Enantioselective synthesis of alkyl-substituted eight-membered lactones by Claisen rearrangement

Article abstract of DOI:10.1055/s-1999-3099

The Claisen rearrangement of alkenyl-substituted ketene acetals (produced in situ by selenoxide elimination from the corresponding phenylselenoacetaldehyde-derived acetals of enantiomerically pure 1,3-diol derivatives) afforded unsaturated eight-membered lactones with control of stereochemistry of methyl substituents at C-4, C-5 and C-7, as well as a fused system.

Full text of DOI:10.1055/s-1999-3099

972
LETTER
Enantioselective Synthesis of Alkyl-substituted Eight-membered Lactones by
Claisen Rearrangement
Justin R. Harrison,a Andrew B. Holmesa* and Ian Collinsb
a University Chemical Laboratory, Lensfield Road,Cambridge CB2 1EW, UK
b Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Harlow CM20 2QR, UK
Fax +44(1223)336362; E-mail: abh1@cus.cam.ac.uk
Received 29 January 1999
Dedicated to Professor Albert Eschenmoser
product 3a were prepared, and the absolute configuration
Abstract: The Claisen rearrangement of alkenyl-substituted ketene
of the secondary alcohol centre was assigned by 500 MHz
acetals (produced in situ by selenoxide elimination from the
1H NMR analysis following the method of Kakisawa.18
Careful chromatographic purification provided the pure
corresponding phenylselenoacetaldehyde-derived acetals of
enantiomerically pure 1,3-diol derivatives) afforded unsaturated
eight-membered lactones with control of stereochemistry of methyl b-hydroxyketones 3a-c, but compound 3d could not easi-
substituents at C-4, C-5 and C-7, as well as a fused system.
ly be separated from isopinocampheol (arising from the
oxidative work-up of the intermediate borates), and it was
used in the crude form.
Key words: [3.3]-sigmatropic, lactone, aldol, boron, enantioselec-
tive
The b-hydroxyketones
3 were then treated with
Me4NHB(OAc)3 to provide the anti diols 4 in good
yield.19 At -35 °C the reduction was complete in 18 h to
afford a single diastereoisomer as judged by H NMR.
Recent efforts in this laboratory have focused on the syn-
thesis of unsaturated medium ring heterocycles (lactones
and lactams) by the Claisen rearrangement involving a
two-atom ring expansion1 of a vinyl-substituted ketene
acetal2-6 (or aminal).7 Owing to the normal preference for
a chair-like transition state and the constraint of a Z-dou-
ble bond in the medium ring product (Fig. 1; R2 = H) enan-
tiomerically pure disubstituted lactones could be obtained
from the corresponding 1,3-diol precursors.5 Other ap-
proaches to unsaturated lactones have been reviewed in
detail.8-10 Among these lactonizations of seco-acids con-
taining a (Z)-alkene have been employed.6,11 Even a satu-
rated seco-acid containing a (presumably) pre-ordered
conformation has been lactonized efficiently.11 Here we
report that the Claisen ring expansion can be applied to
trisubstituted alkene precursors in the efficient prepara-
tion of unsaturated eight-membered lactones with up to
three substituents in four different positions.
1
However, at -30 °C, reduction of the keto-alcohol 3b af-
forded a diastereoisomeric mixture.
Figure 1 Chair-like transition state for the Claisen rearrangement of
vinyl-substituted ketene acetals derived from1,3-diols.
An Ipc-boron mediated aldol reaction12-14 of the enolate
derived from the ketone 18,11 and the commercially avail-
able aldehydes 2a-d provided the 1,4-syn products 3 in
81-84% yields as single diastereoisomers as judged by
NMR (Scheme 1). (R)-(+)- and (S)-(-)-Phenyl-
methoxy(trifluoromethyl) acetate derivatives of the
Scheme 1
Synlett 1999, S1, 972–974 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Eight-membered Lactones by Claisen Rearrangement
973
The diols 4 were converted with phenylselenoacetalde- In summary, a Claisen ring expansion method for the syn-
hyde diethyl acetal1 in the presence of pyridine 4-toluene- thesis of substituted eight-membered lactones is de-
sulfonate (PPTS) in refluxing toluene into the scribed.22 Furthermore, when combined with the powerful
phenylseleno acetals 5 which were purified by chroma- stereochemical control available from the Paterson boron-
tography. The reaction was slow and required a stoichio- mediated aldol reactions12-14 and the Evans reduction of b-
metric quantity of PPTS for complete reaction.
hydroxy ketones to anti-1,3-diols,19 the method lends it-
self to the construction of lactones such as the
octalactins11 and unusual alkene substitution patterns as
may occur in polyketide antibiotics such as discoder-
molide.23 The latter would be farmore difficult to realise
by acyclic versions of the Claisen rearrangement.
Oxidation of the selenides 5 was achieved with sodium
metaperiodate; the resulting selenoxides were used with-
out chromatographic purification.2-7 Selenoxide elimina-
tion in refluxing xylene at 180 °C (sealed tube) in the
presence of K2CO3 and the ketene acetal 75,7,20 afforded the
8-membered unsaturated lactones 6 together with signifi-
cant amounts of the starting selenides 5 (6-49%) which
were thought to be produced by disproportionation reac-
tions.21 Good yields were obtained when the substrate did
not contain a terminal methyl substituent (see 5a, 5b). The
relative stereochemistry of the substituted lactones 6c and
6d, assigned on the basis of 1H NMR NOE enhancements
observed between H-4 and H-8, is in accord with that pre-
dicted from the chair-like transition state depicted in Fig-
ure 1.
Scheme 2 Reagents and conditions: i, 1, (+)-(Ipc)2BCl, Et3N, Et2O, 0
°C, 2 h; ii, 2e, Et2O, -78 °C 1.5 h; iii, H2O2, pH 7 buffer, MeOH, 25
°C, 1 h; iv, Me4NHB(OAc)3, MeCN, AcOH, -35 °C, 18 h (51%, 2
steps); v, PhSeCH2CH(OEt)2, PPTS, DME, 85 °C, 18 h (67%); vi,
NaIO4, EtOAc, MeOH, H2O (3:6:1), 25 °C ; vii, 7, DBU, m-xylene,
180 °C, sealed tube, 5 h, (55%, 2 steps).
Scheme
3 Reagents and conditions: i, 8, (-)-(Ipc)2BOTf,
iPr2NEt,CH2Cl2, 25 °C, 3 h; methacrolein, -5 °C, 18 h; H2O2, pH 7
buffer, MeOH, 25 °C, 1 h (90 %); ii, 8, (Chx)2BCl, Et3N, Et2O, -78
°C, 3 h; methacrolein,-78 °C, 18 h; H2O2, pH 7 buffer, MeOH, RT,
1 h (72 %); iii, Me4NHB(OAc)3, MeCN, AcOH, -35 °C, 18 h (56-
72%); iv, PhSeCH2CH(OEt)2, PPTS, toluene, 110 °C, 18 h (96-99%);
v, NaIO4, EtOAc, MeOH, H2O (3:6:1), 25 °C; vi, 7, DBU, m-xylene,
180 °C, sealed tube, 2.5-5 h (61-95%).
It was found that the use of DBU instead of K2CO3 as base
in the elimination of the selenoxide from 5a increased the
yield of 6a to 71%, probably owing to the improved solu-
bility of the base in xylene. Carrying the reaction out at
138 °C in refluxing xylene reduced the yield to 61%. The
yield of 6d was improved to 33% by use of DBU and a
longer reaction time.
Acknowledgement
We thank the EPSRC for supporting this work and for the provision
of the Swansea Mass Spectrometry Service, and we thank Merck,
Sharp and Dohme (CASE award to JRH) and Pfizer (Sandwich) for
financial support. We thank Dr I. Paterson for helpful discussions
and Professor R. Baker and Dr L. Castro for their interest in this
work.
Fused bicyclic systems can also be prepared. Thus the
commercially available (-)-perilaldehyde 2e was convert-
ed into the bicyclic lactone 6e in 19% yield over 5 steps
(Scheme 2). Although the double bond in the Claisen pre-
cursor is terminally substituted the yield of the Claisen re-
arrangement (55%) was higher than those recorded for References and Notes
precursors carrying terminal methyl substituents (6c,d).
(1) Petrzilka, M. Helv. Chim. Acta 1978, 61, 3075.
(2) Carling, R. W.; Holmes, A. B. J. Chem. Soc., Chem. Commun.
1986, 565.
(3) Curtis, N. R.; Holmes, A. B.; Looney, M. G. Tetrahedron
1991, 47, 7171.
(4) Congreve, M. S.; Holmes, A. B.; Hughes, A. B.; Looney, M.
G. J. Am. Chem. Soc. 1993, 115, 5815.
(5) Fuhry, M. A. M.; Holmes, A. B.; Marshall, D. R. J. Chem.
Soc., Perkin Trans. 1 1993, 2743.
Use of the ethyl analogue 8 of the methyl ketone 1 in the
aldol reaction with methacrolein in the presence of the
Ipc- (syn-aldol) and dicyclohexyl boron ligands (anti-al-
dol) gave respectively the b-hydroxyketones 9 and 11.14
These products were then converted into the correspond-
ing lactones with a stereodefined methyl substituent at C-
7 (Scheme 3).
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974
J. R. Harrison et al.
LETTER
(6) Burton, J. W.; Clark, J. S.; Derrer, S.; Stork, T. C.; Bendall,
J.G.; Holmes, A. B. J. Am. Chem. Soc. 1997, 119, 7483.
(7) Evans, P. A.; Holmes, A. B.; McGeary, R. P.; Nadin, A.;
Russell, K.; O’Hanlon, P. J.; Pearson, N. D. J. Chem. Soc.,
Perkin Trans. 1 1996, 123.
(8) Moody, C. J.; Davies, M. J. In Studies in Natural Product
Chemistry; Atta-ur-Rahman, Ed.; Elsevier Science: 1992;
Vol. 10; pp201-239.
(9) Elliott, M. C. Contemp. Org. Synth. 1994, 1, 457.
(10) Rousseau, G. Tetrahedron 1995, 51, 2777.
(11) Buszek, K. R.; Sato, N.; Jeong, Y. J. Am. Chem. Soc. 1994,
116, 5511.
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Tetrahedron: Asymmetry 1995, 6, 2613.
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M. A. J. Am. Chem. Soc. 1994, 116, 11287.
(15) Prepared in three steps from commercially available (R)-(+)-
methyl-3-hydroxy-2-methylpropionate following the
published procedure,12 but using the method of Williams et
al.16 for the preparation of the Weinreb amide as first reported
by Paterson and McLeod.17
(16) Williams, J. M.; Jobson, R.B.; Yasuda, N.; Marchesini, G.;
Dolling, U. H.; Grabowski, E. J. J. Tetrahedron Lett. 1995, 36,
5461.
and NaHCO3 (2.9 mmol) in EtOAc-MeOH-water (3:6:1) was
stirred vigorously at ambient temperature for 100 min. The
reaction mixture was poured into water (40 ml) and extracted
with EtOAc (3 x 100 ml). The combined organic phases were
washed with brine, dried (MgSO4) and concentrated to afford
an approximately quantitative yield of the corresponding
selenoxide. A solution of the selenoxide and 1-t-butyldi-
methylsiloxy-1-methoxy ethene 716 (5 mmol) in dry p-xylene
(16.5 ml) with K2CO3 (1.9 mmol) was heated under a nitrogen
atmosphere in a sealed tube at 180 °C for 2.5 h. The organic
phase was removed in vacuo, and the residue was subjected to
flash chromatography on silica gel (15% ether-light petroleum
60-80) to yield a mixture of the selenide 5b (0.091 mmol,
27%) and the lactone 6b (0.22 mmol, 64%). Rf (15% ether-
light petroleum 60-80) 0.23; [a]D21 –13.8 (c 0.3 in CHCl3); 1H
NMR (500 MHz, CDCl3) d 7.21-7.35(5H, m), 5.44 (1H, t J =
8 Hz), 4.45-4.55 (1H, m), 4.50 (2H, s), 3.58 (1H, dd, J = 9, 5
Hz), 3.36 (1H, dd, J = 9, 7 Hz), 2.11 (1H, dt, J = 12, 6 Hz),
2.71 (1H, ddd, J = 13, 6, 3 Hz), 2.50-2.46 (2H, m), 2.01-2.12
(2H, m) 1.94 (1H, ddd, J = 12, 5, 3 Hz), 1.72 (3H, s) and 1.04
(3H, d, J = 7 Hz); 13C NMR (62.5 MHz, CDCl3) d 176.8,
140.3, 138.6,128.3, 127.6, 127.5, 122.3, 81.9, 73.2, 72.2, 37.9,
36.6, 32.2, 29.0, 24.2 and 14.2; IR (CDCl3) 1735, 1454, 1219
and 1074 cm-1; m/z (CI, rel intensity) 306 [100, (M + NH4)+],
289 [70, (MH)], 181 (25), and 85 (45); m/z 289.1804
(289.1804 calcd for C18H25O3, MH).
(17) Paterson, I.; McLeod, M. D. Tetrahedron Lett. 1997, 38, 4183.
(18) Ohtani, I.; Kusumi, T.;Kashman, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092.
(19) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem.
Soc. 1988, 110, 3560.
All other compounds described here showed spectroscopic
and analytical data in accord with the assigned structure.
(23) Gunasekera, S. P.; Gunasekera, M.; Longley, R. E. J.
Org.Chem. 1990, 55, 4912. Ibid 1991, 56, 1346.
(20) Danishefsky, S.; Vaughan, K.; Gadwood, R.; Tsuzuki, K. J.
Am. Chem. Soc. 1981, 103, 4136.
Article Identifier:
(21) Paulmier, C. Selenium Reagents and Intermediates in
Organic Synthesis; Pergamon Press: Oxford, 1987, p. 34 and
pp. 136-137.
1437-2096,E;1999,0,S1,0972,0974,ftx,en;W04399ST.pdf
(22) Representative procedure for the Claisen rearrangement.
A mixture of the acetal 5b (0.342 mmol), NaIO4 (2.1 mmol)
Synlett 1999, S1, 972–974 ISSN 0936-5214 © Thieme Stuttgart · New York