Total syntheses of (+)-cylindricines C-E and (-)-lepadiformine through a common intermediate derived from an aza-Prins cyclization and Wharton's rearrangement

Article abstract of DOI:10.1021/ol048353g

(Chemical Equation Presented) Enantioselective total syntheses of (+)-cylindricines C-E and (-)-lepadiformine through a common tricyclic intermediate are described here. These syntheses are concise and feature an aza-Prins cyclization and a seldom-used Wh

Full text of DOI:10.1021/ol048353g

ORGANIC
LETTERS
2004
Vol. 6, No. 22
3989-3992
Total Syntheses of (
+)-Cylindricines
C
−
E and ( )-Lepadiformine through a
−
Common Intermediate Derived from an
aza-Prins Cyclization and Wharton’s
Rearrangement
Jia Liu, Richard P. Hsung,* and Scott D. Peters
Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455
hsung@chem.umn.edu
Received August 18, 2004
ABSTRACT
Enantioselective total syntheses of (+)-cylindricines C−E and (−)-lepadiformine through a common tricyclic intermediate are described here.
These syntheses are concise and feature an aza-Prins cyclization and a seldom-used Wharton rearrangement en route to the common intermediate.
Blackman reported the isolation of (-)-cylindricines A-K
from the marine ascidian ClaVelina cylindrica collected in
Tasmania.1 Cylindricines A [1a] and B [1b] were assigned
by X-ray structures of the corresponding picrates that exist
as a 3:2 equilibrium mixture via the aziridinium intermediate
2 [Figure 1].1a Fasicularin 3 and lepadiformine 4, two
structurally related alkaloids, were isolated from the marine
ascidian Nephteis fasicularis2 and ascidian ClaVelina lep-
adiformis,3 respectively. Given their unique structural motif
and biological activity [3 shows cytotoxicity to Vero cells,
and 4 is cytotoxic toward KB, HT29, and P388 cell lines],2,3
the cylindricines,4-6 fasicularin,7 and lepadiformine8-13 have
already attracted an impressive array of synthetic efforts.
During our pursuit of these alkaloids employing the aza-
[3 + 3] formal cycloaddition strategy,14-16 we recognized
(4) For the first two 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.
(5) For the total synthesis 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.
(6) For a recent synthesis of (+)-cylindricines, see: (a) Trost, B. M.;
Rudd, M. T. Org. Lett. 2003, 5, 4599. (b) Arai, T.; Abe, H.; Aoyagi, S.;
Kibayashi, C. Tetrahedron Lett. 2004, 45, 5921-5924.
(7) For two elegant syntheses of fasicularin, see: (a) Maeng, J.-H, Funk,
R. L. Org. Lett. 2002, 4, 331. (b) Fenster, M. D. B.; Dake, G. R. Org. Lett.
2003, 5, 4313.
(8) For a detailed account on efforts involving the lepadiformine
synthesis, see: Weinreb, S. M. Acc. Chem. Res. 2003, 36, 59.
(9) (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.
(10) (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.
(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) 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.
(3) Biard, J. F.; Guyot, S.; Roussakis, C.; Verbist, J. F.; Vercauteren, J.;
Weber, J. F.; Boukef, K. Tetrahedron Lett. 1994, 35, 2691.
10.1021/ol048353g CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/28/2004

Scheme 1
The common intermediate, the aza-tricycle 5, that would
link together pathways toward (+)-cylindricines [ent-1c-e]
and (-)-lepadiformine [4], is shown in Scheme 1. A C4-
deoxygenation of 5 would lead to (-)-lepadiformine [4],
whereas an appropriate epimerization at C5 would lead to
the ent-cylindricines.
The aza-tricycle 5 was envisioned originally from a
tandem Mannich strategy17-19 starting from amino ketone 8
[8f7f6f5] as outlined in Scheme 2. Although this strategy
Figure 1.
that one issue involving these alkaloids has remained
unexplored. The aza-tricyclic motif in 1, 3, and 4 can be
accessed through a tandem Mannich strategy that has not
been employed in the synthesis of the cylindricines, although
Kibayashi11 and Weinreb12 constructed the C5-10 bond in
the aza-spirocyclic AC-ring of (-)-lepadiformine 4 via a
Mannich-type addition.
Scheme 2
These strategies11,12 appear to selectively provide a relative
C5-10 stereochemistry suitable only for the synthesis of the
trans-fused AB-ring in lepadiformine 4, whereas cylindri-
cines possess the cis-fused 1-aza-decalinic AB-ring. How-
ever, this implies that the cylindricine family, specifically
(+)-cylindricines [ent-1c-e], and (-)-lepadiformine [4] can
be related structurally through an epimerization at C5 of a
suitable common intermediate. We report here total syntheses
of (+)-cylindricines C-E and (-)-lepadiformine via a
common intermediate derived from an aza-Prins cyclization
and Wharton’s rearrangement.
is attractive in alkaloid synthesis18,19 and can allow formation
of two bonds [C5-10 and then C2-3] in a stereoselective
manner, in this specific application, we experienced many
difficulties.
To demonstrate the concept of using 5 as a common
intermediate to access both (+)-cylindricines and (-)-
lepadiformine, we ultimately prepared 5 from 8 through an
aza-Prins cyclization20 followed by Wharton’s rearrange-
ment.21,22
Our synthesis commenced with butyrolactam 1123 as
shown in Scheme 3. Addition of the alkyllithium gen-
(11) (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. For (-)-lepadiformine, see: (c) Abe, H.; Aoyagi, S.; Kibayashi, C.
Angew. Chem., Int. Ed. 2002, 41, 3017.
(12) For a recent total synthesis of (-)-lepadiformine, see: (a) Sun, P.;
Sun, C.; Weinreb, S. M. J. Org. Chem. 2002, 67, 4337. (b) Sun, P.; Sun,
C.; Weinreb, S. M. Org. Lett. 2001, 3, 3507.
(13) For a recent total synthesis of (()-lepadiformine, see: (c) Greshock,
T. J.; Funk, R. L. Org. Lett. 2001, 3, 3511.
(14) For intermolecular formal aza-[3 + 3] cycloadditions, see: (a)
Sydorenko, N.; Hsung R. P.; Darwish, O. S.; Hahn, J. M.; Liu, J. J. Org.
Chem. 2004, 69, ASAP (DOI: 10.1021/jo001219z). (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) Sklenicka, H. M.; Hsung,
R. P.; Wei, L.-L.; McLaughlin, M. J.; Gerasyuto, A. I.; Degen, S. J.; Mulder,
J. A. Org. Lett. 2000, 2, 1161. (d) Hsung, R. P.; Wei, L.-L.; Sklenicka, H.
M.; Douglas, C. J.; McLaughlin, M. J.; Mulder, J. A.; Yao, L. J. Org. Lett.
1999, 1, 509.
(15) For intramolecular formal aza-[3 + 3] cycloaddition, see: Wei, L.-
L.; Sklenicka, H. M.; Gerasyuto, A. I.; Hsung, R. P. Angew. Chem., Int.
Ed. 2001, 40, 1516.
(16) For applications in natural product syntheses, see: (a) Luo, S.;
Zificsak, C. Z.; Hsung, R. P. Org. Lett. 2003, 5, 4709. (b) McLaughlin, M.
J.; Hsung, R. P.; Cole, K. C.; Hahn, J. M.; Wang, J. Org. Lett. 2002, 4,
2017.
(17) Robinson, R. J. Chem. Soc. 1917, 762.
(18) For recent reviews, see: (a) Bur, S. K.; Martin, S. F. Tetrahedron
2001, 57, 3221. (b) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000,
56, 3817. (c) Scholz, U.; Winterfeldt, E. Nat. Prod. Rep. 2000, 17, 349. (d)
Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998, 37,
1044. (e) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367.
(19) For some examples of natural product synthesis that employ a
tandem Mannich strategy, see: (a) Corey, E. J.; Balanson, R. D. J. Am.
Chem. Soc. 1974, 96, 6516. (b) Rykman, D. M.; Stevens, R. V. J. Am.
Chem. Soc. 1987, 109, 4940. (c) Ihara, M.; Suzuki, M.; Fukumoto, K.;
Kabuto, C. J. Am. Chem. Soc. 1990, 112, 1164. (d) Takahashi, I.; Tsuzuki,
M.; Yokota, H.; Kitajima, H. Heterocycles 1994, 37, 933. (e) Takahashi,
I.; Tsuzuki, M.; Yokota, H.; Morita, T.; Kitajima, H. Heterocycles 1996,
43, 71. (f) Scott, R. W.; Epperson, J.; Heathcock, C. H. J. Org. Chem.
1998, 63, 5001.
3990
Org. Lett., Vol. 6, No. 22, 2004

Scheme 3
Scheme 5
erated from iodide 12 to 11 led to the ring-opened Boc-
protected amino ketone 13.11c,24 A subsequent formic acid-
promoted11c,18,20 aza-Prins cyclization led to aza-spirocycle
14 in which the allyl cation intermediate has been trapped
by the formate anion. Removal of the formyl group using
K2CO3 and MeOH led to allyl alcohol 15 in 64% overall
yield.
quent SO3-Pyr/DMSO oxidation of epoxy alcohol 19 af-
forded epoxy ketone 20 [Scheme 5]. The ensuing Wharton’s
rearrangement using 5.0 equiv of hydrazine took place
without the isolation of hydrazone 21 and gave the desired
transposed allyl alcohol 23 in 66% yield. While we observed
exclusively the trans-allyl alcohol 23 in most trials, we did
find the cis-allyl alcohol 22 on one occasion in 42% yield.
We are not certain at this point whether this is a phenomenon
related to the equivalent of HOAc used or to the stereo-
chemistry of the epoxide. We are currently examining this
interesting observation from the Wharton’s rearrange-
ment.21,22 MnO2 oxidation of 23 provided enone 24 in 90%
yield.
TPAP/NMO oxidation of allyl alcohol 15 gave enone 16
in 94% yield [Scheme 4], providing us with the first
Scheme 4
Construction of the key common intermediate is shown
in Scheme 6. Treatment of enone 24 with TFA in CH2Cl2
led to the desired tricycle 2625 in 72% yield with the N-1,4-
addition taking place in situ through the free amine 25.
We also isolated a second product on several occasions.
After some careful examination,25 we learned that the aza-
tricycle 26 actually underwent rapid epimerization at C5 to
give 27, which is the second product, when exposed to silica
gel [entry 1] or basic conditions [entries 2 and 3]. This
opportunity to examine the possibility of epimerizing the C5
stereocenter. However, conditions such as refluxing DBU
in toluene led to decomposition, while LDA or NaH only
deprotonated the R-protons as evident by D2O quenching.
With these failures, we nonetheless moved forward by first
epoxidizing allyl alcohol 15 using m-CPBA, and a subse-
(21) (a) Wharton, P. S.; Bohlen, D. H. J. Org. Chem. 1961, 26, 3615.
(b) Wharton, P. S.; Dunny, S.; Krebs, L. S. J. Org. Chem. 1964, 29, 958.
(22) Also see: (a) Stork, G., Williard, P. J. Am. Chem. Soc. 1977, 99,
7067. (b) Schult-Elte, K. H.; Rautenstrauch, V.; Ohloff, G. HelV. Chim Acta
1971, 54, 1805. (c) Ohloff, G.; Uhde, G. HelV. Chim Act. 1970, 53, 531.
(23) Preparation of 11 was carried out according to: Woo, K.; Jones,
K. Tetrahedron Lett. 1991, 32, 6949.
(20) (a) For a related review, see: Hiemstra, H.; Speckamp, W. N. In
ComprehensiVe Organic Synthesis; Brossi, A., Ed.; Academic Press: San
Diego, 1988; Vol. 2, pp 271-339. For some related examples, see: (b)
Chao, W.; Waldman, J. H.; Weinreb, S. M. Org. lett. 2003, 5, 2915. (c)
Dobbs, A.; Guesne´, S. J. J.; Martinovic, S.; Coles, S. J.; Hursthouse, M. B.
J. Org. Chem. 2003, 68, 7880. (d) Schoemaker, H. E.; Speckamp, W. N.
Tetrahedron 1980, 36, 951. (e) Evans, D. A.; Thomas, E. W. Tetrahedron
Lett. 1979, 20, 411.
(24) All new compounds are characterized by 1H NMR, 13C NMR, FTIR,
23
and mass spectroscopy and [R]D
.
(25) We note here that compound 26 actually has the identical charac-
terizations as penultimate intermediate in Trost’s synthesis [ref 6]. However,
we are comfortable with our assignment of 26 on the basis of the fact that
(1) a total synthesis of (-)-lepadiformine was achieved using 26 and (2)
desilylation of 26 using TBAF directly gave (+)-cylindricine C concomitant
with the C5 epimerization.
Org. Lett., Vol. 6, No. 22, 2004
3991

Scheme 6
Scheme 7
finding establishes one of the two necessary links to the
cylindricines and lepadiformine.
It turned out that (+)-cylindricine C [ent-1c] could be
obtained in 79% yield directly from 26 via desilylation using
TBAF, with the C5-epimeization occurring concomitantly25
[Scheme 7]. Subsequent standard manipulations would lead
to (+)-cylindricines D and E [ent-1d and 1e].
To complete a total synthesis of (-)-lepadiformine 4, we
quantitatively reduced the C4-carbonyl using NaBH4, which
led to the C4-OH group being exclusively â [Scheme 7].
A variety of methods such as Burgess- or Chugaev-type
elimination followed by hydrogenation were explored but
failed to deoxygenate the C4-OH group.
natural products prepared here spectroscopically matched
those reported in the literature.5,6,11,12
We have described here enantioselective syntheses of both
(+)-cylindricines C-E [11.1% overall yield in 9 steps from
11 for C] and (-)-lepadiformine [7.1% overall in 12 steps
from 11] through a common tricyclic intermediate. These
syntheses are short and concise, featuring an aza-Prins
cyclization and a seldom-used Wharton rearrangement.
Acknowledgment. Financial support from Camille Drey-
fus and McKnight Foundations is greatly appreciated.
Ultimately, xanthate 28 was prepared in 72% yield under
standard conditions. Barton-McCombie deoxygenation pro-
tocol26 was then employed, and subsequent desilylation led
to (-)-lepadiformine 4 in a combined 79% yield. All four
Supporting Information Available: Experimental pro-
1
cedures and selected H and 13C NMR spectra as well as
characterizations. This material is available free of charge
via the Internet at http://pubs.acs.org.
(26) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574.
OL048353G
3992
Org. Lett., Vol. 6, No. 22, 2004