Toward an asymmetric general access to azabicyclo[n.2.1]alkanes according to the CN(R,S) method

Article abstract of DOI:10.1002/1099-0690(200205)2002:9<1484::AID-EJOC1484>3.0.CO;2-G

According to the CN(R,S) strategy, a general method for the synthesis of azabicyclo[n.2.1]alkanes of type 4 was described starting from the 2-cyano-5-oxazolopyrrolidine 5. A Mannich-type cyclization allowed an asymmetric access to potent nicotinic acetylcholine receptor agonists like epibatidine 1, ferruginine 2 and anatoxine-a 3. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200205)2002:9<1484::AID-EJOC1484>3.0.CO;2-G

FULL PAPER
Toward an Asymmetric General Access to Azabicyclo[n.2.1]alkanes According
to the CN(R,S) Method
Isabelle Gillaizeau-Gauthier,[a] Jacques Royer,*[a] and Henri-Philippe Husson[a]
Keywords: Nicotinic receptor agonist / Asymmetric synthesis / Fused-ring systems / Mannich reaction / Cyclization
According to the CN(R,S) strategy, a general method for the
nicotinic acetylcholine receptor agonists like epibatidine 1,
synthesis of azabicyclo[n.2.1]alkanes of type 4 was described ferruginine 2 and anatoxine-a 3.
starting from the 2-cyano-5-oxazolopyrrolidine 5. A Man-
(
Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
nich-type cyclization allowed an asymmetric access to potent 2002)
Introduction
Natural aza-bicyclo derivatives have been reported to ex-
hibit agonist activity for nicotinic receptors. (Ϫ)-Epibatid-
ine 1, a 7-azanorbornane analogue of nicotine isolated from
the skin of the Ecuadorian poison frog Epipedobates tricol-
our, has been reported to be an extraordinary non-opioid
analgesic and a very potent nicotinic acetylcholine receptor
(nAChR) agonist.[1,2] Likewise, (ϩ)-ferruginine 2, an 8-aza-
bicyclo[3.2.1]octane extracted from the arboreal species
Darlingiana ferruginea and D. darlingiana, has been used as
an nAChR agonist for the treatment of neurodegenerative
diseases.[3,4]
Another well-known toxin, (ϩ)-anatoxine-a 3, possessing
the 9-azabicyclo[4.2.1]nonane skeleton, produced by the
fresh water cyanobacterium Anabaena Flos aquae, has been
subjected to numerous chemical and biological studies due
to its remarkable activity as an nAChR agonist.[5,6]
The biological activity of these compounds emerges from
their structural similarity with nicotine, namely a nitrogen
atom and a π system (aromatic or conjugated ketone group)
together with an appropriate spatial arrangement. For all
of them, the rigid bicyclic skeleton forces the nitrogen atom
to be at a precise distance from the π electron system. This
distance can be varied by varying n in the general structure
4 (see figure above). It therefore appeared interesting to de-
sign a general access to azabicyclo[n.2.1]alkanes 4 that
could also be valuable for the synthesis of alkaloids 1Ϫ3
and some of their analogues. A strategy for the construction
of bicyclic compounds of type 4 was envisaged starting
from 2-cyano-5-oxazolopyrrolidine 5. The synthetic interest
of this chiral nonracemic starting material has already been
shown in many applications.[7] According to the CN(R,S)
method,[7] our plan consisted of the alkylation of 5 at the
position α to the nitrile function by an alkyl chain con-
taining a nucleophilic group that would be able to add onto
the potential iminium ion 6[8a] and more precisely through
a Mannich reaction as depicted in Scheme 1. It was anti-
cipated that this intramolecular cyclization leading to the
desired azabicyclic compound 4 would be governed by the
empirical rules established by Baldwin.[8b] Nevertheless, at-
tempts to cyclize by 5-, 6- and 7-endo-trig reactions were
also undertaken.
Results and Discussion
[a]
Institut de Chimie des Substances Naturelles, CNRS, 91198
Gif-sur-Yvette, France and Laboratoire de Chimie
The synthesis of the azabicyclo[n.2.1]skeleton started
with the preparation of precursors 10aϪc following the gen-
eral sequence depicted in Scheme 2. Alkylation of the
lithiated anion of 2-cyano-5-oxazolopyrrolidine 5 (LDA 2.6
´
´
´
`
Therapeutique, Unite de Recherche associee au CNRS et a
´
´
´
l’Universite Rene Descartes, Faculte de Pharmacie,
4 avenue de l’Observatoire, 75270 Paris cedex 06, France
Fax: (internat.) ϩ 33-1/4329-1403
E-mail: jroyer@pharmacie.univ-paris5.fr
1484
WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0509Ϫ1484 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2002, 1484Ϫ1489

An Asymmetric General Access to Azabicyclo[n.2.1]alkanes
FULL PAPER
The next step consisted of the opening of the oxazolidine
ring of compound 10 under acidic conditions to generate
the iminium ion 11, which should be able to undergo the
planned
intramolecular
Mannich-type
cyclization
(Scheme 3). Indeed, treatment of 10a,b with methanolic hy-
drochloric acid produced the desired bicyclic derivatives
12a,b in varying yields together with the deprotected ke-
tones 13a,b; 10c failed to undergo the cyclization reaction
(Scheme 3).
Scheme 1
equiv. THF, Ϫ78 °C) in the presence of HMPA (4.2 equiv.)
with haloketals 8aϪc afforded the amino nitriles 9aϪc as
diastereomeric mixtures in good yield (Scheme 2).[9]
Scheme 3
The 7-azabicyclo[2.2.1] skeleton 12a was isolated in 18%
1
yield as a unique stereoisomer as proved by H and 13C
NMR spectroscopy and chromatographic analyses. The exo
1
configuration of the acetyl group was deduced in the H
NMR spectrum from the pattern of the H-2 signal, which
appeared as a doublet of doublets at δ ϭ 2.47 (J ϭ 5.1,
9.8 Hz) corresponding to a coupling with both H-3 protons,
and the apparent absence of coupling with the bridgehead
proton H-1. This observation was found to be in agreement
with the signal pattern of very similar 7-azabicy-
clo[2.2.1]heptane systems.[12] Although the elaboration of
the azanorbornane skeleton was accomplished with success,
Scheme 2
Diastereoselective decyanation of 9aϪc[4,11] was achieved the low yield of the disfavoured 5-endo-trig cyclization was
using Li/NH3 in the presence of ethanol (THF/NH3/EtOH unfortunately incompatible with a multistep synthesis. For
100:10:1) to give compounds 10aϪc as single stereoisomers similar work in this field, Rapoport reported better results
along with unreacted 9. The use of ethanol in this reaction by applying the intramolecular Mannich-type cyclisation
precluded the formation of by-products.[11] A 2R-configura- onto a more electrophilic acyliminium ion.[13]
tion could be assigned for the pyrrolidine 10 in analogy to
Using the same strategy as above, the 8-azabicyclo[3.2.1]
previous results in this series. This was the desired config- skeleton 12b was successfully isolated in 66% yield. This
uration for the C-1 carbon in the target bicyclic compounds transformation was totally stereoselective: only one ste-
of type 4. Some attempts were made to improve the yield reoisomer was present in the crude mixture as indicated by
of this decyanation step by using sodium metal or by vary- 1H and 13C NMR spectrosopcy. The endo configuration of
1
ing the reaction temperature, without success.
the acetyl group was deduced from the H NMR spectrum
Eur. J. Org. Chem. 2002, 1484Ϫ1489
1485

I. Gillaizeau-Gauthier, J. Royer, H.-P. Husson
FULL PAPER
1
and thermodynamic stability hypotheses: in the H NMR ifically converted into the oxazolidine 16 in two steps in
spectrum, the diagnostic H-2 proton exhibited coupling 28% overall yield (Scheme 5). The presence of a single ste-
constants of 2.1 Hz with H-1 and 5.6 Hz and 11.5 Hz with reoisomer was proved by NMR spectroscopy and chroma-
H-3, which clearly indicated that H-2 occupied an axial po- tography; some aminonitrile 15 was also recovered (20%
sition. The reaction conditions (MeOH, HCl 1 , 60 °C) of yield). Treatment of the acetal function of compound 16
the intramolecular cyclization of the iminium ion 11b led with dilute hydrochloric acid provided the crude aldehyde,
to the formation of the thermodynamically more stable tro- which was immediately submitted to HornerϪ
pane 12b in which the acetyl group occupies an equatorial WadsworthϪEmmons
conditions
(iPr2NEt,
LiCl,
position on the six-membered ring.[14] Removal of the chiral MeCN)[16] to afford the enone 17 in 70% overall yield. The
appendage of 12b by hydrogenolysis and reprotection of the 7-endo-trig cyclization step carried out with methanolic sul-
secondary amine as tert-butylcarbamate afforded the N- furic acid provided the two bicyclic derivatives 18 and 19,
BOC bicyclic compound 14 in 85% yield in a one-pot reac- which were isolated as an inseparable mixture in approxim-
tion (Scheme 4). A formal diastereoselective synthesis of ately 24% yield. These nonoptimized results potentially pro-
(ϩ)-ferruginine could thus be achieved, since Rapoport et vide an easy access to N-methylanatoxine.
al. have described the conversion of 14 into the target alkal-
oid.[15] This short synthesis also appears very interesting for
the synthesis of tropane analogues of epibatidine which
could also be easily accessible in this manner.
Scheme 4
The 7-endo-trig type cyclization required for the con-
struction of the 9-azabicyclo[4.2.1] skeleton was more diffi-
cult than would be expected from Baldwin’s empirical rules.
Indeed, the methanolic hydrochloric acid treatment of the
amino ether 10c was ineffective for the desired cyclization:
no trace of cyclization product could be found and only
deprotected ketone 13c (60% yield), together with decom-
position products, were isolated. Since reactions of iminium
ion species with nucleophiles can generally be conducted
with improved yields under anhydrous conditions, or, in
some cases, even better with polar nonprotic solvents, we
Scheme 5
Conclusion
By following the CN(R,S) method we have developed a
examined these alternatives. Nevertheless, all attempts to short and original access to compounds possessing the aza-
promote the 7-endo-trig cyclization failed, even in the pres- bicyclo[n.2.1] skeleton. The key step of our strategy, which
ence of Lewis acid catalysts.
is based on an intramolecular cyclization of a nucleophile
Our attention then turned to the intramolecular cycliza- group onto an alkyliminium ion, allowed us to achieve a
tion of an α,β-unsaturated ketone onto an iminium ion on formal synthesis of (ϩ)-ferruginine.[4] Our general method
the basis of our previous published total synthesis of (ϩ)- has potential for the synthesis of various analogues of nat-
ferruginine.[4] 2-Cyano-5-oxazolidine (5) was diastereospec- ural bicyclic alkaloids.
1486
Eur. J. Org. Chem. 2002, 1484Ϫ1489

An Asymmetric General Access to Azabicyclo[n.2.1]alkanes
FULL PAPER
126.1, 127.3, 128.6, 141.3. C21H28N2O3 (356.5): calcd. C 70.76, H
7.96, N 7.86; found C 70.34, H 7.69, N 8.12.
Experimental Section
General: Tetrahydrofuran was distilled from sodium/benzophenone
ketyl immediately prior to use. Diisopropylamine was distilled from
and stored over KOH. Acetonitrile was distilled from CaH2 and
methanol and ethanol from magnesium turnings. Flash chromato-
graphy was carried out using 230Ϫ400 mesh silica gel. Optical rota-
tions were carried out at 20 °C in a 1 dm cell. Microanalyses were
carried out at the ‘‘Service de Microanalyse’’ at the ‘‘Institut de
Chimie des Substances Naturelles’’.
General Reductive Decyanation Procedure for Compounds 9: A solu-
tion of the oxazolopyrrolidine 9 (10.4 mmol) in THF (39 mL) was
added to liquid ammonia (360 mL) at Ϫ40 °C, followed by dry
ethanol (3.6 mL). After stirring for 5 min lithium metal (174 mg,
25.0 mmol) was introduced. Stirring was continued at Ϫ78° C for
30 min, and then the ammonia was evaporated before the reaction
was quenched with saturated aqueous NH4Cl. The mixture was
extracted with CH2Cl2, the combined organic phases were dried
and concentrated under vacuum and purified by flash chromato-
graphy (heptane/EtOAc 8:2).
General Alkylation Procedure of Amino Nitrile (5): A solution of 5
(3 g, 14.0 mmol) in THF (24 mL) at Ϫ78 °C was added dropwise to
a
stirred solution of LDA [prepared from diisopropylamine
5-{2-(2-Methyl-[1,3]dioxolan-2-yl)ethyl}-3-phenylhexahydropyrrolo-
[2,1-b]oxazole (10a): The general decyanation procedure was ap-
plied to 9a (3.4 g, 10.4 mmol) to give 10a (1.20 g, 38% yield) as a
colourless oil (accompanied by starting material 9a isolated in 20%
yield). [α]D ϭ Ϫ35 (CHCl3, c ϭ 1.1). IR (neat): ν˜ ϭ 2947, 2850,
1600, 1445, 1365, 1210, 1100 cmϪ1. MS (EI): m/z ϭ 304 (100), 273
(5.1 mL, 36.4 mmol) and 1.6  nBuLi (22.8 mL, 36.4 mmol) in
hexane] in THF (12 mL) and HMPA (10.3 mL, 58.8 mmol). After
30 min, a solution of 8 (16.8 mmol) in THF (5 mL) was added.
After stirring for 4 hours at Ϫ78 °C, the mixture was quenched by
saturated aqueous NH4Cl and extracted with CH2Cl2. The organic
layers were combined, dried and concentrated under vacuum. The
crude oil was then purified by flash chromatography
1
(10), 260 (42), 188 (78) [MHϩ]. H NMR (250 MHz, CDCl3): δ ϭ
7.21Ϫ7.40 (m, 5 H), 5.00 (dd, J ϭ 2.2, 5.3 Hz, 1 H), 4.35 (t, J ϭ
7.6 Hz, 1 H), 4.18 (t, J ϭ 6.6 Hz, 1 H), 3.64Ϫ3.90 (m, 4 H), 3.61
(dd, J ϭ 6.2, 8.2 Hz, 1 H), 2.90 (m, 1 H), 1.37Ϫ2.20 (m, 8 H), 1.22
(s, 3 H). 13C NMR (62.5 MHz, CDCl3): δ ϭ 23.6, 29.9, 30.0, 30.1,
35.4, 64.4, 66.4, 67.9, 72.8, 98.8, 109.8, 126.5, 126.7, 128.3, 143.0.
5-{2-(2-Methyl-[1,3]dioxolan-2-yl)ethyl}-3-phenylhexahydropyrrolo-
[2,1-b]oxazole-5-carbonitrile (9a): The general alkylation procedure
was applied to 5 (3 g, 14 mmol) and 8a (3.3 mL, 16.8 mmol) to give
9a (3.41 g, 74% yield) as a 6:4 mixture of diastereomers and as a
colourless oil after flash chromatography (heptane/EtOAc 7:3).
(more polar diastereomer) [α]D ϭ Ϫ57 (CHCl3, c ϭ 1.0). IR (neat):
HRMS (CI) calcd. for C18H25NO3
304.1913.
ϩ
Hϩ 304.1912; found
ν ϭ 2979, 2950, 2880, 2235, 1449, 1379, 1065 cmϪ1. MS (CI):
˜
m/z ϭ 329 [MHϩ], 302, 188. 1H NMR (250 MHz, CDCl3): δ ϭ
7.20Ϫ7.40 (m, 5 H), 5.04 (dd, J ϭ 3.7 Hz, 1 H), 4.54 (t, J ϭ 7.4 Hz,
1 H), 4.28 (t, J ϭ 7.7 Hz, 1 H), 3.70Ϫ3.90 (m, 4 H), 3.48 (t, J ϭ
8.0 Hz, 1 H), 1.80Ϫ2.30 (m, 8 H), 1.24 (s, 3 H). 13C NMR
(62.5 MHz, CDCl3): δ ϭ 23.9, 28.5, 29.1, 35.4, 35.6, 61.1, 64.7,
65.4, 74.2, 97.9, 108.9, 122.0, 126.2, 127.3, 128.6, 141.4. HRMS
(CI) calcd. for C19H24N2O3 ϩ Hϩ 329.1865; found 329.1846.
5-{3-(2-Methyl-[1,3]dioxolan-2-yl)propyl}-3-phenylhexa-
hydropyrrolo[2,1-b]oxazole (10b): The general decyanation proced-
ure was applied to 9b (2 g, 5.9 mmol) to give 10b (795 mg, 42%
yield) as a colourless oil [accompanied by starting material 9b
(35%)]: [α]D ϭ Ϫ42 (CHCl3, c ϭ 1.6). IR (neat): ν˜ ϭ 2944, 2875,
1600, 1491, 1456, 1375, 1068 cmϪ1. MS (CI): m/z ϭ 318 [MHϩ],
1
198. H NMR (250 MHz, CDCl3): δ ϭ 7.21Ϫ7.39 (m, 5 H), 5.00
(dd, J ϭ 2.3, 5.3 Hz, 1 H), 4.35 (t, J ϭ 7.7 Hz, 1 H), 4.14 (t, J ϭ
6.8 Hz, 1 H), 3.80Ϫ3.93 (m, 4 H), 3.60 (dd, J ϭ 6.5, 8.3 Hz, 1 H),
2.88 (m, 1 H), 1.25Ϫ2.20 (m, 10 H), 1.22 (s, 3 H). 13C NMR
(62.5 MHz, CDCl3): δ ϭ 21.1, 23.7, 30.1, 30.5, 36.3, 39.4, 64.6,
66.9, 68.4, 73.1, 98.9, 110.1, 126.6, 126.9, 128.2, 143.2. C19H27NO3
(317.4): calcd. C 71.89, H 8.57, N 4.41; found C 71.59, H 8.28,
N 4.29.
5-{3-(2-Methyl-[1,3]dioxolan-2-yl)propyl}-3-phenylhexahydro-
pyrrolo[2,1-b]oxazole-5-carbonitrile (9b): The general alkylation
procedure was applied to 5 (1.5 g, 6.9 mmol) and 8b (2 mL,
8.4 mmol) to give 9b (1.83 g, 84% yield) as a 7:3 mixture of diaster-
eomers and as a colourless oil after flash chromatography (heptane/
EtOAc 7:3). (more polar diastereomer) [α]D ϭ Ϫ60 (CHCl3, c ϭ
0.28). IR (neat): ν˜ ϭ 2947, 2880, 2231, 1604, 1492, 1453, 1380,
1
1066 cmϪ1. MS (CI): m/z ϭ 343 [MHϩ], 316, 195, 188. H NMR
5-{4-(2-Methyl-[1,3]dioxolan-2-yl)butyl}-3-phenyl-exahydropyrrolo-
[2,1-b]oxazole (10c): The general decyanation procedure was ap-
plied to oxazolopyrrolidine 9c (1.5 g, 4.2 mmol) to give 10c
(667 mg, 48% yield) as a colourless oil: [α]D ϭ Ϫ34 (CHCl3, c ϭ
1.1) {ref.:[9] [α]D ϭ Ϫ34 (CHCl3, c ϭ 2.1)}. IR (neat): ν˜ ϭ 2947,
2873, 1453, 1144, 1030 cm-1. MS (CI): m/z ϭ 332 [MHϩ]. 1H NMR
(250 MHz, CDCl3): δ ϭ 7.20Ϫ7.40 (m, 5 H), 5.01 (dd, J ϭ 2.3,
5.3 Hz, 1 H), 4.36 (dd, J ϭ 7.1, 8.1 Hz, 1 H), 4.16 (t, J ϭ 6.7 Hz,
1 H), 3.91 (m, 4 H), 3.63 (dd, J ϭ 6.2, 8.2 Hz, 1 H), 2.88 (m, 1 H),
1.16Ϫ2.21 (m, 12 H), 1.22 (s, 3 H). 13C NMR (62.5 MHz, CDCl3):
δ ϭ 23.8, 24.4, 26.8, 30.2, 30.6, 36.1, 39.3, 64.7, 66.8, 68.2, 73.0,
99.0, 110.2, 126.7, 126.9, 128.5, 143.3. C20H29NO3 (331.5): calcd.
C 72.47, H 8.82, N 4.23; found C 72.10, H 8.48, N 4.55.
(250 MHz, CDCl3): δ ϭ 7.20Ϫ7.40 (m, 5 H), 5.04 (dd, J ϭ 1.9,
3.6 Hz, 1 H), 4.52 (t, J ϭ 7.4 Hz, 1 H), 4.27 (dd, J ϭ 7.3, 8.3 Hz,
1 H), 3.79Ϫ3.92 (m, 4 H), 3.47 (t, J ϭ 8.1 Hz, 1 H), 1.20Ϫ2.29 (m,
10 H), 1.23 (s, 3 H). 13C NMR (62.5 MHz, CDCl3): δ ϭ 20.7, 23.8,
29.2, 34.2, 35.5, 38.9, 61.2, 64.6, 65.8, 74.2, 97.9, 109.5, 122.2,
126.2, 127.4, 128.7, 141.3. C20H26N2O3 (342.4): calcd. C 70.15, H
7.65, N 8.18; found C 69.85, H 7.52, N 7.59.
5-{4-(2-Methyl-[1,3]dioxolan-2-yl)butyl}-3-phenylhexahydropyrrolo-
[2,1-b]oxazole-5-carbonitrile (9c): The general alkylation procedure
was applied to 5 (2.9 g, 13.5 mmol) and 8c (2.9 mL) to give 9c
(3.51 g, 73% yield) as a 7:3 mixture of diastereomers and as a col-
ourless oil after flash chromatography (heptane/EtOAc 7:3). (more
˜
polar diastereomer) [α]D ϭ Ϫ54 (CHCl3, c ϭ 6.6). IR (neat): ν ϭ
General Cyclization Procedure for Compounds 10: A solution of 10
2950, 2870, 2230, 1149, 1375, 1080 cmϪ1. MS (CI): m/z ϭ 357 (0.33 mmol) and 1  HCl (2.2 mL) in MeOH (10 mL) was refluxed
[MHϩ], 330. 1H NMR (250 MHz, CDCl3): δ ϭ 7.24Ϫ7.41(m, 5 at 60 °C for 18 hours. The mixture was then cooled, poured into
H), 5.03 (d, J ϭ 3.5 Hz, 1 H), 4.54 (t, J ϭ 7.3 Hz, 1 H), 4.27 (t, J ϭ saturated aqueous NaHCO3 and extracted with CH2Cl2. The or-
8.3 Hz, 1 H), 3.88 (m, 4 H), 3.48 (t, J ϭ 7.9 Hz, 1 H), 1.29Ϫ2.28 (m, ganic layers were dried and the solvents evaporated under vacuum.
12 H), 1.26 (s, 3 H). 13C NMR (62.5 MHz, CDCl3): δ ϭ 23.7, 24.1,
26.3, 29.1, 34.1, 35.4, 38.7, 61.1, 64.5, 65.7, 74.1, 97.8, 109.7, 122.2,
The residue was purified by flash chromatography (heptane/EtOAc
7:3 and 2:8).
Eur. J. Org. Chem. 2002, 1484Ϫ1489
1487

I. Gillaizeau-Gauthier, J. Royer, H.-P. Husson
FULL PAPER
1-{7-(2-Hydroxy-1-phenylethyl)-7-azabicyclo[2.2.1]hept-2-yl}-
white solid: m.p. 62 °C. [α]D ϭ ϩ115 (CHCl3, c ϭ 0.86) {ref.:[14]
˜
[α]D ϭ ϩ112 (CHCl3, c ϭ 1)}. IR (neat): ν ϭ 2975, 2881, 1697,
ethanone (12a): The general cyclization procedure was applied to
1
10a (100 mg, 0.33 mmol) to afford, after purification, the depro- 1680, 1404, 1171 cmϪ1. MS (CI): m/z ϭ 254 [MHϩ], 198, 154. H
tected product 13a (20.5 mg, 24%) and the bicycle 12a (15.4 mg,
NMR (400 MHz, CDCl3 at 0 °C): δ (two rotamers) ϭ 4.37 (br. d,
J ϭ 6.2 Hz, 1 H), 4.28 (br. d, J ϭ 4.8 Hz, 1 H), 4.15 (br. s, 1 H),
4.05 (br. d, J ϭ 5.9 Hz, 1 H), 2.82 (br. d, J ϭ 11.8 Hz, 1 H), 2.68
18%) as a colourless oil.
12a: IR (neat): ν ϭ 3430, 2958, 2875, 1704, 1450, 1370 cmϪ1. MS
˜
(CI): m/z ϭ 260 [MHϩ]. 1H NMR (250 MHz, CDCl3): δ ϭ (br. d, J ϭ 10.6 Hz, 1 H), 2.09 (s, 3 H), 2.08 (s, 3 H), 1.20Ϫ1.91 (m,
7.26Ϫ7.40 (m, 5 H), 3.97 (J ϭ 4.5, 11.0 Hz, 1 H), 3.90 (d, J ϭ
16 H), 1.41 (s, 9 H), 1.40 (s, 9 H). 13C NMR (62.5 MHz, CDCl3): δ
4.6 Hz, 1 H), 3.59 (m, 1 H), 3.36 (m, 1 H), 3.15 (m, 1 H), 2.47 (dd, (two rotamers) ϭ 18.0, 18.3, 24.5, 25.3, 27.3, 27.9, 28.2, 28.4, 28.6,
J ϭ 5.1, 9.8 Hz, 1 H), 2.12 (s, 3 H), 1.33Ϫ2.15 (m, 7 H). 13C NMR 29.1, 29.7, 51.9, 53.0, 53.7, 54.2, 54.7, 79.4, 152.9, 153.3, 208.9,
(62.8 MHz, CDCl3): δ ϭ 26.3, 26.9, 29.8, 33.4, 55.6, 57.7, 58.4, 209.2. C14H23NO3 (253.3): calcd. C 66.37, H 9.15, N 5.53; found
60.9, 65.8, 127.5, 128.2, 128.4, 140.3, 215.0. HRMS (CI) calcd. for C 66.31, H 9.06, N 5.41.
C16H21NO2 ϩ Hϩ 260.1650; found 260.1656.
5-(2-[1,3]-Dioxolan-2-ylethyl)-3-phenylhexahydropyrrolo[2,1-b]-
Ϫ1
˜
13a: IR (neat): ν ϭ 2933, 2868, 1715, 1666, 1454, 1367, 1030 cm
.
oxazole-5-carbonitrile (15): The general alkylation procedure was
applied to 5 (2.1 g, 9.7 mmol) and 2-bromoethyl[1,3]dioxolane
(1.2 mL, 10.6 mmol) to afford, after purification, 15 (2.19 g, 72%
yield) as a 7:3 mixture of diastereomers and as a colourless oil.
These isomers could be separated to furnish analytical sample of
each epimer.
MS (CI): m/z ϭ 260 [MHϩ], 188. 1H NMR (250 MHz, CDCl3):
δ ϭ 7.23Ϫ7.39 (m, 5 H), 5.01 (dd, J ϭ 1.8, 2.5 Hz, 1 H), 4.32 (dd,
J ϭ 7.2, 8.2 Hz, 1 H), 4.09 (t, J ϭ 6.9 Hz, 1 H), 3.57 (dd, J ϭ 7.0,
8.3 Hz, 1 H), 2.93 (quint, J ϭ 6.5 Hz, 1 H), 2.32Ϫ2.41 (m, 2 H),
1.50Ϫ2.16 (m, 6 H), 1.93 (s, 3 H). 13C NMR (62.5 MHz, CDCl3):
δ ϭ 29.4, 29.8, 30.2, 40.2, 66.2, 69.1, 73.5, 99.1, 126.8, 127.1, 128.6,
142.9, 208.9.
Major compound (more polar): [α]D ϭ Ϫ41 (CHCl3, c ϭ 0.11). IR
(neat): ν ϭ 2950, 2881, 2225, 1606, 1450, 1137, 1044 cmϪ1. MS
˜
1-{8-(2-Hydroxy-1-phenylethyl)-8-azabicyclo[3.2.1]oct-2-yl}- (CI): m/z ϭ 315 [MHϩ]. 1H NMR (250 MHz, CDCl3): δ ϭ
ethanone (12b): The general cyclization procedure was applied to 7.27Ϫ7.41 (m, 5 H), 5.04 (d, J ϭ 3.6 Hz, 1 H), 4.85 (t, J ϭ 3.9 Hz,
10b (778 mg, 2.5 mmol) to afford, after purification, the depro- 1 H), 4.59 (t, J ϭ 7.3 Hz, 1 H), 4.29 (t, J ϭ 7.8 Hz, 1 H), 3.79Ϫ3.90
tected product 13b (87 mg, 13%) and the bicycle 12b (401 mg, 66%)
as a colourless oil.
(m, 4 H), 3.49 (t, J ϭ 7.9 Hz, 1 H), 1.79Ϫ2.31 (m, 8 H). 13C NMR
(62.5 MHz, CDCl3): δ ϭ 28.0, 28.9, 30.5, 35.7, 61.0, 64.9, 65.3,
˜
12b: [α]D ϭ ϩ21 (CHCl3, c ϭ 0.45). IR (neat): ν ϭ 3443, 2952, 74.2, 97.9, 103.1, 121.9, 126.2, 127.3, 128.7, 141.4. C18H22N2O3
2878, 1705, 1453, 1355 cmϪ1. MS (CI): m/z ϭ 274 [MHϩ], 256,
242. H NMR (250 MHz, CDCl3): δ ϭ 7.25Ϫ7.45 (m, 5 H), 3.88 N 8.53.
(m, 1 H), 3.68Ϫ3.78 (m, 2 H), 3.59 (m, 1 H), 3.23 (m, 1 H), 2.85 Minor compound (less polar): H NMR (250 MHz, CDCl3): δ ϭ
(dd, J ϭ 2.3, 10.2 Hz, 1 H), 1.87 (s, 3 H), 1.30Ϫ1.87 (m, 9 H). 13C
7.20Ϫ7.40 (m, 5 H), 5.06 (dd, J ϭ 3.5, 5.6 Hz, 1 H), 4.75 (t, J ϭ
NMR (62.5 MHz, CDCl3): δ ϭ 18.7, 24.3, 27.3, 28.1, 28.3, 51.9, 3.8 Hz, 1 H), 4.67 (t, J ϭ 7.9 Hz, 1 H), 4.56 (t, J ϭ 7.1 Hz, 1 H),
55.6, 58.1, 63.8, 64.5, 127.8, 128.4, 128.6, 140.7, 209.9. C17H23NO2 3.80 (m, 4 H), 3.59 (dd, J ϭ 6.7, 8.2 Hz, 1 H), 1.00Ϫ2.50 (m, 8 H).
(273.4): calcd. C 74.69, H 8.48, N 5.12; found C 74.32, H 7.87, 13C NMR (62.5 MHz, CDCl3): δ ϭ 28.9, 29.1, 33.4, 37.3, 63.8,
(314.4): calcd. C 68.77, H 7.05, N 8.91; found C 68.74, H 7.16,
1
1
N 4.84.
64.7, 65.8, 75.5, 98.3, 103.4, 120.9, 126.2, 127.3, 128.7, 141.9.
˜
13b: [α]D ϭ Ϫ51 (CHCl3, c ϭ 1.25). IR (neat): ν ϭ 2938, 2860,
5-(2-[1,3]-Dioxolan-2-ylethyl)-3-phenylhexahydropyrrolo[2,1-b]-
oxazole (16): The general decyanation procedure was applied to
oxazolopyrrolidine 15 (1.03 g, 5.8 mmol) to give 16 (636 mg, 38%
yield), after flash chromatography (heptane/EtOAc 8:2), as a col-
ourless oil accompanied by starting material 15 (20%): [α]D ϭ Ϫ67
1712, 1448, 1364, 1035 cmϪ1. MS (CI): m/z ϭ 274 [MHϩ], 230,
1
188. H NMR (250 MHz, CDCl3): δ ϭ 7.20Ϫ7.40 (m, 5 H), 5.00
(dd, J ϭ 2.3, 5.3 Hz, 1 H), 4.35 (dd, J ϭ 7.2, 8.2 Hz, 1 H), 4.13 (t,
J ϭ 6.8 Hz, 1 H), 3.59 (dd, J ϭ 6.6, 8.3 Hz, 1 H), 2.89 (m, 1 H),
1.25Ϫ2.46 (m, 10 H), 2.03 (s, 3 H). 13C NMR (62.5 MHz, CDCl3):
δ ϭ 20.7, 29.8, 30.1, 30.3, 35.5, 43.8, 66.6, 68.4, 73.2, 98.9, 126.6,
127.0, 128.5, 143.1, 209.1. C17H23NO2 (273.4): calcd. C 74.69, H
8.49, N 5.12; found C 74.39, H 8.55, N 5.24.
˜
(CHCl3, c ϭ 0.81). IR (neat): ν ϭ 2950, 2867, 1606, 1450, 1375,
1137, 1044 cmϪ1. MS (CI): m/z ϭ 290 [MHϩ], 188. 1H NMR
(250 MHz, CDCl3): δ ϭ 7.20Ϫ7.40 (m, 5 H), 4.98 (dd, J ϭ 2.2,
5.6 Hz, 1 H), 4.76 (t, J ϭ 4.6 Hz, 1 H), 4.33 (dd, J ϭ 7.2, 8.1 Hz,
6-(3-Phenylhexahydropyrrolo[2,1-b]oxazol-5-yl)hexan-2-one (13c): 1 H), 4.17 (t, J ϭ 6.6 Hz, 1 H), 3.63Ϫ3.90 (m, 4 H), 3.60 (dd, J ϭ
The general cyclization procedure was applied to 10c (200 mg,
6.2, 8.2 Hz, 1 H), 2.91 (m, 1 H), 1.38Ϫ1.67 (m, 8 H). 13C NMR
0.61 mmol) to afford, after purification, the deprotected product (62.5 MHz, CDCl3): δ ϭ 30.0, 30.1, 30.2, 30.7, 64.8, 66.3, 68.0,
˜
13c (105 mg, 60%) as a colourless oil: IR (neat): ν ϭ 2935, 2862, 72.9, 98.8, 104.5, 126.5, 126.8, 128.4, 143.1.
1716, 1452, 1373, 1036 cmϪ1. MS (CI): m/z ϭ 288 [MHϩ], 244,
215, 188. H NMR (250 MHz, CDCl3): δ ϭ 7.20Ϫ7.40 (m, 5 H),
6-(5-Phenylhexahydropyrrolizin-3-yl)hex-3-en-2-one (17): A solution
1
of 16 (641 mg, 2.2 mmol) in 5% aqueous HCl (19 mL) was stirred
at room temperature for 15 hours. The mixture was then quenched
with saturated aqueous NaHCO3 and extracted with CH2Cl2. The
combined organic phases were dried and the solvents evaporated
under vacuum to give a yellow oil. Dimethyl (2-oxopropyl)phos-
phonate (0.41 mL, 2.0 mmol), DIPEA (0.485 mL, 5.1 mmol) and
the crude aldehyde in CH3CN (16 mL) were added to a stirred
suspension of LiCl (125 mg, 2.9 mmol) (stored with P2O5) in dry
5.00 (dd, J ϭ 2.0, 6.0 Hz, 1 H), 4.35 (dd, J ϭ 7.0, 8.0 Hz, 1 H),
4.13 (t, J ϭ 6.7 Hz, 1 H), 3.60 (dd, J ϭ 6.5, 8.2 Hz, 1 H), 2.87 (m,
1 H), 1.85Ϫ2.35 (m, 6 H), 2.06 (s, 3 H), 1.18Ϫ1.55 (m, 6 H). 13C
NMR (62.5 MHz, CDCl3): δ ϭ 23.9, 25.9, 29.8, 30.1, 30.4, 35.7,
43.6, 66.6, 68.3, 73.1, 98.9, 126.6, 126.9, 128.4, 143.1, 209.2.
2-Acetyl-8-azabicyclo[3.2.1]octane-8-carboxylic Acid tert-Butyl Es-
ter (14): (BOC)2O (1.27 g) was added to a solution of 12b (401 mg,
1.5 mmol) in MeOH (18 mL) followed by 10% Pd/C (95 mg), and acetonitrile (12 mL) under nitrogen at room temperature,. After
the resulting suspension was hydrogenated (50 psi, room temp.) for stirring for 4 hours, the mixture was quenched with saturated aque-
3 hours. The reaction mixture was filtered, and the filtrate was
ous NH4Cl and extracted with CH2Cl2. The organics layers were
evaporated. The crude oil was purified by flash chromatography combined, dried and concentrated under vacuum. The crude oil
(heptane/EtOAc 8:2) to give the carbamate 14 (316 mg, 85%) as a
was purified by flash chromatography (heptane/ EtOAc 7:3) to pro-
1488
Eur. J. Org. Chem. 2002, 1484Ϫ1489

An Asymmetric General Access to Azabicyclo[n.2.1]alkanes
FULL PAPER
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˜
(CHCl3, c ϭ 1.78). IR (neat): ν ϭ 2936, 2865, 1699, 1675, 1627,
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15.9, 6.9 Hz, 1 H), 5.91 (d, J ϭ 15.9 Hz, 1 H), 5.00 (dd, J ϭ 2.1,
5.1 Hz, 1 H), 4.34 (t, J ϭ 7.7 Hz, 1 H), 4.11 (t, J ϭ 6.9 Hz, 1 H),
3.57 (t, J ϭ 7.4 Hz, 1 H), 2.93 (m, 1 H), 1.44Ϫ2.22 (m, 8 H), 2.16
(s, 3 H). 13C NMR (62.5 MHz, CDCl3): δ ϭ 26.8, 29.1, 30.0, 34.2,
66.2, 68.6, 73.4, 98.8, 126.2, 127.0, 128.4, 131.1, 142.7, 148.1, 198.6.
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˜
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[6b]
(CI): m/z ϭ 318 [MHϩ]. 1H NMR (250 MHz, CDCl3): δ ϭ 7.2Ϫ7.5
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˜
19: IR (neat): ν ϭ 3429, 2950, 2880, 1660, 1631, 1377, 1250 cm
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1489