Enantioselective formal total synthesis of roseophilin.

Article abstract of DOI:10.1021/ol005750s

[formula: see text] An enantioselective formal total synthesis of roseophilin 3 is presented. The 13-membered ring of macrotricycle 1 was formed via an efficient ring-closing metathesis reaction of bicycle 4. A palladium-catalyzed methoxycarbonylation rea

Full text of DOI:10.1021/ol005750s

ORGANIC
LETTERS
2000
Vol. 2, No. 8
1157-1160
Enantioselective Formal Total Synthesis
of Roseophilin
Samantha J. Bamford, Tim Luker, W. Nico Speckamp, and Henk Hiemstra*
Laboratory of Organic Chemistry, Institute of Molecular Chemistry, UniVersity of
Amsterdam, Nieuwe Achtergracht 129, 1018 WS Amsterdam, The Netherlands
henkh@org.chem.uVa.nl
Received March 3, 2000
ABSTRACT
An enantioselective formal total synthesis of roseophilin 3 is presented. The 13-membered ring of macrotricycle 1 was formed via an efficient
ring-closing metathesis reaction of bicycle 4. A palladium-catalyzed methoxycarbonylation reaction of enol triflate 5 was utilized to functionalize
the right-hand ring of bicycle 2. The allyl substituent was introduced by a radical allylation of r-bromoketone 17.
Roseophilin 3 possesses a unique pentacyclic structure,
consisting of a substituted pyrroylfuran unit attached to an
ansa-bridged azafulvene core. This novel antibiotic was
isolated from the culture broth of Streptomyces griseoVirdis
and was shown to exhibit submicromolar cytotoxicity against
several human cancer cell lines.1 Since its isolation in 1992,
roseophilin 3 has attracted considerable synthetic attention,
resulting in a total synthesis by Fu¨rstner et al. and several
syntheses of the macrotricyclic core 1.2 However, all the
reported approaches toward roseophilin 3 as yet have been
racemic. Herein we wish to describe our enantioselective
route to the macrotricyclic core 1.
The work of Fu¨rstner et al. has demonstrated the viability
of the initial disconnection in our retrosynthetic analysis, and
as such a synthesis of macrotricycle 1 constitutes a formal
total synthesis of roseophilin 3 (Scheme 1). We planned to
form the 13-membered ring by a ring-closing metathesis
(RCM) reaction of triene 4, as we had obtained encouraging
results in forming medium-size bridged ring systems using
RCM in our model studies.3 Specifically, we had found that
the presence of a phenyl sulfone directing group provided
good results in obtaining even relatively strained ring
systems. RCM has been employed in several appoaches to
1.2d,2g,2i,4
Lactam-derived enol triflate 5 would be employed to
functionalize the right-hand ring of the chiral nonracemic
bicyclic unit. Previous work in our group has described the
synthesis of bicycle 2 from (R)-1-acetyl-5-isopropoxy-3-
pyrrolin-2-one 6.5 Following a recently reported procedure,
we can now readily obtain multigram quantities of this chiral
building block.6 (S)-1-Acetyl-5-isopropoxy-3-pyrrolin-2-one
is also readily available and would allow the synthesis of
the enantiomer of 3.
Initially, we wished to functionalize the right-hand ring
of bicycle 2, and this was accomplished using methodology
previously developed in our group, namely, the use of lactam-
(1) Hayakawa, Y.; Kawakami, K.; Seto, H.; Furihati, K. Tetrahedron
Lett. 1992, 33, 2701.
(2) (a) Nakatani, S.; Kirihara, M.; Yamada, K.; Terashima, S. Tetrahedron
Lett. 1995, 36, 8461. (b) Mochizuki, T.; Itoh, E.; Shibata, N.; Nakatani, S.;
Katoh, T.; Terashima, S. Tetrahedron Lett. 1998, 39, 6911. (c) Kim, S. H.;
Fuchs, P. L. Tetrahedron Lett. 1996, 37, 2545. (d) Kim, S. H.; Figueroa,
I.; Fuchs, P. L. Tetrahedron Lett. 1997, 38, 2601. (e) Fu¨rstner, A.; Weintritt,
H. J. Am. Chem. Soc. 1997, 119, 2944. (f) Fu¨rstner, A.; Weintritt, H. J.
Am. Chem. Soc. 1998, 120, 2817. (g) Fu¨rstner, A.; Gastner, T.; Weintritt,
H. J. Org. Chem. 1999, 64, 2361. (h) Fagan, M. A.; Knight, D. W.
Tetrahedron Lett. 1999, 40, 6117. (i) Harrington, P. E.; Tius, M. A. Org.
Lett. 1999, 1, 649. (j) Robertson, J.; Hatley, R. J. D. Chem. Commun. 1999,
1455.
(3) Bamford, S. J.; Goubitz, K.; van Lingen, H.; Luker, T.; Hiemstra,
H.; Schenk, H. J. Chem. Soc., Perkin Trans. 1 2000, 345.
(4) For RCM reviews, see: (a) Grubbs, R. H.; Chang, S. Tetrahedron
1998, 54, 4413. (b) Fu¨rstner, A.; Langemann, K. Synthesis 1997, 792. (c)
Armstrong, S. A. J. Chem. Soc., Perkin Trans. 1 1998, 371.
(5) Luker, T.; Koot, W.-J.; Hiemstra, H.; Speckamp, W. N. J. Org. Chem.
1998, 63, 220.
(6) (a) Cuiper, A. D.; Kellogg, R. M.; Feringa, B. L. Chem. Commun.
1998, 655. (b) van der Deen, H.; Cuiper, A. D.; Hof, R. P.; van Oeveren,
A.; Feringa, B. L.; Kellogg, R. M. J. Am. Chem. Soc. 1996, 118, 3801.
10.1021/ol005750s CCC: $19.00 © 2000 American Chemical Society
Published on Web 03/30/2000

Scheme 1. Retrosynthetic Analysis of Roseophilin 3
derived enol triflates.7 1,3-Dioxolane protection of R,â-
performed, followed by protection of the ketone, then triflate
5 could be formed in excellent yield and with full conversion.
Protection of ketone 9 as a 1,3-dioxolane and subjection to
the triflation conditions also gave the corresponding triflate,
but subsequent problems were encountered on attempting
to remove this protecting group.
unsaturated ketone 2, followed by deprotonation and reaction
with 2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropy-
ridine (Comins’ reagent), gave none of the desired triflate 8
(Scheme 2).8 Interestingly, the diphenylenolphosphate of 7
Palladium-catalyzed methoxycarbonylation of triflate 5
gave ester 11 in good yield (Scheme 3). To achieve full
conversion of the triflate to ester 11 during the carbonylation
reaction, thus preventing recovery of lactam 10 and subse-
quent separation problems, this reaction was carried out under
20 atm of carbon monoxide. Standard conditions were then
used to convert ester 11 into sulfone 14 (mp ) 122 °C; [R]D
+131.5, c 1.3, CHCl3). Alkylation of sulfone 14 led to the
isolation of a single diastereomer. The stereochemistry of
the alkylation product is assigned on the basis that a “chiral
relay effect” is operating, as was encountered in our model
studies.3,10 These studies also demonstrated that this config-
uration was essential in bringing about a successful RCM
reaction.
Scheme 2. Formation of Enol Triflate 5a
Removal of the dimethylacetal protecting gave ketone 16,
which then had to be allylated to form the RCM substrate.
Attempts to deprotonate 16 and alkylate with allyl bromide
or allyl iodide were unsuccessful and led to pyrrole formation
via elimination of the p-toluenesulfonyl group (see below)
and to epimerization at the carbon bearing the phenylsulfonyl
group. Also, attempts to form the silyl enol ether at the least
hindered side of the ketone met with failure. Gratifyingly,
R-bromination of ketone 16 using copper(II) bromide gave
a good yield of R-bromoketone 17, as a 1:1 mixture of
diastereomers at the bromine-bearing carbon, which we
planned to use in a radical reaction to introduce the allyl
group.11 Indeed, radical allylation of 17 at 100 °C provided
a moderate yield of the RCM precursor 4 ([R]D +36.9, c
0.65, CHCl3) as a single diastereomer possessing the desired
trans relationship between the allyl and isopropyl substituents
of the five-membered ring.12 The trans stereochemistry was
established by an NOE experiment performed on the
a Key: (a) (TMSOCH2)2, TMSOTf, DCM, -20 °C, 16 h, 88%;
(b) KHMDS, THF, HMPA, -78 °C; Comins’ reagent; (c) CuI,
BF3.Et2O, i-PrMgCl, THF, -78 °C, 83%; (d) HC(OMe)3, MeOH,
TsOH, 98%.
could be readily formed, but attempts to perform a palladium-
catalyzed methoxycarbonylation reaction on this enolphos-
phate, under a range of conditions, were unsuccessful.9
However, if the 1,4-isopropylcuprate addition was first
(7) (a) Luker, T.; Hiemstra, H.; Speckamp, W. N. Tetrahedron Lett. 1996,
37, 8257. (b) Luker, T.; Hiemstra, H.; Speckamp, W. N. J. Org. Chem.
1997, 62, 3592. (c) Luker, T.; Hiemstra, H.; Speckamp, W. N. J. Org. Chem.
1997, 62, 8131.
(8) Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.
(9) Nicolaou, K. C.; Shi, G.-Q.; Namoto, K.; Bernal, F. Chem. Commun.
1998, 1757.
(10) Bull, S. D.; Davies, S. G.; Fox, D. J.; Sellers, T. G. R. Tetrahedron:
Asymmetry 1998, 9, 1483.
(11) (a) Matsumoto, M.; Ishida, Y.; Watanabe, N. Heterocycles 1985,
23, 165. (b) Kochi, J. K. J. Am. Chem. Soc. 1955, 77, 5274.
1158
Org. Lett., Vol. 2, No. 8, 2000

Scheme 3. Attachment of Substituents to Left-and Right-Hand Ring of Bicyclea
a Key: (a) Pd2(dba)3, AsPh3, CO (20 atm), LiCl, Et3N, MeCN, 50 °C, 71% over two steps; (b) DIBALH, THF, 78%; (c) PPh3, imidazole,
I2, Et2O, MeCN, 96%; (d) PhSO2Na, DMF, HMPA, 95%; (e) n-BuLi, HMPA, THF, -78 °C; 1-bromohex-5-ene, 65%; (f) HCl (2 M),
acetone, 60 °C, 99%; (g) CuBr2, EtOAc, 50 °C, 92%; (h) allyltributyltin, AIBN, toluene, 100 °C, 52%; (i) H2, PtO2, EtOAc, 75%.
hydrogenated compound 18, in which a 2.4% NOE enhance-
ment was observed between the protons adjacent to the
ketone functionality, illustrating their cis relationship in the
five-membered ring (Scheme 3).
macrocyclic product 19, as a 3:1 mixture of double bond
isomers. The RCM reaction is particularly favorable due to
the conformationally biasing effect of the sulfone substituent
and the rigid concave shape of the bicyclic core, both factors
which operate to bring the reacting terminal diene moieties
into close proximity.2d,3 Surprisingly, hydrogenation of the
RCM product 19 gave rise to a compound which was
unstable and could not be further transformed to 1. Reaction
of 19 with oxidizing agents such as N-iodosuccinimide or
2,3-dichloro-5,6-dicyano-1,4-benzoquinone failed to provide
the protected pyrrole. However, on treatment of the RCM
product 19 with sodium bis(trimethylsilyl)amide R-keto
deprotonation took place, with subsequent elimation of the
p-toluenesulfonyl group and rearrangement to pyrrole 20.13
Removal of the sulfone group with sodium amalgam and
hydrogenation with a platinum(IV) oxide catalyst gave the
ketopyrrole macrotricycle (-)-1 ([R]D -32.0, c 1.0, CHCl3).
The spectroscopic data for (-)-1 match those previously
reported in the literature for the racemic compound.2
Triene 4 was treated with 10 mol % of Grubbs’ catalyst
in dichloromethane at 40 °C for 16 h, at a concentration of
1 mM (Scheme 4).4a This provided an excellent yield of the
Scheme 4. Ring-Closing Metathesis and Formation of 1a
In summary, we have completed an enantioselective formal
total synthesis of roseophilin 3, which can be used to form
either enantiomer of the natural product. The versatile
synthesis could be readily adapted to produce analogues of
(12) (a) Stack, J. G.; Curran, D. P.; Geib, S. V.; Rebek Jr., J.; Ballester,
P. J. Am. Chem. Soc. 1992, 114, 7007. (b) Keck, G. E.; Enholm, E. J.;
Yates, J. B.; Wiley, M. R. Tetrahedron 1985, 41, 4079.
(13) Fu¨rstner, A.; Szillat, H.; Gabor, B.; Mynott, R. J. Am. Chem. Soc.
1998, 120. 8305.
a Key: (a) 10 mol % (Cy3P)2Cl2RudCHPh, CH2Cl2, 40 °C, 16
h, 91%; (b) NaHMDS, THF, -78 °C, 71%; (c) 6% Na(Hg),
Na2HPO4, THF, MeOH, 0 °C, 90%; (d) PtO2, H2, EtOAc, 99%.
Org. Lett., Vol. 2, No. 8, 2000
1159

the natural product, particularly in modifying the length of
the ansa-bridge by alkylation of sulfone 14 with various alkyl
halides.
Acknowledgment. For financial support of this work we
thank The Royal 1851 Commission (S.J.B.) and The
European Union (TMR fellowship, T.L.).
Conversion of macrotricycle 1 to the roseophilin structure
and comparison of synthetic material with the natural product
will allow the determination of the absolute configuration
of naturally occurring roseophilin 3, which has yet to be
illucidated. Details of these studies will be reported at a later
date.
Supporting Information Available: Experimental pro-
cedures and full characterization data for all new compounds
are given. This material is available free of charge via the
Internet at http://pubs.acs.org.
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