Crotylation, asymmetric

This type of asymmetric conjugate addition of allylic sulfinyl carbanions to cyclopen-tenones has been applied successfully to total synthesis of some natural products. For example, enantiomerically pure (+ )-hirsutene (29) is prepared (via 28) using as a key step conjugate addition of an allylic sulfinyl carbanion to 2-methyl-2-cyclopentenone (equation 28)65, and (+ )-pentalene (31) is prepared using as a key step kinetically controlled conjugate addition of racemic crotyl sulfinyl carbanion to enantiomerically pure cyclopentenone 30 (equation 29) this kinetic resolution of the crotyl sulfoxide is followed by several chemical transformations leading to (+ )-pentalene (31)68. 

Scheme 6/3.33. Asymmetric conversion of crotyl aryl sulfides into tV-allyl-arylsulfonamides using a chiral Ru-catalyst.

The bis(oxazoline) S, 5)-(115) has been used as an external chiral ligand to induce asymmetric diastereoselective lithiation by r-BuLi during [2,3]-Wittig rearrangement of achiral substrates, (fj-crotyl propargylic ethers.It is believed that the enantios-electivity is determined predominantly at the lithiation step. 

Chiral bis(oxazoline) 27 is an effective chiral coordinating agent for enantiocontrol in the [2,3]-Wittig rearrangement. The rearrangement of (Z)-crotyl benzyl ether 84 with f-BuLi/(5, 5)-27 (1.5 equivalents each) in hexane provided [2,3]-shift product (l/ ,25 )-85 in 40% ee (equation 46The feasibility of the asymmetric catalytic version was also examined. In this case, the rearrangement with 20 mol% of 27 in ether was found to provide the same level of enantioselectivity (34% ee). 

It has been demonstrated by Pancrazi, Ardisson and coworkers that an efficient kinetic resolution takes place when an excess (2 equivalents) of the racemic titanated alkenyl carbamate rac-334a (R = Me) is allowed to react with the enantiopure )-hydroxyaldehyde 341 or alternatively the corresponding y-lactol 340, since the mismatched pair contributes to a lower extent to the product ratio (equation 91) . Under best conditions, the ratio of the enantiomerically pure diastereomers 3,4-anti-4,5-syn (342) and 3,4-anti-4,5-anti (343) is close to 14 1. Surprisingly, approximately 9% of the iyw,iyw-diastereomer 344 resulted when the starting (ii)-crotyl carbamate was contaminated by the (Z)-isomer. The reasons which apply here are unknown. Extra base has to be used in order to neutrafize the free hydroxy group. The pure awft, awfi-product 345 was obtained with 85% yield from the reaction of the (W-oxy-substituted titanate rac-334b and lactol 340. 345 is an intermediate in the asymmetric synthesis of tylosine . ... 

In the first step, reagent 7, developed by Hoffmann, is used lor asymmetric crotylation in order selectively to create the stereogcnic centers at C-10 and C-ll (dr >98 2).13 14 This produces compound 24, which is subsequently protected at C-11 as the p-mclh-oxyben/yl ether Protection is accomplished by reaction of the anion of the alcohol with commercially available p-methoxyben/yl chloride.15 16... 

An additional issue of regiocontrol arises in asymmetric induction when the n-allyl complex possesses a primary terminus. Although steric factors favor the formation of the achiral linear product, alkylations with reactive nucleophiles often benefit from electronic effects leading to the branched product [ 147,148]. Of particular interest is the reaction of the crotyl system because... 

Homoallylic alcohols (8, 111-112). The high rltreo-selectivity observed in the reaction of benzaldehyde with crotyl bromide (either irons or cis) is general for relatively unhindered aldehydes (equation I). High threo selectivity is still observed in the reaction with an a-methyl substituted aldehyde, but a-asymmetric induction (at C3) is rather low (2.2 1) with simple aldehydes (equation II).1... 

Kinetic resolution can be accomplished by addition of allyl boronates to aldehyde groups adjacent to the tricarbonyliron fragment [59]. For the synthesis of ikaruga-mycin, Roush and Wada developed an impressive asymmetric crotylboration of a prochiral meso complex using a chiral diisopropyl tartrate-derived crotylborane (Scheme 1.25) [60]. In the course of this synthesis, the stereo-directing effect of the tricarbonyliron fragment has been exploited twice to introduce stereospedfically a crotyl and a vinyl fragment. 

A crotyl group is added to the aldehyde in an asymmetric reaction. 

A terpene-derived pyridine N-oxide catalyses the asymmetric allylation of aldehy- des with allyl- and crotyl-trichlorosilane at —40 C, and the ees hold up well even at ambient temperature.189... 

The allylation reaction between ketones and allylsilanes was achieved in 2005. Yamamoto and Wadamoto developed the asymmetric allylation reaction in the presence of AgF-Difluorphos (Scheme 9.6).12 The reaction of ketones and allyltrimethoxysilane in the presence of AgF and Difluorophos afforded the corresponding tertiary homoallyhc alcohols with high enantioselectivities. Additionally, a,(3-unsaturated ketones could be used as substrates, and this catalytic system could be applied for the asymmetric crotylation reaction to obtain anti adducts preferentially (Schemes 9.7 and 9.8). When a,p-unsaturated ketones were used as substrates, 1,2-addition products were obtained exclusively. As described before, the anti adducts were obtained predominately, regardless of the geometry of crotyltrimethoxysilane. 

Let us turn now to the other coupling partner, aldehyde 58 it was synthesised by the pathway shown in Scheme 17.18. The first step was a Sharpless catalytic asymmetric epoxidation on ( )-crotyl alcohol with the oxidant derived from (—)-diethyl tartrate. An in situ derivatisation with r-butyldiphenylsilylchloride was then performed. The desired epoxide 59 was readily isolated in 76% overall yield after chromatography. Treatment of 59 with 2-lithio-l,3-dithiane in THF and 1,3-dimethyl-3,4,5,6-tetrahydro-2(l/7)-pyrimidinone (DMPU also known as N,N-... 

Several methods promoted by a stoichiometric amount of chiral Lewis acid 38 [51] or chiral Lewis bases 39 [52, 53] and 40 [53] have been developed for enantioselective indium-mediated allylation of aldehydes and ketones by the Loh group. A combination of a chiral trimethylsilyl ether derived from norpseu-doephedrine and allyltrimethylsilane is also convenient for synthesis of enan-tiopure homoallylic alcohols from ketones [54,55]. Asymmetric carbonyl addition by chirally modified allylic metal reagents, to which chiral auxiliaries are covalently bonded, is also an efficient method to obtain enantiomerically enriched homoallylic alcohols and various excellent chiral allylating agents have been developed for example, (lS,2S)-pseudoephedrine- and (lF,2F)-cyclohex-ane-1,2-diamine-derived allylsilanes [56], polymer-supported chiral allylboron reagents [57], and a bisoxazoline-modified chiral allylzinc reagent [58]. An al-lyl transfer reaction from a chiral crotyl donor opened a way to highly enantioselective and a-selective crotylation of aldehydes [59-62]. Enzymatic routes to enantioselective allylation of carbonyl compounds have still not appeared. 

Barrett and Lebold used the Brown asymmetric crotylation to prepare the homoallyhc alcohol 22 in the total synthesis of nikkomycin B 21, a natural product that exhibits fungicidal, insecticidal, and acaricidal activities14 (Scheme 3.1k). 

Asymmetric allylboration has also been applied to y-methoxyallyl derivatives. Isomerically pure (Z)-y-methoxyallyldiisopinocampheylborane (rf31), prepared from Ipc2lSOMe and the lithium anion of allyl methyl ether, reacts with various aldehydes to afford the yyn - j-m e (boxy homoallylic alcohol (32a) in a highly regio- and stereoselective manner17 (Scheme 3.In). This one-pot synthesis of enantiomerically pure 1,2-diol derivatives went as smoothly as the asymmetric Brown crotylation, affording products with uniformly high diastereoselectivity. 

Asymmetric allylation and crotylation reactions using allylic trichlorosilanes and chiral phosphonamides were developed by Denmark and coworkers in 1994 and further refinement of the chiral ligands system was made in 200114 (Scheme 3.2k). The influence of the six-membered chairlike transition state is once again evidenced by the excellent correlation of the geometry of the reacting silanes with the diastereomeric composition of the products. Thus, anti -isomer is obtained from the -allylic silane, and syn-isomer is produced from the Z-silane. Based on... 

Better results (80 % ee) have been reported by Mikami, Nakai and co-workers [3c] for the addition of crotyl silane also catalyzed by complex 1. Yamamoto and co-workers [3b] used chiral acyl-oxy boranes to catalyze the Sakurai-Hosomi-reac-tion. While an excellent 96 % ee was obtained for the addition of 2,3 -disubstituted allyl groups, the conversion with parent allyl silane was low (46 %) and the asymmetric induction mediocre (55 % ee). Gauthier and Carreira [5] then made a big leap forward by using the difluorotita-nium-binaphthol complex 3. The catalyst 3 is prepared in situ via the TiF4-binaphthol adduct 4 and formal HF elimination mediated by allyl silane 5. The addition of 5 to aldehydes 6 ( 7) catalyzed by 10 % of 3 proceeds with 61 - 94 % < e and good yields (69-93 %), the best results being observed for aldehydes with tertiary alkyl residues (Scheme 1). 

Anionic Claisen rearrangement. Acceleration of the Claisen rearrangement of allyl vinyl ethers was originally observed with potassium hydride in HMPT, but even milder conditions are possible using sodium or lithium dimsylate. The catalyzed rearrangement is as stereoselective as the thermal counterpart. Thus vicinal asymmetric centers are formed selectively on rearrangement of (E)- and (Z)-crotyl ethers (equations I and II). 

Another feature that is crucial in considering rearrangements in monosubstituted allyls is the effect on the chirahty and stereochemistry. In crotyl complexes, formation of a a-bond at the unsubstituted terminus provides a path for racemization for the stereogenic center at the substituted terminus (equation 21). Formation of the a-bond at the monosubstituted terminus, however, results in conversion to a different isomer (equation 22). The most stable isomer is the syn isomer (72) and, in the absence of a substituent on the central carbon, the anti isomer (74) will only occur to the extent of f 5Vo. Thus if one considers complexes hke (acac)Pd(allyl), some racemize, whereas others only isomerize because there is no path for racemization (equation 23). These concepts have been used effectively by Bosnich in the design of systems for asymmetric allylic alkylation. These concepts also allow the rationalization of why certain substrates give low enantiomeric yields. It should be noted here that the planar rotation found in some of the molybdenum complexes retains the chirahty in the allyl moiety. 

Asymmetric Pericyclic Reactions. Several reports illustrate the utility of fra/is-2,5-dimethylpyirolidine as a chiral auxiliary in asymmetric Claisen-type rearrangements, [4 + 2], and [2 + 2] cycloaddition reactions. The enantioselective Claisen-type rearrangement of N,0-ketene acetals derived from tram-2,5-dimethylpyrrolidine has been studied. For example, the rearrangement of the iV.O-ketene acetal, formed in situ by the reaction of A-propionyl-fra/w-(25,55)-dimethylpyrrolidine with ( )-crotyl alcohol, affords the [3,3]-rearrangement product in 50% yield and 10 1 diastereoselectivity (eq 9). 

The optimum catalyst for cycloaddition of the A -crotyl dienophile 175 with cyclopentadiene was found to be that generated from diethylaluminum chloride and diol 187. On this basis, the reactions of dienophiles 189 and 181 were examined with cyclopentadiene and furan as indicated in Sch. 20. In addition, catalysts derived from two derivatives of diol 187 were also examined, as shown in Table 11 [43-45]. It was found that all three diols resulted in similar asymmetric induction, with the highest induction not exceeding that observed for the A -crotyl dienophile 175. The A -acrolyl dienophile 189 gave an 83 17 mixture of endo and exo diastereomers, with 21 % ee for the endo adduct, with a catalyst prepared from diol 187. The same catalyst gave 25 % ee for the cycloadduct of furan with 189 and 2 % ee for the adduct of cyclopentadiene and 191, although in the latter example an increase to 27 % ee is possible with sub-stoichiometric amounts of catalyst. 

Solid-supported synthesis has rapidly emerged as an important strategy in synthetic organic chemistry. Solid-phase methodology is aimed at the direct synthesis of libraries of molecularly diverse compounds for biological evaluation in lead discovery. The asymmetric addition of polymer-supported chiral crotylsilanes to acetals and allylation of polymer-bound acetals linked through an ester with the chiral crotylsilanes has been investigated [44d] la can be employed in these crotylation reactions and results in the formation of polymer-supported homoallylic esters with diastereoselec-tivity similar to that of solution-phase reactions. 

The reaction is specific in that the allyl group retains its configuration in the course of transfer. Thus reactions of metallic mercury with an asymmetrically substituted 7r-allylpalladium chloride (for example, crotyl-palladium chloride) might equally afford both cis- and /raMr-2-butenyl-mercury chloride isomers, as well as the 1-butenyl compound. Hence generally three compounds could be expected in the reaction. However, it has been found 161) that essentially the reaction yields only trans-crotylmercury chloride (based on infrared spectra). In the case of 1-phenyl-77-allylpalladium chloride and l-acetyl-2-methyl-7r-allylpalladium chloride, again only the respective y-substituted /raw-allylmercury halides have been found. Since such conditions do not allow the allyl rearrangement 162), formation of the /ra r-allylmercury derivatives is evidence that the... 

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