First asymmetric synthesis of a C2-symmetric 2-endo,6-endo-disubstituted bispidine

Article abstract of DOI:10.1016/j.tetasy.2007.06.010

The enantioselective synthesis of a C₂-symmetric 2-endo,6-endo-disubstituted bispidine (3,7-diazabicyclo[3.3.1]nonane) has been accomplished for the first time. The key step was a Michael addition of the protected β-amino ester methyl (R)-3-{N-

Full text of DOI:10.1016/j.tetasy.2007.06.010

Tetrahedron: Asymmetry 18 (2007) 1410–1418
First asymmetric synthesis of a C2-symmetric
2-endo,6-endo-disubstituted bispidine
Matthias Breuning* and David Hein
Institute of Organic Chemistry, University of Wu¨rzburg, Am Hubland, 97074 Wu¨rzburg, Germany
Received 30 April 2007; accepted 11 June 2007
Abstract—The enantioselective synthesis of a C2-symmetric 2-endo,6-endo-disubstituted bispidine (3,7-diazabicyclo[3.3.1]nonane) has
been accomplished for the first time. The key step was a Michael addition of the protected b-amino ester methyl (R)-3-{N-benzyl-N-
[(S)-1-phenylethyl]amino}-3-phenylpropionate to its a-methylene derivative delivering an anti,anti-configured a,a0-methylene-bridged
bis(b-amino ester) as the major diastereomer. Deprotection, reduction and cyclisation furnished (1R,2R,5R,6R)-2,6-diphenyl-3,7-
bis((S)-1-phenylethyl)-3,7-diazabicyclo[3.3.1]nonane in six steps and 15% overall yield.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
applied in enantioselective allylic substitutions,8 additions
to imines9 and the ring opening of meso-anhydrides.10
Recent developments disclose the use of (ꢀ)-1 as a ligand
in CuI-mediated dynamic kinetic resolutions of racemic
1,10-biaryl-2,20-diols11 and in PdII-catalysed oxidative
kinetic resolutions of secondary alcohols.12 The lack of
an easily accessible source for (+)-sparteine (+)-113 is
compensated by the synthetic diamine (+)-2,14,15 which is
devoid of the axially annelated ring of 1, but offers
a comparably high potential in asymmetric synthesis as
(ꢀ)-1 does. Further simplification of the structure as in
the N,N0-dimethyl-2-endo-methylbispidine (ꢀ)-3 resulted
in a significantly reduced capability to transfer chirality.16
Chiral bispidines (3,7-diazabicyclo[3.3.1]nonanes) have
found manifold applications in asymmetric synthesis.1–3
The most prominent member of this class, the commer-
cially available lupine alkaloid (ꢀ)-sparteine (ꢀ)-1
(Fig. 1),4 is unrivalled as a chiral ligand for organolithium
bases in enantioselective deprotonations,1,5 carbolithia-
tions6 and ortho-metallations.7 It has also successfully been
N
N
N
N
NMe
N
NMe
Me
The stereoselective synthesis of bispidines possessing a chi-
rally modified backbone is still a challenging endeavour.
NMe
´
Four different approaches have been developed: Aube
(+)-sparteine
(–)-sparteine
(+)-2
(–)-3
et al. prepared (+)-sparteine (+)-1 from enantiomerically
pure (S,S)-norbornan-2,5-dione by two successive ring
enlargement reactions,17,18 whereas Michael addition of
an (R)-homopipecolic ester to its oppositely configured a-
methylene derivative was used as the key step in O’Brien’s
synthesis of (ꢀ)-sparteine (ꢀ)-1.19 Diamine (+)-2 is derived
from (ꢀ)-cytisine, a natural product14,20 that is also acces-
sible by total synthesis.21,22 Finally, Kozlowski’s diamine
(ꢀ)-3 was prepared in enantiomerically pure form by reso-
lution of racemic 3, which was obtained from an achiral
bispidine precursor by a-deprotonation and methylation.16
An approach to the C2-symmetric bispidines of the general
formula 4, however, is still missing,23 even though such
(+)-1
(–)-1
R
Ph
5: R = H
6: R =
NR'
NR
Ph
NR'
NR
Ph
Me
R
4
Figure 1. Chiral C1-symmetric bispidines and the C2-symmetric target
diamines 5 and 6.
*
Corresponding author. Tel.: +49 931 888 4761; fax: +49 931 888 4755;
e-mail: breuning@chemie.uni-wuerzburg.de
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.06.010

M. Breuning, D. Hein / Tetrahedron: Asymmetry 18 (2007) 1410–1418
1411
diamines might possess high potential in the asymmetric
transformations mentioned above or as the chiral back-
bone of Lewis acids. Herein we report our studies towards
the enantioselective synthesis of the C2-symmetric 2-endo,6-
endo-diphenylbispidine 5; its N,N0-diprotected derivative 6
was prepared in six steps and 15% overall yield from
known compounds using a Michael addition as the key
step.
7B is required or conditions for a preferred syn-proton-
ation have to be developed.
2.2. Synthesis of the starting materials
Enantiomerically pure b-amino ester 8 is available on large
scale from methyl cinnamate 10 and lithium N-benzyl-(S)-
phenylethylamide (S)-11 according to a procedure devel-
oped by Davies (Scheme 2).25–28 The synthesis of the
Michael acceptor 9 was accomplished by two different
routes: treatment of the zinc enolate of 8 with gaseous
formaldehyde introduced a hydroxymethyl substituent at
the a-position. Mesylation of the OH-group and subse-
quent elimination induced by DBU (1,3-diazabicy-
clo[5.4.0]undecane) gave 9 in 48% yield. An alternative
approach to 9 was established from the cinnamic acid
derivative 12, which is readily accessible from benzalde-
hyde and methyl acrylate.29 Esterification of 12 with
thionyl chloride in methanol afforded a 92:8 mixture of
the a-methoxymethyl-substituted cinnamate 1330 and its
chloro derivative 1431 (87% yield). Slow addition of a
stoichiometric amount of (S)-11 to this mixture gave 9 in
high 81% yield and with excellent stereocontrol (>97:3
dr). The newly formed double bond was not attacked under
these conditions. However, an addition to this double bond
was observed if an excess of (S)-11 was used or if the addi-
tion order was reversed. For example, the addition of esters
13/14 to 1.4 equiv of (S)-11 gave 48% of 9 and 32% of 15
(76:24 dr). The latter preparation of 9 from 12 is superior
to that from 8, since it provides a higher overall yield
(70% vs 48%) and avoids the labour-intensive hydroxyme-
thylation procedure of 8.
2. Results and discussion
2.1. Retrosynthesis and stereochemical considerations
Our retrosynthetic analysis of bispidines 5 and 6 is shown
in Scheme 1. The key intermediate is the anti,anti-config-
ured a,a0-methylene-bridged bis(b-amino ester) 7A, which
should be convertible into 6 and, subsequently, into 5 by
a deprotection, cyclisation and reduction sequence.24 For
the preparation of 7A, we intended to evaluate two chem-
ically related, but stereochemically different routes, both
starting from the readily available b-amino ester 8:25,26
(a) the direct junction of two molecules of 8 by a bridging
a-alkylation using a bifunctional CH2XY-unit and (b) the
Michael addition of 8 to the acrylic ester derivative 9. It
is well known that the a-alkylations of the enolate of 8
and of the related b-amino esters occur highly anti-diaste-
reoselectively.27 Therefore, approach (a), which comprises
of two such a-alkylations, should predominately deliver
the desired anti,anti-configured isomer 7A. By contrast,
the addition of the enolate of 8 to the acrylate 9 generates
a new enolate at the former Michael system, which can be
protonated upon work up. If this protonation proceeds,
like the a-alkylation, anti-selectively, the alignment of the
substituents will be syn thus giving rise to the formation
of the unwanted anti,syn-diastereomer 7B. Such an anti,
syn-connection was successfully applied in the synthesis
of (ꢀ)-sparteine (ꢀ)-1 by O’Brien.19 In order to obtain
the desired anti,anti-diastereomer 7A, an epimerisation of
CO2Me
CO2H
OMe
Ph
Ph
10
12
Me
THF, -78 ˚C
91%, >97:3 dr
SOCl2, MeOH
rt
Ph
NBn
Li
87%
(S)-11
Me
Me
Ph
NBn
CO2Me
CO2Me
Cl
Ph
+
Ph
Ph
NBn
Ph
CO2Me
Ph
NR
Ph
CO2Me
OMe
Ph
NR
Ph
8
13
14
MeO2C
13/14 = 92:8
BnN
Ph
Me
5: R = H
1. LDA, THF
addition of 13/14
to (S)-11
(1.4 equiv.)
THF, -78 ˚C
(S)-11, (1.05 equiv.)
THF, -78 ˚C
81%
7A
-78 ˚C, then
ZnBr2, CH2Ogas.
2. MsCl, DBU
dioxane, 0 ˚C → Δ
48%
Ph
Me
6: R =
Me
NBn
>97:3 dr
Ph
CH2XY
Me
CO2Me
Me
Ph
Ph
NBn
Me
Ph
NBn
*
9
CO2Me
Ph
Ph
Ph
NBn
CO2Me
+
9
Ph
Me
CO2Me
(48%)
Ph
NBn
Ph
Ph
NBn
MeO2C
CO2Me
BnN
Ph
Me
9
Me
Ph
15
7B
8
(32%, 76:24 dr)
Scheme 1. Retrosynthetic analysis of the bispidines 5 and 6.
Scheme 2. Synthesis of the b-amino esters 8 and 9.

1412
M. Breuning, D. Hein / Tetrahedron: Asymmetry 18 (2007) 1410–1418
Table 1. Optimisation of the Michael addition of 8 to 9a
2.3. Preparation of the 2-endo,6-endo-diphenylbispidine 6
Entry
Base
Solvent
7A:7Bb
7Ac (%)
7Bc (%)
The direct junction of two molecules of 8 by a methylene
bridge was attempted (Scheme 3). Deprotonation of 8 with
LDA in THF and treatment with a bifunctional C1-unit
such as CH2I2, ICH2Cl, ICH2OTs or CH2(OTs)2 at
ꢀ78 ꢁC resulted in no reaction.32 At higher temperatures,
decomposition occurred, probably due to carbene forma-
tion. Despite extensive variations of the reaction condi-
tions, no traces of the desired coupling product 7A or of
its diastereomer 7B were detected.
1
2
3
4
5
6
7
8
LDA
THF
THF
THF
n-Hexane
n-Hexane
n-Hexane
n-Hexane
n-Hexane
29:71
28:72
16:84
71:29
71:29
35:65
26:74
70:30
10
10
—
24
25
—
LiHMDS
LiHMDSd
LDAf
LiHMDS
NaHMDS
KHMDS
LDAg
e
e
25
37
11
15
e
e
—
e
—
e
—
52
—
21
a Unless otherwise noted, the following procedure was used: deprotona-
tion of 8 with base (1.25 equiv) at ꢀ30 ꢁC, addition of 9 (1.25 equiv),
warming to rt overnight, and protonation with satd aq NH4Cl at rt.
b Calculated from the 1H NMR spectra of the crude reaction mixtures.
c Isolated yields of the diastereomerically pure compounds.
d Addition of HMPA (1.3 equiv) after deprotonation.
The alternative approach, the Michael addition of lithiated
8 to acrylic ester derivative 9 (Scheme 3 and Table 1), was
expected to predominately give the anti,syn-diastereomer
7B (see discussion, Section 2.1). Indeed, a 29:71 mixture
of 7A:7B was obtained with LDA in THF at ꢀ30 ꢁC to
rt and work up with aqueous NH4Cl at rt (entry 1). Chro-
matographic purification afforded 7B in 24% yield and 7A
in 10% yield. LiHMDS as the base gave an almost identical
result (entry 2). The addition of HMPA (1.3 equiv) to the
enolate of 8 further enhanced the diastereoselectivity
towards the undesired isomer 7B (16:84 dr), albeit at low
conversion (<50%, entry 3).
e Not isolated due to low conversion (<50%).
f The addition of LiClO4 (2.0 equiv) had no effect; protonation with
NH4Cl at ꢀ78 ꢁC or with BHT (2,6-di-tert-butyl-4-methylphenol) at
0 ꢁC resulted in lower diastereomeric ratios.
g 2.5 equiv of LDA and 9 used.
thermodynamically driven epimerisation process, that is
7B!7A, can be excluded. Samples taken at low conver-
sions and at prolonged reaction times did not reveal any
change in the dr. All attempts to further increase the diaste-
reomeric ratio, for example, by protonation with solid
NH4Cl at ꢀ78 ꢁC or with the bulky proton source BHT
(2,6-di-tert-butyl-4-methylphenol) at 0 ꢁC, failed (entry 4).
The addition of LiClO4 (2.0 equiv) to the lithium enolate
of 8 had no effect; the lithium ion as the counter ion, how-
ever, is crucial: deprotonation of 8 with NaHMDS or
KHMDS in n-hexane again gave the undesired anti,syn-
diastereomer 7B as the main isomer (entries 6 and 7). Opti-
mum conditions with respect to the yield were found with
2.5 equiv of LDA and of the Michael acceptor 9 delivering
the anti,anti-diastereomer 7A in good 52% yield and 7B in
21% yield after chromatography.
Me
Ph
NBn
CO2Me
Ph
8
Me
NBn
LDA or LiHMDS
THF or n-hexane, -78 °C
then CH2I2, ICH2Cl
Ph
CO2Me
Ph
ICH2OTs, or CH2(OTs)2
-78 °C → rt
9
base, solvent (additive)
conditions see Table 1
Me
Me
Finally, it should be noted that the unwanted anti,syn-
product 7B is not lost; it can be successively recycled by
epimerisation with KOt-Bu in refluxing t-BuOH to give a
50:50 mixture of 7A and 7B (71% yield).
Ph
NBn
Ph
NBn
CO2Me
Ph
CO2Me
Ph
Ph
Ph
+
MeO2C
MeO2C
BnN
Ph
Me
BnN
Ph
Me
Further construction of the bispidine skeleton was straight-
forward (Scheme 4): oxidative debenzylation of 7A with
CAN (ceric ammonium nitrate) in aqueous acetonitrile
afforded the secondary diamine 16 (74% yield),33 which
was reduced with LiAlH4 to give diol 17 (76% yield). Mesyl-
ation of the two hydroxy groups resulted in a spontaneous
cyclisation delivering the C2-symmetric bispidine 6 in 73%
yield. The alternative cyclisation–reduction sequence via
dilactam 18 was less successful giving 6 in low 17% yield
(vs 56% yield via 17).
7A
7B
KOtBu, tBuOH, Δ
71%, 50:50 dr
Scheme 3. Studies on the preparation of 7A from 8.
A dramatic change in the diastereofacial discrimination
was observed in n-hexane as the solvent. With either
LDA or LiHMDS, the desired anti,anti-isomer 7A was
obtained as the major product (71:29 dr, entries 4 and 5).
Since the formation of a suspension was observed over
the course of the reaction, a possible explanation for this
reversal in diastereoselectivity might be the occurrence of
aggregates, in which the formal syn-protonation leading
to 7A is favoured for steric or stereoelectronic reasons. A
Finally, removal of the chiral protecting groups at the
nitrogen atoms was investigated. Even though two different
types of benzylic C–N bonds, two endo- and two exo-cyclic
ones, are present in 6, we anticipated the latter ones to be
preferentially attacked by hydrogenolysis due to the sensi-
bility of these reactions to steric hindrance.34 However, a
selective cleavage of the endo-cyclic C–N bonds occurred

M. Breuning, D. Hein / Tetrahedron: Asymmetry 18 (2007) 1410–1418
1413
amine 19. Further work in this area will focus on the prep-
aration of target molecule 5 by using a different protection
strategy, on the enantioselective syntheses of derivatives
with other substituents in 2-endo- and 6-endo-position,
and on the application of these bispidines in asymmetric
synthesis.
Me
NR
Ph
LiAlH4, THF
CO2Me
Ph
MeMgBr, Et2O
Ph
-78 °C → rt
0 °C → rt
76%
46%
MeO2C
RN
Ph
Me
4. Experimental
Me
NH
7A (R = Bn)
CAN
MeCN/H2O
rt, 74%
Ph
16 (R = H)
Ph
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 inter-
nal reference. IR spectra were recorded on a Jasco FT-IR-
410 spectrometer. High resolution mass spectra were mea-
sured on a Bruker Daltonics micrOTOF focus. Column
chromatography was carried out on silica gel (63–200
mesh). Microanalyses were performed at the Institute of
Ph
O
N
Ph
HO
OH
Ph
Me
Me
N
Ph
O
Ph
HN
Ph
Me
17
18
Ph
Ph
MsCl, NEt3
CH2Cl2
rt → 40 °C
Inorganic Chemistry, University of Wurzburg. Anhydrous
¨
LiAlH4, THF
N
-78 °C → rt
Me
solvents were prepared using standard procedures. The b-
amino ester 8 (>97 ee, >95% de) was synthesised according
to Ref. 25 and N-benzyl-(S)-phenylamine (>97% ee)
according to Ref. 35. All reactions with anhydrous solvents
were performed under an argon atmosphere. The diaste-
Me
73%
36%
N
Ph
Ph
6
hydrogenationa
or
Na/NH3, -78 °C
1
reomeric ratios of 7 and 9 were determined by H NMR
of the crude reaction mixtures.
Ph
Me
Me
NH
4.1. Methyl (E)-2-methoxymethyl cinnamate 13 and methyl
(E)-2-chloromethyl cinnamate 14
+
Ph
N
N
H
Ph
H
NH
Ph
Ph
Ph
19: 50-75%
5: 0%
Thionyl chloride (17 mL, 27.7 g, 233 mmol) was slowly
added to a solution of 12 (15.0 g, 78.0 mmol) in anhydrous
methanol (50 mL). After 15 h at rt, the reaction mixture
was carefully neutralised with 3 M NaOH (160 mL) and
extracted with EtOAc (2 · 200 mL). The combined organic
layers were washed with brine (100 mL) and dried over
MgSO4. Evaporation of the solvent under reduced pressure
yielded a 92:8 mixture of the known methyl cinnamates
1329 and 1431 (15.3 g, 74.0 mmol, 95%) as a colourless oil.
Scheme 4. Transformation of 7A into the bispidine 6 and the attempted
deprotection of 6 to give 5. Reagents: H2, Pd/C, MeOH; H2, Pd/C, EtOH/
6 N HCl; H2, Pd(OH)2/C, MeOH/AcOH; H2, PtO2, EtOH; NH4HCO2,
Pd/C, MeOH, D.
under all conditions screened thus affording acyclic di-
amine 19 in 50–75% yield. The same result was observed
in the attempted reductive removal of the N-phenylethyl
groups of 6 with sodium in liquid ammonia. Cleavage of
the chiral auxiliary in an earlier stage of the synthesis, that
is in 16, 17 or 18, failed, as well. Inseparable product
mixtures were obtained.
4.2. Methyl 2-{(S)-[N-benzyl-N-((S)-1-phenyl-
ethyl)amino]phenylmethyl}acrylate 9
4.2.1. From b-amino ester 8. A solution of LDA, prepared
from i-Pr2NH (14.2 mL, 10.2 g, 101 mmol) and n-BuLi
(1.6 M in hexanes, 60.3 mL, 96.4 mmol) in anhydrous
THF (100 mL) at ꢀ30 ꢁC to 0 ꢁC, was slowly added at
ꢀ78 ꢁC to a solution of 8 (24.0 g, 64.3 mmol) in anhydrous
THF (500 mL). After 1 h, anhydrous ZnBr2 (21.7 g,
96.4 mmol) was added and stirring was continued for
30 min. In a second flask, attached via a short glass bridge,
paraformaldehyde (29.0 g, 965 mmol) was heated to ca.
180 ꢁC (heatgun) and the resulting monomeric formalde-
hyde transported in an argon stream over the vigorously
stirred reaction mixture. After 1 h at ꢀ78 ꢁC, satd aq
NH4Cl (300 mL) was added and the reaction mixture
extracted with EtOAc (2 · 300 mL). The combined organic
layers were washed with brine (300 mL), dried over MgSO4
and the solvent removed in vacuo. The crude product was
purified by column chromatography (silica gel, n-pentane–
Et2O 2:1) to give the a-hydroxymethyl derivative of 8
(14.7 g, 36.3 mmol, 56%) as a colourless oil.
3. Conclusions
The enantioselective synthesis of the C2-symmetric 2-
endo,6-endo-diphenyl-substituted bispidine 6 was achieved
in six steps and 15% overall yield starting from b-amino
ester 8 and the cinnamic acid 12. The key step was the
Michael addition of 8 to its a-methylene derivative 9, which
was prepared from 12. The desired anti,anti-configured
a,a0-methylene-bridged bis(b-amino ester) 7A was obtained
as the major diastereomer with LDA in n-hexane as the sol-
vent; the anti,syn-isomer 7B was preferentially formed in
THF. Debenzylation, reduction and cyclisation delivered
the N,N0-diprotected bispidine 6. Attempted hydrogeno-
lytic or reductive removal of the chiral protecting groups
caused a cleavage of the bispidine core giving acyclic di-

1414
M. Breuning, D. Hein / Tetrahedron: Asymmetry 18 (2007) 1410–1418
The product (10.1 g, 25 mmol) was dissolved in dioxane
(250 mL) and cooled to 0 ꢁC. MsCl (2.36 mL, 3.44 g,
30.0 mmol) and DBU (1,3-diazabicyclo[5.4.0]undecane,
12.0 mL, 12.2 g, 80.0 mmol) were added slowly. The reac-
tion mixture was stirred for 20 min at 0 ꢁC, 1 h at rt, and
16 h at 60 ꢁC. Satd aq NH4Cl (1 L) was added and the reac-
tion mixture extracted with Et2O (2 · 1 L). The combined
organic layers were washed with brine (250 mL), dried over
MgSO4 and evaporated. Column chromatography (silica
3026, 2967, 2930, 2848, 1736, 1494, 1451, 1372, 1262,
1
748, 698 cmꢀ1. H NMR (400 MHz, CDCl3): d 0.80 (3H,
d, J = 7.0 Hz, CHCH3), 1.18 (3H, d, J = 7.0 Hz, CHCH3),
1.85 (1H, dd, J = 13.3, 3.5 Hz, CHCHH), 2.67 (1H, dd,
J = 13.3, 11.5 Hz, CHCHH), 3.16 (1H, d, J = 13.8 Hz,
CHHPh), 3.26 (1H, td, J = 11.6, 3.5 Hz, 2-H), 3.38 (1H,
d, J = 13.9 Hz, CHHPh), 3.51 (1H, d, J = 14.5 Hz,
CHHPh), 3.56 (3H, s, OCH3), 3.72 (1H, q, J = 7.0 Hz,
CHMePh), 3.82 (1H, d, J = 11.6 Hz, 3-H), 4.04 (2H, m,
CHMePh, CHHPh), 6.92 (2H, m, ArH), 7.11–7.38 (23H,
m, ArH). 13C NMR (100 MHz, CDCl3): d 14.1 (CHCH3),
14.7 (CHCH3), 49.9 (C-2), 50.4 (CH2Ph), 51.1 (OMe), 52.2
(CHCH2), 54.7 (CH2Ph), 55.1 (CHMePh), 58.4
(CHMePh), 61.6 (C-3), 126.3, 126.6, 126.76, 126.77,
127.3, 127.7, 127.8, 127.97, 128.02, 128.04, 128.15,
128.23, 128.8, 128.9, 129.1, 138.8, 139.8, 140.3, 142.1,
144.1 (ArC), 174.3 (C@O). HRMS (ESI, +): calcd for
gel, n-pentane–Et2O 40:1!10:1) delivered
9 (8.20 g,
21
21.3 mmol, 85%) as a colourless oil. ½aꢁD ¼ þ88:7 (c 0.13,
CHCl3). IR (film): m 3084, 3060, 3027, 2970, 2949, 2844,
1721, 1493, 1452, 1283, 1135, 749, 699 cmꢀ1 1H NMR
.
(400 MHz, CDCl3): d 1.20 (3H, d, J = 7.0 Hz, CHCH3),
3.57 (3H, s, OCH3), 3.82 (1H, d, J = 15.2 Hz, CHHPh),
3.87 (1H, d, J = 15.0 Hz, CHHPh), 4.16 (1H, q,
J = 7.0 Hz, CHMePh), 5.04 (1H, s, NCHPh), 5.93 (1H, s,
3-H), 6.28 (1H, s, 3-H0), 7.10–7.40 (15H, m, ArH). 13C
NMR (100 MHz, CDCl3): d 16.9 (CHCH3), 51.3 (CH2Ph),
51.6 (OCH3), 57.6 (CHMePh), 63.8 (NCHPh), 126.2 (C-3),
126.7, 127.1, 127.8, 127.9, 128.0, 128.1, 129.2, 140.2 (ArH),
141.9 (C-2), 142.0, 143.4 (ArC), 167.5 (C@O). HRMS (ESI,
+): calcd for C26H27NO2+Na: 408.1934, found: 408.1938.
Anal. Calcd for C26H27NO2 (385.49): C, 81.01; H, 7.06;
N, 3.63. Found: C, 80.84; H, 7.07; N, 3.56.
C41H44N2O2+Na: 619.3295, found: 619.3305. Slower elut-
22
ing diastereomer of 15: mp 50 ꢁC. ½aꢁD ¼ þ25:9 (c 0.10,
CHCl3). IR (KBr): m 3085, 3060, 3027, 2967, 2935, 2841,
1736, 1494, 1451, 1224, 1029, 749, 699 cmꢀ1 1H NMR
.
(400 MHz, CDCl3): d 0.88 (3H, d, J = 6.8 Hz, CHCH3),
1.24 (3H, d, J = 6.8 Hz, CHCH3), 2.29 (1H, t,
J = 12.6 Hz, CHCHH), 2.97 (3H, s, OCH3), 3.08 (1H,
dd, J = 12.9, 3.9 Hz, CHCHH), 3.24 (1H, d, J = 13.4 Hz,
CHHPh), 3.45 (1H, td, J = 11.3, 3.9 Hz, 2-H), 3.59 (1H,
d, J = 13.8 Hz, CHHPh), 3.67 (1H, d, J = 13.4 Hz,
CHHPh), 3.78 (1H, d, J = 11.0 Hz, 3-H), 3.88 (1H, q,
J = 6.8 Hz, CHMePh), 3.98 (1H, d, J = 13.8 Hz, CHHPh),
4.17 (1H, q, J = 6.8 Hz, CHMePh), 7.10–7.43 (25H, m,
ArH). 13C NMR (100 MHz, CDCl3): d 10.0 (CHCH3),
14.7 (CHCH3), 48.3 (C-2), 50.7 (CHCH2, CH2Ph), 50.9
(OMe), 54.1 (CH2Ph), 55.5 (CHMePh), 55.8 (CHMePh),
61.9 (C-3), 126.3, 126.6, 126.7, 127.0, 127.2, 127.6, 127.8,
127.88, 127.90, 128.1, 128.2, 128.4, 129.08, 129.10, 129.2,
138.7, 140.0, 140.1, 143.4, 144.7 (ArC), 173.3 (C@O).
HRMS (ESI, +): calcd for C41H44N2O2+Na: 619.3295,
found: 619.3312. Anal. Calcd for C41H44N2O2 (596.82):
C, 82.51; H, 7.43; N, 4.69. Found: C, 82.13; H, 7.64; N,
4.42.
4.2.2. From the methyl cinnamates 13 and 14. Amide (S)-
11 was prepared by deprotonation of N-benzyl-(S)-phenyl-
ethylamine (10.8 g, 50.9 mmol) with n-BuLi (1.6 M in hex-
anes, 30.6 mL, 48.9 mmol) in anhydrous THF (80 mL) at
ꢀ78 ꢁC for 30 min. The resulting pink solution was added
over a period of 2 h to a 92:8 mixture of 13 and 14 (10.0 g,
48.5 mmol) in anhydrous THF (80 mL). After 1 h at
ꢀ78 ꢁC, the reaction mixture was quenched with satd aq
NH4Cl (150 mL) and extracted with Et2O–CH2Cl2 (1:1,
2 · 150 mL). The combined organic layers were washed
with brine (200 mL) and dried over MgSO4. Removal of
the solvent in vacuo and column chromatographic purifica-
tion (silica gel, n-pentane–Et2O 40:1!10:1) gave 9 (15.1 g,
39.2 mmol, 81%, >97:3 dr) as a colourless oil.
4.3. Methyl (R)-3-[N-benzyl-N-((S)-1-phenylethyl)amino]-2-
{[N-benzyl-N-((S)-1-phenylethyl)amino]methyl}-3-phenyl-
propionate 15
4.4. Dimethyl (2S,4S)-2,4-bis{(R)-[N-benzyl-N-((S)-1-phen-
ylethyl)amino]phenylmethyl}glutarate 7A and dimethyl
(2S,4R)-2,4-bis{(R)-[N-benzyl-N-((S)-1-phenyl-
ethyl)amino]phenylmethyl}glutarate 7B
A 92:8 mixture of 13 and 14 (4.55 g, 22.0 mmol) in anhy-
drous THF (10 mL) was added at ꢀ78 ꢁC to a pink solu-
tion of (S)-11, prepared by deprotonation of N-benzyl-
(S)-phenylethylamine (6.52 g, 30.9 mmol) with n-BuLi
(1.6 M in hexanes, 18.6 mL, 29.8 mmol) in anhydrous
THF (70 mL) at ꢀ78 ꢁC for 30 min. The reaction was stir-
red for 1 h at ꢀ78 ꢁC, quenched with satd aq NH4Cl
(90 mL) and extracted with Et2O–CH2Cl2 (1:1,
2 · 90 mL). The combined organic layers were washed with
brine (50 mL), dried over MgSO4 and evaporated. Column
chromatography (silica gel, n-pentane–Et2O 40:1!10:1)
delivered in the order of elution 9 (4.04 g, 10.5 mmol,
48%) as a colourless oil and the diastereomers of 15 (faster
eluting diastereomer: 3.10 g, 5.19 mmol, 24%; slower elut-
ing diastereomer: 989 mg, 1.66 mmol, 8%) as colourless sol-
A solution of LDA, prepared from i-Pr2NH (4.39 mL,
3.15 g, 31.2 mmol) and n-BuLi (1.6 M in hexanes,
18.6 mL, 29.8 mmol) in anhydrous n-hexane (100 mL) at
ꢀ30 ꢁC to 0 ꢁC, was added at ꢀ30 ꢁC to a solution of 8
(4.44 g, 11.9 mmol) in anhydrous n-hexane (120 mL). After
30 min, a solution of 9 (11.5 g, 29.8 mmol) in anhydrous n-
hexane (300 mL) was slowly added and the reaction was
warmed to rt overnight giving a white suspension. Satd
aq NH4Cl (350 mL) was added and the reaction mixture
extracted with Et2O (2 · 700 mL). The combined organic
layers were washed with brine (350 mL), dried over MgSO4
and evaporated. Column chromatography (silica gel, n-
pentane–Et2O 10:1!5:1) delivered in the order of elution
7A (4.69 g, 6.18 mmol, 52%) and 7B (1.91 g, 2.52 mmol,
ids. Faster eluting diastereomer of 15: mp 53 ꢁC.
21%) as colourless solids. Compound 7A: mp 59 ꢁC.
22
21
½aꢁD ¼ ꢀ102:2 (c 0.14, CHCl3). IR (KBr): m 3084, 3060,
½aꢁD ¼ þ9:8 (c 0.13, CHCl3). IR (KBr): m 3085, 3060,

M. Breuning, D. Hein / Tetrahedron: Asymmetry 18 (2007) 1410–1418
1415
3027, 2947, 2849, 1737, 1494, 1452, 1162, 762, 699 cmꢀ1
.
was added. The white solid formed, was removed by suc-
tion and washed with Et2O (200 mL). The filtrate was ex-
tracted with Et2O (2 · 400 mL) and the combined organic
layers were washed with brine (250 mL) and dried over
MgSO4. Evaporation of the solvent and purification by col-
umn chromatography (silica gel, n-pentane–EtOAc 10:1)
1H NMR (400 MHz, CDCl3): d 0.82 (6H, d, J = 6.8 Hz,
2 · CHCH3), 1.03 (2H, dd, J = 8.3, 5.9 Hz, 3-H, 3-H0),
3.04 (2H, m, 2-H, 4-H), 3.45 (2H, d, J = 14.2 Hz,
2 · CHHPh), 3.47 (6H, s, 2 · OCH3), 3.76 (2H, d,
J = 11.4 Hz, 2 · NCHPh), 3.89 (2H, d, J = 14.2 Hz,
2 · CHHPh), 4.07 (2H, q, J = 6.8 Hz, 2 · CHMePh),
6.94–6.99 (4H, m, ArH), 7.12–7.31 (26H, m, ArH). 13C
NMR (100 MHz, CDCl3): d 15.4 (CHCH3), 30.8 (C-3),
47.2 (C-2/C-4), 50.5 (CH2Ph), 51.2 (OMe), 55.7
(CHMePh), 63.4 (NCHPh), 126.3, 126.6, 127.4, 127.70,
127.74, 128.0, 128.2, 128.9, 129.0, 137.5, 139.8, 144.4
(ArC), 174.0 (C@O). HRMS (ESI, +): calcd for
C51H54N2O4+H: 759.4156, found: 759.4158. Anal. Calcd
for C51H54N2O4 (758.99): C, 80.71; H, 7.17; N, 3.69.
gave 16 (954 mg, 1.65 mmol, 74%) as a yellowish foamy
19
solid. Mp 39 ꢁC. ½aꢁD ¼ ꢀ40:3 (c 0.18, CHCl3). IR (KBr):
m 3448, 3319, 3083, 3060, 3026, 2968, 2949, 1738, 1452,
1
1262, 1162, 766, 700 cmꢀ1. H NMR (400 MHz, CDCl3):
d 1.17 (6H, d, J = 6.3 Hz, 2 · CHCH3), 1.41 (2H, dd,
J = 8.6, 6.2 Hz, 3-H, 3-H0), 2.56 (2H, m, 2-H, 4-H), 3.44
(2H, q, J = 6.3 Hz, 2 · CHMePh), 3.67 (6H, s,
2 · OCH3), 3.69 (2H, d, J = 9.7 Hz, 2 · NCHPh), 7.01–
7.06 (4H, m, ArH), 7.07–7.11 (4H, m, ArH), 7.14–7.22
(6H, m, ArH), 7.25–7.32 (6H, m, ArH). 13C NMR
(100 MHz, CDCl3): d 22.0 (CHCH3), 29.7 (C-3), 51.36
(C-2/C-4), 51.39 (OMe), 54.3 (CHMePh), 62.1 (NCHPh),
126.5, 126.8, 127.2, 127.4, 128.2, 128.5, 141.1, 146.3
(ArC), 174.5 (C@O). HRMS (ESI, +): calcd for
C37H42N2O4+H: 579.3217, found: 579.3211.
Found: C, 80.69; H, 7.31; N, 3.39. Compound 7B: mp
21
136 ꢁC. ½aꢁD ¼ þ29:9 (c 0.14, CHCl3). IR (KBr): m 3085,
3060, 3027, 2970, 2854, 1728, 1494, 1450, 1122, 749,
700 cmꢀ1 1H NMR (400 MHz, CDCl3): d 0.82 (3H, d,
.
J = 7.0 Hz, CHCH3), 0.86 (3H, d, J = 7.0 Hz, CHCH3),
1.33 (1H, m, 3-H), 1.91 (1H, dt, J = 14.0, 3.0 Hz, 3-H),
2.79 (1H, td, J = 10.5, 2.5 Hz, 2-H or 4-H), 3.06 (3H, s,
OCH3), 3.14 (1H, td, J = 11.0, 3.8 Hz, 2-H or 4-H), 3.40
(3H, s, OCH3), 3.44 (1H, d, J = 13.9 Hz, CHHPh), 3.57
(1H, d, J = 10.9 Hz, NCHPh), 3.58 (1H, d, J = 13.9 Hz,
CHHPh), 3.70 (1H, d, J = 13.9 Hz, CHHPh), 3.88 (1H,
q, J = 7.0 Hz, CHMePh), 3.93 (1H, d, J = 11.4 Hz,
NCHPh), 4.11 (2H, m, CHMePh, CHHPh), 6.85–6.91
(2H, m, ArH), 7.02–7.11 (4H, m, ArH), 7.14–7.38 (21H,
m, ArH), 7.43–7.51 (3H, m, ArH). 13C NMR (100 MHz,
CDCl3): d 14.2 (CHCH3), 15.6 (CHCH3), 31.0 (C-3), 48.3
(C-2 or C-4), 48.5 (C-2 or C-4), 50.7 (CH2Ph), 50.9
(OMe), 51.0 (OMe), 51.1 (CH2Ph), 55.5 (CHMePh), 56.8
(CHMePh), 63.7 (NCHPh), 64.3 (NCHPh), 126.4, 126.7,
127.2, 127.60, 127.63, 127.7, 127.8, 128.0, 128.15, 128.17,
128.3, 128.4, 128.5, 128.7, 129.0, 129.4, 129.5, 138.1,
138.8, 139.8, 144.4 (ArC), 174.0 (C@O), 174.2 (C@O).
HRMS (ESI, +): calcd for C51H54N2O4+Na: 781.3976,
found: 781.3978.
4.7. (2S,4S)-2,4-Bis[(R)-phenyl-((S)-1-phenylethyl-
amino)methyl]pentane-1,5-diol 17
LiAlH4 (1.0 M in THF, 2.58 mL, 2.58 mmol) was added at
ꢀ78 ꢁC to a solution of 16 (750 mg, 1.29 mmol) in anhy-
drous THF (40 mL). After 30 min, the reaction was
warmed to rt and stirred for 16 h. The reaction mixture
was quenched with satd aq NH4Cl (120 mL) and extracted
with EtOAc (2 · 350 mL). The combined organic layers
were washed with brine (200 mL), dried over MgSO4 and
evaporated to give 17 (515 mg, 985 lmol, 76%) as a slightly
21
yellowish solid. Mp 102 ꢁC. ½aꢁD ¼ ꢀ125:5 (c 0.06, CHCl3).
IR (KBr): m 3422, 2926, 2854, 1602, 1452, 1082, 768,
1
700 cmꢀ1. H NMR (400 MHz, CDCl3): d 0.37 (2H, dd,
J = 7.4, 5.2 Hz, 3-H, 3-H0), 1.29 (6H, d, J = 6.4 Hz,
2 · CHCH3), 1.80 (2H, m, 2-H/4-H), 3.23 (2H, dd,
J = 11.2, 9.1 Hz, 1-H/5-H), 3.32 (2H, d, J = 10.2 Hz,
2 · NCHPh), 3.41 (2H, q, J = 6.4 Hz, 2 · CHMePh), 3.61
(2H, dd, J = 11.2, 2.8 Hz, 1-H0/5-H0), 6.91–7.01 (6H, m,
ArH), 7.07–7.31 (14H, m, ArH). 13C NMR (100 MHz,
CDCl3): d 21.0 (CHCH3), 28.2 (C-3), 43.4 (C-2/C-4), 54.7
(CHMePh), 67.1 (NCHPh), 67.6 (C-1/C-5), 126.4, 127.0,
127.3, 127.6, 128.5, 128.8, 141.9, 144.9 (ArC). HRMS
(ESI, +): calcd for C35H42N2O2+H: 523.3319, found:
523.3323.
Modifications of this procedure (see Table 1) were per-
formed on a 200–500 lmol scale.
4.5. Epimerisation of 7B
Compound 7B (500 mg, 659 lmol) was dissolved in warm
t-BuOH (25 mL) after which KOt-Bu (37.0 mg, 330 lmol)
was added. After reflux for 72 h, the reaction was quenched
with satd aq NH4Cl (100 mL) and extracted with EtOAc
(2 · 100 mL). The combined organic layers were washed
with brine (50 mL), dried over MgSO4 and the solvent re-
moved under reduced pressure to give a 50:50 mixture of
7A and 7B. Column chromatography (silica gel, n-pen-
tane–Et2O 10:1!5:1) delivered 7A (155 mg, 204 lmol,
31%) and 7B (148 mg, 195 lmol, 30%) as colourless solids.
4.8. (1S,4R,5S,8R)-4,8-Diphenyl-3,7-bis((S)-1-phenylethyl)-
3,7-diazabicyclo[3.3.1]nonane-2,6-dione 18
MeMgBr (3.0 M in THF, 2.40 mL, 8.00 mmol) was slowly
added at 0 ꢁC to a solution of 16 (580 mg, 1.00 mmol) in
anhydrous Et2O (60 mL). The reaction was stirred for
30 min at 0 ꢁC and for 18 h at rt. Satd aq NH4Cl
(100 mL) was added and the reaction mixture extracted
with Et2O (2 · 200 mL). The combined organic layers were
washed with brine (150 mL), dried over MgSO4 and the
solvent was evaporated under reduced pressure. Column
chromatography (silica gel, n-pentane–Et2O 2:1) delivered
4.6. Dimethyl (2S,4S)-2,4-bis[(R)-phenyl-((S)-1-phenyl-
ethylamino)methyl]glutarate 16
CAN [Ce(NH4)2(NO3)6, 6.26 g, 11.4 mmol] was added to a
solution of 7A (1.70 g, 2.24 mmol) in acetonitrile/water
(5:1, 42 mL). After 7 h at rt, satd aq NaHCO3 (340 mL)
18 (239 mg, 491 lmol, 46%) as a colourless solid. Mp
21
66 ꢁC. ½aꢁD ¼ þ15:7 (c 0.10, CHCl3). IR (KBr): m 3063,

1416
M. Breuning, D. Hein / Tetrahedron: Asymmetry 18 (2007) 1410–1418
3030, 2926, 2855, 1740, 1456, 1381, 1219, 768, 699 cmꢀ1
.
759, 699, 460, 423, 411 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d 1.17 (2H, t, J = 6.7 Hz, 3-H, 3-H0), 1.22 (6H, d,
J = 6.6 Hz, 2 · CHCH3), 1.71 (2H, m, 2-H/4-H), 2.16
(2H, dd, J = 12.0, 6.6 Hz, 1-H/5-H), 2.29 (2H, dd,
J = 12.0, 4.3 Hz, 1-H0/5-H0), 2.39 (2H, dd, J = 13.5,
7.1 Hz, 2 · CHHPh), 2.67 (2H, dd, J = 13.5, 7.0 Hz,
2 · CHHPh), 3.56 (2H, q, J = 6.6 Hz, 2 · CHMePh),
7.04–7.10 (4H, m, ArH), 7.12–7.32 (16H, m, ArH). 13C
NMR (100 MHz, CDCl3): d 24.3 (CHCH3), 35.1 (C-3),
37.8 (C-2/C-4), 39.8 (CH2Ph), 50.7 (C-1/C-5), 58.2
(CHMePh), 125.7, 126.6, 126.7, 128.2, 128.3, 129.1,
141.2, 146.0 (ArC). MS (ESI, +): m/z 491 [100, M+H]+,
387 (29), 266 (17). HRMS (ESI, +): calcd for
C35H42N2+H: 491.3426, found: 491.3431.
1H NMR (400 MHz, CDCl3): d 1.24 (6H, d, J = 7.2 Hz,
2 · CHCH3), 1.97 (2H, t, J = 7.9 Hz, 9-H, 9-H0), 2.93
(2H, dt, J = 7.9, 2.1 Hz, 1-H/5-H), 3.89 (2H, d, J =
2.2 Hz, 4-H/8-H), 4.95 (2H, q, J = 7.2 Hz, 2 · CHMePh),
7.04–7.08 (4H, m, ArH), 7.09–7.16 (10H, m, ArH), 7.24–
7.28 (6H, m, ArH). 13C NMR (100 MHz, CDCl3): d 18.5
(CHCH3), 27.2 (C-9), 51.9 (CHMePh), 57.6 (C-1/C-5),
60.4 (C-4/C-8), 126.3, 127.0, 127.6, 128.0, 128.4, 128.5,
138.6, 139.7 (ArC), 169.3 (C@O). HRMS (ESI, +): calcd
for C35H34N2O2+Na: 537.2513, found: 537.2516.
4.9. (1R,2R,5R,6R)-2,6-Diphenyl-3,7-bis((S)-1-phenylethyl)-
3,7-diazabicyclo[3.3.1]nonane 6
4.9.1. From diol 17. Et3N (268 lL, 193.2 mg, 1.91 mmol)
and MsCl (89.2 lL, 132 mg, 1.15 mmol) were slowly added
at 0 ꢁC to a solution of 17 (200 mg, 382 lmol) in anhydrous
CH2Cl2 (20 mL). The reaction was stirred for 2 h at rt and
refluxed for 22 h. The reaction was quenched with satd aq
NH4Cl (40 mL) and extracted with EtOAc (3 · 90 mL).
The combined organic layers were washed with brine
(30 mL), dried over MgSO4 and the solvent removed in
Hydrogenation of 6 with H2 (3 bar) and Pd/C (10 wt %) in
MeOH at 40 ꢁC, with H2 (1 bar) and Pd/C (10 wt %) in
EtOH/6 N HCl at 65 ꢁC, with H2 (1 bar) and Pd(OH)2/C
(10 wt %) in MeOH/AcOH (2:1) at rt, and with NH4HCO2
and Pd/C (10 wt %) in MeOH at 60 ꢁC delivered 19 in 50–
75% yield.
4.10.2. Birch reduction of 6. A solution of 6 (30.0 mg,
61.6 mmol) in anhydrous THF (1 mL) was added at
ꢀ78 ꢁC to liquid ammonia (20 mL). Sodium (2 · 14 mg,
1.22 mmol) was then added in two portions. The reaction
mixture was warmed to rt overnight, quenched with satd
aq NH4Cl (20 mL), and extracted with CH2Cl2
(2 · 30 mL). The combined organic layers were washed
with brine (20 mL), dried over MgSO4 and evaporated.
Column chromatography (silica gel, n-pentane–Et2O 1:1)
delivered 19 (14.5 mg, 29.6 lmol, 48%) as a yellowish oil.
vacuo to give 6 (136 mg, 280 lmol, 73%) as a yellowish
21
solid. Mp 88 ꢁC. ½aꢁD ¼ ꢀ5:5 (c 0.10, CHCl3). IR (KBr):
1
m 2926, 2854, 1656, 1450, 1368, 1261, 1075, 692 cmꢀ1. H
NMR (400 MHz, CDCl3): d 1.18 (6H, d, J = 6.6 Hz,
2 · CHCH3), 1.66 (2H, t, J = 7.2 Hz, 9-H, 9-H0), 2.23
(2H, sext, J = 7.6 Hz, 1-H/5-H), 2.49 (2H, dd, J = 8.6,
6.7 Hz, 4-H/8-H), 3.27 (2H, q, J = 6.6 Hz, CHMePh),
3.40 (2H, d, J = 7.8 Hz, 2-H/6-H), 3.49 (2H, t,
J = 6.9 Hz, 4-H0/8-H0), 6.87–6.95 (10H, m, ArH), 6.95–
7.09 (10H, m, ArH). 13C NMR (100 MHz, CDCl3): d
20.3 (CHCH3), 37.3 (C-9), 38.6 (C-1/C-5), 56.9 (C-4/C-8),
68.7 (CHMePh), 75.5 (C-2/C-6), 126.4, 126.7, 127.3,
127.39, 127.41, 127.9, 142.3, 142.4 (ArC). HRMS (ESI,
+): calcd for C35H38N2+H: 487.3108, found: 487.3110.
Acknowledgements
This work was supported by the Deutsche Forschungs-
gemeinschaft DFG (Emmy Noether fellowship to M.B.)
and the Fonds der Chemischen Industrie. The technical
assistance of Patricia Altenberger is acknowledged.
4.9.2. From the bispidine dilactam 18. Dilactam 18
(106 mg, 205 lmol) was dissolved in anhydrous THF
(2 mL) and cooled to ꢀ78 ꢁC. LiAlH4 (1.0 M in THF,
410 ll, 410 lmol) was added. After 1 h at ꢀ78 ꢁC and 2 h
at rt, the reaction was quenched with satd aq NH4Cl
(20 mL) and extracted with EtOAc (2 · 30 mL). The com-
bined organic layers were washed with brine (30 mL) and
dried over MgSO4. Removal of the solvent under a reduced
pressure and column chromatography (silica gel, n-pen-
tane–EtOAc 1:1) yielded 6 (35.9 mg, 73.7 lmol, 36%) as a
yellowish solid.
References
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¨
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4.10. (2R,4R)-2,4-Dibenzyl-N,N0-bis((S)-1-phenylethyl)-
pentane-1,5-diamine 19
4.10.1. Hydrogenation of 6. A solution of 6 (30.0 mg,
61.6 lmol) in anhydrous EtOH (10 mL) was hydrogenated
over PtO2 (5 mg) under 4 bar H2 pressure for 6 h at 65 ꢁC.
The mixture was filtered through a pad of Celite and
washed with CH2Cl2 (60 mL). Removal of the solvent in
vacuo and column chromatography (silica gel, n-pentane–
2. For the synthesis and application of bispidines with chiral
side chains at the nitrogen atoms, see: (a) Huttenloch, O.;
Spieler, J.; Waldmann, H. Chem. Eur. J. 2001, 7, 671–675; (b)
Spieler, J.; Huttenloch, O.; Waldmann, H. Eur. J. Org. Chem.
2000, 391–399; See also: (c) Huttenloch, O.; Laxman, E.;
Waldmann, H. Chem. Commun. 2002, 673–675; (d) Hutten-
Et2O 1:1) delivered 19 (22.7 mg, 46.2 lmol, 75%) as a yel-
22
lowish oil. ½aꢁD ¼ þ26:9 (c 0.10, CHCl3). IR (KBr): m
3433, 3026, 2924, 2852, 1640, 1494, 1452, 1123, 1030,

M. Breuning, D. Hein / Tetrahedron: Asymmetry 18 (2007) 1410–1418
1417
loch, O.; Laxman, E.; Waldmann, H. Chem. Eur. J. 2002, 8,
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3. For the enantioselective preparation of C1-symmetric 2-
phenyl-9-oxabispidines, see: Breuning, M.; Steiner, M. Syn-
thesis 2007, 1702–1706.
4. (a) Stenhaus, J. Ann. Chem. Pharm. 1851, 78, 1–30; (b) Mills,
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Heterocycles 1992, 33, 1101–1128.
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32. There is only a single literature precedence for the (albeit non-
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1418
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