Homoaldol

Similarly, (A )-( )-3-(2-methoxymethyl-l-pyrrolidinyl)-l-phenylpropene118 121, after lithia-tion and addition of acetone, acidic hydrolysis and oxidation of the intermediate lactol, gives (5)-dihydro-5,5-dimethyl-4-phenyl-2(3/f)-furanone with 98% ee and 54% overall yield. Thus, these sequences constitute asymmetric homoaldol addition. 

The lithium-TMEDA complex 1, obtained by deprotonation of (S)-(E)-1 -methyl-2-butenyl diisopropylcarbamate (84% ee), affords, after metal exchange by tetraisopropoxytitanium and addition to 2-methylpropanal, the homoaldol adduct ( + )-4 with 73% ee, whereas (-)-4 (53 % ee) is obtained when chlorotris(diethylamino)titanium is used104. 

The reagents prepared by lithiation (see Section 1.3.3.3.1.2.) and titanium exchange of (S)-(Z)-l-methyl-2-butenyl diisopropylcarbamate106 show a diminished reactivity when compared with those derived from the ( -isomer, indicating that in both metalation steps the doublebond geometry is retained16. After treatment of the lithium -TMEDA complex with chlorotris-(diethylamino)titanium and 2-methylpropanal, the homoaldol adduct (3S,47f)-(Z)-4-hydroxy-1,3,5-trimethyl-l-hexenyl diisopropylcarbamate [( + )-4], is formed with 88% ee16. 

The problem can be solved by the transformation of the lithium carbanions into the more reactive trichlorotitanium intermediates via the stannanes. Finally, the (- )-sparteine complex of (5)-( )-l-methyl-2-butenyl diisopropylcarbamate105 (Section 1.3.3.3.1.2.) is apparently transmetalated by tetraisopropoxytitanium with inversion of configuration, leading to homoaldol products with moderate diastereomeric excess103. 

Enantiomerically and diastereomerically enriched lithium-(-)-sparteine complexes of primary 2-alkenylcarbamates, which are configurationally stable as solids (Section 1.3.3.3.1.2.), are transmetalated stereospecifcally by tetraisopropoxytitanium. The resulting titanates are stable in solution and give rise to homoaldol adducts with enantiomeric purities up to 94 % ee107,107a. 

The homoaldol products (3S,47T)-(Z)-4-hydroxy-3-methyl-l-octenyl and (35, 4/ )-(Z)-4-hydroxy-3,7-dimethyl-l,6-octadienyl diisopropylcarbamate are easily converted into the naturally occurring y-lactones quercus lactone A1073 and ( + )-eldanolide120, respectively. 

Only few allyltitanium reagents bearing a removable chiral auxiliary at the allylic residue are known. The outstanding example is a metalated 1-alkyl-2-imidazolinone14, derived from (—)-ephedrine, representing a valuable homoenolate reagent. After deprotonation by butyllithium, metal exchange with chlorotris(diethylamino)titanium, and aldehyde or ketone addition, the homoaldol adducts are formed with 94 to 98% diastereoselectivity. 

Lithiated allylic carbamates (35) (prepared as shown) react with aldehydes or ketones (R C0R ), in a reaction accompanied by an allylic rearrangement, to give (after hydrolysis) y-hydroxy aldehydes or ketones. The reaction is called the homoaldol reaction, since the product is a homolog of the product... 

Though several intermolecular catalytic reductive aldol additions are reported, corresponding reductive cyclizations have received less attention. The first reported reductive aldol cyclization involves use of a (diketonato)cobalt(ll) precatalyst in conjunction with PhSiHj as terminal reductant.48,486 The reductive cyclization is applicable to aromatic and heteroaromatic enone partners to form five- and six-membered rings. As demonstrated by the reductive cyclization of mono-enone mono-aldehyde 65a to afford aldol 65b, exceptionally high levels of ty -diastereoselectivity are observed. Interestingly, exposure of the substrate 65a to low-valent nickel in the presence of excess Et2Zn provides the isomeric homoaldol cyclization product 65c via reductive coupling to the enone /3-position (Scheme 43).47a... 

Titanated allyl carbamates are reported to react regio- and stereospecifically with aldehydes [52]. An elegant and synthetically useful method based on diastereoselective and en-antioselective homoaldol reactions has been developed (Scheme 13.25) [53]. 

Scheme 13.25. Diastereoselective and enantioselective homoaldol reactions using titanated allyl carbamates.

Scheme 13.26. Highly enantioselective homoaldol addition with a chiral titanium N-allylurea reagent.

Further elaborations on the dipeptide-azepinone theme present in 29 and 32 have been described. Benzodiazepine 33 was transformed through SAR studies to the more potent a-substituted analog 34 and the potent carboxamide 35 (IC50 = 1.2 nM), which demonstrated 22% bioavailability in rats, but poor brain levels (plasma and brain AUC = 2.9 vs. 0.17 (iM h, respectively) [94,95]. Potent homoaldol 36 (Ap IC50 = 0.06 nM) and related benzodiazepine derivatives have been reported [96]. Caprolactam 37 (Ap IC50 = 17 nM) resulted from modification... 

When the protocol is applied to allylcarbamates 170, the deprotonation in the presence of (—)-sparteine does not occur with kinetic preference. Indeed, a dynamic resolntion by crystallization takes place. The epimeric allylfithinm componnds 171 and 172 are eqni-librating, whereby one of them crystallizes predominantly. Under optimized conditions, when n-butyllithium is used for the deprotonation and cyclohexane serves as a cosolvent, the preference of the diastereomer 172 leads to snbstimtion products in 90-94% gg393-395 enantioselective homoaldol reaction has been developed based on this protocol Transmetalation of the organolithium into the titaninm compound occnrring nnder inversion of the configuration (172 173) and subseqnent addition to aldehydes leads to... 

SCHEME 24. (-)-Sparteine-induced deprotonation of allyl carbamate 170. Dynamic resolution by crystallization and enantioselective homoaldol reaction... 

Homoaldol reaction with enantioenriched l-metallo-2-alkenyl... 

The most important reaction, the homoaldol reaction of the titanium derivatives, proceeds as an efficient syn-S process and will be discussed separately (see Section IV.C.5). Reactions with further electrophiles will be presented very briefly. The silylation of primary substrates 302 by different chlorotriorganosilanes proceeds with good a-selectivity and with inversion of the configuration ... 

Since enol carbamates of 4-hydroxyalkanals (or y-hydroxyalkanones) are produced by formation of the C(3)—C(4) bond, we named the process homoaldol reaction 244-246... 

When employing enantioenriched l-titano-2-alkenyl carbamates 334 in carbonyl addition, the selectivity depends on the enantiomeric purity that was achieved in its preparation (see Section IV.C.l). The (ii)-crotyl derivative (R)-334a has been employed several times (equation 92)224,252,253 optically active homoaldol products 346 are easily converted into y-lactones 347 by four different pathways, which require an oxidation step (see Section IV.C.6). Appfications in target synthesis include the natural products (-b)-quercus... 

Some alkenyl carbamates leading to configurationally labile lithium intermediates could be subjected to asymmetric homoaldol reaction with less efficiency (Scheme 6) these reactions have not been optimized yet Azs... 

These add to aldehydes providing the homoaldol products 351 with high stereoselectivity following the expected stereochemical course, as could be elucidated by several X-ray crystal structure analyses under anomalous dispersion (equation 93). It is currently unknown why the yields are relatively low (21-35%), since we could not detect side products besides traces of starting material. The corresponding lithium-TMEDA complexes, after titanation, deliver good yields (71-79%). The homoaldol products are easily converted to enantioenriched bicyclic y-lactones of type 352 °. 

According to results published by Fer6zou and coworkers, the iV,iV-diisopropylcarba-moyl group of homoaldol adducts can be directly attacked by slim nucleophiles such as lithium ethynylide or excess methyllithium (equation 98) . The TIPS ether 359 was treated with three equivalents of methyllithium to yield [via the (Z)-enolate 360] the aldehyde 361. Trapping of 360 by TBSCl gives rise to the synthetically valuable (Z)-silyl enol ether 362. 

Z)-awh-4-Hydroxy-l-aIkenyl carbamates 363, when subjected to substrate-directed, vanadyl-catalysed epoxidation , lead to diastereomerically pure epoxides of type 364 (equation 99)247,252,269 qqjggg epoxides are highly reactive in the presence of Lewis or Brpnsted acids to form -hydroxylactol ethers 366 in some cases the intermediate lactol carbamates 365 could be isolated . However, most epoxides 364 survive purification by silica gel chromatography . The asymmetric homoaldol reaction, coupled with directed epoxidation, and solvolysis rapidly leads to high stereochemical complexity. Some examples are collected in equation 99. The furanosides 368 and 370, readily available from (/f)-0-benzyl lactaldehyde via the corresponding enol carbamates 367 and 369, respectively, have been employed in a short synthesis of the key intermediates of the Kinoshita rifamycin S synthesis . 1,5-Dienyl carbamates such as 371, obtained from 2-substituted enals, provide a facile access to branched carbohydrate analogues . 

According to equation 102, stereochemically homogeneous 3-carbonyl-substimted tetrahydrofurans are constructed in a brick-box system by sequential homoaldol and aldol reaction. The metallated aUyl carbamate serves as an equivalent for the chiral dianion A, which accepts two different aldehydes B and C in a highly controlled manner. ... 

In comparison to other vinylic compounds , the vinyl proton in 1-alkenyl carbamates, deprotonation has a very high kinetic acidity . After protection of the 4-hydroxy group in the homoaldol products by silylation, deprotonation (w-BuLi, TMEDA, diethyl ether or THF) of enol carbamate 384 is complete at —78 °C (equation 103), and the resulting vinyUithium 385 can be kept at this temperature without decomposition for several hours. Stannylation , silylation , methoxycarbonylation (with methyl chloroformate) ... 

These reactions involve metallate rearrangements , migratory insertion and transition metal-catalysed vinylic substitution reactions. They also perform well in applications in natural product synthesis . Many useful synthetic possibilities arise from application of ring-closing olefin metathesis (RCM) to unsaturated homoaldol products and their derivatives by means of the Grubbs catalyst 3942 4-286 Equation 105 presents some examples. ... 

Lithium-metal exchange in the lithium-)—)-sparteine complexes 399 or 402, respectively, by diethylaluminium chloride or triisopropoxytitanium chloride proceeds with inversion providing useful reagents for enantioselective homoaldol reactions... 

In 1996, McWilliams and coworkers described a very interesting tandem asymmetric transformation whereby an asymmetric 1,2-migration from a higher-order zincate 60 was coupled with a stereoselective homoaldol reaction (equation 26)29. 

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