Total Synthesis of (+)-MPC1001B

Article abstract of DOI:10.1002/anie.201507830

The first total synthesis of an epidithiodiketopiperazine alkaloid, (+)-MPC1001B, was accomplished. This synthesis features a tetra-n-butylammonium fluoride mediated intramolecular aldol reaction for forming the 15-membered macrolactone ring, and the construction of an epidithiodiketopiperazine substructure through a stepwise sulfenylation reaction involving a novel trityl trisulfide (TrSSS)-group transfer.

Full text of DOI:10.1002/anie.201507830

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201507830
German Edition: DOI: 10.1002/ange.201507830
Alkaloid Synthesis
Total Synthesis of (+)-MPC1001B
Taichi Kurogi, Shun Okaya, Hideto Fujiwara, Kentaro Okano, and Hidetoshi Tokuyama*
Abstract: The first total synthesis of an epidithiodiketopiper-
azine alkaloid, (+)-MPC1001B, was accomplished. This syn-
thesis features a tetra-n-butylammonium fluoride mediated
intramolecular aldol reaction for forming the 15-membered
macrolactone ring, and the construction of an epidithiodike-
topiperazine substructure through a stepwise sulfenylation
reaction involving a novel trityl trisulfide (TrSSS)-group
transfer.
ing effect toward the HCT116 colon cancer cell line.[9]
Therefore, substantial efforts have been made to develop
routes to these dihydrooxepine natural products.[10] To date,
only two total syntheses of acetylaranotin (3) have been
reported, one by Reisman et al. and the other by our group.[11]
Some synthetic studies of pyrrolidine-fused dihydrooxepines
have also been reported.[2b,10b,c,12] No synthesis of the sub-
family of dihydrooxepine natural products with a character-
istic 15-membered macrolactone (1 and 2) has been achieved.
During our work on ETPs, we became particularly interested
in MPC1001B (1) and MPC1001 (2a), which were isolated by
Onodera and Kanda et al. in 2004.[3] Herein, we report the
first total synthesis of MPC1001B (1), which was accom-
plished through a TBAF-mediated aldol macrocyclization
and the stepwise introduction of two sulfur moieties.
The major challenges for synthesizing MPC1001s include
diastereoselective construction of the characteristic 15-mem-
bered ring, and the labile aldol substructure in dithiodiketo-
piperazine. Because the disulfide bond is unstable in the
presence of bases, nucleophiles, and oxidants,[2a] we planned
to introduce this sulfur functionality toward the end of the
synthesis (Scheme 1). We envisaged that an intramolecular
E
pidithiodiketopiperazines (ETPs) have attracted consider-
able attention owing to their broad range of biological
activities and diverse structures.[1,2] This family of compounds
includes MPC1001s [MPC1001B (1) and MPC1001 (2a)],[3]
emestrin (2b),[4] acetylaranotin (3),[5] SCH64874 (4),[6] com-
pound 5,[7] emethallicin A (6),[8] and acetylapoaranotin (7;
Figure 1).[9] These compounds possess unique seven-mem-
Figure 1. MPC1001 and related dihydrooxepine ETPs.
bered dihydrooxepines, and they display biological activities
such as antiproliferative activity against the DU145 human
prostate cancer cell line,[3] chemokine receptor (CCR2)
antagonist activity,[4c] inhibitory activity against viral RNA
polymerase,[5] epidermal growth factor receptor (EGFR)
antagonist activity,[6] potent antituberculous activity,[7] inhib-
itory activity of histamine release,[8] and an apoptosis-induc-
Scheme 1. Retrosynthetic analysis. TBS=tert-butyldimethylsilyl,
Cbz=benzyloxycarbonyl.
Mitsunobu reaction[13] could provide macrocycle 8 from seco-
acid 9. This would be prepared from dihydrooxepine unit 10,
which is a synthetic intermediate in our total synthesis of
acetylaranotin (3),[11b] and b-hydroxy amino acid derivative
11.
[*] T. Kurogi, S. Okaya, Dr. H. Fujiwara, Dr. K. Okano,
Prof. Dr. H. Tokuyama
Graduate School of Pharmaceutical Sciences, Tohoku University
Aoba 6-3, Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
E-mail: tokuyama@m.tohoku.ac.jp
We first prepared seco-acid 15, which is the substrate for
an intramolecular Mitsunobu reaction, from carboxylic acid
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201507830.
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Scheme 3. Intramolecular aldol strategy for macrocyclization.
À
execute an intramolecular aldol reaction to form the C3 C7’’
bond. Retrosynthetic disconnection of the ester in substrate
19 leads to the anisic acid derivative 20 and dihydrooxepine
21, which should be readily accessible from compound 10.
The synthesis of substrate 19 for the key aldol cyclization
commenced with the condensation of carboxylic acid 10 and
sarcosine methyl ester by using BOP-Cl (Scheme 4). Removal
of the Cbz group and the TBS group gave alcohol 22.
Scheme 2. Unsuccessful Mitsunobu cyclization strategy. Reagents and
conditions: a) BOP-Cl, Et3N, CH2Cl2, RT, 67%; b) Et3SiH, cat. Pd-
(OAc)2, cat. Et3N, CH2Cl2, reflux; c) TBAF, AcOH, THF, RT, 71%
(2 steps); d) 2-methoxypropene, cat. PPTS, CH2Cl2, 08C; e) TBAF, THF,
08C, 74% (2 steps); f) Me3SnOH, DCE, 808C; g) PMe3, DEAD, THF/
toluene, RT, 74%. BOP-Cl=bis(2-oxo-3-oxazolidinyl)phosphonyl chlo-
ride, MOP=2-methoxy-2-propyl, TBAF=tetra-n-butylammonium fluo-
ride, PPTS=pyridinium 4-toluenesulfonate, DEAD=diethyl azodicar-
boxylate, THF=tetrahydrofuran.
10[11] and
a
b-hydroxyphenylalanine derivative 11[14]
(Scheme 2). Carboxylic acid 10 was then condensed with
amine 11 in the presence of BOP-Cl to afford the corre-
sponding amide 12. Diketopiperazine 13 was prepared
through Pd-catalyzed hydrogenolysis of the Cbz group,
which was followed by treatment with TBAF to promote
cyclization. Because the unprotected benzylic alcohol 13
À
underwent a retro-aldol-type fragmentation of the C3 C7’’
bond after treatment with TBAF, we protected alcohol 13 as
a 2-methoxy-2-propyl (MOP) acetal 14. Removal of the TBS
group and subsequent hydrolysis with Me3SnOH[15] provided
the corresponding seco-acid 15. However, the desired 15-
membered macrocycle 16 was not obtained under Mitsunobu
conditions; instead the regioisomer 17 was isolated in 74%
yield. Note that macrolactonization of the C6-epimer of 15
under Shiinaꢀs conditions was unsuccessful.[16]
The failure of the Mitsunobu cyclization strategy led us to
investigate an alternative strategy for constructing the 15-
membered ring (Scheme 3). We then focused on the aldol
structure in the proposed key intermediate 18 and planned to
Scheme 4. Construction of the 15-membered ring. Reagents and
conditions: a) sarcosine (N-methylglycine) methyl ester·HCl, BOP-Cl,
Et3N, CH2Cl2, RT, 95%; b) Et3SiH, cat. Pd(OAc)2, cat. Et3N, CH2Cl2,
reflux, 94%; c) TBAF, THF, RT, 97%; d) cat. nor-AZADO, PhI(OAc)2,
CH2Cl2, RT, 86%; e) NaBH4, CeCl3·7H2O, CH2Cl2/EtOH, À788C, 93%;
f) 20, WSCD, cat. DMAP, CH2Cl2, RT, quant; g) TBAF, THF, RT, 71%.
nor-AZADO=9-azanoradamantane-N-oxyl, WSCD=water soluble car-
bodiimide, DMAP=4-dimethylaminopyridine.
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Stereochemical inversion of the hydroxy group was per-
formed in two steps;[11b] nor-AZADO-catalyzed oxidation[17]
and Luche reduction afforded 21, which was condensed with
carboxylic acid 20[18] to provide 19. To our delight, the crucial
formation of the 15-membered ring was effected by
TBAF[19,20] to afford the desired compound 23 as a single
diastereomer in 71% yield. However, X-ray crystallographic
analysis revealed that the stereochemistries of the C3 and C7’’
positions were opposite to those of MPC1001B.[21] Never-
theless, we examined the introduction of the sulfur function-
ality before inversion of the stereochemistry at the C7’’
position.
Based on Nicolaouꢀs previously reported methods,[2b, 22] we
attempted to introduce sulfur moieties under basic conditions.
À
However, we observed cleavage of the C3 C7’’ bond of 23
through a retro-aldol reaction.[23] To prevent this undesired
reaction, we planned to introduce the two requisite sulfur
moieties after oxidation of the secondary alcohol 23 to the
corresponding ketone (Scheme 5). Moreover, we expected
a smooth deprotonation/sulfenylation reaction owing to the
properties of the 1,3-ketoamide structure.[24] The secondary
alcohol was oxidized by using catalytic AZADO in a CH2Cl2/
phosphate buffer (pH 7.4) to afford the dicarbonyl compound
24.[17,25] Consecutive treatment of diketopiperazine 24 with
LiHMDS at À788C and TrSSSCl[26] afforded 25 in 88% yield.
The desired bis(trisulfide) 28 was obtained in 60% yield
through another successive cycle of LiHMDS and TrSSSCl
treatments.
During our investigation on the second sulfenylation
reaction, we found that the TrSSS group migrated from the C3
position to the C11a position.[27] Compound 25 was thus
completely consumed when it was subjected to LiHMDS.
After an acidic workup with aqueous ammonium chloride,
compound 29 was isolated in 41% yield. The unexpected
trisulfide migration might have proceeded via enolate 27,
because the anionic species is better stabilized by its two
adjacent carbonyl groups compared to the initial enolate
26.[28]
We finally achieved the total synthesis of MPC1001B (1)
through reduction of the ketone and formation of the
disulfide bond (Scheme 6). The carbonyl group in 28 was
chemo- and diastereoselectively reduced under Luche con-
ditions at À788C in CH2Cl2/EtOH,[11] without affecting the
trisulfide moiety.[29,30] The final formation of the disulfide
Scheme 5. Stepwise introduction of two TrSSS-groups. Reagents and
conditions: a) cat. AZADO, PhI(OAc)2, CH2Cl2, pH 7.4 phosphate
buffer, RT, 79% (d.r.=9:1); b) LiHMDS, TrSSSCl, THF, À788C, 88%;
c) LiHMDS, TrSSSCl, THF, À788C, 60% (25!28); LiHMDS, THF,
À788C, then aq. NH4Cl, 41% (25!29). AZADO=2-azaadamantane-
N-oxyl, LiHMDS=lithium hexamethyldisilazanide, TrSSSCl=chloro(tri-
phenylmethyl)trisulfane.
Acknowledgements
This work was financially supported by the Cabinet Office,
Government of Japan through its “Funding Program for Next
Generation World-Leading Researchers” (LS008), a Grant-in
aid for Scientific Research (A) (26253001) and (C)
(25460003), the Platform Project for Supporting in Drug
Discovery and Life Science Research(Platform for Drug
Discovery, Informatics, and Structural Life Science from the
Ministry of Education, Culture, Sports, Science and Technol-
ogy (MEXT) and Japan Agency for Medical Research and
development (AMED), The Research Foundation for Phar-
maceutical Sciences, and the JSPS predoctoral fellowship. We
thank Professor Dr. Y. Iwabuchi (Tohoku University) for
generously gifting us with 2-azaadamantane-N-oxyl and 9-
azanoradamantane-N-oxyl. Dr. M. Yoshida (Tohoku Univer-
sity) is also thanked for HRMS measurements.
À
bond was sluggish because of concomitant C S bond cleavage
at the C3 position and retro-aldol-type fragmentation with
[2b,22]
conventional reagents such as NaBH4
or 1,3-propane-
dithiol.[11] Further investigation revealed that sodium 2-
mercaptoethanesulfonate (MESNa),[31] which has been used
in the cleavage of a disulfide bond in a complex glycopeptide,
successfully facilitated the removal of the TrSS groups. The
resultant dithiol was treated with oxygen to afford
MPC1001B (1) in 33% yield.
In conclusion, we accomplished the total synthesis of
(+)-MPC1001B (1) for the first time. This synthesis features
TBAF-mediated formation of the 15-membered ring and
stepwise introduction of bis-trisulfide through migration of
the trisulfide group.
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Scheme 6. Total synthesis of MPC1001B (1). Reagents and conditions:
a) NaBH4, CeCl3·7H2O, CH2Cl2/EtOH, À788C, quant; b) MESNa, cat.
DIPEA, DMF/H2O, RT; c) O2, AcOEt/MeOH, RT, 33% (2 steps). MES-
Na=sodium 2-mercaptoethanesulfonate, DIPEA=N,N-diispropylethyl-
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Keywords: aldol reaction · alkaloids · dithiodiketopiperazine ·
macrolactones · total synthesis
How to cite: Angew. Chem. Int. Ed. 2016, 55, 283–287
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all under conditions without TrSSSCl (25!29), we speculated
that this migration (26!27) occurs in an intramolecular fashion.
Moreover, a preliminary crossover experiment with two analo-
gous trisulfides (see below) did not afford any intermolecular
sulfur transfer products upon treatment with LiHMDS, which
also strongly supports an intramolecular transfer process..
[29] The stereochemistries of compounds 25, 28, 29, and 30 are
tentatively assigned as shown in Scheme 5 and 6 based on the
fact that MPC1001B (1) was obtained from compound 25
through 28 and 30.
[30] The diastereoselectivity of this reduction is discussed in the
Supporting Information.
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Received: August 21, 2015
Published online: October 23, 2015
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