Asymmetric synthesis of substituted tropinones using the intramolecular mannich cyclization reaction and acyclic N-sulfinyl β-amino ketone ketals

Article abstract of DOI:10.1021/ol9002948

Sulfinimine-derived, enantiopure N-sulfinyl β-amino ketone ketals on hydrolysis give dehydropyrrolidine ketones that on treatment with. (Boc) ₂O /DMAP afford substituted tropinones in good yield.

Full text of DOI:10.1021/ol9002948

ORGANIC
LETTERS
2009
Vol. 11, No. 7
1647-1650
Asymmetric Synthesis of Substituted
Tropinones Using the Intramolecular
Mannich Cyclization Reaction and Acyclic
N-Sulfinyl ꢀ-Amino Ketone Ketals
Franklin A. Davis,* Naresh Theddu, and Paul M. Gaspari
Department of Chemistry, Temple UniVersity, Philadelphia, PennsylVania 19122
fdaVis@temple.edu
Received February 11, 2009
ABSTRACT
Sulfinimine-derived, enantiopure N-sulfinyl ꢀ-amino ketone ketals on hydrolysis give dehydropyrrolidine ketones that on treatment with (Boc)2O/
DMAP afford substituted tropinones in good yield.
The continuing interest in the synthesis and biosynthesis of
the tropane alkaloids, the 8-azabicyclo[3.2.1]octane ring
system, is because of the significant biological properties of
several members of this class of heterocycles including (-)-
cocaine (1) and atropine (2) (Figure 1).1 The impetus for
most of the synthetic studies has been the search for useful
procedures to access the tropane skeleton include cycload-
dition and intramolecular nucleophilic substitution reactions,
Michael addition reactions, iminium ion cyclizations, and
ring-closing metathesis procedures.3 Relatively few of these
methods are asymmetric.3
Rapoport prepared (-)-1 from glutamic acid using an
intramolecular nucleophilic substitution reaction to form the
tropane ring.4 Cha prepared (+)-cocaine (1) by desymmetri-
zation of tropinone using a chiral lithium base and an aldol
reaction to install the axial carbomethoxy group.5 Most asym-
metric syntheses of this ring system employ some type of a
cycloaddition reaction.3,6-10 For example, Mans and Pearson
synthesized (+)-cocaine (1) in 86% ee using a 2-azaallyl-
lithium [3 + 2] cycloaddition reaction to prepare a meso-
(2) For a review of these methods, see: Singh, S. Chem. ReV. 2000,
100, 925.
Figure 1
.
Important tropanes.
(3) For an excellent summary of these reactions, see: (a) Mans, D. M.;
Pearson, W. H. Org. Lett. 2004, 6, 3305. (b) Mans, D. M. Aza-Bridged
Bicyclic Amines From (2-Azaallyl)stannanes and the Total Synthesis of
(+)-Cocaine. Ph.D. Thesis, Univ. Michigan, Ann Arbor, MI, USA, 2004.
(4) Lin, R.; Castells, J.; Rapoport, H. J. Org. Chem. 1998, 63, 4069.
(5) Lee, J. C.; Lee, K.; Cha, J. K. J. Org. Chem. 2000, 65, 4773.
(6) Takahashi, T.; Kitano, K.; Hagi, T.; Nihonmatsu, H.; Koizumi, T.
cocaine-type analogues (antagonists and agonists). Many
syntheses of cocaine analogues employ advanced starting
materials such as tropinone and cocaine itself.2 Other
Chem. Lett. 1989, 597
(7) Takahashi, T.; Fujii, A.; Sugita, J.; Hagi, T.; Kitano, K.; Arai, Y.;
Koizumi, T.; Shiro, M. Tetrahedron: Asymmetry 1991, 2, 1379
(8) Pham, V. C.; Charlton, J. L. J. Org. Chem. 1995, 60, 8051
(9) Rigby, J. H.; Pigge, F. C. J. Org. Chem. 1995, 60, 7392
.
.
(1) For reviews see: (a) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435.
(b) Humphrey, A. J.; O’Hagan, D. Nat. Prod. Rep. 2001, 18, 494–502.
.
.
10.1021/ol9002948 CCC: $40.75
Published on Web 03/11/2009
2009 American Chemical Society

pyrrolidine dialdehyde which was then subjected to an
asymmetric proline-catalyzed intramolecular enol-exo-aldol
reaction.3a Recently, Reddy and Davies described the enan-
tioselective synthesis of substituted tropanes using a rhodium-
catalyzed [4 + 3] cycloaddition reaction of vinyldiazoacetates
with N-Boc pyrroles.10a With few exceptions,10 most syn-
theses are multistep, low overall yielding procedures which
do not provide easy access to ring-substituted examples,
particularly at the bridgehead positions of the tropane
skeleton. We describe here the application of acyclic
N-sulfinyl ꢀ-amino ketone ketals and the intramolecular
Mannich cyclization reaction for the asymmetric synthesis
of substituted tropanones.
isolated yields, respectively. This contrasts with earlier
studies where δ-amino ꢀ-ketoesters were prepared in excel-
lent yield and high de by reaction of sulfinimines with an
excess of the sodium enolate.21
When the N-sulfinyl δ-amino ꢀ-ketoester ketals (SS,S)-
(+)-3 were treated with 3 N HCl/MeOH in THF at rt for
3 h, the tropinone was not formed, but rather the dehydro-
pyrrolidines (S)-(+)-4a and (S)-(-)-4b in 80 and 66% yields,
respectively (Scheme 1). Evidence for the formation of 4,
rather than the isomeric tropinone, is the presence of the
imino carbons at δ 171-179 ppm in 13C NMR in addition
to the keto and ester carbons at δ 200-210 and δ 165 ppm,
respectively. In the 1H NMR spectra, the Me protons in (-)-
4b appear downfield at δ 2 ppm compared to δ 1.0-1.3 ppm
for these protons in the corresponding tropinones (see below).
Surprisingly, when (S)-(+)-4a was hydrogenated (Pd-C) at
100 psi for 8 h, hydroxy dehydropyrrolidine (+)-5 was
formed as a single isomer in 60-70% yield (Scheme 1).22
The acid-catalyzed intramolecular Mannich cyclization
reaction between an N-sulfinyl ꢀ-amino ketone and an
aldehyde is an important method for the asymmetric synthesis
of stereodefined substituted piperidines (Figure 2).11-13 We
employed this protocol in highly efficient asymmetric
Scheme 1
.
Synthesis of N-Sulfinyl δ-Amino ꢀ-Ketoester Ketals
and Their Hydrolysis
Figure 2. Intramolecular Mannich cyclizations.
syntheses of the trisubstituted piperidine, (-)-nupharamine,14
and indolizidine alkaloids (-)-209B15 and (-)-223A.16
Enantiopure N-sulfinyl ꢀ-amino ketones are prepared by
reaction of Grignard reagents with N-sulfinyl ꢀ-amino
Weinreb amides.17,18 We reasoned that substituted tropinones
would result if the Mannich cyclization were to occur at a
pyrrolidine ring iminium ion that is also attached to the
ketone unit. Hydrolysis of an acyclic N-sulfinyl ꢀ-amino
ketone ketal could generate such a dehydropyrrolidine
species, which under acidic conditions would form an
iminium ion that could cyclize to the tropinone (Figure 2).19
Treatment of masked oxo sulfinimines (S)-(+)-1a (R )
Ph) and (S)-(+)-1b (R ) Me) with an excess of the sodium
enolate of methyl acetate gave mixtures of the ꢀ-amino ester
2 and the desired N-sulfinyl δ-amino ꢀ-ketoester ketals (SS,S)-
(+)-3.20 In these cases, the solution was recooled to -78
°C, and an additional 5 equiv of the enolate was added,
affording (SS,S)-(+)-3a and (SS,S)-(+)-3b in 69% and 80%
Evidence for the reduction of a keto group rather than the
imine is the presence of the imino carbon at δ 171 ppm and
the absence of the keto carbon at δ 201 ppm.
Reaction of imine (S)-(+)-4a with (Boc)2O and a
catalytic amount of DMAP resulted in formation of enol
carbonate (S)-(+)-6 in 70% yield. The vinylic proton at
1
δ 5.9 ppm in the H NMR and the dehydropyrrolidine
carbon at δ 175 ppm in the 13C NMR support this
structural assignment. NOE studies are consistent with the
E-geometry for (+)-6. Importantly, when (S)-(-)-4b was
(10) (a) Reddy, R. P.; Davies, H. M. L. J. Am. Chem. Soc. 2007, 129,
10312. (b) Antoline, J. E.; Hsung, R. P.; Huang, J.; Song, Z.; Li, G. Org.
Lett. 2007, 9, 1275.
(11) Davis, F. A. J. Org. Chem. 2006, 71, 8993.
1648
Org. Lett., Vol. 11, No. 7, 2009

treated with (Boc)2O/cat.-DMAP, the Mannich cyclization
resulted in tropinone (+)-7 in excellent yield (Scheme 2).
However, (+)-7 was formed as a 70:30 inseparable
Scheme 3. Synthesis of ꢀ-Amino Ketone Ketals
Scheme 2. Mannich Cyclization of Dehydropyrrolidines
mixture of tropinones that are epimeric at C-2. The major
epimer is assigned as having the C-2 carbomethoxy group
in the axial position in analogy to the related tropinone
reported by Thomas et al. in their racemic approaches to
the alkaloid stemofoline.19 It is likely that the imino phenyl
group in (S)-(+)-4a sterically inhibits the Mannich cy-
clization.
Scheme 4. Mannich Cyclization of Dehydropyrrolidine Ketones
To further define the scope of the Mannich cyclization of
dehydropyrrolidine ketone, the keto moiety was next varied.
Masked oxo Weinreb amides (SS,S)-(+)-8 and (SS,2R,3S)-
(+)-9 were prepared in good yield and high dr by reaction
of (S)-(+)-1b with the potassium enolate of N-methoxy-N-
methylacetamide17a and the lithium enolate of N-methoxy-
N-methylpropylamide,17b respectively (Scheme 3).
TreatmentoftheWeinrebamides(SS,S)-(+)-8and(SS,2R,3S)-
(+)-9 with benzylmagnesium chloride gave ketones (SS,S)-
(+)-10 and (SS,3R,3S)-(+)-12 in excellent yield, while
ethylmagnesium chloride with (SS,2S,3S)-(+)-8 gave ketone
(SS,3S)-(+)-11 in good yield (Scheme 3).
As expected, reacting ketones 10-12 with 3 N HCl-MeOH
in THF gave the corresponding dehydropyrrolidine ketones
13-15 in good yield (Scheme 4). When (S)-(+)-13 was
treated with (Boc)2O/cat.-DMAP, the enol carbonate (S)-(+)-
16 resulted in 77% yield (Scheme 4). There was no reaction
of (S)-(+)-14 with (Boc)2O/cat.-DMAP. However, reaction
with p-nitrobenzoyl chloride (p-NO2-Bz-Cl) and 1.1 equiv
of DMAP, to generate a more electrophilic acyliminium ion
species, failed to give the tropinone, but gave the isomeric
enamide (S)-(+)-17 in 70% yield. Evidence for the
enamide structure comes from HMQC experiments which
show the enamide proton at 4.97 ppm and the carbon
attached to it at 112.8 ppm. The quaternary C-N carbon
is coupled to the vinyl hydrogen. The pyrrolidine Me and
C-2 protons are broadened due to the amide rotamers.
Under acidic conditions, the enamide hydrolysis product,
(R)-(-)-18, was also formed. This product is apparently
formed in the workup because it was not detected in the
crude reaction mixture.
Org. Lett., Vol. 11, No. 7, 2009
1649

Remarkably, (3R,4S)-(+)-15 gave tropinone (+)-19 as a
single isomer in 60% yield with (Boc)2O/cat.-DMAP, and
with p-nitrobenzoyl chloride/DMAP a 95% yield of tropinone
(-)-20 was formed. NOE studies suggest a syn relationship
between C-2 and C-4 protons where the Ph and Me
substituents occupy the equatorial positions in (+)-19 and
(-)-20. These results were confirmed by an X-ray crystal
structure of (-)-20 (see Supporting Information).
In (S)-(+)-13, the bulky phenyl group may inhibit the
Mannich cyclization favoring enol carbonate formation. In
(S)-(+)-14, enamide formation is apparently much faster than
enolizaton due to the greater acidity of the intermediate
pyrrolidine C-2 acyliminium ion proton (Scheme 4). How-
ever, the fact that (3R,4S)-(+)-15 gave tropinone (+)-19 in
good yield suggests that other factors may be of importance
in determining whether the intermediate acyliminium ion
forms the enol carbonate, deprotonates, or undergoes the
Mannich cyclization. One thought is that the R-Me group in
(+)-15 somehow inhibits enol carbonate formation favoring
the Mannich cyclization.
In summary, sulfinimine-derived N-sulfinyl ꢀ-amino ke-
tone ketals and the intramolecular Mannich cyclization
reaction represent a valuable new method for the asymmetric
synthesis of substituted tropinones including those having
substituents at the bridgehead positions.
Acknowledgment. We thank Dr. Charles DeBrosse,
Director of Temple NMR facilities, for aid with the NOE
experiments. This work was supported by a grant from the
National Institutes of General Medicinal Sciences (GM
57870) and Boehringer Ingelheim Pharmaceuticals, Inc.
(12) For related studies using aldehydes and ꢀ-aminoketals, see: (a)
Abrunhosa-Thomas, I.; Roy, O.; Barra, M.; Besset, T.; Chalard, P.; Troin,
Y. Synlett 2007, 1613. (b) Al-Sarabi, A. E.; Bariau, A.; Gabant, M.; Wypych,
J.-C.; Chalard, P.; Troin, Y. ARKIVOC 2007, 119. (c) Bariau, A.; Canet,
J.-L.; Chalard, P.; Troin, Y. Tetrahedron: Asymmetry 2005, 16, 3650.
(13) For reviews on the Mannich reaction, see: (a) Speckamp, W. N.;
Hiemstra, H. Tetrahedron 1985, 41, 4367. (b) Arend, M.; Westermann, B.;
Risch, N. Angew. Chem., Int. Ed. 1998, 37, 1044.
Supporting Information Available: Full experimental
and spectroscopic data for all new compounds are provided.
X-ray data, ORTEP, and CIF for compound (S)-(-)-20 are
provided. This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) Davis, F. A.; Santhanaraman, M. J. Org. Chem. 2006, 71, 4222.
(15) Davis, F. A.; Yang, B. Org. Lett. 2003, 5, 5011.
OL9002948
(16) Davis, F. A.; Yang, B. J. Am. Chem. Soc. 2005, 127, 8398.
(17) (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.
(20) For applications of masked oxo sulfinimines in asymmetric
synthesis, see: (a) Davis, F. A.; Zhang, H.; Lee, S. H. Org. Lett. 2001, 3,
759. (b) Davis, F. A.; Lee, S. H.; Xu, H. J. Org. Chem. 2004, 69, 3774. (c)
Ref 18.
(21) (a) Davis, F. A.; Chao, B.; Fang, T.; Szewcsyk, J. M. Org. Lett.
2000, 2, 1041. (b) Davis, F. A.; Chao, B.; Rao, A. Org. Lett. 2001, 3, 3169.
(c) Davis, F. A.; Fang, T.; Chao, B.; Burns, D. M. Synthesis 2000, 2106.
(22) For leading references to the catalyytic hydrogenation of ꢀ-ke-
toesters, see: Thomassigny, C.; Greck, C. Tetrahedron: Asymmetry 2004,
15, 199.
(18) Davis, F. A.; Gaspari, P. M.; Nolt, B.; Xu, P. J. Org. Chem. 2008,
73, 9619.
(19) In racemic approaches to the alkaloid stemofoline, Thomas et al.
used a similar approach and observed the rearrangement of a depyrrolidine
to a tropinone. Baylis, A. M.; Davies, M. P. H.; Thomas, E. J. Org. Biomol.
Chem. 2007, 5, 3139.
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