Total synthesis and structural elucidation of the antifungal agent papulacandin D

1082

J . Org. Chem. 1996, 61, 1082-1100

Tota l Syn th esis a n d Str u ctu r a l Elu cid a tion of th e An tifu n ga l

Agen t P a p u la ca n d in D

Anthony G. M. Barrett,*^,†Michael Pen˜a,^‡and J . Adam Willardsen^†

Department of Chemistry, Imperial College of Science Technology and Medicine, London SW7 2AY, UK,

and Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523

Received October 24, 1995^X

Condensation of the aryllithium reagents, prepared from the bromides 10 and 11 and tert-

butyllithium, with lactone 19 and acid-catalyzed spirocyclization gave the papulacandin spiroketals

14 and 15. Subsequent protection using di-tert-butylsilyl bis(trifluoromethanesulfonate) gave the

diols 31 and 30. Isoleucine (37) was converted using a double Wittig reaction sequence and

propargylation of the intermediate aldehyde 46 into the alkynol 47. Separation of the C-7 epimers

of 47 was achieved using kinetic resolution via Sharpless epoxidation. Both alkynol epimers 53

and 57 were converted into the papulacandin side chain esters 65 and 66 using a hydrozirconation

and palladium(0)-catalyzed coupling sequence. Comparisons of Mosher ester derivatives of 65 and

66 with the Mosher ester derivative of the natural papulacandin side chain and further degradation

were consistent with the stereochemistry of the natural product being 7S,14S. Esterification of

the spiroketals with the mixed anhydride 70 and global deprotection gave papulacandin D (1).

The papulacandins are a group of antifungal antibiotics

unit via a hetero-Diels-Alder reaction. Friesen^9-11and

Beau^12,13have independently reported the palladium(0)-

catalyzed coupling of (tributylstannyl)glucal derivatives

with aryl bromides and subsequent oxidative spirocy-

clization as a key strategy. Schmidt¹⁴has reported the

elaboration of the papulacandin tricycle via the homolo-

gation of 2,3,4,5,6-penta-O-benzyl-^D-glucose. Finally,

ourselves,^15-17Bihovsky,¹⁸and Czernecki¹⁹have each

independently reported a concise approach to the papu-

lacandin D spirocycle. This methodology utilizes the

condensation of an aryl anion with a suitably protected

gluconolactone to yield, on acification, the 1,7-dioxaspiro-

[5.4]decane unit of papulacandin D (1). Herein we report

full experimental details for the structural elucidation

and total synthesis of papulacandin D (1) previously

reported in communication format.^16,17

We considered that papulacandin D (1) should be

obtained on the selective O-3′-esterification of the spiro-

ketal 2 using the fatty acid 5. In turn, spiroketal 2

should be easy to synthesise from the condensation of

the gluconolactone derivative 3 and the aryl bromide 4.

We have utilized related carbanion-lactone condensation

chemistry in other approaches to spiroketal arrays.^20-23

The fatty acid 5 should be available from isoleucine (7)

via sequential Wittig olefination reactions, or equivalent

extracted from the fermentation broth of the fungus

Papularia spherosperma.¹This family of compounds

shows potent activity against fungi and yeasts such as

Candida albicans, Candida tropicalis, and Microsporum

canis¹among others.^2-4Such opportunistic fungal infec-

tions are responsible for increased morbidity and mortal-

ity among AIDS and other immunocompromised pa-

tients.⁵Recently a related compound, L-687,781,⁶has

been shown to be effective in treating Pneumocystis

carinii-induced pneumonia, a life threatening secondary

fungal infection acquired by AIDS patients. The papu-

lacandins antifungal activity stems from their ability to

inhibit 1,3-â-^D-glucan synthase, an enzyme crucial for the

construction of fungal cell walls. Since eukaryotic sys-

tems do not utilize 1,3-â-^D-glucans, the papulacandins

are important lead compounds for the development of

novel antifungal drugs.^2-4Structurally papulacandin D

(1) is a 1,7-dioxaspiro[5.4]decane derivative containing

a glucose residue. The O-3′ hydroxyl of the glucose

moiety is esterified with a branched C₁₈tetraunsaturated

fatty acyl side chain. Neither the relative nor absolute

configuration of the C-7′′ hydroxyl nor the C-14′′ methyl

groups of the acyl side chain were established by the

group at Ciba Geigy.⁷We have undertaken a total

synthesis of papulacandin D (1) in order to resolve these

stereochemical ambiguities and to provide general meth-

odology for the synthesis of analogs.

(7) Traxler, P.; Fritz, H.; Fuhrer, H.; Richter, W. J . J . Antibiot. 1980,

33, 967.

(8) Danishefsky, S.; Philips, G.; Ciufolini, M. Carbohydr. Res. 1987,

171, 317.

(9) Friesen, R. W.; Sturino, C. F. J . Org. Chem. 1990, 55, 5808.

(10) Friesen, R. W.; Loo, R. W.; Sturino, C. F. Can. J . Chem. 1994,

72, 1262.

Several methods for the elaboration of the tricyclic

spiroketal nucleus of papulacandin D (1) have been

reported. Danishefsky⁸prepared the racemic-spiroketal

(11) Friesen, R. W.; Daljeet, A. K. Tetrahedron Lett. 1990, 31, 6133.

(12) Dubois, E.; Beau, J .-M. Tetrahedron Lett. 1990, 31, 5165.

(13) Dubois, E.; Beau, J .-M. Carbohydr. Res. 1992, 223, 157.

(14) Schmidt, R. R.; Frick, W. Tetrahedron 1988, 44, 7163.

(15) (a) Barrett, A. G. M.; Pen˜a, M.; Willardsen, J . A. In Recent

Advances in the Chemistry of Anti-Infective Agents; Bentley, P. H.,

Ponsford, R., Eds.; The Royal Society of Chemistry: London, 1993; pp

234-248. (b) Barrett, A. G. M.; Dhanak, D.; Lebold, S. A.; Pen˜a, M.;

Pilipauskas, D. Pest. Sci. 1991, 31, 581.

^†Imperial College.

^‡Colorado State University.

^XAbstract published in Advance ACS Abstracts, J anuary 15, 1996.

(1) Traxler, P.; Gruner, J .; Auden, J . A. L. J . Antibiot. 1977, 30,

289.

(2) Pe´rez, P.; Varona, R.; Garcia-Acha, I.; Dura´n, A. FEBS Lett.

1981, 129, 249.

(3) Varona, R.; Pe´rez, P.; Dura´n, A. FEMS Microbiol. Lett. 1983,

20, 243.

(16) Barrett, A. G. M.; Pen˜a, M.; Willardsen, J . A. J . Chem. Soc.,

Chem. Commun. 1995, 1145.

(4) Baguley, B. C.; Rommele, G.; Gruner, J .; Wehrli, W. Eur. J .

Biochem. 1979, 97, 345.

(5) Debono, M.; Gordee, R. S. Annu. Rev. Microbiol. 1994, 48, 471.

(6) Schmatz, D. M.; Romancheck, M. A.; Pittarelli, L. A.; Schwartz,

R. E.; Fromtling, R. A.; Nollstadt, K. H.; Vanmiddlesworth, F. L.;

Wilson, K. E.; Turner, M. J . Proc. Natl. Acad. Sci. U.S.A. 1990, 87,

5950.

(17) Barrett, A. G. M.; Pen˜a, M.; Willardsen, J . A. J . Chem. Soc.,

Chem. Commun. 1995, 1147.

(18) Rosenblum, S. B.; Bihovsky, R. J . Am. Chem. Soc. 1990, 112,

2746.

(19) Czernecki, S.; Perlat, M.-C. J . Org. Chem. 1991, 56, 6289.

(20) Attwood, S. V.; Barrett, A. G. M.; Florent, J .-C. J . Chem. Soc.,

Chem. Commun. 1981, 556.

Synthesis of the Antifungal Agent Papulacandin D

J . Org. Chem., Vol. 61, No. 3, 1996 1083

Ch a r t 1

Sch em e 1^a,b

yield (Scheme 2). It is reasonable to assume that the

spirocyclization reaction was reversible and therefore

subject to thermodynamic control via the anomeric ef-

fect^26,27thereby providing a single spirane stereoisomer,

albeit in modest yield. In the light of this successful

result, the synthesis was repeated with the tris(tert-

butyldimethylsilyl)-protected aryl bromide 10. tert-Bu-

tyldimethylsilylation of the diphenol 8 followed by re-

duction, electrophilic bromination, and further silyl

protection gave the aryl bromide 10. Again, lithium-

bromine exchange of bromide 10 with tert-butyllithium

at -78 °C followed by addition to the protected glucono-

lactone 19 and subsequent acidification produced the

corresponding spiroketal. As before, this was conve-

niently isolated as its tetraacetate derivative 17 in 34%

yield (Scheme 2). It was also observed that chilling (solid

CO₂) the cannula used to transfer the aryllithium reagent

to the lactone 19 improved the yield of the spiroketal 17

to 45%. If the aryllithium reagent was allowed to warm

above -78 °C, a major byproduct was produced which

has spectral properties (¹H NMR and MS) consistent with

the silane 20.

a

Reagents and Conditions: (i) CH₃I, K₂CO₃, acetone or R₃SiCl,

imidazole, DMAP, DMF; (ii) LiAlH₄, Et₂O; (iii) NBS, CCl₄; (iv)

b

TBSCl, imidazole, DMAP. In all structures TMS ) Me₃Si, TES

) Et₃Si, TBS ) t-BuMe₂Si, TIPS ) i-Pr₃Si.

homologation processes, the intermediacy of the triene

6 and organopalladium-catalyzed coupling with a â-stan-

nylacrylate ester (X ) Br or I, etc.) or â-bromoacrylate

ester (X ) SnMe₃or ZrCp₂Cl, etc.). Such an approach

has the advantage that the synthesis can be readily

adapted to any of the four possible C-7′′,C-14′′ stereo-

isomers.

Syn th esis of P a p u la ca n d in D Sp ir ok eta l Ar r a ys

As a model study, methyl 3,5-dihydroxybenzoate (8)

was protected as its dimethyl ether which, after reduction

with lithium aluminum hydride and electrophilic bromi-

nation,²⁴could be transformed to the desired benzylic silyl

ether 9 (Scheme 1). Treatment of a solution of aryl

bromide 9 in diethyl ether, with tert-butyllithium at -78

°C, followed by addition of the resultant solution to a

precooled (-78 °C) solution of gluconolactone 19²⁵in

diethyl ether, resulted in a nucleophilic addition. The

intermediate, presumably 12, was treated with an acidic

ion-exchange resin which induced spirocyclization giving

the tetraol 13. Due to difficulties in isolation, the crude

reaction mixture was treated with acetic anhydride and

pyridine to produce the tetraacetate derivative 16 in 44%

The tetraacetate 17 and all other spiroketals were

1

shown to be the correct anomers by analysis of their H

1

NMR spectra. For example, H-¹H coupling constants

of the glucose ring in spiroketal 17 were particularly

diagnostic. The key coupling constants (J _2,3) 9.9, J _3,4

) 9.8, and, J _4,5) 10.0 Hz) were consistent with a chair

conformation (J _2-3∼ J _3-4∼ J _4-5∼ 9.9 Hz). If spiroketal

17 was the opposite anomer, a distorted chair conforma-

tion would have resulted with different coupling con-

stants (J _2-3∼ 7.5 Hz, J _3-4∼ 8.4 Hz, J _4-5∼ 9.5 Hz).¹²

With a route to the spiroketal carbon skeleton in place,

attention was turned to the problem of selective esteri-

(21) Attwood, S. V.; Barrett, A. G. M.; Carr, R. A. E.; Richardson,

G. J . Chem. Soc., Chem. Commun. 1986, 479.

(22) Barrett, A. G. M.; Carr, R. A. E.; Attwood, S. V.; Richardson,

G.; Walshe, N. D. A. J . Org. Chem. 1986, 51, 4840.

(23) Barrett, A. G. M.; Raynham, T. M. Tetrahedron Lett. 1987, 28,

5615.

(26) Kirby, A. J . The Anomeric Effect and Related Stereoelectronic

Effects at Oxygen; Springer-Verlag: New York, 1983.

(27) Deslongchamps, P. Stereoelectronic Effects in Organic Chem-

istry; Pergamon: Toronto, 1983; Chapter 2.

(24) Chapman, N. B.; Williams, J . F. A. J . Chem. Soc. 1952, 5044.

(25) Horton, D.; Priebe, W. Carbohydr. Res. 1981, 94, 27.

1084 J . Org. Chem., Vol. 61, No. 3, 1996

Barrett et al.

Sch em e 2^a

Sch em e 4^a

a

Reagents and Conditions: (i) NaOMe, MeOH; (ii) (ⁱPr₂)SiCl]₂O,

pyridine.

Sch em e 5^a

a

Reagents and Conditions: (i) tert-BuLi, Et₂O, -78 °C; (ii) 19,

Et₂O, -78 °C; (iii) Amberlite IR-120 (Plus), MeOH; (iv) Ac₂O,

pyridine.

Sch em e 3^a

a

Reagents and Conditions: (i) Ac₂O, pyridine, 94%.

gave the spiroketal tetraol 15. Again, isolation proved

easier after conversion of the crude tetraol 15 into the

tetraacetate 18. Again only the required anomer was

isolated albeit in only modest yield (34%). Zemplen

methanolysis and condensation of the tetraol 15 with

1,1,3,3-tetraisopropyl-1,3-dichlorodisiloxane in pyridine

gave the protected spiroketal 23 in 71% yield (Scheme

4). As proof of structure, acetylation of 23 with acetic

anhydride in pyridine gave diacetate 25. ¹H NMR

analysis of 25 showed a large downfield shift of the C-2

and C-3 hydrogens indicating that the C-2,3 diol unit had

indeed been esterified and therefore the 4,6-diol unit was

indeed protected as the disiloxane unit depicted (Scheme

5). Upon dissolving diol 23 in pyridine and acetic

anhydride, TLC showed the rapid formation of a monoac-

etate and this was slowly converted into the less polar

diacetate 25. Isolation of the intermediate confirmed its

structure as the undesired O-2′ monoacetate 24. In

addition, reaction of the diol 23 with cinnamic acid, 2,4,6-

trichlorobenzoyl chloride,³⁴and triethylamine gave the

O-2′ monocinnamate ester 28 and a minor monoester

tentatively assigned as the O-3′ monocinnamate ester 27

(81%, 10:1) (Scheme 6). Clearly, monoesterification of

diol 23 proceeded with the undesired regioselectivity.

Silylation of diol 23 with triethylsilyl trifluoromethane-

sulfonate and pyridine gave only the O-2′ protected silyl

ether 29 (84%, Scheme 7). Unfortunately, attempted

cinnamoylation of 29 using cinnamoyl 2,4,6-trichloroben-

zoyl mixed anhydride (26) was unsuccessful and only

resulted in recovery of starting material. Presumably,

the globally protected spiroketal alcohol 29 was just too

hindered. The use of spiroketals 22 and 23 were aban-

doned, and alternative protection was investigated.

Zemplen methanolysis of tetraacetate 18 and conden-

sation with di-tert-butylsilyl bis(trifluoromethanesul-

fonate)^35,36and 2,6-lutidine gave spiroketal 30 (85%,

Scheme 8). Reaction of diol 30 with acetic anhydride and

a

Reagents and Conditions: (i) NaOMe, MeOH; Amberlite IR

120 (H⁺); (ii) PhCHO, ZnCl₂, 0-95%.

fication of the C-3′ hydroxyl of the glucose moiety.

Protection of the 4,6-diol as the benzylidene acetal and

subsequent monoesterification seemed the obvious choice.

Methanolysis of tetraacetate 17 gave the corresponding

crude tetraol 14 which was directly condensed with

benzaldehyde in the presence of zinc chloride to provide

the benzylidene acetal 21 (Scheme 3). Unfortunately,

formation of the acetal 21 was capricious (0-95%) and

proceeded with partial but variable desilylation. At-

tempts to convert the crude tetraol 14 into the corre-

sponding acetals with anisaldehyde,²⁸2,4-dimethoxyben-

zaldehyde,²⁹or 4-methoxyacetophenone³⁰also proceeded

in variable yet low yields. Saponification of the tetraac-

etate 17 gave the crude tetraol 14 which was directly

condensed with 1,1,3,3-tetraisopropyl-1,3-dichlorodisi-

loxane.^{31,32 1}H NMR spectroscopy of the crude reaction

mixture was consistent with partial de-tert-butylsilyla-

tion, and chromatography gave a spiroketal tentatively

assigned as the adduct 22 in only modest yield (50%). It

is clear from these results that the Zemplen methanolysis

step was the source of the trouble rather than acid-

mediated de-tert-butylsilylation during acetal formation.

In order to alleviate this problem, more robust phenol

protection was examined.

Methyl 3,5-dihydroxybenzoate (8) was protected as the

bis(triisopropylsilyl) ether, reduced, brominated, and

further protected as the tert-butyldimethylsilyl ether to

yield 11. Spirocyclization was carried out exactly as

described previously (Scheme 2). Thus lithium-bromine

exchange³³of the aryl bromide 11 with tert-butyllithium

at -78 °C, addition to the lactone 19, and acidification

(28) Kloosterman, M.; Slaghek, T.; Hermans, J . P. G.; Van Boom,

J . H. Recl. J . R. Neth. Chem. Soc. 1984, 103, 355.

(29) Smith, M.; Rammler, D. H.; Goldberg, I. H.; Khorana, J . J . Am.

Chem. Soc. 1962, 84, 430.

(30) Lipshutz, B.; Morey, M. C. J . Org. Chem. 1981, 46, 2419.

(31) Oltvoort, J . J .; Kloosterman, M.; Van Bloom, J . H. Recl. J . R.

Neth. Chem. Soc. 1983, 102, 501.

(33) Purham, W. E.; Sayed, Y.; J ones, L. D. J . Org. Chem. 1974, 39,

2053.

(34) Inanaga, J .; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.

Bull. Chem. Soc. J pn. 1979, 52, 1989.

(32) van Boeckel, C. A. A.; van Boom, J . H. Tetrahedron 1985, 41,

4545, 4557.

(35) Corey, E. J .; Hopkins, P. B. Tetrahedron Lett. 1982, 23, 4871.

(36) Trost, B. M., Caldwell, C. D. Tetrahedron Lett. 1981, 22, 4999.

Synthesis of the Antifungal Agent Papulacandin D

J . Org. Chem., Vol. 61, No. 3, 1996 1085

Sch em e 6

Sch em e 9^a

a

Reagents and Conditions: (i) NaNO₂, HCl, H₂O, 0 °C, 78 %;

(ii) LiAlH₄, Et₂O, 80%; (iii) (a) TsCl, pyridine, (b) LiBr, acetone,

81%; (iv) (a) Mg, THF, (b) Fe(CO)₅, THF, AcOH; (v) trans-

(Li)CHdCH(TMS), THF, -78 °C; (vi) (a) PhSCl, Et₃N, Et₂O, 0 °C,

(b) AgNO₃, CH₃CN, H₂O, 62% (from bromide); (vii)

Ph₃PdC(CH₃)CO₂Et, CH₂Cl₂, 85%, 92:8 (E:Z).

Sch em e 7^a

synthesis and also overcame the problems associated

with partial de-tert-butylsilylation on Zemplen metha-

nolysis of 17 to regenerate 14. With this modification,

the tetraol 14, directly from the spirocyclization reaction,

was allowed to react with di-tert-butylsilyl bis(trifluo-

romethanesulfonate)^35,36and 2,6-lutidine to produce the

spiroketal 31 (81%). In contrast to diol 30, cinnamoyla-

tion of diol 31 proceeded with low regioselectivity and

gave monoesters 35 and 36 (1:1). It is clear from these

results that spiroketals 21, 30, and 31 should be suitable

precusors for conversion into papulacandin D (1).

a

Reagents and Conditions: (i) TESOTf, pyridine, -10 °C, 84%.

Sch em e 8^a

Syn th esis a n d Ster eoch em ica l Assign m en t of th e

P a p u la ca n d in Sid e Ch a in

We initially sought to prepare the papulacandin D

carboxylic acid with the 14S-stereochemistry since it is

reasonable to speculate³⁷that L-isoleucine is the biosyn-

thetic precusor for this unit of the natural product.

Therefore, ^L-isoleucine (37) was converted into the alde-

hyde 40 via the known (S)-methylpentanol (38),³⁸toluene-

4-sulfonylation, S_N2 displacement using lithium bromide,

and carbonylation of the Grignard reagent derived from

bromide 39 (Scheme 9). Subsequent addition of (E)-1-

lithio-2-(trimethylsilyl)ethylene³⁹gave the allylic alcohol

41 which was converted into the enal 42 on sequential

reaction with phenylsulfenyl chloride and silver nitrate.

This transformation, which involves an allyl sulfenate

to allyl sulfoxide [2,3] sigmatropic rearrangement, silyl-

Pummerer rearrangement, and silver nitrate-mediated

hydrolysis, is modeled upon chemistry previously pub-

lished by Parsons.⁴⁰Aldehyde 42 was treated with (car-

bethoxyethylidene)triphenylphosphorane to yield the di-

ene ester 43. On a large scale, ester 43 was more conven-

iently prepared from alcohol 38 via reaction of the derived

4-toluenesulfonate with potassium cyanide followed by

DIBAL-H reduction (Scheme 10). The resultant alde-

hyde 40 was homologated by reaction with (carbethoxy-

a

Reagents and Conditions: (i) (t-Bu)₂Si(OTf)₂, 2,6-lutidine,

CH₂Cl₂, 0 °C; (ii) 26, DMAP, DMF; (iii) Ac₂O, pyridine, 89%.

pyridine yielded the corresponding diacetate 32 with a

spectroscopic signature that confirmed the constitution

of 30. Esterification of diol 30 with anhydride 26

proceeded smoothly in DMF at 25 °C to give both the O-3′

33 and O-2′ 34 esters (67%, 6.7:1). Clearly, protection

as the silylene-spiroketal 30, and esterification resulted

in formation of the correct papulacandin monoester.

At this point in time the δ-lactone to spiroketal

condensation reaction was modified, and this allowed for

the isolation of the spiroketal tetraols 14 and 15 directly

without the need for tetraacetylation and subsequent

Zemplen methanolysis. Clearly, this shortened this

methylene)triphenylphosphorane yielding

a

readily

separable mixture of isomeric esters 45 (E:Z ) 98:2).

(37) Cane, D. E.; Laing, T.-C.; Kaplan, L.; Nallin, M. K.; Schulman,

M. D.; Hensens, O. D.; Douglas, A. W.; Albers-Scho¨nberger, G. J . Am.

Chem. Soc. 1983, 105, 4110.

(38) Koppenhoefer, B.; Weber, R.; Schurig, V. Synthesis 1982, 316.

(39) Cunico, R. F.; Clayton, F. J . J . Org. Chem. 1976, 41, 1480.

(40) Cutting, I.; Parsons, P. J . Tetrahedron Lett. 1981, 22, 2021.

1086 J . Org. Chem., Vol. 61, No. 3, 1996

Barrett et al.

Sch em e 10^a

coupled with methyl (3E)-(tributylstanyl)acrylate in the

presence of bis(triphenylphosphine)palladium dichloride

in DMF solution. The reaction mixture instantaneously

turned black. Chromatography after 18 h at 25 °C gave

the tetraene ester 50 in low and variable overall yield

(<30%). In consequence of these failings, an alternative

method was examined. The vinyl zirconocene, obtained

from hydrozirconation of alkyne 49 was allowed to react

with zinc chloride⁴⁵to produce the corresponding vinyl

zinc reagent. Without isolation this was treated with

methyl (3E)-bromoacrylate⁴⁶in the presence of tetrakis-

(triphenylphosphine)palladium to provide the diene ester

51 in superior yield (64%). In this reaction it was not

clear whether the transmetalation reaction (Zr f Zn) was

actually necessary, thus an attempt was made to couple

the vinyl zirconocene intermediate directly. Hydrozir-

conation of alkyne 49 and direct coupling with methyl

(3E)-bromoacrylate in the presence of the palladium(0)

catalyst derived from bis(triphenylphosphine)palladium

dichloride and DIBAL-H⁴⁷gave the tetraene ester 51.

Much to our delight this was obtained in a superior 82%

yield (Scheme 11).

a

Reagents and Conditions: (i) TsCl, pyridine; (ii) KCN, 18-

crown-6, THF, 67 °C, 80% (two steps); (iii) DIBAL-H, Et₂O, -78

°C; (iv) Ph₃PdCHCO₂Et, CH₂Cl₂, 85% (two steps), 98:2 (E:Z); (v)

DIBAL-H, Et₂O, -78 °C, 95%; (vi) PCC, CH₂Cl₂, 80%; (vii)

Ph₃PdC(CH₃)CO₂Et, CH₂Cl₂, 85%, 92:8 (E:Z).

Sch em e 11^a

It is clear from these results that alkyne hydrometa-

lation and palladium(0)-catalyzed coupling is a secure

strategy to assemble the delicate tetraene ester unit of

the papulacandins. There remain, however, stereochem-

ical ambiguities in structure that need to be resolved. In

addition, the current synthesis gave rise to an insepa-

rable mixture of C-7 epimers. We considered that the

C-7 stereochemistry could be defined via asymmetric

propynylation of aldehyde 46. Unfortunately, condensa-

tion of the aldehyde 46 with chiral allenylborane re-

agents⁴⁸were only marginally successful (<62% de).

Since the actual stereochemistry of the papulacandin side

chain needed to be elucidated, it was essential to obtain

the tetraene esters 50/51 in very high diastereoisomeric

purity. Therefore, with such modest selectivities, the use

of chiral allenylborane reagents was abandoned.

Several derivatives of the alcohol 47 were prepared so

as to allow the separation of the two diastereoisomers.

Of the esters examined only the (R)-O-methylmandelates

were amenable to chromatographic separation. Thus

reaction of alcohol 47 with (R)-O-methylmandelic acid,

pyridine, and trifluoromethanesulfonic anhydride⁴⁹in the

presence of 4-(N,N-dimethylamino)pyridine gave the

diastereoisomeric esters 55 and 56 (30%). These deriva-

tives were separated by chromatography in very modest

yield. Unfortunately, the separation was not convenient

for large scale use and, additionally, the esterification

reaction proceeded with partial racemization of the (R)-

O-methylmandelic acid.⁵⁰In consequence, the diastereo-

isomeric enrichment of the C-4 epimers of alcohol 47 was

incomplete (ds < 89%) and this method of epimer

separation was abandoned.

a

Reagents and Conditions: (i) DIBAL-H, Et₂O, -78 °C, 94%;

(ii) MnO₂, CH₂Cl₂, 95%; (iii) Zn dust, propargyl bromide, THF, 0

°C, 95%; (iv) TBSCl, imidazole, DMAP, CH₂Cl₂, 85%; (v) TESCl,

imidazole, DMAP, CH₂Cl₂, 95%; (vi) (a) Cp₂Zr(H)Cl, THF, (b) I₂,

THF, (c) (E)-Bu₃SnCHdCHCO₂Me, (CH₃CN)₂PdCl₂, THF, 30%;

(vii) Cp₂Zr(H)Cl, (E)-BrCHdCHCO₂Me, [(Ph₃P)₂PdCl₂, DIBAL-H],

THF, 82%.

DIBAL-H reduction of the pure trans-unsaturated ester

45 to the corresponding allylic alcohol, followed by

reoxidation to the aldehyde 42 and condensation with

(carbethoxyethylidene)triphenylphosphorane gave the di-

ene ester 43 which was chromatographically separated

from trace amounts of the Z-isomer (∼8%).

Reduction of the diene ester 43 and reoxidation of the

resultant allylic alcohol yielded the diene aldehyde 46

(Scheme 11). Addition of the diene aldehyde 46 to a

mixture of activated zinc dust and propargyl bromide,⁴¹

at reduced temperatures, gave the homopropargylic

alcohol 47 as an inseparable mixture of C-4 diastereo-

isomers. In addition, this alkyne was contaminated with

variable amounts (2-8%) of the isomeric allenyl alcohols.

However, these allene contaminants were easily removed

by chromatography following tert-butyldimethylsilyla-

tion⁴²to produce silyl ether 48. In the same way alkyne

was converted into the triethylsilyl ether 49. Although

both 48 and 49 each consisted of two inseparable dias-

tereoisomers, these were indistinguishable by normal

spectroscopic techniques. Hydrozirconation^43,44of alkyne

48 followed by iodine-metal exchange produced the

corresponding unstable vinyl iodide. This was not puri-

fied but, after filtration through alumina, was directly

As an alternative strategy, kinetic resolution under

Sharpless epoxidation conditions^51-54was examined.

(45) Hegedus, L. S. Transition Metals in the Synthesis of Complex

Organic Molecules; University Science Books: Mill Valley, 1994; p 91.

(46) Bowden, K. Can. J . Chem. 1966, 44, 661.

(47) Negishi, E.-I.; Takahashi, T.; Baba, S.; Van Horn, V.; Okukado,

N. J . Am. Chem. Soc. 1987, 109, 2393 and references therein.

(48) Corey, E. J .; Yu, C.-M.; Kim, S. S. J . Am. Chem. Soc. 1989,

111, 5495.

(41) Friedrich, L. E.; de Vera, N.; Hamilton, M. Synth. Commun.

1980, 10, 637.

(42) Corey, E. J .; Venkateswarlu, A. J . Am. Chem. Soc. 1972, 94,

6190.

(43) Hart, D. W.; Blackburn, T. F.; Schwartz, J . J . Am. Chem. Soc.

1975, 97, 679.

(44) Buchwald, S. L.; LaMarie, S. J .; Nielson, R. B.; Watson, B. T.;

King, S. M. Tetrahedron Lett. 1987, 28, 3895.

(49) Quagliato, D. A.; Humber, L. G.; J oslyn, B. L.; Soil, R. M.;

Browne, E. M. C.; Shaw, C. C.; Van Engen, D. Bioorg. Med. Chem.

Lett. 1991, 1, 39.

(50) Trost, B. M.; Belletire, J . L.; Godleski, S.; McDougal, P. G.;

Balkovec, J . M.; Baldwin, J . J .; Christy, M. E.; Ponticello, G. S.; Varga,

S. L.; Springer, J . P. J . Org. Chem. 1986, 51, 2370.

Synthesis of the Antifungal Agent Papulacandin D

J . Org. Chem., Vol. 61, No. 3, 1996 1087

Sch em e 12^a

Sch em e 13^a

a

Reagents and Conditions: (i) Ti(O-i-Pr)₄, D-(-)-DIPT, t-

BuOOH, 4 Å mol sieves, CH₂Cl₂, -50 °C, 45% alcohol and 14%

epoxide; (ii) TESCl, imidazole, DMAP, CH₂Cl₂, 94%; (iii) Cp₂Zr(H)Cl,

[(Ph₃P)₂PdCl₂+ DIBAL-H], methyl 3-bromo-E-acrylate, THF, 70%.

Thus the allylic alcohol 47 was allowed to react with

titanium tetraisopropoxide, ^D-(-)-diisopropyl tartrate,

and tert-butyl hydroperoxide in dichloromethane at -50

°C for 3 days. This led to the recovery of alcohol 53 (45%,

90% of theory) along with of the corresponding epoxide

52 (14%, 28% of theory) (Scheme 12). The diastereoiso-

meric purity of the alcohol 53 was determined by conver-

sion into the (R)-Mosher ester^55,56and ¹H NMR and

HPLC analysis. Both these analyses were consistent

with alcohol 53 having a diastereoisomeric ratio of 96:4.

Sharpless kinetic resolution using ^L-(+)-diisopropyl tar-

trate gave the corresponding epimeric alcohol 57. Again

Mosher ester analysis was consistent with a diastereo-

isomeric ratio of at least 96:4. Both alcohols 53 and 57

were separately converted into the corresponding tet-

raene esters 54 and 58 via triethylsilylation, hydrozir-

conation, and palladium(0)-catalyzed coupling with meth-

yl (3E)-bromoacrylate.

a

Reagents and Conditions: (i) S-(+)-PhC(OMe)(CF₃)COCl,

DMAP, CH₂Cl₂, 93%; (ii) O₃, -78 °C, MeOH; Me₂S, -78 °C to 25

°C; (iii) (2,4-dinitrophenyl)hydrazine, H₂SO₄, 63% (both steps).

Sch em e 14^a

a

Reagents and Conditions: (i) TBAF, THF, 0 °C, quant; (ii)

S-(+)-PhC(OMe)(CF₃)COCl, DMAP, CH₂Cl₂, 89%; (iii) O₃, -78 °C,

MeOH; Me₂S, -78 °C to 25 °C; (iv) (2,4-dinitrophenyl)hydrazine,

H₂SO₄, 65% (both steps).

ma and chromatography^7,57gave a crude fraction con-

taining several papulacandins. Without further separa-

tion, this was subject to saponification (LiOH) and

methylation (CH₂N₂) to produce the authentic ester 59.^1,7

This was converted into the (R)-Mosher ester 60 (Scheme

13). ¹H NMR and HPLC analyses showed this compound

to consist of only one diastereoisomer.^55,56In parallel,

the synthetic tetraene esters 54 and 58 were converted

into the corresponding (R)-Mosher esters 62 and 63 via

tetrabutylammonium fluoride-mediated desilylation and

esterification using (S)-R-methoxy-R-(trifluoromethyl)-

phenylacetyl chloride and DMAP (Scheme 14). ¹H NMR

and HPLC analyses of each of these compounds was

At this point we sought to establish the stereochem-

istry of papulacandin by correlation of the synthetic

esters with the natural side chain obtained by degrada-

tion. Since we had only very limited access to authentic

papulacandin D (1), we were obliged to obtain additional

materials by reisolation. Fermentation of P. spherosper-

(51) Hanson, R. M.; Sharpless, K. B. J . Org. Chem. 1986, 51, 1922.

(52) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko, S. Y.; Masamune,

H.; Sharpless, K. B. J . Am. Chem. Soc. 1987, 109, 5765.

(53) Katsuki, T.; Sharpless, K. B. J . Am. Chem. Soc. 1980, 102, 5974.

(54) Martin, V. S.; Woodward, S. S.; Katsuki, T.; Yamada, Y.; Ikeda,

M.; Sharpless, K. B. J . Am. Chem. Soc. 1981, 103, 6237.

(55) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512.

(56) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,

2543.

(57) Traxler, P.; Gruner J .; Nu¨esch, J . Ger. Offen. 1976, 2609611.

1088 J . Org. Chem., Vol. 61, No. 3, 1996

Barrett et al.

stereochemistry of the R-methoxy-R-(trifluoromethyl)-

phenylacetic acid is known, detailed analysis of ¹H NMR

spectra is useful in the assignment of the stereochemistry

1

of secondary alcohols. The H NMR spectra for Mosher

esters 67 and 68 are summarized in Table 1. In ester

67 H-1, H-3a, and H-3b are all at lower field and 5-CH₃,

H-6, H-7, H-8, H-9a, and H-9b are all at higher field than

1

the corresponding resonances for ester 68. The H NMR

spectra for Mosher esters 62 and 63 are given in Table

2. In ester 62 H-2, H-3, H-4, and H-5 are all at lower

field and 8-CH₃, H-10, H-12a, and H-12b are all at higher

field than the corresponding resonances for ester 63. All

these facts are consistent with the ester 54 derived using

(^D)-diisopropyl tartrate having the 7S-stereochemistry

and the ester 58 derived using (^L)-diisopropyl tartrate

having the 7R-stereochemistry. All these facts are in full

accord with the stereochemical assignments of both

synthetic diesters 62 and 63 and the determination of

the natural C-7 stereochemistry as S.

F igu r e 1.

The C-14 stereochemistry of the natural ester 60 was

established to be S by further degradation. Thus ozo-

nolysis of 60 and condensation of the resultant aldehyde

with (2,4-dinitrophenyl)hydrazine gave the hydrazone

derivative 61 {[R_D] ) +13.2 (c ) 0.29 in CHCl₃)}. This

substance was identical in all respects with an authentic

sample {[R_D] ) +12.6 (c ) 0.30 in CHCl₃)} prepared from

the aldehyde 40 derived from ^L-isoleucine (37). In

addition, ozonolysis of the synthetic diesters 62 and 63

and condensation of the resultant aldehyde with (2,4-

dinitrophenyl)hydrazine gave exactly the same hydra-

zone derivative 64. Finally, circular dichroic studies

showed that the natural side chain 59 and the synthetic

side chain 65 were identical. Therefore, the stereochem-

istry of the papulacandin fatty acid side chain is 7S,14S.

F igu r e 2.

consistent with high diastereoisomeric purity (>98%). In

addition both compounds were very clearly distinguish-

able by NMR and base-line separable by HPLC. Finally,

one of the diesters 62 was completely identical with the

diester 60 derived from degradation of the natural

papulacandins. On this basis it is reasonable to set the

papulacandin side chain stereochemistry as 7S.

Com p letion of th e Syn th esis of P a p u la ca n d in

D (1)

It is necessary at this point to comment on the

assignment of stereochemistry of the synthetic diesters

62 and 63; otherwise, the complete determination of

configuration is a fragile house of cards. Kinetic resolu-

tion of 47 via Sharpless epoxidation using ^D-(-)-diiso-

propyl tartrate should proceed with selective epoxidation

of the R-alcohol and selective recovery of the S-epimer

53. Such an expectation is securely based upon the

highly reliable Sharpless model and legions of exam-

ples.^51-54In exactly the same way Sharpless kinetic

resolution using ^L-(+)-diisopropyl tartrate should lead to

recovery of the R-epimer 57. Secondly, the C-7 stereo-

chemical assignments of the two pairs of diesters 67 and

The unsaturated ester 54 was cleanly hydrolyzed to

acid 69 using potassium trimethylsilanolate⁵⁸and con-

verted to the corresponding mixed anhydride 70 with

2,4,6-trichlorobenzoyl chloride³⁴(Scheme 15). Addition

of 70 to a mixture of the spiroketal diol 31 and 4-(di-

methylamino)pyridine suprisingly resulted in the forma-

tion of a 1:1 mixture of O-3′ 71 and O-2′ 72 esters. In

contrast, reaction of the mixed anhydride 70 with the

spiroketal 30 in the presence of DMAP proceeded with

good O-3′ selectivity to give the papulacandin D deriva-

tive 73 (57%) and the corresponding O-2 ester 74 (14%).

Deprotection of ester 73 using tetra-n-butylammonium

fluoride in THF gave crude papulacandin D (1), but

chromatographic separation from the tetra-n-butylam-

monium salts was nontrivial. However tris(dimethy-

lamino)sulfonium difluorotrimethylsilicate⁵⁹was much

more useful. Thus global deprotection of spiroketal 73

using this reagent provided pure papulacandin D (1)

(64%). It is germane at this point to further comment

on issues of protection. Firstly, while spiroketal 21

underwent selective O-3′ esterification using the mixed

1

68, and 62 and 63, were confirmed by analysis of the H

NMR spectra according to the Mosher model.^55,56In this

analysis Mosher esters have a preferred conformation in

which the trifluoromethyl group, carbonyl, and the

hydrogen will be eclipsed (Figures 1 and 2). In this

conformation some hydrogens of the acyl side chain are

juxtaposed with the phenyl ring and others by the

methoxy group of the R-methoxy-R-(trifluoromethyl)-

1

phenylacetic ester. In the H NMR spectrum hydrogen

atoms adjacent to the phenyl substituent will be seen at

higher field than the corresponding hydrogen atoms

adjacent to the methoxy functionality. Since the absolute

(58) Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984, 25, 5831.

(59) Middleton, W. J . Org. Synth. 1985, 64, 221.

Synthesis of the Antifungal Agent Papulacandin D

J . Org. Chem., Vol. 61, No. 3, 1996 1089

Ta ble 1. NMR Sp ectr a for Ester s 67 a n d 68

compound 67 from D-(-)-diisopropyl tartrate compound 68 from L-(+)-diisopropyl tartrate

proton number

chemical shift

multiplicity

chemical shift

multiplicity

1

3

2.02

t, J ) 2.6 Hz

1.93

t, J ) 2.7 Hz

H_3a2.66

H_3a2.54

6.02

6.15

5.68

ddd, J ) 2.6, 8.5, 17.0 Hz

ddd, J ) 2.7, 5.1, 17.1 Hz

d, J ) 10.9 Hz

H_3a2.62

H_3a2.50

6.12-6.25

5.78

multiplet

dt, J ) 6.9, 14 Hz

multiplet

singlet

6

7

8

9

dd, J ) 10.9, 15.0 Hz

dt, J ) 7.0, 15.0 Hz

multiplet

2.10-2.15

1.59

2.05-2.20

1.76

5-Me

singlet

Ta ble 2. NMR Sp ectr a for Ester s 62 a n d 63

compound 63 from L-(+)-diisopropyl tartrate

compound 62 from D-(-)-diisopropyl tartrate

proton number

chemical shift

multiplicity

chemical shift

multiplicity

2

3

4

5

6

5.80

7.25

5.72

5.44-5.50

H_6a2.24

H_6b1.95-2.05

6.14-6.24

5.64

d, J ) 15.4 Hz

5.81

7.30

5.78

5.51

H_6a2.26

H_6b1.94-2.10

6.08

6.19

5.61

d, J ) 15.4 Hz

dd, J ) 11.0, 15.3 Hz

dd, J ) 11.2, 15.1 Hz

multiplet with H₉

dt, J ) 7.3, 14.7 Hz

multiplet with H_13aand H_13b

multiplet with H₁₀

multiplet with H₉

dt, J ) 7.0, 14.0 Hz

multiplet with H_6b

singlet

dd, J ) 11.0, 15.3 Hz

dd, J ) 11.0, 15.2 Hz

dt, J ) 7.2, 14.7 Hz

dd, J ) 7.4, 14.8 Hz

multiplet with H_13aand H_13b

d, J ) 10.9 Hz

9

10

11

12

dd, J ) 10.9, 14.9 Hz

dt, J ) 7.0, 14.4 Hz

multiplet with H_6b

singlet

1.95-2.05

1.58

1.94-2.10

1.46

8-Me

Sch em e 15^a

a

Reagents and Conditions: (i) KOTMS (10 equiv), THF, quant; (ii) 2,4,6-trichlorobenzoyl chloride, Et₃N; (iii) 30 or 31, DMAP; (iv)

TASF, THF, 0 °C, 64%.

anhydride 70, acidic deprotection to remove the ben-

zylidene group resulted in extensive degradation due to

the acid lability of the side chain.¹⁵Secondly, the mixed

anhydride derived from the ester 50 could also be used

in spiroketal monoesterification. However deprotection

to produce papulacandin D (1) was inefficient due to slow

and incomplete cleavage of the side chain tert-butyldim-

ethylsilyl ether. For these reasons, the protecting groups

of choice for papulacandin D (1) synthesis are O-7′′

triethylsilyl, O-4′′,O-6′′-di-tert-butylsilylene, and phenol

tris(triisopropylsilyl).

an authentic sample of the natural product. However,

we observed a specific rotation different from the one

reported for the natural product. Traxler, Gruner, and

Auden^1,57reported an [R]_Dvalue for papulacandin D (1)

of +7 ( 1(MeOH) and +7 ( 1 (c ) 0.250, CHCl₃). In our

hands synthetic 1 was insufficiently soluble in chloroform

to record an [R]_D. In MeOH solution, the synthetic

compound showed [R]_D) +27.5 (c ) 0.245, MeOH) which

is significantly greater than the literature value. Un-

fortunately, we had access to only very limited quantities

of natural 1 (<500 µg), and this has precluded us from

obtaining an accurate rotation. This sample showed [R]_D

) +17 (c ) 0.09, MeOH), but this is clearly of dubious

The synthetic sample of papulacandin D (1) was

spectroscopically and chromatographically identical with

1090 J . Org. Chem., Vol. 61, No. 3, 1996

Barrett et al.

accuracy. Nonetheless, it is believed that an [R]²⁰of

for g10 h or by recrystallization. Zinc dust was activated by

washing with 1 M hydrochloric acid, acetone, and ether,

followed by drying at 110 °C for 6 h.⁶²2,4-Dinitrophenylhy-

drazone derivatives were prepared using aliquots of a solution

of (2,4-dinitrophenyl)hydrazine (5 g) in concentrated sulfuric

acid (25 mL), water (35 mL), and ethanol (125 mL, 95%).

ter t-Bu tyl[(2-br om o-3,5-d im eth oxyben zyl)oxy]d im eth -

ylsila n e (9). 2-Bromo-3,5-dimethoxybenzyl alcohol⁶³(31.0 g,

125.0 mmol) was dissolved in DMF (600 mL) followed by the

addition of tert-butyldimethylsilyl chloride (20.8 g, 0.138 mol)

and imidazole (25.5 g, 0.376 mol). The reaction mixture was

stirred for 18 h at room temperature, poured into water, and

stirred for a further 10 min. After the addition of Et₂O (800

mL), the two layers were separated and the organic phase was

washed with water (5×). After drying the organic phase and

concentrating the solvents, the crude oil was chromatographed

(5% EtOAc in hexanes) to yield 9 (40.5 g, 90%) as a colorless

oil: R_f) (10% EtOAc in hexanes); IR (thin film) 2930, 2856,

1589, 1455, 1329, 1199, 1159, 1077, 1024, 836 cm^-1; ¹H NMR

(CDCl₃, 300 MHz) δ 6.80 (d, 1H, J ) 2.8 Hz), 6.38 (d, 1H, J )

2.8 Hz), 4.71 (s, 2H), 3.84 (s, 3H), 3.79 (s, 3H), 0.95 (s, 9H),

0.11 (s, 6H); ¹³C NMR (CDCl₃, 75 MHz) δ 159.8, 156.1, 142.5,

103.6, 100.6, 98.2, 64.8, 56.2, 55.4, 25.9, 18.3, -5.4; MS (EI)

m/ e 362, 360 (M⁺), 305, 275, 209, 135; HRMS (EI) calcd for

C₁₅H₂₅⁷⁹BrO₃Si: (M^•+), 360.0757; found: (M^•+), 360.0767. Anal.

Calcd for C₁₅H₂₅BrO₃Si: C, 49.86; H, 6.97. Found: C, 50.02;

H, 7.11%.

D

+27.5 is very reasonable given that the specific rotations

for papulacandin A (75), methyl R-^D-glucopyranoside (76),

and methyl R-^D-lactopyranoside (77) are, respectively, 30

( 1 (c ) 0.419, MeOH),^1,57159 (H₂O),⁶⁰and 115 (c ) 1.03,

H₂O).⁶⁰It is clear from 76 and 77 that O-4-(â-D-

galactopyranosylation leads to a decrease in specific

rotation not increase. By analogy the rotation of papu-

lacandin D (1) should not be significantly lower than

papulacandin A (75) but rather higher.

1,1-An h yd r o-1-C-[6-(h yd r oxym et h yl)-2,4-d im et h oxy-

ph en yl]-2,3,4,6-tetr a-O-acetyl-â-^D-glu copyr an ose (16). Bro-

mide 9 (3.6 g, 10.0 mmol) was dissolved in Et₂O (50 mL) and

cooled to -78 °C. tert-Butyllithium (1.7 M in hexanes, 12.35

mL, 2.1 equiv) was added, and the mixture was stirred for 0.5

h. The resultant solution was added, via cannula, to lactone

19²⁵(4.66 g, 10.0 mmol) in Et₂O (50 mL) at -78 °C. The

transfer cannula was maintained at -78 °C with a dry ice

pack. The mixture was stirred for 12 h at -78 °C, before being

warmed up to room temperature, and quenched with water

(10 mL). After the layers were separated, the organic phase

was washed with brine and dried. Filtration and evaporation

gave a crude yellow oil which was dissolved in MeOH (175

mL) and stirred with Amberlite IR 120 (65 g) (the Amberlite

was prewashed with MeOH). After 16 h, the Amberlite was

removed by filtration and the MeOH evaporated. The remain-

ing dark green oil was further evaporated at <1 mm for 5 h

and dissolved in pyridine (40 mL), acetic anhydride (25 mL)

was added, and the mixture was stirred with slight warming

(not exceeding 45 °C) for 3 h. The reaction mixture was added

to water and extracted with Et₂O. After separating the layers,

the organic phase was washed with water (2×) before being

dried. After filtration and evaporation, the crude oil was

chromatographed (50% EtOAc in hexanes) to yield 16 (2.18 g,

44% yield) as a colorless solid: mp 166-168 °C; R_f) 0.36 (50%

EtOAc in hexanes); [R]²⁵_D) +7.4 (c ) 1.47 in CHCl₃); IR (KBr)

2973, 2875, 1752, 1609, 1367, 1227, 1157, 1035 cm^-1; ¹H NMR

(CDCl₃, 400 MHz) δ 6.32 (s, 1H), 6.30 (s, 1H), 5.90 (d, 1H, J )

10.1 Hz), 5.57 (t, 1H, J ) 9.8 Hz), 5.32 (t, 1H, J ) 9.8 Hz),

5.17 (d, 1H, J ) 12.7 Hz), 5.06 (d, 1H, J ) 12.6 Hz), 4.30 (m,

2H), 4.31 (m, 1H), 3.85 (s, 3H), 3.79 (s, 3H), 2.07 (s, 3H), 2.05

(s, 3H), 2.01 (s, 3H), 1.76 (s, 3H); ¹³C NMR (CDCl₃, 101 MHz)

δ 171.2, 170.6, 170.1, 169.6, 163.7, 156.6, 143.8, 115.8, 109.3,

98.6, 97.0, 73.8, 72.6, 70.9, 70.0, 69.0, 62.6, 55.99, 59.96, 21.2,

21.13, 21.10, 20.8; MS (CI) m/ e 497 ([M + H]⁺), 195, 60; HRMS

(CI) m/ e calcd for C₂₃H₂₉O₁₂: ([M + H]⁺), 497.1659; found: ([M

+ H]⁺), 497.1700.

Con clu sion

It is clear from these studies that the full structure of

papulacandin D is represented by 1. The side chain

carboxylic acid 69 was available from ^L-isoleucine (37)

using Wittig reactions, hydrozirconation, and palladium-

(0) coupling to establish the tetraene backbone with

excellent geometric control. Kinetic resolution using

Sharpless asymmetric epoxidation was used to separate

the O-7′′ epimers. The papulacandin spiroketals 14 and

15 were very conveniently prepared albeit in modest

yields from the condensation reactions of lactone 19 with

the aryllithium reagents derived from bromides 10 and

11. Additionally, the derived diol 30 was monoesterified,

using the mixed anhydride 70, to provide, on deprotec-

tion, papulacandin D (1).

Exp er im en ta l Section

All reactions were carried out under a dry argon or nitrogen

atmosphere at ambient temperature unless otherwise stated.

Low reaction temperatures were recorded as bath tempera-

tures. Chromatography was carried out on E. Merck or BDH

silica gel 60, 230-400 mesh ASTM, using flash chromatogra-

phy techniques.⁶¹Analytical thin-layer chromatography (TLC)

was performed on E. Merck precoated silica gel 60 F₂₅₄plates.

Hexanes, dichloromethane (CH₂Cl₂), ethyl acetate (EtOAc),

and diethyl ether (Et₂O) used as eluants were ACS reagent

grade solvent or GPR grade from BDH and redistilled. The

following reaction solvents were purified by distillation: metha-

nol (MeOH) (from Mg, N₂), dimethylformamide (DMF) (from

CaH₂, N₂), dichloromethane (CH₂Cl₂) (from CaH₂, N₂), diethyl

ether (Et₂O) (from Ph₂CO-Na, N₂), and tetrahydrofuran (THF)

(from Ph₂CO-K, N₂). Organic extracts were dried over anhy-

drous magnesium sulfate, filtered, and rotary evaporated at

e50 °C bath temperature; involatile oils were further evapo-

rated at <1 mmHg. Samples for combustion analysis were

purified further by chromatography with rotary evaporation

of the appropriate fraction and further evaporation (e1 mmHg)

Meth yl 3,5-Bis[(ter t-bu tyld im eth ylsilyl)oxy]ben zoa te.

Methyl 3,5-dihydroxybenzoate (8) (27.0 g, 0.160 mol), tert-

butyldimethylsilyl chloride (51.3 g, 0.340 mol), imidazole (22.1

g, 0.330 mol), and 4-(dimethylamino)pyridine (500 mg) in DMF

(300 mL) were stirred at room temperature for 15 h at which

time water (200 mL) and Et₂O (200 mL) were added. The

layers were separated, and the organic phase was washed with

(62) Furniss, B. S.; Hannaford, A. J . P.; Smith, W. G.; Tatchell, A.

R. Vogel’s Textbook of Practical Organic Chemistry, 5th ed.; Longman

Scientific and Technical: London, 1989; p 467.

(60) Collins, P. M. Ed. Carbohydrates; Chapman and Hall: London,

1987; p 312, 362.

(61) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

(63) Noire, P. D.; Frank, R. W. Synthesis 1980, 882.

Synthesis of the Antifungal Agent Papulacandin D

J . Org. Chem., Vol. 61, No. 3, 1996 1091

hydrochloric acid (1 M, 100 mL) and water (100 mL). The

organic phase was dried, filtered, and chromatographed (5%

EtOAc in hexanes) to yield the title compound (68 g, 98%) as

a colorless oil: IR (thin film) 2955, 2931, 2859, 1729, 1590,

glu cop yr a n ose (17). tert-Butyllithium (1.7 M in hexanes,

18.53 mL, 2.1 equiv) was added to bromide 10 (8.4 g, 15.0

mmol) in Et₂O (75 mL) at -78 °C, and the mixture was stirred

for 0.5 h. This solution was added, via cannula, to lactone 19

(7.0 g, 15.0 mmol) in Et₂O (75 mL) at -78 °C. The cannula

was maintained at -78 °C with a dry ice pack. The mixture

was stirred for 12 h at -78 °C before being warmed up to room

temperature and quenched with water (10 mL). The organic

phase was dried, filtered, and evaporated. The resultant

yellow oil was dissolved in MeOH (200 mL) followed by the

addition of Amberlite IR 120 (75 g). After being stirred for 16

h, the Amberlite was removed by filtration and the MeOH

evaporated. The remaining residue was dissolved in pyridine

(50 mL) and Ac₂O (50 mL) and maintained at ambient

temperature for 13 h. The reaction mixture was added to Et₂O

and water and, after the layers were separated, the organic

phase was washed an additional two times with water before

being dried. Filtration, evaporation, and chromatography

(25% EtOAc in hexanes) gave 17 (4.4 g, 45% yield) as a

colorless solid: mp 42-44 °C; [R]²⁵_D) -27.8 (c ) 2.4 in Et₂O);

IR (thin film) 1756, 1600, 1474, 1227, 1035, 965 cm^-1; ¹H NMR

(CDCl₃, 300 MHz) δ 6.24 (d, 1H, J ) 1.7Hz), 6.17 (d, 1H, J )

1.8Hz), 5.82 (d, 1H, J ) 9.9 Hz), 5.52 (app t, 1H, J ) 9.7 Hz),

5.2 (app t, 1H, J ) 9.7 Hz), 5.10, 5.0 (ABq, 1H, J ) 12.7), 4.3

(m, 2H), 4.0 (m, 1H), 2.02 (s, 3H), 2.01 (s, 3H), 1.95 (s, 3H),

1.70 (s, 3H), 1.06 (s, 9H), 0.94 (s, 9H), 0.29 (s, 3H), 0.27 (s,

3H), 0.16 (s, 6H); ¹³C NMR (CDCl₃, 75 MHz) δ 170.8, 170.4,

169.5, 168.9, 158.7, 152.3, 143.5, 118.2, 109.9, 109.0, 104.8,

73.2, 72.4, 71.0, 69.6, 68.5, 62.3, 25.8, 25.6, 20.8, 20.7, 20.2,

18.2, -4.3, -4.4, -4.5; MS (FAB) m/ e 697 ([M + H]⁺), 639,

395, 379, 337, 73; HRMS (FAB) m/ e calcd for C₃₃H₅₃O₁₂Si₂:

([M + H]⁺), 697.3075; found: ([M + H]⁺), 697.3076. Anal.

Calcd for C₃₃H₅₂O₁₂Si₂: C, 56.87; H, 7.52. Found: C, 56.64;

H, 7.59%.

1446, 1341, 1254, 1168, 1030, 1013, 929, 831, 782 cm^-^{1 1}H

;

NMR (CDCl₃, 300 MHz) δ 7.10 (dd, 2H, J ) 2.2, 0.5 Hz), 6.50

(dt, 1H, J ) 2.4, 0.6 Hz), 3.86 (d, 3H, J ) 0.5 Hz), 0.96 (s,

18H), 0.18 (s, 12H); ¹³C NMR (CDCl₃, 75 MHz) δ 166.8, 156.5,

131.8, 116.8, 114.5, 52.1, 25.6, 18.2, -4.5; MS (EI) m/ e 396

(M^•+), 339, 307, 283, 89, 73; HRMS (EI) calcd for C₂₀H₃₆O₄Si₂:

(M^•+), 396.2152; found: (M^•+), 396.2140. Anal. Calcd for

C₂₀H₃₆O₄Si₂: C, 60.55; H, 9.14. Found: C, 60.63; H, 9.19%.

3,5-Bis[(ter t-b u t yld im et h ylsilyl)oxy]b en zyl Alcoh ol.

Methyl 3,5-bis[(tert-butyldimethylsilyl)oxy]benzoate (69 g, 175

mmol) in Et₂O (30 mL) and slowly added to a slurry of lithium

aluminum hydride (7.9 g, 210 mmol) in Et₂O (1.0 L). After

the addition was complete, the mixture was stirred for 1 h prior

to being heated to reflux for 3 h. Upon being cooled in an ice

bath, water (100 mL) was slowly added followed by aqueous

KOH (1.0 M, 50 mL). The resulting slurry was filtered

through Celite, the layers were separated, and the organic

phase was dried. Concentration and chromatography (10%

EtOAc in hexanes) yielded 3,5-bis[(tert-butyldimethylsilyl)oxy]-

benzyl alcohol (52.2 g, 83%) as a viscous oil: R_f) 0.56 (30%

EtOAc in hexanes); IR (thin film) 3328, 2930, 2886, 2858, 1590,

1452, 1361, 1335, 1254, 1164, 1029, 1004, 982, 832, 780 cm^-1

;

¹H NMR (CDCl₃, 400 MHz) δ 6.47 (d, 2H, J ) 2.4 Hz), 6.25 (t,

1H, J ) 2.4 Hz), 4.56 (d, 2H, J ) 6.0 Hz), 1.56 (t, 1H, J ) 6

Hz), 0.98 (s, 18H), 0.19 (s, 12H); ¹³C NMR (CDCl₃, 75 MHz) δ

156.7, 143.1, 111.7, 111.1, 65.0, 25.7, 25.5, 18.1, -4.0, -4.4.

MS (EI) m/ e 368 (M^•+), 311, 255, 133, 73; HRMS (EI) calcd

for C₁₉H₃₆O₃Si₂: (M^•+), 368.2203; found: (M^•+), 368.2205. Anal.

Calcd for C₁₉H₃₆O₃Si₂: C, 61.90; H, 9.84. Found: C, 61.91; H,

9.86%.

2-Br om o-3,5-bis[(ter t-bu tyldim eth ylsilyl)oxy]ben zyl Al-

coh ol. NBS (1.38 g, 7.8 mmol) was added slowly in small

portions to 3,5-bis[(tert-butyldimethylsilyl)oxy]benzyl alcohol

(2.73 g, 7.4 mmol) in CCl₄(25 mL). After the addition was

complete, the reaction mixture was stirred for 3 h and

quenched with water (5 mL). The organic phase was washed

with water (2×) and dried. Filtration and evaporation gave

2-bromo-3,5-bis[(tert-butyldimethylsilyl)oxy]benzyl alcohol as

a yellow oil which was used directly in the next step without

purification: R_f) 0.25 (12% EtOAc in hexanes); IR (thin film)

4,6-O-Ben zyliden e-1,1-an h ydr o-1-C-[6-(h ydr oxym eth yl)-

2,4-bis[(ter t-bu tyld im eth ylsilyl)oxy]p h en yl]-â-^D-glu cop y-

r a n ose (21). Tetraacetate 17 (0.690 g, 1.00 mmol), MeOH

(20 mL), and NaOMe (catalyst) were allowed to react over-

night. The solution was filtered through Amberlite IR 120

with MeOH and evaporated and the yellow residue stirred at

room temperature with benzaldehyde (5 mL) and ZnCl₂(0.1

g) for 2 h and quenched by pouring into H₂O and Et₂O. The

organic phase was dried (MgSO₄), filtered, and evaporated to

leave a yellow oil. Chromatography (50% EtOAc in hexanes)

gave 21 (0.604 g, 98%) as a white solid: mp 105-107 °C; R_f)

0.60 (50% EtOAc in hexanes), [R)_D) +23.2 (c ) 0.25, MeOH);

IR (thin film) 3418, 2930, 2859, 1600, 1473, 1367, 1253, 1163,

1086, 998, 867, 834, 781, 698 cm^-1; ¹H NMR (CDCl₃, 300 MHz)

δ 7.5-7.3 (m, 5H), 6.3 (d, 1H, J ) 2 Hz), 6.21 (d, 1H, J ) 2

Hz), 5.5 (s, 1H), 5.13, 5.0 (ABq, 2H, J ) 12.8 Hz), 4.4 (t, 1H,

J ) 9.1 Hz), 4.3 (dd, 1H, J ) 4.9, 10.3 Hz), 4.1 (m, 2H), 3.65

(m, 2H), 1.03 (s, 9H), 0.95 (s, 9H), 0.28 (s, 3H), 0.27 (s, 3H),

0.17 (s, 6H); ¹³C NMR (CDCl₃, 75 MHz) δ 158.4, 151.9, 143.5,

137.2, 129.0, 128.2, 126.3, 119.5, 110.9, 110.1, 105.3, 101.9,

81.0, 73.2, 72.9, 72.6, 69.0, 64.6, 25.8, 25.6, 18.3, 18.1, -4.0,

-4.1, -4.5; MS (FAB) m/ e 639 ([M + Na]⁺), 617 ([M + H]⁺),

559, 512, 395, 379, 337; HRMS (FAB) m/ e calcd for C₃₂H₄₈O₈-

Si₂: ([M + H]⁺), 617.2966; found: ([M + H]⁺), 617.2915. Anal.

Calcd for C₃₂H₄₈O₈Si₂: C, 62.30; H, 7.84. Found: C, 62.34; H,

7.88%.

1,1-An h yd r o-1-C-{6-(h yd r oxym et h yl)-2,4-b is[(ter t-b u -

tyld im eth ylsilyl)oxy]p h en yl}-4,6-O-(tetr a isop r op yld isi-

loxa n e-1,3-d iyl)-â-^D-glu cop yr a n ose (22). NaOMe in MeOH

(30%, 2 drops) was added to tetraacetate 17 (89 mg, 0.143

mmol) in MeOH (2 mL). After 3 h, citric acid (2 crystals) was

added and the mixture stirred for 5 min. After filtration, the

solution was evaporated under high vacuum for 2 h and the

residue dissolved in pyridine (2 mL) and cooled to 0 °C. 1,1,3,3-

Tetraisopropyl-1,3-dichlorodisiloxane³¹(50.5 µL, 0.158 mmol)

was added at 0 °C, and the mixture was stirred for 3 h at room

temperature. The mixture was poured into water and ex-

tracted with EtOAc. The organic phase was washed with

water (2×) and aqueous copper sulfate (1 M, 2×), dried,

filtered, and evaporated to yield an oil. Chromatography (15%

EtOAc in hexanes) gave a colorless foam (55 mg, 50%)

tentatively assigned as the diol 22: ¹H NMR (CDCl₃, 500 MHz)

3344, 3074, 2956, 2930, 2886, 1463, 1391, 1362, 1053 cm^-1

;

¹H NMR (CDCl₃, 300 MHz) δ 6.50 (d, 1H, J ) 2.7 Hz), 6.31 (d,

1H, J ) 2.6 Hz), 4.63 (d, 2H, J ) 6.6 Hz), 1.02 (s, 9H), 0.95 (s,

9H), 0.23 (s, 6H), 0.17 (s, 6H); ¹³C NMR (CDCl₃, 75 MHz) δ

155.6, 153.1, 141.7, 113.4, 111.0, 106.8, 65.4, 25.67, 25.65, 18.3,

18.2, -4.3, -4.4; MS (EI) m/ e 448, 446 (M^•+), 431, 391, 309,

195, 139, 73, 57; HRMS (EI) m/ e calcd for C₁₉H₃₅⁷⁹BrO₃Si₂:

(M^•+), 446.1308; found: (M^•+), 446.1297. Anal. Calcd for

C₁₉H₃₅BrO₃Si₂: C, 50.98; H, 7.88. Found: C, 50.94 H, 7.90%.

ter t-Bu t yl{[2-br om o-3,5-b is[(ter t-b u t yld im et h ylsilyl)-

oxy]ben zyl]oxy}d im eth ylsila n e (10). tert-Butyldimethyl-

silyl chloride (1.28 g, 8.5 mmol) and 4-(dimethylamino)pyridine

(25 mg) were added to crude 2-bromo-3,5-bis[(tert-butyldi-

methylsilyl)oxy]benzyl alcohol (from above) and imidazole (1.57

g, 23.0 mmol) in DMF (25 mL). The mixture was stirred at

25 °C for 18 h and added to Et₂O (50 mL) and water (50 mL).

After vigorous shaking the layers were separated, and the

organic phase was washed with water (2×) and dried. Filtra-

tion, concentration of solvents, and chromatography (5%

EtOAc in hexanes) gave 10 (3.9 g, 93%) as a colorless solid:

mp 46-47 °C; R_f) 0.73 (10% EtOAc in hexanes); IR (thin film)

2956, 2930, 2858, 1583, 1442, 1344, 1254, 1166, 1025, 1002,

835, 814, 780 cm^-1; ¹H NMR (CDCl₃, 400 MHz) δ 6.74 (d, 1H,

J ) 2.8 Hz), 6.30 (d, 1H, J ) 2.8 Hz), 4.65 (s, 2H), 1.03 (s,

9H), 0.97 (s, 9H), 0.96 (s, 9H), 0.23 (s, 6H), 0.19 (s, 6H), 0.12

(s, 6H); ¹³C NMR (CDCl₃, 75 MHz) δ 155.5, 152.6, 142.3, 112.1,

110.4, 105.3, 64.8, 25.9, 25.8, 25.7, 18.4, 18.3, -4.2, -4.4, -5.3;

HRMS (EI) calcd for C₂₅H₄₉⁷⁹BrO₃Si₃: (M^•+), 560.2172; found:

(M^•+), 560.2170. Anal. Calcd for C₂₅H₄₉BrO₃Si₃: C, 53.44; H,

8.79. Found: C, 53.29; H, 8.76%.

1,1-An h yd r o-1-C-{6-(h yd r oxym et h yl)-2,4-b is[(ter t-b u -

t yld im et h ylsilyl)oxy]p h en yl}-2,3,4,6-t et r a -O-a cet yl-â-^D-

1092 J . Org. Chem., Vol. 61, No. 3, 1996

Barrett et al.

δ 6.28 (d, 1H, J ) 1.8 Hz), 6.25 (d, 1H, J ) 2.0 Hz), 5.05 (d,

1H, J ) 12.6 Hz), 4.91 (d, 1H, J ) 12.6 Hz), 4.39 (d, 1H, J )

9 Hz), 4.0-3.7 (m, 5H), 1.5-0.7 (m), 0.29 (2s, 6H), 0.18 (s, 6H);

¹³C NMR (CDCl₃, 125 MHz) δ 158.1, 151.9, 143.7, 120.2, 110.4,

110.3, 105.3, 76.3, 74.4, 72.2, 71.9, 69.9, 61.0, 26.0, 25.6, 18.3,

18.1, 17.6, 17.5, 17.4, 17.35, 17.30, 17.18, 17.13, 17.05, 13.5,

13.3, 13.1, 13.0, 12.1, -3.8, -4.2, -4.4.

2946, 2868, 1729, 1589, 1451, 1345, 1240, 1175, 1032, 1014,

882, 771, 681 cm^-1; ¹H NMR (CDCl₃, 500 MHz) δ 7.15 (d, 2H,

J ) 2.6 Hz), 6.61 (t, 1H, J ) 2.4 Hz), 3.88 (s, 3H), 1.32-1.15

(m, 6H), 1.10 (d, 36H, J ) 7.4 Hz); ¹³C NMR (CDCl₃, 125 MHz)

δ 166.9, 156.9 131.7, 116.3, 114.1, 52.1, 17.9, 12.6; MS (CI)

m/ e 481 ([M + H]⁺), 454, 437; HRMS (CI) m/ e calcd for

C₂₉H₄₉O₄Si₂: ([M + H]⁺), 481.3169; found: ([M + H]⁺),

481.3185. The crude ester (58.0 g, 121.0 mmol) in Et₂O (400

mL) was slowly added to a slurry of LiAlH₄(5.5 g, 145.0 mmol)

in Et₂O (500 mL). After the addition was complete, the

mixture was stirred for 1 h prior to being heated at reflux for

3 h. Upon being cooled in an ice bath, water (100 mL) was

slowly added followed by aqueous KOH (1.0 M, 50 mL). The

resulting slurry was filtered through Celite, the layers were

separated, and the organic phase was dried. Filtration and

concentration of solvents gave the title compound as a viscous

oil, which was used directly in the next step: R_f) 0.31 (10%

EtOAc in hexanes); IR (thin film) 3335, 2948, 2890, 1590, 1460,

1337, 1170, 1031, 1004, 985, 882, 855, 823, 765, 686 cm^-1; ¹H

NMR (CDCl₃, 500 MHz) δ 6.49 (d, 2H, J ) 1.9 Hz), 6.34 (t,

1H, J ) 2.1 Hz), 4.56 (s, 2H), 1.3-1.0 (m, 42H); ¹³C NMR

(CDCl₃, 125 MHz) δ 157.1, 143.0, 111.4, 110.8, 65.2, 17.9, 17.7,

12.7, 12.3; MS (CI) m/ e 453 ([M + H]⁺), 426, 255, 148, 94;

HRMS (CI) m/ e calcd for C₂₅H₄₉O₃Si₂: ([M + H]⁺), 453.3220;

found: ([M + H]⁺), 453.3258. Anal. Calcd for C₂₅H₄₈O₃Si₂:

C, 66.33; H, 10.70. Found: C, 66.63; H, 10.56%.

2-Br om o-3,5-bis[(tr iisop r op ylsilyl)oxy]ben zyl Alcoh ol.

NBS (1.38 g, 7.8 mmol) was slowly added in small portions to

3,5-bis[(triisopropylsilyl)oxy]benzyl alcohol (2.73 g, 7.4 mmol)

in CCl₄(25 mL), the mixture was stirred for 3 h and quenched

with water (5 mL), and the separated organic phase was dried.

Filtration and evaporation gave 2-bromo-3,5-bis[(triisopropyl-

silyl)oxy]benzyl alcohol as a yellow oil, which was used directly

in the next step: R_f) 0.40 (10% EtOAc in hexanes); IR (thin

film) 3331, 2945, 2867, 1578, 1463, 1442, 1421, 1348, 1174,

1016, 997, 882, 821, 768, 684 cm^-1; ¹H NMR (CDCl₃, 500 MHz)

δ 6.65 (d, 1H, J ) 2.6 Hz), 6.41 (d, 1H, J ) 2.8 Hz), 4.66 (s,

2H), 1.3 (sept, 3H, J ) 7.5 Hz), 1.2 (sept, 3H, J ) 7.5 Hz),

1.14 (d, 18H, J ) 7.4 Hz), 1.05 (d, 18H, J ) 7.3 Hz); ¹³C NMR

(CDCl₃, 125 MHz) δ 156.0, 153.4, 141.6, 113.0, 110.4, 106.3,

65.5, 18.0, 17.9, 17.7, 13.0, 12.7, 12.3; MS (CI) m/ e 533, 531

([M + H]⁺), 506, 589, 459, 91, 76, 58; HRMS (CI) m/ e calcd

for C₂₅H₄₈⁸¹BrO₃Si₂: ([M + H]⁺), 533.2305; found: ([M + H]⁺),

533.2330. Anal. Calcd for C₂₅H₄₇BrO₃Si₂: C, 56.58; H, 8.93.

Found: C, 56.67; H, 8.96%.

1,1-An h yd r o-1-C-{6-(h yd r oxym et h yl)-2,4-b is[(ter t-b u -

tyldim eth ylsilyl)oxy]ph en yl}-â-^D-glu copyr an ose (14). tert-

Butyllithium (1.7 M in hexanes, 18.53 mL, 2.1 equiv) was

added to bromide 10 (8.4 g, 15.0 mmol) in Et₂O (75 mL) at

-78 °C. The mixture was stirred for 0.5 h and added, via

cannula, to lactone 19 (7.0 g, 15.0 mmol) in Et₂O (75 mL) at

-78 °C. The cannula was maintained at -78 °C with a dry

ice pack. The mixture was stirred for 12 h at -78 °C before

being warmed up to room temperature and quenched with

water (10 mL). The separated organic phase was dried,

filtered, evaporated, dissolved in MeOH (200 mL), and stirred

with Amberlite IR 120 (75 g). After 16 h, the Amberlite was

removed by filtration and the MeOH evaporated. The crude

oil was dissolved in EtOAc and extracted with water (2×) and

brine before being dried and purified by gradient chromatog-

raphy (5-10% MeOH in CHCl₃) to yield the title compound

14 (3.32 g, 45%): mp ) 199-202 °C (fine needles from MeOH/

water); R_f) 0.62 (13% MeOH in CHCl₃); [R]²⁵) +39.9 (c )

D

1.1 in CHCl₃); IR (KBr) 3361, 2956, 2940, 2890, 2861, 1604,

1473, 1434, 1365, 1251, 1162, 1076, 1060, 1035, 1000, 863, 835

1

cm^-1; H NMR (CDCl₃, 500 MHz) δ 6.27 (d, 1H, J ) 1.6 Hz),

6.21 (d, 1H, J ) 1.8 Hz), 5.06 (d, 1H, J ) 12.8 Hz), 4.90 (d,

1H, J ) 12.8 Hz), 4.23 (t, 1H, J ) 9.1 Hz), 4.16 (br s, 1H),

3.81-3.91 (m, 3H), 3.71-3.76 (m, 1H), 3.60 (td, 1H, J ) 9.48,

3.63 Hz), 2.79 (d, 1H J ) 8.5 Hz), 2.32 (t, 1H, J ) 6.4 Hz),

2.09 (br s, 1H), 1.00, 0.97 (2s, 18H), 0.27 (s, 3H), 0.25 (s, 3H),

0.91 (s, 6H); ¹³C NMR (CDCl₃, 125 MHz) δ 158.3, 151.9, 143.6,

119.9, 110.4, 110.0, 105.3, 75.5, 73.4, 72.6, 72.4, 71.4, 62.9, 25.8,

25.6, 18.3, 18.1, -4.0, -4.1, -4.4; MS (CI) m/ e 529 ([M + H]⁺),

471, 409, 395, 337; HRMS (CI) m/ e calcd for C₂₅H₄₅O₈Si₂: ([M

+ H]⁺), 529.2653; found: ([M + H]⁺), 529.2698. Anal. Calcd

for C₂₅H₄₄O₈Si₂: C, 56.79; H, 8.39. Found: C, 56.53; H, 8.10%.

1,1-An h yd r o-1-C-{6-(h yd r oxym et h yl)-2,4-b is[(ter t-b u -

t y ld im e t h y ls ily l)o x y ]p h e n y l}-4,6-O -(d i-t er t -b u t y ls i-

lylen e)-â-^D-glu cop yr a n ose (31). Di-tert-butylsilyl bis(trif-

luoromethanesulfonate) was added to a stirred solution of

tetraol 14 (1.0 g, 1.89 mmol) and 2,6-lutidine (607 mg, 5.67

mmol) in CH₂Cl₂(30 mL) at 0 °C. After 30 min the mixture

was warmed up to room temperature and water (15 mL) was

added. The aqueous solution was extracted with EtOAc, and

the organic layer was washed with water and brine before

being dried. Filtration, evaporation, and chromatography

(20% EtOAc in hexanes) gave 31 (1.0 g, 81%): mp ) 205-207

t er t -Bu t yl{[2-b r om o-3,5-b is[(t r iisop r op ylsilyl)oxy]-

ben zyl]oxy}d im eth ylsila n e (11). The crude 3,5-bis[(triiso-

propylsilyl)oxy]benzyl alcohol (29.0 g, 55.3 mmol), imidazole

(11.3 g, 166.0 mmol), tert-butyldimethylsilyl chloride (10.0 g,

66.4 mmol), and 4-(dimethylamino)pyridine (100 mg) in CH₂-

Cl₂(300 mL) were stirred at 25 °C for 18 h. EtOAc (300 mL)

and water (300 mL) were added and, after vigorous shaking,

the separated organic phase was washed with brine and dried.

Filtration, evaporation, and chromatography (2.5% EtOAc in

hexanes) yielded 11 (29.0 g, 80%, three steps) as a colorless

oil: bp ) 210 °C at 0.10 mmHg (Kugelrohr); R_f) 0.26

(hexanes); IR (thin film) 2946, 2867, 1582, 1463, 1442, 1366,

1347, 1257, 1172, 1055, 1026, 1004, 882, 858, 837, 774, 684

°C (fine needles); R_f) 0.39 (25% EtOAc in hexanes); [R]²⁵

)

D

+23.7 (c ) 0.86, CHCl₃); IR (KBr) 3544, 3507, 2938, 2861, 1600,

1473, 1432, 1353, 1253, 1155, 1089, 1070, 1039, 998, 962, 863,

1

835, 782 cm^-1; H NMR (CDCl₃, 500 MHz) δ 6.30 (d, 1H, J )

1.4 Hz), 6.20 (d, 1H, J ) 1.7 Hz), 5.12 (d, 1H, J ) 12.7 Hz),

5.00 (d, 1H J ) 12.7 Hz), 4.33 (t, 1H, J ) 8.5 Hz), 4.11 (dd,

1H, J ) 9.9, 5.0 Hz), 4.00-3.92 (m, 1H), 3.88-3.80 (m, 3H),

1.09-0.92 (4s, 36H), 0.28 (s, 3H), 0.23 (s, 3H), 0.19 (s, 6H);

¹³C NMR (CDCl₃, 125 MHz) δ 158.4, 151.9, 143.4, 119.7, 110.6,

110.0, 105.2, 76.8, 75.6, 73.0, 72.5, 68.5, 66.6, 27.5, 27.2, 27.1,

25.8, 25.6, 22.7, 19.9, 19.8, 18.3, 18.1, -3.9, -4.3, -4.4; MS

(CI) m/ e 669 ([M + H]⁺), 611, 395; HRMS (CI) m/ e calcd for

C₃₃H₆₁O₈Si₃: ([M + H]⁺), 669.3674; found: ([M + H]⁺),

669.3732. Anal. Calcd for C₃₃H₆₀O₈Si₃: C, 59.24; H, 9.04.

Found: C, 59.13; H, 8.90%.

3,5-Bis[(tr iisop r op ylsilyl)oxy]ben zyl Alcoh ol. Methyl

3,5-dihydroxybenzoate (8) (20.0 g, 119.0 mmol), triisopropyl-

silyl chloride (48.0 g, 53.5 mL, 250.0 mmol), imidazole (22.1

g, 476 mmol), and 4-(dimethylamino)pyridine (∼500 mg) in

DMF (100 mL) were stirred at room temperature for 24 h.

Water (200 mL) and EtOAc (200 mL) were added, the layers

were separated, and the organic phase was washed with water

(3×) and dried. After filtration and concentration, purification

was accomplished by gradient chromatography (2.5-10%

EtOAc in hexanes) to yield the title ester (53 g, 93%) as a

colorless oil: R_f) 0.5 (5% EtOAc in hexanes); IR (thin film)

1

cm^-1; H NMR (CDCl₃, 500 MHz) δ 6.77 (d, 1H, J ) 2.7 Hz),

6.38 (d, 1H, J ) 2.8 Hz), 4.67 (s, 2H), 1.33 (sept, 3H, J ) 7.7

Hz), 1.25 (sept, 3H, J ) 7.8 Hz), 1.12 (d, 18H, J ) 7.4 Hz),

1.09 (d, 18H, J ) 7.3 Hz), 0.96 (s, 9H), 0.12 (s, 6H); ¹³C NMR

(CDCl₃, 125 MHz) δ 155.8, 152.9, 142.2, 111.7, 109.8, 104.7,

64.9, 25.9, 18.3, 18.0, 17.9, 13.0, 12.7, -5.4; MS (CI) m/ e 647,

645 ([M + H]⁺), 606, 589, 532, 90; HRMS (CI) m/ e calcd for

C₃₁H₆₂⁸¹BrO₃Si₃: ([M + H]⁺), 647.3169; found: ([M + H]⁺),

647.3206.

1,1-An h yd r o-1-C-{6-(h ydr oxym eth yl)-2,4-bis[(tr iisop r o-

p ylsilyl)oxy]p h en yl}-2,3,4,6-t et r a -O-a cet yl-â-^D-glu cop y-

r a n ose (18). tert-Butyllithium (1.7 M in pentane, 15.65 mL,

2.2 equiv) was added to bromide 11 (8.0 g, 12.1 mmol) in Et₂O

(85 mL) at -78 °C. After 0.5 h, the solution was added, via

cannula, to lactone 19 (5.66 g, 12.1 mmol) in Et₂O (85 mL) at

-78 °C. The cannula was maintained at -78 °C with a dry

ice pack. The reaction mixture was stirred for 12 h at -78 °C

before being warmed up to room temperature, quenched with

Synthesis of the Antifungal Agent Papulacandin D

J . Org. Chem., Vol. 61, No. 3, 1996 1093

water (100 mL), and extracted with EtOAc. The organic phase

was washed with brine, and the separated organic phase was

dried, filtered, and concentrated. The resultant crude yellow

oil was dissolved in MeOH (150 mL) and Amberlite IR 120

(75 g) added. After being stirred for 16 h, the Amberlite was

removed by filtration and the MeOH evaporated. The remain-

ing dark green oil was further evaporated at <1 mmHg for 5

h before being dissolved in pyridine (50 mL) and Ac₂O (50 mL)

and stirred overnight. The mixture was added to EtOAc and

water, and the layers were separated. The organic phase was

washed with water (2×), dried, filtered, and evaporated to

leave an oil. Chromatography (25% EtOAc in hexanes) gave

18 (3.00 g, 33% yield) as a colorless foam: R_f) 0.14 (25%

71%): R_f) 0.26 (15% EtOAc in hexanes); [R]²⁵) +20.2 (c )

D

1.44 in CHCl₃); IR (KBr) 3400, 2940, 2868, 1597, 1461, 1357,

1

1167, 1070, 1029, 1000, 891, 687 cm^-1; H NMR (CDCl₃, 300

MHz) δ 6.22 (d, 1H, J ) 1.7 Hz), 6.15 (d, 1H, J ) 1.8 Hz), 5.00

(d, 1H J ) 12.5 Hz), 4.85 (d, 1H, J ) 12.5 Hz), 4.34 (d, 1H, J

) 9.0 Hz), 4.1-3.65 (m, 5H), 1.30-0.8 (m); ¹³C NMR (CDCl₃,

75 MHz) δ 158.5, 152.4, 143.7, 119.5, 110.5, 109.4, 104.8, 76.5,

74.4, 72.3, 72.1, 70.2, 61.2, 21.1, 18.2, 17.9, 17.6, 17.5, 17.43,

17.36, 17.32, 17.23, 17.19, 17.17, 14.2, 13.5, 13.23, 13.17, 12.7,

12.6; MS (CI) m/ e 855 ([M + H]⁺), 811, 479, 435, 380; HRMS

(FAB) m/ e calcd for C₄₃H₈₃O₉Si₄: ([M + H]⁺), 855.5114;

found: ([M + H]⁺), 855.5181.

1,1-An h yd r o-1-C-{6-(h ydr oxym eth yl)-2,4-bis[(tr iisop r o-

p ylsilyl)oxy]p h en yl}-2-O-a cet yl-4,6-O-(t et r a isop r op yl-

d isiloxa n e-1,3-d iyl)-â-^D-glu cop yr a n ose (24) a n d 1,1-

An h y d r o -1-C-{6-(h y d r o x y m e t h y l)-2,4-b is [(t r iis o p r o -

p ylsilyl)oxy]p h en yl}-2,3-d i-O-a cet yl-4,6-O-(t et r a isop r o-

p yld isiloxa n e-1,3-d iyl)-â-^D-glu cop yr a n ose (25). Ac₂O (0.75

mL) was added to diol 23 (50 mg) in pyridine (1 mL) and the

mixture stirred at room temperature for 8 h and poured into

water. The mixture was extracted with EtOAc and the organic

phase was extracted with water (3×), aqueous copper sulfate

(1 M), and brine. Drying, filtration, and evaporation gave a

yellow oil which was chromatographed (10% EtOAc in hex-

anes) to give 24 and 25 both as colorless foams. The 2-ester

24 showed: R_f) 0.42 (10% EtOAc in hexanes); IR (KBr) 3516,

2944, 2867, 1752, 1599, 1465, 1369, 1249, 1166, 1031, 1000,

EtOAc in hexanes); [R]²⁵) -21.0 (c ) 0.50 in CHCl₃); IR

D

(KBr) 2943, 2868, 1748, 1599, 1476, 1381, 1363, 1235, 1167,

1

1066, 1031, 1003, 880, 837, 686, 666 cm^-1; H NMR (CDCl₃,

500 MHz) δ 6.29 (d, 1H, J ) 1.5 Hz), 6.23 (d, 1H, J ) 1.7 Hz),

5.84 (d, 1H, J ) 9.9 Hz), 5.54 (t, 1H, J ) 9.7 Hz), 5.23 (t, 1H,

J ) 9.8 Hz), 5.11 (d, 1H, J ) 12.6 Hz), 5.02 (d, 1H, J ) 12.6

Hz), 4.40-4.30 (m, 2H), 3.90 (dd, 1H, J ) 1.8, 10.0 Hz), 2.03

(s, 3H), 2.02 (s, 3H), 1.98 (s, 3H), 1.72 (s, 3H), 1.40-1.25 (m,

42H); ¹³C NMR (CDCl₃, 125 MHz) δ 170.7, 170.4, 169.5, 168.8,

159.1, 152.6, 143.4, 117.9, 109.7, 109.1, 104.5, 73.3, 72.5, 71.2,

69.6, 68.7, 62.6, 20.7, 20.6, 20.2, 18.05, 17.97, 17.8, 13.1, 12.6;

MS (FAB) m/ e 781([M + H]⁺), 737, 479, 435, 173, 87, 73, 59;

HRMS (FAB) m/ e calcd for C₃₉H₆₅O₁₂Si₂: ([M + H]⁺), 781.4015;

found: ([M + H]⁺), 781.4017. Anal. Calcd for C₃₉H₆₄O₁₂Si₂:

C, 59.97; H, 8.26. Found: C, 60.32; H, 7.81%.

1

884, 690 cm^-1; H NMR (CDCl₃, 300 MHz) δ 6.30 (d, 1H, J )

1,1-An h ydr o-1-C-{6-(h yd r oxym eth yl)-2,4-bis[(tr iisopr o-

p ylsilyl)oxy]p h en yl}-â-^D-glu cop yr a n ose (15). tert-Butyl-

lithium (1.7 M in pentane, 15.65 mL, 2.2 equiv) was added to

bromide 11 (8.0 g, 12.1 mmol) in Et₂O (85 mL) at -78 °C and

the mixture was stirred for 0.5 h before being added, via

cannula, to lactone 19 (5.66 g, 12.1 mmol) in Et₂O (85 mL) at

-78 °C. The cannula was maintained at -78 °C with a dry

ice pack. The mixture was stirred for 12 h at -78 °C and then

warmed up to room temperature, quenched with water (100

mL), and extracted with EtOAc. The organic phase was

washed with brine, dried, filtered, and concentrated. The

resultant yellow oil was dissolved in MeOH (150 mL), and

Amberlite IR 120 (75 g) was added. After stirring for 16 h,

the Amberlite was removed by filtration and the MeOH

evaporated. The oil was dissolved in EtOAc and extracted with

water (2×) and brine. The organic layer was dried and

purified by gradient chromatography (5-10% MeOH in CHCl₃)

to give the title tetraol 15 (3.04 g, 34%) as an oil: R_f) 0.45

1.6 Hz), 6.24 (d, 1H, J ) 1.7 Hz), 5.72 (d, 1H, J ) 9.7 Hz),

5.08, 5.00 (ABq, 2H, J ) 12.5 Hz), 4.11-3.86 (m, 5H), 1.83 (s,

3H), 0.87-0.61 (m, 70H); ¹³C NMR (CDCl₃, 75 MHz) δ 170.7,

158.6, 152.6, 143.5, 118.9, 109.6, 109.4, 104.5, 74.8, 74.2, 73.9,

72.6, 71.5, 61.6, 29.7, 20.6, 18.1, 17.8, 17.7, 17.4, 17.3, 17.2,

13.5, 13.2, 13.1, 12.6; MS (FAB) m/ e 897 ([M + H]⁺), 853, 837,

535, 479, 435, 261, 173, 115, 87, 73, 59; HRMS (FAB) m/ e

calcd for C₄₅H₈₅O₁₀Si₄: ([M + H]⁺), 897.5258; found: ([M +

H]⁺), 897.5258. The diester 25 showed: R_f) 0.50 (10% EtOAc

in hexanes); IR (KBr) 2949, 2867, 1753, 1599, 1465, 1367,

1241, 1030, 1002, 883, 837, 690 cm^-^{1 1}H NMR (CDCl₃, 300

;

MHz) δ 6.29 (d, 1H, J ) 1.5 Hz), 6.23 (d, 1H, J ) 1.6 Hz), 5.80

(d, 1H, J ) 9.9 Hz), 5.51 (t, 1H, H ) 9.4 Hz), 5.10, 5.00 (ABq,

2H, J )12.5 Hz), 4.20 (t, 1H, J ) 9.4 Hz), 4.08 (dd, 1H, J )

2.5, 12.5 Hz), 4.00 (d, 1H, J ) 9.6 Hz), 3.90 (d, 1H, J ) 12.5

Hz), 2.03 (s, 3H), 1.74 (s, 3H), 1.61-0.88 (m, 70H); ¹³C NMR

(CDCl₃, 75 MHz) δ 170.3, 169.3, 158.7, 152.6, 143.6, 118.5,

109.6, 109.3, 104.5, 75.2, 74.2, 72.8, 72.1, 68.9, 61.7, 21.1, 20.4,

18.1, 18.0, 17.8, 17.6, 17.4, 17.3, 17.2, 17.1, 17.0, 13.6, 13.5,

13.2, 13.1, 12.6; MS (FAB) m/ e 939 ([M + H]⁺), 895, 479, 435,

303, 277, 261, 173, 115, 87, 73, 59; HRMS (FAB) m/ e calcd

for C₄₇H₈₇O₁₁Si₄: ([M + H]⁺), 939.5326; found: ([M + H]⁺),

939.5329.

(13% MeOH in CHCl₃); [R]²⁵) +14.2 (c ) 1.03 in CHCl₃); IR

D

(KBr) 3369, 2942, 2867, 1598, 1465, 1363, 1168, 1060, 1000,

881, 846, 686 cm^-^{1 1}H NMR (CD₃OD, 500 MHz) δ 6.36 (d,

;

1H, J ) 1.5 Hz), 6.26 (d, 1H, J ) 1.7 Hz), 5.07 (d, 1H, J )

12.6 Hz), 5.00 (d, 1H, J ) 12.6 Hz), 4.24 (d, 1H J ) 9.6 Hz),

3.89-3.83 (m, 2H), 3.73 (t, 1H, J ) 9.3 Hz), 3.56 (dd, 1H, J )

12.2, 7.9 Hz), 3.30 (m, 1H), 1.35 (sept, 3H, J ) 7.5 Hz), 1.25

(sept, 3H, J ) 7.5 Hz), 1.20-1.10 (m, 36H); ¹³C NMR (CD₃-

OD, 125 MHz) δ 159.7, 153.6, 145.8, 121.9, 112.0, 110.3, 105.8,

76.6, 76.3, 73.8, 73.6, 72.8, 64.0, 18.68, 18.66, 18.4, 14.5, 14.0;

MS (CI) m/ e 613 ([M + H]⁺), 493, 479, 435, 148; HRMS (CI)

m/ e calcd for C₃₁H₅₇O₈Si₂: ([M + H]⁺), 613.3592; found: ([M

+ H]⁺), 613.3611. Anal. Calcd for C₃₁H₅₆O₈Si₂: C, 60.75; H,

9.21. Found: C, 60.54; H, 9.09%.

1,1-An h yd r o-1-C-{6-h yd r oxym eth yl-2,4-bis[(tr iisop r o-

p ylsilyl)oxy]p h en yl}-2-O-cin n a m oyl-4,6-O-(t et r a isop r o-

p yld isiloxa n e-1,3-d iyl)-r-^D-glu cop yr a n ose (28). Et₃N (25

µL, 0.175 mmol) and 2,4,6-trichlorobenzoyl chloride (18 µL,

0.117 mmol) were added to trans-cinnamic acid (17.3 mg, 0.117

mmol) in THF (0.3 mL). After 30 min, the solvent was

evaporated under high vacuum and the residue dissolved in

CH₂Cl₂(0.3 mL) and added, via a cannula, to diol 23 (100 mg,

0.12 mmol) and 4-(dimethylamino)pyridine (29 mg, 0.23 mmol)

in CH₂Cl₂(1 mL). After 3 h, the mixture was added to water

and extracted with EtOAc. The organic phase was washed

with brine and dried, filtered, concentrated, and purified by

gradient chromatography (5-15% EtOAc in hexanes) to yield

ester 28 (83.6 mg, 73%): R_f) 0.21 (5% EtOAc in hexanes);

[R]²⁵_D) -51.6 (c ) 1.18 in CHCl₃); IR (KBr) 2952, 2948, 2937,

2866, 1724, 1698, 1465, 1364, 1167, 1032, 998, 883, 839, 687

1,1-An h ydr o-1-C-{6-(h yd r oxym eth yl)-2,4-bis[(tr iisopr o-

p ylsilyl)oxy]p h en yl}-4,6-O-(tetr a isop r op yld isiloxa n e-1,3-

d iyl)-â-^D-glu cop yr a n ose (23). NaOMe in MeOH (30%, 1

drop) was added to a stirred solution of tetraacetate 18 (100

mg, 0.128 mmol) in MeOH (1 mL). After 5 h, excess Amberlite

120 IR ion exchange resin (H⁺form) was added and the

mixture stirred for 5 min. After filtration, the solution was

evaporated under high vacuum for 2 h and the residue

dissolved in pyridine (2 mL) and cooled to 0 °C. 1,1,3,3-

Tetraisopropyl-1,3-dichlorodisiloxane³¹(45.1 µL, 0.141 mmol)

was added, and the mixture was stirred for 1 h at 0 °C and 6

h at room temperature. The mixture was poured into water

and extracted with EtOAc. The organic phase was washed

with water (2×) and aqueous copper sulfate (1 M, 2×), dried,

filtered, and evaporated to yield an oil. Chromatography (15%

EtOAc in hexanes) gave diol 23 as a colorless foam (78 mg,

1

cm^-1; H NMR (CDCl₃, 500 MHz) δ 7.50-7.30 (m, 6H), 6.25

(d, 1H, J ) 1.7 Hz), 6.23 (s, 1H), 6.20 (d, 1H, J ) 2.1 Hz), 5.80

(d, 1H, J ) 9.8 Hz), 5.16 (d, 1H, J ) 12.6 Hz), 5.10 (d, 1H, J

) 12.6 Hz), 4.20-4.05 (m, 3H), 3.98 (t, 1H, J ) 9.2 Hz), 3.88

(t, 1H, J ) 10.0 Hz), 1.38-1.30 (m, 2H), 0.98-1.20 (m, 70 H);

¹³C NMR (CDCl₃, 125 MHz) δ 165.6, 158.9, 152.5, 144.7, 143.1,

134.5, 130.1, 128.7, 128.0, 118.4, 117.7, 109.7, 109.6, 104.5,

77.5, 73.6, 68.5, 66.6, 27.4, 27.1, 22.8, 20.0, 18.13, 18.06, 17.8,

13.2, 12.6; MS (FAB) m/ e 985 ([M + H]⁺), 941, 837, 623, 505,

1094 J . Org. Chem., Vol. 61, No. 3, 1996

Barrett et al.

461, 131, 103, 59; HRMS (FAB) m/ e calcd for C₅₂H₈₉O₁₀Si₄:

([M + H]⁺), 985.5533; found: ([M + H]⁺), 985.5560.

10 min, 2,4,6-trichlorobenzoyl chloride (23 µL, 36 mg, 0.15

mmol) were added to trans-cinnamic acid (22 mg, 0.145 mmol)

in THF (0.5 mL). After 45 min at room temperature, the

mixture was evaporated and the residue dissolved in CH₂Cl₂

(1 mL). This solution was added to diol 30 (100 mg, 0.13 mmol)

and 4-(dimethylamino)pyridine (36 mg, 0.29 mmol) in DMF

(5 mL). After 15 h at room temperature, the mixture was

added to water and extracted with EtOAc, and the organic

phase was washed with water (2×) and brine. The solution

was dried, evaporated, and purified by gradient chromatog-

raphy (5-10% EtOAc in hexanes) giving 33 (49 mg, 42%) and

34 (28 mg, 24%) [67%, 6.7:1 ratio, (3-ester:2-ester)]. The

1,1-An h ydr o-1-C-{6-(h yd r oxym eth yl)-2,4-bis[(tr iisop r o-

p ylsilyl)oxy]p h en yl}-4,6-O-(tetr a isop r op yld isiloxa n e-1,3-

d iyl)-2-O-[(tr ieth ylsilyl)oxy]-â-^D-glu cop yr a n ose (29). Tri-

ethylsilyl trifluoromethanesulfonate (22.5 µL, 26.2 mL, 0.10

mmol) was added to diol 22 (77 mg, 0.09 mmol) in pyridine (2

mL) at -10 °C. After 2 h, the mixture was added to water

and extracted with EtOAc (2×). The organic phase was

washed with aqueous copper sulfate (1 M, 2×), water (1×),

and brine and dried. Filtration, evaporation, and chromatog-

raphy (5% EtOAc in hexanes) gave 29 (55 mg, 84%): R_f) 0.46

3-ester 33 showed: R_f) 0.24 (10% EtOAc in hexanes); [R]²⁵

(5% EtOAc in hexanes); [R]²⁵) -5.2 (c ) 1.25 in CHCl₃); IR

D

) +1.4 (c ) 1.46 in CHCl₃); IR (KBr) 3463, 2946, 2865, 1720,

3621, 3467, 2942, 2869, 1600, 1465, 1365, 1249, 1164, 1091,

1029, 1002, 883, 686 cm^-1; ¹H NMR (CDCl₃, 300 MHz) δ 6.31

(d, 1H, J ) 1.5 Hz), 6.26 (d, 1H, J ) 1.6 Hz), 5.12, 4.98 (ABq,

2H, J ) 12.5 Hz), 4.29 (d, 1H, J ) 8.6 Hz), 4.00 (dd, 1H, J )

10.0, 2.2 Hz), 3.90-3.80 (m, 4H), 2.17 (br s, 1H), 1.4-0.9 (m,

70 H), 0.77 (t, 9H, J ) 7.9 Hz), 0.09-0.37 (m, 6H); ¹³C NMR

(CDCl₃, 75 MHz) δ 158.3, 152.3, 144.0, 120.7, 111.3, 109.8,

104.7, 76.8, 76.6, 74.5, 73.8, 73.1, 70.9, 62.3, 18.3, 18.2, 17.9,

17.7, 17.5, 17.3, 17.2, 16.7, 13.7, 13.5, 13.2, 13.1, 12.8, 6.8, 4.9;

MS (FAB) m/ e 969 ([M + H]⁺), 925, 837, 479, 435, 261, 87,

59; HRMS (FAB) m/ e calcd for C₄₉H₉₇O₉Si₅: ([M + H]⁺),

569.5979; found: ([M + H]⁺), 569.6009.

1637, 1600, 1477, 1434, 1365, 1309, 1251, 1172, 1074, 1000,

883, 833, 767, 686, 655 cm^-^{1 1}H NMR (CDCl₃, 300 MHz) δ

;

7.75 (d, 1H, J ) 16.0 Hz), 7.78-7.57 (m, 2H), 7.43-7.38 (m,

3H), 6.55 (d, 1H J ) 16.0 Hz), 6.35 (d, 1H, J ) 1.5 Hz), 6.28

(d, 1H, J ) 1.7 Hz), 5.42 (t, 1H, J ) 9.4 Hz), 5.20 (d, 1H, J )

12.8 Hz), 5.05 (d, 1H, J ) 12.8 Hz), 4.50 (t, 1H, J ) 10Hz),

4.25-4.10 (m, 3H), 3.90-3.84 (m, 1H), 2.02 (d, 1H, J ) 10.4

Hz), 1.5-1.0 (m, 60H); ¹³C NMR (CDCl₃, 75 MHz) δ 167.2,

158.8, 152.2, 144.8, 143.3, 134.7, 130.1, 128.8, 128.1, 119.2,

118.5, 111.1, 109.6, 104.9, 76.8, 76.6, 74.9, 73.4, 71.6, 86.9, 66.8,

30.4, 29.7, 27.4, 27.0, 22.8, 20.0, 18.1, 17.9, 13.2, 12.7; MS

(FAB) m/ e 883 ([M + H]⁺), 479, 435, 199, 131; HRMS (FAB)

m/ e calcd for C₄₈H₇₉O₉Si₃: ([M + H]⁺), 883.5031; found: ([M

+ H]⁺), 883.5043. Anal. Calcd for C₄₈H₇₈O₉Si₃: C, 65.27; H,

8.91. Found: C, 64.98; H, 8.16%. The 2-ester 34 showed: R_f

1,1-An h ydr o-1-C-{6-(h yd r oxym eth yl)-2,4-bis[(tr iisopr o-

p ylsilyl)oxy]p h en yl}-4,6-O-(d i-ter t-bu tylsilylen e)-â-^D-glu -

cop yr a n ose (30). 2,6-Lutidine (335 µL, 308 mg, 2.88 mmol)

and di-tert-butylsilyl bis(trifluoromethanesulfonate) (419 µL,

507 mg, 1.15 mmol) were added sequentially to tetraol 15 (590

mg, 0.56 mmol) in CH₂Cl₂(10 mL) at 0 °C. After 30 min, the

solution was allowed to warm up to room temperature and

added to water. The mixture was extracted with EtOAc, and

the organic phase was washed with water and brine and dried.

Filtration, concentration, and chromatography (20% EtOAc in

hexanes) gave 30 (605 mg, 85%): R_f) 0.38 (25% EtOAc in

) 0.29 (10% EtOAc in hexanes); [R]²⁵) -65.0 (c ) 0.95 in

D

CHCl₃); IR (thin film) 3473, 2944, 2866, 1726, 1639, 1601,

1474, 1367, 1167, 1070, 1001, 828, 767, 684, 653 cm^-1; ¹H NMR

(CDCl₃, 300 MHz) δ 7.40-7.30 (m, 5H), 7.45 (d, 1H, J ) 15.9

Hz), 6.28 (d, 1H, J ) 1.7 Hz), 6.22 (d, 1H, J ) 1.7 Hz), 6.24 (d,

1H, J ) 15.9 Hz), 5.83 (d, 1H, J ) 9.7 Hz), 5.20, 5.10 (ABq,

2H, J ) 12.6 Hz), 4.21-3.87 (m, 5H), 2.73 (br s, 1H), 1.45-

1.26 (m, 6H), 1.2-1.0 (m, 54H); ¹³C NMR (CDCl₃, 75 MHz) δ

165.6, 158.9, 152.5, 144.7, 143.1, 134.5, 130.1, 128.8, 128.0,

118.4, 117.7, 109.71, 109.65, 104.5, 73.6, 73.5, 73.4, 68.5, 66.6,

27.5, 27.1, 22.8, 20.0, 18.2, 18.1, 17.8, 13.2, 12.6; MS (FAB)

m/ e 883 ([M + H]⁺), 839, 735, 623, 435, 131, 103, 73, 59;

HRMS (FAB) m/ e calcd for C₄₈H₇₉O₉Si₃: ([M + H]⁺), 883.5032;

found: ([M + H]⁺), 883.5054. Anal. Calcd for C₄₈H₇₈O₉Si₃:

C, 65.27; H, 8.91. Found: C, 65.50; H, 8.61%.

hexanes), 0.18 (15% EtOAc in hexanes); [R]²⁵) +20.9 (c )

D

1.15 in CHCl₃); IR (KBr) 2949, 2867, 1613, 1599, 1471, 1362,

1166, 1084, 1068, 1001, 881, 827, 768, 687, 653 cm^-1; ¹H NMR

(CDCl₃, 500 MHz) δ 6.31 (d, 1H, J ) 1.6 Hz), 6.24 (d, 1H, J )

1.8 Hz), 5.12 (d, 1H, J ) 12.6 Hz), 5.00 (d, 1H, J ) 12.6 Hz),

4.35 (br s, 1H), 4.14-4.09 (m, 1H), 4.00-3.9 (m, 1H), 3.89-

3.79 (m, 3H), 1.00-1.38 (m, 60H); ¹³C NMR (CDCl₃, 125 MHz)

δ 158.8, 152.3, 143.4, 119.1, 110.7, 109.5, 104.8, 75.6, 73.1, 72.5,

68.5, 66.7, 27.5, 27.1, 22.8, 20.0, 18.0, 17.9, 13.2, 12.7; MS (CI)

m/ e 753 ([M + H]⁺), 479, 336, 278, 215, 148; HRMS (CI) m/ e

calcd for C₃₉H₇₃O₈Si₃: ([M + H]⁺), 753.4613; found: ([M + H]⁺),

753.4648. Anal. Calcd for C₃₉H₇₂O₈Si₃: C, 62.19; H, 9.63.

Found: C, 61.96; H, 9.64%.

1,1-An h yd r o-1-C-{6-(h yd r oxym et h yl)-2,4-b is[(ter t-b u -

t yld im et h ylsilyl)oxy]p h en yl}-3-O-cin n a m oyl-4,6-O-b is-

(ter t-bu tylsilylen e)-â-^D-glu cop yr a n ose (35) a n d 1,1-An -

h y d r o -1-C -{6-(h y d r o x y m e t h y l)-2,4-b i s [(t er t -b u t y l-

d im eth ylsilyl)oxy]p h en yl}-2-O-cin n a m oyl-4,6-O-bis(ter t-

bu tylsilylen e)-â-^D-glu cop yr a n ose (36). Et₃N (81 µL, 59 mg,

0.57 mmol) and 2,4,6-trichlorobenzoyl chloride (61 µL, 95 mg,

0.39 mmol) were added sequentially to trans-cinnamic acid

(50 mg, 0.34 mmol) in DMF (2 mL). After 45 min, the solution

was added to diol 31 (271 mg, 0.41 mmol) in DMF (5 mL).

After 15 h, water (10 mL) was added and the mixture extracted

with EtOAc. The organic phase was washed with water (3×)

and brine and dried. Filtration, evaporation, and chromatog-

raphy (10% EtOAc in hexanes) gave 35 and 36 (195 mg, 1:1,

1,1-An h ydr o-1-C-{6-(h yd r oxym eth yl)-2,4-bis[(tr iisop r o-

p ylsilyl)oxy]p h en yl}-2,3-d i-O-a cetyl-4,6-O-(d i-ter t-bu tyl-

silylen e)-â-^D-glu cop yr a n ose (32). Ac₂O (1.5 mL) was added

to diol 30 (88 mg, 0.12 mmol) in pyridine (2 mL). After being

stirred overnight, the mixture was added to water and

extracted with EtOAc. The organic phase was washed with

aqueous copper sulfate (1 M, 2×), water (2×), and brine and

dried. Filtration, evaporation, and chromatography (10%

EtOAc in hexanes) gave 32 (86 mg, 88%): R_f) 0.16 (5% EtOAc

in hexanes); ¹H NMR (CDCl₃, 500 MHz) δ 6.27 (d, 1H, J ) 1.3

Hz), 6.20 (d, 1H, J ) 1.6 Hz), 5.73 (d, 1H, J ) 9.9 Hz), 5.46 (t,

1H, J ) 9.6 Hz), 5.12, 5.03 (ABq, 2H, J ) 12.6 Hz), 4.15 (m,

2H), 4.05 (t, 1H, J ) 9.4 Hz), 3.85 (m, 1H), 2.05 (s, 3H), 1.72

(s, 3H), 1.00-1.32 (m, 60H); ¹³C NMR (CDCl₃, 125 MHz) δ

170.3, 169.0, 159.0, 152.5, 143.4, 118.1, 109.7, 109.5, 104.5,

75.1, 73.9, 73.4, 71.6, 68.7, 66.6, 27.3, 27.0, 22.7, 20.8, 20.2,

20.0, 18.1, 18.0, 17.8, 13.4, 13.2, 13.0, 12.9, 12.6, 12.4; MS

(FAB) m/ e 837 ([M + H]⁺), 793, 479, 435; HRMS (FAB) m/ e

calcd for C₄₃H₇₇O₁₀Si₃: ([M + H]⁺), 837.4824; found: ([M +

H]⁺), 837.4817. Anal. Calcd for C₄₃H₇₆O₁₀Si₃: C, 61.69; H,

9.16. Found: C, 61.81; H, 8.98%.

72%). Fractions containing the 3-ester 35 showed: R_f

)

0.22 (10% EtOAc in hexanes); [R]²⁵) +8.4 (c ) 1.53 in

D

CHCl₃); IR (KBr) 3473, 2958, 2886, 2863, 1722, 1640, 1600,

1473, 1363, 1255, 1166, 1076, 1033, 1000, 865, 838, 781, 653

cm^-1; ¹H NMR (CDCl₃, 300 MHz) δ 7.73 (d, 1H, J ) 16.0 Hz),

7.60-7.50 (m, 2H), 7.5-7.2 (m, 3H), 6.55 (d, 1H, J ) 16.0 Hz),

6.31 (d, 1H, J ) 1.4 Hz), 6.21 (d, 1H, J ) 1.6 Hz), 5.38 (t, 1H,

J ) 9.3 Hz), 5.20 (d, 1H, J ) 12.7 Hz), 4.89 (d, 1H, J ) 12.7

Hz), 4.44 (t, 1H, J ) 10.1 Hz), 4.05-3.60 (m, 3H), 3.95-3.80

(m, 1H), 2.02 (d, 1H, J ) 9.6 Hz), 1.06 (s, 9H), 1.04 (s, 9H),

1.01 (s, 9H), 0.98 (s, 9H), 0.31 (s, 3H), 0.27 (s, 3H), 0.20 (s,

6H); ¹³C NMR (CDCl₃, 75 MHz) δ 167.2, 158.4, 151.8, 144.8,

143.3, 134.6, 130.1, 128.8, 128.1, 119.7, 118.3, 110.9, 109.9,

105.2, 76.7, 74.8, 73.3, 71.6, 68.8, 66.7, 27.4, 27.0, 25.8, 25.6,

22.7, 19.9, 18.3, 18.1, -3.9, -4.3, -4.4; MS (FAB) m/ e 799

([M + H]⁺), 651, 593, 395, 379, 337, 199, 131, 103, 73; HRMS

(FAB) m/ e calcd for C₄₂H₆₇O₉Si₃: ([M + H]⁺), 799.4093;

found: ([M + H]⁺), 799.4078. Anal. Calcd for C₄₂H₆₆O₉Si₃:

1,1-An h ydr o-1-C-{6-(h yd r oxym eth yl)-2,4-bis[(tr iisopr o-

p ylsilyl)oxy]p h en yl}-3-O-cin n a m oyl-4,6-O-(d i-ter t-bu tyl-

silylen e)-â-^D-glu cop yr a n ose (33) a n d 1,1-An h yd r o-1-C-{6-

(h yd r oxym eth yl)-2,4-bis[(tr iisop r op ylsilyl)oxy]p h en yl}-

2-O-cin n a m oyl-4,6-O-(d i-ter t-b u t ylsilyle n e )-â-^D-glu co-

p yr a n ose (34). Et₃N (32 µL, 33 mg, 0.23 mmol) and, after

Synthesis of the Antifungal Agent Papulacandin D

J . Org. Chem., Vol. 61, No. 3, 1996 1095

C, 63.12; H, 8.32. Found: C, 62.81; H, 8.15%. Fractions

aldehyde 40 (2.85 g, 25 mmol) in Et₂O (100 mL) was added

dropwise (cannula), and the solution was subsequently allowed

to warm up to room temperature over 1.5 h. The solution was

added to aqueous NH₄Cl and Et₂O, and the aqueous phase

was extracted with H₂O. The combined organic extracts were

washed with H₂O, dried, filtered, and evaporated. Chroma-

tography (4% EtOAc in hexanes) gave 41 (4.37 g, 82%) as a

pale yellow oil: R_f) 0.61 (12% EtOAc in hexanes); bp 89 °C

at 0.06 mmHg; IR (neat) 3360, 2980, 1630, 1470, 1260, 1000,

875, 850 cm^-1; ¹H (CDCl₃) δ 5.9 (dd, 1H, J ) 5.0, 18.5 Hz), 5.7

(d, 1H, J ) 18.7 Hz), 4.0 (br s, 1H), 3.4 (q, 1H J ) 7.5 Hz),

1.5-1.0 (m, 7H), 0.8 (m, 6H), 0.0 (s, 9H); ¹³C (CDCl₃) δ 148.73,

148.67, 129.1, 129.0, 75.00, 74.96, 34.4, 34.3, 32.1, 32.0, 29.4,

29.3, 19.2, 19.1, 11.3, -1.3; MS (EI) m/ e 214 (M^•+), 199, 157,

144, 129; HRMS (EI) calcd for C₁₂H₂₆OSi: (M^•+), 214.1753;

found: (M^•+), 214.1739.

containing the 2-ester 36 showed: R_f) 0.28 (10% EtOAc in

hexanes); [R]²⁵) -62.2 (c ) 1.49 in CHCl₃); IR (thin film)

D

3484, 2929, 2859, 1725, 1604, 1473, 1367, 1255, 1164, 1070,

1000, 962, 867, 836, 781, 655 cm^-1; ¹H NMR (CDCl₃, 300 MHz)

δ 7.50 (d, 1H, J ) 16.0 Hz), 7.43-7.37 (m, 2H), 7.37-7.28 (m,

3H), 6.26 (d, 1H, J ) 16.0 Hz), 6.25 (d, 1H, J ) 1.7 Hz), 6.19

(d, 1H, J ) 1.8 Hz), 5.84 (d, 1H, J ) 9.8 Hz), 5.18, 5.10 (ABq,

2H, J ) 12.6 Hz), 4.22 (dd, 1H, J ) 4.9, 9.5 Hz), 4.18-4.08

(m, 2H), 4.02 (d, 1H, J ) 9.1 Hz), 4.0-3.9 (m, 1H), 2.71 (b rs,

1H), 1.12 (s, 9H), 1.11 (s, 9H), 1.06 (s, 9H), 0.94 (s, 9H), 0.39

(s, 3H), 0.29 (s, 3H), 0.14 (s, 6H); ¹³C NMR (CDCl₃, 75 MHz)

δ 165.5, 158.5, 152.3, 144.7, 143.2, 134.4, 130.1, 128.8, 128.0,

118.7, 117.7, 109.7, 109.6, 104.7, 77.4, 73.5, 73.4, 73.2, 68.5,

66.6, 27.5, 27.1, 25.8, 25.6, 22.8, 20.0, 18.2, 18.1, -4.6, -5.1,

-5.3, -5.5; MS (FAB) m/ e 799 ([M + H]⁺), 741, 651, 395, 379,

337, 131, 103, 73; HRMS (FAB) m/ e calcd for C₄₂H₆₇O₉Si₃: ([M

+ H]⁺), 799.4093; found: ([M + H]⁺), 799.4070. Anal. Calcd

for C₄₂H₆₆O₉Si₃: C, 63.12; H, 8.32. Found: C, 63.14; H, 8.60%.

(3S)-1-Br om o-3-m eth ylp en ta n e (39). Alcohol 38³⁸(32.6

g, 320 mmol), TsCl (66.6 g, 350 mmol), and pyridine (77 mL)

in CH₂Cl₂(50 mL) were stirred for 2 days under N₂. The

mixture was added to water and Et₂O, and the aqueous layer

was extracted with several portions of Et₂O. The combined

organic layers were washed with water, dried, filtered, and

evaporated in vacuo to leave the crude tosylate as a light

brown oil. This was dissolved in Me₂CO (250 mL), and LiBr

(70 g, 800 mmol) was added. The mixture was stirred over-

night at room temperature, diluted with pentane, and washed

with several portions of water. The pentane layers were dried

(MgSO₄), filtered, and evaporated in vacuo to leave a dark pink

liquid. Double fractional distillation gave bromide 39 (30.8 g,

69%) as a clear liquid: bp 134 °C at 760 mmHg; [R]²²_D) +21.8

(neat); IR (neat) 2980, 2940, 1470, 1390, 1260 cm^-1; ¹H (CDCl₃)

δ 3.39-3.49 (m, 2H), 1.89-1.86 (m, 1H), 1.69-1.64 (m, 1H),

1.6-1.5 (m, 1H), 1.40-1.33 (m, 1H), 1.22-1.16 (m, 1H), 0.90-

0.87 (m, 6H); ¹³C NMR (CDCl₃, 75 MHz) δ 39.6, 33.1, 31.9,

28.9, 18.3, 11.1; HRMS (EI) calcd for C₆H₁₃⁷⁹Br: (M^•+),

164.0201, C₆H₁₃⁸¹Br: (M^•+), 166.0180; found: (M^•+), 166.0178,

164.0195.

(6S)-6-Meth yl-2E-octen a l (42). PhSCl (0.431 g, 2.98

mmol) was added to alcohol 41 (0.533 g, 2.48 mmol) and Et₃N

(0.52 mL, 3.72 mmol) in Et₂O (20 mL) at 0 °C. The white

slurry was stirred at 0 ° for 0.5 h and at 25 °C for 2 h and

washed with H₂O (3×) and the organic phase evaporated. The

resultant oil was dissolved in MeCN and water (3:1; 20 mL),

and AgNO₃(0.422 g, 2.5 mmol) was added. After stirring

overnight, the mixture was diluted with water and extracted

with Et₂O (3×). The organic phase was washed with water,

dried, filtered, and evaporated. Chromatography (12% EtOAc

in hexanes) gave 42 (246 mg, 77%) as an oil: R_f) 0.16 (2.5%

EtOAc in hexanes); IR (thin film) 2962, 2928, 2875, 2810, 2731,

1693, 1637, 1462, 1146, 1100, 976 cm^-1; ¹H NMR (CDCl₃, 300

MHz) δ 9.50 (d, 1H, J ) 7.4 Hz), 6.80 (dt, 1H, J ) 6.8, 15.6

Hz), 6.10 (ddt, 1H, J ) 1.3, 7.4, 15.6 Hz), 3.00-2.29 (m, 2H),

1.62-1.45 (m, 1H), 1.31-1.23 (m, 3H), 1.25-1.05 (m, 1H),

1.00-0.90 (m, 6H); ¹³C NMR (CDCl₃, 75 MHz) δ 194.0, 159.2,

132.8, 34.5, 33.9, 30.4, 29.2, 18.9, 11.2; MS (EI) m/ e 140 ([M

+ H]⁺). 2,4-Dinitrophenylhydrazone: mp ) 127-129 °C (fine

needles from EtOH); R_f) 0.24 (10% EtOAc in hexanes); [R]²⁵

D

) +12.3 (c ) 1.47, CHCl₃); IR (KBr) 3283, 2960, 2927, 2871,

1615, 1591, 1515, 1504, 1329, 1311, 1139, 1069, 990, 828 cm^-1

;

¹H NMR (CDCl₃, 500 MHz) δ 11.07 (s, 1H), 9.10 (d, 1H, J )

2.5 Hz), 8.28 (dd, 1H, J ) 2.5, 9.6 Hz), 7.90 (d, 1H, J ) 9.5

Hz), 7.75 (d, 1H, J ) 8.6 Hz), 6.49-6.22 (m, 2H), 2.38-2.22

(m, 2H), 1.52-1.47 (m, 1H), 1.42-1.23 (m, 3H), 1.23-1.12 (m,

1H), 0.95-0.92 (m, 6H); ¹³C NMR (CDCl₃, 125 MHz) δ 150.3,

146.5, 144.8, 138.0, 129.9, 129.2, 126.3, 123.4, 116.6, 35.3, 33.9,

30.7, 29.3, 19.0, 11.3; MS (EI) m/ e 321 ([M + H]⁺), 302, 291,

212, 140, 69; HRMS (EI) m/ e calcd for C₁₅H₂₁N₄O₄: ([M + H]⁺),

321.1563; found: ([M + H]⁺), 321.1575; calcd for C₁₅H₂₄N₅O₄:

([M + NH₄]⁺), 338.1828; found: ([M + NH₄]⁺), 338.1825. Anal.

Calcd for C₁₅H₂₀N₄O₄: C, 56.24; H, 6.29; N, 17.48. Found: C,

56.17; H, 6.28; N, 17.44%.

(4S)-Meth ylh exa n a l (40). Bromide 39 (4.0 g, 24.2 mmol)

in THF (5 mL) was added dropwise to Mg turnings (0.64 g,

26.6 mmol) and THF (30 mL) to maintain reflux. The mixture

was subsequently heated to reflux for 1 h and cooled to 25 °C,

and Fe(CO)₅(3.35 mL, 25.4 mmol) was added. The resultant

black mixture was stirred at 25 °C for 2 h, HOAc (3mL) was

added, and the green solution was partitioned between Et₂O

and H₂O. The aqueous layer was further extracted with Et₂O

(3×) and the combined organic solutions were dried, filtered,

and evaporated. Chromatography of the green residue (4%

EtOAc in hexanes) and distillation gave aldehyde 40 (1.78 g,

64.5%) as a clear liquid: bp 84 °C at 45 mmHg; R_f) 0.42 (12%

(S)-4-Meth ylh exa n en itr ile (44). TsCl (72.3 g, 0.38 mol)

and pyridine (75.3 mL, 73.7 g, 0.93 mol) were added to (S)-3-

methylpentanol³⁸(38) (34.9 g, 0.35 mol) in dry CH₂Cl₂(500

mL), and the mixture was stirred for 15 h at room tempera-

ture. The brown suspension was added to hydrochloric acid

(1 M, 200 mL) and, after being shaken, the layers were

separated. The organic layer was washed with water (2×) and

dried. Filtration and evaporation gave a light brown oil, which

was used without further purification. The crude tosylate and

18-crown-6 (1 g) were dissolved in THF (800 mL), and KCN

(37.0 g, 0.56 mmol) was added. The mixture was heated to

reflux for 2 days, at which point GC-MS analysis showed that

all tosylate had been consumed. The mixture was added to

Et₂O and water (1:1). The organic layer was extracted with

water (4×), dried, filtered, and concentrated by distillation at

ambient pressure. Fractional distillation gave nitrile 44 (30.8

EtOAc in hexanes); [R]²⁵) +7.2 (neat); IR (thin film) 2975,

D

2925, 2870, 2710, 1740, 1725, 1460, 1370, 1245, 1050 cm^-1

;

¹H NMR (300 MHz, CDCl₃) δ 9.77 (t, 1H, J ) 1.9 Hz), 2.46-

2.39 (m, 2H), 1.80-1.65 (m, 1H), 1.55-1.22 (m, 3H), 1.30-

1.15 (m, 1H), 0.88 (t, 3H, J ) 7.1 Hz), 0.88 (d, 3H, J ) 6.4 Hz);

¹³C NMR (75 MHz, CDCl₃) δ 202.4, 41.5, 33.8, 29.0, 28.3, 18.6,

11.0; MS (EI) m/z 114 (M^•+), 96, 70. 2,4-Dinitrophenylhydra-

zone: mp ) 79-82 °C (plates from EtOH); R_f) 0.41 (10%

EtOAc in hexanes); [R]²⁵) +12.6 (c ) 0.30 in CHCl₃); IR

D

(KBr) 3292, 2962, 2920, 1620, 1592, 1514, 1335, 1307, 1269

1

cm^-1; H NMR (CDCl₃, 500 MHz) δ 11.0 (s, 1H), 9.10 (d, 1H,

J ) 2.5 Hz), 8.29 (dd, 1H, J ) 2.5, 9.6 Hz), 7.92 (d, 1H, J )

9.6 Hz), 7.54 (t, 1H, J ) 5.4 Hz), 2.51-2.38 (m, 2H), 1.69-

1.60 (m, 1H), 1.46-1.36 (m, 3H), 1.27-1.18 (m, 1H), 0.98-

0.88 (m, 6H); ¹³C NMR (CDCl₃, 125 MHz) δ 152.9, 145.1, 137.8,

130.0, 128.8, 123.5, 116.5, 34.0, 32.9, 30.2, 29.2, 18.9, 11.3; MS

(CI) m/ e 295 ([M + H]⁺), 265, 259, 231, 171, 154, 114; HRMS

(EI) m/ e calcd for C₁₃H₁₉N₄O₄: ([M + H]⁺), 295.1406; found:

([M + H]⁺), 295.1408. Anal. Calcd for C₁₃H₁₈N₄O₄: C, 53.05;

H, 6.16; N, 19.03. Found: C, 52.99; H, 6.15; N, 19.11%.

(3RS,6S)-6-Meth yl-1-(tr im eth ylsilyl)-1E-octen -3-ol (41).

BuLi (1.8 M, 13.8 mL, 25 mmol) was added dropwise to 1E-

(tributylstannyl)-2-(trimethylsilyl)ethene³⁹(9.73 g, 25 mmol)

in Et₂O (70 mL) and THF (70 mL) at -78 °C. After 1.5 h,

g, 80%) as a colorless liquid: bp 167 °C; [R]²⁵) +12.4 (c )

D

1.86 CHCl₃); IR (thin film) 2964, 2933, 2878, 2246, 1464, 1428,

1

1382 cm^-1; H NMR (CDCl₃, 300 MHz) δ 2.38-2.31 (m, 2H),

1.71-1.62 (m, 1H), 1.51-1.27 (m, 3H), 1.21-1.09 (m, 1H),

0.92-0.87 (m, 6H); ¹³C NMR (CDCl₃, 75 MHz) δ 120.0, 33.5,

31.8, 28.7, 18.3, 14.9, 11.1; MS (EI) (m/z) 112 ([M + H]⁺), 96,

82, 69, 55, 41; HRMS calcd for C₇H₁₄N: ([M + H]⁺), 112.1126

and ([M - H]⁺), 110.0970; found: ([M + H]⁺) 112.1114 and

([M - H]⁺), 110.0969.

1096 J . Org. Chem., Vol. 61, No. 3, 1996

Barrett et al.

Eth yl (S)-6-Meth yl-2E-octen oa te (45). DIBAL-H (1 M

in hexanes, 79.0 mL, 79.0 mmol) was slowly added to nitrile

44 (8.0 g, 72.0 mmol) in Et₂O (250 mL) at -78 °C. The mixture

was stirred for 2 h, at which time GC-MS analysis showed no

44 remaining. After warming up to 0 °C, sulfuric acid (5 N,

200 mL) was cautiously added, and the mixture was stirred

vigorously for 1.5 h. The layers were separated, and the

organic layer was washed with water (2×) and saturated

aqueous NaHCO₃. The organic phase was dried to leave the

crude aldehyde 40, which was used without further purifica-

tion. [(Ethoxycarbonyl)methylene]triphenylphosphorane (35.1

g, 100.0 mmol) was added to the crude aldehyde 40 in CH₂Cl₂

(100 mL), and the mixture was stirred overnight at room

temperature. After concentration, the residue was dissolved

in hexanes, and solids were removed by filtration. The filtrate

was concentrated and the resultant yellow oil chromato-

graphed (5% Et₂O in hexanes) to give ester 45 (11.3 g, 85%)

mmol) in Et₂O (5 mL) at -78 °C. After 30 min at -78 °C and

30 min at 0 °C, water (5 mL) was added, the gelatinous

mixture was filtered through Celite, and the layers were

separated. The organic solution was washed with water and

brine, dried, and evaporated. Chromatography (10 to 25%

EtOAc in hexanes) gave the title dienol (156 mg, 98%) as a

colorless, unstable oil: R_f) 0.14 (10% EtOAc in hexanes);

[R]²⁵) +10.1 (c ) 0.082, ether); IR (thin film) 3317, 2960,

D

1462, 1377, 1008, 967 cm^-1; ¹H NMR (CDCl₃, 300 MHz) δ 6.25

(ddt, 1H, J ) 10.9, 15.0, 1.3 Hz), 6.00 (d, 1H, J ) 10.7 Hz),

5.70 (dt, 1H, J ) 15.0, 7.0 Hz), 4.01 (s, 2H), 2.20-2.00 (m,

2H), 1.78 (s, 3H), 1.68 (s, 1H), 1.42-1.28 (m, 3H), 1.22-1.08

(m, 2H), 0.84 (t, 3H, J ) 7.2 Hz), 0.84 (d, 3H, J ) 6.4 Hz); ¹³

C

NMR (CDCl₃, 75 MHz) δ 135.5, 134.6, 125.6, 125.3, 68.6, 36.2,

33.8, 30.5, 29.3, 19.0, 14.0, 11.3; MS (CI) m/ e 181 ([M + H]⁺),

163, 110, 95, 81, 58, 44; HRMS (CI) m/ e calcd for C₁₂H₂₁O:

([M + H]⁺), 181.1592; found: ([M + H]⁺), 181.1609.

as a colorless oil: R_f) 0.65 (10% EtOAc in hexanes); [R]²⁵

)

(S)-2,8-Dim eth yl-2E,4E-d ien a l (46). Manganese dioxide

(671 mg, 7.72 mmol) was added to (S)-2,8-dimethyldeca-2E,4E-

dienol (174 mg, 0.96 mmol) in CH₂Cl₂(20 mL) and the mixture

stirred for 18 h. Filtration through silica gel (20% EtOAc in

hexanes), evaporation, and chromatography (5% EtOAc in hex-

anes) gave 46 (166 mg, 96%) as a colorless oil: R_f) 0.48 (10%

D

+10.7 (c ) 2.22, CHCl₃); IR (thin film) 2962, 2931, 1724, 1655,

1266, 1175, 1048 cm^-1; ¹H NMR (CDCl₃, 300 MHz) δ 6.95 (dt,

1H, J ) 7.0, 15.6 Hz), 5.78 (dt, 1H, J ) 1.6, 15.6 Hz), 4.14 (q,

2H, J ) 7.1 Hz), 2.28-2.08 (m, 2H), 1.50-1.05 (m, 8H), 1.25

(t, 3H, J ) 7.1 Hz), 0.83 (t, 3H, J ) 7.2 Hz), 0.83 (d, 3H, J )

6.2 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 166.8, 149.7, 121.0, 60.1,

34.7, 33.8, 29.8, 29.2, 18.9, 14.2, 11.2; MS (CI) m/ e 185 ([M +

H]⁺), 173, 156, 139, 110, 96, 81; HRMS (CI) m/ e calcd for

C₁₁H₂₁O₂: ([M + H]⁺), 185.1542; found: ([M + H]⁺), 185.1558.

Anal. Calcd for C₁₁H₂₀O₂: C, 71.70; H, 10.94. Found: C,

71.51; H, 10.89%.

EtOAc in hexanes); [R]²⁵) +10.1 (c ) 0.135, Et₂O); IR (thin

D

film) 2960, 2925, 2874, 2708, 1681, 1634, 1461, 1211, 1008,

1

967 cm^-1; H NMR (CDCl₃, 300 MHz) δ 9.37 (s, 1H), 6.82 (d,

1H, J ) 10.9 Hz), 6.52 (ddt, 1H, J ) 11.1, 15.0, 1.4 Hz), 6.20

(dt, 1H, J ) 7.0, 15.0 Hz), 2.30-2.10 (m, 2H), 1.79 (s, 3H),

1.50-1.05 (m, 5H), 0.90-0.80 (m, 6H); ¹³C NMR (CDCl₃, 75

MHz) δ 195.0, 149.3, 146.2, 135.8, 125.6, 35.5, 33.9, 31.0, 29.2,

18.9, 11.2, 9.3; MS (EI) m/ e 180 (M^•+), 151, 95, 82, 55, 41;

HRMS (EI) m/ e calcd for C₁₂H₂₀O: (M^•+), 180.1513; found:

(M^•+), 180.1514. 2,4-Dinitrophenylhydrazone: mp ) 128-130

°C (fine needles from EtOH); R_f) 0.29 (10% EtOAc in

hexanes); [R]²⁵_D) +16.1 (c ) 0.16, CHCl₃); IR (KBr disk) 3293,

2964, 2853, 1615, 1599, 1512, 1332, 1135, 1081, 977, 829, 741,

723, 608 cm^-1; ¹H NMR (CDCl₃, 500 MHz) δ 11.15 (br s, 1H),

9.10 (d, 1H, J ) 2.3 Hz), 8.30 (dd, 1H, J ) 2.5, 9.6 Hz), 7.95

(d, 1H, J ) 9.6 Hz), 7.71 (s, 1H), 6.49 (m, 1H), 6.38 (d, 1H, J

) 11.1 Hz), 6.00 (dt, 1H, J ) 7.2, 14.3 Hz), 2.35-2.15 (m, 2H),

2.05 (s, 3H), 1.55-1.15 (m, 5H), 0.85 (m, 6H); ¹³C NMR (CDCl₃,

125 MHz) δ 153.0, 144.7, 141.9, 139.5, 137.9, 130.8, 129.9,

129.1, 125.9, 123.5, 116.7, 35.9, 34.0, 31.0, 29.3, 19.0, 11.6, 11.3;

MS (CI) 361 ([M + H]⁺), 331, 212, 180, 171, 94; HRMS (CI)

m/ e calcd for C₁₈H₂₅N₄O₄: ([M + H]⁺), 361.1876; found: ([M

+ H]⁺), 361.1902. Anal. Calcd for C₁₈H₂₄N₄O₄: C, 59.98; H,

6.71; N, 15.54. Found: C, 59.97; H, 6.72; N, 15.46%.

(S)-6-Meth yl-2E-octen -1-ol. DIBAL-H (1 M in hexanes,

120 mL, 120.0 mmol) was added dropwise to ester 45 (9.57 g,

52.0 mmol) in Et₂O (200 mL) at -78 °C. After 30 min, the

mixture was allowed to warm up to 0 °C and stirred for an

additional 30 min. Water (40 mL) was slowly added at 0 °C,

and the mixture was vigorously stirred for 20 min. The result-

ing gelatinous precipitate was removed by filtration through

Celite, and the two layers were separated. The organic phase

was washed a second time with water followed by brine.

Drying, filtration, evaporation, and chromatography (10%

EtOAc in hexanes) gave the title alcohol (7.30 g, 97%) as a

colorless oil: R_f) 0.15 (10% EtOAc in hexanes); [R]²⁵_D) +11.1

(c ) 1.55, CHCl₃); IR (thin film) 3325, 2961, 2924, 2874, 2856,

1462, 1377, 1089, 1004, 970 cm^-1; ¹H NMR (CDCl₃, 300 MHz)

δ 5.73-5.52 (m, 2H), 4.04 (d, 2H, J ) 4.6 Hz), 2.10-1.90 (m,

2H), 1.59 (s, 1H), 1.41-1.22 (m, 5H), 0.83 (t, 3H, J ) 7.2 Hz),

0.83 (d, 3H, J ) 6.4 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 133.7,

128.6, 63.8, 35.9, 33.9, 29.7, 29.3, 19.0, 11.3; MS (EI) m/ e 142

(M^•+), 124, 109, 95, 83, 70, 57, 43; HRMS (EI) m/ e calcd for

C₉H₁₈O: (M^•+), 142.1358; found: (M^•+), 142.1339. Anal. Calcd

for C₉H₁₈O: C, 76.00; H, 12.76. Found: C, 75.70; H, 12.46%.

Eth yl (S)-2,8-Dim eth yld eca -2E,4E-d ien oa te (43). Py-

ridinium chlorochromate (16.40 g, 76.0 mmol) was added in

small portions to (S)-6-methyl-2E-octenol (7.18 g 50.6 mmol),

silica gel (50 g), and CH₂Cl₂(200 mL). The slurry was stirred

at 25 °C for 3 h, filtered through silica, and evaporated to leave

crude aldehyde 42 identical with the previous sample and

which was used without further purification. [(Ethoxycarbo-

nyl)ethylidene]triphenylphosphorane (22.0 g, 60.7 mmol) was

added to 42 in CH₂Cl₂(200 mL). After being stirred overnight

at room temperature, the mixture was evaporated and the

residue was dissolved in hexanes. Filtration through Celite,

concentration, and chromatography (2% EtOAc in hexanes)

gave ester 43 (7.60 g, 67%) as a colorless oil: R_f) 0.32 (4%

Sta n d a r d p r ep a r a tion of (R)-Mosh er Ester s fr om Al-

coh ols. (N,N-Dimethylamino)pyridine (0.33 mmol) and (S)-

R-methoxy-R-(trifluoromethyl)phenylacetyl chloride (0.33 mmol)

were added to the alcohol (0.11 mmol) in CH₂Cl₂(1 mL). After

2 h at room temperature, water (5 mL) and EtOAc (5 mL) were

added. The organic phase was washed with saturated aqueous

NaHCO₃(2×), dried, and filtered. The crude ester fraction

was filtered through silica to provide the Mosher ester for ¹H

NMR analysis.

(4RS,11S)-5,11-Dim et h ylt r id eca -5E,7E-d ien -1-yn -4-ol

(47). Propargyl bromide (9.40 mL, 1.05 mmol) was added to

activated zinc dust (66.7 mg, 1.05 mmol) in THF (5 mL) at 0

°C, and the mixture was stirred for 1 h. Aldehyde 46 (95.0

mg, 0.52 mmol) in THF (2 mL) was added, and the mixture

stirred for 1 h at 0 °C. After warming up to room temperature,

saturated aqueous NH₄Cl (5 mL) and EtOAc (20 mL) were

added. The organic phase was washed with water (2×) and

brine, dried, filtered, and evaporated. Chromatography (10%

EtOAc in hexanes) gave 47 (120 mg, 96%) as a colorless,

unstable oil: R_f) 0.21 (10% EtOAc in hexanes); IR (thin film)

3312, 3026, 2961, 2918, 2874, 2221, 1462, 1378, 1015, 965

EtOAc in hexanes); [R]²⁵) +9.8 (neat); IR (thin film) 2985,

D

1720, 1650, 1250, 1115, 985, 760 cm^-1; H NMR (CDCl₃, 300

1

MHz) δ 7.10 (d, 1H, J ) 11.1 Hz), 6.30 (dd, 1H, J ) 11.2, 15.0

Hz), 6.09 (m, 1H), 4.20 (q, 2H, J ) 7.1 Hz), 2.30-2.10 (m, 2H),

1.92 (s, 3H), 1.58-1.05 (m, 5H), 1.29 (t, 3H, J ) 7.2 Hz), 0.85

(d, 3H, J ) 6.1 Hz), 0.80 (t, 3H, J ) 7.2 Hz); ¹³C NMR (CDCl₃,

100 MHz) δ 168.4, 143.2, 138.4, 125.7, 60.2, 35.6, 33.8, 30.8,

29.2, 18.8, 14.2, 12.4, 11.2; MS (EI) m/ e 224 (M^•+), 179, 139;

HRMS (EI) m/ e calcd for C₁₄H₂₄O₂: (M^•+), 224.1776; found:

(M^•+), 224.1764. Anal. Calcd for C₁₄H₂₄O₂: C, 74.95; H, 10.78.

Found: C, 74.86; H, 10.80%.

1

cm^-1; H NMR (CDCl₃, 300 MHz) δ 6.22 (ddt, 1H, J ) 11.1,

14.5, 1.4 Hz), 6.05 (d, 1H, J ) 10.8 Hz), 5.70 (dt, 1H, J ) 7.0,

14.3 Hz), 4.19 (t, 1H, J ) 6.7 Hz), 2.45 (dd, 2H, J ) 2.5, 6.4

Hz), 2.20-2.03 (m, 2H), 2.03 (t, 1H, J ) 2.4 Hz), 1.72 (s, 3H),

1.50-1.08 (m, 5H), 0.89 (d, 3H, J ) 5.8 Hz), 0.83 (t, 3H, J )

7.0 Hz); ¹³C NMR (CDCl₃, 300 MHz) δ 136.1, 134.8, 126.3,

125.4, 80.8, 75.1, 70.5, 36.1, 33.9, 30.5, 29.3, 25.8, 19.0, 12.1,

11.2; MS (CI) m/ e 220 ([M + NH₄- H₂O]⁺), 203, 181, 163,

(S)-2,8-Dim eth yld eca -2E,4E-d ien -1-ol. DIBAL-H (1 M in

hexanes, 2.20 mL) was slowly added to ester 43 (200 mg, 0.89

Synthesis of the Antifungal Agent Papulacandin D

J . Org. Chem., Vol. 61, No. 3, 1996 1097

133, 119, 93, 81; HRMS (CI) m/ e calcd for C₁₅H₂₆N: ([M -

H₂O + NH₄]⁺), 220.2065; found: ([M - H₂O + NH₄]⁺),

220.2054. The mixture of Mosher esters 67 and 68 was pre-

MHz) δ 167.6, 145.1, 141.1, 136.6, 135.1, 132.4, 130.1, 125.6,

125.5, 119.0, 77.5, 51.3, 40.6, 36.2, 34.0, 30.6, 29.3, 25.8, 19.0,

18.1, 11.9, 11.3, -4.7, -5.1; MS (FAB) m/ e 419, 363, 295;

HRMS (FAB) m/ e calcd for C₁₈H₃₅OSi: ([M - C₇H₉O₂]⁺),

295.2457; found: ([M - C₇H₉O₂]⁺), 295.2432.

1

pared according to the general procedure, key H NMR data

are listed in Table 1; HPLC (Apex silica 5U, EtOAc:hexanes

) 2.5:97.5, 1 mL min^-1) retention times 14.21, 15.57 min (ratio

31:32).

Meth yl (7RS,14S)-8,14-Dim eth yl-7-[(tr ieth ylsilyl)oxy]-

2E,4E,8E,10E-h exa d eca n et et r a en oa t e (51). Alkyne 49

(500 mg, 1.49 mmol) in THF (5 mL) was added, via a cannula,

to a slurry of Cp₂Zr(H)Cl (462 mg, 1.79 mmol) in THF (5 mL).

The mixture was stirred in the dark at room temperature until

a homogenous solution was formed (45 min). Separately,

DIBAL-H (1 M in hexanes, 300 µL, 0.30 mmol) was added to

a slurry of (Ph₃P)₂PdCl₂(104 mg, 0.15 mmol) in THF (1 mL)

at room temperature. After stirring for 10 min, the black

palladium mixture followed by a solution of methyl 3-bromo-

E-acrylate⁴⁶(296 mg, 1.79 mmol) in THF (1 mL) were added,

via a cannula, to the zirconocene derivative. The reaction

mixture was left to stir in the dark, at room temperature for

15 h and poured into water and EtOAc. The organic phase

was washed with brine, dried, evaporated, and chromato-

graphed (2.5% EtOAc in hexanes) to give 51 (514 mg, 82%) as

a viscous oil: R_f) 0.45 (5% EtOAc in hexanes); IR (thin film)

2954, 2911, 2875, 1722, 1644, 1459, 1434, 1261, 1241, 1133,

1064, 1000, 964, 725 cm^-1; ¹H NMR (CDCl₃, 500 MHz) δ 7.25

(dd, 1H, J ) 10.8, 15.3 Hz), 6.15-6.08 (m, 2H), 6.10-6.02 (m,

1H), 5.91 (d, 1H, J ) 10.8 Hz), 5.79 (d, 1H, J ) 15.4), 5.64 (dt,

1H, J ) 7.0, 15.0 Hz), 4.05 (t, 1H, J ) 5.8 Hz), 3.76 (s, 3H),

2.43-2.30 (m, 2H), 2.18-2.02 (m, 2H), 1.69 (s, 3H), 1.48-1.30

(m, 3H), 1.28-1.10 (m, 2H), 0.98-0.85 (m, 15H), 0.60-0.50

(m 6H); ¹³C NMR (CDCl₃, 125 MHz) δ 167.7, 145.1, 141.1,

136.7, 135.2, 130.0, 125.6, 125.5, 119.1, 77.4, 51.4, 40.5, 36.2,

34.1, 30.6, 29.4, 19.1, 11.9, 11.3, 6.8, 4.8; MS (CI) m/ e 421 ([M

+ H]⁺), 391, 306, 289, 229, 132; HRMS (CI) m/ e calcd for

C₂₅H₄₅O₃Si: ([M + H]⁺), 421.3138; found: ([M + H]⁺), 421.3102.

Anal. Calcd for C₂₅H₄₄O₃Si: C, 71.37; H, 10.54. Found: C,

71.32; H, 10.56%.

ter t-Bu t yld im et h yl[[(4RS,11S)-5,11-d im et h ylt r id eca -

5E,7E-d ien -1-yn -4-yl]oxy]sila n e (48). tert-Butyldimethyl-

silyl chloride (249 mg, 1.65 mmol), imidazole (126 mg, 1.86

mmol), and 4-(dimethylamino)pyridine (10 mg) were added to

alcohol 47 (340 mg, 1.50 mmol) in CH₂Cl₂(10 mL). The

mixture was stirred at room temperature for 4.5 h, quenched

by the addition of saturated aqueous NH₄Cl (2 mL), and

extracted with Et₂O (3×). The organic extracts were washed

with water (3×), dried, filtered, and evaporated. The resultant

pale yellow oil was chromatographed (5% EtOAc in hexanes)

to yield 48 (500 mg, 95%) as a colorless, viscous oil: R_f) 0.25

(neat hexanes); IR (thin film) 3314, 2958, 2929, 2857, 1471,

1463, 1388, 1378, 1361, 1252 1078, 1006, 966, 937, 838, 777,

635 cm^-1; ¹H NMR (CDCl₃, 300 MHz) δ 6.20 (ddt, 1H, J ) 1.4,

10.8, 15.0 Hz), 5.95 (d, 1H, J ) 10.7 Hz) 5.65 (dt, 1H, J ) 6.9,

14.9 Hz), 4.17 (t, 1H, J ) 6.5 Hz), 2.50-2.30 (m, 2H), 2.20-

2.00 (m, 2H), 1.94 (t, 1H, J ) 2.6 Hz), 1.69 (s, 3H), 1.50-1.10

(m, 5H), 0.95-0.80 (m, 15H), 0.07 (2s, 6H); ¹³C NMR (CDCl₃,

75 MHz) δ 135.9, 135.3, 126.2, 125.7, 81.9, 77.1, 69.6, 36.2,

34.1, 30.6, 29.4, 27.1, 25.8, 19.1, 18.2, 11.5, 11.3, -4.8, -5.0.

Anal. Calcd for C₂₁H₃₈OSi: C, 75.37; H, 11.44. Found: C,

75.28; H, 11.42%.

[[(4RS,11S)-5,11-Dim eth yltr ideca-5E,7E-dien -1-yn -4-yl]-

oxy]tr ieth ylsila n e (49). Et₃SiCl (252 mg, 281 µL, 1.68

mmol), imidazole (274 mg, 2.23 mmol), and 4-(dimethylamino)-

pyridine (114 mg, 1.67 mmol) were added to alcohol 47 (246

mg, 1.11 mmol) in CH₂Cl₂(5 mL). After 30 min, water (2 mL)

was added and the mixture extracted with EtOAc. The organic

layer was washed with water and brine, dried, filtered, and

evaporated. Chromatography (5% CH₂Cl₂in hexanes) gave

49 (355 mg, 95%) as a colorless, viscous oil: R_f) 0.25

(hexanes); IR (thin film) 3314, 2956, 2876, 2100, 1460, 1239,

1074, 1006, 966, 743, 635 cm^-1; ¹H NMR (CDCl₃, 500 MHz) δ

6.20 (ddt, 1H, J ) 1.4, 12.3, 15.1 Hz), 5.95 (d, 1H, J ) 10.9

Hz), 5.65 (dt, 1H, J ) 6.9, 15.0 Hz), 4.15 (t, 1H, J ) 6.6), 2.42-

2.30 (m, 2H), 2.18-2.00 (m, 2H), 1.92 (t, 1H, J ) 2.6 Hz), 1.68

(s, 3H), 1.45-1.10 (m, 5H), 0.96-0.90 (m, 6H), 0.81-0.88 (m,

9H), 0.60-0.53 (m, 6H); ¹³C NMR (CDCl₃, 125 MHz) δ 135.9,

135.4, 126.2, 125.6, 81.8, 69.6, 36.2, 34.0, 30.6, 29.4, 27.0, 19.1,

11.5, 11.3, 6.8, 4.8; MS (CI) m/ e 352 ([M + NH₄]⁺), 295, 205;

HRMS (CI) m/ e calcd for C₂₁H₄₂NOSi: ([M + NH₄]⁺), 252.3036;

found: ([M + NH₄]⁺), 252.3067. Anal. Calcd for C₂₁H₃₈OSi₄:

C, 75.38; H, 11.45. Found: C, 75.45; H, 11.73.

Meth yl (7RS,14S)-8,14-Dim eth yl-7-[(ter t-bu tyld im eth -

ylsilyl)oxy]-2E,4E,8E, 10E-h exa d eca n etetr a en oa te (50).

Alkyne 48 (500 mg, 1.5 mmol) in THF (10 mL) was added, via

a cannula, to a slurry of Cp₂Zr(H)Cl (420 mg, 1.63 mmol) in

THF (20 mL) at 0 °C. The mixture was stirred in the dark at

room temperature for 6 h, cooled to 0 °C, and I₂(390 mg, 1.5

mmol) in THF (10 mL) was added dropwise. The solution was

partitioned between aqueous sodium thiosulfate and Et₂O and

the aqueous phase reextracted with Et₂O (2×). The combined

organic extracts were washed with water, dried, and evapo-

rated to leave a yellow oil. This was dissolved in DMF (10

mL) to which was added methyl 3-(tributylstannyl)-E-acry-

late⁶⁴(560 mg, 1.5 mmol) and (MeCN)₂PdCl₂(10 mg, 5 mol

%). After 1 h, the black reaction mixture was added to aqueous

ammonia and extracted with Et₂O (3×). The combined organic

extracts were washed with water, dried, evaporated, and

chromatographed (4% EtOAc in hexanes) to give ester 50 (120

mg, 30%) as a yellow oil: R_f) 0.41 (4% EtOAc in hexanes);

IR (thin film) 2956, 2929, 2856, 1723, 1645, 1259, 1136, 1067,

1001, 966, 836 cm^-1; ¹H NMR (CDCl₃, 300 MHz) δ 7.31-7.24

(dd, 1H, J ) 10.7, 15.4 Hz), 6.26-6.17 (m, 2H), 6.13-6.07

(pentet, 1H, J ) 7.4, 14.8 Hz), 5.95 (d, 1H, J ) 11.3 Hz), 5.8

(d, 1H, J ) 15.4 Hz), 5.7-5.6 (app pentet, 1H, J ) 7.2, 14.6

Hz), 4.1 (dt, 1H, J ) 5.2, 7.2 Hz), 3.77 (s, 3H), 2.5-2.3 (m,

2H), 2.2-2.0 (m, 2H), 1.71 (s, 3H), 1.5-1.1 (m, 5H), 0.90 (m

with s, 15H), 0.04 (s, 3H), 0.03 (s, 3H); ¹³C NMR (CDCl₃, 125

(4S ,11S )-5,11-Dim e t h yl-4-t r id e ca -5E ,7E -d ie n -1-yn -

4-yl (R)-2-Meth oxy-2-p h en yla ceta te (55) a n d (4R,11S)-5,-

11-Dim eth yl-4-tr ideca-5E,7E-dien -1-yn -4-yl (R)-2-Meth oxy-

2-p h en yla ceta te (56). Trifluoromethanesulfonic anhydride

(141 µL, 209 mg, 0.99 mmol) was added dropwise to (R)-O-

methylmandelic acid (116 mg, 0.99 mmol) and pyridine (161

µL, 157 mg, 1.99 mmol) in CH₂Cl₂(4 mL) at -78 °C. The

mixture was stirred at -78 °C for 10 min and then added, via

cannula, to the alcohol 47 (110 mg, 0.50 mmol) in CH₂Cl₂(2

mL) at -78 °C. The mixture was slowly warmed up to room

temperature when saturated aqueous NaHCO₃(1 mL) and

Et₂O (25 mL) were added. The separated organic phase was

washed with aqueous calcium sulfate (1 M, 5 mL) and dried.

Filtration, evaporation, and chromatography (5% EtOAc in

hexanes) gave the more polar diastereoisomer (26 mg, 14%)

and the less polar diastereoisomer (29 mg, 16%). The more

polar diastereoisomer showed: R_f) 0.28 (10% EtOAc in

hexanes); IR (film) 3311, 2360, 1754, 1455, 1248, 1171, 1029,

967 cm^-^{1 1}H NMR (CDCl₃, 300 MHz) δ 7.50-7.30 (m, 5H),

;

6.05 (dd, 1H, J ) 10.8, 14.8 Hz), 5.75 (d, 1H, J ) 10.9 Hz),

5.55 (dt, 1H, J ) 6.9, 15.0 Hz), 5.34 (t, 1H, J ) 6.7 Hz), 4.79

(s, 1H), 3.41 (s, 3H), 2.52-2.33 (m, 2H), 2.20-1.95 (m, 2H),

1.95 (t, 1H, J ) 2.1 Hz), 1.49 (s, 3H), 1.50-1.00 (m, 5H), 0.90

(m, 6H); ¹³C NMR (CDCl₃, 75 MHz) δ 169.5, 137.1, 136.2, 130.2,

128.6, 128.4, 128.3, 127.0, 124.9, 82.5, 79.0, 77.1, 70.3, 57.2,

35.9, 33.7, 30.4, 29.2, 22.9, 18.9, 12.3, 11.1; HRMS calcd for

C₂₄H₃₂O₃: (M^•+), 368.2351; found: (M^•+), 368.2357. The less

polar diastereoisomer showed: R_f) 0.33 (EtOAc in hexanes);

IR (thin film) 3311, 2360, 1754, 1455, 1248, 1171, 1029, 967

1

cm^-1; H NMR (CDCl₃, 300 MHz) δ 7.50 -7.20 (m, 5H), 6.15

(dd, 1H, J ) 10.9, 12.9 Hz), 6.00 (d, 1H, J ) 10.9 Hz), 5.70 (dt,

1H, J ) 7.0, 14.8 Hz), 5.35 (t, 1H, J ) 6.8 Hz), 4.77 (s, 1H),

3.43 (s, 3H), 2.50-2.30 (m, 2H), 2.30-2.20 (m, 2H), 1.78 (t,

1H, J ) 2.3 Hz), 1.64 (s, 3H), 1.50-1.00 (m, 5H), 0.90 (m, 6H);

¹³C NMR (CDCl₃, 75 MHz) δ 169.2, 136.7, 136.1 130.1, 128.4,

128.3, 127.9, 127.2, 124.8, 82.3, 79.3, 76.7, 70.3, 57.0, 35.9, 33.7,

29.2, 23.2, 18.8, 12.2, 11.1; HRMS calcd for C₂₄H₃₂O₃: (M^•+),

368.2351; found: (M^•+), 368.2357.

(64) Curran, D. P. Synthesis 1988, 417, 489.

1098 J . Org. Chem., Vol. 61, No. 3, 1996

Barrett et al.

(4S,11S)-5,11-Dim eth yltr ideca-5E,7E-dien -1-yn -4-ol (53).

Titanium tetraisopropoxide (1.30 g, 4.56 mmol), ^D-(-)-diiso-

propyl tartrate (1.83 g, 5.48 mmol) and tert-butyl hydroper-

oxide in CH₂Cl₂(4.26 M; 1.29 mL) were added to a slurry of

powdered 4 Å molecular sieves (1.5 g) in CH₂Cl₂(40 mL) at

-20 °C. After 30 min, alcohol 47 (2.0 g, 9.13 mmol) in CH₂-

Cl₂(10 mL) and slowly added to the mixture at -50 °C via a

syringe pump (4 mL/h). The reaction mixture was stirred at

-50 °C for 70 h and quenched with water (6 mL) at -50 °C.

After being warmed up to room temperature, the mixture was

filtered through Celite, and the filtrate was partitioned

between EtOAc and brine. The organic phase was dried,

filtered, evaporated, and chromatographed (10% EtOAc in

hexanes) to give 53 (900 mg, 45%) and epoxide 52 (307 mg,

added to water and EtOAc. The organic phase was washed

with brine, dried, and evaporated. Chromatography (2.5%

EtOAc in hexanes) gave 54 (176 mg, 70%) as a viscous oil:

[R]²⁵) +16.0 (c ) 0.85 in CHCl₃); other spectroscopic data

D

were identical with those from 51.

Meth yl (7RS,14S)-8,14-Dim eth yl-4-h yd r oxy-2E,4E,8E,-

10E-h exa d eca n etetr a en oa te (65/66). Tetrabutylammoni-

um fluoride in THF (1 M; 200 µL) was added to ether 51 (42

mg, 0.10 mmol) in THF (1 mL) at 0 °C. After 30 min, the

solution was added to water and extracted with EtOAc (3×).

The combined organic layers were washed with brine, dried,

filtered, and evaporated. Chromatography (25% EtOAc in

hexanes) gave the title alcohol (36 mg, 100%): R_f) 0.31 (25%

EtOAc in hexanes); IR (thin film) 3440, 2959, 2924, 2874, 1721,

1644, 1617, 1434, 1262, 1135, 1000, 966 cm^-1; ¹H NMR (CDCl₃,

500 MHz) δ 7.25 (dd, 1H, J ) 10.5, 14.5 Hz), 6.31-6.19 (m,

2H), 6.14-6.05 (m, 1H), 6.0 (d, 1H, J ) 10.8 Hz), 5.82 (d, 1H,

J ) 15.4 Hz), 5.72 (dt, 1H, J ) 7.0, 15.0 Hz), 4.14 (t, 1H, J )

6.5 Hz), 3.74 (s, 3H), 2.45 (t, 2H, J ) 6.9 Hz), 2.25-2.05 (m,

2H), 1.75 (d, 3H, J ) 0.5 Hz), 1.5-1.3 (m, 3H), 1.3-1.1 (m,

2H), 0.95-0.70 (m, 6H); ¹³C NMR (CDCl₃, 125 MHz) δ 167.6,

144.8, 140.0, 136.2, 136.0, 130.7, 126.1, 125.4, 119.6, 77.0, 51.5,

38.9, 36.3, 34.0, 30.6, 29.4, 19.1, 12.2, 11.3; MS (CI) m/ e 324

([M + NH₄]⁺), 307 ([M + H]⁺), 289, 229, 181, 163, 126, 93;

HRMS (CI) m/ e calcd for C₁₉H₃₄NO₃: ([M + NH₄]⁺), 324.2539;

found: 324.2543; calcd for C₁₉H₃₁O₃: ([M + H]⁺), 307.2273;

found: ([M + H]⁺), 307.2291. The mixture of Mosher esters

62 and 63 was prepared according to the general procedure;

14%) both as viscous, colorless oils. Alcohol 53 showed: [R]²⁵

D

) +16.5 (c ) 1.49, CHCl₃); all spectroscopic data were identical

with those from 47. The Mosher ester 67 was prepared

according to the general procedure, key ¹H NMR data are listed

in Table 1; HPLC (Apex silica 5U, EtOAc:hexanes ) 2.5:97.5,

1 mL min^-1) retention times 14.21, 15.57 min (ratio 66:3).

Epoxide 52 showed: R_f) 0.12 (10% EtOAc in hexanes); IR

(thin film) 3458, 3313, 2962, 2924, 2874, 1462, 1380, 1069, 969,

-1

849, 727, 633 cm

;

¹H NMR (CDCl₃, 300 MHz) δ 5.95 (dt,

1H, J ) 7.0, 15.5 Hz), 5.35 (ddt, 1H, J ) 1.4, 8.0, 15.4 Hz),

3.90-3.80 (m, 1H), 3.59 (d, 1H, J ) 8.0 Hz), 2.52-2.35 (m,

3H), 2.21-2.00 (m, 3H), 1.50-1.08 (m, 7H), 0.95-0.72 (m, 6H);

¹³C NMR (CDCl₃, 75 MHz) δ 142.5, 139.6, 129.7, 126.7, 83.6,

78.5, 74.6, 73.9, 72.8, 66.9, 63.4, 39.1, 37.3, 33.6, 31.7, 26.2,

22.4, 17.7, 15.6, 14.6; MS (CI) m/ e 237 ([M + H]⁺), 219, 197,

179, 167, 151, 135, 123, 109, 95, 81; HRMS (EI) calcd for

C₁₅H₂₅O₂: ([M + H]⁺), 237.1855; found: ([M + H]⁺), 237.1846.

(4R,11S)-5,11-Dim eth yltr ideca-5E,7E-dien -1-yn -4-ol (57).

Reaction of titanium tetraisopropoxide (202 µL, 0.68 mmol),

L-(+)-diisopropyl tartrate (172 µL, 0.82 mmol), tert-butyl hydro-

peroxide in CH₂Cl₂(4.27 M; 191 µL), and 4 Å molecular sieves

(0.3 g) in CH₂Cl₂(2 mL) with alcohol 47 (300 mg, 1.36 mmol)

in CH₂Cl₂(8 mL) at -20 °C and workup as for 53 gave alcohol

57 (121 mg, 40%) and an epoxide (53 mg, 33%) both as viscous,

HPLC (Apex silica 5U, EtOAc:hexanes ) 2.5:97.5, 1 mL min^-1

retention times 22.1, 26.4 min (ratio 20.4:21.4).

)

Meth yl (7S,14S)-8,14-Dim eth yl-4-h yd r oxyh exa d eca n e-

2E,4E,8E,10E-tetr a en oa te (65). Tetrabutylammonium fluo-

ride in THF (1 M; 238 µL) and silyl ether 54 (50 mg, 0.12

mmol) in THF (1 mL) were stirred at 0 °C for 30 min and added

to water, and the resulting mixture was extracted with EtOAc

(3×). The combined organic layers were washed with brine,

dried, filtered, and chromatographed (25% EtOAc in hexanes)

to give alcohol 65 (43 mg, 100%): [R]²⁵) +4.9 (c ) 1.31 in

D

colorless oils. The alcohol 57 showed [R]²⁵) +4.5 (c ) 1.07,

CHCl₃, 96% de); all spectroscopic data were identical with

D

CHCl₃), with other spectroscopic data identical with that for

47 and 53. The Mosher ester 68 was prepared according to

the general procedure, key ¹H NMR data are listed in Table

1. The epoxide side product was not characterized further.

{[(4S,11S)-5,11-Dim eth yltr id eca -5E,7E-d ien -1-yn -4-yl]-

oxy}tr ieth ylsila n e. Et₃SiCl (923 mg, 1.02 mL, 6.13 mmol),

imidazole (1.00 g, 8.17 mmol), 4-(dimethylamino)pyridine (417

mg, 6.13 mmol), and alcohol 53 (900 mg, 4.09 mmol) in CH₂-

Cl₂(12 mL) were allowed to react at room temperature for 0.5

h before being quenched by the addition of water (10 mL) and

extracted with EtOAc. The organic phase was washed with

water and brine, dried, filtered, and evaporated. Chromatog-

raphy (5% CH₂Cl₂in hexanes) gave the title ether (1.34 g, 98%)

those from 65/66. The Mosher ester 62 was prepared accord-

1

ing to the general procedure; key H NMR data are listed in

Table 2; HPLC (Apex silica 5U, EtOAc:hexanes ) 2.5:97.5, 1

1

mL min^-1) retention times 22.1, 26.1 min (ratio 2.1:95.2); H

NMR (CDCl₃, 500 MHz) see Table 2; ¹³C NMR (C₆D₆, 125 MHz)

δ 166.8, 165.7, 144.2, 137.7, 137.5, 133.0, 131.7, 130.9, 129.7,

129.6, 128.5, 128.3, 128.2, 128.0, 127.8, 125.4, 123.1, 121.0,

80.6, 55.5, 51.0, 36.5, 36.4, 34.2, 30.9, 29.7, 19.1, 12.2, 11.5.

Meth yl (7R,14S)-8,14-Dim eth yl-4-h yd r oxyh exa d eca n e-

2E,4E,8E,10E-tetr a en oa te (66). The ester 66 was prepared

from alcohol 57 via the corresponding triethylsilyl ether and

58 and desilylation using exactly the same methods as for the

epimer 65. Alcohol 66 was spectroscopically identical with the

both the mixture of 65 and 66 and the sample of 65 derived

via Sharpless epoxidation. The Mosher ester 63 was prepared

as a colorless, viscous oil: [R]²⁵) +15.2 (c ) 1.26 in CHCl₃);

D

other spoectroscopic data were identical with those from 49.

{[(4R,11S)-5,11-Dim eth yltr id eca -5E,7E-d ien -1-yn -4-yl]-

oxy}tr ieth ylsila n e. Reaction of Et₃SiCl (111 µL, 0.66 mmol),

imidazole (112 mg, 1.65 mmol), 4-(dimethylamino)pyridine (80

mg, 0.66 mmol), and alcohol 55 (121 mg, 0.55 mmol) in

CH₂Cl₂(1 mL) and workup as in the preceding experiment

according to the general procedure; [R]²⁵) +45.0 (c ) 1.65

D

in CHCl₃); key ¹H NMR data are listed in Table 2; HPLC (Apex

silica 5U, EtOAc:hexanes ) 2.5:97.5, 1 mL min^-1) retention

1

time 22.1 min only; H NMR (CDCl₃, 500 MHz) see Table 2;

¹³C NMR (C₆D₆, 125 MHz) δ 166.8, 165.9, 144.3, 138.0, 137.1,

133.1, 131.6, 130.8, 130.2, 129.7, 128.6, 128.3, 128.2, 128.0,

127.8, 125.4, 120.9, 80.5, 55.3, 51.0, 36.4, 36.3, 34.2, 30.9, 30.2,

29.6, 19.1, 12.3, 11.4.

gave the title silane (165 mg, 90%): [R]²⁵) -4.0 (c ) 0.885

D

in CHCl₃) with all other data identical with that for 49 and

the (4S)-epimer.

Met h yl (7S,14S)-8,14-Dim et h yl-7-[(t r iet h ylsilyl)oxy]-

2E,4E,8E,10E-h exa d eca n et et r a en oa t e (54). {[(4S,11S)-

5,11-Dim et h ylt r ideca -5E ,7E -dien -1-yn -4-yl]oxy}t r iet h -

ylsilane (200 mg, 0.60 mmol) in THF (2.0 mL) was added, via

a cannula, to a slurry of Cp₂Zr(H)Cl (170 mg, 0.66 mmol) in

THF (2.5 mL). The mixture was stirred at room temperature

in the dark until a homogenous solution was formed (45 min).

Separately, DIBAL-H (1 M in hexanes, 120 µL, 0.12 mmol)

was added to a slurry of (Ph₃P)₂PdCl₂(42 mg, 0.06 mmol) in

THF (1 mL) at room temperature. After 10 min, the black

palladium mixture was transferred, via a cannula, into the

zirconium mixture followed by a solution of methyl 3-bromo-

E-acrylate⁴⁶(118 mg, 0.72 mmol) in THF (1 mL). After stirring

in the dark at room temperature for 15 h, the mixture was

F er m en ta tion of P . sph er osper m a . P. spherosperma was

obtained stored at 4 °C as slants from the United States

Department of Agriculture, Peoria, IL (NRRL 8086). An agar

medium (200 mL) consisted of yeast extract (0.8 g), malt

extract (2 g), glucose (0.8 g), and agar (4 g) adjusted to pH 8

before sterilization. The slants were incubated at 25 °C, and

growth was observed after 48 h, with exponential growth being

observed after 6 days at which point the slopes were cooled to

4 °C for storage. A nutrient broth (1300 mL) containing soy-

bean meal (2%, 26 g) and mannitol (2%, 26 g) was prepared

and adjusted to pH 8.2, with NaOH (1 M), before being divided

into five flasks: Two Erlenmeyer flasks (2 L) with four baffles

each containing 500 mL of broth and three Erlenmeyer flasks

(500 mL) each containing nutrient broth (100 mL) were steri-

Synthesis of the Antifungal Agent Papulacandin D

J . Org. Chem., Vol. 61, No. 3, 1996 1099

lized. Two of the 500 mL flasks, from above, were inoculated

with P. spherosperma by washing one of the previously pre-

pared slants with pH 7 buffer (5 mL), agitating the surface

and transferring the liquid to the flask. A separate culture

slant was used for each flask of nutrient broth and they were

labeled A and B. Flasks A and B were then shaken at 450

rpm at 24 °C for 2 days. A small amount of the liquid used to

inoculate flasks A and B was inspected for bacterial contami-

nation by incubating at 37 °C on a nutrient agar. However,

after 4 days no growth was seen. The two 2 L flasks (contain-

ing 500 mL of broth) were inoculated with the two day old

broth (A and B) and these flasks were labeled A′ and B′. A′

and B′ were shaken at 750 rpm at 24 °C for 2 days. Again,

both inoculants were examined for bacterial contamination

and, as before, no growth was observed. A 20 L fermenter was

filled with nutrient broth (15 L) made from mannitol (300 g)

and soybean meal (300 g). The fermenter and nutrient broth

were sterilized and inoculated with the two day old cultures

A′ and B′ (500 mL of each). The mixture was stirred at 390

rpm with 0.5 L/L/min of air passing through the solution. Due

to extreme foaming of the mixture, polyethylene glycol (25 mL)

was added as an antifoaming agent, but due to the persistence

of the foam, Dow Corning 1510 silicone antifoam (2 mL) was

also added. The mixture was stirred for two days at which

point the pH started to drop, and mass spectrum analysis of

the efluent gases showed the presence of CO₂, while O₂and

N₂levels remained constant. After 4 and 5 days, respectively,

the pH had reached 6.5 and 7.8, and the mixture became very

viscous.

The fungus was harvested and filtered through Celite to

remove the mycelium which was washed with copious amounts

of MeOH and the MeOH washes were concentrated, in vacuo,

to an aqueous residue. This residue was extracted with EtOAc

(3×, 1000 mL), at which time an emulsion occurred, and

repeated filtrations were needed to obtain separation of the

aqueous and organic phases. The organic phase was concen-

trated to a dark oil. The aqueous filtrate from the fermenter

was also extracted with EtOAc (3 × 1000 mL), and again

multiple filtrations were needed to break down emulsions.

After concentration of these extracts, the oily residue was

combined with the residue from the mycelium extracts and

the mixture was dissolved in EtOAc (2000 mL) and dried.

Filtration and concentration left a yellow oil which was

dissolved in aqueous MeOH (85% MeOH) and extracted with

hexanes (3 × 800 mL) to remove nonpolar impurities. Evapo-

ration of the MeOH/water layer left an aqueous phase which

was extracted with EtOAc (3 × 1000 mL), and these combined

extracts were dried and filtered. Evaporation gave a yellow

oil which was chromatographed (20% MeOH in CHCl₃) col-

lecting all fractions with a R_fbetween 1.4 and 2.5 (developing

solvent 20% MeOH in CHCl₃). These combined fractions were

evaporated, and the residue was rechromatographed using

gradient elution (10-20% MeOH in CHCl₃). Again fractions

which contained compounds with R_fvalues between 1.4 and

2.5 were combined and evaporated. The resultant residue (1.2

g) was shown to contain a mixture of components with HPLC/

UV characteristics (Spher ODS 2, H₂O:MeOH ) 1:3) consistent

with the papulacandins A, B, C, and D (1). This crude mixture

was used directly in the experiments to follow.

prepared according to the general procedure; the ¹H and ¹³C

NMR spectra were identical with those from 62 and nonidenti-

cal with those from 63; HPLC (Apex silica 5U, EtOAc:hexanes

) 2.5:97.5, 1 mL min^-1) retention time 26.1 min only.

(S)-4-Meth ylh exan al 2,4-Din itr oph en ylh ydr azon e fr om

th e Au th en tic P a p u la ca n d in Diester (60). Ozone was

bubbled through the Mosher ester 60 (79 mg) in MeOH (5 mL)

at -78 °C until a faint blue color was observed. Me₂S (217

µL, 187 mg, 3.02 mmol) was added, and the mixture was

allowed to slowly warm up to room temperature. After 2 h,

(2,4-dinitrophenyl)hydrazine solution (30 mL) was added and

the mixture stirred overnight. The solution was added to

water and extracted with EtOAc (3×). The combined organic

layers were washed with water and brine, dried, and chro-

matographed (10% EtOAc in hexanes) to give 61 (27.6 mg,

62%): mp ) 79-82 °C (plates from EtOH); [R]²⁵) +13.2 (c

D

) 0.29 in CHCl₃), with all spectroscopic data identical with a

sample prepared from 40.

(S)-4-Meth ylh exan al 2,4-Din itr oph en ylh ydr azon e fr om

th e Syn th etic Diester Mixtu r e 62/63. Ozonolysis of 62/63

(79 mg) as for 60 gave the corresponding aldehyde isolated as

the 2,4-dinitrophenylhydrazone 64 (21 mg, 50%) identical with

the sample prepared from isoleucine (37) via 38, 39, and 40.

(7S,14S)-8,14-Dim eth yl-4-[(tr ieth ylsilyl)oxy]h exadecan e-

2E,4E, 8E,10E-tetr a en oic Acid (69). KOSiMe₃(320 mg, 2.40

mmol) and ester 54 (100 mg, 0.24 mmol) in THF (4 mL) were

allowed to react at room temperature for 3 h when aqueous

citric acid (0.5 M, 5 mL) was added. The mixture was

extracted with EtOAc and the organic layer washed with brine,

dried, filtered, and evaporated. The residue was rapidly chro-

matographed (50% EtOAc in hexanes) to give the unstable acid

69 (98 mg, 100%) as a pale yellow oil which was used directly

without further purification: R_f) 0.55 (50% EtOAc in hex-

anes); ¹H NMR (CDCl₃, 300 MHz) δ 7.35 (dd, 1H J ) 10.2,

15.3 Hz), 6.33-6.10 (m, 2H), 5.93 (d, 1H, J ) 10.8 Hz), 5.80

(d, 1H, J ) 15.3 Hz), 5.67 (dt, 1H, J ) 6.9, 15.0 Hz), 4.13 (t,

1H, J ) 7.1 Hz), 2.55-2.30 (m, 2H), 2.25-2.05 (m, 2H), 1.71

(s, 3H), 1.50-1.10 (m, 5H), 1.00-0.83 (m, 15H), 0.58 (m, 6H);

¹³C NMR (CDCl₃, 75 MHz) δ 172.6, 147.2, 142.4, 136.6, 135.3,

130.0, 125.6, 118.6, 40.5, 36.2, 34.0, 30.6, 29.4, 19.1, 11.9, 11.3,

6.8, 4.8.

1,1-An h yd r o-1-C-{6-(h yd r oxym et h yl)-2,4-b is[(ter t-b u -

tyldim eth ylsilyl)oxy]ph en yl}-4,6-O-(di-ter t-bu tylsilylen e)-

3-O-{(7S,14S)-8,14-dim eth yl-7-[(tr ieth ylsilyl)oxy]h exadeca-

2E,4E,8E,10E-tetr a en oyl}-â-^D-glu cop yr a n ose (71) a n d 1,1-

An h yd r o-1-C-{6-(h yd r oxym e t h yl)-2,4-b is[(t er t -b u t yl-

d im eth ylsilyl)oxy]p h en yl}-4,6-O-(d i-ter t-bu tylsilylen e)-

2-O-{(7S,14S)-8,14-dim eth yl-7-[(tr ieth ylsilyl)oxy]h exadeca-

2E,4E,8E,10E-tetr a en oyl}-â-^D-glu cop yr a n ose (72). Et₃N

(50 µL, 36 mg, 0.36 mmol) and, after 10 min, 2,4,6-trichlo-

robenzoyl chloride (40 µL, 64 mg, 0.26 mmol) were added to

acid 69 (96 mg, 0.24 mmol) in THF (3 mL). After 1 h, solvent

was evaporated and the residue in DMF (2 mL) was added,

via cannula, to diol 31 (238 mg, 0.36 mmol) and 4-(dimethyl-

amino)pyridine (52 mg, 0.43 mmol) in DMF (1 mL). Water

was added after 17 h, and the resulting mixture was extracted

with EtOAc. The organic phase was washed with water and

brine, dried, filtered, and evaporated. The resultant oil was

purified by gradient chromatography (5-10% EtOAc in hex-

anes) to yield the esters 71 and 72 (130 mg, 1:1, 60%). Frac-

tions containing the 3-ester 71 showed: R_f) 0.20 (10% EtOAc

in hexanes); IR (KBr) 3471, 2962, 2938, 2861, 1720, 1644, 1602,

1471, 1434, 1363, 1259, 1164, 1076, 1000, 970, 835, 781, 744,

655 cm^-1; ¹H NMR (CDCl₃, 500 MHz) δ 7.27 (dd, 1H, J ) 15.3,

10.9 Hz), 6.29 (d, 1H, J ) 1.6 Hz), 6.24-6.16 (m, 2H), 6.19 (d,

1H, J ) 1.8 Hz), 6.20-6.02 (m, 1H), 5.92 (d, 1H, J ) 10.8 Hz),

5.88 (d, 1H, J ) 15.4 Hz), 5.65 (dt, 1H, J ) 6.9, 15.0), 5.29 (t,

1H, J ) 9.1 Hz), 5.14 (d, 1H, J ) 12.7 Hz), 4.38 (t, 1H, J )

10.1 Hz), 4.13 (dd, 1H, J ) 4.7, 9.9 Hz), 4.10-3.96 (m, 3H),

3.85 (t, 1H, J ) 9.9 Hz), 2.45-2.30 (m, 2H), 2.20-2.04 (m, 2H),

2.00 (d, 1H, J ) 10.5 Hz), 1.69 (s, 3H), 1.42-1.10 (m, 5H),

1.02 (s, 18H), 0.99 (s, 9H), 0.98 (s, 9H), 0.92 (t, 6H, J ) 7.9

Hz), 0.90-0.84 (m, 6H), 0.55 (q, 9H, J ) 7.9 Hz), 0.28 (s, 3H),

0.25 (s, 3H), 0.18 (s, 6H); ¹³C NMR (CDCl₃, 125 MHz) δ 167.6,

158.4, 151.8, 145.1, 143.4, 140.9, 136.8, 135.2, 130.2, 125.6,

125.5, 119.7, 119.6, 110.9, 109.9, 105.2, 77.5, 76.5, 74.8, 73.3,

P r ep a r a tion of th e Au th en tic Sid e Ch a in Ester (59).

LiOH‚H₂O (372 mg) was added to the crude papulacandin

fraction (621 mg) in THF (8 mL) and water (16 mL), and the

mixture was stirred at ambient temperature for 4 h. The pH

of the solution was adjusted to 6 with hydrochloric acid (1 M),

and the aqueous mixture was extracted with EtOAc (4×). The

organic phases were combined, washed with brine, and dried.

After filtration and evaporation, the residue was dissolved in

Et₂O (50 mL) and while being stirred, a large excess of

diazomethane [from N-nitroso-N-methylurea (621 mg), Et₂O

(15 mL), and aqueous KOH (40%, 15 mL)] was added. After

13 h, saturated aqueous NaHCO₃was added and the organic

phase washed with water and brine, dried, filtered, and

evaporated. Chromatography (25% EtOAc in hexanes) gave

the natural side chain methyl ester 59 (31 mg): [R]²⁵_D) +5.02

(c ) 1.05, CHCl₃); with all spectroscopic data identical with

the samples of 65/66, 65, and 66. The Mosher ester 60 was

1100 J . Org. Chem., Vol. 61, No. 3, 1996

Barrett et al.

71.6, 68.8, 66.7, 40.5, 36.2, 34.1, 30.6, 30.3, 29.3, 27.4, 27.0,

25.8, 25.6, 22.7, 19.9, 19.1, 18.3, 18.2, 11.9, 11.3, 6.8, 4.8, -3.9,

-4.3, -4.4; MS (FAB) m/ e 1057 ([M + H]⁺), 651, 593, 395,

379, 295, 115, 87, 73; HRMS (FAB) calcd for C₅₇H₁₀₁O₁₀Si₄:

([M + H]⁺), 1057.6455; found: ([M + H]⁺), 1057.6361. Frac-

tions containing the 2-ester 72 showed: R_f) 0.38 (10% EtOAc

in hexanes); [R]²⁵_D) -30.6 (c ) 1.70 in CHCl₃); IR (KBr) 3598,

3467, 2950, 2900, 2859, 1725, 1643, 1604, 1473, 1365, 1261,

1H, J ) 15.4 Hz), 5.12 (d, 1H, J ) 15.5 Hz), 5.00 (d, 1H, J )

12.5 Hz), 4.14 (dd, 1H, J ) 9.9, 5.1 Hz), 4.10-3.92 (m, 4H),

3.86 (t, 1H, J ) 10.1 Hz), 2.40-2.24 (m, 2H), 2.20-2.02 (m,

2H), 1.69 (s, 3H), 1.15-1.40 (m, 11H), 1.20-1.00 (m, 54H), 0.90

(t, 9H, J ) 8.0 Hz), 0.90-0.84 (m, 6H), 0.60-0.50 (m, 6H); ¹³

C

NMR (CDCl₃, 125 MHz) δ 165.9, 158.8, 152.5, 145.0, 143.1,

140.7, 136.7, 135.2, 130.0, 125.6, 125.5, 119.0, 118.5, 109.6,

104.4, 77.6, 77.5, 73.7, 73.3, 68.4, 66.6, 40.4, 36.2, 34.1, 30.6,

29.4, 27.44, 27.39, 27.1, 27.0, 22.8, 20.0, 19.1, 18.1, 18.0, 17.9,

17.8, 17.7, 13.2, 12.7, 12.6, 11.8, 11.3, 6.8, 4.8; MS (FAB) m/ e

1141 ([M + H]⁺), 735, 435, 295, 115, 87, 75, 59.

1

1160, 1076, 1002, 964, 836, 782, 742 cm^-1; H NMR (CDCl₃,

500 MHz) δ 7.04 (dd, 1H, J ) 10.7, 12.3 Hz), 6.20 (d, 1H, J )

1.7 Hz), 6.22-6.14 (m, 1H), 6.14 (d, 1H, J ) 1.8 Hz), 6.10-

5.92 (m, 2H), 5.89 (d, 1H, J ) 10.9 Hz), 5.73 (d, 1H, J ) 9.8

Hz), 5.64 (dt, 1H, J ) 6.9, 15.0), 5.56 (d, 1H, J ) 15.3 Hz),

5.11 (d, 1H, J ) 12.6 Hz), 5.00 (d, 1H, J ) 12.5 Hz), 4.16 (dd,

1H, J ) 5.0, 9.9 Hz), 4.10-3.85 (m, 5H), 2.63 (br s, 1H), 2.40-

2.24 (m, 2H), 2.20-2.00 (m, 2H), 1.67 (s, 3H), 1.45-1.10 (m,

5H), 1.07 (s, 9H), 1.05 (s, 9H), 1.02 (s, 9H), 0.94 (s, 9H), 0.90

(t, 9H, J ) 8.0 Hz), 0.89-0.84 (m, 6H), 0.53 (q, 6H, J ) 7.9

Hz), 0.32 (s, 3H), 0.24 (s, 3H), 0.14 (s, 6H); ¹³C NMR (CDCl₃,

125 MHz) δ 165.8, 158.4, 152.2, 145.0, 143.2, 140.8, 136.6,

135.2, 130.0, 125.6, 125.5, 118.9, 118.6, 109.6, 109.5, 104.7,

77.6, 77.4, 73.6, 73.3, 73.0, 68.4, 66.6, 40.4, 36.2, 34.0, 30.6,

30.3, 29.7, 29.4, 27.5, 27.1, 25.8, 25.6, 22.8, 20.0, 19.0, 18.2,

18.2, 11.9, 11.8, 11.3, 6.8, 4.8, -4.1, -4.3, -4.5; MS (FAB) m/ e

1057 ([M + H]⁺), 1020, 925, 651, 379, 295, 136, 115, 73.

1,1-An h yd r o-1-C-[6-(h yd r oxym et h yl)-2,4-d ih yd r oxy-

p h en yl]-3-O-[(7S,14S)-8,14-d im eth yl-7-h yd r oxyh exa d eca -

2E,4E,8E,10E-tetr a en oyl]-â-^D-glu cop yr a n ose [P a p u la ca n -

d in D (1)]. Tris(dimethylamino)sulfonium difluorotrimethyl-

silicate (TASF) (99 mg, 0.36 mmol) and ester 73 (68 mg, 0.06

mmol) in THF (4 mL) were allowed to react at 0 °C for 4 h.

Since TLC showed that the deprotection was not complete

additional amount of TASF (40 mg, 0.15 mmol) was added.

After 1 h, MeOH (5 mL) was added. Evaporation and chrom-

atography (10% MeOH in CHCl₃) gave a colorless foam which

was dissolved in EtOAc and filtered (removing traces of silica

gel) to leave papulacandin D (1) (22 mg, 64%): R_f) 0.24 (10%

MeOH in CHCl₃); [R]²⁵) +27.5 (c ) 0.25 in MeOH); IR (thin

D

film) 3329, 2959, 2926, 2874, 1698, 1639, 1615, 1463, 1377,

1

1347, 1304, 1261, 1205, 1153, 1070, 1005, 977, 838 cm^-1; H

1,1-An h ydr o-1-C-{6-(h yd r oxym eth yl)-2,4-bis[(tr iisopr o-

pylsilyl)oxy]ph en yl}-4,6-O-(di-ter t-bu tylsilylen e)-3-O-{(7S,-

14S )-8,14-d im e t h y l-7-[(t r ie t h y ls ily l)o x y ]h e x a d e c a -

2E,4E,8E,10E-tetr a en oyl}-â-^D-glu cop yr a n ose (73) a n d 1,1-

An h yd r o1-C-{6-(h yd r oxym eth yl)-2,4-bis[(tr iisop r op ylsi-

lyl)oxy]p h en yl}-4,6-O-(d i-ter t-b u t ylsilylen e)-2-O-{(7S,-

14S )-8,14-d im e t h y l-7-[(t r ie t h y ls ily l)o x y ]h e x a d e c a -

2E,4E,8E,10E-t et r a en oyl}-â-^D-glu cop yr a n ose (74). Acid

69 (94 mg, 0.23 mmol), Et₃N (51 µL, 40 mg, 0.39 mmol), 2,4,6-

trichlorobenzoyl chloride (43 µL, 68 mg, 0.28 mmol), and

4-(dimethylamino)pyridine (5 mg) in THF (3 mL) were allowed

to react at room temperature for 1 h. The mixture was

concentrated via high vacuum (0.1 mmHg), and the remaining

mixed anhydride 70 in DMF (2 mL) was added, via a cannula,

to diol 30 (260 mg, 0.34 mmol) and 4-(dimethylamino)pyridine

(62 mg, 0.51 mmol) in DMF (3 mL). The resulting mixture

was stirred overnight at room temperature, quenched with

water, and extracted with EtOAc. The organic phase was

washed with water (2×) and brine, dried, filtered, and evapo-

rated. Chromatography (5% EtOAc in hexanes) gave the

esters 73 and 74 [157 mg, 60%, 4:1 (3-ester:2-ester)] which

were separated by further chromatography. The 3-ester 73

NMR (CD₃OD, 500 MHz) δ 7.30 (dd, 1H, J ) 10.1, 15.2 Hz),

6.25 (ddt, 1H, J ) 1.3, 10.8, 15.0 Hz), 6.23 (dd, 1H, J ) 10.7,

14.7 Hz), 6.20 (m, 1H), 6.19 (m, 1H), 6.12 (dt, 1H, J ) 14.7,

15.2 Hz), 6.00 (dd, 1H, J ) 0.7, 10.8 Hz), 5.92 (d, 1H, J ) 15.3

Hz), 5.66 (dt, 1H, J ) 7.0, 15.0 Hz), 5.34 (t, 1H, J ) 9.7 Hz),

5.05, 4.99 (ABq, 2H, J ) 12.6 Hz), 4.33 (d, 1H, J ) 10.0 Hz),

4.07 (t, 1H, J ) 6.6 Hz), 3.87 (ddd, 1H, J ) 2.3, 4.8, 10.1 Hz),

3.70-3.66 (m, 2H), 3.68 (t, 1H, J ) 9.7 Hz), 2.42 (t, 2H, J )

7.0 Hz), 2.18-2.04 (m, 2H), 1.71 (d, 3H, J ) 0.5 Hz), 1.49-

1.29 (m, 3H), 1.28-1.11 (m, 2H), 0.87 (t, 3H, J ) 7.3 Hz), 0.87

(d, 3H, J ) 6.6 Hz); ¹³C NMR (CD₃OD, 125 MHz) δ 169.0,

161.5, 154.7, 146.4, 145.5, 141.8, 137.5, 136.2, 131.5, 127.1,

127.0, 120.9, 116.7, 112.1, 103.0, 99.9, 78.4, 77.5, 75.8, 73.8,

71.9, 69.8, 62.5, 40.0, 37.5, 35.2, 31.6, 30.4, 19.4, 12.2, 11.7;

MS (FAB) m/ e 575 ([M + H]⁺), 394, 205, 181, 167, 89, 77, 55;

HRMS (FAB) m/ e calcd for C₃₁H₄₃O₁₀: ([M + H]⁺), 575.2856;

found: ([M + H]⁺) 579.2908.

Ack n ow led gm en t. We thank Myco Pharmaceutical

Inc. for continued generous support of our programs on

antifungal compounds and Ciba-Geigy Pharmaceutical

Company Ltd. for a sample of papulacandin D (1), the

United States Department of Agriculture-Agriculture

Research Service for supplying a culture of P. spherosper-

ma (NRRL 8086), Dr. David Leak and Mr. J ames

Mansfield at Imperial College Department of Biochem-

istry for their help in growing this culture, Dr. Alex F.

Drake and Dr. Giuliano Siligardi at the EPSRC Na-

tional Chiroptical Centre for performing the circular

dichroism experiments, Dr. J ason M. Hill for carrying

out back-up synthetic work on the early stages of the

side chain synthesis, Glaxo Group Research Ltd. for the

most generous endowment (to A.G.M.B.), the Wolfson

Foundation for establishing the Wolfson Centre for

Organic Chemistry in Medical Science at Imperial

College, and the National Institutes of Health (AI-

22252) for support when this work started in the U.S.A.

showed R_f) 0.22 (5% EtOAc in hexanes); [R]²⁵) -1.4 (c )

D

1.36 in CHCl₃); IR (thin film) 3457, 2946, 2868, 1721, 1644,

1599, 1463, 1366, 1355, 1248, 1169, 1075, 999, 970, 835, 768

1

cm^-1; H NMR (CDCl₃, 500 MHz) δ 7.27 (dd, 1H, H ) 10.9,

15.3 Hz), 6.31 (s, 1H), 6.25-6.15 (m, 2H), 6.10-6.00 (m, 1H),

5.92 (d, 1H, J ) 10.8 Hz), 5.88 (d, 1H, J ) 15.4 Hz), 5.65 (dt,

1H, J ) 6.9, 15.0 Hz), 5.30 (t, 1H, J ) 9.3 Hz), 5.15 (d, 1H, J

) 12.7 Hz), 5.02 (d, 1H, J ) 12.7 Hz), 4.41 (t, 1H, J ) 9.8 Hz),

4.13 (dd, 1H, J ) 4.7, 9.9 Hz), 4.10-3.95 (m, 2H), 3.82 (t, 1H,

J ) 9.8 Hz), 2.50-2.30 (m, 2H), 2.20-2.00 (m, 2H), 1.97 (d,

1H, J ) 10.3 Hz), 1.70 (s, 3H), 1.45-1.18 (m, 11H), 1.13 (2d,

18H, H ) 7.5Hz), 1.08 (d, 18H, J ) 7.3 Hz), 1.02 (s, 9H), 0.99

(s, 9H), 0.92 (t, 9H, J ) 7.9 Hz), 0.90-0.60 (m, 6H), 0.55 (q,

6H, J ) 7.9 Hz); ¹³C NMR (CDCl₃, 125 MHz) δ 167.5, 158.7,

152.1, 145.0, 143.3, 140.7, 136.8, 135.2, 130.2, 125.6, 125.5,

119.7, 119.2, 111.0, 109.6, 104.9, 77.5, 76.5, 74.8, 73.3, 71.5,

68.8, 66.8, 40.5, 36.2, 34.1, 30.6, 30.3, 29.3, 27.4, 27.0, 22.7,

19.9, 19.1, 18.0, 17.9, 17.7, 13.2, 12.7, 11.9, 11.3, 6.8, 4.8; MS

(FAB) m/ e 1141 (M^•+), 735, 677, 505, 435, 295, 115, 103, 87,

75, 59; HRMS (FAB) m/ e calcd for C₆₃H₁₁₃O₁₀Si₄: ([M + H]⁺),

1141.7411; found: ([M + H]⁺), 1141.7554. Anal. Calcd for

C₆₃H₁₁₂O₁₀Si₄: C, 66.27; H, 9.90. Found: C, 65.99; H, 9.95%.

Su p p or tin g In for m a tion Ava ila ble: Copies of ¹H and ¹³C

NMR spectra of 11, 16, 23, 24, 25, 28, 29, 39, 41, 44, (8S)-

2,8-dimethyl-2E,4E-decadien-1-ol, 47, 50, 55, 56, 60, 62, 63,

65/66, 67, 67/68, 71, 72, 73, 74, and 1 (63 pages). This

material is contained in libraries on microfiche, immediately

follows this article in the microfilm version of the journal, and

can be ordered from the ACS; see any current masthead page

for ordering information.

The 2-ester 74 showed R_f) 0.29 (5% EtOAc in hexanes); [R]²⁵

D

) -30.0 (c ) 1.36 in CHCl₃); IR (thin film) 3484, 2946, 2867,

1727, 1643, 1601, 1465, 1366, 1257, 1166, 1070, 1001, 962, 882,

828, 768 cm^-1; ¹H NMR (CDCl₃, 500 MHz) δ 7.01 (dd, 1H, J )

10.7, 15.3 Hz), 6.24 (d, 1H, J ) 1.5 Hz), 6.18 (d, 1H, J ) 1.8

Hz), 6.26-6.16 (m, 1H), 6.10-5.92 (m, 3H), 5.88 (d, 1H, J )

10.9 Hz), 5.73 (d, 1H, J ) 9.8 Hz), 5.70-5.60 (m, 1H), 5.55 (d,

J O951895E

Article Doi

Total synthesis and structural elucidation of the antifungal agent papulacandin D

DOI: 10.1021/jo951895e

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Article abstract of DOI:10.1021/jo951895e

Full text of DOI:10.1021/jo951895e

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