A novel fragmentation-cyclization reaction of steroidal α-hydroxy oximes

TETRAHEDRON LETTERS Pergamon

Tetrahedron Letters 39 (1998) 9759-9760

A Novel Fragmentation-Cyclization Reaction of Steroidal ~-Hydroxy Oximes

Katarina Penov-Gaii a, Du[an Miljkovig a, Ljubiea Medi~-Mija~evig b, Evgenija Durendig*, Julijana Petrovig', Vjera Pejanovig b, Slobodanka Stankovig c, Du~an Lazar c ainstituteof Chemistry,Faculty of Sciences,University of Novi Sad, 21000 Novi Sad, Trg Dositeja Obradovi6a3, Yugoslavia. blCN Jugoslavija,Institute, 11000 Beograd, 29. Novembar 111, Yugoslavia. Cinstituteof Physics, Faculty of Sciences, Universityof Novi Sad, 21000 Novi Sad, Trg Dositeja Obradovi~a2, Yugoslavia. Received 9 July 1998; accepted 12 October 1998 Abstract: By a novel "one pot" fragmentation-cyelizationreaction 1713-hydroxy-17ct-substituted-16-oximinoderivatives

in the androstane and estrane series were converted to a new type of D-homo derivative. © 1998 Elsevier Science Ltd. All rights reserved.

In our previous work 1 lactone 8 was prepared directly from the corresponding 17[3-hydroxy-16-oximino derivative 3 and potassium hydroxide in boiling ethylene glycol (Scheme 1). In the present work, examining the chemical behaviour of 17[3-hydroxy-17co-substituted-16-oximino derivatives 4-7 and potassium hydroxide in boiling ethylene glycol, we unexpectedly discovered a ilovel "one pot" fragrnentation-cyclization reaction. Instead of the formation of the corresponding lactones, a new type of Dhomo derivative 9-12 possessing 16-amino functionality were obtained. Starting ct-hydroxy oximes 4-7 were prepared by stereospecific addition of c~-picolyllithium and benzyllithium to the C-17 carbonyl group of 1 and 2 (Scheme 1)2.

The X-ray structural analysis of 12 unambiguously proved the structure of these new D-homo steroids (Fig. 1). Detailed X-my structural analysis of 12 will be published separately.

Figure 1 A perspective view of the molecular structure of compound 12

0040-4039/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved. PII: S0040-4039(98)02166-2

9760

R

I

Oor0orC

d J

OH

8, R 2, only in the case

r C N

R

H

Rj

|, R ! = The residual part of 3 ~-hydroxy-5mldrostene-I 7-keto-16-o×im¢ 2, R 2 = The residual part of 3-naethoxyestra-1,3,5(10)-triene-I 7-keto-16-oxime

H

3, R 2, R 3 = H (77%, mp 215°C) 4, R I, R 3 = CH2PY (78%, mp 235°C) 5, R 2, R 3 = CH2PY (83%, nap 203°C) 6, R I, R 3 = Bn (65%, nap 253°C) 7, R 2, R 3 = Bn (68%, nap 202°C)

, IIO ~ [ ~

.R 4

NH 2 R 9, R I, R 4 = Py (52%, mp 203°C)

10, R2, R4 = Py (79%, nap 238°C) 11, R I, R 4 = Ph (84%, nap 317°C) 12, R 2, R 4 = Ph (84%, mp 249°C)

Scheme 1 a) ct-PyCH2Li, ether, THF, -10°C; b) BnLi, THF, -10°C; c) NaBI-h, HEO-MeOH, KOH; d) KOH (315 mol equiv.), HOCH2CH2OH, 160°C, H20. We suppose that the relative thermodynamic instability of initial compounds (4-7), having 17ct-bulky substituents (R 3 ;~ H), and the relatively high reaction temperature lead to the formation of the intermediate seco-cyano ketones (4a-7a) which, underwent intramolecular aldol cyclization through the intermediates b and e, and finally afforded the D-homo derivatives (Scheme 2).

4-7

GO1FI~ [ I ~ H

LL

I[ ' k ~ .

-N 4a - 7a

9 - 12 ~

4=phor

4]

4b - 7b

..

R

~

1t20

[_L/ c NHJ 4e - 7e Scheme 2

References: 1.

Miljkovid, D.; Petrovid, J. J. Org. Chem. 1977, 42, 2101-2102.

2.

Miljkovi6, D.; Penov-Gagi, K.; Durendid, E.; Saka~, M.; Medid-Mija~evid, Lj.; Pejanovid, V.; Stankovid, S.; Lazar, D. Tetrahedron Lett. 1997, 38, 4683-4684.