Highly 1,4-syn diastereoselective, phosphoramide-catalyzed aldol additions of chiral methyl ketone enolates

Full text of DOI:10.1021/jo981739i

9524
J . Org. Chem. 1998, 63, 9524-9527
Notes
High ly 1,4-Syn Dia ster eoselective,
P h osp h or a m id e-Ca ta lyzed Ald ol Ad d ition s
of Ch ir a l Meth yl Keton e En ola tes†
Scott E. Denmark* and Robert A. Stavenger
Roger Adams Laboratory, Department of Chemistry,
University of Illinois, Urbana, Illinois 61801
1. We recently reported that treatment of TMS enol
Sch em e 1a
Received August 25, 1998
Recent reports from these laboratories have disclosed
the design and development of a new class of asymmetric
aldol additions catalyzed by chiral Lewis bases.1 In
particular, the stilbenediamine-derived phosphoramide
11a has emerged as a highly selective and general catalyst
for the aldol addition of trichlorosilyl enolates of ketones
to aldehydes. This transformation is believed to involve
a closed, chairlike transition structure with enolate,
aldehyde, and phosphoramide organized around a hexa-
coordinate silicon center.1b The addition of enolates
bearing a stereogenic center is clearly of great importance
in the application of the aldol addition to synthesis.
Although general success has been realized with chiral
propanoate/ethyl ketone systems,2 the related methyl
ketone substrates have been less thoroughly investi-
gated.3 Given our recent report of enantioselective aldol
additions with methyl ketone-derived enolates1d,4 and our
hypothesis that the reaction takes place via a closed
transition structure, we investigated the feasibility of
using chiral methyl ketones in conjunction with the
catalyst 1 to afford protected 1,4-dihydroxypentanones.
Synthesis of the requisite substrates proceeded accord-
ing to literature precedent. Protection of (S)-methyl
lactate,5 followed by addition of MeLi at -110 °C6 and
silylation with TMSOTf and Et3N in benzene,3d provided
the TMS enol ethers 3a -c in good overall yield, Scheme
a
Key: (a) MeLi/TMSCl/THF/Et2O/-110 °C; (b) TMSOTf/Et3N/
PhH/0 °C.
ethers with 2 equiv of SiCl4 and 1 mol % Hg(OAc)2 cleanly
provides the corresponding trichlorosilyl enolates in good
yield.1d,4 In the current studies, we briefly investigated
even lower catalyst loading, and found that although 0.25
mol % was effective, the reaction was somewhat slower
(4-5 h), especially starting from 3b or 3c. After 1 h
reaction was complete and removal of the volatile com-
ponents provided the crude trichlorosilyl enolate, which
could be used directly in aldol reactions. Thus, addition
of CH2Cl2 and benzaldehyde led to the formation of aldol
adducts 4 in 8 h at room temperature, Table 1. The
Ta ble 1. Un ca ta lyzed Ad d ition s of Tr ich lor osilyl
En ola tes to Ben za ld eh yd ea ,b
† The Chemistry of Trichlorosilyl Enolates. 8.
(1) (a) Denmark, S. E.; Winter, S. B. D.; Su, X.; Wong, K.-T. J . Am.
Chem. Soc. 1996, 118, 7404. (b) Denmark, S. E.; Wong, K.-T.;
Stavenger, R. A. J . Am. Chem. Soc. 1997, 119, 2333. (c) Denmark, S.
E.; Winter, S. B. D. Synlett 1997, 1087. (d) Denmark, S. E.; Stavenger,
R. A.; Wong, K.-T. J . Org. Chem. 1998, 63, 918. (e) Denmark, S. E.;
Stavenger, R. A.; Wong, K.-T. Tetrahedron 1998, 54, 10389.
(2) (a) Cowden, C. J .; Paterson, I. Org. React. 1997, 51, 1. (b)
Franklin, A. S.; Paterson, I. Contemp. Org. Synth. 1994, 1, 317. (c)
Braun, M. In Stereoselective Synthesis, Methods in Organic Chemistry
(Houben-Weyl), E21 ed.; Helmchen, G., Hoffmann, R., Mulzer, J .,
Schaumann, E., Eds.; Thieme: Stuttgart, 1996; Vol. 3; p 1603.
(3) (a) Heathcock, C. H.; Pirrung, M. C.; Lampe, J .; Buse, C. T.;
Young, S. D. J . Org. Chem. 1981, 46, 2290. (b) Evans, D. A.; Nelson,
J . V.; Vogel, E.; Taber, T. R. J . Am. Chem. Soc. 1981, 103, 3099. (c)
Paterson, I.; Goodman, J . M.; Isaka, M. Tetrahedron Lett. 1989, 30,
7121. (d) Trost, B. M.; Urabe, H. J . Org. Chem. 1990, 55, 3982. (e)
Lagu, B. R.; Crane, H. M.; Liotta, D. C. J . Org. Chem. 1993, 58, 4191.
(f) Gustin, D. J .; VanNieuwenhze, M. S.; Roush, W. R. Tetrahedron
Lett. 1995, 36, 3443. For a review on R-unsubstituted chiral enolates
see: (g) Braun, M. Angew. Chem., Int. Ed. Engl. 1987, 26, 24.
(4) Denmark, S. E.; Stavenger, R. A.; Winter, S. B. D.; Wong, K.-T.;
Barsanti, P. A. J . Org. Chem. 1998, 63, 9517.
entry
R
Hg(OAc)2 (mol %) products syn/anti yield, %
1
2
3
TBS
Piv
Bn
0.25
0.5
0.5
4a
4b
4c
1/1.2c
1/2.4d
1/3.4d
82
71
75
a
b
2.0 equiv of SiCl4/1 M CH2Cl2/1 h. 1.0 equiv of PhCHO/1 M
CH2Cl2/8 h. c Determined by CSP SFC analysis. dDetermined by
1H NMR analysis.
products were isolated as mixtures of diastereomers in
good yield with poor diastereoselectivity, favoring the anti
product. The assignment of configuration is based on an
X-ray crystal structure of syn-4b; other assignments were
made by deprotecting and correlating the syn and anti
diols to the established pivalate-derived diol. The lack
of selectivity was somewhat surprising as we (and
others)7 have previously asserted that uncatalyzed reac-
tions of such silyl enolates proceed through closed,
(5) (a) Massad, S. K.; Hawkins, L. D.; Baker, D. C. J . Org. Chem.
1983, 48, 5180. (b) Chen, P.; Cheng, P. T. W.; Amam, M.; Beyer, B. D.;
Bianchi, G. S. J . Med. Chem. 1996, 39, 1991.
(6) Hopkins, M. H.; Overman, L. A.; Rishton, G. M. J . Am. Chem.
Soc. 1991, 113, 5354.
(7) (a) Myers, A. G.; Widdowson, K. L.; Kukkola, P. J . J . Am. Chem.
Soc. 1992, 114, 2765. (b) Gung, B. W.; Zhu, Z.; Fouch, R. A. J . Org.
Chem. 1995, 60, 2860.
10.1021/jo981739i CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/24/1998

Notes
J . Org. Chem., Vol. 63, No. 25, 1998 9525
Ta ble 2. Ca ta lyzed Ad d ition s of Tr ich lor osilyl En ola tes
to Ben za ld eh yd ea ,b
Sch em e 2
Hg(OAc)2
entry
R
(mol %) catalyst products syn/anti yield, %
Ta ble 3. Ald ol Ad d ition s w ith TMS En ol Eth er 3a
1
2
3
4
5
6
TBS
Piv
Bn
TBS
Piv
Bn
0.5
1
1
0.5
1
1
(S,S)-1
(S,S)-1
(S,S)-1
(R,R)-1
(R,R)-1
(R,R)-1
4a
4b
4c
4a
4b
4c
1.5/1c
3.4/1d
1/1.1d
73/1c
20/1d
11/1d
85
78
78
85
78
77
a
b
syn/ yield,
2.0 equiv of SiCl4/1 M CH2Cl2/1 h. 1.0 equiv of PhCHO/5
mol % 1/0.5 M CH2Cl2/3 h. c Determined by CSP SFC analysis.
entry
R
cat.
T, °C products anti
%
Determined by 1H NMR analysis.
d
1
2
3
4
C6H11
none
rt
rt
5
6
6
6
1/3c
55
66
80
81
(E)-CHdCHCH3 none
(E)-CHdCHCH3 (S,S)-1 -78
(E)-CHdCHCH3 (R,R)-1 -78
2.3/1d
1.3/1d
6.2/1d
boatlike transition structures where good information
transfer from the resident stereogenic center on the
enolate was expected.
a
b
0.5 mol % Hg(OAc)2/2.0 equiv of SiCl4/1 M CH2Cl2/1 h. 1.0
equiv of RCHO/5 mol % 1/0.5 M CH2Cl2/3 h. c Determined by 1H
NMR analysis. dDetermined by CSP SFC analysis of the corre-
sponding benzoate.
Attempts were made to control the diastereoselectivity
of the process by using 5 mol % of (S,S)-1. Although rates
were accelerated (reaction time: 2-3 h at -78 °C) and
good yields of aldol adducts were obtained, poor diaste-
reoselectivities were again observed, Table 2, entries 1-3.
It was also surprising that the syn diastereomer pre-
dominated, since in achiral enolate systems (S,S,)-1
preferentially produces the S-aldol adducts, which would
correspond to the anti diastereomer in the present series.
These catalyzed reactions are envisioned to proceed
through closed, chairlike transition structures organized
around a hexacoordinate silicon atom. The combination
of the stereogenic center on the enolate backbone and the
hexacoordinate arrangement of groups around silicon
apparently favors formation of the syn diastereomer even
though the intrinsic selectivity of the catalyst is for
formation of the epimeric adduct.
The enantiomeric catalyst, (R,R)-1, was next employed
in anticipation that its preference for forming the R-aldol
adduct combined with the same intrinsic preference of
the substrates (in the catalyzed reactions) would lead to
high selectivity. Indeed, this was found to be the case.
When 5 mol % of (R,R)-1 was used, high syn selectivity
was observed for all substrates, Table 2, entries 4-6. The
highest selectivity was realized with the silyl enol ether
3a , providing the aldol adducts in a 73/1 syn/anti ratio.
Apparently, this represents a “matched case” of double
stereodifferentiation.8
The reduced yields of these reactions were disturbing
since the pure, isolated trichlorosilyl enolates provide
adducts in greater than 90% yield in almost all cases.
We thought the problem might lie in the mercury-
catalyzed metathesis reaction as a modest amount (10-
15%) of the bis(enoxy)dichlorosilane is formed, along
with the desired mono(enoxy)trichlorosilane. As the bis-
(enoxy)dichlorosilanes are much less reactive than the
corresponding enoxytrichlorosilanes in the aldol addition,
we were confident that their formation would have no
bearing on the selectivities of the in situ reactions, though
the maximum yields were effected. To confirm that the
reactions under study here were also clean and efficient,
we prepared and purified the trichlorosilyl enolate de-
rived from 3a and used it in an aldol reaction with (R,R)-1
as the catalyst, Scheme 2. The aldol adduct syn-4a was
isolated with excellent syn-diastereoselectivity (70/1) and
in very good yield.
In the hope that such trends were general, the addition
of the TBS-protected enolate to other aldehydes was
briefly investigated. Unpromoted reactions were, as
before, unselective with either cyclohexanecarboxalde-
hyde or (E)-2-butenal as the acceptor, Table 3, entries 1
and 2. Unfortunately, as observed previously with cyclic
ketone substrates, the catalyzed reactions with cyclohex-
anecarboxaldehyde were unsuccessful, with only small
amounts (<10%) of the aldol adducts isolated, probably
due to competitive enolization. However, when (E)-2-
butenal was used as the acceptor, the catalyzed reactions
proceeded in good yield with 5 mol % of (S,S)-1 and
(R,R)-1 providing 1.3/1 and 6.2/1 syn/anti ratios of the
aldol adducts, respectively. Although matched and mis-
matched cases were again observed, the selectivity in the
matched case was somewhat disappointing given the high
selectivity observed with benzaldehyde as the acceptor.
As stated above, the uncatalyzed reaction is viewed to
proceed though a boatlike closed transition structure with
aldehyde coordinated apically to a trigonal bipyramidal
silicon center. The low diastereoselectivities make pro-
posals for transition structure arrangements speculative
at best. In a simplistic picture, if the oxygenated sub-
stituent eclipses the double bond to minimize dipoles then
the major product would arise from reaction of the
enolate face away from the blocking methyl group (i). In
the process catalyzed by the chiral phosphoramides, we
are still unclear as to the origin of stereoselection with
achiral substrates, though we do believe the reactions
proceed with aldehyde, enolate, and phosphoramide in a
fac arrangement about an octahedral silicon center. If a
similar eclipsed conformation of the enolate is assumed,
then, as a result of the chair-boat flip, the major (now
syn) diastereomer is predicted (ii). However, in view of
the dramatic dependence on the configuration of 1
employed, this is most likely an incomplete analysis.
In conclusion, very high (up to 73/1) syn diastereo-
selectivity can be obtained in the aldol addition of
(8) Masamune, S.; Choy, W.; Peterson, J . S.; Sita, L. R. Angew.
Chem., Int. Ed. Engl. 1985, 24, 1.

9526 J . Org. Chem., Vol. 63, No. 25, 1998
Notes
warmed to room temperature and stirred for an additional 20
min. The two-phase mixture was then poured into H2O (20 mL)
and extracted with pentane (3 × 20 mL). The organic phases
were combined and washed consecutively with H2O (30 mL),
saturated aqueous CuSO4 (2 × 50 mL), H2O (50 mL), and brine
(50 mL). The organic phase was then dried over Na2SO4, filtered,
and concentrated to provide an oil that was purified by distil-
lation (bulb-to-bulb) to give 2.33 g (94%) of the silyl enol ether
3a as a clear, colorless liquid: bp 95 °C ABT (0.3 mmHg); [R]24
D
-10.7 ° (c ) 3.13, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 4.41 (s,
1 H), 4.09 (s, 1 H), 4.01 (q, J ) 6.4, 1 H), 1.24 (d, J ) 6.4, 3 H),
0.91 (s, 9 H), 0.21 (s, 9 H), 0.07 (s, 3 H), 0.06 (s, 3 H); 13C NMR
(CDCl3, 126 MHz) δ 161.90, 87.71, 69.59, 25.83, 22.42, 18.25,
0.13, -4.89, -5.00; IR (neat) 1634 (m) cm-1; MS (CI) m/z 275
(M+ + 1, 19), 217 (100); TLC Rf 0.66 (hexane/EtOAc 19/1). Anal.
Calcd for C13H30O2Si2 (274.55): C, 56.87; H, 11.01. Found: C,
56.82; H, 11.06.
R-oxygenated methyl ketone enolates to conjugated al-
dehydes in the presence of catalytic quantities of a chiral
Lewis base. In addition, the trichlorosilyl enolate/phos-
phoramide technology is compatible with common pro-
tecting groups, and isolation and purification of the
trichlorosilyl enolates are not necessary when the mercury-
catalyzed silyl transfer reaction is used.
Da ta for (-)-(S)-1-m eth yl-2-[(tr im eth ylsilyl)oxy]-2-p r o-
p en yl 2,2-d im eth ylp r op a n oa te (3b): bp 85 °C ABT (0.3
1
mmHg); [R]24 -21.0° (c ) 1.66, CHCl3); H NMR (CDCl3, 500
D
Exp er im en ta l Section
MHz) δ 5.11 (q, J ) 6.6, 1 H), 4.30 (s, 1 H), 4.14 (d, J ) 1.5, 1
H), 1.31 (d, J ) 6.6, 3 H), 1.21 (s, 9 H), 0.22 (s, 9 H); 13C NMR
(CDCl3, 126 MHz) δ 177.46, 157.57, 89.48, 70.54, 38.63, 27.09,
18.16, 0.03; IR (neat) 1736 (s), 1641 (s) cm-1; MS (EI) m/z 244
(M+, 26), 57 (100); TLC Rf 0.55 (hexane/EtOAc 19/1). Anal. Calcd
for C12H24O3Si (244.41): C, 58.97; H, 9.90. Found: C, 58.81; H,
9.86.
Gen er a l Meth od s. See the Supporting Information.
(-)-(S)-3-[[Dim et h yl(1,1-d im et h ylet h yl)silyl]oxy]-2-b u -
ta n on e (2a ). Methyllithium (1.30 M in Et2O, 25.4 mL, 33.0
mmol, 1.1 equiv) was added dropwise, via cannula, to a cold
(-108 °C, internal) solution of (S)-methyl 2-[[dimethyl(1,1-
dimethylethyl)silyl]oxy]propanoate6b (6.55 g, 30.0 mmol) in THF
(90 mL), such that the temperature did not rise above -105 °C
(total addition time: 45 min). After the addition, the now cloudy
mixture was stirred at -107 °C for 15 min, and then TMSCl
(11.4 mL, 90.0 mmol, 3.0 equiv) was added dropwise such that
the temperature of the mixture did not rise above -105 °C, 30
min. After the addition of TMSCl was complete, the mixture was
stirred at -105 °C for 2 min and then was allowed to warm to
room temperature and stir for 25 min, during which time a white
precipitate formed. The reaction was quenched by the addition
of 1 M aqueous HCl (90 mL), and the resulting mixture was
stirred vigorously for 1 h at room temperature, after which time
it was neutralized with solid NaHCO3 and the layers were
separated. The aqueous phase was extracted with TBME (3 ×
50 mL), and the combined organic layers were washed with H2O
(75 mL) followed by brine (75 mL), dried over Na2SO4, filtered,
and concentrated. The crude product was purified by column
chromatography (SiO2, 19/1 hexane/EtOAc) followed by distil-
lation (bulb-to-bulb) to give 4.64 g (76%) of the methyl ketone
Da ta for (-)-(S)-tr im eth yl-[[1-[(p h en ylm eth oxy)eth yl]-
eth en yl]oxy]sila n e (3c): bp 135 °C ABT (0.35 mmHg); [R]24
D
1
-51.9 ° (c ) 3.10, CHCl3); H NMR (CDCl3, 500 MHz) δ 7.38-
7.26 (m, 5 H), 4.65 (d, J ) 12.1, 1 H), 4.42 (d, J ) 12.1, 1 H),
4.36 (d, J ) 1.1, 1 H), 4.24 (d, J ) 1.1, 1 H), 3.76 (q, J ) 6.4, 1
H), 1.31 (d, J ) 6.4, 3 H), 0.25 (s, 9 H); 13C NMR (CDCl3, 126
MHz) δ 158.42, 138.79, 128.30, 127.63, 127.38, 90.22, 76.33,
70.32, 19.53, 0.14; IR (neat) 1633 (s) cm-1; MS (CI) m/z 251 (M+
+ 1, 5), 91 (100); TLC Rf 0.57 (hexane/EtOAc 9/1). Anal. Calcd
for C14H22O2Si (250.41): C, 67.15; H, 8.85. Found: C, 66.95; H,
8.82.
Rep r esen ta tive P r oced u r e for Un p r om oted Ald ol Ad -
d ition s. (1S,4S)-1-Hyd r oxy-4-[[d im eth yl(1,1-d im eth yleth -
yl)silyl]oxy]-1-p h en yl-3-p en ta n on e (a n ti-4a ) a n d (1R,4S)-
1-H yd r oxy-4-[[d im e t h yl(1,1-d im e t h yle t h yl)silyl]oxy]-1-
p h en yl-3-p en ta n on e (syn -4a ). Silyl enol ether 3a (549 mg, 2.0
mmol) was added dropwise over 1 min to a stirred suspension
of SiCl4 (460 µL, 4.0 mmol, 2.0 equiv) and Hg(OAc)2 (1.6 mg, 5
µmol, 0.0025 equiv) in CH2Cl2 (2.0 mL) at room temperature.
After addition, the reaction mixture was stirred at room tem-
perature for 1 h and then the volatile components were removed
under reduced pressure (0.1 mmHg) to give a cloudy residue.
CH2Cl2 (2.0 mL) was added, followed by benzaldehyde (203 µL,
2.0 mmol), and the reaction mixture was allowed to stir at room
temperature for 9 h. The reaction mixture was then poured into
cold (0 °C) saturated aqueous NaHCO3 solution and was stirred
for 15 min. The heterogeneous mixture was filtered through
Celite, the organic phase was separated, and the aqueous phase
was extracted with CH2Cl2 (3 × 50 mL). The organic phases were
combined, dried (Na2SO4), filtered, and concentrated to give a
crude oil. Purification by column chromatography (SiO2, hexane/
EtOAc 8/1) afforded 503.1 mg (82%) of a mixture of diastereo-
mers 4a as a clear, colorless oil: 1H NMR (DMSO-d6, 500 MHz)
δ 7.35-7.20 (m, 5 H, HAr), 2.59 (d, J ) 4.2), 5.28 (d, J ) 4.6),
5.04-4.06 (m, 1 H), 4.17 (q, J ) 6.6), 4.14 (d, J ) 6.8), 2.96 (dd,
J ) 16.3, 8.6), 2.89 (dd, J ) 16.3, 8.4), 2.75 (dd, J ) 16.3, 5.1),
2.61 (dd, J ) 16.5, 4.6), 1.15 (d, J ) 6.8), 1.11 (d, J ) 6.8), 0.83
(s), 0.82 (s), 0.05 (s) 0.02 (s), 0.00 (s); 13C NMR (DMSO-d6, 126
MHz) δ 210.07, 209.86, 145.51, 145.41, 128.07, 126.93, 126.90,
125.79, 125.75, 74.35, 74.24, 68.50, 68.43, 46.99, 46.60, 25.63,
19.87, 19.71, 17.75, -4.96, -5.04; IR (neat) 1716 (s) cm-1; MS
(FAB) 309 m/z (M+ + 1, 5), 159 (100); TLC Rf 0.44 (hexane/EtOAc
3/1); SFC tR (1R,4S)-4a 6.39 min (45.2%); tR (1S,4S)-4a 7.64 min
(54.8%) (R,R-Whelk-01, 1% MeOH in CO2, 150 bar, 40 °C, 3.0
mL min-1). Anal. Calcd for C17H28O3Si (308.49): C, 66.19; H,
9.15. Found: C, 65.91; H, 9.03.
2a as a clear, colorless oil: bp 95 °C ABT (6.0 mmHg); [R]24
D
-7.1° (c ) 2.16, CHCl3); 1H NMR (CDCl3, 500 MHz) δ 4.11 (q, J
) 6.8, 1 H), 2.18 (s, 3 H), 1.27 (d, J ) 6.8, 3 H), 0.91 (s, 9 H),
0.07 (s, 6 H); 13C NMR (CDCl3, 126 MHz) δ 212.74, 75.00, 25.67,
24.79, 20.63, 18.01, -4.79, -5.14; IR (neat) 1721 (s) cm-1; MS
(CI) m/z 231 (M+ + 1, 4), 187 (100); TLC Rf 0.32 (hexane/EtOAc
9/1). Anal. Calcd for C10H22O2Si (202.37): C, 59.35; H, 10.96.
Found: 59.42; H, 10.86.
Da ta for (-)-(S)-1-m eth yl-2-oxop r op yl 2,2-d im eth ylp r o-
p a n oa te (2b): bp 90 °C ABT (6 mmHg); [R]24D -24.5° (c ) 3.03,
CHCl3); 1H NMR (CDCl3, 500 MHz) δ 5.04 (q, J ) 7.1, 1 H),
2.15 (s, 3 H), 1.38 (d, J ) 7.1, 3 H), 1.25 (s, 9 H); 13C NMR (CDCl3,
126 MHz) δ 206.07, 177.87, 74.74, 38.53, 26.99, 25.60, 15.84; IR
(neat) 1728 (s) cm-1; MS (CI) m/z 173 (M+ + 1, 6), 57 (100); TLC
Rf 0.43 (hexane/EtOAc 9/1). Anal. Calcd for C9H16O3 (172.22):
C, 62.77; H, 9.36. Found: C, 62.55; H, 9.32.
Da ta for (-)-(S)-3-(p h en ylm eth oxy)-2-bu ta n on e (2c): bp
110 °C ABT (2.0 mmHg); [R]24 -35.2 ° (c ) 2.51, CHCl3); 1H
D
NMR (CDCl3, 500 MHz) δ 7.38-7.29 (m, 5 H), 4.57 (AB, J )
11.7, 1 H), 4.50 (AB, J ) 11.7, 1 H), 3.91 (q, J ) 6.9, 1 H), 2.20
(s, 3 H), 1.35 (d, J ) 6.9, 3 H); 13C NMR (CDCl3, 126 MHz) δ
211.27, 137.54, 128.50, 127.90, 127.74, 80.82, 71.83, 24.97, 17.26;
IR (neat) 1719 (s) cm-1; MS (CI) 179 m/z (M+ + 1, 3), 91 (100);
TLC Rf 0.18 (hexane/EtOAc 9/1). Anal. Calcd for C11H14O2
(178.23): C, 74.13; H, 7.92. Found: C, 74.10; H, 7.89.
(-)-(S)-[[1-[[Dim eth yl(1,1-d im eth yleth yl)silyl]oxy]eth yl]-
eth en yl]oxy]tr im eth ylsila n e (3a ). Ketone 2a (1.82 g, 9.00
mol) was added dropwise over 10 min to a cold (0 °C) solution of
TMSOTf (1.95 mL, 10.8 mmol, 1.2 equiv) and Et3N (1.88 mL,
13.5 mmol, 1.5 equiv) in benzene (20 mL). During the addition,
an oily lower phase appeared. After the addition, the reaction
mixture was allowed to stir at 0 °C for 10 min, and then it was
Da ta for (1S,4S)-1-h yd r oxy-1-p h en yl-4-[(2,2-d im eth yl-
p r op a n oyl)oxy]-3-p en ta n on e (a n ti-4b) a n d (1R,4S)-1-h y-
d r oxy-1-p h e n yl-4-[(2,2-d im e t h ylp r op a n oyl)oxy]-3-p e n -
ta n on e (syn -4b): 1H NMR (DMSO-d6, 500 MHz) δ 7.35-7.20

Notes
J . Org. Chem., Vol. 63, No. 25, 1998 9527
(m, 5 H), 5.37 (d, J ) 4.9), 5.34 (d, J ) 4.6), 5.08-4.96 (m, 2 H),
2.90 (dd, J ) 16.4, 9.0), 2.89 (dd, J ) 16.4, 8.6), 2.67 (dd, J )
16.1, 4.6), 2.64 (dd, J ) 16.1, 3.9), 1.28 (d, J ) 7.1), 1.22 (d, J )
6.9), 1.16 (s), 1.16 (s); 13C NMR (DMSO-d6, 126 MHz) δ 205.36,
205.27, 176.79, 145.19, 145.16, 128.14, 127.01, 125.81, 125.75,
74.45, 74.31, 68.23, 47.73, 47.62, 37.99, 26.76, 15.13, 15.10; IR
(neat) 1726 (s) cm-1; MS (CI) 279 m/z (M+ + 1, 2), 57 (100); TLC
Rf 0.36 (hexane/EtOAc 3/1). Anal. Calcd for C16H22O4 (278.35):
C, 69.04; H, 7.97. Found: C, 69.12; H, 7.97.
Data for (1S,4S)-1-h ydr oxy-1-ph en yl-4-(ph en ylm eth oxy)-
3-p en ta n on e (a n ti-4c) a n d (1R,4S)-1-h yd r oxy-1-p h en yl-4-
(p h en ylm eth oxy)-3-p en ta n on e (syn -4c): 1H NMR (DMSO-
d6, 500 MHz) δ 7.36-7.20 (m, 10 H), 5.42 (d, J ) 4.6), 5.41 (d,
J ) 4.9), 5.09-5.01 (m, 1 H), 4.52 (d, J ) 11.7), 4.46 (AB, J )
11.7), 4.40 (AB, J ) 11.5), 4.38 (d, J ) 11.7), 4.03 (q, J ) 7.1),
3.98 (q, J ) 7.1), 3.00 (dd, J ) 16.1, 9.0), 2.97 (dd, J ) 16.1,
8.8), 2.78 (dd, J ) 16.1, 4.6), 2.67 (dd, J ) 15.9, 4.4), 1.21 (d, J
) 6.8), 1.18 (d, J ) 7.1); 13C NMR (DMSO-d6, 126 MHz) δ 209.96,
145.35, 138.14, 128.29, 128.11, 127.67, 127.58, 126.99, 125.83,
125.79, 80.16, 80.01, 70.75, 68.78, 68.53, 47.34, 16.59, 16.42; IR
(neat) 1719 (s) cm-1; MS (FAB) m/z 285 (M+ + 1, 2), 154 (100);
TLC Rf 0.21 (hexane/EtOAc 3/1). Anal. Calcd for C18H20O3
(284.38): C, 76.03; H, 7.09. Found: C, 76.03; H, 7.10.
Da ta for (1S,4S)-1-cycloh exyl-1-h yd r oxy-4-[[d im eth yl-
(1,1-d im et h ylet h yl)silyl]oxy]-3-p en t a n on e (a n ti-5) a n d
(1R,4S)-1-cycloh exyl-1-h yd r oxy-4-[[d im eth yl(1,1-d im eth yl-
eth yl)silyl]oxy]-3-p en ta n on e (syn -5): 1H NMR (C6D6, 500
MHz) δ 4.02-3.95 (m, 1 H), 3.89-3.82 (m, 1 H), 2.98 (br, OH),
2.70-2.62 (m, 2 H), 1.98-1.85 (m), 1.72-1.55 (m), 1.35-1.28
(m), 1.16 (d, J ) 7.0), 1.14 (d, J ) 6.8), 1.20-1.02 (m); 0.91 (s),
0.90 (s), -0.02 (s), -0.04 (s), -0.06 (s), -0.06 (s); 13C NMR (C6D6,
126 MHz) δ 214.33, 214.25, 75.38, 75.25, 71.60, 43.63, 43.57,
41.44, 41.16, 29.29, 29.22, 28.50, 28.28, 26.84, 26.61, 26.57, 26.50,
26.48, 25.79, 20.46, 20.41, 18.12, -4.80, -5.08; IR (neat) 1714
(s) cm-1; MS (CI) m/z 315 (M+ + 1, 7), 159 (100); TLC Rf 0.30
(hexane/EtOAc 9/1). Anal. Calcd for C17H34O3Si (314.54): C,
64.92; H, 10.89. Found: C, 64.83; H, 10.89.
134.82, 134.71, 124.08, 123.98, 74.32, 74.25, 67.00, 66.98, 45.43,
44.86, 25.65, 19.90, 19.79, 17.79, 17.38, -4.89, -5.02; IR (neat)
1719 (s) cm-1; MS (CI) 271 m/z (M+ + 1, 3), 159 (100); TLC Rf
0.45 (hexane/EtOAc 3/1). Anal. Calcd for C14H28O3Si (272.46):
C, 61.72; H, 10.36. Found: C, 61.53; H, 10.29.
Rep r esen ta tive P r oced u r e for Ca ta lyzed Ald ol Ad d i-
tion s. (1S,4S)-1-Hyd r oxy-4-[[d im eth yl(1,1-d im eth yleth yl)-
silyl]oxy]-1-p h en yl-3-p en t a n on e (a n ti-4a ) a n d (1R,4S)-1-
Hydr oxy-4-[[dim eth yl(1,1-dim eth yleth yl)silyl]oxy]-1-ph en yl-
3-p en ta n on e (syn -4a ). Silyl enol ether 3a (550.0 mg, 2.0 mmol)
was added dropwise over 2 min to a stirred suspension of SiCl4
(460 µL, 4.0 mmol, 2.0 equiv) and Hg(OAc)2 (3.4 mg, 11 µmol,
0.005 equiv) in CH2Cl2 (2.0 mL) at room temperature. After
complete addition, the reaction mixture was stirred at room
temperature for 90 min, and then the volatile components were
removed under reduced pressure (0.3 mmHg) to give a cloudy
residue. Dichloromethane (2.0 mL) was added, and the mixture
was cooled to -76 °C. A solution of (S,S)-1 (37.0 mg, 0.1 mmol,
0.05 equiv, dried at 0.1 mmHg for 12 h) in CH2Cl2 (1.0 mL) was
then added over 1 min via cannula. A solution of benzaldehyde
(203 µL, 2.0 mmol) in CH2Cl2 (1.0 mL) was then added over 2
min via cannula, and the reaction mixture was stirred at -75
°C for 3 h. The reaction mixture was then rapidly poured into
cold (0 °C) saturated aqueous NaHCO3 solution and was stirred
for 15 min. The heterogeneous mixture was filtered through
Celite, the organic phase was separated, and the aqueous phase
was extracted with CH2Cl2 (3 × 50 mL). The organic phases were
combined, dried over Na2SO4, filtered, and concentrated to give
a
crude oil. Purification by column chromatography (SiO2,
hexane/EtOAc 8/1) afforded 525.0 mg (85%) of a mixture of
diastereomers 4a as a clear, colorless oil, SFC: tR (1R,4S)-4a
5.97 min (60.7%); tR (1S,4R)-4a 7.18 min (39.3%) (R,R-Whelk-
01, 1% MeOH in CO2, 150 bar, 40 °C, 3.0 mL min-1).
Ack n ow led gm en t. We are grateful to the National
Science Foundation (CHE 9500397 and CHE 9803124)
for support of this research.
Da ta for (2S,5S)-5-h yd r oxy-2-[[d im eth yl(1,1-d im eth yl-
eth yl)silyl]oxy]-6-octen -3-on e (a n ti-6) a n d (2S,5R)-5-h y-
d r oxy-2-[[d im eth yl(1,1-d im eth yleth yl)silyl]oxy]-6-octen -3-
on e (syn -6): 1H NMR (C6D6, 500 MHz) δ 5.68-5.60 (m, 1 H),
5.51-5.45 (m, 1 H), 4.63-4.54 (m, 1 H), 3.98 (d, J ) 6.6), 3.95
(q, J ) 6.8), 2.79 (dd, J ) 17.4, 8.5), 2.78-2.68 (m), 2.67-2.64
(m), 2.60 (dd, J ) 17.3, 3.4), 1.50 (br d, J ) 6.3, 3 H), 1.12 (d, J
) 6.6), 1.11 (d, J ) 6.8), 0.89 (s), 0.88 (s), -0.05 (s), -0.06 (s),
-0.08 (s); 13C NMR (DMSO-d6, 126 MHz) δ 210.33, 210.20,
Su p p or tin g In for m a tion Ava ila ble: Full experimental
procedures and characterization data for all compounds de-
scribed (36 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
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J O981739I