Enantioselective total synthesis of the tricyclic 9-oxabispidine (1R,2S,9S)-11-methyl-13-oxa-7,11-diazatricyclo[7.3.1.02,7]tridecane

Article abstract of DOI:10.1016/j.tetasy.2008.08.002

The enantiomerically pure tricyclic 9-oxabispidine (1R,2S,9S)-11-methyl-13-oxa-7,11-diazatricyclo[7.3.1.0^2,7]tridecane, a potential substitute for (+)-sparteine in asymmetric synthesis, was prepared in 7 steps and in 11% overall yield from a chiral epoxy alcohol and (S)-epichlorohydrin. The key intermediate was a bicyclic 9-oxabispidine with an appropriately functionalized, endo-oriented side chain.

Full text of DOI:10.1016/j.tetasy.2008.08.002

Tetrahedron: Asymmetry 19 (2008) 1978–1983
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective total synthesis of the tricyclic 9-oxabispidine
(1R,2S,9S)-11-methyl-13-oxa-7,11-diazatricyclo[7.3.1.02,7]tridecane
*
Matthias Breuning , Melanie Steiner
Institute of Organic Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantiomerically pure tricyclic 9-oxabispidine (1R,2S,9S)-11-methyl-13-oxa-7,11-diazatricy-
clo[7.3.1.02,7]tridecane, a potential substitute for (+)-sparteine in asymmetric synthesis, was prepared
in 7 steps and in 11% overall yield from a chiral epoxy alcohol and (S)-epichlorohydrin. The key interme-
diate was a bicyclic 9-oxabispidine with an appropriately functionalized, endo-oriented side chain.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 11 July 2008
Accepted 5 August 2008
Available online 29 August 2008
Dedicated to Professor E. J. Corey on the
occasion of his 80th birthday
1. Introduction
of secondary alcohols,7 and dynamic thermodynamic resolutions
of 1,10-biaryl-2,20-diols.8
In 1990, Hoppe et al. discovered the first highly enantioselective
deprotonation/electrophilic trapping reactions of prochiral O-alkyl
carbamates with s-BuLi in the presence of a stoichiometric amount
of the chiral lupine alkaloid,1 (ꢀ)-sparteine (ꢀ)-1 (Fig. 1).2 This pio-
neering work opened up a new era in the asymmetric organolith-
ium chemistry, leading to hundreds of successful applications,
which are documented in a number of reviews.3 In tandem with
other metals such as Mg, Zn, Cu, and Pd, highly enantioselective
transformations have also been realized using (ꢀ)-1 as the chiral
ligand; for example, desymmetrizations of meso-anhydrides,4
Reformatsky5 and Henry6 reactions, oxidative kinetic resolutions
Characteristic of the structure of (ꢀ)-sparteine (ꢀ)-1 is the cen-
tral bispidine (3,7-diazabicyclo[3.3.1]nonane) core. Of the two
fused rings, the endo-positioned one plays the decisive role in chi-
rality transfer,9,10 as obvious from the tricyclic bispidine 2, which
was introduced by O’Brien et al. as an equally effective substitute
for the less readily available enantiomer of (ꢀ)-1, (+)-sparteine11
(+)-1.12 Diamine 2 can be obtained in three steps by partial synthe-
sis from the natural source (ꢀ)-cytisine;10,12,13 its enantioselective
total synthesis, however, is still a challenging and time-consuming
task. Three approaches have been reported, two of which were
developed by Lesma et al. Starting from a piperidine-3,5-dimetha-
nol precursor, 2 was prepared in P9 steps and in 67% overall
yield.14 O’Brien et al. used a different strategy via a chiral homo-
pipecolic ester, accessing 2 in 8 steps and in 15% overall yield.15
Despite all these efforts, a generally applicable route that allows
a flexible approach to a broad variety of tri- and tetracyclic bispi-
dines in enantiomerically pure form is still missing.16
As yet, almost no attention has been paid to the closely related
9-oxabispidines of type 4,17 which, similar to the well-investigated
bispidines, might possess a high potential as chiral ligands in
asymmetric synthesis.18 Replacement of the remote methylene
bridge by an oxygen atom should not change the architecture,
but the additional functionality offers new synthetic options, thus
allowing a more convenient access. This advantage was previously
demonstrated in the preparation of the bicyclic 2-endo-phenyl-
substituted 9-oxabispidines 5, which are available from (R,R)-3-
phenylglycidol in just 3–5 steps and in 35–40% yield.19 Herein,
we report on an important extension of this method: the tricyclic
9-oxabispidine 6,17 the oxa analogue of the successful (+)-sparteine
surrogate 2, was synthesized in enantiomerically pure form from a
known epoxy alcohol precursor and (S)-epichlorohydrin in 7 steps
and in 11% overall yield.
N
N
NMe
N
NH
N
N
N
O
(–)-sparteine
(+)-sparteine
2
(–)-cytisine
3
–
( )-1
(+) -1
NR''
NR'
NMe
N
O
O
O
NR'
R
NR
Ph
4
5
6
R, R' = H, Me, Bn
Figure 1.
* Corresponding author. Tel.: +49 931 888 4761; fax: +49 931 888 4755.
E-mail address: breuning@chemie.uni-wuerzburg.de (M. Breuning).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.08.002

M. Breuning, M. Steiner / Tetrahedron: Asymmetry 19 (2008) 1978–1983
1979
2. Results and discussion
2.1. Retrosynthetic analysis
TBSO
TBSO
H
BnN
OH
OH
O
a
Cl
OH
b
O
11
9a
10
Cl
The retrosynthetic analysis of the targeted tricyclic 9-oxabispi-
dine 6 is depicted in Scheme 1. Disconnection of the methylamino
function allows a first simplification of the molecule leading to the
cis-configured morpholine-2,6-dimethanol 8 as the key intermedi-
ate. This compound should be accessible from the amino diol 9 by
cyclization with a chiral 1,2,3-trifunctionalized three-carbon build-
ing block possessing two neighboring electrophilic positions. Previ-
ous investigations on the enantioselective synthesis of 5 (see
Fig. 1)19 and of morpholine-2-methanols from b-amino alcohols20
revealed (S)-epichlorohydrin 10 to be well suited for this purpose.
The endo-fused piperidine ring in 6 can be implemented either
after or before the construction of the bispidine core. In the first
case, a bicyclic bispidine intermediate such as 7 with an appropri-
ately functionalized side chain is required, which should be avail-
able via the morpholine 8a from an acyclic amino diol such as 9a.
The tricyclic bispidine 6 might also be prepared via the morpholine
8b from the piperidine-derived amino diol 9b, in which the anellat-
ed ring is already incorporated. This route would allow a direct
conversion of 8b into the targeted bispidine 6.
TBSO
O
OH
TBSO
OH
OH
BnN
BnN
OH
OH
13
12
OH
OMs
TBSO
TBSO
c
BnN
O
BnN
O
d
OH
OMs
8a
14
NMe
NBn
NMe
NBn
g
O
O
OH
OTBS
OTBS
16
17
7
e
h
OH
Cl
NMe
NH
NMe
N
NMe
NH
i
f
NMe
O
10
O
O
O
O
R'N
R
O
OH
R'NH OH
NR'
R
6
15
OH
R
OH
6, 7
8a,b
9a,b
Scheme 2. Reagents and conditions: (a) BnNH2, LiClO4, MeCN, 65 °C, 16 h; (b) 10,
LiClO4, toluene, 70 °C, 22 h, then KOtBu, tBuOH, rt, 24 h; (c) MsCl, NEt3, CH2Cl2,
0 °C?rt, 4 h, 25% from 11; (d) MeNH2, EtOH, 50 °C, 36 h, 75%; (e) H2 (1 bar),
Pd(OH)2/C, EtOAc, rt, 5 h, 99%; (f) TBAF, THF, rt, 36 h, 84%; (g) TBAF, THF, rt, 48 h,
85%; (h) H2 (1 bar), Pd(OH)2/C, EtOAc, rt, 14 h, 90%; (i) PPh3, DIAD, toluene, rt, 24 h,
80%.
7 8a 9a
,
,
: R = (CH2)4OTBS, R' = Bn
: R
6 8b 9b
,
,
R' = (CH2)4
Scheme 1.
3 steps and in 61% yield from 7. The enantiomeric purity of 6 is
P98%, as deduced from the 19F NMR spectra of the (S)- and (R)-
Mosher amides of the precursor 15.
2.2. Enantioselective total synthesis of 6 via the bicyclic
bispidine 7
The synthesis of 6 via the bicyclic bispidine intermediate 7 com-
menced with the known enantiomerically pure epoxy alcohol 11
(Scheme 2).21 Ring opening of 11 with benzylamine in the presence
of the Lewis acid LiClO4 furnished an inseparable 85:15-mixture of
the desired amino alcohol 9a and a by-product, presumably the
regioisomer of 9a, resulting from the less favorable ring opening
of 11 at C-2. This mixture was subjected to a one-pot multi-stage
cyclization with (S)-epichlorohydrin 10 to give the all-cis-config-
ured morpholine-2,6-dimethanol 8a. In agreement with the mech-
anistic studies on related reactions,20 heating of the two reactants
with LiClO4 in toluene induced a regioselective nucleophilic attack
of the nitrogen atom at C-3 of the epoxide to give the chlorohydrin
12. Upon addition of tBuOH and KOtBu, this intermediate under-
went a base-mediated domino reaction delivering 8a via the epox-
ide 13. After purification by fast column chromatography through
deactivated silica gel, crude 8a was bis-mesylated to set the stage
for the ring closure to the bicyclic bispidine 7, which occurred
smoothly by heating 14 in ethanolic methylamine. The overall
yield for this sequence was 19%.
The transformation of 7 into the N,O-unprotected derivative 17
was achieved either via 15 by using a debenzylation/desilylation
procedure or in reverse order via the intermediate 16. Even though
the latter route delivered 17 in slightly lower yield (77% vs 83%),
this sequence is advantageous since the latter dehydrogenation
step gave the polar product 17 in >90% purity without the necessity
of further purification. The final ring closure was realized under
Mitsunobu conditions to afford the tricyclic target bispidine 6 in
2.3. Attempted synthesis of 6 from the homopipecolic ester 18
For an alternative approach, in which the endo-fused ring
of 6 is already incorporated in the amino diol precursor, the
Me
NR* OH
a
Me
NR*
CO2Me
CO2Me
e
N
19
18
S
20
b
O
O2
NR OH
NH OH
OH
CO2Me
d
d
22
21: R = R*
9b: R = H
c
OH
N
O
6
Ph
Me
R
R* =
8b
23
: R = CH2OH
: R = CO2Me
Scheme 3. Reagents and conditions: (a) LiHMDS, THF, 0 °C, 30 min, then 20,
ꢀ78 °C?rt, 16 h, 80%; (b) LiAlH4, THF, ꢀ20 °C?rt, 4 h, 80%; (c) H2 (3 bar), Pd/C,
MeOH, 40 °C, 3 h, 76%; (d) 10, LiClO4, toluene, 70 °C, 16 h, then KOtBu, tBuOH, rt,
23 h; (e) H2 (3 bar), Pd/C, MeOH, 40 °C, 7 h, 98%.

1980
M. Breuning, M. Steiner / Tetrahedron: Asymmetry 19 (2008) 1978–1983
N-(R)-phenylethyl-protected homopipecolic ester 18, readily avail-
able in large quantities,22 was chosen as the starting material
(Scheme 3). Introduction of the required alcohol function next to
5-H, 6-H), 2.60 (br s, 3H, OH, OH, NH), 2.85 (m, 1H, 3-H), 3.60 (t,
J = 6.2 Hz, 2H, 7-H), 3.67 (m, 2H, 1-H, 2-H), 3.77 (m, 1H, 1-H),
3.82 (d, J = 12.8 Hz, 1H, NCHHPh), 3.90 (d, J = 12.8 Hz, 1H,
NCHHPh), 7.31 (m, 5H, Ph-H). 13C NMR (100 MHz, CDCl3): d ꢀ5.3
(SiMe2), 18.3 (CMe3), 22.4 (C-5), 26.0 (CMe3), 30.3 (C-4), 32.7 (C-
6), 52.7 (NCH2Ph), 60.9 (C-3), 62.7 (C-7), 64.1 (C-1), 71.3 (C-2),
the ester group was accomplished in 80% yield by
of the lithium enolate of 18 with (1R)-(ꢀ)-(camphorylsulfon-
yl)oxaziridine 20. In accordance with the related -functionaliza-
a-hydroxylation
a
tions of homopipecolic esters,15,23 this reaction occurred highly
diastereoselectively giving 19 as the sole product. The cyclization
precursor 9b24 was prepared from 19 in two steps, by reduction
and hydrogenolytic N-deprotection. In contrast to the successful
morpholine syntheses from (S)-epichlorohydrin 10 and many other
b-amino alcohols,19,20 the cyclization of 9b with 10 failed. The
desired product 8b (or any precursors to it, cf. Scheme 2) was
not detected under a variety of reaction conditions. Apparently,
the piperidine ring in 9b impedes the attack of the nitrogen atom
at the epoxide function of 10 for steric or electronic reasons. In
addition, there was also no morpholine of type 23 formed in the
127.5, 128.3, 128.6, 139.2 (C-Ph). IR (ATR): m 3343, 2927, 2856,
1461, 1253, 1094, 1006, 833, 773, 698 cmꢀ1. HRMS (ESI, +) calcd
for [C20H37NO3Si+H]+: 368.2616, found: 368.2618. Anal. Calcd for
C20H37NO3Si (367.60): C, 65.35; H, 10.15; N, 3.81. Found: C,
65.27; H, 10.22; N, 4.07.
4.2. (2S,3S,6R)-4-Benzyl-3-(4-tert-butyldimethylsiloxybutyl)-
2,6-di(methanesulfonyloxymethyl)morpholine 14
The crude mixture of 9a (1.57 g) from the preceding experiment
was dissolved in anhydrous toluene (45 mL) and treated at rt with
analogous reaction of the
a-hydroxy homopipecolic ester 22,
(S)-epichlorohydrin (10, 412 lL, 474 mg, 5.12 mmol) and LiClO4
which was prepared from 19 by N-deprotection.
(545 mg, 5.13 mmol). The reaction was stirred for 22 h at 70 °C.
tBuOH (45 mL) and KOtBu (2.16 g, 19.2 mmol) were introduced
at rt, and stirring was continued for 24 h. After the addition of
water (150 mL), the reaction mixture was extracted with CH2Cl2
(3 ꢁ 150 mL). The combined organic layers were dried over Na2SO4
and evaporated. The resulting morpholine 8a was purified by fast
column chromatography (silica gel, CH2Cl2/MeOH 100:0?95:5),
and dissolved in CH2Cl2 (40 mL). NEt3 (2.05 mL, 1.49 g, 14.7 mmol)
3. Conclusions
The tricyclic 9-oxabispidine 6, which might possess a compara-
bly high potential in asymmetric transformations as the well-
known bispidines (ꢀ)-sparteine (ꢀ)-1 and 2, was prepared in 7
steps and in 11% overall yield starting from the enantiomerically
pure epoxy alcohol 11. The key step was a one-pot multi-stage
cyclization of the amino diol 9a with (S)-epichlorohydrin 10 deliv-
ering an all-cis-configured morpholine-2,6-dimethanol derivative.
The related ring closure reaction of the piperidine-derived b-amino
alcohols 9b and 22 failed. Applications of 6 in enantioselective
transformations are currently under investigation.
and MsCl (759 lL, 1.12 g, 9.80 mmol) were slowly added at 0 °C.
After 4 h at rt, the reaction mixture was diluted with water
(200 mL) and extracted with Et2O (3 ꢁ 200 mL). The organic layers
were combined, washed with brine (200 mL), dried over Na2SO4,
and evaporated. Column chromatography (1. silica gel, Et2O/MeOH
100:0?10:1; 2. silica gel, CH2Cl2/MeOH 100:0?10:1) gave 14
(754 mg, 1.30 mmol, 30%) as a yellowish foam. ½a D22
¼ ꢀ8:0 (c
ꢂ
0.30, MeOH). 1H NMR (400 MHz, CDCl3): d 0.06 (s, 6H, SiMe2),
0.90 (s, 9H, CMe3), 1.21–1.46 (m, 2H, 20-H), 1.47–1.54 (m, 2H, 30-
H), 1.65–1.72 (m, 2H, 10-H), 2.44 (m, 1H, 5-H), 2.54 (m, 1H, 5-H),
2.95 (m, 1H, 3-H), 3.04 (s, 3H, SO2Me), 3.05 (s, 3H, SO2Me), 3.61
(m, 2H, 40-H), 3.70 (d, J = 13.5 Hz, 1H, NCHHPh), 3.82 (d,
J = 13.5 Hz, 1H, NCHHPh), 3.98 (m, 1H, 6-H), 4.08–4.24 (m, 5H, 2-
H, 2-CH2, 6-CH2), 7.24–7.35 (m, 5H, Ph-H). 13C NMR (100 MHz,
CDCl3): d ꢀ5.3 (SiMe2), 18.3 (CMe3), 22.2 (C-20), 24.4 (C-10), 26.0
(CMe3), 33.0 (C-30), 37.0 (SO2Me), 37.8 (SO2Me), 45.7 (C-5), 57.4
(C-3), 58.4 (4-CH2), 62.8 (C-40), 69.8 (2-CH2 or 6-CH2), 70.1 (2-
CH2 or 6-CH2), 72.1 (C-6), 75.9 (C-2), 127.4, 128.4, 128.7, 138.1
4. Experimental
Optical rotations (10 cm cell) were measured on a Jasco P-1020
polarimeter. All NMR spectra were acquired at 20 °C on a Bruker
AV 400 instrument using CDCl3 as the internal reference. IR spectra
were recorded on a Jasco FT-IR-410 spectrometer. High resolution
mass spectra were measured on a Bruker Daltonics micrOTOF
focus. Column chromatography was done on silica gel (63–200
mesh). Microanalyses were performed at the Institute of Inorganic
Chemistry, University of Würzburg. Anhydrous solvents were pre-
pared using the standard procedures. The epoxy alcohol 11 (>95%
ee) was synthesized according to Ref. 21, and the homopipecolic
ester derivative 18 (>96% ee) was synthesized according to Ref.
22. All reactions with anhydrous solvents were performed under
an argon atmosphere.
(C-Ph). IR (KBr):
m 3029, 2934, 2857, 1463, 1357, 1255, 1176,
1098, 968, 836, 777, 738, 702, 661 cmꢀ1. HRMS (ESI, +) calcd for
[C25H45NO8S2Si+H]+: 580.2429, found: 580.2428.
4.3. (1R,2S,5S)-3-Benzyl-2-(4-tert-butyldimethylsiloxybutyl)-7-
methyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane 7
4.1. (2S,3S)-3-Benzylamino-7-tert-butyldimethylsiloxyheptane-
1,2-diol 9a
A solution of ethanolic MeNH2 (33 w/w %, 50 mL) and 14
(649 mg, 1.12 mmol) in EtOH (100 mL) was stirred for 36 h at
50 °C. The reaction mixture was concentrated in vacuo and water
(100 mL) was added. After extraction with Et2O (4 ꢁ 100 mL), the
combined organic layers were dried over MgSO4 and the solvent
was removed in vacuo. Column chromatography [silica gel, deacti-
vated with conc. NH3 (7.5 w/w %), Et2O/MeOH 100:0?99:1] deliv-
LiClO4 (7.18 g, 67.5 mmol) was added to a solution of 11 (2.24 g,
9.64 mmol) and BnNH2 (7.37 mL, 7.23 g, 67.5 mmol) in MeCN
(90 mL). After 16 h at 65 °C, water (100 mL) was added and the
reaction mixture was extracted with Et2O (2 ꢁ 100 mL). The com-
bined organic layers were dried over Na2SO4, and the solvent and
excess BnNH2 were removed under reduced pressure. Column
chromatography [silica gel, deactivated with concd NH3 (7.5
w/w %), CH2Cl2/MeOH 10:1] delivered a colorless foam (2.91 g)
consisting of an inseparable 85:15-mixture of the desired amino
diol 9a and a by-product, presumably a regioisomer of 9a. Com-
pound 9a was characterized in this mixture, and used in the next
step without further purification. 1H NMR (400 MHz, CDCl3): d
0.05 (s, 6H, SiMe2), 0.89 (s, 9H, CMe3), 1.31–1.63 (m, 6H, 4-H,
ered 7 (350 mg, 836
l
mol, 75%) as a colorless oil. ½a D22
¼ þ66:9 (c
ꢂ
0.31, MeOH). 1H NMR (400 MHz, CDCl3): d 0.04 (s, 6H, SiMe2),
0.89 (s, 9H, CMe3), 1.29–1.61 (m, 5H, 10-H, 20-H, 30-H), 1.94 (m,
1H, 10-H), 2.22 (s, 3H, NMe), 2.30 (dd, J = 11.6, 4.4 Hz, 1H, 8-Hexo),
2.41 (ddd, J = 11.3, 4.5, 1.1 Hz, 1H, 6-Hexo), 2.58 (dd, J = 11.5,
4.2 Hz, 1H, 4-Hexo), 2.70 (m, 3H, 2-H, 4-Hendo, 6-Hendo), 2.96 (d,
J = 11.6 Hz, 1H, 8-Hendo), 3.33 (d, J = 14.1 Hz, 1H, NCHHPh), 3.62
(t, J = 6.3 Hz, 2H, 40-H), 3.74 (br t, J = 3.4 Hz, 1H, 1-H), 3.78 (br t,

M. Breuning, M. Steiner / Tetrahedron: Asymmetry 19 (2008) 1978–1983
1981
J = 4.3 Hz, 1H, 5-H), 4.05 (d, J = 14.1 Hz, 1H, NCHHPh), 7.25 (m, 1H,
Ph-H), 7.28–7.35 (m, 4H, Ph-H). 13C NMR (100 MHz, CDCl3): d ꢀ5.3
(SiMe2), 18.3 (CMe3), 22.1 (C-20), 25.9 (CMe3), 29.4 (C-10), 33.2 (C-
30), 47.1 (NMe), 53.9 (C-8), 55.4 (C-4), 58.2 (C-6), 58.3 (NCH2Ph),
61.6 (C-2), 62.7 (C-40), 68.5 (C-5), 70.4 (C-1), 126.7, 128.1, 129.2,
J = 11.3, 3.6 Hz, 1H, 6-Hexo), 2.59 (ddd, J = 11.6, 4.2, 1.5 Hz, 1H, 4-
exo), 2.70–2.81 (m, 3H, 2-H, 4-Hendo, 6-Hendo), 3.04 (d, J = 11.8 Hz,
H
1H, 8-Hendo), 3.33 (d, J = 14.0 Hz, 1H, NCHHPh), 3.67 (t, J = 6.4 Hz,
2H, 40-H), 3.76 (t, J = 3.4 Hz, 1H, 1-H), 3.80 (t, J = 4.2 Hz, 5-H),
4.12 (d, J = 14.0 Hz, 1H, NCHHPh), 7.24 (m, 1H, Ph-H), 7.29–
13
138.0 (C-Ph). IR (film):
m
3061, 3026, 2931, 2785, 1494, 1461,
7.36 (m, 4H, Ph-H). C NMR (100 MHz, CDCl3): d 22.1 (C-20),
1360, 1254, 1094, 835, 775, 729, 698, 661 cmꢀ1. HRMS (ESI, +)
calcd for [C24H42N2O2Si+H]+: 419.3088, found: 419.3088.
29.4 (C-10), 33.0 (C-30), 47.1 (NMe), 53.8 (C-8), 55.3 (C-4),
58.1 (C-6), 58.2 (NCH2), 61.8 (C-2), 62.4 (C-40), 68.3 (C-5), 70.2
(C-1), 126.9, 128.2, 129.3, 137.6 (C-Ph). IR (film):
m 3387, 2985,
4.4. (1R,2S,5R)-2-(4-tert-Butyldimethylsiloxybutyl)-7-methyl-
9-oxa-3,7-diazabicyclo[3.3.1]nonane 15
2793, 1495, 1453, 1377, 1278, 1093, 975, 911, 841, 730,
700 cmꢀ1. HRMS (ESI, +) calcd for [C17H28N2O2+H]+: 305.2224,
found: 305.2221.
The 9-oxabispidine 7 (100 mg, 239 lmol) was dissolved in
EtOAc (6 mL) and hydrogenated over Pd(OH)2/C (20 w/w %,
28.0 mg) under 1 bar H2 pressure for 5 h at rt. The mixture was fil-
tered through a pad of Celite and washed with MeOH (100 mL).
Evaporation of the solvent delivered 15 (77.9 mg, 237 mmol,
4.7. (1R,2S,5R)-2-(4-Hydroxybutyl)-7-methyl-9-oxa-3,7-
diazabicyclo[3.3.1]nonane 17
4.7.1. Desilylation of 15
99%) as a yellowish oil. ½a D22
ꢂ
¼ þ4:0 (c 0.56, MeOH). 1H NMR
At first, TBAFꢃH2O (75.0 mg, 287
l
mol) was added at rt to a
(400 MHz, CDCl3): d 0.03 (s, 6H, SiMe2), 0.88 (s, 9H, CMe3), 1.25–
1.56 (m, 6H, 10-H, 20-H, 30-H), 2.11 (s, 3H, NMe), 2.38 (ddd,
J = 11.7, 3.5, 1.0 Hz, 1H, 8-Hexo), 2.49 (dt, J = 11.3, 3.0 Hz, 1H, 6-
solution of the bispidine 15 (45.0 mg, 137
lmol) in anhydrous
THF (5 mL). The reaction mixture was stirred for 36 h at rt, diluted
with water (100 mL), and extracted with Et2O (3 ꢁ 100 mL). The
organic layers were discarded; the aqueous one was concentrated
under reduced pressure to one-third of its volume and extracted
with CHCl3 (3 ꢁ 100 mL). The organic layers were combined and
evaporated to give a 65:35-mixture of a tetrabutylammonium salt
Hexo), 2.70–3.00 (br s, 1H, NH), 2.81 (d, J = 11.2 Hz, 1H, 6-Hendo),
2.83 (br s, 1H, NH), 2.90 (d, J = 11.7 Hz, 1H, 8-Hendo), 2.98 (d,
J = 13.7 Hz, 1H, 4-Hendo), 3.10 (m, 1H, 2-H), 3.27 (m, 1H, 4-Hexo),
3.47 (t, J = 3.0 Hz, 1-H), 3.60 (m, 3H, 5-H, 40-H). 13C NMR
(100 MHz, CDCl3): d ꢀ5.3 (SiMe2), 18.3 (CMe3), 22.3 (CH2), 25.9
(CMe3), 32.9 (CH2), 33.2 (CH2), 47.0 (NMe), 50.4 (C-4), 55.2 (C-8),
57.9 (C-2), 59.6 (C-6), 62.9 (C-40), 67.3 (C-5), 70.6 (C-1). IR (film):
and 17 [75.0 mg, containing ca. 25 mg (115 lmol, 84%) of 17]. Fur-
ther attempts to purify 17 have not been undertaken.
m
3413, 2925, 2854, 2790, 1713, 1668, 1462, 1254, 1099, 837,
4.7.2. Hydrogenolytic deprotection of 16
775 cmꢀ1. HRMS (ESI, +) calcd for [C17H36N2O2Si+H]+: 329.2619,
found: 329.2619.
A solution of 16 (80.0 mg, 263 lmol) in EtOAc (4 mL) was
hydrogenated over Pd(OH)2/C (20 w/w %, 44.0 mg) under 1 bar
H2 pressure for 14 h at rt. The mixture was filtered through a pad
of Celite and washed with MeOH (100 mL). Evaporation of the sol-
vent delivered 17 (50.7 mg, 237 mmol, 90%) as a colorless oil.
4.5. (R)- and (S)-Mosher amides of 15
(S)-3,3,3-Trifluoro-2-methoxy-2-phenylpropionyl chloride [(S)-
½
a 2D2
ꢂ
¼ þ3:7 (c 0.15, MeOH). 1H NMR (400 MHz, CDCl3): d 1.30–
Mosher chloride, 99% ee, 12.5
(9.5 L, 6.9 mg, 68 mol) and a catalytic amount of DMAP were
added at rt to a solution of 15 (11.0 mg, 33.5 mol) in CH2Cl2
(1 mL). After 5 h, the reaction mixture was diluted with water
(10 mL) and extracted with Et2O (3 ꢁ 10 mL). The organic layers
were combined, washed with brine (25 mL), dried over Na2SO4,
and evaporated to give, after chromatographic purification (silica
gel, n-pentane/Et2O 5:1?0:1), the (R)-Mosher amide of 15
lL, 16.9 mg, 67.0
lmol], NEt3
1.72 (m, 6H, 10-H, 20-H, 30-H), 1.85–2.40 (br s, 2H, NH, OH), 2.19
(s, 3H, NMe), 2.48 (ddd, J = 12.0, 3.5, 1.2 Hz, 1H, 8-Hexo), 2.57 (dt,
J = 11.7, 3.0 Hz, 1H, 6-Hexo), 2.90 (d, J = 11.4 Hz, 1H, 6-Hendo), 2.97
(d, J = 12.1 Hz, 1H, 8-Hendo), 3.24 (d, J = 13.6 Hz, 1H, 4-Hendo), 3.35
(m, 1H, 2-H), 3.38 (dm, J = 13.7 Hz, 1H, 4-Hexo), 3.69 (m, 1H, 1-H),
3.67 (t, J = 5.6 Hz, 2H, 40-H), 3.83 (br t, J = 3.1 Hz, 1H, 5-H). 13C
NMR (100 MHz, CDCl3): d = 21.9 (CH2), 31.4 (CH2), 32.0 (CH2),
46.5 (NMe), 49.3 (C-4), 55.0 (C-8), 58.1 (C-2), 59.2 (C-6), 61.9 (C-
l
l
l
(12.0 mg, 22.0
CDCl3): d ꢀ71.08 (s, CF3).
l
mol, 73%) as a yellowish oil. 19F NMR (376 MHz,
40), 66.3 (C-5), 69.7 (C-1). IR (ATR):
m 3346, 2925, 2854, 1652,
1456, 1273, 1159, 1073, 1042, 862 cmꢀ1. HRMS (ESI, +) calcd for
[C11H22N2O2+H]+: 215.1754, found: 215.1754.
The (S)-Mosher amide of 15 (6.0 mg, 11.0
l
mol, 37%) was anal-
mol) and (R)-3,3,3-tri-
fluoro-2-methoxy-2-phenylpropionyl chloride [(R)-Mosher chlo-
ride, 99% ee, 12.5 L, 16.9 mg, 67.0
mol]. 19F NMR (376 MHz,
ogously prepared from 15 (11.0 mg, 33.5
l
4.8. (1R,2S,9S)-11-Methyl-13-oxa-7,11-diazatricyclo-
l
l
[7.3.1.02,7]tridecane 6
CDCl3): d ꢀ70.30 (s, CF3).
According to 19F NMR, the diastereomeric purities of both
At first, PPh3 (91.7 mg, 350
l
mol) and DIAD (68.8 mL, 70.7 mg,
mol)
Mosher amides of 15 were >98%.
350 mol) were added at rt to a solution of 17 (40.0 mg, 187 l
l
in anhydrous toluene (1 mL). After 24 h of stirring, the solvent was
removed under reduced pressure and the residue was chromato-
graphed (basic Al2O3, activity V, n-pentane/EtOAc 1:0?2:1) deliv-
4.6. (1R,2S,5S)-3-Benzyl-2-(4-hydroxybutyl)-7-methyl-9-oxa-
3,7-diazabicyclo[3.3.1]nonane 16
ering 6 (29.4 mg, 150 lmol, 80%) as a colorless solid, mp 36–38 °C.
A solution of 7 (168 mg, 401
l
mol) in anhydrous THF (16 mL)
½
a 2D2
ꢂ
¼ þ19:0 (c 1.2, MeOH). 1H NMR (400 MHz, CDCl3): 1.36 (m,
was treated at rt with TBAFꢃH2O (220 mg, 841
lmol) and stirred
3H, 3-H, 4-H), 1.56 (m, 1H, 5-H), 1.69–1.85 (m, 3H, 4-H, 5-H, 6-
H), 2.19 (s, 3H, NMe), 2.25 (dd, J = 11.7, 4.3 Hz, 1H, 12-Hexo), 2.27
(m, 1H, 2-H), 2.40 (ddd, J = 11.5, 4.2, 1.7 Hz, 1H, 10-Hexo), 2.56
(ddd, J = 11.6, 4.4, 1.7 Hz, 1H, 8-Hexo), 2.82 (d, J = 11.7 Hz, 1H, 8-
for 2 d. After dilution with water (40 mL) and extraction with
EtOAc (4 ꢁ 40 mL), the combined organic layers were dried over
Na2SO4. Removal of the solvent under reduced pressure and col-
umn chromatography (silica gel, CH2Cl2/MeOH 10:1?0:1) afforded
H
endo), 2.89 (m, 1H, 6-H), 2.92 (d, J = 12.0 Hz, 2H, 10-Hendo, 12-Hendo),
16 (104 mg, 342
l
mol, 85%) as a yellowish oil. ½a D22
ꢂ
¼ þ62:2 (c
3.47 (t, J = 3.7 Hz, 1H, 1-H), 3.85 (t, J = 4.2 Hz, 1H, 9-H). 13C NMR
(100 MHz, CDCl3): d 24.8 (C-4), 25.3 (C-5), 28.4 (C-3), 47.6 (NMe),
54.6 (C-12), 57.3 (C-6), 58.0 (C-8), 58.5 (C-10), 65.0 (C-2), 68.9
(C-9), 72.1 (C-1). IR (ATR): 2929, 2780, 2754, 1459, 1438, 1361,
1
0.20, MeOH). H NMR (400 MHz, CDCl3): d 1.30–1.70 (m, 5H, 10-
H, 20-H, 30-H), 1.99 (m, 1H, 10-H), 2.05–2.40 (br s, 1H, OH), 2.29
(s, 3H, NMe), 2.37 (dd, 1H, J = 11.6, 4.3 Hz, 8-Hexo), 2.46 (dd,

1982
M. Breuning, M. Steiner / Tetrahedron: Asymmetry 19 (2008) 1978–1983
1282, 1144, 1123, 1092, 1043, 979, 879, 816, 742, 721 cmꢀ1. HRMS
(ESI, +) calcd for [C11H20N2O+H]+: 197.1648, found: 197.1650.
(100 MHz, MeOD): d 25.0 (C-4), 26.6 (C-5), 27.3 (C-3), 47.4 (C-6),
60.2 (C-2), 64.6 (C- ), 74.8 (C-b). IR (ATR): 3302, 2928, 1440,
a
m
1307, 1139, 1109, 1089, 1072, 1042, 1011, 958, 930, 874,
809 cmꢀ1. HRMS (ESI, +) calcd for [C7H15NO2+H]+: 146.1176,
found: 146.1178.
4.9. Methyl (
2-acetate 19
aS,2S)-a-hydroxy-1-[(R)-1-phenylethyl]piperidine-
A solution of the b-amino ester 18 (2.28 g, 8.72 mmol) in anhy-
drous THF (50 mL) was deprotonated at 0 °C for 30 min with
LiHMDS (1.0 M in hexanes, 13.1 mL, 13.1 mmol). (1R)-(ꢀ)-(Camp-
horylsulfonyl)oxaziridine 20 (3.00 g, 13.1 mmol) was added at
ꢀ78 °C. The mixture was warmed to rt overnight, quenched with
satd aq NH4Cl (200 mL), and extracted with EtOAc (2 ꢁ 200 mL).
The combined organic layers were washed with brine (100 mL),
dried over MgSO4, and evaporated. Column chromatography (silica
gel, n-pentane/Et2O 2:1?1:1) gave 19 (1.94 g, 6.98 mmol, 80%) as a
4.12. Methyl (aS,2S)-a-hydroxypiperidine-2-acetate 22
The diol 19 (374 mg, 1.35 mmol) was dissolved in MeOH
(10 mL) and hydrogenated over Pd/C (10 w/w %, 27.0 mg) under
3 bar H2 pressure at 40 °C for 7 h. Removal of the catalyst by filtra-
tion through a pad of Celite, washing with MeOH (150 mL), and
evaporation of the solvent afforded 22 (228 mg, 1.32 mmol, 98%)
as a colorless solid, mp. 235–238 °C (dec). ½a D22
¼ ꢀ21:2 (c 0.40,
ꢂ
MeOH). 1H NMR (400 MHz, CDCl3): d 1.29–1.47 (m, 4H, CH), 1.57
yellowish oil. ½a D20
ꢂ
¼ ꢀ2:0 (c 0.20, CHCl3). 1H NMR (400 MHz,
(m, 1H, CH), 1.85 (m, 1H, CH), 2.64 (m, 1H, 6-H), 2.89 (m, 1H, 2-
CDCl3): d 1.27 (m, 2H, 4-H, 5-H), 1.38 (d, J = 6.8 Hz, 3H, CHMe),
1.45 (m, 2H, 3-H, 4-H), 1.65 (m, 1H, 3-H), 1.76 (m, 1H, 5-H), 2.31
(td, J = 11.1, 2.8 Hz, 1H, 6-H), 2.58 (m, 1H, 6-H), 3.00 (dt, J = 9.7,
3.7 Hz, 1H, 2-H), 3.25 (br s, 1H, OH), 3.81 (s, 3H, OMe), 4.33 (q,
H), 3.12 (m, 1H, 6-H), 3.81 (s, 1H, OMe), 4.17 (d, J = 4.4 Hz, 1H,
H). 13C NMR (100 MHz, CDCl3): d 24.3 (CH2), 26.38 (CH2), 26.44
(CH2), 46.8 (C-6), 52.4 (OMe), 59.0 (C-2), 73.7 (C- ), 173.7 (CO2).
a-
a
IR (Film):
m 3352, 2935, 2857, 1739, 1640, 1451, 1322, 1136, 809,
J = 6.8 Hz, 1H, CHMe), 4.67 (d, J = 3.8 Hz, 1H,
a
-H), 7.23 (m, 1H,
734 cmꢀ1. HRMS (ESI, +) calcd for [C8H15NO3+H]+: 174.1125,
found: 174.1128.
Ph-H), 7.32 (m, 2H, Ph-H), 7.39 (m, 2H, Ph-H). 13C NMR
(100 MHz, CDCl3): d 10.7 (CHMe), 23.5 (C-5), 24.9 (C-3 or C-4),
25.0 (C-3 or C-4), 44.2 (C-6), 52.2 (OMe), 55.0 (CHMe), 59.1 (C-2),
4.13. Attempted cyclizations of 9b and 22 with 10
70.0 (C-a), 126.7, 127.7, 128.1, 143.5 (C-Ph), 173.7 (CO2). IR (Film):
m
3400, 3059, 2936, 2857, 1739, 1625, 1494, 1449, 1267, 1224,
A suspension of 9b (50.0 mg, 344
413 mol) in anhydrous toluene (3.5 mL) was treated at rt with
(S)-epichlorohydrin (10, 32.4 L, 38.2 mg, 413 mol) and stirred
for 16 h at 70 °C. tBuOH (3.5 mL) and KOtBu (97.0 mg, 864 mol)
lmol) and LiClO4 (44.0 g,
1136, 1086, 1034, 736, 701 cmꢀ1
.
HRMS (ESI, +) calcd for
l
[C16H23NO3+H]+: 278.1751, found: 278.1747.
l
l
l
4.10. (bS,2S)-b-Hydroxy-1-[(R)-1-phenylethyl]piperidine-2-
ethanol 21
were introduced at rt and stirring was continued for 23 h. The reac-
tion mixture was diluted with water (100 mL) and extracted with
CH2Cl2 (3 ꢁ 50 mL). The organic layers were combined, washed
with satd aq NaHCO3 (100 mL) and brine (100 mL), dried over
MgSO4, and concentrated in vacuo to give an inseparable mixture
of compounds, in which neither the morpholine 8b nor any
other addition product of 9b to 10 was detected by 1H NMR
spectroscopy.
At first, LiAlH4 (384 mg, 10.1 mmol) was added at ꢀ20 °C to a
solution of 19 (1.40 g, 5.05 mmol) in anhydrous THF (25 mL). The
reaction mixture was warmed to rt within 4 h, quenched with sat-
urated aq NH4Cl (200 mL) and extracted with EtOAc (4 ꢁ 200 mL).
The combined organic layers were washed with brine (100 mL) and
dried over MgSO4. Evaporation of the solvent, purification of the
residue by column chromatography (silica gel, n-pentane/EtOAc/
NEt3 33:65:2), and crystallization (CH2Cl2/n-pentane, ꢀ20 °C)
afforded 21 (1.00 g, 4.04 mmol, 80%) as colorless crystals, mp
The analogous cyclization of 22 (50.0 mg, 290
lmol) with 10
(27.3 L, 32.2 mg, 348 mol) also failed to produce the morpholine
l
l
23 or other addition products of 22 to 10.
112–116 °C. ½a 2D0
ꢂ
¼ þ21:2 (c 0.37, CHCl3). 1H NMR (400 MHz,
References
CDCl3): d 1.33 (m, 1H, 3-H or 4-H or 5-H), 1.38 (d, J = 6.7 Hz, 3H,
CHMe), 1.49–1.79 (m, 5H, 3-H, 4-H, 5-H), 2.60 (m, 1H, 2-H),
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2.80–2.90 (m, 2H, 6-H), 3.45 (dd, J = 10.8, 6.3 Hz, 1H,
a-H), 3.70
(dd, J = 10.8, 5.5 Hz, 1H,
a-H), 4.16 (m, 1H, b-H), 4.30 (q,
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a), 67.7
(C-b), 127.2, 127.4, 128.6, 144.2 (C-Ph). IR (KBr): 3057, 2949,
m
2861, 1493, 1450, 1373, 1331, 1269, 1183, 1073, 1031, 937, 895,
833, 788, 757, 703 cmꢀ1. HRMS (ESI, +) calcd for [C15H23NO2+H]+:
250.1802, found: 250.1796.
4.11. (bS,2S)-b-Hydroxypiperidine-2-ethanol 9b
At first, Pd/C (10 w/w %, 90.0 mg) was added to a solution of 21
(400 mg, 1.60 mmol) in MeOH (50 mL). The reaction mixture was
hydrogenated under 3 bar H2 pressure for 3 h at 40 °C, filtered
through a pad of Celite, and washed with MeOH (150 mL). After
evaporation of the solvent, the residue was crystallized three times
from warm Et2O to give 9b24 (177 mg, 1.22 mmol, 76%) as a color-
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less solid, mp 82–84 °C. ½a D22
ꢂ
¼ ꢀ17:7 (c 0.15, MeOH). 1H NMR
(400 MHz, MeOD): d 1.29–1.52 (m, 3H, 3-H, 4-H, 5-H), 1.65 (m,
1H, 5-H), 1.77 (m, 1H, 3-H), 1.86 (m, 1H, 4-H), 2.62–2.78 (m, 2H,
2-H, 6-H), 3.10 (m, 1H, 6-H), 3.54 (m, 3H,
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