Utilization of a Michael addition: Dipolar cycloaddition cascade for the synthesis of (±)-cylindricine C

Article abstract of DOI:10.1021/ol8006056

A new approach to the marine alkaloid (±)-cylindricine C has been devised. The key element of the synthesis consists of a Michael addition/ dipolar cycloaddition cascade between 2,3-bis(phenylsulfonyl)-1,3-butadiene and 9-triisopropylsilanyloxy-non-1-en-5-one oxime. The resulting cycloadduct was converted into (±)-cylindricine C by a sequence of reactions including a reductive cyclization, intramolecular enolate alkylation, and conjugate addition to introduce the n-hexyl side chain.

Full text of DOI:10.1021/ol8006056

ORGANIC
LETTERS
2008
Vol. 10, No. 9
1871-1874
Utilization of a Michael Addition: Dipolar
Cycloaddition Cascade for the Synthesis
of (()-Cylindricine C
Andrew C. Flick, Maria Jose´ Arevalo Caballero, and Albert Padwa*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
Received March 17, 2008
ABSTRACT
A new approach to the marine alkaloid (()-cylindricine C has been devised. The key element of the synthesis consists of a Michael addition/
dipolar cycloaddition cascade between 2,3-bis(phenylsulfonyl)-1,3-butadiene and 9-triisopropylsilanyloxy-non-1-en-5-one oxime. The resulting
cycloadduct was converted into (()-cylindricine C by a sequence of reactions including a reductive cyclization, intramolecular enolate alkylation,
and conjugate addition to introduce the n-hexyl side chain.
The cylindricines A-K represent a family of alkaloids that
were isolated by Blackman and co-workers from the ascidian
ClaVelina cylindrica found in Tasmania in the early 1990s.1
Members of this family possess either the pyrrolo or
pyrido[2,1-j]quinoline tricyclic framework and are readily
interconverted via an aziridinium ion intermediate.2 Among
this class of alkaloids, cylindricine C (1) represents an
intriguing target.3 This natural product is closely related to
the marine tricyclic alkaloid lepadiformine (2) differing only
in the cis/trans stereorelationship of the perhydroquinoline
ring system and the functionality at C4 (Figure 1).4 Given
the unique structural motif, cylindricine C (1) and the related
lepadiformine (2) have already attracted an impressive array
of synthetic efforts.5,6 The Molander5a and Trost groups5b
utilized a double Michael addition to create the tricyclic
skeleton from a monocyclic substrate. Independent work by
Kibayashi5c,d and Hsung5e made use of a pivotal N-acyl-
iminium ion/diene cyclization protocol. An oxidative spiro-
cyclization of a phenolic primary amine was the key strategy
used by Ciufolini5i and co-workers in their asymmetric
synthesis of (-)-cylindricine C. Despite these earlier efforts,
new and efficient approaches toward the tricyclic core of
the cylindricines are still important as they would allow not
only the synthesis of other members of this family of natural
products but also related non-natural analogues possessing
biological activity. In this communication, we report a
concise stereocontrolled synthesis of (()-cylindricine C (1)
where an efficient tandem Michael addition/dipolar cycload-
dition sequence developed in our laboratory plays a crucial
role.7
(1) (a) Blackman, A. J.; Li, C.; Hockless, D. C. R.; Skelton, B. W.;
White, A. H. Tetrahedron 1993, 49, 8645. (b) Li, C.; Blackman, A. J. Aust.
J. Chem. 1995, 48, 955.
(2) (a) For a recent review, see: Weinreb, S. M. Chem. ReV. 2006, 106,
2531. (b) Werner, K. M.; de los Santos, J. M.; Weinreb, S. M.; Shang, M.
J. Org. Chem. 1999, 64, 686.
(3) Li, C.; Blackman, A. J. Aust. J. Chem. 1994, 47, 1355.
(4) Biard, J. F.; Guyot, S.; Roussakis, C.; Verbist, J. F.; Vercauteren,
J.; Weber, J. F.; Boukef, K. Tetrahedron Lett. 1994, 35, 2691.
Figure 1. Marine tricyclic alkaloid framework.
10.1021/ol8006056 CCC: $40.75
Published on Web 04/10/2008
2008 American Chemical Society

Our approach to cylindricine C was guided by a long-
standing interest in the intramolecular [3 + 2]-cycloaddition
of alkenyl nitrones for natural product synthesis.8 In earlier
work, we had described the formation of 7-oxa-1-azanor-
bornanes (i.e., 5) from the reaction of oximes with 2,3-
bis(phenylsulfonyl)-1,3-butadiene (3).9 The formation of the
bicyclic isoxazolidine 5 involves conjugate addition of the
oxime with the activated diene 3 to give a transient nitrone
4 which then undergoes a further intramolecular 1,3-dipolar
cycloaddition onto the adjacent vinyl sulfone (Scheme 1).
Scheme 2
Scheme 1
distinguishable tethered groups at the congested C2 stereo-
genic center. 2,3-Bis(phenylsulfonyl)diene 3 and oxime 7
(R ) TIPS) were considered as the two building blocks for
the construction of cycloadduct 8. Challenges to overcome
in this approach would include the construction of the
remaining A- and C-rings around the 4-piperidone periphery.
There would also be the need to leverage potential epimer-
ization at the C5 and C13 stereocenters within the azatricyclic
core to geometries that would adopt the energetically
preferred arrangement relative to the central tetrasubstituted
C10 carbon prior to the late-stage n-hexyl group installation
at the C2 position.
Raney-Ni reduction of the 7-oxa-1-azanorbornane cycload-
duct 5 results in sequential nitrogen-oxygen bond cleavage
followed by desulfonylation to furnish a 2,2-disubstituted
4-piperidone of type 6.
Our retrosynthetic analysis (Scheme 2) reveals a potentially
convenient route to cylindricine C based on the above
Michael addition/dipolar cycloaddition cascade. The cylin-
dricine C core was envisioned to evolve from the easily
accessible 4-piperidonyl B-ring precursor 9 which bears two
Following this approach, we prepared oxime 7 starting
from δ-valerolactone by a tractable four-step sequence which
proceeded in 62% overall yield. The known 5-hydroxy-N,O-
dimethyl-pentanohydroxamic acid10 derived from δ-valero-
lactone and N,O-dimethylhydroxylamine was converted to
the corresponding TIPS protected alcohol in 79% yield for
the two-step sequence (Scheme 3). Reaction of 11 with
(5) (a) Molander, G. A.; Ronn, M. J. Org. Chem. 1999, 64, 5183. (b)
Trost, B. M.; Rudd, M. T. Org. Lett. 2003, 5, 4599. (c) Arai, T.; Abe, H.;
Aoyagi, S.; Kibayashi, C. Tetrahedron Lett. 2004, 45, 5921. (d) Abe, H.;
Aoyagi, S.; Kibayashi, C. J. Am. Chem. Soc. 2005, 127, 1473. (e) Liu, J.;
Hsung, R. P.; Peters, S. D. Org. Lett. 2004, 6, 3989. (f) Liu, J.; Swidorski,
J. J.; Peters, S. D.; Hsung, R. P. J. Org. Chem. 2005, 70, 3898. (g) Wang,
J.; Swidorski, J. J.; Sydorenko, N.; Hsung, R. P.; Coverdale, H. A.; Kuyava,
J. M.; Liu, J. Heterocycles 2006, 70, 423. (h) Swidorski, J. J.; Wang, J.;
Hsung, R. P. Org. Lett. 2006, 8, 777. (i) Canesi, S.; Bouchu, D.; Ciufolini,
M. A. Angew. Chem., Int. Ed. 2004, 43, 4336. (j) Mihara, H.; Shibuguchi,
T.; Kuramochi, A.; Ohshima, T.; Shibasaki, M. Heterocycles 2007, 72, 421.
(k) Shibuguchi, T.; Mihara, H.; Kuramochi, A.; Sakuraba, S.; Takashi, O.;
Shibasaki, M. Angew. Chem., Int. Ed. 2006, 45, 4635.
Scheme 3
(6) (a) Pearson, W. H.; Ren, Y. J. Org. Chem. 1999, 64, 688. (b) Werner,
K. M.; de los Santos, J. M.; Weinreb, S. M.; Shang, M. J. Org. Chem.
1999, 64, 4865. (c) Sun, P.; Sun, C.; Weinreb, S. M. J. Org. Chem. 2002,
67, 4337. (d) Greshock, T. J.; Funk, R. L Org. Lett. 2001, 3, 3511. (e)
Abe, H.; Aoyagi, S.; Kibayashi, C. J. Am. Chem. Soc. 2000, 122, 4583. (f)
Abe, H.; Aoyagi, S.; Kibayashi, C. Angew Chem., Int. Ed. 2002, 41, 3017.
(7) (a) Padwa, A.; Norman, B. H. Tetrahedron Lett. 1988, 29, 2417.
(b) Norman, B. H.; Gareau, Y.; Padwa, A. J. Org. Chem. 1991, 56, 2154.
(8) (a) Tufariello, J. J. In 1,3-Dipolar Cycloaddition Chemistry; Padwa,
A., Ed.; Wiley: New York, 1984; Vol 2, pp 83-168. (b) Jones, R. C. F.;
Martin, J. N. In Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry Towards Heterocycles and Natural Products; Padwa, A., Pearson,
W. H., Eds; Wiley: New York, 2002; Chapter 1.
3-butenyl magnesium bromide gave ketone 12 in 98% yield
which, in turn, was transformed into the corresponding oxime
7 (80%) when treated with NH2OH·HCl. Heating a sample
(9) (a) Padwa, A.; Watterson, S. H.; Ni, Z. Org. Synth. 1997, 74, 147.
(b) Jeganathan, S.; Okamura, W. H. Tetrahedron Lett. 1982, 23, 4763.
1872
Org. Lett., Vol. 10, No. 9, 2008

of oxime 7 and bis(phenylsulfonyl)diene 3 in CHCl3 at 90
°C in a sealed tube for 12 h afforded the expected cycload-
duct 8 as a 1:1 mixture of diastereomers in 75% yield. In a
series of papers, Stack and co-workers showed that terminal
olefins can be rapidly and efficiently epoxidized using
manganese phenanthroline with commercially available per-
acetic acid in CH3CN at room temperature.11 Using these
conditions, the alkenyl group present in cycloadduct 8 was
epoxidized to give primarily 13 as a single diastereomer in
26% isolated yield.12 The epoxidation of 7 proceeds with
high exo-selectivity, and this is probably a result of different
steric interactions in the transition state with the MnII
complex for the two different diastereomers. In addition,
complexation of the manganese catalyst with the N-O bond
of the oxa-azanorbornene might also help to direct the facial
selectivity of the epoxidation reaction.
by column chromatography.
Desilylation of 17 with TBAF followed by tosylation of
the resulting primary alcohol 18 furnished the expected
tosylate 19 in 76% overall yield. We next carried out a base-
induced cyclization of 19 so as to construct the core
azadecalin ring system 21 by means of an intramolecular
enolate alkylation reaction.15 Thus, treatment of tosylate 19
with 2 equiv of t-BuOK in benzene followed by an aqueous
workup afforded 21 in 69% yield (Scheme 5). This reaction
Scheme 5
With epoxide 13 in hand, treating a sample with excess
zinc dust in an aqueous ammonium chloride-THF mixture13
at 70 °C triggered a reductiVe-cyclization cascade whereby
scission of the N-O bond was followed by the spontaneous
ejection of phenyl sulfenic acid to furnish 4-piperidone 14
as a transient intermediate. Attack of the basic nitrogen atom
of the 4-piperidone onto the epoxide ring proceeded rapidly
and established the indolizidine ring system.14 This was
followed by a further reduction of the remaining phenylsul-
fonyl group in 15 to give 16 in 76% overall yield as a 9:1
mixture of diastereomers. The major isomer coincides with
the hydroxymethylene geometry at the C13 position of the
cylindricine C motif (Scheme 4). Esterification of alcohol
presumably proceeds via the initially formed trans-1-
azadecalin 20 which readily epimerizes to the thermody-
namically more stable isomer 214,5d,e possessing the stere-
ochemistry required for the structure of cylindricine C.
To complete the total synthesis of (()-cylindricine C (1),
oxidation of 21 to the corresponding 2H-piperidonyl enone
22 had to be affected to introduce the n-hexyl side chain. A
variety of standard methods such as IBX, CAN, and PhSeCl/
NaIO4 were explored but failed to produce the required
unsaturated enone. Ultimately, 22 was prepared in 95% yield
by treating 21 with Hg(OAc)2 in the presence of EDTA
(Scheme 6).16 Finally, the n-hexyl side chain was introduced
by taking advantage of the tricyclic topography of 22 so as
to influence the pseudoequatorial approach of the organo-
metallic reagent. Thus, conjugate addition of the n-hexyl
cuprate reagent to enone 22 using a modified Donohoe
procedure17 followed by alkaline saponification furnished a
3:1 mixture of cylindricine C (1) and 2-epi-cylindricine C
Scheme 4
16 with benzoyl chloride gave the corresponding ester 17,
and this allowed for the separation of the two diastereomers
(14) Several examples of amplified nitrogen nucleophilicity under
reductive conditions have been reported in the literature, particularly with
substrates that bear a tethered electrophile. For some select cases, see:(a)
Pearson, W. H.; Hines, J. V. J. Org. Chem. 2000, 65, 5785. (b) Denmark,
S. E.; Martinborough, E. A. J. Am. Chem. Soc. 1999, 121, 3046. (c) Martin,
S. F.; Chen, H. J.; Yang, C.-P. J. Org. Chem. 1993, 58, 2876. (d) Martin,
S. F.; Chen, H. J.; Lynch, V. M. J. Org. Chem. 1995, 60, 276. (e) Smith,
A. B.; Kim, D. S Org. Lett. 2004, 6, 1493. (f) Smith, A. B.; Kim, D. S.
Org. Lett. 2005, 7, 3247. (g) Smith, A. B.; Kim, D. S. J. Org. Chem. 2006,
71, 2547.
(10) Molander, G. A.; McWilliams, J. C.; Noll, B. C. J. Am. Chem.
Soc. 1997, 119, 1265.
(11) (a) Terry, T. J.; Dubois, G.; Murphy, A.; Stack, T. D. P. Angew.
Chem., Int. Ed. 2007, 46, 945. (b) Murphy, A.; Stack, T. D. P. J. Mol.
Catal. A. 2006, 251, 78. (c) Murphy, A.; Pace, A.; Stack, T. D. P. Org.
Lett. 2004, 6, 3119. (d) Dubois, G.; Murphy, A.; Stack, T. D. P. Org. Lett.
2003, 5, 2469. (e) Murphy, A.; Dubois, G.; Stack, T. D. P. J. Am. Chem.
Soc. 2003, 125, 5250.
(12) The low yield of 13 can be attributed to the recovery of a substantial
amount of the endo-starting alkene 8 as well as some decomposition products
derived from an N-oxide intermediate.
(15) Also see: (a) Vite, G. D.; Spencer, T. A. J. Org. Chem. 1988, 53,
2555. (b) Conia, J. M.; Rouessac, F. Tetrahedron 1961, 16, 45.
(16) Mo¨hrle, H.; Claas, M. Pharmazie 1988, 43, 749.
(13) White, J. D.; Hansen, J. D. J. Org. Chem. 2005, 70, 1963.
Org. Lett., Vol. 10, No. 9, 2008
1873

synthesis consists of a Michael addition/dipolar cycloaddition
cascade of 2,3-bis(phenylsulfonyl)-1,3-butadiene with 9-tri-
isopropylsilanyloxy-non-1-en-5-one oxime. The resulting
cycloadduct was converted into cylindricine C by: (1) a
reductive-cyclization cascade to set the BC-ring skeleton,
(2) a base-induced cyclization to construct the tricyclic core,
and (3) an oxidation-conjugate addition of the n-hexyl side
chain. The applicability of the new methodology to other
alkaloidal targets is currently under study and will be the
subject of future reports.
Scheme 6
Acknowledgment. We appreciate the financial support
provided by the National Science Foundation (CHE-
0742663).
Supporting Information Available: Spectroscopic data
and experimental details for the preparation of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(23) in 84% yield. The synthetic material displayed spec-
troscopic data identical to those reported for the natural
product.4
OL8006056
In summary, a new approach to the marine alkaloid (()-
cylindricine C has been devised. The key element of the
(17) Donohoe, T. J.; Johnson, D. J.; Mace, L. H.; Bamford, M. J.;
Ichihara, O. Org. Lett. 2005, 7, 435.
1874
Org. Lett., Vol. 10, No. 9, 2008