A STEREOSELECTIVE KING X SYXTHESIS
Xug. 20, 19.X
-!I 1 1
potasiiurii Iiydroxitlc :in11 crystallizntion from ncetonereaction niixturr. was refluxed for :ihours a t i d t h e w l u t i w i alcohol; iri.p. 144- 146" ( i i o t clear abuve 2811"); [el'; +%.(lo poured into hydruchloric acid. Then the solution was ( c 0.9 CHClJ), umBp 3380 an.-' in S u j o l . This is a C8-, treated a s previously described. The residue, obtained by reinoval of the solvent, was cri tallizeti twice from methaClr- or C1;-isomer of cholestanol. Anal. Calcd. for C2;H4~O:C , 83.,50; H , 12.37. Found: nol to yield X S V I , 1n.p. 236 No,!.ield 100 m g . , vnlkiY :~1) bonate catalyst containing 2VG palladium, and 0.0164 mole -113'. of hydrogen was introduced a t atmospheric pressure and 25'. -4naZ. Calcd. for C18H240a: C, 75.0; H , 8.4. Found: The catalyst was removed by filtration, and the solvent was C, 74.9; H, 8.5. removed in Z ~ ~ C Z L tOo give the oily saturated aldehyde. ( - )-anti-trans-l,Z,3,4,4a,4b ,5,8,8a,9-Decahydro- 1 @, 8a- IVithout purification. this oil was dissolved in 50 ml. of dioxane, and 100 ml. of benzene mas added along with 1.0 ml. dimethyl-2-oxophenanthrene-I-propionic Acid (II).-The of ethylene glycol and 0.12 g. of p-toluenesulfonic acid. methylanilinomethylene blocking group was introduced in the 3-position of VI1 in the usual manner.*l3 Both the The reaction mixture was heated and the water azeotrope slowly distilled during a 1 hr. period. After the remainder formyl compound and the methylanilinomethylene comof the solvents were removed iiz vacno, the residue was taken pound were oils. The yields were essentially quantitative, but the compounds were not purified. The methyl group up in chloroform and washed with 5YGsodium bicarbonate solution and water. Evaporation of the dried solvent gave was introduced by adding to a slurry of 0.57 g. of potassium amide in 100 ml. of ether 1.4.g. of the blocked X'II. T h e 3.26 g. (697cj of the ethyleneglycol acetal X I I I a , m.p. 1:38139'. mixture was refluxed for 3 hr., cooled to 25" and 3.0 g. of methyl iodide in 10 ml. of ether was added. The mixture A n a l . Calcd. for CI9H2603: C, 74.4; H , 9.0. Found: w a s stirred For 16 hr. Water was then added, the layers C, 74.4; H , 9.0. separated and the aqueous layer was acidified and stirred dl-anti-trans-( 1,3-Dioxolane-Z-yl)-2,3,3a,4,6,7,8,9,9a,9bwith ether for 1 hr. to cleave S-methylaniline from the moledecahydro-6a,3a-dimethyl-?-oxo-( lH)benz[e]indene - 6-procule. The ether laver was separated and the ether was repionic Acid (XIVa).-To a solution of 35 ml. of dioxane conmoved in D Q C I L O . The residual oil was refluxed for 3 hr. taining 0.60 ml. of acrylonitrile was added 2.00 g. of X I I I a , with 50 ml. of a 15el KOH solution. T h e solution was and the solution was cooled to 0-5'. Then 0.5 ml. of Triton cooled, acidified, extracted with ether and the ether solutinn B was added and the mixture was stirred at room temperawas washed with water and dried. One gram of oily mateture under a nitrogen atmosphere for 65 hours.g Dioxane rial was obtained from the ether. The desired acid I1 was was removed in '~"acz~o, and the residue was taken up in 60 isolated from the mixture b y using the quinine salt method of ml. of chloroform, washed thrice n-ith 20-ml. portions o f separation,2 yield 0.12 g. (ll.5%), m.p. 123-1263', Mixed saturated sodium chloride, dried and the solvent was remelting point showed no depression with material previously moved in z'ucuo to give an oily nitrile. The nitrile (2.086 preparG6.2 g . ) was refluxed with 50 ml. of 10Vo potassium hydroxide dZ-anti-trans-4,4a,4b,S ,6,?,8,8a-Octahydro-60,7P-dihy-for 8 hr. under nitrogen. T h e alkaline aqueous phase was droxv - 1S a - dimethvl - Z(3H)uhenanthrone (VIIIa).2-This extracted with ether, and the ether phase was worked up to material was m a d e from tge tricyclic ketone VIa using give 0.360 g. of starting material. T o the aqueous phase either osmium tetroxide according to the Woodward2 prowas added 100 ml. of ether, and after cooling t o 0-5", the cedure or better with silver acetate and iodine (reference 3, mixture was acidified with cold dilute sulfuric acid. hfter footnote 9). For the most part, we used the 0-cis-glycol separating the layers, the ethereal extract was washed with which corresponded to the minor osmium product of LVood- water, dried and the solvent was removed to give 1.892 g. ward, although the a-cis-glycol worked equally well. of acids. Trituration with ether and filtration gave 1.067 dr'-~~~cti-trans-4,4a,4b,5,6,?.8,8a,9,10-Decahydro-6~,?Bg. (57.5%) of acid XIf7a, m.p. 15S-16I0. dihydroxy- 1,8a -dimethyl-2 -(3Hjphenanthrone (XIa).-.l Anal. Calcd. for C21HsaO:,:C , 69.6; H , 8.3. Found: slurry of 7.0 g. of palladium-on-strontium carbonate conC, 69.7; H, 8.5. taining 2% palladium in 300 ml. of isopropyl alcohol was pre-reduced with hydrogen. Then 3.27 ml. of 10% sodium dl-anti-tmns-( 1,3-Dioxolane-2-yl)-2,3,3a,4,6,9,9a,9b-octahydroxide and 32.7 g . (0.125 mole) of VIITa were added and hvdro-7-hydroxy-6n ,3a-dimethyl-( 1H)benz [elindene - 6-pro0.125 mole of hydrogen was ahsorbed a t 25'. The mixture pionic Acid &Lactone (XVa).-The crystalline keto acid was filtered and the filtrate mas neutralized with acetic acid. XIVa (0.300 g . ) was dissolved in 20 ml. of acetic anhydride
Azx
containing 0.010 g. of anhydrous sodium acetate and the iiiisture !vas refluxed for 4 lir. under a n atmosphere of riitrogen. -1fter the acetic anhydride was removed i n zmczio, tlie residue was taken up in ether and washed n-ith 5 S ; sodium carboiiate solution and water. Drying and removal of the solvent gave a crystalline residue. The residue was dissolved in 2.0 nil. of acetone, 2.0 ml. of Skellysolve B was then added :inti the solution was refrigerated tsvcriiight. After filtering and drying, there was obtained 0.2,XJ g. (80.7',;) of enol lactone XT'a, ni.p. 151.5-15?". A n d . Calcd. for C?1H.s04: C, 73.4; 11, 8.2. Found: C, 73.6; H , 8.5. Trcatiiient of this cnol lactoiie acciirtliiig to tlie procedure given for the preparation of tetracyclic kctone X I 7 gni-e ii crystalline compound whose infrared spectruiii shon-et1 strong hydroxyl absorption a n d the absence of a,p-unsaturated carbonyl absorption. This fact in addition t o the similarity of infrared spectra of XVa in the 7.5 p region with the enol lactone from I11 showed t h a t this enol lactone !vas in the 10-epi-methyl or unnatural s e r i e ~ . ~ , ~ ( - )-Methyl anti-trans-2,3,4,4a,4b,5,8,8a-Octahydro-8amethyl- 2 - oxo - 1 - phenanthrenepropionate (VIc).-Thirty grams of T-Ih was esterified by refluxing for 2.5 h r . with 512 g. of methanol and 17 g. of drJ- hydrogen chloride. T h e , the residue was excess methanol was removed in Z ~ U C I I C Iand taken u p in ether and washed with 5C-i bicarbonate solution and then with water. Removal of the ether gave 31.7 g. of oil (100Tc) xyhich did not crystallize and \vas used without purification. ( - )-Methyl nnti-ti.ans-l,2,3,6a,7,7a,lOa,ll,l l a , llbDecahydro-3 - oxo- 6a,9.9 - trimethylphenanthro- [2,3]- [ 1,3jdioxole-4-propionate (IX).-To a solution of 31.7 g. of ester I T c in 1165 ml. of glacial acetic acid and 3.6 ml. nf water was added 38.2 g. of silver acetate and over a period of 30 minutes, 27.2 g. of iodine. T h e mixture was stirred 1 hr. a t 20-25" t o consume all the iodine and then \vas heated a t 90-95" for 3 hr. After cooling and filtering, the bulk of the acetic acid \vas removed in z'acuo. The residue was dissolved in 500 ml. of methanol, filtered and neutralized t o PH 9 with niethanolic potassium hydroxide. .in additional 13.6 g. of potassium hydroxide in 300 nil. of tnethnnol as added and t h e mixture stirred 16 hr. under nitrogen at Xfter neutralizing with aceticacid, the methanol wasreniorcd under vacuum and the crude cis-glycol was taken u p in chloroform. T h e organic phase after washing with water and bicarbonate was dried and evaporated under vacuum t o give 20.6 g. of crude neutral glycol T'IIIc. A%citlificatioii of the bicarbonate wash yielded a thick water-insoluble gum. This acidic material ( Y I I I h ) \vas re-esterified by first dehydrating with benzene and then treating with inethanolic hydrogen chloride as above to give niore neutrxl oil>-
carbonate solution, dilute sulfuric acid solution, water :inti finally dried, T h e solvent wis rerii(ivci1 itr w c u o :ind t i l ? residue was taken u p in 600 ml. of benzene. Xfter heating the solution to 60", 1 ml. OF acetic acid and 2.8 ml. of piperidine were added, and the water was azeotroped out in a slow stream of nitrogen during a 1-hr. period. T h e reaction mixt lire was cooled, washed successivel!. with tliliitc hytlroc!iliiric ;tcitl, tlilute sodiuni tiicarbonate solutiiiii, \v:tter a t i i i finally dried. .\fter retnovul of the solvent in i ' t m ~ um i t l trituration of the residue with ether-Skellysolve B , there was obtained 2.13 g. (S2r: )of X I I b . m . p . 71-73', [ a ! % +61.3". .117iii. C.ilcc!. for C13H1.0!: C, 72.1; 11, 7.7. Found: C , 72.1; 1-1, 7.8. ( - )-Methyl ii~ifi--irnii,s-3-( 1,3-DioxoIane-Z-y1)-2,3,3a,4,5,7,8,9,9a,9b-decahydro-3a-methyl- 7-oxo-( LH)benz [ elindene-6-propionate (XIIIb).--The aldcliyde X I I b was converted b - the procedure used for X I I a to XIIIa, involving first a reduction and then reaction with ethylene glycol, to X I I I b , m.p. 100-101",[ C Y ] ~ -21.5'. ~D Calcd. for CnlFLOi: C , 69.6; H , 8.3. Found:
--iinns-3-( 1,3-Dioxolar?e-2-y1)-2,3,3a,4,6,7,8,9,9a,9bdecahydro-6p,3a-dimethyl-7-oxo( l H ) b e n z [ e ]indene - 6-pro-
pionic Acid (XIVb1.--The keto ester X I I I b (1.222 g . ) 1 ~ : ~ s dissolred in -1-0nil. r i f Iicnzene containing 14 rnl. of f-hutyl alcohol, a n d 28.4 inl. c i f 0.467 S potassium t-butoxide solution w a s added. Tlic misture \vas refluxed under it nitrogen atmosphere. :ind 1.8 nil. of nietliyl iodide was added. -1fter refluxing for 5 minutes, 20 nil. of water was added, and the mixture \viis stirred for 20 minutes while it n ; i s cooling t i i rootii teinperature. Tlie layers wcre separated and :iftcr the aqueous layer TWS extracted with ether, it was cooled tii 0-5' and acidified in the presence of 50 ml. of ether with dilute sulfuric acid. .lfter the layers werc i e p w i t e d , t h e tiqucous layer was extracted with 50 ml. of ether and t h e combined extracts were washed lvitli water a n d dried. Keiiioval of the solvent gave 1.196 g. (97.8(;) of a n nil whose infrared spectrum shon-ed no a,B-unsaturated carbonyl group. Thii oil \ v r i i useti in t!ic iicx; i t c p \yitliout purific:it ion. nnti--irnii.s-3-( 1,3-Dioxolane-2-yl)2,3,3a,4,6,9,9a,9b-octahydro-7-hydroxy-68,3a-dimethyl(1H)benz [e]indene - 6-propionic Acid &Lactone (XVb'I.-The oil!- keto acid X1T.h (1.191 g , ) w i b dissolved in 1.5 1111. i i f :icetic aiili>-tiridecontaining 0.010 g. o f :tiihydrou.; xritiiutn :icct:ttc, :Iiicl the niixturf was refluxctl for 1 hr. under a n atmosphcrc i i f nitrogen. .\fter the acetic :itih>-dritlc \v'i\ taken up iii ether anti n z i i t l water. Tlrying an(i r g. (8X', 1 o f :in i i i l w l ~ t i ~infrared c spertruni shon.ctl that it \vas mainly t h e enol 1,ictiiiic X \ - h but that i t cont;iiiicd some ;riihydritles a< Ire11 a s m i n e cnril 1:ictotic X\.:I. Tlii5 oil \v:is s a t cr~-stal!ization, used in the next step without further purification. ith acetone a ~ i dan( )A$ ,:l-Dehydro-21-norprogesterone-20-ethyleneGlycol hydrous copper sulfate.283 The crude crystalline acctonidc e prcviiiu.;l>- obtained crudc (lily ,@-enol after trituration with ether weighed 21.1 g., 1n.p. 120-122'. g . ) i\-:isrlissolvctl in 100 in1. o f ether conChromatography of the mother liquors g:ive 0.8 g. more, enzerie, and after cooling tlie mixtiire to amounting to 5 5 5 over-all yield from the acid STb. Re- 3i1°. 3,(1 nil. of 4.0 -1f i7ietli>-linagnesiumbromide solution crystallization from methanol gave a pure sample of the was :tdded m e r ;t 20-ininutc periinti . 'The mixture T W S acetonide, m.p. 12.7-124°, !cY]'~D -242". >tirrctl for 1 lir. a t --clicketone XI-1, i1i.p. 176-170". I c Y ] ? ~I -~T~f j " . the acetonidc group givirlg the glycol S I b . Subsequently, The m.p.. iniseti rn.p., optical riitatioii ant1 infrnretl 300 i d . of 50c,; acetic acid was added, the reacspectrum were itleiitical irith those of tlic tetracyclic ketone tion mixture was cooled t o 0-5" and 9.8 g. of lead tetrarlcrired from (f700dward's ( ) ~ ~ ( ' l ) ~ l ~ - l , i s t i e l i ~ r l r o - L ' l - n o r acetate was added. After stirring for 15 minutes, 250 ml. of progesterone, whose preparation is described below. ice-water \vas added and the mixture was extracted twice .Anal. Calcd. for C2?HsnO:: C, 77.2; H , 8.8. Found: with 100 ml. of chloroform. T h e combined chloroform exC, 77.0; H, 8.9. tract was washed successively with water, dilute sodium bi-
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M. L. WOLFROM AND A. THOMPSON
4116
Vol. 78
A@(11~-Dehydro-21-norprogesterone.--rl slurry of 0.08 g. of recrystallized from methanol, m.p. 177-180°, [ a I 2 6$79.1’. ~ palladium-on-strontium carbonate containing 2% palladium Anal. Calcd. for C&roOl: C, 77.2; H, 8.8. Found: in 4 ml. of isopropyl alcohol was hydrogenated a t atmosC, 76.8; H, 8.9. pheric pressure a t 25’. Then 0.350 g. of Ag(11)v16-bisdehyAcknowledgment.-We thank Dr. R. H. Munch, dro-21-norprogesterone (XVII) was added and washed in Mr. G. W. Ashworth and Mr. 0. E. Kinast for with 2 ml. of isopropyl alcohol, and the hydrogenation was continued until one molecular equivalent of hydrogen was their help with the numerous spectra required added. The reaction mixture was filtered and the isopropyl in this work. We are also indebted to Dr. R. B. alcohol was removed in vacuo. Trituration with ether Woodward for much valuable advice and assistance yielded 0.17 g. of crystals, m.p. 127-131°, [ a 1 2 54-120”. ~ and to Dr. 0. J. Weinkauff, Associate Director of A@~11~-Dehydro-21-norprogesterone-20-ethylene Glycol Acetal (XVI).-The procedure for the reaction between AY(llJ- Research, whose interest and coBperation made this dehydro-21-norprogesterone and ethylene glycol was the work possible. same as for the preparation of XIII. A 71% yield of XVI was obtained, m.p. 173-176”. The analytical sample was ST. LOUIS4, Mo.
[ COSTRIBUTION FROM
THE
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DEPARTMENT O F CHEMISTRY O F THEOHIO STATE UNIVERSITY]
Occurrence of the (1
3)-Linkage in Starches1
BY M. L. WOLFROM AND A. THOMPSON~ RECEIVEDFEBRUARY 2, 1956 The presence of a small number of CY-D-(1 + 3)-linkages in amylopectin is shown by the isolation, by means of carbon and silicate column chromatography, of 3-0-a-~-glucopyranosyl-~-glucose (nigerose), as its P-D-octaacetate, from the acid hydrolyzate of amylopectin under conditions in which its formation by reversion is negligible.
It is now generally accepted, on the basis of or (1 -P 3)-linkages. NigeroseI2 (“sakebiose”13 ~~.~~ m e t h ~ l a t i o n ~and - ~ rotational6 studies, that the or the sugar of the “ y - a ~ e t a t e , ”3-O-a-D-ghlco.principal linkage in starch is a - ~ - (+ l 4), in agree- pyranosyl-D-glucose) has been isolated1* from the ment with the long known fact that enzymic deg- acid hydrolyzate of the polysaccharide “mycodexradation of starch produces maltose7 as the major tran” or “nigeran” produced by the action of product. Freudenberg and co-workers4found that Aspergillus niger on sucrose. Periodate oxidation completely methylated potato starch, upon hydrol- of amylopectin16followed by reduction and hydrolysis produces a small amount of D-glucose, which, ysis, yields 9OyG of 2,3,6-tri-0-methyl-~-glucose, 5% of 2,3,4,6-tetra-O-methyl-~-glucose and ap- assuming complete reaction, indicates the presence proximately 5% of a mixture of di-0-methyl-D- of either (1 -+ 3)-linkage alone or of both (1 + 2)glucoses, consisting mainly of 2,3-di-O-methyl-~- or (1 3)- and (1 4)-linkages in the same D-glUglucose. These data indicate that a glycosidic copyranose unit. We wish t o present herein definitive evidence for linkage may occur a t both carbons 6 and 4 in a small proportion of the D-glucose units later shown* the presence of the 3-0-a-~-glucopyranosyllinkage to be located in the predominant amylopectin frac- in the amylopectin molecule. This evidence contion of the starch. This observation has been sists of the isolation of 3-O-a-~-glucopyranosyl-~confirmed by later workersg who have isolated iso- glucose as its crystalline ,8-D-octaacetate from an maltose (6-O-cu-~-g~ycopyranosy~-D-g~ucose) as its amylopectin (waxy maize starch) acid hydrolyzat,e crystalline p-D-octaacetate from the acetylated acid produced under conditions in which the formation hydrolyzate of amylopectin, prepared under con- of this disaccharide during the hydrolysis is ditions minimizing reversion products t o a negligi- negligible.10,14 Therefore, a small amount of an ble quantity.lO C Z - D - ( ~+ 3)-linkage exists preformed in the amyloEvidence obtained from periodate oxidation” pectin molecule. The finding17 that intestinal exindicates that some of the dextrans contain (I + 2)- tracts hydrolyze nigerose offers further support for the presence of this linkage in starches. (1) Preliminary communication: M.L. Wolfrom and A. Thompson,
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THISJOURNAL, 77, 6403 (1955). (2) Research Associate of the Corn Industries Research Foundation. (3) W. N . Haworth, E. L. Hirst and J. I. Webb, J. Chem. SOL.,2081
(1928). (4) K . Freudenberg and H . Boppel, Ber., 79, 609 (1940); K. Freudenberg and G. Hull, i b i d . , 74, 237 (1941); K . Freudenberg, ibid., 7 6 8 , 71 (1943). (5) C. C. Barker, E. L. Hirst and G. T. Young, N o f u r e , 147, 296 (1941). (6) K. Freudenberg, Chern.-Zlg., 60, 853, 875 (1936). (7) C. O’Sullivan, J . Chem. SOL.,25, 579 (1872): 29, 478 (1876). ( 8 ) K . Meyer, M. Wertheim and P. Bernfeld, Hclv. Chirn. A d a , !2S, 865 (1940). (9) M .L. Wolfrom, J. T. Tyree, T . T. Galkowski and A. N. O’Neill, THISJOURNAL, 78, 1427 (1950); 73,4927 (1951). (lo) A. Thompson, M. L. Wolfrom and E . J. Quinn. ibid., 75, 3003 (1953). (11) Allene Jeans, W. C. Haynes, C. A. Wilham, J. C . Rankin, E. H. Melvin, Marjorie J. Austin, J. E. Cluskey, B. E. Fisher, H . M . Tsuchiya and C. E. Rist, ibid., 76, 5041 (1954).
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Experimental 3-O-a-~-Glucopyranosyl-~-~-glucose Octaacetate from Amylopectin Acid Hydrolyzate.-Amylopectin (32.4 g. of waxy maize starch, equivalent to 36 g. of D-glucose) was suspended in 9000 ml. of 0.1 N hydrochloric acid solution and stirred in a boiling water-bath. The hydrolysis was followed by (12) S. A. Barker, E. J. Bourne and M. Stacey, J . Chem. S O L . ,3084 (1953). (13) K . Matsuda, G. Hiroshima. K. Shibasaki and K . Aso, J. Fermentation Tcchnol. (Japan), 32, 498 (1954); Tohoku J . A g r . Rcs c a ~ c h 6, , 239 (1954); C. A , , 49, 8554 (1955). (14) A. Thompson, Kimiko Anno, M . L. Wolfrom and M. Inatome. TRISJOURNAL, 76, 1309 (1954). (15) S. Peat, W. J. Whelan and Kathleen A. Hinson, Chemisfry 6’ Industry. 385 (1955). (16) M. Abdel-Akher, J. K. Hamilton, R. Montgomery and F. 74, 4970 (1952). Smith, THISJOURNAL, (17) J. Larner and R. E. Gillespie, ibid., 7 8 , 882 (1956).
