An asymmetric synthesis of the tricyclic core and a formal total synthesis of roseophilin via an enyne metathesis

Article abstract of DOI:10.1021/ja9941781

A formal synthesis of roseophilin, a novel pentacyclic structure possessing significant antitumor activity, starting from 3- cycloundecenylcarboxylic acid has been completed. The acid was converted diastereoselectively to the corresponding menthol ester via the ketene which, in turn, provided (S)-3-cycloundecenylcarboxaldehyde. Diastereoselective propargylation with propargyltriphenylstannane promoted by an asymmetric boron reagent prepared in situ from boron tribromide and the bis-p- toluenesulfonamide of (S,S)-stilbenediamine gave (1S, 1'R)-1-cycloundec-2'- enylbut-3-yn-1-ol which set the stage for the key metathesis reaction. Platinum-catalyzed enyne metathesis via a formal [2 + 2] cycloaddition to a cyclobutene followed by conrotatory ring opening created the corresponding bicyclo[10.2.1]pentadeca-1(15),2-diene. Regioselective epoxidation of the less reactive double bond of the 1,3-diene was accomplished by 1,4- bromohydrin formation followed by base. Cuprate opening regio- and stereospecifically installed the isopropyl substituent. Standard procedures converted this intermediate to (1R, 12R, 13R, 15R)- 13-(tert- butyldimethylsiloxy)-15-isopropylbicyclo[10.2.1]pentadecane-3,14-dione. This diketone was converted to the corresponding unstable pyrrole by condensation with ammonium acetate, and the pyrrole nitrogen immediately alkylated with SEM-chloride. The formal synthesis was completed by conversion of the siloxy group to the corresponding ketone which previously had been condensed with the heterocyclic side chain to complete a synthesis of roseophilin. By having access to the tricyclic core asymmetrically for the first time, this route provides the opportunity to establish the absolute configuration of the natural product.

Full text of DOI:10.1021/ja9941781

VOLUME 122, NUMBER 16
APRIL 26, 2000
© Copyright 2000 by the
American Chemical Society
An Asymmetric Synthesis of the Tricyclic Core and a Formal Total
Synthesis of Roseophilin via an Enyne Metathesis
Barry M. Trost* and George A. Doherty
Contribution from the Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
ReceiVed NoVember 29, 1999
Abstract: A formal synthesis of roseophilin, a novel pentacyclic structure possessing significant antitumor
activity, starting from 3-cycloundecenylcarboxylic acid has been completed. The acid was converted
diastereoselectively to the corresponding menthol ester via the ketene which, in turn, provided (S)-3-
cycloundecenylcarboxaldehyde. Diastereoselective propargylation with propargyltriphenylstannane promoted
by an asymmetric boron reagent prepared in situ from boron tribromide and the bis-p-toluenesulfonamide of
(S,S)-stilbenediamine gave (1S,1′R)-1-cycloundec-2′-enylbut-3-yn-1-ol which set the stage for the key metathesis
reaction. Platinum-catalyzed enyne metathesis via a formal [2 + 2] cycloaddition to a cyclobutene followed
by conrotatory ring opening created the corresponding bicyclo[10.2.1]pentadeca-1(15),2-diene. Regioselective
epoxidation of the less reactive double bond of the 1,3-diene was accomplished by 1,4-bromohydrin formation
followed by base. Cuprate opening regio- and stereospecifically installed the isopropyl substituent. Standard
procedures converted this intermediate to (1R,12R,13R,15R)-13-(tert-butyldimethylsiloxy)-15-isopropylbicyclo-
[10.2.1]pentadecane-3,14-dione. This diketone was converted to the corresponding unstable pyrrole by
condensation with ammonium acetate, and the pyrrole nitrogen immediately alkylated with SEM-chloride.
The formal synthesis was completed by conversion of the siloxy group to the corresponding ketone which
previously had been condensed with the heterocyclic side chain to complete a synthesis of roseophilin. By
having access to the tricyclic core asymmetrically for the first time, this route provides the opportunity to
establish the absolute configuration of the natural product.
In exploring the culture broth of Streptomyces griseoViridis,
Hayakawa, Kawakami, and Seto isolated a deeply colored
hydrochloride salt that showed significant cytotoxicity against
K562 human erythroid leukemia cells and KB human epider-
moid carcinoma cells.1 The structure of the compound, named
roseophilin (1), was assigned solely by spectroscopy, largely
NMR. While the relative stereochemistry was assigned by NMR
spectroscopy, the absolute stereochemistry remained unresolved.
The unusual nature of the structure makes it an interesting lead
structure for exploitation of its biological profile as an antitumor
agent. This fact stimulated a number of synthetic efforts,
including our own.2 At the time we embarked upon this
synthesis, no synthetic work had been recorded.
Scheme 1 represents our retrosynthetic analysis. An obvious
disconnection involves two pieces, the unit 2 that constitutes
(2) (a) Nakatani, S.; Kirihara, M.; Yamada, K.; Terashima, S. Tetrahedron
Lett. 1995, 36, 8461. (b) Kim, S. H.; Fuchs, P. L. Tetrahedron Lett. 1996,
37, 2545. (c) Kim, S. H.; Figueroa, I.; Fuchs, P. L. Tetrahedron Lett. 1997,
38, 2601. (d) Fu¨rstner, A.; Weintritt, H. J. Am. Chem. Soc. 1997, 119, 2944.
(e) Luker, T.; Koot, W.-J.; Hiemstra, H.; Speckamp, W. N. J. Org. Chem.
1998, 63, 220. (f) Fu¨rstner, A.; Weintritt, H. J. Am. Chem. Soc. 1998, 120,
2817. (g) Mochizuki, T.; Itoh, E.; Shibata, N.; Nakatani, S.; Katoh, T.;
Terashima, S. Tetrahedron Lett. 1998, 39, 6911. (h) Fu¨rstner, A.; Gastner,
T.; Weintritt, H. J. Org. Chem. 1999, 64, 2361. (i) Robertson, J.; Hatley,
R. J. D. Chem. Commun. 1999, 1455. (j) Harrington, P. E.; Tius, M. A.
Org. Lett. 1999, 1, 649. (k) Fagan, M. A.; Knight, D. W. Tetrahedron Lett.
1999, 40, 6117.
(1) Hayakawa, Y.; Kawakami, K.; Seto, H.; Furihata, K. Tetrahedron
Lett. 1992, 33, 2701.
10.1021/ja9941781 CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/05/2000

3802 J. Am. Chem. Soc., Vol. 122, No. 16, 2000
Scheme 1. Retrosynthetic Analysis of Roseophilin
Trost and Doherty
Table 1. Esterification of Deconjugated Acid 10b with Chiral
Alcohols via Ketene
the heterocyclic side chain and the tricyclic core 3. Several
methods including the classical Paal-Knorr condensation can
be envisioned to form the pyrrole moiety from the allyl alcohol
4. Using the macrocyclic bridge to control stereochemistry of
introduction of the isopropyl group allows diene 5 to be a
precursor of 4. This bridged bicycle, 5, may derive from an
enyne metathesis of 7 via cyclobutene 6. Since 7 can derive
from a diastereoselective addition of a propargyl anion to an
aldehyde and the latter can derive from an ester, the known
enoate 83 becomes an attractive starting material. First, it is
readily available in two steps from cyclododecanone, a com-
mercially available starting material. Second, the absolute
stereochemistry is set during the deconjugation, thus providing
access to either enantiomer of the product. Since the stereo-
chemistry of roseophilin is unknown, a strategy which involves
de novo creation of the absolute configuration is preferable to
one from the chiral pool because it allows access to either
enantiomer.
Synthesis of the Metathesis Substrate. The transformation
of enoate 8 to enyne 7 requires deconjugation of the double
bond and appending a propargyl group. The deconjugation step
sets the chirality for the entire synthesis. The enolate from ester
8a (R ) CH3)3a or the dianion from acid 8b (R ) H)3b was
inversely quenched into aqueous sodium bisulfate which gener-
ated the â,γ-unsaturated derivatives 10a and 10b.4 The 15.7
Hz coupling between the vinyl protons indicated an E-alkene
geometrysin contrast to the normally observed Z-alkene
geometry in most deconjugations with acyclic esters.
to utilize the method described by Vedejs5a employing quench-
ing of a lithium enolate of an amide with a chiral tetrahydroiso-
quinoline failed. Use of a chiral auxiliary to influence proto-
nation led to the preparation of the N-acyloxazolidine-2-one 11.5b
Unfortunately, the harshness of the conditions required for
deprotonation of this conjugated substrate only decomposed it
and led to the examination of the corresponding deconjugated
derivatives 12 and 13 which derived from the â,γ-unsaturated
acid 10b. Even these derivatives were of insufficient acidity to
be enolized without decomposition. On the other hand, they
were easily separable and could, therefore, serve as a resolution
protocol. However, this avenue was unattractive because of
problems in removing the chiral auxiliary.
Additions of chiral alcohols to ketenes may serve as an
effective asymmetric synthesis.6 When the carboxylic acid 10b
was mixed with DCC, elimination of dicyclohexylurea occurred
within minutes at 0 °C. Addition of a chiral nonracemic alcohol
to the ketene can generate nonequal amounts of diastereomeric
esters (see Table 1). The ketene was remarkably unreactive, but
in the presence of a catalytic amount of DMAP, the reaction
proceeded well. Although pantolactone proved effective for
acylketenes,6b it was nonselective in this case (entry 5). The
best result was obtained with (-)-borneol (entry 4) and (-)-
menthol (entry 1). Interestingly, there was a significant solvent
effect; dichloromethane proved sufficiently better than the
nonpolar pentane. Surprisingly, (-)-menthol was better than
9-phenylmenthol. The dr of menthol ester 14 was enriched to
7:1 by one recrystallization, but enrichment to optical purity
Conversion of the deconjugation into an asymmetric process
requires control of the stereochemistry of protonation. Attempts
(5) (a) Vedejs, E.; Lee, N.; Sakata, S. T. J. Am. Chem. Soc. 1994, 116,
2175. (b) Gosh, A. K.; Liu, W. J. Org. Chem. 1995, 60, 6198.
(6) (a) Ja¨hme, J.; Ru¨chardt, C. Angew. Chem., Int. Ed. Engl. 1981, 20,
885. (b) Larsen, R. D.; Corley, E. G.; Davis, P.; Reider, P. J.; Grawbowski,
E. J. J. Am. Chem. Soc. 1989, 111, 7650. (c) For related work involving
thiols, see: Stempf, I.; Galindo, J. Angew. Chem., Int. Ed. Engl. 1993, 32,
1044. (d) For an overview, see: Fehr, C. Angew. Chem., Int. Ed. Engl.
1996, 35, 2566.
(3) (a) Garbisch, E.; Wohllebe, J. Chem. Commun. 1968, 306. Garbisch,
E.; Wohllebe, J. J. Org. Chem. 1968, 33, 2157. Wohllebe, J.; Garbisch, E.
Org. Synth. 56, 107. (b) Also see: Ziegenbein, W. Chem. Ber. 1961, 94, 9.
(4) (a) Ikeda, Y.; Ukai, J.; Ikeda, N.; Yamamoto, H. Tetrahedron Lett.
1987, 28, 743. (b) Rathke, M. W.; Sullivan, D. Tetrahedron Lett. 1972, 14,
4249. (c) Herrmann, J. L.; Kieczykowski, G. R.; Schlessinger, R. H.
Tetrahedron Lett. 1973, 15, 2433.

Formal Total Synthesis of Roseophilin
J. Am. Chem. Soc., Vol. 122, No. 16, 2000 3803
led to significant loss of material. Thus, further upgrading of
the ee was postponed to a later step in the synthesis. LAH
reduction led to recovery of the menthol and the desired alcohol
15 (er 7:1) which was oxidized with the Dess-Martin perio-
dinane to give aldehyde 16. The racemate of aldehyde 16 (rac-
16) was also available quantitatively by direct reduction of
methyl ester 10a with DIBAL-H.
diastereoselectivity.9 The erytho stereochemistry of the product
was assigned by comparison to the previously obtained dia-
stereomer. This stereochemistry corresponds to a Felkin-Anh
mode of addition.
A diastereocontrolled propargylation of aldehyde 16, using
a reagent-controlled approach, also constitutes a reasonable
strategy. The available methods require stoichiometric chiral
nonracemic reagentssa fact that indicates there is a need for
further developments here. The Yamamoto method based on a
chiral boron reagent has the disadvantage of requiring excess
aldehyde.10 On the other hand, the Corey procedure has the
disadvantages of preparation of a more complicated reagent and
the use of toxic tin reagents.11 Nonetheless, the more favorable
stoichiometry of this process led us to employ it. As shown in
eq 5, utilizing the allenylborane derived from the (S,S)-stein
The diastereoselectivity of the propargylation was investigated
with allenylmagnesium bromide and allenyltri-n-stannane, the
latter catalyzed by boron trifluoride (eq 3). Not unexpectedly,
(22) boron tribromide and propynyltriphenylstannane gave two
diastereomers in a 7:1 ratio, reflective of the enantiopurity of
the starting aldehyde. The major diastereomer, the erythro, was
separated from the minor diastereomer, the threo, by chroma-
tography of the corresponding silyl ethers 23 and 24. The
enantiopurity of silyl ether 23 was determined by conversion
to O-methylmandelate 25 which indicated an ee of 96%.
Mandelate esters 25 and 26 allowed the assignment of the
absolute configuration as depicted.12 In particular, the low-field
shifts of the protons of the propynyl group in 25 compared to
those in 26 and the reverse for the vinyl protons are consistent
with the mnemonic established for the O-methylmandelates. The
assignment of the S configuration for the homopropargylic
alcohol also is consistent with the observed stereochemistry in
the additions reported by Corey, Yu, and Lee.
neither method gave any significant selectivity (17:18, 45:55
and 55:45, respectively). Changing the Lewis acid to MAD7
did increase the diastereoselectivity but at the expense of yield
(15%). In principle, this stereocenter is irrelevant since it is
ultimately lost.
Nevertheless, complications of carrying through a mixture
of diastereomers made obtention of a single diastereomer
desirable. Attempts to invert one epimer to the other failed due
to competing eliminations. Inversion via an oxidation-reduction
also failed due to virtually instantaneous isomerization of the
propargyl ketone to an allenyl ketone.
An alternative strategy focused on a diastereoselective
reduction of an alkynyl ketone as shown in eq 4. The requisite
As an aside, the two diastereomeric mandelates 25 and 26
obtained as a 1:1 mixture by esterification of racemic alcohol
17 with S-O-methylmandelic acid were easily separated by
column chromatography. Hydrolysis of either one with metha-
nolic sodium hydroxide gave alcohol 17 enantiomerically pure.
alkynyl ketone 20 was formed via Weinreb amide 19 and
1-propyne which was generated via a convenient in situ
procedure.8 Good diastereoselectivity (9:1) favoring the depicted
isomer was observed using L-Selectride. Importantly, zipping
the acetylenic linkage to the terminus occurred with no loss of
(9) Midland, M. M.; Halterman, R. L. Tetrahedron Lett. 1981, 22, 4171.
(10) Ikeda, N.; Arai, I.; Yamamoto, H. J. Am. Chem. Soc. 1986, 108,
438.
(11) Corey, E. J.; Yu, C.-M.; Lee, D.-M. J. Am. Chem. Soc. 1990, 112,
878.
(7) Maruoka, K.; Concepcion, A. B.; Murase, N.; Oishi, M.; Hirayama,
N.; Yamamoto, H. J. Am. Soc. Chem. Soc. 1993, 115, 3943.
(8) Suffert, J.; Toussaint, D. J. Org. Chem. 1995, 60, 3550.
(12) Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.;
Balkovec, J. M.; Baldwin, J. J.; Christy, M. E.; Ponticello, G. S.; Varga, S.
L.; Springer, J. P. J. Org. Chem. 1986, 51, 2370.

3804 J. Am. Chem. Soc., Vol. 122, No. 16, 2000
Trost and Doherty
While the enynes 17, 18, 23, and 24 constitute valid
metathesis substrates, the corresponding ynoate 27 was also
considered a desirable target since such ynoates are sometimes
better metathesis substrates.14b The requisite compound was
easily accessed as summarized in eq 6.
dichloroethane or toluene, the Alder ene product 30 was the
exclusive product. A similar result was obtained with (p-cymene)
ruthenium dichloride dimer (31) and tri-o-tolyl phosphite; only
30 was observed. On the other hand, the same catalyst in toluene
at 80 °C gave a 25:75 ratio of 29 and 30 which increased in
favor of the methathesis product 29 as the temperature was
increased (PhCH3 at 110 °C, 95:5, p-cymene at 130 °C, 98:2).
Both the ruthenium and platinum catalyst systems converted
substrates 23 (eq 11) and 24 (eq 12) to the metathesis products
32 and 33, respectively, essentially quantitatively. It was at this
Enyne Metathesis. There are two mechanistic paths for an
enyne metathesis. The common metathesis reactions using
alkylidene metal complexes of ruthenium and molybdenum
normally proceed via a metalacyclobutene intermediate.13 An
alternative mechanism involving palladium and platinum com-
plexes invokes a formal [2 + 2] cycloaddition to a cyclobutene
followed by a [2 + 2] cycloreversion (eqs 7 and 8).14 These
point that the relative stereochemistry of the propargyl addition
product could be established. Ha in diastereomer 32 appeared
as a quartet (J ) 7.7 Hz) at δ 4.68, whereas this proton appeared
as a doublet (J ) 6.0 Hz) at δ 4.15 in 33. A molecular mechanics
calculation on 32 revealed a dihedral angle of nearly 0° between
Ha-Hb and Ha-Hd and one of 145° between Ha-Hd, creating
a quartet as expected. On the other hand, the same calculation
on diastereomer 33 revealed a dihedral angle of about 90°
between Ha-Hb and Ha-Hc but one of about 0° between Ha-
Hd. A doublet with coupling only to Hd was then consistent.
1,4-Hydroxyalkylation of Diene. The next step requires a
regio- and diastereocontrolled addition of a hydroxyl and an
isopropyl group across the diene. To effect this transformation,
cuprate addition from the least hindered face of monoepoxide
35 was envisioned (eq 13). This selectivity required a chemose-
reactions, which invoke a metallacyclopentene intermediate, also
appear to involve a series of potential equilibria involving
valence isomerization of the metallacycle and thus account for
the diverse array of possible products observed. One of these
paths is a collapse to a cyclobutene which then represents an
equivalent of a [2 + 2] process. After the completion of our
work, Murai developed both a ruthenium and a platinum catalyst
that appears to involve a similar mechanism (eq 9).15
Studies were initiated with ynoate 27 as substrate. Using the
palladacycle 28 as catalyst, the metathesis product (29) was not
observed at temperatures up to 60 °C. At 100-110 °C in 1,2-
lective epoxidation of the less reactive double bond of the dienes
32 and 33. For this selectivity, we envisioned a 1,4-halohydrin
formation initiated by attack of the bromonium ion on the more
reactive double bond to give 34 followed by base-catalyzed
elimination as shown in eq 13.
In the event, diene 32 was treated with NBS in wet THF to
give the bromohydrin(s). The instability of these adducts led

Formal Total Synthesis of Roseophilin
J. Am. Chem. Soc., Vol. 122, No. 16, 2000 3805
us to treat them directly with aqueous sodium hydroxide to form
the two regioisomeric epoxides, 37 and 38, in a 9:1 ratio (as
determined by the ratio of the vinyl protons). Further, the
regioisomeric epoxide 37 was a 75:25 ratio of diastereomers
tentatively assigned as 37a and 37b (eq 14). Curiously, the
alternative diastereomer 33 gave a 55:45 ratio of the two
regioisomeric epoxides. Since 32 was available stereoselectively,
it was employed for the synthesis.
(eq 14) was directly subjected to a copper-catalyzed addition
of isopropylmagnesium chloride. The very minor product which
arose from reaction of 38 was easily removed, and the two
desired isomers 41 and 42 were easily separated chromato-
graphically. Oxidation of the allylic hydroxyl group in both
products produced the corresponding ketones 43 and 44. Ha
appeared as a doublet (43, δ 2.09, J ) 9.7 Hz; 44, δ 2.90, J )
9.1 Hz) in both cases which revealed no coupling to the
bridgehead hydrogen. This same pattern was observed in
roseophilin. The lower field shift of this proton in 44 compared
to that in 43 is in agreement with the assignment of the alkene
geometry as depicted.
Construction of Pyrrole and Completion of the Roseo-
philin Core. The completion of the synthesis requires the
construction of the pyrrole unit. Fortunately, there are many
ways to achieve this task. An attractive method considers the
introduction of the requisite amino group via an intramolecular
insertion of an acylnitrene.18 We initially targeted formation of
the azidoformate derived from 45 but were thwarted by its ease
of dehydration to dienone 46 upon attempted derivatization of
the hydroxyl group (eq 18). After saturation of the double bond
(H2, 5% Pd/C, 95%) to form 47a, the corresponding saturated
alcohol 47b (HF, CH3CN, 71%) readily formed the azidoformate
47c (Cl3COCO2CCl3, then LiN3). However, neither photolysis
nor thermolysis afforded any oxazolidine 48.
Both diastereomeric epoxides 37 are trans as determined by
the 2.2 Hz coupling between the epoxide hydrogens in the H
1
NMR spectra. Thus, they must represent the two facial isomers.
Molecular modeling showed that diene 32 possessed an inner
and outer face with respect to the chain of carbons constituting
the ring with only the outer face accessible for attack. A syn
selectivity for the addition of the elements of HOBr in a 1,4
fashion in analogy to 1,4-bromination of dienes16 led us to
suggest that the two diastereomeric bromohydrins are 39 and
40 which arose from addition to the s-trans and s-cis conformers
of the diene (eq 15). Base treatment then generated the two
diastereomeric epoxides 37a and 37b, respectively.
Since cuprate additions to vinyl epoxides occur syn to the
epoxide oxygen,17 the isopropyl group was introduced on the
same face of the cyclopentene of both diastereomeric epoxides
which generated different alkene geometries as depicted in eqs
16 and 17. In practice, the crude mixture of 37a, 37b, and 38
(13) For recent reviews on RCM, see: (a) Grubbs, R. H.; Chang, S.
Tetrahedron 1988, 54, 4413. (b) Fu¨rstner, A. Top. Catal. 1997, 4, 285. (c)
Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2036.
(14) (a) Trost, B. M.; Tanoury, G. J. J. Am. Chem. Soc. 1988, 110, 1636.
(b) Trost, B. M.; Trost, M. K. J. Am. Chem. Soc. 1991, 113, 1850. (c)
Trost, B. M.; Trost, M. K. Tetrahedron Lett. 1991, 32, 3647. (d) Trost, B.
M.; Chang, V. K. Synthesis 1993, 824. (e) Trost, B. M.; Yanai, M.;
Hoogsteen J. Am. Chem. Soc. 1993, 115, 9294. (f) Trost, B. M.; Hashmi,
S. K. Angew. Chem., Int. Ed. Engl. 1993, 32, 1085.
(15) (a) Chatani, N.; Morimoto, T.; Muto, T.; Murai, S. J. Am. Chem.
Soc. 1994, 116, 6049. (b) Chatani, N.; Furukawa, N.; Sakurai, H.; Murai,
S. Organometallics 1996, 15, 901. (c) For its application to streptorubin B
and metacycloprodigiosin, see: Fu¨rstner, A.; Szillat, H.; Gabor, B.; Mynott,
R. J. Am. Chem. Soc. 1998, 120, 8305.
(16) Heasley, G. E.; Heasley, V. L.; Manatt, S. C.; Day, H. A.; Hodges,
R. V.; Kroon, P. A.; Redfield, D. A.; Rold, T. L.; Williamson, D. E. J.
Org. Chem. 1973, 38, 4109.
Our discovery that the mixture of alcohols 41 and 42 smoothly
underwent regioselective elimination to diene 49 upon attempted
alcohol displacement led to our exploration of the dihydroisox-
azines 50 as suitable pyrrole precursors.19 Preparatively, the
(18) (a) Edwards, O. E.; Paryzek, Z. Can. J. Chem. 1973, 51, 3866. (b)
Wright, J. J.; Morton, J. B. Chem. Commun. 1976, 116, 668.
(17) Marshall, J. A.; Audia, V. H. J. Org. Chem. 1987, 52, 1106.
(19) Kresze, G.; Firl, J. Angew. Chem., Int. Ed. Engl. 1964, 3, 382.

3806 J. Am. Chem. Soc., Vol. 122, No. 16, 2000
Trost and Doherty
the equilibrium between the R,â- and â,γ-unsaturated ketones.
Such a route was initially rejected because of our fear of
â-elimination of the siloxy group, a fear fully verified by the
obtention of diene 56 upon treatment of 43-44 with TBAF in
quantitative yield (eq 21). On the other hand, heating an
acetonitrile solution of a mixture of 43 and 44 with 50 mol %
of DBU at 80 °C gave a 75:25 mixture of deconjugated ketone
57 and conjugated enone 44. Surprisingly, elimination to diene
56 was not a problem at all under these conditions.
Enone 57 proved remarkably inert toward epoxidation,
resisting MCPBA, trifluoroperacetic acid,22 and dimethyldiox-
irane.23 However, it succumbed to epoxidation with methyl
trifluoromethyldioxirane24 to give epoxide 58 (eq 22). Base-
elimination proceeded readily by treating alcohols 41 and 42
with methanesulfonyl chloride. The coupling pattern of the three
vinyl protons of the diene [δ 6.18, d, J ) 15.4 Hz; δ 5.71, ddd,
J ) 15.4, 10.5, 4.1 Hz; δ 5.44, bs] and the collapse of the
methine proton adjacent to the siloxy group to a broad doublet
(δ 5.08, d, J ) 5.5 Hz) verified the position of the double bonds.
Oxidation of the hydroxamic acids with periodate in the presence
of the diene gave the cycloadducts as single regio- and
diastereomers.20 For adduct 50a, the proton adjacent to the
oxygen of the dihydroisoxazine, Ha (δ 4.66, dd, J ) 7.5, 2.7
Hz), showed coupling to Hb (δ 4.50, t, J ) 7.1 Hz), whereas
the proton adjacent to nitrogen, Hc (δ 3.62, dd, J ) 9.2, 5.4
Hz, 1H), did not. Thus, the regioisomer was the one depicted.
Blocking of the R-face of the diene by the ring carbons directed
addition to the â-face. The regioselectivity then derived from
unfavorable steric interactions between the nitrogen substituent
and the isopropyl group that would have developed in forming
the other isomer. Conversion of the siloxy group to ketone 51
catalyzed elimination to enone 59 followed by standard oxida-
tion then puts the second carbonyl group in place (i.e., 60).
Hydrogenation occurred from the outside face of the alkene to
give saturated diketone 61 even though it is cis to the isopropyl
group. The absence of observable coupling between Ha and Hb
supported this assignment.
A shorter sequence employed hydroboration as a key step
(eq 23). Borane added to both the alkene and the carbonyl group
to give diol 62 as a diastereomeric mixture after the usual work
up with basic hydrogen peroxide. Upon oxidation with catalytic
TPAP,25 this stereocenter was destroyed and the single diketone
61 was obtained in excellent overall yield.
was envisioned to set the stage for a fragmentation to diketone
52 which could then ring close to give pyrrole 53. Unfortunately,
ketone 51 spontaneously underwent a cycloreversion to the
diene. Hydrogenolysis to 54 followed by oxidation generated
the desired ketones 55a,b. However, all attempts to convert
amidoketone 55 to pyrroles failed.
While additional sequences can be readily envisioned and
several more explored, we focused on the classical Paal-Knorr
condensation of an amine and a 1,4-diketone.21 The regiose-
lectivity of the elimination to the diene induced us to ascertain
Initial experiments to form the parent pyrrole 63a misled us
to believe that the reaction proceeded poorly because of the
(22) Cooper, M. S.; Heanley, H.; Newbold, A. J.; Sanderson, W. R.
Synlett 1990, 533.
(20) (a) Baldwin, J. E.; Adlington, R. M.; Mellor, L. C. Tetrahedron
1994, 50, 5049. (b) Kirby, G. W.; McGuigan, H.; MacKinnon, J. W. M.;
McLean, D.; Sharma, R. P. J. Chem. Soc., Perkin Trans. 1 1985, 1437. (c)
Viaud, M. C.; Rollin, P. Synthesis 1990, 130.
(21) (a) Paal, G. Chem. Ber. 1884, 17, 2756. (b) Knorr, L. Chem. Ber.
1884, 17, 2863.
(23) (a) Murray, R. W.; Jeyaraman, R. J. Org. Chem. 1985, 50, 2847.
(b) Adam, W.; Bialas, J.; Hadjiarapoglou, L. Chem. Ber. 1991, 124, 2377.
(24) Mello, R.; Fiorentino, M. Sciacovelli, O.; Curci, R. J. Org. Chem.
1988, 53, 3891.
(25) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.

Formal Total Synthesis of Roseophilin
J. Am. Chem. Soc., Vol. 122, No. 16, 2000 3807
instability of the product. Thus, substituted amines were
employed that could be appropriately deprotected subsequently
with the belief that these N-alkylpyrroles would be more stable.
Indeed, the pyrroles 63b-d formed smoothly under a standard
set of reaction conditions (eq 24, HOAc, 4 Å MS, CH3OH, 50
selective reductions of alkynyl ketones proceed readily. Com-
bining this result with the ease of zipping an acetylene then
constitutes an equivalent of such a diastereoselective addition.
This strategy serves as an alternative to a reagent-controlled
diastereoselective addition. While it requires more steps, it does
not require stoichiometric amounts of chiral reagents that
themselves may not be so readily available and also may be
expensive. The chemoselective epoxidation of the less reactive
double bond of a 1,3-diene has also been accomplished using a
simple protocol.
The current route to the macrocyclic core of roseophilin also
constitutes a formal total synthesis since it intersects the same
intermediate employed by Fu¨rstner and Weintritt.2f Since our
route provides the macrocyclic core enantiomerically pure and
of known configuration, it offers the opportunity to define the
absolute stereochemistry of roseophilin, a subject for future
studies. Our route provides the first asymmetric synthesis of
the core primed for coupling in 17 steps and 4.4% overall yield
from the known acid 8b.
°C). Removal of the silyl ether proceeded smoothly with 63b-
d, and the resulting alcohols were oxidized to the desired ketones
64b-d. The data of the benzyl derivative prepared herein, 64b,
were identical to those reported by Fu¨rstner and Weintritt.2f
While the benzyl derivative 64b had been converted to the
parent pyrrole 64a using calcium in liquid ammonia, the process
also reduced the ketone, thereby necessitating a reoxidation. The
fact that it proceeded in only 50% yield at 69% conversion led
us to synthesize the methoxylated benzyl derivatives 64b and
64c in the hope of improving their removal by alternative
methods. Unfortunately, this did not prove to be the case. The
ability to remove the arylsulfonylethyl substituent with base led
to the synthesis of the corresponding pyrrole 63e. However,
attempts to effect desilylation only led to decomposition.
As a result, we returned to the parent pyrrole 63a. Monitoring
the reaction revealed that using ammonium acetate and catalytic
CSA in methanol at 50 °C generated 63a in 86% crude yield
with minimal workup. Immediate protection with SEM-Cl gave
a stable pyrrole 63f that was isolated pure in 54% yield for the
two steps. Desilylation and MnO2 oxidation gave the ketone
64f whose data are in full accord with those recorded for the
racemic compound.
Experimental Section
Preparation of (1S,1′R)-1-Cycloundec-2′-enylbut-3-yn-1-ol (17)
and erythro-1-Cycloundec-2′-enylbut-3-yn-1-ol (18). From the Al-
lenyltin Addition to Cycloundec-2-enylcarboxaldehyde (16). Boron
trifluoride diethyl etherate (3.40 mL, 26.83 mmol) was added dropwise
to a solution of cycloundec-2-enylcarboxaldehyde 16 (4.15 g, 23.02
mmol) and allenyltributyltin27 (8.33 g, 25.33 mmol) in 50 mL of
methylene chloride at -78 °C. After the addition of ∼50% of the Lewis
acid, the reaction was judged complete by thin-layer chromatography.
The reaction was allowed to warm to room temperature and diluted
with 50 mL of diethyl ether. The reaction was washed with 1 N sodium
hydroxide (3 × 100 mL) and a saturated sodium chloride solution (100
mL), dried over magnesium sulfate, and concentrated in vacuo to give
6.619 g of a yellow oil. 1H NMR indicated that a 55:45 diastereomeric
mixture resulted. Upon sitting at 0 °C, the oil solidified. The solid was
recrystallized from pentane to give 2.12 g (9.60 mmol) of rac-18 as a
white solid, mp 76-77 °C (pentane). The pentane was concentrated in
vacuo and chromatographed over silica gel (hexane/ethyl acetate 10:
1) to give 1.92 g (8.70 mmol) of rac-17 as a colorless oil. The total
yield was 4.03 g (18.30 mmol, 80%).
From the Asymmetric Propargylation of (1S)-Cycloundec-2-
enylcarboxaldehyde (16). The bis-p-toluenesulfonamide of (S,S)-1,2-
diphenyl-1,2-diaminoethane (S,S-stein, 1.85 g, 3.57 mmol) was sus-
pended in 10 mL of methylene chloride and cooled to 0 °C. Boron
tribromide (3.40 mL, 3.43 mmol, 1.0 M in methylene chloride) was
added dropwise. After 15 min of stirring at 0 °C, the reaction was
allowed to warm to room temperature and stirred for an additional 45
min. The solvent was removed in vacuo through a needle inserted
through the septum. The resulting yellow solid was dissolved in 5 mL
of methylene chloride, and the solvent was removed again as above.
The resulting solid was dissolved in 10 mL of methylene chloride and
cooled to 0 °C. Propargyltriphenyltin (1.28 g, 3.29 mmol) in 2 mL of
methylene chloride was added and the reaction stirred at room
temperature for 4 h. The solution was cooled to -78 °C and (1S)-
cycloundec-2-enylcarboxaldehyde 16 (0.36 g, 2.02 mmol) in 2 mL of
methylene chloride was added. After 2 h at -78 °C, the reaction was
quenched with 10% aqueous sodium bisulfate (10 mL) and the product
extracted into methylene chloride (25 mL). The organic layer was
concentrated in vacuo followed by the addition of 3:1 hexane/ethyl
acetate which led to the precipitation of the (S,S)-stein which was
collected by filtration. The resulting solution was stirred with aqueous
potassium fluoride which caused a precipitate to form. The resulting
solid was removed by filtration, and the resulting solution was washed
with aqueous potassium fluoride, dried over magnesium sulfate, and
concentrated in vacuo. Chromatography over silica gel (petroleum ether/
Discussion
The enyne metathesis proceeding via a metallacyclopentene
that results in a formal [2 + 2] cycloaddition followed by an
electrocyclic ring opening of the cyclobutene constitutes a useful
method for making bridged bicycles.26 As noted earlier, previous
observations in the case of Pd indicate that this initial pallada-
cycle does exist in equilibria with cyclopropylalkylidene
complexes that can lead to other products as well as metathesis
type products involving skeletal rearrangements. Similar skeletal
rearrangements are observed with all three systems, palladium,
ruthenium, and platinum. The fact that cyclobutenes can be
isolated in good yield in the case of palladium leads us to favor
this mechanistic manifold at present.14 Among the three methods
available, the platinum-based method appears to be the mildest
in terms of temperature and the most convenient. Ligandless
platinum (+2) is more effective than using a salt in the presence
of triphenylphosphine. This method should prove to be generally
useful.
A new strategy for the equivalent of a diastereoselective
propargylation of an aldehyde has been developed. Diastereo-
(26) Murai and co-workers prefer a mechanism invoking a slipped η1-
alkyne-metal bond creating a positive charge at the B vinylic carbon.15a,b
Also, see: ref 15c for an alternative mechanism.
(27) Carofiglio, T.; Marton, D.; Tagliavini, G. Organometallics 1992,
11, 2961.

3808 J. Am. Chem. Soc., Vol. 122, No. 16, 2000
Trost and Doherty
ethyl acetate 10:1) yielded 0.36 g (1.62 mmol, 80%) of a pale yellow
(d, J ) 17.0 Hz, 1H), 1.7-1.9 (m, 3H), 1.0-1.4 (m, 12H), 0.90 (s,
9H), 0.08 (s, 6H). 13C NMR (75.5 MHz, CDCl3): δ 139.9, 130.8, 129.4,
128.1, 77.3, 55.8, 43.6, 34.1, 32.0, 29.5, 28.6, 27.8, 26.4, 26.0(3), 25.9,
25.5, 18.4, -4.5, -4.6. Anal. Calcd for C21H38OSi: C, 75.38; H, 11.45.
Found: C, 75.37; H, 11.24.
oil as a 6.8:1 mixture of 17, [R]25 -36.6 (c ) 1.15, CHCl3), and 18.
D
From threo-Cycloundec-2′-enylbut-2-yn-1-ol (21). Potassium hy-
dride (4.92 g, 122.85 mmol) was added to 150 mL of 1,3-diamino-
propane (freshly distilled from calcium hydride) at room temperature.
After 2 h, the brownish-yellow solution was cooled to 0 °C and a
solution of threo-cycloundec-2′-enylbut-2-yn-1-ol 21 (6.77 g, 30.71
mmol) in 10 mL of THF was added which caused a deep red color to
form. After 1 h, the reaction was quenched by being poured into 250
mL of water and the product was extracted into methylene chloride (3
× 100 mL). The combined organic layers were washed with water
(150 mL) and saturated aqueous sodium chloride (150 mL), dried over
magnesium sulfate, and concentrated in vacuo. Chromatography over
silica gel (petroleum ether/ethyl acetate 5:1) yielded 5.85 g (26.55 mmol,
86%) of rac-17 as a yellow oil.
From (S)-Methoxyphenylacetic Acid (1S,1′R)-1-Cycloundec-2′-
enylbut-3-ynyl Ester (25). Sodium hydroxide (0.5 mL, 1.5 mmol, 3
N) was added to a solution of (S)-methoxyphenylacetic acid (1S,1′R)-
1-cycloundec-2′-enylbut-3-ynyl ester 25 (0.34 g, 0.921 mmol) in 2 mL
of methanol. After 12 h at room temperature, the reaction was diluted
with 20 mL of ethyl ether, washed with 1 N sodium hydroxide (10
mL) and saturated aqueous sodium chloride (10 mL), dried over
magnesium sulfate, and concentrated in vacuo to give 0.20 g (0.91
mmol, 99%) of 17 as a colorless oil.
Preparation of (3R,12R,13S,15R)-13-(tert-Butyldimethylsilyloxy)-
15-isopropylbicyclo[10.2.1]pentadec-1-en-3-ol (41) and (3S,12R,13S,-
15R)-13-(tert-Butyldimethylsilyloxy)-15-isopropylbicyclo[10.2.1]-
pentadec-1-en-3-ol (42). N-Bromosuccinimide (0.58 g, 3.27 mmol) was
added to a solution of rac-(12R,13S)-13-(tert-butyldimethylsilyloxy)-
bicyclo[10.2.1]pentadeca-1(15),2-diene 32 (1.00 g, 2.97 mmol) in 6
mL of THF/water (5:1) at 0 °C. The resulting yellow solution was stirred
for 3 h at this temperature. Sodium hydroxide (0.60 g, 14.86 mmol)
was added, and the resulting solution was vigorously stirred for 3 h.
The solution was diluted with 25 mL of ether and washed with water
(25 mL), saturated aqueous sodium bicarbonate (25 mL), and saturated
aqueous sodium chloride (25 mL). The organic layer was dried over
magnesium sulfate, and the solvent was removed in vacuo to give 1.04
g of a yellow oil. This oil was dissolved in 5 mL of THF and cooled
to 0 °C. CuBr‚DMS (61 mg, 0.30 mmol, 1%) was added followed by
the dropwise addition of 2.2 mL of a 2.0 M solution of isopropylmag-
nesium chloride in THF. After a total reaction time of 30 min, the
reaction was quenched with 5 mL of water. The product was extracted
into ether (25 mL) and washed with 10% aqueous sodium bisulfate
solution (25 mL) and saturated aqueous sodium chloride (25 mL). The
organic layer was dried over magnesium sulfate, and the solvent was
removed in vacuo. Chromatography over silica gel (hexane/ethyl acetate
15:1-10:1) yielded 0.73 g (1.84 mmol, 62%) of a mixture of 41 and
42 as a sticky oil. Careful chromatography of the mixture of 41 and 42
over silica gel (hexane/ethyl acetate 15:1-10:1) yielded a small sample
of each diastereomer. The same reaction performed using enantiomeri-
cally pure 32 (0.87 g, 2.61 mmol) gave 0.45 g (44%) of enantiomerically
pure 41 and 42.
Physical Data for (1S,1′R)-1-Cycloundec-2′-enylbut-3-yn-1-ol
1
(17). IR (neat): 3310, 2926, 2857, 2127, 1462, 1041, 983 cm-1. H
NMR (300 MHz, CDCl3): δ 5.57 (ddd, J ) 4.7, 9.8, 14.8 Hz, 1H),
5.30 (dd, J ) 9.9, 15.3 Hz, 1H), 3.57 (dd, J ) 5.3, 10.4 Hz, 1H),
1.9-2.5 (m, 7H), 1.1-1.7 (m, 14H). 13C NMR (75.5 MHz, CDCl3): δ
134.5, 129.6, 72.6, 70.2, 50.4, 34.0, 29.7, 26.5, 26.4, 25.7, 25.6, 25.4,
25.1, 24.9, 24.4. HRMS: calcd for C15H24O (M+) 220.1819. Found:
220.1827.
Physical Data for erythro-1-Cycloundec-2′-enylbut-3-yn-1-ol (18).
1
IR (CDCl3): 3574, 3307, 2250, 2121, 1462.8, 1263 cm-1. H NMR
Physical Data for (3R,12R,13S,15R)-13-(tert-Butyldimethylsilyl-
oxy)-15-isopropylbicyclo[10.2.1]pentadec-1-en-3-ol (41) (Major Di-
(300 MHz, CDCl3): δ 5.54 (ddd, J ) 5.0, 9.6, 14.8 Hz, 1H), 5.18 (dd,
J ) 9.9, 15.4 Hz, 1H), 3.4-3.6 (m, 1H), 2.48 (ddd, J ) 2.7, 3.6, 17.0
Hz, 1H), 2.27 (ddd, J ) 2.6, 7.4, 16.8 Hz, 1H), 1.9-2.2 (m, 5H), 1.0-
1.7 (m, 14H). 13C NMR (75.5 MHz, CDCl3): δ 133.3, 130.6, 81.4,
72.8, 70.6, 51.2, 34.0, 29.0, 26.5, 26.3, 25.8 (2C), 25.5, 25.4, 24.3.
Anal. Calcd for C15H24O: C, 81.76; H, 10.98. Found: C, 81.57; H,
10.73.
1
astereomer). IR (neat): 3343, 1463, 1251, 1100, 836, 775 cm-1. H
NMR (300 MHz, CDCl3): δ 5.19 (d, J ) 10.2 Hz, 1H), 4.40 (td, J )
7.1, 9.3 Hz, 1H), 4.29 (td, J ) 3.9, 10.4 Hz, 1H), 2.71 (ddd, J ) 1.7,
8.7, 17.4 Hz, 1H), 2.29 (d, J ) 9.9 Hz, 1H), 2.10 (dd, J ) 7.4, 17.7
Hz, 1H), 1.93 (dd, J ) 6.4, 11.3 Hz, 1H), 1.65-1.75 (m, 1H), 1.2-1.5
(m, 17H), 0.95 (d, J ) 5.0 Hz, 3H), 0.93 (d, J ) 4.8 Hz, 3H), 0.89 (s,
6H), 0.42 (s, 6H). 13C NMR (75.5 MHz, CDCl3): δ 146.6, 127.9, 78.0,
69.5, 53.3, 47.8, 39.3, 38.1, 30.8, 30.4, 29.9, 29.4, 26.6, 26.5(3), 25.4,
24.0, 22.8, 22.7, 21.8, 18.8, -4.25, -4.35. HRMS: calcd for C24H46O3-
Si (M+) 394.3267. Found: 394.3274.
Physical Data for (3S,12R,13S,15R)-13-(tert-Butyldimethylsilyl-
oxy)-15-isopropylbicyclo[10.2.1]pentadec-1-en-3-ol (42) (Minor Di-
astereomer). IR (neat): 3332, 1462, 1385, 362, 1250 cm-1. 1H NMR
(300 MHz, CDCl3): δ 5.17 (d, J ) 9.6 Hz, 1H), 4.41 (q, J ) 8.2 Hz,
1H,), 4.19 (dt, J ) 3.8, 9.7 Hz, 1H), 2.62 (ddd, J ) 2.5, 9.3, 17.6 Hz,
1H), 2.19 (ddd, J ) 2.5, 7.8, 17.6 Hz, 1H), 2.00 (d, J ) 9.3 Hz, 1H),
1.90-2.0 (m, 1H), 1.0-1.5 (m, 15H), 0.90 (d, J ) 5.8 Hz, 3H), 0.89
(s, 9H), 0.86 (d, J ) 6.7 Hz, 3H), 0.04 (s, 9H). 13C NMR (75.5 MHz,
CDCl3): δ 145.3, 127.8, 73.3, 71.0, 57.1, 44.9, 36.6, 35.9, 30.0, 28.7,
28.2, 27.2, 25.8(3), 25.6, 25.4, 24.8, 22.5, 21.7, 20.7, 18.1, -4.9, -5.0.
HRMS: calcd for C24H46O2Si 394.3267. Found: 394.3252.
Preparation of (12R,13S,15R,1E)-13-(tert-Butyldimethylsilyloxy)-
15-isopropylbicyclo[10.2.1]pentadec-1-en-3-one (43) and (12R,13S,-
15R,1Z)-13-(tert-Butyldimethylsilyloxy)-15-isopropylbicyclo[10.2.1]-
pentadec-1-en-3-one (44). TPAP (1 mg, 0.029 mmol, 2.5%) was added
to a solution of a mixture of (3R,12S,13S,15R)-13-(tert-butyldimeth-
ylsilyloxy)-15-isopropylbicyclo[10.2.1]pentadec-1-en-3-ol 41 and (3S,-
12R,13S,15R)-13-(tert-butyldimethylsilyloxy)-15-isopropylbicyclo[10.2.1]-
pentadec-1-en-3-ol 42 (0.451 g, 1.143 mmol), NMO (0.161 g, 1.372
mmol), and 4 Å molecular sieves (0.500 g) in 2 mL of methylene
chloride. The reaction was stirred at room temperature for 2.5 h. The
reaction was filtered through silica gel (methylene chloride) and
concentrated in vacuo to give the crude product. Chromatography over
silica gel (petroleum ether/ethyl acetate 10:1) yielded 0.392 g (0.998
mmol, 87%) of a colorless oil as a mixture of 43 and 44. Additional
silica gel chromatography allowed the isolation of a pure sample of 43
Preparation of (12R,13S)-13-(tert-Butyldimethylsilyloxy)bicyclo-
[10.2.1]pentadeca-1(15),2-diene (32). Platinum chloride (0.035 g, 0.133
mmol, 5%) was added to a solution of (1S,1′R)-1-(tert-butyldimethyl-
silyloxy)-1-cycloundec-2′-enylbut-3-yne 23 (0.891 g, 2.664 mmol) in
5 mL of toluene. The solution was heated to 80 °C and stirred for 1 h.
The solution was cooled and filtered through Florisil (petroleum ether).
Concentration in vacuo yielded 0.874 g (2.612 mmol, 98%) of the
metathesis product 32 as a pale yellow oil, [R]24 13.3° (c ) 0.35,
D
1
CHCl3). IR (neat): 1462, 1257, 1251 cm-1
.
H NMR (300 MHz,
CDCl3): δ 6.18 (d, J ) 15.7 Hz, 1H), 5.48 (s, 1H), 5.40 (ddd, J ) 4.4,
10.7, 15.3 Hz, 1H), 4.68 (q, J ) 7.7 Hz, 1H), 2.79 (s, 1H), 2.60 (dd,
J ) 8.8, 15.9 Hz, 1H), 2.48 (dd, J ) 7.8, 15.7 Hz, 1H), 2.3-2.4 (m,
1H), 2.0-2.1 (m, 1H), 1.7-1.85 (m, 2H), 1.0-1.4 (m, 12H), 0.9 (s,
9H), 0.1 (s, 6H). 13C NMR (75.5 MHz, CDCl3): δ 139.4, 130.9, 129.6,
128.4, 73.5, 48.6, 41.6, 34.0, 29.4, 28.65, 58.57, 27.9, 26.9, 26.5, 26.3,
25.9 (3), 18.4, -4.8, -5.0.
Preparation of anti-13-(tert-Butyldimethylsilyloxy)bicyclo[10.2.1]-
pentadeca-1(15),2-diene (33). [(p-cymene)RuCl2]2 (46 mg, 0.075
mmol, 1.25%) was added to a solution of erythro-1-(tert-butyldimeth-
ylsilyloxy)-1-cycloundec-2′-enylbut-3-yne 24 (2.011 g, 5.997 mmol)
in 30 mL of toluene. The reaction was placed under carbon monoxide
at 1 atm and submersed in an oil bath preheated to 110 °C. As the
solution warmed, the catalyst dissolved and the solution went from a
red to a yellow color. After 15 min, the solution was cooled, filtered
through a short plug of silica gel (pentane), and then concentrated in
vacuo to yield 2.118 g (6.330 mmol, 100%) of 33 as a pale yellow
solid, mp 74-76 °C (toluene). IR (CDCl3): 1471, 1457, 1252 cm-1
.
1H NMR (300 MHz, CDCl3): δ 6.26 (d, J ) 15.7 Hz, 1H), 5.50 (s,
1H), 5.38 (ddd, J ) 4.4, 10.9, 15.4 Hz, 1H), 4.15 (d, J ) 6.0 Hz, 1H),
2.91 (dd, J ) 6.9, 17.1 Hz, 1H), 2.78 (s, 1H), 2.35-2.4 (m, 1H), 2.27

Formal Total Synthesis of Roseophilin
J. Am. Chem. Soc., Vol. 122, No. 16, 2000 3809
as a colorless oil, [R]20D 22.4° (c ) 0.88, CHCl3), and 44 as a colorless
oil, [R]20D -77.6° (c ) 1.12, CHCl3), with the minor diastereomer 44
eluting first.
reaction was carefully quenched by the addition of 5 mL of water.
Sodium bromate 0.125 g (0.810 mmol) was added, and the reaction
was heated to 50 °C for 2.5 h. The product was extracted into ethyl
ether (10 mL), washed with water (2 × 10 mL) and saturated aqueous
sodium chloride (10 mL), dried over magnesium sulfate, and concen-
trated in vacuo. Chromatography over silica gel (petroleum ether/ethyl
acetate 2:1) yielded 197 mg 0.477 mmol, 70%) of a white solid
containing a mixture of the two epimeric diols 62. Additional
chromatography over silica gel (petroleum ether/ethyl acetate 2:1)
allowed the isolation of a pure sample of 62a as a white solid, mp
122-123 °C, [R]24D 37.5° (c ) 1.02, CHCl3), and pure sample of 62b
Physical Data for (12R,13S,15R,1E)-13-(tert-Butyldimethylsilyl-
oxy)-15-isopropylbicyclo[10.2.1]pentadec-1-en-3-one (43) (Major
1
Diastereomer). IR (neat): 1683, 1619, 1471, 1462, 1251 cm-1. H
NMR (300 MHz, CDCl3): δ 6.27 (s, 1H), 4.51 (td, J ) 6.8, 9.4 Hz,
1H), 2.96 (ddd, J ) 2.5, 9.4, 20.4 Hz, 1H), 2.53 (dt, J ) 5.2, 13.8 Hz,
1H), 2.44 (dd, J ) 6.8, 20.6 Hz, 1H), 2.1-2.2 (m, 2H), 2.08 (d, J )
9.7 Hz, 1H), 1.6-1.7 (m, 2H), 1.0-1.5 (m, 13H), 0.90 (d, J ) 6.6 Hz,
3H), 0.85 (s, 9H), 0.83 (d, J ) 7.1 Hz, 3H), 0.02 (s, 3H), 0.01 (s, 3H).
13C NMR (75.5 MHz, CDCl3): δ 202.6, 164.9, 123.3, 72.9, 60.3, 44.2,
43.3, 39.9, 29.7, 29.1, 28.6, 27.3, 27.2, 26.5, 25.9, 25.7(3), 24.0, 21.4,
21.0, 17.9, -5.0, -5.2. HRMS: calcd for C24H44O2Si (Μ+) 392.3111.
Found: 392.3116.
as a white solid, mp 125 °C, [R]24 -24.0° (c ) 0.86, CHCl3).
D
Physical Data for (1R,3R,12R,13R,14R,15R)-13-(tert-Butyldi-
methylsilyloxy)-15-isopropylbicyclo[10.2.1]pentadecane-3,14-diol (62a).
1
IR (neat): 3361, 1463, 1250 cm-1. H NMR (300 MHz, CDCl3): δ
3.92 (t, J ) 9.3 Hz, 1H), 3.73 (t, J ) 8.0 Hz, 1H), 3.60-3.70 (b, 1H),
2.90 (b, 1H), 2.40 (b, 1H), 1.85 (d, J ) 8.3 Hz, 1H), 1.0-1.7 (m,
Physical Data for (12R,13S,15R,1Z)-13-(tert-Butyldimethylsilyl-
oxy)-15-isopropylbicyclo[10.2.1]pentadec-1-en-3-one (44) (Minor
18H), 0.89 (s, 9H), 0.83-0.89 (m, 6H), 0.06 (s, 3H), 0.04 (s, 3H). 13
C
1
Diastereomer). IR (neat): 1685, 1620, 1462, 1251 cm-1. H NMR
NMR (75.5 MHz, CDCl3): δ 78.9, 77.1, 68.8, 47.7, 42.7, 41.8, 38.0,
36.3, 33.2, 26.3, 26.0(3), 25.9, 25.0, 24.0, 22.4, 22.1, 22.0, 20.5, 20.4,
18.3, -4.6, -4.7. Anal. Calcd for C24H48O3Si: C, 69.84; H, 11.72.
Found: C, 69.70; H, 11.62.
(300 MHz, CDC3): δ 6.24 (s, 1H), 4.50 (dt, J ) 6.5, 9.7 Hz, 1H),
2.90 (d, J ) 9.1 Hz, 1H), 2.85 (dd, J ) 9.9, 19.8 Hz, 1H), 2.50 (ddd,
J ) 4.6, 8.8, 12.9 Hz, 1H), 2.25 (ddd, J ) 4.6, 7.9, 12.6 Hz, 1H), 2.18
(dd, J ) 6.5, 18.7 Hz, 1H), 1.93 (ddd, J ) 2.5, 6.4, 8.9 Hz, 1H), 1.0-
1.8 (m, 15H), 0.97 (d, J ) 6.6 Hz, 3H), 0.94 (d, J ) 6.8 Hz, 3H), 0.89
(s, 9H), 0.04 (s, 6H); 13C NMR (75.5 MHz, CDCl3): δ 202.7, 164.5,
125.4, 70.8, 54.3, 46.8, 44.5, 40.7, 30.7, 29.6, 27.0, 26.2, 25.8(3), 25.0,
24.3, 23.4, 23.2, 21.2, 21.1, 18.1, -5.0, -5.1. HRMS: calcd for
C24H44O2Si (Μ+) 392.3111. Found: 392.3107.
Physical Data for (1R,3S,12R,13R,14R,15R)-13-(tert-Butyldi-
methylsilyloxy)-15-isopropylbicyclo[10.2.1]pentadecane-3,14-diol (62b).
1
IR (KBr): 3386, 1465, 1251 cm-1
.
H NMR (300 MHz, CDCl3): δ
3.88 (t, J ) 7.3 Hz, 1H), 3.81 (b, 1H), 3.71 (t, J ) 6.8 Hz, 1H), 2.0 (b,
1H), 1.1-1.9 (m, 32H), 0.94 (d, J ) 6.3 Hz, 3H), 0.89 (s, 9H), 0.88
(d, J ) 6.3 Hz, 3H), 0.06 (s, 3H), 0.04 (s, 3H). 13C NMR (75.5 MHz,
CDCl3): δ 84.5, 80.1, 68.9, 48.3, 43.8, 42.7, 41.6, 37.2, 32.8, 27.3,
26.8, 26.6, 25.9(3), 24.24, 24.18, 23.4, 22.4, 21.5, 20.5, 18.2, -4.7(2).
Anal. Calcd for C24H46O3Si: C, 39.84; H, 11.72. Found: C, 69.63; H,
11.57.
Preparation of (1R,12R,13R,15R)-13-(tert-Butyldimethylsilyloxy)-
15-isopropylbicyclo[10.2.1]pentadecane-3,14-dione (61). From the
Reduction of rac-(1Z,12R,13R,15R)-13-(tert-Butyldimethylsilyloxy)-
15-isopropylbicyclo[10.2.1]pentadec-1-ene-3-14-dione (60). Pal-
ladium on carbon (10 mg, 10%) was added to a solution of 13-(tert-
butyldimethylsilyloxy)-15-isopropylbicyclo[10.2.1]pentadec-1-ene-3,14-
dione 60 (25 mg, 0.062 mmol) in 0.5 mL of ethyl acetate. The reaction
was stirred at room temperature under hydrogen at 1 atm. After 30
min at room temperature, the reaction was filtered through Florisil (ethyl
acetate) and concentrated in vacuo. The product, which has the same
Rf as the substrate but is not UV active, was purified by Florisil
chromatography (hexane/ethyl acetate 50:1) to yield 19 mg (0.046
mmol, 74%) of rac-61 as a colorless oil.
Preparation of (12R,13R,15R)-13-tert-Butyldimethylsilyloxy)-15-
isopropylbicyclo[10.2.1]pentadec-1(14)-en-3-one (57). DBU (33 µL,
0.222 mmol, 0.5 equiv) was added to a solution of rac-(12R,13S,-
15R,1E)-13-(tert-butyldimethylsilyloxy)-15-isopropylbicyclo[10.2.1]-
pentadec-1-en-3-one 43 and (12R,13S,15R,1Z)-13-(tert-butyldimethyl-
silyloxy)-15-isopropylbicyclo[10.2.1]pentadec-1-en-3-one 44 (0.175 g,
0.445 mmol) in 1 mL of acetonitrile at 75 °C. After 4 h, the reaction
was cooled and concentrated in vacuo. The residue was chromato-
graphed over silica gel (hexane/ethyl acetate 50:1) to yield 0.119 g
(0.303 mmol, 68%, 91% brsm) of the product as a colorless oil along
with 0.044 g (0.112 mmol, 25%) of the starting material. Performing
the reaction with DBU (75 µL, 0.499 mmol, 0.5 equiv) and enantio-
merically pure 43-44 (0.392 g, 0.992 mmol) in 1 mL of acetonitrile
at 60 °C gave 0.265 g (0.674 mmol, 68%) of the product as a colorless
oil which solidified upon sitting, mp 50 °C [R]24 1.1° (c ) 1.05,
D
CHCl3). IR (neat): 1717, 1462, 1365, 1251 cm-1. 1H NMR (300 MHz,
CDCl3): δ 5.53 (s, 1H), 4.84 (m, 1H), 3.26 (d, J ) 12.0 Hz, 1H), 2.89
(d, J ) 12.0 Hz, 1H), 2.79 (ddd, J ) 3.6, 10.2, 19.0 Hz, 1H), 2.32 (dt,
J ) 5.1, 18.9 Hz, 1H), 2.23 (s, 1H), 2.10-2.18 (m, 1H), 1.85-2.0 (m,
2H), 1.05-1.5 (m, 13H), 0.96 (d, J ) 6.8 Hz, 3H), 0.90 (s, 9H), 0.69
(d, J ) 6.9 Hz, 3H), 0.06 (s, 3H), 0.05 (s, 3H). 13C NMR (75.5 MHz,
CDCl3): δ 208.1, 139.9, 134.3, 78.1, 57.0, 45.2, 43.0, 38.9, 28.4, 28.2,
27.1, 25.9(3), 25.7, 25.1, 23.6, 22.9, 21.5, 20.6, 18.2, 17.3, -4.9, -5.1.
Anal. Calcd for C24H44O2Si: C, 73.41; H, 11.29. Found: C, 73.52; H,
11.27.
From the Oxidation of 13-(tert-Butyldimethylsilyloxy)-15-iso-
propylbicyclo[10.2.1]pentadecane-3,14-diol (62). TPAP (2 mg, 0.002
mmol, 5%) was added to a solution of a diastereomeric mixture of
diols 62 (50 mg, 0.121 mmol), NMO (35 mg, 0.303 mmol), and 4 Å
molecular sieves (100 mg) in 0.25 mL of methylene chloride. After 8
h at room temperature, the reaction was placed onto silica gel and eluted
with petroleum ether/ethyl acetate (10:1) to yield 46 mg (0.113 mmol,
93%) of a colorless oil.
Preparation of (1R,3R,12R,13R,14R,15R)-13-(tert-Butyldimeth-
ylsilyloxy)-15-isopropylbicyclo[10.2.1]pentadecane-3,14-diol (62a)
and (1R,3S,12R,13R,14R,15R)-13-(tert-Butyldimethylsilyloxy)-15-
isopropylbicyclo[10.2.1]pentadecane-3,14-diol (62b). Borane dimethyl
sulfide complex (0.127 mL, 1.273 mmol, 10.0 M) was added to a
solution of (12R,13R,15R)-13-(tert-butyldimethylsilyloxy)-15-iso-
propylbicyclo[10.2.1]pentadec-1(14)-en-3-one 57 (100 mg, 0.255 mmol)
in 5 mL of ethyl ether. After 22 h of stirring, the reaction was carefully
quenched by the addition of 0.25 mL of methanol. Sodium hydroxide
(0.85 mL, 2.546 mmol, 3 N) and hydrogen peroxide (0.22 mL, 6.366
mmol, 30% aqueous solution) were added, and stirring was continued
for an additional 20 h at room temperature. The product was extracted
into ethyl ether (4 × 5 mL), dried over magnesium sulfate, and
concentrated in vacuo. Chromatography over silica gel (petroleum ether/
ethyl acetate 2:1) yielded 57 mg of 62a and 36 mg of 62b for a total
yield of 93 mg (0.226 mmol, 89%).
Performing the same reaction using TPAP (2.9 mg, 0.008 mmol,
5%), enantiomerically pure diol 62 (70 mg, 0.170 mmol), NMO (50
mg, 0.424 mmol), and 4 Å molecular sieves (100 mg) in 0.5 mL of
methylene chloride yielded 54 mg (0.132 mmol, 78%) of a colorless
oil, [R]20 -19.2° (c ) 1.81, CHCl3). IR (neat): 1752, 1711, 1463,
D
1
1366, 1362 cm-1. H NMR (300 MHz, CDCl3): δ 4.39 (dd, J ) 2.0,
8.3 Hz, 1H), 2.76 (d, J ) 5.2 Hz, 1H), 2.83 (d, J ) 1.7 Hz, 1H), 2.48
(ddd, J ) 3.6, 8.2, 14.8 Hz, 1H), 2.38-2.45 (m, 1H), 2.23 (ddd, J )
3.4, 9.4, 14.9 Hz, 1H), 1.9-2.3 (m, 2H), 1.75-1.9 (m, 1H), 1.69 (dd,
J ) 3.5, 5.8 Hz, 1H), 1.5-1.6 (m, 2H), 1.1-1.5 (m, 11H), 1.02 (d, J
) 6.8 Hz, 3H), 0.91 (d, J ) 6.9 Hz, 3H), 0.13 (s, 3H), 0.06 (s, 3H).
13C NMR (75.5 MHz, CDCl3): δ 216.2, 210.6, 78.0, 45.5, 44.2, 43.7,
42.3, 40.0, 32.3, 26.7, 27.0, 25.9, 25.7(3), 24.7, 23.6, 23.1, 22.8, 21.2,
19.6, 16.4, -4.8, -5.5. HRMS: calcd for C24H44O3Si (M+ - CH3)
393.2826. Found: 393.2833.
The reaction was performed with borane dimethyl sulfide complex
(0.170 mL, 1.69 mmol, 10.0 M) and enantiomerically pure 57 (265
mg, 0.675 mmol) in 1 mL of ethyl ether. After 16 h of stirring, the
Preparation of (12R,13R,15R)-2-Benzyl-15-(tert-butyldimethyl-
silyloxy)-13-isopropyl-2-azatricyclo[10.2.1.113,14]hexadeca-1(14),3-
(16)-diene (63b).. Benzylamine (0.038 mL, 0.350 mmol) was added

3810 J. Am. Chem. Soc., Vol. 122, No. 16, 2000
Trost and Doherty
to a solution of rac-(1R,12R,13R,15R)-13-(tert-butyldimethylsilyloxy)-
15-isopropylbicyclo[10.2.1]pentadecane-3,14-dione 62 (29 mg, 0.070
mmol), glacial acetic acid (20 µL, 0.350 mmol), and 4 Å molecular
sieves (100 mg) in 0.25 mL of methanol. The reaction was heated to
50 °C for 3 h and then allowed to proceed at room temperature for 12
h. The reaction was filtered through silica gel using petroleum ether/
ethyl acetate (10:1) and concentrated in vacuo. Chromatography over
silica gel (petroleum ether/ethyl acetate 50:1) yielded 20 mg (0.042
mmol, 60%) of a colorless oil. The enantiomerically pure sample had
J ) 7.3, 14.7 Hz, 1H), 2.39 (d, J ) 7.1 Hz, 1H), 1.80-1.95 (m, 1H),
1.60-1.75 (m, 1H), 1.1-1.6 (m, 5H), 0.8-1.1 (m, 22H), 0.15 (s, 3H),
0.10 (s, 3H), -0.02 (s, 9H). 13C NMR (75.5 MHz, CDCl3): δ 138.1,
135.1, 126.4, 107.3, 72.9, 72.6, 64.6, 54.3, 51.4, 32.7, 29.7, 28.1, 28.0,
27.8, 26.9, 26.4, 26.0(3), 25.5, 24.9, 21.7, 20.3, 18.0, 17.9, -1.5(3),
-4.2, -5.0. HRMS: calcd for C30H57NO2Si2 (M+) 519.3928. Found:
519.3929.
Preparation of (12R,13R)-13-Isopropyl-2-(2-trimethylsilanyl-
ethoxymethyl)-2-azatricyclo[10.2.1.13,14]hexadeca-1(14),3(16)-dien-
15-one (64f). TBAF (0.26 mL, 0.26 mmol, 1.0 M in THF) was added
to a solution of (12R,13R,15R)-15-(tert-butyldimethylsilyloxy)-13-
isopropyl-2-(2-trimethylsilanylethoxymethyl)-2-azatricyclo[10.2.1.13,14]-
hexadeca-1(14),3(16)-diene 63f (45 mg, 0.087 mmol) and 4 Å molecular
sieves (50 mg) in 0.1 mL of THF. The reaction was stirred at room
temperature for 14 h and then filtered through Florisil and concentrated
in vacuo. The resulting alcohol was immediately dissolved in 0.2 mL
of methylene chloride and treated with manganese dioxide (75 mg,
0.863 mmol). The reaction was stirred at room temperature for 1 h
after which time it was filtered through a plug of silica gel (ethyl ether)
and concentrated in vacuo. Chromatography over silica gel (petroleum
ether/ethyl acetate 10:1) yielded 18 mg (0.046 mmol, 54%) of a
colorless oil with an identical 1H NMR spectrum to that of the
[R]20 -59.4° (c ) 1.77, CHCl3). IR (neat): 1456, 1361, 1257 cm-1
.
D
1H NMR (300 MHz, CDCl3): δ7.14-7.27 (m, 3H), 6.85 (d, J ) 7.3
Hz, 2H), 5.74 (s, 1H), 5.42 (d, J ) 6.3 Hz, 1H), 5.41 (d, J ) 17.1 Hz,
1H), 4.94 (d, J ) 17.1 Hz, 1H), 2.60-2.62 (m, 1H), 2.42-2.76 (m,
3H), 1.80-1.92 (m, 1H), 1.68-1.80 (m, 1H), 0.8-1.5 (m, 13H), 0.97
(d, J ) 6.8 Hz, 3H), 0.90 (d, J ) 4.9 Hz, 3H), 0.89 (s, 9H), -0.002 (s,
3H), -0.33 (s, 3H). 13C NMR (75.5 MHz, CDCl3): δ 139.9, 137.5,
134.3, 128.5(2), 126.6, 125.8, 125.4(2), 106.6, 72.8, 54.2, 51.3, 46.4,
32.8, 29.8, 28.2, 28.0, 27.6, 26.9, 26.4, 25.9(3), 25.3, 25.0, 21.6, 20.3,
17.9, -4.4, -5.9. HRMS: calcd for C31H49NOSi (M+) 479.3583.
Found: 479.3584.
Preparation of (12R,13R,15R)-15-(tert-Butyldimethylsilyloxy)-13-
isopropyl-2-(2-trimethylsilanylethoxymethyl)-2-azatricyclo[10.2.1.13,14]-
hexadeca-1(14),3(16)-diene (63f). Ammonium acetate (97 mg, 1.350
mmol) was added to a solution of (1R,12R,13R,15R)-13-(tert-butyldi-
methylsilyloxy)-15-isopropylbicyclo[10.2.1]pentadecane-3,14-dione 62
(55 mg, 0.135 mmol), camphorsulfonic acid (3 mg, 0.135 mmol, 0.1
equiv), and 4 Å molecular sieves (100 mg) in 0.5 mL of methanol.
The reaction was heated to 50 °C for 5 h. The reaction was cooled to
room temperature, filtered through Florisil (petroleum ether/ethyl acetate
10:1), and concentrated in vacuo to give 45 mg (0.115 mmol, 85.5%)
of a colorless oil. This oil was immediately dissolved in 0.5 mL of
DMF, cooled to 0 °C, and treated with potassium hydride (9.1 mg,
0.228 mmol). After 10 min, 2-(trimethylsilyl)ethoxymethyl chloride
(38 mg, 0.040 mL, 0.228 mmol) was added and the reaction was
allowed to warm to room temperature and stirred for 40 min. The
reaction was quenched with 1 mL of saturated aqueous sodium
bicarbonate and the product extracted into ether (3 × 1 mL). The
combined organic layers were dried over magnesium sulfate and
concentrated in vacuo. Chromatography over silica gel (petroleum ether/
ethyl acetate 50:1) yielded 45 mg (0.087 mmol 76%) of a colorless
compound reported by Fu¨rstner:2f [R]20 -66.0° (c ) 0.28, CHCl3).
D
IR (neat): 1678, 1471, 1248.4 cm-1. 1H NMR (300 MHz, CDCl3): δ
5.99 (s, 1H), 5.66 (d, J ) 10.7 Hz, 1H), 5.31 (d, J ) 11.0 Hz, 1H),
3.64 (td, J ) 5.6, 10.5 Hz, 1H), 3.51 (td, J ) 6.3, 9.8 Hz, 1H), 2.70-
2.76 (m, 3H), 2.60 (d, J ) 6.1 Hz, 1H), 2.0-1.40 (m, 5H), 1.30-0.45
(m, 12H), 0.98 (d, J ) 6.6 Hz, 3H), 0.84 (d, J ) 6.6 Hz, 3H), -0.02
(s, 9H).
Acknowledgment. We thank the National Institutes of
Health, General Medical Sciences, for their generous support
of our programs. Mass spectra were provided by the Mass
Spectrometry Regional Center of the University of Californias
San Francisco supported by the NIH Division of Research
Resources. We also thank Professor A. Fu¨rstner for making
copies of his full paper available to us prior to publication.
Supporting Information Available: Procedures for the
preparation of 10a, 10b, 14-16, 19-21, 23-27, 29, 50a, 54a,
55a, 59, 60, and 64b. This material is available free of charge
via the Internet at http://pubs.acs.org.
oil, [R]20D -36° (c ) 0.77, CHCl3). IR (neat): 1472, 1367, 1250 cm-1
.
1H NMR (300 MHz, CDCl3): δ 5.69 (s, 1H), 5.55 (d, J ) 5.9 Hz,
1H), 5.36 (d, J ) 10.5 Hz, 1H), 5.10 (d, J ) 10.7 Hz, 1H), 3.30-4.58
(m, 2H), 2.69 (td, J ) 7.2, 14.7 Hz, 1H), 2.60-2.65 (m, 1H), 2.53 (td,
JA9941781