Chiral propargyl alcohol

Equation (81)), while the other two C=C double bonds in the structure are intact. Under the same reaction conditions, the racemic carvone is also resolved kinetically with a KR/KS ratio of 33 1. Asymmetric hydrogenation of a,/Tacetylenic ketones to chiral propargylic alcohols is still unavailable. 

A stereoselective synthesis of the enantiomerically enriched allenic hydrocarbons was described in 2001 (Scheme 18.11) [37]. For example, hydrostannylation of the chiral propargylic alcohol 28 (obtained with 82% ee by enantioselective reduction of... 

Scheme 18.11 Synthesis of (R)-(—)-tricosa-9,l 0-diene (27a) from chiral propargylic alcohol 28 (AlBN = azobisisobutyronitrile) [37].

Alkynyl ketones 63 are reduced to chiral propargylic alcohols with the same reagent in high optical and synthetic yields (82). The results are shown in Table 7. Reagent (S)-56 gave (S)-alkynylcarbinols, whereas (R)-56 gave the (R)-al-cohols. Several of the acetylenic alcohols are useful for transformation into insect pheromones. 

In 1993, Nicholas and his co-worker developed the stereospecific propargylic alkylation of chiral propargylic alcohols 30 with enol silanes 31 by using a stoichiometric amount of [Co2(CO)5L] (L = phosphite), but separation procedures of the produced diastereoisomers are necessary twice on the way to obtain the compounds specifically alkylated at the propargylic position 32 (Scheme 5). In 2001, Montana and his co-worker reported the diastereo-selective Nicholas alkylation of propargylic acetal complexes 33 bearing a chiral auxiliary with various enol silanes 34 (Equation (14)). A high diastereoselectivity is observed, but unfortunately, only low to moderate enantioselec-tivities are achieved in all cases. 

Scheme 2.2.4.4 Reduction of alkynones to chiral propargylic alcohols using LB-ADH. NADPH regeneration was performed using 2-propanol as co-substrate.

Chiral propargylic alcohols. The ketals (2) obtained from propargylic ketones and (2R, 4R)-2,4-pentanediol (1) are cleaved by DIBAH or Br2AlH to the ethers (3) diastereoselectively ( 96 4). The chiral auxiliary is removed by oxidation (PCC) and hydrolysis to furnish optically pure propargylic alcohols with the (R)-configuration.1... 

Recently Carreira reported the first catalytic and highly enantioselective alkynylation. Thus, in the presence of a catalytic amount of Zn(II) salt and N-methylephedrine (21), the reaction of aldehydes and terminal acetylenes proceeds to give various chiral propargyl alcohols with high ee (Scheme 8) [30]. A... 

Isomerization of chiral propargyl alcohols.1 The isomerization of chiral alcohols of the type RCHOHC,=C(CH2)nCH3 to terminal acetylenic alcohols, RCHOH(CH2)n + 1C=CH, in the presence of KAPA occurs with no significant loss of enantiomeric purity. Evidently, formation of the alkoxide suppresses racemization. Retention of configuration is observed even when the triple bond moves through several methylene groups. 

Several other asymmetric Mannich-type processes have been described. Propargyl alcohols (11) undergo an addition to imines (12), to give 2-acylallylic carbamates (13), using an oxovanadium catalyst.28 The reaction always gave the (Z)-enone, but a trial with a chiral propargyl alcohol showed virtually no enantioselectivity. 

The synthesis of a new enantiopure, conformationally constrained 1,4-amino alcohol (25) has been reported, starting from commercially available reagents from the chiral pool.107 This 1,4-amino alcohol has been used as a chiral ligand in the addition of Et2Zn to aldehydes (best ee 98%) and in the synthesis of chiral propargylic alcohols (best ee 70%) by alkynylzinc species. 

Smith has employed a related process using the ligand 3 developed by Jiang to obtain a chiral propargyl alcohol. This served as a key building block in an elegant synthesis of (-)-indolizidine 223AB (Eq. 21) [26],... 

This reduction was applied to the synthesis of some natural products. Cate-cholborane reduction is also effective for the synthesis of chiral propargylic alcohols (Scheme 7). In this case the catalyst of choice is 59 (Fig. 3) [85]. 

A direct synthesis of chiral propargylic alcohols from 1-alkynes and aldehydes in the presence of Zn(OTf)2, EtjN, and (+)-A-methylephedrine has a broad scope. Several new ligands are found suitable for inducing asymmetric addition of R2Zn (mostly diethylzinc) to aldehydes. These include 42, 43, 44, 45, and Other (3-amino alcohols that show desirable features are S-ew-morpholinoisoborneol, which is more stable in air than the dimethylamino analogue, (S)-2-(pyrrolidin-l-yl)-l,2,2-triph-enylethanol, and a polymer-supported A-alkyl-a,a-diphenyl-L-prolinols. A,A-Dibutyl-norephedrine is useful in a solvent-free reaction. ... 

More highly functionalised chiral propargyl alcohols are available by the chiral pool approach. For example, both fragments (34) and (35) were prepared from D-xylose, as intemediates for the synthesis of LTB (Scheme 55). ... 

Toda has used alkaloids [brucine (22), sparteine (25)] to enantioselectively enclathrate chiral propargylic alcohols (Fig. 10). Hydrogen bonding is an essential part of the lattice build-up. In view of the large pool of natural alkaloids, the potential of the method is obvious. 

Figures 21.1 to 21.3 show several arachidonic acid-derived and other bioactive natural products synthesized using chiral propargyl alcohol (CPA) in the authors own group (Fig. 21.1) and other groups (Figs. 21.2 and 21.3).

The major strategies for constructing chiral propargyl alcohol can be classified as follows ... 

One of the most practical ways to achieve chiral propargyl alcohol is to add acetylene anion to a carbonyl group in an enantiofacial manner. This art was well demonstrated by Mukayama et al. in 1979 using (2S,2 S)-2-hydroxymethyl-l-[(l-methylpyrrolidine-2-yl)methyl]pyrrohdine as a chiral ligand. The addition of lithium trimethylsilyl acetylide to benzaldehyde afforded the corresponding alkynol in over 92% optical yield. It is noted that the enantioselectivity of the present reaction depended predominantly on the trialkylsilyl group of the acetylene. Scheme 21.7 confirms these observations. 

Torn et al. have utilized the asymmetric sulfoxide precursor for the synthesis of chiral propargylic alcohol (Scheme 21.15). The e.e. values of the products was greater than 99% in a few cases. The reaction of the a-carbanion derived from (irimethylsilyl)vinyl sulfoxides with aldehydes afforded a diastereomeric mixture of products R-4 and S-5. They were... 

Chan et al. " have developed a simple and practical method to make chiral propargyl alcohols. In the presence of titanium alkoxide complex prepared in situ from titanium... 

Chiral disulfide oxazolidine ligands were developed by Braga et al. more recently. The ligand was prepared from / -cysteine in a few steps (Scheme 21.18). The / ,/ -oxazolidine (2) was efficient in the presence of diethyl zinc to furnish chiral propargyl alcohols with moderate to good selectivity. 

Other efforts in asymmetric alkynation using sterically congested BINOL were reported independently by Pu et al. and Jiang et al. The structures of the ligands are shown in Scheme 21.19. Again the e.e. values of the chiral propargyl alcohols were moderate to excellent. 

DESYMMETRIZATION AND ENZYMATIC STRATEGIES FOR CHIRAL PROPARGYL ALCOHOL SYNTHESIS... 

In this chapter we have highlighted several practical approaches for the synthesis of chiral propargyl alcohols by various methods, the most practical ones being the asymmetric alkynation of carbonyl compounds in the presence of chiral auxiliaries and the p-eUmination of stereochemically well-defined a,p-dioxyhalides. These two approaches have been utilized efficiently in the synthesis of several bioactive natural products. 

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