An expedient and practical approach to functionalized 3-aza-, 3-oxa-, and 3-thiabicyclo[33.1]nonane systems

Article abstract of DOI:10.1055/s-0034-1379456

The synthesis of a number of heterobicyclo[3.3.1]nonane derivatives possessing carbonyl, amino, or carboxyl groups is reported. The synthetic scheme is concise and practical, based on optimized reaction conditions for each step and an orthogonal protectio

Full text of DOI:10.1055/s-0034-1379456

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 367–376
paper
367
A. Yu. Ishchenko et al.
Paper
Synthesis
An Expedient and Practical Approach to Functionalized 3-Aza-,
3-Oxa-, and 3-Thiabicyclo[3.3.1]nonane Systems
Aleksandr Yu. Ishchenkoa,b
Stanislav Yanikc,†
Eduard B. Rusanovd
Igor V. Komarov*a
Anthony J. Kirbye
Q
Q
Br
+
OBn
a Institute of High Technologies, Taras Shevchenko National Uni-
versity of Kyiv, Volodymyrska 60, 01601 Kyiv, Ukraine
ik214@yahoo.com
O
O
three points
of variation
Q = O, S, N-R
b Enamine Ltd., Aleksandra Matrosova 23, 01103 Kyiv, Ukraine
c Chemistry Department, Taras Shevchenko National University
of Kyiv, Volodymyrska 64, 01601 Kyiv, Ukraine
d Institute of Organic Chemistry of NAS of Ukraine, Murmanska
5, 02094 Kyiv, Ukraine
e University Chemical Laboratory, Cambridge CB2 1EW, UK
Received: 02.08.2014
cept of diversity-oriented synthesis (DOS) was introduced,
designating preparation of collections of structurally com-
plex and diverse compounds from simple starting materi-
als.4 The bicyclic compounds described in this paper could
be introduced into DOS by linear or branching functional-
ization methodology.5 We explore this potential, aiming at
improvements of known synthetic procedures and design-
ing new ones.
Accepted after revision: 22.10.2014
Published online: 14.11.2014
DOI: 10.1055/s-0034-1379456; Art ID: ss-2014-n0487-op
Abstract The synthesis of a number of heterobicyclo[3.3.1]nonane
derivatives possessing carbonyl, amino, or carboxyl groups is reported.
The synthetic scheme is concise and practical, based on optimized reac-
tion conditions for each step and an orthogonal protection group strat-
egy. Procedures for the key synthetic steps (double annulation of α-bro-
Construction of the [3.3.1]bicyclic system was per-
formed by a well-documented strategy, based on the double
annulation of α-bromomethyl acrylates 2 to enamines 3
(Scheme 1). The strategy was elaborated almost a half a
century ago for synthesis of carbo-bicyclic derivatives,6 and
has already proved its efficiency in preparations of 3-azabi-
cyclo[3.3.1]nonanes,7 3-oxabicyclo[3.3.1]nonanes,8 and 3-
phenyl-3-phosphabicyclo[3.3.1]nonane-3-oxide.9 A formal
[3+3] cycloaddition annulation was also reported recently
for rapid direct construction of the bicyclo[3.3.1] skeleton.10
The synthesis of 3-thiabicyclo[3.3.1]nonanes and the corre-
sponding sulfones has not so far been described in the open
literature, but has been the subject of a patent application,11
showcasing the importance of the compounds for drug de-
sign.
momethyl acrylates to enamines and
a Caglioti reaction) were
improved significantly. This makes the compounds attractive for medic-
inal chemistry as potential chemically diverse 3D-scaffolds applicable in
drug design.
Key words bicyclic compounds, annulation, Caglioti reaction, diversi-
ty-oriented synthesis, medicinal chemistry
Saturated carbo- and heterobicyclic systems are used
frequently in contemporary drug design. These systems
represent the so-called 3D-scaffolds;1 when functionalized
at appropriate positions they can interact efficiently with
biological targets. In principle, bicyclic scaffolds allow for
wide variations of the functional group disposition in space,
enhancing the chances of finding derivatives with optimal
pharmacological characteristics. In order to exploit this po-
tential to the full, chemists have developed flexible and
practical synthetic approaches to bicyclic scaffolds func-
tionalized at different positions.2 We report here on the
synthesis of a library of bicyclo[3.3.1]nonane-derived com-
pounds possessing heteroatoms N, O, and S in the bicyclic
skeleton (target compounds 1). Structural and chemical di-
versity of the synthesized library could be of great value for
finding derivatives with improved pharmacokinetic proper-
ties, and enhanced efficiency and selectivity of interaction
with biological targets. Such diversity has been the focus of
the drug discovery process over the past decade.3 The con-
Q
Q3
Br
4
R1
+
2
5
6
OPG3
R2
9
7
N
1
8
O
R3
2
1, Q = N-PG1, O, SO2
R1 = CO2H, NH-PG2
R2, R3 = H, NH2
3
R2+R3 = O
PG1,2,3 = different protecting groups
Scheme 1 Retrosynthetic disconnection of the target compounds
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 367–376

368
A. Yu. Ishchenko et al.
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Synthesis
The strategy outlined in Scheme 1 is particularly attrac-
tive to our purpose, because the key intermediate com-
pounds have vast potential for functionalization, using the
very rich chemistry of the carbonyl and carboxyl groups.
Specific control of the stereochemistry at positions 7 and 9
is also possible, as demonstrated earlier in the literature.12
This opens the way to chemically and structurally diverse
arrays of the derivatives of 1. The protection group strategy
in our synthesis aimed at regioselectivity of further func-
tionalization of the scaffolds, needed for the search of new
drug candidates by systematic variation of the functional
group type and position.
Our synthetic route to compounds 1 is shown in Scheme
2. Like previous syntheses of analogous [3.3.1]bicyclic de-
rivatives, it is based on the double annulation reaction of 2
and 3 as the key synthetic step, but differs in several details,
which make it more attractive and more practical for the
needs of medicinal chemistry.
Second, the annulation reaction was carried out under
conditions allowing the isolation of the iminium salts 5a–c
before their smooth and clean transformation into the key
intermediate compounds. The salts, formed in good yields
and sufficiently pure, were transformed cleanly into 6a–c;
no purification steps were needed at this step of the syn-
thesis.
The benzyl protecting groups in 6a,b can then be re-
moved by hydrogenolysis, setting the stage for the carbox-
ylic group functionalization in the obtained compounds
1a,b. Compound 6c resisted deprotection, probably due to
poisoning of the catalyst by the sulfide moiety. Therefore,
the sulfur atom was oxidized in the C=O protected interme-
diate 7c (protection of the carbonyl group was needed to
avoid the Baeyer–Villiger reaction during the sulfur oxida-
tion, which was observed under a variety of conditions).
The obtained sulfone 8d was smoothly deprotected to give
the scaffold 1d.
First, the α-bromomethyl acrylate 2 (PG3 = Bn) was syn-
thesized by a different route, from the corresponding hy-
droxymethyl acrylate 4, in turn obtained by a Morita–Bayl-
lis–Hillman (MBH) reaction between formaldehyde and
benzyl acrylate. The MBH reaction was chosen because it
has already demonstrated high yields and scalability in sim-
ilar syntheses.13,14 Benzyl is a protecting group for CO2H,
which is easily cleaved without epimerization at position 7
during the final transformations.
The Curtius rearrangement was used to transform com-
pounds 1a,b,d into the (protected) amino-substituted de-
rivatives 1e,f,g. The amino groups in 1e are orthogonally
protected, so they can be addressed selectively in further
transformations.
The carbonyl group in compounds 1e,f,g can be used
(like the carboxylic group in 1a,b,d) either for the synthesis
of compound libraries, or for further modification of the
scaffold. In order to modify the scaffold, the C=O was trans-
Q
N
Q
HO
Br
CO2Bn
H
a
b
OBn
3a–c
OBn
OBn
N+
c
O
Br–
5a–c
O
O
Q
4
2
d
Q
NHPG2
Q
NHPG2
COOH
H
h, i
Q
g
CO2Bn
H
e
H
H
(Q = O, NBoc)
H2N
O
O
O
6a–c
1a,b,d
1h Q = NBoc, PG2 = Cbz
1i Q = O, PG2 = Boc
1j Q = SO2, PG2 = Boc
1e Q = NBoc, PG2 = Cbz
1f Q = O, PG2 = Boc
1g Q = SO2, PG2 = Boc
a Q = NBoc
b Q = O
c Q = S
e, f
j
(Q = S)
O
d Q = SO2
S
O
S
k
CO2Bn
CO2Bn
O
O
H
H
8d
O
O
7c
Scheme 2 Synthesis of the target compounds 1. Reagents and conditions: (a) paraformaldehyde, DABCO, H2O–1,4-dioxane, 24 h, 47%; (b) PBr3, Et2O,
10 °C to r.t., 1 h, 85%; (c) DIPEA, MeCN, reflux, 3 h, 47–68%; (d) H2O/MTBE (4:1), 1 h, quant; (e) 1 atm H2, Pd/C (10%), THF or MeOH, 8 h, 92–98%;
(f) concd HCl, reflux, 2 h, 83%; (g) DPPA, DIPEA, benzene, r.t., 0.5 h, reflux, then BnOH (for 1e) or t-BuOH, DPPA, Et3N, reflux, 18 h (for 1f,g), 70–43%;
(h) NH2OH, H2O–EtOH, reflux, 3 h, quant; (i) 40 atm H2, Raney Ni, MeOH–NH3 (10%), 5 h, 75–89%; (j) TMSO(CH2)3OTMS, TMSOTf, CH2Cl2, –78 °C to r.t.,
3 h, quant; (k) m-CPBA, CH2Cl2, 5 °C to r.t., 8 h, 85%.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 367–376

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A. Yu. Ishchenko et al.
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Synthesis
formed into an amino group in two steps, as shown in
Scheme 2. The resulting compounds 1h–j were formed as
mixtures of epimers at position 9. The isomers thus ob-
tained are derivatives of different scaffolds possessing three
points of variation.
The molecular structure of 10a was established by X-ray
crystallography, proving the endo-configuration at C(7)
(Figure 1, a). Characteristic of this configuration is the vici-
nal coupling constant displayed by the C(7)-H signal in the
1H NMR spectrum of 10a (10.0 Hz, equatorial-equatorial
coupling). Similar coupling constants were observed in the
1H NMR spectra of the analogous compounds obtained (J =
7.5 Hz for 6b; J = 6.0 Hz for 1b) indicating that the endo-
configuration at C(7) is the most probable for them as well.
This is consistent with the formation of the bicyclic com-
pounds with the C(7)-endo configuration by the double an-
nulation reaction between 2 and 3 reported previously.6
Notably, the mild conditions used, especially at the depro-
tection steps, prevented the epimerization at C(7) observed
in earlier syntheses.7b The epimerization of 9a, however,
can be achieved almost completely in the presence of a
The carbonyl group can also be reduced to give the de-
oxygenated scaffolds. This was demonstrated with com-
pound 6a (Scheme 3) through the formation of the p-tolyl-
sulfonylhydrazone followed by reductive cleavage. This
method (the Caglioti reaction) is well known,15 but we de-
veloped a one-pot modification, which led to compound 9a
in quantitative yield. Thus, the p-tolylsulfonylhydrazone of
9a was reduced with NaBH3CN in the presence of one
equivalent of HCl in anhydrous methanol. Acetyl chloride
was used as a convenient source of HCl; it can easily be
quantified, and the intermediate hydrazine formed very
cleanly. Thus, the hydrazine was transformed to the deoxy-
genated 9a by reflux with sodium acetate in the same flask
without isolation. Notably the acid-labile protecting group
(Boc) tolerated the conditions of the carbonyl group remov-
al. The NBoc and OBn groups were subsequently cleaved to
obtain the deoxygenated amino acid (N-protected 1k or ful-
ly deprotected 10a).
base, as described previously for
a carbocyclic ana-
logue.6b,c,12 The epimerized compound can also be depro-
tected stepwise, to give partly 1l or fully deprotected amino
acid 11a. The molecular structure of 11a·HCl was also con-
firmed by X-ray crystallography (Figure 1, b). The vicinal
coupling constant for C(7)-H (axial-axial coupling) ob-
served in the 1H NMR spectrum of this compound (J = 12.5
+NH2
COO–
NBoc
CO2H
NBoc
CO2Bn
NBoc
CO2Bn
a, b
d
c
H
H
H
H
O
6a
9a
1k
10a
e
Cl–
+NH2
NBoc
H
f
H
CO2H
11a·HCl
CO2H
1l
Scheme 3 Further modifications of the scaffolds. Reagents and conditions: (a) TsSO2NHNH2, anhydrous EtOH, reflux, 0.5 h, quant; (b) NaBH3CN, AcCl,
MeOH, 0 °C, 0.5 h, then NaOAc·3H2O, reflux, 3 h, quant; (c) 1 atm H2, Pd/C (10%), THF, 8 h, 98%; (d) H2O, reflux, 24 h, quant; (e) NaOMe in MeOH,
reflux, 12 h, then H2O, reflux, 5 h, citric acid to pH 5, 59%; (f) 10% HCl in 1,4-dioxane, r.t., 1 h, quant.
Figure 1 Molecular structures of 10a (a) and 11a·HCl (b) as determined by X-ray diffraction studies
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A. Yu. Ishchenko et al.
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Hz) as well as in 1l (J = 13.0 Hz) is larger than the C(7)-H
(equatorial-equatorial coupling) in the spectrum of 10a (see
above). Notably, the six-membered rings in 11a·HCl adopt
perfect chair conformations, while one of the six-mem-
bered rings in 10a is considerably flattened, as can be seen
from the molecular structures. The ring flattening in 10a is
clearly the result of steric interactions between the func-
tional groups. Both non-natural amino acids 10a and 11a
can be used for synthesis of isomeric peptidomimetics, pro-
viding the rigid scaffolds for unusual secondary structure
elements.16
In conclusion, we have developed a practical synthetic
procedure leading to functionalized 3-aza-, 3-oxa-, and 3-
thiabicyclo[3.3.1]nonanes 1a,b,d–l. The overall yield of the
key intermediate products 6a–c is 40%, and these are readi-
ly transformed further to generate chemically very diverse
libraries of compounds for biological screening.
under stirring, keeping the temperature of the reaction mixture at 10
± 2 °C. After the addition, the cooling bath was removed, and the mix-
ture was stirred for ~1 h. After completion of the reaction (TLC, elu-
ent: hexane–EtOAc, 2:1), H2O (50 mL) was carefully added, the mix-
ture was stirred for 10 min, and then diluted with hexane (100 mL).
The organic layer was separated and washed with H2O (3 × 50 mL),
dried (Na2SO4), and evaporated on a rotary evaporator. The residue
was dissolved in MTBE (100 mL) and filtered through a silica gel pad
(230–400 mesh, ~300 g on a glass sinter filter), and the pad was
washed with MTBE (50 mL). The filtrate was evaporated and kept un-
der vacuum (0.5 mmHg, 23 °C, 3 h). The product 2 was used in the
next step without further purification; yield: 73.7 g (85%). Analytical
and spectral data for the obtained compound were identical to those
described in the literature.19
1H NMR (500 MHz, CDCl3): δ = 7.42–7.33 (m, 5 H), 6.39 (s, 1 H), 5.98
(s, 1 H), 5.27 (s, 2 H), 4.21 (s, 2 H).
13C NMR (124.9 MHz, CDCl3): δ = 164.7, 137.4, 135.6, 129.5, 128.7,
128.4, 128.2, 67.1, 29.3.
Iminium Salts 5a–c; General Procedure
The freshly prepared enamine 3a, 3b, or 3c (prepared analogously to
the procedure described7b for the corresponding N-Bz derivative, 1
equiv) and DIPEA (i-Pr2NEt; 0.1 equiv) were dissolved in MeCN (fresh-
ly distilled over P2O5) and the solution was heated to 60 °C under an
argon atmosphere. 2-Bromomethylacrylic acid benzyl ester (2; 1
equiv) was added dropwise to the warm stirred mixture at the rate to
maintain gentle reflux of the mixture (the reaction was exothermic).
The mixture was refluxed for 3 h after the addition, then left for 8 h at
r.t. The crystalline product 5a, 5b, or 5c was filtered, washed on the
filter (with anhydrous MeCN in the case of 5a and anhydrous MTBE in
the case of 5b,c) and dried at 90 °C in vacuum. The obtained products
were used in the next step without further purification. The salts are
highly sensitive to moisture, therefore, their NMR spectra were mea-
sured in carefully dried (CD3)2SO (distilled over pyromellitic anhy-
dride). Despite the precautions, traces of the hydrolyzed products
were still observed in the 1H and 13C NMR spectra of 5b,c (below, only
the assigned iminium salt signals are listed). Elemental analysis and
IR spectra measurements should also be carried out with careful pro-
tection from moisture.
Solvents were purified according to standard procedures.17 Melting
points were measured on an automated melting point system and are
uncorrected. Analytical TLC was performed using Polychrom SI F254
plates. Column chromatography was performed using silica gel (230–
400 mesh) as the stationary phase. 1H, 13C NMR, and all 2D NMR spec-
tra were recorded at 499.9 or 400.4 MHz for 1H and 124.9 or 100.4
MHz for 13C. Chemical shifts are reported in ppm downfield from TMS
(1H, 13C) as an internal standard. Mass spectra were recorded either
on an Agilent 1100 LC/MSD SL instrument by chemical ionization (CI)
or on a GCMS instrument with electron impact ionization (EI). CHN-
analysis was done on an Elementar VarioMICRO Cube analyzer. IR
spectra were recorded on a Perkin-Elmer Spectrum 100 FTIR spectro-
photometer.
2-Hydroxymethylacrylic Acid Benzyl Ester (4)
A 1 L round-bottomed flask was charged with paraformaldehyde
(15.42 g, 0.51 mol), DABCO (57.2 g, 0.51 mol), and H2O (250 mL). The
contents of the flask were stirred for a few minutes until the DABCO
had dissolved, then 1,4-dioxane (250 mL) and benzyl acrylate (249.9
g, 1.54 mol)18 were added. The mixture was stirred at r.t. for 24 h. The
organic layer was separated on a separatory funnel and the aqueous
layer was extracted with MTBE (4 × 100 mL). The combined extracts
and organic layer were evaporated on a rotary evaporator. The residue
was dissolved in MTBE (500 mL) and washed with aq 10% citric acid
(150 mL), and sat. aq NaHCO3 (100 mL). The organic layer was dried
(Na2SO4) and evaporated. Pure 4 was obtained by vacuum distillation;
yield: 46 g (47%); bp 136–142 °C/0.5 mmHg. Analytical and spectral
data for the obtained compound were identical to those described in
the literature.19
7-endo-1-(7-Benzyloxycarbonyl-3-tert-butoxycarbonyl-3-azabicy-
clo[3.3.1]non-9-ylidene)pyrrolidinium Bromide (5a)
Prepared from 2 (73.7 g, 0.29 mol), 3a (0.29 mol, prepared from 57.58
g of N-Boc-4-piperidone), and DIPEA (3.73 g, 5.0 mL, 0.029 mol) in
MeCN (400 mL); yield: 101.5 g (68%); white crystals; mp >235 °C
(dec.).
IR (KBr): 2978, 2941, 2867 (CH), 1731 (C=O), 1688 (C=N+), 1400, 1277,
1186, 1175 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 7.37 (m, 5 Harom), 5.08 (s, PhCH2, 2
H), 4.12, 4.04 [2 m, N+(CH2)2 + 2(4)-H, 6 H], 3.39 and 3.27 [2 m, 1,5-H
+ 2(4)-H, 4 H], 2.65 (m, 7-H, 1 H), 2.44 (m, 2 H), 2.15 (m, 2 H), 2.08 [m,
(CH2)2, 4 H], 1.41 (s, t-C4H9, 9 H).
13C NMR (124.9 MHz, DMSO-d6): δ = 190.5, 186.4, 172.5, 154.8, 136.0,
128.6, 128.2, 128.1, 80.2, 66.0, 54.1, 49.8 (br), 38.1, 35.9, 31.9, 28.0,
24.0.
1H NMR (500 MHz, CDCl3): δ = 7.38–7.33 (m, 5 H), 6.31 (d, J = 1 Hz, 1
H), 5.87 (d, J = 1 Hz, 1 H), 5.22 (s, 2 H), 4.35 (d, J = 5.2 Hz, 2 H), 2.75 (t,
J = 5.2 Hz, 1 H).
13C NMR (124.9 MHz, CDCl3): δ = 166.0, 139.5, 135.7, 128.5, 128.2,
128.0, 125.7, 66.5, 61.8.
Anal. Calcd for C25H35BrN2O4: C, 59.17; H, 6.95; N, 5.52. Found: C,
59.30; H, 7.02; N, 5.43.
2-Bromomethylacrylic Acid Benzyl Ester (2)
Ester 4 (65 g, 0.34 mol) was dissolved in anhydrous Et2O (500 mL) un-
der argon, and the solution was cooled to –10 °C (ice/MeOH bath).
PBr3 (45.77 g, 16 mL, 0.17 mol) was added dropwise to the solution
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A. Yu. Ishchenko et al.
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7-endo-1-(7-Benzyloxycarbonyl-3-oxabicyclo[3.3.1]non-9-
ylidene)pyrrolidinium Bromide (5b)
Anal. Calcd for C21H27NO5: C, 67.54; H, 7.29; N, 3.75. Found: C, 67.06;
H, 7.58; N, 3.84.
Prepared from 2 (71.1 g, 0.28 mol), 3b (0.28 mol, prepared from 27.9
g of 4-pyranone), and DIPEA (3.6 g, 4.8 mL, 0.028 mol) in MeCN (400
mL); yield: 52.0 g (47%); yellowish powder; mp 185–186 °C.
7-endo-9-Oxo-3-oxabicyclo[3.3.1]nonane-7-carboxylic Acid Ben-
zyl Ester (6b)
IR (KBr): 2929, 2752 (CH), 1729 (C=O), 1692 (C=N+),1448, 1234, 1190
Prepared from 5b (52.0 g, 0.129 mol) in a mixture of H2O/MTBE (1:5,
180 mL); yield: 35.4 g (quant); yellowish powder; mp 64–65 °C.
cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 7.39–7.34 (m, 5 Harom), 5.09 (s,
PhCH2, 2 H), 4.04 [m, N+(CH2)2, 4 H], 3.96 (d, J = 11 Hz, 2,4-H, 2 H), 3.86
(d, J = 11 Hz, 2,4-H, 2 H), 3.11 (s, 1,5-H, 2 H), 2.75 (m, 6,8-H + 7-H, 3
H), 2.39 (m, 6,8-H, 2 H), 2.07 [m, (CH2)2, 4 H].
13C NMR (124.9 MHz, DMSO-d6): δ = 189.1, 171.9, 136.3, 128.6, 128.1,
128.0, 71.9, 65.9, 53.6, 36.2, 32.1, 23.9.
IR (KBr): 3035, 2962, 2858 (CH), 1729 (C=O), 1448, 1312, 1234, 1189
cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.36 (m, 5 Harom), 5.14 (s, PhCH2, 2 H),
4.15 (d, J = 11.5 Hz, 2,4-H, 2 H), 3.68 (d, J = 11.5 Hz, 2,4-H, 2 H), 2.97
(d, J = 14 Hz, 6,8-H, 2 H), 2.63 (t, J = 7.5 Hz, 7-H, 1 H), 2.32 (br s, 1,5-H,
2 H), 2.20 (dt, J = 17, 7.5 Hz, 6,8-H, 2 H).
13C NMR (124.9 MHz, CDCl3): δ = 213.5, 172.0, 135.7, 128.1, 128.0,
127.8, 73.6, 66.3, 48.1, 36.9, 32.6.
Anal. Calcd for C20H26BrNO3: C, 58.83; H, 6.42; N, 3.43. Found: C,
58.76; H, 6.33; N, 3.16.
LC-MS (CI, + scan): m/z = 275.2 (M + 1).
7-endo-1-(7-Benzyloxycarbonyl-3-thiabicyclo[3.3.1]non-9-
ylidene)pyrrolidinium Bromide (5c)
Anal. Calcd for C16H18O4: C, 70.06; H, 6.61. Found: C, 70.44; H, 6.75.
Prepared from 2 (36.68 g, 0.144 mol), 3c (0.144 mol, prepared from
16.7 g of 4-thiapyranone), and DIPEA (1.86 g, 2.5 mL, 0.014 mol) in
MeCN (180 mL); yield: 39.0 g (64%); white flakes; mp 191–194 °C.
7-endo-9-Oxo-3-thiabicyclo[3.3.1]nonane-7-carboxylic Acid Ben-
zyl Ester (6c)
Prepared from 5c (39.0 g, 0.092 mol) in a mixture of H2O/MTBE (1:5;
180 mL); yield: 26.7 g (quant); yellow powder; mp 71–72.5 °C.
IR (KBr): 2980, 2755 (CH), 1714 (C=O), 1688 (C=N+), 1432, 1319, 1168
cm–1
.
IR (KBr): 3033, 2940, 2909 (CH), 1714 (C=O), 1432, 1319, 1168 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 7.37 (m, 5 Harom), 5.12 (s, PhCH2, 2
H), 4.20 and 3.91 [2 m, N+(CH2)2, 2 H and 2 H], 3.68 (m, 1,5-H, 2 H),
3.36 (d, J = 13.0 Hz, 2,4-H, 2 H), 2.79 (d, J = 13.0 Hz, 2,4-H, 2 H), 2.61
(m, 7-H, 1 H), 2.40 (m, 6,8-H, 2 H), 2.24 (m, 6,8-H, 2 H), 2.04 [m,
(CH2)2, 4 H].
13C NMR (124.9 MHz, DMSO-d6): δ = 192.6, 173.2, 136.1, 128.6, 128.1,
127.9, 65.9, 54.4, 127.9, 38.3, 38.0, 36.6, 31.1, 24.0.
1H NMR (500 MHz, CDCl3): δ = 7.34 (m, 5 Harom), 5.14 (s, PhCH2, 2 H),
3.20 (d, J = 12 Hz, 6,8-H, 2 H), 2.76 (m, 1,5-H, 2 H), 2.5–2.7 (m, 6,8-H +
2,4-H, 4 H), 2.40 (m, 7-H + 2,4-H, 3 H).
13C NMR (124.9 MHz, CDCl3): δ = 216.7, 173.1, 135.4, 128.2, 127.9,
127.7, 66.13, 44.6, 39.3, 37.1, 30.8.
LC-MS (CI, + scan): m/z = 291.2 (M + 1), 313.2 (M + Na).
Anal. Calcd for C16H18O3S: C, 66.18; H, 6.25, S, 11.04. Found: C, 66.53;
H, 6.55, S, 11.42.
Anal. Calcd for C20H26BrNO2S: C, 56.60; H, 6.18; N, 3.30; S, 7.56.
Found: C, 56.25; H, 6.01; N, 2.98; S, 7.18.
OBn Deprotection of Compounds 6a,b; General Procedure
Hydrolysis of the Iminium Salts 5a–c; General Procedure
The respective keto ester 6a,b was dissolved in THF under an argon
atmosphere. Pd/C (10%) was added, the flask was charged with H2 gas
and the content was shaken under H2 (1 atm) for 8 h. After no starting
material was left in the mixture (TLC, eluent: hexane–EtOAc, 1:1), the
catalyst was filtered off, washed with warm MeOH (50 mL), and the
filtrate was evaporated on a rotary evaporator by keeping the tem-
perature not higher that 80 °C in the bath for 1a (the Boc protection
might cleave off at higher temperatures). The products were suffi-
ciently pure for the further transformations. They were crystallized
from MeOH for analytical purpose.
The iminium salts 5a–c were hydrolyzed in a mixture H2O/MTBE (4:1,
5 L in the case of 5a and 1:5, 180 mL in the case of 5b,c) under vigor-
ous stirring for 1 h. The organic layer was separated, and the aqueous
layer was extracted with MTBE (3 × 200 mL). The combined extracts
and the organic layer were dried (Na2SO4) and evaporated on a rotary
evaporator. The obtained compounds 6a–c (quantitative yields) were
used for the next step without further purification. They were crys-
tallized for analytical purpose from cold MTBE.
7-endo-9-Oxo-3-azabicyclo[3.3.1]nonane-3,7-dicarboxylic Acid 7-
Benzyl Ester 3-tert-Butyl Ester (6a)
7-endo-9-Oxo-3-azabicyclo[3.3.1]nonane-3,7-dicarboxylic Acid 3-
tert-Butyl Ester (1a)
Prepared from 5a (101.5 g, 0.2 mol) in a mixture of H2O/MTBE (4:1; 5
L); yield: 74.0 g (quant); white crystals; mp 95–97 °C.
Prepared from 6a (74 g, 0.2 mol) in THF (500 mL) in the presence of
10% Pd/C catalyst (27 g); yield: 55.0 g (98%); white crystals; mp
126 °C.
IR (KBr): 2981, 2858 (CH), 1729 (C=O), 1688 (C=O), 1437, 1389, 1365,
1231, 1162 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 7.37 (m, 5 Harom), 5.09 (s, PhCH2, 2
H), 4.16 (br s, 2,4-H, 2 H), 3.04 (br s, 2,4-H, 2 H), 2.43 (m, 3 H), 2.34 (m,
2 H), 2.18 (m, 2 H), 1.42 (s, t-C4H9, 9 H).
13C NMR (124.9 MHz, DMSO-d6): δ = 215.4, 173.3, 155.4, 136.6, 128.9,
128.5, 128.2, 80.1, 66.2, 51.4 (br), 50.2 (br), 45.0, 36.9, 32.2, 28.4.
IR (KBr): 2992, 2833 (CH), 1708 (C=O), 1436, 1392, 1368, 1222, 1174
cm–1
.
1H NMR (500 MHz, CDCl3): δ = 4.34 (br s, 2 H), 3.07 (d, J = 9.3 Hz, 2 H),
2.50 (s, 2 H), 2.43–2.37 (5 H), 1.48 (s, 9 H).
13C NMR (124.9 MHz, CDCl3): δ = 215.3, 177.5, 155.2, 80.6, 50.9 (br),
44.5, 36.4, 31.6, 27.9.
LC-MS (CI, + scan): m/z = 274.2 (M – Boc + 1), 336.1, 374.1 (M + 1),
397.1 (M + Na), 414.1 (M + 39).
LC-MS (CI, – scan): m/z = 282.1 (M – 1).
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Anal. Calcd for C14H21NO5: C, 59.35; H, 7.47; N, 4.94. Found: C, 59.39;
H, 7.44; N, 4.93.
13C NMR (124.9 MHz, CDCl3): δ = 174.4 (C=O), 135.7, 128.2, 127.7,
127.6 (arom), 95.8 (spiro-C), 65.9, 59.2, 54.5, 32.7, 31.1, 25.0, 24.3.
LC-MS (CI, + scan): m/z = 273.2, 381.2 (M + 1).
7-endo-9-Oxo-3-oxabicyclo[3.3.1]nonane-7-carboxylic Acid (1b)
Anal. Calcd for C19H24O6S: C, 59.98; H, 6.36, S, 8.43. Found: C, 59.94; H,
6.38, S, 8.45.
Prepared from 6b (35.4 g, 0.129 mol) in THF (400 mL) in the presence
of 10% Pd/C catalyst (15 g); yield: 21.9 g (92%); white powder; mp
191 °C.
IR (KBr): 3021, 2941, 2854 (CH), 1712 (C=O), 1443, 1313, 1135 cm–1
7-endo-9-Oxo-3-thiabicyclo[3.3.1]nonane-7-carboxylic Acid 3,3-
Dioxide (1d)
.
1H NMR (500 MHz, CDCl3): δ = 11.74 (br s, CO2H, 1 H), 4.27 (d, J = 10.5
Hz, 2,4-H, 2 H), 3.73 (d, J = 10.5 Hz, 2,4-H, 2 H), 2.95 (d, J = 14.0 Hz,
6,8-H, 2 H), 2.66 (t, J = 6.0 Hz, 7-H, 1 H), 2.36 (s, 1,5-H, 2 H), 2.22 (dd,
J = 6.0, 14.0 Hz, 6,8-H, 2 H).
13C NMR (124.9 MHz, CDCl3): δ = 213.6 (C=O), 178.2 (CO2H), 73.6,
48.0, 36.8, 32.4.
Compound 8d (9.04 g, 23.8 mmol) was dissolved in MeOH (50 mL),
the solution was combined with 10% Pd/C (3 g), and hydrogenated (1
atm H2) for 8 h. The catalyst was filtered off, washed several times
with warm MeOH (50 mL), and the filtrate was evaporated to obtain
7′-endo-spiro[1,3-dioxane-2,9′-[3]thiabicyclo[3.3.1]nonane]-7′-carbox-
ylic acid 3′,3′-dioxide (6.9 g, quant), sufficiently pure for the next
transformations (contained residual MeOH, <3 mol%).
1H NMR (500 MHz, CDCl3): δ = 3.88 (m, OCH2, 4 H), 3.23 (d, J = 13.0
Hz, 2,4-H, 2 H), 2.99 (d, J = 13.0 Hz, 2,4-H, 2 H), 2,92 (d, J = 10.0 Hz,
1,5-H, 2 H), 2.82 (tt, J = 8.0, 11.0 Hz, 7-H, 1 H), 2.19 (m, 6,8-H, 2 H),
2.10 (m, 6,8-H, 2 H), 1.64 (m, CH2CH2CH2, 2 H).
LC-MS (CI, – scan): m/z = 183.0 (M – 1).
Anal. Calcd for C9H12O4: C, 58.69; H, 6.57. Found: C, 58.66; H, 6.60.
Benzyl 7′-endo-Spiro[1,3-dioxane-2,9′-[3]thiabicyclo[3.3.1]non-
ane]-7′-carboxylate (7c)20
13C NMR (124.9 MHz, CDCl3): δ = 176.5 (CO2H), 96.1 (OCO), 59.2, 59.0,
Compound 6c (11.13 g, 38.3 mmol) and 1,3-bis(trimethylsilyloxypro-
pane) (10.14 g, 46 mmol) were dissolved in anhydrous CH2Cl2 (90 mL)
under an argon atmosphere. The solution was cooled to –78 °C (ace-
tone/dry ice bath) and then trimethylsilyl triflate (0.5 g, 2 mmol) was
added under stirring. The cooling bath was not removed; no more dry
ice was added to it, and the mixture was stirred until the internal
temperature became around 0 °C (it took approximately 3 h). Sat. aq
NaHCO3 (90 mL) was added, the mixture was stirred vigorously for 1 h
at r.t., then the organic layer was separated, and the aqueous layer
was extracted with CH2Cl2 (3 × 100 mL). The combined organic layer
and extracts were dried (Na2SO4), the solvent was evaporated, and the
residue was kept at 100 °C under vacuum (0.2 mm Hg). The obtained
compound 7c (quant) was sufficiently pure for the next transforma-
tions; yield: 14.0 g (quant); colorless oil; crystallized on standing; mp
82 °C.
1H NMR (500 MHz, CDCl3): δ = 7.35 (m, 5 Harom), 5.11 (s, PhCH2, 2 H),
3.88 [m, O(CH2)2, 4 H], 3.24 (d, J = 12 Hz, 6′,8′-H, 2 H), 2.72 (m, 1 H),
2.48 (m, 2 H), 2.43 (m, 4 H), 2.25 (d, J = 12 Hz, 2 H), 2.19 (m, 2 H), 1.71
(m, 2 H).
13C NMR (124.9 MHz, CDCl3): δ = 174.4 (C=O), 136.0, 128.1, 127.8,
127.6 (arom), 96.3 (spiro-C), 66.1, 58.1, 57.7, 35.6, 31.5, 30.4, 26.4,
24.8.
54.7, 32.6, 30.8, 25.3, 24.4).
This intermediate compound was suspended in concd HCl (100 mL),
and set to a gentle reflux under stirring. The starting carboxylic acid
dissolved first, then the product 1d started to precipitate. After 2 h of
the reflux, the reaction mixture was cooled in an ice bath, filtered,
and the product was washed thoroughly on the filter with cold H2O (5
× 30 mL), dried at 50 °C under vacuum (0.2 mmHg) for 5 h to afford
1d; yield: 4.5 g (83%); white crystals; mp 286–287 °C.
IR (KBr): 3028, 2944 (CH), 1705 (C=O), 1412, 1325 (S=O), 1319, 1140
cm–1 (S=O).
1H NMR (400.4 MHz, DMSO-d6): δ = 3.68 (dd, J = 5.2, 14.4 Hz, 2,4-H, 2
H), 3.56 (d, J = 14.4 Hz, 2,4-H, 2 H), 2.83 (m, 1,5-H, 2 H), 2.76 (pent, J =
13.2 Hz, 6,8-H, 2 H), 2.32 (m, 6,8-H + 7-H, 3 H).
13C NMR (100.4 MHz, DMSO-d6): δ = 211.4 (C=O), 175.0 (CO2H), 56.0,
41.3, 35.3, 30.3.
LC-MS (CI, – scan): m/z = 231.2 (M – 1).
Anal. Calcd for C12H18O6S: C, 49.64; H, 6.25, S, 11.04. Found: C, 49.66;
H, 6.28, S, 11.00.
Curtius Rearrangement of Compound 1a;21 tert-Butyl 7-endo-7-
{[(Benzyloxy)carbonyl]amino}-9-oxo-3-azabicyclo[3.3.1]nonane-
3-carboxylate (1e)
GC-MS (EI): m/z (%) = 348 (M+, 25), 113 (100), 91 (88), 55 (30).
LC-MS (CI, + scan): m/z (%) = 371.1 (M + Na, 77), 349.2 (M + 1, 100).
A mixture of the keto acid 1a (55.0 g, 0.194 mol), DPPA (64.1 g, 50.2
mL, 0.233 mol), and DIPEA (diphenyl phosphoryl azide; 30.1 g, 40.57
mL, 0.233 mol) in anhydrous benzene (500 mL) was stirred at r.t. for
0.5 h, and then refluxed for another 0.5 h. Benzyl alcohol (25.19 g,
24.1 mL, 0.233 mol) was added to the reaction mixture and the reflux
continued for another 17 h. The mixture was cooled, washed with 5%
aq citric acid (2 × 100 mL), sat. aq NaHCO3 (100 mL), H2O (100 mL),
and brine (100 mL). The organic layer was dried (Na2SO4) and evapo-
rated. The residue was crystallized from MTBE–benzene mixure
(1:10) to obtain the pure product 1e; yield: 53.0 g (70%); white crys-
tals; mp 136 °C.
Benzyl 7′-endo-Spiro[1,3-dioxane-2,9′-[3]thiabicyclo[3.3.1]non-
ane]-7′-carboxylate 3′,3′-Dioxide (8d)
Compound 7c (11.68 g, 34 mmol) was dissolved in CH2Cl2 (50 mL),
and the solution was cooled in an ice bath (1–5 °C internal temp). m-
Chloroperbenzoic acid (17.3 g, 100 mmol) in CH2Cl2 (50 mL) was add-
ed to the solution under stirring. The cooling bath was removed and
the mixture was stirred for 8 h at r.t. The reaction mixture was
washed with sat. aq Na2SO3 (5 × 50 mL), dried (Na2SO4), and evaporat-
ed. The residue was recrystallized from benzene to afford 8d; yield:
11 g (85%); white crystals; mp 134–135 °C.
1H NMR (500 MHz CDCl3): δ = 7.35 (m, 5 Harom), 5.11 (s, PhCH2, 2 H),
3.90 [m, O(CH2)2, 4 H], 3.47 (d, J = 12 Hz, 6′,8′-H, 2 H), 3.12 (m, 1 H),
2.91 (m, 4 H), 2.51 (t, J = 12 Hz, 2 H), 2.33 (m, 2 H), 1.77 (m, 2 H).
1H NMR (500 MHz, CDCl3): δ = 7.36–7.30 (5 Harom), 5.07 (s, PhCH2, 2
H), 4.71 (s, 1 H), 4.32 (d, J = 10.2 Hz, 2 H), 3.62 (s, 1 H), 3.02 (d, J = 12.3
Hz, 2 H), 2.5–2.4 (m, 4 H), 1.77 (t, J = 10.2 Hz, 2 H), 1.49 (s, 9 H, t-
C4H9).
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13C NMR (124.9 MHz, CDCl3): δ = 214.5, 155.3, 154.9, 135.9, 128.2,
127.9, 80.1, 66.5, 51.3, 44.5, 43.9, 35.3, 28.0.
and the residue was kept in vacuum at 75 °C. The obtained oximes
(light yellow solids; quantitative chemical yields) were used in the
next step without further purification.
LC-MS (CI, + scan): m/z = 289.0 (M – Boc + 1), 411.0 (M + Na).
Anal. Calcd for C21H28N2O5: C, 64.93; H, 7.27; N, 7.21. Found: C, 64.95;
H, 7.23; N, 7.25.
tert-Butyl 7-endo-7-(Benzyloxycarbonyl)-9-(hydroxyimino)-
3-azabicyclo[3.3.1]nonane-3-carboxylate
1H NMR (500 MHz, CDCl3): δ = 9.24 (s, NOH, 1 H), 7.32 (m, 5 Harom),
5.06 (s, OCH2, 2 H), 4.86 (d, J = 8.0 Hz, NH, 1 H), 4.12 (m, 2,4-H, 2 H),
3.68 [d, J = 8.5 Hz, 1(5)-H, 1 H], 3.58 (br s, 7-H, 1 H), 2.86 (m, 2,4-H, 2
H), 2.64 [d, J = 8.5 Hz, 5(1)-H, 1 H], 2.37 (m, 6,8-H, 2 H), 1.46 (m, t-
C4H9 + 6,8-H, 11 H).
13C NMR (124.9 MHz, CDCl3): δ = 159.8, 155.7, 155.3, 136.0, 128.2,
127.9, 127.8, 80.12, 66.4, 51.2 (br), 49.5 (br), 44.2, 34.7, 34.6, 33.9,
28.0, 27.6.
Curtius Rearrangement of Compounds 1b,d;21 General Procedure
A mixture of the keto acid 1b or 1d (1 equiv), DPPA (1 equiv), Et3N
(1.05 equiv), and freshly distilled t-BuOH (32 equiv) was refluxed for
18 h, and then evaporated. The residue was taken up in benzene (200
mL), washed with sat. aq NaHCO3 (4 × 50 mL), H2O (50 mL) and brine
(50 mL), dried (Na2SO4), and evaporated. The products were crystal-
lized from benzene to obtain the pure product 1f or 1g as white crys-
tals.
tert-Butyl 7-endo-9-(Hydroxyimino)-3-oxabicyclo[3.3.1]nonan-7-
ylcarbamate
1H NMR (500 MHz CDCl3): δ = 9.05 (s, NOH, 1 H), 6.69 (d, J = 10.5 Hz,
NH, 1 H), 3.90–4.20 (m, 2,4-H + 7-H, 3 H), 3.71 and 3.68 (2 d, J = 11.5
Hz, 2,4-H, 2 H), 3.43 [s, 1(5)-H, 1 H], 2.43 [s, 5(1)-H, 1 H], 2.27 (m, 6,8-
H, 2 H), 1.93 and 1.90 (2 d, J = 14 Hz, 6,8-H, 2 H), 1.44 (s, t-C4H9, 9 H).
7-endo-7-{[(tert-Butyloxy)carbonyl]amino}-9-oxo-3-oxabicy-
clo[3.3.1]nonane (1f)
Prepared from 1b (52.7 g, 0.29 mol), DPPA (78.74 g, 61.66 mL, 0.29
mol), and Et3N (30.4 g, 41.8 mL, 0.3 mol) in t-BuOH (860 mL); yield:
33 g (45%); mp 154 °C.
1H NMR (500 MHz, CDCl3): δ = 6.61 (d, J = 9 Hz, NH, 1 H), 4.19 (br d, J =
11.5 Hz,, 2,4-H, 2 H), 4.03 (br s, 7-H, 1 H), 3.83 (d, J = 9 Hz, NH, 1 H),
2.47 (m, 6,8-H, 2 H), 2.39 (s, 1,5-H, 2 H), 2.13 (d, J = 14.5 Hz, 6,8-H, 2
H), 1.45 (s, t-C4H9, 9 H).
13C NMR (124.9 MHz, CDCl3): δ = 160.4, 155.3, 78.6, 72.8, 71.3, 41.26,
37.9, 36.8, 36.5, 30.6, 28.1.
tert-Butyl 7-endo-9-(Hydroxyimino)-3,3-dioxido-3-thiabicy-
clo[3.3.1]nonan-7-ylcarbamate
1H NMR (500 MHz, DMSO-d6): δ = 11.09 (s, NOH, 1 H), 6.97 (br s, NH,
1 H), 3.99 (m, 7-H, 1 H), 3.25 [m overlapped with H2O residual signal,
2,4-H + 1(5)-H, 3 H], 3.11 [m, 2,4-H + 5(1)-H, 3 H], 2.17 and 2.03 (m, 3
H and 1 H, 6,8-CH2), 1.34 (s, t-Bu-H, 9 H).
13C NMR (124.9 MHz, CDCl3): δ = 213.3, 155.1, 78.8, 73.4, 47.9, 40.8,
38.8, 28.1.
LC-MS (CI, + scan): m/z = 200.1 (M – t-Bu + 1), 278.1 (M + Na), 296.1
(M + Na + H2O).
Anal. Calcd for C13H21NO4: C, 61.16; H, 8.29; N, 5.49. Found: C, 61.55;
H, 8.61; N, 5.58.
13C NMR (124.9 MHz, DMSO-d6): δ = 155.0, 154.5, 77.7, 58.4, 56.6,
44.2, 33.3, 31.07, 30.0, 28.3, 25.0).
tert-Butyl 7-endo-(3,3-Dioxido-9-oxo-3-thiabicyclo[3.3.1]non-7-
The oximes obtained as described above were hydrogenated in an au-
toclave at 40 atm of H2 and r.t. in a 10% ammonia solution in MeOH in
the presence of a freshly prepared Raney Ni (~10% of the weight of the
substrate). The progress of the reaction was monitored by TLC (elu-
ent: hexane–EtOAc, 1:2). After the disappearance of the starting ox-
ime (~8 h), the mixture was filtered through a silica gel pad, and
evaporated on a rotary evaporator. The residue was dissolved in MTBE
(100 mL) and the solution was washed with H2O (50 mL). The organic
layer was then dried (Na2SO4) and evaporated on a rotary evaporator,
keeping the bath temperature not higher than 50 °C. Glassy colourless
solids, 88–93% yield.
yl)carbamate (1g)
Prepared from 1d (21.3 g, 0.092 mol), DPPA (25.24 g, 19.76 mL, 0.092
mol), and Et3N (9.74 g, 13.4 mL, 0.096 mol) in t-BuOH (275 mL); yield:
12.0 g (43%); mp 213–214 °C.
1H NMR (500 MHz, CDCl3): δ = 4.59 (br s, NH, 1 H), 3.67 (br s, 7-H, 1
H), 3.55 (d, J = 14 Hz, 2,4-H, 2 H), 3.36 (d, J = 14 Hz, 2,4-H, 2 H), 2.95 (d,
J = 9.5 Hz, 1,5-H, 2 H), 2.72 (pent, J = 12.5 Hz, 6,8-H, 2 H), 2.49 (dd, J =
12.5, 9.5 Hz, 6,8-H, 2 H), 1.42 (s, t-C4H9, 9 H).
13C NMR (124.9 MHz, CDCl3): δ = 210.2 (C=O), 154.5 (NHCO), 79.6
[C(CH3)3], 57.9, 42.8, 41.2, 32.2, 28.0.
LC-MS (CI, + scan): m/z = 248.2 (M – t-Bu + 1).
tert-Butyl 7-endo-9-Amino-7-{[(benzyloxy)carbonyl]amino}-
3-azabicyclo[3.3.1]nonane-3-carboxylate (1h, mixture of epimers)
Anal. Calcd for C13H21NO5S: C, 51.47; H, 6.98; N, 4.62; S, 10.57. Found:
C, 51.44; H, 6.99; N, 4.66; S, 10.55.
The oxime was prepared from 1e (16.0 g, 0.039 mol) in EtOH (50 mL),
combined with a solution of NH2OH·HCl (3.75 g, 0.054 mol) and
NaHCO3 (4.54 g, 0.054 mol) in H2O (50 mL). The oxime obtained (16 g)
was hydrogenated in a 10% ammonia solution in MeOH (100 mL) to
give 1h; yield: 13.5 g (0.035 mol, 89%); glassy solid.
1H NMR (500 MHz, CDCl3): δ = 7.25 (m, 5 Harom), 5.48 (t, J = 12 Hz, NH,
1 H), 4.97 (s, OCH2, 2 H), 3.99 (br s, 0.5 H), 3.90 (br s, 0.5 H), 3.81 (d, J =
13 Hz, 1 H), 3.51 (d, J = 12.5 Hz, 1 H), 3.27 (d, J = 12.5 Hz, 1 H), 2.93 (m,
2 H), 2.31 (m, 1 H), 2.03 (m, 1 H), 1.72 (m, 2 H), 1.65 (d, J = 13 Hz, 1 H),
1.38 (m, 2 H), 1.30 (s, t-C4H9, 9 H), 1.14 (br m, 2 H).
Reductive Amination of Compounds 1e, 1f, and 1g; General Proce-
dure
A suspension of the carbonyl compound 1e, 1f, or 1g (1 equiv) in
EtOH (50 mL) was combined with a solution of NH2OH, separately
prepared by neutralization of an aqueous solution of NH2OH·HCl (1.4
equiv) with NaHCO3 (1.4 equiv). The mixture was refluxed for 3 h.
Then, the mixture was evaporated to half the volume on a rotary
evaporator, diluted with brine (100 mL), and the product (in the case
of 1e,f) was extracted with MTBE (4 × 70 mL) or filtered (in the case of
1g). The combined organic extracts were dried (Na2SO4), evaporated,
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13C NMR (124.9 MHz, CDCl3): δ = 156.1, 156.0, 155.4, 155.3, 136.3,
136.2, 127.92, 127.90, 127.86, 127.80, 127.77, 127.5, 127.4, 80.0, 79.7,
65.95, 65.9, 50.1, 49.1, 48.4, 42.0, 41.93, 41.92, 41.3, 41.1, 35.9, 33.1,
33.0, 28.8, 28.0, 27.8.
1H NMR (500 MHz, DMSO-d6): δ = 10.4 (s, NH, 1 H), 7.74 (d, J = 8 Hz,
o-Ts, 2 H), 7.38 (m, 7 Harom), 5.04 (s, PhCH2, 2 H), 3.97 (br s, 2,4-H, 2 H),
3.25 (s, 1 H), 2.74 (br s, 2,4-H, 2 H), 2.42 (s, 1 H), 2.36 (s, CH3, 3 H),
2.08 (m, 3 H), 1.88 (m, 2 H), 1.38, (s, t-C4H9, 9 H).
LC-MS (CI, + scan): m/z = 290.1 (M – Boc + 1).
13C NMR (124.9 MHz, DMSO-d6): δ = 173.5, 164.2, 155.5, 143.6, 136.8,
136.6, 129.9, 128.9, 128.5, 128.3, 127.9, 79.8, 66.1, 51.4 (br), 50.6 (br),
49.9 (br), 49.0 (br), 37.6, 37.2, 31.6, 31.4, 30.8, 28.5, 21.5.
Anal. Calcd for C21H31N3O4: C, 64.76; H, 8.02; N, 10.79. Found: C,
64.72; H, 8.06; N, 10.76.
LC-MS (CI, + scan): m/z = 542.1 (M + 1).
LC-MS (CI, – scan): m/z = 540.2 (M – 1).
7-endo-(9-Amino-3-oxabicyclo[3.3.1]non-7-yl)carbamic Acid tert-
Butyl Ester (1i, mixture of epimers)
The obtained p-tolylsulfonylhydrazone (33.7 g, 62.2 mmol) and
NaBH3CN (7.82 g, 124.4 mmol) were dissolved in anhydrous MeOH
(300 mL) in a 1 L round-bottomed flask under argon. The mixture was
cooled to –10 °C (dry ice/acetone bath). AcCl (4.88 g, 4.42 mL, 62.2
mmol) was added to the mixture at a rate by keeping the temperature
not higher than 0 °C under stirring. The stirring was continued for 1 h
at 0 °C, then NaOAc·3H2O (84 g, 622 mmol) and MeOH (300 mL) were
added, and the mixture was refluxed for 3 h. The mixture was then
evaporated on a rotary evaporator, H2O (200 mL) was added to the
residue, and the product 9a was extracted with MTBE (4 × 300 mL).
The combined organic extracts were dried (Na2SO4) and evaporated in
vacuum; yield: 22.4 g (quant); white crystals. The product 9a was
crystallized from MTBE for analytical purpose; white crystals; mp
97–100 °C.
The oxime was prepared from 1f (13.3 g, 0.052 mol) in EtOH (50 mL),
combined with a solution of NH2OH·HCl (5.06 g, 0.073 mol) and
NaHCO3 (6.12 g, 0.073 mol) in H2O (50 mL). The oxime obtained (13.1
g) was hydrogenated in a 10% ammonia solution in MeOH (100 mL) to
give 1i; yield: 10.0 g (0.039 mol, 75%); glassy colourless solid.
1H NMR (500 MHz, CDCl3): δ = 7.00 and 6.89 (2 d, J = 10.0 Hz, NH, 0.5
H and 0.5 H), 4.12 and 3.95 (2 d, J = 11.0 Hz, 2,4-H, 1 H and 1 H), 4.02
(m, 7-H, 1 H), 3.67 and 3.62 (2 d, J = 11.0 Hz, 2,4-H, 1 H and 1 H), 3.08
(s, 9-H, 0.5 H), 2.94 (s, 9-H, 0.5 H), 2.34 [m, 6(8)-H, 1 H], 2.11 [m, 6(8)-
H, 1 H], 1.83 [d, J = 14 Hz, 6(8)-H, 1 H], 1.61 [s, 1(5)-H, 1 H], 0.75–1.55
[overlapped m, 6(8)-H, 5(1)-H, NH2, t-C4H9, 13 H].
13C NMR (124.9 MHz, CDCl3): δ = 155.5, 155.4, 78.1, 71.7, 64.3, 50.2,
49.8, 40.5, 40.2, 36.8, 35.0, 34.9, 28.8, 28.2.
IR (KBr): 2976, 2909, 2860 (CH), 1720 (C=O), 1689 (C=O), 1455, 1394,
LC-MS (CI, + scan): m/z = 157.2 (M – Boc + 1), 200.1 (M – t-Bu + 1),
279.1 (M + Na).
1318, 1181 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 7.45–7.30 (m, 5 Harom), 5.02 (s,
PhCH2, 2 H), 3.78 (d, J = 12 Hz, 2,4-H, 2 H), 2.79 (d, J = 12 Hz, 2,4-H, 2
H), 2.59 (m, 1 H), 2.01 (m, 2 H), 1.93 (m, 4 H), 1.63 (d, J = 12 Hz, 9-H, 1
H), 1.40 (m, t-C4H9 + 9-H, 10 H).
13C NMR (124.9 MHz, DMSO-d6): δ = 174.0, 156.0, 136.9, 128.9, 128.3,
128.2, 78.9, 65.9, 49.9 (br), 49.0 (br), 36.3, 30.2, 29.7, 28.6, 26.5.
Anal. Calcd for C13H24N2O3: C, 60.91; H, 9.44; N, 10.93. Found: C,
60.95; H, 9.47; N, 10.90.
7-endo-(9-Amino-3,3-dioxo-3-thiabicyclo[3.3.1]non-7-yl)carbam-
ic Acid tert-Butyl Ester (1j; mixture of epimers)
The oxime was prepared from 1g (11.69 g, 0.039 mol) in EtOH (50
mL), combined with a solution of NH2OH·HCl (3.75 g, 0.054 mol) and
NaHCO3 (4.54 g, 0.054 mol) in H2O (50 mL). The oxime obtained (11.5
g) was hydrogenated in a 10% ammonia solution in MeOH (400 mL) to
give 1j; yield: 9.0 g (0.03 mol, 76%); glassy colourless solid.
LC-MS (CI, + scan): m/z = 304.2 (M – t-Bu + 2).
Anal. Calcd for C21H29NO4: C, 70.17; H, 8.13; N, 3.90. Found: C, 70.48;
H, 8.02; N, 4.08.
1H NMR (500 MHz, CDCl3): δ = 4.66 (m, 7-H, 0.86 H), 4.58 (d, J = 8.5
Hz, NH, 0.59 H), 4.52 (d, J = 11 Hz, NH, 0.19 H), 3.70 (d, J = 13 Hz, 2,4-
H, 0.36 H), 3.48 (t, J = 3 Hz, 9-H, 0.19 H), 3.22 (d, J = 13 Hz and br m,
2.17 H), 3.01 (d, J = 13 Hz, 2,4-H, 1.54 H), 2.69 (d, J = 13 Hz, 2,8-H, 0.36
H), 2.49 (m, 1.78 H), 2.21–2.40 (m, 1.93 H), 1.95 (t, J = 13 Hz, 0.46 H),
1.75–1.82 (m, 3.22 H), 1.38 (s, t-C4H9, 9 H).
7-endo-3-(tert-Butoxycarbonyl)-3-azabicyclo[3.3.1]nonane-7-car-
boxylic Acid (1k)
This compound was obtained by the hydrogentaion of 9a (5.0 g, 0.014
mol) in THF (50 mL) in the presence of 10% Pd/C (1.0 g) as a catalyst,
as described above for 6a,b; yield: 3.67 g (98%); white crystals; mp
145–146 °C.
13C NMR (124.9 MHz, CDCl3): δ = 155.1, 154.9, 78.9, 78.7, 57.9, 51.5,
51.4, 42.5, 40.9, 39.6, 33.2, 29.9, 29.2, 28.0.
IR (KBr): 3223 (OH), 2944, 2872 (CH), 1732 (C=O), 1647 (C=O), 1443,
1371, 1250, 1168 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 11.56 (br s, CO2H, 1 H), 3.77 (br s,
2,4-H, 2 H), 2.78 and 2.65 (br s, 2,4-H, 2 H), 2.38 (br s, 1 H), 1.93 (br m,
4 H), 1.60–1.70 (m, 3 H), 1.39 (s, t-C4H9, 9 H), 1.30 (d, J = 13 Hz, 9-H, 1
H).
LC-MS (CI, + scan): m/z = 249.1 (M – t-Bu + 1).
Anal. Calcd for C13H24N2O4S: C, 51.29; H, 7.95; N, 9.20; S, 10.53.
Found: C, 51.33; H, 7.94; N, 9.22; S, 10.57.
Modified Caglioti Reaction; 7-Benzyl 3-tert-Butyl 7-endo-3-Azabi-
13C NMR (124.9 MHz, DMSO-d6): δ = 176.3, 155.6, 78.7, 50.6 (br), 49.6
cyclo[3.3.1]nonane-3,7-dicarboxylate (9a)
(br), 35.8, 29.2, 28.7, 28.6, 26.1.
The keto ester 6a (27 g, 78.6 mmol) and p-tolylsulfonylhydrazine (16
g, 86.4 mmol) were dissolved in anhydrous EtOH (80 mL) in a 250 mL
round-bottomed flask. The mixture was refluxed for 0.5 h, then left
standing at r.t. for 18 h. The crystalline precipitate was filtered,
washed with cold EtOH (20 mL), and dried in vacuum. The product, 7-
benzyl 3-tert-butyl 7-endo-9-{[(4-methylphenyl)sulfonyl]hydrazo-
no}-3-azabicyclo[3.3.1]nonane-3,7-dicarboxylate, proved to be suffi-
ciently pure for the further transformations; yield: 34.1 g (80%);
white crystals; mp 173 °C.
LC-MS (CI, – scan): m/z = 268.0 (M – 1).
Anal. Calcd for C14H23NO4: C, 62.43; H, 8.61; N, 5.20. Found: C, 62.32;
H, 8.89; N, 4.95.
7-endo-3-Azabicyclo[3.3.1]nonane-7-carboxylic Acid (10a)
The N-Boc-protected amino acid 1k (1 g, 3.7 mmol) was refluxed in
distilled H2O (70 mL) for 24 h. At the end of this period, all the insolu-
ble starting material was dissolved. The reaction mixture was evapo-
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375
A. Yu. Ishchenko et al.
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Synthesis
rated in vacuum, and the residue was kept in a dessicator over P2O5
for 24 h to give 10a; yield: 0.63 g (quant); yellow powder; mp >300 °C
(dec.).
Anal. Calcd for C14H23NO4: C, 62.43; H, 8.61; N, 5.20. Found: C, 62.40;
H, 8.66; N, 5.22.
7-exo-3-Azabicyclo[3.3.1]nonane-7-carboxylic Acid Hydrochloride
(11a·HCl)
IR (KBr): 3421 (NH), 2924 (CH), 1639 (C=O), 1552 (C=O), 1405, 1240
cm–1
.
1H NMR (500 MHz, D2O): δ = 3.13 (d, J = 12.5 Hz, 2,4-H, 2 H), 3.04 (dd,
J = 12.5, 2.5 Hz, 2,4-H, 2 H), 2.69 (tt, J = 10.0, 2.5 Hz, 7-H, 1 H), 2.16
(dd, J = 15.0, 10.0 Hz, 6,8e-H, 2 H), 2.11 (s, 1,5-H, 2 H), 1.70 (d, J = 15.0
Hz, 6,8a-H, 2 H), 1.62 (s, 9-CH2, 2 H).
13C NMR (124.9 MHz, D2O): δ = 187.6 (CO2H), 48.2, 36.3, 28.7, 27.6,
24.3.
Compound 1l (500 mg, 1.86 mmol) was dissolved in a 10% solution of
HCl in 1,4-dioxane (20 mL). The mixture was left standing for 1 h,
then cooled in an ice bath. The precipitate of 11a·HCl was filtered,
washed with anhydrous MTBE (20 mL) on the filter, and dried at 40 °C
in vacuum. The yield of the crude product was quantitative (382 mg).
Pure 11a·HCl for analytical purposes was obtained by crystallization
from H2O followed by drying at 40 °C in vacuum; white crystals; mp
>280 °C (dec.).
1H NMR (500 MHz, D2O): δ = 3.27 (d, J = 13.5 Hz, 2,4-H, 2 H), 3.18 (d,
J = 13.5 Hz, 2,4-H, 2 H), 2.87, (tt, J = 8, 12.5 Hz, 7-H, 1 H), 2.15 (s, 1,5-H,
2 H), 1.97 (d, J = 11 Hz, 6,8-H, 2 H), 1.62–1.83 (m, 6,8-H + 9-H, 3 H),
1.60 (d, J = 12.5 Hz, 9-H, 1 H).
Anal. Calcd for C9H15NO2: C, 63.88; H, 8.93; N, 8.28. Found: C, 63.59;
H, 8.87; N, 7.99.
X-ray Structure Determination22
Crystal data: C9H15NO2, M = 169.22, monoclinic, space group P21/c, а =
9.4108(13), b = 7.0766(7), c = 12.5232(15) Å, β = 93.129(6)°, V =
832.76(17) Å3, Z = 4, dc = 1.35 g·cm–3, μ = 0.095 mm–1, F(000) = 368,
crystal size ca. 0.42 × 0.29 × 0.25 mm. The measurements were per-
formed on a SMART APEX II diffractometer at room temperature us-
ing Mo-Kα radiation with the omega scans technique. Intensity data
of 7145 reflections were collected within range 2.17≤θ≤27.80° (1975
unique reflections Rmerg = 0.063). Data were corrected for Lorenz and
polarization effects. The structure was solved by direct methods and
refined by full-matrix least-squares technique in the anisotropic ap-
proximation for non-hydrogen atoms using SHELXS97 and SHELXL97
programs.23 All CH hydrogen atoms were placed at calculated posi-
tions and refined as ‘riding’ model, two NH hydrogen atoms were
found in difference Fourier map and refined isotropically. Conver-
gence was obtained at R1 = 0.0515 and wR2 = 0.1191, GOF = 1.035 for
1375 reflections with I ≥ 2σ(I) (117 parameters; observed/variable ra-
tio 11.7). The largest and minimal peaks in the final difference map
13C NMR (124.9 MHz, D2O): δ = 179.2 (CO2H), 46.9, 36.4, 30.5, 28.3,
24.7.
Anal. Calcd for C9H16ClNO2: C, 52.56; H, 7.84; N, 6.81. Found: C, 52.58;
H, 7.88; N, 6.80.
X-ray Structure Determination22
Crystal data: C9H18ClNO3, M=223.69, monoclinic, space group P21/n,
а = 8.5696(4), b = 11.8842(4), c = 10.6926(3) Å, β = 101.297(2)°, V =
1067.87(7) Å3, Z = 4, dc = 1.391 g·cm–3, μ = 0.341 mm–1, F(000) = 480,
crystal size is ca. 0.42 × 0.29 × 0.25 mm. The measurements were per-
formed on a SMART APEX II diffractometer at room temperature us-
ing Mo-Kα radiation with the omega scans technique. Intensity data
of 5223 reflections were collected within range 2.59≤θ≤26.37° (2175
unique reflections Rmerg = 0.0208). Data were corrected for Lorenz and
polarization effects. The structure was solved by direct methods and
refined by full-matrix least-squares technique in the anisotropic ap-
proximation for non-hydrogen atoms using SHELXS97 and SHELXL97
programs.23 Hydrogen atoms were found in difference Fourier maps
and refined isotropically. Convergence was obtained at R1 = 0.0350
and wR2 = 0.0857, GOF = 1.055 for 1835 reflections with I ≥ 2σ(I) (199
parameters; observed/variable ratio 9.22). The largest and minimal
peaks in the final difference map 0.48 and –0.19 e/Å3, weighting
scheme ω = 1/[ρ2(Fo2) + (0.041P)2 + 0.337Р], where Р = (Fo2 + 2Fc2)/3.
0.26 and –0.21 e/Å3, weighting scheme ω = 1/[ρ2(Fo2) + (0.0495P)2
0.3067Р], where Р = (Fo2 + 2Fc2)/3.
+
7-exo-3-(tert-Butoxycarbonyl)-3-azabicyclo[3.3.1]nonane-7-car-
boxylic Acid (1l)
Na (2.4 g, 0.104 mol) was dissolved in anhydrous MeOH (100 mL) un-
der an argon atmosphere. Compound 9a (2 g, 5.6 mmol) was added,
and the mixture was refluxed for 12 h (13C NMR control). H2O (50 mL)
was carefully added, and the reflux continued for 5 h. The mixture
was then evaporated to half the volume, washed with MTBE (2 × 50
mL), and acidified with concd aq citric acid till pH ~5. The precipitate
formed was filtered, washed with H2O (10 mL), and dried in air. The
crude product thus obtained contained compounds 1l and 1k in ~9:1
molar ratio; yield: 0.86 g (59%). Pure 1l was obtained from the crude
product by crystallization from a CH2Cl2–hexane mixture (3:1) as
white crystals; mp 138–140 °C.
Acknowledgment
Financial assistance from Enamine Ltd. (www.enamine.net) is grate-
fully acknowledged.
Supporting Information
IR (KBr): 3253 (OH), 2948, 2876 (CH), 1734 (C=O), 1646 (C=O), 1440,
1377, 1255, 1166 cm–1
.
Supporting information for this article is available online at
1H NMR (500 MHz, DMSO-d6): δ = 11.98 (br s, CO2H, 1 H), 3.93 (br m,
2,4-H, 2 H), 3.00 and 2.88 (br s, 2,4-H, 2 H), 2.75 (tt, J = 13.0, 5.0 Hz, 7-
H, 1 H), 1.88 (m, 4 H), 1.62 (m, 3 H), 1.53 (d, J = 14 Hz, 1 H), 1.39 (s, t-
C4H9, 9 H).
http://dx.doi.org/10.1055/s-0034-1379456.
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References
13C NMR (124.9 MHz, DMSO-d6): δ = 177.0 (CO2H), 154.2 (NC=O), 78.7
[C(CH3)3], 49.0 [br, 4(8)-C], 47.8 [br, 8(4)-C], 36.6, 33.1, 31.7, 28.3,
27.3.
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Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 367–376