Sakurai addition

Scott G. Nelson of the University of Pittsburgh has developed (J. Org. Chem. 2005, 70,4375) a highly diastereocontrolled route to substituted cyclohexanones using the intramolecular Sakurai reaction. The requisite ally silane 12 was prepared by Claisen rearrangement of the allylic alcohol 10, followed by homologation. The Ti enolate from the Sakurai addition was trapped with isobutyraldehyde to give 13. Although 32 diastereomers of 13 are possible, the diastereomer illustrated was the dominant product from the cylization. Note that use of the enantiomerically-pure form of the alcohol 10 would have led to enantiomerically-pure 13. 

Organ, M. G., Dragan, V., Miller, M., Froese, R. D. J., Goddard, J. D. Sakurai Addition and Ring Annulation of Aiiyisiianes with a, 3-Unsaturated Esters. Experimental Results and ab Initio Theoretical Predictions Examining Allylsilane Reactivity. J. Org. Chem. 2000, 65, 3666-3678. 

A-Acyl aldimines undergo Hosomi-Sakurai addition of allyltrimethylsilane in up to 98% ee, using chiral Brpnsted acid catalysis. iyn-Diastereoselective crotylations are 0 also reported. 0... 

Usually, carbanions with good leaving groups in the beta position do not couple efficiently, but just eliminate. Scott D. Rychnovsky of the University of California, Irvine has found Organic Lett. 2007, 9, 4757) that initial protection of 6 as the alkoxide allowed smooth reduction of the sulfide and addition of the derived alkyl lithium to the amide 7 to give 8. Doubly-activated Michael acceptors such as 11 are often too unstable to isolate. J. S. Yadav of the Indian Institute of Chemical Technology, Hyderabad has shown Tetrahedron Lett. 2007, 48, 7546) that Baylis-Hillman adducts such as 9 can be oxidized in situ, with concomitant Sakurai addition to give 12. Rather than use the usual Li or Na or... 

Evans DA, Aye Y, Wu J. Asymmetric, anti-selective scandium-catalyzed Sakurai additions to glyoxyamide. Applications to the syntheses of N-Boc o-alloisoleucine and D-isoleucine. Org. Lett. 2006 8 2071-2073. 

Catalysis of Intramolecular Sakurai Reactions. Et AICI2 has been extensively used as a catalyst for intramolecular Sakurai additions. Enones (eqs 12 and 13) have been most extensively explored. Different products are often obtained with fluoride or Lewis acid catalysis. EtAlCl2 is the Lewis acid used most often although TiCLi and BF3 have also been used. EtAlCl2 also catalyzes intramolecular Sakurai reactions with ketones and other electrophiles. The cyclization of electrophilic centers onto alkylstannanes and Prins-type additions to vinylsilanes are also catalyzed by EtAlCl2. 

Conventional synthetic schemes to produce 1,6-disubstituted products, e.g. reaction of a - with d -synthons, are largely unsuccessful. An exception is the following reaction, which provides a useful alternative when Michael type additions fail, e. g., at angular or other tertiary carbon atoms. In such cases the addition of allylsilanes catalyzed by titanium tetrachloride, the Sakurai reaction, is most appropriate (A. Hosomi, 1977). Isomerization of the double bond with bis(benzonitrile-N)dichloropalladium gives the y-double bond in excellent yield. Subsequent ozonolysis provides a pathway to 1,4-dicarbonyl compounds. Thus 1,6-, 1,5- and 1,4-difunctional compounds are accessible by this reaction. 

This section describes Michael-analogous processes in which, mostly under electrophilic conditions, ally - or alkynylsilanes undergo addition to enones or dienones (Sakurai reactions). The intramolecular addition of allylsilanes is an extremely useful reaction especially for the construction of carbocyclic ring systems, which occurs in a diastereoselective manner, in many cases with complete asymmetric induction. 

Almost 15 years ago Sakurai and Hosomi, in pioneering work, showed that intermolecular addition of an allylsilane to a,j6-unsaturated ketones in the presence of titanium(IV) chloride as the Lewis acid gave the desired 1,4-addition products1 4. In the case of 4,4a,5,6,7,8-hexahy-dro-2(3//)-naphthalenone, reaction was shown to proceed by 1,4-addition with exclusive production of the ris-fused product in high chemical yield. 

In the Sakurai reaction, the product-determining step should be the nucleophilic addition of the allylsilane to the Lewis acid coordinated enone28. 

Additions of silylated ketene acetals to lactones such as valerolactone in the presence of triphenylmethyl perchlorate in combination with either allyltrimethylsilane 82, trimethylsilyl cyanide 18, or triethylsilane 84b, to afford substituted cyclic ethers in high yields have already been discussed in Section 4.8. Aldehydes or ketones such as cyclohexanone condense in a modified Sakurai-cyclization with the silylated homoallylic alcohol 640 in the presence of TMSOTf 20, via 641, to give unsaturated cyclic spiro ethers 642 and HMDSO 7, whereas the 0,0-diethyllactone acetal 643 gives, with 640, the spiroacetal 644 and ethoxytrimethylsilane 13b [176-181]... 

In the presence of In powder 2-cycIohexen-l-one is converted by allyl iodide and Me3SiCI 14, in 63% yield, into the 1,4-addition product 2179 [84], which is also obtained in 73% yield by Sakurai 1,4-addition ofallyltrimethylsilane 82 to 2-cyclohexene-l-one in the presence of excess Me3SiCl 14 and catalytic amounts of InCl3 [85] (Scheme 13.25). Ytterbium] 111) triflate-catalyzed imino-ene reactions of N-tosylaldimines with a-methylstyrene are dramatically accelerated on addition of Me3SiCl 14 [85 a]. 

Wada, M., Sakurai, Y., Akiba, K.-y. (1984) Addition of Alkynyl Anions to Aldimines Containing A-Hydrogens A Novel Synthesis offi-Aminoacetylenes. Tetrahedron Letters, 25, 1083-1084. 

A variety of electrophilic catalysts promote the addition of allylic silanes to carbonyl compounds.86 The original catalysts included typical Lewis acids such as TiCl4 or BFj.87 This reaction is often referred to as the Sakurai reaction. 

Sakurai et al. have provided what is probably the most important mechanistic finding in the area of intermolecular additions of silenes in recent years, namely a detailed proposal for the mechanism of alcohol addition to the silicon-carbon double bond.68 A cyclic silene 116 was synthesized in the presence of various amounts of methanol and other alcohols, and varying proportions of methanol adducts 117 and 118 were obtained. It was concluded that the methanolysis involved two steps, the first being the association of the oxygen lone pairs with the sp 2-hybridized silicon atom of the silene. The second step, proton transfer, could occur in two ways. If the proton was transferred from the complexed methanol molecule (path a) its delivery would result in syn addition. However, if a second molecule of methanol participated (path b), it would deliver its proton... 

This result predicts that mixtures of syn and anti adducts would be expected from the methanolysis the proportions of the isomers would depend on the amount of methanol present, larger amounts of methanol favoring more anti addition, as was shown experimentally. The evidence and arguments presented by Sakurai are very persuasive. Further studies of alcohol additions have recently been reported by Leigh.6 3 The Jones results can be interpreted with the example depicted in Eq. (43). 

Allylation of aldehydes or ketones using allylsilanes, known as the Hosomi-Sakurai reaction, is a useful method for obtaining homoallylic alcohols. TiIV compounds have been successfully applied to this reaction (Scheme 21) 80 Besides aldehydes and ketones, acylsilanes, 0,0-acetals, and A-,(7-acetals can be employed.81-83 1,4-Addition of an allyl group to an a,/ -unsaturated ketone has been also reported.84... 

The bromoallene (-)-kumausallene (62) was isolated in 1983 from the red alga Laurencia nipponica Yamada [64a], The synthesis of the racemic natural product by Overman and co-workers once again employed the SN2 -substitution of a propargyl mesylate with lithium dibromocuprate (Scheme 18.22) [79]. Thus, starting from the unsymmetrically substituted 2,6-dioxabicyclo[3.3.0]octane derivative 69, the first side chain was introduced by Swern oxidation and subsequent Sakurai reaction with the allylsilane 70. The resulting alcohol 71 was protected and the second side chain was attached via diastereoselective addition of a titanium acetylide. The synthesis was concluded by the introduction of two bromine atoms anti-selective S -substitution of the bulky propargyl mesylate 72 was followed by Appel bromination (tetrabromo-methane-triphenylphosphine) of the alcohol derived from deprotection of the bromoallene 73. 

Lewis acid-mediated addition of allylsilanes to carbon nucleophiles. Also known as the Hosomi-Sakurai reaction. The allylsilane will add to the carbonyl compound directly if it is not part of an a,P-unsaturated system (Example 2), giving rise to an alcohol. 

Allyl- and vinylsilane chemistry was one of the first areas of reagent synthesis impacted by CM methodology. Allylsilanes are commonly employed in nucleophilic additions to carbonyl compounds, epoxides, and Michael acceptors (the Sakurai reaction) vinylsilanes are useful reagents for palladium-coupling reactions. As the ubiquitous application of CM to this substrate class has recently been described in several excellent reviews, this topic will not be discussed in detail, with the exception of the use of silane moieties to direct CM stereoselectivity (previously discussed in Section 11.06.3.2). 

---