Lipase-catalyzed kinetic resolution of 2-phenylethanol derivatives and chiral oxa-Pictet-Spengler reaction as the key steps in the synthesis of enantiomerically pure tricyclic amines

Article abstract of DOI:10.1002/ejoc.201101800

A series of 5,6,7,8,9,10-hexahydro-5,9-epoxybenzocycloocten-6-amines have been synthesized and pharmacologically evaluated in receptor binding studies (σ₁, σ₂, NMDA, κ, and μ receptors). The first key step of the synthesis was a chir

Full text of DOI:10.1002/ejoc.201101800

FULL PAPER
DOI: 10.1002/ejoc.201101800
Lipase-Catalyzed Kinetic Resolution of 2-Phenylethanol Derivatives and Chiral
Oxa-Pictet–Spengler Reaction as the Key Steps in the Synthesis of
Enantiomerically Pure Tricyclic Amines
Christian Ketterer[a] and Bernhard Wünsch*[a]
Keywords: Medicinal chemistry / Heterocycles / Amines / Enzyme catalysis / Kinetic resolution / Circular dichroism
A
series of 5,6,7,8,9,10-hexahydro-5,9-epoxybenzocyclo-
enantioselective acetylation of racemic alcohol 14 catalyzed
by Pseudomonas fluorescens lipase and enantioselective hy-
drolysis of racemic acetate 16 catalyzed by Candida rugosa
lipase. The absolute configurations were determined by
theoretical calculations of the specific optical rotation and CD
spectra, as well as by X-ray crystal structure analysis of
(S,S,S)-25 by the three-beam interference method. Although
octen-6-amines have been synthesized and pharmacologi-
cally evaluated in receptor binding studies (σ1, σ2, NMDA, κ,
and μ receptors). The first key step of the synthesis was a
chiral oxa-Pictet–Spengler reaction with enantiomerically
pure 2-phenylethanol derivatives (S)- and (R)-14. After trans-
formation of the dimethylamide 18 into the ester 19, the tricy-
clic system 20 was established by Dieckmann cyclization re- enantiomerically pure dimethylamines (S,R,S)- and (R,S,R)-
action. Finally, amino moieties were introduced diastereo- 29 with an axial amino moiety showed low-to-moderate af-
selectively into the 6-position by reductive amination and
SN2 reaction. The enantiomerically pure building blocks (S)-
14 (Ͼ99.0% ee) and (R)-14 (98.4% ee) were synthesized by
finity towards σ1 and σ2 receptors, a promising σ2 affinity (Ki
= 2.9 μ ) was found for (S,S,S)-24 with an equatorially ori-
ented dimethylamino group.
M
receptor to the σ1 receptor.[3] Within the benzomorphan
system the 2-phenylethylamine substructure represents an
important pharmacophoric element. Moreover, the tricyclic
benzomorphan system also contains the 3-phenylpropyl-
amine substructure.
Introduction
The tricyclic benzomorphan system 1 represents a sub-
structure of the pentacyclic natural product morphine
(Scheme 1). Originally benzomorphans were synthesized to
increase the analgesic activity of morphine and to reduce
its adverse side-effects, such as respiratory depression, con-
stipation, dysphoria, and the development of tolerance and
dependency. In addition to their analgesic activity, benzo-
morphans and their analogues produce manifold effects on
the central nervous system (CNS).[1] These effects originate
from their interaction with different CNS receptors, in par-
ticular opioid, NMDA, and σ receptors, depending on the
substitution pattern and the stereochemistry of the benzo-
morphan system. (R,R,R)-Configured ketocyclazocine with
an N-cyclopropylmethyl residue is a potent κ-opioid recep-
tor agonist, which gave name to this opioid receptor sub-
type.[2] Benzomorphan derivatives with the (S,S,S) configu-
ration and bearing a proton or a small methyl group at the
N atom interact with high affinity with the phencyclidine
binding site of the NMDA receptor. A larger N residue (di-
methylallyl, benzyl) at the (S,S,S)-configured benzomor-
phan system shifts the receptor affinity from the NMDA
Scheme 1. Structural development of 5,9-epoxybenzocycloocten-6-
amines 3 from a combination of benzomorphans (1) and tricyclic
amines 2.
[a] Institut für Pharmazeutische und Medizinische Chemie der
Westfälischen Wilhelms-Universität Münster,
Hittorfstrasse 58–62, 48149 Münster, Germany
Fax: +49-251-8332144
In an effort to find pharmacologically interesting com-
pounds with new scaffolds analogous to benzomorphan,[4]
we have focused our interest on 5,9-epoxybenzocycloocten-
amines 2 and 3. The three-dimensional structure of epoxy-
E-mail: wuensch@uni-muenster.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101800.
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Chiral Oxa-Pictet–Spengler Reaction
benzocyclooctenamines is very similar to that of benzo-
morphans. However, 2 and 3 differ from benzomorphans
(1) by the replacement of the methano bridge with an epoxy
bridge. Some years ago we reported on the synthesis of ep-
oxybenzocycloocten-7-amines 2 with axially and equatori-
ally oriented amino moieties. It was found that compounds
2a [NR2 = N(CH3)2, axial, Ki = 0.58 μm] and 2b [NR2 =
N(CH3)2, equatorial, Ki = 2.49 μm] with a 3-phenylpropyl-
amine substructure showed moderate affinity towards σ1 re-
ceptors.[5] Based on these results the regioisomeric 5,9-ep-
oxybenzocycloocten-6-amines 3 containing the 2-phenyl-
ethylamine substructure were envisaged. We report herein
the synthesis of tricyclic amines of type 3 in enantiomer-
ically pure form and their affinities towards σ1 and σ2 re-
ceptors, the phencyclidine binding site of the NMDA recep-
tor, and κ- and μ-opioid receptors. Preliminary results have
already been outlined in a short communication.[6]
Scheme 2. Plan for the synthesis of 5,9-epoxybenzocycloocten-6-
amines 3 .
Synthesis of γ-Hydroxy Amide 14
A one-step synthesis of γ-lactone 11 by reaction of allyl-
benzene (12) with acetic acid in the presence of Mn(OAc)3
has been reported in the literature (Scheme 3).[7] The Mn3+
–
salt was prepared in situ by conproportionation of MnO4
and Mn2+. By using this method the γ-lactone 11 was ob-
tained in 44% yield. Due to the moderate yields, the use of
the toxic heavy metal Mn in a stoichiometric amount, and
the inconvenient separation of Mn salts during the work-
up procedure, an alternative route was investigated. Accord-
Chemistry
Synthetic Plan
The plan for the synthesis of 5,9-epoxybenzocycloocten- ing to a procedure described in a patent,[8] phenylacetoni-
6-amines 3 is depicted in Scheme 2. In the first key step, the trile (7) was treated with diethyl succinate (8) in the pres-
oxa-Pictet–Spengler reactions of 4-hydroxy-5-phenyl- ence of NaOEt. After stirring the reaction mixture for 16 h
pentanoic acid derivatives 4 with glyoxylic acid derivative 5 at room temperature, concentrated HCl and acetic acid
provide 2-benzopyrans with two ester moieties. Dieckmann were added to give the γ-keto acid 9. Treatment of the γ-
cyclization and subsequent decarboxylation gives the tri- keto acid 9 with NaBH4 afforded the γ-hydroxy acid 10,
cyclic ketone 6, which is converted diastereoselectively into which cyclized quantitatively upon treatment with dilute
the tricyclic amines 3 with equatorially and axially oriented HCl to form the γ-lactone 11. After optimization of each
amino moieties. To obtain enantiomerically pure products step, this four-step procedure led to the γ-lactone 11 in 60%
3, enantiomerically pure 4-hydroxy-5-phenylpentanoic acid overall yield. Because a heavy metal was not required and
derivatives 4 will be used for the oxa-Pictet–Spengler reac- the overall yield was higher than the yield resulting from
tions. Kinetic resolution of γ-hydroxypentanoates 4 with li- the Mn3+-induced synthesis of lactone 11, this procedure
pases represents a key step in the synthetic strategy.
was used for the large-scale preparation of 11.
Scheme 3. Reagents and conditions: (a) NaOEt, EtOH, room temp., overnight; (b) NaBH4, CH3OH, room temp., overnight, then HCl,
room temp., 30 min, 60% (related to phenylacetonitrile 7); (c) Mn(OAc)3, HOAc, ref.[7c] 44%; (d) EtOH, NEt3, reflux, 20 h, 6%; (e) (H3C)2-
NH, EtOH, room temp., 24 h, 94%; (f) NaBrO3, (NH4)2Ce(NO3)6, acetonitrile, H2O, reflux, 45 min, 91%.
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For the synthesis of the γ-hydroxy ester 13, which was ume, and separation temperature, the γ-hydroxy amide
required for the oxa-Pictet–Spengler reaction, the γ-lactone enantiomers (S)- and (R)-14 were separated with a resolu-
11 was treated with ethanol in the presence of NEt3 tion of 1.47 by using the mobile phase n-hexane/THF
(Scheme 3). However, these reaction conditions led to an (92.5:7.5; Figure 1, A). The addition of acidic or basic addi-
equilibrium of the γ-lactone 11 and the γ-hydroxy ester 13 tives did not improve the resolution or the tailing.
in a ratio of about 3:1 and the γ-hydroxy ester 13 could be
The γ-acetoxy amide enantiomers (S)- and (R)-16 as well
isolated in only 6% yield. This equilibrium could not be as the γ-lactone enantiomers (S)- and (R)-11 were separated
shifted towards the ester 13 by variation of the reaction by using the same stationary phase at a lower temperature.
conditions (e.g., time, temperature), the nucleophile (e.g., At 5 °C, resolutions of 1.32 (16) and 1.69 (11) were
NaOEt), or the alcohol component (e.g., NaOiPr, achieved, sufficient to determine the ratios of the enantio-
NaOtBu). Because it was expected that the γ-hydroxy ester mers.
13 would also produce the γ-lactone 11 very quickly during
the acid-catalyzed oxa-Pictet–Spengler reaction, the γ-lact-
Lipase-Catalyzed Kinetic Resolution of 14
one 11 was alternatively treated with dimethylamine to af-
ford the dimethylamide 14 in 94% yield. Owing to the high
yield and low tendency to form the γ-lactone 11, racemic
γ-hydroxy amide 14 was employed in the lipase-catalyzed
kinetic resolution.
To synthesize the enantiomerically pure tricyclic amines
3, the key intermediate 14 had to be synthesized in enantio-
merically pure form. At first the γ-hydroxy amide 14 was
oxidized with NaBrO3 and catalytic amounts of (NH4)2-
Ce(NO3)6 in aqueous acetonitrile[10] to afford the γ-keto
amide 15 in 91% yield (Scheme 3). Reduction of γ-keto
amide 15 with DIP chloride[11] [yield 11%, ee (S) 96%],
Development of Chiral HPLC Methods
To find a strategy for the production of enantiomerically CBS-oxazaborolidine[12] (yield 22%, ee 0%), and baker’s
pure γ-hydroxypentanoate derivatives, chiral HPLC meth- yeast[13] (yield 7%, ee 60%) did not produce the γ-hydroxy
ods for the quantification of the enantiomeric γ-hydroxy amide 14 in satisfactory yield and enantiopurity.
amides (S)-14/(R)-14, γ-acetoxy amides (S)-16/(R)-16, and
γ-lactones (S)-11/(R)-11 were developed.
Therefore kinetic resolution[14] of the racemic γ-hydroxy
amide 14 was carried out by lipase-catalyzed enantioselec-
The chiral stationary phase Kromasil® CHI-TBB[9] tive acetylation. At first the suitability of different lipases
turned out to give the best separations of the enantiomers. was screened. In this screening process, the γ-hydroxy amide
Kromasil® CHI-TBB is a three-dimensional network pro- 14 (100 mg) was shaken with the corresponding lipase
duced by the polymerization of (2R,3R)-O,OЈ-bis(4-tert- (400 mg) at room temperature in the solvent tert-butyl
butylbenzoyl)-N,NЈ-diallyltartaramide monomers. After op- methyl ether (TBME). Vinyl acetate and isopropenyl acetate
timization of the mobile phase, the flow rate, injection vol- were used as irreversible acylating agents. The results of the
Figure 1. HPLC separation of racemic γ-hydroxyamide 14. Kromasil® CHI-TBB, n-hexane/THF (92.5:7.5), flow rate 0.5 mL/min, injection
volume 7.5 μL, T = 20 °C, detection at λ = 254 nm. A: racemic mixture of 14; B: enantiomerically pure alcohol (S)-14 produced by
Pseudomonas fluorescens lipase catalyzed kinetic resolution.
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Chiral Oxa-Pictet–Spengler Reaction
Table 1. Screening of various lipases for the enantioselective acetylation of racemic alcohol 14.
Entry Lipase
Time Conversion [%][a]
(S)-14
Yield [%][b]
(R)-16
Yield [%][b]
E[c]
ee [%]
ee [%]
1
2
3
4
5
6
7
8
9
10
Candida antarctica lipase B,
24 h
24 h
144 h
78 h
27 d
12 d
93 h
82 h
356 h
141 h
33.6
33.6
38.8
68.8
7.6
49
49
48
26
8
42
29
29
28
53
4
83
16.2
16.2
immobilized (Chirazyme L-2)[d]
Candida antarctica lipase B,
immobilized (Chirazyme L-2)[e]
Candida antarctica lipase A,
immobilized (Chirazyme L-3)[e]
Candida rugosa lipase
42
44
83
71
9.0
Ͼ99
6
45
12.1
(Chirazyme L-5)[d]
Porcine pancreas lipase
73
6.8
(Chirazyme-7)[d]
Pseudomonas cepacia lipase
(Amano PS)[d,f]
Pseudomonas cepacia lipase,
immobilized (Amano PS-CII)[e]
Pseudomonas fluorescens
lipase (Amano AK)[e]
Pseudomonas fluorescens
lipase (Amano AK)[e,f]
Pseudomonas fluorescens
lipase (Amano AK)[e,g]
14.9
53.2
50.2
50.5
50.2
65
30
41
24
40
17
14
47
38
44
46
97.0
87
77.6
99.1
Ͼ99
Ͼ99
Ͼ99
74.8
98.4
97.1
98.4
ϾϾ100
ϾϾ100
ϾϾ100
[a] Yields after flash chromatographic purification. [b] Vinyl acetate. [c] Isopropenyl acetate. [d] 200 mg enzyme. [e] 5.0 g of racemic
alcohol 14 were employed, for details see the Exp. Sect. [f] Enantioselectivity E: E = ln[1 – c(1 + eeP)]/ln[1 – c(1 – eeP)].[15] [g] Conversion
c: c = eeS/eeS + eeP.[15]
screening process are summarized in Table 1. In general, all alcohol 14 with Pseudomonas fluorescens lipase for 82 h in
lipases converted the (R)-configured alcohol (R)-14 faster TBME at room temperature provided (S)-14 and (R)-16 in
than the (S)-configured enantiomer. Although Candida 41 and 38% yields with Ͼ99.0 and 98.4% ee, respectively
rugosa lipase catalyzed a fast transformation of alcohol (R)- (entry 8). The use of a reduced amount of lipase (200 mg)
14 to give enantiomerically pure alcohol (S)-14 in 26% yield required a longer reaction time (356 h) to complete the
(E[15] = 12.1, entry 4), Pseudomonas cepacia lipase produced transformation (entry 9). However, prolonged reaction
the acetate (R)-16 with high enantiomeric purity but in low times generally led to an increased formation of γ-lactone
yield (E = 77.6, entry 6). Immobilization of Pseudomonas 11, which could be isolated in chiral nonracemic form.
cepacia lipase (Amano PS-CII) on ceramic particles in-
For the large-scale preparation of (S)-14 and (R)-16, the
creased the catalytic activity leading to high yields and ee Pseudomonas fluorescens lipase catalyzed acetylation was
values for both the alcohol (S)-14 and the acetate (R)-16 (E optimized. Finally, racemic γ-hydroxy amide 14 (5.0 g) was
= 74.8, entry 7). However, Pseudomonas fluorescens lipase treated with isopropenyl acetate (7 equiv.) and Pseudomonas
(Amano AK) turned out to be the best catalyst for this fluorescens lipase (3.75 g) in TBME at room temperature.
transformation giving the highest enantioselectivity (E Ͼ The transformation was monitored by TLC and HPLC.
100) and enantiomeric excess. Treatment of the racemic The development of the enantiomeric excess of the alcohol
Figure 2. Development of the enantiomeric excess of (S)-14 during the acetylation of racemic alcohol 14 with isopropenyl acetate in the
presence of Pseudomonas fluorescens lipase.
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C. Ketterer, B. Wünsch
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Scheme 4. Reagents and conditions: (a) Pseudomonas fluorescens lipase (Amano AK lipase), isopropenyl acetate, TBME, room temp.,
141 h, 40% [(S)-14], 46% [(R)-16], 10% [(S)-11]; (b) Ac2O, NEt3, DMAP, CH2Cl2, room temp., 4 h, 98%; (c) Candida rugosa lipase,
(Chirazyme L-5), acetone, phosphate buffer pH 7, 37 °C, 96 h, 47% [(S)-16], 50% [(R)-14]; (d) Ac2O, NEt3, DMAP, CH2Cl2, room temp.,
6 h, 90%; (e) CH3OH, H2O, K2CO3, room temp., 24 h, 92%.
Table 2. Screening of various lipases for the enantioselective hydrolysis of acetate 16.
Entry Lipase
Time [h]
Conversion [%][a]
(R)-14
Yield [%][b]
(S)-16
Yield [%][b]
E[c]
ee [%]
ee [%]
1
2
3
4
5
6
7
Candida antarctica lipase B,
262
263
96
2.7
1.8
2
71
49
55
47
70
78
87
77
2
6.0
3.4
immobilized (Chirazyme L-2)
Candida antarctica lipase A,
immobilized (Chirazyme L-3)
Candida rugosa lipase
(Chirazyme L-5)
Porcine pancreas lipase
(Chirazyme L-7)
Pseudomonas cepacia lipase
(Amano PS)
Pseudomonas cepacia lipase,
immobilized (Amano PS-CII)
Pseudomonas fluorescens
lipase (Amano AK)
1
54
95.3
57
1
Ͼ99
10
2
51.0
14.9
6.5
50
12
6
ϾϾ100
4.0
141
260
216
190
29
1.9
3.5
4
82
3
10.4
12.1
18.0
16
82
18
[a] Conversion c: c = eeS/eeS + eeP.[15] [b] Yield after FC purification. [c] E = ln[1 – c(1 + eeP)]/ln[1 – c(1 – eeP)].[15]
(S)-14 during the transformation is shown in Figure 2. The
In conclusion, the enantioselective acetylation of racemic
transformation was terminated when the (R)-configured alcohol 14 catalyzed by Pseudomonas fluorescens lipase and
alcohol (R)-14 had been completely consumed (ca. 140– the enantioselective hydrolysis of racemic acetate 16 cata-
160 h). Exemplarily, after shaking the reaction mixture for lyzed by Candida rugosa lipase represent complementary
141 h the alcohol (S)-14 and the ester (R)-16 were isolated procedures for the synthesis of enantiomeric alcohols (S)-
in 40 and 46% yields with Ͼ99 and 98.4% ee, respectively and (R)-14 as well as enantiomeric acetates (R)- and (S)-
(Table 1, entry 10, Figure 1, B). Furthermore, the γ-lactone 16. Because the direct acetylation of alcohol 14 was experi-
(S)-11 was isolated in 10% yield and 72% ee.
mentally more convenient than the hydrolysis of acetate 16,
In addition, the enantioselectivities of the hydrolysis of the Pseudomonas fluorescens lipase catalyzed acetylation
racemic acetate 16, which should produce the (R)-config- was optimized for the large-scale production of alcohol (S)-
ured alcohol (R)-14 and the (S)-configured ester (S)-16, 14 and acetate (R)-16. Subsequently, the corresponding en-
with various lipases were determined (Scheme 4). After antiomeric alcohol (R)-14 and enantiomeric acetate (S)-16
acetylation of racemic alcohol 14 with Ac2O, the racemic were synthesized by hydrolysis of (R)-16 and acetylation of
acetate 16 was treated with the same lipases as used for the (S)-14, respectively (Scheme 4).
acetylation step (Table 2). The transformations were per-
formed in phosphate buffer at pH 7.0 and 37 °C. All lipases
showed a preference for the hydrolysis of the (R)-configured
ester (R)-16 to give the alcohol (R)-14. Although Pseudom-
Synthesis of the Tricyclic Amines
onas fluorescens lipase gave only low enantioselectivity (E =
To synthesize the tricyclic scaffold, oxa-Pictet–Spengler
12.1; Table 2, entry 7), the lipase of Candida rugosa showed reaction of the γ-hydroxy amide (S)-14 was envisaged. Some
excellent enantioselectivity (E Ͼ 100, entry 3) in the hydrol- examples of chiral oxa-Pictet–Spengler reactions have been
ysis step. After flash chromatographic purification, the reported in the literature. Most of these procedures used
alcohol (R)-14 and acetate (S)-16 were isolated in 50 and either donor-substituted benzene derivatives or electron-
47% yields with 95.3 and Ͼ99.0% ee, respectively.
rich heterocycles.[16] However, only very few cyclizations of
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Chiral Oxa-Pictet–Spengler Reaction
Scheme 5. Reagents and conditions: (a) CH2Cl2, BF3·OEt2, room temp., 6 h, then 40 °C, 4 d, 93%; (b) Tf2O, CH2Cl2, pyridine, –40 °C,
2 h, 0 °C, 12 h, then EtOH, room temp., 12 h, 83%; (c) NaH, EtOH, toluene, reflux, 2.5 h, 62%; (d) NaOH, EtOH, reflux, 3 h, 91%.
nonactivated benzene derivatives have been reported.[17] In mass spectrum, and, moreover, the common product (S,S)-
this work, enantiomerically pure phenylethanol derivative 21 proved unequivocally the existence of 20 in three iso-
(S)-14, without activation of the benzene moiety, was meric forms.
treated with ethyl glyoxylate (17a) in the presence of
The tricyclic ketone (S,S)-21, which represents the cen-
BF3·Et2O to form 2-benzopyran (S,S)-18 in 93% yield tral intermediate in the synthesis of tricyclic amines, was
(Scheme 5). The same yield (88%) was obtained with the
corresponding diethyl acetal 17b as carbonyl component.
Both reactions provided exclusively the thermodynamically
favored cis-configured 2-benzopyran (S,S)-18. The cis ori-
entation of the protons in the 1- and 3-positions (1-H, 3-
H) was unequivocally shown by a positive nuclear Over-
hauser effect after irradiation at δ = 5.37 ppm (1-H, increase
of 3-H signal) and 3.76 ppm (3-H, increase of 1-H signal).
In the next step a Dieckmann cyclization of the amido
ester (S,S)-18 should produce the tricyclic system. However,
all attempts to cyclize the amido ester (S,S)-18 directly did
not result in the formation of the desired tricyclic com-
pound. Therefore the amide (S,S)-18 was converted into the
ethyl ester (S,S)-19 by treatment with Tf2O and sub-
sequently with ethanol.[18] This procedure led to the diester
(S,S)-19 in 83% yield.
Several reaction conditions had to be investigated for the
Dieckmann cyclization of diester (S,S)-19 because decom-
position (NaOEt) and isomerization (KOtBu, KHMDS) to
the trans isomer (1R,3S)-19 occurred. Treatment of the dies-
ter (S,S)-19 with 3.2 equiv. of NaH and 0.6 equiv. of eth-
anol in toluene at reflux for 2.5 h gave the tricyclic β-keto
ester 20 in 69% yield. However, the interpretation of the
NMR spectra of the resulting product 20 turned out to be
very difficult due to the existence of three isomeric com-
Scheme 6. Reagents and conditions: (a) NH4OAc, NaBH3CN,
CH3OH, room temp., 69 h, 38% (S,S,S)-22; (b) H3CNH2 or (H3C)2-
pounds: Two diastereomeric β-keto esters (S,S,S)-20a and
(S,R,S)-20b and the enol ester (S,R)-20c. The NMR spectra
NH, Ti(OiPr)4, 4 Å mol. sieves, room temp., 63 h, then NaBH4,
recorded in CDCl3 show a 20:15:65 ratio of the three com-
pounds [(S,S,S)-20a/(S,R,S)-20b/(S,R)-20c], with the enol
ester (S,R)-20c being the main component. The constant
ratio of the three compounds in different samples, the dif-
ferent ratio of signals after recording the NMR spectra in
room temp., 23–24 h, 65% [(S,S,S)-23], 72% [(S,S,S)-24];
(c) NaBH4, CH3OH, room temp., 90 min, 86%; (d) p-TolSO2Cl,
CH2Cl2, NEt3, DMAP, room temp., 60 min, 72%: (e) H3CSO2Cl,
CH2Cl2, NEt3, 0 °C, 60 min, 97%; (f) (S,S,S)-26b, NaN3, DMF,
reflux, 38 h, 36%; (g) NH4HCO2, CH3OH, Pd/C, reflux, 4 h, 80%;
(h) H2C=O/H2O (37%), NaBH3CN, acetonitrile, room temp., 24 h,
DMSO (39:36:25), a molecular peak at m/z = 260 in the 68%.
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C. Ketterer, B. Wünsch
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formed by heating the β-keto ester 20 with NaOH in eth- ditions with methyl- or dimethylamine provided very low
anol for 3 h. The yield of 91% could only be achieved when yields of the amines (S,S,S)-23 and (S,S,S)-24. A consider-
all three compounds (S,S)-20a,b and (S,R)-20c had been able improvement in the yields was achieved by activation
converted into the ketone (S,S)-21.
of the ketone (S,S)-21 and methyl- or dimethylamine with
Reductive amination of the tricyclic ketone (S,S)-21 with the Lewis acid Ti(OiPr)4 and subsequent reduction with
NH4OAc and NaBH3CN[19] led to the primary amine NaBH4.[20] By this method the secondary and tertiary
(S,S,S)-22 in 38% yield (Scheme 6). The same reaction con- amines (S,S,S)-23 and (S,S,S)-24 were prepared in 65 and
Figure 3. Comparison of (A) the calculated CD spectrum of (S,S,S)-25 with the recorded CD spectra of (B) (S,S,S)-25 (c = 3.46 mmol,
CH3OH) and (C) (R,R,R)-25 (c = 3.46 mmol, CH3OH).
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Chiral Oxa-Pictet–Spengler Reaction
72% yields, respectively. However, decreased yields of the stituents.[23] Application of this empirical rule to the sec-
primary amine (S,S,S)-22 were obtained by using the Lewis ondary alcohol 14 is problematic, because both substituents
acid Ti(OiPr)4 for the reductive amination of (S,S)-21 with at the CHOH group of 14 start with a CH2 moiety. There-
NH4OAc and NaBH4.
fore the specific optical rotation for the (S,S,S)-configured
The amines (S,S,S)-22–24 were produced with excellent alcohol (S,S,S)-25 was calculated theoretically ([α]D
=
diastereoselectivity. With respect to the tetrahydropyran –13.2°mLdm–1 g–1, TDDFT/B3LYP level)[6] and compared
ring, the phenyl moiety of (S,S)-21 is axially oriented and with the recorded value ([α]D = –71.8°mLdm–1 g–1).
thus is shielding the Si face of the carbonyl moiety. There-
In addition, the CD spectra of (S,S,S)- and (R,R,R)-25
fore nucleophiles (e.g., hydride equivalents) can only attack were recorded and compared with the theoretically calcu-
the intermediate imines or iminium ions from the Re face lated CD spectrum of (S,S,S)-25 [double-hybrid time-de-
leading exclusively to the equatorial orientation of the pendent (TD)DFT level using the B2PLYP functional;[24]
amino moiety. The equatorial orientation of the dimeth- Figure 3]. Both the calculated and recorded spectra of the
ylamino moiety of (S,S,S)-24 is deduced from characteristic (S,S,S)-configured alcohol (S,S,S)-25 show a positive Cot-
1
signals in the H NMR spectrum. In particular, the signals ton effect at around 230 nm.
for 5-H (δ =4.97 ppm, d, J = 4.0 Hz), 6-Hax (δ =2.54 ppm,
Finally, an X-ray crystal structure analysis of (S,S,S)-25
dt, J = 12.5, 3.8 Hz), and 7-Hax (δ =1.19 ppm, qd, J = 12.9, using the three-beam interference method showed the abso-
4.7 Hz) clearly demonstrate the axial orientation of the pro- lute configuration (S,S,S) for the crystallized compound.[6]
ton in the 6-position (i.e., equatorial orientation of the Altogether, these data prove unequivocally the (S) configu-
amino moiety).
ration of the enantiomerically pure alcohol (S)-14 as well
To synthesize the corresponding diastereomers (S,R,S)- as the absolute configuration of all the intermediates and
28 and (S,R,S)-29 with axially oriented amino moieties, the final products.
ketone (S,S)-21 was reduced with NaBH4 to form the
alcohol (S,S,S)-25 with excellent diastereoselectivity
(Scheme 6). After activation of the alcohol (S,S,S)-25 as the
tosylate (S,S,S)-26a or mesylate (S,S,S)-26b, SN2 substitu-
Receptor Affinity
tion with inversion of the configuration at C-6 should pro-
The affinities of the enantiomerically pure tricyclic
vide the axially substituted tricyclic compounds. However, amines 22–24, 28, and 29 towards selected receptor systems
the direct substitution of both sulfonates (S,S,S)-26 with (σ1,[25] σ2,[25] NMDA,[26] κ-opioid,[27] and μ-opioid recep-
methylamine or dimethylamine did not lead to the corre- tors,[27] see Introduction) were investigated in competitive
sponding substitution products. Therefore NaN3 was em- receptor binding studies. In these assays a tritium-labeled
ployed for the SN2 reaction. In fact, both sulfonates (S,S,S)- radioligand with high affinity and selectivity for a particu-
26a and (S,S,S)-26b reacted with the azide nucleophile with lar receptor was incubated together with the test compound
inversion of the configuration to form (S,R,S)-27 with the and receptor preparation. At first, inhibition of radioligand
axially oriented azido group. Reduction of the azide binding at a rather high concentration of the test compound
(S,R,S)-27 under transfer hydrogenation conditions with (10 μm) was recorded. Competition curves for six concen-
ammonium formate and Pd/C[21] led to the primary amine trations were recorded only for the test compounds, which
(S,R,S)-28, which was methylated with formaldehyde and showed an inhibition of radioligand binding greater than
NaBH3CN[22] to afford the dimethylamine (S,R,S)-29. The 50% at 10 μm in the first screening experiment.
axial orientation of the dimethylamino moiety of (S,R,S)-
The inhibition of radioligand binding to the σ1, σ2,
1
29 is clearly shown by the H NMR signals for 5-H (δ = NMDA, κ, and μ receptors in the presence of the test com-
4.97 ppm, br. s), 6-Heq (δ = 2.07 ppm, td, J = 4.1, 1.7 Hz), pounds is summarized in Table 3. In general, at a concen-
and 7-Hax (δ = 1.53 ppm, ddt, J = 14.5, 12.3, 4.3 Hz). In tration of 10 μm, the test compounds did not compete
particular, a large 1,2-diaxial coupling constant for two ad- strongly with the radioligands for the receptor sites, which
jacent axially oriented protons is missing in the signal for indicates very low σ1, σ2, NMDA, κ, and μ receptor affinity.
6-Heq.
As an exception, the amines (S,R,S)- and (R,S,R)-29 with
The enantiomeric tricyclic amines (R,R,R)-22–24, axially oriented dimethylamino moieties and (S,S,S)-24
(R,S,R)-28, and (R,S,R)-29 were synthesized in the same with an equatorial orientation of the amino group showed
manner starting with the enantiomeric γ-hydroxy amide considerably reduced (+)-[3H]pentazocine binding in the σ1
(R)-14.
assay and [3H]ditolylguanidine binding in the σ2 assay.
Therefore the corresponding Ki values were determined by
recording the competition curves for six concentrations. In
the σ1 assay, Ki values of 41 and 14 μm were found for
(S,R,S)- and (R,S,R)-29, respectively, which indicates low
Absolute Configuration
The empirical rule for predicting which enantiomer of a σ1 affinity. Despite promising results in the first screening,
secondary alcohol reacts faster in lipase-catalyzed reactions (S,R,S)- and (R,S,R)-29 showed only low affinity in the σ2
is based on the size of the substituents. It suggests that li- assay (Ki Ͼ 50 μm, Ki = 28 μm). Interestingly, the equatori-
pases distinguish between enantiomers of secondary ally substituted dimethylamine (S,S,S)-24 represents the
alcohols primarily by comparing the sizes of the two sub- most potent σ2 ligand of this series of test compounds with
Eur. J. Org. Chem. 2012, 2428–2444
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2435

C. Ketterer, B. Wünsch
FULL PAPER
Table 3. σ1, σ2, NMDA, κ-opioid and μ-opioid receptor affinities of 5,9-epoxybenzocycloocten-6-amines.
Inhibition of radioligand binding [%][a]
σ1
σ2
NMDA
κ
μ
(S,S,S)-22
(R,R,R)-22
(S,S,S)-23
(R,R,R)-23
(S,S,S)-24
(R,R,R)-24
(S,R,S)-28
(R,S,R)-28
(S,R,S)-29
(R,S,R)-29
Haloperidol
(+)-Pentazocine
(+)-MK-801
Naloxone
11
9
6
9
6
6
37
28
2
3
19
12
9
19
13
21
18
20
9
0
7
2
7
0
24
24
2
2
–
–
7
0
4
0
9
4
22
22
3
61[b]
14
24
6
21
46[c]
45[d]
11
10
–
3
3
–
–
–
54[e]
56[f]
2.2Ϯ0.31[g]
34Ϯ2.3[g]
3.6Ϯ0.20[g]
–
–
–
–
5.2 nm[h]
–
–
–
–
0.68Ϯ0.04 nm[g]
3.2 nm[h]
[a] All compounds were tested at a concentration of 10 μm of HCl salt. [b] For the reference compounds, Ki values are given, n = 3. [c]
The given Ki values result from a single experiment. [d] Ki(σ1) = 41Ϯ14 μm (n = 3). [e] Ki(σ1) = 14Ϯ3.9 μm (n = 3). [f] Ki(σ2) =
2.9Ϯ0.01 μm (n = 3). [g] Ki(σ2) Ͼ 50 μm (n = 3). [h] Ki(σ2) = 28Ϯ0.1 μm (n = 3).
(Perkin–Elmer), and Vario EL (Elementaranalysesysteme GmbH).
MS: MAT 448, MAT 312, MAT 8200, and TSQ 7000 spectrome-
ters (Finnigan). EI = electron impact, CI = chemical ionization.
HRMS: MAT 8200 spectrometer (Finnigan). IR: 1605 FT-IR and
2000 FT-ATR spectrophotometers (Perkin–Elmer); s = strong, m
= medium, w = weak. 1H (300 MHz) and 13C NMR (75 MHz):
Unity 300 FT NMR spectrometer (Varian): δ in ppm relative to
tetramethylsilane, coupling constants are given with 0.5 Hz resolu-
tion; the 13C and 1H NMR assignments are supported by 2D NMR
techniques. Polarimetry: PE 241 polarimeter (Perkin–Elmer): d =
1 dm, λ = 589 nm, the unit of the specific optical rotation
(°mLdm–1 g–1) has been omitted for clarity. CD spectroscopy: CD6
circular dichrograph (Jobin Yvon Instruments S.A.). Microwave ap-
paratus: CEM Discover LabMate Synthesizer, single mode cavity;
Discover PC software (CEM Corporation, NC); reactions were
performed in glass vessels (capacity 10 mL) sealed with the corre-
sponding pressure adaptor. The pressure was controlled by using a
piezoelectric pressure sensor. The temperature of the vessel con-
tents was monitored by using an external infrared temperature con-
trol. HPLC: Waters equipment: UV detector: Waters 2487 Dual
Absorbance detector; autosampler: Waters 710; pump: Waters 515,
double piston pump, degasser: Waters inline degasser, 4-channel;
Jetstream 2 plus, Peltier column thermostat; Software ChromStar
light version 4.05. Enantiomerically pure compounds were synthe-
sized by using procedures that had been optimized with racemic
compounds.
an Ki value of 2.9 μm. Clearly, moderate-to-good σ2 affinity
of tricyclic amines is attained with an optimal stereochemis-
try [equatorially oriented amino moiety, (S,S,S) configura-
tion] and the correct substitution pattern of the amino
moiety. The tricyclic dimethylamine (S,S,S)-24 represents a
promising lead compound for the development of novel po-
tent and selective σ2 ligands in a second optimization cycle.
Conclusion
Seven-to-ten reaction steps were required to synthesize
the tricyclic amines 22–24, 28, and 29, which are derivatives
of the tricyclic benzomorphan scaffold. Although the sizes
of the substituents at the secondary alcohol 14 and the acet-
ate 16 are very similar (benzyl, 2-carbamoylethyl), the li-
pases of Pseudomonas fluorescens and Candida rugosa are
able to differentiate the corresponding enantiomers. Chiral
oxa-Pictet–Spengler reaction, Dieckmann condensation,
and stereoselective introduction of amino moieties repre-
sent the key steps of the synthesis. Investigation of the affin-
ity towards σ1, σ2, NMDA, κ, and μ receptors revealed that
the orientation and substitution pattern of the amino moi-
ety and the absolute configuration of the ring system are
responsible for high σ2 receptor affinity: The dimethylamine
(S,S,S)-24 with equatorially oriented amino moiety showed
remarkable σ2 affinity in the low micromolar range (Ki =
2.9 μm).
4-Oxo-5-phenylpentanoic Acid (9):[8] Phenylacetonitrile (7; 6.0 mL,
52 mmol) and diethyl succinate (8; 13.4 mL, 80 mmol) were added
to a solution of sodium metal (1.53 g, 66.6 mmol) in absolute eth-
anol (25 mL). The mixture was stirred overnight at room temp. and
diluted with cold water (50 mL). The aqueous layer was extracted
with toluene (3ϫ15 mL) and acidified with 2 m H2SO4. The re-
sulting oil was separated and the aqueous layer was extracted with
Et2O (3ϫ50 mL). The Et2O layer was dried (Na2SO4) and the sol-
vent was evaporated. The residue was dissolved in a mixture of
H2O (15 mL), conc. HCl (17 mL), and glacial acetic acid (52 mL).
Then the mixture was heated at reflux for 48 h. The mixture was
diluted with water (100 mL) and extracted with CH2Cl2
(4ϫ40 mL). The combined organic layers were dried (Na2SO4) and
the solvent was removed under reduced pressure. The crude prod-
uct (8.02 g) was recrystallized from petroleum ether. [After
Experimental Section
General Chemistry: Unless otherwise noted, moisture-sensitive re-
actions were conducted under dry nitrogen. Petroleum ether refers
to the fraction boiling at 40–60 °C. Lipases were commercially
available from Sigma–Aldrich and Alfa Aesar. TLC: Silica gel 60
F254 plates (Merck). Flash chromatography (FC): Silica gel 60,
0.040–0.063 mm (Merck); data in parentheses represent diameter
of the column [cm], eluent, fraction size [mL], Rf. Melting points:
SMP 2 apparatus (Stuart Scientific). Elemental analyses: CHN-
Elementaranalysator Rapid (Heraeus), Elemental Analyzer 240 recrystallization, the yield of 9 was rather low (Ͻ10%), so the crude
2436 Eur. J. Org. Chem. 2012, 2428–2444
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chiral Oxa-Pictet–Spengler Reaction
product was used in the following transformation without purifica-
tion.] Colorless needles, m.p. 55 °C (petroleum ether; ref.[28] 55–
in ethanol (5.6 m, 18.8 mL, 105 mmol) was stirred for 24 h at room
temp. The mixture was acidified with diluted HCl (pH 1–2) and
56 °C). IR: ν = 3414 (νO–H), 3029 (νC–H arom.), 2958 (νC–Haliph.), extracted with CH2Cl2 (5ϫ40 mL). The combined organic layers
˜
1714 (νC=O), 744, 699 (γmonosubst. arom.) cm–1. H NMR (CDCl3): δ
= 2.61 (t, J = 6.4 Hz, 2 H, 2-H), 2.76 (t, J = 6.4 Hz, 2 H, 3-H), 3.75
(s, 2 H, 5-H), 7.21–7.38 (m, 5 H, arom.) ppm. 13C NMR (CDCl3): δ
= 27.8 (1 C, C-2), 36.1 (1 C, C-3), 49.9 (1 C, C-5), 127.1 (1 C, C-
4Ј), 128.7 (2 C, C-3Ј, C-5Ј), 129.4 (2 C, C-2Ј, C-6Ј), 133.9 (1 C, C-
were dried (Na2SO4), concentrated in vacuo, and the residue (5.7 g)
was purified by FC (5.5 cm, ethyl acetate/acetone = 3:1, 30 mL, Rf
1
= 0.30). Colorless oil, yield 5.48 g (94%). IR (film): ν = 3393
˜
(νO–H), 3028 (νC–H arom.), 2928 (νC–Haliph.), 1622 (νC=O), 1084
(νC–O), 747, 702 (γmonosubst. arom.) cm–1. 1H NMR (CDCl3): δ = 1.76
1Ј), 178.7 (1 C, C-1), 206.3 (1 C, C-4) ppm. MS (EI): m/z (%) = (dddd, J = 14.4, 8.9, 7.3, 6.1 Hz, 1 H, 3-H), 1.90 (dddd, J = 14.4,
192 (37) [M]+, 174 (22) [M – H2O]+, 101 (100) [M – CH2Ph]+, 91
(75) [CH2Ph]+. C11H12O3 (192.21): calcd. C 68.74, H 6.29; found
C 68.25, H 6.56.
7.3, 5.8, 3.1 Hz, 1 H, 3-H), 2.44 (ddd, J = 16.2, 7.3, 5.8 Hz, 1 H,
2-H), 2.54 (ddd, J = 16.2, 7.3, 6.1 Hz, 1 H, 2-H), 2.76 (dd, J =
13.5, 6.1 Hz, 1 H, 5-H), 2.82 (dd, J = 13.5, 7.0 Hz, 1 H, 5-H), 2.95
(s, 3 H, NCH3), 3.00 (s, 3 H, NCH3), 3.86 (dtd, J = 8.9, 6.1, 3.1 Hz,
1 H, 4-H), 7.18–7.32 (m, 5 H, arom.) ppm. 13C NMR (CDCl3): δ
= 29.9 (1 C, C-2), 31.0 (1 C, C-3), 35.3 (1 C, NCH3), 37.1 (1 C,
NCH3), 44.1 (1 C, C-5), 72.1 (1 C, C-4), 126.0 (1 C, C-4Ј), 128.1
(2 C, C-3Ј, C-5Ј), 129.2 (2 C, C-2Ј, C-6Ј), 138.5 (1 C, C-1Ј), 173.4
(1 C, C-1) ppm. MS (EI): m/z (%) = 203 (22) [M – H2O]+, 130 (100)
[M – CH2Ph]+, 91 (29) [CH2Ph]+. MS (CI, NH3): m/z = 222 [M +
H]+. C13H19NO2 (221.30): calcd. C 70.56, H 8.65, N 6.33; found C
70.25, H 8.90, N 5.93. HPLC: Kromasil® CHI-TBB, 5 μm,
250ϫ4.6 mm (Akzo Nobel), mobile phase: n-hexane/THF =
92.5:7.5, flow rate 0.5 mL/min, T = 20 °C, c = 1.08 mg/mL, injec-
tion volume 7.5 μL, detection at λ = 254 nm, retention times: (R)-
14 t = 55.4 min, (S)-14 t = 58.7 min.
(RS)-(؎)-5-Benzyltetrahydrofuran-2-one (11):[8] NaBH4 (7.91 g,
209 mmol) was added to a solution of unpurified γ-keto acid 9
(8.02 g, 41.7 mmol) in methanol (250 mL) and the mixture was
stirred for 15 h at room temp. After removal of the solvent in
vacuo, the residue was dissolved in water (50 mL) and acidified
with diluted HCl (pH Ͻ 2). After 30 min the suspension was ex-
tracted with Et2O (4ϫ50 mL). The combined organic layers were
dried (Na2SO4), concentrated in vacuo, and the residue (8.13 g) was
purified by FC (5.5 cm, petroleum ether/ethyl acetate = 3:1, 45 mL,
Rf = 0.50). Colorless oil that solidified upon storage in the refriger-
ator as a colorless solid, m.p. 33 °C (ref.[7] 33 °C), yield 5.56 g (60%,
based on phenylacetonitrile). IR (film): ν = 3029 (νC–H arom.), 2942
˜
1
(νC–Haliph.), 1770 (νC=O), 750, 702 (γmonosubst. arom.) cm–1. H NMR
(CDCl3): δ = 1.94 (dtd, J = 12.8, 9.4, 7.5 Hz, 1 H, 4-H), 2.23 (dddd,
J = 12.8, 9.4, 6.7, 4.7 Hz, 1 H, 4-H), 2.35 (ddd, J = 17.7, 9.2,
4.7 Hz, 1 H, 3-H), 2.45 (dt, J = 17.7, 9.4 Hz, 1 H, 3-H), 2.91 (dd,
J = 14.0, 6.1 Hz, 1 H, Ar-CH2), 3.06 (dd, J = 14.0, 6.1 Hz, 1 H,
Ar-CH2), 4.72 (dq, J = 7.5, 6.4 Hz, 1 H, 5-H), 7.19–7.34 (m, 5 H,
arom.) ppm. 13C NMR (CDCl3): δ = 26.9 (1 C, C-4), 28.4 (1 C, C-
3), 41.1 (1 C, Ar-CH2), 80.6 (1 C, C-5), 126.7 (1 C, C-4Ј), 128.4 (2
C, C-3Ј, C-5Ј), 129.2 (2 C, C-2Ј, C-6Ј), 135.8 (1 C, C-1Ј), 176.9 (1
C, C-2) ppm. MS (EI): m/z (%) = 176 (23) [M]+, 91 (20)
[CH2Ph]+, 85 (100) [M – CH2Ph]+, 57 (11) [OCHCH2CH2]+.
C11H12O2 (176.21): calcd. C 74.98, H 6.86; found C 74.68, H 6.81.
HPLC: Kromasil® CHI-TBB, 5 μm, 250ϫ4.6 mm (Akzo Nobel),
mobile phase: n-hexane/TBME = 90:10, flow rate 0.5 mL/min, T =
5 °C, c = 1.0 mg/mL, injection volume 7.5 μL, detection at λ =
254 nm, retention times: (R)-11 t = 40.7 min, (S)-11 t = 43.2 min.
N,N-Dimethyl-4-oxo-5-phenylpentaneamide (15): NaBrO3 (0.68 g,
4.57 mmol) and (NH4)2Ce(NO3)6 (0.25 g, 0.45 mmol) were added
to a solution of alcohol 14 (0.91 g, 4.12 mmol) in a mixture of
acetonitrile/water (30 mL, 7:3). The mixture was heated at reflux
for 45 min, diluted with H2O (20 mL), and extracted with CH2Cl2
(50 mL). The organic layer was washed with a solution of saturated
NaHCO3 (30 mL) and brine (30 mL). The combined water layers
were extracted with CH2Cl2 (3ϫ50 mL) and the organic layer was
dried (Na2SO4), concentrated in vacuo, and the residue (0.97 g)
purified by FC (4 cm, ethyl acetate/petroleum ether = 5:1, 20 mL,
Rf = 0.36). Pale-yellow oil, yield 0.82 g (91%). IR (KBr): ν˜ = 3029
(νC–H arom.), 2922 (νC–H aliph.), 1713 (νC=O), 1639 (νC=O), 745, 699
1
(γmonosubst. arom.) cm–1. H NMR (CDCl3): δ = 2.57 (t, J = 6.4 Hz,
2 H, 2-H), 2.77 (t, J = 6.4 Hz, 2 H, 3-H), 2.92 (s, 3 H, NCH3), 3.00
(s, 3 H, NCH3), 3.79 (s, 2 H, 5-H), 7.20–7.34 (m, 5 H, arom.) ppm.
13C NMR (CDCl3): δ = 27.2 (1 C, C-2), 35.4 (1 C, NCH3), 36.6 (1
C, C-3), 36.9 (1 C, NCH3), 50.1 (1 C, C-5), 126.8 (1 C, C-4Ј), 128.5
(2 C, C-3Ј, C-5Ј), 129.4 (2 C, C-2Ј, C-6Ј), 134.2 (1 C, C-1Ј), 171.4
(1 C, C-1), 207.6 (1 C, C-4) ppm. MS (EI): m/z (%) = 174 (7) [M –
HNMe2]+, 128 (100) [M – CH2Ph]+, 100 (36) [CH2CH2CONMe2]+,
91 (20) [CH2Ph]+. MS (CI, NH3): m/z = 220 [M + H]+. C13H17NO2
(219.28): calcd. C 71.20, H 7.81, N 6.39; found C 71.07, H 8.03, N
6.28.
Ethyl (RS)-(؎)-4-Hydroxy-5-phenylpentanoate (13): A mixture of
11 (374 mg, 2.12 mmol), ethanol (20 mL), and NEt3 (1.0 mL,
7.21 mmol) was heated at reflux for 20 h. After removal of the sol-
vent in vacuo, the residue was purified by FC (2 cm, petroleum
ether/ethyl acetate = 5:1, 5 mL, Rf = 0.44). Colorless oil, yield
29 mg (6%). IR: ν = 3445 (νO–H), 3028 (νC–H arom.), 2980, 2929
˜
(νC–Haliph.), 1730 (νC=O), 1081 (νC–O), 744, 699 (γmonosubst. arom.
)
cm–1. 1H NMR (CDCl3): δ = 1.26 (t, J = 7.2 Hz, 3 H, OCH2CH3),
1.77 (ddt, J = 14.2, 8.7, 7.1 Hz, 1 H, 3-H), 1.92 (dddd, J = 14.4,
10.8, 7.2, 3.5 Hz, 1 H, 3-H), 2.43–2.54 (m, 2 H, 2-H), 2.71 (dd, J
= 13.6, 8.1 Hz, 1 H, 5-H), 2.83 (dd, J = 13.6, 4.7 Hz, 1 H, 5-H),
3.86 (tdd, J = 8.4, 4.5, 3.9 Hz, 1 H, 4-H), 4.14 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 7.19–7.35 (m, 5 H, arom.) ppm. 13C NMR (CDCl3): δ
= 14.2 (1 C, OCH2CH3), 30.8 (1 C, C-2), 31.6 (1 C, C-3), 44.1 (1
C, C-5), 60.4 (1 C, OCH2CH3), 72.0 (1 C, C-4), 126.5 (1 C, C-4Ј),
128.6 (2 C, C-3Ј, C-5Ј), 129.4 (2 C, C-2Ј, C-6Ј), 138.1 (1 C, C-1Ј),
174.0 (1 C, C-1). MS (EI): m/z (%) = 204 (4) [M – H2O]+, 176 (9)
[M – EtOH]+, 131 (100) [M – CH2Ph]+, 91 (35) [CH2Ph]+. MS (CI,
NH3): m/z (%) = 223 (85) [M + H]+, 205 (93) [M + H – H2O]+,
177 (100) [M + H – EtOH]+. C13H18O3 (222.28): calcd. C 70.25, H
8.16; found C 70.27, H 7.91.
(RS)-(؎)-[4-(Dimethylcarbamoyl)-1-phenyl-2-butyl] Acetate (16):
Ac2O (2.2 mL, 22.6 mmol) and 4-(dimethylamino)pyridine
(205 mg, 1.68 mmol) were added to a solution of alcohol 14 (2.00 g,
9.04 mmol) in CH2Cl2 (40 mL) and triethylamine (5 mL,
36.2 mmol). After stirring for 4 h at room temp., the mixture was
diluted with Et2O (40 mL), washed with diluted HCl (50 mL) and
H2O (50 mL), and the organic layer was dried (Na2SO4), concen-
trated in vacuo, and the residue (2.69 g) purified by FC (4 cm, ethyl
acetate/petroleum ether = 5:1, 20 mL, Rf = 0.34). Colorless oil that
solidified in the refrigerator as a colorless solid, m.p. 61 °C, yield
2.33 g (98%). IR (film):
ν = 3026 (νC–H arom.), 2970, 2930
˜
(νC–H aliph.), 1728 (νC=O), 1645 (νC=O), 752, 710 (γmonosubst. arom.).
1H NMR (CDCl3): δ = 1.76–2.08 (m, 2 H, 3-H), 1.97 (s, 3 H,
O=CCH3), 2.27 (dt, J = 15.7, 6.4 Hz, 1 H, 2-H), 2.36 (dt, J = 16.0,
6.4 Hz, 1 H, 2-H), 2.81 (dd, J = 13.7, 6.1 Hz, 1 H, 5-H), 2.89 (s, 3
(RS)-(؎)-4-Hydroxy-N,N-dimethyl-5-phenylpentanamide (14):
A
mixture of 11 (4.62 g, 26.2 mmol) and a solution of dimethylamine
Eur. J. Org. Chem. 2012, 2428–2444
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2437

C. Ketterer, B. Wünsch
FULL PAPER
H, NCH3), 2.90 (dd, J = 13.7, 6.7 Hz, 1 H, 5-H), 2.92 (s, 3 H, centrated in vacuo and the residue (246 mg) was purified by FC
NCH3), 5.10 (dtd, J = 8.9, 6.5, 3.9 Hz, 1 H, 4-H), 7.15–7.29 (m, 5 (2 cm, ethyl acetate/petroleum ether = 5:1, 2.5 mL, Rf = 0.34). Col-
H, arom.) ppm. 13C NMR (CDCl3): δ = 21.0 (1 C, O=CCH3), 29.0,
orless oil, yield 231 mg (90%), Ͼ99% ee. [α]589 = –3.5 (c = 10.5 mg/
29.2 (2 C, C-2, C-3), 35.3 (1 C, NCH3), 37.0 (1 C, NCH3), 40.7 (1 mL CH3OH).
C, C-5), 74.3 (1 C, C-4), 126.4 (1 C, C-4Ј), 128.2 (2 C, C-3Ј, C-5Ј),
Ethyl (1RS,3RS)-(؎)-3-[2-(Dimethylcarbamoyl)ethyl]-3,4-dihydro-
129.3 (2 C, C-2Ј, C-6Ј), 137.2 (1 C, C-1Ј), 170.5 (1 C, O=CCH3),
171.9 (1 C, C-1) ppm. MS (EI): m/z (%) = 203 (100) [M –
CH3COOH]+, 159 (20) [M – CH3COOH – N(CH3)2]+, 130 (43)
[M – CH3COOH – N(CH3)2 – CO – H]+, 91 (21) [CH2Ph]+. MS
(CI, NH3): m/z = 264 [M + H]+. C15H21NO3 (263.34): calcd. C
68.42, H 8.04, N 5.32; found C 68.36, H 8.28, N 5.20. HPLC:
Kromasil® CHI-TBB, 5 μm, 250ϫ4.6 mm (Akzo Nobel), mobile
phase: n-hexane/THF = 92.5:7.5, flow rate 0.5 mL/min, T = 5 °C,
c = 1.16 mg/mL, injection volume 7.5 μL, detection at λ = 254 nm,
retention times: (S)-16 t = 42.1 min, (R)-16 t = 44.3 min.
1H-2-benzopyran-1-carboxylate (18): Under N2 a solution of ethyl
glyoxylate (17a; 50% in toluene, 9.0 mL, 45.2 mmol) was added to
a solution of 14 (2.04 g, 9.2 mmol) in CH2Cl2 (40 mL). After stir-
ring for 30 min at 0 °C, BF3·OEt2 (9.2 mL, 72.3 mmol) was added
dropwise. The mixture was stirred for 6 h at room temp. and then
for 4 d at 40 °C. After diluting with 2 m HCl (70 mL), the organic
layer was separated and the aqueous layer was extracted with
CH2Cl2 (3ϫ50 mL). The combined organic layers were dried
(Na2SO4), concentrated in vacuo, and the residue purified by FC
(5.5 cm, ethyl acetate/petroleum ether = 4:1, 25 mL, Rf = 0.30). The
same yield was obtained by the same procedure by using diethyl
acetal 17b instead of the aldehyde 17a. Colorless oil that solidified
upon standing in the refrigerator, m.p. 64–65 °C, yield 2.64 g
Pseudomonas fluorescens Lipase Catalyzed Kinetic Resolution of
Racemic γ-Hydroxy Amide 14 (Enantioselective Acetylation of 14):
Isopropenyl acetate (17.5 mL, 159 mmol) and Amano AK lipase
(3.75 g) were added to a solution of racemic alcohol 14 (5.00 g,
22.6 mmol) in TBME (200 mL). The suspension was shaken
(150 rpm) for 141 h at room temp. Then the lipase was filtered off,
the filtrate was concentrated in vacuo, and the residue (6.81 g) was
purified by FC (5.5 cm, ethyl acetate/acetone = 3:1, 45 mL).
(88%). IR: ν = 2927 (νC–Haliph.), 1751 (νC=O), 1650 (νC=O), 1175
˜
1
(νC–O ester), 733 (γ1,2-disubst. arom.) cm–1. H NMR (CDCl3): δ = 1.29
(t,
J = 7.1 Hz, 3 H, OCH2CH3), 1.92–2.16 (m, 2 H,
CH2CH2CONMe2), 2.47–2.64 (m, 2 H, CH2CH2CONMe2), 2.67–
2.90 (m, 2 H, 4-H), 2.94 (s, 3 H, NCH3), 3.00 (s, 3 H, NCH3), 3.76
(ddt, J = 11.2, 8.3, 3.1 Hz, 1 H, 3-H), 4.25 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 5.37 (s, 1 H, 1-H), 7.10 (dd, J = 6.7, 1.5 Hz, 1 H, 5-
H), 7.15–7.22 (m, 2 H, 6-H, 7-H), 7.25 (dd, J = 6.9, 1.7 Hz, 1 H,
8-H) ppm. 13C NMR (CDCl3): δ = 14.1 (1 C, OCH2CH3), 28.8 (1
C, CH2CH2CONMe2), 30.9 (1 C, CH2CH2CONMe2), 34.1 (1 C,
C-4), 35.3 (1 C, NCH3), 37.1 (1 C, NCH3), 61.3 (1 C, OCH2CH3),
73.6 (1 C, C-3), 77.4 (1 C, C-1), 124.3 (1 C, C-8), 126.3, 127.4, (2
C, C-6, C-7), 129.0 (1 C, C-5), 131.6, 134.3 (2 C, C-4a, C-8a), 170.6
(1 C, COOEt), 172.6 (1 C, CONMe2) ppm. MS (EI): m/z (%) = 305
(25) [M]+, 232 (100) [M – COOEt]+, 214 (72) [M – CH2Ph]+, 91
(29) [CH2Ph]+, 46 (98) [NH2Me2]+. C17H23NO4 (305.37): calcd. C
66.86, H 7.59, N 4.59; found C 66.76, H 7.36, N 4.22.
(S)-14: Rf = 0.30. Colorless oil that solidified in the refrigerator as
a colorless solid, m.p. 47 °C, yield 2.02 g (40%), Ͼ99% ee. [α]589
–9.7 (c = 10.2 mg/mL, CH3OH).
=
(R)-16: Rf = 0.34 (ethyl acetate/petroleum ether = 5:1), colorless
oil, yield 2.75 g (46%), 98.4% ee. [α]589 = +3.4 (c = 9.9 mg/mL,
CH3OH).
(S)-11: Rf = 0.79 (ethyl acetate/petroleum ether = 5:1), colorless
oil, yield 0.41 g (10%), 72% ee.
Candida rugosa Lipase Catalyzed Kinetic Resolution of Racemic γ-
Acetoxy Amide 16 (Enantioselective Hydrolysis of 16): A mixture of
Candida rugosa lipase (Chirazyme L-5, 400 mg) and racemic ester
16 (99 mg, 0.37 mmol) in acetone (1 mL) and phosphate buffer
pH 7.0 (10 mL) was shaken for 96 h at 37 °C. The enzyme was fil-
tered off, the filtrate was extracted with Et2O (5ϫ15 mL), and the
combined organic layers were dried (Na2SO4), concentrated in
vacuo, and the residue (92 mg) purified by FC (2 cm, ethyl acetate/
petroleum ether = 5:1, 2.5 mL).
Ethyl (1S,3S)-(+)-3-[2-(Dimethylcarbamoyl)ethyl]-3,4-dihydro-1H-
2-benzopyran-1-carboxylate [(S,S)-18]: Compound (S,S)-18 was
prepared as described for (Ϯ)-18: (S)-14 (2.04 g, 9.21 mmol) was
treated with a solution of 17a (9.0 mL, 45.2 mmol) and BF3·OEt2
(9.2 mL, 72.5 mmol). Colorless oil that solidified upon storage in
the refrigerator as a colorless resin, yield 2.64 g (93%). [α]589 = +8.2
(c = 10.2 mg/mL, CH3OH).
(S)-16: Rf = 0.34, colorless oil, yield 46 mg (47%), Ͼ99% ee. [α]589
= –3.5 (c = 10.5 mg/mL, CH3OH).
Ethyl (1R,3R)-(–)-3-[2-(Dimethylcarbamoyl)ethyl]-3,4-dihydro-1H-
2-benzopyran-1-carboxylate [(R,R)-18]: Compound (R,R)-18 was
prepared as described for (Ϯ)-18: (R)-14 (3.60 g, 16.2 mmol) was
treated with a solution of 17a (16.1 mL, 81.2 mmol) and BF3·OEt2
(16.5 mL, 130 mmol). Colorless oil that solidified in the refrigerator
as a colorless resin, yield 4.28 g (86%). [α]589 = –7.9 (c = 10.0 mg/
mL, CH3OH).
(R)-14: Rf = 0.30 (ethyl acetate/acetone = 3:1), colorless oil, 95.3%
ee, yield 42 mg (50%).
(R)-(+)-4-Hydroxy-N,N-dimethyl-5-phenylpentaneamide [(R)-14]:
H2O (3 mL) and K2CO3 (494 mg, 3.58 mmol) were added to a solu-
tion of ester (R)-16 (182 mg, 0.69 mmol) in methanol (5 mL). The
mixture was stirred for 24 h at room temp. After the addition of
NaOH (0.01 m, 5 mL), the mixture was extracted with CH2Cl2
(3ϫ10 mL). The organic layer was dried (Na2SO4), concentrated
in vacuo, and the residue (153 mg) was purified by FC (2 cm, ethyl
acetate/acetone = 3:1, 2.5 mL, Rf = 0.30). Colorless oil, yield
141 mg (92%), 98.4% ee. [α]589 = +9.7 (c = 9.75 mg/mL, CH3OH).
Ethyl (1RS,3RS)-(؎)-3-[2-(Ethoxycarbonyl)ethyl]-3,4-dihydro-1H-
2-benzopyran-1-carboxylate (19): Under N2 the amido ester 18
(3.74 g, 12.2 mmol) was dissolved in CH2Cl2 (50 mL) and pyridine
(3.0 mL, 36.7 mmol) was added. At –40 °C, trifluoromethanesulfo-
nic anhydride (3.1 mL, 18.3 mmol) was added slowly. The mixture
was warmed to 0 °C over 2 h and stirred for an additional 12 h at
0 °C. Then ethanol (21.3 mL) was added and the mixture was
stirred for 12 h at room temp. After addition of Et2O (50 mL), the
mixture was washed with a solution of 1 m HCl (50 mL) and a
saturated solution of NaHCO3 (2ϫ50 mL). The organic layer was
dried (Na2SO4), concentrated in vacuo, and the residue was puri-
fied by FC (5.5 cm, petroleum ether/ethyl acetate = 6:1, 25 mL, Rf
(S)-(–)-[4-(Dimethylcarbamoyl)-1-phenyl-2-butyl] Acetate [(S)-16]:
Triethylamine (0.5 mL, 3.6 mmol), acetic anhydride (0.25 mL,
2.64 mmol), and 4-(dimethylamino)pyridine (28 mg, 0.23 mmol)
were added to a solution of alcohol (S)-14 (216 mg, 0.97 mmol) in
CH2Cl2 (6 mL), After stirring for 6 h at room temp., the mixture
was diluted with Et2O (10 mL), the organic layer was washed with
diluted HCl (10 mL) and H2O (10 mL), dried (Na2SO4), and con- = 0.41). Colorless oil that crystallized in the refrigerator as a color-
2438 Eur. J. Org. Chem. 2012, 2428–2444
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chiral Oxa-Pictet–Spengler Reaction
less solid (iPr O), m.p. 42 °C, yield 3.22 g (86%). IR: ν = 2982,
2), 4.13 (q, J = 7.0 Hz, 0.3 H, OCH2CH3, keto ester 2), 4.19 (q, J
= 7.0 Hz, 1.3 H, OCH2CH3, enol), 4.26 (q, J = 7.0 Hz, 0.4 H,
˜
2
2925 (νC–H aliph.), 1755 (νC=O), 1724 (νC=O), 1168 (νC–O), 743
1
(γ1,2-disubst. arom.) cm–1. H NMR (CDCl3): δ = 1.25 (t, J = 7.2 Hz, OCH2CH3, keto ester 1), 4.70–4.77 (m, 1 H, 9-H, enol + keto ester
3 H, OCH2CH3, ester at C-3), 1.30 (t, J = 7.2 Hz, 3 H, OCH2CH3,
ester at C-1), 2.00–2.09 (m, 2 H, CH2CH2COOEt), 2.47–2.65 (m,
2 H, CH2CH2COOEt), 2.69 (dd, J = 15.9, 2.4 Hz, 1 H, 4-H), 2.90
(dd, J = 15.9, 11.0 Hz, 1 H, 4-H), 3.73 (dddd, J = 10.8, 7.7, 4.8,
2.9 Hz, 1 H, 3-H), 4.14 (q, J = 7.2 Hz, 2 H, OCH2CH3, ester at C-
1 + 2), 4.97 (s, 0.65 H, 5-H, enol), 5.00 (s, 0.15 H, 5-H, keto ester
2), 5.02 (s, 0.2 H, 5-H, keto ester 1), 7.11–7.32 (m, 4 H, arom.),
11.73 (s, 0.65 H, OH, enol) ppm. 13C NMR (CDCl3): δ = 14.05
(0.2 C, OCH2CH3, keto ester 2), 14.11 (0.15 C, OCH2CH3, keto
ester 1), 14.22 (0.65 C, OCH2CH3, enol), 26.63 (0.15 C, C-8, keto
3), 4.27 (q, J = 7.2 Hz, 2 H, OCH2CH3, ester at C-1), 5.38 (s, 1 H, ester 1), 28.62 (0.2 C, C-8, keto ester 2), 29.66 (0.65 C, C-8, enol),
1-H), 7.11 (dd, J = 6.1, 2.1 Hz, 1 H, 5-H), 7.18–7.23 (m, 2 H, 6-H, 32.32 (0.65 C, C-10, enol), 33.00 (0.2 C, C-10, keto ester 2), 33.05
7-H), 7.28 (dd, J = 6.7, 1.8 Hz, 1 H, 8-H) ppm. 13C NMR (CDCl3):
(0.15 C, C-10, keto ester 1), 48.99 (0.15 C, C-7, keto ester 1), 49.43
δ = 14.1 (2 C, OCH2CH3), 30.2 (1 C, CH2CH2COOEt), 30.6 (1 C, (0.2 C, C-7, keto ester 2), 60.51 (0.65 C, OCH2CH3, enol), 61.32
CH2CH2COOEt), 34.0 (1 C, C-4), 60.2 (1 C, OCH2CH3, ester at (0.15 C, OCH2CH3, keto ester 1), 61.73 (0.2 C, OCH2CH3, keto
C-3), 61.3 (1 C, OCH2CH3, ester at C-1), 73.3 (1 C, C-3), 77.4 (1
C, C-1), 124.4 (1 C, C-8), 126.3, 127.4, (2 C, C-6, C-7), 128.9 (1 C,
C-5), 131.6, 134.0 (2 C, C-4a, C-8a), 170.4 (1 C, COOEt, ester at
ester 2), 65.24 (0.2 C, C-9, keto ester 2), 65.89 (0.15 C, C-9, keto
ester 1), 66.14 (0.65 C, C-9, enol), 70.19 (0.65 C, C-5, enol), 77.88
(0.2 C, C-5, keto ester 2), 77.99 (0.15 C, C-5, keto ester 1), 92.61
C-1), 173.3 (1 C, COOEt, ester at C-3) ppm. MS (EI): m/z (%) = (0.65 C, C-7, enol), 125.71, 125.73, 126.22, 126.29, 126.68, 126.74,
306 (4) [M]+, 233 (100) [M – COOEt]+, 215 (74) [M – CH2Ph]+,
187 (29) [M – PhCH=CO]+. C17H22O5 (306.36): calcd. C 66.65, H
7.24; found C 66.44, H 7.13.
127.72, 128.11, 128.18, 128.68, 129.78, 129.97, (4 C, C-1, C-2, C-3,
C-4), 130.65, 131.01, 131.14, 131.53, 132.25, 135.67 (2 C, C-4a,
C-10a), 167.94 (0.2 C, COOC2H5, keto ester 2), 169.00 (0.15 C,
COOC2H5, keto ester 1), 170.02 (0.65 C, COOC2H5, enol), 171.68
(0.65 C, C-6, enol), 203.98 (0.2 C, C-6, keto ester 2), 204.78 (0.15
C, C-6, keto ester 1) ppm. MS (EI): m/z (%) = 260 (60) [M]+, 232
(75) [M – C2H4]+, 186 (51) [M – COOC2H5 – H]+, 169 (17) [M –
CH2Ph]+, 141 (50) [M – CH2Ph – C2H4]+, 132 (100) [2-benzopy-
ran – 2H]+, 91 (46) [CH2Ph]+. C15H16O4 (260.28): calcd. C 69.22,
H 6.20; found C 69.09, H 6.22.
Ethyl
(1S,3S)-(+)-3-[2-(Ethoxycarbonyl)ethyl]-3,4-dihydro-1H-2-
benzopyran-1-carboxylate [(S,S)-19]: Compound (S,S)-19 was pre-
pared as described for (Ϯ)-19: (S)-18 (1.97 g, 6.45 mmol) was
treated with pyridine (1.6 mL, 19.4 mmol), trifluoromethanesulfo-
nic acid anhydride (1.6 mL, 9.5 mmol), and ethanol (15 mL). Col-
orless oil that froze in the refrigerator and melted at room temp.,
yield 1.63 g (83%). [α]589 = +9.1 (c = 9.6 mg/mL, CH3OH).
Ethyl (5S,7S,9S)-6-Oxo-5,6,7,8,9,10-hexahydro-5,9-epoxybenzocy-
clooctene-7-carboxylate [(S,S,S)-20a], Ethyl (5S,7R,9S)-6-Oxo-
5,6,7,8,9,10-hexahydro-5,9-epoxybenzocyclooctene-7-carboxylate
[(S,R,S)-20b], and Ethyl (5S,9R)-6-Hydroxy-5,8,9,10-tetrahydro-
5,9-epoxybenzocyclooctene-7-carboxylate [(S,R)-20c]: The Dieck-
mann cyclization of (S,S)-19 was performed as described for the
synthesis of (Ϯ)-20a/20b/20c: (S,S)-19 (3.61 g, 11.8 mmol) was
treated with NaH (60% dispersion, 1.42 g, 35.5 mmol) and abso-
lute ethanol (430 μL, 7.4 mmol). Colorless oil, yield 1.90 g (62%).
[α]589 = –62.4 (c = 7.4 mg/mL, CH3OH).
Ethyl
(1R,3R)-(–)-3-[2-(Ethoxycarbonyl)ethyl]-3,4-dihydro-1H-2-
benzopyran-1-carboxylate [(R,R)-19]: Compound (R,R)-19 was pre-
pared as described for (Ϯ)-19: (R)-18 (4.28 g, 14.0 mmol) was
treated with pyridine (3.4 mL, 42.1 mmol), trifluoromethanesulf-
onic acid anhydride (3.6 mL, 21.0 mmol), and ethanol (30 mL).
Colorless oil that froze in the refrigerator and melted at room
temp., yield 3.39 g (79%). [α]589 = –9.4 (c = 10.2 mg/mL, CH3OH).
Ethyl (5RS,7RS,9RS)-(؎)-6-Oxo-5,6,7,8,9,10-hexahydro-5,9-epoxy-
benzocyclooctene-7-carboxylate (20a), Ethyl (5RS,7SR,9RS)-(؎)-6-
Oxo-5,6,7,8,9,10-hexahydro-5,9-epoxybenzocyclooctene-7-carboxyl-
ate (20b), and Ethyl (5RS,9SR)-(؎)-6-Hydroxy-5,8,9,10-tetrahydro-
5,9-epoxybenzocyclooctene-7-carboxylate (20c): Under N2 NaH
(1.24 g, 31.1 mmol, 60% dispersion in mineral oil, which was re-
moved by washing several times with petroleum ether before use)
was suspended in toluene (100 mL). After 5 min a solution of 19
(3.04 g, 9.9 mmol) in toluene (30 mL) was added dropwise followed
by the addition of absolute ethanol (360 μL). When the evolution
of gas had finished, the mixture was heated at reflux for 2.5 h.
Diluted HCl (75 mL) was added and the organic layer was sepa-
rated, dried (Na2SO4), concentrated in vacuo, and the residue
(2.68 g) was purified by FC (5.5 cm, petroleum ether/ethyl acetate
= 10:1, 25 mL, Rf = 0.38). Colorless oil, yield 2.03 g (78%). The
Ethyl (5R,7R,9R)-6-Oxo-5,6,7,8,9,10-hexahydro-5,9-epoxybenzocy-
clooctene-7-carboxylate [(R,R,R)-20a], Ethyl (5R,7S,9R)-6-Oxo-
5,6,7,8,9,10-hexahydro-5,9-epoxybenzocyclooctene-7-carboxylate
[(R,S,R)-20b], and Ethyl (5R,9S)-6-Hydroxy-5,8,9,10-tetrahydro-
5,9-epoxybenzocyclooctene-7-carboxylate [(R,S)-20c]: The Dieck-
mann cyclization of (R,R)-19 was performed as described for the
synthesis of (Ϯ)-20a/20b/20c: (R,R)-19 (3.38 g, 11.0 mmol) was
treated with NaH (60% dispersion, 1.41 g, 35.3 mmol) and abso-
lute ethanol (410 μL, 7.0 mmol). Colorless oil, yield 1.99 g (69%).
[α]589 = +58.6 (c = 10.3 mg/mL, CH3OH).
(5RS,9RS)-(؎)-7,8,9,10-Tetrahydro-5,9-epoxybenzocycloocten-
6(5H)-one (21): A 0.1 m NaOH solution (20 mL) was added to a
solution of 20a/20b/20c (0.98 g, 5.21 mmol) in ethanol (12 mL) and
the mixture was heated at reflux for 3 h. After cooling to room
ratio of 20a/20b/20c was 20:15:65. IR: ν = 3023 (νC–H arom.), 2935
(νC–Haliph.), 1747 (νC=O), 1728 (νC=O), 1662 (νC=O), 1623 (νC=C),
˜
1213 (νC–O ester), 1087 (νC–O–C), 735 (γ1,2-disubst. arom.) cm–1. 1H temp., the mixture was extracted with Et2O (3ϫ40 mL). The or-
NMR (CDCl3): δ = 1.23 (t, J = 7.0 Hz, 0.4 H, OCH2CH3, keto
ester 2), 1.28 (t, J = 7.0 Hz, 1.95 H, OCH2CH3, enol), 1.29 (t, J =
7.0 Hz, 0.6 H, OCH2CH3, keto ester 1), 1.77 (ddd, J = 14.0, 6.1,
ganic extracts were dried (Na2SO4), concentrated in vacuo, and the
residue (0.68 g) was purified by FC (4 cm, petroleum ether, 20 mL,
Rf = 0.41). Colorless oil that froze in the refrigerator as a colorless
4.9 Hz, 0.2 H, 8-H, keto ester), 2.15 (d, J = 16.2 Hz, 0.65 H, 8-H, solid, m.p. 50–51 °C, yield 0.66 g (93%). IR: ν = 3023 (νC–H arom.),
˜
enol), 2.52–2.63 (m, 0.2 H, 8-H, keto ester), 2.60 (d, J = 17.7 Hz,
1.2 H, 10-H, enol + keto ester 1 + 2), 2.89–3.00 (m, 0.3 H, 8-H,
keto ester), 2.93 (dd, J = 16.2, 6.7 Hz, 0.65 H, 8-H, enol), 3.27 (t,
J = 4.9 Hz, 0.2 H, 7-H, keto ester 1), 3.34 (m, 0.3 H, 10-H, enol +
keto ester 1 + 2), 3.37 (dd, J = 16.8, 6.1 Hz, 0.5 H, 10-H, enol +
keto ester 1 + 2), 3.88 (dd, J = 13.1, 6.1 Hz, 0.15 H, 7-H, keto ester
2 9 3 3 ( ν C – H a l i p h . ) , 1 7 2 4 ( ν C = O ) , 1 0 8 1 ( ν C – O – C ) , 7 4 5
1
(γ1,2-disubst. arom.) cm–1. H NMR (CDCl3): δ = 1.74 (ddt, J = 13.7,
10.4, 5.2 Hz, 1 H, 8-Hax), 2.30 (dt, J = 15.6, 5.5 Hz, 1 H, 7-Heq),
2.46 (ddt, J = 13.7, 7.9, 6.1 Hz, 1 H, 8-Heq), 2.60 (d, J = 16.8 Hz,
1 H, 10-Hps. eq), 2.63 (ddd, J = 16.2, 10.0, 6.1 Hz, 1 H, 7-Hax), 3.39
(dd, J = 16.8, 6.4 Hz, 1 H, 10-Hps. ax), 4.64 (dt, J = 7.7, 5.8 Hz, 1
Eur. J. Org. Chem. 2012, 2428–2444
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2439

C. Ketterer, B. Wünsch
FULL PAPER
H, 9-H), 4.92 (s, 1 H, 5-H), 7.11–7.26 (m, 4 H, arom.) ppm. 13C
25 °C). (R,R,R)-22·HCl (225.72): calcd. C 63.86, H 7.14, N 6.21;
NMR (CDCl3): δ = 26.7 (1 C, C-8), 32.5, 32.7 (2 C, C-10, C-7), found C 63.51, H 7.30, N 6.00.
65.8 (1 C, C-9), 78.8 (1 C, C-5), 126.0, 126.4, 127.9, 129.6 (4 C, C-
(5RS,6RS,9RS)-(؎)-N-Methyl-5,6,7,8,9,10-hexahydro-5,9-epoxy-
1, C-2, C-3, C-4), 131.7, 131.8 (2 C, C-4a, C-10a), 209.2 (1 C, C-
6) ppm. MS (EI): m/z (%) = 188 (39) [M]+, 160 (63) [M – C=O]+,
131 (100) [benzopyrylium]+, 91 (23) [CH2Ph]+. C12H12O2 (188.23):
calcd. C 76.57, H 6.43; found C 76.47, H 6.52.
benzocycloocten-6-amine (23): Ti(OiPr)4 (0.32 mL, 1.07 mmol) was
added to an ethanolic solution of methylamine (8 m, 0.25 mL,
2.00 mmol). Then ketone 21 (99 mg, 0.53 mmol) and 4 Å molecular
sieves were added. After stirring at room temp. for 63 h, NaBH4
(22 mg, 0.57 mmol) was added and stirring was continued for 24 h.
H2O was added and the precipitate was filtered off and washed
with H2O and Et2O. The organic layer of the filtrate was separated
and the aqueous layer was extracted with Et2O (2ϫ25 mL). The
Et2O layer was extracted with dilute HCl (2ϫ30 mL). Then solid
NaOH was added to the aqueous layer and it was extracted with
Et2O (3ϫ30 mL). The combined Et2O layers were dried (Na2SO4),
concentrated in vacuo, and the residue (87 mg) was purified by FC
(2 cm, ethyl acetate/ethanol = 1:1, 2.5 mL, Rf = 0.26). Colorless,
viscous oil, yield 69 mg (65%). The residue was dissolved in ethyl
acetate and 23·HCl was formed by addition of a solution of HCl
in Et2O. 23·HCl: Colorless solid, decomposed at Ͼ275 °C.
(5S,9S)-(–)-7,8,9,10-Tetrahydro-5,9-epoxybenzocycloocten-6(5H)-
one [(S,S)-21]: Compound (S,S)-21 was prepared as described for
(Ϯ)-21: (S,S,S)-20a/(S,R,S)-20b/(S,R)-20c (1.73 g, 6.65 mmol) was
treated with ethanol (24 mL) and 0.1 m NaOH (40 mL). Colorless
oil, yield 1.14 g (91%). [α]589 = –221.0 (c = 4.9 mg/mL, CH3OH).
(5R,9R)-(+)-7,8,9,10-Tetrahydro-5,9-epoxybenzocycloocten-6(5H)-
one [(R,R)-21]: Compound (R,R)-21 was prepared as described for
(Ϯ)-21: (R,R,R)-20a/(R,S,R)-20b/(R,S)-20c (1.92 g, 7.38 mmol) was
treated with ethanol (24 mL) and 0.1 m NaOH (40 mL). Colorless
oil, yield 1.24 g (89%). [α]589 = +222.2 (c = 10.0 mg/mL, CH3OH).
(5RS,6RS,9RS)-(؎)-5,6,7,8,9,10-Hexahydro-5,9-epoxybenzocyclo-
octen-6-amine (22): A mixture of ketone 21 (100 mg, 0.53 mmol),
NH4OAc (412 mg, 5.35 mmol) and NaBH3CN (75 mg, 1.19 mmol)
in absolute methanol (5 mL) was stirred at room temp. for 69 h.
The mixture was acidified with conc. HCl and the solvent was re-
moved in vacuo. The residue was dissolved in H2O (15 mL), the
aqueous layer was washed with Et2O (3ϫ10 mL), and KOH (solid)
was added to the aqueous layer, which was then extracted with
Et2O (3 ϫ 20 mL). The combined organic layers were dried
(Na2SO4), concentrated in vacuo, and the residue (73 mg) was puri-
fied by FC (2 cm, ethyl acetate/ethanol = 1:5, 2.5 mL, Rf = 0.26).
Colorless solid, m.p. 109 °C, yield 39 mg (39%). The residue was
dissolved in ethyl acetate and 22·HCl was formed by addition of a
solution of HCl in Et2O. 22·HCl: Colorless solid, decomposed at
H–N+
23·HCl: IR: ν = 3029 (νC–H arom.), 2937 (νC–H aliph.), 2705 (ν
),
˜
1074 (νC–O–C), 733 (γ1,2-disubst. arom.) cm–1. 23: 1H NMR (CDCl3): δ
= 0.96 (qd, J = 12.9, 4.6 Hz, 1 H, 7-Hax), 1.03 (s, 1 H, NH), 1.68–
1.76 (m, 2 H, 7-Heq, 8-Heq), 2.08 (tt, J = 13.4, 5.3 Hz, 1 H, 8-Hax),
2.54 (s, 3 H, NCH3), 2.56 (d, J = 17.4 Hz, 1 H, 10-Hps. eq), 2.92
(td, J = 4.3, 12.2 Hz, 1 H, 6-Hax), 3.32 (dd, J = 7.9, 17.4 Hz, 1 H,
10-Hps. ax), 4.37 (dd, J = 7.9, 5.5 Hz, 1 H, 9-H), 4.90 (d, J = 4.3 Hz,
1 H, 5-H), 6.99–7.02 (m, 1 H, 4-H), 7.10–7.22 (m, 3 H, 1-H, 2-H,
3-H) ppm. 23: 13C NMR (CDCl3): δ = 23.0 (1 C, C-7), 31.9 (1 C,
C-10), 32.4 (1 C, C-8), 33.5 (1 C, NCH3), 59.1 (1 C, C-6), 66.8 (1
C, C-9), 72.0 (1 C, C-5), 124.9, 126.9, 128.0 (3 C, C-1, C-2, C-3),
126.1 (1 C, C-4), 133.6, 134.8 (2 C, C-4a, C-10a) ppm. 23: MS: (EI):
m / z ( % ) = 2 0 3 ( 4 7 ) [ M ] + , 9 1 ( 6 ) [ C H 2 P h ] + , 5 7 ( 1 0 0 )
[H3CNHCHCH2]+. 23: C13H17NO (203.28). 23·HCl: C13H18ClNO
(239.74). 23·HCl (239.74): calcd. C 65.13, H 7.57, N 5.84; found C
64.89, H 7.44, N 5.71.
Ͼ280 °C. 22·HCl: IR (KBr): ν = 2926 (νC–H aliph.), 1636 (δN–H),
˜
1072 (νC–O–C as.), 735 (γ1,2-disubst. arom.) cm–1. 22: 1H NMR (CDCl3):
δ = 1.07 (qd, J = 12.8, 4.5 Hz, 1 H, 7-Hax), 1.18 (s, 2 H, NH2),
1.60–1.72 (m, 2 H, 7-Heq, 8-Heq), 2.10 (tt, J = 13.6, 4.8 Hz, 1 H,
8-Hax), 2.59 (d, J = 17.4 Hz, 1 H, 10-Hps. eq), 3.20 (dt, J = 11.9,
4.3 Hz, 1 H, 6-Hax), 3.34 (dd, J = 17.7, 7.9 Hz, 1 H, 10-Hps. ax),
4.38 (dd, J = 7.9, 4.9 Hz, 1 H, 9-H), 4.68 (d, J = 4.6 Hz, 1 H, 5-
H), 7.05–7.26 (m, 4 H, arom.) ppm. 22: 13C NMR (CDCl3): δ =
26.2 (1 C, C-7), 31.9 (1 C, C-10), 32.6 (1 C, C-8), 51.2 (1 C, C-6),
66.5 (1 C, C-9), 75.3 (1 C, C-5), 124.8, 126.8, 127.2, 128.2 (4 C, C-
1, C-2, C-3, C-4), 133.0, 135.1 (2 C, C-4a, C-10a) ppm. 22: MS:
(EI): m/z (%) = 189 (100) [M]+, 172 (80) [M – NH3]+, 91 (32)
[CH2Ph]+. 22: C12H15NO (189.26). 22·HCl: C12H16ClNO (225.72).
22·HCl (225.72): calcd. C 63.86, H 7.14, N 6.21; found C 63.46, H
7.38, N 5.85.
(5S,6S,9S)-(–)-N-Methyl-5,6,7,8,9,10-hexahydro-5,9-epoxybenzocy-
cloocten-6-amine [(S,S,S)-23]: Compound (S,S,S)-23 was prepared
as described for (Ϯ)-23: Ketone (S,S)-21 (100 mg, 0.53 mmol) was
treated with Ti(OiPr)4 (0.32 mL, 1.01 mmol), an ethanolic solution
of methylamine (8 m, 0.25 mL, 2.0 mmol), and NaBH4 (24 mg,
0.64 mmol). Colorless oil that froze in the refrigerator as a colorless
solid, m.p. 50 °C, yield 70 mg (65%). (S,S,S)-23·HCl: Colorless so-
lid, decomposed at Ͼ270 °C. (S,S,S)-23·HCl: [α]589 = –40.8 (c =
2.5 mg/mL, CH3OH, T = 24 °C). (S,S,S)-23·HCl (239.74): calcd C
65.13, H 7.57, N 5.84; found C 65.10, H 7.47, N 5.57.
(5R,6R,9R)-(+)-N-Methyl-5,6,7,8,9,10-hexahydro-5,9-epoxybenzo-
cycloocten-6-amine [(R,R,R)-23]: Compound (R,R,R)-23 was pre-
pared as described for (Ϯ)-23: Ketone (R,R)-21 (100 mg,
0.53 mmol) was treated with Ti(OiPr)4 (0.32 mL, 1.01 mmol), an
ethanolic solution of methylamine (8 m, 0.25 mL, 2.0 mmol), and
NaBH4 (27 mg, 0.71 mmol). Colorless oil that froze in the refriger-
ator as a colorless solid, m.p. 53 °C, yield 92 mg (68%). (S,S,S)-
23·HCl: Colorless solid, decomposed at Ͼ275 °C. (R,R,R)-23·HCl:
[α]589 = +41.2 (c = 2.6 mg/mL, CH3OH, T = 24 °C). (R,R,R)-
23·HCl (239.74): calcd C 65.13, H 7.57, N 5.84; found C 65.07, H
7.55, N 5.64.
(5S,6S,9S)-(–)-5,6,7,8,9,10-Hexahydro-5,9-epoxybenzocycloocten-6-
amine [(S,S,S)-22]: Compound (S,S,S)-22 was prepared as de-
scribed for (Ϯ)-22: Ketone (S,S)-21 (105 mg, 0.56 mmol) was
treated with NH4OAc (438 mg, 5.68 mmol) and NaBH3CN (79 mg,
1.25 mmol) in absolute methanol (5 mL). Colorless solid, m.p.
80 °C, yield 40 mg (38%). (S,S,S)-22·HCl: Colorless solid, decom-
posed at Ͼ270 °C. [α]589 = –46.7 (c = 2.55 mg/mL, CH3OH, T =
24 °C). (S,S,S)-22·HCl (225.72): calcd. C 63.86, H 7.14, N 6.21;
found C 63.82, H 7.67, N 5.85.
(5R,6R,9R)-(+)-5,6,7,8,9,10-Hexahydro-5,9-epoxybenzocycloocten-
6-amine [(+)-(R,R,R)-22]: Compound (R,R,R)-22 was prepared as
described for (Ϯ)-22: Ketone (R,R)-21 (106 mg, 0.56 mmol) was
(5RS,6RS,9RS)-(؎)-N,N-Dimethyl-5,6,7,8,9,10-hexahydro-5,9-ep-
oxybenzocycloocten-6-amine (24): Ti(OiPr)4 (0.32 mL, 1.07 mmol)
treated with NH4OAc (453 mg, 5.87 mmol) and NaBH3CN (98 mg, was added to an ethanolic solution of dimethylamine (5.6 m,
1.55 mmol) in absolute methanol (5 mL). Colorless solid, m.p.
86 °C, yield 46 mg (43%). (R,R,R)-22·HCl: Colorless solid, decom-
posed at Ͼ280 °C. [α]589 = +44.7 (c = 2.75 mg/mL, CH3OH, T =
0.38 mL, 2.13 mmol). Then ketone 21 (102 mg, 0.54 mmol) and 4 Å
molecular sieves were added. After stirring at room temp. for 63 h,
NaBH4 (21 mg, 0.55 mmol) was added and stirring was continued
2440
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2428–2444

Chiral Oxa-Pictet–Spengler Reaction
for 23 h. H2O was added and the precipitate was filtered off and
washed with H2O and Et2O. The organic layer of the filtrate was
separated and the aqueous layer was extracted with Et2O
(2 ϫ 25 mL). The Et2O layer was extracted with dilute HCl
(2ϫ30 mL). Then solid NaOH was added to the aqueous layer and
it was extracted with Et2O (3ϫ30 mL). The combined Et2O layers
were dried (Na2SO4) and concentrated in vacuo. Colorless oil that
froze in the refrigerator as a colorless solid, m.p. 50 °C, yield 81 mg
(69%). The residue was dissolved in ethyl acetate and 24·HCl was
formed by addition of a solution of HCl in Et2O. 24·HCl: Colorless
Hps. eq), 3.35 (dd, J = 17.4, 7.9 Hz, 1 H, 10-Hps. ax), 4.02 (dt, J =
11.6, 4.7 Hz, 1 H, 6-H), 4.35 (br. dd, J = 7.9, 4.9 Hz, 1 H, 9-H),
4.77 (d, J = 5.2 Hz, 1 H, 5-H), 7.08–7.26 (m, 4 H, arom.) ppm; a
signal for the OH group was not detected. 13C NMR (CDCl3): δ =
25.6 (1 C, C-7), 31.8 (1 C, C-10), 32.0 (1 C, C-8), 66.4 (1 C, C-9),
69.1 (1 C, C-6), 73.6 (1 C, C-5), 125.1, 127.0, 127.3, 128.1 (4 C, C-
1, C-2, C-3, C-4), 132.7, 134.9 (2 C, C-4a, C-10a) ppm. MS (EI):
m/z (%) = 190 (100) [M]+, 172 (78) [M – H2O]+, 145 (66) [M –
HOCHCH2 – H]+, 131 (94) [benzopyrylium]+, 91 (22) [CH2Ph]+.
C12H14O2 (190.25): calcd. C 75.76, H 7.42; found C 75.71, H 7.64.
solid, decomposed at Ͼ215 °C. 24·HCl: IR (KBr): ν = 2947
˜
(5S,6S,9S)-(–)-5,6,7,8,9,10-Hexahydro-5,9-epoxybenzocycloocten-6-
ol [(S,S,S)-25]: Compound (S,S,S)-25 was prepared as described
for (Ϯ)-25: Ketone (S,S)-21 (222 mg, 1.18 mmol) was treated with
NaBH4 (182 mg, 4.82 mmol) in methanol (4 mL). Colorless solid,
m.p. 158 °C, yield 193 mg (86%). [α]589 = –71.8 (c = 4.7 mg/mL,
CH3OH). C12H14O2 (190.25): calcd. C 75.76, H 7.42; found C
75.50, H 7.25.
H–N+
(νC–H aliph.), 2462 (ν
), 1636 (δN–H), 1070 (νC–O–C), 744
(γ1,2-disubst. arom.) cm–1. 24: 1H NMR (CDCl3): δ = 1.19 (qd, J =
12.9, 4.7 Hz, 1 H, 7-Hax), 1.67–1.77 (m, 2 H, 7-Heq, 8-Heq), 2.06
(tt, J = 13.2, 4.9 Hz, 1 H, 8-Hax), 2.26 [s, 6 H, N(CH3)2], 2.54 (dt,
J = 12.5, 3.8 Hz, 1 H, 6-H), 2.56 (d, J = 17.4 Hz, 1 H, 10-Hps. eq),
3.33 (dd, J = 17.4, 7.9 Hz, 1 H, 10-Hps. ax), 4.35 (br. dd, J = 7.9,
5.2 Hz, 1 H, 9-H), 4.97 (d, J = 4.0 Hz, 1 H, 5-H), 7.07–7.20 (m, 4
H, arom.) ppm. 24: 13C NMR (CDCl3): δ = 20.1 (1 C, C-7), 32.3
(1 C, C-10), 32.4 (1 C, C-8), 43.3 [2 C, N(CH3)2], 66.1 (1 C, C-6),
66.6 (1 C, C-9), 71.4 (1 C, C-5), 124.7, 126.5, 127.5, 127.7 (4 C, C-
1, C-2, C-3, C-4), 134.2, 134.8 (2 C, C-4a, C-10a) ppm. 24: MS:
(EI): m/z (%) = 217 (81) [M]+, 84 (49) [Me2NCH(CH)CH2]+, 71
(100) [Me2NCHCH2]+. 24: MS: (CI, NH3): m/z = 218 [M +
H]+. 24: C14H19NO (217.31). 24·HCl: C14H20ClNO (253.77).
24·HCl (253.77): calcd. C 66.26, H 7.94, N 5.52; found C 66.03, H
7.98, N 5.37.
(5R,6R,9R)-(+)-5,6,7,8,9,10-Hexahydro-5,9-epoxybenzocycloocten-
6-ol [(R,R,R)-25]: Compound (R,R,R)-25 was prepared as de-
scribed for (Ϯ)-25: Ketone (R,R)-21 (43 mg, 0.23 mmol) was
treated with NaBH4 (34 mg, 0.90 mmol) in methanol (3 mL). Col-
orless solid, m.p. 155 °C, yield 41 mg (95%). [α]589 = +71.7 (c =
4.6 mg/mL, CH3OH). C12H14O2 (190.25): calcd. C 75.76, H 7.42;
found C 75.21, H 7.51.
(؎)-[(5RS,6RS,9RS)-5,6,7,8,9,10-Hexahydro-5,9-epoxybenzocyclo-
octen-6-yl] 4-Methylbenzenesulfonate (26a): p-Toluenesulfonyl
chloride (301 mg, 1.58 mmol), NEt3 (0.35 mL, 2.52 mmol), and 4-
(dimethylamino)pyridine (209 mg, 1.71 mmol) were added to a
solution of alcohol 25 (49 mg, 0.26 mmol) in CH2Cl2 (10 mL). Af-
ter stirring at room temp. for 60 min, the mixture was diluted with
Et2O and washed with 0.5 m HCl (2ϫ25 mL) and 0.5 m NaOH
(25 mL). The organic layer was dried (Na2SO4), concentrated in
vacuo, and the residue was purified by FC (2 cm, petroleum ether/
ethyl acetate = 5:1, 2.5 mL, Rf = 0.32). Colorless solid, m.p. 116 °C,
(5S,6S,9S)-(–)-N,N-Dimethyl-5,6,7,8,9,10-hexahydro-5,9-epoxy-
benzocycloocten-6-amine [(S,S,S)-24]: Compound (S,S,S)-24 was
prepared as described for (Ϯ)-24: Ketone (S,S)-21 (95 mg,
0.50 mmol) was treated with Ti(OiPr)4 (0.32 mL, 1.01 mmol), an
ethanolic solution of dimethylamine (5.6 m, 0.38 mL, 2.13 mmol),
and NaBH4 (22 mg, 0.59 mmol). Colorless oil that froze in the re-
frigerator as a colorless solid, m.p. 40 °C, yield 79 mg (72 %).
(S,S,S)-24·HCl: Colorless solid, decomposed at Ͼ235 °C. (S,S,S)-
24·HCl: [α]589 = –40.4 (c = 2.6 mg/mL, CH3OH, T = 25 °C).
(S,S,S)-24·HCl (253.77): calcd. C 66.26, H 7.94, N 5.52; found C
66.36, H 7.99, N 5.29.
yield 64 mg (72 %). IR: ν = 3032 (νC–H arom. ), 2953, 2918
˜
(νC–H aliph.), 1352, 1176 (δ ), 767 (γ1,2-disubst. arom.) cm–1. 1H NMR
SO2
(CDCl3): δ = 1.47 (br. qd, J = 12.4, 4.9 Hz, 1 H, 7-Hax), 1.61–1.73
(m, 2 H, 7-Heq, 8-Heq), 2.05 (tt, J = 13.9, 5.3 Hz, 1 H, 8-Hax), 2.44
(s, 3 H, Ar-CH3), 2.54 (d, J = 17.7 Hz, 1 H, 10-Hps. eq), 3.32 (dd,
J = 17.7, 7.9 Hz, 1 H, 10-Hps. ax), 4.30 (dd, J = 7.9, 5.5 Hz, 1 H,
9-H), 4.79 (dt, J = 11.4, 4.7 Hz, 1 H, 6-Hax), 4.84 (d, J = 4.6 Hz,
1 H, 5-H), 7.13–7.27 (m, 4 H, 1-H, 2-H, 3-H, 4-H), 7.35 (d, J =
8.2 Hz, 2 H, 3Ј-H, 5Ј-H), 7.82 (d, J = 8.5 Hz, 2 H, 2Ј-H, 6Ј-H) ppm.
13C NMR (CDCl3): δ = 21.6 (1 C, Ar-CH3), 22.6 (1 C, C-7), 31.5
(1 C, C-10), 31.8 (1 C, C-8), 66.4 (1 C, C-9), 70.8 (1 C, C-5), 78.0
(1 C, C-6), 125.3, 127.5, 127.8, 128.0 (4 C, C-1, C-2, C-3, C-4),
127.7 (2 C, C-2Ј, C-6Ј), 129.9 (2 C, C-3Ј, C-5Ј), 131.5, 134.0 (2 C,
C-4a, C-10a), 134.1 (1 C, C-4Ј), 144.8 (1 C, C-1Ј) ppm. MS (EI):
m/z (%) = 212 (29) [CH2CH2CHOTos]+, 155 (63) [CH3C4H4SO2]+,
91 (100) [CH2Ph]+. MS (CI, NH3): m/z = 362 [M + H + NH3]+.
C19H20O4S (344.43): calcd. C 66.26, H 5.85, S 9.31; found C 65.86,
H 5.92, S 9.19.
(5R,6R,9R)-(+)-N,N-Dimethyl-5,6,7,8,9,10-hexahydro-5,9-epoxy-
benzocycloocten-6-amine [(R,R,R)-24]: Compound (R,R,R)-24 was
prepared as described for (Ϯ)-24: Ketone (R,R)-21 (102 mg,
0.54 mmol) was treated with Ti(OiPr)4 (0.32 mL, 1.01 mmol), an
ethanolic solution of dimethylamine (5.6 m, 0.38 mL, 2.13 mmol),
and NaBH4 (24 mg, 0.63 mmol). Colorless oil that froze in the re-
frigerator as a colorless solid, m.p. 40 °C, yield 92 mg (78 %).
(R,R,R)-24·HCl: Colorless solid, decomposed at Ͼ250 °C. (R,R,R)-
24·HCl: [α]589 = +39.4 (c = 2.6 mg/mL, CH3OH, T = 25 °C).
(S,S,S)-24·HCl (253.77): calcd. C 66.26, H 7.94, N 5.52; found C
66.02, H 8.09, N 5.44.
(5RS,6RS,9RS)-(؎)-5,6,7,8,9,10-Hexahydro-5,9-epoxybenzocyclo-
octen-6-ol (25): NaBH4 (86 mg, 2.28 mmol) was added to a solution
of ketone 21 (202 mg, 1.07 mmol) in methanol (10 mL) and the
mixture was stirred at room temp. for 90 min. The mixture was
concentrated in vacuo, the residue was dissolved in H2O, and the
aqueous layer was extracted with CH2Cl2 (5ϫ10 mL). The com-
bined organic layers were dried (Na2SO4), concentrated in vacuo,
and the residue was purified by FC (2 cm, petroleum ether/ethyl
acetate = 1:1, 2.5 mL, Rf = 0.47). Colorless solid, m.p. 122 °C, yield
(؎)-[(5RS,6RS,9RS)-5,6,7,8,9,10-Hexahydro-5,9-epoxybenzocyclo-
octen-6-yl] Methanesulfonate (26b): NEt3 (0.6 mL, 4.33 mmol) and
methanesulfonyl chloride (200 μL, 2.58 mmol) were added to a
solution of alcohol 25 (201 mg, 1.05 mmol) in CH2Cl2 (10 mL) at
0 °C. The mixture was stirred at 0 °C for 60 min. Then the solvent
was removed in vacuo and the residue was purified by FC (2 cm,
petroleum ether/ethyl acetate = 2:1, 2.5 mL, Rf = 0.30). Colorless
oil that froze in the refrigerator, m.p. 105 °C, yield 282 mg (97%).
187 mg (92%). IR: ν = 3231 (νO–H), 2930 (νC–Haliph.), 1046 (νC–O),
˜
765 (γ1,2-disubst. arom.) cm–1. 1H NMR (CDCl3): δ = 1.15 (br. qd, J
= 12.8, 4.5 Hz, 1 H, 7-Hax), 1.69–1.81 (m, 2 H, 7-Heq, 8-Heq), 2.10
(tt, J = 13.9, 5.3 Hz, 1 H, 8-Hax), 2.58 (d, J = 17.7 Hz, 1 H, 10-
IR: ν = 3010 (νC–H arom.), 2965, 2930 (νC–Haliph.), 1352, 1172 (δSO ),
˜
2
761 (γ1,2-disubst. arom.) cm–1. H NMR (CDCl3): δ = 1.58 (dddd, J =
1
Eur. J. Org. Chem. 2012, 2428–2444
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2441

C. Ketterer, B. Wünsch
FULL PAPER
13.7, 12.5, 11.4, 4.6 Hz, 1 H, 7-Hax), 1.69–1.81 (m, 2 H, 7-Heq, 8-
Heq), 2.19 (tt, J = 13.9, 5.7 Hz, 1 H, 8-Hax), 2.60 (d, J = 17.7 Hz,
1 H, 10-Hps. eq), 3.03 (s, 3 H, SO2CH3), 3.37 (dd, J = 17.4, 7.9 Hz,
1 H, 10-Hps. ax), 4.37 (dd, J = 7.9, 5.5 Hz, 1 H, 9-H), 5.00 (d, J =
treated with NaN3 (7.0 g, 107.7 mmol) in DMF (40 mL). Colorless
oil that solidified in the refrigerator as a colorless solid, m.p. 54 °C,
yield 321 mg (41%). [α]589 = +42.8 (c = 3.0 mg/mL, CH3OH, T =
25 °C). In addition, (R,R,R)-25 (155 mg, 23%, petroleum ether/
4.6 Hz, 1 H, 5-H), 5.04 (dt, J = 11.3, 4.3 Hz, 1 H, 6-Hax), 7.13– ethyl acetate = 1:1, Rf = 0.47) was isolated.
7.27 (m, 4 H, arom.) ppm. 13C NMR (CDCl3): δ = 22.9 (1 C, C-
(5RS,6SR,9RS)-(؎)-5,6,7,8,9,10-Hexahydro-5,9-epoxybenzocyclo-
7), 31.6 (1 C, C-10), 31.8 (1 C, C-8), 38.6 (1 C, SO2CH3), 66.4 (1 C,
C-9), 71.1 (1 C, C-5), 77.3 (1 C, C-6), 125.3, 127.6, 127.88, 127.91 (4
C, C-1, C-2, C-3, C-4), 131.6, 134.3 (2 C, C-4a, C-10a) ppm. MS
(EI): m/z (%) = 268 (26) [M]+, 189 (54) [M – CH3 – SO2]+, 129 (100)
[C6H4CH=CHCH=CH2]+, 91 (17) [CH2Ph]+. C13H16O4S (268.33):
calcd. C 58.19, H 6.01, S 11.95; found C 58.36, H 6.11, S 11.71.
octen-6-amine (28): Ammonium formate (1.31 g, 20.8 mmol) and
Pd/C (10 %, 261 mg) were added to a solution of the azide 27
(442 mg, 2.05 mmol) in methanol (40 mL) and the mixture was
heated at reflux for 4 h. After filtration the solvent was evaporated
in vacuo and the residue (374 mg) was purified by FC (3 cm, ethyl
acetate/ethanol = 1:5, 7.5 mL, Rf = 0.17). Colorless oil, yield
304 mg (78 %). The residue was dissolved in ethyl acetate and
28·HCl was formed by addition of a solution of HCl in Et2O.
(–)-[(5S,6S,9S)-5,6,7,8,9,10-Hexahydro-5,9-epoxybenzocycloocten-
6-yl] Methanesulfonate [(S,S,S)-26b]: Compound (S,S,S)-26b was
prepared as described for (Ϯ)-26b: Alcohol (S,S,S)-25 (520 mg,
2.73 mmol) was treated with NEt3 (1.5 mL, 10.8 mmol) and meth-
anesulfonyl chloride (0.6 mL, 7.89 mmol) in CH2Cl2 (20 mL). Col-
orless oil, yield 710 mg (97%). [α]589 = –107.7 (c = 3.25 mg/mL,
CH3OH, T = 24 °C).
28·HCl: Colorless solid, decomposed at Ͼ215 °C. 28·HCl: IR: ν =
˜
3 3 8 9 ( ν N – H ) , 2 9 3 3 ( ν C – H a l i p h . ) , 1 0 4 0 ( ν C – O – C ) , 7 3 8
1
(γ1,2-disubst. arom.) cm–1. 28: H NMR (CDCl3): δ = 1.30–1.45 (m, 2
H, 7-Heq, 8-Heq), 1.60–1.72 (tt, J = 14.0, 4.3 Hz, 1 H, 7-Hax), 2.26–
2.39 (m, 3 H, 8-Hax, NH2), 2.56 (d, J = 17.4 Hz, 1 H, 10-Hps. eq),
2.87 (m, 1 H, 6-H), 3.36 (dd, J = 17.4, 7.9 Hz, 1 H, 10-Hps. ax), 4.38
(br. t, J = 6.8 Hz, 1 H, 9-H), 4.61 (s, 1 H, 5-H), 6.96–6.98 (m, 1 H,
4-H), 7.08–7.19 (m, 3 H, 1-H, 2-H, 3-H) ppm. 28: 13C NMR
(CDCl3): δ = 22.5 (1 C, C-7), 25.9 (1 C, C-8), 31.7 (1 C, C-10), 50.7
(1 C, C-6), 67.2 (1 C, C-9), 76.0 (1 C, C-5), 125.0 (1 C, C-4), 125.5,
126.6, 128.1 (3 C, C-1, C-2, C-3), 133.9, 137.0 (2 C, C-4a, C-
10a) ppm. 28: MS: (EI): m/z (%) = 189 (100) [M]+, 172 (82) [M –
NH3]+, 91 (22) [CH2Ph]+. 28: C12H15NO (189.26). 28·HCl:
C12H16ClNO (225.72). 28·HCl (225.72): calcd. C 63.86, H 7.14, N
6.21; found C 63.67, H 7.21, N 6.28.
(+)-[(5R,6R,9R)-5,6,7,8,9,10-Hexahydro-5,9-epoxybenzocycloocten-
6-yl] Methanesulfonate [(R,R,R)-26b]: Compound (R,R,R)-26b was
prepared as described for (Ϯ)-26b: Alcohol (R,R,R)-25 (700 mg,
3.68 mmol) was treated with NEt3 (2.0 mL, 14.7 mmol) and meth-
anesulfonyl chloride (0.42 mL, 5.52 mmol) in CH2Cl2 (20 mL).
Colorless oil, yield 977 mg (99%). [α]589 = +104.9 (c = 3.25 mg/mL,
CH3OH, T = 24 °C).
(5RS,6SR,9RS)-(؎)-6-Azido-5,6,7,8,9,10-hexahydro-5,9-epoxybenzo-
cyclooctene (27): NaN3 (5.79 g, 89.1 mmol) was added to a solution
of mesylate 26b (0.84 g, 3.15 mmol) in DMF (40 mL). After son-
ification for 5 min, the suspension was heated at reflux for 38 h.
Then H2O (40 mL) was added, the mixture was extracted with Et2O
(5ϫ50 mL), the combined organic layers were dried (Na2SO4) and
concentrated in vacuo, and the residue was purified by FC (3 cm,
petroleum ether/ethyl acetate = 30:1, 7.5 mL, Rf = 0.19). In ad-
dition to the azide 27, alcohol 25 (182 mg, 30%, petroleum ether/
ethyl acetate = 1:1, Rf = 0.47) was isolated. Colorless oil, yield
(5S,6R,9S)-(–)-5,6,7,8,9,10-Hexahydro-5,9-epoxybenzocycloocten-6-
amine [(S,R,S)-28]: Compound (S,R,S)-28 was prepared as de-
scribed for (Ϯ)-28: Azide (S,R,S)-27 (203 mg, 0.94 mmol) was
treated with ammonium formate (0.62 g, 9.80 mmol) and Pd/C
(10%, 127 mg) in methanol (30 mL). Colorless oil that solidified in
the refrigerator as a colorless solid, m.p. 33 °C, yield 142 mg (80%).
(S,R,S)-28·HCl: Colorless solid, decomposed at Ͼ230 °C. (S,R,S)-
28·HCl: [α]589 = –7.2 (c = 2.65 mg/mL, CH3OH, T = 23 °C).
(S,R,S)-28·HCl (225.72): calcd. C 63.86, H 7.14, N 6.21; found C
63.64, H 7.25, N 6.06.
332 mg (49%). IR: ν = 3024 (νC–H arom.), 2934 (νC–H aliph.), 2090
˜
(νN3 sym.), 1098 (νC–O–C), 763 (γ1,2-disubst. arom.) cm–1 1H NMR
.
(CDCl3): δ = 1.45–1.52 (m, 1 H, 8-Heq), 1.60–1.78 (m, 2 H, 7-Heq,
7-Hax), 2.38 (tt, J = 13.0, 6.4 Hz, 1 H, 8-Hax), 2.61 (d, J = 17.7 Hz,
1 H, 10-Hps. eq), 3.42 (dd, J = 17.7, 7.9 Hz, 1 H, 10-Hps. ax), 3.52
(m, 1 H, 6-H), 4.46 (br. t, J = 6.6 Hz, 1 H, 9-H), 4.83 (s, 1 H, 5-
H), 6.97–7.00 (m, 1 H, 4-H), 7.13–7.24 (m, 3 H, 1-H, 2-H, 3-
H) ppm. 13C NMR (CDCl3): δ = 19.4 (1 C, C-7), 26.7 (1 C, C-8),
31.5 (1 C, C-10), 60.2 (1 C, C-6), 67.0 (1 C, C-9), 72.2 (1 C, C-5),
125.1 (1 C, C-4), 125.8, 127.3, 128.5 (3 C, C-1, C-2, C-3), 134.4,
135.0 (2 C, C-4a, C-10a) ppm. MS (EI): m/z (%) = 144 (32) [M –
N3CHCH2 – 2H]+, 131 (100) [benzopyrylium]+, 104 (31)
[PhCH=CH2]+, 91 (29) [CH2Ph]+. MS (CI, NH3): m/z = 233 [M +
H + NH3]+, 188 [M – N2, + H]+. C12H13N3O (215.25): calcd. C
66.96, H 6.09, N 19.52; found C 66.94, H 6.25, N 19.26.
(5R,6S,9R)-(+)-5,6,7,8,9,10-Hexahydro-5,9-epoxybenzocycloocten-
6-amine [(R,S,R)-28]: Compound (R,S,R)-28 was prepared as de-
scribed for (Ϯ)-28: Azide (R,S,R)-27 (322 mg, 1.49 mmol) was
treated with ammonium formate (0.96 g, 15.2 mmol) and Pd/C
(10%, 187 mg) in methanol (30 mL). Colorless oil that solidified in
the refrigerator as a colorless solid, m.p. 35 °C, yield 244 mg (91%).
(R,S,R)-28·HCl: Colorless solid, decomposed at Ͼ230 °C. (R,S,R)-
28·HCl: [α]589 = +6.8 (c = 3.25 mg/mL, CH3OH, T = 23 °C).
(R,S,R)-28·HCl (225.72): calcd. C 63.86, H 7.14, N 6.21; found C
64.08, H 7.21, N 6.12.
(5RS,6SR,9RS)-(؎)-N,N-Dimethyl-5,6,7,8,9,10-hexahydro-5,9-ep-
oxybenzocycloocten-6-amine (29): A solution of formaldehyde in
water (formalin 37%, 1.3 mL, 16.7 mmol) and NaBH3CN (145 mg,
2.31 mmol) were added to a solution of primary amine 28 (100 mg,
0.53 mmol) in acetonitrile (5 mL) and the mixture was stirred at
room temp. for 24 h. Then 1 m NaOH (10 mL) was added, the mix-
ture was extracted with Et2O (3ϫ20 mL), the combined organic
layers were dried (Na2SO4) and concentrated in vacuo, and the resi-
due (130 mg) was purified by FC (2 cm, ethyl acetate/ethanol = 1:5,
2.5 mL, Rf = 0.19). Colorless oil, yield 92 mg (80%). The residue
(5S,6R,9S)-(–)-6-Azido-5,6,7,8,9,10-hexahydro-5,9-epoxybenzo-
cyclooctene [(S,R,S)-27]: Azide (S,R,S)-27 was prepared as de-
scribed for (Ϯ)-27: Mesylate (S,S,S)-26b (710 mg, 2.65 mmol) was
treated with NaN3 (6.14 g, 94.5 mmol) in DMF (40 mL). Colorless
oil that solidified in the refrigerator as a colorless solid, m.p. 53 °C,
yield 203 mg (36%). [α]589 = –42.1 (c = 3.0 mg/mL, CH3OH, T =
25 °C). In addition, (S,S,S)-25 (159 mg, 31%, petroleum ether/ethyl
acetate = 1:1, Rf = 0.47) was isolated.
(5R,6S,9R)-(+)-6-Azido-5,6,7,8,9,10-hexahydro-5,9-epoxybenzo- was dissolved in ethyl acetate and 29·HCl was formed by addition
cyclooctene [(R,S,R)-27]: Azide (R,S,R)-27 was prepared as de-
scribed for (Ϯ)-27: Mesylate (R,R,R)-26b (977 mg, 3.64 mmol) was
of a solution of HCl in Et2O. 29·HCl: Colorless solid, decomposed
at Ͼ220 °C. 29·HCl: IR: ν = 2944 (νC–Haliph.), 2667 (ν ), 1157
H–N+
˜
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2428–2444

Chiral Oxa-Pictet–Spengler Reaction
(νC–O–C), 754 (γ1,2-disubst. arom.) cm–1. 29: 1H NMR (CDCl3): δ =
1.30–1.38 (m, 1 H, 8-Heq), 1.53 (ddt, J = 14.5, 12.3, 4.3 Hz, 1 H,
7-Hax), 1.70 (br. dq, J = 14.4, 4.8 Hz, 1 H, 7 Heq), 2.07 (td, J =
4.1, 1.7 Hz, 1 H, 6-Heq), 2.29 (tt, J = 12.2, 6.1 Hz, 1 H, 8-Hax),
2.46 [s, 6 H, N(CH3)2], 2.56 (d, J = 17.2 Hz, 1 H, 10-Hps. eq), 3.37
(dd, J = 17.2, 7.3 Hz, 1 H, 10-Hps. ax), 4.45 (td, J = 6.8, 2.4 Hz, 1
H, 9-H), 4.97 (br. s, 1 H, 5-H), 6.94–6.96 (m, 1 H, 4-H), 7.10–7.19
(m, 3 H, 1-H, 2-H, 3-H) ppm. 29: 13C NMR (CDCl3): δ = 17.8 (1
C, C-7), 26.5 (1 C, C-8), 32.4 (1 C, C-10), 43.4 [2 C, N(CH3)2], 65.8
(1 C, C-6), 66.8 (1 C, C-9), 70.6 (1 C, C-5), 125.0 (1 C, C-4), 125.4,
126.4, 128.5 (3 C, C-1, C-2, C-3), 134.1, 138.0 (2 C, C-4a, C-
10a) ppm. 29: MS: (EI): m/z (%) = 217 (49) [M]+, 84 (57)
[Me2NCH(CH)CH2]+, 71 (100) [Me2NCHCH2]+. 29: HRMS:
calcd. 217.1467; found 217.1468. 29: C14H19NO (217.31). 29·HCl:
C14H20ClNO (253.77). 29·HCl (253.77): calcd. C 66.26, H 7.94, N
5.52; found C 66.01, H 8.10, N 5.58.
This work was financially supported by the Deutsche Forschungs-
gemeinschaft (DFG), which is gratefully acknowledged.
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benzocycloocten-6-amine [(S,R,S)-29]: Compound (S,R,S)-29 was
prepared as described for (Ϯ)-29: Amine (S,R,S)-28 (106 mg,
0.56 mmol) was treated with formalin (37%, 1.3 mL, 16.7 mmol)
and NaBH3CN (143 mg, 2.23 mmol) in acetonitrile (10 mL). Col-
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Thanks are due to Degussa AG, Janssen-Cilag GmbH, and Bristol-
Myers Squibb for donation of chemicals and reference compounds.
Eur. J. Org. Chem. 2012, 2428–2444
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Received: December 14, 2011
Published Online: March 12, 2012
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2428–2444