Ester dienolate [2,3]-Wittig rearrangement in natural product synthesis: Diastereoselective total synthesis of the triester of viridiofungin A, A 2, and A4

DOI: 10.1021/jo0505270

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Journal of Organic Chemistry p. 5579 - 5591 (2005)

Update date:2022-08-05

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Authors:

Pollex, Annett

Millet, Agnes

Mueller, Jana

Hiersemann, Martin

Abraham, Lars

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Article abstract of DOI:10.1021/jo0505270

An ester dienolate [2,3]-Wittig rearrangement was utilized to access the alkylated citric acid skeleton 6 that is characteristic for the viridiofungins and other members of the alkyl citrate family of secondary natural products. The [2,3]-sigmatropic rearrangement of (Z,Z)-15 provided the rearrangement product (±)-syn-16 in moderate yield and with very good diastereoselectivity. A Julia-Kocienski olefination efficiently served to connect the polar head (±)-syn-26 with the lipophilic tail (32a-c) of the viridiofungins. Amide formation between the racemic viridiofungin precursors 35a-c and the enantiomerically pure amino acid L-tyrosine methyl ester followed by preparative reversed-phase HPLC provided the isopropyl dimethyl ester of viridiofungin A ((+)-39a), A₂ ((+)-39b), and A₄ ((+)-39c) as well as the nonnatural diastereomers (-)-38a-c.

Full text of DOI:10.1021/jo0505270

Ester Dienolate [2,3]-Wittig Rearrangement in Natural Product

Synthesis: Diastereoselective Total Synthesis of the Triester of

Viridiofungin A, A₂, and A₄

Annett Pollex, Agne`s Millet,^†Jana Mu¨ller,^†Martin Hiersemann,* and Lars Abraham^‡

Institut fu¨r Organische Chemie, Technische Universita¨t Dresden, 01062 Dresden, Germany

martin.hiersemann@chemie.tu-dresden.de

Received March 15, 2005

An ester dienolate [2,3]-Wittig rearrangement was utilized to access the alkylated citric acid skeleton

6 that is characteristic for the viridiofungins and other members of the alkyl citrate family of

secondary natural products. The [2,3]-sigmatropic rearrangement of (Z,Z)-15 provided the rear-

rangement product (()-syn-16 in moderate yield and with very good diastereoselectivity. A Julia-

Kocienski olefination efficiently served to connect the polar head (()-syn-26 with the lipophilic tail

(32a-c) of the viridiofungins. Amide formation between the racemic viridiofungin precursors 35a-c

and the enantiomerically pure amino acid ^L-tyrosine methyl ester followed by preparative reversed-

phase HPLC provided the isopropyl dimethyl ester of viridiofungin A ((+)-39a), A₂((+)-39b), and

A₄((+)-39c) as well as the nonnatural diastereomers (-)-38a-c.

Introduction

The viridiofungins 1a-i are secondary metabolites that

have been isolated from the widely distributed filamen-

tous soil fungi Trichoderma viride by solid fermentation

(Figure 1).¹The two-dimensional structure of VF_A-C(1a-

c) as well as the trimethyl ester derivative of VF_A(Me₃-

1a) was originally assigned on the basis of NMR studies

and mass spectrometry.²The viridiofungins 1d-i were

isolated as minor compounds from the solid fermentation

of T. viride.³The relative and absolute configuration of

VF_A(1a) was assigned by comparison of the spectroscopic

data of semi-synthetic and synthetic Me₃-1a. The first

synthesis of Me₃-1a was accomplished by Hatakeyama

in 1998.⁴The reported synthesis required a linear

sequence of 27 steps and utilized a Katsuki-Sharpless

FIGURE 1. Reported structures of the viridiofungins 1a-i.

asymmetric epoxidation⁵(87% ee) to set the absolute

configuration of the crucial stereogenic quaternary carbon

atom C3. In 2005, Hatakeyama reported a modified

synthesis of the tri-tert-butyl ester (t-Bu)₃-1a and, fol-

lowing acidic hydrolysis of the tert-butyl ester function-

alities, of (-)-viridiofungin A (1a).⁶Hatakeyama’s second

generation synthesis of VF_A(1a) required 22 steps and

^†Undergraduate research participants.

^‡Deceased on September 28, 2003.

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Published on Web 06/16/2005

J. Org. Chem. 2005, 70, 5579-5591

5579

Pollex et al.

elegantly utilized a cross-metathesis strategy to construct

the isolated C5/C6 double bond with an E/Z-ratio of 88/

12.

The viridiofungins are potent broad spectrum fungi-

cidal compounds and were originally isolated as part of

a natural product screening program toward inhibitors

of the squalene synthase.⁷The viridiofungins A-C (1a-

c) inhibit in vitro the squalene synthase of Saccharomy-

ces cerevisiae and Candida albicans in micromolar con-

centrations. However, they are 1000-fold less active then

zaragozic acid A (5).⁸Furthermore, it was demonstrated

that the antifungal activity of the viridiofungins in vivo

is not a consequence of the squalene synthase inhibition.

Further analysis of the molecular mode of action of the

viridiofungins revealed that they are nanomolar inhibi-

tors of the serine palmitoyltranferase (SPT) of C. albicans

and HeLa cells in vitro.³Interestingly, the SPT of S.

cerevisiae is much less sensitive to the viridiofungins and

the antifungal activity in this case is apparently a

consequence of multiple mechanisms of action. The SPT

is a pyridoxal 5′-phosphate-dependent enzyme that con-

denses serine with palmitoyl-CoA as first step of the

sphingolipid biosynthesis in mammalian and fungal

cells.⁹Besides their ability to interfere with the sphin-

golipide and the squalene biosynthesis, the viridiofungins

are also inhibitors of the farnesyl transferase and the

farnesylation of the oncogenic Ras protein and thus

potentially useful in treating cancer.^10,11

Structurally, the viridiofungins (1) are members of the

alkyl citrate family of natural products. Other represen-

tatives of this class of secondary metabolites are trach-

yspic acid (2),^12,13citrafungin A (3),¹⁴L-731,120 (4),¹⁵and

zaragozic acid A (5)^16,17,18(Figure 2). Natural products

1-5 contain a citric acid structural element 6 (Figure 3)

that is alkylated in the 2-position with a lipophilic tail

(7) For a review concerning inhibitors of the squalene biosynthesis,

see: Abe, I.; Tomesch, J. C.; Wattanasin, S.; Prestwich, G. D. Nat. Prod.

Rep. 1994, 11, 279-302.

(8) Onishi, J. C.; Milligan, J. A.; Basilio, A.; Bergstrom, J.; Curotto,

J.; Huang, L.; Meinz, M.; Nallin-Omstead, M.; Pelaez, F.; Rew, D.;

Salvatore, M.; Thompson, J.; Vicente, F.; Kurtz, M. B. J. Antibiot. 1997,

50, 335-338.

(9) For reviews concerning the bisynthesis and the biological func-

tions of sphingolipids, see: (a) Kolter, T.; Sandhoff, K. Angew. Chem.,

Int. Ed. 1999, 38, 1532-1568. (b) Chen, J. K.; Lane, W. S.; Schreiber,

S. L. Chem. Biol. 1999, 6, 221-235. (c) Linn, S. C.; Kim, H. S.; Keane,

E. M.; Andras, L. M.; Wang, E.; Merrill, A. H. Biochem. Soc. Trans.

2001, 29, 831-835. (d) Merrill, A. H. J. Biol. Chem. 2002, 277, 25843-

25846. Radin, N. S. Biochem. J. 2003, 371, 243-256.

(10) Meinz, M. S.; Pelaez, F.; Omstead, M. N.; Milligan, J. A.; Diez,

M. T.; Onishi, J. C.; Bergstrom, J. A.; Jenkins, R. F.; Harris, G. H.;

Jones, E. T. T.; Huang, L.; Kong, Y. L.; Lingham, R. B.; Zink, D. Eur.

Pat. Appl. EP 526,936 (Cl. C07C235/76), 1993; Chem. Abstr. 1993, 118,

183428t.

(11) For reviews concerned with the potential of farnesyltransferase

inhibitors in cancer chemotherapy, see: (a) Wittinghofer, A.; Wald-

mann, H. Angew. Chem., Int. Ed. 2000, 39, 4192-4214. (b) Bell, I. M.

J. Med. Chem. 2004, 47, 1869-1878.

(12) Isolation, see: Shiozawa, H.; Takahashi, M.; Takatsu, T.;

Kinoshita, T.; Tanzawa, K.; Hosoya, T.; Furuya, K.; Takahashi, S.;

Furihata, K.; Seto, H. J. Antibiotics 1995, 48, 357-362.

(13) Total synthesis, see: Hirai, K.; Ooi, H.; Esumi, T.; Iwabuchi,

Y.; Hatakeyama, S. Org. Lett. 2003, 5, 857-859.

(14) Singh, S. B.; Zink, D. L.; Doss, G. A.; Polishook, J. D.; Ruby,

C.; Register, E.; Kelly, T. M.; Bonfiglio, C.; Williamson, J. M.; Kelly,

R. Org. Lett. 2004, 6, 337-340.

FIGURE 2. Natural products containing the alkyl citrate

structural element.

featuring a varying number of carbon atoms and different

further functional groups. In the case of zaragozic acid

A (5), the hydroxylation of carbon atoms C2 and C4 leads

to the formation of the characteristic bicyclic ring system

by an intramolecular ketalization. The viridiofungins (1)

are distinguished from the other alkylated citric acid

natural products 2-5 by the presence of an aromatic

amino acid.

For the past several years, we have been investigating

the ester dienolate [2,3]-Wittig rearrangement as a tool

for the diastereoselective construction of 3-alkoxycarbon-

yl-3-hydroxy-substituted 1,5-hexadienes.¹⁹To demon-

strate the usefulness of this novel variation of the

classical [2,3]-Wittig rearrangement in target-oriented

(18) The biosynthesis of zaragozic acid A has been investigated;

see: Byrne, K. M.; Arison, B. H.; Nallin-Omstead, M.; Kaplan, L. J.

Org. Chem. 1993, 58, 1019-1024. Although details of the biosynthesis

of the viridiofungins have not been reported, analogies may be

reasonable.

(19) (a) Hiersemann, M.; Abraham, L.; Pollex, A. Synlett 2003,

1088-1095. (b) Hiersemann, M. Eur. J. Org. Chem. 2001, 483-491.

Lauterbach, C.; Pollex, A. Eur. J. Org. Chem. 1999, 2713-2724. (e)

Hiersemann, M. Tetrahedron 1999, 55, 2625-2638.

(15) Harris, G. H.; Dufresne, C.; Joshua, H.; Koch, L. A.; Zink, D.

L.; Salmon, P. M.; Goklen, K. E.; Kurtz, M. M.; Rew, D. J.; Bergstrom,

J. D.; Wilson, K. E. Bioorg. Med. Chem. Lett. 1995, 5, 2403-2408.

(16) Wilson, K. E.; Burk, R. M.; Biftu, T.; Ball, R. G.; Hoogsteen, K.

J. Org. Chem. 1992, 57, 7151-7158.

(17) For a recent review on the total synthesis of zaragozic acids,

see: Jotterand, N.; Vogel, P. Curr. Org. Chem. 2001, 5, 637-661.

5580 J. Org. Chem., Vol. 70, No. 14, 2005

Total Synthesis of the Triester of Viridiofungin A, A₂, and A₄

SCHEME 1. Synthesis of 15

FIGURE 3. Proposed synthetic access to alkylated citric acids

(6).

synthesis,^20-22we designed a synthetic plan toward the

viridiofungins which may be generalized to provide access

to other members of the alkyl citrate family. As depicted

in Figure 3, we envisioned that the generation of the ester

dienolate 8 by treatment of the R-allyloxy-substituted R,â-

unsaturated ester 9 with a suitable base would be

followed by a [2,3]-Wittig rearrangement to afford the

highly substituted 1,5-hexadiene 7. The rearrangement

product 7 already contains the major structural elements

required for synthetic access to alkylated citric acids (6).

The tertiary alcohol at C3 along with the vicinal stereo-

genic carbon atom C2 are generated by the CC-connecting

sigmatropic event. The relative configuration of the two

stereogenic centers (C3, C2) would be a consequence of

the simple diastereoselectivity of the [2,3]-Wittig rear-

rangement. The crucial carboxylic acid functions are

introduced as an ester (C3′), an enol ether (C5), and a

protected alcohol (C1) and, therefore, are easily to

manipulate individually. Finally, our plan was to utilize

the vinyl substituent at the C2 as a versatile connecting

point for the introduction of the lipophilic segment (R¹)

that is characteristic for natural products of the alkyl

citrate family. In the context of the viridiofungin syn-

thesis, we intended to exploit this highly convergent

approach for the synthesis of viridiofungin A (for com-

parison of authentic synthetic and semisynthetic mate-

rial), A₂(lacking the C13-keto carbonyl group), and A₄

(containing a C₂₂-carbon chain) which have not been

synthesized previously.²³Viridiofungin A₄is a minor

compound from the viridiofungin fermentation but is the

most potent compound in inhibiting the C. albicans SPT

(IC₅₀3.2 ng/mL).³

details of the synthesis of triesters of viridiofungin A, A₂,

and A₄as well as three nonnatural diastereomers thereof.²⁴

Results and Discussion

The envisaged dienolate [2,3]-Wittig rearrangement

required convenient multigram access to the R-alloxy-

substituted R,â-unsaturated ester 15 (Scheme 1). There-

fore, we developed a five-step sequence to 15 that was

routinely performed on a 10 g scale. The synthesis

embarked with the etherification of the mono-benzylated

(Z)-2-butene-1,4-diol (10) with the commercially available

sodium salt of iodoacetic acid followed by esterification

with 2-propanol in the presence of DCC and catalytic

amounts of DMAP²⁵to provide the allyloxy acetate 11.

An aldol condensation process was recruited to construct

the vinyl ether double bond of 15. The three-step proce-

dure consisted of an aldol addition of 11 with benzyloxy

acetaldehyde 13 followed by mesylation of the â-hydroxy

ester 14 and DBU-mediated elimination of the corre-

sponding mesylate. It was pivotal for the success of the

aldol reaction to maintain the reaction temperature below

-70 °C in order to prevent the competing ester enolate

[2,3]-Wittig rearrangement of the intermediate allyloxy-

substitued enolate 12.²²The aldol condensation afforded

the allyl vinyl ether 15 as a 1/1 mixture of vinyl ether

double bond isomers. The double-bond diastereomers

To demonstrate the feasibilty of our approach toward

alkylated citric acid derivatives, we report complete

(20) Wittig, G.; Do¨ser, H.; Lorenz, I. Justus Liebigs Ann. Chem.

1949, 562, 192-205.

(21) First examples of an ester enolate [2,3]-Wittig rearrangement,

see: (a) Takahashi, O.; Saka, T.; Mikami, K.; Nakai, T. Chem. Lett.

1986, 9, 1599-1602. (b) Raucher, S.; Gustavson, L. M. Tetrahedron

Lett. 1986, 27, 1557-1560. (c) Uchikawa, M.; Katsuki, T.; Yamaguchi,

M. Tetrahedron Lett. 1986, 27, 4581-4582.

(22) For reviews, see: (a) Nakai, T.; Mikami, K. Chem. Rev. 1986,

86, 885-902. (b) Mikami, K.; Nakai, T. Synthesis 1991, 594-604.

(23) The configuration of viridiofungin A₂and A₄was assigned in

analogy to the known configuration of viridiofungin A.

(24) For a preliminary communication, see: Pollex, A.; Abraham,

L.; Mu¨ller, J.; Hiersemann, M. Tetrahedron Lett. 2004, 45, 6915-6918.

(25) Neises, B.; Steglich, W. Angew. Chem. 1978, 90, 556-557.

J. Org. Chem, Vol. 70, No. 14, 2005 5581

Pollex et al.

SCHEME 2. Ester Dienolate [2,3]-Wittig

Rearrangement

FIGURE 4. Diastereoselective generation of the ester dieno-

late 21.

configuration of the rearrangement product is defined by

the configuration of the allylic ether double bond. The

discussed stereochemical course of the rearrangement is

in accordance with previous mechanistic work concerned

with the ester dienolate [2,3]-Wittig rearrangement.

These studies revealed a general relationship between

the allylic ether double bond configuration and the

relative configuration of the rearrangement product (“E

to anti” and “Z to syn”).¹⁹

Although not of primary importance for the course of

the viridiofungin synthesis, it is worth mentioning that

the rearrangement product 16 was isolated exclusively

with an E-configured enol ether double bond. The E-

configuration was assigned based on NOE spectroscopy.

As depicted in Figure 4, the 1,3-allylic strain²⁷between

the benzyloxy and the allyloxy (OR) substituent in 22

destabilizes the corresponding transition state that would

lead to the (Z,E)-configured ester dienolate 23. Alterna-

tively, the preferred formation of the (E,E)-configured

dienolate 21 could also be the consequence of thermody-

namic isomerization process between the dienolates 21

and 23.

After having successfully realized the key C-C-con-

necting transformation, it was required to convert the

enol ether into a carboxyl group at C1. As depicted in

Scheme 3, acidic hydrolysis of the benzyl vinyl ether

afforded an aldehyde that was immediately oxidized to

the corresponding acid which was then esterificated²⁵to

afford the methyl ester (()-syn-24. It was anticipated to

complete the carbon skeleton of the viridiofungins by

coupling of a C5 aldehyde with the lipophilic C6-

C20(C22) segments. In compliance with this plan, the

tertiary alcohol was protected²⁸as a silyl ether²⁹and the

oxidative cleavage of the terminal double bond by ozo-

nolysis provided the desired instable C-5 aldehyde (()-

syn-26 that was immediately used for the succeeding

attachment of the lipophilic segment.

(E,Z)- and (Z,Z)-15 can be separated by preparative

HPLC or carefully performed flash chromatography.²⁶

With the double bond isomerically pure allyl vinyl

ether (E)- and (Z)-15 in hand, the crucial ester dienolate

[2,3]-Wittig rearrangement was next investigated (Scheme

2). In the event, a variety of different bases, solvents, and

temperature protocols were utilized. However, none of

the employed conditions improved the chemoselectivity

of the rearrangement compared to the simplest procedure

(slight excess of LDA, THF, -78 to -10 °C). Furthermore

and somewhat surprisingly, the chemoselectivity de-

pended considerably on the vinyl ether double-bond

configuration. Whereas (E,Z)-15 underwent the rear-

rangement in low yield with varying amounts of reiso-

lated starting material and a multitude of unidentified

decomposition products, (Z,Z)-15 afforded the product

(()-syn-16 of the ester dienolate [2,3]-Wittig rearrange-

ment in acceptable yield and excellent simple diastereo-

selectivity in favor of the desired syn-configured diaste-

reomer. The exact reason(s) of the discrepancy remains

speculative, but we assume the deprotonation rather

than the rearrangement as the decisive step. The con-

sistency of yield and diastereoselectivity for the rear-

rangement of (Z,Z)-15 in the absence of additional Lewis

bases or metal salts even on a 5 g scale accounts for the

usefulness of the rearrangement. Although the rear-

rangement can be performed with the mixture of double

bond diastereomers (E,Z)- and (Z,Z)-15, we generally

preferred to utilize the double bond isomerically pure

(Z,Z)-15 as substrate for the rearrangement.

The qualitative analysis of the stereochemical course

of the rearrangement rests on the formation of the

chelated lithium ester dienolate 17 (Scheme 2). The

rearrangement would then proceed through the bicyclo-

[3.3.0]octane-type transition state (3Re,4Si)-19 in which

the bulky benzyloxymethyl group at C4 preferentially

adopts a position directed toward the convex face of the

bicyclic transition state (3Re,4Si)-19. Thus, the relative

The isolated E-configured C5-C6 double bond that joins

together the polar head with the lipophilic tail of the

viridiofungins was the second key C-C-connecting trans-

(27) (a) Johnson, F.; Malhotra, S. K. J. Am. Chem. Soc. 1965, 87,

5492-5493. (b) Malhotra, S. K.; Johnson, F. J. Am. Chem. Soc. 1965,

87, 5493-5495. (c) Johnson, F. Chem. Rev. 1968, 68, 375-413. (d)

Hoffmann, R. W. Chem. Rev. 1989, 89, 1841-1860.

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1981, 22, 3455-3458.

(29) Nelson, T. D.; Crouch, R. D. Synthesis 1996, 1031-1069.

(26) For details, see the Experimental Section.

5582 J. Org. Chem., Vol. 70, No. 14, 2005

Total Synthesis of the Triester of Viridiofungin A, A₂, and A₄

SCHEME 3. Preparation of the Aldehyde

SCHEME 4. Preparation of the Sulfones 32a,b

(()-syn-26^a

Required for the Julia-Kocienski Olefination^a

^aKey: TBS ) tert-butyldimethylsilyl.

formation we faced. Kocienski’s modification³⁰of the Julia

olefination³¹is being applied frequently³²to construct

isolated E-configured double bonds. Therefore, we decided

to follow this proven path and to attempt a construction

of the C5-C6 double bond by a Julia-Kocienski olefi-

nation.³³

The sulfones 32a,b required for the envisioned olefi-

nation were synthesized by a strategy that relied on a

sequential 1,3-dithiane alkylation (Scheme 4).³⁴The

initial alkylation of the lithiated 1,3-dithiane 27 with

either 1-bromoheptane 28a or 1-bromononane 28b was

realized according to the original Corey-Seebach proce-

dure.³⁵The second alkylation with the alkyl iodide 29

required the modified conditions (t-BuLi, HMPA) origi-

nally described by Williams.³⁶Cleavage of the tert-

butyldiphenylsilyl (TPS) protecting group afforded the

alcohols 30a,b that were converted into the 5-alkylsul-

fanyl-1-phenyl-1H-tetrazole derivatives 31a,b by a high-

yielding Mitsunobu procedure.^30,37Our initial attempts

to chemoselectively oxidize the sulfide to the sulfone in

the presence of the thioketal were unsuccessful. There-

fore, the thioketal was cleaved by treatment with Cu^II

^aKey: TPS ) tert-butyldiphenylsilyl, PTSH ) 1-phenyl-1H-

tetrazole-5-thiol, DIAD ) diisopropyl azodicarboxylate.

SCHEME 5. Preparation of the Sulfone 32c

(30) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett

1998, 26-28.

in water³⁸followed by the oxidation of the sulfide to the

sulfone. Not surprisingly, all attempts to perform the

following Julia-Kocienski olefination in the presence of

the unprotected ketone failed to provide the desired

coupling product. Therefore, the keto carbonyl group of

the sulfone was converted into the cyclic ketales 32a,b

utilizing Noyori’s conditions.³⁹Accordingly, the sulfone

32c required for the synthesis of viridiofungin A₂was

prepared from the commercially available 1-pentadecanol

in two steps (Scheme 5).

Our original proposal that a Julia-Kocienski olefina-

tion may be suitable in order to connect the polar head

with the lipophilic tail of the viridiofungins proved to be

correct (Scheme 6). Treatment of either one of the

sulfones 33a-c with potassium hexamethyldisilazide

(31) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron

Lett. 1991, 32, 1175-1178.

(32) (a) Gao, X.; Hall, D. G. J. Am. Chem. Soc. 2005, 127, 1628-

1629. (b) Jasper, C.; Wittenberg, R.; Quitschalle, M.; Jakupovic, J.;

Kirschning, A. Org. Lett. 2005, 7, 479-482. (c) Compostella, F.;

Franchini, L.; Panza, L.; Prosperi, D.; Ronchetti, F. Tetrahedron 2002,

58, 4425-4428. (d) Hayes, P. Y.; Kitching, W. J. Am. Chem. Soc. 2002,

124, 9718-9719. (e) Liu, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2001,

123, 10772-10773. (f) Smith, A. B.; Wan, Z. J. Org. Chem. 2000, 65,

3738-3753.

(33) An attempted cross-metathesis gave reisolated starting material

only, see: Rai, A. N.; Basu, A. Org. Lett. 2004, 6, 2861-2863.

(34) For reviews concerning the application of lithiated 1,3-dithianes

in natural product synthesis, see: (a) Smith, A. B.; Adams, C. M. Acc.

Chem. Res. 2004, 37, 365-377. (b) Yus, M.; Najera, C.; Foubelo, F.

Tetrahedron 2003, 59, 6147-6212. (c) Smith, A. B.; Condon, S. M.;

McCauley, J. A. Acc. Chem. Res. 1998, 31, 35-46.

(35) (a) Corey, E. J.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1965,

4, 1077-1078. (b) Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40,

231-237.

(36) Williams, D. R.; Sit, S. Y. J. Am. Chem. Soc. 1984, 106, 2949-

2954.

(37) Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40,

2380-2382.

(38) Mukaiyama, T.; Narasaka, K.; Furusato, M. J. Am. Chem. Soc.

1972, 94, 8641-8642.

(39) Tsunoda, T.; Suzuki, M.; Noyori, R. Tetrahedron Lett. 1980, 21,

1357-1358.

J. Org. Chem, Vol. 70, No. 14, 2005 5583

Pollex et al.

SCHEME 6. Julia-Kociensky Olefination^a

SCHEME 8. Undesired Lactonization

SCHEME 9. Final Steps of the Synthesis of

Triesters of Natural 39a-c and Nonnatural

Viridiofungin Diastereoisomers 38a-c

^aKey: KHMDS ) K[N(SiMe₃)₂].

SCHEME 7. Generation of the 4′-Carboxyl

Function

ammonium perruthenate (TPAP) and N-methylmorpho-

line N-oxide (NMO) without purification.⁴¹Oxidation of

the aldehydes afforded the stable acids (()-35a-c. At-

tempts to purify the alcohols 34a-c by flash chromatog-

raphy inevitable led to the formation of the corresponding

lactone 36 (Scheme 8).

The concluding steps of the synthesis are depicted in

Scheme 9. The remaining TBS and ketale protecting

group of 35a,b were removed in a single step with HF in

pyridine to afford the acids 37a,b. The removal of the

silyl protecting group of the acid 35c provided the acid

37c which represents the diester derivative of (()-

viridiofungin Z₂(1h). The appropriate reagent combina-

tion for amide bond formation between the acids 37a-c

and ^L-tyrosine methyl ester (L-TyrMe) was identified

after some experimentation.⁴²Benzotriazolyloxytris(pyr-

(KHMDS) at low temperature followed by the addition

of the aldehyde (()-syn-26 provided the coupling products

33a-c in good yield and as a single E-configured double-

bond isomer.⁴⁰

Having completely assembled the carbon skeleton of

the viridiofungins, the 4′-benzyloxymethyl group had to

be converted into a carboxyl function in preparation of

the amide formation with ^L-tyrosine methyl ester (Scheme

7). For this purpose, the benzyl protecting group was

chemoselectively removed in the presence of the isolated

double bond by hydrogenolysis. The primary alcohols (()-

34a-c were immediately oxidized with tetra-n-propyl-

(40) To validate the exclusive formation of the (E)-configured double

bond, the corresponding (Z)-configured double bond isomer was

synthesized by a Wittig olefination. NOE spectroscopy and comparison

of the coupling constants of the vinylic protons support the assignment

of the double bond configuration and demonstrate the very high and

dependable preference of the Julia-Kocienski olefination for the

formation of the (E)-configured olefin (()-syn-33a. See the Supporting

Information for details. Utilizing LiHMDS instead of KHMDS for the

Julia-Kocienski olefination led to inferior E/Z selectivities.

(41) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis

1994, 639-666.

(42) For a recent review on peptide coupling reagents in organic

synthesis, see: Han, S.-Y.; Kim, Y.-A. Tetrahedron 2004, 60, 2447-

2467.

5584 J. Org. Chem., Vol. 70, No. 14, 2005

Total Synthesis of the Triester of Viridiofungin A, A₂, and A₄

CH₃); IR (in substance) ν 2980-2860, 1750 cm^-1. Anal. Calcd

rolidino)phosphonium hexafluorophosphate (PyBOP)⁴³in

combination with N-methylmorpholine (NMM) mediated

the coupling of the racemic acids 37a-c with the enan-

tiomerically pure ^L-TyrMe to afford diastereomeric mix-

tures of the natural (39a-c) and nonnatural (38a-c)

viridiofungin A, A₂, and A₄triester derivatives. Prepara-

tive reversed-phase HPLC was employed to separate the

mixture of diastereoisomers. Thus, the triester deriva-

tives of the natural (-)-viridiofungin A (39a), (-)-A₄

(39b), and (-)-A₂(39c) as well as the nonnatural dia-

stereoisomers thereof ((+)-38a-c) were isolated as single

diastereoisomers. Comparison of the spectroscopic data

of the isopropyl dimethyl ester 39a with data reported⁴⁴

for the synthetic viridiofungin A trimethyl (-)-Me₃-1a

and tri-tert-butyl ester⁶(-)-(tert-Bu)₃-1a support the

structural assignment of 39a as the diastereoisomer with

the natural configuration.

In summary, we have established a short, reliable, and

flexible approach toward four natural and three non-

natural viridiofungins. The ester dienolate [2,3]-Wittig

rearrangement effectively served to construct the polar

head of the viridiofungins A, A₄, A₂, and Z. Our highly

convergent approach is suitable for the diversified syn-

thesis of further viridiofungins which provides opportu-

nity to study the pharmacological properties of a wide

variety of natural and nonnatural viridiofungins.

for C₁₆H₂₂O₄: C, 69.04; H, 7.97. Found: C, 69.06; H, 8.19.

â-Hydroxy Ester 14. To a stirred solution of LDA [prepared

in situ from diisopropylamine (7.8 mL, 55.4 mmol, 1.3 equiv)

and n-BuLi (2.31 M in hexane, 22.2 mL, 51.2 mmol, 1.2 equiv)]

in THF (1 mL/mmol 11) was added a cooled solution (-78 °C)

of the ester 11 (11.86 g, 42.6 mmol, 1.0 equiv) in THF (1 mL/

mmol 11) at -78 °C. The solution was stirred for 15 min, and

the freshly prepared aldehyde 13 (8.31 g, 55.4 mmol, 1.2 equiv)

was added as cooled solution (-78 °C) in THF (0.5 mL/mmol

13). The mixture was stirred for 30 min at -78 °C and then

quenched by the addition of saturated aq NH₄Cl at -78 °C.

After dilution with H₂O and CH₂Cl₂, the layers were separated

and the aqueous phase was extracted with CH₂Cl₂(3 × 100

mL). The combined organic phases were dried over MgSO₄and

concentrated. Flash chromatography (heptane/ethyl acetate 3/1

to 1/1) afforded the â-hydroxy ester 14 [15.0 g, 34.9 mmol, 82%,

mixture of diastereomers (dr 55:45)] as pale yellow oil:. R_f0.35

heptane/ethyl acetate 1/1; ¹H NMR (500 MHz, CDCl₃) mixture

of diastereomers δ 7.38-7.27 (m, 10H), 5.84-5.75 (m, 1H),

5.73-5.67 (m, 1H), 5.08 (br sept, J ) 6.3 Hz, 1H), 4.52 (dd, J

) 8.2, 4.4 Hz, 2H), 4.48 (d, J ) 1.6 Hz, 2H), 4.28 (dd, J )

12.5, 5.8 Hz, 1 H^minor), 4.21 (dd, J ) 12.1, 6.2 Hz, 1 H^major),

4.11-3.93 (m, 4H), 4.00 (d, J ) 3.6 Hz, 1H^minor) 3.96 (d, J )

5.8 Hz, 1H^major), 3.64-3.53 (m, 2H), 2.58 (d, J ) 6.5 Hz, 1H^major),

2.46 (d, J ) 7.5 Hz, 1H^minor), 1.28-1.16 (m, 6H); ¹³C NMR (75

MHz, CDCl₃) mixture of diastereomers δ 170.3 (C-minor),

170.2 (C-major), 138.0 (C), 137.8 (C), 130.33 (CH-major), 130.28

(CH-minor), 128.5 (2 × CH), 128.4 (4 × CH), 127.80 (2 × CH),

127.76 (2 × CH), 127.7 (CH), 78.9 (CH-major), 77.8 (CH-

minor), 73.45 (CH₂-major), 73.42 (CH₂-minor), 72.4 (CH₂), 71.2

(CH), 70.1 (CH₂-minor), 70.0 (CH₂-major), 68.92 (CH-minor),

68.88 (CH-major), 66.43 (CH₂-minor), 66.40 (CH₂-major), 65.7

(CH₂), 21.8 (CH₃), 21.7 (CH₃); IR (in substance) ν 3550-3420,

2980-2875, 1730 cm^-1. Anal. Calcd for C₂₅H₃₂O₆: C, 70.07;

H, 7.53. found: C, 70.26; H, 7.83.

Allyl Vinyl Ether 15. To a solution of the diastereomeric

â-hydroxy ester 14 (15.03 g, 35.1 mmol, 1.0 equiv) in CH₂Cl₂

(3 mL/mmol 14) at 0 °C were added Et₃N (6.3 mL, 45.6 mmol,

1.3 equiv) and MsCl (3.3 mL, 42.1 mmol, 1.2 equiv). The

reaction mixture was stirred for 30 min at ambient temper-

ature, quenched with saturated aq NaHCO₃, and extracted

with CH₂Cl₂(2 × 50 mL). The combined organic phases were

dried over MgSO₄and concentrated under reduced pressure

to afford the crude mesylate 43 which was dissolved in THF

(2 mL/mmol of the mesylate) and cooled to 0 °C. DBU (16 mL,

105 mmol, 3.0 equiv) was added at 0 °C. The reaction mixture

was stirred at ambient temperature until TLC indicated

complete consumption of the starting material (about 12 h).

The reaction was then quenched with H₂O (70 mL) and

extracted with CH₂Cl₂(2 × 50 mL). The combined organic

phases were dried over MgSO₄and concentrated. Flash

chromatography (heptane/ethyl acetate 10/1) afforded the allyl

vinyl ether 15 (11.8 g, 28.8 mmol, 82%) as mixture of double

bond isomers (E,Z/Z,Z ) 50:50): R_f0.59 heptane/ethyl acetate

1/1. The double-bond isomers were separated by preparative

HPLC, column: 32 × 250 mm, Nucleosil 50-5, 5 µm, solvent:

(heptane/ethyl acetate 4/1, flow: 30 mL/min, t_R(Z,Z-15) ∼ 16

min, t_R(E,Z-15) ∼ 19 min, performance: ∼ 1 g/h).

Experimental Section⁴⁵

Ester 11. To a stirred solution of (Z)-4-benzyloxybut-2-en-

1-ol 10 (11.11 g, 62.2 mmol, 1.0 equiv) in THF (1 mL/mmol)

was added n-BuLi (2.4 M in hexane, 25.9 mL, 62.2 mmol, 1.0

equiv) at -78 °C followed by the addition of solid iodoacetic

acid sodium salt (13.57 g, 65.3 mmol, 1.05 equiv). The cooling

bath was removed, and the suspension was allowed to stir

overnight. The reaction was then quenched by the addition of

aq 1 N KOH (90 mL). The phases were separated, and the

organic phase was extracted twice with aq 1 N KOH (30 mL).

The aqueous phase was acidified by the addition of concd HCl

(pH < 4) and extracted with CH₂Cl₂(3 × 100 mL). The

combined organic phases were dried over MgSO₄, and the

solvent was removed under reduced pressure. Purification by

Kugelrohr distillation (150 °C, 0.1 mbar) afforded (Z)-(4-

benzyloxybut-2-enyloxy)acetic acid (14.02 g, 59.3 mmol, 95%)

as a brown oil.

To an ice-cooled solution of the acid (7.10 g, 30.1 mmol, 1.0

equiv) in CH₂Cl₂(2 mL/mmol of the acid) at 0 °C were added

DMAP (0.18 g, 1.5 mmol, 0.05 equiv), DCC (6.83 g, 33.1 mmol,

1.1 equiv), and the 2-propanol (4.6 mL, 60.2 mmol, 2.0 equiv).

The resulting mixture was stirred for 30 min at ambient

temperature. The precipitate was then removed by filtration

and washed with CH₂Cl₂, and the solvent was evaporated

under reduced pressure. Flash chromatography (heptane/ethyl

acetate 5/1) afforded the ester 11 (7.9 g, 28.4 mmol, 94%) as a

yellow oil: R_f0.65 heptane/ethyl acetate 1/1; ¹H NMR (300

MHz, CDCl₃) δ 7.36-7.23 (m, 5H), 5.88-5.70 (m, 2H), 5.10

(sept, J ) 6.3 Hz, 1H), 4.50 (s, 2H), 4.15 (d, J ) 5.7 Hz, 2H),

4.09 (d, J ) 5.6 Hz, 2H), 4.01 (s, 2H), 1.25 (d, J ) 6.2 Hz, 6H);

¹³C NMR (75 MHz, CDCl₃) δ 169.8 (C), 138.1 (C), 130.3 (CH),

128.6 (CH), 128.4 (2 × CH), 127.8 (2 × CH), 127.7 (CH), 72.3

(CH₂), 68.5 (CH₂), 67.5 (CH₂), 66.9 (CH), 65.7 (CH₂), 21.8 (2 ×

(E,Z)-15: ¹H NMR (500 MHz, CDCl₃) δ 7.34-7.26 (m, 10H,

CH-Ar), 5.81-5.79 (m, 2H, 4- and 5-CHd), 5.29 (t, J ) 5.8

Hz, 1H, 2′-CHd), 5.10 (sept, J ) 6.3 Hz, 1H, OiPrCH), 4.53

(s, 2H, 2′′-CH₂Ph), 4.51 (s, 2H, 6-CH₂Ph), 4.48 (d, J ) 5.8 Hz,

2H, 2′′-CH₂OBn), 4.34 (br d, J ) 3.7 Hz, 2H, 3-CH₂), 4.10 (br

d, J ) 4.3 Hz, 2H, 6-CH₂OBn), 1.26 (d, J ) 6.3 Hz, 6H,

OiPrCH₃); ¹³C NMR (126 MHz, CDCl₃) δ 162.7 (1-C), 145.4

(2-Cd), 138.1 (C-Ar), 137.9 (C-Ar), 129.8 (5-CHd), 128.41 (2

× CH-Ar), 128.39 (2 × CH-Ar), 127.83 (2 × CH-Ar), 127.77 (2

× CH-Ar), 127.70 (CH-Ar), 127.67 (CH-Ar), 127.4 (4-CHd),

112.1 (2′-CHd), 72.5 (2′′-CH₂Ph), 72.4 (6-CH₂Ph), 69.1 (OiPrCH),

66.6 (2′′-CH₂), 65.9 (6-CH₂), 64.7 (3-CH₂), 21.7 (2 × OiPrCH₃);

(43) Coste, J.; Le-Nguyen, D.; Castro, B. Tetrahedron Lett. 1990,

31, 205-208.

(44) We thank Prof. Susumi Hatakeyama for providing us with

copies of NMR spectra of the synthetic viridiofungin A trimethylester

Me₃-1a.

(45) For general experimental methods consult the Supporting

Information.

J. Org. Chem, Vol. 70, No. 14, 2005 5585

Pollex et al.

IR (in substance) ν 3090-3030, 2980-2860, 1720 cm^-1. Anal.

Calcd for C₂₅H₃₀O₅: C, 73.15; H, 7.37. Found: C, 73.31; H,

7.64.

MeOH (1 mL, 15.9 mmol, 2.0 equiv). The resulting suspension

was stirred for 30 min at ambient temperature. The precipitate

was then removed by filtration and washed with CH₂Cl₂, and

the solvent was evaporated under reduced pressure. Flash

chromatography (heptane/ethyl acetate 10/1 to 5/1) afforded

of the ester 24 (1.5 g, 4.3 mmol, 81%): R_f0.32 heptane/ethyl

(Z,Z)-15: ¹H NMR (500 MHz, CDCl₃) δ 7.34-7.28 (m, 10H,

CH-Ar), 6.35 (t, J ) 6.3 Hz, 1H, 2′-CHd), 5.80-5.73 (m, 2H,

4- and 5-CHd), 5.07 (sept, J ) 6.3 Hz, 1H, OiPrCH), 4.50 (s,

2H, 2′′-CH₂Ph), 4.47 (s, 2H, 6-CH₂Ph), 4.44 (d, J ) 6.2 Hz,

2H, 3-CH₂), 4.24 (d, J ) 6.3 Hz, 2H, 2′′-CH₂), 4.06 (d, J ) 6.4

Hz, 2H, 6-CH₂), 1.27 (d, J ) 6.3 Hz, 6H, OiPrCH₃); ¹³C NMR

(126 MHz, CDCl₃) δ 162.6 (1-C), 145.7 (2-Cd), 138.0 (C-Ar),

137.9 (C-Ar), 130.6 (5-CHd), 128.43 (2 × CH-Ar), 128.41 (2 ×

CH-Ar), 127.9 (CH-Ar), 127.83 (2 × CH-Ar), 127.78 (CH-Ar),

127.76 (2 × CH-Ar), 127.7 (4-CHd), 124.3 (2′-CHd), 72.8 (2′′-

CH₂Ph), 72.4 (6-CH₂Ph), 68.9 (OiPrCH), 67.5 (3-CH₂), 65.6 (6-

CH₂), 64.5 (2′′-CH₂), 21.8 (2 × OiPrCH₃); IR (in substance) ν

3090-3030, 2980-2860, 1720 cm^-1. Anal. Calcd for C₂₅H₃₀O₅:

C, 73.15; H, 7.37. Found: C, 73.03; H, 7.58.

acetate 1/1; H NMR (500 MHz, CDCl₃) δ 7.34-7.24 (m, 5H),

5.77 (ddd, J ) 16.8, 10.3, 10.3 Hz, 1H), 5.15 (s, 1H), 5.13 (dd,

J ) 8.7, 1.6 Hz, 1H), 5.04 (sept, J ) 6.3 Hz, 1H), 4.50 (d^AB, J

) 12.0 Hz, 1H), 4.45 (d^AB, J ) 11.7 Hz, 1H), 4.00 (s, 1H), 3.70

(dd^AB, J ) 9.6, 6.5 Hz, 1H), 3.64 (s, 3H), 3.52 (dd^AB, J ) 9.8,

5.4 Hz, 1H), 2.94 (d^AB, J ) 16.8 Hz, 1H), 2.86 (d^AB, J ) 16.1

Hz, 1H), 2.67-2.61 (m, 1H), 1.29 (d, J ) 6.0 Hz, 3H), 1.21 (d,

J ) 6.0 Hz, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 173.4 (C), 171.1

(C), 137.9 (C), 134.5 (CH), 128.3 (2 × CH), 127.7 (2 × CH),

127.6 (CH), 119.0 (CH₂), 76.1 (C), 73.3 (CH₂), 69.9 (CH₂), 52.4

(CH or CH₃), 51.7 (CH or CH₃), 42.4 (CH₂), 21.7 (CH₃), 21.6

(CH₃); IR (in substance) ν 3480-2980, 2920-2835, 1740 cm^-1

R-Hydroxyester (()-syn-16. To a stirred solution of LDA

[prepared in situ from diisopropylamine (1.7 mL, 12.0 mmol,

1.2 equiv) and n-BuLi (2.3 M in hexane, 4.6 mL, 10.5 mmol,

1.05 equiv)] in THF (4 mL/mmol 15) was added a cooled

solution (-78 °C) of the allyl vinyl ether (Z,Z)-15 (4.11 g, 10.0

mmol, 1.0 equiv) in THF (2 mL/mmol 15) at -78 °C. The

solution was allowed to warm to -10 °C overnight, quenched

with saturated aq NH₄Cl, and extracted with CH₂Cl₂(3 × 30

mL). The combined organic phases were dried over MgSO₄and

concentrated. Flash chromatography (heptane/ethyl acetate

20/1 to 10/1) afforded the rearrangement product 16 (2.36 g,

5.7 mmol, 57%, syn/anti ) 95:5): R_f0.59 heptane/ethyl acetate

1/1; ¹H NMR (500 MHz, CDCl₃) δ 7.37-7.24 (m, 10H), 6.71

(d, J ) 12.7 Hz, 1H, 2′′-CHd), 5.84 (ddd, J ) 16.8, 10.5, 9.4

Hz, 1H, 4-CHd), 5.18 (d, J ) 1.3 Hz, 1H, 5-CH₂d), 5.15 (dd, J

) 9.7, 1.9 Hz, 1H, 5-CH₂d), 4.99 (d, J ) 12.5 Hz, 1H, 2′-CHd

), 4.99 (sept, J ) 6.3 Hz, 1H, OiPrCH), 4.74 (d^AB, J ) 11.9 Hz,

1H, 2′′′-CH₂Ph), 4.70 (d^AB, J ) 12.0 Hz, 1H, 2′′′-CH₂Ph), 4.48

(d^AB, J ) 11.9 Hz, 1H, 3′′-CH₂Ph), 4.42 (d^AB, J ) 11.7 Hz, 1H,

3′′-CH₂Ph), 3.71 (dd^AB, J ) 9.6, 4.1 Hz, 1H, 3′′-CH₂OBn), 3.65

(s, 1H), 3.57 (dd^AB, J ) 9.4, 7.5 Hz, 1H, 3′′-CH₂OBn), 2.75 -

2.65 (m, 1H, 3-CH), 1.23 (d, J ) 6.2 Hz, 3H, OiPr-CH₃), 1.17

(d, J ) 6.2 Hz, 3H, OiPrCH₃); ¹³C NMR (126 MHz, CDCl₃) δ

174.0 (1-C), 148.4 (2′′-CHd), 138.2 (C-Ar), 136.7 (C-Ar), 135.2

(4-CHd), 128.5 (2 × CH-Ar), 128.3 (2 × CH-Ar), 127.9 (CH-

Ar), 127.6 (2 × CH-Ar), 127.5 (CH-Ar,), 127.4 (2 × CH-Ar),

118.9 (5-CH₂d), 105.3 (2′-CHd), 77.1 (2-C), 73.2 (2′′′-CH₂Ph),

71.6 (3′′-CH₂Ph), 70.0 (OiPrCH), 69.8 (3′-CH₂), 51.6 (3-CH),

21.6 (2 × OiPrCH₃); IR (in substance) ν 3500, 3070-3030,

2980-2870, 1720, cm^-1. Anal. Calcd for C₂₅H₃₀O₅: C, 73.15;

H, 7.37. Found: C, 73.09; H, 7.80.

Anal. Calcd for C₁₉H₂₆O₆: C, 65.13; H, 7.37. Found: C, 65.17;

H, 7.65.

Silyl Ether (()-syn-25. To an ice-cooled solution of the ester

24 (1.08 g, 3.1 mmol, 1.0 equiv) in CH₂Cl₂(5 mL/mmol 24)

were added 2,6-lutidine (1.4 mL, 12.4 mmol, 4.0 equiv) and

TBSOTf (2.45 g, 9.3 mmol, 3.0 equiv). The resulting mixture

was stirred at ambient temperature until TLC indicated

complete consumption of the starting material (∼3 h). The

reaction was quenched with saturated aq NaHCO₃and

extracted with CH₂Cl₂(3 × 10 mL). The combined organic

layers were dried over MgSO₄and concentrated. Flash chro-

matography (heptane/ethyl acetate 20/1 to 10/1) afforded 1.39

g (3.0 mmol, 97%) of silyl ether 25: R_f0.79 heptane/ethyl

acetate 1/1; H NMR (300 MHz, CDCl₃) δ 7.21-7.04 (m, 5H),

5.61 (ddd, J ) 16.9, 10.2, 10.2 Hz, 1H), 4.97 (d, J ) 1.9 Hz,

1H), 4.94 (dd, J ) 10.2, 1.8 Hz, 1H), 4.80 (sept, J ) 6.3 Hz,

1H), 4.30 (s, 2H), 3.63 (dd^AB, J ) 5.4, 9.6 Hz, 1H), 3.44 (s, 3H),

3.28 (dd^AB, J ) 6.5, 9.7 Hz, 1H), 2.81 (d^AB, J ) 15.3 Hz, 1H),

2.68 (d^AB, J ) 15.3 Hz, 1H), 2.61-2.51 (m, 1H), 1.06 (d, J )

6.5 Hz, 3H), 1.02 (d, J ) 6.5 Hz, 3H), 0.64 (s, 9H), 0.00 (s,

3H), -0.12 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 171.9 (C),

170.4 (C), 138.1 (C), 135.7 (CH), 128.3 (2 × CH), 127.7 (2 ×

CH), 127.6 (CH), 118.5 (CH₂), 79.8 (C), 73.1 (CH₂), 69.5 (CH₂),

69.1 (CH), 53.5 (CH or CH₃), 51.5 (CH or CH₃), 43.9 (CH₂),

26.0 (3 × CH₃), 21.8 (CH₃), 21.7 (CH₃), 18.9 (C), -2.5 (CH₃),

-2.9 (CH₃); IR (in substance) ν 2975-2855, 1745 cm^-1. Anal.

Calcd for C₂₅H₄₀O₆Si: C, 64.62; H, 8.68. Found: C, 64.68; H,

8.85.

C₁₅-Alcohol 30a. To a stirred solution of 1,3-dithiane (27)

(0.76 g, 6.3 mmol, 1.0 equiv) in THF (2 mL/mmol 27) was

added n-BuLi (2.45 M in hexane, 2.7 mL, 6.6 mmol, 1.05 equiv)

at -78 °C and the mixture stirred for 1 h at -5 °C. 1-Bromo-

heptane (28a) (1.01 mL, 6.4 mmol, 1.01 equiv) was added at

-78 °C, and the reaction mixture was allowed to warm to

ambient temperature over 3 h. The reaction was quenched

with water (5 mL) and extracted with CH₂Cl₂(3 × 25 mL).

The combined organic phases were dried over MgSO₄and

concentrated. Flash chromatography (heptane) afforded dithiane

46a (1.27 g, 5.8 mmol, 93%) as a pale yellow oil: R_f0.47

heptane/ethyl acetate 20/1.

Ester (()-syn-24. To an ice-cooled solution of the benzyl

enol ether 16 (2.36 g, 5.8 mmol, 1.0 equiv) in THF (0.5 mL/

mmol 16) was added aq HCl (1.94 M, 4.3 mL, 8.4 mmol, 1.5

equiv) and the mixture stirred for 72 h at ambient tempera-

ture. The reaction mixture was then quenched with saturated

aq NaHCO₃and extracted with CH₂Cl₂(3 × 30 mL). The

combined organic phases were dried over MgSO₄and concen-

trated under reduced pressure to afford the crude aldehyde

that was used without further purification: R_f0.44 heptane/

ethyl acetate 1/1.

To a stirred solution of the monoalkylated dithiane (1.31 g,

6.0 mmol, 2.0 equiv) in HMPA (2.9 mL, 16 mmol, 8 equiv) and

THF (7.5 mL/mmol 29) was added t-BuLi (1.5 M in pentane,

12.0 mL, 18.0 mmol, 3 equiv) at -78 °C. Within 1 min, a cooled

solution (-78 °C) of iodide 29 (1.92 g, 4.0 mmol, 1.0 equiv) in

THF (5 mL) was added via cannula. The reaction mixture was

stirred for 1 h at -78 °C and then quenched with saturated

aq NH₄Cl and extracted with CH₂Cl₂(3 × 75 mL). The

combined organic phases were dried over MgSO₄and concen-

trated.

The resulting crude product was diluted with THF (5 mL/

mmol 29) and solid tetrabutylammonium fluoride (1.27 g, 4.0

mmol, 1 equiv) was added. After the mixture was stirred for 1

h at rt, the reaction was quenched with saturated aq NaHCO₃

To a solution of the crude aldehyde (5.8 mmol, 1.0 equiv) in

t-BuOH (10 mL/mmol aldehyde) and 2-methyl-2-butene (10

mL/mmol aldehyde) was added a solution of NaClO₂(5.20 g,

57.5 mmol, 10.0 equiv) and NaH₂PO₄‚H₂O (5.55 g, 40.2 mmol,

7.0 equiv) in water (20 mL/mmol aldehyde). The reaction

mixture was stirred at ambient temperature for 12 h, diluted

with water, and extracted with CH₂Cl₂(3 × 50 mL). The

combined organic phases were dried over MgSO₄and concen-

trated. Purification by flash chromatography (heptane/ethyl

acetate 10/1 to 1/2) provided the acid (1.79 g, 5.3 mmol, 93%):

R_f0.09 heptane/ethyl acetate 1/1.

To an ice-cooled solution of the acid (1.79 g, 5.3 mmol, 1.0

equiv) in CH₂Cl₂(4 mL/mmol acid) were added DMAP (32 mg,

0,3 mmol, 0.05 equiv), DCC (1.21 g, 5.9 mmol, 1.1 equiv), and

5586 J. Org. Chem., Vol. 70, No. 14, 2005

Total Synthesis of the Triester of Viridiofungin A, A₂, and A₄

and extracted with CH₂Cl₂(3 × 75 mL). The combined organic

phases were dried over MgSO₄and concentrated. Flash

chromatography (heptane/ethyl acetate 10/1 to 5/1) afforded

alcohol 30a (1.22 g, 3.7 mmol, 92%) as a colorless oil: R_f0.52

(CH₂), 28.9 (CH₂), 28.6 (CH₂), 26.0 (2 × CH₂), 25.6 (CH₂), 24.1

(CH₂), 24.0 (CH₂), 22.6 (CH₂), 14.1 (CH₃); IR (in substance) ν

2925-2850 cm^-1. Anal. Calcd for C₂₇H₄₄N₄S₃: C, 62.26; H,

8.51; N, 10.76; S, 18.47. Found: C, 62.32; H, 8.59; N, 10.96; S,

18.45.

heptane/ethyl acetate 1/1; H NMR (300 MHz, CDCl₃) δ 3.63

(t, J ) 6.5 Hz, 2H), 2.84-2.73 (m, 4H), 1.99-1.89 (m, 2H),

1.89-1.79 (m, 4H), 1.63-1.20 (series of m, 20H), 0.87 (t, J )

6.7 Hz, 3H) no OH-resonance observed; ¹³C NMR (75 MHz,

CDCl₃) δ 63.0 (CH₂), 53.4 (C), 38.2 (2 × CH₂), 32.8 (CH₂), 31.8

(CH₂), 29.8 (2 × CH₂), 29.3 (CH₂), 29.2 (CH₂), 26.0 (2 × CH₂),

25.7 (CH₂), 25.6 (CH₂), 24.1 (CH₂), 24.0 (CH₂), 22.6 (CH₂), 14.1

(CH₃); IR (in substance) ν 3345, 2925-2855 cm^-1. Anal. Calcd

for C₁₈H₃₆OS₂: C, 65.00; H, 10.91; S, 19.28. Found: C, 65.28;

H, 11.15; S, 18.95.

Sulfone 32a. To a solution of 1,3-dithiane 31a (1.00 g, 2.0

mmol, 1.0 equiv) in acetone/water (v/v ) 99/1, 8 mL/mmol of

the dithiane) were added CuCl₂(546 mg, 4.1 mmol, 2.0 equiv)

and CuO (646 mg, 8.1 mmol, 4.0 equiv). The mixture was

stirred at rt for 45 min and filtered through a Celite pad. The

pad was washed with Et₂O, and the combined organic phases

were concentrated under reduced pressure. The residue was

dissolved in CH₂Cl₂(75 mL) and extracted with saturated aq

NaHCO₃(10 mL). The aqueous layer was extracted with

CH₂Cl₂(3 × 15 mL), and the combined organic phases were

dried over MgSO₄and concentrated. Flash chromatography

(heptane/ethyl acetate 10/1) afforded the corresponding ketone

(701 mg, 1.7 mmol, 86%) as pale yellow oil: R_f0.44 heptane/

ethyl acetate 1/1.

The ketone (1.63 g, 4.1 mmol, 1.0 equiv) in ethanol (10 mL/

mmol ketone) was cooled to 0 °C and treated with (NH₄)₆-

Mo₇O₂₄‚H₂O (501 mg, 0.4 mmol, 0.1 equiv) in hydrogen

peroxide (30%, 4.5 mL, 41 mmol, 10.0 equiv). The resultant

suspension was stirred at ambient temperature for 24 h and

then added to brine (30 mL) and extracted with CH₂Cl₂(3 ×

30 mL). The combined organic phases were dried over MgSO₄

and concentrated. Flash chromatography (heptane/ethyl ac-

etate 3/1) afforded the corresponding sulfone (1.74 g, 4.1 mmol,

99%) as pale yellow oil: R_f0.29 heptane/ethyl acetate 1/1.

A solution of the sulfone (1.74 g, 4.0 mmol, 1.0 equiv) and

1,2-bis-trimethylsilyloxyethane (2.48 g, 12.0 mmol, 3.0 equiv)

in CH₂Cl₂(2 mL/mmol sulfone) was cooled to -5 °C and treated

with TMSOTf (88 mg, 0.4 mmol, 0.1 equiv). The mixture was

stirred for 24 h at -5 °C. The reaction was then quenched by

the addition of pyridine (1 mL/mmol sulfone) and added to

saturated aq NaHCO₃. The aqueous layer was extracted with

CH₂Cl₂(3 × 25 mL). The combined organic phases were dried

over MgSO₄and concentrated. Flash chromatography (hep-

tane/ethyl acetate 5/1) provided ketal 32a (1.91 g, 4.0 mmol,

98%) as a pale yellow oil: R_f0.29 heptane/ethyl acetate 1/1;

¹H NMR (300 MHz, CDCl₃) δ 7.72-7.58 (m, 5H), 3.91 (s, 4H),

3.76-3.67 (m, 2H), 2.00-1.88 (m, 2H), 1.62-1.20 (series of m,

22H), 0.88 (br t, J ) 6.8 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃)

δ 153.5 (C), 133.0 (C), 131.4 (CH), 129.7 (2 × CH), 125.0 (2 ×

CH), 111.7 (C), 64.9 (2 × CH₂), 56.0 (CH₂), 37.2 (CH₂), 37.0

(CH₂), 31.8 (CH₂), 29.9 (CH₂), 29.4 (CH₂), 29.3 (CH₂), 28.9

(CH₂), 28.0 (CH₂), 23.9 (CH₂), 23.6 (CH₂), 22.6 (CH₂), 21.9

(CH₂), 14.1 (CH₃); IR (in substance) ν 2925-2855 cm^-1. Anal.

Calcd for C₂₄H₃₈N₄O₄S: C, 60.22; H, 8.00; N, 11.71; S, 6.70.

Found: C, 60.27; H, 8.13; N, 11.83; S, 6.38.

Sulfone 32b. As described for the synthesis of ketale 32a

in the preceding paragraph, 1,3-dithiane 31b (1.24 g, 2.4 mmol,

1 equiv) was treated with CuCl₂(645 mg, 4.8 mmol, 2 equiv)

and CuO (760 mg, 9.2 mmol, 4 equiv). Flash chromatography

(heptane/ethyl acetate 10/1) provided the corresponding ketone

(876 mg, 2.0 mmol, 85%) as a pale yellow oil: R_f0.36 heptane/

ethyl acetate 1/1. The ketone (840 mg, 1.9 mmol) was then

treated with (NH₄)₆Mo₇O₂₄‚H₂O (251 mg, 0.19 mmol, 0.1 equiv)

in hydrogen peroxide (30%, 2.30 mL, 20.3 mmol, 10,7 equiv).

Flash chromatography (heptane/ethyl acetate 5/1) afforded the

corresponding sulfone 51b (766 mg, 1.7 mmol, 85%) as a pale

yellow oil: R_f0.56 heptane/ethyl acetate 1/1. The sulfone (660

mg, 1.4 mmol) was then subjected to 1,2-bis-trimethylsilanyl-

oxyethane (883 mg, 4.3 mmol, 3.1 equiv) and TMSOTf (32 mg,

0.14 mmol, 0.1 equiv). Flash chromatography (heptane/ethyl

acetate 5/1) afforded ketal 32b (670 mg, 1.3 mmol, 92%) as a

pale yellow oil: R_f0.61 heptane/ethyl acetate 1/1; ¹H NMR

(300 MHz, CDCl₃) δ 7.69-7.57 (m, 5H), 3.91 (s, 4H), 3.73-

3.70 (m, 2H), 1.97-1.91 (m, 2H), 1.59-1.22 (series of m, 26H),

0.86 (br t, J ) 6.9 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 153.5

(C), 133.1 (C), 131.4 (CH), 129.7 (2 × CH), 125.1 (2 × CH),

111.8 (C), 64.9 (2 × CH₂), 56.0 (CH₂), 37.2 (CH₂), 37.0 (CH₂),

C₁₇-Alcohol 30b. As described in the preceding paragraph,

consecutive treatment of 1,3-dithiane (27) (3.0 g, 25.0 mmol)

with n-BuLi (2.36 M in hexane, 11.1 mL, 26.2 mmol) and

1-bromononane 28b (5.3 g, 25.5 mmol) afforded the monoalky-

lated dithiane (5.97 g, 24.2 mmol, 97%) as a pale yellow oil:

R_f0.36 heptane/ethyl acetate 20/1. The monoalkylated dithiane

(1.12 g, 4.6 mmol) in HMPA (2.2 mL, 12.1 mmol) and THF

was then treated with t-BuLi (1.5 M in pentane, 6.0 mL, 9.0

mmol) and iodide 29 (1.46 g, 3.0 mmol). The crude product

was subjected to tetrabutylammonium fluoride (0.96 g, 3.0

mmol). Flash chromatography provided 30b (0.94 g, 2.6 mmol,

86%) as a colorless oil: R_f0.49 heptane/ethyl acetate 1/1; H

NMR (300 MHz, CDCl₃) δ 3.56 (dt, J ) 5.7, 5.7 Hz, 2H), 2.74-

2.66 (m, 4H), 1.90-1.80 (m, 2H), 1.79-1.70 (m, 4H), 1.53-

1.09 (series of m, 24H), 0.79 (t, J ) 6.7 Hz, 3H) no HO-

resonance observed; ¹³C NMR (75 MHz, CDCl₃) δ 63.0 (CH₂),

53.4 (C), 38.2 (CH₂), 32.8 (CH₂), 31.9 (CH₂), 29.81 (CH₂), 29.78

(CH₂), 29.54 (CH₂), 29.47 (CH₂), 29.3 (CH₂), 26.0 (CH₂), 25.7

(CH₂), 25.6 (CH₂), 24.1 (CH₂), 24.0 (CH₂), 22.6 (CH₂), 14.1 (CH₃)

(several overlapping signals between 38.2 and 22.7, total

number (CH₂): 18); IR (in substance) ν 3345, 2925-2850 cm^-1

Anal. Calcd for C₂₀H₄₀OS₂: C, 66.60; H, 11.18; S, 17.78.

Found: C, 66.26; H, 11.38; S, 17.58.

Phenyl-1H-tetrazole 31a. An icecooled solution of alcohol

30a (1.44 g, 4.3 mmol, 1.0 equiv) in THF (1 mL/mmol 30a)

was treated with PPh₃(1.35 g, 5.2 mmol, 1.2 equiv), 1-phenyl-

1H-tetrazole-5-thiol (1.15 g, 6.5 mmol, 1.5 equiv), and diiso-

propyl azodicarboxylate (1.13 g, 5.6 mmol, 1.3 equiv). After

10 min of stirring, saturated aq NaHCO₃(5 mL) was added

and the aqueous layer was extracted with CH₂Cl₂(3 × 20 mL).

The combined organic phases were dried over MgSO₄and

concentrated. Flash chromatography (heptane/ethyl acetate 10/

1) afforded tetrazole 31a (2.1 g, 4.3 mmol, 100%) as a yellow

oil: R_f0.33 heptane/ethyl acetate 1/1; ¹H NMR (300 MHz,

CDCl₃) δ 7.63-7.50 (m, 5H), 3.39 (t, J ) 7.5 Hz, 2H), 2.88-

2.75 (m, 4H), 1.99-1.89 (m, 2H), 1.88-1.78 (m, 6H), 1.67-

1.17 (series of m, 18H), 0.87 (t, J ) 7.0 Hz, 3H); ¹³C NMR (75

MHz, CDCl₃) δ 154.5 (C), 133.8 (C), 130.1 (CH), 129.8 (2 ×

CH), 123.9 (2 × CH), 53.3 (C), 38.2 (CH₂), 38.1 (CH₂), 33.3

(CH₂), 31.8 (CH₂), 29.8 (CH₂), 29.6 (CH₂), 29.2 (CH₂), 29.1

(CH₂), 29.0 (CH₂), 28.9 (CH₂), 28.6 (CH₂), 26.0 (CH₂), 25.6

(CH₂), 24.1 (CH₂), 24.0 (CH₂), 22.6 (CH₂), 14.1 (CH₃); IR (in

substance)

ν . Anal. Calcd for

3055, 2925-2855 cm^-1

C₂₅H₄₀N₄S₃: C, 60.93; H, 8.18; N, 11.37; S, 19.52. Found: C,

61.15; H, 8.40; N, 11.63; S, 19.67.

Phenyl-1H-tetrazole 31b. As described for tetrazole 31a,

alcohol 30b (905 mg, 2.5 mmol, 1 equiv) was treated with PPh₃

(787 g, 3.0 mmol, 1.2 equiv), 1-phenyl-1H-tetrazole-5-thiol (668

mg, 3.8 mmol, 1.5 equiv), and diisopropylazodicarboxylate (657

mg, 3.3 mmol, 1.3 equiv). Flash chromatography provided the

tetrazole 31b (1.28 g, 2.5 mmol, 98%) as a yellow oil: R_f0.53

heptane/ethyl acetate 1/1; ¹H NMR (300 MHz, CDCl₃) δ 7.60-

7.50 (m, 5H), 3.38 (t, J ) 7.3 Hz, 2H), 2.83-2.73 (m, 4H), 1.98-

1.88 (m, 2H), 1.87-1.76 (m, 6H), 1.52-1.18 (series of m, 22H),

0.87 (t, J ) 6.7 Hz, 3H); ¹³C NMR (CDCl₃, 75 MHz) δ 154.4

(C), 142.6 (C), 130.0 (CH), 129.7 (2 × CH), 123.9 (2 × CH),

53.4 (C), 38.3 (CH₂), 38.2 (CH₂), 33.3 (CH₂), 31.9 (CH₂), 29.8

(CH₂), 29.6 (CH₂), 29.53 (CH₂), 29.47 (CH₂), 29.3 (CH₂), 29.1

J. Org. Chem, Vol. 70, No. 14, 2005 5587

Pollex et al.

31.9 (CH₂), 29.9 (CH₂), 29.6 (CH₂), 29.5 (CH₂), 29.4 (CH₂), 29.3

(CH₂), 28.8 (CH₂), 28.0 (CH₂), 23.9 (CH₂), 23.6 (CH₂), 22.6

(CH₂), 21.9 (CH₂), 14.1 (CH₃); IR (in substance) ν 2925-2855,

1710 cm^-1. Anal. Calcd for C₂₆H₄₂N₄O₄S: C, 61.63; H, 8.35;

N, 11.06;, S, 6.33. Found: C, 61.85; H, 8.15; N, 11.27; S, 6.39.

BuC), 14.1 (20-CH₃), -2.4 (SiCH₃), -2.9 (SiCH₃); IR (in

substance) ν 2930-2850, 1745 cm^-1. Anal. Calcd for C₄₁H₇₀O₈-

Si: C, 68.48; H, 9.81. Found: C, 68.63; H, 9.98.

Olefin (()-33b. As outlined for the preparation of olefin

33a, sulfone 32b (182 mg, 0.36 mmol, 1.05 equiv) was treated

with KHMDS (0.5 M solution in THF, 0.7 mL, 0.34 mmol, 1.0

equiv) and the aldehyde 26 (0.36 mmol, 1.05 equiv). Flash

chromatography afforded olefin 33b (190 mg, 0.3 mmol, 71%)

Sulfone 32c. As described for tetrazole 31a, pentadecanol

(914 mg, 4.0 mmol, 1 equiv) was treated with PPh₃(1.26 g,

4.8 mmol, 1.2 equiv), 1-phenyl-1H-tetrazole-5-thiol (1.07 g, 6.0

mmol, 1.5 equiv), and diisopropyl azodicarboxylate (1.05 g, 5.2

mmol, 1.3 equiv). Flash chromatography (heptane/ethyl acetate

5/1) afforded the corresponding phenyl-1H-tetrazole (1.55 g,

4.0 mmol, 99%) as a white solid: R_f0.70 heptane/ethyl acetate

1/1. The tetrazole (1.55 g, 4.0 mmol, 1 equiv) was then treated

with (NH₄)₆Mo₇O₂₄‚H₂O (494 mg, 0.4 mmol, 0.1 equiv) and 30%

aq hydrogen peroxide (4.4 mL, 40.0 mmol, 10 equiv) to provide

sulfone 32c (1.44 g, 3.4 mmol, 86%) as a white solid: R_f0.68

heptane/ethyl acetate 1/1; ¹H NMR (300 MHz, CDCl₃) δ 7.71-

7.57 (m, 5H), 3.76-3.69 (m, 2H), 2.00-1.88 (m, 2H), 1.54-

as a colorless oil: R_f0.35 heptane/ethyl acetate 3/1; H NMR

(300 MHz, CDCl₃) δ 7.33-7.29 (m, 5H), 5.47 (ddd, J ) 14.9,

6.6, 6.6 Hz, 1H), 5.29 (dd, J ) 15.4, 9.6 Hz, 1H) 4.96 (sept, J

) 6.2 Hz, 1H), 4.47 (s, 2H), 3.92 (s, 4H), 3.78 (dd^AB, J ) 9.6,

5.7 Hz, 1H), 3.62 (s, 3H), 3.38 (dd^AB, J ) 9.6, 6.2 Hz, 1H), 2.95

(d^AB, J ) 15.2 Hz, 1H), 2.86 (d^AB, J ) 15.2 Hz, 1H), 2.72-2.64

(m, 1H), 1.97 (ddd, J ) 6.6, 6.5, 6.5 Hz, 2H), 1.61-1.55 (m,

4H), 1.38-1.13 (m, 22H), 1.23 (d, J ) 6.1 Hz, 3H), 1.21 (d, J

) 6.1 Hz, 3H), 0.82 (s, 9H), 0.88 (t, J ) 6.7 Hz, 3H), 0.18 (s,

3H), 0.05 (s, 3H); ¹³C NMR (75 MHz, CDCl3) δ 172.0 (C), 170.6

(C), 138.3 (C), 134.4 (CH), 128.3 (2 × CH), 127.7 (2 × CH),

127.5 (CH), 127.0 (CH), 111.9 (C), 80.3 (C), 73.0 (CH₂), 70.1

(CH₂), 68.9 (CH), 64.9 (2 × CH₂), 52.3 (CH or CH₃), 51.3 (CH

or CH₃), 44.0 (CH₂), 37.2 (2 × CH₂), 34.1 (CH₂), 32.6 (CH₂),

31.9 (CH₂), 30.0 (CH₂), 29.8 (CH₂), 29.61 (CH₂), 29.55 (CH₂),

29.3 (CH₂), 29.23 (CH₂), 29.16 (CH₂), 26.1 (3 × CH₃), 23.8

(CH₂), 22.7 (CH₂), 21.8 (CH₃), 21.7 (CH₃), 19.0 (C), 14.1 (CH₃),

-2.4 (CH₃), -2.9 (CH₃); IR (in substance) ν 2955-2855, 1745

cm^-1. Anal. Calcd for C₄₃H₇₄O₈Si: C, 69.13; H, 9.98, Found:

C, 69.37; H, 10.03.

1.43 (m, 2H), 1.39-1.20 (m, 22H), 0.87 (t, J ) 6.7 Hz, 3H); ¹³

NMR (75 MHz, CDCl₃) δ 153.6 (C), 133.1 (C), 131.4 (CH), 129.7

(2 × CH), 125.1 (2 × CH), 56.0 (CH₂), 31.9 (CH₂), 29.7 (CH₂),

29.62 (CH₂), 29.59 (CH₂), 29.5 (CH₂), 29.4 (CH₂), 29.3 (CH₂),

29.2 (CH₂), 28.9 (CH₂), 28.1 (CH₂), 22.6 (CH₂), 21.9 (CH₂), 14.1

(CH₃) (several overlapping signals between 31.9 and 22.0, total

number (CH₂): 14); IR (in substance) ν 2920-2850 cm^-1. Anal.

Calcd for C₂₂H₃₆N₄O₂S: C, 62.82; H, 8.63; N, 13.32; S, 7.62.

Found: C, 63.12; H, 8.71; N, 13.43; S, 7.61.

Olefin (()-33a. Through a solution of the terminal olefin

25 (225 mg, 0.5 mmol, 1.0 equiv) in CH₂Cl₂and MeOH (v/v )

4/1, 20 mL/mmol 25) at -78 °C was bubbled a stream of ozone

until the color of the reaction mixture turned blue (∼10 min).

The excess ozone was removed by a nitrogen stream (disap-

pearance of the blue color), and then Me₂S (0.3 mL, 4.0 mmol,

8.0 equiv) was added at -78 °C. The reaction mixture was

allowed to warm to ambient temperature and stirred at this

temperature until TLC indicated complete consumption of the

ozonide (∼3 h). The reaction mixture was then concentrated

at reduced pressure to provide the crude aldehyde (()-syn-26

which was used without further purification: R_f0.23 heptane/

ethyl acetate 5/1.

Olefin (()-33c. Analogous to the procedure for the prepara-

tion of olefin 33a, sulfon 32c (284 mg, 0.7 mmol, 1.35 equiv)

was treated with KHMDS (0.5 M solution in THF, 1.3 mL,

0.7 mmol, 1.3 equiv) and the aldehyde 26 (0.5 mmol, 1.0 equiv).

Flash chromatography afforded olefin 33c (232 mg, 0.35 mmol,

70%) as a colorless oil: R_f0.56 heptane/ethyl acetate 5/1; H

NMR (500 MHz, CDCl₃) δ 7.34-7.23 (m, 5H), 5.50 (dt, J )

15.1, 6.2 Hz, 1H), 5.31 (dd, J ) 15.3, 9.6 Hz, 1H), 4.95 (sept,

J ) 6.2 Hz, 1H), 4.46 (s, 2H), 3.79 (dd^AB, J ) 9.6, 5.8 Hz, 1H),

3.61 (s, 3H), 3.39 (dd^AB, J ) 9.5, 6.3 Hz, 1H), 2.95 (d^AB, J )

15.1 Hz, 1H), 2.86 (d^AB, J ) 15.1 Hz, 1H), 2.69 (ddd, J ) 9.7,

5.9 Hz, 1H), 1.97 (dt, J ) 6.8, 6.8 Hz, 2H), 1.40-1.16 (m, 30H),

0.88 (t, J ) 6.9 Hz, 3H), 0.81 (s, 9H), 0.17 (s, 3H), 0.04 (s, 3H);

¹³C NMR (75 MHz, CDCl₃) δ 171.9 (C), 170.5 (C), 138.4 (C),

134.4 (CH), 128.2 (2 × CH), 127.7 (2 × CH), 127.4 (CH), 127.0

(CH), 80.3 (C), 73.0 (CH₂), 70.2 (CH₂), 68.9 (CH), 52.3 (CH or

CH₃), 51.2 (CH or CH₃), 43.9 (CH₂), 32.6 (CH₂), 31.9 (CH₂),

29.63 (CH₂), 29.60 (CH₂), 29.58 (CH₂), 29.5 (CH₂), 29.3 (CH₂),

29.2 (CH₂), 26.1 (3 × CH₃), 22.6 (CH₂) (several overlapping

signals between 44.0 and 22.7, total number (CH₂): 16), 21.8

(CH₃), 21.6 (CH₃), 18.9 (C), 14.0 (CH₃), -2.5 (CH₃), -2.9 (CH₃);

IR (in substance) ν 2925-2855, 1745 cm^-1. Anal. Calcd for

C₃₉H₆₈O₆Si: C, 70.86; H, 10.37. Found: C, 70.63; H, 10.62.

To a solution of the sulfon 32a (231 mg, 0.5 mmol, 1.0 equiv)

in THF (10 mL/mmol 32a) at -78 °C was added KHMDS (0.5

M solution in THF, 0.9 mL, 0.5 mmol, 1.05 equiv), and the

resulting mixture was stirred for 30 min. A cooled (-78 °C)

solution of the aldehyde 26 in THF (5 mL/mmol 26) was then

added, and the mixture was warmed to ambient temperature

overnight. The resulting slurry was diluted with water, the

phases were separated, and the organic layer was washed with

brine (2 × 10 mL), dried over MgSO₄, and then concentrated.

Flash chromatography (heptane/ethyl acetate 20/1) afforded

the olefin 33a (292 mg, 0.4 mmol, 84%) as a colorless oil: R_f

Acid (()-35a. To a solution of the olefin 33a (186 mg, 0.26

mmol, 1.0 equiv) in DMF (20 mL/mmol 33a) was added

palladium on activated carbon (Pd/C) (110 mg, 50 mg/0.1

mmol). The flask was then equipped with a three way faucet

connected to a hydrogen balloon. The suspension was carefully

degassed, recharged with hydrogen, and vigorously stirred

until TLC indicated complete consumption of the starting

material (R_f0.56 heptane/ethyl acetate 1/1). The Pd/C catalyst

was removed by filtration and the solvents were evaporated

under high vacuum at ambient temperature in order to avoid

lactonization. The crude alcohol 34a (R_f0.38 heptane/ethyl

acetate 1/1) was immediately used for the next reaction due

to its susceptibility to lactonization.

To a solution of the crude alcohol 34a in CH₂Cl₂(20 mL/

mmol 34a) were added freshly activated 4 Å molecular sieves

(200 mg), N-methylmorpholine-N-oxide (NMO) (61 mg, 0.51

mmol, 2.0 equiv), and tetrapropylammoniumperuthenate

(TPAP) (12.7 mg, 0.03 mmol, 0.1 equiv). The resulting black

suspension was stirred for 20 min at rt and then filtrated

through a plug of silica gel (washing with heptane/ethyl acetate

20/1). The solvents were then evaporated under reduced

0.38 heptane/ethyl acetate 5/1; H NMR (500 MHz, CDCl₃) δ

7.31-7.18 (m, 5H, CH-Ar), 5.44 (ddd, J ) 15.0, 6.5, 6.5 Hz,

1H, 6-CHd), 5.24 (ddd, J ) 15.2, 9.6 Hz, 1H, 5-CHd), 4.91

(sept, J ) 6.3 Hz, 1H, OiPrCH), 4.41 (s, 2H, 4′′-CH₂Ph), 3.87

(s, 4H, 13′-CH₂), 3.73 (dd^AB, J ) 9.6, 5.4 Hz, 1H, 4′-CH₂), 3.56

(s, 3H, CO₂CH₃), 3.32 (dd^AB, J ) 9.6, 6.3 Hz, 1H, 4′-CH₂), 2.89

(d^AB, J ) 15.3 Hz, 1H, 2-CH₂), 2.80 (d^AB, J ) 15.3 Hz, 1H,

2-CH₂), 2.68-2.57 (m, 1H, 4-CH), 1.98-1.86 (m, 2H, 7-CH₂),

1.58-1.46 (m, 4H, 12- and 14-CH₂), 1.36-1.24 (m, 18H, 8-,9-

,10-,11- and 15-,16-,17-,18-,19-CH₂), 1.22 (d, J ) 6.3 Hz, 3H,

OiPrCH₃), 1.20 (d, J ) 6.3 Hz, 3H, OiPrCH₃), 0.87 (t, J ) 6.9

Hz, 3H, 20-CH₃), 0.81 (s, 9H, SitBuCH₃), 0.13 (s, 3H, SiCH₃),

0.00 (s, 3H, SiCH₃); ¹³C NMR (126 MHz, CDCl₃) δ 172.0

(CO₂iPr, 170.6 (CO₂Me), 138.3 (C-Ar), 134.4 (6-CHd), 128.3

(2 × CH-Ar), 127.7 (2 × CH-Ar), 127.5 (CH-Ar), 127.0 (5-CHd

), 111.9 (13-C), 80.3 (3-C), 73.0 (4′′-CH₂), 70.0 (4′-CH₂), 68.9

(CHiPr), 64.9 (2 × 13′-CH₂), 52.2 (4-CH), 51.4 (OCH₃), 44.0

(2-CH₂), 37.1 (12- and 14-CH₂), 32.6 (7-CH₂), 31.8 (18-CH₂),

29.9 (CH₂), 29.8 (CH₂), 29.3 (CH₂), 29.23 (CH₂), 29.16 (CH₂),

26.0 (3 × SitBuCH₃), 23.84 (11- or 15-CH₂), 23.82 (11- or 15-

CH₂), 22.6 (CH₂), 21.9 (OiPrCH₃), 21.7 (OiPrCH₃), 19.0 (Sit-

5588 J. Org. Chem., Vol. 70, No. 14, 2005

Total Synthesis of the Triester of Viridiofungin A, A₂, and A₄

pressure, and the crude aldehyde 53a (R_f0.59 heptane/ethyl

acetate 1/1) was dissolved in t-BuOH (20 mL/mmol 33a) and

2-methyl-2-butene (4 mL/mmol 33a) to which a solution of

NaClO₂(235 mg, 2.6 mmol, 10.0 equiv) and NaH₂PO₄‚H₂O (248

mg, 1.8 mmol, 7.0 equiv) in water (4 mL/mmol 33a) was added.

The suspension was vigorously stirred at ambient temperature

for 12 h, diluted with water, and extracted with CH₂Cl₂(3 ×

20 mL). The combined extracts were dried over MgSO₄and

concentrated. Flash chromatography (heptane/ethyl acetate

10/1 to 5/1 to 1/1) afforded the acid 35a (134 mg, 0.21 mmol,

81%) as pale yellow oil: R_f0.29 heptane/ethyl acetate 1/1; ¹H

NMR (500 MHz, CDCl₃) δ 5.50-5.42 (m, 2H), 4.94 (sept, J )

6.2 Hz, 1H), 3.82 (s, 4H), 3.55 (s, 3H), 3.36 (d, J ) 8.3 Hz,

1H), 2.95 (d^AB, J ) 15.2 Hz, 1H), 2.72 (d^AB, J ) 15.2 Hz, 1H),

1.91 (ddd, J ) 7.0, 6.7, 6.7 Hz, 2H), 1.51-1.49 (m, 4H), 1.27-

1.14 (m, 24H), 0.91 (t, J ) 6.6 Hz, 3H), 0.75 (s, 9H), 0.11 (s,

3H), 0.00 (s, 3H) no CO₂H-resonance observed; ¹³C NMR (126

MHz, CDCl₃) δ 175.0 (C), 170.7 (C), 170.1 (C), 137.1 (C), 122.7

(CH), 111.9 (C), 79.7 (C), 69.7 (CH), 64.9 (2 × CH₂), 58.3 (CH

or CH₃), 51.7 (CH or CH₃), 43.4 (CH₂), 37.14 (CH₂), 37.08 (CH₂),

32.5 (CH₂), 31.8 (CH₂), 29.9 (CH₂), 29.7 (CH₂), 29.3 (CH₂), 29.1

(CH₂), 28.8 (CH₂), 25.9 (3 × CH₃), 23.84 (CH₂), 23.76 (CH₂),

22.6 (CH₂), 21.8 (CH₃), 21.6 (CH₃), 18.8 (C), 14.1 (CH₃), -2.7

(CH₃), -2.9 (CH₃); IR (in substance) ν 2930-2855, 1750, 1715

cm^-1. Anal. Calcd for C₃₄H₆₂O₉Si: C, 63.52; H, 9.72. Found:

C, 63.45; H, 9.41.

(several overlapping signals between 43.4 and 22.6, total

number of (CH₂): 14) 21.7 (CH₃), 21.6 (CH₃), 18.8 (C), 14.0

(CH₃), -2.7 (CH₃), -2.9 (CH₃); IR (in substance) ν 2980-2855,

1748, 1710 cm^-1. Anal. Calcd for C₃₂H₆₀O₇Si: C, 65.71; H,

10.34. Found: C, 65.98; H, 10.53.

â-Hydroxy Acid (()-37a. To a solution of the acid 35a (60

mg, 0.09 mmol, 1.0 equiv) in THF (4 mL/0.1 mmol 35a) was

added HF‚pyridine (0.15 mL, 0.15 mL/0.1 mmol 35a) at 0 °C.

The reaction mixture was stirred overnight at 45 °C. If TLC

indicated incomplete consumption of the starting material,

additional HF‚pyridine (0.15 mL, 0.15 mL/0.1 mmol 35a) was

added and stirring was continued for another 3 h at 45 °C.

The reaction was quenched by the careful addition of saturated

aq NaHCO₃and extracted with CH₂Cl₂(3 × 5 mL). The

combined organic layers were dried over MgSO₄and concen-

trated. Flash chromatography (heptane/ethyl acetate 1/1 to

pure ethyl acetate) afforded the â-hydroxy acid 37a (22 mg,

0.045 mmol, 51%) as a colorless oil: R_f0.21 ethyl acetate; H

NMR (300 MHz, CDCl₃) δ 5.65 (ddd, J ) 15.1, 6.6, 6.6 Hz,

1H), 5.52 (dd, J ) 15.3, 9.6 Hz, 1H), 5.08 (sept, J ) 6.3 Hz,

1H), 4.25 (s, 1H (OH)), 3.66 (s, 3H), 3.32 (d, J ) 9.6 Hz, 1H),

3.00 (d^AB, J ) 16.3 Hz, 1H), 2.83 (d^AB, J ) 16.3 Hz, 1H), 2.37

(t, J ) 7.5 Hz, 4H), 2.00 (ddd, J ) 6.9, 6.8, 6.8 Hz, 2H), 1.57-

1.50 (m, 4H), 1.35-1.23 (m, 20H), 0.86 (t, J ) 6.9 Hz, 3H) no

CO₂H-resonance observed; ¹³C NMR (75 MHz, CDCl₃) δ 211.8

(C), 173.8 (C), 171.7 (C), 170.3 (C), 138.1 (CH), 121.2 (CH),

75.7 (C), 70.8 (CH), 56.9 (CH or CH₃), 51.9 (CH or CH₃), 42.8

(CH₂), 42.7 (CH₂), 41.6 (CH₂), 32.4 (CH₂), 31.7 (CH₂), 29.2

(CH₂), 29.1 (CH₂), 29.0 (CH₂), 28.9 (CH₂), 28.6 (CH₂), 23.9

(CH₂), 23.7 (CH₂), 22.6 (CH₂), 21.7 (CH₃), 21.5 (CH₃), 14.1

Acid (()-35b. As described for the preparation of the acid

35a, olefin 33b (79 mg, 0.11 mmol, R_f0.67 heptane/ethyl

acetate 1/1) was debenzylated to afford the corresponding

alcohol 34b (R_f0.50 heptane/ethyl acetate 1/1). The alcohol

was then treated with NMO (25 mg, 0.21 mmol) and TPAP (4

mg, 0.01 mmol). The resulting crude aldehyde (R_f0.62 heptane/

ethyl acetate 1/1) was oxidized with NaClO₂(96 mg, 1.1 mmol)

and NaH₂PO₄‚H₂O (101 mg, 0.7 mmol). Flash chromatography

(heptane/ethyl acetate 10/1 to 1/1) afforded the acid 35b (49

mg, 0.07 mmol, 69%) as pale yellow oil: R_f0.38 heptane/ethyl

(CH₃); IR (in substance) ν 3495, 2930-2855, 1740, 1715 cm^-1

Anal. Calcd for C₂₆H₄₄O₈: C, 64.44; H, 9.15. Found: C, 64.50;

H, 9.18.

â-Hydroxy Acid (()-37b. As described for the â-hydroxy

acid 37a, the acid 35b (55 mg, 0.08 mmol) was treated with

HF‚pyridine (0.12 mL). Flash chromatography (heptane/ethyl

acetate 1/1 to pure ethyl acetate) afforded the â-hydroxy acid

37b (23 mg, 0.45 mmol, 56%) as a colorless oil: R_f0.26 ethyl

acetate; ¹H NMR (300 MHz, CDCl₃) δ 5.70-5.51 (m, 2H), 5.10

(sept, J ) 6.2 Hz, 1H), 4.23 (br s, 1H (OH)), 3.67 (s, 3H), 3.33

(d, J ) 9.0 Hz, 1H), 3.02 (d^AB, J ) 16.2 Hz, 1H), 2.85 (d^AB, J )

16.2 Hz, 1H), 2.38 (t, J ) 7.4 Hz, 4H), 2.02 (ddd, J ) 6.6, 6.4,

6.4 Hz, 2H), 1.61-1.50 (m, 4H), 1.31-1.24 (m, 24H), 0.88 (t, J

) 6.6 Hz, 3H) no signals for COOH observed; ¹³C NMR (75

MHz, CDCl₃) δ 211.7 (C), 174.5 (C), 171.8 (C), 170.4 (C), 137.9

(CH), 121.5 (CH), 75.8 (C), 70.7 (CH), 57.0 (CH or CH₃), 51.9

(CH or CH₃), 42.8 (CH₂), 42.7 (CH₂), 41.6 (CH₂), 32.4 (CH₂),

31.8 (CH₂), 31.6 (CH₂), 29.4 (CH₂), 29.2 (CH₂), 29.04 (CH₂),

28.99 (CH₂), 28.8 (CH₂), 28.6 (CH₂), 23.9 (CH₂), 23.7 (CH₂),

22.6 (CH₂), 21.7 (CH₃), 21.5 (CH₃), 14.0 (CH₃); IR (in substance)

acetate 1/1; H NMR (300 MHz, CDCl₃) δ 5.58-5.54 (m, 2H),

5.02 (sept, J ) 6.3 Hz, 1H), 3.90 (s, 4H), 3.62 (s, 3H), 3.40 (d,

J ) 8.9 Hz, 1H), 3.04 (d, J ) 15.2 Hz, 1H), 2.80 (d, J ) 15.3

Hz, 1H) 2.01-1.97 (m, 2H), 1.58-1.53 (m, 4H), 1.35-1.22 (m,

28H), 0.82 (s, 9H), 0.86 (t, J ) 6.9 Hz, 3H), 0.18 (s, 3H), 0.07

(s, 3H) no CO₂H-resonance observed; ¹³C NMR (75 MHz,

CDCl₃) δ 175.2 (C), 170.7 (C), 170.1 (C), 137.1 (CH), 122.7 (CH),

111.9 (C), 79.7 (C), 69.7 (CH), 64.9 (2 × CH₂), 58.4 (CH or CH₃),

51.6 (CH or CH₃), 43.4 (CH₂), 37.2 (CH₂), 37.1 (CH₂), 32.5

(CH₂), 31.9 (CH₂), 30.0 (CH₂), 29.7 (CH₂), 29.5 (CH₂), 29.4

(CH₂), 29.3 (CH₂), 29.1 (CH₂), 28.8 (CH₂), 25.9 (3 × CH₃), 23.8

(CH₂), 23.7 (CH₂), 22.7 (CH₂), 21.8 (CH₃), 21.6 (CH₃), 18.8 (C),

14.1 (CH₃), -2.7 (CH₃), -2.9 (CH₃); IR (in substance) ν 2925-

2855, 1745, 1710 cm^-1. Anal. Calcd for C₃₆H₆₆O₉Si: C, 64.49;

H, 9.92. Found: C, 64.18; H, 9.92.

3480, 2925-2855, 1735, 1710 cm^-1

. Anal. Calcd for

C₂₈H₄₈O₈: C, 65.60; H, 9.44. Found: C, 65.70; H, 9.57.

Acid (()-35c. As described for the preparation of the acid

35a, olefin 33c (351 mg, 0.53 mmol, 1 equiv) (R_f0.71 heptane/

ethyl acetate 1/1) was debenzylated to provide the correspond-

ing alcohol (R_f0.50 heptane/ethyl acetate 1/1) that was treated

with NMO (130 mg, 1.1 mmol) and TPAP (26 mg, 0.05 mmol).

The resulting crude aldehyde 53c (R_f0.59 heptane/ethyl

acetate 1/1) was subjected to NaClO₂(160 mg, 5.3 mmol) and

NaH₂PO₄‚H₂O (130 mg, 3.7 mmol). Flash chromatography

(heptane/ethyl acetate 10/1 to 1/1) afforded the acid 35c (218

mg, 0.37 mmol, 70%) as a pale yellow oil: R_f0.35 heptane/

â-Hydroxy Acid (()-37c. According to the procedure for

the preparation of â-hydroxy acid 37a, acid 35c (50 mg, 0.09

mmol) was treated with HF‚pyridine (0.13 mL). Flash chro-

matography (heptane/ethyl acetate 1/1 to pure ethyl acetate)

afforded â-hydroxy acid 37c (31 mg, 0.07 mmol, 76%) as a

colorless oil: R_f0.23 ethyl acetate; ¹H NMR (300 MHz, CDCl₃)

δ 5.70 (ddd, J ) 15.3, 6.8, 6.8 Hz, 1H), 5.51 (dd, J ) 15.3, 9.7

Hz, 1H), 5.01 (sept, J ) 6.2 Hz, 1H), 4.37 (br s, 1H), 3.67 (s,

3H), 3.34 (d, J ) 9.8 Hz, 1H), 3.02 (d^AB, J ) 16.1 Hz, 1H), 2.83

(d^AB, J ) 16.1 Hz, 1H), 2.01 (td, J ) 7.2, 7.2 Hz, 2H), 1.36-

1.17 (m, 30 H), 0.86 (t, J ) 7.1 Hz, 3H) no COOH-resonance

observed; ¹³C NMR (75 MHz, CDCl₃) δ 171.8 (C), 171.5 (C),

170.2 (C), 138.6 (CH), 120.6 (CH), 75.7 (C), 71.0 (CH), 56.7

(CH or CH₃), 52.0 (CH or CH₃), 41.5 (CH₂), 32.5 (CH₂), 31.9

(CH₂), 29.68 (CH₂), 29.65 (CH₂), 29.6 (CH₂), 29.43 (CH₂), 29.36

(CH₂), 29.1 (CH₂), 28.8 (CH₂), 22.7 (CH₂), (several overlapping

signals between 41.5 and 22.7, total number of (CH₂): 14) 21.7

(CH₃), 21.5 (CH₃), 14.1 (CH₃); IR (in substance) ν 2980-2855,

1745 cm^-1. Anla. Calcd for C₂₆H₄₆O₇: C, 66.35; H, 9.85.

Found: C, 66.43; H, 9.69.

ethyl acetate 1/1; H NMR (300 MHz, CDCl₃) δ 5.70 (dt, J )

15.3, 6.8 Hz, 1H), 5.51 (dd, J ) 15.3, 9.7 Hz, 1H), 5.01 (sept,

J ) 6.2 Hz, 1H), 4.37 (br s, 1H), 3.67 (s, 3H), 3.34 (d, J ) 9.8

Hz, 1H), 3.02 (d^AB, J ) 16.1 Hz, 1H), 2.83 (d^AB, J ) 15.3 Hz,

1H), 2.02 (td, J ) 6.6, 6.6 Hz, 2H), 1.29-1.21 (m, 30H), 0.88

(t, J ) 7.1 Hz, 3H), 0.84 (s, 9H), 0.20 (s, 3H), 0.09 (s, 3H) no

CO₂H-resonance observed; ¹³C NMR (75 MHz, CDCl₃) δ 174.1

(C), 170.6 (C), 170.0 (C), 137.3 (CH), 122.6 (CH), 79.7 (C), 69.7

(CH), 58.2 (CH or CH₃), 51.5 (CH or CH₃), 43.4 (CH₂), 32.5

(CH₂), 31.9 (CH₂), 29.6 (CH₂), 29.5 (CH₂), 29.4 (CH₂), 29.3

(CH₂), 29.2 (CH₂), 28.8 (CH₂), 25.9 (3 × CH₃), 22.6 (CH₂),

J. Org. Chem, Vol. 70, No. 14, 2005 5589

Pollex et al.

Viridiofungin A ester (+)-38a and (-)-39a. To a solution

of the â-hydroxy acid 37a (27 mg, 0.06 mmol, 1.0 equiv) in

CH₂Cl₂(20 mL/mmol 37a) were added benzotriazol-1-yloxy-

tripyrolidinophosphonium hexaflurophosphate (PyBOP) (44

mg, 0 08 mmol, 1.5 equiv), N-methylmorpholine (NMM) (27

µL, 0.24 mmol, 4.4 equiv), and ^L-tyrosine methyl ester (16 mg,

0.08 mmol, 1.5 equiv) at ambient temperature. The resulting

mixture was stirred overnight and then added to saturated

aq NaHCO₃. The aqueous layer was extracted with CH₂Cl₂(3

× 5 mL). The combined organic phases were dried over MgSO₄

and concentrated. Flash chromatography (heptane/ethyl ac-

etate 1/1 to pure ethyl acetate) afforded 38a and 39a as a 1:1

mixture (26 mg, 0.04 mmol, 71%): R_f0.53 ethyl acetate. The

diastereomers were separated by reversed-phase HPLC. For

details, see the Supporting Information.

to pure ethyl acetate) afforded 38b and 39b as a 1:1 mixture

(28 mg, 0.04 mmol, 90%): R_f0.38 ethyl acetate. The diaster-

eomers were separated by reversed-phase HPLC; see the

Supporting Information for details.

(+)-38b: H NMR (500 MHz, CDCl₃) δ 7.06 (d, J ) 7.7 Hz,

1H, NH), 6.93 (d, J ) 8.4 Hz, 2H, 5′-CH-Ar), 6.77 (d, J ) 8.4

Hz, 2H, 6′-CH-Ar), 5.54 (ddd, J ) 15.2, 6.4, 6.4 Hz, 1H, 6-CHd

), 5.23 (dd, J ) 15.3, 9.6 Hz, 1H, 5-CHd), 5.03 (sept, J ) 6.3

Hz, 1H, OiPr-CH), 4.73 (ddd, J ) 7.8, 7.8, 4.7 Hz, 1H, 2′-H),

4.23 (s, 1H, 3-OH), 3.75 (s, 3H, 1′-CO₂CH₃), 3.64 (s, 3H, 1-CO₂-

CH₃), 3.16 (dd^AB, J ) 14.3, 4.7 Hz, 1H, 3′-CH₂), 3.13 (d, J )

9.6 Hz, 1H, 4-H), 3.05 (d^AB, J ) 16.4 Hz, 1H, 2-CH₂), 2.89 (d^AB

J ) 16.4 Hz, 1 H, 2-CH₂), 2.88 (dd^AB, J ) 14.4, 8.0 Hz, 1H,

3′-CH₂) 2.45 (t, J ) 7.0 Hz, 2H, 12- or 14-CH₂), 2.42 (t, J ) 7.6

Hz, 2H, 12- or 14-CH₂), 1.91-1.86 (m, 2H, 7-CH₂), 1.59-1.52

(m, 4H, 11- and 15-CH₂), 1.29-1.20 (m, 24H, OiPr-CH₃, 8-,9-

,10-CH₂and 16-,17-,18-,19-,20-,21-CH₂), 0.86 (t, J ) 7.0 Hz,

3H, 22-CH₃), no signal detected for 7′-OH; ¹³C NMR (CDCl₃,

125.8 MHz) δ 214.2 (13-CdO), 172.3 (CO₂iPr), 171.9 (1′-CO₂-

CH₃), 170.6 (1-CO₂CH₃), 170.4 (CONH), 155.6 (7′-COH), 137.1

(6-CH), 130.2 (2 × 5′-CH), 127.1 (4′-C), 121.6 (5-CH), 115.4 (2

× 6′-CH), 75.8 (3-C), 70.5 (OiPr-CH), 58.0 (4-CH), 53.2 (2′-

CH), 52.4 (CO₂CH₃), 51.8 (CO₂CH₃), 43.0 (12- or 14-CH₂), 42.7

(12- or 14-CH₂), 41.0 (2-CH₂), 36.5 (3′-CH₂), 32.3 (7-CH₂), 31.8

(20-CH₂), 29.4 (CH₂), 29.3 (CH₂), 29.24 (CH₂), 29.20 (CH₂), 28.8

(CH₂), 28.7 (CH₂), 28.0 (CH₂), 23.9 (11- or 15-CH₂), 23.4 (11-

or 15-CH₂), 22.6 (21-CH₂), 21.7 (OiPr-CH₃), 21.5 (OiPr-CH₃),

14.1 (22-CH₃); IR (in substance) ν 3354, 2926, 2490, 2854,

(+)-38a: H NMR (500 MHz, CDCl₃) δ 7.05 (d, J ) 7.7 Hz,

1H, NH), 7.01 (br s, 1H, Ph-OH), 6.94 (d, J ) 8.5 Hz, 2H, 5′-

CH-Ar), 6.77 (d, J ) 8.5 Hz, 2H, 6′-CH-Ar), 5.55 (ddd, J )

15.2, 6.4, 6.4 Hz, 1H, 6-CHd), 5.23 (dd, J ) 15.3, 9.6 Hz, 1H,

5-CHd), 5.03 (sept, J ) 6.2 Hz, 1H, OiPr-CH), 4.73 (ddd, J )

7.9, 7.9, 4.7 Hz, 1H, 2′-CH), 4.23 (s, 1H, 3-OH), 3.75 (s, 3H,

1′-CO₂CH₃), 3.64 (s, 3H, 1-CO₂CH₃), 3.15-3.08 (m, 1H, 3′-CH₂),

3.13 (d, J ) 9.5 Hz, 1H, 4-CH), 3.05 (d, J ) 16.3 Hz, 1H,

2-CH₂), 2.89 (d, J ) 16.1 Hz, 1H, 2-CH₂), 2.91-2.86 (m, 1H,

3′-CH₂) 2.45 (t, J ) 7.0 Hz, 2H, 12- or 14-CH₂), 2.43 (t, J ) 7.5

Hz, 2H, 12- or 14-CH₂), 1.92-1.83 (m, 2H, 7-CH₂), 1.62-1.48

(m, 4H, 11- and 15-CH₂), 1.30-1.15 (m, 20H, OiPr-CH₃, 8-,9-

,10-CH₂and 16-,17-,18-,19-CH₂), 0.86 (t, J ) 6.9 Hz, 3H, 20-

CH₃) ¹³C NMR (CDCl₃, 125.8 MHz) δ 214.3 (13-CdO), 172.3

(CO₂iPr), 171.9 (1′-CO₂CH₃), 170.6 (1-CO₂CH₃), 170.4 (CONH),

155.6 (7′-COH-Ar), 137.1 (6-CHd), 130.2 (2 × 5′-CH-Ar), 127.1

(4′-C-Ar), 121.6 (5-CHd), 115.4 (2 × 6′-CH-Ar), 75.9 (3-C), 70.5

(OiPr-CH), 58.0 (4-CH), 53.2 (2′-CH), 52.4 (CO₂CH₃), 51.8

(CO₂CH₃), 43.0 (12- or 14-CH₂), 42.7 (12- or 14-CH₂), 41.0 (2-

CH₂), 36.5 (3′-CH₂), 32.3 (7-CH₂), 31.6 (18-CH₂), 29.2 (CH₂),

29.0 (CH₂), 28.8 (CH₂), 28.7 (CH₂), 28.0 (CH₂), 23.9 (11- or 15-

CH₂), 23.4 (11- or 15-CH₂), 22.6 (19-CH₂), 21.8 (OiPr-CH₃), 21.5

(OiPr-CH₃), 14.0 (20-CH₃); IR (in substance) ν 3372, 2931,

2491, 1742 cm^-1; [R]²⁵_D+52.9 (c 0.51, CHCl₃). Anal. Calcd for

C₃₆H₅₅NO₁₀: C, 65.33; H, 8.38. Found: C, 65.06; H, 8.48.

1741^-1; [R]²⁵+22.9 (c 1.0, CHCl₃). Anal. Calcd for C₃₈H₅₉-

NO₁₀: C, 66.16; H, 8.62; N, 2.03. Found: C, 66.55; H, 8.62; N,

2.01.

(-)-39b: ¹H NMR (500 MHz, CDCl₃) δ 6.95 (d, J ) 8.4 Hz,

2H, 5′-CH-Ar), 6.75 (d, J ) 9.0 Hz, 1H, NH), 6.74 (d, J ) 8.5

Hz, 2H, 6′-CH-Ar), 5.62 (ddd, J ) 15.2, 6.6, 6.6 Hz, 1H, 6-CHd

), 5.48 (dd, J ) 15.3, 9.5 Hz, 1H, 5-CHd), 5.04 (sept, J ) 6.3

Hz, 1H, CO₂iPr-CH), 4.76 (ddd, J ) 7.5, 7.4, 5.0 Hz, 1H, 2′-

CH), 4.47 (s, 1H, 3-OH), 3.72 (s, 3 H, 1′-CO₂CH₃), 3.65 (s, 3H,

1-CO₂CH₃), 3.15 (d, J ) 9.5 Hz, 1H, 4-H), 3.09 (dd^AB, J ) 14.2,

4.9 Hz, 1H, 3′-CH₂), 2.98 (dd^AB, J ) 14.1, 6.8 Hz, 1H, 3′-CH₂),

2.83 (d^AB, J ) 16.0 Hz, 1H, 2-CH₂), 2.62 (d^AB, J ) 16.0 Hz, 1H,

2-CH₂), 2.45 (t, J ) 7.2 Hz, 2H, 12- or 14-CH₂), 2.43 (t, J ) 7.5

Hz, 2H, 12- or 14-CH₂), 1.98-1.92 (m, 2H, 7-CH₂), 1.58-1.50

(m, 4H, 11- and 15-CH₂), 1.29-1.20 (m, 24H, OiPr-CH₃, 8-,9-

,10-CH₂and 16-,17-,18-,19-,20-,21-CH₂), 0.86 (t, J ) 6.9 Hz,

3H, 22-CH₃) no signal detected for 7′-OH; ¹³C NMR (CDCl₃,

125.8 MHz) δ 213.3 (13-CdO), 172.1 (CO₂iPr), 171.6 (1′-CO₂-

CH₃), 170.7 (CONH), 170.5 (1-CO₂CH₃), 155.5 (7′-COH-Ar),

137.8 (6-CHd), 130.4 (2 × 5′-CH-Ar), 127.1 (4′-C-Ar), 122.3

(5-CHd), 115.5 (2 × 6′-CH-Ar), 76.1 (3-C), 70.2 (OiPr-CH), 57.6

(4-CH), 53.3 (2′-CH), 52.3 (CO₂CH₃), 51.8 (CO₂CH₃), 43.0 (12-

or 14-CH₂), 42.7 (12- or 14-CH₂), 41.5 (2-CH₂), 36.7 (3′-CH₂),

32.4 (7-CH₂), 31.8 (20-CH₂), 29.40 (CH₂), 29.36 (CH₂), 29.24

(CH₂), 29.20 (CH₂), 28.9 (2 × CH₂), 28.6 (CH₂), 23.9 (11- or

15-CH₂), 23.5 (11- or 15-CH₂), 22.6 (21-CH₂), 21.7 (OiPr-CH₃),

21.5 (OiPr-CH₃), 14.1 (22-CH₃); IR (in substance) ν 3346, 2926,

(-)-39a: ¹H NMR (500 MHz, CDCl₃) δ 6.95 (d, J ) 8.4 Hz,

2H, 5′-CH-Ar), 6.76 (d, J ) 8.5 Hz, 2H, 6′-CH-Ar), 6.67 (d, J )

7.9 Hz, 1H, NH), 6.34 (s, 1H, Ph-OH), 5.63 (ddd, J ) 15.2, 6.6,

6.6 Hz, H, 6-CHd), 5.49 (dd, J ) 15.3, 9.6 Hz, 1H, 5-CHd),

5.05 (sept, J ) 6.3 Hz, 1H, CO₂iPr-CH), 4.74 (ddd, J ) 7.1,

7.0, 5.1 Hz, 1H, 2′-CH), 4.49 (s, 1H, 3-OH), 3.72 (s, 3H, 1′-

CO₂CH₃), 3.65 (s, 3H, 1-CO₂CH₃), 3.16 (d, J ) 9.5 Hz, 1H,

4-CH), 3.09 (dd^AB, J ) 14.1, 4.9 Hz, 1H, 3′-CH₂), 3.00 (dd^AB, J

) 14.1, 6.8 Hz, 1H, 3′-CH₂), 2.85 (d^AB, J ) 16.0 Hz, 1H, 2-CH₂),

2.68 (d^AB, J ) 16.0 Hz, 1H, 2-CH₂), 2.42 (t, J ) 7.2 Hz, 2H,

12- or 14-CH₂), 2.41 (t, J ) 7.4 Hz, 2H, 12- or 14-CH₂), 2.01-

1.92 (m, 2H, 7-CH₂), 1.59-1.48 (m, 4H, 11- and 15-CH₂), 1.34-

1.18 (m, 20 H, OiPr-CH₃, 8-,9-,10-CH₂and 16-,17-,18-,19-CH₂),

0.86 (t, J ) 6.9 Hz, 3H, 20-CH₃); ¹³C NMR (CDCl₃, 125.8 MHz)

δ 213.4 (13-CdO), 172.2 (CO₂iPr), 171.6 (1′-CO₂CH₃), 170.6

(CONH), 170.5 (1-CO₂CH₃), 155.4 (7′-COH-Ar), 137.8 (6-CHd

), 130.4 (2 × 5′-CH-Ar), 127.3 (4′-C-Ar), 122.4 (5-CHd), 115.5

(2 × 6′-CH-Ar), 76.1 (3-C), 70.2 (OiPr-CH), 57.6 (4-CH), 53.3

(2′-CH), 52.3 (CO₂CH₃), 51.8 (CO₂CH₃), 43.0 (12- or 14-CH₂),

42.7 (12- or 14-CH₂), 41.6 (2-CH₂), 36.6 (3′-CH₂), 32.5 (7-CH₂),

31.7 (18-CH₂), 29.7 (CH₂), 29.2 (CH₂), 29.0 (CH₂), 28.9 (CH₂),

28.5 (CH₂), 23.9 (11- or 15-CH₂), 23.5 (11- or 15-CH₂), 22.6 (19-

CH₂), 21.7 (OiPr-CH₃), 21.6 (OiPr-CH₃), 14.1 (20-CH₃); IR (in

substance) ν 3334, 2926, 2464, 1743 cm^-1; [R]²⁵_D-6.6 (c 0.15,

CHCl₃) (lit. trimethyl ester [R]²⁵_D-23.0 (c 0.47, MeOH)). Anal.

Calcd for C₃₆H₅₅NO₁₀: C, 65.33; H, 8.38. Found: C, 65.47; H,

8.48.

2854, 1741 cm^-1; [R]²⁵-5.1 (c 1.4, CHCl₃). Anal. Calcd for

C₃₈H₅₉NO₁₀: C, 66.16; H, 8.62; N, 2.03. Found: C, 66.50; H,

8.78; N, 2.09.

Viridiofungin A₂Ester (+)-38c and (-)-39c. As described

for the preparation of 38a and 39a, â-hydroxy acid 37c (30

mg, 0.06 mmol) was treated with PyBOP (50 mg, 0.10 mmol),

NMM (31 µL, 0.28 mmol), and ^L-tyrosine methyl ester (19 mg,

0.10 mmol). Flash chromatography (heptane/ethyl acetate 1/1

to ethyl acetate) afforded 38c and 39c as a 1:1 mixture (33

mg, 0.05 mmol, 80%): R_f0.38 ethyl acetate. The diastereomers

were separated by reversed-phase HPLC; see the Supporting

Information for details.

Viridiofungin A₄Ester (+)-38b and (-)-39b. As described

for the preparation of 38a and 39a, â-hydroxy acid 37b (22

mg, 0.045 mmol) was treated with PyBOP (36 mg, 0.07 mmol),

NMM (23 µL, 0.2 mmol), and ^L-tyrosine methyl ester (13 mg,

0.07 mmol). Flash chromatography (heptane/ethyl acetate 1/1

(+)-38c: ¹H NMR (500 MHz, CDCl₃) δ 7.06 (d, J ) 7.9 Hz,

1H, NH), 6.96 (d, J ) 8.5 Hz, 2H, 5′-CH-Ar), 6.71 (d, J ) 8.5

Hz, 2H, 6′-CH-Ar), 5.56 (ddd, J ) 14.8, 6.6, 6.6 Hz, 1H, 6-CHd

), 5.31 (dd, J ) 15.2, 9.6 Hz, 1H, 5-CHd), 5.04 (sept, J ) 6.2

Hz, 1H, OiPr-CH), 5.02 (br s, 1H, 7′-OH), 4.77 (ddd, J ) 7.1,

5590 J. Org. Chem., Vol. 70, No. 14, 2005

Total Synthesis of the Triester of Viridiofungin A, A₂, and A₄

7.1, 5.6 Hz, 1H, 2′-H), 4.24 (s, 1H, 3-OH), 3.73 (s, 3H, 1′-CO₂-

CH₃), 3.63 (s, 3H, 1-CO₂CH₃), 3.14 (d, J ) 9.6 Hz, 1H, 4-H),

3.08 (dd^AB, J ) 14.1, 5.4 Hz, 1H, 3′-CH₂), 2.98 (d^AB, J ) 16.3

Hz, 1H, 2-CH₂), 2.97 (dd^AB, J ) 14.0, 7.0 Hz, 1H, 3′-CH₂), 2.87

(d^AB, J ) 16.3 Hz, 1H, 2-CH₂), 1.96-1.91 (m, 2H, 7-CH₂), 1.27-

1.21 (m, 30H, OiPr-CH₃, 8-,9-,10-,11-,12-,13-,14-,15-,16-,17-,

18-,19-,20-,21-CH₂), 0.87 (t, J ) 6.9 Hz, 3H, 20-CH₃); ¹³C NMR

(CDCl₃, 125.8 MHz) δ 172.3 (CO₂iPr), 171.9 (1′-CO₂CH₃), 170.6

(CONH or 1-CO₂CH₃), 170.5 (1-CO₂CH₃or CONH), 154.8 (7′-

COH), 137.5 (6-CH), 130.4 (2 × 5′-CH), 127.8 (4′-C), 121.9 (5-

CH), 115.4 (2 × 6′-CH), 75.9 (3-C), 70.5 (OiPr-CH), 58.1 (4-

CH), 53.1 (2′-CH), 52.3 (CO₂CH₃), 51.8 (CO₂CH₃), 41.1 (2-CH₂),

36.7 (3′-CH₂), 32.6 (7-CH₂), 31.9 (18-CH₂), 29.69 (CH₂), 29.65

(CH₂), 29.6 (CH₂), 29.5 (CH₂), 29.4 (CH₂), 29.2 (CH₂), 29.0 (CH₂)

(several overlapping signals between 29.7 and 29.0, total

number of (CH₂): 15), 22.7 (19-CH₂), 21.8 (OiPr-CH₃), 21.5

(OiPr-CH₃), 14.1 (20-CH₃); IR (in substance) ν 3343, 2925,

2853, 1743 cm^-1; [R]²⁵_D+20.7 (c 0.14, CHCl₃). Anal. Calcd for

C₃₆H₅₇NO₉: C, 66.74; H, 8.87. Found: C, 66.35; H, 8.87.

(-)-39c: ¹H NMR (500 MHz, CDCl₃) δ 7.01 (d, J ) 8.4 Hz,

2H, 5′-CH-Ar), 6.90 (d, J ) 8.1 Hz, 1H, NH), 6.71 (d, J ) 8.5

Hz, 2H, 6′-CH-Ar), 5.63 (ddd, J ) 15.3, 6.6, 6.6 Hz, 1H, 6-CHd

), 5.45 (dd, J ) 15.1, 9.7 Hz, 1H, 5-CHd), 5.03 (sept, J ) 6.5

Hz, 1H, CO₂iPr-CH), 5.01 (br s, 1H, 7′-OH), 4.80 (ddd, J )

7.8, 7.8, 5.3 Hz, 1H, 2′-CH), 4.29 (s, 1H, 3-OH), 3.71 (s, 3H,

1′-CO₂CH₃), 3.66 (s, 3H, 1-CO₂CH₃), 3.13 (d, J ) 9.4 Hz, 1H,

4-H), 3.11 (dd^AB, J ) 13.9, 5.7 Hz, 1H, 3′-CH₂), 2.96 (dd^AB, J )

14.1, 7.5 Hz, 1H, 3′-CH₂), 2.81 (d^AB, J ) 16.1 Hz, 1H, 2-CH₂),

2.52 (d^AB, J ) 16.3 Hz, 1H, 2-CH₂), 2.01-1.94 (m, 2H, 7-CH₂),

1.27-1.21 (m, 30H, OiPr-CH₃, 8-,9-,10-,11-,12-,13-,14-,15-,16-

,17-,18-,19-CH₂), 0.87 (t, J ) 6.9 Hz, 3H, 20-CH₃); ¹³C NMR

(CDCl₃, 125.8 MHz) δ 172.2 (CO₂iPr), 171.8 (1′-CO₂CH₃), 170.5

(CONH or 1-CO₂CH₃), 170.4 (1-CO₂CH₃or CONH), 154.8 (7′-

COH-Ar), 137.8 (6-CHd), 130.5 (2 × 5′-CH-Ar), 127.9 (4′-C-

Ar), 122.0 (5-CHd), 115.5 (2 × 6′-CH-Ar), 75.9 (3-C), 70.4

(OiPr-CH), 57.9 (4-CH), 53.3 (2′-CH), 52.3 (CO₂CH₃), 51.8

(CO₂CH₃), 41.3 (2-CH₂), 37.0 (3′-CH₂), 32.6 (7-CH₂), 31.9 (18-

CH₂), 29.69 (CH₂), 29.65 (CH₂), 29.6 (CH₂), 29.5 (CH₂), 29.4

(CH₂), 29.2 (CH₂), 29.0 (CH₂) (several overlapping signals

between 29.7 and 29.0, total number of (CH₂): 15), 22.7 (19-

CH₂), 21.7 (OiPr-CH₃), 21.5 (OiPr-CH₃), 14.1 (20-CH₃); IR (in

substance) ν 3343, 2924, 2854, 1743 cm^-1; [R]²⁵_D-3.9 (c 0.19,

CHCl₃). Anal. Calcd for C₃₆H₅₇NO₉: C, 66.74; H, 8.87. Found:

C, 65.47; H, 8.48.

Acknowledgment. Very generous financial support

from the German Research Foundation (DFG), the Fund

of the Chemical Industry (FCI), and the Dr. Otto Ro¨hm

Memorial Fund is gratefully acknowledged. M.H. is a

Heisenberg fellow of the DFG.

Supporting Information Available: General experimen-

tal methods, experimental procedures and spectroscopic data

for all new compounds that are not included in the Experi-

mental Section, copies of H and ¹³C NMR spectra of all new

compounds, and details of the assignment of the double-bond

configuration of compound 33. This material is available free

of charge via the Internet at http://pubs.acs.org.

JO0505270

J. Org. Chem, Vol. 70, No. 14, 2005 5591

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