J . Org. Chem., Vol. 43, No. 9, 1978 1653
10,19-Dihydrovitamins Related t o Vitamin D2
Studies on Vitamin D (Calciferol) and Its Analogues. 14. On The 10,19-DihydrovitaminsRelated to Vitamin D2 Including Dihydrotachystero121*2 Antonio Mourifio3 a n d William H. Okamura*
Department of Chemistry, C‘niuersity of Californiu, Riuerside, California 92521 Received September 27,1977 Vitamin Dz (la), its benzoate (lb), 5,6-trans-vitamin Dz (2a),and its benzoate (2b) were each treated with 9-borabicyclo[3.3.l]nonaneand then oxidized with basic hydrogen peroxide to afford the following pairs of stereoisomeric: 10,19-dihydrovitamin Dz’s: 3a-4a, 3b-4b, 5a-6a, and 5b-6b, respectively. Catalytic reduction of la and 2a afforded the stereoisomeric pairs 3d-4d and 5d-6d, respectively. The four benzoyloxy alcohols 3b-6b were each individually converted to their p-toluenesulfonates 3c-6c, respectively, and then each diester was subjected to lithium triethylborohydride reduction to afford 3d, 7,5d, and 8, respectively. Finally, saponification of 4b produced 4a and 6b gave 6a. How these chemical transformations including spectral analyses definitively establish the absolute configurations of 3-6 is discussed. The relationship of 3d-6d to the substances referred to in the old literature as DHTa. DHV2-11, DHV2-111, DHV2-IV, and DT-66 is also discussed. Vitamin D2 (la, e r g o ~ a l c i f e r o l )is ~ utilized extensively as a dietary supplement in foods. Two of its analogues, (5E)-vitamin 112 (2a)5and dihydrotachysterol2 (5d, DHT2), ?a
Scheme 1. Chemical Transformations0 l a A- (3a, 43%) + (4a, 43%) 2a 2- (5a, 33%) + (6a, 39%) 1 b L (4b, 51%)+ (3b, 33%) 2b a ,(6b, 39%) + (5b, 1 8 % ) (3d, 54%) + (4d, 35%) la (6d, 25%) + (5d, 3 5 % ) 2a 4b 4a ( n o t 3a) 6 b L 6a ( n o t 5 a ) 3 b b 7 3b3d (not 4 d ) 6b% 8 5b 5d ( n o t 6 d )
a
la, R = H b, R = C,H;CO
2a, R = H b, R = C,H,CO
have found clinical applications. In fact 5d was marketed as early as 1934 under t h e trade name A. T. 10 by E. Merck (Darmstadt) a s a n antitetany agents6T h i s substance (5d) is one of t h e four possible stereoisomers (3d-6d) which could result from saturation of t h e 10,19 double bond of l a a n d 2a. T h e corresponding stereoisomers in t h e natural vitamin D3 series have recently been fully characterizedlb by this laboratory, b u t there remained uncertainty in t h e identity of t h e 10J9-dihydrovitamins in t h e D2 series referred t o in t h e older literature a s DHT2, DHV2-11, DHV2-111, DHV2-IV, and DT-66.7.8 Thi.; paper not only describes t h e full stereoN
4 z
5
structural characterization of 3d-6d and related derivatives b u t also delineates improved synthetic procedures incorporating a strategy t h a t should allow t h e convenient preparations of new 19-substituted dihydrovitamins with potential antagonist properties.9
Results and Discussion
h
3
a, R, = b, R , C, R , = d, R ,
a The absolute yields of products are given in parentheses. The first product given of each pair in eq 1-6 corresponds t o the less polar component obtained under the column chromatography conditions used for the separation. Reactions: ( a ) 9-BBN, HO-/H,O,; ( b ) H,/C,H,/[ (C,H,),P] RhC1; ( c ) KOH/CH,OH; (d)p-TsC1, C,H,N; ( e ) Li(CH,CH,),BH.
6
H; R, = CH,OH C,H,CO; R, = CH,OH C,H,CO; R, = CH,OSO,C,H,-p-CH, H; R, = CH,
T h e chemical transformations carried out in this study are outlined in Scheme I. T h e following observations are pertinent: (1)Each of t h e reactions (catalytic hydrogenation8 or hydroboration-oxidationlb) of 1 a n d 2 results in two a n d only two stereoisomeric products. T h u s t h e stereochemical integrity of t h e A58’-diene is retained in each case (eq 1-6). ( 2 ) Equations 7,8,10, a n d 12 prove t h a t members of each of t h e following triads possess t h e same relative stereochemistry: 3a-3b-3d, 4a-4b-4d, 5a-5b-5d, a n d 6a-6b-6d. (3) Our earlier I H - N M R resultslb in t h e vitamin D3 series of dihydrovitamins lend considerable confidence on t h e basis of spectral comparisons t o the Clo configurational assignments given t o t h e four monoalcohols 3d-6d. T h e transformations given in eq 9-12 now also provide definitive chemical evidence for these assignments. T h i s requires, of course, that t h e structures of t h e cyclization products 7 a n d 8 are assigned correctly. Their spectral d a t a ( N M R , UV, MS) are certainly in line with the assigned structures and moreover this kind of
0022-326317811943-1653$01.00/0 0 1978 American Chemical Society
1654 J . Org. Chem., Vol. 43, No. 9, 1978
Mourino and Okamura
T a b l e I. Chemical Shifts a n d Bandwidths of the Haa Resonance
_______ (5Z,7E-dienes) Trans (CH3, OH), 3d Cis (CH3, OH), 4d Trans (CHzOH, OH), 3a Cis (CHzOH, OH), 4a Trans (CHzOH, OBz), 3b Cis (CH20H, OBz), 4b Trans ( C H ~ O T SOBz), , 3c Cis (CHzOTs, OBz), 40 (5E,7EE-dienes) Trans (CH3, OH), 5d Cis (CH3, OH). 6d rans (CHzOH, OH), 5a Cis (CH*OH, OH), 6a Trans (CHzOH, OBz), 5b Cis (CHzOH, OBz), 6b Trans (CHzOTs, OBz), 5c Cis (CHzOTs, OBz), 6c
Registry no. 65377-86-8 65377-87-9 75338-35-4 65377-88-0 65338-36-5 65377-89-1 65338-37-6 65377-90-4
-W3m
Hz
W3,
5.97 7.7 6.4 20 5.92 9 (6.2-6.6)" b 4.67 9 5.0 23 -4.8
