An N-acyliminium cyclization approach to a total synthesis of (+)-cylindricine C

Article abstract of DOI:10.1021/jo0501846

Details of problems and solutions encountered during the development of an enantioselective total synthesis of (+)-cylindricine C are described here. The total synthesis itself was accomplished in 8 steps, featuring an N-acyliminium cyclization strategy,

Full text of DOI:10.1021/jo0501846

An N-Acyliminium Cyclization Approach to a Total Synthesis of
(+)-Cylindricine C
Jia Liu, Jacob J. Swidorski, Scott D. Peters, and Richard P. Hsung*
Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455
hsung@chem.umn.edu
Received January 28, 2005
Details of problems and solutions encountered during the development of an enantioselective total
synthesis of (+)-cylindricine C are described here. The total synthesis itself was accomplished in 8
steps, featuring an N-acyliminium cyclization strategy, the seldom-used Wharton rearrangement,
and a key epimerization at C5.
Introduction
(-)-Cylindricines A-K were isolated from the marine
ascidian Clavelina cylindrica collected in Tasmania1 with
the picrate salts of A [1a] and B [1b] assigned by X-ray
structures [Figure 1].1a Their unique structural motif has
attracted an impressive array of synthetic efforts.2-5 We
became interested in cylindricine alkaloids because of an
intriguing observation that the powerful N-acyliminium
cyclization approach6 has been exclusively employed in
total syntheses of the related alkaloid (-)-lepadiformine
[5]7-13 and never for any of the cylindricine family
members.2-5
(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) For a detailed account on efforts involving the cylindricine
synthesis, see: Liu, J.; Hsung, R. P. ChemTracts 2005, 18, in press.
(3) 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.
FIGURE 1.
Specifically, Kibayashi11 and Weinreb12 constructed the
C5-10 bond in the aza-spirocyclic AC-ring of (-)-lepadi-
formine 5 via an N-acyliminium cyclization of 4. It
appears that this strategy is feasible for the synthesis of
(4) 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.
(5) For recent syntheses 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. (c) See ref 17.
(6) For reviews, see: (a) Royer, J.; Bonin, M.; Micouin, L. Chem.
Rev. 2004, 104, 2311. (b) Bur, S. K.; Martin, S. F. Tetrahedron 2001,
57, 3221. (c) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000,
56, 3817. (d) Scholz, U.; Winterfeldt, E. Nat. Prod. Rep. 2000, 17, 349.
(e) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998,
37, 1044. (f) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41,
4367.
(8) (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.
(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.
(7) For isolation of lepadiformine, see: Biard, J. F.; Guyot, S.;
Roussakis, C.; Verbist, J. F.; Vercauteren, J.; Weber, J. F.; Boukef, K.
Tetrahedron Lett. 1994, 35, 2691.
10.1021/jo0501846 CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/09/2005
3898
J. Org. Chem. 2005, 70, 3898-3902

Total Synthesis of (+)-Cylindricine C
SCHEME 1
SCHEME 2
(-)-lepadiformine 5 because it provides the desired trans
relative stereochemistry at C5-10. On the other hand,
the AB-ring is cis-fused at C5-10 in cylindricines,
thereby implying that an N-acyliminium cyclization
approach may not be suitable. However, we wanted to
examine the validity of this speculation because we
intended to pursue a tandem Mannich approach6 en route
to cylindricines. As shown in Scheme 1, ent-1c-e could
be envisioned from a tandem Mannich strategy starting
from the N-acyliminium intermediate 6 [6 f 7 f 8,
counteranion omitted for clarity]. This seldom used
tandem strategy is attractive in alkaloid synthesis14,15
and can lead to the formation of two σ-bonds [C5-10 and
then C2-3] in a stereoselective manner.
TABLE 1
The critical issues in this approach are (1) the feasibil-
ity of such a tandem process for the synthesis of cylin-
dricines and (2) the stereochemical outcome for the
N-acyliminium cyclization in the first Mannich addition
for constructing the C5-10 bond. While cis-7 cannot be
readily precluded as a result of the Mannich-type N-
acyliminium addition, if trans-7 indeed predominates as
suggested from Kibayashi11 and Weinreb’s12 syntheses,
an epimerization of C-5 would then be needed. We
recently communicated the success in using trans-8 as a
common intermediate en route to both (-)-lepadiformine
and (+)-cylindricines C-E.16,17 We disclose here full
details of our failures that ultimately led to the success
in executing an N-acyliminium cyclization approach
toward an enantioselective total synthesis of (+)-cylin-
dricine C.
Results and Discussion
To pursue the tandem Mannich concept, we prepared
enamide 10 from lactam 918 in 62% yield [Scheme 2].
Formation of hemiaminal 12 was accomplished in situ
via addition of lithiated 11 to enamide 10. Hemiaminal
12 should be suitable in generating the two iminium
intermediates required for the tandem Mannich addi-
tions: in the direction toward C10 via eliminating the
hydroxyl group [12 f 13, counteranion omitted for
clarity] and toward C2 via protonation of the enamide
[13 f 14].
However, under a range of conditions, we did not
observe any Mannich-related products that could be
derived from 13 or 14. Instead, the cyclic imine 15 was
found in most cases [Table 1]. Lewis acid conditions such
as BF3-2AcOH [entry 1] or protic conditions such as aq
HCl [entry 2] led to 15 as the only discernible product
along with recovered starting enamide 10. The use of
TFA [entry 3] led to 16 in which the ketal was hydrolyzed
to ketone. The formation of 15 suggests that the enamine
was being hydrolyzed likely via intermediates 17 and 18
under these reaction conditions. Attempts to isolate
hemiaminal 12 via neutral aqueous conditions also failed
and gave only 15.
(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.; Kiba-
yashi, C. Angew. Chem., Int. Ed. 2002, 41, 3017. (d) See ref 17.
(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: Greshock,
T. J.; Funk, R. L. Org. Lett. 2001, 3, 3511.
(14) Robinson, R. J. Chem. Soc. 1917, 762.
(15) For some examples of natural product synthesis that employ
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.
(16) Liu, J.; Hsung, R. P.; Peters, S. D. Org. Lett. 2004, 6, 3989.
(17) For a recent account employing a similar concept of achieving
total syntheses of both (-)-lepadiformine and (+)-cylindricines C-E
via a aza-spirocyclic common intermediate, see: Abe, H.; Aoyagi, S.;
Kibayashi, C. J. Am. Chem. Soc. 2005, 127, 1473.
With this information in hand, we abandoned the
enamide approach and directly pursued the synthesis of
(18) Woo, K.; Jones, K. Tetrahedron Lett. 1991, 32, 6949.
J. Org. Chem, Vol. 70, No. 10, 2005 3899

Liu et al.
SCHEME 3
SCHEME 5
SCHEME 4
similar difficulties. For an example, the use of Lewis acids
such as ZnCl2 to mediate the aminal formation with an
acetal to generate the iminium intermediate 26, which
is capable of two Mannich additions, gave again only
alcohol 23 in good yield.
To discourage this undesired aldol pathway, chloride
28 was prepared from the addition of lithiated 27 to
lactam 20 in 90% yield [Scheme 5]. Ketoester 29 was
generated from 28 in three steps with an overall yield of
16% along with, interestingly, alcohol 30 as the other
isolable product in 27% yield via the related undesired
aldol pathway, thereby implying that we were going down
the wrong aldol pathway again. In hindsight, this design
suffers from having to construct two adjacent quaternary
centers shown at C5 and C10 in 31 [see the box in
Scheme 5].
These failures suggest that not only significant modi-
fications of our precursors are needed, but also more
importantly, the Mannich-type N-acyliminium addition
may not be the best approach. Thus, we turned our
attention to aza-Prins-type N-acyliminium addition.6,19
Toward this goal, we prepared alkyne 34 from the
addition of lithiated 32 to lactam 20 [Scheme 6]. How-
ever, no desired aza-Prins cyclization product 35 was
found by using a variety of initiation methods. Attempted
aza-Prins cyclization with enamide 36, prepared from 34,
was also unsuccessful.20,21
15 and/or 16. As shown in Scheme 3, while the addition
of lithiated 11 to thiol-imidate 19 failed to give 15, the
addition to lactam 20 led to ketone 21 [the initial
hemiaminal intermediate evidently had ring-opened] in
66% yield. Treatment of 21 with 10 equiv of TFA afforded
diketone 22 in 95% yield, whereas the cyclic imine 16
was obtained in 49% yield along with an unknown
isolated in 30% yield that was later assigned as alcohol
23 [see Scheme 4] when TFA was used as cosolvent.
However, diketone 22 failed to provide the desired aza-
spirocycle 25 that could be derived from a single Mannich
addition involving iminium ion 24 [Scheme 4]. Instead
surprisingly, alcohol 23 was obtained in 53% yield as a
single diastereomer via an intramolecular aldol of cyclic
imine 16. Interestingly, retro-aldol occurred to regenerate
16 when alcohol 23 was refluxed with 0.5 equiv of DBU
in toluene, but 16 did not proceed further to give any
Mannich addition product under these conditions.
While being stymied by this undesired aldol pathway,
attempts to use the cyclic imine 16 in achieving the
tandem Mannich concept were pursued but also met with
The failures here suggest that either we were not
successful in executing the formation of the desired
N-acyliminium ion from 34 or 36, or the alkyne itself was
not sufficiently reactive under these conditions to trap
(19) (a) For a related review, see: (a) Hiemstra, H.; Speckamp, W.
N. In Comprehensive Organic Synthesis; Brossi, A., Ed.; Academic
Press: San Diego, CA, 1988; Vol. 2, pp 271-339. For some 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.
(20) For examples of alkynes in aza-Prins-type cyclizations, see: (a)
Schoemaker, H. E.; Boer-Terpstra, Tj.; Dijkink, J.; Speckamp, W. N.
Tetrahedron 1980, 36, 143. (b) Hamersma, J. A. M.; Speckamp, W. N.
Tetrahedron 1982, 38, 3255. (c) Dijkink, J.; Speckamp, W. N. Hetero-
cycles 1979, 12, 1147. (d) Wijnberg, B. P.; Speckamp, W. N. Tetrahedron
Lett. 1980, 21, 1987. (e) Wijnberg, B. P.; Speckamp, W. N.; Oostveen,
A. R. C. Tetrahedron 1982, 38, 209. (f) Hamersma, J. A. M.; Nossin, P.
M. M.; Speckamp, W. N. Tetrahedron 1985, 41, 1999.
3900 J. Org. Chem., Vol. 70, No. 10, 2005

Total Synthesis of (+)-Cylindricine C
SCHEME 6
SCHEME 7
out the N-acyliminium intermediate. This particular
N-acyliminium cyclization process presumably would
generate a vinyl cation-like intermediate, which is en-
ergetically uphill, prior to being trapped by the X group.
It is noteworthy that there are only a few examples with
alkynes in aza-Prins-type N-acyliminium addition.22
While we experimented some with more commonly
used alkenes,21,22 we focused our attention to N-acylimin-
ium additions utilizing dienes.6,19,11 As shown in Scheme
7, preparations of both ketones 39a and 39b from
additions of lithiated 38a and 38b, respectively, to lactam
20 were pursued, but only 39b was obtained in a
synthetically useful manner. The aza-Prins cyclization
of 39b, promoted using formic acid, gave the desired aza-
spirocycles 41 in 64% yield after removal of the formyl
group using K2CO3 in MeOH. Enone 42 was obtained in
94% yield from 41 via TPAP/NMO oxidation, which
provided access to the epimerization of the C5 stereo-
center. However, various epimerization conditions, such
as refluxing DBU in toluene, led to only decomposition.23
While this was a big set back, we speculated that the
C5-H may not be as acidic as a normal γ-proton would
have been because enone 42 should prefer conformation
I and not conformation II or worse conformation III
[Scheme 8] given the severe A1,3-strain present in both
latter conformations, although the C5-H is more aligned
stereoelectronically and should be more acidic in both
SCHEME 8
conformation II and III. Therefore, the acidity of the
C5-H may be improved in enone 44 given that confor-
mations 44-I-III are more comparable in which both
conformation II and III [likely a little less stable with
more gauche-type interaction] could be suitable in al-
lowing a successful deprotonation of C5-H.
While our conformation analysis might not have been
completely accurate, it encouraged us to examine enone
44. Toward this goal, we turned to the seldom-used
Wharton’s rearrangement24,25 to transpose allyl alcohol
41. As shown in Scheme 9, m-CPBA epoxidation of 41
followed by SO3-Pyr/DMSO oxidation gave epoxy ketone
46. Hydrazone formation occurred with 5.0 equiv of
hydrazine in the presence of 0.5 equiv of HOAc, and
without any isolation, hydrazone 47 rearranged exclu-
sively to the trans allyl alcohol 48 with an overall yield
of 66%.
(21) The use of alkenes for the aza-Prins-type N-acyliminium
addition in this case also failed. Please refer to ref 6c for numerous
examples of addition of alkenes to N-acyliminium intermediates.
(24) (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.
(25) 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 Acta
1970, 53, 531.
(22) Kibayashi also reported similar difficulties with alkenes and
unsubstituted dienes: see ref 17.
(23) LDA or NaH only deprotonated the R-protons as is evident by
D2O quenching instead of the desired the γ-proton.
J. Org. Chem, Vol. 70, No. 10, 2005 3901

Liu et al.
SCHEME 9
successfully achieve an enantioselective total synthesis
of (-)-lepadiformine 5 via a stepwise sequence that
featured Barton’s deoxygenation26 to remove the C4-
carbonyl of aza-tricycle 51.16 This also confirms our
assignment of the relative stereochemistry at C2 and C5.
However, to succeed in a total synthesis of cylindricine,
we had to return to the C5-epimerization issue one last
time.
Fortuitously, we observed a side product during the
isolation and purification of aza-tricycle 51. It turned out
that the side product was a result of rapid epimerization
at C5 when 51 was exposed to silica gel. There are two
possible rationales for this rapid epimerization. First, the
C5-H is perfectly aligned stereoelectronically in aza-
tricycle 51, thereby possessing the desired kinetic acidity
for a rapid deprotonation. Second, there is an inherent
preference for the cylindricine family of alkaloids to
assume a cis-fusion for the 1-azadecalin AB-ring.1 For
related aza-tricycles, Kibayashi17 reported that the aza-
tricycle with a cis-fused 1-azadecalin AB-ring is about
5.5 kal mol-1 more stable than that of trans-fused.
Ultimately, we found that epimerization at the C5
position of aza-tricycle 51 occurred under the TBAF [2.0
equiv] conditions for removing the TBDPS group in 51,
leading directly to (+)-cylindricine C [ent-1c] in 91% yield
[Scheme 10]. This finding establishes a unique and
potentially biogenetic link between the cylindricines and
lepadiformine, and that C5-H can be epimerized but
likely only with an aza-tricyclic intermediate.
SCHEME 10
Conclusions
We have provided here details of problems and solu-
tions encountered in an effort to achieve an enantio-
selective synthesis of (+)-cylindricine C via an N-acyl-
iminium cyclization strategy. The total synthesis is
accomplished in 8 steps with an overall yield of 11.1%,
and in addition to the aza-Prins-type N-acyliminium
cyclization, the synthesis features the seldom-used Whar-
ton rearrangement and a key epimerization at C5 after
the aza-tricycle formation.
Subsequent MnO2 oxidation of allyl alcohol 48 provided
the desired enone 44 in 90% yield, allowing us to
reexamine the C5-epimerization issue. However, it was
quickly evident that standard epimerization conditions
such as refluxing DBU and low-temperature LHMDS
also could not epimerize the C5-H in 44. This outcome
prompted us to investigate the aza-tricycle preparation
followed by epimerization of the C5-H.
Treatment of enone 44 with TFA in CH2Cl2 led to the
desired aza-tricycle 51 in 72% yield with the N-1,4-
addition taking place in situ through the free amine 50
[Scheme 10]. NOE experiment unambiguously estab-
lished the relative stereochemistry at C2 and C5 to be
syn. With aza-tricycle 51 in hand, we were able to
Acknowledgment. Financial support from the
Camille Dreyfus and the McKnight Foundations is
greatly appreciated.
Supporting Information Available: Experimental pro-
cedures and 1H NMR spectra and characterizations for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO0501846
(26) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans.
1 1975, 1574.
3902 J. Org. Chem., Vol. 70, No. 10, 2005