Enantioselective total synthesis of (+)-dibromophakellstatin

Article abstract of DOI:10.1021/ja034575i

The first enantioselective total synthesis of (+)-phakellstatin and (+)-dibromophakellstatin was achieved. Key steps in the synthesis were a desymmetrization of the diketopiperazine (S,S)-cyclo (Pro, Pro) via a diastereoselective acylation, an intramolecu

Full text of DOI:10.1021/ja034575i

Published on Web 05/02/2003
Enantioselective Total Synthesis of (+)-Dibromophakellstatin
Karine G. Poullennec and Daniel Romo*
Department of Chemistry, Texas A&M UniVersity, College Station, Texas 77842-3012
Received February 8, 2003; E-mail: romo@mail.chem.tamu.edu
The oroidin family of marine alkaloids is a diverse and complex
class of bioactive secondary metabolites, and no studies regarding
their biological mechanism of action have been reported. One
member of this family is (-)-dibromophakellstatin (1a), an anti-
neoplastic agent, isolated by Pettit from the Indian Ocean sponge
Phakellia mauritiana1 along with the structurally related and
previously isolated guanidine, (-)-dibromophakellin2 (2a) (Figure
1). Dibromophakellstatin exhibits potent cell growth inhibitory
activity against a variety of human cancer cell lines (ED50 0.28-
3.9 µM). The structure and absolute stereochemistry of dibro-
mophakellstatin were determined by single-crystal X-ray analysis.
This tetracyclic alkaloid poses a considerable synthetic challenge
due to its compact size and corresponding dense polar functionality
including two vicinal, stereogenic aminal centers. Van Soest3 and
more recently Al Mourabit and Potier4 recognized that dibro-
mophakellin (2a) could be derived biosynthetically from oroidin
(3). Synthetic studies of these alkaloids date back to 1982 with an
elegant synthesis of racemic dibromophakellin involving a bio-
mimetic cyclization of dihydrooroidin by Bu¨chi.5 Other studies
toward these alkaloids have been reported; however, no enantio-
selective syntheses have been described.6 We targeted the enanti-
oselective synthesis of these alkaloids and structural derivatives to
enable biological investigations including mode of action studies.
Furthermore, our interest in palau’amine (4) provided further
impetus for developing routes to these substructures, as they could
reveal potential strategies for phakellin annulation.7 Herein, we
describe the first enantioselective synthesis of (+)-dibromophakell-
statin (1a), the unnatural optical isomer. The synthesis proceeds
through (+)-phakellstatin (1b), which has not been isolated but is
likely present in these organisms on the basis of the presence of
nonbrominated, structurally related metabolites, for example,
palau’amine (4).
Our strategy toward dibromophakellstatin was premised on the
observation that a prolyl proline anhydride[cyclo (Pro, Pro)] was
embedded within its structure and thus may be accessed via
desymmetrization of a C2-symmetric diketopiperazine (DKP), (R,R)-
cyclo (Pro, Pro) ((+)-9) (Scheme 1). Our approach would involve
a diastereoselective, desymmetrization process entailing acylation
of the enolate derived from DKP (+)-9.8 The ester at C10 would
enable construction of the C6 aminal and then serve as a latent
amine via Hofmann rearrangement. This strategy was premised on
studies in our group and also those of Lindel9 and Evans10
demonstrating the unusual stability of pyrrole carbinolamines, for
example, 6. Following dehydrogenation and introduction of the C6
aminal, Hofmann rearrangement would give an isocyanate to be
trapped by a pendant amine providing phakellstatin (1b) and then
dibromophakellstatin (1a) via bromination.
Figure 1. Structures of oroidin (3) and oroidin-derived alkaloids.
Scheme 1
and high diastereoselectivity (92% de).8 Having served the purpose
of controlling stereochemistry during acylation, the R-stereogenic
center could be destroyed by dehydrogenation to pyrrole 10 in one
step using DDQ12 in refluxing toluene; however, yields were low
(20-30%), and purification proved difficult. A more efficient,
stepwise sequence was developed employing a selenation-oxida-
tion-elimination sequence to provide an intermediate pyrroline,
which was then oxidized upon exposure to SeO2.13 With acyl pyrrole
10 in hand, diastereoselective reduction was accomplished with
NaBH4 at low temperature.14 Acetylation to give acetate 12 enabled
confirmation of the expected cis relative stereochemistry of the
â-acetoxy ester by single-crystal X-ray analysis (Scheme 2).
Hydride addition occurs from the concaVe face of the slightly
puckered tricyclic system presumably due to steric effects induced
by the aromatic ring that is folded over the DKP ring in solution.15
A trans arrangement of the â-acetoxy ester was required for the
anticipated intramolecular Mitsunobu process, and so an epimer-
ization of the carbinolamine center would be required. Fortuitously,
a method for achieving this was discovered during early studies
that suggested the need to introduce the C10 aminal late in the
synthesis. Hydrogenolysis of benzyl ester 12 followed by treatment
of the resulting acid 13 with the Shioiri16 reagent at 85 °C produced
an isocyanate, which was immediately trapped with benzylamine
to deliver urea 14. Aminolysis of the acetate 14 gave carbinolamine
15; however, attempts to cyclize urea 15 under a variety of
conditions led to decomposition due to the lability of the quaternary
aminal center presumably via acyliminium chemistry. Under one
The synthesis of unnatural dibromophakellstatin ((+)-1a) began
with (S,S)-cyclo (Pro, Pro) ((-)-9) obtained in three steps by a
modified, known procedure from less expensive L-proline.11
A
subsequent acylation with benzylchloroformate, as previously
described, delivered the functionalized DKP 8 in good yield (70%)
9
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J. AM. CHEM. SOC. 2003, 125, 6344-6345
10.1021/ja034575i CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2 a
nation with NBS delivered (+)-dibromophakellstatin (ent-1a). This
material exhibited spectroscopic and physical properties identical
to those of the natural product with the exception of optical rotation
(syn. [R]25 +68.7°; nat. [R]25 -70.4°).
D
D
In summary, key steps in the first enantioselective synthesis of
(+)-phakellstatin and (+)-dibromophakellstatin included desym-
metrization of cyclo (Pro, Pro) via a diastereoselective acylation,
an intramolecular Mitsunobu reaction to introduce the C6 aminal,
and a tandem Hofmann rearrangement/cyclization to simultaneously
introduce the C10 quaternary aminal center and deliver the cyclic
urea. The synthesis also demonstrates the unusual stability of pyrrolo
aminals, for example, 23-24. Importantly, this strategy has the
potential for producing phakellstatin derivatives, derived from (R,
R)-cyclo (Pro, Pro), necessary for biological studies. The total
synthesis also provides a phakellin annulation method applicable
to the synthesis of palau’amine. Studies toward these goals will be
reported in due course.
a (a) Reference 8; (b) KHMDS, THF, -78 °C; PhSeBr (73%); (c)
DMDO, CH2Cl2, -78 f 0 °C (93%); (d) SeO2, dioxane, reflux (65%); (e)
NaBH4, MeOH, -40 °C (88%); (f) Ac2O, py., CH2Cl2 (66%); (g) H2, 10%
Pd/C, EtOAc; (h) TEA, DPPA, PhCH3, 4 Å MS, 85 °C; BnNH2, 23 °C
(50%, two steps); (i) NH3, MeOH, (86%); (j) KOt-Bu, t-BuOH, 25 °C
(99%).
Acknowledgment. We thank the NIH (GM 52964-06) and
Pfizer for support of these investigations. D.R. is an Alfred P. Sloan
Fellow and a Camille-Henry Dreyfus Teacher-Scholar. We thank
Dr. George Pettit (Arizona Cancer Res. Inst.) and Dr. David Horne
(Oregon State) for samples and spectral data of dibromophakell-
statin, respectively. We thank Dr. Joe Reibenspies for X-ray
structure determination using instruments obtained with funds from
the NSF (CHE-9807975). The NSF (CHE-0077917) provided funds
for purchase of NMR instrumentation.
Scheme 3 a
Supporting Information Available: Selected experimental pro-
cedures and characterization data (including 1H and 13C NMR spectra)
for compounds 10, 11, 18, 20, 21, 24, (+)-1b, (+)-1a, and comparison
spectra with natural (-)-1a and derived (-)-1b (PDF). This material
is available free of charge via the Internet at http://pubs.acs.org.
a (a) KOt-Bu, t-BuOH; (b) Ac2O, py., CH2Cl2 (58%, two steps); (c) H2,
10% Pd/C, EtOAc/EtOH (1:1); (d) (i) (COCl)2, DMFcat, CH2Cl2; (ii)
CbzNHOH, DMAP (77%, two steps); (e) NH3, MeOH, 0 °C (90%); (f)
DIAD, PPh3, THF, reflux; (g) NH3, MeOH, 0 °C; (h) TiCl3, KOAc, THF/
H2O (1:1), 23 °C (53%, three steps); (i) PhI(O2CCF3)2, py., CH3CN; (j)
H2, 10% Pd/C, MeOH (50%, two steps); (k) NBS (2.0 equiv), THF (69%).
References
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set of conditions, exposure to KOt-Bu following attempted alcohol
activation did not induce cyclization to the cyclic urea, but led
instead to epimerization at C6 in quantitative yield, suggesting
thermodynamic preference for trans-carbinolamine 16.
With these epimerization conditions in hand and the information
suggesting the instability of the aminal at C10, we explored a
different strategy to complete the synthesis of phakellstatin which
entailed introduction of the more stable C6 aminal followed by
introduction of the more labile C10 aminal. Toward this goal,
epimerization to carbinolamine 17 and subsequent acylation gave
trans-acetoxyester 18 (Scheme 3). The benzyl group was removed,
and acid 19 was subsequently coupled with benzyl N-hydroxy-
carbamate to give the hydroxamate 20. Following aminolysis and
exposure of the N-hydroxy ester to Mitsunobu conditions (DIAD,
PPh3),17 tetracyclic intermediate 22 was formed but was not readily
isolated due to instability. Hence, it was immediately subjected to
18
aminolysis and then N-O bond cleavage with TiCl3 to deliver
â-amino amide 24. Pleasingly, amide 24 smoothly underwent
Hofmann rearrangement using PhI(O2CCF3)219 and in situ cycliza-
tion giving Cbz-(+)-phakellstatin (26), which was hydrogenolyzed
directly to deliver (+)-phakellstatin (ent-1b). Subsequent bromi-
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