A stereoselective approach to the azaspiro[5.5]undecane ring system using a conjugate addition/dipolar cycloaddition cascade: Application to the total synthesis of (±)-2,7,8-epi-perhydrohistrionicotoxin

Article abstract of DOI:10.1021/jo801295e

(Chemical Equation Presented) An efficient stereocontrolled route to the spirocyclic perhydrohistrionicotoxin derivative (±)-2,7,8-epi- PHTx (4) is described. The reaction of 2-butyl-3-(methoxymethoxy)cyclohexanone oxime with 2,3-bis(phenylsulfonyl)-1,3-b

Full text of DOI:10.1021/jo801295e

A Stereoselective Approach to the Azaspiro[5.5]undecane Ring
System Using a Conjugate Addition/Dipolar Cycloaddition Cascade:
Application to the Total Synthesis of
(()-2,7,8-epi-Perhydrohistrionicotoxin†
Michael S. Wilson and Albert Padwa*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
ReceiVed June 17, 2008
An efficient stereocontrolled route to the spirocyclic perhydrohistrionicotoxin derivative (()-2,7,8-epi-
PHTx (4) is described. The reaction of 2-butyl-3-(methoxymethoxy)cyclohexanone oxime with 2,3-
bis(phenylsulfonyl)-1,3-butadiene gives rise to a 7-oxa-1-azanorbornane cycloadduct in high yield. The
formation of the bicyclic isoxazolidine arises from conjugate addition of the oxime onto the diene to
give a transient nitrone which then undergoes an intramolecular dipolar cycloaddition. Treatment of the
cycloadduct with 5% Na/Hg results in reductive nitrogen-oxygen bond cleavage to furnish an
azaspiro[5.5]undecane. Elaboration to the dihydropyridin-4(1H)-one 24 was followed by stereoselective
conjugate addition using n-pentyl cuprate to give azaspirocycle 25. The stereochemistry of the product
was deduced from an X-ray crystal structure of the corresponding N-tosylhydrazone derivative. The
dominant factor controlling the stereochemistry of the conjugate addition is the A(1,3)-strain present in
the planar vinylogous amide. A stereoelectronically preferred axial attack by the organocuprate at the
ꢀ-position leads to the observed diastereoselectivity. Azaspirocycle 25 was transformed into 2,7,8-epi-
PHTx (4) in five additional steps. Utilizing this tandem conjugate addition/dipolar cycloaddition cascade,
we have also successfully synthesized azaspiro[5.5]undecane 36, which had previously been converted
into (()-perhydrohistrionicotoxin (2), thereby completing a formal total synthesis of this alkaloid.
Introduction
and vary primarily in the length and degree of saturation in the
side chain.4 The significant interest in histrionicotoxin deriva-
tives stems from their remarkable neurophysical properties,5
their low natural abundance, and their unique structural frame-
work containing the azaspiro[5.5]undecane ring system.4 Thus,
these alkaloids have been attractive and popular targets for
synthetic chemists for many years. The majority of synthetic
The azaspirocycle alkaloid (-)-histrionicotoxin (1, Figure 1),
isolated from skin extracts of the brightly colored neotropical
frog Dendrobates histrionicus, is a potent noncompetitive
blocker of nicotinic receptor-gated channels.1-3 Other members
of this family also contain the unique spiropiperidine structure
† Dedicated to the memory of Albert I. Meyers, an outstanding scientist, a
mentor to many, and a good friend.
(1) (a) Witkop, B. Experientia 1971, 27, 1121. (b) Witkop, B.; Go¨ssinger,
E. In The Alkaloids; Brossi, A., Ed.; Academic Press: New York, 1983; pp 139-
251. (c) Karle, I. J. Am. Chem. Soc. 1973, 95, 4036.
(2) (a) Daly, J. W.; Karle, I. L.; Meyers, W.; Tokuyama, T.; Waters, J. A.;
Witkop, B Proc. Natl. Acad. Sci. U.S.A. 1971, 68, 1870. (b) Tokuyama, T.;
Venoyama, K.; Brown, G.; Daly, J. W.; Witkop, B. HelV. Chim. Acta 1974, 57,
2597. (c) Daly, J. W.; Spande, T. F.; Whittaker, N.; Highet, R. J.; Feigl, D.;
Nishimori, N.; Tokuyama, T. J. Nat. Prod. 1986, 49, 265. (d) Daly, J. W. J.
Nat. Prod. 1998, 61, 162.
(3) (a) Tokuyama, T.; Uenoyama, K.; Brown, G.; Daly, J. W.; Witkop, B.
HelV. Chim. Acta 1974, 57, 2597. (b) Daly, J. W.; Witkop, B.; Tokuyama, T.;
Nishikawa, T.; Karle, I. L. HelV. Chim. Acta 1977, 60, 1128. (c) Tokuyama, T.;
Yamamoto, J.; Daly, J. W.; Highet, R. J. Tetrahedron 1983, 39, 49. (d)
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Tetrahedron 1986, 42, 3453. (e) Spande, T. F.; Garraffo, H. M.; Daly, J. W.;
Tokuyama, T.; Shimada, A. Tetrahedron 1992, 48, 1823.
(4) For some reviews, see: (a) Inubushi, Y.; Ibuka, T. Heterocycles 1982,
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10.1021/jo801295e CCC: $40.75
Published on Web 08/21/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 9601–9609 9601

Wilson and Padwa
SCHEME 1
FIGURE 1
strategy developed in our laboratory.13 We report herein a new
approach for the synthesis of azaspirocyclic piperidines and its
application in the formal synthesis of (()-perhydrohistrionic-
otoxin (2) and a total synthesis of (()-2,7,8-epi-perhydrohis-
trionicotoxin (4)
efforts have been aimed at the perhydro (2)- and depentylper-
hydrohistrionicotoxin (3) derivatives since these saturated
materials display levels of biological activity quite similar to
that of the parent alkaloid.6-10 The first total synthesis of (()-
perhydrohistrionicotoxin (2) (PHTx) was described by Corey
in 1975,7 and a wide range of approaches to this compound
have been reported since.8-11 In this context, we have been
interested for some time in developing new strategies for the
synthesis of various piperidine alkaloids.12 Our plan toward
perhydrohistrionicotoxin is based on a [3 + 2]-annulation
Results and Discussion
Our synthetic strategy toward the PHTx family is founded
on a renewed interest in the conjugate addition-dipolar cy-
cloaddition cascade that we had previously used to prepare
2-substituted-4-piperidones.13 This cascade utilizes 2,3-bis(phe-
nylsulfonyl)-1,3-butadiene (5)14 as a key reactant which func-
tions as both a Michael acceptor and a dipolarophile. Thus,
conjugate addition of an oxime to diene 5 followed by proton
transfer creates a transient nitrone 6 that undergoes a 1,3-dipolar
cycloaddition with the tethered vinyl sulfone (Scheme 1).15,16
The regiochemistry of the internal cycloaddition is presumably
controlled by entropic factors. N,O-Bond cleavage of the
resulting cycloadduct 7 provides efficient access to the 2,2-
disubstituted 4-piperidone skeleton.13 For cycloalkanone-derived
(5) (a) Lapa, A. J.; Albuquerque, E. X.; Sarvey, J.; Daly, J. W.; Witkop, B.
Exp. Neurol. 1975, 47, 558. (b) Takahashi, K.; Witkop, B.; Brossi, A.; Maleque,
M. A.; Albuquerque, E. X. HelV. Chim. Acta 1982, 65, 252. (c) Spivak, C. E.;
Maleque, M. A.; Oliveria, A. C.; Masukawa, M.; Tokuyama, J.; Daly, J. W.;
Albuquerque, E. X. Mol. Pharmacol. 1982, 21, 351. (d) Takahashi, K.; Jacobson,
A. E.; Mak, C. P.; Witkop, B.; Brossi, A.; Albuquerque, E. X.; Warnick, J. E.;
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Karatholuvhu, M. S.; Sinclair, A.; Newton, A. F.; Alcaraz, M.-L.; Stockman,
R. A.; Fuchs, P. L. J. Am. Chem. Soc. 2006, 128, 12656.
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J. Org. Chem. 2004, 69, 1598. (b) Schoemaker, H. E.; Speckamp, W. N.
Tetrahedron Lett. 1978, 19, 4841. (c) Evans, D. A.; Thomas, E. W. Tetrahedron
Lett. 1979, 20, 411. (d) Evans, D. A.; Thomas, E. W.; Cherpeck, R. E. J. Am.
Chem. Soc. 1982, 104, 3695. (e) Tanis, S. P.; Dixon, L. A. Tetrahedron Lett.
1987, 28, 2495. (f) Comins, D. L.; Zheng, X. J. Chem. Soc., Chem. Commun.
1994, 2681. (g) Comins, D. L.; Zhang, Y.-M.; Zheng, X. Chem. Commun. 1998,
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Dhimane, H.; Vanucci-Bacque, C.; Lhommet, G. Heterocycles 2001, 55, 941.
(j) Horsley, H. T.; Holmes, A. B.; Davies, J. E.; Goodman, J. M.; Silva, M. A.;
Pascu, S. I.; Collins, I. Org. Biomol. Chem. 2004, 2, 1259. (k) Mclaughlin, M. J.;
Hsung, R. P.; Cole, K. P.; Hahn, J. M.; Wang, J. Org. Lett. 2002, 4, 2017.
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80, 686. (i) Kim, S.; Ko, H.; Lee, T.; Kim, D. J. Org. Chem. 2005, 70, 5756.
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Norman, B. H.; Gareau, Y.; Padwa, A. J. Org. Chem. 1991, 56, 2154. (c) Flick,
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1998; Collect. Vol. IX, p 82; Vol. 74, 147.
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(b) Grigg, R.; Gunaratne, H. Q.; Kemp, J. J. Chem. Soc., Perkin Trans. 1 1984,
41. (c) Grigg, R. Chem. Soc. ReV. 1987, 16, 89. (d) Donegan, G.; Grigg, R.;
Heaney, F.; Surendrakumar, S.; Warnock, W. J. Tetrahedron Lett. 1989, 30,
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S.; Sridhararan, V.; Surendrakumar, S. Tetrahedron Lett. 1988, 4323. (f) Grigg,
R.; Markandu, J.; Perrior, T.; Surendrakumar, S.; Warnock, W. J. Tetrahedron
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9602 J. Org. Chem. Vol. 73, No. 24, 2008

Total Synthesis of (()-2,7,8-epi-Perhydrohistrionicotoxin
SCHEME 2
SCHEME 4
a sealed tube to provide cycloadduct 17 as a 3:2 mixture of
diastereomers in 72% yield.
SCHEME 3
Since the diastereomeric mixture of cycloadducts only
differed in terms of the oxido bridge (and C3 sulfone) stereo-
chemistry, which would be subsequently destroyed upon reduc-
tive cleavage, separation of the mixture was unnecessary.
Nevertheless, since the two diastereomeric cycloadducts were
highly crystalline, X-ray quality crystals were easily obtained.
The X-ray data showed that the overall dipolar cycloaddition
had proceeded with complete stereocontrol producing the
undesired relative stereochemistry about the azaspirocyclic
skeleton. However, we believed that this setback could be easily
overcome at a later stage of the synthesis by making use of an
oxidation-epimerization-reduction sequence analogous to that
used previously by Godleski and co-workers for perhydrohis-
trionicotoxin (2).21 Unfortunately, all of our attempts to carry
out a reductive N,O-cleavage of cycloadduct 17 were unsuc-
cessful, leading only to recovered starting material and oily tars.
In order to get around this difficulty, we prepared the MOM-
protected oxime 19 with the hope that the diminished steric
interactions would facilitate the desired reduction. Heating a
sample of oxime 19 with diene 5 afforded the expected
cycloadduct 20 in 82% yield as a 1:1 mixture of diastereomers.
Now, the N,O reduction could be readily accomplished by using
5% Na/Hg in a 2:1 mixture of THF/ethanol which furnished
piperidinone 21 (69%) along with the over-reduction product
22. Conversion of 21 to 22 was readily accomplished in 82%
yield using radical reduction conditions (Scheme 4).22
At this stage, we judged it prudent to protect piperidinone
22 as the corresponding benzamide in order to set the stage for
the upcoming oxidation step. The desired dihydropyridin-4(1H)-
one 24 was easily accessed via a Saegusa-Ito oxidation23 of
the corresponding silyl enol ether derived from 23. Introduction
of the final stereocenter was achieved by conjugate addition of
n-pentyl cuprate to the vinylogous amide 24. Thus, treatment
of 24 with n-pentylmagnesium bromide, CuBr·SMe2, and
BF3 ·OEt2 provided 25 as the sole product in 92% yield (Scheme
4). The stereochemistry of the resulting piperidinone 25 was
not unequivocally discernible from its spectral data. Conse-
quently, we prepared the highly crystalline N-tosyl hydrazone
derivative 27 (Scheme 5), and X-ray analysis of this compound
confirmed the fact that the cuprate addition had proceeded with
oximes, this methodology provides facile access to 2-substituted
azaspirocycles with a high degree of flexibility.
Our retrosynthetic analysis (Scheme 2) reveals a potentially
convenient route to (()-7,8-epi-perhydrohistrionicotoxin (4)
based on the above conjugate addition-dipolar cycloaddition
cascade. Our plan involves formation of the dipolar cycloadduct
10 derived from the reaction of diene 5 with oxime 9. This
would be followed by reductive N,O-bond cleavage and a
subsequent Saegusa oxidation in order to obtain azaspirocycle
11. Conjugate addition of n-pentyl cuprate to the vinylogous
amide should furnish 12 which, after suitable manipulation of
the protecting groups and reduction of the carbonyl group, would
be expected to provide (()-epi-PHTx 4.17
The required oxime 15 was prepared from a procedure
described by Wender and co-workers.18 This involved formation
of the lithium enolate of 1319 using LDA followed by a
regioselective ring opening of the epoxide with n-butyllithium.
The resulting 3-hydroxy ketone 14 was immediately protected
as the TBS ether 1520 and was then converted to the corre-
sponding oxime 16 by condensation with hydroxylamine
hydrochloride (Scheme 3). The desired cascade sequence was
achieved by heating 16 with diene 5 in acetonitrile at 90 °C in
(17) Duhamel, P.; Kotera, M.; Monteil, T.; Marabout, B. J. Org. Chem. 1989,
54, 4419.
(18) Wender, P. A.; Erhardt, J. M.; Letendre, L. J. J. Am. Chem. Soc. 1981,
103, 2114.
(21) (a) Godleski, S. A.; Heacock, D. J. J. Org. Chem. 1982, 47, 4822. (b)
Godleski, S. A.; Heacock, D. J.; Meinhart, J. D.; Wallendael, S. V. J. Org. Chem.
1983, 48, 2101.
(19) House, H. O.; Wasson, R. L. J. Am. Chem. Soc. 1957, 79, 1488.
(20) Tanner, D.; Sellen, M.; Backvall, J.-E. J. Org. Chem. 1989, 54, 3374.
(22) Smith III, A. B.; Hale, K. J. Tetrahedron Lett. 1989, 30, 5579.
(23) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011.
J. Org. Chem. Vol. 73, No. 24, 2008 9603

Wilson and Padwa
SCHEME 6
FIGURE 2. Stereoelectronically preferred axial attack.
SCHEME 5
efficiency of the synthesis of 29 by combining two reductive
transformations into a single step, the overall reaction was
somewhat capricious and the yield of 29 was found to be quite
variable. An alternative method, which turned out to be much
more reliable, involved the conversion of 25 into a mixture of
enol triflates 30. Hydrogenolysis of 30 afforded 31 which then
furnished 29 in 84% yield upon treatment with LiAlH4.
Deprotection of the MOM ether in 29 with TMSBr gave 32
which was further reduced to afford (()-2,7,8-epi-PHTx (4) in
73% yield for the two-step sequence.
An alternative route to (()-depentylperhydrohistrionicotoxin
(3) was also carried out starting with the readily available
intermediate 23. This compound was converted to piperidinone
34 in 80% yield by formation of a mixture of vinyl triflates 33
followed by catalytic hydrogenation. Lithium aluminum hydride
reduction of the benzoyl amide present in 34 gave 35, and this
was followed by MOM deprotection to furnish alcohol 36
(Scheme 6), thereby intercepting the Godleski route toward 3.21
The formation of intermediate 36 also represents a formal
synthesis of (()-perhydrohistrionicotoxin (2) since (()-depentyl-
PHTx (3) had been carried on to (()-PHTx (2) by Corey and
co-workers.7
In conclusion, a synthesis of (()-2,7,8-epi-perhydrohistri-
onicotoxin (4) has been accomplished. The key element of the
synthesis consists of a conjugate addition-dipolar cycloaddition
of 2,3-bis(phenylsulfonyl)-1,3-butadiene with 2-butyl-3-(meth-
oxymethoxy)cyclohexane oxime. The resulting cycloadduct was
converted into (()-2,7,8-epi-PHTx (4) by (1) reductive cleavage
of the bicyclic isoxazolidine adduct, (2) oxidation followed by
conjugate addition of the n-pentyl side chain, and (3) reduction
of the carbonyl group in the piperidone ring. We have also
described a formal synthesis of (()-perhydrohistrionicotoxin (2)
that intercepts Godleski’s intermediate 36 in several steps from
the starting oxime 19. The applicability of the new methodology
to other alkaloid targets is currently under study and will be
the subject of future reports.
high selectivity giving rise to 25 exclusively. With this system,
the overriding steric interaction corresponds to the A(1,3) strain
associated with the vinylogous amide present in 24. The bulkier
group prefers to be in the axial position in order to avoid this
interaction, thereby accounting for the high selectivity associated
with the formation of 25. Thus, a stereoelectronically preferred
axial attack by the organocuprate at the ꢀ-position of 24 results
in the observed diastereoselectivity (Figure 2). This outcome is
perfectly consistent with previous results reported in the
literature by Comins and co-workers with related N-acyl-2,3-
dihydro-4-pyridones.24
The formation of piperidone 25 represents an opportunity to
complete a synthesis of (()-2,7,8-epi-PHTx (4). Non-natural
perhydrohistrionicotoxin derivatives such as 4 have proven to
be extremely useful for probing the mechanism of trans-synaptic
transmission of neuromuscular impulses.25 Toward this end,
N-tosylhydrazone 27 was subjected to LiAlH4 reduction. The
initial product formed was the N-benzylazaspiro[5.5]undecane
28, which could be further reduced to afford 29 in 49% overall
yield. While this sequence was intended to increase the
(24) (a) Comins, D. L.; Brown, J. D. Tetrahedron Lett. 1986, 27, 4549. (b)
Brown, J. D.; Foley, M. A.; Comins, D. L. J. Am. Chem. Soc. 1988, 110, 7445.
(c) Comins, D. L.; LaMunyon, D. H. Tetrahedron Lett. 1989, 30, 5053. (d)
Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1991, 32, 5697. (e) Comins,
D. L.; Dehghani, A. J. Org. Chem. 1995, 60, 794. (f) Comins, D. L.; LaMunyon,
D. H.; Chen, X. J. Org. Chem. 1997, 62, 8182.
(25) (a) Rapier, C.; Wannacot, S.; Lunt, G. G.; Alburquerque, E. X. FEBS
Lett. 1987, 212, 292. (b) Oliviera, L.; Madison, B. W.; Kapai, H.; Sherby, S. M.;
Swanson, K. L.; Edelfraui, M. E.; Alburquerque, E. X. Eur. J. Pharmacol. 1987,
140, 331. (c) Sobel, A.; Heidmann, T.; Hofler, J.; Changeaux, J. P. Proc Nat.
Acad. Sci. U.S.A. 1978, 75, 510.
9604 J. Org. Chem. Vol. 73, No. 24, 2008

Total Synthesis of (()-2,7,8-epi-Perhydrohistrionicotoxin
1H), 2.18 (d, 1H, J ) 12.5 Hz), 3.01-3.08 (m, 2H), 3.51 (dd, 1H,
J ) 13.0 and 11.0 Hz), 3.86 (d, 1H, J ) 2.5 Hz), 3.97 (dd, 1H, J
) 12.5 and 5.0 Hz), 4.13 (dd, 1H, J ) 11.0 and 5.0 Hz), 7.48 (t,
2H, J ) 7.5 Hz), 7.62 (t, 2H J ) 7.5 Hz), 7.65 (t, 1H, J ) 7.5 Hz),
7.71 (t, 1H, J ) 7.5 Hz), 7.74 (d, 2H, J ) 7.5 Hz), and 7.97 (d,
2H, J ) 7.5 Hz); 13C NMR (CDCl3, 150 MHz) δ -5.1, -4.6, 14.0,
18.0, 18.1, 22.4, 26.0, 26.6, 27.5, 27.9, 31.5, 39.1, 48.7, 52.3, 67.7,
71.3, 74.1, 105.1, 128.8, 128.9, 129.2, 130.0, 134.3, 135.2, and
139.4. Anal. Calcd for C32H47NO6S2Si: C, 60.63; H, 7.47; N, 2.21.
Found: C, 60.59; H, 7.41; N, 2.23.
2-Butyl-3-(methoxymethoxy)cyclohexanone (18). To a solution
of 16 g (94 mmol) of trans-2-butyl-3-hydroxy-1-cyclohexanone
(14)9d in 500 mL of CH2Cl2 at 0 °C was added 50 mL (282 mmol)
of diisopropylethylamine, followed by 14 mL (188 mmol) of freshly
distilled MOMCl. The reaction mixture was slowly warmed to 25
°C and was stirred overnight. The solution was cooled to 0 °C and
was quenched with a saturated aqueous NH4Cl solution. The
aqueous layer was separated and extracted with Et2O, and the
combined organic extracts were dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified using
flash silica gel chromatography to furnish 17.7 g (88%) of 2-butyl-
3-(methoxymethoxy)cyclohexanone (18) as a pale yellow oil: IR
(neat) 1711, 1456, 1148, 1101, and 1039 cm-1; 1H NMR (CDCl3,
300 MHz) δ 0.44 (t, 3H, J ) 6.8 Hz), 0.78-0.91 (m, 4H),
1.10-1.25 (m, 3H), 1.25-1.38 (m, 1H), 1.51-1.70 (m, 2H),
1.78-1.86 (m, 1H), 1.90-2.01 (m, 2H), 2.92 (s, 3H), 3.27 (dt,
1H, J ) 6.8 and 2.9 Hz), 4.18 (d, 1H, J ) 6.8 Hz), and 4.25 (d,
1H, J ) 6.8 Hz); 13C NMR (CDCl3, 75 MHz) δ 13.8, 20.8, 22.7,
27.3, 28.2, 29.6, 39.4, 55.3, 56.8, 78.6, 94.9, and 211.3; HRMS
calcd for [(C12H22O3) + H]+ 215.1642, found 215.1642.
Experimental Section
2-Butyl-3-(tert-butyldimethylsilyloxy)cyclohexanone (15). To
a solution of 9.4 g (55 mmol) of trans-2-butyl-3-hydroxy-1-
cyclohexanone (14)9d in 60 mL of DMF at 0 °C was added 10 g
(66 mmol) of TBSCl followed by 9.2 g (135 mmol) of imidazole.
The reaction mixture was slowly warmed to 25 °C over a period
of 3 h. The solution was cooled to 0 °C and diluted with Et2O,
water was added, and the aqueous layer was separated and extracted
with Et2O. The combined organic extracts were dried over MgSO4,
filtered, and concentrated under reduced pressure. The residue was
purified using flash silica gel chromatography to furnish 11.4 g
(73%) of 2-butyl-3-(tert-butyldimethylsilyloxy)cyclohexanone (15)
1
as a pale yellow oil: H NMR (CDCl3, 400 MHz) δ 003 (s, 6H),
0.83-0.91 (m, 3H), 0.86 (s, 9H), 1.14-1.38 (m, 4H), 1.45-1.72
(m, 4H), 1.92-2.10 (m, 2H), 2.17-2.40 (m, 3H), and 3.78 (dt,
1H, J ) 6.8 and 2.8 Hz); 13C NMR (CDCl3, 100 MHz) δ -4.5,
-4.9, 13.9, 17.9, 20.7, 22.8, 25.7, 27.4, 29.8, 31.5, 39.7, 59.6, 74.3,
and 212.2.
2-Butyl-3-(tert-butyldimethylsilyloxy)cyclohexanone Oxime
(16). To a solution of 10.6 g (37 mmol) of ketone 15 in 360 mL of
a 1:1 EtOH/water mixture was added 7.8 g (112 mmol) of
hydroxylamine hydrochloride followed by 9.2 g (112 mmol) of
sodium acetate. The reaction mixture was heated at reflux at 90 °C
for 6 h and cooled to 25 °C, the solvent was removed under reduced
pressure, and the residue was diluted with CH2Cl2. The solution
was washed with water, dried over MgSO4, filtered, and concen-
trated under reduced pressure. The residue was purified using flash
silica gel chromatography to furnish 10.5 g (94%) of 2-butyl-3-
(tert-butyldimethylsilyloxy)cyclohexanone oxime (16) as a colorless
oil: IR (neat) 3256, 1662, 1463, 1254, and 1088 cm-1; H NMR
1
2-Butyl-3-(methoxymethoxy)cyclohexanone Oxime (19). To
a solution of 5.9 g (27 mmol) of ketone 18 in 140 mL of dry EtOH
was added 2.0 g (29 mmol) of hydroxylamine hydrochloride
followed by 6.4 mL (78 mmol) of freshly distilled pyridine. The
reaction mixture was heated at reflux at 100 °C for 2 h and cooled
to 25 °C, the solvent was removed under reduced pressure, and
the residue was diluted with CH2Cl2. The residue was washed with
water, dried over MgSO4, filtered, concentrated under reduced
pressure, and purified using flash silica gel chromatography to
furnish 6.0 g (96%) of 2-butyl-3-(methoxymethoxy)cyclohexanone
oxime (19) as a colorless oil: IR (neat) 3388, 1656, 1456, 1099,
(CDCl3, 400 MHz) δ 0.03 (s, 3H), 0.05 (s, 3H), 0.86-0.91 (m,
3H), 0.88 (s, 9H), 1.18-1.38 (m, 4H), 1.40-1.62 (m, 4H),
1.74-1.92 (m, 2H), 2.10-2.26 (m, 2H), 2.76 (dt, 1H, J ) 14.0
and 4.8 Hz), 3.75-3.82 (m, 1H), and 8.84 (brs, 1H); 13C NMR
(CDCl3, 100 MHz) δ -4.8, -4.7, 13.9, 18.0, 20.0, 21.5, 22.7, 25.8,
29.0, 29.5, 30.5, 49.6, 72.9, and 160.4.
4,5-endo-Di(phenylsulfonyl)-2-spiro-1′-(8-butyl-9-(tert-butyl-
dimethylsilyloxy)cyclohexane)-7-oxo-1-azabicyclo[2.2.1]-heptane
(17). A solution of 1.05 g (3.5 mmol) of oxime 16 and 1.17 g (3.5
mmol) of 2,3-bis(phenylsulfonyl)-1,3-butadiene14 (5) in 12 mL of
CH3CN was heated at 90 °C for 72 h, cooled to room temperature,
and concentrated under reduced pressure. The residue was purified
using flash silica gel chromatography to furnish 1.61 g (72%) of a
3:2-mixture of 4,5-endo-di(phenylsulfonyl)-2-spiro-1′-(8-butyl-9-
(tert-butyldimethylsilyloxy)cyclohexane)-7-oxo-1-
azabicyclo[2.2.1]heptane (17) as a white solid. The two diastere-
omers were easily separated by silica gel chromatography. The
major diastereomer 17a was a white solid: mp 144-145 °C; IR
and 1037 cm-1 1H NMR (CDCl3, 300 MHz) δ 0.86 (t, 3H),
;
1.22-1.37 (m, 4H), 1.41-1.54 (m, 2H), 1.55-1.65 (m, 1H),
1.68-1.87 (m, 3H), 1.92-2.05 (m, 1H), 2.37-2.45 (m, 1H), 2.97
(d, 1H, J ) 14.0 Hz), 3.35 (s, 3H), 3.76 (s, 1H), 4.64 (s, 2H), and
8.93 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 13.9, 20.0, 20.8, 22.6,
22.7, 25.7, 26.6, 27.9, 29.4, 29.7, 37.8, 46.2, 55.3, 75.6, 76.8, 94.3,
94.6, 160.3, and 160.8; HRMS calcd for [(C12H23NO3) + H]+
230.1751, found 230.1751.
(neat) 1470, 1445, 1332, and 1154 cm-1; H NMR (CDCl3, 600
1
4,5-endo-(Diphenylsulfonyl)-2-spiro-1′-(8-butyl-9-(methoxy-
methoxy)cyclohexane)-7-oxo-1-azabicyclo[2.2.1]heptane (20). A
10 mL sealed tube was charged 0.15 g (0.65 mmol) of oxime 19,
0.22 g (0.66 mmol) of 2,3-bis(phenylsulfonyl)-1,3-butadiene (5),
and 2.0 mL of CH2Cl2. The resulting solution was heated at 100
°C for 24 h, cooled to 25 °C, and concentrated under reduced
pressure. The residue was purified using flash silica gel chroma-
tography to furnish 0.25 g (68%) of an approximately 1:1-mixture
of 4,5-endo-di(phenylsulfonyl)-2-spiro-1′-(8-butyl-9-(methoxymethox-
y)cyclohexane)-7-oxo-1-azabicyclo[2.2.1]heptane (20) as a white
solid in 82% yield: mp 136-140 °C; IR (neat) 1584, 1446, 1322,
MHz) δ 0.10 (s, 3H), 0.20 (s, 3H), 0.83 (d, 1H, J ) 12.0 Hz), 0.91
(t, 3H, J ) 6.6 Hz), 0.99 (s, 9H), 1.14-1.52 (m, 10H), 1.55 (s,
2H), 2.04 (dd, 1H, J ) 13.8 and 2.4 Hz), 2.26 (d, 1H, J ) 10.8
Hz), 3.40 (d, 1H, J ) 13.8 Hz), 3.68 (t, 1H, J ) 12.0 Hz), 3.87
(dd, 1H, J ) 12.0 and 4.8 Hz), 4.02 (d, 1H, J ) 2.4 Hz), 4.26
(ddd, 1H, J ) 11.4, 4.8 and 1.8 Hz), 7.50 (t, 2H, J ) 7.5 Hz), 7.61
(t, 2H J ) 7.5 Hz), 7.65 (t, 1H, J ) 7.5 Hz), 7.71 (t, 1H, J ) 7.5
Hz), 7.75 (d, 2H, J ) 7.5 Hz), and 7.97 (d, 2H, J ) 7.5 Hz); 13C
NMR (CDCl3, 150 MHz) δ -5.4, -4.9, 14.0, 15.2, 18.1, 23.0,
26.0, 26.6, 27.5, 30.6, 32.4, 37.4, 44.5, 52.0, 66.3, 69.2, 74.3, 104.1,
128.7, 129.0, 129.1, 130.1, 134.3, 134.6, and 139.3. Anal. Calcd
for C32H47NO6S2Si: C, 60.63; H, 7.47; N, 2.21. Found: C, 60.81;
H, 7.41; N, 2.23.
1
1148, and 1040 cm-1; H NMR (CDCl3, 300 MHz) δ 0.78 (t, 3H
J ) 6.6 Hz), 0.96-1.14 (m, 5H), 1.19-1.50 (m, 4H), 1.56-1.80
(m, 5H), 2.15 (d, 1H, J ) 12.0 Hz), 2.74 (d, 1H, J ) 13.4 Hz),
3.01 (d, 1H, J ) 13.4 Hz), 3.26 (d, 3H, J ) 1.5 Hz), 3.58-3.70
(m, 2H), 4.00 (dd, 1H, J ) 12.6 and 3.8 Hz), 4.26 (dd, 1H, J ) 6.6
and 1.5 Hz), 4.42 (dd, 2H, J ) 6.6 and 1.5 Hz), 7.49 (t, 2H, J )
7.5 Hz), 7.58-7.75 (m, 4H), 7.82 (d, 2H, J ) 7.5 Hz), and 8.00
(d, 2H, J ) 7.5 Hz); 13C NMR (CDCl3, 75 MHz) δ 14.0, 18.8,
22.3, 24.5, 26.3, 27.3, 31.2, 38.6, 45.9, 52.2, 55.2, 66.9, 74.4, 74.9,
The minor diastereomer 17b was also a white solid: mp 150-152
°C; IR (neat) 1463, 1447, 1329, 1311, and 1155 cm-1; H NMR
1
(CDCl3, 600 MHz) δ 0.02 (s, 6H), 0.76-0.81 (m, 1H), 0.80 (t,
3H, J ) 6.5 Hz), 0.94 (s, 9H), 1.15-1.04 (m, 4H), 1.32 (dt, 1H, J
) 13.0 and 4.0 Hz), 1.36-1.40 (m, 1H), 1.44-1.50 (m, 1H), 1.62
(dt, 1H, J ) 13.5 and 3.5 Hz), 1.73-1.80 (m, 1H), 1.80-1.90 (m,
J. Org. Chem. Vol. 73, No. 24, 2008 9605

Wilson and Padwa
94.1, 104.3, 128.5, and 128.7. Anal. Calcd for C28H37NO7S2: C,
59.66; H, 6.62; N, 2.48; Found: C, 60.02; H, 6.74; N, 2.48.
3-Benzenesulfonyl-7-butyl-8-(methoxymethoxy)-1-azaspiro-
[5.5]undecan-4-one (21). To a suspension of 3.4 g (24 mmol) of
Na2HPO4 and 2.7 g (4.8 mmol) of the above mixture of cycload-
ducts (20) in 50 mL of 2:1 THF/EtOH at 0 °C was added 7.7 g (17
mmol) of 5% Na/Hg amalgam. The resulting yellow suspension
was slowly warmed to 25 °C and was stirred vigorously for 19 h.
The reaction mixture was filtered through a Celite plug and rinsed
with Et2O followed by CH2Cl2. The filtrate was concentrated under
reduced pressure. The residue was purified using flash silica gel
chromatography to furnish 1.4 g (69%) of 3-benzenesulfonyl-7-
butyl-8-(methoxymethoxy)-1-azaspiro[5.5]undecan-4-one (21) as a
colorless oil along with 0.24 g (18%) of 7-butyl-8-(methoxymethoxy)-
1-azaspiro[5.5]undecan-4-one (22). Compound 21 exhibited the
following spectral properties: IR (neat) 1710, 1308, 1447, 1148,
and 1035 cm-1; 1H NMR (CDCl3, 300 MHz) [major diastereomer]
δ 0.94 (t, 3H, J ) 7.0 Hz), 1.03-1.52 (m, 10H), 1.52-1.67 (2H),
1.67-1.81 (m, 1H), 2.01-2.11 (m, 1H), 2.21 (d, 1H, J ) 13.5
Hz), 3.14 (d, 1H, J ) 13.5 Hz), 3.18 (dd, 1H, J ) 15.6 and 4.6
Hz), 3.38 (s, 3H), 3.60 (d, 1H, J ) 4.6 Hz), 3.72 (dt, 1H, J ) 9.9
and 4.6 Hz), 3.85 (d, 1H, J ) 15.6 Hz) and 4.60 (d, J ) 6.9 Hz);
[minor diastereomer (distinct peaks)] δ 0.85 (t, J ) 6.9 Hz), 2.39
(d, J ) 13.5 Hz), and 3.31 (s); 13C NMR (CDCl3, 75 MHz) δ 14.1,
18.6, 23.1, 27.0, 32.3, 33.0, 34.0, 41.3, 51.6, 52.2, 55.6, 62.1, 72.2,
78.4, 95.6, and 128.2; HRMS calcd for [(C22H33NO5S) + H]+
424.2152, found 424.2147.
[minor rotamer (distinct peaks)] δ 3.38 (s); 13C NMR (CDCl3, 75
MHz) δ 14.2, 14.4, 17.5, 17.9, 23.5, 24.8, 25.7, 27.1, 30.3, 31.1,
31.7, 41.1, 43.3, 43.6, 43.9, 44.4, 49.0, 50.8, 53.7, 55.6, 63.3, 65.4,
73.8, 74.1, 94.6, 127.2, 128.4, 128.6, 129.0, 130.3, 130.4, 131.2,
133.7, 138.8, 174.2, 176.0, 208.3, and 209.7; HRMS calcd for
[(C23H33NO4) + H]+ 388.2482, found 388.2480.
1-Benzoyl-7-butyl-8-(methoxymethoxy)-1-azaspiro[5.5]-
undec-2-en-4-one (24). To a solution of 610 µL (3.6 mmol) of
2,2,6,6-tetramethylpiperidine in 16 mL of THF at 0 °C was added
1.5 mL (3.4 mmol) of 2.25 M n-BuLi. After being stirred for 1 h
at 0 °C, the reaction mixture was cooled to -78 °C and 430 µL
(3.4 mmol) of TMSCl and a solution of 0.93 g (2.4 mmol) of ketone
18 in 18 mL of THF was added sequentially. After being stirred
for 2 h at -78 °C and then 1 h at 25 °C, the reaction mixture was
cooled to 0 °C and quenched with a saturated aqueous NH4Cl
solution. The aqueous layer was separated and extracted with Et2O.
The combined organic extracts were dried over MgSO4, filtered,
and concentrated under reduced pressure to furnish the crude silyl
enol ether.
To a solution of the above compound in 6 mL of a 3:1 CH3CN/
DMSO mixture was added 0.65 g (2.9 mmol) of Pd(OAc)2. The
resulting solution was stirred for 41 h at 25 °C. The resulting
suspension was diluted with Et2O and filtered through a Celite plug.
The filtrate was concentrated under reduced pressure and washed
with a saturated NaHCO3 solution. The biphasic mixture was
extracted with Et2O, and the combined extracts were dried over
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified using flash silica gel chromatography to furnish
7-Butyl-8-(methoxymethoxy)-1-azaspiro[5.5]undecan-4-one (22).
To a solution of 1.3 g (3.1 mmol) of sulfone 21 in 110 mL of dry
toluene was added 3.4 mL (12.5 mmol) of n-Bu3SnH. The reaction
mixture was heated at reflux (130 °C) before 0.4 g (2.4 mmol) of
AIBN was added. After the mixture was heated at reflux for 5 min,
an additional 0.25 g (1.52 mmol) of AIBN was added. After a
further 20 min, an additional 0.2 g (1.22 mmol) of AIBN was added.
The resulting solution was heated at reflux for 3 h, cooled to 25
°C, and concentrated under reduced pressure. The residue was
purified using flash silica gel chromatography to furnish 0.72 g
(82%) of 7-butyl-8-(methoxymethoxy)-1-azaspiro[5.5]undecan-4-
one (22) as a pale yellow oil: IR (neat) 3341, 1708, 1463, 1142,
0.73
g (76%) of 1-benzoyl-7-butyl-8-(methoxymethoxy)-1-
azaspiro[5.5]undec-2-en-4-one (24) as a white solid in 84% yield:
mp 113.5-115 °C; IR (neat) 1669, 1595, 1314, 1242, and 1032
1
cm-1; H NMR (CDCl3, 300 MHz) δ 0.86 (t, 3H, J ) 7.0 Hz),
1.09-1.91 (m, 12H), 2.30 (d, 1H, J ) 12.0 Hz), 2.54 (d, 1H, J )
16.1 Hz), 3.33 (s, 3H), 3.34-3.42 (m, 1H), 3.83 (d, 1H, J ) 16.1
Hz), 3.95 (d, 1H, J ) 2.6 Hz), 4.55 (d, 1H, J ) 7.0 Hz), 4.58 (d,
1H, J ) 7.0 Hz), 5.29 (d, 1H, J ) 8.1 Hz), 7.16 (d, 1H, J ) 8.1
Hz), and 7.42-7.63 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 14.0,
18.0, 22.7, 26.0, 28.8, 31.1, 39.7, 48.5, 55.3, 69.0, 74.4, 94.4, 107.0,
128.8, 129.3, 132.2, 136.2, 146.5, 172.2, and 194.7. Anal. Calcd
for C23H31NO4: C, 71.66; H, 8.11; N, 3.63. Found: C, 71.39; H,
8.20; N, 3.57.
1
and 1038 cm-1; H NMR (CDCl3, 300 MHz) δ 0.84 (t, 3H, J )
7.1 Hz), 0.98-1.10 (m, 1H), 1.10-1.35 (m, 8H), 1.35-1.58 (m,
5H), 1.62 (dt, 1H, J ) 13.3 and 4.1 Hz), 1.90-1.98 (m, 1H), 2.00
(d, 1H, J ) 13.3 Hz), 2.25 (dd, 2H, J ) 7.1 and 5.1 Hz), 2.64 (d,
1H, J ) 13.3 Hz), 2.91 (dt, 1H, J ) 13.3 and 7.1 Hz), 3.12 (dt,
1H, J ) 13.3 and 5.1 Hz), 3.32 (s, 3H), 3.59 (dt, 1H, J ) 9.1 and
4.1 Hz), 4.53 (d, 1H, J ) 7.1 Hz), and 4.66 (d, 1H, J ) 7.1 Hz);
13C NMR (CDCl3, 75 MHz) δ 14.0, 18.3, 23.2, 27.4, 31.3, 32.5,
33.6, 40.2, 42.7, 50.2, 52.8, 55.4, 60.6, 77.6, 95.2, and 210.1; HRMS
calcd for [(C16H29NO3) + H]+ 284.2220, found 284.2220.
1-Benzoyl-7-butyl-8-(methoxymethoxy)-2-pentyl-1-azaspiro-
[5.5]undecan-4-one (25). To a solution of 0.63 g (1.7 mmol) of
enone 24 in 16.5 mL of dry THF was added 1.4 g (6.6 mmol) of
CuBr-SMe2. The resulting suspension was stirred for 1 h at room
temperature and cooled to -78 °C, and 900 µL (6.7 mmol) of
BF3 ·Et2O was added. After the mixture was stirred for 1 h at -78
°C, 2.7 mL (4.9 mmol) of a solution of pentylmagnesium bromide
(2.0 M in Et2O) was slowly added. The suspension was stirred at
-78 °C for an additional 3 h before being quenched with 8 mL of
a 9:1 saturated aqueous NH4Cl/concd NH4OH solution. Upon
warming to 25 °C, the biphasic mixture was diluted with a further
15 mL of a 9:1 saturated aqueous NH4Cl/concd NH4OH solution
and then extracted with Et2O. The combined organic extracts were
dried over MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified using flash silica gel chroma-
tography to furnish 0.68 g (92%) of 1-benzoyl-7-butyl-8-(meth-
oxymethoxy)-2-pentyl-1-azaspiro[5.5]undecan-4-one (25) as a pale
1-Benzoyl-7-butyl-8-(methoxymethoxy)-1-azaspiro[5.5]-
undecan-4-one (23). To a solution of 0.14 g (0.49 mmol) of
piperidone 22 and 280 µL (2.0 mmol) of Et3N in 3 mL of CH3CN
at 0 °C was added 0.03 g (0.15 mmol) of DMAP followed by 170
µL (1.5 mmol) of freshly distilled benzoyl chloride. The resulting
solution was slowly warmed to 25 °C and stirred for 22 h. The
solution was concentrated under reduced pressure and diluted with
EtOAc, and the precipitated triethylammonium salts were filtered.
The filtrate was concentrated under reduced pressure, and the
residue was purified using flash silica gel chromatography to furnish
1
yellow oil: IR (neat) 1722, 1645, 1398, 1348, and 1039 cm-1; H
0.15
g
(81%) of 1-benzoyl-7-butyl-8-(methoxymethoxy)-1-
NMR (CDCl3, 400 MHz) δ 0.79 (t, 3H, J ) 7.2 Hz), 0.94 (t, 3H,
J ) 7.2 Hz), 0.97-1.10 (m, 2H), 1.10-1.20 (m, 1H), 1.22-1.46
(m, 4H), 1.51-1.67 (m, 4H), 1.74-1.83 (m, 2H), 1.94-2.05 (m,
1H), 2.37 (dd, 1H, J ) 17.3 and 2.4 Hz), 2.62 (d, 1H, J ) 16.3
Hz), 2.63 (dd, 1H, J ) 19.2 and 3.6 Hz), 2.81-2.90 (m, 1H), 3.26
(d, 1H, J ) 16.3 Hz), 3.37 (s, 3H), 4.04-4.11 (m, 1H), 4.22-4.28
(m, 1H), 4.26 (d, 1H, J ) 6.7 Hz), 4.68 (d, 1H, J ) 6.7 Hz),
7.29-7.33 (m, 2H), and 7.37-7.42 (m, 3H); 13C NMR (CDCl3,
100 MHz) δ 13.8, 14.1, 18.2, 22.3, 23.4, 26.6, 28.3, 29.7, 31.1,
32.5, 35.1, 37.8, 42.2, 50.7, 52.1, 55.6, 56.5, 64.9, 77.5, 95.6,
azaspiro[5.5]undecan-4-one (23) as a colorless oil: IR (neat) 1712,
1650, 1371, 1303, and 1036 cm-1; 1H NMR (CDCl3, 300 MHz) δ
0.76 (t, 1H, J ) 6.5 Hz), 0.94 (t, 3H, J ) 7.1 Hz), 1.03-1.29 (m,
3H), 1.29-1.43 (m, 3H), 1.43-1.83 (m, 5H), 2.18 (d, 1H, J ) 6.5
Hz), 2.22 (d, 1H, J ) 19.5 Hz), 2.30-2.48 (m, 1H), 2.61 (d, 1H,
J ) 12.8 Hz), 2.66 (d, 1H, J ) 14.2 Hz), 3.17 (d, 1H, J ) 15.5
Hz), 3.36 (s, 3H), 3.50 (d, 1H, J ) 15.5 Hz), 3.58 (d, 1H, J ) 14.2
Hz), 3.87 (dd, 1H, J ) 14.2 and 6.5 Hz), 3.94 (d, 1H, J ) 19.5
Hz), 4.62 (dt, 2H, J ) 15.5 and 6.5 Hz), and 7.38-7.63 (m, 5H);
9606 J. Org. Chem. Vol. 73, No. 24, 2008

Total Synthesis of (()-2,7,8-epi-Perhydrohistrionicotoxin
125.3, 128.7, 129.1, 139.5, 173.1, and 208.7; HRMS calcd for
[(C28H43NO4) + H]+ 458.3265. Found: 458.3261.
Hz), 1.03-1.30 (m, 10H), 1.40-1.81 (m, 12H), 1.84-1.93 (m, 2H),
3.35 (s, 3H), 3.77 (s, 1H), 3.81 (d, 1H, J ) 17.1 Hz), 4.57 (d, 1H,
J ) 6.7 Hz), 4.59 (d, 1H, J ) 6.7 Hz), 7.14 (t, 1H, J ) 7.6 Hz),
7.25 (t, 2H, J ) 7.6 Hz), and 7.39 (d, 2H, J ) 7.6 Hz); 13C NMR
(CDCl3, 150 MHz) δ 13.9, 14.0, 18.5, 22.6, 23.2, 26.3, 27.8, 29.7,
31.8, 32.1, 47.9, 55.1, 76.0, 94.9, 125.7, 127.1, 127.8, and 144.5;
HRMS calcd for [(C28H47NO2) + H]+ 430.3680, found 430.3680.
1-Benzoyl-7-butyl-8-(methoxymethoxy)-2-pentyl-1-aza-
spiro[5.5]undecan-4-N-p-toluenesulfonylhydrazone (27). To a
solution of 0.16 g (0.35 mmol) of ketone 25 in 800 µL of EtOH
was added 0.9 g (0.43 mmol) of p-toluenesulfonyl hydrazide. The
resulting suspension was heated to reflux at 90 °C and stirred for
1.5 h. The reaction mixture was cooled to 25 °C, diluted with
CH2Cl2 and concentrated under reduced pressure. The residue was
purified using flash silica gel chromatography to furnish 0.21 g
(95%) of 1-benzoyl-7-butyl-8-(methoxymethoxy)-2-pentyl-1-aza-
spiro[5.5]undecan-4-N-p-toluenesulfonylhydrazone (27) as a white
solid: mp 128-130 °C; IR (neat) 3110, 1640, 1344, 1168 and 1001
Trifluoromethanesulfonic Acid 1-Benzoyl-7-butyl-8-(methoxy-
methoxy)-2-pentyl-1-azaspiro[5.5]undec-3-en-4-yl Ester (30). To
a solution of 0.23 g (0.49 mmol) of ketone 25 in 5 mL of dry THF
at -78 °C was added 1.2 mL (0.59 mmol) of a solution of KHMDS
(0.5 M in toluene) over a period of 15 min. After the mixture was
stirred for 45 min, 0.023 g (0.64 mmol) of PhNTf2 was added all
at once. The resulting solution was slowly warmed to 25 °C and
stirred for 17 h before being diluted with CH2Cl2 and filtered
through a plug of neutral alumina. The filtrate was concentrated
under reduced pressure, and the residue was purified using flash
silica gel chromatography to furnish 0.025 g (85%) of a 1.5:1
mixture of trifluoromethanesulfonic acid 1-benzoyl-7-butyl-8-
(methoxymethoxy)-2-pentyl-1-azaspiro[5.5]undec-3-en-4-yl ester
(30a) as well as trifluoromethanesulfonic acid 1-benzoyl-7-butyl-
8-(methoxymethoxy)-2-pentyl-1-azaspiro[5.5]undec-4-en-4-yl ester
(30b) as a colorless oil: IR (neat) 1657, 1418, 1211, 1143, and
1
cm-1; H NMR (CDCl3, 300 MHz) δ 0.78 (t, 3H, J ) 7.1 Hz),
0.92 (t, 3H, J ) 7.1 Hz), 0.96-1.47 (m, 10H), 1.51-1.80 (m, 5H),
1.91 (d, 1H, J ) 13.5 Hz), 2.08 (d, 1H, J ) 11.6 Hz), 2.18 (d, 1H,
J ) 12.8 Hz), 2.39 (s, 3H), 2.39-2.50 (m, 1H), 3.53 (s, 3H), 3.81
(dd, 1H, J ) 13.5 and 1.8 Hz), 3.91 (s, 1H), 4.01-4.12 (m, 1H),
4.86 (d, 1H, J ) 7.1 Hz), 5.16 (d, 1H, J ) 7.1 Hz), 7.25 (d, 2H,
J ) 8.2 Hz), 7.31-7.40 (m, 5H), 7.78 (d, 2H, J ) 8.2 Hz) and
9.98 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 14.0, 14.4, 17.7, 21.6,
22.5, 23.1, 24.6, 27.1, 29.6, 31.3, 31.6, 34.2, 35.4, 37.9, 39.6, 49.6,
56.5, 59.9, 67.1, 78.3, 96.1, 126.1, 127.7, 128.6, 129.3, 129.7, 135.7,
139.9, 143.2, 152.7 and 174.4. Anal. Calcd for C35H51N3O5S: C,
67.17; H, 8.21; N, 6.71. Found: C, 66.96; H, 8.25; N, 6.62.
1-Benzyl-7-butyl-8-(methoxymethoxy)-2-pentyl-1-aza-spiro-
[5.5]undecan-4-N-p-toluenesulfonylhydrazone (28). To a solution
of 0.15 g (0.24 mmol) of tosyl hydrazone 27 in 2.5 mL of dry
THF at 0 °C was added 0.06 g (1.4 mmol) of LiAlH4. The reaction
mixture was heated at reflux for 12 h, cooled to 0 °C and then
carefully quenched with 60 µL of water, followed by 60 µL of
15% aqueous NaOH, followed by an additional 180 µL of water.
The resulting suspension was warmed to 25 °C and was stirred for
an additional 30 min. A portion of MgSO4 was added and the
suspension was stirred for an additional 30 min before being diluted
with Et2O and filtered through a plug of Celite. The filtrate was
concentrated under reduced pressure. The residue was purified using
flash silica gel chromatography to furnish 0.08 g (56%) of 1-benzyl-
7-butyl-8-(methoxymethoxy)-2-pentyl-1-aza-spiro[5.5]-undecan-4-
N-p-toluenesulfonylhydrazone (28) as a colorless oil: IR (neat) 1455,
1
1028 cm-1; H NMR (CDCl3, 300 MHz) δ 0.78 (t, 3H, J ) 7.2
Hz), 0.92 (t, 3H, J ) 7.2 Hz), 0.85-1.04 (m, 2H), 1.05-1.23 (m,
4H), 1.29-1.80 (m, 13H), 1.92 (d, 1H, J ) 10.9 Hz), 2.44 (dt, 1H,
J ) 16.7 and 3.1 Hz), 3.20-3.34 (m, 1H), 3.35 (s, 3H), 3.88 (d,
1H, J ) 16.7 Hz), 3.93 (s, 1H), 4.53-4.64 (m, 1H), 4.59 (s, 2H),
5.64 (t, 1H, J ) 3.1 Hz), and 7.34-7.45 (m, 5H); 13C NMR (CDCl3,
75 MHz) δ 13.9, 14.2, 18.7, 22.4, 23.4, 24.8, 26.4, 28.1, 30.8, 31.1,
33.4, 37.8, 39.1, 44.3, 55.4, 57.0, 63.8, 73.5, 94.5, 114.5, 126.7,
127.1, 128.5, 129.8, 138.9, 145.9, and 174.1; HRMS calcd for
[(C29H42NO6F3S) + H]+ 590.2758, found 590.2756.
7-(Butyl-8-(methoxymethoxy)-2-pentyl-1-azaspiro[5.5]-
undec-1-yl)phenylmethanone (31). To a solution of 0.026 g (0.44
mmol) of the above triflate mixture in 21 mL of EtOAc was added
0.065 g (0.88 mmol) of Li2CO3 and 0.38 g (3.5 mmol, 40 mol%)
of 5% Pd/C. The resulting suspension was stirred for 20 h under
an atmosphere of hydrogen (50 psi). The reaction mixture was
diluted with CH2Cl2 and filtered through a Celite plug. The filtrate
was concentrated under reduced pressure, and the resulting residue
was purified using flash silica gel chromatography to give 0.18 g
(92%) of (7-butyl-8-(methoxymethoxy)-2-pentyl-1-azaspiro[5.5]undec-
1-yl)phenylmethanone (31) as a pale yellow oil: IR (neat) 1642,
1462, 1351, 1151, and 1039 cm-1; 1H NMR (CDCl3, 300 MHz) δ
0.79 (t, 3H, J ) 7.2 Hz), 0.94 (t, 3H, J ) 7.2 Hz), 0.98-1.10 (m,
2H), 1.10-1.46 (m, 10H), 1.46-1.72 (m, 10H), 1.72-1.88 (m, 3H),
2.02 (d, 1H, J ) 10.9 Hz), 2.94 (d, 1H, J ) 13.0 Hz), 3.38 (s, 3H),
3.77-3.88 (m, 1H), 3.95 (d, 1H, J ) 2.1 Hz), 4.60 (d, J ) 6.6
Hz), 4.65 (d, J ) 6.6 Hz), 7.31-7.42 (m, 5H); 13C NMR (CDCl3,
75 MHz) δ 14.0, 14.4, 15.5, 18.5, 22.5, 23.4, 26.1, 27.5, 27.7, 29.1,
31.5, 31.9, 34.0, 36.2, 36.7, 46.5, 55.3, 57.2, 63.7, 75.3, 94.7, 125.9,
128.3, 128.6, 141.0, and 174.1; HRMS calcd for [(C28H45NO3) +
H]+ 444.3472, found 444.3469.
Compound 31 was easily reduced to azapiro[5.5]undecane 29
using LiAlH4. To a solution of 0.03 g (0.06 mmol) of amide 31 in
900 µL of dry THF at 0 °C was added 0.03 g (0.81 mmol) of
LiAlH4. The reaction mixture was heated at reflux overnight for
15 h, cooled to 0 °C, and then carefully quenched with 50 µL of
water followed by 50 µL of 15% aqueous NaOH, and this was
followed by an additional 150 µL of water. The resulting suspension
was warmed to 25 °C and stirred for an additional 30 min. A portion
of MgSO4 was added, and the suspension was stirred for an
additional 30 min before being diluted with Et2O and filtered
through a plug of Celite. The filtrate was concentrated under reduced
pressure. The residue was purified using flash silica gel chroma-
tography to furnish 0.024 g (92%) of 1-benzyl-7-butyl-8-(meth-
oxymethoxy)-2-pentyl-1-azapiro[5.5]undecane (29) as a colorless
1
1344, 1168, 1041 and 1009 cm-1; H NMR (CDCl3, 300 MHz) δ
0.86 (t, 3H, J ) 7.2 Hz), 0.89-1.11 (m, 10H), 1.12-1.37 (m, 8H),
1.37-1.56 (m, 5H), 1.71 (d, 1H, J ) 13.0 Hz), 1.82 (d, 1H, J )
13.0 Hz), 2.01 (d, 1H, J ) 12.3 Hz), 2.24 (d, 1H, J ) 12.3 Hz),
2.36 (dd, 1H, J ) 12.3 and 6.4 Hz), 2.41 (s, 3H), 2.81-2.90 (m,
1H), 3.52 (s, 3H), 3.57 (d, 1H, J ) 12.3 Hz), 3.78 (d, 1H, J ) 16.8
Hz), 3.81 (s, 1H), 4.31 (d, 1H, J ) 16.8 Hz), 4.82 (d, 1H, J ) 7.2
Hz), 5.16 (d, 1H, J ) 7.2 Hz), 7.16-7.34 (m, 5H), 7.24 (d, 2H, J
) 8.3 Hz), 7.80 (d, 2H, J ) 8.3 Hz) and 9.88 (s, 1H); 13C NMR
(CDCl3, 75 MHz) δ 14.0, 14.3, 17.7, 21.5, 22.6, 23.2, 24.5, 27.5,
28.0, 30.1, 31.1, 31.8, 34.6, 38.2, 39.7, 50.4, 52.5, 56.4, 58.9, 62.3
78.6, 96.8, 126.3, 127.6, 128.2 and 129.2; HRMS calcd for
[(C35H53N3O4S) + H]+ 612.3830, found 612.3826.
1-Benzyl-7-butyl-8-(methoxymethoxy)-2-pentyl-1-azaspiro-
[5.5]undecane (29). A solution of 0.042 g (0.07 mmol) of tosyl
hydrazone 28 in 700 µL of dry THF at 0 °C was treated with 0.035
g (0.92 mmol) of LiAlH4. The reaction mixture was heated at reflux
for 15 h, cooled to 0 °C, and then carefully quenched with 50 µL
of water, followed by 50 µL of 15% aqueous NaOH, and this was
followed by an additional 150 µL of water. The resulting suspension
was warmed to room temperature and stirred for an additional 30
min. A portion of MgSO4 was added and the suspension was stirred
for an additional 30 min before being diluted with Et2O and filtered
through a plug of Celite. The filtrate was concentrated under reduced
pressure. The residue was purified using flash silica gel chroma-
tography to furnish 0.014 g (49%) of 1-benzyl-7-butyl-8-(meth-
oxymethoxy)-2-pentyl-1-azaspiro[5.5]undecane (29) as a colorless
1
oil: IR (neat) 1732, 1462, 1150, 1096, and 1041 cm-1; H NMR
(CDCl3, 600 MHz) δ 0.68-0.87 (m, 2H), 0.85 (t, 3H, J ) 7.6
J. Org. Chem. Vol. 73, No. 24, 2008 9607

Wilson and Padwa
oil whose properties were identical to those of a sample of 29
prepared from the reduction of hydrazone 28.
1-azaspiro[5.5]undec-4-en-4-yl ester (33b) as a colorless oil: IR
1
(neat) 1628, 1496, 1418, 1211, 1144, and 1033 cm-1; H NMR
(CDCl3, 300 MHz) δ 0.75 (t, 6H, J ) 7.0 Hz), 0.82-0.91 (m, 4H),
0.93-1.0 (m, 4H), 1.09-1.85 (m, 16H), 1.69 (s, 2H), 1.70 (s, 2H),
1.93-2.12 (m, 4H), 2.71-2.84 (m, 2H), 3.12 (d, 1H, J ) 18.4
Hz), 3.21 (d, 1H, J ) 18.4 Hz), 3.29 (d, 1H, J ) 8.3 Hz), 3.34 (s,
3H), 3.40 (s, 3H), 3.59 (d, 1H, J ) 17.5 Hz), 3.65 (d, 1H, J ) 18.4
Hz), 3.65 (d, 1H, J ) 18.4 Hz), 3.83 (d, 1H, J ) 18.4 Hz), 3.94 (s,
1H), 4.01 (d, 1H, J ) 18.4 Hz), 4.14 (d, 1H, J ) 17.5 Hz), 4.58
(d, 1H, J ) 7.6 Hz), 4.61 (d, 1H, J ) 7.6 Hz), 4.63 (d, 1H, J ) 7.0
Hz), 4.70 (d, 1H, J ) 7.0 Hz), 5.59 (s, 1H), 5.62 (s, 1H), 7.36-7.49
(m, 8H), and 7.53 (d, 2H, J ) 7.0 Hz); 13C NMR (CDCl3, 100
MHz) δ 13.8, 14.1, 17.3, 17.7, 22.6, 23.0, 23.3, 24.5, 24.7, 26.5,
26.7, 27.0, 30.6, 31.4, 31.6, 31.8, 34.8, 36.9, 41.3, 43.4, 44.3, 44.5,
55.5, 60.7, 62.2, 73.8, 94.6, 113.4, 114.9, 116.9, 120.0, 127.4, 128.2,
128.6, 128.7, 130.4, 131.0, 137.1, 138.2, 148.3, 149.6, 173.5, and
175.3.
1-Benzyl-7-butyl-2-pentyl-1-azaspiro[5.5]undecan-8-ol (32).
To a suspension of 0.02 g (0.05 mmol) of MOM ether 29 and 0.08 g
of powdered 4 Å molecular sieves in 0.5 mL of dry CH2Cl2 at
-20 °C was added 50 mL (0.39 mmol) of freshly distilled TMSBr.
The resulting suspension was stirred for 3 h at -20 °C before being
warmed to 0 °C. After being stirred for an additional 2 h, the
reaction mixture was quenched with a saturated aqueous NaHCO3
solution. The biphasic mixture was diluted with CH2Cl2 and filtered
through a Celite plug. The filtrate was extracted with CH2Cl2, and
the combined organic layer was dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified using
flash silica gel chromatography to furnish 0.014 g (74%) of
1-benzyl-7-butyl-2-pentyl-1-azaspiro[5.5]undecan-8-ol (32) as a
colorless oil: IR (neat) 3386, 1451, 1352, 1110, and 1026 cm-1
;
1H NMR (CDCl3, 600 MHz) δ 0.68-0.85 (m, 2H), 0.84 (t, 3H, J
) 7.6 Hz), 0.86-0.98 (m, 2H), 1.11 (d, 1H, J ) 3.8 Hz) 1.04-1.17
(m, 4H), 1.17-1.29 (m, 6H), 1.41-1.57 (m, 8H), 1.57-1.70 (m,
4H), 1.70-1.82 (m, 2H), 1.93 (t, 1H, J ) 8.6 Hz), 3.82 (d, 1H, J
) 17.1 Hz), 3.97-4.01 (m, 1H), 4.03 (brs, 1H), 7.13 (t, 1H, J )
7.6 Hz), 7.25 (t, 2H, J ) 7.6 Hz), and 7.38 (d, 2H, J ) 7.6 Hz);
13C NMR (CDCl3, 150 MHz) δ 14.0, 14.1, 22.6, 22.7, 23.6, 25.7,
27.5, 29.3, 29.4, 29.6, 29.7, 30.3, 31.9, 32.8, 34.3, 49.9, 55.2, 63.1,
71.1, 125.5, 127.0, 127.6, and 143.9; HRMS calcd for [(C26H43NO)
+ H]+ 386.3417, found 386.3419.
7-(Butyl-8-(methoxymethoxy)-1-azaspiro[5.5]undec-1-yl)-
phenylmethanone (34). To a solution of 0.51 g (0.99 mmol) of
the above triflate mixture in 45 mL of EtOAc was added 0.15 g
(2.0 mmol) of Li2CO3 and 0.85 g (0.4 mmol, 40 mol%) of 5%
Pd/C. The resulting suspension was stirred for 48 h under an
atmosphere of hydrogen (60 psi). The reaction mixture was diluted
with CH2Cl2 and filtered through a Celite plug. The filtrate was
concentrated, and the resulting residue was purified using flash silica
gel chromatography to give 0.34 g (91%) of (7-butyl-8-(meth-
oxymethoxy)-1-azaspiro[5.5]undec-1-yl)phenylmethanone (34) as
Another method that was used to prepare32 involved the
treatment of a solution of 0.025 g (0.05 mmol) of MOM ether 29
in 600 mL of Me2S at -10 °C with 100 mL of BF3 ·OEt2. The
resulting suspension was stirred for 2 h at -10 °C before being
warmed to 0 °C. After being stirred for an additional 2.5 h, the
reaction was quenched with a saturated aqueous NaHCO3 solution.
The biphasic mixture was diluted with CH2Cl2 and filtered through
a Celite plug. The filtrate was extracted with CH2Cl2, and the
combined organic layer was dried over MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified using
flash silica gel chromatography to furnish 0.017 g (74%) of 32 as
a colorless oil.
a pale yellow oil: IR (neat) 1642, 1390, 1271, 1096, and 1034 cm-1
;
1H NMR (CDCl3, 600 MHz) δ 0.94 (t, 3H, J ) 7.6 Hz), 1.21-1.81
(m, 15H), 1.97 (d, 1H, J ) 14.3 Hz), 2.32 (d, 1H, J ) 10.5 Hz),
2.76 (dt, 1H, J ) 14.3 and 2.9 Hz), 2.94-3.03 (m, 2H), 3.38 (s,
3H), 3.45 (dt, 1H, J ) 14.3 and 2.9 Hz), 3.95-3.98 (m, 1H), 4.61
(d, 1H, J ) 6.7 Hz), 4.65 (d, J ) 6.7 Hz), and 7.37-7.40 (m, 5H);
13C NMR (CDCl3, 100 MHz) δ 14.1, 18.1, 20.1, 23.1, 25.6, 25.9,
27.0, 31.5, 33.3, 35.5, 40.6, 45.1, 55.2, 64.0, 74.9, 94.6, 126.3,
128.3, 128.9, 140.3, and 173.0; HRMS calcd for [(C23H35NO3) +
H]+ 374.2690, found 374.2700.
1-Benzyl-7-butyl-8-(methoxymethoxy)-1-azaspiro[5.5]-
undecane (35). To a solution of 0.13 g (0.35 mmol) of amide 34
in 5.5 mL of dry THF at 0 °C was added 0.08 g (2.1 mmol) of
LiAlH4. The reaction mixture was heated at reflux for 14 h, and
then the suspension was cooled to 0 °C and was carefully quenched
with 100 µL of water, followed by 100 µL of 15% aqueous NaOH,
and this was followed by an additional 300 µL of water. The
resulting suspension was warmed to 25 °C and stirred for an
additional 30 min. A portion of MgSO4 was added, and the
suspension was stirred for an additional 30 min before being diluted
with Et2O and filtered through a plug of Celite. The filtrate was
concentrated under reduced pressure. The residue was purified using
flash silica gel chromatography to give 0.12 g (93%) of 1-benzyl-
7-butyl-8-(methoxymethoxy)-1-azaspiro[5.5]undecane (35) as a
colorless oil: IR (neat) 1465, 1450, 1216, 1152, 1098, and 1041
7-Butyl-2-pentyl-1-azaspiro[5.5]undecan-8-ol
(2,7,8-epi-
PHTx, 4). To a solution of 0.04 g (0.0.4 mmol) of the above alcohol
32 in 7 mL of EtOH was added 0.07 g of 10% Pd/C. The reaction
flask was evacuated and purged with hydrogen three times. The
reaction mixture was stirred under an atmosphere of hydrogen gas
for 18 h. The resulting mixture was filtered through a Celite plug
and concentrated under reduced pressure to furnish 0.03 g (97%)
of 4 as a colorless oil: IR (neat) 3351, 1460, 1355, 1261, 1119,
and 1033 cm-1; 1H NMR (CDCl3, 600 MHz) δ 0.76-0.92 (m, 2H),
0.878 (t, 3H, J ) 7.5 Hz), 0.90 (t, 3H, J ) 7.5 Hz), 1.07-1.15 (m,
1H), 1.16-1.36 (m, 16H), 1.39-1.48 (m, 2H), 1.51 (dt, 1H, J )
13.5 and 4.0 Hz), 1.54-1.61 (m, 4H), 1.67-1.75 (m, 1H),
1.93-1.99 (m, 1H), 2.22 (d, 1H, J ) 13.5 Hz), 2.46-2.53 (m,
1H), and 3.60 (dt, 1H, J ) 10.0 and 4.0 Hz); 13C NMR (CDCl3,
150 MHz) δ 14.1, 14.2, 18.9, 20.6, 22.6, 23.3, 25.7, 27.0, 29.7,
30.8, 32.0, 33.3, 34.5, 35.1, 35.9, 37.8, 49.3, 54.9, 56.4, and 72.6.;
HRMS calcd for [(C19H37NO) + H]+ 296.2953, found 296.2949.
Trifluoromethanesulfonic Acid 1-Benzoyl-7-butyl-8-(methoxy-
methoxy)-1-azaspiro[5.5]undec-3-en-4-yl Ester (33). To a solution
of 0.44 mg (1.12 mmol) of ketone 23 in 10 mL of dry THF at -78
°C was added 3.0 mL (1.5 mmol) of a solution of KHMDS (0.5 M
in toluene) over a period of 15 min. After the mixture was stirred
for 45 min, 0.52 g (1.5 mmol) of PhNTf2 was added all at once.
The resulting solution was slowly warmed to 25 °C and stirred for
22 h before being diluted with CH2Cl2 and filtered through a plug
of neutral alumina. The filtrate was concentrated under reduced
pressure, and the residue was purified using flash silica gel
chromatography to furnish 0.51 g (88%) of an approximately 3:2
mixture of trifluoromethanesulfonic acid 1-benzoyl-7-butyl-8-
(methoxymethoxy)-1-azaspiro[5.5]undec-3-en-4-yl ester (33a) and
trifluoromethanesulfonic acid 1-benzoyl-7-butyl-8-(methoxymethoxy)-
1
cm-1; H NMR (CDCl3, 400 MHz) δ 0.90 (t, 3H, J ) 6.4 Hz),
0.95-1.09 (m, 1H), 1.19-1.79 (m, 15H), 1.89-2.10 (m, 2H),
2.10-2.23 (m, 1H), 2.44-2.58 (m, 1H), 3.37 (s, 3H), 3.66 (d, 1H,
J ) 14.0 Hz), 3.83-3.89 (m, 1H), 3.92 (d, 1H, J ) 14.0 Hz), 4.63
(d, 1H, J ) 7.0 Hz), 4.65 (d, 1H, J ) 7.0 Hz), 7.20 (t, 1H, J ) 7.0
Hz), 7.28 (t, 1H, J ) 6.4 Hz), 7.30 (d, 1H, J ) 7.0 Hz), and 7.35
(d, 2H, J ) 7.0 Hz); 13C NMR (CDCl3, 150 MHz) δ 14.0, 18.5,
20.4, 20.7, 23.4, 26.3, 27.0, 31.0, 31.6, 32.6, 44.0, 51.2, 55.2, 57.8,
76.6, 95.0, 126.2, 128.0, 128.1, and 142.8; HRMS calcd for
[(C23H37NO2) + H]+ 360.2897, found 360.2892.
1-Benzyl-7-butyl-1-azaspiro[5.5]undecan-8-ol (36). To a sus-
pension of 0.12 g (0.33 mmol) of MOM ether 35 and 0.55 g of
powdered 4 Å molecular sieves in 2.6 mL of dry CH2Cl2 at -20
°C was added 400 mL (2.7 mmol) of freshly distilled TMSBr. The
resulting suspension was stirred for 3 h at -20 °C before being
warmed to 0 °C. After being stirred for an additional 2 h, the
reaction mixture was quenched with a saturated aqueous NaHCO3
9608 J. Org. Chem. Vol. 73, No. 24, 2008

Total Synthesis of (()-2,7,8-epi-Perhydrohistrionicotoxin
solution. The biphasic mixture was diluted with CH2Cl2 and filtered
through a Celite plug. The filtrate was extracted with CH2Cl2, and
the combined organic extracts were dried over MgSO4, filtered,
and concentrated under reduced pressure. The residue was purified
using flash silica gel chromatography to furnish 0.072 g (71%) of
1-benzyl-7-butyl-1-azaspiro[5.5]undecan-8-ol (36) as a colorless oil:
IR (neat) 3386, 1451, 1352, 1110, and 1026 cm-1; 1H NMR (CDCl3,
300 MHz) δ 0.92 (t, 3H, J ) 7.0 Hz), 1.02-1.18 (m, 1H),
1.18-1.95 (m, 16H), 1.95-2.13 (m, 1H), 2.17-2.28 (m, 1H),
2.42-2.56 (m, 1H), 2.56-2.69 (m, 1H), 3.61 (d, 1H, J ) 14.0
Hz), 3.93 (d, 1H, J ) 14.0 Hz), 4.04 (dd, 1H, J ) 9.5 and 5.0 Hz),
7.21 (t, 1H, J ) 7.0 Hz), 7.30 (t, 2H, J ) 7.6 Hz), and 7.36 (d, 2H,
J ) 7.0 Hz); 13C NMR (CDCl3, 150 MHz) δ 14.0, 19.0, 20.8, 21.4,
23.4, 27.0, 29.7, 30.9, 31.4, 33.3, 33.7, 44.3, 49.0, 52.7, 58.6, 72.5,
126.3, 128.0, 128.1, and 142.3.
Acknowledgment. The financial support provided by the
National Science Foundation (CHE-0742663) is greatly ap-
preciated.
Supporting Information Available: 1H and 13C NMR data
of various key compounds lacking CHN analyses together with
ORTEP drawings for compounds 17a, 17b, and 27 as well as
the corresponding CIF files. Atomic coordinates for all three
compounds will be deposited with the Cambridge Crystal-
lographic Data Centre. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO801295E
J. Org. Chem. Vol. 73, No. 24, 2008 9609