Multigram-scale stereoselective synthesis of meso-1,3-butadiene bisepoxide

Article abstract of DOI:10.1081/SCC-120012996

meso-1,3-Butadiene bisepoxide, a potential building block for natural product synthesis and of interest as a toxic metabolite of butadiene, was synthesized in multi-gram scale in two steps from meso-erythritol in good overall yield.

Full text of DOI:10.1081/SCC-120012996

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MULTIGRAM-SCALE STEREOSELECTIVE SYNTHESIS OF
MESO-1,3-BUTADIENE BISEPOXIDE
David J. Claffey a
a Dept. of Pharmaceutical Sciences , University of Colorado Health Sciences Center , 4200 E.
Ninth Avenue, Box C238, Denver, CO, 80262, U.S.A.
Published online: 16 Aug 2006.
To cite this article: David J. Claffey (2002) MULTIGRAM-SCALE STEREOSELECTIVE SYNTHESIS OF MESO-1,3-BUTADIENE
BISEPOXIDE, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
32:19, 3041-3045, DOI: 10.1081/SCC-120012996
To link to this article: http://dx.doi.org/10.1081/SCC-120012996
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 19, pp. 3041–3045, 2002
MULTIGRAM-SCALE
STEREOSELECTIVE SYNTHESIS OF
MESO-1,3-BUTADIENE BISEPOXIDE
David J. Claffey
University of Colorado Health Sciences Center,
Dept. of Pharmaceutical Sciences, 4200 E.
Ninth Avenue, Box C238, Denver, CO 80262, USA
E-mail: david.claffey@uchsc.edu
ABSTRACT
meso-1,3-Butadiene bisepoxide, a potential building block for
natural product synthesis and of interest as a toxic metabolite
of butadiene, was synthesized in multi-gram scale in two steps
from meso-erythritol in good overall yield.
Key Words: Mesobutadiene bisepoxide; Synthesis; Metabo-
lite; Butadiene
INTRODUCTION
meso-1,3-Butadiene bisepoxide (meso-BBO) is a small symmetrical
reactive compound that has significant potential as a building block for
natural product synthesis.[1] It, along with its diastereoisomers, is also of
great interest to toxicologists at present.[2,3] BBO is a highly toxic metabolite
of butadiene, a widely used monomer in the polymer industry. Several
epidemiological studies have suggested an excess mortality for lymphatic
and hematopoetic cancers in the 65,000 workers that are potentially
3041
DOI: 10.1081/SCC-120012996
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3042
CLAFFEY
exposed to butadiene in the United States.[4] Arange of oxygenated
butadiene metabolites, including meso-BBO were synthesized in our labora-
tory by Sharpless epoxidation of 1-tosyloxy-2-hydroxy-3-butene, followed
by treatment with base.[5,6] This procedure sufficed for the milligram quan-
tities of meso-BBO needed for in vitro studies.[6,7] However, it was not
practical to scale-up these reactions for the multi-gram quantities needed
for in vivo inhalation exposure studies, or indeed for multistep organic
syntheses. Asuitable alternative synthesis of meso-BBO could not be
found in the literature. It has been produced as an isomeric mixture,
generally through the epoxidation of butadiene[8] or butadiene monoxide,[9]
or from base catalyzed cyclization of dichlorobutanediol.[10] This commu-
nication will describe a practical synthesis of gram quantities of meso-BBO
in good yield starting from meso-erythritol.
RESULTS AND DISCUSSION
meso-Erythritol 1 was treated with 1.9 equivalents of tosyl chloride in
pyridine. Larger amounts of tosylate generally gave reduced yields. The
reaction easily afforded a mixture of the bis-tosylate 2 in good yield and
adequate purity along with small amounts of mainly mono-, tri-, and tetra-
tosylate (Sch. 1). The reaction mixture did not require any further purifica-
tion, as these by-products would ultimately give non-volatile products
upon reaction with potassium hydroxide. The final step was safely carried
out, by suspending the bis-tosyl reaction mixture in dichloromethane, and
adding 2 equivalents of freshly powdered potassium hydroxide. The result-
ing insoluble potassium tosylate was easily filtered to give a dichloro-
methane solution of the bis-epoxide. The former was concentrated by
evaporation in a fumehood, leaving a more manageable volume of the
epoxide, with trace dichloromethane. The remaining solvent was removed
from the reaction mixture by fractional distillation. The product distilled as
a clear liquid. Its diastereomeric purity (95%) was determined by integration
of the 13C signals of the meso-BBO with those of the diastereomeric
D,L-BBO at ꢀ 43.9 and 50.9 ppm. The identity of the signals of its diaste-
Scheme 1.

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MESO-1,3-BUTADIENE BISEPOXIDE
3043
reoisomers were confirmed by comparison with an NMR spectrum of
D,L-butadiene bisepoxide (Aldrich Chemical Co., Milwaukee, WI). Much
of the D,L-BBO may have been produced as a result of the reaction of the
by-product, 1,3-O-tosyl-erythritol, with KOH. If higher diastereomeric
purity is required, the crude bis-tosylate could be further purified
by recrystallization before reaction with base. meso-BBO required storage
at ꢀ20ꢁC.
Though established synthetic steps were used in this synthesis,[11,12] the
strength of this procedure is that it allows for the synthesis and isolation to a
high degree of physical and optical purity of this highly volatile and toxic
compound to be achieved relatively economically, in good yield, and with a
relatively high degree of safety.
EXPERIMENTAL
Note: meso-BBO is a suspected carcinogen. All operations must be
conducted with adequate safety precautions.
Asolution of meso-erythritol (100 g, 0.82 mol) in pyridine (3000 mL)
was cooled to 5ꢁC with stirring (magnetic). Tosyl chloride (296 g, 1.56 mol)
was added portionwise over 4 h while maintaining the temperature at
5–7ꢁC. Aclear solution resulted which became opaque, 30 min after the
last portion of chloride was added. The mixture was stirred for 12 h at
3–5ꢁC then was allowed to warm to room temperature. The resulting thick
suspension was evaporated under reduced pressure at 50ꢁC to give a thick
orange syrup (ca. 500 mL). This was dissolved in ethyl acetate (2000 mL)
and 5 M HCl was added dropwise with vigorous stirring (magnetic) until
the aqueous solution became acidic. The mixture was poured into a sepa-
rating funnel, the organic portion was removed and washed once with
distilled water (200 mL). The ethyl acetate solution was dried over magne-
sium sulfate, filtered, and evaporated under reduction pressure to give the
crude bis-tosylate as a thick orange syrup (223 g). This was suspended in
dichloromethane (1500 mL) and freshly powdered KOH (56 g, 1 mol) was
added over 30 min with vigorous stirring (magnetic). The mixture was
stirred for 2 h until TLC (silica; ethyl acetate : hexanes 1 : 1) showed that
no bis-tosylate (2) remained (Rf 0.5). The suspension was filtered and the
solid washed with dichloromethane. The dichloromethane was allowed to
evaporate in a fume hood (under a dry ice trap) to give an orange liquid.
This material was distilled under reduced pressure with vigorous stirring
using a fractionating column. meso-BBO (3) distilled as a clear liquid
between 26 and 28ꢁC (30 mmHg) (26 g, 37% yield). H NMR (300 MHz,
1
CDCl3): ꢀ 2.57 (2H, m), 2.70 (2H, m), 2.86 (2H, m). 13C NMR (75 MHz,
CDCl3): ꢀ 44.5, 50.42.

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3044
CLAFFEY
ACKNOWLEDGMENTS
This work was supported in part by agreement 99-5 from the Health
Effects Institute and Lovelace Respiratory Research Institute, Albuquerque,
New Mexico 87185, USA.
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Received in the USASeptember 18, 2001

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