A Novel and Highly Stereoselective Approach to Aza-Spirocycles. A Short Total Synthesis of 2-epi-(±)-Perhydrohistrionicotoxin and an Unprecedented Decarboxylation of 2-Pyrones

Article abstract of DOI:10.1021/ol020052o

(Matrix Presented) A novel and highly stereoselective synthesis of aza-spirocycles is described. An application of this methodology is illustrated as a short and concise total synthesis of 2-epi-(±)-perhydrohistrionicotoxin with high diastereomeric contro

Full text of DOI:10.1021/ol020052o

ORGANIC
LETTERS
2002
Vol. 4, No. 12
2017-2020
A Novel and Highly Stereoselective
Approach to Aza-Spirocycles. A Short
Total Synthesis of
2-epi-(±)-Perhydrohistrionicotoxin and
an Unprecedented Decarboxylation of
2-Pyrones
,†
Michael J. McLaughlin, Richard P. Hsung,* Kevin P. Cole, Juliet M. Hahn, and
Jiashi Wang
Department of Chemistry, UniVersity of Minnesota, Minneapolis, Minnesota 55455
hsung@chem.umn.edu
Received March 8, 2002
ABSTRACT
A novel and highly stereoselective synthesis of aza-spirocycles is described. An application of this methodology is illustrated as a short and
concise total synthesis of 2-epi-(±)-perhydrohistrionicotoxin with high diastereomeric control at the aza-spirocenter. An unprecedented
decarboxylation of the 2-pyrone ring is observed in this total synthesis effort.
Annulation reaction of vinylogous amides 1 with R,â-
unsaturated iminium salts 2 represents a highly convergent
approach to dihydropyridines 3 (Scheme 1).1-3 This reaction
stitutes a stepwise formal [3 + 3] cycloaddition6-8 in which
two σ-bonds are constructed in addition to a new stereocenter
adjacent to nitrogen. Not only have we demonstrated that
(1) 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.
(2) 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.
(3) For applications in natural product synthesis, see: (a) Zehnder, L.
R.; Hsung, R. P.; Wang, J.-S.; Golding, G. M. Angew. Chem., Int. Ed. 2000,
39, 3876. (b) McLaughlin, M. J.; Hsung, R. P. J. Org. Chem. 2001, 42,
1049. (c) Wang, J.; Cole, K. P.; Wei, L. L.; Zehnder, L. R.; Hsung, R. P.
Tetrahedron Lett. 2002, 43, 3337. (d) Cole, K. P.; Hsung, R. P.; Yang,
X.-F. Tetrahedron Lett. 2002, 43, 3341.
Scheme 1
(4) For electrocyclic ring closures involving 1-oxa- or 1-aza-trienes,
see: (a) Shishido, K.; Ito, M.; Shimada, S.-I.; Fukumoto, K.; Kametani, T.
Chem. Lett. 1984, 1943. (b) Maynard, D. F.; Okamura, W. H. J. Org. Chem.
1995, 60, 1763.
(5) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32,
131; Angew. Chem. 1993, 105, 137.
(6) (a) Hsung, R. P.; Wei, L.-L.; Sklenicka, H. M.; Shen, H. C.;
McLaughlin, M. J.; Zehnder, L. R. In Trends in Heterocyclic Chemistry;
Research Trends: Poojapura, Trivandrum, India, 2001; Vol. 7, pp 1-24.
(b) For [3 + 3] carbocycloaddition, see: Filippini, M.-H.; Rodriguez, J.
Chem. ReV. 1999, 99, 27. Also see: (c) Seebach, D.; Missbach, M.;
Calderari, G.; Eberle, M. J. Am. Chem. Soc. 1990, 112, 7625. (d)
Landesman, H. K.; Stork, G. J. Am. Chem. Soc. 1956, 78, 5129.
involves a Knoevenagel condensation followed by a 6π-
electron electrocyclic ring closure of the 1-azatriene inter-
mediate.4 This sequential anionic-pericyclic strategy5 con-
† A recipient of 2001 Camille Dreyfus Teacher-Scholar Award.
10.1021/ol020052o CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/18/2002

this reaction can be rendered intramolecular,9 but more
significantly, a highly stereoselective variant of this reaction
(1 + 2 f 3) was recently unveiled using chiral vinylogous
amides.2
Scheme 3a
Using cycloalkylidene R,â-unsaturated iminium salts in
this formal cycloaddition has efficiently led to aza- and oxa-
spirocycles.1,10 However, it has not been possible to achieve
good diastereomeric control at the new hetero spirocenter.11
Achieving such a diastereomeric control would signify a
novel and stereoselective formation of hetero spirocenters,
particularly the aza-spirocenter (4 f 5a/b in Scheme 2).12
a (a) NaH, (EtO)2POCH2COOEt, THF, reflux, 4 h; (b) DIBAL-
H, CH2Cl2, 0 °C, 2 h; (c) Dess-Martin periodinane, CH2Cl2, rt, 30
min.
Scheme 2
Cyclopentylidene R,â-unsaturated iminium salts 9a and
9b gave encouraging but different results. The C-2 methyl
group of 9a effectively led to aza-spirocycle 11 with a
Table 1
We report here this highly diastereoselective approach to aza-
spirocycles, an application to total synthesis of 2-epi-(()-
perhydrohistrionicotoxin, and an unprecedented decarboxy-
lation of 2-pyrones.
To demonstrate the feasibility of such a stereoselective
approach to aza-spirocycles, a variety of cycloalkylidene R,â-
unsaturated aldehydes 8a-f,13 precursors to iminium salts
9a-f that contain a substituent at either C-2 or C-3 position,
were prepared from corresponding cycloalkanones 6a-f in
three efficient steps (Scheme 3). Cycloalkylidene R,â-
unsaturated iminium salts 9a-f, prepared from 8a-f using
piperidine and Ac2O, were reacted with aminopyrones 10,
and 15-1714 (Table 1).
(7) For recent notable studies, see: (a) Cravotto, G.; Nano, G. M.;
Tagliapietra, S. Synthesis 2001, 49. (b) Hua, D. H.; Chen, Y.; Sin, H.-S.;
Robinson, P. D.; Meyers, C. Y.; Perchellet, E. M.; Perchellet, J.-P.; Chiang,
P. K.; Biellmann, J.-P. Acta Crystallogr. 1999, C55, 1698 and reference
therein. (c) Benovsky, P.; Stephenson, G. A.; Stille, J. R. J. Am. Chem.
Soc. 1998, 120, 2493. (d) Moorhoff, C. M. Synthesis 1997, 685. (e)
Jonassohn, M.; Sterner, O.; Anke, H. Tetrahedron 1996, 52, 1473. (f) Heber,
D.; Berghaus, Th. J. Heterocycl. Chem. 1994, 31, 1353.
(8) For some earlier studies, see: (a) de March, P.; Moreno-Man˜as, M.;
Casado, J.; Pleixats, R.; Roca, J. L.; Trius, A. J. Heterocycl. Chem. 1984,
21, 1369. (b) Tietze, L. F.; Kiedrowski, G. v.; Berger, B. Synthesis 1982,
683. (c) de Groot, A.; Jansen, B. J. M. Tetrahedron Lett. 1975, 16, 3407.
(9) Wei, L.-L.; Hsung, R. P.; Sklenicka, H. M.; Gerasyuto, A. I. Angew.
Chem., Int. Ed. 2001, 40, 1516.
(10) (a) Hsung, R. P.; Shen, H. C.; Douglas, C. J.; Morgan, C. D.; Degen,
S. J.; Yao, L. J. J. Org. Chem. 1999, 64, 690. (b) Zehnder, L. R.; Dahl, J.
W.; Hsung, R. P. Tetrahedron Lett. 2000, 41, 1901.
a Iminium salts were generated using 1.0 equiv of piperidine and 1.0
equiv of Ac2O at 85 °C for 1 h. Reaction time is 62 h for entry 5. b Isolated
yields. c Rations were determined using 1H/13C NMR. Stereochemistry was
assigned via X-ray of 14 and 21, NOE, and 1H NMR correlations. d At
250 °C. ND: not detected. e [R]20D ) 55.0°. f 6-Methyl-4-hydroxy-2-pyrone
was used. Stereochemistry of 22 was unassigned [ref 11].
(11) McLaughlin, M. J.; Hsung, R. P. Tetrahedron Lett. 2001, 42, 609.
(12) Kotera, M. Bull. Soc. Chim. Fr. 1989, 370.
(13) New compounds are characterized by 1H and 13C NMR, IR, and
MS. See Supporting Information for procedures and yields.
2018
Org. Lett., Vol. 4, No. 12, 2002

90:10 diastereomeric ratio (entry 1), whereas the remote C-3
methyl group in 9b did not influence the stereoselectivity in
12 (entry 2). On the other hand, aza-spirocycles 13 and 14
were obtained as single diastereomers when cyclohexylidene
iminium salts 9c and 9d were used, respectively (entries 3
and 4). The nitrogen and alkyl groups are trans for major
isomers of 11, 13, and 14.
The size of the P group in aminopyrones did not appear
to affect stereochemical outcome. As shown in entry 5 in
Table 1, aminopyrone 1514c with a smaller methyl group on
the nitrogen atom also led to 18 in 74% yield with a ratio of
95:5. However, in this case, the minor isomer could be
observed when the reaction was prematurely terminated. The
minor isomer was found to equilibrate completely to the
major isomer after heating in toluene-d8 at 150 °C for 19 h.
While a large dibenzylidene group in aminopyrone 16
effectively shut down the cycloaddition, the aminopyrone
17 containing an acetyl group also appeared to be ineffective
in this reaction (entries 6 and 7). These results suggest that
a bulky nitrogen substituent does hinder the ring closure of
the 1-azatriene intermediate4b,10a and that an electron-deficient
nitrogen substituent could impede the initial Knoevenagel
condensation.
Most intriguingly, enantiomerically pure cyclohexylidene
iminium salt 9e with a C-3 methyl group led to aza-spirocycle
21 as a single diastereomer (entry 8). It is noteworthy that
the nitrogen and methyl groups are now cis for the major
isomer of 21. This finding is in contrast with not only the
result from cyclopentylidene iminium salt 9b (entry 2) but
also the result we obtained earlier using 6-methyl-4-hydroxy-
2-pyrone (entry 9).11 This represents a unique asymmetric
construction of aza-spiroundecanes.12 Finally, cycloheptyl-
idene iminium salt 9f also effectively gave aza-spirocycle
23, although in lower diastereoselectivity (entry 10). The
generality of this stereoselective reaction is established using
vinylogous amide 24 or urethane 26 (derived from tetronic
acid 25) as shown in Scheme 4. Aza-spirocycles 27-29 were
obtained in good yields as well as high diastereoselectivities.
Figure 1. Equatorial approach of the N atom during ring closure.
nagel condensation of the amino pyrone 10 with cycloalkyli-
dene iminium salts 9c and 9e, respectively (Figure 1). Both
sets of 1-azatrienes 30/31 and 32/33 represent two possible
conformers with 30 or 32 having either R1 or R2 in an
equatorial position and with 31 or 33 having either R1 or R2
in an axial position for each set. PM3 calculations indicate
that the 1-azatriene conformers 30 and 31 (R1 ) Me and R2
) H) are quite comparable energetically (∼0.11 Kcal mol-1
in favor of 31) presumably because 30 experiences some
A1,3 strain at the exocyclic olefin and 31 suffers from flagpole
interactions. On the other hand, the 1-azatriene conformer
32 (R1 ) H and R2 ) Me) is favored over 33 by 1.12 Kcal
mol-1 given a stronger equatorial preference for the R2 group
in 32.
From the onset, on the basis of a similar assumption made
by Stork regarding a preferred equatorial approach of the
nitrogen atom in an imino allyl sulfide [2,3] sigmatropic
rearrangement,15 these equilibrating conformers could have
played a significant role in the stereochemical outcome as
observed in our previous work using 4-hydroxy-2-pyrones.11
However, in these current reactions using amino pyrones,
both aza-spirocycles 13 and 21 were obtained in high
diastereoselectivity (in favor of the stereoisomer a) inde-
pendent of the initially preferred conformation of 1-aza-
trienes. Thus, it could be more cleanly explained that the
observed high stereoselectivity for these reactions is a result
of thermodynamic control based on the reversibility of such
pericyclic ring closures.2 This mechanistic assertion is
supported by the aforementioned equilibration study using
18. In addition, AM1 calculations indicate that the aza-
spirocycle 18a is favored over 18b by 2.8 Kcal mol-1, while
13a is more favored by 4.2 Kcal mol-1.
The diastereoselectivity is most likely determined during
6π-electron electrocyclic ring closure of 1-azatriene inter-
mediates 30/31 and 32/33 derived from the initial Knoeve-
Scheme 4
To demonstrate synthetic potential of this new approach
to aza-spirocycles, cyclohexylidene R,â-unsaturated iminium
salt 34 was obtained from 2-cyclohexenone in 51% overall
(14) (a) Cervera, M.; Moreno-Man˜as, M.; Pleixats, R. Tetrahedron 1990,
46, 7885. (b) Sato, A.; Morone, M.; Azuma, Y. Heterocycles 1997, 45,
2209. (c) Cimarelli, C.; Palmieri, G. Tetrahedron 1997, 53, 6893.
(15) Cvetovich, R. J. Diss. Abstr. Int. B. 1979, 39(8), 3837; Chem. Abstr.
1979, 90, 186758q.
Org. Lett., Vol. 4, No. 12, 2002
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Scheme 5
Scheme 6
yield for the six steps16,17 with an E:Z ratio of 2:1 (Scheme
5). The E-isomer of 34 (readily separable from the Z-isomer)
reacted with 10 and 3518 to give aza-spirocycles 36a and
36b in 57-78% yield as single diastereomers unambiguously
assigned using NOE experiment. Hydrogenation of 36a and
36b led to 37a and 37b quantitatively, thereby furnishing in
a very short sequence three contiguous stereocenters of
perhydrohistrionicotoxin.12,19-22 In comparison to known
approaches to this natural product,12,20-22 this represents a
novel approach to aza-spiroundecane ring systems with a
high level of diastereomeric control at the aza-spiro center.
Transformation of the 2-pyrone ring of 37b to the desired
simple n-amyl side chain proved to be challenging. However,
we encountered a unique if not unprecedented decarboxy-
lation protocol when 37b was treated with LAH. After a
simple quenching with ethanol followed by filtration through
Celite, the crude mixture was subjected to 60 psi of H2 in
the presence of Pd-C (Scheme 6). The product 38 was
isolated in a repeatable manner with a consistent yield in
the range of 40-60%. The compound 38 was not unambigu-
ously assigned until the subsequent acidic desilylation
followed by debenzylation of 39 using Pearlman’s catalyst
led to 2-epi-(()-perhydrohistrionicotoxin 4022 in 90% overall
yield. This completes an 11-step total synthesis of 40 in 21%
yield.
It is not clear, however, how the decarboxylation of the
2-pyrone ring had occurred. To simply balance the equation,
losing CO2 from 37b could give an amino diene intermediate
41, and addition of 2 equiv of hydrogen would then lead to
38. Although any discussions at this point are all quite
speculative, the presence of this amino diene intermediate
41 does lend support to the observed stereochemical outcome
in the hydrogenation. The subsequent hydrogenation of 41
should occur from the back face away from the TBSO (and/
or n-Bu) group, leading to 38 with an exclusive epi
stereoselection at C2.
(16) Wender, P. A.; Erhardt, J. M.; Letendre, L. J. Am. Chem. Soc. 1981,
103, 2114.
(17) Tanner, D.; Hagberg, L.; Poulsen, A. Tetrahedron 1999, 55, 1427.
(18) The N-benzyl aminopyrone 35 was prepared by treating 4-trimeth-
ylsilyloxy-6methyl-2-pyone with n-BuLi followed by quenching with EtI.
Subsequent transformation to the corresponding N-benzyl aminopyrone was
carried according to ref 14a.
We have described here a highly stereoselective and novel
approach to aza-spirocycles. An application toward synthesis
of 2-epi-perhydrohistrionicotoxin was completed with the
finding of an unprecedented decarboxylation of the 2-pyrone
ring. Efforts toward synthesis of relevant spirocyclic nitrogen
alkaloids and understanding of this decarboxylation process
are underway.
(19) For isolation, see: Daly, J. W.; Karle, I.; Myer, C. W.; Tokuyama,
T.; Waters, J. A.; Witkop, B. Proc. Natl. Acad. Sci. U.S.A. 1971, 68, 1870.
(20) For the first syntheses of (()-perhydrohistrionicotoxin, see: (a)
Coery, E. J.; Arnett, J. F.; Widiger, G. N. J. Am. Chem. Soc. 1975, 97,
430. (b) Aratani, M.; Dunkerton, L. V.; Fukuyama, T.; Kishi, Y.; Kakoi,
H.; Sugiura, S.; Inoue, S. J. Org. Chem. 1975, 40, 2009.
(21) For recent efforts in total synthesis of perhydrohistrionicotoxin or
histrionicotoxin, see: (a) Williams, G. M.; Roughley, S. D.; Davies, J. E.;
Holmes, A. B.; Adams, J. P. J. Am. Chem. Soc. 1999, 121, 4900. (b) Comins,
D. L.; Zhang, Y.-M.; Zheng, X. J. Chem. Soc., Chem. Commun. 1998, 2509.
(c) Tanner, D.; Hagberg, L. Tetrahedron 1998, 54, 7907. (d) Comins, D.
L.; Zheng, X. J. Chem. Soc., Chem. Commun. 1994, 2681. (e) Stork, G.;
Zhao, K. J. Am. Chem. Soc. 1990, 112, 5875. (f) Winkler, J. D.; Hershberger,
P. M. J. Am. Chem. Soc. 1989, 111, 4852. (g) Tanner, D.; Selle´n, M.;
Ba¨ckvall, J.-E. J. Org. Chem. 1989, 54, 3374. (h) Duhamel, P.; Kotera,
M.; Monteil, T.; Marabout, B. J. Org. Chem. 1989, 54, 4419. For the first
synthesis of (()-histrionicotoxin, see: (i) Carey, S. C.; Aratani, M.; Kishi,
Y. Tetrahedron Lett. 1985, 26, 5887.
Acknowledgment. R.P.H. thanks National Institutes of
Health (NS38049) and ACS PRF-Type-G for financial
support. Authors also thank Mr. William B. Brennessel for
providing the X-ray structural analysis.
Supporting Information Available: Experimental pro-
cedures, NMR spectral characterization data, and X-ray data
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(22) For matching the characterization 2-epi-(()-perhydrohistrionic-
otoxin, see: Takahashi, K.; Wiktop, B.; Brossi, A.; Maleque, M. A.;
Albuquerque, E. X. HelV. Chim. Acta 1982, 6, 252.
OL020052O
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Org. Lett., Vol. 4, No. 12, 2002