Medium ring stereocontrol in the functionalisation of eight-membered lactones

Article abstract of DOI:10.1016/S0040-4039(99)01988-7

Medium ring lactones with up to three substituents have been prepared as single diastereoisomers via Claisen rearrangement. Application of medium ring stereocontrol to a γ,δ-unsaturated eight-membered ring lactone prepared by this route enabled the overall diastereoselective functionalisation of all but one of the ring positions. A comparison of the ring-induced selectivity was made with that of the corresponding acyclic hydroxy ester which exhibited an overall reversal of stereoselectivity. This methodology provides access to highly substituted polyketide fragments.

Full text of DOI:10.1016/S0040-4039(99)01988-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 117–121
Medium ring stereocontrol in the functionalisation of
eight-membered lactones
Edward A. Anderson,a Andrew B. Holmes a,∗ and Ian Collins b
aUniversity Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, UK
bMerck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Harlow CM20 2QR, UK
Received 12 October 1999; accepted 19 October 1999
Abstract
Medium ring lactones with up to three substituents have been prepared as single diastereoisomers via Claisen
rearrangement. Application of medium ring stereocontrol to a γ,δ-unsaturated eight-membered ring lactone
prepared by this route enabled the overall diastereoselective functionalisation of all but one of the ring positions.
A comparison of the ring-induced selectivity was made with that of the corresponding acyclic hydroxy ester which
exhibited an overall reversal of stereoselectivity. This methodology provides access to highly substituted polyketide
fragments. © 1999 Elsevier Science Ltd. All rights reserved.
Keywords: asymmetric induction; lactones; stereocontrol; oxygenation.
Medium rings exhibit well-defined conformational preferences1 which lead to impressive diastereo-
selectivity in the functionalisation of these systems.2–5 Substrate control of functionality has been widely
exploited in asymmetric synthesis.6 However, the facial selectivity for medium rings is less predictable
than for smaller ring substrates, and less attention has been focused in this area. Medium ring systems
form the core of many natural products and the reliable stereoselective functionalisation of such rings is
therefore an important and desirable aim. We report here the diastereoselective functionalisation of the
unsaturated eight-membered lactone 1 and the comparison of these results with the corresponding acyclic
hydroxy ester 2.
The lactone 1 has been synthesised via the Claisen rearrangement of a ketene acetal prepared by in
situ thermal selenoxide elimination from a seleno acetal.7 Reaction of 1 with potassium carbonate in
∗
Corresponding author. Tel: +44 1223 336404; fax: +44 1223 336362; e-mail: abh1@cus.cam.ac.uk
0040-4039/00/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)01988-7

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Figure 1. Global minima of the lactone 1 and the enol 3 calculated using Macromodel®. Molecular modelling was carried out
with in vacuo simulation
methanol gave quantitative conversion to the methyl ester 2. The preferred conformation of the lactone
was determined via a Monte Carlo8 conformational search using the MM2 forcefield9 in Macromodel®
version 5.5.10 The global minimum clearly shows that the β-face (as drawn) is more exposed owing to
the cup-like conformation adopted by the lactone ring and should, therefore, be attacked preferentially
(Fig. 1). Similar modelling was carried out on the enol 3 of the lactone 1; the global minimum of the enol
shows that the β-face of the enol double bond is more exposed to electrophilic attack at C-3.
C-3 functionalisation. Functionality at C-3 could be introduced through enolate formation and
subsequent reaction with an electrophile. Certain enolates of eight-membered lactones have been found
to be relatively unstable to elimination to the ketene, and formation of the enolate itself can be
extremely substrate-dependent.11 Hydroxylation of the lactone 1 was accomplished by oxidation of the
potassium enolate (formed by use of KHMDS in toluene) with the Davis oxaziridine,12 followed by
a camphorsulfonic acid quench at −78°C, which gave the hydroxylactone 4 in 91% yield.† When a
saturated ammonium chloride solution was used to quench the reaction at the same temperature the yield
was reduced to 61%. Methylation of the lactone at C-3 was effected using KHMDS in THF to generate
the potassium enolate. Subsequent addition of methyl iodide gave the methyl-substituted lactone 5 in
65% yield. Under the same conditions with toluene as solvent, an inferior yield of 20% was obtained.
Both reactions afforded single diastereomers, the stereochemistries of which were assigned by 1H NMR
nOe experiments (Scheme 1).
C-5–C-6 functionalisation. Dihydroxylation of the double bond of the lactone 1 was effected by treat-
ment with a catalytic quantity of osmium tetroxide and 4 equivalents of N-methylmorpholine-N-oxide
in acetone:pH7 buffer, 4:1.13 The initial dihydroxylation products underwent in situ translactonisation to
give a mixture of diols (Scheme 2). The observed facial selectivity was approximately 19:1 in favour of
attack from the β-face of the lactone (as drawn) in agreement with the modelling prediction. The major
product, following ring-contraction, was the six-membered ring lactone 6. The structures of the lactones
1
were assigned through H NMR and IR evidence; the carbonyl stretching frequencies of the lactones 7
1
and 8 occurred at 1770 cm−1 which is characteristic of five-membered ring lactones. H NMR COSY
experiments also confirmed the ring sizes through assignment of the C-6 protons as endo- or exo-cyclic.
The relative configurations of the lactones were confirmed via 1H NMR nOe enhancements.
†
Full characterisation (1H NMR, COSY, 13C NMR, IR, microanalysis) was obtained on compounds 2, 4, 6, 9 and 10; (1H
NMR, COSY, 13C NMR, IR, mass spectrometry) on compounds 5, 7, 8, and 11.

119
Scheme 1. C3 functionalisation of the lactone 1 with nOe evidence for product stereochemistry
Scheme 2. Dihydroxylation of the lactone 1 with nOe evidence for assignment of stereochemistry of the products 6, 7 and 8
By contrast, the methyl ester 2 predominantly gave the five-membered lactone 8 when subjected to
the same osmylation conditions, with a small amount of 6 also being observed (Scheme 3). Presumably,
direction of attack to the α-face of 2 is mediated by the homoallylic OH group.14,15 The reversal of
selectivity complements the near exclusive attack from the β-face observed upon dihydroxylation of
the lactone 1. No six-membered lactone was formed following attack on the α-face of 2. In contrast
to the formation of the six-membered lactone following dihydroxylation of the β-face of the lactone 1,
the corresponding dihydroxylation of the α-face of 2 afforded only five-membered ring products. This
observation may reflect an unfavourable conformation for cyclisation of the acyclic precursor to the
(unobserved) six-membered product.
Scheme 3. Dihydroxylation of the methyl ester 2
Epoxidation of the unsaturated lactone 1 was carried out using m-CPBA in CH2Cl2. The epoxide
9 was isolated as a single diastereomer in 81% yield. The configuration of the epoxide was again
1
determined by H NMR nOe enhancements to be the product of attack on the β-face of the olefin, as

120
predicted. The epoxylactone was opened with methanolic potassium carbonate to give the epoxyester
10 in quantitative yield. This sequence is to be compared with the epoxidation of the acyclic olefin 2
which gave a mixture of epoxides 10 and 11, the identities of which were confirmed by comparison with
the spectra of 10 prepared via lactone epoxidation/ring opening (Scheme 4). Interestingly, the overall
selectivity of functionalisation was again reversed for the methyl ester compared with the lactone. The
ratio of products 10:11 was 1:1.75, a lower selectivity for epoxidation of 2 from the α-face than that of
dihydroxylation.
Scheme 4. Epoxidation of the lactone 1 and methyl ester 2
Conclusion. The conformational preference of the lactone 1 enabled highly diastereoselective functio-
nalisation at the C-3, C-5 and C-6 positions. The stereochemistries of all products were unambiguously
determined via nOe experiments. High facial selectivity was observed for reaction of the lactone double
bond compared with the acyclic methyl ester 2 which showed a reversal of diastereoselectivity. This
powerful methodology enables reliable functionalisation of eight-membered lactones at all of the availa-
ble ring positions. Investigation is ongoing into highly functionalised fragments of this type, which may
serve as precursors for polyketides and other natural products.
Acknowledgements
We thank the EPSRC for supporting this research and provision of the Swansea Mass Spectrometry
Service, Merck Sharp and Dohme for a CASE award (to E.A.A.), and Pfizer (Sandwich) for financial
support. We thank Dr. I. Paterson for helpful suggestions.
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