Total Synthesis of Spirotryprostatins through Organomediated Intramolecular Umpolung Cyclization

Article abstract of DOI:10.1002/chem.201806411

Cyclodipeptide 2,5-diketopiperazines (DKP) are privileged structural units present in drugs and natural alkaloids. This work reports a new method for the synthesis of biologically important DKP scaffolds based on an intramolecular nucleophilic α-addition of general amides towards an alkynamide system. The utility of this umpolung cyclization mediated by trimethyl phosphine and l-glutamic acid is highlighted by its application to the concise total syntheses of 6-methoxyspirotryprostatin B (the first total synthesis), spirotryprostatin A, and spirotryprostatin B.

Full text of DOI:10.1002/chem.201806411

A Journal of
Accepted Article
Title: Total Synthesis of Spirotryprostatins Via Organomediated
Intramolecular Umpolung Cyclization
Authors: Hong Bin Zhang, Yong-Kai Xi, Rui-Xi Li, Shi-Yuan Kang, Jin
Li, and Yan Li
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DOI: 10.1002/chem.200((will be filled in by the editorial staff))
Alkaloid Synthesis
Total Synthesis of Spirotryprostatins Via Organomediated Intramolecular
Umpolung Cyclization 
Yong-Kai Xi, Hongbin Zhang*, Rui-Xi Li, Shi-Yuan Kang, Jin Li, Yan Li
ABSTRACT: The cyclodipeptide 2,5-diketopiperazines (DKP) are
privileged structure units presented in drugs and natural alkaloids.
Herein, we report a new method for the synthesis of biologically
important DKP scaffolds based on an intramolecular nucleophilic
-addition of general amides towards alkynamide system. The utility
of this umpolung cyclization mediated by trimethyl phosphine and L-
glutamic acid is highlighted by its application to the concise total
syntheses of 6-methoxyspirotryprostatin B (the first total synthesis),
spirotryprostatin A and spirotryprostatin B.
acrylamide units. In this paper, we report an organo-mediated
intramolecular C-N bond formation to construct the DKP derivatives
bearing an -amido acrylamide units, and concise total syntheses of
spirotryprostatins and related alkaloids based on this new process.
Our synthetic analysis for natural DKP alkaloids is outlined in
Scheme 1. We plan to synthesize the desired 3-ylidene-2,5-diketo-
piperazines by an umpolung intramolecular cyclization between
amide moiety and alkynamide subunit (Scheme 1, transformation of
intermediate 9 to 10).
A large number of alkaloids isolated from fungi, bacteria and the
plant kingdom contain 2,5-diketopiperazine (DKP) structure units (1,
Scheme 1).[1] Some of these natural products are biologically active
due to the presence of DKP ring system.[2] Representative
compounds are indicated in Scheme 1, such as 6-methoxy-
spirotryprostatin B (3) and spirotryprostatin B (4), two antitumor
agents,[3] fumitremorgin B (5), displays potent activity against multi-
drug resistant (MDR) cancer cell lines.[4] The DKP units have been
identified as privileged structure by medicinal chemists in drug
development,[1] and have also been found in a number of important
drugs (7: for treatment of erectile dysfunction, 8: an anti-cancer
drug) and drug candidates.[2] Owing to its important role in
biological activities, numerous efforts have been directed towards
the synthesis of highly substituted DKPs. These endeavours have
also served as topics for several reviews and book chapters.[1e,f,g,i,5]
However, new methods directly leading to the synthesis of DKPs
containing -amido acrylamide moiety, subunits presented in
spirotryprostatins (3 and 4), spirobrocazine C (2) and plinabulin (8)
are rather limited.[1e,2b,6] Although spirotryprostatin B has been the
target of several elegant syntheses,[7] the synthetic efficiency or
stereoselectivities still need to be improved in the viewpoint of
practical synthesis. There is no report for the total synthesis of 6-
methoxyspirotryprostatin B. It is therefore our goal to develop a
flexible and stereoselective strategy towards the synthesis of
spirotryprostatin alkaloids, especially the 6-methoxyspiro-
tryprostatin B (3) and spirotryprostatin B (4) bearing -amido
O
O
O
H
R1
R2
R3
R6
R5
N
Ph
NH N
N
NH
HN
N
N
N
R4
H
O
O
O
8: Plinabulin
1: 2,5-Diketopiperazines
O
O
N
O
H
7: Tadalafil
H
O
N
O
OH
N
R
O
N
N
O
O
H
H
3: R = OMe, 6-Methoxyspirotryprostatin B
4: R = H, Spirotryprostatin B
2: Spirobrocazine C
OH
OH
O
O
E
N
N
D
N
H
R
N
N
C
H
O
H
O
H
A
B
N
R
H
5: R = OMe, Fumitremorgin B
6: R = H, Cyclotryprostatin C
11
O
proposed -addition
of amide towards
alkynamide
O
N
N
H
H
HN
N
O
O
organo catalysts
R1 = H, Alkyl
R1
R1
N
N
R
R = H, OMe
R
H
H
9
10
Scheme 1 DKP alkaloids or drugs and our synthetic analysis.
In 1997, Trost’s group reported the first umpolung intermolecular
-additon reaction of alkynoates with phthalimide derivatives and
[9]
sulfonamides (Scheme 2, eq.1).[8] Various nucleophiles
[]
Prof. Dr. H. Zhang, Mr. Y.-K. Xi, Mr. R.-X. Li, Ms. S.-Y.
Kang, Mr. J. Li and Ms. Y. Li
(amines,[9d,e] alcohols,[9f,g,h] thiols,[9i] thioureas,[9j] purine and
thymine [9k]) have been used in the intermolecular -addition
towards alkynoates after Trost’s pioneering contribution. To the best
of our knowledge, however, only three examples were reported in
the literature using -addition of amides towards alkynamides
(Scheme 2, eq. 2 and 3).[10] No example has ever been documented
for the synthesis of 3-ylidene-2,5-diketo-piperazine rings using an
intramolecular umpolung cyclization between general amide moiety
and alkynamide unit as proposed in Scheme 1.
Key Laboratory of Medicinal Chemistry for Natural
Resource, Ministry of Education and Yunnan province,
State Key Laboratory for Conservation and Utilization of
Bio-Resources in Yunnan, School of Chemical Science and
Technology, Yunnan University, Kunming, Yunnan 650091,
P. R. China
E-mail: zhanghb@ynu.edu.cn
[] This work was supported by grants from the Program for
Changjiang Scholars and Innovative Research Team in
University (IRT17R94), Natural Science Foundation of
China (21332007, U1702286 and 21572197), Yun-Ling
scholar of Yunnan Province.
Given the importance of DKP structure units, we decided to
explore the proposed intramolecular cyclization using alkynamide
12 as a model substrate. There are two key stereochemistry issues
associated with DKPs containing -amido acrylamide unit, namely
to control the double bond E/Z isomerization and the DKP ring
Supporting information for this article is available on the
WWW under http://www.angewandte.org or from the
author.((Please delete if not appropriate))
1
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10.1002/chem.201806411
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epimerization.[11] We initially conducted the reaction under
Yajima’s and Trost’s reaction conditions (Table 1, entry 1-3),
unfortunately, no reactions were observed. Next, less hindered tri-n-
butyl phosphine was used instead of Ph3P. To our delight, this
modification gave the desired product in 23% yield (Table 1, entry
4). Further investigation finally led to the optimal reaction
conditions, the combination of trimethyl phosphine with L-glutamic
acid in toluene and DMF (entry 10). This reaction provided 13a and
13b in 93% isolated yields (13a : 13b > 10 :1, no epimerization was
observed).[12] Although the exact role of L-glutamic acid is unclear,
we believe that besides providing and accepting proton more
efficiently, glutamic acid might also serve as a molecular bridge
which brings together the Michael donor and the acceptor and
activates the substrates through ion pairs and hydrogen bonds
(proposed model in Scheme 3).
[a] Yields represent isolated yields. Cyclization reactions were conducted
at 0.5 mmol scale in a Teflon cap sealed tube. [b] Reactions were carried out
in the presence of NaOAc (0.5 eq) and HOAc (0.5 eq) for 6 hours at 105 ºC
oil bath. [c] Reactions were carried out for 6 hours at 100 ºC oil bath. [d]
Reactions were carried out for 6 hours at 80 ºC oil bath.
Next, we turned our attention to substrate scope, and a number of
3-ylidene-2,5-diketo-piperazines were synthesized under the optimal
reaction conditions. The primary amides worked equally well
(Scheme 3, R = H). A number of functional groups such as OH, Ac,
TBS, PMB and nitro groups were compatible with our reaction
conditions. The geometric structures of 13a and 13b were
established by 1H-NMR and X-ray crystallography (13a),[12] and the
remaining examples were assigned by analogy (see supporting
information for detail assignment).[13] We found that the E/Z
geometry could be controlled to some extent by introduction of
steric hindrance on amides, for example, when R = H, Z geometric
compounds were dominated (14, 17, 18, 24, 25, 29 and 30), while
with R = aromatic or alkyl groups, E geometric products (the rest of
examples in Scheme 3) became the major products.
Scheme 2 Previous -addition towards alkynoate derivatives.
Table 1 Optimization of reaction conditions for alkynamide 12a
entry
solvents, R3P
additives
yields (%) ration
13a+13b 13a/13b
1
2
3
CH2Cl2, Ph3P
Toluene, Ph3P
None, 40 ºC
NaOAc, HOAc
NaOAc, HOAc
Recovery of 12
Recovery of 12 b
Recovery of 12 b
Toluene : DMF
(6:1), Ph3P
4
5
6
7
Toluene, nBu3P
Toluene, Me3P
Toluene, Me3P
Toluene, Me3P
NaOAc, HOAc
NaOAc, HOAc
L-proline
23%
33%
33%
6 : 1 b
6 : 1 b
7 : 1 c
Scheme 3 Substrate Scope (Z/E ratios determined by 1H-NMR).
Having established the intramolecular cyclization procedure, we
began to explore the total synthesis of spirotryprostatin B related
alkaloids. Treatment of indoles 36a and 36b with iodine followed by
Boc anhydride afforded iodo-indoles (Scheme 4, 37a and 37b) in
93% yield.[14] Coupling 37a and 37b with trimethylsilyl acetylene
respectively in DMF in the presence of palladium and copper
Sodium L-
68% 10 : 1 c
Glutamate
8
9
Toluene : DMF
(6:1), Me3P
Sodium L-
92% 10 : 1 c
Glutamate
afforded alkynylsilanes (38a and 38b) in 92% yield.[14b,15]
Toluene : DMF
(6:1), Me3P
None
28%
6 : 1 c
[16]
Carboxylation of alkynylsilanes with carbon dioxide
provided
acid 38c (unstable, used directly without purification), after
condensation with S-prolinamide in the presence of DCC, amides
(39a and 39b) were obtained in 70-72% yields. Treatment of
alkynamides (39a and 39b) under our intramolecular umpolung
10
Toluene : DMF
(6:1), Me3P
L-Glutamic acid
93% 10 : 1 d
2
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cyclization conditions gave the 3-ylidene-2,5-diketo-piperazine Z-
isomers (40a and 40b) together with its E-isomers (40a′ and 40b′)
in 90-92% combined yields.
With 40a and 40b in hand, the stage was now set for the
construction of the common intermediate 11 (Scheme 1). We
decided to explore a sequential procedure involving Grignard-
addition-dehydration-Friedel-Crafts reactions to form the prenyl
moiety and the C-ring together. Treatment of 40a and 40b with 3-
butyn-2-one in the presence of DMAP provided 41a and 41b in
excellent yields (Scheme 5).[17] For electron rich compound 41b,
addition of MeMgBr followed by acid induced cyclization gave 11b
in 76 % yield. For intermediate 41a, although one-pot procedure
could lead to desired 11a in 25% yield, better yield (73%, two steps)
could be obtained by treatment of 42a, the isolated pure adduct, in
acetonitrile with p-toluenesulfonic acid monohydrate.
Scheme 5 Total syntheses of natural spirotryprostatins.
Scheme
6
Formal syntheses of cyclotryprostatin
C
and
fumitremorgin B.
In conclusion, we have developed a concise, stereoselective and
practical approach towards the synthesis of spirotryprostatins with
the highest overall yields. This synthetic route features with an
organo-mediated intramolecular umplolung cyclization to construct
the DKP ring system, a Grignard addition-dehydration-Friedel-
Crafts cyclization procedure to establish the C-ring and the prenyl
moiety, and finally a regioselective oxidation and MW mediated
rearrangement to afford the spiro-oxindole system. Our
methodology also constitutes a formal synthesis of fumitremorgin B
and cyclotryprostatin C. The intramolecular umpolung cyclization
developed in this work will provide efficient access to structurally
related DKP alkaloids as well as its derivatives and analogues.
Scheme 4 Gram-scale syntheses of indolyl DKP intermediates.
With key intermediate 11a and 11b in hand, we next attempted
the regio-selective oxidation of indoles in the presence of double
bonds susceptible to oxidation.[18] After a few experiments, we
found that dihydroxylation of 11a and 11b with catalytic amount of
OsO4 in THF-t-BuOH-H2O at elevated temperature (35 ºC oil bath)
provided 43a and 43b in 80% and 76% yield respectively. Reaction
of 43b in ethanol at 135 ºC under microwave conditions
stereospecifically finalized the first total synthesis of 3 (Scheme 5,
18% overall yields over 8 steps). Similar operations provided
spirotryprostatin B (19% overall yields over 9 steps from simple
commercially available material 36a, 7 steps from known material
38a). Hydrogenation of 3 in the presence of Pd/C afforded
spirotryprostatin A in 95% yield.[19] The NMR spectra of our
synthetic sample were consistent with those reported in the
literature.[3,7,19] Removal of the Boc group in 11a and 11b gave the
late stage intermediates (11c and 11d) for the synthesis of
fumitremorgin B and cyclotryprostatin C (Scheme 6).[20]
Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
Keywords: Total synthesis, spirotryprostatins, umplolung cyclization,
cascade cyclization, alkaloids.
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10.1002/chem.201806411
Chemistry - A European Journal
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Alkaloid Synthesis
Yong-Kai Xi, Hongbin Zhang*, Rui-Xi Li,
Shi-Yuan Kang, Jin Li, Yan Li
__________ Page – Page
Total Synthesis of Spirotryprostatins Via
Organomediated Intramolecular
Umpolung Cyclization
In this paper, we report a concise and practical approach towards the synthesis of
spirotryprostatins. This synthetic route features with a novel organo-mediated
intramolecular umplolung cyclization to construct the DKP ring system, a Grignard
addition-dehydration-Friedel-Crafts reaction procedure to establish the C-ring and
the prenyl moiety, and a regioselective oxidation and MW mediated stereospecific
rearrangement to afford the spiro-oxindole system.
5
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