Synthesis of aryl spiroketals related to the papulacandins via allylation of phthalides

Article abstract of DOI:10.1016/S0040-4039(00)00483-4

The synthesis of a range of aryl spiroacetals related to the papulacandins is reported. Key steps involve treatment of a phthalide acetate with an allylstannane followed by a hydroboration/oxidative cyclization sequence. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00483-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3955–3958
Synthesis of aryl spiroketals related to the papulacandins via
allylation of phthalides
Margaret A. Brimble,∗ Vittorio E. Caprio, Andrew D. Johnston and Matthew H. Sidford
Department of Chemistry, University of Auckland, 23 Symonds St., Auckland, New Zealand
Received 2 March 2000; accepted 21 March 2000
Abstract
The synthesis of a range of aryl spiroacetals related to the papulacandins is reported. Key steps involve treatment
of a phthalide acetate with an allylstannane followed by a hydroboration/oxidative cyclization sequence. © 2000
Elsevier Science Ltd. All rights reserved.
Keywords: allyl stannanes; aryl spiroacetals; papulacandins; oxidative cyclization; phthalides.
Many metabolites produced by a wide variety of microbes, insects, plants, fungi and microorganisms
incorporate spiroacetal units.1 The C-arylglycosyl spiroacetal antifungal agents papulacandins A 1, B
2, C 3, D 4 and E were isolated from Papularia spherosperma2 and were found to exhibit potent in
vitro activity against Candida albicans and related microorganisms.3,4 More recent members of the
papulacandin family, Mer-WF3010 5 and L-687,781 65 were found to overcome Pneumoocystis carinii
pneumonia, the common opportunistic infection in AIDS patients. The simplest member of this family
of antibiotics, papulacandin D 4 exhibits significant antifungal activity, hence the synthesis of simpler
analogues of papulacandin D 4 may lead to improved biological activity.
The tricyclic C-arylglycosyl spiroacetal nucleus has been assembled via a Diels–Alder reaction,6 a
palladium(0) catalyzed coupling of an aryl halide with a stannyl glucal7–9 and the reaction of a 2-
bromobenzyl ether with an appropriately protected gluconolactone.10–12 Recently, the [4.5]spiroacetal
moiety of the papulacandins was assembled by condensation of a D-arabino-1,4-lactone with an α-
lithiated carbanion of a β-phenylsulfonyldihydrofuran.13
∗
Corresponding author. Fax: +64 9 3737422; e-mail: m.brimble@auckland.ac.nz (M. A. Brimble)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00483-4
tetl 16765

3956
We have reported an efficient two-step synthesis of a range of aryl spiroacetals related to the
papulacandins, via the addition of ortho-lithiated tertiary benzamides 7 to lactones followed by acid-
catalyzed cyclization of the resultant keto alcohols (Scheme 1).14 This approach was unsuitable for the
preparation of the arylspiroacetals with a similar oxygenation pattern to that present in the papulacandins
in that this required the addition of the bulky lactone electrophile to the ortho position of amides 8 and 9
which suffered from steric hindrance by the neighbouring methoxy group.
Scheme 1. Reagents and conditions: (i) tBuLi, THF, TMEDA, −78°C, then lactone; (ii) p-TSA, THF, H2O
The focus of the present work was to prepare arylspiroacetals with the correct oxygenation pattern as
that present in the papulacandins adopting an alternative strategy. We therefore herein report the synthesis
of arylspiroacetals related to papulacandin D 4 starting from phthalide acetates 12 and 13 which are
readily prepared via acetylation of the known hydroxyphthalides 10 and 1115 (Scheme 2). The key step
involved Lewis acid mediated addition of an allylstannane to the phthalide acetates 12 and 13, thereby
capitalizing on the electron donating effect of the requisite methoxy groups(s) to stabilize the resultant
oxocarbenium ion. The resultant alkene was converted to a primary alcohol by hydroboration thereby
facilitating formation of a tricyclic arylspiroacetal via oxidative cyclization using iodobenzene diacetate
and iodine under photolytic conditions (Table 1).16
Allylstannanes 14, 15 and 16 were prepared following the method reported by Naruta et al.17 and
allylstannane 17 was prepared following the procedure of Weigand and Bruckener.18 The optimum
procedure19 for reaction of phthalide acetates 12 and 13 with allyltributylstannanes 14–17 involved
the use of trimethylsilyl trifluoromethanesulfonate (TMSOTf) as the Lewis acid in dichloromethane
at −78°C using 2 equivalents of the stannane. We believe this is the first report of the addition of an

3957
Scheme 2. Reagents and conditions: (i) Ac2O, Et3N; (ii) Me3SiOTf, CH2Cl2, −78°C; (iii) BH3·THF, 0°C; (iv) PhI(OAc)2, I2,
hν
Table 1

3958
allylstannane to an oxocarbenium ion generated from a phthalide acetate providing a facile preparation
of functionalized 1(3H)-isobenzofuranones.
The presence of a substituent at C2 or C3 on the allylstannane (15 and 16, respectively) did not affect
the outcome of the allylation reaction although a lower yield was obtained in the latter case with allyl
phthalide 27 only being obtained in 43% yield. Use of methyl substituted allylstannanes 15 and 16 finally
led to the formation of arylspiroacetals 26 and 29, respectively, as a 1:1 mixture of diastereomers.
In the present work our goal was to convert the allylated 1(3H)-isobenzofuranones to aryl spiroacetals.
Hydroboration of alkenes 18, 21, 24 and 27 with BH3·THF cleanly afforded the primary alcohols 19,
22, 25 and 28, respectively. Conversion of these primary alcohols to aryl spiroacetals 20, 23, 26 and
29 was then effected by oxidative cyclization using iodobenzene diacetate and iodine under photolytic
conditions. Similar oxidative cyclizations have been used by this research group as a method to prepare
bis-spiroacetals.20
Whilst oxidative cyclization of alcohols 19, 22, 25 and 28 led to the formation of a
spiro[1(3H)isobenzofuran, 20-tetrahydrofuran] ring system, the homologous spiro[1(3H)isobenzofuran,
20-tetrahydropyran] ring system that is present in the papulacandins was formed by oxidative cyclization
of alcohol 31. Alcohol 31 was obtained by desilylation of silyl ether 30 which in turn was prepared via
treatment of phthalide acetate 13 with functionalized allylstannane 17.
In conclusion, we have developed an efficient procedure for the synthesis of arylspiroacetals similar to
those present in the potent antifungal agents, the papulacandins. The methodology combines the use of a
novel allylation of phthalide acetates followed by an oxidative cyclization.
References
1. For reviews on the synthesis of spiroacetals, see: (a) Perron, F.; Albizati, K. F. Chem Rev. 1989, 89, 1617; (b) Boivin, T. L.
B. Tetrahedron 1987, 43, 3309; (c) Kluge, A. F. Heterocycles 1986, 24, 1699.
2. Traxler, P.; Gruner, J.; Auden, J. A. L. J. Antibiot. 1977, 30, 289.
3. Rommele, G.; Traxler, P.; Wehrli, W. J. Antibiot. 1983, 36, 1539.
4. Van Middlesworth, F.; Olmstead, M. N.; Schmatz, D.; Bartizal, R.; Fromtling, R.; Bills, G.; Nolstadt, K.; Honeycutt, S.;
Zweernik, M.; Garrity, G.; Wilson, K. J. Antibiot. 1991, 44, 45.
5. Kaneto, R.; Chiba, H.; Agematu, H.; Shibamoto, N.; Yoshioka, T.; Nishada, H.; Okamoto, M. J. Antibiot. 1993, 46, 247.
6. Danishefsky, S.; Philips, G.; Ciufolini, M. Carbohydrate Res. 1987, 171, 317.
7. Friesen, R. W.; Sturino, C. F. J. Org. Chem. 1990, 55, 5808.
8. Dubois, E.; Beau, J.-M. Carbohydrate Res. 1992, 223, 157.
9. Rosenblum, S. B.; Bihovsky, R. J. Am. Chem. Soc. 1990, 112, 2746.
10. Czernecki, S.; Perlat, M.-C. J. Org. Chem. 1991, 56, 6289.
11. Schmidt, R. R.; Frick, W. Tetrahedron 1988, 44, 7163.
12. Barrett, A. G. M.; Pena, M.; Willardsen, J. A. J. Chem. Soc., Chem. Commun. 1995, 1147.
13. Carretero, J. C.; de Diego, J. E.; Hamdouchi, C. Tetrahedron 1999, 55, 15159.
14. Brimble, M. A.; Robertson, S. G. Tetrahedron 1996, 52, 9553.
15. Freskos, J. N.; Morrow, G. W.; Swenton, J. S. J. Org. Chem. 1985, 50, 805. Khanapure, S. P.; Reddy, R. T.; Biehl, E. R. J.
Org. Chem. 1987, 52, 5685.
16. Concepcion, J. J.; Francisco, C. G.; Hernandez, R.; Salazar, J. A.; Suarez, E. Tetrahedron Lett. 1984, 25, 1953.
17. Naruta, Y.; Nishigaichi, Y.; Maruyama, K. Chem. Lett. 1986, 1857.
18. Weigand, S.; Bruckener, R. Synthesis 1995, 475.
19. All new compounds gave satisfactory spectroscopic and analytical data.
20. For a review on the synthesis of bis-spiroacetals, see: Brimble, M. A.; Fares, F. A. Tetrahedron 1999, 55, 7661.