Asymmetrie synthesis of substituted homotropinones from W-Sulfinyl β-Amino ketone ketals. (-)-Euphococcinine and (-)-Adaline

Article abstract of DOI:10.1021/ol902910w

Sulflnlmlne-derived N-sulflnyl βamlno ketone ketals on heating with NH₄OAc:HOAc undergo a four-step intramolecular Mannich cyclization cascade reaction to give homotroplnones, such as (-)-euphococclnlne, in excellent yields as single isomers. 10.1021/ol902910w

Full text of DOI:10.1021/ol902910w

ORGANIC
LETTERS
2010
Vol. 12, No. 4
848-851
Asymmetric Synthesis of Substituted
Homotropinones from N-Sulfinyl ꢀ-Amino
Ketone Ketals. (-)-Euphococcinine and
(-)-Adaline
Franklin A. Davis* and Ram Edupuganti
Department of Chemistry, Temple UniVersity, Philadelphia, PennsylVania 19122
fdaVis@temple.edu
Received December 17, 2009
ABSTRACT
Sulfinimine-derived N-sulfinyl ꢀ-amino ketone ketals on heating with NH4OAc:HOAc undergo a four-step intramolecular Mannich cyclization
cascade reaction to give homotropinones, such as (-)-euphococcinine, in excellent yields as single isomers.
The alkaloids (+)-euphococcinine (1) and (-)-adaline (3)
are examples of the 9-azabicyclo[3.3.1]nonane ring system
having a quaternary stereocenter bearing a nitrogen atom
(Figure 1).1 These homotropinones are found in secretions
of the Coccinellid beetles (lady bugs) and are potent
deterrents to both spiders and ants.2 Biosynthetic studies
indicate that these alkaloids are polyacetate in origin and
suggest that a piperideine ketone could be a key intermediate
in their biosynthesis.3 The piperideine ketone undergoes an
intramolecular Mannich cyclization to form homotropinone.
Intramolecular Mannich cyclizations have been used in the
syntheses of (+)-1,4 (-)-2,5 and (-)-3.5 However, the
preparation of the chiral Mannich precursors is sometimes
problematic and not easily adaptable to the preparation of
analogues. Furthermore, retro-Mannich side products have
been reported.5 Other syntheses of the homotropinones
include the use of ring-closing alkene metathesis and metal-
mediated semipinacol rearrangements.6-8
Figure 1. Homotropinones.
Recently, we introduced acyclic N-sulfinyl ꢀ-amino ketone
ketals as new building blocks for the asymmetric synthesis of
substituted tropinones (Figure 2).9-11 Acid hydrolysis afforded
(1) For a review on the asymmetric synthesis of quaternary carbon
stereocenters bearing a nitrogen atom, see: (a) Ramon, D. J.; Yus, M. C.
Current Org. Chem. 2004, 8, 149. (b) For leading references, see: Roy, S.;
Spino, C. Org. Lett. 2006, 8, 939.
(6) For racemic syntheses of (()-euphococcinine and (()-adaline, see:
(a) Davison, E. C.; Holmes, A. B.; Forbes, I. T. Tetrahedron Lett. 1995,
36, 9047. (b) Gossinger, E.; Witkop, B. Monatsh. Chem. 1980, 111, 803.
(c) Gnecco Medina, D. H.; Grierson, D. S.; Husson, H.-P. Tetrahedron
(2) King, A. G.; Meinwald, J. Chem. ReV. 1996, 96, 1105.
(3) (a) Laurent, P.; Lebrun, B.; Brakeman, J.-C.; Daloze, D.; Pastells,
J. M. Tetrahedron 2001, 57, 3403. (b) Tursch, B.; Daloze, D.; Braekman,
J. C.; Hotele, C.; Pasteels, J. M. Tetrahedron 1975, 31, 1541.
(4) Mechelke, M. F.; Meyers, A. I. Tetrahedron Lett. 2000, 41, 4339.
(5) Yue, C.; Royer, J.; Husson, H.-P. J. Org. Chem. 1992, 57, 4211.
Lett. 1983, 24, 2099
.
(7) (+)-Euphococcinine, see: (a) Murahashi, S.-I.; Sun, J.; Kurosawa,
H.; Imada, Y. Heterocycles 2000, 52, 557. (b) Arbour, M.; Roy, S.; Godbout,
C.; Spino, C. J. Org. Chem. 2009, 74, 3806
.
10.1021/ol902910w  2010 American Chemical Society
Published on Web 01/21/2010

Table 1. Synthesis of the ꢀ-Amino Weinreb Amide at -78 °C
R1
R2 base solvent solvent dra b % yield
,
entry
1
2
3
4
5
6
7
8
Me
H
LiHMDS
NaHMDS
KHMDS
THF
Et2O
THF
Et2O
THF
Et2O
THF
Et2O
Et2O
THF
Et2O
THF
Et2O
88:12
74:26
75:25
89:11
92:8
96:4
95:5
93:7
88:12
94:6
76
75
78
76
73
73
71
71
n-C5H11
H
H
Me
KHMDS
KHMDS
LiHMDS
9
Me
Figure 2. Intramolecular Mannich cyclization.
10
11
12
13
76
LDA
84:16
86:14
78:22
stable pyrrolideine ketones (n ) 0) that rearranged to the
tropinones (n ) 0) on formation of the corresponding acylimin-
ium ions via a Mannich cyclization. We report here the
application of these building blocks for the asymmetric synthesis
of substituted homotropinones (n ) 1), including (-)-2 and
(-)-3. Furthermore, we demonstrate that the buffer NH4OAc:
HOAc is able to initiate a four-step intramolecular Mannich
cyclization cascade reaction of the N-sulfinyl ꢀ-amino ketone
ketal to form the substituted homotropinone in excellent yield
and stereoselectivity.
Our synthesis begins with addition of masked oxo-sulfinimine
(S)-(+)-412 and (+)-513 to a -78 °C solution of the preformed
enolate of N-methoxy-N-methylacetamide 6 (R2 ) H) to give
N-sulfinyl ꢀ-amino Weinreb amide ketals (+)-7 and (+)-9,
respectively, in good yield and high dr (Scheme 1).14 As can
KHMDS
a Determined by 1H NMR on the crude reaction mixture. b Inseparable
diastereoisomers. c For entries 9-13, syn:anti ratio.
potassium enolate in ether giving the best selectivity (Table
1: entries 6 and 8). Addition of (S)-(+)-4 to the prochiral
enolate of N-methoxy-N-methylpropylamide 6 (R2 ) Me)
afforded (+)-8 having the syn geometry based on early
studies (Scheme 1).15 Here the lithium enolate of 6 in THF
gave the best selectivity (Table 1: entry 10). However, all
the diastereoisomers proved to be inseparable, and in only
one example (+)-12 did the dr improve on further transfor-
mation. Reaction of these N-sulfinyl ꢀ-amino Weinreb amide
ketals with 5 equiv of methylmagnesium bromide gave the
corresponding methyl ketones (+)-10 (92% de), (+)-11 (86%
de), and (+)-12 (92% de) in excellent yields (Scheme 1).
Treatment of amino ketone (+)-10 with 3 N aqueous HCl
in MeOH and THF did not give the homotropinone but
afforded the corresponding piperideine ketone (S)-(-)-13 in
excellent yield (Scheme 2). As we observed in the formation
of tropinones from pyrrolidine ketones (Figure 2), it was
necessary to first generate a reactive acyliminium ion species
to effect the Mannich cyclization.9 However, treatment of
(-)-13 with (Boc)2O/DMAP resulted in no reaction and the
recovery of starting material. To generate a more reactive
Scheme 1
.
Synthesis of ꢀ-Amino Ketals and ꢀ-Amino Ketone
Ketals
(8) (-)- and (+)-Adaline: (a) Ref 7b. (b) Coombs, T. C.; Zhang, Y.;
Garnier-Amblard, E. C.; Liebeskind, L. S. J. Am. Chem. Soc. 2009, 131,
876. (c) Itoh, T.; Yamazaki, N.; Kibayashi, C. Org. Lett. 2002, 4, 2469. (d)
Hill, R. K.; Renbaum, L. A. Tetrahedron 1982, 38, 1959.
(9) Davis, F. A.; Theddu, N.; Gaspari, P. M. Org. Lett. 2009, 11, 1647.
(10) For a review on S-N chemistry, which includes sulfinimines and
sulfinimine-derived chiral building blocks, see: Davis, F. A. J. Org. Chem.
2006, 71, 8993.
(11) For recent reviews on sulfinimine-derived chiral building blocks,
see: (a) Davis, F. A.; Chao, B.; Andemichael, Y. W.; Mohanty, P. K.; Fang,
T.; Burns, D. M.; Rao, A.; Szewczyk, J. M. Heteroat. Chem. 2002, 13,
486. (b) Davis, F. A.; Yang, B.; Deng, J.; Zhang, J. ARKIVOC 2006, 120.
(12) Davis, F. A.; Zhang, H.; Lee, S. H. Org. Lett. 2001, 3, 759.
(13) For the synthesis of (S)-(+)-5, see the Supporting Information
section.
(14) For applications of Weinreb enolates in the synthesis of N-sulfinyl
ꢀ-amino Weinreb amides, see: (a) Davis, F. A.; Nolt, M. B.; Wu, Y.; Prasad,
K. R.; Li, D.; Yang, B.; Bowen, K.; Lee, S. H.; Eardley, J. H. J. Org.
Chem. 2005, 70, 2184. (b) Davis, F. A.; Song, M. Org. Lett. 2007, 9, 2413.
(15) Prochiral enolates, including Weinreb amide enolates, afford the
syn product in addition to sulfinimines. See: (a) Davis, F. A.; Yang, B.
J. Am. Chem. Soc. 2005, 127, 8398. (b) Davis, F. A.; Zhang, Y.; Qiu, H.
Org. Lett. 2007, 9, 833. (c) Ref 11b. (d) Davis, F. A.; Song, M.; Qiu, H.;
Chai, J. Org. Biomol. Chem. 2009, 7, 5067.
be seen from the results summarized in Table 1, the dr’s
were dependent on the counterion and solvent with the
Org. Lett., Vol. 12, No. 4, 2010
849

Scheme 2
.
Generation of Acyliminium Ions
Scheme 3
.
Asymmetric Synthesis of Substituted
Homotropinones
acyliminium ion, (-)-13 was treated with p-nitrobenzoyl
chloride/DMAP. To our surprise, two new compounds, (S)-
(+)-14 and (S)-(-)-15, were isolated resulting from C-
acylation, rather than N-acylation (Scheme 2). C-Acylation
has been reported for the reaction of piperideines with
isocyanates and isothiocyanates.16 Enamino ketone (+)-14
exhibits strong NH absorption at 3325 cm-1 in the IR
spectrum, and both (+)-14 and (-)-15 have exchangeable
protons (D2O). The enolic proton in piperideine (-)-15
1
appears at δ 11.9 ppm in the 400 MHz H NMR and is
similar to that found in a related enolic piperideine.17
Furthermore, in (-)-13 the C-2 methyl group appears as
a doublet at δ 1.86 ppm (CDCl3), whereas in (-)-15 this
group is replaced by a vinylic singlet proton at δ 5.58 ppm.
The13C NMR spectra of these piperideines provide additional
support for the proposed structures. In (+)-14, the C-2 and
C-3 carbons appear at δ 148.4 and at δ 102.2 ppm,
respectively, which is characteristic for enamino ketones.18
The C-2 carbon in (-)-15 (CD2Cl2) is at δ 167.1 ppm in the
100 MHz spectrum and is similar to the value of the C-2
carbon in (-)-13; i.e., δ 168.3 ppm. Reaction of (-)-13 with
p-NO2BzCl-Et3N at 0 °C for 2 h resulted in (S)-(-)-16 and
its hydrolysis product (S)-(-)-17 (Scheme 2). Compound
(-)-16 most likely results from the formation of a very
reactive N-acyliminium ion that eliminates a proton to give
the enamide (Scheme 2).
In their synthesis of (+)-euphococcinine (1), Mechelke
and Meyers used 10 equiv of ammonium acetate in acetic
acid at 75 °C to initiate the Mannich cyclization.4 When
piperideine ketone (-)-13 was subjected to these conditions,
less than 20% of the homotropinone (-)-2 was formed.
However, with 25 equiv of ammonium acetate in 1:1 HOAc:
EtOH (0.01 mmol) for 36 h (-)-euphococcinine (2) was
isolated in 93% yield (Scheme 3). When (-)-2 was resub-
jected to these conditions (NH4OAc:HOAc) for varying
lengths of time, retro-Mannich products were not detected,
and (-)-2 was recovered quantitatively. These results suggest
that the homotropinone is the thermodynamically most stable
product. We speculate that the buffer solution, NH4OAc:HOAc,
generates a moderately reactive piperideine iminium ion while
simultaneously promoting ketone enolization, all under ther-
modynamic conditions. By contrast, p-NO2BzCl-DMAP or
p-NO2BzCl-Et3N generates a very reactive N-acyliminium ion
that reacts kinetically to give C-acylation products or eliminates
a proton to give the enamide (Scheme 2).
(16) (a) Harada, K.; Mizoe, Y.; Furukawa, J.; Yamshita, S. Tetrahedron
1970, 26, 1579. (b) Tohda, Y.; Kawashima, T.; Ariga, M.; Akiyama, R.;
Shudoh, H.; Mori, Y. Bull. Chem. Soc. Jpn. 1984, 57, 2329.
(17) A similar enolic piperideine has been reported in the synthesis of
alkaloid (-)-cassine. See: Herdeis, C.; Kupper, P.; Ple, S. Org. Biomol.
Chem. 2006, 4, 524.
Significantly, when the acyclic N-sulfinyl ꢀ-amino ketone
ketal (+)-10 was subjected to the rearrangement conditions
for 36 h, a 90% yield of (-)-2 was realized. Similar treatment
of (+)-12 gave (-)-adaline (3) in 85% yield (Scheme 3).
(18) (a) Dabrowski, J.; Kamienska-Trela, K.; Kozerski, L. Org. Magn.
Reson. 1974, 6, 499. (b) Tourwe, D.; Binst, G. V.; De Graaf, S. A. G.;
Pandit, U. K. Org. Magn. Reson. 1975, 7, 433.
850
Org. Lett., Vol. 12, No. 4, 2010

This methodology is also adaptable to the synthesis of more
substituted homotropinones where (+)-11 gave 18 as a single
isomer. However, 18 could not be separated from an
unknown impurity, so the reaction mixture was treated with
p-NO2BzCl-Et3N to afford amide (1R,4R,5S)-(-)-19 in 82%
yield for the two-step sequence (Scheme 3). COSY and NOE
experiments confirm the structure of (-)-19 (see Supporting
Information).
In summary, sulfinimine-derived N-sulfinyl ꢀ-amino ke-
tone ketals, on heating with the buffer solution NH4OAc:
HOAc, afforded homotropinones (-)-euphoccocinine (2),
(-)-adaline (3), and substituted homotropinone 18 in excel-
lent yields.
asymmetric syntheses of substituted homotropinones. The
fact that intermediates such as (-)-13 are involved in the
formation of the homotropinones provides additional support
for the hypothesis that piperideine ketones are involved in
the biosynthesis of this class of heterocycles.3
Acknowledgment. We thank Dr. Charles DeBrosse,
Director of Temple NMR facilities, for aid with the COSY
and NOE experiments. This work was supported by a grant
from the National Institutes of General Medicinal Sciences
(GM 57870) and Boehringer Ingelheim Pharmaceuticals, Inc.
Supporting Information Available: Experimental pro-
cedures, characterization and spectroscopic data for all new
compounds are provided. This material is available free of
charge via the Internet at http://pubs.acs.org.
The conversion of these N-sulfinyl ꢀ-amino ketone ketals
directly to the corresponding homotropinones represents a
four-step intramolecular Mannich cyclization cascade reac-
tion and is the most efficient method to date for the
OL902910W
Org. Lett., Vol. 12, No. 4, 2010
851