Recent developments in dynamic kinetic resolution

This critical review aims at presenting recent developments in intramolecular aromatic homolytic substitution which has become one of the common methodologies in modern synthesis. The application of Bu3SnH-mediated cyclisations have proved especially useful. The critical review illustrates the mechanistic considerations required for planning synthetic applications and a wide range of synthetic protocols and natural product syntheses are shown. The latest evidence for the mechanisms involved in aromatic homolytic substitution are presented. (152 references).

Synthesis using aromatic homolytic substitution—recent advances

In the past decade, the asymmetric synthesis of chiral nonracemic isoquinoline alkaloids, a family of natural products showing a wide range of structural diversity and biological and pharmaceutical activity, has been based either on continuation or improvement of known traditional methods or on new, recently developed, strategies. Both diastereoselective and enantioselective catalytic methods have been applied. This review describes the stereochemically modified traditional syntheses (the Pictet–Spengler, the Bischler–Napieralski, and the Pomeranz–Fritsch–Bobbitt) along with strategies based on closing of the nitrogen-containing ring B of the isoquinoline core by the formation of bonds between C1–N2, N2–C3, C1–N2/N2–C3, and C1–N2/C4–C4a atoms. Methods involving introduction of substituents at the C1 carbon of isoquinoline core along with syntheses applying various biocatalytic techniques have also been reviewed.

Asymmetric Synthesis of Isoquinoline Alkaloids: 2004–2015

http://su.diva-portal.org/smash/get/diva2:469764/FULLTEXT01.pdf

Hypervalent iodine reagents in the total synthesis of natural products.

The role of 1,3-dithianes in natural product synthesis

Frogs of the neotropical family Dendrobatidae produce a remarkably diverse array of biologically active alkaloids. One of the major classes of these amphibian alkaloids are the decahydroquinolines, which have been isolated not only from skin extracts of dendrobatid and mantelline frogs but also from bufonid toads, tunicates, marine flatworms, and myrmicine ants. They possess either a cis or trans decahydroquinoline ring fusion, with a side chain substituent at both the C-2 and C-5 positions and, in the lepadin series, an acylated hydroxy group at the C-3 position. The most representative decahydroquinoline alkaloid is cis-195A (formerly called pumiliotoxin C), first isolated in 1969 from a Panamanian population of Dendrobates pumilio. The source of amphibian alkaloids remains an unresolved and challenging question, in particular after the discovery that some of these alkaloids also occur in ants, thus strengthening a dietary hypothesis for their origin in frogs. Although there are no conclusive studies concerning the biosynthesis of these toxins and, consequently, little is known about the biosynthetic pathways, there has been speculation as to possible derivation from the polyketide route by aminocyclization of polycarbonyl intermediates (A), leading to either 2,5-disubstituted decahydroquinolines (C) or spiropiperidines (histrionicotoxins). In accordance with this hypothesis, a plausible biosynthetic pathway to the decahydroquinoline class of dendrobatid alkaloids is depicted in Scheme 1. The structural diversity and pharmacological activity associated with this class of alkaloids, as well as the limited amounts available from natural sources, have stimulated considerable synthetic effort in this area, including some biomimetic approaches. In this context we present herein a biomimetic enantioselective approach to the decahydroquinoline class of dendrobatid alkaloids, which has culminated in the biomimetic synthesis of ()-pumiliotoxin C. Our synthetic approach involves the use of an appropriate 1,5polycarbonyl derivative as a synthetic equivalent of the hypothetical biogenetic polyketide intermediate A and (R)-phenylglycinol as a chiral latent form of ammonia to induce the key enantioselective biomimetic aminocyclization to the target hydroquinoline system. To evaluate the feasibility of our proposal, we initially used 1,5tetracarbonyl compound 2 [A: R = OEt; R = (CH2)3CO2Et], which was easily accessible in excellent yield (82%) by reaction of glutaryl dichloride with 4-ethoxy-4-oxobutylzinc bromide (1) in the presence of Pd(PPh3)4 as the catalyst (Scheme 2). To our delight, heating a benzene solution of 2 and (R)phenylglycinol under Dean-Stark conditions in the presence of a catalytic amount of AcOH, resulted in the straightforward construction of the hydroquinoline ring system, with generation of two stereogenic centers, leading directly to the enantiopure tricyclic lactam 3 in 35% yield. Cyclohexenone 4 (22%) and hydroquinolone 5 (25% yield; nearly equimolecular mixture of stereoisomers) were also isolated. Formation of 3 can be rationalized by considering that, after an initial aldol cyclization from the symmetrical starting diketone 2, the resulting -oxoester 4 undergoes a phenylglycinolpromoted cyclocondensation reaction, in a process that mimics the proposed biosynthetic pathway depicted in Scheme 1. In accordance with this interpretation, 2 was first cyclized to cyclohexenone 4 in excellent yield (90%), by treatment with 1N aqueous LiOH followed by reesterification, and then converted to lactam 3 (60% yield) by reaction with (R)-phenylglycinol in refluxing C6H6-cat AcOH. [12] On the other hand, the formation of 5 in the direct reaction of 2 with (R)phenylglycinol is a consequence of the initial generation of an oxazolidine, which then undergoes two successive cyclizations as depicted in Scheme 3. By choosing the appropriate 1,5-polycarbonyl derivative, the above biomimetic double cyclocondensation can be adapted to the enantioselective synthesis of a variety of 2,5-disubstituted decahydroquinoline derivatives, as exemplified by the synthesis of the decahydroquinoline alkaloid cis-195A outlined in Scheme 4. The required diketoester 6 was prepared in 65% yield by Pd-catalyzed coupling of 5-oxohexanoyl chloride with the functionalized organozinc derivative 1 and stereoselectively converted as in the above series to a tricyclic hydroquinolone lactam (8) in excellent overall yield. Thus, the initial aldol cyclocondensation took place in [ [*] Prof. Dr. M. Amat, Dr. R. Griera, R. Fabregat, Prof. Dr. J. Bosch* Laboratory of Organic Chemistry, Faculty of Pharmacy, and Institute of Biomedicine (IBUB), University of Barcelona Av. Joan XXIII s/n, 08028-Barcelona (Spain) Fax: (+34)93-402-45-39 E-mail: amat@ub.edu joanbosch@ub.edu www.ub.edu/farmaco/grupos/amatbosch/indice.htm

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A Biomimetic Enantioselective Approach to the Decahydroquinoline Class of Dendrobatid Alkaloids

Biogenetically inspired enantioselective approach to Indolo[2,3-a]- and benzo[a]quinolizidine alkaloids from a synthetic equivalent of secologanin.

The generation of 3-indolylacyl radicals from the corresponding phenyl selenoesters and the scope of their participation in intermolecular addition reactions to carbon-carbon double bonds under both reductive and nonreductive conditions have been studied.

Generation and intermolecular reactions of 3-indolylacyl radicals.

The stereochemical outcome of the alkylation of a variety of phenylglycinol-derived oxazolopiperidone lactams is studied. The influence of the configuration of the C-8a stereocenter and the effect of the substituents at the C-8 and C-8a positions on the stereoselectivity of the reaction are discussed. The synthetic utility of these alkylation reactions is illustrated with the synthesis of cis and trans 3,5-disubstituted, 2,5-disubstituted, and 2,3,5-trisubstituted enantiopure piperidines, and the indole alkaloids 20R- and 20S-dihydrocleavamine.

Alkylation of Phenylglycinol-Derived Oxazolopiperidone Lactams. Enantioselective Synthesis of β-Substituted Piperidines

The straightforward enantioselective construction of the hydroquinoline ring system from 1,5-polycarbonyl derivatives, using (R)-phenyglycinol as a chiral latent form of ammonia, is reported. The process mimics the key steps believed to occur in nature in the biosynthesis of amphibian decahydroquinoline alkaloids. Diastereodivergent routes to enantiopure cis-2,5-disubstituted decahydroquinolines, including the alkaloid pumiliotoxin C (cis-195A), are developed.

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Rosa Griera

Papers

A Biomimetic Enantioselective Approach to the Decahydroquinoline Class of Dendrobatid Alkaloids

Biogenetically inspired enantioselective approach to Indolo[2,3-a]- and benzo[a]quinolizidine alkaloids from a synthetic equivalent of secologanin.

Generation and intermolecular reactions of 3-indolylacyl radicals.

Alkylation of Phenylglycinol-Derived Oxazolopiperidone Lactams. Enantioselective Synthesis of β-Substituted Piperidines

Biomimetic construction of the hydroquinoline ring system. Diastereodivergent enantioselective synthesis of 2,5-disubstituted cis-decahydroquinolines.