Lewis base catalyzed enantioselective aldol addition of acetaldehyde-derived silyl enol ether to aldehydes

Article abstract of DOI:10.1021/jo0517500

Chiral phosphoramide catalyzed-enantioselective aldol addition of an acetaldehyde-derived trialkylsilyl enol ether to aromatic aldehydes provides protected aldol products in good yields with good to excellent enantioselectivities. Preliminary studies show that the aldolization intermediate (a chlorohydrin adduct) can be trapped with tert-butyl isocyanide to form an α-hydroxy lactone with good selectivity in a singlepot operation.

Full text of DOI:10.1021/jo0517500

of aldehydes employ either enzymes6 or chiral amines7
as catalysts. In 1994, Wong et al. reported an enzyme-
catalyzed aldol reaction of acetaldehyde with itself in
rather low yield, limiting the synthetic utility of this
method.6c Barbas et al. reported the proline-catalyzed
aldol addition of acetaldehyde to aldehydes in good
enantioselectivity albeit low yield.8 Notable successes
have been achieved by MacMillan and co-workers,7a,9 who
have disclosed proline-catalyzed aldehyde-aldehyde al-
dol reactions to provide aldol products in synthetically
useful yield and selectivity, although controlling the rate
of the addition of aldehydes is required for these reac-
tions.
Lewis Base Catalyzed Enantioselective
Aldol Addition of Acetaldehyde-Derived
Silyl Enol Ether to Aldehydes
Scott E. Denmark* and Tommy Bui
Roger Adams Laboratory, Department of Chemistry,
600 South Mathews Avenue, University of Illinois,
Urbana, Illinois 61801
denmark@scs.uiuc.edu
Received August 19, 2005
In recent years, Lewis base catalysis has emerged as
a viable strategy for catalytic, enantioselective aldol
additions including directed, crossed aldol reactions of
aldehydes.10 Previous studies from these laboratories
have shown that chiral phosphoramide-catalyzed aldol
additions of preformed trichlorosilyl enolates derived
from aldehydes to a variety of aliphatic and aromatic
aldehydes provide aldol products in high yield with
moderate to good enantioselectivity and high diastereo-
selectivity.10b,c Contemporaneous studies led to the de-
velopment of a new concept, the Lewis base activation
of Lewis acids,11 which has afforded great success in the
enantio- and diastereoselective aldol addition of silyl
ketene acetals derived from esters11 and ketones12 to
aldehydes as well as enantioselective Passerini-type
reactions.13 The generality of these reactions as well as
the creation of desired products in high yield and
selectivity significantly enhance the synthetic potential
of this approach. The extension of these methods to the
aldol addition of the trimethylsilyl enol ether of acetal-
dehyde to other aldehydes is investigated, and the results
are reported herein. In addition, preliminary studies of
the in situ trapping of the aldolate intermediate with an
Chiral phosphoramide catalyzed-enantioselective aldol ad-
dition of an acetaldehyde-derived trialkylsilyl enol ether to
aromatic aldehydes provides protected aldol products in good
yields with good to excellent enantioselectivities. Preliminary
studies show that the aldolization intermediate (a chloro-
hydrin adduct) can be trapped with tert-butyl isocyanide to
form an R-hydroxy lactone with good selectivity in a single-
pot operation.
Despite recent advances in the catalytic, enantioselec-
tive aldol additions of ketone and ester derived silyl enol
ethers to aldehydes,1 the analogous transformation em-
ploying silyl enol ethers derived from aldehydes is rather
limited. Several competing reaction pathways are associ-
ated with the latter reaction, namely: (1) self-condensa-
tion of the starting aldehyde to provide homo aldol
products,2 (2) dehydration of the desired aldol product,3
(3) multiple addition of the aldehyde-derived enolate to
the desired aldol product leading to the formation of
oligomers,2,4 and (4) Tischenko-type processes.5
(6) (a) Silvestri, M. G.; Desantis, G.; Mitchell, M.; Wong, C.-H. In
Topics in Stereochemistry; Denmark, S. E., Ed.; Wiley-Interscience:
New York, 2003; Vol. 23, Chapter 5. (b) Fessner, W.-D. In Modern Aldol
Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim, 2004; Vol. 1;
Chapter 5. (c) Wong, C.-H.; Gijsen, H. J. M. J. Am. Chem. Soc. 1994,
116, 8422-8423.
(7) (a) MacMillan, D. W. C.; Northrup, A. B. J. Am. Chem. Soc. 2002,
124, 6798-6799. (b) Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem.
Res. 2004, 37, 580-591. The use of chiral amines in catalytic asym-
metric aldol reactions of ketones and aldehydes, see: (c) List, B. In
Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim,
2004; Vol. 1, Chapter 4. (d) List, B. Tetrahedron 2002, 58, 5573-5590.
(8) Barbas, C. F., III; Mase, N.; Tanaka, F. Angew. Chem., Int. Ed.
2004, 43, 2420-2423.
(9) MacMillan, D. W. C.; Northrup, A. B. Science 2004, 305, 1752-
1755.
(10) (a) Denmark, S. E.; Fujimori, S. In Modern Aldol Reactions;
Mahrwald, R., Ed.; Wiley-VCH: Weinheim, 2004; Vol. 2, Chapter 7.
(b) Denmark, S. E., Ghosh, S. K. Angew. Chem., Int. Ed. 2001, 40,
4759-4762. (c) Denmark, S. E.; Bui, T. Pro. Nat. Acad. Sci. U.S.A.
2004, 101, 5439-5444.
(11) (a) Denmark, S. E.; Wynn, T. J. Am. Chem. Soc. 2001, 123,
6199-6200. (b) Denmark, S. E.; Wynn, T.; Beutner, G. L. J. Am. Chem.
Soc. 2002, 124, 13405-13407. (c) Denmark, S. E.; Beutner, G. L. J.
Am. Chem. Soc. 2003, 125, 7800-7801. (d) Denmark, S. E.; Beutner,
G. L.; Wynn, T.; Eastgate, M. D. J. Am. Chem. Soc. 2005, 127, 3774-
3789.
Two existing strategies that have found some success
for the catalytic, enantioselective crossed aldol reaction
(1) For reviews on catalytic, enantioselective aldol reactions, see:
(a) Shibasaski, M.; Erasmus, M. V.; Groger, H. Chem. Eur. J. 1998, 7,
1137-1141. (b) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357-
389. (c) Wong, C.-H.; Machajewski, T. D. Angew. Chem., Int. Ed. 2000,
39, 1352-1374. (d) Evans, D. A.; Johnson, J. S. Acc. Chem. Res. 2000,
33, 325-335. (e) Alcaide, B.; Almendros, P. Angew. Chem., Int. Ed.
2003, 42, 858-860. (f) Carreira, E. M. In Catalytic Asymmetric
Synthesis; Ojima, I., Ed.; John Wiley & Sons: New York, 2000; p 513.
(e) Carreira, E. M. In Comprehensive Asymmetric Catalysis; Jacobsen,
E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Heidelberg, 1999; Vol.
3, Chapter 29.1. (f) Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-
VCH: Weinheim, 2004.
(2) Heathcock, C. H. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Chapter
1.5, pp 133-179.
(3) Barbas, C. F., III; Cordova, A.; Notz, W. J. Org. Chem. 2002, 67,
301-303.
(4) Nielsen, A. J. Am. Chem. Soc. 1957, 79, 2518-2524.
(5) (a) Merger, F.; Fouquet, G.; Platz, R. Liebigs Ann. Chem. 1979,
1591-1601. (b) Day, A. R.; Lin, I. J. Am. Chem. Soc. 1952, 74, 5133-
5135. (c) Mahrwald, R. In Modern Aldol Reactions; Mahrwald, R., Ed.;
Wiley-VCH: Weinheim, 2004; Vol. 2; Chapter 8.
(12) (a) Denmark, S. E.; Heemstra, J. R. Jr. Org. Lett. 2003, 5, 2303.
(b) Denmark, S. E.; Heemstra, J. R., Jr. Synlett. 2004, 2411-2416.
(13) (a) Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2003, 125, 7825-
7827. (b) Denmark, S. E.; Fan, Y. J. Org. Chem. 2005, 70, ASAP; DOI:
10.1021/jo050549m.
10.1021/jo0517500 CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/03/2005
10190
J. Org. Chem. 2005, 70, 10190-10193

TABLE 1. Survey of Trialkylsilyl Group in Aldol
Addition
15 mol % of the dimeric catalyst at -67 °C for 24 h
afforded the desired aldol product in 72% yield (entry 5).
Although a slight decrease in enantioselectivity was
observed at this temperature, the reaction time was
reduced significantly as compared to those run at -78
°C (entry 5 vs entry 1).
TABLE 2. Effect of Hu1 nig Base on Yield and
Enantioselectivity
entry
R3Si-
T, °C
yield,a %
erb
77c
15c
5c
92.7/7.3
nde
entry
i-Pr2EtN, equiv
yield,a %
erb
1
2
3
4
5
Me3Si- (1a)
Et3Si- (1b)
PhMe2Si- (1c)
t-BuMe2Si- (1d)
Me3Si- (1a)
-78
-78
-78
-78
-67
1
2
3
none
0.2
1.0
72
85
84
88.3/11.7
92.6/7.4
97.1/2.9
nd
5c
nd
72d
88.3/11.7
a Isolated yield from column chromatography. b er determined
by CSP-SFC, OD column.
a Yield of aldol products after column chromatography. b er
determined by CSP-SFC, OD column. c After 35 h. d After 24 h.
e Not determined.
Previous studies from these laboratories have demon-
strated that Hu¨nig base (i-Pr2EtN) can be used to prevent
the cleavage of trialkylsilyl enol ethers and thus improve
the yield of the aldol addition products.12 In the present
case, adventitious acid could destroy the TMS enol ether
1a and also catalyze the aldol addition, thus providing a
nonselective pathway that could lead to erosion in
selectivity. To test this hypothesis, the aldol reaction
between 1a and benzaldehyde was run in the presence
of various amounts of Hu¨nig base (Table 2). Gratifyingly,
the enantiomeric ratio of the aldol product 4a substan-
tially increased (entry 3, Table 2). Both the yield and the
selectivity improved in these crossed aldol reactions as
compared to those run in the absence of Hu¨nig base.
With the improved reaction conditions in hand, the
scope of the chiral phosphoramide-catalyzed aldol addi-
tion was examined. Aromatic aldehydes of varying elec-
tronic nature afforded aldol products in moderate to good
yields with excellent enantioselectivities (Table 3). Aro-
matic aldehydes underwent aldol additions to give the
desired aldol products in good yields and selectivities
(Table 3, entries 1-3). The aldol product of 1-naphthal-
isocyanide to afford the desired lactone and/or hydroxy
amide are also reported.
According to Mayr’s nucleophilicity scale,14 aldehyde-
derived enolates are considerably less reactive toward
electrophiles than ketone or ester-derived counterparts
and therefore create an additional challenge for the
intended crossed aldol addition. With this in mind, we
initially aimed to establish the viability of this aldol
process through studies of various factors that can
influence the rate of the aldol addition, including reaction
temperature and the steric bulk of the trialkylsilyl groups
of the enol ethers.15 Gratifyingly, in the presence of 15
mol % of chiral phosphoramide (R,R)-3, the aldol addition
of trimethylsilyl enol ether 1a to benzaldehyde 2a went
to completion within 35 h to afford aldol product 4a in
77% yield with good enantioselectivity (entry 1, Table 1).
The stable and isolable aldol product 4a was obtained
by quenching the reaction with methanol.10b Control
experiments revealed that no aldol product was formed
in the absence of the dimeric phosphoramide catalyst at
-50 °C after 5 h, highlighting the crucial role of the Lewis
base in effecting this aldol addition.
TABLE 3. Enantioselective Aldol Additions of 1a
Interestingly, the steric bulk of the trialkylsilyl groups
of the enol ethers 1b-d had a dramatic effect on the yield
and rate of the aldol addition (entries 2-4). The remain-
ing mass balance in these cases was benzaldehyde
recovered in the form of its dimethyl acetal after workup.
These results suggest that either the increased steric
hindrance of the nucleophile slows down a rate-determin-
ing C-C bond-forming step or the turnover-limiting step
is the capture of the trialkylsilyl group by chloride after
the aldolization.16 Finally, it was found that carrying out
the reaction of 1a with benzaldehyde in the presence of
entry
R
product
yield,a %
erb
1
2
3
4
5
6
7
8
9
C6H4
4a
4b
4c
4d
4e
4f
4g
4h
4i
80
85
97.1/2.9
97.1/2.9
92.2/7.8
98.1/1.9
97.9/2.1
98.2/1.8
91.2/8.8
ndc
2-naphthyl
1-naphthyl
4-CF3C6H4
4-ClC6H4
78
84
81
(14) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66-
77.
(15) Other factors include the reaction concentration and catalyst
loadings. It was found that the aldol addition can be run at 0.25-0.5
M with 15% mol catalyst to afford aldol products in good yield and
selectivity.
(16) The second mechanistic scenario implies reversible aldolization,
which is very unlikely on the basis of the high enantioselectivity
observed in the reaction.
cinnamyl
60
4-MeOC6H4
a-methylcinnamyl
n-butyl
30
<10
nrd
a Yield of analytically pure materials. b er determined by CSP-
SFC, Daicel Chiralpak, OD, AS, and AD columns. c Not deter-
mined. d No reaction.
J. Org. Chem, Vol. 70, No. 24, 2005 10191

dehyde was formed in slightly lower yield and selectivity
than that of 2-naphthaldehyde (entries 2 vs 3) although
the overall selectivity is good. Electron-deficient alde-
hydes gave rise to aldol products with good yield and
enantioselectivities as well (entries 4 and 5). Although
the yield of aldol product from cinnamaldehyde was
modest, excellent enantioselectivity was preserved (entry
6). Electron-rich aromatic aldehydes such as anisalde-
hyde afforded the desired aldol product in rather low
yield with modest enantioselectivity (entry 7).17 Finally,
R-methylcinnamaldehyde and pentanal were unreactive
(entries 8 and 9). Increasing the reaction temperature
and concentration did not improve the results signifi-
cantly.
difference NOE experiments.22 Because the absolute
configuration at C(5) has been established previously, the
syn configuration allows for the full description of the
stereostructure of the product.
SCHEME 2
The absolute configuration of aldol products was
determined through correlation with the known diol 5,18
which was obtained by direct in situ reduction of the
aldolate intermediate i with sodium borohydride (Scheme
1). The dextrorotatory diol has been unambiguously
assigned the R configuration, thus allowing for the
assignment of configuration of 4a as R as well.19
The origin of the observed diastereoselectivity can be
interpreted through either of two limiting mechanistic
hypotheses for the addition of tert-butyl isocyanide to the
chlorohydrin intermediate i. In these hypotheses, the
isocyanide either displaces chloride in an SN2-type fash-
ion from intermediate i or through an oxocarbenium
intermediate such as species ii in an SN1-type process
(Scheme 3). Low-temperature 1H NMR analysis indicated
that the diastereomeric chlorohydrins i are formed in a
ca. 1:1 ratio.20 Therefore, in the limiting SN2-type mech-
anism, they must interconvert and react preferentially
via the cis isomer to account for the diastereoselectivity
observed for 6. In the limiting SN1-type process, the
selectivity depends on the relative rate of axial and
equatorial attack of the nucleophile on intermediate ii
(Scheme 3). Axial attack leads directly to chairlike
conformer of the product, thus favoring the formation of
the R,R (l) diastereomer.
SCHEME 1
One of the unique features of this type of aldol reaction
is the formation of the chlorohydrin intermediate i,20
a
masked aldol adduct which plays a crucial role in
preventing side reactions such as multiple enolate addi-
tions. However, the intermediacy of i also presents an
intriguing opportunity for a second C-C bond-forming
process if it were reactive toward strong nucleophiles
such as isocyanides13 or silyl ketene acetals.11 Low-
temperature 1H NMR experiments revealed that tert-
butyl isocyanide can add to the chlorohydrin intermediate
i at about -46 °C to provide lactone 6 and hydroxy amide
721 in a single-pot operation after workup (Scheme 2).
The diastereoselectivity of formation of lactone 6 was
determined through 1H NMR analysis of the crude
material, and the relative syn configuration of the two
stereogenic centers of the lactone was established through
SCHEME 3
(17) There are two problems associated with this class of aldehyde.
First is the inherent low reactivity because of the poorer electrophilicity
of the aldehyde carbonyl group. Second, the electron-rich nature of the
aromatic ring facilitates the ionization of the hydroxyl group of the
aldol product under acidic quenching conditions to generate a methanol
adduct. Attempts to buffer the methanol during the quench were
fruitless.
In summary, chiral phosphoramide-catalyzed aldol
reactions of the TMS enol ether derived from acetalde-
hyde with aromatic aldehydes provides aldol products in
high yield and enantioselectivity. Aldol products obtained
in these cases are of R configuration. The chemistry
described herein provides the first example of stereo-
selective multiple carbon-carbon bond formation by
trapping an aldolate intermediate in situ with an iso-
(18) Masamune, S.; Sato, T.; Kim, B. M. Wollmann, T. A. J. Am.
Chem. Soc. 1986, 108, 8279-8281.
(19) The configuration of other aldol products was assigned by
analogy.
(20) Although this intermediate has been detected previously in
reactions of trichlorosilyl enolates (ref 10), we have independently
identified it in these additions as well. Interestingly, i exists as a
mixture of diastereomers; see the Supporting Information.
(21) The configuration of the R-carbon bearing a hydroxyl group in
7 has not been established. Selective formation of either 6 or 7 under
different quenching conditions is being investigated.
(22) See the Supporting Information for details. The identity of the
lactone was further confirmed by comparison of its spectroscopic data
with those previously reported: Casy, G. Tetrahedron Lett. 1992, 33,
8159-8162.
10192 J. Org. Chem., Vol. 70, No. 24, 2005

Teflon-coated thermocouple was added silicon tetrachloride (229
µL, 2.0 mmol) slowly via syringe at -60 °C. The resulting
solution was stirred for a few minutes before enolate 1a (179
µL, 1.2 mmol, 1.2 equiv) was added dropwise. The reaction
mixture was stirred at -60 °C under N2 for 16 h. Next, a solution
of tert-butyl isocyanide (170 µL, 1.5 mmol, 1.5 equiv) in 1 mL of
dry methylene chloride was added slowly, and the reaction
mixture was allowed to warm to -46 °C and was then stirred
at this temperature for 8 h. The mixture was first cooled to -75
°C, and dry methanol (3 mL) was then added dropwise. The
resulting solution was stirred at this temperature for ∼40 min.
Next, the reaction mixture was transferred slowly to a vigorously
stirred, cold, saturated, aqueous sodium bicarbonate solution (25
mL) via a cannula. The mixture was then stirred at room
temperature for about 1 h and then was filtered through Celite.
The aqueous layer of the filtrate was separated and extracted
with methylene chloride (3 × 25 mL). The combined organic
layers were dried over sodium sulfate, filtered, and concentrated
in vacuo. Purification of the product by silica gel column
chromatography (ether/hexane, 3/2) followed by recrystallization
(hexane/ethyl acetate, 4/1) afforded 89.1 mg (50%) of 6 and 25.1
mg (10%) of 7 as a white solid. Data for 6: mp 100 °C; 1H NMR
(500 MHz, CDCl3) 7.36-7.44 (m, 5 H, H-aryl), 5.37 (dd, J ) 10.9,
5.1, 1 H, HC(4)), 4.70 (ddd, J ) 11.2, 8.1, 2.9, 1 H, HC(2)), 3.01
(ddd, J ) 12.6, 8.3, 5.7, 1 H, H2C(3)), 2.77 (d, J ) 2.9, 1 H, (OH)),
2.21-2.30 (m, 1 H, H2C(3)); 13C NMR (500 MHz, CDCl3) 176.9
(C(1)), 137.7 (C(5)), 129.1 (C(7)), 128.9 (C(6)), 125.9 (C(8)), 77.7
(C(4)), 69.0 (C(2)), 39.5 (C(3)); IR (Nujol) 3411 (br), 2952 (s), 2924
(s), 2854 (s), 1760 (w), 1459 (m), 1377 (w), 1324 (w), 1310 (w),
1223 (w), 1195 (w), 1124 (w), 992 (w), 937 (w); MS (FI) 178 (100);
[R]24D +38.02 (c ) 1.38, EtOH); TLC Rf 0.12 (hexane/Et2O, 2/3)
cyanide to provide direct access to lactones and hydroxy
amides from aldehydes in a one pot operation. These
results highlight the synthetic utility of this method. The
expansion of scope of aldehyde structure is currently
being investigated.
Experimental Section
General Experimental Procedures. See the Supporting
Information.
General Procedure for the Aldol Addition of 1a to
Benzaldehyde. (R)-(2,2-Dimethoxyethyl)benzenemethanol
(4a). A 10-mL, two-necked, round-bottomed flask fitted with a
magnetic stirbar, rubber septum, nitrogen inlet, and Teflon-
coated thermocouple was charged with a stirred solution of 3
(126.4 mg, 0.15 mmol, 0.15 equiv), freshly distilled benzaldehyde
(102 µL, 1.0 mmol), and i-Pr2EtN (174 µL, 1.0 mmol) in 2 mL of
dry methylene chloride at -65 °C. Silicon tetrachloride (229 µL,
2.0 mmol, 2.0 equiv) was added slowly via syringe. The resulting
solution was stirred for a few minutes before enol ether 1a (179
µL, 1.2 mmol, 1.2 equiv) was added dropwise via syringe. The
reaction mixture was stirred at -65 °C under N2 for 24 h and
then was cooled to -78 °C, whereupon dry methanol (10 mL)
was added slowly such that the internal temperature was
maintained below -50 °C during the addition. The resulting
mixture was stirred for 30 min and then allowed to warm to
room temperature (23 °C). Next, the methanolic mixture was
quickly poured into a vigorously stirred, cold, saturated, aqueous
sodium bicarbonate solution (40 mL), and the resulting mixture
was stirred at room temperature for about 30 min. A cloudy
white solution was observed during this period. The mixture was
filtered through Celite, and the aqueous layer was separated
and extracted with methylene chloride (3 × 20 mL). The
combined organic layers were dried over sodium sulfate, filtered,
and concentrated in vacuo. Silica gel column chromatography
(hexanes/ethyl acetate, 3/1) followed by bulb-to-bulb distillation
afforded 157.0 mg (80%) of 4a as a clear, colorless oil. Data for
[silica gel, ceric ammonium molybdate]. Anal. Calcd for C10H10
-
O3: C, 67.41; H, 5.66. Found: C, 67.19; H, 5.34. Data for 7: mp
126 °C; 1H NMR (400 MHz, CDCl3) δ 7.27-7.34 (m, 5 H, H-aryl),
6.63 (br, 1 H, (HN)), 4.99 (dd, J ) 10.3, 2.2, 1 H, HC(4)), 4.57
(br, 1 H, (OH)), 4.23 (dd, J ) 9.8, 2.2, 1 H, HC(2)), 3.23 (br, 1 H,
(OH)), 2.26 (dt, J ) 14.6, 2.4, 1 H, H2C(3)), 1.82-1.91 (m, 1 H,
H2C(3)), 1.34 (s, 9 H, 3 × (H3C(10)); 13C NMR (400 MHz, CDCl3)
δ 172.2 (C(1)), 143.7 (C(5)), 128.6 (C(7)), 127.9 (C(6)), 125.5 (C(8)),
75.3 (C(4)), 72.9 (C(2)), 50.7 (C(9)), 42.8 (C(3)), 28.6 (C(10)); IR
(Nujol) 3359 (br), 3194 (br), 2917 (s), 2855 (s), 2725 (w), 2672
(w), 2362 (w), 1955 (w), 1891 (w), 1651 (m), 1532 (w), 1461 (s),
1376 (s), 1366 (m), 1342 (w), 1293 (w), 1283 (w), 1228 (w), 1213
(w), 1200 (w), 1170 (w), 1151 (w), 1094 (w), 1070 (w), 1024 (w),
1
4a: bp 140 °C (0.25 mmHg, ABT); H NMR (400 MHz, CDCl3)
7.22-7.28 (m, 4 H, H-aryl), 7.15-7.20 (m, 1 H, H-aryl), 4.78 (dd,
J ) 9.0, 3.2, 1 H, HC(1)), 4.46 (t, J ) 5.6, 1 H, HC(3)), 3.29 (s,
3 H, H3C(3)), 3.25 (s, 3 H, H3C(3)), 3.22 (s, br, 1H, (OH)), 1.85-
2.02 (m, 2 H, H2C(2)); 13C NMR (400 MHz, CDCl3) 144.1 (C(5)),
128.4 (C(7)), 127.4 (C(6)), 125.6 (C(8)), 103.4 (C(3)), 70.8 (C(1)),
53.6 (C(4)), 52.9 (C(4)), 41.5 (C(2)); IR (neat) 3446 (br), 3088 (w),
3064 (w), 3030 (m), 2934 (s), 2834 (s), 2360 (w), 1957 (w), 1651
(w), 1668 (w), 1604 (w), 1495 (w), 1455 (m), 1386 (w), 1193 (w),
1125 (w), 1047 (w), 941 (w), 914 (w), 846 (w), 760 (m); MS (FI)
196 (M+, 18), 184 (8), 164 (100), 121 (17), 75 (56); [R]24D +35.21
(c ) 1.46, EtOH); TLC Rf 0.28 (hexane/EtOAc, 3/1) [silica gel,
DNP]; SFC (R)-4a, tR 3.84 min (97.1%); (S)-4a, tR 4.53 min (2.9%)
(column: OD, MeOH 5%, pressure 125 psi, flow 2.5 mL/min).
Anal. Calcd for C11H16O3: C, 67.32; H, 8.22. Found: C, 67.28;
H, 8.20.
1008 (w), 996 (w); MS (FI) 251 (100); [R]24 +38.64 (c ) 2.5,
D
EtOH); TLC Rf 0.17 (ether/hexane, 3/2) [silica gel, ceric ammo-
niun molybdate]. Anal. Calcd for C14H24NO3: C, 66.91; H, 8.42;
N, 5.57. Found: C, 66.60; H, 8.55; N, 5.66.
Acknowledgment. We are grateful to the National
Science Foundation (NSF CHE 041440) for generous
financial support.
In Situ Trapping of the Aldolate Intermediate with tert-
Butyl Isocyanide. To a stirred solution of 3 (168.5 mg, 0.20
mmol, 0.20 equiv), freshly distilled benzaldehyde (102 µL, 1
mmol), and i-Pr2EtN (87 µL, 0.5 mmol) in 2 mL of dry methylene
chloride in a 10-mL, two-necked, round-bottomed flask fitted
with a magnetic stirbar, rubber septum, nitrogen inlet, and
Supporting Information Available: Full experimental
procedures and characterization data for all aldol products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO0517500
J. Org. Chem, Vol. 70, No. 24, 2005 10193