Carbocyclizations complex polycyclic products

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 identification of novel ways to incorporate an asymmetric intramolecular Mizoroki-Heck reaction as part of a cascade cyclization sequence has led to attractive approaches for assembling complex polycyclic molecules. Keay and coworkers [54] reported the use of a double Mizoroki-Heck cyclization as the pivotal step in the asymmetric total synthesis of xestoquinone (93), a reduced congener of halenaquinone (Scheme 16.20). In this step, naphthyl triflate 90 was cyclized with Pd2(dba)3 (dba = dibenzylideneace-tone), (5 )-BINAP and 1,2,2,6,6-pentamethylpiperidine (PMP) in toluene at 110°C to give pentacyclic product 92 with impressive efficiency and moderate enantioselectivity. This conversion proceeds by initial asymmetric 6-exo Mizoroki-Heck cyclization to form the central six-membered carbocycle and install the benzylic quaternary stereocentre. The first cyclization event is followed by a second Mizoroki-Heck reaction in which neopentyl... 

The transition metal catalyzed cycloaddition-carbocyclization reaction is an effective technique for the formation of complex polycyclic systems [4]. Various versions of these reactions are described below, including [2+2+2+1] [154], [4+2+2] [155], [5+1+2+1] [156], [3+3+1] [157] and [5+2+1] [158] cycloaddition. These reactions are often used for the synthesis of complex molecules and natural products [158]. On the other hand, the discovery of natural 5-7-6-S tetracyclic condensed system, such as Caribenol A [159], contribute to the development of highly efficient synthetic methods for the creation of polycyclic cores in one step starting with the enediynes [160]. 

The Rh-catalyzed intramolecular cycloaddition has proven reliable for the construction of polycyclic carbocycles and heterocycles. The cascade processes involving this reaction have also been achieved. A recent example is the cascade intramolecular hetero-[5 + 2] cycloaddition/Claisen rearrangement reaction of vinylic oxirane-aUcyne substrates 73, which uses the rhodium NHC complex as catalyst and provides atom-economical, regiospecific, and diastereoselective access to [3.1.0] bicyclic products 74 (Scheme 5.50) [48]. 

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