Enzymatic resolution of chlorohydrins for the synthesis of enantiomerically enriched 2-vinyloxiranes

Article abstract of DOI:10.1055/s-2007-1000845

A series of vinylchlorohydrins are resolved by enzymatic kinetic resolution. The resulting R-alcohols, obtained in up to 99% ee, are stereoselectively converted into vinyloxiranes in high yield. The S-acetates, obtained in up to 99% ee were either deprotected to S-alcohols, or cyclized directly to vinyl oxiranes under basic conditions, with moderate to no loss in ee. The results are consistent with a racemization mechanism involving reversible migration of the acetate during deprotection. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-1000845

LETTER
289
Enzymatic Resolution of Chlorohydrins for the Synthesis of Enantiomerically
Enriched 2-Vinyloxiranes
E
nzymatic
.
Resolution
Aof Chlorohydrins dam McCubbin, Matthew L. Maddess, Mark Lautens*
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, M5S 3H6, Canada
Fax +1(416)9468185; E-mail: mlautens@chem.utoronto.ca
Received 24 August 2007
and R2, reacted very slowly, even at 60 °C, but the acetate
(S)-2f was isolated in high ee (entry 6). Alkyl-substituted
chlorohydrins 1g and 1h (entries 7 and 8) were found to
react at significantly higher rates, but with decreased se-
Abstract: A series of vinylchlorohydrins are resolved by enzymatic
kinetic resolution. The resulting R-alcohols, obtained in up to 99%
ee, are stereoselectively converted into vinyloxiranes in high yield.
The S-acetates, obtained in up to 99% ee were either deprotected to
S-alcohols, or cyclized directly to vinyl oxiranes under basic condi- lectivity relative to the aromatic compounds 1a and 1b.
tions, with moderate to no loss in ee. The results are consistent with
a racemization mechanism involving reversible migration of the
acetate during deprotection.
Tertiary alcohols 1i and 1j (entries 14 and 15) failed to re-
act under any of the conditions tested.
With the resolved chlorohydrins in hand, we initiated
studies toward their ring closure to enantiomerically en-
riched vinyloxiranes. Using the same conditions previous-
ly used for the racemic compounds,8 we tested various
Key words: enzymes, epoxides, kinetic resolution, alcohols, acyla-
tion
enantiomerically enriched substrates (R)-1a–f (Table 2)
in the epoxide-forming reaction (Table 2).
Epoxides are important building blocks in organic synthe-
sis because of their prominence in biologically active mol-
In general, excellent yields were obtained with no detect-
able loss in ee. Furthermore, all of the products (R)-3a–f
were obtained in sufficiently high purity for further trans-
formations after a simple aqueous workup.
ecules and the variety of stereoselective transformations
that they undergo.1 Enantiomerically enriched oxiranes
are of particular interest and a variety or powerful meth-
ods exist for their preparation.2 In contrast, the synthesis
of enantiomerically enriched vinyloxiranes has received
less attention,3 despite the rich chemistry that the olefin
and epoxide each provide.4
We next turned our attention to the preparation of the S-
enantiomers. Given the instability of vinyloxiranes 1 to
chromatography,8 and the high purity afforded by the ep-
oxide-forming reactions described in Table 2, we envi-
sioned a two-step process for the conversion of acetates
(S)-2 into vinyloxiranes (S)-3. Compound (S)-2a (97% ee)
was subjected to a variety of deprotection protocols to af-
ford 1a in near quantitative yield, unfortunately with vary-
ing degrees of racemization. Strong reducing agents
[DIBAL-H, LiEt3BH, Li(t-BuO)3AlH, RED-Al] all be-
haved similarly, with the best results obtained (89% ee) in
noncoordinating solvents (heptane). Variation of the reac-
tion temperature (–78 °C to 0 °C) had little effect on the
degree of racemization. Both the acetate and the alcohol
were found to be configurationally stable under these re-
action conditions.12 Weaker reducing agents (LiBH4) af-
forded inferior results as did the use of protic acids (e.g.
TsOH in MeOH). Lewis acids (e.g. BF3·OEt2 in MeCN)
resulted in complete racemization. Nucleophilic condi-
tions (K2CO3 in MeOH) resulted in racemization to the
same extent as with DIBAL-H. Not surprisingly, the nu-
cleophilic conditions resulted in conversion of (S)-1a di-
rectly into the vinyloxirane product (S)-3a (vide infra).
Even the use of lipases to effect deprotection, at various
temperatures and pH values, resulted in partial racemiza-
tion of the product.13
We speculated that enzymatic resolution of various
vinylchlorohydrins5 followed by ring closure could pro-
vide a general and operationally convenient alternative to
existing methods for the synthesis of vinyloxiranes. Li-
pase resolution6 offers several advantages, including the
potential for high optical purity of the products in both
enantiomeric forms, and predictability of absolute stereo-
chemistry.
For this purpose we selected Amano lipase AK because of
its commercial availability and success in related sys-
tems.7 Racemic chlorohydrins 1a–j8 were subjected to the
enzyme catalyst in neat vinyl acetate at various tempera-
tures (Table 1).
Substrates bearing a single aryl substituent R1 (1a–c, en-
tries 1–3) showed excellent selectivities at low tempera-
ture. The nitro-substituted 1c (entry 3) reacted slowly and
required heating to 60 °C to achieve an acceptable reac-
tion rate, in which case only moderate selectivity was ob-
served.9 Substrates with substitution at R1 and R3 (1d and
1e) also required elevated reaction temperatures, however
for these substrates, high selectivities were attained (en-
tries, 4 and 5). Compound 1f, with large substituents at R1
The conditions found to minimize the ee erosion were
then applied to the deprotection of various acetates [(S)-
2a–h, Table 3]. The reactions were clean and afforded the
corresponding alcohols [(S)-1a–h] in excellent yields. We
SYNLETT 2008, No. 2, pp 0289–0293
Advanced online publication: 21.12.2007
DOI: 10.1055/s-2007-1000845; Art ID: S06007ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
8

290
J. A. McCubbin et al.
LETTER
Table 1 Enzymatic Resolution of Chlorohydrins10
R3
X
R3
X
R3
X
OAc
R1
R1
R1
Amano lipase AK
Temp, time
R4
R4
R4
OAc
+
R2
OH
(R)-1
R2
OH
R2
1
(S)-2
Entry
1
R1
Ph
R2
H
R3
R4
X
Temp
(°C)
Time
(h)
Conv.
(%)
Yield of (R)-1
Yield of (S)-2
s
(%,a ee)
(%,a ee)
1
2
1a
1b
1c
1d
1e
1f
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
5
125
124
168
183
196
336
38
52
48
47
53
53
30
47
55
0
1a, 45 (99)
1b, 49 (99)
1c, 49 (77)
1d, 44 (98)
1e, 40 (97)
1f, 60 (27)
1g, 51 (80)b
1h, 43 (94)b
–
2a, 48 (97)
2b, 46 (99)
2c, 43 (77)
2d, 49 (92)
2e, 46 (92)
2f, 26 (90)
2g, 41 (84)
2h, 53 (75)
–
116
154
33
65
55
6
o-OMeC6H4
H
H
H
H
Ph
H
H
5
3
o-NO2C6H4
H
60
25
25
60
5
4
Ph
Ph
Ph
Bu
Br
Me
H
5
6
7
1g
1h
1i
H
48
27
–
8
R1 to R3 = (CH2)4, R2 and R4 = H
5
96
9
Ph
Ph
Ph
H
H
H
H
H
H
Me
60
60
5
72
10
11
1j
CH2OBn Cl
72
0
–
–
–
1k
H
H
90
56
k, 41 (99)
k, 50 (90)
41
a Isolated yields.
b The ee values were determined by chiral stationary phase (CSP) HPLC analysis of 4-nitrobenzoate derivatives of the resolved alcohol.
Table 2 Ring-Closing Reactions of Resolved Chlorohydrins11
Table 3 Reductive Deacylation14
R3
R3
Cl
R3
Cl
R3
DIBAL-H
NaH (1.1 equiv)
R1
R1
R4
R1
R4
R1
NaI (0.1 equiv)
THF, 0 °C
heptane
–78 °C
Cl
O
R4
R2
(R)-1
R2
(S)-2
OAc
R2
(S)-1
OH
R2 R4
(R)-3
HO
Entry (R)-1
ee (%)
99
(R)-3
Yield (%) ee (%)
Entry (S)-2
ee (%)
97
(S)-1
Yield (%) ee (%)
1
2
3
4
5
6
(R)-1a
(R)-1b
(R)-1c
(R)-1d
(R)-1e
(R)-1f
(R)-3a
(R)-3b
(R)-3c
(R)-3d
(R)-3e
(R)-3f
99
99
99
77
98
97
27
1
2
3
4
5
6
7
8
(S)-2a
(S)-2b
(S)-2c
(S)-2d
(S)-2e
(S)-2f
(S)-2g
(S)-2h
(S)-1a
(S)-1b
(S)-1c
(S)-1d
(S)-1e
(S)-1f
(S)-1g
(S)-1h
97
94
91
99
96
99
87
91
89
99
72
69
69
60
84a
75a
99
94
89
97
95
98
99
77
99
98
92
97
92
27
90
84
were pleased to observe that deprotection of electron rich
(S)-2b afforded (S)-1b (entry 2) without detectable loss of
ee. However, when the electron-poor substrate (S)-2c was
subjected to the reaction conditions, a ca. 30% loss of ee
was observed in the product. Similarly large decreases in
product ee were observed in the deprotection of (S)-2d
and (S)-2e (entries 4 and 5, respectively). Compound (S)-
2f underwent even greater ee erosion during deprotection
75
a The ee were determined by CSP-HPLC analysis of 4-nitrobenzoate
derivatives of the alcohol.
sponding (S)-vinyloxiranes as previously described
(Table 2).
to (S)-1f (entry 6). The aliphatic acetates (S)-2g,h under- The observation that treatment of (S)-2a with K2CO3 in
went deacetylation to afford (S)-1g and (S)-1h with no MeOH resulted in deprotection and subsequent ring clo-
loss of ee (entries 7 and 8). All of the resulting chlorohy- sure to cleanly afford (S)-3a, prompted us to test this reac-
drins (1a–h) could be cleanly converted into the corre- tion on some of our other substrates (Table 4). In general,
Synlett 2008, No. 2, 289–293 © Thieme Stuttgart · New York

LETTER
Enzymatic Resolution of Chlorohydrins
291
Me Nu
–O
these reactions afforded products (S)-3a–f upon workup,
in excellent yields and without the need for further purifi-
cation. The erosion of ee was nearly identical to that ob-
served for the reductive deprotection in all cases (see
Table 3 for comparison).
Me Nu
OH
O–
O
O
Ph
Ph
4a
Ph
Cl
Cl
5a
Cl
1a
Scheme 1
Table 4 Ring-Closing Reactions of Acetylated Chlorohydrins15
R3
Cl
R4
R3
matic ring, thus minimizing racemization in these cases.
Conversely, electron-withdrawing substituents on the ar-
omatic ring would favor alkoxide attack by reducing the
electron density of the double bond.
K2CO3
R1
R1
MeOH, 0 °C
O
R2
(S)-2
OAc
R2
(S)-3
R4
In summary, we have developed an efficient method for
the resolution of vinyl chlorohydrins, which are converted
into (R)-vinyloxiranes in high yield and ee. Monoaryl-
substituted allylic chlorohydrins are resolved with high
selectivity, whereas more highly substituted examples re-
quire higher temperatures and longer reaction times and
result in somewhat lower selectivities. The resulting (S)-
acetylchlorohydrins are either deacetylated to afford the
corresponding chlorohydrins or are cyclized directly to vi-
nyloxiranes in high yield, and with undetectable to mod-
erate loss of ee. These results are consistent with a
racemization mechanism that occurs by reversible rear-
rangement of an alkoxide intermediate.
Entry (S)-2
ee (%)
97
(S)-3
Yield (%) ee (%)
1
2
3
4
5
6
(S)-2a
(S)-2b
(S)-2c
(S)-2d
(S)-2e
(S)-2f
(S)-3a
(S)-3b
(S)-3c
(S)-3d
(S)-3e
(S)-3f
99
96
91
97
96
99
89
99
74
69
71
62
99
99
92
92
90
Of note, it was reported16 that acetate (S)-1k (Table 1, en-
try 11) was reductively deprotected (DIBAL-H, CH2Cl2,
0 °C) to afford (S)-1k without erosion of ee. To confirm
this result, we prepared the optically enriched acetate (S)-
1k by our resolution method in 50% yield and 90% ee. In
our hands, subjecting it to the literature conditions17 re-
sulted in a substantial decrease in the ee of the product al-
cohol (S)-1k to 59%. This suggests that racemization
during the reductive deprotection is unrelated to the pres-
ence of the chloride.
Acknowledgment
M.L. thanks Merck Frosst Canada and NSERC (Canada) for an In-
dustrial Research Chair, and the University of Toronto for financial
support of this work. M.M. thanks NSERC (Canada) for financial
support in the form of a postgraduate fellowship.
References and Notes
To our knowledge, no direct precedent for ee erosion of
this type has been reported. However, allylic acetates are
known to rearrange thermally18 or under acidic condi-
tions.19 Moreover, alkoxides have been shown to add con-
jugately, in an intermolecular fashion, to allylic acetates
under transition-metal-free conditions.20 Given these re-
ports, and our experimental observations, we propose an
intramolecular mechanism for racemization of the allylic
acetates (Scheme 1). Cleavage of an acetate [e.g. (S)-2a]
under reductive or nucleophilic conditions normally oc-
curs by a BAC2 mechanism,21 which requires the interme-
diacy of a tetrahedral intermediate of general structure 4a.
It may be possible for 4a to reversibly rearrange to form
5a. If the rearrangement (or its reverse) is not completely
stereoselective, then subsequent equilibration back to 4a
would result in partial racemization. Completion of the re-
action and aqueous workup would afford partially racem-
ized 1a.22
(1) (a) Yudin, A. K. Aziridines and Epoxides in Organic
Synthesis; Wiley-VCH: Weinheim Germany, 2006.
(b) Pineschi, M. Eur. J. Org. Chem. 2006, 3747.
(c) Gansäuer, A.; Fan, C. A.; Keller, F.; Karbaum, P. Chem.
Eur. J. 2007, 13, 8084. (d) Eissler, S.; Stronicius, A.;
Nahrwold, A.; Sewald, N. Synthesis 2006, 3747.
(e) Miyashita, K.; Imanishi, T. Chem. Rev. 2005, 105, 4515.
(f) Watkins, E. B.; Chittiboyina, A. G.; Avery, M. A. Eur. J.
Org. Chem. 2006, 4071.
(2) For recent examples, see: (a) Burke, C. P.; Shu, L.; Shi, Y. J.
Org. Chem. 2007, 72, 6320. (b) Colladon, M.; Scarso, A.;
Sgarbossa, P.; Michelin, R. A.; Strukul, G. J. Am. Chem.
Soc. 2007, 129, 7680. (c) Zhang, W.; Yamamoto, H. J. Am.
Chem. Soc. 2007, 129, 286. (d) Barlan, A. V.; Basak, A.;
Yamamoto, H. Angew. Chem. Int. Ed. 2006, 45, 5849.
(e) Gelacha, F. G.; Bitterlich, B.; Anilkumar, G.; Tse, M. K.;
Beller, M. Angew. Chem. Int. Ed. 2007, 46, 7293.
(f) Sawada, Y.; Matsumoto, K.; Katsuki, T. Angew. Chem.
Int. Ed. 2007, 46, 4559. (g) Peris, G.; Jakobische, C. E.;
Miller, S. J. J. Am. Chem. Soc. 2007, 129, 8710. (h) Taber,
D. F.; Liang, J. J. Org. Chem. 2007, 72, 431. Reviews:
(i) Shi, Y. In Handbook of Chiral Chemicals, Vol. 2; Ager,
D., Ed.; CRC Press: Boca Raton Florida, 2006.
This mechanism is consistent with the similar results ob-
served for deprotection (Table 3) and for the deprotec-
tion–cyclization (Table 4) of acetates (S)-2. Moreover, it
is consistent with the results for the deprotection of (S)-2b
and (S)-2c. Alkoxide attack of the double bond would be
disfavored by electron-donating substituents on the aro-
(j) McGarrigle, E. M.; Gilheany, D. G. Chem. Rev. 2005,
105, 1563. (k) Xia, Q.-H.; Ge, H.-Q.; Ye, C.-P.; Liu, Z.-M.;
Su, K.-X. Chem. Rev. 2005, 105, 1603. (l) Marco-
Contelles, J.; Molina, M. T.; Anjum, S. Chem. Rev. 2004,
104, 2857.
Synlett 2008, No. 2, 289–293 © Thieme Stuttgart · New York

292
J. A. McCubbin et al.
LETTER
by CSP-HPLC. At approximately 50% conversion, the
(3) For enantioselective syntheses of vinyloxiranes, see:
(a) Evans, D. A.; Aye, Y. J. Am. Chem. Soc. 2007, 129,
9606. (b) Burke, C. P.; Shi, Y. Angew. Chem. Int. Ed. 2006,
45, 4475. (c) Zenardi, J.; Lamazure, D.; Minière, S.; Reboul,
V.; Metzner, P. J. Org. Chem. 2002, 67, 9083. (d) Solladié-
Cavallo, A.; Bouérat, L.; Roje, M. Tetrahedron Lett. 2000,
41, 7309. (e) Trost, B. M.; McEachern, E. J. J. Am. Chem.
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1307. (g) Ready, J. M.; Jacobsen, E. N. J. Am. Chem. Soc.
2001, 123, 2687.
(4) For examples of stereoselective reactions of vinyloxiranes,
see: (a) Fedorov, A.; Fu, C.; Heimgartner, H. Helv. Chim.
Acta 2006, 89, 456. (b) Marié, J.-C.; Courillon, C.;
Malacria, M. Eur. J. Org. Chem. 2006, 463. (c) Nagumo,
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K.; Ahn, J. H.; Kim, S. S.; Choi, J.-K. Tetrahedron Lett.
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suspension was filtered through a pad of Celite, washing
with EtOAc (100 mL). The solution was concentrated in
vacuo and the crude residue was purified by flash
chromatography (5–10% EtOAc–hexane) to afford two
fractions: (S)-2 (acetate, 1st eluted) and (R)-1 (alcohol, 2nd
eluted). The alcohols (R)-1a–h displayed spectral properties
in accordance with the racemates (see ref. 8). The acetates
(S)-2a–h were characterized by 1H and 13C NMR, HRMS
and CSP-HPLC.
Compound (S)-2a: 1H NMR (400 MHz, CDCl3): d = 7.34–
7.29 (m, 2 H), 7.28–7.18 (m, 3 H), 6.67–6.61 (d, J = 15.9 Hz,
1 H), 6.12–6.05 (dd, J = 15.9, 6.1 Hz, 1 H), 5.57–5.52 (dt,
J = 6.1, 6.1 Hz, 2 H), 2.06 (s, 3 H). 13C NMR (100 MHz,
CDCl3): d = 170.0, 135.7, 134.9, 128.7, 128.5, 126.8, 123.7,
73.7, 45.6, 21.1. HRMS (EI): m/z calcd for C12H13ClO2 [M+]:
224.0604; found: 224.0608. HPLC [CHIRALCEL OD, 1.0
mL/min, hexane–i-PrOH (98:2), 30 °C, 1 mL injection] tR1
(minor) = 12.4 min, tR2 (major) = 15.1 min; 99% ee.
(11) The procedure reported in ref. 8 was used, and afforded the
vinyloxiranes (R)-3a–f with spectral data consistent with
that reported therein.
(12) If the reaction was quenched before completion, the ee of the
unreacted acetate was identical to that of the starting acetate
before addition of the reducing agent. Deprotection was
complete after 15 min, but the ee of the alcohol remained
unchanged if left unquenched for a full hour.
(13) See for example: Lopez, R.; Montero, E.; Sanchez, F.;
Canada, J.; Fernandez-Mayoralas, A. J. Org. Chem. 1994,
59, 7027.
(5) For examples of lipase-mediated resolution of simple
chlorohydrins, see: (a) Pamies, O.; Bäckvall, J.-E. J. Org.
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Tetrahedron: Asymmetry 1992, 3, 521. (c) Chen, C. S.; Liu,
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Biotech. Lett. 1994, 16, 1299. (f) Scilimati, A.; Di Bono, G.
Synthesis 1995, 699. (g) Kamal, A.; Chouhan, G.
(14) General Procedure
A dry flask was charged with resolved acetate (S)-2 and
heptane (10 mL/mmol). The resulting solution was cooled to
–78 °C under Ar and DIBAL-H as a 1.0 M solution in
heptane (1.1 equiv) was added dropwise via syringe. The
solution was stirred at –78 °C for 15 min, followed by the
addition of an equal volume of a sat. aq solution of
Rochelle’s salt. The mixture was transferred to a separatory
funnel and extracted twice with Et2O (25 mL). The
combined organic extracts were dried (MgSO4) and
concentrated in vacuo. The crude residue was purified by
flash chromatography (10% EtOAc–hexane) to afford the
desired alcohol (S)-1. The products displayed spectral
characteristics in accord with the racemate (see ref. 8).
(15) General Procedure
Tetrahedron: Asymmetry 2005, 16, 2784. (h) Pederson, R.
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Asymmetry 1996, 7, 1683. (j) Haak, R. M.; Tarabiono, C.;
Janssen, D. B.; Minnaard, A. J.; de Vries, J. G.; Feringa, B.
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To a round-bottom flask was added resolved acetate (S)-2
and MeOH (10 mL/mmol) and the reaction vessel cooled in
an ice bath. Then, K2CO3 (1.1 equiv) was added portionwise
as a solid. The heterogeneous reaction was stirred at 0 °C
and the progress monitored by TLC for the consumption of
starting material. After 1 h, the reaction was quenched
carefully by the addition of sat. aq NH4Cl, and after an equal
volume had been introduced the reaction mixture was
concentrated, diluted with Et2O and transferred to a
separatory funnel. The organic layer was isolated, the
aqueous layer extracted with Et2O and the combined
organics dried with MgSO4, filtered, and concentrated in
vacuo to afford the desired vinyloxirane (S)-3 in sufficient
purity for subsequent reactions. The product displayed
spectral characteristics in accord with the racemates (see ref.
8).
(6) For reviews, see: (a) Schoffers, E.; Golebiowski, A.;
Johnson, C. R. Tetrahedron 1996, 52, 3769. (b) Johnson, C.
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New York, 1994.
(7) (a) Taber, D. F.; Jiang, Q. J. Org. Chem. 2001, 66, 1876.
(b) Zhu, B.; Panek, J. S. Tetrahedron Lett. 2000, 12, 1863.
(8) Lautens, M.; Maddess, M. L.; Sauer, E. L. O.; Ouellet, S. G.
Org. Lett. 2002, 4, 83.
(9) When 1a was subjected to the resolution conditions at 60 °C,
no selectivity was observed.
(10) General Procedure
(16) Zhu, L.; Kedenburg, J. P.; Xian, M.; Wang, P. G.
Tetrahedron Lett. 2005, 46, 811.
A dry flask was charged with racemic alcohol 1 and vinyl
acetate (1.0 mL/mmol). The resulting solution was stirred at
5, 25, or 60 °C and Amano lipase AK (3.0 mass equiv) was
added as a single portion. Reaction progress was monitored
(17) The experimental details for this reaction were not included
in ref. 16; however, they were obtained through personal
communication with the authors.
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Enzymatic Resolution of Chlorohydrins
293
(18) (a) Goering, H. L.; Doi, J. T.; McMichael, K. D. J. Am.
Chem. Soc. 1964, 86, 1951. (b) Lewis, E. S.; Hill, J. T.
J. Am. Chem. Soc. 1969, 91, 7458.
(20) Chevrin, C.; Le Bras, J.; Hénin, F.; Muzart, J. Tetrahedron
Lett. 2003, 44, 8099.
(21) March, J. Advanced Organic Chemistry, 4th ed.; Wiley:
New York, 1992.
(19) Babler, J. H.; Olsen, D. O.; Arnold, W. H. J. Org. Chem.
1974, 32, 1656.
(22) Alternatively, racemization could occur under certain
conditions via ionization of 4a, followed by internal return.
Synlett 2008, No. 2, 289–293 © Thieme Stuttgart · New York

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