Teaahednm Letters. Vo1.31, No.36, pi 5165-5168.1990 Printed in Great Britain

oo40-4039190 $3.00 + .oo Pcrgamlm Press plc

ARYIATION OF I-TRIBUTYLSTANNYL GLYCALS CATALYZED BY PALLADIUM: A SYNTHETIC

ROUTE TO THE BASIC SKELETON OF THE PAPULACANDINS AND CHAETIACANDIN

Eric Dnbois and Jean-Marie Beau* Unbersitt? d ‘Orl~ans, Laboratoire de Biochimie Structwale

awocik au CNRS, BP 6759,45067 Orlkans Ckdex 2, France

Summary: The palladium-catalyzed coupling reaction of 4,6-O-benzylidene-3-O-tert-butyldimethylsilyl-l- tri-n-butylstannyl-D-ghrcal 7 with 3,5-dibenzyloxy-2-bromo-benzyl alcohol 8 gave a 78% yield of the C- arylated glycal 11, stereoselectively transformed into the structural units of the papulacandins and chaetiecandin.

Papulacandins A-D 1 and Z1 and the chaetiacandin 32 represent closely related antibiotics

isolated from cultures of Papulatia sphaerosperma and Monochaetia dimorphospora, respectively. They

both display strong antibiotic activities against yeasts, especiaily against Candida albicans. Papulacandin

B, the major component of the antibiotic complex, has been shown to inhibit the 8-glucan biosynthesis in

various organisms. 3 The unsaturated acy! residue at O-3 is crucial for biological activity. Although the 6-

0-acyl-S-D-galactosyl residue at O-4 in 1 is essential for inhibiting fungal growth, it is not required for

activity against glucan biosynthesis. 1q3d

\

” ,‘, ft?O” -ill_ 0

0

L = a-0-acyl-B-D-galact~yl R = 6-0-acyl-gala&pyanosyi lPapdacadiaA,B,C R = L 3(Iaetiae 2 Pqmlacaudin D R=H SChelllel

Interest in these substances has stimulated recent synthetic investigations including a total

synthesis of a racemic spiroketal moiety by a hetero Diels-Alder reaction,4 or coupling of aryl

nucleophiles with adapted electrophilic carbohydrates5

Following our study in evaluating the synthesis of C-glycosyl compounds from anionic anomeric

species6f7 and initial work in this area,8 we anticipated that the structural units of both papulacandins

and the chaetiacandin could be constructed from suitably protected l-C-arylated glucals C (Scheme 2) by

a stereoselective functionalization of the glycal double bond. Preliminary work on model substances 89 9

indicated that these l-substituted glycals undergo epoxidation (+D) or hydroboration (+E) from the

desired a-face.8~9~10 The 1Garylated glucal C could, in tnm, be derived from a mild and efficient

palladium-catalyzed arylation8sg of the l-(t&z-butyls~l)-D-ghtcal A. 7s10a We now report our results

on this projected route.

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5166

epoxidation- ROW”

nirnlrrtnlirntinn _ RO

OH HV

A B c hvdrobc

- 1 ,I ..- /

Q = ’ OR\

, _. ~_ wation-

oxidation R = protecting groups

“” HO’

E

scheme2

Regioselective silylation and methylation of the 4,6-O-benzylidene-1-thio-s-Pglucopyranoside

4 l1 readily available from D-glucose, provided thioglucoside 5 in excellent yield1%13 (Scheme 3).

Sllfur oxidation and base-induced elimination of methanol led to the unsaturated phenylsulfone 6. The

tin reagent required for the coupling reaction was obtained by tri+butyltin hydride treatment7 of 6

which provided the 1-tri+butylstaunyl glucal 7, [a]D -32” (71%), together with the starting sulfone 6

(26%). The aromatic partner, 3,5_dibenzyloxy-2-bromo-benzyl alcohol S,14. was obtained by

regioselective bromination15 (NBS, CCl4, reflux, 0.5 h, 97%) of 3,5-dibenzyloxybenzyl alcohol prepared

from commercial 3J-dihydroxybemic acid according to Lee et (rL16

phIi-z3+&B” ‘ - ph~oB: ph- Bn - CHxPh

11 TBS - t-butyldimothylrilyl

~tr~cuditlou ‘* \ l3 Y OBn

1)1.TBscI,imibaolt,D~,9146;2M~B;ro-lyoHh,DMp,O~4h,9456

b) 1. mCPBA, 22 quiv., NaHCO3, CH$& RT, 86% 2 nBuLi, THF, -78 ‘C, 03 b, SO%. Ac

c) Bu3SnH, 25 quiv., AIBN, PhCH3, reflux, 3 h, 71%.

d) Pd(Ph3p)4,0.1 qti.. PhCH3, retlux, 12 h, 72%.

-_cy#J

e) Pdo4,O.l quiv., Nezco3,7 quiv- PhCH3, reflux, 3 b, 78%. 14

f)mcpBA,13q~~N~~cH2c12,5h,-78a~C,70460E,~%ofW.

g) BQUF, TI1F, RT, 10 h; HB Pd/C, AcOJZtMeQH, 2l, RT; 40, pyridine; 7956. Scheme 3

Coupling of 1-stannylglycal 717 with aryl bromide 8 provided, after a reflex of 12 h, a product

which was readily identified with the bicycloketal 918 (72%) as the Q& stereoisomer at the spiro center,

with some of the homocoupling product 10 (15%). This one-step construction of a Zdeoxy analogue of

5167

the tricyclic skeleton of papulacandins may be reasonably explained by an acid-catalyzed1g ketalization

of 11, the initial product of the reaction. When the Pd(0) catalyzed reaction was buffered with sodium

bicarbonate, the expected arylated glycal 11 was then obtained in good yield (78%), accompanied by

dimer 10 (18%).

The next stereoselective epoxidation of 11 was best accomplished with 3-chloroperbenzoic acid at

low temperature, to provide exclusively the two isomers 1228 (70%) and &o (12%) with the D-gkco

configuration. While acid-catalyzed isomerization of the unnatural spirocyclic isomer 13 to 12 failed,

both 12 and 13 gave, after desilylation, hydrogenolysis and acetylation the same21 hexaacetate 14 m.p.

197 “C, [a] -9.5” (c 1.09, C!HCl3), a compound identical with the hexaacetate obtained from the natural !!2 antibiotics.

Regioselective access to a 3-O-a@ derivative of the tricyclic skeleton, as found in papulacandins,

proved to be unexpectedly troublesome by a standard protection-deprotection sequence on 12 under a

variety of conditions due to a O-3 to O-2 silyl migration. This undesired rearrangement was used

advantageously by forcing the mixture towards the 2-O-silylated product 15 (68% yield, Scheme 4).

Acylation of 15 with stearic acid, acidic treatment and hydrogenolysis gave the deprotected papulacandin

D aIIdOgue 16, [o]D -3’, characterized by its pent&O-acetate 17.

12 a _‘“=&gIr” b CH;<CH),EqoR

15

cc 16 R - H

17 R =Ac

11 d _Ph~zoBn e _ <woBn

aalatrd_ 18 ~)NNlfI,15q~~THp;RT,1h,reputadoacc,68%.

b) Steak acid, 1.6 quiv., DCC, DMAP, CH&, XT, I2 h, 8696;

TPAzH20, lo:& RT, 1 h then H> Pd/C, AcOEkMeOH, 1:1, RT, 80%.

c) 40, pydine, 55% overau from 15.

d) BH$THP, 4 quiv- RT, 1 h then H202, aq. NaOH workup, 75%.

e) MeOHzq. HCl 1 N, 4:l, RT, 10 h, then AC.+, pyridk, 68%.

Scheme 4

19

Bn = CH,Ph TBS - t-butyldimetylsilyl

Rather than the above epoxidation, hydroboration-oxidation of 1-C-arylated glycal 11 gave the

corresponding l-C-aryl anbydro-D-ghxitol18 as the only stereoisomer, representing the structural unit

of the chaetiacandin 3.23 This compound was characterized by its penta-O-acetate 19, [o]D -23”.

Further efforts on the stereoselective synthesis of biologically important C-a@ glycosides using

the Pd(0) catalyzed arylation of 1-stannylated glycals are presently being worked out in our group.

Ackrwwledgmen&: We express our gratitude to Dr. K. Scbeibli and Dr. J. Szeszak of Ciba-Geigy Limited (Basel) for providing a sample of papulacandin B and to Dr. G. Keravis, Centre de Mesures Physiques, Universit6 d’Grl&urs, for mass spectroscopic data.

5168

R4ferences and Notes

1.

2.

3.

4. 5.

6.

7. 8.

9. 10.

11. 12.

13.

14. 15. 16.

17. 18.

19.

20.

21.

22. 23.

(a) P. Trader, W. Tosch and 0. Zak, J. Antibiotics, 40 (1987) 1146-1164 and references cited therein; (b) P. Traxler, H. Fritz, H. Fuhrer and W.J. Richter, L Atiioticr, 33 (1980) 967-978. T. Komori, M. Yamashita, Y. Tsurumi and M. Kohsaka, I. Antibiorics, 38 (1985) 455-459; T. Komori and Y. Hoh, J. Antibiotics, 38 (1985) 544-546. (a) B.C. Baguley, G. Riimmele, J. Gnmer and W. Wehrli, Eur. J. Biochem., 97 (1979) 345-351; (b) P. Perez, R. Varona, I. Garcia-Acha and A. Duran, FEBS Let& I29 (1981) 249-252; (c) R. Varona, P. Pkrez and A. Duran, FEMS MicmbioL Let& 20 (1983) 243-247 (d) G. Riimmele, P. Traxler and W. Wehrli, L Antibiotics, 36 (1983) 1539-1542. S. Danishefsky, G. Phillips and M. Ciufolini, Carbohy&. Res., 17X(1987) 317-327. (a) R.R. Schmidt and W. Frick, Tetrahedron, 44 (1988) 7163-7169; (b) S.B. Rosenblum and R. Bihovsb, J. Am. Chem. Sot., I12 (1990) 2746-2748. J.-M. Beau and P. Sirray, Tetiedron Lett., 26 (1985) 61856188; 61896192; 61936196; P. Lesimple, J.-M. Beau and P. Sinaj;, J Chem. Sot, Chem. Comma, (1985) 894-895. P. Lesimple, J.-M. Beau, G. Jaurand and P. Sinay, Tetiedron Lett., 27 (1986) 6201-6204. E. Dubois and J.-M. Beau, Seventh IUPAC Conference on Organic Synthesis, Nancy, France, 1988, Abstract 7-R9. E. Dubois and J.-M. Beau, J Chcm. Sot., Chem. Commun, in press. See also (a) S. Hanessian, M. Martin and R.C. Desai, J. Chem. Sot., Chem. Commuq (1986) 926- 927; (b) R. Preuss and R.R. Schmidt, LiebrgS Ann. Chem., (1989) 429-434. A. Liptak, I. Jodai, J. Harangi and P. Nanasi, Acta Chim. Hung., II3 (1983) 415-422. A small extent of O-3 to O-2 silyl migration occurred under the methylation conditions, leading to the regioisomer (5, regioisomer ratio, 35:l) easily eliminated in the following oxidation step. All new compounds gave satisfactory microanaiyticai and spectral data. Optical rotations were measured for solutions in CHC13 at room temperature, ‘H-NMR spectroscopy was performed at 300 MHz with a Bruker AM-300 WB spectrometer. AK. Sinhababu and R.T. Borchardt, .I Org. Chcm., 48 (1983) 23562360. P.D. Noire and R.W. Fran&, Sjwthesk, (1980) 882-883. F.G.H. Lee, D.E. Dickson, J. Suzuki, A. Zimis and AA Manian, .I Heterocyd Chem., IO (1973) 649-654; see also Reference 4. Coupling reactions have been performed on a one mm01 scale of stannane 7. Selected IH-n.m.r. data for 9 (C6D6): 6 2.56 (dd, J,, 3 5.3, J2e 2a 13.1 Hz, H-2e); 3.33 (dd, J2a3 11.0, J2q2e 13.1 Hz, H-2a); 3.77 (dd, 13 4 8.9, J4 5 9.8 Hz, H4. The configuration of the spiro- center was deduced from NOE differeice speda on spiroketal 9 (OBn = H) obtained under identical conditions. Slow thermal decomposition of the initially formed tributyltin bromide may provide acidic species catai The Y

ing the bicycloketalization. H-n.m.r. spectrum (C6D6) of 12 provided a coupling pattern (J2 3 - J3 4 - J4 5 - 9 Hz)

consistent with a 4Cl (D) conformation Of the pyranose ring in 12. Thi J valuks for i3 (J2,3 7.5, J3 4 8.5, J4 5 9.8 Hz) strongly suggests a distorted chair conformation as expected for this isomer which would otherwise experience a strong steric interaction between the pyranose ring and a benzyloxy substituent of the aromatic ring. These assigmnents are confirmed by transformation of 12 to the known hexaacetate 1422 and 13 to either 14 or its stereoisomer under non-anomerizing conditions (see Reference 21). We believe that the anomerization of the spiro center in 13 occurred during the hydrogenolytic step. If buffered conditions are used in this step, the anomeric configuration in 13 is preserved. See Reference 5(a): m.p. 199 “C, [o],,22 -7.5“ (c 1, CHC13). For a non-selective construction of this structural unit, see R.R. Schmidt and G. Effenberger, Cadohydr. Res., 171(1987) 59-79.

(Received in France 8 June 1990)