Ketones tetrasubstituted

The Wittig reaction is extremely general, and a great many monosubstituted, disubstituted, and trisubstituted alkenes can be prepared from the appropriate combination of phosphorane and aldehyde or ketone. Tetrasubstituted alkenes can t be prepared, however, because of steric hindrance during the reaction. 

Treatment of the diethylketal of methyl isobutyryl ketone with morpholine did not give the above condensation product (63), but led to a mixture of di- and tetrasubstituted isomers (124 and 125). 

Morpholine enamine of methyl isopropyl ketone prepared by this method was found to be a 3 7 mixture of di- and tetrasubstituted isomers (126 and 127). 

Another example of a [2s+2sh-1c+1co] cycloaddition reaction was observed by Barluenga et al. in the sequential coupling reaction of a Fischer carbene complex, a ketone enolate and allylmagnesium bromide [120]. This reaction produces cyclopentanol derivatives in a [2S+2SH-1C] cycloaddition process when -substituted lithium enolates are used (see Sect. 3.1). However, the analogous reaction with /J-unsubstituted lithium enolates leads to the diastereoselective synthesis of 1,3,3,5-tetrasubstituted cyclohexane- 1,4-diols. The ring skeleton of these compounds combines the carbene ligand, the enolate framework, two carbons of the allyl unit and a carbonyl ligand. Overall, the process can be considered as a for-... 

It follows that tetrasubstituted alkenes do not normally give ozonides. However, they do give the normal cleavage products (ketones) by the other pathways. For the preparation of... 

Oxidative cyclization of acylhydrazones 110a, derived from aldehydes or ketones, with the use of lead tetraacetate (LTA) has been developed into a useful route to several disubstituted and tetrasubstituted oxadiazole derivatives 122, being a convenient source of relatively stable carbenes, like N(0)C , S(0)C , 0(0)C , or S(S)C <2000J(P1)2161 >. Some representative recent examples of the syntheses are collected in Table 2. 

The signature application for the G-H insertion in synthesis is probably the total synthesis of (—)-tetrodotoxin 126 by Du Bois and Hinman.233 Two stereospecific G-H activation steps, rhodium-catalyzed carbene G-H insertion and carbamate-based nitrene C-H insertion, have been used to install the two tetrasubstituted centers C6 and C8a (Scheme 12). Diazoketone 122 was treated with 1.5mol% Rh2(HNCOCPh3)4, and cyclic ketone 123 was selectively formed in high yield without purification. The reaction of carbamate 124 with 10mol% Rh2(HNCOCF3)4, PhI(OAc)4, and MgO in C6H6 solvent furnished the insertion product 125 in 77% yield. 

Dienes such as 90 can be accessed by a multi-component reaction under ruthenium catalysis involving an allene 88 and an enone (methyl vinyl ketone in this case), with cerium(m) chloride as an additive in DMF (Scheme 26).95,96 With an allene concentration of 0.25 M, yields are moderate to good. Different ruthenium catalysts and additives were tested in order to optimize this reaction. CpRu(COD)Cl 89 and CpRu(MeCN)3PF6 appeared to be more versatile ones. The mono-, di-, tri-, and tetrasubstituted allenes have been investigated with methyl vinyl... 

Trost et alJ2 also explored the compatibility of di-, tri-, and tetrasubstituted allenes with their intermolecular Alder-ene protocol. Multiple substituents present the opportunity for a mixture of products to arise from differing regio- and chemoselectivity. 1,1-Disubstituted allenes were coupled to methyl vinyl ketone with excellent chemo-selectivity only when one set of /3-hydrogens was activated by an cy-ester or amide (Equation (69)). If the /3-hydrogens were of similar acidity, a mixture of products was obtained, as in the coupling of allenol 103 with methyl vinyl ketone dienes 104 and 105 are produced in a 1.3 1 mixture (Equation (70)). 

The ruthenium carbene catalysts 1 developed by Grubbs are distinguished by an exceptional tolerance towards polar functional groups [3]. Although generalizations are difficult and further experimental data are necessary in order to obtain a fully comprehensive picture, some trends may be deduced from the literature reports. Thus, many examples indicate that ethers, silyl ethers, acetals, esters, amides, carbamates, sulfonamides, silanes and various heterocyclic entities do not disturb. Moreover, ketones and even aldehyde functions are compatible, in contrast to reactions catalyzed by the molybdenum alkylidene complex 24 which is known to react with these groups under certain conditions [26]. Even unprotected alcohols and free carboxylic acids seem to be tolerated by 1. It should also be emphasized that the sensitivity of 1 toward the substitution pattern of alkenes outlined above usually leaves pre-existing di-, tri- and tetrasubstituted double bonds in the substrates unaffected. A nice example that illustrates many of these features is the clean dimerization of FK-506 45 to compound 46 reported by Schreiber et al. (Scheme 12) [27]. 

Bppfoh and bppfa derivatives have been applied most successfully for the Rh-catalyzed hydrogenation of dehydro amino acid derivatives such as MAC (ee 97%) and of functionalized ketones [7]. The nature of the amino group has a significant effect on enantioselectivity and often also on activity, and is used to tailor the ligand for a particular substrate. Rh-bppfa complexes were among the first catalysts able to hydrogenate tetrasubstituted C=C bonds, albeit with relatively low activity (Table 25.2, entries 2.1-2.3). Ferrophos, one of the very few li-... 

In marked contrast to the above results, double nitrile insertion into both the titanium-alkyl and titanium—vinyl bonds occurs to form the diazatitanacycles 74. Treatment of these titanacycles with dry hydrogen chloride affords the tetrasubstituted pyridine derivatives 75 (Scheme 14.32) [74], On the other hand, 2,3-diphenyltitanacyclobutene reacts with various nitriles to afford the products of mono-insertion, which afford the corresponding unsaturated ketones upon hydrolysis [73,74]. 

We reported a catalytic enantioselective cyanosUylation of ketones that produces chiral tetrasubstituted carbons from a wide range of substrate ketones [Eq. (13.31)]. The catalyst is a titanium complex of a D-glucose-derived ligand 47. It was proposed that the reaction proceeds through a dual activation of substrate ketone by the titanium and TMSCN by the phosphine oxide (51), thus producing (l )-ketone cyanohydrins ... 

Ozonolysis of acyclic ketoximes 43 in the presence of ketones resulted in the formation of tetrasubstituted cross-ozonolides (1,2,4-trioxolanes) 44 in yields up to 73% (equation 20). Ozonolysis of 0-methylated monooximes of 1,4-, 1,5- and 1,6-dicarbonyl compounds afforded bicyclic oxonides . ... 

Tetrasubstituted organotin compounds are not sufficiently reactive to add directly to aldehydes and ketones, although reactions with aldehydes do occur with heating. 

Trimethyl(prop-l-en-2-yloxy)silane afforded (3-amino ketone 24u in good yield (Table 5, entry 10). Silyl enol ethers derived from 3-pentanone and cyclopentanone smoothly afforded (3-amino ketones 24v and 24w, respectively (Table 5, entries 11 and 12). Tetrasubstituted silyl enol ethers readily produced the expected products 24x and 24g (Table 5, entries 13 and 14). 

The trisubstituted alkene of 10 was more readily oxidized than was the congested tetrasubstituted alkene, so the more reactive alkene was temporarily epoxidized. After ozonolysis, the epoxide was reduced off using the Sharpless protocol. It is a tribute to the specificity of this reagent that the easily-reduced a-acetoxy ketone is not affected. Selective silylation of the more accessible ketone followed by melhylenation, hydrolysis and addition of methyl lithium to the outside face of the previously protected carbonyl then delivered 1. 

---