Asymmetrische Synthesen uber heterocyclische Zwischenstufen, XXIVI). -Enantioselektive Synthese von (R)-a-Methyltryptophan-methylester und D-Tryptophan-methylester nach der Bislactimether-MethodeDie Titelverbindungen wurden durch asymmetrische Synthese nach der Bislactimether-Methode hergestellt (e.e. iiber 95% bzw. etwa 90%).Recently, Brana et al.2) reported on the asymmetric synthesis of a-methyltryptophane (by methylation of the lithium derivative of N-benzylidenetryptophane methyl ester). However, in our hands this method gives -as expected -essentially racemic material3). This communication describes the asymmetric synthesis of methyl (R)-a-methyltryptophanate (8a; e. e. > 95 Yo) and of methyl D-tryptophanate (8b; e.e. ca. 88%) starting with the lithiated bislactim ethers 2 a and 2 b of cycle(-L-Val-Ala-) and cyclo(-~-Val-Gly-)4). Upon alkylation of 2a or 2 b with N-Boc-3-(bromomethy1)indole (3) the alkylation products 4 a and 4 b with (3R) configuration are formed with d.e. more than 95% and ca. 88070; respectively 1d.e. = 070 (3R) -To (3S)I.The configuration of the main (3R) isomer of the compounds 4 can be assigned by 'H NMR spectroscopy using -as in analogous cases5) -the fact that the (3R) isomer has a "folded" conformation (type 5) with the 6-H located within the shielding cone of the heteroaromatic indole ring; consequently its 'H NMR signal suffers an upfield shift.On acid hydrolysis (4a: 0.1 N HCI, 2 equivalents, room temperature, 14 days; 4b: 0.1 N HCI, 2 equivalents, room temperature, 5 days) 4a and b are cleaved to give methyl L-valinate (6), N-Boc-protected methyl (R)-a-methyltryptophanate (7a; e. e. > 95 %), and methyl o-tryptophanate (7b; e.e. ca. 90%). In both cases L-valinate 6 could be separated by fractional bulb-tobulb destillation. With 4 N HCI at room temperature the Boc protecting group is removed to give methyl (R)-a-methyltryptophanate (8a) ( Methyl (R)-a-methyltryptophanate (8a) was alternatively obtained from the lithiated bislactim ether 9 of cyclo(-~-Ala-~-Ala-)~) by the analogous route tlia 10. The bislactim ether 10 is more readily hydrolyzed than 4a, but the degree of asymmetric induction is somewhat lower (d.e. ca. 90%).

The lithiated bislactim ethers 5, 10, 12, and 23 were alkylated with a variety of alkylating agents 6 to give the alkylated bislactim ethers 7, 11, 13, and 24 with a high degree of asymmetric induction (up to 99 %). Upon hydrolysis these furnished the optically active amino acid methyl esters of type 8, 14, or 25. Some of these amino acid esters were further hydrolyzed to yield the amino acids. Asymmetrische Synthesen iiber heterocyclische Zwischenstufen, XXXI I). -Asymmetrische Synthese verschiedener nicht-proteinogener Aminosaure-methylester (funktionalisiert in der Kohlenstoffkette) und Aminosauren nach dem Bislactimether-VerfahrenDie lithiierten Bislactimether 5, 10, 12 und 23 wurden mit verschiedenartigen Aikylhalogeniden 6 zu den alkylierten Bislactimethern 7,11,13 und 24 umgesetzt. Die asymnietrischen Induktionen bei der Alkylierung sind relativ hoch (bis zu 99%). Bei der Hydrolyse der alkylierten Bislactimether erhielt man die optisch aktiven Aminosaure-methylester 8, 14 oder 25, von denen einige zu den Aminosiiuren weiter hydrolysiert wurden. + R'-CH-CO,CH, $ 1 R' I i -C3H, t -C, H, $ 1 VCH Verlagsgesellschaft mbH, D-6940 Weinheim, 1986 Liebigs Ann. Chem. 1986 141 Methyl (R)-( -)-2-amino-4-(diethoxyphosphoryl) butanoate (8a): 1.0 g (2.9 mmol) of 7a. Hydrolysis with 0.25 N HCl(23.0 mmol) for 1 h. Yield: 0.74 g (64%) of 8a. B. p. 13O"C/O.1 Torr. Only one enantiomer detectable in the 'H-NMR spectrum with 5-100 mol-% Eu(hfc),; e.c. >95%. [ u ] g = -9.5 (c = 0.7, ethanol). -A shift experiment with racemic 8a proved that the OCH3 signal shifts and splits with 20 mol-Yo Eu(hfc),. -'H NMR: 6 = 1.32 [t, J = 7 Hz; 6H, OP(OCH,CH,),], 1.72 (broad; 2H, NH2), 1.65-2.10 (m; 4H, CH2CH2P), 3.49 (X of ABX, J A X = 7 Hz, JBx = 4 Hz; 1 H, 2-H), 3.71 (s; 3 H, OCH,), 4.08 [dq, 3 J H H = 7 Hz, 3 J~p = 7 Hz; 4H, OP(OCH,CH,)z]. C9H20N05P (253.2) Calc. C 42.69 H 7.96 Found C 41.96 H 7.81 Methyl ( R ) -( -)-2-amino-4-(diethoxyphosphoryl/-2-methylbutanoate (14a): 0.72 g of 13a. Hydrolysis for 20 h with 16 ml (4.0 mmol) of 0.25 N HCl. Yield: 0.42 g (79%) of 14a. B.p. 13OoC/0.1 Torr; e.e. >95%. [a]E = -14.2 (c = 1.0, ethanol). -'H NMR: 6 = 1.34 [t, J = 7 Hz; 6H, OP(OCH2CHI)J, 1.34 (s; 3H, CH,), 1.67 (broad; 2H, NH,), 1.58-2.10 (m; 4H, CHZCHIP), 3.72 (s; 3H, OCHI), 4.09 [dq, 3J~~13 = 7 Hz, ' J H p = 7 Hz; 4H, OP(OCH,CH,),]. C10H2,NOSP (267.3) Calc. C 44.94 H 8.30 Found C 44.94 H 8.13 (25a): 0.82 g of 24a. Hydrolysis for 16 d with 24 ml (6.0 mmol) of 0.25 N HC1. Yield: 0.48 g (70%) of 25a. B.p. 170"C/0.1 Torr; e.e. = 81%. [a13 = +4.3 (c = 1.0, ethanol). -'H NMR: 6 = 1.32 [t, J = 0.7 Hz; 6H, OP(OCH,CH,),], 1.50-2.45 (m; 6H, CHzCHzP and NH,), 2.75 and 3.17 (AB, JAB = 13 Hz; 2H, CH~C~HS), 3.69 (S; 3H, OCH3), 4.09 [dq, ,JHH = 7 Hz, 3 J~p = 7 Hz; 4H, OP(OCH,CH,),]. -MS (70 cV): m/z = 343.154862 (M ' , calc. 343.154862 for CI~HXNOSP). Methyl (S)-( +)-2-allyl-2-amino-#-(diethoxyphosphoryl)butanoate (25b): 0.78 g of 24b. Hydrolysis with 20 ml (5.0 mmol) of 0.25 N HCl for 55 h. Yield: 0.49 g (84%) of 25b. B.p. 13OoC/0.1 Torr; e.e. >%YO. [a]g = ...

guration of the attacking C atom of the alkylating agent.Retention was observed for alkylation with B-phenylalkyl halides: in the first step, intramolecular alkylation with inversion results in the formation of a cyclohexadienylium intermediate, which, in the second step, again with inversion, reacts with the aromatic In the alkylation of benzene with the triflates of the Nphthaloylthreonines l a , b and the N-phthaloylallothreonine methyl esters lc,d, we obtained in every case the Bmethyl-N-phthaloyl phenylalanine methyl esters 2. The overall yields of 2 are between 20 and 40%, because, in addition to the substitution of 1 to give 2, substantial elimination occurs to give a$-(25-30%) and b,y-dehydroamino acid esters (35-40%).Whereas the configuration at C-2-as previously mentioned-is maintained upon the reactions of la-d to give 2, the threonine ( l a , b ) and allothreonine (1c,d) derivatives show diverse behavior upon alkylation with respect t o the stereochemistry at C-3.The threonine derivatives l a , b react largely with retention at C-3, whereas the allothreonine derivatives lc,d afford diastereomeric mixtures in the ratio of 2 : 3. The characterization and structural assignments of the four diastereomers 2a-d were determined by comparison of their optical rotations and 'H-NMR data with literature v a l~e s .~~~ For 2a, we confirmed the configuration by carrying out a n X-ray structure analysis.'61 Furthermore, we were able to show that the product obtained by acid hydrolysis of 2a, removal of the phthaloyl protecting group, and acetylation is identical with the reported (2S,3S)-N-acetyl-p-methylphenylalanine.i71The high stereoselectivity observed in the alkylation of benzene with l a , b and the different behavior of lc, d can be explained in terms of the different conformations of the carbenium ions B and D, which are formed as intermediates in the alkylation.He:H3 E D Alkylation of benzene with (S)and (R)-l-methyl-2phthaloylaminomethyl triflate 3 results in partial retention, whereas with methyl (S)-3-trifluoromethanesulfonyloxybutyrate, (S)-4, complete racemization is observed. We conclude from this that, in the dissociation step, the threonine derivatives l a , b prefer conformation A, whereas the allothreonine derivatives 1c,d prefer conformation C. In the carbenium ion B formed from A, rotation is rendered difficult by the two large neighboring substituents (CH,, CO,CH,); moreover, the aromatic compound can react only from the bottom side with B, because the cationic center is blocked from above by the Nphthaloyl group. This explains the retention observed in the reactions of la,b. For the cationic intermediate D, on the other hand, no or at most only a small hindrance to rotation is expected, which is confirmed by the results of the reactions of lc,d.In analogy to the reactions of benzene, alkyl-and alkoxybenzenes can also undergo reaction with the triflates 1 of the threonine ester. In a one-pot procedure, it is also possible to synthesize phenylalanines and B-methylphenylalanines such as 2 from t...

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Durch Umsetzung der lithiierten Bislactimether (Ia)‐(Ic) mit dem Bromid (III) werden stereoselektiv die Alkylierungsprodukte (IVa)‐(IVc) erhalten, die nach Spaltung des Pyrazinsystems und Abspaltung der Schutzgruppe die im Titel genannten Aminosäuren (VIa) und (VIb) ergeben.