Studies toward the synthesis of roseophilin: Lactam formation and Wittig/aldol methodology

Article abstract of DOI:10.1016/j.tetlet.2004.06.013

In this communication, we introduce our retrosynthetic approach to the synthesis of roseophilin. An interesting, new Wittig/aldol methodology is described. Also discussed is macrocyclization of an azide acid to form an unsaturated lactam.

Full text of DOI:10.1016/j.tetlet.2004.06.013

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6051–6053
Studies toward the synthesis of roseophilin: lactam formation
and Wittig/aldol methodology
Christopher A. Dykea,* and Thomas A. Brysonb
aCenter for Nanoscale Science and Technology, Rice University, Houston, TX 77005 USA
bDepartment of Chemistry, University of South Carolina, Columbia, SC 29208 USA
Received 29 April 2004; revised 27 May 2004; accepted 2 June 2004
Available online 25 June 2004
Abstract—In this communication, we introduce our retrosynthetic approach to the synthesis of roseophilin. An interesting, new
Wittig/aldol methodology is described. Also discussed is macrocyclization of an azide acid to form an unsaturated lactam.
Ó 2004 Elsevier Ltd. All rights reserved.
In 1992, Hayawa, Kawakami, and Seto isolated roseo-
philin (1) from the culture broth of Streptomyces gri-
seoviridis. The hydrochloride salt of the pentacyclic
compound showed submicromolar cytotoxicity in vitro
against K562 human erythroid leukemia and KB human
epidermoid carcinoma cell lines.1 The antitumor agent 1
possesses a unique structure consisting of a strained
macrotricyclic core attached to a substituted pyrrolefu-
ran moiety. The unusual nature of the structure coupled
with its antitumor characteristics make roseophilin an
attractive synthetic target and a lead structure in the
search for cancer drugs. This is supported by the mag-
nitude of synthetic efforts reported to date.2–13
Our first obvious retrosynthetic cut disconnects the fu-
ranpyrrole moiety 2 from the macrotricyclic core 3
(Scheme 1). In the first reported total synthesis of
€
roseophilin, Furstner and Weintritt obtained 1 through
Scheme 1. Retrosynthetic analysis of roseophilin.
Keywords: Wittig; Aldol; Roseophilin; Lactam; Cyclization.
* Corresponding author. Tel.: +1-713-2034125; fax: +1-713-3486250; e-mail: dyke@rice.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.013

6052
C. A. Dyke, T. A. Bryson / Tetrahedron Letters 45 (2004) 6051–6053
Scheme 2. Wittig/aldol.
condensation of the two segments 2 and 3.7 We envi-
sioned delivery of ketopyrrole 3 using 1,3-dipolarcyclo-
addition methodologies on the amino acid 4. Unlike all
other synthetic efforts to obtain compound 3, we chose
to investigate macrocyclization via connecting two polar
end groups tethered by an aliphatic chain. Considering
the hydrophobic nature of the tether, we surmised that
coiling of cyclization precursors such as 5 in polar
protic solvents would promote macrocyclization. Also,
cis-unsaturation in the aliphatic tether, where the dashed
line in compounds 4 and 5 denote the site of unsatura-
tion, could deliver substrates that have a propensity for
intramolecular reactivity. We now report the formation
of macrolactams as well as an interesting Wittig/aldol
methodology (Scheme 2) we observed while generating
cis-olefins.
process led to an ability to either optimize or inhibit the
Wittig/aldol pathway. By increasing the number of
equivalents of LDA from two to three and increasing
the number of equivalents of aldehyde from one to two,
we were able to solely produce the Wittig/aldol product
9. Suppression of this pathway was accomplished by
forming the carboxylate anion with sodium hydride,
thereby generating the more ionic sodium carboxylate as
opposed to the lithium carboxylate. Formation of the
sodium carboxylate decreases the acidity of the protons
alpha to the carboxylic acid. Therefore, upon addition
of 1 equiv of LDA, the ylide is generated instead of the
carboxylate dianion. Using this methodology, the major
product is the cis-olefin 8, and the aldol product is no
longer observed.
With the ability to either solely produce benzyl ether
acid 8 or functionalized ether acids such as 9, we pro-
ceeded to investigate lactam formation. After disap-
pointing initial attempts to form 13-membered lactams
from simple amino acids employing peptide coupling
reagents, we chose to cyclize an azide acid, which was
shown to deliver macrolactams by Vilarrasa and co-
workers.15 The cyclization precursor was generated from
the unsubstituted Wittig product 8. First, reduction of
the acid 8 generated the benzyl ether alcohol 10 with the
low yield attributed to benzyl ether cleavage. The alco-
hol was then converted to the iodide,16 and the iodide
was displaced with azide17 ion to generate the masked
amine 12. Benzyl ether cleavage followed by oxidation
of the resultant alcohol 13 generated the cyclization
precursor 14 (Scheme 3).
During the formation of cis-olefins for macrocyclization
studies, an interesting observation was made. The use of
LDA to generate the carboxylate anion and ylide of
Wittig salt 6 followed by addition of aldehyde 7 led to
the formation of a significant amount of side product
(Scheme 2). Isolation and characterization of this side
product led to the realization that the Wittig reaction
was occurring efficiently giving enoic acid 8, but an aldol
reaction14 was taking place simultaneously, generating
the enol acid 9. We performed the standard Wittig
reaction, and an aliquot was taken after addition of
0.25 equiv of the aldehyde and the Wittig/aldol product
9 was already observed. We concluded that the LDA
was basic enough to generate the ylide as well as the
carboxylate dianion. Further investigation into this
Scheme 3. Formation of azide acid.

C. A. Dyke, T. A. Bryson / Tetrahedron Letters 45 (2004) 6051–6053
6053
References and notes
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Scheme 4. Macrolactamization.
Following the work of Vilarrasa and co-workers15 we
produced lactam 15 (Scheme 4). High dilution condi-
tions were followed as well as generation of the anhy-
dride that is used in Yamaguchi lactonization18
protocols. Unlike Yamaguchi lactonization, tributyl-
phosphine was introduced to the cyclization flask; tri-
butylphosphine unmasks the amine in situ. We initially
formed an unsaturated lactam, and the yield of lactam
formation was similar to that reported by Vilarrasa
(57%). In the case of azide acid 14, the cis-olefin did not
considerably increase the yield, but it also did not
interfere with or inhibit lactam formation. The synthesis
of 15 establishes an ability to form 13-membered
unsaturated lactams, and thus the feasibility of our
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In conclusion, we have demonstrated the ability to
harness the Wittig/aldol reaction in order to generate
substituted and unsubstituted cis-olefins. We also gen-
erated a cis-unsaturated lactam following published
protocols where the unsaturation did not interfere with
the lactamization pathway. These findings should prove
beneficial in our efforts to synthesize roseophilin.
ꢀ
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