Stereoselective syntheses of pinane-based 1,3-diamines and their application as chiral ligands in the enantioselective addition of diethylzinc to benzaldehyde

Article abstract of DOI:10.1016/j.tetasy.2013.04.003

A library of 1,3-difunctionalized pinane derivatives was synthesized and applied as chiral catalysts in the addition of diethylzinc to benzaldehyde. The key intermediate β-lactam 2 was prepared regio- and stereoselectively from (-)-apopinene 1. The treatment of 2 with di-tert-butyl dicarbonate afforded N-Boc β-lactam 3, while acid-catalyzed ring opening of 2 resulted in amino acid 4. Nucleophilic ring opening of 3 with dimethylamine, followed by deprotection and benzylation, furnished β-amino amides 5, 8, and 11, which were transformed in two steps into the corresponding N-tosyldiamines 7, 10, and 13, respectively. Since the use of other amines, such as diethylamine, to study the influence of dialkyl substitution was unsuccessful, an alternative synthetic route was applied. Amidation of tosylated β-amino acid 14 furnished amides 15-25. Reduction of 15, 16, 19, 20, and 24 resulted in N-tosyl diamines 26-30. The β-amino amides and N-tosylated diamines were used as chiral ligands in the enantioselective alkylation of benzaldehyde with diethylzinc, resulting in (R)- and (S)-1-phenyl-1-propanol. The (R)-enantiomer was predominant except when 17, 22, 23, and 25 were used as ligands, in which case the opposite stereochemistry was observed. The best ee values (up to 83%) were obtained when 17, 20, 23, and 25 were used as catalysts.

Full text of DOI:10.1016/j.tetasy.2013.04.003

Tetrahedron: Asymmetry 24 (2013) 553–561
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Tetrahedron: Asymmetry
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Stereoselective syntheses of pinane-based 1,3-diamines and their application
as chiral ligands in the enantioselective addition of diethylzinc to benzaldehyde
Kinga Csillag a, Zsolt Szakonyi a, , Ferenc Fülöp a,b,
⇑
⇑
a Institute of Pharmaceutical Chemistry, University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary
b Research Group of Stereochemistry of the Hungarian Academy of Sciences, University of Szeged, H-6720 Szeged, Eötvös u. 6, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 February 2013
Accepted 8 April 2013
A library of 1,3-difunctionalized pinane derivatives was synthesized and applied as chiral catalysts in the
addition of diethylzinc to benzaldehyde. The key intermediate b-lactam 2 was prepared regio- and
stereoselectively from (ꢀ)-apopinene 1. The treatment of 2 with di-tert-butyl dicarbonate afforded N-
Boc b-lactam 3, while acid-catalyzed ring opening of 2 resulted in amino acid 4. Nucleophilic ring opening
of 3 with dimethylamine, followed by deprotection and benzylation, furnished b-amino amides 5, 8, and
11, which were transformed in two steps into the corresponding N-tosyldiamines 7, 10, and 13, respec-
tively. Since the use of other amines, such as diethylamine, to study the influence of dialkyl substitution
was unsuccessful, an alternative synthetic route was applied. Amidation of tosylated b-amino acid 14 fur-
nished amides 15–25. Reduction of 15, 16, 19, 20, and 24 resulted in N-tosyl diamines 26–30. The b-
amino amides and N-tosylated diamines were used as chiral ligands in the enantioselective alkylation
of benzaldehyde with diethylzinc, resulting in (R)- and (S)-1-phenyl-1-propanol. The (R)-enantiomer
was predominant except when 17, 22, 23, and 25 were used as ligands, in which case the opposite ste-
reochemistry was observed. The best ee values (up to 83%) were obtained when 17, 20, 23, and 25 were
used as catalysts.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
that in some cases only one enantiomer of the starting material is
available. Recent reports have demonstrated the possibility of
Over the past several decades, carbon–carbon bond formation
has become an intensively examined topic. Among the enantiose-
lective transformations investigated, the alkylation of aldehydes
with diethylzinc has proven to be a useful prototype reaction, pro-
viding a good opportunity for the comparison of a wide range of
catalysts.1
Since Oguni and Omi reported the first enantioselective addi-
tion of diethylzinc to benzaldehyde catalyzed by a 1,2-difunction-
alized chiral ligand, a great number of catalysts have been
developed.2 Following a breakthrough in asymmetric catalysis, it
became a challenge to synthesize chiral ligands from natural com-
pounds. Among a variety of methods, the incorporation of chirality
into ligands was achieved by using naturally-occurring, enantio-
merically pure terpenes as starting materials. Several diamines
and amino alcohols obtained from chiral terpenes, such as
(+)-pulegone, fenchone–camphor, and limonene, have been found
to be effective chiral promoters for various chemical transforma-
tions.3 It is believed that a chiral catalyst with uniform chirality af-
fords only one enantiomer of the product. However, the application
of chiral catalysts derived from natural products has the limitation
accessing both enantiomers of a product by using the same chiral
promoter. Hirose et al. observed the switching of enantioselectivity
by exchanging the positions of the amine and sulfonamide groups
in ligands with the same chirality.4
Although many types of 1,2-difunctionalized chiral auxiliaries
have already been tested in enantioselective reactions, the use of
1,3-difunctionalized ligands is less well explored.5 While amino
alcohols are the most commonly employed catalysts in the alkyl-
ation of aldehydes, diamines have received less attention, despite
the usefulness of such ligands. Asami et al. have successfully
applied aromatic 1,2-diamines in the model reaction of diethylzinc
addition to benzaldehyde.6 Hirose et al. achieved higher selectivity
by applying 1,3-amino sulfonamides, where the highly acidic proton
of the sulfonamido group was necessary for effective catalytic
activity.4
We previously reported on the transformation of enantiomeri-
cally pure monoterpenes such as
a-pinene, apopinene, myrtenal,
and (+)-3-carene into b-amino acid derivatives, for example,
1,3-amino alcohols and diamines. These 1,2-disubstituted, 1,3-
difunctional chiral synthons were successfully applied as catalysts
in the enantioselective synthesis of secondary alcohols.7
Herein our aim was to synthesize a library of 1,3-diamines from
(ꢀ)-apopinene and evaluate them as catalysts in the asymmetric
addition of diethylzinc to benzaldehyde.
⇑
Corresponding authors. Tel.: +36 62 545564; fax: +36 62 545705.
E-mail addresses: szakonyi@pharm.u-szeged.hu (Z. Szakonyi), fulop@pharm.
u-szeged.hu (F. Fülöp).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.04.003

554
K. Csillag et al. / Tetrahedron: Asymmetry 24 (2013) 553–561
The conformationally constrained pinane ring system was cho-
the starting material for the synthesis of additional tosylated dia-
mines and amides. Sulfonation of the primary amino group in 8
led to tosylated N,N-dimethylamide 9. Amide 12 was obtained
through two different routes: the primary amino group in 8 was
transformed into a secondary one by reductive amination, result-
ing in 11, which was followed by tosylation; N-benzylation of 9
gave 12 in higher yield. The transformation of 9 and 12 into tosy-
lated 1,3-diamines 10 and 13 was accomplished by reduction with
LiAlH4.
sen because better chiral induction was expected. Our previous re-
sults led us to expect that the disadvantages of the 2-methyl
substituent in the pinane derivatives could be reduced by applying
apo derivatives. Additionally, both (ꢀ)- and (+)-apopinene are
available from commercial sources via one or two-step syntheses,
but we have only applied (ꢀ)-apopinene as the starting material.8
2. Results and discussion
The attempted ring opening of lactam 3 with diethylamine was
unsuccessful, probably because of steric hindrance. Efforts to re-
2.1. Syntheses of pinane-based tosylated diamines and amides
The syntheses of 3 and 4 were performed by using literature
methods starting from commercially available (ꢀ)-myrtenal via
(ꢀ)-apopinene 1 (Fig. 1).8 The cycloaddition of chlorosulfonyl iso-
cyanate (CSI) proceeded highly regio- and stereospecifically (as re-
vealed by NMR and GC studies on the crude product 2), resulting in
only b-lactam 2. The N-Boc b-lactam 3 was obtained from 2 by
treatment with di-tert-butyl dicarbonate, while the transformation
of 2 into amino acid 4 was achieved with aqueous HCl.
b-Lactam 3 was readily converted into derivatives bearing an
N,N-dimethylamino and a sulfonamido group (Scheme 1). b-Lac-
tam 3 underwent nucleophilic ring opening with dimethylamine
to give amide 5 in good yield, either in aqueous or ethanolic solu-
tion. Reduction of 5 with LiAlH4 furnished 1,3-diamine 6. Sulfona-
tion of the secondary amino group in 6 with p-toluenesulfonyl
chloride resulted in the tosylated 1,3-diamine 7 in a good yield.
Deprotection of 5 with 5% aqueous HCl gave 8, which served as
CSI,
NH
dry Et2O,
r.t., 7 days
O
2
1
Boc2O, TEA,
DMAP
THF,
r.t., 6 h
18% HCl
r.t., 2 h
NH2*HCl
NBoc
O
COOH
4
3
Figure 1. Transformation of a b-lactam into 3 and 4.
3
A: 33% Me2NH/EtOH,
B: 40% Me2NH/H2O,
r.t., 24 h,
86% (A); 89% (B)
Ts
H
N
TsCl, TEA,
DMAP,
N
NHBoc
LiAlH4,
N
N
N
dry THF,
reflux, 6 h,
85%
dry CHCl3
reflux, 6 h,
78%
5
6
7
O
Et2O, r.t.,
24 h, 93%
5% HCl
aq.
NH2
N
NHTs
N
TsCl, TEA,
DMAP,
NHTs
N
LiAlH4,
dry CHCl3
reflux, 6 h,
72%
dry THF,
r.t., 2 h,
69%
8
O
9
O
10
PhCHO,
EtOH,
r.t., 2 h
then NaBH4,
EtOH, r.t., 6 h,
67%
BnBr,
Cs2CO3,
dry acetone,
reflux, 7 h, 76%
Ts
H
Ts
N
TsCl, TEA,
DMAP,
N
Ph
N
Ph
Ph
LiAlH4,
N
N
N
dry CHCl3,
reflux, 20 h,
51%
dry THF,
r.t., 20 h
53%
11
12
13
O
O
Scheme 1. Syntheses of pinane-type tosylated diamines and amides.

K. Csillag et al. / Tetrahedron: Asymmetry 24 (2013) 553–561
555
duce amides 8 and 11 to diamines with a primary and secondary
amino functionality were also unsuccessful. The starting material
could not be recovered; an inseparable mixture of amine-type
compounds was obtained. In order to extend the library of desired
ligands, an alternative pathway was devised for the syntheses of
15–30 (Scheme 2).
Following the introduction of a methyl group, or even a bulkier
benzyl group onto the sulfonamido moiety 7 and 13, weak catalytic
activity was observed. The enantioselectivity was higher when li-
gands 9 and 10 were applied, which revealed that the acidic proton
on the sulfonamide nitrogen was necessary for a reasonable level
of catalytic activity.
In two or three reaction steps, b-amino acid 4 was converted
into tosylated primary, secondary, or tertiary amides 15–25 and
tosylated tertiary amines 26–30. The sulfonation of 4 afforded
tosylated amino acid 14, which underwent amidation via the acid
chloride to give 15–25. b-Amino amides 15–19 and 21–24 were
prepared under reflux conditions, but in the syntheses of 20 and
25, microwave activation was necessary. Reduction of amides 15,
16, 19, 20, and 24 with LiAlH4 resulted in tertiary 1,3-diamines
26–30, whereas the attempted reductions of 17, 18, 21–23, and
25 to secondary or primary amines were unsuccessful with only
an inseparable mixture of amine-type compounds being obtained.
These results encouraged us to investigate the effect of sub-
stituents on the aminomethyl or amido group on the stereose-
lectivity of the alkylation of benzaldehyde by using chiral
auxiliaries 15–30.
Chiral ligands bearing a tertiary amide function 15, 16, 19, 20,
and 24 furnished products in low to moderate ee, with (R)-selectiv-
ity. The highest asymmetric induction was achieved when N-ben-
zyl-N-methyl derivative 20 was used (ee 65%). Chiral ligand 18
hardly influenced the selectivity at all, probably because of the ab-
sence of a substituent on the primary amide group.
Catalysts 17, 22, 23, and 25, containing a secondary amide
group, resulted in the best ee values, while the direction of the
enantioselectivity turned from (R) to (S). A marked increase in
the enantioselectivity was observed with the N-phenyl derivative
25 (ee 83%).
2.2. Application of tosylated diamines and amides as chiral
ligands in the enantioselective addition of diethylzinc to
benzaldehyde
However, when a new asymmetric center was introduced by
utilizing (R)- and (S)-1-phenylethylamine, the catalytic effects of
21 and 22 proved to be unsatisfactory, probably because of the
greater steric hindrance of the substituent. When diamines 26–
30 were explored as chiral auxiliaries in the addition of diethylzinc
to benzaldehyde, lower ee values were obtained.
When compared with previously reported applications of
monoterpene-based 1,3-aminoalcohols5c,7a or sulfonated diamine-
s,4a the present N-tosyldiamines have less influence on the stere-
oselectivity of the model reaction. Somewhat higher ee values
were obtained when tosylated amino amides were applied. To
the best of our knowledge, this is the first example of the use of
b-amino amides as catalysts in the reaction of diethylzinc with
aldehydes.
The application of sulfonated diamines 7, 9, 10, 12, 13, 15–25,
and 26–30 as catalysts in the ethylation of benzaldehyde resulted
in 1-phenyl-1-propanol enantiomers 32 and 33 (Scheme 3).
The enantiomeric purity of the secondary alcohol obtained was
determined by GC on a Chirasil-DEX CB column, according to the lit-
erature.9 Catalysts 7, 9, 10, 12, 13, 15–25, and 26–30 were applied in
a 10% molar ratio and the reactions were carried out in n-hexane at
room temperature. The results are presented in Table 1.
When diamines 7, 10, and 13 were applied as chiral ligands in
the addition of diethylzinc to benzaldehyde, low to moderate
enantioselectivities were achieved. The asymmetric induction
was similarly weak when amides 9 and 12 were used. The forma-
tion of the (R)-enantiomer 33 was predominant in each case.
TsCl, TEA,
NH2*HCl
NHTs
DMAP,
1.SOCl2,
dry CHCl3,
r.t., 24 h,
50%
COOH
COOH
dry toluene,
14
60 oC, 3 h
2.NHR1R2
dry DCM,
4
NHTs
NHTs
NR1R2
reflux, 8 or 20 h,
or MW, 20 or 95 min
40-90%
LiAlH4,
NR1R2
dry THF,
r.t. or reflux,
2 or 20 h, 41-80%
26-30
O
15-25
15,16,19,20,24
15 and 26: R1 = R2 = Et; 16 and 27: R1R2 = (CH2)4; 17: R1 = H, R2 = Bn;
: R1 = R2 = H;
and : R1 = Me, R2 = Bn;
28
and : R1 = Me, R2 = Ph;
29
18
21
19
20
: R1 = H, R2 = CH(Me)Ph (R); : R1 = H, R2 = CH(Me)Ph (S);
22
23: R1 = H, R2 = Me; 24 and 30: R1R2 = (CH2)5; 25: R1 = H, R2 = Ph
Scheme 2. Synthesis of derivatives 15–30.
O
OH
OH
Et2Zn/n-hexane,
H
+
10 mol% catalyst
7,9,10,12,13,15-25,26-30,
r.t., Ar atm., 70-93%
31
32: (S)
33: (R)
Scheme 3. Catalyzed addition of diethylzinc to benzaldehyde.

556
K. Csillag et al. / Tetrahedron: Asymmetry 24 (2013) 553–561
Table 1
Addition of diethylzinc to benzaldehyde, catalyzed by various types of 1,3-diamines and b-amino amides
Entry
Catalyst (10 mol %)
Yielda (%)
eeb (%)
Configuration of the major productc
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
7
9
89
90
81
83
88
79
82
80
93
77
75
80
86
75
78
90
85
92
74
70
72
5
35
38
6
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(S)
(R)
(R)
(R)
(R)
(S)
(S)
(R)
(S)
(R)
(S)
(R)
(R)
(R)
10
12
13
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
8
48
30
76
27
32
65
23
14
63
36
83
29
6
26
10
5
a
b
c
Yields after silica column chromatography.
Determined on the crude product by GC (Chirasil-DEX CB column).
Determined by comparing the GC analysis tR and the specific rotation with literature data.9
4.2. Preparationoftert-butyl(1R,2R,3S,5R)-3-(dimethylcarbamoyl)-
3. Conclusions
6,6-dimethylbicyclo[3.1.1]heptan-2-ylcarbamate 5
In conclusion we have developed a library of new chiral pinane-
based sulfonated diamines and b-amino amides 7, 9, 10, 12, 13, 15–
25, and 26–30 and successfully applied them as chiral ligands for
the enantioselective addition of diethylzinc to benzaldehyde,
affording optically active secondary alcohols. Significantly higher
enantioselectivities were observed when secondary amides were
used as compared with primary, tertiary amides, and tertiary dia-
mines. Ligands with a uniform absolute configuration showed
switching of the enantioselectivity, when the substituents on the
amide function were exchanged. Primary and tertiary amides or
tertiary diamines preferred the formation of (R)-1-phenyl-1-propa-
nol, while chiral auxiliaries bearing a secondary amide group gave
the (S)-enantiomer as the main product.
A: N-Boc b-lactam 3 (5.00 g, 18.84 mmol) was dissolved in a 33%
solution of Me2NH in dry EtOH (250 mL). After stirring for 24 h at
room temperature, the solvent was evaporated off.
B: N-Boc b-lactam 3 (5.00 g, 18.84 mmol) was dissolved in Et2O
(5 mL), and a 40% solution of Me2NH in H2O (150 mL) was then
added. After stirring for 24 h at room temperature, the solvent
was evaporated off.
The crude product was purified by column chromatography on
silica gel (n-hexane/EtOAc = 4:1), resulting in 5 as a white crystal-
line product. Yield: 86% (A) (5.02 g); yield: 89% (B) (5.19 g); a white
solid; mp: 77–80 °C;
½
a 2D0
ꢂ
¼ þ31 (c 0.125, MeOH); 1H NMR
(400.1 MHz, CDCl3): d = 0.95 (s, 3H), 1.22 (s, 3H), 1.39 (s, 9H),
1.63 (d, 1H, J = 11.0 Hz), 1.85–1.93 (m, 3H), 2.11–2.17 (m, 1H),
2.23–2.28 (m, 1H), 2.95 (s, 3H), 3.07 (s, 3H), 3.59 (dt, 1H, J = 4.4,
10.5 Hz), 4.40 (t, 1H, J = 10.3 Hz), 5.15 (d, 1H, J = 10.6 Hz). 13C
NMR (100.6 MHz, CDCl3): d = 20.6, 24.9, 26.4, 28.5, 29.0, 34.8,
36.3, 38.2, 39.08, 39.7, 46.9, 48.5, 79.1, 155.2, 175.4. Anal. Calcd
for C17H30N2O3 (310.43): C, 65.77; H, 9.74; N, 9.02%. Found: C,
65.52; H, 9.89; N, 9.10%.
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded on a Bruker Avance DRX
400 spectrometer (400 MHz, d = 0 (TMS)), in the solvents indicated.
Chemical shifts are expressed in ppm (d) relative to TMS as an
internal reference. J values are given in Hz. Elemental analyses
were performed on a Perkin–Elmer 2400 Elemental Analyzer.
GC measurements were made on a Perkin–Elmer Autosystem
XL GC, consisting of a Flame Ionization Detector and a Turbochrom
Workstation data system (Perkin–Elmer Corporation Norwalk,
USA). The column used for the direct separation of enantiomers
was a Chirasil-DEX CB column (2500 ꢁ 0.25 mm I.D.).
4.3. Method A: general procedure for reduction of amides
To a stirred suspension of LiAlH4 (0.09 g, 2.5 mmol in the
synthesis of 10, 13, 26, 27, 29, and 30, or 0.18 g, 5 mmol, in the syn-
theses of 6 and 28) in dry THF (10 mL), a solution of amides 5, 9, 12,
15, 16, 19, 20, or 24 (1 mmol) in dry THF (10 mL) was added at 0 °C.
The reaction mixture was stirred for 2 h for 10, 26, 27, and 30 or
20 h for 13 and 29 at room temperature or at reflux for 6 h for 6
and 28, monitored by TLC, and a mixture of H2O (0.5 mL) and THF
(25 mL) was then added dropwise with cooling. The inorganic
material was filtered off and washed with THF. The filtrate was
dried (Na2SO4) and evaporated to dryness. The crude products were
purified by column chromatography on silica gel or recrystallized.
Microwave (MW) experiments were carried out in a CEM Dis-
cover SP MW reactor. Optical rotations were obtained with a Per-
kin–Elmer 341 polarimeter. Melting points were determined on a
Kofler apparatus and are uncorrected. Chromatographic separa-
tions were carried out on Merck Kieselgel 60 (230–400 mesh
ASTM). Reactions were monitored with Merck Kieselgel 60 F254-
precoated TLC plates (0.25 mm thickness). All the chemicals and
solvents were used as supplied.
4.3.1. Preparation of (1R,2R,3S,5R)-3-((dimethylamino)methyl)-
N,6,6-trimethylbicyclo[3.1.1]heptan-2-amine 6
Compounds 1–4 were prepared according to literature meth-
Compound 6 was prepared from 5 according to Method A. The
product obtained was used as a crude material in the next step.
ods, and were identical with those reported therein.8

K. Csillag et al. / Tetrahedron: Asymmetry 24 (2013) 553–561
557
A colorless oil, yield 85% (0.18 g); ½a D20
ꢂ
¼ ꢀ132 (c 0.125, MeOH); 1H
1.99–2.08 (m, 2H), 2.13–2.18 (m, 2H), 2.35–2.49 (m, 8H), 3.09–
3.16 (m, 1H), 3.62 (d, 1H, J = 10.2 Hz), 7.27 (d, 2H, J = 8.8 Hz), 7.69
(d, 2H, J = 8.8 Hz). 13C NMR (100.6 MHz, CDCl3): d = 20.2, 21.6,
23.6, 25.0, 26.5, 26.9, 32.0, 37.8, 40.1, 45.8, 53.0, 54.9, 63.4, 127.2,
129.4, 137.8, 142.7. Anal. Calcd for C21H32N2O2S (376.56): C, 66.98;
H, 8.57; N, 7.44; S, 8.52%. Found: C, 66.87; H, 8.52; N, 7.56; S, 8.59%.
NMR (400.1 MHz, CDCl3): d = 0.93 (s, 3H), 1.18 (d, 1H, J = 9.3 Hz),
1.22 (s, 3H), 1.28–1.34 (m, 1H), 1.84–1.89 (m, 2H), 1.99–2.10 (m,
3H), 2.19 (s, 6H), 2.25 (s, 3H), 2.34–2.44 (m, 1H), 2.81 (t, 1H,
J = 11.0 Hz), 3.03–3.06 (m, 1H). 13C NMR (100.6 MHz, CDCl3):
d = 20.8, 26.6, 27.4, 28.2, 30.4, 33.3, 35.0, 37.8, 41.3, 44.1, 45.3,
60.5, 66.3. Anal. Calcd for C13H26N2 (210.36): C, 74.23; H, 12.46;
N, 13.32%. Found: C, 74.09; H, 12.57; N, 13.37%.
4.3.6. Preparation of N-((1R,2R,3S,5R)-3-((benzyl(methyl)
amino)methyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)-4-
methylbenzenesulfonamide 28
4.3.2. Preparation of N-((1R,2R,3S,5R)-3-((dimethylamino)
methyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)-4-methyl
benzenesulfonamide 10
Compound 28 was prepared from 19 according to Method A. The
crude product was purified by column chromatography on silica
gel (DCM/MeOH = 19:1). A white solid, yield 60% (0.25 g); mp:
Compound 10 was prepared from 9 according to Method A. The
crude product was purified by column chromatography on silica
gel (n-hexane/EtOAc = 1:1). A white solid, yield 69% (0.24 g); mp:
102–105 °C; ½a 2D0
ꢂ
¼ þ12 (c 0.125, MeOH); 1H NMR (400.1 MHz,
CDCl3): d = 0.79 (s, 3H), 1.16–1.20 (s, 4H), 1.24–1.28 (m, 1H), 1.57
(s, 1H), 1.82–1.86 (m, 1H), 1.98–2.05 (m, 5H), 2.12–2.16 (m, 1H),
2.26–2.35 (m, 2H), 2.38 (s, 3H), 2.98 (t, 1H, J = 12.7 Hz), 3.39 (d,
1H, J = 12.7 Hz), 3.60 (d, 1H, J = 12.7 Hz), 3.64 (d, 1H, J = 12.7 Hz),
7.18 (d, 2H, J = 8.2 Hz), 7.28–7.32 (m, 1H), 7.36–7.42 (m, 4H),
7.62 (d, 2H, J = 8.2 Hz). 13C NMR (100.6 MHz, CDCl3): d = 20.2,
21.5, 25.1, 25.4, 26.5, 32.1, 37.7, 39.8, 40.1, 45.6, 54.8, 62.9, 65.3,
127.2, 127.7, 128.6, 129.3, 129.7, 137.2, 137.9, 142.6. Anal. Calcd
for C25H34N2O2S (426.61): C, 70.3; H, 8.03; N, 6.57; S, 7.52%. Found:
C, 70.30; H, 8.07; N, 6.55; S, 7.63%.
126–129 °C; ½a 2D0
ꢂ
¼ ꢀ5 (c 0.125, MeOH); 1H NMR (400.1 MHz,
CDCl3): d = 0.78 (s, 3H), 1.17 (s, 3H), 1.22–1.27 (m, 2H), 1.82–1.86
(m, 1H), 1.97–2.06 (m, 3H), 2.16 (s, 7H), 2.30–2.35 (m, 1H), 2.41
(s, 3H), 2.80–2.87 (m, 1H), 3.60 (d, 1H, J = 9.7 Hz), 7.27 (d, 2H,
J = 8.5 Hz), 7.70 (d, 2H, J = 8.5 Hz). 13C NMR (100.6 MHz, CDCl3):
d = 20.2, 21.6, 25.0, 25.4, 26.5, 31.9, 37.7, 40.1, 44.4, 45.8, 54.8,
67.0, 127.2, 129.4, 137.8, 142.7. Anal. Calcd for C20H32N2O2S
(350.52): C, 65.10; H, 8.63; N, 7.99; S, 9.15%. Found: C, 65.27; H,
8.59; N, 7.83 S, 9.09%.
4.3.3. Preparation of N-((1R,2R,3S,5R)-3-((diethylamino)
methyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)-4-methyl
benzenesulfonamide 26
4.3.7. Preparation of N-((1R,2R,3S,5R)-6,6-dimethyl-3-((methyl
(phenyl)amino)methyl)bicyclo[3.1.1]heptan-2-yl)-4-methyl
benzenesulfonamide 29
Compound 26 was prepared from 15 according to Method A. The
crude product was purified by column chromatography on silica
gel (DCM/MeOH = 9:1). A white solid, yield 80% (0.30 g); mp: 99–
Compound 29 was prepared from 20 according to Method A. The
crude product was recrystallized from n-hexane–iPr2O. A white so-
lid, yield 41% (0.17 g); mp: 164–166 °C; ½a D20
¼ þ17 (c 0.125,
ꢂ
101 °C; ½a 2D0
ꢂ
¼ ꢀ24 (c 0.125, MeOH); 1H NMR (400.1 MHz, CDCl3):
MeOH); 1H NMR (400.1 MHz, CDCl3): d = 0.80 (s, 3H), 0.86 (s,
1H), 1.07–1.10 (m, 4H), 1.56–1.66 (m, 1H), 1.79 (s, 1H), 1.86–1.91
(m, 1H), 2.10–2.15 (m, 1H), 2.42 (m, 3H), 2.57–2.62 (m, 1H), 2.86
(s, 3H), 3.08 (t, 1H, J = 10.6 Hz), 3.59–3.67 (m, 1H), 3.87–3.93 (m,
1H), 5.34 (d, 1H, J = 6.9 Hz), 6.67–6.74 (m, 3H), 7.20 (t, 2H,
J = 7.7 Hz), 7.29 (d, 2H, J = 8.1 Hz), 7.74 (d, 2H, J = 8.1 Hz). 13C
NMR (100.6 MHz, CDCl3): d = 20.7, 21.6, 26.1, 26.3, 28.1, 31.2,
33.2, 38.5, 40.1, 40.6, 47.9, 54.2, 54.7, 59.2, 65.3, 113.8, 117.4,
127.1, 129.3, 129.8, 136.9, 142.6, 148.8. Anal. Calcd for
d = 0.79 (s, 3H), 1.04 (t, 6H, J = 7.1 Hz), 1.16 (s, 3H), 1.20–1.28 (m,
2H), 1.57 (s, 1H), 1.82–1.86 (m, 1H), 1.97–2.04 (m, 2H), 2.20–2.41
(m, 8H), 2.62–2.70 (m, 2H), 2.84 (t, 1H, J = 13.1 Hz), 3.65 (d, 1H,
J = 10.0 Hz), 7.26 (d, 2H, J = 8.4 Hz), 7.69 (d, 2H, J = 8.4 Hz). 13C
NMR (100.6 MHz, CDCl3): d = 10.6, 20.3, 21.6, 24.8, 25.1, 26.6,
32.2, 37.7, 40.2, 45.3, 45.6, 54.9, 60.4, 127.2, 129.4, 138.6, 142.5.
Anal. Calcd for C21H34N2O2S (378.57): C, 66.63; H, 9.05; N, 7.40;
S, 8.47%. Found: C, 66.59; H, 9.10; N, 7.43; S, 8.40%.
C24H32N2O2S (412.59): C, 69.87; H, 7.82; N, 6.79; S, 7.77%. Found:
4.3.4. Preparation of N-benzyl-N-((1R,2R,3S,5R)-3-((dimethyl
amino)methyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)-4-
methylbenzenesulfonamide 13
Compound 13 was prepared from 12 according to Method A. The
crude product was purified by column chromatography on silica
C, 69.82; H, 7.85; N, 6.75; S, 7.80%.
4.3.8. Preparation of N-((1R,2R,3S,5R)-6,6-dimethyl-3-(piperidin
-1-ylmethyl)bicyclo[3.1.1]heptan-2-yl)-4-methylbenzene sulf-
onamide 30
gel (DCM/MeOH = 19:1).
A
colorless oil, yield 53% (0.23 g);
Compound 30 was prepared from 24 according to Method A. The
crude product was purified by column chromatography on silica
gel (DCM/MeOH = 9:1). A white solid, yield 78% (0.30 g); mp:
½
a 2D0
ꢂ
¼ þ37 (c 0.125, MeOH); 1H NMR (400.1 MHz, CDCl3):
d = 0.82 (s, 3H, CH3), 1.11 (s, 3H, CH3), 1.25–1.29 (m, 1H), 1.65–
1.68 (m, 1H), 1.83–1.91 (m, 4H), 2.07 (s, 6H), 2.12–2.18 (m, 1H),
2.33–2.40 (m, 5H), 4.20 (d, 1H, J = 16.1 Hz), 4.40 (d, 1H,
J = 10.0 Hz), 4.50 (d, 1H, J = 16.1 Hz), 7.21–7.27 (m, 5H), 7.33–
7.36 (m, 2H), 7.56 (d, 2H, J = 8.2 Hz). 13C NMR (100.6 MHz, CDCl3):
d = 20.5, 21.5, 26.4, 26.9, 29.3, 30.7, 39.8, 40.3, 45.6, 45.8, 50.1, 59.3,
66.6, 127.1, 127.5, 128.2, 129.3, 129.6, 137.9, 138.1, 143.0. Anal.
Calcd for C26H36N2O2S (440.64): C, 70.87; H, 8.23; N, 6.36; S,
7.28%. Found: C, 70.90; H, 8.17; N, 6.72; S, 7.10%.
125–130 °C; ½a 2D0
ꢂ
¼ ꢀ29 (c 0.125, MeOH); 1H NMR (400.1 MHz,
CDCl3): d = 0.77 (s, 3H), 1.15 (s, 3H), 1.20–1.28 (m, 3H), 1.41–1.48
(m, 3H), 1.53–1.70 (m, 4H), 1.81–1.86 (m, 1H), 1.96–2.03 (m,
2H), 2.13 (dd, 1H, J = 4.5, 12.8 Hz), 2.26–2.34 (m, 4H), 2.42 (s,
3H), 2.45–2.54 (m, 1H), 2.80 (t, 1H, J = 12.8 Hz), 3.64 (d, 1H,
J = 9.6 Hz), 7.26 (d, 2H, J = 8.1 Hz), 7.72 (d, 2H, J = 8.1 Hz). 13C
NMR (100.6 MHz, CDCl3): d = 20.3, 21.7, 24.4, 24.5, 25.0, 25.9,
26.6, 31.9, 37.7, 40.3, 45.2, 53.7, 54.8, 66.8, 127.3, 129.4, quaternary
C at 138.0 and 142.2 was detected from HMBC. Anal. Calcd for
4.3.5. Preparation of N-((1R,2R,3S,5R)-6,6-dimethyl-3-(pyrro
lidin-1-ylmethyl)bicyclo[3.1.1]heptan-2-yl)-4-methylbenzene
sulfonamide 27
C22H34N2O2S (390.58): C, 67.65; H, 8.77; N, 7.17; S, 8.21%. Found:
C, 67.59; H, 8.80; N, 7.21; S, 8.14%.
Compound 27 was prepared from 16 according to Method A. The
crude product was purified by column chromatography on silica gel
(DCM/MeOH = 9:1). A white solid, yield 78% (0.29 g); mp: 114–
4.4. Method B: synthesis of sulfonamides 7, 9 and 12
To a solution of 6, 8, or 11 (1 mmol), TEA (0.12 g, 1.2 mmol), and
DMAP (0.01 g, 0.1 mmol) in CHCl3 (10 mL), tosyl chloride (0.21 g,
1.1 mmol) was added at 0 °C. The mixture was refluxed for 9 h
116 °C; ½a 2D0
ꢂ
¼ ꢀ20 (c 0.125, MeOH); 1H NMR (400.1 MHz, CDCl3):
d = 0.79 (s, 3H), 1.18 (s, 3H), 1.25–1.31 (m, 2H), 1.78–1.85 (m, 5H),

558
K. Csillag et al. / Tetrahedron: Asymmetry 24 (2013) 553–561
for 7 and 9 or 20 h for 12. After completion of the tosylation (as
indicated by TLC), the reaction was quenched by the addition of
1 M aqueous NaOH (5 mL), and the organic layer was washed with
1 M aqueous NaOH (2 ꢁ 10 mL). The combined organic phase was
dried (Na2SO4) and evaporated to dryness. The crude product was
purified by column chromatography on silica gel, or by
recrystallization.
4.5. Preparation of (1R,2R,3S,5R)-6,6-dimethyl-2-(4-methyl
phenylsulfonamido)bicyclo[3.1.1]heptane-3-carboxylic acid 14
To a solution of 4 (0.22 g, 1 mmol) and TEA (0.30 g, 3 mmol) in
DCM (10 mL), tosyl chloride (0.21 g, 1.1 mmol) was added at 0 °C,
and the mixture was stirred for 24 h at room temperature. After
completion of the tosylation (as indicated by TLC), the organic
layer was washed with 5% aqueous HCl (3 ꢁ 10 mL). The combined
organic phase was dried (Na2SO4) and evaporated to dryness. The
crude product was purified by column chromatography on silica
gel (n-hexane/EtOAc = 9:1 followed by n-hexane/EtOAc = 1:1). A
4.4.1. Preparation of N-((1R,2R,3S,5R)-3-((dimethylamino)
methyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)-N,4-dimethyl
benzenesulfonamide 7
Compound 7 was prepared from 6 according to Method B. The
crude product was recrystallized from n-hexane. A yellow solid,
white solid, yield 50% (0.16 g); mp: 127–130 °C; ½a D20
¼ ꢀ55 (c
ꢂ
0.125, MeOH); 1H NMR (400.1 MHz, CDCl3): d = 0.72 (d, 1H,
J = 10.8 Hz), 0.83 (s, 3H), 1.25 (s, 3H), 1.79–1.91 (m, 3H), 2.09–
2.14 (m, 1H), 2.44 (s, 3H), 2.48–2.52 (m, 1H), 3.34- 3.38 (m, 1H),
4.46–4.48 (m, 1H), 7.33 (d, 2H, J = 8.0 Hz), 7.85 (d, 2H, J = 8.0 Hz).
13C NMR (100.6 MHz, CDCl3): d = 19.9, 21.8, 23.9, 25.0, 26.7, 39.3,
40.7, 42.4, 44.0, 59.3, 127.5, 129.9, 136.0, 145.0, 168.4. Anal. Calcd
for C17H23NO4S (337.43): C, 60.51; H, 6.87; N, 4.15; S, 9.50%. Found:
C, 60.45; H, 6.90; N, 4.20; S, 9.41%.
yield 78% (0.28 g); mp: 85–87 °C; ½a D20
¼ þ121 (c 0.125, MeOH);
ꢂ
1H NMR (400.1 MHz, CDCl3): d = 0.85 (s, 3H), 1.09 (s, 3H), 1.27
(d, 1H, J = 10.4 Hz), 1.27–1.34 (m, 1H), 1.86–1.93 (m, 3H), 2.13–
2.19 (m, 1H), 2.25 (s, 6H), 2.40–2.44 (m, 5H), 2.62–2.65 (m,
1H), 2.74 (s, 3H), 4.37–4.39 (m, 1H), 7.28 (d, 2H, J = 8.8 Hz),
7.63 (d, 2H, J = 8.8 Hz). 13C NMR (100.6 MHz, CDCl3): d = 20.6,
21.5, 26.3, 26.8, 29.5, 31.3, 32.5, 40.0, 40.2, 44.5, 45.8, 56.8,
65.4, 126.9, 129.6, 136.6, 143.1. Anal. Calcd for C20H32N2O2S
(364.55): C, 65.89; H, 8.85; N, 7.68; S, 8.80%. Found: C, 65.93;
H, 8.75; N, 7.75 S, 8.71%.
4.6. Preparation of (1R,2R,3S,5R)-2-amino-N,N,6,6-tetramethyl
bicyclo[3.1.1]heptane-3-carboxamide 8
4.4.2. Preparation of (1R,2R,3S,5R)-N,N,6,6-tetramethyl-2-(4-
methylphenylsulfonamido)bicyclo[3.1.1]heptane-3-carbox-
amide 9
To a stirred solution of N-Boc amide 5 (5.0 g, 16 mmol) in Et2O
(50 mL), 5% aqueous HCl (250 mL) was added. The reaction mixture
was stirred vigorously for 24 h at room temperature and then
evaporated to dryness. The solid product obtained was dissolved
in H2O, and the solution was made alkaline with 15% aqueous
KOH and extracted with DCM (3 ꢁ 100 mL). The combined organic
phase was dried (Na2SO4) and evaporated to dryness. The product
obtained was used as crude material in the next step. A yellow so-
Compound 9 was prepared from 8 according to Method B. The
crude product was purified by column chromatography on silica
gel (n-hexane/EtOAc = 2:1). A white solid, yield 72% (0.26 g); mp:
161–164 °C; ½a 2D0
ꢂ
¼ þ21 (c 0.125, MeOH); 1H NMR (400.1 MHz,
CDCl3): d = 0.87 (s, 3H), 1.15 (s, 3H), 1.74–1.79 (m, 2H), 1.84–
1.88 (m, 1H), 1.92–2.01 (m, 2H), 2.04–2.10 (m, 1H), 2.41 (s,
3H), 2.80 (s, 3H), 2.85 (s, 3H), 3.31–3.38 (m, 1H), 4.00–4.03
(m, 1H), 6.16 (s, 1H), 7.25–7.28 (m, 2H), 7.67–7.69 (m, 2H).
13C NMR (100.6 MHz, CDCl3): d = 20.4, 21.5, 24.4, 26.2, 29.6,
33.3, 36.13, 37.7, 39.1, 39.3, 47.4, 52.4, 126.9, 129.6, 139.4,
142.9, 175.5. Anal. Calcd for C19H28N2O3S (364.50): C, 62.61; H,
7.74; N, 7.69; S, 8.80%. Found: C, 62.23; H, 7.94; N, 7.84; S,
8.98%.
lid, yield 93% (3.12 g); mp: 68–74 °C; ½a D20
¼ ꢀ12 (c 0.125, MeOH);
ꢂ
1H NMR (400.6 MHz, CDCl3): d = 0.90 (s, 3H), 1.22 (s, 3H), 1.40 (s,
2H), 1.59 (d, 1H, J = 10.2 Hz), 1.80–1.86 (m, 2H), 1.90–1.94 (m,
1H), 2.06–2.12 (m, 1H), 2.29–2.34 (m, 1H), 2.97 (s, 3H), 3.09 (s,
3H), 3.42–3.51 (m, 2H). 13C NMR (100.6 MHz, CDCl3): d = 20.5,
24.8, 26.8, 29.2, 39.0, 36.0, 36.2, 37.8, 40.5, 50.2, 50.6, 180.7. Anal.
Calcd for C12H22N2O (210.32): C, 68.53; H, 10.54; N, 13.32%. Found:
C, 68.22; H, 10.79; N, 13.40%.
4.4.3. Preparation of (1R,2R,3S,5R)-2-(N-benzyl-4-methyl
phenylsulfonamido)-N,N,6,6-tetramethylbicyclo [3.1.1] hept-
ane-3-carboxamide 12
4.7. Preparation of (1R,2R,3S,5R)-2-(benzylamino)-N,N,6,6-
tetramethylbicyclo[3.1.1]heptane-3-carboxamide 11
To a suspension of Cs2CO3 (2.75 g, 8.45 mmol) in dry acetone
(25 mL), a solution of 9 (0.5 g, 1.37 mmol) in dry acetone (25 mL)
was added and the mixture was stirred vigorously for 30 min at
room temperature. Benzyl bromide (0.35 g, 2.05 mmol) was then
added and the mixture was refluxed for 7 h. The inorganic part
was filtered off and washed several times with acetone. The com-
bined filtrate was concentrated under reduced pressure. The crude
product was purified by column chromatography (n-hexane/
EtOAc = 2:1). A colorless oil, yield 76% (0.47 g); Method B: yield
To a solution of 8 (0.21 g, 1 mmol) in dry EtOH (10 mL), benzal-
dehyde (0.11 g, 1.05 mmol) was added and the mixture was stirred
at room temperature. After 2 h, the solvent was removed under re-
duced pressure, the residue was dissolved in dry EtOH (10 mL),
NaBH4 (0.08 g, 2.00 mmol) was added, and the solution was stirred
for 24 h at room temperature. The solvent was then evaporated off
and the residue was dissolved in H2O (10 mL) and extracted with
DCM (3 ꢁ 15 mL). The organic layer was dried (Na2SO4) and evap-
orated to dryness. The crude product was purified by column chro-
matography on silica gel (n-hexane/EtOAc = 1:1). A colorless oil,
51% (0.23 g); ½a 2D0
ꢂ
¼ ꢀ69 (c 0.125, MeOH); 1H NMR (400.1 MHz,
CDCl3): d = 0.90 (s, 3H), 1.13 (s, 3H), 1.60 (t, 1H, J = 5.4 Hz), 1.84–
1.88 (m, 1H), 1.92–1.98 (m, 1H), 2.07–2.11 (m, 1H), 2.15–2.21
(m, 1H), 2.34 (s, 3H), 2.54 (d, 1H, J = 9.9 Hz), 2.90 (s, 3H), 3.26 (s,
3H), 3.76 (dt, 1H, J = 2.5, 10.2 Hz), 4.50 (s, 2H), 4.68 (d, 1H,
J = 10.2 Hz), 7.06–7.13 (m, 7H), 7.30 (d, 2H, J = 8.6 Hz). 13C NMR
(100.6 MHz, CDCl3): d = 20.3, 21.4, 25.8, 26.5, 29.5, 35.5, 36.5,
38.6, 38.8, 40.8, 44.8, 50.0, 58.5, 126.7, 127.0, 127.7, 128.8, 129.1,
137.9, 138.3, 142.7, 175.1. Anal. Calcd for C26H34N2O3S (454.62):
C, 68.69; H, 7.54; N, 6.16; S, 7.05%. Found: C, 68.54; H, 7.60; N,
6.21; S, 7.00%.
yield 67% (0.20 g);
½
a 2D0
ꢂ
¼ ꢀ29 (c 0.125, MeOH); 1H NMR
(400.1 MHz, CDCl3): d = 0.89 (s, 3H), 1.26 (s, 3H), 1.65 (d, 1H,
J = 11.2 Hz), 1.80–1.87 (m, 1H), 1.91–1.96 (m, 1H), 2.06–2.11 (m,
1H), 2.20–2.24 (m, 1H), 2.33 (dt, 1H, J = 3.6; 13.2 Hz), 2.97 (s,
3H), 2.98 (s, 3H), 3.30 (d, 1H, J = 10.6 Hz), 3.50 (dt, 1H, J = 3.9,
10.4 Hz), 3.54 (d, 1H, J = 13.2 Hz), 3.79 (d, 1H, J = 13.2 Hz), 7.17–
7.26 (m, 5H). 13C NMR (100.6 MHz, CDCl3): d = 20.5, 24.8, 26.8,
29.1, 35.7, 36.1, 38.0, 38.8, 40.3, 43.6, 51.3, 56.0, 126.8, 128.2,
141.1, 176.4. Anal. Calcd for C19H28N2O (300.44): C, 75.96; H,
9.39; N, 9.32%. Found: C, 75.77; H, 9.50; N, 9.37%.

K. Csillag et al. / Tetrahedron: Asymmetry 24 (2013) 553–561
559
4.8. Method C: general procedure for the amidation
4.8.4. Preparation of (1R,2R,3S,5R)-6,6-dimethyl-2-(4-methyl
phenylsulfonamido)bicyclo[3.1.1]heptane-3-carboxamide 18
Compound 18 was prepared according to Method C, and purified
by column chromatography on silica gel (n-hexane/EtOAc = 2:1). A
At first, N-tosyl amino acid 14 (0.50 g, 1.48 mmol) in dry tolu-
ene (15 mL) was transformed into the acid chloride by the addition
of SOCl2 (0.41 g, 3.44 mmol). The mixture was stirred for 3 h at
60 °C and then evaporated to dryness. The residue was dissolved
in DCM (15 mL), the appropriate amine (3 equiv in the syntheses
of 21 and 22, or 10 equiv in the synthesis of 15–17, 19 and 24)
was added, and the mixture was refluxed for 8 h for 15–17, 19,
and 24 or 20 h for 21 and 22. In the case of 18, NH3 gas was intro-
duced into the reaction mixture, which was stirred for 5 h at room
temperature. In the synthesis of 23, a 40% solution of MeNH2 in
H2O (5 mL) was added to the reaction mixture, which was then
stirred for 20 h at room temperature. The mixture was then evap-
orated to dryness and the crude product was purified by column
chromatography or recrystallized.
white solid, yield 66% (0.32 g); mp: 198–221 °C; ½a D20
¼ þ13 (c
ꢂ
0.125, MeOH); 1H NMR (400.1 MHz, CDCl3): d = 0.76 (s, 3H), 1.08
(s, 3H), 1.49–1.52 (m, 1H), 1.83–1.90 (m, 3H), 2.04–2.10 (m, 1H),
2.22–2.27 (m, 1H), 2.41 (s, 3H), 3.04 (dt, 1H, J = 2.8, 10.6 Hz), 3.94
(t, 1H, J = 10.6 Hz), 5.72 (s, 1H), 6.57 (s, 1H), 7.26 (d, 2H,
J = 8.5 Hz), 7.32 (d, 1H, J = 10.5 Hz), 7.72 (d, 2H, J = 8.5 Hz). 13C
NMR (100.6 MHz, CDCl3): d = 20.2, 21.5, 24.1, 26.1, 27.8, 39.0,
39.3, 40.1, 46.2, 52.6, 126.9, 129.6, 138.9, 143.0, 178.1. Anal. Calcd
for C17H24N2O3S (336.45): C, 60.69; H, 7.19; N, 8.33; S, 9.53%.
Found: C, 60.45; H, 7.31; N, 8.21; S, 9.40%.
4.8.5. Preparation of (1R,2R,3S,5R)-N-benzyl-N,6,6-trimethyl-2-
(4-methylphenylsulfonamido)bicyclo[3.1.1]heptane-3-carbox-
amide 19
4.8.1. Preparation of (1R,2R,3S,5R)-N,N-diethyl-6,6-dimethyl-2-
(4-methylphenylsulfonamido)bicyclo[3.1.1]heptane-3-carbox-
amide 15
Compound 19 was prepared according to Method C, and purified
by column chromatography on silica gel (n-hexane/EtOAc = 3:1). A
Compound 15 was prepared according to Method C, and purified
by column chromatography on silica gel (n-hexane/EtOAc = 3:1). A
white solid, yield 87% (0.56 g); mp: 101–103 °C; ½a D20
¼ ꢀ3 (c
ꢂ
0.125, MeOH); 1H NMR (400.1 MHz, CDCl3, 2 rotamers): d = 0.76
(s, 2H, minor), 0.86 (s, 3H, major), 1.11 (s, 2H, minor), 1.15 (s,
3H, major), 1.25 (t, 1H, J = 7.15 Hz, minor), 1.66–1.69 (m, 1H, min-
or), 1.73–1.76 (m, 1H, major), 1.81–1.91 (m, 1H, major/minor),
1.97–1.99 (m, 1H, major/minor), 2.02–2.11 (m, 3H, major/minor),
2.41 (s, 3H, major), 2.43 (s, 2H, minor), 2.77 (s, 3H, major), 2.94
(s, 2H, minor), 3.41 (dt, 1H, J = 4.2, 10.02 Hz), 3.50 (dt, 1H, J = 4.2,
10.0 Hz), 4.00–4.06 (m, 2H, major), 4.09–4.20 (m, 2H, minor),
4.68 (d, 1H, J = 17.4 Hz, minor), 4.85 (d, 1H, J = 14.5 Hz), 5.70 (d,
1H, J = 10.4 Hz), 6.16 (d, 1H, J = 10.4 Hz), 7.11 (d, 1H, J = 7.9 Hz,
minor), 7.21 (d, 2H, J = 7.9 Hz, major), 7.25–7.36 (m, 10H, major/
minor), 7.66 (d, 2H, J = 7.9 Hz, major), 7.70 (d, 1H, J = 7.9 Hz, min-
or). 13C NMR (100.6 MHz, CDCl3, 2 rotamers): d = 20.3, 21.6, 24.3,
24.4, 26.2, 26.3, 29.8, 30.1, 33.6, 34.2, 34.9, 35.3, 39.3, 47.0, 47.1,
51.5, 52.3, 52.4, 54.0, 126.3, 126.8, 127.0, 127.5, 127.7, 128. 2,
128.8, 129.0, 129.6, 129.7, 139.9, 137.2, 142.9, 175.8, 175.9. Anal.
Calcd for C25H32N2O3S (440.60): C, 68.15; H, 7.32; N, 6.36; S,
7.28%. Found: C, 68.23; H, 7.21; N, 6.50; S, 7.37%.
white solid, yield 66% (0.38 g); mp: 88–90 °C; ½a D20
¼ þ15 (c 0.125,
ꢂ
MeOH); 1H NMR (400.1 MHz, CDCl3): d = 0.86 (s, 3H), 1.07 (t, 3H,
J = 7.2 Hz), 1.14 (s overlapped with t, 6H, J = 6.7 Hz), 1.68–1.71
(m, 1H), 1.82–1.88 (m, 2H), 1.96–1.99 (m, 2H), 2.02–2.08 (m,
1H), 2.40 (m, 3H), 3.04–3.13 (m, 1H), 3.22–3.44 (m, 4H), 3.99 (t,
1H, J = 10.9 Hz), 6.02 (d, 1H, J = 10.2 Hz), 7.24 (d, 2H, J = 8.4 Hz),
7.66 (d, 2H, J = 8.4 Hz). 13C NMR (100.6 MHz, CDCl3): d = 13.1,
15.0, 20.4, 21.6, 24.3, 26.3, 30.4, 33.5, 39.0, 39.4, 41.4, 42.8, 47.1,
52.4, 126.9, 129.6, 139.4, 142.9, 174.7. Anal. Calcd for C21H32N2O3S
(392.56): C, 64.25; H, 8.22; N, 7.14; S, 8.17%. Found: C, 64.13; H,
8.26; N, 7.19; S, 8.10%.
4.8.2. Preparation of N-((1R,2R,3S,5R)-6,6-dimethyl-3-(pyrrol
idine-1-carbonyl)bicyclo[3.1.1]heptan-2-yl)-4-methylbenzene
sulfonamide 16
Compound 16 was prepared according to Method C, and purified
by column chromatography on silica gel (n-hexane/EtOAc = 3:1). A
white solid, yield 72% (0.41 g); mp: 183–185 °C; ½a D20
¼ þ12 (c
ꢂ
0.125, MeOH); 1H NMR (400.1 MHz, CDCl3): d = 0.86 (s, 3H), 1.15
(s, 3H), 1.59 (s, 1H), 1.73–1.88 (m, 7H), 1.95–1.99 (m, 2H), 2.03–
2.10 (m, 1H), 2.40 (m, 3H), 3.16–3.31 (m, 3H), 3.38 (t, 1H,
J = 6.9 Hz), 4.04 (t, 1H, J = 9.2 Hz), 6.19 (d, 1H, J = 10.0 Hz), 7.25
(d, 2H, J = 8.5 Hz), 7.68 (d, 2H, J = 8.5 Hz). 13C NMR (100.6 MHz,
CDCl3): d = 20.4, 21.6, 24.4, 24.5, 26.0, 26.2, 29.4, 35.8, 39.1, 39.3,
46.1, 46.8, 47.3, 52.4, 126.8, 129.6, 139.5, 142.7, 173.8. Anal. Calcd
for C21H30N2O3S (390.54): C, 64.58; H, 7.74; N, 7.17; S, 8.21%.
Found: C, 64.50; H, 7.78; N, 7.29; S, 8.42%.
4.8.6. Preparation of (1R,2R,3S,5R)-6,6-dimethyl-2-(4-methyl
phenylsulfonamido)-N-((R)-1-phenylethyl)bicyclo[3.1.1] hept-
ane-3-carboxamide 21
Compound 21 was prepared with 3 equiv (0.54 g, 4.44 mmol) of
(R)-1-phenylethylamine according to Method C, and recrystallized
from n-hexane. A white solid, yield 78% (0.51 g); mp: 153–
155 °C; ½a 2D0
ꢂ
¼ þ108 (c 0.125, MeOH); 1H NMR (400.1 MHz, CDCl3):
d = 0.77 (s, 3H), 1.09 (s, 3H), 1.54 (d, 4H, J = 6.1 Hz), 1.78–1.85 (m,
2H), 1.88–1.95 (m, 1H), 2.01–2.10 (m, 2H), 2.42 (s, 3H), 2.95 (dt,
1H, J = 3.4, 10.3 Hz), 3.96 (t, 1H, J = 10.0 Hz), 5.02–5.09 (m, 1H),
5.48 (d, 1H, J = 10.7 Hz), 5.95 (d, 1H, J = 7.4 Hz), 7.23–7.35 (m,
7H), 7.70 (d, 2H, J = 8.2 Hz). 13C NMR (100.6 MHz, CDCl3):
d = 20.1, 21.6, 21.9, 24.2, 26.1, 29.0, 39.0, 39.2, 40.4, 46.5, 49.7,
52.6, 126.2, 126.8, 127.4, 128.8, 129.7, 138.9, 143.1, 143.6, 173.9.
Anal. Calcd for C25H32N2O3S (440.60): C, 68.15; H, 7.32; N, 6.36;
S, 7.28%. Found: C, 68.23; H, 7.16; N, 6.32; S, 7.50%.
4.8.3. Preparation of (1R,2R,3S,5R)-N-benzyl-6,6-dimethyl-2-(4-
methylphenylsulfonamido)bicyclo[3.1.1]heptane-3-carbox-
amide 17
Compound 17 was prepared according to Method C and purified
by column chromatography on silica gel (n-hexane/EtOAc = 3:1). A
white solid, yield 85% (0.53 g); mp: 165–167 °C; ½a D20
¼ þ70 (c
ꢂ
0.125, MeOH); 1H NMR (400.1 MHz, CDCl3): d = 0.79 (s, 3H), 1.13
(s, 3H), 1.58 (s, 1H), 1.63–1.66 (m, 1H), 1.82–1.88 (m, 2H), 1.97 (t,
1H, J = 11.9 Hz), 2.06–2.14 (m, 2H), 2.39 (s, 3H), 2.91 (dt, 1H,
J = 3.5, 10.5 Hz), 3.99 (t, 1H, J = 9.8 Hz), 4.19 (dd, 1H, J = 4.5,
14.8 Hz), 4.57 (dd, 1H, J = 6.5, 14.8 Hz), 5.54 (d, 1H, J = 10.0 Hz),
5.81 (s, 1H), 7.23–7.36 (m, 7H), 7.68 (d, 2H, J = 8.2 Hz). 13C NMR
(100.6 MHz, CDCl3): d = 20.2, 21.6, 24.4, 26.1, 29.3, 39.1, 39.3, 40.5,
44.3, 46.7, 52.7, 126.8, 127.7, 128.1, 128.8, 129.6, 137.9, 139.1,
143.1, 174.8. Anal. Calcd for C24H30N2O3S (426.57): C, 67.58; H,
7.09; N, 6.57; S, 7.52%. Found: C, 67.45; H, 7.14; N, 6.70; S, 7.41%.
4.8.7. Preparation of (1R,2R,3S,5R)-6,6-dimethyl-2-(4-methyl
phenylsulfonamido)-N-((S)-1-phenylethyl)bicyclo[3.1.1] hept-
ane-3-carboxamide 22
Compound 22 was prepared with 3 equiv (0.54 g, 4.44 mmol) of
(S)-1-phenylethylamine according to Method C, and recrystallized
from n-hexane. A white solid, yield 85% (0.55 g); mp: 141–
143 °C; ½a 2D0
ꢂ
¼ ꢀ6 (c 0.125, MeOH); 1H NMR (400.1 MHz, CDCl3):
d = 0.77 (s, 3H), 1.11 (s, 3H), 1.49 (d, 3H, J = 6.9 Hz), 1.58–1.62 (m,
1H), 1.83–1.89 (m, 2H), 2.01–2.07 (m, 3H), 2.31 (s, 3H), 2.79–2.85

560
K. Csillag et al. / Tetrahedron: Asymmetry 24 (2013) 553–561
(m, 1H), 3.89 (t, 1H, J = 9.1 Hz), 5.01–5.08 (m, 1H), 5.73–5.77 (m,
2H), 7.08 (d, 2H, J = 8.3 Hz), 7.28–7.33 (m, 1H), 7.38–7.40 (m,
4H), 7.58 (d, 2H, J = 8.3 Hz). 13C NMR (100.6 MHz, CDCl3):
d = 20.0, 21.5, 21.7, 24.2, 26.1, 29.9, 39.1, 39.2, 39.9, 46.5, 49.8,
52.3, 126.7, 126.9, 127.6, 128.9, 129.5, 138.7, 142.5, 142.9, 174.3.
Anal. Calcd for C25H32N2O3S (440.60): C, 68.15; H, 7.32; N, 6.36;
S, 7.28%. Found: C, 68.07; H, 7.48; N, 6.30; S, 7.20%.
67.58; H, 7.09; N, 6.57; S, 7.52%. Found: C, 67.47; H, 7.15; N,
6.65; S, 7.60%.
4.9.2. Preparation of (1R,2R,3S,5R)-6,6-dimethyl-2-(4-methyl
phenylsulfonamido)-N-phenylbicyclo[3.1.1]heptane-3-carbox-
amide 25
Compound 25 was prepared according to Method D. The crude
product was recrystallized from n-hexane. A white solid, yield
4.8.8. Preparation of (1R,2R,3S,5R)-N,6,6-trimethyl-2-(4-methyl
phenylsulfonamido)bicyclo[3.1.1]heptane-3-carboxamide 23
Compound 23 was prepared according to Method C, and recrys-
tallized from n-hexane. A white solid, yield 90% (0.46 g); mp: 164–
40% (0.24 g); mp: 218–220 °C; ½a D20
ꢂ
¼ þ97 (c 0.125, MeOH); 1H
NMR (400.1 MHz, CDCl3): d = 0.84 (s, 3H), 1.15 (s, 3H), 1.66–1.77
(m, 3H), 1.91 (s, 1H), 2.02 (t, 1H, J = 11.3 Hz), 2.09–2.14 (m, 1H),
2.20–2.24 (m, 1H), 2.32 (s, 3H), 3.04 (dt, 1H, J = 3.2, 10.3 Hz), 4.06
(t, 1H, J = 8.4 Hz), 5.53 (d, 1H, J = 10.1 Hz), 7.09–7.13 (m, 3H),
7.25–7.32 (m, 2H), 7.45 (t, 2H, J = 8.1 Hz), 7.63 (t, 2H, J = 8.1 Hz).
13C NMR (100.6 MHz, CDCl3): d = 20.3, 21.6, 24.4, 26.1, 29.2, 39.1,
39.3, 41.3, 47.1, 52.7, 120.3, 124.6, 126.9, 129.0, 129.7, 137.9,
138.5, 143.1, 173.2. Anal. Calcd for C23H28N2O3S (440.60): C,
66.96; H, 6.84; N, 6.79; S, 7.77%. Found: C, 66.87; H, 6.80; N,
6.72; S, 7.81%.
166 °C; ½a 2D0
ꢂ
¼ þ67 (c 0.125, MeOH); 1H NMR (400.1 MHz, CDCl3):
d = 0.81 (s, 3H), 1.13 (s, 3H), 1.65–1.68 (m, 1H), 1.79 (d, 1H,
J = 10.5 Hz) 1.84–1.88 (m, 1H), 1.91–1.97 (m, 1H), 2.05–2.11 (m,
2H), 2.41 (s, 3H), 2.73 (d, 3H, J = 4.6 Hz), 2.89 (dt, 1H, J = 3.6,
10.0 Hz), 3.98 (t, 1H, J = 10.3 Hz), 5.50–5.57 (m, 2H), 7.26 (d, 2H,
J = 8.3 Hz), 7.68 (d, 2H, J = 8.3 Hz). 13C NMR (100.6 MHz, CDCl3):
d = 20.2, 21.6, 24.3, 26.1, 29.7, 29.1, 39.1, 39.5, 40.3, 46.9, 52.6,
126.8, 129.6, 138.8, 142.7, 175.7. Anal. Calcd for C18H26N2O3S
(350.48): C, 61.69; H, 7.48; N, 7.99; S, 9.15%. Found: C, 61.51; H,
7.55; N, 7.80; S, 9.30%.
4.10. General procedure for the reactions of benzaldehyde with
diethylzinc in the presence of chiral catalyst 7, 9, 10, or 12–30
To the respective catalyst (0.1 mmol) 7, 9, 10, or 12–30, a 1 M
solution of Et2Zn in n-hexane (3 mL, 3 mmol) was added under
an Ar atmosphere at room temperature. The reaction mixture
was stirred for 25 min at room temperature, and then benzalde-
hyde (0.10 g, 1 mmol) was added, followed by stirring at room
temperature for a further 20 h. The reaction was quenched with
saturated NH4Cl solution (15 mL) and the mixture was extracted
with EtOAc (2 ꢁ 20 mL). The combined organic phase was washed
with H2O (10 mL), dried (Na2SO4), and evaporated under vacuum.
The crude secondary alcohols obtained were purified by flash col-
umn chromatography on silica gel (n-hexane/EtOAc = 4:1). The
enantiomeric excess and absolute configuration of the resulting
material were determined by chiral GC, using a chiral stationary
phase (Chirasil-Dex CB column) at 90 °C for 1-phenyl-1-propanol
32 and 33 [tR1 = 23.2 min for the (S)-isomer, tR2 = 24.1 min for the
(R)-isomer].9 The sign of the specific rotation of each product
was also measured.
4.8.9. Preparation of N-((1R,2R,3S,5R)-6,6-dimethyl-3-(piperi
dine-1-carbonyl)bicyclo[3.1.1]heptan-2-yl)-4-methylbenzene
sulfonamide 24
Compound 24 was prepared according to Method C, and recrys-
tallized from n-hexane. A white solid, yield 89% (0.53 g); mp: 157–
160 °C; ½a 2D0
ꢂ
¼ þ21 (c 0.125, MeOH); 1H NMR (400.1 MHz, CDCl3):
d = 0.86 (s, 3H), 1.14 (s, 3H), 1.41–1.63 (m, 6H), 1.74–1.79 (m, 2H),
1.84–2.08 (m, 4H), 2.41 (s, 3H), 3.07–3.13 (m, 1H), 3.19–3.26 (m,
1H), 3.31–3.37 (m, 2H), 3.67–3.73 (m, 1H), 4.01 (t, 1H,
J = 10.0 Hz), 6.42 (d, 1H, J = 10.0 Hz), 7.25 (d, 2H, J = 8.6 Hz), 7.67
(d, 2H, J = 8.6 Hz). 13C NMR (100.6 MHz, CDCl3): d = 20.4, 21.6,
24.4, 24.7, 25.6, 26.3, 26.5, 30.2, 32.6, 39.2, 39.5, 43.3, 47.4, 47.5,
52.7, 126.9, 129.6, 139.8, 142.7, 173.8. Anal. Calcd for C22H32N2O3S
(404.57): C, 65.31; H, 7.97; N, 6.92; S, 7.93%. Found: C, 65.52; H,
7.76; N, 7.13; S, 7.69%.
4.9. Method D: microwave-assisted synthesis of amides
Acknowledgments
N-Tosyl amino acid 14 (0.50 g, 1.48 mmol) in dry toluene
(15 mL) was transformed into the acid chloride by the addition
of SOCl2 (0.41 g, 3.44 mmol). The mixture was stirred for 3 h at
60 °C and then evaporated to dryness. To the residue thus ob-
tained, the appropriate amine (10 equiv) was added and the reac-
tion mixture was heated in a CEM Discover SP MW reactor. In
the case of 20, the mixture was irradiated at 200 W for 20 min at
150 °C, while for 25 the reaction mixture was irradiated at
200 W for 95 min at 110 °C.
We are grateful to the Hungarian Research Foundation (OTKA
NK81371) and TÁMOP-4.2.2/B-10/1-2010-0012 for financial sup-
port and acknowledge the receipt of a Bolyai János Fellowship for
Z.S. We thank A. Fischer for her assistance in the experimental
work.
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