Total synthesis of roseophilin

Article abstract of DOI:10.1021/ja973846k

The first total synthesis of the antitumor agent roseophilin 1 is reported. Its intricate macrotricyclic core 2 is obtained by means of a new palladium-catalyzed manifold for the formation of ansa-bridged pyrroles which proceeds via vinyl oxirane 8 and allyl lactone 11 as key intermediates. After conversion of the latter into pyrrolophane 14, a base-induced elimination of the sulfone group followed by the Michael addition of a zincate onto the resulting enone 18 installs the isopropyl substituent in a stereoselective manner. The pyrrolylfuran side chain 3 of roseophilin is prepared from 4- methoxy-2(5H)-furanone (24) and methyl 4-chloropyrrole-2-carboxylate (26) as the starting materials. The appropriate building blocks 25a and 28 derived thereof are combined via a sequence comprising a directed metal-halogen exchange reaction, transmetalation of the resulting lithiopyrrole to the corresponding organozinc compound, a palladium-catalyzed cross coupling of the latter, and a subsequent acid-catalyzed closure of the resulting ketone 29 leading to the furan entity of the target. The triisopropylsilyl- protected side chain 3b is first deprotonated with n-BuLl and then transmetalated with CeCl₃ to give a highly nucleophilic organocerium reagent, which readily attacks the sterically hindered 2- (trimethylsilyl)ethoxymethyl-protected keto pyrrole 2c. Deprotection and final dehydration of the tertiary alcohol derivative 30 thus obtained leads to the intact azafulvene chromophore of the natural product and completes our total synthesis of this alkaloid.

Full text of DOI:10.1021/ja973846k

J. Am. Chem. Soc. 1998, 120, 2817-2825
2817
Total Synthesis of Roseophilin
Alois Fu1rstner* and Holger Weintritt
Contribution from the Max-Planck-Institut fu¨r Kohlenforschung, Kaiser-Wilhelm-Platz 1,
D-45470 Mu¨lheim/Ruhr, Germany
ReceiVed NoVember 10, 1997
Abstract: The first total synthesis of the antitumor agent roseophilin 1 is reported. Its intricate macrotricyclic
core 2 is obtained by means of a new palladium-catalyzed manifold for the formation of ansa-bridged pyrroles
which proceeds via vinyl oxirane 8 and allyl lactone 11 as key intermediates. After conversion of the latter
into pyrrolophane 14, a base-induced elimination of the sulfone group followed by the Michael addition of a
zincate onto the resulting enone 18 installs the isopropyl substituent in a stereoselective manner. The
pyrrolylfuran side chain 3 of roseophilin is prepared from 4-methoxy-2(5H)-furanone (24) and methyl
4-chloropyrrole-2-carboxylate (26) as the starting materials. The appropriate building blocks 25a and 28 derived
thereof are combined via a sequence comprising a directed metal-halogen exchange reaction, transmetalation
of the resulting lithiopyrrole to the corresponding organozinc compound, a palladium-catalyzed cross coupling
of the latter, and a subsequent acid-catalyzed closure of the resulting ketone 29 leading to the furan entity of
the target. The triisopropylsilyl-protected side chain 3b is first deprotonated with n-BuLi and then transmetalated
with CeCl3 to give a highly nucleophilic organocerium reagent, which readily attacks the sterically hindered
2-(trimethylsilyl)ethoxymethyl-protected keto pyrrole 2c. Deprotection and final dehydration of the tertiary
alcohol derivative 30 thus obtained leads to the intact azafulvene chromophore of the natural product and
completes our total synthesis of this alkaloid.
Introduction
keto pyrrole segment 2 with the appropriately substituted
heterocyclic side chain 3 (Scheme 1).
In 1992, Seto et al. disclosed the structure of roseophilin (1),
a novel antibiotic isolated from Streptomyces griseoViridis.1 This
alkaloid possesses a topologically unique skeleton combining
a rather strained macrocyclic entity with an extended hetero-
cyclic chromophore and exhibits very promising cytotoxicity
in vitro against K562 human erythroid leukemia and KB human
epidermoid carcinoma cell lines in the sub-micromolar range.
These properties render roseophilin a new lead structure in the
search for anticancer agents and a rewarding target for total
synthesis.
Model reactions corroborate the viability of this approach:
acid-catalyzed reactions of 3a (R2 ) Ts) with simple 2-acylpyr-
roles lead to the desired chromophore, albeit in rather low
yields.2a With this background in mind, the development of a
concise synthesis of the ansa-bridged keto pyrrole core 2 seemed
to be the major challenge en route to roseophilin. Two different
approaches to this complex macrotricyclic segment have been
described so far, both of which are based on efficient transition
metal catalyzed C-C-bond formations as the key steps. We
have recently outlined a flexible synthesis of 2 relying on a
new palladium-catalyzed manifold for the formation of m-
pyrrolophanes.3 An alternative route to this intricate target
published by Fuchs et al. shortly afterward is based on ring
closing olefin metathesis (RCM),2c thus providing further
evidence for the notion that RCM is likely to evolve into an
attractive method for the formation of macrocyclic systems.4,5
Described below is the first total synthesis of racemic
roseophilin. Specifically, we outline the rationale of our
synthetic blueprint, provide full details of our approach to the
keto pyrrole entity 2, disclose a practical route to the heterocyclic
side chain 3, and report a reliable procedure for the condensation
Although considerable efforts have been directed toward
roseophilin,2,3 no total synthesis of this intriguing alkaloid has
yet been achieved. Since it incorporates an azafulvene-type
chromophore, 1 may likely be formed by the condensation of a
(4) For macrocyclization reactions via RCM from our laboratory, see:
(a) Fu¨rstner, A.; Langemann, K. J. Org. Chem. 1996, 61, 3942-3943. (b)
Fu¨rstner, A.; Langemann, K. Synthesis 1997, 792-803. (c) Fu¨rstner, A.;
Kindler, N. Tetrahedron Lett. 1996, 7005-7008. (d) Fu¨rstner, A.; Lange-
mann, K. J. Org. Chem. 1996, 61, 8746-8749. (e) Fu¨rstner, A.; Mu¨ller,
Th. Synlett 1997, 1010-1012. (f) Fu¨rstner, A.; Langemann, K. J. Am. Chem.
Soc. 1997, 119, 9130-9136. (g) Fu¨rstner, A.; Koch, D.; Langemann, K.;
Leitner, W.; Six, Ch. Angew. Chem. 1997, 109, 2562-2565. (h) Fu¨rstner,
A.; Mu¨ller, Th. J. Org. Chem. 1998, 63, 424-425.
(1) Hayakawa, Y.; Kawakami, K.; Seto, H.; Furihata, K. Tetrahedron
Lett. 1992, 33, 2701-2704.
(2) (a) Nakatani, S.; Kirihara, M.; Yamada, K.; Terashima, S. Tetrahedron
Lett. 1995, 36, 8461-8464. (b) Kim, S. H.; Fuchs, P. L. Tetrahedron Lett.
1996, 37, 2545-2548. (c) Kim, S. H.; Figueroa, I.; Fuchs, P. L. Tetrahedron
Lett. 1997, 38, 2601-2604.
(5) For reviews on RCM, see: (a) Grubbs, R. H.; Miller, S. J.; Fu, G.
C. Acc. Chem. Res. 1995, 28, 446-452. (b) Fu¨rstner, A. Top. Catal. 1997,
4, 285-299.
(3) Fu¨rstner, A.; Weintritt, H. J. Am. Chem. Soc. 1997, 119, 2944-2945.
S0002-7863(97)03846-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/12/1998

2818 J. Am. Chem. Soc., Vol. 120, No. 12, 1998
Fu¨rstner and Weintritt
Scheme 1
ring encoded in the 1,4-dioxygen functionality of the substrate
(III f IV f V),9 but will also liberate the acid for an ensuing
intramolecular acylation of the pyrrole C-2 position (V f VI).
This overall concept allows to forge the macrocyclic entity
before the strain in the molecule is built-up, which occurs during
the kinetically favored formation of the five-membered rings.
In contrast, the metathesis approach to 2 reported by Fuchs et
al. starts out with a cyclopentene template and forms the fairly
rigid ansa-chain later on during the synthesis. This strategy
succeeded only after the macrocyclization reaction had been
conformationally strongly biased in order to override the
unfavorable increase in enthalpy during this step.
Scheme 2
Our synthetic plan was reduced to practice as shown in
Scheme 3. O-Silylation of the known alcohol 410 with tert-
butyldimethylsilyl chloride (TBDMSCl), followed by a chloride
for iodide exchange and subsequent reaction of the rather
unstable allylic iodide with tetrahydrothiophene in the presence
of AgBF4 in thoroughly dried acetone afforded the nicely
crystalline sulfonium salt 6 in good overall yield.11 Its depro-
tonation with t-BuLi in THF at -78 °C followed by trapping
of the sulfur ylide12 formed in situ with 9-bromononanal gave
the desired vinyl oxirane 7 in 84% isolated yield which was
alkylated with methyl (phenylsulfonyl)acetate in DMF under
standard conditions at the bromide terminus without affecting
the labile functionality at the other end of the chain.8a This
simple sequence provided gram amounts of compound 8, which
was suitable to test the palladium manifold outlined above.
Gratifyingly, substrate 8 cyclized smoothly to the 13-
membered carbocyclic ring 9 in highly reproducible 85%
isolated yield when slowly added to a refluxing solution of
catalytic amounts of Pd(PPh3)4 and dppe (dppe ) bis(diphe-
nylphosphino)ethane) in THF over a period of 6 h (∼0.0014 M
final concentration).13 The observed, selective activation of the
vinyl oxirane group was consistent with our prediction. Some
preliminary experiments employing polymer-bound Pd(0) pre-
catalysts previously recommended to facilitate macrocyclization
reactions by pseudo-high-dilution8a,b led to significantly lower
yields. Desilylation of 9 afforded the somewhat strained lactone
10. The best results in this pivotal step were obtained in a
buffered medium with a mixture of TBAF/NH4F (TBAF )
tetrabutylammonium fluoride) as the reagents, whereas TBAF
alone led to substantial decomposition of the rather sensitive
product. A subsequent oxidation of the OH group with the
of these two segments to the intact azafulvene chromophore.
This transformation had to be carried out under conditions that
are entirely different from those suggested by the model studies
in the literature.2a Finally, we show that the enantiomers of 1
can be conveniently separated by means of HPLC on a chiral
support.
Results and Discussion
Synthesis of the Macrotricyclic Segment. Our plan was
to effect the macrocyclization such that it also sets the stage
for a convenient construction of the keto pyrrolic entity of the
target. On the basis of the subtle differences in reactivity of
various allylic precursors in palladium-catalyzed substitution
reactions,6 we perceived a well-orchestrated manifold to achieve
this goal (Scheme 2).
Driven by the release of ring strain, the oxidative addition of
Pd(0) into a difunctional substrate of the general type I should
occur in a regioselective manner at the vinyl oxirane site,7
provided that the allylic OR′ group is properly tuned. The
alkoxide II thus formed should deprotonate the tethered
prenucleophilic malonate entity which will attack the allylpal-
ladium complex and lead to the formation of a macrocyclic ring
according to literature precedent.8 By taking advantage of the
juxtaposition of the OR′ group and the incoming ester, a simple
lactonization of these entities will activate the remaining allylic
position. A second palladium-catalyzed reaction with an amine
as the nucleophile will then not only deliver the desired pyrrole
(8) For leading references, see: (a) Trost, B. M.; Warner, R. W. J. Am.
Chem. Soc. 1982, 104, 6112-6114. (b) Trost, B. M.; Warner, R. W. J.
Am. Chem. Soc. 1983, 105, 5940-5942. (c) Kende, A. S.; Kaldor, I.;
Aslanian, R. J. Am. Chem. Soc. 1988, 110, 6265-6266. (d) Trost, B. M.;
Hane, J. T.; Metz, P. Tetrahedron Lett. 1986, 27, 5695-5698. (e) For a
review, see: Trost, B. M. Angew. Chem. 1989, 101, 1199-1219.
(9) (a) For another palladium-catalyzed pyrrole synthesis, see: Trost,
B. M.; Keinan, E. J. Org. Chem. 1980, 45, 2741-2746. (b) For a timely
compilation of pyrrole chemistry, see: Gossauer, A. In Houben-Weyl,
Methoden der Organischen Chemie; Kreher, R. R., Ed.; Thieme: Stuttgart,
1994; Vol. E 6a, Part 1, pp 556-798.
(10) Prepared from 2-(chloromethyl)allyl chloride according to the
following: Chalova, O. B.; Christoedova, G. B.; Kiladze, T. K.; Germash,
E. V.; Kantor, E. A.; Rakhmankulov, D. L. Zh. Prikl. Khim. 1988, 61, 934-
937; Chem. Abstr. 1989, 110, 38603b
(11) Rosenberger, M.; Newkom, C., Aig, E. R. J. Am. Chem. Soc. 1983,
105, 3656-3661. Since the excess of tetrahydrothiophene can be removed
in vacuo, this sulfide is preferred over the nonvolatile PhSPh for practical
reasons.
(12) (a) t-BuLi was recommended as the deprotonating agent of choice,
cf.: LaRochelle, R. W.; Trost, B. M.; Krepski, L. J. Org. Chem. 1971, 36,
1126-1136. (b) For a review, see: Trost, B. M.; Melvin, L. S. Sulfur Ylides;
Academic Press: New York, 1975; Organic Chemistry Series, Vol. 31.
(13) Products 7-11 shown in Scheme 3 were obtained as mixtures of
all possible stereoisomers. Since all of them lead to the final product, no
attempts were made to separate the individual compounds.
(6) For a review, see: Tsuji, J. Palladium Reagents and Catalysts;
Wiley: New York, 1995.
(7) (a) Trost, B. M.; Molander, G. A. J. Am. Chem. Soc. 1981, 103,
5969-5972. (b) Tsuji, J.; Kataoka, H.; Kobayashi, Y. Tetrahedron Lett.
1981, 22, 2575-2578.

Total Synthesis of Roseophilin
J. Am. Chem. Soc., Vol. 120, No. 12, 1998 2819
Scheme 3
Scheme 4
Scheme 5
Dess-Martin periodinane14 provided ketone 11 in 83% yield
and set the stage for the envisaged palladium-catalyzed pyrrole
formation.
with SnCl4 in refluxing 1,2-dichloroethane cleanly afforded the
tricyclic ketone 14 in 76% yield by an intramolecular Friedel-
Crafts acylation. This reaction must have occurred regioselec-
tively at C-2 rather than C-4 of the pyrrole ring as can be
unambiguously deduced from the observed JC,H correlated
NMR spectra of 2a (vide infra).
Treatment of 11 with benzylamine in the presence of catalytic
amounts of Pd(PPh3)4 in THF resulted in the clean formation
of the desired pyrrole carboxylic acid 12 in 70% yield. The
reaction is best carried out at ∼35 °C to avoid problems caused
by premature base-induced elimination of the sulfone group and/
or concomitant decarboxylation of the acid formed. Benzyl-
amine was selected as the nucleophile because (i) it is known
to react readily in palladium catalyzed allylic substitution
reactions,6,9a (ii) N-benzylpyrrole derivatives are stable both
under basic and acidic conditions,9b (iii) model reactions with
2-acetyl-1-benzylpyrrole (15, Scheme 4) have shown that this
protecting group can be cleaved either by transalkylation (AlCl3
in benzene)15 or under reductive conditions (Ca in NH3).9,16
N-Tosylamine and the potassium salt thereof were considered
as possible alternatives to benzylamine; however, the former
did not participate in the palladium-catalyzed pyrrole formation,
while the latter turned out to be too basic and led to the
formation of pyrone 17 as the major product via elimination of
the sulfone moiety and subsequent rearrangement of the
preexisting double bond (Scheme 5).
n
We intended to use the sulfone moiety at C-22 (roseophilin
numbering) in order to introduce the missing isopropyl sub-
stituent at the adjacent position. A base-induced elimination
of PhSO2H followed by a 1,4-addition of an appropriate
nucleophile to the resulting enone 18 was expected to effect
this transformation. Because the shielding exerted by the fairly
rigid ansa-chain provides effective facial guidance in the
Michael addition step and also forces the protonation of the
resulting enolate 19 to occur from the same side, the proper
relative configuration of the newly formed chiral centers at C-22
and C-23 is likely to ensue (Scheme 6).
However, our initial attempts along these lines revealed that
the tricyclic enone 18 formed upon elimination of the sulfone
group with t-BuOK in THF at ambient temperature exhibits a
peculiar reactivity due to its highly strained character; only a
mixture of two dimeric products was formed as suggested by
GC/MS analysis of the reaction mixture.18 We hoped to
circumvent this problem by effecting the crucial elimination step
Compound 12 was then converted into the acid chloride under
neutral conditions using the highly convenient R-chloroenamine
reagent 13 introduced by Ghosez et al.17 Subsequent treatment
(17) Devos, A.; Remion, J.; Frisque-Hesbain, A.-M.; Colens, A.; Ghosez,
L. J. Chem. Soc., Chem. Commun. 1979, 1180-1181.
(14) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-4156.
(b) Meyer, S. D.; Schreiber, S. L. J. Org. Chem. 1994, 59, 7549-7552.
(15) Murakami, Y.; Watanabe, T.; Kobayashi, A.; Yokoyama, Y.
Synthesis 1984, 738-740.
(16) Hwu, J. R.; Chua, V.; Schroeder, J. E.; Barrans, R. E.; Khoudary,
K. P.; Wang, N.; Wetzel, J. M. J. Org. Chem. 1986, 51, 4731-4733.
(18) We did not investigate the structure of these dimers any further.
However, there is some precedence in the literature that structurally related
heterocyclic ketones are prone to dimerization, cf.: (a) Comer, M. C.;
Despinoy, X. L. M.; Gould, R. O.; McNab, H.; Parsons, S. J. Chem. Soc.
Chem. Commun. 1996, 1083-1084. (b) Neidlein, R.; Jeromin, G. Chem.
Ber. 1982, 115, 706-713.

2820 J. Am. Chem. Soc., Vol. 120, No. 12, 1998
Fu¨rstner and Weintritt
Scheme 6
Scheme 8
Scheme 9
Scheme 7
The synthesis of this complex target has thus been achieved in
only 11 steps by merging the potential of an established
palladium-catalyzed macrocyclization reaction with a conceptu-
ally new entry into substituted keto pyrroles. Notably, this
strategy is flexible enough to give access to various analogues
of 2 as needed for the study of the structure/activity profile of
roseophilin.
Structural Investigations. A major concern in this approach
to 2 was the regiochemical outcome of the base-induced
elimination of the sulfone group (14 f 18). One could argue
that strain and/or antiaromaticity might prevent the formation
of the desired enone 18, thereby forcing the elimination to occur
into the ansa-chain. If the resulting product 20 is intercepted
by the zincate, this pathway would give rise to a compound of
type 21 (Scheme 8).
in the presence of an appropriate nucleophile, thereby intercept-
ing enone 18 directly upon its formation. Cuprates turned out
to be unsuitable for this purpose because of their insufficient
thermal stability at temperatures where the elimination of the
sulfone could be effected.19 Under these conditions, cuprate
decomposition triggers the undesirable reductive cleavage of
the sulfone, most likely via single electron-transfer pathways.
Zincates, which are excellent Michael donors and are known
to be thermally more robust, were found to constitute an
attractive alternative.20 Specifically, addition of an excess of
t-BuOK to a solution of the substrate and i-PrMe2ZnMgCl
(formed in situ from ZnCl2‚TMEDA, 2MeLi, and i-PrMgCl)
in THF at ambient temperature afforded the desired product 2a
in 51% isolated yield as a single diastereoisomer together with
some dimeric byproducts (Scheme 7). The structural integrity
of 2a was unambiguously assigned by extensive 2D NMR
investigations (vide infra).
The debenzylation of this compound turned out to be more
difficult than anticipated. Since we had verified in model studies
that 2-acetyl-1-benzylpyrrole 15 is readily and cleanly depro-
tected on treatment with AlCl3 in benzene (Scheme 4), it was
surprising to find that compound 2a did not react at all under
these conditions. However, the reductive cleavage with Ca in
liquid ammonia followed by reoxidation of the adjacent carbonyl
group led to the desired macrotricyclic core 2b of roseophilin.
Yet another question related to the intramolecular Friedel-
Crafts acylation: although the C-2 position of an N-benzylated
pyrrole ring is generally activated for electrophilic substitution,
acylation of C-4 leading to compound 22 and subsequently to
23 could not be ruled out (Scheme 8).
We have addressed these issues by extensive 2D NMR
investigations. The results obtained rigorously exclude any
undesirable scenario and establish the structural integrity of
compound 2a. A schematic representation of the long-range
couplings observed in the nJH,C correlated spectra of 2a, which
define the site of acylation of the pyrrole ring and the location
of the isopropyl side chain within the cyclopentanone ring, is
given in Scheme 9. Specifically, the observed cross-peaks of
H-23 with two pyrrolic C-atoms give an unambiguous proof of
the site of attachment of the isopropyl group. Moreover, the
coupling pattern of H-23 in the 1H NMR spectrum at 600 MHz
(d, 2.63 ppm) of 3JH22,H23 ≈ 0 Hz matches that observed in the
spectrum of roseophilin itself1 and confirms the proper relative
configuration at these chiral centers.
(19) For a comprehensive review on the use of cuprates in 1,4-additions,
see: Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 135-631.
(20) (a) Kjonaas, R. A.; Hoffer, R. K. J. Org. Chem. 1988, 53, 4133-
4135. See also: (b) Kjonaas, R. A.; Vawter, E. J. J. Org. Chem. 1986, 51,
3993-3996. (c) Morita, Y.; Suzuki, M.; Noyori, R. J. Org. Chem. 1989,
54, 1785-1787. (d) Isobe, M.; Kondo, S.; Nagasawa, N.; Goto, T. Chem.
Lett. 1977, 679-682. (e) Tu¨ckwantel, W.; Oshima, K.; Nozaki, H. Chem.
Ber. 1986, 119, 1581-1593. For a study on the interaction of organozinc
reagents with t-BuOK, see: (f) Rathke, M. W.; Yu, H. J. Org. Chem. 1972,
37, 1732-1734.

Total Synthesis of Roseophilin
J. Am. Chem. Soc., Vol. 120, No. 12, 1998 2821
Scheme 10
Scheme 11
formed afforded a very labile dihalopyrrole which had to be
stabilized by tosylation prior to workup. This particular
N-substituent also helped to direct the subsequent metal-
halogen exchange reaction with n-BuLi exclusively to the
bromine substituent at the 2-position of the heteroarene 28
without affecting the vicinal chlorine group. The resulting
functionalized lithiopyrrole was first transmetalated with ZnCl2
and then cross-coupled in the presence of catalytic amounts of
Pd(0)23 with the crude acid chloride 25b formed in situ from
25a on treatment with 1-N,N-(dimethylamino)-1-chloro-2-me-
thylpropene (13).17 This provided compound 29 in a somewhat
variable yield (43-61%), depending on the scale of the reaction.
Cleavage of the silyl group on exposure to pyridinium p-
toluenesulfonate (PPTS) in MeOH24 led to the cyclization of
the side chain with spontaneous aromatization of the newly
formed ring to the desired methoxyfuran entity by loss of H2O
and MeOH. This afforded the pyrrolylfuran derivative 3a on a
reasonable scale. This compound had already been employed
in previous model studies directed toward roseophilin analogues.2a
Completion of the Total Synthesis. It has been reported in
the literature that acid-catalyzed condensations of 3a with simple
keto pyrrole derivatives lead to the formation of azafulvene
chromophores.2a However, our preliminary assays showed that
these conditions do not apply to the total synthesis of roseophilin
itself since no reaction with the sterically encumbered ketone
group of 2 was observed, while the side chain decomposed over
prolonged reaction times or under more forcing conditions.
Therefore, we had to develop an alternative method for the
end game of our synthesis. We chose an organometallic strategy
for the condensation of segments 2 and 3 (Scheme 11), although
previous attempts in this direction had been unsuccessful.25 To
secure a regioselective reaction, the N-tosyl group in 3a was
replaced by a (i-Pr)3Si-substituent (Scheme 10) which should
prevent the metalation of the activated 2-position of the pyrrole
for steric reasons.26 Gratifyingly, deprotonation of compound
3b with n-BuLi at low temperature proceeded in fact exclusively
on the furan ring. Subsequent transmetalation of the resulting
lithium compound 3c with CeCl3 provided a more highly
nucleophilic organocerium species 3d.27 Although this reagent
added to the potassium salt of 2-acetylpyrrole,28 no reaction with
the potassium salt of 2b could be achieved. Gratifyingly,
Similar arguments can be advanced to establish the site of
acylation of the pyrrole ring. In product 2a, cross-peaks are
observed between the N-CH2Ph (H-11) and two quarternary
R-C-atoms of the trisubstituted pyrrole ring (C-7, C-10), while
a cross-peak with the dCH atom (C-9) is missing. This
excludes the possibility that acylation had occurred at C-4 of
the pyrrole and rules out the formation of the isomeric product
23. Finally, it should be mentioned that the successful comple-
tion of this total synthesis and the direct comparison of our
synthetic material with an authentic sample of roseophilin
confirm the deductions outlined above.
Synthesis of the Heterocyclic Side Chain. Our synthesis
of 3 (Scheme 10) started from commercially available 4-meth-
oxy-2(5H)-furanone (24), which was converted into acid 25a
on a multigram scale by saponification and subsequent adjust-
ment of the silyl protecting groups as shown in Scheme 10.
The pyrrole building block was derived from the easily
accessible carboxylate 2621 which was regioselectively bromi-
nated under standard conditions.22 Saponification of the result-
ing ester 27 followed by decarboxylation of the crude acid thus
(22) Compare: Hodge, P.; Rickards, R. W. J. Chem. Soc. 1965, 459-
470.
(23) (a) Negishi, E.-I.; Bagheri, V.; Chatterjee, S.; Luo, F.-T.; Miller, J.
A.; Stoll, A. T. Tetrahedron Lett. 1983, 24, 5181-5184. (b) Grey, R. A. J.
Org. Chem. 1984, 49, 2288-2289.
(24) Prakash, C.; Saleh, S.; Blair, I. A. Tetrahedron Lett. 1989, 30, 19-
22.
(25) Terashima et al.2a report that they were unable to achieve coupling
reactions with model keto pyrroles using lithiated 3a.
(26) Muchowski, J. M.; Solas, D. R. Tetrahedron Lett. 1983, 24, 3455-
3456.
(21) Prepared according to: Be´langer, P. Tetrahedron Lett. 1979, 2505-
2508.

2822 J. Am. Chem. Soc., Vol. 120, No. 12, 1998
Fu¨rstner and Weintritt
however, 3d readily added to the sterically hindered ketone
group of the N-SEM protected (SEM ) 2-(trimethylsilyl)-
ethoxymethyl) macrotricyclic ketone 2c29 in good yield. Al-
though the resulting tertiary alcohol 3030 could be isolated by
flash chromatography, it turned out to be rather sensitive and
was therefore processed without delay. Thus, exposure of 30
to TBAF in THF at ambient temperature readily cleaved the
N-Si(i-Pr)3 substituent, whereas the SEM group was removed
upon warming to ∼60 °C. Addition of aqueous HCl then led
to the instantaneous appearance of an intense red-orange,
fluorescent color which indicated the formation of the protonated
azafulvene chromophore of 1 by loss of H2O. This transforma-
tion completed the first total synthesis of the structurally unique
target alkaloid. The analytical and spectroscopic data of
roseophilin hydrochloride thus obtained match those of an
authentic sample in all respects.
Separation of the Enantiomers. The absolute configuration
of 1 has not yet been elucidated. However, it is possible to
distinguish between the natural and the unnatural enantiomer
by HPLC on a Chiraspher column with baseline separation of
the antipodes (for details see the Experimental Section and the
Supporting Information). This method has also been used on
a semipreparative scale to deliver sufficient amounts of (+)-1
and (-)-1 for further biological evaluation. Details concerning
the physiological activity of unnatural roseophilin as well as of
several roseophilin analogues will be reported in due course.
Experimental Section
General. All reactions were carried out under Ar using Schlenk
techniques. All commercially available reagents (Aldrich, Fluka) were
used as received. AgBF4 purchased from ACROS gave well-reproduc-
ible results in the formation of compound 6, while samples purchased
from other suppliers led to erroneous results. The solvents were dried
by distillation over the following drying agents and were transferred
under Ar: Et2O (Mg-anthracene), CH2Cl2 (P4O10), THF (Mg-an-
thracene), acetonitrile (CaH2), toluene (Na), DMF (Desmodur/dibutyltin
dilaurate), pyridine (KOH), triethylamine (KOH). Flash chromato-
graphy was performed with Merck silica gel 60 (230-400 mesh) using
hexane/ethyl acetate in various proportions as the eluent. For the
instrumentation used, see the Supporting Information.
tert-Butyl((2-(chloromethyl)allyl)oxy)dimethylsilane (5). To a
solution of alcohol 4 (4.452 g, 41.8 mmol) in CH2Cl2 (80 mL) was
added dropwise a solution of TBDMSCl (6.933 g, 46.0 mmol) and
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 6.88 mL, 46.0 mmol) in CH2-
Cl2 (20 mL) over a period of 1 h at room temperature (rt). After an
additional 15 min of stirring, the reaction mixture was poured into
NaHCO3 (saturated), the aqueous layer was extracted with CH2Cl2, and
the organic phases were dried over Na2SO4 and evaporated. Purification
of the residue by flash chromatography (SiO2, pentane/ether ) 20/1)
afforded compound 5 (8.186 g, 90%) as a colorless liquid. 1H NMR
(200 MHz, CDCl3): δ 5.22-5.18 (m, 2H), 4.22 (m, 2H), 4.07 (m,
2H), 0.90 (s, 9H), 0.07 (s, 6H). 13C NMR (75 MHz, CDCl3): δ 144.6,
114.4, 63.4, 45.0, 25.9, 18.3, -5.4. Anal. Calcd for C10H21ClOSi:
C, 54.39; H, 9.59. Found: C, 54.55; H, 9.56.
1-[2-(((tert-Butyldimethylsilanyl)oxy)methyl)allyl]tetra-
hydrothiophenium Tetrafluoroborate (6). A solution of allyl chloride
5 (1.369 g, 6.21 mmol) and NaI (0.932 g, 6.21 mmol) in acetone (10
mL) was stirred at 50 °C for 16 h. After the reaction was cooled to rt,
the precipitated NaCl was filtered off under argon and washed with
acetone (10 mL). Tetrahydrothiophene (1.10 mL, 12.42 mmol) was
added to the yellow solution of the allyl iodide, and the flask was
wrapped with aluminum foil. After addition of AgBF4 (1.209 g, 6.21
mmol), the resulting suspension was stirred for 1 h. The reaction
mixture was diluted with CH2Cl2 (20 mL), the precipitated AgI was
filtered off, and the solvent was evaporated. The crude solid was
washed with hexane, the solvent was removed by decantation, and the
resulting colorless crystals of the sulfonium salt 6 were dried in vacuo
(1.639 g, 73%): mp ) 91-92 °C. 1H NMR (200 MHz, THF-d8): δ
5.55 (d, J ) 1.0 Hz, 1H), 5.51 (dd, J ) 2.8, 1.5 Hz, 1H), 4.29 (s, 2H),
4.02 (s, 2H), 3.65-3.39 (m, 4H), 2.52-2.22 (m, 4H), 0.95 (s, 9H),
0.12 (s, 6H). 13C NMR (50 MHz, THF-d8): δ 139.7, 120.8, 65.8, 45.7,
44.2, 29.4, 26.6, 19.3, -5.0. Anal. Calcd for C14H29BF4OSSi. C,
46.67; H, 8.11. Found: C, 46.53; H, 8.06.
Summary and Outlook
In summary, we have achieved the first total synthesis of the
promising antitumor alkaloid roseophilin 1 by a convergent and
highly modular approach. The key strategic element for the
formation of its macrocyclic entity is a properly balanced
palladium manifold leading to the complex pyrrole core. The
efficiency and the economy of steps of this sequence are
noteworthy. Our synthesis also illustrates that it may require a
whole arsenal of organometallic reactions to overcome the
problems posed by a seemingly simple heteroaromatic com-
pound such as 3. Moreover, it should be mentioned that we
have been misled by model studies on several occasions during
the course of this synthesis, most importantly in the planning
of the final steps. This clearly features a still limited capacity
to properly assess the extent of homology between recorded
and projected cases. Finally, the concept described above may
be adapted to afford various analogues of 1 and can also be
useful for the synthesis of other natural products containing
m-pyrrolophane units as found, e.g., in the prodigiosin series.31
We are presently pursuing some of these possibilities.32,33
{2-[3-(8-Bromooctyl)oxiranyl]allyloxy}-tert-butyldimethylsi-
lane (7). To a solution of the sulfonium salt 6 (1.507 g, 4.19 mmol)
in THF (50 mL) was added t-BuLi (2.79 mL, 4.19 mmol, 1.5 M in
hexane) via syringe at -78 °C. After 15 min of stirring at -78 °C,
9-bromononanal (0.842 g, 3.81 mmol) in THF (5 mL) was added, and
the mixture was stirred for an additional 15 min at -78 °C and then
slowly warmed to rt. The reaction mixture was extracted with H2O/
ethyl acetate, and the organic layer was dried over Na2SO4 and
evaporated. Purification of the crude product by flash chromatography
(SiO2, hexane/ethyl acetate ) 50/1) afforded vinyl oxirane 7 (1.299 g,
84%, mixture of diastereoisomers) as a colorless oil. 1H NMR (200
MHz, CDCl3): δ 5.21-5.15 (m, 1.5H), 4.99 (m, 0.5H), 4.16 (s, 1H),
4.09 (m, 1H), 3.44 (m, 0.5H), 3.38 (t, J ) 6.8 Hz, 2H), 3.14 (d, J )
2.1 Hz, 0.5H), 3.03 (m, 0.5H), 2.85 (td, J ) 5.3, 2.2 Hz, 0.5H), 1.83
(m, 2H), 1.53-1.18 (m, 12H), 0.90 (s, 4.5H), 0.89 (s, 4.5H), 0.06 (s,
3H), 0.05 (s, 3H). 13C NMR (50 MHz, CDCl3): δ 144.9, 142.2, 111.9,
111.2, 64.5, 62.7, 60.1, 58.8, 58.4, 56.3, 33.9, 32.8, 32.2, 29.4, 29.3,
(27) For reviews, see: (a) Molander, G. A. Chem. ReV. 1992, 92, 29-
68. (b) Imamoto, T. Lanthanides in Organic Synthesis; Academic Press:
New York, 1994.
(28) Fu¨rstner, A.; Weintritt, H. Unpublished results.
(29) The SEM group was chosen because it does not further increase
the steric hindrance around the carbonyl group and it can be deprotected
simultaneously with the TIPS substituent on the side chain by using fluoride.
For a previous application of SEM-protected pyrroles, see: Edwards, M.
P.; Doherty, A. M.; Ley, S. V.; Organ, H. M. Tetrahedron 1986, 42, 3723-
3729.
(30) The stereochemistry of the newly formed t-alcohol has not been
rigorously assigned; the configuration shown in Scheme 11 is suggested
by the inspection of molecular models.
(31) The prodigiosin tripyrrole pigments are the closest relatives to
roseophilin, cf.: (a) Wasserman, H. H.; Keith, D. D.; Nadelson, J. J. Am.
Chem. Soc. 1969, 91, 1264-1265. (b) Laatsch, H.; Kellner, M.; Weyland,
H. J. Antibiot. 1991, 44, 187-191. (c) Wasserman, H. H.; Keith, D. D.;
Nadelson, J. Tetrahedron 1976, 32, 1867-1871. (d) Gerber, N.; N.;
McInnes, A. G.; Smith, D. G.; Walter, J. A.; Wright, J. L. C.; Vining, L.
C. Can. J. Chem. 1978, 56, 1155-1163 and literature cited therein.
(32) Fu¨rstner, A.; Krause, H.; Weintritt, H. Unpublished results.
(33) For syntheses of other bioactive natural products from this laboratory
see ref 4 and the following: (a) Fu¨rstner, A.; Weintritt, H.; Hupperts, A. J.
Org. Chem. 1995, 60, 6637-6641. (b) Fu¨rstner, A.; Ernst, A. Tetrahedron
1995, 51, 773-786. (c) Fu¨rstner, A.; Ernst, A.; Krause, H.; Ptock, A.
Tetrahedron 1996, 52, 7329-7344. (d) Fu¨rstner, A.; Konetzki, I. Tetra-
hedron 1996, 52, 15071-15078. (e) Fu¨rstner, A.; Seidel, G. J. Org. Chem.
1997, 62, 2332-2336.

Total Synthesis of Roseophilin
J. Am. Chem. Soc., Vol. 120, No. 12, 1998 2823
28.6, 28.1, 26.6, 26.2, 25.9, 18.4, 18.3, -5.4. Anal. Calcd for C19H37-
BrO2Si. C, 56.28; H, 9.20. Found: C, 56.32; H, 9.15.
13C NMR (100 MHz, CD2Cl2): δ 166.60, 166.45, 165.85, 136.28,
135.54, 135.28, 134.63, 134.53, 134.42, 134.35, 134.29, 133.72, 133.37,
133.32, 131.61, 131.45, 131.24, 131.20, 129.50, 129.27, 128.88, 128.76,
128.65, 128.62, 127.92, 127.87, 127.24, 75.73, 74.65, 72.81, 72.76,
72.36, 71.96, 71.88, 70.90, 70.54, 68.52, 67.43, 65.38, 38.32, 37.50,
36.53, 36.23, 35.86, 35.67, 35.38, 34.96, 33.46, 29.82, 29.03, 27.83,
27.76, 27.53, 27.24, 27.02, 26.92, 26.68, 26.03, 25.84, 25.83, 25.36,
25.05, 24.58, 24.39, 24.27, 24.18: 23.63, 23.30, 23.24, 22.71, 22.12.
MS: m/z (rel intensity) 252 (16), 251 (100), 250 (60), 234 (13), 233
(76), 232 (50), 222 (11), 206 (15), 205 (31), 187 (24), 152 (22), 149
(10), 145 (11), 143 (26), 135 (12), 131 (12), 125 (16), 124 (11), 123
(10), 121 (15), 119 (12), 109 (16), 108 (14), 107 (19), 105 (15), 95
(34), 93 (24), 91 (23), 83 (11), 82 (21), 81 (43), 79 (39), 78 (12), 77
(43), 69 (21), 67 (41), 57 (18), 55 (55), 53 (13), 43 (33), 41 (57), 39
(12), 29 (20). IR: 3515, 3066, 2932, 2860, 1730, 1584, 1448, 1307,
1143, 1080, 1000, 722, 689 cm-1. Anal. Calcd for C21H28O5S: C,
64.26; H, 7.19. Found: C, 64.15; H, 7.26.
2-(Benzenesulfonyl)-10-{3-[1-(((tert-butyldimethylsilanyl)oxy)-
methyl)vinyl]oxiranyl}decanoic Acid Methyl Ester (8). Methyl
(phenylsulfonyl)acetate (0.656 g, 3.06 mmol) was added to KH
(0.123 g, 3.06 mmol) in DMF (15 mL) at rt. After the hydrogen
formation had ceased, substrate 7 (1.238 g, 3.06 mmol) in DMF (5
mL) was added and the solution was stirred for 72 h at rt. The mixture
was extracted with H2O/ethyl acetate, and the organic layer was dried
over Na2SO4 and evaporated. Purification of the residue by flash
chromatography (SiO2, hexane/ethyl acetate ) 10/1) afforded compound
8 (1.112 g, 68%, mixture of diastereoisomers) as a colorless oil. 1H
NMR (300 MHz, CDCl3): δ 7.86-7.82 (m, 2H), 7.68-7.62 (m, 1H),
7.57-7.51 (m, 2H), 5.19-5.13 (m, 1.5H), 4.97 (m, 0.5H), 4.14-4.06
(m, 2H), 3.90 (dd, J ) 10.7, 4.3 Hz, 1H), 3.63 (s, 3H), 3.41 (ddd, J )
4.3, 1.2, 0.6 Hz, 0.5H), 3.12 (d, J ) 2.1 Hz, 0.5H), 3.02 (m, 0.5H),
2.83 (m, 0.5H), 1.99-1.91 (m, 2H), 1.59-1.48 (m, 1H), 1.37-1.23
(m, 13H), 0.88 (s, 4.5H), 0.87 (s, 4.5H), 0.04 (s, 3H), 0.03 (s, 3H). 13
C
Ketone 11. Dess-Martin periodinane (825 mg, 1.94 mmol)14 was
added to a solution of alcohol 10 (304 mg, 0.78 mmol) in CH2Cl2 (50
mL) at rt. After 3.5 h of stirring, the reaction mixture was filtered
through a short pad of silica, the residues were washed with CH2Cl2,
and the combined organic layers were extracted with saturated aqueous
NaHCO3 and dried over Na2SO4. The solvent was evaporated, and
the crude product purified by flash chromatography (SiO2, hexane/ethyl
acetate ) 6/1 f 4/1) affording ketone 11 (251 mg, 83%, mixture of
diastereoisomers) as a colorless foam. 1H NMR (300 MHz, CDCl3):
δ 7.97-7.93 (m, 2H), 7.72-7.65 (m, 1H), 7.58-7.55 (m, 1H), 6.55
(m), 6.40 (d, J ) 2.7 Hz) [1H], 5.58-5.52 (m), 5.13-5.02 (m), 4.50
(dd, J ) 12.2, 2.7 Hz) [2H], 3.70-3.47 (m, 2H), 2.94 (dd, J ) 13.0,
1.5 Hz), 2.85 (ddd, J ) 16.0, 10.7, 3.1 Hz), 2.70 (m) [2H], 2.35-2.24
(m, 1H), 2.11-1.91 (m, 2H), 1.86-1.66 (m, 1H), 1.62-0.78 (m, 10H).
13C NMR (75 MHz, CDCl3): δ 202.2, 201.8, 166.2, 165.4, 143.8, 141.3,
134.9, 134.6, 134.5, 133.9, 131.5, 131.2, 129.2, 128.6, 128.5, 127.5,
73.4, 73.1, 70.9, 70.3, 41.8, 40.8, 38.4, 34.6, 34.1, 30.7, 26.4, 26.2,
26.0, 25.8, 25.3, 25.2, 24.8, 23.7, 22.9, 22.4, 22.3, 22.0. MS: m/z (rel
intensity) 250 (16), 249 (100), 248 (92), 221 (16), 220 (11), 151 (14),
150 (15), 142 (11), 137 (21), 136 (11), 124 (21), 123 (18), 122 (11),
119 (10), 107 (11), 105 (13), 95 (14), 94 (14), 93 (15), 91 (22), 81
(18), 79 (28), 78 (18), 77 (54), 69 (11), 67 (30), 66 (12), 65 (16), 55
(42), 53 (13), 51 (17), 43 (25), 41 (51), 39 (19), 29 (16), 27 (12). IR
(KBr): 3066, 2941, 2862, 1738, 1688, 1641, 1584, 1447, 1306, 1181,
1142, 1080, 754, 721 cm-1. Anal. Calcd for C21H26O5S: C, 64.59;
H, 6.71. Found: C, 64.38; H, 6.86.
Pyrrole 12. A solution of Pd(PPh3)4 (175 mg, 0.15 mmol) and
benzylamine (132 µL, 1.21 mmol) in THF (10 mL) was added to a
solution of compound 11 (392 mg, 1.01 mmol) in THF (60 mL) at
35 °C. After 1.5 h of stirring, the reaction mixture was extracted with
NH4Cl/ethyl acetate, and the organic layer was dried over Na2SO4 and
evaporated. After purification of the residue by flash chromatography
(SiO2, hexane/ethyl acetate/acetic acid ) 2/1/0 f 2/1/0.1), toluene and
then CH2Cl2 were successively and repeatedly stripped off in vacuo in
order to remove aceotropically any traces of HOAc. The resulting acid
12 was dried in vacuo to yield a yellow solid (340 mg, 70%). 1H NMR
(400 MHz, THF-d8): δ 7.84-7.81 (m, 2H), 7.62-7.57 (m, 1H), 7.51-
7.47 (m, 2H), 7.21-7.10 (m, 3H), 6.95-6.93 (m, 2H), 6.46 (d, J )
2.0 Hz, 1H), 5.84 (d, J ) 2.0 Hz, 1H), 4.97 (d, AB, J ) 16.2 Hz, 1H),
4.91 (d, AB, J ) 16.2 Hz, 1H), 3.42 (d, J ) 13.8 Hz, 1H), 3.01 (d, J
) 13.8 Hz, 1H), 2.52-2.46 (m, 1H), 2.42-2.35 (m, 1H), 2.22-2.14
(m, 1H), 1.65-1.60 (m, 1H), 1.32-0.85 (m, 1H), 0.65-0.62 (m, 1H).
13C NMR (100 MHz, THF-d8): δ 169.9, 140.5, 138.6, 134.5, 132.4,
131.9, 129.5, 129.4, 128.1, 127.5, 122.3, 117.0, 113.3, 77.8, 51.2, 31.6,
30.3, 28.3, 27.8, 27.7, 27.6, 27.2, 26.7, 23.2. MS: m/z (rel intensity)
480 (16), 479 ([M+], 47), 339 (19), 338 (78), 337 (24), 91 (100), 44
(11). IR (KBr): 3400-2500, 3065, 2931, 2848, 1701, 1448, 1322,
1307, 1147, 1079, 811, 731, 688 cm-1. HRMS (C28H33NO4S): calcd
479.21303; found 479.21177.
NMR (75 MHz, CDCl3): δ 166.5, 144.8, 142.2, 137.1, 134.2, 129.3,
129.0, 111.9, 111.1, 70.9, 64.4, 62.7, 60.0, 58.7, 58.3, 56.2, 52.8, 32.2,
29.3, 29.2, 29.0, 28.9, 26.8, 26.7, 26.6, 26.2, 25.9, 25.8, 18.3, 18.2,
-5.39, -5.42. MS: m/z (rel intensity) 483 (14), 482 (32), 481 (100),
199 (38), 143 (44), 135 (22), 125 (11), 95 (10), 81 (11), 77 (19), 75
(39), 73 (30), 67 (11), 55 (12). IR: 3093, 2952, 2929, 2856, 1745,
1463, 1448, 1327, 1311, 1257, 1150, 1084, 838, 778, 723, 689 cm-1
.
Anal. Calcd for C28H46O6SSi: C, 62.42; H, 8.61. Found: C, 62.32;
H, 8.67.
Macrocycle 9. To a refluxing solution of Pd(PPh3)4 (23 mg, 0.02
mmol) and dppe (16 mg, 0.04 mmol) in THF (100 mL) was added a
solution of substrate 8 (108 mg, 0.20 mmol) in THF (40 mL) dropwise
over a period of 6 h. The reaction mixture was refluxed for additional
10 h, cooled to rt, and extracted with H2O/ethyl acetate, and the organic
layer was dried over Na2SO4. After evaporation of the solvent, the
crude product was purified by flash chromatography (SiO2, hexane/
ethyl acetate ) 3/1) affording product 7 (92 mg, 85%, mixture of
diastereoisomers) as a pale yellow foam. 1H NMR (400 MHz, CD2-
Cl2): δ 7.83-7.76 (m, 2H), 7.70-7.67 (m, 1H), 7.59-7.54 (m, 2H),
5.89 (d, J ) 8.8 Hz), 5.71 (dd, J ) 9.6, 1.5 Hz), 5.61 (d, J ) 9.0 Hz),
5.25 (d, J ) 7.7 Hz) [1H], 4.56-4.07 (m), 4.01 (s), 3.85-3.72 (m)
[3H], 3.60 (s), 3.57 (s), 3.56 (s), 3.50 (s) [3H], 3.13-2.78 (m, 2H),
2.20-1.21 (m, 17H), 0.95 (s), 0.92 (s), 0.84 (s), 0.81 (s) [9H], 0.119
(s), 0.117 (s), 0.114 (s), 0.108 (s), 0.014 (s), -0.003 (s), -0.010 (s),
-0.015 (s) [6H]. 13C NMR (100 MHz, CD2Cl2): δ 169.21, 169.18,
168.92, 168.83, 140.06, 137.45, 137.26, 137.11, 136.73, 136.67, 136.66,
135.94, 135.74, 135.18, 134.45, 134.40, 134.33, 133.96, 132.55, 130.64,
130.57, 130.47, 130.37, 129.21, 129.08, 129.06, 129.01, 77.38, 76.71,
76.47, 76.21, 68.27, 67.94, 67.81, 66.77, 66.34, 66.28, 62.67, 60.52,
38.54, 37.29, 36.85, 36.30, 36.20, 33.95, 31.85, 31.10, 31.07, 30.80,
29.84, 29.30, 29.21, 29.04, 28.63, 27.94, 27.85, 27.43, 27.19, 26.88,
26.72, 26.45, 26.09, 25.99, 25.97, 25.47, 25.14, 24.97, 24.80, 24.67,
24.59, 24.29, 24.13, 24.08, 23.57, 23.41, 21.69, 21.06, 20.57, 18.65,
18.58, 18.44, 18.36, -5.17, -5.19, -5.25, -5.27, -5.30, -5.35, -5.30.
MS: m/z (rel intensity) 481 (17), 431 (16), 339 (28), 322 (11), 321
(42), 307 (16), 265 (30), 233 (29), 200 (15), 199 (100), 187 (18) 135
(30), 91 (11), 81 (11), 79 (11), 75 (49), 73 (39), 67 (12), 55 (12), 41
(10). IR: 3527, 3429, 3065, 2930, 2857, 1736, 1585, 1463, 1447, 1308,
1252, 1144, 1079, 1038, 1005, 838, 778, 721, 691, 610 cm-1. Anal.
Calcd for C28H46O6SSi: C, 62.42; H, 8.61. Found: C, 62.36; H, 8.54.
Allyllactone 10. To a solution of silyl ether 9 (736 mg, 1.37 mmol)
in THF (125 mL) was successively added NH4F (253 mg, 6.84 mmol)
and TBAF (6.85 mL, 6.85 mmol, 1 M in THF) at rt. After 30 min of
stirring, the reaction mixture was extracted with saturated aqueous NaCl/
ethyl acetate, and the organic layer was dried over Na2SO4 and
evaporated. Purification of the residue by flash chromatography (SiO2,
hexane/ethyl acetate ) 2/1 f 1/1) afforded lactone 10 (338 mg, 63%,
mixture of diastereoisomers) as a colorless foam. 1H NMR (400 MHz,
CD2Cl2): δ 7.94-7.84 (m, 2H), 7.73-7.69 (m, 1H), 7.61-7.55 (m,
2H), 5.77-5.69 (m, 1H), 5.08 (dd, J ) 13.3, 1.6 Hz), 4.98-4.84 (m),
4.73-4.69 (m), 4.58-4.45 (m), 4.36 (td, J ) 9.5, 3.2 Hz) [3H], 3.92
(dd, J ) 16.3, 2.6 Hz), 3.75-3.72 (m), 3.53-3.45 (m), 3.42-3.32 (m)
3.02 (dd, J ) 16.1, 2.8 Hz), 2.81-2.72 (m) [2H], 2.07-0.89 (m, 17H).
Pyrone 17. A solution of Pd(PPH3)4 (23 mg, 0.02 mmol) in THF
(1 mL) and ketone 11 (50 mg, 0.13 mmol) were successively added to
a solution of TsNHK (33 mg, 0.16 mmol) and TsNH2 (2 mg, 0.01
mmol) in THF (9 mL) and DMSO (2 mL). The mixture was stirred at
rt for 24 h, the reaction was quenched with aqueous saturated NaHCO3,

2824 J. Am. Chem. Soc., Vol. 120, No. 12, 1998
Fu¨rstner and Weintritt
the aqueous layer was extracted with ether, the combined organic layers
were dried (Na2SO4), and evaporated, and the crude product was
purified by flash chromatography (hexane/ethyl actetate 4/1) to afford
pure 17 as a pale yellow solid (12 mg, 37%). 1H NMR (400 MHz,
CDCl3): δ 7.33 (m, 1H), 6.99 (m, 1H), 3.25 (s, 2H), 2.54-2.48 (m,
4H), 1.69-1.57 (m, 4H), 1.25-1.03 (m, 8H). 13C NMR (100 MHz,
CDCl3): δ 208.1, 162.3, 147.3, 139.4, 129.5, 113.1, 43.5, 42.1, 29.1,
26.1, 25.9, 25.7, 24.9, 23.7, 23.2.
substrate 2a (18 mg). 1H NMR (400 MHz, CD2Cl2): δ 10.52 (br s,
1H), 6.00 (d, J ) 1.6 Hz, 1H), 2.89-2.83 (m, 1H), 2.72 (vt, J ) 4.2
Hz, 1H), 2.63 (d, J ) 6.7 Hz, 1H), 2.61-2.55 (m, 1H), 1.89-1.74 (m,
4H), 1.36-1.19 (m, 4H), 1.04-0.81 (m, 5H), 1.01 (d, J ) 6.6 Hz,
3H), 0.89 (d, J ) 6.7 Hz, 3H), 0.45-0.42 (m, 2H). 13C NMR (100
MHz, THF-d8): δ 192.7, 154.9, 147.6, 136.1, 107.4, 59.9, 49.4, 34.5,
32.9, 29.53, 29.46, 29.0, 28.8, 28.5, 26.9, 26.3, 22.1, 20.5. MS: m/z
(rel intensity) 274 (22), 273 ([M+], 100), 258 (35), 231 (25), 230 (37),
202 (14).
Macrotricycle 14. 1-(N,N-dimethylamino)-1-chloro-2-methylprop-
1-ene (13) (92 mg, 0.69 mmol) in CH2Cl2 (2 mL) was added to a
solution of acid 12 (300 mg, 0.63 mmol) in CH2Cl2 (35 mL) at rt.
After 2 h of stirring, the solvent was removed in vacuo (10-2 mbar) at
rt, and the resulting oil was dried for 2 h. The acid chloride thus
obtained was dissolved in refluxing 1,2-dichloroethane (40 mL) and
treated dropwise with SnCl4 (82 µL, 0.7 mmol) via syringe. After 1 h
of reaction time, the solution was cooled to rt, extracted with aqueous
saturated NaHCO3/CH2Cl2, and the organic layer was dried over
Na2SO4 and evaporated. Purification of the residue by flash chromato-
graphy (SiO2, hexane/ethyl acetate ) 6/1) afforded keto pyrrole 14
(222 mg, 76%) as a colorless foam. 1H NMR (300 MHz, CD2Cl2): δ
7.98-7.94 (m, 2H), 7.67-7.61 (m, 1H), 7.55-7.49 (m, 2H), 7.35-
7.28 (m, 3H), 7.15-7.12 (m, 2H), 6.03 (s, 1H), 5.59 (d, J ) 15.3 Hz,
1H), 4.96 (d, J ) 15.3 Hz, 1H), 3.51 (d, J ) 16.4 Hz, 1H), 2.90 (d, J
) 16.4 Hz, 1H), 2.75-2.55 (m, 2H), 2.23-2.12 (m, 2H), 1.81-1.73
(m, 1H), 1.49-1.44 (m, 1H), 1.28-1.09 (m, 3H), 0.96-0.83 (m, 4H),
0.77-0.68 (m, 2H), 0.44-0.39 (m, 1H). 13C NMR (75 MHz, CD2-
Cl2): δ 182.3, 150.3, 149.0, 137.4, 137.1, 133.7, 130.8, 128.8, 128.6,
127.9, 127.1, 108.1, 82.2, 47.9, 31.9, 29.8, 28.0, 27.5, 27.3, 26.4, 25.2,
24.7. MS: m/z (rel intensity) 461 ([M+], 25), 321 (14), 320 (65), 319
(80), 91 (100). IR (KBr): 2928, 2856, 1680, 1623, 1484, 1457, 1446,
1391, 1301, 1261, 1143, 1084, 720, 689 cm-1. HRMS (C28H31NO3S):
calcd 461.20247; found 461.19802.
Macrotricycle 2c. A solution of compound 2b (11 mg, 0.04 mmol)
in DMF (1.5 mL) was added to KH (3.2 mg, 0.08 mmol) at rt. After
5 min of stirring, SEMCl (14 µL, 0.08 mmol) was introduced, and the
mixture was stirred for an additional 45 min and extracted with 5%
Na2CO3/ether. The organic layer was dried over Na2SO4 and evapo-
rated, and the residue was purified by flash chromatography (SiO2,
hexane/ethyl acetate ) 15/1) affording 2c (13 mg, 81%) as a colorless
oil. 1H NMR (200 MHz, CD2Cl2): δ 6.01 (s, 1H), 5.63 (d, J ) 10.7
Hz, 1H), 5.29 (d, J ) 10.7 Hz, 1H), 3.65-3.45 (m, 2H), 2.77-2.60
(m, 4H), 1.85-1.50 (m, 5H), 1.25-0.45 (m, 12H), 0.99 (d, J ) 6.6
Hz, 3H), 0.87 (d, J ) 6.7 Hz, 3H), -0.05 (s, 9H). 13C NMR (75 MHz,
CD2Cl2): δ 193.5, 154.2, 147.4, 140.7, 109.7, 72.5, 65.8, 59.4, 48.3,
33.2, 31.8, 28.2, 27.6, 27.5, 27.2, 25.5, 25.1, 25.0, 21.2, 19.5, 17.8,
-1.7. MS: m/z (rel intensity) 302 (10), 288 (23), 287 (100), 259 (15),
244 (20), 73 (41). HRMS (C24H41NO2Si): calcd 403.29066; found
403.29082.
5-Bromo-4-chloro-1-(toluene-4-sulfonyl)-1H-pyrrole-2-carboxy-
lic Acid Methyl Ester (27). To a solution of 26 (2.905 g, 18.2 mmol)
in acetic acid (60 mL) was added dropwise a solution of bromine (1.03
mL, 20.0 mmol) in acetic acid (20 mL) at rt. The resulting mixture
was stirred at 60 °C for 15 min, cooled to rt, poured into water, and
extracted with ether. The organic layer was neutralized with aqueous
saturated NaHCO3, dried over Na2SO4, and evaporated, and the residue
was purified by flash chromatography (SiO2, hexane/ethyl acetate )
10/1) thus affording 27 (3.911 g, 90%) as colorless crystals. 1H NMR
(300 MHz, CDCl3): δ 9.89 (br s, 1H), 6.80 (d, J ) 3.0 Hz, 1H), 3.87
(s, 3H). 13C NMR (75 MHz, CDCl3): δ 160.5, 122.6, 115.3, 115.0,
104.6, 52.1. Anal. Calcd for C6H5BrClNO2: C, 36.22; H, 2.11; N,
5.87. Found: C, 30.28; H, 2.06; N, 5.84.
2-Bromo-3-chloro-1-(toluene-4-sulfonyl)-1H-pyrrole (28). Pyrrole
27 (3.170 g, 13.3 mmol) was stirred with a solution of NaOH (4.3 g,
0.11 mol) in water (65 mL) at 70 °C for 3 h. After cooling to rt, the
solution was extracted with ether, and the aqueous layer was acidified
to pH ≈1 with 10% HCl and extracted with ether. The organic layer
was dried over Na2SO4, and the solvent evaporated affording the crude
acid as pale purple solid (2.764 g, 93%). The crude acid (2.359 g,
10.5 mmol) was heated with copper chromite (329 mg, 1.05 mmol) in
quinoline (13 mL) to 180 °C under argon for 30 min, the resulting
suspension was cooled to rt, diluted with ether, and filtered through a
short pad of silica, and the residues were washed with ether. The
combined organic layers were extracted twice with 10% HCl, neutral-
ized with NaHCO3, dried over Na2SO4, and concentrated at rt in vacuo
to a volume of approximately 15 mL. To the dark brown solution
were added acetonitrile (100 mL), Et3N (3.25 mL, 23.2 mmol),
4-(dimethylamino)pyridine (DMAP) (cat.), and tosyl chloride (2.212
g, 11.6 mmol), and the mixture was stirred at rt for 16 h. After
extraction with CH2Cl2/10% HCl, the organic layer was stirred with
NaHCO3 (sat.) for 45 min, dried over Na2SO4 and evaporated.
Purification of the residue by flash chromatography (SiO2, hexane/
ethyl acetate ) 10/1) furnished 28 (2.347 g, 67%, 62% overall yield)
as colorless crystals. 1H NMR (200 MHz, CDCl3): δ 7.80 (d, J ) 8.5
Hz, 2H), 7.46 (d, J ) 3.8 Hz, 1H), 7.31 (d, J ) 8.1 Hz, 2H), 6.30 (d,
J ) 3.7 Hz, 1H), 2.42 (s, 3H). 13C NMR (50 MHz, CDCl3): δ 146.0,
134.5, 130.0, 128.0, 127.9, 123.2, 112.7, 99.2, 21.7. HRMS
(C11H9BrClNO2S): calcd 332.92260; found 332.92372.
Macrotricyle 2a. To a solution of ZnCl2‚TMEDA (394 mg, 1.56
mmol) in THF (60 mL) was added MeLi (1950 µL, 3.12 mmol, 1.5 M
in ether) at 0 °C, and the solution was stirred for 15 min. i-PrMgCl
(780 µL, 1.56 mmol, 2 M in THF) was then introduced, and the
resulting solution was stirred for an additional 5 min prior to the addition
of a solution of sulfone 14 (60 mg, 0.13 mmol) in THF (3 mL). After
the reaction was warmed to ambient temperature, a solution of t-BuOK
(875 mg, 8.00 mmol) in THF (10 mL) was added, and the resulting
mixture was stirred for 2 h. A standard extractive workup followed
by flash chromatography (SiO2, hexane/ethyl acetate ) 20/1) afforded
product 2a (24 mg, 51%) as a colorless oil. 1H NMR (600 MHz, CD2-
Cl2): δ 7.32-7.29 (m, 2H), 7.27-7.24 (m, 1H), 7.20-7.18 (m, 2H),
6.00 (s, 1H), 5.67 (d, J ) 15.6 Hz, 1H), 4.98 (d, J ) 15.6 Hz, 1H),
2.70-2.65 (m, 2H), 2.63 (d, J ) 6.6 Hz, 1H), 2.62-2.57 (m, 1H),
1.98-1.93 (m, 1H), 1.81-1.68 (m, 3H), 1.55-1.48 (m, 1H), 1.26-
1.21 (m, 1H), 1.11-0.99 (m, 3H), 1.00 (d, J ) 6.7 Hz, 3H), 0.94-
0.89 (m, 3H), 0.88 (d, J ) 6.7 Hz, 3H), 0.78-0.69 (m, 2H), 0.61-
0.55 (m, 1H). 13C NMR (150 MHz, CD2Cl2): δ 193.41 (s), 153.87
(s), 146.72 (s), 138.40 (s), 134.87 (s), 128.74 (d), 127.55 (d), 126.90
(d), 109.13 (d), 59.44 (d), 48.39 (d), 47.67 (t), 33.28 (d), 31.82 (t),
28.17 (t), 27.73 (t), 27.44 (t), 27.18 (t), 25.46 (t), 25.16 (t), 25.06 (t),
21.20 (q), 19.68 (q). MS: m/z (rel intensity) 364 (29), 363 ([M+],
100), 348 (16), 321 (36), 320 (58), 91 (84). IR (KBr): 3064, 3031,
2929, 2856, 1673, 1496, 1473, 1456, 1391, 1260, 723, 697 cm-1
HRMS (C25H33NO): calcd 363.25621; found 363.25401.
.
Compound 2b. To a solution of calcium (20 mg, 0.5 mmol) in
liquid ammonia (5 mL) was added a solution of 2a (58 mg, 0.16 mmol)
in THF (2 mL) at -30 °C. The dry ice/acetone bath was removed,
and the resulting mixture was stirred for 2 h in refluxing ammonia
using a dry ice condenser. The solution was diluted with THF (5 mL),
slowly warmed to rt, carefully hydrolyzed with aqueous saturated
NH4Cl, and extracted with ether. The organic layer was dried over
Na2SO4, concentrated to a small volume, diluted with CH2Cl2 (10 mL),
and treated with pyridinium dichromate (PDC, 126 mg, 0.34 mmol).
After 1 h of stirring at rt, the reaction mixture was extracted with
CH2Cl2/H2O, the organic layer was washed with 10% HCl and aqueous
saturated NaHCO3 and evaporated, and the residue purified by flash
chromatography (SiO2, hexane/ethyl acetate ) 4/1) affording 2b2c (15
mg, 50% based on 69% conversion) as colorless oil and unreacted
4-((tert-Butyldimethylsilyl)oxy)-3,3-dimethoxybutanoic Acid (25a).
4-Methoxyfuran-2(5H)-one 24 (4.00 g, 35.1 mmol) was refluxed with
a solution of NaOH (1.67 g, 41.8 mmol) in MeOH (40 mL) for 16 h.
The solvent was removed at rt in vacuo, the residue was suspended in
DMF (120 mL), TBDMSCl (18.4 g, 0.12 mol) and imidazole (16.6 g,
0.24 mol) were added, and the suspension was stirred for 3 d at rt. The
mixture was poured into water and extracted with ether, the organic

Total Synthesis of Roseophilin
J. Am. Chem. Soc., Vol. 120, No. 12, 1998 2825
layer was dried over Na2SO4, the solvent was evaporated, and the
residue was purified by flash chromatography (SiO2, hexane/ethyl
acetate ) 30/1). The resulting disilylated compound (8.13 g, 20.7
mmol, colorless oil) was dissolved in MeOH/THF/H2O (3/1/1, 330 mL)
and stirred with K2CO3 (10.2 g, 73.9 mmol) at rt for 30 min. The
mixture was concentrated to about 70 mL and extracted with ether (ca.
30 mL), and the aqueous layer was diluted with brine (200 mL),
acidified with 1 M KHSO4 to pH ≈ 4, and extracted with ether. Drying
of the organic layer over Na2SO4 and evaporation of the solvent afforded
pure acid 25a (5.06 g, 52%) as a colorless oil. 1H NMR (200 MHz,
CDCl3): δ 3.69 (s, 2H), 3.26 (s, 6H), 2.77 (s, 2H), 0.88 (s, 9H), 0.06
(s, 6H). 13C NMR (50 MHz, CDCl3): δ 173.0, 100.8, 62.4, 48.5, 38.5,
25.7, 18.2, -5.7. Anal. Calcd for C12H26O2Si: C, 51.77; H, 9.41.
Found: C, 51.64; H, 9.36.
Keto Pyrrole 29. To a solution of acid 25a (147 mg, 0.53 mmol)
in CH2Cl2 (5 mL) was added a solution of 1-N,N-(dimethylamino)-1-
chloro-2-methyl-1-propene (13) (74 mg, 0.55 mmol)17 in CH2Cl2
(1 mL) under argon. The mixture was stirred at rt for 1.5 h, the solvent
was removed in vacuo at rt and the resulting crude acid chloride 25b
was dissolved in THF (5 mL).
Hz, 18H). 13C NMR (50 MHz, THF-d8): δ 152.7, 145.4, 127.6, 124.7,
123.4, 117.7, 111.9, 106.5, 58.4, 19.0, 13.9. HRMS (C18H28ClNO2-
Si): calcd 353.15779; found 353.15697.
Roseophilin‚HCl (1). To a solution of pyrrolylfuran 3b (47 mg,
0.133 mmol) in THF (1.5 mL) was added n-BuLi (83 µL, 0.133 mmol,
1.6 M in hexane) at -50 °C. After 5 h of stirring at this temperature,
this solution was added via cannula to a suspension of dry CeCl3 (33
mg, 0.133 mmol) in THF (1.5 mL) at -78 °C, which had been stirred
for 5 h at rt prior to use. After 2 h at -78 °C, a solution of 2c (13 mg,
0.032 mmol) in THF (3 mL) was introduced, and the suspension was
allowed to warm to rt overnight. The mixture was extracted with
aqueous saturated NH4Cl/ether, the organic layer was dried over Na2-
SO4 and evaporated, and the residue was purified by flash chromatog-
raphy (Al2O3 (neutral), hexane/ethyl acetate ) 40/1f20/1) affording
30 (15 mg, 62%) as nearly colorless oil which was used without further
characterization.
To a solution of 30 (15 mg, 0.02 mmol) in THF (2.5 mL) was added
TBAF (0.08 mL, 0.08 mmol, 1 M in THF). After 10 min of stirring,
the mixture was heated to 60 °C for additional 45 min, cooled to rt,
and extracted with 5% Na2CO3/ether. The organic layer was treated
with several drops of 10% HCl for 5 min, neutralized with 5% Na2-
CO3, dried over Na2SO4, and evaporated. The residue was purified by
flash chromatography (Al2O3 (neutral), hexane/ethyl acetate ) 1.5/1),
and the combined fractions were treated with HCl (1.1 M in THF)
after concentration to a small volume. Removal of the solvent afforded
analytically pure 1 (7.4 mg, 76%) as red salt. Its spectroscopic data
are in full agreement with those reported in the literature and with those
To a solution of pyrrole 28 (146 mg, 0.44 mmol) in THF (5 mL)
was added n-BuLi (1.6 M in hexane, 175 µL, 0.44 mmol) via syringe
at -78 °C under argon. After 30 min of stirring at this temperature,
this solution was added to dry ZnCl2 (60 mg, 0.44 mmol) in THF
(5 mL) via cannula at -78 °C, and the resulting mixture was stirred at
0 °C for 1 h. Pd(PPh3)4 (25 mg, 0.02 mmol) in THF (1 mL) and the
solution of the crude 25b were successively added at rt, and the mixture
was stirred for 3 h. After extraction with aqueous saturated NH4Cl/
ether, the organic layer was dried over Na2SO4, the solvent was
evaporated, and the residue was purified by flash chromatography (SiO2,
hexane/ethyl acetate ) 20/1) affording 29 (138 mg, 61%) as a yellow
oil. 1H NMR (200 MHz, CDCl3): δ 7.86 (d, J ) 8.5 Hz, 2H), 7.51
(d, J ) 3.5 Hz, 1H), 7.29 (d, J ) 8.6 Hz, 2H), 6.23 (d, J ) 3.4 Hz,
1H), 3.74 (s, 2H), 3.38 (s, 2H), 3.20 (s, 6H), 2.40 (s, 3H), 0.83 (s, 9H),
-0.01 (s, 6H). 13C NMR (50 MHz, CDCl3): δ 187.6, 145.1, 135.8,
130.4, 129.4, 128.4, 126.4, 122.2, 112.7, 101.7, 61.3, 48.2, 42.9, 25.8,
21.7, 18.2, -5.6. Anal. Calcd for C23H34ClNO6SSi: C, 53.52; H, 6.64;
N, 2.71. Found: C, 53.42; H, 6.61; N, 2.78.
1
of an authentic sample. H NMR (600 MHz, CDCl3): δ 13.89 (br s,
1H), 13.66 (br s, 1H), 7.26 (vt, J ) 3.1 Hz, 1H), 6.93 (s, 1H), 6.29 (vt,
J ) 2.5 Hz, 1H), 6.19 (s, 1H), 4.14 (s, 3H), 3.83 (dd, J ) 4.8, 3.2 Hz,
1H), 3.59 (ddd, J ) 13.1, 11.0, 6.2 Hz, 1H), 2.84 (ddd, J ) 13.0, 5.6,
3.8 Hz, 1H), 2.71 (d, J ) 6.3 Hz, 1H), 2.10 (m, 1H), 2.02 (m, 1H),
1.81 (m, 2H), 1.33 (m, 2H), 1.20 (m, 1H), 1.01 (m, 2H), 1.00 (d, J )
6.7 Hz, 3H), 0.92 (m, 2H), 0.80 (m, 2H), 0.79 (d, J ) 6.7 Hz, 3H),
0.41 (m, 2H). 13C NMR (150 MHz, CDCl3): δ 166.7 (s), 166.0 (s),
160.3 (s), 159.3 (s), 144.7 (s), 135.7 (s), 132.9 (s), 126.8 (d), 119.5
(s), 116.8 (s), 112.1 (d), 110.9 (d), 96.3 (d), 60.0 (q), 55.5 (d), 51.6
(d), 34.1 (t), 33.1 (d), 28.25 (t), 28.2 (t), 27.9 (t), 27.5 (t), 26.9 (t),
24.9 (t), 24.4 (t), 21.4 (q), 19.6 (q). MS (ESI/pos): m/z (rel intensity)
453.2 ([M + H+], 100).
3-Chloro-2-(4-methoxyfuran-2-yl)-1-tosyl-1H-pyrrole (3a).2a
A
solution of compound 29 (527 mg, 1.02 mmol) and pyridinium
p-toluenesulfonate (109 mg, 0.43 mmol) in MeOH (5 mL) was stirred
at 55 °C for 14 h. For workup, the mixture was extracted with H2O/
ether, the organic layer was dried over Na2SO4 and evaporated, and
the residue was purified by flash chromatography (SiO2, hexane/ethyl
acetate ) 10/1) affording 3a (273 mg, 76%) as a yellow oil. 1H NMR
(200 MHz, THF-d8): δ 7.60 (d, J ) 8.4 Hz, 2H), 7.50 (d, J ) 3.5 Hz,
1H), 7.33 (d, J ) 8.1 Hz, 2H), 7.27 (d, J ) 1.1 Hz, 1H), 6.37 (d, J )
3.6 Hz, 1H), 6.32 (d, J ) 1.1 Hz, 1H), 3.72 (s, 3H), 2.39 (s, 3H).
3-Chloro-2-(4-methoxyfuran-2-yl)-1-(triisopropylsilyl)-1H-pyr-
role (3b). A solution of 3a (436 mg, 1.24 mmol) in MeOH (16 mL)
was stirred with K2CO3 (379 mg, 2.75 mmol) for 24 h. The reaction
mixture was extracted with brine/ether, and the organic layer was dried
over Na2SO4, concentrated to a small volume, and purified by flash
chromatography (SiO2, hexane/ethyl acetate ) 6/1), providing the
unprotected side chain as colorless solid (195 mg, 0.99 mmol). KH
(44 mg, 1.09 mmol) was added to a solution of this fairly labile
compound in THF (20 mL) at 0 °C, followed by TIPSCl (233 µL,
1.09 mmol). After 30 min of stirring, the solution was extracted with
aqueous saturated NH4Cl/ether, and the organic layer was extracted
with aqueous saturated NaHCO3, dried over Na2SO4, and evaporated.
Purification of the residue by flash chromatography (SiO2, hexane/
ethyl acetate ) 25/1) afforded 3b (271 mg, 62% overall yield) as a
colorless syrup. 1H NMR (200 MHz, THF-d8): δ 7.27 (d, J ) 1.1
Hz, 1H), 6.93 (d, J ) 3.1 Hz, 1H), 6.34 (d, J ) 1.1 Hz, 1H), 6.26 (d,
J ) 3.0 Hz, 1H), 3.71 (s, 3H), 1.41-1.23 (m, 3H), 1.09 (d, J ) 6.9
Separation of Enantiomers of 1. The semipreparative HPLC
separation of 1 has been carried out on a Shimadzu LC-10A apparatus
using a Chiraspher column (250 mm, i.d. 4.6 mm) with n-heptane/2-
propanol/triethylamine ) 80/20/0.1 as the eluent (flow rate 0.5 mL/
min; T ) 293 K; pressure ) 2.5 Mpa; detection: DAD, 300 nm)
affording the enantiomers of 1 as free base each.
Acknowledgment. We thank Prof. H. Seto, University of
Tokyo, for kindly providing an authentic sample of roseophilin
and Dr. S. Terashima, Sagami Chemical Research Center, for
an exchange of information. H.W. is indebted to the Fonds der
Chemischen Industrie, Frankfurt, for a stipend. We thank Mr.
A. Deege and Ms. H. Hinrichs, Mu¨lheim, for performing the
HPLC separation.
Supporting Information Available: Compilation of the MS
and IR data of compounds 3b, 5-7, 17, 25a, 27-29; copies of
the NMR spectra of the side chain 3b and of roseophilin 1;
HPLC plot of the separation of the enantiomers of 1 and
comparison with the natural product (8 pages). See any current
masthead page for ordering information and Web access
instructions.
JA973846K