Enantioselective synthesis of 2-phenyl-9-oxabispidines

Article abstract of DOI:10.1055/s-2007-966040

A small selection of enantiomerically pure 2-phenyl-9-oxabispidines was synthesized in a three to five step procedure from commercially available starting materials. Ring opening of (R,R)-3-phenylglycidol with benzylamine, condensation with (S)-epichloroh

Full text of DOI:10.1055/s-2007-966040

1702
PAPER
Enantioselective Synthesis of 2-Phenyl-9-oxabispidines
E
nantioselective Synth
a
e
sis of 2-Ph
t
enyl-9
t
-
oxabi
h
Institute of Organic Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany
Fax +49(931)8884755; E-mail: breuning@chemie.uni-wuerzburg.de
Received 9 January 2007; revised 26 March 2007
Abstract: A small selection of enantiomerically pure 2-phenyl-9-
oxabispidines was synthesized in a three to five step procedure from
commercially available starting materials. Ring opening of (R,R)-3-
phenylglycidol with benzylamine, condensation with (S)-epichloro-
Me
N
N
N
N
N
N
hydrin to the corresponding cis-2,6-bis(hydroxymethyl)-substituted
morpholine intermediate, and final cyclization with a primary
amine delivered the desired 2-phenyl-9-oxabispidines in good
yields. The substituents at the nitrogen atoms were varied by de-
benzylation and subsequent alkylation.
(–)-sparteine [(–)-1]
(+)-sparteine [(+)-1]
2
R''
R'
R''
R'
N
N
N
N
Key words: 9-oxabispidines, stereoselective synthesis, bicyclic
compounds, heterocycles, sparteine
O
R
R
A
B
The lupine alkaloid (–)-sparteine [(–)-1]1 (Figure 1) is the
ligand of choice for many asymmetric transformations.2
In combination with organolithium reagents, highly enan-
tioselective deprotonation–electrophilic trapping reac-
tions,2,3 additions to C=C bonds,4 and desymmetrizations
of meso-epoxides5 and anhydrides6 have been achieved.
The diamine (–)-1 was also successfully used in Cu-medi-
ated dynamic thermodynamic resolutions of racemic biar-
yl-2,2¢-diols7 and in Pd-catalyzed kinetic resolutions of
secondary alcohols.8 The breadth of its applicability, how-
ever, suffers from the non-availability of its enantiomer
(+)-1.9,10 The two known stereoselective syntheses of (–)-
111 and (+)-112 are multi-step and, thus, not economical.
The intensive search for simplified surrogates of (+)-1 fi-
nally led to the diamine 2, which is devoid of the axially
annulated ring of 1. It can be synthesized in three steps
from the natural product (–)-cytisine and offers a compa-
rably high potential in asymmetric transformations as (–)-
1 does.13,14 The compounds 1 and 2 share the same three-
dimensional architecture created by the chirally modified
bispidine (3,7-diazabicyclo[3.3.1]nonane) skeleton A,
which might be one of the privileged backbone structures
for chiral ligands. Despite all synthetic efforts, efficient
stereoselective routes to compounds of type A that are not
based on a natural product precursor are still missing.15
Figure 1 Chiral bispidines of the general formula A and the targeted
9-oxa analogues B
report on the first enantioselective preparation of a small
collection of C1-symmetric 2-phenyl-9-oxabispidines B
(R = Ph) in just three to five steps from commercially
available starting materials.
Recently, we developed a one-pot procedure to chiral 2-
hydroxymethyl-substituted morpholines by nucleophilic
ring opening of enantiomerically pure epichlorohydrin
with 1,2-amino alcohols.16 It seemed feasible to extend
this method to the synthesis of 2-substituted 9-oxa-
bispidines B as depicted in the retrosynthetic analysis in
Scheme 1. The bicyclic framework of B should be con-
structible from the heterocycle C by ring closure with a
primary amine. This reduces the synthetic problem to the
stereoselective preparation of a cis-2,6-bis(hydroxymeth-
yl)-substituted morpholine C, which should be accessible
according to our method16 by condensation of (S)-epichlo-
rohydrin [(S)-3] with an appropriately substituted 3-ami-
no-1,2-diol D. The latter compound can be synthesized in
enantiomerically pure form by ring opening of a chiral ep-
oxy alcohol with a primary amine.
The commercially available epoxy alcohol (R,R)-3-phe-
nylglycidol [(R,R)-4] was chosen as the starting material
for validating our synthetic concept (Scheme 2). Treat-
ment of (R,R)-4 with benzylamine in MeOH at 70 °C af-
On the contrary, no attention has yet been paid to chiral 9-
oxabispidines of type B, in which the methylene bridge is
replaced by an oxygen atom. These compounds should
create a similar asymmetric environment and, thus, might
provide versatile surrogates for the bispidines A. The ad-
ditional heteroatom in the bridge, thereby, offers new op-
tions for a more convenient synthetic access. Herein we
Cl
OH
OH
OH
R''
R'
N
N
HO
O
O
O
+
R'N
H
R
R
N
R
R'
SYNTHESIS 2007, No. 11, pp 1702–1706
x
x.
x
x
.
2
0
0
7
B
C
(S)-3
D
Advanced online publication: 02.05.2007
DOI: 10.1055/s-2007-966040; Art ID: T00407SS
Scheme 1 Retrosynthetic analysis of B
© Georg Thieme Verlag Stuttgart · New York

PAPER
Enantioselective Synthesis of 2-Phenyl-9-oxabispidines
1703
HO
OH
Ph
Cl
OH
Ph
H H
O O
Cl
(S)-3
HO
BnNH2, MeOH
O
KOt-Bu, t-BuOH
r.t., 24 h
O
∆, 16 h
LiClO4, toluene
70 °C, 16 h
BnN
H
N
Ph
98%
Bn
OH
Ph
5
6
(R,R)-4
H
O
O
(S)-3, LiClO4, toluene, 70 °C, 16 h
then KOt-Bu, t-BuOH, r.t., 24 h
then MsCl, Et3N, r.t., 1 h
N
Bn
46%
7
OH
OH
Ph
OMs
BnNH2, toluene, ∆, 36 h
or
OMs
Ph
R
N
O
O
MsCl, Et3N
r.t., 1 h
O
aq MeNH2, 50 °C, 36 h
N
Bn
Ph
N
N
Bn
Bn
10a: R = Bn (87%)
10b: R = Me (90%)
9
8
Scheme 2 Enantioselective synthesis of the 2-phenyl-9-oxabispidines 10a and 10b from (R,R)-3-phenylglycidol [(R,R)-4] and (S)-epichloro-
hydrin [(S)-3]
forded the 3-amino-1,2-diol 5 as a single regioisomer in possessing two N-methyl functionalities (87% overall
excellent 98% yield.17 The transformation of 5 into the yield from 10b).
morpholine 8 and its activation as the dimesylate 9 was
In conclusion, a small collection of enantiomerically pure
accomplished in a three-step one-pot reaction sequence:
2-phenyl-9-oxabispidines with different substituents at
LiClO4-mediated addition of 5 to (S)-epichlorohydrin
the nitrogen atoms were conveniently synthesized in three
to five steps (35–41% yield) from commercially available
[(S)-3] in toluene at 70 °C delivered the chloroalcohol 6,
which, upon treatment with KOt-Bu/t-BuOH, cyclized to
(R,R)-3-phenylglycidol [(R,R)-4] and (S)-epichlorohydrin
give the epoxide 7 and, subsequently, the morpholine 8.
[(S)-3]. A variation of the substituent in position 2 should
Mesylation of the two alcohol functions with MsCl/Et3N
be possible by starting from the respective chiral epoxy al-
delivered 9 in 46% overall yield. An isolation of the inter-
cohols easily available by Sharpless asymmetric epoxida-
mediates 6–8 is possible, but time-consuming and results
in a significantly reduced yield. The final ring closure of
9 to 10a and 10b was achieved with benzylamine in re-
fluxing toluene (87% yield) and aqueous methylamine at
50 °C (90% yield), respectively. Thus, starting from com-
mercially available (R,R)-4 and (S)-3, an efficient three-
step route to the enantiomerically pure 2-phenyl-9-oxa-
bispidines 10a and 10b in 39 and 41% overall yield was
established.
tion of allylic alcohols.18 Investigations on the preparation
of the latter compounds and on the application of the 2-
phenyl-9-oxabispidines as chiral auxiliaries and ligands in
asymmetric synthesis are in progress.
Optical rotations (10 cm cell) were measured on a Jasco P-1020 po-
larimeter. 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 fo-
cus. Rf values refer to TLC on aluminum foil-backed silica gel
plates. Column chromatography was performed on silica gel (63–
200 mesh). Microanalyses were performed at the Institute of Inor-
ganic Chemistry, University of Würzburg. All reactions were per-
formed under argon in anhyd solvents. (S)-Epichlorohydrin [(S)-3,
97% ee] and (R,R)-3-phenylglycidol [(R,R)-4, >96% ee] are com-
mercially available and were used as received.
The N-benzyl groups in 10a and 10b allow further modi-
fications of the substituents at the nitrogen atoms
(Scheme 3). Hydrogenolytic debenzylation of 10a with
Pearlman’s catalyst liberated the free diamine 10c in 90%
yield, while deprotection of 10b led to the monoamine
10d, which was methylated to give the 9-oxabispidine 10e
H2 (3 bar)
Pd(OH)2/C
Bn
(+)-(2S,3S)-3-(Benzylamino)-3-phenylpropane-1,2-diol (5)
A solution of (R,R)-3-phenylglycidol [(R,R)-4, 10.0 g, 66.6 mmol]
and benzylamine (8.00 mL, 7.85 g, 73.3 mmol) in MeOH (100 mL)
was refluxed for 24 h. The solvent was removed in vacuo and the
resulting oil was crystallized from Et2O–n-pentane to give 5 (16.8
NH
N
N
O
O
MeOH
45 °C, 20 h
90%
NH
Ph
Bn
Ph
10a
10c
20
g, 98%) as a white solid; mp 87–89 °C (Lit.17 mp 89–90 °C); [a]D
20
+61.6 (c = 0.89, EtOH) {Lit.17 [a]D +68.0 (c = 1.00, EtOH)};
MeI
K2CO3
H2 (3 bar)
Pd(OH)2/C
Me
Bn
Me
Me
Me
N
N
N
N
Rf = 0.24 (CH2Cl2–MeOH, 95:5).
IR (KBr): 3269, 3065, 2849, 2421, 1453, 1047 cm–1.
O
O
O
N
MeOH
45 °C, 20 h
98%
NH
CH2Cl2
r.t., 3 h
90%
1H NMR (400 MHz, CDCl3): d = 2.23–3.18 (br s, 3 H, NH,
2 × OH), 3.55 (d, 1 H, J = 12.8 Hz, NCHHPh), 3.23 (dd, 1 H,
J = 11.4, 4.8 Hz, CHHOH), 3.56 (dd, 1 H, J = 11.5, 4.9 Hz,
CHHOH), 3.75 (d, 1 H, J = 13.0 Hz, NCHHPh), 3.82 (m, 1 H,
Ph
Ph
Ph
10d
10e
10b
Scheme 3 Derivatization of 10a and 10b
Synthesis 2007, No. 11, 1702–1706 © Thieme Stuttgart · New York

1704
M. Breuning, M. Steiner
PAPER
CHOH), 3.88 (d, 1 H, J = 5.9 Hz, NCHPh), 7.25 (m, 3 H, ArH), 7.32
J = 13.6 Hz, NCHHPh), 7.16–7.41 (m, 10 H, ArH), 7.45 (m, 2 H,
(m, 5 H, ArH), 7.40 (m, 2 H, ArH).
ArH), 7.52 (m, 2 H, ArH), 7.95 (br s, 1 H, ArH).
13C NMR (100 MHz, CDCl3): d = 51.40, 64.59, 65.91, 73.47, 127.2,
13C NMR (100 MHz, CDCl3): d = 52.68, 55.70, 56.35, 61.03, 63.90,
69.90, 69.52, 70.10, 73.83, 126.8, 127.1, 127.5, 128.31, 128.33,
128.7, 129.4, 138.8, 139.5, 140.9.
MS (ESI, +): m/z (%) = 385.2264 ([M + H]+, 100).
HRMS (ESI, +): m/z [M + H]+ calcd for C26H29N2O: 385.2280;
127.6, 127.9, 128.2, 128.5, 128.8, 139.3, 139.5.
MS (ESI, +): m/z (%) = 258.1488 ([M + H]+, 100).
HRMS (ESI, +): m/z [M + H]+ calcd for C16H20NO2: 258.1494;
found: 258.1488.
found: 385.2264.
(–)-(2S,3S,6R)-4-Benzyl-2,6-bis(methanesulfonyloxymethyl)-3-
phenylmorpholine (9)
Anal. Calcd for C26H28N2O: C, 81.21; H, 7.34; N, 7.29. Found: C,
81.37; H, 7.28; N, 7.02.
LiClO4 (4.96 g, 46.6 mmol) was added to a solution of 5 (10.0 g,
38.9 mmol) in toluene (700 mL). (S)-Epichlorohydrin [(S)-3; 3.66
mL, 4.31 g, 46.6 mmol] was introduced and the mixture was heated
at 70 °C for 16 h. t-BuOH (700 mL) and KOt-Bu (10.9 g, 97.2
mmol) were added at r.t. and stirring was continued for 24 h. Et3N
(32.5 mL, 23.6 g, 233 mmol) and MsCl (12.0 mL, 17.8 g, 155
mmol) were added slowly. After 1 h at r.t., the mixture was diluted
with H2O (1 L) and extracted with CH2Cl2 (3 × 500 mL). The com-
bined organic layers were washed with sat. aq NaHCO3 (1 L) and
brine (1 L), dried (MgSO4), and concentrated in vacuo. Purification
by flash chromatography [1. silica gel, CH2Cl2–MeOH (100:0 →
10:1); 2. silica gel, n-pentane–Et2O (1:2 → 0:100)] afforded 9 (8.38
(+)-(1R,2S,5S)-3-Benzyl-7-methyl-2-phenyl-9-oxa-3,7-diazabi-
cyclo[3.3.1]nonane (10b)
A solution of aqueous methylamine (40%, 48 mL, 556 mmol) and
9 (3.44 g, 7.34 mmol) was stirred for 36 h at 50 °C. The mixture was
diluted with H2O (150 mL) and extracted with Et2O (3 × 300 mL).
The combined organic layers were washed with brine (200 mL),
dried (Na2SO4), and concentrated in vacuo. Purification by column
chromatography [silica gel, deactivated with concd NH3 (7.5 wt%),
n-pentane–Et2O (3:1 → 1:3)] afforded 10b (2.05 g, 90%) as a slight-
ly yellow oil; [a]D22 +26.8 (c = 0.16, CHCl3); Rf = 0.90 (Et2O, deac-
tivated with NH3).
20
g, 46%) as a white foamy solid; mp 53–58 °C; [a]D –10.7 (c =
IR (film): 3038, 2791, 1496, 1453, 996 cm–1.
0.11, CHCl3); Rf = 0.53 (n-pentane–Et2O, 1:3).
1H NMR (400 MHz, CDCl3): d = 2.02 (dd, 1 H, J = 11.8, 3.7 Hz,
NCHH), 2.19 (s, 3 H, NCH3), 2.43 (ddd, 1 H, J = 11.2, 4.0, 1.7 Hz,
NCHH), 2.65 (m, 2 H, NCH2), 2.84 (d, 1 H, J = 11.2 Hz, NCHH),
2.95 (dd, 1 H, J = 11.5, 0.8 Hz, NCHH), 2.97 (d, 1 H, J = 14.1 Hz,
NCHHPh), 3.71 (m, 1 H, OCH), 3.87 (m, 3 H, NCHHPh, NCHPh,
OCH), 7.15–7.40 (m, 9 H, ArH), 7.80–8.20 (br s, 1 H, ArH).
13C NMR (100 MHz, CDCl3): d = 46.86, 54.17, 55.30, 58.30, 58.56,
60.28, 69.08, 69.29, 73.59, 126.8, 127.5, 128.3, 128.7, 128.9, 138.7,
140.9.
IR (KBr): 3025, 1363, 1181, 999, 969 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.49 (dd, 1 H, J = 12.0, 3.2 Hz,
NCHH), 2.70 (pseudo-t, 1 H, J = 11.6 Hz, NCHH), 2.89 (s, 3 H,
CH3SO2), 3.09 (s, 3 H, CH3SO2), 3.13 (d, 1 H, J = 13.6 Hz, CHH-
Ph), 3.54 (d, 1 H, J = 13.6 Hz, CHHPh), 3.72 (d, 1 H, J = 3.2 Hz,
NCH), 3.88 (dd, 1 H, J = 11.2, 3.7 Hz, CHHOMs), 4.02 (dd, 1 H,
J = 11.2, 8.0 Hz, CHHOMs), 4.13 (m, 1 H, OCH), 4.33 (dd, 1 H,
J = 11.2, 3.5 Hz, CHHOMs), 4.33 (dd, 1 H, J = 11.2, 5.4 Hz,
CHHOMs), 4.42 (m, 1 H, OCH), 7.25–7.40 (m, 10 H, ArH).
MS (ESI, +): m/z (%) = 309.1956 ([M + H]+, 100), 217.1323 ([M –
13C NMR (100 MHz, CDCl3): d = 37.50, 37.94, 46.20, 58.68, 61.19,
70.00, 70.39, 74.63, 77.65, 127.5, 128.5, 128.56, 128.64, 128.9,
137.9.
CH2Ph]+, 2).
HRMS (ESI, +): m/z [M + H]+ calcd for C20H25N2O: 309.1967;
found: 309.1956.
MS (ESI, +): m/z (%) = 492.1133 ([M + Na]+, 100), 374.1414 ([M
– OMs – H]+, 40).
Anal. Calcd for C20H24N2O: C, 77.89; H, 7.84; N, 9.08. Found: C,
77.88; H, 7.62; N, 8.91.
HRMS (ESI, +): m/z [M + Na]+ calcd for C21H27NO7S2 + Na:
492.1127; found: 492.1133.
(+)-(1R,2S,5S)-2-Phenyl-9-oxa-3,7-diazabicyclo[3.3.1]nonane
(10c)
Anal. Calcd for C21H27NO7S: C, 53.71; H, 5.80; N, 2.98; S, 13.66.
Found: C, 53.94; H, 5.81; N, 2.96; S, 13.35.
A solution of 10a (103 mg, 226 mmol) in MeOH (5 mL) was hydro-
genated over Pd(OH)2/C (20%, 50 mg) under 3.5 bar H2 pressure for
20 h at 45 °C. The mixture was filtered through a pad of Celite and
washed with MeOH (3 × 10 mL). Removal of the solvent under re-
duced pressure delivered 10c (48.9 mg, 90%) as a white solid; mp
(+)-(1R,2S,5S)-3,7-Dibenzyl-2-phenyl-9-oxa-3,7-diazabicy-
clo[3.3.1]nonane (10a)
A solution of 9 (4.62 g, 9.85 mmol) and benzylamine (16.6 mL, 16.3
g, 152 mmol) in toluene (100 mL) was refluxed for 24 h. The mix-
ture was diluted with H2O (100 mL) and extracted with Et2O (3 ×
100 mL). The combined organic layers were washed with brine
(100 mL), dried (Na2SO4), and concentrated in vacuo. Purification
by column chromatography [silica gel, deactivated with concd NH3
(7.5 wt%), n-pentane–Et2O (10:1 → 1:1)] afforded 10a (3.33 g,
87%) as a yellowish solid, which can be crystallized from i-PrOH
to give colorless needles; mp 92–94 °C; [a]D +34.6 (c = 0.10,
CHCl3); Rf = 0.74 [n-pentane–Et2O (3:1), deactivated with NH3].
IR (KBr): 3025, 2926, 1463, 1099, 1091, 700 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.25 (dd, 1 H, J = 11.6, 3.5 Hz,
NCHH), 2.44 (ddd, 1 H, J = 11.2, 3.9, 1.5 Hz, NCHH), 2.55 (ddd, 1
H, J = 11.6, 4.2, 1.6 Hz, NCHH), 2.75 (d, 1 H, J = 13.6 Hz, NCH-
HPh), 2.77 (d, 1 H, J = 11.6 Hz, NCHH), 2.82 (d, 1 H, J = 11.2 Hz,
NCHH), 2.91 (d, 1 H, J = 11.6 Hz, NCHH), 3.28 (d, 1 H, J = 12.9
Hz, NCHHPh), 3.50 (d, 1 H, J = 12.9 Hz, NCHHPh), 3.76 (m, 1 H,
OCH), 3.86 (d, 1 H, NCHPh), 3.88 (m, 1 H, OCH), 3.97 (d, 1 H,
20
85 °C; [a]D +27.4 (c = 0.18, MeOH); Rf = 0.50 [CH2Cl2–MeOH
(9:1), deactivated with NH3].
IR (KBr): 3419, 2955, 2827, 1452, 1070, 859 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.59 (br s, 1 H, 2 × NH), 2.82 (d,
1 H, J = 13.7 Hz, NCHH), 3.02 (ddd, 1 H, J = 13.7, 3.7, 1.3 Hz,
NCHH), 3.14 (d, 1 H, J = 13.3 Hz, NCHH), 3.34 (d, 1 H, J = 11.6
Hz, NCHH), 3.39 (dt, 1 H, J = 13.3, 2.9 Hz, NCHH), 3.59 (m, 1 H,
OCH), 3.64 (dt, 1 H, J = 11.7, 2.9 Hz, NCHH), 3.67 (m, 1 H, OCH),
4.58 (d, 1 H, J = 2.3 Hz, NCHPh), 7.26–7.29 (m, 1 H, ArH), 7.34–
7.41 (m, 4 H, ArH).
13C NMR (100 MHz, CDCl3): d = 45.23, 50.44, 51.16, 63.92, 66.92,
72.23, 126.5, 127.4, 128.7, 140.9.
MS (ESI, +): m/z (%) = 205.1336 ([M + H]+, 100).
HRMS (ESI, +): m/z [M + H]+ calcd for C12H17N2O: 205.1341;
20
found: 205.1336.
Synthesis 2007, No. 11, 1702–1706 © Thieme Stuttgart · New York

PAPER
Enantioselective Synthesis of 2-Phenyl-9-oxabispidines
1705
(+)-(1R,2S,5S)-7-Methyl-2-phenyl-9-oxa-3,7-diazabicy-
clo[3.3.1]nonane (10d)
Compound 10b (1.38 g, 4.47 mmol) in MeOH (60 mL) was hydro-
genated over Pd(OH)2/C (20%, 500 mg) under 3 bar H2 pressure for
20 h at 45 °C. The crude product was sucked through a pad of Celite
and washed with MeOH (300 mL). Removal of the solvent in vacuo
delivered 10d (955 mg, 98%) as a white solid; mp 35 °C; [a]D
+42.3 (c = 0.17, MeOH); Rf = 0.43 [Et2O–MeOH (10:1), deactivat-
ed with NH3].
IR (KBr): 3296, 2931, 2793, 1484, 1458, 1066 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.10 (s, 3 H, NCH3), 2.24 (ddd, 1
H, J = 11.8, 3.8, 1.6 Hz, NCHH), 2.57 (ddd, 1 H, J = 11.3, 3.4, 2.8
Hz, NCHH), 2.65 (d, 1 H, J = 11.7 Hz, NCHH), 2.94 (d, 1 H,
J = 11.3 Hz, NCHH), 3.24 (d, 1 H, J = 13.8 Hz, NCHH), 3.48 (ddd,
1 H, J = 13.8, 3.9, 2.5 Hz, NCHH), 3.72 (br t, 1 H, J = 3.7 Hz,
OCH), 3.79 (br t, 1 H, J = 3.6 Hz, OCH), 4.43 (br d, 1 H, J = 8.5 Hz,
NCHPh), 7.23–7.29 (m, 3 H, ArH), 7.33–7.37 (m, 2 H, ArH).
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(d) Tsukazaki, M.; Tinkl, M.; Roglans, A.; Chapell, B. J.;
Taylor, N. J.; Snieckus, V. J. Am. Chem. Soc. 1996, 18, 685.
(e) Imamoto, T.; Watanabe, J.; Wada, Y.; Masuda, H.;
Yamada, H.; Tsurata, H.; Matsukawa, S.; Yamaguchi, K. J.
Am. Chem. Soc. 1998, 120, 1635. (f) Tomooka, K.;
Shimizu, H.; Inoue, T.; Shibata, H.; Nakai, T. Chem. Lett.
1999, 759. (g) Metallinos, C.; Szillat, H.; Taylor, N. J.;
Snieckus, V. Adv. Synth. Catal. 2003, 345, 370.
(h) Wilkinson, J. A.; Rossington, S. B.; Ducki, S.; Leonard,
J.; Hussain, N. Tetrahedron: Asymmetry 2004, 15, 3011.
(4) (a) Klein, S.; Marek, I.; Poisson, J.-F.; Normant, J.-F. J. Am.
Chem. Soc. 1995, 117, 8853. (b) Norsikian, S.; Marek, I.;
Poisson, J.-F.; Normant, J. F. J. Org. Chem. 1997, 62, 4898.
(c) Norsikian, S.; Marek, I.; Normant, J.-F. Tetrahedron
Lett. 1997, 38, 7523. (d) Norsikian, S.; Marek, I.; Klein, S.;
Poisson, J. F.; Normant, J. F. Chem. Eur. J. 1999, 5, 2055.
(5) (a) Hodgson, D. M.; Lee, G. P.; Mariott, R. E.; Thompson,
A. J.; Wisedale, R.; Witherington, J. J. Chem. Soc., Perkin
Trans. 1 1998, 2151. (b) Hodgson, D. M.; Gras, E. Synthesis
2002, 1625. (c) Hodgson, D. M.; Buxton, T. J.; Cameron, I.
D.; Gras, E.; Kirton, E. H. M. Org. Biomol. Chem. 2003, 1,
4293. (d) Hodgson, D. M.; Paruch, E. Tetrahedron 2004, 60,
5185.
13C NMR (100 MHz, CDCl3): d = 46.92, 51.08, 54.70, 59.70, 62.64,
67.19, 72.31, 126.3, 127.0, 128.6, 140.2.
MS (ESI, +): m/z (%) = 219.1488 ([M + H]+, 100).
HRMS (ESI, +): m/z [M + H]+ calcd for C13H19N2SO: 219.1497;
found: 219.1488.
Anal. Calcd for C13H18N2O: C, 71.53; H, 8.31; N, 12.83. Found: C,
70.87; H, 8.27; N, 12.78.
(+)-(1R,2S,5S)-3,7-Dimethyl-2-phenyl-9-oxa-3,7-diazabicy-
clo[3.3.1]nonane (10e)
K2CO3 (778 mg, 5.63 mmol) and MeI (351 mL, 799 mg, 5.63 mmol)
were added to a solution of 10d (878 mg, 4.02 mmol) in CH2Cl2 (12
mL). After 3 h at r.t., H2O (50 mL) was added and the mixture was
extracted with CH2Cl2 (4 × 30 mL). The combined organic layers
were washed with brine (50 mL), dried (Na2SO4), and concentrated
in vacuo to give 10e (859 mg, 92%) as white needles; mp 65 °C;
[a]D20 +154.4 (c = 1.15, MeOH); Rf = 0.48 (Et2O, deactivated with
NH3).
IR (KBr): 2937, 2780, 1451, 1266, 1088, 1062 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.01 (dd, 1 H, J = 11.9, 3.8 Hz,
NCHH), 2.08 (s, 3 H, NCH3), 2.20 (s, 3 H, NCH3), 2.45 (ddd, 1 H,
J = 11.4, 3.9, 1.6 Hz, NCHH), 2.70 (ddd, 1 H, J = 11.8, 4.5, 1.7 Hz,
NCHH), 2.72 (br d, 1 H, J = 11.8 Hz, NCHH), 3.03 (d, 1 H, J = 11.4
Hz, NCHH), 3.14 (d, 1 H, J = 11.7 Hz, NCHH), 3.46 (d, 1 H, J = 4.0
Hz, NCHPh), 3.67 (br t, 1 H, J = 3.7 Hz, OCH), 3.95 (br t, 1 H,
J = 4.1 Hz, OCH), 7.23–7.41 (m, 4 H, ArH), 7.44 (br s, 1 H, ArH).
13C NMR (100 MHz, CDCl3): d = 42.89, 45.88, 47.32, 53.93, 58.51,
58.95, 68.89, 72.31, 73.19, 127.3, 128.4, 129.4.
MS (ESI, +): m/z (%) = 233.1648 ([M + H]+, 100).
HRMS (ESI, +): m/z [M + H]+ calcd for C14H21N2O: 233.1654;
(6) Shintani, R.; Fu, G. Angew. Chem. Int. Ed. 2002, 41, 1057.
(7) Zhang, Y.; Yeung, S.-M.; Wu, H.; Heller, D. P.; Wu, C.;
Wulff, W. D. Org. Lett. 2003, 5, 1813.
(8) (a) Sigman, M. S.; Jensen, D. R. Acc. Chem. Res. 2006, 39,
221. (b) Ferraira, E. M.; Stoltz, B. M. J. Am. Chem. Soc.
2001, 123, 7725. (c) Jensen, D. R.; Pugsley, J. S.; Sigman,
M. S. J. Am. Chem. Soc. 2001, 123, 7475. (d) For a recent
application in natural product synthesis, see: Tambar, U. K.;
Ebner, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128,
11752.
found: 233.1648.
Anal. Calcd for C14H20N2O: C, 72.38; H, 8.68; N, 12.06. Found: C,
71.75; H, 8.61; N, 11.88.
(9) The alkaloid (+)-sparteine [(+)-1] is also a natural product,
albeit with a low abundance: Orechoff, A.; Rabinowitch, M.;
Kolowanowa, R. Ber. Dtsch. Chem. Ges. 1933, 66, 621.
(10) (+)-Sparteine [(+)-1] is not commercially available. It can be
prepared according to literature11,12 and by reduction and
resolution of the naturally occurring alkaloid rac-lupanine,
see: Ebner, T.; Eichelbaum, M.; Fischer, P.; Meese, C. O.
Arch. Pharm. (Weinheim) 1989, 322, 399.
Acknowledgment
This work was supported by the Deutsche Forschungsgemeinschaft
DFG (Emmy Noether fellowship to M.B.) and the Fonds der
Chemischen Industrie. The technical assistance of Julia Jakob is
acknowledged.
(11) Hermet, J.-P. R.; McGrath, M. J.; O’Brien, P.; Porter, D. W.;
Gilday, J. Chem. Commun. 2004, 1830; this route should be
also applicable to the synthesis of (+)-sparteine [(+)-1].
Synthesis 2007, No. 11, 1702–1706 © Thieme Stuttgart · New York

1706
M. Breuning, M. Steiner
PAPER
(15) The most popular approach, the Mannich reaction of a
piperidin-4-one with formaldehyde and an amine, cannot be
applied to the enantioselective preparation of chiral 2-
substituted bispidines since any stereochemical information
in a chirally modified piperidin-4-one is lost under the harsh
reaction conditions: Harrison, J. R.; O’Brien, P.; Porter, D.
W.; Smith, N. M. J. Chem. Soc., Perkin Trans. 1 1999, 3623.
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A.; Reddy, B. V. S. Tetrahedron Lett. 2001, 42, 6385.
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(13) (a) Dixon, A. J.; McGrath, M. J.; O’Brien, P. Org. Synth.
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(14) Several other diamines have been screened in the
enantioselective deprotonation of N-Boc-pyrrolidine, but all
provided significantly lower levels of enantioselection:
(a) Hermet, J. R.; Porter, D. W.; Dearden, M. J.; Harrison, J.
R.; Koplin, T.; O’Brien, P.; Parmene, J.; Tyurin, V.;
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Synthesis 2007, No. 11, 1702–1706 © Thieme Stuttgart · New York