Concise, enantioselective total syntheses of both the proposed and revised structures of (?)-versiquinazoline H

Article abstract of DOI:10.1016/j.cclet.2019.06.043

The enantioselective total synthesis of the putative structure of versiquinazoline H and three diastereomers has been achieved, which allowed the revision of the stereochemistry of this natural product. This six-step total synthesis relied on the evolution of the strategy that we previously developed, which features a DMDO-triggered tandem reaction. The modification of the lactamization step resulted in a significant improvement of yield that ensured the efficient total synthesis.

Full text of DOI:10.1016/j.cclet.2019.06.043

Accepted Manuscript
Title: Concise, enantioselective total syntheses of both the
proposed and revised structures of (null)-versiquinazoline H
Authors: Jiang-Feng Wu, Pei-Qiang Huang
PII:
DOI:
Reference:
S1001-8417(19)30373-0
https://doi.org/10.1016/j.cclet.2019.06.043
CCLET 5074
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Chinese Chemical Letters
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22 May 2019
15 June 2019
24 June 2019
Please cite this article as: Wu J-Feng, Huang P-Qiang, Concise, enantioselective total
syntheses of both the proposed and revised structures of (horbar;)-versiquinazoline H,
Chinese Chemical Letters (2019), https://doi.org/10.1016/j.cclet.2019.06.043
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Communication
Concise, enantioselective total syntheses of both the proposed and revised structures
of ()-versiquinazoline H
Jiang-Feng Wu, Pei-Qiang Huang
Department of Chemistry, Fujian Provincial Key Laboratory of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University, Xiamen
361005, China
ARTICLE INFO
ABSTRACT
Article history:
The enantioselective total synthesis of the putative structure of versiquinazoline H and three
diastereomers has been achieved, which allowed the revision of the stereochemistry of this
natural product. This six-step total synthesis relied on the evolution of the strategy that we
previously developed, which features a DMDO-triggered tandem reaction. The modification of
the lactamization step resulted in a significant improvement of yield that ensured the efficient
total synthesis.
Received 22 May 2019
Received in revised form 14 June 2019
Accepted 18 June 2019
Available online
Keywords:
Alkaloids
Total synthesis
Tandem reaction
Structural revision
Protecting group-free
Efficiency is the major concern of contemporary organic
synthesis [1]. Tandem/cascade/domino reaction [2] is an
effective strategy to achieve high efficiency. ()-Chaetominine
(1 in Fig. 1) is a hexacyclic fungal tripeptidal alkaloid isolated
from endophytes of different origins. Following the isolation of
chaetominine [3], its homologues and diastereomers ()-
isochaetominines A−C (2-4) and (+)-14-epi-isochaetominine C
(5) were isolated from the solid-substrate culture of an
Aspergillus sp. Fungus [4]. In 2016, Lin and coworkers reported
that during a screening of their marine microorganism library,
the gorgonian (Pseudopterogorgia sp.)-derived fungus
Aspergillus versicolor LZD-14-1 was found to possess inhibitory
effects against thioredoxin reductase (TrxR), a potential target
for the treatment of cancer, AIDS, and autoimmune diseases. The
investigation led to the isolation of eleven new fumiquinazoline-
type alkaloids named versiquinazolines A−K [5]. Among them,
()-versiquinazoline H (6, the structure displayed in the original
paper [5]) also belongs to the chaetominine family. Its relative
stereochemistry was determined by 2D NMR techniques, and the
absolute configuration was determined to be 14S,16S,17S,26R
(referring to 2S,3S,11R,14S according to the numbering system
used for compounds 1-4) based on the comparison with a known
compound [()-isochaetominine C (4)] [6], and on a comparison
of the experimental ECD data with those of calculated for 6 and its
(Ile) unit was determined to be L by analysis of the degradation
product.
Fig. 1. Some chaetominine-family alkaloids.
The enantioselective total synthesis of ()-chaetominine has
been reported by several groups [7], and the diastereodivergent
synthesis of this family of alkaloids has been achieved by the
enantiomer. On the other hand, the configuration of the isoleucine
———

Corresponding author.
E-mail address: pqhuang@xmu.edu.cn (P.-Q. Huang)

Huang group [6,8]. We have developed three enantioselective
approaches to the chaetominine-family alkaloids. The first-
generation approach is the four-step total synthesis of ()-
chaetominine from D-tryptophan (Trp) [7c,f,i,8a]. The second
approach involves the first total synthesis of ()-chaetominine
from L-Trp [7g]. The third-generation method resides in using
amino acid benzyl esters as components that allows accessing
C2/C14 cis-stereochemistry of the isochaetominine series of
alkaloids [8b]. On the basis of these precedents, we report herein
the fourth-generation total synthesis. Through this improved
approach, we have achieved the first total synthesis of ()-
versiquinazoline H (7) and the proposed structure (6) as well as
their diastereomers. The puzzle about the stereochemistry of ()-
versiquinazoline H has been clarified.
We opted for the total synthesis of the displayed structure
(2S,3S,11R,12S,14S)-versiquinazoline H (6, Fig. 1) as the first
objective of this investigation. For this purpose, Huang’s third
generation approach was adopted [8b]. Thus, the synthesis
commenced with the known N-aroyl-L-tryptophan 8 [7g],
prepared by aroylation of L-tryptophan (L-Trp) with o-
nitrobenzoyl chloride (Scheme 1). The coupling of the mixed
intermediates with an aqueous Na2SO3 [8] at 45 C for 2 h
afforded, in one-pot, the double cyclization product 11 along
with monocyclization product 12 in 32% and 33% yield,
respectively. O-Debenzylation of 12 under catalytic
hydrogenolytic conditions yielded the corresponding acid
derivative 13, which, without isolation, was subjected to
lactamization conditions. However, under the previously used
lactamization conditions [(COCl)2 (1.5 equiv.), DIPEA (2.0
equiv.), cat. DMF, DCM (0.04 mol/L), 10 ºC, 45 min], the
desired product 6 was obtained in only 29% yield. Increasing
(COCl)2 from 1.5 equiv. to 3.0 equiv. led to an even lower yield
(20%). Employing the Ye coupling reagent (DEPBT) [(2.0 equiv.)
[11], DIPEA (2.0 equiv.), DCM (0.04 mol/L), 25 ºC, 8 h]
resulted in a higher yield of 54%. Finally, it was found that
another coupling method employing HOAt (6.0 equiv.) and
EDCI (3.0 equiv.) in dichloromethane (0.05 mol/L) (30 ºC, 12 h)
produced the proposed structure of versiquinazoline H (6) in 95%
yield over two steps. The sense of optical rotation {[α]D20 69.6 (c
0.1, CH3OH)} and spectral (1H and 13C NMR) data of our
synthetic compound are different from those reported for the
20
natural ()-versiquinazoline H {[]D 100 (c 0.1, MeOH) [5]},
anhydride, generated in situ from
8
and i-BuOCOCl/N-
suggesting that the originally proposed stereochemistry (6) for
methylmorpholine (NMM), with benzyl D-allo-isoleucinate p-
toluenesulfonic acid salt (THF, 20 C, 12 h) afforded 9 in 92%
yield. The low-valent Ti-reagent mediated-quinazolinone
formation [9] (Zn/TiCl4 and trimethyl orthoformate, THF) [7c]
proceeded smoothly at 0 C to give 10 in 95% yield. Exposure of
10 to DMDO [8,10] at 78 C followed by treating the resultant
()-versiquinazoline H was incorrect.
To address the enantioselective total synthesis of the natural
()-versiquinazoline H, we commenced with the identification of
the stereoisomers of the amino acids present in ()-
versiquinazoline H.
Scheme 1. The enantioselective total synthesis of the proposed structure of versiquinazoline H (6).
A closer inspection of the original paper [5] showed that the
evidences provided and conclusion obtained about the
stereochemistry of ()-versiquinazoline H are contradictory.
First, the authors stated: “the absolute configuration was
determined to be 14S,16S,17S,26R based on the closely similar
ECD and specific rotation data of ()-versiquinazoline H and
()-isochaetominine C (4)” [6]. However, as can been seen from
Fig. 1, in terms of stereochemistry, the ring system of ()-
isochaetominine C (4) appears to be an “enantiomer” of the
proposed structure of “()-versiquinazoline H” (6) for the on-
ring stereogenic centers. Second, they described: “the
configuration of the isoleucine unit has been determined to be L
by the advanced Marfey’s method”. However, the proposed
structure of “()-versiquinazoline H” (6) contains a D-allo-Ile
instead of an L-Ile residue. This analysis allowed us to suggest
stereoisomer 7 as the actual structure of the natural ()-
versiquinazoline H.
To further confirm the structure of the natural ()-
versiquinazoline H, we proceeded to synthesize the stereoisomer
7 containing D-Trp and L-Ile residues. Under the standard
conditions [7f], the coupling of the known (R)-8 with benzyl L-
isoleucinate p-toluenesulfonic acid salt yielded compound 14 in
93% yield. The latter was converted to 15 in 95% yield. The
DMDO oxidation of 15 followed by treating the resulting

mixture with a saturated aqueous solution of Na2SO3 at 45 C for
produced the double cyclization product 16 and
those reported for the natural versiquinazoline H, but a difference
exists for the values of specific rotation {synthetic 7: []2D0 74.6
(c 0.1, MeOH); natural product (colorless oil): []2D0 100 (c 0.1,
MeOH) [5]}. The results allowed us to conclude that the
stereochemistry of the natural ()-versiquinazoline H to be
2R,3R,11S,12S,14R as represented by 7. It is worth noting that,
H14, H19, H25, C13, C14, C17, C18, and C23 of compounds 11
and 16 are very broad, which are similar to the observations
noted by Tan [3a], Snider [7a], and Huang for chaetominine
[3a,7a,8b].
2
h
monocyclization product 17 in 32% and 35% yield, respectively.
O-Debenzylation of 17 under catalytic hydrogenolytic conditions
yielded the corresponding amino acid, which, without separation,
was subjected to our newly established lactamization conditions
[HOAt (6.0 equiv.), EDCI (3.0 equiv.), DCM (0.05 mol/L), 30
ºC, 12 h], which produced compound 7 as a white solid in 97%
yield over two steps. The sense of optical rotation and spectral
(1H and 13C NMR) data of our synthetic compound fully matched
Scheme 2. The enantioselective total synthesis of ()-versiquinazoline H (7).
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In summary, through evolution of our previously developed
strategy, we have completed the first total synthesis of both the
proposed and the revised structures of versiquinazoline H both in
six steps with an overall yield of 24.4% and 27.3%, respectively.
Through this fourth-generation strategy, the stereochemistry of
this natural product has been revised to 2R,3R,11S,12S,14R.
Work is in progress in our laboratories to further extdend this
efficient strategy [12], and results will be reported in due course.
Acknowledgments
The authors are grateful for the financial support from the
National Natural Science Foundation of China (Nos. 21672176
and 21332007) and the National Key R&D Program of China
(No. 2017YFA0207302). We thank Ms. Yan-Jiao Gao for
assistance in the preparation of this manuscript.
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Graphical Abstract
The first enantioselective total synthesis of the putative
structure of versiquinazoline H and three diastereomers has
been achieved, which allowed revising the stereochemistry of
this natural product.