Total synthesis of rhizoxin D, a potent antimitotic agent from the fungus Rhizopus chinensis

Article abstract of DOI:10.1021/jo020537q

Rhizoxin D (2) was synthesized from four subunits, A, B, C, and D representing C3-C9, C10-C13, C14-C19, and C20-C27, respectively. Subunit A was prepared by cyclization of iodo acetal 21, which set the configuration at C5 of 2 through a stereoselective addition of the radical derived from dehalogenation of 21 at the β carbon of the (Z)-α,β-unsaturated ester. Aldehyde 29 was obtained from phenylthioacetal 24 and condensed with phosphorane 30, representing subunit B, in a Wittig reaction that gave the (E,E)-dienoate 31. This ester was converted to aldehyde 33 in preparation for coupling with subunit C. The latter in the form of methyl ketone 55 was obtained in six steps from propargyl alcohol. An aldol reaction of 33 with the enolate of 55 prepared with (+)-DIPCl gave the desired β-hydroxy ketone 56 bearing a (13S)-configuration in a 17-20:1 ratio with its (13R)-diastereomer. After reduction to anti diol 57 and selective protection as TIPS ether 58, the C15 hydroxyl was esterified to give phosphonate 59. An intramolecular Wadsworth-Emmons reaction of aldehyde 62, derived from δ-lactone 60, furnished macrolactone 63, which was coupled in a Stille reaction with stannane 68 to give 2 after cleavage of the TIPS ether.

Full text of DOI:10.1021/jo020537q

Tota l Syn th esis of Rh izoxin D, a P oten t An tim itotic Agen t fr om
th e F u n gu s Rh izopu s ch in en sis
J ames D. White,* Paul R. Blakemore, Neal J . Green, E. Bryan Hauser, Mark A. Holoboski,
Linda E. Keown, Christine S. Nylund Kolz,† and Barton W. Phillips
Department of Chemistry, Oregon State University, Corvallis, Oregon 97331-4003
james.white@orst.edu
Received August 12, 2002
Rhizoxin D (2) was synthesized from four subunits, A, B, C, and D representing C3-C9, C10-
C13, C14-C19, and C20-C27, respectively. Subunit A was prepared by cyclization of iodo acetal
21, which set the configuration at C5 of 2 through a stereoselective addition of the radical derived
from dehalogenation of 21 at the â carbon of the (Z)-R,â-unsaturated ester. Aldehyde 29 was obtained
from phenylthioacetal 24 and condensed with phosphorane 30, representing subunit B, in a Wittig
reaction that gave the (E,E)-dienoate 31. This ester was converted to aldehyde 33 in preparation
for coupling with subunit C. The latter in the form of methyl ketone 55 was obtained in six steps
from propargyl alcohol. An aldol reaction of 33 with the enolate of 55 prepared with (+)-DIPCl
gave the desired â-hydroxy ketone 56 bearing a (13S)-configuration in a 17-20:1 ratio with its
(13R)-diastereomer. After reduction to anti diol 57 and selective protection as TIPS ether 58, the
C15 hydroxyl was esterified to give phosphonate 59. An intramolecular Wadsworth-Emmons
reaction of aldehyde 62, derived from δ-lactone 60, furnished macrolactone 63, which was coupled
in a Stille reaction with stannane 68 to give 2 after cleavage of the TIPS ether.
In tr od u ction
evaluation6 despite the conjecture that it may possess
therapeutic properties superior to those of 1.7 Rhizoxin
is believed to bind to tubulin âs and to inhibit the
assembly of microtubules in a manner similar to that of
maytansine and ansamitocin P-3.8 The stereostructure
of rhizoxin, including its absolute configuration, was
established by careful NMR studies and by a single-
crystal X-ray determination in the course of the pioneer-
ing studies of the Tokyo group.1
Despite the intense synthetic interest focused on this
pair of macrolides, only one total synthesis of rhizoxin
(1) has been reported.9 However, five completed syntheses
of rhizoxin D (2) have been described,10 and publications
detailing the preparation of subunits for eventual as-
In 1984, an unusual 16-membered macrolide was
isolated by Okuda et al. from the fungus Rhizopus
chinensis Rh-2 and was named rhizoxin (1).1 Although
interest in 1 was initially kindled by its role as a
pathogen of rice seedling blight, its antifungal activity
was found to be much less compelling than its remark-
able antimitotic properties.2 Subsequently, a second
metabolite was discovered in R. chinensis that was
identified as the didesepoxy derivative and probable
biogenetic precursor of 1.3 Rhizoxin D (2) and rhizoxin
(1) are now recognized as equipotent antimitotic agents
with considerable promise as lead candidates for the
treatment of human carcinomas,4 especially those resis-
tant to therapies involving the dimeric vinca alkaloids
vincristine and vinblastine and adriamycin.2b Rhizoxin
(1) has undergone extensive clinical trials,5 but the less
abundant rhizoxin D (2) has received only limited clinical
(5) McLeod, H. L.; Murray, L. S.; Wanders, J .; Setanoians, A.;
Graham, M. A.; Pavlidis, N.; Heinrich, B.; Huinink, W. W. T.; Wagener,
D. J . T.; Aamdal, S.; Verweij, J . British J . Cancer 1996, 74, 1944 and
references cited therein.
(6) Kato, Y.; Ogawa, Y.; Imada, T.; Iwasaki, S.; Shimazaki, N.;
Kobayashi, T.; Komai, T. J . Antibiot. 1991, 44, 66.
(7) (a) Kurihara, A.; Shibayama, Y.; Mizota, A.; Yasuno, A.; Ikeda,
M.; Hisaoka, M. Biol. Pharm. Bull. 1996, 19, 252. (b) Tokui, T.; Maeda,
N.; Kuriowa, C.; Sasagawa, K.; Inoue, T.; Kawai, K.; Ikeda, T.; Komai,
T. Pharm. Res. 1995, 12, 370. (c) Takatori, T.; Koizumi, T.; Kokui, T.;
Mitsuhashi, Y.; Shiraishi, A.; Tsuruo, T. Cancer Chemother. Pharmocol.
1995, 35, 283.
(8) (a) Sullivan, A. S.; Prasad, V.; Roach, M. C.; Takahashi, M.;
Iwasaki, S.; Luduen˜a, R. F. Cancer Res. 1990, 50, 4277. (b) Takahashi,
M.; Iwasaki, S.; Kobayashi, H.; Okuda, S.; Murai, T.; Sato, Y. Biochim.
Biophys. Acta 1987, 926, 215. (c) Bai, R.; Pettit, G. R.; Hamel, E. J .
Biol. Chem. 1990, 265, 17141. (d) Bai, R.; Pettit, G. R.; Hamel, E.
Biochem. Pharmacol. 1990, 39, 1941. (e) Sawada, T.; Hashimoto, Y.;
Li, Y.; Kobayashi, H.; Iwasaki, S. Biochem. Biophys. Res. Commun.
1991, 178, 558.
† Formerly Christine S. Nylund.
(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.; Itai, A.; Kasuya, A.; Iitaka, Y.; Sato, Z. J . Antibiot. 1986, 39, 424.
(2) (a) Takahashi, M.; Iwasaki, S.; Kobayashi, H.; Okuda, S.; Murai,
T.; Sato, Y.; Haraguchi-Hiraoka, T.; Nagano, H. J . Antibiot. 1987, 40,
66. (b) 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.
(3) (a) Iwasaki, S.; Namikoshi, M.; Kobayashi, H.; Furukawa, J .;
Okuda, S. Chem. Pharm. Bull. 1986, 34, 1384. (b) Kiyoto, S.; Kawai,
Y.; Kawakita, T.; Kino, E.; Okuhara, M.; Uchida, I.; Tanaka, H.;
Hashimoto, M.; Terano, H.; Kohsaka, M.; Aoki, H.; Imanaka, H. J .
Antibiot. 1986, 39, 762.
(9) (a) Nakada, M.; Kobayashi, S.; Iwasaki, S.; Ohuo, M. Tetrahedron
Lett. 1993, 34, 1035. (b) Nakada, M.; Kobayashi, S.; Shibasaki, M.;
Iwasaki, S.; Ohno, M. Tetrahedron Lett. 1993, 34, 1039.
(4) Onozawa, C.; Shimanura, M.; Iwasaki, S.; Oikawa, T. J pn. J .
Cancer Res. 1997, 88, 1125 and references cited therein.
10.1021/jo020537q CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/28/2002
7750
J . Org. Chem. 2002, 67, 7750-7760

Total Synthesis of Rhizoxin D
SCHEME 1
sembly into the rhizoxin macrocycle have appeared from
several laboratories.11 We now present a detailed account
of our own efforts that have extended our earlier studies
directed toward the rhizoxins12 and have resulted in the
total synthesis of 2.
Our plan diagrammed in Scheme 1 envisioned the
synthesis and assembly of subunits A-D for the con-
struction of 2, the coalescence of C with a subunit
representing [A + B] being the most critical of the four
projected fusions. After some initially unproductive ef-
forts to establish the [AB] + C linkage, an aldol coupling
was selected for this process in the hope that it would be
possible to effect good stereocontrol at both C13 and C15
of 2 by this means. This strategy not only offers the
advantage that it isolates the stereocenters of 2 to
segments A and C where stereocontrol can be exercised
independently but also allows for the incorporation of
functional handles that facilitate subunit coupling via
Wittig (A + B) and Stille (C + D) reactions. Closure of
the 16-membered lactone was projected via an intramo-
lecular Wadsworth-Emmons condensation, a feature of
all five previous syntheses of 2.10
SCHEME 2
most demanding in terms of stereocontrol. The principal
stereochemical issue to be confronted in this fragment
is setting the cis relationship of alkyl chains at C5 and
C7 of the δ-lactone. This provided us with an opportunity
to examine a protocol in which a 6-exo radical cyclization
is programmed to set the C5 stereocenter of 2 in the
required (R)-configuration. The concept is expressed in
Scheme 2 where the product is a cyclic acetal bearing an
appendage CH2X attached to the carbon destined to
become C5 of 2. Rama Rao in his construction of the C1-
C9 subunit of rhizoxin also employed a radical cyclization
of the type shown in Scheme 2,11c,d but underlying
stereochemical questions implicit in this reaction such
as the import of (E)- vs (Z)-configurations of the double
bond were not addressed.
The initial task of setting the syn relationship between
C7 and C8 of 2 was first approached indirectly using the
method of Keck in which anti homoallylic alcohol 3,
prepared in high diastereomeric excess by reacting (R)-
3-benzyloxy-2-methylpropanal with allyltri-n-butylstan-
nane in the presence of stannic chloride, is subjected to
Mitsunobu inversion with p-nitrobenzoic acid to furnish
4 (Scheme 3).13 Attempts to obtain the syn stereoisomer
of 3 directly by reagent-controlled allylation of the same
aldehyde with either the allyl boronate derived from
Syn th esis of Su bu n its. Of the four rhizoxin segments
identified in Scheme 1, subunit A was considered the
(10) (a) Kende, A. S.; Blass, B. E.; Henry J . R. Tetrahedron Lett.
1995, 36, 4741. (b) Williams, D. R.; Werner, K. M.; Feng, B. Tetrahe-
dron Lett. 1997, 38, 6825. (c) Lafontaine, J . A.; Provencal, D. P.;
Gardelli, C.; Leahy, J . W. Tetrahedron Lett. 1999, 40, 4145. (d) Keck,
G. E.; Wager, C. A.; Wager, T. T.; Savin, K. A.; Covel, J . A.; McClaws,
M. D.; Krishnamurthy, D.; Cee, V. J . Angew. Chem., Int. Ed. 2001,
40, 231. (e) Mitchell, I. S.; Pattenden, G.; Stonehouse, J . P. Tetrahedron
Lett. 2002, 43, 493.
(11) (a) Boger, D. L.; Curran, T. T. J . Org. Chem. 1992, 57, 2235.
(b) Rama Rao, A. V.; Sharma, G. V. M.; Bhanu, M. N. Tetrahedron
Lett. 1992, 33, 3907. (c) Rama Rao, A. V.; Bhanu, M. N.; Sharma, G.
V. M. Tetrahedron Lett. 1993, 34, 701. (d) Rao, S. P.; Murthy, V. S.;
Rama Rao, A. V. Indian J . Chem. 1994, 33B, 820. (e) Burke, S. D.;
Hong. J .; Mongin, A. P. Tetrahedron Lett. 1998, 39, 2239. (f) Burke, S.
D.; Hong, J .; Lennox, J . R.; Mongin, A. P. J . Org. Chem. 1998, 63, 6952.
(12) (a) White, J . D.; Nylund, C. S.; Green, N. J . Tetrahedron Lett.
1997, 38, 7329. (b) White, J . D.; Holoboski, M. A.; Green, N. J .
Tetrahedron Lett. 1997, 38, 7333.
J . Org. Chem, Vol. 67, No. 22, 2002 7751

White et al.
SCHEME 3a
SCHEME 4a
a
Reaction conditions: (i) NaH, p-BrC6H4CH2Br, Bu4NI, THF,
0 °C f rt, 15 h, 88%; (ii) Ti(Oi-Pr)4, t-BuOOH, L-DIPT, CH2Cl2, 4
Å mol sieves, -35 °C, 20 h, 72%; (iii) MeMgBr, CuI (10 mol %),
Et2O-THF, -40 °C, then NaIO4, 62%; (iv) TBSCl, Et3N, DMAP
(cat), CH2Cl2, 89%; (v) Na, NH3, t-BuOH-THF, -70 °C, 89%; (vi)
MsCl, collidine, 0 °C, then K2CO3, MeOH, 93%; (vii) CH2dCHMgBr,
CuI (5 mol %), Et2O-THF, -78 °C f -20 °C, 90%.
a
Reaction conditions: (i) Bu3SnCH2CHdCH2, SnCl4, CH2Cl2,
-90 °C, 92%; (ii) Ph3P, EtO2CNdNCO2Et, p-O2NC6H4CO2H, THF,
65%; (iii) BCl3, tol, -78 °C f 0 °C, 85%; (iv) TBSCl, imidazole,
DMF, 83%; (v) NaOH, MeOH, 0 °C f rt, 86%.
SCHEME 5a
(S,S)-tartrate14 or a chiral allylborane15 resulted in lower
diastereoselectivity and/or diminished yield. The benzyl
ether of 4 was removed using boron trichloride,16 but the
expected product 5 was accompanied by ca. 10% of the
secondary alcohol 6 in which migration of the p-nitroben-
zoate had occurred. Alcohol 5 was silylated, and the
resulting ether 7 was saponified to yield syn homoallyl
alcohol 8.
The tedious chromatographic separation required to
remove the unwanted p-nitrobenzoate 6 from 5 prompted
a search for an improved synthesis of 8, and the epoxide
9, obtained enantiopure after a single crystallization
following Sharpless asymmetric epoxidation of the mono
p-bromobenzyl ether of cis-buten-1,4-diol,17 provided the
starting point for a new approach as shown in Scheme
4. Exposure of 9 to methylmagnesium bromide and
cuprous iodide afforded a 3:1 mixture of 1,3- and 1,2-diols,
from which the undesired 1,2-diol was easily removed by
oxidative cleavage with sodium periodate. The crystalline
syn diol 10 was selectively protected as its primary silyl
ether 11, and the p-bromobenzyl ether was removed with
sodium-ammonia to yield 12. Conversion of 12 to its
primary mesylate followed by exposure to base produced
epoxide 13, which underwent opening with vinylmagne-
sium bromide in the presence of cuprous iodide to furnish
8.
Alcohol 8 was advanced to iodoacetal 14 with the initial
goal of effecting exo radical cyclization followed by
entrapment of the resulting primary radical with tert-
butylisocyanide (Scheme 5).18 In the event, exposure of
14, prepared from 8 with ethyl vinyl ether and N-
iodosuccinimide, to tri-n-butylstannane, tert-butylisocy-
a
Reaction conditions: (i) NIS, CH2dCHOEt, CH2Cl2, -20
°C f 0 °C, 92%; (ii) OsO4 (cat), NaIO4, THF-H2O (1:1), 97%; (iii)
Ph3PCHCN, tol, 70 °C, 77% of 16; (iv) Ph3PCHCO2Me, tol, 60 °C,
50% of 20; (v) (CF3CH2O) 2P(O)CH2CO2Me, (22) KH, 18-crown-6,
THF, -78 °C, 65% of 21; (vi) n-Bu3SnH, AIBN, tol, 80 °C; (vii)
PhSH, MgBr2‚OEt2 (see Table 1).
(13) Keck, G. E.; Park, M.; Krishnamurthy, D. J . Org. Chem. 1993,
58, 3787.
(14) Roush, W. R.; Hoong, L. K.; Palmer, M. A. J .; Park, J . C. J .
Org. Chem. 1990, 55, 4109.
(15) Brown, H. C.; J adhav, P. K. J . Am. Chem. Soc. 1983, 105, 2092.
(16) Panek, J . S.; Beresis, R. T.; Celatka, C. A. J . Org. Chem. 1996,
61, 6494.
(17) Chong, J . M.; Wong, S. J . Org. Chem. 1987, 52, 2596.
(18) Stork, G.; Sher, P. M. J . Am. Chem. Soc. 1983, 105, 6765.
anide, and AIBN, produced only a low yield of an
inseparable mixture of three stereoisomeric tetrahydro-
pyrans in a ratio of 6:3:1. A complicating feature of this
7752 J . Org. Chem., Vol. 67, No. 22, 2002

Total Synthesis of Rhizoxin D
SCHEME 6a
TABLE 1. Ra d ica l Cycliza tion of Iod oa ceta ls 16, 20, a n d
21 a n d Su bsequ en t Keta liza tion w ith Th iop h en ol
compound
products
yield (%)
ratio
16
20
21
18 + 19
24 + 25
24 + 25
80
92
93
1.7:1
1:1
15:1
F IGURE 1. Three modes of radical cyclization of 21: si-face
attack (A) and re-face attack (B and C). Only the major
pseudoaxial anomer is shown.
reaction was reduction of both the initial radical species
from 14 and that produced after cyclization.
Precedent suggested that a more favorable entry to the
tetrahydropyran nucleus of subunit A via a radical
cyclization pathway would be found if an electron-
withdrawing group were attached to the alkene terminus
of 14.19 To this end, the vinyl group of 14 was cleaved
oxidatively to aldehyde 15, and the latter was subjected
to a Wittig reaction with cyanotriphenylphosphorane to
give (E)-R,â-unsaturated nitrile 16. However, although
16 afforded an improved yield of cyclization product 17,
this material again proved to be an inseparable mixture
of stereoisomers at both the anomeric carbon and the new
stereocenter. The mixture was simplified after treatment
of 17 with thiophenol and magnesium dibromide due to
the formation of a single (presumably axial) phenylthio
anomer, and this result permitted assessment of the
stereoisomeric ratio of 18:19 as 1.7:1 by 13C NMR.
Assignment of configuration to the major isomer 18 was
made on the basis of a 5.6% NOE between HA and HB in
this compound; no NOE was observed in 19.
a
Reaction conditions: (i) NaBH4, CaCl2, EtOH-THF, 0 °C, 92%;
(ii) t-BuPh2SiCl, Et3N, DMAP, 76%; (iii) AcOH, THF, H2O, 93%;
(iv) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C, 71%; (v) (E)-
Ph3PCHCHdC(Me)CO2Me (30), THF, ∆, 77%; (vi) DIBALH, Et2O,
-78 °C, 92%; (vii) MnO2, Et2O, 90%; (viii) TMSCN, ZnI2, 92%.
disfavored by steric compression of pseudoaxial substit-
uents (B) or a stereoelectronically poor alignment of the
ester in an endo-like chair transition state (C). A similar
steric argument cannot be made for 16 and 20 where the
(E)-configuration of the double bond results in only a
small difference in energy between re- and si-modes of
radical attack.
Our remaining task in the construction of subunit A
was the straightforward transformation of the protected
C9 alcohol to an aldehyde so that segment B could be
attached to produce the required (E,E)-diene moiety. For
this purpose, ester 24 was first reduced with calcium
borohydride to primary alcohol 26, which was protected
as its tert-butyldiphenylsilyl ether 27 (Scheme 6). After
selective unmasking of the primary tert-butyldimethyl-
silyl ether, oxidation of 28 gave aldehyde 29. Wittig
reaction of 29 with phosphorane 3021 afforded a good yield
of the (E,E)-diene 31, which was advanced via alcohol
32 to aldehyde 33.
Our initial plan was to employ the enolate of cyano-
hydrin derivative 34, prepared in good yield from alde-
hyde 33 with trimethylsilyl cyanide in the presence of
zinc iodide,22 as a nucleophile for reaction with an
alkylating agent representing C14-C19 of 2. Attention
was therefore turned toward an appropriate coupling
partner for 34 with the goal of preparing a subunit that
contained the three contiguous stereogenic centers at
C15, C16, and C17. For this we chose the known (4R,5R)-
lactone 3523 as our point of departure (Scheme 7). Sub-
strate-directed R-hydroxylation of 35 with racemic 2-phen-
ylsulfonyl-3-phenyloxaziridine gave both 36 and the
epimeric alcohol, but asymmetric hydroxylation with (-)-
For comparison with the radical cyclization of 16,
aldehyde 15 was converted to both (E)- and (Z)-R,â-
unsaturated methyl esters 20 and 21, the latter obtained
using the Gennari-Still phosphonate 22 as shown in
Scheme 5.20 Not surprisingly, radical cyclization of (E)-
ester 20 produced a stereoisomeric mixture of 23 little
different from the ratio observed with nitrile 16 (see
Table 1), a result that conflicts with that reported by
Rama Rao,11d who obtained a single δ-lactone after
hydrolysis of the acetal of 23 and oxidation. By contrast,
cyclization of (Z)-ester 21 furnished 24 and 25 after ketal
exchange of 23 with thiophenol as a 15:1 mixture in good
yield, the major stereoisomer again corresponding closely
1
with 18 according to H NMR. An explanation for the
higher stereoselectivity in the cyclization of (Z)-ester 21
can be found in a preference by the intermediate radical
for conformation A in which the branched chain at C5 is
pseudoequatorial and the si-face of the double bond is
exposed to attack (see Figure 1). Alternative conforma-
tions such as B or C required for re-face attack would be
(21) Buchta, E.; Andree, F. Chem. Ber. 1960, 93, 1349.
(22) Evans, D. A.; Truesdale, L. K.; Carroll, G. L. J . Chem. Soc.,
Chem. Commun. 1973, 55.
(23) Mitome, H.; Miyaoka, H.; Nakano, M.; Yamada, Y. Tetrahedron
Lett. 1995, 36, 8231.
(19) (a) Beckwith, A. L. J .; Roberts, D. H. J . Am. Chem. Soc. 1986,
108, 5893. (b) Park, S.; Chung, S.; Newcomb, M. J . Am. Chem. Soc.
1986, 108, 240.
(20) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
J . Org. Chem, Vol. 67, No. 22, 2002 7753

White et al.
SCHEME 7a
SCHEME 8a
a
Reaction conditions: (i) MeOH, CSA, 77%; (ii) MsCl, collidine,
CH2Cl2, 88%; (iii) K2CO3, MeOH, 90%; (iv) 2,4,6-Me3C6H2SO2Cl,
DMAP, CH2Cl2, 84%; (v) TBSOTf, 2,6-lutidine, CH2Cl2, 91%.
subsequent methylation of the intermediate (E)-stan-
nylvinylcopper species28 afforded 45 as the sole isomer
in good yield. Iodination of this substance then gave 43
free of its (Z)-isomer. Acidic methanolysis removed the
acetonide from 43, and diol 46 was converted to its
primary mesylate 47 and then to epoxide 48 (Scheme 8).
Unfortunately, 48 proved to be inert toward the enolate
of 34, and Lewis acid catalysts that could have facilitated
opening of the epoxide led only to decomposition of 34.
The primary mesitylenesulfonate 49, prepared from 46
and protected as silyl ether 50, was also inert toward 34,
leading us to conclude that the carbanion from 34 was
too highly delocalized to serve as a nucleophile for
alkylation.
These disappointing results prompted us to consider
an alternative scheme for coupling the [A + B] subunit
with C in which the polarity of the carbon-carbon bond-
forming process was reversed. Specifically, aldehyde 33
would now serve as an electrophile in an aldol coupling
with a suitable methyl ketone enolate to forge the C13-
C14 bond and generate the desired (S)-configuration at
C13. In this revised plan, there remained the issue of
the configuration at C15 since this new mode of coupling
would allow inclusion of only two of three stereocenters
in the C15-C17 triad. Our hope was that the (S)-
stereocenter produced at C13 could induce the correct (S)-
configuration at C15, and this indeed proved to be the
case.
a
Reaction conditions: (i) NaHMDS, (1R)-(-)-(10-camphorsul-
fonyl)oxaziridine, THF, 68%; (ii) CH2N2, BF3‚OEt2, Et2O, 90%; (iii)
LiAlH4, THF, then 10% HCl; (iv) Me2CO, CuSO4, p-TsOH, 84%
from 37; (v) Dess-Martin periodinane, CH2Cl2; (vi) MeMgBr, Et2O,
-78 °C, 83%; (vii) Dess-Martin periodinane, CH2Cl2, 91%; (viii)
(MeO)2 P(O)CHN2, t-BuOK, THF, -78 °C f rt, 87% from 39; (ix)
CrCl2, CHI3, THF, 45%; (x) (Bu3Sn)2CuCNLi2, DMPU, MeI 79%;
(xi) I2, Et2O, 67%.
camphorsulfonyloxaziridine resulted in 36 with excellent
stereoselectivity.24 This alcohol was converted to its
methyl ether 37 with diazomethane in the presence of
boron trifluoride etherate,25 and the lactone was then
reduced to triol 38 with lithium aluminum hydride.
Protection of the 1,2-diol moiety as its acetonide 39 was
followed by oxidation to aldehyde 40. Two routes from
40 were examined for advancing this aldehyde toward
an (E)-trisubstituted iodoalkene suitable for eventual
linkage to segment D. The first approach employed a
Grignard reaction of 40 with methylmagnesium bromide
followed by oxidation of the resultant secondary alcohol
41 to give methyl ketone 42. The latter was subjected to
a Takai reaction26 with chromous chloride and iodoform,
but this gave a 2:1 mixture of (E)-iodoalkene 43 and its
(Z) isomer from which pure 43 could be obtained in only
modest yield. In an alternative approach to 43, a route
via alkyne 44, prepared by treatment of 40 with Ohira’s
reagent,27 was explored. Stannylcupration of 44 and
Subunit C now became a straightforward target for
synthesis, which commenced from (E)-aldehyde 51 pre-
pared by zirconation-methylation-iodination of pro-
pargyl alcohol followed by oxidation of the allylic alcohol29
with manganese dioxide (Scheme 9). An asymmetric aldol
coupling of 51 with the di-n-butylboron enolate of (R)-4-
benzyl-3-propionyloxazolidin-2-one furnished syn product
52 in high yield,30 and this was converted directly to
(27) Gilbert, J . C.; Weerasooriya, U. J . Org. Chem. 1979, 44, 4997.
(28) Harris, L.; J arowicki, K.; Kocienski, P.; Bell, R. Synlett. 1996,
903.
(24) Davis, F. A.; Chen, B. Chem. Rev. 1992, 92, 919.
(25) Neeman, M.; Hashimoto, Y. J . Am. Chem. Soc. 1962, 84, 2972.
(26) Takai, K.; Nitta, K.; Utimoto, K. J . Am. Chem. Soc. 1986, 108,
7408.
(29) Negishi, E.; Van Horn, D. E.; King, A. O.; Okukado, N. Synthesis
1979, 501.
(30) Evans, D. A.; Rieger, D. L.; J ones, T. K.; Kaldor, S. W. J . Org.
Chem. 1990, 55, 6260.
7754 J . Org. Chem., Vol. 67, No. 22, 2002

Total Synthesis of Rhizoxin D
SCHEME 9a
SCHEME 10a
a
Reaction conditions: (i) Cp2ZrCl2, Me3Al, then I2, Et2O, -30
°C, 60%; (ii) MnO2, Et2O, 0 °C, 89%; (iii) (R)-4-benzyl-3-propion-
yloxazolidin-2-one, n-Bu2BOTf, Et3N, CH2Cl2, -78 °C, 77%; (iv)
MeNH(OMe)‚HCl, Me3Al, CH2Cl2, 0 °C, 85%; (v) MeOTf, 2,6-di-
tert-butyl-4-methylpyridine, tol, 70 °C, 91%; (vi) MeMgBr, THF,
-20 °C f 0 °C, 91%.
Weinreb amide 53.31 Exposure of 53 to methyl triflate in
base at elevated temperature gave methyl ether 54 in
near quantitative yield, and a Grignard reaction of 54
with methylmagnesium bromide produced the desired
ketone 55.
a
Reaction conditions: (i) 55, (+)-DlPCl, Et3N, Et2O, 0 °C, 3 h,
Before investing 33 in an aldol reaction with 55, a
model study with tiglaldehyde and the enolate of methyl
ketone 55 was carried out to ascertain conditions that
would afford optimal stereoinduction of the resulting
â-hydroxy ketone. Modest stereoselectivity (3:1 in favor
of the (S)-alcohol) was observed when the di-n-butylboron
enolate of 55 was used with tiglaldehyde, but this
improved to 8:1 when the enolate of 55 prepared with
(+)-chlorodiisopinocampheylborane (DIP-Cl)32 was em-
ployed (Scheme 10). The enolate of 55 prepared with (-)-
DIP-Cl gave a 1:1 mixture of stereoisomeric hydroxy
ketones with tiglaldehyde, confirming that the enolate
from (+)-DIP-Cl represents the “matched” case. Opti-
mization of the reaction of the (+)-DIP enolate of 55 with
aldehyde 33 necessitated careful adjustment of reaction
conditions, and it was found that when the reaction was
run at -20 °C for 6-10 h, the yield of 56 was consistently
in the range 60-70%. The ratio of 56 to its (13R)-epimer
was typically 17-20:1. The major hydroxy ketone was
easily separated from its minor diastereomer by flash
chromatography, and the configuration of the C13 ste-
reocenter in 56 was ascertained by esterification of this
alcohol with (R)- and (S)-O-methylmandelic acids. The
Mosher model as applied to mandelates by Trost33
predicts that the C11 proton of 56 will be shielded by
then 33, -20 °C, 6 h, 65%; (ii) Me4NBH(OAc)3, AcOH-MeCN-
THF, -25 °C f -10 °C, 74%; (iii) TIPSOTf (1 equiv), 2,6-lutidine,
CH2Cl2, -8 °C, 92%; (iv) (EtO)2P(O)CH2COCl, pyr-CH2Cl2, rt, 36
h, 78%.
1
the phenyl ring current in the H NMR spectrum of the
(S)-O-methylmandelate relative to the corresponding (R)-
ester, and this was indeed the case (∆δ 0.25 ppm).
Reduction of ketone 56 with tetramethylammonium
acetoxyborohydride required extensive experimentation
in order to achieve good anti selectivity for the desired
1,3-diol, and when this reduction was conducted in a
mixture of acetic acid, acetonitrile, and THF at -20 °C,
57 was obtained in excellent yield as shown in Scheme
10. The more sterically accessible hydroxyl group at C13
was selectively protected as its triisopropylsilyl ether 58,
and the remaining C15 alcohol was esterified with diethyl
phosphonoacetyl chloride34 to furnish 59.
An issue that confronted us at this stage was the choice
of a sequence that would modify both the appendage at
C5 of the tetrahydropyran moiety of 58 and the thiophen-
yl substituent. To advance 59 toward a substrate suitable
for the intramolecular Wadsworth-Emmons condensa-
tion projected for the macrolactonization step (Scheme
1), oxidation of the protected alcohol at C3 to the aldehyde
level must take place. Because the sulfur atom of 59 could
potentially interfere in that oxidation, it was decided to
first transmute the phenylthioacetal moiety to the δ-lac-
(31) Evans, D. A.; Bender, S. L.; Morris, J . J . Am. Chem. Soc. 1988,
110, 2506.
(32) Paterson, I.; Goodman, J . M.; Lister, M. A.; Schumann, R. C.;
McClure, C. K.; Norcross, R. D. Tetrahedron 1990, 46, 4663.
(33) Trost, B. M.; Curran, D. P. Tetrahedron Lett. 1981, 22, 4929.
(34) Cooke, M. P., J r.; Biciunas, K. P. Synthesis 1981, 283.
J . Org. Chem, Vol. 67, No. 22, 2002 7755

White et al.
SCHEME 11a
SCHEME 12a
a
Reaction conditions: (i) Ph3PdC(Me3)CHO (65), C6H6, ∆, 93%;
(ii) CrCl2, CHI3, THF, 0 °C, 71%; (iii) (Me3Sn)2, (Ph3P)2PdCl2, THF,
50 °C, 96%.
SCHEME 13a
a
Reaction conditions: (i) 68, PdCl2 (MeCN)2, DMF, 84%; (ii)
HF‚pyr, THF, 0 °C f rt, 59%.
plastic vessel, since adventitious hydrofluoric acid formed
from contact of TASF with glass contributed to cleavage
of both silyl ethers of 60. Dess-Martin oxidation of 61
gave aldehyde 62, our putative macrolactonization pre-
cursor, and a variety of reaction conditions designed to
effect intramolecular Wadsworth-Emmons condensation
of 62 were investigated for this purpose. The most
efficient of these employed Hunig’s base and a large
excess of lithium chloride in acetonitrile.37 This protocol
produced R,â-unsaturated macrolactone 63 as a single
(E)-isomer in high yield, whereas other conditions (par-
ticularly the use of DBU as the base) resulted in a
mixture of (E)- and (Z)-R,â-unsaturated lactones.
The final segment D (Scheme 1) required to complete
the synthesis of 2 was prepared from 2-methyloxazole-
4-carboxaldehyde (64) (Scheme 12).38 A Wittig reaction
of 64 with phosphorane 6539 gave (E)-Râ-unsaturated
aldehyde 66, which was subjected to a Takai reaction26
with chromium(II) chloride and iodoform to provide (E,E)-
iododiene 67 in good yield. Halogen-metal exchange with
hexamethylditin in the presence of bis(triphenylphos-
phine)palladium dichloride40 furnished stannane 68 in
virtually quantitative yield (Scheme 12). Stille coupling41
of this stannane with iodolactone 63 in the presence of
palladium(II) chloride bis(acetonitrile), as shown in
Scheme 13, gave triisopropylsilylrhizoxin D (69), whose
1H NMR spectrum exactly matched that of the same
substance previously prepared by Leahy.10c Final depro-
a
Reaction conditions: (i) AgNO3, 2,6-lutidine, THF-H2O (5:
1), rt, 15 min, then TPAP (cat), NMO, 4 Å mol sieves, CH2Cl2,
71%; (ii) TASF, DMF, 0 °C, 10 h, 70%; (iii) Dess-Martin periodi-
nane, CH2Cl2, 100%; (iv) (i-Pr)2NEt, LiCl, MeCN, 57%.
tone present in 2. This was accomplished very efficiently
by silver nitrate-catalyzed hydrolysis of 59 to a mixture
(1.5:1) of stereoisomeric hemiacetals, which yielded a
single δ-lactone 60 upon oxidation with the Ley reagent
(Scheme 11).35
Selective unmasking of the tert-butyldiphenylsilyl ether
of 60 in the presence of the triisopropylsilyl ether at C13
took advantage of the increased propensity of a silicon
atom bearing aryl groups to undergo nucleophilic attack
in comparison to those bearing only alkyl substituents.
This distinction permitted selective deprotection of 60
with the mild fluoride source tris(dimethylamino)sulfur
(trimethylsilyl)difluoride (TASF)36 and furnished alcohol
61 in good yield. An important prerequisite for success
in this reaction was that it should be conducted in a
(37) Blanchette, M. A.; Choy, W.; Davis, J . T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,
2183.
(38) Boger, D. L.; Curran, T. T. J . Org. Chem. 1992, 57, 2235.
(39) Schlessinger, R. H.; Poss, M. A.; Richardson, S.; Lin, P.
Tetrahedron Lett. 1985, 26, 2391.
(35) Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
(36) Scheidt, K. A.; Chen, H.; Follows, B. C.; Chemler, S. R.; Coffey,
D. S.; Roush, W. R. J . Org. Chem. 1998, 63, 6436.
(40) Azizian, H.; Eaborn, C. E.; Pidcock, A. J . Organometall. Chem.
1981, 215, 49.
(41) Farina, V.; Krishnamurthy, V.; Scott, W. J . Org. React. 1997,
50, 1.
7756 J . Org. Chem., Vol. 67, No. 22, 2002

Total Synthesis of Rhizoxin D
termperature. The mixture was extracted with Et2O (3 × 200
mL), and the combined extract was washed with brine and
dried (Na2SO4). Removal of the solvent in vacuo and chroma-
tography of the residue (hexanes to 5% EtOAc/hexane) gave
2.56 g (65%) of 21: IR (film) 2951, 1720, 1642, 1435, 1251,
tection of this material with HF-pyridine complex af-
forded rhizoxin D (2) with 1H and 13C NMR spectra
essentially identical to those of 2 synthesized by Williams
(Scheme 13)10b and with a specific rotation in good
agreement with that recorded in the literature.
In summary, a modular synthesis of 2 has been
accomplished in which the longest linear sequence is 17
steps. An asymmetric aldol reaction was used as the key
reaction to couple two principal segments and led to a
synthesis of rhizoxin D that is 27 steps from 9. The
modular design of this route affords opportunities to
incorporate additional structural features into the rhizox-
in scaffold, including the two epoxide functions that
characterize 1.
1
1175, 842, 778 cm-1; H NMR (300 MHz, CDCl3, two diaster-
omers) δ -0.02-0.05 (m, 6H), 0.08-0.98 (m, 12H), 1.25-1.35
(m, 3H), 1.65-1.75 (m, 1H), 2.85-3.02 (m, 2H), 3.10-3.19 (m,
2H), 3.39-3.48 (m, 1H), 3.51-3.65 (m, 3H), 3.67-3.68 (s, 3H),
3.71-3.79 (m, 1H), 4.61-4.70 (m, 1H), 5.82-5.89 (m, 1H),
6.30-6.41 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 5.4, 5.5, 5.9,
6.4, 10.6, 11.5, 15.1, 18.1, 25.8, 25.8, 30.8, 32.0, 39.4, 39.5, 50.9,
51.0, 62.1, 62.5, 64.4, 64.4, 76.0, 76.3, 100.3, 102.0, 120.1, 120.8,
146.1, 146.9, 166.4, 166.5; HRMS (CI) m/z found 485.1218,
calcd for C18H34IO5Si m/z 485.1220.
Tetr a h yd r op yr a n 23. To a deoxygenated solution of 21
(1.29 g, 2.58 mmol) and AIBN (42 mg, 0.26 mol) in toluene
(130 mL) at 80 °C was added tri-n-butylstannane (1.04 mL,
3.87 mmol) in one portion. The mixture was stirred for 2 h at
80 °C, and the toluene was removed by distillation. The residue
was taken up in CH2Cl2 (50 mL), and the solution was washed
with 10% aqueous sodium thiosulfate (20 mL) and brine and
dried (MgSO4). Removal of the solvent in vacuo left 830 mg
(86%) of 23 as a mixture of inseparable anomers: IR (film)
Exp er im en ta l Section
Gen er a l. Solvents were dried by distillation immediately
prior to use. Tetrahydrofuran (THF) and diethyl ether were
distilled from sodium and benzophenone under an argon
atmosphere. Triethylamine, diisopropylethylamine, toluene,
benzene, and dichloromethane were distilled from calcium
hydride under argon. Acetone was distilled from calcium
sulfate. Methanol and ethanol were distilled from magnesium
turnings. Analytical thin-layer chromatography (TLC) was
conducted using 1.5 × 5.0 cm precoated aluminum TLC plates
(0.2 mm layer thickness of silica gel 60 F-254). Flash chroma-
tography was carried out using silica gel 60 (230-400 mesh
ASTM). Melting points are uncorrected. Infrared (IR) spectra
were recorded with a FT-IR spectrometer. 1H and 13C NMR
spectra were measured on either a 300 MHz or a 400 MHz
spectrometer. Low resolution mass spectra (MS) were mea-
sured at an ionization potential of 70 eV. High-resolution mass
spectra (HRMS) were recorded using either CI or FAB.
Iod o Aceta l 14. To a stirred suspension of 8 (3.32 g, 0.013
mol) and N-iodosuccinimide (3.40 g, 0.015 mol) in dry CH2Cl2
(60 mL) at -23 °C was added freshly distilled ethyl vinyl ether
(2.75 mL, 0.024 mmol) over a period of 10 min. The mixture
was stirred at -23 °C for 4 h and at 0 °C for 11 h. A saturated
solution of aqueous NaHCO3 (55 mL) was added, and the
aqueous phase was extracted with CH2Cl2 (3 × 45 mL). The
combined extract was washed with 10% aqueous sodium
thiosulfate and dried (MgSO4). Removal of the solvent in vacuo
and chromatography of the residue gave 5.30 g (92%) of 14
(mixture of two diastereomers) as a colorless oil: 1H NMR (300
MHz, CDCl3) δ 0.02 (m, 6H), 0.85 (m, 12H), 1.22 (dt, J ) 7, 2
Hz, 3H), 1.85-1.6 (m, 1H), 2.5-2.2 (m, 2H), 3.27-3.18 (m, 2H),
3.77-3.48 (m, 5H), 4.67-4.61 (m, 1H), 5.11-5.02 (m, 2H), 5.78
(m, 1H).
Ald eh yd e 15. To solution of 14 (4.10 g, 9.25 mmol) in THF
(95 mL) and H2O (80 mL) was added a solution of OsO4 (125
mg) in H2O (10 mL), followed by sodium periodate (1.97 g, 9.25
mmol). After 1 h, an additional quantity of sodium periodate
(5.91 g, 27.8 mmol) was added, and the mixture was stirred
for 13 h. The reaction was quenched with saturated aqueous
sodium thiosulfate (50 mL), and the layers were separated.
The aqueous layer was extracted with 25% hexanes in Et2O
(3 × 200 mL), and the combined extract was dried (Na2SO4)
and filtered through a plug of silica. The filtrate was concen-
trated in vacuo to yield 4.01 g (97%) of 15, which was used
immediately in the next reaction.
R,â-Un sa tu r a ted Ester 21. To a solution of methyl bis-
(2,2,2-trifluoroethoxy)phosphonyl acetate (1.88 mL, 8.90 mmol)
and 18-crown-6 (1.07 g, 4.05 mmol) in THF (200 mL) at -78
°C was added KHMDS (0.5 M in toluene, 17.8 mL, 8.90 mmol)
over a period of 10 min. The yellow solution was stirred for 30
min, and a solution of 15 prepared above (3.60 g, 8.11 mmol)
in THF (1.0 mL) was added over a period of 10 min. After 45
min, the orange solution was diluted with saturated aqueous
NH4Cl, and the mixture was allowed to warm slowly to room
2955, 1733, 1475, 1260, 1056, 837, 776 cm-1 1H NMR (300
;
MHz, CDCl3, two diasteromers) δ 0.00 (s, 2H), 0.01 (s, 4H),
0.81-0.96 (m, 12H), 0.97-1.13 (m, 1H), 1.18 (t, J ) 7 Hz, 2H),
1.20 (t, J ) 7 Hz, 1H), 1.24-1.41 (m, 2H), 1.45-1.87 (m, 4H),
2.00-2.27 (m, 2H), 2.27-2.49 (m, 0.8H), 2.49-2.63 (m, 0.2H),
3.25-3.60 (m, 3.5H), 3.62-3.67 (m, 3H), 3.70 (dd, J ) 6, 4H,
0.6H), 3.80 (ddd, J ) 12, 5, 2 Hz, 0.5H), 3.84-3.98 (m, 0.5H),
4.38 (dd, J ) 10, 2 Hz, 0.3H), 4.84 (d, J ) 3 Hz, 0.7H); 13C
NMR (75 MHz, CDCl3) δ -5.5, 11.8, 11.9, 15.0, 15.2, 18.2, 25.8,
27.2, 31.4, 34.5, 34.8, 36.3, 37.6, 40.4, 40.5, 40.9, 41.4, 51.3,
51.4, 61.8, 64.0, 64.9, 64.9, 68.2, 74.8, 96.4, 101.3, 172.6; MS
(EI) 373 (M - I), 329, 271, 243, 157; HRMS (EI) m/z found
373.2411, calcd for C19H37O5Si m/z 373.2410.
Th iop h en yl Aceta l 24. To a solution of 23 (7:1 mixture of
stereoisomers, 53 mg, 0.14 mmol) and MgBr2‚OEt2 (36 mg, 0.14
mmol) in Et2O (1.5 mL) at room temperature under argon was
added thiophenol (17 µL, 0.16 mmol) via syringe. After 2 h,
the mixture was diluted with Et2O and washed with saturated
NaHCO3. The organic solution was dried (MgSO4), and the
1
solvent was removed in vacuo to leave an oily residue that H
NMR showed to be a 15:1 mixture of stereoisomers. This was
purified by chromatography (5% EtOAc/hexanes) to give 54
mg (87%) of pure 24 as a colorless oil: [R]D23
-19.9 (c 1.00,
CHCl3); IR (film) 3059, 2921, 1739, 1585, 1469, 1431, 1161,
1
837 cm-1; H NMR (400 MHz, CDCl3) δ 0.00 (s, 6H), 0.87 (s,
12H), 0.87-0.9 (m, 1H), 1.10-1.30 (m, 2H), 1.60-1.72 (m, 3H),
2.02-2.08 (m, 1H), 2.23 (d, J ) 4 Hz, 1H), 2.25 (d, J ) 2 Hz,
1H), 2.31-2.42 (m, 1H), 3.38 (dd, J ) 10, 7 Hz, 1H), 3.49 (dd,
J ) 10, 6 Hz, 1H), 3.71 (s, 1H), 4.24 (ddd, J ) 10, 5, 2 Hz, 1H),
5.69 (d, J ) 5 Hz, 1H), 7.20-7.30 (m, 3H), 7.40-7.50 (m, 2H);
13C NMR (75 MHz, CDCl3) δ -5.5, 11.9, 18.2, 25.9, 28.6, 35.2,
37.3, 40.5, 41.3, 51.6, 65.3, 69.9, 84.8, 126.5, 128.7, 130.8, 135.9,
172.4. There was also obtained 4 mg (6%) of 25.
Dien e Ester 31. To a solution of 29 (60 mg, 0.113 mmol)
in THF (6 mL) was added 30 (126 mg, 0.336 mmol), and the
yellow solution was heated at reflux for 16 h. After cooling to
room temperature, the mixture was filtered through a plug of
silica, and the filtrate was concentrated to leave an orange
oil. This was purified by chromatography (hexanes to 5%
EtOAc/hexanes) to give 50 mg (77%) of 31 as an off-white
semisolid: IR (film) 2954, 1708, 1637, 1428, 1250, 1100 cm-1
;
1H NMR (300 MHz, CDCl3) δ 0.98 (d, J ) 7 Hz, 3H), 1.01-
1.10 (s, 9H), 1.45-1.5 (m, 2H), 1.57-1.69 (m, 3H), 1.88-1.96
(m, 3H), 1.95-2.10 (m, 2H), 2.31 (quint, J ) 7 Hz, 1H), 3.70
(t, J ) 8 Hz, 2H), 3.77 (s, 3H), 4.06 (ddd, J ) 11, 6, 2 Hz, 1H),
5.95 (dd, J ) 15, 8 Hz, 1H), 6.33 (dd, J ) 14, 11 Hz, 1H), 7.14
(d, J ) 11 Hz, 1H), 7.17-7.80 (m, 15H); 13C NMR δ 12.7, 15.7,
19.2, 26.9, 28.0, 35.8, 37.6, 39.4, 42.4, 51.8, 61.0, 73.3, 85.5,
J . Org. Chem, Vol. 67, No. 22, 2002 7757

White et al.
125.3, 125.6, 126.5, 127.7, 128.8, 129.6, 130.5, 130.9, 133.9,
135.6, 136.0, 138.9, 145.0, 169.0; MS (Cl) m/z 627, 571, 519,
197, 183, 135; HRMS (CI) m/z found 627.2962 (M - 1), calcd
for C38H47O4SSi m/z 627.2964.
(3R,4R)-(E)-3,5-Dim eth yl-6-iod oh ex-5-en -2-on e (55). A
solution of methylmagnesium bromide in Et2O (3.0 M, 0.60
mL, 1.8 mmol) was diluted with THF (1.5 mL) and cooled to
-20 °C, and a solution of 54 (165 mg, 0.505 mmol) in THF (5
mL) was added dropwise. The mixture was allowed to warm
slowly to 0 °C, and after 1 h the reaction was quenched with
saturated NH4Cl. The mixture was diluted with Et2O (20 mL);
the layers were separated, and the aqueous layer was ex-
tracted with Et2O (2 × 10 mL). The combined extract was
washed with aqueous citric acid and brine and dried (Na2SO4).
The solvent was removed in vacuo to give 130 mg (91%) of
pure 55 as a colorless oil: [R]2D3 +32.2 (c 0.36, CHCl3); IR
(film) 3052, 2976, 2875, 1701, 1355, 1258, 1092 cm-1; 1H NMR
(300 MHz, CDCl3) δ 1.15 (d, J ) 7 Hz, 3H), 1.75 (s, 3H), 2.12
(s, 3H), 2.73 (m, 1H), 3.21 (s, 3H), 3.86 (d, J ) 8 Hz, 1H), 6.22
(s, 1H); 13C NMR (100 MHz, CDCl3) δ 12.1, 20.0, 50.1, 57.0,
80.3, 86.3, 106.0, 145.3, 210.0; MS (CI) m/z 283 (M + 1), 211,
155; HRMS (CI) m/z found 283.0173, calcd for C9H16IO2 m/z
283.0195.
3-[(E)-(2R,3R)-2,4-Dim et h yl-5-iod o-3-h yd r oxyp en t -4-
en oyl]-(R)-4-ben zyloxa zolid in -2-on e (52). To a solution of
(R)-4-benzyl-3-propionyloxazolidin-2-one (3.03 g, 13.0 mmol)
in CH2Cl2 (25 mL) at 0 °C was added dropwise di-n-butylboron
triflate (15 mL, 15 mmol) during 10 min. To this solution was
slowly added Et3N (2.35 mL, 17.0 mmol), and the resulting
yellow mixture was cooled to -78 °C. A solution of 51 (3.80 g,
19.6 mmol) in CH2Cl2 (30 mL) was added, and the mixture
was stirred for 30 min at -78 °C and for 1 h at 0 °C. The
reaction was quenched by the addition of pH 7 phosphate
buffer (15 mL) followed by MeOH (45 mL), and a precooled
solution of 30% H2O in MeOH (45 mL) was added slowly. This
mixture was stirred for 1 h at 0 °C, and the solvent was
removed under vacuum to leave a slurry that was extracted
with Et2O (3 × 75 mL). The combined extract was washed with
saturated sodium thiosulfate and brine and dried (MgSO4).
Removal of the solvent in vacuo and chromatography of the
residue (20% EtOAc/hexanes) gave 4.30 g (77%) of 52: [R]D23
-30.0 (c 0.16, CHCl3); IR (neat) 3496, 2919, 1779, 1694, 1456,
Ald ol Con d en sa tion of 33 a n d 55. Hyd r oxy Keton e 56.
To a solution of (+)-DIP-Cl (205.6 mg, 0.641 mmol) in Et2O
(0.25 mL) at 0 °C was added Et3N (90.0 µL, 0.641 mmol),
followed by a solution of 55 (113 mg, 0.400 mmol) in Et2O (0.5
mL). The mixture was stirred at 0 °C for 3 h and then cooled
to -40 °C. A solution of 33 (236 mg, 0.395 mmol) in Et2O (0.5
mL) was added, and the mixture was allowed to warm slowly
to -10 °C and stirred at this temperature for 3 h. The reaction
was quenched with MeOH (7.5 mL) and pH 7.0 buffer (3 mL),
after which the solution was cooled to 0 °C, 30% H2O2 (0.75
mL) was added, and the mixture was stirred for 10 min at 0
°C and at room temperature for 1 h. The mixture was poured
into H2O (20 mL) and extracted with EtOAc-hexanes (1:1,
5 × 30 mL), and the combined extract was washed with H2O
and brine and dried (Na2SO4). The solvent was removed in
vacuo, and the residue was purified by chromatography (5%
EtOAc in hexanes) to give 226 mg (65%) of pure 56: [R]D23
-84.3 (c 0.82, CH2Cl2); IR (film) 3394, 2929, 2856, 1715, 1458,
1382, 1212, 1106, 1003, 971, 702 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 1.19 (d, J ) 7 Hz, 3H), 1.82 (d, J ) 1 Hz, 3H), 2.81
(dd, J ) 13, 9 Hz, 1H), 3.16 (d, J ) 3 Hz, 1H), 3.27 (dd, J )
13, 3 Hz, 1H), 4.01 (qd, J ) 7, 3 Hz, 1H), 4.22 (dd, J ) 9, 3 Hz,
1H), 4.27 (dd, J ) 9, 7 Hz, 1H), 4.50-4.54 (m, 1H), 4.71 (ddt,
J ) 9, 7, 3 Hz, 1H), 6.45 (quintet, J ) 1 Hz, 1H), 7.19-7.40
(m, 5H); 13C NMR (100 MHz, CDCl3) δ 10.5, 21.8, 38.0, 40.2,
55.4, 66.5, 75.3, 79.5, 127.7, 129.2 (2C), 129.6 (2C), 135.1, 145.8,
153.1, 176.9; MS (FAB) m/z 412 (M - 17), 282, 235, 178; HRMS
(FAB) m/z found 412.0418, calcd for C17H19INO3 m/z 412.0410.
(2R,3R)-N-Meth oxy-N-m eth yl (E)-2,4-Dim eth yl-5-iod o-
3-h ydr oxypen t-4-en am ide (53). N,O-Dimethylhydroxylamine
(377 mg, 3.86 mmol) in THF (2 mL) was cooled to 0 °C, and a
solution of trimethylaluminum in toluene (2.0M, 1.93 mL, 3.86
mmol) was added. The homogeneous solution was stirred at
room temperature for 30 min and then cooled to 0 °C, and a
precooled solution of 52 (415 mg, 0.966 mmol) in THF (1 mL)
was added via cannula. The mixture was stirred for 2 h and
transferred into a mixture of EtOAc (90 mL) and sodium
potassium tartrate (90 mL). The mixture was stirred vigor-
ously for 30 min; the layers were separated, and the aqueous
layer was extracted with EtOAc (3 × 100 mL). The combined
extract was washed with brine, dried (MgSO4), and concen-
trated in vacuo to leave an amorphous solid that was purified
by chromatography (50% CH2Cl2/hexanes) to give 256 mg
(85%) of 53 as an amorphous white solid: 1H NMR (300 MHz,
CDCl3) δ 1.09 (d, J ) 7 Hz, 3H), 1.80 (s, 3H), 3.10 (m, 1H),
3.22 (s, 3H), 3.74 (s, 3H), 4.4 (m, 1H), 6.44 (s, 1H); 13C NMR
(75 MHz, CDCl3) δ 10.2, 32.0, 39.4, 61.6, 75.3, 79.3, 106.1,
145.3, 177.2.
(2R,3R)-N-Meth oxy-N-m eth yl-(E)-2,4-d im eth yl-5-iod o-
3-m eth oxyp en t-4-en a m id e (54). To a solution of 53 (100 mg,
0.319 mmol) in toluene (2 mL) was added 4-methyl-2,6-di-tert-
butylpyridine (656 mg, 3.20 mmol) and methyl triflate (181
mL, 1.60 mmol), and the mixture was stirred at 70 °C for 26
h. After the mixture had cooled to room temperature, the
reaction was quenched with MeOH that was saturated with
NH3. The mixture was diluted with Et2O (20 mL), and the
solution was washed with water (10 mL) and brine (10 mL)
and dried (MgSO4). The solvent was removed in vacuo, and
the residue was purified by chromatography (10% EtOAc in
hexanes) to give 95 mg (91%) of 54 as a colorless oil: IR (film)
2978, 2879, 1660, 1091; 1H NMR (300 MHz, CDCl3) δ 1.21 (d,
J ) 7 Hz, 3H), 1.73 (s, 3H), 3.10 (s, 3H), 3.13-3.17 (m, 1H),
3.20 (s, 3H), 3.62 (s, 3H) 3.79 (d, J ) 10 Hz, 1H), 6.19 (s, 1H);
13C NMR (100 MHz, CDCl3) δ 14.5, 22.0, 31.5, 61.6, 76.6, 80.7,
87.1, 106.1, 146.2, 175.1; MS (FAB) m/z 328 (M + 1), 296, 211,
154; HRMS (FAB) m/z found 328.0407, calcd for C10H19INO3
m/z 328.0409.
1
1427, 1111, 702; H NMR (400 MHz, CDCl3) δ 0.97 (d, J ) 7
Hz, 3H), 1.06 (s, 9H), 1.13 (d, J ) 7 Hz, 3H), 2.53 (dd, J ) 17,
3 Hz, 1H), 2.67 (dd, J ) 17, 9 Hz, 1H), 2.76 (sextet, J ) 7 Hz,
1H), 3.20 (s, 3H), 3.70 (t, J ) 6 Hz, 2H), 3.85 (d, J ) 7 Hz,
1H), 4.00 (ddd, J ) 11, 7, 2 Hz, 1H), 4.45 (bd, J ) 9 Hz, 1H),
5.59 (dd, J ) 15, 8 Hz, 1H), 5.71 (d, J ) 5 Hz, 1H), 6.06 (bd,
J ) 11 Hz, 1H), 6.22 (s, 1H), 6.23 (ddd, J ) 15, 11, 1 Hz, 1H),
7.18-7.20 (m, 1H), 7.25-7.30 (m, 1H), 7.38-7.44 (m, 6H),
7.46-7.50 (m, 3H), 7.66-7.70 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ 12.2, 13.0, 19.2, 19.9, 26.9, 28.0, 36.0, 37.6, 39.5, 42.3,
47.6, 50.1, 57.0, 61.1, 72.2, 72.8, 80.6, 85.6, 86.3, 125.5, 125.6,
126.4, 127.7, 128.7, 129.6, 130.7, 133.9, 135.6, 135.8, 136.3,
137.4, 145.3, 212.8; MS (FAB) m/z 863 (M - 17), 753, 611, 475,
211; HRMS (FAB) m/z found 863.3034, calcd for C46H60IO4-
SSi m/z 863.3026.
P h osp h on a te 59. To diethylphosphonoacetic acid (0.20 mL,
1.24 mmol) was added benzene (5 mL), and after dissolution
was complete the mixture was concentrated in vacuo and the
residue taken up in anhydrous CH2Cl2 (4 mL). To the solution
were added anhydrous DMF (2 drops) and activated 4 Å
molecular sieves (100 mg), and the mixture was stirred at room
temperature for 25 min. The supernatant was transferred to
a flame-dried flask, and the solution was cooled to 0 °C.
Freshly distilled oxalyl chloride (0.540 mL, 6.22 mmol) was
added, and the solution was allowed to warm to room tem-
perature over a period of 1 h. The solvent was removed under
vacuum; the residue was taken up into benzene (5 mL), and
the solvent was again removed under vacuum. The resulting
brown residue was dissolved in anhydrous CH2Cl2 (3 mL) to
yield a ca. 0.4 M solution of diethylphosphonoacetyl chloride.
To a solution of 58 (6.5 mg, 6.3 µmol) and anhydrous
pyridine (25 µL, 0.32 mmol) in anhydrous CH2Cl2 (1 mL) at
room temperature was added a solution of diethylphospho-
noacetyl chloride prepared above (0.11 mL, 0.40 M in CH2Cl2,
44 µmol), and the mixture was stirred for 4 h, during which
7758 J . Org. Chem., Vol. 67, No. 22, 2002

Total Synthesis of Rhizoxin D
time most of the CH2Cl2 was allowed to evaporate. To the
residue was added EtOAc (5 mL) and pH 7 phosphate buffer
(5 mL, 1 M); the layers were shaken and separated, and the
aqueous phase was extracted with EtOAc (5 mL). The com-
bined extract was dried (Na2SO4); the solvent was removed in
vacuo, and the residue was purified by chromatography (33%
EtOAc in hexanes) to yield 6.1 mg (78%) of 59 as a colorless
oil: [R]2D3 - 63.6 (c 0.36, CH2Cl2); IR (film) 2930, 2864, 1735,
1462, 1389, 1263, 1111, 739 cm-1; 1H NMR (300 MHz, CDCl3)
δ 0.94 (d, J ) 7 Hz, 3H), 0.97 (d, J ) 7 Hz, 3H), 0.98-1.06 (m,
23H), 1.08 (s, 9H), 1.20-1.85 (m, 5H), 1.31 (td, J ) 7, 4 Hz,
6H), 1.70 (bs, 3H), 1.82 (bs, 3H), 2.00-2.07 (m, 2H), 2.26
(sextet, J ) 7 Hz, 1H), 2.76 (dd, J ) 22, 14 Hz, 1H), 2.86 (dd,
J ) 22, 14 Hz, 1H), 3.18 (s, 3H), 3.44 (d, J ) 7 Hz, 1H), 3.70
(t, J ) 6 Hz, 2H), 4.01 (ddd, J ) 11, 7, 2 Hz, 1H), 4.06-4.18
(m, 6H), 4.79 (ddd, J ) 10, 4, 1 Hz, 1H), 5.56 (dd, J ) 15, 8
Hz, 1H), 5.71 (d, J ) 5 Hz, 1H), 5.83 (bd, J ) 11 Hz, 1H), 6.16
(dd, J ) 15, 10 Hz, 1H), 6.17 (bs, 1H), 7.17-7.23 (m, 1H), 7.25-
7.32 (m, 2H), 7.36-7.45 (m, 6H), 7.46-7.52 (m, 2H), 7.65-
7.71 (m, 4H); 13C NMR (75 MHz, CDCl3, one signal obscured
by CHCl3 resonance) δ 9.9, 11.8, 12.7 (3C), 14.4, 16.6 (2C), 16.7,
18.3 (3C), 18.4 (3C), 19.4, 27.1 (3C), 28.1, 34.8 (d, J ) 133 Hz),
35.9, 36.1, 37.8, 39.1, 39.8, 42.2, 56.9, 60.6, 62.7 (2C), 73.1,
74.1, 79.2, 85.8, 87.3, 125.8, 126.0, 126.6, 127.8 (4C), 128.9 (2C),
129.8 (2C), 130.9 (2C), 134.1 (2C), 135.8 (4C), 136.5, 136.8,
138.1, 146.6, 165.0 (d, J ) 6 Hz); MS (FAB) m/z 1159
(M - 57), 933, 645, 475, 309; HRMS (FAB) m/z found
1159.3283, calcd for C58H73IO9PSSi2 m/z 1159.3263.
δ-La cton e 60. To a solution of 59 (6.0 mg, 4.9 µmol) and
2,6-lutidine (20 µL, 0.17 mmol) in THF-H2O (5:1, 1.2 mL) at
room temperature was added silver(I) nitrate (17 mg, 0.10
mmol), and the mixture was stirred for 15 min. The mixture
was partitioned between EtOAc (10 mL) and H2O (10 mL);
the layers were shaken and separated, and the aqueous phase
was extracted with EtOAc (2 × 5 mL). The combined extract
was washed with brine (5 mL) and dried (Na2SO4); the solvent
was removed in vacuo, and the crude lactol (5.3 mg) was taken
up in anhydrous CH2Cl2 (1 mL). To this solution were added
N-methylmorpholine N-oxide (3.4 mg, 29 µmol) and activated
4 Å molecular sieves (10 mg), and the suspension was stirred
for 10 min. Tetra-n-propylammonium perruthenate (0.4 mg,
1.1 µmol) was added, and the suspension was stirred for an
additional 1 h. The mixture was diluted with CH2Cl2 (1 mL),
and the solution was filtered through a pad of silica. The pad
was washed successively with CH2Cl2 (3 × 2 mL) and Et2O
(2 × 2 mL); the combined filtrate was concentrated in vacuo,
and the residue was purified by chromatography (50% EtOAc
in hexanes) to yield 3.9 mg (71%) of 60 as a colorless oil:
[R]2D3 +18.1 (c 0.31, CH2Cl2); IR (film) 2932, 2864, 1735, 1462,
1389, 1263, 1111, 703 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.94
(d, J ) 7 Hz, 3H), 0.99-1.05 (m, 23H), 1.06 (s, 9H), 1.11 (d,
J ) 7 Hz, 3H), 1.32 (td, J ) 7, 2 Hz, 6H), 1.45-1.90 (m, 3H),
1.72 (s, 3H), 1.82 (s, 3H), 1.97-2.15 (m, 4H), 2.50 (sextet, J )
7 Hz, 1H), 2.66 (dd, J ) 17, 5 Hz, 1H), 2.76 (dd, J ) 22, 14 Hz,
1H), 2.86 (dd, J ) 22, 14 Hz, 1H), 3.18 (s, 3H), 3.44 (d, J ) 7
Hz, 1H), 3.71 (t, J ) 6 Hz, 2H), 4.07-4.20 (m, 6H), 4.79 (ddd,
J ) 10, 4, 2 Hz, 1H), 5.59 (dd, J ) 15, 8 Hz, 1H), 5.87 (bd,
J ) 10 Hz, 1H), 6.18 (s, 1H), 6.24 (dd, J ) 15, 11 Hz, 1H),
7.36-7.48 (m, 6H), 7.63-7.67 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ 9.9, 11.9, 12.6 (3C), 14.3, 16.5 (3C), 18.3 (3C), 18.4
(3C), 19.4, 27.1 (3C), 28.6, 32.2, 34.7 (d, J ) 133 Hz), 36.1,
36.6, 39.1 (2C), 41.9, 56.9, 61.0, 62.9 (2C), 74.0, 76.7, 79.2, 83.9,
87.3, 125.7, 127.1, 127.9 (4C), 130.0 (2C), 133.7, 134.2, 135.7
(5C), 139.3, 146.6, 165.0 (d, J ) 6 Hz), 171.5; MS (FAB) m/z
1123 (M + 1), 1067, 911, 309, 211; HRMS (FAB) m/z found
1067.4207, calcd for C51H81IO10PSi2 m/z 1067.4151.
separated; the aqueous phase was extracted with EtOAc (2 ×
10 mL), and the combined extract was washed with H2O (3 ×
5 mL) and dried (Na2SO4). The solvent was removed in vacuo,
and the residue was purified by chromatography (1-5%
MeOH/CH2Cl2) to yield 19.0 mg (54%) of 61 and 16.2 mg (36%)
of 60. The recovered starting material was resubjected to the
above reactions conditions (twice), and the combined product
from all runs was purified by column chromatography (1-5%
MeOH/CH2Cl2) to yield 24.0 mg (68%) of 61 as a colorless oil:
[R]2D3 +24.3 (c 0.07, CHCl3); IR (film) 3421, 2918, 2866, 1731,
1
1461, 1383, 1254, 1087, 1054, 1024, 969, 891 cm-1; H NMR
(300 MHz, CDCl3) δ 0.96 (d, J ) 7 Hz, 3H), 1.00-1.06 (m, 23H),
1.16 (d, J ) 7 Hz, 3H), 1.34 (q, J ) 7 Hz, 6H), 1.45-1.70 (m,
3H), 1.71 (s, 3H), 1.82 (s, 3H), 1.95-2.20 (m, 5H), 2.31-2.48
(m, 1H), 2.72 (dd, J ) 22, 14 Hz, 1H), 2.81 (dd, J ) 22, 14 Hz,
1H), 3.18 (s, 3H), 3.41 (d, J ) 7 Hz, 1H), 3.70 (t, J ) 6 Hz,
2H), 4.03-4.20 (m, 6H), 4.72 (ddd, J ) 10, 4, 2 Hz, 1H), 5.49
(dd, J ) 15, 9 Hz, 1H), 5.81 (d, J ) 11 Hz, 1H), 6.18 (s, 1H),
6.23 (dd, J ) 15, 11 Hz, 1H); 13C NMR (75 MHz, CDCl3, one
signal obscured by CHCl3 resonance) δ 10.0, 11.5, 12.6 (3C),
16.5 (2C), 17.0, 18.2 (3C), 18.3 (3C), 19.8, 28.5, 33.2, 34.7 (d,
J ) 133 Hz), 35.7, 36.5, 39.1, 39.4, 43.3, 56.9, 59.7, 62.9 (br,
2C), 73.9, 79.3, 83.6, 87.4, 125.7, 127.2, 134.6, 139.1, 146.7,
164.8, 171.7; MS (FAB) m/z 885 (M + 1), 750, 649, 423, 309;
HRMS (FAB) m/z found 869.3288 (M - CH3)+, calcd for C38
67IO10PSi m/z 869.3286.
Ald eh yd e 62. To a solution of 61 (1.6 mg, 1.8 µmol) in
-
H
anhydrous CH2Cl2 (0.5 mL) at room temperature was added
Dess-Martin periodinane (3 mg, 7.1 µmol), and the mixture
was stirred for 10 min. The solution was diluted with CH2Cl2
(2 mL); a mixture of saturated sodium thiosulfate and NaHCO3
(2 mL) was added, and the solution was stirred vigorously for
10 min. To this mixture were added H2O (5 mL) and CH2Cl2
(5 mL); the layers were separated, and the aqueous phase was
extracted with CH2Cl2 (2 × 5 mL). The combined extract was
washed with saturated NaHCO3 (5 mL) and dried (Na2SO4);
the solvent was removed in vacuo, and the residue was purified
by chromatography (5% MeOH/CH2Cl2) to yield 1.6 mg (100%)
of 62 as a colorless oil: [R]2D3 +22.9 (c 0.07, CHCl3); IR (film)
2930, 2858, 1736, 1463, 1377, 1255, 1086, 1050, 1021, 971, 884
cm-1 1H NMR (400 MHz, CDCl3) δ 0.94 (d, J ) 7 Hz, 3H),
;
1.01-1.06 (m, 22H), 1.14 (d, J ) 7 Hz, 3H), 1.33 (t, J ) 7 Hz,
3H), 1.34 (t, J ) 7 Hz, 3H), 1.68-1.88 (m, 2H), 1.71 (s, 3H),
1.82 (s, 3H), 1.96-2.07 (m, 3H), 2.13 (dd, J ) 17 Hz, 1H), 2.47-
2.59 (m, 3H), 2.74 (dd, J ) 22, 14 Hz, 1H), 2.79 (dd, J ) 17, 2
Hz, 1H), 2.84 (dd, J ) 22, 14 Hz, 1H), 3.19 (s, 3H), 3.43 (d,
J ) 7 Hz, 1H), 4.08-4.21 (m, 6H), 4.75 (ddd, J ) 10, 4, 2 Hz,
1H), 5.54 (dd, J ) 15, 8 Hz, 1H), 5.85 (d, J ) 11 Hz, 1H), 6.17
(s, 1H), 6.24 (dd, J ) 15, 11 Hz, 1H), 9.78 (s, 1H); 13C NMR
(100 MHz, CDCl3, one signal obscured by CHCl3 resonance) δ
9.9, 11.8, 12.6 (3C), 16.2, 16.6 (2C), 18.3 (3C), 18.4 (3C), 19.9,
26.1, 32.1, 34.7 (d, J ) 133 Hz), 36.1 (2C), 39.1, 42.2, 50.0,
56.9, 62.8 (2C), 74.0, 79.3, 83.5, 87.3, 125.6, 127.4, 133.9, 139.4,
146.7, 164.9, 170.6, 199.9; MS (FAB) m/z 883 (M + 1), 613,
309, 219, 210; HRMS (FAB) m/z found 883.3406, calcd for
C
39H69IO10PSi m/z 883.3442.
R,â-Un sa tu r a ted La cton e 63. To a stirred suspension of
anhydrous LiCl (7.0 mg, 0.16 mmol) in anhydrous MeCN (8
mL) was added a solution of 62 (2.6 mg, 2.9 µmol) in anhydrous
MeCN (2 mL). After 15 min, diisopropylethylamine (10 µL, 58
µmol) was added, the mixture stirred for 24 h, and the reaction
quenched with saturated NH4Cl (5 mL). The mixture was
partitioned between brine (10 mL) and Et2O (10 mL); the
layers were separated, and the aqueous phase was extracted
with Et2O (2 × 10 mL). The combined extract was washed with
brine (10 mL) and dried (Na2SO4); the solvent was removed
in vacuo, and the residue was purified by chromatography
(70-100% Et2O in hexanes) to yield 1.2 mg (57%) of 63 as a
colorless oil: [R]2D3 +4.3 (c 0.14, CH2Cl2); IR (film) 2928, 2867,
1729, 1711, 1467, 1377, 1319, 1255, 1223, 1162, 1072, 1050,
Alcoh ol 61. To a stirred solution of 60 (44.7 mg, 2.3 µmol)
in anhydrous DMF 3.3 mL) at 0 °C was added a solution of
tris(dimethylamino)sulfur (trimethylsilyl)difluoride (TASF,
376 µL, 0.11 M in DMF, 39.8 µmol). After 10 h, the mixture
was diluted with EtOAc (10 mL) and pH 7 phosphate buffer
(10 mL, 1M) and stirred vigorously for 5 min. The layers were
978, 878, 803, 684 cm-1 1H NMR (400 MHz, CDCl3) δ 0.69
;
(dt, J ) 14, 12 Hz, 1H), 0.98 (d, J ) 7 Hz, 3H), 1.02-1.17 (m,
J . Org. Chem, Vol. 67, No. 22, 2002 7759

White et al.
21H), 1.23 (d, J ) 6 Hz, 3H), 1.61 (dd, J ) 15, 3 Hz, 1H), 1.71-
1.77 (m, 1H), 1.78 (bs, 3H), 1.81-1.87 (m, 1H), 1.92 (bs, 3H),
2.02 (dq, J ) 14, 2 Hz, 1H), 2.10 (dd, J ) 18, 12 Hz, 1H), 2.16
(dt, J ) 15, 11 Hz, 1H), 2.22-2.32 (m, 2H), 2.51-2.56 (m, 1H),
2.78 (ddd, J ) 18, 5, 2 Hz, 1H), 3.18 (s, 3H), 3.36 (d, J ) 9 Hz,
1H), 3.70 (ddd, J ) 12, 9, 3 Hz, 1H), 4.03 (dd, J ) 11, 3 Hz,
1H), 4.47 (dd, J ) 11, 3 Hz, 1H), 5.16 (dd, J ) 15, 10 Hz, 1H),
5.62 (d, J ) 16 Hz, 1H), 5.75 (bd, J ) 11 Hz, 1H), 6.17 (bs,
1H), 6.24 (dd, J ) 15, 11 Hz, 1H), 6.77 (ddd, J ) 16, 11, 5 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 10.0, 11.4, 12.6 (3C), 16.9,
18.3 (3C), 18.4 (3C), 19.1, 30.0, 34.5, 34.8, 37.1, 38.4, 38.9, 45.5,
56.7, 73.8, 78.8, 79.5, 83.6, 88.7, 124.8, 124.9, 130.2, 133.7,
140.1, 146.2, 147.4, 165.8, 170.6; MS (FAB) m/z 729 (M+1),
697, 601, 569, 463; HRMS (FAB) m/z found 729.3062, calcd
for C35H58IO6Si m/z 729.3048.
Hz, 1H), 6.63 (dd, J ) 15, 11 Hz, 1H), 6.76 (ddd, J ) 16, 11, 5
Hz, 1H), 7.55 (s, 1H); MS (FAB) m/z 750 (M + 1), 551, 463,
282, 232; HRMS (FAB) m/z found 750.4784, calcd for C44H68
NO7Si m/z 750.4765.
-
Rh izoxin D (2). To a stirred solution of 69 (5.9 mg, 7.86
mmol) in anhydrous THF (0.6 mL) in a polyethylene container
was added pyridine (0.6 mL), and the mixture was cooled to 0
°C. To this solution was added HF‚pyridine (0.3 mL), and the
mixture was allowed to warm to room temperature and stirred
for 24 h. The mixture was diluted with Et2O (10 mL) and H2O
(10 mL) and stirred vigorously for 5 min. The layers were
separated, and the organic phase was washed with saturated
aqueous CuSO4 (5 mL), saturated aqueous NaHCO3 (5 mL),
H2O (5 mL), and brine (5 mL) and then dried (Na2SO4). The
solvent was removed in vacuo, and the residue was purified
by chromatography (3% MeOH/CH2Cl2) to yield 3.0 mg (59%)
of 2: [R]2D3 +174.1 (c 0.27, MeOH), with 1H and 13C NMR
spectra identical to those of an authentic sample.
O-Tr iisop r op ylsilylr h izoxin D (69). To a solution of 68
(6.6 mg, 20.3 µmol) and 63 (7.4 mg, 10.1 µmol) in DMF (0.6
mL) was added a solution of bis(acetonitrile)palladium(II)
dichloride (260 µL, 1.96 µmol/mL in DMF, 0.508 µmol, 5 mol
%), and the mixture was stirred at room temperature for 14 h
in the dark. The solution was diluted with Et2O (10 mL);
saturated NaHCO3 (10 mL) was added, and the layers were
separated. The aqueous phase was extracted with Et2O (10
mL), and the extract was washed with H2O (5 × 2 mL) and
dried (Na2SO4). The solvent was removed in vacuo, and the
residue was purified by chromatography (from 50% CH2Cl2/
hexanes to 2% MeOH/CH2Cl2) to yield 6.4 mg (84%) of 69 as
Ack n ow led gm en t. We are indebted to Professor
David R. Williams, Indiana University, for NMR spec-
tra of rhizoxin D and to Dr. J ames W. Leahy, Exelixis,
for the 1H NMR spectrum of 69. National Institutes
of Health Postdoctoral Fellowships to C.S.N.
(F32GM17825), N.J .G. (F2GM15263), and B.W.P.
(F32CA76742) are gratefully acknowledged. Financial
support was provided by the National Institutes of
Health through Grant GM50574.
a pale yellow oil: [R]D23 +97.1 (c 0.35, CHCl3); H NMR (400
1
MHz, CDCl3) δ 0.65-0.75 (m, 1H), 1.00 (d, J ) 7 Hz, 3H),
1.02-1.06 (m, 21H), 1.21 (d, J ) 6 Hz, 3H), 1.40-1.75 (m, 2H),
1.77 (s, 3H), 1.91 (s, 3H), 1.96-2.13 (m, 3H), 2.14 (s, 3H), 2.18-
2.40 (m, 3H), 2.48 (s, 3H), 2.50-2.56 (m, 1H), 2.77 (ddd, J )
18, 5, 2 Hz, 1H), 3.17 (s, 3H), 3.22 (d, J ) 9 Hz, 1H), 3.67
(ddd, J ) 12, 9, 3 Hz, 1H), 4.01 (dd, J ) 11, 3 Hz, 1H), 4.56
(dd, J ) 11, 3 Hz, 1H), 5.10 (dd, J ) 15, 10 Hz, 1H), 5.62 (d,
J ) 16 Hz, 1H), 5.71 (bd, J ) 11 Hz, 1H), 6.07 (bd, J ) 11 Hz,
1H), 6.22 (dd, J ) 15, 11 Hz, 1H), 6.26 (s, 1H), 6.35 (d, J ) 15
Su p p or tin g In for m a tion Ava ila ble: Complete experi-
mental descriptions of transformations not included in the
Experimental Section and characterization for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O020537Q
7760 J . Org. Chem., Vol. 67, No. 22, 2002