SH - ResearchSpace

(1)

http://researchspace.auckland.ac.nz

ResearchSpace@Auckland

Copyright Statement

The digital copy of this thesis is protected by the Copyright Act 1994 (New Zealand).

This thesis may be consulted by you, provided you comply with the provisions of the Act and the following conditions of use:

• Any use you make of these documents or images must be for research or private study purposes only, and you may not make them available to any other person.

• Authors control the copyright of their thesis. You will recognise the author's right to be identified as the author of this thesis, and due acknowledgement will be made to the author where appropriate.

• You will obtain the author's permission before publishing any material from their thesis.

To request permissions please use the Feedback form on our webpage.

http://researchspace.auckland.ac.nz/feedback

General copyright and disclaimer

In addition to the above conditions, authors give their consent for the digital copy of

their work to be used subject to the conditions specified on the Library Thesis

Consent Form.

(2)

(3)

(4)

(5)

A B S T R A C T

T h i s t h e s i s i s concerned w i t h a s t u d y o f the o x i d a t i o n of ring-A a r o m a t i c s t e r o i d s u s i n g e i t h e r chromium trioxide-aqueous s u l p h u r i c a c i d - a c e t o n e o r chroinium t r i o x i d e - a q u e o u s acetic acid mixtures

.

I t was found t h a t chromic a c i d o x i d a t i o n of ring-A a r o m a t i c s t e r o i d s s u b s t i t u t e d w i t h a s t r o n g e l e c t r o n - d o n a t i n g group, g i v e s

r i s e

t o p r o d u c t s w i t h the site o f o x i d a t i o n b e i n g predominantly t h a t t o t h e a c t i v a t i n g group. Thus C-3 methoxy ring-A a r o m a t i c s t e r c l d s g i v e the c o r r e s p o n d i n g 9P-hydroxy-11-0x0 and 9-0x0-9,11 -seco-1 1 - o i c a c i d d e r i v a t i v e s as t h e major p r o d u c t s a n d t h e 6-0x0 d e r i v a t i v e as a minor o x i d a t i o n p r o d u c t . However, a k e t o l was n o t formed if a C-3 methoxy ring-A a r o m a t i c steroid also contained a subs t i tu e n t a t C-1

.

^The^C-I-methoxy-4-methyl ring-A a r o m a t i c s t e r o i d s g i v e the 4 - c a r b o : ~ d e r i v a t i v e as the major p r o d u c t and again _thr:6-0x0 compound as

a minor

n e u t r a l p r o d u c t . The a c e t o x y and methyl s u b s t i t u t e d ring-A a r o m a t i c s t e r o i d s , however, a l l g i v e r i s e t o t h e 6-0x0 d e r i v a t i v e s as t h e major

p r o d u c t s . The u s u a l o x l d a t i o n p r o d u c t o f a ring-A a r o m a t i c s t e r o i d i s t h e r e f o r e t h e 6-0x0 p r o d u c t unless i t i s s u b s t i t u t e d w i t h

a

methoxy group i n a p o s i t i o n ^whichwill s t a b i l i s e an e l e c t r o n deficiency 62 a t a s i t e o t h e r than C-6. O x i d a t i o n will t h e n

occur

(6)

predominantly at the s t a b i l i s e d s i t e unless i t i s s t e r i c a l l y blocked.

A mechanism f o r t h e f o r m a t i o n of r i n g 4 oxygenated products obtained from o x i d a t i o n of ring-A a r o m a t i c s t e r o i d s i s proposed.

The i n i t i a l p r o d u c t o f chromic acid o x i d a t i o n o f a t e r t i a r y

b e n z y l i c carbon atom i s t h e c o r r e s p o n d i n g t e r t i a r y a l c o h o l and i t seems p r o b a b l e t h e r e f o r e t h a t t h e 9-hydroxy-11-0x0 steroid

d e r i v a t i v e s a r e formed by initial hydroxylation at the C-9 p o s i t i o n . Dehydration would then a f f o r d t h e A 9 , l l - u n s a t u r a t e d s t e r o i d which could t h e n be converted into t h e k e t o l by further d i r e c t o x i d a t i o n . A l t e r n a t i v e l y t h e g(11 )-alkene could be oxidised t o a 9 ( 1 1 ) - e p x i d e and opened t o a d i o l b e f o r e f u r t h e r oxidation t o t h e k e t o l .

I n seeking s u p p o r t f o r t h e suggested pathway, t h e

p r e p a r a t i o n and o x i d a t i o n of

a

s e r i e s of 3-methoxyestra-1,3, ~ ( 7

o),

9(11 ) - t e t r a e n s was i n v e s t i g a t e d . The same major p r o d u c t s were isolated from o x i d a t i o n o f these 3-methoxyestra-l,3,5(7 0) ,9(11)- tetraenes as from o x i d a t i o n

of

the corresponding 3-mcthoxyes tra- 1

,3,5(10)-trienes .

These r e s u l t s p r o v i d e evidence f o r

i n t e r m e d i a t e 9,ll-alkcne f o r m a t i o n when ring-C oxygenated products a r e o b t a i n e d from o x i d a t i o n of a ring-A aromatic s t e r o i d . The

(7)

o x i d a t i o n o f a n e s t r a - 1 , 3 , ~ ( I o ) , 9 ( l l ) - t e t r a m e w i t h an a c e t a t e group p a r a t o t h e o x i d a t i o n s i t e g i v e s t h e s a n e major p r o d u c t s as f o r a methoxy gr0u.p i n t h i s p o s i t i o n e x c e p t t h a t now t h e

o r i e n t a t i o n o f t h e C-9 hydroxyl group i s d i f f e r e n t . T h i s r e s u l t i n d i c a t e s t h a t once t h e 9(11)-double bond i s formed i n the o x i d a t i o n o f a ring-A a r o m a t i c s t e r o i d , i t i s r a p i d l y o x i d i s e d f u r t h c r

.

The 9-0x0-11-oic a c i d d e r i v a t i v e s could a r i s e as t h e

expected C-9,11 cleavage p r o d u c t s of t h e C-9,11 alkene o r diol, o r through f u r t h e r o x i d a t i o n

of

the k e t o l i t s e l f . Evidence f o r t h i s last p o s s i b i l i t y was o b t a i n e d by o x i d a t i o n o f a k e t o l under t h e same c o n d i t i o n s as f o r t h e o t h e r s t e r o i d s s t u d i e d , when 3%

c o n v e r s i o n t o the 9-oxo-l l - o i c a c i d o c c u r r e d ,

During t h e p r e p a r a t i o n

of

one

of

t h e e s t r a t e t r a e n e s , an i n t e r e s t i n g a r o m a t i s a t i o n r e a c t i o n was found. Both e s t r o n e ( 4 h ) and estrone-3-methyl e t h e r ( 4 c ) on t r e a t m e n t w i t h 2,3-dichloro-

5,

6 - d i c y a n o : b c n z a q ~ u i n o ~ ~ ~ g i v e t h e c o r r e s p o n d i n g 9 ( l l wehydro- d e r i v a t i v e s (2%) and (84a) i n good y i e l d . O t h e r ring-A a r o m a t i c s t e r o i d s have undergone ring-D-fissi~n-C-aromatisation r e a c t i o n s w i t h D.D.Q. ( s e e

p . 7 3 ) , cven

i n systems capable o f undergoing ring-C a r o m a t i s a t i o n w i t h o u t ring-D opcning. I n t h e p r e s e n t work,

(8)

D .D

.Q. treatrncnt o f 3-methcxyestra-1 , 3 , 5 ( 1 0 ) - t r i c n c ( 4 e ) gzve, as well as a small amount of t h e expected 9(11)dchydro-compound, t h e s t e r o i d a l dil1ydrophcnantIlre;1~' 3-nt:thoxy-I 2-methyl-I R-norestra- 1 , 3 , 5 ( 1 9 ) ,P, 1 .I , 1 3 - h e x a e n e ( l 3 8 ) , an6 t h e p h e n a n t h r ~ n e 3-methoxy- 12-methyl-I 8-norestra-1 ^;3 ,

5,7,s9l I ,

1 3-hcptaene(! 39)

,

vhcre ring-C a r o m a t i s a t i o n had o c c u r ~ e d 5 y a shift of the C-18 methyl group without cleavage of rinz-D.

(9)

(10)

(11)

(12)

(13)

(14)

(15)

(16)

(17)

(18)

(19)

(20)

(21)

(22)

(23)

(24)

(25)

(26)

(27)

(28)

(29)

(30)

(31)

(32)

(33)

(34)

(35)

(36)

(37)

(38)

(39)

(40)

(41)

(42)

(43)

(44)

(45)

(46)

(47)

(48)

(49)

(50)

(51)

(52)

(53)

(54)

(55)

(56)

(57)

(58)

(59)

(60)

(61)

(62)

(63)

(64)

(65)

(66)

(67)

(68)

(69)

(70)

(71)

(72)

(73)

(74)

(75)

(76)

(77)

(78)

(79)

(80)

(81)

(82)

(83)

(84)

(85)

(86)

(87)

(88)

(89)

(90)

(91)

(92)

(93)

(94)

(95)

(96)

(97)

(98)

(99)

(100)

(101)

(102)

(103)

(104)

(105)

(106)

(107)

(108)

(109)

(110)

(111)

(112)

(113)

(114)

(115)

(116)

(117)

(118)

(119)

(120)

(121)

(122)

(123)

(124)

(125)

(126)

(127)

(128)

(129)

(130)

(131)

(132)

(133)

(134)

(135)

(136)

(137)

(138)

(139)

(140)

(141)

(142)

(143)

(144)

(145)

(146)

(147)

(148)

(149)

(150)

(151)

(152)

(153)

(154)

(155)

(156)

(157)

(158)

(159)

(160)

(161)

(162)

(163)

(164)

(165)

(166)

(167)

(168)

(169)

(170)

(171)

(172)

(173)

(174)

(175)

(176)

(177)

(178)

(179)

(180)

(181)

(182)

(183)

(184)

(185)

(186)

(187)

(188)

(189)

(190)

(191)

(192)

(193)

(194)

(195)

(196)

(197)

(198)

(199)

(200)