Synthesis of enantiomerically pure 1,5,7-trimethyl-3-azabicyclo[3.3.1]nonan-2-ones as chiral host compounds for enantioselective photochemical reactions in solution

Article abstract of DOI:10.1055/s-2001-15231

The synthesis of the title compounds is described. As common starting material, 1,5,7-trimethyl-2,4-dioxo-3-azabicyclo[3.3.1]-nonan-7-carboxylic acid chloride (4) was employed which is in turn available from cis,cis-1,3,5-trimethylcyclohexane-1,3,5-tricarboxylic acid (Kemp's triacid). For the synthesis of the diastereomeric menthyl esters 1 and 2, the chloride 4 was initially substituted by (-)-menthol and its imide part was subsequently reduced to an amide by consecutive treatment with sodium borohydride and triethylsilane. The enantiomerically pure hosts 3a and 3b were obtained from the racemate by resolution of their N-menthoxycarbonyl derivatives. The racemic compounds rac-3a and rac-3b were prepared from the acid chloride 4 and the ortho-hydroxyanilines 9a and 9b via amide formation, condensation to the oxazole and reduction. Structural data are provided which prove the absolute configuration of compound ent-3b and the relative configuration of compound rac-3a.

Full text of DOI:10.1055/s-2001-15231

PAPER
1395
Synthesis of Enantiomerically Pure 1,5,7-Trimethyl-3-azabicyclo[3.3.1]nonan-
2-ones as Chiral Host Compounds for Enantioselective Photochemical
Reactions in Solution
Synthesis of
En
h
o
ly
P
ure 1,5,7
r
-Trimeth
s
yl-3-azab
t
icyclo[3
e
.3.1]nonan
n
-
2-ones Bach,*a Hermann Bergmann,b Benjamin Grosch,a Klaus Harms,b,1a Eberhardt Herdtweckc,1b
a
b
c
Technische Universität München, Lehrstuhl für Organische Chemie I, Lichtenbergstr. 4, 85747 Garching, Germany
Philipps-Universität Marburg, Fachbereich Chemie, 35032 Marburg, Germany
Technische Universität München, Lehrstuhl für Anorganische Chemie, Lichtenbergstr. 4, 85747 Garching, Germany
Fax +49(89)28913315; E-mail: thorsten.bach@ch.tum.de
Received 5 February 2001; revised 21 February 2001
Dedicated to Professor Dieter Hoppe on the occasion of his 60th birthday
Abstract: The synthesis of the title compounds is described. As
common starting material, 1,5,7-trimethyl-2,4-dioxo-3-azabicyc-
lo[3.3.1]-nonan-7-carboxylic acid chloride (4) was employed which
is in turn available from cis,cis-1,3,5-trimethylcyclohexane-1,3,5-
tricarboxylic acid (Kemp’s triacid). For the synthesis of the diaste-
reomeric menthyl esters 1 and 2, the chloride 4 was initially substi-
tuted by (–)-menthol and its imide part was subsequently reduced to
an amide by consecutive treatment with sodium borohydride and
triethylsilane. The enantiomerically pure hosts 3a and 3b were ob-
tained from the racemate by resolution of their N-menthoxycarbon-
yl derivatives. The racemic compounds rac-3a and rac-3b were
prepared from the acid chloride 4 and the ortho-hydroxyanilines 9a
and 9b via amide formation, condensation to the oxazole and reduc-
tion. Structural data are provided which prove the absolute config-
uration of compound ent-3b and the relative configuration of
compound rac-3a.
Figure 1 Model of a projected host for the differentiation of enan-
tiotopic faces in prochiral lactams
hibits an effective sterically demanding “shield”. The
requirements for a conceivable host are depicted in
Figure 1.
Key words: supramolecular chemistry, amides, enantiomeric reso-
lution, reductions, photochemistry
In essence, the host should consist of three spatially
aligned substituents (drawn in bold) and a rigid backbone.
One of the most common and easily accessible com-
pounds which offers this spatial alignment is cis,cis-1,3,5-
trimethylcyclohexane-1,3,5-tricarboxylic acid (Kemp’s
triacid).4 Chiral derivatives thereof have been used in mo-
lecular recognition studies5 and have been employed in
enantioselective protonation6 and auxiliary-induced enan-
tioselective C-C-bond forming reactions.7 Our first target
compounds which were conceived to fulfill the require-
ments provided in Figure 1 were the diastereomeric men-
thyl esters 1 and 2 (Figure 2). Since they exhibit opposite
chirality in the bicyclic lactam part we expected them to
behave as if they were enantiomers. In preliminary exper-
iments they proved to be valuable hosts which were supe-
riour to most of the previously used complexing agents.8
Still, a second generation of host compounds 3 was syn-
thesized whose “shield” was flat and due to its greater di-
ameter more effective (Figure 2). They were prepared in
racemic form and subsequently resolved by derivatiza-
tion.
Introduction
In the course of stereoselective organic transformations, a
defined spatial arrangement of substituents is required to
guarantee the differentiation of stereoheterotopic faces.2
Ground state conformations often serve as useful models
to predict the stereochemical outcome of a reaction. This
is the more true if the reacting centre of a molecule is rig-
idly attached to a bulky substituent.
In a recently launched research project, we planned to dif-
ferentiate the enantiotopic faces of lactams by hydrogen
bonding to a suitable chiral host. The goal was to conduct
light-induced reactions within the host-guest complex in a
stereoselective fashion. The host was to serve as a non-co-
valently bound, stoichiometric complexing agent. Previ-
ous attempts to achieve enantioselective photochemical
reactions in solution by chiral complexing agents had en-
countered little success.3 We hoped to overcome the prob-
lems associated with the high conformational flexibility
of many systems by using a rigid host which offers an eas-
ily accessible binding site and which simultaneously ex-
Unfortunately, host 3a turned out to be photochemically
unstable.8 Contrary to that, compound 3b and its enanti-
omer ent-3b were stable. They are currently the premier
chiral complexing agents in use and induced enantioselec-
tivities up to 98% ee in photocycloaddition reactions of
prochiral lactams.9
Synthesis 2001, No. 9, 29 06 2001. Article Identifier:
1437-210X,E;2001,0,09,1395,1405,ftx,en;Z01801SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1396
T. Bach et al.
PAPER
Figure 3 A molecule of compound 5 in the crystal (ORTEP dra-
wing)11
Figure 2 Chiral host compounds 1, 2, and 3 synthesized
previously provided for the above-mentioned imide re-
ductions.11
In this account we report on the synthesis of the host com-
pounds 1, 2 and 3. In addition, structural data are provided
which prove the constitution of lactam rac-3a and the ab-
solute configuration of lactam ent-3b.
With regard to the facial diastereoselectivity the hydride
transfer appears to occur exclusively from one face. As a
consequence only two out of four possible diastereoiso-
mers were isolated. Their relative configuration was not
assigned. Further reduction of the diastereoisomers 6 and
7 with triethylsilane in trifluoroacetic acid (TFA) yielded
the lactams 1 and 2 the ratio of which was identical to the
diastereomeric ratio of their precursors. The lactams were
separated by flash chromatography. The relative configu-
ration of compound 1 was elucidated by single crystal X-
ray crystallography.9a As the absolute configuration of the
menthyl group is known the X-ray analysis provided the
absolute configuration of the 3-azabicyclo[3.3.1]nonan-2-
one skeleton. It additionally proved the regioselectivity of
the above-mentioned borohydride reduction step.
Results and Discussion
Preparation of the Hosts 1 and 2: The synthesis of the di-
astereomeric hosts 1 and 2 is summarized in Scheme 1. It
starts with the alkoxydechlorination of the known acid
chloride 4.7d The menthyl ester 5 was obtained in 79%
yield. Unexpectedly, the reduction of the imide group
with sodium borohydride in methanol occurred with con-
siderable regioselectivity. One diastereotopic carbonyl
group was reduced with a preference of 4:1. Provided that
the major conformer in solution is similar to the solid state
conformation depicted in Figure 3,10 the hydride attack
took place at the carbonyl group which is in proximity to
the bulky iso-propyl group of the menthyl substituent. The
more readily accessible carbonyl group is not reduced. In
succinimide and maleimide reductions, there is prece-
dence for a similar reaction course. The carbonyl group
adjacent to the most substituted carbon is reduced by so-
dium borohydride with significant regioselectivity.11 Con-
trary to that, succinimide12 and glutarimide13 reductions
which were conducted with di-iso-butylaluminum hy-
dride (Dibal-H) or lithium tri(sec-butyl)borohydride (L-
Selectride) occurred at the carbonyl group remote from
the larger ring substituent. Chelation14 and complexation15
have been shown to play an important role in the regiose-
lectivity of these reactions. We have not further studied
the effect of the counter ion on the regioselectivity of the
borohydride reductions nor have we investigated the in-
fluence of the reducing agent more closely. To account for
the observed regioselectivity we rely on the explanation
The saponification of the menthyl esters 1 and 2 was fa-
vorably conducted with sodium hydroxide in DMSO
(Scheme 1). The acid 8 was obtained from ester 1. Ester 2
yielded the enantiomeric acid ent-8. As we considered the
acids to be suitable precursors for the synthesis of ox-
azoles 3 and ent-3 we looked into possible activation
methods for the carboxyl group. It turned out that all the
methods we successfully employed [SOCl2; oxalyl chlo-
ride, DMF (cat.); Yamaguchi procedure] led to racemiza-
tion. Presumably, the activation facilitates an
intramolecular attack of the amide nitrogen atom at the
carboxyl group.16 Potential intermediates formed by this
process have a plane of symmetry and consequently yield
racemic products.
Preparation of the Hosts 3: Due to the facile racemization
upon activation of the carboxylic acids 8 and ent-8 the
preparation of the oxazoles was attempted via convention-
al oxazole synthesis and subsequent resolution of the ra-
cemic products. The protocol of Rebek, Curran et al. was
followed which relies on a resolution via the correspond-
ing N-menthoxycarbonyl derivatives.7d Starting again
Synthesis 2001, No. 9, 1395–1405 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Enantiomerically Pure 1,5,7-Trimethyl-3-azabicyclo[3.3.1]nonan-2-ones
1397
R
R
R
(−)-Menthol
DMAP
R
4, py (THF)
H
H
O
N
O
COCl
OH
N
(CH2Cl2)
O
O
H
OH
O
97%
93%
O
O
O
NH
N
O
NH2
79%
4
5
9
10
a:
R, R =
b: R, R =
NaBH4
+
(MeOH)
H
H
O
OH
O
O
O
N
N
O
HO
O
97%
R
R
N
SOCl2, py
(PhH)
1. NaBH4 (EtOH)
2. Et3SiH (TFA)
6
7
rac-3
H
O
96%
87%
73%
88%
N
O
O
Et3SiH
(TFA)
separation of
diastereoisomers
1
+
2
11
95%
BuLi (THF)
63%
77%
NaOH
R
R
R
R
N
(DMSO)
OCOCl
+
H
H
N
N
R*O
O
O
O
R*O
O
COOH
COOH
O
= R*OCOCl
O
N
O
O
N
N
8
ent-8
68%
91%
Scheme 1
12
13
81%
85%
85%
95%
TFA (CH2Cl2)
with the known acid chloride 4 the aminodechlorination
by the corresponding anilines 9a and 9b17 gave the anil-
ides 10 in excellent yields (Scheme 2). In our hands, it
proved advantageous to conduct the oxazole formation
prior to the reduction of the imide. Consequently, the
amides 10 were treated with thionyl chloride to provide
the oxazole imides 11. The reduction sequence (NaBH4,
3a (14% overall)
3b (28% overall)
ent-3a (15% overall)
ent-3b (30% overall)
Scheme 2
MeOH; Et3SiH, TFA) previously employed for the related Crystallographic Studies: With the advent of modern
imides 6 and 7 furnished the desired oxazole lactams rac- crystallographic techniques and equipment the determina-
3. The resolution proceeded uneventfully and enabled ac- tion of absolute configuration by anomalous X-ray dif-
cess to the enantiomerically pure hosts 3a, 3b, ent-3a and fraction experiments has become possible for compounds
ent-3b. Since compounds 3a and ent-3a were not photo- that do not carry a heavy atom. Due to this development
stable their resolution was conducted only once and the we were able to assign the absolute configuration depicted
yields given in Scheme 2 are not optimized. The synthesis in Figure 4 to the enantiomerically pure compound ent-
of 3b and ent-3b is carried out on a routine basis in our 3b.18 The result is in line with our earlier assignment
laboratories and proved reproducible. Overall, each enan- based on the specific rotation.
tiomer is obtained in ca. 30% yield from the acid chloride
4.
Crystals suitable for X-ray analysis were also obtained
from the racemic host rac-3a. The structure depicted in
The assignment of the absolute configuration of com- Figure 5 nicely illustrates the two key features of our
pounds 3 was initially based on the correlation of their chiral complexing agent.19 First, the naphthalene unit acts
20
specific rotation {3a: [ ]D +42.3 (c = 1, CH2Cl2); 3b: as a fully planar “shield” which covers the back of the host
20
[ ]D +7.4 (c = 1, CHCl3)} with the specific rotation of compound. Secondly, the lactam part of the host binds ef-
20
the known dextrorotatory benzoxazole 3c (R = H) {[ ]D
ficiently to other lactams via hydrogen bonds. In the case
+7.4 (c = 2, CHCl3)} whose absolute configuration had shown, host 3a binds to its sterically complementary
been reported.7d Unfortunately, we could not achieve the enantiomer ent-3a. If enantiomerically pure host com-
crystallization of the diastereomeric compounds 12 or 13. pounds are employed in solution this type of binding is
We finally achieved the crystallization of the enantiomer- impossible due to severe interactions of the naphthalene
ically pure host ent-3b and of the racemic host rac-3a.
backbone. Instead, the photochemical substrate coordi-
nates to the host, a fact which in turn enables the differen-
tiation of the enantiotopic faces.
Synthesis 2001, No. 9, 1395–1405 ISSN 0039-7881 © Thieme Stuttgart · New York

1398
T. Bach et al.
PAPER
Conclusion and Outlook
In summary, we have described the synthesis of the host
compounds 1, 2 and 3, which are valuable chiral complex-
ing agents used in photochemical transformations. The
starting material for all syntheses is the achiral imide 4,
which is readily available from Kemp’s triacid. Modifica-
tions of the host systems for application in other thermal
and photochemical reactions are possible and are project-
ed in the course of further investigations. Results of these
studies will be reported in due course.
All reactions involving water-sensitive compounds were carried out
in flame-dried glassware with magnetic stirring under Ar. Common
solvents (TBME = t-BuOMe, Et2O, P = pentane, CH2Cl2, MeOH
and EtOH) were distilled prior to use. Anhyd CH2Cl2 was distilled
from CaH2, anhyd benzene and THF from Na prior to use. Et3N was
distilled from CaH2. All other reagents and solvents were used as re-
ceived. Melting points (uncorrected): Reichert hot bench. IR: Bruk-
er IFS 88 FT-IR or Nicolet 510M FT-IR. MS: Varian CH7 (EI). 1H
and 13C NMR: Bruker ARX-200, Bruker AC-300, Bruker AM-400,
Bruker AMX-500, Varian unit plus 600. 1H and 13C NMR spectra
were recorded in CDCl3 as solvent at ambient temperature unless
stated otherwise. Chemical shifts are reported relative to TMS as an
internal reference. Elemental analysis: Elementar vario EL. Optical
rotations: Perkin-Elmer 241, determined at r.t. HPLC: Merck-Hita-
chi L6200A equipped with an UV spectrometer detector (254 nm).
Column: Daicel Chiralcel OD. TLC: Merck aluminum sheets (0.2
mm silica gel 60 F254. Detection: by UV or by coloration with ceric
ammonium molybdate (CAM). Flash chromatography:20 Merck sil-
ica gel 60 (230–400 mesh ASTM) (ca 50 g for 1 g of material to be
separated).
Figure 4 ORTEP drawing of the molecular structure of ent-3b in
the solid state. Thermal ellipsoids are at the 30 % probability level18
Imide Ester 5 by Esterification of Acid Chloride 4 with
(–)-Menthol
Acid chloride 47d (17.9 mmol, 4.60 g), (–)-menthol (32.0 mmol,
5.00 g) and N,N-dimethylaminopyridine (DMAP) (18.0 mmol, 2.20
g) were dissolved in anhyd CH2Cl2 (100 mL) and the solution was
refluxed. After 24 h another lot of DMAP (2.20 g, 18.0 mmol) was
added and after additional 24 h of reflux the solution was allowed
to cool to r.t. H2O (100 mL) and CH2Cl2 (400 mL) were added, the
layers separated and the aqueous layer was extracted with CH2Cl2
(2 100 mL). The combined organic layers were washed with H2O
(25 mL), 1 N HCl (25 mL), sat. aq NaHCO3 solution (25 mL) and
brine (25 mL). The combined aqueous layers were extracted with
CH2Cl2 (100 mL), were washed with brine (50 mL), dried (MgSO4)
and concentrated in vacuo to give a yellow oil (9.40 g). Purification
of this material by flash chromatography (P–TBME, 3:1) gave a
white solid (5.31 g, 79%); Rf 0.14 (P–TBME, 75:25); mp 154°C;
[ ]D20–40.6 (c = 1.1, CH2Cl2).
IR (KBr): = 3212 (m, br, NH), 3098 (m, NH), 2959 (s, CH), 2930
(s, CH), 2872 (s, CH), 1719 (s, C=O), 1696 (vs, C=O), 1462 (m),
1383 (m), 1208 (vs), 1179 cm–1 (s).
1H NMR (500 MHz, CDCl3): = 0.62 (d, 3 H, 3J = 7.0 Hz,
CH3CHCH3), 0.78–0.82 (m, 1 H, CH3CHCHHCH2), 0.83 (d, 3 H,
3J = 7.0 Hz, CH3CHCH3), 0.86 [d, 3 H, 3J = 6.6 Hz, CH3CH(CH2)2],
0.89–0.96 (m, 2 H, CO2CHCHHCH, CH3CHCH2CHH), 1.07 (d, 1
2
H, J = 14.0 Hz, OCOCCHH), 1.12–1.16 (m, 1 H, OCOCCHH),
1.16 (s, 3 H, CH3CCO2), 1.19 (s, 3 H, CH3CCONH), 1.20 (s, 3 H,
2
CH3CCONH), 1.31 (d, 1 H, J = 13.3 Hz, NHCOCCHHCCONH),
1.31–1.40 [m, 2 H, (CH3)2CHCH, CH3CH(CH2)2], 1.53–1.65 (m, 2
Figure 5 Two molecules of compound 3a and ent-3a in the crystal
3
3
(ORTEP drawing)19
H, CH3CHCHHCHH), 1.78 [dsep, 1 H, J = 7.0 Hz, J = 2.8 Hz,
(CH3)2CH], 1.87–1.96 (m, 1 H, CO2CHCHH), 1.92 (d, 1 H,
2
2J = 13.3 Hz, NHCOCCHHCCONH), 2.62 (d, 1 H, J = 14.1 Hz,
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Synthesis of Enantiomerically Pure 1,5,7-Trimethyl-3-azabicyclo[3.3.1]nonan-2-ones
1399
OCOCCHH), 2.68 (d, 1 H, 2J = 14.0 Hz, OCOCCHH), 4.52 (dt, 1 H,
3J = 10.9 Hz, 3J = 4.4 Hz, CO2CH), 7.91 (br s, 1 H, NH).
NHCHOHCHHCCO2), 4.49 (d, 1 H, 3J = 13.0 Hz, CONHCHOH),
3
4.57–4.63 (m, 1 H, CO2CH), 4.79 (d, J = 13.0 Hz, 1 H, CONH-
1
CHOH), 5.26 (br s, 1 H, NH). All other H NMR signals overlap
13C NMR (125 MHz, CDCl3): = 15.3 (q, CH3CHCH3), 20.6 (q,
CH3CHCH3), 21.8 [q, CH3CH(CH2)2], 22.5 (t, CH3CHCH2CH2),
24.1 (q, CH3CCONH), 24.2 (q, CH3CCONH), 25.3 (d,
CH3CHCH3), 30.8 (q, CH3CO2), 31.0 [d, CH3CH(CH2)2], 33.8 (t,
CH3CHCH2CH2), 39.1 (t, CO2CHCH2CH), 39.5 (s, CCONH), 39.6
(s, CCONH), 41.8 (s, OCOCCH3), 43.0 (t, OCOCCH2), 43.6 (t,
OCOCCH2), 44.1 (t, CH2CCONH), 46.5 (d, (CH3)2CHCH), 75.2 (d,
CO2CH), 174.2 (s, OCO), 175.7 (s, CONH), 176.1 (s, CONH).
with signals of the major diastereoisomer 6.
13C NMR (125 MHz, CDCl3): = 15.6 (q, CH3CHCH3), 20.9 (q,
CH3CHCH3), 21.9 (q, CH3CH(CH2)2), 22.6 (t, CH3CHCH2CH2),
24.7 (d, CH3CHCH3), 24.8 (q, CH3CCONH), 27.3 (q,
CH3CCHOHNH), 31.4 [d, CH3CH(CH2)2], 32.4 (q, CH3CCO2),
34.0 (t, CH3CHCH2CH2), 35.8 (s, CCHOHNH), 38.2 (s, CCONH),
39.2 (t, CO2CHCH2CH), 40.0 (t, NHCHOHCCH2CCO2), 42.6 (s,
CH3CCO2), 44.5 (t, NHCOCCH2CCHOHNH), 44.8 (t,
NHCOCCH2), 46.5 [d, (CH3)2CHCH], 76.7 (d, CO2CH), 84.9 (d,
CHOH), 174.6 (s, OCO), 179.0 (s, CONHCHOH).
MS (EI, 70 eV): m/z (%) = 240 (71), 194 (84), 166 (48), 138 (75),
123 (41), 110 (41), 95 (70), 83 (100), 69 (60), 57 (63), 41 (43).
Anal. Calcd for C22H35NO4 (377.5): C, 69.99; H, 9.34; N, 3.71.
Found C, 69.71; H, 9.29; N, 3.60.
Chiral Hosts 1 and 2 by Reduction of N,O-Hemiacetals 6 and 7
The mixture of diastereoisomers 6/7 (7.24 mmol, 2.75 g) was dis-
solved in TFA (25 mL) and triethylsilane (9 mL, 6.54 g, 56.2 mmol)
was added. The mixture was stirred vigorously at r.t. for 5 h.
CH2Cl2 (250 mL) and sat. aq NaHCO3 solution (100 mL) were add-
ed. Solid NaHCO3 was added until gas formation ceased and the pH
value was adjusted to 6–7. The precipitate was filtered off, and the
layers were separated. The aqueous layer was extracted with
CH2Cl2 (3 50 mL). The combined organic layers were washed
with brine (25 mL), dried (MgSO4) and concentrated in vacuo to
give a yellow oil (3.68 g), consisting of the two diastereoisomers.
The crude product was purified and separated by flash chromatog-
raphy (P–TBME, 3:1) to give the diastereoisomers 1 (2.01 g, 76%)
and 2 (0.50 g, 19%) as white solids.
N,O-Hemiacetals 6 and 7 by Reduction of Imide 5
Solid NaBH4 (45.0 mmol, 1.70 g) was added in small portions over
2 h to a stirred solution of imide 5 (1.19 mmol, 450 mg) in MeOH
(40 mL) at 0 °C. The mixture was stirred overnight (H2 formation)
and poured into cold water (150 mL). A white precipitate formed.
After filtration, CH2Cl2 (100 mL) was added to the filtrate. The lay-
ers were separated and the aqueous layer was extracted with CH2Cl2
(3 50 mL). The combined organic layers were washed with sat. aq
NaHCO3 solution (25 mL) and brine (25 mL), dried (MgSO4) and
concentrated in vacuo to give a white solid (440 mg, 97%), consist-
ing of two diastereoisomers (dr 6/7 = 4:1) which were not separated;
Rf 0.39 (P–TBME, 1:3); mp 176 °C.
IR (KBr): = 3117 (s, br, NH), 3000 (s, CH), 1723 (s, C=O), 1436
(m), 1404 (m), 1241 (s), 1191 (s), 1164 (s), 1052 cm–1 (s).
MS (EI, 70 eV): m/z (%) = 379 (0.8) [M+], 362 (0.2) [M+ – OH], 361
(2), 242 (11), 224 (100) [M+ – menthyl], 196 (34) [224 – CO], 168
(20), 123 (40), 95 (22), 83 (42), 69 (20), 55 (31), 41 (21).
(1R,5S,7S)-1,5,7-Trimethyl-2-oxo-3-azabicyclo[3.3.1]-nonan-7-
carboxylic Acid Menthyl Ester (1)
Rf 0.27 (P–TBME, 1:1); mp 122 °C; [ ]D20–14.5 (c = 1, CH2Cl2).
IR (KBr): = 3375 (s, NH), 2959 (s, CH), 2866 (s, CH), 1720 (s,
C=O), 1666 (s, C=O), 1486 (m), 1454 (m), 1268 (s), 1188 cm–1(s).
Anal. Calcd for C22H37NO4 (379.5): C, 69.62; H, 9.82; N, 3.69.
Found C, 69.77; H, 9.60; N, 3.59.
1H NMR (500 MHz, CDCl3): = 0.61 (d, 3 H, 3J = 7.0 Hz,
CH3CHCH3), 0.76–0.80 (m, 1 H, CH3CHCHHCH2CH), 0.79 (d, 3
H, 3J = 7.0 Hz, CH3CHCH3), 0.83 [d,
3
H, 3J = 6.6 Hz,
Major Diastereoisomer 6
1H NMR (500 MHz, CDCl3): = 0.64 (d, 3 H, 3J = 7.0 Hz,
CH3CHCH3), 0.83 (d, 3 H, 3J = 7.0 Hz, CH3CHCH3), 0.83–0.87 (m,
2 H, CH3CHCH2CHHCH, NHCHOHCCHHCCO2), 0.88 [d, 3 H,
3J = 6.6 Hz, CH3CH(CH2)2], 0.90–0.96 (m, 1 H, CH3CHCHHCH2),
CH3CH(CH2)2], 0.89 (s, 3 H, NHCH2CCH3), 0.90–0.96 (m, 2 H,
CH3CHCH2CHH, NHCOCCHHCCO2), 0.97 (d, 1 H, 2J = 13.9 Hz,
CONHCH2CCHHCCO2), 1.05–1.09 (m, 1 H, CO2OCHCHH), 1.06
(s, 3 H, NHCOCCH3), 1.08 (s, 3 H, CH3CCO2), 1.15 (d, 1 H,
2J = 12.8 Hz, NHCOCHHCCHOHNH), 1.30–1.44 (m, 2 H,
1.00 (s,
3
H, NHCHOHCCH3), 1.04–1.13 (m,
2
H,
[CH3)2CHCH,
CH3CHCHHCHHCH), 1.63 (d,
CH3CH(CH2)2],
1.53–1.59
(m,
2
H,
NHCOCCHHCCO2, CO2CHCHH), 1.08 (s, 3 H, NHCOCCH3),
1.16 (s, 3 H, CH3CCO2), 1.23 (d, 1 H, 2J = 13.4 Hz, NHCOCCHH-
CCHOHNH), 1.37–1.40 [m, 1 H, CH3CH(CH2)2], 1.40–1.44 [m, 1
H, (CH3)2CHCH], 1.57–1.63 (m, 2 H, CH3CHCHHCHH), 1.71 (d,
1
H, 2J = 12.8 Hz,
3
3
NHCOCCHHCCH2NH), 1.82 [dsep, 1 H, J = 6.9 Hz, J = 2.6 Hz,
(CH3)2CH], 1.85–1.91 (m, 1 H, CO2CHCHH), 2.47 (d, 1 H,
2J = 14.0 Hz, NHCOCCHHCCO2), 2.54 (d, 1 H, 2J = 13.9 Hz,
CONHCH2CCHHCCO2), 2.94 (d, 1 H, 2J = 11.3 Hz, CONHCHH),
3.14 (d, 1 H, 2J = 11.3 Hz, CONHCHH), 4.44 (dt, 1H, 3J = 11.0 Hz,
3J = 4.3 Hz, CO2CH), 4.97 (br s, 1 H, NH).
2
1 H, J = 13.4 Hz, NHCOCCHHCCHOHNH), 1.80 [dsep, 1 H,
3J = 7.0 Hz, 3J = 2.9 Hz, (CH3)2CH], 1.93–1.98 (m,
1 H,
CO2CHCHH), 2.59 (d, 1 H, 2J = 14.0 Hz, NHCOCCHHCCO2), 2.62
(d, 1 H, 2J = 15.1 Hz, NHCHOHCCHHCCO2), 4.50 (d, 1 H,
3J = 13.0 Hz, CONHCHOH), 4.54 (dt, 1 H, 3J = 11.0 Hz, 3J = 4.4 Hz,
CO2CH), 4.84 (d, 1 H, 3J = 13.0 Hz, CONHCHOH), 5.32 (br s, 1 H,
NH).
13C NMR (125 MHz, CDCl3): = 15.4 (q, CH3CHCH3), 20.7 (q,
CH3CHCH3), 21.9 [q, CH3CH(CH2)2], 22.7 (t, CH3CHCH2CH2),
24.9 (q, CH3CCONH), 25.6 (d, CH3CHCH3), 28.8 (q,
CH3CCH2NH), 30.3 (s, CCH2NH), 31.3 [d, CH3CH(CH2)2], 31.6
(q, CH3CCO2), 33.9 (t, CH3CHCH2CH2), 38.1 (s, CCONH), 39.0 (t,
CO2CHCH2CH), 42.4 (s, CH3CCO2), 44.6 (t, NHCH2CCH2), 45.0
(t, NHCOCCH2CCH2NH), 46.2 (t, NHCOCCH2), 46.4 [d,
(CH3)2CHCH], 52.9 (t, CONHCH2), 75.1 (d, CO2CH), 174.7 (s,
OCO), 175.5 (s, CONH).
13C NMR (125 MHz, CDCl3): = 15.4 (q, CH3CHCH3), 20.7 (q,
CH3CHCH3), 21.9 [q, CH3CH(CH2)2], 22.8 (t, CH3CHCH2CHH),
24.6 (q, CH3CCONH), 25.7 (d, CH3CHCH3), 27.3 (q,
CH3CCHOHNH), 31.3 [d, CH3CH(CH2)2], 31.7 (q, CH3CCO2),
33.9 (t, CH3CHCH2CH2), 35.8 (s, CCHOHNH), 38.1 (s, CCONH),
38.8 (t, CO2CHCH2CH), 39.6 (t, NHCHOHCCHH), 42.7 (s,
CH3CCO2), 44.5 (t, NHCOCCH2CCHOHCNH), 44.7 (t,
NHCOCCH2), 46.4 [d, (CH3)2CHCH], 76.7 (d, CO2CH), 84.9 (d,
CHOH), 174.5 (s, OCO), 179.4 (s, CONHCHOH).
MS (EI, 70 eV): m/z (%) = 363 (26) [M+], 225 (100) [RCO2H+], 208
(14) [M+ – menthyl], 180 (31) [208 – CO], 151 (30), 124 (21), 107
(9), 96 (11), 83 (27), 70 (42), 55 (33).
Anal. Calcd for C22H37NO3 (363.5): C, 72.69; H, 10.26; N, 3.85.
Found C, 72.41; H, 10.09; N, 4.13.
Minor Diastereoisomer 7
1H NMR (500 MHz, CDCl3): = 2.55 (d, 1 H, 2J = 15.7 Hz,
NHCOCCHHCCO2),
2.58
(d,
1
H,
2J = 16.1
Hz,
Synthesis 2001, No. 9, 1395–1405 ISSN 0039-7881 © Thieme Stuttgart · New York

1400
T. Bach et al.
PAPER
(1S,5R,7R)-1,5,7-Trimethyl-2-oxo-3-azabicyclo[3.3.1]-nonan-7-
ent-8
carboxylic Acid Menthyl Ester (2)
Rf 0.13 (P–TBME, 1:1); mp 176 °C; [ ]D
The chiral ester 2 (1.10 mmol, 0.40 g) was saponified in analogy to
the aforementioned procedure to give a white solid of the acid ent-
8 (308 mg, 7%); [ ]D20–166 (c = 1.98, CH2Cl2).
20
5.4 (c = 1, CH2Cl2).
IR (KBr): = 3208 (m, NH), 3087 (m, NH), 2957 (s, CH), 2928 (s,
CH), 1728 (s, C=O), 1673 (s, C=O), 1495 (w), 1458 (w), 1272 (m),
1191 cm–1 (s).
1H NMR (500 MHz, CDCl3): = 0.64 (d, 3 H, 3J = 6.4 Hz,
CH3CHCH3), 0.77–0.79 (m, 1 H, CH3CHCHHCH2), 0.80–0.85 [m,
6 H, CH3CHCH3, CH3CH(CH2)], 0.86–0.88 (m, 1 H, CO2CHCHH),
Anilides 10 by Aminodechlorination of the Acid Chloride 4 with
the Anilines 9
1,5,7-Trimethyl-2,4-dioxo-3-azabicyclo[3.3.1]-nonan-7-carboxylic
Acid (3´-Hydroxynaphthalene-2´-yl)amide (10a)
0.91 (s,
3
H, CONHCH2CCH3), 0.92–0.96 (m,
2
H,
A stirred solution of acid chloride 4 (1.77 mmol, 465 mg) in THF
(15 mL) was treated with 9a (2.25 mmol, 370 mg) and pyridine
(0.21 mL, 206 mg, 2.60 mmol). The mixture was heated under re-
flux for 15 h and evaporated. Without further workup, the crude
product was purified by flash chromatography (TBME–P, 1:1
TBME) to give a white solid (656 mg, 97%); Rf 0.12 (P–TBME,
1:1); mp 264–266 °C.
CONHCH2CCHHCCO2, CH3CHCH2CHH), 1.01–1.03 (m, 1 H,
NHCOCCHHCCOC), 1.07 (s, 3 H, NHCOCCH3), 1.09 (s, 3 H,
OCOCCH3), 1.15–1.19 (m, 1 H, NHCOCCHHCCH2NH), 1.29–
1.37 [m, 1 H, (CH3)2CHCH], 1.38–1.45 [m, 1 H, CH3CH(CH2)2],
1.58–1.66 (m, 3 H, NHCOCCHHCCH2NH, CH3CHCHHCHH),
1.87–1.95 [m, 2 H, CO2CHCHH, (CH3)2CH], 2.42 (d, 1 H, 2J = 14.1
Hz, NHCOCCHHCCO2), 2.59 (d,
1
H, 2J = 13.9 Hz,
CONHCH2CCHHCCO2), 2.98 (d, 1 H, 2J = 11.4 Hz, CONHCHH),
3.12 (d, 1 H, 2J = 11.4 Hz, CONHCHH), 4.60 (dt, 1 H, 3J = 10.8 Hz,
3J = 4.2 Hz, CO2CH), 5.24 (br s, 1 H, NH).
IR (KBr): = 3419 (m, NH), 3197 (m, NH), 2968 (m, CH), 2870
(m, CH), 1730 (s, C=O), 1698 (vs, C=O), 1589 (s), 1240 (m), 1204
cm–1 (s).
13C NMR (125 MHz, CDCl3): = 15.5 (q, CH3CHCH3), 20.8 (q,
CH3CHCH3), 21.9 [q, CH3CH(CH2)2], 22.7 (t, CH3CHCH2CH2),
25.0 (q, CH3CCONH), 25.0 (d, CH3CHCH3), 28.8 (q,
CH3CCH2NH), 30.3 (s, CCH2NH), 31.2 [d, CH3CH(CH2)2], 31.7
(q, CH3CCO2), 34.1 (t, CH3CHCH2CH2), 38.1 (s, CCONH), 40.2 (t,
1H NMR (500 MHz, DMSO-d6): = 1.13 (s, 6 H, CH3), 1.24 (s, 3
H, CH3), 1.35 (d, 2 H, 2J = 14.1 Hz, CHH), 1.44 (d, 1 H, 2J = 12.9
Hz, CHH), 1.91 (d, 1 H, 2J = 12.9 Hz, CHH), 2.54 (d, 2 H, 2J = 14.1
Hz, CHH), 7.16 (s, 1 H, arom H), 7.26 (virt. t, 1 H, 3J = 6.6 Hz, arom
H), 7.31 (virt. t, 1 H, 3J = 6.8 Hz, arom H), 7.63 (d, 1 H, 3J = 7.9 Hz,
arom H), 7.69 (d, 1 H, 3J = 7.9 Hz, arom H), 8.30 (s, 1 H, arom H),
8.59 (s, 1 H, NH), 10.30 (br s, 1 H, OH), 10.41 (s, 1 H, NH).
13C NMR (125 MHz, DMSO-d6): = 24.6 (q, 2 C, CH3), 27.0 (s, C),
31.3 (q, CH3), 42.9 (s, 2 C, C), 43.4 (t, 2 C, CH2), 43.5 (t, CH2),
108.8 (d, CHar), 119.1 (d, CHar), 123.4 (d, CHar), 125.1 (d, CHar),
125.8 (d, CHar), 127.3 (d, CHar), 127.9 (s, Car), 128.0 (s, Car), 131.1
(s, Car), 147.6 (s, Car), 173.0 (s, CO), 177.0 (s, 2 C, CO).
CO2CHCH2CH),
42.3
(s,
CH3CCO2),
45.1
(t,
NHCOCCH2CCH2NH), 45.3 (t, NHCH2CCH2), 45.9 (t,
NHCOCCH2), 47.0 (d, (CH3)2CHCH), 52.9 (t, CONHCH2), 74.4 (d,
CO2CH), 174.8 (s, OCO), 175.2 (s, CONH).
MS (EI, 70 eV): m/z (%) = 363 (8) [M+], 225 (100) [RCO2H+], 208
(30) [M+ – menthyl], 180 (36) [208 – CO], 151 (27), 123 (23), 107
(12), 95 (18), 83 (22), 70 (26), 55 (27).
Anal. Calcd for C22H37NO3 (363.5): C, 72.69; H, 10.26; N, 3.85.
Found C, 72.41; H, 10.50; N, 3.82.
MS (EI, 70 eV): m/z (%) = 380 (21) [M+], 194 (4) [M+ – CON-
HArOH], 166 (12), 159 (100) [NH2ArOH+], 110 (27).
Anal. Calcd for C22H24N2O4 (380.4): C, 69.46; H, 6.36; N, 7.36.
Found C, 68.93; H, 6.37; N, 7.40.
Acids 8 and ent-8 by Saponification of the Chiral Hosts 1 and 2
A solution of chiral host 1 (7.43 mmol, 2.70 g) in 2 N NaOH (100
mL) and DMSO (180 mL) was heated under reflux for 4 h and al-
lowed to cool to r.t. H2O (100 mL) was added, and the mixture was
extracted with TBME (100 mL). The layers were separated and the
organic layer was discarded. The aqueous layer was adjusted to pH
1 with 1 N HCl and extracted with TBME (3 200 mL). The com-
bined organic layers were washed with brine, dried (MgSO4) and
concentrated in vacuo to give 8 as a white solid (1.05 g, 63%); mp
250–255 °C; [ ]D20 +167 (c = 1, CH2Cl2).
HRMS (EI): C22H24N2O4, m/z calcd 380.1736, found 380.1733;
C2113C1H24N2O4, m/z calcd 381.1769, found 381.1765.
1,5,7-Trimethyl-2,4-dioxo-3-azabicyclo[3.3.1]-nonan-7-carboxylic
Acid (3´-Hydroxy-5´,6´,7´,8´-tetrahydronaphthalene-2´-yl) Amide
(10b)
A solution of 9b18 (5.90 mmol, 1.44 g) in THF (60 mL) and pyridine
(1.11 mL, 1.09 g, 13.7 mmol) was added to a stirred solution of the
acid chloride 4 (4.90 mmol, 1.26 g) in THF (30 mL). The mixture
was heated under reflux for 16 h and evaporated. The crude product
was dissolved in CH2Cl2 (80 mL) and washed with H2O (2 20
mL), 1 N HCl (3 20 mL) and brine (20 mL). The organic layer was
dried (MgSO4), concentrated in vacuo, and purified by flash chro-
matography (TBME–P, 1:1 TBME) to give a white solid (1.75 g,
93%); Rf 0.13 (P–TBME, 1:1); mp 210 °C.
IR (KBr): = 3263 (m, br, NH), 3198 (m, br, NH), 2960 (m, CH),
2929 (m, CH), 1693 (s, C=O), 1629 (m, C=O), 1493 (m), 1458 (m),
1213 cm–1 (m).
1H NMR (500 MHz, CDCl3): = 0.91 (s, 3 H, CH3), 0.91–0.94 (m,
2
1 H, CHH), 1.00 (d, 1 H, J = 13.8 Hz, CHH), 1.09 (s, 3 H, CH3),
1.13 (s, 3 H, CH3), 1.16 (d, 1 H, 2J = 12.8 Hz, CHH), 1.63 (d, 1 H,
2J = 12.8 Hz, CHH), 2.36 (d, 1 H, 2J = 14.1 Hz, CHH), 2.60 (d, 1 H,
2J = 13.8 Hz, CHH), 2.96 (d, 1 H, 2J = 12.1 Hz, CONHCHH), 3.18
(d, 1 H, 2J = 12.1 Hz, CONHCHH), 8.57 (br s, 1 H, NH).
IR (KBr): = 3400 (m, NH), 3182 (m, NH), 2918 (m, CH), 1721 (s,
C=O), 1695 (vs, C=O), 1380 (m), 1211 cm–1 (s).
1H NMR (500 MHz, CDCl3): = 1.27 (s, 6 H, CH3), 1.33 (s, 3 H,
CH3), 1.34 (d, 2 H, 2J = 14.5 Hz, CHH), 1.41 (d, 1 H, 2J = 13.3 Hz,
CHH), 1.69–1.77 (m, 4 H, ArCH2CH2CH2), 1.99 (d, 1 H, 2J = 13.3
Hz, CHH), 2.58–2.71 (m, 6 H, ArCH2CH2CH2CH2, CHH), 6.66 (s,
1 H, arom H), 6.80 (s, 1 H, arom H), 7.56, 7.59, 7.93 (br s, 3 H, NH,
NH, OH).
13C NMR (125 MHz, CDCl3): = 23.0 (t, ArCH2CH2), 23.2 (t,
ArCH2CH2), 24.2 (q, 2 C, CH3), 28.5 (t, ArCH2), 28.9 (t, ArCH2),
31.8 (q, CH3), 40.1 (s, 2 C, C), 42.9 (s, C), 44.3 (t, 3 C, CH2), 105.0
13C NMR (125 MHz, CDCl3): = 24.3 (q, CH3), 29.0 (q, CH3), 30.2
(s, C), 31.2 (q, CH3), 38.3 (s, C), 42.4 (s, C), 44.5 (t, CH2), 45.4 (t,
CH2), 45.5 (t, CH2), 52.9 (t, CONHCH2), 178.7 (s, CO), 181.7 (s,
CO).
MS (EI, 70 eV): m/z (%) = 252 (46) [M+], 208 (7) [M+ – CO2], 207
(20), 181 (7), 180 (16), 151 (39), 124 (79), 123 (57), 121 (34), 109
(23), 107 (39), 95 (43), 81 (40), 70 (100), 55 (34), 41 (52).
HRMS (EI): C12H19NO3, m/z calcd 225.1365, found 225.1363;
C1113C1H19NO3, m/z calcd 226.1399, found 226.1395.
Synthesis 2001, No. 9, 1395–1405 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Enantiomerically Pure 1,5,7-Trimethyl-3-azabicyclo[3.3.1]nonan-2-ones
1401
(s, Car), 119.5 (d, CHar), 123.0 (d, CHar), 129.4 (s, Car), 136.3 (s, Car),
146.6 (s, Car), 173.8 (s, CO), 176.6 (s, 2 C, CO).
(t, CH2), 110.0 (d, CHar), 119.4 (d, CHar), 133.6 (s, Car), 134.6 (s,
Car), 138.9 (s, Car), 148.6 (s, Car), 168.5 (s, CN), 175.8 (s, 2 C, CO).
MS (EI, 70 eV): m/z (%) = 384 (19) [M+], 163 (100)
MS (EI, 70 eV): m/z (%) = 366 (100) [M+], 351 (5), 267 (8), 214
(43), 187 (5), 174 (6), 145 (10), 110 (7), 81 (2).
[NH2C10H10OH+], 135 (3), 110 (11).
Anal. Calcd for C22H28N2O4 (384.5): C, 68.73; H, 7.34; N, 7.29.
Found C, 68.47; H, 7.21; N, 7.31.
Anal. Calcd for C22H26N2O3 (366.5): C, 72.11; H, 7.15; N, 7.64.
Found C, 71.86; H, 7.02; N, 7.49.
Oxazoles 11 by Cyclization of the 2-Hydroxyanilides 10
Chiral Hosts rac-3 by Reduction of the Oxazole Imides 11;
Typical Procedure
1,5,7-Trimethyl-7-(1´-oxa-3´-azacyclopenta[b]naphthalene-2´-yl)-
3-azabicyclo[3.3.1]nonan-2,4-dione (11a)
1,5,7-Trimethyl-7-(1´-oxa-3´-azacyclopenta[b]naphthalene-2´-yl)-
3-azabicyclo[3.3.1]nonan-2-one (rac-3a)
Under argon, 2-hydroxyanilide 10a (2.47 mmol, 941 mg) was sus-
pended in benzene (15 mL). Pyridine (1.31 mL, 1.29 g, 16.2 mmol)
and SOCl2 (0.94 mL, 1.54 g, 12.9 mmol) were added successively.
The mixture was heated under reflux for 2 h, and the solvent was re-
moved under reduced pressure. The residue was partitioned be-
tween CH2Cl2 (80 mL) and 1 N HCl (40 mL). The layers were
separated, and the aqueous layer was extracted with CH2Cl2 (20
mL). The combined organic layers were washed with 1 N HCl (40
mL), sat. aq NaHCO3 solution (40 mL), and brine (40 mL), dried
(MgSO4), and concentrated in vacuo to give a brownish solid (857
mg, 96%). This material was sufficiently pure for further use. If re-
quired it can be purified by flash chromatography (TBME–P, 1:1);
Rf 0.55 (P–TBME, 1:3); mp 318–319 °C.
Under argon, oxazole imide 11a (2.30 mmol, 832 mg) was suspend-
ed in anhyd EtOH (200 mL). NaBH4 (92.1 mmol, 3.48 g) was added
in small portions over 1 h at r.t., and the suspension was stirred for
15 h. The mixture was poured into cold H2O (300 mL) and extracted
with CHCl3 (250 mL). The layers were separated, and the aqueous
layer was extracted with an additional amount of CHCl3 (100 mL).
The combined organic layers were washed with sat. aq NaHCO3 so-
lution and brine, dried (MgSO4), and concentrated in vacuo to give
a cream colored solid (888 mg). This material was suspended in
TFA (8 mL), and triethylsilane (3.0 ml, 2.20 g, 18.6 mmol) was add-
ed. The mixture was stirred at r.t. for 4 h. CH2Cl2 (100 mL) and sat.
aq NaHCO3 solution (40 mL) were added. Solid NaHCO3 was add-
ed until gas formation had ceased and a pH value of 6–7 was mea-
sured. The layers were separated, and the aqueous layer was
extracted with CH2Cl2 (3 20 mL). The combined organic layers
were washed with brine (30 mL), dried (MgSO4), and concentrated
in vacuo. The crude product was purified by flash chromatography
(1. TBME–P, 1:1; 2. EtOAc) to give a white solid (582 mg, 73%);
Rf 0.08 (P–TBME, 1:1); mp 292–294 °C.
IR (KBr): = 3434 (m, NH), 3193 (m, NH), 2966 (m, CH), 1696
(vs, C=O), 1322 (m), 1207 cm–1(s).
1H NMR (500 MHz, CD2Cl2): = 0.95 (s, 6 H, CH3), 1.17 (d, 1 H,
2J = 13.1 Hz, CHH), 1.28 (s, 3 H, CH3), 1.32 (d, 2 H, 2J = 14.2 Hz,
CHH), 1.41 (d, 1 H, 2J = 13.1 Hz, CHH), 2.87 (d, 2 H, 2J = 14.2 Hz,
CHH), 7.34–7.40 (m, 2 H, arom H), 7.68 (s, 1 H, arom H), 7.69 (br
s, 1 H, NH), 7.80 (m, 1 H, arom H), 7.85 (m, 1 H, arom H), 7.89 (s,
1 H, arom H).
13C NMR (125 MHz, CD2Cl2): = 24.5 (q, 2 C, CH3), 32.7 (q, CH3),
37.9 (s, C), 40.2 (s, 2 C, C), 44.4 (t, CH2), 44.9 (t, 2 C, CH2), 106.8
(d, CHar), 117.5 (d, CHar), 125.2 (d, CHar), 125.9 (d, CHar), 128.5 (d,
CHar), 129.0 (d, CHar), 131.8 (s, Car), 132.0 (s, Car), 141.7 (s, Car),
149.7 (s, Car), 172.5 (s, CN), 176.8 (s, 2 C, CO).
IR (KBr): = 3440 (m, NH), 3189 (m, NH), 2985 (m, CH), 2952
(m, CH), 1668 (s, C=O), 1560 (m), 1249 cm–1 (m).
1H NMR (500 MHz, CDCl3): = 0.84 (s, 3 H, CH3), 1.01 (s, 3 H,
CH3), 1.09–1.13 (m, 1 H, CHH), 1.20–1.30 (m, 2 H, CHH, CHH),
1.32–1.36 (m, 1 H, CHH), 1.33 (s, 3 H, CH3), 2.77 (d, 1 H, 2J = 11.0
Hz, NHCHH), 2.89 (d, 2 H, 2J = 13.1 Hz, CHH, CHH), 3.22 (d, 1 H,
2J = 11.0 Hz, NHCHH), 5.61 (s, 1 H, NH), 7.40–7.46 (m, 2 H, arom
H), 7.79 (s, 1 H, arom. H), 7.85–7.88 (m, 1 H, arom H), 7.91–7.93
(m, 1 H, arom H), 8.00 (s, 1 H, arom H).
MS (EI, 70 eV): m/z (%) = 362 (100) [M+], 210 (22), 169 (14), 141
(4), 107 (7), 81 (3), 55 (3).
13C NMR (125 MHz, CDCl3): = 24.5 (q, CH3), 29.1 (q, CH3), 30.5
(s, C), 33.1 (q, CH3), 37.7 (s, C), 38.0 (s, C), 44.7 (t, CH2), 45.9 (t,
CH2), 47.0 (t, CH2), 52.6 (t, NCH2), 106.3 (d, CHar), 116.5 (d, CHar),
124.3 (d, CHar), 125.0 (d, CHar), 127.9 (d, CHar), 128.4 (d, CHar),
131.1 (s, Car), 131.2 (s, Car), 141.4 (s, Car), 149.3 (s, Car), 173.4,
174.8 (s, 2 C, CN, CO).
HRMS (EI): C22H22N2O3, m/z calcd 362.1630, found 362.1622;
C2213C1H22N2O3, m/z calcd 363.1663, found 363.1661.
1,5,7-Trimethyl-7-(5´,6´,7´,8´-tetrahydro-1´-oxa-3´-azacyclo-
penta[b]naphthalene-2´-yl)-3-azabicyclo[3.3.1]nonan-2,4-dione
(11b)
Under argon, 2-hydroxyanilide 10b (4.13 mmol, 1.59 g) was sus-
pended in benzene (20 mL), and pyridine (2.17 mL, 2.13 g, 26.9
mmol) and SOCl2 (1.50 mL, 2.45 g, 20.7 mmol) were added. The
mixture was heated under reflux for 3 h, and the solvent was re-
moved under reduced pressure. Without further workup the residue
MS (EI, 70 eV): m/z (%) = 348 (100) [M+], 320 (12) [M+ – CO], 293
(5), 251 (32), 210 (76), 170 (13), 124 (20), 111 (47), 107 (17), 96
(21), 70 (15), 55 (21).
HRMS (EI): C22H24N2O2, m/z calcd 348.1838, found 348.1843;
C2113C1H24N2O2, m/z calcd 349.1871, found 349.1865.
was purified by flash chromatography (TBME–P, 1:2
2:1) to
give a white solid (1.31 g, 87%); Rf 0.27 (P–TBME, 1:1); mp
259 °C.
1,5,7-Trimethyl-7-(5´,6´,7´,8´-tetrahydro-1´-oxa-3´-azacyclopen-
ta[b]naphthalene-2´-yl)-3-azabicyclo[3.3.1]nonan-2-one (rac-3b)
The reduction of the oxazole imide 11b (3.55 mmol, 1.30 g) was
conducted in analogy to the aforementioned preparation of rac-3a.
The crude product was purified by flash chromatography (TBME–
P, 1:1 2:1) to give a white solid (1.08 g, 88%); Rf 0.08 (P–TBME,
1:1); mp 228 °C.
IR (KBr): = 3410 (m, NH), 3182 (m, NH), 2964 (m, CH), 2930
(m, CH), 1702 (s, C=O), 1463 (m), 1377 (m), 1205 cm–1 (m).
1H NMR (500 MHz, CDCl3): = 1.31 (s, 6 H, CH3), 1.38 (s, 3 H,
CH3), 1.44–1.49 (m,
3 H, CHH), 1.78–1.81 (m, 4 H,
ArCH2CH2CH2), 1.99 (virt. dt, 1 H, 2J = 13.3 Hz, 4J = 2.2 Hz, CHH),
2.82–2.88 (m, 4 H, ArCH2CH2CH2CH2), 3.04–3.09 (m, 2H, CHH),
7.01 (br s, 1 H, NH), 7.14 (s, 1 H, arom H), 7.31 (s, 1 H, arom H).
IR (KBr): = 3448 (s, NH), 3199 (m, NH), 2925 (s, CH), 1674 (vs,
C=O), 1556 (m), 1464 cm–1 (s).
1H NMR (500 MHz, CDCl3): = 1.06 (s, 3 H, CH3), 1.21 (s, 3 H,
13C NMR (125 MHz, CDCl3): = 23.0 (t, ArCH2CH2), 23.1 (t,
ArCH2CH2), 24.5 (q, 2 C, CH3), 29.7 (t, ArCH2), 30.0 (t, ArCH2),
32.5 (q, CH3), 37.1 (s, C), 40.0 (s, 2 C, C), 44.5 (t, 2 C, CH2), 44.7
CH3), 1.32 (s, 3 H, CH3), 1.32–1.35 (m, 2 H, CHH), 1.39 (dd, 1 H,
4
2
2J = 14.2 Hz, J = 1.6 Hz, CHH), 1.74 (virt. dt, 1 H, J = 12.8 Hz,
Synthesis 2001, No. 9, 1395–1405 ISSN 0039-7881 © Thieme Stuttgart · New York

1402
T. Bach et al.
PAPER
4J = 2.0 Hz, CHH), 1.78–1.83 (m, 4 H, ArCH2CH2CH2), 2.83–2.88
(m, 4 H, ArCH2CH2CH2CH2), 2.88–2.94 (m, 2 H, CHH, NHCHH),
2.97 (virt. dt, 1 H, 2J = 14.1 Hz, 4J = 1.9 Hz, CHH), 3.25 (virt. dt, 1
H, 2J = 11.4 Hz, 4J = 2.4 Hz, NHCHH), 4.71 (br s, 1 H, NH), 7.18 (s,
1 H, arom H), 7.27 (s, 1 H, arom H).
(s, Car), 150.0 (s, Car), 154.5 (s, NCO2), 173.3, 173.4 (s, 2 C, CO,
CN).
MS (EI, 70 eV): m/z (%) = 530 (4) [M+], 348 (100) [MH+ – CO-
menthyl], 320 (15) [348 – CO], 251 (10), 210 (39), 170 (17), 111
(28), 83 (74), 69 (41), 55 (37).
13C NMR (125 MHz, CDCl3): = 23.1 (t, ArCH2CH2), 23.2 (t,
ArCH2CH2), 25.1 (q, CH3), 29.1 (q, CH3), 29.8 (t, ArCH2), 30.0 (t,
ArCH2), 30.7 (s, C), 33.3 (q, CH3), 37.5 (s, C), 38.4 (s, C), 45.1 (t,
CH2), 45.9 (t, CH2), 47.2 (t, CH2), 52.7 (t, NCH2), 110.3 (d, CHar),
118.7 (d, CHar), 133.1 (s, Car), 134.0 (s, Car), 139.2 (s, Car), 148.7 (s,
Car), 170.5, 174.8 (s, 2 C, CN, CO).
MS (EI, 70 eV): m/z (%) = 352 (64) [M+], 337 (5), 297 (7), 255 (19),
228 (27), 214 (100), 187 (9), 174 (13), 124 (9), 111 (31), 96 (11), 70
(5).
HRMS (EI): C33H42N2O4, m/z calcd 530.3145, found 530.3141;
C3213C1H42N2O4, m/z calcd 531.3179, found 531.3177.
More Polar Diastereoisomer: (1R,5R,7S)-12a
Rf 0.47 (P–TBME, 1:3); mp 73–75 °C; [ ]D20–52.8 (c = 1.0,
CH2Cl2).
IR (KBr): = 2958 (s, CH), 2930 (m, CH), 1772 (s, C=O), 1712 (s,
C=O), 1564 (m), 1458 (m), 1248 cm–1 (s).
1H NMR (500 MHz, CDCl3): = 0.24 (d, 3 H, 3J = 7.0 Hz,
CH3CHCH3), 0.26 (virt. q, 1 H, 2J 3J 12.0 Hz, CHH-menthyl),
0.45–0.55 (m, 1 H, CHH-menthyl), 0.47 (d, 3 H, 3J = 6.6 Hz,
CH2CHCH3), 0.60 (d, 3 H, 3J = 7.0 Hz, CH3CHCH3), 0.63–0.68 (m,
1 H, CHH-menthyl), 0.90–1.03 (m, 2 H, CH-menthyl, CH-menth-
yl), 1.05–1.11 (m, 1 H, CHH-menthyl), 1.08 (s, 3 H, CH3), 1.24 (s,
3 H, CH3), 1.30 (s, 3 H, CH3), 1.30–1.47 (m, 4 H, CHH, CHH,
Anal. Calcd for C22H28N2O2 (352.5): C, 74.97; H, 8.01; N, 7.95.
Found C, 74.66; H, 7.81; N, 8.22.
1,5,7-Trimethyl-2-oxo-7-(1´-oxa-3´-azacyclopenta[b]naphth-
alene-2´-yl)-3-azabicyclo[3.3.1]nonan-3-carboxylic Acid-(–)-
menthyl Esters (12a and 13a); Typical Procedure
BuLi (0.69 mL, 1.72 M in hexanes, 1.19 mmol) was added dropwise
to a stirred solution of the chiral host rac-3a (1.08 mmol, 377 mg)
in THF (20 mL) at –78 °C. After 0.5 h, (–)-menthyl chloroformate
(276 L, 285 mg, 1.30 mmol) was added dropwise. The mixture
was stirred at –78 °C for 45 min and then at 0 °C for 1 h. The reac-
tion was quenched by the addition of sat. aq NH4Cl solution (2 mL),
and concentrated in vacuo. The residue was partitioned between
CH2Cl2 (40 mL) and sat. aq NaHCO3 solution (10 mL). The layers
were separated, and the aqueous layer was extracted with CH2Cl2 (2
10 mL). The combined organic layers were washed with sat. aq
NaHCO3 solution (10 mL) and brine (10 mL), dried (MgSO4), and
concentrated in vacuo. The crude product was purified by flash
chromatography (TBME–P, 1:8 1:3) to yield 12a (196 mg, 34%)
and 13a (196 mg, 34%) as white solids.
2
CHH-menthyl, CHH-menthyl), 1.35 (d, 1 H, J = 14.3 Hz, CHH),
1.43 (dsep, 1 H, 3J = 7.0 Hz, 3J = 2.7 Hz, CH3CHCH3), 1.75 (d, 1 H,
2J = 12.8 Hz, CHH), 2.94 (d, 1 H, 2J = 14.3 Hz, CHH), 3.03 (d, 1 H,
2
4
2J = 14.2 Hz, CHH), 3.08 (dd, 1 H, J = 12.3 Hz, J = 1.5 Hz, NH-
CHH), 3.79 (dd, 1 H, 2J = 12.3 Hz, 4J = 2.2 Hz, NHCHH), 3.95 (dt,
1 H, 3J = 10.9 Hz, 3J = 4.4 Hz, CO2CH), 7.30–7.38 (m, 2 H, arom H),
7.79 (s, 1 H, arom H), 7.79–7.83 (m, 2 H, arom H), 7.94 (s, 1 H,
arom H).
13C NMR (125 MHz, CDCl3): = 15.5 (q, CH3CHCH3), 20.6 (q,
CH3CHCH3), 21.6 (q, CH3CHCH2), 22.7 (t, CH2-menthyl), 25.6 (d,
CH3CHCH3), 26.2 (q, CH3), 29.8 (q, CH3), 30.6 (s, C), 30.8 (d, CH-
menthyl), 33.6 (q, CH3), 33.9 (t, CH2-menthyl), 37.7 (s, C), 39.7 (t,
CH2-menthyl), 41.0 (s, C), 44.0 (t, CH2), 46.2 (t, CH2), 46.3 (d, CH-
menthyl), 47.0 (t, CH2), 57.2 (t, NCH2), 76.6 (d, NCO2CH), 106.5
(d, CHar), 116.6 (d, CHar), 124.3 (d, CHar), 125.0 (d, CHar), 128.0 (d,
CHar), 128.4 (d, CHar), 131.0 (s, Car), 131.4 (s, Car), 141.2 (s, Car),
149.7 (s, Car), 151.8 (s, NCO2), 172.9, 173.9 (s, 2 C, CO, CN).
Less Polar Diastereoisomer: (1S,5S,7R)-13a
Rf 0.57 (P–TBME, 1:3); mp 66–69 °C; [ ]D20–37.4 (c = 1.0,
CH2Cl2).
MS (EI, 70 eV): m/z (%) = 530 (10) [M+], 375 (8), 348 (100) [MH+
– CO-menthyl], 320 (50) [348 – CO], 295 (23), 251 (22), 210 (60),
170 (19), 138 (20), 111 (40), 95 (32), 83 (74), 69 (44), 55 (86).
IR (KBr): = 2957 (s, CH), 2931 (m, CH), 1715 (br, vs, C=O),
1564 (m), 1459 (m), 1264 cm–1 (s).
1H NMR (500 MHz, CDCl3): = -0.65 (virt. q, 1 H, 2J 3J 11.7
Hz, CHH-menthyl), 0.10–0.17 (m, 1 H, CHH-menthyl), 0.12 (d, 3
H, 3J = 6.6 Hz, CH2CHCH3), 0.52 (d, 3 H, 3J = 7.0 Hz, CH3CHCH3),
0.64–0.74 (m, 2 H, CHH-menthyl, CHH-menthyl), 0.80 (d, 3 H,
3J = 7.0 Hz, CH3CHCH3), 0.80–0.94 (m, 2 H, CH-menthyl, CH-
menthyl), 1.16 (s, 3 H, CH3), 1.22–1.27 (m, 1 H, CHH-menthyl),
1.29 (s, 3 H, CH3), 1.35 (s, 3 H, CH3), 1.35–1.39 (m, 1 H, CHH-
menthyl), 1.41 (dd, 1 H, 2J = 12.9 Hz, 4J = 2.5 Hz, CHH), 1.44 (d, 1
HRMS (EI): C33H42N2O4, calcd 530.3145, m/z found 530.3139;
C3213C1H42N2O4, m/z calcd 531.3179, found 531.3174.
1,5,7-Trimethyl-2-oxo-7-(5´,6´,7´,8´-tetrahydro-1´-oxa-3´-
azacyclopenta[b]naphthalene-2´-yl)-3-azabicyclo[3.3.1]nonan-
3-carboxylic Acid-(–)-menthyl Esters (12b and 13b)
The acylation of chiral host rac-3b (1.73 mmol, 605 mg) was per-
formed in analogy to the aforementioned procedure and yielded
compounds 12b (421 mg, 46%) and 13b (419 mg, 45%).
2
2
4
H, J = 14.4 Hz, CHH), 1.47 (dd, 1 H, J = 14.4 Hz, J = 1.8 Hz,
2
3
CHH), 1.84 (d, 1 H, J = 12.9 Hz, CHH), 1.97 (dsep, 1 H, J = 7.0
Hz, 3J = 2.9 Hz, CH3CHCH3), 3.04 (d, 1 H, 2J = 14.4 Hz, CHH), 3.11
(d, 1 H, 2J = 14.4 Hz, CHH), 3.34 (dd, 1 H, 2J = 12.4 Hz, 4J = 1.7 Hz,
NHCHH), 3.72 (dd, 1 H, 2J = 12.4 Hz, 4J = 2.4 Hz, NHCHH), 4.00
(virt. dt, 1 H, 3J = 10.9 Hz, 3J = 4.3 Hz, CO2CH), 7.39–7.45 (m, 2 H,
arom H), 7.84 (s, 1 H, arom H), 7.87–7.93 (m, 2 H, arom H), 8.02
(s, 1 H, arom H).
Less Polar Diastereoisomer (1S,5S,7R)-13b
Rf 0.53 (P–TBME, 1:1); mp 83 °C; [ ]D20–34.7 (c = 1.0, CH2Cl2).
IR (KBr): = 2956 (s, CH), 2931 (m, CH), 2869 (m, CH), 1717 (br,
vs, C=O), 1558 (m), 1464 (s), 1265 cm–1 (s).
1H NMR (500 MHz, CDCl3): = 0.09 (virt. q, 1 H, 2J 3J 11.7 Hz,
13C NMR (125 MHz, CDCl3): = 15.5 (q, CH3CHCH3), 20.9 (q,
CH3CHCH3), 21.0 (q, CH3CHCH2), 22.4 (t, CH2-menthyl), 24.8 (d,
CH3CHCH3), 26.3 (q, CH3), 29.4 (q, CH3), 30.6 (d, CH-menthyl),
30.7 (s, C), 33.5 (t, CH2-menthyl), 34.0 (q, CH3), 37.7 (s, C), 38.3
(t, CH2-menthyl), 41.1 (s, C), 44.7 (t, CH2), 45.9 (d, CH-menthyl),
46.1 (t, CH2), 46.5 (t, CH2), 57.8 (t, NCH2), 77.7 (d, NCO2CH),
106.4 (d, CHar), 116.7 (d, CHar), 124.5 (d, CHar), 125.2 (d, CHar),
127.9 (d, CHar), 128.5 (d, CHar), 131.3 (s, Car), 131.4 (s, Car), 141.5
CHH-menthyl), 0.62 (d, 3 H, 3J = 7.0 Hz, CH3-menthyl), 0.63–0.73
3
(m, 1 H, CHH-menthyl), 0.81 (d, 3 H, J = 6.7 Hz, CH3-menthyl),
0.83–0.91 (m, 1 H, CHH-menthyl), 0.89 (d, 3 H, 3J = 7.1 Hz, CH3-
menthyl), 1.03–1.13 (m, 1 H, CH-menthyl), 1.15 (s, 3 H, CH3),
1.19–1.30 (m, 1 H, CH-menthyl), 1.28 (s, 3 H, CH3), 1.29 (s, 3 H,
CH3), 1.32–1.38 (m, 1 H, CHH-menthyl), 1.40 (d, 2 H, 2J = 14.2 Hz,
CHH, CHH), 1.44 (d, 1 H, 2J = 14.7 Hz, CHH), 1.53–1.61 (m, 2 H,
CHH-menthyl, CHH-menthyl), 1.75–1.89 (m, 5 H, ArCH2CH2CH2,
CHH), 2.00 (dsep, 1 H, 3J = 7.0 Hz, 3J = 2.5 Hz, CH3CHCH3), 2.86–
Synthesis 2001, No. 9, 1395–1405 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Enantiomerically Pure 1,5,7-Trimethyl-3-azabicyclo[3.3.1]nonan-2-ones
1403
2.90 (m, 4 H, ArCH2CH2CH2CH2), 2.99 (d, 1 H, 2J = 14.0 Hz,
CHH), 3.06 (d, 1 H, 2J = 14.2 Hz, CHH), 3.33 (d, 1 H, 2J = 12.4 Hz,
CONCHH), 3.67 (dd, 1 H, J = 12.4 Hz, J = 1.8 Hz, CONCHH),
4.12 (virt. dt, 1 H, 3J = 10.9 Hz, 3J = 4.3 Hz, CO2CH), 7.16 (s, 1 H,
arom H), 7.28 (s, 1 H, arom H).
13C NMR (125 MHz, CDCl3): = 15.6 (q, CH3-menthyl), 20.9 (q,
CH3-menthyl), 22.0 (q, CH3-menthyl), 22.6 (t, CH2-menthyl), 23.0
(t, ArCH2CH2), 23.1 (t, ArCH2CH2), 24.9 (d, (CH3)2CH), 26.2 (q,
CH3), 29.5 (q, CH3), 29.6 (t, ArCH2), 29.9 (t, ArCH2), 30.5 (d, CH-
menthyl), 31.0 (s, C), 34.0 (q, CH3), 34.1 (t, CH2-menthyl), 37.4 (s,
C), 39.1 (t, CH2-menthyl), 40.9 (s, C), 44.6 (t, CH2), 46.0 (t, CH2),
46.1 (d, CH-menthyl), 46.6 (t, CH2), 57.6 (t, CONCH2), 77.5 (d,
CO2CH), 110.0 (d, CHar), 118.9 (d, CHar), 132.7 (s, Car), 133.6 (s,
Car), 139.6 (s, Car), 149.4 (s, Car), 154.2 (s, NCO2), 173.3, 173.4 (s,
2 C, CO, CN).
partitioned between CH2Cl2 (20 mL) and H2O (10 mL). The layers
were separated, and the aqueous layer was extracted with CH2Cl2 (2
10 mL). The combined organic layers were washed with H2O (2
10 mL), sat. aq NaHCO3 solution (2 10 mL), and brine (10 mL),
dried (MgSO4), and concentrated in vacuo to give the chiral acid
ent-3a (65 mg, 62%) and starting material 13a (36 mg, 23%);
[ ]D20–44.3 (c = 1.0, CH2Cl2); HPLC: tR = 18.6 min (hexane–iso-
propyl alcohol, 92:8) [265 nm].
2
4
(+)-(1R,5R,7S)-1,5,7-Trimethyl-7-(1´-oxa-3´-azacyclopenta[b]-
naphthalene-2´-yl)-3-azabicyclo[3.3.1]nonan-2-one (3a)
The hydrolysis of the N-menthoxycarbonyl amide 12a (0.17 mmol,
90 mg) was performed in analogy to the aforementioned procedure
20
and yielded 3a (48 mg, 81%); [ ]D +42.3 (c = 0.99, CH2Cl2);
HPLC: tR = 22.2 min (hexane–iso-propyl alcohol, 92:8) [265 nm].
MS (EI, 70 eV): m/z (%) = 534 (4) [M+], 352 (100) [MH+ – CO-
menthyl], 297 (2), 255 (6), 228 (11), 214 (25), 174 (8), 111 (14), 83
(24), 69 (13), 55 (19).
(–)-(1S,5S,7R)- 1,5,7-Trimethyl-7-(5´,6´,7´,8´-tetrahydro-1´-oxa-
3´-azacyclopenta[b]naphthalene-2´-yl)-3-azabicyclo[3.3.1]nonan-
2-one (ent-3b)
The hydrolysis of the N-menthoxycarbonyl amide 13b (3.18 mmol,
1.70 g) was performed in analogy to the aforementioned procedure
and yielded ent-3b (1.07 g, 95%);[ ]D20–21.9 (c = 0.90, CH2Cl2);
HPLC: tR = 17.4 min (hexane–iso-propyl alcohol, 98:2) [265 nm].
HRMS (EI): C33H46N2O4, m/z calcd 534.3458, found 534.3454;
C3213C1H46N2O4, m/z calcd 535.3491, found 535.3488.
More Polar Diastereoisomer (1R,5R,7S)-12b
Rf 0.43 (P–TBME, 1:1); mp 73–76 °C; [ ]D20–76.1 (c = 1.0,
CH2Cl2).
(+)-(1R, 5R, 7S)- 1,5,7-Trimethyl-7-(5´,6´,7´,8´-tetrahydro-1´-oxa-
3´-azacyclopenta[b]naphthalene-2´-yl)-3-azabicyclo[3.3.1]nonan-
2-one (3b)
IR (KBr): = 2955 (s, CH), 2930 (s, CH), 2868 (m, CH), 1772 (s,
C=O), 1713 (s, C=O), 1559 (m), 1463 (s), 1263 cm–1 (s).
The hydrolysis of the N-menthoxycarbonyl amide 12b (2.66 mmol,
1.42 g) was performed in analogy to the aforementioned procedure
3
1H NMR (500 MHz, CDCl3): = 0.50 (d, 3 H, J = 7.1 Hz, CH3-
menthyl), 0.66 (virt. q, 1 H, 2J 3J 11.6 Hz, CHH-menthyl), 0.75–
20
and yielded 3b (795 mg, 85%); [ ]D +20.5 (c = 0.90, CH2Cl2);
0.85 (m, 1 H, CHH-menthyl), 0.79 (d, 3 H, 3J = 7.0 Hz, CH3-menth-
20
[ ]D +7.4 (c = 1.0, CHCl3); HPLC: tR = 19.0 min (hexane–iso-pro-
3
yl), 0.87 (d, 3 H, J = 6.6 Hz, CH3-menthyl), 0.88–0.94 (m, 1 H,
pyl alcohol, 98:2) [265 nm].
CHH-menthyl), 1.14 (s, 3 H, CH3), 1.16–1.24 (m, 1 H, CH-menth-
yl), 1.26–1.33 (m, 1 H, CH-menthyl), 1.29 (s, 6 H, CH3, CH3), 1.37
(dd, 1 H, 2J = 12.7 Hz, 4J = 1.8 Hz, CHH), 1.38 (d, 1 H, 2J = 14.1 Hz,
CHH), 1.41 (d, 1 H, 2J = 14.4 Hz, CHH), 1.52–1.63 (m, 3 H, CHH-
X-Ray Single Crystal Structure Determination of Chiral Host
ent-3b 1/3H2O
The measurements were carried out on our standard device (Stoe &
Cie. IPDS camera, rotating anode, 173 K, Mo-K radiation). During
the final refinement cycles we located and refined freely: 1) all hy-
drogen atoms, 2) a very small disorder of the cyclohexene group
with a ratio of 91:9, and 3) a solvent water molecule with a site oc-
cupancy factor of 1/3. The hydrogen atoms attached to the atoms in-
volved in the disorder were calculated in ideal positions. The
hydrogen atoms bound to the water molecule could be located but
not refined. With this knowledge we started with the same crystal a
new measurement on our CAD4 diffractometer (sealed tube, 293 K,
Cu-K radiation, whole sphere). The results fit very well the results
of the low temperature measurement. But now the disorder of the
cyclohexene group increased to a ratio of 75:25. Flack's parameter
now verified the choice of the right enantiomer. Finally, to recheck
the results we started a series of psi-scans from 12 Friedel pairs with
a significant difference in their intensities. 544 reflections were col-
lected. The R-values calculated from the final model proved the
choice of the enantiomer (right handed model: R1 = 0.0278,
wR2 = 0.0721; left handed model: R1 = 0.0279, wR2 = 0.0775).
3
menthyl, CHH-menthyl, CHH-menthyl), 1.66 (dsep, 1 H, J = 7.0
Hz, 3J = 2.6 Hz, CH3CHCH3), 1.75–1.84 (m, 5 H, ArCH2CH2CH2,
CHH), 2.77–2.89 (m, 4 H, ArCH2CH2CH2CH2), 2.94 (d, 1 H,
2J = 14.2 Hz, CHH), 3.03 (d, 1 H, 2J = 14.1 Hz, CHH), 3.14 (d, 1 H,
2
4
2J = 12.3 Hz, CONCHH), 3.88 (dd, 1 H, J = 12.3 Hz, J = 1.7 Hz,
CONCHH), 4.22 (virt. dt, 1 H, J = 10.9 Hz, 3J = 4.3 Hz, CO2CH),
3
7.17 (s, 1 H, arom H), 7.26 (s, 1 H, arom H).
13C NMR (125 MHz, CDCl3): = 15.7 (q, CH3-menthyl), 20.8 (q,
CH3-menthyl), 22.1 (q, CH3-menthyl), 22.8 (t, CH2-menthyl), 23.1
(t, ArCH2CH2), 23.2 (t, ArCH2CH2), 25.6 (d, (CH3)2CH), 26.3 (q,
CH3), 29.8 (t, ArCH2), 29.9 (q, CH3), 30.0 (t, ArCH2), 30.6 (s, C),
31.2 (d, CH-menthyl), 33.7 (q, CH3), 34.1 (t, CH2-menthyl), 37.4 (s,
C), 40.1 (t, CH2-menthyl), 41.0 (s, C), 44.0 (t, CH2), 46.4 (t, CH2),
46.5 (d, CH-menthyl), 46.9 (t, CH2), 57.3 (t, CONCH2), 76.5 (d,
CO2CH), 110.2 (d, CHar), 118.8 (d, CHar), 132.8 (s, Car), 134.0 (s,
Car), 139.1 (s, Car), 149.0 (s, Car), 151.9 (s, NCO2), 169.8, 174.1 (s,
2 C, CO, CN).
MS (EI, 70 eV): m/z (%) = 534 (5) [M+], 352 (100) [MH+ – CO-
menthyl], 297 (1), 255 (5), 228 (9), 214 (20), 174 (6), 111 (11), 83
(20), 69 (12), 55 (17).
X-Ray Single Crystal Structure Determination of Chiral Host
ent-3b 1/3H2O at 293 K19
Crystal Data: C22H28N2O2 1/3H2O, Mr = 358.41, orthorhombic,
space group P212121, a = 761.83(2), b = 1609.20(6), c = 1648.87(6)
pm, V = 2021.4(1) 106 pm3, Z = 4, calcd = 1.178 gcm–3, F000 = 773.3,
(Cu K ) = 154.184 pm, = 0.604 mm-1.
HRMS (EI): C33H46N2O4, m/z calcd 534.3458, found 534.3464;
C3213C1H46N2O4, m/z calcd 535.3491, found 535.3499.
Enantiomerically Pure Chiral Hosts 3 by Hydrolysis of the N-
Menthoxycarbonyl Amides 12 and 13; Typical Procedure
Data Collection and Reduction: Crystal size: 0.18 0.36 0.61
mm, Theta range: 3.84° to 64.97°, Index ranges: –8
h 8, –18 k
(–)-(1S,5S,7R)-1,5,7-Trimethyl-7-(1´-oxa-3´-azacyclopenta[b]-
naphthalene-2´-yl)-3-azabicyclo[3.3.1]nonan-2-one (ent-3a)
N-Menthoxycarbonyl amide 13a (0.30 mmol, 160 mg) was dis-
solved in TFA (4 mL) and stirred for 22 h at r.t. The mixture was
18, –19 19, Reflections collected: 13177, Independent reflec-
l
tions: 3421 [Rint = 0.0366], Absorption correction: DIFABS strategy
[Tmin/max = 0.193/0.663], Refinement method: Full-matrix least-
squares on F2, Data/restraints/parameters: 3421/0/376, Final R indi-
Synthesis 2001, No. 9, 1395–1405 ISSN 0039-7881 © Thieme Stuttgart · New York

1404
T. Bach et al.
PAPER
ces [I > 2 (I)]: R1 = 0.0306, wR2 = 0.0783, GOF on F2: 1.113, Final
R indices (all data): R1 = 0.0335, wR2 = 0.0807, GOF on F2: 1.113,
Extinction parameter: 0.0018(4), Absolute structure parameter:
0.0(2), Largest diff. peak and hole: 0.08 eÅ-3 and -0.08 eÅ-3.
Photochemistry, Vol. 3; Ramamurthy, V., Schanze, K. S.,
Eds.; Dekker: New York, 1999, 71. (b) Inoue, Y. Chem.
Rev. 1992, 92, 741. (c) Rau, H. Chem. Rev. 1983, 83, 535.
(4) Kemp, D. S.; Petrakis, K. S. J. Org. Chem. 1981, 46, 5140.
(5) (a) Rebek, J. Jr. Pure Appl. Chem. 1989, 61, 1517.
(b) Rebek, J. Jr. Angew. Chem. Int. Ed. Engl. 1990, 29, 245.
(c) Jeong, K.-S.; Tjivikua, T.; Rebek, J. Jr. J. Am. Chem. Soc.
1990, 112, 3215. (d) Park, T. K.; Schroeder, J.; Rebek, J. Jr.
Tetrahedron 1991, 47, 2507. (e) Jeong, K. S.; Tjivikua, T.;
Muehldorf, A.; Deslongchamps, G.; Famulok, M.; Rebek, J.
Jr. J. Am. Chem. Soc. 1991, 113, 201.
Measurement, Computing and Graphics: Measurement device:
NONIUS CAD4, Computing cell refinement: CAD4 Operating
System [unix version, 1997], Computing data reduction: CADLP
(U. Müller et al., 1986), Computing structure solution: SIR92 (Gia-
covazzo et al., 1994), Computing structure refinement: SHELXL-
97 (Sheldrick, 1998), Computing molecular graphic: Platon (Spek,
2000).
(6) (a) Potin, D.; Williams, K.; Rebek, J. Jr. Angew. Chem. Int.
Ed. Engl. 1990, 29, 1420. (b) Yanagisawa, A.; Kikuchi, T.;
Watanabe, T.; Yamamoto, H. Bull. Chem. Soc. Jpn. 1999,
72, 2337.
X-Ray Single Crystal Structure Determination of Chiral Host
ent-3b 1/3H2O at 173 K
Crystal Data: C22H28N2O2 1/3H2O, Mr = 358.41, orthorhombic,
(7) (a) Curran, D. P.; Jeong, K.-S.; Heffner, T. A.; Rebek, J. Jr.
J. Am. Chem. Soc. 1989, 111, 9238. (b) Jeong, K.-S.; Parris,
K.; Ballester, P.; Rebek, J. Jr. Angew. Chem., Int. Ed. Engl.
1990, 29, 555. (c) Stack, J. G.; Curran, D. P.; Rebek, J. Jr.;
Ballester, P. J. Am. Chem. Soc. 1991, 113, 5918. (d) Stack,
J. G.; Curran, D. P.; Geib, S. V.; Rebek, J. Jr.; Ballester, P.
J. Am. Chem. Soc. 1992, 114, 7007. (e)Curran, D. P.;Yoon,
M.-H. Tetrahedron 1997, 53, 1971.
(8) Bergmann, H. Ph. D. Thesis; Universität Marburg: Marburg,
2001.
(9) (a) Bach, T.; Bergmann, H.; Harms, K. Angew. Chem., Int.
Ed. 2000, 39, 2302. (b) Bach T., Bergmann H.; J. Am.
Chem. Soc.; 2000, 122: 11525. (c) Bach, T.; Bergmann, H.;
Harms, K. J. Org. Lett. 2001, 3, 601–603.
space
group
P212121,
a = 760.41(8),
b = 1593.42(11),
c = 1645.92(11) pm, V = 1994.3(3) 106 pm3, Z = 4, calcd = 1.194
gcm-3, F000 = 773.3, (Mo K ) = 71.073 pm, = 0.077 mm-1.
Data Collection and Reduction: Crystal size: 0.18 0.36 0.61
mm, Theta range: 2.47° to 25.66°, Index ranges: –9
19, –19 20, Reflections collected: 17122, Independent reflec-
tions: 3756 [Rint = 0.0471], Absorption correction: None, Refine-
ment method: Full-matrix least-squares on F2, Data/restraints/
parameters: 3756/0/376, Final R indices [I > 2 (I)]: R1 = 0.0305,
wR2 = 0.0703, GOF on F2: 1.004, Final R indices (all data):
R1 = 0.0363, wR2 = 0.0722, GOF on F2: 1.004, Extinction parame-
ter: 0.005(3), Absolute structure parameter: 0.2(9), Largest diff.
peak and hole: 0.14 eÅ-3 and -0.14 eÅ-3.
h 9, –19 k
l
(10) 5: C22H35NO4; Crystal Data: colorless prism; rhombohedral,
R3, a = b = 2822.4(1)pm, c = 1526.2(1)pm; Z = 6; R = 5.16%;
GOF = 1.034. Data collection: Data were collected on an
Enraf Nonius CAD4 instrument at 293 K employing Cu K
irradiation (154.178 pm). -scan, 6287 reflections (-h, +k,
l), max = 65°, 5754 independent and 4128 observed
reflections [F 4 (F)], 521 refined parameters,
Measurement, Computing and Graphics: Measurement device:
IPDS – 2.8 (STOE & Cie., 1997), Computing cell refinement: IPDS
– 2.8 (STOE & Cie., 1997), Computing data reduction: IPDS – 2.8
(STOE & Cie., 1997), Computing structure solution: SIR92 (Giaco-
vazzo et al., 1994), Computing structure refinement: SHELXL-97
(Sheldrick, 1998), Computing molecular graphic: PLATON (Spek,
2000).
wR2 = 0.1373, residual electron density 0.174 eÅ-3, direct
methods, hydrogen atoms calculated. Further details of the
crystal structure investigations related to this compound may
be obtained from the Director of the Cambridge
Crystallographic Data Centre, 12 Union Road, GB-
Cambridge CB2 1EZ, on quoting the full literature citation
(CCDC-157021)
Deposition of Data: Crystallographic data (excluding structure fac-
tors) for the structures reported here have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publica-
tion no. CCDC-158291 (ent-3b-293) and no. CCDC-158292 (ent-
3b-173). Copies of the data can be obtained free of charge on appli-
cation to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax:
+44(1223)336033; e-mail: deposit@ccdc.cam.ac.uk).
(11) (a) Wijnberg, J. B. P. A.; Schoemaker, H. E.; Speckamp, W.
N. Tetrahedron 1978, 34, 179. (b) Rosenfield, R. E. Jr.;
Dunitz, J. D. Helv. Chim. Acta 1978, 61, 2176.
Acknowledgement
(c) Nagasaka, T.; Esumi, S.; Ozawa, N.; Kosugi, Y.;
Hamaguchi, F. Heterocycles 1981, 16, 1987. (d) Weinreb,
S. M.; Kim, M. Y.; Starret, J. E. J. Org. Chem. 1981, 46,
5383.
This work was supported by the Deutsche Forschungsgemeinschaft
(Ba 1372/3–2) and by the Fonds der Chemischen Industrie. Thanks
are due to Stefanie Neumann for her help during the X-ray experi-
ments of compound ent-3b.
(12) (a) Dockner, M.; Meyer, T.; Nemes, P.; Otten, M. G.;
Winterfeldt, E. Bull Soc. Chim Belg. 1994, 103, 379.
(b) Winterfeldt, E. Chem. Rev. 1993, 93, 827. (c) Hungate,
R. W.; Chen, J. L.; Starbuck, K. E.; Macaluso, S. A.; Rubino,
R. S. Tetrahedron Lett. 1996, 37, 4113.
(13) (a) Wanner, M. J.; Koomen, G.-J. J. Org. Chem. 1994, 59,
7479. (b) Adams, D. J.; Simpkins, N. S.; Smith, T. J. N.
Chem. Commun. 1998, 1605.
(14) (a) Goto, T.; Konno, M.; Saito, M.; Sato, R. Bull. Chem. Soc.
Jpn. 1989, 62, 1205. (b) Koot, W.-J.; Hiemstra, H.;
Speckamp, W. N. J. Org. Chem. 1992, 57, 1059.
(15) Ducrot, P.; Thal, C. Tetrahedron Lett. 1999, 40, 9037.
(16) (a) Ballester, P.; Tadayoni, M.; Branda, N.; Rebek, J. Jr. J.
Am. Chem. Soc. 1990, 112, 3685. (b) Kirby, A. J.;
Komarov, I. V.; Feeder, N. J. Am. Chem. Soc. 1998, 120,
7101.
References
(1) (a) To whom inquiries about the X-ray analyses of
compound 5 and rac-3a should be addressed at the Philipps-
Universität, Marburg (b) To whom inquiries about the X-ray
analysis of compound ent-3b should be addressed at the
Technische Universität München
(2) (a) Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann,
E. Eds. Houben-Weyl, 4th ed., Vol. E21; Thieme: Stuttgart,
1995. (b) Winterfeldt, E. Prinzipien und Methoden der
stereoselektiven Synthese; Vieweg: Braunschweig, 1988.
(3) Reviews: (a) Everitt, S. R. L.; Inoue, Y. In Molecular and
Supramolecular Photochemistry: Organic Molecular
Synthesis 2001, No. 9, 1395–1405 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Enantiomerically Pure 1,5,7-Trimethyl-3-azabicyclo[3.3.1]nonan-2-ones
1405
(17) Kajino, M.; Shibouta, Y.; Nishikawa, K.; Meguro, K. Chem.
Pharm. Bull. Jpn. 1991, 39, 2896.
(19) rac-3a: C22H24N2O2; Crystal Data: yellowish prism;
monoclinic, P21/c, a = 1137.2(2)pm, b = 1491.2(1)pm,
c = 1154.5(3)pm; = 111.7(2)°; Z = 4; R = 6.49%;
(18) (a) The structure was resolved by direct methods, carbon
bound hydrogen atoms and N-H atom were refined. Further
details regarding the crystal structure determination are
provided in the Experimental section. (b) Straver, L. Enraf-
Nonius CAD4 Operating System Unix Version, B. V. Enraf-
Nonius, Delft, The Netherlands, 1997. (c) IPDS Operating
System Version 2.8., Stoe&Cie. GmbH, Darmstadt,
Germany, 1997. (d) Müller, U.; Schmidt, R. E.; Massa, W.;
Herdtweck, E. CADLP: A Program to Correct X-Ray Raw
Data for LP-Terms and Decay; University of Marburg and
TU München: München, Germany, 1986. (e) Altomare, A.;
Cascarano, G.; Giacovazzo, C.; Guagliardi, A.; Burla, M. C.;
Polidori, G.; Camalli, M. SIR92 J. Appl. Cryst. 1994, 27,
435. (f) International Tables for Crystallography, C; Tables
6.1.1.4 (pp. 500-502), 4.2.6.8 (pp. 219-222), and 4.2.4.2 (pp.
193-199)Wilson, A. J. C., Ed.; Kluwer Academic
GOF = 1.044. Data collection: Data were collected on an
Enraf Nonius CAD4 instrument at 223 K employing Cu K
irradiation (154.178 pm), -scan, 2410 reflections ( h, +k,
l), max = 55°, 2276 independent and 1659 observed
reflections [F 4 (F)], 242 refined parameters,
wR2 = 0.2057, residual electron density 0.225 eÅ-3. The
structure was resolved by direct methods with carbon bound
hydrogen atoms calculated and N-H atom refined. Further
details of the crystal structure investigations related to this
compound may be obtained from the Director of the
Cambridge Crystallographic Data Centre, 12 Union Road,
GB-Cambridge CB2 1EZ, on quoting the full literature
citation (CCDC-157022)
(20) Still, W. C.; Kahn, M.; Mitra, A. J. J. Org. Chem. 1978, 43,
2923.
Publishers: Dordrecht, The Netherlands, 1992.
(g) Sheldrick, G. M. SHELXL-97, University of Göttingen,
Göttingen, Germany, 1998. (h) Spek, A. L. PLATON: A
Multipurpose Crystallographic Tool, Utrecht University,
Utrecht, The Netherlands, 2000.
Synthesis 2001, No. 9, 1395–1405 ISSN 0039-7881 © Thieme Stuttgart · New York