Total synthesis of (+)-cocaine via desymmetrization of a meso-dialdehyde

Article abstract of DOI:10.1021/ol048777a

(Chemical Equation Presented) The total synthesis of (+)-cocaine is described. An extension of the recently reported proline catalyzed intramolecular enol-exo-aldol reaction to a meso-dialdehyde provided the tropane ring skeleton directly with good enanti

Full text of DOI:10.1021/ol048777a

ORGANIC
LETTERS
2004
Vol. 6, No. 19
3305-3308
Total Synthesis of (+)-Cocaine via
Desymmetrization of a meso-Dialdehyde
,†
Douglas M. Mans and William H. Pearson*
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109-1055
wpearson@berryassoc.com
Received June 27, 2004
ABSTRACT
The total synthesis of (+)-cocaine is described. An extension of the recently reported proline catalyzed intramolecular enol−exo-aldol reaction
to a meso-dialdehyde provided the tropane ring skeleton directly with good enantiomeric excess. The meso-dialdehyde was prepared using
a 2-azaallyllithium [3 + 2] cycloaddition to generate a cis-2,5-disubstituted pyrrolidine. Overall, the synthesis proceeded in 6.5% yield and 86%
ee over 14 linear steps starting from commercially available 3-benzyloxy-1-propanol.
There have been numerous reports of the synthesis of cocaine
in the literature. A common approach has been to use rather
advanced starting materials such as tropinone and anhydro-
ecgonine (a cocaine degradation product).1 A few examples
of total syntheses have been reported, including the classic
biomimetic approach by Wilsta¨tter,2 Tufariello’s consecutive
nitrone cycloaddition approach,3 Rapoport’s enantiospecific
synthesis from glutamic acid,4 and Cha’s asymmetric syn-
thesis via enantioselective deprotonation of tropinone.5 In
addition, considerable work has been done on the synthesis
of cocaine analogues.6 To this end, most efforts have relied
upon derivatization of natural cocaine and/or resolution/
separation of racemic or diastereomeric mixtures. Numerous
approaches involving cycloadditions to access the tropane
ring skeleton have been developed including higher order
cycloaddition reactions,7 [4 + 3] oxyallyl cation cycloaddi-
tions,8 and 1,3-dipolar cycloadditions.3,9 In addition, intra-
molecular nucleophilic substitution reactions,10 intramolecular
Michael addition reactions,1b,11 rhodium carbenoid reac-
tions,12 intramolecular 6-endo-trig radical cyclizations,13
(7) Rigby, J. H.; Pigge, F. C. Synlett 1996, 631.
(8) (a) Hayakawa, Y.; Baba, Y.; Makino, S.; Noyori, R. J. Am. Chem.
Soc. 1978, 100, 1786. (b) Mann, J.; de Almeida Barbosa, L.-C. J. Chem.
Soc., Perkin Trans. 1 1992, 787. (c) Cramer, N.; Laschat, S.; Baro, A.;
Frey, W. Synlett 2003, 2175. (d) Paparin, J.-L.; Crevisy, C.; Toupet, L.;
Gree, R. Eur. J. Org. Chem. 2000, 3909.
(9) (a) Iida, H.; Watanabe, Y.; Kibayashi, C. J. Org. Chem. 1985, 50,
1818. (b) Takahashi, T.; Fuji, A.; Sugita, J.; Hagi, T.; Kitano, K.; Arai, Y.;
Koizumi, T. Tetrahedron: Asymmetry 1991, 2, 1379. (c) Jung, M.; Longmei,
Z.; Tangsheng, P.; Huiyan, Z.; Yan, L. J. Org. Chem. 1992, 57, 3528. (d)
Charlton, J. L.; Pham, V. C. J. Org. Chem. 1995, 60, 8051. (e) Lomenzo,
S. A.; Enmon, J. L.; Troyer, M. C.; Trudell, M. L. Synth. Commun. 1995,
25, 3681. (f) Rumbo, A.; Mourino, A.; Castedo, L.; Mascarenas, J. L. J.
Org. Chem. 1996, 61, 6114. (g) Kozikowski, A. P.; Araldi, G. L.; Ball, R.
G. J. Org. Chem. 1997, 62, 503. (h) Smith, M. P.; George, C.; Kozikowski,
A. P. Tetrahedron Lett. 1998, 39, 197.
(10) (a) Iida, H.; Watanabe, Y.; Kibayashi, C. Tetrahedron Lett. 1984,
25, 5091. (b) Schink, H. E.; Pettersson, H.; Backvall, J.-E. J. Org. Chem.
1991, 56, 2769. (c) Boyer, F.-D.; Lallemand, J.-Y. Tetrahedron 1994, 50,
10443. (d) Campbell, J. A.; Rapoport, H. J. Org. Chem. 1996, 61, 6313.
(e) Justice, D. E.; Malpass, J. R. Tetrahedron 1996, 52, 11963. (f) Justice,
D. A.; Malpass, J. R. Tetrahedron 1996, 52, 11977. (g) Albertini, E.; Barco,
A.; Benetti, S.; De Risi, C.; Pollini, G. P.; Zanirato, V. Tetrahedron 1997,
53, 17177. (h) Hart, B. P.; Rapoport, H. J. Org. Chem. 1999, 64, 2050. (i)
Boyer, F.-D.; Hanna, I. Tetrahedron Lett. 2001, 42, 1275.
† Current Address: Berry and Associates, Inc., 2434 Bishop Circle East,
Dexter, MI 48130.
(1) (a) Lewin, A. H.; Naseree, T.; Carroll, F. I. J. Heterocycl. Chem.
1987, 24, 19. (b) Majewski, M.; Lazny, R. Synlett 1996, 785. (c) Majewski,
M.; Lazny, R.; Ulaczyk, A. Can. J. Chem. 1997, 75, 754. (d) Katoh, T.;
Kakiya, K.; Nakai, T.; Nakamura, S.; Nishide, K.; Node, M. Tetrahedron:
Asymmetry 2002, 13, 2351.
(2) Wilsta¨tter, R.; Wolfes, O.; Mader, H. Anal. Chem. 1923, 484, 111.
(3) 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.
(4) Lin, R.; Castells, J.; Rapoport, H. J. Org. Chem. 1998, 63, 4069.
(5) Cha, J. K.; Lee, J. C.; Lee, K. J. Org. Chem. 2000, 65, 4773.
(6) For a leading reference on cocaine analogues, see: (a) Singh, S. Chem.
ReV. 2000, 100, 925. (b) Carroll, F. I.; Lewin, A. H.; Kuhar, M. J. Med.
Chem. Res. 1998, 8, 59. (c) Carroll, F. I.; Lewin, A. H.; Boja, J. W.; Kuhar,
M. J. J. Med. Chem. 1992, 35, 969.
(11) Parker, W.; Raphael, R. A.; Wilkinson, D. I. J. Chem. Soc. 1959,
2433.
10.1021/ol048777a CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/19/2004

cyclizations onto iminium ions,14 and Grubb’s ring-closing
metathesis reactions15 have also been explored as methods
to generate the tropane ring skeleton. However, asymmetric
methods are still rare, suffer from lengthy routes, and lack
generality.
We felt that application of our 2-azaallyllithium cyclo-
addition methodology in conjunction with an intramolecular
enol-exo-aldol desymmetrization reaction would allow a
concise synthesis of a tropane skeleton with appropriate
functionalization for elaboration into cocaine. Beyond the
well-known difficulties in setting and retaining the delicate
stereochemistry found in cocaine, a second obstacle that
needed to be overcome was the efficient production of cis-
2,5-disubstituted pyrrolidine 3 (Scheme 1). Unlike the
with rather poor cis/trans selectivities. However our [3 +
2] cycloaddition methodology allows access to either the cis-
or trans-2,5-disubstituted pyrrolidines. Previous reports have
demonstrated that using (2-azaallyl)stannanes in azomethine
ylide [3 + 2] cycloadditions leads predominantly to the trans-
2,5-disubstituted pyrrolidines, while 2-azaallyllithium [3 +
2] cycloadditions provide the cis-2,5-disubstituted pyrro-
lidines as the sole products.20 With an efficient and highly
selective route to the desired cis-2,5-disubstituted pyrrolidine
3, the synthesis of cocaine was pursued and is reported
herein.
Our retrosynthetic plan hinged on the formation of
â-hydroxy aldehyde 2 and meso-dialdehyde 3 (Scheme 1).
â-Hydroxy aldehyde 2 was envisioned to arise from an
intramolecular aldol reaction of the meso-dialdehyde 3. A
2-azaallyllithium [3 + 2] cycloaddition between the (2-
azaallyl)stannane 4 and phenyl vinyl sulfide 5 would provide
the requisite cis-2,5-disubstituted pyrrolidine 3 after depro-
tection and oxidation. Both “sides” of the (2-azaallyl)-
stannane 4 would arise from the same suitably protected
aldehyde using methodology previously reported.21
Thus, 3-benzyloxypropionaldehyde 6 (Scheme 2),22 pre-
pared from commercially available 3-benzyloxy-1-propanol,
Scheme 1. Retrosynthesis of Cocaine
Scheme 2. Total Synthesis of (+)-Cocaine
homologous cis-2,6-disubstituted piperidines,16 methods to
access cis-2,5-disubstituted pyrrolidines are rather limited.17
Many of these methods involve nucleophilic addition to a
cyclic iminium species18 or reduction of 1-pyrrolines,19 but
(12) (a) Davies, H. M. L.; Huby, N. J. S. Tetrahedron Lett. 1992, 33,
6935. (b) Davies, H. M. L.; Matasi, J. J.; Hodges, L. M.; Huby, N. J. S.;
Thornley, C.; Kong, N.; Houser, J. H. J. Org. Chem. 1997, 62, 1095. (c)
Davies, H. M. L.; Hodges, L. M. J. Org. Chem. 2002, 67, 5683.
(13) (a) Sato, T.; Mori, T.; Sugiyama, T.; Ishibashi, H.; Ikeda, M.
Heterocycles 1994, 37, 245. (b) Hoepping, A.; Johnson, K. M.; George,
C.; Flippen-Anderson, J. L.; Kozikowski, A. P. J. Med. Chem. 2000, 43,
2064. (c) Hoepping, A.; George, C.; Flippen-Anderson, J. L.; Kozikowski,
A. P. Tetrahedron Lett. 2000, 41, 7427.
(14) (a) Peterson, J. S.; Fels, G.; Rapoport, H. J. Am. Chem. Soc. 1984,
106, 4539. (b) Hernandez, A.; Rapoport, H. J. Org. Chem. 1994, 59, 1058.
(c) Hernandez, A.; Marcos, M.; Rapoport, H. J. Org. Chem. 1995, 60, 2683.
(d) Esch, P. M.; Hiemstra, H.; Klaver, W. J.; Speckamp, W. N. Heterocycles
1987, 26, 75. (e) Mikami, K.; Ohmura, H. Chem. Commun. 2002, 2626. (f)
Cramer, N.; Laschat, S.; Baro, A. Synlett 2003, 2178. (g) Albrecht, U.;
Armbrust, H.; Langer, P. Synlett 2004, 143.
was treated with tributylstannyllithium to give an intermedi-
ate R-hydroxy stannane in 50% yield. A Mitsunobu reaction
(15) (a) Neipp, C. E.; Martin, S. F. Tetrahedron Lett. 2002, 43, 1779.
(b) Neipp, C. E.; Martin, S. F. J. Org. Chem. 2003, 68, 8867. (c) Brenneman,
J. B.; Martin, S. F. Org. Lett. 2004, 6, 1329. (d) Aggarwal, V. K.; Astle, C.
J.; Rogers-Evans, M. Org. Lett. 2004, 6(9), 1469..
(16) See ref 15b and references therein.
(17) For a leading reference, see: Pichon, M.; Figadere, B. Tetra-
hedron: Asymmetry 1996, 7, 927.
(18) For examples of nucleophilic addition to N-acyliminium ions, see:
(a) Asada, S.; Kato, M.; Asai, K.; Ineyama, T.; Nishi, S.; Izawa, K.; Shono,
T. J. Chem. Soc., Chem. Commun. 1989, 486. (b) Chiesa, M. V.; Mazoni,
L.; Scolastico, C. Synlett 1996, 441. (c) Speckamp, W. N.; Moolenaar, M.
J. Tetrahedron 2000, 56, 3817. (d) Harris, P. W. R.; Brimble, M. A.;
Gluckman, P. D. Org. Lett. 2003, 5, 1847.
3306
Org. Lett., Vol. 6, No. 19, 2004

with phthalimide then provided the R-stannyl phthalimide 7
in 98% isolated yield. In general, the tin addition/Mitsunobu
reaction can be carried out without purification of the
intermediate R-hydroxy stannane. However, in this instance,
the overall yield for the two steps was improved by purifying
the intermediate R-hydroxy stannane prior to the Mitsunobu
reaction.23
Table 1. Diastereoselectivity Studies for the Aldol Reaction
Phthalimide 7 was then deprotected by hydrazinolysis to
give the R-amino stannane 8 in 96% yield (Scheme 2).
Condensation of 1 equiv of 3-benzyloxypropionaldehyde 6
with 8 generated (2-azaallyl)stannane 9 in 95% yield after
simple filtration. Gratifyingly, treatment of imine 9 with
n-butyllithium and phenyl vinyl sulfide led to the [3 + 2]
cycloaddition and formation of cis-pyrrolidine 10 in 97%
yield as a 1:1 mixture of C(3)-isomers. Following protection
of the secondary amine as the Boc carbamate, dissolving
metal reduction removed both benzyl ethers and the phen-
ylthio group in excellent yield to give a meso-diol, which
was oxidized to dialdehyde 12. Oxidation to 12 proved to
be less straightforward than anticipated. Treatment of the
diol with Dess-Martin periodinane led only to decomposi-
tion, whereas attempted Swern oxidation returned a complex
mixture of products. Oxidation with PCC was rather slow,
requiring 12 h at room temperature to reach completion, but
provided the dialdehyde 12 in 67% yield after eluting through
a short silica plug. In addition, PDC was also examined but
proved prohibitively slow, needing 36 h to reach completion
with no improvement in yield. Ultimately, oxidation with
TPAP/NMO24 gave 12 with the quickest reaction time (4 h)
and modest yields (62%).
L-proline
T
time yielda
ratio
entry solvent (mol %) (°C) (h)
(%) (12/13a x/13eq/16)b
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DMF
DMF
PhCH3
PhCH3
5
20
20
20
20
20
20
20
25 14
18
-10 30
-20 N.R.
-20 N.R.
87
82
64
0:1:1:0
0:1:1:0
0:1:1:0
0
0
12
1:0:0:1
0:1:1:0
-10 N.R.
25 24
91
a Yield reported is of the crude product obatined after aqueous workup.
b Based on H NMR of crude aldol products.
1
Due to their instability, the 1:1 mixture of crude aldol
products 13ax/eq were immediately converted to the methyl
esters via oxidation to the acid followed by esterification to
provide â-hydroxy esters 14ax/eq in 76% overall yield from
12 (Scheme 2). Unfortunately, separation of the diastereo-
mers was not possible at this stage. Gratifyingly, benzoylation
with benzoic anhydride and DMAP provided a 60% yield
of Boc-protected tropane compounds 15ax/eq, which were
now separable by HPLC. Removal of the Boc carbamate
from the desired 15ax with trifluoroacetic acid followed by
reductive amination provided cocaine 1 in 74% yield over
two steps with spectral properties matching that reported in
the literature.26,27 However, determination of the enantiomeric
excess revealed that instead of (-)-cocaine we had actually
synthesized the (+)-isomer.28 Indeed, separation of the
enantiomers by chiral HPLC4 showed an 86% ee for the (+)-
cocaine isomer.29 This result was puzzling since on the basis
of the proposed transition-state model25 using L-proline, the
(-)-isomer was predicted to be the favored aldol product
(Figure 1).
With the key meso-dialdehyde 12 now in hand, the proline-
catalyzed aldol reaction was attempted. Using the conditions
reported by List and co-workers,25 an 87% yield of aldol
products 13ax/eq as a 1:1 mixture of inseparable C(2)-
epimers was obtained (Table 1, entry 1). Attempts to separate
and/or purify the aldol products 13ax/eq led only to
decomposition. Various other solvents, concentrations, cata-
lyst loadings, and temperatures were evaluated in attempts
to improve the diastereoselectivity, but to no avail. More
polar solvents such as DMF (entries 5 and 6) led only to the
dehydration product. However, it was found that use of
toluene as solvent gave the highest yields and cleanest
1
reactions by H NMR analysis of the crude mixture (Table
1, entry 8).
(19) For examples of reductions of 1-pyrrolines, see: (a) Shiosaki, K.;
Rapoport, H. J. Org. Chem. 1985, 50, 1229. (b) Bacos, D.; Celerier, J. P.;
Marx, E.; Saliou, C.; Lhommet, G. Tetrahedron Lett. 1989, 30, 1081. (c)
Li, H.; Sakamoto, T.; Kikugawa, Y. Tetrahedron Lett. 1997, 38, 6677. (d)
ref 14c.
(20) For a leading reference, see: (a) Pearson, W. H.; Stoy, P. Synlett
2003, 903. See also: (b) Pearson, W. H.; Mi, Y. Tetrahedron Lett. 1997
38, 5441. (c) Pearson, W. H.; Clark, R. B. Tetrahedon Lett. 1997, 38, 7669.
(21) (a) Chong, J. M.; Park, S. B. J. Org. Chem. 1992, 57, 2220. (b)
Pearson, W. H.; Postich, M. J. J. Org. Chem. 1992, 57, 6354.
(22) Kozikowski, A. P.; Stein, P. D. J. Org. Chem. 1984, 49(13), 2301.
(23) Attempts to improve the tin addition step by varying temperature,
concentration, order and rate of addition, and counterion on the tributyltin
anion were unsuccessful.
(24) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639.
(25) Pidathala, C.; Hoang, L.; Vignola, N.; List, B. Angew. Chem., Int.
Ed. 2003, 42, 2785.
Figure 1. Predicted aldol transition states.
Org. Lett., Vol. 6, No. 19, 2004
3307

On the basis of work done by List and Houk,25,30,31
enamine formation leads to two possible chairlike conforma-
tions in which H-bonding can occur between the acid and
free aldehyde (Figure 1) with the anti-arrangement being
slightly preferred. The anti and syn terminology refer to the
dihedral angle of the acid moiety and the terminal carbon of
the olefin.32 In this instance, the anti-arrangement (cf.
H-bondanti) is predicted to be destabilized by an A1,3-
interaction with the pyrrolidine ring, whereas no such
interaction is present in the syn-arrangement (cf. H-bondsyn),
but may still be disfavored due to the axial placement of the
bulky enamine. These transition-state models, though, still
predict the (-)-enantiomers to be formed. However, the
presence of the Boc carbamate would provide a more Lewis
basic site that may dominate in the formation of hydrogen
bonding with the carboxylic acid (cf. Bocanti and Bocsyn,
Figure 2) forcing enamine formation to occur on the opposite
as H-bondanti, whereas the Bocanti arrangement might also
be disfavored sterically due to the placement of the bulky
enamine in an axial position leading to a 1:1 distribution of
C(2)-epimers. However, a word of caution is needed, since
the rationale just explored has only considered the most likely
transition states. To fully explain the reversal in predicted
enantioselectivity and moderate diastereoselectivity, calcula-
tion of the relative energies of all reasonable transition states
would be required.34
In conclusion, an efficient and rapid total synthesis of (+)-
cocaine has been described using a highly stereoselective
2-azaallyllithium [3 + 2] cycloaddition to generate the
desired meso-dialdehyde 12 followed by an intramolecular
enol-exo-proline-catalyzed aldolization reaction to establish
the tropane skeleton with good enantioselectivity and moder-
ate diastereoselectivity. The aldol reaction represents the first
use of the intramolecular proline-catalyzed aldol reaction to
generate aza-bridged bicyclic structures. The versatility in
the synthesis of cycloaddition precursors (i.e., 9),20 variety
of dipolarophiles that can be used in the cycloaddition, and
the easily modifiable functionality of the cycloadducts and
aldol products combined with the relatively short synthetic
route should allow for rapid and varied synthesis of enan-
tioenriched cocaine analogues.
Acknowledgment. We thank the National Institutes of
Health (GM-52491) for funding and Abbott Laboratories for
a graduate fellowship for D.M. (2002-2003).
Supporting Information Available: Experimental pro-
1
cedures as well as H NMR spectra for (+)-1 and 6-15.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL048777A
Figure 2. Aldol transition states with H-bonding to the carbamate.35
(31) For experimental and theoretical work on the proline-catalyzed aldol
transition states, see: (a) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc.
2001, 123, 9922. (b) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001,
123, 11273. (c) Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. J. Am.
Chem. Soc. 2003, 125, 2475. (d) Hoang, L.; Bahmanyar, S.; Houk, K. N.;
List, B. J. Am. Chem. Soc. 2003, 125, 16.
aldehyde.33 Both transition-state models would now lead to
the formation of the (+)-enantiomers. The Bocsyn arrange-
ment would suffer from the same type of steric interactions
(32) A dihedral angle of 180° is termed anti, while an angle of 0° refers
to the syn arrangement.
(33) Preliminary investigations to test the rationale with other N-
protecting groups (i.e. N-H, N-Me, and N-CHO) were thwarted as attempted
oxidation to the meso-dialdehyde led only to the recovery of starting material
or decomposition products. Another possibility not investigated by us would
be to use a proline derivative incapable of forming such H-bonds such as
the methyl ester of L-proline to see if any asymmetric induction occurs at
all.
(34) One must consider the issues of the E/Z enamine geometry, boat/
chair conformations, syn/anti relationship of the carboxylic acid to the olefin,
equatorial versus axial placement of substituents, and the issue of H-bond
acceptor (Boc carbonyl versus aldehyde) quickly causes the number of
reasonable transition states possible to become extremely large. See ref 31
for more detailed discussions.
(26) Carroll, F. I.; Coleman, M. L.; Lewin, A. H. J. Org. Chem. 1982,
47, 13.
(27) A similar sequence with 15eq would lead to the synthesis of
pseudococaine.
(28) [R]23 ) +14.5 (c 0.72, CHCl3) [Lit.1a [R]23 ) +15.5 (c 1.0,
D
D
CHCl3)].
(29) It should be noted that although the ee’s for 15ax and 15eq were
not determined, optical rotations for both were determined: 15ax, [R]23
D
) +4.5 (c 2.1, CHCl3), 15eq, [R]23D ) +1.5 (c 2.1, CHCl3). Although by
no means definitive, these results seem to indicate that 15eq (arising from
aldol 13eq) would lead to the (+)-isomer of pseudococaine with an ee
similar to that obtained for (+)-cocaine.
(30) For a review of proline catalyzed reactions, see: List, B. Tetrahedron
2002, 58, 5573.
(35) Based on these rationale, one would expect to obtain (-)-cocaine
if D-proline was used instead.
3308
Org. Lett., Vol. 6, No. 19, 2004