Stereoselective synthesis of 4-substituted 4-hydroxypiperidines via epoxidation-ring opening of 4-methylenepiperidines

Article abstract of DOI:10.1055/s-0030-1258778

Reaction of 9-methylene-3-azabicyclo[3.3.1]nonanes with trifluoroperacetic acid results in stereoselective epoxidation to give the syn-epoxide. Intermolecular hydrogen bonding between the protonated tertiary amine and the peracid is responsible for the hi

Full text of DOI:10.1055/s-0030-1258778

LETTER
2631
Stereoselective Synthesis of 4-Substituted 4-Hydroxypiperidines via
Epoxidation–Ring Opening of 4-Methylenepiperidines
Stereoselective
Sy
i
nthesis
cof 4-Subst
t
4
o
-Hydroxypip
r
e
ridinesia A. McKay, Sarah J. Thompson, Phuong Minh Tran, Kirsten J. Goodall, Margaret A. Brimble, David Barker*
Department of Chemistry, The University of Auckland, 23 Symonds St, Auckland, New Zealand
Fax +64(9)3737422; E-mail: d.barker@auckland.ac.nz
Received 2 August 2010
ucts 6 (example given using PhMgBr) with the 4-hydroxy
group syn to the piperidine ring (Scheme 1).7 Conversely
piperidone 4, with a fused seven-membered ring gives
only anti products 7. Piperidone 5, however, with a fused
six-membered ring, gives mixtures of both syn- and anti-
alcohols 8 and 9 with the major isomer alcohol 8 resulting
from attack over the less hindered face. We herein report
a method for the stereoselective synthesis of 4-substituted
4-hydroxypiperidines via a stereoselective epoxidation–
ring-opening protocol.
Abstract: Reaction of 9-methylene-3-azabicyclo[3.3.1]nonanes
with trifluoroperacetic acid results in stereoselective epoxidation to
give the syn-epoxide. Intermolecular hydrogen bonding between
the protonated tertiary amine and the peracid is responsible for the
high levels of stereoselectivity.
Key words: stereoselective epoxidation, homoallylic epoxidation,
bicyclic amines, 4-hydroxypiperidines
4-Hydroxypiperidines are a common structural motif
found in many bioactive drugs, such as the antidiarrhoeal
loperamide (1), the schizophrenia medication haloperidol
and benztropine (2), a drug used in the treatment of
Parkinson’s disease (Figure 1). Compounds with this mo-
tif have also recently been reported to act as histamine1
and chemokine CCR52 receptor antagonists, to inhibit
serine hydrolases3 and to target opioid receptors.4 4-Hydroxy-
piperidines have also been used in the stereospecific syn-
thesis of 4-phenyl- and 4-alkylpiperidines, where the
configuration of the 4-hydroxy group is important in de-
fining the stereochemistry in the desired nonhydroxy
product.5
PhMgBr
NMe
NMe
Ph
O
OH
6
7
3
PhMgBr
NMe
NMe
NMe
NMe
HO
O
O
Ph
4
5
PhMgBr
R1
R2
Cl
8, R1 = OH, R2 = Ph
9, R1 = Ph, R2 = OH
OH
H
Scheme 1 Products from nucleophilic addition to bicyclic 4-
piperidones7
CHPh2
O
MeN
Me2NO2C
N
Ph
Ph
benzatropine (2)
The synthesis began by preparing substituted 4-piperi-
dones via the Lewis acid catalysed double-Mannich reac-
tion of benzyl bisaminol ether 10 with acylic8 11 and
cyclic9 12–14 b-keto esters. Using 1.5 equivalents of both
MeSiCl3 and aminol ether 10 gave monocyclic piperidone
16 in 82% yield, whilst differently ring-sized azabicycles
17, 18, and 19 were generated in 81%, 97% and 99%
yields, respectively (Scheme 2). These piperidones 16–19
then underwent Wittig olefination10 using methyl triphe-
nylphosphonium bromide to give 4-methylene piperidines
loperamide (1)
Figure 1 Drugs containing a 4-hydroxypiperidine motif
In general, 4-substituted 4-hydroxypiperidines are pre-
pared from the nucleophilic addition of an organometallic
reagent (e.g., a Grignard reagent) onto a 4-ketopiperidine
(4-piperidone). Regardless of whether the 4-ketopiperi-
dine is found in a mono- or bicyclic ring system, these ad-
ditions invariably lead to mixtures of diastereomers being
produced.6 Additions to azabicyclic ketones 3–5 are
known to be controlled by steric effects; thus piperidone
3, with a fused five-membered ring, affords addition prod-
1
20–23 in 70–83% yields. It is noteworthy that the H
NMR showed the configuration of monocyclic alkene 20
to have an axial ester, the same as that found in the starting
ketone 16.8
We began our epoxidation study on 3-azabicyc-
lo[3.3.1]nonane 22, as this 6,6-ring system is found in a
number of neurally active natural alkaloids11 and keto de-
rivates such as 18 are known to react nonspecifically with
SYNLETT 2010, No. 17, pp 2631–2635
Advanced online publication: 30.09.2010
DOI: 10.1055/s-0030-1258778; Art ID: D20610ST
x
x
.x
x
.2
0
1
0
© Georg Thieme Verlag Stuttgart · New York

2632
V. A. McKay et al.
LETTER
nucleophiles.6,7 Firstly, the use of meta-chloroperbenzoic
acid (MCPBA) in CH2Cl2 was attempted, and after one
hour of reaction this resulted in exclusive formation of
methylene N-oxide 24 in 95% yield. When N-oxide 24
was further reacted with additional MCPBA no epoxida-
tion of the methylene group was observed, even after ex-
tended reaction times.12
MCPBA
22
22
EtO2C
24
CH2Cl2
95%
N
Bn
O
H
CF3CO3H
LiAlH4
HO
H
NBn
NBn
EtO2C
O
H3C
CH2Cl2
> 99%
THF
92%
OH
25
31
O
O
Scheme 3 Peracid oxidation of alkene 22 and conversion of epoxide
25 to diol 31, with key NOE correlations shown
CO2Et
CO2Et
12, n = 0
13, n = 1
14, n = 2
OR
n
Analysis of the 1H NMR 2D NOESY spectra of epoxides
25–28 showed no interactions between the methylene
group on the epoxide and protons elsewhere in the mole-
cule. To determine the stereochemistry, it was therefore
decided to open the epoxide ring to form a tertiary alco-
hol. In previous work on 9-alkyl-9-hydroxy-3-azabicyc-
lo[3.3.1]nonanes we have observed strong NOE
interactions between the 9-alkyl substituent and the pro-
tons in the bicyclic ring structure.6a The stereochemistry
of the 9-hydroxy group can also be determined by exami-
nation of the 13C NMR data. This is due to the g-gauche
effect the 9-OH has on the chemical shift of the carbons in
the bicyclic ring structure that are syn to the hydroxy
group.17 Ring opening was effected by lithium aluminium
hydride reduction of epoxides 25–28 to give diols 29–32
in 70–93% yield.
11
MeSiCl3
MeCN
N
OEt
Bn
2
10
O
n
CO2Et
17, n = 0, 81%
NBn
EtO2C
O
18, n = 1, 97%
19, n = 2, 99%
or
N
Bn
16, 82%
n-BuLi
THF
MePPh3Br
NBn
n
CO2Et
21, n = 0, 70%
NBn 22, n = 1, 83%
23, n = 2, 76%
EtO2C
20, 75%
Scheme 2 Synthesis of 4-methylenepiperidines
HO
H
2
CO2Et
H
3
CF3CO3H
NBn
NBn
LiAlH4
H3C
H3C
In an attempt to avoid this N-oxidation, the MCPBA reac-
tion was repeated with the addition of trifluoroacetic acid
(TFA), a reagent combination which has been previously
used for alkene epoxidation in alkaloid systems.13 Unfor-
tunately, only a complex mixture of products was ob-
tained. Replacing the TFA with AcOH or by using the
preformed HCl salt of bicycle 22 produced a similar com-
plex mixture. Quick et al.14 reported similar results in their
attempts to use MCPBA to oxidize an alkene within a
quinolizidine, with either the N-oxide or mixtures being
produced. They noted that the use of trifluoroperactic acid
was successful in generating the desired epoxide. When
the published conditions were used upon alkene 22, a sin-
gle epoxide product 25 was obtained in low yield with no
signs of N-oxidation. Optimisation of the conditions using
five equivalents of trifluoroperacetic acid in CH2Cl2 at
0 °C for two hours resulted in quantitative formation of
epoxide 25 (Scheme 3).15
20
23
6
CH2Cl2, 30 h
95%
H
THF
93%
O
OH
H
26
29
H
CF3CO3H
HO
H
LiAlH4
NBn
NBn
NBn
EtO2C
O
H3C
CH2Cl2, 2 h
> 99%
THF
91%
32
OH
28
HO
NBn
EtO2C
O
CF3CO3H
LiAlH4
21
major
OH major
CH2Cl2, 24 h
53%
THF
70%
HO
HO
NBn
NBn
minor
EtO2C
O
minor
30
2:1 inseparable mixture
27
2:1 inseparable mixture
Epoxidation of alkene 23 occurred in a similar time frame
as the reaction of 22, giving a single epoxide product 28
again in quantitative yield (Scheme 4). The epoxidation of
monocyclic alkene 20 gave a single epoxide 26 in 95%
yield; however, the reaction required at least 30 hours to
go to completion. Similarly, epoxidation of alkene 21 un-
der the same conditions took 24 hours before the starting
material was completely consumed but, in this case, gave
an inseparable 2:1 mixture of epoxides 27 in 53% yield.16
Scheme 4 Synthesis of epoxides 26–28 and diols 29, 30, and 32,
showing key NOE correlations used for stereochemical determination
Examination of the NMR spectra of diols 31 and 32
showed NOE interactions between the chiral methyl
group and the spatially adjacent protons on the carbocy-
clic ring of the bicyclic system, confirming the orientation
between the tertiary alcohol and amine to be syn
(Schemes 3 and 4). The diastereomers of diol 30 were not
Synlett 2010, No. 17, 2631–2635 © Thieme Stuttgart · New York

LETTER
Stereoselective Synthesis of 4-Substituted 4-Hydroxypiperidines
2633
separable, however, NMR analysis again showed the ma- was observed experimentally. Protonation of the amine in
jor diastereomer to have the same syn orientation as diols alkene 23 also results in unfavourable steric interactions
31 and 32. The stereochemistry of piperidine diol 29 was between the quaternary amine 23a and the protons on the
determined by a combination of NMR experiments and by carbocyclic ring. A chair-to-boat ring flip of the piperi-
comparison with similar piperidine diols.8 In the 1H NMR dine ring results in the similar conformation 23b where
2D NOESY spectrum, strong NOE cross peaks were ob- the peracid is directed to one face of the alkene. In the case
served between the protons of 3-methylenehydroxy group of alkene 21, the protonated psuedo-chair in amine 21a
and the axial H5 and also between the 3- and 4-methyl has far less steric interactions with the carbocyclic ring
groups, whilst the downfield shift of the axial H2 and H6 and would not be expected to undergo such a rapid ring
protons showed their close spatial arrangement with the 4- flip to form a boat-shaped conformer 21b as alkenes 22
OH group.
and 23. It would appear that ring flip does occur, however,
slowly, as the predominant epoxide is syn to the nitrogen
in the piperidine ring. The slow reaction may, however,
allow epoxidation to occur from the carbocyclic face.
With the stereochemistry of alcohols 29–32 and therefore
epoxides 25–28 determined, we were able to rationalise
the stereoselective nature of the epoxidation. For the reac-
tion of bicyclic alkene 22, in which the epoxidation was In the case of monocyclic piperidine alkene 20 epoxida-
fast and completely selective, we theorised that under the tion could occur by a hydrogen bonded mechanism or
acidic conditions formation of an ammonium salt 22a steric interactions only, with the axial ester group block-
would ensue. Due to steric interaction between the now ing the bottom face of the alkene. Either case results in the
quaternary amine and the axial H7 of the salt 22a, the pre- same product, as a ring flip from chair 20a to boat 20b
ferred structure would change from the normal chair– would also favour the attack from the face opposite the es-
chair17 conformation to a chair–boat 22b (Scheme 5).
ter.
To explore the selectivity of the epoxidation further, we
attempted the reaction on keto alkene 33, where Baeyer–
Villiger oxidation is a competing process, as well as
styrenes18 34 and 35 (Scheme 6). In all cases the reaction
was rapid and, again, completely selective, giving syn-ep-
oxides 36–38 in 87–95% yields.19 In a preliminary explo-
ration of the utility of theses epoxides in the synthesis of
other 4-hydroxy 4-substituted piperidines, epoxide 25 was
reacted specifically at the epoxide with lithium dibutyl-
7
H
H
N
Ph
EtO2C
EtO2C
25
N
Ph
22b
H
O
22a
H
O
O
CF3
H
cyanocuprate to afford
a
tertiary alcohol-ester
H
H
(Scheme 6), which was reduced to give diol 39 in 79%
N
Ph
28
EtO2C
EtO2C
overall yield over the two steps.20
N
Ph
23b
H
O
23a
H
O
O
O
O
NBn
NBn
CF3CO3H
CF3
CH2Cl2
95%
O
36
33
H
H
H
N
27
Ph
EtO2C
EtO2C
N
Ph
EtO2C
H
N
Ph
CF3CO3H
CH2Cl2
EtO2C
N
3
Ph
21b
3
H
H
O
21a
34, R = OMe
35, R = Cl
37, R = OMe, 87%
38, R = Cl, 91%
R
R
CO2Et H
N
CO2Et
Ph
20a
26
HO
i) Bu2CNCuLi, 84%
ii) LiAlH4, 94%
NBn
N
Ph
EtO2C
O
NBn
less
hindered
face
O
H
O
H
Bu
20b
OH
39
25
O
CF3
Scheme 6 Synthesis of epoxides 36–38 and diol 39
Scheme 5 Proposed ring conformations resulting in syn-epoxidation
In summary, the epoxidation of 4-methylenepiperidines in
constrained systems with trifluoroperacetic acid is stereo-
selective, allowing access to 4-substituted 4-hydroxy-
piperidines in a stereodefined manner. In particular, aza-
bicyclic ketones of the types 4 and 5 can be converted into
In this conformation hydrogen bonding between the N–H
and the peracid can occur, placing the reactive oxygen of
the peracid in a favourable position directly above one
face of the alkene. Under these circumstances we would
expect epoxidation to be rapid and selective, exactly what
Synlett 2010, No. 17, 2631–2635 © Thieme Stuttgart · New York

2634
V. A. McKay et al.
LETTER
mixture was allowed to warm to r.t. and stirred for a further
4 h. The reaction was then quenched by careful additon of
sat. aq NaHCO3 and stirred until cessation of bubbles
occurred. The volatiles were then removed in vacuo and the
resultant aqueous solution extracted with EtOAc (2 × 20
mL). The combined organic phase were washed with sat. aq
NaHCO3, H2O and brine, dried (MgSO4), and concentrated
in vacuo to afford the crude product, which was purified by
flash chromatography.
4-hydroxypiperidines with opposite stereochemistry to
that given by nucleophilic addition to the ketone itself.
Acknowledgment
We wish to thank the University of Auckland, in particular Staff
Research Fund (#3607881), for financial assistance with the pro-
ject.
Synthesis of Alcohol 39 from Epoxide 25
n-BuLi (1.6 M in hexanes, 0.6 mL, 0.95mmol) was added
dropwise to a suspension of copper cyanide (43 mg, 0.48
mmol) in THF (0.5 mL) at –78 °C. The suspension was
allowed to warm to 0 °C and stirred for 30 min, cooled to
–78 °C followed by dropwise addition of epoxide 25 in THF
(0.5 mL). The solution was stirred for a further 15 min and
quenched with a 9:1 mixture of sat. aq NH4Cl and aq NH4OH
and concentrated in vacuo. The residue was dissolved in
EtOAc, washed with sat. aq NH4Cl, H2O and brine, then
dried (MgSO4), and concentrated in vacuo. The crude
product was purified by flash chromatography (5:1,
hexanes–EtOAc; Rf = 0.7) to afford an alcohol (0.38 g, 89%)
which was reduced with LiAlH4 (58 mg, 2.2 mmol) in THF
(2 mL) at 0 °C. After stirring for 15 min the reaction, was
quenched with sat. aq Na2SO4 and filtered through Celite
and the solvent removed in vacuo. The residue was dissolved
in EtOAc, washed with H2O and brine, then dried (MgSO4)
and concentrated in vacuo to yield crude product which was
purified by flash chromatography (5:1, hexanes–EtOAc;
Rf = 0.2) to give diol 39 (0.3g, 92%).
References and Notes
(1) Maslowsaka-Lipowicz, I.; Figlus, M.; Zuiderveld, O. P.;
Walkczynski, K. Arch. Pharm. Chem. Life Sci. 2008, 341,
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May, K.; Onuffer, J.; Phillips, G.; Subramanyam, B.; Tseng,
J.-L.; Wei, R. G.; Wei, M.; Ye, B. Bioorg. Med. Chem. Lett.
2007, 1883.
(3) (a) Furegati, S.; Ganci, W.; Gorla, F.; Ringeisen, U.; Rüedi,
P. Helv. Chim. Acta 2004, 87, 2629. (b) Clerc, C.;
Matarazzo, I.; Rüedi, P. Helv. Chim. Acta 2009, 92, 14.
(4) Chen, Z.; Davies, E.; Miller, W. S.; Shan, S.; Valenzano,
K. J.; Kyle, D. J. Bioorg. Med. Chem. Lett. 2004, 5275.
(5) (a) Wenzel, B.; Sorger, D.; Heinitz, K.; Scheunemann, M.;
Schliebs, R.; Steinbach, J.; Sabri, O. Eur. J. Med. Chem.
2005, 1197. (b) Kim, D.-I.; Schweri, M. M.; Deutsch, H. M.
J. Med. Chem. 2003, 46, 1456. (c) Sakhteman, A.;
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Shafiee, A. Bioorg. Med. Chem. 2009, 17, 6908.
(6) (a) Lehmann, A.; Brocke, C.; Barker, D.; Brimble, M. A.
Eur. J. Org. Chem. 2006, 3205. (b) Williams, C. M.; Heim,
R.; Bernhardt, P. V. Tetrahedron 2005, 61, 3771.
(c) Barker, D.; Brimble, M. A.; McLeod, M. D.; Savage, G.
P. Org. Biomol. Chem. 2004, 2, 1659. (d) Kraus, G. A.; Shi,
J. J. Org. Chem. 1991, 56, 4147. (e) Ho, G. D.; Anthes, J.;
Bercovici, A.; Caldwell, J. P.; Cheng, K.-C.; Cui, X.; Fawzi,
A.; Fernandez, X.; Greenlee, W. J.; Hey, J.; Korfmacher, W.;
Lu, S. X.; McLeod, R. L.; Ng, F.; Torhan, A. S.; Tan, Z.;
Tulshian, D.; Varty, G. B.; Xu, X.; Zhang, H. Bioorg. Med.
Chem. Lett. 2009, 19, 2519.
(16) Spectroscopic Data for Selected Products
Ethyl (1R*,2¢S*,5R*)-3-Benzyl-3-azaspiro[bicyclo-
[3.3.1]nonane-9,2¢-oxirane]-1-carboxylate (25)
1H NMR (300 MHz, CDCl3): d = 1.21 (3 H, t, J = 7.2 Hz,
OCH2CH3), 1.26–1.31 (1 H, m, 5-H), 1.56–1.64 (1 H, m,
7A-H), 1.77–2.01 (3 H, m, 8A-H, 6-CH2), 2.24 (1 H, ddt,
J = 13.5, 6.6, 2.1 Hz, 8B-H), 2.51 (1 H, d, J = 3.0 Hz, 4A-H),
2.55 (1 H, d, J = 4.8 Hz, 2¢A-H), 2.87 (3 H, m, 7B-H, 2A-H,
4B-H), 3.05 (1 H, d, J = 11.7 Hz, 2B-H), 3.18 (1 H, d, J = 4.8
Hz, 2¢B-H), 3.43 (1 H, d, J = 13.5 Hz, PhCHA), 3.53 (1 H, d,
J = 13.5 Hz, PhCHB), 4.06 (2 H, dq, J = 7.2, 1.5 Hz,
OCH2CH3), 7.23–7.35 (5 H, m, ArH). 13C NMR (75 MHz,
CDCl3): d = 14.0 (OCH2CH3), 21.0 (C-7), 31.1 (C-6), 34.8
(C-8), 38.5 (C-5), 46.9 (C-1), 52.91 (C-2¢), 56.3 (C-4), 58.5
(C-2), 60.7 (OCH2CH3), 62.2 (C-9), 63.3 (PhCH2), 126.8
(ArCH), 128.2 (ArCH), 128.7 (ArCH), 138.4 (ArC), 172.5
(C=O). ESI-MS: m/z (%) = 316 (100) [M+], 338 (20)
[MNa+]. MS: m/z calcd for C19H26NO3: 316.1907 [M]+;
found: 316.1912.
(7) House, H. O.; Bryant, W. M. III J. Org. Chem. 1965, 30,
3634.
(8) Chan, Y.; Guthmann, H.; Brimble, M. A.; Barker, D. Synlett
2008, 2601.
(9) Brimble, M. A.; Brocke, C. Eur. J. Org. Chem. 2005, 2385.
(10) Barker, D.; Lin, D. H.-S.; Carland, J. E.; Chu, C. P.-Y.;
Chebib, M.; Brimble, M. A.; Savage, G. P.; McLeod, M. D.
Bioorg. Med. Chem. 2005, 13, 4565.
Ethyl (1R*,2¢S*,6R*)-8-Benzyl-8-azaspiro[bicyclo-
[4.3.1]decane-10,2¢-oxirane]-1-carboxylate (28)
(11) Goodall, K. J.; Barker, D.; Brimble, M. A. Synlett 2005,
1809.
1H NMR (300 MHz, CDCl3): d = 1.22 (3 H, t, J = 7.2 Hz,
OCH2CH3), 1.41–1.51 (1 H, m, 6-H, 6-CH2), 1.56–1.77 (5
H, m, 2A-H, 5-H2, 3-CH2), 1.92–2.16 (3 H, m, 4-CH2, 2B-H),
2.47 (2 H, dd, J = 11.1, 4.5 Hz, 7A-H), 2.52 (1 H, d, J = 4.8
Hz, 2¢A-H), 2.64 (1 H, td, J = 12.0, 0.9 Hz, 7B-H), 2.71 (2 H,
m, 9-CH2), 3.31 (1 H, d, J = 4.8 Hz, 2¢B-H), 3.53 (2 H, s,
PhCH2), 4.06 (2 H, q, J = 7.2 Hz, OCH2CH3), 7.25–7.38 (5
H, m, Ar-H). 13C NMR (75 MHz, CDCl3): d = 14.0
(OCH2CH3), 26.4 (C-5), 26.5 (C-4), 33.0 (C-3), 35.8 (C-2),
42.2 (C-6), 50.1 (C-1), 51.6 (C-2¢), 57.8 (C-7), 58.7 (C-10),
60.4 (C-9), 60.6 (OCH2CH3), 63.5 (PhCH2), 127.0 (ArCH),
128.2 (ArCH), 129.1 (ArCH), 138.9 (ArC), 173.6 (C=O).
ESI-MS: m/z (%) = 330 (100) [M+], 352 (22) [MNa+]. MS:
m/z calcd for C20H27NO3: 330.2064 [M+]; found 330.2074.
(12) After a 48 h reaction >80% N-oxide 24 was returned with the
remaining material being unidentified decomposition
products.
(13) (a) Carretero, J. C.; Arrayás, R. G.; de Gracia, I. S.
Tetrahedron Lett. 1997, 38, 8537. (b) Aciro, C.; Claridge,
T. D. W.; Davies, S. G.; Roberts, P. M.; Russell, A. J.;
Thomson, J. E. Org. Biomol. Chem. 2008, 6, 3751.
(14) Quick, J.; Khandelwal, Y.; Meltzer, P. C.; Weinberg, J. S.
J. Org. Chem. 1983, 48, 5199.
(15) General Procedure for the Epoxidation of 4-
Methylenepiperidines
Trifluoroacetic anhydride (6 equiv) was added dropwise to a
stirred solution of 30% w/w H2O2 (5 equiv) in CH2Cl2 (1
mL/mmol alkene) at 0 °C. The solution was stirred for 1 h
prior to the dropwise addition of a solution of 4-methylene-
piperidine (1 equiv) in CH2Cl2 (1 mL/mmol alkene). The
Synlett 2010, No. 17, 2631–2635 © Thieme Stuttgart · New York

LETTER
Stereoselective Synthesis of 4-Substituted 4-Hydroxypiperidines
2635
(1S*,5R*,9S*)-3-Benzyl-1-(hydroxymethyl)-9-methyl-3-
azabicyclo[3.3.1]nonan-9-ol (29)
PhCH2), 7.23–7.34 (5 H, m, ArH). 13C NMR (75 MHz,
CDCl3): d = 21.1 (C-7), 29.5 (O=CCH3), 31.1 (C-6), 33.1
(C-8), 38.6 (C-5), 51.1 (C-1), 52.3 (C-2¢), 56.6 (C-4), 59.2
(C-2), 62.7 (C-9), 63.5 (PhCH2), 127.0 (ArCH), 128.3
(ArCH), 128.6 (ArCH), 138.7 (ArC), 209.9 (C=O). ESI-MS:
m/z (%) = 285 (100) [M+]. MS: m/z calcd for C18H23NO2:
285.1728 [M+]; found: 285.1728.
1H NMR (300 MHz, CDCl3): d = 1.23–1.32 (1 H, m, 7A-H),
1.35 (3 H, s, 9-CH3) 1.42–1.58 (3 H, m, 6-CH2, 8A-H), 1.67–
1.79 (2 H, m, 5-H, 8B-H), 2.30–2.47 (3 H, m, 2A-H, 4 A-H,
7B-H), 2.93 (1 H, dd, J = 10.8, 2.4 Hz, 4B-H), 3.10–3.18 (3
H, m, CHAOH, 2B-H, OH), 3.41 (1 H, d, J = 13.2 Hz, Ph-
CHA), 3.58 (1 H, d, J = 13.2 Hz, PhCHB), 3.80 (1 H, d,
J = 11.1, 2.4 Hz, CHBOH). 13C NMR (75 MHz, CDCl3):
d = 18.2 (C-6), 22.1 (C9-CH3), 28.3 (C-8), 32.0 (C-7), 39.0
(C-1), 41.4 (C-5), 54.2 (C-4), 57.1 (C-2), 62.8 (PhCH2), 70.0
(CH2OH), 74.0 (C-9), 127.0 (ArCH), 128.3 (ArCH), 128.7
(ArCH), 138.7 (ArC). ESI-MS: m/z (%) = 276 (100) [MH+].
MS: m/z calcd for C17H26NO2: 276.1958 [MH+]; found:
276.1941.
(1S*,5R*,9S*)-3-Benzyl-1-(hydroxymethyl)-9-pentyl-3-
azabicyclo[3.3.1]nonan-9-ol (39)
1H NMR (300 MHz, CDCl3): d = 0.86–0.94 [4 H, m,
(CH2)4CH3, CH2CHA(CH2)2CH3), 1.15–1.60 [10 H, m, 6-
CH2, 8A-H, CH2 (CH2)3CH3, CH2CHB(CH2)2CH3,
(CH2)2CH2CH2CH3, (CH2)3CH2CH3], 1.81–1.90 (2 H, m, 5-
H, 8B-H), 2.34 (1 H, d, J = 10.8 Hz, CHAOH), 2.36–2.52 (3
H, m, 4A-H, 7A-H, OH), 2.50 (1 H, dd, J = 11.0 Hz, 2A-H),
2.85 (1 H, dd, J = 11.4, 2.1 Hz, 4B-H), 3.04 (1 H, d, J = 10.8
Hz, CHBOH), 3.12 (1 H, dd, J = 11.4, 2.1 Hz 2B-H), 3.38 (1
H, d, J = 13.2, PhCHA), 3.54 (1 H, d, J = 13.2 Hz, PhCHB),
7.19–7.28 (5 H, m, ArH). 13C NMR (75 MHz, CDCl3):
d = 14.1 [(CH2)4CH3], 18.7 (C-7), 21.5 [CH2 (CH2)3CH3],
22.7 [CH2CH2 (CH2)2CH3], 27.8 (C-6), 31.7
(1S*,6R*,10S*)-8-Benzyl-1-(hydroxymethyl)-10-methyl-
8-azabicyclo[4.3.1]decan-10-ol (32)
1H NMR (300 MHz, CDCl3): d = 1.23–1.60 (7 H, m, 6-H, 5-
CH2, 4-CH2, 3-CH2), 1.42 (3 H, s, 10-CH3) 2.08–2.15 (2 H,
m, 2-CH2), 2.24 (1 H, dd, J = 11.1, 1.0 Hz, 9A-H), 2.42 (1 H,
dd, J = 11.4, 1.0 Hz, 7A-H), 2.78 (1 H, dd, J = 11.4, 6.3 Hz,
7B-H), 3.16–3.24 (3 H, m, CHAOH, 9B-H, OH), 3.39 (1 H, d,
J = 13.2 Hz, PhCHA), 3.56 (1 H, d, J = 13.2 Hz, PhCHB),
3.89 (1 H, d, J = 11.1, 2.4 Hz, CHBOH). 13C NMR (75 MHz,
CDCl3): d = 23.16 (C10-CH3), 25.2, 25.3, 29.6, and 35.5 (C-
2, C-3, C-4, C-5), 44.1 (C-1), 46.3 (C-6), 56.5 (C-7), 59.0
(C-9) 63.3 (PhCH2), 70.3 (CH2OH), 77.9 (C-10), 127.0
(ArCH), 128.2 (ArCH), 128.9 (ArCH), 138.7 (ArC). ESI-
MS: m/z (%) = 290 (100) [MH+], 272 (5) [M – OH]. MS:
m/z calcd for C18H28NO2: 290.2115 [MH+]; found:
290.2105.
[(CH2)2CH2CH2CH3], 32.5 [(CH2)3CH2CH3], 32.5 (C-8),
35.9 (C-5), 40.9 (C-1), 54.3 (C-4), 57.3 (C-2), 62.9 (PhCH2),
69.4 (CH2OH), 76.0 (C-9), 126.8 (ArCH), 128.2 (ArCH),
128.7 (ArCH), 139.0 (ArC). ESI-MS: m/z (%) = 332 (100)
[MH+]. MS: m/z calcd for C21H34NO2: 332.2584 [MH+];
found: 332.2590.
(17) (a) Arias-Pérez, M. S.; Alejo, A.; Maroto, A. Tetrahedron
1997, 53, 13099. (b) Jeyaraman, R.; Jawaharsingh, C. B.;
Avila, S.; Eliel, E. L.; Manoharan, M.; Morris-Natschke, S.
J. Heterocycl. Chem. 1982, 19, 449. (c) Goodall, K. J.;
Brimble, M. A.; Barker, D. Magn. Reson. Chem. 2008, 46,
75.
(18) Guthmann, H.; Conole, D.; Wright, E.; Körber, K.; Barker,
D.; Brimble, M. A. Eur. J. Org. Chem. 2009, 1944.
(19) The stereochemistry was again determined by analysis of the
ring-opened tertiary alcohols.
1-{(1R*,2'S*,5R*)-3-Benzyl-3-azaspiro[bicyclo-
[3.3.1]nonane-9,2'-oxirane]-1-yl}ethanone (36)
1H NMR (400 MHz, CDCl3): d = 1.27–1.29 (1 H, m, 5-H),
1.62 (1 H, m, 7A-H), 1.74–1.83 (2 H, m, 8A-H, 6A-H), 1.92 (1
H, m, 6B-H), 2.09 (3 H, s, O=CCH3), 2.18 (1 H, m, 8B-H),
2.54 (1 H, d, J = 4.2 Hz, 2¢A-H), 2.63 (1 H, m, 4B-H), 2.69 (1
H, d, J = 4.2 Hz, 2¢B-H), 2.83 (1 H, m 7B-H), 2.90 (1 H, d,
J = 11.4 Hz, 4B-H), 2.94–3.00 (2 H, m, 2-CH2), 3.50 (2 H, s,
(20) Diols such as 29, 32, and 39 can be esterified selectively in
high yields at the primary alcohol.
Synlett 2010, No. 17, 2631–2635 © Thieme Stuttgart · New York

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