Synthetic studies of antitumor macrolide rhizoxin: Stereoselective syntheses of the C(1)-C(9) and C(12)-C(26) subunits

6952

J . Org. Chem. 1998, 63, 6952-6967

Syn th etic Stu d ies of An titu m or Ma cr olid e Rh izoxin :

Ster eoselective Syn th eses of th e C(1)-C(9) a n d C(12)-C(26)

Su bu n its

Steven D. Burke,* J ian Hong, J oseph R. Lennox,^†and Andrew P. Mongin

Department of Chemistry, University of WisconsinsMadison, Madison, Wisconsin 53706, and

Department of Chemical Sciences, Wyeth-Ayerst Research, Princeton, New J ersey 08543-8000

Received April 21, 1998

A triply convergent synthetic approach which culminates in the enantioselective syntheses of the

C(1)-C(9) and C(12)-C(26) subunits of the macrolide antitumor agent rhizoxin is described. The

central C(12)-C(20) subunit 4 has been prepared efficiently via diastereoselective enzymatic acetate

hydrolysis of 15 with porcine pancreatic lipase, a chelation-controlled Ireland-Claisen rearrange-

ment (10 f 12) combined with kinetic bromolactonization (12 f 14), and Mitsunobu inversion (23

f 26) to introduce the three contiguous C(15)-C(17) stereocenters. Formation of the C(18)-C(19)

trisubstituted (E)-olefin was achieved by a stereoselective Horner-Wadsworth-Emmons reaction.

The central segment 4 and the oxazole chromophore side chain 3 were coupled using another highly

stereoselective Horner-Wadsworth-Emmons reaction. Two different lactone subunits [C(1)-C(9)

segment 5 and C(3)-C(10) segment 47] were also prepared, employing a thermodynamically

controlled diastereotopic group differentiation tactic for establishing the C(5) stereochemistry.

Ch a r t 1

In tr od u ction

Rhizoxin (NSC-332598) and its congeners constitute a

family of 16-membered macrolactones first isolated from

the plant pathogenic fungus Rhizopus chinensis by

Iwasaki and co-workers in 1984.¹This pathogenic fungus

causes a disease known as rice seedling blight. The

characteristic symptom of this disease is abnormal swell-

ing of the seedling roots, which is thought to be caused

by inhibition of cell division. The relative and absolute

configurations of rhizoxin and related compounds have

been determined by single-crystal X-ray analysis and

degradation studies.²The unprecedented structure of

rhizoxin contains 11 stereogenic centers, 2 epoxides, a

δ-lactone, a 16-membered macrocyclic lactone, and an

oxazole-terminated chromophore side chain. Interest-

ingly, didesepoxyrhizoxin (rhizoxin D, 2), a biosynthetic

precursor to the bis-epoxide 1, was isolated from the same

fungus and has the same level of biological activity.

Studies detailing the biosynthesis of rhizoxin have also

been reported.³

Rhizoxin is a tubulin-interactive antimitotic agent

which exhibits pronounced antimicrobial and antifungal

activity as well as potent in vitro cytotoxicity and in vivo

antitumor activity.⁴Moderate-to-good in vivo activities

have been demonstrated by rhizoxin in preclinical studies

against murine tumors such as B16 melanoma, M5076

sarcoma, L1210 and P388 leukemias, and MH134 mouse

hepatoma. It is also active against several human tumor

xenografts, including LOX melanoma, MX-1 mammary

carcinoma, A549 non-small-cell lung tumors, and LXFS605

and LXFS650 small-cell lung tumors. One impressive

observation is that rhizoxin is effective against vincris-

tine- and adriamycin-resistant tumor cells in vitro and

in vivo, while other antimitotic agents such as may-

tansine have been found to be ineffective.⁵On the basis

of these preclinical studies in the National Cancer

Institute disease-oriented screening, rhizoxin has been

selected for clinical evaluation. Rhizoxin has gone through

^†Wyeth-Ayerst Research.

(1) (a) Iwasaki, S.; Kobayashi, H.; Furukawa, J .; Namikoshi, M.;

Okuda, S.; Sato, Z.; Matsuda, I.; Noda, T. J . Antibiot. 1984, 37, 354.

(b) Iwasaki, S.; Namikoshi, M.; Kobayashi, H.; Furukawa, J .; Okuda,

S. Chem. Pharm. Bull. 1986, 34, 1387. (c) Kiyoto, S.; Kawai, Y.;

Kawakita, T.; Kino, E.; Okuhara, M.; Uchida, I.; Tanaka, H.; Hash-

imoto, M.; Terano, H.; Kohsaka, M.; Aoki, H.; Imanaka, H. J . Antibiot.

1986, 39, 762. (d) Takahashi, M.; Iwasaki, S.; Kobayashi, H.; Okuda,

S.; Murai, T.; Sato, Y.; Haraguchi-Hiraoka, T.; Nagano, H. J . Antibiot.

1987, 40, 66.

(2) Iwasaki, S.; Namikoshi, M.; Kobayashi, H.; Furukawa, J .; Kuda,

S.; Itai, A.; Kasuya, A.; Iitaka, Y.; Sato, Z. J . Antibiot. 1986, 39, 424.

(3) Kobayashi, H.; Iwasaki, S.; Yamada, E.; Okuda, S. Chem.

Commun. 1986, 1702.

(4) Hendriks, H. R.; Plowman, J .; Berger, D. P.; Paull, K. D.; Fiebig,

H. H.; Fodstad, O.; Dreef-van der Meulen, H. C.; Henrar, R. E. C.;

Pinedo, H. M.; Schwartsmann, G. Ann. Oncol. 1992, 3, 755.

(5) Tsuruo, T.; Oh-hara, T.; Iida, H.; Tsukagoshi, S.; Sato, Z.;

Matsuda, I.; Iwasaki, S.; Okuda, S.; Shimizu, F.; Sasagawa, K.;

Fukami, M.; Fukuda, K.; Arakawa, M. Cancer Res. 1986, 46, 381.

Published on Web 09/05/1998

Synthetic Studies of Antitumor Macrolide Rhizoxin

J . Org. Chem., Vol. 63, No. 20, 1998 6953

Ch a r t 2

both Phase I and Phase II clinical trials for ovarian

cancer, colorectal and renal cancer, breast cancer and

melanoma, head and neck cancer, and non-small-cell lung

cancer and is currently being evaluated in Phase III

clinical trials.^6,7

Rhizoxin binds to â-tubulin at the vinca domain.^8a,b

The mechanism of action is believed to be its complex-

ation with tubulin to prevent tubulin polymerization,

leading to the inhibition of microtubule formation and

thereby blocking cell mitosis. The common binding site

shared by rhizoxin and maytansine is different from the

receptor for other tubulin inhibitors such as vinblastine

and halichondrin B. Recently, rhizoxin was found to be

a novel inhibitor of angiogenesis, thus suggesting another

therapeutic mechanism of action.^8cLimited structure-

activity relationship (SAR) studies have been reported.⁹

Classical antimitotic drugs such as vinblastine and

vincristine have serious side effects, especially on the

neurological system; thus it is highly desirable to discover

and develop new antitumor drugs which are more effec-

tive and less toxic. Rhizoxin and its congeners represent

a new class of very promising lead compounds for this

purpose. Strongly promoted by rhizoxin’s significant

biological activity, great potential as a chemotherapeutic

agent, and its unique structural features, total syntheses

of rhizoxin and rhizoxin D, along with several synthetic

efforts, have been reported.^10-12

tioselective synthesis of C(12)-C(26) subunit 35 and

C(1)-C(9) subunit 5, featuring a chelation-controlled

Ireland-Claisen rearrangement, a highly stereoselective

Horner-Wadsworth-Emmons reaction for incorporation

of the oxazole chromophore side chain, and a diaste-

reotopic group differentiation strategy for establishing

the C(5) stereocenter.

As part of a continuing synthetic program focused upon

tubulin-binding natural products,¹³we now disclose our

studies describing a convergent approach for the enan-

Resu lts a n d Discu ssion

(6) (a) Graham, M. A.; Bissett, D.; Setanoians, A.; Hamilton, T.; Kerr,

D. J .; Henrar, R.; Kaye, S. B. J . Natl. Cancer Inst. 1992, 84, 494. (b)

Bissett, D.; Graham, M. A.; Setanoians, A.; Chadwick, G. A.; Wilson,

P.; Koier, I.; Henrar, R.; Schwartsmann, G.; Cassidy, J .; Kaye, S. B.;

Kerr, D. J . Cancer Res. 1992, 52, 2894. (c) Beijnen, J . H.; Flora, K. P.;

Halbert, G. W.; Henrar, R. E. C.; Slack, J . A. Br. J . Cancer 1995, 72,

210.

(7) (a) McLeod, H. L.; Murray, L. S.; Wanders, J .; Setanoians, A.;

Graham, M. A.; Pavlidis, N.; Heinrich, B.; Huininl, W. W. T.; Wagener,

D. J . T.; Aamdal, S.; Verweij, J . Br. J . Cancer 1996, 74, 1944. (b)

Hanauske, A. R.; Catimel, G.; Aamdal, S.; Huinink, W. T.; Paridaens,

R.; Pavlidis, N.; Kaye, S. B.; Tevelde, A.; Wanders, J .; Verweij, J . Br.

J . Cancer 1996, 73, 397. (c) Verweij, J .; Wanders, J .; Gil, J .; Schoffski,

P.; Catimel, G.; Tevelde, A.; Demulder, P. H. M. Br. J . Cancer 1996,

73, 400. (d) Kaplan, S.; Hanauske, A. R.; Pavlidis, N.; Bruntsch, U.;

Tevelde, A.; Wanders, J .; Heinrich, B.; Verweij, J . Br. J . Cancer 1996,

73, 403. (e) Kerr, D. J .; Rustin, G. J .; Kaye, S. B.; Selby, P.; Bleehen,

N. M.; Harper, P.; Brampton, M. H. Br. J . Cancer 1995, 72, 1267.

(8) (a) Takahashi, M.; Iwasaki, S.; Kobayashi, H.; Okuda, S.; Murai,

T.; Sato, Y. Biochim. Biophys. Acta 1987, 926, 215. (b) Sullivan, A. S.;

Prasad, V.; Roach, M. C.; Takahashi, M.; Iwasaki, S.; Luduena, R. F.

Cancer Res. 1990, 50, 4277. (c) Onozawa, C.; Shimamura, M.; Iwasaki,

S.; Oikawa, T. J pn. J . Cancer Res. 1997, 88, 1125.

Outlined in Scheme 1 is our triply convergent approach

to rhizoxin and its congeners, which includes a Horner-

Wadsworth-Emmons coupling of phosphonate 3 and

enal 4, thereby leaving the protected diol moiety of 4 to

be oxidized and homologated by two carbons to the

corresponding terminal enal of the C(10)-C(26) subunit.

Fragment coupling of the resultant C(10)-C(26) aldehyde

with the C(1)-C(9) subunit 5 via a modified J ulia

procedure and macrolactonization was expected to com-

plete the carbon skeleton of rhizoxin and its congeners.

All three major segments, 3, 4, and 5, which comprise

most of the stereogenic centers and all but two backbone

carbons of rhizoxin, were derivable from readily available

starting materials.

On the basis of the analysis detailed in Scheme 1, our

initial efforts on the synthesis of rhizoxin have focused

on the preparation of the central C(12)-C(20) subunit 4

with control of the relative and absolute configuration

of the three contiguous C(15)-C(17) stereocenters and

introduction of the C(18)-C(19) trisubstituted (E)-olefin.

We anticipated that appropriate functional and stereo-

chemical elements for these purposes could be introduced

via a sequence of chelation-controlled glycolate-enolate

Claisen rearrangement and halolactonization, as detailed

in Scheme 2. The synthesis began with protected ^D-

glyceraldehyde 7.¹⁴Addition of trans-propenyllithium in

the presence of ZnBr₂gave the anti-alcohol 9 with 8:1

diastereoselectivity.¹⁵Acylation with methoxyacetyl chlo-

(9) (a) Iwasaki, S. Med. Res. Rev. 1993, 13, 183. (b) Hamel, E.

Pharmacol. Ther. 1992, 55, 31. (c) Nakada, M. Yakugaku Kenkyu no

Shinpo 1996, 13, 37.

(10) For preliminary communication of portions of this research,

see: Burke, S. D.; Hong, J .; Mongin, A. P. Tetrahedron Lett. 1998, 39,

2239.

(11) For total syntheses of rhizoxin, see: (a) Nakada, M.; Kobayashi,

S.; Iwasaki, S.; Ohno, M. Tetrahedron Lett. 1993, 34, 1035. (b) Nakada,

M.; Kobayashi, S.; Shibasaki, M.; Iwasaki, S.; Ohno, M. Tetrahedron

Lett. 1993, 34, 1039. For total syntheses of rhizoxin D, see: (c) Kende,

A. S.; Blass, B. E.; Henry, J . R. Tetrahedron Lett. 1995, 36, 4741. (d)

Williams, D. R.; Werner, K. M.; Feng, B. Tetrahedron Lett. 1997, 38,

6825.

(12) (a) Rama Rao, A. V.; Sharma, G. V. M.; Bhanu, M. N.

Tetrahedron Lett. 1992, 33, 3907. (b) Rama Rao, A. V.; Bhanu, M. N.;

Sharma, G. V. M. Tetrahedron Lett. 1993, 34, 707. (c) Boger, D. L.;

Curran, T. T. J . Org. Chem. 1992, 57, 2235. (d) Keck, G. E.; Park, M.;

Krishnamurthy, D. J . Org. Chem. 1993, 58, 3787. (e) Keck, G. E.; Savin,

K. A.; Weglarz, M. A.; Cressman, E. N. K. Tetrahedron Lett. 1996, 37,

3291. (f) Lafontaine, J . A.; Leahy, J . W. Tetrahedron Lett. 1995, 36,

6029. (g) Provencal, D. P.; Gardelli, C.; Lafontaine, J . A.; Leahy, J . W.

Tetrahedron Lett. 1995, 36, 6033. (h) White, J . D.; Nylund, C. S.; Green,

N. J . Tetrahedron Lett. 1997, 38, 7329. (i) White, J . D.; Holoboski, M.

A.; Green, N. J . Tetrahedron Lett. 1997, 38, 7333.

(13) (a) Burke, S. D.; Buchanan, J . L.; Rovin, J . D. Tetrahedron Lett.

1991, 32, 3961. (b) Burke, S. D.; J ung, K. W.; Phillips, J . R.; Perri, R.

E. Tetrahedron Lett. 1994, 35, 703. (c) Burke, S. D.; Zhang, G.;

Buchanan, J . L. Tetrahedron Lett. 1995, 36, 7023. (d) Burke, S. D.;

Austad, B. C. Presented at the 214th National Meeting of the American

Chemical Society, Las Vegas, Sept 1997; ORGN 013.

(14) Schmid, C. R.; Bradley, D. A. Synthesis 1992, 587.

6954 J . Org. Chem., Vol. 63, No. 20, 1998

Burke et al.

Sch em e 1

Sch em e 3^a

and 14 in an approximately 1:1 ratio.¹⁷These were

separated by flash chromatography, and recycling of 13

via 12 can be accomplished by reductive fragmentation

with zinc dust.¹⁸The structures of 13 and 14 were

differentiated by complete assignment of all the protons

via analysis of ¹H and 2D-COSY NMR spectra. The

absolute configuration of the newly formed C(15) stereo-

center was confirmed using the Kakisawa modification

of Mosher’s method (vide infra).¹⁹

An alternative route from glyceraldehyde 7 to alcohol

9 with high diastereomeric purity was also investigated

in order to improve the diastereoselectivity of our crucial

Ireland-Claisen rearrangement. Mulzer and co-workers

have reported the selective enzymatic hydrolysis of a 1:1

diastereomeric mixture of propargylic acetates with

greater than 95% de (eq 1).^20aWe have demonstrated

Sch em e 2^a

that the 1:1 diastereomeric mixture of acetates 15

(Scheme 3), structurally similar to Mulzer’s substrate,

can be selectively hydrolyzed with porcine pancreatic

lipase (PPL) to afford either the syn-alcohol 16 or the

(15) Suzuki, K.; Yoichi, Y.; Mukaiyama, T. Chem. Lett. 1981, 1529.

(16) (a) Burke, S. D.; Fobare, W. F.; Pacofsky, G. J . J . Org. Chem.

1983, 48, 5221. (b) Pereira, S.; Srebnik, M. Aldrichimica Acta 1993,

26, 17. (c) Gould, T. J .; Balestra, M.; Wittman, M. D.; Gary, J . A.;

Rossano, L. T.; Kallmerten, J . J . Org. Chem. 1987, 52, 3889.

(17) Snider, B. B.; J ohnston, M. I. Tetrahedron Lett. 1985, 26, 5497.

(18) Ham, P. In Encyclopedia of Reagents for Organic Synthesis;

Paquette, L. A., Ed.; J ohn Wiley & Sons: New York, 1995; pp 5531-

5534.

(19) (a) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J . Am.

Chem. Soc. 1991, 113, 4092. (b) Ohtani, I.; Kusumi, T.; Kashman, Y.;

Kakisawa, H. J . Org. Chem. 1991, 56, 1296.

(20) (a) Mulzer, J .; Greifenberg, S.; Beckstett, A.; Gottwald, M.

Liebigs Ann. Chem. 1992, 1131. (b) Sih, C. J .; Wu, S.-H. In Topics in

Stereochemistry; Eliel, E. L., Wilen, S. H., Eds.; Wiley: New York, 1989;

Vol. 19, pp 63-125.

ride provided the allylic glycolate ester 10. The crucial

chelation-controlled Ireland-Claisen rearrrangement¹⁶

proceeded smoothly via the silyl ketene acetal derived

from enolate 11, affording acid 12 in 83% yield with 6:1

diastereoselectivity. Subsequent bromolactonization with

NBS under kinetic conditions gave δ- and γ-lactones 13

Synthetic Studies of Antitumor Macrolide Rhizoxin

J . Org. Chem., Vol. 63, No. 20, 1998 6955

Sch em e 4^a

Sch em e 5

high purity (Scheme 4).²³The diastereoselectivity of the

Ireland-Claisen rearrangement (10 to 12) was improved

to 30:1 by using diastereomerically pure substrate pre-

pared from 9.

Our result from kinetic bromolactonization of acid 12

implied that both substrate conformation and the nature

of the electrophile influenced the stereoselectivity.²⁴Both

γ-lactone 14 and δ-lactone 13 are the result of attack by

the internal nucleophile on the same face of the E double

bond. The diastereofacial selectivity of this reaction can

be rationalized by the reactive intermediate structures

shown in Scheme 5. The stereochemical outcome ob-

served in the formation of 13 and 14 requires the π-facial

attack depicted in structure 20. The conformation 20 is

likely to be favored over conformation 19 in the transition

state because of the diminished unfavorable steric inter-

actions of the C(3) methyl group and C(7) methylene

group with the electrophile-π complex. It should be

noted that iodolactonization under kinetic conditions

tended to give more γ-lactone over δ-lactone than does

bromolactonization, probably because the nature of the

electrophile dictates a difference in rate-limiting steps.^17,25

Efforts to improve the regioselectivity of this reaction via

the use of iodolactonization conditions are currently

under investigation.

anti-acetate 17 in a highly stereoselective manner.

Selective production of either 16 or 17 in high diastere-

omeric purity and high mass recovery from substrate 15

was accomplished by varying the pH and reaction time

of the enzymatic hydrolysis.^20bTo obtain pure alcohol

16, the hydrolysis was run to about 40% conversion; pure

acetate 17 was obtained by running the reaction to about

60% conversion. When the reaction was performed in a

pH 5.1 KH₂PO₄buffer solution for 3 h, the syn-alcohol

16 was isolated in 38% yield with 93% de. These

conditions did not allow conversions over 50%, whereas

PPL hydrolysis at pH 7 led to overhydrolysis. However,

when the reaction was performed in a pH 6.0 KH₂PO₄

buffer solution for 6.5 h, the acetate of anti-isomer 17

could be isolated in 35% yield with 97% de. These

conditions afforded the intermediate hydrolysis rate

needed for the production of 17 in high de.

Alcohol 16 and acetate 17 were readily separated by

simple flash chromatography. The absolute stereochem-

ical outcome of this reaction was determined by the

Kakisawa modification of Mosher’s method¹⁹and was

found to be opposite to Mulzer’s observed stereoselectivity

at the carbinol center. Our rationale for the reversal in

enzymatic stereochemical recognition is that the pentyl-

idene group of our substrate 15 is larger than the

propynyl group, but the acetonide group of Mulzer’s

substrate is relatively smaller than the trimethylsilyl

acetylene group.

Radical dehalogenation²⁶of bromolactone 14 gave

lactone 21, which was then reduced with lithium alumi-

num hydride.²⁷The primary hydroxyl group of the

resulting diol 22 was selectively protected as TBS ether

23 (Scheme 6), and the absolute stereochemistry at the

C(15) stereocenter was determined by the Kakisawa

modification of Mosher’s method.¹⁹Treatment of alcohol

23 with both (R)-(+)- and (S)-(-)-R-methoxy-R-(trifluo-

romethyl)phenylacetic (MTPA) acid under standard es-

terification conditions afforded Mosher esters 24 and 25,

respectively (Scheme 7).²⁸On the basis of the data points

from our analysis of the ¹H chemical shifts for these

MTPA esters and according to Kakisawa’s model A in

Chart 2, the absolute configuration of the C(15) stereo-

center was revealed to be R, which is opposite to the

natural S configuration found in rhizoxin.

An optimized route to 9, based upon the observation

above, is detailed in Scheme 4. Addition of propynyl-

magnesium bromide to glyceraldehyde 7 gave a 1:1

diastereomeric mixture of alcohols, which was oxidized

to ketone 18 in 86% overall yield.²¹Asymmetric reduc-

tion and subsequent acylation led to a mixture of acetates

15 enriched with the desired anti-isomer in a 4.6:1 ratio.²²

PPL-mediated enzymatic hydrolysis of the minor com-

ponent in this mixture afforded the desired anti-acetate

17 in 70% yield with 95% de. Acetate 17 was then

reduced with LiAlH₄to give trans-propenyl alcohol 9 with

(24) For general reviews of this topic, see: (a) Dowle, M. D.; Davies,

D. I. Chem. Soc. Rev. 1979, 8, 171. (b) Bartlett, P. A. In Asymmetric

Synthesis; Morrison, J . D., Ed.; Academic Press: New York, 1984; Vol.

3, pp 411-454. (c) Cardillo, G.; Orena, M. Tetrahedron 1990, 46, 3321.

(d) Harding, K. E.; Tiner, T. H. In Comprehensive Organic Synthesis;

Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 6,

pp 363-421. (e) Cardillo, G.; Orena, M. In Stereoselective Synthesis;

Helmchen, G., Hoffmann, R. W., Mulzer, J ., Schaumann, E., Eds.;

Georg Thieme Verlag: Stuttgart, New York, 1996; pp 4698-4817.

(25) Kono, T.; Kitazume, T. Tetrahedron: Asymmetry 1997, 8, 223.

(26) Hart, D. J .; Leroy, V.; Merriman, G. H.; Young, D. G. J . J . Org.

Chem. 1992, 57, 5670.

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6956 J . Org. Chem., Vol. 63, No. 20, 1998

Burke et al.

Sch em e 6^a

Sch em e 8^a

Sch em e 7

transformed to aldehyde 29 using the Swern oxidation.³²

Methyl ketone 30 was prepared by the addition of

methylmagnesium bromide to aldehyde 29, followed by

TPAP oxidation.³³

The key Horner-Wadsworth-Emmons chain exten-

sion for introduction of the C(18)-C(19) trisubstituted

(E)-olefin was studied in detail.³⁴Only trace amounts

of the desired product 31 were formed when the reaction

was performed using more than 10 equiv of the Wittig

reagent at room temperature for 24 h. When the reaction

mixture was heated to 60 °C for 3 h, a 64% yield of the

desired product 31 was obtained. The yield of the desired

(E)-trisubstituted olefin 31 was improved to 87% by

heating the reaction at 60 °C for 24 h. The ester 31 was

reduced with diisobutylaluminum hydride to the corre-

sponding alcohol,³⁵and subsequent TPAP oxidation³³

provided the C(12)-C(20) aldehyde 4.

We examined many variations on the classical Mit-

sunobu reaction for inverting the C(15) stereogenic center

of alcohol 23 (Scheme 8).²⁹Since the C(15) hydroxyl

group is in the middle of a long, highly branched chain,

steric hindrance was expected to impede the reaction. It

was decided that modified reaction conditions would have

to be applied to achieve the inversion. The best condi-

tions found were those described by Martin, utilizing

p-nitrobenzoic acid as the nucleophile with 5 equiv of

reagents and a reaction time of 72 h at ambient temper-

ature.³⁰This allowed us to obtain a 52% yield of the

desired product 26 with a 34% yield of recovered starting

material 23. The resulting alcohol 26 was protected as

its p-methoxybenzyl ether 27,³¹and subsequent silyl

group removal afforded primary alcohol 28, which was

The preparation of the C(21)-C(26) phosphonate 3

from the known enal 32^12cis shown in Scheme 9.

Reduction of 32 with diisobutylaluminum hydride³⁵af-

forded allylic alcohol 33, which was converted to allylic

chloride 34 upon treatment with mesyl chloride.³⁶Sub-

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(34) (a) White, J . D.; J effrey, S. C. J . Org. Chem. 1996, 61, 2600. (b)

Wadsworth, W. S., J r.; Emmons, W. D. J . Am. Chem. Soc. 1961, 83,

1733.

(35) Winterfeldt, E. Synthesis 1975, 617.

(36) (a) Hwang, C. K.; Li, W. S.; Nicolaou, K. C. Tetrahedron Lett.

1984, 25, 2295. (b) Collington, E. W.; Meyers, A. I. J . Org. Chem. 1971,

56, 3044.

Synthetic Studies of Antitumor Macrolide Rhizoxin

J . Org. Chem., Vol. 63, No. 20, 1998 6957

Sch em e 9^a

Sch em e 11^a

Sch em e 10

Sch em e 12^a

sequent displacement with sodium dimethyl phosphite

provided phosphonate 3 in 73% yield.³⁷

A second Horner-Wadsworth-Emmons coupling reac-

tion completed the introduction of the (E,E,E)-triene to

afford the desired C(12)-C(26) segment 35 (Scheme 10).³⁸

Treatment of aldehyde 4 and phosphonate 3 with t-BuOK

in DME gave only triene stereoisomer 35. The solvent

employed for this coupling reaction proved to be impor-

tant. For instance, when THF was used, a 1:1 mixture

of alkene stereoisomers was formed.

Our preparations of the lactone subunits were mainly

focused on a desymmetrization strategy to establish the

C(5) stereocenter.³⁹The initial synthetic studies of the

C(3)-C(10) fragment are indicated in Schemes 11 and

12. The synthesis started with the known ethyl ester

8.⁴⁰Methanolic ozonolysis, acid-catalyzed degradation

(37) Scarlato, G. R.; DeMattei, J . A.; Chong, L. S.; Ogawa, A. K.;

Lin, M. R.; Armstrong, R. W. J . Org. Chem. 1996, 61, 6139.

(38) (a) Roush, W. R.; Peseckis, S. M. Tetrahedron Lett. 1982, 23,

4879. (b) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863.

(39) (a) Magnuson, S. R. Tetrahedron 1995, 51, 2167. (b) Poss, C.

S.; Schreiber, S. L. Acc. Chem. Res. 1994, 27, 9. (c) Schreiber, S. L.

Chem. Scr. 1987, 27, 563. (d) Ho, T. L. Symmetry: A Basis for Synthesis

Design; J ohn Wiley & Sons: New York, 1995.

(40) (a) Krapcho, A. P.; Glynn, G. A.; Grenon, B. J . Tetrahedron Lett.

1967, 215. (b) Krapcho, A. P.; Weimaster, J . F.; Lovey, A. J .; Stephens,

W. P. J . Org. Chem. 1978, 43, 138. (c) Stork, G.; Schoofs, A. R. J . Am.

Chem. Soc. 1979, 101, 5081.

of the intermediate ozonide,⁴¹and concomitant transes-

terification followed by a novel hydrolytic cyclization gave

the mixed bis(acetal) 36 in an overall 73% yield. An

efficient, selective reduction⁴²of the methyl ester afforded

6958 J . Org. Chem., Vol. 63, No. 20, 1998

Burke et al.

Sch em e 13^a

aldehyde 37 in high yield. Condensation of the lithiated

Horner-Wittig reagent 38⁴³with 37 produced a 1,2

adduct that underwent KH-facilitated elimination to the

corresponding enamine, submission of which to flash

chromatography on silica gel afforded the labile homolo-

gated aldehyde 39 in 74% yield. Treatment of 39 with

the (Z)-crotylboronate 40⁴⁴gave 41 as a 1:1 mixture of

the diastereomers.⁴⁵The two methoxy groups of 41 have

an anti relationship, thereby generating a pair of dia-

stereomers due to the R,R and S,S configurations present

in the mixed bis(acetal) ring system. Homoallylic alcohol

41 was then protected as the corresponding TBS ether

42.

A two-step oxidation sequence applied to the olefin 42

provided aldehyde 44 via 43 (Scheme 12) in 90% yield.⁴⁶

Treatment of 44 with TMSCHBr₂and CrCl₂in the

presence of LiI, followed by sonication, afforded vinylsi-

lane 45.⁴⁷Deprotection of 45 using TBAF, followed by

treatment of the resultant alcohol 46 with 2,2-dimeth-

oxypropane under acidic conditions, produced a complex

mixture of products, from which could be isolated the

desired bis(acetal) 47 (43%) and its diastereomeric coun-

terpart 48 in a 2:1 ratio.

Following our initial experience on the C(3)-C(10)

lactone fragment, an alternative preparation of the C(1)-

C(9) lactone subunit 5 was also investigated (Scheme 13).

The synthesis of 5 began with the known diol 49.^12dThe

primary hydroxyl group of 49 was selectively protected

as its TBS ether to afford the diene 50. C(5) diaste-

reotopic group differentiation was accomplished by one-

pot ozonolysis and TPAP oxidation to provide lactone

aldehyde 51 in 45% overall yield.⁴⁸This tactic for

establishing the C(5) stereocenter is analogous to those

employed by Keck^12dand Williams^11dand relies upon

thermodynamic diequatorial deployment of the side

chains. The resultant lactone aldehyde 51 was subjected

to a Wittig chain extension reaction to give ester 52.⁴⁹

Removal of the TBS group with aqueous HF in acetoni-

trile⁵⁰afforded primary alcohol 53, which was converted

to the corresponding benzothiazole sulfide under Mit-

sunobu conditions.⁵¹Subsequent m-CPBA oxidation to

the sulfone provided the C(1)-C(9) subunit 5 as a

modified J ulia coupling partner.⁵²

Con clu sion

We have successfully achieved the stereoselective

syntheses of the C(1)-C(9) and C(12)-C(26) subunits in

our effort directed toward the total synthesis of rhizoxin.

Studies for the extension of 35 to include the C(10)-C(11)

carbons, fragment coupling with 5 via a modified J ulia

procedure,⁵²and macrolactonization are being pursued

actively in our laboratories to complete this synthetic

route.

(41) Whitesell, J . K.; Allen, D. E. J . Am. Chem. Soc. 1988, 110, 3585.

(42) (a) Kim, S. H.; Hyo, J .; Yoon, N. M. Bull. Korean Chem. Soc.

1989, 10, 117. (b) Hann, M. M.; Sammes, P. G.; Kennewell, P. D.;

Taylor, J . B. J . Chem. Soc., Perkin Trans. 1 1982, 307. (c) Zakharkin,

L. I.; Sorokina, L. P. Zh. Obshch. Kim. 1967, 37, 561.

Exp er im en ta l Section

Gen er a l Meth od s. Melting points (mp) are uncorrected.

Optical rotations were measured on a digital polarimeter;

concentrations (c) are reported in g/100 mL. Infrared (IR)

spectra were recorded on an FT-IR spectrometer and are

reported in wavenumbers (cm^-1) with broad signals denoted

by (br). Proton nuclear magnetic resonance (¹H NMR) spectra

were recorded in deuterated solvents at 300 or 400 MHz, as

indicated. Carbon-13 nuclear magnetic resonance (¹³C NMR)

spectra were recorded at 75 or 100 MHz, as indicated.

Chemical shifts are reported in parts per million (ppm, δ)

relative to Me₄Si (δ 0.00) Mass spectra (MS) were obtained

using electron impact (EI) at 70 eV. Fast atom bombardment

(43) (a) Broekhof, N. L. J . M.; van der Gen, A. Recl. Trav. Chim.

Pays-Bas 1984, 103, 305. (b) Broekhof, N. L. J . M.; van Elburg, P.;

van der Gan, A. Recl. Trav. Chim. Pays-Bas 1984, 103, 312.

(44) (a) Roush, W. R.; Ando, K.; Powers, D. B.; Halterman, R. L.;

Palkowitz, A. D. Tetrahedron Lett. 1988, 29, 5579. (b) Roush, W. R.;

Hoong, L. K.; Palmer, M. A. J .; Park, J . C. J . Org. Chem. 1990, 55,

4109. (c) Roush, W. R.; Hoong, L. K.; Palmer, M. A. J .; Straub, J . A.;

Palkowitz, A. D. J . Org. Chem. 1990, 55, 4117. (d) Roush, W. R.;

Palkowitz, A. D.; Ando, K. J . Am. Chem. Soc. 1990, 112, 6348.

(45) (a) Beckwith, A. L. J .; Moad, G. J . Chem. Soc., Perkin Trans. 2

1975, 1726. (b) Van der Eycken, E.; Van der Eycken, J .; Vandewalle,

M. J . J . Chem. Soc., Chem. Commun. 1985, 1719. (c) Van der Eycken,

E.; De Bruyn, A.; Van der Eycken, J .; Callant, P.; Vandewalle, M.

Tetrahedron 1986, 42, 5385. (d) Van der Eycken, E.; J anssens, A.;

Vandewalle, M. Tetrahedron Lett. 1987, 28, 3519. (e) Curran, D.;

J acobs, P. B.; Elliot, R. L.; Kim, B. H. J . Am. Chem. Soc. 1987, 109,

5280.

(46) Pianetti, P.; Rollin, P.; Pougny, J . R. Tetrahedron Lett. 1986,

27, 5853.

(47) (a) Takai, K.; Nitta, K.; Utimoto, K. J . Am. Chem. Soc. 1986,

108, 7408. (b) Cliff, M. D.; Pyne, S. G. Tetrahedron Lett. 1995, 36, 763.

(c) Hodgson, M. D. Tetrahedron Lett. 1992, 33, 5603.

(48) (a) Murray, R. W. Acc. Chem. Res. 1968, 1, 313. (b) Lee, D. G.;

Chen, T. In Comprehensive Organic Synthesis; Trost, B. M., Fleming,

I., Eds.; Pergamon Press: Oxford, 1991; Vol. 7, pp 541-591.

(49) (a) Wadsworth, W. S., J r. Org. React. 1977, 25, 73. (b) Kelly, S.

E. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;

Pergamon: Oxford, 1991; Vol. 1, pp 729-818.

(50) Davenport, K. G. In Encyclopedia of Reagents for Organic

Synthesis; Paquette, L. A., Ed.; J ohn Wiley & Sons: New York, 1995;

pp 2711-2715.

(51) (a) Besson, T.; Al Neirabeyeh, M.; Viaud, M.-C.; Rollin, P. Synth.

Commun. 1990, 20, 1631. (b) Dancy, I.; Laupichler, L.; Rollin, P.;

Thiem, J . Liebigs Ann. Chem. 1993, 343.

(52) (a) Baudin, J . B.; Hareau, G.; J ulia, S. A.; Ruel, O. Tetrahedron

Lett. 1991, 32, 1175. (b) Baudin, J . B.; Hareau, G.; J ulia, S. A.; Ruel,

O. Bull. Soc. Chim. Fr. 1993, 130, 336. (c) Baudin, J . B.; Hareau, G.;

J ulia, S. A.; Lorne, R.; Ruel, O. Bull. Soc. Chim. Fr. 1993, 130, 856.

(d) Bellingham, R.; J arowiski, K.; Kocienski, P.; Martin, V. Synthesis

1996, 285. (e) Blakemore, P. R.; Cole, W. J .; Kocienski, P. J .; Morley,

A. Synlett 1998, 26.

Synthetic Studies of Antitumor Macrolide Rhizoxin

J . Org. Chem., Vol. 63, No. 20, 1998 6959

mass spectra (FAB) were obtained using xenon carrier gas and

an 8 kV ion acceptation voltage.

filtered, and washed with Et₂O. The filtrate was concentrated

in vacuo. The residue was diluted in Et₂O, dried (MgSO₄),

and filtered. The solvent was removed in vacuo, and the

residue was purified by Kugelrohr distillation to give 2.37 g

(11.8 mmol, 98%) of alcohol 9 as a colorless oil. Data for 9: R_f

All moisture-sensitive reactions were performed in flame-

dried glassware under a stream of nitrogen, unless indicated

otherwise. Bath temperatures were used to record the reaction

temperature in all cases. All reactions were stirred magneti-

cally unless otherwise indicated. Ozonolysis was performed

using a commercial ozonator. Reactions requiring ultrasound

facilitation were done using either an ultrasonic cell disrupter

(50 W maximum output) or an ultrasonic bath (9.5 L, 115 V,

50/50 Hz; 29.2 cm w × 24.1 cm d × 15.2 cm h). When

prolonged cooling was necessary, an immersion cooler was

employed. Analytical thin-layer chromatography (TLC) was

carried out on E. Merck (Darmstadt) TLC plates precoated

with silica gel 60 F₂₅₄(250-µm layer thickness). Preparative

TLC was carried out using 0.5 and 2.0 mm × 10 cm × 10 cm

E. Merck precoated silica gel 60 F₂₅₄plates. TLC visualization

was accomplished using either a UV lamp, iodine adsorbed

on silica gel or charring solution [p-anisaldehyde (PAA)/

phosphomolybdic acid (PMA)]. Flash chromatography was

performed according to the procedure by Still⁵³on EM Science

silica gel 60 (230-400 mesh) or Florisil (100-200 mesh)

purchased from Aldrich. When indicated, further purification

was effected using a Rainin Dynamax HPLC system.

Tetrahydrofuran (THF), diethyl ether (Et₂O), and benzene

(PhH) were distilled from sodium/benzophenone ketyl. Tolu-

ene (PhCH₃) was distilled from sodium metal. Triethylamine

(Et₃N), diisopropylethylamine (i-Pr₂NEt, Hu¨nig’s base), pyri-

dine, 1,2-dichloroethane, dichloromethane (CH₂Cl₂), 1,2-

dimethoxyethane (DME), and acetonitrile (CH₃CN) were dis-

tilled from calcium hydride. Dimethyl sulfoxide (DMSO) and

N,N-dimethylformamide (DMF) were distilled under reduced

pressure from calcium hydride and stored over 4 Å molecular

sieves. Deuteriochloroform (chloroform-d, CDCl₃), deuterio-

acetone (acetone-d₆), and deuteriobenzene (benzene-d₆, C₆D₆)

were stored over 4 Å molecular sieves before use. Deuteri-

omethanol (methanol-d₄) was used as received from Aldrich

in glass ampules. Chlorotrimethylsilane (Me₃SiCl, TMSCl)

was distilled from calcium hydride and stored over 4 Å

molecular sieves prior to use. Methanesulfonyl chloride (MsCl)

was distilled under reduced pressure prior to use. Methanol

(MeOH) was distilled from magnesium methoxide. Hexanes

were distilled at atmospheric pressure. 1,1,1,3,3,3-Hexa-

methyldisilazane (HMDS) was distilled from calcium hydride

and stored over 4 Å molecular sieves. All other commercially

obtained reagents and solvents were used as received without

further purification unless indicated otherwise.

(1S,2E)-1-[(1R)-3,3-Diet h yl-2,4-d ioxola n yl]b u t -2-en -1-

ol (9). To a cooled (0 °C) solution of ZnBr₂in THF (31 mL)

was added a solution of trans-propenyllithium (0.70 M solution

in Et₂O, 84.0 mL, 109 mmol). The mixture was stirred at 0

°C for 1 h. A solution of aldehyde 7 (8.7 g) in THF (18 mL)

was added in a dropwise manner via cannula. The mixture

was stirred at 0 °C for 48 h and then quenched with saturated

aqueous NH₄Cl (200 mL). The aqueous layer was separated

and extracted with Et₂O (3 × 200 mL). The combined organic

layers were dried (MgSO₄) and filtered. The solvent was

removed in vacuo, and the residue was purified by flash

chromatography (silica gel, elution with 17% Et₂O in hexanes)

to give 6.80 g (34.0 mmol, 63%, ds ) 8:1) of alcohol 9 as a

yellowish oil.

An analytical sample was prepared from acetate 17 accord-

ing to the following procedure. To a vigorously stirred slurry

of LiAlH₄(2.28 g, 60.0 mmol) in THF (150 mL) at 0 °C was

added a solution of ester 17 (2.88 g, 12.0 mmol) in THF (21

mL) in a dropwise manner via cannula. The mixture was

stirred at 0 °C for 0.5 h and then allowed to warm to ambient

temperature and heated to reflux for 20 h. The gray slurry

was then cooled to 0 °C and cautiously quenched by the

sequential dropwise addition of H₂O (2.3 mL), 15% aqueous

NaOH solution (2.3 mL), and then H₂O (6.9 mL). The

resulting white suspension was stirred rapidly for 0.5 h,

0.31 (50% Et₂O in hexanes/PMA); [R]²²+20.7 (c 1.77, CH₂-

D

Cl₂); IR (thin film) 3435 (br) cm^-1; ¹H NMR (CDCl₃, 300 MHz)

δ 5.78 (ddq, 1H, J ) 15.4, 6.6, 1.1 Hz), 5.39 (ddq, 1H, J ) 15.1,

6.6, 1.5 Hz), 4.24 (m, 1H), 4.04 (ddd, 1H, J ) 7.4, 6.3, 4.0 Hz),

3.94 (A portion of ABX, 1H, J _AB) 8.1 Hz, J _AX) 6.3 Hz), 3.84

(B portion of ABX, 1H, J _AB) 8.1 Hz, J _BX) 7.7 Hz), 2.11 (bs,

1H), 1.69 (m, 3H), 1.65 (m, 2H), 1.59 (q, 2H, J ) 7.4 Hz), 0.90

(t, 3H, J ) 7.4 Hz), 0.86 (t, 3H, J ) 7.4 Hz); ¹³C NMR (C₆D₆,

75 MHz) δ 130.4, 127.5, 113.1, 79.2, 72.2, 66.0, 29.9, 29.4, 17.8,

8.4, 8.2; HRMS (EI) exact mass calcd for C₁₁H₂₁O₃(M⁺+ H)

requires 201.1491, found 201.1469.

(1S,2E)-[(1R)-3,3-Diethyl-2,4-dioxolanyl]but-2-enyl2-meth-

oxya ceta te (10). To a cooled (0 °C) solution of alcohol 9 (2.0

g, 10.0 mmol) in CH₂Cl₂(36.2 mL) and pyridine (1.62 mL, 20.0

mmol) was added 2-methoxyacetyl chloride (1.1 mL, 12.0

mmol) in a dropwise fashion via syringe. After the reaction

mixture had been stirred at 0 °C for 1 h and 25 °C for 16 h,

the solvent was removed in vacuo. The residue was dissolved

in Et₂O (100 mL). The ether layer was washed with a

saturated CuSO₄solution (2 × 50 mL), dried (MgSO₄), filtered,

and concentrated in vacuo. The residue was purified by flash

column chromatography (silica gel, elution with 17% Et₂O in

hexanes) to give 2.61 g (9.6 mmol, 96%) of 10 as a colorless

oil. Data for 10: R_f0.42 (50% Et₂O in hexanes/PMA); [R]²²

D

+32.4 (c 2.07, CH₂Cl₂); IR (thin film) 1759 cm^-1

;

¹H NMR

(CDCl₃, 300 MHz) δ 5.83 (m, 1H), 5.40 (m, 2H), 4.17 (dt, 1H,

J ) 6.6, 4.4 Hz), 4.03 (dd, 1H, J ) 8.1, 6.6 Hz), 4.02 (s, 2H),

3.73 (dd, 1H, J ) 8.1, 7.4 Hz), 3.43 (s, 3H), 1.70 (m, 2H), 1.59

(q, 2H, J ) 7.4 Hz), 0.88 (t, 3H, J ) 7.4 Hz), 0.86 (t, 3H, J )

7.4 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 169.1, 132.0, 124.8, 113.5,

76.7, 74.2, 69.6, 65.9, 59.2, 29.3, 28.8, 17.7, 7.9, 7.8; HRMS

(EI) exact mass calcd for C₁₂H₁₉O₅(M⁺- C₂H₅) requires

243.1233, found 243.1239.

(2R,3S,4E)-5-[(1S)-3,3-Dieth yl-2,4-d ioxola n yl]-2-m eth -

oxy-3-m eth ylp en t-4-en oic Acid (12). To a solution of ester

10 (88.4 mg, 0.325 mmol) in THF (2.6 mL) at -100 °C (Et₂O/

dry ice bath) was added LHMDS solution (1.0 M in THF, 0.65

mL, 0.65 mmol) in a dropwise fashion. After the mixture had

been stirred at -100 °C for 0.5 h, 0.4 mL of the supernatant

from the centrifugation of a 1:1 (v/v) mixture of Me₃SiCl and

Et₃N was added. The mixture was stirred at -100 °C for 1 h,

allowed to warm to 25 °C, and stirred for 16 h. A 2.5% aqueous

HCl solution (5.0 mL) was added. The mixture was stirred

for 5 min. The aqueous layer was separated and extracted

with EtOAc (3 × 25 mL). The combined organic layers were

dried (MgSO₄), filtered, and concentrated in vacuo. Purifica-

tion by flash column chromatography (silica gel, elution with

50% Et₂O in hexanes, followed by 50% EtOAc and 1% HOAc

in hexane) and azeotropic removal of HOAc with benzene

afforded 73.6 mg (0.271 mmol, 83%, ds ) 6:1) of the desired

acid 12 as a yellowish oil. An analytical sample was prepared

from diastereomerically pure 10 using the same procedure.

Data for acid 12: R_f0.18 (6.0 mL of 50% EtOAc in hexanes

with 3 drops of AcOH/PMA); [R]²²+21.4 (c 2.57, CH₂Cl₂); IR

D

(thin film) 3195, 1753 cm^-1; ¹H NMR (CDCl₃, 300 MHz) δ 8.51

(bs, 1H), 5.76 (dd, 1H, J ) 15.4, 7.7 Hz), 5.52 (dd, 1H, J )

15.4, 7.7 Hz), 4.46 (dd, 1H, J ) 14.3, 8.1 Hz), 4.06 (dd, 1H, J

) 8.1, 6.3 Hz), 3.56 (d, 1H, J ) 4.8 Hz), 3.49 (t, 1H, J ) 8.1

Hz), 3.42 (s, 3H), 2.68 (m, 1H), 1.64 (q, 2H, J ) 7.7 Hz), 1.62

(q, 2H, J ) 7.4 Hz), 1.08 (d, 3H, J ) 6.8 Hz), 0.89 (t, 3H, J )

7.4 Hz), 0.88 (t, 3H, J ) 7.7 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ

176.1, 135.2, 128.5, 113.1, 83.9, 76.4, 69.7, 58.7, 39.5, 29.7, 29.6,

14.8, 7.9, 7.8; HRMS (EI) exact mass calcd for C₁₂H₁₉O₅(M⁺

- C₂H₅) requires 243.1233, found 243.1228.

To a solution of bromolactone 13 (1.14 g, 3.25 mmol) in THF

(54 mL) was added Zn dust (6.37 g, 97.5 mmol). To this rapidly

stirred solution was added aqueous 1 M NH₄OAc (11 mL)

slowly. The resulting solution was stirred at 25 °C for 5 h.

EtOAc (20 mL) and an aqueous pH 4 buffer solution (50 mL,

a 48:2 (v/v) mixture of 1 M NaH₂PO₄and 1 M NaHSO₄) were

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

6960 J . Org. Chem., Vol. 63, No. 20, 1998

Burke et al.

added. The mixture was filtered through Celite with EtOAc.

The aqueous layer was separated and adjusted to pH 4 with

the slow addition of 1 M NaHSO₄solution. The resultant

aqueous layer was extracted with EtOAc (3 × 100 mL). The

combined organic extracts were dried (MgSO₄), filtered, and

concentrated in vacuo. Purification by flash chromatography

(silica gel, elution with 50% EtOAc and 1% HOAc in hexanes),

followed by azeotropic removal of HOAc with PhH, afforded

0.77 g (2.83 mmol, 87%) of acid 12 as a colorless oil. Data for

the acid 12 match that of the previous procedure.

(MgSO₄), filtered, and concentrated in vacuo. Purification by

Kugelrohr distillation afforded 9.99 g (41.6 mmol, 93%) of ester

15 (1:1 diastereomeric mixture) as a colorless oil. Data for

15: R_f0.52 (50% Et₂O in hexanes/PMA); ¹H NMR (CDCl₃, 300

MHz) δ 5.49-5.31 (m, 1H), 4.23 (m, 1H) 4.09 (m, 1H), 3.88

(m, 1H), 2.09 (m, 3H), 1.81 (m, 3H), 1.62 (m, 4H), 0.87 (m,

6H).

(1R)-1-[(1R)-3,3-Dieth yl-2,4-dioxolan yl]bu t-2-yn -1-ol (16)

a n d (1S)-1-[(1R)-3,3-Dieth yl-2,4-d ioxola n yl]bu t-2-yn yl Ac-

eta te (17). Preparation of pure 16 via diastereoselective

saponification reaction of 15 (120 mg, 0.5 mmol, 1:1 diaster-

eomeric mixture) with porcine pancreatic lipase (PPL, EC

3.1.1.3, Type II, Sigma, 40 mg) was carried out at 23 °C with

KH₂PO₄buffer (0.2 M, pH 5.1, 10 mL) under air. The mixture

was stirred for 3 h and quenched by the addition of Et₂O. The

aqueous layer was separated and extracted with Et₂O (3 × 20

mL). The combined organic layers were dried (MgSO₄),

filtered, and concentrated in vacuo. The residue was purified

by flash chromatography (silica gel, gradient elution with 13%

Et₂O in hexanes and 20% Et₂O in hexanes) to afford 38 mg

(0.192 mmol, 38%, 93% de) of pure alcohol 16 and recovered

acetate 17 as a colorless oil. Data for 16: R_f0.31 (50% Et₂O

(3R,4S,5R,6R)-6-[(1R)-3,3-Dieth yl-2,4-d ioxola n yl]-5-br o-

m o-3-m eth oxy-4-m eth yloxola n -2-on e (13) a n d (3R,4S,5S)-

5-{[(1S)-3,3-Dieth yl-2,4-dioxolan yl]br om om eth yl}-3-m eth -

oxy-4-m eth yloxola n -2-on e (14). To a solution of acid 12

(3.02 g, 11.1 mmol) in CCl₄(44.4 mL) were added NaHCO₃

(1.87 g, 22.2 mmol) and NBS (3.95 g, 22.2 mmol) at room

temperature. The reaction solution was protected from light

and stirred for 20 h. The mixture was diluted with hexanes,

filtered, and concentrated in vacuo. The residue was purified

by flash chromatography (silica gel, gradient elution with 11%

and 20% Et₂O in hexanes) to afford 1.48 g (4.20 mmol, 38%)

of 13 and 1.49 g (4.23 mmol, 38%) of 14 as a colorless oil. Data

for bromolactone 13: R_f0.40 (50% Et₂O in hexanes/PMA);

[R]²²_D+36.6 (c 1.37, CH₂Cl₂); IR (thin film) 1791 cm^-1; ¹H NMR

(CDCl₃, 300 MHz) δ 4.36 (ddd, 1H, J ) 7.4, 6.6, 2.9 Hz), 4.30

(dd, 1H, J ) 9.6, 4.8 Hz), 4.07 (dd, 1H, J ) 8.1, 6.6 Hz), 4.04

(dd, 1H, J ) 9.6, 2.9 Hz), 3.81 (dd, 1H, J ) 8.1, 7.7 Hz), 3.57

(s, 3H), 3.56 (d, 1H, J ) 5.1 Hz), 2.59 (m, 1H), 1.72 (dq, 2H, J

) 7.4, 1.5 Hz), 1.61 (q, 2H, J ) 7.4 Hz), 1.32 (d, 3H, J ) 7.0

Hz), 0.89 (t, 3H, J ) 7.4 Hz), 0.88 (t, 3H, J ) 7.7 Hz); ¹³C

NMR (CDCl₃, 75 MHz) δ 173.0, 113.6, 83.4, 82.0, 73.6, 67.9,

58.5, 55.4, 40.6, 29.2, 28.6, 17.5, 8.0, 7.9; MS (FAB) m/e

(relative intensity, assignment) 352.0 (25, M⁺), 350.0 (25, M⁺

- 2), 323.0 (100, M⁺- C₂H₅), 321.0 (100, (M⁺- 2) - C₂H₅);

experimental isotope pattern calculated for C₁₄H₂₃O₅Br matches

that observed; HRMS (EI) exact mass calcd for C₁₂H₁₈O₅Br

(M⁺- C₂H₅) requires 323.0320, found 323.0343. Data for

in hexanes/PMA); [R]²²+27.9 (c 0.85, CH₂Cl₂); IR (thin film)

D

3435 cm^-1; H NMR (CDCl₃, 300 MHz) δ 4.23 (m, 1H), 4.12

1

(dd, 1H, J ) 7.4, 6.6 Hz), 4.07 (dd, 1H, J ) 12.9, 9.5 Hz), 3.77

(ddd, 1H, J ) 13.2, 6.6, 5.2 Hz), 2.42 (bs, 1H), 1.81 (d, 3H, J

) 2.2 Hz), 1.64 (q, 2H, J ) 7.7 Hz), 1.60 (q, 2H, J ) 7.4 Hz),

0.88 (t, 3H, J ) 7.4 Hz), 0.87 (t, 3H, J ) 7.4 Hz); ¹³C NMR

(CDCl₃, 75 MHz) δ 114.1, 82.5, 79.0, 76.0, 66.4, 29.3, 29.0, 7.87,

7.61, 3.30; HRMS (EI) exact mass calcd for C₁₁H₁₉O₃(M⁺

H) requires 199.1335, found 199.1333.

+

Preparation of pure 17 via diastereoselective saponification

of 15 was accomplished similarly. To a suspension of 15 (9.99

g, 41.6 mmol, 1:1 diastereomeric mixture) in KH₂PO₄buffer

(0.2 M, pH 6.0, 420 mL) and H₂O (420 mL) was added porcine

pancreatic lipase (PPL, EC 3.1.1.3, Type II, Sigma, 5.0 g). The

mixture was stirred under air at 23 °C for 6.5 h and quenched

by the addition of Et₂O. The mixture was filtered through a

Buchner funnel and extracted with Et₂O (4 × 200 mL). The

combined organic layers were dried (MgSO₄), filtered, and

concentrated in vacuo. The residue was purified by flash

chromatography (silica gel, gradient elution with 13% Et₂O

in hexanes and 20% Et₂O in hexanes) to affored 3.49 g (14.5

mmol, 35%, 97% de) of pure acetate 17 and recovered alcohol

16 as a colorless oil. Data for 17: R_f0.52 (50% Et₂O in

bromolactone 14: R_f0.60 (50% Et₂O in hexanes/PMA); [R]²²

D

+68.4 (c 1.80, CH₂Cl₂); IR (thin film) 1792 cm^-1

;

¹H NMR

(CDCl₃, 300 MHz) δ 4.69 (dd, 1H, J ) 8.8, 5.5 Hz), 4.41 (ddd,

1H, J ) 7.0, 6.3, 5.5 Hz), 4.18 (dd, 1H, J ) 8.8, 5.2 Hz), 4.13

(dd, 1H, J ) 8.1, 6.3 Hz), 3.85 (dd, 1H, J ) 8.1, 7.4 Hz), 3.71

(d, 1H, J ) 3.7 Hz), 3.52 (s, 3H), 2.69 (ddq, 1H, J ) 7.4, 5.9,

3.7 Hz), 1.70 (dq, 2H, J ) 7.7, 1.8 Hz), 1.60 (q, 2H, J ) 7.4

Hz), 1.13 (d, 3H, J ) 7.4 Hz), 0.92 (t, 3H, J ) 7.4 Hz), 0.87 (t,

3H, J ) 7.7 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 172.9, 114.2,

81.7, 80.3, 74.8, 67.3, 58.2, 51.3, 39.3, 39.8, 29.4, 28.7, 10.1,

8.0, 7.9; MS (FAB) m/e (relative intensity, assignment) 352.0

(25, M⁺), 350.0 (26, M⁺- 2), 323.0 (100, M⁺- C₂H₅), 321.0

(100, (M⁺- 2) - C₂H₅); experimental isotope pattern calcu-

lated for C₁₄H₂₃O₅Br matches that observed; HRMS (EI) exact

mass calcd for C₁₂H₁₈O₅Br (M⁺- C₂H₅) requires 323.0320,

found 323.0305.

1-[(1R)-3,3-Diet h yl-2,4-d ioxola n yl]b u t -2-yn yl Acet a t e

(15). To a cooled (0 °C) solution of 1-propynylmagnesium

bromide (0.5 M solution in THF, 182 mL, 91.2 mmol) was

added a solution of aldehyde (9.73 g, 60.8 mmol) in THF (21

mL) slowly over a period of 30 min. The solution was then

allowed to warm to 25 °C and stirred for 6 h. The reaction

was quenched by the slow addition of saturated aqueous NH₄-

Cl (150 mL). The aqueous layer was separated and extracted

with Et₂O (3 × 100 mL), and the combined organic extracts

were dried (MgSO₄), filtered, and concentrated in vacuo.

Purification by Kugelrohr distillation afforded 10.8 g (54.5

mmol, 88%) of a 1:1 diastereomeric mixture of propargyl

alcohols as a colorless oil.

hexanes/PMA); [R]²²+86.4 (c 3.16, CH₂Cl₂); IR (thin film)

D

2244, 1748 cm^-1; ¹H NMR (CDCl₃, 300 MHz) δ 5.48 (dq, 1H, J

) 4.4, 2.2 Hz), 4.25 (dt, 1H, J ) 6.6, 4.1 Hz), 4.08 (dd, 1H, J

) 8.5, 6.6 Hz), 3.89 (dd, 1H, J ) 8.1, 7.0 Hz), 2.08 (s, 3H), 1.82

(d, 3H, J ) 2.2 Hz), 1.62 (m, 4H), 0.88 (t, 3H, J ) 7.4 Hz),

0.87 (t, 3H, J ) 7.4 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 169.6,

114.0, 83.1, 76.7, 73.3, 65.7, 63.4, 29.3, 28.9, 20.8, 7.8, 7.7, 3.5;

HRMS (EI) exact mass calcd for C₁₃H₂₀O₄(M⁺) requires

240.1362, found 240.1389.

1-[(1R)-3,3-Dieth yl-2,4-d ioxola n yl]bu t-2-yn -1-on e (18).

To a cooled (0 °C) solution of 1-propynylmagnesium bromide

(0.5 M solution in THF, 182 mL, 91.2 mmol) was added a

solution of aldehyde (9.73 g, 60.8 mmol) in THF (21 mL) slowly

over a period of 30 min. The solution was then allowed to

warm to 25 °C and stirred for 6 h. The reaction was quenched

by the slow addition of saturated aqueous NH₄Cl (150 mL).

The aqueous layer was separated and extracted with Et₂O (3

× 100 mL), and the combined organic extracts were dried

(MgSO₄), filtered, and concentrated in vacuo. Purification by

Kugelrohr distillation afforded 10.8 g (54.5 mmol, 88%) of a

1:1 diastereomeric mixture of propargyl alcohols as a colorless

oil.

To a suspension of Dess-Martin periodinane (321 mg, 0.758

mmol) in CH₂Cl₂(3.0 mL) was added a solution of the above

propargyl alcohol diastereomeric mixture (100 mg, 0.505 mmol)

in CH₂Cl₂(2.0 mL) in a dropwise fashion via cannula at 25

°C. The reaction mixture was stirred at 25 °C for 2 h and was

quenched with a saturated aqueous NaHCO₃solution (50 mL).

The aqueous layer was separated and extracted with Et₂O (3

× 50 mL). The combined organic layers were dried (MgSO₄),

To a cooled (0 °C) 1:1 diastereomeric mixture of the

propargyl alcohols (8.84 g, 44.7 mmol), DMAP (0.55 g, 4.47

mmol), and Et₃N (9.32 mL, 67.0 mmol) was added Ac₂O (6.33

mL, 67.0 mmol) in a dropwise manner. The mixture was

stirred at 0 °C for 0.5 h, allowed to warm to ambient

temperature, and stirred for 18 h. The reaction mixture was

diluted with Et₂O (200 mL) and quenched with H₂O (100 mL).

The aqueous layer was separated and extracted with Et₂O (3

× 100 mL). The combined organic extracts were dried

Synthetic Studies of Antitumor Macrolide Rhizoxin

J . Org. Chem., Vol. 63, No. 20, 1998 6961

filtered, and concentrated in vacuo. The residue was purified

by Kugelrohr distillation to afford 97 mg (0.496 mmol, 98%)

of ketone 18 as a colorless oil. Data for ketone 18: R_f0.53

11.3, 8.0, 7.8; HRMS (EI) exact mass calcd for C₁₄H₂₄O₅(M⁺)

requires 272.1624, found 272.1641.

(2R,3S,4R)-5-[(1S)-3,3-Dieth yl-2,4-d ioxola n yl]-2-m eth -

oxy-3-m eth ylp en ta n e-1,4-d iol (22). LiAlH₄(35 mg, 0.92

mmol) was suspended in THF (0.84 mL) at -78 °C, and a

solution of the lactone 21 (50 mg, 0.184 mmol) in THF (1.0

mL) was added via cannula. The mixture was stirred at -78

°C for 0.5 h and 0 °C for 2 h, and stirring was then continued

for 20 h, while the temperature was allowed to rise to room

temperature. The reaction was quenched by the addition of a

saturated aqueous potassium sodium tartrate solution (Roch-

elle’s salt solution, 20 mL) and EtOAc (20 mL). The mixture

was vigorously stirred until two clear layers formed. The

aqueous layer was separated and extracted with EtOAc (3 ×

30 mL). The combined organic layers were dried (MgSO₄),

filtered, and concentrated in vacuo. The residue was purified

by flash chromatography (silica gel, elution with 50% EtOAc

in hexanes) to give 46 mg (0.167 mmol, 91%) of diol 22 as a

colorless oil. Data for 22: R_f0.27 (17% EtOAc in hexanes/

(50% Et₂O in hexanes/PMA); [R]²²+49.5 (c 2.53, CH₂Cl₂); IR

D

(thin film) 2216, 1674 cm^-1; ¹H NMR (CDCl₃, 300 MHz) δ 4.50

(dd, 1H, J ) 7.7, 6.3 Hz), 4.23 (dd, 1H, J ) 8.5, 7.7 Hz), 4.05

(dd, 1H, J ) 8.5, 5.9 Hz), 2.05 (s, 3H), 1.72 (q, 2H, J ) 7.4

Hz), 1.65 (q, 2H, J ) 7.4 Hz), 0.95 (t, 3H, J ) 7.4 Hz), 0.89 (t,

3H, J ) 7.4 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 186.0, 115.5,

94.8, 80.9, 78.1, 66.6, 29.1, 28.5, 7.86, 7.68, 4.09; HRMS (EI)

exact mass calcd for C₁₁H₁₇O₃(M⁺+ H) requires 197.1178,

found 197.1175.

(1S)-1-[(1R)-3,3-Dieth yl-2,4-d ioxola n yl]bu t-2-yn yl Ac-

eta te (17). To a 25-mL round-bottom flask were added ketone

18 (288 mg, 1.46 mmol) and (R)-Alpine borane (5.82 mL, 0.5

M in THF, 2.91 mmol). The mixture was stirred at room

temperature for 40 h. Acetaldehyde (0.5 mL) was added to

this solution, and the mixture was allowed to stir for 30 min.

Et₂O (10 mL) was then added. This solution was cooled in an

ice bath and treated with ethanolamine (0.66 mL), which

caused a white precipitate to form. The mixture was stirred

for 1 h at 0 °C, suction filtered, and washed with pentane. The

filtrate was concentrated in vacuo. The residue was purified

by Kugelrohr distillation to give 389 mg (R/â ) 4.6:1) of crude

alcohol mixture.

To the crude mixture of alcohols (389 mg), Et₃N (1.0 mL,

2.91 mmol), and DMAP (17.8 mg) was added Ac₂O (0.69 mL,

2.91 mmol) at 0 °C. The mixture was stirred for 20 min,

warmed to room temperature, and stirred for 18 h. The

reaction mixture was diluted with Et₂O (50 mL) and H₂O (50

mL). The aqueous layer was separated and extracted with

Et₂O (3 × 50 mL). The combined organic layers were dried

(MgSO₄), filtered, and concentrated in vacuo. The residue was

purified by Kugelrohr distillation to afford 339 mg (1.41 mmol,

97%, R/â ) 4.6:1 diastereomeric mixture) of acetetes as a

colorless oil. R_f0.52 (50% Et₂O in hexanes/PMA).

To a suspension of the above diastereomeric mixture of

acetates (50 mg, 0.208 mmol, 4.6:1 diastereomeric mixture)

in KH₂PO₄buffer (0.1 M, pH 6.0, 4.0 mL) was added porcine

pancreatic lipase (PPL, EC 3.1.1.3, Type II, Sigma, 20 mg).

The mixture was stirred under air at 23 °C for 6.5 h and

quenched by the addition of Et₂O (30 mL). The mixture was

extracted with Et₂O (3 × 30 mL). The combined organic layers

were dried (MgSO₄), filtered, and concentrated in vacuo. The

residue was purified by flash chromatography (silica gel,

gradient elution with 13% Et₂O in hexanes and 20% Et₂O in

hexanes) to afford 35 mg (0.146 mmol, 70%, 95% de) of pure

acetate 17 and recovered alcohol 16 as a colorless oil. All data

for the acetate 17 are identical to those of the previous

procedure.

(3R,4S,5R)-5-{[(1S)-3,3-Dieth yl-2,4-d ioxola n yl]m eth yl}-

3-m eth oxy-4-m eth yloxola n -2-on e (21). To a solution of

bromolactone 14 (2.16 g, 6.15 mmol) in PhH (41 mL) were

added ⁿBu₃SnH (3.31 mL, 12.3 mmol) and AlBN (51 mg, 0.31

mmol). The solution was heated to reflux for 16 h and cooled

to room temperature. The solvent was removed in vacuo. The

residue was diluted in Et₂O (50 mL) and treated with excess

aqueous KF solution (5 g of KF in 50 mL of H₂O). The

resulting white precipitate was removed by filtration with Et₂O

wash. The aqueous layer was extracted with Et₂O (3 × 100

mL). The combined organic layers were dried (MgSO₄),

filtered, and concentrated in vacuo. The residue was purified

by flash chromatography (silica gel, elution with 33% Et₂O in

hexanes) to give 1.75 g (5.29 mmol, 86%) of lactone 21 as a

colorless oil. Data for 21: R_f0.23 (50% Et₂O in hexanes/PMA);

[R]²²_D+118.9 (c 1.0, CH₂Cl₂); IR (thin film) 1779 cm^-1; ¹H NMR

(CDCl₃, 300 MHz) δ 4.61 (ddd, 1H, J ) 10.7, 6.3, 4.4 Hz), 4.23

(tt, 1H, J ) 7.7, 5.9 Hz), 4.11 (dd, 1H, J ) 7.7, 5.9 Hz), 3.60

(d, 1H, J ) 5.5 Hz), 3.56 (s, 3H), 3.55 (t, 1H, J ) 7.7 Hz), 2.53

(m, 1H), 2.00 (ddd, 1H, J ) 14.3, 9.9, 5.5 Hz), 1.75 (ddd, 1H,

J ) 14.3, 7.4, 4.4 Hz), 1.63 (q, 2H, J ) 7.7 Hz), 1.59 (q, 2H, J

) 7.4 Hz), 1.06 (d, 3H, J ) 7.4 Hz), 0.89 (t, 3H, J ) 7.4 Hz),

0.87 (t, 3H, J ) 7.4 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 173.7,

112.8, 83.4, 81.6, 77.8, 72.5, 69.2, 58.2, 39.3, 33.5, 29.6, 29.3,

PMA); [R]²²-1.26 (c 6.1, CH₂Cl₂); IR (thin film) 3417 (br)

D

1

cm^-1; H NMR (C₆D₆, 300 MHz) δ 4.10 (dt, 1H, J ) 9.6, 2.6

Hz), 3.99 (m, 1H), 3.81 (bs, 1H), 3.80 (dd, 1H, J ) 8.1, 6.3 Hz),

3.72 (bm, 2H), 3.28 (t, 1H, J ) 8.1 Hz), 3.19 (bs, 1H), 3.16 (s,

3H), 3.08 (dt, 1H, J ) 5.9, 4.0 Hz), 1.79 (m, 1H), 1.73 (m, 1H),

1.57 (q, 1H, J ) 7.7 Hz), 1.54 (q, 1H, J ) 7.4 Hz), 1.24 (ddd,

1H, J ) 13.6, 4.0, 2.6 Hz), 0.99 (d, 3H, J ) 7.4 Hz), 0.90 (t,

3H, J ) 7.4 Hz), 0.85 (t, 3H, J ) 7.4 Hz); ¹³C NMR (C₆D₆, 75

MHz) δ 113.2, 84.3, 76.3, 70.4, 69.9, 60.4, 57.1, 40.4, 38.5, 30.3,

29.9, 9.6, 8.4, 8.2; HRMS (EI) exact mass calcd for C₁₂H₂₃O₅

(M⁺) requires 247.1546, found 247.1542.

(1R,2S,3R)-1-[(1S)-3,3-Dieth yl-2,4-d ioxola n yl]-4-m eth -

oxy-3-m eth yl-5-(1,1,2,2-tetr am eth yl-1-silapr opoxy)pen tan -

2-ol (23). To a solution of diol 22 (0.882 g, 3.19 mmol) in

CH₂Cl₂(24.5 mL) were added DMAP (0.195 g, 1.60 mmol) and

Et₃N (0.89 mL, 6.38 mmol). The resulting solution was cooled

to 0 °C and treated with TBSCl (0.721 g, 4.79 mmol). The

mixture was allowed to warm to room temperature and stirred

for 18 h. H₂O (50 mL) was added to the reaction mixture. The

aqueous phase was separated and extracted with Et₂O (3 ×

100 mL). The combined organic layers were dried (MgSO₄),

filtered, and concentrated in vacuo. The residue was purified

by flash chromatography (silica gel, gradient elution with 13%

Et₂O in hexanes and 17% Et₂O in hexanes) to give 1.17 g (3.0

mmol, 94%) of alcohol 23 as a colorless oil. Data for 23: R_f

0.45 (50% Et₂O in hexanes/PMA); [R]²²+19.7 (c 1.91, CH₂-

D

Cl₂); IR (thin film) 3519 (br) cm^-1; ¹H NMR (CDCl₃, 300 MHz)

δ 4.22 (m, 1H), 4.09 (dd, 1H, J ) 7.4, 5.9 Hz), 3.90 (dt, 1H, J

) 9.6, 3.3 Hz), 3.74 (A portion of ABX, 1H, J _AB) 10.7 Hz, J _AX

) 5.0 Hz), 3.63 (B portion of ABX, 1H, J _AB) 10.7 Hz, J _BX

)

5.3 Hz), 3.51 (t, 1H, J ) 7.7 Hz), 3.48 (bs, 1H), 3.41 (s, 3H),

3.30 (q, 1H, J ) 5.2 Hz), 1.85 (ddd, 1H, J ) 14.0, 9.6, 7.7 Hz),

1.75 (m, 1H), 1.62 (q, 1H, J ) 7.4 Hz), 1.59 (q, 1H, J ) 7.4

Hz), 1.56 (ddd, 1H, J ) 7.4, 5.5, 3.7 Hz), 0.90 (d, 3H, J ) 7.4

Hz), 0.88 (t, 3H, J ) 7.4 Hz), 0.87 (s, 9H), 0.86 (t, 3H, J ) 7.7

Hz), 0.047 (s, 6H); ¹³C NMR (C₆D₆, 75 MHz) δ 112.6, 84.8, 74.9,

71.2, 70.0, 62.5, 58.0, 39.2, 37.7, 29.7, 29.5, 25.6, 18.0, 8.0, 7.8,

7.5, -5.7; HRMS (EI) exact mass calcd for C₁₈H₃₉O₅Si (M⁺

C₂H₅) requires 361.2410, found 361.2411.

-

(2R)-[(1R,2S,3R)-1-{[(1S)-3,3-Diet h yl-2,4-d ioxola n yl]-

methyl}-3-methoxy-2-methyl-4-(1,1,2,2-tetramethyl-1-silapro-

p oxy)b u t yl]

3,3,3-Tr iflu or o-2-m et h oxy-2-p h en ylp r o-

p a n oa te (24). To a solution of alcohol 23 (20 mg, 0.051 mmol)

in CH₂Cl₂(0.7 mL) at 23 °C were added DMAP (14.3 mg, 0.117

mmol), (R)-(+)-MTPA (55.5 mg, 0.234 mmol), and DIC (18.3

µL, 0.117 mmol). The resulting mixture was stirred at 23 °C

for 18 h and then diluted with Et₂O (30 mL) and H₂O (30 mL).

The aqueous layer was separated and extracted with Et₂O (3

× 30 mL). The combined organic layers were dried (MgSO₄),

filtered, and concentrated in vacuo. The residue was purified

by flash chromatography (silica gel, elution with 9% Et₂O in

hexanes) to give 29 mg (0.048 mmol, 95%) of ester 24 as a

colorless oil. Data for 24: R_f0.62 (50% Et₂O in hexanes/PMA);

[R]²²_D-5.46 (c 1.87, CH₂Cl₂); IR (thin film) 1745 cm^-1; ¹H NMR

(CDCl₃, 300 MHz) δ 7.55 (m, 2H), 7.37 (m, 3H), 5.17 (dt, 1H,

J ) 8.1, 4.4 Hz), 3.97 (dd, 1H, J ) 7.7, 5.9 Hz), 3.82 (quin, 1H,

6962 J . Org. Chem., Vol. 63, No. 20, 1998

Burke et al.

J ) 6.3 Hz), 3.66 (A portion of ABX, 1H, J _AB) 10.7 Hz, J _AX

)

74.1, 71.8, 70.5, 62.6, 58.2, 39.1, 38.9, 29.7, 29.5, 25.6, 17.9,

11.7, 8.0, 7.7, -5.7, -5.8; HRMS (EI) exact mass calcd for

C₂₀H₄₃O₅Si (M⁺+ H) requires 391.2880, found 391.2854; exact

mass calcd for C₁₈H₃₇O₅Si (M⁺- C₂H₅) requires 361.2410,

found 361.2375.

5.1 Hz), 3.54 (B portion of ABX, 1H, J _AB) 10.7 Hz, J _BX) 5.5

Hz), 3.54 (d, 3H, J ) 1.1 Hz), 3.35 (t, 1H, J ) 7.7 Hz), 3.32 (s,

3H), 3.20 (q, 1H, J ) 5.2 Hz), 2.05 (m, 1H), 2.03 (ddd, 1H, J )

14.3, 6.3, 4.4 Hz), 1.72 (ddd, 1H, J ) 14.3, 7.0, 4.4 Hz), 1.56

(q, 2H, J ) 7.7 Hz), 1.47 (q, 2H, J ) 7.7 Hz), 0.91 (d, 3H, J )

7.0 Hz), 0.86 (s, 9H), 0.84 (t, 3H, J ) 7.7 Hz), 0.79 (t, 3H, J )

7.4 Hz), 0.032 (s, 3H), 0.026 (s, 3H); ¹³C NMR (CDCl₃, 75 MHz)

δ 166.0, 131.9, 129.4, 128.2, 127.2, 112.6, 81.9, 72.6, 69.9, 62.1,

58.0, 55.3, 37.1, 35.3, 29.7, 29.5, 18.0, 8.8, 8.0, 7.7, -5.6, -5.7;

HRMS (EI) exact mass calcd for C₂₈H₄₄O₇F₃Si (M⁺- C₂H₅)

requires 577.2809, found 577.2860.

(1S,2S,3R)-1-{[(1S)-3,3-Dieth yl-2,4-d ioxola n yl]m eth yl}-

3-m et h oxy-1-[(4-m et h oxyp h en yl)m et h oxy]-2-m et h yl-4-

(1,1,2,2-tetr a m eth yl-1-sila p r op oxy)bu ta n e (27). Prepara-

tion of p-methoxybenzyl bromide (PMBBr)was as follows.

Anisyl alcohol (3.0 g, 21.9 mmol) in Et₂O (4.7 mL) was added

slowly to 48% aqueous HBr (5.0 g) in Et₂O (4.7 mL) and stirred

for 1 h. The reaction mixture was then quenched with a

saturated aqueous NaHCO₃solution. The aqueous layer was

separated and extracted with Et₂O (3 × 50 mL). The combined

organic layers were washed with H₂O and saturated NaBr

solution and then dried (MgSO₄). The solvent was removed

in vacuo (<30 °C bath temperature). The crude p-methoxy-

benzyl bromide was essentially pure and could be used directly.

To a cooled (0 °C) solution of the alcohol 26 (236 mg, 0.605

mmol) and PMBBr (243 mg, 1.21 mmol) in THF (1.21 mL) and

DMF (0.605 mL) was added NaHMDS (1.21 mL, 1.0 M in THF,

1.21 mmol). The mixture was allowed to warm to room

temperature and stirred for 3 h. A saturated aqueous NH₄Cl

solution and Et₂O were added. The aqueous layer was

separated and extracted with Et₂O (3 × 50 mL). The combined

organic layers were washed with H₂O (80 mL), dried (MgSO₄),

and filtered. The solvent was removed in vacuo. The residue

was purified by flash chromatography (silica gel, elution with

6% Et₂O in hexanes) to afford 305 mg (0.598 mmol, 99%) of

27 as a colorless oil. Data for 27: R_f0.64 (50% Et₂O in

(2S)-[(1R,2S,3R)-1-{[(1S)-3,3-Diet h yl-2,4-d ioxola n yl]-

methyl}-3-methoxy-2-methyl-4-(1,1,2,2-tetramethyl-1-silapro-

p oxy)b u t yl]

3,3,3-Tr iflu or o-2-m et h oxy-2-p h en ylp r o-

p a n oa te (25). To a solution of alcohol 23 (20 mg, 0.051 mmol)

in CH₂Cl₂(0.7 mL) at 23 °C were added DMAP (14.3 mg, 0.117

mmol), (S)-(-)-MTPA (55.5 mg, 0.234 mmol), and DIC (18.3

µL, 0.117 mmol). The resulting mixture was stirred at 23 °C

for 18 h and then diluted with Et₂O (30 mL) and H₂O (30 mL).

The aqueous layer was separated and extracted with Et₂O (3

× 30 mL). The combined organic layers were dried (MgSO₄),

filtered, and concentrated in vacuo. The residue was purified

by flash chromatography (silica gel, elution with 9% Et₂O in

hexanes) to give 28 mg (0.046 mmol, 91%) of ester 25 as a

colorless oil. Data for 25: R_f0.62 (50% Et₂O in hexanes/PMA);

[R]²²_D+36.2 (c 1.8, CH₂Cl₂); IR (thin film) 1743 cm^-1; ¹H NMR

(CDCl₃, 300 MHz) δ 7.55 (m, 2H), 7.38 (m, 3H), 5.19 (dt, 1H,

J ) 8.1, 4.4 Hz), 4.05 (t, 1H, J ) 5.9 Hz), 4.03 (m, 1H), 3.57 (A

portion of ABX, 1H, J _AB) 11.1 Hz, J _AX) 5.2 Hz), 3.53 (B

portion of ABX, 1H, J _AB) 11.1 Hz, J _BX) 4.1 Hz), 3.54 (d, 3H,

J ) 1.1 Hz), 3.42 (t, 1H, J ) 6.6 Hz), 3.28 (s, 3H), 2.98 (q, 1H,

J ) 4.8 Hz), 2.09 (ddd, 1H, J ) 14.3, 7.7, 6.3 Hz), 2.00 (m,

1H), 1.80 (ddd, 1H, J ) 14.3, 6.3, 4.4 Hz), 1.59 (q, 2H, J ) 7.0

Hz), 1.53 (q, 2H, J ) 7.4 Hz), 0.87 (t, 3H, J ) 8.1 Hz), 0.86 (s,

9H), 0.85 (d, 3H, J ) 5.5 Hz), 0.83 (t, 3H, J ) 7.4 Hz), 0.028

(s, 3H), 0.021 (s, 3H); ¹³C NMR (CDCl₃, 75 MHz) δ 165.7, 131.8,

129.3, 128.1, 127.0, 112.7, 81.5, 76.0, 72.9, 69.9, 62.0, 57.9, 55.1,

37.2, 35.4, 29.7, 29.6, 29.4, 25.5, 17.9, 9.0, 7.8, 7.6, -5.9; HRMS

(EI) exact mass calcd for C₂₈H₄₄O₇F₃Si (M⁺- C₂H₅) requires

577.2809, found 577.2813.

(1S,2S,3R)-1-[(1S)-3,3-Diet h yl-2,4-d ioxola n yl]-4-m et h -

oxy-3-m eth yl-5-(1,1,2,2-tetr am eth yl-1-silapr opoxy)pen tan -

2-ol (26). To a stirred solution of alcohol 23 (64.4 mg, 0.165

mmol), Ph₃P (217 mg, 0.826 mmol), and p-nitrobenzoic acid

(138 mg, 0.826 mmol) in dry benzene (1.0 mL) at room

temperature was added diethylazodicarboxylate (DEAD) drop-

wise (0.13 mL, 0.826 mmol). The resulting solution was stirred

at room temperature for 72 h. The solvent was removed in

vacuo. The residue was diluted in Et₂O (10 mL), and the white

solid that formed was filtered off. The filtrate was concen-

trated in vacuo. The residue was purified by flash chroma-

tography (silica gel, elution with 10% and 20% Et₂O in

hexanes) to afford 48 mg (0.891 mmol, 54%) of the desired

p-nitrobenzoate and 22 mg (0.0564 mmol, 34%) of the recov-

ered starting alcohol 23.

hexanes/PMA); [R]²²-31.1 (c 1.68, CH₂Cl₂); IR (thin film)

D

2930, 2882, 1614, 1514, 1078, 837 cm^-1; ¹H NMR (CDCl₃, 300

MHz) δ 7.25 (m, 2H), 6.85 (m, 2H), 4.44 (ABq, 2H, J _AB) 10.7

Hz, ∆ν_AB) 42.2 Hz), 4.22 (m, 1H), 4.01 (dd, 1H, J ) 5.9, 8.1

Hz), 3.78 (s, 3H), 3.69 (A portion of ABX, 1H, J _AB) 10.7 Hz,

J _AX) 5.1 Hz), 3.62 (B portion of ABX, 1H, J _AB) 10.7 Hz, J _BX

) 5.5 Hz), 3.68 (m, 1H), 3.43 (t, 1H, J ) 8.1 Hz), 3.40 (s, 3H),

3.18 (q, 1H, J ) 5.2 Hz), 2.13 (m, 1H), 1.66 (m, 2H), 1.61 (q,

2H, J ) 7.4 Hz), 1.59 (q, 2H, J ) 7.4 Hz), 0.89 (s, 9H), 0.88 (d,

3H, J ) 7.0 Hz), 0.87 (t, 3H, J ) 7.7 Hz), 0.06 (s, 6H); ¹³C

NMR (CDCl₃, 75 MHz) δ 158.9, 130.7, 129.2, 113.6, 112.0, 82.6,

77.8, 73.7, 71.2, 70.6, 62.4, 58.2, 55.1, 36.5, 35.2, 29.7, 25.7,

18.1, 8.5, 8.1, 7.8, -5.6; HRMS (EI) exact mass calcd for

C

₂₈H₅₀O₆Si (M⁺) requires 510.3377, found 510.3374.

(2R,3S,4S)-5-[(1S)-3,3-Diet h yl-2,4-d ioxola n yl]-2-m et h -

oxy-4-[(4-m et h oxyp h en yl)m et h oxy]-3-m et h ylp en t a n -1-

ol (28). To a solution of TBS ether 27 (510 mg, 1.0 mmol) in

THF (15.6 mL) was added TBAF‚3H₂O (784 mg, 3.0 mmol).

The mixture was stirred at room temperature for 1 h. The

solvent was removed in vacuo. The residue was purified by

flash chromatography (silica gel, elution with 25% EtOAc in

hexanes) to give 363 mg (0.92 mmol, 92%) of alcohol 28 as a

colorless oil. Data for alcohol 28: R_f0.28 (50% EtOAc in

hexanes/PMA); [R]²²-46.6 (c 1.71, CH₂Cl₂); IR (thin film)

D

3480 (br) cm^-1

;

¹H NMR (CDCl₃, 300 MHz) δ 7.23 (m, 2H),

6.84 (m, 2H), 4.44 (AB_q, 2H, J _AB) 11.0 Hz, ∆ν_AB) 35.5 Hz),

4.18 (m, 1H), 4.01 (dd, 1H, J ) 7.7, 5.9 Hz), 3.77 (s, 3H), 3.73

(A portion of ABX, 1H, J _AB) 11.8 Hz, J _AX) 4.0 Hz), 3.59 (B

portion of ABX, 1H, J _AB) 11.8 Hz, J _BX) 4.8 Hz), 3.67 (ddd,

1H, J ) 9.9, 4.4, 2.6 Hz), 3.42 (t, 1H, J ) 8.1 Hz), 3.41 (s, 3H),

3.12 (dt, 1H, J ) 6.6, 4.8 Hz), 2.12 (tq, 1H, J ) 7.0, 4.4 Hz),

2.04 (bs, 1H), 1.63 (q, 2H), 1.60 (q, 2H, J ) 7.4 Hz), 1.57 (q,

2H, J ) 7.4 Hz), 0.96 (d, 3H, J ) 7.0 Hz), 0.86 (t, 3H, J ) 7.4

Hz), 0.85 (t, 3H, J ) 7.4 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ

158.9, 130.3, 129.1, 113.5, 112.0, 83.0, 76.6, 73.4, 71.1, 70.3,

61.3, 58.0, 54.9, 36.8, 34.9, 29.7, 29.5, 9.9, 8.0, 7.6; HRMS (EI)

exact mass calcd for C₂₂H₃₆O₆(M⁺) requires 396.2512, found

396.2529.

(2R,3S,4S)-5-[(1S)-3,3-Diet h yl-2,4-d ioxola n yl]-2-m et h -

oxy-4-[(4-m eth oxyph en yl)m eth oxy]-3-m eth ylpen tan al (29).

To a cooled (-78 °C) solution of oxalyl chloride (0.51 mL, 2.0

M in CH₂Cl₂, 1.01 mmol) in CH₂Cl₂(1.4 mL) was added DMSO

(0.16 mL, 2.02 mmol). The mixture was stirred at -78 °C for

10 min before a solution of alcohol 28 (100 mg, 0.253 mmol)

in CH₂Cl₂(1.4 mL) was added. The resulting mixture was

To a solution of the p-nitrobenzoate (48 mg, 0.0891 mmol)

in MeOH (1.5 mL) and Et₂O (0.5 mL) was added saturated

aqueous K₂CO₃solution (1.0 mL). The mixture was stirred

at room temperature for 18 h and diluted with a saturated

aqueous NH₄Cl solution (50 mL) and Et₂O (50 mL). The

aqueous layer was separated and extracted with Et₂O (3 × 50

mL). The combined organic layers were dried (MgSO₄),

filtered, and concentrated in vacuo. The residue was purified

by flash chromatography (silica gel, 17% Et₂O in hexanes) to

give 33 mg (0.085 mmol, 96%) of alcohol 22 as a yellowish oil.

Data for 26: R_f0.41 (50% Et₂O in hexanes/PMA); [R]²²+0.6

D

(c 1.0, CH₂Cl₂); IR (thin film) 3496 (br) cm^-1; ¹H NMR (CDCl₃,

300 MHz) δ 4.28 (m, 1H), 4.11 (dd, 1H, J ) 8.1, 6.3 Hz), 3.76

(dd, 1H, J ) 10.3, 5.9 Hz), 3.72 (m, 1H), 3.62 (dd, 1H, J )

10.7, 5.2 Hz), 3.53 (dd, 1H, J ) 8.5, 5.5 Hz), 3.52 (t, 1H, J )

8.1 Hz), 3.44 (s, 3H), 1.83 (m, 2H), 1.64 (q, 2H, J ) 7.0 Hz),

1.63 (m, 1H), 1.59 (q, 2H, J ) 7.4 Hz), 0.90 (d, 3H, J ) 7.4

Hz), 0.89 (t, 3H, J ) 7.4 Hz), 0.88 (t, 3H, J ) 7.4 Hz), 0.88 (s,

9H), 0.05 (s, 6H); ¹³C NMR (CDCl₃, 75 MHz) δ 120.0, 83.3,

Synthetic Studies of Antitumor Macrolide Rhizoxin

J . Org. Chem., Vol. 63, No. 20, 1998 6963

stirred at -78 °C for 30 min before Et₃N (0.422 mL, 3.03 mmol)

was added. The mixture was then allowed to warm to room

temperature and stirred for 10 min. Et₂O (50 mL) and H₂O

(50 mL) were added. The aqueous layer was separated and

extracted with Et₂O (3 × 50 mL). The combined organic layers

were washed with a saturated aqueous NaCl solution and

dried (MgSO₄). The solvent was removed in vacuo. The

residue was purified by flash chromatography (silica gel,

elution with 17% Et₂O in hexanes) to give 98 mg (0.249 mmol,

99%) of aldehyde 29 as a colorless oil. Data for 29: R_f0.33

(0.388 mmol, 87%) of the desired methyl ester 31 and 22 mg

(0.054 mmol, 12%) of the recovered ketone 26 as colorless oils.

Data for 31: R_f0.45 (50% Et₂O in hexanes/PMA); [R]²²_D-13.4

(c 1.28, CH₂Cl₂); IR (thin film) 1720, 1653, 1612 cm^-1; ¹H NMR

(C₆D₆, 300 MHz) δ 7.25 (m, 2H), 6.80 (m, 2H), 6.02 (s, 1H),

4.42 (AB_q, 2H, J _AB) 11.0 Hz, ∆ν_AB) 7.4 Hz), 4.30 (m, 1H),

3.88 (dd, 1H, J ) 7.7, 5.9 Hz), 3.64 (ddd, 1H, J ) 10.3, 5.9, 2.6

Hz), 3.44 (s, 3H), 3.43 (d, 1H, J ) 4.8 Hz), 3.37 (t, 1H, J ) 8.1

Hz), 3.29 (s, 3H), 2.95 (s, 3H), 2.18 (d, 3H, J ) 1.5 Hz), 1.98

(m, 1H), 1.69 (q, 2H, J ) 7.4 Hz), 1.66 (q, 2H, J ) 7.7 Hz),

1.63 (m, 1H), 1.49 (m, 1H), 1.00 (t, 3H, J ) 7.4 Hz), 0.98 (d,

3H, J ) 7.0 Hz), 0.97 (t, 3H, J ) 7.4 Hz); ¹³C NMR (C₆D₆, 75

MHz) δ 166.4, 159.7, 156.9, 131.4, 129.4, 117.5, 114.1, 112.5,

87.1, 77.6, 73.9, 72.0, 70.9, 56.6, 54.8, 50.5, 39.1, 36.0, 30.5,

30.3, 15.3, 9.4, 8.6, 8.3; HRMS (EI) exact mass calcd for

(50% Et₂O in hexanes/PMA); [R]²²-13.4 (c 1.45, CH₂Cl₂); IR

D

(thin film) 1733 cm^-1; H NMR (CDCl₃, 300 MHz) δ 9.63 (d,

1

1H, J ) 1.1 Hz), 7.25 (m, 2H), 6.86 (m, 2H), 4.50 (AB_q, 2H,

J _AB) 11.0 Hz, ∆ν_AB) 24.5 Hz), 4.28 (m, 1H), 4.04 (dd, 1H, J

) 7.7, 5.9 Hz), 3.81 (dd, 1H, J ) 3.3, 1.1 Hz), 3.78 (s, 3H), 3.64

(ddd, 1H, J ) 9.9, 7.4, 2.6 Hz), 3.46 (t, 1H, J ) 7.7 Hz), 3.40

(s, 3H), 2.13 (tq, 1H, J ) 7.0, 3.3 Hz), 1.84 (ddd, 1H, J ) 14.0,

8.5, 2.6 Hz), 1.66 (m, 1H), 1.62 (q, 1H, J ) 7.7 Hz), 1.61 (q,

1H, J ) 7.4 Hz), 0.89 (t, 6H, J ) 7.7 Hz), 0.88 (d, 3H, J ) 7.4

Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 203.6, 159.3, 130.5, 129.3,

113.9, 112.6, 86.5, 77.6, 73.1, 72.7, 70.6, 58.4, 55.3, 39.2, 36.9,

30.0, 29.9, 29.5, 10.5, 8.4, 7.9; HRMS (EI) exact mass calcd

for C₂₂H₃₄O₆(M⁺) requires 394.2355, found 394.2355.

C

₂₆H₄₀O₇(M⁺) requires 464.2774, found 464.2751.

(4R,5S,6S)-7-[(1S)-3,3-Diet h yl-2,4-d ioxola n yl]-4-m et h -

oxy-6-[(4-m eth oxyp h en yl)m eth oxy]-3,5-d im eth ylh ep t-2-

en a l (4). To a cooled solution (-78 °C) of ester 31 (67 mg,

0.144 mmol) in Et₂O (4.8 mL) was added DIBAL-H (0.722 mL,

1.0 M in hexane, 0.722 mmol) in a dropwise fashion. The

mixture was stirred at -78 °C for 1 h and 0 °C for 1.5 h. A

saturated aqueous potassium sodium tartrate solution (50 mL)

and Et₂O (30 mL) were added. The mixture was stirred for 2

h until two clear layers formed. The aqueous layer was

separated and extracted with Et₂O (3 × 50 mL). The combined

organic layers were dried (MgSO₄), filtered, and concentrated

in vacuo. The residue was purified by flash chromatography

(silica gel, elution with 33% Et₂O in hexanes) to give 60 mg

(0.138 mmol, 96%) of the desired allylic alcohol as a colorless

oil. R_f0.39 (50% EtOAc in hexanes).

(3R,4S,5S)-6-[(1S)-3,3-Diet h yl-2,4-d ioxola n yl]-3-m et h -

oxy-5-[(4-m et h oxyp h en yl)m et h oxy]-4-m et h ylh exa n -2-

on e (30). To a cooled (-78 °C) solution of MeMgBr (0.42 mL,

3.0 M in Et₂O, 1.24 mmol) in Et₂O (1.0 mL) was added a

solution of aldehyde 29 (98 mg, 0.249 mmol) in Et₂O (1.4 mL)

in a dropwise fashion via cannula. The mixture was stirred

at -78 °C for 0.5 h, allowed to warm to 25 °C, and stirred for

1.5 h. A saturated aqueous NH₄Cl solution (50 mL) and Et₂O

(50 mL) were added. The aqueous layer was separated and

extracted with Et₂O (3 × 50 mL). The combined organic layers

were dried (MgSO₄), filtered, and concentrated in vacuo. The

residue was purified by flash chromatography (silica gel,

elution with 50% Et₂O in hexanes) to afford 94 mg (0.229

mmol, 92%) of the desired secondary alcohol as a colorless oil.

To a solution of the secondary alcohol (94 mg, 0.229 mmol)

in CH₂Cl₂(2.55 mL) was added crushed 4 Å molecular sieves

(100 mg). The resulting slurry was stirred at 25 °C for 10 min

before the addition of NMO (73 mg, 0.619 mmol). After 10

min, TPAP (16.1 mg, 0.0459 mmol) was added and the

greenish black slurry was stirred at 25 °C for 20 min. The

black suspension was then filtered through a short plug of

silica gel and washed with Et₂O. The filtrate was concentrated

in vacuo. The residue was purified by flash chromatography

(silica gel, elution with 25% Et₂O in hexanes) to give 87 mg

(0.213 mmol, 93%) of ketone 30 as a colorless oil. Data for

To a solution of the allylic alcohol (60 mg, 0.318 mmol) in

CH₂Cl₂(1.5 mL) was added crushed 4 Å molecular sieves (90

mg). The slurry was stirred at 25 °C for 10 min before the

addition of NMO (32 mg, 0.275 mmol). After 10 min, TPAP

(9.7 mg, 0.0275 mmol) was added and the greenish black slurry

was stirred at 25 °C for 20 min. The balck suspension was

then filtered through a short plug of silica gel and washed with

Et₂O. The filtrate was concentrated in vacuo. The residue

was purified by flash chromatography (silica gel, elution with

25% Et₂O in hexanes) to afford 48.4 mg (0.112 mmol, 82%) of

aldehyde 4 as a colorless oil. Data for aldehyde 4: R_f0.37

(50% Et₂O in hexanes/PMA); [R]²²+6.62 (c 1.36, CH₂Cl₂); IR

D

1

(thin film) 1676, 1612 cm^-1; H NMR (C₆D₆, 300 MHz) δ 9.91

(d, 1H, J ) 7.7 Hz), 7.24 (m, 2H), 6.81 (m, 2H), 6.03 (d, 1H, J

) 7.7 Hz), 4.45 (AB_q, 2H, J _AB) 11.4 Hz, ∆ν_AB) 13.4 Hz), 4.30

(m, 1H), 3.87 (dd, 1H, J ) 7.7, 5.9 Hz), 3.60 (ddd, 1H, J ) 9.9,

5.9, 2.2 Hz), 3.37 (d, 1H, J ) 5.5 Hz), 3.36 (t, 1H, J ) 7.7 Hz),

2.87 (s, 3H), 1.83 (m, 1H), 1.70 (q, 2H, J ) 7.4 Hz), 1.65 (q,

2H, J ) 7.4 Hz), 1.60 (m, 1H), 1.56 (d, 3H, J ) 1.5 Hz), 1.47

(m, 1H), 1.01 (t, 3H, J ) 7.4 Hz), 0.96 (t, 3H, J ) 7.7 Hz), 0.89

(d, 3H, J ) 7.0 Hz); ¹³C NMR (C₆D₆, 75 MHz) δ 189.5, 159.8,

158.4, 131.3, 129.3, 128.2, 114.1, 112.6, 86.5, 77.5, 73.6, 72.2,

70.8, 56.7, 54.8, 39.5, 36.1, 30.5, 30.3, 13.4, 9.4, 8.6, 8.4; HRMS

(EI) exact mass calcd for C₂₅H₃₈O₆(M⁺) requires 434.2668,

found 434.2683.

30: R_f0.30 (50% Et₂O in hexanes/PMA); [R]²²-23.3 (c 1.53,

D

CH₂Cl₂); IR (thin film) 1723 cm^-1; ¹H NMR (CDCl₃, 300 MHz)

δ 7.25 (m, 2H), 6.86 (m, 2H), 4.49 (AB_q, 2H, J _AB) 10.7 Hz,

∆ν_AB) 21.8 Hz), 4.27 (m, 1H), 4.04 (dd, 1H, J ) 7.7, 5.9 Hz),

3.84 (d, 1H, J ) 3.3 Hz), 3.78 (s, 3H), 3.61 (ddd, 1H, J ) 9.9,

7.4, 2.6 Hz), 3.46 (t, 1H, J ) 7.7 Hz), 3.32 (s, 3H), 2.10 (s, 3H),

2.03 (tq, 1H, J ) 7.0, 3.7 Hz), 1.84 (ddd, 1H, J ) 14.0, 8.5, 2.6

Hz), 1.63 (q, 2H, J ) 7.4 Hz), 1.60 (q, 2H, J ) 7.7 Hz), 1.58

(m, 1H), 0.88 (t, 6H, J ) 7.4 Hz), 0.83 (d, 3H, J ) 7.0 Hz); ¹³

C

2-Meth yl-3-[4-m eth yl(3,5-oxa zolyl)]p r op -2-en -1-ol (33).

To a cooled (-78 °C) solution of aldehyde 32 (286 mg, 1.89

mmol) in Et₂O (6.4 mL) was added DIBAL-H (1.0 M in hexane,

5.68 mL, 5.68 mmol) in a dropwise manner over 10 min. The

mixture was stirred at -78 °C for 2 h and treated with MeOH

(2.0 mL). A saturated aqueous potassium sodium tartrate

solution (10 mL) was added. The mixture was stirred until

two clear layers formed. The aqueous phase was separated

and extracted with EtOAc (3 × 30 mL). The combined organic

phases were dried (MgSO₄), filtered, and concentrated in

vacuo. Purification of the residue by flash column chroma-

tography (silica gel, elution with 50% EtOAc in hexanes)

afforded 272 mg (1.78 mmol, 94%) of allylic alcohol 33 as a

colorless oil. Data for 33: R_f0.14 (50% EtOAc in hexanes/

NMR (CDCl₃, 75 MHz) δ 210.3, 159.0, 130.4, 129.1, 113.7,

112.3, 87.4, 77.4, 73.0, 72.3, 70.5, 58.2, 55.1, 40.0, 36.4, 30.0,

29.7, 26.2, 9.9, 8.2, 7.8; HRMS (EI) exact mass calcd for

C

₂₃H₃₆O₆(M⁺) requires 408.2512, found 408.2525.

(4R,5S,6S)-Meth yl 7-[(1S)-3,3-Dieth yl-2,4-d ioxola n yl]-

4-m eth oxy-6-[(4-m eth oxyp h en yl)m eth oxy]-3,5-d im eth yl-

h ep t-2-en oa te (31). To a solution of trimethyl phosphono-

acetate (968 mg, 5.32 mmol) in THF (12.5 mL) was added NaH

(112 mg, 95%, 4.43 mmol). The mixture was stirred at 25 °C

for 0.5 h. A solution of ketone 30 (181 mg, 4.43 mmol) in THF

(2.3 mL) was added dropwise via cannula. The mixture was

stirred at 25 °C for 1 h and allowed to warm to 60 °C for 24 h.

A saturated aqueous NH₄Cl solution (100 mL) was added to

quench the reaction. The aqueous layer was separated and

extracted with Et₂O (3 × 100 mL). The combined organic

layers were dried (MgSO₄), filtered, and concentrated in vacuo.

The residue was purified by flash chromatography (silica gel,

elution with 14% and 25% Et₂O in hexanes) to give 180 mg

1

PMA); IR (thin film) 3324 (br), 1583 cm^-1; H NMR (CDCl₃,

300 MHz) δ 7.43 (s, 1H), 6.27 (m, 1H), 3.59 (bs, 1H), 2.42 (s,

3H), 1.86 (s, 3H); ¹³C NMR (CDCl₃, 75 MHz) δ 160.7, 140.0,

137.4, 134.9, 113.5, 67.5, 15.9, 13.5; HRMS (EI) exact mass

calcd for C₈H₁₁NO₂(M⁺) requires 153.0790, found 153.0793.

6964 J . Org. Chem., Vol. 63, No. 20, 1998

Burke et al.

4-(3-Ch lor o-2-m e t h ylp r op -1-e n yl)-2-m e t h yl-1,3-ox-

a zole (34). To a cooled (0 °C) solution of allylic alcohol 33

(570 mg, 3.73 mmol) in CH₂Cl₂(18.0 mL) was added Et₃N (1.04

mL, 7.45 mmol), followed by methanesulfonyl chloride (0.433

mL, 5.59 mmol). The reaction mixture was warmed to room

temperature and allowed to stir for 8 h. The reaction mixture

was quenched with a saturated aqueous NaCl solution (50

mL). The aqueous layer was extracted with Et₂O (3 × 50 mL).

The combined organic layers were dried (MgSO₄), filtered, and

concentrated in vacuo. The residue was purified by flash

column chromatography (silica gel, elution with 14% and 20%

Et₂O in hexanes) to afford 410 mg (2.39 mmol, 64%) of chloride

34 as a colorless solid. Data for chloride 34: R_f0.41 (50% Et₂O

tr a n s-2,6-Dim eth oxytetr ah ydr opyr an -4-car boxylic Acid

Meth yl Ester (36). Through a homogeneous solution of 1,6-

heptadiene-4-carboxylic acid ethyl ester (8) (12.5 mL, d 0.896

g/cm³, 66.5 mmol) and anhydrous MeOH (500 mL) in a two-

necked 1-L round-bottom flask fitted with a gas dispersion tube

and drying tube was bubbled ozone (pressure 8 psig, flow 1.6-

1.8 L/min, potential 100V) at -78 °C until the solution turned

blue. Ozonation was ceased, and the solution was purged with

dry nitrogen for 20 min, whereupon DMS (20 mL, 272 mmol)

and p-TsOH (3.16 g, 16.6 mmol) were added consecutively. The

reaction mixture was then warmed to room temperature,

stirred for 12 h, and then heated to reflux for 17 h. All MeOH

was removed by rotary evaporation and was replaced with

MeCN (750 mL) having a 0.02% water content as determined

by Karl Fisher analysis. The resultant mixture was stirred

for 12 h, concentrated by rotary evaporation, taken up in

toluene (750 mL), and then concentrated to an oil, which was

submitted immediately to flash chromatography (elution with

20% ether in hexanes) to yield 9.88 g (73%) of the dimeth-

oxytetrahydropyran 36 as a clear, colorless oil. Data for 36:

1

in hexanes); IR (thin film) 1585 cm^-1; H NMR (CDCl₃, 300

MHz) δ 7.49 (s, 1H), 6.30 (s, 1H), 4.12 (s, 2H), 2.43 (s, 3H),

2.04 (d, 3H, J ) 1.1 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 161.0,

137.4, 136.2, 135.3, 118.9, 52.3, 16.8, 13.8, 13.7; HRMS (EI)

exact mass calcd for C₈H₁₀NOCl (M⁺) requires 171.0451, found

171.0454.

Dim eth oxy[2-m eth yl-3-(4-m eth yl(3,5-oxa zolyl)p r op -2-

en yl]p h osp h in e 1-Oxid e (3). Dimethyl phosphite (0.89 mL,

9.69 mmol) was added slowly to a suspension of NaH (245 mg,

95%, 9.69 mmol) in THF (16.0 mL). This mixture was stirred

at room temperature for 2 h to give a clear solution, which

was transferred via cannula into a solution of chloride 34 (373

mg, 2.18 mmol) in THF (1.75 mL). The resulting mixture was

heated to 45 °C for 1.5 h. A saturated aqueous NH₄Cl (50 mL)

solution was added to quench the reaction. The aqueous layer

was separated and extracted with Et₂O (3 × 50 mL). The

combined organic layers were dried (MgSO₄), filtered, and

concentrated in vacuo. The residue was purified by flash

column chromatography (silica gel, gradient elution with 50%

Et₂O in hexanes and 50% acetone in hexanes) to give 386 mg

(1.58 mmol, 73%) of the phosphonate 3 as a yellow oil. Data

for 3: R_f0.42 (acetone/PMA); IR (thin film) 1586, 1250, 1105,

R_f0.24 (40% ether in hexanes/PAA); IR (thin film) 1737 cm^-1

;

¹H NMR (400 MHz, CDCl₃) δ 4.93 (dd, 1H, J ) 5.7, 2.9 Hz),

4.72 (dd, 1H, J ) 9.2, 2.6 Hz), 3.69 (s, 3H), 3.49 (s, 3H), 3.44

(s, 3H), 2.94 (tt, 1 H, J ) 11.7, 4.1 Hz), 2.07-2.14 (m, 1H),

1.90-1.97 (m, 1H), 1.76-1.86 (m, 1H), 1.58-1.69 (m, 1H); ¹³

C

NMR (100 MHz, CDCl₃) δ 174.40, 98.29, 96.50, 55.95, 54.82,

51.85, 34.82, 32.83, 31.51; HRMS (FAB) exact mass calcd for

C₉H₁₆O₅Na (M⁺+ Na) requires 227.0896, found 227.0903.

tr a n s-2,6-Dim et h oxyt et r a h yd r op yr a n -4-ca r b oxa ld e-

h yd e (37). To a 500-mL round-bottom flask (to obtain optimal

selectivity in this reaction, it was absolutely imperative to

ensure maximum cooling by using a round-bottom flask which

was at least four times the volume of the total reaction

mixture) charged with methyl ester 36 (5.00 mL, d 1.12 g/cm³,

27.5 mmol), anhydrous hexanes (29 mL), and anhydrous

toluene (58 mL) at -78 °C was added over 25 min via syringe

pump 1.0 M DIBAL-H (29 mL, 29.0 mmol) in hexanes. The

cold reaction mixture was quenched with 2-propanol (2.5 mL)

immediately following the completed addition (addition time

should be restricted to no more than 30 min, followed by

immediate quench, to avoid the formation of an unsymmetrical

dimeric product), whereupon the cold bath was removed, and

a 30% aqueous sodium-potassium tartrate solution (120 mL)

was added. The resultant mixture was stirred vigorously for

30 min, poured into a separatory funnel, and extracted with

EtOAc (200 mL). The aqueous phase was saturated with solid

NaCl and then extracted further with EtOAc (3 × 200 mL).

The combined organic extracts were washed with brine (200

mL), dried over Na₂SO₄, and concentrated to an oil. The crude

aldehyde was taken up in 50% ether in petroleum ether (200

mL) and passed through a short pad of silica gel via vacuum

filtration directly into an oven-dried round-bottom flask. The

pad was then eluted with 50% ether/petroleum ether (200 mL),

and the resultant solution (alcohol-free) was concentrated to

afford 4.447 g (93%) of the aldehyde 37 as a pale yellow oil

which was used without further purification. Data for 37: R_f

1

1030 cm^-1; H NMR (CDCl₃, 300 MHz) δ 7.39 (d, 1H, J ) 1.8

Hz), 6.08 (d, 1H, J ) 5.9 Hz), 3.68 (d, 6H, J ) 11.0 Hz), 2.66

(d, 2H, J ) 22.8 Hz), 2.37 (s, 3H), 2.02 (dd, 3H, J ) 4.0, 0.7

Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 160.6, 137.3, 135.2, 130.7,

130.5, 119.0, 118.7, 52.6, 52.5, 37.7, 35.9, 19.8, 13.5; HRMS

(EI) exact mass calcd for C₁₀H₁₆NO₄P (M⁺) requires 245.0817,

found 245.0807.

(4S,2S,3R)-1-{[(1S)-3,3-Dieth yl-2,4-d ioxola n yl]m eth yl}-

3-m eth oxy-1-[(4-m eth oxyph en yl)m eth oxy]-2,4,8-tr im eth yl-

9-[4-m eth yl(3,5-oxa zolyl)]n on a -4,6,8-tr ien e (35). To a so-

t

lution of BuOK (30 mg, 0.266 mmol) in DME (0.21 mL) was

added a solution of phosphonate 3 (33 mg, 0.133 mmol) and

aldehyde 4 (19.2 mg, 0.0442 mmol) in DME (0.3 mL) in a

dropwise fashion at 0 °C. The mixture was stirred at 0 °C for

2 h, allowed to warm to 60 °C, and stirred for 0.5 h.

A

saturated aqueous NH₄Cl solution (50 mL) was added, and

the mixture was extracted with Et₂O (3 × 50 mL). The

combined organic layers were dried (MgSO₄), filtered, and

concentrated in vacuo. The residue was purified by flash

chromatography (silica gel, elution with 20% Et₂O in hexanes)

to give 13.5 mg (0.0244 mmol, 55%) of the desired triene 35

as a colorless oil. Data for triene 35: R_f0.31 (50% Et₂O in

1

0.17 (40% ether-hexanes/PAA); IR (thin film) 1725 cm^-1; H

hexanes/PMA); [R]²²+36.2 (c 0.90, CH₂Cl₂); IR (thin film)

NMR (400 MHz, CDCl₃) δ 9.61 (s, 1H), 4.85-4.87 (m, 1H), 4.77

(dd, 1H, J ) 7.4, 2.8 Hz), 3.44 (s, 3H), 3.43 (s, 3H), 2.76-2.84

(m, 1H), 2.09 (1H, ddd, J ) 13.2, 4.7, 2.7 Hz), 1.83-1.85 (m,

2H), 1.63 (ddd, 1H, J ) 13.2, 9.7, 7.3 Hz); ¹³C NMR (100 MHz,

CDCl₃) δ 201.82, 97.25, 96.89, 55.59, 55.11, 42.33, 29.95, 28.82;

HRMS (FAB) exact mass calcd for C₈H₁₄O₄Na (M⁺+ Na)

requires 197.0790, found 197.0814.

D

1612, 1514 cm^-1

;

¹H NMR (C₆D₆, 300 MHz) δ 7.25 (m, 2H),

7.07 (s, 1H), 6.79 (m, 2H), 6.68 (dd, 1H, J ) 15.1, 10.7 Hz),

6.45 (d, 1H, J ) 15.4 Hz), 6.40 (s, 1H), 6.17 (d, 1H, J ) 10.7

Hz), 4.42 (AB_q, 2H, J _AB) 11.0 Hz, ∆ν_AB) 48.4 Hz), 4.32 (m,

1H), 3.93 (dd, 1H, J ) 8.1, 6.3 Hz), 3.65 (dt, 1H, J ) 8.1, 4.0

Hz), 3.46 (t, 1H, J ) 8.1 Hz), 3.35 (d, 1H, J ) 7.7 Hz), 3.29 (s,

3H), 3.13 (s, 3H), 2.32 (s, 3H), 2.29 (m, 1H), 1.97 (s, 3H), 1.72

(d, 3H, J ) 0.7 Hz), 1.70 (q, 2H, J ) 7.7 Hz), 1.69 (m, 2H),

1.62 (q, 2H, J ) 7.4 Hz), 1.22 (d, 3H, J ) 7.0 Hz), 1.01 (t, 3H,

J ) 7.4 Hz), 0.94 (t, 3H, J ) 7.4 Hz); ¹³C NMR (C₆D₆, 75 MHz)

δ 161.0, 159.8, 140.0, 138.4, 137.2, 13.6, 136.2, 131.6, 129.6,

124.4, 120.8, 114.2, 112.4, 89.1, 77.3, 74.4, 71.7, 71.2, 56.2, 54.7,

38.6, 35.1, 30.8, 30.5, 30.3, 14.5, 13.5, 12.5, 10.5, 8.8, 8.6;

HRMS (EI) exact mass calcd for C₃₃H₄₇NO₆(M⁺) requires

553.3403, found 553.3382; exact mass calcd for C₃₃H₄₈NO₆(M⁺

+ H) requires 554.3481, found 554.3437; exact mass calcd for

tr a n s-(2,6-Dim et h oxyt et r a h yd r op yr a n -4-yl)a cet a ld e-

h yd e (39). To a 250-mL round-bottom flask (argon atmo-

sphere) charged with

a thick slurry of N-(morpholino)-

methyldiphenylphosphine oxide (38) (8.22 g, 27.3 mmol) and

THF (60 mL) at 0 °C was added via syringe pump over 20

min 2.5 M n-butyllithium (10.5 mL, 26.1 mmol) in hexanes.

The resultant orange anion, which became less heterogeneous

upon continued addition, was stirred an additional 30 min

upon completed addition. The temperature of the resultant

dark red homogeneous solution was lowered to -10 °C, and

then the aldehyde 37 (3.48 g, 20.0 mmol) was added as a

C

₃₁H₄₂NO₆(M⁺- C₂H₅) requires 524.3012, found 524.3047.

Synthetic Studies of Antitumor Macrolide Rhizoxin

J . Org. Chem., Vol. 63, No. 20, 1998 6965

homogeneous solution in THF (10 mL) via syringe over 25 min.

Upon completed addition, the reaction mixture was stirred for

1 h at -5 °C, whereupon it was concentrated and then

partitioned between CH₂Cl₂(150 mL) and saturated NH₄Cl

(100 mL). The aqueous phase was extracted with CH₂Cl₂(150

mL), and the combined organic extracts were washed with

brine (100 mL) and dried over Na₂SO₄and Norit. This solution

was filtered through Celite directly into an oven-dried round-

bottom flask, concentrated to an amorphous solid, taken up

in ether (300 mL), and finally concentrated to a foam. Fol-

lowing residual solvent removal under high vacuum, the

intermediate 1,2-adduct was dissolved in THF (25 mL) (on a

larger scale, a solution of the 1,2-adduct in THF sometimes

forms a precipitate of the pure compound during addition) and

added to a 250-mL round-bottom flask containing a hetero-

geneous mixture of potassium hydride (3.13 g, 27.3 mmol), as

a 25% suspension in mineral oil (prewashed, 3 × 20 mL

anhydrous hexane), in THF (75 mL) at 0 °C. The resultant

mixture was warmed to room temperature and then stirred

for 12 h, whereupon it was diluted to 250 mL with THF and

vacuum filtered through a short pad of silica gel. The pad was

eluted with THF (100 mL), and the resultant solution was

concentrated to a solid material which was adsorbed onto silica

gel and then submitted to flash chromatography (solid load,

gradient elution, 30-35-40% ether in petroleum ether) to

afford 3.17 g (74%) of the homologated aldehyde 39 (the

homologated aldehyde must be used immediately or frozen in

a benzene matrix to prevent decomposition) as a clear, colorless

oil. Data for 39: R_f0.18 (50% ether-hexanes/PAA); IR (thin

film) 1723 cm^-1; ¹H NMR (400 MHz, CDCl₃) δ 9.73 (t, 1H, 3.51,

1.76 Hz), 4.86 (dd, 1H, J ) 3.3, 1.3 Hz), 4.71 (dd, 1H, J ) 9.6,

2.5 Hz), 3.47 (s, 3H), 3.41 (s, 3H), 2.53-2.57 (m, 1H), 2.34-

2.36 (m, 2H), 1.87-1.93 (m, 1H), 1.72-1.77 (m, 1H), 1.32-

1.39 (m, 1H), 1.15-1.23 (m, 1H); ¹³C NMR (100 MHz, CDCl₃)

δ 200.96, 98.78, 96.71, 56.07, 54.73, 49.99, 36.89, 35.44, 24.03;

HRMS (FAB) exact mass calcd for C₉H₁₆O₄Na (M⁺+ Na)

requires 211.0947, found 211.0913.

DMF (10 mL). The reaction mixture was stirred at room

temperature for 72 h, poured into water (250 mL), and

partitioned with EtOAc (500 mL). The organic phase was

extracted further with water (3 × 250 mL), diluted with

hexanes (100 mL), washed consecutively with water (100 mL)

and brine (100 mL), dried over Na₂SO₄, and finally filtered

through Celite. Subjection to flash chromatography (gradient

elution, 7.5-10% ether in petroleum ether) afforded 10.72 g

(95%) of TBS ether 42 as a clear, colorless oil. Note: The

following NMR spectra are representative of ring diastereo-

mers R,R and S,S which are manifest via complex overlapping

resonances in the ¹H NMR and by doubling of signals in the

¹³C NMR. Data for 42: R_f0.50 (40% ether in hexanes/PAA);

1

[R]²⁵+23.2° (c 1.91, CH₂Cl₂); IR (film) 1640 cm^-1; H NMR

D

(400 MHz, CDCl₃) δ 5.83-5.92 (m, 1H), 4.96-5.02 (m, 2H),

4.84-4.86 (m, 1H), 4.62-4.67 (m, 1H), 3.63-3.67 (m, 1H), 3.49

(s, 3H), 3.40 (s, 3H), 2.27-2.33 (m, 1H), 1.91-2.10 (m, 1H),

1.63-1.89 (m, 2H), 0.98-1.34 (m, 4H), 0.93 (d, 3H, J ) 6.8

Hz), 0.88 (s, 9H), 0.03-0.04 (m, 6H); ¹³C NMR (100 MHz,

CDCl₃) δ 141.28/140.98, 113.95/113.88, 99.32/99.29, 97.05,

72.91/72.83, 55.96, 54.62/54.60, 42.58/42.32, 40.57/40.19, 37.95/

37.32, 36.61/36.07, 25.87, 25.41/25.20, 14.11/13.94, -4.28,

-4.36, -4.38; HRMS (FAB) exact mass calcd for C₁₉H₃₇O₄Si

(M⁺- H) requires 357.2461, found 357.2520.

(2R/S,3R,4R)-4-(ter t-Bu tyld im eth ylsiloxy)-5-(tr a n s-2,6-

d im et h oxyt et r a h yd r op yr a n -4-yl)-3-m et h ylp en t a n e-1,2-

d iol (43). To a 25-mL round-bottom flask charged with NMO

(182 mg, 1.55 mmol) was added consecutively acetone (10.0

mL), 4% aqueous OsO₄(432 µL, 0.071 mmol), and water (331

µL, 18.4 mmol) at 0 °C. This mixture was cooled to -5 °C

and then treated with a solution of the olefin 42 (507 mg, 1.41

mmol) in acetone (4.0 mL). The reaction mixture was stirred

at -5 °C for 15 min, warmed to room temperature, and stirred

for 12 h. It was then diluted with EtOAc (200 mL), treated

with saturated Na₂S₂O₃(28 mL), and stirred vigorously for

approximately 15 min. The phases were separated, and the

aqueous phase was stirred vigorously with EtOAc (100 mL)

for 15 min. The phases were separated, and the combined

organic extracts were brine washed and dried over Na₂SO₄.

Vacuum filtration through a short pad of silica gel followed

by concentration provided 533 mg (96%) of the diol 43 as a

light tan viscous oil, which was used without further purifica-

tion. Note: The following NMR spectra are representative of

ring diasteromers R,R and S,S which are manifest via complex

overlapping resonances in the ¹H NMR and by doubling of

signals in the ¹³C NMR. In addition, there is a 1:1 ratio of

tr a n s-(2R,3R)-1-(2,6-Dim eth oxytetr a h yd r op yr a n -4-yl)-

3-m eth ylp en t-4-en -2-ol (41). To a 500-mL round-bottom

flask charged with 0.84 M (Z)-crotylboronate (40) in toluene

(29 mL, 24.3 mmol), activated 4 Å molecular sieves (2.50 g),

and toluene (30 mL) was added via syringe pump over 1 h a

solution of aldehyde 39 (3.52 g, 18.7 mmol) in toluene (12 mL)

at -78 °C. Upon completed addition, the reaction mixture was

transferred to a -78 °C CyroCool for 6 h, whereupon it was

quenched with 2.5 M NaOH (21 mL). The resultant mixture

was warmed to room temperature, stirred vigorously for 1 h,

and vacuum filtered through a short pad of Celite, which was

washed with EtOAc (100 mL). The biphasic mixture was

partitioned with EtOAc (100 mL) and then the aqueous phase

was extracted with EtOAc (2 × 100 mL). The combined

organic extracts were washed with brine (50 mL), dried over

Na₂SO₄, filtered through Celite, and concentrated to a viscous

residue which was submitted to flash chromatography (elution

with 40% ether in petroleum ether), yielding 4.51 g (99%) of

the homoallyl alcohol 41 as a clear, colorless oil. Note: The

following NMR spectra are representative of ring diasteromers

R,R and S,S which are manifest via complex overlapping

resonances in the ¹H NMR and by doubling of signals in the

¹³C NMR. Data for 41: R_f0.13 (50% ether in hexanes/PAA);

alcohol diastereomers. Data for 43: R_f0.28 (ether/PAA); [R]²⁵

D

+4.62° (c 1.73, CH₂Cl₂); IR (thin film) 3446 cm^-1; ¹H NMR (400

MHz, CDCl₃) δ 4.85 (br s, 1H), 4.62-4.69 (m, 1H), 4.28 (d, 1H,

J ) 20.8 Hz), 3.85-3.90 (m, 1H), 3.56-3.70 (m, 2H), 3.47 (s,

3H), 3.38-3.39 (m, 3H), 1.00-2.32 (m, 10H), 0.88 (s, 9H), 0.75

(dd, 3H, J ) 7.0, 1.3 Hz), 0.06-0.11 (m, 6H); ¹³C NMR (100

MHz, CDCl₃) δ 99.12, 97.03, 96.89, 73.85, 73.77, 73.73, 73.55,

64.81, 55.98, 54.66, 54.62, 54.58, 38.77, 38.67, 38.31, 38.11,

36.95, 36.67, 35.66, 25.73, 25.37, 25.19, 17.85, 12.76, 12.59,

-4.39, -4.69, -4.80; HRMS (FAB) exact mass calcd for

C

₁₉H₄₀O₆SiNa (M⁺+ Na) requires 415.2492, found 415.2487.

(2R,3R)-3-(ter t-Bu t yld im et h ylsiloxy)-4-(tr a n s-2,6-d i-

m e t h o x y t e t r a h y d r o p y r a n -4-y l)-2-m e t h y lb u t y r a ld e -

h yd e (44). To a 50-mL round-bottom flask charged with

Pb(OAc)₄(944 mg, 2.13 mmol), Na₂CO₃(414 mg, 3.90 mmol),

activated 4 Å molecular sieves (1.0 g), and CH₂Cl₂(13 mL) at

-10 °C was added dropwise diol 43 (519 mg, 1.77 mmol) as a

solution in CH₂Cl₂(5 mL). The reaction mixture was stirred

between -10 and 0 °C for 1 h, diluted to 50 mL with ether,

and poured into a rapidly stirring mixture of EtOAc (50 mL)

and pH 7 phosphate buffer (75 mL). The resultant brown

heterogeneous mixture was stirred for 15 min, vacuum filtered

through a short pad of Celite, and washed with EtOAc (100

mL) and then ether (100 mL). The two phases were separated,

and the aqueous phase was extracted by vigorous stirring with

EtOAc (2 × 100 mL). The combined organic extracts were

brine washed, dried over Na₂SO₄, vacuum filtered through a

short pad of Florisil, and then concentrated to give 433 mg

(94%) of the aldehyde 44 as a yellow oil, which was used

[R]²⁵+17.4° (c 1.42, CH₂Cl₂); IR (thin film) 3447, 1639 cm^-1

;

D

¹H NMR (400 MHz, CDCl₃) δ 5.69-5.79 (m, 1H), 5.07-5.08

(m, 1H), 5.03-5.07 (m, 1H), 4.85-4.87 (m, 1H), 4.68 (ddd, 1H,

J ) 9.7, 3.8, 2.1 Hz), 3.54-3.62 (m, 1H), 3.47 (s, 3H), 3.40 (s,

3H), 2.14-2.27 (m, 2H), 1.02-1.98 (m, 7H), 1.00 (d, 3H, J )

6.9 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 140.71/140.57, 115.60/

115.44, 99.30/99.25, 97.22/97.17, 71.55/71.50, 56.08/56.03,

54.68/54.66, 43.87/43.75, 40.74/40.49, 38.08, 36.80/36.68, 35.42,

26.07/25.99; HRMS (FAB) exact mass calcd for C₁₃H₂₄O₄Na

(M⁺+ Na) requires 267.1573, found 267.1619.

tr a n s-(2R,3R)-4-[2-(ter t-Bu tyld im eth ylsiloxy)-3-m eth -

ylp en t-4-en yl]-2,6-d im eth oxytetr a h yd r op yr a n (42). To a

100-mL round-bottom flask charged with TBDMSCl (9.53 g,

63.2 mmol), imidazole (6.46 g, 94.8 mmol), and DMF (22 mL),

was added the alcohol 41 (7.72 g, 31.6 mmol) as a solution in

6966 J . Org. Chem., Vol. 63, No. 20, 1998

Burke et al.

without further purification. Note: The following NMR

spectra are representative of ring diasteromers R,R and S,S

which are manifest via complex overlapping resonances in the

¹H NMR and by doubling of signals in the ¹³C NMR. Data for

44: R_f0.34 (50% ether in hexanes/PAA); [R]²⁵_D+24.8° (c 2.18,

CH₂Cl₂); IR (thin film) 1727 cm^-1; ¹H NMR (400 MHz, CDCl₃)

δ 9.74/9.75 (d, 1H, J ) 3.29 Hz), 4.86 (br s, 1H), 4.65 (dt, 1H,

J ) 9.66, 2.64 Hz), 4.20-4.23 (m, 1H), 3.48 (s, 3H), 3.40 (s,

3H), 2.38-2.47 (m, 1H), 1.70-2.06 (m, 3H), 1.03-1.47 (m, 8H),

0.84/0.85 (s, 9H), 0.06 (s, 3H), 0.01/0.03 (s, 3H); ¹³C NMR (100

MHz, CDCl₃) δ 205.04/205.00, 99.09/99.07, 96.87/96.84, 69.04/

68.89, 56.09/56.04, 54.70/54.68, 51.03/50.91, 41.30/41.13, 37.50/

37.36, 36.16/36.04, 25.72, 25.64/25.53, 17.97, -4.25, -4.34/-

4.58, -4.64; HRMS (FAB) exact mass calcd for C₁₈H₃₆O₅SiNa

(M⁺+ Na) requires 383.2230, found 383.2273.

through a short pad of Na₂SO₄, concentrated to a light tan

oil, filtered through Celite, and submitted to flash chroma-

tography (elution with 50% ether in petroleum ether) to

provide 917 mg (98%) of homoallyl alcohol 46 as a pale yellow

viscous oil. Data for 46: R_f0.19 (50% ether in hexanes/PAA);

[R]²⁵+22.2 (c 0.898, CH₂Cl₂); IR (thin film) 3450, 1613 cm^-1

.

D

Note: The following NMR spectra are representative of ring

diastereomers R,R and S,S which are manifest via complex

overlapping resonances in the ¹H NMR and by doubling of

signals in the ¹³C NMR. ¹H NMR (400 MHz, CDCl₃) δ 5.90-

5.98 (m, 1H), 5.68-5.73 (m, 1H), 4.86-4.88 (m, 1H), 4.66-

4.70 (m, 1H), 3.58-3.61 (m, 1H), 3.48 (s, 3H), 3.41 (s, 3H),

2.15-2.25 (m, 2H), 1.95-1.97 (m, 1H), 1.72-1.89 (m, 2H), 1.54

(br s, 1H), 1.05-1.38 (m, 4H), 0.99 (d, 3H, J ) 6.8 Hz), 0.04

(s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 148.62/148.44, 131.33/

131.08, 99.31/99.26, 97.22/97.20, 71.39/71.37, 56.09/56.03,

54.69/54.67, 46.05/45.83, 40.94/40.70, 38.08, 36.87/36.68, 35.51,

26.10/26.02, 13.87/13.64, -1.20; HRMS (FAB) exact mass calcd

for C₁₆H₃₂O₄SiNa (M⁺+ Na) requires 339.1968, found 339.1933.

(E)-(2R,4S,6R)-6-[(R)-3-Bu t-1-en yltr im eth ylsilyl-4-(2,2-

d im eth oxyeth yl)]-2-m eth oxytetr a h yd r op yr a n (47). To a

100-mL round-bottom flask fitted with a reflux condenser and

charged with homoallylic alcohol 46 (702 mg, 2.22 mmol), CSA

(51.5 mg, 0.222 mmol), and benzene (44 mL) at room temper-

ature was added 2,2-dimethoxypropane (2.73 mL, 22.2 mmol).

The resultant mixture was heated to 80 °C and stirred for a

total of 22 h, whereupon it was concentrated to a dark brown

residue which was treated with hexanes (200 mL) and then

(E)-(2R,3R)-4-[2-(ter t-Bu tyld im eth ysiloxy)-3-m eth yl-5-

tr im eth ylsilylp en t-4-en yl]-tr a n s-2,6-d im eth oxytetr a h y-

d r op yr a n (45). To a 200-mL round-bottom flask charged with

anhydrous CrCl₂(6.19 g, 50.3 mmol) was added THF (36 mL)

at room temperature, resulting in an exotherm. This hetero-

geneous mixture was stirred for 1 h and then treated with

DMF (3.90 mL, 50.3 mmol), resulting in the formation of an

extremely thick mixture which thinned out after 45 min,

whereupon a solution of Me₃SiCHBr₂(1.50 mL, d 1.57 g/cm³,

9.59 mmol) and aldehyde 44 (1.73 g, 4.79 mmol) in THF (18

mL) was added dropwise. The flask was then covered com-

pletely with aluminum foil, and anhydrous LiI (2.57 g, 19.2

mmol) as a solution in THF (18 mL) was added at room

temperature over 5 min. The reaction mixture was then

stirred in the dark for 18 h, whereupon TLC analysis of the

reaction mixture indicated the presence of some remaining

starting material. The flask was, therefore, immersed in an

ultrasound bath for 2 h (sonication of the reaction mixture

should be limited to a maximum of 2 h to avoid excessive loss

of product due to â-elimination of the OTBS group) over which

time the water temperature increased from 24.1 to 35.0 °C.

The mixture was then diluted with ether (200 mL) and poured

into a vigorously stirring mixture of ether (400 mL) and water

(400 mL). The aqueous phase was extracted further with ether

(2 × 400 mL) by vigorous “stir-partitioning”. The combined

organic extracts were diluted with hexanes (200 mL), washed

with water (200 mL) followed by brine (200 mL), dried over

Na₂SO₄, filtered through Celite, and concentrated to a light

tan oil, which was submitted to flash chromatography (elution

with 5% ether in petroleum ether), affording 1.2125 g (67%)

of (E)-vinylsilane 45 as a clear, colorless oil. Note: The

following NMR spectra are representative of ring diastereo-

mers R,R and S,S which are manifest via complex overlapping

resonances in the ¹H NMR and by doubling of signals in the

¹³C NMR. Data for 45: R_f0.35 (20% ether in hexanes/PAA);

[R]²⁵_D+22.4° (c 0.891, CH₂Cl₂); IR (thin film) 2953, 2896, 1155,

filtered through

a plug of glass wool. The filtrate was

concentrated via rotary evaporation, and the crude product

was submitted to flash chromatography (elution with 10%

ether-hexanes) to give 507 mg of a mixture of stereoisomers.

The stereoisomerically impure mixture was dissolved in hex-

anes (2.0 mL) and injected onto a 41.4-mm i.d. Dynamax Si

83-141-C HPLC column fitted with a Si 83-141-G guard

module (elution with 4% EtOAc in hexanes) running at 30 mL/

min, using two channels of UV (254 and 280 nm), and

collecting 144 fractions at a rate of 1 fraction per min.

Concentration of the desired fractions and removal of residual

solvent in vacuo afforded 304 mg (41%) of the rearrangement

product 47 as a pale yellow oil. Data for 47: R_f0.29 (15%

EtOAc in hexanes/PAA); [R]²⁵_D-45.0° (c 1.00, CH₂Cl₂); IR (thin

1

film) 2944, 2827, 1612, 1126, 1057 cm^-1; H NMR (400 MHz,

CDCl₃) δ 5.94 (dd, 1H, J ) 18.9, 7.5 Hz), 5.67 (dd, 1H, J )

18.7, 1.1 Hz), 4.74 (d, 1H, J ) 3.1 Hz), 4.43 (t, 1H, J ) 5.7

Hz), 3.52 (ddd, 1H, J ) 11.4, 6.8, 2.0 Hz), 3.32 (s, 3H), 3.30 (s,

3H), 3.28 (s, 3H), 2.15-2.20 (m, 1H), 1.84-2.04 (m, 1H), 1.63-

1.78 (m, 2H), 1.45-1.49 (m, 1H), 1.22-1.30 (m, 1H), 1.05 (d,

3H, J ) 6.6 Hz), 0.94 (q, 2H, J ) 11.9 Hz), 0.04 (s, 9H); ¹³C

NMR (100 MHz, CDCl₃) δ 149.14, 129.80, 102.52, 98.45, 71.53,

54.28, 52.79, 52.27, 45.58, 39.69, 36.61, 35.66, 26.19, 15.37,

-1.15; HRMS (FAB) exact mass calcd for C₁₇H₃₄O₄SiNa (M⁺

+ Na) requires 353.2124, found 353.2194.

1

1097, 1021, 1006 cm^-1; H NMR (400 MHz, CDCl₃) δ 6.02-

6.09 (m, 1H), 5.58-5.63 (m, 1H), 4.85-4.86 (m, 1H), 4.62-

4.67 (m, 1H), 3.67-3.71 (m, 1H), 3.49 (d, 3H, J ) 2.9 Hz), 3.40

(s, 3H), 2.24-2.29 (m, 1H), 2.02-2.06 (m, 1H), 1.67-1.77 (m,

1H), 0.96-1.38 (m, 2H), 0.92 (d, 3H, J ) 6.8 Hz), 0.87 (d, 9H,

J ) 2.4 Hz), 0.00-0.45 (m, 18H); ¹³C NMR (100 MHz, CDCl₃)

δ 150.07/149.68, 128.91/128.82, 99.36/99.34, 97.10/97.04, 72.78/

72.74, 56.06/56.04, 54.67, 44.70/44.40, 41.26/40.88, 37.75/37.53,

36.52/36.31, 25.92, 25.56/25.34, 18.12, -1.19, -4.20, -4.26,

(2R,3R)-2-Meth yl-5-(pr op-2-en yl)-1-(1,1,2,2-tetr am eth yl-

1-sila p r op oxy)oct-7-en -3-ol (50). To a solution of diol 49^12d

(2.01 g, 10.2 mmol) in CH₂Cl₂(127 mL) were added DMAP

(0.62 g, 5.1 mmol) and Et₃N (2.83 mL, 20.3 mmol). The

resulting solution was cooled to 0 °C and treated with TBSCl

(3.07 g, 20.3 mmol). The mixture was allowed to warm to room

temperature and stirred for 18 h. H₂O (150 mL) was added

to the reaction mixture. The aqueous phase was separated

and extracted with Et₂O (3 × 100 mL). The combined organic

layers were dried (MgSO₄), filtered, and concentrated in vacuo.

The residue was purified by flash chromatography (silica gel,

elution with 6% Et₂O in hexanes) to give 2.71 g (8.68 mmol,

85%) of alcohol 50 as a colorless oil. Data for 50: R_f0.44 (17%

-4.35; HRMS (FAB) exact mass calcd for C₂₂H₄₅O₄Si₂(M⁺

H) requires 429.2856, found 429.2986.

-

(E)-(2R,3R)-1-(tr a n s-2,6-Dim eth oxytetr a h yd r op yr a n -4-

yl)-3-m eth yl-5-tr im eth ylsilylp en t-4-en -2-ol (46). To a 50-

mL round-bottom flask containing TBS ether 45 (1.28 g, 3.00

mmol) was added 1.0 M TBAF (20.8 mL, 20.8 mmol) in THF

at 0 °C, whereupon the mixture was slowly warmed to room

temperature and stirred for 12 h. The reaction mixture was

diluted with ether (20 mL) and then poured into a rapidly

stirring mixture of 33% CH₂Cl₂-ether (400 mL) and saturated

NH₄Cl (100 mL). The two phases were separated, and the

aqueous phase was again “stir-partitioned” with 33% CH₂Cl₂-

ether (3 × 400 mL). The combined organic extracts were

washed with brine (100 mL), dried over Na₂SO₄, concentrated

to a solid-oil mixture, taken up in benzene (100 mL), passed

Et₂O in hexanes/PMA); [R]²²+9.64 (c 2.53, CH₂Cl₂); IR (thin

D

film) 3471 (br), 1639 cm^-1; ¹H NMR (CDCl₃, 300 MHz) δ 5.76

(m, 2H), 5.02-4.97 (m, 4H), 3.72 (A portion of ABX, 1H, J _AB

) 9.9 Hz, J _AX) 3.7 Hz), 3.64 (B portion of ABX, 1H, J _AB) 9.9

Hz, J _BX) 5.9 Hz), 2.98 (d, 1H, J ) 4.4 Hz), 2.08 (m, 4H), 1.74

(m, 2H), 1.48 (ddd, 1H, J ) 14.0, 9.6, 5.2 Hz), 1.23 (ddd, 1H,

J ) 13.6, 8.5, 3.7 Hz), 0.88 (s, 9H), 0.86 (d, 3H, J ) 7.0 Hz),

0.05 (s, 6H); ¹³C NMR (CDCl₃, 75 MHz) δ 137.0, 136.6, 116.1,

115.9, 72.0, 67.9, 39.0, 38.3, 37.1, 33.5, 25.6, 17.9, 10.3, -5.8,

Synthetic Studies of Antitumor Macrolide Rhizoxin

J . Org. Chem., Vol. 63, No. 20, 1998 6967

-5.9; HRMS (EI) exact mass calcd for C₁₈H₃₆O₂Si (M⁺) requires

312.2485, found 312.2490.

with 20% hexanes in EtOAc) to give 26 mg (0.101 mmol, 95%)

of alcohol 53 as a colorless oil. Data for alcohol 53: R_f0.18

2-{(1S,5R)-5-[(1R)-1-Meth yl-2-(1,1,2,2-tetr a m eth yl-1-si-

la p r op oxy)eth yl]-3-oxo-4-oxa n yl}eth a n a l (51). A solution

of diene 50 (50 mg, 0.160 mmol) in CH₂Cl₂(6.0 mL) was cooled

to -78 °C. Ozone was bubbled through the solution until a

distinct blue color persisted for 5 min. Nitrogen was bubbled

through the solution to dissipate the excess ozone until the

solution became colorless. Me₂S (0.3 mL) was added. The

mixture was allowed to warm to room temperature and stirred

for 3 h. The solvent and excess Me₂S were removed in vacuo.

The resulting colorless residue was dissolved in CH₂Cl₂(15.4

mL) and heated at reflux (oil bath temperature 45 °C) for 6 h.

The mixture was cooled to 25 °C and concentrated in vacuo.

The resulting colorless residue was dissolved in CH₂Cl₂(2.5

mL). Crushed 4 Å molecular sieves (156 mg) were added, and

the slurry was stirred at 25 °C for 10 min before the addition

of NMO (52 mg, 0.444 mmol). After 10 min, TPAP (18.8 mg,

0.0535 mmol) was added and the greenish black slurry was

stirred for 20 min at 25 °C. The black suspension was then

filtered through a short plug of silica gel and washed with

EtOAc. The filtrate was concentrated in vacuo. The residue

was purified by flash chromatography (silica gel, elution with

20% EtOAc in hexanes) to afford 23 mg (0.027 mmol, 45% for

2 steps) of aldehyde 51 as a colorless oil. Data for 51: R_f0.30

(17% hexanes in EtOAc/PMA); [R]²²19.4 (c 0.80, CH₂Cl₂); IR

D

1

(thin film) 3446 (br), 1716, 1653 cm^-1; H NMR (CDCl₃, 300

MHz) δ 6.85 (dt, 1H, J ) 15.4, 7.4 Hz), 5.86 (dt, 1H, J ) 15.8,

2.9 Hz), 4.50 (dt, 1H, J ) 12.1, 2.9 Hz), 3.72 (s, 3H), 3.68 (A

portion of ABX, 1H, J _AB) 11.0 Hz, J _AX) 7.7 Hz), 3.59 (B

portion of ABX, 1H, J _AB) 11.0 Hz, J _BX) 5.5 Hz), 2.69 (m,

1H), 2.26-2.04 (m, 4H), 1.86 (m, 2H), 1.38 (m, 1H), 0.93 (d,

3H, J ) 7.0 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 170.6, 166.3,

144.5, 123.5, 79.9, 64.0, 51.4, 39.6, 38.4, 35.8, 31.8, 31.0, 10.3;

HRMS (EI) exact mass calcd for C₁₃H₂₀NO₅(M⁺) requires

256.1311, found 256.1287; exact mass calcd for C₁₃H₂₁NO₅(M⁺

+ H) requires 257.1389, found 257.1416.

Meth yl 4-{(1S,5R)-5-[(1R)-2-(Ben zoth iazol-2-ylsu lfon yl)-

isop r op yl]-3-oxo-4-oxa n yl}bu t-2-en oa te (5). To a solution

of alcohol 53 (16.4 mg, 0.0641 mmol), Ph₃P (25.2 mg, 0.0961

mmol), and 2-mercaptobenzothiazole (16.1 mg, 0.0961 mmol)

in THF (0.825 mL) was added DEAD (0.0151 mL, 0.0961

mmol) dropwise at room temperature. The solution was

stirred at room temperature for 18 h and then concentrated

in vacuo. The residue was purified by flash column chroma-

tography (silica gel, elution with 17% EtOAc in hexanes) to

give 21.3 mg (0.0526 mmol, 82%) of the desired thioether as a

colorless oil: R_f0.35 (50% EtOAc in hexanes/PMA).

(50% EtOAc in hexanes/PMA); [R]²²-23.9 (c 0.93, CH₂Cl₂);

D

To a solution of the thioether (21.3 mg, 0.0526 mmol) in CH₂-

Cl₂(0.0862 mL) was added NaHCO₃(22.1 mg, 0.263 mmol),

followed by m-CPBA (22.7 mg, 0.132 mmol). The mixture was

stirred at room temperature for 18 h and then poured into a

mixture of saturated aqueous NaHCO₃(10 mL) and saturated

aqueous sodium thiosulfate (10 mL). The aqueous layer was

separated and extracted with CH₂Cl₂(3 × 15 mL). The

combined organic extracts were dried (MgSO₄), filtered, and

concentrated in vacuo. The residue was purified by flash

column chromatography (silica gel, elution with 33% EtOAc

in hexanes) to give 16.8 mg (0.0386 mmol, 75%) of sulfone 5

as a colorless oil. Data for sulfone 5: R_f0.23 (50% EtOAc in

IR (thin film) 2929, 2856, 1732 cm^-1

;

¹H NMR (CDCl₃, 300

MHz) δ 9.75 (s, 1H), 4.47 (ddd, 1H, J ) 12.1, 3.7, 2.9 Hz), 3.59

(A portion of ABX, 1H, J _AB) 9.9 Hz, J _AX) 7.4 Hz), 3.52 (B

portion of ABX, 1H, J _AB) 9.9 Hz, J _BX) 5.1 Hz), 2.76 (ddd,

1H, J ) 17.3, 5.9, 1.8 Hz), 2.55 (m, 2H), 2.09 (dd, 1H, J )

17.3, 9.9 Hz), 1.92 (m, 1H), 1.78 (m, 1H), 1.39 (ddd, 1H, J )

13.2, 11.4, 11.0 Hz), 0.91 (d, 3H, J ) 7.0 Hz), 0.86 (s, 9H),

0.85 (m, 1H), 0.02 (s, 6H); ¹³C NMR (CDCl₃, 75 MHz) δ 199.4,

170.4, 79.7, 64.4, 49.8, 40.0, 35.7, 32.1, 26.0, 25.7, 18.1, 10.6,

-5.7; HRMS (EI) exact mass calcd for C₁₆H₃₁O₄Si (M⁺+ H)

requires 315.1992, found 315.2014.

hexanes/PMA); [R]²²-24.6 (c 1.12, CH₂Cl₂); IR (thin film)

Meth yl 4-{(1S,5R)-5-[(1R)-1-Meth yl-2-(1,1,2,2-tetr am eth -

yl-1-sila p r op oxy)eth yl]-3-oxo-4-oxa n yl}bu t-2-en oa te (52).

To a solution of aldehyde 51 (178 mg, 0.567 mmol) in CH₂Cl₂

(5.0 mL) was added methyl (triphenylphosphoranylidene)-

acetate (569 mg, 1.7 mmol) at room temperature. The result-

ing mixture was stirred at room temperature for 24 h. The

solvent was removed in vacuo. The residue was subjected to

flash column chromatography (silica gel, elution with 50%

Et₂O in hexanes) to afford 174 mg (0.471 mmol, 83%) of methyl

ester 52 as a colorless oil. Data for 52: R_f0.49 (50% EtOAc

D

1723, 1657, 1237, 1147, 1082 cm^-1; ¹H NMR (CDCl₃, 300 MHz)

δ 8.19 (m, 1H), 8.00 (m, 1H), 7.61 (dq, 2H, J ) 7.4, 1.5 Hz),

6.82 (dt, 1H, J ) 15.8, 6.6 Hz), 5.86 (d, 1H, J ) 15.8 Hz), 4.60

(dt, 1H, J ) 11.8, 2.6 Hz), 3.81 (dd, 1H, J ) 14.3, 6.3 Hz), 3.72

(s, 3H), 3.47 (dd, 1H, J ) 14.3, 6.3 Hz), 2.70 (m, 1H), 2.62 (m,

1H), 2.17 (m, 1H), 1.88 (m, 1H), 1.33 (m, 1H), 1.16 (d, 3H, J )

7.0 Hz); ¹³C NMR (CDCl₃, 75 MHz) δ 169.7, 166.1, 165.7, 152.3,

144.0, 136.4, 127.9, 127.5, 123.7, 122.1, 80.6, 57.1, 51.4, 38.2,

35.6, 32.3, 31.3, 30.6, 13.4; HRMS (EI) exact mass calcd for

in hexanes/PMA); [R]²²-27.3 (c 0.80, CH₂Cl₂); IR (thin film)

C

₂₀H₂₃NO₆S₂(M⁺) requires 437.0967, found 437.0978.

D

1728, 1659 cm^-1; ¹H NMR (CDCl₃, 300 MHz) δ 6.86 (dt, 1H, J

) 15.8, 7.0 Hz), 5.86 (d, 1H, J ) 15.8 Hz), 4.42 (dt, 1H, J )

Ack n ow led gm en t. We gratefully acknowledge sup-

12.1, 3.3 Hz), 3.72 (s, 3H), 3.59 (A portion of ABX, 1H, J _AB

)

port of this work provided by NIH (Grants GM 31998

and CA 74394), Merck, and a Pfizer Research Award.

We also thank Wyeth-Ayerst Research for substantial

financial and technical support of this project. The NIH

(ISIO RRO 8389-01), NSF (CHE-9208463), and the

Chemistry Department of the University of Wisconsins

Madison are acknowledged for NMR facility support.

9.9 Hz, J _AX) 7.5 Hz), 3.53 (B portion of ABX, 1H, J _AB) 9.9

Hz, J _BX) 5.0 Hz), 2.69 (m, 1H), 2.26-2.04 (m, 4H), 1.87 (m,

1H), 1.79 (m, 1H), 1.36 (m, 1H), 0.94 (d, 3H, J ) 9.6 Hz), 0.86

(s, 9H), 0.02 (s, 6H); ¹³C NMR (CDCl₃, 75 MHz) δ 170.7, 166.3,

144.6, 123.5, 79.8, 64.0, 51.4, 40.0, 38.5, 35.9, 32.1, 31.0, 25.7,

18.1, 10.7, -5.7; HRMS (EI) exact mass calcd for C₁₉H₃₅NO₅-

Si (M⁺+ H) requires 371.2254, found 371.2243.

Meth yl 4-{(1S,5R)-5-[(1R)-2-Hyd r oxyisop r op yl]-3-oxo-

4-oxa n yl}bu t-2-en oa te (53). To a solution of TBS ether 52

(39.4 mg, 0.107 mmol) in CH₃CN (3.94 mL) was added HF

(52% aqueous solution, 0.394 mL). The mixture was stirred

at room temperature for 1 h. A saturated aqueous NaHCO₃

solution was added slowly, and the mixture was extracted with

EtOAc (3 × 50 mL). The combined organic phases were dried

(MgSO₄), filtered, and concentrated in vacuo. The residue was

purified by flash column chromatography (silica gel, elution

Su p p or tin g In for m a tion Ava ila ble: Characterization

data including ¹H and ¹³C NMR spectra of all new compounds

(81 pages). This material is contained in libraries on micro-

fiche, 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.

J O980754K

Article Doi

Synthetic studies of antitumor macrolide rhizoxin: Stereoselective syntheses of the C(1)-C(9) and C(12)-C(26) subunits

DOI: 10.1021/jo980754k

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