Chiral allylic bromides

Table 2. 1,2-Disubslituted 3-Butcnols From Chiral Allyl Bromides and Achiral Aldehydes (CrCl3/LiAlH4) 2...

Table 3. 3-Subslituted 1-(a-IIydroxyalkyl)-3-bulcnols from Chiral Allyl Bromides and Chiral Aldehydes (CrCl2)12...

For the synthesis of the second required building block, the chiral allylic bromide 31, we again used our SAMP/RAMP hydrazone methodology for the construction of the stereogenic center. The a-alkylation of the SAMP hydrazones of O-protected 4-hydroxybutanal 40a,b with iodomethane led to the desired products 41 with very good yields and very high stereoselectivities and with the required... 

The addition of chiral allylic bromides of the general type 247 to achiral aldehydes mediated by CrCb proceeds with a high degree of stereocontrol in which the bromide acts as the stereodominant component (Scheme 10-81) [148]. In all cases examined, major diastereomer 248 has an all-.vyn arrangement of the y-vinyl and <5-methyl substituents. On the basis of this stereochemical outcome the following conclusions can be drawn (1) the <5-center determines the stereochemical outcome of the newly created stereocenters (y and //), (2) the relative dia-stereoselection of the reaction is not affected by the presence of stereogenic centers in the allylic bromide, and (3) additional stereocenters in the e- and c-posi-tions of the bromide increase the diastereofacial selectivity but have no influence on the sense of the asymmetric induction. 

The chromium(II)-mediated addition (Hiyama reaction) of chiral allylic bromide 835 to lactaldehyde 831 proceeds with high Felkin—Anh selectivity to furnish exclusively adduct 836 [230]. In addition to the Felkin model, the high stereoselectivity is also explained by the effect of matched pairing of the two reaction partners. If the corresponding R-enantiomer of THP-lactaldehyde 831 is employed ( mismatched pair ), a mixture of three diastereomers (3 1 1) is produced. The THP group of 836 can be removed in the presence of the TBPS protecting group by treatment with PPTS in methanol (54% yield). 

In contrast, the reactions between Mo(CO)3(CH3CN)3 and chiral allylic bromides proceed via inversion with respect to cleavage of the allylic carbon-halide bond. Examples are provided by the work of Liebeskind as shown in Scheme 5. TTie ring conformation is important for the reaction, and an interesting case is the chiral trans bromide isomer 7 whose pseudoaxial bromide group is displaced by Mo(CO)3(CH3CN)3 presumably according to an S 2 mechanism, whereas the cis isomer 9... 

Mulzer J, Kattner L, Strecker AR, Schroder C, Buschmann J, Lehmann C, Luger P (1991) Highly Felkin-Anh selective Hiyama additions of chiral allylic bromides to aldehydes. Application to the first synthesis of nephromopsinic acid and its enantiomer. J Am Chem Soc 113 4218-4229... 

Thia-Claisen rearrangements of N-benzylpyrrolidine-2-thione and chiral allylic bromides derived from D-mannitol have been reported. Introduction of a bromine atom 0 onto the double bond of the allyhc bromide reverses the sense of diastereoselectivity in the [3,3]-sigmatropic rearrangement and DFT calculations rationalize the selectivity in terms of a Cieplak effect (Scheme 34). 

Mulzer et al. 553) synthesized (-)-nephromopsinic acid by the addition of a chiral allylic bromide to tetradecanal (see Scheme 36). The same group 628, 666) also described total syntheses of (-)- and (+)-roccellaric acid and (-)-dihydroprotolichesterinic acid and secured the relative configuration of (+)-roccellaric acid by an X-ray analysis. One route started from (2S,3E)-l,2-isopropylidene-5-0-benzyl-3-pentene-1,2,5-triol (42) (see Scheme 37). The second route included the ozonisation of methyl-(2RS,3R,4E)-3-benzyloxy-5-hydroxy-oxolan-3-one and subsequent condensation with tridecyltriphenylphosponium bromide (see Scheme 38). Finally they synthesized (-t-)-roccellaric acid and (-l-)-dihydroprotolichesterinic acid from D-glucose as the chiral pool (552) (see Scheme 39). 

The application of this strategy to the synthesis of chiral cyclohexadienes has been demonstrated by Kiindig. Addition of MeLi to the Cr(CO)3-complexed chiral phenyl oxazoline 43 followed by reaction with allyl bromide produced cyclohexadiene 44 in 69% yield and >98% de. ... 

An example for synthesis of the chiral p-keto ester 69 is illustrated in equation 64. It involves conjugate addition of the dipotassium / -keto ester 68 to vinyl sulfone 67 followed by in situ quenching with allyl bromide . The method provides a new procedure to sevenring annulation product 70 that is a potential precursor for (l)-(—)-cytochalasin C. 

Normally, the addition of C-nucleophiles to chiral a-alkoxyaldehydes in organic solvents is opposite to Cram s rule (Scheme 8.15). The anti-Cram selectivity has been rationalized on the basis of chelation control.142 The same anti preference was observed in the reactions of a-alkoxyaldehydes with allyl bromide/indium in water.143 However, for the allylation of a-hydroxyaldehydes with allyl bromide/indium, the syn isomer is the major product. The syn selectivity can be as high as 10 1 syn anti) in the reaction of arabinose. It is argued that in this case, the allylindium intermediate coordinates with both the hydroxy and the carbonyl function leading to the syn adduct. 

The chiral 1,3-divinylallene (1,3,4,6-heptatetraene) (3) is obtained when the vinylace-tylene Grignard reagent 198 is first coupled to allyl bromide (199) and the resulting skipped enyne is subsequently isomerized under basic conditions (Scheme 5.29) [74]. 

With additive combination, the effects do not influence each other, for example, in the Hiyama addition of a chirally substituted allylic bromide to benzaldehyde60. 

The Hiyama addition of allyl bromide 20 to (7 )-2-(methoxymethoxy)hexanal to give 21 with high stereoselectivity. Both the starting allyl bromide and the aldehyde are chiral and were used in nonracemic form. The relative configuration of the two stereogenic centers created in this reaction (c and d) had to be determined128 (see pp 463 and 483). 

The oxazolidin-2-ones 53 (R = H=CCH=CH2 or COEt) are obtained in a one-pot reaction of amino alcohol carbamates 52 with sodium hydroxide, followed by allyl bromide or propi-onyl chloride (94TL9533). A modified procedure for the preparation of chiral oxazolidin-2-ones 56 from a-amino acids 54, which avoids the hazardous reduction of the acids with borane and the intermediacy of water-soluble amino alcohols, is treatment of the methyl ester of the amino acid with ethyl chloro-formate to give 55, followed by reduction with sodium borohydride and thermal ring-closure of the resulting carbamate f95SC561). The 2-prop-ynylcarbamates 57 (R = Ts, Ac, Bz, Ph or allyl) cyclize to the methyleneoxazolidinones 58 under the influence of silver cyanate or copper(I) chloride/triethylamine (94BCJ2838). 

The industrial production of Crixivan (9 H2S04) took advantage of the chirality of (IS,2R)-aminoindanol to set the two central chiral centers of 9 by an efficient diastereoselective alkylation-epoxidation sequence.17 The lithium enolate of 12 reacted with allyl bromide to give 13 in 94% yield and 96 4 diastereoselective ratio. Treatment of a mixture of olefin 13 and V-chlorosuccinimide in isopropyl acetate-aqueous sodium carbonate with an aqueous solution of sodium iodide led to the desired iodohydrin in 92% yield and 97 3 diastereoselectivity. The resulting compound was converted to the epoxide 14 in quantitative yield. Epoxide opening with piperazine 15 in refluxing methanol followed by Boc-removal gave 16 in 94% yield. Finally, treatment of piperazine derivative 16 with 3-picolyl chloride in sulfuric acid afforded Indinavir sulfate in 75% yield from epoxide 14 and 56% yield for the overall process (Scheme 24.1).17-22... 

Schiff base 52 in one-pot under mild phase-transfer conditions. For example, the initial treatment of a toluene solution of 52 and (S,S)-32e (1 mol%) with allyl bromide (1 equiv.) and CsOHH20 at —10 °C, and the subsequent reaction with benzyl bromide (1.2 equiv.) at 0 °C, resulted in formation of the double alkylation product 53 in 80% yield with 98% ee after hydrolysis. Notably, in the double alkylation of 52 by the addition of the halides in reverse order, the absolute configuration of the product 53 was confirmed to be opposite, indicating intervention of the chiral ammonium enolate 54 at the second alkylation stage (Scheme 4.17) [50]. 

Reaction of [FeCp(C6Me6)][PF6] [33-35] with excess KOH (or tBuOK) in THF or DME and excess alkyl iodide, allyl bromide, or benzyl bromide leads to one-pot hexasubstitution (Scheme 5a) [36-38]. With allyl bromide (or iodide) in DME, the hexaallylated complex has been isolated and its X-ray crystal structure determined, but the extremely bulky dodeca-allylation [52] product can also be reached when the reaction time is extended to two weeks at 40 °C. The chains are fixed in a directionality such that conversion to the enantiomer is not possible, thus making the metal complex chiral (Scheme 5b). 

Highly enantioselective Rh-catalyzed intramolecular Alder-ene reactions for the synthesis of chiral 3-alkylidene-4-vinyltetrahydrofurans were reported by Zhang, as illustrated below <02AG(E)3457>. Metallic indium was also shown to mediate the intramolecular cyclization of tethered allyl bromides onto terminal alkynes to afford 3-methylene-4-vinyltetrahydrofurans in 50-62% yield <02SL2068>. 

Aldimines react with allyl bromide in the presence of metallic bismuth and tetrabutylammonium bromide in acetonitrile to give homoallyl amines (Equation (42)).77 When a chiral imine derived from benzaldehyde and (S)-valine methyl ester is used as the substrate, the allylation with allylic bismuth(m) species takes place smoothly by the assistance of a Lewis acid such as BF3-OEt2 and A1C13 to afford a chiral homoallylic amine with high diastereoselec-tivity (Equation (43)).78... 

As mentioned in Section 9.12.2.1.1, the boron-zinc exchange can be performed stereoselectively if diisopropyl-zinc instead of diethylzinc is used. For example, hydroboration of the chiral, racemic endocyclic olefin 134 with diethylzinc, followed by twofold transmetallation and electrophilic capture of the resulting copper intermediate with allyl bromide was used for the highly diastereoselective formation of the stereotriad in product 136 (Scheme 35).35,35a 103 QorreSp0nding enantioselective transformations were carried out with chiral boranes and catalytic amounts of copper salts (see Section 9.12.2.2.2).36... 

Prenyl bromide affords better chemical yields and better enantioselectivities than allyl bromide (Table 6). The best result (99% yield, 90% (R) ee) is obtained when benzaldehyde is treated with prenyl bromide in the presence of (—)-cinchonidine. A similar enantioselective propargylation reaction of aldehydes with enantioselectivity up to 85% has been achieved in organic solvents by using stoichiometric amounts of (—)-cinchonidine as the chiral source (Table 7).190... 

By using (chiral source, high enantioselectivity (up to 92% ee) has been attained in an aqueous medium H20-EtOH (1 1) (Scheme 46).191 Changing to other mixed solvents leads to lower selectivities (72% ee in H20-MeCN (1 1), 76% ee H20-THF (1 1), and 66% ee in H20-EtOH (1 9)). The reaction of allyl iodide in place of allyl bromide decreases the selectivity from 92% to 76% ee. 

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