1684
JOHN
H. FRIED, GLEN E. -ART11
constant (8 hr.). T h e solution was neutralized (BaC03) ;mtl evaporated t o :L sirup which was extracted once with mcthanol to remove a sinal1 amount of inorganic niatter. A mixture of the methylated sugars (0.353 g.) was dissulverl it1 butanone-water azeotrope ( 2 nil.) cuntaininga few drops o f methanol and added to the top of a cellulose-hydrocellulose column (40 X 2.8 cm. i.d.). Two drops of Sudan I\' was added to mark the front and the column developed with butanone-water azeotrope. The column was jacketed a t 30" and t h e front time was 3.5 hr. with a rate of flow of 25 ml./hr. Tubes 1 (from the dye)-50 were collected every 15 min. and thereafter a t 30-min. intervals, Tyith the results shown in Table 111.
TABLE I11 SEPARATION OF XEUTRAL SUGARS Tube iiiinilrcr
Component niirnlrt~
3-11
1
13-27 60-85
2 3
Identity
2,3,5-Tri-O-methyl-~-arabiiiose 2,3,4-Tri-O-methyl-~-xylose 2,3-Di-O-methyl-~-xylose 2- and 3-0-171ethgl-~-sylc,se
Component 1.-The sirup (40.3 mg.), which had a very slight positive rotation, was shown readily by paper chromatography (butanone-water) t o be a mixture. Using the values [.ID -38.5' (c 1 in methanol) for 2,3,5-tri-O-methyIL-arabinose and [ a ]18.5" ~ (c 1 in methanol) for 2,3,4-trI0-methyl-D-xylose, i t was concluded from the rotation of the sirup t h a t there were present ca. 13 mg. of the arabinose derivative and 27 mg. of t h e xylose derivative. mrhen the sirup was dissolved in methanol containing 1% HCI, the solution became strongly positive in rotation and reached a constant value in 3.5 hr. -4fter neutralization
[CONTRIBUTIONFROM
THE
MERCK, S H A R P
-1ND
LEWISH.S h R E T T
l7Ol. 82
(.4g*c03) the mixture of neutral sugar arid furanoside was separated (111 the cellulose -hydrocellulose coluiiiii . 'Tile tlcutral sugar r w s dctectctl witli p-:iilisidinc > p r : ~ yi l l t1Ilws 10-31 (10 i n i l l . frartirrris) a t i d the fiirwosidr i l l 1u1w- 1 S (positive hlolisch : i d negative p-anisitline). Component la. 2,3,Ei-Tri-O-methylsirup obtained in tubes 1-8 was hydrol acid and oii chromatographic examinatit consist of a single component and t o Ijehavc in the same n a y as an authentic sample of 2,3,5-tri-0-niethyl-r-arabi11~~se. Component 1b. 2,3,4-Tri-O-methyl-~-xylose.-The sirup from tubes 10-21 (20 rng.) partly crystallized on seeding anti was characterized as the crystalline 2,3,i-tri-O-metliyl-Nphenyl-D-xylosylamine, m .p. and mised m.p. 98-100'. Component 2. 2,3-Di-O-methyl-~-xylose.-This component (256 ing.) crystallized on seeding and after rccryst:illization had m.p. and mixed m.p. 7 5 - i i o . Component 3. Mixture of 2- and 3-O-Methyl-~-xyloses. --The sirup (36 rng.) had [ o ] * ~ D +19.8" and was shown by paper chrornatography for 20 hr. in hutanone-water t(Jbe :t mixture of monometh~lu~-loses.Froin tuhes (30-62 and 81.8.5 it mas possible to obtain chrom:~tograpliicallypurc saniples corresponding to 3- and 2-O-methyl-~-xylose, respectively, but not in sufficicnt quantity to prepare any crystalline derivatives. From t h e rotation of the sirup i t was judged t o contain ca. 78%; 3-0-ineth~i-D-sylosearid 22%, 20-methyl-n-xylose.
Acknowledgment.-The authors are grateful to the National Research Council of Canada for continued financial support and to Dr. J. E=. N. Jones F.R.S. for the gift of crystalline 2,."s-tli-O-~riethyl-Dxylose. T'ASCOUVER,
AVD
E.e.,CASAl).3
DOHMERESEARCH LABORA rORIE'3l
Alkylated Adrenal Hormones. The Synthesis of 5-Methylated Pregnanes BY JOHN H. FRIED, GLEXE. ARTH AND LEWISH. S.IRETT RECEIVED AUGUST14, 1959 The synthesis of 5-methylpregnane-llP,17o1,2l-triol-3,20-dione acetate and 5-methyl-l-pregtietie-l1B,l~o1,21-triol-3,20dione acetate via angular niethylation of a suitably protected 6-ketone I1 is described.
Although there is no evidence that allo-dihydro- ing material for the projected synthesis. Although hydrocortisone exhibits anti-inflammatory activity I1 possesses carbonyl functions a t C-6 and C - l l l when administered systemically to animals, local ac- selective alkylation of the 6-ketone was judged to tivity has been demonstrated with this compound.' be the more likely possibility due to the relatively The possibility that the lack of systemic activity unreactive character of saturated 1l-ketosteroids4a; could be due to rapid reduction of the 3-ketone furthermore, on the basis of the stabilitiesdbof the function, prompted us to prepare the sterically enolates involved and in the absence of over-riding hindered 5-methyl analog. This paper describes steric effects, preferential methylation of I1 at C-5 The two possible the synthesis of 5-methylpregnane-11P,17aJ2l-appeared to be indicated.5 triol-3,20-dione 2 1-acetate and 5-methyl-1- p e g - enolic forms of the C-G ketone have double bonds nene-1 lp,17a,21-triol-3,20-dione 21-acetate. Chu- between carbons five and six and six and seven. man2 has described the preparation of &-methyl- Turner6 has shown that in the cholestane series the cholestane-3@,6P-diolby reaction of cholesteryl-@- former is La. 1.5 kcal. more stable than the latter. oxide and methylmagnesium iodide. Attempts to This is in agreement with the initial formation of a utilize this reaction with 17aJ20,20,21-bismethyl- C-5 substituted bromide as the result of brominaenedioxy - 3 - ethylenedioxy - 5,6p - oxidopregnane- tion of 6-ketosteroids.' Initial attempts to methylate I1 using either po110-01(I) did not give the desired 5a-methyl product tassium t-butoxide in t-butyl alcohol or sodium hybut a compound of unknown constitution. However, 17a,20,20,21-bismethylenedioxy-3-dride in benzene were unsuccessful; however, addiethylenedioxy-allo-pregnane-6,1l-dione(II), re(4) (a) Private comrnunicntion from Dr. R. E. Rcyler; cf., howcently r e p ~ r t e d appeared ,~ to be a suitable start- ever, E . R . H. Jones, G. D 3,.leakins and J . S. Stephenson, J . Chein. (1) J. 1.. Hollander, E. AI. Brown, Jr., R. A . Jessar, L. Udell, S . Smukler and M. A . Bowie, A n i t . Rherimalir Diseases, 13, 297 (1954). (2) 31 C h u m a n , J . C h e m . .Tor. J n f i n i i . P z i ~ eC h e w Sect., 7 0 , 2:,8 ( 1 8.49).
f X ) J. 11. Pried, G. I%.'iR (l!l,i!i)
R. Arth : m i I.. €1. Sarett, THISJ C J I ~ R U A I . .81,
.So
