Total synthesis of (-)-cocaine and (-)-ferruginine

Article abstract of DOI:10.1021/jo200069m

Total synthesis of tropane alkaloids (-)-cocaine and (-)-ferruginine were accomplished in nine steps each and in 55% and 46% overall yields, respectively, starting from the known Betti base derivative (+)-(7aR,10R,12S)-10-(1H- benzotriazol-1-yl)-7a,8,9,10-tetrahydro-12-phenyl-12H-naphtho[1,2-e]pyrrolo[2, 1-b][1,3]oxazine. In this novel route, RCM reaction and 1,3-dipolar cycloaddition were employed as key steps for the enantioselective construction of tropane skeleton and the regioselective introduction of 3-bromo-2-isoxazoline ring as masked cis-2,3-disubstituents. To obtain the desired precursor (2S,5R)-2-allyl-5-vinylpyrrolidine for RCM reaction, we developed a general and practical method for the preparation of enantiopure cis-2,5-disubstituted pyrrolidines bearing alkene- and/or alkyne-containing substituents. We also offered two highly efficient pathways for the conversion of the 3-bromo-2-isoxazoline ring into the desired cis-2,3-disubstituted groups in (-)-cocaine and (-)-ferruginine.

Full text of DOI:10.1021/jo200069m

ARTICLE
pubs.acs.org/joc
Total Synthesis of (ꢀ)-Cocaine and (ꢀ)-Ferruginine
Guolin Cheng, Xinyan Wang,* Rui Zhu, Changwei Shao, Jimin Xu, and Yuefei Hu*
Department of Chemistry, Tsinghua University, Beijing 100084, People’s Republic of China
S Supporting Information
b
ABSTRACT: Total synthesis of tropane alkaloids (ꢀ)-cocaine
and (ꢀ)-ferruginine were accomplished in nine steps each and
in 55% and 46% overall yields, respectively, starting from the
known Betti base derivative (þ)-(7aR,10R,12S)-10-(1H-ben-
zotriazol-1-yl)-7a,8,9,10-tetrahydro-12-phenyl-12H-naphtho-
[1,2-e]pyrrolo[2,1-b][1,3]oxazine. In this novel route, RCM
reaction and 1,3-dipolar cycloaddition were employed as key
steps for the enantioselective construction of tropane skeleton
and the regioselective introduction of 3-bromo-2-isoxazoline
ring as masked cis-2,3-disubstituents. To obtain the desired
precursor (2S,5R)-2-allyl-5-vinylpyrrolidine for RCM reaction,
we developed a general and practical method for the prepara-
tion of enantiopure cis-2,5-disubstituted pyrrolidines bearing alkene- and/or alkyne-containing substituents. We also offered two
highly efficient pathways for the conversion of the 3-bromo-2-isoxazoline ring into the desired cis-2,3-disubstituted groups in (ꢀ)-
cocaine and (ꢀ)-ferruginine.
’ INTRODUCTION
the preparation of 3b is still a challenging project to date and the
functional group transformations of 5a are associated with
tedious performances.
Many tropane alkaloids exhibit biologically important proper-
ties and serve as lead compounds in drug discovery. As shown in
Chart 1, the natural (ꢀ)-cocaine (1)1 is a serotonin-norepi-
nephrine-dopamine reuptake inhibitor, which mediates function-
ality of these neurotransmitters and leads to cocaine abuse. The
unnatural (ꢀ)-ferruginine (2)2 has proved to be a potent agonist
for nicotinic acetylcholine receptor (nAchR), although its natural
enantiomer has a negligible affinity for nAchR. For a long time,
their typical structures and biologically important properties have
made them highly attractive targets for total synthesis.3
Herein, we would like to report a novel route for the total
synthesis of 1 and 2, in which RCM reaction and 1,3-dipolar
cycloaddition mentioned in Scheme 1 were used together as key
steps. Meanwhile, we also developed a practical method for the
preparation of enantiopure 3b and offered the 2-isoxazoline
derivative 5b as a versatile precursor, by which 1 and 2 were
synthesized by controlling selectivity with highly efficient func-
tional group transformations.
Both alkaloids 1 and 2 have identical nonracemic tropane
skeleton, but different substituents on C2 and C3. In fact, the first
asymmetric synthesis4 of 2 was started from 1 in 1977. In recent
years, many asymmetric routes have been reported for total
synthesis of 1,5 2,6 and their enantiomers by using different
strategies. On the basis of the published works, a highly efficient
route may be expected to have three key points: (a) highly
stereoselective construction of the tropane skeleton; (b) highly
regioselective introduction of cis-2,3-disubstituents on the tro-
pane ring; and (c) highly efficient functional group transforma-
tions. According to this opinion, two references attracted our
attention as shown in Scheme 1. Aggarwal6b reported that the
tropene derivative 4 could be stereoselectively constructed by
RCM reaction of cis-2-allyl-5-vinylpyrrolidine derivative 3b.
Rapoport5d reported that 1,3-dipolar cycloaddition of 4 yielded
the tricyclic 5a, in which the cis-2,3-disubstituents on the tropane
ring were regioselectively introduced as an 2-isoxazoline ring.
However, these two excellent transformations have never been
used together for total synthesis of 1 or 2, most possibly because
’ RESULTS AND DISCUSSION
Efficient Preparation of Enantiopure (2S,5R)-2-Allyl-5-
vinyl-N-Boc-pyrrolidine (3b). In recent years, RCM reaction
of cis-2,5-disubstituted pyrrolidines has emerged as an efficient
method in the synthesis of azabicyclics.6b,7,8 Depending on whether
the substituent was alkene or alkyne, as well as the chain lengths,
different sized andsubstituted azabicyclics were prepared. However,
the method was rarely employed to construct the nonracemic
azabicyclics because the preparation of the corresponding nonra-
cemic cis-2,5-disubstituted pyrrolidines still remains a challenging
task to date.6b,8,9 In a few examples,6b,8 the RCM reaction was
so efficient that the method was indeed the preparation of the
corresponding nonracemic cis-2,5-disubstituted pyrrolidines.
Received: January 11, 2011
Published: March 10, 2011
r
2011 American Chemical Society
2694
dx.doi.org/10.1021/jo200069m J. Org. Chem. 2011, 76, 2694–2700
|

The Journal of Organic Chemistry
ARTICLE
Chart 1
Scheme 3
Scheme 1
Scheme 2a
10 at 25 °C. The later two could stop at the monoalkylation stage
regioselectively at ꢀ40 °C, but the epimeric mixtures were obtained
[3:1 ratio of 11a and its epimer for (H2CdCH)2Zn; 3:2 ratio of
(R)- and (S)-allyl substituted on C10 for H2CdCHCH2TMS/
a Conditions: (i) RMgBr, THF, 0 °C; (ii) RMgBr, Et2O, 0 °C; (iii) (a)
aq NaOH, MeOH, THF, 60 °C, (b) Boc2O, K2CO3, CH2Cl2, rt.
BF3 Et2O]. On the basis of these results, we suggested that the
3
alkylation may go through an iminium salt pathway that may be
caused by the Lewis acid properties of the ZnBr2 and BF3 Et2O.
Recently, we reported a general three-step method10 for the
preparation of enantiopure cis-2,6-disubstituted piperidines bear-
ing alkene- and/or alkyne-containing substituents from Betti
base derivative 6.11 As shown in Scheme 2, when 6 underwent
two solvent-controlled regioselective alkylations, the alkene- or
alkyne-containing substituent was introduced to C11 (7) or C7a
(8), respectively. Finally, the desired product 9 was obtained by a
novel base-catalyzed N-debenzylation of 8. Encouraged by this
success, we tried to use the same strategy to prepare the required
(2S,5R)-2-allyl-5-vinyl-N-Boc-pyrrolidine (3b).
Thus, Betti base derivative 10, which contains a pyrrolidine
ring, was prepared in 93% yield as a single diastereomer by the
reported procedure.11d Unfortunately, no solvent-controlled
regioselectivity was observed in the alkylation of 10 with vinyl
or allyl Grignard reagent. As shown in Scheme 3, when 10 was
treated with H2CdCHMgBr in THF below ꢀ40 °C, no reaction
occurred at all. Instead of the expected 11a, a mixture of trans- and
cis-dialkylated product 12a was obtained when the reaction pro-
ceeded above ꢀ40 °C. Although a single product was obtained in
the alkylation of 10 with H2CdCHCH2MgBr at ꢀ78 °C, it was
assigned as dialkylated product 12b. These results may be caused by
the fact that the pyrrolidine ring in 10 has a planar configuration,
which led to higher reactivity and less selectivity. Thus, several less
active organometallic reagents were tested for the alkylation of 10,
such as (H2CdCH)2CuLi (from H2CdCHLi and CuI in situ),
(H2CdCH)2Zn (from H2CdCHMgBr and ZnBr2 in situ), and
3
Therefore, Nuꢀ could attack both sides of the iminium salt
intermediate to give an epimeric mixture. Luckily, when 10 was
treated with HCtCMgBr in THF at ꢀ40 °C, a highly regioselec-
tive and diastereoselective alkylation occurred on C10 to give 11b in
92% yield as a single product. Similarly, 11c and 11d were obtained
when MeCtCMgBr and PhCtCMgBr were used as alkylation
reagents, respectively. These alkylations may go through the SN2
mechanism because the Bt-group in 10 was replaced by an alkynyl
group with complete inversion of configuration. Finally, the required
intermediate 11a was obtained in almost quantitative yield by
hydrogenation of 11b over Lindlar catalyst.
As shown in Scheme 4, when 11aꢀd were treated with different
allyl Grignard reagents in Et2O, 2,5-disubstituted pyrrolidine inter-
mediates 12cꢀg were obtained smoothly. Since 12bꢀg showed
ambiguous NMR spectra caused by the unusual coalescence
phenomenon,11c they were directly used in the next step without
characterization. As was expected, their N-debenzylations pro-
ceeded much easier than that of the counterpart 8. When the
mixtures of 12bꢀg in aq NaOHꢀMeOHꢀTHF (1:2:2 by v/v)10
were heated at 60 °C for 1 h, the N-debenzylations of 12bꢀg were
finished completely. The crude products were then captured by
Boc2O in situ to give 2,5-disubstituted N-Boc-pyrrolidines 3aꢀf in
high yields for two steps. Since the two chiral carbons were formed
in separated steps, 3aꢀf were easily confirmed to be enantiopure
products by their 1H and 13C NMR spectra.
Efficient Preparation of the Tropene Derivative 4 by RCM
and the Versatile Precursor 3-Bromo-2-isoxazoline Deriva-
tive 5b by 1,3-Dipolar Cycloaddition. In practice, the precursor
H2CdCHCH2TMS/BF3 Et2O. However, the former one was
3
inert at 0 °C or gave a complicated mixture along with unreacted
2695
dx.doi.org/10.1021/jo200069m |J. Org. Chem. 2011, 76, 2694–2700

The Journal of Organic Chemistry
ARTICLE
Scheme 4a
Scheme 6
a Conditions: (i) H2CdCHCH2MgBr or H2CdC(Me)CH2MgBr,
Et2O, ꢀ40 °C, 1 h; (ii) (a) 6 M aq NaOH, MeOH, THF, 60 °C, 1 h,
(b) Boc2O, K2CO3, CH2Cl2, rt, 30 min, 80ꢀ87% yields for two steps.
Scheme 5
Figure 1. The structure and stereochemistry of 5b.
of 5b was further confirmed by the single-crystal X-ray diffraction
analysis.
Total Synthesis of (ꢀ)-Cocaine. It has been reported that
3-bromo-2-isoxazolines can be easily converted into 3-alkoxy-2-
isoxazolines under base conditions.12a,c,d,14c As shown in Scheme 7,
when the mixture of 5b and NaOMe in MeOH was refluxed for 8 h,
3-methoxy-2-isoxazoline derivative 13 was obtained in 99% yield. In
literature, the reductive cleavage of 3-methoxyisoxazoline into the
corresponding β-hydroxy ester can be affected by several protocols.13
We found that the Raney-Ni-catalyzed hydrogenation originally
reported by Curran13d,15 was the most practical one, by which the
quantitative conversion of 13 into 14 was achieved in the presence of
H3BO3. After 14 was esterified with BzCl, its product 15 was
subjected to carry out a deprotection and a reductive amination in
one-pot to give (ꢀ)-cocaine (1) in excellent yield. Thus, the total
synthesis of (ꢀ)-cocaine (1) was accomplished in nine steps and in
55% overall yield (starting from 10).
Total Synthesis of (ꢀ)-Ferruginine (2). To obtain the best
result, three practical protocols for the conversion of 3-bromo-2-
isoxazoline into β-hydroxyl nitrile were tested. When 5b was
treated with NaSEt14d or NaI-TMSCl,14b the former gave the
desired product 16 in moderate yield (63%) and the latter led to a
mixture because N-Boc was partially cleaved. However, when 5b
was hydrogenated in the presence of Raney-Ni and H3BO3,14c,15
16 was obtained in quantitative yield (Scheme 8).
3b can be prepared in gram scale within a few hours from the
intermediate 10. As shown in Scheme 5, when 3b was treated
with Grubbs II catalyst in refluxed CH2Cl2 for 12 h, the desired
tropene derivative 4 was obtained in 95% yield.
In 1998, Rapoport5d reported that 1,3-dipolar cycloaddition
between 4 and EtO2C(Cl)CdNOH yielded 3-carboethoxy-2-
isoxazoline derivative 5a. Since the 2-isoxazoline ring can be
opened easily, it in fact is a masked cis-2,3-disubstituent. How-
ever, 5a seriously suffered from tedious functional group trans-
formations to remove an extra carbon under very mild
conditions, by which the epimerization of the 3-carbomethoxy
group [which occupies the thermodyamically unfavorable axial
position in (ꢀ)-cocaine (1)] could be avoided. Since this draw-
back comes from the structural nature of the reagent EtO2C-
(Cl)CdNOH rather than from the strategy, we believed that it
may be overcome by using an alternative reagent.
In the further investigation, the one-carbon 1,3-dipolar precursor
dibromoformaldoxime (Br2CdNOH) attracted our attention,
which can take place by 1,3-dipolar cycloaddition with alkenes to
yield the corresponding 3-bromo-2-isoxazolines under base
conditions.12ꢀ14 The most important to us is that 3-bromo-2-
isoxazoline can be converted into the β-hydroxy ester13 or
β-hydroxy nitrile14 by different ring-opening methods. By a series
of conditional experiments, we found that the regioselectivity of 1,3-
dipolar cycloaddition between 4 and Br2CdNOH significantly
benefited from the reaction temperature. When it proceeded at
10 °C, the desired precursor 5b was prepared in 91% yield
(Scheme 6). As shown in Figure 1, the structure and stereochemistry
Although a reported conversion of β-hydroxyl nitrile into
R,β-unsaturated nitrile with excess MeMgCl is very attractive,16
it failed in our hands. Thus, 17 was prepared in 85% yield by
treatment of 16 with MsCl in the presence of Et3N. Under the
mild conditions, R,β-unsaturated ketone 18 was obtained in 87%
yield by reaction of 17 with an excess of MeLi followed by a
PPTS-catalyzed hydrolysis. In the one-pot reaction, 18 was
2696
dx.doi.org/10.1021/jo200069m |J. Org. Chem. 2011, 76, 2694–2700

The Journal of Organic Chemistry
ARTICLE
Scheme 7a
a Conditions: (i) NaOMe, MeOH, reflux, 8 h, 99%; (ii) Raney-Ni, H2 (balloon), H3BO3, aq MeOH, rt, 3 h, 100%; (iii) BzCl, DMAP, Et3N, CH2Cl2, rt,
12 h, 96%; (iv) (a) TFA, CH2Cl2, rt, 1 h, (b) 37% aq CH2O, NaBH3CN, rt, 1 h, 85%.
Scheme 8a
Preparation of (7aR,10R,12S)-7a,8,9,10-Tetrahydro-10-
ethynyl-12-phenyl-12H-naphtho[1,2-e]pyrrolo[2,1-b][1,3]-
oxazine (11b). To a solution of 10 (2.09g, 5mmol) indryTHF(50mL)
was added a solution of HCtCMgCl in THF (1.0 M, 25 mmol) dropwise
under nitrogen at ꢀ40 °C. After the reaction was stirred at 0 °C for 1 h
(monitored by TLC), a saturated aqueous solution of NH4Cl (10 mL) was
added to quench the reaction. The resulting mixture was then extracted with
a Conditions: (i) Raney-Ni, H2 (balloon), H3BO3, aq MeOH, rt, 3 h,
99%; (ii) MsCl, Et3N, CH2Cl2, 0 °C, 1 h, then rt, 12 h, 85%; (iii) (a)
MeLi, Et2O, 0ꢀ25 °C, 2 h, (b) aq PPTS, rt, 12 h, 87%; (iv) (a) TFA,
CH2Cl2, rt, 1 h, (b) 37% aq CH2O, NaBH3CN, rt, 1 h, 91%.
Et2O (2 ꢁ 30 mL). Combined organic layers were washed with brine (2 ꢁ
30 mL) and dried over anhydrous Na2SO4. After the removal of the solvent,
the residue was purified by recrystallization to give product 11b (1.49 g, 92%)
as colorless crystals. Mp 160ꢀ162 °C (Et2O); [R]25 þ294.5 (c 0.2,
D
CHCl3); IR ν 3205, 2935, 2104, 1622, 1599 cmꢀ1; 1H NMR δ 7.71ꢀ7.66
(m, 2H), 7.40ꢀ7.32 (m, 1H), 7.26ꢀ7.16 (m, 7H), 7.09 (d, J = 8.9 Hz, 1H),
5.65 (s, 1H), 5.04 (d, J = 4.8 Hz, 1H), 4.20ꢀ4.15 (m, 1H), 2.30ꢀ2.14 (m,
3H), 2.11ꢀ1.96 (m, 1H), 1.84 (d, J= 2.0 Hz, 1H); 13CNMRδ152.9, 142.4,
131.7, 129.0, 128.9, 128.8, 128.7 (2C), 128.4 (2C), 127.2, 126.2, 123.1,
122.9, 118.8, 113.1, 84.9, 84.2, 71.6, 55.7, 51.1, 30.6, 29.4; MS m/z (%) 325
(Mþ, 4.88), 231 (100). Anal. Calcd for C23H19NO: C, 84.89; H, 5.89; N,
4.30. Found: C, 84.62; H, 6.01; N, 4.42.
subjected to carry out a deprotection and a reductive amination
to give (ꢀ)-ferruginine (2) in excellent yield. Thus, the total
synthesis of (ꢀ)-ferruginine (2) was accomplished in nine steps
and in 46% overall yield (starting from 10).
’ CONCLUSION
By a similar procedure as that used for 11b, compounds 11c,d were
prepared.
A general and practical method for the preparation of en-
antiopure cis-2,5-disubstituted pyrrolidines bearing alkene- and/
or alkyne-containing substituents (3aꢀf) was developed. The
desired tropene derivative 4 was constructed in excellent yield
by RCM reaction of (2S,5R)-2-allyl-5-vinylpyrrolidine (3b).
When 4 reacted with dibromoformaldoxime, the 1,3-dipolar
cycloadduct 5b was obtained regioselectively. The 3-bromo-2-
isoxazoline unit in 5b has been proved to be an excellent masked
cis-β-hydroxy ester or cis-β-hydroxyl nitrile. Finally, total syn-
thesis of the tropane alkaloids (ꢀ)-cocaine (1) and (ꢀ)-ferru-
ginine (2) was accomplished in nine steps each from 10. The
novel route was characterized to employ the RCM reaction and
1,3-dipolar cycloaddition together as key steps and had the
highest overall yields.
Preparation of (7aR,10R,12S)-7a,8,9,10-Tetrahydro-10-
(prop-1-ynyl)-12-phenyl-12H-naphtho[1,2-e]pyrrolo[2,1-b]-
[1,3]oxazine (11c). By reaction of 10 with MeCꢂCMgCl at ꢀ15 °C
for 2 h, 11c was obtained in 90% yield. Mp 144ꢀ146 °C (Et2O); [R]25
D
þ378.9 (c 0.2, CHCl3); IR ν 2993, 2962, 2195, 1622, 1597 cmꢀ1; 1H
NMR δ 7.75ꢀ7.65 (m, 2H), 7.43ꢀ7.36 (m, 1H), 7.28ꢀ7.16 (m, 7H),
7.10 (d, J = 8.9 Hz, 1H), 5.67 (s, 1H), 5.04 (d, J = 4.1 Hz, 1H), 4.11ꢀ4.06
(m, 1H), 2.23ꢀ2.11 (m, 3H), 2.10ꢀ1.90 (m, 1H), 1.20 (d, J = 3.1 Hz,
3H); 13C NMR δ 152.9, 142.2, 131.8, 128.9 (2C), 128.5, 128.3 (2C),
128.2 (2C), 127.2, 126.2, 123.0, 122.8, 118.9, 113.5, 85.1, 80.1, 79.5,
55.7, 51.5, 30.6, 29.4, 2.9; MS m/z (%) 339 (Mþ, 10.8), 231 (100). Anal.
Calcd for C24H21NO: C, 84.92; H, 6.24; N, 4.13. Found: C, 84.75; H,
6.40; N, 4.14.
Preparation of (7aR,10R,12S)-7a,8,9,10-Tetrahydro-10-
phenylethynyl-12-phenyl-12H-naphtho[1,2-e]pyrrolo[2,1-b]-
[1,3]oxazine (11d). By reaction of 10 with PhCtCMgCl at 0 °C for
’ EXPERIMENTAL SECTION
1 h, 11d was obtained in 90% yield. Mp 166ꢀ168 °C (Et2O); [R]25
Preparation of (7aR,10R,12S)-7a,8,9,10-Tetrahydro-10-vi-
nyl-12-phenyl-12H-naphtho[1,2-e]pyrrolo[2,1-b][1,3]oxa-
zine (11a). A stirred mixture of 11b (6.50 g, 20 mmol) and 5% Lindler
catalyst (16.3 mg, 2.5 wt %) in THF (50 mL) was hydrogenated at room
temperature and atmospheric pressure until the hydrogen-absorbing
rate was suddenly reduced (ca. 10 min). After the catalyst was filtered
out, the filtrate was evaporated to give product 11a (6.48 g, 99%) as
D
1
þ488.1 (c 0.2, CHCl3); IR ν 3467, 2948, 2208, 1623, 1597 cmꢀ1; H
NMR δ 7.80ꢀ7.59 (m, 2H), 7.43ꢀ7.34 (m, 1H), 7.33ꢀ7.15 (m, 7H),
7.13ꢀ7.05 (m, 1H), 7.04ꢀ6.96 (m, 1H), 6.95ꢀ6.84 (m, 2H), 6.46 (d, J =
7.2 Hz, 2H), 5.74 (s, 1H), 5.12 (d, J = 3.8 Hz, 1H), 4.57ꢀ4.53 (m, 1H),
2.40ꢀ2.18 (m, 3H), 2.16ꢀ2.01 (m, 1H); 13C NMR δ 153.1, 143.1, 131.8,
131.0 (2C), 129.1, 128.7 (2C), 128.6, 128.4 (2C), 128.3, 127.6 (2C),
127.4, 127.2, 126.4, 123.1, 122.9, 122.6, 118.9, 113.2, 90.0, 85.3, 83.8, 55.5,
52.4, 31.1, 29.7; MS m/z (%) 401 (Mþ, 11.7), 231 (100). Anal. Calcd for
C29H23NO: C, 86.75; H, 5.77; N, 3.49. Found: C, 86.49; H, 5.68; N, 3.54.
Preparation of (2S,5R)-2,5-Diallylpyrrolidine-1-carboxylic
Acid tert-Butyl Ester (3a). To a stirred solution of H2CdCHCH2-
MgBr made from Mg (1.20 g, 50 mmol) and H2CdCHCH2Br (5.05 g,
50 mmol) in anhydrous Et2O (30 mL) was added dropwise a solution
of 10 (2.09 g, 5 mmol) in anhydrous toluene (50 mL) at ꢀ78 °C within
10 min. Then a saturated aqueous solution of NH4Cl (30 mL) was
added to quench the reaction at 0 °C. The separated organic layer was
colorless crystals. Mp 103ꢀ105 °C (Et2O); [R]25 þ231.4 (c 0.2,
D
CHCl3); IR ν 3059, 2976, 1620, 1597 cmꢀ1; 1H NMR δ 7.70ꢀ7.63 (m,
2H), 7.33ꢀ7.26 (m, 1H), 7.22ꢀ7.12 (m, 7H), 7.08 (d, J = 8.7 Hz, 1H),
5.66ꢀ5.55 (m, 1H), 5.42 (s, 1H), 5.19ꢀ5.07 (m, 2H), 4.88ꢀ4.83
(m, 1H), 3.86ꢀ3.79 (m, 1H), 2.14ꢀ1.92 (m, 3H), 1.90ꢀ1.78 (m, 1H);
13C NMR δ 153.0, 142.6, 141.1, 131.5, 128.9 (2C), 128.8 (2C), 128.3,
128.2 (2C), 127.0, 126.2, 123.0, 122.9, 119.1, 116.9, 114.2, 85.6,
64.6, 54.8, 30.4, 28.7; MS m/z (%) 327 (Mþ, 6.49), 231 (100). Anal.
Calcd for C23H21NO: C, 84.37; H, 6.46; N, 4.28. Found: C, 84.60; H,
6.39; N, 4.16.
2697
dx.doi.org/10.1021/jo200069m |J. Org. Chem. 2011, 76, 2694–2700

The Journal of Organic Chemistry
ARTICLE
washed with H2O and brine, then dried over anhydrous Na2SO4.
Removal of the solvent gave the crude product 12b as a yellowish solid
(1.84 g, 96%), which was used in the next step without characterization.
To an aqueous solution of NaOH (6.0 M, 1 mL), THF (2 mL), and
MeOH (2 mL) was added the crude 12b (384 mg, 1 mmol). The
resulting mixture was heated at 60 °C for 1 h and then cooled to room
temperature. (Boc)2O (655 mg, 3 mmol) was then added and the mixture
was stirred for another 0.5 h. After the organic solvent was removed, the
residue was diluted with Et2O (20 mL) and H2O (20 mL). The separated
organic layer was washed with brine and dried over anhydrous Na2SO4.
After the removal of the solvent, the residue was purified by chromatog-
raphy (silica gel, EtOAcꢀPE) to give product 3a (219 mg, 87%). IR ν 2975,
1693, 1390 cmꢀ1; 1H NMR (50 °C) δ 5.80ꢀ5.71 (m, 2H), 5.07ꢀ5.02 (m,
4H), 3.82 (br, 2H), 2.54 (br, 2H), 2.16ꢀ2.10 (m, 2H), 1.89ꢀ1.83 (m, 2H),
1.70ꢀ1.65 (m, 2H), 1.47 (s, 9H); 13C NMR (50 °C) δ 154.7, 135.3 (2C),
116.6 (2C), 79.0, 58.2 (2C), 39.8 (2C), 28.5 (5C); MS m/z (%) 252 (M þ
1, 2.18), 57 (100). Anal. Calcd for C15H25NO2: C, 71.67; H, 10.02; N, 5.57.
Found: C, 71.49; H, 10.21; N, 5.50.
3H), 1.48 (s, 9H); 13C NMR δ 153.6, 142.7, 112.4, 84.6, 79.5, 69.5, 56.3,
48.1, 43.1, 31.6, 29.2, 28.2 (3C), 22.1; MS m/z (%) 249 (Mþ, 0.02), 57
(100). Anal. Calcd for C15H23NO2: C, 72.25; H, 9.30; N, 5.62. Found:
C, 72.10; H, 9.35; N, 5.74.
Preparation of (2S,5R)-2-Allyl-5-(prop-1-ynyl)-pyrroli-
dine-1-carboxylic Acid tert-Butyl Ester (3e). From 11c and
H2CdCHCH2MgBr, 3e was obtained asa yellowish oil. [R]25D þ28.9
(c 0.2, CHCl3);IRν3292, 2978, 2237, 1783, 1713 cmꢀ1;1HNMR(50°C)
δ 5.86ꢀ5.72 (m, 1H), 5.11ꢀ5.01 (m, 2H), 4.48 (br, 1H), 3.84ꢀ3.75 (m,
1H), 2.66ꢀ2.60 (m, 1H), 2.31ꢀ2.20 (m, 1H), 2.02ꢀ1.83 (m, 4H),
1.80ꢀ1.79 (m, 3H), 1.48 (s, 9H); 13C NMR (50 °C) δ 154.0, 135.2,
116.6, 80.1, 79.4, 77.2, 57.6, 49.1, 39.4, 32.2, 29.4, 28.5 (3C), 3.4; MS m/z
(%) 235 (M, 0.01), 84 (92.99), 57 (100). Anal. Calcd for C15H23NO2: C,
72.25; H, 9.30; N, 5.62. Found: C, 72.04; H, 9.47; N, 5.48.
Preparation of (2S,5R)-2-Allyl-5-phenylethynylpyrroli-
dine-1-carboxylic Acid tert-Butyl Ester (3f). From 11d and
H2CdCHCH2MgBr, 3f was obtained as a yellowish oil. [R]25D þ37.7 (c
1
0.2, CHCl3); IR ν 3075, 2976, 2214, 1783, 1720, 1695 cmꢀ1; H NMR
(50 °C) δ 7.32ꢀ7.30 (m, 2H), 7.19ꢀ7.17 (m, 3H), 5.80ꢀ5.71 (m, 1H),
5.04ꢀ4.93 (m, 2H), 4.66 (br, 1H), 3.81 (br, 1H), 2.61ꢀ2.54 (m, 1H),
2.32ꢀ2.27 (m, 1H), 2.06ꢀ1.96 (m, 2H), 1.95ꢀ1.83 (m, 2H), 1.40 (s, 9H);
13C NMR (50 °C) δ 154.0, 135.0, 131.5 (2C), 128.1 (2C), 127.9, 123.5,
116.9, 90.5, 81.9, 79.7, 57.7, 49.5, 39.2, 32.2, 29.5, 28.5 (3C); MS m/z (%)
311 (Mþ, 1.08), 170 (100). Anal. Calcd for C20H25NO2: C, 77.14; H, 8.09;
N, 4.50. Found: C, 76.87; H, 8.02; N, 4.68.
Preparation of (2S,5R)-2-Allyl-5-vinylpyrrolidine-1-car-
boxylic Acid tert-Butyl Ester (3b). To a stirred solution of 11a
(655 mg, 2.0 mmol) in anhydrous Et2O (20 mL) was added dropwise a
solution of H2CdCHCH2MgBr made from Mg (0.24 g, 10 mmol) and
H2CdCHCH2Br (1.21 g, 10 mmol) in anhydrous Et2O (15 mL) at
ꢀ40 °C. After the reaction was stirred at ꢀ40 °C for 1.0 h (monitored by
TLC), a saturated aqueous solution of NH4Cl (10 mL) was added to
quench the reaction. The separated organic layer was washed with H2O
and brine, then dried over anhydrous Na2SO4. Removal of the solvent
gave the crude product 12c as a yellowish solid (709 mg, 96%), which
was used in the next step without characterization.
To an aqueous solution of NaOH (6.0 M, 1 mL), THF (2 mL), and
MeOH (2 mL) was added the crude 12c (370 mg, 1.0 mmol). The
resulting mixture was heated at 60 °C for 1 h, and then cooled to room
temperature. (Boc)2O (655 mg, 3 mmol) was then added and the
mixture was stirred for another 0.5 h. After the organic solvent was
removed, the residue was diluted with Et2O (20 mL) and H2O (20 mL).
The separated organic layer was washed with brine and dried over anhydrous
Na2SO4. After the removal of the solvent, the residue was purified by
chromatography (silica gel, EtOAcꢀPE) to give the desired product 3b (209
mg, 88%) as a yellow oil; [R]25D ꢀ45.1 (c 0.2, CHCl3) {lit.6b [R]20D þ40.7
(c 0.2, CHCl3) for the enantioisomer}; IR ν 3077, 2975, 1692, 1641,
1478 cmꢀ1; 1H NMR (50 °C) δ 5.81ꢀ5.72 (m, 2H), 5.15ꢀ5.00 (m, 4H),
4.28 (br, 1H), 3.86 (br, 1H), 2.63 (br, 1H), 2.15ꢀ2.08 (m, 1H), 2.02ꢀ1.94
(m, 1H), 1.93ꢀ1.87 (m, 1H), 1.73ꢀ1.64 (m, 2H), 1.45 (s, 9H); 13C NMR
(50 °C) δ 154.7, 140.1, 135.3, 116.6, 113.7, 77.2, 60.5, 58.2, 39.7, 30.4, 28.9,
28.4 (3C); MS m/z (%) 273 (Mþ, 0.15), 96 (100). Anal. Calcd for
C14H23NO2: C, 70.85; H, 9.77; N, 5.90. Found: C, 70.56; H, 9.73; N, 5.98.
By a similar procedure as that used for 3b, compounds 3cꢀf were
prepared.
Preparation of (1R,5S)-8-Azabicyclo[3.2.1]-2-octene-8-
carboxylic Acid tert-Butyl Ester (4). To a stirred solution of 3b
(2.37 g, 10 mmol) in CH2Cl2 (15 mL) was added Grubbs 2nd
generation catalyst (212 mg, 0.25 mmol) in one portion at room
temperature under N2. After the resulting mixture was refluxed for 12
h, it was cooled to room temperature and the solvent was evaporated
under vacuum. The residue was purified by chromatography (silica gel,
16% EtOAc in PE) to give the product 4 (1.98 g, 95%) as colorless
crystals. Mp 35ꢀ36 °C (hexaneꢀEtOAc), [R]25D þ3.6 (c 0.2, CHCl3)
{lit.5d [R]20D þ3.0 (c 1.0, CHCl3)}; IR (KBr) ν 2977, 1697, 1391 cmꢀ1
;
1H NMR δ 5.98 (br, 1H), 5.50ꢀ5.53 (m, 1H), 4.32 (br, 1H), 4.25 (br,
1H), 2.65ꢀ2.85 (m, 1H), 2.15 (br, 1H), 1.60ꢀ2.05 (m, 4H), 1.45 (s,
9H); 13C NMR δ 154.0, 133.0, 132.4, 123.9, 123.4, 79.0, 53.5, 52.7, 51.8,
34.9, 34.5, 34.2, 33.9, 30.2, 29.0, 28.3 (3C); MS m/z (%) 210 (M þ 1,
1.03), 57 (100).
Preparation of (3aS,3bR,5aS,6aS)-3-Bromo-7-azabicyclo-
[3.2.1]octane[2,3-d]isoxazole-7-carboxylic Acid tert-Butyl
Ester (5b). The mixture of 4 (2.1 g, 10 mmol), Br2CdNOH (4.2 g,
20 mmol), and NaHCO3 (8.4 g, 100 mmol) in EtOAc (30 mL) was
stirred vigorously at 10 °C for 40 h. After the reaction was finished
(monitored by TLC), H2O (50 mL) was added. The organic layer was
separated and dried over anhydrous Na2SO4. After the removal of the
solvent, the residue was purified by chromatography (silica gel, 20% EtOAc
in PE) to give 5b (3.0 g, 81%) as colorless crystals. Mp 103ꢀ104 °C
Preparation of (2S,5R)-2-Allyl-5-ethynylpyrrolidine-1-carbo-
xylic Acid tert-Butyl Ester (3c). From 11b and H2CdCHCH2MgBr, 3c
(hexaneꢀEtOAc), [R]25 þ3.7 (c 0.2, CHCl3); IR ν 2973, 2930, 1697,
D
was obtained as a yellowish oil, [R]25D þ32.6 (c 0.2, CHCl3) {lit.6b [R]20
1378 cmꢀ1; 1H NMR δ 4.93ꢀ5.01 (m, 1H), 4.69 (br, 1H), 4.38 (br, 1H),
3.35 (d, 1H, J = 8.94 Hz), 1.55ꢀ2.19 (m, 6H), 1.48 (s, 9H); 13C NMR δ
152.7, 141.0, 80.1, 75.8, 58.0, 51.8, 50.3, 36.6, 29.8, 28.2 (3C), 27.2; MS m/z
(%) 330(Mþ, 0.04), 57 (100). Anal. Calcd for C13H19BrN2O3: C, 47.14; H,
5.78; N, 8.46. Found: C, 47.31; H, 5.69; N, 8.52.
D
ꢀ30 (c 0.2, CH3Cl2) for the enantioisomer}; IR ν 3295, 2978, 2117, 1685,
1639 cmꢀ1; 1H NMR δ 5.80ꢀ5.64 (m, 1H), 5.14ꢀ5.05 (m, 2H), 4.51 (br,
1H), 3.83 (br, 1H), 2.63 (br, 1H), 2.35ꢀ2.20 (m, 2H), 2.08ꢀ1.80 (m, 4H),
1.52 (s, 9H); 13CNMRδ153.7, 134.7, 116.9, 84.5, 79.6, 69.6, 57.5, 48.4, 39.5,
38.8, 31.6, 29.6, 28.8, 28.2 (3C); MS m/z (%) 194 (23.92), 57 (100). Anal.
Calcd for C14H21NO2: C, 71.46; H, 8.99; N, 5.95. Found: C, 71.29; H, 9.13;
N, 6.07.
Preparation of (3aS,3bR,5aS,6aS)-3-Methoxyl-7-azabi-
cyclo[3.2.1]octane[2,3-d]isoxazole-7-carboxylic Acid tert-
Butyl Ester (13). To a solution of 5a (1.0 g, 3 mmol) in dry MeOH
(20 mL) was added NaOMe (810 mg, 15 mmol) at room temperature
and the resulting mixture was refluxed for 8 h (monitored by TLC). After
the reaction was cooled to 0 °C, H2O (60 mL) was added. The aqueous
mixture was extracted with Et2O (3 ꢁ 20 mL) and the combined organic
layers were washed with brine and dried over anhydrous Na2SO4. After
the removal of the solvent under vacuum, the product 13 (850 mg, 99%)
Preparation of (2S,5R)-2-(2-Methyl-2-propenyl)-5-ethy-
nylpyrrolidine-1-carboxylic Acid tert-Butyl Ester (3d). From
11b and H2CdC(Me)CH2MgBr, 3d was obtained as a yellowish oil.
[R]25 þ14.6 (c 0.2, CHCl3); IR ν 3252, 2976, 2935, 2123, 1781,
D
1690 cmꢀ1; 1H NMR δ 4.75 (d, J = 11.3 Hz, 2H), 4.49 (br, 1H), 3.96 (br,
1H), 2.68 (br, 1H), 2.26ꢀ2.27 (m, 1H), 1.80ꢀ2.18 (m, 5H), 1.76 (s,
2698
dx.doi.org/10.1021/jo200069m |J. Org. Chem. 2011, 76, 2694–2700

The Journal of Organic Chemistry
ARTICLE
was obtained as a colorless oil, which was pure enough for most analytic
purposes. The analytical sample was purified by chromatography (silica
gel, 20% EtOAc in PE). [R]25D þ36.3 (c 0.2, CHCl3); IR ν 2975, 1695,
and the aqueous layer was extracted with CH2Cl2 (5 ꢁ 10 mL). The
combined organic layers were washed with brine and dried over
anhydrous Na2SO4. After removal of the solvent under vacuum, the
residue was purified by chromatography (silica gel, Et3N:MeOH:
CH2Cl2 = 0.25:1:100) to give (ꢀ)-cocaine (1) (330 mg, 85%) as color-
less crystals. Mp 97ꢀ98 °C (Et2O) (lit.5d mp 93ꢀ94 °C); [R]25D ꢀ16.5
(c 0.2, CHCl3) {lit.5d [R]25D ꢀ16.2 (c 1.2, CHCl3)}; IR ν 2946, 1737,
1709 cmꢀ1; 1H NMR δ 8.02 (dd, 2H, J = 8.22, 1.38 Hz), 7.53 (tt, 1H, J =
7.56, 1.51 Hz), 7.42 (t, 2H, J = 7.56 Hz), 5.25 (m, 1H), 3.71 (s, 3H),
3.56ꢀ3.57 (m, 1H), 3.30 (br, 1H), 3.00ꢀ3.03 (m, 1H), 2.43 (td, 1H, J =
10.35, 2.70 Hz), 2.23 (s, 3H), 2.08ꢀ2.21 (m, 2H), 1.85ꢀ1.90 (m, 1H),
1.70ꢀ1.73 (m, 2H); 13C NMR δ 170.7, 166.1, 132.8, 130.2, 129.6,
128.2, 66.8, 64.8, 61.5, 51.3, 50.1, 41.1, 35.5, 25.4, 25.2; MS m/z (%) 303
(Mþ, 4), 82 (100).
Preparation of (1R,2R,3S,5S)-2-Cyano-3-hydroxy-8-aza-
bicyclo[3.2.1]octane-8-carboxylic Acid tert-Butyl Ester (16).
To a solution of 5b (330 mg, 1.0 mmol) in H2OꢀMeOH (1:5 by v/v,
10 mL) was added H3BO3 (190 mg, 3 mmol) and wet W-2 Raney nickel
(40 mg). The resulting suspension was hydrogenated for 3 h under
atmospheric pressure (balloon) and room temperature. After the
catalyst was filtered off, the filtrate was diluted with H2O (30 mL) and
the mixture was extracted with Et2O (3 ꢁ 20 mL). The combined
organic layers were washed with brine and dried over anhydrous
Na2SO4. Removal of the solvent under vacuum gave 16 (250 mg,
99%) as colorless crystals. Mp 140ꢀ141 °C (hexaneꢀEtOAc) (lit.5d mp
139ꢀ140 °C); [R]25D ꢀ10.2 (c 0.2, CHCl3) {lit.5d [R]25D ꢀ9.0 (c 1.0,
CHCl3)}; IR ν 2977, 2240, 1685 cmꢀ1; 1H NMR δ 4.53ꢀ4.61 (m, 1H),
4.32ꢀ4.45 (m, 1H), 4.15ꢀ4.26 (m, 1H), 3.71 (d, 1H, J = 5.16 Hz), 3.12
(br, 1H), 1.75ꢀ2.05 (m, 4H), 1.58ꢀ1.65 (d, 2H, J = 7.56 Hz), 1.49 (s,
9H); 13C NMR δ 152.2, 117.8, 80.4, 62.6, 53.7, 51.5 41.5, 37.6, 28.1
(3C), 27.5 (2C); MS m/z (%) 252 (Mþ, 0.65), 57 (100).
1
1618, 1415 cmꢀ1; H NMR δ 4.88ꢀ4.97 (m, 1H), 4.60 (br, 1H),
4.23ꢀ4.39 (m, 1H), 3.87 (s, 3H), 3.31 (d, 1H, J = 8.94 Hz), 1.85ꢀ2.11
(m, 4H), 1.55ꢀ1.78 (m, 2H), 1.46 (s, 9H); 13C NMR δ 167.0, 151.9,
78.8, 75.3, 56.6, 51.2, 50.7, 50.0, 36.1, 29.6, 27.7 (3C), 26.4; MS m/z (%)
282 (Mþ, 3), 83 (100). Anal. Calcd for C14H22N2O4: C, 59.56; H, 7.85;
N, 9.92. Found: C, 59.44; H, 7.91; N, 9.83.
Preparation of (1R,2R,3S,5S)-3-Hydroxy-8-azabicyclo[3.2.1]-
octane-2,8-dicarboxylic Acid 8-tert-Butyl Ester 2-Methyl Es-
ter (14). To a solution of 13 (520 mg, 1.84 mmol) in H2OꢀMeOH
(1:5 by v/v, 12 mL) was added H3BO3 (250 mg, 4 mmol) and wet W-2
Raney nickel (50 mg). The resulting suspension was hydrogenated for
3 h under atmospheric pressure (balloon) and room temperature. After the
catalyst was filtered off, the filtrate was diluted with H2O (30 mL) and the
aqueous mixture was extracted with Et2O (3 ꢁ 20 mL). The combined
organic layers were washed with brine and dried over anhydrous Na2SO4.
Removal of the solvent under vacuum gave 14 (530 mg, 100%) as a
colorless oil, which was pure enough for most analytic purpose. The
analytical sample was purified by chromatography (silica gel, 20% EtOAc
in PE). [R]25D ꢀ10.9 (c 0.2, CHCl3); IR ν 2990, 1737, 1672, 1419 cmꢀ1
;
1HNMRδ4.66 (br, 1H), 4.20ꢀ4.45 (m, 1H), 3.95ꢀ4.10 (m, 1H), 3.70 (s,
3H), 3.17 (d, 1H, J = 10.98 Hz), 2.85ꢀ2.91 (m, 1H), 1.80ꢀ2.18 (m, 4H),
1.52ꢀ1.70 (m, 2H), 1.43 (s, 4.5H), 1.41 (s, 4.5H); 13C NMR δ 172.5,
152.3, 79.1, 63.6, 54.6, 52.8, 51.5, 50.9, 37.8, 28.0 (3C), 27.6, 27.3; MS m/z
(%) 285 (Mþ, 4), 83 (100). Anal. Calcd for C14H23NO5: C, 58.93; H, 8.12;
N, 4.91. Found: C, 59.01; H, 8.00; N, 4.99.
Preparation of (1R,2R,3S,5S)-3-Benzoyloxy-8-aza-bicyclo-
[3.2.1]octane-2,8-dicarboxylic Acid 8-tert-Butyl Ester 2-Methyl
Ester (15). To a solution of 14 (390 mg, 1.4 mmol) in DCM (5 mL) was
added PhCOCl (300 mg, 2.1 mmol), TEA (710 mg, 7.0 mmol), and
4-dimethylaminopyridine (30 mg, 0.25 mmol). After the mixture was stirred
at room temperature for 12 h, it was diluted with DCM (30 mL) and
washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL).
The organic phase was dried with anhydrous Na2SO4 and concentrated to
afford 15 (510 mg, 96%) as colorless crystals. Mp 128ꢀ129 °C (hexaneꢀ
EtOAc); [R]25D ꢀ11.4 (c 0.2, CHCl3) {lit.5b [R]23D þ4.3 (no concentra-
tion and solvent were reported) for the enantioisomer}; IR ν 2977, 1744,
1719, 1680, 1410, 1275 cmꢀ1; 1H NMR δ 7.96ꢀ7.98 (m, 2H), 7.53 (t, 1H,
J = 7.23 Hz), 7.40 (t, 2H, J = 7.56 Hz), 5.48 (m, 1H), 4.68 (d, 0.5H, J = 5.16
Hz), 4.55 (s, 1H), 4.37 (s, 0.5H), 3.70 (s, 1.5H), 3.69 (s, 1.5H), 3.07 (d, 1H,
J = 5.49 Hz), 2.57 (td, 1H, J = 12.0, 3.0 Hz), 1.77ꢀ2.14 (m, 5H), 1.47 (s,
4.5H), 1.45 (s, 4.5H); 13C NMR δ 170.1, 170.0, 165.7, 152.4, 152.0, 133.0,
129.8, 129.5, 128.3, 79.5, 79.4, 66.6, 54.4, 52.6, 51.7, 51.5, 49.0, 48.8, 33.4,
33.3, 28.8, 28.3 (3C), 28.0, 27.8, 27.1; MS m/z (%) 389 (Mþ, 2), 57 (100).
Anal. Calcd for C21H27NO6: C, 64.77; H, 6.99; N, 3.60. Found: C, 64.63; H,
7.03; N, 3.81.
Preparation of (1R,5S)-2-Cyano-8-azabicyclo[3.2.1]-2-oc-
tene-8-carboxylic Acid tert-Butyl Ester (17). To a solution of 16
(1.30 g, 5.20 mmol) in CH2Cl2 (40 mL) was successively added Et3N
(1.04 g, 10.4 mmol) and MeSO2Cl (1.2 g, 1.04 mmol) at 0 °C. After the
resulting mixture was stirred at 0 °C for 1 h, it was allowed to stir at room
temperature for another 12 h. Then it was quenched with iceꢀwater and
extracted with CH2Cl2 (3 ꢁ 20 mL). The combined organic layers were
washed with H2O and brine and dried over Na2SO4. After removal of the
solvent, the residue was purified by chromatography (silica gel, 16%
EtOAc) to give pure 17 (1.04 g, 85%) as colorless crystals. Mp
96ꢀ97 °C (hexaneꢀEtOAc); [R]25 ꢀ94.4 (c 0.2, CHCl3); IR ν
D
1
2971, 2209, 1693 cmꢀ1; H NMR δ 6.50 (br, 1H), 4.45 (br, 1H),
4.34 (br, 1H), 2.87 (br, 1H), 1.97ꢀ2.35 (m, 4H), 1.62ꢀ1.75 (m, 1H),
1.46 (s, 9H); 13C NMR δ 153.2, 141.9, 118.8, 116.8, 80.0, 54.8, 50.9,
34.4, 33.6, 29.1, 27.9 (3C); MS m/z (%) 234 (Mþ, 0.10), 57 (100). Anal.
Calcd for C13H18N2O2: C, 66.64; H, 7.74; N, 11.96. Found: C, 66.77; H,
7.80; N, 12.10.
Preparation of (1R,5S)-2-Acetyl-8-azabicyclo[3.2.1]-2-oc-
tene-8-carboxylic Acid tert-Butyl Ester (18). To a stirred solution
of 17 (230 mg, 1.0 mmol) in Et2O (10 mL) was added a solution of MeLi in
Et2O (1.6 M, 3.0 mL, 4.80 mmol) dropwise at 0 °C under N2. After the
resulting mixture was warmed to room temperature and stirred for 2 h, it
was quenched with H2O (3 mL) at 0 °C. PPTS (10 mg, 0.04 mmol) was
then added and the new mixture was stirred for another 12 h at room
temperature. The organic layer was separated and the aqueous layer was
extracted with Et2O (3 ꢁ 30 mL). The combined organic layers were
washed with brine and dried over Na2SO4. After removal of the solvent,
the residue was purified by chromatography (silica gel, 16% EtOAc) to
give pure 18 (220 mg, 87%) as colorless crystals. Mp 62ꢀ63 °C
(hexaneꢀEtOAc) (lit.6f mp 64ꢀ65 °C); [R]25D ꢀ114.5 (c 0.2, CHCl3)
{lit.6f [R]25D ꢀ126.8 (c 1.0, CHCl3)}; IR ν 2977, 1699, 1660 cmꢀ1; 1H
NMR δ (as rotamers) 6.67 (s, 1H), 4.91 (d, 1H, J = 5.83 Hz), 4.35 (s, 1H),
2.93 (m, 1H), 2.27 (s, 3H), 2.10ꢀ2.20 (m, 3H), 1.80 (dt, 1H, J = 2.4, 10.98
Preparation of (ꢀ)-Cocaine (1). To a solution of 15 (510 mg,
1.3 mmol) in CH2Cl2 (15 mL) was added dropwise CF3CO2H (5.0 g,
43.9 mmol) and the resulting solution was stirred at room temperature for 1
h. After the reaction system was diluted by CH2Cl2 (15 mL), saturated
aqueous NaHCO3 was added dropwise. The organic layer was separated
and the aqueous layer was extracted with CH2Cl2 (4 ꢁ 10 mL). The
combined organic layers were washed with brine and dried over anhydrous
Na2SO4. After removal of the solvent under vacuum, the crude amine was
obtained as a yellow oil.
To a solution of the crude amine and formaldehyde (37% aqueous
solution, 0.6 mL, 8 mmol) in MeCN (20 mL) was added NaBH3CN
(170 mg, 2.7 mmol). Then the resulting mixture was stirred for 1 h at
room temperature and acidified to pH 6 with HOAc. After the mixture
was stirred for an additional 0.5 h, it was neutralized to pH 9 with
ammonia. The mixture was diluted by addition of CH2Cl2 (30 mL) and
saturated aqueous NaHCO3 (30 mL). The organic layer was separated
2699
dx.doi.org/10.1021/jo200069m |J. Org. Chem. 2011, 76, 2694–2700

The Journal of Organic Chemistry
ARTICLE
Hz), 1.50ꢀ1.61 (m, 1H), 1.43 (s, 9H); 13C NMR δ (as rotamers) 196.2,
153.6 (0), 145.3, 137.2, 79.4, 51.9, 51.1, 34.7, 34.5, 29.5, 28.2 (3C), 24.7; MS
m/z (%) 251 (Mþ, 0.50), 57 (100).
65, 4773–4775. (d) Lin, R. H.; Castells, J.; Rapoport, H. J. Org. Chem.
1998, 63, 4069–4078.
(6) (a) Piccardi, R.; Renaud, P. Eur. J. Org. Chem. 2007, 4752–4757.
(b) Aggarwal, V. K.; Astle, C. J.; Rogers-Evans, M. Org. Lett. 2004,
6, 1469–1471. (c) Katoh, T.; Kakiya, K.; Nakai, T.; Nakamura, S.;
Nishide, K.; Node, M. Tetrahedron: Asymmetry 2002, 13, 2351–2358.
(d) Gauthier, I.; Royer, J.; Husson, H.-P. J. Org. Chem. 1997,
62, 6704–6705. (e) 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, 1095–1105. (f) Hernandez, A. S.; Thaler, A.; Castells, J.; Rapoport,
H. J. Org. Chem. 1996, 61, 314–323. (g) Rigby, J. H.; Pigge, F. C. J. Org.
Chem. 1995, 60, 7392–7393.
(7) (a) Kaliappan, K. P.; Das, P.; Chavan, S. T.; Sabharwal, S. G.
J. Org. Chem. 2009, 74, 6266–6274. (b) Kuznetsov, N. Y.; Khrustalev,
V. N.; Godovikov, I. A.; Bubnov, Y. N. Eur. J. Org. Chem. 2006, 113–120.
(8) (a) Brenneman, J. B.; Martin, S. F. Org. Lett. 2004, 6, 1329–1331.
(b) Brenneman, J. B.; Machauer, R.; Martin, S. F. Tetrahedron 2004,
60, 7301–7314.
(9) (a) Shu, H.; Noble, A. R.; Zhang, S.; Miao, L.; Trudell, M. L.
Tetrahedron 2010, 66, 4428–4433. (b) Hong, Z.; Liu, L.; Sugiyama, M.;
Fu, Y.; Wong, C.-H. J. Am. Chem. Soc. 2009, 131, 8352–8353. (c) Zhang,
S.; Xu, L.; Miao, L.; Shu, H.; Trudell, M. L. J. Org. Chem. 2007,
72, 3133–3136. (d) Weihofen, R.; Dahnz, A.; Tverskoy, O.; Helmchen,
G. Chem. Commun. 2005, 3541–3543. (e) Weeresakare, G. M.; Liu, Z.;
Rainier, J. D. Org. Lett. 2004, 6, 1625–1627.
(10) (a) Cheng, G.; Wang, X.; Su, D.; Liu, H.; Liu, F.; Hu, Y. J. Org.
Chem. 2010, 75, 1911–1916. (b) Liu, H.; Su, D.; Cheng, G.; Xu, J.;
Wang, X.; Hu, Y. Org. Biomol. Chem. 2010, 1899–1904.
Preparation of (ꢀ)-Ferruginine (2). To a solution of 18 (330
mg, 1.3 mmol) in CH2Cl2 (15 mL) was added dropwise CF3CO2H (5.0
g, 43.86 mmol) and the resulting mixture was stirred for 1 h at room
temperature. After the reaction was diluted by CH2Cl2 (15 mL),
saturated aqueous NaHCO3 was added dropwise. The organic layer
was separated and the aqueous layer was extracted with CH2Cl2 (4 ꢁ
10 mL). The combined organic layers were washed with brine and dried
over anhydrous Na2SO4. After removal of the solvent under vacuum, the
crude amine product was obtained as a yellow oil.
To a solution of the crude amine product and formaldehyde (37%
aqueous solution, 0.6 mL, 8 mmol) in MeCN (20 mL) was added
NaBH3CN (170 mg, 2.7 mmol). Then the resulting mixture was stirred
for 1 h at room temperature and acidified to pH 6 with HOAc. After the
mixture was stirred for an additional 0.5 h, it was neutralized to pH 9 with
ammonia. The mixture was diluted by addition of CH2Cl2 (30 mL) and
saturated aqueous NaHCO3 (30 mL). The organic layer was separated
and the aqueous layer was extracted with CH2Cl2 (5 ꢁ 10 mL). The
combined organic layers were washed with brine and dried over
anhydrous Na2SO4. After removal of the solvent under vacuum, the
residue was purified by chromatography (silica gel, Et3N:MeOH:
CH2Cl2 = 0.5:10:100) to give (ꢀ)-ferruginine (2) (200 mg, 91%) as
a yellow oil. [R]25D ꢀ52.5 (c 0.2, CHCl3) {lit.6e [R]25D ꢀ50.8 (c 0.94,
CHCl3)}; IR ν 2942, 1662 cmꢀ1; 1H NMR δ 6.73 (br, 1H), 3.90 (d, 1H,
J = 4.47), 3.23 (br, 1H), 2.72 (d, 1H, J = 20.79 Hz), 2.32 (s, 3H), 2.26 (s,
3H), 2.05ꢀ2.20 (m, 2H), 1.93 (dd, 1H, J = 19.59, 3.78 Hz), 1.70 (t, 1H,
J = 9.63 Hz), 1.48 (t, 1H, J = 8.91 Hz); 13C NMR δ (as rotamers) 196.9,
143.1, 136.3, 57.0, 56.9, 36.7, 33.2, 32.4, 29.1, 24.4; MS m/z (%) 165
(Mþ, 22), 57 (100).
(11) For the preparation and application of intermediate 6, also see:
(a) Su, D.; Wang, X.; Shao, C.; Xu, J.; Hu, Y. J. Org. Chem. 2011,
76, 188–194. (b) Dong, Y.; Li, R.; Lu, J.; Xu, X.; Wang, X.; Hu, Y. J. Org.
Chem. 2005, 70, 8617–8620. (c) Wang, X.; Dong, Y.; Sun, J.; Li, R.; Xu,
X.; Hu, Y. J. Org. Chem. 2005, 70, 1897–1900. (d) Xu, X.; Lu, J.; Li, R.;
Ge, Z.; Dong, Y.; Hu, Y. Synlett 2004, 122–124.
(12) For selected recent references, see: (a) Dallanoce, C.; Frigerio,
F.; Martelli, G.; Grazioso, G.; Matera, C.; Pome, D. Y.; Pucci, L.;
Clementi, F.; Gotti, C.; De Amici, M. Bioorg. Med. Chem. 2010,
18, 4498–4508. (b) Girardin, M.; Alsabeh, P. G.; Lauzon, S.; Dolman,
S. J.; Ouellet, S. G.; Hughes, G. Org. Lett. 2009, 11, 1159–1162. (c) Pinto,
A.; Conti, P.; De Amici, M.; Tamborini, L.; Madsen, U.; Nielsen, B.;
Christesen, T.; Brauner-Osborne, H.; De Michelia, C. J. Med. Chem. 2008,
51, 2311–2315. (d) Conti, P.; De Amici, M.; Roda, G.; Pinto, A.; Tamborini,
L.; Madsen, U.; Nielsen, B.; Brauner-Osborne, H.; De Michelia, C.
Tetrahedron 2007, 63, 2249–2256. (e) Conti, P.; Caligiuri, A.; Pinto, A.;
Roda, G.; Tamborini, L.; Nielsen, B.; Madsen, U. Eur. J. Med. Chem. 2007,
42, 1059–1068. (f) Conti, P.; De Amici, M.; Pinto, A.; Tamborini, L.;
Grazioso, G.; Frolund, B.; Nielsen, B.; Thomsen, C.; Ebert, B.; De Micheli,
C. Eur. J. Org. Chem. 2006, 5533–5542. (g) Proemmel, S.; Wartchow, R.;
Hoffmann, H. M. R. Tetrahedron 2002, 58, 6199–6206.
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra for
S
b
11aꢀd, 3aꢀf, 4, 5b, 13ꢀ18, 1, and 2, as well as the crystallographic
data of compound 5b. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: wangxinyan@mail.tsinghua.edu.cn and yfh@mail.tsinghua.
edu.cn. Phone: þ86-10-62795380. Fax: þ86-10-62771149.
’ ACKNOWLEDGMENT
(13) For selected recent references, see: (a) Caetano, V. F.; Dem-
nitz, F. W. J.; Diniz, F. B.; Mariz, R. M., Jr.; Navarro, M. Tetrahedron Lett.
2003, 44, 8217–8220. (b) Trost, B. M.; Li, L.; Guile, S. D. J. Am. Chem.
Soc. 1992, 114, 8745–8747. (c) Takahide, N.; Yasuhiro, M. Heterocycles
1989, 29, 1835–42. (d) Curran, D. P.; Scanga, S. A.; Fenk, C. J. J. Org.
Chem. 1984, 49, 3474–3478.
This work was supported by NNSFC (30600779, 20672066)
and by CFKSTIP from Education Ministry of China (706003).
’ REFERENCES
(14) For selected references for β-hydroxy nitriles, see: (a) Maimone,
T. J.; Shi, J.; Ashida, S.; Baran, P. S. J. Am. Chem. Soc. 2009,
131, 17066–17067. (b) Kociolek, M. G.; Kalbarczyk, K. P. Synth. Commun.
2004, 34, 4387–4394. (c) Bacher, E.; Demnitz, F. W. J.; Hurni, T.
Tetrahedron 1997, 53, 14317–14326. (d) Seo, M. H.; Lee, Y. Y.; Goo,
Y. M. Synth. Commun. 1994, 24, 1433–1439. (e) Wade, P. A.; Bereznak,
J. F.; Palfey, B. A.; Carroll, P. J.; Dailey, W. P.; Sivasubramanian, S. J. Org.
Chem. 1990, 55, 3045–3051.
(1) (a) Carroll, F. I.; Lewin, A. H.; Boja, J. W.; Kuharf, M. J. J. Med.
Chem. 1992, 35, 969–981. (b) Koob, G. F.; Bloom, F. E. Science 1988,
242, 715–723.
(2) (a) Daly, D. W. Cell. Mol. Neurobiol. 2005, 25, 513–552. (b)
Gohlke, H.; G€undish, D.; Schwartz, S.; Seitz, G.; Tilotta, M. C.; Wegge,
T. J. Med. Chem. 2002, 45, 1064–1072.
(3) (a) Pollini, G. P.; Benetti, S.; De Risi, C.; Zanirato, V. Chem. Rev.
2006, 106, 2434–2454. (b) Singh, S. Chem. Rev. 2000, 100, 925–1024.
(4) Campbell, H. F.; Edwards, O. E.; Kolt, R. Can. J. Chem. 1977,
55, 1372–1379.
(15) Curran, D. P. J. Am. Chem. Soc. 1983, 105, 5826–5833.
(16) Fleming, F. F.; Shook, B. C. J. Org. Chem. 2002, 67, 3668–3672.
(5) (a) Davis, F. A.; Theddu, N.; Edupuganti, R. Org. Lett. 2010,
12, 4118–4121. (b) Mans, D. M.; Pearson, W. H. Org. Lett. 2004,
6, 3305–3308. (c) Lee, J. C.; Lee, K.; Cha, J. K. J. Org. Chem. 2000,
2700
dx.doi.org/10.1021/jo200069m |J. Org. Chem. 2011, 76, 2694–2700