A NEWSYNTHESIS OF DL-HOMOSERINE
June 30, 1958 [CONTRIBUTION FROM
THE
3147
DEPARTMENT OF ORGANIC CHEMISTRY, THEHEBREWUNIVERSITY]
Synthesis of a-Amino-7-halogenobutyricAcids. A New Synthesis of DL-Homoserine BY MAXFRANKEL AND Y. KNOBLER~ RECEIVED DECEMBER 9, 1957 New syntheses of a-amino-y-halogenobutyric acids and of DL-homoserine are given. Conditions for the opening of the free and t h e N-substituted a-amino-y-butyrolactone to the respective y-halogeno compounds by aqueous hydrohalic acids were studied.
In the course of our investigations on trifunctional a-aminobutyric acids we have worked out new syntheses of a-amino-7-halogenobutyric acids and of DL-homoserine2 (a-amino-y-hydroxybutyric acid). The convenient synthesis of the latter is based on the use of a-amino-y-iodobutyric acid hydroiodide (11). This substance is prepared in 70y0 yield by amination of a-bromo-y-butyrolactone3 (I) and subsequent opening of the intermediate a-amino-y-butyrolactone by prolonged heating with constant boiling hydroiodic acid. Heating of a-amino-y-iodobutyric acid hydroiodide (11) with sodium hydroxide gave a mixture of crude homoserine and sodium iodide, from which pure nL-homoserine was obtained in 7oy0yield. Treatment of the free a-amino-y-iodobutyric acid, or its hydroiodide I1 as well as of the aamino-y-butyrolactone hydroiodide (IV) with silver carbonate and hydrogen sulfide also led to the DL-homoserine. N-Acylated lactone derivatives, c.g., N-carbo0 -
I
CHARTI PhOCH&!H&HCOOH
co
co
I CHzCHXH I I
7V
NH,.HI
I
NHz
CH2CH2CHBr I
0-
ICHICH~CHCOOH
I
I
21,, NHa l KOH 3, 1-1.5 H I
was the preceding intermediate and pure 7-iodo acid hydroiodide I1 could be obtained after prolonged refluxing with a great excess of constant boiling hydroiodic acid. Treatment of a-benzamido-y-butyrolactone (V) with constant boiling hydroiodic acid a t 40" resulted in a-benzamido-y-iodobutyric acid (VI). The chloro and bromo analogs of a-amino-yiodobutyric acid hydroiodide (11) could not be produced from a-amino-y-butyrolactone by treatment with the respective hydrohalic acids in a similar manner to that which led to the acid hydroiodide 11. However, by prior benzoylation of the aamino-y-butyrolactone, the tendency for opening of the lactone ring with simultaneous y-halogenation was greatly enhanced. Heating of a-benzamido-y-butyrolactone (V) with 65% hydrobromic (4oYOhydrochloric) acid in a closed tube a t 100' for seven hours gave a-amino-y-bromo(chloro)butyric acid h y d r ~ b r o m i d e ~ " ,(hydrochloride) ~ (VII) (VIII) in 7OY0yield.
PhCONH VI
14HI
HI(40')
1, NHI 2 , 1 KOH 3, 4 H I
2.5HI
ICHzCHzCHCOOH
I
I1
NH:.HI
1, PhCOCl, NaOH 2, HCl
.
L
I
C
I
O
CHzCHzCH
I
PhCONH or 1, AgZCOs 2, HzS HOCHzCHzCHCOOH
I11
benzoxy- or N-benzoyl- DL-homoserine, can be prepared in good yield by direct treatment of the intermediate a-amino-yiodobutyric acid hydroiodide (11) with carbobenzoxy or benzoyl chloride. a-Amino-y-iodobutyric acid hydroiodide (11) also was obtained by cleavage of a-amino-yphenoxybutyric with an Of 'Onstant hydroiodic acid* In this preparation too, the a-amino-y-butyrolactone hydroiodide (IV) (1) Part of the thesis submitted to The Hebrew University in Partial fulfillment of the requirements for the Ph.D. degree. (2) E. Fischer and H. Blumenthal, Bcr., 40, 106 (1907). (3) J. E. Livak, THISJOURNAL, 87, 2218 (1945). (4) E. P. Painter, ibid., 69, 232 (1947).
XCHzCHzCHCOOH
I
I
NHz
NHt.HX VII, X = Br VIII, x = c1
The three a-amino-7-halogenobutyric acid hydrohalogenides (11, VII, VIII) were esterified by the Fischer method to the respective methyl ester hydrochlorides. Experimental Micro-combustion analyses were made by Drs. Weiler and Strauss. Melting points were determined in a FisherJohns apparatus. The ascending method of paper-chromatography was used (80% phenol). a-Amino-y-iodobutync Acid Hydroiodide (11) .--82.5 g. (0.5 mole) of a-bromo-y-butyrolactone (I) was added to 350 ml. of 25% ammonium hydroxide with cooling and (5) (a) J. M. Gulland and C. J. 0. R . Morris, J . Chcm. Soc., 703 (1835); (b) J. Baddiley and G. A. Jamieson, ibid., 4280 (1954).
shaking antl tlie stoppered solution allowed t o stand for and tlie solution was cncllerl to ti"; 5.6 g. (O.ti5ti mole) of five days; 500 ml of N potassium hydroxide was added, the triethylamine was added and the cl(~uti>solution was kept solution heated with stirring a t 100" for one hour and amin a refrigerator for two days until complete precipitation monium hydroxide removed. The solution was then con- and crystallization. The precipitate was filtered with succentrated to sirupy consistency and 350 nil. of ethanol was tion, dried over phosphorus pentoxide, washed several times added, then 69 ml. (0.5 mole) of constant boiling (c.b.) rvith d r y ether, and dried again over phosphorus pentoside; hydroiodic acid. T h e mixture was warmed t o 40-50" for m.p. 183-185', yield 9.2 g. (goyo). Omission of washing one-half hour, cooled, filtered from potassium bromide, the gave a product riielting a t 05-105", solidifying arid melting filtrate concentrated in Vacuo, cooled and the second crop of again at 183-185'. potassium bromide filtered off. T o the filtrate, 400 nil. of Anal. Calcd. for C,IfJN021: C, 21.0; €1, 3.5; S , 6.1; absolute ethanol was added and the solution concentrated I, 55.4. Foutitl : C, 20.8; 13, 3.6; S,0.1 ; I, 55.0. i?t ~ n c u o ;successive further crops of potassium bromide mere nL-Homoserine a-Amino--,-hydroxybutyric Acid (III).removed by filtrations. Sometimes a third portion of ahout T o a solution of 17.85 g. (0.05 mole) of or-arriino-y-iorlo200-300 ml. of absolute ethanol (dried over inagnesiuin butyric acid hydroiodide (11) in 150 nil. of water was added ethoxide) had t o be used t o separate the rest of potassium bromide with concentration in znczm. This also could he 4.2 g. (0.105 mole) of sodium hydroxide in 50 ml. of water. Tlie solution was concentrated t o dryness on a steam-bath. effected b y digestion with acetonc. After entire removal of thc potassium bromide, the filtrate Most of the sodium iodide was removed b y estraction with :icetone in n Soxhlet apparatus during 3-4 hours. T h e crude was evaporated iiz zmcz~ot o a heavy sirup which mas tiissolveti product was dissolved in little rvater and 13--20 1111. OF ethanol in 206 ml. (1.5 moles) of c.b. liydroiodic acid; 200 ml. of was added followed by a n excess of acetone (or cther) . T h e toluene was added and the misture refluxed for a period of mixture was kept for some d a iri a refrigerator t o complete six hours. It was then stirretl vigorously and hydroiodic precipitation and rrystalli tion. DL-Homoscrinc was acid removed b y azeotropic distillation. After cooling, filtered off :inti washed wit small portions of al~solute toluene was removed by decantation and the remaining dark ethanol-acetone ( 1 : S arid of ether; y mass triturated with boiling chloroform for one-half hour. T h e mixture was cooled, t h e chloroforni removed by decan- based on a-bronio-:.-btityrolsctone (I) Ascending paper chromatography gave a tation and t h e residue purified b y estraction with dry ether d4nnl. Calcd. for CsF19NOa: C, 40.3; 1-1, 7.0; K, 11.76. in a Soxhlet apparatus until a white-yellowish granular prodPound: C, 40.0; H, 7.6; N, 11.3. uct was obtained, m.p. 185-190". T h e latter contained still a very small amount of potassiiun salt, b u t could be Preparations Using the Fischerl Method.-(a) To a soluused directly for most of the following operations; yield tion of 8.92 g. (0.025 mole) of or-aniino--/-iodobutyric acid 125 g. (7070). hydroiodide (11) in 150 1111. of mater \vas added 7.6 g. (2.2 Further purification could be effected by dissolviiig t h e equiv.) of silver carbonate. T h e suspension wa5 stirred substance in a small aniouiit of acetone, filtering and preand allowed to stand until the silver iodide separated out. cipitating with escess of ether. A white-yellowish crystal- Tlie s u p e r n a t m t solution was treated with hydrogen sulfide, line material was obtained by solution in absolute ethaiiol filtered and concentrated on a steam-bath to 5-10 nil. Some (dried over magnesium etlioxitle) arid addition of a large water was added, anti tlir concentrated solution decolorizetl excess of' ether. The hydroiodide IT sep;irateti out during with S o r i t . T o the filtrate n-as added 10-15 ml. of absolute prolonged standing, m . p . 196-200" tlcc. rthanol followed b y :in excess of acetone (or ether) and the inixture kept i n refrigerxtor uiitil complete solidification and ApioI. Calctl. for C4T-19S0 n . T h e crystals were washed with sinnll por1,71.1. I ~ o u n d :C, 131; I I ) etlmiol--ether; yield of pure Dis-lioinnserine The a-amirio-.,-iodobut?-ric acid hytlroiotlitle (11) is soluble ) ; lmsed on a-hrot~io-;-hut\-rol:ictone ( I ) 5057; i u water, alcohol, acetone; insolul~lein ether ant1 petroleum 11i.p. 182"; Zil value 0.66. ether. It is stable i n concentrated liydroitrtlic acid from . l , z d . Calctl. [or C411s)N0,3: S,11.76. Found: S,1 l . n . which i t could be recovered quantitatively. From a solution of I1 dissolved in a small a ~ i i o u nof~ water arid allowed (11) e-.iiniiio--, -butyri~l:ictonehydroiodide (117) (5.73 g., to stand for two hours at a temperature lint cxceeding 20", 0.025 rnolc) was dissolved in Ivater and treated with 3.8 g. the acid hydroiodide I1 could be recovered. .4 mil. Calcd.: (1.1 equiv.) of silver carbonate, subsequently with hydrogen S,3.9; I , 71.1. Found: N,3.9; I , 71.0. From a second sulfide antl worked up as described under (a); yield 1.6 g . sample tlissolved iii cold water and maintaiiied a t 0' for 24 (54vc); hnsetl on n-1)rnino-y-hutyrolactoiie (I), 40:; ; n i . p . hours, acid hydroiodide I1 alsn was recovered. :lnnl. 182'; X , value 0.66. Calctl.: N,3.9; I , 71.2. Fourid: K . 3.0; I , 71.0. F r o m a .Iiznl. C n h l . for C4110SOa:K, 11.76. Pound: K, 1l.i;. solutinii in witer, licatetl t o RO-60' for two hours or to hciil( c ) ~ u - r \ i i i i r i ~ ~ - ~ ~ - i n ~acid I ~ l ~(5.73 ~ ~ t ~g., - r i0.025 c mole) was ing for one hour, only N-3iiiiilil-y-l)iit!-rolact dissolved iri water a n d treated with 3.8 g. (1.1 equiv.) of ( I \ ' ) resulted. ..ltini. Calctl.: S,6.1; I, silver carlinnnte, subsequently with hydrogen sulfide aTrl S, 6.0; I, 56.0. Similarly, ~-ainiii
