Enantioselective retro-synthesis

Inomata100 utilized a tandem retro-Diels-Alder-ene reaction for an enantioselective total synthesis of (+)-methyl jasmonate (Scheme 41). The TMS group on the alkene was essential to the efficiency of the reaction, by producing a higher energy level of the HOMO for the ene reaction. 

The concise enantioselective total synthesis of (+)-monomorine I, a 3,5-dialkyl-substituted indolizidine alkaloid, was completed by S. Blechert et al. using a sequential cross-metathesis double reductive cyclization strategy. The enedione substrate was prepared in two steps. The Stetter reaction between the masked equivalent of acrolein and butyl vinyl ketone was followed by a retro Diels-Alder reaction under flash vacuum pyrolysis (FVP) conditions. 

Enantiomeric excess (e.e.) definition, 107 footnote Enantiosdective retro-synthesis, 200-204 Enantioselective syntheses ... 

Aldol reaction using monoclonal aldolase antibodies, generated against a ketosulfone hapten by reactive immunization, was used to catalyze rapid and highly enantioselective retro-aldol reaction of a thiazole aldol, providing optically pure aldol by kinetic resolution. The product was used for the synthesis of epothilone E (Fig. 10.39(b) and (c)). ... 

The Pictet-Spengler condensation has been of vital importance in the synthesis of numerous P-carboline and isoquinoline compounds in addition to its use in the formation of alkaloid natural products of complex structure. A tandem retro-aldol and Pictet-Spengler sequence was utilized in a concise and enantioselective synthesis of 18-pseudoyohimbone. Amine 49 cyclized under acidic conditions to give the condensation product 50 in good yield. Deprotection of the ketone produced the indole alkaloid 51. 

Uncatalysed Diels-Alder reactions usually have to be carried out at relatively high temperatures (normally around 100 °C)73, often leading to undesired side reactions and retro-Diels-Alder reactions which are entropically favoured. The Diels-Alder reaction became applicable to sensitive substrates only after it was realized that Lewis acids (e.g. A Clg) are catalytically active56. As a consequence, Diels-Alder reactions can now be carried out at temperatures down to — 100°C85. The use of Lewis acid catalysts made the [4 + 2]-cycloaddition applicable to the enantioselective synthesis of many natural compounds51,86. Nowadays, Lewis acid catalysis is the most effective way to accelerate and to stereochemically control Diels-Alder reactions. Rate accelerations of ten-thousand to a million-fold were observed (Table 7, entries A and B). 

CPO has been used occasionally in complex syntheses. An important application of CPO as an enantioselective epoxidation catalyst is the efficient synthesis of (R)-2-mevalonolactone (Scheme 2.26a) [270]. A survey of the literature revealed that the previous methods required many steps to produce the lactone, in low overall yield, with moderate ee, in addition to expensive starting materials. Meanwhile, a retro-synthetic analysis starting with an appropriately functionalized epoxide provided confidence that CPO could rescue the situation if used in the key stereogenic step. Another completed synthesis is depicted in Scheme 2.26b. Again, the epoxide is generated in high yield with conversion to (R)-dimethyl-2-methylaziridine-l,2-dicarboxylate, which may serve as a synthon for P-methylamino acids [283],... 

Since the preparation of enantiomerically pure tertiary aldols remains a challenge, aldolase antibody 38C2 was investigated as a catalyst for the kinetic resolution of racemic tertiary aldols. Ab38C2 was demonstrated to be an efficient catalyst for the retro-aldol reaction of the fluorogenic tertiary aldol /m-methodol (Scheme 5.68) and exhibited an E value of >159 50. At 50% conversion, (R)-terMnethodol is obtained with an enantiomeric excess of >99% ee. Consequently the ability of Ab38C2 to resolve tertiary alcohol was exploited in the enantioselective synthesis of ( )-frontalin (Scheme 5.69).125... 

A method for the enantioselective synthesis of the ftmctionalised carbapenam core 38 from D-serine-derived pyrrolidines has been reported <03JOC187>. Disubstituted pyrrolidines, obtained from the retro Dieckmann reaction of azabicyclo[2.2.1]heptan-2-one-1-carboxylic acid methyl esters, have been used as starting materials to develop concise syntheses of all four stereoisomers of carbapenam-3-carboxylic acid methyl esters <03JOC2889>. The synthesis of 1-methylcarbapenams 39 by intramolecular attack of lactam nitrogen on a 77 -propargylpalladium complex has been reported <03JOC8068>. 

The enantiomeric purity of our synthetic (S)-141, however, was only 59% ee. Acid treatments (H I and 1 141) in the course of the synthesis caused partial racemization due to retro-aldol/aldol and/or retro-Michael/Michael reactions. Unfortunately, milder methods of deprotection such as hot dilute acetic acid or trifluoroacetic acid in dichloromethane were not effective enough to give 141 in appreciable yield. In enantioselective syntheses, retro-aldol/aldol and/or retro-Michael/Michael processes are most dangerous reactions to cause partial racemization. 

An X-ray analysis of the titanium(IV) chloride complex53 of the acrylate of ethyl lactate shows that the. Re-face of the. rvn-periplanar Cx-C double bond is shielded by a chlorine atom, A cooperative effect is observed for the bis[ethyl (JS )-lactate] fumaric ester with cyclopentadi-ene54 This auxiliary has found an application in the enantioselective synthesis of sarkomycin methyl ester via a retro-Diels Alder reaction5". 

As mentioned in the retro-synthetic analysis, the imine derivative 7 is the key intermediate of our enantioselective synthesis strategy. It was obtained by various pathways (Scheme 6.15) ... 

In 1998, Kawahara and Nagumo reported the first total synthesis of a member of the TAN1251 series [63] and five years later both authors revisited the TAN1251A alkaloid by means of a new enantioselective synthesis (see Section 5.6). The retro synthetic analysis of TAN 1251A is outlined in Scheme 37. The target compound could be obtained by aldol reaction of tricyclic lactam 119, whose disconnection at the amide bond led to the bicyclic amino acid 120, which could be prepared from azaspirocyclic compound 121 by means of alkylation of the secondary amine and Mitsunobu-type chemistry. Azabicycle 121 may be prepared by an intramolecular alkylation of 122, which in turn could be available from allyl derivative 123. The latter can be prepared from carboxylic acid 124 by alkylation and subsequent Curtius rearrangement. 

The natural product (+) -chamaecypanone C (223) was first isolated in 2007 by Kuo and coworkers [89] from the heartwood of Chamaecyparis obtusa var. Jbrmosana and shows strong anticancer potency. An enantioselective synthesis of this compound was described by Porco et al. in 2009 ]90] using a retro-Diels-Alder/Diels-Alder reaction as key step (Scheme 14.34). 

Catalytic asymmetric nitroaldol (Henry) reactions of ketones lead to synthetically versatile chiral tertiary nitroaldols. Enantioselective nitroaldol reactions of a-keto esters have been achieved using chiral Cu and Mg complexes, and cinchona alkaloids [140]. However, there are no reports on the asymmetric synthesis of tertiary nitroaldols derived from simple ketones. Even for a racemic version, only a few methodologies with limited substrate scope are available. The difficulty arises from the attenuated reactivity of ketones and their strong tendency toward a retro-nitroaldol reaction under basic conditions. (S)-LLB catalyst was found suitable to promote retro-nitroaldol reaction and a kinetic resolution of racemic tert-nitroaldols was realized. (S)-LLB preferentially converted the matched (R)-enantiomer into ketone and nitromethane, whereas the mismatched (S)-enantiomer remained unchanged and was recovered in an enantiomerically... 

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