Chemoenzymatic routes to cyclopentenols: The role of protecting groups on stereo- and enantioselectivity

Article abstract of DOI:10.1016/j.tetlet.2014.10.105

Enantiopure (R)-4-triisopropylsilyloxycyclopent-2-en-1-one was obtained through short sequences including either the enzymatic resolution of racemic cis-4-triisopropylsilyloxycyclopent-2-en-1-ol or the enzymatic desymmetrization of cis-cyclopent-2-en-1,3-diol. Alternatively, the enantiopure (S)-4-triisopropylsilyloxycyclopent-2-en-1-one was very efficiently obtained from diacetate of cis-cyclopent-2-en-1,3-diol using enzymatic desymmetrization with CAL-B. In these sequences, TIPS proved to be the best protecting group.

Full text of DOI:10.1016/j.tetlet.2014.10.105

Tetrahedron Letters 55 (2014) 6987–6991
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Chemoenzymatic routes to cyclopentenols: the role of protecting
groups on stereo- and enantioselectivity
⇑
⇑
Simon Specklin, Anna Dikova, Aurélien Blanc, Jean-Marc Weibel , Patrick Pale
Laboratoire de Synthèse, Réactivité Organiques, et de Catalyse, Institut de Chimie,UMR7177-CNRS, Université de Strasbourg, 4 Rue Blaise Pascal, 67070 Strasbourg, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantiopure (R)-4-triisopropylsilyloxycyclopent-2-en-1-one was obtained through short sequences
including either the enzymatic resolution of racemic cis-4-triisopropylsilyloxycyclopent-2-en-1-ol or
the enzymatic desymmetrization of cis-cyclopent-2-en-1,3-diol. Alternatively, the enantiopure (S)-4-tri-
isopropylsilyloxycyclopent-2-en-1-one was very efficiently obtained from diacetate of cis-cyclopent-2-
en-1,3-diol using enzymatic desymmetrization with CAL-B. In these sequences, TIPS proved to be the best
protecting group.
Received 11 July 2014
Revised 13 October 2014
Accepted 17 October 2014
Available online 24 October 2014
Keywords:
Cyclopentenol
Enzyme
Ó 2014 Elsevier Ltd. All rights reserved.
Resolution
Desymmetrization
Luche reduction
Furfural rearrangement
Hydroxylated cyclopentanones and cyclopentenones are com-
mon motifs in numerous natural products of various origins. They
can indeed be found in rather simple structures, like in the
antibiotic pentenomycin,1 or in more complex structures such as
prostaglandins,2 the antibiotic viridenomycin,3 or the antitumor
dienediyne family,4 such as neocarzinostatin (NCS) or N1999A2
(Scheme 1).
Initially developed for the synthesis of prostaglandins, the
simple 4-hydroxycyclopent-2-enone ( )-1a and its protected forms
(Scheme 2) could be a common building block toward all these
natural products.5 Both (R)- and (S)-enantiomers have been
reported. They were obtained either from the chiral pool6 or
through enzymatic resolution of racemic hydroxycyclopentenone
1a, protected or not,7 or of monoprotected cis cyclopent-2-
en-1,4-diols.8 Desymmetrization of the cis cyclopent-2-en-1,4-diol
or its corresponding diacetate has also been reported.9 Other
promising sequences have also been described, based on the
resolution of hydroxycyclopent-2-enone either through asymmet-
ric reduction10 or through Pd-catalyzed allylic substitution,11 and
very recently on the metathesis of chiral diol.12 However, these
routes presented drawbacks, such as low yields and/or tedious
processes, while efficient, expeditious and practical sequences
are crucial for their application in total syntheses.
For several ongoing cyclopentanoid asymmetric syntheses, we
explored known routes to each 4-hydroxycyclopent-2-en-1-one
enantiomer and especially its tert-butyldimethylsilyl (TBDMS)
protected form,8 but it turned out that we had to shift to its triiso-
propylsilyl (TIPS) analog. The latter proved more stable owing to
the ease of b-elimination13 and useful in subsequent transforma-
tions,14 including transprotection.15 Surprisingly enough, up to
very recently,12 only one enantiomer was reported. Indeed, in
2003, Aubé co-workers described the preparation of the (S) enan-
tiomer in 7 steps from cyclopentadiene with 23.2% overall yield,
⇑
Corresponding authors. Tel.: +33 368 851586 (J.-M.W.); tel.: +33 368 851517
(P.P.).
Scheme 1. Some natural products exhibiting hydroxylated cyclopentanone or
cyclopentenone motif.
E-mail addresses: jmweibel@unistra.fr (J.-M. Weibel), ppale@unistra.fr (P. Pale).
http://dx.doi.org/10.1016/j.tetlet.2014.10.105
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

6988
S. Specklin et al. / Tetrahedron Letters 55 (2014) 6987–6991
Scheme 2. Chemoenzymatic route to cyclopentanoid derivatives from furfuryl
alcohol via 4-silyloxycyclopent-2-en-1-one enantiomers.
Scheme 3. Route to 4-hydroxycyclopent-2-en-1-one and its derivatives.
the chirality being introduced through enzymatic desymmetriza-
tion of cyclopent-4-en-1,3-diyl diacetate with electric eel cholines-
terase.9j Despite various publications dealing with asymmetric
access to 1a and some of its derivatives, there is no systematic
comparison and no data showing that sequences affording chiral
4-tert-butyldimethylsilyloxycyclopent-2-en-1-one are still effi-
cient for their TIPS analogs. We thus reinvestigated some of these
routes and reported here our own findings, starting from the cheap
2-hydroxymethylfuran, conveniently leading to each enantiomer
in high yields and ee’s (Scheme 2).
Table 1
Screening of conditions for the reduction of 4-hydroxycyclopent-2-en-1-one, pro-
tected or not
As reported,16 2-hydroxymethylfuran can be hydrated in warm
acidic phosphate buffer. However, the useful hydroxycyclopente-
none ( )-1a can only be isolated with modest yields (ꢀ40%) since
numerous side-products are also formed due to the acid-sensitivity
of both the starting alcohol and the product. Furthermore, ( )-1a is
water-soluble and difficult to extract from the resulting mixture.
Those problems could be circumvented by performing the reaction
in pure water at 0.2 M concentration without any additive under
microwave irradiation for 5 min,17 directly followed without any
Entry
R
Conditions
Yielda (%)
cis:transb
1c
2
H
1a
1a
NaBH4 1 equiv; CeCl3 1 equiv
MeOH-THF, rt
68
7:1
95(71)
10:1
78d
5:1
72
9:1
93
8:1
81
3.5:1
84
6.4:1
88
5.8:1
82(74)
8:1
NaBH4 1 equiv; CeCl3 2 equiv
MeOH, À20 °C
3
SiMe3
1b
SitBuMe2
1c
DIBAH 1.1 equiv
Tol., À20 °C
4c
5c
6
DIBAH 1.1 equiv
Tol., À40 °C
work-up by water evaporation and
a rapid chromatography.
1c
NaBH4, 0.5 equiv; CeCl3, 2 equiv
MeOH, À20 °C
Hydroxycyclopentenone ( )-1a can thus be isolated with
drastically improved efficiency in 75% yield on multigram scale
(Scheme 3).
SitBuPh2
1d
1d
DIBAH 1.1 equiv
Tol., À40 to À20 °C
NaBH4, 1.1 equiv; CeCl3, 2 equiv
MeOH, rt
7
Although the racemic hydroxycyclopentenone ( )-1a and its
esters can directly be resolved,7 higher yields and ee’s are often
achieved by desymmetrization of the corresponding meso diol
cis-2a and its esters.9 However, highly stereoselective reduction
of 1a is required to get the cis and not the trans isomer, the former
being required for desymmetrization due to its meso symmetry.
Although already studied,8,18 we found that this reduction could
be performed with high selectivity on the free hydroxycyclopente-
none ( )-1a and on its protected analogs ( )-1b–e. In the latter
cases, the selectivity proved dependent on the size of the protect-
ing group at the 4-position (Table 1).
8
SiiPr3
1e
1e
DIBAH 1.1 equiv
Tol., À40 °C
9
NaBH4, 1.1 equiv; CeCl3, 2 equiv
MeOH, À20 °C
a
b
c
Isolated yields (yield of pure cis isomer).
Determined by 1H NMR on the crude mixture.
From Ref. 8
d
Isolated as deprotected alcohol.
Reported with good yield and cis-trans selectivity (entry 1),8 the
reduction of the free ( )-1a could largely be improved under
adjusted Luche conditions with excess of cerium chloride at low
temperature. Due to the high water solubility of the diol, aqueous
work-up was avoided by only adding silica to destroy or trap
reagents and products. Solvent evaporation and solid deposit chro-
matography then provided the diols in almost quantitative yields
and high selectivity, allowing to isolate pure cis-2a in 71%19 yield
(entry 2). With the trimethylsilyl group, deprotection occurred
under Luche conditions, but the use of DIBAH in toluene proved
effective enough in terms of yield, although not as selective (entry
3 vs 2). Both methods (and others) have been reported for the tert-
butyldimethylsilyl (TBDMS) analog ( )-1c and again the Luche con-
ditions were more efficient (entry 5 vs 4) but the selectivity was
lower than the one achieved without the protecting group (entry
5 vs 2). With the tert-butyldiphenylsilyl (TBDPS) analog ( )-1d,
similar results and conclusion were obtained (entries 6–7), as well
as with the very bulky triisopropylsilyl (TIPS) analog ( )-1e (entries
8–9). Nevertheless, the good yield and selectivity achieved with
the TIPS group allowed us to isolate the pure ( )-cis-2e in 74% yield
(entry 9).20
The meso diol cis-2a was then submitted to acylating agents
(vinyl acetate (VA) or vinyl butyrate (VB)) in the presence of vari-
ous enzymes, leading to the corresponding mono- or diesters
(Scheme 4). The latters were also selectively hydrolyzed by
enzymes. Interestingly, each route provided each enantiomer.
The enantioselective acylation of meso diol cis-2a has been
reported with pancreatin as biocatalyst.9a However, the reported
conditions led to the acetate (À)-2f with a good enantioselectivity
but not high enough for synthetic purposes (Table 2, entry 1).
Using another source of enzyme provided (À)-2f in very high ee
in a reasonable time, but to the detriment of yield due to the
increased formation of the meso diacetate 4f (entry 2).21 Increasing
the reaction time under the same conditions or using vinyl buty-
rate allowed to get the enantiopure monoesters 2f–g, but still with
the same modest yields (entries 3 and 4).

S. Specklin et al. / Tetrahedron Letters 55 (2014) 6987–6991
6989
(98.5).24 Upon silylation, ester cleavage and oxidation, the (S)
enantiomer of 4-triisopropylsilyloxycyclopent-2-en-1-one (S)-1e
20
([a
]
D
À 59.5, c = 1.05 MeOH) could be obtained, with an excellent
yield of 94%. These results thus provided a very efficient route from
furfuryl alcohol with a yield of 48.1% over 7 steps.
Enzymes can also resolve the racemic mixture of 4-triisopropyl-
silyloxycyclopent-2-en-1-ol ( )-2e previously obtained by Luche
reduction (see Table 1). Again, various enzymes have been
screened (Table 3). It is worth mentioning that the standard
pancreatin preparation mentioned above has already been applied
to the resolution of the TBDMS analog, giving very good results,
each enantiomer being obtained with high ee (entry 1).8 However,
when transposed to the TIPS derivative, these conditions led to
almost no transformation (entry 2). Solvent variations as well as
using the more active pancreatin preparation or PPL did not help
(entries 2–6). Such results highlight the sensitivity of enzyme
active site to conformation and bulkiness.
Scheme 4. Chemoenzymatic routes to (R)- or (S)-4-triisopropylsilyloxy cyclopent-
2-enone.
Table 2
Screening of conditions for the enzymatic desymmetrization of cis 4-cyclopent-2-en-
1,4-diol 2a
Interestingly, CAL-B proved very effective for the resolution of
( )-2e despite the large size of the TIPS moiety. As before, this
enzyme was too active in the presence of vinyl acetate, leading
within two hours to the acetate (+)-5fe with 53% yield and 79%
ee and to the enantioenriched hydroxy derivative 2e with 42%
yield (entry 7). Since CAL-B is a lipase known for accommodating
long acyl chain,23 vinyl butyrate was also used as acylating
agent. Rewardingly, excellent results were gained, with very high
enantioselectivity (entries 8–10). An optimum was observed
after 4 h, with the enantiopure product (+)-5ge formed (entry
9).25 Prolonged reaction time was detrimental in term of
enantioselectivity (entry 10 vs 9).
Entry
Conditions
Time (h)
Yielda (%)
2b (ee)
4
1
2
3
4
5
6
7
Pancreatin 1USP, VA
Pancreatin 4 USP, VA
Pancreatin 4 USP, VA
Pancreatin 4 USP, VB
PPL, VA
23
61
(81.5)
53
(99.5)
53
(99.9)
50
(99.2)
56
(99.4)
59
(91.2)
0
—
25
—
43
—
43
—
41
—
42
—
23
—
100
—
15.5
24
15
Table 3
Screening of conditions for the enzymatic resolution of monosilylated cis 4-cyclopent-
2-en-1,4-diol
72
PPL, VB
15
CAL-B, VA
0.5
VA: vinyl acetate; VB: vinyl butyrate; PPL: Pig Pancreas Lipase; CAL: Candida
antartica Lipase.
a
Isolated yields.
b
Determined by GC with Macherey Nagel LIPODEX E column on the crude
Entry
Substrate
Conditionsa
Time (h)
Yieldb (%)
2c (ee) 5c (ee)
mixture.
1d
2
2c
2e
2e
2e
2e
2e
2e
2e
2e
2e
Pancreatin 1USP, VA
Pancreatin 1USP, VA
?
46
48
(96)
Tracese
—
(98)
Tracese
—
Interestingly, the crude lipase from pig pancreas (PPL) offered
improved yield while preserving a very high enantioselectivity,
although with a longer reaction time (entry 5). Shifting from vinyl
acetate to vinyl butyrate further enhanced the yield to 59%, but
with a decreased enantioselectivity (entry 6). In contrast, some
enzymes proved too active. For example, one of the lipases from
Candida antartica (CAL-B),22 known for its enantioselectivity
toward secondary alcohols,23 furnished the meso diacetate 4f in
less than an hour and in quantitative yield (entry 7 vs 5).
56
63
19
24
19
2
3
Pancreatin 1USP, VA
(without solvent)
Pancreatin 1USP, VA
cHex as solvent
Tracese
—
Tracese
—
4
Tracese
—
Tracese
—
5
Pancreatin 4 USP, VA
Tracese
—
Tracese
—
6
PPL, VA
Tracese
—
Tracese
—
7
CAL-B, VA
CAL-B, VB
CAL-B, VB
CAL-B, VB
42
—
55
—
52
—
48
—
53
(79)
43
(99)
47
(99.6)
52
The so-obtained enantiopure monoacetate (À)-2f was then sily-
lated with a triisopropylsilyl group in conventional conditions,
quantitatively leading to (+)-5fe (Scheme 4, top). The acetate was
then cleaved and the corresponding alcohol oxidized as reported,
providing the (R)-4-triisopropylsilyloxycyclopent-2-en-1-one (R)-
8
3
9
4
10
24
1e ([a]
20 + 59.1, c = 1.03 MeOH). The latter was thus obtained in
D
(93)
6 steps from furfuryl alcohol with an overall yield of 28%.
a
b
c
THF, rt, VA for vinyl acetate or VB for vinyl butyrate.
Isolated yields.
Determined by GC with Macherey Nagel LIPODEX E column on the crude
During the course of this work, the meso-diacetate 4f has also
been formed (see Table 2, entry 7). Such compound could also be
used as substrate for enzymatic desymmetrization (Scheme 4,
bottom).9 CAL-B was the most effective biocatalyst, providing in
high yield (96%) the monoacetate (+)-2f with a very high ee
mixture after desilylation.
d
From Ref. 8.
Starting material recovered.
e

6990
S. Specklin et al. / Tetrahedron Letters 55 (2014) 6987–6991
9. From free diols: (a) Theil, F.; Schick, H.; Winter, G.; Reck, G. Tetrahedron 1991,
47, 7569–7582; From diesters: (b) Miura, S.; Kurozumi, S.; Toru, T.; Tanaka, T.;
Kobayashi, M.; Matsubara, S.; Ishimoto, S. Tetrahedron 1976, 32, 1893–1898; (c)
Wang, Y.-F.; Chen, C.-S.; Gidaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1984, 106,
3695–3696; (d) Laumen, K.; Schneider, M. Tetrahedron Lett. 1984, 25, 5875–
5878; (e) Laumen, K.; Reimerdes, E. H.; Schneider, M. Tetrahedron Lett. 1985, 26,
407–410; (f) Laumen, K.; Schneider, M. J. Chem. Soc., Chem. Commun. 1986,
1298–1299; (g) Deardorff, D. R.; Matthews, A. J.; MacMeeken, D. S.; Craney, C. L.
Tetrahedron Lett. 1986, 27, 1255–1256; (h) Johnson, C. J.; Bis, S. J. Tetrahedron
Lett. 1992, 33, 7287–7290; (i) Basra, S. K.; Drew, M. G. B.; Mann, J.; Kane, P. D. J.
Chem. Soc., Perkin Trans. 1 2000, 3592–3598; (j) Gracias, V.; Zeng, Y.; Desai, P.;
Aubé, J. Org. Lett. 2003, 5, 4999–5001.
Scheme 5. Chemoenzymatic routes to (R)-4-triisopropylsilyloxycyclopent-2-en-1-
one using a kinetic resolution.
10. Kitamura, M.; Kasahara, I.; Manabe, K.; Noyori, R.; Takaya, H. J. Org. Chem. 1988,
53, 708–710.
11. Ulbrich, K.; Kreitmeier, P.; Vilaivan, Y.; Reiser, O. J. Org. Chem. 2013, 78, 4202–
4206.
12. Singh, G.; Meyer, A.; Aubé, J. J. Org. Chem. 2014, 79, 452–458.
13. Trost, B. M.; Edstrom, E. D. Angew. Chem., Int. Ed. Engl. 1990, 29, 520–522.
14. (a) Rücker, Ch. Chem. Rev. 1995, 95, 1009–1064; (b) Corey, E. J.; Rücker, Ch.
Tetrahedron Lett. 1982, 23, 719–722; (c) Cunico, R. F.; Bedell, L. J. Org. Chem.
1980, 45, 4797–4798; (d) Yu, J.-Q.; Wu, H.-C.; Corey, E. J. Org. Lett. 2005, 7,
1415–1417.
15. Specklin, S.; Gallier, F.; Mezaache, R.; Harkat, H.; Dembelé, Y. A.; Weibel, J.-M.;
Blanc, A.; Pale, P. Tetrahedron Lett. 2011, 52, 5820–5823.
16. (a) Nanni, M.; Tamachi, H.; Moriyama, S. Jpn Kokai Tokkyo Koho 1982,
57062236; (b) Piancatelli, G.; D’Auria, M.; D’Onofrio, F. Synthesis 1994, 867–
889; (c) Morgan, B. S.; Hoenner, D.; Evans, P.; Roberts, S. M. Tetrahedron:
Asymmetry 2004, 15, 2807–2809.
17. Ulbrich, K.; Kreitmeier, P.; Reiser, O. Synlett 2010, 2037–2040.
18. See also the following patents: (a) Laumen, K. PCT Int. Appl. WO 2008-055874;
(b) Jackson, M.; Dahanukar, V. H.; Joseph, S. C.; Reddy Eda, V. V. V.; Ramdas, S.
K. US Patent 2013-0184476.
19. Another fraction containing a mixture of cis and trans isomers was also isolated
with 24% yield.
The so-obtained enantiopure ester (+)-5ge was then cleaved and
the corresponding alcohol oxidized as reported, providing (R)-4-tri-
isopropylsilyloxycyclopent-2-en-1-one (R)-1e ([a]
20 + 59.4, c = 1.04
D
MeOH) (Scheme 5). The latter was thus obtained in 6 steps from
furfuryl alcohol with an overall yield of 19.4%.
In conclusion, we developed and explored various highly
enantioselective chemoenzymatic routes to both (R)- and (S)-4-tri-
isopropylsilyloxycyclopent-2-enone as preliminary step toward
cyclopentanoid natural products. The resolution route from TIPS
alcohol ( )-2e provided an enantiopure compound (99.6 ee), but
with an overall yield of 19% from furfuryl alcohol in 6 steps. The
desymmetrization of the meso-diol 2a also provided an enantio-
pure compound (99.9 ee), but surprisingly without much increase
in the overall yield (28% over 6 steps). In contrast, desymmetriza-
tion of the meso diacetate 4 proved to be the most efficient in
terms of yield (48% over 7 steps) despite requiring one more step,
but slightly less enantioselective (98.5 ee). It is worth mentioning
that these enzymatic routes could be performed on gram scale
(up to 3 g) without any change in ee and yield compared to the
screening milligram scale.
20. Representative procedure for the Luche reduction of enones (cf Table 1): ( )-
cis-2e: To
a stirred solution of the enone 1e (1.630 g, 6.406 mmol) and
cerium(III) chloride heptahydrate (4.774 g, 12.812 mmol) in methanol (40 mL)
was added at À20 °C sodium borohydride (0.242 g, 6.406 mmol). After stirring
for 30 min at À20 °C, the reaction mixture was quenched with 5% hydrochloric
acid solution (50 mL). After warming to room temperature, the mixture was
extracted with dichloromethane (3 Â 100 mL) and the combined organic layers
were dried over sodium sulfate and concentrated in vacuo. The resulting crude
oil was chromatographed on silica gel (pentane/diethyl ether 9/1 to 2/1) to
yield pure compound ( )-cis-2e as colorless oil (1.210 g, 4.718 mmol, 74%) and
a mixture of isomers (0.131 g, 0.512 mmol, 8%).
We are now focusing our attention to the development of new
syntheses of cyclopentyl natural products from those chiral substi-
tuted cyclopentenones.
Acknowledgments
1H NMR: (300 MHz, CDCl3) d (ppm): 5.97–5.91 (2H, m, H2 and H3), 4.74 (1H, dd,
J = 7.0, 4.4 Hz, H1 or H4), 4.58 (1H, dd, J = 7.0, 4.4 Hz, H1 or H4), 2.71 (1H, dt,
J = 13.7, 7.0 Hz, H5), 1.57 (1H, dt, J = 13.7, 4.4 Hz, H5), 1.14–1.00 (21H, m, TIPS).
13C NMR: (75 MHz, CDCl3) d (ppm): 137.3 (C2 or C3), 135.7 (C2 or C3), 75.3 (C1 or
C4), 75.3 (C1 or C4), 45.1 (C5), 18.1, 12.2 (TIPS).
The authors thank the CNRS, France and the French Ministry of
Research for the financial support. S.S. and A.D. thank the French
Ministry of Research for PhD fellowships.
21. Procedure for the enzymatic desymmetrization of the cis-diol 2a (cf Table 2):
To
a stirred solution of the diol 2a (0.200 g, 1.998 mmol), vinyl acetate
(1.33 mL, 13.983 mmol) and triethylamine (1.95 mL, 13.983 mmol) in dry THF
(5 mL) was added Pancreatin (1.000 g, 5 wt equiv, Sigma 4ÂUSP). The
suspension was stirred for 24 h at room temperature and then filtered over a
pad of CeliteÒ. The solid was washed with ethyl acetate (50 mL) and the filtrate
was concentrated. The oily residue was then chromatographed on silica gel
(cyclohexane/ethyl acetate 4:1 to 2:1) to yield the monoacetate (À)-2f as a
yellow solid (0.150 g, 1.059 mmol, 53%) and the diacetate derivative 4f as
yellow oil (0.160 g, 1.125 mmol, 43%).
References and notes
1. Umino, K.; Furumai, T.; Matsuzawa, N.; Awataguchi, Y.; Ito, Y. J. Antibiotics
1973, 26, 506–512.
2. (a) Lai, S. M.; Manley, P. W. Nat. Prod. Rep. 1984, 1, 409–411; (b) Collins, P. W.;
Djuric, S. W. Chem. Rev. 1993, 93, 1533–1564.
3. (a) Hasegawa, T.; Kamiya, T.; Henmi, T.; Iwasaki, H.; Yamatodani, S. J. Antibiotics
1975, 28, 167–175; (b) Nakagawa, M.; Furihata, K.; Hayakawa, Y.; Seto, H.
Tetrahedron Lett. 1991, 32, 659–662.
4. For reviews, see: (a) Nicolaou, K. C.; Smith, A. L. In Modern Acetylene Chemistry;
Stang, P. J., Diederich, F., Eds.; VCH: Weinheim, 1995; pp 203–283; (b)
Lhermitte, H.; Grierson, D. S. Contemp. Org. Synth. 1996, 3, 41–63 and 93–124;
(c) Smith, A. L.; Nicolaou, K. C. J. Med. Chem. 1996, 39, 2103–2117; (d) Galm, U.;
Hager, M. H.; Van Lanen, S. G.; Ju, J.; Thorson, J. S.; Shen, B. Chem. Rev. 2005, 105,
739–758; (e) Gredicak, M.; Jeric, I. Acta Pharm. 2007, 57, 133–150; (f) Shao, R.-
G. Curr. Mol. Pharmacol. 2008, 1, 50–60; (g) Jean, M.; Tomasi, S.; van de Weghe,
P. Org. Biomol. Chem. 2012, 10, 7453–7456.
5. Roche, S. P.; Aitken, D. J. Eur. J. Org. Chem. 2010, 5339–5358.
6. (a) Khanapure, S. P.; Najafi, N.; Manna, S.; Yang, J-J.; Rokach, J. J. Org. Chem.
1995, 60, 7548–7551; (b) Bertus, P.; Zhang, J. H.; Sir, G.; Weibel, J.-M.; Pale, P.
Tetrahedron Lett. 2003, 44, 3391–3395.
(À)-2f: 1H NMR: (300 MHz, CDCl3) d (ppm): 6.14–6.09 (1H, m, H2), 6.01–5.96
(1H, m, H3), 5.54–5.45 (1H, m, H1), 4.75–4.68 (1H, m, H4), 2.80 (1H, dt, J = 14.7,
7.4 Hz, H5), 2.05 (3H, s, Ac), 1.66 (1H, dt, J = 14.7, 3.8 Hz, H5). 13C NMR:
(75 MHz, CDCl3) d (ppm):170.9 (C@O Ac), 138.6 (C2), 132.6 (C3), 77.2 (C1), 74.9
20
(C4), 40.6 (C5), 21.3 (Ac). [
a
]
À 70.3 (c 1, CHCl3); 99.9 ee determined by GC
D
measurement on the crude product (Lipodex E, 25 m  0.25 mm).
4f: 1H NMR: (300 MHz, CDCl3) d (ppm): 6.07–6.05 (2H, m, H2 and H3), 5.53 (2H,
ddd, J = 7.6, 3.9, 0.9 Hz, H1 and H4), 2.86 (1H, dt, J = 15.0, 7.6 Hz, H5), 2.04 (6H, s,
CH3 Ac), 1.72 (1H, dt, J = 14.8, 3.9 Hz, H5). 13C NMR: (75 MHz, CDCl3) d (ppm):
170.8 (C@O Ac), 134.7 (C2 and C3), 76.7 (C1 and C4), 37.2 (C5), 21.2 (CH3 Ac).
22. Kirk, O.; Christensen, M. W. Org. Process Res. Dev. 2002, 6, 446–451.
23. (a) Uppenberg, J.; Öhrner, N.; Norin, M.; Hult, K.; Kleywegt, G. J.; Patkar, S.;
Waagen, V.; Anthonsen, T.; Jones, T. A. Biochemistry 1995, 34, 16838–16851; (b)
Raza, S.; Fransson, L.; Hult, K. Protein Sci. 2001, 10, 329–338.
7. From the free hydroxy enone: (a) Babiak, K. A.; Ng, J. S.; Dygos, J. H.; Weyker, C.
L.; Wang, Y.-F.; Wong, C.-H. J. Org. Chem. 1990, 55, 3377–3381; (b) Ghorpade, S.
R.; Bastawade, K. B.; Gokhale, D. V.; Shinde, P. D.; Mahajan, V. A.; Kalkote, U. R.;
Ravindranathan, T. Tetrahedron: Asymmetry 1999, 10, 4115–4122; From
corresponding esters: see Ref. 7b and (c) Washausen, P.; Grebe, H.; Kieslich,
K.; Winterfeldt, E. Tetrahedron Lett. 1989, 30, 3777–3778; (d) Sukumaran, J.;
van Gool, J.; Hanefeld, U. Enzyme Microb. Technol. 2005, 37, 254–260; (e)
Kumaraguru, T.; Fadnavis, N. W. Tetrahedron: Asymmetry 2012, 23, 775–779; (f)
Kumaraguru, T.; Babita, P.; Sheelu, G.; Lavanya, K.; Fadnavis, N. W. Org. Process
Res. Dev. 2013, 17, 1526–1530.
24. Procedure for the enzymatic desymmetrization of the cis-diacetate 4f (cf
Scheme 4): To a stirred solution of the diacetate 4f (0.100 g, 0.543 mmol) in
2.7 mL freshly prepared aqueous phosphate buffer solution (0.1 M, pH 8) was
added Candida antarctica CAL-B (5.4 mg). The suspension was stirred for 24 h at
room temperature and then filtered over a pad of CeliteÒ. The solid was
washed with water (10 mL) and then with ethyl acetate (10 mL). The aqueous
layer was extracted with ethyl acetate (4 Â 10 mL). The combined organic
layers were dried over sodium sulfate and concentrated in vacuo. The oily
residue was then chromatographed on silica gel (cyclohexane/ethyl acetate 4:1
to 2:1) to yield the monoacetate (+)-2f as a white solid (0.074 g, 0.521 mmol,
96%). Spectral data are identical to those already reported for (À)-2f
8. Curran, T. T.; Hay, D. A.; Koegel, C. F. Tetrahedron 1997, 53, 1983–2004.

S. Specklin et al. / Tetrahedron Letters 55 (2014) 6987–6991
6991
(see Ref. 16), 98.5 ee determined by GC measurement on the crude product
(Lipodex E, 25 m  0.25 mm).
52%). (À)-5ge: 1H NMR: (300 MHz, CDCl3) d (ppm): 6.02 (1H, dt, J = 5.6, 1.7 Hz,
H2), 5.88 (1H, dt, J = 5.6, 1.3 Hz, H3), 5.49–5.45 (1H, m, H1), 4.81–4.78 (1H, m,
H4), 2.84 (1H, dt, J = 13.7, 7.4 Hz, H5), 2.35 (2H, t, J = 7.3 Hz, H2‘), 1.71–1.59 (3H,
m, H5 and H3‘), 1.10–1.00 (21H, m, TIPS), 0.94 (3H, t, J = 7.4 Hz, H4‘). 13C NMR:
(75 MHz, CDCl3) d (ppm): 173.6 (C1‘), 139.1 (C2), 131.3 (C3), 76.7 (C1), 75.0 (C4),
25. Representative procedure for the enzymatic resolution of monosilylated cis-
diols (cf Table 3): To a stirred mixture of ( )-cis-2e (0.402 g, 1.569 mmol), vinyl
butyrate (1.00 mL, 7.843 mmol), and triethylamine (0.15 mL, 1.098 mmol) in
THF (16 mL) was added Candida antarctica CAL-B (0.044 g). The suspension was
stirred at room temperature for 4 h then filtered over a pad of CeliteÒ. The solid
residue was then washed with ethyl acetate (20 mL) and the filtrate
concentrated in vacuo. The resulting crude oil was chromatographed on
silica gel (cyclohexane/ethyl acetate 9/1) to yield the butyrate derivative (À)-
5ge (0.243 g, 0.744 mmol, 47%) and the alcohol (À)-2e (0.208 g, 0.811 mmol,
41.7 (C5), 36.46 (C2‘), 18.6 (C3‘), 18.1 (CH3 TIPS), 13.8 (C4‘), 12.2 (CH TIPS).
20
[a
]
D
À 3 (c 0.5, MeOH); 99.6 ee determined by GC measurement on the crude
product after desilylation (Lipodex E, 25 m  0.25 mm). (À)-2e: Spectral data
20
are identical to those already reported for ( )-cis-2e (see Ref. 17), [
a
]
À 12.8
D
(c 0.5, MeOH).