Adduct, anti

Intramolecular cycloadditions of substrates with a cleavable tether have also been realized. Thus esters (37a-37d) provided the structurally interesting tricyclic lactones (38-43). It is interesting to note that the cyclododecenyl system (w = 7) proceeded at room temperature whereas all others required refluxing dioxane. In each case, the stereoselectivity with respect to the tether was excellent. As expected, the cyclohexenyl (n=l) and cycloheptenyl (n = 2) gave the syn adducts (38) and (39) almost exclusively. On the other hand, the cyclooctenyl (n = 3) and cyclododecenyl (n = 7) systems favored the anti adducts (41) and (42) instead. The formation of the endocyclic isomer (39, n=l) in the cyclohexenyl case can be explained by the isomerization of the initial adduct (44), which can not cyclize due to ring-strain, to the other 7t-allyl-Pd intermediate (45) which then ring-closes to (39) (Scheme 2.13) [20]. While the yields may not be spectacular, it is still remarkable that these reactions proceeded as well as they did since the substrates do contain another allylic ester moiety which is known to undergo ionization in the presence of the same palladium catalyst. 

J 7i-Cycloadducts at the C4 — C5 azepine positions are also formed with 1,2,3,4-tetra-chloro-5,5-dimethoxycyclopentadiene260 261 and with hexachlorocyclopentadiene.261 The reactivity of ethyl l//-azepine-l-carboxylate towards cyclopentadienones has been studied in terms of frontier molecular orbital theory which predicts that dimethyl 2-oxo-4,5-diphenyl-cyclopenta-1 (5),3-diene-1,3-dicarboxylate (20) should be more reactive towards the 1/f-azepine than other more common cyclopcntadienone derivatives.262 In fact, in refluxing benzene, the cyclopentadienone and ethyl 1/f-azepine-l-carboxylate (1) form a mixture of the [4 + 2] n-endo,anti-adduct 22, produced by Cope rearrangement of the initially formed [2 + 4] 7T-adduct 21, and the c.w-adduct 23, a rare example of a [6 + 4] rc-cycloadduct. At room temperature, only the [6 + 4] adduct 23 and a small amount of the [2 + 4] adduct 21 are obtained, the latter rearranging to the [4 + 2] adduct 22 on warming.262 Other [4 + 2] 7r-adducts with cyclopentadienones have been prepared similarly.263... 

Ethyl 1 /T-azepine-l-carboxylate (1) and l,3-diphenyl-2/7-cyclopenta[/]phenanthren-2-one (26) (phencyclone) in refluxing benzene undergo a rapid peri- and regioselective cycloaddition to give the [4 + 2] 7t-e rfn-adduct 28 and not, as was first proposed, a [6 + 2] 7r-adduct.264 Subsequently, however, it was found that at room temperature a [2 + 4] 7r-cw/<>-adduct 27 is formed which readily undergoes a Cope rearrangement to the [4 + 2] endo,anti-adduct 28. 

Thus, jyn-adducts arise predominantly, as expected, according to the Zimmerman-Traxier model. Provided that either boron or zirconium is the enolate-metal atom, high syn selectivity is achieved. The total amount of anti-adducts is lower than 2% in the case of amides 1 and 2, and it approaches zero when the other reagents arc used94 . The induced stereoselectivities are impressive for the amides and remarkable in the case of the imides. 

The aldol reaction of 2,2-dimethyl-3-pentanone, which is mediated by chiral lithium amide bases, is another route for the formation of nonracemic aldols. Indeed, (lS,2S)-l-hydroxy-2,4,4-trimethyl-l-phenyl-3-pentanone (21) is obtained in 68% ee, if the chiral lithiated amide (/ )-A-isopropyl-n-lithio-2-methoxy-l-phenylethanamine is used in order to chelate the (Z)-lithium cnolate, and which thus promotes the addition to benzaldehyde in an enantioselective manner. No anti-adduct is formed25. 

The conjugate addition of lithium dimethylcuprate to spiroketone 5 gave predominantly (S j-6 [(S)/(R) 92 8] in which methyl group attacked from the side syn to the oxygen atom, whereas the addition of lithium dimethylcuprate-chlorotrimethylsilane afforded exclusively the anti-adduct (S)-621,... 

As an alternative, tin enolates are very useful in these additions. Usually they are prepared in situ from the amide using tin(II) trifluoromethanesulfonate and a base. They are subsequently reacted with an enone, catalyzed by a Lewis acid47-48 (see Table 3). With triinethylsilyl trifluoromethanesulfonate as a catalyst, in the presence of proline derived diamines anti-adducts are formed exclusively49 (see Section 1.5.2.4.3.1.). 

As an alternative to lithium enolates. silyl enolates or ketene acetals may be used in a complementary route to pentanedioates. The reaction requires Lewis acid catalysis, for example aluminum trifluoromethanesulfonate (modest diastereoselectivity with unsaturated esters)72 74 antimony(V) chloride/tin(II) trifluoromethanesulfonate (predominant formation of anti-adducts with the more reactive a,/5-unsaturated thioesters)75 montmorillonite clay (modest to good yields but poor diastereoselectivity with unsaturated esters)76 or high pressure77. 

The geometry of the ester enolate dictates the configuration of the cxtracyclic asymmetric center an (ii)-enolate gives mainly an anti-adduct and a (Z)-cnolate gives a wn-adduct. This is in accordance with the stereochemical results with tram-acyclic esters bearing in mind the fact that in this case a cw-unsaturated ester is present in the cyclic Michael acceptor. 

A diastereomeric ratio (synjanti) of 90 10 is found, whereas within the syn-adduct the ratio between the ( ,5)/(S, )-isomers is 95 5. With methyl (Z)-2-butenoate the diastereomeric ratio (synjanti) is 25 75, and in the anti-adduct the (R,S) (S,S) ratio is 88 12186. These results are consistent with a chelated transition state as shown in Section 1.5.2.4.1. This enantioselcctivc Michael addition was used in the synthesis of 7,20-diisocyanoadocianc18 7. 

The reverse trend is observed with (Z)-enolates. The reaction of the lithium enolate of cyclohexanone with ( )-(2-nitroethenyl)benzene gives a 75 25 mixture of the syn- and anti-adducts. In contrast, the same enolate undergoes addition of ( )-5-(2-nitroethenyl)-l,3-benzo-dioxole to give exclusively the yymaddition product in 93% yield2. 

The 1,3-dipolar cycloaddition of mesitonitrile oxide 575 to benzo[h]thiophene S-oxides 576 in non-stereoselective and both syn and anti adducts 577 are obtained674,675 (equation 366). 

The cycloaddition reaction of heterocyclic propellanes 99 (X = O and S) with iV-phenyltriazolinedione (NN) (Fig. 16) affords the anti adduct with respect to the bridge [166-168]. Replacement of the a-CH groups by carbonyls (that is 100),... 

Branched-chain esters also give mainly anti adducts when the enolates are formed using dicyclohexyliodoborane. 

Derivatives with various substituted sulfonamides have been developed and used to form enolates from esters and thioesters.137 An additional feature of this chiral auxiliary is the ability to select for syn or anti products, depending upon choice of reagents and reaction conditions. The reactions proceed through an acyclic TS, and diastereoselectivity is determined by whether the E- or Z-enolate is formed.138 /-Butyl esters give A-enolates and anti adducts, whereas phenylthiol esters give syn adducts.136... 

A related effect is noted with a-alkoxyacyl derivatives. These compounds give mainly the anti adducts when a second equivalent of TiCl4 is added prior to the aldehyde.144 The anti addition is believe to occur through a TS in which the alkoxy oxygen is chelated. In the absence of excess TiCl4, a nonchelated cyclic TS accounts for the observed syn selectivity. 

The unique feature of the Horner-Wittig reaction is that the addition intermediate can be isolated and purified, which provides a means for control of the reaction s stereochemistry. It is possible to separate the two diastereomeric adducts in order to prepare the pure alkenes. The elimination process is syn, so the stereochemistry of the alkene that is formed depends on the stereochemistry of the adduct. Usually the anti adduct is the major product, so it is the Z-alkene that is favored. The syn adduct is most easily obtained by reduction of (3-ketophosphine oxides.269... 

There have been several studies of the stereochemistry of conjugate addition reactions. If there are substituents on both the nucleophilic enolate and the acceptor, either syn or anti adducts can be formed. 

The reaction shows a dependence on the E- or Z-stereochemistry of the enolate. Z-enolates favor anti adducts and E-enolates favor syn adducts. These tendencies can be understood in terms of an eight-membered chelated TS.299 The enone in this TS is in an s-cis conformation. The stereochemistry is influenced by the s-cis/s-trans equilibria. Bulky R4 groups favor the s-cis con former and enhance the stereoselectivity of the reaction. A computational study on the reaction also suggested an eight-membered TS.300... 

With unhindered aldehydes such as cyclohexanecarboxaldehyde, the diastereoselec-tivity is higher than 95%, with the F-boronate giving the anti adduct and the Z-boronate giving the syn adduct. Enantioselectivity is about 90% for the F-boronate and 80% for the Z-boronate. With more hindered aldehydes, such as pivaldehyde, the diastere-oselectivity is maintained but the enantioselectivity drops somewhat. These reagents also give excellent double stereodifferentiation when used with chiral aldehydes. For example, the aldehydes 3 and 4 give at least 90% enantioselection with both the E- and Z-boronates.43... 

This result predicts that mixtures of syn and anti adducts would be expected from the methanolysis the proportions of the isomers would depend on the amount of methanol present, larger amounts of methanol favoring more anti addition, as was shown experimentally. The evidence and arguments presented by Sakurai are very persuasive. Further studies of alcohol additions have recently been reported by Leigh.6 3 The Jones results can be interpreted with the example depicted in Eq. (43). 

The overall process from 3 gives straightforward access to ot-spirocyclop-ropyl heterocyclic ketones 310 [80], some of which display interesting DNA cleaving activity [80c]. The reaction conditions can be properly controlled in order to isolate the primary adducts 314-320 (Table 25). The cycloaddition to methoxycarbonyl substituted bicyclopropylidene 311 with 256 gave a mixture of the four possible regioisomeric and stereoisomeric anti-adducts 320 (see later) (entry 7). 

Enantioenriched a-alkoxyorganolead compounds have been prepared through lithiation of stannane precursors and trapping of the lithiated species with a triorganolead halide (equation 35)75. In the presence of TiCU, these plumbanes add to aldehydes to afford monoprotected syn- 1,2-diols. The use of BF3OEt2 as a Lewis acid promoter leads mainly to the anti adducts (Table 13)70. 

Stereocontrolled influence of precomplexing additives was used in the synthesis of (2R,3S)- and (2S, 3 S)-2-amino-l,3,4-butanetrioles resulting from a stereo-divergent hydroxymethylation of D-glyceraldehyde nitrones (Fig. 2.24). The obtained syn- and anti-adducts were further converted into C-4 building blocks and to (i-hydroxy-a-amino acids (570). 

The stereochemical outcomes of the above reactions can be explained by the proposed transition states A and B (Fig. 2.25). Model A, derived from the Houk model for nucleophilic addition to olefins, explains the formation of, v y -adducts. Model B, involving a different nitrone conformation, due to the chelation of diethylaluminum chloride, accounts for the formation of anti -adducts (581). 

The stereochemistry of the process was examined by analysis of the products resulting from trapping the lithioallene from a chiral allenylcarbamate with Me3SiCl (Eq. 9.11). Sequential lithiation with BuLi followed by addition of Me3SiCl at -78°C afforded a 75 25 mixture of the syn and anti adducts in 70% yield. On the other hand, deprotonation with LDA at -78 °C in the presence of excess Me3SiCl gave rise to the syn adduct as the sole product in 70% yield. It could therefore be surmised that (1) lithiation proceeds with retention of stereochemistry and (2) syn/anti isomerization of the putative allenyllithium intermediate at -78 °C is slower than silyla-tion (Eq. 9.12). 

Deprotonation of 3-methoxy-3-methylallene with BuLi followed by metal exchange with Ti(OiPr)4 affords a chiral allenyltitanium reagent [31], Addition of this reagent to enantioenriched (S)-2-benzyloxypropanal afforded a mixture of four diastereomeric products in which the anti,syn and anti,anti adducts predominated (Eq. 9.26) [31], The former was shown to derive from the matched pairing of the (S)-aldehyde with the (P)-enantiomer of the allenic titanium reagent. The latter is the major diastereomer of the mismatched (S)/(M) pairing. 

Addition of the racemic allenyltitanium reagent to racemic 2-benzyloxypropanal, on the other hand, afforded a 92 6 mixture of racemic anti,syn and anti,anti adducts as a result of preferred (S)/(P) and (R)/(M) pairing (Eq. 9.27) In both cases, anti adducts are favored. These two experiments show that the allenyltitanium reagent does not racemize under the reaction conditions. If racemization had taken place,... 

The mismatched R/S pairing could lead to the anti,syn adduct through transition state C and the syn,anti adduct via D (Scheme 9.30). The former pathway entails non-Felkin-Anh addition but anti disposed methyl and aldehyde substituents. Transition state D proceeds through the Felkin-Anh mode of carbonyl addition but requires eclipsing of the methyl and aldehyde substituents. This interaction is the more costly one and thus disfavors the syn,anti adduct. 

Reaction of the transient zinc intermediates with various electrophiles yielded the acetylenic substitution products and only minor amounts of allenes (Table 9.49). Reactions with aldehydes were non-selective, affording mixtures of stereo- and regioisomeric adducts. However, prior addition of ZnCl2 resulted in the formation of the homopropargylic alcohol adducts with high preference for the anti adduct, as would be expected for an allenylzinc chloride intermediate (Table 9.50). 

The transmetallations appear to be rapid but the ensuing aldehyde addition is relatively slow. Furthermore, anti adducts of only low or modest ee are obtained. Evidently chiral allenylindium chlorides are more prone to racemize than the corresponding alle-nyltin species. Racemization was less extensive with InBr3 and Inl3 (Table 9.51). 

---