Total synthesis of the epidermal growth factor inhibitor (-)-reveromycin B

Article abstract of DOI:10.1021/jo001646c

The total synthesis of the epidermal growth factor inhibitor reveromycin B (2) in 25 linear steps from chiral methylene pyran 13 is described. The key steps involved an inverse electron demand hetero-Diels-Alder reaction between dienophile 13 and diene 12 to construct the 6,6-spiroketal 11 which upon oxidation with dimethyldioxirane and acid catalyzed rearrangement gave the 5,6-spiroketal aldehyde 9. Lithium acetylide addition followed by oxidation/reduction and protective group manipulation provided the reveromycin B spiroketal core 8 which was converted into the reveromycin A (1) derivative 6 in order to confirm the stereochemistry of the spiroketal segment. Introduction of the C1-C10 side chain began with sequential Wittig reactions to form the C8-C9 and C7-C6 bonds, and a tin mediated asymmetric aldol reaction installed the C4 and C5 stereocenters. The final key steps to the target molecule 2 involved a Stille coupling to introduce the C21-C22 bond, succinoylation, selective deprotection, oxidation, and Wittig condensation to form the final C2-C3 bond. Deprotection was effected by TBAF in DMF to afford reveromycin B (2) in 72% yield.

Full text of DOI:10.1021/jo001646c

2
382
J . Org. Chem. 2001, 66, 2382-2393
Tota l Syn th esis of th e Ep id er m a l Gr ow th F a ctor In h ibitor
(
-)-Rever om ycin B
Anthony N. Cuzzupe, Craig A. Hutton, Michael J . Lilly, Robert K. Mann, Kenneth J . McRae,
Steven C. Zammit, and Mark A. Rizzacasa*
School of Chemistry, The University of Melbourne, Victoria 3010, Australia
masr@unimelb.edu.au
Received November 20, 2000
The total synthesis of the epidermal growth factor inhibitor reveromycin B (2) in 25 linear steps
from chiral methylene pyran 13 is described. The key steps involved an inverse electron demand
hetero-Diels-Alder reaction between dienophile 13 and diene 12 to construct the 6,6-spiroketal 11
which upon oxidation with dimethyldioxirane and acid catalyzed rearrangement gave the
5
,6-spiroketal aldehyde 9. Lithium acetylide addition followed by oxidation/reduction and protective
group manipulation provided the reveromycin B spiroketal core 8 which was converted into the
reveromycin A (1) derivative 6 in order to confirm the stereochemistry of the spiroketal segment.
Introduction of the C1-C10 side chain began with sequential Wittig reactions to form the C8-C9
and C7-C6 bonds, and a tin mediated asymmetric aldol reaction installed the C4 and C5
stereocenters. The final key steps to the target molecule 2 involved a Stille coupling to introduce
the C21-C22 bond, succinoylation, selective deprotection, oxidation, and Wittig condensation to
form the final C2-C3 bond. Deprotection was effected by TBAF in DMF to afford reveromycin B
(2) in 72% yield.
In tr od u ction
Spiroketals or spiroacetals are substructures that occur
The reveromycins act as inhibitors of the mitogenic
activity of epidermal growth factor (EGF).6 Since the
action of most antitumor drugs depends on the difference
in the cell proliferation rate between normal and tumor
cells by acting on DNA or RNA function and synthesis,
compounds which inhibit the growth factors that mediate
such processes, such as transforming growth factor (TGF-
in a wide variety of natural products from many sources
including insects, microbes, plants, fungi and marine
1
organisms. The 1,6-dioxaspiro[4.5]decane (“5,6-spiroket-
al”) and the 1,7-dioxaspiro[5.5]undecane (“6,6-spiroketal”)
moieties in particular occur in diverse biologically active
natural products such as polyether ionophores, insect
pheromones, and antibiotic macrolides. Reveromycins A
1), B (2), C (3), and D (4) are examples of natural
products containing 5,6- and 6,6-spiroketal moieties
7
R) and EGF, are possible targets for antitumor agents.
Reveromycin A (1) also exhibits antiproliferative activity
against human tumor cell lines KB and K562 as well as
antifungal activity against Candida albicans but only at
(
6
low pH. Reveromycin B (2) (IC50 6.0 µg/mL) is 1 order of
isolated from a soil actinomycete belonging to the Srep-
magnitude less active than reveromycin A (1) (IC50 0.7
µg/mL) against EGF but is more selective since it
tomyces genus.2
,3,4
The gross structures of 1-4 were
deduced by spectroscopic analysis while the absolute
6
possesses none of the other activities displayed by 1.
configuration of 1 was assigned following chiroptical and
It has been demonstrated that the reveromycin A (1)
type 6,6-spiroketal system I completely isomerizes to the
reveromycin B (2) 5,6-spiroketal II (Scheme 1). Reductive
ozonolysis of the desuccinoylated reveromycin A tri-
methyl ester 5 followed by acetylation gave the 5,6-
5
spectroscopic analysis of various degradation products.
Other structural features of these compounds include a
common succinate half ester at C18 or C19, a C1-C9
triene acid segment, and a C20-C24 diene acid moiety.
8
spiroketal 6. This result can be explained by considering
(
1) Perron, F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617-1661.
(2) Osada, H.; Koshino, H.; Isono, K.; Takahashi, H.; Kawanishi,
G. J . Antibiot. 1991, 44, 259-261.
(3) Takahasi, H.; Osada, H.; Koshino, H.; Kudo, T.; Amano, S.;
Shimizu, S.; Yoshihama, M.; Isono, K. J . Antibiot. 1992, 45, 1409-
1
413.
(
4) Koshino, H.; Takahashi, H.; Osada, H.; Isono, K. J . Antibiot.
1
992, 45, 1420-1427.
(
5) Ubukata, M.; Koshino, H.; Osada, H.; Isono, K. J . Chem. Soc.,
Chem. Commun. 1994, 1877-1878.
6) Takahashi, T.; Osada, H.; Koshino, H.; Sasaki, M.; Onose, R.;
Nakakoshi, M.; Yoshihama, M.; Isono, K. J . Antibiot. 1992, 45, 1414-
419. Takahashi, H.; Yamashita, Y.; Takaoka, H.; Nakamura, J .;
Yoshihama, M.; Osada, H. Oncol. Res. 1997, 9, 7-11.
7) Marquardt, H.; Hankapiller, M. W.; Hood, L. E.; Twardzik, D.
(
1
(
W.; De Larco, J . E.; Stephenson, J . R.; Todaro, J . Proc. Natl. Acad.
Sci. 1983, 80, 4684-4688. Yoshida, K.; Kyo, E.; Tsuda, T.; Tsujino, T.;
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Modjtahedi, H.; Dean, C. Int. J . Oncol. 1994, 4, 277-296.
1
0.1021/jo001646c CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/03/2001

Total Synthesis of (-)-Reveromycin B
J . Org. Chem., Vol. 66, No. 7, 2001 2383
Sch em e 1
Sch em e 2
the steric interaction present in the reveromycin A
spiroketal I which is alleviated upon acid induced isomer-
ization to the 5,6-spiroketal II. The thermodynamic
preference for the 5,6-spiroketal II might therefore
explain the biosynthetic origin of reveromycin B (2) where
isomerization of the 6,6-spiroketal I of reveromcyin A (1)
occurs prior to succinnoylation. In synthetic studies
toward reveromycin A, formation of the 6,6-spiroketal
system under thermodynamic control where the tertiary
alcohol is protected results in the production of 6,6-
Sch em e 3
9
8
spiroisomers or isomeric acetals as a result of the steric
interaction present in spiroketal I.
The first total synthesis of (-)-reveromycin B (2) was
reported by Theodorakis and Drouet.10 Shimizu, Nakata,
and co-workers then communicated a second independent
total synthesis soon afterward11 and the same group has
also completed the first total synthesis of reveromycin A
1
2
(
1). In this paper, we describe the full details of our
1
3
asymmetric synthesis of reveromycin B (2).
Retr osyn th etic P la n . The key retrosynthetic bond
disconnections for the synthesis of 2 are shown in Scheme
2
. Construction of the C2-C3 bond by a Wittig reaction
would involve the use of the appropriate stabilized ylide
while the C4-C5 bond could be introduced by an asym-
metric syn-aldol reaction. The C21-C22 bond could be
2
2
14
formed by an sp -sp coupling and acylation at C19
oxygen would introduce the succinate residue. These
(
8) Shimizu, T.; Kobayashi, R.; Osako, K.; Osado, H.; Nakata, T.
Tetrahedron Lett. 1996, 37, 6755-6758.
9) Drouet, K. E.; Ling, T.; Tran. H. V.; Theodorakis, E. A. Org. Lett.
000, 2, 207-210.
10) Drouet, K. E.; Theodorakis, E. A. J . Am. Chem. Soc. 1999, 121,
4
1
disconnections lead to diene ester 7 which could arise
from the spiroketal fragment 8, again by Wittig exten-
sion.
(
2
(
Pivotal to our approach was the efficient synthesis of
the key spiroketal fragment 8 (Scheme 3). Acetylide anion
addition to the aldehyde 9 could provide 8 while the
aldehyde 9 could be obtained in a novel and stereoselec-
tive manner by a hetero-Diels-Alder/epoxidation/acid
56-457. Drouet, K. E.; Theodorakis, E. A. Eur. J . Chem. 2000, 6,
987-2001.
(11) Masuda, T.; Osako, K.; Shimizu, T.; Nakata, T. Org. Lett. 1999,
1
2
1
, 941-944.
12) Shimizu, T.; Masuda, T.; Hiramoto, K.; Nakata, T. Org. Lett.
000, 2, 2153-2156.
13) (a) McRae, K. J .; Rizzacasa, M. A. J . Org. Chem. 1997, 62,
196-1197. (b) Cuzzupe, A. N.; Hutton, C. A.; Lilly, M. J .; Mann, R.
(
1
3a,15
(
rearrangement sequence as shown in Scheme 3.
An
K.; Rizzacasa, M. A.; Zammit, S. C. Org. Lett. 2000, 2, 191-194.
14) Knight, D. W. In Comprehensive Organic Syntheses; Trost, B.,
Ed.; Pergamon: Oxford, 1991; Vol. 3, pp 481-520.
(
(15) Ireland, R. E.; Armstrong, J . D.; Lebreton, J .; Meissner, R. S.;
Rizzacasa, M. A. J . Am. Chem. Soc. 1993, 115, 7152-7165.

2
384 J . Org. Chem., Vol. 66, No. 7, 2001
Cuzzupe et al.
inverse electron demand hetero-Diels-Alder reaction16
Sch em e 4
(
HDA) between methylene pyran 13 (derived from lactone
1
1
4) and butylacrolein (12) should provide the spiroketal
1, and it was envisaged that the stereochemistry at the
spiro center would be controlled by axial attack of the
aldehyde oxygen atom due to the anomeric effect.17
Stereoselective epoxidation with dimethyldioxirane pro-
vides the epoxide 10, setting the C18 stereochemistry and
subsequent acid treatment15 should then induce ring-
opening and cyclization via the intermediate oxonium ion
shown to provide the 5,6-spiroketal aldehyde 9.
It is well documented that simple R,â-unsaturated
carbonyl compounds participate in inverse electron de-
mand hetero-Diels-Alder reactions with electron rich
dienophiles.1 This mode of cycloaddition is dominated
by the interaction of the HOMO of the dienophile and
the LUMO of the diene, and consequently, substituents
that raise the HOMO of the dienophile or lower the
LUMO of the diene increase the reaction rate.18 For
example, a C3 electron withdrawing substituent de-
creases the LUMO of the heterodiene thus enhancing
rate and regioselectivity with electron rich dienophiles.1
The HDA synthesis of 6,6-spiroketals has met with
somewhat limited success; however, there is a propensity
for methylene pyrans such as 13 to undergo isomerization
to the more stable endo position, thus thwarting the
desired [4+2]-cyloaddition.1 This issue has been ad-
dressed by Ireland who has employed an R-keto func-
tionality in the dienophile to block isomerization and
6a
6a,18
complex.16k At the onset of this work, HDA reactions
between isomerizable methylene pyrans and simple
2
-alkyl acrolein derivatives had not been reported so we
6c
initiated a model study to test the feasibility of the
13a
proposed approach to the reveromycin B spiroketal.
provide spiroketals by an “acrolein dimerization” type
approach.1
5,19
However, in our case this method would
require the removal of the oxygen atom at a later stage.
Furthermore, byproducts resulting from dienophile dimer-
ization often result.19c,d In 1991, Tietze reported the only
example of a HDA reaction between an isomerizable
chiral methylene pyran dienophile and an activated diene
which provided a mixture of isomeric spiroketals (eq 1).
Pale has pioneered the use of 3,4-epoxy-2-methyleneox-
olanes in the HDA synthesis of 5,6-spiroketals where the
Mod el Stu d y. The reactivity of diene 12 was investi-
1
6f
gated using the known unsubstituted methylene pyran
1
6c,20
1
5
as the dienophile (Scheme 4). Initial attempts at
inducing cycloaddition by heating a mixture of 12 and
5 only yielded the isomerized product 16, even in base
3
,4-epoxy substituent prevents isomerization of the exo-
1
cyclic double bond and Lewis acid catalysts were used to
increase reaction rates.16g,h Reactive heterodienes con-
taining a C3 chiral sulfinyl group have also been utilized
washed glassware. To suppress isomerization, a number
of bases were added to the reaction and a good yield of
spiroketal 17 was finally obtained by heating a neat
mixture of freshly distilled 12 and 15 in the presence of
in the production of enantiopure spiroketals as reported
by Maignan.1
6i,j
Recently, J ørgensen and co-workers
1
2 3
equiv of anhydrous K CO followed by aqueous workup
reported the enantioselective synthesis of 5,6-spiroketals
via asymmetric HDA reactions between an isomerizable
methylene furan dienophile and various â,γ-unsaturated
R-keto esters catalyzed by a chiral bisoxazoline copper
and vacuum distillation. Epoxidation of 17 with anhy-
drous dimethyldioxirane21 then gave the labile epoxide
1
8 as one diastereoisomer to the limits of NMR detection.
Rearrangement then occurred smoothly upon treatment
of 18 with a catalytic amount of PPTS15 to provide the
(16) (a) Boger, D. L.; Weinreb, S. M. Hetero Diels Alder Methodology
5
,6-spiroketal aldehydes 19 in excellent yield as a 1:2
in Organic Synthesis; Academic Press: San Diego, CA, 1987; Chapter
7
. (b) Paul, R.; Tchelitcheff, S. Bull. Soc. Chim. Fr. 1954, 672-678. (c)
mixture at the spiro carbon since there are no equatorial
substituents present to anchor the THP ring. Acetylide
anion addition to 19 occurred in a stereoselective manner
to afford the alkynes 20 after removal of the TMS group,
again as a 1:2 mixture of spiro isomers but with the
opposite relative configuration at the C18 and C19
stereocenters to that found in the reveromycin B system.
Evidence for this configuration arose from the acid
Ireland, R. E.; H a¨ bich, D. Chem. Ber. 1981, 114, 1418-1427. (d) Ireland
R. E.; Thaisrivongs, S. Dussault, P. H. J . Am. Chem. Soc. 1988, 110,
5
768-5779. (e) Sauv e´ , G.; Schwartz, D. A.; Ruest, L.; Deslongchamps,
P. Can. J . Chem. 1984, 62, 2929-2935. (f) Tietze, L. F.; Schneider, C.
J . Org. Chem. 1991, 54, 2476-2481. (g) Pale, P.; Chuche, J . Tetrahe-
dron Lett. 1988, 29, 2947-2950. (h) Pale, P.; Bouquant, J .; Chuche,
J .; Carrupt, P. A.; Vogel, P. Tetrahedron, 1994, 50, 8035-8052. (i)
Hayes, P.; Maignan, C. Synlett 1994, 409-410. (j) Hayes, P. Maignan,
C. Synthesis 1999, 783-786. (k) Audrain, H.; Thorhauge, J .; Hazell,
R. G.; J ørgensen, K. A. J . Org. Chem. 2000, 65, 4487-4497.
17) Deslongchamps, P. Stereoelectronic Effects in Organic Chem-
istry; Pergamon Press: Oxford, England, 1983; Chapter 2.
18) Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
Wiley: Bath, 1980; Chapter 4.
2
2
(
(20) Taskinen, E. Ann. Acad. Sci. Fenn., Ser. A 1972, 163, 3. A
modified procedure for the synthesis of enol ether 15 is detailed in the
Supporting Information.
(
(
19) (a) Ireland, R. E.; Daub, J . P. J . Org. Chem. 1983, 48, 1303-
(21) (a) Murray, R. W.; J eyaraman, R. J . J . Org. Chem. 1985, 50,
2847-2853. (b) Adam, W.; Bialas J .; Hadjiarapoglou, L. Chem. Ber.
1991, 124, 2377.
1
1
312. (b) Ireland, R. E.; H a¨ bich, D.; Norbeck, D. W. J . Am. Chem. Soc.
985, 107, 3271-3278. (c) Ireland, R. E.; Daub, J . P.; Mandel G. S.;
Mandel, N. S. J . Org. Chem. 1983, 48, 1312-1325.
(22) Reveromycin B numbering is used throughout.

Total Synthesis of (-)-Reveromycin B
J . Org. Chem., Vol. 66, No. 7, 2001 2385
Sch em e 5
Sch em e 6
induced isomerization of the 5,6-spiroketal 20 to the 6,6-
spiroketal 21 (1:1 mixture), which showed a large NOE
between H11 and H19. If the relative configuration was
correct, this 5,6 to 6,6-spiroketal isomerization would not
be expected to occur since a strong thermodynamic
preference for the 5,6-spiroketal was found in the natural
product degradation studies described earlier (see Scheme
7
1
). Further evidence for this stereochemistry was ob-
tained upon conversion of 21 into the crystalline MOM
ether 22. A single-crystal Xray structure of 22 was
determined which finally confirmed the stereochemistry
proposed.23 The stereochemistry at C19 will therefore
need to be corrected at some stage.
Asym m etr ic Sp ir ok eta l Syn th esis. Encouraged by
the successful model study, we proceeded with the
asymmetric synthesis of the reveromycin B spiroketal 8
as outlined in Schemes 5 and 6. The initial target was
the chiral methylene pyran 13 required for the critical
Diels-Alder reaction, and the route began with the
2
4
asymmetric crotylmetalation of aldehyde 23 to afford
alkene 24.25 Dihydroxylation of 24, oxidative cleavage,
and Wittig reaction yielded alkene 25 as a mixture of
geometric isomers. This was of no consequence as the
alkene mixture was hydrogenated to provide the corre-
sponding saturated ester which upon acid treatment
cyclized to lactone 14. Methylenation of 14 was best
achieved using dimethyltitanocene as reported by Peta-
sis.26 This gave the methylene pyran 13 in excellent yield
after purification over basic alumina (activity II-III).
Isomerization of 13 to the endo isomer occurs upon
purification over activity I basic alumina or silica gel. The
hetero-Diels-Alder reaction between 13 and 12 pro-
2 3
ceeded smoothly at 110 °C in the presence of K CO to
provide the spiroketal 11 as one diastereoisomer in good
yield. Higher temperatures resulted in the formation of
large amounts of butylacrolein dimer, while at lower
temperatures the reaction was prohibitively slow. Oxida-
tion with anhydrous dimethyldioxirane21 gave epoxide 10
as the only detectable isomer and rearrangement initi-
ated by CSA gave the spiroketal aldehyde 9. PPTS also
effected rapid rearrangement of 10 to a mixture of 5,6-
spiroketal isomers, but complete isomerization to the
(23) Gable, R. W.; McRae, K. J .; Rizzacasa, M. A. Unpublished
results, Cambridge Crystallographic Data Centre deposition number
CCDC-148807 2000. See Supporting Information for ORTEP and
coordinates.
(
24) Brown, H. C.; Bhat, K. S. J . Am. Chem. Soc. 1986, 108, 293-
2
5
6
94.
(25) Andrus, M. B.; Argade, A. B. Tetrahedron Lett. 1996, 37, 5049-
052.
(
26) Petasis, N. A.; Bzowej, E. I. J . Am. Chem. Soc. 1990, 112, 6392-
394. Petasis, N. A.; Lu, S.-P. Tetrahedron Lett. 1995, 36, 2393-2396.

2
386 J . Org. Chem., Vol. 66, No. 7, 2001
Cuzzupe et al.
thermodynamically more stable isomer 9 was best ef-
fected using CSA. Addition of lithium acetylide was
stereoselective providing adduct 26, and subsequent TMS
group removal gave alkyne 27 which upon treatment
with CSA partially isomerized to the 6,6-spiroketal 28.
The stereochemistry at C18 in 5,6-spiroketal 27 was
shown to be correct by the NOE observed between H18
and H11 while the C19 stereochemistry was shown to
be incorrect by the large NOE observed between H11 and
H19 in the 6,6-isomer 28.
Sch em e 7
Attempts at inversion27 of the C19 stereochemistry
failed, so we elected to examine an oxidation-reduction
sequence to correct this problem (Scheme 6). Oxidation
of TMS alkyne 26 with Dess-Martin reagent28 followed
by reduction with L-Selectride and alkyne deprotection
gave a 9:1 inseparable mixture of alcohols 29 and 27.
Silylation of this mixture followed by selective removal
of the primary TBS group afforded the desired spiroketal
the Wittig reaction proceeded to completion in 72 h at
00 °C. Heating at higher temperatures resulted in some
8
along with a small amount of the C19 epimer which
1
were now easily separable by flash chromatography. The
spiroketal 8 was then converted into the known degrada-
tion product 68 by the sequence shown. Desilylation
followed by partial hydrogenation and acetylation gave
the diacetate 30. Ozonolysis, reduction, and acetylation
then provided spiroketal 6, which had identical spectro-
scopic and analytical data to that reported for the
decomposition with little improvement in reaction rate.
A second Wittig reaction then provided diene ester 7
which upon DiBALH reduction followed by Dess-Martin
oxidation afforded the aldehyde 32 ready for aldol reac-
tion. Compound 32 was somewhat sensitive and it was
essential to carry out the Dess-Martin oxidation in the
presence of excess pyridine. In the absence of base, a
small amount of the C8-C9 geometric isomer was
formed. In model studies, we found the tin mediated aldol
reaction using the chiral oxazolidine-2-thione 33 to be
8
9,10
natural and previously synthesized
material confirm-
ing the absolute configuration of key intermediate 8.
Attempted isomerization of spiroketal 29 (9:1 mixture
with 27) failed to provide the reveromycin A spiroketal
30
most effective. Nagao, Fujita, and co-workers have
1
3b
3
1 as expected (eq 2). A similar result was also found
reported optimized conditions for effective aldol conden-
in a more advanced reveromycin B intermediate which
also resisted isomerization to the corresponding 6,6-spiro-
ketal.10
sations with R,â-unsaturated aldehydes without elimina-
30a
tion of the resultant aldol adduct.
The tin enolate
30c,31
derived from 33
triflate and 1.2 equiv N-ethylpiperidine3 at -55 °C for
h, and subsequent condensation with aldehyde 32
was formed using 1.2 equiv tin(II)
0a
3
proceeded effectively to give the adduct 34 in high yield
as one diastereoisomer.
Sid e Ch a in Syn th esis: C20-C24 Dien e. We next
elected to examine both Stille32 and Heck couplings for
the formation of the C21-C22 bond of the C20-C24
diene using a model system (Scheme 8). This study began
with silylation of spiroketal 20 to provide the ether 35
33
3
4
which upon palladium catalyzed hydrostannation gave
the (E)-vinylstannane 36 in good yield along with a small
amount of the proximal isomer (9:1 ratio). The iodide 38
required for the Heck coupling was formed from 36 by
iodine-tin exchange and fluoride deprotection of both 36
and 38 provided the corresponding alcohols 37 and 39.
The iodoesters 40 and 41 used for the Stille coupling
reactions were synthesized from the corresponding E-
Sid e Ch a in Syn th esis: C3-C10 fr a gm en t. The
introduction of the C3-C10 fragment was next initiated
beginning with synthesis of the aldehyde 32 required for
the syn-selective asymmetric aldol reaction (Scheme 7).
Oxidation of the alcohol 8 to the corresponding aldehyde
followed by two step Wittig homologation gave the diene
ester 7. Attempts to secure the ester in one step using a
conjugated ylide1
3b,29
proved unsuccessful. Condensation
(30) (a) Nagao, Y.; Hagiwara, Y.; Kumagi, T.; Ochiai, M.; Inoue, T.;
Hashimoto, K.; Fujita, E. J . Org. Chem. 1986, 51, 2391-2393. (b)
Nagao, Y.; Yamada, S.; Kumagai, T.; Ochiai, M.; Fujita, E. J . Chem.
Soc., Chem. Commun. 1985, 1418-1419. (c) Nagao, Y.; Kumagai, T.;
Yamada, S.; Fujita, E.; Inoue, Y.; Nagase, Y.; Aoyagi, S.; Abe, T. J .
Chem. Soc., Perkin Trans. 1 1985, 2361-2367.
of the aldehyde derived from 8 with 2-(triphenylphos-
phoranylidene)propionaldehyde also proved troublesome
with little or no reaction occurring in solvents such as
benzene or toluene, even at elevated temperatures.
However, when chlorobenzene was employed as solvent,
(
31) The preparation of oxazolidine-2-thione 33 is described in the
Experimental Section.
32) (a) Stille, J . K.; Groh, B. L. J . Am. Chem. Soc. 1987, 109, 813-
17. (b) Stille, J . K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508-524.
(
8
(
27) Mitsunobu, O. Synthesis 1981, 1-28. Martin, S. F.; Dodge, J .
A. Tetrahedron Lett. 1991, 32, 3017-3020.
28) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277-
287.
(c) Farina, V.; Krishnamurthy V. Scott W. J . In Organic Reactions;
Paquette, L. A., Ed.; J ohn Wiley and Sons: New York, 1997; pp 1-652.
(33) Wovkulich, P. M.; Shankaran, K.; Kiegiel, J .; Uskokovic, M. R.
J . Org. Chem. 1993, 58, 832-839. Dirat, O.; Kouklovsky, C.; Langlois,
Y. J . Org. Chem. 1998, 63, 6634-6642.
(34) Zhang, H. X.; Guib e´ , F.; Balavoine, G. J . Org. Chem. 1990, 55,
1857-1867.
(
7
(
29) Buchta, E.; Andree, F. Chem. Ber. 1959, 92, 3111-3116. Le
Corre, M. Tetrahedron Lett. 1974, 1037-1040. Lilly, M. J .; Zammit,
S. C.; Rizzacasa, M. A. Manuscript in preparation.

Total Synthesis of (-)-Reveromycin B
J . Org. Chem., Vol. 66, No. 7, 2001 2387
Ta ble 1
entry
substrate
ester
catalyst
solvent
additives
product
yield
1
2
3
4
5
6
7
36
36
36
37
37
38
39
40
40
40
40
41
42
42
Pd(MeCN)2Cl2
Pd2(dba)3
CuTC
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd2(OAc)2
DMF
NMP
NMP
NMP
NMP
CH2Cl2
CH2Cl2
42%a
72%
53%
84%
93%
62%
73%
P(2-furyl)3
43
43
44
45
43
44
P(2-furyl)3
P(2-furyl)3
Ag2CO3/NEt3
Ag2CO3/NEt3
a
Yield of the Z,E-isomer.
Sch em e 8
Sch em e 9
acid35 by esterification with diazomethane35b or trimeth-
ylsilylethanol and DCC. Compound 41 possesses a tri-
methylsilylethyl (Tmse) ester36 protecting group required
for eventual fluoride mediated deprotection to the car-
boxylic acid.10
The results of these model coupling reactions are
presented in Table 1. Initial experiments were not
encouraging exemplified by the coupling of 36 and 40
using a standard Pd(II) catalyst3 which gave the
isomerized C22-C23 (Z)-isomer as the major product (9:1
ratio) in low yield (entry 1). Gratifyingly, recourse to the
2a
Initially, we decided to complete the C1-C10 side
chain prior to Pd mediated construction of the C21-C22
bond. Although this route did not ultimately afford
reveromycin B (2), the results are worth briefly mention-
ing at this point (Scheme 9). Aldol adduct 34 was
silylated and the chiral auxiliary was removed by reduc-
tion with lithium borohydride. Reduction with sodium
3
7
Pd(0) conditions described by Farina and Krishnan gave
the desired product 43 in good yield with no isomerization
detected (entry 2). No improvement in yield was observed
using the CuTC (copper(I) thiophenecarboxylate) catalyst
3
8
reported by Allred and Liebeskind (entry 3). The best
yields were obtained from the Pd(0) catalyzed37 couplings
between the desilylated stannane 37 and esters 40 and
30c
borohydride gave the corresponding amido alcohol as
the major product. Oxidation and Wittig extension using
a stabilized ylide then provided the methyl ester 46.
Hydrostannation34 of 46 proceeded in moderate yield to
give the stannane 47, but attempted coupling with iodo
ester 40 under conditions developed in the model system
gave the desired diene in low yield with the major product
being iodide 48. A possible explanation for the formation
of iodide 48 is via tin-iodine exchange of stannane 47
4
1 which gave the dienes 44 and 45 in excellent yields
(entries 4 and 5). These results may be attributed to the
reduction in steric hindrance in the stannane or even
some type of polar effect. The corresponding Heck cou-
plings between iodides 38 and 39 and ester 42 under
modified conditions33 also gave acceptable yields (entries
6
and 7), but since the Stille approach gave consistently
better results, this method was utilized for C21-C22
bond construction.
effected by I released from homo-coupling of the vinyl
2
iodide 40. One way to increase the reactivity of the
stannane 47 would be to remove the O19 TBS group, but
this was not possible in the presence of the R,â-unsatur-
ated ester.
Com p letion of th e Tota l Syn th esis of 2. From the
above results it became apparent that the C2-C3 alkene
bond should be formed after the C21-C22 bond, and the
successful route to reveromycin B (2) is detailed in
(
35) (a) LeNoble, W. J . J . Am. Chem. Soc. 1961, 83, 3897-3899. (b)
Chen, S.-H.; Horvath, R. F.; J oglar, J .; Fisher, M. J .; Danishefsky, S.
J . J . Org. Chem. 1991, 56, 5834-5845.
(
36) Sieber, P. Helv. Chim. Acta 1977, 60, 2711-2716.
(37) Farina, V.; Krishnan, B. J . Am. Chem. Soc. 1991, 113, 9585-
9
2
595.
(38) Allred, G. D.; Liebeskind, L. S. J . Am. Chem. Soc. 1996, 118,
748-2749.

2
388 J . Org. Chem., Vol. 66, No. 7, 2001
Cuzzupe et al.
Sch em e 10
subjected to Stille coupling with the Tmse ester 41 under
the conditions reported earlier to provide triol ester 53
in excellent yield. This interesting reaction further
demonstrates the power of the Stille coupling for C-C
bond construction in the presence of multiple free hy-
droxyl groups. The steric hindrance at the C19 OH proved
useful as the triol could be selectively silylated under
standard conditions to provide bis-TBS ether 54.
Succinoylation of 54 using the half ester 55, derived
from the reaction of succinic anhydride and trimethyl-
3
silylethanol in the presence of NEt , DMAP, and N-
hydroxysuccinimide,39 gave bis-Tmse ester 56 in quan-
titative yield, and selective deprotection of the primary
4
0
TBS group using conditions reported by Evans afforded
the alcohol 57 (Scheme 11). This reagent left the Tmse
esters intact; however, a small amount of diol was also
formed. Dess-Martin oxidation of 57 followed by Wittig
reaction with the stabilized Tmse ylide 5841 gave fully
protected reveromycin B 59 in high yield. Deprotection
of 59 with TBAF in DMF then afforded reveromycin B
(
2), which was identical to the natural product in all
3
,4
respects. When TBAF in THF was utilized for the
deprotection, the Tmse groups were removed rapidly but
some C5 OTBS reveromycin B remained even after
prolonged exposure.
Con clu sion
The total synthesis of reveromycin B (2) was achieved
in 25 linear steps from the chiral methylene pyran 13.
Key features of this route include a hetero-Diels-Alder
reaction followed by a novel epoxidation-acid induced
ring contraction sequence to afford the 5,6-spiroketal 9
in a highly convergent and stereoselective manner, a
Stille cross coupling reaction to form the C21-C22 bond
in high yield in the presence of three hydoxyl groups, and
a tin mediated asymmetric aldol reaction to introduce the
C4-C5 syn-propionate. The synthesis also involved use
of only one type of alcohol protecting group (TBS ether).
The hetero-Diels-Alder methodology is currently being
Sch em e 11
4
2
applied to the synthesis of the other reveromycins.
Exp er im en ta l Section
1
Gen er a l. H NMR (300 or 400 MHz) and proton decoupled
C NMR spectra (75.5 or 100 MHz) were recorded in deuterio-
1
3
chloroform solutions (unless otherwise specified), with residual
protonated solvent as internal standard. Melting points were
measured on a Reichert hot stage melting point apparatus and
are uncorrected. Optical rotations were recorded for solutions
in a 10 cm microcell. High-resolution mass spectra (HRMS)
electrospray ionization (ESI) were run on a Bruker 4.7T
BIOAPEX FTMS mass spectrometer at Monash University,
Clayton, Victoria. Microanalyses were carried out at the
University of Otago, Dunedin, New Zealand. All moisture
sensitive reactions were done under an argon atmosphere in
oven dried (150 °C) glassware. Benzene, toluene, THF, and
2
Et O were purified and dried by distillation from sodium
Schemes 10 and 11. Reductive removal of the chiral
benzophenone ketyl. Dichloromethane was distilled from
calcium hydride. Other commercial reagents were used as
supplied. Reactions were monitored by TLC on silica gel 60
auxiliary in compound 34 was effected with sodium
borohydride30c in good yield to provide diol 50. At this
F
254 plates (Merck), and the compounds were detected by
point, we elected to forego protection of the diol in order
to reduce the number of protecting groups utilized. In
fact, the synthesis was completed using the TBS ether
as the only hydroxyl protecting group. Hydrostannation34
of 50 proceeded smoothly to afford stannane 51, which
was then deprotected by treatment with TBAF in warm
THF. The labile crude stannane 52 was then immediately
(
(
39) Guzzo, P. R.; Miller, M. J . J . Org. Chem. 1994, 59, 4862-4867.
40) Evans, D. A.; Gage, J . R.; Leighton, J . L. J . Am. Chem. Soc.
1992, 114, 9434-9453.
41) Hungerb u¨ hler, E.; Seebach, D.; Wasmuth, D. Helv. Chim. Acta
981, 64, 1467-1487.
42) El Sous, M.; Rizzacasa, M. A. Tetrahedron Lett. 2000, 41, 8591-
8594.
(
1
(

Total Synthesis of (-)-Reveromycin B
J . Org. Chem., Vol. 66, No. 7, 2001 2389
treatment with phosphomolybdic acid dip or alkaline potas-
sium permanganate dip followed by strong heating. Flash
chromatography was carried out using silica gel 60, 230-400
mesh (Merck). Petrol refers to petroleum ether, bp 40-60 °C.
Alk en e 24. To a mixture of t-BuOK (3.77 g, 33.4 mmol) and
trans-2-butene (3.25 mL, 34.6 mmol) in THF (35 mL) was
added n-BuLi (2.5 M in hexanes, 13.4 mL, 34 mmol) dropwise
at -78 °C. The resulting orange solution was warmed to -45
Sp ir ok eta l 11. To lactone 14 (218 mg, 0.800 mmol) was
added a solution of dimethyltitanocene44 (0.38 M in toluene,
4.1 mL, 1.6 mmol), and the resultant solution was heated at
65 °C in the dark for 18 h under argon. The orange oil obtained
after removal of the solvent was triturated twice with cold
hexane and the precipitate was removed by filtration through
Celite. The solvents were evaporated to give the crude pyran
as an orange oil. Purification by column chromatography on
°
C, stirred for 10 min, then recooled to -78 °C, and a solution
basic Al
petrol as eluent gave enol ether 13 (210 mg, 97%) as a pale
yellow oil: R (endo isomer) ) 0.44 (silica, EtOAc/petrol (10%));
2 3
O (Brockmann, Activity II-III) using 2.5% EtOAc/
of (-)-â-methoxydiisopinocampheylborane (10.5 g, 33.4 mmol)
in THF (40 mL) was added dropwise via cannula. The reaction
f
1
mixture was stirred at -78 °C for 30 min, and BF
3
‚OEt
2
(5.2
H NMR (300 MHz) δ 0.06 (s, 6H), 0.87 (d, J ) 7.8 Hz, 3H),
0.89 (s, 9H), 1.18-1.35 (m, 1H), 1.47-1.71 (m, 2H), 1.72-1.83
(m, 1H), 1.83-1.98 (m, 1H), 2.10-2.32 (m, 2H), 3.32 (td, J )
9.3, 2.4 Hz, 1H), 3.79 (m, 2H), 4.04 (d, J ) 1.5 Hz, 1H), 4.29
(d, J ) 1.5 Hz, 1H); 13C NMR (75.5 MHz) δ -5.32, -5.28, 17.7,
18.3, 25.9, 29.0, 31.7, 34.2, 36.5, 59.3, 81.5, 90.7, 160.2. A
mL, 45 mmol) was added dropwise, followed by a solution of
4
3
aldehyde 23 (4.20 g, 22.3 mmol) in THF (35 mL), and the
resultant viscous mixture was stirred for a further 2 h.
Saturated aqueous NaHCO (70 mL) and 30% H O (14 mL)
3 2 2
were added, and the mixture was stirred at room temperature
for 18 h. The THF was evaporated and the residue was
2
mixture of enol ether 13 (147 mg, 0.543 mmol), oven dried K -
extracted with Et
washed with water and brine and then dried (MgSO
2
O. The combined organic extracts were
), filtered,
CO
3
5
(82 mg, 0.59 mmol), and freshly distilled butylacrolein
4
12 (0.366 mL, 2.72 mmol) was heated at 110 °C for 2 d under
4
and evaporated to give the crude product as a yellow oil.
Purification by flash chromatography with 5% EtOAc/petrol
2
argon. The cooled suspension was diluted with Et O and the
organic extract was washed with water and brine. The solvents
were evaporated and the resulting oil was pumped for 5 h at
0.1 mmHg to remove the residual butylacrolein. The crude
1
3a
as eluent gave alkene 24 (3.39 g, 68%) as a colorless oil: R
f
2
5
1
)
(
0.29 (5% EtOAc/petrol); [R]
D
3
-9.7 (c 0.64, CHCl ); H NMR
300 MHz) δ 0.05 (s, 6H), 0.87 (s, 9H), 1.01 (d, J ) 5.4 Hz,
product was then purified by column chromatography on Al
(Brockmann, Activity II-III) with 2.5% Et O/petrol as eluent
to give spiroketal 11 (141 mg, 68%) as a colorless oil: R
2 3
O
3
2
H), 1.60 (m, 2H), 2.21 (m, 1H), 3.67 (m, 1H), 3.75-3.89 (m,
2
H), 5.04 (m, 2H), 5.80 (m, 1H); 13C NMR (75.5 MHz) δ -5.59,
f
)
0.69 (silica, 5% EtOAc/petrol); [R]25
1
-
5.57, 15.7, 18.0, 25.8, 35.4, 43.9, 62.7, 74.9, 115.0, 140.6. Anal.
D
3
+99.0 (c 1.0, CHCl ); H
Calcd for C13
1.26.
Meth yl ester 25. To a solution of alkene 24 (1.00 g, 4.09
H
28
O
2
Si: C, 63.87; H, 11.54. Found: C, 64.08; H,
NMR (300 MHz) δ 0.03 (s, 6H), 0.85 (d, J ) 6.3 Hz, 3H), 0.87
(s, 9H), 0.89 (t, J ) 6.6 Hz, 3H), 1.20-1.44 (m, 5H), 1.46-1.66
m, 5H), 1.67-1.81 (m, 3H), 1.81-1.91 (m, 2H), 1.99-2.22 (m,
H), 3.36 (dt, J ) 9.9, 2.1 Hz, 1H), 3.54 (ddd, J ) 15.0, 8.7,
.6 Hz, 1H), 3.72 (ddd, J ) 15.0, 9.9, 5.1 Hz, 1H), 6.01 (s, 1H);
C NMR (300 MHz) δ -5.26, 13.9, 17.6, 18.3, 20.3 22.4, 25.9,
7.8, 30.4, 32.0, 32.6, 34.5, 34.8, 36.5, 60.5, 73.1, 94.6, 113.5,
1
(
2
6
mmol) in THF (12 mL) and water (1.2 mL) was added
N-methylmorpholine-N-oxide (60% ww in water, 1.04 g, 5.3
1
3
mmol) and OsO
the mixture was stirred for 5 h at room temperature. To this
was added NaIO (1.07 g, 5.00 mmol) and water (2.0 mL), and
stirring was continued for 2 h. Et O was added, and the organic
extract was washed with water and brine and then dried (Na
SO
pale brown oil. To a solution of the crude aldehyde in dry CH
Cl
4
(0.20M in t-BuOH, 0.82 mL, 0.16 mmol), and
2
1
34.4. Anal. Calcd for C22
42 3
H O Si: C, 69.05; H, 11.06. Found:
4
C, 69.34; H, 10.78.
Sp ir ok eta l Ald eh yd e 9. To a solution of spiroketal 11 (1.96
2
2
-
-
4
), filtered, and evaporated to give the crude aldehyde as a
2 2
g, 5.12 mmol) in dry CH Cl (50 mL) was added anhydrous
dimethyldioxirane2 (0.084 M in acetone, 67 mL, 5.6 mmol)
1b
2
2
(10 mL) was added methyl (triphenylphosphoranylidene)-
at 0 °C under an argon atmosphere. The solution was stirred
acetate (1.77 g, 5.29 mmol), and the mixture was stirred at
room temperature for 16 h under argon. The solvent was
evaporated and the residue was purified by fast vacuum
filtration on silica to give the crude product as a brown oil.
Purification by flash chromatography with 10% EtOAc/petrol
as eluent gave methyl ester 25 (E-25/Z-25 84:16, 1.04 g, 84%
for 15 min, and then the solvent was evaporated to give crude
1
epoxide 10 (2.04 g, 100% crude yield) as a colorless oil:
H
NMR (300 MHz) δ 0.037 (s, 3H), 0.044 (s, 3H), 0.85 (d, J ) 6.6
Hz, 3H), 0.88 (s, 9H), 0.88 (t, J ) 7.0 Hz, 3H), 1.22-2.50 (m,
17H), 3.51 (dt, J ) 10.2, 2.4 Hz, 1H), 3.63 (m, 1H), 3.75 (ddd,
J ) 9.6, 4.5 Hz, 1H), 4.51 (s, 1H); 13C NMR (75.5 MHz) δ -5.23,
-5.18, 13.9, 17.7, 18.3, 21.4, 22.8, 25.9, 26.0, 27.6, 30.8, 34.7,
35.0, 35.2, 36.4, 60.2, 60.9, 72.9, 79.9, 94.9. To a solution of
for three steps) as a yellow oil: R (E-25) ) 0.25 (10% EtOAc/
f
1
petrol); H NMR (300 MHz) (E-25) δ 0.07 (s, 6H), 0.89 (s, 9H),
1
3
.09 (d, J ) 6.9 Hz, 3H), 1.61 (m, 2H), 2.41 (m, 1H), 3.72 (s,
H), 3.77-3.91 (m, 3H), 5.87 (d, J ) 15.6 Hz, 1H), 7.03 (dd, J
the crude epoxide 10 in dry CH
(59 mg, 0.25 mmol), and the solution was stirred at room
temperature for 30 min. Et O was added, and the organic
extract was washed with saturated aqueous NaHCO , water,
and brine and then dried (Na SO ), filtered, and evaporated
2 2
Cl (40 mL) was added CSA
1
3
)
15.9, 8.1 Hz, 1H); C NMR (75.5 MHz) (E-25) δ -5.61,
2
-
5.57, 15.3, 18.1, 25.8, 35.4, 42.6, 51.4, 62.9, 75.1, 121.2, 151.1,
3
1
67.0. Anal. Calcd for C15
H
30
O
4
Si: C, 59.56; H, 9.99. Found:
2
4
C, 59.25; H, 9.91.
to give crude spiroketal aldehyde 9 (2.02 g, 99% crude yield
La cton e 14. To a solution of unsaturated methyl ester 25
E-25/Z-25 84:16, 1.04 g, 3.43 mmol) in anhydrous EtOAc (10
for two steps) as a pale yellow oil which was used without
1
(
further purification: R
f
) 0.55 (5% EtOAc/petrol); H NMR
mL) was added 5% Pd/C (30 mg), and the suspension was
stirred under a hydrogen atmosphere for 24 h. The catalyst
was removed by filtration and the filtrate was concentrated
to give the crude saturated ester as a yellow oil. The crude
(300 MHz) δ 0.04 (s, 3H), 0.05 (s, 3H), 0.83 (d, J ) 5.1 Hz,
3H), 0.87 (t, J ) 6.6 Hz, 3H), 0.88 (s, 9H), 1.22-1.86 (m, 15H),
2.24 (m, 2H), 3.53-3.80 (m, 3H), 9.59 (s, 1H); 13C NMR (75.5
MHz) δ -5.3, 13.9, 17.7, 18.2, 23.0, 25.3, 25.9, 29.2, 29.4, 33.8,
34.6, 34.8, 36.4, 38.1, 59.5, 73.5, 90.2, 107.0, 205.4.
2 2
ester was dissolved in CH Cl (15 mL) and PPTS (50 mg, 0.19
mmol) was added and the resulting solution was heated at
reflux under argon for 2 h. The solvent was evaporated and
the crude product was purified by flash chromatography with
5,6-Sp ir ok eta l 27. A solution of n-BuLi (2.5 M in hexanes,
0.560 mL, 1.4 mmol) was added dropwise over 5min to a
solution of (trimethylsilyl)acetylene (0.197 mL, 1.38 mmol) in
anhydrous THF (2.0 mL) under argon. After 20 min at -78
°C a solution of crude spiroketal aldehyde 9 (93.0 mg, 0.233
mmol) in THF (2.0 mL) was added via cannula at -78 °C. The
solution was stirred at -78 °C for 1h and then allowed to warm
to 0 °C over 1h. The reaction was quenched with saturated
1
0% EtOAc/petrol as eluent to give lactone 14 (786 mg, 85%
for two steps) as a colorless oil: R ) 0.39 (10% EtOAc/petrol);
); H NMR (300 MHz) δ 0.05 (s, 6H),
.88 (s, 9H), 1.02 (d, J ) 6.6 Hz, 3H), 1.50-2.00 (m, 5H), 2.40-
.66 (m, 2H), 3.77-3.82 (m, 2H), 4.09 (td, J ) 9.3, 2.4 Hz, 1H);
C NMR (75.5 MHz) δ -5.4, 17.4, 18.2, 25.8, 27.8, 29.4, 32.5,
f
2
5
1
[
0
2
R]
D
+55.9 (c 1.1, CHCl
3
1
3
aqueous NaHCO
3 2
and extracted twice with Et O, and then the
3
28 3
6.7, 58.5, 82.6, 186.4. Anal. Calcd for C14H O Si: C, 61.72;
combined organic extracts were washed with 1% aqueous HCl,
H, 10.36. Found: C, 61.82; H, 10.05.
(
2 2
44) For a convenient preparation of Cp TiMe see: Payack, J . F.;
(
43) Pirrung, M. C.; Webster, N. J . G. J . Org. Chem. 1987, 52, 3603-
Hughes, D. L.; Cai, D. W.; Cottrell, I. F.; Verhoeven, T. R.; Org. Prep.
Proced. Int. 1995, 27, 707-709.
3
613.

2
390 J . Org. Chem., Vol. 66, No. 7, 2001
Cuzzupe et al.
water, and brine and then dried (MgSO
evaporated to give crude TMS-alkyne 26 as a pale yellow oil.
The crude TMS-alkyne 26 was dissovled in MeOH (2.0 mL),
4
), filtered, and
mmol), and the mixture was stirred for 2.5 h. Saturated
aqueous NaHCO
extract was washed with water, saturated aqueous CuSO
water, and brine and then dried (MgSO ), filtered, and
3
and water were then added, and the organic
4
,
and K
was stirred at room temperature for 3 h. The solvent was
evaporated, and the resulting slurry was diluted with Et
and washed with water and brine and then dried (MgSO
2
CO
3
(31 mg, 0.23 mmol) was added and the solution
4
evaporated to give the crude products as a yellow oil. Purifica-
tion by flash chromatography with 1%, 2%, and then 5%
EtOAc/petrol as eluent gave a mixture of bisTBS-ethers (90:
2
O
4
),
1
filtered, and evaporated to give the crude product as a yellow
oil. Purification by flash chromatography using 5% EtOAc/
petrol as eluent provided 5,6-spiroketal 27 (76.0 mg, 77% yield
10 by H NMR (300 MHz), 3.84 g, 91%) as a pale yellow oil. A
solution of the crude bisTBS-ethers in THF (89 mL) was added
via cannula to a freshly prepared solution of HF‚pyridine (5.16
g, 178 mmol) buffered with pyridine40 (10.3 mL, 127 mmol) in
THF (21 mL), and the mixture was stirred at room tempera-
for two steps) as a pale yellow oil: R
f
) 0.36 (5% EtOAc/petrol);
2
5
1
[
R]
D
+35.0 (c 0.72, CHCl
3
); H NMR (300 MHz) δ 0.07 (s, 3H),
.08 (s, 3H), 0.86 (d, J ) 6.6 Hz, 3H), 0.90 (s, 9H), 0.90 (t, J )
Hz, 3H), 1.16-1.46 (m, 8H), 1.48-1.92 (m, 7H), 1.94-2.28
0
7
ture for 5 h. Saturated aqueous NaHCO was added and the
3
mixture was diluted with Et O. The aqueous phase was
2
(m, 2H), 2.37 (d, J ) 2.4 Hz, 1H), 3.60 (d, J ) 7.5 Hz, 1H),
extracted with Et O and the combined organic extracts were
2
3
.63 (m, 1H), 3.75 (m, 2H), 4.29 (dd, J ) 7.5, 2.4 Hz, 1H); 13
C
washed with water, saturated aqueous CuSO , water, and
4
NMR (75.5 MHz) δ -5.24, -5.16, 14.1, 17.7, 18.4, 23.2, 25.8,
brine and then dried (Na SO ), filtered, and evaporated to give
2
4
2
7
6.0, 29.2, 29.6, 34.4, 34.5, 34.8, 36.2, 39.7, 59.7, 68.6, 73.0,
3.6, 82.9, 89.7, 107.0. Anal. Calcd for C24 Si: C, 67.87;
the crude products as a yellow oil. Purification by flash
chromatography with 1%, 2%, and then 5% EtOAc/petrol as
eluent gave pure TBS-ether 8 (2.63 g, 80% for two steps) as a
44 4
H O
H, 10.44. Found: C, 67.47; H, 10.43.
,6-Sp ir ok eta l 28. To a solution of 5,6-spiroketal 27 (36.0
mg, 82.0 µmol) in CDCl (1.0 mL) in an NMR tube was added
a solution of CSA (0.04 M in CDCl , 65 µL, 2.6 µmol), and the
equilibration was monitored by H NMR analysis. After 24 h
at room temperature, the solution was diluted with Et O and
washed with saturated aqueous NaHCO , water, and brine and
then dried (MgSO ), filtered, and evaporated to give the
colorless oil: R
0.65, CH Cl ); IR υmax (film) 3448, 3316, 2955, 2859, 1464 cm ;
f
) 0.40 (10% EtOAc/petrol); [R]19
) +36.4 (c
-1
D
6
3
2
2
1
H NMR (300 MHz) δ 0.11 (s, 3H), 0.14 (s, 3H), 0.79 (d, J )
6.3 Hz, 3H), 0.84 (s, 9H), 0.87 (t, J ) 6.9 Hz, 3H), 1.00-1.45
(m, 6H), 1.46-2.05 (m, 11H), 2.35 (d, J ) 1.8 Hz, 1H), 2.95
3
1
2
1
3
3
(br s, 1H), 3.68-3.80 (m, 3H) 4.36 (d, J ) 1.8 Hz, 1H);
C
4
NMR (75.5 MHz) δ -5.5, -4.6, 14.2, 17.6, 17.8, 23.2, 25.4, 25.6,
28.8, 31.5, 32.9, 33.8, 34.5, 34.9, 38.9, 61.2, 70.3, 72.9, 77.1,
product as a yellow oil. Purification by flash chomatography
with 5-15% EtOAc/petrol as eluent afforded recovered 5,6-
spiroketal 27 (17.6 mg, 49%). Further elution gave 6,6-
84.3, 88.2, 106.8; HRMS (ESI) calcd for C24
Na ]: 447.2907. Found: 447.2910. Anal. Calcd for C24
H
44
O
4
SiNa [M +
+
44 4
H O -
spiroketal 28 (14.4 mg, 40%) as a colorless oil: R
f
) 0.18 (5%
); H NMR (400 MHz)
δ 0.06 (s, 3H), 0.07 (s, 3H), 0.86 (d, J ) 6.8 Hz, 3H), 0.91 (s,
Si: C, 67.87; H, 10.44. Found: C, 67.95; H, 10.61. Further
elution gave the epimeric TBS-ether (251 mg, 7% for two steps)
2
5
1
EtOAc/petrol); [R]
D
+35.6 (c 1.0, CHCl
3
1
9
as a colorless oil: R
f
) 0.20 (5% EtOAc/petrol); [R]
D
) +27.4
9
2
2
-
3
H), 0.91 (t, J ) 7.2 Hz, 3H), 1.24-1.85 (m, 17H), 2.45 (d, J )
.0 Hz, 1H), 3.43 (dt, J ) 10.4, 2.4 Hz, 1H), 3.74-3.82 (m,
H), 4.44 (d, J ) 2.0 Hz, 1H); 13C NMR (100 MHz) δ -5.21,
(c 0.76, CH Cl ); IR υmax (film) 3446, 3306, 2951, 2854, 1459
2
2
-
1 1
cm ; H NMR (300 MHz) δ 0.12 (s, 3H), 0.16 (s, 3H), 0.79 (d,
J ) 6.3 Hz, 3H), 0.87 (t, J ) 6.9 Hz, 3H), 0.90 (s, 9H), 1.15-
2.40 (m, 17H), 2.32 (d, J ) 2.1 Hz, 1H), 2.92 (br s, 1H), 3.65-
3.83 (m, 3H), 4.34 (d, J ) 2.4 Hz, 1H).; 13C NMR (75.5 MHz)
δ -5.0, -4.3, 14.2, 17.5, 18.1, 23.3, 25.6, 25.8, 28.8, 31.1, 33.8,
5.12, 13.9, 17.6, 18.3, 23.2, 24.8, 26.0, 27.7, 27.8, 30.9, 34.8,
4.9, 36.2, 38.7, 59.2, 67.4, 69.8, 71.6, 74.6, 80.3, 95.8.
TBS-eth er 8. To a solution of crude 5,6-spiroketal 26 (4.09
3
4.1, 34.3, 34.4, 38.4, 61.0, 70.3, 73.2, 76.8, 83.7, 89.4, 106.7;
]: 447.2907.
Si: C, 67.87; H,
g, 8.24 mmol) in CH
pyridine (3.33 mL, 41.2 mmol) then Dess-Martin reagent
8.74 g, 20.6 mmol), and this was stirred at room temperature
for 3 h. The reaction mixture was diluted with Et O and stirred
with saturated aqueous NaHCO (110 mL) and 1.5 M Na
110 mL) until two clear layers formed. The aqueous phase
2 2
Cl (50 mL) under argon was added
4
6
HRMS (ESI) calcd for C H O SiNa [M + Na
Found: 447.2893. Anal. Calcd for C24
10.44. Found: C, 67.87; H, 10.52.
+
24 44
4
(
44 4
H O
2
3
2
S
2
O
3
Dia ceta te 30. To a solution of TBS-ether 8 (84.0 mg, 0.198
(
mmol) in THF (1.4 mL) under argon was added TBAF‚3H O
2
(125 mg, 0.396 mmol), and the mixture was stirred at room
temperature for 24 h. Water was added, and the aqueous phase
was extracted with Et
were washed with water, saturated aqueous CuSO
and brine and then dried (Na SO
2
O, and the combined organic extracts
, water,
), filtered, and evaporated
4
2
4
was extracted with Et O. The combined organic extracts were
2
to give the crude ketone as a yellow oil. To a solution of the
crude ketone in THF (80 mL) under argon at -78 °C was added
L-Selectride (1.0 M in THF, 16.2 mL, 16 mmol). The reaction
mixture was stirred at -78 °C for 10 min and then warmed
washed with water and brine and then dried (Na SO ), filtered,
2
4
and evaporated to give the crude product as a yellow oil.
Purification by flash chromatography with 40% EtOAc/petrol
as eluent gave the diol (60.8 mg, 99%) as a pale yellow oil: R
f
2
3
to room temperature and diluted with Et
aqueous phase was acidified to pH 3.0 and extracted with
Et O. The combined organic extracts were washed with
saturated aqueous NaHCO , water, and brine and then dried
MgSO ), filtered, and evaporated. The residue was purified
2
O and water. The
) 0.50 (40% EtOAc/petrol); [R]
) +56.3 (c 1.89, CH Cl );
D
2
2
1
H NMR (300 MHz) δ 0.84 (d, J ) 6.3 Hz, 3H), 0.89 (t, J ) 6.8
Hz, 3H), 1.28-2.07 (m, 17H), 2.32-2.45(m, 1H), 2.39 (d, J )
2
3
2.4 Hz, 1H), 2.75 (br s, 1H), 3.68 (m, 2H), 3.79 (dt, J ) 9.0, 3.9
(
4
Hz, 1H), 4.38 (d, J ) 2.1 Hz, 1H); 13C NMR (75.5 MHz) δ 14.0,
by flash chromatography with EtOAc/petrol (1%, 2%, then 5%)
as eluent to give a mixture of 5,6-spiroketal epimers (90:10
17.6, 23.1, 25.3, 28.3, 28.8, 34.5, 35.0, 36.5, 39.0, 59.1, 67.0,
73.3, 75.1, 82.6, 90.5, 107.2. To a solution of the diol in MeOH
(0.75 mL) was added Lindlar’s catalyst (21 mg, 0.010 mmol),
and the mixture was stirred at room temperature under a
hydrogen atmosphere for 6 h. The mixture was filtered through
1
by H NMR (300 MHz), 3.55 g, 87% for two steps) as a pale
yellow oil. To the mixture of 5,6-spiroketal epimers in MeOH
(
2 3
50 mL) was added K CO (988 mg, 7.15 mmol), and the
solution was stirred at room temperature under argon for 2.5
h. The solvent was evaporated and then the residue was
Celite, and the solvent was evaporated to give the crude alkene
1
as a pale yellow oil: R
(
1
f
) 0.15 (20% EtOAc/petrol); H NMR
diluted with Et
2
O and washed with water and brine and then
300 MHz) δ 0.86 (d, J ) 6.6 Hz, 3H), 0.88 (t, J ) 6.6 Hz, 3H),
dried (MgSO ), filtered, and evaporated to give a crude mixture
4
.16-2.07 (m, 16H), 2.20-2.37 (m, 1H), 3.68 (m, 2H), 3.80 (dt,
1
of alkynes 29 (90:10 by H NMR (300 MHz), 2.97 g, 85% crude
J ) 9.0, 3.6 Hz, 1H), 4.13 (d, J ) 6.3 Hz, 1H), 5.19 (d, J )
yield for three steps) as a yellow oil. To a crude mixture of
1
1
2
1
0.5 Hz, 1H), 5.38 (d, J ) 17.1 Hz, 1H), 5.77 (ddd, J ) 17.1,
1
alkynes 29 (90:10 by H NMR (300 MHz), 3.31 g, 7.80 mmol)
13
0.5, 6.3 Hz, 1H); C NMR (75.5 MHz) δ 14.1, 17.7, 23.2, 25.3,
in CH
2 2
Cl (25 mL) at -40 °C under argon was added 2,6-
7.4, 28.9, 34.5, 35.0, 35.1, 37.1, 39.1, 59.2, 75.3, 76.2, 90.9,
06.7, 117.3, 136.4. To a solution of the crude alkene in
lutidine (2.27 mL, 19.5 mmol) and TBSOTf (2.69 mL, 11.7
pyridine (2.0 mL, 25 mmol) was added acetic anhydride (1.0
mL, 11 mmol) and DMAP (5.0 mg, 0.037 mmol), and then the
mixture was stirred at room temperature under argon for 3
h. The solvents were evaporated and the residue was purified
by flash chromatography with 10% EtOAc/petrol as eluent to
(
45) For the preparation of butylacrolein see: Green, M. B.; Hick-
inbottom, W. J . J . Chem. Soc. 1957, 3262-3270.
46) Preparation of Dess-Martin reagent: Ireland, R. E.; Liu, L. J .
Org. Chem. 1993, 58, 2899.
(

Total Synthesis of (-)-Reveromycin B
J . Org. Chem., Vol. 66, No. 7, 2001 2391
give diacetate 30 (59.0 mg, 74% for three steps) as a colorless
72.9, 75.5, 84.3, 87.9, 107.0, 115.0, 133.7, 138.7, 149.8, 167.8;
2
4
+
oil: R
f
) 0.30 (10% EtOAc/petrol); [R]
D
) +41.1 (c 2.29,
); H NMR (300 MHz) δ 0.84 (d, J ) 6.6 Hz, 3H), 0.88
t, J ) 6.6 Hz, 3H), 1.15-1.40 (m, 6H), 1.40-1.85 (m, 8H),
HRMS (ESI) calcd for C30
Found: 541.3315.
H
50
O
5
SiNa [M + Na ]: 541.3325.
1
CHCl
3
(
Oxa zolid in e-2-th ion e 33. To a stirred solution of L-valinol
1
2
6
1
3
1
6
.86-2.10 (m, 3H), 1.99 (s, 3H), 2.08 (s, 3H), 3.52 (td, J ) 9.6,
.4 Hz, 1H), 4.10 (m, 1H), 4.36 (m, 1H), 5.14-5.30 (m, 3H),
.01 (ddd, J ) 15.5, 11.0, 4.4 Hz, 1H); 13C NMR (75.5 MHz) δ
4.2, 17.7, 21.0, 21.1, 23.2, 25.5, 29.2, 31.6, 32.4, 34.2, 34.5,
4.7, 38.6, 61.0, 72.9, 79.4, 86.9, 106.8, 116.0, 134.2, 169.8,
(6.17 g, 59.8 mmol) in CH Cl (75 mL) under argon was added
2
2
NEt3 (10.0 mL, 71.8 mmol) and CS2 (4.0 mL, 66 mmol), and
then the resulting solution was refluxed for 5 h under a drying
tube. Silica (20 g) was added, and the solvent was evaporated.
Purification by flash chromatography with CH Cl as eluent
2
2
71.2. Anal. Calcd for C22
6.39; H, 9.08.
H
36
O
6
: C, 66.64; H, 9.15. Found: C,
gave the (4S)-4-isopropyl-1,3-oxazolidine-2-thione (5.91 g, 68%)
2
0
as a yellow oil: R ) 0.40 (CH Cl ); [R] ) -18.1 (c 0.41,
f
2
2
D
CHCl
3
); lit.3 [R]
0c
16
D
3
) -22.5 (c 0.41, CHCl ) H NMR (300 MHz)
1
Tr ia ceta te 6. A solution of diacetate 30 (59.0 mg, 0.149
mmol) in CH Cl (2.5 mL) and MeOH (0.85 mL) at -78 °C
was bubbled with O gas until the solution turned purple, and
then NaBH (17 mg, 0.45 mmol) was added and the mixture
was warmed to room temperature and stirred for 10 min. The
solvent was evaporated and the residue was diluted with Et
and water. The aqueous phase was acidified with 10% HCl
and extracted with Et O. The combined organic extracts were
washed with saturated aqueous NaHCO , water, and brine and
then dried (Na SO ), filtered and evaporated. The crude alcohol
was dissolved in pyridine (2.0 mL, 25 mmol), and then acetic
anhydride (1.0 mL, 11 mmol) and DMAP (2.0 mg, 0.015 mmol)
were added and the mixture was stirred at room temperature
under argon for 24 h. The solvents were evaporated and the
residue was purified by flash chromatography with 15%
EtOAc/petrol as eluent to give triacetate 6 (60.0 mg, 91% yield
δ 0.90 (d, J ) 6.9 Hz, 3H), 0.95 (d, J ) 6.6 Hz, 3H), 1.80 (m,
1H), 3.84 (m, 1H), 4.35 (dd, J ) 6.6, 9.3 Hz, 1H), 4.66 (dd, J )
9.3, 9.3HZ, 1H), 8.74 (br. s, 1H); 13C NMR (75.5 MHz) δ 17.8,
17.9, 32.1, 62.4, 73.4, 189.5. To a stirred solution of the 1,3-
oxazolidine-2-thione (5.91 g, 40.7 mmol) in benzene (50 mL)
under argon was added pyridine (3.62 mL, 45.0 mmol) and
propionyl chloride (4.24 mL, 49.0 mmol), and stirring was
continued for 5 h. The reaction mixture was quenched by
2
2
3
4
2
O
2
3
adding to water and partitioned with Et
aqueous layer was back extracted twice with Et
combined organic extracts were washed with 10% HCl, water,
saturated aqueous NaHCO , water, and brine and then dried
Na SO ), filtered and evaporated. Purification by flash chro-
2
O, and then the
2
4
2
O. The
3
(
2
4
matography with 10% EtOAc/petrol as eluent followed by
recrystallization from petrol gave oxazolidine-2-thione 33 (4.96
g, 60%) as a crystalline colorless solid: R
f
) 0.80 (33% EtOAc/
for two steps) as colorless prisms: R
petrol); mp 58-59 °C; [R]
f
) 0.30 (15% EtOAc/
petrol); mp 43-44 °C; [R]18 ) +140.2 (c 1.07, CHCl ); H NMR
1
2
0
8
15
) +51.8 (c 1.20, CHCl
3
); lit. [R]
D
D
3
D
1
0
25
(300 MHz) 0.87 (d, J ) 6.9 Hz, 3H), 0.92 (d, J ) 7.2 Hz, 3H),
1.18 (t, J ) 7.2 Hz, 3H), 2.34 (m, 1H), 3.24 (dq, J ) 18.3, 7.2
Hz, 1H), 3.38 (dq, J ) 18.3, 7.2 Hz, 1H), 4.36 (d, J ) 1.5 Hz,
)
+44.3 (c 0.18, CHCl
3
); lit. [R]
D
) +37.5 (c 1.0, CHCl
3
);
1
H NMR (300 MHz) δ 0.84 (d, J ) 6.6 Hz, 3H), 0.89 (t, J ) 6.9
Hz, 3H), 1.14-1.82 (m, 14H), 1.87-1.99 (m, 3H), 2.01 (s, 3H),
1
1
H), 4.38 (s, 1H), 4.70 (m, 1H); 13C NMR (75.5 MHz) 8.59, 14.9,
8.2, 28.9, 31.3, 63.3, 67.6, 174.9, 186.1. Anal. Calcd for
2
.02 (s, 3H), 2.05 (s, 3H), 3.47 (td, J ) 9.2, 2.7 Hz, 1H), 4.15
m, 1H), 4.21 (dd, J ) 12.0, 9.0 Hz, 1H), 4.30 (m, 1H), 4.49
dd, J ) 12.0, 2.1 Hz, 1H), 5.15 (dd, J ) 9.0, 2.1 Hz, 1H); 13
(
(
C H O NS: C, 53.70; H, 7.51; N, 6.96. Found: C, 53.91; H,
9
15
2
C
7
.58; N, 6.97.
NMR (100 MHz) δ 14.1, 17.7, 20.8, 21.0, 21.1, 23.2, 25.5, 29.0,
3
1
1.4, 32.2, 34.2, 34.4, 34.6, 38.4, 61.7, 63.9, 73.6, 76.5, 86.1,
06.9, 170.3, 171.1. Anal. Calcd for C23 : C, 62.42; H, 8.65.
Ald ol Ad d u ct 34. To a solution of the diene ester 7 (418
H
38
O
8
mg, 0.806 mmol) in CH
was added DiBALH (1.0 M in CH
2
Cl
2
(10 mL) under argon at -78 °C
Found: C, 62.19; H, 8.36.
Dien e Ester 7. To a solution of TBS-ether 8 (1.11 g, 2.60
mmol) in CH Cl (38 mL) under argon was added Dess-Martin
reagent (1.76 g, 4.16 mmol) and the mixture was stirred at
room temperature for 2 h. The mixture was diluted with Et
and stirred with saturated aqueous NaHCO (50 mL) and 1.5
M Na (50 mL) until two clear layers formed. The aqueous
phase was extracted with Et O, and the combined organic
extracts were washed with water and brine and then dried
Na SO ), filtered, and evaporated to give the crude aldehyde
2
Cl , 2.42 mL, 2.42 mmol)
2
dropwise. The mixture was stirred at -78 °C for 25 min and
then warmed to room temperature. The DiBALH was quenched
with EtOAc (1.0 mL), and then CH Cl (10 mL) and 0.5 M (+)-
2 2
sodium tartrate (10 mL) were added and stirring was contin-
ued for 15 min. Water was added and the aqueous phase was
2
2
2
O
3
extracted with Et
washed with water and brine and then dried (MgSO
and evaporated to give the crude alcohol as a colorless oil. The
crude alcohol was dissolved in CH Cl (10 mL), and then
2
O. The combined organic extracts were
2
2 3
S O
4
), filtered,
2
2
2
(
2
4
pyridine (0.223 mL, 2.82 mmol) and Dess-Martin reagent (598
mg, 1.41 mmol) were added, and the mixture was stirred at
room temperature under argon for 40 min. The reaction
as a yellow oil. The crude aldehyde was dissolved in chloro-
benzene (20 mL), and 2-(triphenylphosphoranylidene)pro-
pionaldehyde (3.93 g, 12.3 mmol) was added, and then the
mixture was stirred in the dark at 100 °C under argon for 72
h. The solvent was evaporated, and the crude product was
purified by flash chromatography with EtOAc/petrol (2% then
mixture was diluted with Et
aqueous NaHCO (20 mL) and 1.5 M Na
two clear layers formed. The aqueous phase was extracted with
Et O and the combined organic extracts were washed with
water and brine and then dried (Na SO ), filtered and evapo-
rated to give crude aldehyde 32 as a yellow oil. To a suspension
2
O and stirred with saturated
3
2 2 3
S O
(20 mL) until
2
5
%) as eluent to give the dienal (793 mg, 66% for two steps)
1
2
4
as a yellow oil: R ) 0.69 (10% EtOAc/petrol); H NMR (300
f
MHz) δ 0.08 (s, 3H), 0.15 (s, 3H), 0.88 (s, 9H), 0.91 (t, J ) 6.0
Hz, 3H), 1.00-1.45 (m, 10H), 1.50-1.85 (m, 6H), 1.77 (s, 3H),
4
7
of Sn(OTf)
2
2 2
(827 mg, 1.18 mmol) in CH Cl (3.0 mL) under
argon at -55 °C was added N-ethylpiperidine (0.272 mL, 1.98
mmol). A solution of oxazolidine-2-thione 33 (332 mg, 1.65
1
.85-2.05 (m, 2H), 2.36 (d, J ) 2.1 Hz, 1H), 2.53 (m, 2H), 3.78
(
9
m, 1H), 4.36 (d, J ) 2.1 Hz, 1H), 6.69 (t, J ) 7.5 Hz, 1H),
mmol) in CH
mixture was stirred at -55 °C for 1 h and then cooled to -78
C. A solution of the crude aldehyde 32 in CH Cl (3.0 mL) at
78 °C was added via cannula, and the mixture was stirred
2 2
Cl (3.0 mL) was added via cannula, and the
.45 (s, 1H). The dienal was dissolved in benzene (20 mL) and
methyl(triphenylphosphoranylidene)acetate (0.974 g, 2.91 mmol)
was added, and then the mixture was heated at reflux under
argon for 72 h. The solvent was evaporated and the residue
was purified by flash chromatography with EtOAc/petrol (2%
then 5%) as eluent to give diene ester 7 (888 mg, 66% for three
steps) as a yellow oil: R
-
°
2
2
-
at -78 °C for 5 min. The reaction mixture was poured into
pH 7 buffer and stirred for 10 min, and then the emulsion was
) 0.37 (5% EtOAc/petrol); [R]20
filtered through Celite and extracted with CH
bined organic extracts were washed with brine, dried (Na
SO ), filtered, and evaporated to give the crude aldol adduct
2 2
Cl . The com-
f
D
)
2
-
23.8 (c 0.94, CH Cl ); IR υmax (film) 3310, 2956, 2859, 1724,
2
2
-
1
1
4
1
0
1
623 cm ; H NMR (300 MHz) δ 0.08 (s, 3H), 0.14 (s, 3H),
.82 (d, J ) 6.6 Hz, 3H), 0.86 (s, 9H), 0.89 (t, J ) 6.6 Hz, 3H),
.10-1.44 (m, 7H), 1.50-2.40 (m, 8H), 1.77 (s, 3H), 2.24-2.49
as a yellow oil. Purification by flash chromatography with 10%
and then 20% EtOAc/petrol as eluent gave aldol adduct 34 (443
mg, 80% for three steps) as a colorless oil: R
f
) 0.50 (20%
(m, 1H), 2.35 (d, J ) 2.1 Hz, 1H), 2.39 (m, 1H), 3.63-3.73 (m,
EtOAc/petrol); [R]20
) +52.7 (c 3.15, CH Cl ); IR υmax (film)
D
2
2
1
H), 3.72 (s, 3H), 4.34 (d, J ) 2.1 Hz, 1H), 5.78 (d, J ) 15.6
Hz, 1H), 6.05 (t, J ) 6.9 Hz, 1H), 7.35 (d, J ) 15.6 Hz, 1H);
1
3
C NMR (75.5 MHz) δ -5.3, -4.4, 12.3, 14.2, 17.7, 17.9, 23.2,
5.6, 29.1, 29.6, 31.3, 32.8, 32.9, 33.9, 34.2, 38.8, 51.3, 70.1,
(47) For the preparation of Sn(OTf)2 see: Evans, D. A.; Weber, A.
E. J . Am. Chem. Soc. 1986, 108, 6757-6761.
2

2
392 J . Org. Chem., Vol. 66, No. 7, 2001
Cuzzupe et al.
3
480, 3310, 2957, 2861, 1703 cm-1; 1H NMR (300 MHz) δ 0.10
pentane and filtered through Celite. Concentration of the
filtrate gave the crude product which was chomatographed on
(
9
1
s, 3H), 0.16 (s, 3H), 0.80 (d, J ) 6.6 Hz, 3H), 0.83-0.94 (m,
H), 0.88 (s, 9H), 1.06-1.44 (m, 6H), 1.19 (d, J ) 6.9 Hz, 3H),
.49-2.06 (m, 10H), 1.75 (s, 3H), 2.23-2.40 (m, 3H), 2.53 (br
silica using 10% CH
ester 41 (295 mg, 47%) as a colorless oil; R
Cl /petrol); IR υmax (film) 2954, 1715, 1619 cm ; H NMR (300
2
Cl
2
/petrol as eluant to afford the (E)-iodo
f
) 0.29 (10% CH -
2
-1 1
s, 1H), 3.65 (dt, J ) 9.9, 4.8 Hz, 1H), 4.34-4.44 (m, 3H), 4.58-
2
4
.68 (m, 1H), 4.72-4.82 (m, 1H), 4.96-5.11 (m, 1H), 5.59 (dd,
MHz) δ 0.04 (s, 9H), 0.998 (m, 2H), 2.98 (d, J ) 1.5 Hz, 3H),
4.18 (m, 2H), 6.60 (q, J ) 1.5 Hz, 1H); 13C NMR (75.5 MHz) δ
-1.5, 17.2, 30.9, 62.6, 120.1, 131.6, 164.2. Anal. Calcd for
J ) 15.6, 6.6 Hz, 1H), 5.66 (t, J ) 8.7 Hz, 1H), 6.36 (d, J )
1
3
1
1
3
8
5.6 Hz, 1H); C NMR (75.5 MHz) δ -5.2, -4.3, 11.4, 12.6,
4.3, 14.8, 17.6, 18.0, 18.2, 23.3, 25.4, 25.7, 25.6, 29.0, 31.3,
2.0, 33.0, 33.7, 38.9, 42.8, 63.2, 67.3, 70.2, 72.9, 73.9, 75.6,
C
9
H
17IO
2
Si: C, 34.62; H, 5.49. Found: C, 34.62; H, 5.29.
Further elution gave the (Z)-iodo ester (84 mg, 14%) as a
colorless oil: R Cl /petrol); IR υmax (film) 2955,
4.5, 87.8, 107.0, 125.0, 130.0, 133.8, 137.2, 176.7, 186.0;
f
) 0.10 (10% CH
2
2
+
-1 1
HRMS (ESI) calcd for C38
Found: 712.4026. Anal. Calcd for C38
.20; N, 2.03. Found: C, 65.98; H, 9.29; N, 1.98.
Diol 50. To a solution of aldol adduct 34 (577 mg, 0.836
mmol) in THF (8.0 mL) and water (0.80 mL) at 0 °C was added
NaBH (95.0 mg, 2.51 mmol), and the mixture was stirred at
room temperature for 40 min. The solvent was evaporated,
Et O and water were added to the residue, and this was stirred
vigorously for 10 min. The organic extract was washed with
.0 M NaOH, water, and brine and then dried (Na SO ),
H
63NO
6
SSiNa [M + Na ]: 712.4043.
1727, 1630, 1307, 1250, 1169 cm ; H NMR (300 MHz) δ 0.04
(s, 9H), 1.03 (m, 2H), 2.73 (d, J ) 1.2 Hz, 3H), 4.25 (m, 2H),
H
6
63NO SSi: C, 66.14; H,
1
3
9
6.26 (q, J ) 1.2 Hz, 1H); C NMR (75.5 MHz) δ -1.5, 17.3,
3
3
6.5, 62.8, 113.1, 125.6, 164.4. Anal. Calcd for C
4.62; H, 5.49. Found: C, 34.81; H, 5.54.
9 2
H17IO Si: C,
4
Tm se-ester 53. To a solution of vinyl stannane 51 (579 mg,
0.689 mmol) in THF (5.0 mL) under argon was added TBAF‚
3H O (1.31 g, 4.14 mmol), and the mixture was stirred at 50
°C for 72 h. Water was added, and the aqueous phase was
extracted with Et O. The combined organic extracts were
washed with water and brine and then dried (Na SO ), filtered,
2
2
1
2
4
2
filtered, and evaporated to give the crude product as a yellow
oil. Purification by flash chromatography with 20% and then
2
4
and evaporated to give crude triol 52 (484 mg, 97% crude yield)
as a yellow oil. To a solution of crude triol 52 in NMP (10 mL)
was added iodide 41 (0.306 mL, 1.33 mmol), and the mixture
was frozen, degassed, and thawed three times. Tri-2-furyl-
phosphine (30.9 mg, 0.133 mmol) was added to the mixture
followed by tris(dibenzylideneacetone)dipalladium (30.5 mg,
0.033 mmol), and the mixture was stirred at 55 °C under argon
for 30 min. The mixture was diluted with water, and the
4
0% EtOAc/petrol as eluent gave diol 50 (454 mg, 99%) as a
2
0
pale yellow oil: R
f
) 0.50 (40% EtOAc/petrol); [R]
D
) -19.2
-1
(
2 2
c 0.57, CH Cl ); IR υmax (film) 3375, 3312, 2929, 2860 cm ;
1
H NMR (400 MHz) δ 0.09 (s, 3H), 0.15 (s, 3H), 0.80 (d, J )
6
7
.4 Hz, 3H), 0.84-0.92 (m, 6H), 0.86 (s, 9H), 1.14-1.40 (m,
H), 1.50-2.40 (m, 12H), 1.75 (s, 3H), 2.34-2.36 (m, 1H), 2.35
(
d, J ) 2.0 Hz, 1H), 3.61-3.68 (m, 2H), 3.71 (dd, J ) 10.4, 7.2
Hz, 1H), 4.31 (dd, J ) 6.8, 3.2 Hz, 1H), 4.38 (d, J ) 2.0 Hz,
aqueous phase was extracted with Et
extracts were washed with water and brine and then dried
(Na SO ), filtered, and evaporated to give the crude product
2
O. The combined organic
1
6
1
3
8
H), 5.61 (dd, J ) 15.6, 7.2 Hz, 1H), 5.65 (t, J ) 8.8 Hz, 1H),
.31 (d, J ) 15.6 Hz, 1H); 13C NMR (100 MHz) δ -5.2, -4.3,
1.7, 12.7, 14.3, 17.7, 18.0, 23.3, 25.4, 25.7, 25.8, 29.2, 31.3,
2.1, 33.0, 33.8, 39.9, 40.2, 66.4, 70.2, 72.9, 75.6, 77.2, 84.4,
2
4
as a yellow oil. Purification by flash chromatography with 20-
50% EtOAc/petrol as eluent gave Tmse-ester 53 (300 mg, 70%
7.8, 107.1, 125.7, 130.0, 133.7, 137.0; HRMS (ESI) calcd for
for two steps) as a yellow oil: R
f
) 0.33 (40% EtOAc/petrol);
+
20
C
32
H
56
O
5
SiNa [M + Na ]: 571.3795. Found: 571.3792. Anal.
[R]
D
) -41.8 (c 1.29, CH Cl ); IR υmax (film) 3400, 2954, 2874,
2 2
-
1
1
Calcd for C32
0.34.
Vin yl sta n n a n e 51. To a solution of diol 50 (454 mg, 0.827
mmol) in CH Cl (30 mL) at 0 °C under argon was added bis-
triphenylphosphine)palladiumdichloride (59.0 mg, 0.0840
H
56
O
5
Si: C, 70.02; H, 10.28. Found: C, 70.19; H,
1710, 1613 cm ; H NMR (300 MHz) δ 0.04 (s, 9H), 0.82-
0.96 (m, 9H), 0.98-1.04 (m, 2H), 1.18-2.50 (m, 17H), 1.75 (s,
1
3
H), 2.01 (m, 1H), 2.27 (s, 3H), 3.50-3.74 (m, 3H), 4.18-4.23
(
1
6
m, 2H), 4.20 (s, 1H), 4.31 (m, 1H), 5.60 (m, 1H), 5.64 (dd, J )
2
2
5.6, 3.9 Hz, 1H), 5.77 (s, 1H), 5.99 (dd, J ) 15.6, 6.3 Hz, 1H),
.31 (d, J ) 15.6 Hz, 1H), 6.40 (d, J ) 15.6 Hz, 1H); C NMR
(
13
mmol), and the mixture was stirred for 10 min. Tributyltin
hydride (0.890 mL, 3.31 mmol) was added dropwise, and
stirring was continued at 0 °C for 30 min. The solvent was
evaporated, and purification of the crude product by flash
chromatography with EtOAc/petrol (20% then 30%, containing
(100 MHz) δ -1.5, 11.8, 12.7, 13.8, 14.1, 17.3, 17.6, 23.1, 25.3,
2
7
1
6.8, 27.8, 28.9, 31.5, 33.6, 34.6, 37.1, 39.3, 40.1, 61.9, 66.1,
6.2, 76.5, 90.9, 106.9, 119.6, 126.2, 128.6, 134.3, 134.6, 135.0,
36.4, 151.4, 167.2; HRMS (ESI) calcd for C35
60 7
H O SiNa [M
+
+
Na ]: 643.4006. Found: 643.4006.
1
% NEt
a yellow oil: R
.18, CH Cl ); IR υmax (film) 3369, 2956, 2928, 2873, 2858 cm
3
) as eluent gave vinyl stannane 51 (579 mg, 82%) as
2
1
f
) 0.50 (33% EtOAc/petrol); [R]
D
) -40.6 (c
Bis-TBS-eth er 54. To a solution of Tmse-ester 53 (77.0 mg,
-1
0
2
2
;
0.124 mmol) in dry DMF (1.16 mL) under argon was added
imidazole (76.0 mg, 1.12 mmol) and tert-butyldimethylsilyl
chloride (112 mg, 0.744 mmol), and the solution was stirred
at 50 °C under argon for 2 h. The mixture was then diluted
1
H NMR (300 MHz) δ -0.02 (s, 3H), 0.057 (s, 3H), 0.81 (d, J
)
1
6.3 Hz, 3H), 0.88 (t, J ) 7.2 Hz, 12H), 0.89 (s, 9H), 1.12-
.44 (m, 18H), 1.44-2.16 (m, 17H), 2.18-2.52 (m, 2H), 1.76
(
3
3
s, 3H), 2.29 (m, 1H), 2.36-2.48 (m, 1H), 3.46-3.59 (m, 1H),
with water and extracted with Et
extracts were washed with water and brine and then dried
(Na SO ), filtered, and evaporated to give the crude product
2
O, and the combined organic
.59-3.77 (m, 2H), 4.05 (d, J ) 3.3 Hz, 1H), 4.32 (dd, J ) 6.6,
.6 Hz, 1H), 5.63 (dd, J ) 15.9, 7.2 Hz, 1H), 5.66 (t, J ) 8.7
2
4
1
3
Hz, 1H), 6.16 (m, 2H), 6.29 (d, J ) 15.9 Hz, 1H); C NMR
as a yellow oil. Purification by flash chromatography with 2.5%
(75.5 MHz) δ -4.7, -3.7, 9.5, 11.6, 12.7, 13.7, 14.2, 17.8, 18.1,
EtOAc/petrol as eluent gave bis-TBS-ether 54 (63.0 mg, 60%)
1
3
117/119
20
2
3
1
3.5, 25.9, 27.3, 27.3 (d, J ( C-
Sn) ) 53.1 Hz), 29.2, 32.2,
as a colorless oil: R
f
) 0.34 (5% EtOAc/petrol); [R]
D
) -26.5
2.8, 33.5, 34.1, 34.4, 38.7, 40.2, 66.4, 75.6, 82.5, 88.8, 106.6,
(c 2.87, CH Cl ); IR υmax (film) 3468, 2954, 2859, 1712, 1614
cm ; H NMR (400 MHz) δ -0.02 (s, 3H), 0.01 (s, 6H), 0.02
(s, 3H), 0.04 (s, 9H), 0.82-0.92 (m, 9H), 0.87 (s, 9H), 0.88 (s,
2
2
-
1
1
25.8, 127.9, 130.0, 133.6, 136.9, 148.8; HRMS (ESI) calcd for
+
C
44
H
84
O
5
SiSnNa [M + Na ]: 863.5008. Found: 863.5001.
H), 0.98-1.03 (m, 2H), 1.23-2.08 (m, 14H), 1.71 (s, 3H),
.97-2.08 (m, 2H), 2.04 (m, 1H), 2.26 (s, 3H), 2.25-2.31 (m,
H), 2.38 (m, 1H), 3.38 (dd, J ) 9.6, 6.4 Hz, 1H), 3.55-3.59
Iod id e 41. Tetrolic acid (3.10 g, 36.5 mmol) was combined
with hydroiodic acid (55% aq, 6 mL, 43.8 mmol), and the
resulting solution was heated to 90 °C and stirred for 4 h. Cold
water (26 mL) was added, and the product was isolated by
filtration and washed with cold water and then dried under
vacuum for 24 h (0.1 mmHg) to give Z-3-iodo-2-butenoic acid3
5a
as pale yellow needles (6.04 g, 78%). The (Z)-acid was heated
to 135 °C in a sealed tube for 24 h to provide a mixture of
5.9, 26.0, 27.0, 29.0, 31.6, 33.3, 34.6, 37.8, 39.4, 43.0, 61.9,
5.1, 73.8, 76.4, 76.8, 91.4, 107.0, 119.7, 126.7, 129.1, 134.1,
(
)
1
Z)-3-iodo-2-butenoic acid and (E)-3-iodo-2-butenoic acid (Z/E
1:4, 6.04 g, 100%). To a solution of the crude acids (Z/E )
:4, 427 mg, 2.0 mmol) in CH Cl (2 mL) was added trimethyl-
34.6, 134.8, 135.2, 151.4, 167.3. Anal. Calcd for C47
88 7 3
H O Si :
2
2
silylethanol (286 µL, 2.0 mmol) followed by DCC (413 mg, 2.0
mmol) and DMAP (24 mg, 0.19 mmol). The mixure was stirred
at room temperature for 15 h and then diluted with cold

Total Synthesis of (-)-Reveromycin B
J . Org. Chem., Vol. 66, No. 7, 2001 2393
dride (607 mg, 6.1 mmol) in toluene (3.6 mL) was added
N-hydroxysuccinimide (209 mg, 1.8 mmol) and DMAP (74 mg,
saturated aqueous NaHCO
mL) until two clear layers formed. The aqueous phase was
extracted with Et O and the combined organic extracts were
washed with water, saturated aqueous CuSO , water, and
brine and then dried (Na SO ), filtered, and evaporated to give
the crude aldehyde as a yellow oil. The crude aldehyde was
dissolved in CH Cl (3.0 mL), and trimethylsilylethyl(tri-
phenylphosphoranylidene)acetate (58) (405 mg, 0.899 mmol)
was added. Then the resulting solution was stirred at room
temperature under argon for 17 h. The solvent was evaporated,
and purification of the crude product by flash chromatography
with 5-10% EtOAc/petrol as eluent gave triester 59 (85.9 mg,
3 2 2 3
(20 mL) and 1.5 M Na S O (20
0
.66 mmol), and the resulting solution was heated at relux
for 1.5 h. The mixture was then cooled, diluted with Et O, and
washed with water, saturated aqueous CuSO , and brine and
dried. Removal of the solvent gave the crude acid (1.21 g,
00%) which was pure enough to be used without further
purification. R ) 0.25 (10% EtOAc/petrol); IR υmax (film) 3250,
2
2
4
4
2
4
1
2
2
4
1
f
-
1
1
2
0
956, 1737, 1715 cm ; H NMR (300 MHz) δ -0.03 (s, 6H),
13
.98 (m, 2H), 2.56-2.72 (m, 4H), 4.39 (m, 2H); C NMR (75.5
MHz) δ -1.6, 17.1, 28.86, 28.88, 63.0, 172.2, 178.3; HRMS
+
(ESI) calcd for C
9
H
18
O
4
SiNa [M + Na ]: 241.0872. Found:
2
41.0863.
89% for two steps) as a colorless oil: R
f
2
) 0.43 (10% Et O/
Su ccin a te 56. To a solution of bis-TBS-ether 54 (63.0 mg,
petrol); [R]20
D
) -40.6 (c 1.51, CH Cl ); IR υmax (film) 2955,
2
2
-
1 1
0
5
.0742 mmol) in CH Cl (1.3 mL) under argon was added acid
5 (0.180 mL, 0.590 mmol), DMAP (3.6 mg, 0.029 mmol) and
2
2
1737, 1716, 1652, 1615 cm ; H NMR (400 MHz) δ -0.03 (s,
3H), 0.02 (s, 3H), 0.03 (s, 9H), 0.04 (s, 18H), 0.83 (d, J ) 6.4
Hz, 3H), 0.87 (s, 9H), 0.89 (t, J ) 6.4 Hz, 3H), 0.97 (d, J ) 8.0
Hz, 3H), 0.96-1.03 (m, 6H), 1.15-1.85 (m, 14H), 1.69 (s, 3H),
1.95 (m, 1H), 2.28 (d, J ) 0.4 Hz, 3H), 2.30 (m, 1H), 2.43 (m,
1H), 2.61-2.70 (m, 4H), 3.46 (m, 1H), 4.10 (dd, J ) 7.6, 4.0
Hz, 1H), 4.15-4.23 (m, 6H), 5.20 (br s, 1H), 5.38 (dd, J ) 15.6,
7.6 Hz, 1H), 5.52, (s, 1H), 5.65 (dd, J ) 6.8, 6.8 Hz, 1H), 5.75
DCC (123 mg, 0.596 mmol) and then the mixture was stirred
at room temperature under argon for 48 h. Pentane was added,
the suspension was filtered through Celite, and the filtrate
was concentrated. The residue was dissolved in Et
washed with saturated aqueous NaHCO , water, and brine,
and then dried (Na SO ), filtered, and evaporated to give the
2
O and
3
2
4
1
3
crude product as a yellow oil. Purification by flash chroma-
tography with 1% and then 2.5% EtOAc/petrol as eluent gave
(m, 2H), 6.20 (m, 3H), 7.01 (dd, J ) 15.6, 7.2 Hz, 1H); C NMR
(100 MHz) δ -5.0, -4.0, -1.5, -1.48, -1.46, 12.7, 13.8, 13.9,
14.2, 17.2, 17.3, 17.4, 17.8, 18.2, 23.2, 25.3, 25.9, 29.2, 29.3,
31.7, 31.8, 33.7, 34.0, 34.6, 38.7, 43.7, 61.9, 62.2, 63.0, 72.2,
76.3, 77.1, 79.1, 87.1, 107.2, 120.0, 120.9, 126.8, 128.8, 131.3,
succinate 56 (78.0 mg, 100%) as a colorless oil: R
f
) 0.43 (5%
); IR υmax (film)
954, 2859, 1739, 1713, 1615 cm ; H NMR (300 MHz) δ -0.04
s, 3H), 0.004 (s, 6H), 0.01 (s, 3H), 0.02 (s, 9H), 0.04 (s, 9H),
2
0
EtOAc/petrol); [R]
2
D
2 2
) -46.6 (c 2.37, CH Cl
-
1 1
(
134.0, 134.9, 136.4, 151.2, 151.6, 166.9, 167.2, 170.9, 172.2;
+
0
4
.77-0.92 (m, 9H), 0.86 (s, 9H), 0.87 (s, 9H), 0.94-1.02 (m,
HRMS (ESI) calcd for C57
Found: 1097.6389.
H
102
O
11Si
4
Na [M + Na ]: 1097.6397.
H), 1.14-1.88 (m, 12H), 1.70 (s, 3H), 1.88-2.08 (m, 3H), 1.99
(
m, 1H), 2.27 (s, 3H), 2.34 (m, 1H), 2.43 (m, 1H), 2.59-2.69
(-)-Rever om ycin B (2). To a solution of triester 59 (27.9
mg, 0.0259 mmol) in DMF (1.0 mL) at room temperature under
(m, 4H), 3.35 (dd, J ) 9.6, 6.9 Hz, 1H), 3.44-3.50 (m, 1H),
3
.58 (dd, J ) 9.6, 6.0 Hz, 1H), 4.14-4.22 (m, 5H), 5.46 (dd, J
argon was added TBAF‚3H
2
O (65.5 mg, 0.207 mmol), and
O (35.0 mg,
)
15.6, 7.5 Hz, 1H), 5.52 (s, 1H), 5.98 (t, J ) 7.2 Hz, 1H), 5.74
stirring was continued for 18 h. Further TBAF‚3H
2
1
3
(
m, 1H), 6.17 (m, 3H); C NMR (100 MHz) δ -5.4, -5.3, -5.0,
0.111 mmol) was added, and stirring was continued for a total
of 48 h. The reaction mixture was partitioned between EtOAc
-
3.9, -1.5, -1.4, 11.4, 12.7, 13.8, 14.2, 17.3, 17.4, 17.8, 18.2,
8.3, 23.2, 25.4, 25.91, 25.95, 29.3, 31.6, 31.8, 33.5, 34.1, 34.6,
8.6, 43.1, 61.8, 63.0, 65.2, 74.2, 76.3, 79.0, 87.1, 107.2, 120.0,
1
3
1
1
1
and saturated aqueous NH
until pH 3.0 was obtained. The organic extract was washed
with water and brine and then dried (MgSO ), filtered, and
4
Cl, and then 10% HCl was added
27.7, 128.7, 131.3, 134.3, 134.9, 135.0, 151.2, 167.2, 170.9,
4
+
72.2; HRMS (ESI) calcd for C56
071.6604. Found: 1071.6568.
H
104
O
10Si
4
Na [M + Na ]:
evaporated. Purification was carried out by filtration through
a reverse phase column (C18 spherex, 900 mg) with 40-20%
water/methanol as eluant to give (-)-reveromycin B 2 (12.3
Alcoh ol 57. To succinate 56 (78.0 mg, 0.0743 mmol) under
argon was added a freshly prepared solution of HF‚pyridine
108 mg, 3.72 mmol) buffered with pyridine (0.216 mL, 2.69
mmol) in THF (1.87 mL), and the solution was stirred at room
temperature for 6 h. Saturated aqueous NaHCO was added,
the mixture was diluted with Et O, and the aqueous phase
was further extracted with Et O. The combined organic
extracts were washed with water, saturated aqueous CuSO
water, and brine and then dried (Na SO ), filtered, and
mg, 72%) as a white powder: R
[R]20
) -45.3 (c 0.12, MeOH); lit. [R]
MeOH); lit. [R]
(c 0.1, MeOH); IR υmax (film) 3410, 2931, 1722, 1614 cm ; UV
f
) 0.35 (15% MeOH/CH
2
Cl
2
);
11
25
(
D
D
) -51.8 (c 0.3,
1
0
25
3
20
D
) -61.0 (c 0.1, MeOH); lit. [R]
D
) -66
-1
3
4
-1
-1
1
2
λ
max (MeOH) 238 nm (ꢀ 3.45 × 10 Lmol cm ); H NMR (400
2
MHz, CD OD) δ 0.88 (d, J ) 6.4 Hz, 3H), 0.91 (t, J ) 6.8 Hz,
3
4
,
3H), 1.00 (d, J ) 6.8 Hz, 3H), 1.20-2.15 (m, 15H), 1.73 (s,
3H), 2.14-2.26 (m, 1H), 2.22 (s, 3H), 2.48-2.61 (m, 2H), 2.62-
2.70 (m, 4H) 3.44 (ddd, J ) 10.8, 8.8, 2.0 Hz, 1H), 4.07 (dd, J
) 7.6, 5.6 Hz, 1H), 5.46 (dd, J ) 15.6, 7.6 Hz, 1H), 5.56 (d, J
) 3.2 Hz, 1H), 5.76 (dd, J ) 6.8, 6.8 Hz, 1H), 5.78 (br s, 1H),
5.78 (d, J ) 15.6 Hz, 1H), 6.22-6.27 (m, 2H), 6.38 (d, J ) 15.6
2
4
evaporated to give the crude product as a yellow oil. Purifica-
tion by flash chromatography with 5% and then 20% EtOAc/
petrol as eluent gave alcohol 57 (45.0 mg, 65%) as a pale yellow
2
0
oil: R
f
) 0.21 (10% EtOAc/petrol); [R]
D
) -53.8 (c 1.83, CH
2
-
;
-
1
13
Cl ); IR υmax (film) 3535, 2955, 2861, 1738, 1712, 1614 cm
2
Hz, 1H), 6.96 (dd, J ) 15.6, 7.6 Hz, 1H); C NMR (100 MHz,
1
H NMR (300 MHz) δ 0.01 (s, 3H), 0.03 (s, 9H), 0.04 (s, 9H),
3
CD OD) δ 12.7, 14.0, 14.5, 15.1, 18.2, 24.4, 26.6, 30.3, 30.4,
0
(
2
(
4
1
1
1
2
6
1
.06 (s, 3H), 0.75 (d, J ) 6.9 Hz, 3H), 0.80-0.93 (m, 6H), 0.87
30.8, 32.9, 35.2, 35.6, 35.7, 39.8, 44.0, 77.2, 78.4, 80.4, 88.8,
108.6, 121.7, 122.9, 127.2, 130.8, 132.4, 135.2, 136.1, 138.6,
s, 9H), 0.95-1.03 (m, 4H), 1.14-2.10 (m, 16H), 1.73 (s, 3H),
.17-2.27 (m, 1H), 2.26 (s, 3H), 2.47-2.56 (m, 1H), 2.59-2.70
151.9, 152.5, 170.6, 170.7, 173.2, 176.2; HRMS (ESI) calcd for
+
m, 4H), 3.08 (m, 1H), 3.39-3.45 (m, 2H), 3.57-3.67 (m, 1H),
C
36
H
52
O
11Na [M + Na ]: 683.3407. Found: 683.3404.
.14-4.22 (m, 4H), 4.24 (m, 1H), 5.51 (dd, J ) 15.6, 7.8 Hz,
H), 5.52 (br s, 1H), 5.71 (m, 2H), 6.17 (m, 2H), 6.29 (d, J )
Ack n ow led gm en t. We thank the Australian Re-
1
3
5.6 Hz, 1H); C NMR (100 MHz) δ -5.1, -4.0, -1.6, -1.5,
2.5, 12.6, 13.8, 14.2, 17.2, 17.4, 17.9, 18.0, 23.2, 25.3, 25.8,
9.2, 29.26, 29.29, 31.7, 31.8, 34.1, 34.4, 38.8, 41.4, 61.9, 63.0,
5.9, 76.6, 78.2, 79.2, 87.2, 107.2, 119.9, 125.9, 129.2, 131.2,
search Council for financial support. We also thank Dr
Hidetoshi Takahashi (Research Institute of Life Science,
Snow Brand Milk Products Co. Ltd., J apan) for copies
1
13
of the H and C NMR spectra of reveromycin B.
33.9, 134.9, 136.8, 151.1, 167.2, 171.0, 172.2; HRMS (ESI)
+
calcd for
57.5741. Anal. Calcd for C50
Found: C, 64.21; H, 9.63.
Tr iester 59. To a solution of alcohol 57 (84.1 mg, 0.090
mmol) in CH Cl (4.0 mL) under argon was added pyridine
0.073 mL, 0.90 mmol) and Dess-Martin reagent (0.191 g, 0.50
mmol), and the mixture was stirred at room temperature for
h. The mixture was diluted with Et O and stirred with
C
50
H
90
O
10Si
3
Na [M + Na ]: 957.5739. Found:
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the preparation of compounds 15-22, 35-39, and
9
90 3
H O10Si : C, 64.19; H, 9.70.
4
4-45 as well as an ORTEP diagram and X-ray coordinates
1 13
for the structure of 22 and copies of the H and C NMR
spectra of all key intermediates. This material is available free
of charge via Internet at http://pubs.acs.org.
2
2
(
1
2
J O001646C