Preparation of 1-ferrocenyl-2-methyl-1-propylamine,a highly effective chiral template in asymmetrically induced synthesis

The 1-ferrocenyl-2-methyl-1-propylamine (2a)is the most effective chiral template in asymmetrically induced peptide synthesis by stereoselective four component condensation (4CC). Two routes for the synthesis of this amine via its N,N-dimethyl derivative (12a) an described. One route involves the conversion of 12a into the corresponding azide 14a by treatment with methyl iodide/sodium azide in diglyme/water and subsequent reduction of the azide. The preferred other route consists of treating 12a with thioglycolic acid/formic acid to yield the carboxymethylmercapto derivative 9a and transformation of the latter into 2a with aqueous ammonia/ammonium chloride/mercuric chloride. Some related reactions are also discussed.     

The synthesis of 1-alkyl-4a-(4-chlorophenyl)- 4,4a-dihydropyrimido[6,1-a]isoindol-9(3H)-one

The primary amino group of 3-(2-aminoethyl)-3-(4-chlorophenyl)-2,3-dihydro-1H-isoindol-1-one ( 1 ) was acylated with acetyl chloride, benzoyl chloride and phenyl acetyl chloride to form the amides 2a -c, respectively. These were cyclized in phosphorus oxychloride to give the 1-substituted-4a-(4-chlorophenyl)-4,4a-dihydropyrimido [6,1-a]isoindol-9(3H)-ones 3a-c . Heating of 1 in formic acid lead to the formation of 4a-(4-chlorophenyl)-4,4a-dihydropyrimido[6,1-a]isoindol-9(3H) -one (3d) . Heating of 1 in the presence of phosgene lead to the formation of 4a-(4-chlorophenyl)-2,3,4,4a-tetrahydropyrimido[6,1-a]isoindole-1, 9-dione (4).     

Hormone-receptor interactions. Demonstration of two message sequences (active sites) in alpha-melanotropin.

The purpose of this investigation was to elucidate the biological significance of the tripeptide sequence 11–13, -Lys-Pro-Val · NH₂ contained in α-melanocyte-stimulating hormone. To this end the in vitro melanotropic activities of 21 synthetic peptides related to the hormone were determined and compared with one-another and with results reported in the literature. The tripeptide amide, H · Lys-Pro-Val · NH₂, its N^α-acetylderivative, and -weakly, but distinctly-N^α-acetyl-L-lysine-amide were found to be hormonally active. The following conclusions were drawn: (1) α-melanophore-stimulating hormone possesses two message sequences (active sites), -Met-Glu-His-Phe-Arg-Trp-Gly-, and -Lys-Pro-Val · NH₂ which are capable of independently triggering the hormone receptor responsible for melanin dispersion. (2) In correct covalent combination, the two message sequences act in a ‘cooperative’ manner to potentiate their activities on the receptors. (3) -Lys-Pro-Val- is an address sequence in adrenocorticotropic hormone and a message sequence in α-melanocyte-stimulating hormone. This implies that the two receptors (adrenal and melanocyte), albeit recognizing -Met-Glu-His-Phe-Arg-Trp-Gly- as stimulus, differ fundamentally in their response to -Lys-Pro-Val-.     

Asymmetric Synthesis of (S)-5,5,5,5′,5′,5′,5′-Hexafluoroleucine

(S)-5,5,5,5′,5′,5′-Hexafluoroleucine ((S)- 13 ) of 81 % ee is prepared from hexafluoroacetone ( l ) and ethyl bromopyruvate (= ethyl 2-oxopropanoate) in 7 steps with an overall yield of 18% (Schemes 1 and 2). Key step in this sequence is the highly enantioselective reduction of the carbonyl group in α-keto ester 4 either by bakers' yeast (91 % ee) or by ‘catecholborane’ 6 utilizing an oxazaborolidine catalyst, yielding hydroxy ester (R)- 5 with 99% ee. The absolute configuration was determined by X-ray analysis of the HCl adduct (S,R)- 9b of (2S)-N-[(R)- l-phenylethyl]-5,5,5,5′,5′,5′-hexafluoroleucine ethyl ester.     

Synthesis of [D-alanine, 4'-azido-3',5'-ditritio-L-phenylalanine, norvaline4[alpha-melanotropin as a 'photoaffinity probe' for hormone-receptor interactions (author's transl)]

Synthesis of [D -alanine¹, 4′-azido-3′, 5′-ditritio-L -phenylalanine², norvaline⁴]α-melanotropin as a ‘photoaffinity probe’ for hormone-receptor interactions. The synthesis of an α-MSH derivative containing 4′-azido-3′,5′-ditritio-L -phenylalanine is described: Ac · D -Ala-Pap(³H₂)-Ser-Nva-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val · NH₂. This hormone analogue is being used for specific photoaffinity labelling of receptor molecules. The synthesis was performed in a way to minimize the number of radioactive steps and to introduce the radio-active and the photoaffinity label exclusively into position 2. The dipeptide N(α)-acetyl-D -alanyl- (4′-amino-3′,5′-diiodo)-L -phenylalanine was tritriated and transformed into the azido compound, N(α)-acetyl-D -alanyl-(4′-azido-3′,5′-ditritio)-L -phenylalanine which was then condensed with H · Ser-Nva-Glu(OtBu)-His-Phe-Arg-Trp-Gly-Lys(BOC)-Pro-Val · NH₂ to the tridecapeptide. The α-MSH analog displayed a specific activity of 11 Ci/mmol, and a biological activity of about 4 · 10⁹ U/mmol (10% of α-MSH).     

Synthese von radioaktiv markierten Bromacetyl- und Diazoacetyl-α-melanotropin-Derivaten zum Studium von kovalenten Hormon-Makromolekül-Komplexen

Synthesis of radioactive α-melanotropin derivatives containing a bromoacetyl or diazoacetyl group for studies of covalent hormone-macromolecule complexes α-Melanotropin derivatives and fragments covalently bound to human serum albumin through their N-terminal end exhibit almost the same biological activity as the corresponding free N^α-acetylated peptides [6]. The preparation of such complexes requires derivatives with a ‘reactive’ N-terminal acetyl group. We describe here the synthesis of three α-melanotropin fragments and of two specifically tritiated α-melanotropin derivatives containing N^α-bromoacetyl or N^α-diazoacetyl groups: BrCH₂CO · Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val · NH₂, BrCH₂CO · Glu-His-Phe-Arg-Trp-Gly · OH, BrCH₂CO · Trp-Gly-Lys-Pro-Val middot; NH₂, BrCH₂CO · D -Ala-Tyr(³H₂)-Gly-Nva-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val · NH₂, and N₂ = CHCO · Gly-Tyr(³H₂)-Ser-Nva-Glu-His-Phe-Arg-Trp-Gly- Lys-Pro-Val · NH₂. The latter two analogues displayed a specific radioactivity of about 20 and 36 Ci/mmol, and a biological activity of 2 · 10⁹ and 6 · 10⁹ U/mmol respectively. They are also being used for affinity and photoaffinity labelling of receptor molecules and antibody combining sites.     

Batch versus Flow Photochemistry: A Revealing Comparison of Yield and Productivity

The use of flow photochemistry and its apparent superiority over batch has been reported by a number of groups in recent years. To rigorously determine whether flow does indeed have an advantage over batch, a broad range of synthetic photochemical transformations were optimized in both reactor modes and their yields and productivities compared. Surprisingly, yields were essentially identical in all comparative cases. Even more revealing was the observation that the productivity of flow reactors varied very little to that of their batch counterparts when the key reaction parameters were matched. Those with a single layer of fluorinated ethylene propylene (FEP) had an average productivity 20 % lower than that of batch, whereas three‐layer reactors were 20 % more productive. Finally, the utility of flow chemistry was demonstrated in the scale‐up of the ring‐opening reaction of a potentially explosive [1.1.1] propellane with butane‐2,3‐dione.