Oxetane formation in hypoiodite reaction of 3β- and 3α-hydroxy-Δ5-steroids....

Tetrahedron Letters Ro. 42, PP 4139 - 4142, 1973. Pergamon Prees. Printed in &eat Britain,

OXETANE FORMATION IN HYPOIODITE REACTION OF 38- and 3a-HYDROXY-

A5-STEROIDS. OXIDOMETHYLENE-3a,5a-A-NOR-CHOLESTANE. (1)

Hiroshi Suginome and Kimitoshi Kato

Department of Chemistry, Faculty of Science, Hokkaido University

Sapporo, Japan

(Received in Japan 27 July 1973; received in UJI for publication 10 September 1973)

It was briefly mentioned

steroids affords a mixture of

We examined the products

epicholesterol in some detail

that the hypoiodite reaction of 38-hydroxy-A5-

aldehydes. (2)

from the hypoiodite reaction of cholesterol and

and found that besides the expected iodine-con-

taining aldehyde, oxetanes are formed in substantial amounts.

Cholesterol & (1 g) in benzene (150 ml) in the presence of HgO and 12 (each

3 equivalents) was irradiated through Pyrex for 6 hr by a 100-W high pressure Hg

arc lamp while argon was bubbled. Four products, an amorphous 2 (25-34%), a

crystalline &, (a-11%), m.p. 141-143OC, an amorphous 2 (8-11%) and a fourth

compound of still unknown structure (4%), m.p. 239-241°C, were obtained by the

preparative t1c. The hypoiodite reaction of epicholesterol 2 or 3-deuteriocho-

lesterol ;2, (3) by the same procedure afforded the same series of compounds.

(2, g, E and a fourth compound).

2, 2 and s all contained iodine in the molecules and it was

apparent that 9_ was the expected 3,4-seco-4-iodo-cholest-5-en-3-al

P-cleavage of the 3B-O-radical 4, from its nmr and ir spectra (nmr,

CDC13) 79.33, 18-H, 79.01, 19-H, 75.36

methylene protons, '~4.12 (lH)d, (J=6.0

proton; ir, (neat) 1731 cm -1, CHO).

(lH)d, 25.51 (lH)d, (J=12.0

immediately

due to the

(100 MHz,

Hz), c-4-

HZ), C-6-H, Z1.90 (1H) s, C-3-formyl

The structures of 2 and g were confirmed to be 6a-iodo-oxidomethylene-3%

Sa-A-nor-cholestane and the isomeric 68-iodo-oxidomethylene-3a,5a-A-nor-choles-

tane in the following way. Catalytic hydrogenolysis of either 2 or 2 in a

4139

NO. 42

cholesterol 1

epichol.esterZl 2 HgO-12

3-deuteriocholeTterol 3 hy

w

$, R=aH or pH

J

5 R=aD

l # t RQ.j? I' 8 B

T

z R=HorD

from either 6 or 7 N N

15 R=H, 2 NW R=I

2 k=H or D 20 R=HorD

1

ill

1

hqw hV SHor D

16 or 18 15 or 17 NW r"u luu

No. 42 4141

mixed solvent of benzene and ethanol (5:8 in vol.) with Pd-C for 36 hr led to

the identical iodine-free compound l9, indicating that 2 and 2 are isomeric to

each other. The n.m.r. spectra of l.5, 2, and E all showed a pair of doublets

of AB system from 75.8 to 76.9. One of the doublets of each pair collapsed to

a singlet on double irradiation at the resonance frequencies of the centre of

another doublet, and each pair of doublets is assignable to isolated methylene

protons attached to oxygen-bearing carbon. There was another one-proton broad

singlet around 24.5 in 2, 2, and 19. These are assignable to protons attached

to oxygen-bearing carbon at the C-3, since they are not present in the nmr spec-

tra of products g and g from 3-deuteriocholesterol. Moreover, these compounds

-1 all revealed ir bands due to ethereal linkage at around 1100 cm . These

Nmr signals of g, l6, and g (7,Hz) (100 MHz, CDC13)

l8-CH3 19-CH3 C-3$H C-4-methylene C-6-H

z 9.35 9.10 $2: 15.82,d and 6.28,d (JAB=7.5) 5.45,q(J~=6.0,5;;=12.0)

E 9.2% 0.67 GHfz 75.77,d and 6.68,d (JAB=8.1) 5.78, t

2 9.36 9.13 $Hzi 15.89,d and 6.85,d (JAB=7.6)

results together with considerations of the probable mode of the formation of 15

and s and the reaction of 2 suggested that the framework of g and $, is a

hitherto undescribed oxidomethylene-3,5-A-nor-cholestane. The configurations of

the oxetane rings should be 3a,5a since the C-3H appeared as a broad singlet (4)

and the reported spectral data of oxidomethylene-3$,5$-A-nor-cholestane 2 (5)

were different from those of 2. Besides the above signals the nmr spectrum of

z showed one-proton quartet and that of I.& showed one-proton triplet each as-

signable to protons attached to iodine-bearing carbon since in the nmr spectrum

of u these signals vanished (Table). The spin-spin coupling pattern and the

coupling constants of these signals together with the results of spin decoupling

require that the above protons in z and z must be positioned at the 68 and the

6a in the chair form B-ring. This assignment is consistent with the fact that

the 19-CH3 of I& is considerably deshielded by virtue of the 6-axial iodine when

compared with that of s (A=O.43 ppm).

4142 NO. 42

The observed regio- (6) and stereoselectivity shown by the exclusive for-

mation of oxetanes with 38,5/3-configuration would provide us with some clues in

speculations on the reaction pathways which are depicted as in the Scheme.

There will be two probable major pathways A and B for the formations of 2

and 16 from the intermediate 6. - It has already been shown that the product of

the Paterno-Biichi reaction of 3,4-seco-cholest-4-en-3-al z was solely 3p,Sp-

oxetane g (5). This stereo- and regio-selectivity is understandable by con-

sidering the approach of the excited electrophilic oxygen (7) from the a-side

rather than P-side of the olefinic double bond as shown in% and a in the

Scheme since the transition state z would be less stable due to the presence of

the 19-methyl group. If 2 and z are formed via the Paterno-Biichi reaction of

preformed olefins $O_ and 11, the stereochemistry of oxetane formation would be

governed by the analogous stereoelectronic effect to the case of 2 to form

solely 38,5P-isomers. The observed exclusive formation of 3a,5a-isomer, there-

fore, would preclude the pathway B and would make the pathway A more plausible.

The pathway A is considered to involve either successive radical cyclization (8)

(e.g., i-+2+$) to form more stable 3a,5a-oxetane 14 followed by the radical

combination to form ,l& and l6, or the formation of oxetane 14 via attack of

electrophilic oxygen of the excited 6_ on the ally1 radical moiety. We consider

the former is more likely.

11

2) 3)

4)

5)

6) 7)

8)

REFERENCES AND NOTES

Photoinduced Transformations. XXIV, paper XXIII, H. Suginome and T. Uchida, Bull. Chem. Sot. Japan, in press. K. Heusler and J. Kalvoda, Angew. Chem., 76, 518 (1964). R. S. Rosenfeld, D. K. Fukushima, L. Hellman, and T. F. Gallagher, J. Biol. Chem., 211, 301 (1954). Anomalously small J3H 2aH and JgH 2~~ orientation of the a and 8 bonds at'C3

should be mainly ascribable to the with respect to the oxetane ring

oxygen atom. D. H. Williams and N. S. Bhacca, J. Amer. Chem. Sot., 2, 2742 (1964). H. Booth, Tetrahedron Letters, 411 (1965). Y. Kondo, J. A. Waters, B. Witkop, G. Guenard, and R. Beugelmans, Tetra- hedron, 2, 797 (1972). J. A. Marshall and J. P. Arrington, J. Org. Chem., 2, 214 (1971). A. Hassner, J. Org. Chem., 2, 2684 (1968). N. J. Turro, J. C. Dalton, K. Dawes, G. Farrington, R. Hautala, D. Morton, M. Niemczyk, and N. Schore, Accounts Chem. Res., 2, 92 (1972). H. G. Kuivila and E. J. Walsh, Jr., J. Amer. Chem. Sot., E, 571 (1965).

ACKNOWLEDGEMENT

We are grateful to the Ministry of Education of Japan for financial assist- ance. We thank Miss T. Okayama for the measurements of 100 MHz NMR spectra and the spin decoupling.