Formal total synthesis of (+)-boronolide

Article abstract of DOI:10.1016/S0040-4039(00)00749-8

(+)-Boronolide, a polyacetoxy natural product having four contiguous asymmetric centers has been synthesized from D-mannitol. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00749-8

Tetrahedron Letters 41 (2000) 4969±4971
Formal total synthesis of (+)-boronolide
Musti Chandrasekhar, Sushil Raina and Vinod K. Singh*
Department of Chemistry, Indian Institute of Technology Kanpur 208 016, India
Received 6 March 2000; accepted 8 May 2000
Abstract
(+)-Boronolide, a polyacetoxy natural product having four contiguous asymmetric centers has been
synthesized from d-mannitol. # 2000 Elsevier Science Ltd. All rights reserved.
d-Lactonic compounds possessing alkyl and polyhydroxy or polyacetoxy side chains have
attracted much attention from synthetic chemists and medicinal chemists due to their biological
activity. One such compound that created interest recently was (+)-boronolide 1. This was
isolated from the bark and branches of Tetradenia fruticosa1 and the leaves of Tetradenia
barberae,2 which have been used as a local folk medicine in Madgascar and Southern Africa.3 The
extracts of the root of these plants were employed typically by the Zulu as an emetic, while an
infusion of the leaf has been reported to be e€ective against malaria. The absolute con®guration of
1 was determined by X-ray analysis4 and chemical degradation. Three total syntheses of 1 have
been reported in the literature to date.5 The ®rst synthesis is a racemic one, achieved from
acrolein dimer.6 The other two are non-racemic syntheses, the ®rst one starting from d-glucose7
and the second one involving a Sharpless asymmetric dihydroxylation as a key step for the
creation of the asymmetric centers.8 As a part of our continuing interest in the synthesis of d-
lactonic compounds,9 we were interested in a synthesis of (+)-boronolide 1 from d-mannitol.
Our retrosynthetic analysis of (+)-boronolide 1 is shown in Fig. 1. It was conceived that the d-
lactone could be built up from the epoxide 2. Structural mapping of the sub-target 2 was done
with the d-mannitol derivative 5, two transformations being required; the addition of a three
carbon unit as the side chain and inversion of con®guration at one of the chiral centers. The
above strategy was validated and was executed as described in Scheme 1.
1,2,3,4-O-Diisopropylidene-d-mannitol 510 was subjected to selective protection of its primary
hydroxyl group as a benzoate followed by conversion of the secondary hydroxyl group into a
mesylate. Treatment of the resulting ester 7 with K2CO3 in MeOH deprotected the benzoate
giving a hydroxyl group which under the reaction conditions displaced the mesylate group via an
intramolecular SN2 reaction to provide the epoxide 4 with inverted stereochemistry. The three
* Corresponding author. Fax: 91-512-597436; e-mail: vinodks@iitk.ac.in
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00749-8

4970
Figure 1. Retrosynthetic analysis of (+)-boronolide 1
Scheme 1. Formal total synthesis of (+)-boronolide 1. (a) PhCOCl, Py, DCM, ^80±20ꢀC, 4 h (83%); (b) MeSO2Cl,
Et3N, DCM, ^80±20ꢀC, 12 h (95%); (c) K2CO3, MeOH, rt, 2 h (85%); (d) n-PrLi, CuCN, THF, ^80ꢀC, 12 h (95%);
ꢀ
ꢀ
.
(e) PhCH2Br, NaH, THF, rt, 16 h (90%); (f) CuCl2 2H2O, MeOH, 0 C, 40 min (80%); (g) TsCl, Py, DMAP (cat.), 0 C,
ꢀ
ꢀ
.
14 h (65%); (h) K2CO3, MeOH, 0 C, 1 h (90%); (i) Allyl magnesium broꢀmide, CuBr DMS, ^80 C, 8 h (80%);
ꢀ
.
(j) BH3 DMS, 0 C, 12 h, PhH followed by 30% aq. H2O2, NaOH, EtOH, 0 C (75%); (k) AgCO3 on Celite, PhH,
.
re¯ux, 12 h (75%); (l) CuCl2 2H2O, MeCN, rt, 36 h (80%); (m) H2, 10% Pd/C, EtOH, rt, 24 h (95%); (n) Ac2O, Py, rt,
16 h (80%); (o) Refs. 6, 7 and 8
carbon unit was added at this stage. This was initially done by opening the epoxide 4 with n-
.
propylmagnesium bromide/CuBr Me2S, but the reaction was not very clean. However, the use of a
higher order cuprate gave cleanly the expected ring opened product whose hydroxyl was protected
11
.
with a benzyl group to provide 8. The acetonide of 8 was deprotected with CuCl2 2H2O
followed by regioselective activation of the primary hydroxyl as a tosylate group. The resulting
hydroxytosylate 9 was subjected to base induced cyclization to provide the epoxide 10 in 90%
yield. The epoxide 10 has the correct con®guration at all four stereogenic centers and only the
construction of d-lactone unit was required. Initially, we planned to use sulphone acetal chemistry
to build the required lactone unit as has been done earlier in our synthesis of a pheromone.9
Surprisingly, the carbanion generated from a sulphone acetal failed to open the epoxide 10. Other
modi®ed reagents such as a sulphone orthoester12 or propiolic acid13 also proved to be
unsuccessful. The lactone ring was therefore constructed in a di€erent way in which the epoxide
10 was opened with allylcuprate to provide 11 in 80% yield. Terminal hydration of ole®n 11 was

4971
achieved by hydroboration followed by oxidation to provide a diol which was smoothly
lactonized in a single step by oxidation with silver carbonate on celite to 12. The acetonide and
benzyl groups in 12 were deprotected and the resulting triol was acetylated to give the triacetate
23
D
23
D
13,14 ‰ꢀŠ ^20 (c 1.25, EtOH); lit.8 ‰ꢀŠ ^19.5 (c 0.36, EtOH). The conversion of 13 to natural (+)-
boronolide has already been carried by using benzeneseleninic anhydride.6 8
In conclusion we have completed a formal synthesis of (+)-boronolide from a readily available
d-mannitol derivative in an overall yield of more than 5%. Here, we have used the symmetry of
d-mannitol to introduce the side chain and construction of the d-lactone unit.
Acknowledgements
V.K.S thanks DST (Government of India) for the Swarnajayanti Fellowship Award (1998) and
CSIR for a research grant. M.C. thanks UGC for a JRF.
References
1. Franca, N. C.; Polonsky, J. C. R. Hebd. Seances Acad. Sci. Ser. C 1971, 273, 439.
2. Davies-Coleman, M. T.; Rivett, D. E. A. Phytochemistry 1987, 26, 3047.
3. Watt, J. M.; Brandwijk, M. G. The Medicinal and Poisonous Plants of Southern and Eastern Africa; Livingstone:
Edinburgh, 1962; p. 516.
4. Kjaer, A.; Norrestam, R.; Polonsky, J. Acta. Chem. Scand. Ser. B 1985, 39, 745.
5. After this manuscript was accepted for publication, a recently published synthesis of (+)-boronolide from diethyl
d-tartrate was brought to our notice. For reference, see: Ghosh, A. K.; Bilcer, G. Tetrahedron Lett. 2000, 41, 1003.
6. Je€ord, C. W.; Moulin, M.-C. Helv. Chim. Acta 1991, 74, 336.
7. Nagano, H.; Yasui, H. Chem. Lett. 1992, 1045.
8. Honda, T.; Horiuchi, S.; Mizutani, H.; Kanai, K. J. Org. Chem. 1996, 61, 4944.
9. Raina, S.; Singh, V. K. Tetrahedron 1996, 52, 4479.
10. The acetonide 5 was prepared in two steps from d-mannitol in an overall yield of 25% following the literature
procedure. For reference, see: Wiggins, L. J. Chem. Soc. 1946, 13.
11. Saravanan, P.; Chandrasekhar, M.; Anand, R. V.; Singh, V. K. Tetrahedron Lett. 1998, 39, 3091.
12. Carretero, J. C.; Ghosez, L. Tetrahedron Lett. 1988, 29, 2059.
13. Carlson, R. M.; Oyler, A. R.; Peterson, J. R. J. Org. Chem. 1975, 40, 1610.
1
14. The NMR data for 13 is as follows: (a) H NMR (400 MHz, CDCl3) ꢁ 5.35 (dd, J=5.8, 4.2 Hz, 1H); 5.20 (dd,
J=5.8, 4.4 Hz, 1H); 5.02 (q, J=6.4 Hz, 1H); 4.42 (ddd, J=10.7, 5.8, 3.4 Hz, 1H); 2.4±2.6 (m, 2H); 2.13 (s, 3H),
2.10 (s, 3H), 2.07 (s, 3H); 1.27±1.97 (m, 10H); 0.87 (t, J=6.6 Hz, 3H). (b) 13C NMR (100 MHz, CDCl3) ꢁ 170.4,
169.9, 169.75, 169.73, 77.7, 71.7, 71.2, 70.6, 30.2, 29.5, 26.9, 23.3, 22.2, 20.8, 20.6, 20.5, 18.1, 13.7.