Stereoselectivity alkyne reductions

RCM of dienes to cycloalkenes provides a useful method for the syntheses of carbo- and heterocycles and thus has been proved to be extremely effective in total synthesis of various natural products. Usually, however, mixtures of (E)- and (Z)-olefms result. In contrast, ring-closing alkyne metathesis provides a reliable route for synthesis of both (E)- and (Z)-macrocycloalkenes in a stereoslective manner taking advantage of stereoselective partial reduction of resulting cycloalkynes. A Lindlar reduction gives (Z)-cycloalkenes, whereas a hydroboration/ protonation sequence afford ( )-cycloalkenes (Equation (23)). Recently, Trost reported an alternative procedure for the synthesis of (E)-olefins from alkynes through hydrosilylation by a ruthenium catalyst. This procedure converts cycloalkyne 130, for example, to vinylsilane 131 and then to (E)-cycloalkene 132 in a stereoselective manner (Scheme 46)7 ... 

Reduction of an alkyne with MgH -CuI or MgH -CuOtert-Bu in THF at -78° is reported to give the (Z)-alke ne in good yield with very high stereoselectivity (39). Reduction of the triple bond in a conjugated enyne with a large excess of activated powdered zinc in aqueous n-propanol proceeds with Z stereoselectivity (28,40). We have found that (I5)-ll-tetradecen-9-yn-l-ol is reduced under these conditions to (9, llE)-9,ll-tetra-decadien-l-ol with less than 0.1% contamination by other isomers. However, this method appears suited only to small scale work because of the large excess of zinc required. 

The stereoselective trans-reduction of alkynes by dissolving metals52 is a consequence of the drastic LUMO stabilization upon bending, and of the easier transbending of the alkyne molecule. 

The epimeric (+)-a-allokainic acid was constructed by the unsaturated imide/ alkyne alkylative coupling of 9 with trimethylaluminum in 73% yield and 97 3 diastereoselectivity (Scheme 8.11) [33]. This was followed by silyl to carbonate protecting group transposition, stereoselective aUylic reduction, and removal of protecting groups to afford (+)-a-allokainic acid. The complementary nature of these two stereodivergent approaches allowed access to both epimeric natural products. 

An addition to an alkene can form up to two new chiral centers, and a reaction that occurs with only a syn or only an anti addition mechanism will give a product with predictable stereochemistry. Conversion of alkynes to alke-nes can also occur with either syn or anti stereoselectivity. When these alkyne reductions are taken in combination with alkene addition reactions, target molecules with a wide variety of stereochemical relationships can be prepared. 

A different approach to 2-aUcenylanilines makes use of benzoth-iazines derived from the reaction of 1 with alkynes. Reduction of these compounds with sodium amalgam leads directly to the product anilines. Interestingly, for those systems examined which could produce geometrical isomers, these were formed with good-to-exceUent stereoselectivity, in aU cases favoring the Z-isomers (eq 11). 

Catalytic reduction of an alkyne in the presence of the Lindlar catalyst is syn stereoselective Lindlar reduction of an internal alkyne gives a ds-alkene. 

Stereoselective and chemoselective semihydrogenation of the internal alkyne 208 to the ew-alkene 210 is achieved by the Pd-catalyzed reaction of some hydride sources. Tetramethyldihydrosiloxane (TMDHS) (209) i.s used in the presence of AcOH[116]. (EtO)3SiH in aqueous THF is also effective for the reduction of alkynes to di-alkenes[l 17], Semihydrogenation to the d.v-alkene 211 is possible also with triethylammonium formate with Pd on carbon[118]. Good yields and high cis selectivity are obtained by catalysis with Pd2fdba)3-Bu3P[119],... 

In an effort to identify a more stereoselective route to dihydroagarofuran (15), trimethylsilylated alkyne 17 was utilized as a substrate for radical cyclization (Scheme 2). Treatment of 17 with a catalytic amount of AIBN and tri-n-butyltin hydride (1.25 equiv) furnishes a mixture of stereoisomeric vinyl silanes 18 (72% combined yield) along with an uncyclized reduction product (13% yield). The production of stereoisomeric vinyl silanes in this cyclization is inconsequential because both are converted to the same alkene 19 upon protodesiiyiation. Finally, a diastereoselective di-imide reduction of the double bond in 19 furnishes dihydroagaro-... 

Starting from 63, the carbonylation may proceed via coordination and insertion of CO into the vinyl-C-Pd bond to provide an a,P-unsaturated acyl complex. This complex reacts with (ArY) 2, and subsequently the C-Y bond is formed by reductive elimination to give 64 (Scheme 7-14). Because the compound 64 could be directly converted into the corresponding enal 65 by the Pd-catalyzed reduction with BujSnH, this sequence is synthetically equivalent to the regio- and stereoselective thioformy-lation and selenoformylation of alkynes (Eq. 7.49) [53, 54]. 

Abstract Significant advances have been made in the study of catalytic reductive coupling of alkenes and alkynes over the past 10 years. This work will discuss the progress made in early transition metal and lanthanide series catalytic processes using alkyl metals or silanes as the stoichiometric reductants and the progress made in the use of late transition metals for the same reactions using silanes, stannanes and borohydrides as the reductant. The mechanisms for the reactions are discussed along with stereoselective variants of the reactions. 

The very first example of the catalytic reductive cyclization of an acetylenic aldehyde involves the use of a late transition metal catalyst. Exposure of alkynal 78a to a catalytic amount of Rh2Co2(CO)12 in the presence of Et3SiH induces highly stereoselective hydrosilylation-cyclization to provide the allylic alcohol 78b.1 8 This rhodium-based catalytic system is applicable to the cyclization of terminal alkynes to form five-membered rings, thus complementing the scope of the titanocene-catalyzed reaction (Scheme 54). 

The key features of the catalytic cycle are trapping of the radical generated after cycliza-tion by an a,P-unsaturated carbonyl compound, reduction of the enol radical to give an enolate, and subsequent protonation of the titanocene alkoxide and enolate. The diaster-eoselectivity observed is essentially the same as that achieved in the simple cyclization reaction. An important point is that the tandem reactions can be carried out with alkynes as radical acceptors. The trapping of the formed vinyl radical with unsaturated carbonyl compounds occurs with very high stereoselectivity, as shown in Scheme 12.21. 

Computational and catalytic studies of the hydrosilylation of terminal alkynes have been very recently reported, with the use of [ Ir( r-Cl)(Cl)(Cp ) 2] catalyst to afford highly stereoselectively P-Z-vinylsilanes with high yields (>90%) [35]. B-isomers can be also found among the products, due to subsequent Z —> E isomerization under the conditions employed. The catalytic cycle is based on an lr(lll)-lr(V) oxidahve addition and direct reductive elimination of the P-Z-vinylsilane. Other iridium complexes have been found to be active in the hydrosilylation of phenylacetylene and 1-alkynes for example, when phenylacetylene is used as a substrate, dehydrogenative silylation products are also formed (see Scheme 14.5 and Table 14.3). 

This catalyst system was the first to utilize both terminal alkynes and olefins in the intramolecular reaction. Although a mechanistic rationale for the observed stereoselectivity was not offered, the formation of the single stereoisomer 26 may be rationalized through the diastereotopic binding of the rhodium complex to the diene moiety (Scheme 12.3). This facial selective binding of the initial ene-diene would then lead to the formation the metallacycle III, which ultimately isomerizes and reductively eliminates to afford the product [14]. 

Using this catalyst system for ring-closing alkyne metathesis, Fiirstner successfully synthesized ambrettolide and yuzu lactone from alcohol 125. " " Treatment of diyne 126a with Mo(CO)6 (5 mol%) and /i-chlorophenol (1 equiv.) in chlorobenzene at 140 °C leads to cycloalkyne 127a in 69% yield. Subsequent Lindlar reduction proceeds smoothly in a stereoselective manner to afford ambrettolide. Similarly, 126b affords cycloalkyne 127b in 62% yield. From this compound, yuzu lactone has been synthesized (Scheme 45). " " ... 

Skraup quinoline synthesis, 443 Smiles rearrangement, phenothiazine, 534 Spiroalkylation, 222, 280 Spirocyclization, conjugate addition, 386 Spiroimidazolone formation, 335 Spiropyrazolopiperidine, 375 Stannylation, alkyne, 15 Stereoselective dehydration, 198 Grignard addition, 198, 199 reduction, 129, 226 hydroxyketone, 400 iminoketone beta, 553 oxazaborohydride, 585 transfer chirality, 321 Stilbene formation, self alkylation, 525 Stobbe condensation, benzophenone, 103... 

Relatively pure alkene geometric isomers are prepared by stereoselective reduction of alkynes. 

As was discussed in Sections 11.1.5 and 11.2.3, the stereoselective partial hydrogenation of alkynes to either cis or trans alkenes is of key importance. Chemical reductions can also be applied to achieve both selective transformations. 

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