Chiral enyne

Initial attempts to perform the 1,5-substitution enantioselectively with chiral enyne acetates proceeded disappointingly. For example, treatment of the enantio-merically pure substrate 51 with the cyano-Gilman cuprate tBu2CuLi LiCN at -90 °C provided vinylallene 52 as a 1 3 mixture of E and Z isomers with 20 and 74% ee, respectively (Scheme 2.19) [28], As previously described for the corresponding Sn2 substitution of propargylic electrophiles, this unsatisfactory stereoselection may be attributed to a racemization of the allene by the cuprate or other organome-... 

Due to the distance between the stereogenic center and the place of the nucleophilic attack, the enantioselective 1,5-substitution of chiral enyne acetates constitutes one of the rare cases of remote stereocontrol in organocopper chemistry. Moreover, the method is not limited to substrate 51, but can also be applied to the synthesis of enantiomerically enriched or pure vinylallenes 53-57 with variable substituent patterns (Scheme 2.20) [28]. 

Scheme 2.20 Enantiomerically enriched or pure vinylallenes formed by 1,5-substitution of chiral enyne acetates in the presence of tri-n-butylphosphine (53-56) or triethyl phosphite (57).

These are (1) The chiral substrate approach. This approach involves using chiral precursors that transfer their chirality to the final cyclopentenone. This implies the synthesis of chiral substrates, which has generally been made from classic chiral pools. Examples include carbohydrate derivatives like 40 that give 41 with variable yields depending on the substitution pattern. 41 is transformed into cyclopenta[c]pyrane 42, which is the skeleton of iri-doids [93]. In another example epichlorhydrin (43) is used to construct chiral enyne 44 which gives cyclopentenone 45 [94] (Scheme 14). 

Scheme 14 Two examples of the chiral substrate approach a carbohydrates as starting materials for the construction of chiral enynes b epichlorhydrin as source of chirality in assymetric PKRs...

The Trost synthesis of calcitriol (3) is shown in Scheme 5. In a Wittig reaction, the hydroxylated Grundmann s ketone 26 (obtained by partial synthesis) is transformed into the alkenyl bromide 27 with astonishingly high diastereoselec-tivity ElZ >50 1). The chiral enyne 29, which is needed as the second building block for the coupling step, is prepared from the aldehyde 28... 

Keywords Pauson-Khand, Cyclopentenone, Enyne, Titanocene, Ethylene-l,2-bis( 7 -4,5,6,7-tetrahydro-l-indenyl (EBTHI) ligand. Chiral enyne. Chiral auxiliary... 

The diastereocontrolled cyclization of chiral enynes has been extensively studied [11], and its application with optically active enynes represents a major focus in the efforts to synthesize optically active cyclopentenones via the Pauson-Khand reaction. For the purposes of this review, the discussion of this subject... 

The cyclic 2,4-dienoate 184, formed by the Pd-catalyzed cyclization of the 1,6-enyne 183, reacted with 154 to form the azulene derivative 185[118], The 3-methylenepyrrolidine 188 is formed by the reaction of the Zn reagent 186 with the chiral imine 187 with high diastereomeric excess. The structure of the allylic ethers is important for obtaining high diastereoselectivity[l 19],... 

The first examples of macrocyclization by enyne RCM were used in Shair s impressive biomimetic total synthesis of the cytotoxic marine natural product longithorone A (429) [180]. This unique compound features an unusual hep-tacyclic structure which, in addition to the stereogenic centers in rings A-E, is also chiral by atropisomerism arising from hindered rotation of quinone ring G through macrocycle F (Scheme 85). It was assumed that biosynthesis of 429 could occur via an intermolecular Diels-Alder reaction between [12]paracy-... 

Cyclopenta[fc]dioxanes (44) are accessible from the reaction of the dioxenylmolybdenum carbene complex (43) with enynes <96JOC159>, whilst an intramolecular and stereoselective cyclisation of (Ti5-dienyl)tricarbonyliron(l+) cations affords chiral frans-2,3-disubstituted 1,4-dioxanes <96JOC1914>. 2,3-Dimethylidene-2,3-dihydro-1,4-benzodioxin is a precursor of the 3,8-dioxa-lff-cyclopropa[i]anthracene, which readily dimerises to dihydrotetraoxaheptacene (45) and the analogous heptaphene <96AJC533>. 

The hydroboration of enynes yields either of 1,4-addition and 1,2-addition products, the ratio of which dramatically changes with the phosphine ligand as well as the molar ratio of the ligand to the palladium (Scheme 1-8) [46-51]. ( )-l,3-Dienyl-boronate (24) is selectively obtained in the presence of a chelating bisphosphine such as dppf and dppe. On the other hand, a combination of Pdjldba), with Ph2PC6p5 (1-2 equiv. per palladium) yields allenylboronate (23) as the major product. Thus, a double coordination of two C-C unsaturated bonds of enyne to a coordinate unsaturated catalyst affords 1,4-addition product On the other hand, a monocoordination of an acetylenic triple bond to a rhodium(I)/bisphosphine complex leads to 24. Thus, asymmetric hydroboration of l-buten-3-yne giving (R)-allenyl-boronate with 61% ee is carried out by using a chiral monophosphine (S)-(-)-MeO-MOP (MeO-MOP=2-diphenylphosphino-2 -methoxy-l,l -binaphthyl) [52]. 

Based on these preliminary findings, related couplings to pyruvates and iminoacetates were explored as a means of accessing a-hydroxy acids and a-amino acids, respectively. It was found that hydrogenation of 1,3-enynes in the presence of pyruvates using chirally modified cationic rhodium catalysts delivers optically enriched a-hydroxy esters [102]. However, chemical yields were found to improve upon aging of the solvent 1,2-dichloroethane (DCE), which led to the hypothesis that adventitious HC1 may promote re-... 

The MOP series of ligands59 (see Section 9.5.4.2) in conjunction with standard palladium precursors has been reported to catalyze the addition of HBcat to 1,3-enynes. With 1 mol.% catalyst produced by combination of Pd2(dba)3 and the monodentate ligand (Y)-MeO-MOP (22), axially chiral allenyl-boranes are formed (Equation (3)). Subsequent oxidation affords the corresponding alcohols with moderate ee values.60... 

Very recently, Wiedenhoefer272 has devised the first asymmetric 1,6-enyne hydrosilylation/cyclization tandem process using a rhodium(l) catalyst with (R)-276 as chiral ligand where rhodium-BINAP complexes were not effective (Scheme 70). More developments on this reaction are covered in Chapter 11.13. 

This reaction has lent itself to the development of its asymmetric version (Scheme 88). The trick here is to remove the choride ligands from the coordination sphere of the platinum-chiral ligand complex. This makes the metal center more electrophilic, thus reactive reactions can be run at lower temperature. Interestingly, the best ligand was found to be the atropisomeric monophosphine (fJ)-Ph-BINEPINE.312 Enantiomeric excess up to 85% was observed. Very recently, enantioselectivity up to 94% ee has been achieved using [(AuCl)2(Tol-BINAP)] as pre-catalyst for the reaction of another enyne.313... 

A single report appears in the literature regarding the use of chirally modified palladium catalysts in reductive enyne cyclization.60 Upon exposure of 1,6-enyne 36a to the indicated palladium pyridine-oxazoline complex in the presence of EtjSiH, cyclization product 36b is formed in good yield, but with only modest levels of asymmetric induction (Scheme 26). 

A solitary report of enantioselective hydrosilylative cyclization appears in the literature.64 Here, a variety of 1,6-enyne substrates are cyclized in good yields and enantioselectivities, using chirally modified cationic rhodium... 

A hydrosilylation/cyclization process forming a vinylsilane product need not begin with a diyne, and other unsaturation has been examined in a similar reaction. Alkynyl olefins and dienes have been employed,97 and since unlike diynes, enyne substrates generally produce a chiral center, these substrates have recently proved amenable to asymmetric synthesis (Scheme 27). The BINAP-based catalyst employed in the diyne work did not function in enyne systems, but the close relative 6,6 -dimethylbiphenyl-2,2 -diyl-bis(diphenylphosphine) (BIPHEMP) afforded modest yields of enantio-enriched methylene cyclopentane products.104 Other reported catalysts for silylative cyclization include cationic palladium complexes.105 10511 A report has also appeared employing cobalt-rhodium nanoparticles for a similar reaction to produce racemic product.46... 

Asymmetric cyclization-hydrosilylation of 1,6-enyne 91 has been reported with a cationic rhodium catalyst of chiral bisphosphine ligand, biphemp (Scheme 30).85 The reaction gave silylated alkylidenecyclopentanes with up to 92% ee. A mechanism involving silylrhodation of alkyne followed by insertion of alkene into the resulting alkenyl-rhodium bond was proposed for this cyclization. 

Enantioselective hydrogenation of 1,6-enynes using chirally modified cationic rhodium precatalysts enables enantioselective reductive cyclization to afford alky-lidene-substituted carbocycles and heterocycles [27 b, 41, 42]. Good to excellent yields and exceptional levels of asymmetric induction are observed across a structurally diverse set of substrates. For systems that embody 1,2-disubstituted alkenes, competitive /9-hydride elimination en route to products of cycloisomerization is observed. However, related enone-containing substrates cannot engage in /9-hydride elimination, and undergo reductive cyclization in good yield (Table 22.12). 

Subsequently, high chemoselectivity and enantioselectivity have been observed in the asymmetric epoxidation of a variety of conjugated enynes using fructose-derived chiral ketone as the catalyst and Oxone as the oxidant. Reported enantioselectivities range from 89% to 97%, and epoxidation occurs chemoselectively at the olefins. In contrast to certain isolated trisubstituted olefins, high enantioselectivity for trisubstituted enynes is noticeable. This may indicate that the alkyne group is beneficial for these substrates due to both electronic and steric effects. 

The utility of this metallo-ene-type reaction has also been demonstrated by the reaction of 1,6- or 1,7-enynes bearing a chiral 1,2-diphenylethylene acetal moiety as the leaving group. The reaction was found to proceed with excellent chiral induction to give optically active cyclopentane and cydohexane derivatives, respectively, which was followed by reaction of the resulting vinyl titaniums with electrophiles, as exemplified in Eq. 9.60, s.p. 348 [108]. 

Introduction of a double bond between the triple bond and the leaving group leads to enyne electrophiles 45, which would give access to vinylallenes 46 if the attack of the nucleophile takes place at the triple bond in an SN2" (1,5) substitution reaction (Scheme 2.16). In addition to the regioselectivity, two types of stereoselectivity also have to be considered in this transformation, i.e. the configuration of the olefinic double bond of the vinylallene and the (relative or absolute) configuration of the allenic chirality axis. 

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