Utilization of industrial waste materials. Part 14.? Synthesis of -amino alcohols and thiols with a 2-azabicyclo[3.3.0]octane backbone and their application in enantioselective catalysis

Article abstract of DOI:10.1039/a902362c

New, chiral β-tert-amino tert-alcohols have been synthesized from the enantiomerically pure sec-amine (all-R)-lb via the new glycine, alanine and phenylglycine derivatives 2-6. Grignard additions to these esters provided the new rigid amino alcohols 7-11 in fair yields. The absolute configurations of the stereogenic centers, which arose during the alkylation step, were assigned by an independent route leading to some of the optical antipodes of 7-10. Condensation of enantiomerically pure β-amino alcohols 13a-g, 16 and 17 with y-ketoester rac-12 afforded the TV; O-acetals 14a-g, 18 and 19, which were subsequently reduced to the β-/e/7-amino alcohols 10a,c and 15a-g. X-Ray analysis of compound 19 was performed to verify the stereochemistry observed by chemical correlation. The nucleophilic ring opening of enantiomerically pure styrene oxide by amine Ib resulted in the formation of regioisomeric amino alcohols 9a, 21a, and lOa, 21b. Amino thiol derivatives 22 and 25a,b were prepared by treatment of 10a-and 15a,b, respectively, with methanesulfonyl chloride followed by regio- and stereoselective cleavage of the situ formed aziridinium ions with potassium thioacetate. Reduction of these compounds to thiols 23 and 26a,b and subsequent oxidation afforded amino disulfides 24 and 27a,b. Finally, the bicyclic β-amino alcohols and thiols were used as chiral ligands in the enantioselective addition of diethylzinc to benzaldehyde and ee values up to 96% were found. ;.

Full text of DOI:10.1039/a902362c

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Utilization of industrial waste materials. Part 14.† Synthesis of
ꢀ-amino alcohols and thiols with a 2-azabicyclo[3.3.0]octane
backbone and their application in enantioselective catalysis
Michael Kossenjans,a Michael Soeberdt,b Sabine Wallbaum,a Klaus Harms,b Jürgen Martens*a
and Hans Günter Aurich*b
a Fachbereich Chemie der Universität Oldenburg, Carl-von-Ossietzky-Straße 9–11,
D-26129 Oldenburg, Germany. E-mail: martens@uni-oldenburg.de
b Fachbereich Chemie der Universität Marburg, Hans-Meerwein-Straße, D-35032 Marburg,
Germany
Received (in Cambridge) 24th March 1999, Accepted 23rd June 1999
New, chiral β-tert-amino tert-alcohols have been synthesized from the enantiomerically pure sec-amine (all-R)-1b
via the new glycine, alanine and phenylglycine derivatives 2–6. Grignard additions to these esters provided the
new rigid amino alcohols 7–11 in fair yields. The absolute configurations of the stereogenic centers, which arose
during the alkylation step, were assigned by an independent route leading to some of the optical antipodes of 7–10.
Condensation of enantiomerically pure β-amino alcohols 13a–g, 16 and 17 with γ-ketoester rac-12 afforded the
N,O-acetals 14a–g, 18 and 19, which were subsequently reduced to the β-tert-amino alcohols 10a,c and 15a–g.
X-Ray analysis of compound 19 was performed to verify the stereochemistry observed by chemical correlation.
The nucleophilic ring opening of enantiomerically pure styrene oxide by amine 1b resulted in the formation of
regioisomeric amino alcohols 9a, 21a, and 10a, 21b. Amino thiol derivatives 22 and 25a,b were prepared by
treatment of 10a and 15a,b, respectively, with methanesulfonyl chloride followed by regio- and stereoselective
cleavage of the in situ formed aziridinium ions with potassium thioacetate. Reduction of these compounds to thiols
23 and 26a,b and subsequent oxidation afforded amino disulfides 24 and 27a,b. Finally, the bicyclic β-amino alcohols
and thiols were used as chiral ligands in the enantioselective addition of diethylzinc to benzaldehyde and ee values up
to 96% were found.
However, for a few years our interest in this area has been
Introduction
focused on the design of new ligands with a rigid bi- and tri-
During the last decades, the development of new and practical
cyclic nitrogen containing backbone.6 In this paper we report
methods of stereoselective synthesis has been among the most
challenging subjects in organic chemistry. The invention of new
the synthesis of several new ligands with a 2-azabicyclo[3.3.0]-
octane framework by the use of derivatives of proteinogenic
stereoselective reactions via the use of both chiral auxiliaries
and non-proteinogenic α-amino acids, as starting materials.
and chiral catalysts has become a major interest of academic
and industrial investigations, not least for the reason that
enantiomerically pure compounds are of critical importance to
pharmaceutical and agricultural chemistry. This is frequently
due to the fact that biologically important molecules often
show effective activity as one enantiomer whereas the other one
is either ineffective or detrimental.1 Two principal methods were
Two independent routes for the construction of the same
ligands have allowed us to establish the absolute configuration
of the newly formed stereogenic centers. Finally, all the ligands
were tested for their effectiveness as chiral catalysts in the
reaction of benzaldehyde with diethylzinc.
developed for the stereoselective synthesis of enantiomerically
pure compounds: the first one is the chiral-auxiliary-based
stereoselective synthesis (diastereoselective variant) and the
second one is the external chiral-ligand-controlled stereo-
selective synthesis (enantioselective variant). Although both
methods have been intensively studied in a variety of organic
reactions, the synthesis of enantiomerically pure compounds
by stereoselective formation of C–C bonds is still of major
importance.2 Among the several advances made in this area, the
ligand accelerated alkylation of carbonyl compounds (enantio-
selective asymmetric synthesis) has attracted considerable inter-
est during the past decade. Since the first report of a highly
enantioselective amino alcohol catalyzed addition of dialkyl-
zinc reagents to aldehydes,3 there has been a rapid growth of
research aimed at this reaction.4 Much of these efforts have
been directed toward the synthesis of new ligands and so far
many good catalysts have been developed.5
Results and discussion
Synthesis of the ligands
Ligands with (all-R)-2-azabicyclo[3.3.0]octane backbone. For
the three-step synthesis of the diastereomeric β-amino alcohols
7–11 (Scheme 1) we used the enantiomerically pure (all-R)-2-
azabicyclo[3.3.0]octane-3-carboxylic acid 1a, a waste material
which is generated in the process of synthesizing the ACE-
inhibitor Ramipril by Hoechst AG, as the starting material.7
First of all, chiral 1a was converted to the chiral heterocyclic
amine 1b by the known cyclohexen-2-one catalyzed thermal
decarboxylation process.8 In the next step the optically pure
pyrrolidine derivative 1b was N-alkylated by treatment with
methyl 2-bromopropionate or benzyl 2-bromo-2-phenylacetate
respectively (Scheme 1, step ii). Separation of the diastereomers
(dr = 1:1) by column chromatography afforded the new ester
derivatives of alanine 2, 3 and phenylglycine 4, 5 (step iii). As
well as the benzyl ester of phenylglycine derivatives, the methyl
and ethyl esters were synthesized, but only in the case of the
† For part 13 see ref. 7.
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Scheme 2 Reagents, conditions and yields: i, toluene, 16 h reflux,
15–85%; ii, if R3 = R4 = H: LiAlH4 in THF, 3 h reflux, 36 h room temp.,
81–94%; iii, R3 = alkyl or aryl: BH3ؒTHF-complex in THF, 2 h reflux,
3 d room temp., 26–87%; lactams 14b and 14e9 as well as β-amino
alcohol 1812 have been previously described.
stereoselective step is the simultaneous formation of two con-
tiguous stereogenic centers via deracemization of the ketoester.
After treatment of rac-12 with the corresponding β-amino
alcohols 13a–g in refluxing toluene, the tricyclic lactams 14a–g
were isolated in 15–85% yield (Scheme 2, step i). In this context,
the lower yields for 14c,d and g (R3 and R4 = alkyl or aryl, 15–
19%), which are probably due to steric hindrance, are note-
worthy.
In order to provide new ligands, the N,O-acetals 14a–g were
reductively cleaved either by lithium aluminium hydride (step ii,
R3 = R4 = H) or by the borane–tetrahydrofuran complex (step
iii, R3 = alkyl, aryl) affording the functionalized 2-azabicyclo-
[3.3.0]octanes (a mechanistic explanation for the stereoselective
ring opening of N,O-acetals is given by Meyers and Burgess10).
On the basis of their NMR spectra, all these compounds
were obtained diastereomerically pure and because the starting
β-primary-amino alcohols 13 were enantiopure, it follows that
this must hold for the products as well. Their enantiopurity was
further confirmed by the same magnitude but opposite sign of
optical rotation for the independently synthesized optical
antipodes 8a and 15a as well as for 8c, 15c and 8d, 15d (Schemes
1 and 2).
Scheme 1 Reagents, conditions and yields: i, Pd/C, cyclohexen-2-one;8
ii, rac-R2CH(Br)CO2R1 (R1 = R2 = Me; R1 = Bn, R2 = Ph), NEt3, reflux,
67–78%; iii, separation of diastereomers by chromatography; iv,
BrCH2CO2Me–NEt3, reflux, 85%; v, LiAlH4 in THF, 3 h reflux, 82–
96%; vi, R3MgBr in anhydrous THF, 12 h reflux, 43–88%.
benzyl ester was separation of diastereoisomers by column
chromatography possible. Subsequently, these esters were con-
verted either to the β-tert-amino primary alcohols 7a–10a by
lithium aluminium hydride reduction (step v) or to the β-tert-
amino tert-alcohols 7b–d, 8b–d, 9b–d and 10b–d by addition
of the corresponding Grignard reagent in refluxing tetrahydro-
furan (step vi).
In order to discuss the results and effects of the enantio-
selective diethylzinc addition to benzaldehyde catalyzed by
ligands 7–10, the corresponding alcohol-substituted optically
active derivatives of glycinol were also synthesized. Ligands
11a–d were easily provided in two steps by treatment of 1b with
methyl bromoacetate (Scheme 1, step iv), followed by reduction
of the resulting chiral ester 6 to β-amino alcohol 11a or by
addition of the respective Grignard reagents to afford 11b–d
(steps v–vi).
Stereochemical assignment. Based on the assignment of abso-
lute configuration for all compounds synthesized according to
Scheme 211 and on the complete agreement of the analytical
characteristics of the enantiomeric β-amino alcohols obtained
as described in Scheme 1 (8a,c,d) and Scheme 2 (15a,c,d),
we were able to assign the absolute configurations of all the
diastereomeric β-tert-amino alcohols 7a–d and 8a–d and con-
sequently those of the alanine methyl ester derivatives 2 and 3
(R2 = Me). As a result of the fact that (S)-alaninol derivatives
13a,c,d produced (all-S)-configured 15a,c,d in Scheme 2, the
stereochemistry was determined to be (all-R) for 8a–d and 3
and correspondingly (1ЈR,2S,5ЈR) for 7a–d as well as for 2.
Similarly, the absolute configurations of ligands 9a–d and
10a–d and therefore those of the phenylglycine esters 4 and 5
Ligands with an (all-S)-2-azabicyclo[3.3.0]octane backbone.
In Scheme 2 an alternative procedure for the synthesis of new
β-amino alcohols with an (all-S)-2-azabicyclo[3.3.0]octane
backbone is presented. Condensation of the racemic ethyl
2-oxocyclopentaneacetate rac-12 with various enantiopure
β-amino alcohols 13 (derived from the corresponding α-amino
acids) afforded the lactams 14.9 The key feature of this highly
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Table 1 Crystal data for (4R,8S,1R)-19
Compound
(4R,8S,11R)-19
Molecular formula
Molecular mass
Crystal system
Space group
C27H25NO2
395.50
Triclinic
P1
Cell parameters:
a/pm
b/pm
876.6(1) α = 81.71(10)Њ
967.3(1) β = 82.07(10)Њ
c/pm
Z
1264.7(1) γ = 78.91(10)Њ
2
1034.48(3)
1.269
Volume/10Ϫ6 pm3
d/g cmϪ3
Absorption coefficient/mmϪ1
Reflections collected
Independent reflections
Observed reflections
Number of parameters refined
Final R indices [I > 2σ(I)]
Diffractometer used
Radiation
0.623
7298
7298
7228
7298
R = 0.0542, wR2 = 0.1588
Enraf-Nonius CAD4
Cu-Kα (λ = 154.178 pm)
213
Siemens SHELXTL Plus
Direct methods/differences fourier
1.092
Fig. 1 Selected bond lengths (Å): O2–C2 1.213(3), N1–C2 1.371(3),
N1–C8 1.463(3), C8–O9 1.433(3), O9–C10 1.447(3), C10–C11 1.556(3),
C11–N1 1.474(3); selected bond angles (Њ): O9–C8–N1 104.44(17), O9–
C8–C4 118.21(19), N1–C11–C10 99.30(17), C2–N1–C11 120.47(19),
C3–C4–C8 103.7(2), O9–C10–C11 101.80(18), C2–N1–C8 113.52(19),
C8–N1–C11 109.97(18).
Temperature/K
System used
Solution
Goodness-of-fit on F2
(R2 = Ph) were clarified. A) Reduction of 5 afforded the (all-R)-
configured amino alcohol 10a (Scheme 1), which is identical
to the product obtained from the condensation of γ-ketoester
rac-12 with (R)-phenylglycinol (16) and subsequent reduction
of 18.12 B) Likewise, the product 10c obtained from rac-12 and
the α,α-diphenyl-substituted (R)-phenylglycinol 17 via com-
pound 19 (Scheme 2) is identical with that formed from 5 on
treatment with phenylmagnesium bromide (Scheme 1). The
magnitude and sign of the optical rotation of the different
samples of 10a as well as of 10c synthesized on two independ-
ent routes were in complete agreement. Thus, the stereo-
chemistry of the newly formed stereogenic carbon of α-amino
acid ester 5 was established as being R and correspondingly the
ester 4 has to be assigned S-configured at the 2-position.
Although the absolute configurations of the new bicyclic
ligands were proved by chemical correlation, it seemed to be
appropriate to verify the observations by a single crystal X-ray
study. Thus, analysis of the precursor of 10c, the crystalline
N,O-acetal 19, is given in Figs. 1 and 2. Crystallographic data
are given in Table 1.‡ Amazingly, two significantly distinguished
structures were found and as can be seen from the figures the
different orientation of the phenyl groups causes the overall
difference. Moreover, the absolute configuration of com-
pound 19 confirmed the experimental results as described
above. A fixed R configuration in position C-11 (originating
from R-configured phenylglycinol derivative) causes the R
configuration at bridgehead position C-4 (C-4Ј) and S con-
figuration at C-8 (C-8Ј). It can be observed in the conformation
of 19 that the pyrrolidine ring is approximately planar due to
the sp2 hybridized carbonyl group whereas the cyclopentane
and the oxazolidine rings exist in envelope forms.
Fig. 2 In this figure the positions of the atoms are marked with ‘Ј’ (e.g.
O2Ј instead of O2) to stress the difference between this structure and
that in Fig. 1; selected bond length (Å): O2Ј–C2Ј 1.217(3), N1Ј–C2Ј
1.376(3), N1Ј–C8Ј 1.455(3), C8Ј–O9Ј 1.437(3), O9Ј–C10Ј 1.439(3),
C10Ј–C11Ј 1.563(3), C11Ј–N1Ј 1.468(3); selected bond angles (Њ): O9Ј–
C8Ј–N1Ј 104.38(17), O9Ј–C8Ј–C4Ј 117.41(19), N1Ј–C11Ј–C10Ј
98.51(17), C2Ј–N1Ј–C11Ј 120.9(2), C3Ј–C4Ј–C8Ј 104.2(2), O9Ј–C10Ј–
C11Ј 102.76(16), C2Ј–N1Ј–C8Ј 113.66(19), C8Ј–N1Ј–C11Ј 109.73(17).
synthesis of further rigid β-amino alcohols with a 2-azabicyclo-
[3.3.0]octane backbone.
When the chiral amine 1b was refluxed in ethanol with either
enantiomerically pure (R)- or (S)-styrene oxides 20a and 20b,
respectively, in both cases a normal as well as an abnormal ring-
opening was observed as expected (Scheme 3). As a result of the
abnormal nucleophilic attack of 1b at the benzylic position of
the epoxides the formation of the minor regioisomers 9a and
10a, respectively, occurred with inversion of configuration. In
the case of (R)-styrene oxide 20a as starting compound a
regioisomeric ratio of 72:28 in favour of the normal ring-
opened product 21a could be detected (by 1H-NMR spec-
troscopy) and in approximately the same ratio (rr = 69:31)
β-amino alcohols 21b and 10a were obtained in the reaction of
20b with 1b. However, separation of the respective regioisomers
was managed by column chromatography.
Rigid ꢀ-amino alcohols by epoxide ring-opening. The ring-
opening reaction of 1,2-epoxides with amines is one of the most
widely used methods for the synthesis of β-amino alcohols.13
This classical procedure involving the direct heating of epoxides
with amines has some significant limitations in the reaction
with poorly nucleophilic amines. However, due to the previ-
ously reported use of pyrrolidine and piperidine as nucleo-
philes,14,15 we were prompted to use this method for the
‡ CCDC reference number 207/347. See http://www.rsc.org/suppdata/
p1/1999/2353 for crystallographic files in .cif format.
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Scheme 3 Reagents, conditions and yields: i, EtOH, reflux, 51–52%;
ii, separation of regioisomers by chromatography; regioisomeric ratio
of the crude product: 9a:21a = 28:72 and 10a:21b = 31:69.
ꢀ-Amino alcohols and thiols by aziridinium ion ring opening.
Using a procedure developed by Dieter et al. for the synthesis
of chiral 1,2-diamines by nucleophilic ring-opening of aziridin-
ium ions,16 we could successfully use a similar method for the
conversion of amino alcohol 10a into its regioisomer 21b
(Scheme 4, steps i, ii). Treatment of 10a with an excess of
methanesulfonyl chloride and triethylamine afforded first of all
the corresponding aziridinium salt which was directly converted
into the amino alcohol 21b by basic hydrolysis. The spectral
characteristics and optical rotation values of β-amino alcohols
21b obtained by both routes (ring-opening of epoxide vs. ring-
opening of aziridinium ion) were in complete agreement. Thus,
either the mesylation or hydroxy ion displacement proceeded
with inversion of configuration as the hydroxy ion opened the
aziridinium ion regio- and stereospecifically at the benzylic
position. This is in accord with the well known opening of
aziridinium ions by amine nucleophiles.14–16
Bearing in mind the known improvement of enantioselectiv-
ities in the diethylzinc addition to aldehydes in the presence
of β-amino thiols or disulfides in place of amino alcohols,17
we decided to convert some functionalized 2-azabicyclo[3.3.0]-
octanes into the corresponding amino thioacetates, amino
thiols and disulfides. Therefore, the aziridinium ion prepared in
situ from 10a was treated with potassium thioacetate (Scheme
4, step iii). In the same manner as described above for the basic
hydrolysis (step ii), the nucleophilic ring-opening took place
at the benzylic position affording thioester 22,18 which was
reduced by diisobutyl aluminium hydride (DIBAL-H) to β-
amino thiol 23. Subsequently, 23 was converted to disulfide 24
by aerial oxidation while stirring at room temperature for three
days. Identical compounds 22–24 were also formed from the
rearranged amino alcohol 21b using the same procedure. The
retention of configuration during this latter reaction is due to a
double inversion at the carbon atom bearing the phenyl group.
In accordance with amino alcohol 21b the amino alcohols
15a and b afforded the compounds 25a,b to 27a,b, respectively,
without rearrangement, by the same reaction sequence. Thus, in
compounds 25b–27b the configuration at the α-C atom should
be retained (double inversion).
Scheme 4 Reagents, conditions and yields: i, MsCl–NEt3 in Et2O, 0 ЊC,
2 h, without isolation; ii, OHϪ/H2O (pH > 8), 20 h, room temp, 77%;
iii, CH3COSK, 20 h, room temp, 23–73%; iv, DIBAL-H (1 M in
n-hexane), Et2O, Ϫ10 ЊC, 2 h, 61–93%; v, O2 (air), 3 d, room temp,
75–88%.
Scheme 5
about reaction conditions, work-up, determination of the ee
value, etc. see footnotes of tables and the Experimental
section).
The following conclusions concerning the asymmetric
induction of the chiral ligands may therefore be drawn. The
asymmetric induction caused merely by the stereogenic
centers of the bicyclic backbone without a stereogenic center at
the amino alcohol moiety is only poor (entries 17–20, com-
pounds 11a–d). As is indicated by comparison of the effect
of ligands 21a and 21b (entries 25, 26) as well as of ligands 7
and 8 (entries 1–8) or 9 and 10 (entries 9–16) the stereogenic
center of the amino alcohol group dictates whether the (R)-
or the (S)-configured 1-phenylpropanol is formed in excess.
This asymmetric induction is enforced by the two stereogenic
centers of the bicyclic backbone in the (all-R)-configured
compound 8 and 10 (matched situation), but diminished by
the stereogenic centers in 7 and 9 (mismatched situation). In
the compounds with primary alcohol groups 7a–10a as well
as 15e,f the enantioselectivity does not depend significantly
on the bulkiness of the substituent R2 at the stereogenic
center adjacent to the amino group (ee 45–49% and 30–34%,
respectively). However, the introduction of two substituents
in the α-position to the hydroxy group enhances the enantio-
selectivity to a different extent. Surprisingly, this effect is
much more pronounced with the alkyl groups in 8b,d and
10b,d (R3 = R3: Me or R3,R3: –(CH2)4–, respectively) compared
to the sterically more demanding phenyl groups in 8c and 10c.
Thus, the highest enantiomeric excess was achieved with 8d
Enantioselective catalysis
All the presented azabicyclo[3.3.0]octane-based ligands were
tested in the enantioselective addition of diethylzinc to benz-
aldehyde (Scheme 5). The results obtained for this model reac-
tion are summarized in Tables 2 and 3 (for detailed information
(92%) and 10d (91%) containing
a rigid cyclopentanol
framework.
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Table 2 Enantioselective addition of diethylzinc to benzaldehyde in
the presence of catalytic amounts of chiral β-amino alcohols and thiols;
product: 1-phenylpropan-1-ol
Table 3 Enantioselective addition of diethylzinc to benzaldehyde
using various concentrations of β-amino alcohol 8d; product: 1-phenyl-
propan-1-ol
Entrya
Catalyst
Time/h
Yield (%)
Ee (%)b
Concentration
(mol%)
Yield
(%)
Entrya
Time/h
Ee (%)b
1
2
3
4
5
6
7
8
9
7a
7b
42
42
42
42
42
42
42
42
40
40
40
40
40
40
40
40
40
40
40
40
12
12
12
12
42
42
12
12
12
12
12
12
12
12
85
78c
87
46 (R)
36 (R)
35 (R)
71 (R)
49 (S)
80 (S)
39 (S)
92 (S)
45 (R)
38 (R)
32 (R)
52 (R)
46 (S)
80 (S)
66 (S)
91 (S)
4 (S)
35
36
8
37
38
39
10.0
7.5
5.0
2.5
1.0
0.5
24
24
42
48
72
72
95
90
93
86
78
68c
96 (S)
93 (S)
92 (S)
86 (S)
72 (S)
50 (S)
7c
7d
71c
87
8a
8b
91
81
93
8c
8d
a Carried out according to method B. b The ee value of the obtained
1-phenylpropan-1-ol was assigned by chiral GC (see Experimental
section: enantioselective catalysis method B) and the absolute configur-
ation of this optically active alcohol was assigned on the basis of
optical rotation. c 14% benzyl alcohol was formed.
9a
84
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
9b
75c
79
9c
9d
82c
86
10a
10b
10c
10d
11a
11b
11c
11d
15b
15ed
15fd
15gd
21a
21b
25ad
26ad
22
88
92
94
86
90
88
94
100
58c
93
88
83
Experimental
Chemicals
6 (S)
28 (S)
40 (S)
86 (R)
43 (R)
30 (R)
74 (R)
60 (R)
57 (S)
82 (R)
84 (R)
60 (S)
64 (S)e
60 (S)
90 (R)
90 (R)f
86 (R)
(1S,2R)-(ϩ)-Norephedrin (>98% purity) was purchased from
Fluka. (R)-(Ϫ)- and (S)-(ϩ)-styrene oxide, diethylzinc (1.0 M in
hexane fraction and 1.1 M in toluene), methyl 2-bromoacetate
and methyl 2-bromopropionate were purchased from Aldrich;
benzyl 2-bromo-2-phenylacetate was prepared according to
a literature described method;19 rac-ethyl (2-oxocyclopentyl)-
acetate was prepared in four steps from adipinic acid according
to a literature procedure;20 enantiomerically pure amino
alcohols 13a,c–f were performed from the respective α-amino
acids.21
88
100
100
95
100
88
100
100
92
23
24
25b
26b
27b
Instrumentation
General. Due to the fact that the compounds described in
this paper were prepared in two laboratories, different analytical
instruments were used. Melting points (uncorrected) were
determined using either a Linström or Kofler apparatus. Infra-
red spectra were recorded with either a Beckmann IR 4220,
Beckmann IR 33 or Bruker IFS 88-FT-IR spectrometer. NMR
spectra were recorded on either a Bruker AMX 500, ARX 500,
AM 400, AC 300 or AM 300, using the residue of 1H (δ = 7.27)
or of 13C (δ = 77.0) of the solvent CDCl3 or tetramethylsilane
a Entries 1–34 were carried out according to two different methods:
entries 1–20 and 25–26 method A (5 mol% catalyst, room temp), entries
21–24 and 27–34 method B (6 mol% catalyst, 0 ЊC), see Experimental
section. b While the ee value of the obtained 1-phenylpropan-1-ol
was assigned by chiral GC or NMR (see Experimental section:
enantioselective catalysis method A and method B), the absolute
configuration of this optically active alcohol was assigned on the basis
of the optical rotation. c Benzyl alcohol between 4–16% was
formed. d Ref. 6b. e Ligand contained 6% disulfide. f Ligand contained
16% disulfide.
1
(TMS) as internal standard. Unless otherwise stated, the H
NMR spectra were recorded at 300 MHz, the 13C NMR spectra
at 75 MHz. J values are given in Hz. MS were recorded on
either a Varian CH 7 (EI), 711 (FD) or a Finnigan-MAT 212
(datasystem SS 300; CI) spectrometer. Optical rotations were
measured using a Perkin-Elmer 241 polarimeter (MC). Optical
rotations are given in 10Ϫ1 deg cm2 gϪ1. Elemental analyses were
carried out at Division Routine Analytik, Fachbereich Chemie,
University of Marburg using a C,H,N-Analyzer Carlo Erba
Stumentalione (1104). Gas chromatography (GC) was per-
formed using a Shimadzu (GC-15-A) instrument, 25 m column
with the following specifications: SGE Cydex-B (chiral),
ωi = 0.25 mm, film thickness 0.25 µm, 1 µl product in n-hexane,
FID detection, nitrogen carrier gas. Column chromatography
was performed using silica gel 60 (particle size 0.040–0.063 mm)
from Merck. Analytical thin layer chromatography (TLC) was
performed using Merck silica gel 60 F254 aluminium sheets or
Polygram Sil G/UV254 from Machery-Nagel. TLC spots were
detected with UV light and I2.
A comparison of the result with ligand 15b (entry 21,
86% ee) with those of ligands 10c (entry 15, 66% ee) or 8a
(entry 5, 49% ee) reveals the favorable effect of the introduction
of an additional stereogenic center at the amino alcohol
group.
Whereas the displacement of the hydroxy group by a sulfur-
containing substituent brings about a significant improvement
of the ee value for compounds 25a (82% ee) and 26a (84% ee)
compared to 8a (49% ee), this is not true in the case of
the β-amino alcohols 21b and 15b compared to the correspond-
ing sulfur compounds 22–24 and 25b–27b, respectively. Never-
theless, the amino thioacetate 25b, the amino thiol 26b as well
as the amino alcohols 8d and 10d are the most efficient ligands
of the series presented in this paper.
In Table 3 a survey of the results obtained in the addition of
diethylzinc to benzaldehyde in the presence of various concen-
trations of the best ligand 8d is given. Not surprisingly, the
enantiomeric excess as well as the chemical yield is strongly
dependent on the catalyst concentration: A decreased amount
of the ligand affords lower ee’s and chemical yields (entries 35–
39) but nevertheless, satisfying results are also obtained for
relatively low catalyst concentration of 8d (1.0 and 0.5 mol%,
entries 38 and 39) in this stereoselective C–C bond forming
reaction.
Preparation of ꢁ-amino acid esters 2–6: general procedure 1
(GP 1)
A solution of amine 1b (5.55 g, 50 mmol) and triethylamine
(5.56 g, 55 mmol) in 100 ml anhydrous THF was cooled down
to 0 ЊC under an argon atmosphere. Within a period of 60 min a
solution 50 mmol of the respective α-bromo carboxylic acid
ester in 50 ml dry THF was added. The reaction mixture was
J. Chem. Soc., Perkin Trans. 1, 1999, 2353–2365
2357

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heated under reflux for 4 h, then cooled down to room temp
and stirred for a further 16 h. After addition of 100 ml of water
the layers were separated and the organic solvent was removed
in vacuo. The residue was dissolved in 50 ml Et2O, washed
with water and brine (30 ml), dried (MgSO4) and evaporated
once again. The residue was distilled without fractionating
(Kugelröhr distillation) affording the crude product as a 1:1
mixture of diastereomers. Separation of the diastereoisomers
was performed by column chromatography on silica gel. In all
cases, diastereomerically pure amino acid derivatives were
obtained.
Preparation of 15b–d,g and 10c: general procedure 6 (GP 6)
A solution of lactam 14b–d,g or 19 (2.5 mmol) in anhydrous
THF (20 ml) was cooled to Ϫ78 ЊC and treated dropwise with a
1 M solution of BH3ؒTHF (7.5 ml). Stirring was continued at
Ϫ78 ЊC for one hour and after warming up to room temp.
the reaction mixture was stirred for an additional hour. After
heating at reflux for two hours and cooling down again to room
temp. the mixture was stirred for a further three days. At a
temperature of 0 ЊC, 5 ml 2 M HCL was cautiously added and
the reaction mixture was heated to reflux for 1.5 h. The organic
layer was evaporated in vacuo and the resulting aqueous layer
was adjusted to pH >5 by the addition of 5 M NaOH. After
extraction with CH2Cl2 (3×) the combined organic layers were
dried (MgSO4) and concentrated under reduced pressure. The
resulting crude products were purified by chromatography or
recrystallization.
Preparation of amino alcohols 7a–10a: general procedure 2
(GP 2)
To a suspension of LiAlH4 (0.45 g, 12 mmol) in anhydrous
THF (50 ml) the respective α-amino acid esters 2–6 (3 mmol in
20 ml THF) were added under vigorous stirring over a period
of 15 min. After the addition, the reaction mixture was heated
under reflux for 3 h and cooled down to 0 ЊC. With cautious
addition of aqueous KOH solution (10%) the excess reducing
reagent was destroyed. The resulting white solid was filtered off
and washed with ethyl acetate by heating to reflux for 20 min
(2 × 50 ml). The combined organic layers were dried (MgSO4)
and concentrated in vacuo to give the crude amino alcohols
which were purified by short-path distillation (bulb-to-bulb) or
chromatography (silica gel).
Synthesis of amino alcohols 9a, 10a, 21a–b: general procedure 7
(GP 7)
Enantiomerically pure (S)- or (R)-styrene oxide (1.0 g, 8.3
mmol) was added dropwise to a stirred solution of amine 1b
(0.93 g, 8.3 mmol) in EtOH (20 ml) and the resulting mixture
was heated under reflux for 4 h. After cooling to room temp.,
the solvent was evaporated under reduced pressure and the
residue was diluted in Et2O (50 ml). Extraction with saturated
NH4Cl solution followed by drying over MgSO4 and concen-
tration in vacuo afforded the crude product as a mixture of
regioisomers which were separated by column chromatography
on silica gel 60.
Preparation of ꢀ-amino alcohols 7b–d to 11b–d:
general procedure 3 (GP 3)
A dried 250 ml, three-necked, round-bottomed flask was
equipped with a pressure-equalizing 50 ml dropping funnel,
thermometer and reflux condenser. The Grignard reagent was
prepared in the usual manner under an argon atmosphere from
magnesium (30 mmol) and the alkyl- or arylhalogenide (30
mmol, 15 mmol in the case of 1,4-dibromobutane) in Et2O (70
ml). The appropriate α-amino acid ester derivative 2–6 (5
mmol), dissolved in 20 ml dry Et2O, was added over 20 min at 0
to 5 ЊC. After the addition, the cooling bath was removed and
the reaction mixture was refluxed for 16 h. For the work-up, the
mixture was cooled down to 0 ЊC and hydrolyzed with saturated
NH4Cl solution. The organic layer was separated and the aque-
ous layer was extracted with diethyl ether (3 × 40 ml). The
combined organic extracts were washed with brine, dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The crude products were purified by either column
chromatography (silica gel), distillation or recrystallization (see
below).
Preparation of ꢀ-amino thioacetate 22 and 25a,b:
general procedure 8 (GP 8)
Similar to the synthesis of 21b by aziridinium ion ring-opening,
β-amino alcohol 10a, 15a or 15b (3 mmol) was mesylated with
methanesulfonyl chloride (0.52 g, 4.5 mmol) in the presence of
triethylamine (0.61 g, 6 mmol) in Et2O (10 ml) at 0 ЊC for 2 h.
After evaporation of the solvent in vacuo the resulting mesylate
was directly treated with an aqueous solution of potassium
thioacetate (1.03 g, 9 mmol in 10 ml water). The reaction mix-
ture was stirred for 20 h, extracted with Et2O (3×), dried
(MgSO4) and concentrated under reduced pressure. If neces-
sary, the resulting crude product was subsequently purified by
column chromatography.
Synthesis of ꢀ-amino thiols 23 and 26a,b: general procedure 9
(GP 9)
Preparation of tricyclic lactams 14a–g and 19: general procedure
4 (GP 4)
A solution of the respective thioacetate 22 or 25a,b (1.5 mmol)
in anhydrous Et2O (20 ml) was cooled to Ϫ10 ЊC and treated
dropwise with a 1.0 M solution of DIBAL-H in hexane (3.3 ml,
3.3 mmol). After 2 h stirring at 0 ЊC, 0.1 ml of methanol and 0.1
ml of water were added, resulting in the formation of a jelly-like
solid. The solvents were separated by the use of a centrifuge
and the residue was washed three times with Et2O. The dried
(MgSO4) combined organic layers were concentrated in vacuo
affording—after chromatographic work-up (silica gel)—the
oxygen sensitive β-amino thiols.
A mixture of ethyl (2-oxocyclopentyl)acetate (3.41 g, 20 mmol)
and 20 mmol of β-amino alcohol 13a–g was refluxed in toluene
(100 ml) in a flask fitted with a Dean–Stark trap. After 16 h, the
reaction mixture was cooled to room temp. and concentrated in
vacuo. The resulting crude product was purified by recrystalliz-
ation or chromatography.
Preparation of 15a,e,f and 10a: general procedure 5 (GP 5)
To a freshly prepared suspension of LiAlH4 (1.39 g, 36.3 mmol)
in anhydrous THF (50 ml) a solution of tricyclic lactam 14a,e,f
or 18 (16.9 mmol) in THF (20 ml) was added dropwise. After
refluxing for 3 h the stirring was continued for an additional
36 h at room temp. The reaction mixture was cautiously hydro-
lyzed by the addition of an aqueous solution of KOH (20%).
The white residue was filtered off and washed by three times
heating to reflux with Et2O–THF (1:1). The combined organic
layers were dried (MgSO4) and concentrated in vacuo. Purifi-
cation of the crude products by chromatography or Kugelröhr
distillation afforded the analytically pure amino alcohols.
Synthesis of amino disulfides 24 and 27a,b: general procedure 10
(GP 10)
The amino thiol 23 or 26a,b (0.4 g, 1.6 mmol) was dissolved in
CHCl3 (50 ml) and stirred for three days at room temp. under
air atmosphere. The solvent was removed in vacuo and the
resulting crude disulfide was purified by column chromato-
graphy.
Methyl (2S,1ЈR,5ЈR)-(؊)-2-(2Ј-azabicyclo[3.3.0]octan-2Ј-yl)-
propionate 2. Synthesis according to GP 1. Work-up: after
2358
J. Chem. Soc., Perkin Trans. 1, 1999, 2353–2365

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Kugelröhr distillation (120 ЊC/10 mbar) column chrom-
atography, eluent: n-hexane–ethyl acetate 8:2, Rf 0.43; yield
4.08 g (48%) as colorless oil (Found: C 67.01, H 9.68, N 7.12.
Calc. for C11H19NO2: C 66.97, H 9.71, N 7.10%); [α]D20 Ϫ76.3 (c
0.68, CH2Cl2); νmax (NaCl)/cmϪ1 1730; δH (500 MHz, CDCl3)
1.27 (3H, d, J 7.7, CH3), 1.30–1.65 (7H, m, 4Ј-H, 6Ј-H2, 7Ј-H2,
8Ј-H2), 1.89 (1H, m, 4Ј-H), 2.51 (2H, m, 1Ј-H, 3Ј-H), 2.88, 3.12
(2H, m, 3Ј-H, 5Ј-H), 3.42 (1H, q, J 7.7, 2-H), 3.66 (s, 3H,
OCH3); δC (125 MHz, CDCl3) 17.41 (CH3), 24.37, 31.67, 32.62,
32.90 (C-4Ј, C-6Ј, C-7Ј, C-8Ј), 42.36 (C-5Ј), 49.41 (C-3Ј), 50.95
(OCH3), 58.61, 66.31 (C-1Ј, C-2), 174.12 (CO); m/z 198 (100%)
[MHϩ].
3.44 (1H, d, J 14.3, 2-H), 3.69 (3H, s, CH3); δC (75 MHz,
CDCl3) 24.44, 31.75, 32.21, 33.24 (C-4Ј, C-6Ј, C-7Ј, C-8Ј), 42.29
(C-5Ј), 51.35 (OCH3), 54.45, 55.09 (C-2, C-3Ј), 68.79 (C-1Ј),
171.53 (CO); m/z 184 (100%) [MHϩ].
(2S,1ЈR,5ЈR)-(؉)-2-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)propan-
1-ol 7a. Synthesis according to GP 2. Work-up: short-path dis-
tillation, bp(0.02
70 ЊC; yield 0.49 g (96%) as colorless oil
mbar)
(Found: C 70.82, H 11.20, N 8.27. Calc. for C10H19NO: C 70.95,
H 11.31, N 8.27%); [α]D20 ϩ39.8 (c 1.5, CH2Cl2); νmax (NaCl)/cmϪ1
3400; δH (300 MHz, CDCl3) 1.07 (1H, d, J 6.7, 3-H), 1.32–1.68
(7H, m, 5Ј-H, 6Ј-H, 7Ј-H, 8Ј-H), 1.89 (1H, m, 4Ј-H), 2.51 (2H,
m, 3Ј-H, 4Ј-H), 2.77 (1H, m, 3Ј-H), 2.88 (1H, m, 2-H), 3.20 (1H,
m, 1Ј-H), 3.31 (1H, dd, J 6.3 and 10.3, 1-H), 3.55 (1H, dd, J 4.6
and 10.3, 1-H); δC (75 MHz, CDCl3) 13.68 (C-3), 24.77, 31.85,
32.63, 34.45 (C-4Ј, C-6Ј, C-7Ј, C-8Ј), 43.04 (C-5Ј), 53.33 (C-3Ј),
57.96 (C-2), 63.42, 64.55 (C-1, C-1Ј); m/z 170 (100%) [MHϩ].
Methyl (2R,1ЈR,5ЈR)-(؊)-2-(2Ј-azabicyclo[3.3.0]octan-2Ј-yl)-
propionate 3. Synthesis according to GP 1. Work-up: after
Kugelröhr distillation (120 ЊC/10 mbar) column chroma-
tography, eluent: n-hexane–ethyl acetate 8:2, Rf 0.30; yield 2.96
g (30%) as colorless oil (Found: C 66.84, H 9.69, N 7.03. Calc.
for C11H19NO2: C 66.97, H 9.71, N 7.10%); [α]D20 Ϫ17.9 (c 1.53,
CH2Cl2); νmax (NaCl)/cmϪ1 1720; δH (500 MHz, CDCl3) 1.28
(3H, d, J 7.7, CH3), 1.32–1.54 (6H, m, 6Ј-H2, 7Ј-H2, 8Ј-H2), 1.62
(1H, m, 4Ј-H), 1.86 (1H, m, 4Ј-H), 2.42 (1H, m, 3Ј-H), 2.53 (1H,
m, 3Ј-H), 2.88 (1H, m, 5Ј-H), 3.25 (1H, m, 1Ј-H), 3.31 (1H, q,
J 7.7, 2-H), 3.64 (3H, s, OCH3); δC (125 MHz, CDCl3) 16.18
(CH3), 24.78, 31.52, 32.54, 33.05 (C-4Ј, C-6Ј, C-7Ј, C-8Ј), 42.73
(C-5Ј), 51.28 (OCH3), 52.01 (C-3Ј), 60.51, 66.18 (C-1Ј, C-2),
174.53 (CO); m/z 198 (100%) [MHϩ].
(2S,1ЈR,5ЈR)-(؉)-3-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)-2-
methylbutan-2-ol 7b. Synthesis according to GP 3. Work-up:
column chromatography, eluent: n-hexane–triethylamine 9:1,
Rf 0.60; yield 0.56 g (57%) as colorless oil (Found: C 73.10,
H 11.73, N 7.04. Calc. for C12H23NO: C 73.04, H 11.75, N
7.10%); [α]D20 ϩ20.8 (c 1.67, CH2Cl2); νmax (NaCl)/cmϪ1 3500–
3200; δH (300 MHz, CDCl3) 1.03 (3H, d, J 6.7, 3-H3), 1.06, 1.15
(6H, 2s, 2CH3), 1.27–1.85 (8H, m, 4Ј-H, 5Ј-H, 6Ј-H2, 7Ј-H2,
8Ј-H2), 2.49 (m, 1H, 4Ј-H), 2.68 (2H, m, 3Ј-H2), 2.86 (1H, m,
2-H), 3.51 (1H, m, 1Ј-H), 4.52 (1H, br s, OH); δC (75 MHz,
CDCl3) 10.85 (C-3), 24.12, 28.03 (2CH3), 25.23, 31.92, 32.50,
33.01 (C-4Ј, C-5Ј, C-6Ј, C-7Ј), 41.91 (C-5Ј), 51.45 (C-3Ј), 64.07,
65.66 (C-1Ј, C-2Ј), 71.08 (C-1); m/z 198 (100%) [MHϩ].
(2S,1ЈR,5ЈR)-(؉)-Benzyl
2-phenyl-2-(2Ј-azabicyclo[3.3.0]-
octan-2Ј-yl)acetate 4. Synthesis according to GP 1. Work-up:
after Kugelröhr distillation (100 ЊC/0.02 mbar) column chrom-
atography, eluent: n-hexane–ethyl acetate 9:1, addition of 1%
triethylamine, Rf 0.50; yield 4.68 g (28%) as colorless oil,
(2S,1ЈR,5ЈR)-(؊)-2-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)-1,1-
diphenylpropan-1-ol 7c. Synthesis according to GP 3. Work-up:
column chromatography; eluent: n-hexane–diethyl ether 7:3, Rf
0.51; yield 1.12 g (70%) as colorless oil (Found: C 81.98, H
8.50, N 4.32. Calc. for C22H27NO: C 82.20, H 8.47, N 4.36%);
[α]D20 Ϫ64.2 (c 0.83, CH2Cl2); νmax (NaCl)/cmϪ1 3400, 1510, 1450;
δH (500 MHz, CDCl3) 1.04 (3H, d, J 6.6, 3-H3), 0.89, 1.18–1.64
(7H, 2m, 4Ј-H, 6Ј-H2, 7Ј-H2, 8Ј-H2), 1.72 (1H, m, 4Ј-H), 2.27
(1H, m, 3Ј-H), 2.42 (2H, m, 3Ј-H, 5Ј-H), 3.28 (1H, m, 1Ј-H),
3.73 (1H, m, 2-H), 5.56 (1H, br s, OH), 7.14–7.24 (m, 6H, arom.
H), 7.51–7.65 (m, 4H, arom. H); δC (75 MHz, CDCl3) 15.65
(C-3), 24.94, 32.09, 33.18, 33.51 (C-4Ј, C-6Ј, C-7Ј, C-8Ј), 41.58
(C-5Ј), 52.56 (C-3Ј), 62.32 (C-2), 66.57 (C-1Ј), 77.82 (C-1),
125.99, 126.16, 126.35, 127.61, 127.86, 146.02, 148.54 (arom.
C); m/z 322 (100%) [MHϩ].
bp(0.02
105 ЊC (Found: C 78.60, H 7.49, N 4.15. Calc. for
mbar)
C22H25NO2: C 78.78, H 7.51, N 4.18%); [α]D22 ϩ7.24 (c 1.16,
CH2Cl2); νmax (NaCl)/cmϪ1 1760, 1510, 1480; δH (300 MHz,
CDCl3) 1.17–1.62 (7H, m, 4Ј-H, 6Ј-H2, 7Ј-H2, 8Ј-H2), 1.81
(m, 1H, 4Ј-H), 2.59 (2H, m, 3Ј-H2), 2.80 (m, 1H, 5Ј-H), 3.32 (m,
1H, 1Ј-H), 4.41 (s, 1H, 2-H), 5.18 (2H, 2d, J 12.4 and 12.4,
CH2Ph), 7.20–7.51 (m, 10H, arom. H); δC (75 MHz, CDCl3)
25.04, 31.69, 33.16 (C-4Ј, C-6Ј, C-7Ј, C-8Ј), 42.51 (C-5Ј), 50.85
(OCH2Ph), 66.17, 67.17 (C-1Ј, C-3Ј), 69.75 (C-2), 127.89,
128.07, 128.25, 128.41, 128.69, 135.87, 137.60 (arom. C), 171.68
(CO); m/z 336.3 (100%) [MHϩ].
(2R,1ЈR,5ЈR)-(؊)-Benzyl
2-phenyl-2-(2Ј-azabicyclo[3.3.0]-
octan-2Ј-yl)acetate 5. Synthesis according to GP 1. Work-up:
after Kugelröhr distillation (100 ЊC/0.02 mbar) column chrom-
atography, eluent: n-hexane–ethyl acetate 9:1, addition of 1%
triethylamine, Rf 0.40; yield 6.6 g (39%) as colorless oil (Found:
C 78.85, H 7.52, N 4.20. Calc. for C22H25NO2: C 78.78, H 7.51,
N 4.18%); [α]D20 Ϫ37.06 (c 1.53, CH2Cl2); νmax (NaCl)/cmϪ1 1740,
1530, 1500; δH (300 MHz, CDCl3) 1.19–1.68 (7H, m, 4Ј-H,
6Ј-H2, 7Ј-H2, 8Ј-H2), 1.92 (1H, m, 4Ј-H), 2.40 (1H, m, 3Ј-H),
2.57 (1H, m, 3Ј-H), 2.82 (1H, m, 5Ј-H), 3.28 (1H, m, 1Ј-H), 4.35
(1H, s, 2-H), 5.14 (2H, 2d, J 12.4 and 12.5, CH2Ph), 7.17–
7.52 (m, 10H, arom. H); δC (75 MHz, CDCl3) 25.17, 31.19,
31.56, 33.05 (C-4Ј, C-6Ј, C-7Ј, C-8Ј), 42.37 (C-5Ј), 51.92
(OCH2Ph), 66.31, 66.80 (C-1Ј, C-3Ј), 70.88 (C-2), 127.92,
127.98, 128.18, 128.38, 128.67, 129.13, 135.81, 136.52 (arom.
C), 172.00 (CO); m/z 336.3 (100%) [MHϩ].
(1ЈS,1ЉR,5ЉR)-(؉)-1-[1Ј-(2Љ-Azabicyclo[3.3.0]octan-2Љ-yl)-
ethyl]cyclopentanol 7d. Synthesis according to GP 3. Work-up:
column chromatography; eluent: n-hexane–triethylamine 9:1,
Rf 0.74; yield 0.49 g (44%) as colorless oil (Found: C 75.28, H
11.09, N 6.31. Calc. for C14H25NO: C 75.32, H 11.29, N 6.27%);
[α]D20 ϩ4.8 (c 0.54, CH2Cl2); νmax (NaCl)/cmϪ1 3350; δH (300
MHz, CDCl3) 1.07 (3H, d, J 7.0, 2Ј-H3), 1.27–1.92 (16H, m,
2-H2, 3-H2, 4-H2, 5-H2, 4Љ-H, 5Љ-H, 6Љ-H2, 7Љ-H2, 8Љ-H2), 2.53,
2.65 (2H, 2m, 3Љ-H, 4Љ-H), 2.91 (2H, m, 3Љ-H, 1Ј-H), 3.64 (1H,
m, 2Ј-H), 4.58 (1H, br s, OH); δC (75 MHz, CDCl3) 10.78 (C-2Ј),
24.05, 24.90, 31.88, 33.35, 25.00, 32.85, 35.36, 39.54 (C-2, C-3,
C-4, C-5, C-4Љ, C-6Љ, C-7Љ, C-8Љ), 42.54 (C-5Љ), 52.73 (C-3Љ),
62.27, 64.38 (C-1Ј, C-1Љ), 82.19 (C-1); m/z 224 (100%) [MHϩ].
Methyl
(1ЈR,5ЈR)-(؊)-2-(2Ј-azabicyclo[3.3.0]octan-2Ј-yl)-
(2R,1ЈR,5ЈR)-(؊)-2-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)propan-
1-ol 8a. Synthesis according to GP 2. Work-up: short-path dis-
acetate 6. Synthesis according to GP 1. Work-up: short-path
distillation, bp(0.02 mbar) 70 ЊC; yield 7.74 g (85%) as colorless oil
(Found: C 65.28, H 9.34, N 7.72. Calc. for C10H17NO2: C 65.54,
H 9.35, N 7.64%); [α]D20 Ϫ67.7 (c 1.55, CH2Cl2); νmax (NaCl)/cmϪ1
1740; δH (300 MHz, CDCl3) 1.29–1.68 (7H, m, 4Ј-H, 6Ј-H2,
7Ј-H2, 8Ј-H2), 1.95 (1H, m, 4Ј-H), 2.44 (m, 1H, 3Ј-H), 2.54 (1H,
m, 3Ј-H), 3.01 (2H, m, 1Ј-H, 5Ј-H), 3.24 (1H, d, J 14.3, 2-H),
tillation, bp(0.02
75 ЊC; yield 0.48 g (94%) as colorless oil
mbar)
(Found: C 70.89, H 11.28, N 8.33. Calc. for C10H19NO: C 70.95,
H 11.31, N 8.27%); [α]D20 Ϫ80.5 (c 1.5, CH2Cl2); [α]D20 Ϫ44.1 (c 1.1,
EtOH); νmax (NaCl)/cmϪ1 3450, 1450; δH (300 MHz, CDCl3)
0.84 (3H, d, J 6.6, 3-H), 1.18–1.27, 1.38–1.52 (7H, 2m, 4Ј-H,
6Ј-H2, 7Ј-H2, 8Ј-H2), 1.90 (1H, m, 4Ј-H), 2.23 (1H, ddd, J 5.5,
J. Chem. Soc., Perkin Trans. 1, 1999, 2353–2365
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8.6 and 11.4, 3Ј-H), 2.43 (1H, m, 5Ј-H), 2.58 (1H, dd, J 6.7 and
8.6, 3Ј-H), 2.88 (1H, ddq, J 5.0, 6.6 and 10.0, 2-H), 3.08 (1H,
dd, J 6.3 and 8.2, 1Ј-H), 3.15 (1H, t, J 10.0, 1-H), 3.35 (1H, dd,
J 5.0 and 10.0, 1-H); δC (75 MHz, CDCl3) 9.3 (C-3), 23.7,
32.2, 32.7, 33.2 (C-4Ј, C-6Ј, C-7Ј, C-8Ј), 41.6 (C-5Ј), 44.7 (C-3Ј),
54.4 (C-2), 63.5 (C-1), 65.2 (C-1Ј); m/z 170 (100%) [MHϩ].
(2S,1ЈR,5ЈR)-(؊)-2-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)-2-
phenylethanol 9a. Synthesis according to GP 7. Work-up:
column chromatography, eluent: n-hexane–ethyl acetate 1:1, Rf
0.31; yield 0.18 g (9%); [α]D20 Ϫ5.8 (c 1.0, CH2Cl2); the analytical
characteristics were in complete accord with 9a obtained by
GP 2.
(2S,1ЈR,5ЈR)-(؉)-2-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)-1,1-
dimethyl-2-phenylethanol 9b. Synthesis according to GP 3.
Work-up: column chromatography; eluent: n-hexane–ethyl
acetate 8:2, Rf 0.32; yield 0.73 g (56%) as colorless oil (Found:
C 78.53, H 9.77, N 5.38. Calc. for C17H25NO: C 78.72, H 9.71,
N 5.40%); [α]D20 ϩ11.6 (c 1.16, CH2Cl2); νmax (NaCl)/cmϪ1 3280,
1510, 1490; δH (300 MHz, CDCl3) 1.16, 1.19 (6H, 2s, 2CH3),
1.21–1.54 (6H, m, 6Ј-H2, 7Ј-H2, 8Ј-H2), 1.69 (1H, m, 4Ј-H), 1.86
(1H, m, 4Ј-H), 2.41 (1H, m, 3Ј-H), 2.70 (1H, m, 3Ј-H), 2.88 (1H,
m, 5Ј-H), 3.56 (1H, m, 1Ј-H), 3.68 (1H, s, 2-H), 3.89 (1H, br s,
OH), 7.25–7.39 (m, 5H, arom. H); δC (75 MHz, CDCl3) 25.47,
26.18, 29.76, 31.65, 32.26, 33.27 (2 × CH3, C-4Ј, C-6Ј, C-7Ј,
C-8Ј); 41.32 (C-5Ј); 51.91 (C-3Ј); 68.74, 74.98 (C-1Ј, C-2); 72.84
(C-1); 126.97, 127.68, 130.70, 138.56 (arom. C); m/z 260 (100%)
[MHϩ].
(2R,1ЈR,5ЈR)-(؊)-3-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)-2-
methylbutan-1-ol 8b. Synthesis according to GP 3. Work-up:
column chromatography, eluent: n-hexane–triethylamine 95:5,
Rf 0.5; yield 0.87 g (88%) as colorless oil (Found: C 72.90, H
11.84, N 7.16. Calc. for C12H23NO: C 73.04, H 11.75, N 7.10%);
[α]D20 Ϫ95.5 (c 1.5, CH2Cl2); νmax (NaCl)/cmϪ1 3300; δH (300
MHz, CDCl3) 0.96 (3H, d, J 6.6, 3-H3), 1.06, 1.14 (6H, 2s,
2CH3), 1.21–1.71 (7H, m, 5Ј-H, 6Ј-H2, 7Ј-H2, 8Ј-H2), 1.95 (1H,
m, 4Ј-H), 2.37 (1H, m, 4Ј-H), 2.63 (1H, q, J 6.6, 2-H), 2.74, 3.03
(2H, 2m, 3Ј-H2), 4.68 (1H, br s, OH); δC (75 MHz, CDCl3)
7.41 (C-3), 23.35, 28.32, 24.97, 32.69, 32.74, 33.30 (2 × CH3,
C-4Ј, C-5Ј, C-6Ј, C-7Ј), 40.31 (C-5Ј), 47.36 (C-3Ј), 62.52, 68.28
(C-1Ј, C-2Ј), 70.01 (C-1); m/z 198 (100%) [MHϩ].
(2R,1ЈR,5ЈR)-(؊)-2-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)-1,1-
diphenylpropan-1-ol 8c. Synthesis according to GP 3. Work-up:
column chromatography; eluent: n-hexane–triethylamine 8:2,
Rf 0.82; yield 1.22 g (76%) as slightly yellow oil (Found: C
82.03, H 8.44, N 4.30. Calc. for C22H27NO: C 82.20, H 8.47, N
4.36%); [α]D20 Ϫ12.8 (c 1.06, CH2Cl2); [α]D20 Ϫ35.9 (c 1.0, EtOH);
νmax (NaCl)/cmϪ1 3250, 1490, 1450; δH (500 MHz, CDCl3) 1.14
(3H, d, J 6.8, 3-H), 1.34, 1.41–1.73, 1.75–1.88 (8H, 3m, 4Ј-H2,
6Ј-H2, 7Ј-H2, 8Ј-H2), 1.92–2.06 (2H, m, 3Ј-H2), 2.39 (1H, m,
5Ј-H), 3.17 (1H, m, 1Ј-H), 3.73 (1H, q, J 6.8, 2-H), 6.23 (1H, br
s, OH), 7.00–7.28 (6H, m, arom. H), 7.40–7.43 (4H, m, arom.
H); δC (75 MHz, CDCl3) 9.9 (C-3), 23.6, 32.45, 32.58, 33.25
(C-4Ј, C-6Ј, C-7Ј, C-8Ј), 40.54 (C-5Ј), 46.86 (C-3Ј), 61.19 (C-2),
68.10 (C-1Ј), 77.2 (C-1), 126.42, 126.93, 127.10, 127.47, 127.91,
128.27, 145.17, 146.25 (arom. C); m/z 322 (100%) [MHϩ].
(2S,1ЈR,5ЈR)-(؉)-2-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)-1,1,2-
triphenylethanol 9c. Synthesis according to GP 3. Work-up:
column chromatography; eluent: n-hexane–ethyl acetate 8:2,
Rf 0.71; yield 1.26 g (66%) as colorless crystals, mp 134 ЊC
(Found: C 84.22, H 7.68, N 3.61. Calc. for C27H29NO: C 84.55,
H 7.62, N 3.65%); [α]D20 ϩ110.3 (c 1.02, CH2Cl2); νmax (KBr)/cmϪ1
3500–3300, 1600, 1490; δH (300 MHz, CDCl3) 0.99–1.59 (7H,
m, 4Ј-H, 6Ј-H2, 7Ј-H2, 8Ј-H2), 1.72 (1H, m, 4Ј-H), 2.27–2.36
(3H, m, 5Ј-H, 3Ј-H2), 2.98 (1H, m, 1Ј-H), 4.88 (1H, s, 2-H),
6.18 (1H, br s, OH), 6.87–6.96, 7.41–7.82 (15H, 2m,
arom. H); δC (75 MHz, CDCl3) 25.03, 31.74, 32.84, 33.07
(C-4Ј, C-6Ј, C-7Ј, C-8Ј), 41.82 (C-5Ј), 54.87 (C-3Ј), 66.91
(C-1Ј), 75.19 (C-2), 78.06 (C-1), 125.19, 126.05, 126.78,
127.21, 127.33, 128.05, 128.73, 131.26, 131.26, 139.29, 146.50,
150.23 (arom. C); m/z 384 (38%) [MHϩ], 200 (100) [Mϩ Ϫ
C(Ph)2OH].
(1ЈR,1ЉR,5ЉR)-(؊)-1-[1Ј-(2Љ-Azabicyclo[3.3.0]octan-2Љ-yl)-
ethyl]cyclopentanol 8d. Synthesis according to GP 3. Work-up:
column chromatography; eluent: n-hexane–ethyl acetate 7:3, Rf
0.64; yield 0.77 g (69%) as colorless oil (Found: C 75.46, H
11.18, N 6.26. Calc. for C14H25NO: C 75.32, H 11.29, N 6.27%);
[α]D20 Ϫ74.0 (c 0.83, CH2Cl2); [α]D20 Ϫ45.1 (c 0.9, EtOH); νmax
(NaCl)/cmϪ1 3280; δH (300 MHz, CDCl3) 0.89 (3H, d, J 6.9,
2Ј-H), 1.16–1.27, 1.29–1.80 (15H, 2m, 2-H2, 3-H2, 4-H2, 5-H2,
4Љ-H, 6Љ-H2, 7Љ-H2, 8Љ-H2), 1.90 (1H, ddd, J 5.5, 9.1 and 12.0,
4Љ-H), 2.29 (1H, ddd, J 5.5, 8.7 and 11.5, 5Љ-H), 2.32 (1H, m,
3Љ-H), 2.57 (1H, dd, J 6.7, 8.7, 3Љ-H), 2.87 (1H, q, J 6.9, 1Ј-H),
3.02 (1H, dd, J 6.0 and 8.1, 1Љ-H), 4.86 (1H, br s, OH); δC (75
MHz, CDCl3) 6.43 (C-2Ј), 23.40, 23.78, 25.19, 32.56, 32.70,
33.31, 35.18, 38.39 (C-2, C-3, C-4, C-5, C-4Љ, C-6Љ, C-7Љ, C-8Љ),
40.85 (C-5Љ), 46.63 (C-3Љ), 58.98 (C-2Ј), 67.0 (C-1Љ), 81.00 (s,
C-1); m/z 224 (100%) [MHϩ].
(1ЈS,1ЉR,5ЉR)-(؉)-1-[Phenyl(2Љ-azabicyclo[3.3.0]octan-2Љ-
yl)methyl]cyclopentanol 9d. Synthesis according to GP 3. Work-
up: column chromatography; eluent: n-hexane–ethyl acetate
1:1, Rf 0.58; yield 0.73 g (51%) as colorless oil (Found: C 80.02,
H 9.52, N 4.88. Calc. for C19H27NO: C 79.95, H 9.53, N 4.91%);
[α]D20 ϩ3.6 (c 1.03, CH2Cl2); νmax (NaCl)/cmϪ1 3500–3100, 1460;
δH (300 MHz, CDCl3) 1.12–1.78, 1.83–2.04 (16H, 2m, 2-H2,
3-H2, 4-H2, 5-H2, 4Љ-H, 5Љ-H, 6Љ-H2, 7Љ-H2, 8Љ-H2), 2.48 (2H, m,
4Љ-H, 3Љ-H), 2.98 (1H, m, 3 -H), 3.47 (1H, m, 1 -H), 3.56 (1H, s,
1Ј-H), 5.13 (1H, br s, OH), 7.21–7.47 (2m, 5H, arom. H); δC
(75 MHz, CDCl3) 23.21, 24.44, 25.34, 32.89 (C-4Љ, C-6Љ, C-7Љ,
C-8Љ), 31.71, 31.95, 42.14, 42.52 (C-2, C-3, C-4, C-5), 39.22
(C-5Љ), 54.37 (C-3Љ), 68.14, 75.53 (C-1Ј, C-1 ), 82.92 (C-1),
127.25, 127.65, 130.14, 140.34 (arom. C); m/z 286 (92%) [MHϩ],
200 (70) [C14H18N], 175 (100) [C12H15O].
(2S,1ЈR,5ЈR)-(؊)-2-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)-2-
phenylethanol 9a. Synthesis according to GP 2. Work-up:
column chromatography; eluent: n-hexane–ethyl acetate 1:1, Rf
0.22; yield 0.58 g (84%), colorless oil (Found: C 77.9, H 9.16, N
5.97. Calc. for C15H21NO: C 77.87, H 9.14, N 6.05%); [α]D20 Ϫ5.7
(c 1.0, CH2Cl2); νmax (NaCl)/cmϪ1 3350, 1480; δH (500 MHz,
CDCl3) 1.23–1.43, 1.52–1.64 (7H, 2m, 4Ј-H, 6Ј-H2, 7Ј-H2,
8Ј-H2), 1.85 (1H, m, 4Ј-H), 2.43 (1H, m, 3Ј-H), 2.57 (1H, m,
3Ј-H), 2.69 (1H, br s, OH), 2.88 (1H, m, 5Ј-H), 3.16 (1H, m,
1Ј-H), 3.72 (1H, dd, J 6.8 and 13, 2-H), 3.78 (1H, dd, J 6.04 and
16.15, 1-H), 3.92 (1H, dd, J 7.0 and 10.3, 1-H), 7.27–7.36 (m,
5H, arom. H); δC (75 MHz, CDCl3) 25.31, 31.56, 32.59, 32.75
(C-4Ј, C-5Ј, C-6Ј, C-7Ј); 42.68 (C-5Ј), 53.39 (C-3Ј), 63.26 (C-1Ј),
64.67 (C-2), 67.86 (C-1), 127.59, 128.15, 129.14, 138.54 (arom.
C); m/z 232 (100%) [MHϩ].
(2R,1ЈR,5ЈR)-(؊)-2-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)-2-
phenylethanol 10a. Synthesis according to GP 2. Work-up:
column chromatography, eluent: n-hexane–ethyl acetate 1:1, Rf
0.26; yield 0.57 g (82%) as colorless oil; [α]D20 Ϫ49.7 (c 1.08,
EtOH) [lit.12 [α]D25 Ϫ56.2 (c 1.01, EtOH)]; the spectral data are in
complete accord with those described in the literature.12
(2R,1ЈR,5ЈR)-(؊)-2-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)-2-
phenylethanol 10a. Synthesis according to GP 7. Work-up:
column chromatography, eluent: n-hexane–ethyl acetate 1:1, Rf
0.58; yield 0.27 g (16%) as colorless oil; [α]D22 Ϫ69.3 (c 0.98,
CH2Cl2); [α]D20 Ϫ50.2 (c 1.0, EtOH); the analytical data are in
accord with those described in the literature.12
2360
J. Chem. Soc., Perkin Trans. 1, 1999, 2353–2365

View Article Online
(2R,1ЈR,5ЈR)-(؊)-2-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)-1,1-
dimethyl-2-phenylethanol 10b. Synthesis according to GP 3.
Work-up: column chromatography; eluent: n-hexane–ethyl
acetate 8:2, Rf 0.63; yield 0.76 g (59%) as colorless oil (Found:
C 78.49, H 9.80, N 5.41. Calc. for C17H25NO: C 78.72, H 9.71,
N 5.40%); [α]D20 Ϫ102.3 (c 1.04, CH2Cl2); νmax (NaCl)/cmϪ1 3300,
1490; δH (300 MHz, CDCl3) 1.14, 1.31 (6H, 2s, 2CH3), 1.21–
1.70 (7H, m, 4Ј-H, 6Ј-H2, 7Ј-H2, 8Ј-H2), 1.81–1.95 (2H, m, 3Ј-H,
4Ј-H), 2.24 (1H, m, 3Ј-H), 2.96 (1H, m, 5Ј-H), 3.16 (1H, m,
1Ј-H), 3.63 (1H, s, 2-H), 3.92 (1H, br s, OH), 7.33 (5H, m, arom.
H); δC (75 MHz, CDCl3) 23.76, 26.97, 28.98, 31.89, 32.25, 33.21
(2 × CH3, C-4Ј, C-6Ј, C-7Ј, C-8Ј), 39.92 (C-5Ј), 50.10 (C-3Ј),
67.49 (C-1Ј), 71.79 (C-1), 73.61 (C-2), 127.14, 127.51, 131.21,
134.53 (arom. C); m/z 260 (100%) [MHϩ].
short-path distillation, bp(0.02
60 ЊC; yield 0.77 g (85%)
mbar)
as colorless oil (Found: C 71.97, H 11.49, N 7.66. Calc. for
C11H21NO: C 72.08, H 11.55, N 7.64%); [α]D20 Ϫ73.7 (c 1.67,
CH2Cl2); νmax (NaCl)/cmϪ1 3300–3100; δH (300 MHz, CDCl3)
1.15, 1.17 (6H, 2s, 2CH3), 1.32–1.67 (7H, m, 4Ј-H, 6Ј-H2, 7Ј-H2,
8Ј-H2), 1.98 (1H, m, 4Ј-H), 2.32 (1H, m, 5Ј-H), 2.39 (1H, d,
J 13.2, 2Ј-H), 2.48 (1H, m, 1Ј-H), 2.59 (1H, d, J 13.2, 2Ј-H),
3.08, 3.12 (2H, 2m, 3Ј-H2), 3.26 (1H, br s, OH); δC (75 MHz,
CDCl3) 28.31, 29.05 (2CH3), 23.93, 32.39, 33.10, 33.66 (C-4Ј,
C-6Ј, C-7Ј, C-8Ј), 40.84 (C-5Ј), 56.67 (C-3Ј), 65.97 (C-2), 68.59
(C-1), 71.87 (C-1Ј); m/z 184 (100%) [MHϩ].
(1ЈR,5ЈR)-(؊)-2-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)-1,1-
diphenylethanol 11c. Synthesis according to GP 3. Work-up:
recrystallization from diethyl ether–n-hexane; mp 83 ЊC; yield
1.01 g (66%) as slightly yellow solid (Found: C 82.01, H 8.20, N
4.59. Calc. for C21H25NO: C 82.05, H 8.20, N 4.56%); [α]D20 Ϫ11.4
(c 1.20, CH2Cl2); νmax (KBr)/cmϪ1 3500–3300, 1590, 1470;
δH (300 MHz, CDCl3) 1.17–1.78 (7H, m, 4Ј-H, 6Ј-H2, 7Ј-H2,
8Ј-H2), 1.83–2.01 (2H, m, 4Ј-H, 5Ј-H), 2.29 (1H, m, 3Ј-H), 2.47
(1H, m, 1Ј-H), 3.12 (1H, m, 3Ј-H), 3.35 (1H, d, J 12.6, 2-H),
3.52 (1H, d, J 12.7, 2-H), 5.06 (1H, br s, OH), 7.18–7.39, 7.53–
7.67 (10H, 2m, arom. H); δC (75 MHz, CDCl3) 23.85, 32.14,
32.95, 33.52 (C-4Ј, C-6Ј, C-7Ј, C-8Ј), 40.67 (C-5Ј), 54.89 (C-3Ј),
64.80 (C-2), 71.05 (C-1Ј), 73.93 (C-1), 125.46, 125.84, 126.32,
126.54, 127.89, 128.05, 147.28 (arom. C), m/z (100%) [MHϩ].
(2R,1ЈR,5ЈR)-(؊)-2-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)-1,1,2-
triphenylethanol 10c. Synthesis according to GP 3. Work-up:
column chromatography; eluent: n-hexane–triethylamine 9:1,
Rf 0.21; yield 1.36 g (71%) as colorless crystals, mp 142 ЊC
(Found: C 84.49, H 7.42, N 3.80. Calc. for C27H29NO: C 84.56,
H 7.62, N 3.65%); [α]D20 Ϫ16.7 (c 1.01, CH2Cl2); [α]D20 Ϫ12.5 (c 1.1,
CHCl3); νmax (KBr)/cmϪ1 3550, 1450; δH (300 MHz, CDCl3)
1.09–1.66 (7H, m, 4Ј-H, 6Ј-H2, 7Ј-H2, 8Ј-H2), 1.80 (1H, m,
4Ј-H), 2.08 (1H, m, 3Ј-H), 2.21 (1H, m, 3Ј-H), 2.60 (1H, m,
5Ј-H), 3.20 (1H, m, 1Ј-H), 4.68 (1H, s, 2-H), 5.88 (1H, br s,
OH), 7.00–7.33 (13H, m, arom. H), 7.70–7.73 (2H, m, arom. H);
δC (75 MHz, CDCl3) 24.6, 30.4, 32.3, 33.3 (C-4Ј, C-6Ј, C-7Ј,
C-8Ј or C-6Ј), 40.3 (C-5Ј), 50.5 (C-3Ј), 67.9 (C-1Ј), 72.7 (C-2),
78.6 (C-1), 125.8, 126.1, 126.4, 126.9, 127.0, 127.1, 127.2, 127.8,
131.3, 137.0, 145.9, 148.9 (arom. C); m/z 384 (38%) [MHϩ], 200
(100) [C14H18Nϩ].
(1ЉR,5ЉR)-(؊)-1-[Phenyl(2Љ-azabicyclo[3.3.0]octan-2Љ-yl)-
methyl]cyclopentanol 11d. Synthesis according to GP 3. Work-
up: short-path distillation, bp(0.02 mbar) 90 ЊC; yield 0.85 g (81%)
as yellow oil (Found: C 74.49, H 11.11, N 6.65. Calc. for
C13H23NO: C 74.59, H 11.07, N 6.69%); [α]D20 Ϫ69.6 (c 2.32,
CH2Cl2); νmax (NaCl)/cmϪ1 3500–3100; δH (300 MHz, CDCl3)
1.24–1.89 (15H, m, 2-H2, 3-H2, 4-H2, 5-H2, 4Љ-H, 6Љ-H2, 7Љ-H2,
8Љ-H2), 2.01 (1H, m, 4Љ-H), 2.23 (1H, m, 5Љ-H), 2.36 (1H, d,
J 12.7, 1Ј-H), 2.48 (1H, m, 1Љ-H), 2.84 (1H, d, J 12.7, 1Ј-H),
2.98–3.11 (2H, m, 3Љ-H); δC (75 MHz, CDCl3) 23.48, 23.88,
24.70, 32.35, 33.00, 33.61, 39.03, 40.42 (C-2, C-3, C-4, C-5,
C-4Љ, C-5Љ, C-6Љ, C-7Љ), 41.02 (C-5Љ), 55.55 (C-3Љ), 63.75 (C-2Ј),
71.01 (C-1Љ), 78.99 (C-1); m/z 210 (100%) [MHϩ].
(2R,1ЈR,5ЈR)-(؉)-2-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)-1,1,2-
triphenylethanol 10c. Synthesis according to GP 6. Work-up:
recrystallization from ethyl acetate–petroleum ether (40–60 ЊC)
1:1; yield 0.67 g (68%) as colorless needles, mp 159 ЊC; [α]D23
Ϫ11.9 (c 1.0, CHCl3); the spectral characteristics are in accord
with 10c synthesized by GP 3.
(1ЈR,1ЉR,5ЉR)-(؊)-1-[Phenyl(2Љ-azabicyclo[3.3.0]octan-2Љ-
yl)methyl]cyclopentanol 10d. Synthesis according to GP 3.
Work-up: column chromatography; eluent: toluene–ethyl acet-
ate 3:7, Rf 0.56; yield 0.61 g (43%) as colorless oil (Found: C
79.72, H 9.53, N 4.88. Calc. for C19H27NO: C 79.75, H 9.53, N
4.91%); [α]D20 Ϫ80.4 (c 0.46, CH2Cl2); νmax (NaCl)/cmϪ1 3400–
3200, 1480; δH (300 MHz, CDCl3) 1.26–1.97 (16H, m, 2-H2,
3-H2, 4-H2, 5-H2, 4Љ-H, 5Љ-H, 6Љ-H2, 7Љ-H2, 8Љ-H2), 2.27 (1H, m,
4Љ-H), 2.39 (1H, m, 3Љ-H), 2.99 (2H, m, 3Љ-H, 1Љ-H), 3.76 (1H, s,
1Ј-H), 7.33 (5H, m, arom. H); δC (75 MHz, CDCl3) 22.92, 24.02,
24.24, 33.36 (C-4Љ, C-6Љ, C-7Љ, C-8Љ), 31.62, 32.34, 37.36, 39.50
(C-2, C-3, C-4, C-5), 40.43 (C-5Љ), 49.84 (C-3Љ), 66.74, 71.27
(C-1Ј, C-1Љ), 82.87 (C-1), 127.13, 127.57, 131.13, 136.09 (arom.
C); m/z 286 (96%) [MHϩ], 200 (78) [C14H18Nϩ], 175 (100)
[C12H15O].
(4S,8R,11S)-(؉)-11-Methyl-9-oxa-1-azatricyclo[6.3.0.04.8]-
undecan-2-one 14a.§ Synthesis according to GP 4. Work-up:
column chromatography, eluent: ethyl acetate–petroleum ether
(40–60 ЊC) 1:4, Rf 0.20; yield 3.07 g (85%) as colorless oil
(Found: C 65.81, H 8.23, N 7.24. Calc. for C10H15NO2: C 66.29,
H 8.34, N 7.73%); [α]D20 ϩ91.4 (c 1.0, EtOH); νmax (NaCl)/cmϪ1
3492, 2964, 2870, 1710, 1357, 1330, 1228, 1207, 1030; δH (300
MHz, CDCl3) 1.21 (3H, d, J 6.6, CH3), 1.44 (1H, m, 5-H), 1.66–
1.76 (3H, m, 6-H2, 7-H), 1.87–1.94 (2H, m, 5-H, 7-H), 2.29 (1H,
dd, J 6.9 and 17.5, 3-H), 2.53 (1H, m, 4-H), 2.68 (1H, dd, J 10.5
and 17.5, 3-H), 3.53 (1H, dd, J 7.0 and 8.1, 10-H), 4.07 (1H,
ddq, J 6.6, 6.7 and 7.0, 11-H), 4.16 (1H, dd, J 6.7 and 8.1,
10-H); δC (75 MHz, CDCl3) 19.7 (CH3), 24.6 (C-6), 32.0 (C-5),
37.6 (C-7), 40.4 (C-3), 41.7 (C-4), 50.3 (C-11), 73.6 (C-10), 110.1
(C-8), 179.5 (C-2); m/z 152 (100%) [C9H14NOϩ], 181 (24) [Mϩ].
(1ЈR,5ЈR)-(؊)-2-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)ethanol
11a. Synthesis according to GP 2. Work-up: short-path distil-
lation, bp(24
120 ЊC; yield 0.41 g (88%) as colorless oil
mbar)
(4S,8R,11S)-(؊)-11-Methyl-10,10-diphenyl-9-oxa-1-aza-
tricyclo[6.3.0.04.8]undecan-2-one 14c. Synthesis according to GP
4. Work-up: recrystallization from petroleum ether (40–60 ЊC);
yield 4.83 g (72%) as yellow solid, mp 162 ЊC (Found: C 79.13,
H 6.94, N 4.11. Calc. for C22H23NO2: C 79.26, H 6.95, N
4.20%); [α]D20 Ϫ128.3 (c 1.0, EtOH); νmax (NaCl)/cmϪ1 3438, 2969,
2951, 1711, 1449, 1360, 1332, 1227, 1193, 1013, 963, 748, 707;
δH (300 MHz, CDCl3) 0.95 (3H, d, J 7.0, CH3), 1.48 (1H, m,
(Found: C 69.53, H 10.86, N 8.97. Calc. for C9H17NO: C 69.63,
H 11.04, N 9.02%); [α]D20 Ϫ60.6 (c 1.41, CHCl3); νmax (NaCl)/
cmϪ1 3600–3100; δH (300 MHz, CDCl3) 1.29–1.67 (7H, m, 4Ј-H,
6Ј-H2, 7Ј-H2, 8Ј-H2), 1.94–2.18 (2H, m, 4Ј-H, 5Ј-H), 2.46–2.59
(2H, m, 2-H2), 2.77–2.91 (2H, m, 3Ј-H2), 2.96–3.02 (1H, m,
1Ј-H), 3.41 (1H, br s, OH), 3.54–3.67 (2H, m, 1-H2); δC (75
MHz, CDCl3) 24.03, 32.15, 32.30, 33.04 (C-4Ј, C-6Ј, C-7Ј,
C-8Ј), 41.72 (C-5Ј), 53.89 (C-3Ј), 56.51 (C-1Ј), 59.30 (C-1),
69.79 (C-2); m/z 157 (100%) [MHϩ].
§ The IUPAC name for 14a is (1R,4S,8S)-(ϩ)-4-methyl-2-oxa-5-
azatricyclo[6.3.0.0.1.5]undecan-6-one. Compounds 14c, 14d, 14f and 14g
can be named similarly using IUPAC rules.
(1ЈR,5ЈR)-(؊)-2-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)-1,1-
dimethylethanol 11b. Synthesis according to GP 3. Work-up:
J. Chem. Soc., Perkin Trans. 1, 1999, 2353–2365
2361

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5-H), 1.60 (1H, m, 6-H), 1.84–1.92 (2H, m, 5-H, 6-H), 2.02 (1H,
d, J 10.2, 3-H), 2.02 (1H, d, J 8.3, 3-H), 2.13 (1H, m, 7-H), 2.17
(1H, m, 7-H), 2.38 (1H, dddd, J <2, 7.4, 8.3 and 10.2, 4-H), 5.30
(1H, q, J 7.0, 11-H), 7.17–7.36 (8H, m, arom. H), 7.50–7.66
(2H, m, arom. H); δC (75 MHz, CDCl3) 16.4 (CH3), 23.4 (C-6),
31.5 (C-5), 39.0 (C-3), 41.4 (C-7), 43.3 (C-4), 56.7 (C-11),
91.2 (C-10), 109.6 (C-8), 125.9, 126.8, 126.9, 127.5, 128.0,
128.1, 142.0, 143.4 (arom. C), 179.0 (s, C-2); m/z 151 (100%)
[C9H13NOϩ]; (field desorption, FD): m/z [C9H13NOϩ], 333 (1)
[Mϩ].
distillation: bp(0.02
75 ЊC; yield 2.42 g (85%) colorless oil;
mbar)
[α]D20 ϩ44.3 (c 1.0, EtOH); the spectral characteristics are in
accord with 8a.
(1R,2S,1ЈS,5ЈS)-(؉)-2-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)-1-
phenylpropanol 15b. Synthesis according to GP 6 starting from
the known lactam 14b.9 After the reduction of the N,O-acetal,
15b was obtained analytically pure without further purification.
Yield 0.25 g (40%) (Found: C 77.13, H 9.44, N 5.75. Calc. for
C16H23NO: C 78.31, H 9.45, N 5.71%); [α]D20 ϩ41.1 (c 1.0, EtOH);
νmax (neat)/cmϪ1 3438, 2948, 2861, 2811, 1450, 1196, 1062, 1026,
751, 701; δH (300 MHz, CDCl3) 0.78 (3H, d, J 6.7, CH3), 1.20–
1.62 (7H, m, 4Ј-H, 6Ј-H2, 7Ј-H2, 8Ј-H2), 1.82 (1H, m, 4Ј-H), 2.32
(1H, m, 3Ј-H), 2.46 (1H, m, 5Ј-H), 2.63 (1H, m, 3Ј-H), 2.72 (1H,
dq, J 3.9 and 6.7, 2-H), 3.11 (1H, m, 1Ј-H), 3.69 (1H, br s, OH),
4.76 (1H, d, J 3.9, 1-H), 7.12–7.25 (5H, m, arom. H); δC (75
MHz, CDCl3) 11.1 (CH3), 24.5 (C-7Ј), 32.0 (C-4Ј), 32.7, 33.0
(C-8Ј, C-6Ј), 42.0 (C-5Ј), 50.7 (C-3Ј), 63.1 (C-2), 68.5 (C-1Ј),
73.3 (C-1), 126.1, 126.7, 127.8, 142.1 (arom. C); m/z 138 (100%)
[C9H16Nϩ].
(4S,8R,11S)-(؉)-Spiro[cyclopentane-1,10Ј-11Ј-methyl-9Ј-
oxa-1Ј-azatricyclo[6.3.0.04.8]undecan]-2Ј-one 14d. Synthesis
according to GP 4. Work-up: twofold column chromatography,
eluent: diethyl ether–petroleum ether (40–60 ЊC) 1:1, Rf 0.15;
ethyl acetate–petroleum ether (40–60 ЊC) 1:1, Rf 0.63; yield
0.87 g (19%) pale yellow oil; [α]D23 ϩ33.8 (c 1.0, EtOH); νmax
(neat)/cmϪ1 3058, 3032, 2943, 2861, 1493, 1448, 1382, 1327,
1178, 1130, 1099, 1031, 759, 701; δH (300 MHz, CDCl3) 1.15
(3H, d, J 7.1, CH3), 1.32–1.88, 1.90–1.99 (14H, 2m, 5-H2, 6-H2,
7-H2, CH2CH2CH2CH2), 2.17 (1H, dd, J 7.7 and 17.1, 3-H),
2.49 (1H, m, 4-H), 2.65 (1H, dd, J 10.5 and 17.1, 3-H), 4.05
(1H, q, J 7.1, 11-H); δC (75 MHz, CDCl3) 15.8 (CH3), 23.0, 23.2,
23.8, 31.4, 32.6, 38.4 (C-5, C-6, CH2CH2CH2CH2), 39.6 (C-3),
40.8 (C-7), 44.5 (C-4), 58.0 (C-11), 94.6 (C-10), 108.7 (C-8),
179.3 (C-2); m/z 56 (100%), 138 (59) [C9H16Nϩ]; (FD): m/z 138
(100%) [C9H16Nϩ].
(2S,1ЈS,5ЈS)-(؉)-2-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)-1,1-
diphenylpropan-1-ol 15c. Synthesis according to GP 6. Work-
up: column chromatography, eluent: ethyl acetate–petroleum
ether (40–60 ЊC) 1:3, Rf 0.44; yield 0.50 g (61%) as yellow oil;
[α]D22 ϩ35.7 (c 1.0, EtOH); the spectral characteristics are in
accord with 8c.
(4S,8R,11S)-(؉)-11-Benzyl-9-oxa-1-azatricyclo[6.3.0.04.8]-
undecan-2-one 14f. Synthesis according to GP 4. Work-up:
column chromatography, eluent: ethyl acetate–petroleum ether
(40–60 ЊC) 1:3, Rf 0.45; yield 4.13 g (81%) as yellow needles,
mp 26–28 ЊC (Found: C 74.84, H 7.70, N 5.35. Calc. for
C16H19NO2: C 74.69, H 7.44, N 5.44%); [α]D20 ϩ66.8 (c 1.0,
EtOH); νmax (KBr)/cmϪ1 2979, 2951, 1704, 1453, 1346, 1300,
1213, 1160, 1079, 1052, 733, 724; δH (300 MHz, CDCl3) 1.42
(1H, m, 5-H), 1.60–1.74 (4H, m, 6-H2, 7-H2), 1.85–1.91 (1H, m,
5-H), 2.27 (1H, dd, J 6.8 and 17.1, 3-H), 2.52 (1H, m, 4-H), 2.67
(1H, dd, J 10.3 and 17.1, 3-H), 2.70 (1H, dd, J 8.8 and 13.7,
CH2Ph), 3.02 (1H, dd, J 5.6 and 13.7, CH2Ph), 3.68 (1H, dd,
J 6.7 and 8.6, 10-H), 3.95 (1H, dd, J 7.3 and 8.6, 10-H), 4.25
(1H, m, 11-H), 7.12–7.24 (5H, m, arom. H); δC (75 MHz,
CDCl3) 24.5 (C-6), 32.0 (C-5), 37.4 (C-7), 39.6 (CH2Ph), 40.3
(C-3), 41.9 (C-4), 55.7 (C-11), 71.4 (C-10), 110.2 (C-8), 126.5,
128.3, 129.1, 136.9 (arom. C), 179.6 (C-2); m/z 166 (100%)
[C9H12NO2ϩ], 257 (36) [Mϩ].
(1ЈS,1ЉS,5ЉS)-(؉)-1-[1Ј-(2Љ-Azabicyclo[3.3.0]octan-2Љ-yl)-
ethyl]cyclopentanol 15d. Synthesis according to GP 6. Work-up:
column chromatography, eluent: ethyl acetate–petroleum ether
(40–60 ЊC) 1:3, Rf 0.10; yield 0.15 g (26%) as slightly yellow oil;
[α]D25 ϩ44.8 (c 1.0, EtOH); the spectral characteristics are in
accord with 8d.
(2S,1ЈS,5ЈS)-(؉)-2-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)-3-
methylbutanol 15e. Synthesis according to GP 5. Work-up:
column chromatography, eluent: ethyl acetate–petroleum ether
(40–60 ЊC) 1:1, Rf 0.06; yield 2.70 g (81%) as slightly yellow oil
(Found: C 72.94, H 11.62, N 7.38. Calc. for C12H23NO: C 73.05,
H 11.75, N 7.10%); [α]D23 ϩ35.8 (c 1.0, EtOH); νmax (neat)/cmϪ1
3440, 2951, 2863, 1466, 1450, 1385, 1232, 1166, 1130, 1080,
1013; δH (300 MHz, CDCl3) 0.78 (3H, d, J 6.7, CH3), 0.95
(3H, d, J 6.7, CH3), 1.18–1.24, 1.40–1.54 (7H, 2m, 4Ј-H, 6Ј-H2,
7Ј-H2, 8Ј-H2), 1.81 (1H, m, 3-H), 1.91 (1H, ddd, J 3.6, 6.6 and
11.6, 4Ј-H), 2.44–2.52 (3H, m, 2-H, 3Ј-H, 5Ј-H), 2.69 (1H, dd,
J 7.4 and 8.0, 3Ј-H), 3.08 (1H, dd, J 9.9 and 10.5, 1-H), 3.46
(1H, dd, J 5.2 and 9.9, 1-H), 3.40–3.49 (2H, br s, 1Ј-H, OH);
δC (75 MHz, CDCl3) 19.6 (CH3), 22.4 (CH3Ј), 23.4 (C-7Ј), 28.1
(C-3), 32.1, 32.7, 33.0 (C-4Ј, C-6Ј, C-8Ј), 41.5 (C-5Ј), 44.9
(C-3Ј), 59.3 (C-1), 63.7 (C-2), 66.7 (C-1Ј); MS (EI): m/z 154
(100%) [C9H14NOϩ], 197 (2) [Mϩ].
(4S,8R,11S)-(؊)-11-Benzyl-10,10-diphenyl-9-oxa-1-aza-
tricyclo[6.3.0.04.8]undecan-2-one 14g. Synthesis according to
GP 4. Work-up: twofold column chromatography, eluent:
ethyl acetate–petroleum ether (40–60 ЊC) 1:5, Rf 0.18, ethyl
acetate–petroleum ether (40–60 ЊC) 1:3, Rf 0.77; yield 1.19 g
(15%) as colorless needles, mp 146 ЊC (Found: C 81.90, H 6.59,
N 3.33. Calc. for C28H27NO2: C 82.13, H 6.65, N 3.42%); [α]D20
Ϫ96.3 (c 1.0, EtOH); νmax (KBr)/cmϪ1 3483, 3416, 3073, 3031,
2937, 1718, 1639, 1618, 1449, 1351, 762, 701; δH (300 MHz,
CDCl3) 1.40–1.63, 1.79–1.94 (4H, 2m, 5-H2, 6-H2), 1.96 (1H, d,
J 9.0, 3-H), 1.97 (1H, d, J 9.6, 3-H), 2.11–2.30 (2H, m, 7-H2),
2.36–2.44 (1H, m, 4-H), 2.42 (1H, dd, J 4.9 and 15.1, CH2Ph),
2.60 (1H, dd, J 11.3 and 15.1, CH2Ph), 5.53 (1H, dd, J 4.9 and
11.3, 11-H), 7.18–7.30 (13H, m, arom. H), 7.54–7.56 (2H, m,
arom. H); δC (75 MHz, CDCl3) 23.5 (C-6), 31.5 (C-5), 35.3
(CH2Ph), 39.0 (C-3), 40.7 (C-7), 43.4 (C-4), 61.6 (C-11), 91.1
(C-10), 109.7 (C-8), 126.1, 127.0, 127.6, 128.1, 128.2, 128.3,
128.6, 138.0, 141.7, 143.3 (arom. C), 178.9 (s, C-2); m/z 227
(100%) [C15H27NOϩ], 409 (0.3) [Mϩ]; (FD): m/z 409 (100%)
[Mϩ].
(2S,1ЈS,5ЈS)-(؉)-2-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)-3-
phenylpropan-1-ol 15f. Synthesis according to GP 5. Work-up:
column chromatography, eluent: ethyl acetate–petroleum ether
(40–60 ЊC) 2:3, Rf 0.21; yield 3.91 g (94%) as orange oil
(Found: C 78.12, H 9.41, N 5.87. Calc. for C16H23NO: C 78.31,
H 9.45, N 5.71%); [α]D21 ϩ32.2 (c 1.0, EtOH); νmax (neat)/cmϪ1
3432, 3026, 2942, 2860, 1494, 1450, 1411, 1326, 1232, 1161,
1128, 1071, 750, 703; δH (300 MHz, CDCl3) 1.26–1.44, 1.45–
1.61 (7H, 2m, 4Ј-H, 6Ј-H2, 7Ј-H2, 8Ј-H2), 1.99 (1H, ddd, J 5.5,
9.2 and 12.0, 4Ј-H), 2.36 (1H, dd, J 10.1 and 13.1, 3-H), 2.43
(1H, ddd, J 5.5, 8.6 and 11.2, 3Ј-H), 2.50 (1H, m, 5Ј-H), 2.80
(1H, dd, J 6.6 and 8.6, 3Ј-H), 2.92 (1H, dd, J 3.7 and 13.1, 3-H),
2.99 (1H, m, 2-H), 3.24 (1H, dd, J 10.0 and 10.1, 1-H), 3.27
(1H, m, 1Ј-H), 3.37 (1H, d, J 4.7 and 10.1, 1-H), 3.54 (1H, br s,
OH), 6.94–7.27 (5H, m, arom. H); δC (75 MHz, CDCl3) 23.8
(C-7Ј), 31.9, 32.2, 32.6, 33.2 (C-3, C-4Ј, C-6Ј, C-8Ј), 41.7 (C-5Ј),
(2S,1ЈS,5ЈS)-(؉)-2-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)propan-
1-ol 15a. Synthesis according to GP 5. Work-up: short-path
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45.4 (C-3Ј), 60.9 (C-1), 61.3 (C-2), 65.4 (C-1Ј), 126.0, 128.4,
128.9, 139.4 (arom. C); m/z 245 (100%) [Mϩ], 736 (11) [3Mϩ].
Preparation of amino alcohol 21b by aziridinium ion ring-
opening. Under argon atmosphere, β-amino alcohol 10a (0.7 g,
3 mmol) was dissolved in Et2O (10 ml) and cooled to 0 ЊC.
First of all, triethylamine (0.61 g, 6 mmol), then methane-
sulfonyl chloride (0.52 g, 4.5 mmol) was added and the reaction
mixture was vigorously stirred for 2 h at 0 ЊC. At this tem-
perature, the solvent was evaporated under reduced pressure
and the residue was dissolved in water (pH > 8). After stir-
ring for 20 h at room temp. the mixture was extracted with
Et2O (3×) and the combined organic layers were dried
(MgSO4) and finally evaporated in vacuo to give the crude
amino alcohol 21b as a slightly yellow oil. Yield 0.53 g
(77%); [α]D26 Ϫ17.0 (c 1.15, EtOH); [α]D26 ϩ14.6 (c 1.0, CH2Cl2);
further purification was not carried out.
(2S,1ЈS,5ЈS)-(؉)-2-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)-1,1,3-
triphenylpropan-1-ol 15g. Synthesis according to GP 6. Work-
up: column chromatography, eluent: ethyl acetate–petroleum
ether (40–60 ЊC) 1:3, Rf 0.90; yield 5.73 g (87%) as colorless oil;
[α]D22 ϩ81.6 (c 1.0, EtOH); νmax (neat)/cmϪ1 3244, 3086, 3059,
2938, 1494, 1447, 1278, 1162, 1047, 1031, 909, 733, 701; δH (300
MHz, CDCl3) 1.06–1.23, 1.33–1.42, 1.43–1.68, 1.88 (7H, 3m,
dd, J 4.9 and 12.9, 4Ј-H, 6Ј-H2, 7Ј-H2, 8Ј-H2), 1.76 (1H, ddd,
J 5.3, 9.1 and 12.0, 4Ј-H), 2.02–2.18 (2H, m, 3Ј-H, 5Ј-H), 2.49
(1H, ddd, J 5.3, 8.9 and 11.3, 3Ј-H), 2.70 (1H, dd, J 6.3 and 7.7,
1Ј-H), 2.90 (1H, dd, J 11.3 and 14.4, 3-H), 3.20 (1H, dd, J 1.7
and 14.4, 3-HЈ), 4.18 (1H, dd, J 1.7 and 11.3, 2-H), 6.05 (1H, br
s, OH), 7.00–7.38 (11H, m, arom. H), 7.57–7.64 (4H, m, arom.
H); δC (75 MHz, CDCl3) 23.4 (C-7Ј), 32.0, 32.1, 33.0 (C-4Ј,
C-6Ј, C-8Ј), 34.0 (C-3), 40.6 (C-5Ј), 47.0 (C-3Ј), 68.3, 68.7 (C-2,
C-1Ј), 77.6 (C-1), 126.2, 126.8, 127.2, 127.4, 128.1, 128.4, 128.5,
129.0, 140.7, 145.0, 145.7 (arom. C); MS (FD): m/z 182 (100%)
[C13H10Oϩ], 398 (64) [Mϩ].
(1S,1ЈR,5ЈR)-(؉)-[2-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)-1-
phenylethyl]thioacetate 22. Synthesis according to GP 8. Work-
up: further purification was not necessary; yield 0.84 g (97%)
starting from 10a and 0.64 g (73%) starting from 21a, yellow oil
(Found: C 70.38, H 8.10, N 5.05. Calc. for C17H23NOS: C 70.56,
H 8.01, N 4.84%); [α]D26 ϩ83.0 (c 0.7, EtOH); νmax (neat)/cmϪ1
3062, 3028, 2949, 2861, 2811, 1692, 1494, 1452, 1354, 1132,
1103, 952, 696, 631; δH (300 MHz, CDCl3) 1.20–1.50 (7H, m,
4Ј-H, 6Ј-H2, 7Ј-H2, 8Ј-H2), 1.89 (1H, dddd, J 6.0, 12.1, 9.1 and
<2, 4Ј-H), 2.19 (1H, ddd, J 6.0, 8.8 and 10.4, 3Ј-H), 2.27 (3H, s,
CH3), 2.43 (1H, m, 5Ј-H), 2.80 (1H, dd, J 6.2 and 12.6, 2-H),
2.89 (1H, m, 1Ј-H), 2.97 (1H, ddd, J 8.8, 6.1 and <2, 3Ј-H), 3.07
(1H, dd, J 9.6 and 12.6, 2-H), 4.71 (1H, dd, J 6.2 and 9.6, 1-H),
7.20–7.30 (5H, m, arom. H); δC (75 MHz, CDCl3) 24.1 (C-7Ј),
30.4 (CH3), 32.0, 32.3, 33.3 (C-4Ј, C-6Ј, C-8Ј), 41.8 (C-5Ј), 47.0
(C-1), 54.1 (C-3Ј), 59.7 (C-2), 69.8 (C-1Ј), 127.0, 127.9, 128.5,
(4R,8S,11R)-(؊)-10,10,11-Triphenyl-9-oxa-1-azatricyclo-
[6.3.0.04.8]undecan-2-one 19. Synthesis according to GP 4.
Work-up: recrystallization from ethyl acetate; yield 3.29 g
(42%) as colorless crystals, mp 196 ЊC (Found: C 81.81, H 6.60,
N 3.35. Calc. for C27H25NO2: C 82.00, H 6.37, N 3.54%); [α]D23
Ϫ11.5 (c 1.0, CHCl3); νmax (KBr)/cmϪ1 3470, 3087, 3054, 2939,
1705, 1344, 1327, 1044, 723, 701; δH (300 MHz, CDCl3) 1.48–
1.59 (2H, m, 5-H, 6-H), 1.79–1.91 (2H, m, 5-H, 6-H), 2.05 (1H,
d, J 9.5, 3-H), 2.05 (1H, d, J 9.5, 3-H), 2.11–2.24 (2H, m, 7-H2),
2.55 (1H, dd, J 9.4 and 16.9, 4-H), 6.29 (1H, s, 11-H), 6.99–7.31
(13H, m, arom. H), 7.64–7.67 (2H, m, arom. H); δC (75 MHz,
CDCl3) 23.4 (C-6), 31.0 (C-5), 38.8 (C-3), 40.2 (C-7), 44.2 (C-4),
65.9 (C-11), 92.3 (C-10), 110.7 (C-8), 126.4, 126.5, 127.1, 127.5,
127.6, 128.3, 129.4, 136.6, 142.3, 144.0 (arom. C), 179.0 (C-2);
m/z 213 (100%) [C14H15NOϩ], 395 (1) [Mϩ]; (FD): m/z 395
(100%) [Mϩ].
140.8 (arom. C), 194.5 (C᎐O); m/z 124 (100%) [C H Nϩ].
᎐
8
14
(1S,1ЈR,5ЈR)-2-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)-1-phenyl-
ethanethiol 23. Synthesis according to GP 9. Work-up: without
further purification; yield 0.35 g (93%) as slightly yellow oil,
highly sensitive to oxidation (contains 6% disulfide); νmax (neat)/
cmϪ1 2949, 2861, 1493, 1452, 1254, 1258, 1225, 1165, 1125,
1092, 1061, 1028, 759, 698; δH (300 MHz, CDCl3) 1.19–1.56
(7H, m, 4Ј-H, 6Ј-H2, 7Ј-H2, 8Ј-H2), 1.83 (1H, m, 4Ј-H), 2.24
(1H, ddd, J 5.9 and 8.7, 10.2, 3Ј-H), 2.44 (1H, m, 5Ј-H), 2.75
(1H, dd, J 8.5 and 12.5, 2-H), 2.78–2.86 (2H, m, 1Ј-H, 3Ј-H),
2.82 (1H, dd, J 6.6 and 12.5, 2-H), 4.07 (1H, dd, J 6.6 and 8.5
Hz, 1-H), 7.10–7.29 (5H, m, arom. H); δC (75 MHz, CDCl3)
24.5 (C-7Ј), 32.3, 32.6, 33.1 (C-4Ј, C-6Ј, C-8Ј), 42.5 (C-5Ј), 43.9
(C-3Ј), 55.2 (C-1), 64.1 (C-2), 70.2 (C-1Ј); m/z 42 (23%) (100)
[C3H6ϩ], 124 (100) [C8H14Nϩ], 205 (5) [C12H15NSϩ].
(1R,1ЈR,5ЈR)-(؊)-2-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)-1-
phenylethanol 21a. Synthesis according to GP 7. Work-up:
column chromatography, eluent: n-hexane–ethyl acetate 1:1, Rf
0.61; yield 0.82 g (43%) as colorless oil (Found: C 77.86, H
9.30, N 5.98. Calc. for C15H21NO: C 77.87, H 9.14, N 6.05%);
[α]D22 Ϫ119.4 (c 1.61, CH2Cl2); νmax (NaCl)/cmϪ1 3550–3100,
1490, 1450; δH (300 MHz, CDCl3) 1.20–1.71 (7H, m, 4Ј-H,
6Ј-H2, 7Ј-H2, 8Ј-H2), 2.03 (1H, m, 4Ј-H), 2.14 (1H, m, 5Ј-H),
2.47 (1H, dd, J 3.3 and 12.1, 2-H), 2.52 (1H, m, 2-H), 2.68 (1H,
dd, J 11.0 and 12.1, 3Ј-H), 2.93 (1H, dd, J 6.3 and 8.1, 3Ј-H),
3.18 (1H, m, 1Ј-H), 3.98 (1H, br s, OH), 4.63 (1H, dd, J 3.3 and
11.0, 1-H), 7.20–7.39 (5H, m, arom. H); δC (75 MHz, CDCl3)
23.91, 32.25, 32.62, 33.52 (C-4Ј, C-6Ј, C-7Ј, C-8Ј), 41.39 (C-5Ј),
53.26, 63.08 (C-3Ј, C-2), 69.58, 69.85 (C-1, C-1Ј), 125.79,
127.30, 128.18, 142.37 (arom. C); m/z 232 (100%) [MHϩ], 214
(18) [MHϩ Ϫ H2O].
Bis[(1S,1ЈR,5ЈR)-(؊)-2-(2Ј-azabicylo[3.3.0]octan-2Ј-yl)-1-
phenylethyl] disulfide 24. Synthesis according to GP 10. Work-
up: column chromatography, eluent: tert-butyl methyl ether, Rf
0.88; yield 0.33 g (88%) as yellow oil; [α]D22 Ϫ1.5 (c 0.9, EtOH);
νmax (neat)/cmϪ1 3027, 2948, 2861, 2806, 1493, 1452, 1356, 1258,
1224, 1165, 1125, 1098, 1074, 1029, 696; δH (300 MHz, CDCl3)
1.00–1.42 (14H, m, 4Ј-H, 6Ј-H2, 7Ј-H2, 8Ј-H2), 1.76 (2H, m,
4Ј-H), 1.96 (2H, ddd, J 5.9, 8.7 and 10.5, 3Ј-H), 2.32 (2H, m,
5Ј-H), 2.74 (2H, m, 1Ј-H), 2.80 (2H, dd, J 5.6 and 12.6, 2-H),
3.00 (2H, dd, J 9.8 and 12.6, 2-H), 3.53 (2H, dd, J 5.6 and 9.8,
1-H), 7.08–7.28 (10H, m, arom. H); δC (75 MHz, CDCl3) 24.1,
32.0, 32.3, 33.3 (C-4Ј, C-6Ј, C-7Ј, C-8Ј), 41.8 (C-5Ј), 54.0 (C-1);
54.1 (C-3Ј), 58.6 (C-2), 69.8 (C-1Ј), 127.2, 128.1, 128.5, 140.5
(arom. C); m/z 124 (100%) [C8H14Nϩ], 214 (28) [C15H20Nϩ], 246
(16) [C15H20NSϩ], 279 (11) [C15H21NS2ϩ].
(1S,1ЈR,5ЈR)-(؊)-2-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)-1-
phenylethanol 21b. Synthesis according to GP 7. Work-up:
column chromatography, eluent: n-hexane–ethyl acetate 1:1, Rf
0.49; yield 0.67 g (35%) as colorless oil (Found: C 78.05, H
9.32, N 6.04. Calc. for C15H21NO: C 77.87, H 9.14, N 6.05%);
[α]D20 ϩ7.3 (c 1.38, CH2Cl2); νmax (NaCl)/cmϪ1 3620–3160, 3020,
1490; δH (300 MHz, CDCl3) 1.16–1.68 (7H, m, 4Ј-H, 6Ј-H2,
7Ј-H2, 8Ј-H2), 1.86 (1H, m, 4Ј-HЈ), 2.36 (1H, m, 3Ј-H), 2.53 (1H,
m, 5Ј-H), 2.64 (2H, d, J 6.7, 2-H2), 2.72 (1H, m, 3Ј-H), 2.99 (1H,
m, 1Ј-H), 3.92 (1H, br s, OH), 4.63 (1H, t, J 6.7, 1-H), 7.17–7.32
(5H, m, arom. H); δC (75 MHz, CDCl3) 24.8 (C-7Ј), 32.4, 33.0,
33.0, (C-4Ј, C-6Ј, C-8Ј), 42.8 (C-5Ј), 55.9 (C-3Ј), 63.8 (C-2), 70.5
(C-1), 70.5 (C-1Ј), 125.7, 127.2, 128.2, 142.9 (arom. C); m/z 232
(100%) [MHϩ], 214 (20) [MHϩ Ϫ H2O].
(2S,1ЈS,5ЈS)-(؊)-[2-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)propyl]-
thioacetate 25a. Synthesis according to GP 8. Work-up: two-
fold column chromatography, eluent: ethyl acetate–petroleum
ether (40–60 ЊC) 1:1, Rf 0.25; ethyl acetate, Rf 0.23; yield 0.16 g
(23%) as pale yellow oil (Found: C 62.82, H 9.41, N 6.36. Calc.
J. Chem. Soc., Perkin Trans. 1, 1999, 2353–2365
2363

View Article Online
for C12H21NOS: C 63.38, H 9.31, N 6.16%); [α]D25 Ϫ29.6 (c 1.0,
EtOH); νmax (neat)/cmϪ1 2950, 2862, 2812, 1690, 1375, 1353,
1171, 1135, 954, 631; δH (300 MHz, CDCl3) 0.99 (3H, d, J 6.4,
CH3), 1.17–1.64 (7H, m, 4Ј-H, 6Ј-H2, 7Ј-H2, 8Ј-H2), 1.82 (1H,
m, 4Ј-H), 2.23 (3H, s, COCH3), 2.28 (1H, ddd, J 5.6, 8.5 and
10.7, 3Ј-H), 2.41 (1H, m, 5Ј-H), 2.66–2.73 (2H, m, 2-H, 3Ј-H),
2.85 (1H, d, J 6.3 and 13.2, 1-H), 3.03 (1H, m, 1Ј-H), 3.04 (1H,
dd, J 6.9 and 13.2, 1-H); δC (75 MHz, CDCl3) 14.6 (CH3), 24.2
(C-7Ј), 30.5 (COCH3), 31.9, 33.0, 33.2 (C-4Ј, C-6Ј, C-8Ј), 35.2
(C-1), 42.1 (C-5Ј), 48.4 (C-3Ј), 55.2 (C-2), 66.2 (C-1Ј), 196.3
(CO); m/z 138 (100%) [C9H16Nϩ].
4Ј-H), 2.06–2.21 (6H, m, 3Ј-H2, 5Ј-H), 2.89 (2H, m, 1Ј-H), 3.07
(2H, m, 2-H), 3.23 (2H, d, J 9.2, 1-H), 6.97–7.19 (10H, m, arom.
H); δC (75 MHz, CDCl3) 10.9 (C-3), 23.1 (C-7Ј), 32.1, 32.1, 33.2
(C-4Ј, C-6Ј, C-8Ј), 41.3 (C-5Ј), 45.2 (C-3Ј), 56.7, 61.5, 65.3 (C-1,
C-2, C-1Ј), 126.4, 127.4, 128.8, 143.7 (arom. C); m/z 138 (100%)
[C9H16Nϩ], 228 (35) [C16H22Nϩ], 260 (7) [C16H22NSϩ].
Enantioselective catalysis: method A
Commercially available Et2Zn (3.75 mmol) in n-hexane (1.0 M)
or toluene (1.1 M) was added dropwise to a solution of the
chiral ligand (0.15 mmol, 6 mol%) in benzaldehyde (2.5 mmol)
at 0 ЊC under argon atmosphere. After stirring for 12 h at 0 ЊC,
the reaction mixture was hydrolyzed by cautiously adding 1.5
M HCl (10 ml). The organic material was extracted with Et2O
(3 × 50 ml), the combined organic layers were dried (Na2SO4)
and concentrated in vacuo.
(1R,2S,1ЈS,5ЈS)-(؊)-[2-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)-1-
phenylpropyl]thioacetate 25b. Synthesis according to GP 8.
Work-up: column chromatography, eluent: tert-butyl methyl
ether, Rf 0.71; yield 0.80 g (88%) as yellow oil (Found: C 71.18,
H 8.20, N 4.81. Calc. for C18H25NOS: C 71.23, H 8.30, N
4.62%); [α]D23 Ϫ177.8 (c 0.8, EtOH); νmax (neat)/cmϪ1 3084, 3061,
3027, 2950, 2860, 2830, 1694, 1374, 1352, 1130, 954, 697, 633;
δH (300 MHz, CDCl3) 0.88–1.36 (7H, m, 4Ј-H, 6Ј-H2, 7Ј-H2,
8Ј-H2), 1.03 (3H, d, J 6.4, CH3), 1.72 (1H, m, 4Ј-H), 2.22 (3H, s,
COCH3), 2.16–2.32 (2H, m, 3Ј-H, 5Ј-H), 2.56 (1H, m, 3Ј-H),
2.90–3.06 (2H, m, 2-H, 1Ј-H), 4.56 (1H, d, J 8.6, 1-H), 7.08–
7.27 (5H, m, arom. H); δC (75 MHz, CDCl3) 11.0 (CH3), 23.5
(C-7Ј), 30.6 (COCH3), 32.0, 32.0, 33.1 (C-4Ј, C-6Ј, C-8Ј), 41.5
(C-5Ј), 46.2 (C-3Ј), 53.2 (C-1), 58.4 (C-2), 66.2 (C-1Ј), 126.6,
The absolute configuration of the preferentially obtained
1-phenylpropan-1-ol was assigned from optical rotation of the
crude product: [α]D23 ϩ45.45 (c 5.15, CHCl3) for (R)-1-phenyl-
propan-1-ol.22 The enantiomeric excess was determined by
chemical derivatisation and NMR spectroscopy. Therefore, the
crude product (0.094 g, 0.69 mmol) was cooled to 0 ЊC under
argon. Successively, (S)-(ϩ)-O-acetylmandelic acid (0.134 g,
0.69 mmol), N,N-dimethyl-4-aminopyridine (5 mg, 0.04 mmol)
and N,N-dicyclohexylcarbodiimide (0.143 g, 0.69 mmol) dis-
solved in CH2Cl2 (1 ml) each, were added. The reaction mixture
was stirred for 2 h at 0 ЊC and for an additional 20 h at room
temp. Then the solution was separated from the precipitate and
the solvent removed by distillation. Unreacted 1-phenylpropan-
1-ol and other volatile residues were removed at 60–70 ЊC under
reduced pressure (1 Torr) to give the diastereomeric esters (R,S)
and (S,S).
127.8, 128.1, 142.0 (arom. C), 194.4 (C᎐O), 194.5 (C᎐O); m/z
᎐
᎐
138 (100%) [C9H16Nϩ].
(2S,1ЈS,5ЈS)-(؊)-2-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)-
propanethiol 26a. Synthesis according to GP 7 (starting with 3.8
mmol thioacetate). Work-up: column chromatography, eluent:
ethanol, Rf 0.21; yield 0.43 g (61%) as pale yellow oil which
undergoes oxidation in air; [α]D20 Ϫ28.6 (c 1.0, EtOH); νmax (neat)/
cmϪ1 2951, 2861, 2809, 1449, 1435, 1372, 1232, 1169, 1133,
1078; δH (300 MHz, CDCl3) 0.96 (3H, d, J 6.3, CH3), 1.10–1.62
(7H, m, 4Ј-H, 6Ј-H2, 7Ј-H2, 8Ј-H2), 1.76 (1H, m, 4Ј-H), 2.22
(1H, m, 3Ј-H), 2.34 (1H, m, 5Ј-H), 2.53 (1H, dd, J 7.3 and 12.1,
1-H), 2.64 (1H, m, 3Ј-H), 2.81 (1H, m, 2-H), 2.99 (1H, m, 1Ј-H),
3.04 (1H, dd, J 5.9 and 12.1, 1-H); δC (75 MHz, CDCl3) 14.2
(C-3), 24.3 (C-7Ј), 31.9 (C-4Ј), 33.0, 33.2 (C-6Ј, C-8Ј), 42.3
(C-5Ј), 46.2 (C-1), 48.3 (C-3Ј), 55.3 (C-2), 66.0 (C-1Ј); m/z 138
(100%) [C9H16Nϩ]; (FD): m/z 185 (70%) [Mϩ], 368 (15)
[2Mϩ Ϫ 2H (disulfide)].
1H NMR: (R,S), the signals of the diastereomer (S,S) are
given in brackets: δH 0.63 [0.88] (3H, t, J 7.4, CH2CH3), 1.64–
1.85 (2H ϩ 2H, m, CH2CH3), 2.16 [2.18] (3H, s, CH3CO2), 5.66
[5.65] (1H, dd, J 6.0 and 7.4, CH3CH2CHO), 5.97 [5.98] (1H,
s, CH3CH3CH), 6.94–7.50 (10H ϩ 10H, m, arom. H); δC 9.3
[9.6] (CH2CH3), 20.6 (CH3CO2), 29.0 [29.2] (CH2CH3), 74.5
(CH CH CHO), 78.6 [78.7] (PhCHCO ), 168.2 [169.0] (C᎐O),
᎐
3
2
2
170.0 [170.2] (C᎐O), 126–139 (Ar-C).
᎐
The enantiomeric excess of 1-phenylpropan-1-ol (corre-
sponding to the diastereomeric excess of the derivative) was
determined by the relative intensities of the triplets at 0.63 and
1
0.88 ppm in the H NMR spectra. The absolute configuration
of the preferentially obtained 1-phenylpropan-1-ol was again
established to be the (R)-enantiomer.
(1R,2S,1ЈS,5ЈS)-(؉)-2-(2Ј-Azabicyclo[3.3.0]octan-2Ј-yl)-1-
phenylpropanethiol 26b. Synthesis according to GP 9. Work-up:
column chromatography, eluent: ethyl acetate–petroleum ether
1:3, Rf 0.73; yield 0.29 g (73%) as slightly yellow oil, highly
sensitive to oxidation (contains 16% disulfide) (Found: C 73.89,
H 8.81, N 5.70. Calc. for C16H23NS: C 73.52, H 8.87, N 5.36%);
νmax (neat)/cmϪ1 3026, 2950, 2860, 1599, 1491, 1450, 1374, 1353,
1326, 1227, 1176, 1130, 1074, 896, 741, 697; δH (300 MHz,
CDCl3) 0.93–1.50 (7H, m, 4Ј-H, 6Ј-H2, 7Ј-H2, 8Ј-H2), 1.05 (3H,
d, J 6.4, CH3), 1.77 (1H, m, 4Ј-H), 2.18–2.32 (2H, m, 3Ј-H,
5Ј-H), 2.59 (1H, m, 3Ј-H), 2.91 (1H, m, 2-H), 3.01 (1H, m,
1Ј-H), 4.08 (1H, m, 1-H), 7.10–7.26 (5H, m, arom. H); δC (75
MHz, CDCl3) 11.0 (CH3), 23.8 (C-7Ј), 32.0, 32.1, 33.0 (C-4Ј,
C-6Ј, C-8Ј), 41.7 (C-5Ј), 47.4 (C-3Ј), 49.2 (C-1), 61.5 (C-2), 68.9
(C-1Ј), 126.7, 127.8, 127.9, 143.3 (arom. C); m/z 138 (100%)
[C9H16Nϩ].
Enantioselective catalysis: method B
The amino alcohol (0.25 mmol, 5 mol%) was dissolved in 10 ml
anhydrous toluene and cooled to Ϫ15 ЊC under argon atmos-
phere. Et2Zn (9.1 ml of 1.1 M solution in toluene, 10 mmol) was
added dropwise over a period of 10 min. After the addition was
completed the mixture was allowed to reach room temp. After
15 min 0.53 g (5 mmol) of freshly distilled benzaldehyde in 10
ml anhydrous toluene were added within 30 min. The reaction
mixture was stirred for a further 40–42 h at ambient temp. The
reaction was quenched at 0 ЊC with 20 ml 2 M HCl, the layers
were separated and the aqueous layer was extracted three times
with diethyl ether (20 ml). The combined organic phases were
extracted with 4% aqueous sodium hydrogen sulfite (3 × 20 ml),
washed with saturated sodium hydrogen carbonate solution
and brine, then dried (MgSO4) and finally concentrated in
vacuo. The crude product was purified by distillation (bulb-to-
bulb, 125 ЊC/20 mbar) and the enantiomeric excess was deter-
mined by chiral GC (SGE Cydex-B, temperature program
100 ЊC, 4 ЊC minϪ1 up to 125 ЊC, 10 min isotherm; the retention
times were (R)-1-phenlypropan-1-ol 13.12 min, (S)-1-phenyl-
propan-1-ol 13.46 min).
Bis[(1R,2S,1ЈS,5ЈS)-(؊)-2-(2Ј-azabicylo[3.3.0]octan-2Ј-yl)-1-
phenylpropyl] disulfide 27. Synthesis according to GP 10. Work-
up: column chromatography, eluent: tert-butyl methyl ether, Rf
0.87; yield 0.32 g (75%) as yellow oil; [α]D23 Ϫ186.8 (c 0.7, EtOH);
νmax (neat)/cmϪ1 3082, 3059, 3026, 2963, 1599, 1491, 1374, 1228,
897, 738, 694, 615; δH (300 MHz, CDCl3) 0.75–1.36 (14H, m,
4Ј-H, 6Ј-H2, 7Ј-H2 8Ј-H2), 1.04 (6H, d, J 6.3, 3-H), 1.62 (2H, m,
2364
J. Chem. Soc., Perkin Trans. 1, 1999, 2353–2365

View Article Online
for publication; for part 12 see: J. Wilken, H. Gröger, M. Kossenjans
Acknowledgements
We express our thanks to Degussa AG, Hoechst AG, Witco
GmbH and the Fonds der Chemischen Industrie for the generous
providing with chemicals and for the financial support.
and J. Martens, Tetrahedron: Asymmetry, 1997, 8, 2761. The
synthesis of the ACE-inhibitor Ramipril is described in: V. Teetz,
R. Geiger and H. Gaul, Tetrahedron Lett., 1984, 25, 4479 and
H. Urbach and R. Henning, Heterocycles, 1989, 28, 957.
8 S. Wallbaum, T. Mehler and J. Martens, Synth. Commun., 1994, 24,
1381.
9 J. A. Ragan and M. C. Claffey, Heterocycles, 1995, 41, 57.
10 (a) A. I. Meyers and L. E. Burgess, J. Org. Chem., 1991, 56, 2294;
(b) L. E. Burgess and A. I. Meyers, J. Org. Chem., 1992, 57, 1656.
11 The stereochemical outcome of the condensation of γ-ketoester 12
with β-amino alcohols was previously described in the literature: see
ref. 9 and 12.
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7 This paper is part 14 of our series concerning the studies of
the utilization of industrial waste materials. For part 13 see:
M. Kossenjans and J. Martens, Tetrahedron: Asymmetry, submitted
Paper 9/02362C
J. Chem. Soc., Perkin Trans. 1, 1999, 2353–2365
2365