Biomimetic total synthesis

The biomimetic approach to total synthesis draws inspiration from the enzyme-catalyzed conversion of squalene oxide (2) to lanosterol (3) (through polyolefinic cyclization and subsequent rearrangement), a biosynthetic precursor of cholesterol, and the related conversion of squalene oxide (2) to the plant triterpenoid dammaradienol (4) (see Scheme la).3 The dramatic productivity of these enzyme-mediated transformations is obvious in one impressive step, squalene oxide (2), a molecule harboring only a single asymmetric carbon atom, is converted into a stereochemically complex polycyclic framework in a manner that is stereospecific. In both cases, four carbocyclic rings are created at the expense of a single oxirane ring. 

The first examples of macrocyclization by enyne RCM were used in Shair s impressive biomimetic total synthesis of the cytotoxic marine natural product longithorone A (429) [180]. This unique compound features an unusual hep-tacyclic structure which, in addition to the stereogenic centers in rings A-E, is also chiral by atropisomerism arising from hindered rotation of quinone ring G through macrocycle F (Scheme 85). It was assumed that biosynthesis of 429 could occur via an intermolecular Diels-Alder reaction between [12]paracy-... 

Moody and coworkers have employed a biomimetic hetero-Diels-Alder-aroma-tization sequence for the construction of the 2,3-dithiazolepyridine core unit in amythiamicin D and related thiopeptide antibiotics (Scheme 6.243 a) [426]. The key cycloaddition reaction between the azadiene and enamine components was carried out by microwave irradiation at 120 °C for 12 h and gave the required 2,3,6-tris(thi-azolyl)pyridine intermediate in a moderate 33% yield. Coupling of the remaining building blocks then completed the first total synthesis of the thiopeptide antibiotic... 

Gademann K, Bethuel Y, Locher HH, Hubschwerlen C (2007) Biomimetic Total Synthesis and Antimicrobial Evaluation of Anachelin H. J Org Chem 72 8361... 

In the following year, Bringmann et al. showed a further application of a biomimetic oxidative coupling of murrayafoline A (7) to the first total synthesis of murrastifoline F (191) (162). This work also includes the resolution of ( + )-murrastifoline F (191), the stereochemical assignment of its atropisomers, and the determination of the enantiomeric ratio present in an authentic root extract of M. homigii. 

Peschko and Steglich reported the first biomimetic total synthesis of purpurone (281) starting from 3-(3,4-dimethoxyphenyl)pyruvic acid (1084), 2-(4-methoxyphenyl) ethylamine (1085) and 2, 2, 2 -trichloroethyl-2-bromo-2-(3,4-dimethoxyphenyl)acetate... 

Jackson et al. (22) reported the biomimetic total synthesis of ( )-cularine (67) itself (Scheme 11). Benzyolation of isoquinoline 68 in the presence of potassium cyanide gave Reissert compound 69, the anion of which was alkylated with 3-benzyloxy-4-methoxybenzyl chloride, resulting in intermediate 70. After al-... 

The total synthesis of litseaverticillols D, F and G (172 and 173), which are natural products with anti-HIV activity, was achieved recently via a singlet oxygen initiated cascade proposed to be biomimetic (Scheme 64). Finally, allylic alcohols 174a and 174b (Scheme 64) were isolated in a 4/1 ratio via a stereoselective singlet oxygen ene reaction. Stereoisomer 174a is an intermediate in the synthetic route of staurosporine, which is a bioactive alkaloid with hypotensive, antimicrobial and cell cytotoxic properties. 

Total synthesis - particularly along a biomimetic approach - may also serve the fiindamental role of clarifyii natural proces s at molecular level (Hinterding 1998), although cautious notes have been raised to this concern (Lauflfenburger 1998). 

Other approaches to the stereoselective total synthesis of nonaromatic steroids include the carbocationic, biomimetic cyclizntion reactions. Generally, these cyclizations begin with the synthesis of an appropriately functionalized cyclopentenol. Acid-catalyzed cyclization forms the B-C-D rings of the steroid nucleus with the natural relative stereochemistry in a single step. 

Fig. 39 Examples for biomimetic cascade reactions in total synthesis...

A biomimetic total synthesis of gambogin and some analogues has been performed, involving two Claisen rearrangements. Both were observed to be accelerated considerably by protic and particularly by aqueous solvents. This has been attributed... 

Another clue for the biogenesis of steganes was given by the early work of Schlessinger and co-workers, who reported the biomimetic total synthesis of ( )-isostegane, Fig. (7) [84],... 

Nicolaou KC, Montagnon T, Snyder SA (2003) Tandem reactions, cascade sequences, and biomimetic strategies in total synthesis. Chem Commun 5 551... 

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