An improved synthesis of (4S)-4,5-O-isopropylidenepent- (2Z)-enoate

Article abstract of DOI:10.1081/SCC-120003634

(4S)-4,5-O-Isopropylidenepent-(2Z)-enoate (1) has been prepared on a multigram scale from 1,2: 5,6-di-O-isopropylidene-D-mannitol (4) in a one pot, two step sequence with improved selectivity (16:1 Z:E) and yield (71% Z) over previous literature procedures.

Full text of DOI:10.1081/SCC-120003634

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AN IMPROVED SYNTHESIS OF (4S)-4,5-O-
ISOPROPYLIDENEPENT- (2Z)-ENOATE
a
a
a
Stefan G. Koenig , Ralf S. Löwe & David J. Austin
a
Department of Chemistry , Yale University , New Haven, CT, 06520, U.S.A.
Published online: 17 Aug 2006.
To cite this article: Stefan G. Koenig , Ralf S. Löwe & David J. Austin (2002) AN IMPROVED SYNTHESIS OF (4S)-4,5-O-
ISOPROPYLIDENEPENT- (2Z)-ENOATE, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 32:9, 1379-1383, DOI: 10.1081/SCC-120003634
To link to this article: http://dx.doi.org/10.1081/SCC-120003634
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SYNTHETIC COMMUNICATIONS, 32(9), 1379–1383 (2002)
AN IMPROVED SYNTHESIS OF
4S)-4,5-O-ISOPROPYLIDENEPENT-
(
(
2Z)-ENOATE
Stefan G. Koenig, Ralf S. Lo
¨
we, and David J. Austin*
Department of Chemistry, Yale University,
New Haven, CT 06520, USA
ABSTRACT
(
4S)-4,5-O-Isopropylidenepent-(2Z)-enoate (1) has been pre-
pared on a multigram scale from 1,2 : 5,6-di-O-isopropyl-
idene-D-mannitol (4) in a one pot, two step sequence with
improved selectivity (16 : 1 Z : E) and yield (71% Z) over
previous literature procedures.
Multi-functional polyoxygenated a,b-unsaturated carbonyl com-
1
–5
pounds are of great utility in organic synthesis.
6
Generation of chirality
at the oxygen substituents is well precedented; however, control of alkene
7
,8
geometry is often troublesome. During the course of our synthetic endeav-
ors, we sought a selective synthesis of the title compound (1). Wittig olefina-
tion for the construction of the a,b-unsaturated ester is limited by the nature
of the ylide, methyl a-(trimethyl-phosphorylidene)acetate (3), since stabil-
ized ylides tend toward E-olefins. In this report, we show that the predomi-
9
nant reactivity, which affords the E-isomer 2, can be attenuated and even
*
Corresponding author.
1
379
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

¨
KOENIG, LOWE, AND AUSTIN
1
380
reversed with low salt, low temperature, and/or protic solvent systems to
yield the Z-isomer 1.
Initial literature procedures described the assembly of the a,b-
unsaturated ester from (þ)-2,3-O-isopropylidene-D-glyceraldehyde (5) and
the ylide (3) to provide products 1 and 2 with a modest selectivity for the
1
0
Z-isomer (1, 7 : 1). Subsequent reports combined the diol cleavage and ole-
fination into one pot to furnish 1 directly from 1,2 : 5,6-di-O-isopropylidene-
D-mannitol (4), improving the ylide but without a concomitant improvement
1
1
in selectivity (8 : 1). Herein we would like to communicate a modified
procedure, which yields the Z-ester in both greater selectivity and yield.
RESULTS AND DISCUSSION
1,2 : 5,6-di-O-isopropylidene-D-mannitol (4) was treated with sodium
periodate in a buffered biphasic solvent system (Scheme 1). After diol cleav-
age, methyl a-(trimethyl-phosphorylidene)acetate (3) was added to effect the
olefination, as previously reported by Marshall et al. To improve upon this
1
1
established procedure, we (a) sonicated the crude biphasic reaction mixture
ꢀ
and (b) cooled the solution to À60 C prior to the addition of ylide 3.
a
Scheme 1.
1
Ultrasonic irradiation was instituted based on the observation that
2
the final yield of the product (1 and 2) seemed to be limited by the efficiency

(
4S)-4,5-O-ISOPROPYLIDENEPENT-(2Z)-ENOATE
1381
of the periodate cleavage. A higher yield of 5 from the oxidative cleavage
provides more material for the olefination and thus a higher overall output.
The second alteration involves performing the addition at a lower tempera-
ture than had previously been reported. Wittig reactions with stabilized
ylides show a preference for E-olefins; however, this selectivity has been
1
3
shown to be reversed under certain conditions. The literature precedent
utilized protic solvent, low lithium salt and minor cooling conditions to
achieve a modest selectivity for the Z-olefin 1 of 8 : 1. By further cooling
ꢀ
the temperature to À60 C prior to addition of ylide and then maintaining a
ꢀ
low temperature (0 C) throughout the reaction a substantial improvement
in selectivity was obtained, providing a 16 : 1 ratio of products 1 and 2.
EXPERIMENTAL SECTION
General Methods
Organic solvents(anhydrous methanol, ethyl acetate, hexanes, dichloro-
methane) and reagents (methyl a-(trimethyl-phosphorylidene)acetate and
1,2 : 5,6-di-O-isopropylidene-D-mannitol) were used as received from the
Aldrich Chemical Company, Inc. and Mallinckrodt Baker Inc. Inorganic
reagents (sodium bicarbonate and sodium periodate) were used as received
from Mallinckrodt Baker Inc. and Acros Organics. The reactions were stir-
red magnetically and cooling was achieved using ice/water and dry ice/iso-
propanol baths. Organic phases were dried over anhydrous magnesium
sulfate (Mallinckrodt Baker Inc.). Whatman filter paper was used for filtra-
¨
tions and evaporation of solvents was achieved on a Buchi rotary evapora-
tor connected to water aspirator for reduced pressure. TLC analysis was
performed on Si250F glass coated plates with a 254 nm fluorescent indicator
as supplied by J.T. Baker, Inc. Column chromatography was accomplished
˚
on 32–63 D 60 A silica gel from ICN SiliTech (ICN Biomedicals GmbH).
Proton and carbon NMR were completed on an Omega 300-MHz FT
spectrometer in CDCl (Cambridge Isotope Labs Inc.) using the residual
3
solvent signal as the internal standard (d 7.26). IR spectra were recorded on
a MIDAC M1200 FTIR spectrometer.
(
4S)-4,5-O-Isopropylidenepent-(2Z)-enoate (1)
1,2 : 5,6-di-O-isopropylidene-D-mannitol (4, 7.87 g, 30.0 mmol) was
suspended in 150 ml of a 4 : 1 methanol/water solvent system. Sodium bicar-
bonate (7.5 g, 89.3 mmol) was added and the biphasic system was cooled

¨
KOENIG, LOWE, AND AUSTIN
1
382
ꢀ
to 0 C. Sodium periodate (9.00 g, 42.0 mmol), suspended in 45 ml of 1 : 1
methanol/water, was added dropwise to the cooled solution. The reaction
was allowed to stir at room temperature for 3 h and subsequently subjected
ꢀ
to ultrasonic irradiation for 1 h. The suspension was then cooled to À60 C
prior to the slow addition of a solution of the ylide (3, 24.2 g, 72.4 mmol) in
55 ml of methanol. Over the course of 2 h, the temperature was maintained
ꢀ
ꢀ
at À60 C before allowing gradual warming of the mixture to 0 C. This
temperature was maintained for an additional 24 h. Addition of dichloro-
methane allowed the triphenylphosphine oxide precipitate to be removed
by filtration. This mixture was then extracted with dichloromethane
(
3 Â 40 ml). The organic phases were combined and dried over magnesium
sulfate and evaporated. The crude material was purified by column
chromatography on silica gel using a gradient of hexanes/ethyl acetate to
furnish 7.94 g (71%) of Z-isomer 1 and 0.48 g (4%) of the corresponding
1
E-isomer 2. Z-isomer 1: H NMR d 1.32 (s, 3H), 1.38 (s, 3H), 3.55 (dd, 1H,
J ¼ 6.8, 8.2 Hz), 3.65 (s, 3H), 4.31 (dd, 1H, J ¼ 7.0, 8.2 Hz), 5.42 (apparent
dq, 1H, J ¼ 1.7, 6.8 Hz), 5.79 (dd, 1H, J ¼ 1.7, 11.6 Hz), 6.31 (dd, 1H,
1
3
J ¼ 6.6, 11.6 Hz); C NMR d 25.3, 26.4, 51.3, 69.2, 73.4, 109.5, 120.1, 149.5,
À1
20
D
1
1
65.9; IR (neat) 2988, 2953, 2878, 1723, 1209, 1184, 1156, 1060 cm ; [a]
ꢀ
03.1 (c 0.361, CHCl ).
3
ACKNOWLEDGMENTS
The authors gratefully acknowledge financial support from Yale
Corporation and the donors of The Petroleum Research Fund
(
PRF#33988-G1), administered by the American Chemical Society.
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Received in the USA May 10, 2001