactone; see: (a) Nacro, K.; Baltas,
M.; Escudier, J. M.; Gorrichon, L. Tetrahedron 1997, 53, 659. (b) Nacro,
K.; Baltas, M.; Zedde, C.; Gorrichon, L.; Jaud, J. Tetrahedron 1999, 55,
5129. (c) Nacro, K.; Gorrichon, L.; Escudier, J. M.; Baltas, M. Eur. J. Org.
Chem. 2001, 4247.
to the reaction mixture prior to workup were unsuccessful,
(6) Adam, W.; Mitchell, C. M.; Saha-Moller, C. R. J. Org. Chem. 1999,
64, 3699.
(7) Aldol substrates 2a-i prepared via reaction of the boron or
magnesium enolate of an N-propionyloxazolidin-2-one with the correspond-
ing R,ꢀ-unsaturated aldehyde: (a) Caddick, S.; Parr, N. J.; Pritchard, M. C.
Tetrahedron Lett. 2000, 41, 5963. (b) Evans, D. A.; Tedrow, J. S.; Shaw,
J. T.; Downey, C. W. J. Am. Chem. Soc. 2002, 124, 392.
(12) See: (a) Yokomatsu, T.; Iwasawa, H.; Shibuya, S. J. Chem. Soc.,
Chem. Commun. 1992, 728. (b) Moon, H.; Eisenberg, S. W. E.; Wilson,
M. E.; Schore, N. E.; Kurth, M. J. J. Org. Chem. 1994, 59, 6504. (c) Murat,
Y.; Kamino, T.; Aoki, T.; Hosokawa, S.; Kobayashi, S. Angew. Chem.,
Int. Ed. 2004, 43, 3175. (d) Noguchi, N.; Nakada, M. Org. Lett. 2006, 8,
2039.
(8) For a report of a 50:50 mixture of stable diastereoisomeric epoxides
prepared by epoxidation of a γ,δ-unsaturated N-acyloxazolidin-2-one with
m-chloroperoxybenzoic acid, see: Trova, M. P.; Wissner, A.; Casscles,
W. T., Jr.; Hsu, G. C. Bioorg. Med. Chem. Lett. 1994, 4, 903
.
(9) For aldol reaction of the boron enolate of an Evans’ N-acyloxazolidin-
2-one with an R,ꢀ-epoxy aldehyde that gave a stable γ,δ-epoxy aldol
product, see: Taylor, R. E.; Hearn, B. R.; Ciavarri, J. P. Org. Lett. 2002, 4,
(13) ent-Lactones 8b and 8f have been prepared previously via directed
epoxidation of ꢀ-vinyl-syn-aldol esters; see: (a) McCarthy, P. A. Tetrahedron
Lett. 1982, 23, 4199. (b) Nakata, T.; Fukui, M.; Oishi, T. Tetrahedron Lett.
1988, 29, 2219. (c) Reference 4b.
2953
.
(10) For previous reports of γ,δ-epoxides of tertiary amides cyclizing
to afford γ-lactones, see: (a) Cairns, P. M.; Howes, C.; Jenkins, P. R.;
Russell, D. R.; Sherry, L. J. Chem. Soc., Chem. Commun. 1984, 1487. (b)
Majewski, M.; Snieckus, V. Tetrahedron Lett. 1982, 23, 1343.
(14) Adam, W.; Wirth, T. Acc. Chem. Res. 1999, 32, 703.
(15) Repeated attempts to epoxidize a monosubstituted syn-aldol product
derived from acrolein under these conditions were unsuccessful, affording
only recovered starting material.
Org. Lett., Vol. 11, No. 13, 2009
2897

Table 1. Epoxidation of Aldols 2a-i Using VO(acac)2 and tert-Butyl Hydroperoxide To Afford Hydroxy-γ-butyrolactones 8a-i
a All de’s determined by 1H NMR spectroscopic analysis of crude reaction products. b Yields of lactones 8a-i calculated from aldols 2a-i. c ꢁP
Evans’ (S)-4-benzyloxazolidin-2-one. d Yield of pure diastereoisomer 8i after chromatographic purification.
)
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Org. Lett., Vol. 11, No. 13, 2009

and (E)-1,2-disubstituted alkenes resulting in formation of
erythro-epoxy alcohols, while A1,3 strain dominates for (Z)-
1,2-disubstituted and 1,2,2-trisubstituted alkenes to afford
their corresponding threo-epoxy alcohols. Consequently, the
configuration of unstable epoxides 4b-f (not isolated) were
assigned as erythro, while unstable epoxides 4g,h (not
isolated) were assigned as threo. Therefore, it follows that
subsequent intramolecular ring-opening of epoxides 4b-h
(via mechanism shown in Scheme 2) proceeds with inversion
of configuration at their C4 carbons to afford their corre-
sponding lactones 8b-h.16 All lactones 8b-h were formed
with excellent levels of diastereocontrol (>90% de), as
expected for the high diastereoselectivity predicted for
vanadium-catalyzed hydroxyl-directed epoxidation reactions
of their corresponding ꢀ-vinyl-syn-aldols 2a-h. Conversely,
lactone 8i was formed with poorer diastereoselectivity (33%
de) as expected for epoxidation of ꢀ-vinylaldol 2i, whose
(E)-1,2-disubstituted alkene functionality is known to be
epoxidized with poor levels of erythro diastereocontrol under
these conditions.6
temperature for 3 h, followed by filtration to remove polymer
11 and evaporation of the filtrate, gave a clean sample of
lactone 8a in 58% yield over two steps (Scheme 3).19
Scheme 3. Sequential Polymer-Supported Aldol/Epoxidation/
Lactonization Reactions for the Asymmetric Synthesis of
Lactone (S,S,S)-8a
We then demonstrated that this epoxidation/lactonization
methodology could be transferred to solid support using a
polymer-supported Evans oxazolidin-2-one 917 for synthesis.
Therefore, the boron enolate of polymer 9 was treated with
2-ethylacrolein to afford polymer-supported syn-aldol 10,18
which was characterized by reductive cleavage of the N-acyl
side chain of a small portion of resin with NaBH4 in THF/
H2O to afford chiral alcohol 12 in >95% de. Subsequent
treatment of polymer 10 with 10 mol % of VO(acac)2 and 1
equiv of tert-butyl hydroperoxide in benzene at room
In conclusion, a novel three-step aldol/epoxidation/in-
tramolecular lactonization strategy has been developed for
the synthesis of highly functionalized trisubstituted hydroxy-
γ-butyrolactones with excellent levels of diastereocontrol.
Acknowledgment. We thank the EPSRC and Glaxo-
SmithKline for funding.
(16) A NOESY 1H NMR experiment revealed strong (S) interactions
consistent with the proposed (S,S,S) configuration of γ-lactone 8h, which
implies that all of the epoxides 4a-i are ring-opening via the intramolecular
5-exo-tet pathway shown in Scheme 2.11
Supporting Information Available: Experimental details
and spectroscopic characterization for compounds 2a-i/8a-i
and crystal data for 8a (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
OL9008365
(19) For asymmetric syntheses of chiral lactones using other polymer-
supported chiral auxiliaries, see: (a) Moon, H. S.; Schore, N. E.; Kurth,
M. J. J. Org. Chem. 1992, 57, 6088. (b) Moon, H. S.; Schore, N. E.; Kurth,
M. J. Tetrahedron Lett. 1994, 35, 8915. (c) Kerrigan, N. J.; Hutchinson,
P. C.; Heightman, T. D.; Procter, D. J. Chem. Commun. 2003, 1402. (d)
Kerrigan, N. J.; Hutchinson, P. C.; Heightman, T. D.; Procter, D. J. Org.
Biomol. Chem. 2004, 2, 2476.
(17) See: (a) Green, R.; Taylor, P. J. M.; Bull, S. D.; James, T. D.;
Mahon, M. F.; Merritt, A. T. Tetrahedron: Asymmetry 2003, 14, 2619. (b)
Green, R.; Merritt, A. T.; Bull, S. D. Chem. Commun. 2008, 508.
(18) For other polymer-supported oxazolidin-2-one aldol reactions, see:
(a) Purandare, A. V.; Natarajan, S. Tetrahedron Lett. 1997, 38, 8777. (b)
Phoon, C. W.; Abell, C. Tetrahedron Lett. 1998, 39, 2655.
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