A convenient multigram synthesis of highly enantioenriched methyl 3-silylglycidates

Article abstract of DOI:10.1021/jo060134g

A multigram scale synthesis of the four stereoisomers of methyl 3-silylglycidates (epoxysilanes) with high enantiopurity is described. Key reactions include a Sharpless asymmetric epoxidation (SAE) of a trans-vinylsilane and an enzymatic resolution of a r

Full text of DOI:10.1021/jo060134g

A Convenient Multigram Synthesis of Highly
Enantioenriched Methyl 3-Silylglycidates
Jason T. Lowe, Willmen Youngsaye, and James S. Panek*
Department of Chemistry and Center for Chemical Methodology
and Library DeVelopment, Metcalf Center for Science and
Engineering, 590 Commonwealth AVenue, Boston UniVersity,
Boston, Massachusetts 02215
panek@chem.bu.edu
ReceiVed January 20, 2006
FIGURE 1. Representative transformations of epoxysilanes.
Epoxysilanes can also be converted to their lithium anion by
deprotonation with strong base; subsequent electrophilic addition
at the carbon bearing the silicon group affords the substituted
epoxysilane (Eq 2, Figure 1).8 They may also undergo re-
arrangements involving anionic intermediates to form oxetanes
and oxipines (Eq 3, Figure 1).9 Interestingly, silyl-substituted
glycidates as a subclass of epoxysilanes remain undeveloped
(Eq 1, R1 ) CO2R).10
A multigram scale synthesis of the four stereoisomers of
methyl 3-silylglycidates (epoxysilanes) with high enantiopu-
rity is described. Key reactions include a Sharpless asym-
metric epoxidation (SAE) of a trans-vinylsilane and an
enzymatic resolution of a racemic cis-epoxysilane to establish
the desired configurations. Few chromatographic separations
(5 columns out of 13 steps) are required for purification,
establishing a convenient reaction sequence for both the
trans- and cis-isomers.
Epoxysilanes have received attention from the chemical
community due to their ease of preparation and versatility as
building blocks and synthetic intermediates.1 Methods to gener-
ate these substrates in enantioenriched form have also become
widely available.2 This interest is, in part, due to their predictable
behavior in nucleophilic epoxide ring openings, wherein the
steric and electronic effects imparted through the electropositive
nature of silicon may influence the regioselectivity.1f,3 The
synthesis of a wide range of functionalized â-hydroxysilanes
is the direct result of this regiocontrol (eq 1, Figure 1). These
derived â-hydroxysilanes, in turn, have found numerous syn-
thetic applications in the stereocontrolled access to diols,4
alkenes,1f,5 lactones,1c tetrahydrofurans,6 and other functional
groups.7
FIGURE 2. [4 + 2]-Annulations with crotyl- and allylsilane reagents.
Recent efforts in our laboratories have focused on the
preparation of enantioenriched silyl-substituted glycidate and
glycidol derivatives to access novel crotyl- and allylsilane
reagents 1-3 (Figure 2). For instance, organosilanes have been
used for the formation of dihydropyrans 4-6 via a [4 +
2]-annulation strategy, which has been employed in the synthesis
of several complex natural products and advanced intermedi-
ates.11
(1) (a) Chakraborty, T. K.; Laxman, P. Tetrahedron Lett. 2003, 44, 4989.
(b) Hudrlik, P. F.; Gebreselassie, P.; Tafesse, L.; Hudrlik, A. M. Tetrahedron
Lett. 2003, 44, 3409. (c) Kim, K.; Okamoto, S.; Takayama, Y.; Sato, F.
Tetrahedron Lett. 2002, 43, 4237. (d) Whitham, G. H. Sci. Synth. 2002, 4,
633. (e) Babudri, F.; Fiandanese, V.; Marchese, G.; Punzi, A. Tetrahedron
2001, 57, 549. (f) Hudrlik, P. F.; Hudrlik, A. M. AdVances in Silicon
Chemistry; JAI Press: Greenwich, CT, 1993; Vol. 2, p 1. (g) Chakraborty,
T. K.; Reddy, G. V. Tetrahedron Lett. 1990, 31, 1335.
(2) For examples of SAE to generate epoxysilanes, see: (a) Chauret, D.
C.; Chong, J. M.; Ye, Q. Tetrahedron: Asymmetry 1999, 10, 3601. (b)
Kobayashi, Y.; Ito, T.; Yamakawa, I.; Urabe, H.; Sato, F. Synlett 1991,
811. (c) Takeda, Y.; Matsumoto, T.; Sato, F. J. Org. Chem. 1986, 51, 4731.
For an example of Shi epoxidation, see: (d) Heffron, T. P.; Jamison, T. F.
Org. Lett. 2003, 5, 2339. For examples of kinetic resolutions, see: (e)
Carlier, P. R.; Mungall, W. S.; Schroder, G.; Sharpless, K. B. J. Am. Chem.
Soc. 1988, 110, 2978. (f) Kitano, Y.; Matsumoto, T.; Sato, F. J. Chem.
Soc., Chem. Commun. 1986, 17, 1323. For substrate-directed epoxidations
using VO(acac)2, see: (g) Kobayashi, Y.; Uchiyama, H.; Kanbara, H.; Sato,
F. J. Am. Chem. Soc. 1985, 107, 5541.
(4) Tamao, K.; Nakajo, E.; Ito, Y. J. Org. Chem. 1987, 52, 4412.
(5) (a) Chauret, D. C.; Chong, J. M. Tetrahedron Lett. 1993, 34, 3695.
(b) Hudrlik, P. F.; Peterson, D.; Rona, R. J. J. Org. Chem. 1975, 40, 2263.
(6) (a) Shotwell, J. B.; Roush, W. R. Org. Lett. 2004, 6, 3865. (b)
Micalizio, G. C.; Roush, W. R. Org. Lett. 2000, 2, 461. (c) Panek, J. S.;
Yang, M. J. Am. Chem. Soc. 1991, 113, 9868.
(7) â-hydroxysilanes not derived from epoxysilanes, see: (a) Adam,
J.-M.; de Fays, L.; Laguerre, M.; Ghosez, L. Tetrahedron 2004, 60, 7325.
(b) Landais, Y.; Mahieux, C.; Schenk, K.; Surange, S. S. J. Org. Chem.
2003, 68, 2779. (c) Ohi, H.; Inoue, S.; Iwabuchi, Y.; Irie, H.; Hatakeyama,
S. Synlett 1999, 11, 1757 and references therein.
(8) (a) Courillon, C.; Marie´, J. C.; Malacria, M. Tetrahedron 2003, 59,
9759. (b) Marie´, J. C.; Courillon, C.; Malacria, M. Synlett 2002, 4, 553. (c)
Achmatowicz, B.; Jankowski, P.; Wicha, J. Tetrahedron Lett. 1996, 37,
5589. (d) Molander, G. A.; Mautner, K. Pure Appl. Chem. 1990, 62, 707.
(e) Molander, G. A.; Mautner, K. J. Org. Chem. 1989, 54, 4042. (f) Eisch,
J. J.; Galle, J. E. J. Organomet. Chem. 1988, 341, 293. (g) Burford, C.;
Cooke, F.; Roy, G.; Magnus, P. Tetrahedron 1983, 39, 867.
(9) Mordini, A.; Bindi, S.; Capperucci, A.; Nistri, D.; Reginato, G.;
Valacchi, M. J. Org. Chem. 2001, 66, 3201.
(3) Fleming, I.; Barbero, A.; Walter, D. Chem. ReV. 1997, 97, 2063.
10.1021/jo060134g CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/29/2006
J. Org. Chem. 2006, 71, 3639-3642
3639

SCHEME 1. Synthesis of Both Enantiomers of trans-Epoxysilanes using SAE
SCHEME 2. Synthesis of Both Enantiomers of cis-Epoxysilanes using a Enzymatic Resolution
To maximize structural and stereochemical variations in the
synthesis of new organosilane reagents, we designed a route
that had the potential to access all four stereoisomers of the
epoxysilanes. To the best of our knowledge, there is only one
report of a multigram synthesis of an enantioenriched epoxy-
silane12 and no reports describing the synthesis of all four
stereoisomers. Herein, we describe a straightforward multigram
synthesis accessing these versatile building blocks with high
enantiopurity.
The synthesis of both cis- and trans-epoxysilanes began with
commercially available propargyl alcohol. The trans-isomers
were accessed through a syn-hydrosilylation of 7 using previ-
ously described conditions,13 resulting in >95% yield of a single
stereo- and regioisomer (Scheme 1). (E)-Vinylsilane 8 was then
subjected to a SAE using (+)- or (-)-diethyl tartrate under
slightly modified conditions.14 The resulting epoxysilyl alcohols
9 and 10 were obtained in a two-step yield of 87% and with
>98% enantiomeric excess.15
conversion using conditions described for the (E)-vinylsilane.16
Accordingly, we explored the possibility of an enzymatic
resolution of the racemic epoxide. Epoxidation with m-CPBA
gave a racemic mixture of epoxy alcohols 13 that seemed a
suitable substrate for enzymatic resolution.
Several lipase enzymes were surveyed for their ability to
effectively resolve racemic epoxysilyl alcohols.17 Best results
were obtained using Amano PS-D lipase in the presence of vinyl
acetate (a transesterifying agent) to provide primary alcohol 14
and acetate 15 in high yields and enantiomeric excess. Base-
catalyzed methanolysis of the acetate group in 15 gave the
desired cis-epoxysilane 16.18
Completion of the synthesis began with the oxidation of 9
with NaIO4 and catalytic RuCl319 to provide acid 17, which was
immediately esterified to give trans-silyl glycidate 18 (72% from
9, respectively). The trans-epoxides were obtained in an overall
four-step sequence capable of generating >20 g of material in
high enantiopurity (Scheme 3). With an efficient route to the
trans-epoxy esters, we next turned our efforts toward the
synthesis of the cis-isomer.
The cis-epoxide 14 underwent the oxidation/esterification
sequence described for the trans-epoxides to give 20. However,
upon scale-up, a significant amount of aldehyde was observed
(ca. 20%) using previously reported conditions.11a The sequence
resulted in a two-step 55% isolated yield of 20 after DCC
coupling. During the course of oxidation, the reaction solution
became a dark green color with the formation of a black
suspension, suggesting an inactive catalytic system.19 To drive
Generation of the cis-epoxysilane began with the protection
of propargyl alcohol as a THP ether, which was subsequently
silylated to obtain 11 (Scheme 2). This substrate underwent
regio- and stereoselective hydroalumination to give a (Z)-olefin.
Removal of the THP ether yielded the (Z)-vinylsilane 12 in 92%
yield over four steps.
A Sharpless asymmetric epoxidation on the complementary
(Z)-vinylsilane was attempted but provided less than 5%
(10) For references pertaining to the asymmetric synthesis of glycidates
(without silicon), see: Imashiro, R.; Seki, M. J. Org. Chem. 2004, 69, 4216
and references therein.
(11) (a) Lowe, J. T.; Panek, J. S. Org. Lett. 2005, 7, 3231. (b) Su, Q.;
Panek, J. S. Angew. Chem., Int. Ed. 2005, 44, 1223. (c) Su, Q.; Panek, J.
S. J. Am. Chem. Soc. 2004, 126, 2425. (d) Huang, H.; Panek, J. S. Org.
Lett. 2003, 5, 1991. (e) Huang, H.; Panek, J. S. J. Am. Chem. Soc. 2000,
122, 9836.
(12) For the 19.5 g preparation of (2R,3R)-3-(triphenylsilyl)-2,3-ep-
oxypropan-l-ol, see: Raubo, P.; Wicha, J. Tetrahedron: Asymmetry 1995,
6, 577.
(13) Beresis, R. T.; Solomon, J. S.; Yang, M.; Jain, N. F.; Panek, J. S.
Org. Synth. 1997, 75, 78.
(14) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(15) The enantiomeric excess was determined to be 98% for both 9 and
10 as observed using Chiralcel OD 99/1 (hexanes/IPA) at 1 mL/min. (tR
35.92 for 9 and 45.17 for 10).
(16) Elevated temperatures (-20, 0, and +25 °C) did not provide the
desired epoxide.
(17) Lipase AK “Amano” 20, Lipase PS “Amano”, and Lipase PS-D
“Amano” were screened.
(18) The enantiomeric excess was determined to vary between 94 and
96% for both 14 and 16 as observed using Chiralcel OD 85/15 (hexanes/
IPA) at 1 mL/min (tR 5.03 for 14 and 7.08 for 16).
(19) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J.
Org. Chem. 1981, 46, 3936.
3640 J. Org. Chem., Vol. 71, No. 9, 2006

SCHEME 3. Synthesis of Methyl 3-Silyl Glycidates
and concentrated to obtain an oil. The oil was chromatographed
over silica gel using hexanes/ethyl acetate (90/10 to 60/40) to get
82.4 g (92% yield, >98% ee) of 9 as a clear oil: [R]20 -10.2 (c
D
1.48 CHCl3).21 For 10 (92% yield, > 98% ee): [R]20D +9.6 (c 2.39
CHCl3). The 1H and 13C NMR and IR spectra of compounds 9 and
10 were in complete agreement with those found in ref 12.
(2S,3S)-3-(Dimethylphenylsilanyl)oxirane-2-carboxylic Acid
(17). Epoxy alcohol 9 (27.7 g, 133 mmol) was added into a 3 L
round-bottom flask followed by acetonitrile (440 mL), CCl4 (440
mL), and water (660 mL). Sodium metaperiodate (114 g, 532 mmol)
was then added as a solid in one portion followed by ruthenium-
(III) chloride hydrate (0.98 g, 4.3 mmol). The reaction was allowed
to rapidly stir overnight at room temperature. Dichloromethane (500
mL) was then added and the reaction mixture stirred for 30 min
before adding an additional 500 mL of water. The aqueous layer
was then extracted with dichloromethane, combined and dried over
MgSO4, filtered, and concentrated to get 26.2 g of 17 as a colored
(red/pink on dilution) oil which was immediately taken to the next
step: 1H NMR (400 MHz, CDCl3) δ 7.53-7.51 (m, 2H), 7.41-
7.35 (m, 3H), 3.26 (d, J ) 3.2 Hz, 1H), 2.66 (d, J ) 3.6 Hz, 1H),
0.39 (s, 3H), 0.36 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 176.0,
134.0, 133.8, 130.0, 128.1, 51.9, 50.4, -5.4, -5.5; IR (film) νmax
3071, 2582, 1738 cm-1; HRMS(CI, NH3) m/z calcd for C11H14O3-
Si [M]+ 222.0712, found 222.0689; [R]20D -15.96 (c 1.83, CHCl3).
the reaction to completion, catalyst loading was increased and
extended reaction times were explored with little success.
Fortunately, a reset of the catalytic system provided complete
conversion. Thus, applying two sequential catalytic ruthenium
oxidations followed by esterification using DCC/DMAP af-
forded the silyl glycidate 20 in a comparable 66% yield for the
two-step sequence (Scheme 3). This oxidation/esterification
sequence was also successfully applied to the primary alcohols
of 10 and 16 with nearly identical results.
In summary, we have developed a convenient, versatile
synthesis of the stereoisomers of methyl 3-silyl glycidates. These
epoxysilanes possess utility as chiral building blocks in organic
synthesis, portions of which were previously demonstrated. A
Sharpless asymmetric epoxidation and an enzymatic resolution
were employed to obtain the enantiomerically enriched epoxysi-
lyl alcohols, thus providing access to all four stereoisomers in
both the cis/trans series. Each enantiomer was prepared in
greater than 20 g quantities with high enantiomeric purity and
yields for all intermediate substrates.
For ent-17: [R]20 +17.50 (c 2.0, CHCl3).
D
(2S,3S)-Methyl 3-(Dimethylphenylsilanyl)oxirane-2-carboxy-
late (18). A solution of epoxy acid 17 (25.4 g, 114 mmol) in
dichloromethane (325 mL) was slowly added to a solution of DCC
(36.9 g, 179 mmol), DMAP (1.78 g, 14.6 mmol), and methanol
(18.2 mL, 441 mmol) in dichloromethane (70 mL) at 0 °C. The
reaction was allowed to stir overnight at room temperature. The
solution was then filtered and dried in vacuo to yield 18 as a oil.
Further purification over silica gel (hexanes/ethyl acetate 100% to
90/10) gave 21.9 g (81%) of a clear oil: 1H NMR (400 MHz,
CDCl3) δ 7.52 (m, 2H), 7.38 (m, 3H), 3.74 (s, 3H), 3.24 (d, J )
3.2 Hz, 1H), 2.64 (d, J ) 3.2 Hz, 1H), 0.37 (s, 3H), 0.34 (s, 3H);
13C (75 MHz, CDCl3) δ 170.3, 134.2, 133.7, 129.7, 127.8, 52.1,
51.0, 50.6, -5.6, -5.7; IR (film) νmax 1755, 1290, 1207 cm-1
;
HRMS (CI, NH3) m/z calcd for C12H16O3Si [M]+ 236.0869, found
236.0877; [R]20 -26.39 (c 1.95, CHCl3). For ent-18: [R]20
Experimental Section
D
D
(E)-3-(Dimethylphenylsilanyl)prop-2-en-1-ol (8). To a solution
of 2-propyn-1-ol (38 g, 677.8 mmol) in tetrahydrofuran (1000 mL)
were added dimethylphenylsilane (97 g, 712.0 mmol), sodium
(0.020 g), and platinum(0) hydrosilylation catalyst13 (0.14 g, 0.24
mmol) under an atmosphere of nitrogen. The solution was then
refluxed overnight and the solvent removed in vacuo to give an
orange oil. The oil was run over a silica plug with hexanes followed
by 100% ethyl acetate to provide 124.1 g (95%) of 8 as a light
+28.56 (c 1.67, CHCl3).
Dimethylphenyl[3-(tetrahydropyran-2-yloxy)prop-1-ynyl]si-
lane (11). Propargyl alcohol (40.0 g, 713 mmol) and dichlo-
romethane (1400 mL) were added into a 3 L round-bottom flask
and cooled to 0 °C. Dihydropyran (68.3 mL, 749 mmol) was added
followed by p-toluenesulfonic acid (1.23 g, 7.12 mmol) and the
mixture stirred for 1 h. A saturated solution of sodium bicarbonate
was slowly added and the mixture stirred until gas evolution ceased.
The remaining aqueous layer was extracted with dichloromethane
and dried over MgSO4. After filtering, the reaction was concentrated
to get a clean oil (94 g) that was reacted directly.
Tetrahydro-2-(2-propynyloxy)-2H-pyran (ca. 48 g, 340 mmol)
was added to a 2 L round-bottom flask followed by THF (360 mL).
The reaction was cooled to -78 °C, and 1.05 equiv of 2.5 M n-BuLi
in hexanes (140 mL) was slowly added over 2 h via a syringe pump.
After the solution was stirred for 30 min, chlorodimethylphenyl-
silane (59.8 mL, 360 mmol) was added dropwise. The reaction
mixture was stirred for an additional 30 min at -78 °C and then
warmed to room temperature and stirred for 3 h. The resulting
solution was poured into ice-water and diluted with hexanes. The
aqueous layer was extracted with hexanes, and the organics were
dried over MgSO4, filtered, and concentrated in vacuo to yield 93
g (99%) of 11 as a light yellow oil that can be used without further
purification: 1H NMR (400 MHz, CDCl3) δ 7.60 (m, 2H), 7.36
1
yellow oil. The H and 13C NMR and IR spectra of compound 8
were in complete agreement with those found in ref 12.
[(2S,3S)-3-(Dimethylphenylsilanyl)oxiranyl]methanol (9). A
solution of 4 Å molecular sieves (23.1 g) and (+)-diethyl-L-tartrate
(10.5 mL, 50.9 mmol) in dichloromethane (1300 mL) was blanketed
with an atmosphere of argon and cooled to -40 °C. To the above
solution was added titanium tetraisopropoxide (15.0 mL, 50.8
mmol) followed by a slow addition of a 3.5 M solution of tert-
butyl hydroperoxide in toluene20 (242 mL). The solution was
allowed to stir for 1 h before (E)-3-(dimethylphenylsilanyl)prop-
2-en-1-ol 8 (82.5 g, 429 mmol) in dichloromethane (225 mL) was
added via cannula and stirred for an additional 48 h at -40 °C.
The reaction was warmed to 0 °C, and a premixed solution of
ferrous sulfate heptahydrate (144 g, 517 mmol) and tartaric acid
(44.1 g, 294 mmol) in water (435 mL) cooled to 0 °C was slowly
added and stirred for 30 min. The reaction was then filtered through
a pad of Celite and extracted with dichloromethane. The combined
organic layers were again cooled to 0 °C, and a solution containing
126 g of NaOH in 420 mL of a brine solution was added and stirred
for 2 h. The reaction was diluted with 500 mL of water and then
extracted with 1:1 hexane/diethyl ether, dried over MgSO4, filtered,
(20) For the preparation of anhydrous TBHP, see: Hill, J. G.; Rossiter,
B. E.; Sharpless, K. B. J. Org. Chem. 1983, 48, 3607.
(21) Le Bideau, F.; Gilloir, F.; Nilsson, Y.; Aubert, C.; Malacria, M.
Tetrahedron 1996, 52, 7487.
J. Org. Chem, Vol. 71, No. 9, 2006 3641

(m, 3H), 4.82 (t, 3.2 Hz, 1H), 4.34-4.30 (d, Jab) 16 Hz, 1H),
4.28-4.24 (d, Jab) 15.2 Hz, 1H), 3.83 (m, 1H), 3.51 (m, 1H), 1.84-
1.75 (m, 1H), 1.76-1.69 (m, 1H), 1.64-1.59 (m, 2H), 1.56-1.50
(m, 2H), 0.40 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 136.7, 133.6,
129.4, 127.8, 103.3, 96.7, 88.8, 61.9, 54.8, 30.2, 25.3, 19.0, -1.00;
IR (film) νmax 2944, 2176, 1428, 1250, 1118, cm-1; HRMS (CI,
NH3) m/z calcd for C16H22O2Si [M]+ 274.1389, found 274.1366.
(Z)-3-(Dimethylphenylsilanyl)prop-2-en-1-ol (12). Alkyne 11
(95.0 g, 346 mmol) was dissolved in diethyl ether (218 mL) and
cooled to 0 °C. A 1 M solution of DIBAL-H in hexanes (381 mL)
was added and the reaction allowed to reach room temperature and
stir for an additional 24 h. The reaction was then slowly poured
into 1 L of a 1 M HCl/ice solution and allowed to stir until solution
became clear (ca. 2 h). The mixture was extracted with diethyl ether,
dried over MgSO4, filtered over silica, and concentrated to yield
90 g (94%) of an oil that was used without further purification.
This oil (ca. 90 g, 300 mmol) was added into a 1 L round-bottom
flask followed by methanol (580 mL) and a catalytic amount of
p-toluenesulfonic acid (0.620 g, 3.2 mmol). The reaction was
allowed to stir for 3 h before addition of triethylamine (0.45 mL,
3.2 mmol). The reaction was then filtered through a pad of silica
gel and concentrated in vacuo to give 60 g (99%) of 12 as a clear
oil that can be used without further purification: 1H NMR (400
MHz, CDCl3) δ 7.51 (m, 2H), 7.34 (m, 3H), 6.54 (dt, J ) 14.4,
6.0 Hz, 1H), 5.85 (d appt t, 14, 1.2 Hz, 1H), 4.05 (dd, J ) 6.4, 1.6
Hz, 2H), 0.37 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 148.0, 139.1,
133.5, 129.8, 129.1, 127.8, 63.2, -0.97; IR (film) νmax 3346, 2956,
1607 cm-1; HRMS (CI, NH3) m/z calcd for C11H16OSi [M]+
192.0970, found 192.0972.
[3-(Dimethylphenylsilanyl)oxiranyl]methanol (13). A solution
of allylic alcohol 12 (51.3 g, 267 mmol) in dichloromethane (1250
mL) was added into a 3 L round-bottom flask and cooled to 0 °C.
m-CPBA (119 g, 531 mmol of max 77%) was then added. The
solution was allowed to warm to room temperature and stir for an
additional 3.5 h. The entire solution was then poured SLOWLY
into a mixture of saturated Na2S2O3 solution (1 L) where it was
allowed to stir for 30 min. A 1.5-L portion of saturated NaHCO3
was then SLOWLY added, and the combined mixture was stirred
for an additional 1.5 h. The solution was then extracted with
dichloromethane. The combined organics were washed carefully
with saturated NaHCO3, dried over MgSO4, filtered, and concen-
trated in vacuo to get an oil. Further purification over silica gel
(hexanes/ethyl acetate: 95/5 to 50/50) yielded 46.8 g (85%) of 13
as a light yellow oil: 1H NMR (400 MHz, CDCl3) δ 7.55 (m, 2H),
7.40 (m, 3H), 3.68 (q, J ) 9.6 Hz, 1H), 3.37 (m, 2H), 2.71 (br. s,
1H), 2.52 (m, 1H), 0.42 (s, 3H), 0.40 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 136.5, 133.7, 129.6, 128.0, 63.2, 57.7, 49.4, -2.9, -3.3;
IR (film) νmax 3418, 2958, 1427 cm-1; HRMS (CI, NH3) m/z calcd
for C11H16O2Si [M]+ 208.0920, found 208.0881.
[(2S,3R)-3-(Dimethylphenylsilanyl)oxiranyl]methanol (16). A
solution of acetate 15 (58 g, 232 mmol) in methanol (600 mL)
was added to a 2 L round-bottom flask. K2CO3 was added (0.64 g,
4.6 mmol) and the reaction stirred for 2 h at room temperature.
Water was added to the flask followed by ether. The aqueous layer
was subsequently extracted twice more with ether. The combined
organics were then dried over MgSO4, filtered, and concentrated
in vacuo to get an oil. The oil was flashed over silica gel with
hexanes/ethyl acetate (80/20) to get 46.5 g (97%, 94-96% ee) of
1
16 as a clear oil: [R]20 -14.90 (c 1.56, CHCl3). The H and 13C
D
NMR and IR spectra and HRMS of compound 16 were in complete
agreement with those found for 13 as reported above.
(2R,3S)-3-(Dimethylphenylsilanyl)oxirane-2-carboxylic Acid
(19). Epoxy alcohol 14 (47.0 g, 226 mmol) was added into a 5 L
round-bottom flask followed by acetonitrile (750 mL), CCl4 (750
mL), and water (1138 mL). Sodium metaperiodate (193 g, 902
mmol) was then added as a solid in one portion followed by
ruthenium(III) chloride hydrate (3.00 g, 14 mmol). The reaction
was allowed to stir at room temperature for 4 h. Dichloromethane
(2500 mL) was then added and the reaction mixture stirred for an
additional 30 min. The aqueous layer was extracted with dichlo-
romethane, and the combined extracts were dried over MgSO4,
filtered, and concentrated in vacuo to give 45.53 g of a colored
(red/pink) oil (ca. 20% aldehyde). The oil may be taken on crude
or added into a 5 L round-bottom flask with acetonitrile (750 mL),
CCl4 (750 mL), and water (1138 mL). Sodium metaperiodate (43.4
g, 175 mmol) was then added followed by ruthenium(III) chloride
hydrate (0.49 g, 2.2 mmol). The reaction was allowed to stir at
room temperature for 4 h. Workup followed as described above to
give 41.43 g (83%) of 19 as a colored (lavender) oil that was
immediately taken to the next step: 1H NMR (400 MHz, CDCl3)
δ 7.51 (m, 2H), 7.35 (m, 3H), 3.68 (d, J ) 5.2 Hz, 1H), 2.68 (d,
J ) 6.0 Hz, 1H), 0.44 (s, 3H), 0.40 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 175.4, 133.8, 133.7, 129.7, 127.9, 52.1, 51.4, -3.5, -4.8;
IR (film) νmax 3071, 2958, 1723, 1251 cm-1; HRMS (CI, NH3)
m/z calcd for C11H14O3Si [M]+ 222.0712, found 222.0698; [R]20
D
+10.94 (c 1.92, CHCl3). For ent-19: [R]20D -10.23 (c 1.76, CHCl3).
(2R,3S)-Methyl 3-(Dimethylphenylsilanyl)oxirane-2-carboxy-
late (20). A solution of epoxy acid 19 (41.43 g, 186.4 mmol) in
dichloromethane (260 mL) was added to a solution of DCC (57.7
g, 280 mmol), DMAP (2.96 g, 24.2 mmol), and methanol (30.2
mL, 745 mmol) in dichloromethane (104 mL) at 0 °C. The reaction
was allowed to stir overnight at room temperature. The solution
was then filtered and concentrated in vacuo to yield an oil. Further
purification by column chromatography (hexanes/ethyl acetate: 95/
5) gave 35.34 g (80%) of 20 as a clear oil: 1H NMR (400 MHz,
CDCl3) δ 7.50 (m, 2H), 7.35 (m, 3H), 3.65 (d, J ) 5.6 Hz, 1H),
3.48 (s, 3H), 2.68 (d, J ) 5.6 Hz, 1H), 0.42 (s, 3H), 0.38 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 169.4, 135.7, 129.3, 127.7, 52.3,
Acetic Acid (2S,3R)-3-(Dimethylphenylsilanyl)oxiranyl Meth-
yl Ester and [(2R,3S)-3-(Dimethylphenylsilanyl)oxiranyl]methanol
(15 and 14). A solution of racemic epoxide 13 (50 g, 240 mmol)
and vinyl acetate (11 mL, 120 mmol, 0.5 equiv) in diethyl ether
(3000 mL) was added to a 4 L round-bottom flask. After the
addition of lipase PS-D (6 g), the reaction was allowed to stir for
15 h at room temperature. The solution was then filtered and
concentrated in vacuo to get an oil. Further purification over silica
gel (hexanes/ethyl acetate: 95/5 to 80/20) yielded 28.5 g (47%) of
15 as a clear oil and 22.5 g (45%, 94-96% ee) of 14 as a light
yellow oil. Acetate 15: 1H NMR (400 MHz, CDCl3) δ 7.54 (m,
2H), 7.38 (m, 3H), 4.17 (dd, J ) 12, 3.2 Hz, 1H), 3.74 (dd, J )
12, 7.6 Hz, 1H), 3.40 (m, 1H), 2.49 (d, J ) 5.6 Hz, 1H), 2.04 (s,
3H), 0.42 (s, 3H), 0.40 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
170.6, 135.9, 133.7, 129.7, 128.0, 65.1, 54.5, 48.7, 20.7, -3.1, -3.5;
IR (film) νmax 2957, 1740, 1428, 1372, 1232 cm-1; HRMS (CI,
NH3) m/z calcd for C13H18O3Si [M]+ 250.1025, found 250.1021.
51.6, 50.5, -3.3, -5.0; IR (film) νmax 2954, 1756, 1428, 1211 cm-1
;
HRMS (CI, NH3) m/z calcd for C12H16O3Si [M]+ 236.0869, found
236.0877; [R]20D +19.8 (c 1.97, CHCl3). For ent-20: [R]20D -19.9
(c 2.10, CHCl3).
Acknowledgment. We are grateful to Dr. Qibin Su and Dr.
Gary Bohnert for useful suggestions and discussions. Financial
support for this research was obtained from NIH CA56304.
J.S.P. is grateful to Amgen, AstraZeneca, Johnson & Johnson,
Merck Co., Novartis, Pfizer, and GSK for financial support of
our programs.
Supporting Information Available: 1H and 13C NMR and IR
spectra and HPLC data. This material is available free of charge
via the Internet at http://pubs.acs.org.
For 15: [R]20 -8.68 (c 1.51, CHCl3). For spectral properties of
D
14, see 13. For 14: [R]20 +13.2 (c 1.14, CHCl3).
JO060134G
D
3642 J. Org. Chem., Vol. 71, No. 9, 2006