A stereoselective synthesis of (+)-boronolide

Article abstract of DOI:10.1016/S0040-4039(99)02246-7

A stereoselective synthesis of (+)-boronolide is described. The key steps involve a stereoselective reduction of an α-hydroxy ketone, allylation of an α-hydroxy aldehyde and a ring-closing olefin metathesis of a homoallylic alcohol derived acrylate ester

Full text of DOI:10.1016/S0040-4039(99)02246-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1003–1006
A stereoselective synthesis of (+)-boronolide
Arun K. Ghosh ∗ and Geoffrey Bilcer
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607, USA
Received 12 November 1999; accepted 1 December 1999
Abstract
A stereoselective synthesis of (+)-boronolide is described. The key steps involve a stereoselective reduction of
an α-hydroxy ketone, allylation of an α-hydroxy aldehyde and a ring-closing olefin metathesis of a homoallylic
alcohol derived acrylate ester utilizing Grubbs’ catalyst. © 2000 Elsevier Science Ltd. All rights reserved.
The bark and branches of Tetradenia fruticosa and the leaves of Tetradenia barberae are traditional
folk medicines in Madagascar and Southern Africa.1 The active principle, boronolide (1), an α-pyrone
derivative containing a polyacetoxylated side chain, has been isolated from these species since 1971.1a,b
The deacetylated boronolide (2) and 10,20-dideacetylated boronolide (3) have also been isolated from
Iboza riparia, a central-African species ubiquitously used in tribal medicine.2 The root extract of these
plants is traditionally used by the Zulu as an emetic agent and is known to be effective against malaria.1c
The absolute configuration of (+)-boronolide was determined through X-ray crystallographic analysis
and chemical degradation.1b,3b
The biological properties of boronolide and its deacetylated derivatives have fostered significant
interest in their synthesis. Three total syntheses of boronolide have now been reported in the literature.4–6
The first synthesis was carried out in racemic form utilizing acrolein dimer as the starting material.4
The synthesis by Nagano and co-workers utilized the chiral centers of D-glucose.5 The recent synthesis
by Honda et al. utilized Sharpless dihydroxylation as the key steps, however, the synthesis lacks
stereochemical control.6 Herein we report an asymmetric synthesis of (+)-boronolide from diethyl
D-tartrate. The key steps involve a stereoselective allylation of an α-hydroxy aldehyde, asymmetric
reduction of an α-hydroxy ketone and ring-closing olefin metathesis of a homoallylic alcohol derived
acrylate ester utilizing Grubbs’ catalyst.7
A key structural feature of (+)-boronolide is the presence of a substituted α,β-unsaturated δ-lactone
moiety. As shown in Fig. 1, we planned to construct this unsaturated lactone unit by a ring-closing olefin
metathesis of the acrylate ester 4. The syntheses of such α,β-unsaturated γ- and δ-lactones have been
recently developed by both Nicolaou and us.8 Stereoselective synthesis of the acrylate ester 4 would
be achieved from the key starting material, 1-O-benzyl-2,3-O-isopropylidene-D-threitol derivative 5.
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02246-7
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Preparation of 5 in multigram quantities was carried out from diethyl-D-tartrate utilizing the protocol
described by Seebach et al.9
Fig. 1.
Isopropylidene derivative 5 was first converted to Weinreb amide 6 (Scheme 1). Thus, oxidation of
alcohol 5 by Jones’ reagent in aqueous acetone at 0°C afforded the corresponding carboxylic acid in
68% yield.10 The resulting carboxylic acid was then converted into the Weinreb amide 6 by treatment
with isobutyl chloroformate and N-methylpiperidine in a mixture (10:1) of CH2Cl2 and THF followed by
subsequent treatment of the reaction mixture with N-methoxy-N-methylamine and N-methylpiperidine
in CH2Cl2.11 Weinreb amide 6 was isolated in 83% yield after silica gel chromatography. To install the
butyl side chain of (+)-boronolide, Weinreb amide 6 was treated with butylmagnesium bromide in THF
at −20°C to afford the ketone 7 in 96% yield. Reduction of the ketone 7 by L-selectride in THF at −78°C
1
provided the (S)-alcohol 8 stereoselectively (12:1 by 500 MHz H NMR and 13C NMR analysis) in
near quantitative yield.12 Alternatively, Swern oxidation of 5 followed by the treatment of the resulting
aldehyde with nBuLi in THF at −78°C, afforded the (S)-alcohol 8 and its epimer as a 1:1 mixture in
80% yield. Of particular interest, the reaction of the above aldehyde with nBuLi in the presence of ZnBr2
has been shown to provide the corresponding (R)-carbinol selectively.13 The (S)-alcohol 8 so obtained
from the L-selectride reduction, was reacted with acetic anhydride in the presence of triethylamine and a
catalytic amount of DMAP in CH2Cl2 to furnish the acetate derivative 9 in 98% yield.
Scheme 1. (a) CrO3, H2SO4, Me2CO–H2O, 0°C (68%); (b) Me2CHCH2OCOCl, N-methylpiperidine, CH2Cl2–THF (10:1);
(MeO)NHMe·HCl, N-methylpiperidine, CH2Cl2 (83%); (c) CH3(CH2)3MgBr, THF, −20°C (96%); (d) L-selectride, THF,
−78°C (99%); (e) Ac2O, Et3N, DMAP (cat), CH2Cl2 (98%); (f) H2, Pd(OH)2 (cat), EtOAc–MeOH (4:1), (quant.); (g) DMSO,
(COCl)2, Et3N, CH2Cl2, −78°C; (h) allylmagnesium bromide, ZnCl2, THF, −78°C (53% from 8)
For conversion of 9 to aldehyde 10, the benzyl protecting group was removed by a catalytic hydro-
genation of 9 with Pearlman’s catalyst (Pd(OH)2) in a mixture of ethyl acetate and methanol (4:1) under a
hydrogen filled balloon at 23°C for 12 h. Swern oxidation of the resulting alcohol provided the aldehyde

1005
10. The elaboration of the α-pyrone unit with appropriate stereochemistry of (+)-boronolide then required
the stereoselective allylation of 10. Thus, attempted allylation of 10 with allyltrimethylsilane in CH2Cl2
in the presence of TiCl4 at −78°C provided the homoallylic alcohol 11 selectively (selectivity ratio 4:1
1
by 500 MHz H NMR) however, the reaction was sluggish and the conversion was poor (30–35%).
The reaction with allyltributyltin in the presence of SnCl4 at −78°C has also resulted (4:1 mixture of
alcohol 11 and 12) in comparable diastereoselectivities and conversion. The best result was obtained
when the allylation of 10 was carried out with diallyl zinc at −78°C utilizing Kishi’s protocol.14 Thus,
ZnCl2 (7.2 equiv., 1 M solution in Et2O, Aldrich) was added to allylmagnesium bromide (5 equiv., 1 M
solution in Et2O, Aldrich) in THF at 0°C and the mixture was stirred for 30 min, warmed to 23°C and
stirred for an additional 1 h. The resulting diallyl zinc was cooled to −78°C and the aldehyde 10 in THF
was added dropwise over a period of 3 min. The mixture was stirred at −78°C for 12 h and quenched
with water followed by standard work up to furnish the homoallylic alcohol 11 stereoselectively (isomer
ratio 5:1) in 53% yield (from 8). The isomers were separated by silica gel chromatography to provide
diastereomerically pure 11.
The alcohol 11 was converted to its acrylate ester 13, the RCM precursor. Acryloyl chloride followed
by triethylamine were added dropwise to alcohol 11 in CH2Cl2 at 0°C. The mixture was warmed to 23°C
for 30 min to furnish the ester 13 in 80% isolated yield. Olefin metathesis of 13 with commercially
available Grubbs’ catalyst (10 mol%) in the presence of Ti(OiPr)4 (30 mol%) in refluxing CH2Cl2
(0.007 M solution) for 12 h, afforded the α,β-unsaturated-δ-lactone 14 in 84% yield after silica gel
chromatography (Scheme 2).15 In the absence of Ti(OiPr)4, the reaction was substantially slower (50%
conversion after 12 h).8b To complete the synthesis, the removal of the isopropylidene group was effected
by exposure to Dowex 50 W-X8 (H+) resin in H2O at 70°C for 3 h. The resulting crude mixture was
treated with acetic anhydride and triethylamine in CH2Cl2 in the presence of a catalytic amount of DMAP
23
23
at 0°C for 30 min to furnish the synthetic (+)-boronolide 1, [α]D +25 c 0.2, EtOH; lit.1b [α]D +28
c 0.08, EtOH. Spectral data (IR and 500 MHz 1H NMR) for the synthetic boronolide is identical to that
reported for the natural product.1
Scheme 2. (a) CH2_CHCOCl, Et3N, 0°C to 23°C, CH2Cl2 (80%); (b) Cl2(PCy3)2Ru_CHPh (10 mol%), Ti(OiPr)4 (30 mol%),
CH2Cl2, 40°C (84%); (c) Dowex 50 W-X8 (H+), H2O, 70°C; (d) Ac2O, Et3N, DMAP (cat), CH2Cl2, 0°C (quant.)
In conclusion, (+)-boronolide has been synthesized in a diastereoselective manner in 19% overall
yield from the known isopropylidene derivative 5.9 The present synthetic route can easily be amenable
to generate the other stereoisomers and structural variants of boronolide. Stereoselective reduction of
an α-hydroxy ketone, allylation as well as the efficient construction of unsaturated lactones by olefin
metathesis are particularly noteworthy.
Acknowledgements
Financial support for this work was provided by the National Institute of Health (GM 55600).
Additional support from Merck Research Laboratories is also gratefully acknowledged.

1006
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15. All new compounds gave satisfactory spectroscopic and analytical data. Compound 14: [α]D23 +27 c 0.15, CHCl3; 1H NMR
(400 MHz, CDCl3) δ 6.90 (1H, ddd, J=9.8, 4.3, 4.3 Hz), 6.04 (1H, ddd, J=9.8, 1.8, 1.8 Hz), 5.06 (1H, ddd, J=8.7, 5.2, 5.0
Hz), 4.42 (1H, ddd, J=7.8, 7.2, 7.2 Hz), 4.17 (1H, dd, J=6.4, 3.4 Hz), 3.98 (1H, dd, J=6.8, 6.7 Hz), 2.12 (3H, s), 2.53 (2H,
m), 1.62–1.76 (2H, m), 1.44 (3H, s), 1.40 (3H, s), 1.34–1.38 (4H, m), 0.90 (3H, t, J=6.8 Hz); 13C NMR (100 MHz, CDCl3) δ
170.7, 162.7, 144.5, 121.5, 110.6, 80.0, 78.0, 77.3, 72.5, 30.8, 27.6 (2C), 26.9, 26.0, 22.5, 21.0, 14.0; IR (neat) 2923, 2853,
1738, 1461, 1375, 1236 cm−1
.