Polyolefinic cyclization

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. 

An additional impetus for the development of biomimetic polyolefinic cyclizations was provided by the historically significant Stork-Eschenmoser hypothesis,4 a postulate that rationalizes the... 

Chapter 10 considers the role of reactive intermediates—carbocations, carbenes, and radicals—in synthesis. The carbocation reactions covered include the carbonyl-ene reaction, polyolefin cyclization, and carbocation rearrangements. In the carbene section, addition (cyclopropanation) and insertion reactions are emphasized. Recent development of catalysts that provide both selectivity and enantioselectivity are discussed, and both intermolecular and intramolecular (cyclization) addition reactions of radicals are dealt with. The use of atom transfer steps and tandem sequences in synthesis is also illustrated. 

This reaction was used to effect a polyolefin cyclization in a synthesis of the alkaloid yohimbone (3).2 Thus reaction of the trifluoroacetate of 1 with HCHO provides a 63% yield of 2, which was converted into 3 by a six-step sequence (10% overall yield). 

Polyolefin cyclization.1 This Pd(0) catalyst in combination with a phosphine ligand and acetic acid effects cyclization of polyunsaturated substrates to polycyclic products in one step (zipper reaction). However, a triple bond is required for initiation. This polyolefin cyclization has been used to prepare tetra- and pentaspirocycles, as a mixture of only two stereoisomers. 

In continuation9 of the polyolefin cyclization approach10 to steroids, the action of trifluoroacetic acid on (29) in the presence of isohexene yielded the compound (31)... 

Now the stage is set for the allylic rearrangement, presumably of the pyrophosphate, and cyclization either in two steps or in the style of the polyolefin cyclizations in the chapter (pp. 1444—7). In either case we should expect a trans ring junrtion to be preferred. 

Tandem domino and tandem consecutive reactions do not necessarily involve more than one reactant and can be unimolecular, as is exemplified by such processes as polyolefin cyclization [13]. Tandem sequential reactions cannot be unimolecular processes and involve two reactants at least. Both, tandem sequential and higher-order tandem domino reactions are of foremost interest in this text, because they enable the concept of multicomponent reactions (MCRs) to be introduced [4, 7-9]. Depending on the reaction conditions, MCRs can be regarded as a subclass of either tandem sequential (Scheme 17.1a) or higher order tandem domino reactions (Scheme 17.1b). In the former, formation of intermediate AB is followed by addition of a third component C to the reaction mixture to enable formation of reaction product ABC. In the latter, components A, B, and C are simply... 

Farnesyl acetate SCHEME 5 Successive polyolefinic cyclizations. 

Polyolefin cyclizations have been of substantial value in the synthesis of polycyclic natural products of the terpene type. To a large extent, these syntheses probably resemble the processes by which polycyclic compounds are assembled in nature from linear polyolefins. The most dramatic example of biological synthesis of a polycyclic skeleton from an acyclic intermediate is the conversion of squalene oxide to the steroid lanosterol and then to other steroids. Scheme 8.12 gives some... 

Alkenyl-lithiums, which can be prepared by metal-halogen interchange between an appropriate iodide and t-BuLi at — 78°C, undergo cyclizations on warming to room temperature before quenching with a proton source (equation 117) . This cyclization reaction has been extended for the construction of polycyclic alkanes by sequential polyolefinic cyclizations (tandem cyclizations). A propellane system could be constructed in a single step from his-intramolecular cyclization as shown in equation 118 . 

In the aphidicblin synthesis in Scheme 11.23, a key bicycli intermediate is established by a mercuric ion-induced polyolefin cyclization. Steps A-D serve to construct the necessary polyene. As was discussed in Chapter 9, the stereochemistry of such cyclizations is predictable on the basis of the polyene conformation. The... 

Polyolefin Cyclization Route to Steroid Total Synthesis... 

A series of studies were conducted to develop new tactics for conducting polyolefin cyclizations. New initiating groups, solvents and acid promotors were examined. For example, acetal 80 was efficiently converted to 82, whose tricyclic structure resembles the ABC-ring system of the steroids, presumably via an intermediate cation of type 81 (Steroids-16). Advances of this type set the stage for the total synthesis of steroids via polyolefin cyclizations. We will focus largely on progesterone (see Steroids-1 or Steroids-19 for structure). 

This synthesis addresses problems associated with construction of the D-ring in the synthesis of d - 6,17-dehydroprogesterone. Can one tenninate the polyolefin cyclization to directly afford a 5-membered ring ... 

The notion of biomimetic synthesis was introduced in Chapter 2 within the context of polyolefin cyclizations. It was suggested early in this chapter that alkaloid syntheses that employ Mannich reactions may also incorporate (in part) a biomimetic strategy. The synthesis of sparteine shown here is an elegant example of such a strategy. 

Once the structure was known, many syntheses were reported and all of a sudden the literature was loaded with stereoselective methods for olefin synthesis. Although it is only a guess, it is probable that the discovery of Cecropia juvenile hormone (CJH) was responsible (in part) for this burst of activity. Another reason would be the interest in carbocycle synthesis via polyolefin cyclizations (the development of steroid and terpene chemistry) which slightly preceeded the discovery of CJH, We will start by looking at the Trost group synthesis (the first synthesis) of CJH and then examine several other syntheses wherein the focus... 

Perhaps most useful from a synthetic point of view are reactions of polyenes having two or more double bonds positioned in such a way that successive bondforming steps can occur. This process, called polyolefin cyclization, has proven to be an effective way of making polycyclic compounds containing six-membered and, in some cases, five-membered rings. The reaction proceeds through an electrophilic attack and requires that the double bonds that participate in the cyclization be properly positioned. For example, compound 1 is converted quantitatively to 2 on treatment with formic acid. The reaction is initiated by protonation and ionization of the allylic alcohol. 

Since the immediate product of the polyolefin cyclization is a carbocation, it is often found that the final product is a mixture of closely related compounds resulting from the competing modes of reaction of the carbocation, that is, from capture by solvent or other nucleophile or deprotonation to form an alkene. Polyolefin cyclizations can be carried out on reactants which have special structural features in place that facilitate transformation of the carbocation to a stable product. Allylic silanes, for example, are stabilized by desilylation. "... 

Polyolefin cyclizations have been of substantial value in the synthesis of polycyclic natural products of the terpene type. These syntheses resemble the processes by which the polycyclic compounds are assembled in nature. The most dramatic... 

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