Asymmetric Ring Opening of Meso Epoxides with Thiols: Enantiomeric Enrichment Using a Bifunctional Nucleophile

Full text of DOI:10.1021/jo980155d

5252
J . Org. Chem. 1998, 63, 5252-5254
Asym m etr ic Rin g Op en in g of Meso
Ep oxid es w ith Th iols: En a n tiom er ic
En r ich m en t Usin g a Bifu n ction a l
Nu cleop h ile
Michael H. Wu and Eric N. J acobsen*
Department of Chemistry and Chemical Biology, Harvard
University, Cambridge, Massachusetts 02138
Received J anuary 28, 1998
In tr od u ction
The desymmetrization of meso epoxides via nucleo-
philic ring opening is a powerful strategy for establishing
two contiguous stereogenic centers in a single event.1 Our
contributions to this area began with the discovery that
the (salen)Cr(III) complex 1 catalyzes the addition of
TMSN3 to meso epoxides with high enantioselectivity.2
This methodology has been successfully applied to the
kinetic resolution of terminal epoxides3 and to the
synthesis of a variety of biologically important compounds
containing the â-amino alcohol motif.4 We now report
extension of the (salen)Cr-catalyzed asymmetric ring
opening (ARO) technology5 to include alkanethiols as
nucleophiles. In particular, we demonstrate the use of
a bifunctional thiol to afford doubly ring opened products
in good yield and high enantiomeric excess.
F igu r e 1. Double ARO strategy using a dithiol nucleophile.
that benzyl mercaptan afforded the ring-opened product
in highest ee (eq 1).7
Resu lts a n d Discu ssion
An important breakthrough in thiol addition to meso
epoxides was achieved recently by Shibasaki through the
use of a gallium-lithium heterobimetallic binaphthoxide
system.6 Using 10 mol % of the catalyst and 4 Å
molecular sieves, this system was found to effect the
addition of tert-butyl thiol to cyclic and acyclic meso
epoxides in 82-98% enantiomeric excess (ee). Our own
screen of several transition metal-salen complexes using
tert-butyl thiol as the nucleophile and cyclohexene oxide
as the electrophile revealed that Cr catalyst 1 was highly
efficient but only poorly enantioselective (10% ee). After
evaluating a wide range of thiol structures, we identified
Unfortunately, modification of the steric and electronic
properties of the ligand substituents did not lead to any
further improvement in enantioselectivity beyond the
moderate level of 59% ee. We reasoned that the use of a
dithiol would result in addition of 2 equiv of epoxide to
afford mixtures of chiral and meso bis-adducts (Figure
1). Assuming no diastereoselection in the second ring-
opening event, a reaction with a monofunctional thiol
reagent that affords a [x:(1 - x)] ratio of enantiomers will
provide an improved enantiomer ratio of [x2:(1 - x)2] with
a bifunctional nucleophile, along with 2x(1 - x) of the
meso product. This concept has been applied previously,
primarily as a means to improve the optical purity of
partially enriched mixtures of enantiomers via derivati-
zation with a bifunctional acylating reagent.8
(1) (a) Hodgson, D. M.; Gibbs, A. R.; Lee, G. P. Tetrahedron 1996,
52, 1461. (b) Paterson, I.; Berrisford, D. J . Angew. Chem., Int. Ed. Engl.
1992, 31, 1179.
(2) Mart´ınez, L. E.; Leighton, J . L.; Carsten, D. H.; J acobsen, E. N.
J . Am. Chem. Soc. 1995, 117, 5897.
(3) Larrow, J . F.; Schaus, S. E.; J acobsen, E. N. J . Am. Chem. Soc.
1996, 118, 7420.
(4) (a) Schaus, S. E.; J acobsen, E. N. Tetrahedron Lett. 1996, 37,
7937. (b) Wu, M. H.; J acobsen, E. N. Tetrahedron Lett. 1997, 38, 1693.
(5) For asymmetric ring-opening reactions catalyzed by the corre-
sponding Co(salen) complex, see: (a) J acobsen, E. N.; Kakiuchi, F.;
Konsler, R. G.; Larrow, J . F.; Tokunaga, M. Tetrahedron Lett. 1997,
38, 773. (b) Tokunaga, M.; Larrow, J . F.; Kakiuchi, F.; J acobsen, E. N.
Science 1997, 277, 936.
(6) (a) Iida, T.; Yamamoto, N.; Sasai, H.; Shibasaki, M. J . Am. Chem.
Soc. 1997, 119, 4783. For other examples, see: (b) Fukuzawa, S.; Kato,
H.; Ohtaguchi, M.; Hayashi, Y.; Yamazaki, H. J . Chem. Soc., Perkins
Trans. 1 1997, 3059. (c) Yamashita, H.; Mukaiyama, T. Chem. Lett.
1987, 525.
(7) The absolute configuration of this product was determined by
comparison of optical rotation values reported in ref 6c. All other
assignments were made by analogy.
S0022-3263(98)00155-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/25/1998

Notes
J . Org. Chem., Vol. 63, No. 15, 1998 5253
Ta ble 1. Asym m etr ic Rin g Op en in g of Meso Ep oxid es
by Dith iol 2 Ca ta lyzed by (S,S)-(sa len )Cr Com p lex 1
catalyzed ring opening of cyclopentene oxide and related
meso epoxides. The ability of (salen)M(III) complexes to
catalyze highly enantioselective processes ranging from
asymmetric oxidations11 to nucleophile/electrophile reac-
tions2,5 and cycloaddition reactions12 is certainly striking,
and it remains a focus of our continued research efforts.
entry
X
time, h yield,a
%
C2:mesob ee of C2, %
a
CH2CH2
N-BOC
O
24
72
96
24
95
84
69
95
1.8:1
2.1:1
2.2:1
2.8:1
85
89
91
93
b
cc
d
CH2
a
Isolated yield of all stereoisomers after chromatography.
Diastereomeric and enantiomeric ratios were determined by
Exp er im en ta l Section
b
HPLC (see Experimental Section). c A 1:1 TBME/THF solvent
mixture was used with 10 mol % 1.
Rep r esen ta tive P r oced u r e for th e Asym m etr ic Rin g
Op en in g of Ep oxid es by 2. Com p ou n d s 3a a n d 4a . A 50-
mL Schlenk flask equipped with stir bar was charged with 1.19
g (7.0 mmol, 0.35 equiv) of dithiol 2, and this white solid was
then dissolved in 25 mL of TBME. Under an N2 atmosphere,
2.02 mL (20.0 mmol, 1.00 equiv) of cyclohexene oxide was added
via syringe. Solid Catalyst 1 (0.263 g, 0.40 mmol, 0.02 equiv)
was then added in one portion to afford a brown, homogeneous
solution that was quickly degassed by three freeze-pump-thaw
cycles. The reaction was then allowed to stir under an atmo-
sphere of N2 for 24 h, during which time the reaction became
heterogeneous. At this stage, solvent was removed in vacuo,
and the resulting brown oil was loaded directly onto a silica
column (7.5 cm × 12 cm). Elution with 10% EtOAc in CH2Cl2
afforded 2.42 g (6.61 mmol, 95% yield) of 3a and 4a as a mixture
Given the relative success attained with benzyl mer-
captan in the ARO with 1, we chose the p-xylene dithiol
29 as the dithiol derivative to evaluate in the double ARO
strategy. Cyclohexene oxide underwent reaction with 2
in the presence of catalyst 1 to afford the corresponding
bishydroxysulfide in 85% ee and excellent yield. Careful
exclusion of air from the reaction medium was found to
be critical, as trace amounts led to the formation of
disulfide byproducts. Smaller carbocyclic and hetero-
cyclic meso epoxides also proved to be effective sub-
strates, with the ring opening of cyclopentene oxide
affording product in highest ee (Table 1). The chiral
cyclopentyl bishydroxysulfide 3d could be efficiently
separated from the meso diastereomer by means of
preparative HPLC, and the optically pure bishydroxy-
sulfide was obtained by following a single recrystalliza-
tion in 54% overall yield.
that solidified upon solvent removal: mp 99-100 °C; R23
)
;
D
-33.9° (c ) 1.0, CH2Cl2); IR (KBr) 3350 (b), 2932, 2853 cm-1
1H NMR (CDCl3) δ 7.27 (4H, s), 3.76 (4H, m), 3.29 (2H, m), 2.76
(2H, m), 2.47 (2H, m), 2.01-2.07 (4H, m), 1.66-1.71 (4H, m),
1.41-1.45 (2H, m), 1.21-1.27 (6H, m); 13C NMR (CDCl3) 138.0,
129.0, 72.2, 53.0, 34.4, 33.8, 32.6, 26.1, 24.3; exact mass (CI) calcd
for C20H30O2S2 [M + NH4]+ 384.2031, found 384.2031. The
stereoisomers were analyzed by HPLC using two (R,R) Whelko
columns in tandem, eluting with 3% EtOH in hexanes at 1 mL/
min [tR 55.4, 61.2 (meso), 66.0 min]. Analysis of the reaction
mixture showed a C2:meso ratio of 1.8:1, with the chiral products
present in 85% ee.
Com p ou n d s 3b a n d 4b. Flash chromatography (20-60%
EtOAc/CH2Cl2, 5 cm × 10 cm) afforded 3b and 4b in 84% overall
yield: mp 166-170 °C; R23D ) -32.6° (c ) 0.5, CH2Cl2); IR (KBr)
3245 (b), 2976, 2932, 1670 cm-1; 1H NMR (MeOH-d4) δ 7.31 (4H,
s), 4.13 (2H, m), 3.82 (4H, m), 3.40-3.61 (4H, m), 3.19-3.30 (4H,
m), 3.00-3.09 (2H, m), 1.44 (18H, s); 13C NMR (MeOH-d4, 318
K) 154.5, 137.3, 129.1, 79.8, 74.8, 52.1, 50.1, 48.9, 35.9, 28.4;
exact mass (FAB) calcd for C24H40N2O6S2 [M + Na]+ 563.2226,
found 563.2223. The stereoisomers were analyzed as the bis(4-
nitrobenzoate) esters by HPLC using a Chiracel OD column,
eluting with 20% IPA/hexane at 1.2 mL/min [tR 36.3, 42.4 (meso),
54.1 min].
The cyclopentene oxide derived ring-opening product
3d was readily transformed into the free thiol by dis-
solving metal reduction of the silyl ether 5 (eq 3). This
straightforward deprotection strategy allows the synthe-
sis of enantiopure â-hydroxy thiols, which can serve as
conformationally constrained chiral scaffolds for the
synthesis of compounds of potential biological interest or
as ligands for asymmetric catalysis.10
Com p ou n d s 3c a n d 4c. Flash chromatography (60-100%
EtOAc/CH2Cl2, 5 cm × 12 cm) afforded 3c and 4c in 69% overall
yield: mp 129-130 °C; R23D ) +41.0° (c ) 1.0, MeOH); IR (KBr)
3374 (b), 2943, 2880 cm-1 1H NMR (MeOH-d4) δ 7.30 (4H, s),
;
4.19 (2H, m), 4.11 (dd, 2H, J ) 9.2, 6.4 Hz), 3.93 (dd, 2H, J )
9.5, 4.4 Hz), 3.81 (4H, AB quartet, J ) 13.6 Hz), 3.64 (d, 2H, J
) 9.5 Hz), 3.52 (dd, 2H, J ) 9.3, 4.0 Hz), 3.07 (2H, m); 13C NMR
(MeOH-d4) 138.6, 130.2, 78.2, 75.1, 73.3, 51.5, 36.6; exact mass
(CI) calcd for C16H22O4S2 [M + NH4]+ 360.1303;, found 360.1294.
The stereoisomers were analyzed as the bisacetate esters by
HPLC using an (R,R) Whelko column, eluting with 15% EtOH
in hexanes at 1 mL/min [tR 27.0, 29.3 (meso), 34.0 min].
P u r ifica tion of 3d . Flash chromatography (10-20% EtOAc/
CH2Cl2, 7.5 cm × 12 cm) afforded 3d and 4d in 95% yield. The
d,l/meso mixture could be separated by preparative HPLC
(Zorbax silica column, 21.2 mm × 25 cm) eluting with 2% EtOH/
hexanes at 20 mL/min (tR 78.7, 102.4 min). Purification of a
0.25 g (0.74 mmol) sample of 3d /4d afforded 0.16 g of 3d which
was then recrystallized from benzene/ligroin to afford 0.14 g
(0.43 mmol, 54% overall yield from epoxide) of 3d as fine white
Through the use of a bifunctional thiol, very good levels
of enantiomeric purity are attainable in the (salen)Cr-
needles: mp 90 °C; R23 ) -36.7° (c ) 1.0, CH2Cl2); IR (KBr)
D
3367 (b), 2963, 2907, 2863 cm-1
;
1H NMR (CDCl3) δ 7.30 (4H,
(8) (a) D′Arrigo, P.; Feliciotti, L.; Pedrocchi-Fantoni, G.; Servi, S. J .
Org. Chem. 1997, 62, 6394. (b) Soai, K.; Inoue, Y.; Takahashi, T.;
Shibata, T. Tetrahedron 1996, 52, 13355. (c) Fleming, I.; Ghosh, S. K.
J . Chem. Soc., Chem. Commun. 1994, 99.
(9) Houk, J .; Whitesides, G. M. J . Am. Chem. Soc. 1987, 109, 6825.
(10) For examples, see: (a) Spencer, J .; Gramlich, V.; Ha¨usel, R.;
Togni, A. Tetrahedron: Asymmetry 1996, 7, 41. (b) Chelucci, G.; Cabras,
M. A. Ibid 1996, 7, 965.
(11) J acobsen, E. N. In Comprehensive Organometallic Chemistry
II; Wilkinson, G., Stone, F. G. A., Abel, E. W., Hegedus, L. S., Eds.;
Pergamon: New York, 1995; Vol. 12, Chapter 11.1.
(12) Schaus, S. E.; Bra˚nalt, J .; J acobsen, E. N. J . Org. Chem. 1998,
63, 403.

5254 J . Org. Chem., Vol. 63, No. 15, 1998
Notes
s), 3.92 (2H, m), 3.76 (4H, m), 2.72 (2H, m), 2.12 (2H, m), 1.96
(2H, m), 1.96 (2H, s) 1.69 (4H, m), 1.52 (4H, m); 13C NMR (CDCl3)
137.6, 129.1, 78.9, 51.3, 35.9, 33.3, 31.3, 21.8; exact mass (EI)
The reaction was allowed to stir at -78 °C for 5 min and then
warmed to -33 °C for 1.5 h. The excess sodium was then
quenched with solid NH4Cl, and then the ammonia was evapo-
rated over 5 h under a steady stream of N2. The white residue
was then dissolved in 1.0 M NaHSO4 and extracted with 40 mL
of EtOAc. The organic layer was washed with brine, dried over
NaSO4, filtered, and concentrated in vacuo. Flash chromatog-
raphy (2.5 × 10 cm silica, hexanes) afforded 0.077 g (0.28 mmol,
92% yield) of 6 that contained 2% (by 1H NMR) of a dixylene
contaminant. Further chromatography afforded an analytically
calcd for
C
18H26O2S2 [M]+ 338.1374, found 338.1377. The
stereoisomers were analyzed by HPLC using a Chiracel OD
column, eluting with 12% EtOH in hexanes at 1 mL/min [tR 8.9,
13.9 min]. The purified sample was shown to be present in 99%
ee and was diastereomerically pure.
Com p ou n d 4d . The meso diastereomer 4d displayed physi-
cal properties indistinguishable from those of 3d in all respects
except for the following: mp 95 °C; 13C NMR (CDCl3) 137.7,
129.1, 79.0, 51.4, 36.0, 33.3, 31.3, 21.8.
pure sample for characterization: R23 ) -44.0° (c ) 1.0, CH2-
D
Cl2); IR (neat) 2943, 2866 cm-1 1H NMR (CDCl3) δ 4.08 (1H,
;
Com p ou n d 5. A 10 mL round-bottom flask was charged with
0.060 g (0.17 mmol) of 3d , and the white solid was dissolved in
2 mL of CH2Cl2. 2,6-Lutidine (0.12 mL, 1.0 mmol, 6.0 equiv)
was added via syringe, and the solution was cooled to -78 °C.
Syringe additon of TIPSOTf (0.12 mL, 0.44 mmol, 2.5 equiv)
afforded a homogeneous solution that was warmed to room
temperature over 1.5 h. The reaction was diluted with 30 mL
of EtOAc and then washed with 30 mL portions of saturated
NH4Cl, NaHCO3, and NaCl. The organic layer was dried with
NaSO4, filtered, and concentrated in vacuo. Flash chromatog-
raphy (0-2% EtOAc in hexanes) afforded 0.11 g (0.17 mmol, 95%
m), 3.08 (1H, m), 2.23 (1H, m), 2.05 (1H, m), 1.70-1.81 (2H, m),
1.59 (1H, d, J ) 5.7 Hz), 1.48-1.61 (2H, m), 1.05 (21H, m); 13C
NMR (CDCl3) 82.5, 46.2, 33.5, 33.0, 21.4, 18.0, 12.2; exact mass
(CI) calcd for C14H30OSSi [M + NH4]+ 292.3130, found 292.2117.
Analysis of the bisacetate ester by GC (γ-TA column, 120 °C
isothermal, tR ) 7.28, 8.54 min) confirmed the product to be 99%
ee.
Ack n ow led gm en t. This work was supported by the
NIH (GM43214). We thank Eli Lilly for a predoctoral
fellowship to M.H.W.
yield) of 5 as a colorless oil: R23 ) -44.0° (c ) 0.5, CH2Cl2); IR
D
(neat) 2943, 2866 cm-1
;
1H NMR (CDCl3) δ 7.25 (4H, s), 4.18
(2H, m), 3.74 (4H, m), 2.90 (2H, m), 2.10-2.16 (2H, m), 1.91-
1.97 (2H, m), 1.52-1.76 (10H, m), 1.02 (42H, m); 13C NMR
(CDCl3) 137.0, 128.9, 79.5, 52.0, 36.0, 34.5, 30.9, 21.2, 18.1, 18.0,
12.2. Anal. Calcd for C36H66O2S2Si2: C, 66.40; H, 10.22; S, 9.85;
Si, 8.63. Found: C, 66.16; H, 10.07; S, 9.67; Si, 8.84.
(1R,2R)-2-Tr iisopr opylsiloxy-1-m er captocyclopen tan e (6).
A THF solution of 5 (0.10 g, 0.15 mmol) was added to ap-
proximately 20 mL of liquid ammonia at -78 °C. To this
solution was added 0.014 g of sodium metal (0.61 mmol, 4.0
equiv) that dissolved within 5 min to form a deep blue solution.
Su p p or t in g In for m a t ion Ava ila b le: Chromatographic
analyses of racemic and enantiomerically enriched hydroxy-
1
sulfides, as well as H NMR spectra of all new compounds (13
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
J O980155D