Short, enantioselective total synthesis of stephacidin A

Article abstract of DOI:10.1002/anie.200461864

A concise route to the heptacyclic indole alkaloid stephacidin A (1) includes a simple method for the gram-scale synthesis of substituted tryptophans, a remarkable indole annulation, and the first enolate coupling of an amide to an ester. This synthesis s

Full text of DOI:10.1002/anie.200461864

Communications
provided a strong impetus for the design of a concise total
synthesis that employs 1 en route to 2 (Scheme 1) and that
proceeds through the intermediacy of avrainvillamide[7] (3)
and aspergamide B (4).[8]
The heptacyclic alkaloid stephacidin A (1) poses
a
number of challenges for synthesis. Pioneering work from
the Williams laboratory[9] has verified the proposals of Birch[3]
and Sammes[10] that the bicyclo[2.2.2]diazaoctane core of
these alkaloids are likely formed by a Diels–Alder reaction in
Nature. However, this elegant biomimetic approach would be
difficult to employ in an enantioselective laboratory synthesis
of 1, especially as a proposed intermediate in the cascade
sequence is achiral.[11] Furthermore, there is a clear gap in
indole synthesis methodology, as published methods[12,13] for
the preparation of the 6-hydroxytryptophan core require
multistep, tedious procedures. Herein we report a concise,
enantioselective total synthesis of stephacidin A (1) that
Natural Products Synthesis
Short, Enantioselective Total Synthesis of
Stephacidin A**
Phil S. Baran,* Carlos A. Guerrero,
Narendra B. Ambhaikar, and
Benjamin D. Hafensteiner
Prenylated indole alkaloids have been a vibrant
source of inspiration for synthetic chemists for over
half a century.[1] Representative members of this
natural product family include the spirotryprosta-
tins,[2] brevianamides,[3] austamides,[4] and okara-
mines.[5] Stephacidin A and B (1 and 2, respectively
in Scheme 1), recently disclosed by scientists at
Bristol-Myers Squibb, signify a new peak of struc-
tural complexity within this family.[6,7] Isolated from
Scheme 1. Stephacidins and their proposed[6,7] biogenetic relationships.
the fungus Aspergillus ochraceus WC76466, stephacidin B (2)
“represents one of the most structurally complex and novel
alkaloids occurring in Nature”[6] and contains 15 rings, nine
stereogenic centers, and the ubiquitous 6-oxyindole substruc-
ture. Furthermore, compounds 1 and 2 exhibit potent in vitro
cytotoxic activity against a variety of human tumor cell lines.
The bioactivity of the stephacidins is not mediated by p53,
mdr, bcl2, tubulin, or topoisomerase II, which suggests a
novel mechanism of action.[6] Taken together, these facts
establishes its relative configuration and addresses its inher-
ent chemical challenges in a unique way.
The challenge of a practical and rapid synthesis of the 6-
hydroxytryptophan core of 1 was met by modifying a
palladium-catalyzed indole synthesis developed at Merck
(Scheme 2).[14] Thus, after extensive optimization, readily
available pyroglutamate 5 was chemoselectively reduced with
Super Hydride[15] and the crude lactol was immediately
converted into tryptophan 8 in 75% overall yield through
the intermediacy of enamine 7. This enamine could be
isolated, characterized, and converted into 8. The high yield
of this simple process is not diminished even on a multigram
scale. Tetrabutylammonium iodide (3.0 equiv) was vital as the
yield ranged from 10–35% in its absence. The benzopyran
subunit was then installed and subsequently modified for
coupling to the proline subunit through the sequence shown
in Scheme 2. Protection with Boc2O was followed by removal
of the tosylate group.[16] Propargylation of the resulting
[*] Prof. Dr. P. S. Baran, C. A. Guerrero, Dr. N. B. Ambhaikar,
B. D. Hafensteiner
Department of Chemistry
The Scripps Research Institute
10650 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (+1)858-784-7375
E-mail: pbaran@scripps.edu
[**] We thank Dr. D. H. Huang and Dr. L. Pasternack for NMR
spectroscopic assistance, and Dr. G. Siuzdak and Dr. R. Chadha for
mass-spectrometric and X-ray crystallographic assistance, respec-
tively. We are grateful to Biotage for a generous donation of process
vials used extensively during these studies. Financial support for
this work was provided by The Scripps Research Institute, Eli Lilly &
Co, and the NIH (predoctoral fellowship to C.A.G.).
[17]
phenol under standard Cu-catalyzed conditions with 9
furnished 10 in 75% yield over two steps. Allenyl Claisen
rearrangement[18] followed by reprotection of the indole NH
group and subsequent hydrolysis led to the formation of acid
12.
Racemic tryptophan derivative 12 was then coupled with
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
the enantiomerically pure proline derivative 13[19] to afford an
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DOI: 10.1002/anie.200461864
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Chemie
Scheme 2. Synthesis of the benzopyran-tryptophan subunit 12.
Reagents and conditions: a) 1. LiEt3BH (1.1 equiv), THF, ꢀ788C,
10 min; 2. Pd(OAc)2 (0.05 equiv), DABCO (3.0 equiv), 6 (1.1 equiv),
TBAI (3.0 equiv), DMF, 1058C, 4 h, 75% overall; b) Boc2O (1.0 equiv),
DMAP (0.01 equiv), CH2Cl2/CH3CN (1:1), 258C, 30 min, 95%; c) Mg
(10.0 equiv), MeOH, 0!258C, 2.5 h; d) 9 (3.0 equiv), CuCl2
(0.001 equiv), DBU (3.0 equiv), CH3CN, 08C, 24 h, 75% over two
steps; e) AcOH, 1208C, 80 min, 79%; f) Boc2O (1.0 equiv), DMAP
(0.01 equiv), CH2Cl2/CH3CN (1:1), 258C, 30 min, 77%; g) LiOH
(15.0 equiv), THF/H2O (1:1), 08C, 3 h, 100%. DABCO=1,4-diazabicy-
clo[2.2.2]octane; TBAI=tetra-n-butylammonium iodide; DMF=N,N-
dimethylformamide; Boc=tert-butoxycarbonyl; DMAP=4-dimethyl-
aminopyridine; DBU=1,8-diazabicyclo[5.4.0]undec-7-ene.
N-Boc or silyl ether functionalities to provide diketopiper-
azine 15 in 53% yield. Protection of the diketopiperazine NH
function followed by TBAF-mediated removal of the TBS
group and sequential oxidation to the corresponding ester 16
ꢀ
set the stage for a remarkable C C bond-forming event.
Although the metal-mediated oxidative coupling of
enolates has immense potential for synthesis, it has been
employed only sporadically since the seminal reports from the
groups of Mislow and Saegusa.[21,22] Our objective was to
ꢀ
effect the conversion of 16 into 17 by forming the key C6 C22
bond (stephacidin A numbering,[6] see Scheme 3, 17) with
complete stereocontrol through an oxidative coupling. Mech-
anistically, it is believed that such reactions proceed via
radical species, despite a lack of evidence to rule out metal-
bound intermediates. Recent findings in our laboratory[23]
inconsequential mixture of diastereomeric amides 14 in 62%
yield (Scheme 3). The Cbz group was chemoselectively
excised and the diketopiperazine was formed in a single
operation[20] without harm to the benzopyran or to either the
Scheme 3. Enantioselective total synthesis of stephacidin A (1). Reagents and conditions: a) 13 (1.5 equiv), BOPCl (1.1 equiv), iPr2EtN (1.1 equiv),
CH2Cl2, 0!258C, 10 h, 62%; b) [Pd2(dba)3] (0.2 equiv), Et3SiH (40 equiv), Et3N (2.0 equiv), CH2Cl2, 258C, 4 h; then MeOH, reflux, 30 min; then
toluene, reflux, 2 h, 53% overall; c) NaH (1.2 equiv), MOMCl (1.1 equiv), DMF, 08C, 1 h, 65%; d) TBAF (3.0 equiv), THF, 258C, 1 h; then DMP
(1.5 equiv), CH2Cl2, 258C, 2 h; then 2-methyl-2-butene (20 equiv), NaH2PO4·H2O (3.0 equiv), NaClO2 (2.8 equiv), THF, H2O, 20 min; then CH2N2
in Et2O, MeOH, 5 min, 69% overall; e) LDA (2.2 equiv), THF, ꢀ788C, 5 min then [Fe(acac)3] (2.2 equiv), THF, ꢀ78!258C, 1 h, 41% 17 with 15%
recovered 16; f) B-bromocatecholborane (1.5 equiv), CH2Cl2, 08C, 1.5 h, 63%; g) MeMgBr (6.0 equiv), toluene, 258C, 1 h, then Burgess reagent
(2.0 equiv), benzene, 508C, 30 min, 88% overall; h) 2008C, 1 h, 45% 1 with 10% recovered 19. BOP=bis(2-oxo-3-oxazlidinyl)phosphinic chloride;
dba=trans,trans-dibenzylideneacetone; MOM=methoxymethyl; TBAF=tetra-n-butylammonium fluoride; DMP=Dess–Martin periodinane;
LDA=lithium diisopropylamide; acac=acetylacetonate.
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Communications
suggest that some of the metallic oxidants employed (FeIII-
following removal of the MOM group in 63% yield with B-
bromocatecholborane, reaction with MeMgBr cleanly fur-
nished a tertiary alcohol, which was directly dehydrated with
Burgess reagent[27] to afford olefin 18 in 88% overall yield.
Although a variety of acidic conditions are known to effect
ring closure in closely related systems,[28] our efforts to convert
18 or its hydrated precursor into 1 were all thwarted by the
acid-labile nature of the substrate. Remarkably, when 18 was
simply heated at 2008C, in the absence of solvent, for 1 h, 1
was obtained in 45% yield. We believe that thermolytic
removal of the Boc group (through a retro-ene reaction) of 18
occurs first to afford 19 followed by a formal ene reaction
leading to a fleeting spirocyclic intermediate 20 reminiscent of
the venerable Pictet–Spengler reaction. A 1,2-shift then
terminates the cascade and furnishes 1 (Scheme 3). The
exact nature of the latter transformation has not been fully
elucidated. However, this thermal reaction appears to be
general for these types of systems and will be detailed in the
full account. Synthetic 1 has identical spectral properties
(both in [D6]DMSO and CDCl3/CD3OD 4:1) to that reported
by Cutrone et al., thus establishing the relative configuration
as shown in Scheme 1. The absolute configuration could not
be secured as the optical rotation of natural 1 was not
recorded and little or no material remains.[29] Incidentally, 23
could be converted into epibrevianamide by following a
similar pathway, further confirming our assignment of the
relative configuration.[30]
In summary, the first total synthesis of 1 from the
commodity chemicals pyroglutamate and l-proline was
completed in 15 operations. Efforts are now underway to
access the highly oxidized congeners of stephacidin A
(Scheme 1). The journey to stephacidin A was accompanied
by some interesting discoveries and inventions, including: 1) a
general methodology for the rapid and practical synthesis of
tryptophan derivatives from pyroglutamate, 2) a remarkable
deprotection/annulation cascade which occurs simply with
heat to forge the final ring (18!1), and 3) simple, stereo-
controlled assembly of two of the three stereocenters of 1 by a
rare intramolecular oxidative coupling (16!17 and 21!22).
The latter set of transformations proceeds cleanly and
represents the first such couplings of esters to amides. The
counterintuitive strategy employed in this total synthesis
points to an attractive direction for further study in the
and CuII-based) may play a more intimate role in these
reactions. We imagined that the reaction of 16 would proceed
with the desired stereochemical outcome to furnish 17
through a metal-chelated transition state. To probe this
possibility, the model ester 21 (Scheme 4) was synthesized
Scheme 4. Stereocontrolled intramolecular oxidative coupling of the
model ester 21. Reagents and conditions: a) LDA (2.5 equiv), THF,
ꢀ788C, 30 min then [Fe(acac)3] (2.5 equiv), THF, ꢀ78!258C, 1 h,
52% b) B-bromocatecholborane (2.0 equiv), CH2Cl2, 08C, 1 h, 87%.
and subjected to modified oxidative coupling conditions,
which furnished the desired cyclized product 22 in 52% yield.
The stereochemistry was secured upon removal of the MOM
group in 87% yield with B-bromocatecholborane[24] and X-
ray crystallographic analysis of the resulting crystalline
pentacycle 23[25] (colorless needles, m.p. 125–1288C
(EtOAc), see Scheme 4 for ORTEP illustration). Notably,
this reaction fails when using silver salts, iodine, and
ferricinium hexafluorophosphate (an oxidant known to give
radicals from enolates).[26] Participation of the MOM group in
this reaction was ruled out as a PMB group could be used
interchangeably with the same stereochemical outcome and
yield.
ꢀ
With the encouraging reconnaissance gained in the model
study, addition of LDA (2.2 equiv) to a solution of substrate
16 in THFat ꢀ788C followed by [Fe(acac)3] after 5 minutes of
enolization and warming to room temperature led to 17 in
41% yield as a single diastereomer (along with 15% recovery
of 16, Scheme 3). The extremely brief enolization time
(5 min) was essential for the success of this reaction. With
the exception of the benzopyran resonances, the NMR
spectral properties of 17 were nearly identical to the model
compound 22 (Scheme 3); the stereochemistry of the newly
general areas of oxidative C C bond formation and synthetic
design.[31]
Received: September 2, 2004
Published online: December 7, 2004
Keywords: alkaloids · cascade reactions · indoles ·
natural products · total synthesis
.
ꢀ
formed C6 C22 bond of 17 was further verified by the
observed NOE (see 17 in Scheme 3 and Supporting Informa-
tion).
To complete the synthesis of 1, only one ring remained to
be stitched onto 17. The challenge of installing this ring led to
the discovery of a new method for indole annulation. Thus,
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