Hydrozirconation, Schwartz

The total synthesis of apoptolidin was accomplished in the laboratory of K.C. Nicolaou. The key C12-C28 vinyl iodide fragment was prepared using the Schwartz hydrozirconation of an internal alkyne followed by trapping of the alkenylzirconium intermediate with iodine (I2). The vinyl iodide was formed as a 6 1 mixture of regioisomers. Under the reaction conditions, the methyl orthoester was converted to the methyl glycoside moiety at C21, which was presumably facilitated by the complexation of Zr with the pyranoside oxygen atom. 

---

SCHWARTZ Hydrozirconation Hydroafconation wWi Cp2Zr(Cl)H and Michael addition of the Zr reagent... 

The modified Negishi protocoi was used in J.S. Panek s total synthesis of (-)-motuporin to couple the left-hand subunit organozinc compound with the right-hand subunit ( )-vinyl iodide. The left-hand subunit was prepared by the Schwartz hydrozirconation of a disubstituted alkyne to give an ( )-trisubstituted zirconate, which was subsequently transmetalated with anhydrous ZnCl2. The resulting vinylzinc species was immediately treated with one equivalent of the ( )-vinyl iodide in the presence of 5 mol% Pd(PPhs)4 to afford the ( , )-diene coupled product with complete stereoselectivity. 

Schwartz hydrozirconation works on both alkenes and alkynes even at room temperature. It works significantly better in ether solvents than hydrocarbon solvents. In addition, the reaction intermediate can be transmetallated into other organometallics that can be used in palladium-catalyzed reactions or trapped with electrophiles. Review Schwartz, J. Labinger, J. A. Angew. Chem. Int. Ed. 1976,15, 333-340. 

The chemoselectivity of Schwartz s reagent (1) toward alkynes, alkenes, nitriles, and carbonyl groups, and thus its general functional group compatibility, can be modulated. However, it is important to keep in mind that the presence of functional groups may have regiochemical consequences on the hydrozirconation reaction. 

Cp(PMe3)2RuC=CH and the corresponding vinyl compound react with 1 to give the expected hydrozirconated complexes [225, 226]. Hydrozirconation reactions were also observed with the vinyl and acetylenic ferrocenyl complexes [227]. In marked contrast, the iron complex Cp (dppe)Fe-C=CH reacts anomalously with Schwartz s reagent to form acetylide Cj-bridged heterodinuclear complexes (Scheme 8-31) [228]. 

Since the initial reports of Schwartz s reagent ([Cp2Zr(H)Cl]n, 1) over 30 years ago there has been explosive growth of zirconocene chemistry. Hydrozirconation is an efficient method of hydrometalation because of (i) the mild nature of the conditions involved, (ii) the excellent regio- and stereo-chemical control of hydrozirconation, (iii) the one-pot nature of the procedure, and (iv) the price of Zr, which is one of the... 

Hydrozirconation of alkynes with the Schwartz reagent, Cp2Zr(H)Cl (6), and subsequent methylation is also a general method (Eq. 2.5) [16]. 

As an alternative to hydrozirconation of acetylenic tellurides or selenides, Dabdoub and co-workers have more recently described the first additions of the Schwartz reagent (one equivalent) to acetylenic selenide salts 51 (Scheme 4.30) [52]. Subsequent alkylation at selenium produces 1,1-dimetallo intermediates 52, which are cleanly converted in a one-pot process to stereodefined products 53. It is noteworthy that ketene derivatives 52 are of ( )-geometry, the opposite regiochemistry to that which results from hydrozirconation of acetylenic tellurides (vide supra). This new route also avoids the mixtures of regio-isomers observed when seleno ethers are used as educts. The explanation for the stoichiometric use of Cp2Zr(H)Cl in these reactions, in contrast to the requirement for two equivalents with seleno ethers, may be based on cyclic intermediates 54, in which Li—Cl coordination provides an additional driving force. Curiously, attempted hydrozirconation of the corresponding telluride salt 55 under similar conditions was unsuccessful (Scheme 4.31) (Procedure 12, p. 143). 

Acylzirconocene chloride derivatives are easily accessible in a one-pot procedure through the hydrozirconation of alkene or alkyne derivatives with zirconocene chloride hydride (Schwartz reagent) [Cp2Zr(H)Cl, Cp = cyclopentadienyl] and subsequent insertion of carbon monoxide (CO) into the alkyl— or alkenyl—zirconium bond under atmospheric pressure (Scheme 5.1) [2],... 

The first example of a stable 1,1-bidentate Lewis acid based on boron and zirconium has been reported [35]. The synthesis of 22 is outlined in Scheme 7.12. Treatment of hex-l-yne with HBBr2 Me2S followed by conversion of the dibromoboronic ester to the corresponding alkenyl boronic acid and esterification with propane-1,3-diol provided the alkenyl boronic ester. Hydrozirconation of this compound with 3 equivalents of the Schwartz reagent, Cp2Zr(H)Cl [57], afforded the desired product 22 in 86% yield. 

Transmetalation reactions of organozirconium reagents were pioneered by Schwartz [130-132], with improved procedures developed more recently by Lipshutz [133] and Wipf [134]. The hydrozirconation of 1-hexene with H(Cl)ZrCp2 at 25 °C under sonication conditions produces the n-hexylzirconium complex 127, which adds to cyclohexenone in the presence of CuBr-Me2S (10 mol%) to afford the desired product 128 in 79% isolated yield (Scheme 2.61) [134]. 

The above-described procedure is advantageous towards the precedent method since (a) the starting lithium alkynyl selenolate is prepared in situ, avoiding the laborious preparation of the acetylenic selenides and (b) the hydrozirconation step is regio- and stereoselective, in contrast with the previously discussed hydrozirconation of acetylenic selenides resulting in a mixtnre of the regioisomers, and requires only 1 equiv of the Schwartz reagent instead of 2 eqniv of the precedent procednre. 

---