Synthesis of enantiopure isoprene epoxides from (s)-lactic acid via 'dispoke' intermediates

Article abstract of DOI:10.1039/b002133o

'Dispoke protected lactate' derived from (S)-lactic acid was converted into the enantiopure isoprene epoxides (S)2-ethenyl-2-methyloxirane and (2R,2'S)-2-methylbioxirane.

Full text of DOI:10.1039/b002133o

Synthesis of enantiopure isoprene epoxides from (S)-lactic acid via ‘dispoke’
intermediates
Daping Zhang,a Christine Bleasdale,a Bernard T. Golding*a and William P. Watsonb†
a Department of Chemistry, Bedson Building, University of Newcastle upon Tyne, Newcastle upon Tyne, UK
NE1 7RU. E-mail: b.t.golding@ncl.ac.uk
b Shell International Chemicals BV, Shell Research and Technology Centre Amsterdam, Toxicology Department,
PO Box 38000, 1030BN Amsterdam, The Netherlands
Received (in Liverpool, UK) 14th March 2000, Accepted 9th May 2000
‘Dispoke protected lactate’ derived from (S)-lactic acid was
converted into the enantiopure isoprene epoxides (S)-
2-ethenyl-2-methyloxirane and (2R,2AS)-2-methylbioxirane.
effect of the methyl group. We have previously shown
stereochemical differences between rat, mouse and human in
the formation of the mono-epoxides of isoprene by liver
preparations in vitro.13
The mechanistic toxicology of isoprene is a subject of
considerable current importance.1 In this context, samples of
single enantiomers of isoprene epoxides are required for the
preparation of reference standards of DNA adducts. We
describe efficient syntheses of enantiomerically pure (S)-
2-ethenyl-2-methyloxirane 1 and (2R,2AS)-2-methylbioxirane 2,
using as starting material the ‘dispoke protected lactate’ 3
derived from (S)-lactic acid.2 An eight-step synthesis of (S)-
A key intermediate for the preparation of (S)-2-ethenyl-
2-methyloxirane 1 is (S)-2-hydroxy-2-methylbutenoic acid 4.
Several approaches to prepare 4 in enantiopure form were tried
using Evans’ chiral oxazolidinone chemistry,14 but none were
successful. Furthermore, we were unable to resolve racemic
2-hydroxy-2-methylbutenoic acid, either via diastereoisomeric
salts with optically active amines, or by lipase-catalysed
hydrolysis of its esters. The failure of these approaches may be
due to the similarity of the methyl and vinyl groups, which leads
to diastereoisomers derived from 2-hydroxy-2-methylbutenoic
acid having similar physical and chemical properties. However,
(S)-2-hydroxy-2-methylbutenoic acid 4 could be readily pre-
pared from the ‘dispoke protected lactate’ 3 (Scheme 1).‡ Ley
and his coworkers2 have shown that condensation with
acetaldehyde of the carbanion derived by deprotonation of 3
with LDA gives predominately diastereoisomer 5. We con-
verted 5 into its triflate 6, which underwent smooth DBU-
induced elimination to 7. Deprotection of 7 by treatment with
95% TFA gave (S)-2-hydroxy-2-methylbutenoic acid 4. The
synthesis of 1 was completed by reduction of 4 to (S)-
2-methylbut-3-ene-1,2-diol 8, tosylation of 8 to 9, treatment of
9 with base and direct distillation of 1 from the reaction mixture
in the manner described.15 The high enantiomeric purity of 1
{[a]D + 17.6 (c 6.2 g/100 ml in ethyl acetate at 19 °C)} was
confirmed using 1H NMR spectroscopy in conjunction with the
chiral shift reagent europium tris[3-(heptafluoropropylhydroxy-
methylene)-(2)-camphorate] in deuterioacetonitrile.
2-(1-methylethenyl)oxirane (88% ee) from -mannitol has been
D
reported.3 This was oxidised with MCPBA to a mixture of
(2S,2AR)- and (2R,2AR)-2-methylbioxirane.
There is concern about the toxicology of isoprene because of
its structural similarity to buta-1,3-diene, which is a multi-organ
carcinogen in rodents.4,5 This has raised the question of the
effect of the methyl group in isoprene on its toxicity and
carcinogenic potential. Studies with isoprene have shown that
its carcinogenicity towards rodents is much lower than buta-
1,3-diene.6 It is therefore important to determine the sig-
nificance of these findings for the cancer risk from human
exposures to isoprene, which are unavoidable because isoprene
is produced during normal metabolism.7,8 Human exposures
can also occur due to the presence of isoprene in tobacco
smoke,9 automobile exhaust gases,9 emissions from plants and
trees10 and industrial sources.11
In vitro studies have shown that the mammalian metabolism
of isoprene is similar to that of buta-1,3-diene and involves
cytochrome P450 oxidation to mono- and then di-epoxides,
which may be metabolites responsible for toxicity. It is
important to clarify the influence of the stereochemistry of these
epoxides on isoprene’s toxicology, as well as determining the
(2R,2AS)-2-Methylbioxirane 2, was also readily prepared
from the ‘dispoke protected lactate’ 3. Condensation of the
carbanion derived by deprotonation of 3 with LDA with
2-(4-methoxybenzyloxy)acetaldehyde16 gave predominately
diastereoisomer 10, which was converted into lactone 11 by
treatment with 95% TFA. Reduction of 11 to tetraol 12 was
† Present address: AstraZeneca Central Toxicology Laboratory, Alderley
Park, Alderley Edge, Cheshire, UK SK10 4TJ.
Scheme 1 Synthesis of (S)-2-ethenyl-2-methyloxirane 1. Reagents and conditions: i, LDA + DMPU/BunLi in THF; MeCHO, 93% (cf. ref. 2); ii, triflic
anhydride/pyridine in CH2Cl2, 100%; iii, DBU in CH2Cl2 71%; iv, 95% TFA, 88%; v, LiAlH4 in diethyl ether, 100%; vi, TsCl/pyridine in toluene, 51%; vii,
NaOCH2CH2OH in HOCH2CH2OH, 80%.
DOI: 10.1039/b002133o
Chem. Commun., 2000, 1141–1142
This journal is © The Royal Society of Chemistry 2000
1141

Scheme 2 Synthesis of (2R,2AS)-2-methylbioxirane 2. Reagents and conditions: i, LDA + DMPU/BunLi in THF; pmbOCH2CHO, 73%; ii, 95% TFA, 78%;
iii, NaBH4 in MeOH, 100%; iv, MsCl in pyridine, 37%; v, NaOCH2CH2OH in HOCH2CH2OH, 49% (pmb = p-methoxybenzyl).
3 D. Wistuba, K. Weigand and H. Peter, Chem. Res. Toxicol., 1994, 71,
336; [this paper refers to (S)-2-ethenyl-2-methyloxirane, prepared from
followed by selective mesylation of the primary hydroxy groups
to give 13 and finally base-induced ring closures to diepoxide 2.
(S)-2-methylbut-3-ene-1,2-diol, but gives no information on the source
The resulting 2 {[a]D 20.4 (c 5.8 g/100 ml ethyl acetate at
of the latter compound].
19 °C)} was shown to be enantiomerically and diastereomer-
4 P. E. Owen and J. R. Glaister, Environ. Health Perspect., 1990, 86,
19.
5 R. L. Melnick and M. C. Kohn, Carcinogenesis, 1995, 16, 157.
6 P. G. Gervasi, L. Citti, M. Del Monte, V. Longo and D. Benetti, Mutat.
Res., 1985, 156, 77.
7 J. P. Conkle, B. J. Camp and B. E. Welsch, Arch. Environ. Health, 1975,
30, 290.
8 Isoprene is detectable in human breath (0.15 mmol kg21 h21): D.
Gelmont, R. D. Stein and J. F. Mead, Biochem. Biophys. Res. Commun.,
1981, 99, 1456.
9 T. E. Graedel, D. T. Hawkins and L. D. Claxton, Atmospheric Chemical
Compounds. Sources, Occurrence and Bioassay, Academic Press,
Orlando, FL, p. 145.
10 F. Loreto and T. D. Sharkey, Plants Cell Environ., 1993, 16, 563.
11 US National Institute for Occupational Safety and Health (1993)
National Occupational Exposure Survey (1981–1983), Cincinnati,
OH.
1
ically pure using H NMR spectroscopy with the same chiral
shift reagent as above. A racemic reference sample of both
diastereoisomers of 2-methylbioxirane was prepared from rac-
2-ethenyl-2-methyloxirane by oxidation with MCPBA in di-
chloromethane.3
The work described herein makes the isoprene epoxides 1
and 2 available in sufficient amounts for the preparation of
adduct standards from proteins and DNA. The kinetics and
mechanisms of biologically relevant reactions of isoprene
epoxides are currently under study in our laboratory.
This work was supported by Shell International Chemicals
BV. We thank Professor S. V. Ley for a helpful discussion.
12 P. Gervasi and V. Longo, Environ. Health. Perspect., 1990, 86, 85.
13 R. D. Small, B. T. Golding and W. P. Watson, Xenobiotica, 1997, 27,
1155.
14 D. A. Evans, T. C. Britton, J. A. Ellman and R. L. Dorow, J. Am. Chem.
Soc., 1990, 112, 4011.
Notes and references
‡ All new compounds gave analytical and spectroscopic data in accord with
their assigned structure.
15 M. K. Ellis, B. T. Golding, A. B. Maude and W. P. Watson, J. Chem.
Soc., Perkin Trans. 1, 1991, 747.
16 Prepared from rac-2,2-dimethyl-1,3-dioxolane-4-methanol (‘solketal’)
by a sequence of p-methoxybenzylation, acidic hydrolysis and periodate
oxidation.
1 National Toxicology Programme TR-486, Toxicology and Carcinoge-
nesis Studies of Isoprene (CAS No. 78-79-5) in F344/N Rats, 1997.
2 G.-J. Boons, R. Downham, K. S. Kim, S. V. Ley and M. Woods,
Tetrahedron, 1994, 50, 7157.
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Chem. Commun., 2000, 1141–1142