Allyl alcohols 3.3- disubstituted

As expected, the formation of a carbonyl group is not possible with tert-allylic alcohols. Although the aromatic ring bears electron-donating groups, the 2,2-disubstituted chromene 119 was formed smoothly with the tert-allylic alcohol 118[100]. 

Table 11.1 lists some of the reaction conditions which have given prepara-tively useful yields of 3-alkylation. Entries 1-3 are typical alkylations using a magnesium salt and an alkyl halide. Even 2,3-disubstituted indoles are alkylated at C3 under these conditions (Entry 7). Entry 5 represents a more recently developed method in which an allylic alcohol and indole react in the... 

As with i -substituted allyl alcohols, 2,i -substituted allyl alcohols are epoxidized in excellent enantioselectivity. Examples of AE reactions of this class of substrate are shown below. Epoxide 23 was utilized to prepare chiral allene oxides, which were ring opened with TBAF to provide chiral a-fluoroketones. Epoxide 24 was used to prepare 5,8-disubstituted indolizidines and epoxide 25 was utilized in the formal synthesis of macrosphelide A. Epoxide 26 represents an AE reaction on the very electron deficient 2-cyanoallylic alcohols and epoxide 27 was an intermediate in the total synthesis of (+)-varantmycin. 

A valuable feature of the Nin/Crn-mediated Nozaki-Takai-Hiyama-Kishi coupling of vinyl iodides and aldehydes is that the stereochemistry of the vinyl iodide partner is reflected in the allylic alcohol coupling product, at least when disubstituted or trans tri-substituted vinyl iodides are employed.68 It is, therefore, imperative that the trans vinyl iodide stereochemistry in 159 be rigorously defined. Of the various ways in which this objective could be achieved, a regioselective syn addition of the Zr-H bond of Schwartz s reagent (Cp2ZrHCl) to the alkyne function in 165, followed by exposure of the resulting vinylzirconium species to iodine, seemed to constitute a distinctly direct solution to this important problem. Alkyne 165 could conceivably be derived in short order from compound 166, the projected product of an asymmetric crotylboration of achiral aldehyde 168. 

Ten years after Sharpless s discovery of the asymmetric epoxidation of allylic alcohols, Jacobsen and Katsuki independently reported asymmetric epoxidations of unfunctionalized olefins by use of chiral Mn-salen catalysts such as 9 (Scheme 9.3) [14, 15]. The reaction works best on (Z)-disubstituted alkenes, although several tri-and tetrasubstituted olefins have been successfully epoxidized [16]. The reaction often requires ligand optimization for each substrate for high enantioselectivity to be achieved. 

A novel approach was developed very recently by Kita et al. [15]. DKR of allylic alcohols was performed by combining a lipase-catalyzed acylation with a racemization through the formation of allyl vanadate intermediates. Excellent yields and enantioselectivities were obtained. An example is shown in Figure 4.4. A limitation with this approach for the substrates shown in Figure 4.4 is that the allylic alcohol must be equally disubstituted in the allylic position (R = R ) since C—C single bond rotation is required in the tertiary alkoxy intermediate. Alternatively, R or R can be H if the two allylic alcohols formed by migration of the hydroxyl group are enantiomers (e.g. cyclic allylic acetates). 

Although the introduction of a substituent at both C-a and C-P may be expected to destabilize the transoid state of rearrangement due to additional 1,2-allylic interactions, the tendency to form an -double bond exclusively is retained in the synthesis of trisubstituted olefins as well. The first such report, shortly following the initial Evans report , was made by Grieco who achieved a completely stereospecific general synthesis of ( )-y-substituted methallyl alcohols, including the synthesis of racemic ( )-nuciferol (45, equation 24) . Subsequently, other examples of nearly or completely stereospecific syntheses of ( )-) , y-substituted allylic alcohols have also been pub-lished - " . On the other hand, in the synthesis of y,y-disubstituted allylic alcohols a diminished stereoselectivity has been observed. In this case, the /Z ratio depends on the... 

Several catalytic systems have been reported for the enantioselective Simmons Smith cyclopropanation reaction and, among these, only a few could be used in catalytic amounts. Chiral bis(sulfonamides) derived from cyclo-hexanediamine have been successfully employed as promoters of the enantioselective Simmons-Smith cyclopropanation of a series of allylic alcohols. Excellent results in terms of both yield and stereoselectivity were obtained even with disubstituted allylic alcohols, as shown in Scheme 6.20. Moreover, this methodology could be applied to the cyclopropanation of stannyl and silyl-substituted allylic alcohols, providing an entry to the enantioselective route to stannyl- and silyl-substituted cyclopropanes of potential synthetic intermediates. On the other hand, it must be noted that the presence of a methyl substituent at the 2-position of the allylic alcohol was not well tolerated and led to slow reactions and poor enantioselectivities (ee<50% ee). ... 

A very extensive and detailed study of the cationic rhodium(i)-catalyzed isomerization of allylic alcohols demonstrated that mono- and disubstituted allylic alcohols can be efficiently isomerized to the corresponding carbonyl compounds through the corresponding enol compounds (Scheme 20).45 The isomerization using cationic rhodium(l)... 

The enantioselective isomerization of allylic alcohols using cationic rhodium(l)/BINAP complex was reported.9,11 Although the enantioselectivities were lower than those achieved by the isomerization of the corresponding enamines, 3,3 -disubstituted allylic alcohols were isomerized to the corresponding aldehydes in moderate yield and enantioselectivity (Scheme 27). 

The configuration of the product in diastereoselective hydrogenation -whether 1,2-syn or 1,2-anti - is related to the substitution pattern of the starting alkene. The allyl alcohol with a 1,1-disubstituted olefin unit affords the antiproduct, while the syn-product is formed from the allyl alcohol with a trisubsti-tuted olefmic bond (Table 21.8, entries 6-9). The complementarity in diastereoselective hydrogenation of di- and tri-substituted olefins may be rationalized based on the conformation analysis of the intermediary complex (Scheme 21.1)... 

We will describe representative procedures for the epoxidation of a disub-stituted aromatic allylic alcohol (A), a trisubstituted aromatic allylic alcohol (B) and a disubstituted aliphatic allylic alcohol (C). 

Coupling of vinyl iodides with aldehydes (12, 137). Further study1 of this 1,2-addition of alkenylchromium compounds to aldehydes to form allylic alcohols indicates that the reaction is applicable to a-alkoxy and a,(i-bisalkoxy aldehydes by use of a solvent other than DMF, which can promote elimination to an enal. A wide number of other functional groups can also be accommodated. Both vinyl iodides and p-iodo enones can be used as precursors to the alkenylchromium reagent. The reaction is only modestly diastereoselective, but the stereochemistry of a disubstituted vinyl iodide is retained. 

It is interesting to note that no reaction is observed with oxirane 72a if the hydroxyl group is protected. Moreover, whereas deuterium labeling experiments indicate a clean /3-deprotonation process for both oxiranes 69 and 72a, the same enantiomer of base 71 furnishes the corresponding allylic alcohols 70 and 73a with the opposite absolute configurations (Scheme 30 vs. 31). The same studies on vicinal disubstituted analogues 72b,c showed that both the sense and the level of enantioselectivity are unchanged, which... 

The RLi homochiral ligand complexes are seldom used for the base-promoted isomerization of oxiranes into allylic alcohols because their poor chemoselectivity lead to complex mixtures of products. As examples, the treatment of cyclohexene oxide by a 1 1 i-BuLi/(—)-sparteine mixture in ether at low temperature provides a mixture of three different products arising respectively from -deprotonation (75), a-deprotonation (76) and nucleophilic addition (77) (Scheme 32) . When exposed to similar conditions, the disubstituted cyclooctene oxide 78 affords a nearly 1 1 mixture of a- and -deprotonation products (79 and 80) with moderate ee (Scheme 32, entry 1). Further studies have demonstrated that the a//3 ratio depends strongly on the type of ligand used (Scheme 32, entry 1 vs. entry 2) . ... 

Ab initio calculations also confirm that the use of an allyl magnesium alkoxide in place of the alcohol functionality will lead to high or complete stereoselectivity (138). When homoallylic alcohols are used, the Kanemasa protocol afforded the respective isoxazolines with poor stereoselectivity ( 55 45) in the case of terminal aUcenes, but with very high diastereoselectivity (up to 96 4) in the reaction of cis-1,2-disubstituted olefins (136). Extension of this concept to the reaction of a-silyl allyl alcohols also proved feasible and produced the syn (threo) adducts as nearly pure diastereomers (>94 6) (137). Thus, the normal stereoselectivity of the cycloaddition to the Morita-Baylis-Hillman adducts (anti > syn, see above) can be reversed by prior addition of a Grignard reagent (176,177). Both this reversal... 

The magnesium ion-mediated nitrone cycloadditions of an a,y-disubstituted allyl alcohol are stereoselective, and show opposite regioselectivity to that observed when zinc-mediated reactions are examined (Scheme 11.48) (167). The exo-syn-isomer of the isoxazolidine-5-alcohol regioisomer and the exo-syn-isomer of the isoxazolidine-4-alcohol regioisomer are the exclusive cycloadducts in the magnesium- and zinc-mediated reactions, respectively. 

An intramolecular substitution of trimethylamine fix>m 17 gave a bicyclic oxetane 18 in a diastereoselective process <98MI2185>. A [2+2]cycloaddition of 2,2,4,5-tetrasubstituted 2,3-dihydrofuran to aryl aldehydes gave the bicyclic oxetane 19 <98JCS(P1)3261>. 2,2-Disubstituted-3-bromooxetane was obtained by a 4-endo-tcig cyclization process of 3,3 -disubstituted allyl alcohol in the presence of bis(collidine)bromine hexafluorophosphate <99JOC81>. 

Type III (no homodimerization) Acrylonitrile," protected 3° allylamines" Vinyl trialkoxysilanes, vinyl siloxanes 1,1-Disubstituted olefins, " non-bulky trisubstituted olefms, vinyl phosphonates, " vinyl phosphine oxides,phenyl vinyl sulfone, acrylonitrile, 4° allylic carbons (all alkyl substituents), protected 3° allylic alcohols, 7,Aolefm of 2-subst. 1.3- butadienes, 7,Aolefin of electronically deactivated 1.3- butadienes ... 

Type IV (spectators to CM) 1,1-Disubstituted olefms " 1,1-Disubstituted olefms, disub. o ,/ -unsaturated carbonyls, 4° allylic carbon-containing olefins, perfluorinated alkane olefins, 3° allylamines (protected)" Vinyl nitro olefins, protected trisubstituted allyl alcohols, a,/ -olefin of 2-subst. 1.3- butadienes, a,/ -olefm of electronically deactivated 1.3- butadienes ... 

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