Complexity generation by chemical synthesis: A five-step synthesis of (-)-chaetominine from l-tryptophan and its biosynthetic implications

Article abstract of DOI:10.1039/c4ob00314d

We demonstrated, for the first time, that on the basis of chemistry principles, the hexacyclic peptidyl alkaloid (-)-chaetominine (1) can be synthesized in a straightforward manner from l-Trp. The approach features the efficient generation of molecular complexity via a tandem C3/C14 syn-selective epoxidation (dr = 3:2)-annulative ring-opening reaction and a regioselective epimerization at C14. The successful production of (-)-chaetominine (1) from l-Trp could be helpful for revealing how the configuration of l-tryptophan becomes inverted in the biosynthetic pathway of (-)-chaetominine (1). This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00314d

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Complexity generation by chemical synthesis:
a five-step synthesis of (−)-chaetominine from
Cite this: Org. Biomol. Chem., 2014,
12, 2859
L-tryptophan and its biosynthetic implications†‡
Received 11th February 2014,
Accepted 13th February 2014
Chu-Pei Xu,a Shi-Peng Luo,a Ai-E Wanga and Pei-Qiang Huang*a,b
DOI: 10.1039/c4ob00314d
www.rsc.org/obc
We demonstrated, for the first time, that on the basis of chemistry olemda.10,11 Like many other peptidyl alkaloids isolated from
principles, the hexacyclic peptidyl alkaloid (−)-chaetominine (1) the fungal genus Aspergillus,12a (−)-chaetominine also pos-
can be synthesized in a straightforward manner from L-Trp. The sesses a quinazolinone ring system.12 It is interesting that a
approach features the efficient generation of molecular complexity non-proteinogenic D-Trp residue is incorporated in (−)-chaeto-
via a tandem C3/C14 syn-selective epoxidation (dr = 3 : 2)–annula- minine. The synthesis9,11,14 and biosynthesis13 of these com-
tive ring-opening reaction and a regioselective epimerization at pounds have therefore attracted much attention. Thanks to the
C14. The successful production of (−)-chaetominine (1) from L-Trp seminal work of Walsh, Tang and co-workers, efficient biosyn-
could be helpful for revealing how the configuration of L-trypto- thetic pathways for complexity generation have been revealed
phan becomes inverted in the biosynthetic pathway of (−)-chaeto- for several peptidyl alkaloids.13 Tan8a and Walsh/Tang13b have
minine (1).
independently suggested two plausible biosynthetic pathways
to (−)-chaetominine (1) (pathways A and B in Scheme 1), in
which the tetracyclic core is constructed via an intramolecular
oxidative cyclization of nine-membered bislactam A or C.
We envisioned another scenario that involves compound 4
as the direct precursor for intramolecular oxidative cyclization
(Scheme 2). On the basis of this consideration, we have devel-
oped a bio-inspired four-step total synthesis of (−)-chaeto-
minine (1) from D-tryptophan (Scheme 2).9c,f The synthesis
is remarkably concise and efficient, except that the diastereo-
selectivity is unsatisfactory in the epoxidation step, which
gives the desired α-epoxide (α-5) as the minor product.
On the other hand, although L-tryptophan has been
suggested to be the starting material in the biosynthesis of
(−)-chaetominine (1),8a,13a,15 all the reported total syntheses of
(−)-chaetominine (1) used D-Trp as a starting material.9 More-
over, in the proposed biosynthetic pathways, how the configur-
ation of L-tryptophan becomes inverted is still obscure. Since
An ideal synthesis is the ultimate goal in the field of the total
synthesis of complex natural products.1 Biomimetic synthesis
is one of the most efficient strategies for this aim.2 However,
most biogenetic pathways are unknown or unconfirmed by
incorporation experiments.3 Even the biosynthesis of simple
tropane alkaloids remains an unsolved century-old problem.4
A biosynthetic perspective has turned out to be helpful in
designing highly efficient synthetic approaches and tremen-
dous progress has been made recently.2,5,6 In this context, the
total synthesis of natural products plays an important role in
postulating and confirming biogenetic pathways.2,5–7
(−)-Chaetominine (1) (Fig. 1) is a hexacyclic alkaloid iso-
lated first from the solid-substrate culture of Chaetomium sp.
IFB-E015, an endophytic fungus on apparently healthy Adeno-
phora axilliflora leaves,8a,9 and later from the metabolites of
Aspergillus sp. HT-2 collected from Guizhou province, China.8b
The characteristic tetracyclic core structure of (−)-chaetomi-
nine (1) (but with a different stereochemical pattern) is also
found in kapakahines (e.g. 2 and 3 in Fig. 1), a group of seven
cyclic peptides isolated from the marine sponge Cribrochalina
aDepartment of Chemistry, College of Chemistry and Chemical Engineering,
Xiamen University, Xiamen, Fujian 361005, China
bState Key Laboratory of Applied Organic Chemistry, Lanzhou University,
Lanzhou 730000, China. E-mail: pqhuang@xmu.edu.cn; Tel: +86-592-2182240
†Dedicated to Professor Dr Siméon Arseniyadis.
‡Electronic supplementary information (ESI) available: Experimental pro-
cedures, compound characterization data, and 1H and 13C NMR spectra of the
compounds. See DOI: 10.1039/c4ob00314d
Fig. 1 Structures of (−)-chaetominine (1) and kapakahines B and F.
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reaction to produce 8 (Scheme 2). Therefore, it is possible
to undertake an unprecedented total synthesis of (−)-chaeto-
minine (1) starting from L-tryptophan by taking advantage of
both the observed C3/C14 syn-diastereoselective epoxidation
and the base-promoted epimerization at C14.
The synthesis commenced with the aroylation of L-trypto-
phan with o-nitrobenzoyl chloride (THF, 1 M NaOH, 0 °C, 2 h),
which produced compound (S)-9 in 91% yield (Scheme 3).
Treatment of compound 9 with i-BuOCOCl–N-methylmorpho-
line (NMM, THF, −30 °C, 60 min) gave the corresponding acti-
vated ester, which reacted in situ with L-alanine methyl ester
hydrochloride salt (THF, NMM, −20 °C, 12 h) to yield the
dipeptide derivative 10 in 93% yield. The quinazolinone ring
Scheme 1 Key steps of the plausible biosynthetic pathways for system12 was constructed by a minor modification of Shi’s
method.17 10 was thus treated with HC(OMe)3 and low valent
titanium, generated in situ from TiCl4 and Zn powder in THF
(−)-chaetominine (1) proposed by Tan (pathway A) and Walsh/Tang
(pathway B).
at 50 °C, to give the desired quinazolinone 11 in 95% yield. For
the key epoxidation triggered tandem reaction, our previously
established conditions9c,f were modified to improve the yield
there exist three possible ways for
a non-proteinogenic
D-amino acid to be incorporated into a natural product,16 figur-
ing out the origin of the D-tryptophan residue in chaetominine
(1) is important for understanding the biogenetic route of
chaetominine (1). Within this context, we embarked on a
project to see if on the basis of chemistry principles, (−)-chae-
tominine (1) could be synthesized in a straightforward manner
starting from L-Trp. The results of this investigation are
reported herein.
of the desired diastereomer. In this study, the treatment of qui-
nazolinone 11 with DMDO18 in acetone at −78 °C followed by
work-up with aqueous Na2SO3 produced the mono-cyclized
product 12 in 48% yield along with 2,3,14-tri-epi-chaetominine
(8) in 32% yield. A similar result was obtained when the reac-
tion was run at −95 °C. Performing the epoxidation under
Shi’s asymmetric epoxidation conditions,19 or with m-CPBA,
Oxone, hydrogen peroxide and Davis’ N-sulfonyloxaziridine,20
led only to the recovery of the starting material.
We next proceeded to investigate the selective epimerization
at C14 of compound 12. Unexpectedly, the treatment of 12
with MeONa in MeOH at −10 °C produced the C14 and C11
bis-epimerized product (−)-11-epi-chaetominine (ent-8) in 82%
yield. The use of other inorganic bases such as K2CO3 or
organic bases such as Et3N, DBU, DBN and TMG did not give
improved results. After extensive trials, it was found that by
heating a toluene solution of 12 in the presence of 0.1 equiv of
In our first generation total synthesis of (−)-chaetominine
(1) from D-Trp (Scheme 2),9c,f C3/C14 syn-selection was
obtained in the epoxidation of tripeptide 4. In addition, con-
comitant epimerization at C14 was observed in the base-
promoted cyclization of compound 7 to compound 8.9f In con-
nection with the spontaneous formation of (−)-chaetominine
(1) from amino ester 6 observed in the epoxidation step, we
assumed that the epimerization at C14 of 7 occurred first to
give 7a, which facilitated a subsequent tandem lactamization
Scheme 2 The key cascade reaction in our previous four-step total synthesis of (−)-chaetominine (1) from D-tryptophan and a transformation of
compound 7.
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Scheme 3 The five-step synthesis of (−)-chaetominine (1) from L-tryptophan. Reagents and conditions: (i) o-nitrobenzoyl chloride, 1 M NaOH, THF,
i
0 °C; (ii) H-L-Ala-OMe·HCl, ClCO2 Bu, NMM, THF, −20 °C; (iii) HC(OMe)3, Zn/TiCl4, THF, 0 °C; (iv) DMDO, THF, −78 °C, 1 h; Na2SO3 (aq.), 0 °C; (v)
DMAP (0.1 equiv.), tol., reflux, 7 days.
Scheme 4 Plausible biosynthetic pathway of (−)-chaetominine (1) from L-Trp.
DMAP for 7 days, (−)-chaetominine (1) was obtained in a nonyl group. A base-promoted epimerization at C-14 of 7 and
respectable yield of 60%, alongside 19% of the bis-epimerized 12 relieves the steric hindrance and results in tandem lactami-
product (−)-11-epi-chaetominine (ent-8).
zation to give 8 (Scheme 2) and chaetominine (1) (Scheme 3),
Consistent with the results from the epoxidation of quina- respectively.
zolinono-dipeptide 4 (D-Trp-L-Ala-OMe) (Scheme 2),18d,e the
The chemical information we gained during these studies
epoxidation of L-Trp-L-Ala-OMe derivative 11 proceeded with a of the synthesis of (−)-chaetominine (1) allowed us to suggest
3 : 2 C3/C14 syn/anti diastereoselectivity to produce compound a plausible biosynthetic pathway for (−)-chaetominine (1)
12 as the major product (Scheme 3). These results imply that (Scheme 4). Our hypothesis involves epoxidation-triggered
the Trp residue predominates over the Ala residue in asym- lactamization which converts tripeptide derivative E to F, and
metric induction. The syn-stereoselectivity can be explained by the selective epimerization at C14 of the intermediate G
the model11b suggested by Danishefsky.21
that triggers the subsequent lactamization to produce (−)-chae-
In addition, the direct formation of chaetominine (1) from tominine (1).
4 (Scheme 2), and 8 from 11 (Scheme 3) implies that an anti-cis
arrangement of the hydroxyl group at C3 and the quinazolino-
Conclusions
nyl group favors lactamization. By contrast, the syn-diastereo-
mers 7 and 12 failed to lactamize because of the steric
hindrance between the hydroxyl group at C3 and the quinazoli-
In conclusion, we have shown that L-tryptophan, o-nitroben-
zoyl chloride, L-alanine, and anthranilic acid can be assembled
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in five steps to give (−)-chaetominine (1) with an overall yield
of 23.2%, and (−)-11-epi-chaetominine (ent-8) with an overall
yield of 31.7%. This validation of L-Trp as a starting material
in the chemical synthesis of (−)-chaetominine has some impli-
cations for the biosynthesis of (−)-chaetominine: (1) L-Trp
might be the starter unit; (2) instead of an early inversion
of configuration of D-Trp to L-Trp, an epimerization at C-14
of a tripeptide intermediate may possibly establish the
R-configuration at C-14 of (−)-chaetominine; (3) the acyclic
tripeptide derivative 11 (cf. A and C in Scheme 1) may serve as
a ready precursor of (−)-chaetominine. The total synthesis also
serves as a good example of step economy and redox economy,
as well as the protecting-group-free and complexity-generating
synthesis of structurally complex natural products.
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Acknowledgements
The authors are grateful for financial support from the
National Basic Research Program (973 Program) of China
(grant no. 2010CB833200), the Natural Science Foundation of
China (NSFC, grant no. 21332007), and the Program for
Changjiang Scholars and Innovative Research Team in Univer-
sity (PCSIRT) of Ministry of Education, China. We are indebted
to Prof. Z.-H. Guo (HKUST), Prof. Z.-J. Yao (NJU) and Prof. Wen
Liu (SIOC, CAS) for valuable discussion.
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