A novel nonclassical Wittig reaction of dioxolanones: Highly facile and concise enantiospecific synthesis of (3S,4S)-3-hydroxy-4-phenylbutyrolactone

Article abstract of DOI:10.1016/S0040-4039(00)02104-3

A novel and facile Wittig reaction of dioxolanones and an application of this protocol to the synthesis of (3S,4S)-3-hydroxy-4-phenylbutyrolactone is described.

Full text of DOI:10.1016/S0040-4039(00)02104-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 531–532
A novel nonclassical Wittig reaction of dioxolanones: highly
facile and concise enantiospecific synthesis of
(3S,4S)-3-hydroxy-4-phenylbutyrolactone†
G. Vidyasagar Reddy, V. Sreevani and D. S. Iyengar*
Discovery Laboratory, Organic Division-II, Indian Institute of Chemical Technology, Hyderabad 500007, India
Received 12 September 2000; revised 2 November 2000; accepted 15 November 2000
Abstract—A novel and facile Wittig reaction of dioxolanones is described. An application of this protocol to the stereospecific
synthesis in an efficient and practical manner of (3S,4S)-3-hydroxy-4-phenylbutyrolactone is demonstrated. © 2001 Elsevier
Science Ltd. All rights reserved.
In recent years, there has been considerable growing
interest in the synthesis of functionalized butyrolac-
tones because of their wide occurrence in several natu-
ral products, and also their utility as key precursors for
the synthesis of various bioactive molecules1–4 and
HIV-protease inhibitors.5–7 Consequently, a variety of
approaches have been developed for their asymmetric1,2
and racemic8 synthesis. Among them the Sharpless
Scheme 1. Reagents and conditions: (i) (CH2O)n, PTSA, C6H6, reflux, 1 h; (ii) Ph3PꢀCHCO2Et, toluene, reflux, 2 h.
Scheme 2. Reagents and conditions: (i) conc. HCl, EtOH, reflux, 4 h; (ii) NaBH4 (1.2 equiv.), CH3OH, 0°C, 1 h, 86% (for two
steps).
Keywords: asymmetric synthesis; dioxolanones; hydroxy acids; Wittig reaction.
* Corresponding author.
†
IICT communication No. 4385.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02104-3

532
G. Vidyasagar Reddy et al. / Tetrahedron Letters 42 (2001) 531–532
Table 1. Wittig reaction of dioxolanones
b
c
Entry
R
Yielda (%) 2
[h]D
2
Yielda (%) 3
[h]D 3
a
b
c
d
e
Ph
PhCH2
(CH3)2CH
(CH3)2CHCH2
CH3CH2CHCH3
93
97
92
94
95
87
−54
−27
−14
−14
96
95
94
96
94
−35
−82
−96
−44
−10
a Isolated yields.
b Specific rotations are measured with c=1 in methanol.
c Specific rotations are measured with c=0.5 in methanol.
asymmetric dihydroxylation of b,g-unsaturated esters
leading to chiral butyro lactones is of great signifi-
cance.1 In view of the synthetic importance of butyro-
lactone derivatives, we envisioned a new methodology
from readily accessible a-hydroxy acids. In this commu-
nication, we wish to report a novel and facile Wittig
reaction of various dioxolanones (2“3, Scheme 1) and
conversion of the a,b-unsaturated ester 3a to (3S,4S)-3-
hydroxy-4-phenylbutyrolactone 5 (Scheme 2).
ester 3a to acidic hydrolysis to furnish lactone 4, which
was reduced using sodium borohydride to give the
hydroxybutyrolactone as a single enantiomer 5 (Scheme
2). From spectroscopic (1H NMR, IR, mass) data and
the specific rotation [h]D= +36 (c=1, MeOH), lit.1
[h]D= +36 (c=0.98, MeOH) data, the structure and
absolute configuration was found to be (3S,4S)-3-hy-
droxy-4-phenylbutyrolactone (5). The exclusive forma-
tion of 5 in the sodium borohydride reduction of 4 may
be attributed to the diastereofacial selective addition of
hydride.
Thus, the a-hydroxy acids
1 were treated with
paraformaldehyde in presence of catalytic PTSA for 1 h
to obtain the dioxolanones 2‡ in excellent yields (92–
97%, Table 1).
In summary, a novel and facile Wittig reaction of
dioxolanones and a synthesis of (3S,4S)-3-hydroxy-4-
phenylbutyrolactone in a stereospecific and efficient
manner is described. The Wittig products obtained in
the present methodology are a new class of highly
useful versatile intermediates for the synthesis of vari-
ous bioactive molecules. Since both antipodes of chiral
a-hydroxy acids are accessible by several methods, the
present methodology has wide scope and will be
amenable to make all possible stereoisomers and
analogous compounds. Further work on the synthesis
of natural butyrolactones using this methodology is
currently in progress and will be reported in due course.
The Wittig reaction of the dioxolanones 2 with ethoxy-
carbonylmethylenetriphenyl phosphorane afforded the
corresponding a,b-unsaturated esters 3‡ in quantitative
yields (94–96%, Table 1). This reaction is highly facile
and clean and was completed in 2 h in all cases. The
results obtained with various dioxolanones (2a–e)
demonstrating the generality of this reaction, are sum-
marized in Table 1. Compounds 2 and 3 were fully
characterized by 1H NMR, IR, mass spectroscopic
data, and microanalysis, which were in good agreement
with the assigned structures. Important characteristic
1
signals of 3a, H NMR: l 1.25 (t, 3H, J=6.2 Hz), 4.15
Acknowledgements
We wish to thank CSIR (India) for financial assistance.
References
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one stereoisomer. No NOE signal enhancement of the
ring protons was observed on irradiation of the vinylic
proton and hence the olefin geometry was assumed to
have the thermodynamically more stable ‘E’ geometry.
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6
6
6
), 5.5 (s, 1H, -CH2),
6
6
FABMS (m/z): 235 (M+H+); anal. found: C, 66.41; H, 6.18. Calcd
for C13H14O4: C, 66.66; H, 6.02.