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The photochemistry of the methyl esters of N-phthaloylcysteine derivatives 1 b-5b was studied. The results are remarkable, because they prove a pronounced, multiplicity-controlled regioselectivity of the initial CH activation

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The regioselectivity of photoinduced electron-transfer (PET) reactions of unsymmetrical phthalimides is controlled by the spin density distribution of the intermediate radical anions. ROHF ab initio calculations were found to be most suitable for atomic spin density analysis. Intramolecular PET reactions of quinolinic acid imides were studied with the potassium butyrate and hexanoate 1a,b and a cysteine derivative 3. The photocyclizations products 2a,b and 4 were formed with moderate regioselectivities (68:32, 57:43, and 81:19) showing preferential ortho cyclization. The intermolecular reaction of potassium propionate and potassium isobutyrate with N-methylquinolinic acid imide (5) yielded as addition products the dihydropyrrolo[3,4-b]pyridines 6a,b with slight ortho regioselectivity (55:45). In contrast to these low regioselectivities, the PET reaction of potassium propionate with the methyl ester of N-methyltrimellitic acid imide (9) yielded solely the para addition product 10. Likewise, the intramolecular photoreaction of the cysteine derivative 7 gave a 75:25 (para/meta) mixture of regioisomeric cyclization products 8. The regioselectivity originates from donor-acceptor interactions prior to electron transfer and differences in spin densities in the corresponding imide radical anions. The results of DFT and ab initio calculations for the radical anions of the quinolinic acid imide (11(*)(-)) and the methyl ester of trimellitic acid imide (12(*)(-))( )()were in agreement with the latter assumption: spin densities in 11(*)(-) were higher for the imido ortho carbon atoms (indicating preferential ortho coupling); for 12(*)(-) the spin densities were higher for the imido para carbon atoms (indicating preferential para coupling). These correlations became more significant when the additional spin densities at the carbonyl oxygen and the adjacent carbon atoms were taken into account. The cyclization selectivities for 2, 4, and 8 deviate from the intermolecular examples probably because of ground-state and solvent effects.

Enantiomerically pure vinylglycine (4b) can be prepared (S)-homoserine (two-step synthesis). The photoelimination from natural ("chiral pool") amino acids by photoelimination (of HOSMe from 3b and of HX from 3d, e) proceeds quantitaof y-functionalized N-phthaloyl amino acid esters. Two routes tively and leads to N,C-protected vinylglycine 4a in high have been developed: (a) a three-step synthesis of substrate yields. This strategy could also be applied to peptide-bound 3b [PhtN-Met(SO)OMe] from (S)-methionine and subse-substrates as was shown for the protected Met-Gly (5b) quent photolysis, (b) the use of N-phthaloyl activated methyl which was transformed into the N-protected vinylglycine-2-amino-4-chloro-or -4-bromobutanoates 3d, e which are glycine dipeptide 6 in three steps. available from (S)-methionine (four-step synthesis) or fromThe synthesis of P,y-unsaturated amino acids has been a focus of synthetic organic chemistry for several decades [']. These compounds serve as flexible and versatile substrates for the synthesis of enantiomerically pure amino acid derivatives because they offer the a-stereogenic center as well as further options for modification due to the extra C-C double bond [']. Amongst all p, y-unsaturated amino acids it is vinylglycine which has found considerable interest due to several retrosynthetic pathways leading to pharmaceutical active compounds from this starting materialC3I. Vinylglycine, a natural amino acidr41 acts as an inhibitor of pyridoxal dependent aspartate aminotransferase~ [~] and is also considered as an important intermediate in several biogenetic pathways [6]. A number of (thermal) processes leading to vinylglycine have been developed using other amino acids (methi~nine [',~], glutamic acidl91, homoserine[lOl) as substrates. The most successful synthetic route to enantiomerically pure vinylglycine up to now is the thermolysis of n! Cprotected methionine sulfoxide developed [7] and optimized" ' 1 by Rapoport and coworkers.We investigated during the last few years photochemical pathways to P,y-unsaturated amino acids using the Nphthaloyl(chromophore)-activated and C-protected amino acids valine and isoleucine[121. Irradiation of both substrates gave the respective P,y-dehydro isomers by a sequence of yand &hydrogen migrations. This approach, however, was unsuccessful in the case of 2-amino-butyric acid, the logical precursor of the photoisomerization to vinylglycine[121. Assuming, that an increase in the migratory ability or in the leaving group ability of the second fragment after primary hydrogen abstraction should favor vinylglycine formation, we investigated a series of possible substrates. In view of recent results by Giese and coworkers on radical cation and hydroxyl anion formation from P-hydroxy radicals in DNAcleavage processes ['3], the use of appropriate OH-substituted amino acids was investigated. In principle, threonine and homoserine appeared to be suitable substrates by assuming that p-hydroxy radicals were formed via hydrogen abstraction in the primary r...

a-Amino-3-chloro-4,5-dihydro-5-methyl-5-isoxazoleacetic involving the photoisomerization of N-phthaloylvaline acid (8), a ring-methylated analogue of the potent antitumor methyl ester (1). The stereochemical course of the 1,3-dipolar agent acivicin (AT-125), is synthesized in a 6-step procedure cycloaddition is proven by means of a X-ray structure analyin 63% overall yield from (S)-valine. Key step is the 1,3-dipo-sis of the major diastereoisomer ?a formed in the chloronitrile lar addition of bromonitrile oxide to the N,C-protected (S)-oxide cycloaddition. The absolute configuration of the major isodehydrovaline (6) available from (S)-valine in four steps ( u ) diastereomer ?a and the bromo derivative 7b is (aS,5R).

Anhydrous HCI was bubbled through 25 ml of purified HMPA for 25 min. at such a rate that the temperature reached 700 after 4 min. It was then kept between 67-73" for another 21 min. 2 ml of the reaction mixture were taken out as fraction I.The HCI flow was now decreased and the reaction mixture heated to about 16CP for 44 hours. The cooled down mixture was then extracted with 3 x 100 ml of ether. Small amounts of NHMe,.HCI in the ether fraction was filtered off and the ether evaporated. The remaining mixture was fraction 11.A GLC-spectrum (5 % SE-30 DMCS column) of fraction I showed that it contained HMPA and P(O)CI(NMe,), in an approximate ratio of 1 : 2. No peak belonging to P(O)CI,NMe, was found. Further identification was performed by NMR, where the J,, from P(O)(NMe,), was found to be 9.5 Hz [lit. Is: J,, = 9.5 Hz (in CCI,)] and the J,, from P(O)CI(NMe,), was 13.0 Hz [lit. 14: J,, = 13.0 Hz (in CCI,)]. A GLC-spectrum (the same column as for fraction I) of fraction I1 showed that it contained only P(O)CI(NMe,), and P(O)CI,NMe, in an approximate ratio of 5 : 2. No P(O)CI, was found. In a NMRspectrum of the mixture J,, from P(O)CI(NMe,), was found to be 13.0 Hz and J,, from P(O)CI,NMe, was found to be 16.0 Hz [lit. 14: J,, = 15.8 (in CCI,)].Abstract. The coupling of histidine derivatives by the excess mixed anhydride method was investigated with respect to the yield, the racemization, and the formation of by-products. The tert-butyloxycarbonyl-(Boc-), isobutyloxycarbonyl-(i-Boc-), benzyloxycsrbonyl-(Z-), and p-toluenesulfonyl-(Tos-) groups were found to be suitable for protection of the imidazole nucleus.A new way of selective removal of the Ni,-Tos group, with pyridine hydrochloride, is described.