Silicon-directed Nazarov cyclization

J.4 SILICON-DIRECTED NAZAROV CYCLIZATIONS OF DIVINYL KETONES (SDNC)... 

A interesting variation on this theme employing the isomeric enynol acetates (Scheme 24) has been developed by Rautenstrauch. The cyclizations are induced by a Pd" catalyst in warm acetonitrile. The proposed mechanism is intriguing. Reaction is initiated by an anchimerically assisted palladation to (35) followed by opening the dioxolenium ion to a pentadienylic cation (36). The closure of (36) is analogous to the silicon-directed Nazarov cyclization in the ejection of the Pd" electrofuge from (37). Both secondary and tertiary acetates can be employed as well as both acyclic and monocyclic systems. 

The Nazarov cyclization has been featured in a variety of synthetic endeavors involving both natural and unnatural products. In the area of polyquinane natural products ( )-hirsutene (88), ( )-mod-hephene (89), ( )-silphinene (90), ( )-A 2)-capnellene (91) and ( )-cedrene, have all been prepared (Scheme 37). The synthesis of (91) is noteworthy in the iterative use of the silicon-directed Nazarov cyclization. TIk divinyl ketones were constructed by the carbonylation-coupling of enol triflates (92) and (95) with the -silylvinylstannane (Scheme 38). llie diquinane (94), obtained from Nazarov cyclization of (93), was transformed into enol triflate (95) which was coupled with the -silylvinylstaimane as before. Silicon-directed Nazarov cyclization of (96) was highly diastereoselective to provide the cis,anti,cis isomer of (16). The synthesis was completed by routine manipulations. 

Denmark, S. E., Hite, G. A. Silicon-directed Nazarov cyclizations. Fart VI. The anomalous cyclization of vinyl dienyl ketones. Helv. ChIm. Acta 1988, 71, 195-208. 

Recently, an application of the silicon-directed Nazarov cyclization was reported in the stereoselective synthesis of (+ )-pentalene 29. The construction of the angularly fused cyclopentene ring is accomplished in 60% yield via the Nazarov cyclization. 

In cases that provide a mixture of alkene regioisomers or in which the less-substituted alkene is desired, control of the position of the new alkene is possible using a trialkylsilyl group to direct its introduction. Desilylation is generally preferred over deprotonation, and the known (3-cation stabilizing effect of a silyl group helps to reduce side reactions resulting from the intermediate aUyl cation. The silicon-directed Nazarov cyclization has been made use of twice in a synthesis of the sesquiterpene A -capnellene 349 (3.221). ... 

Silicon-directed Nazarov cyclization Activation of the ketone 1 by a Lewis acid catalyst generates a pentadienyl cation, which undergoes a thermally allowed 4Tr-electron conrotatory electrocyclization (Scheme 2.19). This generates a silicon-stabilized cation, which undergoes an elimination reaction of silyl group to give the cyclopentadienol. Subsequent tautomerization of cyclopentadienol produces the cyclopentenone product 2. 

SCHEME 2.19 Silicon-directed Nazarov cyclization reaction in presence of Lewis acid. 

Denmark and co-workers reported a good example of torquoselection in the silicon-directed Nazarov cyclization (see Section 3.4.5.1). They demonstrated that cyclohexenyl-derived divinyl ketones 26 cyclize to give the relative stereoisomer 27 as the major product (see Section 3.4.5.1 for the mechanism of the silicon-directed reaction). The use of bulky alkyl groups (such as /-butyl) and/or bulky silicon substituents gave the best selectivity, at the expense of the chemical yield. It is interesting that the corresponding cyclopentenyl-derived systems gave only poor torque-selectivity. 

Denmark and co-workers have published extensively on the use of (3-silyl substituted divinyl ketones (see 82) in the Nazarov cyclization. Such silyl groups control the collapse of the intermediate cyclopentenylic cations 84, and thus aid the regioselectivity of elimination, as well as the minimization of side reactions (secondary cationic rearrangements). Such stabilization derives from the known P-cation stabilizing effect of silicon, which through stabilization of 84, ensures maximum efficiency of the cyclization, with controlled formation of the final double bond. An important consequence of the final elimination step is that the double bond is placed in the thermodynamically less stable position (see 85). The most common Lewis acid used in the silicon-directed Nazarov cyclization is anhydrous iron(III) chloride, at temperatures below ambient. Alternatively, in cases where the... 

One particularly elegant use of the silicon-directed Nazarov cyclization was in the synthesis of the angular triquinane silphinene (89), by Miesch and co-workers. Addition of a large excess of boron trifluoride etherate in refluxing ethylbenzene to 86 ensured annulation of the required third ring. Notably, the benzyloxy group was also eliminated imder the reaction conditions, and the product 88 was subsequently converted into the natural product 89. 

Rautenstrauch reported another mechanistically intriguing example. Treatment of enynol acetate 111 with a palladium(II) catalyst in warm acetonitrile resulted in the formation of cyclopentenone 115. The proposed mechanism involves generation of divinyl cationic species 113, followed by electrocyclization, and elimination of the palladium(ll) electrofuge in a manner comparable to the silicon-directed Nazarov cyclization (see Section 3.4.5.1). 

Cyclopentenone Synthesis. When activated with Lewis acid catalysts or silver ion, 1-phenylthio-l-trimethylsilylethylene reacts with a,/3-unsaturated acid chlorides at a low temperature in CH2Cl2. The cation intermediates undergo a silicon-directed Nazarov cyclization to give 3-phenylthio-substituted cyclopentenone derivatives (eq 3). The phenylthio moiety at the /3-position of cyclopentenones can be effectively utilized for the introduction of an alkyl substituent by addition/elimination. 

Denmark SE, Wallace MA, Walker CB Jr., Silicon-directed Nazarov cyclizations. 8. Stereoelectronic control of torquo-selectivity. J. Org. Chem. 1990 55 5543-5545. 

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