6754
D. P. Pienaar et al. / Tetrahedron Letters 49 (2008) 6752–6755
The optically active trans-epoxyamide (R,R)-17 was heated at
OH
O
(ii)
reflux in tert-butanol in the presence of potassium tert-butoxide
to afford pyrrolidone 19 in 89% yield (Scheme 4). This 5-exo-tet
cyclisation is similar to a previously reported reaction of an analo-
gous cis-epoxyamine.20 The structure of 19 was confirmed by NMR
spectroscopy and by X-ray crystallography (see Fig. 1). Reduction
of 19 with lithium aluminium hydride afforded the known pyrrol-
idine 20 in high yield. The absolute stereochemistry of 20 (and
hence, that of the precursor pyrrolidone 19) could be deduced by
comparing the NMR and optical data with those in recent
literature.21
Cl
AcO
AcO
(
S
)-5
14
(iii)
(i)
OH
OH
(iv)
O
Cl
HO
HO
13
16
O
15
Scheme 3. Reagents and conditions: (i) lipase (see text), phosphate buffer (pH 7.5),
14 h, 92%; (ii) LiCl, AcOH, THF, 77%; (iii) same as (i), 48 h, 75%; (iv) see Ref. 19, 79%.
Pyrrolidinol 20 is a valuable chiral intermediate for the synthe-
sis of a wide range of pharmacologically active products and inter-
mediates. For example, the transformation of 20 under well-
defined conditions (trifluoroacetic acid anhydride, followed by
NEt3 and NaOH)22 affords ring-expanded 3-hydroxypiperidine 21,
without loss of stereochemical integrity.23 The piperidine 21
can be utilised for the synthesis of non-peptidic substance P inhib-
itors,24 and also for the preparation of trans-(2R,3R)-3-hydroxy-
O
O
(i)
Ph
+
Ph
(R,R)-17
BnHN
OH
O
BnHN
O
17
pipecolic acid, which is a precursor for the
a-D-mannosidase
Ph
inhibitor (À)-swainsonine.25 The new synthesis of pyrrolidinol 21
described above circumvents the requirement for separation of
diastereomers, a problem with earlier synthetic routes to this
material.21,23,26
18
HO
BnHN
H
O
In conclusion, a robust epoxide hydrolase technology has been
developed and applied to the preparation of optically active, func-
tionalised epoxides and vicinal diols. These chiral products are
applicable to the synthesis of pharmacologically important hetero-
cycles. The biocatalytic resolutions were successfully applied at
unprecedented substrate loading and were complete within hours,
demonstrating the efficiencies of the technology and competitive-
ness with chemical methods.
Crystallographic data (excluding structure factors) for the struc-
tures of compounds 18 and 19 have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary publication
numbers CCDC 688482 and 688481, respectively.
Ph
HO
(ii)
(
R
,
R
)-17
O
N
H
Bn
19
(iii)
H
HO
(iv)
Ph
N
Ph
21
N
HO
H
Bn
H
Bn
20
Scheme 4. Reagents and conditions: (i) Oxy-10 EH; (ii) KtBuO, tBuOH, reflux 2 h,
89%; (iii) LAH, THF, reflux 1 h, 96%; (iv) see Refs. 22 and 23.
Acknowledgements
In addition, Y. lipolytica EH (Oxy-10) was employed to selec-
tively hydrolyse the epoxyamide 17 (Scheme 4). In this instance,
the biotransformation (which was run to 50% substrate conver-
sion) was highly enantioselective with optically pure (P99.9%
ee) epoxide and equally pure diol 18 (P99.9% ee) being isolated
in unoptimised yields of 32% and 22%, respectively. The configura-
tion of the epoxide was established as (4R,5R) by further chemical
transformations (see below). X-ray crystallographic analysis re-
vealed that the diol (18) possessed the threo stereochemistry (see
Fig. 1), but the absolute stereochemistry of the compound was
not determined.
Oxyrane UK Ltd are grateful to Professor Stan Roberts (School of
Chemistry, University of Manchester) for his assistance during this
work. We also thank Dr. Madeleine Helliwell at the X-ray Crystal-
lography Facility of the University of Manchester for the crystal
structure determinations.
References and notes
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Figure 1. Mercury generated representations of the structures of compounds 18
and 19.