Total synthesis of rutamycin B, a macrolide antibiotic from Streptomyces aureofaciens

Article abstract of DOI:10.1021/jo0104429

Rutamycin B (2) was synthesized from three principal subunits, spiroketal 75, keto aldehyde 83, and aldehyde 108. First, triol 62 was assembled by Julia coupling of sulfone 56 with aldehyde 58 followed by an acid-catalyzed spiroketalization. The three hydroxyl functions of 62 were successfully differentiated, leading to phosphonate 75. The latter was condensed in a Wadsworth-Emmons reaction with 83, prepared in six steps from (R)-aldehyde 76, to give 92. Coupling of the titanium enolate of 92 with 108 afforded Felkin product 109 with high stereoselectivity in a process that is critically dependent on the presence of the p-methoxybenzyl ether in the aldehyde. Transformation of 109 via aldehyde 116 to vinylboronate 122 was followed by macrocyclization under Suzuki conditions to yield 123. Exhaustive desilylation of the latter yielded rutamycin B.

Full text of DOI:10.1021/jo0104429

J . Org. Chem. 2001, 66, 5217-5231
5217
Tota l Syn th esis of Ru ta m ycin B, a Ma cr olid e An tibiotic fr om
Str eptom yces a u r eofa cien s
J ames D. White,* Roger Hanselmann, Randy W. J ackson, Warren J . Porter, Yoshihiro Ohba,
Thomas Tiller, and Shan Wang
Department of Chemistry, Oregon State University, Corvallis, Oregon 97331-4003
james.white@orst.edu
Received April 30, 2001
Rutamycin B (2) was synthesized from three principal subunits, spiroketal 75, keto aldehyde 83,
and aldehyde 108. First, triol 62 was assembled by J ulia coupling of sulfone 56 with aldehyde 58
followed by an acid-catalyzed spiroketalization. The three hydroxyl functions of 62 were successfully
differentiated, leading to phosphonate 75. The latter was condensed in a Wadsworth-Emmons
reaction with 83, prepared in six steps from (R)-aldehyde 76, to give 92. Coupling of the titanium
enolate of 92 with 108 afforded Felkin product 109 with high stereoselectivity in a process that is
critically dependent on the presence of the p-methoxybenzyl ether in the aldehyde. Transformation
of 109 via aldehyde 116 to vinylboronate 122 was followed by macrocyclization under Suzuki
conditions to yield 123. Exhaustive desilylation of the latter yielded rutamycin B.
The discovery in 1961 of rutamycin A (1) by Thompson
in cultures of Streptomyces griseus1 was followed soon
thereafter by the isolation of a close structural analogue,
rutamycin B (2), from S. aureofaciens by Keller-Schier-
lein.2 The gross structure and relative configuration of 1
were assigned on the basis of X-ray crystallographic
analysis,3 and the relative stereostructure 2 followed from
comparison with 1 utilizing NMR spectroscopy. The
absolute configuration of the rutamycins was determined
by Evans,4 who compared the spiroketal fragment ob-
tained from degradation with the identical substance
prepared by asymmetric synthesis. The integration of a
spiroketal unit into the 26-membered lactone that char-
acterizes 1 and 2 places these substances in the broader
family of macrolide antibiotics that includes the oligo-
synthesis of 2 through a conventional Yamaguchi mac-
rolactonization after all C-C bonds and stereochemistry
were installed. A synthesis of rutamycin B by Panek10
accomplished the same finale from a seco acid precursor
for which a series of crotylsilane additions was used to
fabricate the skeleton. By contrast, our approach to 2
envisioned macrocyclization via a carbon-carbon con-
nection after the spiroketal and polyketide subunits have
been joined through an ester linkage. This plan is
expressed retrosynthetically in Scheme 1, where the
penultimate precursor 3 is projected from three smaller
fragments, 4, 5, and 6, in a sequence that first connects
5 to 6 and then fuses the [5 + 6] composite to 4. This
mode of assembly imposes logistical demands different
from those of the Evans9 and Panek syntheses10 but has
the compensatory advantage that linkages between frag-
ments can be made in ways that afford excellent stereo-
control. The 17 stereogenic centers of 2 are positioned in
sets that make the connections in Scheme 1 a logical
outcome of the methodology selected for key C-C bond
constructions, and we now describe the successful imple-
mentation of a plan for the synthesis of 2 based on this
logic.11
mycins,5 cytovaricin,6 and phthoramycin.7 In common
with cytovaricin, the rutamycins are cytotoxic and have
potent antifungal activity. The action of rutamycin B has
been specifically linked to its inhibition of H+-ATPase,
thereby preventing oxidative phosphorylation in mito-
chondria.8
The challenge presented by total synthesis of the
rutamycins was first met by Evans,9 who completed the
(1) Thompson, R. Q.; Hoehn, M. M.; Higgens, C. E. Antimicrob.
Agents Chemother. 1961, 474.
(2) Wuthier, D.; Keller-Schierlein, W. Helv. Chim. Acta 1984, 67,
1208.
(3) Arnoux, B.; Garcia-Alvarez, M. C.; Marazano, C.; Das, B. C.;
Pascard, C.; Merienne, C.; Staron, T. J . Chem. Soc., Chem. Commun.
1978, 318.
(4) Evans, D. A.; Rieger, D. L.; J ones, T. K.; Kaldor, S. W. J . Org.
Chem. 1990, 55, 6260.
(5) (a) Smith, R. M.; Peterson, W. H.; McCoy, E. Antibiot. Chemother.
1954, 4, 962. (b) Kobayashi, K.; Nishino, C.; Ohya, J .; Sato, S.; Mikawa,
T.; Shiobara, Y.; Kodama, M.; Nishimoto, N. J . Antibiot. 1987, 40, 1053.
(6) Kihara, T.; Kusakabe, H.; Nakamura, G.; Sakurai, T.; Isono, K.
J . Antibiot. 1981, 34, 1073.
(7) Nakagawa, A.; Miura, S.; Imai, H.; Imamura, N.; Omura, S. J .
Antibiot. 1989, 42, 1324.
(8) Kageyama, M.; Tamura, T.; Nantz, M. H.; Roberts, J . C.; Somfai,
P.; Whritenour, D. C.; Masamune, S. J . Am. Chem. Soc. 1990, 112,
7407.
(9) Evans, D. A.; Ng, H. P.; Rieger, D. L. J . Am. Chem. Soc. 1993,
115, 11446.
(10) Panek, J . S.; J ain, N. F. J . Org. Chem. 2001, 66, 2747.
10.1021/jo0104429 CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/04/2001

5218 J . Org. Chem., Vol. 66, No. 15, 2001
White et al.
Sch em e 1
(Scheme 2). The first (route A) sees connection of C25
with C26 via an aldol or analogous process involving 8
and 9, the second links two segments at the C28-C29
bond through an epoxide opening of 10 by 11 (route B),
and the third invokes nucleophilic attack by anionic
species 13 on aldehyde 12 (route C). The first of these
approaches, route A, appeared to be the most direct
avenue to 7, and initial efforts were therefore launched
toward the preparation of aldehyde 8.
The location of the ethyl substituent in 7 mandated
that the configuration at C20 be introduced indepen-
dently of other stereocenters, and this was accomplished
by means of an asymmetric Michael addition of the
titanium enolate of N-butanoyloxazolidinone 14,13 pre-
pared by acylation of the lithio anion of (R)-4-benzylox-
azolidin-2-one with n-butyryl chloride,14 to acrylonitrile
(Scheme 3). The adduct 15 was obtained in good yield as
a single diastereomer, and the chiral adjuvant was
cleaved reductively to furnish hydroxy nitrile 16. The
latter was protected as its silyl ether 17 before reduction
with diisobutylaluminum hydride to yield aldehyde 18.15
Asymmetric crotylation with (Z)-crotylboronate 19 de-
rived from (S,S)-tartrate16 afforded syn homoallylic al-
cohol 20 accompanied by a minor quantity of its anti
isomer (5:1). After conversion of 20 to its bis(silyl) ether
21, ozonolytic cleavage of the vinyl group produced
aldehyde 22, representing the C19-C25 portion of 7.
The second segment required for 7 was prepared from
alcohol 23,17 obtained from methyl (R)-3-hydroxy-2-
methylpropionate by conversion to its silyl ether followed
by reduction with diisobutylaluminum hydride (Scheme
4). The tosylate derived from 23 was advanced to sulfone
24 via displacement of the corresponding iodide with
sodium sulfinate,18 and the anion of 24 was reacted with
racemic propylene oxide to provide hydroxy sulfone 25
as a mixture of stereoisomers.19 Reductive cleavage of the
sulfonyl substituent with sodium-amalgam20 gave 26 as
a 1:1 mixture of stereoisomers that was oxidized to ketone
27 with pyridinium chlorochromate.21 Ketalization fol-
lowed by cleavage of the tert-butyldimethylsilyl ether
yielded primary alcohol 28, which after Swern oxidation22
led to aldehyde 29. Asymmetric allylation of 29 with
boronate 30 from (R,R)-tartrate23 afforded syn homoal-
lylic alcohol 31 and its anti stereoisomer as a 4:1 mixture.
By contrast, allylation of 29 with Brown’s diisocaranylbo-
rane reagent24 gave a syn/anti ratio of 8.6:1 but in only
48% yield. After protection of 31 as its silyl ether 32,
Wacker oxidation25 of the terminal alkene produced
methyl ketone 33 in good yield. Not surprisingly, the
Th e Sp ir ok eta l Segm en t 6. An assumption made at
the outset of our route to 6 was that an open frame such
as 7 would undergo internal ketalization to yield a
substance in which the spiro carbon has the configuration
of the natural product. This expectation was founded on
the fact that the spiro center (C27) of 2 possessing natural
configuration places the larger alkyl substitutents in an
equatorial orientation when maximum anomeric stabi-
lization is conferred upon the spiroketal12 and has been
(13) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J . Am.
Chem. Soc. 1991, 113, 1047.
(14) Gage, J . R.; Evans, D. A. Org. Synth. 1989, 68, 83.
(15) Winterfeldt, E. Synthesis 1975, 617.
(16) (a) Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz, A. D.;
Halterman, R. L. J . Am. Chem. Soc. 1990, 112, 6339. (b) Roush, W.
R.; Palkowitz, A. D.; Ando, K. J . Am. Chem. Soc. 1990, 112, 6348.
(17) See ref 16b, footnote 12a. Cf. Nagoka, H.; Kishi, Y. Tetrahedron
1981, 37, 3873.
9
borne out in both Evans’ and Panek’s10 syntheses of the
(18) White, J . D.; Kawasaki, M. J . Am. Chem. Soc. 1990, 112, 4991.
(19) Mori, K.; Senda, S. Tetrahedron 1985, 41, 541.
(20) Nakata, T.; Saito, K.; Oishi, T. Tetrahedron Lett. 1986, 27, 6345.
(21) Sneeden, R. P. A. Organochromium Compounds; Academic
Press: New York, 1975.
rutamycin-oligomycin spiroketals.
Three general strategies, each uniting a different pair
of subunits, were considered for the assembly of 7
(22) (a) Mancuso, A. J .; Huang, S.-L.; Swern, D. J . Org. Chem. 1978,
43, 2480. (b) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
(23) Roush, W. R.; Hoong, L. K.; Palmer, M. A. J .; Straub, J . A.;
Palkowitz, A. D. J . Org. Chem. 1990, 55, 4117.
(24) Brown, H. C.; Randad, R. S.; Bhat, K. S.; Zaidlewicz, M.;
Racherla, U. S. J . Am. Chem. Soc. 1990, 112, 2389.
(25) Tsuji, J . Synthesis 1984, 369.
(11) Preliminary communications: (a) White, J . D.; Ohba, Y.; Porter,
W. J .; Wang, S. Tetrahedron Lett. 1997, 38, 3167. (b) White, J . D.;
Porter, W. J .; Tiller, T. Synlett 1993, 535. (c) White, J . D.; Tiller, T.;
Ohba, Y.; Porter, W. J .; J ackson, R. W.; Wang, S.; Hanselmann, R.
Chem. Commun. 1998, 79.
(12) Perron, F.; Albizati, K. F. Chem. Rev. 1989, 89, 1617.

Total Synthesis of Rutamycin B
J . Org. Chem., Vol. 66, No. 15, 2001 5219
Sch em e 2
Sch em e 3
34, the chiral borinate of acetone, prepared with (+)-
diisopinocampheylboron triflate,27 was reacted with al-
dehyde 29 to give the aldol product 34 as a 10:1 mixture
of syn and anti isomers in 63% yield. However, this
reaction was not readily amenable to the large-scale
preparation of 34 necessary for advancing the synthesis
toward subunit 9, and we therefore returned to the route
via 31, 32, and 33 for this purpose. Protection of diol 35
as its bis(tert-butyl)silylene derivative 36,28 followed by
acid-catalyzed hydrolysis of the ethylene ketal, furnished
ketone 37, representing the C26-C34 portion of 7.
With aldol partners 22 and 37 in hand, it was assumed
that coupling along lines proposed in path A (Scheme 2)
would lead to 7. In practice, numerous attempts to effect
this aldol coupling using both lithium and boron enolates
of 37 met only with failure, and it became clear that
structural modification would be needed to either or both
reactants if the C25-C26 linkage of 7 was to be forged
as planned. The consistent recovery of starting materials
from the attempted condensation of enolates of 37 with
aldehyde 22 suggested that a means should be found for
imparting irreversibility to this reaction, and an attrac-
tive option for this purpose appeared to be conversion of
22 to a reactive acylating system while modifying 37 to
enhance its nucleophilicity. To this end, 22 was oxidized
to a carboxylic acid, which was condensed with N,O-
dimethylhydroxylamine hydrochloride to furnish Weinreb
amide 38 (Scheme 5).29 In parallel with this transforma-
tion, ketone 37 was condensed with 1,1-dimethylhydra-
zine,30 and the resultant hydrazone 39, without isolation,
Wacker reaction completely failed with the free alcohol
31. The silyl protecting group was removed from 33, and
the resulting â-hydroxy ketone 34 was reduced to anti
diol 35 with tetramethylammonium triacetoxyborohy-
dride.26 In an alternative and more direct approach to
(27) Paterson, I.; Goodman, J . M.; Lister, M. A.; Schumann, R. C.;
McClure, C. K.; Norcross, R. D. Tetrahedron 1990, 46, 4663.
(28) Corey, E. J .; Hopkins, P. B. Tetrahedron Lett. 1982, 23, 4871.
(29) Burke, S. D.; Piscopio, A. D.; Kort, M. E.; Matulenko, M. A.;
Parker, M. H.; Armistead, D. M.; Shankaran, K. J . Org. Chem. 1994,
59, 332.
(26) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J . Am. Chem.
Soc. 1988, 110, 3560.
(30) Newkome, G. R.; Fishel, D. L. J . Org. Chem. 1966, 31, 677.

5220 J . Org. Chem., Vol. 66, No. 15, 2001
White et al.
Sch em e 4
Sch em e 5
the course of Evans’ synthesis of rutamycin B,9 we chose
instead to explore a new pathway that would incorporate
all seven stereocenters in the correct orientation in the
spiroketal precursor. This led us to entertain path B, in
which union is made at C28-C29 between an epoxide
10 and a nucleophilic species 11.
Asymmetric allylation of 22 with Brown’s allyldiiso-
pinocampheylborane31 gave homoallylic alcohol 42 along
with its syn diastereomer (anti/syn 3:1). After protection
of 42 as p-methoxybenzyl ether 43,32 the terminal alkene
was epoxidized to give a 1:1 mixture of stereoisomeric
epoxides 44 (Scheme 6). Since the secondary alcohol that
would be obtained from opening of the epoxide was
destined to become the C27 keto group of 7, no effort was
made to separate these diastereomers. The organome-
tallic species initially envisioned as the coupling partner
for 44 was a cuprate derived from the iodohexane
corresponding to 11, and synthesis of this material was
commenced from (S)-aldehyde 45 (Scheme 7). Asym-
metric allylation of 45 afforded the known alcohol 46,16b
which, after protection as silyl ether 47, was subjected
to a Wacker oxidation.25 The resulting methyl ketone 48
was unmasked to furnish â-hydroxy ketone 49, and
subsequent directed reduction with tetramethylammo-
was treated with halide-free lithium diisopropylamide
and then with 38 to produce enaminone 40. In his route
to the spiroketal moiety of rutamycin B, Evans ac-
complished a similar hydrazone-Weinreb amide union
of two subunits and also noted the importance of using
an amide base free of halide salts.4 Subsequent exposure
of 40 to aqueous HF-acetonitrile led to a single product
assigned structure 41. While it was certain that hydroly-
sis of the enaminone and all silyl protecting groups had
taken place in this reaction, the configuration at the new
stereocenter resulting from spiroketalization remained
unproven. Furthermore, there was the question of ste-
reoselectivity in reduction of the keto group of 41 if a
hydroxyl function of the desired (S) configuration was to
be installed at C25. Although it would have been possible
in principle to correlate 41 with a spiroketal prepared in
(31) Brown, H. C.; Bhat, K. S.; Randad, R. S. J . Org. Chem. 1989,
54, 1570.
(32) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron
Lett. 1988, 29, 4139.

Total Synthesis of Rutamycin B
J . Org. Chem., Vol. 66, No. 15, 2001 5221
Sch em e 6
attempts to open epoxide 44 with this reagent were
unsuccessful. The epoxide was generally recovered intact,
the only new material isolated from this reaction being
the reduced compound 54. This disappointing outcome
led us to consider alternative nucleophilic partners for
44, one of which was sulfone 55. The latter was prepared
from 53 by displacement of iodide with sodium phenyl-
sulfinate; however, the anion of 55 was also inert toward
44 even when the reaction was attempted in the presence
of a Lewis acid. The viability of 55 was confirmed when
its anion reacted cleanly with propylene oxide to produce
a hydroxy sulfone in good yield, and the failure of 55 to
react with 44 under the same conditions is puzzling.
Subtle effects of both steric and electronic origin are
known to impinge upon nucleophilic opening of epoxides
by organometallic species,36 and it appears that these
may be operating in the case of 44.
Although sulfone 55 had failed to react with 44, the
concept embodied in this plan nevertheless seemed
feasible if a homologated sulfone corresponding to 13
(Scheme 2) could be induced to react with aldehyde 12.
In this context, path C of Scheme 2 becomes a well
precedented J ulia coupling37 that joins C27 with C28 and
that should circumvent the difficulties attending ap-
proaches to 7 via paths A and B. Implementation of this
new plan proved to be straightforward (Scheme 7). First,
iodide 53 was reacted with the lithio anion of methyl
phenyl sulfone38 to provide the homologated sulfone 56.
Then, alcohol 42 protected as its tert-butyldimethylsilyl
ether 57 was ozonized to yield aldehyde 58 (Scheme 8).
J ulia coupling of the anion of 56 with 58 in the presence
of boron trifluoride etherate39 afforded hydroxy sulfone
59 as a mixture of stereoisomers in excellent yield. In
the absence of a Lewis acid catalyst, the yield of coupled
product 59 was markedly reduced, and when a J ulia
reaction was attempted between 56 and the aldehyde
prepared by ozonolytic cleavage of 43 the major product
was an R,â-unsaturated aldehyde resulting from elimina-
tion of p-methoxybenzyl alcohol. This observation il-
lustrates the care with which protecting groups must be
chosen for J ulia reactions on carbonyl substrates bearing
a â alkoxy substituent. Oxidation of 59 with catalytic
Ley’s reagent and N-methylmorpholine N-oxide as the
stoichiometric oxidant40 led to a pair of stereoisomeric
keto sulfones 60; reductive removal of the sulfonyl group
with samarium diiodide41 resulted in further simplifica-
tion to give ketone 61 as a pure substance. Surprisingly,
when reductive cleavage of 60 was attempted with
sodium amalgam, the product was not 61 but a trans
alkene. Presumably, rapid reduction of the ketone of 60
occurred with this reagent, returning 59 which then
underwent reductive 1,2-elimination of the hydroxy sul-
fone. Exhaustive deprotection of 61 with HF in acetoni-
Sch em e 7
(35) Lipshutz, B. H.; Kozlowski, J . A.; Parker, D. A.; Nguyen, S. L.;
McCarthy, K. E. J . Organomet. Chem. 1985, 285, 437.
(36) Kigoshi, H.; Ojika, M.; Suenaga, K.; Mutou, T.; Hirano, J .;
Sakakura, A.; Ogawa, T.; Nisiwaki, M.; Yamada, K. Tetrahedron Lett.
1994, 35, 1247.
(37) J ulia, M. Pure Appl. Chem. 1985, 57, 763.
(38) White, J . D.; Kuo, S.-c.; Vedananda, T. R. Tetrahedron Lett.
1987, 28, 3061.
(39) (a) Achmatowicz, B.; Baranowska, E.; Daniewski, A. R.; Pankows-
ki, J .; Wicha, J . Tetrahedron Lett. 1985, 26, 5597. (b) Schreiber, S. L.;
Meyers, H. V. J . Am. Chem. Soc. 1988, 110, 5198.
(40) Ley, S. V.; Norman, J .; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
nium triacetoxyborohydride gave anti diol 50.26 The latter
was protected with bis(tert-butyl)silyl ditriflate as the
silylene 51, which after hydrogenolysis of the benzyl ether
over platinum-on-carbon33 produced alcohol 52. The iodo
derivative 53 obtained from 5234 was converted to a
higher order cuprate by treatment with tert-butyllithium
followed by lithium thienylcopper cyanide,35 but all
(33) Heathcock, C. H.; Ratcliffe, R. J . Am. Chem. Soc. 1971, 93, 1746.
(34) Castro, B. R. Org. React. 1983, 29, 1.
(41) Molander, G. A.; Hahn, G. J . Org. Chem. 1986, 51, 1135.

5222 J . Org. Chem., Vol. 66, No. 15, 2001
White et al.
Sch em e 8
Sch em e 9
reduction with samarium diiodide to yield a single
equatorial alcohol42 assigned structure 68 (Scheme 10).
Esterification of this alcohol with benzoyl chloride gave
benzoate 69, a substance identical with material pre-
pared from the Evans spiroketal 634 by hydrogenolysis
and silylation of alcohol 70. Correlation of 62 with 63
was completed by saponification of 69, which returned
68, and then desilylation to furnish the expected triol 62.
Resilylation of 62 with tert-butyldimethylsilyl triflate
afforded 68 in low yield, the major product being the
primary monosilyl ether.
With the configuration at all eight stereocenters of 62
firmly established, it became essential to devise a means
for distinguishing the three hydroxyl functions of this
spiroketal so that a suitably functionalized and protected
version could be advanced toward 6. A convenient
substance for this purpose was already in hand in the
form of 69, available from 41 or 62 via 68, and methods
were therefore investigated for selective cleavage of the
primary silyl ether from this structure. The most effective
reagent for this purpose was HF-pyridine, which pro-
duced 70 accompanied by diol 71 (Scheme 11). The latter
could be recycled through its return to 69 by resilylation,
resulting in an overall 61% yield for the conversion of
69 to 70. Swern oxidation22 of 70 led to aldehyde 72,
which in a Takai reaction43 with iodoform and chromous
chloride afforded the trans iodoalkene 73 accompanied
by the cis isomer as a 18:1 mixture (Scheme 12). Cleavage
of the benzoate from 73 by saponification was quantita-
tive, and acylation of the resultant alcohol with diethyl
phosphonoacetyl chloride produced ester 75. This func-
tionalized spiroketal now became the dedicated partner
for coupling with keto aldehyde 5 in our plan for as-
sembling the second major segment of rutamycin B.
trile presumably led to a transient pentahydroxy ketone,
from which spontaneous spiroketalization followed to
yield 62.
P olyp r op ion a te Segm en t. The linear section of 2
comprising C3-C17 contains three stereotriads, each
characterized by an alternating array of methyl and
oxygen substituents. This arrangement lends itself to
stereocontrolled synthesis through asymmetric crotyla-
tion methodology, but in order to avoid a fully linear
approach, an aldol coupling was programmed for the
connection of C8 with C9. This plan simplifies elaboration
of the polypropionate subunit to independent prepara-
tions of aldehyde 4 and keto aldehyde 6.
Before proceeding further, it seemed prudent to verify
not only the configuration at the spiro carbon of 62 but
also the stereochemistry of spiroketal 41. This was made
possible by a generous gift of 63 from Professor Evans,
who had previously correlated this substance with the
spiroketal obtained by degradation of rutamycin A.4 First,
63 was saponified to remove the benzoate, and the
resulting alcohol 64 was then oxidized with Ley’s re-
agent40 to ketone 65 (Scheme 9). Hydrogenolysis of the
p-methoxybenzyl ether of 65 over Pearlman’s catalyst
afforded 66, which after cleavage of the silyl ether gave
41. The latter was identical in all respects with the
substance we had obtained from 40. It was further shown
that the bis(silyl) ether 67 derived from 41 underwent
(42) Girard, P.; Namy, J . L.; Kagan, H. B. J . Am. Chem. Soc. 1980,
102, 2693.
(43) Takai, K.; Nitta, K.; Utimoto, K. J . Am. Chem. Soc. 1986, 108,
7408.

Total Synthesis of Rutamycin B
J . Org. Chem., Vol. 66, No. 15, 2001 5223
Sch em e 10
Sch em e 12
Sch em e 13
Sch em e 11
The syn,syn stereotriad at C4-C6 was installed by a
Lewis acid catalyzed reaction of (R)-aldehyde 76 with a
mixture of cis- and trans-(tri-n-butyl)crotylstannanes44
at low temperature. This led to Felkin product 77 with a
diastereoselectivity >15:1 (Scheme 13). After protection
of 77 as silyl ether 78, the primary silyl group was
cleaved selectively with ammonium fluoride in hot metha-
nol,45 and the resulting alcohol 79 was oxidized under
Swern conditions22 to aldehyde 80. A Grignard reaction
of the latter with ethylmagnesium bromide produced a
1:1 mixture of stereoisomeric alcohols 81 that underwent
oxidation to ethyl ketone 82 with Dess-Martin periodi-
(44) Keck, G. E.; Abbott, D. E. Tetrahedron Lett. 1984, 25, 1883.

5224 J . Org. Chem., Vol. 66, No. 15, 2001
White et al.
Sch em e 14
Sch em e 15
nane.46 Ozonolysis of alkene 82 followed by a reductive
workup yielded the keto aldehyde 83, which, due to its
propensity to undergo intramolecular aldol condensation,
was prepared only as needed for its immediate olefination
with phosphonate 75.
The stereopentad corresponding to 4 was also prepared
from (R)-aldehyde 76. Asymmetric crotylation of 76 with
the trans crotylboronate 84 from (S,S)-tartrate16b gave
syn,anti alcohol 85, accompanied by its syn,syn stereoi-
somer, as a 9:1 mixture (Scheme 14). After purification
by chromatography, the silyl ether 86 of the major isomer
was ozonized, and the resulting aldehyde 87 was treated
with the boronate 88 prepared from (R,R)-tartrate in a
matched crotylation16 that produced alcohol 89 as a single
(>98:2) stereoisomer.
The selection of a protecting group for this homoallylic
alcohol now became an issue of pivotal significance for
two reasons. First, the hydroxyl substituent of 89 is
destined to become the ketone at C11 of 2, and a masking
device must therefore be used that is orthogonal to all
other protecting groups in order for it to be removed
selectively at a late stage when virtually the entire
functionality of the macrolide is in place. Second, the
oxygen substituent at C5 of 89 is positioned to play a
key role in the aldol coupling envisioned for the linkage
that creates the C8-C9 bond of 2. It was anticipated that
construction of the syn,syn triad at C8-C10 would be
critically dependent upon the presence in the aldehyde
of a â-alkoxy substituent capable of chelation to the
carbonyl, so that Felkin addition of a ketone enolate to
the aldehyde would predominate. The reasoning that led
to protection of 89 as its p-methoxybenzyl ether 90 was
based on the broad knowledge that this ether is an
excellent chelating ligand for metals typically employed
in enolate formation.47 The aldol partner representing 4
(Scheme 1) therefore became aldehyde 91, obtained by
ozonolysis of alkene 90.
Assem bly of Su bu n its. The sequence of subunit
assembly specified in Scheme 1 was decided primarily
by the instability of 83, which necessitated utilization of
this reactive aldehyde immediately after its preparation
from 82. Wadsworth-Emmons condensation48 of phos-
phonate 75 with 83 gave trans R,â-unsaturated ester 92
as the sole stereoisomer, thus completing the first key
connection and setting the stage for the pivotal aldol
coupling of this ketone with aldehyde 91 (Scheme 15).
The syn,syn,syn relationship of substituents across C6-
C10 of 2 stipulates that if a Z(O) enolate of 92 is to be
employed in this aldol reaction, it must attack the re face
of 91 in a Felkin sense in order to produce the correct
configuration at C8 and C9. Stereoselectivity in double
asymmetric aldol reactions is dependent upon a variety
of factors, including the metal counterion to the enolate,
the nature and configuration of flanking substituents,
and the protecting groups attached to neighboring oxy-
gens. Indeed, Roush showed that the anti-Felkin pathway
is often preferred in these reactions,49 an outcome we
(45) White, J . D.; Amedio, J . C., J r.; Gut, S.; J ayasinghe, L. J . Org.
Chem. 1989, 54, 4268.
(46) (a) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277.
(b) Meyer, S. D.; Schreiber, S. L. J . Org. Chem. 1994, 59, 7549.
(47) For a recent application of this concept, see: White, J . D.;
Carter, R. G.; Sundermann, K. F. J . Org. Chem. 1999, 64, 684.
(48) Wadsworth, W. S., J r. Org. React. 1977, 25, 73.

Total Synthesis of Rutamycin B
J . Org. Chem., Vol. 66, No. 15, 2001 5225
Sch em e 16
F igu r e 1. Proposed transition state for the reaction of 92 with
91 and 108.
wished to avoid. On the other hand, Evans found that
titanium enolates are highly effective in controlling the
stereochemistry of double asymmetric aldol reactions
leading to a syn,syn orientation of substituents,50 and this
was confirmed by Roush in his synthesis of the polypro-
pionate subunit of rutamycin B.51 In our case, the Z(O)-
titanium enolate of 92, prepared with titanium tetra-
chloride in the presence of Hu¨nig’s base, reacted with 91
to give the Felkin aldol product 93 as the only detectable
stereoisomer (>98:2).52 When the p-methoxybenzyl ether
in 91 was replaced by a triethylsilyl ether, the aldol
reaction with 92 produced a complex mixture resulting
from both Felkin and anti-Felkin pathways along with
desilylated products. This result is in agreement with the
observations of Roush.51
A rationale for the high stereoselectivity in the coupling
of 91 with 92 has been advanced that invokes bidentate
chelation of the carbonyl oxygen of aldehyde 91 with a
pair of titanium atoms.11b A representation of the transi-
tion state reflecting this mode of chelation is shown in
Figure 1. Although structural evidence, including that
gleaned from X-ray crystallography, confirms that a
carbonyl oxygen is capable of bidentate chelation with
oxyphilic, electron-deficient metal atoms,53 a reaction
pathway that utilizes this property has not been conclu-
sively demonstrated. Nevertheless, the mechanism de-
picted in Figure 1 explains certain features of the reaction
of 91 with 92, including the observation that both the
yield and stereoselectivity are optimal when a small
excess of titanium tetrachloride is used. If indeed Figure
1 represents an accurate view of the aldol transition state
for the formation of 93, bidentate coordination of the
aldehyde carbonyl with titanium(IV) adds a feature not
considered in existing models for double asymmetric aldol
reactions of R-chiral ethyl ketones with â-alkoxy alde-
hydes. The transition state shown in Figure 1 accords
with the suggestion of Roush that re face (Felkin)
addition to aldehyde 91 by the enolate of 92 is reinforced
by (S) configuration at the center R to the ketone.51 This
matched arrangement is apparently sufficient to over-
come a gauche-pentane interaction between the methyl
substituent R to the aldehyde and the methyl group of
the Z enolate.
way has no direct precedent, it offers an attractive
method for emplacing the conjugated trans,trans diene
unit in a stereocontrolled fashion. The first complication
in this plan arose when it was discovered that fluoride
sources such as HF-pyridine or ammonium fluoride,
which typically exhibit good selectivity in the cleavage
of primary tert-butyldimethylsilyl ethers, removed the
silyl groups at both C15 and C13 of 93 (Scheme 16). The
same outcome was observed when deprotection was
attempted on 94, obtained by silylation of aldol product
93. In neither case were other secondary silyl ethers
cleaved, and it seems reasonable to conclude that silyl
migration occurs from the oxygen at C13 after the
primary alcohol is liberated, and that a second deprotec-
tion ensues to give 95.54 Fortunately, this unanticipated
event had no deleterious consequences, since the primary
alcohol of 95 could be selectively activated as its mesi-
tylenesulfonate 96.55 The remaining secondary alcohols
Our intention with aldol product 93 was to selectively
unmask the primary silyl ether so that activation of the
liberated alcohol could be used to insert an ethylene
synthon between C15 and the distal iodoalkene moiety.
Although closure of the 26-membered macrocycle in this
(49) Roush, W. R. J . Org. Chem. 1991, 56, 4151.
(50) Evans, D. A.; Clark, J . S.; Metternich, R.; Novack, V. J .;
Sheppard, G. S. J . Am. Chem. Soc. 1990, 112, 866.
(51) Gustin, D. J .; Van Nieuwenhze, M. S.; Roush, W. R. Tetrahedron
Lett. 1995, 36, 3447.
(52) For a discussion of double-stereodifferentiating aldol reactions
of a similar type, see: Evans, D. A.; Dart, M. J .; Duffy, J . L.; Rieger,
D. L. J . Am. Chem. Soc. 1995, 117, 9073.
(54) Yamazaki, T.; Oniki, T.; Kitazume, T. Tetrahedron 1996, 52,
11753.
(55) Lohrmann, R.; Khorana, H. G. J . Am. Chem. Soc. 1966, 88, 829.
(53) Tschinkl, M.; Schier, A.; Riede, J .; Gabbai, F. P. Organometallics
1999, 18, 1747, and references cited.

5226 J . Org. Chem., Vol. 66, No. 15, 2001
White et al.
Sch em e 17
Sch em e 18
at C9 and C13 were silylated to give 97, and displacement
of the sulfonate with sodium iodide then yielded the
diiodo compound 98. However, numerous attempts to
replace the primary iodide of 98 with a trans stannyl-
ethylene unit employing cuprate reagents of the type
56
RCu(CHdCHSnBu3) (CN)Li2, where R ) 2-thienyl,
proceeded with very high stereoselectivity and gave
hydroxy ketone 109 as the only stereoisomer detectable
by NMR spectroscopy (Scheme 18).
1-heptynyl, etc. were to no avail. A minor product noted
in most cases resulted from conjugate addition of the
cuprate reagent to the R,â-unsaturated ester of 98.
The failure to homologate 98 by displacement of the
primary iodide forced us to adopt a different tactic for
reaching our seco precursor 3 for macrocyclization, and
to this end a simple revision was made to the route
leading to the C9-C15 polypropionate segment by in-
corporating an additional carbon, C16, at the outset.
Thus, selective deprotection of the primary silyl ether of
86 followed by tosylation of alcohol 99 afforded 100 which
underwent displacement with sodium cyanide to yield
nitrile 101 (Scheme 17). Unlike 93, the bis(silyl) ether
86 did not suffer silyl migration during its exposure to
ammonium fluoride in methanol. Nitrile 101 was reduced
to aldehyde 102, which was further reduced to alcohol
103 and protected as silyl ether 104 before ozonolysis to
furnish aldehyde 105. A matched crotylation of 105 with
boronate 8816 gave homoallylic alcohol 106 with excellent
stereoselectivity, and following the protocol employed
with 89, this alcohol was converted to its p-methoxyben-
zyl ether 107. Subsequent aldol coupling of the aldehyde
108, prepared by ozonolysis of 107, with ketone 92 again
At this point, the route forward diverged from the
pathway from 93 because we were fearful of mishap if
removal of the p-methoxybenzyl group was postponed to
a stage at which the conjugated diene was already in
place. We were also cognizant of the possibility that the
C11 hydroxyl when liberated could form an internal
hemiketal with the C7 ketone, since removal of the
p-methoxybenzyl protection from 94 had led to exactly
that outcome in the form of 110 (Scheme 19). Neverthe-
less, precedent in the work of Evans9 suggested that rapid
oxidation of the C11 alcohol to a ketone could circumvent
hemiketal formation, and this proved to be the case. First,
it was necessary to protect the hydroxyl substituent of
109 in order to avoid unwanted oxidation at C9 in
conjunction with pending formation of the C11 ketone;
this was accomplished by silylation to give pentasilyl
ether 111. The p-methoxybenzyl ether was removed from
111 with dichlorodicyanobenzoquinone, and the resulting
alcohol 112 was immediately oxidized to 113 using Dess-
Martin periodinane.46 The silyl ether at C16 was then
cleaved with HF-pyridine, again with accompanying
silyl migration, to furnish primary alcohol 114 as the
major product and diol 115 as an easily separable
(56) Behling, J . R.; Babiak, K. A.; Ng, J . S.; Campbell, A. L.; Moretti,
R.; Koerner, M.; Lipshutz, B. H. J . Am. Chem. Soc. 1988, 110, 2641.

Total Synthesis of Rutamycin B
J . Org. Chem., Vol. 66, No. 15, 2001 5227
Sch em e 19
Sch em e 20
byproduct. The former was oxidized to aldehyde 116 in
preparation for a one-carbon homologation to produce a
functionalized trans alkene at this terminus. Our hope
was that the rutamycin macrocycle could be closed from
this species using a vinyl-vinyl coupling, and the first
effort along this line was made with the diiodo compound
117, prepared by a Takai reaction43 of 116 with iodoform
and chromous chloride. Following precedent suggested
by recent work of Liebeskind,57 117 was treated with
copper(I) thiophene-2-carboxylate, but no evidence of
intramolecular vinyl-vinyl coupling was seen. A variant
of this approach employing dibromo(tri-n-butylstannyl)-
methane (118)58 was investigated with the goal of closing
the macrocycle via a Stille coupling. However, treatment
of 116 with 118 and chromous chloride gave mainly the
destannylated product 119 accompanied by lesser quan-
tities of the trans stannane 120 and its cis isomer
(Scheme 20).
The remaining option for macrocyclization appeared
to be an intramolecular Suzuki coupling59 of a vinylbo-
ronate derived from aldehyde 116, and implementation
of this plan began with preparation of the known dichlo-
romethylboronate 12160 of pinacol. The latter was con-
densed with 116 in the presence of chromous chloride
and lithium iodide61 to yield the readily isolable trans
vinyl boronate 122 (Scheme 21). Intramolecular coupling
of 122 proceeded smoothly in the presence of catalytic
palladium dichloride acetonitrile complex and tripheny-
larsine to provide the macrocycle 123 in good yield. As
noted by others,62 addition of silver oxide to the reaction
medium was found to improve the efficiency of Suzuki
coupling. That the correctly functionalized skeleton of
rutamycin B had been assembled in this process was
proven by exhaustive silylation of a sample of the natural
material with tert-butyldimethylsilyl triflate, which fur-
nished a substance identical with 123 in all respects.
Final cleavage of the silyl ethers from 123 with HF-
pyridine over 4 days, a process in which successive
cleavage of each of the four ethers could be discerned by
thin-layer chromatography, led to rutamycin B (2).
In summary, a convergent synthesis of rutamycin B
(2) was accomplished from three principal subunitss
spiroketal 75, ketone 83, and aldehyde 108sin 0.22%
overall yield. The longest linear sequence, that leading
to 108, is 12 steps and proceeds in 18% overall yield.
Successful closure of the 26-membered ring of rutamycin
B via intramolecular Suzuki coupling represents an
unconventional strategy among syntheses of macrolides
of this class, and confirms that this carbon-carbon bond
forming reaction can rival traditional macrolactonization
techniques for convenience and efficiency.
Exp er im en ta l Section
Gen er a l Meth od s. Starting materials and reagents were
obtained from commercial sources and were used without
further purification. Solvents were dried by distillation from
the appropriate drying agents immediately prior to use.
Tetrahydrofuran and ether were distilled from sodium or
potassium and benzophenone under an argon atmosphere.
Toluene, diisopropylamine, diisopropylethylamine, triethy-
lamine, pyridine, and dichloromethane were distilled from
calcium hydride under argon. All solvents used for routine
isolation of products and chromatography were reagent grade.
Moisture- and air-sensitive reactions were carried out under
an atmosphere of argon. Reaction flasks were flame dried
under a stream of argon gas, and glass syringes were oven
dried at 120 °C prior to use.
Unless otherwise stated, concentration under reduced pres-
sure refers to a rotary evaporator at water aspirator pressure.
Residual solvent was removed by vacuum pump at a pressure
less than 0.25 mm of mercury.
Analytical thin-layer chromatography (TLC) was conducted
using E. Merck precoated TLC plates (0.2 mm layer thickness
(57) Zhang, S.; Zhang, D.; Liebeskind, L. S. J . Org. Chem. 1997,
62, 2312.
(58) Hodgson, D. M.; Boulton, L. T.; Maw, G. N. Tetrahedron 1995,
51, 3713.
(59) Suzuki, A. Pure Appl. Chem. 1994, 66, 213.
(60) Wuts, P. G. M.; Thompson, P. A. J . Organomet. Chem. 1982,
234, 137.
(61) Takai, K.; Shinomiya, N.; Kaihara, H.; Yoshida, N.; Moriwake,
T. Synlett 1995, 963.
(62) Gillmann, T.; Weeber, T. Synlett 1994, 649.

5228 J . Org. Chem., Vol. 66, No. 15, 2001
White et al.
Kratos MS-50 spectrometer. Elemental analyses were per-
formed by Desert Analytics, Tucson, AZ.
Sch em e 21
(Z)-(2S,8R,9S,12R)-9-[(ter t-Bu tyld im eth ylsilyl)oxy]-12-
[(ter t-b u t yld im et h ylsilyl)oxym et h yl]-2-[(4S,6R)-2,2-d i-
ter t-b u t ylsilylen e-6-m et h yl-1,3-d ioxa n -4-yl]-8-m et h yl-5-
(2,2-d im eth ylh yd r a zin o)-5-tetr a d eca n -7-on e (40). To a
solution of diisopropylamine (0.021 mL, 0.091 mmol) in tet-
rahydrofuran (0.7 mL) under argon at -30 °C was added
dropwise methyllithium (1.35 M in ether, containing less than
0.05M halide, 0.060 mL, 0.081 mmol). The colorless solution
was warmed to 0 °C, stirred for 10 min, cooled to -4 °C, and
added dropwise to a solution of crude 39 (25 mg) in tetrahy-
drofuran (0.7 mL). The yellow solution was stirred for 50 min
at -2 °C, cooled to -78 °C, and transferred into a precooled
(-57 °C) solution of 38 (26 mg, 0.055 mmol) via cannula. The
resulting pale yellow solution was stirred for 20 h at -45 °C,
for 1.5 h at -30 °C, and for 19 h at -18 °C. The mixture was
cooled to -78 °C and was transferred into a rapidly stirred
biphasic solution of ether (20 mL) and saturated ammonium
chloride solution (20 mL) at 0 °C via cannula. The mixture
was stirred for 15 min and was partitioned, and the aqueous
layer was extracted three times with ethyl acetate (20 mL).
The combined organic layers were dried (sodium sulfate), and
the solvent was removed under reduced pressure. Chroma-
tography of the residue on silica gel, with gradient elution from
5% to 30% ethyl acetate in hexane, gave 5.6 mg (67% based
on recovered 38) of 40 as a colorless, unstable oil: 1H NMR
(CDCl3, 300 MHz) δ 0.02 (12H, s), 0.87 (21H, m), 0.91 (3H, d,
J ) 6 Hz), 0.95 (3H, d, J ) 6 Hz), 1.01 (18H, s), 1.06 (3H, d,
J ) 7 Hz), 1.21-1.36 (8H, m), 1.41-1.51 (4H, m), 1.80 (1H,
m), 2.01 (2H, m), 2.30-2.50 (3H, m), 2.53 (3H, s), 3.40-3.50
(2H, m), 3.86-3.95 (1H, m), 4.00-4.10 (1H, m), 4.40 (1H, m),
4.90 (1H, m), 11.29 (1H, s); 13C NMR (CDCl3, 75 MHz) δ -5.5,
-4.8, -4.4 (4C), 11.1, 12.7, 13.9, 18.0, 18.2, 20.7, 21.3, 23.2,
23.4, 25.5, 25.9, 26.0 (6C), 26.1, 27.0, 27.1, 27.2 (6C), 37.5, 38.7,
39.2, 41.1, 41.5, 42.2, 48.7, 65.2, 67.7, 70.7, 71.1, 74.8, 92.1,
167.2, 200.1.
(2S,3R,6R,8S,9S)-3,9-Dim eth yl-8-[(R)-2-h yd r oxy-1-p r o-
p yl]-2-[(R)-3-h yd r oxym et h yl-1-p en t yl]-1,7-d ioxa sp ir o-
[5.5]u n d eca n -4-on e (41). F r om 40. A solution of 40 (3.6 mg,
0.0046 mmol) in a hydrofluoric acid-acetonitrile-water stock
solution [9:1 [95:5 (CH3CN/48%HF)]/H2O, 0.5 mL] was stirred
for 5 d at room temperature, during which time an additional
0.2 mL of the stock solution was added at 20 and 47 h. The
solution was added to saturated aqueous sodium bicarbonate
(2 mL) and water (8 mL), and the mixture was extracted once
with ethyl acetate (15 mL) and twice with ether (15 mL). The
combined organic layers were dried (magnesium sulfate), and
the solvent was removed under reduced pressure. Chroma-
tography of the residue on silica gel, with gradient elution from
15% to 70% ethyl acetate in hexane, gave 1.2 mg (73%) of 41
as a colorless oil: [R]22D -105.5 (c 1.13, CHCl3); IR (neat) 3389,
3382, 2964, 2938, 2878, 1716, 1457, 1377, 1304, 1251, 1085,
972 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.89 (6H, m), 0.98 (1H,
d, J ) 7 Hz), 1.08 (3H, d, J ) 7 Hz), 1.13 (3H, d, J ) 6 Hz),
1.16-1.40 (3H, m), 1.41-1.49 (3H, m), 1.51-1.71 (7H, m),
2.08-2.22 (1H, m, J ) 5 Hz), 2.26-2.60 (1H + 2′OH′, m), 2.30
(1H, d, J ) 14 Hz), 2.50 (1H, d, J ) 14 Hz), 3.43-3.60 (2H,
dtd, J ) 24, 11, 6 Hz), 3.78-3.91 (1H, m, J ) 6, 2 Hz), 3.98-
4.06 (2H, m); 13C NMR (CDCl3, 75 MHz) δ 10.5, 11.0, 11.3,
23.3, 24.8, 26.1, 26.5, 28.0, 29.4, 30.2, 41.8, 42.4, 47.9, 48.3,
63.9, 67.8, 70.6, 74.6, 98.9, 210.9; MS (CI) m/z 357 (M+ + 1),
355, 339, 268, 255, 227, 211, 197, 185, 173, 155, 95; HRMS
(CI) m/z 357.2639 (calcd for C20H36O5 + H+ 357.2642).
F r om 66. A solution of 66 (460 mg, 0.977 mmol) and tetra-
n-butylammonium fluoride (2.05 mL, 2.05 mmol) in tetrahy-
drofuran (15 mL) under argon was stirred for 8.5 h at room
temperature. The mixture was added to ether (45 mL), and
the solution was washed with brine (50 mL). The aqueous
wash was extracted once with ethyl acetate (50 mL) and twice
with ether (50 mL), and the combined organic layers were
dried (sodium sulfate). Removal of the solvent under reduced
pressure was followed by chromatography of the residue on
silica gel, with gradient elution from 30% to 60% ethyl acetate
in hexane, to yield 236 mg (68%) of 41 as a colorless oil.
of silica gel 60 F-254). Compounds were visualized by ultra-
violet light and/or by heating the plate after dipping in a 3-5%
solution of phosphomolybdic acid in ethanol, 10% ammonium
molybdate in water, a 1% solution of vanillin in 0.1 M sulfuric
acid in methanol or 2.5% p-anisaldehyde in 88% ethanol, 5%
water, 3.5% concentrated sulfuric acid, and 1% acetic acid.
Flash chromatography was carried out using either Merck
silica gel 60 (230-400 mesh ASTM) or Scientific Adsorbents
Inc. silica gel (40 µm partical size). Radial chromatography
was carried out on individually prepared rotors with layer
thicknesses of 1, 2, or 4 mm using a Chromatotron manufac-
tured by Harrison Research, Palo Alto, CA.
Melting points were measured using a Bu¨chi melting point
apparatus. Optical rotations were measured with a Perkin-
Elmer 243 polarimeter at ambient temperature using a 0.9998
dm cell with 1 mL capacity. Infrared (IR) spectra were recorded
with a Nicolet 5DXB FT-IR spectrometer. Proton and carbon
nuclear magnetic resonance (NMR) spectra were obtained
using either a Bruker AC-300 or a Bruker AM-400 spectrom-
eter. All chemical shifts are reported in parts per million (ppm)
1
downfield from tetramethylsilane using the δ scale. H NMR
spectral data are reported in the order: chemical shift, number
of protons, multiplicity (s ) singlet, d ) doublet, t ) triplet, q
) quartet, m ) multiplet, and b ) broad), and coupling
constant (J , in hertz).
Chemical ionization (CI) high- and low-resolution mass
spectra (HRMS and MS) were obtained using a Finnigan 4023
spectrometer or a Kratos MS-50 spectrometer with a source
temperature of 120 °C and methane gas as the ionizing source.
Perfluorokerosene was used as a reference. Electron impact
(EI) mass spectra (HRMS and MS) were obtained with a
Varian MAT311 or a Finnegan 4000 spectrometer. Fast atom
bombardment (FAB) mass spectra were obtained using a

Total Synthesis of Rutamycin B
J . Org. Chem., Vol. 66, No. 15, 2001 5229
Hyd r oxy Su lfon e 59. To a solution of 56 (37 mg, 0.090
mmol) in tetrahydrofuran (1 mL) under argon at -78 °C was
added dropwise n-butyllithium (1.58 M in hexane, 0.057 mL,
0.090 mmol). The yellow solution was stirred for 45 min, and
freshly distilled trifluoroboron etherate (0.011 mL, 0.090 mmol)
was added dropwise. The mixture was stirred for 5 min, after
which time a precooled (-78 °C) solution of 58 (20 mg, 0.035
mmol) in tetrahydrofuran (0.8 mL) was added dropwise via
cannula. The pale yellow solution was stirred for 3 h at -78
°C and for 1 h at room temperature. The reaction was
quenched by addition of saturated ammonium chloride solution
(1 mL), diluted with ether (20 mL), and washed with saturated
ammonium chloride solution (20 mL) and brine (20 mL). The
aqueous wash was extracted three times with ether (30 mL),
and the combined ethereal extracts were dried (magnesium
sulfate). Removal of the solvent under reduced pressure was
followed by chromatography of the residue on silica gel, with
gradient elution from 5% to 10% ethyl acetate in hexane, to
yield, 15 mg of recovered 56, and 30 mg (86%) of 59 as a
colorless oil: IR (neat) 3535, 2956, 2933, 2899, 2859, 1480,
1263, 1260, 1160, 1093, 844 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 0.04 (18H, m), 0.71 (4H, dd, J ) 13, 7 Hz), 0.89 (33H, m),
0.99 (18H, s), 1.26 (10H, m), 1.48 (4H, m), 1.75 (3H, m), 2.01
(3H, m), 3.04 (1H, m), 3.48 (2H, m), 3.75 (1H, m), 3.98 (2H,
m), 4.29 (1H, m), 4.38 (1H, m), 7.56 (2H, m), 7.63 (1H, m),
7.88 (2H, m); 13C NMR (CDCl3, 75 MHz) δ -5.5, -4.7, -4.5,
-4.3, -3.9, -3.8, 9.3, 9.8, 11.1, 12.9, 17.9, 18.0, 18.2, 20.7, 21.3,
23.3, 24.6, 25.8, 25.9 (9C), 26.5, 27.1, 27.2 (6C), 31.7, 37.3, 37.4,
42.5, 65.3, 66.1, 67.6, 70.0, 70.6, 70.9, 73.1, 128.5 (2C), 129.1
(2C), 133.7, 138.2; MS (FAB) m/z 1002 (M+ + 1), 1001 (M+),
986, 943, 869, 812, 737, 679, 625, 595, 567, 463, 419, 359, 269,
227.
Keto Su lfon e 60. A suspension of 59 (6.5 mg, 0.0065 mmol),
powdered activated 4 Å molecular sieves, 4-methylmorpholine
N-oxide, and tetra-n-propylammonium perruthenate in dichlo-
romethane (1 mL) under argon was stirred for 2.5 h at room
temperature. The mixture was filtered through a short plug
of Celite that was rinsed with dichloromethane. Removal of
the solvent from the filtrate under reduced pressure followed
by chromatography of the residue on silica gel, with gradient
elution from 3% to 9% ethyl acetate in hexane, afforded 5.6
mg (86%) of 60 as a colorless oil: IR (neat) 2959, 2938, 2892,
2867, 1723, 1475, 1331, 1264, 1149, 1097, 845 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 0.02 (18H, m), 0.83 (9H, s), 0.88 (9H, s),
0.89 (9H, s), 0.94 (18H, s), 0.80-0.97 (8H, m), 1.24 (3H, d, J )
7 Hz), 1.21-1.40 (7H, m), 1.49 (3H, m), 1.65 (1H, m), 1.80 (1H,
m), 2.03 (2H, m), 2.64-3.01 (1H, 2dd, J ) 20, 6 Hz), 3.10-
3.32 (1H, 2dd, J ) 20, 6 Hz), 3.47 (2H, m), 3.84 (1H, m), 3.95
(1H, m), 4.13 (1H, dd, J ) 11.7, 3.1 Hz), 4.25 (1H, m), 4.36
(1H, m), 7.53 (2H, m), 7.66 (1H, m), 7.77 (2H, m); 13C NMR
(CDCl3, 75 MHz) δ -5.5, -4.7, -4.5, -4.3, -4.1, -3.7, 9.4,
11.1, 12.5, 17.9, 18.1, 18.2, 20.6, 21.3, 23.2, 23.3, 25.5, 25.8,
25.9 (9C), 26.0, 27.1, 27.2 (6C), 31.2, 36.9, 41.0, 42.3, 49.9, 51.4,
65.1, 67.9, 68.2, 69.8, 71.2, 72.9, 128.8, 129.2, 134.0, 136.5,
200.5; MS (FAB) m/z 999 (M+ + 1), 997, 941, 887, 867, 735,
728, 643, 611, 595, 575, 549, 519, 503, 429, 413, 323, 253, 217,
201, 181.
warm to room temperature during 1 h and diluted with ether
(20 mL). The ethereal solution was washed with saturated
potassium carbonate solution (20 mL), and the aqueous wash
was extracted three times with ether (20 mL). The combined
ethereal extracts were dried (magnesium sulfate), and the
solvent was removed under reduced pressure. Chromatography
of the residue on silica gel, with gradient elution from 2% to
5% ethyl acetate in hexane, gave 11.0 mg (89%, 97% based on
recovered 60) of 61 as a colorless oil: [R]22 +19.8 (c 0.85,
D
CHCl3); IR (neat) 2963, 2932, 2896, 2860, 1715, 1476, 1386,
1257, 1103, 840 cm-1; 1H NMR (CDCl3, 400 MHz) δ -0.01 (3H,
s), 0.03 (6H, s), 0.06 (6H, s), 0.07 (3H, s), 0.83 (3H, d, J ) 7
Hz), 0.84-0.91 (6H, m), 0.86 (9H, s), 0.89 (9H, s), 0.90 (9H, s),
1.00 (18H, s), 1.15-1.36 (5H, m), 1.29 (3H, d, J ) 7 Hz), 1.37-
1.53 (5H, m), 1.60-1.67 (1H, m), 1.70-1.81 (1H, m), 2.00-
2.08 (1H, ddd, J ) 16, 10, 6 Hz), 2.34-2.54 (2H, m), 2.56-
2.68 (2H, ddd, J ) 20, 16, 4 Hz), 3.48 (2H, ddd, J ) 15, 10, 6
Hz), 3.83 (1H, q, J ) 6 Hz), 4.00 (1H, td), 4.21 (1H, q, J ) 6
Hz), 4.39 (1H, m, J ) 12, 6, 2 Hz); 13C NMR (CDCl3, 100 MHz)
δ -5.5, -5.4, -4.5, -4.4, -4.2, -3.6, 9.9, 11.1, 13.9, 18.0, 18.1,
18.3, 20.8, 21.3, 23.3, 23.5, 25.8, 25.9, 26.0 (9C), 26.8, 27.3 (6C),
32.2, 37.7, 38.9, 41.9, 42.3, 42.4, 47.9, 65.1, 67.7, 70.1, 71.4,
72.1, 209.9; MS (CI) m/z 858 (M+), 844, 802, 728, 670, 630,
596, 538, 498, 471, 359, 269, 227, 199, 147, 115; HRMS (CI)
m/z 801.5738 (calcd for C46H98O6Si4 - C4H9 801.5739).
(2S,3S,4S,6R,8S,9S)-3,9-Dim et h yl-8-[(R)-2-h yd r oxy-1-
pr opyl]-2-[(R)-3-(h ydr oxym eth yl)-1-pen tyl]-1,7-dioxaspir o-
[5.5]u n d eca n -4-ol (62). F r om 61. To a Nalgene vial contain-
ing 61 (10 mg, 0.010 mmol) at room temperature was added a
stock solution of 48% hydrofluoric acid-acetonitrile (1:7, 3 mL).
The mixture was stirred for 48 h, diluted with ether (20 mL),
and washed with brine (15 mL) and water (15 mL). The
aqueous wash was extracted once with ethyl acetate (20 mL)
and twice with ether (20 mL), and the combined organic
extracts were dried (sodium sulfate). Removal of the solvent
under reduced pressure was followed by chromatography of
the residue on silica gel, with gradient elution from 40% to
95% ethyl acetate in hexane to yield 3.4 mg (82%) of 62 as a
white solid: [R]22 -82.5 (c 0.16, CHCl3); IR (neat) 3350 (br),
D
2964, 2940, 2876, 1455, 1386, 1059, 976 cm-1; 1H NMR (CDCl3,
300 MHz) δ 0.82 (3H, d, J ) 7 Hz), 0.87 (3H, m), 0.90 (3H, d,
J ) 8 Hz), 1.19 (3H, d, J ) 6 Hz), 1.24 (2H, t, J ) 7 Hz), 1.30-
1.65 (12H, m), 1.68-1.74 (1H, dd, J ) 13, 5 Hz), 1.82-1.86
(1H, m), 2.03-2.16 (1H, m), 2.56-2.58 (3H, br), 3.44-3.50 (1H,
dd, J ) 11, 4 Hz), 3.55-3.60 (1H, dd, J ) 11, 4 Hz), 3.71-3.97
(1H, m), 4.03-4.77 (2H, m); 13C NMR (CDCl3, 75 MHz) δ 3.9,
11.1, 11.3, 23.3, 24.5, 26.4, 26.6, 29.0, 29.7, 30.7, 37.7, 38.9,
41.9, 42.3, 64.4, 64.5, 67.2, 67.3, 71.2, 97.4; MS (CI) m/z 358
(M+), 341, 323, 270, 228, 211, 171, 113, 95; HRMS (CI) m/z
358.2717 (calcd for C20H38O5 358.2720).
F r om 68. A solution of 68 (127 mg, 0.220 mmol) and tetra-
n-butylammonium fluoride (1.0 M in tetrahydrofuran, 1.10 mL,
1.10 mmol) in tetrahydrofuran (8 mL) under argon was stirred
for 24 h at room temperature. The solution was diluted with
ether (30 mL) and washed with brine (30 mL). The aqueous
wash was extracted once with ethyl acetate (30 mL) and twice
with ether (30 mL), and the combined organic extracts were
dried (sodium sulfate). Removal of the solvent was followed
by chromatography of the residue on silica gel, with gradient
elution from 40% to 90% ethyl acetate in hexane to yield 77.0
(2S,7S,8R,9S,12R)-7,9-Di[(ter t-bu tyld im eth ylsilyl)oxy]-
12-[(ter t-bu tyld im eth ylsilyl)oxym eth yl]-2-[(4S,6R)-2,2-d i-
ter t-bu tylsilylen e-6-m eth yl-1,3-d ioxa n -4-yl]-8-m eth yltet-
r a d eca n -5-on e (61). A flame-dried flask under argon was
charged with samarium (900 mg, 6.00 mmol). The flask was
evacuated under high vacuum for 15 min and was refilled with
argon. This process was repeated three times. Freshly distilled
tetrahydrofuran (30 mL) and diiodomethane (0.244 mL, 3.00
mmol) were added with vigorous stirring at room temperature,
and the dark blue solution was stirred for 1 h. This stock
solution of samarium diiodide could be stored for 3 months
under argon.
To a solution of 60 (14.5 mg, 0.0145 mmol) in tetrahydro-
furan (1.6 mL) and methanol (0.8 mL) under argon at -78 °C
was added a freshly prepared solution of samarium diiodide
(0.10 M in tetrahydrofuran, 0.580 mL, 0.0580 mmol). The
reaction flask was covered with foil, and the dark blue solution
was stirred for 30 min at -78 °C. The solution was allowed to
mg (98%) of 62 as a white solid: [R]22 -82.8 (c 1.01, CHCl3).
D
(2S,3S,4S,6R,8S,9S)-4-[(Dieth ylp h osp h on oa cetyl)oxy]-
3,9-dim eth yl-8-[(R)-2-[(ter t-bu tyldim eth ylsilyl)oxy]-1-pr o-
p yl]-2-[(R)-3-eth yl-5-(E)-iod o-4-p en ten yl]-1,7-d ioxa sp ir o-
[5.5]u n d eca n e (75). A solution of triethyl phosphonoacetate
(5.0 g, 22 mmol) and potassium hydroxide (1.5 g, 24 mmol) in
ethanol (3.5 mL) and water (1.4 mL) was stirred for 15 h at
room temperature. The volatile components were removed
under reduced pressure, and the residue was dissolved in
water (20 mL). The mixture was extracted twice with ether
(30 mL), and the combined organic layers were washed with
water (40 mL) and acidified to pH 1 using 2 N hydrochloric
acid. Brine (50 mL) was added, and after separation the
aqueous layer was extracted three times with dichloromethane
(50 mL). The combined organic layers were dried (magnesium

5230 J . Org. Chem., Vol. 66, No. 15, 2001
White et al.
sulfate), and the solvent was removed under reduced pressure
to give 3.0 g (69%) of diethyl phosphonoacetic acid as a pale
yellow oil.
Hyd r oxy Keton e 93. To a solution of 92 (102 mg, 0.11
mmol) in dichloromethane (700 µL) at -78 °C were added
titanium(IV) chloride (1.0 M in dichloromethane, 135 µL, 0.135
mmol) and triethylamine (23 µL, 0.17 mmol). The mixture was
stirred for 1.5 h at -78 °C, and a solution of 91 (67 mg, 0.12
mmol) in dichloromethane (700 µL) was added. The solution
was stirred for 15 min at -78 °C and then was allowed to
warm to -30 °C during 30 min. The solution was stirred for 2
h at -30 °C, and pH 7 phosphate buffer (2.5 mL) was added.
The mixture was diluted with ether (5 mL), the layers were
separated, and the aqueous layer was extracted three times
with ether (10 mL). The combined extracts were washed with
saturated sodium bicarbonate solution, water, and brine and
were dried (magnesium sulfate). The solvent was evaporated
under reduced pressure, and the residue was chromatographed
on silica gel, eluting with 10% ether in hexane, to give 101
To a solution of the acid prepared above (700 mg, 3.57 mmol)
in dichloromethane (6 mL) at 0 °C was added dropwise oxalyl
chloride (0.477 mL, 5.36 mmol), and the mixture was stirred
for 10 min at 0 °C and for 22 h at room temperature. Removal
of the solvent under reduced pressure gave 766 mg of diethyl
phosphonoacetyl chloride, which was used without purification.
To a solution of 74 (313 mg, 0.526 mmol), 4-(dimethylami-
no)pyridine (480 mg, 3.93 mmol), and pyridine (0.607 mL, 7.85
mmol) in dichloromethane (10 mL) under argon at 0 °C was
added dropwise a solution of diethyl phosphonoacetyl chloride
prepared above (766 mg) in dichloromethane (3 mL). The
yellow solution was stirred for 1 h at 0 °C and was quenched
by addition of saturated sodium bicarbonate solution (5 mL).
The mixture was diluted with dichloromethane (30 mL), and
was washed with saturated sodium bicarbonate solution (30
mL), water (30 mL) and brine (30 mL). The aqueous wash was
extracted three times with dichloromethane (80 mL), and the
combined organic extracts were dried (magnesium sulfate).
Removal of the solvent followed under reduced pressure by
chromatography of the residue on silica gel, using 40% ethyl
acetate in hexane as eluant, gave 392 mg (96%) of 75 as a pale
mg (62%) of 93 as a colorless foam: [R]22 -31.2 (c 0.95,
D
CHCl3); IR (neat) 3495, 2956, 2887, 1717, 1650, 1616, 1252,
1039, 836 cm-1; 1H NMR (CDCl3, 400 MHz) δ 0.01 (3H, s), 0.04
(3H, s), 0.06 (9H, s), 0.07 (3H, s), 0.12 (6H, s), 0.82 (3H, d, J )
7 Hz), 0.85 (3H, d, J ) 7 Hz), 1.10 (3H, d, J ) 7 Hz), 1.13 (3H,
d, J ) 7 Hz), 0.80-1.71 (27H, m), 1.76 (1H, dd, J ) 13, 5 Hz),
1.94 (1H, m), 2.02-2.10 (3H, m), 2.36 (1H, m), 2.66 (1H, m),
2.83 (1H, m), 3.39 (1H, m), 3.46-3.50 (2H, m), 3.61 (1H, s),
3.66 (1H, m), 3.73 (1H, m), 3.79 (3H, s), 3.78-3.85 (2H, m),
4.07 (1H, t, J ) 5 Hz), 4.11 (1H, d, J ) 9 Hz), 4.44 (1H, d, J )
10 Hz), 4.59 (1H, d, J ) 10 Hz), 5.28 (1H, dt, J ) 12, 5 Hz),
5.73 (1H, dd, J ) 15, 1 Hz), 5.95 (1H, d, J ) 14 Hz), 6.26 (1H,
dd, J ) 14, 9 Hz), 6.85 (2H, d, J ) 9 Hz), 6.96 (1H, dd, J ) 15,
7 Hz), 7.22 (2H, d, J ) 9 Hz); 13C NMR (CDCl3, 100 MHz) δ
-5.23, -5.20, -4.4, -4.3, -4.23, -4.20, -3.9, -3.5, 5.0, 11.0,
11.2, 11.5, 12.1, 12.5, 13.4, 13.5, 14.6, 18.1, 18.3, 18.4, 18.4,
24.5, 25.9, 26.0, 26.1, 26.2, 26.4, 27.4, 29.6, 29.7, 30.2, 31.1,
35.1, 35.7, 38.3, 38.4, 41.4, 42.8, 43.2, 48.7, 49.8, 55.3, 66.6,
67.2, 69.5, 70.3, 70.6, 71.7, 72.8, 74.1, 74.2, 75.5, 86.4, 97.5,
113.9, 121.1, 129.2, 130.3, 150.4, 151.6, 159.3, 165.5, 215.2;
HRMS (FAB)m/z1457.8347 (calcd for C74H137IO12Si4 1457.8308).
Hyd r oxy Keton e 109. To a solution of 92 (51.0 mg, 56.3
µmol) in dichloromethane (0.7 mL) was added titanium
tetrachloride (1 M solution in dichloromethane, 61.9 µL, 61.9
µmol), and the brown-red solution was stirred for 1 h at -78
°C. A solution of 108 (34.0 mg, 61.9 µmol) in dichloromethane
(100 µL) was added, and the mixture was stirred for 15 min
at -78 °C and for 30 min at -50 °C. The reaction was
quenched by addition of pH 7 phosphate buffer solution, and
the mixture was extracted three times with ethyl acetate (15
mL). The combined extracts were washed with 5% aqueous
sodium carbonate (5 mL), brine (5 mL), and dried (magnesium
sulfate). The solvent was removed under reduced pressure, and
the residue was purified by column chromatography on silica
gel, eluting with hexanes-ether (9:1 to 8:2), to yield 43.0 mg
(52%) of 109 as a clear oil: 1H NMR (CDCl3, 300 MHz) δ 0.01-
0.15 (24H, m), 0.81-2.15 (88H, m), 2.32-2.41 (1H, m), 2.64-
2.71 (1H, m), 2.82-2.90 (1H, m), 3.50-3.84 (7H, m), 3.79 (3H,
s), 4.07-4.12 (2H, m), 4.43 (1H, d, J ) 10 Hz), 4.60 (1H, d, J
) 10 Hz), 5.27 (1H, td, J ) 10, 5 Hz), 5.74 (1H, d, J ) 16 Hz),
5.95 (1H, d, J ) 14 Hz), 6.26 (1H, dd, J ) 9, 14 Hz), 6.85 (2H,
d, J ) 9 Hz), 6.97 (1H, dd, J ) 6, 16 Hz), 7.23 (2H, d, J ) 9
Hz); 13C NMR (CDCl3, 75 MHz) δ -5.3, -5.2, -4.5, -4.3, -4.2,
-3.9, -3.6, 4.9, 11.0, 11.5, 12.0, 12.9, 13.2, 13.4, 14.1, 15.0,
18.1, 18.3, 24.5, 25.9, 26.0, 26.1, 26.2, 26.4, 27.1, 29.5, 29.7,
30.2, 31.1, 31.8, 35.1, 35.7, 38.0, 38.4, 41.4, 42.4, 43.2, 48.7,
50.3, 55.3, 61.0, 67.2, 69.5, 70.3, 70.5, 72.0, 74.0, 74.2, 75.6,
77.3, 86.6, 97.4, 113.9, 121.0, 129.2, 130.3, 150.4, 151.8, 159.3,
165.5, 215.4. Anal. Calcd for C75H139IO12Si4: C, 61.22; H, 9.46.
Found: C, 60.89; H, 9.64.
yellow oil: [R]22 -42.8 (c 0.56, CHCl3); IR (neat) 2958, 2952,
D
1735, 1273, 1257, 1057, 1028, 971 cm-1; 1H NMR (CDCl3, 300
MHz) δ 0.04 (6H, s), 0.82-0.90 (18H, m), 1.17 (3H, d, J ) 6
Hz), 1.24-1.63 (19H, m), 1.71-1.78 (2H, m), 1.86-2.08 (3H,
m), 2.91 (1H, d, J
) 22 Hz), 3.62 (1H, m), 3.69 (1H, dt, J
P,
H
) 7, 2 Hz), 3.80 (1H, m), 4.15 (1H, quint, J ) 7 Hz), 5.26 (1H,
dt, J ) 12, 5 Hz), 5.94 (1H, d, J ) 14 Hz), 6.26 (1H, dd, J )
14, 9 Hz); 13C NMR (CDCl3, 75 MHz) δ -4.5, -4.3, 4.8, 11.0,
11.5, 16.3 (d, J
) 6 Hz) (2C), 18.1, 24.4, 25.9 (3C), 26.3,
P,
C
27.0, 29.6, 30.1, 31.0, 34.5 (d, J P, C ) 134 Hz), 35.0, 35.5, 43.2,
48.7, 62.6 (d, J ) 6 Hz) (3C), 67.1, 69.4, 70.2, 72.2, 74.2,
P,
C
97.4, 150.3, 164.9 (d, J
) 6 Hz); MS (FAB) m/z 773 (M+
+
P, C
1), 772 (M+), 771, 715, 672, 645, 577, 519, 345, 325, 253, 193;
HRMS (FAB) m/z 773.3078 (calcd for C33H62IO8PSi + H+
773.3074).
Keton e 92. To a solution of diisopropylamine (0.037 mL,
0.026 mmol) in tetrahydrofuran (0.2 mL) under argon at 0 °C
was added dropwise n-butyllithium (1.33 M in hexane, 0.020
mL, 0.027 mmol), and the mixture was stirred for 15 min at 0
°C. The solution was cooled to -78 °C, and a solution of 75
(20 mg, 0.026 mmol) in tetrahydrofuran (0.4 mL) was added
dropwise. The solution was stirred for 45 min at -78 °C, and
a solution of 83 (8.1 mg, 0.028 mmol) in tetrahydrofuran (0.2
mL) was added dropwise. The solution was stirred for 45 min
at -78 °C, slowly warmed to 0 °C during 15 min, and stirred
for 30 min at 0 °C. A saturated ammonium chloride solution
(2 mL) was added, and the mixture was stirred for 15 min
and diluted with ether (20 mL). After separation, the aqueous
layer was extracted three times with ether (10 mL), and the
combined extracts were washed with 5% hydrochloric acid (20
mL), water (20 mL), and brine (20 mL) and dried (magnesium
sulfate). Removal of the solvent under reduced pressure
followed by chromatography of the residue on silica gel, using
7% ether in hexane as eluant, afforded 17 mg (76%) of 92 as
a colorless oil: [R]22 -52.9 (c 1.17, CHCl3); IR (neat) 2958,
D
2930, 1716, 1254, 1095, 834 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 0.01 (3H, s), 0.05 (9H, s), 0.80-1.00 (25H, m), 1.02-1.05 (6H,
m), 1.07 (3H, d, J ) 8 Hz), 1.18 (3H, d, J ) 6 Hz), 1.25-1.66
(15H, m), 1.76 (1H, dd, J ) 13, 5 Hz), 1.89-2.09 (3H, m), 2.37-
2.51 (3H, m), 2.61 (1H, quint, J ) 7 Hz), 3.64-3.74 (2H, m),
3.80 (1H, m), 4.03 (1H, t, J ) 5 Hz), 5.28 (1H, dt, J ) 12, 5
Hz), 5.75 (1H, dd, J ) 16, 1 Hz), 5.94 (1H, d, J ) 14 Hz), 6.25
(1H, dd, J ) 14, 9 Hz), 6.96 (1H, dd, J ) 16, 7 Hz); 13C NMR
(CDCl3, 75 MHz) δ -4.5, -4.3, -4.1 (4C), 4.9, 7.6, 11.0, 11.5,
13.3, 14.1, 18.1, 18.3, 24.5, 25.9, 26.0 (6C), 26.4, 27.0, 29.6,
29.7, 30.2, 31.0, 35.1, 35.3, 35.7, 41.5, 43.2, 48.7, 49.9, 67.2,
69.5, 70.3, 70.6, 74.2, 75.3, 97.5, 121.2, 150.4, 151.5, 165.6,
213.5; MS (FAB) m/z 904 (M+), 890, 876, 847, 820, 759, 703,
637, 577, 519, 445, 403, 373, 345, 325, 267, 229, 193, 159;
HRMS (FAB) m/z 577.2572 [calcd for C44H81IO7Si2 - OC(O)R
(C17H31O4Si) 577.2572].
Ald eh yd e 116. To a solution of 114 (20.0 mg, 14.8 µmol) in
dichloromethane (0.6 mL) were added pyridine (17 µL, 0.22
mmol) and Dess-Martin periodinane (183 mg, 445 µmol). The
mixture was stirred for 7 h at room temperature and quenched
with a 1:1 mixture of saturated sodium carbonate solution and
saturated sodium thiosulfate solution (5 mL). The mixture was
extracted three times with ethyl acetate (5 mL), and the
combined extracts were washed with 5% aqueous sodium
carbonate (3 mL), water (3 mL), and brine (3 mL) and dried

Total Synthesis of Rutamycin B
J . Org. Chem., Vol. 66, No. 15, 2001 5231
(magnesium sulfate). The solvent was evaporated under
reduced pressure, and the residue was chromatographed on
silica gel, eluting with hexanes-ether (2:1), to give 19.5 mg
(99%) of 116 as a clear oil: 1H NMR (CDCl3, 300 MHz) δ -0.02
(3H, s), 0.03 (3H, s), 0.04 (3H, s), 0.06 (3H, s), 0.07 (3H, s),
0.08 (3H, s), 0.09 (3H, s), 0.89-1.80 (65H, m), 1.04 (3H, s),
1.07 (3H, s), 1.09 (3H, s), 1.19 (3H, s), 1.21 (3H, s), 1.26 (3H,
s), 1.94 (1H, m), 2.10 (2H, m), 2.33 (3H, m), 2.78 (1H, dd, J )
5, 16 Hz), 2.71 (1H, dd, J ) 3, 7 Hz), 2.77 (1H, t, J ) 7 Hz),
2.87 (1H, t, J ) 7 Hz), 2.97 (1H, t, J ) 7 Hz), 3.70 (2H, m),
3.82 (1H, dd, J ) 6, 14 Hz), 3.95 (1H, dd, J ) 3, 10 Hz), 4.09
(1H, dd, J ) 3, 6 Hz), 4.32 (1H, dd, J ) 4, 5 Hz), 5.28 (1H, ddt,
J ) 4, 5, 6 Hz), 5.78 (1H, d, J ) 16 Hz), 5.96 (1H, d, J ) 14
Hz), 6.27 (1H, dd, J ) 5, 14 Hz), 7.00 (1H, dd, J ) 7, 16 Hz),
(9H, s), 0.90-0.95 (15H, m), 0.99 (3H, d, J ) 4 Hz), 1.01 (3H,
d, J ) 5 Hz), 1.07 (3H, d, J ) 4 Hz), 1.10 (3H, d, J ) 4 Hz),
1.19 (3H, d, J ) 6 Hz), 1.25-1.69 (12H, m), 1.81 (1H, dd, J )
5, 12 Hz), 1.94-2.15 (5H, m), 2.12-2.22 (2H, m), 2.46-2.51
(1H, m), 2.66-2.71 (1H, m), 2.74-2.82 (2H, m), 2.95 (1H, t, J
) 5 Hz), 3.68-3.74 (2H, m), 3.80-3.86 (1H, m), 3.93 (1H, d, J
) 7 Hz), 4.15 (1H, dd, J ) 2, 8 Hz), 4.28 (1H, d, J ) 6 Hz),
5.26-5.35 (2H, m), 5.40 (1H, ddd, J ) 5, 9, 14 Hz), 5.79 (1H,
d, J ) 16 Hz), 5.95 (1H, dd, J ) 10, 14 Hz), 6.02 (1H, dd, J )
10, 14 Hz), 7.01 (1H, dd, J ) 7, 16 Hz); 13C NMR (CDCl3, 100
MHz) δ -4.1 (2C), -3.8, -3.3, 5.1, 11.0, 11.5, 12.1, 13.1, 14.1,
14.7, 16.0, 18.1, 18.4, 186, 24.5, 25.9 (3C), 26.1 (6C), 26.3 (3C),
27.7, 28.7, 29.6, 29.7, 30.8, 34.9, 35.4, 35.7, 42.6, 43.2, 44.1,
47.1, 50.5, 51.6, 57.2, 69.2, 69.5, 70.3, 71.9, 72.6, 72.9, 97.4,
121.2, 131.3, 131.5, 131.9, 136.1, 150.6, 165.5, 213.2, 213.8;
HRMS (FAB) m/z 1216.8569 (calcd for C68H128O10Si4 1216.8584).
Ru ta m ycin B (2). To a solution of 123 (7.0 mg, 5.75 µmol)
in acetonitrile and dichloromethane (1:1, 3 mL) were added
pyridine (0.05 mL) and hydrogen fluoride-pyridine complex
(38%, 0.55 mL). The solution was stirred for 4 d, during which
time the reaction progress was followed by thin-layer chro-
matography. The reaction was quenched with ice-cold 5%
sodium bicarbonate, and the mixture was extracted three times
with ethyl acetate (5 mL). The combined extracts were washed
with brine and dried (magnesium sulfate), and the solvent was
evaporated under reduced pressure. The residue was chro-
matographed on silica gel, eluting with hexanes-ethyl acetate
(1:1), to give 3.5 mg (70%) of a clear oil that solidified upon
standing. The solid was crystallized from ether to yield 2: mp
126-129 °C; [R]22D -71.4 (c 0.07, CHCl3); IR (neat) 3480, 2970,
2925, 1705, 1650, 1455, 1275 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 0.18-0.85 (6H, m), 0.88 (3H, d, J ) 7 Hz), 0.92 (6H, d, J )
7 Hz), 1.06 (3H, d, J ) 7 Hz), 1.10 (3H, d, J ) 7 Hz), 1.19 (3H,
d, J ) 6 Hz), 1.23-1.27 (6H, m), 1.24-1.95 (16H, m), 2.02-
2.23 (4H, m), 2.31 (1H, m), 2.63-2.76 (2H, m), 2.78-2.89 (2H,
m), 3.78 (1H, d, J ) 10 Hz), 3.81-3.85 (2H, m), 3.91-4.10 (3H,
m), 5.21-5.32 (2H, m), 5.41 (1H, ddd, J ) 4, 11, 15 Hz), 5.81
(1H, d, J ) 16 Hz), 5.94 (1H, dd, J ) 11, 15 Hz), 6.06 (1H, dd,
J ) 11, 15 Hz), 6.61 (1H, J ) 10, 16 Hz); 13C NMR (CDCl3,
100 MHz), δ 5.1, 8.2, 9.6, 11.1, 12.1, 12.7, 13.2, 13.4, 17.6, 24.5,
26.5, 28.4, 29.8, 30.7, 31.1, 35.1, 40.0, 42.6, 45.5, 45.9, 47.3,
48.6, 49.2, 64.7, 67.4, 69.6, 70.6, 71.0, 71.3, 72.9, 97.3, 122.6,
129.5, 130.4, 132.1, 137.4, 148.4, 165.0, 216.0, 221.6.
9.97 (1H, s); HRMS (FAB) m/z 1346.7544 (calcd for C67H127
-
IO11Si4 1346.7500). This compound was unstable and was used
immediately in the next reaction.
Bor on a te 122. To a suspension of chromium(II) chloride
(200 mg, 1.6 mmol) in tetrahydrofuran (5 mL) at room
temperature was added 121 (100 µL, 410 µmol), followed by
116 (20.0 mg, 14.8 µmol) and lithium iodide (108 mg, 820
µmol). The brown suspension was stirred for 5 h at room
temperature, and the reaction was quenched by addition of
ice-cold water (5 mL). The mixture was extracted three times
with ethyl acetate (10 mL), and the combined extracts were
washed with brine (10 mL) and dried (magnesium sulfate).
The solvent was evaporated under reduced pressure, and the
residue was chromatographed on silica gel, eluting with
hexanes-ether (6:1), to yield 17.0 mg (88%) of 122 as a clear
oil: [R]22 -49.2 (c 0.14, CHCl3; IR (neat) 2965, 2850, 1716,
D
1667, 1444 cm-1; 1H NMR (CDCl3, 400 MHz) δ -0.04 (3H, s),
0.02 (3H, s), 0.03 (3H, s), 0.06 (6H, s), 0.07 (3H, s), 0.07 (3H,
s), 0.08 (3H, s), 0.80-0.92 (39H, m), 0.94 (3H, d, J ) 7 Hz),
1.01 (3H, d, J ) 7 Hz), 1.03-1.06 (4H, m), 1.09 (3H, d, J ) 7
Hz), 1.20 (3H, d, J ) 6 Hz), 1.27 (12H, s), 1.29-1.50 (8H, m),
1.53-1.66 (7H, m), 1.76 (3H, dd, J ) 5, 13 Hz), 1.88-1.97 (2H,
m), 2.01-2.12 (5H, m), 2.23-2.33 (2H, m), 2.36-2.44 (2H, m),
2.70 (1H, dd, J ) 3, 7 Hz), 2.76 (1H, t, J ) 7 Hz), 2.86 (1H, t,
J ) 7 Hz), 2.95 (1H, t, J ) 7 Hz), 3.63-3.69 (1H, m), 3.71-
3.78 (1H, m), 3.82 (1 H, dd, J ) 6, 13 Hz), 3.91 (1H, d, J ) 8
Hz), 4.10 (1H, dd, J ) 4, 5 Hz), 4.28 (1H, dd, J ) 3, 7 Hz),
5.25-5.33 (1H, m), 5.44 (1H, d, J ) 18 Hz), 5.78 (1H, d, J )
16 Hz), 5.95 (1H, d, J ) 14 Hz), 6.27 (1H, dd, J ) 9, 14 Hz),
6.55 (1H, ddd, J ) 7, 7, 18 Hz), 7.00 (1H, dd, J ) 7, 16 Hz);
HRMS (FAB)m/z1484.8739(calcd for C75H142BIO12Si4 1484.8716).
Ru tam ycin B Tetr a(ter t-bu tyldim eth yl)silyl Eth er (123).
To a solution of 122 (13.0 mg, 8.80 µmol) in tetrahydrofuran
(10 mL) were added silver(I) oxide (8.0 mg, 35.3 µmol),
triphenylarsine (4.2 mg, 7.1 µmol), palladium(II) chloride bis-
(acetonitrile) (1.0 mg, 3.5 µmol), and water (0.05 mL). The
mixture was stirred for 2 h at room temperature, and the
reaction was quenched by addition of ice-cold water (5 mL).
The mixture was extracted three times with ethyl acetate (25
mL), and the combined extracts were washed with water and
brine and dried (magnesium sulfate). The solvent was evapo-
rated under reduced pressure, and the residue was chromato-
graphed on silica gel, eluting with hexanes-ethyl acetate (9:
Ack n ow led gm en t. We are grateful to Dr. Herbert
Kirst, Eli Lilly and Co., for a sample of natural ruta-
mycin B, to Professor David A. Evans, Harvard Uni-
versity, for a generous gift of 63, and to J ennifer
Shepherd for experimental assistance. Postdoctoral
fellowships to T.T. (Fonds der Chemischen Industrie)
and to R.W.J . (National Research Service Award
F2GM16472) are gratefully acknowledged. Financial
support was provided by the National Institutes of
Health through Grant Nos. AI10964 and GM50574.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for 15-39, 42-58, 64-74,
77-91, 94-108, and 111-115. This material is available free
of charge via the Internet at http://pubs.acs.org.
1), to afford 7.5 mg (70%) of 123 as a clear oil: [R]22 -36.7 (c
D
0.15 CHCl3); IR (neat) 2960, 2855, 1712, 1653, 1459 cm-1; 1H
NMR (CDCl3, 400 MHz) δ -0.02 (9H, s), 0.03 (3H, s), 0.05 (6H,
s), 0.07 (3H, s), 0.13 (3H, s), 0.61 (9H, s), 0.88 (18H, s), 0.89
J O0104429