Highly Diastereoselective Additions to Chiral α-Keto Acetals

Article abstract of DOI:10.1021/jo9701804

A general synthesis of (4R*,5R*)-2-acyl-4,5-diphenyl-1,3-dioxolanes and the addition of alkylmagnesium bromides to these compounds is described. The addition reactions occur with high diastereoselectivity (typical selectivity ca. 90:10). An example addition reaction carried out on an optically active acetal proves the sense of asymmetric induction for addition of organomagnesium reagents to these α-keto acetals. An explanation of the mechanism of asymmetric induction is given.

Full text of DOI:10.1021/jo9701804

J . Org. Chem. 1997, 62, 6041-6045
6041
High ly Dia ster eoselective Ad d ition s to Ch ir a l r-Keto Aceta ls
Kauser M. Akhoon and David C. Myles*
Department of Chemistry and Biochemistry, University of CaliforniasLos Angeles,
Los Angeles, California 90095-1569
Received J anuary 30, 1997
A general synthesis of (4R*,5R*)-2-acyl-4,5-diphenyl-1,3-dioxolanes and the addition of alkylmag-
nesium bromides to these compounds is described. The addition reactions occur with high
diastereoselectivity (typical selectivity ca. 90:10). An example addition reaction carried out on an
optically active acetal proves the sense of asymmetric induction for addition of organomagnesium
reagents to these R-keto acetals. An explanation of the mechanism of asymmetric induction is
given.
In this paper we describe highly diastereoselective
addition reactions to chiral R-keto acetals. The use of
C2-symmetrical diols for the preparation of chiral acetals1
has been investigated in several laboratories.2 The
diastereoselectivities for these reactions were variable.
Using 1,4-dimethoxy-2,3-butanediol, derived from tar-
taric acid, as the diol precursor, the monoacetals of diketo
compounds (Figure 1, R3 ) CH2OCH3) gave good dias-
tereoselectivities in addition reactions with organomag-
F igu r e 1.
nesium reagents, typically ranging from 4:1 to 9:1.
However, for the acetals of keto aldehydes, (Figure 1, R2
) H), the diastereoselectivities were poor, rarely exceed-
ing 1.5:1.
We had two objectives at the outset of this research:
(1) to elevate the diastereoselectivity of the addition by
using a different chiral auxiliary, (2) to develop a chiral
auxiliary that could be cleaved under mild, nonhydrolytic
conditions.3 To determine the best approach to elevate
the diastereoselectivity of the addition reaction, we
examined the trajectories available to the nucleophile for
addition to the carbonyl. Chelation of the metal coun-
F igu r e 2.
terion by the carbonyl oxygen and one or the other of the
acetal oxygens affords a bicyclo[3.3.0] structure. Addition
reactions to the carbonyl should occur from the exo face
of these intermediates. To maximize the selectivity of
the addition reaction, steric hindrance along the trajec-
tory for endo addition must be maximized, and hindrance
for exo addition should be minimized. Previous workers
had invoked a tridentate chelation of the oxygen atom of
the carbonyl and one oxygen of the acetal and methoxy
moieties (structure 4, Figure 2) as the mechanism of
asymmetric induction in the addition.1 Examination of
the trajectories of addition on 4 reveals that there are
competing steric factors along the endo and exo trajec-
tories of addition. In contrast, in chelated intermediate
5, steric factors cooperate to hinder substantially the endo
trajectory. On the basis of this analysis, we could
conclude that large steric bulk and the absence of
chelating heteroatom functionality in R3 would afford the
highest selectivity in the addition reaction. To examine
F igu r e 3.
this hypothesis, we examined that addition reaction of
acetals synthesized from (1R*, 2R*)-1,2-diphenylethanediol
(6).
The synthesis of R-keto acetals is facile from substi-
tuted cinnamaldehydes (Figure 3). Treatment of the
2-alkylcinnamaldehydes 7 or 8 with diol 64,5 in toluene
at reflux in the presence of catalytic p-toluenesulfonic
acid led to clean formation of the acetals 9 or 10 in 94
and 85% yield, respectively. Ozonolysis of these com-
pounds followed by reductive workup with dimethyl
sulfide gave the desired ketoacetals 11 or 12.
X Abstract published in Advance ACS Abstracts, August 1, 1997.
(1) Oxathianes have also been investigated. See Eliel, E. L; Koski-
mies, J . K.; Lohri, B.; Frazee, W. J .; Morris-Natschke, S.; Lynch, J .
E.; Soai, K. In Asymmetric Reactions and Processes in Chemistry; Eliel,
E. L., Otsuka, S., Ed.; ACS Symposium Series 185; Americal Chemical
Society: Washington, DC, 1982; pp 37-53.
(2) (a) Alexakis, A.; Mangeney, P. Tetrahedron: Asymmetry 1990,
1, 477. (b) Heitz, M. P.; Gellibert,F.; Mioskowski, C. Tetrahedron Lett.
1986, 27, 3859. (c) Tamura, Y.; Ko, T.; Annoura, H.; Fuji, M.; Takeuchi,
R.; Fujioka, H. Tetrahedron Lett. 1986, 27, 2117.
(4) Since, at this point, we were primarily interested in examining
the diastereoselectivity of the addition reactions of organomagnesium
reagents to chiral R-keto acetals, we chose to carry out this initial series
of experiments with racemic 6.
(5) (1R*,2R*)-1,2-Diphenylethane-1,2-diol is prepared from trans-
stilbene by treatment with osmium tetraoxide and N-methylmorpho-
line N-oxide in acetone/H2O.
(3) Tamura, Y.; Annoura, H.; Fuji, M.; Yoshida, T.; Takeuchi, R.;
Fujioka, H. Chem. Pharm. Bull. 1987, 35, 4736.
S0022-3263(97)00180-1 CCC: $14.00 © 1997 American Chemical Society

6042 J . Org. Chem., Vol. 62, No. 17, 1997
Akhoon and Myles
Ta ble 1. Dia ster eoselective Ad d ition s to Ch ir a l
of the aldehyde. The diphenyl acetal can be easily
cleaved under hydrogenolytic conditions with Pearlman’s
catalyst12 in ethanol to afford 2-hydroxyaldehyde 17
(Figure 4). Volatile aldehyde 17 could then be reduced
(NaBH4) to furnish diol 18. To prove the sense of
asymmetric induction, we synthesized 18 from 2-methyl-
1-heptene by Sharpless asymmetric dihydroxylation with
AD mix â.13 After conversion to the MTPA esters,14 the
major diastereomeric esters were compared by 19F NMR
and found to be identical. Thus, addition of organomag-
nesium reagents to (4R,5R)-2-acyl-4,5-diphenyl-1,3-diox-
olanes occurs from the si face of the carbonyl.
The high level of diastereoselectivity and the sense of
asymmetric induction observed for the addition of orga-
nomagnesium reagents to these R-keto acetals is consis-
tent with our hypothesis that chelation occurs and that
elimination of heteroatom functionality and increased
bulk in the diol will result in a reversal in and elevation
of diastereoselectivity. In these models, the complexation
of the magnesium ion with the carbonyl oxygen and one
of the oxygens of the acetal results in the formation of a
2-magnesio-1,3,6-trioxabicyclo[3.3.0]oct-3-ene ring sys-
tem. In structure 21, the endo phenyl ring is placed two
bonds away from the bridging C-O bond. In contrast,
the endo-phenyl ring in structure 22 is in the sterically
more encumbered position adjacent to the chelating
magnesium ion and associated solvent ligands (Figure
5). Thus it is likely that 21 rather than 22 is the reactive
chelate. Examination of the trajectories of addition of
nucleophiles to the diastereotopic faces of the carbonyl
in 21 shows that addition to the carbonyl from the endo
side of the bicyclic system proceeds via a highly hindered
trajectory. In contrast, addition from the exo face of 21
is free of steric hindrance.
r-Keto Aceta ls
R1
R4
X
% yield
ratio
no.a
CH3
CH3
CH3
CH3
CH3
(CH2)4CH3
(CH2)4CH3
(CH2)4CH3
(CH2)4CH3
(CH2)4CH3
(CH2)4CH3
phenyl
allyl
vinyl
isopropyl
ethyl
phenyl
allyl
vinyl
isopropyl
ethyl
Cl
Br
Br
Cl
Br
Cl
Br
Br
Cl
Br
Br
94
64
96
92
90
81
94
85
90
100
63
>99:1
50:50
91:9
91:9
91:9
>99:1
60:40
>99:1
92:8
91:9
80:20
13a
13b
13c
13d
13e
15a
15b
15c
15d
15e
15f
methyl
a
Major product.
The results of addition reactions of alkyl-, aryl-, and
vinylmagnesium halides to 11 and 12 are given in the
Table 1 and show that the selectivity of addition is high
for all of these reagents.6 Typical reaction conditions
required for maximum selectivity were the addition of a
solution of excess organomagnesium reagent7 to a pre-
cooled solution of R-keto acetal in toluene. Under these
conditions, we found that the diastereoselectivities and
yields were reproducibly high.8 The exception to this
trend was allylmagnesium bromide (Table 1, entries 2
and 7). The poor selectivity observed for this reagent
stands in sharp contrast to the selectivities observed for
all other examples.9 Only one addition product was
observed for the additions of phenylmagnesium bromide
to 11 and 12 and the addition of vinylmagnesium bromide
to 12.
Having established the high diastereoselectivity of the
addition reactions of organomagnesium reagents to the
diphenyl acetals, we wished to determine the sense of
asymmetric induction. To ascertain this we needed to
synthesize optically active acetals. Diol 6 can be pre-
pared in high enantiomeric excess from stilbene using
Sharpless asymmetric dihydroxylation.10 Treatment of
optically active (1R,2R)-1,2-diphenyl-1,2-ethanediol with
aldehyde 8 under the previously described conditions
afforded optically active acetal 10′.11 Ozonolysis as before
gave the desired R-keto acetal 12′. Addition of methyl-
magnesium bromide to the carbonyl of 12′ furnished 15f′/
16f′ with the same 80:20 diastereoselectivity as was
observed for the racemic acetal 12 (see Table 1).
These experiments show that, through analysis of the
trajectories of addition of nucleophiles to carbonyls
adjacent to acetals, the diastereoselectivity of addition
can be significantly enhanced. In addition, the cleavage
of the acetals of 1,2-diphenyl-1,2-ethanediol can be
achieved easily under catalytic hydrogenation. We are
currently extending this methodology to include other
electrophilic systems and developing applications of this
methodology in synthesis.
Exp er im en ta l Section
Gen er a l Exp er im en ta l. All reactions involving moisture
sensitive reagents were performed in oven-dried or flame-dried
glassware under
a positive pressure of argon. Benzene,
toluene, and dichloromethane were distilled from CaH2. Tet-
rahydrofuran and diethyl ether were distilled form sodium
benzophenone ketyl. All reagents were obtained commercial
sources and used as received. Nuclear magnetic resonance
spectra were taken in CDCl3 at 200, 360, or 400 MHz.
Chemical shifts are reported in ppm from tetramethylsilane
and referenced to the CHCl3. High resolution CI mass spectra
were obtained by members of the UCLA Mass Spectrometry
Facility. Melting points are uncorrected. Thin layer chro-
matograms were visualized using 254 nm ultraviolet light or
by heating samples stained with vanillin solution. Chroma-
tography was performed using 230-245 mesh silica gel and
varying ratios of hexanes/ethyl acetate as eluent.
To prove the facial selectivity of the addition reaction,
we converted the adducts 15f′/16f′ into the corresponding
diols via reductive cleavage of the acetal and reduction
(6) We also examined the impact of a variety of solvents and
temperature combinations on the diastereoselectivity of the addition.
The indicated conditions afforded the highest diastereoselectivities with
the best reproducibility.
Gen er a l P r oced u r e for Acet a l F or m a t ion . Unless
otherwise stated, this protocol was used for synthesis of
(7) See Experimental Section for details.
(8) The diastereomeric ratios were determined by integration of the
1H NMR signals for the acetal protons of the diasteromers.
(9) This change in diastereoselectivity is likely due to a change in
mechanism from inter- to intramolecular delivery of the nucleophile.
(10) Wang, Z. M.; Sharpless, K. B. J . Org. Chem. 1994, 59, 8303.
(11) For compounds that were prepared in both racemic and optically
active forms, a slanted prime following the number indicates that the
compound is optically active.
(12) (a) Mori, K.; Yoshimura, T.; Sugai, T. Liebigs Ann. Chem. 1988,
899. (b) Eid, C. N.; Konopelski, J . P. Tetrahedron 1991, 47, 975.
(13) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J .; J eong, K.; Kwong, H.; Morikawa, K.; Wang, Z.; Xu, D.;
Zhang, X. J . Org. Chem. 1992, 57, 2768.
(14) Ward, D. E.; Rhee, C. K. Tetrahedron Lett. 1991, 32, 7165.

Diastereoselective Additions to Chiral R-Keto Acetals
J . Org. Chem., Vol. 62, No. 17, 1997 6043
F igu r e 4.
3 mL of dimethyl sulfide and allowed to stir overnight at room
temperature. The solution was then diluted with water, and
the mixture was extracted with dichloromethane. The com-
bined organic extracts were washed with brine, dried over
magnesium sulfate, filtered, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
using hexanes:ethyl acetate (10:1) as eluent.
(4R*,5R*)-2-Acetyl-4,5-diph en yl-1,3-dioxolan e (11). Com-
pound 11 was prepared by the ozonolysis protocol above
starting from 9 (443 mg, 1.29 mmol) and sodium bicarbonate
(11 mg, 0.129 mmol) in dichloromethane:methanol (15 mL).
The chromatography provided 11 (330 mg, 95%) as a colorless
oil. Although 11 could be handled for brief periods of time,
we found it to be unstable. It can be stored overnight at a
concentration of 0.1 M in a benzene matrix at -10 °C. 1H
NMR (CDCl3) δ 7.51-7.24 (m, 10H), 5.57 (s, 1H), 4.85 (ABq,
∆ν ) 14.4 Hz, J ab ) 7.2, 2H), 2.42 (s, 3H). 13C NMR (CDCl3)
δ 203.29, 135.89, 135.07, 129.06, 128.70, 128.54, 128.49,
126.63, 126.43, 125.97, 102.51, 86.74, 85.50, 24.55. IR (NaCl)
3065, 3034, 2895, 1813, 1736, 1496, 1456, 1109, 1043, 914, 765,
698 cm-1
F igu r e 5.
acetals. To a stirred solution of an aldehyde (1 equiv, 0.1 M)
in anhydrous benzene in the presence of pyridinium p-
toluenesulfonic acid (0.01 equiv) was added diol (1.2 equiv) at
ambient temperature under argon. A Dean-Stark condenser
was affixed to the flask and the resulting mixture heated at
reflux overnight. The reaction mixture was allowed to cool to
room temperature, quenched with a saturated solution of
sodium bicarbonate, and extracted with diethyl ether (3×). The
combined organic extracts were washed with brine, dried over
magnesium sulfate, filtered, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
using hexanes:ethyl acetate (10:1) as eluent.
(4R*,5R*)-2-[1-Meth yl-2-p h en yleth en yl]-4,5-d ip h en yl-
1,3-d ioxola n e (9). From R-methyl-trans-cinnamaldehyde
(1.25 g, 8.5 mmol) and (1R*, 2R*)-1,2-diphenyl-1,2-ethanediol
(2.00 g, 9.35 mmol) in benzene (190 mL). 9 was obtained (2.73
g, 94%) as colorless crystals (mp 112 °C). 1H NMR (CDCl3) δ
7.48-7.38 (m, 15H), 6.94 (s, 1H), 6.00 (s, 1H), 4.97 (ABq, ∆ν )
7.2 Hz, J ab ) 7.2, 2H), 2.18 (s, 3H). 13C NMR (CDCl3) δ 138.06,
136.59, 136.28, 134.63, 130.62, 129.04, 128.50, 128.45, 128.11,
127.01, 126.32, 108.71, 86.74, 85.58, 12.11. IR (NaCl) 3032,
2883, 1495, 1452, 1348, 1248, 1093, 1076, 1016, 916, 868, 763,
698, 648 cm-1. HRMS (CI) calculated for C22H24O2 (M - H)+
341.1542, observed 341.1536.
(4R*,5R*)-2-P en ta n oyl-4,5-d ip h en yl-1,3-d ioxola n e (12).
Compound 12 was prepared by the ozonolysis protocol above
starting from 10 (751 mg, 1.89 mmol) and sodium bicarbonate
(16 mg, 0.189 mmol) in dichloromethane:methanol (19 mL).
The chromatography provided 12 (610 mg, 99.8%) as a
colorless oil. Although 12 could be handled for brief periods
of time, we found it to be unstable. It can be stored overnight
at a concentration of 0.1 M in a benzene matrix at -10 °C. 1H
NMR (CDCl3) δ 7.38-7.23 (m, 10H), 5.57 (s, 1H), 4.84 (ABq,
∆ν ) 19.1 Hz, J ab ) 8.4, 2H), 2.78 (t, J ) 6.8, 2H), 1.77-1.68
(m, 2H), 1.40-1.33 (m, 4H), 0.93 (t, J ) 1.4, 3H). 13C NMR
(CDCl3) δ 205.51, 136.03, 135.24, 128.67, 128.54, 128.50,
126.71, 126.47, 102.47, 86.77, 85.50, 37.11, 31.28, 22.54, 22.37,
13.84. IR (NaCl) 3065, 3034, 2957, 2932, 2872, 1732, 1496,
1456, 1113, 1022, 762, 698 cm-1
.
(4R,5R)-2-P en ta n oyl-4,5-d ip h en yl-1,3-d ioxola n e (12′).
An identical procedure was used starting from 10′ to furnish
12′. [R]22 +40.6 (c ) 2.42, CHCl3).
D
(4R*,5R*)-2-[1-P en t yl-2-p h en ylet h en yl]-4,5-d ip h en yl-
1,3-d ioxola n e (10). From R-amylcinnamaldehyde (1.72 g, 8.5
mmol) and (1R*, 2R*)-(+)-1,2-diphenyl-1,2-ethanediol (2.00 g,
9.35 mmol) in benzene (190 mL). 10 was obtained (2.87 g,
84.8%) as a colorless oil. 1H NMR (CDCl3) δ 7.44-7.28 (m,
Gen er a l P r oced u r e for th e Ad d ition of Alk ylm a gn e-
siu m Rea gen ts to r-Keto a ceta ls. A solution of R-keto
acetals (0.1 M) in toluene was cooled to -78 °C in dry ice/
acetone bath. Five equivalents of alkylmagnesium reagent
was added dropwise to the solution via syringe. The resulting
solution was stirred 10 min and quenched by the addition of
saturated aqueous ammonium chloride solution, and the
mixture was allowed to warm to room temperature. The
mixture was extracted with diethyl ether (3×). The combined
organic extracts were washed with brine, dried over magne-
sium sulfate, filtered, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel using
hexanes:ethyl acetate (10:1) as eluent.
15H), 6.87 (s, 1H), 6.14 (s, 1H), 4.89 (ABq, ∆ν ) 9 Hz, J ab
)
7.2, 2H), 2.60-2.48 (m, 2H), 1.84-1.71 (m, 2H), 1.49-1.36 (m,
4H), 0.93 (t, J ) 7.6, 3H). 13C NMR (CDCl3) δ 139.83, 138.94,
138.30, 136.78, 136.44, 130.76, 128.81, 128.56, 128.53, 128.25,
128.09, 127.89, 127.06, 126.91, 126.83, 126.44, 108.58, 86.88,
85.27, 79.08, 32.43, 28.99, 27.08, 22.36, 14.07. IR (NaCl) 3063,
3032, 2955, 2930, 2870, 1495, 1454, 1352, 1286, 1101, 1003,
761, 698 cm-1
399.23241, observed 399.23247.
.
HRMS (CI) calculated for C28H31O2 (M+)
(4R,5R)-2-[1-P en tyl-2-p h en yleth en yl]-4,5-d ip h en yl-1,3-
d ioxola n e (10′). An identical procedure was used starting
(4R*,5R*)-2-[(1S*)-1-Hyd r oxy-1-p h en yleth yl]-4,5-d ip h e-
n yl-1,3-dioxolan e (13a) an d (4R*,5R*)-2-[(1R*)-1-Hydr oxy-
1-p h en yleth yl]-4,5-d ip h en yl-1,3-d ioxola n e (14a ). To a
cooled (-78 °C) solution of 11 (24.7 mg, 0.092 mmol) in toluene
(1.00 mL) was added phenylmagnesium chloride in THF (0.200
mL of 25% wt solution, 0.460 mmol) to obtain 30.0 mg (0.087
mmol, 94%) of the alcohols 13a /14a as a colorless oil. 1H NMR
(CDCl3) δ 7.69-7.11 (m, 15H), 5.59 (s, 1H), 4.71 (ABq, ∆ν )
45.2 Hz, J ab ) 8.3, 2H), 2.53 (s, 1H), 1.79 (s, 1H). 13C NMR
(CDCl3) δ 143.12, 137.37, 135.73, 128.59, 128.49, 128.29,
from (1R,2R)-1,2-diphenylethane-1,2-diol to furnish 10′. [R]22
D
+5.78 (c ) 1.35, CHCl3).
Gen er a l P r oced u r e for th e Ozon olysis of Alk en e Ac-
eta ls. A solution of alkene (1 equiv, 0.1 M) in dichlo-
romethane:methanol (10:1) containing sodium bicarbonate
(0.10 equiv) was cooled to -78 °C in dry ice/acetone bath. The
cooled solution was treated with a stream of ozone until a pale
blue color was observed. The solution was then treated with

6044 J . Org. Chem., Vol. 62, No. 17, 1997
Akhoon and Myles
128.03, 127.27, 126.82, 126.42, 125.98, 87.12, 58.56, 75.48,
24.19. IR (NaCl) 3402, 3063, 3032, 2887, 1604, 1496, 1456,
2930, ,2870, 1497, 1456, 1115, 1043, 762, 698 cm-1. HRMS
(CI) calculated for C27H30O3 (M + H)+ 401.2117, observed
401.2112.
1373, 1338, 1101, 1026, 763, 698, 650 cm-1
.
(4R*,5R*)-2-[(1S*)-1-Hyd r oxy-1-m eth yl-3-bu ten yl]-4,5-
d ip h en yl-1,3-d ioxola n e (13b) a n d (4R*,5R*)-2-[(1R*)-1-
H yd r oxy-1-m e t h yl-3-b u t e n yl]-4,5-d ip h e n yl-1,3-d iox-
ola n e (14b). To a cooled (-78 °C) solution of 11 (48.5 mg,
0.181 mmol) in toluene (1.80 mL) was added allylmagnesium
bromide in diethyl ether (0.905 mL of 1.0 M solution, 0.905
mmol) to obtain 35.7 mg (0.115 mmol, 63.6%) of the alcohols
13b/14b as a colorless oil. 1H NMR (CDCl3) δ 7.36-7.21 (m,
10H), 6.07-5.96 (m, 1H), 5.33 (s, 1H), 5.22 (ABq, ∆ν ) 4.0 Hz,
J ab ) 1.4, 1H), 5.18 (d, J ) 1.4, 1H), 4.79-4.75 (m, 2H), 2.56-
2.40 (m, 2H), 2.16 (s, 1H), 1.36 (s, 1H). 13C NMR (CDCl3) δ
137.72, 135.95, 128.66, 128.60, 128.54, 128.28, 126.83, 126.41,
118.67, 107.85, 107.74, 87.03, 85.47, 73.42, 41.93, 41.57, 21.72,
21.35. IR (NaCl) 3456, 3032, 2978, 2891, 1454, 1103, 1028,
914, 761, 698 cm-1. HRMS (CI) calculated for C20H22O3 (M +
H)+ 311.1647, observed 311.1645.
(4R*,5R*)-2-[(1S*)-1-Hyd r oxy-1-(2-p r op en yl)h exyl]-4,5-
d ip h en yl-1,3-d ioxola n e (15b) a n d (4R*,5R*)-2-[(1R*)-1-
H yd r oxy-1-(2-p r op e n yl)h e xyl]-4,5-d ip h e n yl-1,3-d iox-
ola n e (16b). To a cooled (-78 °C) solution of 12 (24.7 mg,
0.076 mmol) in toluene (1.00 mL) was added allylmagnesium
bromide in diethyl ether (0.381 mL of 1.0 M solution, 0.381
mmol) to obtain 26.2 mg (0.072 mmol, 93.9%) of the alcohols
15b/16b as a colorless oil. 1H NMR (CDCl3) δ 7.38-7.21 (m,
10H), 6.05-5.93 (m, 1H), 5.38 (s, 1H), 5.23-5.18 (m, 2H), 4.78
(ABq, ∆ν ) 21.9 Hz, J ab ) 11.6, 2H), 2.59-2.47 (m, 2H), 1.98
(s, 1H), d 1.71 (t, J ) 8.8, 2H), 1.55-1.49 (m, 2H), 1.44-1.32
(m, 4H), 0.91 (t, J ) 6.9, 3H). 13C NMR (CDCl3) δ 138.00,
136.11, 128.60, 128.53, 128.21, 126.88, 126.83, 126.39, 126.31,
118.41, 107.02, 86.92, 85.28, 74.70, 39.52, 39.13, 35.13, 34.64,
32.53, 28.54, 22.61, 22.52, 14.06. IR (NaCl) 3500, 3067, 3034,
2955, 2928, 2872, 1497, 1456, 1171, 1116, 1026, 908, 762, 735,
698, 650 cm-1. HRMS (CI) calculated for C24H30O3 (M - H)+
365.2117, observed 365.2119.
(4R*,5R*)-2-[(1S*)-1-Hydr oxy-1-eth en ylh exyl]-4,5-diph e-
n yl-1,3-dioxolan e (15c) an d (4R*,5R*)-2-[(1R*)-1-Hydr oxy-
1-eth en ylh exyl]-4,5-d ip h en yl-1,3-d ioxola n e (16c). To a
cooled (-78 °C) solution of 12 (20.8 mg, 0.064 mmol) in toluene
(0.650 mL) was added vinylmagnesium bromide in THF (0.321
mL of 1.0 M solution, 0.321 mmol) to obtain 19.1 mg (0.054
mmol, 84.5%) of the alcohols 15c/16c as a colorless oil. 1H
NMR (CDCl3) δ 7.35-7.19 (m, 10H), 6.10-6.02 (m, 1H), 5.45
(ABq, ∆ν ) 47.6 Hz, J ab ) 17.5, 2H), 5.36 (s, 1H), 4.75 (ABq,
∆ν ) 11.6 Hz, J ab ) 8.3, 2H), 2.24 (s, 1H), 1.79-1.75 (m, 2H),
1.48-1.26 (m, 6H), 0.90 (t, J ) 6.8, 3H). 13C NMR (CDCl3) δ
138.96, 137.43, 135.88, 128.55, 126.91, 126.45, 115.39, 107.80,
86.84, 85.72, 35.26, 32.32, 22.63, 22.33, 14.07. IR (NaCl) 3486,
3032, 2953, 2928, 2870, 1456, 1167, 1120, 1026, 1001, 762, 698,
648 cm-1. HRMS (CI) calculated for C23H28O3 (M-H)+ 351.1960,
observed 351.1955.
(4R*,5R*)-2-[(1S*)-1-Hyd r oxy-1-m eth yl-2-p r op en yl]-4,5-
d ip h en yl-1,3-d ioxola n e (13c) a n d (4R*,5R*)-2-[(1R*)-1-
H yd r oxy-1-m e t h yl-2-p r op e n yl]-4,5-d ip h e n yl-1,3-d iox-
ola n e (14c). To a cooled (-78 °C) solution of 11 (54.6 mg,
0.204 mmol) in toluene (2.00 mL) was added vinylmagnesium
bromide in THF (1.018 mL of 1.0 M solution, 1.02 mmol) to
obtain 58.1 mg (0.196 mmol, 96.4 %) of the alcohols 13c/14c
as a colorless oil. 1H NMR (CDCl3) δ 7.36-7.20 (m, 10H),
6.24-6.12 (m, 1H), 5.34 (s, 1H), 5.42 (ABq, ∆ν ) 72 Hz, J ab
)
17.4, 2H), 4.77 (ABq, ∆ν ) 11.5 Hz, J ab ) 8.3, 2H), 2.31 (s,
1H), 1.47 (s, 3H). 13C NMR (CDCl3) δ 140.18, 138.10, 136.55,
128.67, 128.56, 128.54, 128.35, 126.85, 126.48, 114.72, 107.88,
86.94, 85.76, 74.62, 22.46. IR (NaCl) 3460, 3032, 2982, 2883,
1496, 1456, 1101, 1039, 925, 761, 698 cm-1
. HRMS (CI)
calculated for C19H20O3 (M+) 296.1412, observed 296.1416.
(4R*,5R*)-2-[(1S*-1-H yd r oxy-1,2-d im et h ylp r op yl]-4,5-
d ip h en yl-1,3-d ioxola n e (13d ) a n d (4R*,5R*)-2-[(1R*)-1-
H yd r oxy-1,2-d im e t h ylp r op yl]-4,5-d ip h e n yl-1,3-d iox-
ola n e (14d ). To a cooled (-78 °C) solution of 11 (48.5 mg,
0.181 mmol) in toluene (1.80 mL), isopropylmagnesium chlo-
ride in diethyl ether (0.452 mL of 2.0 M solution, 0.905 mmol)
was added to obtain 51.7 mg (0.166 mmol, 91.7%) of the
alcohols 13d /14d as a colorless oil. 1H NMR (CDCl3) δ 7.36-
7.22 (m, 10H), 5.44 (s, 1H), 4.79 (m, 2H), 2.12-2.04 (m, 2H),
1.27 (s, 3H), 1.07-1.00 (m, 6H). 13C NMR (CDCl3) δ 137.98,
136.17, 128.61, 128.54, 128.23, 126.82, 126.82, 126.38, 106.87,
86.99, 85.26, 75.45, 33.86, 17.59, 16.78. IR (NaCl) 3491, 3032,
(4R*,5R*)-2-[(1S*)-1-H yd r oxy-1-isop r op ylh exyl]-4,5-
d ip h en yl-1,3-d ioxola n e (15d ) a n d (4R*,5R*)-2-[(1R*)-1-
H yd r oxy-1-isop r op ylh exyl]-4,5-d ip h en yl-1,3-d ioxola n e
(16d ). To a cooled (-78 °C) solution of 12 (49.4 mg, 0.150
mmol) in toluene (1.50 mL) was added isopropylmagnesium
chloride in diethyl ether (0.381 mL of 2.0 M solution, 0.762
mmol) to obtain 50.5 mg (0.137 mmol, 90%) of the alcohols
15d /16d as a colorless oil. 1H NMR (CDCl3) δ 7.36-7.21 (m,
10H), 5.47 (s, 1H), 4.74 (ABq, ∆ν ) 23.6 Hz, J ab ) 8.2, 2H),
2.20 (s, 1H), 2.15-2.12 (m, 1H), 1.81-1.64 (m, 2H), 1.38-1.31
(m, 4H), 1.08 (t, J ) 4.4, 6H), 0.91 (t, J ) 7.0, 3H). 13C NMR
(CDCl3) δ 138.17, 136.28, 128.57, 128.53, 128.19, 126.74,
126.37, 106.84, 86.98, 84.86, 76.33, 32.98, 32.88, 32.44, 22.69,
17.39, 17.20, 14.11. IR (NaCl) 3501, 3034, 2957, 2928, 1732,
1497, 1456, 1116, 1016, 910, 762, 735, 698, 650 cm-1. MS (CI)
calculated for C24H32O3 (M+) 369.24, observed 369.24.
(4R*,5R*)-2-[(1R*)-1-Hyd r oxy-1-eth ylh exyl]-4,5-d ip h e-
n yl-1,3-d ioxola n e (15e) a n d (4R*,5R*)-2-[(1S*)-1-Hyd r oxy-
1-eth ylh exyl]-4,5-diph en yl-1,3-dioxolan e (16e). To a cooled
(-78 °C) solution of 12 (20.8 mg, 0.064 mmol) in toluene (0.650
mL) was added ethylmagnesium bromide in diethyl ether
(0.107 mL of 3.0 M solution, 0.321 mmol) to obtain 22.7 mg
(0.064 mmol, 100%) of the alcohols 15e/16e as a colorless oil.
1H NMR (CDCl3) δ 7.37-7.21 (m, 10H), 5.38 (s, 1H), 4.78 (ABq,
∆ν ) 9.9 Hz, J ab ) 8.3, 2H), 2.01 (s, 1H), 1.80-1.68 (m, 4H),
1.47-1.43 (m, 2H), 1.39-1.31 (m, 4H), 1.02 (t, J ) 7.5, 3H),
0.91 (t, J ) 7.0, 3H). 13C NMR (CDCl3) δ 138.03, 136.20,
128.59, 128.53, 128.20, 126.85, 126.38, 107.26, 86.87, 85.26,
75.12, 33.80, 32.62, 27.30, 22.69, 22.65, 14.07, 7.58. IR (NaCl)
2968, 2885, 1454, 1122, 1009, 1026, 761, 698 cm-1
.
(4R*,5R*)-2-[(1S*)-1-Hydr oxy-1-m eth ylpr opyl]-4,5-diph e-
n yl-1,3-dioxolan e (13e) an d (4R*,5R*)-2-[(1R*)-1-Hydr oxy-
1-m eth ylp r op yl]-4,5-d ip h en yl-1,3-d ioxola n e (14e). To a
cooled (-78 °C) solution of 11 (48.5 mg, 0.181 mmol) in toluene
(1.80 mL) was added ethylmagnesium bromide in diethyl ether
(0.302 mL of 3.0 M solution, 0.90 mmol) to obtain 51.2 mg
(0.172 mmol, 95.0%) of the alcohols 13e/14e as a colorless oil.
1H NMR (CDCl3) δ 7.37-7.22 (m, 10H), 5.32 (s, 1H), 4.77 (ABq,
∆ν ) 16.4 Hz, J ab ) 8.3, 2H), 2.05 (s, 1H), 1.83-1.65 (m, 2H),
1.34 (s, 3H), 1.05 (t, J ) 7.5, 3H). 13C NMR (CDCl3) δ 137.78,
136.10, 129.21, 128.57, 128.53, 128.27, 126.79, 126.44, 126.06,
108.05, 86.99, 85.43, 73.89, 29.84, 20.54, 7.39. IR (NaCl) 3481,
3034, 2974, 2883, 1813, 1456, 1107, 1057, 1003, 762, 698 cm-1
.
HRMS (CI) calculated for C19H22O3 (M + H)+ 299.1647,
observed 299.1649.
(4R*,5R*)-2-[(1S*)-1-Hydr oxy-1-ph en ylh exyl]-4,5-diph e-
n yl-1,3-dioxolan e (15a) an d (4R*,5R*)-2-[(1R*)-1-Hydr oxy-
1-p h en ylh exyl]-4,5-d ip h en yl-1,3-d ioxola n e (16a ). To a
cooled (-78 °C) solution of 12 (20.8 mg, 0.064 mmol) in toluene
(0.650 mL) was added phenylmagnesium chloride in THF
(0.175 mL of 25% wt solution, 0.321 mmol) to obtain 20.8 mg
(0.052 mmol, 80.6%) of the alcohols 15a /16a as a colorless oil.
1H NMR (CDCl3) δ 7.64-7.04 (m, 15H), 5.59 (s, 1H), 4.68 (ABq,
∆ν ) 54.7 Hz, J ab ) 8.2, 2H), 2.64 (s, 1H), 2.27-1.99 (m, 2H),
1.47-1.42 (m, 1H), 1.30-1.27 (m, 4H), 1.12-1.06 (m, 1H), 0.85
(t, J ) 7.1, 3H). 13C NMR (CDCl3) δ 141.60, 137.54, 135.84,
128.73, 128.59, 128.50, 128.48, 128.24, 127.98, 127.14, 126.99,
126.88, 126.38, 126.36, 108.45, 86.99, 85.49, 77.88, 36.55,
32.30, 22.54, 22.33, 14.03. IR (NaCl) 3491, 3063, 3032, 2953,
3463, 3032, 2932, 1497, 1454, 1117, 1018, 762, 698 cm-1
.
(4R*,5R*)-2-[(1R*)-1-Hydr oxy-1-m eth ylh exyl]-4,5-diph e-
n yl-1,3-d ioxola n e (15f) a n d (4R*,5R*)-2-[(1S*)-1-Hyd r oxy-
1-m eth ylh exyl]-4,5-d ip h en yl-1,3-d ioxola n e (16f). To a
cooled (-78 °C) solution of 12 (244 mg, 0.750 mmol) in toluene
(7.50 mL) was added methylmagnesium bromide in diethyl
ether (1.25 mL of 3.0 M solution, 3.76 mmol) to obtain 160 mg
(0.471 mmol, 62.6%) of the alcohols 15f/16f as a colorless oil.
1H NMR (CDCl3) δ 7.45-7.21 (m, 10H), 5.30 (s, 1H), 4.78 (ABq,
∆ν ) 10 Hz, J ab ) 1.8, 2H), 2.02 (s, 1H), 1.71-1.65 (m, 2H),

Diastereoselective Additions to Chiral R-Keto Acetals
J . Org. Chem., Vol. 62, No. 17, 1997 6045
1.59-1.47 (m, 2H), 1.41-1.31 (m, 6H), 0.92 (t, J ) 7.0, 3H).
13C NMR (CDCl3) δ 137.80, 136.07, 129.22, 128.60, 128.54,
128.25, 126.85, 126.42, 126.06, 108.22, 86.94, 85.43, 73.76,
36.96, 32.54, 22.72, 22.67, 21.39, 14.07. IR (NaCl) 3460, 3032,
(R)-2-Met h yl-1,2-h ep t a n ed iol (S)-r-Met h oxy-r-(t r i-
flu r om eth yl)p h en yla ceta te [MTP A] (19/20). Oxalyl chlo-
ride (22.4 µL, 0.254 mmol) was added to a solution of
(S)-(-)MTPA (25 mg, 0.107 mmol) and DMF (8.5 µL, 0.107
mmol) in hexanes (4.45 mL) at room temperature. A white
precipitate formed immediately. After stirring for 1 h, the
mixture was filtered and the filtrate concentrated. A solution
of 18 (6.5 mg, 0.045 mmol), Et3N (17.8 µL, 0.134 mmol), and
DMAP (ca. 5 mg) in CDCl3 (500 µL) was added to the residue.
After stirring for 2 h at room temperature, the mixture was
analyzed by 19F NMR. Compound 18 was also synthesized
from 2-methyl-1-heptene by Sharpless asymmetric dihydroxy-
lation with AD mix â (see reference 13). After conversion of
this material to its MTPA esters, the major diastereomeric
esters were compared by 19F NMR and found to be identical.
19F NMR (CDCl3) δ (referenced to freon 113) -71.993, -72.029.
2932, 2870, 1815, 1496, 1454, 1373, 1115, 1028, 762, 698 cm-1
.
HRMS (CI) calculated for C22H28O3 (M - H)+ 339.1960,
observed 339.1955.
(4R,5R)-2-[(1R-1-Hyd r oxy-1-m eth ylh exyl]-4,5-d ip h en yl-
1,3-d ioxola n e (15f′) a n d (4R,5R)-2-[(1S)-1-H yd r oxy-1-
m eth ylh exyl]-4,5-d ip h en yl-1,3-d ioxola n e (16f′). An identi-
cal procedure was used to furnish compounds 15f′ and 16f′.
[R]22 +36.6 (c ) 3.11, CHCl3).
D
2-Meth yl-1,2-h ep ta n ed iol (18). To a solution of 15f′ and
16f′ (80 mg, 0.231 mmol) in ether (2 mL) was added Pd(OH)2
(80 mg). The reaction flask was then evacuated and back filled
2× with hydrogen gas. One atmosphere of H2 was maintained
for 18 h over the stirred reaction mixture with a rubber
balloon. The solution was then filtered over Celite and
carefully concentrated under vacuum to avoid loss of the
volatile aldehyde 17. The resulting oil was then dissolved in
ethanol (2 mL), and NaBH4 (10 mg, 0.27 mmol) was added.
The mixture was stirred for 1 h at room temperature. The
solution was then quenched with saturated NH4Cl (5 mL),
diluted with methylene chloride, and extracted (2×). The
combined organic extracts were washed with brine, dried over
anhydrous MgSO4, filtered, and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
using hexanes:ethyl acetate (5:1) as eluent. All spectral data
were consistent with those obtained by Sharpless and co-
workers for 18 (see reference 13).
Ack n ow led gm en t. Financial support was provided
by The Academic Senate of University of California, and
the Office of the Chancellor.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra, IR spectra, and where available mass spectra for
compounds 9-15f (85 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
J O9701804