Total synthesis of (±)-lepadiformine via an amidoacrolein cycloaddition

Article abstract of DOI:10.1021/ol0165903

(matrix presented) The total synthesis of the cytotoxin lepadiformine is described. The intermolecular cycloaddition of a 2-amidoacrolein with the dimethyl acetal of 4,6-heptadienal gave a cycloadduct that was strategically functionalized for elaboration

Full text of DOI:10.1021/ol0165903

ORGANIC
LETTERS
2001
Vol. 3, No. 22
3511-3514
Total Synthesis of (±)-Lepadiformine via
an Amidoacrolein Cycloaddition
T. J. Greshock and Raymond L. Funk*
Department of Chemistry, PennsylVania State UniVersity,
UniVersity Park, PennsylVania 16802
rlf@chem.psu.edu
Received August 15, 2001
ABSTRACT
The total synthesis of the cytotoxin lepadiformine is described. The intermolecular cycloaddition of a 2-amidoacrolein with the dimethyl acetal
of 4,6-heptadienal gave a cycloadduct that was strategically functionalized for elaboration of the tricyclic ring system. These steps include a
diastereoselective addition of an organoytterbium reagent to an aldehyde, cyclization to the trans-perhydroquinoline substructure via a Mitsunobu
reaction, and an iodine-promoted amine cyclization with an alkene to introduce the pyrrolidine ring.
Several structurally intriguing and biologically active tricyclic
alkaloids were discovered in the mid-1990s and include the
cytotoxins lepadiformine,1 fasicularin,2 cylindricines A/B,3
and the immunosuppressent FR901483.4 Not surprisingly,
numerous groups have undertaken total syntheses of these
novel structures.5 Our interest in these natural products
emanated from methodology we had developed for the
preparation of the simplest common substructure among these
natural products, namely, a 1-alkyl-1-aminocyclohexane.
Specifically, we have prepared this central subunit via Diels-
Alder cycloaddition reactions of 2-amidoacroleins with
dienes, work which culminated in the total synthesis of
FR901483.5h We now wish to report on the further applica-
tion of this basic strategy in the total synthesis of (()-
lepadiformine.
Several groups contributed to the structural elucidation of
lepadiformine. Thus, lepadiformine was isolated by Biard
and co-workers from the tunicate ClaVelina lepadiformis and
assigned the rather unusual zwitterionic structure (Figure 1)
primarily on the basis of extensive NMR experiments,1
although the absolute configuration of lepadiformine was not
determined. However, Weinreb and co-workers synthesized
the structure assigned to lepadiformine and found that the
synthetic material was not identical with the natural product,
nor did it exist in a zwitterionic form.6 Moreover, Pearson
and co-workers synthesized three of the four diastereomers
of lepadiformine at C(2) and C(13) and found them to be
different from lepadiformine.7 They speculated that lepadi-
formine was epimeric at C(10) and possessed a trans-
perhydroquinoline substructure like fasicularin.7b This con-
(1) Biard, J. F.; Guyot, S.; Roussakis, C.; Verbist, J. F.; Vercauteren, J.;
Weber, J. F.; Boukef, K. Tetrahedron Lett. 1994, 35, 2691.
(2) Patil, A. D.; Freyer, A. J.; Reichwein, R.; Carte, B.; Killmer, L. B.;
Faucette, L.; Johnson, R. K. Tetrahedron Lett. 1997, 38, 363.
(3) (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.
(4) Sakamoto, K.; Tsujii, E.; Abe, F.; Nakanishi, T.; Yamashita, M.;
Shigematsu, N.; Izumi, S.; Okuhara, M. J. Antibiot. 1996, 49, 37.
(5) For completed total syntheses of lepadiformine and fasicularin, see:
(a) Abe, H.; Aoyagi, S.; Kibayashi, D. J. Am. Chem. Soc. 2000, 122, 4583.
For cylindricines, see: (b) Snider, B. B.; Liu, T. J. Org. Chem. 1997, 62,
5630. (c) Molander, G. A.; Ro¨nn, M. J. Org. Chem. 1999, 64, 5183. (d)
Liu, J. F.; Heathcock, C. H. J. Org. Chem. 1999, 64, 8263. For FR901483,
see: (e) Snider, B. B.; Lin, H. J. Am. Chem. Soc. 1999, 121, 7778. (f)
Scheffler, G.; Seike, H.; Sorensen, E. J. Angew. Chem., Int. Ed. 2000, 39,
4593. (g) Ousmer, M.; Braun, N. A.; Ciufolini, M. A. Org. Lett. 2001, 3,
765. (h) Funk, R. L.; Maeng, J. H. Org. Lett. 2001, 3, 1125.
(6) (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.
(7) (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.
10.1021/ol0165903 CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/02/2001

Scheme 2
Figure 1.
jecture was confirmed by Kibayashi and co-workers, who
reported the total synthesis of the revised structure shown
in Figure 1 and discovered that the corresponding hydro-
chloride salt was identical to the natural product.5a This
structure was unambiguously determined on the basis of
X-ray crystallographic analysis, which also showed that the
trans-perhydroisoquinoline substructure prefers to adopt a
chair-boat conformation.8 Parenthetically we note that these
combined efforts signify the continuing value of contempo-
rary organic synthesis in natural product structure determina-
tions.
We were intrigued to learn that lepadiformine embodies
a trans- rather than cis-perhydroisoquinoline subunit as found
in the cylindricines, since the former stereochemistry is more
accessible using our amidoacrolein-cycloaddition-based meth-
odology. In our retrosynthetic analysis (Scheme 1), we
3-butenyl substituent.9 The hexyl substituent of sulfonamide
2 could be introduced by stereoelectronically controlled10
addition (R via chair vs. â via boat) of an organometallic
reagent to the N-tosyl- (or N-acyl-) iminium ion 3. The
butenyl substituent of 3 could be elaborated by addition of
an allylic organometallic reagent to the activated aziridine
4, in turn, available by Mitsunobu ring closure of the
debenzylated derivative of the tosylamide 5. Finally, tosy-
lamide 5 could be prepared by straightforward application
of our methodology, namely, a regio- and endo-selective
cycloaddition of the amidoacrolein 6 with the diene 7,
thereby establishing the eventual trans-perhydroquinoline
stereochemistry.
Scheme 1
To that end, the amidoacrolein 6 was prepared using our
standard protocol. Thus, 2,2-dimethyl-1,3-dioxin-5-one11 (8)
was condensed with benzylamine to afford the corresponding
imine, which was sulfonylated with tosyl chloride to furnish
the desired 5-amido-1,3-dioxin 9. Retrocycloaddition of
dioxin 9 in refluxing toluene gave the amidoacrolein 6 in
nearly quantitative yield, which when subjected to diene 712
under the influence of high pressure (12 kbar) gave only the
(9) For reviews, see: (a) Bartlett, P. A. in Asymmetric Synthesis;
Morrison, J. D., Ed.; Academic Press: Orlando, FL, 1984; Vol. 3, p 411.
(b) Frederickson, M.; Grigg, R. Org. Prep. Proced. Int. 1997, 29, 33. (c)
Frederickson, M.; Grigg, R. Org. Prep. Proced. Int. 1997, 29, 63.
(10) For reviews, see: (a) Stevens, R. V. Acc. Chem. Res. 1984, 17,
289. (b) Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry;
Pergamon Press: New York, 1983; p 209.
(11) Prepared in two steps from tris(hydroxymethyl)aminomethane
hydrochloride. Hoppe, D.; Schmincke, H.; Kleemann, H.-W. Tetrahedron
1989, 45, 687.
envisaged the pyrrolidine ring of lepadiformine (1) to arise
from a stereoselective electrophile-promoted cyclization of
the amine derived from tosylamide 2 with the angular
(12) Prepared from 4,6-heptadienenitrile (Grieco, P. A.; Larsen, S. D. J.
Org. Chem. 1985, 50, 1768) by DIBALH reduction (CH2Cl2, -60 °C, 88%)
and acetalization of the resulting aldehyde (trimethyl orthoformate, amberlyst
15 ion-exchange resin, 12 h, rt, 98%).
(8) This is likely the solution structure as well. Molecular mechanics
calculations (MMX, PCMODEL) place the chair-chair conformer 4.7 kcal/
mol higher in energy than the chair-boat conformer shown in Figure 1.
3512
Org. Lett., Vol. 3, No. 22, 2001

endo cycloadduct 10 (74%).13 The aldehyde functionality of
10 was reduced (NaBH4) followed by simultaneous debenz-
ylation and reduction of the alkene moiety (Pearlman’s
catalyst, H2) to furnish an alcohol that underwent a Mit-
sunobu-type ring closure to N-tosylaziridine 4 upon treatment
with triphenylphosphine, iodine, and imidazole. Finally, the
butenyl group of tosylamide 11 was installed by nucleophilic
ring opening of N-tosylaziridine 4 with excess allylmagne-
sium bromide.
We had intended to introduce the hexyl substituent of
lepadiformine by subjecting R-methoxytosylamide 12 to BF3
in the presence of a hexyl Grignard or cuprate reagent.14
However, all attempts to cyclize acetal 11 to R-methoxytos-
ylamide 12 using a variety of acid catalysts were unsuccessful
and in many cases afforded the enamide 13 (BF3, 0.5 h, 0
°C, 98%). Moreover, aldehyde 16 (Scheme 3), which could
considerations10 and spectral similarities with tosylamide 2
(vide infra). Unfortunately, all attempts to employ (3-
hexenyl)trimethylsilane (14, R ) Pr)17 in this transformation
gave only recovered enamide 13.18
We also examined an alternative approach to the fully
substituted trans-perhydroquinoline ring system concurrent
with the previously discussed tosyliminium ion strategy,
specifically, stereoselective introduction of the hexyl group
prior to ring closure (Scheme 3). Initial experiments were
not encouraging. For example, treatment of aldehyde 16 with
hexylmagnesium bromide (5 equiv, -78 °C) in THF gave
18 and its inseparable C(13) epimer in a ratio of 1.1:1,
respectively, and an even less desirable ratio (1:2.7) was
obtained using hex2CuLi in ether. The stereoselectivity was
improved somewhat (2.5:1) by using hexylmagnesium
bromide (5 equiv) in ether and, interestingly, even further if
THF (10 equiv) was added (4.1:1). However, the most
dramatic improvement (10.9:1) was observed when an
organoytterbium reagent was employed following the Molan-
der protocol19 (3 equiv of hexMgBr, 3 equiv of Yb(OTf)3,
THF, -78 °C; an inferior ratio of 3.4:1 was obtained if
hexyllithium was used to prepare the organoytterbium
reagent). We tentatively rationalize this stereoselectivity on
the basis of the chelation control depicted in structure 17.20
The superiority of the organoytterbium reagent may be a
consequence of its greater steric bulk as well as attenuated
reactivity with a magnesium-chelated aldehyde (slow dis-
appearance of aldehyde 16 with the organoytterbium reagent
versus instantaneous disappearance with the Grignard re-
agent).
Scheme 3
The stereochemical assignment for alcohol 18 was con-
firmed upon its three-step transformation to lepadiformine
(1). Thus, subjection of alcohol 18 to Mitsunobu conditions
smoothly effected cyclization to the trans-perhydroquinoline
2 (and its separable C(13) epimer in 78% and 5% yields,
respectively), whose tosyl group could be removed using
standard conditions to provide amine 19. Treatment of amine
19 with iodine in ether (-40 °C to room temperature, 1 h)
gave rise to an (iodomethyl)pyrrolidinium salt that was
concentrated and directly taken up in THF and aqueous
NaOH containing 10% tetrabutylammonium iodide to deliver
racemic lepadiformine (77%). This transformation presum-
ably proceeds through regioselective attack of hydroxide on
the aziridinium ion intermediate 20.21 We could not detect
any product derived from ring opening at the more substituted
site (cf. cylindricines A and B). The spectral properties of
be prepared by hydrolysis of acetal 11 (1 M HCl, H2O, THF,
2 h, 98%), showed no tendency to exist in the cyclic
R-hydroxytosylamide form in a variety of solvents (1H NMR)
and could not be converted to R-methoxytosylamide 12.15
Accordingly, we turned to generating tosyliminium ion 3
by protonation of enamide 13 and its interception by an
allylsilane.14-16 Indeed, we were pleased to find that treatment
of enamide 13 with 4 equiv of trifluoroacetic acid and 6 equiv
of allyltrimethylsilane (14, R ) H) in methylene chloride at
-20 °C gave a single product to which we assigned structure
15 on the basis of the aforementioned stereoelectronic
(17) Smith, J. G.; Drozda, S. E.; Petraglia, S. P.; Quinn, N. R.; Rice, E.
M.; Taylor, B. S.; Viswanathan, M. J. Org. Chem. 1984, 49, 4112.
(18) In a competition experiment, (3-hexenyl)trimethylsilane was pref-
erentially consumed over allyltrimethylsilane by trifluoroacetic acid (1H
NMR).
(19) (a) Molander, G. A.; Burkhardt, E. R.; Weinig, P. J. Org. Chem.
1990, 55, 4990. (b) Molander, G. A.; Este´vez-Braun, A. M. Bull. Soc. Chim.
Fr. 1997, 134, 275. (c) For a very recent example of the utility of these
reagents, see: Johnston, D.; Francon, N.; Edmonds, J. J.; Procter, D. J.
Org. Lett. 2001, 3, 2001.
(13) In contrast to other examples of 2-amidoacrolein Diels-Alder
cycloaddition reactions performed in our laboratories,5h the cycloaddition
of 2-tosylamidoacrolein 6 could not be accomplished under thermal
conditions as a result of competing polymerization of dienophile 6 (150
°C). In addition, the acid sensitivity of the acetal functionality of diene 7
precluded the use of Lewis acid catalysts.
(14) Weinreb, S. M. Top. Curr. Chem. 1997, 190, 131.
(15) For the preparation of the parent system by DIBAL-H reduction of
N-tosylcaprolactam to afford the corresponding R-hydroxytosylamide and
further transformation to the R-methoxytosylamide by treatment with
methanol, trimethyl orthoformate, and PPTS, see: Åhman, J.; Somfai, P.
Tetrahedron 1992, 48, 9537.
(20) Kibayashi also invokes chelation control in the stereoselective
addition of hexylmagnesium bromide (2.0:1) to a spirocyclic aldehyde
similar to 16 that possesses a Cbz-protected alkoxypyrrolidine ring; see ref
5a.
(21) For a related example, see: Guo-qiang, L.; Chun-min, A.; Zhi-cai,
S. Heterocycles 1995, 41, 277.
(16) Fleming, I.; Dunogue`s, J.; Smithers, R. Org. React. 1989, 37, 57.
Org. Lett., Vol. 3, No. 22, 2001
3513

compound 1 were identical to those reported by Kibayashi
and the spectra of the hydrochloride salt of 1 were indistin-
guishable from those of authentic material.22
application of this methodology in natural product synthesis
is underway.
In conclusion, we have completed a stereoselective total
synthesis of the cytotoxin (()-lepadiformine in 16 steps in
13% overall yield from ethyl sorbate. Moreover, we have
once again demonstrated that amidoacrolein-derived Diels-
Alder cycloadducts can be easily elaborated to the ring
systems of tricyclic alkaloids. The further development and
Acknowledgment. We appreciate the financial support
provided by the National Institutes of Health (GM28553).
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.
(22) We thank Professor Weinreb for sharing Professor J. F. Biard’s
authentic 1H and 13C NMR spectra of lepadiformine with us. For their
approach to lepadiformine, see the accompanying communication in this
issue: Sun, P.; Sun, C.; Weinreb, S. M. Org. Lett. 3, 3507-3510.
OL0165903
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