FULL PAPER
Enzyme-Triggered Enantioconvergent Transformation of Haloalkyl Epoxides
Sandra F. Mayer,[a] Andreas Steinreiber,[a] Romano V. A. Orru,[b] and Kurt Faber*[a]
Keywords: Domino reaction / Enantioselectivity / Hydrolases / Umpolung
Biocatalytic hydrolysis of 2,3-disubstituted rac-cis- and rac-
trans-haloalkyl epoxides 1a−8a using the epoxide hydrolase
activity of whole bacterial cells furnished the corresponding
vicinal diols 1b−8b as intermediates; these (spontaneously)
through an enzyme-triggered cascade reaction. In particular,
cis-configured substrates (1a, 3a, 5a, 7a) were transformed in
an enantioconvergent fashion, which resulted in the forma-
tion of single stereoisomeric products in 100% des and up to
underwent ring closure to yield cyclic products 1c−6c 92% ees from the racemates.
Introduction
haloalkyl oxiranes (rac-1aϪ8a) were chosen as substrates in
order to study the influence of the following parameters:
(i) relative cis and trans configuration of the oxirane moiety
(ii) length of the haloalkyl spacer
(iii) choice of halogen
(iv) length of the alkyl chain
Reactions that proceed through more than a single step
in a concurrent fashion Ϫ often designated as ‘‘domino’’
or ‘‘cascade’’ reactions Ϫ display the advantage that final
products can be obtained in good yield despite the fact that
the sequence may involve reactive (and thus often unstable)
intermediates.[1] If the cascade is triggered by a chiral cata-
lyst, such as an enzyme, the stereochemical course of the
whole cascade may be directed in an asymmetric fashion,
resulting in a nonracemic product.[2]
During our study of the asymmetric biohydrolysis of (Ϯ)-
2,3-dialkyloxiranes by bacterial epoxide hydrolases, we dis-
covered that (depending on the stereochemistry of the sub-
strate) only single stereoisomers of the corresponding vic-
inal diols were formed, by enantioconvergent pathways and
in 100% theoretical yield from the racemates.[3] In compar-
ison with kinetic resolution, such ‘‘deracemization’’ pro-
cesses show a considerably improved economic balance and
thus have recently attracted considerable attention.[4] From
previous studies, we knew that functional groups, as long
as they are lipophilic, are tolerated well by bacterial epoxide
hydrolases.[5,6] As an attractive alternative, halogenated
compounds seemed to be ideally suited, particularly in view
of the facilitated CϪC coupling due to umpolung at this
position. Much to our surprise, biohydrolysis did not pro-
duce the expected haloalkyl-substituted vicinal diols, but
furnished epoxides and tetrahydrofuran derivatives in non-
racemic forms.[7]
Substrates were prepared as outlined in Scheme 1. Com-
pounds rac-1aϪ4a, bearing n-butyl groups as the alkyl moi-
eties, were synthesized from acetylenes 9 and 10. Nucleo-
philic addition of the lithium acetylide of 1-hexyne (9) onto
formaldehyde gave the (hydroxymethyl)acetylene 11; the hy-
droxyethyl analogue 12 was prepared by alkylation of 3-
butyne-1-ol (10). Reduction of both compounds by catalytic
hydrogenation (Lindlar) or by LiAlH4 gave stereoiso-
merically pure (Z)- and (E)-alkenes 13a, 13b, 15a, and 15b.
Exchange of the primary hydroxy groups in 13a, 13b, 15a,
and 15b by Cl was accomplished via the corresponding me-
sylates, to furnish 14a, 14b, 16a, and 16b, respectively.
Haloalkenes 17b, 17c, 18b, and 18c were accessed from hy-
droxyalkenes 17a and 18a by replacement of the hydroxy
group with the desired halogen as mentioned above. Finally,
epoxidation of haloalkenes 14a, 14b, 16a, 16b, 17b, 17c, 18b,
and 18c resulted in stereoisomerically pure substrates rac-
cis-1a, 3a, 5a, and 7a and rac-trans-2a, 4a, 6a, and 8a in
good overall yields.
Substrates rac-1aϪ8a were screened for biohydrolysis in
Tris buffer at pH ϭ 8.0, using resting cells of a variety of
bacteria known to possess strong secondary metabolic ac-
tivity, in particular Actinomyces spp. (details not shown).
Close examination of the most active strains revealed a
common picture (Scheme 2): Whereas (halomethyl)oxiranes
rac-1a and 2a gave hydroxyepoxides 1c and 2c, respectively,
the corresponding (haloethyl)analogues produced tetrahy-
drofuran derivatives 3cϪ6c as the exclusive products. No
other compounds were formed in notable amounts (Ͻ 5%).
The formation of final products can be explained by intra-
molecular cyclisation of (haloalkyl)diols 1bϪ8b, initially
formed during biohydrolysis. The latter reaction shows
some resemblance to a Payne-type rearrangement.[8,9] De-
pending on the length of the haloalkyl spacer moiety, the
relative rates of hydrolysis versus cyclisation varied to a sig-
Results and Discussion
In order to provide insight into the factors governing the
stereochemical outcome of the reaction, 2,3-disubstituted
[a]
Department of Chemistry, Organic & Bioorganic Chemistry,
University of Graz,
Heinrichstrasse 28, 8010 Graz, Austria
Fax: (internat.) ϩ 43-316/380-9840
E-mail: Kurt.Faber@kfunigraz.ac.at
[b]
Division of Chemistry, Bioorganic Chemistry, Vrije University,
de Boelelaan 1083, 1081 HV Amsterdam, The Netherlands
Supporting information for this article is available on the
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