Total synthesis of dixiamycin B by electrochemical oxidation

Article abstract of DOI:10.1021/ja5013323

N-N-linked dimeric indole alkaloids represent an unexplored class of natural products for which chemical synthesis has no practical solution. To meet this challenge, an electrochemical oxidative dimerization method was developed, which was applied as the pivotal step of the first total synthesis of dixiamycin B. This method is also general for N-N dimerization of substituted carbazoles and β-carbolines, providing entry into seldom explored chemical space.

Full text of DOI:10.1021/ja5013323

Communication
pubs.acs.org/JACS
Total Synthesis of Dixiamycin B by Electrochemical Oxidation
Brandon R. Rosen,‡ Erik W. Werner,‡ Alexander G. O’Brien, and Phil S. Baran*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
S
* Supporting Information
ABSTRACT: N−N-linked dimeric indole alkaloids rep-
resent an unexplored class of natural products for which
chemical synthesis has no practical solution. To meet this
challenge, an electrochemical oxidative dimerization
method was developed, which was applied as the pivotal
step of the first total synthesis of dixiamycin B. This
method is also general for N−N dimerization of
substituted carbazoles and β-carbolines, providing entry
into seldom explored chemical space.
ynthetic chemists have long been enamored by the
structures of oligomeric indole alkaloids. The myriad
S
different C−C (e.g., 1, Figure 1A) and C−N (e.g., 2) linkages
have inspired the development of numerous elegant methods to
enable their chemical production.1 Recently, the atropisomeric
indoloterpenoid natural products dixiamycins A and B were
isolated independently by Zhang and Hertweck (3a/b).2 These
molecules express a new and unexplored dimerization mode: an
N−N linkage. Intriguingly, the N-linked dimeric forms of these
antibacterial natural products are nearly an order of magnitude
more potent than their monomeric siblings.2a The current
toolbox of methods for constructing N−N bonds of this type is
poorly equipped (vide infra) to address the challenge of their
practical preparation. In general, molecules containing an N−N
bond are prepared using hydrazine,3 a non-viable option in a
synthesis of 3a/b due to the overall inefficiency of a linear bis-
functionalization route outward from a hydrazine core. Previous
efforts from this laboratory (Figure 1B) demonstrated the
practicality of an indole alkaloid synthesis plan in which two
fragments were directly cross-coupled by oxidative C−C bond
formation (formal loss of H2).4 In a similar vein, the goal of this
work was to invent a direct oxidative N−N dimerization of
carbazoles to bring two monomers together and liberate H2 as
the sole byproduct. This Communication reports the realization
of this goal through a remarkable electrochemical process that
permits chemoselective access to this unexplored area of
chemical space as exemplified by the first total synthesis of
dixiamycin B (3b).
Figure 1. Inspiration and strategy for the total synthesis of dixiamycins
A and B (3a/b).
Early optimization attempts focused on the dimerization
reaction of the readily available parent carbazole 5 (Figure 2A).
An exhaustive survey of chemical oxidants generally resulted in
little to no substrate conversion (for other failed experiments,
see the Supporting Information). For example, deprotonation
of 5 with LDA and treatment of the resulting anion with copper
2-ethylhexanoate, conditions known to facilitate oxidative C−C
bond formation, resulted only in recovered starting material.4a
Exposure of 5 to KMnO4 in refluxing acetone, an approach
envisioned to be incompatible with xiamycin’s vulnerable
functionality, afforded the corresponding dimer 6a irreprodu-
cibly and in low yield, confirming that the most promising
oxidation method was inadequate.6
A successful synthesis of 3a/b clearly hinges on the ability to
effect an N−N bond-forming event between two molecules of
xiamycin A (4). While KMnO4- or (PhCO2)2-mediated
conversion of 4 to 3a/b is possible, as indicated by HPLC
analysis, these reactions fail to deliver meaningful yields of
product.2a,c Additionally, the synthesis of N9−C4-linked bis-
carbazole dimeric natural product murrastifoline F has been
accomplished by treatment of a simple carbazole derivative with
Pb(OAc)4.5 Initial attention thus turned to the identification of
a reliable oxidant to access N-linked carbazole dimers.
With the failure of chemical transformations, we became
intrigued with the possibility of an electrochemical oxidation
Received: February 7, 2014
Published: April 3, 2014
© 2014 American Chemical Society
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Table 1. Scope of the N−N Dimerization Reaction of
Carbazoles and Carbolines
protons (6d). Anodic oxidation of the parent carbazole 6a was
accomplished in 63% yield, with virtually no change in isolated
yield when conducted on gram scale (61%).11 As a testament to
the chemoselectivity of this transformation, the more sensitive
epoxy−olefin dimer 6f was also prepared, a result that would be
impossible using an oxidant like KMnO4 (vide supra). Bis-β-
carboline products, including the unnamed natural product
7a,11 could also be prepared in reasonable yields (49% + 49%
recovered starting material). Substitution at C1 of the carboline
was tolerated (7c), indicating that steric crowding about the
dimerization site does not inhibit reactivity. In all cases where
comparison is possible, electrochemical oxidation is superior to
any reported means of effecting this transformation, high-
lighting the precise control of oxidation potential allowed by
electrochemistry.
Having established the feasibility of an electrochemical
carbazole N−N dimerization reaction, we pursued the synthesis
of xiamycin A (4). Following the procedure of Tanis and co-
workers,13 enantioenriched alcohol 8 was prepared on greater
than 10 g scale (Scheme 1). Parikh−Doering oxidation and
Wittig olefination afforded diene 9. Hydroboration/Suzuki
coupling with 2-bromocarbazole gave cyclization precursor
carbazole 10 in 75% yield on gram scale. Treatment of this
substrate with BF3·OEt2 resulted in formation of the desired
pentacycle 11 in low yield along with several isomers;
regioselectivity was improved by N-protection with Boc2O
before the cation−olefin cyclization, resulting in an isolated
yield of 11 of 49% (two steps), along with 15% unreacted
starting material. Simple hydrogenolysis of the benzyl group,
two-step oxidation of the primary alcohol, and Boc
deprotection gave xiamycin A (4). Using this sequence, more
than 1 g of 4 has been synthesized to date.
Figure 2. Development of the N−N dimerization reaction of carbazole
5.
leading to dimerization.7 Specifically, we were drawn to
investigations into the reactivity of carbazolium radical ions
by Ambrose and co-workers.7a These studies explored the
dimerization of 3-substituted and 3,6-disubstituted carbazoles at
N, C3, and C6 but lacked information regarding other
substitution patterns or functional group tolerance. This tactic
would have inherent advantages such as the absence of reagents
and a chemoselectivity that can be “dialed in” by running the
reaction at the exact potential required for dimerization.8
Examination of the cyclic voltammogram of 5 provided insight
into the inability of chemical oxidants to selectively deliver the
desired dimerization mode. As shown in Figure 2B, when a
sample of 5 is subjected to potentials above +1.6 V, extensive
decomposition is observed, while experiments employing a
constant potential below +1.1 V result in low conversion.
Gratifyingly, subjecting carbazole 5 to electrochemical
oxidation in DMF−Bu4NBr at a potential of +1.2 V led to
ca. 5% conversion to 6a, along with unreacted 5 (Figure 2C,
entry 1). Employing a new carbon electrode9 and introducing a
small amount of methanol10 further improved conversion to ca.
17% (entry 4), while extending the reaction time to 18 h led to
complete consumption of starting material and 60% isolated
yield of 6a (entry 5; structure verified by X-ray crystallographic
analysis, matching the known structure present in the
Cambridge Crystallographic Data Centre).
In order to test the generality of these reaction conditions,
N−N dimerization reactions of several simple carbazole
derivatives were evaluated (Table 1). These results indicate
that a variety of substituents at C2 are tolerated, including an
ester (6b), an alkyl group (6c), and a sulfone bearing acidic
With substantial quantities of 4 in hand, we next evaluated
the key electrochemical reaction of 4. Analysis of the cyclic
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a
Scheme 1. Total Synthesis of Dixiamycin B (3b) by Electrochemical Oxidation of Xiamycin A (4)
a
Reagents and conditions: (a) SO3·pyr (3 equiv), Et3N (4 equiv), DMSO, DCM; (b) MePPh3I (1.2 equiv), n-BuLi (1.2 equiv), THF; (c) i. 9 (1.75
equiv), 9-BBN (1.75 equiv), THF, then ii. 2-bromocarbazole (1 equiv), Pd(dppf)Cl2 (0.1 equiv), 10% NaOH, 60 °C; (d) Boc2O (1.2 equiv), Et3N
(1.5 equiv), DMAP (0.1 equiv), THF; (e) BF3·OEt2 (2 equiv), DCM, −78 °C; (f) H2 (1 atm), Pd(OH)2/C (0.2 wt equiv), MeOH; (g) TEMPO
(0.15 equiv), NCS (3 equiv), Bu4NI (0.15 equiv), DCM, aq NaHCO3/K2CO3; (h) NaClO2 (6 equiv), NaH2PO4·H2O (10 equiv), 2-methyl-2-
butene (10 equiv), t-BuOH, H2O; (i) H2O, EtOH, 100 °C; (j) carbon electrode, +1150 mV, Et4NBr, DMF, MeOH.
voltammogram of 4 indicated that a potential of +1.2 V would
be appropriate (see inset voltammogram). Thus, anodic
oxidation of 4 for 1 h afforded small amounts of 3b alongside
substantial recovered starting material and several byproducts.
A slight decrease in applied potential (+1.15 V) and an increase
in reaction time (4 h) improved the isolated yield to 28%, along
with 13% recovered 4; furthermore, bromoxiamycin 12 was
isolated in 17% yield. Given that chloroxiamycin (the
chlorinated analogue of 12) has been isolated,2a it is possible
that 12 represents a yet unisolated natural product.
Furthermore, attempts to reproduce the procedure of
Ambrose7a (a challenge due to the “home-built potentiostat”
employed) resulted in no reaction, and attempts to adapt
elements of that procedure to our system (addition of
collidine) led to comparable results. Interestingly, although
we had initially anticipated that any N−N dimerization of 4
would unselectively give a mixture of 3a/b, analysis of the crude
NMR spectrum of the reaction indicated only formation of 3b
along with what appear to be various N−C and C−C dimers.
At this stage it is unclear whether 3a forms under the reaction
conditions and rapidly decomposes or 3b is formed selectively.
The observed atropselectivity is complementary to that
reported by Zhang and co-workers,2a whereby alongside several
side products, trace amounts of 3a were detected by HPLC
analysis of the reaction between 4 and KMnO4 without
detection of 3b.
total synthesis of dixiamycin B (3b), a rare N−N-linked dimeric
natural product. This approach to late-stage N−N bond
formation is strategically unique in that it obviates the need
for bis-functionalization otherwise required by the use of a
hydrazine derivative. Moreover, it is difficult to envision an
alternative chemical means of accomplishing this trans-
formation that would compare with the practicality of anodic
oxidation. Further studies on electrochemical functionalization
of heterocycles for the synthesis of natural products are
currently underway and will be reported in due course.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and analytical data (1H and 13C
NMR) for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
pbaran@scripps.edu
Author Contributions
‡B.R.R. and E.W.W. contributed equally.
Notes
The authors declare no competing financial interest.
Given the infrequent appearance of N−N-linked carbazoles
in the literature, several properties of 6a were investigated. 6a
was found to be stable to acid (excess TFA, 24 h), base (0.5 M
KOH, MeOH, 24 h), light (220 nm, 24 h), and even elevated
temperature (at 165 °C, T1/2 = 8 h). The high stability of 6a
suggests that dimerized carbazoles could represent viable
building blocks for potential use in the pharmaceutical,
agrochemical, and materials industries.
ACKNOWLEDGMENTS
■
Financial support for this work was provided by the NIH/
NIGMS (GM-073949) and the NSF for a predoctoral
fellowship to B.R.R. We are grateful to Pfizer Inc. for a
postdoctoral fellowship to A.G.O. We are grateful to Prof. A.
Rheingold and Dr. C. E. Moore (UCSD) for X-ray crystallo-
graphic analysis, Dr. D.-H. Huang and Dr. L. Pasternack for
assistance with NMR spectroscopy, and Dr. Y. Ishihara for
helpful discussions.
In summary, a unique method of electrochemical dimeriza-
tion of carbazoles and carbolines has been reported. This ability
to selectively “dial in” oxidation potential has enabled the first
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outer layer was scraped with a razor before reuse. For more
information, see the Supporting Information.
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