Chiral non-racemic dihydroxysulfones via hydrolytic kinetic resolutions - Synthesis of oxacyclic ring systems using intramolecular acylation strategies

Article abstract of DOI:10.1016/S0040-4039(01)00856-5

A number of chiral non-racemic 1,2-dihydroxysulfones have been prepared in good yields and high enantiomeric excesses by hydrolytic kinetic resolution of the corresponding epoxysulfones with Jacobsen's (S,S)-salen(Co)III(OAc) catalyst. The intramolecular cyclization reactions of the acyl and ethoxycarbonyl derivatives of these dihydroxysulfones have been exploited to access a variety of functionalized chiral non-racemic cyclic ethers and lactones in good yields.

Full text of DOI:10.1016/S0040-4039(01)00856-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4747–4750
Chiral non-racemic dihydroxysulfones via hydrolytic kinetic
resolutions—synthesis of oxacyclic ring systems using
intramolecular acylation strategies
Chunyang Jin, Raina D. Ramirez and Aravamudan S. Gopalan*
Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, NM 88003-8001, USA
Received 7 May 2001; accepted 10 May 2001
Abstract—A number of chiral non-racemic 1,2-dihydroxysulfones have been prepared in good yields and high enantiomeric
excesses by hydrolytic kinetic resolution of the corresponding epoxysulfones with Jacobsen’s (S,S)-salen(Co)III(OAc) catalyst. The
intramolecular cyclization reactions of the acyl and ethoxycarbonyl derivatives of these dihydroxysulfones have been exploited to
access a variety of functionalized chiral non-racemic cyclic ethers and lactones in good yields. © 2001 Elsevier Science Ltd. All
rights reserved.
A major effort in our laboratory has been the develop-
ment of asymmetric synthetic methods for the prepara-
tion of chiral hydroxysulfones and to exploit the
intramolecular cyclization reactions of their derivatives
to provide functionalized ring systems with stereochem-
ical control.1,2 The intramolecular cyclization reactions
of some simple g and d acyloxysulfones have been shown
to provide a convenient route for the preparation of a
number of functionalized chiral non-racemic dihydro-
furans and dihydropyrans.1b The corresponding cycliza-
tion reactions of the ethoxycarbonyl derivatives is also
a valuable tool for the preparation of a variety of lactones
and bicyclic lactones in good yields.2
The usefulness of these dihydroxysulfones to the synthe-
sis of a number of functionalized chiral cyclic ethers and
lactones is also disclosed.
Asymmetric dihydroxylation (Sharpless AD) of terminal
alkenes is a potentially useful and convenient method for
accessing chiral non-racemic dihydroxysulfones.5 How-
ever, the optical purities of the derived products are often
not high in the Sharpless AD of 1-alkenes and the
reaction is still being optimized.6 The application of the
Sharpless AD reaction to prepare chiral dihydroxysul-
fones of high optical purities was first investigated. A
number of v-phenylsulfonyl-1-alkenes 1a–d were pre-
pared and their oxidation reactions using commercially
available AD-mix-b were studied (Eq. (1)). The enan-
tiomeric excess of the diol products was determined by
derivatization with (R)-(+)-a-methoxy-a-(trifluoro-
methyl)-phenylacetyl chloride followed by 19F NMR
spectral analysis. Unfortunately, in the case of the shorter
chain alkenes 1a–c, the diol products 2a–c were obtained
in good yields but unsatisfactory optical purities. Only
the AD reaction of 1d gave satisfactory yield and high
optical purity of the corresponding product 2d.
A number of publications on the preparation of simple
chiral hydroxysulfones using enzymatic reductions (for
example baker’s yeast) of the corresponding ketones or
lipase catalyzed resolutions have appeared.2,3 On the
other hand, methodology to access chiral 1,2-dihydroxy-
sulfones or other trifunctional hydroxysulfones are still
very limited.4 In this communication, we would like to
report on a convenient way to make chiral 1,2-dihydroxy-
sulfones using hydrolytic kinetic resolution of epoxysul-
fones with Jacobsen’s (S,S)-salen(Co)III(OAc) catalyst.
AD-mix-β, 1:1 tBuOH-H2O
OH
PhSO2
OH
PhSO2
0 oC, 5 to 48 h
(
)
n
(
)
n
(1)
1a n=1
1b n=2
1c n=3
1d n=9
2a n=1, 88% yield, 42% ee
2b n=2, 92% yield, 53% ee
2c n=3, 82% yield, 37% ee
2d n=9, 98% yield, 92% ee
Keywords: hydrolytic kinetic resolution; dihydroxysulfone; intramolecular acylation; oxacyclic ring.
* Corresponding author. Tel.: +1 505 646 2589; fax: +1 505 646 2394; e-mail: agopalan@nmsu.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00856-5

4748
C. Jin et al. / Tetrahedron Letters 42 (2001) 4747–4750
Recently, there has been much interest in the applica-
tions of the hydrolytic kinetic resolution (HKR) of
terminal epoxides with Jacobsen’s salen(Co)III(OAc)
catalysts.7,8 This method is versatile and is based on the
enantioselective ring opening of a terminal epoxide by
water or other simple nucleophiles in the presence of
the chiral metal ligand catalyst. Access to either enan-
tiomer of the desired dihydroxysulfones can be
obtained with a simple change in the chiral catalyst.
The application of this exciting method for the prepara-
tion of chiral dihydroxysulfones was then examined.
its conversion to g-hydroxyvinyl sulfone upon treat-
ment with sodium hydroxide. The epoxide 3a is also
unstable to the HKR reaction conditions and some
formation of the g-hydroxyvinyl sulfone was observed
in the crude product mixture.
With these chiral non-racemic 1,2-dihydroxysulfones in
hand, we were ready to examine the intramolecular
cyclization reactions of their acyl and ethoxycarbonyl
derivatives. The 1,2-di-acyloxysulfones 5b–c were easily
made by esterification of 2b–c with excess butyryl chlo-
O
(S,S)-Salen(Co)III(OAc)
( 1 mole % )
OH
O
PhSO2
+
OH
PhSO2
( )
PhSO2
( )
n
n
THF, H2O (0.55 eq.), rt
( )
n
4a-d
2a-d
3a n=1
3b n=2
3c n=3
3d n=9
(2)
The ( )-epoxysulfones 3a–d required for our study were
easily made from the corresponding v-phenylsulfonyl-
1-alkenes by oxidation with m-CPBA in good yields.
The HKR reaction of these epoxides was carried out as
per published procedures.7 The epoxide in THF was
stirred at room temperature in the presence of (S,S)-
salen(Co)III(OAc) catalyst (1.0 mol%) and H2O (0.55
equiv.) (Eq. (2)). The progress of the reaction was
monitored by TLC, and the reaction worked up after
approximately 50% conversion (10–30 h). The products
1,2-diols and the unreacted epoxide starting materials
were separated by silica-gel chromatography.9 Subse-
quently, the optical purities of the diols 2a–d were
determined by analysis of their di-MTPA esters. Sam-
ples of the epoxides 4a–d were first hydrolyzed to the
corresponding diols with 0.5N NaOH in H2O–tBuOH
(5:1) at 60°C10 and then the optical purities were deter-
mined as described earlier. The absolute configurations
of the products were determined by application of the
models for the HKR reactions as well as comparisons
with literature values of optical rotations in the case of
known compounds.4
ride in the presence of Et3N in CH2Cl2 (Scheme 1). In
a representative sequence, the sulfone 5b was treated
with LHMDS (1.1 equiv.) in THF at −78°C for 3 h and
then, the reaction quenched with saturated ammonium
chloride at −78°C. The crude product that was isolated
was an inseparable mixture of the lactol 6b and the
open chain hydroxy ketone 7b.1b Dehydration of this
mixture with TsOH in benzene gave the chiral dihydro-
furan 8b, as the only product in 74% yield after chro-
matographic purification. Clearly, the dominant
pathway involves the cyclization of the sulfonyl carban-
ion of 5b to give the five-membered ring rather than the
six-membered ring product. Similarly, the cyclization
reaction of 5c followed by dehydration with TsOH gave
dihydropyran 8c rather than the corresponding seven-
membered ring system in 68% yield. Basic hydrolysis of
8b and 8c gave 9b ([h]D=−66.8°, c 1.7, CHCl3) and 9c
([h]D=−117.2°, c 1.5, CHCl3), respectively.11
Intramolecular cyclization to give the larger ring sys-
tems (for example six rather than five) can be achieved
by use of protected monoacyl derivatives of dihydroxy-
sulfones 2b–c. The primary alcohol of 2b–c can be
selectively esterified by reaction with butyryl chloride
(1.0 equiv.) and Et3N (1.0 equiv.) using dibutyltin oxide
(0.02 equiv.) as a catalyst (Scheme 2).12 These reactions
gave 10b–c in good yields with excellent selectivities
(>15:1 for mono to di). Then the secondary alcohol was
protected by treatment with TBDMS or TBDPS chlo-
It is pleasing to note that a number of 1,2-dihydroxy-
sulfones as well as the corresponding epoxides can be
prepared in good yields and high optical purities using
the HKR reactions (Table 1). The only exception is in
the case of the epoxide 4a. The enantiomeric excess of
this compound could not be reliably established due to
Table 1. Hydrolytic kinetic resolution of terminal epoxysulfones
Substrates
Diols 2a–d
ee (%)a
[h]D, c (g/dL)
Epoxides 4a–d
[h]D, c (g/dL)
Yield (%)
EtOH
Yield (%)
ee (%)b
CHCl3
3a
3b
3c
3d
32
44
44
44
95
94
94
+21.0°, 1.4
+23.2°, 1.4
+20.5°, 1.4
+9.1°, 1.4
50
48
48
49
–
95
92
91
−3.8°, 3.3
−24.4°, 3.1
−19.5°, 3.1
−4.9°, 3.3
\98
a Enantiomeric excesses were determined by 19F NMR analysis of the corresponding di-MTPA esters.
b The epoxides were analyzed after conversion to diols.10

C. Jin et al. / Tetrahedron Letters 42 (2001) 4747–4750
4749
O
OH
Butyryl chloride
Et3N, CH2Cl2
O
OH
(
)
n
PhSO2
O
(
)
n
PhSO2
2b n=1
2c n=2
O
5b n=1, 77%
5c n=2, 76%
OH
O
1.1 eq. LHMDS, THF
-78 oC
OH
O
PhSO2
O
C3H7
( )
O
( )
n
PhSO2
n
C3H7
6b n=1
6c n=2
O
7b n=1
7c n=2
O
O
O
CH2OCOC3H7
CH2OH
TsOH, PhH, rt
0.1 N KOH
THF, rt
(
)
n
(
)
n
PhSO2
PhSO2
8b n=1, 74%
8c n=2, 68%
9b n=1, 95%
9c n=2, 97%
Scheme 1.
OH
OH
O
Butyryl chloride, Et3N
Bu2SnO, CH2Cl2, 0 o
OH
C
( )
( )
n
n
PhSO2
PhSO2
O
2b n=1
2c n=2
10b n=1, 85%
10c n=2, 91%
1. 1.1 eq. LHMDS
THF, -78 oC
Imidazole, DMF
TBDMSCl or TBDPSCl
OR
O
2. TsOH, PhH, rt
O
O
( )
PhSO2
n
( )
n
PhSO2
OR
11b n=1, R=TBDMS, 95%
11c n=2, R=TBDPS, 92%
12b n=1, R=TBDMS, 76%
12c n=2, R=TBDPS, 63%
Scheme 2.
ride to give 11b or 11c in high yields. Treatment of 11b
with LHMDS (1.1 equiv.) in THF at −78°C for 2 h
gave a mixture of lactol and the open chain hydroxy
ketone. Subsequent dehydration of the mixture with
TsOH in benzene gave the chiral dihydropyran 12b
([h]D=+33.6°, c 1.1, EtOH) in 76% yield. The cycliza-
tion reaction of 11c followed by dehydration gave the
chiral seven-membered cylic ether 12c ([h]D=−70.7°, c
1.1, EtOH) in 63% yield.
The intramolecular cyclization reaction of diethoxycar-
bonyl derivative of chiral 1,2-dihyroxysulfone 2b has
also been studied and gave some surprising results. The
sulfone substrate 13b was treated with 2.2 equiv. of
LHMDS at −78°C and quenched after 1 h with satu-
rated ammonium chloride (Scheme 3). Unexpectedly, a
diastereomeric mixture of d-lactone 14b (1:1) was iso-
lated as the only product in 95% yield.13 In this case,
cyclization occured to give the larger ring d-lactone
O
Ethyl chloroformate
pyridine, 87%
OH
OEt
O
OH
O
OEt
PhSO2
PhSO2
2b
13b
O
2.2 eq. LHMDS, THF
-78 oC, 95%
O
O
O
PhSO2
O
OEt
14b
Scheme 3.

4750
C. Jin et al. / Tetrahedron Letters 42 (2001) 4747–4750
system and no g-lactone was detected in the product
mixture. This result is opposite to that observed in the
cyclization of the corresponding diacyl derivative 5b,
which favored the formation of the smaller ring. Fur-
ther investigations are necessary to understand the
observed ring selectivity in this cyclization.
8, 3101.
4. (a) Tong, Z.; Chen, Y.; Hentemann, M. F.; Fuchs, P. L.
Tetrahedron Lett. 2000, 41, 7795; (b) Tanikaga, R.; Shi-
bata, N.; Yoneda, T. J. Chem. Soc., Perkin Trans. 1 1997,
2253; (c) Sato, T.; Okumura, Y.; Itai, J.; Fujisawa, T.
Chem. Lett. 1988, 1537.
5. Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483.
In conclusion, Jacobsen’s hydrolytic kinetic resolution
provides an attractive method for the preparation of a
number of chiral non-racemic 1,2-dihydroxysulfones in
high ee. Furthermore, the intramolecular cyclization
reactions of the acyl derivatives of these dihydroxysul-
fones are valuable for the preparation of a number of
functionalized chiral non-racemic cyclic ethers in good
yields. The intramolecular cyclization of ethoxycar-
bonyl derivative 13b also proceeds efficiently but gives
the functionalized d-lactone as the only product in good
yield. By proper choice of protecting groups, these
cyclizations can be controlled to form various ring
systems enhancing the synthetic utility of dihydroxysul-
fones. Finally, applications to the preparation of
macrocyclic ring systems using this methodology are
under investigation.
6. (a) Mehltretter, G. M.; Do¨bler, C.; Sundermeier, U.;
Beller, M. Tetrahedron Lett. 2000, 41, 8083; (b) Hoye, T.
R.; Mayer, M. J.; Vos, T. J.; Ye, Z. H. J. Org. Chem.
1998, 63, 8554; (c) Becker, H.; Sharpless, K. B. Angew.
Chem., Int. Ed. Engl. 1996, 35, 448.
7. Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E.
N. Science 1997, 277, 936.
8. (a) Ready, J. M.; Jacobsen, E. N. J. Am. Chem. Soc.
2001, 123, 2687; (b) Breinbauer, R.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 2000, 39, 3604; (c) Liu, Z. Y.; Ji,
J. X.; Li, B. G. J. Chem. Soc., Perkin Trans. 1 2000, 3519;
(d) Wro´blewski, A. E.; Halajewska-Wosik, A. Tetra-
hedron: Asymmetry 2000, 11, 2053; (e) Wyatt, P. B.;
Blakskjær, P. Tetrahedron Lett. 1999, 40, 6481; (f) Savle,
P. S.; Lamoreaux, M. J.; Berry, J. F.; Gandour, R. D.
Tetrahedron: Asymmetry 1998, 9, 1843.
9. After column chromatography, the diols and epoxides
were contaminated with trace amounts of the catalyst.
They were further purified by washing with hexane (diols
and 4a) or Kugelrohr distillation (epoxides 4b–d)
10. Suzuki, M.; Morita, Y.; Yanagisawa, A.; Baker, B. J.;
Scheuer, P. J.; Noyori, R. J. Org. Chem. 1988, 53, 286.
Acknowledgements
We thank the NIH-MARC Program (GM07667-22)
and the NIH-RISE program (GM61222-01) for their
support (R.D.R.). Dr. Hollie Jacobs is also thanked for
her insightful comments.
1
11. Compound 9b: H NMR (200 MHz, CDCl3): l 7.90–7.45
(m, 5H), 4.80–4.60 (m, 1H), 3.73–3.50 (m, 2H), 2.86 (t,
J=12.1 Hz, 1H), 2.73–2.54 (m, 3H), 2.23 (br, 1H), 1.62
(tq, J=7.7, 7.7 Hz, 2H), 0.96 (t, J=7.0 Hz, 3H). Anal.
calcd for C14H18O4S: C, 59.55; H, 6.43%. Found: C,
59.46; H, 6.60%.
References
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Lett. 2000, 41, 9753; (b) Jacobs, H. K.; Gopalan, A. S. J.
Org. Chem. 1994, 59, 2014 and references therein.
2. (a) Gonzales, S. S.; Jacobs, H. K.; Juarros, L. E.;
Gopalan, A. S. Tetrahedron Lett. 1996, 37, 6827; (b)
Jacobs, H. K.; Mueller, B. H.; Gopalan, A. S. Tetra-
hedron 1992, 48, 8891.
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U. P.; Pawlak, J. M.; Vaidyanathan, R. Org. Lett. 1999,
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13. Compound 14b: 1H NMR (200 MHz, CDCl3): l 7.95–
7.55 (m, 5H), 5.06 (dddd, J=10.0, 7.8, 6.1, 3.9 Hz, 0.5H),
4.82–4.58 (m, 1.5H), 4.31–3.93 (m, 4H), 2.72–2.40 (m,
2H), 1.09 (t, J=7.1 Hz, 1.5H), 1.08 (t, J=7.2 Hz, 1.5H).
Anal. calcd for C14H16O7S: C, 51.21; H, 4.91%. Found:
C, 50.99; H, 4.85%.
.