Concise catalytic asymmetric total synthesis of biologically active tropane alkaloids

Article abstract of DOI:10.1002/adsc.201100917

A general strategy for the total asymmetric synthesis of valuable tropane alkaloids by catalytic stereoselective transformations is disclosed. The power of this approach is exemplified by the concise catalytic enantioselective total syntheses of (+)-methylecgonine, (-)-cocaine and (+)-cocaine as well as the first catalytic asymmetric total syntheses of a cocaine C-1 derivative and (+)-ferruginine starting from 5-oxo-protected-α,β-unsaturated enals using only two and three column chromatographic purification steps, respectively. Copyright

Full text of DOI:10.1002/adsc.201100917

FULL PAPERS
DOI: 10.1002/adsc.201100917
Concise Catalytic Asymmetric Total Synthesis of Biologically
Active Tropane Alkaloids
Armando Cꢀrdova,a,b,c,* Shuangzheng Lin,a,b and Abrehet Tseggaia,b
a
Department of Organic Chemistry, The Arrhenius Laboratory, Stockholm University, 106 91 Stockholm, Sweden
Fax : +(46)-8-154-908; e-mail: acordova@organ.su.se or armando.cordova@miun.se
Berzelii Center EXSELENT on Porous Materials, The Arrhenius Laboratory, Stockholm University, 106 91 Stockholm,
b
Sweden
c
Department of Natural Sciences, Engineering and Mathematics, Mid Sweden University, SE-851 70 Sundsvall, Sweden.
Received: December 1, 2011; Published online: April 19, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201100917.
Abstract: A general strategy for the total asymmetric ing from 5-oxo-protected-a,b-unsaturated enals using
synthesis of valuable tropane alkaloids by catalytic only two and three column chromatographic purifi-
stereoselective transformations is disclosed. The cation steps, respectively.
power of this approach is exemplified by the concise
catalytic enantioselective total syntheses of
(+)-methylecgonine, (À)-cocaine and (+)-cocaine as Keywords: asymmetric catalysis; cocaine; cycloaddi-
well as the first catalytic asymmetric total syntheses tions; ferruginine; multi-component reactions; ste-
of a cocaine C-1 derivative and (+)-ferruginine start- reoselectivity; tandem reactions
Introduction
The tropane (8-azabicycloACTHNURGTNE[UNG 3.2.1]octane) ring-system is
present in several valuable biologically active natural
products and unnatural compounds (e.g., 1–4,
Figure 1).[1,2] Among them, (À)-cocaine 1 is a powerful
analgesic and stimulant of the central nervous
system,[3] (+)-ferruginine 2 has potential in the treat-
ment of the neurodegenerative disorder Alzheimerꢁs
disease[4] and its unnatural enantiomer ent-2 is an ago-
nist for the nicotine acetylcholine receptor.[5] With re-
spect to cocaine 1, a challenge is the search for a ther-
apeutically useful antagonist and partial agonist for
the treatment of its abuse that is a major worldwide
concern. Here the stereochemistry is of the utmost
importance since of the eight possible stereoisomers
of cocaine only the (R)-isomer (À)-1 is addictive.[6]
When cocaine 1 and alcohol have been ingested si-
multaneously the more potent cocaethylene (À)-1a’ is
formed.[7] In addition, cocaine can also be used as the
starting material for the synthesis of valuable biologi-
cally active 2b-substituted-3b-aryltropanes 3.[8] Thus,
there is a need for the development of efficient and
Figure 1. Examples of natural tropane alkaloids and their
derivatives 1–4.
Robinsonꢁs classical total synthesis of tropinone by
versatile methods for the total synthesis of natural means of a multicomponent cascade reaction stands
tropane alkaloids and their derivative in a highly ste- also as an important bench mark in organic synthe-
reoselective fashion. In 1898, Willstꢂtter starting from sis.[10] After these two pioneering works, several ap-
tropinone first accomplished the total synthesis of co- proaches to construct chiral tropane alkaloids have
caine.[9]
been developed.[2e,11] However, traditionally most of
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these syntheses were accomplished on a case by case (+)-methylecgonine, (À)-cocaine, (+)-cocaine, (À)-1-
basis. In this context, there are only a few reports on methylcocaine and (+)-ferruginine] by employment
the asymmetric synthesis of cocaine and only four of this versatile synthetic strategy.
total asymmetric syntheses that do not rely on resolu-
tion to produce enantiomerically pure materials.[12] In
fact, to the best of our knowledge, there is only one Results and Discussion
elegant 14 linear step total synthesis of (+)-cocaine
ent-1 (6.5% overall yield, 1:1 dr and 84% ee) that in- We began our synthesis with the investigation of the
volves a catalytic desymmetrization step.[13] Ferrugi- one-pot catalytic enantioselective three-component
nine 2 is also an attractive target for the synthetic catalytic aza-Michael/Wittig tandem reaction between
community due to its biological activity.[12a,14] Howev- acetal-functionalized enals 5, hydroxylamines 6 and
er, 2 has never been synthesized by means of asym- alkyl 2-(triphenylphosphoranylidene)acetates 7 using
metric catalysis. This is also the case for the valuable chiral amine 12 or ent-12 as the catalysts (Scheme 1,
C-1 cocaine derivatives 4.[12c]
Table 1).[19,20] The acetal-functionalized enals 5 were
The tropane alkaloid biosynthesis is still not re- readily synthesized in five steps from simple chemical
solved. What is known is that it involves iminium for- such as propargyl alcohol and ethyl leuvinate, respec-
mation and cascade reactions.[2] In the case of natural- tively (see the Supporting Information).[12c] Our hy-
ly occurring tropane alkaloids 1, methylecoginine 1b pothesis was that the corresponding a,b-unsaturated
is the natural common biosynthetic intermediate prior d-amino acid derivatives 8 (or ent-8) with a protected
to further enzymatic manipulations (Scheme 1).[2e]
Table 1. Screening of conditions for the one-pot three-com-
ponent reaction between amine 12a, enal 13, and 14.[a]
Scheme 1. Biosynthesis and biomimetic synthetic strategy of
tropane alkaloids.
While for tropanes of type 2, ent-1b is the common
biosynthetic intermediate. Inspired by nature, we en-
visioned an expeditious route for the asymmetric syn-
thesis of both enantiomers of a common advanced
synthetic intermediate (e.g., 1b) by means of one-pot
catalytic multicomponent and stereoselective reaction
sequences[15] (Scheme 2). This would include impor-
[a]
Enal 5a (0.25 mmol), amine 6a (2 mmol), and catalyst
tant “green chemistry” parameters (e.g., reduction of
ent-12a (20 mol%) were stirred in CHCl3 (0.5 mL).
synthetic steps, waste and solvents).[16–18] The common
synthetic intermediate could next be further manipu-
lated to the desired enantiomer of different tropane
alkaloids (e.g., 1–4) by additional transformations.
Herein we disclose the concise catalytic asymmetric
total synthesis of valuable tropane alkaloids [e.g.,
[b]
Isolated yield of pure compound.
Determined by chiral-phase HPLC analysis.
1 mL of CHCl3 and 0.5 mmol 6a.
10 mol% of ent-12a.
1 mmol of enal 5a.
1 mmol of enal 5a and catalyst 12a (20 mol%).
[c]
[d]
[e]
[f]
[g]
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Concise Catalytic Asymmetric Total Synthesis of Biologically Active Tropane Alkaloids
Scheme 2. A general strategy for the gathered total synthesis of tropane alkaloids.
acetal and hydroxylamine functionality could be trig- (triphenylphosphoranylidene)acetate 7b as a compo-
gered to undergo intermolecular nitrone formation by nent afforded d-amino acid derivative 8a’ in 71%
means of in situ deprotection to give nitrones 9 (or yield with 96% ee (entry 9). In fact, this is the catalyt-
ent-9, Scheme 2). Next, a Lewis acid-catalyzed Tufar- ic highly enantioselective entry to the total synthesis
iello–Davis intramolecular [1,3]-dipolar cycloaddition of (R)-cocaethylene 1a’ (Scheme 2),
may set the stage for the assembly of tricyclic inter-
After successful development of the one-pot cata-
mediates 10 (or ent-10)[12c,21] and a subsequent modi- lytic highly enantioselective three-component synthe-
À
fied Davis alkylation/ring-opening N O bond-cleav- sis of 8a, we embarked on the construction of (À)-co-
ACHTUNGTRENNUNG
intermediates 11 (or ent-11). Thereafter both enantio- form nitrone 9a via an in situ deprotection/cyclization
mers of a broad range of different valuable tropane transformation. However, refluxing 8a in an aqueous
derivatives should be accessible by further manipula- HCl solution led to complicated mixtures while per-
tions (e.g., 1–4, Scheme 2).
forming this reaction by stirring at room temperature
To our delight, the reaction between enal 5a, amine resulted in the formation of Cbz-protected hemiacetal
6a and methyl 2-(triphenylphosphoranylidene)acetate 13a. Instead we had to develop a Pd(II)-catalyzed
7a in the presence of a catalytic amount of ent-12a triethylsilane[22] Cbz deprotection, acid-mediated
gave the corresponding a,b-unsaturated d-amino acid acetal and silyl group deprotection and cyclization se-
derivative ent-8a in high ees. We found that the opti- quence for the successful formation of nitrone 9a [Eq.
mal conditions were to perform the reaction in CHCl3 (1)].
at 48C using 4 equivalents of amine 6a, which was re-
cycled. Changing the catalyst from (S)- to (R)-12a did Al
We next continued the synthesis by performing an
(O-t-Bu)3-catalyzed intramolecular [1,3]-dipolar cy-
ACHTUNGTRENNUNG
not affect the enantioselectivity of the reaction (en- cloaddition and methylation sequence using MsOMe
tries 7 and 8, Scheme 2). However, a prolonged reac- as the reagent. We were able to execute the sequence
tion time slightly decreased the ee due to retro-Mi- and compound 10a was formed as a single diastereo-
chael reactions (entries 6 and 7). The one-pot catalytic isomer. Next, a Pd-catalyzed hydrogenation and ben-
enantioselective tandem transformation with ethyl 2- zoylation reaction sequence followed by final purifica-
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Scheme 3. (a) i. 5a (1 equiv.), (R)-12a (20 mol%), 6a (4 equiv.), CHCl3, 48C, 17 h; ii. 7a (1 equiv.), room temperature, 2 h;
(aa) same as (a) but (S)-ent-12a (20 mol%) was the catalyst; (b) i. cat. PdCl2 (10 mol%), Et3N (0.7 equiv.), Et3SiH (4 equiv.),
CH2Cl2, reflux, 6 h; ii. 3M HCl:THF (3:1), room temperature, 2 h.;(c) i. AlACTHNUTRGEN(NUG O-t-Bu)3 (50 mol%), toluene, room temperature,
4 h next 1508C, 64 h; ii. MsOMe (5 equiv.), CH2Cl2, reflux, 24 h; (d) cat. Pd/C, H2 balloon, MeOH, room temperature, 48 h;
(e) PhCOCl (2 equiv.), Et3N (16 equiv.), cat. DMAP, CH2Cl2, room temperature, 17 h; (f) i. 6M HCl, reflux, 6 h; ii. POCl3,
reflux, 4 h; iii. MeO(Me)NH·HCl (5 equiv.), Et3N (10 equiv.), CH2Cl2, room temperature, 2 h; (g) MeLi (2 equiv.), THF,
À788C, 30 min next 08C, 30 min; (h) 6M HCl, room temperature, 17 h; (i) POCl3, reflux, 2.5 h according to ref.[8f]
tion with silica gel column chromatography afforded CHCl3), lit. (S)-cocaine ent-1: [a]2D4: +15.5 (c 1.0,
(R)-(À)-cocaine 1 in 39% yield from 8a. Thus, starting CHCl3)[9b,11d]} in 27% overall yield with 96% ee using
from enal 5a we were able to execute the catalytic only two column chromatographic purification steps.
asymmetric total synthesis of 1 {[a]2D5: À15.3 (c 1.0, The key steps were a catalytic enantioselective aza-
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Concise Catalytic Asymmetric Total Synthesis of Biologically Active Tropane Alkaloids
first catalytic asymmetric total synthesis of 2 and
based on only three column chromatographic steps. In
addition, the disclosed synthetic strategy is also an
entry to anhydroecgonine methyl ester (dehydro-1b)
by simply extending the catalytic reaction sequence to
1b with POCl3-mediated dehydration. In fact, this is
the starting point for the total synthesis of 2b-substi-
tuted-3b-aryltropanes 3, which have attracted consid-
erable attention as inhibitors of dopamine, norepi-
nephrine and serotonin reuptake as well as inhibitors
of the nicotinic acetylcholine receptor.[8] In addition,
Michael/Wittig transformation, a catalytic nitrone-for- the total synthesis of biologically active cocaine deriv-
mation/methylation sequence, a catalytic stereoselec- atives such as 1c can be readily accomplished by
tive intramolecular dipolar cycloaddition and a catalyt- means of the disclosed strategy by just changing the
ic hydrogenation/benzoylation sequence. Using this acylation reagent for the final one-pot esterification
procedure we were also able to isolate methylecgo- of methylecgonine 1b. The total synthesis of C-1 co-
nine 1b in 39% yield starting from 8a. Based on these caine derivatives 4 with a quaternary stereocenter is
results, we decided to investigate the yields of the very challenging and has only been performed using
vide supra described catalytic reaction sequences. chiral auxiliaries.[12c] Thus, we wanted to explore our
Thus, it was possible to isolate 9a in 89% yield start- catalytic strategy for the preparation of these types of
ing from 8a, 10a in 44% yield from 9a, methylecgo- valuable cocaine analogues (Scheme 4).
nine 1b in >99% yield from 10a and cocaine 1 in
The one-pot catalytic enantioselective three-compo-
>99% yield from 1b. The investigation shows that it nent aza-Michael/Wittig transformation using 12a as
was the catalytic intramolecular [1,3]-dipolar cycload- the catalyst gave protected a,b-unsaturated d-amino
dition/methylation sequence that gave the lowest acid derivative 8b in 67% yield with 96% ee. We next
yield. With the above results in hand, we continued continued with the catalytic deprotection and cycliza-
the expeditious total syntheses of tropane alkaloids. tion recation sequence, which afforded nitrone 9b.
Thus, we first synthesized ent-8a using ent-12a as the The subsequent Lewis acid-catalyzed stereoselective
catalyst for the one-pot three-component catalytic intramolecular [1,3]-dipolar cycloaddition was fol-
enantioselective tandem reaction between 5a, 6a and lowed by methylation to deliver tricyclic isoxazoline
7a (Scheme 3). Subsequent conversion of ent-8a ac- 10b via intermediate 15b as a single diastereoisomer.
cording to the above described catalytic transforma- The final catalytic ring-opening/acylation sequence
tions gave (S)-(+)-cocaine ent-1 in 37% yield {[a]2D4: furnished 1-methylcocaine 4a {[a]D25: À8.1 (c 1.0,
+15.3 (c 1.0, CHCl3), lit. (S)-cocaine ent-1: [a]2D5: CHCl3), lit. 4a: [a]20: À8.32 (c 1.25, CHCl3)[12c]} in
+15.5 (c 1.0, CHCl3)[9b,11d]}. In addition, hydrolysis of 51% yield with 96%Dee. Thus, the first catalytic asym-
ent-1b gave (+)-ecgonine ent-1a and subsequent metric synthesis of a C-1 cocaine derivative was ac-
POCl3-mediated[23] anhydroecgonine chloride forma- complished in 34% overall yield employing only two
tion and amidation gave Weinreib amide ent-14a in column chromatographic purification steps. We next
27% yield from ent-8a (Scheme 3 and Eq. [2]).
decided to investigate the catalytic stereoselective in-
Next, natural (+)-ferrunginine 2 {[a]2D5: +50.2 (c tramolecular [1,3]-dipolar cycloaddition and methyla-
1.0, CHCl3), lit. (À)-ferrunginine ent-2: [a]2D5: À50.8 (c tion reaction sequence to see if the conversion to
0.94, CHCl3)[14f]} was obtained in 97% yield using product improved as compared to when 9a was used
Weinrebꢁs conditions. It is noteworthy that this is the as the starting material. Indeed, the tricyclic com-
pound 15b was isolated in 72% yield from 9b and 10b
in 99% yield from 15b, respectively. In this context,
nitrone 9b was isolated in 76% yield from 8b by the
catalytic tandem sequence at the catalytic deprotec-
tion and cyclization reaction sequence.
Conclusions
In summary, we have disclosed a general strategy for
the total synthesis of tropane alkaloids in combination
with catalytic enantioselective and stereoselective re-
action sequences. As in nature it is based on the
asymmetric assembly of an advanced common syn-
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Scheme 4. (a) 1. 5b (1 equiv.), (R)-12a (20 mol%), 6a (4 mmol), CHCl3, 48C, 41 h; ii. 7a (1 equiv.), r.t., 2 h; (b) i) cat. PdCl2
(10 mol%), Et3N (0.7 equiv.), Et3SiH (4 equiv.), CH2Cl2, reflux, 8 h; ii) 3M HCl:THF (3:1), room temperature, 2 h; c) i.
AlACHTUNGTRENNUNG(O-t-Bu)3 (50 mol%), toluene, room temperature, 4 h; ii. 1508C, 64 h; d) MsOMe (3 equiv.), benzene, 858C, 24 h; e) i. cat.
Pd/C, H2 (50–70 psi), MeOH, room temperature, 24 h; ii) PhCOCl (2 equiv.), Et3N (7 equiv.), cat. DMAP, CH2Cl2, room tem-
perature, 17 h.
with a solution of ammoniummolybdate (100 g), CeACHTUNGTRENNUNG(SO4)2
thetic intermediate prior to the final synthesis of the
specific natural product. The versatility of this ap-
proach was demonstrated by the expeditious catalytic
asymmetric total synthesis of methylecgonine, (R)-
(À)-cocaine and (S)-(+)-cocaine starting from 5-oxo-
protected-a,b-unsaturated enals using only two
column chromatographic separation steps, respective-
ly. In addition, the first catalytic enantioselective total
synthesis of (+)-ferruginine and a cocaine C-1 deriva-
tive starting from 5-oxo-protected-a,b-unsaturated
enals was completed with two and three column chro-
matographic purification steps, respectively. The pre-
sented strategy was also applied in the formal catalyt-
ic asymmetric total synthesis of valuable unnatural
3b-aryltropanes 3 and substituted cocaine derivatives
1c. Thus, the versatility of the disclosed total synthesis
approach makes it amenable for combinatorial syn-
thesis as well as the total synthesis of a plethora of co-
caine derivatives. It should also be applicable for the
concise synthesis of the novel haptens that are neces-
sary for the generation of anti-cocaine antibodies.[24]
Further applications of the disclosed synthetic design
approach in catalytic asymmetric total synthesis of
other natural product and medicinal agent classes are
ongoing and will be communicated in due course.
(2 g) and 10% H2SO4 (1 L) followed by heating or by treat-
ment with a solution of potassium permanganate (3 g),
K2CO3 (20 g), 5% aqueous NaOH (5 mL) and water
(300 mL) followed by heating. Flash chromatography was
performed using silica gel Merck 60 (particle size 0.040–
0.063 mm), 1H NMR and 13C NMR spectra were recorded
on a Bruker AM400. Chemical shifts are given in d relative
to tetramethylsilane (TMS), the coupling constants J are
given in Hz. The spectra were recorded in CDCl3 as solvent
at room temperature, CDCl3 served as internal standard
1
(d=7.26 ppm for H NMR and d=77.16 ppm for 13C NMR).
Peaks are labelled as singlet (s), doublet (d), triplet (t),
quartet (q) and multiplet (m). HPLC was carried out using
a Waters 2690 Millenium with photodiode array detector.
Optical rotations were recorded on a Perkin–Elmer 241 po-
larimeter (d=589 nm, 1 dm cell). High-resolution mass
(ESI) spectra were obtained with a Bruker MicroTOF spec-
trometer. The acetal-functionalized enals 5 were made ac-
cording to literature procedures.[12c]
Typical Experimental Procedure for the One-Pot
Three-Component Synthesis of a,b-Unsaturated d-
Amino Acid Derivatives
(E)-6,6-Dimethoxyhex-2-enal (5a) (158 mg, 1 mmol), benzyl
(tert-butyldimethylsilyl)oxycarbamate (1126 mg, 4 mmol),
and (R)-catalyst 12a (65 mg, 0.2 mmol) were vigorously
stirred in CHCl3 for 17 h at 48C (>95% conversion as
1
monitored by H NMR analysis). Next, methyl 2-(triphenyl-
phosphoranylidene)acetate (334 mg, 1 mmol) was added and
the reaction mixture was stirred for 2 h at room tempera-
ture. Next, the reaction mixture was concentrated under re-
duced pressure and loaded up on a silica-gel column and im-
mediate flash chromatography (pentane:EtOAc mixtures,
10:1 to 5:1) gave the excess benzyl (tert-butyldimethylsil-
Experimental Section
General Remarks
Chemicals and solvents were either purchased puriss p.A.
from commercial suppliers or purified by standards tech-
niques. For thin-layer chromatography (TLC), silica gel
plates Merck 60 F254 were used and compounds were vi-
sualized by irradiation with UV light and/or by treatment
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
348 mg (70%, E:Z>20:1); Rf =0.48 (pentane:EtOAc=4:1);
1H NMR: d=7.35–7.29 (m, 5H), 6.95–6.88 (m, 1H), 5.88
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Concise Catalytic Asymmetric Total Synthesis of Biologically Active Tropane Alkaloids
(dt, J=15.6, 1.2 Hz, 1H), 5.11 (t, J=12.3 Hz, 2H), 4.31 (t,
J=11.1 Hz, 1H), 4.06–3.99 (m, 1H), 3.71 (s, 3H), 3.28 (s,
3H), 3.27 (s, 3H), 2.68–2.60 (m, 1H), 2.36–2.29 (m, 1H),
1.83–1.74 (m, 1H), 1.72–1.64 (m, 1H), 1.61–1.55 (m, 1H),
1.54–1.45 (m, 1H), 0.90 (s, 9H), 0.11 (s, 3H), 0.09 (s, 3H);
13C NMR: d=166.8, 159.2, 145.6, 135.8, 128.7, 128.6, 128.5,
123.4, 104.3, 68.1, 61.7, 53.3, 52.7, 51.6, 35.4, 29.5, 27.3, 26.1,
18.5, À4.2, À4.3; HR-MS (ESI): m/z=518.2550, calcd. for
[M+Na]+ (C25H41NO7SiNa): 518.2545. [a]2D5: 7.1 (c=1.0,
CHCl3) for an enantiomerically enriched sample of 96% ee.
The enantiomeric excess was determined by HPLC analysis
in comparison with authentic racemic material (ODH
column, 99.5/0.5 i-hexane/i-PrOH, 0.5 mLminÀ1, 210.5 nm):
tr (major enantiomer)=105.4 min, tr (minor enantiomer)=
123.9 min.
(ESI): m/z=206.0781, calcd. for [M+Na]+ (C9H13NO3Na):
206.0788; [a]2D5: À5.5 (c 1.0, CH2Cl2).
Representative Procedure for the Catalytic Dipolar/
Methylation Reaction
The crude nitrone 9a (114 mg, 0.62 mmol) was dissolved in
anhydrous toluene (31 mL) and transferred to a pressure
tube. AlACTHNURTGNENG(U O-t-Bu)3 (76 mg, 0.31 mmol) was added and the
tube was sealed. The reaction mixture was stirred at room
temperature for 4 h and then heated at 1508C for 64 h.
After cooling to room temperature, the mixture was extract-
ed with aqueous 1M HCl (10 mLꢄ3). The aqueous layers
were neutralized with solid Na2CO3, and extracted with
CH2Cl2 (15 mLꢄ3). The CH2Cl2 extracts were combined,
dried with Na2SO4, filtered, and refluxed with MsOMe
(0.26 mL, 3.1 mmol) under an N2 atmosphere for 24 h. The
solution was cooled to room temperature and extracted with
water (50 mL). The aqueous phase was concentrated under
reduced pressure to give the methylated product 10a; yield:
ACHTUNGTRENNUNG(S,E)-Ethyl 5-{[(benzyloxy)carbonyl][(tert-butyldimethyl-
silyl)oxy]amino}-8,8-dimethoxyoct-2-enoate (8a’): Rf =0.20
(pentane:EtOAc=10:1); 1H NMR: d=7.35–7.29 (m, 5H),
6.94–6.88 (m, 1H), 5.86 (dt, J=12.5, 1.0 Hz, 1H), 5.11 (dd,
J=10.7, 9.6 Hz, 2H), 4.31 (t, J=4.4 Hz, 1H), 4.17 (q, J=
5.7 Hz, 2H), 4.04–3.98 (m, 1H), 3.28 (s, 3H), 3.27 (s, 3H),
2.67–2.61 (m, 1H), 2.35–2.30 (m, 1H), 1.83–1.75 (m, 1H),
1.71–1.64 (m, 1H), 1.60–1.46 (m, 2H), 1.27 (t, J=5.7 Hz,
3H), 0.90 (s, 9H), 0.11 (s, 3H), 0.09 (s, 3H); 13C NMR: d
166.4, 159.2, 145.2, 135.9, 128.7, 128.6, 128.4, 123.8, 104.3,
68.1, 61.8, 60.3, 53.3, 52.7, 35.4, 29.5, 27.2, 26.1, 18.5, 14.4,
À4.25, À4.30; HR-MS (ESI): m/z=532.2708, calcd. for [M+
Na]+ (C26H43NO7SiNa): 532.2701. [a]D25: 6.9 (c=1.0, CHCl3)
for an enantiomerically enriched sample of 96% ee. The
enantiomeric excess was determined by HPLC analysis in
comparison with authentic racemic material (AD column,
1
80 mg (44%). H NMR: d=5.57 (d, J=5.2 Hz, 1H), 4.74–
4.72 (m, 1H), 4.43–4.38 (m, 1H), 3.81 (s, 3H), 3.66 (s, 3H),
3.50 (d, J=3.2 Hz, 1H), 2.93–2.86 (m, 1H), 2.70 (s, 3H),
2.66–2.36 (m, 4H), 2.21 (dd, J=12.8, 2.8 Hz, 1H);
13C NMR: d=170.7, 84.6, 79.4, 76.8, 58.7, 53.6, 44.6, 40.5,
39.5, 26.1, 25.4; HR-MS (ESI): m/z=198.1127, calcd. for
[M]+ (C10H16NO3): 198.1125; [a]2D5: 25.4 (c 1.0, MeOH). The
opposite enantiomer was obtained using the same proce-
dures; yield: 45% yield; [a]2D5: À25.0 (c 1.0, MeOH).
98/2 n-hexane/i-PrOH, 1.0 mLminÀ1, 210.5 nm): tr (major Representative Procedures for the Catalytic
enantiomer)=10.5 min, tr (minor enantiomer)=12.9 min.
Hydrogenation/Benzoylation Sequence
24 mg of the above product were dissolved in MeOH
(5 mL). Pd/C (10%, 5 mg) was added. The hydrogenation
was conducted under an H2 atmosphere (balloon) for 48 h.
Upon completion, the solution was filtered through celite,
and concentrated to give methylecgonine 1b; yield: 25 mg
(>99%). 1H NMR: d=4.33–4.27 (m, 1H), 4.05 (brd, J=
7.2 Hz, 1H), 3.88–3.86 (m, 1H), 3.75 (s, 3H), 3.27 (br, 1H),
3.17–3.15 (m, 1H), 2.78 (s, 3H), 2.66 (s, 4H), 2.40–2.23 (m,
2H), 2.19–1.98 (m, 4H); 13C NMR: d=175.4, 65.5, 64.8,
61.6, 53.1, 50.6, 39.4, 36.8, 29.9, 25.0, 24.0; HR-MS (ESI): m/
z=200.1284, calcd. for [M]+ (C10H18NO3): 200.1281; [a]D25:
5.7 (c 1.0, MeOH).
Catalytic Nitrone Synthesis
Under an N2 atmosphere, (S,E)-methyl 5-{[(benzyloxy)car-
bonyl][(tert-butyldimethylsilyl)oxy]amino}-8,8-dimethoxyoct-
2-enoate 8a (348 mg, 0.70 mmol), Et3N (68 mL, 0.49 mmol)
and Et3SiH (0.45 mL, 2.8 mmol) were stirred in dry CH2Cl2
(7 mL). To this solution, PdCl2 (12 mg, 0.07 mmol) was
added. Next, the reaction mixture was refluxed for 6 h.
After cooling the reaction mixture to room temperature, the
solution was washed with saturated aqueous NH4Cl solution
(10 mL). The aqueous layer was extracted with CH2Cl2
(5 mLꢄ2). The organic phases were combined, and concen-
trated to give an oily residue, which was then used in the
next step without purification.
This oill residue was stirred in aqueous HCl (3M, 3 mL)
and THF (1 mL) for 2 h at room temperature. The solution
was then washed with Et2O (5 mLꢄ2) to remove Et3SiH.
The aqueous layer was neutralized with excess solid Na2CO3
and then extracted with CH2Cl2 (6 mLꢄ3). The organic
phases were combined, dried with Na2SO4, filtered, and con-
centrated to give the nitrone product (S,E)-2-(4-methoxy-4-
oxobut-2-en-1-yl)-3,4-dihydro-2H-pyrrole 1-oxide (9a) which
was then used in the next step without purification; yield:
The unnatural (À)-methylecgonine (ent-1b) was obtained
using the same procedures; yield: quantitative yield; [a]2D5:
À6.0 (c 1.0, MeOH).
Next, the methylecgonine (0.085 mmol) was stirred with
Et3N (0.2 mL, 1.4 mmol) and DMAP (2 mg, 0.017 mmol) in
CH2Cl2 (1 mL) at 08C. Benzoyl chloride (20 mL, 0.17 mmol)
was added dropwise. The mixture was stirred at room tem-
perature for 17 h, and then purified with flash chromatogra-
phy on silica gel (CH2Cl2:MeOH mixtures, 10:1 to 5:1) to
furnish (R)-(À)-cocaine as a white solid; yield: 25 mg (>
99%); mp 97–988C; Rf =0.48 (CH2Cl2:MeOH=5:1).
1H NMR: d=8.03–8.01 (m, 2H), 7.56–7.51 (m, 1H), 7.41 (t,
J=7.8 Hz, 2H), 5.27–5.21 (m, 1H), 3.71 (s, 3H), 3.57–3.55
(m, 1H), 3.29 (br, 1H), 3.02 (dd, J=5.2, 3.6 Hz, 1H), 2.43
(td, J=11.8, 2.8 Hz, 1H), 2.23 (s, 3H), 2.20–2.06 (m, 2H),
1.89–1.84 (m, 1H), 1.76–1.67 (m, 2H); 13C NMR: d=170.9,
166.4, 133.1, 130.5, 129.9, 128.5, 67.1, 65.0, 61.7, 51.6, 50.4,
114 mg
(89%);
Rf =0.54
(MeOH:NH3·H2O=50:1);
1H NMR: d=6.89–6.82 (m, 2H), 5.95 (d, J=16.0 Hz, 1H),
4.10 (br, 1H), 3.71 (s, 3H), 2.98–2.93 (m, 1H), 2.67–2.60 (m,
3H), 2.42–2.33 (m, 1H), 1.97–1.88 (m, 1H); 13C NMR: d=
166.4, 142.6, 134.2, 124.8, 70.9, 51.7, 34.7, 26.5, 24.3; HR-MS
Adv. Synth. Catal. 2012, 354, 1363 – 1372
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1369

Armando Cꢀrdova et al.
FULL PAPERS
41.3, 35.7, 25.6, 25.4; HR-MS (ESI): m/z=304.1545, calcd.
for [M+H]+ (C17H22NO4): 304.1543; [a]2D5: À15.3 (c 1.0,
CHCl3).
(S)-(+)-Cocaine was obtained using the same procedures;
yield: 98%; [a]2D5: +15.3 (c 1.0, CHCl3) {lit. (S)-cocaine:
[a]25: +15.5 (c 1.0, CHCl3)[9b,11d]}.
under reduce pressure to give the product 10b; yield: 66 mg
(99%). H NMR: d=5.44 (d, J=4.0 Hz, 1H), 4.51–4.47 (m,
1
1H), 3.78 (s, 3H), 3.56 (s, 1H), 3.48 (s, 3H), 2.87–2.80 (m,
1H), 2.72–2.66 (m, 4H), 2.62–2.54 (m, 1H), 2.38–2.28 (m,
2H), 2.18 (dd, J=10.0, 1.6 Hz, 1H), 1.51 (s, 3H); 13C NMR:
d=170.2, 87.8, 83.8, 78.0, 60.6, 53.1, 41.6, 41.3, 39.6, 33.9,
25.4, 18.2; HR-MS (ESI): m/z=212.1276, calcd. for [M]+
(C11H18NO3): 212.1281; [a]25: À2.6 (c 2.0, MeOH).
A
5-{[(benzyloxy)carbonyl][(tert-butyldime-
thylsilyl)oxy]amino}-7-(2-methyl-1,3-dioxolan-2-yl)hept-2-
enoate (8b): Prepared using the representative catalytic
asymmetric tandem aza-Michael/Wittig reaction; yield:
67%; E:Z >20:1; Rf =0.19 (pentane:EtOAc=10:1).
1H NMR: d=7.35–7.29 (m, 5H), 6.95–6.88 (m, 1H), 5.87 (d,
J=15.6 Hz, 1H), 5.10 (s, 2H), 4.09–4.02 (m, 1H), 3.93–3.82
(m, 4H), 3.70 (s, 3H), 2.67–2.59 (m, 1H), 2.35–2.28 (m, 1H),
1.87–1.78 (m, 1H), 1.76–1.68 (m, 1H), 1.62–1.48 (m, 2H),
1.27 (s, 3H), 0.90 (s, 9H), 0.12 (s, 3H), 0.09 (s, 3H);
13C NMR: d=166.8, 159.2, 145.7, 135.9, 128.64, 128.59,
128.4, 123.3, 109.8, 68.1, 64.7, 61.9, 51.5, 36.0, 35.4, 27.0, 26.1,
24.0, 18.5, À4.26, À4.28; HR-MS (ESI): m/z=530.2534,
calcd. for [M+Na]+ (C26H41NO7SiNa): 530.2545; [a]25: 4.5 (c
1.0, CHCl3) for an enantiomerically enriched sampleDof 96%
ee. The enantiomeric excess was determined by HPLC anal-
ysis in comparison with authentic racemic material (AD
column, 98/2 hexane/iPrOH, 1.0 mLminÀ1, 210.5 nm): tr
(major enantiomer)=12.5 min, tr (minor enantiomer)=
14.1 min.
The above compound (6D6 mg, 0.20 mmol) was dissolved in
MeOH (10 mL). Pd/C (10%, 10 mg) was added. The hydro-
genation was conducted under H2 atmosphere (50–70 psi)
for 24 h. Upon completion, the solution was filtered through
celite, and concentrated to give the hydrogenation product
(yield: 66 mg), which was then dispersed in anhydrous
CH2Cl2 (2 mL). With stirring, Et3N (0.2 mL, 1.4 mmol) and
DMAP (5 mg, 0.04 mmol) were added, followed by drop-
wise addtion of benzoyl chloride (47 mL, 0.41 mmol) at 08C.
The mixture was stirred at room temperature for 17 h, then
concentrated and purified with flash chromatography on
silica gel (CH2Cl2:MeOH mixtures, 10:1 to 5:1) to furnish
the desired 1-methylcocaine {(1R,2R,3S,5S)-methyl 3-(ben-
zoyloxy)-1,8-dimethyl-8-azabicycloACHTNUTGRNEUNG[3.2.1]octane-2-carboxyl-
ate (4a)}; yield: 60 mg (94%); Rf =0.33 (CH2Cl2:MeOH=
1
10:1). H NMR: d=7.97–7.94 (m, 2H), 7.57–7.51 (m, 1H),
7.43–7.39 (m, 2H), 5.39–5.33 (m, 1H), 3.64 (s, 3H), 3.39–
3.36 (m, 1H), 2.95 (d, J=6.8 Hz, 1H), 2.49 (td, J=11.7,
2.5 Hz, 1H), 2.26 (s, 3H), 2.21–2.10 (m, 1H), 1.92–1.87 (m,
1H), 1.86–1.77 (m, 2H), 1.75–1.67 (m, 1H), 1.28 (s, 3H);
13C NMR: d=170.6, 166.1, 133.1, 130.3, 129.7, 128.5, 68.7,
65.1, 63.0, 55.7, 51.3, 37.0, 34.7, 34.4, 26.9, 22.9; HR-MS
(ESI): m/z=318.1711, calcd. for [M+H]+ (C18H24NO4):
318.1700; [a]2D5: À8.1 (c 1.0, CHCl3) {lit. 4a: [a]D20: À8.32 (c
1.25, CHCl3)[12c]}.
ACHTUNGTRENNUNG(S,E)-2-(4-Methoxy-4-oxobut-2-en-1-yl)-5-methyl-3,4-dihy-
dro-2H-pyrrole 1-oxide (9b): Prepared using the representa-
tive catalytic nitrone tandem synthesis procedures; yield:
1
76%; Rf =0.23 (EtOAc:MeOH=3:1). H NMR: d=6.86 (dt,
J=15.6, 7.4 Hz, 1H), 5.95 (dt, J=15.6, 1.5 Hz, 1H), 4.17–
4.08 (m, 1H), 3.72 (s, 3H), 3.06–2.99 (m, 1H), 2.66–2.56 (m,
3H), 2.30–2.21 (m, 1H), 2.04 (s, 3H), 1.84–1.75 (m, 1H);
13C NMR: d=166.1, 144.0, 142.9, 124.2, 70.5, 51.3, 34.8, 30.9,
22.0, 12.6; HR-MS (ESI): m/z=220.0947, calcd. for [M+
H]+ (C10H15NO3Na): 220.0944 found; [a]2D5: À19.5 (c 1.0,
CHCl3).
The above crude nitrone 9b (89 mg, 0.46 mmol) was dis-
solved in anhydrous toluene (23 mL) and transferred to
a pressure tube. AlACHTUNGTRENNUNG(O-t-Bu)3 (56 mg, 0.23 mmol) was added
Experimental Procedures for the Tandem Synthesis
of Ferruginine from Methylecgonine
Ecgonine methyl ester ent-1b (50 mg, 0.17 mmol), which had
been prepared as described above, was heated to reflux in
2 mL of 6M HCl for 6 h. After cooling to room tempera-
ture, the solution was washed with Et2O (2 mL), and then
concentrated under reduced pressure to give the natural
product (+)-ecgonine (ent-1a).
The crude acid product was then refluxed with 2 mL of
POCl3 for 4 h. The excess POCl3 was then removed under
reduced pressure. The residue was stirred with
MeO(Me)NH·HCl (83 mg, 0.85 mmol) and Et3N (0.24 mL,
1.7 mmol) in anhydrous CH2Cl2 (2 mL) for 2 h. The solution
was washed with NH3·H2O (1 mL), and the aqueous layer
was extracted with CH2Cl2 (2 mL). The combined organic
phase was dried with anhydrous Na2SO4, filtered, concen-
trated, and purified by flash chromatography on silica gel
(NH3·H2O:MeOH mixtures, 20:1) to furnish the amide prod-
and the tube was sealed. The reaction mixture was stirred at
room temperature for 4 h and then heated at 1508C for
64 h. After cooling to room temperature, the mixture was
extracted with aqueous 1M HCl (10 mLꢄ3). The aqueous
layers were neutralized with solid Na2CO3, and extracted
with CH2Cl2 (15 mLꢄ3). The CH2Cl2 extracts were com-
bined, dried with Na2SO4, filtered, and concentrated to give
the isoxazoline product 15b which can be used in the next
step without purification; yield: 64 mg (72%. An analytical
sample of 15b could be obtained with flash chromatography
1
on silica gel (EtOAc); Rf =0.47 (EtOAc). H NMR: d=4.92
(d, J=3.6 Hz, 1H), 3.67 (s, 3H), 3.61–3.57 (m, 1H), 2.43 (s,
1H), 2.21–2.12 (m, 3H), 1.83–1.74 (m, 2H), 1.25–1.22 (m,
4H); 13C NMR: d=171.8, 81.7, 75.8, 62.8, 61.3, 51.7, 42.1,
33.9, 26.2, 22.1; HR-MS (ESI): m/z=198.1129, calcd. for
[M+H]+ (C10H16NO3): 198.1125 found; [a]2D5: À52.7 (c 1.0,
CHCl3).
uct (1S,5R)-N-methoxy-N,8-dimethyl-8-azabicycloACTHNUTRGENUG[N 3.2.1]oct-
2-ene-2-carboxamide (ent-14a): yield: 25 mg (70%); Rf =
1
0.30 (CH2Cl2:MeOH=5:1). H NMR: d=6.21 (t, J=3.0 Hz,
The above crude isoxazoline (40 mg, 0.20 mmol) was
heated with MsOMe (52 mL, 0.61 mmol) in anhydrous ben-
zene (10 mL) in a sealed pressure tube at 858C for 24 h. The
solution was cooled to room temperature and extracted with
water (25 mLꢄ2). The aqueous phase was concentrated
1H), 3.65 (s, 3H), 3.62 (d, J=5.2 Hz, 1H), 3.27 (t, J=
5.6 Hz, 1H), 3.23 (s, 3H), 2.60 (brd, J=18.8 Hz, 1H), 2.43
(s, 3H), 2.23–2.11 (m, 2H), 2.09–2.01 (m, 1H), 1.78 (dd, J=
19.0, 4.2 Hz, 1H), 1.62–1.54 (m, 1H); 13C NMR: d=169.7,
136.6, 128.0, 61.3, 60.6, 57.0, 35.6, 35.0, 33.6, 30.5, 30.4; HR-
1370
asc.wiley-vch.de
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 1363 – 1372

Concise Catalytic Asymmetric Total Synthesis of Biologically Active Tropane Alkaloids
MS (ESI): m/z=211.1443, calcd. for [M+H]+ (C11H19N2O2):
211.1441; [a]25: 0.4 (c 1.0, CHCl3).
[7] S. C. Laizure, T. Mandrell, N. M. Gades, R. B. Parker,
Drug Metab. Dispos. 2003, 31, 16, and references cited
therein.
Under anD N2 atmosphere, the above amide (25 mg,
0.12 mmol) was dissolved in anhydrous THF (2 mL) at
À788C. To this solution, MeLi (1.6M in Et2O, 0.15 mL,
0.24 mmol) was added dropwise over 5 min. The reaction
mixture was stirred at this temperature for 30 min and then
at 08C for 30 min. After quenching with saturated aqueous
NH4Cl (2 mL), the solution was extracted with CH2Cl2
(5 mLꢄ3). The organic phases were combined, dried with
anhydrous Na2SO4, filtered, concentrated, and purified flash
chromatography on silica gel (NH3·H2O:MeOH mixtures,
20:1) to furnish (+)-ferruginine; yield: 19 mg (97%); Rf =
[8] a) F. I. Carroll, B. E. Blough, S. W. Mascarella, H. A.
Navarro, J. B. Eaton, R. J. Lukas, M. I. Damaj, J. Med.
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1
0.27 (CH2Cl2:MeOH=5:1). H NMR: d=6.70 (t, J=3.2 Hz,
1H), 3.91 (d, J=5.2 hz, 1H), 3.25 (t, J=5.2 Hz, 1H), 2.72
(brd, J=19.2 Hz, 1H), 2.32 (s, 3H), 2.25 (s, 3H), 2.19–2.09
(m, 2H), 1.92 (dd, J=19.8, 4.2 Hz, 1H), 1.71 (t, J=9.4 Hz,
1H), 1.52–1.42 (m, 1H); 13C NMR: d=197.7, 143.9, 136.8,
57.7, 57.6, 37.4, 33.8, 33.2, 29.7, 25.0; HR-MS (ESI): m/z=
166.1229, calcd. for [M+H]+ (C10H16NO): 166.1226; [a]D25:
50.2 (c 1.0, CHCl3) {lit. (À)-Ferrunginine ent-2: [a]2D5: À50.8
(c 0.94, CHCl3)[14f]}.
¨
[9] a) R. Willstꢂtter, W. Muller, Ber. Dtsch. Chem. Ges.
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Acknowledgements
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We gratefully acknowledge the Swedish National Research
Council and Wenner-Gren-Foundation for financial support.
The Berzelii Center EXSELENT is financially supported by
VR and the Swedish Governmental Agency for Innovation
Systems (VINNOVA).
[13] This approach failed to control the stereochemistry of
the carbomethoxy group at C-2 of ent-1 always result-
ing in a 1:1 mixture of epimers; see ref.[12d]
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Adv. Synth. Catal. 2012, 354, 1363 – 1372