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A flexible and practical protocol for the asymmetric synthesis of renieramycin-type antitumor alkaloids is described, in which the stereoselective Pictet-Spengler cyclization of amino ester 16 and aldehyde 15 by regulating temperature and the automatic lactamization after N-deprotection of the cyclization product are exploited to rapidly construct the common pentacyclic framework. (-)-Renieramycin G and (-)-jorunnamycin A, as representative members of the two subgroup renieramycin-type alkaloids, are obtained in 19 steps from l-tyrosine with 15.8% and 14.3% overall yield respectively.

Three renieramycin-type antitumor alkaloids, (-)-jorunnamycins A (1) and C (2) and (-)-jorumycin (3), have been synthesized by a new convergent approach, which features a highly regio- and stereoselective Pictet-Spengler cyclization to couple the isoquinoline and the trisubstituted phenylalaninol partners. This synthetic strategy opens an economical access to these important antitumor alkaloids with high yields: (-)-jorunnamycin A, as a common precursor to other renieramycin-type alkaloids and their analogues, is obtained with 18.1% overall yield from l-tyrosine.

An efficient synthesis of a fully functionalized tetracycle (A-B-C-H) 7 containing a 1,4-bridged 10-membered lactone was developed. Phenolic aldol condensation between 2-methylsesamol (15) and Garner's aldehyde provided the protected amino diol 16, which was converted to free amine 11 in excellent yield. A Pictet-Spengler reaction between 11 and ethyl glyoxylate under carefully controlled conditions (LiCl, toluene, 1,1,1,3,3,3-hexafluoro-2-propanol, room temperature) provided the acid-sensitive tetrahydroisoquinoline (18) in high yield, which was converted to the amino alcohol 9. Enantioselective alkylation of a glycine template in the presence of a catalytic amount of chiral cinchonidium salt was the key step for the access of enantiomerically pure amino aldehyde 10. Union of the two fragments 9 and 10 via oxazolidine intermediate afforded amino nitrile 39, which upon esterification of the primary alcohol with (R)-N-(S-4,4',4' '-trimethoxyltrityl) Cys (42) afforded 43. Cyclization of 43 (1% trifluoroacetic acid in trifluoroethanol) provided compound 44 by a domino process involving (a) unmasking of the S-trimethoxytrityl group, (b) fragmentation of dioxane assisted by an electron-rich aromatic ring, and (c) formation of a 1,4-bridged 10-membered lactone via formation of a sulfide linkage. Treatment of 7, obtained in two steps from 44b, under acidic conditions (0.5% methyl sulfonic acid in acetonitrile) afforded the pentacyclic compound 51 via fragmentation of the 10-membered cyclic sulfide followed by an intramolecular Pictet-Spengler reaction.

A flexible approach to both type II and III lepadin alkaloids is developed for the first time. A key Diels–Alder reaction based on a novel chiral ketolactone dienophile is employed to obtain the desirable all- cis -trisubstituted cyclohexene with excellent regio- and stereoselectivity. As the subsequent closure of the piperidine ring is devised at the N1 and C2 position via an intramolecular nucleophilic amination, the two stereochemical types of lepadin frameworks with the opposite configuration at C2 can be conveniently accessible from a common intermediate. By the approach, lepadins D, E (type II) and F (type III) are stereo-selectively synthesized from ethyl l -lactate. [ABSTRACT FROM AUTHOR]

An efficient approach to the type III lepadin alkaloids (lepadins F and G) has been developed through a key Diels–Alder reaction, in which a novel ketolactone‐type dienophile with chiral diol unit is employed to generate the desirable all‐cis‐trisubstituted cyclohexene with excellent regio‐ and stereoselectivity control. The subsequent selective sulfonylation of the diol unit followed by SN2 cyclization under hydrogenation conditions could construct the substituted piperidine ring. By using this approach, (−)‐lepadin F is synthesized from ethyl l‐lactate for the first time. [ABSTRACT FROM AUTHOR]

A new practical synthesis of Pt-650, zalypsis and renieramycin T is achieved by employing a Pictet−Spengler cyclization coupling of the tetrahydroisoquinoline and phenylalaninol partners with good yield and reproducibility, in which both the two coupling partners are prepared by a common route. Moreover, a one-pot Mitsunobu displacement/photolysis sequence of methoxyquinone alcohol intermediate implements the introduction of the amino functionality at C-22 and A-ring modification in one step. By the approach, Pt-650, zalypsis and renieramycin T are synthesized with 21–24 total synthetic steps from N -Cbz- l -tyrosine in good overall yield respectively. [Display omitted] [ABSTRACT FROM AUTHOR]

A flexible protocol for the asymmetric synthesis of renieramycin-type alkaloids, such as Renieramycin G (III) and Jorunnamycin A (IV), in which the spontaneous lactamization of (I) after N-deprotection is employed to construct the pentacyclic framework is described. [ABSTRACT FROM AUTHOR]

Abstract: A practical procedure to regioselectively install a methyl group and a phenolic hydroxyl group onto l-tyrosine was developed. By using this approach, protected l-3-hydroxy-4-methoxy-5-methyl-phenylalanine and l-3-hydroxy-4-methoxy-5-methyl-phenylalanol, which are utilized in efficient syntheses of the relevant tetrahydroisoquinoline alkaloids, were prepared conveniently with high yield. [Copyright &y& Elsevier]