A novel and simple method to prepare γ-hydroxy-α,β-(E)-alkenoic esters from γ-keto-alkynoic esters

Article abstract of DOI:10.1016/S0040-4039(02)02602-3

A method to convert γ-keto-alkynoic esters to γ-hydroxy-α,β-(E)-alkenoic esters is described. This functional group transformation was accomplished in one step by means of NaBH₄ reduction in methanol.

Full text of DOI:10.1016/S0040-4039(02)02602-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 443–445
A novel and simple method to prepare
g-hydroxy-a,b-(E)-alkenoic esters from g-keto-alkynoic esters
Tadaatsu Naka and Kazunori Koide*
Department of Chemistry, University of Pittsburgh, 219 Parkman Avenue, Pittsburgh, PA 15260, USA
Received 19 October 2002; revised 15 November 2002; accepted 18 November 2002
Abstract—A method to convert g-keto-alkynoic esters to g-hydroxy-a,b-(E)-alkenoic esters is described. This functional group
transformation was accomplished in one step by means of NaBH4 reduction in methanol. © 2002 Elsevier Science Ltd. All rights
reserved.
g-Hydroxy-a,b-(E)-enoates 1 (Scheme 1) are versatile
synthetic intermediates1–17 and part of many natural
products.18–28 This functionality has been prepared
mostly by means of Wittig reactions,29 rearrangements
via vinylic sulfoxides,30 reduction of g-keto-a,b-(E)-
alkenoates with NaBH4, or the Nozaki–Hiyama–Kishi
reaction.10 Due to the lack of a synthetic method to
convert ynoates to a,b-(E)-enoates, ynoate inter-
mediates have not been used as precursors for a,b-(E)-
enoates.
Herein we report that methyl 4-oxo-2-ynoates can be
converted to methyl 4-hydroxy-2-(E)-alkenoates 1 in one
step by means of NaBH4 reduction. This method should
render g-keto-ynoic esters as viable precursors for the
preparation of g-hydroxy-a,b-(E)-alkenoic esters.
In an attempt to prepare a racemic form of compound
2a (Fig. 1) during our synthetic studies toward
FR901464, we synthesized keto ynoate 6a31 by coupling
silver acetylide 4,† prepared from the corresponding
Scheme 1. Known methods to prepare 4-hydroxy-(E)-2-alkenoic ester 1.
* Corresponding author. E-mail: koide@pitt.edu
†
It is noteworthy to comment on the safety of silver acetylide 4. Since some silver acetylides are potentially explosive with a shock (especially
using a metal spatula in the labs) and/or heat, we tested the safety of this silver acetylide; 20 mg of dry acetylide 4 was stirred in a glass vial
with a sharp needle made of steel at 150°C. Although the color of this compound changed from pale pink to black upon heating, acetylide 4
did not exhibit any nature of explosiveness under these conditions. While it may be premature to draw a conclusion about the safety of acetylide
4 from this experiment, we have not had any accidents associated with this compound in our laboratory.
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02602-3

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T. Naka, K. Koide / Tetrahedron Letters 44 (2003) 443–445
were identical to the literature.33 We were unable to
detect either the corresponding Z-enoate or the desired
ynoate 2a by NMR analysis of the crude reaction
mixture.
To investigate the generality of this novel functional
group transformation, we prepared ketones 6b, 6c and
6d, which were subjected to the similar conditions. The
result is summarized in Scheme 3. For these bulkier
ketones, more equivalents of NaBH4 were necessary.
With only 1–2 equivalents of NaBH4 in the reduction of
6b, we isolated alcohol 2b (Fig. 1) in addition to alcohol
1b. The stereoselectivity of this reduction with these
two substrates was determined to be 5.5:1 in favor of
trans. Although the chemical yields of these reduction
reactions are modest to good, we did not observe any
by-products by NMR analysis of the crude mixture.
Figure 1. Structures of methyl 4-hydroxy-2-alkynoates.
alkyne 3, with acetyl chloride in refluxing CCl4 (Scheme
2).32 This protocol does not require the use of a strong
base such as LDA to deprotonate the acetylenic proton
to form the CꢀC bond, which often results in undesired
products. This one-step method to prepare ynones is
more efficient than conventional two-step protocol (1.
addition of metal acetylide to an aldehyde; 2. oxidation
of the resulting alcohol).
With ketone 6a in hand, we attempted to prepare
alcohol 2a by the action of NaBH4. In effect, upon
addition of 1.2 equiv. of NaBH4 to ketone 6a, we
isolated E-enoate 1a as a single product in 70% yield
(Scheme 3). The spectroscopic data of compound 1a
This simple functional group conversion reported
herein should be applicable to syntheses of a wide
variety of g-hydroxy-a,b-(E)-alkenoic esters. Further
studies of this methodology will be reported in due
course.
Experimental: Sodium borohydride (203 mg; 5.36
mmol) was added to a solution of ketone 6b (208 mg;
1.07 mmol) in methanol (3.6 mL) in one portion at
−72°C. The temperature of the reaction mixture was
then gradually raised to 0°C over 30 min, and the
reaction mixture was stirred at the same temperature
for an additional 30 min. The reaction mixture was
quenched by the addition of diethyl ether (20 mL) and
saturated aqueous NH4Cl (8 mL) at 0°C, and the
resulting solution was stirred at room temperature for 1
h. This mixture was separated, and the organic layer
was washed with saturated aqueous NaHCO3 (10 mL×
1) and brine (10 mL×1), and dried over Na2SO4. The
organic layer was then concentrated in vacuo, and the
resulting residue was purified by silica gel column chro-
matography (5“15% ethyl acetate in hexanes) to afford
an inseparable mixture of alcohol 1b and lactone 7b
(159 mg; 75% yield) as colorless oil. Data for com-
1
Scheme 2. Preparation of 4-oxo-2-alkynoates 6.
pound 1b: Rf 0.28 (20% ethyl acetate in hexanes); H
Scheme 3. Reduction of methyl 4-oxo-2-alkynoates 6.

T. Naka, K. Koide / Tetrahedron Letters 44 (2003) 443–445
445
NMR (300 MHz, 293 K, CDCl3) l=6.97 (dd, 1H,
J=15.7, 5.2 Hz), 6.04 (dd, 1H, J=15.7, 1.7 Hz), 4.10
(broad dd, 1H, J=8.9, 5.2 Hz), 3.75 (s, 3H), 1.99–1.01
(m, 11H); HRMS (CI+) calcd for C10H15O2 (M+−OMe)
167.1072; found 167.1072 m/z.
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