Diastereoselective synthesis of pyrrolidines using a nitrone/cyclopropane cycloaddition: Synthesis of the tetracyclic core of nakadomarin A

Article abstract of DOI:10.1021/ol0501018

(Chemical Equation Presented) The synthesis of the tetracyclic core of nakadomarin A is described. The core contains all the heterocycles and the required stereocenters found in the natural product and provides a promising route to the target itself. The strategy utilizes a general, diastereoselective pyrrolidine synthesis that proceeds via a homo 3 + 2 dipolar cycloaddition. The scope of this methodology is also described.

Full text of DOI:10.1021/ol0501018

ORGANIC
LETTERS
2005
Vol. 7, No. 5
953-955
Diastereoselective Synthesis
of Pyrrolidines Using a
Nitrone/Cyclopropane Cycloaddition:
Synthesis of the Tetracyclic Core of
Nakadomarin A
Ian S. Young, Justin L. Williams, and Michael A. Kerr*
Department of Chemistry, The UniVersity of Western Ontario, London,
Ontario, Canada N6A 5B7
makerr@uwo.ca
Received January 18, 2005
ABSTRACT
The synthesis of the tetracyclic core of nakadomarin A is described. The core contains all the heterocycles and the required stereocenters
found in the natural product and provides a promising route to the target itself. The strategy utilizes a general, diastereoselective pyrrolidine
synthesis that proceeds via a homo 3
+ 2 dipolar cycloaddition. The scope of this methodology is also described.
The pyrrolidine ring is an enormously ubiquitous member
of the community of naturally occurring alkaloids. From
proline to the indolizidine and pyrrolizidine alkaloids to
other classes of compounds, the natural products con-
taining a pyrrolidine are too numerous to list.1 Our interest
in the pyrrolidine ring as a synthetic target stems from its
position at the core of the natural product nakadomarin A,
its biogenetic relatives, the manzamines, and the biogenetic
parent ircinal.
Of interest to us as synthetic chemists is the challenging
molecular structure, which consists of a compact, angularly
fused 6/5/5/5 ring system (containing three different hetero-
cycles) with fused 8-membered and bridging 15-membered
rings. Others have also been intrigued by the synthetic
challenge posed by nakadomarin A,3 and Nishida has recently
Nakadomarin A was isolated by Kobayashi from an
Okinawan sea sponge in 19972 and is the only manzamine
alkaloid to contain a furan ring. While nakadomarin A
contains a range of potentially useful bioactivities (anticancer,
antifungal, and antibacterial), the paucity of natural material
has made a full screening prohibitive.
(3) (a) Ahrendt, K. A.; Williams, R. M. Org. Lett. 2004, 6, 4539. (b)
Leclerc, E.; Tius, M. A. Org. Lett. 2003, 5, 1171. (c) Magnus, P.; Fielding,
M. R.; Wells, C.; Lynch, V. Tetrahedron Lett. 2002, 43, 947. (d) Fu¨rstner,
A.; Guth, O.; Duffels, A.; Seidel, G.; Liebl, M.; Gabor, G.; Mynott, R.
Chem. Eur. J. 2001, 7, 4811. (e) Fu¨rstner, A.; Guth, O.; Rumbo, A.; Seidel,
G. J. Am. Chem. Soc. 1999, 121, 11108.
(1) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435 and previous reports in
this series.
(2) Kobayashi, J.; Watanabe, D.; Kawasaki, N.; Tsuda, M. J. Org. Chem.
1997, 62, 9236.
10.1021/ol0501018 CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/01/2005

been successful in preparing both the unnatural and natural
enantiomers.4
Recently, we reported a homo 3 + 2 dipolar cycloaddition
of nitrones 3 with cyclopropanes 4, a process resulting in
high yields of tetrahydrooxazines 5 with excellent diastereo-
selectivity (Scheme 1).5 The requisite nitrones can be formed
to a compound such as 9, which could arise from 10 by the
pyrrolidine synthesis outlined in Scheme 1 and a Heck-type
ring closure. The Heck substrate would arise from the diester
11, which is simply the product of a three-component
coupling of a suitable hydroxylamine, furfural 12, and 1,1-
cyclopropanediester 4.
To demonstrate the feasibility and generality of the
proposed pyrrolidine synthesis, a variety of tetrahydroox-
azines were prepared using our method (Scheme 3). Upon
Scheme 1. Synthesis of Pyrrolidines via a Nitrone/
Cyclopropane Cycloaddition
Scheme 3. Diastereoselective Pyrrolidine Synthesis
in situ from hydroxylamines 1 and aldehydes 2, reducing
the process to a simple three-component coupling.6 It
occurred to us (as it has to others7) that cleavage of the N-O
bond, conversion of the resultant hydroxyl functionality to
a leaving group, and subsequent ring closure would result
in the formation of a pyrrolidine ring. In our case, since the
tetrahydrooxazines are formed as the cis products, ring
closure with inversion of stereochemistry would result in the
preparation of 2,5-trans-substituted pyrrolidines. An analysis
of the structure of nakadomarin A reveals a pyrrolidine as a
central structural feature with the same trans stereochemistry.
Moreover, the diester moiety present in the cycloadducts
would allow access to the required quaternary center.
Our retrosynthesis of nakadomarin A is shown in Scheme
2. Like Nishida, we envision formation of the 8- and 15-
treatment of the N-O bond in 5 with a variety of typical
reducing agents, we were met with disappointment. Hydro-
genation conditions and the use of molybdenum hexacar-
bonyl,8 activated zinc,9 and samarium iodide10 failed to
produce the desired product. Raney nickel did indeed reduce
the N-O bond in some cases, but the product amino alcohol
underwent a retro-Mannich-type fragmentation as a result
of the disposition of the amino group â to the diester moiety.
The diester group in 5 was therefore reduced and the 1,3-
diol 13 protected as an acetonide, providing a more suitable
substrate 14 for our study. Treatment of 14 with either Raney
Scheme 2. Retrosynthesis of Nakadomarin A
(4) (a) Nagata, T.; Nakagawa, M.; Nishida, A. J. Am. Chem. Soc. 2003,
125, 7484. (b) Ono, K.; Nakagawa, M.; Nishida, A. Angew. Chem., Int.
Ed. 2004, 43, 2020.
(5) Young, I. S.; Kerr, M. A. Angew. Chem., Int. Ed. 2003, 42, 3023.
(6) Young, I. S.; Kerr, M. A. Org. Lett. 2004, 6, 139.
(7) For examples, see: (a) Pulz, R.; Al-Harrasi, A.; Reissig, H.-U. Org.
Lett. 2002, 4, 2353. (b) Abe, H.; Aoyagi, S.; Kibayashi, C. J. Am. Chem.
Soc. 2000, 122, 4583.
(8) Cicchi, S.; Goti, A.; Brandi, A.; Guarna, A.; De Sarlo, F. Tetrahedron
Lett. 1990, 31, 3351.
(9) Wuts, P. G. M.; Jung, Y.-W. J. Org. Chem. 1988, 53, 1957.
(10) (a) Keck, G. E.; McHardy, S. F.; Wagner, T. T. Tetrahedron Lett.
1995, 36, 7419. (b) Chiara, J. L.; Destabel, C.; Gallego, P.; Marco-Contelles,
J. J. Org. Chem. 1996, 61, 359.
membered rings to take place via ring-closing metathesis,
giving 8 as a key intermediate. Excision of the nitrogen leads
954
Org. Lett., Vol. 7, No. 5, 2005

nickel or SmI2 successfully cleaved the N-O bond, with
SmI2 being the method of choice. Generation of an alkoxide
and quenching with methanesulfonyl chloride gave an amino
mesylate that was not isolable but quickly cyclized to produce
the desired pyrrolidine. A short series of pyrrolidines
prepared using this method is shown in Scheme 3. The
relative stereochemistry of the products was confirmed by
X-ray analysis of a number of these compounds.
With an optimized procedure for conversion of the 1,2-
tetrahydrooxazines to pyrrolidines in hand, we turned our
attention to the task of applying this method to the synthesis
of the core structure of nakadomarin A (Scheme 4). If our
The synthesis of the nakadomarin A core commences with
the three-component coupling of phenylhydroxylamine,
furfural 16,11 and cyclopropane 1712 to produce the adduct
18 in 74% yield. Selective DIBAL reduction of the equatorial
ester13 to the aldehyde 19 and Horner-Emmons olefination
produces enoate 20, which undergoes smooth Heck cycliza-
tion to 21. The presence of Ag2SO4 as an additive was
essential for the success of the Heck reaction.14 Cleavage of
the N-O bond and recyclization to the pyrrolidine proceeds
efficiently to give the tricyclic compound 22. Interestingly,
the best method for the N-O bond reduction in this instance
was hydrogenation over a palladium catalyst. The increased
strain in the tricycle 21 is suspected to be the source of the
increased N-O bond lability. The last required stereocenter
was set via reduction of the enoate double bond with nickel
boride,15 yielding saturated diester 23. The stereochemistry
was confirmed by X-ray analysis of 23. At first glance, it
seems that the hydride must be approaching from the concave
face of 22; however, the ring system is fairly flat, and
approach is anti to the adjacent methyl ester to yield the
desired isomer. Formation of the piperidine ring was
straightforward via ester reduction to diol 24, preparation
of dimesylate 25, and double displacement with benzylamine.
Thus, a nakadomarin A tetracyclic core model was produced
in 10 steps from the readily available furfural 16.
Scheme 4. Synthesis of the Tetracyclic Nakadomarin A Core
In summary, we have reported a general and diastereo-
selective synthesis of pyrrolidines. This method should be
generally useful for alkaloid synthesis, and we have il-
lustrated this with a synthesis of the tetracyclic core of
nakadomarin A. Our efforts toward the preparation of the
natural product will be reported in due course.
Acknowledgment. We gratefully acknowledge the fi-
nancial support of the Natural Sciences and Engineering
Research Council (NSERC), The Ontario Ministry of Science
and Technology, and MedMira Laboratories. I.S.Y and
J.L.W. are NSERC CGS-D and PGS-A awardees, respec-
tively.
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
approach was to be successful for the synthesis of the natural
product, we needed to address the issues of relative stereo-
chemistry in a conclusive manner. We therefore chose phen-
ylhydroxylamine and the phenyl cyclopropane diester 17 for
our study since the cycloaddition product and subsequent
compounds were more likely to yield crystals suitable for
X-ray analysis. The synthesis of the natural product itself
will require the use of a hydroxylamine and cyclopropane
with substituents that may be elaborated to the eight-
membered ring. We have shown that such cycloadditions
work very well.
OL0501018
(11) Furfural 16 was prepared using a combination of methods: (a)
Chiarello, J.; Joullie, M. M. Tetrahedron 1998, 44, 41. (b) Zaluski, M.-C.;
Robba, M.; Bonhomme, M. Bull. Soc. Chim. Fr. 1970, 1838.
(12) Landor, S. R.; Punja, N. J. Chem. Soc. C 1967, 23, 2495.
(13) We have seen this selectivity in selective hydrolysis as well, the
origin of which is not obvious on the basis of analysis of models.
(14) Abelman, M. M.; Oh, T.; Overman, L. E. J. Org. Chem. 1987, 52,
1430.
(15) (a) Schlesinger, H. I.; Brown, H. C.; Finholt, A. E.; Galbreath, J.
R.; Hoekstra, H. R.; Hyde, E. K. J. Am. Chem. Soc. 1953, 75, 215. (b)
Schreifels, J. A.; Maybury, P. C.; Swartz, W. E., Jr. J. Org. Chem. 1981,
46, 1263.
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