Asymmetric total synthesis of (-)-cribrostatin 4 (renieramycin H)

Article abstract of DOI:10.1002/anie.200604126

(Chemical Equation Presented) Out of the blue: The convergent asymmetric total synthesis of the antitumor antibiotic (-)-cribrostatin 4 from the blue sponge Cribrochalina features asymmetric Staudinger and Pictet-Spengler reactions to form the tetrahydroisoquinoline moiety. These reactions were followed by a reductive opening/elimination of a tricyclic β-lactam and a Pictet-Spengler cyclization to access the unsaturated pentacyclic core.

Full text of DOI:10.1002/anie.200604126

Angewandte
Chemie
DOI: 10.1002/anie.200604126
Tetrahydroisoquinoline Alkaloids
Asymmetric Total Synthesis of (À)-Cribrostatin 4 (Renieramycin H)**
Guillaume Vincent and Robert M. Williams*
Dedicated to Professor Yoshito Kishi on the occasion of his 70th birthday
The tetrahydroisoquinoline family of alka-
loids that include the renieramycins (1, 2a–
c), ecteinascidin-743 (Et-743, 3), jorumycin
(4), saframycins (5a–c), safracins (6a–b),
bioxalomycins (7a–b), quinocarcin (8), and
tetrazomine (9, Scheme 1) has attracted
significant attention from the synthetic
community over the past 30 years because
of the potent antitumor and antimicrobial
activities that this family of agents dis-
plays.[1] Among them, Et-743 (3) is a highly
potent antitumor agent which is currently
in phase II/III human clinical trials.[2]
Our research group has long been
involved in the chemistry and biology of
the tetrahydroisoquinoline antitumor anti-
biotics. Our interest in this field has culmi-
nated in the total syntheses of (Æ )-quino-
carcinamide,[3] (À)-tetrazomine (9),[4] (À)-
renieramycin G (2c), and (À)-jorumycin
(4),[5a] as well as 3-epi-renieramycin G, 3-
epi-jorumycin,[5] and other biologically rel-
evant analogues.[6] In addition, promising
synthetic studies toward Et-743 (3) are
currently being investigated[7] along with
studies to further understand the biochem-
ical and cellular modes of action of these
agents.[4b,6,8] Herein we report a concise
asymmetric total synthesis of (À)-cribro-
statin 4 (renieramycin H, 1) as a part of a
broad study into this family of biologically
active compounds.
Scheme 1. Some examples of tetrahydroisoquinolines alkaloids.
In 1998, two renieramycin derivatives were isolated by
Parameswaran et al. from the bright-blue sponge Haliclona
cribicutis.[9] The structures 10 and 11 (Scheme 2) that were
originally assigned were given the names renieramycin H and
I, respectively. Kubo and co-workers subsequently revised the
structure of renieramycin H to that of 1 (Scheme 1) from
[*] Dr. G. Vincent, Prof. R. M. Williams
Department of Chemistry
Colorado State University
Fort Collins, CO 80523 (USA)
and
The University of Colorado Cancer Center
Aurora, CO 80045 (USA)
Fax: (+1)970-491-3944
E-mail: rmw@lamar.colostate.edu
Homepage: http://rwindigo1.chm.colostate.edu/
[**] We gratefully acknowledge financial support from the National
Institutes of Health (Grant CA85419). Mass spectra were obtained
on instruments supported by the National Institutes of Health
Shared Instrumentation Grant No. GM49631.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 2. The structures of cribrostatin 4 (renieramycin H) and
renieramycin I.
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13C NMR studies.[10] Independently, Pettit et al. reported the
quinoline 14.[15] The highly functionalized tyrosine derivative
15 was to originate from the coupling of aryl iodide 20 and an
enolate derived from the chiral glycine template 19.[16]
We have previously described asymmetric syntheses of the
tetrahydroisoquinoline 21 and the amino acid derivative 22 in
two separate reports following the retrosynthesis outlined in
Scheme 3.[5a,13] After completion of the syntheses of the two
fragments, the next step was their assembly (Scheme 4).
Amino acid 22 was converted into the corresponding acid
chloride, which was coupled with tetrahydroisoquinoline 21 in
79% yield without noticeable epimerization at the C13
stereogenic center. Removal of both the TBS and Fmoc
protecting groups was effected with TBAF to afford the
peptide 23 in 92% yield, which set the stage for the key
formation of the pentacycle. Reduction of the b-lactam with
LiEt3BH, followed by workup with aqueous ammonium
chloride, delivered the pentacycle 24 bearing the required
C3–C4 alkene in 62% yield.
isolation of cribrostatin 4 from the blue sponge Cribrochalina
collected from reef passages in the Republic of Maldives.[11]
The structure of cribrostatin 4 was determined by X-ray
analysis, which revealed that this substance is identical to
renieramycin H (1).
=
The C3 C4 benzylic olefin present in compounds 1 and 11
is not present in any other naturally occurring member of the
tetrahydroisoquinoline family of antitumor compounds. Cri-
brostatin 4 (renieramycin H, 1) displays low-micromolar
cytotoxic and antimicrobial activities. In 2005, Danishefsky
and co-workers reported the first total synthesis of cribros-
tatin 4 (1) by using a lynchpin Mannich cyclization to establish
the pentacyclic core.[12]
Our strategy was an elaboration of the methodology we
developed to form pentacyclic tetrahydroisoquinolines bear-
=
ing the C3 C4 alkene that is present in cribrostatin 4 and
renieramycin I (Scheme 3).[13] The key step was thus envi-
Two pathways could be envisioned to explain the origin of
the benzylic alkene. In the first, b-elimination of the benzyl-
amine residue at the C4 position via the incipient aldehyde is
plausible prior to the formation of the pentacycle. The Pictet–
Spengler cyclization would thus be realized on an intermedi-
ate a,b-unsaturated iminium ion. An alternative pathway
would involve the elimination of the C4 benzylamine after
formation of the pentacycle through a mechanism involving
an ortho-quinone methide intermediate. Some preliminary
evidence suggests that this second pathway may be operating,
and current studies might provide more information and will
be reported in due course.
At this point, only a few transformations were required to
reach cribrostatin 4 (1, Scheme 5). Simultaneous hydrogeno-
lytic removal of both of the benzyl groups on the phenol and
primary alcohol with palladium chloride (H2, 1 atm) led to 25
[17]
=
(99% yield), leaving the C3 C4 alkene intact.
Both
phenols were then oxidized with bis(trifluoroacetoxy)iodo-
benzene (PIFA) to form the bisquinone 26 in 40% yield.[18]
Other oxidants, such as 2,3-dichloro-5,6-dicyano-1,4-benzo-
quinone (DDQ) and ceric ammonium nitrate (CAN) also
provided the desired product 26, but in lower yields. Treat-
ment with angeloyl chloride 29 subsequently furnished
product 27 in 56% yield.[19] Attempts to realize this esterifi-
cation using modified Yamaguchi conditions, as reported by
Greene and co-workers,[20] were disappointing (10% yield)
because of the formation of undetermined by-products.
In contrast to the route reported by Danishefsky and co-
workers,[12] our substrate 26 was more stable than their b-
dicarbonyl (C14–C21) substrate, and the esterification to
Scheme 3. Retrosynthetic analysis of 1. Bn=benzyl.
À
sioned to be the reductive opening/elimination of the C3 C4
b-lactam in 13, immediately followed by spontaneous for-
mation of the iminium ion 12 and Pictet–Spengler cyclization,
to afford the pentacyclic skeleton of 1. The tetrahydroisoqui-
noline core 14 was targeted by using an asymmetric Stau-
dinger reaction[14] between imine 17 and a ketene derived
from 18 to generate the cis-fused b-lactam 16; Pictet–Spengler
cyclization would then ultimately furnish the tetrahydroiso-
Scheme 4. Construction of the pentacyclic framework. DMF=N,N-dimethylformamide, Fmoc=9-fluorenylmethyloxycarbonyl, TBS=tert-butyldime-
thylsilyl, TBAF=tetrabutylammonium fluoride.
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Angewandte
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Scheme 5. Completion of the synthesis of (À)-cribrostatin 4 (1).
form the angelate ester 27 proceeded in synthetically useful
yield without the need to fine-tune the A ring. Oxidation of 27
with selenium dioxide proved to be chemo-, regio-, and
diastereoselective at the C14 position, and delivered 28 in
73% yield. The stereochemistry of the hydroxy group at C14
was assigned on the basis that no coupling constant was
observed between H14 and H13. This oxidation method was
first introduced by Kubo, Saito, and co-workers in their
conversion of saframycin B into saframycin D,[21] and was
subsequently used by Danishefsky and co-workers in their
synthesis of 1.[12]
Finally, (À)-cribrostatin 4 (1) was obtained in 84% yield
by treating 28 with Dess–Martin periodinane (DMP) to
oxidize the alcohol group at C14 into a ketone,[22] followed by
the addition of an aqueous solution of sodium thiosulfate to
reduce the quinone of the E ring into the desired hydro-
quinone. The high stability of the hydroquinone E ring is
attributable to the presence of the keto group at C14, while
related hydroquinones at the A ring have been shown to
rapidly oxidize in air to the corresponding quinone.[23] The
spectroscopic data of the synthetic (À)-cribrostatin 4 (1) are
consistent with those reported for the natural product.
The asymmetric total synthesis of (À)-cribrostatin 4 (1)
has been realized in 17 steps in the longest linear sequence
from the known 2,4-dimethoxy-3-methyl-5-benzyloxybenzal-
deyde in 1.4% overall yield (or 25 steps from the commer-
cially available 2,6-dimethoxytoluene in 1% overall yield).
This concise synthesis compares very favorably to the syn-
thesis reported by Danishefsky and co-workers of thirty-two
steps in the longest linear sequence and 1.7% overall yield
from the commercially available 2,3-dimethoxytoluene. This
study features sequential asymmetric Staudinger and Pictet–
Spengler reactions to form the tetrahydroisoquinoline and a
reductive opening/elimination of a b-lactam immediately
followed by a Pictet-Spengler cyclization to access the
unsaturated pentacyclic framework. Efforts to extend the
chemistry described herein to the preparation of analogues of
the natural product are currently underway in our research
group. We have previously reported the synthesis of 3-epi-
renieramycin G and 3-epi-jorumycin.[5] To complete this
study, the synthesis of analogues of renieramycin G (2c)
=
and jorumycin (4) which bear a C3 C4 alkene would be
valuable to understand more fully the influence of the
stereochemistry at the C3 position on the cytotoxicity and
biochemical reactivity. Moreover, it is speculated that the
antitumor activity of cribrostatin 4 (1) could be substantially
increased by introducing a carbinolamine or cyano function at
the C21 position in place of the amide carbonyl residue
present in the natural product. This modification would allow
the formation of a potent electrophilic iminium ion species,
implicated in the formation of covalent bonds with DNA, as
observed in other members of the tetrahydroisoquinoline
family.[1] These and other mechanistically-inspired studies
into analogues are underway.
Received: October 7, 2006
Published online: January 19, 2007
Keywords: antitumor agents · heterocycles · natural products ·
.
Pictet–Spengler reaction · total synthesis
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