Asymmetric synthesis of chiral δ-lactones containing multiple contiguous stereocenters

Article abstract of DOI:10.1021/ol2012023

A versatile methodology for the asymmetric synthesis of chiral δ-lactones containing multiple contiguous stereocenters has been developed that relies on a series of Evans' aldol, hydroxyl-directed cyclopropanation, methanolysis, and Hg(II) mediated cyclopropane ring-opening reactions for stereocontrol.

Full text of DOI:10.1021/ol2012023

ORGANIC
LETTERS
2011
Vol. 13, No. 14
3592–3595
Asymmetric Synthesis of Chiral
δ-Lactones Containing Multiple
Contiguous Stereocenters
†
†
†
†
~ꢀ
Jennifer Peed, Ignacio Perinan Domınguez, Iwan R. Davies, Matt Cheeseman,
´
†
James E. Taylor, Gabriele Kociok-Kohn, and Steven D. Bull*
‡
,†
€
Department of Chemistry, University of Bath, Bath, BA2 7AY, U.K., and
Department of Chemical Crystallography, University of Bath, Bath, BA2 7AY, U.K.
s.d.bull@bath.ac.uk
Received May 6, 2011
ABSTRACT
A versatile methodology for the asymmetric synthesis of chiral δ-lactones containing multiple contiguous stereocenters has been developed that relies on
a series of Evans’ aldol, hydroxyl-directed cyclopropanation, methanolysis, and Hg(II) mediated cyclopropane ring-opening reactions for stereocontrol.
The δ-lactone functional group appears as a fragment in
many natural products that exhibit a wide range of biolo-
gical activity.1 Many of these structurally complex δ-lac-
tones contain multiple contiguous stereocenters, which
means that their asymmetric synthesis can represent a
significant challenge.2 Consequently, a wide range of meth-
odology hasbeen developed for theirsynthesis,3 with chiral
N-acyl-oxazolidin-2-ones having often been used to pre-
pare δ-lactones as intermediates for natural product synth-
esis. These protocols are generally based on the stereoselective
addition of enolates of chiral N-acyl-oxazolidin-2-ones to
enantiopure electrophiles4 or stereoselective aldol reactions
of chiral β-keto-N-acyl-oxazolidin-2-one enolates.5 We
now report herein an alternative strategy that employs a
chiral N-acyl-oxazolidin-2-one to prepare enantiomeri-
cally pure cyclopropane esters that undergo regioselective
Hg(II) ring-openingreactionstoaffordδ-lactonescontain-
ing up tofourcontiguous stereocenters withexcellentlevels
of stereocontrol.
We have recently reported the development of novel
synthetic strategies that employ the reversible generation of
“temporary stereocenters” for the asymmetric synthesis of
chiral aldehydes.6 One of these protocols employs highly
diastereoselective hydroxyl-directed syn-cyclopropanation
reactions of β-alkenyl-β-hydroxyl-N-acyl-oxazolidin-2-ones
1 as a key reaction (Scheme 1, reaction 1) for the asymmetric
synthesis of chiral cyclopropane carboxaldehydes.7 It has
† Department of Chemistry.
‡ Department of Chemical Crystallography.
(1) (a) Chiu, P.; Leung, L. T.; Ko, C. B. B. Nat. Prod. Rep. 2010, 27,
1066–1083. (b) Florence, G. J.; Gardner, N. M.; Paterson, I. Nat. Prod.
Rep. 2008, 25, 342–375. (c) Boucard, V.; Broustal, G.; Campagne, J. M.
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Smith, A. B., III; Beauchamp, T. J.; LaMarche, M. J.; Kaufman, M. D.;
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Leadlay, P. F.; Staunton, J. Tetrahedron Lett. 1998, 39, 9827–9830. (d)
Mukai, C.; Hirai, S.; Hanaoka, M. J. Org. Chem. 1997, 62, 6619–6626.
(3) (a) El-Awa, A.; Mollat du Jourdin, X.; Fuchs, P. L. J. Am. Chem.
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A. D. Org. Biomol. Chem. 2004, 2, 3385–3400.
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(6) Niyadurupola, D. G.; Davies, I. R.; Wisedale, R.; Bull, S. D. Eur.
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P.; Johnson, A, L.; Bull, S. D. Org. Biomol. Chem. 2009, 7, 3537–3548. (c)
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Feuillet, F. J. P.; Johnson, A. L.; Bull, S. D. Chem. Commun. 2005, 2372–
2374. (e) Green, R.; Cheeseman, M.; Duffill, S.; Merritt, A.; Bull, S. D.
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r
10.1021/ol2012023
Published on Web 06/14/2011
2011 American Chemical Society

Scheme 1. Synthesis and Ring-Opening Reactions of a Range of
Chiral Cyclopropanes and Epoxides
Scheme 2. Treatment of Cyclopropane-Aldol 2a with
Hg(OCOCF3)2 Results in Intramolecular Cyclopropane Ring
Opening and Dehydration To Afford R,β-Unsaturated Lactone 9
been reported that treatment of γ-cyclopropyl carboxylic
acid derivatives such as 3 with Hg(II) salts results in
regioselective cyclopropane ring opening to afford δ-lac-
tones such as 4 (Scheme 1, reaction 2).8 We have also
reported that treatment of β-alkenyl-β-hydroxy-N-acylox-
azolidin-2-ones with VO(acac)2 and tert-butyl hydroper-
oxide results in formation of unstable epoxides 5, which
are ring opened by intramolecular nucleophilic attack of
their exocyclic carbonyl fragments to afford hydroxy-γ-
butyrolactones 6 (Scheme 1, reaction 3).9 Consequently,
it was decided to investigate whether treatment of β-
cyclopropyl-β-hydroxyl-N-acyl-oxazolidin-2-ones 2 with
a Hg(II) species would result in regioselective intra-
molecular ring opening of their cyclopropane rings to
afford chiral δ-lactones containing up to four contiguous
stereocenters.
8a/b10 withtheircorresponding R,β-unsaturated aldehydes
(Table 1).11 These aldols 1aꢀh were then cyclopropanated
via treatment with Et2Zn and CH2I2 to afford cyclopropyl-
aldols 2aꢀh in >95% de (Table 1).12 Treatment of cyclo-
propyl-aldol 2a with 1 equiv of Hg(OCOCF3)2 in CH2Cl2
resulted in regioselective ring-opening of the cyclopropane
ring to afford a 50:50 mixture of the organomercurial R,
β-unsaturated lactone 9 and the parent oxazolidin-2-one 7
(Scheme 2). It is proposed that coordination of Hg(II) to
the cyclopropane ring of 2a facilitates intramolecular
nucleophilic attack by the endocyclic carbonyl group,
resulting in regioselective ring opening of the cyclopropane
ring. This affords an iminium species 10 that undergoes a
rapid E1cB elimination reaction to afford R,β-unsaturated
lactone 9 (Scheme 2).
Since oxymercuration of β-cyclopropyl-β-hydroxy-
N-acyl-oxazolidin-2-one 2a had resulted in the loss of
two stereocenters, we decided to investigate oxymercura-
tion of its corresponding methyl ester 11a, with the aim of
isolating a δ-lactone 12a retaining all four stereocenters.
Therefore, treatment of cyclopropyl-aldol 2a with sodium
methoxide gave ester 11a that was subsequently treated
with Hg(OCOCF3)2 to afford the desired δ-lactone 12a in
good yield (Scheme 3). Reductive demercuration8d of
δ-lactone 12a via treatment with a solution of NaBH4 in
aqueous NaOH/MeOH resulted in δ-lactone 14a, whose
absolute configuration was confirmed by X-ray crystal-
lography which clearly showed the (3S,4R,5R,6R)-config-
uration of its four contiguous stereocenters (Figure 1).
Aseriesof(syn)-and(anti)-aldols 1aꢀhwere prepared via
literature procedures, involving reaction of boron or mag-
nesium enolates of 5,5-dimethyl-N-acyl-oxazolidin-2-ones
(8) (a) Meyer, C.; Blanchard, N.; Defosseux, M.; Cossy, J. Acc.
Chem. Res. 2003, 36, 766–772. (b) Defosseux, M.; Blanchard, N.; Meyer,
C.; Cossy, J. Tetrahedron 2005, 61, 7632–7653. (c) Cossy, J.; Blanchard,
N.; Meyer, C. Org. Lett. 2001, 3, 2567–2569. (d) Collum, D. B.;
Mohamadi, F.; Hallock, J. S. J. Am. Chem. Soc. 1983, 105, 6882–6889.
(9) See: Davies, I. R.; Cheeseman, M.; Green, R.; Mahon, M. F.;
Merritt, A.; Bull, S. D. Org. Lett. 2009, 11, 2896–2899 and references
cited therein.
(10) For selected reports on the use of 5,5-dimethyloxazolidin-2-ones
(SuperQuat) for asymmetric synthesis, see: (a) Bull, S. D.; Davies, S. G.;
Garner, A. C.; Kruchinin, D.; Key, M. S.; Roberts, P. M.; Savory, E. D.;
Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2006, 4, 2945–2964. (b)
Bull, S. D.; Davies, S. G.; Key, M. S.; Nicholson, R. L.; Savory, E. D.
Chem. Commun. 2000, 1721–1722. (c) Bull, S. D.; Davies, S. G.; Jones,
S.; Sanganee, H. J. J. Chem. Soc., Perkin Trans. 1 1999, 387–398.
Org. Lett., Vol. 13, No. 14, 2011
3593

Table 1. Asymmetric Synthesis of Chiral δ-Lactones Containing Multiple Contiguous Stereocenters
a Isolated yields. b Isolated yields over two steps.
Itisproposed thattheoxymercuration reaction ofester11a
proceeds via a different mechanism to 2a involving nucleo-
philic attack of the trifluoroacetate counterion at its
cyclopropane ring to afford intermediate 13, which is
hydrolyzed upon workup to afford the observed δ-lactone
12a (Scheme 3).13 This occurs because the ester group of
11a is a poorer nucleophile than the corresponding N-acyl-
oxazolidin-2-one fragment of 2a and therefore is less likely
3594
Org. Lett., Vol. 13, No. 14, 2011

Scheme 3. Treatment of Methyl Ester 11a with Hg(OCOCF3)2
Results in Intramolecular Cyclopropane Ring Opening To
Afford δ-Lactone 12a
Scheme 4. Asymmetric Synthesis of (þ)-Prelactone B
We have used this methodology to prepare (þ)-Prelac-
tone B 15, which is a highly functionalized δ-lactone that
has been isolated as a shunt metabolite of polyketide
metabolism from the bafilomycin-producing organism Strep-
tomyces griseus.18 Therefore, the boron enolate of R-chlor-
opropionyl-N-acyl-oxazolidin-2-one 8c was reacted with
(E)-4-methylpent-2-enal to afford (syn)-aldol 16, which
was converted into cyclopropyl ester 17 via a series of
cyclopropanation, dechlorination,19 and methanolysis
reactions. Subsequent treatment of 17 with Hg(OCOCF3)2/
NaCl(aq), followed by reductive demercuration with alka-
line NaBH4, resulted in formation of (þ)-Prelactone B 15 in
>95% de (Scheme 4).20
Figure 1. X-ray crystal structure of (3S,4R,5R,6R)-δ-lactone 14a.
In conclusion, we have developed a versatile metho-
dology for the asymmetric synthesis of chiral δ-lactones
containing up to four contiguous stereocenters. This
approach relies on a combination of Evans’ aldol,
cyclopropanation and Hg(II)-mediated cyclopropane
ring-opening reactions for stereocontrol, with its utility
having been demonstrated for the asymmetric synthesis
of (þ)-Prelactone B.
to participate as an anchimeric nucleophile to facilitate
intramolecular cyclopropane ring opening.
In order to demonstrate the scope and limitation of this
methodology, the remaining cyclopropyl aldols 2bꢀh were
converted into their corresponding methyl esters 11bꢀh
and subjected to oxymercuration/reductive demercuration
to afford a series of δ-lactones 14bꢀh in >95% de
(Table 1). Access to δ-lactone 14g is particularly note-
worthy since its terminal O-benzyl group will enable it
to function as a bifunctional chiral building block for
introducing (syn)-(syn)-(anti)-stereotetrad fragments into
analogues of numerous polyketide natural products.14
Acknowledgment. We would like to thank the EPSRC
and the University of Bath for funding.
Supporting Information Available. Experimental de-
tails, spectroscopic data, and crystal data. This material is
available free of charge via the Internet at http://pubs.acs.
org.
(11) See: (a) Ref 7. (b) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.;
Downey, C. W. J. Am. Chem. Soc. 2002, 124, 392–393. (c) Caddick, S.;
Parr, N. J.; Pritchard, M. C. Tetrahedron Lett. 2000, 41, 5963–5966.
(12) See: (a) Ref 7. (b) Son, J. B.; Hwang, M. H.; Lee, W.; Lee, D. H.
Org. Lett. 2007, 9, 3897–3900.
(13) For a report where the trifluoroacetate counterion of Hg-
(OCOCF3)2 acts as a nucleophile to facilitate ring opening of a cyclo-
propane ester, see: Ref 8d.
(14) Koskinen,A.M.P.;Karisalmi,K.Chem. Soc. Rev. 2005,34, 677–690.
(15) It was found that 5,5-dimethyloxazolidin-2-one 7 (SuperQuat)
coeluted with methyl ester 11f, therefore Evans auxiliary was used.
(16) An alternative method was used for the synthesis of aldol 1g
using Et3N instead of N(iPr)2Et. For synthesis of (E)-4-(benzyloxy)but-
2-enal see: Anderson, J. C.; McDermott, B. P.; Griffin, E. J. Tetrahedron
2000, 56, 8747–8767.
(17) (anti)-Aldol 1h was prepared via treatment of the magnesium
enolate of N-acyl-oxazolidin-2-one 8a with cinnamaldehyde, see ref 11b.
(18) (a) Boddien, C.; Gerber-Nolte, J.; Zeeck, A. Liebigs Ann. 1996,
1381–1384. (b) Bindseil, K. U.; Zeeck, A. Helv. Chim. Acta 1993, 76,
150–157.
(19) Crich, D.; Jiao, X.-Y.; Bruncko, M. Tetrahedron 1997, 53, 7127–
7138.
(20) For previous syntheses of (þ)-Prelactone B see: Li, Y.-J.; Hung,
H-Y; Liu, Y.-W.; Lin, P.-J.; Huang, H.-J. Tetrahedron, 2011, 67, 927-935
and references cited therein.
Org. Lett., Vol. 13, No. 14, 2011
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