Scalable synthesis of enantiomerically pure syn -2,3-dihydroxybutyrate by sharpless asymmetric dihydroxylation of p -phenylbenzyl crotonate

Article abstract of DOI:10.1021/jo2016746

An efficient four-step synthetic route to the useful chiral building block (2R,3S)-dihydroxybutyric acid acetonide in >95% ee is detailed. The sequence is readily scaled, requires no chromatography, and allows for efficient recycling of p-phenylbenzyl alcohol, an expedient for enantio- and diastereoenrichment by recrystallization.

Full text of DOI:10.1021/jo2016746

NOTE
pubs.acs.org/joc
Scalable Synthesis of Enantiomerically Pure syn-2,3-
Dihydroxybutyrate by Sharpless Asymmetric Dihydroxylation
of p-Phenylbenzyl Crotonate
Daniel J. Smaltz and Andrew G. Myers*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States
S Supporting Information
b
ABSTRACT: An efficient four-step synthetic route to the useful
chiral building block (2R,3S)-dihydroxybutyric acid acetonide
in >95% ee is detailed. The sequence is readily scaled, requires
no chromatography, and allows for efficient recycling of
p-phenylbenzyl alcohol, an expedient for enantio- and diaster-
eoenrichment by recrystallization.
(2R,3S)-Dihydroxybutyric acid acetonide ((+)-1) and its enan-
tiomer serve as valuable building blocks for the construction of
complex carbohydrates and other densely oxygenated molecules.1
Three prior enantioselective routes to syn-2,3-dihydroxybutyric
acid or its methyl ester are summarized in Scheme 1.2ꢀ4 Only the
first of these, involving diazotizationꢀhydrolysis of threonine,2
has been routinely employed for multigram scale synthesis of 1,
so far as we are aware, and this route is typically used to
synthesize the levorotatory form of 1 (from L-threonine), as D-
threonine is a less readily available starting material. We required
(+)-1 for a projected route to the rare sugar trioxacarcinose A5
and so were led to consider alternative routes for its preparation.
The Sharpless asymmetric dihydroxylation6 of crotonic acid
esters appeared to be an attractive and general solution, poten-
tially providing access to 1 of either enantiomeric series. As part
of their efforts to synthesize natural products of the bengazole
family, Ley and co-workers reported that Sharpless asymmetric
dihydroxylation of ethyl crotonate with AD-mix-β at 0 °C
afforded (ꢀ)-1 ethyl ester7 in 96% yield (>95% ee, 3-g scale).
Relatively large volumes of organic extractant were necessary to
isolate the highly water-soluble product, and chromatographic
purification was required.8 In light of this precedent, we began a
broader survey of different crotonate esters and reaction condi-
tions in order to develop a procedure optimized toward ease of
purification, suitability for large-scale synthesis, and degree of
enantiomeric purity of the product.
trans-n-hexyl crotonate under identical conditions afforded a
higher yield of product (88%), but the enantioselectivity of the
transformation was too low for our purposes (80% ee, entry 2).
The enantioselectivity of the dihydroxylation reaction employing
(DHQ)2AQN as ligand (entry 3) was, as expected, slightly higher
than that of the corresponding transformation with (DHQ)2-
PHAL.12 For optimization studies we prepared several esters
from a number of different alcohols and commercial crotonoyl
chloride, which is inexpensive but impure (∼20:1 mixture of
trans and cis isomers, respectively; 90% purity). For example,
dihydroxylation of benzyl crotonate prepared in this way and
used without purification afforded diol of 92% ee (entry 4).13
This promising result led us to examine several substituted
benzyl crotonate esters (p-methoxybenzyl, p-nitrobenzyl, benz-
hydryl, and p-phenylbenzyl), all of which were dihydroxylated to
form diol products of 87ꢀ92% ee. Most encouraging was the
dihydroxylation of p-phenylbenzyl crotonate (used without puri-
fication), which afforded a highly crystalline diol product of 87% ee.
A single recrystallization of the product from dichloromethaneꢀ
hexanes afforded p-phenylbenzyl (2R,3S)-dihydroxybutyrate of
>95% ee (entry 5).
Dihydroxylation of p-phenylbenzyl crotonate was easily con-
ducted on a multigram scale. For example, in one experiment
p-phenylbenzyl alcohol (22 g, 119 mmol) was esterified with com-
mercial crotonoylchloride(∼20:1 E:Z; 90% purity) in the presence
of potassium carbonate (2.0 equiv) and a catalytic quantity of
4-(dimethylamino)pyridine (10 mol %) (Scheme 2). The crude
ester, a ∼17:1 mixture of E and Z isomers, was subjected to
conditions for the Sharpless asymmetric dihydroxylation. Complete
conversion to the diol was achieved with low catalyst loading (0.25
mol % potassium osmate, 0.50 mol % (DHQ)2AQN), an extended
reaction time (∼5 days), and distributed addition of potassium
ferricyanide (6 equiv).14 We found that methanesulfonamide
could be removed by a sequence of aqueous washes.15 The
Methyl, ethyl, and n-hexyl crotonate esters are each commer-
cially available in geometrically pure form (reported purity 100%
trans). We observed that dihydroxylation of trans-methyl croto-
nate with potassium osmate (0.50 mol %), (DHQ)2PHAL9 (1.0
mol %), methanesulfonamide (1 equiv), potassium ferricyanide
(3 equiv), and potassium carbonate (3 equiv), conditions reported
by Sharpless and co-workers,10 afforded the syn diol in 89% ee11
and 45% yield (Table 1, entry 1). We attribute the low yield to the
poor efficiency of our extraction of the water-soluble product
from the aqueous reaction mixture. Dihydroxylation of commercial
Received: August 10, 2011
Published: September 07, 2011
r
2011 American Chemical Society
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|

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NOTE
Scheme 1. Prior Syntheses of syn-2,3-Dihydroxybutyrate and Its Methyl Ester
Table 1. Dihydroxylation of trans-Crotonate Esters a
Scheme 2. Synthesis of Carboxylic Acid 1
entry
R
ligand
yield (%)
ee (%)b
c
1
2
3
4
5
CH3
(DHQ)2PHAL
(DHQ)2PHAL
(DHQ)2AQN
(DHQ)2AQN
(DHQ)2AQN
45
88
90
77
81
89
c
c
(CH2)5CH3
(CH2)5CH3
Bnd
80
85
92
87f, >95g
(p-Ph)Bnd,e
a Conditions: K2OsO4 2H2O (0.50 mol %), ligand (1.0 mol %), K3Fe-
3
(CN)6 (3 equiv), K2CO3 (3 equiv), CH3SO2NH2 (1 equiv), t-BuOHꢀ
H2O, 4 f 23 °C. b Determined by integration of the 1H NMR spectrum
of the corresponding bis-Mosher ester. c The alkene substrate was 100%
trans, from a commercial source. d The substrate was prepared from
commercial crotonoyl chloride (∼20:1 E:Z; 90% purity) and was
(DHQ)2AQN, and 6 equiv of K3Fe(CN)6 were used. f Before
purification. g After a single recrystallization of the product from
dichloromethaneꢀhexanes.
carboxylic acid (+)-1. First, (+)-2 was transformed into the
corresponding acetonide p-phenylbenzyl ester 3 in quantita-
tive yield by stirring with 2,2-dimethoxypropane and p-tolue-
nesulfonic acid monohydrate (5 mol %). Saponification of the
latter product in aqueous lithium hydroxide at 0 °C provided
the acid (+)-1 in 99% yield after extractive isolation (15-g
batch, [α]D = +34.2° (c 0.61, CHCl3), lit.16 [α]D = +31.2° (c 1,
CHCl3)). p-Phenylbenzyl alcohol, a white solid, was recov-
ered in 91% yield (g95% purity, 73% net recovery over the
three-step sequence).
The benefits of the optimized Sharpless asymmetric dihydroxy-
lation reaction—excellent yield and enantioselectivity—were
somewhat offset by the length of the reaction time in the optimized
protocol (∼5 days), referred to as “method A” (Table 2, entry 1).
We briefly investigated modification of the conditions to shorten
the reaction time. More rapid warming of the reaction mixture
used without purification. e 0.25 mol % K2OsO4 2H2O, 0.50 mol %
3
unpurified diol was found to be of 87% ee by 1H NMR analysis
of the corresponding bis-Mosher ester. A single recrystalliza-
tion of the solid product from dichloromethaneꢀhexanes
furnished pure diol (+)-2 of >95% ee in 81% yield (from
p-phenylbenzyl alcohol, 27.8-g batch, [α]D = +22.7° (c 1.04,
CH2Cl2)).
With an efficient and scalable procedure for the preparation
of enantiomerically pure (+)-2, we found that a short sequence
of standard transformations led efficiently to the desired
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NOTE
Table 2. Protocols for Large-Scale Dihydroxylationa
K2OsO4 2H2O
(DHQ)2AQN
(mol %)
K3Fe(CN)6
(equiv)
yieldb
(%)
eec
3
entry
method
(mol %)
time at 4 °C
time at 23 °C
(%)
1
2
A
B
0.25
1.0
0.50
1.0
6
3
2 d
3 d
81
60
>95
>95
30 min
25 h
a The starting material, p-phenylbenzyl crotonate, was prepared from commercially available crotonoyl chloride (∼20:1 E:Z; 90% purity) and used
without purification. Reactions were performed on a scale of at least 0.1 mol. b Isolated yield of pure product, after recrystallization. c Determined by
integration of the 1H NMR spectrum of the corresponding bis-Mosher ester.
Scheme 3. Transformations of Carboxylic Acid 1
during the dihydroxylation under otherwise identical conditions
(0.1-mol scale) led to poorer conversion, and p-phenylbenzyl
alcohol was observed in the crude product mixture. The latter
byproduct presumably formed as the result of saponification of
the diol product (2) or the substrate under the moderately basic
conditions of the dihydroxylation reaction.17 Sharpless and co-
workers have noted that for electron-poor olefins turnover can be
increased with little or no diminution in enantioselectivity by
increasing the loading of osmium.18 Using increased catalyst
loading (1.0 mol % potassium osmate, 1.0 mol % (DHQ)2AQN),
and adding sodium bicarbonate (3 equiv) to buffer the aqueous
phase, we observed that the large-scale dihydroxylation reaction
was complete within 25 h. The crude product mixture contained
e3% p-phenylbenzyl alcohol, as determined by integration of its
1H NMR spectrum. Recrystallization of the product mixture from
dichloromethaneꢀhexanes afforded pure diol 2 in 60% yield and
>95% ee (Table 2, entry 2, “method B”). We believe that this
protocol, with a shorter reaction time and a lower yield, provides a
viable alternative to the more lengthybut higheryieldingmethod A.
Finally, we have demonstrated that the acid (+)-1 can be
transformed into a variety of useful enantiopure building blocks.
For example, the corresponding Weinreb amide (4) was formed in
excellent yield by stirring (+)-1with N-(3-dimethylaminopropyl)-N0-
ethylcarbodiimide hydrochloride (EDC) and N-methylmorpholine
(17.4-g batch, Scheme 3).19,20 This product in turn provides ready
access to ketones such as the methyl ketone 521 and the allyl ketone 6,
for which we provide detail in the Experimental Section.
for enantioenrichment by recrystallization and is readily recycled.
Due to its operational ease, we believe this method provides a
useful complement to existing methods for the preparation of
1 of either enantiomeric series as well as chiral building blocks
derived from these substances.
’ EXPERIMENTAL SECTION
General Experimental Procedures. Reactions were run in
round-bottom flasks fitted with rubber septa under a positive pressure
of argon, unless otherwise noted. Air- and moisture-sensitive liquids
were transferred by syringe or stainless steel cannula. Organic solutions
were concentrated by rotary evaporation (house vacuum, ca. 25ꢀ40
Torr) at ambient temperature, unless otherwise noted. Analytical thin-
layer chromatography (TLC) was performed using glass plates pre-
coated with silica gel (0.25 mm, 60 Å pore size, 230ꢀ400 mesh, Merck
KGA) impregnated with a fluorescent indicator (254 nm). TLC plates
were visualized by exposure to ultraviolet light and then were stained by
submersion in aqueous ceric ammonium molybdate (CAM) or potas-
sium permanganate solutions followed by brief heating on a hot plate.
Flash-column chromatography was performed as described by Still
et al.,22 employing silica gel (60 Å, 32ꢀ63 μM, standard grade, Dynamic
Adsorbents, Inc.). Tetrahydrofuran, dichloromethane, and ether were
purified by the method of Pangborn et al.23 Proton nuclear magnetic
resonance (1H NMR) spectra were recorded at 500 MHz at 23 °C.
Proton chemical shifts are expressed in parts per million (ppm, δ scale)
and are referenced to residual protium in the NMR solvent (CHCl3,
δ 7.26 ppm). Data are represented as follows: chemical shift, multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet and/or
multiple resonances), integration, coupling constant (J) in Hertz. Carbon
nuclear magnetic resonance (13C NMR) spectra were recorded at 125
MHz at 23 °C. Carbon chemical shifts are expressed in parts per million
(ppm, δ scale) and are referenced to the carbon resonances of the NMR
In summary, we have developed a practical sequence to
prepare the useful building block (2R,3S)-dihydroxybutyric
acid acetonide ((+)-1) in enantiomerically pure form, using
as the key step the Sharpless asymmetric dihydroxylation
reaction. p-Phenylbenzyl alcohol serves as a useful expedient
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NOTE
solvent (CDCl3, δ 77.0). Infrared (IR) spectral data are represented as
follows: frequency of absorption (cmꢀ1), intensity of absorption (vs =
very strong, s = strong, m = medium, w = weak, br = broad).
saturated aqueous sodium bicarbonate solution (5 mL), water (5 mL),
and then saturated aqueous sodium chloride solution (5 mL), and the
washed solution was dried over sodium sulfate. The dried solution was
1
(2R,3S)-Biphenyl-4-ylmethyl 2,3-Dihydroxybutanoate
(2). Method A. 4-(Dimethylamino)pyridine (1.46 g, 11.9 mmol, 0.1 equiv)
was added to a suspension of crotonoyl chloride (technical grade,
14.0 mL, 146 mmol, 1.22 equiv), p-phenylbenzyl alcohol (22.0 g, 119
mmol, 1 equiv), and potassium carbonate (33.0 g, 239 mmol, 2.0 equiv)
in dichloromethane (240 mL) at 23 °C. After 7 h, a second portion of
crotonoyl chloride (12.7 mL, 133 mmol, 1.11 equiv) was added. After
15 h, water (200 mL) was added. The layers were separated. The aqueous
layer was extracted with dichloromethane (200 mL). The organic layers
were combined. The combined solution was washed sequentially with
saturated aqueous sodium bicarbonate solution (200 mL), 1.0 M aqueous
hydrochloric acid solution (200 mL), water (200 mL), and then
saturated aqueous sodium chloride solution (200 mL), and the washed
solution was dried over sodium sulfate. The dried solution was filtered,
and the filtrate was concentrated. The residue was dissolved in a mixture
of tert-butyl alcohol (240 mL) and water (240 mL). Potassium carbonate
(49.5 g, 358 mmol, 3.0 equiv), potassium ferricyanide (118 g, 358 mmol,
3.0 equiv), and (DHQ)2AQN (511 mg, 0.596 mmol, 0.005 equiv) were
added in sequence, and the mixture was cooled to 4 °C. Potassium
osmate dihydrate (110 mg, 0.928 mmol, 0.0025 equiv) was added. After
10 min, methanesulfonamide (5.67 g, 59.6 mmol, 0.5 equiv) was added.
After 48 h, the cooling bath was removed and the reaction flask was
warmed to 23 °C. After 23 h, a second portion of potassium ferricyanide
(59.0 g, 179 mmol, 1.5 equiv) was added. After 18 h, a third portion of
potassium ferricyanide (59.0 g, 179 mmol, 1.5 equiv) was added. After 25 h,
the reaction flask was cooled in an ice bath. Sodium sulfite (150 g, 1.19
mol, 10 equiv) was added slowly. After 1 h, the product mixture was
extracted with ethyl acetate (6 ꢁ 500 mL). The organic layers were
combined. The combined solution was washed sequentially with 1.0 M
aqueous sodium hydroxide solution (1.5 L) and then saturated aqueous
sodium chloride solution (1.0 L), and the washed solution was dried
over sodium sulfate. The dried solution was filtered, and the filtrate was
concentrated. The residue was dissolved in a minimal amount of hot
dichloromethane (∼200 mL, 35 °C). The resulting solution was heated
to boiling in an oil bath at 65 °C, and hexanes was added slowly such that
boiling was maintained. Upon the first appearance of a white precipitate,
an amount of dichloromethane sufficient to dissolve the precipitate was
added (∼20 mL). The oil bath was removed, and the flask was cooled to
23 °C. The flask was further cooled to ꢀ20 °C. After 15 h, a light yellow
crystalline solid had precipitated from the yellow supernatant. The
mixture was filtered, and the solid was washed with cold hexanes
(100 mL, ꢀ20 °C) to provide the product, (2R,3S)-biphenyl-4-
ylmethyl 2,3-dihydroxybutanoate (2), as light yellow needles (27.8
g, 81% yield based on p-phenylbenzyl alcohol): [α]D = +22.7° (c 1.04,
CH2Cl2); mp 100.0ꢀ101.0 °C; TLC (30% ethyl acetateꢀ70%
filtered, and the filtrate was concentrated. Analysis of the H NMR
spectrum of the crude product established that complete conversion to
the bis-Mosher ester had occurred. The product was determined to be of
49:1 dr (1H NMR analysis (500 MHz, CDCl3) δ 5.76 (qd, 1H, J = 6.8,
2.4 Hz (2S,3R, minor)), 5.70 (qd, 1H, J = 6.4, 2.0 Hz (2R,3S, major))),
from which we concluded that the starting diol, (2R,3S)-biphenyl-4-
ylmethyl 2,3-dihydroxybutanoate (2), was of >95% ee.
Method B. 4-(Dimethylamino)pyridine (1.46 g, 11.9 mmol, 0.1
equiv) was added to a suspension of crotonoyl chloride (technical grade,
34.3 mL, 358 mmol, 3.0 equiv), p-phenylbenzyl alcohol (22.0 g, 119
mmol, 1 equiv), and potassium carbonate (33.0 g, 239 mmol, 2.0 equiv)
in dichloromethane (240 mL) at 23 °C. After 12 h, water (200 mL) was
added. The layers were separated. The aqueous layer was extracted with
dichloromethane (200 mL). The organic layers were combined. The
combined solution was washed sequentially with saturated aqueous
sodium bicarbonate solution (200 mL), 1.0 M aqueous hydrochloric
acid solution (200 mL), water (200 mL), and then saturated aqueous
sodium chloride solution (200 mL), and the washed solution was dried
over sodium sulfate. The dried solution was filtered, and the filtrate was
concentrated. The residue was dissolved in a mixture of tert-butyl alcohol
(240 mL) and water (240 mL). Potassium carbonate (49.5 g, 358 mmol,
3.0 equiv), sodium bicarbonate (30.1 g, 358 mmol, 3.0 equiv), potassium
ferricyanide (118 g, 358 mmol, 3.0 equiv), and (DHQ)2AQN (1.02 g,
1.19 mmol, 0.01 equiv) were added in sequence, and the mixture was
cooled to 4 °C. Potassium osmate dihydrate (440 mg, 1.19 mmol, 0.01
equiv) was added. After 20 min, methanesulfonamide (11.4 g, 119
mmol, 1.0 equiv) was added. After 10 min, the cooling bath was removed
and the reaction flask was warmed to 23 °C. After 25 h, the reaction flask
was cooled in an ice bath. Sodium sulfite (150 g, 1.19 mol, 10 equiv) was
added slowly. After 30 min, the product mixture was extracted with ethyl
acetate (6 ꢁ 500 mL). The organic layers were combined. The
combined solution was washed sequentially with 1.0 M aqueous sodium
hydroxide solution (1.5 L), 1.0 M hydrochloric acid (1.0 L), and then
saturated aqueous sodium chloride solution (1.0 L), and the washed
solution was dried over sodium sulfate. The dried solution was filtered,
and the filtrate was concentrated. The residue was recrystallized from
dichloromethaneꢀhexanes as in method A to provide the product,
(2R,3S)-biphenyl-4-ylmethyl 2,3-dihydroxybutanoate (2), as light yel-
low needles (20.6 g, 60% based on p-phenylbenzyl alcohol). The
recrystallized product was of >95% ee by formation of the corresponding
bis-Mosher ester as in method A.
(4R,5S)-Biphenyl-4-ylmethyl 2,2,5-Trimethyl-1,3-dioxolane-
4-carboxylate (3). p-Toluenesulfonic acid monohydrate (923 mg,
4.85 mmol, 0.05 equiv) was added to a suspension of (2R,3S)-biphenyl-
4-ylmethyl 2,3-dihydroxybutanoate (2; 27.8 g, 97.1 mmol, 1 equiv) in
2,2-dimethoxypropane (350 mL) at 23 °C. After 40 min, triethylamine
(677 μL, 4.85 mmol, 0.05 equiv) was added. The product solution was
filtered through a pad of silica gel (length 8 cm; diameter 8 cm), with
ethyl acetate as eluent (2 L). The filtrate was concentrated to provide the
product, (4R,5S)-biphenyl-4-ylmethyl 2,2,5-trimethyl-1,3-dioxolane-4-
carboxylate (3), as a colorless oil (31.4 g, 99%): TLC (30% ethyl
acetateꢀ70% hexanes) Rf = 0.67 (CAM); 1H NMR (500 MHz, CDCl3)
δ 7.59 (m, 4H), 7.44 (m, 4H), 7.36 (m, 1H), 5.26 (m, 2H), 4.22 (dq, 1H,
J = 8.2, 6.0 Hz), 4.11 (d, 1H, J = 7.8 Hz), 1.48 (s, 3H), 1.45 (s, 3H), 1.44
(d, 3H, J = 6.0 Hz); 13C NMR (125 MHz, CDCl3) δ 170.3, 141.3, 140.4,
134.2, 128.7, 128.7, 127.4, 127.3, 127, 110.6, 80.3, 75.1, 66.6, 27.1, 25.6,
18.5; FTIR (neat; cmꢀ1) 2988 (w), 1757 (s), 1184 (s), 1099 (s), 850 (s),
762 (s), 698 (s); HRMS (ESI) m/z calcd for (C20H22O4 + Na)+
349.1410, found 349.1416.
1
hexanes) Rf 0.11 (CAM); H NMR (500 MHz, CDCl3) δ 7.60 (t,
4H, J = 8.3 Hz), 7.46 (m, 4H), 7.38 (m, 1H), 5.33ꢀ5.28 (m, 2H), 4.17
(br, 1H), 4.11 (br, 1H), 3.46 (br, 1H), 2.57 (br, 1H), 1.33 (d, 3H, J =
6.4 Hz); 13C NMR (125 MHz, CDCl3) δ 173.2, 141.5, 140.4, 133.9,
128.8, 128.8, 127.5, 127.3, 127, 74.5, 68.7, 67.3, 19.6; FTIR (neat; cmꢀ1
)
3335 (br), 1701 (s), 1292 (s), 1138 (m), 1067 (m), 1018 (m), 978 (m),
827 (m); HRMS (ESI) m/z calcd for (C17H18O4 + Na)+ 309.1097,
found 309.1100.
To determine the enantiomeric excess, (S)-3,3,3-trifluoro-2-meth-
oxy-2-phenylpropanoyl chloride (6.3 μL, 34 μmol, 2.4 equiv) was added
to a solution of (2R,3S)-biphenyl-4-ylmethyl 2,3-dihydroxybutanoate
(2; 4 mg, 14 μmol, 1 equiv) and 4-(dimethylamino)pyridine (8.2 mg,
67 μmol, 4.8 equiv) in dichloromethane (280 μL) at 23 °C. After 90 min,
the product solution was partitioned between ethyl acetate (20 mL) and
water (5 mL). The layers were separated. The organic layer was washed
sequentially with 1.0 M aqueous hydrochloric acid solution (5 mL),
(4R,5S)-2,2,5-Trimethyl-1,3-dioxolane-4-carboxylic Acid (1).
Lithium hydroxide (1.0 M in water, 192 mL, 192 mmol, 2.0 equiv) was
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NOTE
added over 5 min to an ice-cooled solution of (4R,5S)-biphenyl-4-
ylmethyl 2,2,5-trimethyl-1,3-dioxolane-4-carboxylate (3; 31.4 g, 96.0
mmol, 1 equiv) in a mixture of tetrahydrofuran (380 mL) and methanol
(190 mL). After 10 min, the product mixture was concentrated to
remove organic solvents. The aqueous residue was diluted with ether
(1 L). The layers were separated. The aqueous layer was extracted with
ether (500 mL). The organic layers were combined. The combined
solution was dried over sodium sulfate. The dried solution was filtered,
and the filtrate was concentrated to provide p-phenylbenzyl alcohol as a
white solid (16.1 g, 91%). The aqueous layer was acidified to pH ∼2 by
addition of 1.0 M aqueous hydrochloric acid solution (∼100 mL). The
acidified solution was extracted with ethyl acetate (500 mL). The pH of
the aqueous layer was observed to increase to ∼4 after extraction of the
acidic product. The aqueous layer was again acidified to pH ∼2 by
addition of 1.0 M aqueous hydrochloric acid solution (∼50 mL). The
acidified solution was extracted with ethyl acetate (3 ꢁ 500 mL). The
organic layers were combined. The combined solution was dried over
sodium sulfate. The dried solution was filtered, and the filtrate was
concentrated to provide the product, (4R,5S)-2,2,5-trimethyl-1,3-diox-
1-((4R,5S)-2,2,5-Trimethyl-1,3-dioxolan-4-yl)but-3-en-1-one
(6). Allylmagnesium chloride (2.0 M solution in tetrahydrofuran, 1.48 mL,
2.95 mmol, 3.0 equiv) was added dropwise to a solution of (4R,5S)-N-
methoxy-N,2,2,5-tetramethyl-1,3-dioxolane-4-carboxamide (4; 200 mg,
0.984 mmol, 1 equiv) in tetrahydrofuran (10 mL) at ꢀ78 °C. After
25 min, saturated aqueous ammonium chloride (5 mL) was added, and the
reaction flask was warmed to 23 °C. Water (2 mL) was added, and the
product mixture was extracted with ethyl acetate (2 ꢁ 20 mL). The organic
layers were combined. The combined solution was dried over sodium
sulfate. The dried solution was filtered, and the filtrate was concentrated.
The residue was purified by flash-column chromatography (4% ethyl
acetateꢀ96% hexanes) to provide the product, 1-((4R,5S)-2,2,5-trimethyl-
1,3-dioxolan-4-yl)but-3-en-1-one (6), as a colorless oil (113 mg, 62%):
TLC (30% ethyl acetateꢀ70% hexanes) Rf = 0.75 (CAM); 1H NMR (500
MHz, CDCl3) δ 5.94 (m, 1H), 5.22ꢀ5.14 (m, 2H), 4.05 (dq, 1H, J = 8.3,
6.4 Hz), 3.93 (dd, 1H, J = 8.3, 1.0 Hz), 3.43 (m, 2H), 1.46 (s, 3H), 1.44 (s,
3H), 1.39 (d, 3H, J = 5.9 Hz); 13C NMR (125 MHz, CDCl3) δ 207.7,
129.7, 119.1, 110.1, 86.3, 74.3, 43.3, 27.2, 26.3, 18.5; FTIR (neat; cmꢀ1
)
2987 (m), 1719 (s), 1382 (s), 1242 (s), 1099 (s), 856 (s); HRMS (ESI)
m/z calcd for (C10H16O3 + H)+ 185.1172, found 185.1179.
olane-4-carboxylic acid (1), as a colorless oil (15.2 g, 99%). 1H and 13
C
NMR data were in agreement with previously reported values:16 [α]D =
+34.2° (c 0.61, CHCl3), lit.16 [α]D = +31.2° (c 1, CHCl3); TLC (ethyl
acetate) Rf = 0.13 (CAM); 1H NMR (500 MHz, CDCl3) δ 10.23 (br,
1H), 4.24 (dq, 1H, J = 8.3, 5.9 Hz), 4.09 (d, 1H, J = 8.3 Hz), 1.49 (s, 3H),
1.48 (d, 3H, J = 5.9 Hz), 1.46 (s, 3H); 13C NMR (125 MHz, CDCl3)
δ 175.0, 111.0, 79.8, 75.2, 27.1, 25.6, 18.5; FTIR (neat; cmꢀ1) 3158 (br),
2990 (w), 1734 (s), 1383 (m), 1219 (s), 1173 (m), 1099 (s), 853 (m);
HRMS (ESI) m/z calcd for (C7H12O4 + H)+ 161.0808, found 161.0816.
(4R,5S)-N-Methoxy-N,2,2,5-tetramethyl-1,3-dioxolane-4-
carboxamide (4). N-(3-(Dimethylamino)propyl)-N0-ethylcarbodii-
mide hydrochloride (20.1 g, 105 mmol, 1.1 equiv) was added over
2 min to a solution of (4R,5S)-2,2,5-trimethyl-1,3-dioxolane-4-carboxylic
acid (1; 15.2 g, 95.2 mmol, 1 equiv) and N-methylmorpholine (11.5 mL,
105 mmol, 1.1 equiv) in dichloromethane (475 mL) at ꢀ20 °C. After
3.5 h, 1.0 M aqueous hydrochloric acid solution (150 mL) was added.
The cooling bath was removed, and the reaction flask was warmed to
23 °C. The layers were separated. The aqueous layer was extracted with
dichloromethane (400 mL). The organic layers were combined. The
combined solution was washed with saturated aqueous sodium bicar-
bonate solution (150 mL), and the washed solution was dried over
sodium sulfate. The dried solution was filtered and the filtrate was con-
centrated to provide the product, (4R,5S)-N-methoxy-N,2,2,5-tetra-
methyl-1,3-dioxolane-4-carboxamide (4), as a pale yellow oil (17.4 g,
90%):24 TLC (40% ethyl acetateꢀ60% hexanes) Rf = 0.36 (CAM); 1H
NMR (500 MHz, CDCl3) δ 4.40 (m, 2H), 3.73 (s, 3H), 3.22 (s, 3H),
1.47 (s, 3H), 1.46 (s, 3H), 1.37 (d, 3H, J = 5.9 Hz); 13C NMR (125
MHz, CDCl3) δ 170.0, 109.9, 78.2, 74.5, 61.3, 32.0, 27.2, 25.8, 17.9;
FTIR (neat; cmꢀ1) 2986 (w), 2938 (w), 1670 (s), 1371 (m), 1171 (s),
1055 (m), 854 (m); HRMS (ESI) m/z calcd for (C9H17NO4 + Na)+
226.1050, found 226.1050.
1-((4R,5S)-2,2,5-Trimethyl-1,3-dioxolan-4-yl)ethanone (5).
Methylmagnesium chloride (3.0 M solution in tetrahydrofuran, 6.25 mL,
18.7 mmol, 3.0 equiv) was added dropwise to an ice-cooled solution
of (4R,5S)-N-methoxy-N,2,2,5-tetramethyl-1,3-dioxolane-4-carboxamide
(4; 1.27 g, 6.25 mmol, 1 equiv) in tetrahydrofuran (60 mL). After 35 min,
saturated aqueous ammonium chloride solution (30 mL) was added,
and the reaction flask was warmed to 23 °C. The product mixture was
extracted with ethyl acetate (3 ꢁ 70 mL). The organic layers were com-
bined. The combined solution was dried over sodium sulfate. The dried
solution was filtered, and the filtrate was concentrated to provide the
product, 1-((4R,5S)-2,2,5-trimethyl-1,3-dioxolan-4-yl)ethanone (5), as a
colorless oil (770 mg, 79%). 1H NMR, 13C NMR, IR, and MS data were
in agreement with previously reported values.25 TLC (30% ethyl
acetateꢀ70% hexanes): Rf = 0.70 (CAM).
’ ASSOCIATED CONTENT
1
S
Supporting Information. Figures giving complete H
b
and 13C NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: myers@chemistry.harvard.edu.
’ ACKNOWLEDGMENT
D.J.S. acknowledges fellowship support from the DoD, Air
Force Office of Scientific Research, National Defense Science
and Engineering Graduate (NDSEG) Fellowship (No. 32 CFR
168a). Financial support from the National Institutes of Health
(Grant No. CA047148) is gratefully acknowledged.
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The Journal of Organic Chemistry
NOTE
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3
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8559
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