Enantioselective synthesis of functionalized tropanes by rhodium(II) carboxylate-catalyzed decomposition of vinyldiazomethanes in the presence of pyrroles

Article abstract of DOI:10.1021/jo961920w

A series of enantiomerically enriched tropanes was synthesized by the rhodium(II) octanoate-catalyzed reaction of various N-BOC-protected pyrroles with vinyldiazomethanes. The overall 3 + 4 annulation occurs by a tandem cyclopropanation/Cope rearrangement. Asymmetric induction was best achieved in these transformations by using either (S)-lactate or (R)-pantolactone as a chiral auxiliary on the vinyldiazomethanes. Reactions carried out with the chiral catalyst tetrakis-[N-(4-tert-butylbenzenesulfonyl)-(L)-prolinato]dirhodium (2) provided moderate asymmetric induction, but also resulted in the formation of isomeric azabicyclooctane side products. The utility of the synthetic process was demonstrated through the asymmetric synthesis of (-)-anhydroecgonine methyl ester and (-)-ferruginine.

Full text of DOI:10.1021/jo961920w

J . Org. Chem. 1997, 62, 1095-1105
1095
En a n tioselective Syn th esis of F u n ction a lized Tr op a n es by
Rh od iu m (II) Ca r boxyla te-Ca ta lyzed Decom p osition of
Vin yld ia zom eth a n es in th e P r esen ce of P yr r oles
Huw M. L. Davies,*,† J ulius J . Matasi,† L. Mark Hodges,† Nicholas J . S. Huby,‡
Craig Thornley,‡,§ Norman Kong,† and J effrey H. Houser†
Department of Chemistry, State University of New York at Buffalo Buffalo, New York 14260-3000 and
Department of Chemistry, Wake Forest University Box 7486, Winston-Salem, North Carolina 27109
Received October 10, 1996X
A series of enantiomerically enriched tropanes was synthesized by the rhodium(II) octanoate-
catalyzed reaction of various N-BOC-protected pyrroles with vinyldiazomethanes. The overall 3 +
4 annulation occurs by a tandem cyclopropanation/Cope rearrangement. Asymmetric induction
was best achieved in these transformations by using either (S)-lactate or (R)-pantolactone as a
chiral auxiliary on the vinyldiazomethanes. Reactions carried out with the chiral catalyst tetrakis-
[N-(4-tert-butylbenzenesulfonyl)-(L)-prolinato]dirhodium (2) provided moderate asymmetric induc-
tion, but also resulted in the formation of isomeric azabicyclooctane side products. The utility of
the synthetic process was demonstrated through the asymmetric synthesis of (-)-anhydroecgonine
methyl ester and (-)-ferruginine.
In tr od u ction
stitued-3â-aryltropanes has been through conjugate ad-
dition of aryl Grignard reagents to anhydroecgonine
methyl ester,2c-h which is synthesized from (-)-cocaine.5
We have shown that the 2â-acyl-3â-aryltropanes display
very promising biological activity,2a,b and consequently,
we required a practical asymmetric approach to these
compounds that can be carried out on a multigram scale.
In this paper we report that the rhodium(II) carboxylate-
catalyzed reaction between vinyldiazomethanes and pyr-
roles can be used to achieve a general asymmetric
synthesis of tropanes as illustrated in eq 1.6
The tropane nucleus is found in numerous naturally
occurring alkaloids, many of which possess potent bio-
logical activity.1 Of particular current interest are the
2â-substituted-3â-aryltropanes 1, as these compounds are
useful probes to study the neurochemistry of drug ad-
diction.2 A number of classic methods have been devel-
oped for the construction of the tropane system,3 and
three asymmetric routes to tropanes have been reported
within the last two years.4 Even so, the most commonly
employed procedure for the synthesis of the 2â-sub-
† State University of New York.
‡ Wake Forest University.
§ Deceased October 19, 1996.
X Abstract published in Advance ACS Abstracts, February 1, 1997.
(1) For a general review, see: (a) Lounasmaa, M.; Tamminen, T.
Alkaloids 1993, 44, 1. (b) Lounasmaa, M. Alkaloids 1988, 33, 1.
(2) (a) Davies, H. M. L.; Saikali, E.; Huby, N. J . S.; Gilliatt, V. J .;
Matasi, J . J .; Sexton, T.; Childers, S. R. J . Med. Chem. 1994, 37, 1262.
(b) Davies, H. M. L.; Kuhn, L. A.; Thornley, C.; Matasi, J . J .; Sexton,
T.; Childers, S. R. J . Med. Chem. 1996, 39, 2554. (c) Carroll, F. I.;
Lewin, A. H.; Boja, J . W.; Kuhar, M. J . J . Med. Chem. 1992, 35, 969.
(d) Carroll, F. I.; Kotian, P.; Dehghani, A.; Gray, J . L.; Kuzemko, M.
A.; Parham, K. A.; Abraham, P.; Lewin, A. H.; Boja, J . W.; Kuhar, M.
J . J . Med. Chem. 1995, 38, 379. (e) Kozikowski, A. P.; Roberti, M.;
J ohnson, K. M.; Bergmann, J . S.; Ball, R. G. Biorg. Med. Chem. Lett.
1993, 3, 1327. (f) Kozikowski, A. P.; Roberti, M.; Xiang, L.; Bergmann,
J . S.; Callahan, P. M.; Cunningham, K. A.; J ohnson, K. M. J . Med.
Chem. 1992, 35, 4764. (g) Kelkar, S. V.; Izenwasser, S.; Katz, J . L.;
Klein, C. L.; Zhu, N.; Trudell, M. L. J . Med. Chem. 1994, 37, 3875. (h)
Meltzer, P. C.; Liang, A. Y.; Brownell, A.-L.; Elmaleh, D. R.; Madras,
B. K. J . Med. Chem. 1993, 36, 855.
(3) (a) Willstatter, R. Ber. 1896, 29, 936. (b) Willstatter, R. J ustus
Liebigs Ann. Chem. 1903, 326, 23. (c) Robinson, R. J . Chem. Soc. 1917,
111, 762. (d) Hayakawa, Y.; Baba, Y.; Makino, S.; Noyori, R. J . Am.
Chem. Soc. 1978, 100, 1786. (e) Tufariello, J . J .; Mullen, G. B.; Tegeler,
J . J .; Trybulski, E. J .; Wong, S. C.; Asrof Ali, S. J . Am. Chem. Soc.
1979, 101, 2435. (f) Iida, H.; Watanabe, Y.; Kibayashi, C. J . Org. Chem.
1985, 50, 1818. (g) Petersen, J . S.; Toteberg-Kaulen, S.; Rapoport, H.
J . Org. Chem. 1984, 49, 2948. (h) Rumbo, A.; Mourino, A.; Castedo,
L.; Mascarenas, J . L. J . Org. Chem. 1996, 61, 6114. (i) Dennis, N.;
Katritzky, A. R.; Takeuchi, Y. Angew. Chem., Int. Ed. Engl. 1976, 15,
1. (j) Rumbo, A.; Mourino, A.; Castedo, L.; Mascarenas, J . L. J . Org.
Chem. 1996, 61, 6114.
Since our recent publication on the racemic synthesis
of tropanes,7 we have developed two complimentary
methods to achieve asymmetric vinylcarbenoid cyclopro-
panations by using either a chiral rhodium catalyst8 or
a chiral auxiliary on the vinylcarbenoid.9 Consequently,
the vinylcarbenoid chemistry has matured to a stage
whereby an asymmetric synthesis of tropanes is feasible.
(4) (a) Hernandez, A. S.; Thaler, A.; Castells, J .; Rapoport, H. J .
Org. Chem. 1996, 61, 314. (b) Majewski, M.; Lazny, R. J . Org. Chem.
1995, 60, 5825. (c) Rigby, J . H.; Pigge, F. C. J . Org. Chem. 1995, 60,
7392.
(5) Campbell, H. F.; Edwards, O. E.; Kolt, R. Can. J . Chem. 1977,
55, 1372.
(6) For preliminary accounts of portions of this work, see: (a) Davies,
H. M. L.; Huby, N. J . S. Tetrahedron Lett. 1992, 33, 6935. (b) Davies,
H. M. L.; Matasi, J . J .; Thornley, C. Tetrahedron Lett. 1995, 36, 7205.
(7) Davies, H. M. L.; Saikali, E.; Young, W. B. J . Org. Chem. 1991,
56, 5696.
(8) (a) Davies, H. M. L.; Hutcheson, D. K. Tetrahedron Lett. 1993,
34, 7243. (b) Davies, H. M. L.; Peng, Z.; Houser, J . H. Tetrahedron
Lett. 1994, 35, 8939. (c) Davies, H. M. L.; Bruzinski, P. R.; Lake, D.
H.; Kong, N.; Fall, M. J . J . Am. Chem. Soc. 1996, 118, 6897.
(9) (a) Davies, H. M. L.; Huby, N. J . S.; Cantrell, W. R., J r.; Olive,
J . L. J . Am. Chem. Soc. 1993, 115, 9468. (b) Davies, H. M. L.; Ahmed,
G.; Churchill, M. R. J . Am. Chem. Soc. 1996, 118, 10774.
S0022-3263(96)01920-2 CCC: $14.00 © 1997 American Chemical Society

1096 J . Org. Chem., Vol. 62, No. 4, 1997
Davies et al.
The realization of such an asymmetric approach to
tropanes is the focus of this paper, which also emphasizes
the range of pyrroles that may be used and the scale-up
potential of this chemistry.
(12, 17% ee) or N-methanesulfonyl (13, 29% ee), no
overall improvement in enantioselectivity or yield was
observed.
Resu lts
Due to the obvious advantages that would be associ-
ated with an asymmetric approach to tropanes using
chiral catalysis, a study was undertaken to explore if the
rhodium(II) prolinate catalyst 28 would be effective for
this chemistry. Earlier studies have shown that a methyl
ester-substituted vinyldiazomethane resulted in the high-
est levels of enantioselectivity;8a,c therefore, the vinyl-
diazomethane 3 was used as the test substrate. All of
the test reactions were carried out using hydrocarbon
solvents because the use of a nonpolar solvent both
enhances the enantioselectivity8a,c and limits side reac-
tions occurring through initial attack of the pyrrole at
the vinyl terminus of the vinylcarbenoid.7
The formation of bicyclo[3.3.0]octane and bicyclo[4.2.0]-
octane side products places a serious limitation on the
chiral catalyst approach for the asymmetric synthesis of
tropanes. Bicyclo[4.2.0]octane formation has been ob-
served in intramolecular reactions between vinylcar-
benoids and pyrroles,10 and it was postulated that they
form via zwitterionic intermediates arising from electro-
philic attack by the carbenoid at the R-position [C(2)] of
the pyrrole ring (eq 5). The initial zwitterionic interme-
In contrast to the previous results with achiral cata-
lysts,7 rhodium(II) prolinate (2)-catalyzed decomposition
of the vinyldiazomethane 3 in the presence of N-(BOC)-
pyrrole (4a ) failed to form the tropane product cleanly
(eq 2). In addition to the desired tropane 5 (42% yield),
diate 14 first undergoes a ring opening to generate a
trienimine species, which undergoes successive 8π and
6π electrocyclic reactions to eventually form the bicyclo-
[4.2.0]octane nucleus.10 The formation of bicyclo[3.3.0]-
octanes could also be envisioned to occur via zwitterionic
intermediates, but the regiochemistry observed in the
formation of 9 would require electrophilic attack of the
carbenoid at the â-position [C(3)] of the pyrrole ring to
form 15 followed by ring closure at C(2) (eq 6). Presum-
ably, the occurence of products derived from zwitterionic
intermediates would be enhanced by using electron-
deficient catalysts such as the prolinate catalyst 2.
the isomeric azabicyclo[3.3.0]octane 6 (12% yield) was
formed.6b Furthermore, the enantioselectivity for the
formation of 5 was rather moderate (51% ee), particularly
in comparison to the values that have been obtained for
the asymmetric cyclopropanation of styrene.8a,c Side
reactions became even more prevalent when 2-methyl-
N-BOC-pyrrole (4b) was used as substrate (eq 3). Rhod-
ium(II) prolinate (2)-catalyzed decomposition of 3 in the
presence of 4b resulted in the formation of two isomeric
tropanes, 7 (24% yield) and 8 (6% yield), as well as two
other products. The structure of these isomeric products
were shown to be the bicyclo[3.3.0]octane 9 (19% yield)6b
and the bicyclo[4.2.0]octane 10 (21% yield).6b,10
Due to the mixed results that were obtained using the
prolinate catalyst (2), attention was then turned to the
complimentary method that we have developed for asym-
metric vinylcarbenoid transformations using R-hydroxy
esters as chiral auxiliaries on the vinylcarbenoid.9 The
cost-effective (S)-lactate and (R)-pantolactone chiral aux-
iliaries can offer subtle benefits in addition to serving as
the source of chiral induction. During the decomposition
of vinyldiazomethanes containing these auxiliaries, the
ester carbonyl of the auxiliary is considered to interact
with the vinylcarbenoid moiety to form a rigid intermedi-
ate, which leads to the possibility of not only high
asymmetric induction, but also more selective carbenoid
reactivity.6b
A series of experiments was then directed to determine
if the N-BOC protecting group on the pyrrole was the
most appropriate for this chemistry (eq 4). Although
some changes in the enantioselectivity were observed on
modifying the protecting group on the pyrrole from
N-BOC (5, 51% ee) to N-COOMe (11, 42% ee), N-acetyl
Vinyldiazomethanes containing the appropriate chiral
auxiliaries were prepared by a slight modification of the
established procedure (eq 7).9b As reasonably large scale
(10) Davies, H. M. L.; Matasi, J . J .; Ahmed, G. J . Org. Chem. 1996,
61, 2305.

Enantioselective Synthesis of Functionalized Tropanes
J . Org. Chem., Vol. 62, No. 4, 1997 1097
Ta ble 1. Rh od iu m (II) Octa n oa te-Ca ta lyzed
Decom p osition of 18a or 19a in th e P r esen ce of P yr r oles
Accor d in g to Eq 8
reactions were envisioned, diketene-acetone adduct
(2,2,6-trimethyl-4H-1,3-dioxin-4-one) was used as the
starting material instead of diketene. Reaction of this
reagent with ethyl (S)-lactate (16a ) followed by p-
acetamidobenzenesulfonyl azide11 (p-ABSA), a shock
insensitive diazo transfer agent, resulted in the formation
of up to 133 g (76% overall yield) of diazocetoacetate 17a .
Conversion of 17a to the vinyldiazomethane 18a was
readily achieved on a 23 g (100 mmol) scale in 70% yield
by successive treatment with sodium borohydride and
pyrrole
R1
R2 R3
X
product yield, % de, %
4a
4b
4c
4d
4e
4f
4g
4h
4a
4b
4d
4e
4f
H
Me
CH2OTBS
Ph
Ac
Me
H
-(CH2)4-
H
Me
Ph
H
H
H
H
H
H
Me
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OTBS
OTBS
OTBS
OTBS
20a
20b
20c
20d
20e
20f
20g
20h
21a
21b
21d
21e
21f
82
54
62
64
30
33
19
48
64
55
74
58
30
66
59
70
53
67
25
52
55
66
58
52
79
52
H
H
H
H
H
Ac
Me
Me OTBS
Ta ble 2. Rh od iu m (II) Octa n oa te-Ca ta lyzed
Decom p osition of 18b or 19b in th e P r esen ce of P yr r oles
Accor d in g to Eq 9
pyrrole
R1
R2
R3
X
product yield, % de, %
4a
4a
4d
4e
4h
H
H
H
H
H
H
H
H
H
H
H
H
22a
23a
23d
23e
23h
64
66
56
69
31
69
68
52
78
37
OTBS
OTBS
OTBS
OTBS
Ph
Ac
-(CH2)4-
phosphorus oxychloride. Silylation of 17a resulted in the
formation of the siloxy-substituted vinyldiazomethane
19a in essentially quantitative yield. The vinyldiaz-
omethanes 18b and 19b containing the (R)-pantolactone
auxiliary were prepared on a somewhat smaller scale
starting from the alcohol 16b using diketene, and lithium
tri-(tert-butoxy)aluminium hydride was used instead of
sodium borohydride for the initial reduction of 17b.
Slow addition of the vinyldiazomethane 18a to a stirred
solution of rhodium(II) octanoate and N-(BOC)pyrrole
(4a ) in refluxing hexanes resulted in the formation of the
tropane 20a in 82% yield (eq 8, Table 1).6a Even though
rhodium(II)-catalyzed decomposition of vinyldiazo-
methanes can occur at temperatures as low as -78 °C,
high temperatures and slow addition of the vinyldiaz-
omethane is required in this case in order to avoid bis-
cyclopropanation of the pyrrole.7 In spite of the rather
vigorous reaction conditions, the tropane is formed with
a good level of asymmetric induction (66% de) and has
been scaled up to produce 37 g (75% yield) of 20a per
reaction. As has been shown previously in other sys-
tems,9 the reaction of 18a with 4a is not susceptible to
improved stereoselectivity by double stereodifferentiation
using either the (S)-prolinate catalyst 2 (69% de) or its
enantiomer (63% de). The reaction is applicable to a
series of 2-substituted pyrroles as shown in Table 1,
leading to the formation of tropanes 20b-e in 53-70%
de. Unlike the results seen with the prolinate catalysts
(eq 2 and 3), no [3.3.0]- or [4.2.0]-bicyclic products are
formed in these reactions. Furthermore, the tropane
regioselectivity is greater than 10:1 favoring products
derived from initial cyclopropanation at the unsubsti-
tuted double bond of the pyrrole. Some complications
were observed in the reactions of 18a with 2,5-dimethyl-
N-(BOC)pyrrole (4f) and 3-methyl-N-(BOC)pyrrole (4g).
Unlike the reaction of 18a with 2-substituted pyrroles,
the reaction with 4f resulted in the formation of both the
tropane 20f and an unstable [3.3.0]bicyclic product
analogous to 9 in approximately a 1:1 mixture. Further-
more, the asymmetric induction for the formation of 20f
was significantly lower (25% de) than the values obtained
in earlier systems. In the case of the 3-substituted
pyrrole 4g, the vinylcarbenoid was inefficiently captured
(19% yield), but the diastereoselectivity for the formation
of 20g was reasonable (52% de). The reaction could also
be extended to the more elaborate pyrrole 4h , from which
the desired tricyclic tropane 20h was obtained in 48%
yield and 55% de.
These reactions were subsequently extended to the
2-(siloxyvinyl)diazomethane 19a (eq 8, Table 1). Once
again, reasonable yields and diastereoselectivities of the
tropanes 21 were seen with pyrrole and 2-substituted
pyrrole derivatives. The highest diastereoselectivity was
obtained for the reaction with 2-acetylpyrrole (4e). In
this case, moderate double stereodifferentiation was
observed where the diastereoselectivity for 21e improved
from 79% to 88% de on changing the catalyst from
rhodium(II) octanoate to the (S)-prolinate derivative 2.
The enantiomeric series of tropanes were obtained
starting from vinyldiazomethanes 18b and 19b contain-
ing (R)-pantolactone as the chiral auxiliary (eq 9, Table
2). The diastereoselectivity of the tropanes 22 and 23
obtained from these diazomethanes and various pyrroles
was roughly parallel to the results observed with the (S)-
lactate auxiliary and ranged from 37-78% de.
The absolute stereochemistry of the tropanes was
determined by conversion of selected members to known
compounds and/or by comparison of chemical shift dif-
ferences of Mosher amide derivatives for a series of
compounds. The synthetic interconversions are sum-
marized in Scheme 1. Verification that the same sense
of asymmetric induction was obtained from both the
(11) Davies, H. M. L.; Cantrell, W. R., J r.; Romines, K. R.; Baum,
J . S. Org. Synth. 1991, 70, 93.

1098 J . Org. Chem., Vol. 62, No. 4, 1997
Davies et al.
Sch em e 1
siloxy- and unsubstituted vinyldiazomethanes was con-
firmed by conversion of both 20a and 21a to tropane 24a .
addition to 20a was deemed to be necessary. This was
achieved by the procedure developed by Hoye et al.12
Tropanes 20 were converted to the secondary amines 30
and then to their (R)- and (S)-Mosher [methoxy(trifluo-
romethyl)phenylacetyl] amides (36, 37) by treatment of
the corresponding amine with the appropriate acid
chloride in the presence of diisopropylethylamine (Scheme
1).13 As is observed for other secondary amines,12 each
Mosher amide adopts a conformation where the trifluo-
romethyl group is syn-periplanar to the carbonyl group.
1
Consequently, specific H NMR resonances for the tro-
pane ring are predictably shifted upfield by the presence
of the phenyl group on the Mosher amide.12a,14 In the
case of enantiomerically pure demethylated (-)-anhy-
droecgonine methyl ester (30a ), each Mosher amide exists
as a mixture of two rotamers where the major rotamer
has the Mosher amide stereogenic center syn to the C(2)-
carbomethoxy substituent.15 The major rotamer for the
S-Mosher amide 37a is characterized by a strongly
High field 1H NMR analysis of both samples of 24a at
95 °C (to avoid broadening of signals due to hindered
amide rotation) showed that in both cases the same
diastereomer predominated. The absolute stereochem-
istry of the major diastereomer of 24a was determined
by conversion to (-)-anhydroecgonine methyl ester (33a )
by removal of both the chiral auxiliary and BOC group
followed by reductive methylation. In a similar series
of reactions on 22a , it was possible to show that (R)-
pantolactone auxiliary resulted in tropane formation with
opposite asymmetric induction to that obtained with the
(S)-lactate auxiliary.6a
The absolute stereochemistry determined for 20a is
opposite to that expected from the model we have
developed for asymmetric induction in related reactions
(See Discussion). Consequently, the determination of the
absolute stereochemistry for a series of compounds in
(12) (a) Hoye, T. R.; Renner, M. K. J . Org. Chem. 1996, 61, 2056
and references therein. (b) Hoye, T. R.; Renner, M. K. J . Org. Chem.,
in press. (c) Rauk, A.; Tavares, D. F.; Khan, M. A.; Borkent, A. J .; Olson,
J . F. Can. J . Chem. 1983, 61, 2572.
(13) Due to the differences in the priority assigned to a dialkylamino
group versus a chloro group, the R-acid chloride produces the S-Mosher
amide.
(14) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J . Am.
Chem. Soc. 1991, 113, 4092.
(15) The opposite rotamer is observed exclusively for the Mosher
amides of norcocaine described in ref 12b, presumably due to the
presence of â-substituents at C2 and C3.

Enantioselective Synthesis of Functionalized Tropanes
J . Org. Chem., Vol. 62, No. 4, 1997 1099
Ta ble 3. 1H NMR Ch em ica l Sh ift Differ en ces (δS - δR) of Mosh er Am id es of Selected Tr op a n es (syn r ota m er )
tropane
R1
R2
R3
H(1)
H(3)
H(4â)
H(4R)
H(5)
H(7â)
R(1)
R(2)
30a
30b
30d
30e
30g
30h
H
H
H
H
H
H
H
H
H
H
H
-0.11
-0.15
-0.28
-0.42
-0.11
-0.32
+0.35
+0.28
+0.34
+0.41
+0.34
+0.27
-0.07
-0.11
-0.03
0.00
-0.07
-0.33
+0.12
+0.09
+0.05
+0.06
+0.14
+0.08
+0.17
-
-0.93
-0.97
-0.82
-0.72
-0.92
-0.91
-
-
-
Me
Ph
Ac
H
+0.07
-
-
-
-
+0.15
-
+0.02
-
-
-
-0.03
-
Me
-(CH2)4-
Ta ble 4. 1H NMR Ch em ica l Sh ift Differ en ces (δS - δR) of Mosh er Am id es of Selected Tr op a n es (a n ti r ota m er )
tropane
R1
R2
R3
H(1)
H(3)
H(4â)
H(4R)
H(5)
R(2)
30a
30g
H
H
H
Me
H
H
-0.12
-0.11
-0.28
-0.29
-1.87
-1.88
-0.55
-
+0.47
+0.44
-
+0.20
shielded 7â proton resonance which is 0.93 ppm upfield
(500 MHz, CDCl3) from the corresponding resonance for
the R-amide 36a . The minor rotamer of 37a , where the
phenyl group is shielding the 4-position, also shows
distinctly shifted proton resonances. In this compound,
the 4â proton resonance appears at 0.89 ppm, 1.87 ppm
upfield from the corresponding resonance of the R-
derivative. Taken together, these data are consistent
with 30a having the established (1R,5S)-absolute ster-
eochemistry.5
cally pure tropanes 33-35 were easily obtained via
reductive methylation of 30-32.
Discu ssion
The reaction of vinyldiazomethanes with suitably
protected pyrroles has proven to be a valuable and
efficient route into the tropane ring system. During the
course of the study, this reaction has been optimized and
improved to the point where multigram quantities of
enantiomerically enriched tropanes with a variety of
substitution patterns can be synthesized with relative
ease. This has been achieved even though the electron-
rich nature of the pyrrole system shows a tendency
toward formation of stabilized zwitterionic intermediates
leading to the formation of [3.3.0]- and [4.2.0]-bicyclic side
products. The formation of these products is further
amplified when the chemistry is carried out with the
chiral prolinate catalyst 2, which is presumably more
electrophilic than the rhodium octanoate catalyst. This
problem was circumvented to a great extent by employing
a chiral R-hydroxy ester functionality on the vinyl car-
benoid system. These auxiliaries not only result in
enhanced formation of tropanes, but also enable the
transformation to be carried out with a reasonable level
of asymmetric induction. Several of the enantioenriched
tropanes were conveniently resolved to the pure enanti-
omers.
Using this method, the absolute stereochemistry of
tropanes 30b,d ,e,g,h , all generated using the lactate
chiral auxiliary, was evaluated. While the analysis was
slightly more complicated due to the fact that these
tropanes were enriched rather than enantiomerically
pure, this was mitigated by the fact that in most cases
only one amide rotamer was observed for each enanti-
omer.16 In all cases, the absolute stereochemistry was
1
assigned to be 1R. Selected H NMR data for all of the
Mosher amides prepared are summarized in Tables 3 and
4.
The impetus behind this research was to develop a
practical asymmetric synthesis of the tropanes 30-35,
as these are the key starting materials for our collabora-
tive projects directed toward the development of medica-
tions for the treatment of cocaine addiction.17 Normethyl
anhydroecgonine methyl ester (30a ) was routinely ob-
tained in 20 g quantities in 60-70% ee from 18a and
was resolved into enantiomerically pure form by recrys-
tallization (three times) of its diastereomeric di-p-toluoyl-
D-tartrate salt (38a ). Enriched BOC-protected anhydro-
ecgonine methyl ester (25a ) was converted to either 31a
or 32a by initial hydrolysis to the acid (26a ) followed by
conversion to the acid chloride (27a ). Alkylation was
achieved either by the corresponding organocuprate or
dialkyl zinc reagent, which was subsequently followed
by removal of the BOC group. The conversion of 25a to
the deprotected enriched tropane 32a has been carried
out on up to a 10 g scale in 45-55% overall yields. The
resolution of 31a and 32a was also achieved via recrys-
tallization of their di-p-toluoyl tartrate salts; in the case
of 32a , enantiomerically pure tropane has been obtained
on a gram scale in up to 48% overall yield from the pure
BOC-protected enriched intermediate 29a . Enantiomeri-
The use of R-hydroxyesters as chiral auxiliaries for
carbenoid reactions is becoming well established.9 The
high asymmetric induction that occurs using these
auxiliaries is considered to be due to an interaction
between the ester carbonyl of the auxiliary and the
carbenoid, resulting in a rigid orientation (41) during the
cyclopropanation step. However, the asymmetric induc-
tion observed in these reactions with pyrroles is opposite
to what has been found in related systems. For example,
the reaction of vinyldiazomethane 18a with furan results
in the formation of a (1S)-oxabicyclo[3.2.1]octane product
in 80% de,9b but the reaction of 18a with pyrroles results
in the predominant formation of (1R)-tropanes. In the
standard model,9 as illustrated in Figure 1 for the lactate
auxiliary, the favored interaction of the auxiliary with
the carbenoid has the methyl group of the stereogenic
center pointing away from the bulk of the catalyst such
that only one face of the carbenoid is open. Even with
(16) The major rotamer observed with one Mosher amide derived
from one enantiomer of tropane is enantiomeric with the major rotamer
derived from the opposite enantiomer of tropane with the opposite
Mosher amide. Since these two compounds have identical NMR
spectra, mixtures of Mosher amides can striaghtforwardly be assigned.
(17) (a) Porrino, L. J .; Migliarese, K.; Davies, H. M. L.; Saikali, E.;
Childers, S. R. Life Sci. 1994, 54, 511-517. (b) Hemby, S. E.; Co, C.;
Reboussin, D.; Davies, H. M. L.; Dworkin, S. I.; Smith, J . E. J .
Pharmacol. Exp. Ther. 1995, 272, 1176-1186. (c) Porrino, L. J .; Davies,
H. M. L.; Childers, S. R. J . Pharmacol. Exp. Ther. 1995, 272, 901.

1100 J . Org. Chem., Vol. 62, No. 4, 1997
Davies et al.
tent with the formation of zwitterionic intermediates
through attack at the R-position of the pyrrole. Conse-
quently, Pirrung proposed that the reactions occurred
through initial cyclopropanation followed by ring-opening
of the pyrrolocyclopropane 43 to a zwitterionic intermedi-
ate 44. However, the regiochemical issue is still prob-
lematical, and furthermore, the carbenoid derived from
diazodimedone is highly electrophilic such that the
reaction with pyrrole would be expected to directly form
zwitterionic intermediates. A very plausible explanation
for this apparently unusual regiochemistry is that the
reaction is simply an example of a bulky rhodium-
carbenoid complex reacting at the â-position of the
pyrrole, leading directly to the zwitterionic intermediate
44.
F igu r e 1.
one face of the carbenoid fully blocked, it is still possible
for the reaction with pyrrole to result in the formation
of either enantiomer of the tropane depending on how
the pyrrole approaches the open face of the carbenoid.
As shown in Figure 1, two enantiomeric tropanes could
be formed depending on whether the nonsynchronous
cyclopropanation occurs with greater initial bonding to
the R or the â position of the pyrrole. Normally, electro-
philic attack at the R-position of the pyrrole is electroni-
cally favored, but it has been previously established that
bulky substituents on the pyrrole redirect electrophilic
attack to the â-position.18 The observed asymmetric
induction would require the nonsynchronous cyclopro-
panation to occur with greater initial bond formation at
the â-position of 4, which is reasonable considering the
presence of the bulky BOC-substituent present on the
nitrogen and the large size of the electrophilic carbenoid
species. Furthermore, electron-withdrawing substituents
at the 2-position of pyrroles are known to direct electro-
philic attack to the â-position on the opposite side of the
ring.18 It is therefore not surprising that the highest
diastereoselectivities are obtained with the 2-acetylpyr-
role 4e. Certainly, the formation of [3.3.0]-bicyclic prod-
ucts 6 and 9 in the reactions using the prolinate catalyst
2 demonstrate that it is feasible for carbenoids to react
at the â-position of this pyrrole system.
In summary, the reaction between rhodium-stabilized
vinylcarbenoids and pyrroles leads to the general syn-
thesis of tropanes. Of the two complimentary methods
available for asymmetric vinylcarbenoid transformations,
the most effective for pyrroles is the use of R-hydroxy
esters as chiral auxiliaries on the carbenoid.
Exp er im en ta l Section
1H NMR spectra were run at either 200, 300, 400, or 500
MHz, and 13C NMR at either 50, 75, or 125 MHz in CDCl3
unless otherwise noted. Mass spectral determinations were
carried out at 70 eV. Hexanes, THF, and Et2O were dried over
and distilled from sodium metal with benzophenone as the
indicator. Acetonitrile and methylene chloride were dried over
and distilled from CaH2. Pentane was dried over activated
molecular sieves (4 Å) for 24 h prior to use. Column chroma-
tography was carried out on Merck silica gel 60 (230-400
mesh). Commercially available reagents were used without
additional purification unless noted. Melting points are
uncorrected. p-Acetamidobenzenesulfonyl azide (p-ABSA),11
the chiral rhodium prolinate catalyst 2,8c vinyl diazomethanes
3,7 19a ,9b 19b,9b N-(methoxycarbonyl)pyrrole,20 N-acetylpyr-
role,21 N-(methanesulfonyl)pyrrole,22 2-phenylpyrrole,23 2,5-
dimethyl-1-[(1,1-dimethylethoxy)carbonyl]pyrrole (4f),24 and
4,5,6,7-tetrahydroindole (4h )23 were prepared by literature
procedures. 2-Methyl and 3-methylpyrrole were prepared from
the corresponding carboxaldehydes via Wolff-Kishner reduc-
tion.18,25 Unless otherwise stated, enantiomeric excesses of the
[3.2.1] ring systems were determined by gas chromatography
on a permethylated â-cyclodextrin (â-PH) column obtained
from Astec Separations connected to a Hewlett-Packard 5890
Series II Plus gas chromatograph.
The observation that carbenoids are capable of elec-
trophilic attack at the 3-position of N-BOC-pyrrole may
shed light on other carbenoid reactions that have stood
out as rather unusual transformations. For example,
Pirrung and co-workers have discovered a very useful 3
+ 2 annulation between diazodimedone and N-(ethoxy-
carbonyl)pyrrole leading to the tricyclic product 42 (eq
10).19 The regiochemistry of the reactions is not consis-
(20) Acheson, R. M.; Vernon, J . M. J . Chem. Soc. 1961, 457.
(21) Reddy, G. S. Chem. Ind. 1965, 1426.
(22) Prinzbach, H.; Kaupp, G.; Fuchs, R.; J oyeux, M.; Kitzing, R.;
Markert, J . Chem Ber. 1973, 106, 3824.
(23) Mikhaleva, A. I.; Trofimov, B. A.; Vasil’ev, A. N.; Komarova,
G. A.; Skorobogatova, V. I. Khim. Geterotsikl. Soedin. 1983, 920.
(24) Chen, W.; Cava, W. P. Tetrahedron Lett. 1987, 28, 6025.
(25) Cornforth, J . W.; Firth, M. E. J . Chem. Soc. 1958, 1091.
(18) Bray, B. L.; Mathies, P. H.; Naef, R.; Solas, D. R.; Tidwell, T.
T.; Artis, D. R.; Muchowski, J . M. J . Org. Chem. 1990, 55, 6317 and
references therein.
(19) Pirrung, M. C.; Zhang, J .; Lackey, K.; Sternbach, D. D.; Brown,
F. J . Org. Chem. 1995, 60, 2112.

Enantioselective Synthesis of Functionalized Tropanes
J . Org. Chem., Vol. 62, No. 4, 1997 1101
Syn th esis of N-BOC-P r otected P yr r oles (4). Typ ica l
P r oced u r e.2a A solution of 2-methylpyrrole (14.0 g, 173
mmol) and 4-(dimethylamino)pyridine (DMAP, 1.59 g, 13.0
mmol) in dry acetonitrile (25 mL) was prepared, and di-tert-
butyl dicarbonate (46.8 g, 204 mmol) was added. The reaction
was stirred at rt for 4 days, and the solvent was removed under
vacuum. The crude product was purified by silica gel chro-
matography (petroleum ether mobile phase) to give 1-[(1,1-
Dim eth yleth oxy)ca r bon yl]-2-m eth ylp yr r ole (4b) as an oil.
Yield: 22.4 g (124 mmol, 71%). 1H NMR (200 MHz, CDCl3) δ
7.18 (br t, J ) 2.1 Hz, 1H), 6.05 (dd, J ) 3.4, 2.1 Hz, 1H), 5.92
(br s, 1H), 2.40 (s, 3H), 1.58 (s, 9H); 13C NMR (50 MHz, CDCl3)
δ 149.7, 131.5, 120.5, 111.8, 109.9, 83.1, 28.0, 15.4; IR (neat)
atmosphere of argon. After the addition was complete, the
mixture was refluxed for 1 h. The solvent was removed under
reduced pressure, and the excess pyrrole was removed from
the crude reaction mixture either by Kugelrohr distillation or
flash chromatography on silica gel using petroleum ether as
the eluant. The remaining organics were eluted with either
petroleum ether/Et2O or hexanes/EtOAc as the eluant. For
compounds 5-13, 20a , 21a , 22a , and 23a , the catalyst,
chromatography solvent system, isolated quantity of product,
yield, and diastereoselectivity/enantioselectivity for each reac-
tion are presented in that order in parentheses. This informa-
tion, as well as characterization data for the remaining
tropanes are provided in the Supporting Information.
Meth yl 8-[(1,1-Dim eth yleth oxy)car bon yl]-8-azabicyclo-
[3.2.1]octa -2,6-d ien e-2-ca r boxyla te (5) a n d Meth yl 1-[(1,1-
Dim e t h yle t h oxy)ca r b on yl]-1,3,6,6a -t e t r a h yd r ocyclo-
p en ta [b]p yr r ole-4-ca r boxyla te (6) (2, 9:1-4:1 pentane/
Et2O):
3110, 2981, 2929, 2867, 1740, 1584, 1497, 1403, 1372 cm-1
HRMS calcd for C10H15NO2 181.1103; found 181.1104.
;
Pyrroles 4b, 4d , 4e, 4g, and 4h were prepared using a
similar procedure; the chromatography solvent system, amount
of material, and yield of these compounds are given in
parentheses.
1
5: 0.479 g, 42% yield, 51% ee; H NMR (200 MHz, CDCl3)
2-[(ter t-Bu tyld im eth ylsiloxy)m eth yl]-1-[(1,1-d im eth yl-
eth oxy)ca r bon yl]p yr r ole (4c). Imidazole (3.16 g, 46.4
mmol) was added to a solution of 2-(hydroxymethyl)-N-BOC-
pyrrole10 (4.57 g, 23.2 mmol) and tert-butyldimethylsilyl
chloride (5.25 g, 34.8 mmol) in anhydrous DMF (30 mL). The
mixture was stirred for 20 h and then diluted with Et2O and
washed with water and brine. The ether solution was dried
(MgSO4) and evaporated. The crude product was then chro-
matographed (9:1 petroleum ether/Et2O) to give the title
product as an oil. Yield: 6.52 g (20.9 mmol, 90%). 1H NMR
(200 MHz, CDCl3) δ 7.19 (m, 1H), 6.22 (m, 1H), 6.13 (t, J )
3.3 Hz, 1H), 4.89 (s, 2H), 1.59 (s, 9H), 0.93 (s, 9H), 0.09 (s,
6H); 13C NMR (75 MHz, CDCl3) δ 149.3, 135.5, 121.0, 111.1,
110.3, 83.5, 60.1, 27.8, 25.8, 18.2, -5.5; IR (neat) 3157, 3116,
2960, 2929, 2883, 2862, 1745, 1502, 1476, 1419, 1372, 1336
cm-1. Anal. Calcd for C16H29NO3Si: C, 61.69; H, 9.38; N, 4.50.
Found: C, 61.57; H, 9.37; N, 4.52.
δ 6.47 (br s, 1H), 6.38 (br s, 1H), 5.88 (br s, 1H), 4.93 (br s,
1H), 4.55 (br s, 1H), 3.69 (s, 3H), 2.80 (br d, J ) 19.4 Hz, 1H),
1.85 (br d, J ) 19.8 Hz, 1H), 1.35 (s, 9H); IR (neat) 2985, 1700,
1625, 1435, 1375, 1315, 1230, 1160, 1095, 1070, 1030 cm-1
;
MS m/e 279 (M+), 207, 167, 149, 113, 112, 83, 71, 70, 69, 57,
43. Anal. Calcd for C14H19NO4: C, 63.38; H, 7.22; N, 5.28.
Found: C, 63.24; H, 7.18; N, 5.23.
1
6: 0.141 g, 12%; H NMR (200 MHz, CDCl3) δ 6.69 (t, J )
2.2 Hz, 1H), 6.53 (dd, J ) 4.2, 1.6 Hz, 0.4H, minor rotamer),
6.41 (dd, J ) 4.2, 1.6 Hz, 0.6H, major rotamer), 5.19 (m, 1H),
4.74 (qd, J ) 9.3, 2.7 Hz, 1H), 4.24 (br t, J ) 9.6 Hz, 1H), 3.72
(s, 3H), 3.02 (dd, J ) 20.0, 9.9 Hz, 1H), 2.76 (br d, J )18 Hz,
0.6H, major rotamer), 2.67 (br d, J ) 18 Hz, 0.4H, minor
rotamer), 1.44 (s, 9H); IR (CDCl3) 2980, 2953, 1691, 1613, 1439,
1409, 1384, 1257, 1132, 1030 cm-1 ; MS m/e 265 (M+), 234,
209, 192, 177, 149, 133, 105, 77, 57. HRMS calcd for C14H19
NO4 265.1314; found 265.1315.
-
1-[(1,1-Dim eth yleth oxy)car bon yl]-2-ph en ylpyr r ole (4d)
(petroleum ether, 2.43 g, 77%). 1H NMR (500 MHz, CDCl3) δ
7.35-7.38 (m, 5H), 7.32 (dd, J ) 3.4, 1.8 Hz, 1H), 6.24 (dd, J
) 3.4, 3.1 Hz, 1H), 6.20 (dd, J ) 3.1, 1.8 Hz, 1H), 1.36 (s, 9H);
13C NMR (75 MHz, CDCl3) δ 150.1, 135.7, 135.1, 129.8, 128.1,
127.7, 123.1, 114.9, 111.0, 83.9, 27.8; IR (neat) 3069, 3028,
2981, 2940, 1740, 1610, 1512, 1471, 1393, 1347 cm-1. HRMS
calcd for C15H17NO2 243.1259; found 243.1253.
2-Acetyl-1-[(1,1-d im eth yleth oxy)ca r bon yl]p yr r ole (4e)
(hexane/Et2O, 9:1-4:1, 19.2 g, 100%). 1H NMR (400 MHz,
CDCl3) δ 7.31 (m, 1H), 6.84 (m, 1H), 6.16 (t, J ) 3.4 Hz, 1H),
2.44 (s, 3H), 1.57 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 188.8,
149.2, 134.4, 128.0, 121.2, 110.0, 84.8, 27.7, 27.3; IR (neat)
3131, 2981, 2934, 1750, 1678, 1543, 1481, 1450, 1419, 1310,
1150 cm-1. Anal. Calcd for C11H15NO3: C, 63.14; H, 7.23; N,
6.69. Found: C, 63.24; H, 7.24; N, 6.72.
1-[(1,1-Dim eth yleth oxy)car bon yl]-3-m eth ylpyr r ole (4g)
(petroleum ether, 2.74 g, 49%). 1H NMR (200 MHz, CDCl3) δ
7.12 (t, J ) 2.7 Hz, 1H), 6.95 (m, 1H), 6.03 (dd, J ) 3.1, 1.8
Hz, 1H), 2.04 (s, 3H), 1.56 (s, 9H); 13C NMR (75 MHz, CDCl3)
δ 149.1, 122.5, 120.0, 117.3, 114.1, 83.0, 27.7, 11.5; IR (neat)
3152, 2986, 2924, 2878, 1740, 1559, 1491, 1393, 1346, 1253
cm-1. HRMS calcd for C10H15NO2 181.1103; found 181.1101.
1-[(1,1-Dim eth yleth oxy)ca r bon yl]-4,5,6,7-tetr a h yd r oin -
d ole (4h ) (petroleum ether, 7.30 g, 93%). 1H NMR (300 MHz,
CDCl3) δ 7.10 (d, J ) 3.4 Hz, 1H), 5.95 (d, J ) 3.4 Hz, 1H),
2.79 (t, J ) 6.4 Hz, 2H), 2.42 (t, J ) 6.0 Hz, 2H) 1.74 (m, 2H),
1.68 (m, 2H), 1.55 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 149.53,
129.33, 121.95, 119.08, 110.84, 82.54, 27.77, 24.52, 23.16,
22.60; IR (neat) 2971, 2933, 2851, 1734, 1368, 1324, 1160, 1128
cm-1; MS m/e (relative intensity) 221 (M+) (8), 166 (4), 165
(38), 148 (4), 121 (19), 120 (18), 93 (63), 57 (100). Anal. Calcd
for C13H19NO2: C, 70.56; H, 8.65; N, 6.33. Found: C, 70.34;
H, 8.69; N, 6.10.
Meth yl 8-[(1,1-Dim eth yleth oxy)ca r bon yl]-5-m eth yl-8-
a za bicyclo[3.2.1]octa -2,6-d ien e-2-ca r boxyla te (7), Meth yl
8-[(1,1-Dim eth yleth oxy)ca r bon yl]-1-m eth yl-8-a za bicyclo-
[3.2.1]octa -2,6-d ien e-2-ca r boxyla te (8), Meth yl 1-[(1,1-
Dim eth yleth oxy)ca r bon yl]-2-m eth yl-1,3,6,6a -tetr a h yd r o-
cyclop en t a [b ]p yr r ole-4-ca r b oxyla t e (9), a n d Met h yl
7-[(1,1-D i m e t h y le t h o x y )c a r b o n y l]-6-m e t h y l-7-a z a -
b icyclo[4.2.0]oct a -2,4-d ien e-2-ca r b oxyla t e (10) (2, 4:1
pentane/Et2O):
1
7: 0.241 g, 24% yield, 46% ee; H NMR (200 MHz, CDCl3)
δ 6.60 (br t, J ) 3.6 Hz, 1H), 6.24 (dd, J ) 6.1, 2.7 Hz, 1H),
5.57 (d, J ) 6.1 Hz, 1H), 5.00 (br s, 1H), 3.72 (s, 3H), 2.82 (br
d, J ) 19.8 Hz, 1H), 1.92 (dd, J ) 19.8, 3.8 Hz, 1H), 1.65 (s,
3H), 1.35 (s, 9H); 13C NMR (50 MHz, CDCl3) δ 165.4, 154.8,
137.5, 135.2, 134.0, 79.9, 63.4, 59.8, 51.7, 28.3, 22.7; IR (CDCl3)
3157, 2954, 2904, 1794, 1701, 1628, 1607, 1561, 1476, 1457
cm-1; MS m/e: 279 (M+), 248, 223, 191, 179, 147, 119, 91, 77,
57. Anal. Calcd for C15H21NO4: C, 64.48; H, 7.58; N, 5.02.
Found: C, 64.73; H, 7.63; N, 4.91.
8: 0.060 g, 6% yield, ∼0% ee; 1H NMR (200 MHz, CDCl3) δ
6.34 (br s, 1H), 6.18 (d, J ) 6.1 Hz, 1H), 5.78 (dd, J ) 6.1, 2.6
Hz, 1H), 5.59 (m, 1H), 3.70 (s, 3H), 2.90 (br d, J ) 15.3 Hz,
1H), 1.81 (s, 3H), overlapping a doublet of doublet at δ 1.85
(dd, J ) 15.3, 3.2 Hz, 1H), 1.42 (s, 9H); 13C NMR (50 MHz,
CDCl3) δ 166.2, 154.3, 144.0, 140.7, 134.9, 124.9, 79.8, 63.9,
59.2, 51.4, 28.2, 26.9, 20.5; IR (CDCl3) 2982, 2953, 1712, 1612,
1475, 1457, 1437, 1412, 1382, 1369 cm-1; MS m/e: 279 (M+),
223, 191, 179, 163, 147, 119, 91, 77, 57.
9: 19%; 1H NMR (200 MHz, CDCl3) δ 6.68 (m, 1H), 4.90
(dd, J ) 2.4, 1.2 Hz, 1H), 4.82 (ddd, J ) 9.8, 9.8, 3.0 Hz, 1H),
4.05 (m, 1H), 3.70 (s, 3H), 2.55-2.90 (m, 2H), 2.05 (br s, 3H),
1.37 (s, 9H). Compound 9 could not be isolated in pure form
and fully characterized due to its decomposition during chro-
matography. The structural assignment is based on the
similarity of the NMR data of 9 to that of 6, and the yield was
calculated from integration of the 1H NMR spectrum of the
crude reaction mixture.
Rh od iu m (II) Ca r boxyla te-Ca ta lyzed Decom p osition of
Vin yld ia zom eth a n es in th e P r esen ce of P yr r oles. Typ i-
ca l P r oced u r e. A solution of vinyldiazomethane (2.4 mmol)
in dry hexanes (50 mL) was added dropwise over 1 h to a
refluxing solution of pyrrole (12.0 mmol) and rhodium(II)
carboxylate (0.01 equiv) in dry hexanes (50 mL) under an
1
10: 0.211 g, 21%; H NMR (200 MHz, DMSO-d6) δ 6.89 (d,
J ) 5.4 Hz, 1H), 6.08 (m, 2H), 4.45 (dd, J ) 7.9, 6.7 Hz, 1H),
4.12 (dd, J ) 7.9, 7.9 Hz, 1H), 3.71 (s, 3H), 3.32 (dd, J ) 7.9,

1102 J . Org. Chem., Vol. 62, No. 4, 1997
Davies et al.
6.7 Hz, 1H), 1.56 (s, 3H), 1.41 (s, 9H); IR (CDCl3) 3154, 3046,
2979, 2954, 2931, 1792, 1587, 1499, 1475, 1458 cm-1. Com-
pound 10 decomposes to give methyl 3-methylbenzoate.
(neat) 2960, 2920, 1785, 1750, 1715, 1145, 1080 cm-1. Anal.
Calcd for C10H14O5: C, 56.07; H, 6.59. Found: C, 56.18; H,
6.64.
A solution of (R)-tetrahydro-4,4-dimethyl-2-oxo-3-furanyl
3-oxobutanoate (10.1 g, 46.9 mmol) in dry acetonitrile (150 mL)
was prepared and cooled to 0 °C. p-ABSA (11.8 g, 49.3 mmol)
was added followed by Et3N (6.25 mL, 44.8 mmol) with
stirring, giving a tan precipitate. The reaction mixture was
stirred for 1 h, and NH4Cl (saturated aqueous 10 mL) was
added. The reaction mixture was filtered, and the precipitate
washed with 1:1 petroleum ether/Et2O. To the filtrate was
added water (400 mL), and the layers were separated. The
aqueous layer extracted with CH2Cl2 (3 × 100 mL), and the
organic layers were combined, dried (Na2SO4), and evaporated
under reduced pressure. The residue was triturated with 1:1
petroleum ether/Et2O and then chromatographed (1:1 petro-
leum ether/Et2O) to give the title product as a colorless solid.
Recrystallization from Et2O/petroleum ether gave pure color-
less solid (mp ) 96-97 °C). Yield: 9.12 g (38.0 mmol, 81%,
61% overall). 1H NMR (200 MHz, CDCl3) δ 5.46 (s, 1H), 4.08
(s, 2H), 2.50 (s, 3H), 1.26 (s, 3H), 1.13 (s, 3H); 13C NMR (50
MHz, CDCl3) δ 189.2, 171.7, 160.2, 85.9, 76.1, 75.6, 40.1, 28.3,
Meth yl 8-(Meth oxyca r bon yl)-8-a za bicyclo[3.2.1]octa -
2,6-d ien e-2-ca r boxyla te7 (11) (2, 4:1-1:1 pentane/Et2O,
0.396 g, 44% yield, 42% ee).
Met h yl 8-Acet yl-8-a za b icyclo[3.2.1]oct a -2,6-d ien e-2-
ca r boxyla te (12) (2, 3:1-9:1 EtOAc/hexanes, 0.262 g, 46%
yield, 17% ee). 1H NMR (200 MHz, CDCl3, rotamers) δ 6.54
(m, 1H), 6.45 (dd, J ) 6.0, 2.6 Hz, 1H), 5.94 (dd, J ) 6.0, 2.6
Hz, 1H), 5.42 (m, 0.25H), 4.97 (t, J ) 1.1, 1.5H), 4.58 (m,
0.25H), 3.74 (s, 3H), 2.86 (ddd, J ) 20.0, 5.8, 3.1 Hz, 0.75H),
2.68 (ddd, J ) 19.5, 5.4, 2.9 Hz, 0.25H), 2.07 (dd, J ) 19.7, 4.0
Hz, 0.25H), 2.02 (s, 0.75H), 1.97 (s, 2.25H), 1.92 (dd, J ) 20.0,
4.0 Hz, 0.75H). HRMS calcd for C11H13NO3 207.0895; found
207.0895.
Meth yl 8-(Meth ylsu lfon yl)-8-a za bicyclo[3.2.1]octa -2,6-
d ien e-2-ca r boxyla te (13) (2, 1:1-1:4 pentane/Et2O, 0.134 g,
1
34% yield, 29% ee as determined by H NMR using 17 mol %
Pr(hfc)3 in CDCl3). 1H NMR (200 MHz, CDCl3) δ 6.56 (m, 1H),
6.53 (dd, J ) 5.8, 2.1 Hz, 1H), 5.93 (dd, J ) 5.8, 2.1 Hz, 1H),
5.11 (d, J ) 1.1 Hz, 1H), 4.70 (d, J ) 6.0 Hz, 1H), 3.75 (s, 3H),
2.86 (ddd, J ) 19.8, 5.8, 2.9 Hz, 1H), 2.67 (s, 3H), 2.07 (dd, J
) 19.6, 3.9 Hz, 1H); 13C NMR (50 MHz, CDCl3) δ 164.4, 138.3,
135.7, 130.0, 127.6, 59.7, 58.9, 52.0, 38.4, 29.0. Anal. Calcd
for C10H13NO4S: C, 49.37; H, 5.39; N, 5.76. Found: C, 49.31;
H, 5.43; N, 5.65.
22.9, 19.8; IR (neat) 2960, 2135, 1775, 1720, 1640, 1095 cm-1
;
[R]25 ) +4.6° (CDCl3, c 2.29). Anal. Calcd for C10H12N2O5:
D
C, 50.00; H, 5.05; N, 11.66. Found: C, 49.96; H, 4.99; N, 11.66.
(1S)-2-Eth oxy-1-m eth yl-2-oxoeth yl 2-Diazo-3-bu ten oate6a
(18a ). A solution of 17a (23.0 g, 101 mmol) in absolute ethanol
(125 mL) was prepared and cooled to 0 °C. Sodium borohy-
dride (4.25 g, 112 mmol) was added in portions with stirring
over 10 min. After 2 h, the reaction mixture was poured into
500 mL of cold NH4Cl (saturated aqueous), and the mixture
was extracted with CH2Cl2 (4 × 150 mL). The organic layers
were combined and back-extracted with 150 mL of brine, dried
(MgSO4), and the solvent evaporated at 25 °C under reduced
pressure to give a light yellow oil.26
(1S)-2-E t h oxy-1-m et h yl-2-oxoet h yl 2-d ia zo-3-oxob u -
ta n oa te (17a ). A solution of (S)-ethyl lactate (100 g, 0.848
mol) and 2,2,6-trimethyl-4H-1,3-dioxin-4-one (diketene-ac-
etone adduct, 100 mL, 0.766 mol) was prepared in 400 mL
toluene. The reaction was heated to reflux for 2 h and then
allowed to cool to room temperature. The solvent was evapo-
rated under reduced pressure to give (1S)-2-Ethoxy-1-methyl-
2-oxoethyl 3-oxobutanoate (150 g) as a dark oil, which was used
without further purification for the next step.
The oil was dissolved in dry CH2Cl2 (125 mL), and triethyl-
amine (75 mL, 538 mmol) was added. The solution was cooled
to 0 °C in an ice bath, and a solution of POCl3 (21 mL, 0.23
mol) in CH2Cl2, (10 mL) was added dropwise with stirring over
15 min. The mixture was stirred overnight while slowly
warming to room temperature. The reaction was then slowly
added to cold H2O (500 mL). The layers were separated, and
the aqueous layer was extracted with CH2Cl2 (100 mL). The
organic layers were combined and washed with cold NaHCO3
(saturated aqueous 250 mL) followed by cold brine (400 mL).
The solvent was then evaporated under reduced presure to
give a brown oil. The crude product was triturated with 4:1
petroleum ether/Et2O and then chromatographed (4:1 petro-
leum ether/Et2O) to give the title compound as a yellow-orange
oil. Yield: 15.0 g (70.7 mmol, 70%). Once characterized (1H
NMR), the product can be stored for several weeks in solution
at -20 °C without decomposition. 1H NMR (200 MHz, CDCl3)
δ 6.09 (dd, J ) 17.4, 11.0 Hz, 1H), 5.09 (q, J ) 7.1 Hz, 1H),
5.04 (d, J ) 11.0 Hz, 1H), 4.80 (d, J ) 17.4 Hz, 1H), 4.12 (q, J
) 7.2 Hz, 2H), 1.43 (d, J ) 7.1 Hz, 3H), 1.19 (t, J ) 7.2 Hz,
3H); 13C NMR (50 MHz, CDCl3) δ 170.4, 163.9, 120.0, 107.6,
69.0, 61.3, 52.2, 16.8, 13.9; IR (neat) 2975, 2080, 1740, 1695,
A solution of all of the above material in 2 L acetonitrile
was prepared, and p-acetamidobenzenesulfonyl azide (p-ABSA,
194 g, 0.808 mol) was added with mechanical stirring. Tri-
ethylamine (116 mL, 832 mmol) was then added, and a cream-
colored precipitate formed within 1 min. The reaction was
stirred for 12 h at room temperature. The reaction mixture
was filtered, and the filter cake washed with Et2O. The filtrate
was evaporated to give a tacky, oily solid which was triturated
thoroughly with 1:1 petroleum ether/Et2O and filtered. The
filtrate was evaporated to give a light brown oil, which was
then chromatographed on silica gel (4:1 petroleum ether/Et2O)
to give the title compound as a pale yellow oil. Yield: 133 g
(0.583 mol, 76% overall). 1H NMR (200 MHz, CDCl3) δ 5.18
(q, J ) 7.1 Hz, 1H), 4.21 (q, J ) 7.1 Hz, 2H), 2.45 (s, 3H), 1.52
(d, J ) 7.1 Hz, 3H),1.27 (t, J ) 7.1 Hz, 3H); 13C NMR (50 MHz,
CDCl3) δ 189.0, 170.0, 160.3, 75.7, 68.9, 65.3, 27.6, 16.4, 14.8,
13.6; IR (neat) 2980, 2135, 1715, 1655, 1360, 1210, 1095 cm-1
;
[R]25 ) +31.4° (CDCl3, c 5.06). Anal. Calcd for C9H12N2O5:
D
C, 47.37; H, 5.30; N, 12.28. Found: C, 47.43; H, 5.35; N, 12.18.
(R)-Tetr a h yd r o-4,4-d im eth yl-2-oxofu r a n yl 2-Dia zo-3-
oxobu ta n oa te (17b). To a solution of (R)-pantolactone (20.0
g, 0.154 mol) and pyridine (1.5 mL, 18.5 mmol) in dry
acetonitrile (150 mL) was added diketene (14.2 g, 0.169 mol),
and the mixture was heated to reflux for 2 h. Additional
diketene (11.6 g, 0.138 mol) was added, and the heating was
continued for an additional 2 h. The reaction mixture was
concentrated under reduced pressure, and the residue was
dissolved in CH2Cl2 (400 mL), washed with CuSO4 (aqueous
100 mL), NaHCO3 (saturated aqueous 100 mL), dried (Na2-
SO4), and concentrated to give a brown oil (46.2 g). Distillation
(120-130 °C, 0.2 mmHg) gave an impure acetoacetate which
was further purified by trituration with 10% Et2O in pentane
to give pure (R)-tetrahydro-4,4-dimethyl-2-oxo-3-furanyl 3-
oxobutanoate (16.3 g, 75%) as a pale yellow solid (mp ) 38-
44 °C). 1H NMR (200 MHz, CDCl3) δ 5.41 (s, 1H), 4.04 (s, 2H),
3.62 (s, 1H), 3.60 (s, 1H), 2.30 (s, 3H), 1.24 (s, 3H), 1.10 (s,
3H); 13C NMR (50 MHz, CDCl3) δ 199.5, 171.7, 165.6, 75.8,
75.2, 49.2, 40.1, 29.9, 22.4, 19.5; MS m/e (relative intensity)
1610, 1100 cm-1; [R]25 ) +40.5° (CDCl3, c 2.32). Due to lack
D
of stability, elemental analysis was not attempted on 18a .
(Tetr a h yd r o-4,4-d im eth yl-2-oxo-3-fu r a n yl) 2-Dia zo-3-
bu ten oa te6a (18b). To a solution of 17b (1.00 g, 4.16 mmol)
in THF (75 mL) at 0 °C was added lithium tri-tert-butoxyalu-
minum hydride (3.18 g, 12.51 mmol). After 1 h, NH4Cl
(saturated aqueous 10 mL) was added, and the aluminum salts
were removed by filtration through Celite. The filtrate was
then poured into water (300 mL), extracted with CHCl3 (4 ×
100 mL), dried (Na2SO4), and concentrated under reduced
pressure to give a yellow oil (1.16 g). The oil was redissolved
in freshly distilled CH2Cl2 (50 mL), and Et3N (2.5 mL, 17.9
mmol) was added. The mixture was stirred under argon at
-20 °C for 10 min, and freshly distilled POCl3 (0.50 mL, 5.4
mmol) in CH2Cl2 (10 mL) was added dropwise over 10 min.
The mixture was allowed to warm to rt and left to stir for 24
h. The reaction mixture was poured into ice-water (500 mL),
extracted with CH2Cl2 (3 × 100 mL), dried (Na2SO4), and
concentrated under reduced pressure to give a red oil. The
71 (100), 57 (22), 43 (70), [R]25 ) -15.1° (CDCl3, c 4.0); IR
D

Enantioselective Synthesis of Functionalized Tropanes
J . Org. Chem., Vol. 62, No. 4, 1997 1103
crude product was purified by silica gel chromatography
(column washed prior to use with 5% Et3N in petroleum ether
to remove acidic sites) using 4:1 petroleum ether/Et2O to give
the title compound as a yellow oil. Yield: 307 mg (1.37 mmol,
33%). 1H NMR (200 MHz, CDCl3) δ 6.17 (dd, J ) 17.4, 11.0
Hz, 1H), 5.47 (s, 1H), 5.18 (d, J ) 11.0 Hz, 1H), 4.93 (d, J )
17.4 Hz, 1H), 4.07 (s, 2H), 1.24 (s, 3H), 1.12 (s, 3H); 13C NMR
(50 MHz, CDCl3) δ 171.9, 163.1, 119.4, 108.1, 75.6, 75.2, 39.9,
22.4, 19.4; IR (neat) 2960, 2920, 2090, 1780, 1700, 1300, 1115
cm-1; [R]25D ) +5.70° (CDCl3, c 1.08). Due to lack of stability,
elemental analysis was not attempted on 18b.
ethanol. The flask was pressurized to 45 psi with hydrogen
and agitated for 24 h. The solvent was then removed under
reduced pressure to give the crude product, which was purified
by column chromatography (4:1-1:1 petroleum ether/Et2O) to
give the title compound as an oil. Yield: 0.78 g (2.12 mmol,
83%). 1H NMR (300 MHz, CDCl3) δ 6.85 (m, 1H), 5.08 (q, J )
7.1 Hz, 1H), 4.98 (d, J ) 6.0 Hz, 1H), 4.50 (q, J ) 7.1 Hz, 2H),
2.87 (br d, J ) 19.5 Hz, 1H), 2.01 (dd J ) 19.5, 4.2 Hz, 1H),
1.62-2.02 (m, 4H), 1.59 (s, 3H), 1.52 (d, J ) 7.1 Hz, 3H), 1.38
(s, 9H), 1.24 (t, J ) 7.1 Hz, 3H). Anal. Calcd for C19H29NO6:
C, 62.11; H, 7.96; N, 3.81. Found: C, 61.98; H, 7.92; N, 3.74.
All of the other tropanes were hydrogenated using a similar
procedure except for 20h , where Pd/C was used. Tropane 20c
was not further derivatized. Purification and full character-
ization were carried out on 24d and 24h . Characterization
data, solvent for chromatographic purification, amount of
product and reaction yields are provided in the Supporting
Information.
(1S)-2-Eth oxy-1-m eth yl-2-oxoeth yl (1R,5R)-8-[(1,1-Di-
m eth yleth oxy)car bon yl]-8-azabicyclo[3.2.1]octa-2,6-dien e-
2-ca r boxyla te (20a ) (Rh(OOct)4, 37.0 g, 75% yield, 66% de).
1H NMR (200 MHz, CDCl3) δ 6.62 (br s, 1H), 6.43 (br s, 1H),
5.92 (br d, J ) 2.9 Hz, 1H), 5.10 (q, J ) 7.0 Hz, 1H), 4.99 (br
s, 1H), 4.60 (br s, 1H), 4.18 (q, J ) 7.1 Hz, 2H), 3.05 - 2.60 (br
m, 1H), 1.91 (br dd, J ) 19.8, 3.4 Hz, 1H), 1.50 (d, J ) 7.0 Hz,
3H), 1.41 (s, 9H), 1.25 (t, J ) 7.1 Hz, 3H); 1H NMR (200 MHz,
toluene-d8, 95 °C) δ 6.64 (br s, 1H), 6.46 (dd, J ) 6.1, 2.5 Hz,
0.17H, minor diastereomer), 6.41 (dd, J ) 6.1, 2.5 Hz, 0.83H,
major diastereomer), 5.71 (dd, J ) 6.1, 2.5 Hz, 1H), 5.39 (br s,
1H), 5.32 (q, J ) 7.0 Hz, 1H), 4.62 (br s, 1H), 4.15 (q, J ) 7.1
Hz, 2H), 2.85 (br d, J ) 20 Hz, 1H), 1.61 (br dd, 1H, J ) 20,
3.7 Hz), 1.60 (s, 9H), 1.52 (d, J ) 7.0 Hz, 1H), 1.19 (t, J ) 7.1
Met h yl (1R,5S)-8-[(1,1-Dim et h ylet h oxy)ca r b on yl]-8-
a za bicyclo[3.2.1]octa -2-en e-2-ca r boxyla te (25a ). To a so-
lution of NaOMe (77.6 g, 1.44 mol) in dry methanol (850 mL)
at 0 °C was added a solution of 24a (67 g, 0.18 mol) in
methanol (200 mL) over 15 min. The reaction was stirred for
1 h, and the mixture was then concentrated under reduced
pressure. The mixture was added to NH4Cl (saturated aque-
ous 1L), and the aqueous solution was extracted with Et2O (3
× 300 mL). The organic extracts were combined, back-
extracted with brine (500 mL), dried (MgSO4), and filtered
through a pad of silica gel. The filtrate was evaporated to give
the title compound as an orange oil. Yield: 43.5 g (0.163 mol,
90%). 1H NMR (200 MHz, CDCl3) δ 6.74 (br t, J ) 2.8 Hz,
1H), 4.79 (br d, J ) 2.8 Hz, 1H), 4.30 (br s, 1H), 3.73 (s, 3H),
3.00-2.65 (br m, 1H), 2.19-1.44 (m, 5H), 1.41 (s, 9H); IR (neat)
Hz, 3H); IR (neat) 2965, 1710, 1620, 1440, 1365, 1090 cm-1
;
[R]25 ) +33.8° (CHCl3, c 2.32). Anal. Calcd for C18H25NO6:
D
C, 61.52; H, 7.17; N, 3.93. Found: C, 61.63; H, 7.22; N, 3.93.
(1S)-2-Eth oxy-1-m eth yl-2-oxoeth yl (1R,5R)-8-[(1,1-Di-
m eth yleth oxy)ca r bon yl]-3-[(1,1-d im eth yleth oxy)siloxy]-
8-azabicyclo[3.2.1]octa-2,6-dien e-2-car boxylate (21a). (Rh2-
(OOct)4, 9:1-4:1 petroleum ether/Et2O, 1.45 g, 64% yield, 66%
de). 1H NMR (500 MHz, toluene-d8, 95 °C) δ 6.42 (br s, 0.17H,
minor diastereomer), 6.30 (dd, J ) 5.7, 1.5 Hz, 0.83H, major
diastereomer), 5.54 (dd, J ) 5.7, 2.4 Hz, 1H), 5.35 (br s, 1H),
5.14 (q, J ) 7.0 Hz, 1H), 4.50 (br s, 1H), 3.96 (q, J ) 7.2 Hz,
2H), 2.84 (br d, J ) 18.0 Hz, 1H), 1.56 (d, J ) 18.0 Hz, 1H),
1.45 (s, 9H), 1.33 (d, J ) 7.0 Hz, 3H), 1.01 (t, J ) 7.2 Hz, 3H),
0.93 (s, 9H), 0.19 (s, 3H), 0.15 (s, 3H); IR (neat) 2984, 2943,
2870, 1690, 1245, 1160, 1095, 975, 875, 755 cm-1; [R]25
)
D
-47.2° (CHCl3, c 2.45); MS m/e (relative intensity) 211 (31),
138 (47), 57 (100). Anal. Calcd for C14H21NO4: C, 62.90; H,
7.92; N, 5.24. Found: C, 62.66; H, 7.95; N, 5.29.
Methanolysis was carried out on all of the other tropanes
using a similar procedure. Purification and full characteriza-
tion was carried out on 25b, 25g, and 25h . Chromatography
solvents, amounts, and reaction yields are provided in the
Supporting Information.
2855, 1760, 1714, 1604, 1374, 1262 cm-1
. Anal. Calcd for
C24H39NO7Si: C, 59.85; H, 8.16; N, 2.91. Found: C, 59.75; H,
8.14; N, 2.80.
(3R)-Tetr a h yd r o-4,4-d im eth yl-2-oxo-3-fu r a n yl (1S,5S)-
8-[(1,1-Dim eth yleth oxy)car bon yl]-8-azabicyclo[3.2.1]octa-
2,6-d ien e-2-ca r boxyla te (22a ). (Rh2(OOct)4, 9:1-1:1 petro-
leum ether/Et2O, 21 mg, 64% yield, 69% de). 1H NMR (200
MHz, CDCl3) δ 6.64 (br s, 1H), 6.39 (br s, 1H), 5.92 (br s, 1H),
5.37 (s, 1H), 4.96 (br s, 1H), 4.59 (br s, 1H), 4.01 (s, 2H), 2.90
(br d, J ) 24 Hz, 1H), 1.89 (br dd, J ) 20.1, 3.3 Hz, 1H), 1.37
(s, 9H), 1.18 (s, 3H), 1.07 (s, 3H); 1H NMR (200 MHz, toluene-
d8, 95 °C) δ 6.66 (br s, 1H), 6.44 (dd, J ) 6.1, 2.4 Hz, 0.16H,
minor diastereomer), 6.35 (dd, J ) 6.1, 2.4 Hz, 0.84H, major
diastereomer), 5.68 (dd, J ) 6.1, 2.4 Hz, 1H), 5.33 (br s, 2H),
4.60 (br s, 1H), 3.68 (br s, 2H), 2.82 (br d, J ) 20 Hz, 1H), 1.58
(s, 9H), 1.56 (br dd, J ) 17.5, 3.9 Hz, 1H), 0.98 (s, 3H), 0.92 (s,
(1R,5S)-[(1,1-Dim eth yleth oxy)ca r bon yl]-8-a za bicyclo-
[3.2.1]octa -2-en e-2-ca r boxylic Acid (26a ). A solution of 25a
(19.9 g, 74.4 mmol) and LiOH‚H2O (4.7 g, 0.11 mol) in
methanol/water (3:1, 200 mL) was heated under reflux for 7
h. The mixture was cooled to rt, poured into water (400 mL),
and extracted with CH2Cl2 (75 mL). The aqueous solution was
slowly acidified with concd HCl to pH 2,27 and then extracted
with CH2Cl2 (3 × 125 mL). The organic extracts were
combined, dried (MgSO4), and evaporated to give 26a as a tan
solid (mp 154-158 °C). Yield: 18.1 g (71.5 mmol, 96%). 1H
NMR (CDCl3) δ 6.89 (br s, 1H), 4.80 (br s, 1H), 4.38-4.28 (br
d, 1H), 3.00-2.90 (br s, 1H), 2.20 (m, 1H), 2.12-1.80 (m, 3H),
1.60 (br s, 1H), 1.45 (s, 9H). IR (neat) 3600-2400 (broad),
3H); [R]25 ) -14.0° (CHCl3, c 1.83). HRMS calcd for C19H25
-
1700, 1696, 1636, 1419, 1411, 1394 cm-1
. Anal. Calcd for
D
NO6 363.1682; found 363.1691.
C13H19NO4: C, 61.64; H, 7.56; N, 5.53. Found: C, 61.52; H,
7.59; N, 5.44.
(3R)-Tetr a h yd r o-4,4-d im eth yl-2-oxo-3-fu r a n yl (1S,5S)-
8-(1,1-Dim e t h yl-e t h oxyca r b on yl)-3-[(1,1-d im e t h yle t h -
oxy)siloxy]-8-a za bicyclo[3.2.1]octa -2,6-d ien e-2-ca r boxy-
la te (23a ) (Rh2(OOct)4, 9:1-4:1 petroleum ether/Et2O, 4.08 g,
66% yield, 68% de). 1H NMR (500 MHz, toluene-d8, 95 °C) δ
6.41 (dd, J ) 6.1, 2.4 Hz, 0.16H, minor diastereomer), 6.25
(dd, J ) 6.0, 2.3 Hz, 0.84H, major diastereomer), 5.56 (dd, J
) 6.0, 2.6 Hz, 1H), 5.30 (br s, 1H), 5.15 (s, 1H), 4.50 (br d, J )
2.3 Hz, 1H), 3.43 (d, J ) 8.9 Hz, 1H), 3.29 (d, J ) 8.9 Hz, 1H),
2.88 (br d, J ) 18.0 Hz, 1H), 1.57 (d, J ) 18.0 Hz, 1H), 1.45 (s,
9H), 0.93 (s, 9H), 0.79 (s, 3H), 0.74 (s, 3H), 0.21 (s, 3H), 0.16
(s, 3H); IR (neat) 2966, 2934, 2857, 1797, 1724, 1698, 1600,
(1R ,5S )-2-Ace t yl-[(1,1-d im e t h yle t h oxy)ca r b on yl]-8-
a za bicyclo[3.2.1]octa -2-en e4a (28a ). A solution of 26a (2.54
g, 10.0 mmol) in 50 mL of dry CH2Cl2 was prepared, and SOCl2
(1.1 mL, 15 mmol) was added. The mixture was heated to
reflux for 1 h. After the reaction cooled to rt, the solvent was
evaporated, and excess SOCl2 was removed under vacuum to
give the acid chloride (27a ), which was characterized by 1H
NMR and used without further purification. 1H NMR (CDCl3)
δ 7.20 (br s, 1H), 4.83 (br s, 1H), 4.36 (br s, 1H), 3.0 (br s, 1H),
2.25-2.05 (m, 3H), 1.92 (m, 1H), 1.59-1.65 (m, 1H), 1.43 (s,
9H).
A 250 mL, three-necked flask was charged with CuBr‚SMe2
(2.45 g, 11.9 mmol) and cooled to -78 °C under argon. With
mechanical stirring, a solution of MeMgBr in Et2O (Aldrich,
10 mL, 30 mmol) was added, giving a yellow paste. A solution
of 27a in 50 mL of dry THF was added dropwise over 30 min
via a pressure-equalized addition funnel with stirring. The
reaction was stirred for 2 h at -78 °C and then quenched with
1471, 1367, 1253 cm-1
. Anal. Calcd for C25H39NO7Si: C,
60.82; H, 7.96; N, 2.84. Found: C, 60.71; H, 8.01; N, 2.76.
(1S)-2-E t h oxy-1-m et h yl-2-oxoet h yl (1R,5S)-8-[(1,1-Di-
m eth yleth oxy)car bon yl]-5-m eth yl-8-azabicyclo[3.2.1]octa-
2-en e-2-ca r boxyla te (24b). A Parr hydrogenator flask was
charged with a solution of 20b (0.937 g, 2.55 mmol) and
(PPh3)3RhCl (47 mg, 0.051 mmol, 2 mol %) in 45 mL absolute

1104 J . Org. Chem., Vol. 62, No. 4, 1997
Davies et al.
75 mL of NH4Cl (saturated aqueous). The reaction was
warmed to rt and 100 mL of Et2O added. The mixture was
filtered, and the layers were separated. The aqueous layer
was extracted with Et2O (2 × 50 mL). The organic layers were
combined, back-extracted with 100 mL of brine, and dried
(MgSO4), and the solvent evaporated. The crude product was
chromatographed (2:1 petroleum ether/Et2O) to give the title
compound as a yellow oil. Yield: 1.88 g (7.47 mmol, 75% from
26a ).
(1R,5S)-[(1,1-Dim eth yleth oxy)ca r bon yl]-2-p r op ion yl-8-
a za bicyclo[3.2.1]octa -2-en e2a (29a ). A sample of 26a (10.1
g, 40.0 mmol) was converted to the acid chloride (27a ) as
described above. A solution of 27a in 100 mL dry of THF was
prepared, and Pd2(dba)3 (550 mg, 0.600 mmol, 1.5 mol %) was
added. The reaction mixture was cooled to 0 °C, and a solution
of diethylzinc in hexanes (Aldrich, 40 mL, 40 mmol) was added
with stirring. After 30 min, the reaction was quenched at 0
°C by addition of 300 mL of NaHCO3 (saturated aqueous) The
mixture was stirred for 1 h, and Et2O (300 mL) was added.
The layers were separated, and the aqueous layer was
extracted with Et2O (2 × 150 mL). The organic layers were
combined, back-extracted with 150 mL of brine, dried (MgSO4),
and evaporated. The crude product was purified by column
chromatography (2:1 petroleum ether/Et2O) to give the title
compound as a yellow oil. Yield: 5.0 g (18.8 mmol, 47% overall
from 26a ).
Meth yl (1R,5S)-8-Aza bicyclo[3.2.1]octa -2-en e-2-ca r box-
yla te7 (30a ). A solution of 25a (4.02 g, 15.0 mmol) in dry CH2-
Cl2 (40 mL) was prepared and TFA (12 mL, 156 mmol, 10
equiv) added. The reaction was stirred for 1 h and poured
into H2O (40 mL). The layers were separated, and the organic
layer was washed with H2O (30 mL). The aqueous layers were
combined, and brine (40 mL) was added. The solution was
basified with concd NH4OH (aqueous) and extracted with CH2-
Cl2 (4 × 50 mL). The solution was dried (MgSO4), and
evaporated to give the title compound as a light yellow oil.
Yield: 2.08 g (12.4 mmol, 83%).
The other tropanes were deprotected using a similar pro-
cedure. Purification was achieved via either column chroma-
tography, Kugelrohr distillation, or recrystallization. Chro-
matography solvents, amounts, and overall yields from the
starting tropanes 20 are given in parentheses.
Meth yl (1R,5R,6R)-6-Meth yl-8-a za bicyclo[3.2.1]octa -2-
en e-2-ca r boxyla te (30g) (19:1-9:1 Et2O/Et3N, 0.43 g, 60%
overall from 20g). 1H NMR (300 MHz, CDCl3) δ 6.72 (m, 1H),
4.02 (d, J ) 6.4 Hz, 1H), 3.73 (s, 3H), 3.55 (t, J ) 6.0 Hz, 1H),
2.43-2.48 (m, 2H), 2.22-2.78 (m, 2H), 1.74 (br s, 1H), 1.34
(dd, J ) 12.2, 4.3 Hz, 1H), 1.03 (d, J ) 7.0 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 166.1, 140.1, 136.4, 56.1, 52.9, 51.5, 42.3,
36.2, 29.4, 18.1; IR (neat) 3307, 3224, 2955, 2872, 1714, 1647,
1445, 1378, 1274, 1171 cm-1. Anal. Calcd for C10H15NO2: C,
66.27; H, 8.34; N, 7.73. Found: C, 66.17; H, 8.40; N, 7.63.
The triplet at δ 3.55 for the bridgehead proton confirms the
endo-stereochemistry of the methyl group.
Met h yl (1R,5R,7R)-12-Aza t r icyclo[5.4.11.5.01.7]d od eca -
3-en e-4-ca r boxyla te (30h ) (9:1 hexane/EtOAc, 0.35 g, 57%
overall from 20h ). 1H (300 MHz, CDCl3) δ 6.63 (d, J ) 3.7
Hz, 1H), 4.12 (dd, J ) 7.5, 1.4 Hz, 1H), 3.69 (s, 3H), 2.59 (dd,
J ) 20.5, 3.6 Hz, 1H), 2.24 (ddd, J ) 12.2, 10.6, 7.4 Hz, 1H),
2.07 (ddd, J ) 20.5, 4.0, 1.4 Hz, 1H), 1.81-1.62 (m, 6H), 1.49-
1.36 (m, 2H), 1.32-1.22 (m, 2H), 1.19-1.15 (m, 1H); 13C NMR
(300 MHz, CDCl3) δ 165.7, 143.0, 137.0, 59.0, 51.3, 51.2, 49.6,
38.8, 38.1, 33.1, 26.2, 25.2, 21.0; IR (neat) 3297, 3219, 2939,
2851, 1708, 1652, 1434, 1258, 1191, 1072 cm-1; MS m/e 221
(M+) (100), 220 (66), 206 (28), 192 (10), 190 (13), 178 (25), 164
(47), 162 (41), 161 (43), 151 (28), 106 (7). HRMS calcd for
C13H19NO2 221.1415; found: 221.1398.
(1R,5S)-2-Acetyl-8-a za bicyclo[3.2.1]octa -2-en e4a,7 (31a ).
Prepared from 28a in 99% yield using the general BOC-
deprotection procedure described above.
(1R,5S)-2-P r opion yl-8-azabicyclo[3.2.1]octa-2-en e2a (32a).
Prepared from 29a in quantitative yield using the general
BOC-deprotection procedure described above.
Con ver sion of 21a to 24a . A sample of 21a was first
hydrogenated using the general hydrogenation procedure
described above to give (1S)-2-ethoxy-1-methyl-2-oxoethyl
(1R,5R)-8-[(1,1-dimethylethoxy)carbonyl]-3-[(1,1-dimethyl-
ethoxy)siloxy]-8-azabicyclo[3.2.1]octa-2-ene-2-carboxylate, which
was then desilyated using the following procedure: To a
solution of the above tropane (3.38 g, 7.0 mmol) in dry THF
(25 mL) was added a 1 M solution of TBAF (7.0 mL, 7.0 mmol)
in THF dropwise. The mixture was stirred at rt for 15 min,
and H2O (100 mL) was added. The mixture was extracted with
Et2O (3 × 100 mL), and the organic extracts were combined,
dried (MgSO4), and evaporated. The crude product was
purified by column chromatography (1:1 petroleum ether/Et2O)
to give the desired product as a mixture of tautomers. Yield:
1.92 g (5.20 mmol, 74%).
To a solution of the above material (2.44 g, 6.61 mmol) in
THF (25 mL) was added a solution of NaHMDS (1.0M, 7.0 mL,
7.0 mmol) in THF at -78 °C. After stirring for 30 min at -78
°C, the mixture was warmed to rt. N-Phenyltrifluoromethane-
sulfonimide (2.36 g, 6.61 mmol) was added all at once, and
the mixture was stirred overnight. The reaction was diluted
with NH4Cl (saturated aqueous) and H2O and then extracted
with CH2Cl2 (3 × 150 mL). The organic extracts were
combined, dried (MgSO4), and evaporated to give the crude
3-triflato derivative, which was used for the next step without
purification.
To a mixture of the crude triflate derivative (1.20 g, 2.39
mmol), tri-n-butylamine (2.0 mL, 8.64 mmol), triphenylphos-
phine (31 mg, 0.012 mmol), and PdCl2 (12 mg, 0.068 mmol) in
DMF (15 mL) was added 88% formic acid (0.24 mL, 5.8 mmol)
at rt. The mixture was heated for 2 h at 60 °C. The reaction
was cooled to rt, and EtOAc and H2O were added. The organic
layer was separated, washed with H2O, dried (MgSO4), and
evaporated to give crude 24a , which was purified by column
chromatography (9:1-7:3 petroleum ether/Et2O). Tropane 24a
was subsequently converted to 30a , whose absolute stereo-
chemistry was confirmed via conversion to its Mosher amide.
Syn th esis of Tr op a n e/Di-p-Tolu oyl Ta r tr a te Sa lts.
Gen er a l P r oced u r e. A solution of the enriched tropane in
absolute ethanol (15-25 mL/g) was prepared and the desired
enantiomer of di-p-toluoyl tartaric acid (1.1 equiv) added with
stirring. The reaction mixture was gently warmed to produce
a homogenous solution, and the solvent was evaporated. The
resulting solid was triturated with Et2O, filtered, washed with
Et2O, and dried in vacuo, producing the diastereomeric salt
Meth yl (1R,5S)-5-Meth yl-8-a za bicyclo[3.2.1]octa -2-en e-
2-ca r boxyla te (30b) (purified by Kugelrohr distillation, 96
°C, 0.75 torr; 0.21 g, 49% overall from 20b). 1H NMR (300
MHz, CDCl3) δ 6.69 (dd, J ) 4.5, 2.9 Hz, 1H), 4.10 (d, J ) 5.9
Hz, 1H), 3.66 (s, 3H), 2.30 (br d, J ) 19.3 Hz, 1H), 2.06 (dd, J
) 19.3, 4.5 Hz, 1H), 1.90 (m, 1H), 1.82 (m, 1H), 1.45-1.65 (m,
3H), 1.26 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.3, 137.8,
136.9, 57.5, 54.8, 51.2, 42.7, 36.5, 36.4, 27.0; IR (neat) 3302,
3229, 2955, 1715, 1647, 1440, 1274, 1239 cm-1. Anal. Calcd
for C10H15NO2: C, 66.26; H, 8.35; N, 7.73. Found: C, 66.00;
H, 8.39; N, 7.55.
Meth yl (1R,5S)-5-P h en yl-8-a za bicyclo[3.2.1]octa -2,6-d i-
en e-2-ca r boxyla te (30d ) (crystallized from hexane/Et2O, 1.11
g, 69% overall from 20d ). Mp ) 84-87 °C. 1H NMR (500
MHz, CDCl3) δ 7.46 (d, J ) 7.7 Hz, 2H), 7.36 (t, J ) 7.7 Hz,
3H), 6.83 (dd, J ) 4.2, 2.7 Hz, 1H), 4.38 (d, J ) 5.5 Hz, 1H),
3.78 (s, 3H), 2.60 (br dd, J ) 19.2, 2.7 Hz, 1H), 2.54 (dd, J )
19.2, 4.2 Hz, 1H), 2.02-2.20 (m, 4H), 1.73 (br s, 1H); 13C NMR
(75 MHz, CDCl3) δ 162.2, 147.8, 137.9, 136.5, 126.6, 124.9,
83.1, 54.5, 51.4, 44.0, 37.7, 36.0; IR (neat) 3416, 3064, 2950,
1714, 1652, 1440, 1367, 1238, 1088 cm-1
. Anal. Calcd for
C15H17NO2: C, 74.05; H, 7.04; N, 5.76. Found: C, 74.13; H,
7.08; N, 5.69.
Meth yl (1R,5S)-5-Acetyl-8-a za bicyclo[3.2.1]octa -2-en e-
2-ca r boxyla te (30e) (crystallized from hexane/Et2O, 0.43 g,
52% overall yield from 20e). Mp ) 64-68 °C. 1H NMR (500
MHz, CDCl3) δ 6.72 (dd, J ) 4.4, 2.8 Hz, 1H), 4.22 (d, J ) 5.5
Hz, 1H), 3.69 (s, 3H), 2.54 (br d, J ) 19.2 Hz, 1H), 2.36 (dd, J
) 19.2, 4.4 Hz, 1H), 2.21 (s, 3H), 1.85-2.05 (m, 4H), 1.72 (m,
1H); 13C NMR (125 MHz, CDCl3) δ 210.0, 165.6, 137.7, 135.4,
68.6, 54.8, 51.5, 37.3, 35.7, 34.0, 24.9; IR (neat) 3297, 2950,
2872, 1709, 1651, 1440, 1357, 1248, 1093 cm-1. Anal. Calcd
for C11H15NO3: C, 63.14; H, 7.23; N, 6.69. Found: C, 63.22;
H, 7.27; N, 6.62.

Enantioselective Synthesis of Functionalized Tropanes
J . Org. Chem., Vol. 62, No. 4, 1997 1105
as an off-white powder in 75-95% yield. The diastereomeric
Cl2 (5 mL), and added to 10 mL of NH4Cl (saturated aqueous).
The mixture was stirred for 30 min and the layers were
separated. The aqueous solution was extracted with CH2Cl2
(3 mL), and the organic layers were combined, dried (MgSO4),
and filtered through a silica plug in a 15 mL medium porosity
frit. The frit was washed with Et2O (2 × 5 mL), and the
filtrate was evaporated to give the R-Mosher amide, which was
characterized by 1H NMR (500 MHz). The S-Mosher amide
was prepared by repeating the reaction conditions with the
R-acid chloride. 1H NMR data for the Mosher amides studied
is presented in Tables 3 and 4.
purity was determined by integration of the diastereomeric
1
H(3) resonances in the H NMR spectrum (500 MHz, DMSO-
d6). The pure major diastereomer was obtained by performing
two or three successive recrystallizations by dissolving the salt
in a minimum amount of refluxing absolute ethanol and
allowing the solution to slowly cool to room temperature while
stirring. The crystallization can be seeded with a sample of
pure diastereomeric salt if available. After the slurry had
completely cooled to room temperature (∼2 h), it was filtered,
washed with a small amount of cold absolute ethanol followed
by Et2O, and dried in vacuo. The recovery yield of resolved
salt was typically approximately 40-55% after three crystal-
lizations.
(-)-An h yd r oecgon in e Meth yl Ester 6a,7 (33a ). A solution
of enantiomerically pure 30a (219 mg, 1.31 mmol) was
prepared in 20 mL of dry acetonitrile. An aqueous solution of
HCHO (37%, 0.5 mL, 6 mmol) was added and the solution
stirred for 5 min. Na(CN)BH3 (128 mg, 2.0 mmol) was added
with stirring, and the reaction was stirred for 1 h. The
reaction was quenched by slow addition of 20 mL of glacial
HOAc over 1 h. The reaction was diluted with H2O (50 mL),
neutralized by addition of NaHCO3 (s), and basified to pH 12
with 1 M NaOH (aqueous). The aqueous solution was ex-
tracted with CH2Cl2 (4 × 60 mL), and the organic extracts were
combined, dried (MgSO4), and evaporated to give the crude
product, which was chromatographed (10% Et3N in Et2O) to
give the title compound as a colorless oil. Yield: 177 mg (0.977
The enantiomerically pure tropane was recovered by dis-
solving the salt in concentrated NH4OH (aqueous) (10-15
mL/g of salt) and extracting with CH2Cl2 (3×). The organic
layers were combined, dried (MgSO4), and evaporated to give
the enantiomerically pure tropane in ∼90% yield.
Meth yl (1R,5S)-8-Aza bicyclo[3.2.1]octa -2-en e-2-ca r box-
1
yla te/Di-p-tolu oyl-D-ta r tr a te (38a ). Mp ) 154-160 °C. H
NMR (500 MHz, DMSO-d6) δ 7.82 (d, J ) 7.9 Hz, 4H), 7.31 (d,
J ) 8.2 Hz, 4H), 6.78 (dd, J ) 3.5, 3.5 Hz, 1H), 5.60 (s, 2H),
4.44 (d, J ) 5.2 Hz, 1H), 4.02 (br t, 1H), 3.70 (s, 3H), 2.76 (d,
J ) 19.8 Hz, 1H), 2.36 (s, 6H), 2.27 (dd, J ) 20.1, 4.3 Hz, 1H),
2.08-1.88 (m, 3H), 1.60-1.68 (m, 1H); 13C NMR (75 MHz,
DMSO-d6) δ 168.85, 165.32, 164.26, 144.01, 136.99, 131.36,
129.58, 129.48, 127.27, 72.51, 51.88 (2 carbons), 51.46, 32.99,
32.85, 27.54, 21.04. Anal. Calcd for C29H31NO10‚0.5H2O: C,
61.92; H, 5.73; N, 2.49. Found: C, 61.80; H, 6.05; N, 2.27.
(1R,5S)-2-Acetyl-8-azabicyclo[3.2.1]octa-2-en e/Di-p-tolu -
oyl-D-ta r tr a te (39a ). Mp ) 161-2 °C. 1H NMR (500 MHz,
DMSO-d6) δ 7.80 (d, J ) 8.5 Hz, 4H), 7.29 (d, J ) 9.0 Hz, 4H),
6.93 (dd, J ) 3.4, 3.4 Hz, 1H), 5.59 (s, 2H), 4.52 (d, J ) 6.0
Hz, 1H), 4.03 (dd, J ) 6.0, 5.5 Hz, 1H), 2.81 (d, J ) 20.5 Hz,
1H), 2.34 (s, 6H), 2.23 (s, 3H), 2.22 (dd, 1H, partially over-
lapped), 2.10-1.95 (m, 2H), 1.80 (m, 1H), 1.63 (m, 1H); 13C
NMR (75 MHz, DMSO-d6) δ 196.0, 168.6, 165.3, 144.1, 139.7,
137.8, 129.6, 129.5, 127.19, 51.7, 50.8, 33.1, 32.6, 27.6, 24.8,
21.0. Anal. Calcd for C29H31NO9‚0.5H2O: C, 63.73; H, 5.90;
N, 2.56. Found: C, 63.62; H, 6.21; N, 2.46.
mmol, 74%). Optical rotation: [R]25 ) -41.7° (c 1.50, CH3-
D
OH), lit. [R]25 ) -43°.5
D
(-)-F er r u gin in e7 (34a ). Prepared from 31a in 71% yield
using a procedure similar to that used for the synthesis of 33a .
Optical rotation: [R]25 ) -50.8° (c 0.94, CHCl3), lit. [R]19
)
D
D
-37°.28
(1R,5S)-8-Meth yl-2-p r op ion yl-8-a za bicyclo[3.2.1]octa -
2-en e (35a ). Prepared from 32a in 79% yield using a
procedure similar to that used for the synthesis of 33a .
Ack n ow led gm en t. This research was supported by
grants from the National Institute on Drug Abuse (DA-
06301, DA-06634) and the National Science Foundation
(CHE-9596192). We thank Dr. T. Hoye for helpful
discussions and making available to us preprints of his
publications on the stereochemical assignment of sec-
ondary amines using Mosher amides.
(1R,5S)-2-P r op ion yl-8-a za bicyclo[3.2.1]octa -2-en e/Di-p-
tolu oyl-D-ta r tr a te (40a ). Mp ) 126.5-129.5 °C. 1H NMR
(500 MHz, DMSO-d6) δ 7.79 (d, J ) 8.1 Hz, 4H), 7.28 (d, J )
8.1 Hz, 4H), 6.93 (dd, J ) 3.7, 3.4 Hz, 1H), 5.58 (s, 2H), 4.52
(d, J ) 5.8 Hz, 1H), 4.03 (dd, J ) 6.1, 5.5 Hz, 1H), 2.81 (d, J
) 20.1 Hz, 1H), 2.65 (q, J ) 7.3 Hz, 2H), 2.34 (s, 6H), 2.31
(dd, J ) 4.5, 20.8 Hz, 1H), 2.15-1.92 (m, 2H), 1.81 (m, 1H),
1.65 (m, 1H), 0.95 (t, J ) 7.2 Hz, 3H); 13C NMR (75 MHz,
DMSO-d6) δ 198.6, 168.6, 165.3, 144.0, 139.1, 136.4, 129.53,
129.46, 127.2, 71.9, 56.0, 51.8, 51.0, 33.1, 32.7, 29.4, 27.6, 21.0,
7.9. Anal. Calcd for C30H33NO9‚0.5H2O: C, 64.28; H, 6.11;
N, 2.50. Found: C, 64.03; H, 6.19; N, 2.42.
Su p p or tin g In for m a tion Ava ila ble: Experimental and
characterization data of tropanes 20b-h , 21b, 21d -f, 23d ,
23e, 23h , 24d , 24h , 25b, 25g, and 25h as well as copies of 1H
NMR spectra of 4b, 4d , 4g, 6, 12, 20h , 22a , 23h , and 30h (16
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of this
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
J O961920W
Syn th esis of Mosh er Am id es. Gen er a l P r oced u r e. In
a 1 dram vial, a solution of tropane (15-25 mg) and diiso-
propylethylamine (2.5-3.5 equiv) was prepared in 0.5 mL of
dry CH2Cl2. (S)-R-methoxy-R-(trifluoromethyl)phenylacetyl
chloride (Aldrich, 1.5-2 equiv) was added, and a stream of
argon was blown over the reaction mixture for 30 s. The
reaction was allowed to stand for 24-48 h, diluted with CH2-
(26) While the intermediate alcohol is not thermally stable, care
must be taken to remove all of the ethanol before the elimination step.
Typically, the crude oil was pumped under high vacuum (∼0.5 torr)
for at least 30 min before the next step.
(27) Note that at lower pH, the BOC protecting group will be
removed.
(28) Bick, I. R. C.; Gillard, J . W.; Leow, H. M. Aust. J . Chem. 1979,
32, 2537.