Ugi-4-component reaction enabling rapid access to the core fragment of massadine

Article abstract of DOI:10.1021/ol102577q

A rapid method to access the densely functionalized core structure of massadine (1) has been developed. The use of the Ugi-4-component reaction involving a convertible isonitrile and an end-group differentiating ozonolysis constitute the key operations to

Full text of DOI:10.1021/ol102577q

ORGANIC
LETTERS
2011
Vol. 13, No. 1
78-81
Ugi-4-Component Reaction Enabling
Rapid Access to the Core Fragment of
Massadine
Gary M. Chinigo, Alexander Breder, and Erick M. Carreira*
Laboratorium fu¨r Organische Chemie, ETH Zu¨rich, CH-8093 Zu¨rich, Switzerland
carreira@org.chem.ethz.ch
Received October 25, 2010
ABSTRACT
A rapid method to access the densely functionalized core structure of massadine (1) has been developed. The use of the Ugi-4-component
reaction involving a convertible isonitrile and an end-group differentiating ozonolysis constitute the key operations toward the synthesis of
the D-ring subunit.
Massadine (1), which belongs to the class of pyrrole-
imidazole alkaloids, was isolated in 2003 from the marine
sponge Stylissa aff. massa.1 The ornate and complex
architecture of 1 and other congeners such as axinellamine
A (2) and B (3) as well as palau’amine (4) (Figure 1) in
combination with their potent biological activity placed these
natural products into the focus of total synthesis studies.2
To date, various approaches toward the construction of
the cyclopentane core of 2-4, which all have the presence
of a secondary chloro substituent in common, have been
reported in the literature. Among these, the first enantiose-
lective synthesis of such an intermediate was accomplished
in our laboratories.2a In contrast, massadine (1) possesses a
secondary hydroxyl function instead of the chloride. Apart
from our previously reported approach to a similar interme-
diate,3 there have been no reports on the enantioselective
synthesis of a fully decorated core fragment of 1 possessing
the correct configuration at each of the five stereogenic
centers. Herein, we report the development of a facile and
enantioselective route to the core fragment of 1 involving
the Ugi-4-component reaction.
From earlier studies we had learned that rapid access to
an orthogonally functionalized cyclopentane ring can be
gained through end-group differentiating ozonolysis of
appropriately functionalized norbornene derivatives.3 We
were interested in harnessing the powerful discriminating
characteristics of this transformation as a key step in the
enantioselective synthesis of 1. To access such an ozonolysis
precursor we initially developed a strategy that involved a
Strecker aminocyanation for the concomitant introduction
of a carboxyl and an amino substituent at C7 of the
norbornenone nucleus. However, this approach necessitated
the implementation of a sequence involving various func-
tional group interconversion steps in the synthesis. For
example, the nitrogen at C7 underwent four separate opera-
tions in order to properly manage its reactivity. In order to
overcome the disadvantages encountered in this approach, a
reevaluation of the strategy for the elaboration of the C7
carbonyl was required. The investigations began with
examination of the related Ugi-4-component reaction em-
(1) Nishimura, S.; Matsunaga, S.; Shibazaki, M.; Suzuki, K.; Furihata,
K.; van Soest, R. W. M.; Fusetani, N. Org. Lett. 2003, 5, 2255.
10.1021/ol102577q  2011 American Chemical Society
Published on Web 12/07/2010

Ketone 5, the Ugi precursor, was accessed in enantioen-
riched form by a four-step procedure as reported previously
by us.3 With norbornenone 5 in hand, the stage was set for
investigating the Ugi-4-component reaction. In preliminary
experiments racemic 5 was reacted with 4-phenyl-1-isocy-
anocyclohexene, chloroacetic acid, and dimethoxybenzy-
lamine (DMBNH2) to give the corresponding Ugi-adduct 6
(Scheme 1).
Scheme 1. Attempted Amide Manipulations
Figure 1. Oroidin alkaloids massadine (1), axinellamine A (2) and
B (3), and palau’amine (4).
ploying “convertible isonitriles”. In the typical Ugi-4-
component sequence the amide bonds formed during the
reaction are difficult to further elaborate, as harsh conditions
are required for the subsequent synthetic manipulations.
These conditions, however, would be incompatible with a
complex structure containing sensitive functionalities. Thus,
we became interested in examining the use of “convertible
isonitriles” that would lead to amides amenable to subsequent
facile and mild manipulation.
Diamides similar to 6 have been reported to be susceptible
to nucleophilic attack in acidic media through the interme-
diacy of a mu¨nchnone.4 However, when 6 was subjected to
HCl in ether, we merely recorded the loss of the cyclohexenyl
group leading to primary amide 8 as the sole product
(Scheme 1).
(2) (a) Starr, J. T.; Koch, G.; Carreira, E. M. J. Am. Chem. Soc. 2000,
122, 8793. (b) Koenig, S. G.; Miller, S. M.; Leonard, K. A.; Lowe, R. S.;
Chen, B. C.; Austin, D. J. Org. Lett. 2003, 5, 2203. (c) Dilley, A. S.; Romo,
D. Org. Lett. 2001, 3, 1535. (d) Poullennec, K. G.; Romo, D. J. Am. Chem.
Soc. 2003, 125, 6344. (e) Dransfield, P. J.; Wang, S.; Dilley, A.; Romo, D.
Org. Lett. 2005, 7, 1679. (f) Dransfield, P. J.; Dilley, A. S.; Wang, S.; Romo,
D. Tetrahedron 2006, 62, 5223. (g) Wang, S.; Dilley, A. S.; Poullenec,
K. G.; Romo, D. Tetrahedron 2006, 62, 7155. (h) Garrido-Hernandez, H.;
Nakadai, M.; Vimolratana, M.; Li, Q.; Doundoulakis, T.; Harran, P. G.
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2006, 965. (k) Sivappa, R.; Hernandez, N. M.; He, Y.; Lovely, C. J. Org.
Lett. 2007, 9, 3861. (l) Lovely, C. J.; Du, H.; Dias, H. V. R. Org. Lett.
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Lovely, C. J. J. Org. Chem. 2007, 72, 3741. (o) Overman, L. E.; Rogers,
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O’Malley, D. P. J. Am. Chem. Soc. 2004, 126, 3726. (t) Northrop, B. H.;
O’Malley, D. P.; Zografos, A. L.; Baran, P. S.; Houk, K. N. Angew. Chem.,
Int. Ed. 2006, 45, 4126. (u) Yamaguchi, J.; Seiple, I. B.; Young, I. S.;
O’Malley, D. P.; Maue, M.; Baran, P. S. Angew. Chem., Int. Ed. 2008, 47,
3578. (v) O’Malley, D. P.; Yamaguchi, J.; Young, I. S.; Seiple, I. B.; Baran,
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Bultman, M. S.; Ma, J.; Gin, D. Y. Angew. Chem., Int. Ed. 2008, 47, 6821.
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Chem., Int. Ed. 2008, 47, 8514.
The use of 2-(tert-butyldimethylsilyloxymethyl)phenyl-
isonitrile under otherwise identical conditions for the Ugi-
reaction gave 7 in 63% yield. The aniline moiety within 7
was shown to undergo intramolecular transesterification in
related systems under acidic conditions.5 Thus, 7 was
exposed to acidic methanol at 35 °C, which resulted in an
overall displacement of the TBS ether with chloride at the
benzylic position (9, Scheme 1). After screening several other
isonitriles, we found 2-nitrophenylisonitrile to efficiently
participate in the Ugi-reaction (79%, Scheme 2). More
importantly, subsequent conversion of amide 11 to alcohol
13 proceeded without any difficulty.6 The reduction of the
amide was realized in two steps starting with SnCl2 mediated
reduction of the nitro group within the Boc-carbamate
derived from 11 (70%). In the second operation the arylamino
function was allowed to react with isoamyl nitrite to give
the corresponding benzotriazole intermediate A, which upon
(4) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1996, 118,
2574.
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336.
(6) Gilley, C. B.; Kobayashi, Y. J. Org. Chem. 2008, 73, 4198.
Org. Lett., Vol. 13, No. 1, 2011
79

treatment with NaBH4 furnished 13 (87%) in a total number
of four steps from ketone 5. Further elaboration of 13
Scheme 3
. Mechanistic Proposal for the Regioselective
Breakdown of the Primary Ozonide
Scheme 2. Synthesis of the Ozonolysis Precursor 15
ation in an atmosphere of oxygen occurs with net retention
of configuration most likely controlled by the endo-
oriented benzyloxymethyl group. Hence, following Pinnick
oxidation of ester/aldehyde 19, the resulting ester/acid was
subjected to Barton’s decarboxylation conditions furnish-
ing alcohol 20 in 65% yield (Scheme 4).10 At this point
Scheme 4. Completion of the Core Fragment of 1
included silylation of the primary alcohol, LiBH4 mediated
reduction of the esters, and protection of the resulting diol
using Dudley’s reagent to afford norbornene 15 in good yield
(71%).7
It is noteworthy that this approach enables access to 15 in
only 11 steps, which constitutes a significant improvement
in step economy when compared to the synthesis of an
analogous structure reported previously (15 steps).3 In order
to convert 15 to the necessary cyclopentane ring, it was
subjected to ozonolytic conditions entailing an oxidative
workup protocol. This procedure provided ester/aldehyde 19
in 76% yield as the only isolable isomer (Scheme 4).8 We
speculate that the endo-oriented benzyloxy group influences
the breakdown of primary ozonide 16, which leads to the
formation of methylhydroperoxy hemiacetal 18.3 This in-
termediate is further converted to corresponding methyl ester
19 upon treatment with Ac2O and base (Scheme 3).
For the introduction of the secondary hydroxyl function
present in the D-ring subunit of massadine (1), we envisioned
the application of Barton’s radical decarboxylation/oxygen-
ation chemistry.9
From preliminary studies in this direction we found that
hydroxyl installation through oxidative radical decarboxyl-
remaining operations for completion of the core structure
of 1 included conversion of the benzyl ethers into
protected amino groups and epimerization of the ester
(7) Poon, K. W. C.; Dudley, G. B. J. Org. Chem. 2006, 71, 3923.
(8) (a) Schreiber, S. L.; Claus, R. E.; Reagan, J. Tetrahedron Lett. 1982,
23, 3867. (b) Wu, H. J.; Lin, C. C. J. Org. Chem. 1996, 61, 3820. (c) Lin,
C. C.; Wu, H. J. Tetrahedron Lett. 1995, 36, 9353. (d) Wu, H. J.; Chern,
J. H.; Wu, C. Y. Tetrahedron 1997, 53, 2401. (e) Bailey, P. S.; Ferrell,
T. M. J. Am. Chem. Soc. 1978, 100, 899. (f) Lattimer, R. P.; Kuczkowski,
R. L.; Gillies, C. L. J. Am. Chem. Soc. 1974, 96, 348. (g) Cremer, D. J. Am.
Chem. Soc. 1981, 103, 3619. (h) Testero, S. A.; Sua´rez, A. G.; Spanevello,
R. A.; Mangione, M. I. Trends Org. Chem. 2003, 10, 35. (i) Testero, S. A.;
Spanevello, R. A. Org. Lett. 2006, 8, 3793. (j) Testero, S. A.; Mangione,
M. I.; Poeylaut-Palena, A. A.; Gonzalez Sierra, M.; Spanevello, R. A.
Tetrahedron 2007, 63, 11410.
(9) (a) Barton, D. H. R.; Serebryakov, E. P. A. Proc. Chem. Soc. 1962,
309. (b) Barton, D. H. R.; Dowlatshahi, H. A.; Motherwell, W. B.; Villemin,
D. A. J. Chem. Soc., Chem. Commun. 1980, 732. (c) Barton, D. H. R.;
Crich, D.; Motherwell, W. B. Tetrahedron Lett. 1983, 24, 4979. (d) Barton,
D. H. R.; Crich, D.; Motherwell, W. B. J. Chem. Soc., Chem. Commun.
1983, 939.
(10) Compounds 20-23 have been synthesized by a nonasymmetric
route, starting from ketone (()-5 (R ) Me).
80
Org. Lett., Vol. 13, No. 1, 2011

bearing stereogenic center. Accordingly, silyl protection
of 20 was followed by base-induced epimerization of the
methyl ester group using Cs2CO3 in methanol (84%) and
hydrogenolytic removal of the benzyl ethers, affording diol
22 in good yields. Finally, introduction of the nitrogen
substituents was accomplished by mesylation of 22 (65%)
and subsequent SN2-displacement of the mesylates with
azides (67%), which completed the enantioselective
synthesis of the D-ring subunit 23.
The enantioselective route toward core fragment 20 consists
of only 19 linear steps, which underscores the efficiency
applied in this synthesis.
Acknowledgment. The authors would like to gratefully
acknowledge Johannes Burkhard [ETH Zu¨rich] for his
assistance with the analytical data for this manuscript. We
thank ETH Zürich for support of this research program.
Supporting Information Available: Experimental pro-
cedures and characterization for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, we have disclosed a concise approach to the
core fragment of massadine (1). The application of an Ugi-
4-component reaction involving a convertible isonitrile
enables the facile C7 functionalization of a norbornenone.
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