D-hl.\NNOSA\IINE .4ND D-GLUCOSZVINF
Slay 5, 1060
curred spontaneously during this process. Recrystallization from 35 ml. of absolute ethanol yielded 10.1 g. (83%) of material, m.p. 119-120'.
[CONTRIBUTION FROM
THE
1303
A n a l . Calcd. for C4131001(122.1): C, 39.34; H, 8.25. Found: c , 39.57; H , 8.08. BERKELEY,CALIF.
DEPARTMENT OF CHEMISTRY, WASHINGTON UNIVERSITY, ST.LOUIS,Mo.]
Concerning the Synthesis of D-Mannosamhe and D-Glucosamine from D-ara bo-3,4,5,6Tetraacetoxy- 1-nitro- 1-hexene BY
JOHN
c. SOWDEN AND MARVIN L. OFTEDAHL RECEIVED SOVEMRER 9, 1959
The action of methanolic ammonia on D-arabo-3,4,5,6-tetraacetoxy-l-nitro-l-hexene yields both 2-acetamido-1,2-dideoxy1-nitro-D-mannitol and 2-acetamido-1,2-dideoxy-l-nitro-~-glucitol, with the former predominating in a ratio of about 6 : 1. The action of hydrochloric acid on the sodium salts of these two compounds (Nef reaction and N-acetyl hydrolysis) yields, respectively, D-mannosamine hydrochloride and D-glucosamine hydrochloride in high yield.
Considerable biochemical interest in D-man- is difficult to detect. The epimeric substances nosamine (2-amino-2-deoxy-~-mannose) has been are, however, readily separated by fractional aroused by the recent observation that i t occurs crystallization from absolute ethanol, in which the naturally as a structural component of N-acetyl- D-glUGO isomer is considerably more soluble than neuraminic acid.' Consequently, the develop- is its epimer. ment of reasonable methods for the laboratory Application of the Nef reaction, using hydrosynthesis of the aminosugar assumes new impor- chloric acid rather than sulfuric acid, to the epitance. Of the methods developed to date2-6 the meric acetamidonitroalcohols, followed by heating preparation based on D-arabinose reported by to hydrolyze the amide linkage yields, respectively, O'NeillS appears to be the best route to D-man- D-mannosamine hydrochloride and D-glucosamine nosamine. This method involves the conversion hydrochloride in high yield. The acidic hydrolyof D-arabinose to ~-arabo-3,4,5,6-tetraacetoxy-lsis of the N-acetyl group in N-acetyl-D-glucosamnitro-l-hexenej6 reaction of the latter with alco- ine was observed to be much slower than in N holic ammonia to give 2-acetamido-1,2-dideoxy-l- acetyl-D-mannosamine. nitro-D-mannitol and, finally, application of the The addition of ammonia to the acetylated sugar Nef reaction followed by acetylation to give D- nitroiilefins is reminiscent of its similar addition t o mannosamine pentaacetate. The latter was con- the acetylated sugar disulfone olefins.' I t is verted to D-mannosamine hydrochloride by hy- noteworthy, however, that whereas the addition to drolysis with hydrochloric acid. D -arabo-3,4,5,6 - tetraacetoxy- 1 , l -bis- (ethanesulWe had independently studied the synthetic fonyl)-1-hexene apparently gives exclusively a route reported by O'Neill but had reached some- product with the D-glUGO configuration, the addiwhat different conclusions regarding the course of tion to the double bond of ~-arabo-3,4,5,6-tetrnthe reaction of ~-arabo-3,4,5,6-tetraacetoxy-l-niacetoxy-1-nitro-1-hexenegives preponderantly a tro-1-hexene with ammonia. In view of this, and product with the D-manno configuration. The since we had developed a somewhat more direct stereospecificity in the former case has been exroute from the acetylated sugar nitroolefin to plained by Hough and Taylors on the basis of neighD-mannosamine hydrochloride, i t seems appropri- boring group participation, whereas the latter case ate to record briefly our experiences with the has been rationalized by O'Neill on the basis of synthesis. rotational conformation. It is apparent that no Contrary to the findings of O'Neill, who con- single explanation is appropriate for both cases. cluded that the addition of ammonia to D-araboWe are a t present examining the addition of am3,4,5,6-tetraacetoxy-l-nitro-l-hexene is stereospe- monia and various amines to other sugar nitrocific and gives only the D-manno isomer, we found olefins and plan to report on these studies a t a rather that the addition is simply stereoselective later date. and that the yield of D-manno:D-gluco isomer is Experimental approximately 6 :l. We observed further that the 2-Acetamido-l,2-dideoxy-l-nitro-~-mannitol and P-Acet2-acetamido-l,2-dideoxy-l-nitro-~-mannitol (m.p. amido-l,2-dideoxy-l-nitro-~-glucitol.-Fifteen grams of D172-173', [cY]"D -16.8') does not depress the arabo-3,4,5,6-tetraacetoxp-l-nitro-l-hexene,~m.p. 114melting point of 2-acetamido-1,2-dideoxy-l-nitro-115', was covered with lEj0 ml. of absolute methanol and the mixture was cooled t o 0 . Anhydrous ammonia was bubD-glucitol (m.p. 155-156", [a]2 s ~ 12.7"), so that bled into the mixture t o approximate saturation, during slight contamination of the former by the latter which operation the acetylated nitroolefin dissolved. The (1) D. G. Comb and S. Roseman, THISJOURNAL, 80, 497, 3166 (1958). (2) P. A. Levene, J . B i d . Chem., 36, 73 (1918); 39, 69 (1919). (3) R . Kuhn and W. Kirschenlohr, A n n . , 600, 115 (1966); R. Kuhn and W. Bister, ibid., 602, 217 (1957). (4) C. T. Spivak and S. Roseman, THISJOURNAL, 81, 2403 (1959). ( 5 ) A. N. O'Neill, Can. J . Chem., 37, 1747 (1969). 69, 1048 (6) J. C. Sowden and H. 0. L. Fischer, THIS JOURNAL, (1947): J. C. Sowden, U. S. Patent 2,$30,342 (Aug. 29, 1947).
resulting solution was protected from moisture with a dryingtube and allowed t o warm t o room temperature. After standing overnight, the solution was concentrated in a stream of dry air t o a semi-crystalline mass. Filtration, washing with absolute ethanol and recrystallization from absolute ethanol (about 300 ml.) yielded 5.3 g. of pure 2(7) D. L. MacDonald and H. 0. L. Pischer, THISJ O U R N A74,2057 L, (1952). (8) L. Hough and T. J. Taylor, J. Chcm. SOL, 970 (1956).
acetamido-l,Z-dideoxy-l-iiitro-D-mannitol, m.p. 172-173" brought t o crystallization by the gradual addition of aceand [ a I z 5 D -16.8" in water ( c 2.4). O'Neille reports m.p. tone. Seeding crystals of ~-mannosamine hydrochloride 172-173' and -13.2' in water (c 1.1) for this com- are advantageous in this initial crystallization. There w:ts pciulltl. obtained 7.6 g. (93%) of nearly pure D-mannosamine hydrc!The iiiotlirr liquors from the initial reaction mixture were chloride, [ a I z 6 D -2.9" in water (c 11). -4 single recrystallicrmcentratcd to a semi-crystalline mass and extracted sev- zation from moist ethanol with the addition of acetone gave e r d times by trituration a t room temperature with chloro- material with [ a ] 2 5 D -3.2" in water (c 10). The reportedD form t o remove acetamide. The resulting residue was com- value in water is - 3'. The product gave an X-ray powder billed with the above recrystallization mother liquors, con- diffraction pattern identical with that of D-mnnnosamine liycentrated and recrystallized from ethanol to yield 2.7 g. of drochloride prepared by the alkaline isomerization of A'mixed :~cetamidonitroalcohols, m.p. 158-165". Fractional acetyl-~-glucosamine.4J0 2-Alcetamido-l,2-dideoxy-l-nitro-D-glucitol was converted recrystallization of the latter from absolute ethanol yielded a t o D-glucosamine hydrochloride by the process just defurther 0.75 g. of 2-acetamido-l,2-dideoxy-l-nitro-~-mdnnitill (total yield, 57.570), m.p. 172-173', and 1 1 g. (10.4%) scribed except that the acidic solution from the Sef reaction of %-c~cetamido-l,2-dideoxy-l-r~itro-n-glucito1, m.p. 155- was refluxed for 4 hours t o complete the hydrolysis of the N acetyl function. Crystallized from a small amount of water 156' and [ C U ] ~ ~ D12.7" in water ( c 3.6). the addition of ethanol, the product (85yoyield) shoyetl Anal. Calcd. for C8HI6O7NY: C, 38.1; 13, 6.39; N, 11.1. by [ a [ * 5+68" ~ equil. in water (c 1.7). A single recrystallizaFound: C,38.1; H, 6.68; N, 10.7. tion from water-ethanol raised this t o the reported9 value of D-Mannosamine Hydrochloride and D-Glucosamine Hy- +72". The product gave an X-ray powder diffraction patdrochloride.--A solution of 9.5 g. of 2-acetamido-1 ,2-di- tern identical with that of a coinmercial sample of D-glucosdeoxy-1-nitro-D-mannitol in 23 ml. of 2 Ai sodium hydroxide amine hydrochloride (Eastman Organic Chemicals, Rocheswas added dropwise t o 19.5 ml. of Concentrated hydrochloric ter, K. Y . ) . acid with vigorous stirring. After the addition, the soluAcknowledgment.-The authors are pleased to tion was brought briefly t o the boiling point, again cooled t o room temperature and saturated with hydrogen chloride gas. acknowledge the generous support of the Corn The precipitated sodium chloride was removed by filtration Industries Research Foundation, Washington, D.C., (IT'hatman no. 42 paper) and the filtrate, after dilution with during the course of this work. an equal volume of water, was decolorized by filtration through a layer of Celite and decolorizing carbon. The solu(9) R. Kubn, W. Bister and H. Fischer, A n n . , 617, 109 (1958). tion was concentrated at reduced pressure and residual hy(10) We are indebted t o Dr. Saul Roseman, Rackham Arthritis Redrogen chloride was removed from ther esulting sirup in wucuo search Unit, University of Michigan, for this latter sample and t o over potassium hydroxide. The sirup was dissolved in 15- MI. A. V. Guzzo of this Laboratory for the X-ray diffraction measure20 ml. of methanol containing a few drops of water and ments.
s. A . ] Steroids. CXXX1.l A New Series of 6-Substituted Progesterone Analogs [CONTRIBUTION FROM
B Y JOHN
RESEARCH LABORATORIES, SYNTEX,
4.ZDERIC
AND
DINORAH CHAVEZ LIMON
RECEIVED JUNE 18, 1959 Treatment of 5a,6a-oxidoprogesterone bis-ethyleneketal with acetylene dimagnesium bromide led to 6B-ethynylpregnane5a-ol-3,ZO-dione bis-ethyleneketal which, following hydrolysis of the ketal functions and dehydration of the 5 ~ h y d r o x y l group, provided 6@-ethynylprogesterone. While this substance could not be inverted to the corresponding 6a-ethynyl epimer, it was capable of conversion to Sa-( 1-chloroviny1)-progesteroneand 6a-acetyl-progesterone. By controlled reductions of the original ethynylated fission product either 68-vinyl or 6P-ethylpregnane-5a-ol-3,20-dionebis-ethyleneketal could be obtained. These compounds were then converted by appropriate manipulation to 6a-ethylprogesterone and 6Pvinylprogesterone.
Our recent observation2 that steroid 5a,Gaepoxides upon treatment with phenylmagnesium bromide may be readily opened to provide G phenylated steroids, prompted us to undertake a similar investigation of epoxide openings employing acetylene dimagnesium bromide. While a priori i t was conceivable that the use of this reagent could lead to a bis-substituted ethyne the possibility appeared remote since it had already been observed3 that steroidal 17-ketones upon treatment with acetylene dimagnesium bromide provided exclusively the monosubstituted ethyne. On the basis of this earlier work as well as the present instance where only a monosubstituted ethyne was formed, it appears that the steric environment of the reactive center is the controlling factor governing mono- or di~ubstitution.~
Thus when 5a,Ga-oxidopregnene-3,20-dione bisethyleneketa15 was treated with acetylene dimagnesium bromide in tetrahydrofuran a t reflux temperature the epoxide generally was smoothly opened bisto provide G@-ethynylpregnane-5a-ol-3,20-dione ethyleneketal (IIa) in 85% yield. Unexplicably on occasion the yields were less than 10% and in these cases the residues were non-crystalline and on the basis of infrared spectroscopy appeared to be free of either mono- or disubstituted ethynes.6 No attempt was made to characterize this material. Upon treatment of IIa with aqueous perchloric acid in tetrahydrofuran' the ketal functions were hydrolyzed in high yield to provide the corresponding dione IIIa. Dehydration of IIIa with thionyl chloride in pyridine then led to Gp-ethynylprogesterone (IVa) ; fully characterized by elemental
(1) Paper C X X X , J. A. Zderic, H. Carpio and C. Djerassi, THIS JOURNAL, 82, 446 (1960). (2) J. A. Zderic and D. Chdvez Limbn, ibid., 81, 4570 (1959). (3) F. Sondbeimer, 0. Mancera, H . Flores and G Rosenkranz, ibid., 78, 1742 (1956). (4) For an example of disubstitution see, 0. Isler, H. Lindlar, Id. Montavon, R. Riiegg and P. Zeller, Helu. Chim. A d a , 39, 249 (1956).
(5) A. Bowers, L. C. Ibhfiez and H. J. Ringold, Tetrahedron, 7 , 138 (1959). (6) For a description of the bands associated with ethynes see L. J. Bellamy, "The Infra-red Spectra of Complex Molecules," 2nd Ed., 1958,pp. 57-62. John Wiley and Sons, Inc., New York, N. Y., (7) G. I. Poos, G. E. Arth, R E. Reyler and L. H. Sarett, THIS JOURNAL, '75, 422 (1953).
