Highly selective syn glycolate aldol reactions with boron enolates of Masamune norephedrine esters

Article abstract of DOI:10.1016/S0040-4039(01)01521-0

Boron enolates of norephedrine-based glycolate esters reacted with various aldehydes to produce syn aldol products in high yield and selectivity. The outcome is consistent with a Z enolate reacting through a closed transition state with reversal of the enolate facial selectivity relative to the propionate enolates.

Full text of DOI:10.1016/S0040-4039(01)01521-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7197–7201
Highly selective syn glycolate aldol reactions with boron enolates
of Masamune norephedrine esters
Merritt B. Andrus,* B. B. V. Soma Sekhar, Timothy M. Turner and Erik L. Meredith
Brigham Young University, Department of Chemistry and Biochemistry, C100 BNSN, Provo, UT 84602-5700, USA
Received 12 July 2001; revised 14 August 2001; accepted 15 August 2001
Abstract—Boron enolates of norephedrine-based glycolate esters reacted with various aldehydes to produce syn aldol products in
high yield and selectivity. The outcome is consistent with a Z enolate reacting through a closed transition state with reversal of
the enolate facial selectivity relative to the propionate enolates. © 2001 Elsevier Science Ltd. All rights reserved.
Aldol reactions with glycolate esters and aldehydes
have been used extensively to produce differentially
protected 1,2-diol products. Various auxiliary and lig-
and-based approaches have been successful with pre-
formed enolates being the most common.1 While some
success has been found for anti stereoselection, the
majority of cases involve syn outcomes using a boron
enolate of Evans’ oxazolidinone glycolate.2 A system-
atic study examining a range of aldehydes has not been
reported in this case. We recently reported the use of a
4-oxapyrone auxiliary, constrained to an E enolate to
produce anti products.3 Catalytic glycolate aldols have
been very limited with only a few cases reported.
Kobayashi’s tin glycolates with good selectivity for
either the syn or anti diols remain the prime examples.4
Recently proline catalysis has been extended to
hydroxy-ketone aldol reactions.5 We now report the use
of norephedrine glycolate esters to produce syn prod-
ucts with a range of aldehydes (Scheme 1). The
stereoinduction is consistent with a reversal of the
enolate facial selectivity.6
the
E
enolate giving product with (2S,3R)
stereochemistry.
The methyl and benzyl glycolate esters were made using
carbodiimide (EDCI, ethyldimethylaminocarbodiimide
hydrochloride)
coupling
with
the
Masamune
norephedrine amide 1 (Mes, mesityl)6a and 2 (Scheme
3).7 Conditions for the aldol reaction included various
combinations of boron triflates and amine bases (Table
Ph
O
O
OH
RCHO
Me
Bn
OP
O
NO
R
R2BOTf,
base
NSO2Mes
OP
1S,2R
1S,2R syn
Scheme 1.
Masamune
Ph
O
OH
O
H
O
NO
Me
O
An ester auxiliary allows for both E and Z enolates
leading to either anti or syn aldol products (Scheme
2).6a Masamune reported that with dicyclohexylboron
triflate and triethylamine the E enolate produces anti
product. In this case, the (1S,2R) propionyl substrate,
derived from (1S,2R)-(+)-norephedrine, gives the S,S-
product. Di-n-butylboron triflate and Hu¨nig’s base,
forms the Z enolate and produces syn products with
moderate selectivity. It is important to note that the
facial selectivity of the Z enolate is reversed relative to
NSO2Mes
98% 49:1
c-Hex2BOTf,
Et3N, -78
C
Bn
°
1S,2S anti
1S,2R
O
OH
O
H
NO
"
n-Bu2BOTf,
i-Pr2NEt, -78
80% 7:1
°
C
1S,2R syn
Keywords: aldol reaction; glycolate; enolate; diols; diastereoselection.
* Corresponding author. E-mail: mbandrus@chemdept.byu.edu
Scheme 2.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01521-0

7198
M. B. Andrus et al. / Tetrahedron Letters 42 (2001) 7197–7201
ucts in high yield and selectivity. With isovaleraldehyde
Ph
Ph
O
O
(entry 3) the selectivity fell off to 14:1. Benzaldehyde
(entry 4) reacts with very high selectivity. Cinnamalde-
hyde drops off to 9:1. Phenylacetylene carboxaldehyde
goes down to 2:1 selectivity (entry 6). Other unsatu-
rated aldehydes investigated show trends that are in
accord with these results. Methacrolein also gave high
selectivity at 24:1. Tiglic aldehyde shows reduced 9:1
selectivity, as with isovaleraldehyde, and b-methylbute-
nal is much reduced to 2:1. a-Methyl cinnamaldehyde
(entry 9) gives good selectivity at 9:1 with 83% yield. In
contrast, the methoxy glycolate oxazolidinone with this
substrate gave a 3:2:2:1 mixture in this case. Branched
unsaturated aldehydes with this auxiliary have also
been problematic.2f
Me
Bn
OP
Me
Bn
OP2
O
HO
EDCI, DMAP
OH
NSO2Mes
NSO2Mes
90% P=Me
83% =Bn
3
1
Scheme 3.
1). The optimal combination was freshly prepared dicy-
clohexyl boron triflate8 and either triethylamine or
Hu¨nig’s base (diisopropylethylamine). An enolization
time of 2 h was critical where the glycolate, boron
triflate, and base were allowed to react before addition
of the aldehyde. Yields were dramatically reduced if
shorter times were used. Entry 1 shows an isolated yield
of 98% with a ratio of 19:1. Only two isomers were
observed. Lower amounts of base or triflate gave lower
yields with comparable selectivities (entry 2). Hu¨nig’s
base also produced the syn diastereomer (entry 3).
Di-n-butylboron triflate (3 equiv.) gave product in
much lower yield (entry 4, 30%) and selectivity. Di-n-
butylboron triflate and triethylamine gave only a trace
of product. The methyl glycolate (P=Me) also gave
high yields and selectivity similar to the benzyl ether
(entry 6). TBS ethers were also explored and only a
trace amount of product was obtained even over
extended times and at warmer temperatures. Titanium
tetrachloride, tin triflate, and boron chlorides with base,
known conditions for E enolate formation, were also
ineffective.9
The relative and the absolute stereochemistry were
1
established by acetonide formation and H NMR J-
coupling constant measurement (Scheme 4).11 A cis
equatorial–axial relationship was observed showing a
Table 2.
Ph
O
Me
Bn
OMe
O
OH
Ph
O
O
NSO2Mes
Me
Bn
3
O
R
R
H
c-Hex2BOTf 3 eq.
Et3N 2.5 eq., CH2Cl2
-78 C / H2O2
NSO2Mes
OMe
1.2 equiv.
4
°
drb
yield%a
entry
R
The optimal conditions were applied to a range of
aldehydes using the methyl glycolate auxiliary derived
from (+)-norephedrine (Table 2).10 Alkyl aldehydes
including branched substrates gave (1S,2R) syn prod-
1
2
3
i-Pr-
Et-
88
84
25:1
16:1
92
87
14:1
37:1
4
5
Ph-
Ph
Table 1.
Ph
O
81
75
9:1
2:1
Me
Bn
OP
O
Ph
6
7
OH
Ph
O
NSO2Mes
3
O
Me
Bn
O
R
76
92
24:1
9:1
R2BOTf 3 eq., CH2Cl2
base 2.5 eq. -78 C
/ H2O2
NSO2Mes
R
H
OMe
°
4
8
1.2 equiv.
drb
9
Ph
Ald. Enolate Borane
base
yield%a
83
9:1
2:1
Entry
R
P
R
10
1
2
i-Pr
i-Pr
Bn
Bn
c-Hex
c-Hex
Et3N
Et3N
98%
66%
19:1
20:1c
19:1
3:1
85
aIsolated, chromatographed material. bDetermined by 1H NMR.
3
4
5
6
7
i-Pr
i-Pr
Bn
Bn
c-Hex
n-Bu
i-Pr2NEt
i-Pr2NEt
88%
30%
°
[α]D +77.2
Jab = 1.9 Hz
Ph
OH
Ph
1) LAH 96%
2) CSA
O
O
O
i-Pr
i-Pr
Ph
Bn
Me
n-Bu
Et3N
>3%
88%
>3%
ND
Me
Bn
Ph
MeO
O
c-Hex
c-Hex
i-Pr2NEt
25:1
OMe
NSO2Mes
OMe
Hb
OMe
Ha
72%
TBS
Et3N
ND
5
ent-4
aIsolated, chromatographed material. bDetermined by 1H NMR.
c2.0 equiv. base used.
Scheme 4.

M. B. Andrus et al. / Tetrahedron Letters 42 (2001) 7197–7201
7199
low 1.9 Hz value revealing the syn stereochemistry of
the precursor.12 Using the enantiomeric (1R,2S)-(−)-
norephedrine glycolate, the aldol adduct ent-4 with
benzaldehyde was produced. The known acetonide 5
then was made and its optical rotation (+77.2°) was
compared with the literature value (+77.7°)13 to estab-
lish the absolute stereochemistry as (1R,2S).
same anti isomer is formed when one or more equiva-
lents are used.
The glycolate syn aldol pathway begins with Z enolate
formation (Fig. 2). Under all conditions investigated
with the glycolate–auxiliary substrate, including various
boron compounds and bases, only syn products have
been obtained. The Lewis basic ether forms a five-mem-
bered ring coordinated enolate overriding any steric
effect imposed by the ligands on boron.15 Two options
for product formation can be considered, either a
closed transition state or an antiperiplanar open
arrangement. The same S,R product is again obtained
when either 1 or 3 equiv. of boron and base are used
and the yield and selectivity increases as the number of
equivalents are increased. The lack of reactivity when 1
equiv. of base and three of boron were used is most
likely the result of a favorable boron–amine complex
equilibrium that prevents enolate formation.16 On the
other hand, excess base with boron triflate favors com-
plete enolization and the reaction proceeds through a
A more detailed study was made on the stoichiometry
dependence of the reagents (Table 3). With 1 equiv. of
boron triflate and amine a low 59% yield was obtained
with 17:1 selectivity with the (1R,2S) isomer as product.
When 1 equiv. of base together with 3 equiv. of boron
triflate were used the reaction did not occur. When run
with 2.5 equiv. of base and one of triflate a yield of 65%
was obtained with high 24:1 selectivity. Only when
using 2.5 equiv. of base with excess borane was product
obtained in high yield and selectivity.
The propionate diastereoselectivity follows the classic
Zimmerman–Traxler model (Fig. 1). The E enolate
from dicyclohexylboron triflate gives anti product
through a closed arrangement with boron acting as
Lewis acid (line A). The less hindered di-n-butylboron
triflate gives the Z enolate and forms syn product
through a six-ring process. However, the expected
product where the stereocenter at C-2 is inverted giving
1R,2S is not obtained (line B). Instead, the 1S,2R
isomer is formed with 7:1 selectivity. Two transition
state arrangements can account for the face reversal.
Path C is the opposite chair arrangement that uses the
opposite enolate face. An open path D involves two
boron groups in an antiperiplanar alignment. The Z
enolate in path B, with the methyl group now in a
pseudoaxial position, incurs an unfavorable steric inter-
action with the axial n-butyl group on boron and the
phenyl group of the auxiliary. The opposite enolate face
adopts a more favorable conformation now with the
butyl and phenyl groups in remote positions (line C).14
The n-butylboron–base combination was not further
studied for stoichiometry dependence to distinguish
between C and D.6a With dicyclohexylboron triflate, the
E
W/ c-Hex2BOTf, Et3N
O
OH
Me
O
H
c-hex
B
NO
Bn
A
B
N
O
O
SO2Ar
Me
c-hex
Ph
R
H
S,S-anti
W/ n-Bu2BOTf, i-Pr2NEt
Z
Me
H
O
Me
O
OH
O
Bn
N
SO2Ar
n-Bu
O
B
Ph
NO
n-Bu
R
not favored
Me
H
R,S-syn
n-Bu
n-Bu
B
O
H
O
H
O
R
C
D
Bn
N
Me
SO2Ar
Ph
O
OH
chair
or
NO
R
O
Me
H
O BnBu2
S,R-syn
O
Bn
N
SO2Ar
Me
Table 3.
Ph
B
n-Bu
anti-peri
n-Bu
Ph
O
Me
Bn
OMe
Figure 1. Propionate Masamune aldol T.S.
O
Ph
OH
O
NSO2Mes
B-c-Hex2
O
O
OH
Me
Bn
Ph
O
O
Ph
Me
Bn
OMe
NO
c-Hex2BOTf, CH2Cl2
Et3N, -78 C /H2O2
NSO2Mes
H
Ph
OMe
O
°
OMe
ent-4
Z
NSO2Mes
S,R syn
yield%a
drb
equiv. Et3N
equiv. c-Hex2BOTf
RCHO
c-hex or
1.0
1.0
1.0
3.0
59%
0
17:1
-
c-hex
chair
Me
Me
N
H
O
R
O
B
O
BcHex2
O
H
H
Bn
OMe
R
O
SO2Ar
Ph
B
2.5
3.0
1.0
3.0
65%
92%
24:1
37:1
O
Bn
N
SO2Ar
c-hex
OMe
c-hex
anti-peri
Ph
aIsolated, chromatographed material. bDetermined by 1H NMR.
Figure 2. Glycolate aldol T.S.

7200
M. B. Andrus et al. / Tetrahedron Letters 42 (2001) 7197–7201
closed transition state. Partitioning to other isomers
would be seen if open arrangements with excess boron
triflate Lewis acid activation were operative. In sum-
mary a new asymmetric glycolate aldol process with
high yields and selectivities is reported. The ease of
synthesis, protection, and convenient auxiliary removal
through ester cleavage with lithium hydroxide or
DIBAL will lead to applications where differentially
protected syn diols are needed.
4. (a) Kobayashi, S.; Kawasuji, T. Tetrahedron Lett. 1994,
35, 3329; (b) Kobayashi, S.; Hayashi, T. J. Org. Chem.
1995, 60, 1098; (c) Gennari, C.; Vulpetti, A.; Pain, G.
Tetrahedron 1997, 53, 5909.
5. List, B.; Lerner, R. A.; Barbas, C. F. J. Am. Chem. Soc.
2000, 122, 2395.
6. (a) Abiko, A.; Liu, J.-F.; Masamune, S. J. Am. Chem.
Soc. 1997, 119, 2586; (b) Yoshimitsu, T.; Song, J. J.;
Wang, G.-Q.; Masamune, S. J. Org. Chem. 1997, 62,
8978; (c) Abiko, A.; Liu, J.-F.; Buske, D. C.; Moriyama,
S.; Masamune, S. J. Am. Chem. Soc. 1999, 121, 7168; (d)
Liu, J.-F.; Abiko, A.; Pei, Z.; Buske, D. C.; Masamune,
S. Tetrahedron Lett. 1998, 39, 1873.
Acknowledgements
7. Preparation of glycolate esters 3: A solution of alcohol 1
(10.0 g, 23.6 mmol), methoxyacetic acid (2.58 g, 2.2 mL,
28.67 mmol) and DMAP (0.288 g, 2.35 mmol) in CH2Cl2
(150 mL) was cooled to 0°C and treated with EDCI (5.43
g, 28.32 mmol). The reaction mixture was stirred at 0°C
for 2 h and then at 25°C for 6 h. The solution was
concentrated and the residue was dissolved in EtOAc
(750 mL) and water (150 mL). Organic layer was sepa-
rated, washed with satd NH4Cl (150 mL) and brine (100
mL). The organic layer was dried (Na2SO4) and concen-
trated. Purification of the concentrate by silica gel
column chromatography gave 3 (10.53 g, 90%) as a fine
white solid; Rf 0.40 (35% EtOAc/Hexanes); mp 87–89°C;
We wish to thank the National Institutes of Health
(GM57275) and the Brigham Young University Cancer
Center for funding and Dr. Bruce Jackson for mass
spectrometry.
References
1. (a) Gennari, C. In Comprehensive Organic Synthesis;
Trost, B. M.; Fleming, I., Eds.; Pergamon Press: New
York, 1991; Vol. 2, Chapter 2.4; (b) Cameron, J. C.;
Paterson, I. Org. React. 1997, 51, 1.
1
[h]D −3.6 (c 6.6, CHCl3); H NMR (300 MHz, CDCl3): l
2. syn-Versions: (a) Evans, D. A.; Bender, S. L.; Morris, J.
J. Am. Chem. Soc. 1988, 110, 2506; (b) Ku, T. W.;
Kondrad, K. H.; Gleason, J. G. J. Org. Chem. 1989, 54,
3487; (c) Andrus, M. B.; Schreiber, S. L. J. Am. Chem.
Soc. 1993, 115, 10420; (d) Evans, D. A.; Barrow, J. C.;
Leighton, J. L.; Robichaud, A. J.; Sefkow, M. J. Am.
Chem. Soc. 1994, 116, 12111–12112; (e) Rudge, A. J.;
Collins, I.; Holmes, A. B.; Baker, R. Angew. Chem. Int.
Ed. Engl. 1994, 33, 2320–2322; (f) Martin, S. F.; Dodge,
J. A.; Burgess, L. E.; Limberakis, C.; Hartmann, M.
Tetrahedron 1996, 52, 3229–3246; (g) Crimmins, M. T.;
Choy, A. L. J. Org. Chem. 1997, 62, 7548–7549; (h)
Nakamura, Y.; Hirata, M.; Kuwano, E.; Taniguchi, E.
Biosci. Biotechnol. Biochem. 1998, 62, 1550–1554; (i)
Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc. 1999,
121, 5653–5660; (j) Haight, D.; Birrell, H. C.; Cantello, B.
C. C.; Eggleston, D. S.; Haltiwanger, R. C.; Hindley, R.
M.; Ramaswany, A.; Stevens, N. C. Tetrahedron: Asym-
metry 1999, 10, 1353–1367; anti-Versions: (k) Danda, H.;
Hansen, M. M.; Heathcock, C. H. J. Org. Chem. 1990,
55, 173. anti-Glycolate: (l) Evans, D. A.; Kaldor, S. W.;
Jones, T. K.; Clardy, J.; Stout, T. J. J. Am. Chem. Soc.
1990, 112, 7001; (m) Evans, D. A.; Gage, J. R.; Leighton,
J. L.; Kim, A. S. J. Org. Chem. 1992, 57, 1961; (n) Evans,
D. A.; Weber, A. E. J. Am. Chem. Soc. 1986, 108, 6757;
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I.; Hayakawa, K. Bioorg. Med. Chem. Lett. 1993, 3, 2129;
(p) Li, Z.; Wu, R.; Michalczyk, R.; Dunlap, R. B.;
Odom, J. D.; Silks, III, L. A. J. Am. Chem. Soc. 2000,
122, 386. Diastereoselective Ti glycolate: (q) Annunziata,
R.; Cinquini, M.; Cozzi, F.; Borgia, A. L. J. Org. Chem.
1992, 57, 6339.
7.35–7.17 (m, 8H), 6.96–6.93 (m, 2H), 6.87 (s, 2H), 5.93
(d, 1H, J=4.1 Hz), 4.64 (AB q, 2 H, J=17.3 Hz), 4.05
(dq, 1 H, J=4.1 and 6.8 Hz), 3.82 and 3.68 (AB q, 2 H,
J=16.3 Hz), 3.32 (s, 3H), 2.51 (s, 6H), 2.26 (s, 3H), 1.12
(d, 3 H, J=6.8 Hz); 13C NMR (75 MHz, CDCl3): l
168.90, 142.75, 140.33, 138.79, 138.10, 133.42, 132.33,
128.62, 128.58, 128.16, 127.44, 127.34, 126.11, 78.64,
69.63, 59.49, 56.74, 48.20, 23.16, 21.03, 12.75; HRMS
(FAB) calcd for C28H33NNaO5S (M++Na) 518.1977,
found 518.1990. Anal. calcd for C28H33NO5S: C, 67.85;
H, 6.71; N, 2.83. Found: C, 67.78; H, 6.82, N, 2.91%. The
benzyl and TBS glycolates were made in a similar
fashion.
8. (a) Brown, H. C.; Ganesan, K.; Dhar, R. K. J. Org.
Chem. 1993, 58, 147; (b) Brown, H. C.; Dhar, R. K.;
Ganesan, K.; Singaram, B. J. Org. Chem. 1992, 57, 499.
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1993, 58, 147.
10. General procedure: To a stirred solution of 3 (100 mg,
0.20 mmol) in CH2Cl2 (15 mL) cooled to −78°C was
added NEt3 (51.08 mg, 0.07 mL, 0.50 mmol) dropwise for
5 min. The reaction mixture was stirred for another 5 min
after the addition. A solution of c-Hex2BOTf (1.0 M in
hexane, 0.6 mL, 0.60 mmol) was added dropwise over
5–7 min and the reaction mixture was allowed to stir for
2–3 h at −78°C. Aldehyde (0.24–0.26 mmol) in CH2Cl2 (2
mL) was precooled to −78°C and added via cannula to
the enolate solution over 5 min. The reaction mixture was
stirred at −78°C for 2 h and at 0°C for 2 h. The reaction
was quenched by addition of pH 7.0 buffer (1 mL),
followed by MeOH (1 mL) and 30% H2O2 (0.5 mL) and
allowed to warm to rt. The reaction mixture was diluted
with CH2Cl2 (75 mL) and washed with aq. NaHCO3 (5
mL). The organic layer was separated and the aqueous
layer was back extracted with ether. The combined
organic extracts were treated with aq. HCl (10%, 10 mL)
3. (a) Andrus, M. B.; Soma Sekhar, B. B. V.; Meredith, E.
L.; Dalley, N. K. Org. Lett. 2000, 2, 3035–3037; (b)
Andrus, M. B.; Meredith, E. L.; Soma Sekhar, B. B. V.
Org. Lett. 2001, 3, 259–262.

M. B. Andrus et al. / Tetrahedron Letters 42 (2001) 7197–7201
7201
and brine (20 mL). The ether layer was dried over
anhydrous Na2SO4 and concentrated. Radial chromato-
graphic purification provided the aldol products whose
1H NMR characterization provided the diastereomeric
ratio. Benzaldehyde major isomer: white foam; Rf 0.32
(35% EtOAc/Hexanes); [h]D +43.5 (c 1.2, CHCl3); 1H
NMR (300 MHz, CDCl3): l 7.30–7.18 (m, 11H), 7.13–
7.08 (m, 2H), 6.83 (s, 2H), 6.78–6.76 (m, 2H), 5.73 (d, 1
H, J=5.8 Hz), 4.86 (apparent dd, 1 H, J=5.4 and 4.8
Hz), 4.63 (A of AB q, 1 H, J=16.3 Hz), 4.33 (A of AB
q, 1 H, J=16.3 Hz), 4.14–4.05 (m, 1H), 3.78 (d, 1 H,
J=5.8 Hz), 3.26 (s, 3H), 3.02 (d, 1 H, D2O exchangeable,
J=4.6 Hz), 2.39 (s, 6H), 2.28 (s, 3H), 1.03 (d, 3 H, J=6.8
Hz); 13C NMR (75 MHz, CDCl3): l 169.13, 142.75,
140.55, 138.78, 138.39, 137.60, 132.99, 132.31, 128.60,
128.57, 128.48, 128.41, 128.32, 128.22, 127.51, 126.87,
85.31, 78.80, 74.08, 59.37, 56.49, 48.09, 23.07, 21.07,
14.38; HRMS (FAB) calcd for C35H39NNaO6S (M++Na)
624.2396, found 624.2380. Adducts from other aldehydes
were adequately characterized by NMR, MS, and optical
rotation.
183.1021, found 183.1035. To the solution of diol (0.039
g, 0.21 mmol) in CH2Cl2 (6 mL) was added 2,2-
dimethoxypropane (0.20 g, 0.25 mL, 1.9 mmol) and
camphor sulfonic acid (0.005 g, 0.021 mmol). After 2 h,
the reaction was quenched with NEt3 (0.2 mL) and
concentrated. Flash chromatographic purification gave
acetonide 5 (0.034 g, 72%) as an oil; Rf 0.58 (50%
EtOAc/Hexanes); [h]D +77.2 (c 3.4, CHCl3) (lit. (see Ref.
14) [h]D +77.7 (c 1.2, CHCl3)); 1H NMR (300 MHz,
CDCl3): l 7.45–7.24 (m, 5H), 5.02 (d, 1 H, J=1.9 Hz),
4.13 (dd, J=1.9 and 12.7 Hz), 4.08 (dd, 1 H, J=1.9 and
12.7 Hz), 3.19 (q, 1 H, J=1.9 Hz), 3.06 (s, 3H), 1.56 (s,
3H), 1.55 (s, 1H); 13C NMR (75 MHz, CDCl3): l 138.96,
128.25. 127.57, 126.67, 99.25, 75.70, 73.47, 62.37, 58.46,
29.45, 19.08; HRMS (FAB) calcd for C13H19O3 (M++H)
223.1334, found 223.1336.
12. Karplus, M. J. Am. Chem. Soc. 1963, 85, 2870.
13. Barrett, A. G. M.; Rys, D. J. J. Chem. Soc., Perkin
Trans. 1 1995, 1009.
14. A similar reversal effect has been seen with diazaboro-
lidine aldol reactions: Corey, E. J.; Lee, D.-H. Tetra-
hedron Lett. 1993, 34, 1737.
15. (a) Kallmertin, J. L.; Gould, T. J. Tetrahedron Lett. 1983,
24, 5177. In contrast, the presence of two basic ethers
allows for the formation of the E enolate: (b) Paterson, I.;
Tillyer, R. D. J. Org. Chem. 1993, 58, 4182. E enolates of
thio TBS glycolates are also known: (c) Gennari, C.;
Vulpetti, A.; Moresca, D. Tetrahedron Lett. 1994, 35,
4857.
11. ent-4 (0.133 g, 0.22 mmol) in THF at 0°C was reduced
with LiAlH4 (0.025 g, 0.66 mmol) to give, after work-up
and purification, a diol (0.039 g, 96%); Rf 0.12 (50%
EtOAc/Hexanes); [h]D +53.3 (c 3.9, CHCl3); 1H NMR
(300 MHz, CDCl3): l 7.41–7.26 (m, 5H), 4.78 (d, 1 H,
J=6.6 Hz), 3.71 (dd, 1 H, J=3.6 and 11.9 Hz), 3.46 (s,
3H), 3.41 (dd, 1 H, J=3.9 and 11.9 Hz), 3.34 (td, 1 H,
J=3.9 and 6.6 Hz), 2.82 (b, 2H); 13C NMR (75 MHz,
CDCl3): l 140.51, 128.64, 128.19, 126.97, 85.89, 73.99,
60.31, 58.91; HRMS (FAB) calcd for C10H15O3 (M++H)
16. Danda, H.; Hansen, M. M.; Heathcock, C. H. J. Org.
Chem. 1990, 55, 173.