Diastereoselective aldol addition reactions of a chiral methyl ketone trichlorosilyl enolate under lewis base catalysis

Article abstract of DOI:10.1055/s-2001-14652

The trichlorosilyl enolate of a chiral methyl ketone bearing an oxygen substituent (OTBS) on the β-position undergoes highly diastereoselective aldol addition to a variety of achiral aldehydes in good yield. The stereochemical course of the reaction is primarily controlled by the configuration of the chiral phosphoramide which serves as an effective catalyst for this transformation.

Full text of DOI:10.1055/s-2001-14652

1024
LETTER
Diastereoselective Aldol Addition Reactions of a Chiral Methyl Ketone
Trichlorosilyl Enolate under Lewis Base Catalysis
Scott E. Denmark,* Shinji Fujimori
Roger Adams Laboratory, Department of Chemistry, University of Illinois, Urbana, IL 61801, USA
Fax (217) 333-3984; E-mail: sdenmark@uiuc.edu
Received 7 February 2001
phosphoramide (R,R)-1a (Chart 1) to generate the aldol
product iii with high 1,4-syn diastereoselection. However,
it was not possible to reverse the sense of diastereoselec-
tion by the use of (S,S)-1a.
Abstract: The trichlorosilyl enolate of a chiral methyl ketone bear-
ing an oxygen substituent (OTBS) on the -position undergoes
highly diastereoselective aldol addition to a variety of achiral alde-
hydes in good yield. The stereochemical course of the reaction is
primarily controlled by the configuration of the chiral phosphor-
amide which serves as an effective catalyst for this transformation.
Key words: aldol addition, trichlorosilyl enolate, Lewis base
catalysis, diastereoselection
The stereocontrolled aldol addition reaction remains one
of the most powerful and versatile carbon-carbon bond
forming reactions in organic synthesis.1 Among the mani-
fold variants of this venerable process, the addition of un-
substituted (i.e. methyl ketone) enolates has presented a
particular challenge.2 Although the reasons for this behav-
ior are still under investigation, one popular rationaliza-
tion is the availability of competing diastereomeric
transition structures (twist-boats) resulting from the re-
duced steric demand of the nucleophile.3
Scheme 2
In continuation of our generalization of this process, we
have now extended the scope of chiral methyl ketone
structures to include those bearing an oxygen substituent
at the -position, 2, Figure 1. Whereas structures of this
type do not give highly diastereoselective aldol additions
as their lithium enolates,5 Paterson has shown that the di-
cyclohexylboron enolates can give good 1,4-syn diastere-
As part of our exploration of the chemistry of enoxy- oselection.6 Interestingly, the use of the ( )-IPC ligand
trichlorosilanes,4a we have recently described a broad in- significantly improves selectivity, but the (+)-IPC ligand
vestigation of the catalytic enantioselective addition of gives the same selectivity as the achiral group. We de-
methyl ketone trichlorosilyl enolates, Scheme 1.4b These scribe herein the in-situ generation and aldol reaction of
reactive enolates can be generated in situ by simple mer- the trichlorosilyl enolate 4 derived from 2 and the ability
curic acetate catalyzed exchange of the TMS enol ethers of chiral phosphoramides to control the diastereoselectiv-
with silicon tetrachloride. Subsequent aldol reactions are ity of the addition.
catalyzed by chiral phosphoramides to afford the addition
products in excellent yield and good enantioselectivities
(3.2-24.0/1 er).
Figure 1
Scheme 1
The methyl ketone 2 was easily prepared in three steps
from enantiopure (S)-(+)-methyl -hydroxyisobutyrate,
Scheme 3. Conversion of the methyl ester to the Weinreb
amide 57 proceeded in 88% yield with the agency of tri-
methylaluminum. Following protection of 5 as a tert-bu-
To expand the synthetic utility of these enolates, we also
studied the addition reactions of chiral methyl ketone eno-
lates bearing an oxygen substituent, e.g. ii, Scheme 2.
This enolate (also readily generated in situ from the TMS
enol ether i) undergoes addition in the matched case with
Synlett 2001, SI, 1024–1029 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Diastereoselective Aldol Addition Reactions
1025
Table 1 Optimization of Aldol Additions of 4 with Phosphoramides
1a, 1b, 1c.
tyldimethylsilyl ether, 6, the amide was converted to the
methyl ketone 2 by controlled addition of methylmagne-
sium bromide in 91% yield. Regioselective formation of
the unsubstituted trimethylsilyl enol ether 3 was effected
by the combination of LDA and TMSCl at 78 °C.
a
yield of chromatographically homogeneous material. b determined
by supercritical fluid chromatography (Chiralpak® OD; 175 bar, 2.5
mL/min, 1.7% MeOH, = 220 nm). c incomplete reaction.
Scheme 3
For initial studies, the trichlorosilyl enolate 4 was pre-
pared in bulk and purified by distillation. By following
our established procedure8 (1 mol% Hg(OAc)2, 2.0 equiv
SiCl4) the metathesis of 3 to 4 proceeded readily, but the
distilled product was contaminated with residual
Hg(OAc)2. This problem was circumvented by the use of
Pd(OAc)2 (5 mol%) which we have found also to be an ef-
fective catalyst for this transformation.9
The rate, yield and selectivity of the aldol reactions of 3
were sufficiently interesting to examine the generality of
the process with other aromatic, olefinic, acetylenic and
aliphatic aldehydes possessing various substitution pat-
terns (Figure 2). However, to further illustrate the synthet-
ic utility of these reagents, we performed all of these
additions with in-situ-generated 4. For this purpose, we
returned to the use of Hg(OAc)2 because lower loadings
were needed to accomplish the metathesis compared to
Pd(OAc)2 (1 mol% vs. 5 mol%) and we wished to avoid
complications arising from phosphoramide poisoning by
the metal salt. To assure complete reaction with a variety
of aldehydes, we chose to use 10 mol% catalyst at 0.5 M
concentration as the standard condition and simply varied
reaction time. The results of this study are collected in
Table 2.11
Scheme 4
Optimization of the aldol addition reactions of 4 with
benzaldehyde involved a survey of the reaction concentra-
tion, catalyst loading and structure. The results are collect-
ed in Table 1. The chiral phosphoramide (R,R)-1a could
effectively promote the addition with as little as 5 mol%
catalyst at a 0.5 M reaction concentration. The configura-
tional assignment of the major diastereomer as syn-7 was
secured by single crystal X-ray analysis of the diol ob-
tained by deprotection with PPTS in EtOH. Interestingly,
the reaction selectivity was not dependent on the loading
of the catalyst (cf. entries 2-4). The enantiomeric catalyst
(S,S)-1a, was also effective in promoting the addition with
as little as 5 mol% at 0.5 M concentration. Lower reaction
concentrations can be used if the catalyst loading is in-
creased. Although the selectivities are not as high as from
(R,R)-1a, we were pleased that the catalyst was able to re-
verse stereoselectivity seen with (R,R)-1a and produce the
anti-7 as the major product. To establish the intrinsic, in-
ternal diastereoselectivity10 in this catalyzed process the
achiral phosphoramides 1b and 1c were tested. The meth-
yl derivative 1b showed as similar reactivity as (R,R)-1a
and produced syn-7 with modest selectivity as the major
isomer.
Figure 2
The first entry in Table 2 shows clearly that the in-situ
procedure is not only operationally simpler, but also leads
to superior results. The overall yield for reaction with
benzaldehyde is higher and the selectivities for both
Synlett 2001, SI, 1024–1029 ISSN 0936-5214 © Thieme Stuttgart · New York

1026
S. E. Denmark, S. Fujimori
LETTER
Table 2 Survey of Aldehyde Structure in the Aldol Additions of
In-situ Generated 4 with (R,R)-1a, (S,S)-1a, and 1b.
boron enolates. The ability of a non-covalently attached
and conformationally ill-defined additive to influence the
stereochemical course of a reaction in a way that large, co-
valently attached modifiers cannot, serves to illustrate the
power of asymmetric catalysis and to provide an impor-
tant lesson for understanding the origin of stereocontrol in
these fundamental processes.
Extension of these studies to chiral ethyl ketones as well
as chiral ketones with more remote stereocenters is in
progress.
Preparation of (+)-(S)-N-Methoxy-N-methyl-3-tert-butyldime-
thyl-silyloxy-2-methyl-propionamide (6)
To a solution of the hydroxy amide 5 (5.84 g, 39.7 mmol) in 120 mL
of THF were added tert-butyldimethylchlorosilane (7.78 g, 51.6
mmol, 1.3 equiv), 4-dimethylaminopyridine (485 mg, 3.97 mmol,
0.1 equiv) and triethylamine (13.8 mL, 99.3 mmol, 2.5 equiv). The
reaction mixture was stirred at r.t. for 12 h. The solvent was re-
moved under reduced pressure and the residue was triturated in 100
mL of ether. The insoluble material was removed by filtration. The
filtrate was washed sequentially with 10 mL of 15% v/v aqueous
acetic acid, 10 mL of water and 10 mL of sat. aq. NaHCO3. The
ether solution was dried (MgSO4) and was concentrated to give 12.3
g of crude material. The crude product was distilled to afford the si-
lyloxy amide 6 (10.0 g, 97%) as a colorless oil. Data for 6: bp:
103 °C/0.6 mmHg, 1H NMR: (500 MHz, CDCl3) 3.82 - 3.85, 3.51 -
3.54 (ABX, 2 H); 3.71 (s, 3H); 3.19 (s, 3H); 3.13 - 3.22 (m, 1H);
1.07 (d, J = 6.9, 3H); 0.87 (s, 9H); 0.04 (d, J = 4.9, 6H), 13C NMR:
(125 MHz, CDCl3) 176.29; 65.90; 61.68; 38.23; 31.17; 26.03;
18.43; 13.95; -5.29, -5.31, IR: (neat) 1666 (s), MS: (FI) 261 (M+,
b
aYield of analytically pure material. Determined by supercritical
fluid chromatography (Chiralpak® OD; 150 bar, 3.0 mL/min,
= 220 nm). cDetermined by supercritical fluid chromatography on
the benzoate. dincomplete reaction. eDetermined by 1H NMR analy-
sis in benzene-d6. f10 mol% 1b used as catalyst.
24
0.57), [ ]D +24.4° (CHCl3, c = 1.0) Anal. Calc for C12H27NO3Si
catalysts is markedly improved. Similarly 1-naphthalde-
hyde gives high yields and good selectivities in both di-
rections. The olefinic aldehydes (entries 3-7) all give good
yields, but selectivities are quite variable and generally
much better for the (R,R) catalyst. The beneficial effect of
an -substituent is seen by comparison of entries 3 and 4
as well as 5 and 7. The high selectivity for methacrolein
itself (entry 6) further supports the importance of branch-
ing near the carbonyl group. Not surprisingly then, the
acetylenic aldehyde is the least selective of the cases (en-
try 8). In the aliphatic series, the yields were significantly
lower and in entries 9 and 10 the reactions were still not
complete after 10 h.12 Nonetheless, the selectivities follow
the same trend, increasing with increasing -branching.
The internal selectivity was also established under these
conditions by reaction of 3 with benzaldehyde under
catalysis by 1b (entry 12). The preference for formation of
the syn isomer was seen again at the same level compared
to entry 9, Table 1.
(261.43), Calc. C 55.13%; H 10.41%; N 5.36%, Found: C 55.05%;
H 10.16%; N 5.35%
Preparation of (+)-(S)-4-tert-Butyldimethylsilyloxy-3-methyl-2-
butanone (2)
The amide 6 (2.70 g, 10.3 mmol) was dissolved in 30 mL of diethyl
ether at 0 °C. To this solution was slowly added 3.0 M solution of
MeMgBr in ether (4.48 mL, 13.4 mmol, 1.3 equiv). The reaction
mixture was stirred at 0 °C for 1 h, then was gradually warmed up
to r.t. over 11 hours. The reaction mixture was quenched by slow
addition of sat. aq. NH4Cl (ca. 30 mL). The layers were separated
and the aqueous layer was extracted twice with 50 mL of ether. The
extracts were combined, dried (MgSO4) and concentrated to give
2.48 g of crude oil. The crude product was purified by chromatog-
raphy (pentane/ether, 3/1, SiO2) followed by distillation to afford 2
(2.02, 91%) as a colorless liquid. Data for 2: bp: 55 °C/1.0 mmHg,
1H NMR: (500 MHz, CDCl3) 3.63 - 3.74 (ABX, 2H); 2.74 (sext,
J = 7.1, 1H); 2.18 (s, 3H); 1.07 (d, J = 6.8, 3H); 0.87 (s, 9H); 0.03
(d, J = 4.4, 6H), 13C NMR: (125 MHz, CDCl3) 212.24; 65.65;
49.53; 29.78; 26.02; 18.40; 13.13; -5.29, -5.31, IR: (neat) 1718 (s),
MS: (FI) 217 (M+, 2.51), [ ]D24 +33.5° (CHCl3, c = 1.0) Anal. Calc
for C11H24O2Si (216.39), Calc. C 61.05%; H 11.18%, Found: C
60.99%; H 11.29%
With the exception of the unhindered aliphatic aldehydes,
the yields for all these reactions are synthetically useful.
Moreover, the selectivities for production of the syn iso-
mer make this a viable method for acyclic stereocontrol
competitive with the best auxiliary-based methods.6 In
that context, it is interesting to note that, despite the mod-
est selectivities, we were able to reverse the intrinsic inter-
nal preference with a chiral catalyst, clearly a result of
dominant external control.10 This stands in contrast to
the persistence of internal control with chirally modified
Preparation of (S)-4-tert-Butyldimethylsilyloxy-3-methyl-2-tri-
methylsilyloxy-1-butene (3)
n-Butyllithium (1.54 M in hexane, 11.1 mL, 7.18 mmol, 1.4 equiv)
was added dropwise to a solution of diisopropylamine (1.67 mL,
11.9 mmol, 1.5 equiv) in 30 mL of THF at 0 °C. The reaction mix-
ture was stirred at 0 °C for 10 min then was cooled to 78 °C. To
the reaction mixture were added TMSCl (1.51 mL, 11.9 mmol, 1.5
equiv) and the ketone 2 (1.71 g, 7.90 mmol) and the reaction mix-
ture was stirred for 30 min. The reaction mixture was gradually
warmed up to 0 °C and was quenched with 40 mL of cold H2O. The
layers were separated and the aqueous layer was extracted twice
Synlett 2001, SI, 1024–1029 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Diastereoselective Aldol Addition Reactions
1027
with pentane. The combined extracts were washed with 50 mL of
sat. aq. CuSO4, 25 mL of water and 50 mL of brine. The organic ex-
tracts were dried (Na2SO4) and were concentrated to give 2.32 g of
crude oil. After distillation the enolate 3 (1.94, 85%) was obtained
(d, J = 3.9, 6H), SFC (12.5% MeOH): tR (2S, 5S)-anti-7b 3.23 min
(6%); (2S, 5R)-syn-7b 4.12 min (94%), Anal. Calc for C22H32O3Si
(372.57), Calc. C 70.92%; H 8.66%, Found: C 70.74%; H 8.60%
(2S,5S)-1-tert-Butyldimethylsilyloxy-2-methyl-5-hydroxy-5-(1-
naphthyl)-3-pentanone (7b)
1
as colorless oil. Data for 3: bp: 64 °C/1.0 mmHg, H NMR: (500
MHz, CDCl3) 4.05 (d, J = 0.7, 1H); 4.03 (d, J = 1.0, 1H); 3.36 - 3.70
(ABX, 2H); 2.27 (sext, J = 6.8, 1H); 1.01 (d, J = 6.8, 3H); 0.89 (s,
9H); 0.20 (s, 9H); 0.04 (s, 6H), 13C NMR: (125 MHz, CDCl3)
160.75; 89.39; 66.02; 43.14; 25.92 18.34; 14.99; 0.13; 5.37, IR:
(neat) 1657 (w); 1626 (m), MS: (FI) 289 (M+, 100), Anal. Calc for
C14H32O2Si2 (288.57), Calc. C 58.27%; H 11.18%, Found: C
58.05%; H 11.02%
1H NMR: (500 MHz, CDCl3) 7.47 8.02 (m, 7H); 5.98 (m, J = 9.5,
1H); 3.69 - 3.79 (ABX, 2H); 3.68 (d, J = 2.8, 1H); 3.01 3.09
(ABX, 2H); 2.82 (m, 1H); 1.07 (d, J = 7.1, 3H); 0.88 (s, 9H); 0.05
(d, J = 3.9, 6H, SiCH3), SFC (12.5% MeOH): tR (2S, 5S)-anti-7b
3.15 min (89%); (2S, 5R)-syn-7b 4.11 min (11%), Anal. Calc for
C22H32O3Si (372.57), Calc. C 70.92%; H 8.66%, Found: C 70.63%;
H 8.58%
Preparation of (S)-4-tert-Butyldimethylsilyloxy-3-methyl-2-tri-
chlorosilyloxy-1-butene (4)
(2S,5R,6E)-1-tert-Butyldimethylsilyloxy-2-methyl-5-hydroxy-7-
phenyl-6-hepten-3-one (syn-7c)
Silicon tetrachloride (1.74 mL, 15.1 mmol, 2 equiv) was added to a
solution of Pd(OAc)2 (85 mg, 0.38 mmol, 0.05 equiv) in 7.57 mL of
CH2Cl2. The trimethylsilyl enol ether 3 (2.18 g, 7.57 mmol) was
added to the reaction mixture using a cannula, and the reaction mix-
ture was stirred at r.t. for 1 h. The trichlorosilyl enol ether 4 (1.88 g,
71%) was obtained by fractional distillation of the reaction mixture
1H NMR: (500 MHz, CDCl3) 7.37 (d, J = 8.6, 1H); 7.37 (d, J = 5.6,
1H); 7.30 (t, J = 7.7, 2H); 7.23 (t, J = 7.2, 1H); 6.65 (d, J = 16.2,
1H); 6.21 (dd, J = 16.0, 6.0, 1H); 4.77 (m, 1H); 3.66 - 3.77 (ABX,
2H); 3.31 (d, J = 3.4, 1H); 2.75 2.90 (ABX, 2H); 2.82 (m, 1H);
1.06 (d, J = 7.1, 3H); 0.88 (s, 9H); 0.05 (d, J = 5.7, 6H), SFC (7.5%
MeOH): tR (2S, 5R)-syn-7c 2.74 min (89%); (2S, 5S)-anti-7c 3.26
min (11%), Anal. Calc for C20H32O3Si (348.55), Calc. C 68.92%; H
9.38%, Found: C 68.59%; H 9.02%
1
as a clear liquid. Data for 4: bp: 70 - 72 °C/0.1 mmHg, H NMR:
(400 MHz, CDCl3) 4.58 (d, J = 2.4, 1H); 4.55 (d, J = 2.4, 1H); 3.46
3.68 (ABX, 2H); 2.39 (sext, J = 6.6, 1H); 1.07 (d, J = 6.8, 3H);
0.89 (s, 9H); 0.04 (s, 6H)
General Procedure for the Aldol Reaction of 3:13 (2S,5R)-1-tert-
Butyldimethylsilyloxy-2-methyl-5-hydroxy-5-phenyl-3-pen-
tanone (syn-7a)
(2S,5S,6E)-1-tert-Butyldimethylsilyloxy-2-methyl-5-hydroxy-7-
phenyl-6-hepten-3-one (anti-7c)
1H NMR: (500 MHz, CDCl3) 7.37 (d, J = 8.6, 1.0, 1H); 7.37 (d,
J = 7.7, 1.0, 1H); 7.31 (t, J = 7.7, 2H); 7.23 (t, J = 7.2, 1H); 6.67
(dd, J = 16.1, 1.4, 1H); 6.22 (dd, J = 15.9, 6.0, 1H); 4.75 (m, 1H);
3.67 - 3.78 (ABX, 2H); 3.34 (d, J = 3.4, 1H); 2.77 2.92 (ABX,
2H); 2.84 (m, 1H); 1.07 (d, J = 7.1, 3H); 0.88 (s, 9H); 0.05 (d,
J = 3.7, 6H), SFC (7.5% MeOH): tR (2S, 5R)-syn-7c 2.55 min
(19%); (2S, 5S)-anti-7c 2.96 min (81%), Anal. Calc for C20H32O3Si
(348.55), Calc. C 68.92%; H 9.38%, Found: C 68.56%; H 9.14%
To a suspension of mercury(II) acetate (3.2 mg, 0.01 mmol, 0.01
equiv) in 1 mL of CH2Cl2 were added SiCl4 (0.23 mL, 2.0 mmol, 2.0
equiv) and the trimethylsilyl enol ether 3 (288 mg, 1.00 mmol). The
reaction mixture was stirred at r.t. for 30 min. The excess SiCl4 and
the solvent were removed under vacuum. To the residue was added
solution of (R,R)-1a (36.9 mg, 0.10 mmol, 0.10 equiv) in 2 mL of
CH2Cl2 via a cannula. The reaction mixture was cooled to 78 °C
before the addition of benzaldehyde (102 µL, 1.00 mmol, 1 equiv).
The reaction mixture was stirred at 78 °C for 2.5 h, and then was
quenched by pouring into a vigorously stirring 5 mL of cold sat. aq.
NaHCO3. The resulting slurry was stirred for 1 h and was filtered
through Celite. The layers were separated and the aqueous layer was
extracted with 20 mL of CH2Cl2. The combined organic extracts
were washed with 5 mL of brine, dried (Na2SO4) and concentrated.
The crude product was chromatographed (hexane/ether, 5/1, SiO2)
to give 7a (268 mg, 0.83 mmol, 83%) as viscous colorless oil. Data
for syn-7a: 1H NMR: (500 MHz, CDCl3) 7.23 7.47 (m, 5H); 5.17
(dt, J = 8.8, 3.2, 1H); 3.65 - 3.76 (ABX, 2H); 3.49 (d, J = 2.9, 1H);
2.86 2.96 (ABX, 2H); 2.78 (m, 1H); 1.03 (d, J = 6.9, 3H); 0.87 (s,
9H); 0.04 (d, J = 2, 6H), 13C NMR: (125 MHz, CDCl3) 214.67;
142.85, 128.47, 127.52, 125.60; 69.68; 65.56; 51.40; 48.98; 25.78;
18.16; 12.59; -5.59, IR: (neat) 1708 (m), MS: (FI) 322 (1.7, M+),
[ ]D24 +69.11° (CHCl3, c = 1.0); TLC: Rf = 0.19 (hexane/EtOAc, 5/
1, SiO2), SFC (1.4% MeOH): tR (2S, 5R)-syn-7a 4.74 min (95%);
(2S, 5S)-anti-7a 5.21 min (5%), Anal. Calc for C18H30O3Si
(322.51), Calc. C 67.03%; H 9.38%, Found: C 66.94%; H 9.42%
(2S,5R,6E)-1-tert-Butyldimethylsilyloxy-2,6-dimethyl-5-hy-
droxy-7-phenyl-6-hepten-3-one (syn-7d)
1H NMR: (500 MHz, CDCl3) 7.33 (t, J = 7.7, 2H); 7.27 (d, J = 5.4,
2H); 7.21 (t, J = 7.4, 1H); 6.58 (s, 1H); 4.64 (dt, J = 9.5, 2.6 1H);
3.67 - 3.77 (ABX, 2H); 3.27 (d, J = 3.0, 1H); 2.77 2.89 (m, 3H);
1.88 (s, 3H); 1.06 (d, J = 7.1, 3H); 0.88 (s, 9H); 0.06 (d, J = 5.1,
6H), SFC (7.5% MeOH): tR (2S, 5R)-syn-7d 2.76 min (91%); (2S,
5S)-anti-7d 3.03 min (9%), Anal. Calc for C21H34O3Si (362.58),
Calc. C 69.56%; H 9.45%, Found: C 69.53%; H 9.45%
(2S,5S,6E)-1-tert-Butyldimethylsilyloxy-2,6-dimethyl-5-hy-
droxy-7-phenyl-6-hepten-3-one (anti-7d)
1H NMR: (500 MHz, CDCl3) 7.33 (t, J = 7.6, 2H); 7.27 (d, J = 6.6,
2H); 7.21 (t, J = 7.2, 1H); 6.58 (s, 1H); 4.62 (dt, J = 9.0, 2.8 1H);
3.68 - 3.78 (ABX, 2H); 3.30 (d, J = 2.9, 1H); 2.78 2.88 (m, 3H);
1.88 (d, J = 1.3, 3H); 1.08 (d, J = 7.1, 3H); 0.89 (s, 9H); 0.06 (d,
J = 5.1, 6H), SFC (7.5% MeOH): tR (2S, 5R)-syn-7d 2.65 min
(13%); (2S, 5S)-anti-7d 2.91 min (87%), Anal. Calc for C21H34O3Si
(362.58), Calc. C 69.56%; H 9.45%, Found: C 69.52%; H 9.49%
(2S,5R,6E)-1-tert-Butyldimethylsilyloxy-2-methyl-5-hydroxy-6-
octen-3-one (syn-7e)
1H NMR: (500 MHz, CDCl3); 5.71 (dqd, J = 15.4, 6.6, 1.0, 1H);
5.49 (ddq, J = 15.5, 6.6, 1.4, 1H); 4.52 (m, 1H); 3.63 - 3.74 (ABX,
2H); 3.13 (d, J = 3.4, 1H); 2.64 2.78 (ABX, 2H); 2.78 (m, 1H);
1.69 (dt, J = 6.6, 0.8, 3H); 1.02 (d, J = 6.8, 3H); 0.87 (s, 9H); 0.03
(d, J = 6.4, 6H), SFC (5-benzoyloxy-7e, 1.5% MeOH): tR (2S, 5R)-
syn-5-benzoyloxy-7e 4.44 min (83%); (2S, 5S)-anti-5-benzoyloxy-
7e 5.26 min (17%), Anal. Calc for C15H20O3Si (286.48), Calc. C
62.89%; H 10.55%, Found: C 62.69%; H 10.67%
(2S,5S)-1-tert-Butyldimethylsilyloxy-2-methyl-5-hydroxy-5-
phenyl-3-pentanone (anti-7a)
1H NMR: (500 MHz, CDCl3) 7.27 7.38 (m, 5H); 5.14 (dt, J = 9.6,
2.8, 1H); 3.67 - 3.77 (ABX, 2H); 3.50 (d, J = 3.0, 1H); 2.84 2.97
(ABX, 2H); 2.78 (m, 1H); 1.05 (d, J = 7.1, 3H); 0.88 (s, 9H); 0.05
(d, J = 2, 6H), SFC (1.4% MeOH):tR (2S, 5R)-syn-7a 4.81 min
(12%); (2S, 5S)-anti-7a 5.16 min (88%), Anal. Calc for C18H30O3Si
(322.51), Calc. C 67.03%; H 9.38%, Found: C 66.81%; H 9.20%
(2S,5R)-1-tert-Butyldimethylsilyloxy-2-methyl-5-hydroxy-5-(1-
naphthyl)-3-pentanone (syn-7b)
(2S,5S,6E)-1-tert-Butyldimethylsilyloxy-2-methyl-5-hydroxy-6-
octen-3-one (anti-7e)
1H NMR: (500 MHz, CDCl3) 7.47 8.02 (m, 7H); 5.97 (dt, J = 9.5,
2.5, 1H); 3.68 - 3.80 (ABX, 2H); 3.58 (d, J = 2.9, 1H); 2.98 3.13
(ABX, 2H); 2.79 (m, 1H); 1.06 (d, J = 7.1, 3H); 0.86 (s, 9H); 0.04
1H NMR: (500 MHz, CDCl3); 5.69 (dqd, J = 15.1, 6.6, 1.0, 1H);
5.48 (ddq, J = 15.5, 6.6, 1.2, 1H); 4.47 (m, 1H); 3.61 - 3.74 (ABX,
2H); 3.15 (d, J = 3.4, 1H); 2.62 2.77 (m, 3H); 1.67 (dd, J = 6.3,
Synlett 2001, SI, 1024–1029 ISSN 0936-5214 © Thieme Stuttgart · New York

1028
S. E. Denmark, S. Fujimori
LETTER
0.7, 3H); 1.02 (dd, J = 6.9, 1.0, 3H); 0.85 (d, J = 0.9, 9H); 0.02 (d,
J = 3.2, 6H), SFC (5-benzoyloxy-7e, 1.5% MeOH): tR (2S, 5R)-syn-
5-benzoyloxy-7e 4.47 min (26%); (2S, 5S)-anti-5-benzoyloxy-7e
5.14 min (74%), Anal. Calc for C15H20O3Si (286.48), Calc. C
62.89%; H 10.55%, Found: C 62.70%; H 10.57%
(d, J = 9.0, 6H), SFC (5% MeOH): tR (2S,5R)-syn-7i 3.45 min
(91%); (2S,5S)-anti-7i 3.87 min (9%), Anal. Calc for C20H34O3Si
(350.57), Calc. C 68.52%; H 9.78%, Found: C 68.59%; H 9.91%
(2S,5S)-1-tert-Butyldimethylsilyloxy-2-methyl-5-hydroxy-7-
phenyl-3-heptanone (anti-7i)
(2S,5R)-1-tert-Butyldimethylsilyloxy-2,6-dimethyl-5-hydroxy-
6-hepten-3-one (syn-7f)
1H NMR: (500 MHz, CDCl3) 7.17 7.30 (m, 5H); 4.03 (m, 1H);
3.62 - 3.75 (ABX, 2H); 3.28 (dd, J = 3.2, 0.7, 1H); 2.56 2.85 (m,
5H); 1.66 1.87 (2m, 2H); 1.03 (d, J = 7.0, 3H); 0.87 (s, 9H); 0.04
(d, J = 3.2, 6H), SFC (5% MeOH): tR (2S,5R)-syn-7i 3.51 min
(29%); (2S,5S)-anti-7i 3.88 min (71%), Anal. Calc for C20H34O3Si
(350.57), Calc. C 68.52%; H 9.78%, Found: C 68.64%; H 9.78%
1H NMR: (500 MHz, CDCl3); 5.01 (s, 1H); 4.86 (s, 1H); 4.51 (d,
J = 9.5, 1H); 3.65 - 3.74 (ABX, 2H); 3.17 (d, J = 3.2, 1H); 2.80 (m,
1H); 2.67 2.82 (ABX, 2H); 1.75 (s, 3H); 1.03 (d, J = 6.8, 3H);
0.87 (s, 9H); 0.04 (d, J = 5.8, 6H), SFC (5-benzoyloxy-7f, 1.5%
MeOH): tR (2S, 5S)-anti-5-benzoyloxy-7f 5.26 min (6%); (2S, 5R)-
syn-5-benzoyloxy-7f 4.44 min (94%), Anal. Calc for C15H20O3Si
(286.48), Calc. C 62.89%; H 10.55%, Found: C 62.81%; H 10.68%
(2S,5R)-1-tert-Butyldimethylsilyloxy-2-methyl-5-hydroxy-5-cy-
clohexyl-3-pentanone (syn-7j)
1H NMR: (500 MHz, CDCl3) 3.83 (m, 1H); 3.64 - 3.76 (ABX, 2H);
3.12 (d, J = 3.4, 1H); 2.82 (m, 1H); 2.54 2.77 (ABX, 2H); 1.66
1.89 (5H); 1.00 1.38 (6H); 1.03 (d, J = 7.1, 3H); 0.88 (s, 9H); 0.05
(d, J = 5.6, 6H), SFC (5-benzoyloxy-7j, 2% MeOH): tR (2S, 5R)-
syn-5-benzoyloxy-7j 4.59 min (94%); (2S, 5S)-anti-5-benzoyloxy-
7j 5.52 min (6%), Anal. Calc for C18H36O3Si (328.56), Calc. C
65.80%; H 11.04%, Found: C 65.92%; H 11.26%
(2S,5S)-1-tert-Butyldimethylsilyloxy-2,6-dimethyl-5-hydroxy-
6-hepten-3-one (anti-7f)
1H NMR: (500 MHz, CDCl3); 5.01 (m, 1H); 4.86 (t, J = 1.2, 1H);
4.49 (m, 1H); 3.65 - 3.76 (ABX, 2H); 3.21 (d, J = 3.2, 1H); 2.80 (m,
1H); 2.67 2.75 (ABX, 2H); 1.75 (s, 3H); 1.05 (d, J = 6.9, 3H);
0.87 (s, 9H); 0.04 (d, J = 3.6, 6H), SFC (5-benzoyloxy-7f, 1.5%
MeOH): tR (2S, 5S)-anti-5-benzoyloxy-7f 5.26 min (89%); (2S,
5R)-syn-5-benzoyloxy-7f 4.44 min (11%), Anal. Calc for
C15H20O3Si (286.48), Calc. C 62.89%; H 10.55%, Found: C
62.50%; H 10.51%
(2S,5S)-1-tert-Butyldimethylsilyloxy-2-methyl-5-hydroxy-5-cy-
clohexyl-3-pentanone (anti-7j)
1H NMR: (500 MHz, CDCl3) 3.81 (m, 1H); 3.64 - 3.78 (ABX, 2H);
3.15 (d, J = 3.5, 1H); 2.81 (m, 1H); 2.54 2.73 (ABX, 2H); 1.66
1.89 (5H); 0.97 1.42 (6H); 1.05 (d, J = 7.0, 3H); 0.89 (s, 9H); 0.06
(d, J = 2.7, 6H), SFC (5-benzoyloxy-7j, 2% MeOH): tR (2S, 5R)-
syn-5-benzoyloxy-7j 4.41 min (20%); (2S, 5S)-anti-5-benzoyloxy-
7j 5.17 min (80%), Anal. Calc for C18H36O3Si (328.56), Calc. C
65.80%; H 11.04%, Found: C 65.80%; H 11.19%
(2S,5R,6E)-1-tert-Butyldimethylsilyloxy-2,6-dimethyl-5-hy-
droxy-6-octen-3-one (syn-7g)
(500 MHz, CDCl3); 5.53 (qt, J = 6.5, 1.2, 1H); 4.46 (td, J = 6.4, 1.5,
1H); 3.64 - 3.74 (ABX, 2H); 3.06 (d, J = 2.7, 1H); 2.79 (m, 1H);
2.64 2.76 (ABX, 2H); 1.63 (d, J = 1.0, 3H); 1.61 (d, J = 6.6, 3H);
1.03 (d, J = 7.1, 3H); 0.87 (s, 9H); 0.03 (d, J = 6.9, 6H), SFC (5-
benzoyloxy-7g, 2.5% MeOH): tR (2S, 5R)-syn-5-benzoyloxy-7g
2.94 min (96%); (2S, 5S)-anti-5-benzoyloxy-7g 3.45 min (4%),
Anal. Calc for C15H20O3Si (300.51), Calc. C 63.95%; H 10.73%,
Found: C 64.04%; H 10.86%
(2S,5R)-1-tert-Butyldimethylsilyloxy-2,6,6-trimethyl-5-hy-
droxy-3-heptanone (syn-7k)
1H NMR: (500 MHz, benzene-d6) 3.84 (dt, J = 10.5, 2.2, 1H); 3.41
- 3.64 (ABX, 2H); 3.17 (d, J = 2.9, 1H,); 2.37 2.59 (ABX, 2H);
2.48 (m, 1H); 0.95 (s, 9H); 0.91 (s, 9H); 0.82 (d, J = 6.8, 3H); -0.01
(d, J = 1.9, 6H), Anal. Calc for C16H34O3Si (302.52), Calc. C
63.52%; H 11.33%, Found: C 63.41%; H 11.44%
(2S,5S,6E)-1-tert-Butyldimethylsilyloxy-2,6-dimethyl-5-hy-
droxy-6-octen-3-one (anti-7g)
(500 MHz, CDCl3); 5.54 (qd, J = 6.7, 1.0, 1H); 4.44 (d, J = 9.8,
1H); 3.64 - 3.76 (ABX, 2H); 3.11 (d, J = 2.7, 1H); 2.79 (m, 1H);
2.64 2.80 (ABX, 2H); 1.63 (d, J = 1.0, 3H); 1.61 (d, J = 6.8, 3H);
1.05 (d, J = 7.0, 3H); 0.88 (s, 9); 0.04 (d, J = 3.7, 6H), SFC (5-ben-
zoyloxy-7g, 2.5% MeOH): tR (2S, 5R)-syn-5-benzoyloxy-7g 3.03
min (18%); (2S, 5S)-anti-5-benzoyloxy-7g 3.48 min (82%), Anal.
Calc for C15H20O3Si (300.51), Calc. C 63.95%; H 10.73%, Found:
C 64.75%; H 10.87%
(2S,5S)-1-tert-Butyldimethylsilyloxy-2,6,6-trimethyl-5-hy-
droxy-3-heptanone (anti-7k)
1H NMR: (500 MHz, benzene-d6) 3.77 (dt, J = 9.2, 3.2, 1H); 3.44 -
3.64 (ABX, 2H); 3.24 (d, J = 3.0, 1H); 2.37 2.59 (m, 3H); 0.94 (s,
9H); 0.93 (s, 9H); 0.85 (d, J = 6.8, 3H); 0.01 (s, 6H), Anal. Calc for
C16H34O3Si (302.52), Calc. C 63.52%; H 11.33%, Found: C
63.27%; H 11.43%
(2S,5R)-1-tert-Butyldimethylsilyloxy-2-methyl-5-hydroxy-7-
phenyl-6-heptyn-3-one (syn-7h)
Acknowledgement
1H NMR: (500 MHz, CDCl3) 7.28 7.43 (m, 5H); 5.01 5.06 (m,
1H); 3.67 - 3.77 (ABX, 2H); 3.33 (d, J = 5.1, 1H); 2.96 3.13
(ABX, 2H); 2.82 (m, 1H); 1.08 (d, J = 7.1, 3H); 0.88 (s, 9H); 0.06
(d, J = 5.1, 6H), SFC (7.5% MeOH): tR (2S, 5R)-syn-7h 3.35 min
(76%); (2S, 5S)-anti-7h 3.82 min (24%), Anal. Calc for C20H30O3Si
(346.54), Calc. C 69.32%; H 8.73%, Found: C 69.20%; H 8.77%
We are grateful to the National Science Foundation (NSF CHE-
9803124) for generous financial support. S.F. thanks the Abbott La-
boratories for a Graduate Fellowship in Synthetic Organic Chemi-
stry. We also thank Dr. Alan Walker (Kaneka America) for a gift of
(+)-methyl -hydroxyisobutyrate.
(2S,5S)-1-tert-Butyldimethylsilyloxy-2-methyl-5-hydroxy-7-
phenyl-6-heptyn-3-one (anti-7h)
References and Notes
1H NMR: (500 MHz, CDCl3) 7.28 7.43 (m, 5H); 5.01 5.06 (m,
1H); 3.67 - 3.79 (ABX, 2H); 3.29 (d, J = 5.1, 1H); 2.97 3.13
(ABX, 2H); 2.82 (m, 1H); 1.09 (d, J = 7.1, 3H); 0.88 (s, 9H); 0.05
(d, J = 3.9, 6H), SFC (7.5% MeOH): tR (2S, 5R)-syn-7h 3.47 min
(43%); (2S, 5S)-anti-7h 3.94 min (57%), Anal. Calc for C20H30O3Si
(346.54), Calc. C 69.32%; H 8.73%, Found: C 69.13%; H 8.75%
(1) Reviews: (a) Paterson, I.; Cowden, C. J.;. Wallace, D. J. In
Modern Carbonyl Chemistry, Otera, J., Ed.; Wiley-VCH:
Weinheim, 2000; Chapt. 9. (b) Cowden, C. J.; Paterson, I.
Org. React. 1997, 51, 1.
(2) For aldol reactions of -unsubstituted enolates, see: (a) Braun,
M. Angew. Chem., Int. Ed. Engl. 1987, 26, 24-37. (b) Braun,
M. In Stereoselective Synthesis, Methods of Organic
Chemistry (Houben-Weyl); Edition E21; Helmchen, G.;
Hoffman, R.; Mulzer, J.; Schaumann, E. Eds.; Thieme:
Stuttgart, 1996; Vol. 3; pp 1622-1624. (c) Corey, E. J.; Cywin,
C. L.; Roper, T. D. Tetrahedron Lett. 1992, 33, 6907.
(2S,5R)-1-tert-Butyldimethylsilyloxy-2-methyl-5-hydroxy-7-
phenyl-3-heptanone (syn-7i)
1H NMR: (500 MHz, CDCl3) 7.17 7.30 (m, 5H); 4.07 (m, 1H);
3.62 - 3.73 (ABX, 2H); 3.24 (dd, J = 3.5, 0.8, 1H); 2.56 2.85 (m,
5H); 1.65 1.86 (2m, 2H); 1.02 (d, J = 7.0, 3H); 0.86 (s, 9H); 0.03
Synlett 2001, SI, 1024–1029 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
(d) Ishihara, K.; Maruyama, T.; Mouri, M.; Gao, Q.; Furuta,
Diastereoselective Aldol Addition Reactions
1029
(5) (a) Heathcock, C. H.; White, C. T.; Morrison, J. J.
K.; Yamamoto, H. Bull. Chem. Soc. Jpn. 1993, 66, 3483.
(e) Mikami, K.; Matsukawa, S. J. Am. Chem. Soc. 1993, 115,
7039. (f) Carreira, E. M.; Lee, W.; Singer, R. A. J. Am. Chem.
Soc. 1995, 117, 3649. (g) Sodeoka, M.; Tokunoh, R.;
Miyazaki, F.; Hagiwara, E.; Shibasaki, M. Synlett 1997, 463.
(h) Ando, A.; Miura, T.; Tatematsu, T.; Shioiri, T.
Tetrahedron Lett. 1993, 34, 1507. (i) Yamamoto, H.;
Yanagisawa, A.; Matsumoto, Y.; Nakashima, H.; Asakawa,
K. J. Am. Chem. Soc. 1997, 119, 9319. (j) Yamada, Y. M. A.;
Yoshikawa, N.; Sasai, H.; Shibasaki, M. Angew. Chem., Int.
Ed. Engl. 1997, 36, 1871
VanDerveer, D. J. Org. Chem. 1981, 56, 1296. (b) Heathcock,
C. H.; Pirrung, M. C.; Lampe, J.; Buse, C. T.; Young, S. D. J.
Org. Chem. 1981, 56, 2290. (c) Martin, V. A.; Albizati, K. F.
J. Org. Chem. 1988, 53, 5986.
(6) (a) Paterson, I.; Goodman, J. M.; Isaka, M. Tetrahedron Lett.
1989, 30, 7121. (b) Paterson, I.; Oballa, R. M. Tetrahedron
Lett. 1997, 38, 8421.
(7) Luke, G. P.; Morris, J. J. Org. Chem. 1995, 60, 3013.
(8) Denmark, S. E.; Stavenger, R. A.; Winter, S. B. D.; Wong, K.-
T.; Barsanti, P. A. J. Org. Chem. 1998, 63, 9517-9523.
(9) Denmark. S. E.; Pham, S. M. Unpublished results.
(10) For a definition of these terms see: Denmark, S. E.; Almstead,
N. G. In Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-
VCH: Weinheim, 2000; Chapt. 10.
(3) For a general discussion of the aldol transition structures see:
(a) Evans, D. A; Nelson, J. V.; Taber, T. R. Stereoselective
Aldol Condensations. In Topics in Stereochemistry; Eliel, E.
L., Wilen, S. H., Eds.; Wiley Interscience: New York, 1982;
Vol. 13, 1-116. (b) Carreira, E. M. In Modern Carbonyl
Chemistry, Otera, J., Ed.; Wiley-VCH: Weinheim, 2000;
Chapt. 8. (c) Ref 2b pp 1603-1612. (d) Li, Y.; Paddon-Row,
M. N.; Houk, K. N. J. Org. Chem. 1990, 55, 481.
(11) Assignment of the major diastereomer in all cases is based on
analogy to benzaldehyde.
(12) We believe that the slow rate seen for aliphatic aldehydes in
general in these reactions does not arise from enolization, but
rather from formation of chlorohydrin-type adducts. T. Wynn,
S. K. Ghosh, unpublished results from these laboratories.
(13) All chiral stationary phase analytical chromatographic
determinations were performed on a Berger Instruments
Supercritical Fluid Chromatograph (SFC) operating at 150 bar
and 3.0 mL/min fitted with a Chiralpak OD column.
(4) (a) Denmark, S. E.; Stavenger, R. A. Acc. Chem. Res. 2000,
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Article Identifier:
1437-2096,E;2001,0,SI,1024,1029,ftx,en;Y05001ST.pdf
Synlett 2001, SI, 1024–1029 ISSN 0936-5214 © Thieme Stuttgart · New York