synthesis, spectral and biochemical studies of …
TRANSCRIPT
SYNTHESIS, SPECTRAL AND BIOCHEMICAL STUDIES OF MODIFIED STEROIDS
DISSERTATION submitted in partial fulfilment of the requirements
for the award of the degree of
idasiter of $I}tIogopi)p IN
CHEMISTRY
BY
JAMAb FIROZ
DEPARTMENT OF CHEMISTRY ALIGARH MUSLIM UNIVERSITY
ALIGARH (INDIA) 1994
DS2583
xJediealed to tnif ueloifed
Dr. SHAFIULLAH Professor of Chemistry
Steroid Research Laboratory Department of Chemistry
Tel 25515
AUGARH 202 002 U. P. INDIA
Dated 16.2.1995
C E R T I F I C A T E •**•*••****••***•*•**••
The dissertation entitled 'SYNTHESIS,
SPECTRAL AND BIOCHEMICAL STUDIES OF MODIFIED-
STEROIDS', by Mr. Jamal Firoz is suitable
for Submission for the degree of Master of
Philosophy in Chemistry.
(Prof. Shafiullah)
ACKNOWLEDGEMENT
I am fortunate to have connoisseur guidence of
Prof. Shafiullah Department of Chemistry, A.M.U., Aligarh, who
enabled me to produce this research work with equanimity. His
directions, discussions and his new sense of scientific
approach are his greatest gift to me for which I will remain
obliged life long and highly indebted.
I remain highly greateful to Prof. M.S. Ahmad. The wizard of
chemistry, for his ever extending help, his beneficial
criticism and for his unending support - who spoke chemistry
and taught me life.
I sincerely thank Dr. M. Mushfiq for his generous and
kind support also the chairman. Prof, N. Islam, department of
chemistry for providing me necessary research facilities.
My deepest sense of appriciation are for Mr. Omair
Zubairi, Mr. M. Samiullah, Mr. Ajax K. Mohammad, Mr. M.S. Alam,
Mr. Mahmood Ahmad, Mr. Khurshed A. Khan, Mr. Syed M.A. Razi,
Ms. Sheeba Salamat and Ms. Afrin Shamim, who stood by me
through this tedious task and also my lab colleague Mr. Rao Uwais A.
Khan for his erudite support.
My words fail to express my feelings; for my parents who
lighted the lamp of my education and stood by me with
solidarity and unbending support, the expectations and love of
my brothers and sisters which kept me going.
I also thank Mr. Mohd. Ayub Khan for typing the
manuscript with patience.
(JAMAL FIROZ)
C O N T E N T S • « • * « * • « « • • « « « •
PAGE NO.
CHAPTER-ONE : OXIDATION OF STEROIDAL OLEFINS
A : WITH PDC
THEORETICAL
DISCUSSION
EXPERIMENTAL
REFERENCES
1
14
20
28
13
19
27
31
B WITH MOLECULAR OXYGEN
THEORETICAL
DISCUSSION
EXPERIMENTAL
REFERENCES
32
37
40
42
36
39
41
44
CHAPTER-TWO : OXYMERCURATION-DEMERCURATION
OF STEROIDAL OLEFINS
THEORETICAL
DISCUSSION
EXPERIMENTAL
REFERENCES
45
62
69
73
61
68
n 77
INTRODUCTION
INTRODUCTION
The explosive growth of natural and synthetic chemistry
in the field of steroids during the present century has been
the result of concerted efforts of all the leading organic
chemists. The problem of isolation of the steroid entities
from natural sources, their great value in modern medicine and
the interesting pharmacological properties have brought about
an increasing interest. The synthetic modification of natu
rally occurring steroids, with the hope of improving pharma
cological essentialities, has resulted in preparation and
discovery of a number of diverse pharmacologically active,
potent, highly specific commercially important therapeutic
agents. The physiological activity of steroidal harmones
depends on a number of factors. Among those of primary impor
tance are stereochemistry and over all shape of the molecule.
Thus, any really fundamental change (introduction of double
bond, hydroxy group, acetate group and ring enlargement and
contraction etc.) in the steroid nucleus should alter the
stereochemistry as little as possible. Since these involve
the modification of the basic carbon skeleton of the steroid
nucleus itself, it provided an opportunity to deal with many
problems of fundamental organic chemistry such as mechanistic
and stereochemical aspects of transformations. Moreover, the
deep involvement of modern spectroscopic tools (UV, IR, H-NMR,
C-NMR and Mass spectrometry) in the structure elucidation of
steroidal compounds is envisaged.
During the last decade the mazor efforts of the chemists
were directed towards modification in the structure of steroids
in order to enhance their non-hormonal activity and to increase
the selectivity of certain biologically active compounds. The
broad spectrum of the biological activity found in these com
pounds and the multiplicity of action displayed by certain
individual members make them one of the most intriguing class
of compounds.
Our laboratory concerned mainly with the syntheses of
steroidal compounds and their identification by chemical and
spectral studies, has reported the preparation of a number of
heterosteroids. The fusion of any heterocyclic ring system to
steroid or to introduce any heteroatom such as sulpher, oxygen,
nitrogen or halogen found to augement the biological and
industrial range of them. Hence innumerable methods started
developing across the world to find the better substitutes
for already existing steroids. As a matter of fact steroid
chemistry was always proved to be much inviting to chemists
and industries fascinated us to under take the work in this
direction.
CHAPTER-I
PART-A
THEORETICAL
THEORITICAL :
Oxidation of Steroidal Olefins
The development of new reaction pathways in the synthetic
organic chemistry by oxidation methods had been very much use
ful for the organic chemists. Succeptibility of alkenes and
hydroxy group to the electrophilic attach and their capability
to reduce most of the oxidants motivated the chemists to study
the oxidising effects of transition metal ions and oxides on
alkenes and hydroxy group. The importance of metal ion as
oxidants was due to their low cost, stability and considerably
selectivity with respect to functional groups by virtue of
their action.
The most commonly used inorganic oxidants are potassium
permanganate, Osmium tetraoxide, Ruthenium tetraoxide, Palla
dium chloride, Potassium peroxydisulphate and certain Chromium
and Mercury salts. Besides these, some organic complexes of
these metals were also used for example Pyridinium dichromate.
Butyl chromate etc.
The oxidation of alcohols mainly give carbonyl compounds.
The primary alcohols gave rise to the aldehydes and secondary
alcohols yielded ketones. While alkenes undergo either exhaus
tive oxidation or allylic oxidation depending upon the reaction
conditions, reagents used and also upon the nature of oxidants.
In some cases, the reaction took place at room temperature but
in most of the cases, the reactions are carried out at elevated
temperatures and in some of the cases the reactions even take
place at low temperatures to avoid the extensive oxidation.
The products of these oxidations from olefins were ketones,
a-ketols and other degraded products.
2 Windus and Naggatz reported the oxidation of cholesteryl
acetate (l) with chromic acid in acetic acid which yielded
cholesta-3,b-dien-7-one (II).
CgHj y
V^^^:>^, 0 ( i ; (ii;
Fieser et al. ' identified the oxidation products of
Windus and Naggatz obtained by chromic acid oxidation from
epicholesteryl acetate (III) as 5-acetoxy-5a-cholestan-3,7-
dione (IV) and suggested the intramolecular C^ - C^ acyl
migration.
CoH 8" 17
AcO
(III)
OAc
(IV)
The formation of a,p-unsaturated ketones had also been
reported from the oxidation of steroidal alkenes with chromic
acid. Marshall et al. reported the introduction of ketone
(VI) at C-7 of pregnelone acetate (V) using sodium chromate
8—14 in acetic acid - acetic anhydride solution ( /\ ).
Cholesteryl acetate (VII) with chromium trioxide and acetic
acid yielded five products^ (VIII-XII). Cholesteryl acetate
(I) with chromic acid gave 5,6-seco product (VIII).
: 4
AcO
\=0
AcC
(V) (VI)
CgH^y
AcO AcO
(vii; (VIII)
CQH^J
'•^
98^17
(IX) (X)
: 5
^8^17 ^8^17
(XI) (XII)
CgHj y
AcO' COOH
(I) (XIII)
8 Corey and Suggs had studied the use of Pyridinium chloro-
chromate as oxidant. They reported the advantage of this
reagent over others and showed that it can be prepared easily,
safely and also possesses high capability to convert primary
alcohols into aldehydes in better yield.
Py Cr03 + HCl .^
R - CH
OH
R'
HCrO^Cl
[CrO^Cl]"
N^ [CrOgCl]
R - C - R'
0
William and Co-workers r e p o r t e d t h e o x i d a t i o n of o l e f i n s
( I , XIV-XXVl) with chromium t r i o x i d e - p y r i d i n e complex a t room
tempera tu re and ob ta ined the fo l lowing products (XXVII-XLV) in
good t o moderate y i e l d .
OLEFIN KETONE
AcO
(XIV) (XXVII)
AcO
( I ) (XXVIII)
7 9 f •
Ss^i?
(XV) (XXIX;
(XVI)
0 ^ ^ ^
(XXX)
//
(XVII) (XXXI)
: 8
.CHO
(XVIII)
(XIX)
(XX)
0.
(XXXIII)
(XXXV)
(XXXII)
(XXXIV)
(XXXVI)
(XXI)
. - ^ ^
(XXXVII)
0
0 x (XXII) (XXXVIII) (XXXIX)
: 9
^ - ^
H5C6 ^^6%
(xxiii;
V^^
5 6
(XL)
H5C6 '^6"5
(XLI)
V O
C6H5
(XXIV) (XLII)
0, 0
(XXVI) (XLIV) (XLV)
10
Wender et al. reported the oxidation of 1,4-diene
(XLVI) by pyridinium chlorochromate and obtained dienones
(XLVII) and (XLVIII). Marshall and Wuts'''''" reported on ana
logous behaviour of 1,4-diene (XLIX) with pyridinium chloro
chromate which yielded two products (L and Ll).
c/X) oc6„ (XLVI)
COOR
(XLIX)
(XLVII)
(L) (LI)
12 Djerassi and Lenk reported the use of N-iodosuccinimide
for the synthesis of iodoketones. They treated steroidal end
acetate (LII) with N-iodosuccinimide and obtained 21-iodo-
pregenolone acetate (LIII). Muller and Jones"^^ prepared,
a-iodoketone (LV) from the enol acetate (LV).
11
OAC
(LII) (LIII)
OAc
AcO^'
0
(LIV) (LV)
14 Siemann et al. reported the preparation of 3p-substituted
(20S)-20-[(benzenesulphonyl)methyl]pregn-5-en-7-one (LVII) from
respective 3p-substituted (20S)-20-[(benzenesulphonyl)methyl]
pregen-5-ene (LVI).
OPh
AcO
(LVI) (Lvii;
12
Cholesterol (LVIII) ubiquitously present in mammalian
tissues was subjected to autoxidation by air, peroxidation
in vivo and metabolism. These intriguing events and biolo
gically active oxysterols (LIX-LXXIV) thus produced, were
reviewed in detail 15-17
CQH^J
y,
^
OOH
(LVIII) CoH 8"17
(LIX)
"OOH
(LX)
/
(Lxi; CQH 8" 17
(LXII) (LXIII)
(LXIV) (LXV) (LXVI)
13
CoH 8" 17
(DCVII) (LXVIII)
OOH
(LXIX) (LKX) (LXXI)
0 H
(D(XII) (LXXIII) (LXXIV)
DISCUSSION
DISCUSSION
Since the development of new pathways in synthetic
organic chemistry by oxidation methods had been very useful.
So, an attempt had been made to synthesise the steroidal
ketones with the help of PDC in different aprotic polar
organic solvents and also to judge the effect of PDC in
different solvents. In this work the solvents namely Ether,
Chloroform, Dichloromethane, Carbontetrachloride, Acetone,
Tetrahydrofuran, Dimethylsulfoxide/ether and 1,4-Dioxane were
chosen the best oxidising effect of PDC was noticed in N,N-
Dimethylformamide which afforded the diketone (cholest-4--en-
3,6-dione, LXXII.l)from cholesterol in excellent yield. In
dichloromethane PDC oxidised cholesterol to cholest-4-ene-3-
one (LXVIII) in 40?» yield. The rest cholesterol was recovered
as unreacted. The cholesterol on treatment with PDC in ether
afforded diketone (3.5%, LXXIII) and the rest of the cholesterol
was recovered. It might be due to insolubility of PDC in
18 ether . In chloroform the diketone (40%, LXXIII) was obtained
while in carbon tetrachloride both ketones (LKVIII) and (DCXIII)
were obtained in 75% and 20% respectively. When another aprotic
: 15 :
polar solvent, acetone was taken, provided the ketones (LXVIII,
209 ) and (LXXIII, 32.59^). In tetrahydrofuran the ketones were
obtained (DCVIII, 4.5% and LXXIII, 17.5%). When a mixture of
dimethylsulfoxide and ether was chosen as aprotic polar solvent
the same ketones were obtained (LXVIII, 5.5% and LXXIII, 18.5%).
Here in this case the mixture of solvents was taken because in
DtASO the cholesterol was not soluble while PDC was soluble and
in ether vice versa. The yield as the mixture of ketones was
very poor although no starting cholesterol was obtained. While
in the case of 1,4-dioxane, the ketones were obtained (LXVIII,
4.75% and LXXIII, 13%). The results are summarized in table and
schemes for reactions and mass fragmentation are given. The
mechanism for the formation of ketones is also suggested.
CgHjL7
Dichloromethan
Solvents : Ether CCl^ Acetone THF DMSO 1,4-dioxan Chloroform
5CHEME-I
16
The two compounds obtained from different polar aprotic
solvents showed m.p. 79-"81°C and 125°C.
Characterisation of the compound having m.p. 79-81 C as
Cholest-4-en-3-one (LXVIII) :
The compound (LXVIII), m.p. 79-81 C was correctly ana
lysed for CrjyH. .0. The IR spectrum showed bands at 1680 and
1615 cm " CC=C-C=0)^*^. The " H-NMR spectrum showed a singlet
21 at d 5.9 for C.-vinylic proton . Methyl protons were observed
at d 1.12 CCIO-CH3), 0.68 (CIS-CH^), 0.94 and 0.82 (other
methyl protons). On the basis of elemental and spectral data
the structure of the compound was suggested as cholest-4-en-
3-one (LKVIIi;.
Characterisation of the compound (LXXIII) having m.p. 125°C
as cholest-4-en-3.6-dione :
The compound m.p. 125 C was correctly analysed for
*^27^42^2* ^^^ ^•^* spectrum showed /I max at 250.5 and IR
spectrum of the compound showed bands at 1700 and 1620 cm
(C=C-C=0). Its H-NMR spectrum exhibited a singlet integra
ting for one proton at 5 6.15 and was assigned to the
C4-vinylic proton. The methyl protons appeared at 1,15
(CIO-CH3) and 0.71 (CIS-CH^), 0.91, 0.86 and 0.84 (for other
methyl protons). The mass spectrum of the compound gave
17
molecular ion and some important fragment ions at m/z 398
(Mt), 397, 396, 383, 382, 381, 370, 369, 2&5, 284, 283, 270^
269 and 257. The formation of the fragment ions were explain
ed in the Scheme-2. On the basis of these values, the com
pound, m.p. 125 C was identified as cholest-4-en-3,6-dione
(LXXIII).
m/z 269
-H
m/z 270
-CH3
m,
-H
m/z 284
-H'
m/z 283
"^8^17 /z 285 <^
0 ) ^ ^ ^ X ^
+ M* 398
-CH^ m/z 368 f
-CH,
m/z 383
C8H17
-H
"^8"l7 -CO
m/z 242
-CO
m/z 257
-CgHj y
«
-H /z 370 >m/z 36
^ m/z382--H
- ^ m/z 381
SCHEME-2
18
Cr20y NT
- - " ^
^ N ^
+ 2H-*- + 0X20^
0 0
HO-C-O-Cr-O II ii
0 0
4-
^ s . \ ^r 0 0 II II
HO-Cr-O-Cr
v
""0-Cr-O-Cr-O-H ii II
0 0
' ^ ^ J c -- >
0=Cr=0 0 H
: 19 :
2H +
- H '
H b-H
0-H
PDC
EXPERIMENTAL
EXPERIMENTAL
All the melting points were observed on a Kofler hot
block apparatus and are uncorrected. IR spectra were obtained
in Nujol with a Pye-Unicam SP3-100 Spectrophotometer. IR
values are given in cm" . H-NMR spectra were run in CDCl^
with Me.Si as internal standard values are given in PPM (d;
TLC plates were coated with silica gel and sprayed with 20%
aqueous solution of perchloric acid.
Preparation of PDC (Pvridinium dichromate) :
Chromiumtrioxide (50 g) was dissolved in 50 ml of water
and cooled, then 40.6 ml of pyridine is added. The resulting
solution was cooled to -20 C by external cooling and then
200 ml of acetone is added and filtered immediately under
suction, providing dark red shining crystals, m.p. 156°C.
Reaction of cholesterol with PDC :
To a solution of cholesterol {,2 g) in 44 ml of aprotic
polar solvents, 8.8 g of PDC was added and the reaction mix
ture was stirred at room temperature under anhydrous conditions
21
for 6 hours. The reaction was monitered with the help of
TLC plates. After 6 hours 440 ml of water was added and
the reaction mixture was worked up with the organic solvent
reported in the Table-1 and was washed with water, sodium
bicarbonate solution (10? ) and again with water. The solution
was also washed with dil. HCl, water, sodium bicarbonate
solution and water again and dried over anhydrous sodium
sulphate. The solvent was evoparated under reduced pressure.
The residues, so obtained were column chromatographed over
silica gel. The results of the oxidation of cholesterol withPDC,
in different aprotic polar solvents are summarized in Table-i.
Reaction of cholesterol with PDC t Cholest-4-en-3.6-dione
(DCXIII) :
To a solution of cholesterol (2 g) in 44 ml of aprotic
polar solvents like ether, chloroform, carbontetrachloride,
acetone, tetrahydrofuran, dimethylsulfoxide and 1,4-dioxan,
8,8 g of PDC, was added as shown in Scheme-I and the reaction
mixture was stirred at room temperature under anhydrous con
ditions for 6 hours. The reaction was monitored with the
help of TLC plates. After 6 hours, 440 ml of water was added
and the reaction mixture was worked up with organic solvent
reported in the Table-I in the usual manner. The organic
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26
solution was dried over anhydrous sodium sulphate. After
evaporation of solvent under reduced pressure, the residues
so obtained were column chromatographed over silica gel.
Elution with light petroleum ether : ether (10:1) afforded
o 43 cholest-4-en-3,6-dione having m.p. 125 C (reported , m.p.
122-123°C).
Analysis found : C, 81.4; H, 10.6
Required : C, 81.2; H, 10.85^
U.V. y^max 250.8 nm.
IR : -^max 1700 and 1620 cm"" (C=C-C=0)
-••H-NMR : d 6.15 (s, IH, C4-vinylic), 1.15 (s, 3H, ClO-CH^) (CDCl )
and 0.71 (s, 3H, C13-CH
(other methyl protonsj.
and 0.71 (s, 3H, CI3-CH3), 0.91, 0.86 and 0,84
•"• C-NMR : 161.052 and 125.404 for C5 and C4 respectively.
Mass : m/z 398 [Mtj, 397, 396, 383, 381, 370, 369, 368,
285, 284, 283, 270, 269 and 257.
Reaction of cholesterol with PDC ; Cholest-4-en-3-one (DCVIII)
To a solution of cholesterol (2 g) in 44 ml of aprotic
polar solvents like dichloromethane, carbontetrachloride,
acetone, tetrahydrofuran, dimethylsulfoxide\ether and
27
1,4-Dioxane, 8.8 g of PDC was added as shown in Scheme-I and
the reaction mixture was stirred at room temperature under
anhydrous conditions for 6 hours. The reaction was monitored
with the help of TLC plates. After 6 hours, 440 ml of water
was added and the reaction mixture was worked up with organic
solvents as reported in the Table-I in the usual manner. The
organic solution was dried over anhydrous sodium sulphate.
After evaporation of solvent under reduced pressure, the
residues so obtained were column chromatographed over silica
gel. Elution with light petroleum ether - ether (15:1)
afforded cholest-4-en-3-one having m.p. 79-81°C.
Analysis found : C, 84.21; H, 11.32
^27^44^ required ; C, 84.37; H, 11.46^
IR : -5 max 1680, 1615 cm"- (C=C-C=0)^^.
^H-NMR : d 5.9 (s, C4-vinylic H)^^, 1.12 (s, CIO-CH3),
0.68 (s, CI3-CH3), 0.94 and 0.82 (other methyl
protons).
REFERENCES
REFERENCES
1. Augustine, R.L., *Oxidation Techniques and Applications
in Organic Synthesis*, Marcel Delker, Inc., New York 1,
(1969).
2. Windus, A. and Naggatz, J. Annalen., 542. 204 (1939).
3. Fieser, L.F., Fieser, M, and Rajagopalan, S.J.,
Org. Chem., 13, 800 (1948).
4. Tarlton, E.J., Fieser, M, and Fieser, L.F., J. Am. Chem.
Soc, 75, 4423 (1953).
5. Marshall, C.W., Ray, R.E., Laos, I. and Riegel, B.,
J. Am. Chem. Soc, 79, 6308 (1957).
6. Wintersterner, 0. and Mone, M.J., J. Am. Chem. Soc,
65, 1513 (1943).
7. Elks, J., Phillips, G.H, Taylor, D.A.H. and Wyman, L.J.
J. Chem. Soc, 1739 (1954).
8. Corey, E.J. and Suggs, J.W,, Tetrahedron Letters, 2647
(1975).
29
9. William, G.D., Milton, L. and Dwight, S.F., J. Org.
Chem., 34, 3587 (1969).
10. Wender, P.A., Eissenstat, M.A. and Filosa, M.P.,
J.Am.Chem.Soc, 101. 2196 (1979).
11. Marshall, J.A. and Wuts, P.G.M., J. Org. Chem., 42,
1794 (1977).
12. Djerrasi, C. and Lenk, C.T., J. Am. Chem. Soc, 7^,
3493 (1953).
13. Muller, G.P. and Johns, W.F., J. Org. Chem., 26, 2403
(1961).
14. Siemann, H.J., Schoenecker, B. and Rau, M., Ger. (East)
DD 262, 431, Chem. Abst., Ill, 11567327 (1989).
15. Smith, L.L., Chemistry and Physics of Lipids, 44, 87
(1987).
16. Peng, S.K. and Taylor, C.B., World Rev., Nutz. Diet.,
44, 117-154 (1984).
17. Smith, L.L., 'Cholesterol Autoxidation', Plenum Press,
New York, (1981).
18. Corey, E.J. and G. Schmidt, Tetrahedron Letters,
399-402 (1979).
30
19. L.F. Fieser, J. Am. Chem. Soc., 75, 5421 (1953;.
20. L.J. Bellamy, The Infrared Spectroscopy of Complex
Molecules' (John Wiley, New Yorkj, 136 (1958).
21. N.S. Bhacca, D.H. Williams;'Applications of NMR
Spectroscopy in Organic Chemistry' (Holden-Day, San
Francisco) 79 (1964).
22. E.J. Corey and D.L. Boger, 'Tetrahedron Letters',
2461 (1978).
23. J.G. Moffatt, in 'Oxidation', R.L. Augustine, Ed. Vol,
2, Cap. I, Marcel Dekker, New York (1971).
24. K. Omura and D. Swern, Tetrahedron, 34, 1651 (1978).
25. A.K. Sharma, T. Kv, A.D. Dawson and D, Swern, J. Org.
Chem., 40, 2758 (1975).
26. E.J. Corey and C.U. Kim, J. Am. Chem. Soc, 94, 7586
(1972).
27. G.I. Poos, G.E. Arth, R.E. Beyler and L.H. Sarett,
J. Am. Chem. Soc, 75, 422 (1953).
28. R.H. Cornforth, J.W. Cornforth and G. Popjak,
Tetrahedron, 18, 1351 (1962).
29. W.M. Coates and J.R. Corrigan, Chem. and Ind., 1594
(1969).
31
30. F.A. Miller and C.H. Wilkins, Anal. Chem., 24, 1253
(1952).
31. J.C. Collins, W.W. Hess and F.J. Frank, Tetrahedron
Letters, 3363 (1968).
32. The use of DMF as a Solvent for some chromic acid
Oxidations has been reported by G. Snatzke, Chem, Ber.,
94, 729 (1961).
33. A.J. Fatiadi, Synthesis, 65, 133 (1976).
CHAPTER-I
PART-B
THEORETICAL
THEORITICAL
A.G. Gonzalez et. al. had isolated a new natural aromatic
diterpene, 11,12-dimethoxyabieta-6,8,11,13-tetra-20-oic acid
methyl ester (l) , from the plant Salvia canaliensis L., and
studied the oxidation reactions of this and related compounds
when left to crystallize in air and light in n-Hexane-EtOAc (l)
was transformed into a mixture of three products. The less
polar minor product was identical with the starting material
and formulated as the ketone (IV). Another product of inter
mediate polarity was proposed hydroperoxide structure (III).
Since the reaction took place with 100^ transposition of the
allyl group, a radical mechanism can be discounted. Thus the
autoxidation mechanism of (I) may be considered as a reaction 3
with oxygen in the singlet state , either concerted or with the
intervention of the perepoxide intermediate (II).
33
Scheme-1
OMe
0=0
(I)
M^
(I) +
(III)
M« W^eO^^y^
\ \ ^ UeO^C I 4
\ HO
+
-H 0 2 ^
Me02C
k^^ 0
(IV)
The analogous autoxidation of 1-abietic acid derivative
4 has been described but in this case no intermediate hydroperoxide Was detected.
As part of a study of the synthesis of carnosic acid deri
vatives, the diacetate of carnosic acid methyl ester (V) was
treated with lithium aluminium hydride in tetrahydrofuran in an
34
inert atmosphere to give two products. The less polar and
major compound was the expected triol (Vl). The more polar
product was assigned the structure (VII). When the triol (Vl)
dissolved in n-Hexane-EtOAc (1:3) was left in air it eventually-
changed into (VII). This formation of (VIl) from (Vl) can be
explained in terms of oxidation of (Vl) by the oxygen in the
air to form the orthoquinone (VIIl) and the subsequent collapse
of the C-20 hydroxy group on to the C--7 carbon of the tauto
meric semiquinone methide (IX) in accordance with the proposal
2 of Wenkert et.al. for the formation of carnosol from carnosic
OAc
M e O a c T I )
_:
\
(IX)
35
Baeyer-Villiger oxidation of ketones to esters or lactones
has been developed by using various reagents, e.g., hydrogen
peroxide, peroxy acids and metal catalysts . Recently 5
Kiyotomi Kaneda et-al. studied that a combination system of
molecular oxygen and aldehydes was an efficient oxidant for both 9 10
the oxidative cleavage and the epoxidation of olefines '
Using the above oxidant, they studied a selective synthesis of
lactones or esters from ketones in the absence of metal cata
lyst (Scheme-l) and that addition of benzoyl chloride remarkably
increases yields of the Baeyer-Villiger products. This oxida
tion system, in situ generation of peracids is a very convenient
method for Baeyer-Villiger oxidation, compared with other oxidi-
11-19 zing reagents . They had reported that both epoxidation
and oxidative cleavage of olefins using the system consisting
of aldehydes and molecular oxygen were strongly dependent on
9 10 the kinds of aldehyde used * . Typical results were shown in
Table-1.
0 II C
R. \
R.
CHO
CCl + 0 ^ > R.
"^ 20-40 C •'•
0
l - O H
\
R2 + ^
" ^ ^
Scheme-2
36
Table-1 : Effect of various aldehydes on Baeyer-Vil l iger
Oxidation of cyclohexanone and Epoxidation of
2-octene.
Yield of oxidation products %
Aldehyde Baeyer-Villiger
Oxidation
Epoxidation
PhCHO
m-ClPhCHO
p-CH^PhCHO
(CH3)2CHCH0
(CH^j^CHCH^CHO
78
53
58
38
30
50
36
32
94
Quantitative
It was conceivable that this Baeyer-Villiger oxidation
occurs mainly by an organic peracid generated from the reaction
20 of an aldehyde with molecular oxygen . The three-component
sysgem of aldehyde, molecular oxygen and chlorohydrocarbon
plays as a useful monoxygenation type reagent for both Baeyer-
Villiger oxidation of ketones and epoxidation of olefins even
in the absence of metal catalysts''" * •'.
DISCUSSION
DISCUSSION
Development of the new oxidation pathways in the synthetic
organic chemistry were of great importance. Here an attempt
had been made to oxidize the steroidal olefin with the help
of molecular oxygen and benzaldehyde to yield hydroxy ketone.
The scheme of the reaction which had been carried out is as
follows:
C«H 8" 17
O2, benzaldehyde
CCl., benzoylchloride ji
(X) (XI)
38
Reaction of cholesterol with oxygen and benzaldehyde in
presence of benzolyl chloride (as catalyst) :
A three necked flask fitted with a reflux condenser was
cooled to -15 C and into it, benzaldehyde and carbon tetra
chloride were placed and oxygen was bubbled into the constantly
stirred solution at room temperature for 1 hour. A solution of
cholesterol in carbontetrachloride was added along with benzoyl
chloride used as catalyst and the resulting solution was sti
rred for further 8 hours with constant bubbling of oxygen at
room temperature. Benzoic acid formed during reaction was
removed by the successive treatment of the reaction mixture with
sodium sulphite solution (5%) and sodium bicarbonate solution
(5%) and the CCl. layer was passed through anhydrous sodium
sulphate. Evaporation of the solvent under reduced pressure
provided an oil which was chromatographed yielding solid com
pound, m.p. 237-239°C.
Characterization of the compound having m.p. 237-239°C as
33.5-dihvdroxy-5tt-cholestan-6-one :
The compound having m.p. 237-239°C was analysed for
'^27^46^3' ^^ ^^^ ^^ spectrum a strong and broad absorption
peak at 3350 cm was observed, assigned to hydroxy group.
Another strong absorption peak at 1700 cm" was due to the
39
presence of carbonyl group. The compound showed the m.p.
and mixed m.p. same to the authentic sample of 3p,5-dihydroxy-
5a-cholestan-6-one. So on the basis of above evidences the
compound was characterized as Sp,5-dihydroxy-5a-cholestan-6-
one.
Mechanism :
(X)
N/*
vi
(XI)
EXPERIMENTAL
EXPERIMENTAL
Reaction of cholesterol with oxygen and benzaldehvde in
presence of benzoyl chloride (as catalyst) ! 30.5-Dihvdroxv-
5a-cholestan-6-one (XI) :
A three necked flask fitted with a reflux condenser was
cooled to -15 C and into it, benzaldehyde (2 ml) and carbon-
tetrachloride (10 ml) were placed and oxygen was bubbled into
the constantly stirred solution at room temperature for 1 hour,
A carbon tetrachloride solution (5 ml) of cholesterol (2 g)
was added along with benzoyl chloride (0.1 ml) and the result
ing solution was stirred for further 8 hours with bubbling of
oxygen at room temperature. Benzoic acid was removed by the
successive treatment of the reaction mixture with sodium
sulphite solution (5%) and sodiumbicarbonate solution (5%) and
the CCl^ layer was passed through anhydrous sodium sulphate so
as to remove any traces of water. The solvent was evaporated
under reduced pressure giving an oil (1.8 g) which was chromato-
graphed over silica gel (40 g). Elution with methyl alcohol
gave a solid compound, 3p,5-dihydroxy-5a-cholestan-6-one which
Was recrystallised from methanol, 1,1 g, m.p. and mixed m.p,
237-239°C (reported -'-, 231-233°).
41
Analysis found : C, 77.5; H, 11.0
Required : C, 77.6; H, ll.OJI
IR : -J) max 3350 (OH) and 1700 cm""'- (C=0)
REFERENCES
REFERENCES
1. A.G, Gonzalez, CM. Rodriguez and J.G. Luis,
Phytochemistry, 26, 1471 (1987).
2. E. Wenkert, A. Fuchs and J.D. Mcchesney, J. Org. Chem.,
30, 2931 (1965).
3. J. Hamer, •1,4-Cycloaddition Reactions', Academic Press,
New York and London, p. 255 (1967).
4. T. Ohsawo, M, Kawashara and A. Tahara, Chem. Pharm.
Bull., ai» 487 (1973).
5. K. Kaneda, S, Ueno, T. Imanaka, E. Shimotsuma, Y.
Nishiyama and Y. Ishii, Vol. 59, Number 11, (1994).
6. R.A. Sheldon, J.K. Kochi, Metal-Catalyzed Oxidation of
Organic Compounds, Academic Press, New York (1981).
7. M. Hudlicky, Oxidations in Organic Chemistry, ACS
Monograph, 186, Am. Chem. Soc, Washington, D.C.,
(1990).
43
8. G.R. Krow, Organic Reactions, John Willey and Sons,
New York, Vol. 43, p 251 (1993).
9. K. Kaneda, S. Haruna, T. Imanaka, K. Kawamato,
J. Chem. Soc, Chem. Commun., 1467 (1990).
10. K. Kaneda, S. Haruna, T. Imanaka, M. Hamamoto, Y.
Nishiyama, Y. Ishii, Tet. Lett., 33, 6827 (1992).
11. T. Yamada, K. Takashashi, K. Kato, T. Takai, S. Inoki,
Mukaiyama, T. Chem. Lett., 641 (1991).
12. S.I. Murahashi, Y. Oda, T. Naota, Tet. Lett., 33,
7557 (1992).
13. M. Hamamota, K. Nakayama, Y. Nishiyama, Y. Ishii,
J. Org. Chem., 5^, 6421 (1993).
14. Union Carbide Corp. U.S., Patent 3025306 (1962).
15. A.G. Knapsack, U.S., Patent 3483222 (1969).
16. N.V. Stamicarbon, J.P. Patent Tokkosho, 46-12456 (1971).
17. Mitsubishi Kasei Co. J.P. Patent Tokkosho 47-47896, 1972
and Tokkosho, 56-14095 (1981).
18. Mitsubishi, Gasukagaku Co. J.P. Patent Tokkaihei
5-65245
: 44
19. C. Bolm, G. Schlinglott, K. Weickhardt, Tet. Lett.,
34, 3405 (1993).
20. D. Swern, T.W. Findley, J.T. Scanlan, J. Am. Chem.
Soc, 66, 1925 (1944).
21. L.F. Fieser and S. Rajagopalan, J. Am. Chem. Soc, 71,
3938 (1949).
CHAPTER-n
THEORETICAL
THEORITICAL
Oxvmercuration--Demercuration of Steroidal Alkenes :
Oxymercuration-Demercuration is an effective and effi
cient method for Markovnikov hydration of alkenes. This
reaction was developed and elaborated mainly by H.C. Brown
1-3 and his coworkers . Other workers also made significant 4
contribution in this area of research .
Implicit in the name is the fact that it is a two-stage
process. The first stage, called 'Oxymercuration' involves
the addition of -OH and -HgOAc groups to the carbon-carbon
double bond and the second stage, called 'Demercuration* is
brought about by sodium borohydride (NaBH^), through which the
C-HgOAc bond is replaced by C-H bond. The net result is the
addition of water across a carbon-carbon double bond.
>C=C< + H^O + Hg(OAc)„ Oxymercurgtion ^ _i _ Q-^ i I
HO Hg I
L ' OAc -C - C-' ' . Demercuration Organomercurial
"^ " NaBH^ compound Alcohol
46
The r e a c t i o n i s f a s t and y i e l d i s u sua l l y high in t h e range
of about 90%. The organomercur ia l compound i s u s u a l l y not i s o
l a t e d but i s reduced in s i t u by sodium borohydr ide . Some of the
commonly c i t e d examples of Oxymercurat ion-Demercurat ion are
l i s t e d below :
CH3-(CH2)3-CH=CH2
( I )
1-Hexene
1) H2O, Hg(OAc)
2) NaBH^ 2-> CH3-(CH2)3-CH-CH3
( I I ) OH
2-Hexanol
CH, 1) H_0, Hg(QAc)„ I ^
CH^-CH_-C=CH_ ^ ^—> CH„~CH^-C-CH^ ^ z z 2) NaBH^ ^ ^ I ^
( I I I )
2 -Methy l - I -bu tene
CH^-C~CH=CH_
CHo
1) H^O, Hg(0Ac)2
2) NaBH^
(V)
3 , 3 - D i m e t h y l - l - b u t e n e
OH
(IV)
t - P e n t y l a l c o h o l
CH. I ^
•> CH„-C-CH-CH„ 3 , , 3
H3C OH
(VI)
3 ,3 -Dimethy l -2 -bu tano l
Mercura t ion , when conducted in d i f f e r e n t s o l v e n t s ( o t h e r
t han water ) r e s u l t s in the format ion of o the r compounds. In
such s i t u a t i o n t h e term 'So lvomercu ra t i on ' i s used.
47
The reactivity of alkenes towards oxymercuration appears
to be governed by a combination of steric and electronic
factors.
Table-1 records the observation regarding relative activity
of some of the alkenes.
Table-1
Relative Reactivity of Some Alkenes in Oxymercuration
Cyclohexene 1
1-Pentene 6.6
2-Methyl-l~pentene 48
Cis-2-pentene 0.56
Tran-2-pentene 0.17
2-Methyl-2-pentene 1.27
Oxymercuration-Demercuration process of alkenes has been
claimed to be highly regioselective (Table-2)
Table-2
Regioselectivity in formation of alcohols by oxymercuration-
Demercuration :
Alkene Alcohol Composition
CH3-(CH2)3-CH=CH2 > CH3-(CH2)3-CH-CH3 + CH3-(CH2)4-CH2-0H
(I) (II) °" (VII)
(99.5? ) (0.5^)
1-Hexanol
48
1
1 CH3
(V)
H„C OH 1 1
> L.n--H->-<^n—uii^
H3C
(VI)
(97%)
1
+
CH, 1
CH3-C-CH2-CH2OH
^"3
(VIII) {3%)
3,3-Dimethyl-l-butanol
CH,
HX-C-CH=CH~CH^
CH.
CH. CH,
•> CH„-C-CH-CH^-CH^ + CH_-C-CH^-CH-CH^ O i l 2 0 O I Z I O
H3C OH CH^ OH
(IX) (X) (5%) (XI) (95%)
4,4-Dimethyl-2-pentene
2,2-Dimethyl-3- 4,4-Dimethyl-2-pentanol pentanol
CH3-CH2-CH=CH-CH3
(XII)
Pen t -2 -ene
•> CH3-CH2-CH-C%CH3 + CH3-CH2-CH2-CH-CH3
OH OH
(XI I I ) (44%) (XIV) (56%)
P e n t a n - 3 - o l P e n t a n - 2 - o l
CH„ I ^
Ph-C=CH.
(XV)
CH^ I ^
Ph-C-CH, I
OH
(XVI)
1-Methyl-l-phenyletbene 2-Phenyl-2-propanol
49
It has been noted that despite the stereospecificity of
the first stage, the overall in general is not stereospecific
Rearrangements are seldom noted, if at all. The reaction of
(V) illustrates the absence of the rearrangements that are
typical of electrophilic addition involving carbonium ion
intermediate.
In case of conformationally rigid cyclic systems , as
distinct from unhindered a cyclic alkenes where oxymercuration
proceeds with no rearrangements and amazingly high regiosele-
ctivity, the results are very variable. The effect of sub
stitution on the course of oxymercuration reaction has been 7
visualized in some cases , For example, 4-methylcyclohexane
(XVII) undergoes oxymercuration-demercuration in a remarkably
stereoselective but non-regioselective manner to give a mixture
of cis and trans isomers.
CH-
1) H^O, HgCOAc)^
X ^ 2) NaBH4
CH. CH-
'"OH
(XVII) (XVIII) (1%) (XIX) (47? )
CH-
OH (XX) (51%)
CH.
OH
(XXI)(1%)
50
On the other hand, 3-methylcyclohexene (XXIl) undergoes
hydration in a regio and stereoselective manner forming
3-methyl-cyclohexanol (XXVI) because of torsional effects.
CH.
(XXII)
1) H2O, Hg(0Ac)2
2) NaBH4
/
CH3
,0H
(32? ) (XXIII)
CHo
(XXV) (6%) (XXVI) (78%)
The presence or absence of regio and stereoselectivity is
intricately dependent upon the nature of the alkenes and the
position and size of the substituents. Some useful generali
zations have been made on the basis of continued study on
'Oxymercuration-Demercuration' on a very large number of alkenes
having different structural features and molecular constraints.
They may be briefly summed up in the following manner.
51
A) Addition is cis if the alkene is strained and bicyclic 8-10
B) Norbornene (XXVIl) undergoes cis addition to give
exo-norborneol (XXVIII)
1) H20,Hg(0Ac^ ^
2) NaBH^
H
(XXII) (XXVIII)
C) Both the c i s and t rans addi t ions occur in the case of
bicyclo [2 .2 .2 ] oct-2-ene (XXIX).
1)H 0,Hg(OAc)
> ' 2) NaBH.
H (XXX)
(XXXI) OH
D) Cyclohexene gives t rans addit ion products
Dissociat ion of mercuric acetate
: 52 :
0 II
0
Hg(0-C-CH„) 3'2 <^
J^ +' 0 II
Hg-0-C-CH3 + CH^-C-O
C=CH-R + Hg-0-C-CH^ [ C - CH-R
R R y
]
Hg~0-C-CH3
0
-H"
H2O
R OH • \ I
C-CH-R
R Hg-0-C-CH3
0
NaBH
R OH \ l
C-CH^R
R
(Product)
53
Mechanisms
It is obvious that any mechanistic suggestion of Oxymer-
curation-Demercuration has to consider the two stages separa
tely. Oxymercuration involves electrophilic addition of
mercuric ion. The absence of rearrangement, and the high
degree of stereospecificity (anti-addition) in the first stage
suggests a bridged mercurinium ion intermediate, analogous to
the cyclic halonium ion intermediate. The high preference for
anti-addition is supported by the observation that 4-t-butyl-
cyclohexene (XXXII) gives the two possible diaxial products
(XXXIII) and (XXXIV) •'•'~-'-.
H20,Hg(0Ac
HgOAc
(XXXIII) (XXXIV)
This stereochemical behaviour is typical of nucleophilic
opening of 3-membered rings in the cyclohexane series.
: 54 :
RCH = CH.
(XXXV)
Hg^
-> R-CH.; CH^ or R~CH - CH2
Hg*
(XXXVI) (XXXVII)
Solvent
Product
It is however, not entirely certain whether the initial
intermediate is a bridged-mercurinium ion (XXXVl) or an open
carbonium ion (XXXVIl) . To continue with the assumption
that the cyclic mercurinium ion is an intermediate (Say XXXVI),
it is next attacked by the solvent molecule (water for instance)
from the back-side (unless hindered due to the structural
features) resulting in net anti-addition. The nucleophilic
2 solvent attacks in SN manner and yet the attack occurs at a
more crowded carbon of the bridged mercurinium ion intermediate
as if a free carbonium ion intermediate is involved. The forma
tion of cyclic mercurinium ion in the first place is difficult
to achieve in view of the hybridization of mercury. Secondly,
there is no lone pair of electrons available on mercury to give
cyclic intermediate analogous to halonium ion intermediate.
In addition to these short comings, some additional
comments are inevitable. The oxymercuration reaction is highly
regio and stereoselective and occurs without rearrangement.
55
The c y c l i c i n t e r m e d i a t e may wel l account for non-occurrance of
rearrangement and high degree of s t e r e o s e l e c t i v i t y ( i n t h i s
case t r a n s or a n t i - a d d i t i o n ) .
But i t w i l l not account for *Markovnikov' a d d i t i o n . I n
volvement of c y c l i c bromonium ion i n t e r m e d i a t e , fo r example,
may lead t o ant i-Markovnikov a d d i t i o n .
Br-OH
Br
CH2OH
(XXXVIII) (XXXIX)
This observation which came strongly in support of cyclic
bromonium ion intermediate can be rationalized in the following
manner:
(XXXVIII)
C Br' )
(XL)
Br
—CH^OH
(XXXIX)
56 :
It is understandable that the nucleophilic part of the
reagent (CH) attacks from the less hindered side to give anti-
Mark ovnikov addition products. It is said that such a reaction
has considerable SN character. Attack occurs not at the less
hindered carbon but at the carbon which can best accomodate
the positive charge.
To reconcile with these contradictory situations it has
been suggested that in the transition state in the reaction
of such unstable three-membered rings. There is found much
SN character. Example can be cited from the ring opening of
an epoxide in an acid-catalysed process (SN cleavage)
Nu Nu Nu: ' '
>C — C< > ^LS+
I H
>c"-: c< > -c - c-' I
OH " 0 ^
H
Bond-breaking exceeds
bond-making, positive
charge on carbon.
To make a strong parallel between oxymercuration and
the above scheme is not free from hazard and a very indefen
sible attempt has been made in the following scheme:
57
+ I >C = C< + [Hg""*" 20Ac] > [ >C - C- > >C_7..C<]
.+ Hg-OAc Hg' I OAc
Nu
Nu
Nu .6+ I I 4
> >c C< > -C - C- > Product
\ / . I I
Hg6+ HgOAc 1
I
OAc
A cyclic cationic intermediate of another kind can also
be visualized in which acetate function may participate. This
can be shown according to the following scheme:
Hg(OAc)„ L I I ' >C = c< ^ > -C - C- < > -C - C-
C.:0: Hg 0 Hg II I II I
H3C-C- 0 ^3^"^ 0
ic I w'A H^ H -C - C- "2° ^ \ ^ + ^ ^ ^—> 0 , -H I T 0 j-- Hg >C - C-
H3C-C — 0 0 "g
H3C-C - 0
OH NaBH.
-C C- f—> Alcohol (Product) I ' Hg
OAc
58
Demercuration
The demercuration reaction has eluded full understanding.
The mechanism of the reductive replacement of mercury by hydro
gen (demercuration) most likely, involves a free radical inter-17
mediate produced by decomposition of alkyl mercury intermediate.
RHgX + NaBH^ > RHgH
RHgH > R* + 'HgCDH
R*+RHgH > RH + Hg° + R'
Support in favour of the free radical mechanism from the
observation that oxygen, an efficient radical Scavenger, can
divert the reaction. Further, the stereochemical study
using NaBD. as the reducing agent in consistent with radical
intermediate. For example, 1:1 mixture of erythro and threo-
3-deuterio-2-butanols (XLIII and XLIV) is obtained by mercura-
tion of either cis- or trans-2-butene followed by reduction
with NaflD .
59
H C H HX HgOAc \ / ^ 'N y NaBD.
(XLII)
Cis-eut-2-ene
c - c.
"3=/ H
HQ
" 7 \ •" HO CH,
H CH3
(XLI)
trans-B ut-2-ene
HX^ H H C D
^ \ / ^ ' . y MO — 0 , > t j ^ C — 0 - - ,j_j
H^ NH3 V \ "" HO HO CH3
(XLIII)
H^ H H HgOAc
C = C > ^0 - C. ^
H3C^ ^ C H 3 "3^/ \ ; H
•>
HO CH3
H
> "^^c •
HO
D
- C
<="3
(XLIV)
60
Allvllc Oxidation of Alkenes
The oxymercuration-demercuration stages have also been
used for affecting allylic oxidation of alkenes. Such as
oxidation is a part of the general oxidation of alkenes by
the salts of multivalent metals. These reactions first yield
20 stable mercury adducts . Which on demercuration lead to an
allylic compound depending upon the alkene, the nature of the
21-23 reaction medium and the time of the reaction . The whole
sequence is best illustrated by the oxymercuration-demercura
tion of cyclohexene (XLV) in acetic acid,, which gave in the end
, -24 3-acetoxycyclohexene (XLVI; , an allylic acetate and metallic
mercury.
^ Hg(OAc)^ /^"\>igOAc(NaBH^)
AcOH I J-OAc -OAc
(XLV) (adduct) (XLVI)
+
Hg + AcOH
g.g-Unsaturated Ketones
An interesting yet surprising side reaction could be the
formation of an a,p-unsaturated ketone during oxymercuration-
demercuration stages. This unexpected reaction has been exp
lained by the involvement of allylic ix-complex' .
: 61 :
C = C / \
H - C - H R I H
Hg(OAc),
H \
C / \
H - C - H I H
HO
/
\+ / Hg I OAc
H
R
-H O
H Hg' 1 OAc
<N-> Hg ^ > " "9^ R
H C = C
,0^H
H ( Hg
X R
0 •> RCH = CH-C-R + Hg
DISCUSSION
DISCUSSION
A number of steroidal hydroxyethers were prepared
27-29 earlier by mixed hydride reduction of cyclic acetals
The preparation of these hydroxyethers involved a number
of steps as shown in scheme-1.
Scheme-1
^8^17
HNO, Zn-HOAc
H20,A
(XLVII)
r OH, Bz p-TsOH
^
LiAlH^-AlCl3
63
The scheme of oxymercuration-demercuration of steroidal
alkenes with the sole purpose of obtaining hydroxyethers such
as (XLVIII) was also initiated as shown in Scheme-2.
Scheme-2
CQH^J
1) HgCOAc)^*
2) NaBH,
r-OH
L-OH
(XLVII) (XLVIII)
This scheme offered a much more attractive alternative
route for such steroidal hydroxyethers.
The present work is aimed at oxymercuration-demercuration
of cholest-5-ene (XLVIl) which afforded steroidal hydroxyether
(XLVIII), its acetate derivative (L) and 5a-acetoxyhydroxy-
ether (XLIX) as shown in scheme-3.
Scheme-3
64
CoH 8" 17 pOH
Hq(OAc)^,
reflux 5 hrs
NaBH4, stirred at r.t. 6 hrs
(XLVII)
Acd
(XLIX) O-CH^-CH^
OH
H O-CH,
ACO-CH2
(L)
HO—CH2
(XLVIII)
Reaction of cholest-5-ene (XLVIl) with Hg(0Ac)2, Ethylene
glycol and NaBH^ :
Cholest-5-ene (XLVII) was dissolved in tetrahydrofuran
and ethylene glycol was added to the alkene solution. The
solution was gently warmed on waterbath and mercuric acetate
was added in portions with shaking. After the addition of
mercuric acetate, the reaction mixture was heated under reflux
and worked up. Removal of the solvents afforded organomercu-
ric acetate adduct. This adduct was dissolved in tetrahydro-
furan and sodium Dorohydride was added to this solution. The
reaction mixture was stirred at room temperature for 6 hours.
It was poured into water and the organic matter was extracted
65
with ether. The ethereal solution was washed several times
with water and dried over anhydrous sodium sulphate. The
removal of the dessicant and the solvent gave a sticky semi
solid material which was subjected to column chromatography
on silica gel. Elution with light petroleum gave a small
amount of the unreacted cholest-5-ene (XLVIl), m.p. and mixed
m.p. 94-95°C (reported , m.p. 96°C). Elution with light
petroleum ether : ether (5:1) afforded compound (XLIX) as
semi-solid. Further elution with chloroform provided the
compound (L) as non-crystallizable oil. Finally elution with
methyl alcohol gave (XLVIII) as solid.
Characterization of compound (semi-solid) as 5-acetoxv-6B-
(2'-hydroxyethoxv)-5a-cholestane (XLIX) :
The semi-solid compound (XLIX) was analysed for C^,Hp,.0^.
Its IR gave absorption band at 33CX) cm" as a broad peak
suggested for OH group. Another peaks at 1725 and 1235 cm"""
were suggested for acetate and a peak at 1020 cm"-'" was assigned
for ether linkage. So on the basis of these analytical and
spectral evidences the compound was tentatively characterised
as 5-acetoxy-6p-(2*-hydfoxyethoxy)-5a-cholestane.
66
Characterization of compound (oil) as 66-(2*-Acetoxvethoxv)-5a-
cholestane (L) :
Non-crystallizable oil was analysed for C^iHc^O^. Its IR
spectrum showed the strong absorption peaks at 1725 and 1240
cm" for acetate and a peak at 1040 cm" for ether linkage.
Thus on the basis of above information, the compound was tenta
tively characterized as 6p-(2'-Acetoxyethoxy)-5a-cholestane.
Characterization of compound, m.p. 65 as 6B-(2*-hvdroxvethoxv)-
5a-cholestane (XLVIII) :
The compound, m.p. 65 C was analysed for C^QH^^^*^^. The
IR spectrum showed a broad peak at 3300 cm" assigned for
OH gr6up and peak at 1040 cm" for ether linkage.
Thus on the basis of above studies, the structure of
the compound (XLVIII) was assigned as 6p-(2'-hydroxyethoxy)-
5a-cholestane.
The formation of these compounds were explained on the
basis of mechanism given below :
Mechanism
67
CQH^J
++ + Hg 20Ac
HgOAc
(XLVII)
AcO / CH.
CH2-OH
• ^
-H
c OH
OH
^
NaBH
^ ^ O-CH2-CH2-OH
AcO
H O-CH2-CH2-OH
(XLVIII)
OR
68
(XLVII)
Hg(OAc)
/K
f-OH
-OH
H
N
0 Hg r, f, / "* 0+- H
H3C-C-O CH2-CH2-OH
^
I II 0 - C-CH
NaBH,
AcO CH2-CH2-OH
^
CH2-CH-OH
(XLVIII)
EXPERIMENTAL
EXPERIMENTAL
3B-Chlorocholest-5-ene :
Freshly purified thionyl chloride (75 ml) was added
gradually to cholesterol (100 g) at room temperature in a
round bottomed flask with an up right condenser provided
with CaCl^ tube. A vigorous reaction ensured with evolution
of gaseous products. When the reaction slackened, the reac
tion mixture was gently heated at a temperature of 50-60 C
on a water bath for one hour and then poured into crushed
ice-water mixture with stirring. The yellow solid thus
obtained was filtered under suction and washed several times
with ice-cold water and air dried. Recrystallization of crude
product from acetone gave compound (95.5 g), m.p. 95-96°
(reported , m.p. 96 ). It gave positive Beilstein test and
a yellow colour with tetranitromethane in chloroform.
Cholest-5-ene :
3p-Chlorocholest-5-ene (15.0 g) was dissolved in warm
70
amyl alcohol (300 ml) and sodium metal (35.0 g) was added in
small portions to the solution with continous stirring over a
period of 8 hours. In between the reaction mixture was kept
warm in order to keep the sodium metal dissolved. When the
added sodium metal was dissolved, about 30 ml of ethanol
added to destroy any remaining sodium metal. The reaction
mixture yellowish in colour, was poured into water, acidified
with HCl and allowed to stand overnight. A white crystalline
solid was obtained which was filtered under suction and washed
thoroughly with water and dried. Recrystallization of crude
material from acetone gave compound in cubes (10.8 g), m.p.
93° (reported" ®, m.p. 89.5-91.5°).
Oxymercuration of cholest-5-ene (XLVIl) :
Cholest-5-ene (XLVIl) (6 g:; 16.21 m mol) was dissolved in
tetrahydrofuran (40 ml) and ethylene glycol (50 ml) added to
the alkene solution. The solution was gently warmed on water
bath and mercuric acetate (6 gr 18.83 m mol) was added in
portions with shaking. After the addition of mercuric acetate,
the reaction mixture was heated under reflux for about 5 hours.
The reaction mixture, after allowing to attain room temperature
was poured into water and the organic layer was washed succe
ssively with Water, sodium bicarbonate solution {b%) and water.
71 :
The organic layer was dried over anhydrous sodium sulphate.
After the removal of the desiccant by filtration and the
solvent by evaporation under reduced pressure, the organo-
mercury acetate adduct as a brownish coloured gum (9.2 g =
13.36 m mol) was obtained. No attempt was made to purify the
adduct and it was used as such for the demercuration reactions.
Demercuration of cholest-5-ene (XLVII) - Hg(0Ac)2 adduct with
NaBH. : 5-Acetoxy-6p-(2'-hydroxyethoxy)-5a-cholestane (XLIX),
6g-(2*-acetoxyethoxv)-5a-cholestane (L) and 6S-(2*-hvdroxy-
ethoxv)-5a-cholestane (XLVIIl) :
The organomercury acetate adduct (5 g) of cholest-5-ene
(XLVIl) was dissolved in tetrahydrofuran (60 ml) sodiumboro-
hydride (4 g) was added to this solution. The reaction mixture
was stirred at room temperature for 6 hours. It was poured
into water and the organic matter extracted with ether. The
ethereal solution was washed several times with water and
dried over anhydrous sodium sulphate. The removal of the
desiccant and the solvent gave a sticky semi-solid material
(3.2 g) which was subjected to column chromatography on silica
gel (65 g). Elution with light petroleum gave a small amount
of the unreacted cholest-5-ene (XLVIl), m.p. and m.m.p. 94-95°C
72
(reported , m.p. 96°C). Elution with light petroleum ether :
ether (5:l) afforded a semi-solid compound, 5-acetoxy-6p-(2'-
hydroxyethoxy)-5a-cholestane (XLIX).
Analysis found : C, 75.9; H, 11,.0
Required : C, 76.0; H, 11.0?i
IR : '^max 3300 (br, OH group), 1725 and 1235 (acetate) and
1020 cm""'" (ether linkage).
Elution with chloroform afforded 6P-(2'-acetoxyethoxy)-
5a-cholestane (L) as a non crystallizable oil.
Analysis found : C, 78.5; H, 11.4
Required : C, 78.48; H, 11.3%.
IR : ' max 1725 and 1240 (acetate), 1030 cm""'" (ether
linkage).
Elution with methanol yielded a solid compound which was
recrystallized from methyl alcohol to give 6p-(2'-hydroxy-
ethoxy)--5a-cholestane (XLVIII) m.p. and mixed m.p. 65°C.
Analysis found : C, 80.5; H, 12.0
Required : c, 80.6; H, 11.9%.
IR :iimax3300 (broad, OH group), 1040 tm"" (ether linkage).
REFERENCES
REFERENCES
1. H.C. Brown and P.J. Geoghegan Jr., J. Org. Chem.,
35, 1844 (1970).
2. H.C. Brown, P.J. Geoghegan Jr., J.K. Kurek and G.J. Lynch,
Organometal Chem. Synth., 1, 7 (1970/71).
3. H.C. Brown, P.J. Geoghegan Jr., G.J. Lynch and J.T. Kurek,
J. Org. Chem., 37, 1941 (1972).
4. W. Kitching, Organomet. Chem. Rev., 3, 61 (1968).
5. H.C. Brown and P.J. Geoghegan, J. Org. Chem., 37, 1937
(1972).
6. D.J. Pasto and J.A. Gontarz, J. Am. Chem. Soc, 93,
6902 (1971).
7. H.C. Brown, G.J. Lynch, W.J. Hammer and L.C. Liu,
J. Org. Chem., 44, 1910 (1979).
8. A. Factor and T.G. Traylor, J. Org. Chem., 33, 2607
(1968).
74
9. T.T. Tidwell and T.G. Traylor, J. Org. Chem., 33, 2614
(1968).
10. T.G. Traylor and A.W. Baker, J. Am. Chem. Soc, 8^, 2746
(1963).
11. K.C. Pande and S. Winstein, Tetrahedron Lett., 3393
(1964).
12. J.K. Sille and S.C. Stinson, Tetrahedron, 20, 1387 (1964).
13. M.M. Anderson and P.M. Henry, Chem. and Ind., 2053 (1961).
14. D.J. Pasto and J.A. Gontarz, J. Am. Chem. Soc, 22» ^^80
(1970).
lb. W.L. Waters, T.G. Traylor and A. Factor, J. Org. Chem.,
38, 2306 (1973).
16. H.C. Brown and J.H, Kawakami, J. Am. Chem. Soc, £5, 8665
(1973).
17. C.L. Hill and G.M. Whitesides, J. Am. Chem. Soc, 96,
870 (1974).
18. D.J. Pasto and J.A. Gontarz, J. Am. Chem. Soc, 91, 719
(1969).
19. G.A. Gray and W.R. Jackson, J. Am. Chem. Soc, 9JL, 6205
(1969).
75
20. K.A. Hofmann and J. S§nd, Chem. Ber., 33, 1340 (1900).
21. P. Kanner and C.H. Eugster, Helv. Chem. Acta., 34,
1400 (1951).
22. H. Inhoffen and W. Arned, Annalen., 578, 177 (1952).
23. W. Triebs, G. Lucius, H. Kogler and H. Breslauer,
Annalen., 581» 59 (1953).
24. D.H. Barton and W.J. Rosenfelder, J. Chem. Soc, 2381
(1951).
25. J.C. Strini and J. Metzger, Bull. Soc. Chim. France,
3150 (1966).
26. M.S. Ahmad, Private Communication.
27. M.S. Ahmad, Shafiullah and S.C. Logani, Australian J.
Chem., 21, 1909 (1968).
28. M.S. Ahmad, S.C. Logani and G.A.S. Ansari, Ind. J. Chem.,
B, 9, 1329 (1971).
29. M.S. Ahmad and S.C. Logani, Australian J. Chem., 24, 143
(1971).
30. L.F. Fieser and M. Fieser, 'Steroids*, Reinhold, New York
(1959).
76
31. L.J. Bellamy, 'The Infrared Spectra of Complex Molecules'
John Willey and Sons, Inc. New York (1959).
32. N.S. Bhacca and D.H. Williams, 'Application of NMR
Spectroscopy in Organic Chemistry', Holden-Day, San
Francisco, 1964.
33. C.W. Shoppee and G.H.R. Summers, J. Chem. Soc., 3361
(1952).
34. D.N. Jones, J.R. Lewis, C.W. Shoppee and G.H. Summers,
J. Chem. Soc, 2876 (1955).
35. M.S. Ahmad, N.Z. Khan and Zafar Alam, J. Chem. Res.,
(5), 191 (1985).
36. H. Reich, F. Walker and R.W. Collins, J. Org. Chem.,
16, 1753 (1951).
37. M.S. Ahmad and S. Zia Ahmad, J. Chem. Res., (5), 374
(1984).
38. M.S. Ahmad, Zafar Alam and N.Z. Khan, J. Chem. Res.,
(5), (1989).
39. Q.R. Patersen and C.T. Chin, J. Am. Chem. Soc, 77,
2557 (1955).
40. C.W. Shoppee and G.H.R. Summers, J. Chem. Soc, 1786
(1952).
: 77 :
41. A.P.I. Plattner, H. Heusser and M. Feuner, Helv.
Chemica. Acta., 32, 587 (1949).
42. J.C. Strini and J.H. Metzger, Bull. Soc. Chim., France,
3150 (1966).
43. R.H. Baker and E.N. Squire, J. Am. Chem. Soc, 70, 1487
(1948).
44. C.E. Anangnostopoulos and L.F. Fieser, J. Am. Chem. Soc,
76, 532 (1954).
45. L.F. Fieser, M. Fieser and R.N. Chakravarty, J. Am. Chem.
Soc, 71, 2226 (1949).
46. P.L. Ruddock and Paul B. Reese, J. Chem. Research,
442-43 (1994).
47. H. Reich, F.E. Walker and R.W. Collins, J. Org. Chem.,
16, 1753 (1951).
48. A. Bowers and H.J. Ringold, Tetrahedron, 3J 14 (1958).