Asymmetric total synthesis of (S)-(+)-cocaine and the first synthesis of cocaine C-1 analogs from N -sulfinyl β-amino ester ketals

Article abstract of DOI:10.1021/ol1017118

Sulfinimine-derived α,β-unsaturated pyrrolidine nitrones, on heating with Al(O-t-Bu)₃, undergo a highly stereoselective intramolecular [3 + 2] cycloaddition to give tricyclic isoxazolidines, which are transformed in three-steps to give C-1 substituted cocaine analogs.

Full text of DOI:10.1021/ol1017118

ORGANIC
LETTERS
2010
Vol. 12, No. 18
4118-4121
Asymmetric Total Synthesis of
(S)-(+)-Cocaine and the First Synthesis
of Cocaine C-1 Analogs from N-Sulfinyl
ꢀ-Amino Ester Ketals
Franklin A. Davis,* Naresh Theddu, and Ram Edupuganti
Department of Chemistry, Temple UniVersity, Philadelphia, PennsylVania 19122
fdaVis@temple.edu
Received July 22, 2010
ABSTRACT
Sulfinimine-derived r,ꢀ-unsaturated pyrrolidine nitrones, on heating with Al(O-t-Bu)3, undergo a highly stereoselective intramolecular [3 + 2]
cycloaddition to give tricyclic isoxazolidines, which are transformed in three-steps to give C-1 substituted cocaine analogs.
The synthesis of the tropane alkaloid (R)-(-)-cocaine (1)
and its analogs has been a subject of significant focus for
nearly a century (Figure 1).1 In the past, the reasons for this
interest were the intellectual challenge of accessing the
tropane skeleton and the difficulty of introducing substituents
into the ring stereoselectively. More recently the challenge
has been the search for therapeutically useful antagonists and
partial agonists for the treatment of cocaine abuse, a major
problem in the United States and of worldwide concern.2
There are eight stereoisomers of cocaine, but only the
R-isomer (-)-1 is addictive.2,3 The enantiomer, S-isomer
(+)-2, is 155 less potent than (-)-1 and is rapidly metabo-
lized.4
Figure 1. Cocaine and its enantiomer.
between the C-2 and C-3 substituents where the C-2
carbomethoxy group occupies the thermodyamically unfa-
vorable axial position. For this reason, most nonracemic
cocaine analogs are prepared from natural cocaine (R)-(-)-
1.3 While many analogs of cocaine have been prepared using
this approach and have provided useful information on the
cocaine-binding site, the types of substituents that can be
introduced are severely limited, that is, bridgehead or C-1
substituents. To date, no therapeutically useful cocaine
derivatives have been reported.2
The major difficulty in the asymmetric synthesis of cocaine
and cocaine analogs is the aforementioned problem of
introducing substituents into the tropane skeleton. Specifi-
cally, this relates to the necessity for a cis relationship
(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. (c)
Hemscheidt, T. Top. Curr. Chem. 2000, 209, 175.
(2) For a review of these methods, see: Singh, S. Chem. ReV. 2000,
100, 925.
(3) Carroll, F. I.; Lewin, A. H.; Abraham, P.; Parham, K.; Boja, J. W.;
There are few asymmetric syntheses of cocaine and only
two total asymmetric syntheses5a,6 that do not rely on
resolution to produce enantiomerically pure materials.5 Mans
Kuhar, M. J. J. Med. Chem. 1991, 34, 883
.
(4) Gatley, S. J.; MacGregor, R. R.; Fowler, J. S.; Wolf, A. P.; Dewey,
S. L.; Schlyer, J. J. J. Neurochem. 1990, 54, 720.
10.1021/ol1017118  2010 American Chemical Society
Published on Web 08/23/2010

and Pearson synthesized (S)-(+)-cocaine (2) in 86% ee using
a 2-azaallyllithium [3 + 2] cycloaddition reaction to prepare
a meso-pyrrolidine dialdehyde that was subjected to an
asymmetric proline-catalyzed intramolecular enol-exo-aldol
reaction. This required separation of a 1:1 mixture of epimers
at C-2.5a Rapoport prepared (-)-1 from glutamic acid using
an intramolecular nucleophilic substitution reaction to form
the tropane ring.6 They controlled the relative stereochemistry
at C-2 and C-3 in (-)-1 by a [3 + 2] cycloaddition of an in
situ generated nitrile N-oxide to a nonracemic tropene. Cha
prepared (+)-cocaine (2) by desymmetrization of tropinone,
an advanced intermediate, using a chiral lithium base and
an aldol reaction to install the axial carbomethoxy group.7
In the late 1970s, Tufariello and co-workers introduced
perhaps the most innovative method to control the stereo-
chemistry at C-2 and C-3 in their synthesis of (()-cocaine.8
On heating, R,ꢀ-unsaturated isoxazolidine 3 undergoes a
[3 + 2] cycloreversion to give an intermediate nitrone that
cyclizes to tricyclic isoxazolidine 4, which was transformed
into (()-cocaine (Scheme 1). It would be very difficult to
Scheme 2. Dehydropyrrolidine Synthesis
Scheme 1. Tufariello Synthesis
epimerization at the C-N stereocenter. When aldehyde (+)-
7a was subjected to the Roush-Masamune modification of
the Horner-Wadsworth-Emmons olefination reaction (DBU-
LiCl)13 with trimethylphosphonoacetate, R,ꢀ-unsaturated
N-sulfinyl amino ketal (SS,5S)-(+)-8a was isolated as an
inseparable 9:1 E:Z mixture of isomers. The 16 Hz coupling
constant observed for the olefinic protons in (+)-8a is
consistent with the major isomer having the desired E-
geometry.13 It is noteworthy that when LiCl was omitted
from the HWE reaction only the E-isomer of (+)-8a was
obtained in >90% yield (Scheme 2). Similar results were
observed in the preparation of (+)-8b. Hydrolysis of R,ꢀ-
unsaturated N-sulfinyl amino ketals (SS,5S)-(+)-8 with 3 N
HCl gave the corresponding dehydropyrrolidines (S)-(+)-
9a (R ) Me) and (S)-(+)-9b (R ) n-Pr) in excellent yields.
With the dehydropyrrolidines (+)-9 in hand the idea was
to oxidize them to the corresponding nitrones with the
expectation that on heating they would undergo an intramo-
lecular [3 + 2] cycloaddition to give tricyclic isoxazolidines.
While most oxidations of imines lead to oxaziridines,14 Goti
and co-workers recently described the catalytic oxidation of
imines to nitrones with urea hydrogen peroxide (UHP)
catalyzed by methyltrioxorhenium (MTO).15 Oxidation of
(+)-9 with 3.3 equiv of UHP and cat. MTO in anhydrous
MeOH for 15 h gave nitrones 10, which were used crude in
the next step because attempted purification resulted in
install functionality at other positions in the cocaine skeleton
with this synthesis, which is also true of the asymmetric
routes to this molecule. Recently, we described a new method
for the asymmetric syntheses of substituted tropinones9 and
homotropinones10 from N-sulfinyl ꢀ-amino ketone ketals via
an intramolecular Mannich cyclization reaction.11 We report
here application of N-sulfinyl ꢀ-amino ester ketals for the
asymmetric synthesis of (S)-(+)-cocaine (2) and the first
syntheses of cocaine analogs to have a C-1 bridgehead
substituent.
Our synthesis of C-1 cocaine analogs begins with masked
oxo-sulfinimines (S)-(+)-5.12 On treatment with an excess
of the sodium enolate of methyl acetate in Et2O at -78 °C,
(+)-5 afforded the corresponding N-sulfinyl ꢀ-amino ester
ketals (SS,3S)-(+)-6 as single diastereoisomers (Scheme 2).
Reduction of (+)-6 with DIBAL-H in toluene at -78 °C
gave aldehydes (+)-(SS,3S)-(+)-7 in good yield without
(5) For leading references and an excellent summary of methods used
in the synthesis and asymmetric synthesis of cocaine, 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, University of Michigan, Ann Arbor, MI, 2004.
(6) Lin, R.; Castells, J.; Rapoport, H. J. Org. Chem. 1998, 63, 4069.
(7) Lee, J. C.; Lee, K.; Cha, J. K. J. Org. Chem. 2000, 65, 4773.
(8) Tufariello, J. J.; Mullen, G. B.; Tegeler, J. J.; Trybulski, E. J.; Wong,
S. C.; Ali, S. A. J. Am. Chem. Soc. 1979, 101, 2435.
(12) 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)
Davis, F. A.; Gaspari, P. M.; Nolt, B.; Xu, P. J. Org. Chem. 2008, 73,
9619. (d) Reference 9. (e) Reference 10.
(13) Blanchette, M. A.; Choy, W.; Davis, J. T.; Esssenfield, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25, 2183.
(14) Davis, F. A.; Chen, B.-C.; Zhou, P. Oxaziridines and Oxazirines.
In ComprehensiVe Heterocyclic Chemistry III, Katritzky, A. R., Ramsden,
C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.; Elsevier: Oxford, 2008;
Vol. 1, p 559.
(9) Davis, F. A.; Theddu, N.; Gaspari, P. A. Org. Lett. 2009, 11, 1647.
(10) Davis, F. A.; Edupuganti, R. Org. Lett. 2010, 12, 848.
(11) For leading references to the chemistry of N-sulfinyl imines see:
Davis, F. A. J. Org. Chem. 2006, 71, 8993.
(15) Soldaini, G.; Cardona, F.; Goti, A. Org. Lett. 2007, 9, 473.
Org. Lett., Vol. 12, No. 18, 2010
4119

decomposition (Scheme 3).16 Refluxing 10a (R ) Me) in
toluene for 48 h afforded tricyclic isoxazolidine (1S,2R,3R,6S)-
14 in 90-98% yield (Scheme 4). Hydrogenolysis (Pd-C/
H2) cleaved the N-O bond affording (-)-15 in excellent
Scheme 4. Cocaine C-1 Substituted Analog Synthesis
Scheme 3. Isoxazolidine Synthesis
(-)-11a in 45-50% yield. The structure of (-)-11a is
supported by characteristic proton resonances at δ 4.93 ppm
for the C-1 (doublet) and at δ 2.44 ppm C-2 (singlet) in the
1H NMR spectra.8 Nitrone 10b (R ) n-Pr) did not give the
tricyclic isoxazolidines on heating but amide (S)-(+)-12 in
40% yield as a single isomer (Scheme 3). The olefinic
protons in (+)-12 are present at δ 6.96 and δ 5.90 ppm in
yield, which was transformed into the C-1 cocaine analogs
(-)-16a (R ) Me) and (-)-16b (R ) n-Pr) with benzoyl
chloride and pyridine in 94 and 92% yields, respectively
(Scheme 4).19
(S)-(+)-Cocaine (2) was prepared from masked oxo
sulfinimine (RS)-(-)-17 (Scheme 5). Sulfinimine (RS)-(-)-
1
the H NMR and in the 13C NMR the amide CdO carbon
appears at δ 179.5 ppm. On heating, it is known that nitrones
rearrange to oxaziridines, and oxaziridines rearrange to
amides.14 However, heating oxaziridine 13 under the reaction
conditions resulted in no reaction. When 13 was heated at
110 °C for 96 h in the presence of a catalytic amount of
peroxorhenium complex amide (S)-(+)-12 was obtained in
51% yield.17 Oxaziridine 13 was prepared in 77% yield, as
a 2.5:1 mixture of isomers, by m-CPBA oxidation of (S)-
(+)-9b. Intramolecular [3 + 2] cycloaddition of the nitrone
to form the isoxazolidines apparently competes with rear-
rangement to the oxaziridine. The n-propyl group in 10b may
sterically inhibit the cycloaddition reaction.
Scheme 5. Synthesis of (S)-(+)-Cocaine (2)
Lewis acids catalyze 1,3-dipolar cycloadditions by activa-
tion of the R,ꢀ-unsaturated carbonyl functionality.18 Because
the Lewis acid can also coordinate to the nitrone, it was
thought that a bulky Lewis acid, such as aluminum t-butoxide
[(Al(O-t-Bu)3], might preferentially activate the R,ꢀ-unsatur-
ated ester group in 10. Heating 10a (R ) Me) in toluene
with 0.5 equiv of Al(O-t-Bu)3 for 96 h improved the yield
of (-)-11a from 45-50% to >70% yield (Scheme 4).
Significantly, under similar conditions, tricyclic isoxazo-
lidines (-)-11b (R ) n-Pr) was obtained in 65% and amide
(+)-12 was not detected.
Heating (-)-11 with 10 equiv of methylmethanesulfonate
(MeSO3Me) in benzene afforded methanesulfonate salts (-)-
(16) The nitrone is assumed to be formed quantitatively based on TLC
and 13C NMR.
4120
Org. Lett., Vol. 12, No. 18, 2010

17 was transformed, as before (Scheme 2), to dehydropyrro-
lidine imine (-)-18 in 55% yield for the four steps. Oxidation
and heating afforded the tricyclic isoxazolidine intermediate,
which, because of its volatility, was transformed into the
methanesulfonate salt (-)-19 with MeSO3Me. Hydrogenolyses
(Pd-C/H2) gave (-)-20 which was treated in crude form with
benzoyl chloride to give (S)-(+)-cocaine (2) in 9 steps (8
operations) in 25% overall yield from sulfinimine (-)-17. This
represents the most efficient enantioselective route to cocaine
from acyclic starting materials.
(S)-(+)-cocaine (2) were prepared in 9 steps from masked
oxo sulfinimines. The key step in this reaction is the highly
stereoselective intramolecular [3 + 2] cycloaddition of a
nitrone to R,ꢀ-unsaturated esters to give tricyclic isox-
azolidines which establishes the cis arrangement of
substituents at the C-2 and C-3 positions in the tropane
skeleton.
Acknowledgment. We thank Narendra V. Gaddiraju
Temple University for preliminary studies on the nitrone
rearrangement. This research was supported in part by the
National Institutes of General Medicinal Sciences (GM
57870).
In conclusion, the first enantiopure C-1 analogs of
cocaine, (+)-16a (R ) Me) and (+)-16b (R ) n-Pr), and
(17) Oxaziridines in the presence of radicals rearrange to amides. For
leading references, see: Black, D. StC.; Edwards, G. L.; Lannman, S. M.
Synthesis 2006, 1981.
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.
(18) For a review and leading references to the use of Lewis acid in
nitrone 1,3-dipolar cycloadditions see: Gothelf, K. V.; Jorgensen, K. A.
Chem. Commun. 2000, 1449.
(19) Lewin, A. H.; Naseree, T.; Carroll, F. I. J. Heterocyclic Chem. 1987,
24, 19.
OL1017118
Org. Lett., Vol. 12, No. 18, 2010
4121