3450
J. Org. Chem. 1988,53,3450-3457
heated at reflux for 1 h, cooled, and poured into 40 mL of 10% ammonium chloride saturated with sodium chloride. Extraction with 3 X 20 mL of dichloromethaneand concentration of the dried (MgS04)extracts under vacuum at 42 "C gave a crude product which was subjected to centrifugal chromatography on a 1-mm alumina plate. Elution with dichloromethane-methanol (99:1) at 0.6mL/min and concentration of fractions 6-23 gave 0.050 mg (88% yield) of (1)-cephalotaxine, mp 122-124 "C (lit.19320mp 115-117,116-118 "C), which gave Et,NMR and mass spectra that matched those of a sample of natural cephalotaxine.
Acknowledgment. We thank Professor Jon Bordner for a n X-ray CrYstdlOgraPhic S t ~ ~ c t u rofe t h e (2,4-dinitropheny1)hydrazone of t h e keto lactam 20. Dr. Percy Manchand kindly hydrogenated our 3,4-(methylenedi0xy)nitrostyrene under high dilution at Hoffmann LaRoche. We are indebted t o Dr. Richard Powell, US. Department of Agriculture, Northern Regional Research Center, for comparison samples of natural cephalotaxine a n d cephalotaxinone. Some of t h e mass spectra were provided by Patricia Matson, Bruce Pitner, Karen LeBoulluec, and Deborah Frasier of our group. The work was
supported by Grant R01 12010 from the National Cancer Institute. Registry No. (1)-1;38848-21-4; 5,13838-23-8;(&)-6,5871201-9;(1)-6(acid), 114942-61-9; 7,1484-85-1;(1)-8,114942-62-0; (1)-9,114942-63-1;10, 6612-99-3;11, 10333-13-8;(&)-lla, 114942-67-5;(f)-12,114942-64-2;13, 114942-65-3;(&)-14, 114942-66-4;(&)-19, 114942-68-6;(&)-20, 114942-69-7;21, 114942-70-0; 22,114942-71-1; (&)-22 (4a D-isomer), 114942-72-2; (1)-24,114942-73-3; (1)-25,114942-74-4; (1)-26,114942-75-5; 27, 114942-76-6;(1)-30,114942-77-7;(1)-31,114942-78-8;(&)-32, 114942-79-9;(&)-33,114942-80-2;(1)-35,114942-81-3;(&)-36, 114942-82-4; (f)-37,114978-16-4; (1)-37(diacetate),114978-17-5; (1)-38,114956-74-0;(&)-39,114942-83-5;(1)-40,114942-84-6; 2-[(p-tolylsulfonyl)oxy]-l-[3,4-(methylenedioxy)phenyl]ethane, 57587-09-4;4,5,6,7-tetrahydrocyclopenta[b]pyran-2(3H)-one, 5587-71-3;(~)-2-(2-cyanoethyl)cyclopentanone, 58734-78-4;2[3~4-(methy1enedioxy)phenY1]ethanOl~ 6006-82-2. Supplementary Material Available: X-ray crystallographic data for compounds 13 and 33 (17 pages). Ordering information is given on any current masthead page.
Novel Convergent Synthesis of Side-Chain-ModifiedAnalogues of 1a,25-Dihydroxycholecalciferoland la,25-Dihydro~yergocalciferol~ Andrzej Kutner,2a Kat0 L. Perlman, Amparo Lago,2bRafal R. Sicinski, Heinrich K. Schnoes, a n d H. F. DeLuca* Department of Biochemistry, College of Agricultural a n d Life Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53706 Received F e b r u a r y 2, 1988
A novel synthetic strategy for the preparation of side-chain-modifiedanalogues of la,25-dihydroxycholecalciferol and la,25dihy&oxyergocalciferol was developed as a part of the extensive synthetic search for vitamin D analogues of potential anticancer activity. In the methodology developed, the preparation of both series of analogues proceeds conveniently through the partially protected la-hydroxyvitaminD C-22alcohol 5 as the common key intermediate. were obtained by alkylation The 24dihomo and 25-cyclopentaneanalogues 1 and 2 of 1a,25-dihydroxycholecalciferol of sulfones 22 and 31,respectively, with tosylate 6. Swern oxidation of alcohol 5 afforded la-hydroxyvitamin D C-22aldehyde 7 as a novel useful precursor for side-chain-modifiedanalogues of la,25-dihydroxyergocalciferol. As a representative example of this series, the 24R analogue 3 was obtained by the condensation of aldehyde 7 with the chiral sulfone 39. Preliminary studies from this laboratory on human leukemia HL-60cells reveal 1 as the most active vitamin D analogue to induce the differentiation of human leukemia HL-60cells with markedly diminished calcemic activity. Recent discoveries from this3 and other laboratories4of valuable biological activity of la-hydroxy analogues of vitamin D modified in the aliphatic side chain have further stimulated our interest in this area. Our extensive studies5 on t h e effect of various analogues of la,25-dihydroxy(1)For a preliminary account of this work, see: Kutner, A.; Perlman, K. L.; Sicinski, R. R.; Phelps, M. E.; Schnoes, H. K.; DeLuca, H. F. Tetrahedron Lett. 1987, 28, 6129. (2)Present address oE (a) A.K., Institute of pharmaceutical Industry, Rydygiera 8,01-793Warszawa, Poland. (b) A.L., Stanford University, Department of Chemistry, Stanford, CA 94305. (3)(a) Sicinski, R. R.; DeLuca, H. F.; Schnoes, H. K.; Tanaka, Y.; Smith, C. M. Bioorg. Chem. 1987,15, 152. (b) Ostrem, V.;Tanaka, Y.; Prahl, J.; DeLuca, H. F.; Ikekawa, N. Roc. Natl. Acad. Sci. U.S.A. 1987, 84,2610. (c) Sai, H.; Takatsuto, S.; Ikekawa, N.; Tanaka, Y.; DeLuca, H. F. Chem. Pharm. Bull. 1986,34,4508. (4)Sai, H.; Takatsuto, S.; Hara, N.; Ikekawa, N. Chem. Pharm. Bull. 1985,33,878. (5)Ostrem, V. K.;Lau, W. F.; Lee, S. H.; Perlman, K.; Prahl, J.; Schnoes, H. K.; DeLuca, H. F. J. Biol. Chem. 1987,262, 14164.
vitamin D on differentiation of human leukemia HL-60 cells led us to the conclusion that the elongation of the side chain of (5Z,7E)-la-hydroxyvitamin D improves significantly its activity. T o further investigate this effect we designed two (2-29 homologues with two additional carbon atoms added t o t h e side chain in both aliphatic a n d alicyclic manner. The novel synthetic strategy developed for t h e preparation of 24-dihomo analogue 1 (Chart I) a n d 25-cyclopentane analogue 2 allows also for t h e more efficient preparation of analogue 36 as well as for further variations of the side chain part of the vitamin D molecule. In our strategy t h e key vitamin D synthons for t h e preparation of all side-chain analogues are C-22 vitamin D like compounds 4-7. These, in turn, can be obtained from commercially available steroid 8 by the classical approach. (6) Sicinski, R. R.; Tanaka, Y.; Schnoes, H. K.; DeLuca, H. F. Bioorg. Chem. 1985,13,158.
0022-3263/88/l953-3450$01.50/00 1988 American Chemical Society
J. Org. Chem., Vol. 53, No. 15, 1988 3451
1,25-(OH),Ds and 1,25-(OH)2D2Side-Chain-Modified Analogues
Scheme I. Preparation of Diprotected Triol 5 O
a '9.
10
R ' = A ~ , R'=H
R'=t-BuMe,Si,
11. R=H
ivc12R=Ts
Rz=CH,
+
Ix t-BuMe2Si0
OSi- t-BuMe2
\\"
5 a Reagents and conditions: (i) KOH, MeOH; HzS04, MeOH; t-BuMezSiC1, imidazole, DMF; (ii) dibromantin, KHC03, hexane, 4 nBu4NBr, THF; n-Bu4NF, s-collidine; (iii) hu, CsHs-Et20; EtOH, A; (iv) p-TsC1, py, 4 "C; (v) KHCOB,MeOH, CH,Cl,, 55 "C; (vi) t-BuOOH, SeOz, CH2Cl2,py; (vii) AcOH, 55 "C; (viii) KOH, MeOH-Et20; (ix) t-BuMezSiC1, imidazole, DMF, 55 "C; (x) LiAlH4, THF, 0 "C.
Scheme 11. Preparation of Side-Chain Fragment 22"
Chart I. Synthetic Strategy
&
roHF
OH
18 ii
...
19. R'=CI,
( 20.
2
R =H 2
R'=PhS, R =H
/I/ ,
22. R' =PhS02, R2=SiEt3
v
OReagents and conditions: (i) MeMgBr, THF; (ii) PhSH, tBuOK, DMF; (iii) MCPBA, CH,Cl,; (iv) Et,SiCl, imidazole, DMF. 4.
5. 6. 7. t-BuMe2Si0 ""
21. R'=PhS02, R 2 = H
IV
3
R=COzCH, R=CH,OH R=CH20Ts R=CHO
OSi-t-BuMe2
a AcO
8
Thus, the 3~-acetoxy-22,23-dinor-5-cholen-24-oic acid (8) was converted t o the silyl ester 9 (Scheme I). Allylic
bromination of 9 a n d dehydrobromination catalyzed by fluoride ion7 afforded 5,7-diene 10 in 48% overall yield from 8. Irradiation of diene 10 and thermolytic [5,7]-sigmatropic hydrogen shift of the resulting previtamin (not shown) provided vitamin D ester 11 in 36% yield.* Stereoselective la-hydroxylation was accomplished by allylic oxidation of the 3,5-cyclovitamin 13 (obtained by buffered solvolysis of tosylate 12) with a selenium dioxide and tert-butyl hydroperoxide ~ y s t e m . Cycloreversion ~ of l a ( 7 ) Rappapold, M. p.; Hoogendorf, J.; Pauli, L. F. In V i t a m i n D. Chemical Biological and Clinical Endocrinology of Calcium Metabolism; Walter de Gruyter and Co.: Berlin, 1982; p 1133. ( 8 ) DeLuca, H. F.; Schnoes, H. K.; Lee, S.-H. US. Pat. 4512925,1985; Chem. Abstr. 1985, 103, 105227~. (9) (a) Paaren, H.; DeLuca, H. F.; Schnoes, H. K. J. Org. Chem. 1980, 45, 3253. (b) Esvelt, R. P.; Paaren, H. E.; DeLuca, H. F. J. Org. Chem. 1981, 46, 456.
Kutner et al.
3452 J . Org. Chem., Vol. 53,No. 15, 1988 S c h e m e 111. Preparation of Vitamin D3 Analogue 1"
4
6-
OR
t-BuMe2Si0
\\'\
22 + il
+
OSiEt,
23
24
\
OSi-t-BuMe2
OSlEtj
S02Ph
jiii OSIEt3
35-
25
i
jV
HO 1 OReagents and conditions: (i) p-TsC1, py, 5 "C; (ii) LDA, T H F , -20 "C; (iii) 5% Na/Hg, Na2HP04,MeOH: (iv) n-Bu4NF, T H F , 50 "C.
hydroxyvitamin 14 in glacial acetic acid as a proton source and nucleophile gave predominantly acetoxy alcohol 15 (in 19% yield from 11) with t h e desired 52,7E geometry of the triene system and 5E,7Z minor isomer 16 in the ratio of 2.5:l. To improve the overall yield of the hydroxylation sequence (11-15) ester 16 can be converted t o 15 by the known triplet-photosensitized irradiation.'O After partial hydrolysis of the 3P-acetoxy group in 15, both l a - and 3P-hydroxyls in 17 were protected with tert-butyldimethylsilyl chloride. Lithium aluminum hydride reduction of protected ester 4 afforded alcohol 5 in an excellent yield. Our synthesis of the side-chain fragment of analogue 1 started from 5-chlorovaleryl chloride (18) as the readily available C-5 synthon (Scheme 11). Preparation of the terminal tertiary hydroxyl was easily accomplished by Grignard reaction of 18 with methylmagnesium bromide. Chloride 19 thus obtained was converted t o sulfone 21 by the standard method, i.e. 19 was treated with potassium thiophenoxide in alkaline DMF to give sulfide 20, which in turn was oxidized with 3-chloroperbenzoic acid to afford t h e sulfone 21 in 67% yield from 18. Triethylsilyl ether was selected for the protection of the tertiary hydroxyl in sulfone 21. We anticipated the simultaneous deprotection of all three hydroxyls (la, 3/3, a n d 25) in the final step of our synthesis of analogue 1. T h e construction of the side-chain part of analogue 1 was accomplished by the alkylation of the protected sulfone 22 with the vitamin D tosylate 6.l' Alkylation of sulfone 22 (Scheme 111) and deprotonated with lithium diisopropylamide with tosylate 6 afforded the mixture of C-23 epimeric sulfones 23 a n d 24 in the ratio (10)Gielen, J. W. J.; Kmlstra, R. B.; Jacobs, H. J. C.; Havinga, E. Recl. J . R. Neth. Chem. SOC.1980, 99, 306. (11) The preparation of a similar bis(triethylsily1)C-22 tosylate has been reported after our work on 6 was completed. Andres, D. R.; Barton, D. H. R., Hesse, R. H., Pechet, M. M. J . Org. Chem. 1986, 51, 4819.
Scheme
IV. Preparation of Side-Chain F r a g m e n t 314
26 ii iii iv
c
