Stereoselective synthesis of brevianamide e

Article abstract of DOI:10.1021/ol202880y

The hydroxypyrroloindolenine (Hpi) motif forms the fundamental core of the pentacyclic natural product, brevianamide E, the concise stereoselective synthesis of which, via oxidative cyclization, is described.

Full text of DOI:10.1021/ol202880y

ORGANIC
LETTERS
2012
Vol. 14, No. 1
90–93
Stereoselective Synthesis of
Brevianamide E
Liang Zhao, Jonathan P. May, Jack Huang, and David M. Perrin*
Department of Chemistry, 2036 Main Mall, University of British Columbia, Vancouver,
B.C. V6T 1Z1, Canada
dperrin@chem.ubc.ca
Received October 25, 2011
ABSTRACT
The hydroxypyrroloindolenine (Hpi) motif forms the fundamental core of the pentacyclic natural product, brevianamide E, the concise
stereoselective synthesis of which, via oxidative cyclization, is described.
The brevianamides comprise a series of multicyclic
natural products originally isolated from Penicillium
brevicompactum.1,2 These compounds represent challen-
ging targets in terms of a concise organic synthesis. In
particular, the pentacyclic natural product brevianamide E
(1, Figure 1) represents an interesting challenge for the
construction of five fused rings and four stereogenic
centers, comprising a syn-cis configured hydroxypyrro-
loindolenine (Hpi) core (shown in red in abstract graphic
and Figure 1). Moreover, the Hpi represents a “toxico-
phoric” motif in numerous other natural products of
abiding and current general interest.3À18 The interest in
brevianamide E itself is underscored by the fact that it has
been the subject of a number of syntheses over the past 30
years and still presents a challenge for creating a syn-cis
Hpi.1,19À23 Previous syntheses exploited a common strat-
egy predicated on the formal construction of the reduced
deoxybrevianamide E, as the penultimate product 2
(Figure 1), which is oxidatively cyclized to the title
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2825.
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Miller, S. J. J. Am. Chem. Soc. 2011, 133, 9104.
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r
10.1021/ol202880y
Published on Web 11/29/2011
2011 American Chemical Society

compound containing the Hpi-DKP (diketopiperazine)
fused ring system. Several reports describing this transfor-
mation include photo-oxidation with the singlet oxygen
sensitizer, Rose Bengal, in an O2 atmosphere20,21 and milder
oxidation at low temperature with dimethyldioxirane
(DMDO).22 In addition, fluorinated analogues have been
made using a fluoropyridinium salt.24 Nevertheless, oxida-
tive cyclization of deoxybrevianamide E always produced a
mixture of diastereomers: syn-cis brevianamide E 1 and anti-
cis epi-brevianamide E iso-1 (Figure 1). Moreover, DMDO
oxidation of 2 gave the undesired anti-cis diastereomer iso-1
in 80% excess.22
pentacycle 4, which is closely related to brevianamide E
(Scheme 1). This result motivated us to investigate a concise
stereoselective synthesis of brevianamide E with identical
syn-cis stereochemistry to the natural product.
Scheme 1. Stereoselective Synthesis of the Pentacyclic Core of
Brevianamide E
Hence, our efforts focused on oxidative cyclization of a
reverse prenylated tryptophan-proline derivative with a
view to providing a stereoselective route to brevianamide
E. Initially, we opted for a route via NR-Phth-Trp-Pro-
OMe, as reported by Casimir et al.;27 NR-phthaloyl-tryp-
tophan was first coupled to proline methyl ester in good
yield using EDC/HOBt. Next, we attempted previously
reported methods used to reverse-prenylate NR-Phth-Trp-
OMe.22,28,29 Whereas reverse prenylation of NR-Phth-Trp-
Pro-OMe was successful, yields were suboptimal. More
unfortunate was the lability of the phthalimide which,
during workup, underwent DKP formation to yield deox-
ybrevianamide E 2. Consequently, we could not selectively
tritylate the R-nitrogen needed to prevent its oxidation
while preserving sufficient nucleophilicity for cyclization, a
feature that may be critical to stereoselective ring closure
(vide infra). DKP formation notwithstanding, deoxybre-
vianamide E 2 is a known precursor to brevianamide E,
which can be carried forward in a nondiastereoselective
synthesis of 1 and iso-1, as in all previously reported
cases.20À22,24
Figure 1. Brevianamide E (1), iso-brevianamide E (iso-1), and
deoxybrevianamide E (2).
Herein, we exploit a stereoselective approach where a
reverse prenylated NR-Trt-Trp-Pro-OMe dipeptide is oxi-
dized and deprotected to provide the title compound in a
manner that provides, to the best of our knowledge, the
first stereoselective synthesis of brevianamide E.
Previously, we reported the synthesis of various hydro-
xypyrroloindolenine dipeptides via DMDO oxidation of
NR-Trt-Xaa-OMe (where Xaa is one of 12 standard amino
acids including valine).25 Through these studies we noted
thatoxidativecyclization affords a high yielding mixture of
diastereomers (syn-cis and anti-cis) with very modest dia-
stereoselectivity at best. Notable exceptions to this trend
were NR-Trt-Trp-Pro-OMe and NR-Trt-Trp-Src-OMe
(Src = sarcosine, i.e. NR-methyl glycine).26 In these cases,
we observed highly selective oxidative cyclization to the
syn-cis diastereomer (dr >10:1), in near-quantitative yield,
suggesting utility in the construction of structurally related
compounds. In addition, we discovered that treatment of the
syn-cis NR-Trt-Hpi-Pro-OMe 3 with HFIP simultaneously
removed the trityl and induced diketopiperizination to give
We therefore avoided this route in favor of a new
strategy that started with reverse prenylated tryptophan
(Scheme 2). To that end, NR-phthaloyl-tryptophan methyl
ester 5 was reverse prenylated in the presence of freshly
prepared prenyl-9-BBN in excellent yield.22 The phthaloyl
and methyl groups were removed from compound 6 under
basic conditions to give the lithium salt of 2-isoprenyl-
tryptophan 7 in situ which, following flash chromatogra-
phy (MeOH/CH2Cl2 1% triethylamine), was converted to
the triethylammonium hydrogen salt and then tritylated,22
followed by reaction with proline methyl ester under
standard EDC/HOBt coupling conditions to give dipep-
tide 8. Dipeptide 8 was thensubjectedtoDMDOoxidation
at low temperature (À78 °C), whereupon Hpi formation
ensued, resulting in a predominant product 9, found to
be in the syn-cis configuration (yield 82%, dr >8:1,
(24) Shibata, N.; Tarui, T.; Doi, Y.; Kirk, K. L. Angew. Chem., Int.
Ed. 2001, 40, 4461.
(25) May, J. P.; Fournier, P.; Pellicelli, J.; Patrick, B. O.; Perrin,
(27) Casimir, J. R.; Guichard, G.; Briand, J. P. J. Org. Chem. 2002,
67, 3764.
D. M. J. Org. Chem. 2005, 70, 8424.
(26) May, J. P.; Patrick, B. O.; Perrin, D. M. Synlett 2006, 3403.
(28) Walling, C.; Mintz, M. J. J. Am. Chem. Soc. 1967, 89, 1515.
(29) Kramer, G. W.; Brown, H. C. J. Organomet. Chem. 1977, 132, 9.
Org. Lett., Vol. 14, No. 1, 2012
91

OMe to the pyrroloindolenine phenylselenyl ether in the
syn-cis configuration, which was then deliberately desele-
nated by m-CPBA with retention of configuration to give
the desired Hpi.31 Subsequently, this approach has been
used extensively by others.9,17,32À35 Danishefsky’s explana-
tion for stereoselective selenation invoked kinetic resolution
of two rapidly equilibrating 2,3-phenylepiselenonium ions
that form reversibly on either indole face. Minimization of
steric compression between the CR-methyl ester and the
indole ring ultimately favors episelenonium ring opening to
give the syn-cis configuration.
Scheme 2. Stereoselective Synthesis of Brevianamide E
Unlike selenating agents, DMDO reacts with trypto-
phan in an irreversible manner to give a 2,3-epoxide, or the
more stable, ring-open 3-hydroxyindolenyl-2,3-imine,
either of which would be subsequently intercepted
by the R-nitrogen to give the Hpi in either configuration.
Therefore, kinetic resolution of two rapidly equilibrating
diastereomeric 2,3-epoxides (or 3-hydroxyindolenyl-2,3-
imines) is implausible, although not entirely impossible.
Due to the kinetic irreversibility of DMDO oxidation,
our observed diastereoselectivity can only result if
either (i) the indole face is facially blocked in a ground
state conformation that is limited to secondary amides
(or tert-butyl esters) and distinct from that of primary
amides, or (ii) pyrrole ring closure occurs concomitantly
with oxidation in a transition state that will favor the
less sterically congested diastereomer. Previous exam-
ination of the crystal structures of NR-Trt-Trp-Gly-
OMe and NR-Trt-Trp-Src-OMe revealed that, in each,
the indole is positioned to favor C3 oxidation to give an
Hpi-dipeptide in the syn-cis conformation. Yet two very
similar conformations cannot explain why DMDO
oxidation is facially selective only for the latter. In terms
of the diastereoselectivity herein, molecular modeling
did not provide any evidence of a preferential ground
state conformation that would engender facially selec-
tive indole oxidation (data not shown).
the configurations of each diastereomer were determined
by running 1D NOE experiments).25 HFIP treatment re-
moved the trityl to give Hpi-dipeptide which, in the pre-
sence of DIPEA, cleanly gave brevianamide E 1. The syn-
cis configuration of brevianamide E was confirmed by 1H
and 13C NMR spectroscopy which provided spectra iden-
tical to those previously reported by Danishefsky et al.22
Furthermore, the C4a carbon and proton chemical shifts
identified by HSQC and HMBC experiments were consis-
tent with previously reported values (see Supporting
Information).21
Taken together, these findings argue against a ground
state conformation that ensures facially selective oxidation.
Instead, the diastereoselectivity likely arises from a transi-
tion state in which DMDO oxidation and pyrrole ring
closure are synchronized to favor the syn-cis product; such
synchronicity accounts for steric compression. Inasmuch as
NR-Trt-Trp-Src-OMe, NR-Trt-Trp-Pro-OMe, and NR-Trt-
Trp-OtBu are more sterically congested than normal pep-
tide substrates, increased steric bulk greatly favors one
diastereomeric transition state.
The stereochemical outcome of this oxidation is consis-
tent with reports by Danishefsky et al.; in their elegant
reports on himastatin, they found that DMDO oxidatively
cyclized NR-Trt-Trp-OtBu to the corresponding Hpi-ester
with a nearly exclusive syn-cis configuration (dr 15:1) in a
modest 55% yield.5,8 In contrast, DMDO oxidation of
compound 2 predominantly gave the undesired anti-cis
stereochemistry, and hence Danishefsky et al. exploited
electrophilic phenylselenium reagents, also described by
Crich and Huang,30 to selectively cyclize N1,NR-Boc-Trp-
Based on these results, we suggest that a nucleophilic
R-nitrogen, as in dipeptide 8, may further promote facial
indole reactivity in a transition state (Figure 2) that
(31) Depew, K. M.; Marsden, S. P.; Zatorska, D.; Zatorski, A.;
Bornmann, W. G.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121,
11953.
(32) Jones, A. D.; Redfern, A. L.; Knight, D. W.; Morgan, I. R.;
Williams, A. C. Tetrahedron 2006, 62, 9247.
(33) Hong, W. X.; Chen, L. J.; Zhong, C. L.; Yao, Z. J. Org. Lett.
2006, 8, 4919.
(34) Ley, S. V.; Cleator, E.; Hewitt, P. R. Org. Biomol. Chem. 2003, 1,
3492.
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A. R. Org. Lett. 2008, 10, 77.
(30) Crich, D.; Huang, X. H. J. Org. Chem. 1999, 64, 7218.
92
Org. Lett., Vol. 14, No. 1, 2012

highly selective DMDO oxidation. This result should
be broadly applicable to those seeking diastereoselec-
tive indole oxidations en route to natural products
containing a syn-cis configured Hpi and may obviate
the need for selenation and subsequent oxidative dese-
lenation. In addition, these results may have mechan-
istic implications for enzyme catalyzed biosyntheses of
the same.
Acknowledgment. J.P.M. was supported by a postdoc-
toral fellowship from The Royal Society (UK); D.M.P.
received a Senior Career Award from the Michael Smith
Foundation for Health Research in B.C.; this work was
supported by UBC start-up funds, funding from the
Michael Smith Foundation for Health Research in B.C.,
and funding from the Canadian Institute of Health Re-
search. The authors thank Professor Marco Ciufolini
(UBC Chemistry) for helpful discussions.
Figure 2. Concerted transition state of DMDO attack at the re-
face mediates cyclization to the syn-cis product.
resembles the less sterically congested syn-cis product. In
the absence of a nucleophilic nitrogen (e.g., in the case of
2), DMDO may react with the indole with less selectivity
prior to pyrrole ring closure. Such a transition state is
consistent with the kinetic irreversibility of DMDO oxida-
tion and steric considerations that favor the syn-cis con-
figuration for more sterically hindered peptides such as 8.
In summary, we report the first stereoselective syn-
thesis of the natural product brevianamide E based on a
Supporting Information Available. Experimental de-
tails and characterization of compounds. This material is
available free of charge via the Internet at http://pubs.acs.
org.
Org. Lett., Vol. 14, No. 1, 2012
93