A concise total synthesis of (-)-cylindricine C through a stereoselective intramolecular aza-[3 + 3] annulation strategy

Article abstract of DOI:10.1021/ol053059p

An enantioselective total synthesis of (-)-cylindricine C is described, featuring a diastereoselective intramolecular aza-[3 + 3] annulation strategy and an interesting halohydrin formation of the C4-5 olefin for construction of C4-ketone. This work provi

Full text of DOI:10.1021/ol053059p

ORGANIC
LETTERS
2006
Vol. 8, No. 4
777-780
A Concise Total Synthesis of
)-Cylindricine C through a
Stereoselective Intramolecular
Aza-[3 3] Annulation Strategy
(−
+
Jacob J. Swidorski, Jiashi Wang, and Richard P. Hsung*
DiVision of Pharmaceutical Sciences and Department of Chemistry, UniVersity of
Wisconsin, Madison, Wisconsin 53705
rhsung@wisc.edu
Received December 18, 2005
ABSTRACT
An enantioselective total synthesis of (−)-cylindricine C is described, featuring a diastereoselective intramolecular aza-[3
+
3] annulation
strategy and an interesting halohydrin formation of the C4−5 olefin for construction of C4-ketone. This work provides a unique approach to
this family of natural products.
Isolations of cylindricines A-K, from the marine ascidian
ClaVelina cylindrica collected in Tasmania, were first
reported by Blackman in 1993.1 Cylindricines A (1) and
cylindricine B (7) exist as a 3:2 equilibrium mixture
presumably via the aziridinium intermediate 6.1a Two related
marine alkaloids, lepadiformine 8b and fasicularin 9, were
isolated from the marine ascidian ClaVelina lepadiformis2
and the Micronesian ascidian Nephteis fasicularis,3 respec-
tively. While 8b possesses moderate cytotoxicity toward
tumor cell lines in vitro,2 9 shows cytotoxicity to Vero cells
with IC50 of 14µg/mL.3 The correct structure of lepadiformine
was established to be 8b independently by Weinreb,4
Pearson,5 and Kibayashi.6 Given their unique tricyclic struc-
tural motif, biological activity, and low natural abundance,
lepadiformine 8b,4-7 fasicularin 9,8 and the cylindricines9-11
(4) (a) Werner, K. M.; De Los Santos, J. M.; Weinreb, S. M.; Shang,
M. J. Org. Chem. 1999, 64, 686. (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. Org. Lett. 2001, 3, 3507.For their recent total syntheses
of (-)-lepadiformine, see: (d) Sun, P.; Sun, C.; Weinreb, S. M. J. Org.
Chem. 2002, 67, 4337.
(5) (a) Pearson, W. H.; Barta, N. S.; Kampf, J. W. Tetrahedron Lett.
1997, 38, 3369. (b) Pearson, W. H.; Ren, Y. J. Org. Chem. 1999, 64, 688.
(6) (a) Abe, H.; Aoyagi, S.; Kibayashi, C. Tetrahedron Lett. 2000, 41,
1205. (b) Abe, H.; Aoyagi, S.; Kibayashi, C. J. Am. Chem. Soc. 2000, 122,
4583. (c) For a synthesis of (-)-lepadiformine, see: Abe, H.; Aoyagi, S.;
Kibayashi, C. Angew. Chem., Int. Ed. 2002, 41, 3017. (d) For a recent
account on total syntheses of both (-)-lepadiformine and (+)-cylindricines
C-E via an aza-spirocyclic common intermediate, see: Abe, H.; Aoyagi,
S.; Kibayashi, C. J. Am. Chem. Soc. 2005, 127, 1473.
(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. 1994, 47, 1355. (c) Li, C.; Blackman, A. J. Aust. J. Chem. 1995, 48,
955.
(2) Biard, J. F.; Guyot, S.; Roussakis, C.; Verbist, J. F.; Vercauteren, J.;
Weber, J. F.; Boukef, K. Tetrahedron Lett. 1994, 35, 2691.
(3) Patil, A. D.; Freyer, A. J.; Reichwein, R.; Carte, B.; Killmer, L. B.;
Faucette, L.; Johnson, R. K.; Faulkner, D. J. Tetrahedron Lett. 1997, 38,
363.
(7) (a) For a detailed account on efforts involving the lepadiformine
synthesis, see: (a) Weinreb, S. M. Acc. Chem. Res. 2003, 36, 59. (b) Also
see: Kibayashi, C.; Aoyagi, S.; Abe, H. Bull. Chem. Soc. Jpn. 2003, 76,
2059. For another synthesis of (()-lepadiformine, see: Sun Greshock, T.
J.; Funk, R. L. Org. Lett. 2001, 3, 3511.
(8) For total syntheses of fasicularin, see: (a) Maeng, J.-H, Funk, R. L.
Org. Lett. 2002, 4, 331. (b) Fenster, M. D. B.; Dake, Gregory R. Chem.-
Eur. J. 2005, 11, 639. (c) Fenster, M. D. B.; Dake, Gregory R. Org. Lett.
2003, 5, 4313.
10.1021/ol053059p CCC: $33.50
© 2006 American Chemical Society
Published on Web 01/27/2006

have attracted much effort from many synthetic groups.
for a wide range of nitrogen heterocycles (15a-e) including
the motif found in lepadiformine or cylindricines 15e. We
report here the total synthesis of (-)-cylindricine C featuring
a stereoselective intramolecular aza-[3 + 3] annulation
strategy.
Scheme 2. Retrosynthetic Analysis
We envisioned an application of the aza-[3 + 3] annulation
reaction12-16 [vinylogous amides 10 + vinyl iminium ions
11 f 12 in Scheme 1] in the synthesis of cylindricines.
Scheme 1. Aza-[3 + 3] Annulation Strategy
Our plan is outlined in Scheme 2.Tricycle 16, a key
versatile intermediate leading to the cylindricines, can be
produced via an intramolecular aza-[3 + 3] formal cycload-
dition of chiral vinylogous amides 17 that is tethered to the
vinyl iminium ion. A range of vinylogous amides 17 could
be prepared from chiral amine 18, which can be prepared
from the known vinyloxazoline 19.17 For the end game of
the total synthesis, we intend to access the C4-carbonyl group
via a sequence that would feature a halohydrin formation of
the C4-5 olefin.
Scheme 3. Synthesis of the Protected Allyl Alcohol 23
Specifically, we intended to utilize an intramolecular aza-[3
+ 3] annulation16 strategy (13 f 14) that could be suited
(9) For total syntheses of (()-cylindricines, see: (a) Snider, B. B.; Liu,
T. J. Org. Chem. 1997, 62, 5630. (b) Liu, J. F.; Heathcock, C. H. J. Org.
Chem. 1999, 64, 8263.
(10) For total syntheses of (-)-cylindricines, see: (a) Molander, G. A.;
Ronn, M. J. Org. Chem. 1999, 64, 5183. (b) Canesi, S.; Bouchu, D.;
Ciufolini, M. A. Angew. Chem., Int Ed. 2004, 43, 4336. For a recent
synthesis of (+)-cylindricines, see: (c) Trost, B. M.; Rudd, M. T. Org.
Lett. 2003, 5, 4599. (d) Arai, T.; Abe, H.; Aoyagi, S. Kibayashi, C.
Tetrahedron Lett. 2004, 45, 5921. (e) Also see 6d. (f) Taniguchi, T.; Tamura,
O.; Uchiyama, M.; Muraoka, O.; Tanabe, G.; Ishibashi, H. Synlett 2005,
1179.
(11) For total syntheses of both (+)-cylindricines and (-)-lepadiformine
via a common aza-tricyclic intermediate, see: (a) Liu, J.; Hsung, R. P.;
Peters, S. D. Org. Lett. 2004, 6, 3989. (b) Liu, J.; Swidorski, J. J.; Peter, S.
D.; Hsung, R. P. J. Org. Chem. 2005, 70, 3898.
(12) For reviews, see: (a) Harrity, J. P. A.; Provoost, O. Org. Biomol.
Chem. 2005, 3, 1349. (b) Hsung, R. P.; Kurdyumov, A. V.; Sydorenko, N.
Eur. J. Org. Chem. 2005, 23.
As shown in Scheme 3, our total synthesis commenced
with hydroboration of vinyl oxazoline 19 (five steps from
L-serine in 60% yield overall17) with 9-BBN followed by a
Suzuki-Miyaura18 coupling with vinyl triflate 20 to give
ester 21.19 Subsequent removal of the acetonide group using
778
Org. Lett., Vol. 8, No. 4, 2006

PPTS gave the Boc-protected amino alcohol 22 in 75% yield
over two steps. The free primary alcohol 22 was capped with
a TBDPS group followed by a Dibal-H reduction of the ester
intermediate to afford allyl alcohol 23 in 81% yield over
two steps.
18 with 6-n-butyl-4-bromo-2-pyrone 2419 was pursued to give
amino pyrone 25 in 61% yield. Deacylation and Ley-
Griffith’s oxidation20 provided enal 26 in 85% yield over
two steps.
With the annulation precursor enal 26 in hand, the key
intramolecular aza-[3 + 3] annulation was found to proceed
smoothly in toluene with 0.5 equiv of piperidinium acetate
as the catalyst for vinyliminium ion formation. After the
mixtre was heated at 150 °C for 12 h, tetracyclic annulation
product 27 was obtained in 68% yield as two separable
diastereomers in a ratio of 9:1 over several runs favoring of
the desired isomer as shown. The relative stereochemistry
of the major isomer was assigned rigorously using X-ray at
a later stage (see Scheme 5).
Protection of 23 using Ac2O followed by removal of the
Boc group using TFA led to chiral amine 18 (Scheme 4).
Scheme 4. Key Intramolecular Aza-[3 + 3] Annulation
Scheme 5. Installation of the C4-Carbonyl Group
The access to chiral amine 18 provides a significant
flexibility in choosing an appropriate vinylogous amide (see
17 in Scheme 2). We elected to use bromopyrone 24 because
we had already developed a protocol for reductive ring-
opening of R-pyrones.15c Accordingly, condensation of amine
(13) For a review on vinylogous amide chemistry, see: Kucklander, U.
Enaminones as Synthons. In The Chemistry of Functional Groups: The
Chemistry of Enamines; Rappoport, Z., Ed.; John Wiley & Sons: New York,
1994; Part I, p 523.
(14) For recent studies in this area, see: (a) Goodenough, K. M.; Moran,
W. J.; Raubo, P.; Harrity, J. P. A. J. Org. Chem. 2005, 70, 207. (b) Bose,
G.; Nguyen, V. T. H.; Ullah, E.; Lahiri, S.; Go¨rls, H.; Langer, P. J. Org.
Chem. 2004, 69, 9128. (c) Abelman, M. M.; Curtis, J. K.; James, D. R.
Tetrahedron Lett. 2003, 44, 6527. (d) Hedley, S. J.; Moran, W. J.; Price,
D. A.; Harrity, J. P. A. J. Org. Chem. 2003, 68, 4286.
(15) For leading references on intermolecular aza-[3 + 3], see: (a)
Sydorenko, N.; Hsung R. P.; Darwish, O. S.; Hahn, J. M.; Liu, J. J. Org.
Chem. 2004, 69, 6732. (b) Sklenicka, H. M.; Hsung, R. P.; McLaughlin,
M. J.; Wei, L.-L.; Gerasyuto, A. I.; Brennessel, W. W. J. Am. Chem. Soc.
2002, 124, 10435. (c) McLaughlin, M. J.; Hsung, R. P.; Cole, K. C.;
Hahn, J. M.; Wang, J. Org. Lett. 2002, 4, 2017. (d) Wei, L.-L.; Hsung,
R. P.; Xiong, H.; Mulder, J. A.; Nkansah, N. T. Org. Lett. 1999, 1,
2145.
(16) For intramolecular aza-[3 + 3], see: (a) Wei, L.-L.; Sklenicka, H.
M.; Gerasyuto, A. I.; Hsung, R. P. Angew. Chem., Int. Ed. 2001, 40, 1516.
(b) Gerasyuto, A. I.; Hsung, R. P.; Sydorenko, N.; Slafer, B. W. J. Org.
Chem. 2005, 70, 4248. For some simple applications, see: (c) Sydorenko,
N.; Zificsak, C. A.; Gerasyuto, A. I.; Hsung, R. P. Organic Biomol. Chem.
2005, 3, 2140. (d) Luo, S.; Zificsak, C. Z.; Hsung, R. P. Org. Lett. 2003,
5, 4709.
Success in this key intramolecular aza-[3 + 3] annulation
reaction provided us with an opportunity to complete our
total synthesis of (-)-cylindricine C. The remaining goal is
to install the desired ketone functionality at C4. However,
this proved to be the most challenging facet of this endeavor.
We ultimately were able to employ an interesting sequence
that entails a halohydrin formation specifically using NCS
in t-BuOH/H2O (Scheme 5). This led to the chlorohydrin
28 in 76% yields as a single diastereomer.21 TPAP-oxida-
tion20 followed by a reductive removal of the tertiary Cl
(20) Griffith, W. P.; Ley, S. V. Aldrichim. Acta 1990, 23, 13.
(21) Although we did not rigorously assign the relative stereochemistry
at C4 and C5, we believed that NCS should have approached from the less
hindered bottom face as observed in the hydrogenation of 27 that gave i in
90% yield as a single diastereomer. The relative stereochemistry C4 and
C5 is unambiguous on the basis of coupling constants obtained for H4a
and H4b.
(17) (a) Campbell, A. D.; Raynham, T. M.; Taylor, R. J. K. Synthesis
1998, 1707. (b) McKillop, A.; Taylor, R. J. K.; Watson, R. J.; Lewis, N. J.
Synthesis 1994, 31.
(18) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11, 513.
(19) See the Supporting Information.
Org. Lett., Vol. 8, No. 4, 2006
779

group using Zn and HOAc afforded ketone 29 as a single
diastereomer. NOE was suggestive, but an X-ray structure
of 29 was obtained, thereby removing any doubts in the
structural and stereochemical assignments.
To complete the total synthesis, a Stork-Crabtree-directed
hydrogenation24,25 of dihydro-4-pyridone 33 was carried out
(entry i in Scheme 7). Instead of what we had hoped, we
With ketone 29 in hand, we were poised to execute a
reductive ring opening of R-pyrones that we had developed
using LAH and 4 atm of H2 (Scheme 6).15c However, this
Scheme 7. Completion of the Total Synthesis
Scheme 6. Reductive Decarboxylation of the R-Prone Ring
obtained (-)-2-epi-cylindricine C 3526 in 54% yield (33 was
recovered in 35% yield). On the other hand, a remote
hydroxyl-directed reduction using Na(OAc)BH310b gave (-)-
cylindricine 2 in 83% yield (entry ii). While 35 spectroscopi-
cally matched those reported by Weinreb4b and Ciufolini,10b
(-)-cylindricine 2 matched Molander’s report.10a
We have described here an enantioselective total synthesis
of (-)-cylindricine C, featuring the first application of a
stereoselective intramolecular aza-[3 + 3] annulation strategy
with an overall yield of 7.4% in 17 steps (from 19, or 4.5%
overall yield in 22 steps from L-serine), and an interesting
halohydrin formation for the construction of the C4-carbonyl
group. This work provides a novel approach to this family
of alkaloids.
was completely unsuccessful using ketone 29. Alternatively,
we carried out a stepwise sequence: (1) Hydrogenation with
60 psi of H2 gave dihydropyrone 31, which was not very
stable, as a 2:1 isomeric mixture. (2) Without purification,
an ensuing NaCNBH3 reduction was carried out with HCl
(or HOAc). This led to dihydro-4-pyridone 32 in 92% overall
yield, and a subsequent desilylation gave alcohol 33 in 93%
yield.22
Acknowledgment. We thank the NIH [NS38049], PRF-
G, and Camille Dreyfus Foundation for funding. J.W. thanks
UMN for a Lester and Joan Krogh Fellowship. This work
was carried out at the University of Minnesota.
This reductive decarboxylation of the R-pyrone ring had
likely proceeded through decarboxylation of intermediate 34
after a selective reduction ring opening of the lactone (solid
arrow in 31 in the brackets) despite three other possibilities
for reductions (dotted arrows).23 Over-reduction did occur
at C2 (solid arrow in 34) when the reaction time was
prolonged.
Supporting Information Available: Experimental and
1H NMR spectral and characterizations for all new com-
pounds as well as X-ray structrural data. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL053059P
(24) (a) Stork, G.; Kahne, D. E. J. Am. Chem. Soc. 1983, 105, 1072. (b)
Crabtree, R. H.; Davis, M. J. Org. Chem. 1986, 51, 2655. (c) Crabtree, R.
H.; Felkin, H.; Fellebeen-Khan, T.; Morris, G. E. J. Organomet. Chem.
1979, 168, 183.
(22) The deprotection was carried out earlier than expected because we
could not do anything with 33 in completing the total synthesis.
(23) There was a slight confusion initially as to if the decarboxylation
had occurred. Attempted thermal “decarboxylation” of 32 led to no change
in the proton NMR. For reasons unknown, the C3-H evidently was
broadened in CDCl3 and, thus, appeared to be missing. It shows up at 5.50
ppm in toluene-d8.
(25) For some recent examples, see: (a) Ginn, J. D.; Padwa, A. Org.
Lett. 2002, 4, 1515. (b) Evans, D. A.; Morrissey, M. M. J. Am. Chem. Soc.
1984, 106, 3866.
(26) For (-)-2-epi-cylindricine C 35: [R]20D ) -12.4 (c 0.15, CHCl3).
Ciufolini’s value is: [R]20 ) -39.0 (c 0.5, CH2Cl2) (see ref 10b).
D
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Org. Lett., Vol. 8, No. 4, 2006