synthesis and spectral studies on the alicyclic …
TRANSCRIPT
SYNTHESIS AND SPECTRAL STUDIES ON THE ALICYCLIC COMPOUNDS WITH
SPECIAL REFERENCE TO STEROIDS
DISSERTATION
SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE AWARD OF THE DEGREE OF
w \ f IN ^!^'-' 0- / 'i
CHEMISTRY
By
MEHNAZ NAQVI
DEPARTMENT OF CHEMISTRY ALIGARH MUSLIM UNIVERSITY
ALIGARH (INDIA)
2005
? 0 JUL ?009
DS3629
Ot. ,y^. ^ua^^'a .xO-'fe^ Tel. : 0571-7035
DEPARTMENT OF CHEMISTR
^ Professor of Chemistry ^ . . .
— ALIGARH MUSLIM UNIVERSITY ' • ' " ' ' ^ ' • " " ALIGARH
Certificate
This is to certify that the work embodied in this dissertation
entitled "Synthesis and Spectral Studies on the Alicyclic
Compounds With Special Reference to Steroids'' is the ori£final
work of Miss Mehnaz Naqvi carried out under my supervision.
The dissertation is suitable for the submission for the award of the
degree of Master ofPhilosophy in Chemistry.
(ProfTM. Mushfiq)
/?«. ; B.2. M.IG. FlatsTniggiRoad. Aligarh-202001 (U.P.i, INDIA Tel 0571^01726 Email: [email protected] < vD/i^^nu2t>
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CONTENTS
Acknowledgement
Introduction
Page No
1-3
CHAPTER ONE Synthesis of Steroidal fi-epoxides
Theoretical
Discussion
Experimental
References
CHAPTER TWO Synthesis of Steroidal Dimers
Theoretical
Discussion
Experimental
References
4-53
54-66
67-72
73-84
85-98
99-107
108-111
112-114
Introduction
The chemistry of steroids is a fast expanding field providing one
of the most interesting and thoroughly explored area for organic
chemists. The steroids form a group of structurally related compounds
which are widely distributed in nature. They play an important role in
vital activities of living organisms. They constitute a family of
substances critically important to plant and animal life. Steroids
include sterols, vitamin D, bile acids and a number of sex-hormones.
Sterols are the crystalline alcohols isolated from unsaponified
residues of lipids derived from animals and plants. Most of them are
C27-C29 compounds having one 2° alcoholic group. Most of them are
saturated, others contain one or two double bonds. Saturated members
of sterol series are known as stanols, like cholestanol. Those that
contain one double bond are stenols. Thus the term sterol embraces
both saturated and unsaturated members of the series.
Cholesterol is a mono-unsaturated sterol known as stenol of the
formula C27H45OH (m.p.= 149°C). It was so named because it is a
predominant constituent of human gall stones deposited in the bile
duct. Cholesterol is the only major sterol of higher animals. It is a
constituent of all normal tissues of animals. The total amount of
cholesterol present in a man weighing 180 lbs. is ~240g. It is present as
free alcohol in some parts and esterified with higher fatty acids in other
parts. It is the first steroidal compound to be known and was reported
by cherreul in 1812.
Biological and physiological activities''-' (antigestogens,
antimineralo, anticancer, antimalarials, in cardiac diseases, skin
diseases or disorders and as inflammation inhibitors) associated with
steroidal molecules was well received by chemists, specially for
modification in the structure of known steroids and their study. The
biological and physiological studies resulted in a race for synthesis of
unknown steroidal molecules specially those containing hetero-atoms
at various sites and as a part of the skeleton at various positions.
Syntheses of oxa^'^^''', aza'^'""'"', imidazole'^, benzothiazopine
derivatives'^ are reported.
With the same interest our laboratories have been engaged in
standardisation of procedures for specific changes in the steroidal
structures. Over the years more than 300 new molecules have been
reported resulting from various reactions and these have been
characterized on the basis of their chemical properties and spectral
behaviour. The physical methods used in our studies include UV, ORD,
I.R., H N.M.R., Mass fragmentation techniques in general and '•'C
N.M.R. in a few cases.
In continuation to the previous studies this dissertation gives a
short account of relevant recent literature concerning the proposed
research work which includes preliminary attempt to use new methods
for the preparation of (1) steroidal epoxides (2) steroidal dimers in a
selective way and their chemical transformations. It is proposed to
characterize the compounds obtained by using chemical and physical
methods. It is also proposed that these compounds can be screened for
their biological activities at the later stages.
Theoretical
Epoxides are cyclic ethers in which the ethereal oxygen is a part
of three membered ring. Epoxides are also known as 'oxiranes'. They
are readily prepared from alkenes. That's why they are commonly
known as alkene oxides. The prefix "epoxy" denotes the oxygen
functional group. In lUPAC system, they are named as alkyl oxiranes
or oxacyclopropanes. Substituents on oxirane ring require a numbering
system. The oxygen atom is given the number-1. But these can be
named as epoxy derivatives of the parent hydrocarbons also as given
below:
A
CH-l -CHo CH3CH; CH2C2H5
(I)
(Oxirane)
Or (Ethylene oxide)
Or (1,2 epoxy ethane)
(11)
(2-methyl 3-ethyl (2,3 cyclohexaoxirane) oxirane)
Or Or (2,3 epoxy pentane) (1,2 epoxy cyclohcxanc)
(IV) (2,3-(5,6) cholestano oxirane)
They are ethers, but the three membered ring gives them unusual
properties, that makes them an exceedingly important class of
compounds.
The various reagents used for the synthesis of aliphatic and
alicyclic epoxides are as follows:
1. From Alkenes:
A. Per acid"*"'^ (a) Perbenzoic acid, CgHjCOOzH
(b) Peracetic acid, CH3COO2H
(c) p-nitroperbenzoicacid, 02N.C(,ll5C()02lI
(d) m-chloroperphthalic acid, CI.HO2C.C6H3COO2H
(e) Mono perphthalic acid, HO2C.C6H4COO2H
B. (-) Dimethyl tartrate with t-butyl hydroperoxide, (CH3)3COOH and
titanium alkoxides, Ti(0Pr-i)4'^
C. Acid halide, HOC! followed by treatment with base'^.
D. Direct oxidation over silver catalyst^".
E. Alkyl peroxide with oxygen catalysed by a complex of V, Mo, Ti, Co^'.
F. Titanium isopropoxide, t-butylperoxide and one enantiomer of
tartaric ester^^.
G. Chromium Complexes, PhIO, PPNO 23
, CH2CI2, MezCO, 0°-20°C, ^2 . (
2. From Ketones and Aldehydes: O
A. Sodium ethoxide or sodamide with an a-halogen ester^^
B. Diazomethane^^.
C. Sulphonium ylides^^.
D. Dimethyl sulphoxonium methylide"'.
28 E. From NaOH and ether
F. Alkaline H202^^'^'.
3. From Halohydrins:
A. X2/H2O followed by treatment with a base^^.
The use of different reagents as given earlier for the preparation
of epoxides follow different mechanisms. Some of them are described
below:
(i) The use of peracids for the preparation of epoxides follows the
concerted mechanism as shown:
/ ^ < \ — ^ 9Lc_QH4Cl(m) X Q<=>C-C6H4Cl(m) \
The above mechanism^^ was proposed by Bartlett '*. The
evidences in favour o f Bartlett' mechanism are as follows"' :
(a) The reaction is second order, but if the ionization were
R.D.S., it would be first order.
(b) Reaction rapidly takes place in non-polar solvents, where
formation of ion is inhibited.
(c) Measurements of the effect on the reaction rate of changes in
substrate structure show that there is no carbocation
character in transition state^^.
(d) The addition is stereospecific i.e. trans alkene gives a trans
epoxide and cis alkene, a cis epoxide.
(ii) According to Ballester et al. (1955), when aldehydes and ketones
react with a-haloester in presence of base, epoxide is obtained by
following path^^:
C2H5O" 0 Cl.CHzCOOCzH;^ - ^ CI.CH2COOC2H5
R2CO
c? ^Cl
R2C—CHCOOC2H5-«-=^^- R2C-CH.COOC2H5
o ^
(iii) When diazomelhane reacts with aldehydes and ketones, an
26. epoxide is obtained by following path" :
O +
R2C + CH2-N=N ? a R
-N.
I • + R j C - C H j - N ^ N
-N2
O
R-C-CH2R
R=H (I) R=CH3(III)
(iv) By the use of sulphonium ylides, with carbonyl compounds we
77
obtain epoxides by following pathway :
Me2S = CH2+ CR2 = 0-
O
•* Me2S —CH2 —CR2
Me2S + CH2; :CRo
O
R==H (I) R=CH3 (III)
(v) Formation of epoxides by the use of dimethyl sulphoxonium
methylide, with carbonyl compounds follows the route given
below":
-H^
O Mel + NaNHo "
Me2S0 - M e L _ ^ j ^ S Q l — r ^ Me2S:?CH2 \ R2CO
-R MejSO + R2C; :CHo
O
R=H (I) R=CH3 (III)
O
MeoS^CHj-CC
(vi) From halohydrins, by the use of a base, the epoxides are
32. obtained and its formation is explained as follows :
X2 R2C=CR2 ^^
^ ^ H.O
R ( X R
\ R-yC: :CR,
RO 7 R
(Vicinal halohydrin)
O
•R=H (I)
R=CH3 (V)
29-31 (vii) Formation of epoxides, by the use of alkaline H2O2 ' , is a
nucleophilic addition. It involves Michael type mechanism involving
the attack by HO; ^ - ^
Ri-C=C-C-R4 + HO2"
R2R3O
r y-OH
R,-c-cr=c^4 —I RoR.O-'' ^2*^3 t
OH- + R, -(
R. R3O
R,=R2=R3=R4=H (a) Rl=R2=R3=R4=CH3 (b)
(VI)
10
ABBREVIATIONS USED
An
Anhyd
aq.
BMD
Bz
Chf
cone.
dil.
Diox
Et
Ac
LAH
Me
NBS
Ni(R)
^
quant
THF
Ts
Xs
DMSO
PBA
MPA
Ms
acetone
anhydrous
aqueous
bismethylenedioxy group
benzoyl (C6H5CO-)
chloroform
concentrated
dilute
dioxane
ethyl
acetate
lithium aluminium hydride
methyl
N-bromosuccinimide
Raney nickel
phenyl
quantitative
tetrahydrofuran
p-toluene sulfonyj
Excess
dimethyl sulfoxide
pcrbenzoic acid
monoperphalic acid
methanesulfonyl (CH3SO2-)
11
These described methods have been used for preparation of steroidal
epoxides also and the recent interesting examples can be summarized
as follows:
In the first investigation of the reaction of perbenzoic acid with
cholesteryl acetate, two products , described as corresponding ' a '
(VIII) and 'p ' (IX) epoxides were reported but their configurations
were not assigned.
PBA
(VII) (VIII) (IX)
Subsequently Ruzicka and Bosshard'* , prepared and studied only
one product, ' a ' epoxide (VIII). Later Hattori'^', Baxter and Spring"^,
also reported the formation of two products. The configurations could
be assigned only on the results of hydrogenation by Plattner and
Lang^^
12
The reaction of cholesterol with monoperphthalic acid in ether
x44 affords the a-epoxide (XI) . The reagent is recommended for the ease
of preparation and because the progress of a reaction is indicated by
the separation of phthalic acid.
Another route to the a-epoxide (XI) involves reaction of trans-
triol 3-acetate with mesityl chloride in pyridine followed by reaction of
6-mesylate (X) with potassium hydroxide in methanol, 75% yield is
reported for this reaction 45
AcO
KOH-CH3OH
OSO2CH3
(X) (XI)
Cholesterol p-epoxide is easily prepared from cholestane-3p, 5a, 6p
triol, a method developed in androstane series by Davis and Petrow"* .
Another route was developed by Mori'* , who found that shaking
an ethereal solution of cholesteryl acetate or benzoate with an aq.
suspension of bleaching powder acidified with acetic acid affords 5 a-
chlorocholestane-3p, 6p-diol, 4-acetate or benzoate. The chlorohydrins
are convertible by base into corresponding P-epoxide.
13
aq. Bleaching •
Powder, CH3COOH UO
Y = OAc (VII) OBz (VIF)
Y = OAc (VII") OBz (VIF")
OH
(Xr) Y = OAc (a) OBz (b)
Some of the steroidal epoxides prepared and reported recently
from different steroidal substrates can be summarized as following:
(XIV)
C«H 8"17
BzOOH, fH 49
O M
(XIII)
97% (XV)
14
cr (XVI)
49 BzOOH, (|).H
(XVII)
AcO
AcCT
AcO
AcO
OAc
(XVIII)
C«H 8"^17 51
Xs BzOOH o
(XXI)
QHjy
52
MPA, Chf,
(XXIII)
15
CsH
^^^^--^^.z^. o
8"17
53,54
MPA, Et.O-Chf 1—± ^
(XXIV) (XXV)
(XXVI)
C«H 8"17
55 KOH, aq. MeOH
AcO O
(XXVII)
(XXVIII)
CoH 8"17 56
NaOH, EtOH,
(XXIX)
(XXX)
16
MsO
(XXXII)
AcO
MsO
(XXXIV)
C«H 8"I7
59
H2O2, NaOH,
(XXXVI)
17
C«H 8"17
60
BzOOH, (|..H
(XXXVII)
O (Low yield)
(XXXVIII)
OAc
Br (XXXIX)
61
l)NaBH4,Et20
2) KOH, MeOH
(XLI)
(XLIII)
C«H 8"17
62
BzOOII, Chf,
BMD
63
BzOOH, (j).H
30%
(XLII)
5,6 a(a) 45% 5,6 p(b) 33%
(XLIV)
18
C«H
HO
8"17
(XLV)
64
BzOOH, (1).H
HO HO OBz
10% (XL VII)
COOMe 65
BzOOH, EtjO-Chf ^
(XLVIII) (XLIX)
MeO
CoH 9"17
66
BzOOH, fH
MeO
(L) (LI)
19
C«H 8"17
51
BzOOH
H
(LII) (LIII)
O.
0
(LIV)
O 1
o-k„_J 67 S
MPA, Et20-(1).H Q
O 31%
(LV)
O.
O O"
37%
(LVII)
+ O.
:0
O O" 2%
(LVI)
20
(LVIII)
68
MP A, Chf,
+ (LIX)
r—OAc
MP A, Chf,
(LXI)
8^17
AcO
(LXIII)
MPA, EtjO
21
AcO
MP A, EtjO 71
AcO
(LXVIa)
(LXVIII)
C = C H VOH
72
MP A, CH2CI2
48%
(LXIX)
AcO
(LXVIb)
MPA, Et20 73
AcO
87%
(LXX)
AcO'
8^17
74 MPA, Et2,0
AcO'
22
AcO
(LXXIII)
AcOOH, AcOK, 75
AcO'
(LXXV)
^OAc
iPj.CHjClj
2) Zn-AcOH
76,67
(LXXVI)
8"17
1) Q3, CH2CI2
2) Zn-AcOH
76
AcO
23
(LXXVII)
77 CrOj, H2SO4, An,
77
CrOj, H2SO4, An,
(LXXVIII)
(LXXIX)
(LXXX)
H
8^17
Cr03, AcOH,
(|).H
78
AcO'^'^--i"-^0 H
16%
(LXXXI)
+
H 18%
(LXXXII)
24
8"17
AcO
79 S0Cl2,Py,
AcO-^^X o-" C^CH
(LXXXV) 5,6a (LXXXVI) 5,6P
S^l?
AcO
(VII)
AcO
80 AcOBr, CCI4
AcO
(LXXXVIi;
l)NaOH,MeOH
2) AC2O
AcO ^ I AcO
OAc
34%
(IX)
OAc
KOH, aq. MeOH
73%
(LXXXVIII) (LXXXIX)
25
AcO
AcO
(XC)
(XCII)
:H
H
(XCIV)
82 KOH, MeOH
Xs BzOOH, Chf.
,60- 83
BzOOH, (t).H
AcO
84,85
Curvularia
Lunata
34%
(XCIII)
Q
H
20%
(XCV)
(XCVI) (XCVII)
26
(XCVIII)
86
AcOK, An
(XCIX)
(C)
BMD
87 K2CO3, aq. MeOH,
50%
(CI)
(CII)
l)NaOMe,MeOH,N2
2) AcOH
OAc
(CIV)
BMD
89
NaOMe, MeOH,
BMD
27
HCOQ
Br
(CVI)
-OAc =0 'OH
90
NaOH, aq. MeOH,
OHCQ 91
MaOl I. aq. MeOI 1,
(cvr)
OAc
l)AcOK,EtOH
2) AC2O
9%
(CVI 11)
+
28
(CXIII)
AcO
COOMe 92
AcO'
1. NaBH4, MeOH, AcjO -> 73%
2. KOH, MeOH, CHjNj, AcjO -^ 70%
3. Liq. NH3, -» 80%
?->
H
(CXV)
CQH 9"19
93
LAH, EtjO
32%
(CXVI) (CXVII)
29
? N
(CXXII)
AcO
(CXXIV)
MD
l)LiBH4,THF
2) aq. K2CO3, MeOM
= 0
(CXIX)
87 MD MeLi, Et20-THF
N^
33% (CXXI)
95
H2O2, NaOH, aq. MeOH
84%
(CXXIII)
96
I2O2, NaOl 1, aq. MeOl
+ :0 -0
2%
(CXXVl)
30
H2O2, KOH
aq. t.BuOH
97 o N-H
= 0 .0
67%
(CXXVIl) (CXXVHI)
AcO
98
BzOOH, (t).H
(CXXX)
AcO.
AcO"
(CXXXI)
Ac
99
BzOOH, Chf,
(CXXXll)
100
BzOOH, Chf,
63%
(CXXXIV)
31
101, 102
BzOOH, Chf,
^^0
103
BzOOH, Chf,
(CXXXVI)
69%
(CXXXVIII)
AcO
(CXXXIX)
104
MPA, Et20-CH2Cl2
80%
(CXL)
AcO
105
NBS
(CXLII)
32
84,85
Curvularia
Lunata
-OH :0 ,0H
T r
o
(CXLIII) (CXLIV)
106 Base
•?
(CXLVI)
AcO"
(CXLVll)
1=0 Br
-OH 96
KOH, MeOH
6 1 %
(CXI.VIII)
~"Br 107
KOH, MeOH, .0
61%
(CL)~ quant
33
MeO
(CLI)
•Br 108
KOH, MeOH
Br 109
KOH, MeOH
10
KOH, MeOH,
(CLVI)
(CLVII)
i i ;
l)K2C03,aq.MeOH
2) AC2O '
=0
-?
H 70%
(CLVIII)
34
(CLIX)
l,K2C03,aq. MeOH f
2) AC2O
96
Py
Br
OAc 80 l)K2C03,aq.MeOH
2) AC2O
107
KOH, MeOH
:0
(CXXV)
:() ,0
71% (CLXI)
(CLXIII)
SCN 112
KOH, MeOH
:0 .0
(cxLviir)
35
T-OAc
BzOOH, (1).H
114 MPA, EtjO
98%
(CLXV)
AcOi^. O
Ac(
T-OAc
MPA, Chf, 115
(CLXVII)
AcO"
(CLXIX)
116 KCN, AcOK,
EtOH-HjO
36
The epoxides obtained are very iielpful in the formation of
various steroidal derivatives which can be siimmari2.cd as following:
o:
(XXXIV)
117
48% HBr, HoO-Chf
(CLXXllI)
IIH
Py. HBr, EtOM
(CLXXIV)
(CLXXV)
40% HBr, Chf
(CLXXVl)
(CLXXVll)
HBr 56
38%
(CLXXVIII)
37
(XXV)
(CLXXX)
HBr, AcOH S3
2% HBr, AcOH-
Et,0
120
35%
(CLXXIX)
(CLXXXI)
I'y. HCI. Chr 12/
(CLxxxin ^.5a(a) 4.53(6)
(CLXXXIII) (CLXXXIV)
AcO
An, HzSO , HoO
(CLXXXV) (CLXXXVl)
3J
(XXXVl)
(XXIII)
(CXC)
LAH, EtjO
LAH, THF
LAH, Diox.
(CLXXXVII)
OH
52%
(CLXXXVUn
95
55
BF3, ^-H
I C O /
39
DMSO 123
BFjCCatalyst)
(CXCIV) (CXCV)
+ H O ^ ^ ^ ^ v ^ i ^ A / ^
10%
+
(CXCVl) (CXCVII)
N2H4.H20
No
U4
KSCN. ElOH 125
+
40
(CCII)
HCKAcOH 72,
17% (CCIII)
OCEt
(CCIV)
AcO'
(CCVI)
AcO
Cone. HCI. ElCOOH n
U6 anhyd. HF, THF-Chf
•
C«H 8 " 17
HSCN, EUO U7
OQcEt
HO ^ I HO
AcO
F
68%
(CCVII)
41
OCLVl)
?x'^l7
64-
BzOH,BzOOH. d)H, ^
HCIO4, An. 76
(CCXIl)
73
HCIO4, McOll
OMc
^ccxnn
8"I7
A C O " ^ ^ - ^ ^ ^ ^ - ^ "
H
(LXXII)
74
HCIO4, THF
(CCXIV)
42
AcO
8"17
44
HIO4, An
(CCXV)
128
Fuming HNO3
El,0 AcO
(CCXVI) (XC)
0 '
(LXXIV)
N
MeMgBr, 0,OMe 75
(CCXVll)
C«H 8 " 17
MeMgBr, THF U9
(CCXiAj
43
(CCXX)
MeMgl, Et,0 130
131
MeMgBr, HC^CH, THF
C=CH
(CCXVlll) (CCXXII)
0'MgBr, THF 132.
(CCXX III)
133.
HCsC-CHjMgBr. Et20-(|)H,
CHJ-CHCH
(CCXVIU) (CCXX IV)
44
AcO
134
LAH, THF-Diox.
(CCXXV)
(CCXXVl)
Li, EtNH2 135
H2, Pt02, AcOH
(CCXXVl J)
(CCXXIX)
(CCXXX)
Hj, PtOj, AcOEt
H2SO4
(CCXV "
45
(VIII)
BF3, DMF 137
AcO
OCHO
90%
(CCXXXII)
BF3, ROH 137
AcO
OR
(CCXXXIII)
R=El(a) 94% R=Mc(b) 78%
CVfll)
11
BF3, (^-H-EljO
78%
(CCXXXIV)
KCN, Ethylene glycol
(CCXXXV)
HO I (CCXXXVl)
46
130
Piperidine, Ethylene glycol ^
(CCXXXVll)
12.9
Me2NH, Ethylene glycol
(CCXXXIX)
NMe2
(ccxx>^vm}
89
48% HBr, CH2O, ^'0
Chf, CH2CI2 *"
BMD M
(CCXL)
AcO
CI
3NHG1. Diox. 140
AcO'
47
(XCVII)
(CCXLIV)
HSCN, AcOH
28%
(CCXLlll)
AcO
(CCXLVI)
142 Ag20,Mel
l)HBr, AcOH, CH2CI2 143
2) Ni(R), MeOH
90% (CCXLVII)
(CCXLVJll)
HCl 144- = 0
<y1 -OH CI
(CCXLIX)
48
(CCL)
145 HF, Chf. EtOH
^ O
-OH
37%
(CCLI)
(CCLll)
(CCLII)
146
HI, aq. Diox.
(CCLlll)
146
HCOOH
:0 OH
OHCO
(CCLIV)
^N-
AcC H
(CCLV)
•9
AcOH, H2SO4 147
OAc
(CCLVI)
49
AcO'
(CCLVU)
Aq. HCIO4, Diox 148 ,50
F O -OH
45%
(CCLVIIJ) +
:CH,
AcO
(CCLIX)
I-I2SO4, Diox ''19 ,1^0
(CCLX)
AcO
yx DHjSO,, MeOH
2) AC2O
OAc
78%
(CCLXil)
50
AcO
TsOH. <p.^. 151,152
O
on
(CCLfX) (CCLX)
AcO
TsOH. Ac^O '^^
= 0
OAc
(CXXV)
AcO
37%
(CCLXIII)
HO+H
-OH
(CXXV) (CCLXIV)
Zn-AcOH 105 O
(CCLXV) (CCLXVI)
51
(CCLXVII)
l)CrCl2,H20 155
2) An, HCI
63%
(CCLXVm)
(CCLXVII)
CrCl2, AcOH 156
57%
(CCLXVIII)
(CXLVIU)
157
Cr(0Ac)2, aq. AcOH
^ O
-OH
62%
(CCLXIX)
52
(CCLXX)
2I0°C 100
+
<P^° 4%
(CCLXXII)
102
NajCOj, aq. l-BuOH
A, I hr,N2
(CCLXXIII)
74%
(CCLXXIV)
53
158 85% N2H4.H2O
Dielhylene glycol, KOil, A, 4 hr.
-OH
(CXLVIll') (CCLXXV)
48%, HF, H-,0 159
HO~'
(CCLXXVI) (CCLXXVll)
54
Discussion
Survey of lileralure on epoxide formalions and iis synthelic
ulilily reveals that a number of studies show the formation of P-
epoxides in the steroidal series. However, a satisfactory explanation
for this stereochemical preference has not been furnished.
A mixture of KMnO^-CuSOj in dichloromethane in presence of
l-hulyl alcohol and a catalytic amount of water has been found to be a
convenient and effective method to provide steroidal p-epoxides in
high yields'^"''''^ Syamala et all^" proposed that this cpoxidation
occurred in omega phase, which was formed by water and t-butanol
over the surface of inorganic salt, t-butanol functioning as a phase-
transfer catalyst'^". The face selectivity of this oxidizing reagent
systeni results from the initial copper ion (or other metal ion) co
ordination on the less hindered a- face of the double bond and the
copper ion. The subsequent permanganate attack on ihc p-face results
in ihe p-cpoxide. The oxidation has been rationalized"'^ in -terms of
the formation of D-coniplex and then a melal-carbon bond Ibrmation
between the manganese and the alkene. The formation of a IT -
complex also weakens the double bond and makes the permanganate
attack possible.
55
Hanson'" proposed that the stereospecificity was caused by the
permanganate which initially attacked the alkenes in an axial
direction and that the epoxide formation occurred via manganate
cslcr'^'•'•"'^ in the case of his study the axial positions are C-4p in the
normal series and C-4a in the retro-steroid, C-6(i in the normal scries
and C-6a in the p -nor steroid. However, this assumption could not
explain, why the p-selectivity was lowered by (i-allylic accloxy
groups.
With a view to verify the suggested pathways, we have carried out the
similar epoxidationof some mciore. easily accessible steroidal 5-enes [(VII),
(XLl), (CCLXXIX), (CCLXXXI)l. The compounds obtained have been
characterized on the basis of their elemental composition, I.R. and 'H N . M . R .
The steroidal 5-enes [(VII), (XLI), (CCLXXIX), (CCLXXXI)], when
subjcclcd lo the oxidation conditions with KMn04 in the presence of different
metal sails, it is observed that the ease of formation of epoxide is varying with
the metal ion change and the anion change as shown in the table-1.
11 is very evident ihal epoxidalion lakes place only in presence of
Uansilion mcial ion and Cd is observed to be most cfficicnl giving
highest 92% yield while Cu is in close contest with it. As far as the
anions are concerned the siudy (Table-1) clearly shows Ihal sulfate
,( Ace. No ;^/
56
salts are most effective while phosphates and oxalate decrease the yield
of epoxide to a great extent even when it is the same transition metal.
The detailed discussion and characterization of compounds is
illustrated with KMn04-CuS04 combination as the suitable example.
The other combinations are mentioned in the table-1.
It is pertinent to mention that it can be concluded that transition
metal ion 7t-bond complex being formed on the less hindered side
leads to the formation of P-epoxide(IX) oriented towards the more
CtowcLid. side as shown in the mechanism.
KMn04 . . K^+MnOr
AcO
(Vll)
AcO
MnO,
AcO
^ Mn
0 0 0
AcO'
Mn—OH
-HoO
,^-\ Mn
O O
AcO 0 '
(IX)
67
(Table-1)
Epoxidation of steroidal 5-enes with potassium permanganate and
various transition metal salts
Metal salts
CUSO4
Cu(N03)
Cu(0Ac)2
CiiCO,
CUCI2
CU.-,(P04)2
CdS04
Cd(N03)2
Cd (0Ac)2
ZnSOj
Zn(0Ac)2
ZnCl2
3P-acetoxycholest-
5-ene
Reaction
time
30 min
30 min
24 hr.
24 hr.
1 hr.
1 hr.
30 min.
30 min.
24 hr.
30 min.
24 hr.
1 hr.
(VII)
% yield
82
84
No
reaction
No
reaction
70
60
90
87
No
reaction
85
No
reaction
68
3p-chlorocholest-
5-ene
Reaction
time
30 min
30 min
24 hr.
24 hr.
1 hr.
1 hr.
30 min.
30 min.
24 hr.
30 min.
24 hr.
1 hr.
(XII)
% yield
80
83
No
reaction
No
reaction
70
62
92
89
No
reaction
85
No
reaction
68
Cholest-5-ene
(CCLXXIX)
Reaction
time
30 min
30 min
24 hr.
24 hr.
Ihr.
1 hr.
30 min.
30 min.
24 hr.
30 min.
24 hr.
Ihr.
% yield
83
82
No
reaction
No
reaction
73
60
93
90
No
reaction
87
No
reaction
65
3p-tosyloxy cholest-5-
ene (CCLXXXI)
Reaction
time
30 min
30 min
24 hr.
24 hr.
1 hr.
1 hr.
30 min.
30 min.
24 hr.
30 min
24 hr.
I hr.
% yield
85
82
No
reaction
No
reaction
71
60
90
90
No
reaction
84
No
reaction
68
58
C0C03
COCl:
C03(P04):
CO(C204)
Fe2(S04)
Ni(N03)2
Na2S04
NaNOj
Na(0Ac)2
NajCOj
MgS04
KHPO4
24 hr.
1 hr.
1 hr.
45 min.
30min.
30 min.
48 hr.
48 hr.
48 hr.
48 hr.
48 hr.
48 hr.
No
reaction
72
60
65
88
85
No
reaction
No
reaction
No
reaction
No
reaction
No
reaction
No
reaction
24 hr.
Ihr.
1 hr.
45 min.
30 min.
30 min.
48 hr.
48 hr.
48 hr.
48 hr.
48 hr.
48 hr.
No
reaction
70
62
62
86
86
No
reaction
No
reaction
No
reaction
No
reaction
No
reaction
No
reaction
24 hr.
Ihr.
1 hr.
45 min.
30 min.
30 min.
48 hr.
48 hr.
48 hr.
48 hr.
48 hr.
48 hr.
No
reaction
74
60
65
85
85
No
reaction
No
reaction
No
reaction
No
reaction
No
reaction
No
reaction
24 hr.
1 hr.
1 hr.
45 min.
30 min.
30 min.
48 hr.
48 hr.
48 hr.
48 hr.
48 hr.
48 hr.
No
reaction
70
60
63
85
85
No
reaction
No
reaction
No
reaction
No
reaction
No
reaction
No
reaction
59
Reaction of 36-acetoxvcholest-S-cnc (Vfl) with K|Vln04-CuSQ4_ijl
nresencc of t-butanol. dichloromethane and water: 3B-acctoxv-S,6p-
enoxv-5 B - cholestane (IX):
A mixture of KMnO^ and CUSO4 was gviiulcd to a fine
powder, water was added and then slightly wet mixture was stirred
with steroidal substrate (Vll) and t-butanol in dichloromethane at
room temperature for about 30 minutes. The reaction mixture after
work up afforded a single compound, m.p.="-l 12°C.
«"17
KMnO^-CuSOj. FJ O t-butanol
^'•'^ Dichloromethaae r.t.,30min. AcO'
(VII) ( I X ]
Characteri/ation of the compound, m.p. = il2''C as 33-ace(oxv-
5,60- epoxv-5g-cho)estane (IX):
The compound, m.p. = 112"C was analysed for Cjvll jxOa. The
composition indicated the incorporation of one O-atom. The l.K. specnum
of ihe compound exhibited bands at 910-928 cm'' indicating ihe presence
of epoxide ring, 1038 cm'' for C-0 stretching, 1243 cm"' for p -acetoxy
group and 1726 cm"' for carbonyl group of acetate.
The N.M.R. spectrum showed a multiplet at 5 4.66 (w^^-*-ii,Hz)
ascribable to C3a-H equitorially oriented, a peak as a distorted
60
singlcl at 6 3.0^wi/^*8Hx)indicating C6a-ll (cqualoiial)in (iX)'l'urlhcr
a singlet at ft 2.0 indicating carbonyl group of acetate, a singlet at 5
1.0 for ClO-methyl protons, a singlet at 5 0.6 indicating C13-methyl
proton's. Other methyl groups signals were observed at 5 0.91, 0.92
and 0:93.
On the basis of above discussion the conii)ound, nip.
II2"C has been characterized as 33-acetoxy-5,6p-epoxy-
5p-cholestane (IX/^.
Reaction of 3B-cholorocholest-5-ene(XLn with KiMnOj-CuSOj in
presence of t-butanol, dichloromethane and water: 3B-chloro-
5.6g-enoxv-5B-cholestane(CCLXXVin:
With steroidal substrate (XLl), same above procedure was
repeated. Ihe reaction mixture after work up alTorded a single
compound, m.p.=90 "C.
8"17
KMii04-CuS04, il.O t-butanol
^ Oichloromclhunc
r.t., 30 mill. ^'
(XLl) (CXXXXVlli)
61
Characterization of the compound, in.i).= 90"C as 3(^hloro-
5,6Q-enoxv-5B-cholestane(CCLXXVIM):
The compound,ni.p. = 90"C was analyzed for C:7H.t50 CI. The
composition indicated the incorporation of one 0-atom. The l.R.
spectrum of the compound exhibited bands at 865 cm'' indicating the
presence of epoxide ring, at 759 cm"'and 704 cm''showing the
presence of C-Cl bond and at 1168 cm"' showing C-0 stretching.
The N.M.Il spectrum Showed a peak as a singlet appeared at
5 3.0(w^^--^•6Hz)ascribable to C6a-H (equatorial) in (CCLXXVlll) and
a multiplel at 6 3.8 (WJ' =i9H2:)to C3a-H (equatorial). Further a sharp
singlet at 51.1 for ClO-methyl protons, another sharp singlet at 6 0.6
for C13-methyl protons. Other methyl group signals were observed at
5O.8l5O-8ZaYiaO.84.
On the basis of above discussion the compound, m.p.=90'T
may be tentatively characterized as 3(3-chloro-5,6p-epoxy-
5p-cholestane (CCLXXVHI), Traces of a- epoxide are also present,
indicated by broad multiplet in the N.M.R. at 5 4.8 and a doublet like
signal at 6 2.91 ascribable to the C3a-H axial and CGfi-tl axial in the
corresponding a-epoxide (XLII).
63
On the basis of above discussion the compound, m.p.= 76°C
may be tentatively characterized as 5,6p epoxy 5p-cholestane
(CCLXXX).
Reaction of 3B-tosvloxvchoIest-5-ene (CCLXXXI) with KMnO^-
CuSO^ in presence of t-butanol, dichloromethane and water: 33-
tosvloxv-5,6B-epoxv-5 B-cholestane (CCLXXXII)
With steroidal substrate (CCLXXXI), once again same above
procedure as described earlier was repeated. The reaction mixture
after work up afforded a single compound, m.p. = 126°C .
'8^17
TsO
8^17
KMn04-CuS04, HjO
t-tubanol, Dichloromethane , ^ ^ ' \ p ^ ' \ f ^ r.t. 30 min.
TsO
(CCLXXXI) (CCLXXXII)
Characterization of compound, m.p. = 126''C, as 3B-tosyloxy-5,6B-
epoxv-5B-chlolestane (CCLXXXII);
The compound, m.p. = 126°C was analysed for C34H52O4S. The
composition indicated the incorporation of one 0-atom. The I.R.
spectrum of the compound exhibited bands at 883 cm'' indicating the
presence of epoxide ring at 1168 cm"' for C-0 stretching and 1595,
1190 and 1180 cm'' for tosylate.
64
The N.M.R. spectrum shows a muMplet at 6 4.66 ascribable to C3a-H
(w Vi = 14 Hz) (equatorial), a peak as a singlet at 6 2.8 to C6a-H (equatorial)
(w V2 = 8.2 Hz), a singlet at 5 1.0 for ClO-methyl protons, a singlet at 6 0.6 for
C13-methyl protons. Singlet at 6 2.58 and a doublet at 5 7.0 for toxylate.
Other methyl group signals were observed as at 6 0.92, and 5 0.93.
On the basis of discussion the compound, m.p. = 126**C may be
tentatively characterized as 3P-tosyloxy-5,6P epoxy-Sp-cholestane
(CCLXXXII).
65
Proposal for extension of work;
Further work lo support this, is underhand for which it is proposed
U) Uikc more steroidal alkcnes like 4-cncs and 6-enes as well as 3,5 dicnes
aiul 4.6 dicnes lo compare the reactivity of double bonds.
(CCLXXXIll) Y = H (a)
Br(b) CI (XIV) OAc (c)
(CCLXXXV)
(CCLXXXIV) Y = H(d)
Br (c) CI (XV) OAc(i)
+
(CCLXXXVl) 3,4a (a) 3,4P(b)
(CCLXXXVli) 5,6a (a) 5,6P(b)
(CCLXXXVllI) 3,4a and 5,6a (a) 3.4a and 5.6(J (b) 3,4p and 5.6a (c) 3.40 euul 5.6(Wd)
66
(CCLXXXV) (CCLXxxvr) 4,5a (a) 4,5P(b)
4-
+
(CCLxxxvir) 6,7a (a) 6,7P (b)
(CCLXXxviir) 4,5a and 6,7a (a) 4,5a and 6,7p (b) 4,513 and 6,7a (c) 4,5(3 and 6,73 (d)
67
Experimental
All melting points are uncoiTected, l.R. spectra were determined in
Klir with Perkin-Elmer-237 spectrophotometer. N.M.R. spectra were rim in
CD(.'l.i on Gemini-200 MHz with TMS as internal standard
I'LC plates were coated with silica gel. Light petroleum refers to a
fraction of b.p.-"= 60"-80 "C, N.M.R. values are given inpp-nv(s ^ Singlet, d =
doublet, m = multiplet, br = broad). l.R. values are given in cm"'.
General oxidation procedure:'*'' "' ^
A mixture of potassium permanganate (5g) and the metal salt
(3g) was ground to a fine powder'in a mortor using a pestle. Water
(0.5ml) was added and slightly damp mixture was transferred to a
flask which- contained dichloromethane (60ml). The steroidal
substrate (Ig) was added, followed by t-butanol (3ml). The mixture
was stirred at room temperature. The completion of the reaction was
confirmed by TLC. The reaction mixture was then filtered in a conical
flask and the solvent was removed by evaporation. Crystallization
from methanol gave the corresponding epoxide as needles.
33-acetoxvcholest-5-ene (VIIV.
A mixture of cholesterol (CCLXXXIX), (lOOg) in pyridine
(150ml.) and acetic anhydride (lOOml) was heated on a water bath for
68
2hrs. The reaction mixture was poured into ice-cooled water and
obtained solid mass. It was filtered under suction, washed with water
and air-dried. Crystallization of crude product from acetone gave 3(3-
acetoxycholest-5-ene (VII), 93g., m.p.=113°C.
3B-acetoxv-5,6 B-epoxv-5B-cholestane (IX);
A mixture of potassium permanganate (5g) and the copper
sulfate (3g) was ground to a fine powder in a mortor using a pestle.
Water (0.5ml) was added and slightly damp mixture was transferred
to a flask which contained dichloromethane (60ml). The steroidal
substrate (VII) (Ig) was added, followed by t-butanol (3ml). The
mixture was stirred at room temperature for 30 min. The completion
of the reaction was confirmed by TLC. The reaction mixture was then
filtered in a conical flask and the solvent was removed by
evaporation. Crystallization from methanol gave the epoxide (IX) as
needles (0.820g), m.p.=112°C(reported='" 111-112°C).
Vmax 910-928 cm'' (epoxide ring), 1243 cm'' (p-acetoxy), 1038 cm"'
(C-0 stretching), 1726 cm''(carbonyl group of acetate).
5 4.66(m, w /2 = 13 Hz, C3a-H), 3.0(s, w '/2 = 8 Hz, C6a-H), O
2.0 (s, -CH3-c-O),1.0 (s, ClO-Me), 0.6(s, C13-Me), signals at
0.91, 0.92 and 0.93 for other methyls.
Analysis found: C (78.28%), H( 10.84%)
69
calculated for: C (78.32%), H( 10.88%)
3 (l-cholorocholest-5-ene (XLI);
Freshly distilled thionyl chloride (75 ml) was added gradually to
crystallized cholesterol (CCLXXXIX), (lOg) at room temperature. A
vigorous reaction ensured with the evolution of gaseous products.
When the reaction mixture was slackened, it was healed gently al 50°-
60"C on a water bath for 1 hr. and then poured into water with
continuous stirring. The yellow solid thus obtained was filtered under
suction and air dried.
Recrystallization from acetone gave 3fi-chlorocliolest-5-ene
(85g) (XLI), m.p. = 95"C.
3B-chlorocholest-5, 6P-e[)o.\v-5P-cholestane (CCLXXVlll);
A mixture of potassium permanganate(S^) and the copper sulfate
(3g) was ground to a fine powder in a mortar using a pestle. Water (0.5
ml.) was added and slightly damp mixture was transferred to flask
which contained dichloromethane (60 ml.). The steroidal substrate
(XL!), (Ig) was added, followed by t-butanol (3 ml.). The mixture was
stirred al room temperature for 30 minute. The completion of the
reaction was confirmed by TLC. The reaction mixture was then filtered
in a conical flask and the solvent was removed by evaporation.
70
Crystallization from methanol gave the epoxide (CCLXXVIII) as
needles. (0.800 g), m.p. = 90°C.
Vmax: 865 cm'' (epoxide ring), 759 cm'' and 703 cm'' (C-Cl bond),
1168 cm"' (C-0 streching).
5: 3.0 (s, w V-i = 6.6 Hz, C6a-H), 3.8 (t, w '^ = 19 Hz, C3a-H),
1.1 (s, ClO-Me), 0.6 (s, C13-Me), signals at 0.8, 0.82, 0.84
for other methyls,[5 4.8 (s) and 2.91 d for C3a-H axial and
C6P-H axial the corresponding a-epoxide].
Analysis found: C (76.87%), H( 10.63%)
calculated for: C (76.91%), H( 10.67%)
C27H45OCI
Cholest-5-ene (CCLXXIX);
A solution of 3p-chlorocholest-5-ene (lOg) (XLI) was dissolved
in warm isoamyl alcohol (250 ml) and sodium metal (20 g.) was added
to the solution with continuous stirring over a period of 8 hrs. The
reaction mixture was warmed occasionally. When all sodium metal was
dissolved, the reaction mixture was poured into water acidified with
cone. HCl and then allowed to stand over night. A white crystallized
solid thus obtained was filtered under suction and washed thoroughly
with water and air dried. The crude product was crystallized from
acetone to give cholest-5-ene (CCLXXIX) (7 g.), m.p. = 92°C-93°C.
71 5, 6B-epoxv-S6-choIestane (CCLXXX);
A mixture of potassium permanganate (5g.) and copper sulfate
(3g.) was ground to a fine powder in a mortor using a pestle. Water
(0.5 ml.) was added and slightly damp mixture was transferred to flask
which contained dichloromethane (60 ml.). The steroidal substrate
(CCLXXVII), (Ig.) was added, followed by t-butanol (3ml.). The
mixture was stirred at room temperature for 30 minutes. The
completion of the reaction was confirmed by TLC. The mixture was
then filtered in a conical flask and the solvent was removed by
evaporation crystallization from methanol gave the epoxide
(CCLXXX) as needles (0.830g) m.p.=76°C.
Vmax: 883 cm'' and 933 cm'' (epoxide ring), 1168 cm"' (C-0
stretching), signals at 0.52, 0.53 for other methyls.
6: 2.9 (s, w '/2 = 9 Hz, C6a-H), 0.9 (s, ClO-Me), 0.51 (s, C13-Me).
Analysis found: C (83.90%), H(l 1.87%)
calculated for: C (84.94%), H(11.91%)
C27H46O
3B-tosyloxvcholest-5-ene(CCLXXXI);
To a solution of cholesterol (CCLXXXIX) (4g) in dry pyridine
(10ml) p-toluene sulfonyl chloride (4g) was added and then the mixture
was shaken. With in 5 minutes a white crystalline precipitate begins to
form. After that, the reaction mixture was allowed to stand over night.
12
Then it was taken in ether and ethereal solution was washed
successively with dilute H2SO4, NaHCOa (5%) and water and dried
over Na2S04. Evaporation of ether left an only residue which was
crystallized from petroleum ether (yield = 3.7g and m.p. = 130°-
132°G).
3B-tosvloxv-5.6B-epoxy 5B-cholestane (CCLXXXII)
A mixture of potassium permanganate (5g) and the metal salt
(3g) was ground to a fine powder in a mortor using a pestle. Water
(0,5ml) was added and slightly damp mixture was transferred to a
flask which contained dichloromethane (60ml). The steroidal
substrate (CCLXXXI) (Ig) was added, followed by t-butanol (3ml).
The mixture was stirred at room temperature. The completion of the
reaction was confirmed by TLC. The reaction mixture was then
filtered in a conical flask and the solvent was removed by
evaporation. Crystallization from methanol gave the corresponding
epoxide as needles. Yield = 0.850g, m.p. = 126°C.
Vmax: 883 cm"' (epoxide ring), 1168 cm"' (C-0 stretching), 1595,
1190, 1180 cm"' (tosylate)
5: 4.66 (m, w V^ = 14 Hz, C3a-H), 2.9 (s, w V2 = 8.2 Hz, C6a-H),
1.0 (s, ClO-Me), 0.6 (s, C13-Me), 2.58(s) & 7.0(d) (Ts), 0.92,
0.93 for other methyls.
Analysis found: C (74.76%), H(9.58%)
calculated for: C (73.83%), H(9.66%)
C34H52O4S
73
References
1. Rhode, Ralph, Annen Klaus, Neef Guenter, Wiechert Rudolf,
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85
Theoretical
This chapter gives an account of the preliminary attempts made
for preparation of steroidal dimers along with the recent interesting
examples of such compounds reported in literature.
Dimerization is an association of two identical molecules in such
a way that they behave as single unit. This may take place by a number
of ways i.e. simple association of two units, by self condensation or by
condensation of two molecules or more involving other simple
bifunctional moieties. Fieser et al. in 1959 and Crabbe et al. in 1961
1 7
were first to report dimeric steroids as by products '*•. This was
followed by a number of discoveries of such compounds from natural
as well as synthetic sources . The dimeric steroids have been shown to
exhibit such unique characteristics as detergents'*, miceUular"\
medicinal^, catalytic^ and liquid crystal properties^ that may lead to
important applications. This resulted in the increase of interests of
chemists to synthesize such dimeric or oligomeric steroids*^" '. A brief
survey of recent interesting examples is as follows:
ABBREVIATIONS USED
86
THP
PCC
MTO
DPMSCl
TBAF
DCE
Ts
Py
hr
: Tetrahydropyranyl group
Pyridinium chlorochromate
Methyl rehinium trioxide
: Diphenylmethylsilyl chloride
Tetrabutyl ammonium fluoride
Dichloroethane
: Tosyl
Pyridine
Hour
Ra et.al proposed the formation of a cyclic steroidal dimmer by
the combination of two molecules of lithocholic acid by two ethylene
glycol units. The reaction occurs by reduction followed by cyclizaton.
87
l.LiAlH4,Et2O,0°C
2. Ethylene glycol mono p-tosylate THP-ether, NaH (60%),
THF, 65°C, 3 days
(ID
88
Shawakfeh et al. described the synthesis of new steroidal dimer via
1,3 diaminopropane bridge:
(III)
+ H2N(CH2)„NH2-NaBH (0Ac)3,
DCE, acetic acid
NH(CH2)„HN^Nr' ' '
n = 3 (IV) n = 6 (V)
The choice of NaBH(0Ac)3 as a reducing agent was crucial due to its
selectivity in reducing imines intermediate 14
In analogy new dimer was also obtained from stigmasterol by using
modified method of Parish 15.
89
(VI)
PCC, CaC03
CH2CI2
(VII) H2N(CH2)n NH2, NaBH(0Ac)3,
X DCE, acetic acid
NH(CH2)nHN
n = 3 (VIII) n = 6 (IX)
This method was also applied on cholesterol'^"'^:
(X)
PCC, CaCOs
CH2CI2 ' H2N(CH2)nNH2, NaBH(0Ac)3, DCE, acetic acid
NH(CH2)nHN
n = 3 (XII) n = 6 (XIII)
90
The formation of hydroxylated dimers ' of cholesterol and stigmastenol
is also explained by the conversion of olefinic double bonds to rans-1,2
diols by the oxidation with H202/CH3Re03 (MTO) followed by hydration:
NH(CH2)4HN
(XIV)
CH3Re03/H202 HCIO4, THF
NH(CH2)4HN
(XV)
NH(CH2)3 HN
(XVI)
CH3Re03/H202 HCIO4, THF
NH(CH2)3 HN
(XVII)
91
These hydroxylated dimers are expected to be biologically active 23
24 Heathcock et. al. described the formation of a special type of
steroidal dimer known as cephalostatin in the following manner
starting from 2a-azido-6a-cholestan-3-one: Me V8 >7
(XVIII)
PPh3,H20, THF, r.t.
Me Y8 i7
CgHn^ Me (XIX) 24 Another route for the preparation of the same dimer envolved the
reaction of 3-amino-5a-cholestan-2-one oxime with 3p-acetoxy-2,3a-
oxido-5a-cholestane under thermal conditions:
92
Me V8^i7
+ AcO'
(XXI)
toluene, 85°C, 24 hr.
Me V8^'7
C«H 8^17
Me V8"i7
CgHiT^ Me
10% (XXII)
+ Me V8^17
(XXIII)
93
The dimer (XIX) can also be obtained by following pathway 24.
Me V8 >7
H2N., BH3, THF
(83%)
Me V8^i7
(XXVI) (XXVII)
Me V8^i7
toluene, 110°C,24hr.
(XIX)
28%
94
Formation of this dimer (XIX) is also possible in the following
manner^'*: Me V8^i7
C.U,-( Me • -S"!? (XIX)
Me V8"i7
Following route is also proposed for the preparation of dimer (XIX)
-8^17
NeONHj. HCl, Ny,,
Py,0°C(100%)
OMe
Me V8 i7
(XXV)
PPhj, H2O, THF, r.t. *
(89%)
toluene
I H OMe
140°C, 24 hr. (87%)
-*• (XIX)
(XXVI)
95
25 Dieter et al. gave the synthesis of a steroidal dimer,
cholacyclopeptide by the combination of two molecules of 3a-amino
lithocholic acid with equimolar phenyl alanine:
HoN '''
(XXVIII)
O ^ N /
H' PhCHo
O
'NH
< ^ ^
Phenylalanine
^ v ^ ^ C H ^ P h
/ ^ , O
(XXIX)
96
Another dimer derived from cholic acid is described by Davis
(XXX) Guthrie et al.^ described the formation of another steroidal dimer
having the following structure
NH3 +
(XXXI)
NH
97
,26,27 Another dimer of cholic acid was synthesized ' having the following
structure:
(XXXII) ,28-30
Cholic acid can also give a dimer ' having the following structure
98
Formation of porphyrin substituted steroidal dimers has also been
reported
(XXXIV)
1) DPMSCl, imidazole, CH2CI2, r.t. 12 hr.
2) TiClj, LiAlH4, THF, reflux, 24 hi 3) TBAF, THF, r.t., 3 hr.
(R = Porphyrin)
(XXXV)
99
Discussion
Dimeric steroids have been long investigated because of their useful
biological activities. Since they are obtained by the use of many
reagents, this sustained interest in them prompted us to develop a new
synthetic approach to obtain steroidal dimers. The reaction was carried
out on 3p-tosyloxycholest-5-ene (XXXVI) and 3p-tosyloxystigma-5-
ene (XXXIX), with acetic acid and CUCI2 in dichloromethane in the
presence of 1,3-dibromoprapane. 1,3-Dibromopropane has proved a
good reagent for the synthesis of steroidal dimers in excellent yield.
The availability and safety of reagents and mild reaction conditions
make it a suitable method for the preparation of steroidal dimers.
The formation of the dimer with ether linkages was confirmed by
Rdst's method and can be explained by the formation of oxygen free
radical from tosylate and then the substitution of bromine in the 1,3-
dibromopropane at the two ends by alkoxy free radicals (scheme 1)
100
*- CH3-C-O-CU-CI ^
H
O
CH3-C-0|CuCl+HCl
CHj-C-O* + 'CuCl
R'-O* CH,COO*+ CuCl
R'-a
R 0 - R
Scheme 1 (R = steroidal ring)
101
Reaction of 3B-tosvloxvcholest-5-ene (XXXVI) with 1,3-dibromoDropane
and CuCi?. in presence of acid and dichloromethane; 3,3'-
dipropoxvcholestane OQCXVID and Cholesta-4,6-diene (XXXVIID;
To a solution of 3p-tosyloxycholest-5-ene(XXXVI) in dichloromethane,
CuCli, acetic acid and 1,3-dibromopropane was added. The reaction
mixture was then refluxed with constant stirring for 72 hrs. The reaction
mixture after work up and column chloromatography over silica gel
afforded two compounds, m.p. = 93°C and 80°C.
TsO
g'^i?
(XXXVI)
BrCH2CH2CH2Br, CUCI2
Dichloromethane, acetic acid
+ (XXXVn) gHn 80%
8^17
(XXXVffl)
102
Characterization of the comound, m.p. = SCC as 3,3'-dipropoxv-
cholestane (XXXVII);
The compound m.p. 80°C was analyzed for C57 H96O2. The composition
indicated the incorporation of three carbon atoms and six hydrogen
atoms.
The I.R. spectrum of compound exhibited bands at 1095 cm'
indicating the presence of ether linkage, at 1184 cm'' for C-0
stretching and at 1652 cm'' showing C=C bond.
The N.M.R. spectrum showed a singlet at 6 5.36 showing the
presence of vinylic protons, a broad singlet at 6 4.76 showing the
presence of-OCH2, a sharp singlet at 5 3.35 indicating the C4-2H, a
multiple at 6 3.09, indicating C3a-H, two triplets at 5 2.37 and 2.02
indicating the presence of -CH2 protons. Other methyl group signals
were observed at 5 0.97, 0.98 and 0.99.
According to Rfl.st's method:
1000A;,w 1000*, w Molecular wt = "/"' ^""""-z'
AT,W (/, -t,)W
t2 = m.p. of mixture = ]10''C
ti = m.p. of pure camphor = 175*0
w = wt of solute = 0-1 o.
W = wt of solvent = 1-0 p .
Molecular wt =
103
1000x39.7x0.1 3970
5x1 5
Molecular wt = 794.
On the basis of above spectral data and Ras-t's method the
compound, m.p. = 80°C may be tentatively characterized as 3,3'-
dipropoxycholestane (XXXVII).
Characterization of the compound, m.p. 93"C as cholesta-4,6-diene
(XXXVIII);
The compound m.p. = 93*'C was analysed for C27H44. The
composition indicated the removal of one oxygen aton and two
hydrogen atoms.
The I.R. spectrum of the compound exhibited band at 1635 cm''
indicating the presence of-C=C-C=C- bond.
The N.M.R. spectrum showed a multiplet at 6 2.49 showing the
presence of C3-H2, a broad singlet at 5 4.76 indicating C4-H and C6-H,
a sharp singlet at 5 5.37 for C7-H and a singlet at 6 3.76 for C8-H.
Other methyl group signals were observed at 5 0.85, 0.86 and 0.87.
On the basis of above spectral data the compound, m.p. = 93°C
may be tentatively characterized as cholesta-4,6-diene (XXXVIII).
104
Reaction of 3g-tosvloxvstigma-5-ene (XXXIX) with 1,3-
dibromopropane and CuCl? in presence of acetic acid,
dichloromethane; 3,3'-dipropoxvstigmastane (XL) and stigma-4,6-
diene (XLI);
To a solution of 3P-tosyloxystigma-5-ene (XXXIX) in
dichloromethane, acetic acid, CUCI2 and 1,3-dibromopropane was added.
The reaction mixture was then refluxed with constant stirring for 72 hrs.
The reaction mixture after work up and coluimn chromatography over
silica gel afforded two compounds, m.p. = 96°C and 88°C.
'10^21
BrCH2CH2CH2Br, CuClj
TsO Dichloromethane, acetic acid
(XXXIX)
(XLI) 30%
105
Characterization of compound, m.p. = SS^C as 3,3'-dipropoxv-
stigmastane (XL):
The compound m.p. = 88°C was analysed for C61H104O2. The
composition indicated the incorporation of three carbon atoms and six
hydrogen atoms.
The I.R. spectrum of the compound exhibited bands at 1107 cm"'
indicating the presence of ether linkage and at 1184 cm"' for C-0
stretching.
The N.M.R. spectrum showed a singlet at 5 5.38 showing the
presence of vinylic protons, a broad singlet at 6 4.79 showing -OCH2
protons, a sharp singlet at 5 3.39 indicating C4-2H, a multiplet pointed
at 5 3.35 indicating C3a-H, two triplets at 5 2.41 and 2.10 indicating
the presence of -CH2 protons. Other methyl group signals were
observed at 6 0.99, 1.00 and 1.02.
According to RESt's method:
, , . , 1000A:.w IGGQyt.w Molecular wt = — = —
ti = m.p. of mixture = i7o-5''c
ti = m.p. of pure camphor = n5°C
w = wt of solute = 0 • i p .
W = wt of solvent = I- 0 p •
Molecular wt =
106
1000x39.7x0.1 3970 4-5x1 4-5
Molecular wt= Q%1-
On the basis of above spectral data and RdSl's method the
compound, m.p.=88°C may be tentatively characterized as 3,3'-
dipropoxystigmastane (XL).
Characterization of the compound, m.p. = 96°C as stigma-4,6-diene
(XLI);
The compound m.p. = 96°C was analysed for C29H48. The
composition indicated the removal of one oxygen atom and three
hydrogen atoms.
The I.R. spectrum of the compound exhibited band at 1628 cm''
indicating the presence of-C=C-C=C- bond.
The N.M.R. spectrum of the compound showed a multiplet at
5 2.56 indicating the presence of C3-H2, a broad singlet 5 4.76 showing
the presence of C4-H and C6-H, a sharp singlet at 5 5.37 for C7-H and
a singlet at 5 3.73 for C8-H. Other methyl group signals were observed
at 5 0.89, 0.90 and 0.91.
On the basis of above spectral data the compound, m.p. = 96°C
may be tentatively characterized as stigma-5,6-diene (XLI).
107
Proposal for extension of work:
Further work to support this is underhand for which it is
proposed to take more steroidal substrates like :
TsO OTs
(XLII)
TsO
8"17 8"17
R = OAc(a) Cl(b) H(c)
R=OAc(a) Cl(b) H(c)
108
Experimental
3B-tosvloxvcholest-S-ene(XXXVI)^^
To a solution of cholesterol (4g) (X) in dry pyridine (10ml), p-
tosylchloride (4g) was added and then the mixture was shaken. Within
5-10 minutes a white precipitate was obtained. After that the reaction
mixture was allowed to stand over might. Then it was taken in ether
and ethereal solution was washed successively with dil. H2SO4,
NaHCOs (5%) and water and dried over Na2S04. Evaporation of ether
left an oily residue, which was crystallized from petroleum ether. Yield
= 3.7g, m.p. 130°C (reported m.p. = 130°-132°C)'.
3.3'-dipropoxvcholestane (XXXVII) and cholesta-4.6-diene (XXXVIII):
To a solution of 3P-tosyloxycholest-5-ene (XXXVI) (Ig) in
dichloromethane (30ml), 1,3 dibromopropane (0.20ml), CuCb (0.50g)
and acetic acid (0.20ml) was added and the reaction mixture was
refluxed with constant stirring for 72 hr. The completion of the
reaction was checked by TLC. The reaction mixture after work up and
column chromatography over silica gel afforded two products. Elution
with light petroleum (100%) afforded a solid which was crystallized
109
from methanol to give cholesta-4,6 diene (XXXVIII) (0.200g), m.p. ==
93°C, (reported m.p. = 92.5°C)'
v„,ax: 1635 cm-' (-C=C-C=C- bond)
6 : 2.49 (m,C3-2H), 4.76 br. (s, C4-H and C6-H), 5.37
(s, C7-H), 3.76 (s, C8-H). Signals at 0.85, 0.86 and
0.87 for other methyls.
Analysis found: C(88.00%), H (11.91%)
Calculated for: C(88.04%), H(l 1.95%)
C27H44
Further elution with petroleum ether: ether (98:2) afforded a
solid which was crystallized for methanol to give 3,3'-dipropoxy-
cholestane (XXXVII), (0.800g), m.p. = 80°C.
v^ax: 1095 cm"' (ether linkage), 1184 cm"' (C-0
stretching), 1652.87 cm"' (C=C bond).
5 : 5.36 (s, C6-H (vinylic proton), 4.76 (br s, -OCH2),
3.35 (s, C4-2H), 3.35 (m, C3a-H), 2.37 (t, -CH2)
and 2.02 (t, -CH2). Signals at 0.97, 0.98 and 0.99
for other methyls.
Analysis found: C(84.19%), H (11.78%)
Calculated for: C(84.23%), H(l 1.82%)
C57H96 O2
110
3B-tosvloxvstigma-5-ene(XXXIX)^';
To a solution of stigmasterol (VI) (4g) in dry pyridine (10ml), p-
tosylchloride (4g) was added and then the mixture was shaken. With in
5-10 minutes a white precipitate was obtained. After that, the reaction
mixture was allowed to stand over night. Then, it was taken in ether
and ethereal solution was washed successively with dil. H2SO4,
NaHCOs (5%) and water and dried over Na2S04. Evaporation of the
left an oily residue, which was crystallized from petroleum ether. Yield
= 3.5g, m.p. = 133°C (reported m.p. = IBO^-ISZ^C)'
3.3'-dipropoxvstigmastane (XL) and Stigma-4,6-diene (XLI):
To a solution of 3P-toxyloxy-stigma-5-ene (Ig) (XXXIX) in
dichloromethane (30 ml), 1,3-dibromopropane (0.20 ml) CuCli (0.50g)
and acetic acid (0.20 ml) was added and the reaction mixture was
refluxed with the constant stirring for 72 hrs. The completion of the
reaction was checked by TLC. The reaction mixture after work up and
column chromatography over silica gel afforded two products.
Elution with light petroleum ether (100%) afforded a solid which
was crystallized from methanol to give stigma-4,6 diene (XLI)
(0.300g), m.p. = 96°C.
Vmax: 1628 cm~' ( - C = C - C = C - bond).
111
5 : 2.56 (m, C3-2H), 4.76(s, C4-H and C6-H), 5.37
(s, C7-H, 3.73 (s, C8-H). Signals at 0.89, 0.90 and
0.91 for other methyls.
Analysis found: C(87.85%), H (12.10%)
Calculated for: C(87.87%), H(12.12%)
C29H48
Further elution with petroleum ether:ether (98:2) afforded a
solid, which was crystallized from methanol to give 3,3'-dipropoxy-
stigmastane (XL), (0.700g), m.p. = 88°C.
v„,ax: 1107 cm"* (ether linkage), 1184 cm"' (C-0
stretching).
5 : 5.36 (s, C6-H), 4.79 (brs,-0CH2), 3.39 (s, C4-2H),
3.35 (m, C3a-H), 2.41 (t, -CH2) 2.10 (t, -CH2).
Signals at 0.99, 1.00 and 1.02 for other methyls
Analysis found: C(84.29%), H (11.94%)
Calculated for: C(84.33%), H(l 1.98%)
C61H104O2
112
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