Unified Total Synthesis of Madangamines A, C, and E

Article abstract of DOI:10.1021/jacs.7b00807

A stereodivergent strategy for the synthesis of skipped dienes is developed. The method consists of hydroboration of allenes and Migita-Kosugi-Stille coupling, which allows for access to all four possible stereoisomers of the skipped dienes. The hydroboration is especially useful for providing both E-allylic and Z-allylic alcohols from the same allene by simply changing the organoborane reagent. The strategy was successfully applied to a unified total synthesis of the madangamine alkaloids via a common ABCE-tetracyclic intermediate with a (Z,Z)-skipped diene. The late-stage variation of the D-ring enabled the supply of synthetic madangamines A, C, and E for the first time.

Full text of DOI:10.1021/jacs.7b00807

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Communication
A Unified Total Synthesis of Madangamines A, C and E
Takahiro Suto, Yuta Yanagita, Yoshiyuki Nagashima, Shinsaku Takikawa,
Yasuhiro Kurosu, Naoya Matsuo, Takaaki Sato, and Noritaka Chida
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b00807 • Publication Date (Web): 11 Feb 2017
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A Unified Total Synthesis of Madangamines A, C and E
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Takahiro Suto, Yuta Yanagita, Yoshiyuki Nagashima, Shinsaku Takikawa, Yasuhiro Kurosu, Naoya
Matsuo, Takaaki Sato* and Noritaka Chida*
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Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1, Hiyoshi, Kohoku-ku, Yoko-
hama 223-8522, Japan
Supporting Information Placeholder
5
lylic alcohols 2. The subsequent Migita-Kosugi-Stille coupling re-
ABSTRACT: A stereodivergent strategy for the synthesis of
skipped dienes is developed. The method consists of hydroboration
of allenes and Migita-Kosugi-Stille coupling, which allows for ac-
cess to all four possible stereoisomers of the skipped dienes. The
hydroboration is especially useful for providing both E-allylic and
Z-allylic alcohols from the same allene by simply changing the or-
ganoborane reagent. The strategy was successfully applied to a uni-
fied total synthesis of the madangamine alkaloids via a common
ABCE-tetracyclic intermediate with a (Z,E)-skipped diene. The
late-stage variation of the D-ring enabled the supply of synthetic
madangamines A, C and E for the first time.
6
action with vinyl stannanes 3 would lead to the formation of vari-
ous skipped dienes 4. Brown and co-workers reported that hydrob-
oration of allene 1 with 9-BBN resulted in the formation of ther-
modynamically stable allyl borane (E)-5 (Scheme 1B). Mecha-
nistically, the hydroboration of 1 with 9-BBN took place from the
less hindered side. The generated (Z)-5 quickly underwent two al-
lylic rearrangements via 6 under equilibrium conditions, leading
to allyl borane (E)-5, which was subsequently used as an allylating
reagent with acetone. The Roush group demonstrated that the
proper choice of substituents on the boron could efficiently inhibit
5
c
5,7
5
g,h,l
the isomerization of kinetically favored (Z)-5.
Based on these
landmark precedents, we envisioned that, if both stereoisomers of
allylic compound (E)-2 and (Z)-2 were accessible from the same
allene 1 by simply changing the borane reagents, the overall strat-
egy would become highly stereodivergent when associated with the
Migita-Kosugi-Stille coupling.
A skipped diene is an important functional group widely distributed
1
in biologically active natural products such as madangamines, cor-
2
3
allopyronins and ripostatins (Figure 1). The skipped dienes in
these natural products exist as various types of stereoisomers de-
rived from the two olefins. An ideal method to construct the
skipped dienes must be stereodivergent, i.e., start from the same
compound and give all four possible stereoisomers, as well as be
highly convergent for the efficient synthesis of complex mole-
Scheme 1. (A) Stereodivergent Approach to Skipped Dienes.
(B) Mechanism for Hydroboration of Allenes
4
cules. Although a number of synthetic methods have been reported,
the development of approaches to provide all four possible stereo-
isomers of a skipped diene still remains a major challenge in syn-
thetic organic chemistry. In this communication, we reported a
practical stereodivergent strategy that provides access to skipped
dienes. The method was successfully applied to a unified total syn-
thesis of the madangamine alkaloids.
To test the feasibility of our strategy, we evaluated the reaction
sequence using 1,1-disubstituted allene 7 (Scheme 2). Treatment of
7 with 9-BBN at room temperature followed by oxidative work-up
induced E-selective hydroboration to afford allylic alcohol (E)-8 in
Figure 1. Representative Natural Products with Skipped Dienes.
Our stereodivergent strategy for the synthesis of skipped dienes
is shown in Scheme 1A. Hydroboration of allene 1 would give al-
9
3% yield with E/Z = 12.9:1. Gratifyingly, we found that Z-selec-
tive hydroboration of allene 7 was possible when HB(Sia) was em-
ployed at 0 °C, furnishing (Z)-8 as a single isomer (95%). Allylic
2
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alcohol (E)-8 was transformed to carbonate (E)-9, which under-
went the Migita-Kosugi-Stille coupling with both vinyl stannanes
(E)-10 and (Z)-10, providing skipped dienes (E,E)-11 and (E,Z)-
stereoselective formation of the skipped diene, especially for the
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trisubstituted Z-olefin, has remained an unsolved issue. To
achieve these two synthetic tasks, we planned to take advantage of
N-acyliminium cyclization of a propargylsilane. Protonation of N-
Boc enamine 12 would form highly electrophilic N-acyliminium
ion 13, which readily undergoes the cyclization to give the diazatri-
cyclic structure 14. The resulting 1,1-disubstituted allene of 14
would be converted to skipped diene 16 by Z-selective hydrobora-
1
1, respectively. The geometry of the allylic carbonate was pre-
served in this palladium-catalyzed coupling reaction. Allylic alco-
hol (Z)-8 was also converted to skipped dienes (Z,E)-11 and (Z,Z)-
1
1 through the same sequence. It is noteworthy that most of the
skipped dienes seen in biologically active natural products contain
a trisubstituted olefin, for which controlling the stereoselectivity is
highly challenging (Figure 1). However, our stereodivergent
method was applicable to syntheses of all four stereoisomers of
skipped diene 11 with high levels of stereoselectivities. Indeed, the
geometry of (Z,E)-11 corresponds to that of corallopyronin A.
2
tion with HB(Sia) and the Migita-Kosugi-Stille coupling with Z-
vinyl stannane 15. Considering a universal route toward the
madangamine alkaloids with their various D-rings, it would be rea-
sonable to establish ABCE-tetracyclic compound 17 as the com-
mon intermediate, and construct the D-ring at the end of the syn-
thesis.
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Scheme 2. Stereodivergent Syntheses of Four Skipped
Dienes 11 from 1,1-Disubstituted Allene 7
Scheme 3. Plan for the Unified Total Synthesis of
Madangamine Alkaloids
Reagents and conditions: a) 9-BBN, THF, rt; H
b) HB(Sia) , THF, 0 °C; H , NaOH aq; c) ClCO Me, py, CH
0 °C; d) 10, cat. Pd (dba) ·CHCl , LiCl, DMF, rt.
2
O
2
, NaOH aq;
2
2
O
2
2
2
Cl ,
2
2
3
3
Having a promising strategy to construct skipped dienes in hand,
we took an interest in a unified total synthesis of the madangamine
alkaloids (Scheme 3). The first isolation of the madangamine alka-
The unified total synthesis of the madangamine alkaloids com-
menced with formation of propargylsilane 12 from aldehyde 18
11
(95% ee) by a two-step procedure including the Ohira-Bestmann
1a
12
loids was documented by Andersen and co-workers in 1994. They
reaction
and alkylation with (iodomethyl)trimethylsilane
isolated madangamines A-E from the sponge Xestospongia ingens
(Scheme 4). We then investigated the pivotal N-acyliminium cy-
clization and subsequent construction of the skipped diene. Treat-
ment of N-Boc enamine 12 with TFA in MeCN and EtOH at 50 °C
successfully afforded the diazatricyclic structure 14 in 85% yield.
The resulting allene group of 14 was subjected to Z-selective hy-
1
b,c
on the reefs of Madang, Papua New Guinea.
These alkaloids
share a common ABCE-tetracyclic structure but contain a variety
of different D-rings. They also reported that madangamine A ex-
1
a
hibited cytotoxicity against a variety of human cancer cell lines.
Unfortunately, biological activities of other members of the
madangamine family have not been tested due to the scarcity of the
natural products. However, Amat recently achieved the landmark
first total synthesis of madangamine D, and provided a pure sample
2
droboration with HB(Sia) . The reaction took place from the oppo-
site side of the sterically hindered N-Boc group, and gave allylic
13
alcohol 20 as a kinetic product in 93% yield (Z:E= 20.4:1). Allylic
alcohol 20 was then converted to the carbonate, which underwent
8
9d
for biological studies. These tests revealed that madangamine D
the Migita-Kosugi-Stille coupling with Z-vinyl stannane 15 to
also showed cytotoxicity against human cancer cell lines, but with
a different cytotoxic spectrum. Further biological investigation of
other members of the madangamine alkaloids has been anticipated
through the supply of synthetic samples.
give (Z,Z)-skipped diene 16 in high yield. Thus, we achieved the
first stereoselective control of the skipped diene of the
madangamine alkaloids as a fully functionalized intermediates. Af-
ter hydrolysis of methyl ester 16, TMSOTf-mediated removal of
the Boc group provided the amino acid. After extensive investiga-
tions of the macrolactamization, the best result was obtained with
the Mukaiyama reagent (2-chloro-1-methylpyridinium iodide,
Significant issues in the total synthesis of the madangamine al-
kaloids are: i) construction of the unprecedented diazatricyclic
ABC-ring and ii) stereoselectivity of the skipped diene (Scheme 3).
14
9
h
CMPI) to form the E-ring of the madangamine alkaloids in 75%
A number of solutions, including our racemic sequence, have
9
yield over two steps. The TIPS group was selectively removed in
been reported for the synthesis of the diazatricyclic core. However,
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the presence of the Teoc group with CSA in MeOH at 40 °C, giving
the common intermediate 17 in quantitative yield.
corresponding carboxylic acid for the subsequent macrolactamiza-
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tion resulted in significant decomposition due to the sensitive
skipped triene. However, we found that the macrocyclic alkylation
was also effective for madangamine A. After the formation of the
tosylate from primary alcohol 29, cleavage of the Teoc group with
The remaining issue toward the unified total synthesis is the con-
struction of a variety of macrocyclic D-rings from the common in-
termediate 17. The synthesis of madangamine C was achieved
through a conventional macrolactamization (Scheme 5A). Iwabu-
BF
3
·Et
2
O provided the secondary amine, which underwent macro-
NEt at 70 °C. Finally, the total synthesis
1
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cyclic alkylation with iPr
2
chi oxidation of 17 with AZADO and subsequent Wittig reaction
with 23 gave cis-olefin 24 bearing the D-ring carbon unit. After
cleavage of the methyl and Teoc groups, the macrolactamization
with EDCI and HOBt provided the pentacyclic compound in 71%
of madangamine A was accomplished by LiAlH
remaining macrolactam.
4
reduction of the
8c
yield (2 steps). Finally, the total synthesis of madangamine C was
Scheme 5. The Unified Total Synthesis of Madangamine
Alkaloids.
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achieved by LiAlH -reduction of the two macrolactams.
Scheme 4. Synthesis of the Common Intermediate by Stere-
oselective Synthesis of the Skipped Diene.
The synthesis of madangamine E with the saturated D-ring was
not trivial because it has no functional bias such as a cis-olefin to
assist the macrocyclization (Scheme 5B). Indeed, the attempted
macrolactamization used in the synthesis of madangamine C re-
sulted in the formation of a significant amount of the dimer through
intermolecular coupling. However, we found that the following
macrocyclic alkylation was most effective in the case of
madangamine E. First, the saturated D-ring carbon unit was in-
stalled by bromination of alcohol 17 and copper-mediated alkyla-
1
6
In conclusion, we have developed a stereodivergent strategy to
yield all four possible stereoisomers of a skipped diene by combi-
nation of the hydroboration of an allene and the Migita-Kosugi-
Stille coupling. The method was successfully applied to a unified
total synthesis of the madangamine alkaloids with the high stere-
ocontrol of a skipped diene including the challenging trisubstituted
olefin. Our synthetic route via a common ABCE-tetracyclic inter-
mediate enabled the late-stage installation of various macrocyclic
D-rings, and supplied sufficient amounts of madangamines A, C
and E for the first time for biological tests, which are now ongoing.
tion under Cahiez’s conditions. The TIPS-protected hydroxy
group of 26 was then converted to tosylate 27 in two steps. After
removal of the Teoc group with BF
tion took place in the presence of K
3
·Et
2
O, the macrocyclic alkyla-
at 80 °C in 61% yield (2
2
CO
3
steps). The total synthesis of madangamine E was accomplished by
reduction of the amide carbonyl.
We then turned our attention to the synthesis of madangamine A
(Scheme 5C). The skipped triene unit was installed by the Wittig
reaction of aldehyde 22 and the cleavage of the TIPS group, giving
2
9 in 69% yield over two steps. Although a number of approaches
have been reported for the construction of macrocyclic compounds,
the case including the skipped triene proved to be highly challeng-
ing. For example, attempted oxidation of primary alcohol 29 to the
ASSOCIATED CONTENT
Supporting Information
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Experimental procedures and copies of H NMR and 13C NMR
spectra of new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
1
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AUTHOR INFORMATION
Corresponding Author
*
E-mail: takaakis@applc.keio.ac.jp; chida@applc.keio.ac.jp
(8) (a) Amat, M.; Pérez, M.; Minaglia, A. T.; Casamitjana, N.; Bosch, J.
Org. Lett. 2005, 7, 3653–3656. (b) Amat, M.; Pérez, M.; Proto, S.; Gatti,
T.; Bosch, J. Chem. Eur. J. 2010, 16, 9438–9441. (c) Proto, S.; Amat, M.;
Pérez, M.; Ballette, R.; Romagnoli, F.; Mancinelli, A.; Bosch, J. Org. Lett.
Notes
The authors declare no competing financial interests.
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012, 14, 3916–3919. (d) Amat, M.; Ballette, R.; Proto, S.; Pérez, M.;
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ACKNOWLEDGMENT
Bosch, J. Chem. Commun. 2013, 49, 3149–3151. (e) Ballette, R.; Pérez, M.;
Proto, S.; Amat, M.; Bosch, J. Angew. Chem. Int. Ed. 2014, 53, 6202–6205.
(9) (a) Matzanke, N.; Gregg, R. J.; Weinreb, S. M.; Parvez, M. J. Org.
Chem. 1997, 62, 1920–1921. (b) Yamazaki, N.; Kusanagi, T.; Kibayashi, C.
Tetrahedron Lett. 2004, 45, 6509–6512. (c) Tong, H. M.; Martin, M.-T.;
Chiaroni, A.; Bénéchie, M.; Marazano, C. Org. Lett. 2005, 7, 2437–2440.
This research was supported by the Otsuka Pharmaceutical Co.
Award in Synthetic Organic Chemistry, Japan. We thank Prof.
Raymond J. Andersen, The University of British Columbia, Can-
ada for giving H and C NMR spectra of madangamine alkaloids,
and precious advice. Synthetic assistance from T. Matsumoto, S.
Hiraoka and Y. Komiya is gratefully acknowledged.
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rahedron Lett. 2006, 47, 3489–3492. (e) Yoshimura, Y.; Kusanagi, T.;
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