Chemical modification of oximes with N-protected amino acids

Article abstract of DOI:10.1016/j.tet.2014.07.040

The modification of oximes, including 5α-steroids, with N-protected amino acids, in solution phase, using benzotriazole methodology is reported.

Full text of DOI:10.1016/j.tet.2014.07.040

Tetrahedron 70 (2014) 7181e7184
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Chemical modification of oximes with N-protected amino acids
,
Nana N. Barbakadze a b, Rachel A. Jones a, Nicole Rivera Rosario a, Nanuli Sh Nadaraia b,
,
a
,
c
,
y
Meri L. Kakhabrishvili b, C. Dennis Hall a , Alan R. Katritzky
*
a Center for Heterocyclic Compounds, University of Florida, Department of Chemistry, Gainesville, FL 32611-7200, USA
b Tbilisi State Medical University, Iovel Kutateladze Institute of Pharmacochemistry, Georgia
c Chemistry Department, Faculty of Science, King Abdulaziz University, PO Box 80203, Jeddah 21589, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 April 2014
Received in revised form 3 July 2014
Accepted 9 July 2014
The modification of oximes, including 5
benzotriazole methodology is reported.
a
-steroids, with N-protected amino acids, in solution phase, using
Ó 2014 Elsevier Ltd. All rights reserved.
Available online 28 July 2014
Keywords:
Amino acids
Steroids
Oximes
Benzotriazole (Bt) methodology
1. Introduction
2. Results and discussion
Steroids are a class of organic compound found in animals, plants
and fungi that have important therapeutic applications against
N-Acylbenzotriazoles have been used extensively for the N-ac-
ylation of amines29 and amides,30,31 and the esterification of ste-
roids with N-acylbenzotriazoles has been achieved using
a microwave-assisted protocol.32 To date, however, there have been
no reports of the benzotriazole-mediated acylation of oximes. It
was proposed that this would be a suitable method for the prepa-
ration of a series of novel 5a-steroids with N-protected amino acids,
and in order to test the viability of this strategy, O-acylations were
first attempted with simple, commercially available oximes. To that
a range of pathogens.15 -Steroids2 have been shown to exhibit anti-
a
bacterial, anti-tubercular,3 anti-cancer4 and anti-tumour activities,5
as well as anti-arrhythmic,6 anaesthetic,7 hypertensive, anti-
inflammatory and fungicidal activities.8 Peptides and proteins play
important roles in biological and physiological processes9 and
combinations of amino acids, peptides and steroids have given rise
to an interesting class of biologically relevant compounds.10 In par-
ticular, amino acids have been coupled with steroids with the aim of
preparing potential therapeutic agents that exhibit lower toxicity
whilst retaining the original activity of the parent compound.6,11
Oximes have been evaluated for potential cytotoxicity,12 and
oxime derivatives of steroids have been reported to exhibit anti-
bacterial,13 anti-inflammatory and anti-cancer activities.14e23 The
acylation of aminosteroids with protected amino acids has been
achieved previously using mixed anhydride methodology.11 Ste-
roidal oximes have been selectively acylated with Ac2O in the
presence of alcohols24 or by the use of coupling agents.25 However,
there are relatively few literature examples of reactions of steroidal
oximes with protected amino acids.26e28
end, five N-protected (a-aminoacyl)benzotriazoles 2ae2e were
synthesized following a previously reported method (Table 1).33
Table 1
Preparation of N-acylbenzotriazoles 2aee
Entry
Product 2aee
Isolated
yield %
Mp (ꢀC)
Lit. Mp (ꢀC)
1
2
3
4
5
Cbz-
Cbz-
Cbz-
L
L
L
-Ala-Bt, 2a
-Val-Bt, 2b
-Phe-Bt, 2c
90
85
82
80
69
115e116
106e107
150e152
109e112
74
114e11534
107e10835
151e15234
106e10836
74e8337
* Corresponding author. E-mail address: charlesdennishall@gmail.com (C. Dennis
Cbz-Gly-Bt, 2d
Cbz- -Lys(Cbz)-Bt, 2e
Hall).
L
y
Professor Alan R. Katritzky passed away on 10th February 2014.
http://dx.doi.org/10.1016/j.tet.2014.07.040
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

7182
N.N. Barbakadze et al. / Tetrahedron 70 (2014) 7181e7184
Table 4
The N-acylbenzotriazoles were subsequently coupled with
Preparation of O-acyl derivatives of 17-hydroximino-5
a
-androstan-3
b
-ol, 8ae8c
commercially available cyclohexanone oxime (3a) and benzalde-
hyde oxime (3b) to afford four acylated oximes in yields of 62e73%,
thus demonstrating the applicability of this procedure to a range of
oximes and amino acids (Table 2).
R
O
N
NOH
NHCbz
O
2a - c, Et3N
H
H
Table 2
THF, 65 °C
HO
HO
Reaction of N-acylbenzotriazoles with commercially available oximes
H
H
7
8a - 8c
Entry
Amino acid, 2
Product, 8
Isolated
yield %
Mp (ꢀC)
1
2
3
Cbz-
Cbz-
Cbz-
L
L
L
-Ala-Bt, 2a
-Val-Bt, 2b
-Phe-Bt, 2c
8a
8b
8c
65
73
52
105e107
154e156
85e88
Entry
Amino acid, 2
Oxime, 3
Product, 4
Isolated
yield %
4. Experimental section
4.1. General remarks
1
2
3
4
Cbz-
Cbz-
L
L
-Ala-Bt, 2a
-Val-Bt, 2b
3a
3b
3a
3b
4a
4b
4c
4d
73
62
70
72
Cbz-Gly-Bt, 2d
Cbz- -Lys(Cbz)-Bt, 2e
L
Commercial reagents were purchased from SigmaeAldrich and
were used without purification. Solvents were purified by distilla-
tion. Melting points were determined on a capillary point appara-
tus equipped with a digital thermometer. NMR spectra were
recorded in CDCl3 on Mercury or Gemini NMR spectrometers op-
erating at 300 MHz for 1H (with TMS as an internal standard) and
75 MHz for 13C. Elemental analyses were performed on a Carlo
Erba-EA1108 instrument. Analytical TLC was performed on E.
Merck silica gel 60 F254 plates and visualized by UV and vanillin
staining. Mass spectrometry was performed using electrospray
ionization (ESI).
Having demonstrated that O-acylation of oximes is possible
without the use of coupling agents,38 we turned our attention to
the acylation of 5
derivatives of 5 -pregnene was achieved by coupling N-protected
-aminoacyl)benzotriazoles 2aec with 3 -ol and 3 -acetoxy-20-
hydroximino-5
-pregn-16-en-20-ones 5a and 5b at 65 ꢀC in the
a
-steroids.19,5 The O-acylation of 20-hydroximino
a
(a
b
b
a
presence of Et3N to afford 6aef in yields of 44e57% after re-
crystallization (Table 3). In the case of compound 5a, the acylations
proceeded chemoselectively towards the oxime in the presence of
the free hydroxyl group, as observed by TLC and 1H NMR of the
crude product.
4.2. General procedure for the synthesis of compounds 2aee
(Table 1)
Table 3
Preparation of O-acyl derivatives of 3
pregn-16-en-20-ones, 6ae6f
b
-ol and 3
b
-acetoxy-20-hydroximino-5a-
Thionyl chloride (1.2 mmol) was added dropwise to a solution of
BtH (4.5 mmol) in anhydrous THF (10 mL per 10 g of BtH) under an
atmosphere of N2. The reaction mixture was stirred at rt for 30 min
O
N
N
OH
O
NHCbz
prior to the addition of Cbz-L-amino acid (1 mmol). Stirring was
R2
2a - c, Et3N
continued at rt until complete consumption of the starting material
was observed by TLC (n-hexanes/EtOAc, 1:1, v/v). The reaction
mixture was filtered and the filtrate was concentrated in vacuo. The
H
H
THF, 65 °C
R1O
H
R1O
H
residue was taken up in EtOAc and washed with Na2CO3(satd
aq)
5a: R1 = H
6a - 6f
(3ꢁ30 mL), dried (Na2SO4), filtered and concentrated in vacuo to
afford the desired N-acylbenzotriazole derivatives. 1H, 13C and mp
were in accordance with the reported literature data for com-
pounds 2aee.34,37,35
5b: R1 = Ac
Entry
Amino acid, 2
Product, 6
Isolated
yield %
Mp (ꢀC)
1
2
3
4
5
6
Cbz-
Cbz-
Cbz-
Cbz-
Cbz-
Cbz-
L-Ala-Bt, 2a
L-Val-Bt, 2b
L-Phe-Bt, 2c
L-Ala-Bt, 2a
L-Val-Bt, 2b
L-Phe-Bt, 2c
6a: R1¼H
6b: R1¼H
6c: R1¼H
6d: R1¼Ac
6e: R1¼Ac
6f: R1¼Ac
44
46
53
44
57
46
94e96
145e146
135e137
159e160
181e183
170e171
4.3. General procedure for the synthesis of compounds 4aed
(Table 2)
A mixture of the appropriate oxime (1 mmol) and N-protected
amino acid (1 mmol) was heated under reflux in anhydrous THF
(30 mL) for 24 h in the presence of Et3N (2.5 mmol). The reaction
mixture was allowed to cool to rt and quenched with ice water
(5 mL). The resulting solution was concentrated under reduced
pressure and the residue was taken up in EtOAc (40 mL). The so-
lution was washed with HCl (1 M) (3ꢁ20 mL), dried (Na2SO4), fil-
tered and concentrated under reduced pressure to afford acylated
oximes 4aed.
The O-acylation of 17-hydroximino-5a-androstan-3b-ol 7
with N-protected (a-aminoacyl)benzotriazoles 2aec in the pres-
ence of Et3N at 65 ꢀC afforded 8aec in yields of 52e73%, after re-
crystallization (Table 4).
3. Conclusions
To conclude, N-acylbenzotriazoles of protected amino acids
have been utilised in the successful acylation of oximes. The re-
actions proceed in reasonable yields with complete chemo-
selectivity in the presence of alcohols. The biological evaluation of
these compounds is currently underway and will be reported in
due course.
4.3.1. Benzyl (S)-(1-((cyclohexylideneamino)oxy)-1-oxopropan-2-yl)
carbamate (4a) (Table 2, entry 1). Cyclohexanone oxime (3a) (0.20 g,
1.77 mmol) and Cbz-L-Ala-Bt (0.57 g, 1.77 mmol) were employed to
afford 0.41 g (73%) of the indicated product as colourless oil: 1H NMR
(300 MHz, CDCl3) dH 7.29 (br s, 5H), 5.54 (d, J¼8.0 Hz,1H), 5.07 (s, 2H),

N.N. Barbakadze et al. / Tetrahedron 70 (2014) 7181e7184
7183
4.53 (quint, J¼7.3 Hz, 1H), 2.50e2.43 (m, 2H), 2.33 (dd, J¼7.3, 5.4 Hz,
54.7, 48.8, 47.1, 45.0, 38.1, 36.7, 35.6, 35.4, 33.8, 32.1, 31.9, 31.5, 28.6,
21.2, 18.9, 16.0, 13.4, 12.2; HRMS (ESI-TOF) m/z for C32H44N2O5Na
[MþNa]þ calcd 559.3142, found 559.3144.
2H), 1.78e1.64 (m, 2H), 1.63e1.54 (m, 4H), 1.42 (d, J¼7.2 Hz, 3H); 13
C
NMR (75 MHz, CDCl3) dC 170.1, 170.0, 155.5, 136.2, 128.5, 128.2, 128.0,
66.9, 48.8, 32.0, 26.9, 26.7, 25.7, 25.3, 19.0; HRMS (ESI-TOF) m/z for
C
17H22N2O4Na [MþNa]þ calcd 319.1652, found 319.1641.
4.4.2. 20-(Na-Carboxybenzyl-
(6b) (Table 3, entry 2). 20-Hydroximino-5
(5a) (0.10 g, 0.30 mmol) and Cbz- -Val-Bt (0.11 g, 0.30 mmol) were
L
-valyl)oximino-5
a
-pregn-16-en-3
b-ol
a-pregn-16-en-3b-ol-20-on
4.3.2. Benzyl (S)-(3-methyl-1-(((3-nitrobenzylidene)amino)oxy)-1-
L
oxobutan-2-yl)carbamate (4b) (Table 2, entry 2). Benzaldehyde ox-
ime (3b) (0.10 g, 0.83 mmol) and Cbz-L-Val-Bt (0.29 g, 0.83 mmol)
employed to afford 0.08 g (46%) of the indicated product as white
solid following recrystallization from EtOAc/n-hexanes (1:2): mp
145e146 ꢀC.1H NMR (300 MHz, CDCl3) dH 7.35 (s, 5H), 6.30 (dd, J¼3.4,
1.8 Hz, 1H), 5.37 (d, J¼9.3 Hz, 1H), 5.12 (s, 2H), 4.51 (dd, J¼9.3, 4.9 Hz,
1H), 3.64e3.53 (m, 1H), 2.50 (d, J¼10.4 Hz, 1H), 2.25 (ddd, J¼16.6, 6.5,
3.2 Hz, 1H), 2.19e2.14 (m, 1H), 2.08 (s, 3H), 2.02e1.92 (m, 2H),
1.83e1.75 (m, 1H), 1.73e1.28 (m, 16H), 1.22e1.07 (m, 1H), 1.13e0.90
(m, 9H), 0.72 (td, J¼11.0,10.6, 4.3 Hz,1H); 13C NMR (75 MHz, CDCl3) dC
167.0, 160.4, 156.2, 150.8, 138.1, 136.2, 128.5, 128.2, 128.1, 71.3, 67.0,
58.1, 56.9, 54.7, 47.1, 45.0, 38.1, 36.7, 35.6, 35.4, 33.8, 32.1, 31.9, 31.5,
31.3, 28.6, 21.2,19.1,17.5,16.0,13.5,12.2. Anal. Calcd for C34H48N2O5: C,
72.31; H, 8.57; N, 4.96. Found: C, 72.18; H, 9.02; N, 4.81.
were employed to afford 0.18 g (62%) of the indicated product as
yellow oil: 1H NMR (300 MHz, CDCl3) dH 8.40 (s,1H), 7.75 (d, J¼7.4 Hz,
2H), 7.53e7.42 (m, 3H), 7.37 (s, 5H), 5.37 (d, J¼9.3 Hz,1H), 5.14 (s, 2H),
4.48 (dd, J¼9.3, 5.1 Hz, 1H), 2.30e2.17 (m, 1H), 1.06 (d, J¼6.8 Hz, 3H),
1.01 (d, J¼6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) dC 169.7, 157.1, 156.2,
136.1, 131.9, 129.6, 128.6, 128.45, 128.40, 128.1, 128.0, 67.1, 58.1, 31.4,
18.9, 17.6; HRMS (ESI-TOF) m/z for C20H22N2O5Na [MþNa]þ calcd
377.1472, found 377.1473.
4.3.3. Benzyl (2-((cyclohexylideneamino)oxy)-2-oxoethyl)carbamate
(4c) (Table 2, entry 3). Cyclohexanone oxime (3a) (0.10 g, 0.88 mmol)
and Cbz-Gly-Bt (0.27 g, 0.88 mmol) were employed to afford 0.19 g
(70%) of the indicated product as colourless oil: 1H NMR (300 MHz,
CDCl3) dH 7.43e7.19 (m, 5H), 5.63 (t, J¼5.8 Hz, 1H), 5.07 (s, 2H), 4.05
(d, J¼5.7 Hz, 2H), 2.45 (t, J¼6.1 Hz, 2H), 2.36e2.14 (m, 2H), 1.75e1.62
(m, 2H), 1.66e1.50 (m, 4H); 13C NMR (75 MHz, CDCl3) dC 169.4, 168.5,
156.1, 136.0, 128.2, 127.9, 127.8, 66.7, 41.8, 31.7, 26.6, 26.5, 25.5, 25.0.
Anal. Calcd for C16H20N2O4: C, 63.14; H, 6.62; N, 9.20. Found: C, 63.14;
H, 6.94; N, 9.16.
4.4.3. 20-(Na-Carboxybenzyl-
en-3 -ol (6c) (Table 3, entry 3). 20-Hydroximino-5
-ol-20-on (5a) (0.09 g, 0.27 mmol) and Cbz- -Phe-Bt (0.11 g,
L
-phenylalanyl)oximino-5
a-pregn-16-
b
a
-pregn-16-en-
3b
L
0.26 mmol) were employed to afford 0.09 g (53%) of the indicated
product as white solid following recrystallization from diethyl
ether/n-hexanes (1:2): mp 135e137 ꢀC. 1H NMR (300 MHz, CDCl3)
dH 7.33e7.25 (m, 8H), 7.16 (d, J¼7.2 Hz, 2H), 6.28 (s, 1H), 5.32 (d,
J¼8.5 Hz, 1H), 5.09 (s, 2H), 4.85 (q, J¼7.0 Hz, 1H), 3.63e3.49 (m, 1H),
3.14 (d, J¼6.5 Hz, 2H), 2.49 (d, J¼10.5 Hz, 1H), 2.25 (ddd, J¼16.6, 6.5,
3.4 Hz, 1H), 2.01e1.94 (m, 1H), 1.90 (s, 3H), 1.84e1.21 (m, 16H), 0.97
(s, 3H), 0.84 (s, 3H), 0.75e0.67 (m, 1H); 13C NMR (75 MHz, CDCl3) dC
169.7, 160.6, 155.6, 150.7, 138.1, 136.2, 135.6, 129.4, 128.6, 128.5,
128.2, 128.0, 127.1, 71.3, 67.0, 56.9, 54.7, 54.0, 47.1, 45.0, 38.7, 38.2,
36.7, 35.6, 35.4, 33.8, 32.1, 31.9, 31.5, 28.6, 21.2, 15.9, 13.2, 12.3. Anal.
Calcd for C38H48N2O5: C, 74.48; H, 7.89; N, 4.57. Found: C, 74.13; H,
8.23; N, 4.41.
4.3.4. Dibenzyl (6-((benzylideneamino)oxy)-6-oxohexane-1,5-diyl)(S)-
dicarbamate (4d) (Table 2, entry 4). Benzaldehyde oxime (3b) (0.10 g,
0.83 mmol) and Cbz-L-Lys(Cbz)-Bt (0.43 g, 0.83 mmol) were
employed to afford 0.31 g (72%) of the indicated product as colourless
oil: 1H NMR (300 MHz, CDCl3) dH 8.37 (s, 1H), 7.72 (d, J¼7.2 Hz, 2H),
7.51e7.38 (m, 3H), 7.34 (br s, 5H), 7.32 (br s, 5H), 5.74 (d, J¼8.3 Hz,1H),
5.13 (s, 2H), 5.08 (s, 2H), 4.55 (td, J¼8.2, 4.9 Hz,1H), 3.22e3.11 (m, 2H),
1.99e1.73 (m 2H), 1.59e1.45 (m, 4H); 13C NMR (75 MHz, CDCl3) dC
170.1, 157.2, 156.5, 156.0, 136.4, 136.0, 131.9, 129.5, 128.8, 128.35,
128.34, 128.23, 128.0, 127.7, 127.9, 66.9, 66.4, 52.7, 40.3, 31.8, 29.2,
4.4.4. 3
16-en (6d) (Table 3, entry 4). 3
16-en-20-one (5b) (0.06 g, 0.16 mmol) and Cbz-
b
-Acetoxy-20-(Na-carboxybenzyl-
-Acetoxy-20-hydroximino-5
-Ala-Bt (0.05 g,
L
-alanyl)oximino-5
a
-pregn-
b
a-pregn-
22.2; HRMS (ESI-TOF) m/z for
540.2105, found 540.2108.
C
29H31N3O6Na [MþNa]þ calcd
L
0.16 mmol) were employed to afford 0.04 g (44%) of the indicated
product as white solid following recrystallization from EtOAc/n-
hexanes (1:2): mp 159e160 ꢀC. 1H NMR (300 MHz, CDCl3) dH 7.35 (s,
5H), 6.63e6.17 (m, 1H), 5.39 (d, J¼8.2 Hz, 1H), 5.12 (s, 2H), 4.75e4.56
(m, 2H), 2.67e2.41 (m, 1H), 2.25 (ddd, J¼16.5, 6.4, 3.5 Hz,1H), 2.07 (s,
3H), 2.02 (s, 3H), 1.99e1.88 (m, 1H), 1.48 (d, J¼7.1 Hz, 3H), 1.92e1.12
(m, 15H), 1.10e0.99 (m, 1H), 0.96 (s, 3H), 0.85 (s, 3H), 0.73 (td, J¼11.0,
4.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) dC 171.1, 170.7, 160.6, 155.5,
150.7, 138.2, 128.5, 128.1, 128.0, 73.7, 66.9, 56.8, 54.6, 48.8, 47.1, 44.8,
36.5, 35.6, 35.4, 34.0, 33.8, 32.0, 31.8, 29.7, 28.5, 27.4, 21.5, 21.1, 18.9,
16.0, 13.3, 12.1. Anal. Calcd for C34H46N2O6: C, 70.56; H, 8.01; N, 4.84.
Found: C, 70.41; H, 8.38; N, 4.71.
4.4. General procedure for the synthesis of compounds 6aef
and 8aec (Tables 3 and 4)
A mixture of the appropriate steroid (1 mmol)19,5 and N-pro-
tected amino acid (1 mmol) was heated under reflux in anhydrous
THF (30 mL) for 24 h in the presence of Et3N (1 mmol). The reaction
mixture was allowed to cool to rt and was quenched with ice water
(5 mL). The resulting white precipitate was collected by vacuum
filtration and washed on the filter with 5% Na2CO3(aq) (10 mL) and
H2O (10 mL). The precipitate was dried under high vacuum and, if
required, recrystallized from an appropriate solvent to afford ac-
ylated steroids 6aef and 8aec.
4.4.5. 3
16-en (6e) (Table 3, entry 5). 3
pregn-16-en-20-one (5b) (0.06 g, 0.16 mmol) and Cbz-
b
-Acetoxy-20-(Na-carboxybenzyl-
-Acetoxy-20-hydroximino-5
-Val-Bt
L-valyl)oximino-5a-pregn-
b
a-
4.4.1. 20-(Na-Carboxybenzyl-
(6a) (Table 3, entry 1). 20-Hydroximino-5
(5a) (0.07 g, 0.21 mmol) and Cbz- -Ala-Bt (0.07 g, 0.21 mmol) were
L
-alanyl)oximino-5
a
-pregn-16-en-3
b
-ol
L
a-pregn-16-en-3b-ol-20-on
(0.06 g, 0.16 mmol) were employed to afford 0.06 g (57%) of the
indicated product as white solid following recrystallization from
EtOAc/n-hexanes (1:2): mp 181e183 ꢀC. 1H NMR (300 MHz, CDCl3)
dH 7.35 (s, 5H), 6.30 (s, 1H), 5.38 (d, J¼9.4 Hz, 1H), 5.12 (s, 2H),
4.76e4.64 (m, 1H), 4.52 (dd, J¼9.3, 4.9 Hz, 1H), 2.51 (d, J¼9.9 Hz,
1H), 2.35e2.15 (m, 2H), 2.08 (s, 3H), 2.02 (s, 3H), 2.00e1.23 (m,
23H), 1.03e0.95 (m, 9H), 0.85 (s, 3H), 0.77e0.70 (m, 1H); 13C NMR
(75 MHz, CDCl3) dC 170.6, 170.1, 160.3, 156.2, 150.7, 138.0, 136.2,
128.5, 128.1, 128.0, 73.6, 67.0, 58.1, 56.8, 54.5, 47.0, 44.8, 36.4, 35.6,
35.3, 34.0, 33.8, 32.0, 31.7, 31.3, 28.4, 27.4, 21.4, 21.1, 19.1, 17.5, 15.9,
L
employed to afford 0.05 g (44%) of the indicated product as white
solid following recrystallization from EtOAc/n-hexanes (1:2): mp
94e96 ꢀC. 1H NMR (300 MHz, CDCl3) dH 7.35 (s, 5H), 6.31 (br s, 1H),
5.41 (d, J¼8.2 Hz, 1H), 5.12 (s, 2H), 4.62 (quint, J¼7.4 Hz, 1H),
3.64e3.53 (m, 1H), 2.48 (d, J¼10.3 Hz, 1H), 2.25 (ddd, J¼16.5, 6.5,
3.5 Hz, 1H), 2.07 (s, 3H), 1.48 (d, J¼7.0 Hz, 3H), 2.05e0.87 (m, 17H),
0.96 (s, 3H), 0.83 (s, 3H), 0.76e0.67 (m,1H); 13C NMR (75 MHz, CDCl3)
dC 171.0, 160.6, 150.7, 138.2, 136.2, 128.5, 128.1, 128.1, 71.3, 66.9, 56.9,

7184
N.N. Barbakadze et al. / Tetrahedron 70 (2014) 7181e7184
13.5, 12.1. Anal. Calcd for C35H56N2O6: C, 71.26; H, 8.31; N, 4.62.
Found: C, 71.28; H, 8.36; N, 4.56.
31.4, 28.4, 27.0, 22.9, 20.6, 17.0, 12.3; HRMS (ESI-TOF) m/z for
C
36H46N2O5Na [MþNa]þ calcd 609.3299, found 609.3292.
4.4.6. 3
pregn-16-en (6f) (Table 3, entry 6). 3
pregn-16-en-20-one (5b) (0.10 g, 0.27 mmol) and Cbz-
b
-Acetoxy-20-(Na-carboxybenzyl-
-Acetoxy-20-hydroximino-5
L
-phenylalanyl)oximino-5
a
-
Acknowledgements
b
a-
L-Phe-Bt
We thank the University of Florida, Tbilisi State Medical Uni-
versity, Iovel Kutateladze Institute of Pharmacochemistry and the
Kenan Foundation for financial support.
(0.11 g, 0.27 mmol) were employed to afford 0.08 g (46%) of the in-
dicated product as white solid following recrystallization from EtOAc/
n-hexanes (1:2): mp 170e171 ꢀC. 1H NMR (300 MHz, CDCl3) dH 7.34
(s, 5H), 7.27 (s, 3H), 7.16 (d, J¼6.9 Hz, 2H), 6.29 (s, 1H), 5.30 (d,
J¼8.8 Hz, 1H), 5.10 (s, 2H), 4.87 (q, J¼6.8 Hz, 1H), 4.75e4.64 (m, 1H),
3.16 (d, J¼6.4 Hz, 2H), 2.50 (d, J¼9.9 Hz, 1H), 2.26 (ddd, J¼16.5, 6.7,
3.5, Hz, 1H), 2.03 (s, 3H), 1.91 (s, 3H), 1.89e1.02 (m, 17H), 0.97 (s, 3H),
0.86 (s, 3H), 0.82e0.66 (m, 1H); 13C NMR (75 MHz, CDCl3) dC 170.7,
169.5, 160.5, 155.6, 150.6, 138.1, 136.2, 135.6, 129.3, 128.6, 128.5, 128.1,
128.0, 127.1, 73.7, 67.0, 56.8, 54.6, 54.0, 47.1, 44.8, 38.7, 36.5, 35.6, 35.4,
34.0, 33.8, 32.0, 31.8, 28.5, 27.4, 21.5, 21.2, 15.9, 13.2, 12.1. Anal. Calcd
for C40H50N2O6: C, 73.37; H, 7.70; N, 4.28. Found: C, 73.10; H, 7.94; N,
4.30.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.07.040.
References and notes
~
1. Salvador, J. A. R.; Carvalho, J. F. S.; Neves, M. A. C.; Silvestre, S. M.; Leitao, A. J.;
ꢀ
Silva, M. M. C.; Sa e Melo, M. L. Nat. Prod. Rep. 2013, 30, 324e374.
2. Holland, H. L.; Dore, S.; Xu, W.; Brown, F. M. Steroids 1994, 59, 642e647.
3. Sikharulidze, M. I.; Nadaraia, N. Sh; Kakhabrishvili, M. L. Chem. Nat. Compd.
2012, 48, 423e425.
4. Carvalho, J. F. S.; Silva, M. M. C.; Moreira, J. N.; Simoes, S.; Sa e Melo, M. L. J. Med.
Chem. 2010, 53, 7632e7638.
4.4.7. 17-(Na-Carboxybenzyl-
(8a) (Table 4, entry 1). 17-Hydroximino-5-
(0.05 g, 0.16 mmol) and Cbz- -Ala-Bt (0.05 g, 0.16 mmol) were
L
-alanyl)oximino-5
a
-androstan-3
b-ol
-ol (7)
ꢀ
a
-androstan-3
b
L
5. Merlani, M. I.; Amiranashvili, L. Sh.; Mulkidzhanyan, K. G.; Kemertelidze, E. P.
employed to afford 0.06 g (65%) of the indicated product as white
solid following recrystallization from EtOAc/n-hexanes (1:2): mp
105e107 ꢀC. 1H NMR (300 MHz, CDCl3) dH 7.34 (s, 5H), 5.46 (d,
J¼8.1 Hz, 1H), 5.10 (s, 2H), 4.49 (quint, J¼7.6, 6.7 Hz, 1H), 3.65e3.50
(m, 1H), 2.64e2.42 (m, 2H), 2.06 (d, J¼11.8 Hz, 1H), 1.92e1.13 (m,
Chem. Nat. Compd. 2006, 42, 322e324.
6. Mokotoff, M.; Zhao, M.; Marshall, R. J.; Winslow, E.; Wong, L. K.; Liao, Q. J.
Steroids 1990, 55, 399e404.
7. Zeng, C.; Manion, B. D.; Benz, A.; Evers, A. S.; Zorumski, C. F.; Mennerick, S.;
Covey, D. F. J. Med. Chem. 2005, 48, 3051e3059.
8. Merlani, M. I.; Davitishvili, M. G.; Nadaraia, N. Sh; Sikharulidze, M. I.; Papado-
pulos, K. Chem. Nat. Compd. 2004, 40, 144e146.
21H), 0.98 (s, 3H), 0.82 (s, 3H), 0.71 (td, J¼11.4, 10.9, 3.9 Hz, 1H); 13
C
9. Kimmerlin, T.; Seebach, D. J. Pept. Res. 2005, 65, 229e260.
10. Ye, Y. H.; Huang, Y. S.; Wang, Z. Q.; Chen, S. M.; Tian, Y. Steroids 1993, 58, 35e39.
11. Vincze, I.; Hackler, L.; Szendi, Z.; Schneider, G. Steroids 1996, 61, 697e702.
12. Dimmock, J. R.; Sidhu, K. K.; Chen, M.; Li, J.; Quail, J. W.; Allen, T. M.; Kao, G. Y.
J. Pharm. Sci. 1994, 83, 852e858.
13. Khan, S. A.; Asiri, A. M.; Saleem, K. J. Saudi Chem. Soc. 2012, 16, 7e11.
14. Hartmann, R. W.; Hector, M.; Haidar, S.; Ehmer, P. B.; Reichert, W.; Jose, J. J. Med.
Chem. 2000, 43, 4266e4277.
NMR (75 MHz, CDCl3) dC 180.0, 170.9, 155.5, 136.2, 128.4, 128.1, 128.0,
71.0, 66.9, 54.2, 53.7, 48.7, 45.4, 44.7, 37.9, 36.8, 35.5, 34.9, 33.6, 31.4,
31.3, 28.3, 27.1, 22.9, 20.6, 18.8, 16.9, 12.2.; HRMS (ESI-TOF) m/z for
C
30H42N2O5Na [MþNa]þ calcd 533.2986, found 533.2984.
4.4.8. 17-(Na-Carboxybenzyl-
(Table 4, entry 2). 17-Hydroximino-5-
0.23 mmol) and Cbz- -Val-Bt (0.08 g, 0.23 mmol) were employed to
L
-valyl)oximino-5a-androstan-3b-ol (8b)
15. Deive, N.; Rodriguez, J.; Jimenez, C. J. Med. Chem. 2001, 44, 2612e2618.
16. Jindal, D. P.; Chattopadhaya, R.; Guleria, S.; Gupta, R. Eur. J. Med. Chem. 2003, 38,
1025e1034.
a-androstan-3b-ol (7) (0.07 g,
L
17. Krstic, N. M.; Bjelakovic, M. S.; Zizak, Z.; Pavlovic, M. D.; Juranic, Z. D.; Pavlovic,
afford 0.09 g (73%) of the indicated product as white solid following
recrystallization from EtOAc/n-hexanes (1:2): mp 154e156 ꢀC. 1H
NMR (300 MHz, CDCl3) dH 7.35 (s, 5H), 5.37 (d, J¼9.3 Hz, 1H), 5.11 (s,
2H), 4.36 (dd, J¼9.4, 5.1 Hz, 1H), 3.59 (tt, J¼10.8, 4.2 Hz, 1H),
2.75e2.43 (m, 2H), 2.32e1.96 (m, 2H), 1.92e1.07 (m, 18H), 1.01e0.94
(m, 9H), 0.82 (s, 3H), 0.71 (td, J¼11.4, 3.7 Hz, 1H); 13C NMR (75 MHz,
CDCl3) dC 179.9, 169.8, 156.7, 136.2, 128.5, 128.1, 128.0, 71.1, 67.0, 58.2,
54.2, 53.7, 45.5, 44.7, 38.0, 36.9, 35.6, 34.9, 33.6, 31.5, 31.4, 28.4, 27.4,
23.0, 20.6, 19.0, 17.7, 17.0, 12.3. Anal. Calcd for C32H46N2O5: C, 71.34; H,
8.61; N, 5.20. Found: C, 70.91; H, 9.01; N, 5.29.
V. D. Steroids 2007, 72, 406e414.
18. Cui, J.; Huang, L.; Fan, L.; Zhou, A. Steroids 2008, 73, 252e256.
19. Merlani, M. I.; Amiranashvili, L. Sh; Mulkidzhanyan, K. G.; Shelar, A. R. Chem.
Nat. Compd. 2008, 44, 819e820.
20. Cui, J. G.; Fan, L.; Huang, L. L.; Liu, H. L.; Zhou, A. M. Steroids 2009, 74, 62e72.
21. Cui, J.; Fan, L.; Huang, Y.; Xin, Y.; Zhou, A. Steroids 2009, 74, 989e995.
22. Sikharulidze, M. I.; Nadaraia, N. S.; Kakhabrishvili, M. L.; Barbakadze, N. N.;
Mulkidzhanyan, K. G. Chem. Nat. Compd. 2010, 46, 493e494.
23. Pokhrel, M.; Ma, E. Molecules 2011, 16, 9868e9885.
24. Kuchkova, K. I.; Aryku, A. N.; Vlad, P. F.; Deleanu, K.; Nikolescu, A. Chem. Nat.
Compd. 2010, 46, 539e544.
25. Guthrie, D. B.; Stein, D. G.; Liotta, D. C.; Lockwood, M. A.; Sayeed, I.; Atif, F.;
Arrendale, R. F.; Reddy, G. P.; Evers, T. J.; Marengo, J. R.; Howard, R. B.; Culver, D.
G.; Natchus, M. G. ACS Med. Chem. Lett. 2012, 3, 362e366.
26. Hayashi, I.; Ogihara, K.; Shimizu, K. Bull. Chem. Soc. Jpn. 1983, 56, 2432e2437.
27. Hayashi, I.; Shimizu, K. Bull. Chem. Soc. Jpn. 1983, 56, 3197e3198.
28. Chen, S.-T.; Tsai, C.-F.; Wang, K.-T. Chem. Commun. 1996, 165e166.
29. Katritzky, A. R.; He, H. Y.; Suzuki, K. J. Org. Chem. 2000, 65, 8210e8213.
30. Katritzky, A. R.; Yang, H. F.; Zhang, S.; Wang, M. Arkivoc 2002, xi, 39e44.
31. Katritzky, A. R.; Hoffmann, S.; Suzuki, K. Arkivoc 2004, xii, 14e22.
32. Katritzky, A. R.; Angrish, P. Steroids 2006, 71, 660e669.
33. Katritzky, A. R.; Zhang, Y. M.; Singh, S. K. Synthesis 2003, 18, 2795e2798.
34. Katritzky, A. R.; Suzuki, K.; Singh, S. K. Synthesis 2004, 16, 2645e2652.
35. Katritzky, A. R.; El-Nachef, C.; Bajaj, K.; Kubik, J.; Haase, D. N. J. Org. Chem. 2010,
75, 6009e6011.
4.4.9. 17-(Na-Carboxybenzyl-
-ol (8c) (Table 4, entry 3). 17-Hydroximino-5-
(0.08 g, 0.26 mmol) and Cbz- -Phe-Bt (0.11 g, 0.27 mmol) were
L
-phenylalanyl)oximino-5
a-androstan-
3b
a-androstan-3b-ol (7)
L
employed to afford 0.08 g (52%) of the indicated product as white
solid following recrystallization from diethyl ether/n-hexanes (1:2):
mp 85e88 ꢀC. 1H NMR (300 MHz, CDCl3) dH 7.34 (br s, 5H), 7.26 (br s,
3H), 7.17 (d, J¼6.8 Hz, 2H), 5.31 (d, J¼8.7 Hz, 1H), 5.09 (s, 2H), 4.74 (q,
J¼7.1 Hz, 1H), 3.66e3.54 (m, 1H), 3.12 (d, J¼6.6 Hz, 2H), 2.30 (d,
J¼8.3 Hz, 2H), 2.06 (d, J¼12.1 Hz, 1H), 1.92e1.10 (m, 18H), 0.96 (s, 3H),
0.83 (s, 3H), 0.71 (td, J¼11.3, 4.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) dC
180.0, 169.6, 155.6, 136.2, 135.7, 129.4, 128.6, 128.5, 128.2, 128.0, 127.0,
71.1, 67.0, 54.2, 53.7, 45.4, 44.8, 38.9, 38.0, 36.9, 35.6, 34.9, 33.6, 31.5,
36. Katritzky, A. R.; Angrish, P.; Todadze, E. Synlett 2009, 2392e2411.
37. Katritzky, A. R.; Bajaj, K.; Charpentier, M.; Zadeh, E. G. J. Org. Chem. 2010, 75,
3938e3940.
38. Fujino, M.; Nishimur, O. Chem. Pharm. Bull. 1969, 17, 1937e1941.