1. Kinetic resolution of tert-butyl (RS)-3-alkylcyclopentene-1-carboxylates for the synthesis of homochiral 3-alkyl-cispentacin and 3-alkyl-transpentacin derivatives
Mark E Bunnage, Stephen G Davies, Richard M Parkin, Paul M Roberts, Andrew D Smith, Jonathan M Withey Org Biomol Chem. 2004 Nov 21;2(22):3337-54. doi: 10.1039/B407559E. Epub 2004 Oct 20.
High levels of stereocontrol are observed in the conjugate addition of lithium dibenzylamide to tert-butyl (RS)-3-alkylcyclopentene-1-carboxylates (alkyl = Et, Bn), with addition occurring exclusively anti- to the 3-alkyl substituent. Treatment of a range of tert-butyl (RS)-3-alkylcyclopentene-1-carboxylates (alkyl = Et, Bn, (i)Pr, (t)Bu) with lithium (RS)-N-benzyl-N-[small alpha]-methylbenzylamide indicates that good enantiorecognition is observed (E > 80) in their mutual kinetic resolution. In these reactions, conjugate addition of the lithium amide occurs exclusively anti- to the 3-alkyl substituent, with subsequent C(1)-protonation occurring preferably anti- to the 2-amino group in the 3-Et, 3-Bn and 3-(i)Pr cases, giving predominantly the corresponding 1,2-syn-2,3-anti-diastereoisomers. Conjugate addition to (RS)-3-tert-butyl cyclopentene-1-carboxylate results in exclusive 2,3-anti -addition and a reversal in C(1)-protonation selectivity, giving predominantly the 1,2-anti-2,3-anti-diastereoisomer. Furthermore, the kinetic resolution of the tert-butyl (RS)-3-alkylcyclopentene-1-carboxylates (alkyl = Et, Bn, (i)Pr, (t)Bu) with lithium (S)-N-benzyl-N-alpha-methylbenzylamide proceeds efficiently, giving, at between 47 and 51% conversion, the resolved 3-alkylcyclopentene-1-carboxylates in >85 to >98% ee and the beta-amino ester products of conjugate addition in high de, consistent with E > 80 in each case. Subsequent deprotection of the 1,2-syn-2,3-anti-3-alkyl-beta-amino esters (alkyl = Et, Bn, (i)Pr) by hydrogenolysis and ester hydrolysis gives the corresponding 1,2-syn-2,3-anti-3-alkylcispentacins in >98% de and 98 +/- 1% ee. Selective epimerisation of the 1,2-syn-2,3-anti-3-alkyl-beta-amino esters (alkyl = Et, Bn, (i)Pr, (t)Bu) by treatment with KO(t)Bu in (t)BuOH gives the corresponding 1,2-anti-2,3-anti-3-alkyl-beta-amino esters in quantitative yield and in >98% de, with subsequent deprotection by hydrogenolysis and ester hydrolysis giving the corresponding 1,2-anti-2,3-anti-3-alkylcispentacin hydrochlorides in >98% de.
2. New synthesis of (RS)-carnitine chloride
S G Boots, M R Boots J Pharm Sci. 1975 Jul;64(7):1262-4. doi: 10.1002/jps.2600640737.
A four-step synthesis of (RS)-carnitine chloride was developed using extremely mild reaction conditions and versatile intermediates. Crotyl chloride was converted to tert-butyl 3-butenoate using tert-butyl alcohol and triethylamine in ether. Treatment of tert-butyl 3-butenoate with m-chloroperbenzoic acid in chloroform afforded tert-butyl 3,4-epoxybutyrate. Reaction of this compound with trimethylamine hydrochloride in methanol, followed by mild acid hydrolysis of the tert-butyl ester, afforded (RS)-carnitine chloride.
3. Synthesis and characterization of novel chitosan-dopamine or chitosan-tyrosine conjugates for potential nose-to-brain delivery
Roberta Cassano, et al. Int J Pharm. 2020 Nov 15;589:119829. doi: 10.1016/j.ijpharm.2020.119829. Epub 2020 Aug 30.
This work aims to the synthesis of novel carboxylated chitosan-dopamine (DA) and -tyrosine (Tyr) conjugates as systems for improving the brain delivery of the neurotransmitter DA following nasal administration. For this purpose, ester or amide conjugates were synthesized by N,N-dicyclohexylcarbodiimide (DCC) mediated coupling reactions between the appropriate N-tert-butyloxycarbonyl (Boc) protected starting polymers N,O-carboxymethyl chitosan and 6-carboxy chitosan and DA or O-tert-Butyl-L-tyrosine-tert-butyl ester hydrochloride. The resulting conjugates were characterized by FT-IR and 1H- and 13C NMR spectroscopies and their in vitro mucoadhesive properties in simulated nasal fluid (SNF), toxicity and uptake from Olfactory Ensheathing Cells (OECs) were assessed. Results demonstrated that N,O-carboxymethyl chitosan-DA conjugate was the most mucoadhesive polymer in the series examined and, together with the 6-carboxy chitosan-DA-conjugate were able to release the neurotransmitter in SNF. The MTT assay showed that the starting polymers as well as all the prepared conjugates in OECs resulted not toxic at any concentration tested. Likewise, the three synthesized conjugates were not cytotoxic as well. Cytofluorimetric analysis revealed that the N,O-carboxymethyl chitosan DA conjugate was internalized by OECs in a superior manner at 24 h as compared with the starting polymer. Overall, the N,O-CMCS-DA conjugate seems promising for improving the delivery of DA by nose-to-brain administration.
