Prolines stereoselectivity

A highly stereoselective proline-catalyzed acetone aldol reaction has recently been used in the synthesis of sugar derivatives such as 141 (Scheme 4.28) [124]. 

Similar stereoselectivities are achieved in the allylation of enantiomerically pure proline-derived a-oxoamides47. l-Bromo-3-methy]-2-butcne reacts with clean allylic inversion. Since pinacol-type coupling products are also produced under the reaction conditions, this was taken as evidence for a radical addition mechanism47. 

Aldol additions of various lithium enolates performed in the presence of (S.S)-l, 4-bisdimethyl-amino-2,3-dimethoxypentane or (.SVS )-1,2,3,4-tctramethoxybutane display only modest reagent-induced stereoselectivity (<20% ee)21. Significant improvement results from the use of the proline derived diamines 2,3 and 4 as additives in tin(II) mediated aldol additions of silyl enol ethers22 23. 

The utility of lOOC reactions in the synthesis of fused rings containing a bridgehead N atom such as pyrrolizidines, indolizidines, and quinolizidines which occur widely in a number of alkaloids has been demonstrated [64]. Substrates 242 a-d, that possess properly positioned aldoxime and alkene functions, were prepared from proline or pipecolinic acid 240 (Eq. 27). Esterification of 240 and introduction of unsaturation on N by AT-alkylation produced 241 which was followed by conversion of the carbethoxy function to an aldoxime 242. lOOC reaction of 242 led to stereoselective formation of various tricyclic systems 243. This versatile method thus allows attachment of various unsaturated side chains that can serve for generation of functionalized five- or six-membered (possibly even larger) rings. 

A DFT study found a corresponding TS to be the lowest energy.167 This study also points to the importance of the solvent, DMSO, in stabilizing the charge buildup that occurs. A further computational study analyzed the stereoselectivity of the proline-catalyzed aldol addition reactions of cyclohexanone with acetaldehyde, isobu-tyraldehyde, and benzaldehyde on the basis of a similar TS.168 Another study, which explored the role of proline in intramolecular aldol reactions, is discussed in the next section.169... 

Cycloaddition of the cyclic nitrone derived from proline benzyl ester with alkenes proceeds readily to give isoxazolidines with good regio-and stereoselectivity (Eq. 8.47).68 The reaction favors exo-mode addition. However, certain cycloadditions are reversible and therefore the product distribution may reflect thermodynamic rather than kinetic control. 

The three-component reaction between isatin 432a, a-aminoacids 433 (proline and thioproline) and dipolarophiles in methanol/water medium was carried out by heating at 90 °C to afford the pyrrolidine-2-spiro-3 -(2-oxindoles) 51. The first step of the reaction is the formation of oxazlidinones 448. Loss of carbon dioxide from oxazolidinone proceeds via a stereospecific 1,3-cycloreversion to produce the formation of oxazolidinones almost exclusively with /razw-stereoselectivity. This /f-azomethine ylide undergo 1,3-dipolar cycloaddition with dipolarophiles to yield the pyrrohdinc-2-r/ V -3-(2-oxindolcs) 51. (Scheme 101) <2004EJ0413>. 

A very interesting organocatalyzed one-pot Michael addition/aldol condensation/Darzens condensation has been reported for the asymmetric synthesis of epoxy-ketones <06JA5475>. An initial asymmetric Michael condensation between 16 and 17 is catalyzed by proline derivative 18. Intermediate 19 then undergoes an aldol condensation followed by a stereoselective Darzens condensation to provide epoxy-ketone 20 in moderate yield and with surprisingly good enantiomeric excess. 

The addition of a titanium homoenolate 115 to a proline derivative 114 proved to be a feasible approach for the formal synthesis of pumiliotoxin 251D. The addition proceeded with high stereoselectivity (Scheme 30) <1999JOC1410>. 

There are several reports dealing with the use of tetrahydropyrrolo[l,4]oxazinones derived from natural proline or prolinol as chiral auxiliaries for the synthesis of enantiomerically pure compounds. The preparation of the heterocycle is described in Scheme 33 (Section 11.11.7.4). The presence of a rigid bicyclic skeleton allows stereoselective introduction of different substituents. The final ring opening of the system (generally by hydrolysis) provides enantiomerically pure compounds with the possibility of recycling the starting chiral auxiliary. 

Enantiomerically pure tetrahydro-l//-pyrrolo[2, l -acrylamides derived from proline (see Section 11.11.7.4), are versatile intermediates for the synthesis of natural products or drugs. Compound 86a was submitted to debromination with Bu3SnH followed by ring opening in KOH and further reduction with BHj to give diol 89 that was then easily transformed into (A)-4-(2,2,4-trimethyl-l,3-dioxolan-4-yl)-lT>utanol 90, a key intermediate for )-frontalin, <2002TA155>,... 

A method for highly efficient asymmetric cyclopropanation with control of both relative and absolute stereochemistry uses vinyldiazomethanes and inexpensive a-hydroxy esters as chiral auxiliaries263. This method was also applied for stereoselective preparation of dihydroazulenes. A further improvement of this approach involves an enantioselective construction of seven-membered carbocycles (540) by incorporating an initial asymmetric cyclopropanation step into the tandem cyclopropanation-Cope rearrangement process using rhodium(II)-(5 )-N-[p-(tert-butyl)phenylsulfonyl]prolinate [RhjtS — TBSP)4] 539 as a chiral catalyst (equation 212)264. 

Y. Sasaki, A. Niida, T. Tsuji, A. Shigenaga, N. Fujii, A. Otaka, Stereoselective synthesis of (Z)-alkene-containing proline dipeptide mimetics, J. Org. Chem. 71 (2006) 4969 979. 

X.J. Wang, S.A. Hart, B. Xu, M.D. Mason, J.R. Goodell, F.A. Etzkorn, Serine-c/s-proline and Serine-frans-proline isosteres Stereoselective synthesis of (Z)- and ( )-alkene mimics by still-wittig and ireland-claisen rearrangements, J. Org. Chem. 

The methyl and benzyl esters of proline were also used as chiral auxiliaries in respective acrylamides, but the isoxazoline cycloadducts were obtained with only poor to modest stereoselectivity (189,190). The related indoline-2-carboxylic acid derivative 33, however, showed excellent ability to direct nitrile oxide attack, favoring one rotamer (Scheme 6.37), and thereby leading to 3-phenylisoxazoline-5-carboxamide... 

Stereoselective addition of hydrogen to a C=C double bond of an (S)-proline derivation was applied in the total synthesis of gephyrotoxin, a biologically active alkaloid 87). Optically active pyrrolizidine bases have been synthesized by Robins and Sakdarat88) from chiral hydroxyproline derivatives by hydrogenation (ds > 60 %). 

The (R)- and (S)-enantiomers of (E)-4.6-dimethyl-6-octene-3-one (147), a defense substance of spiders (known commonly as daddy longlegs Leiobunum vittatum and L. calcar) were recently synthesized by Enders and Baus 163> using the (R)-proline derivative RAMP and the (S)-proline derivative SAMP (137) as chiral auxiliary, respectively. (S)- and (R)-enantiomers of (147) have been obtained in an overall chemical yield of 70% and in very high stereoselectivities of 95% e.e., respectively. 

Enders and Lotter174) developed an asymmetric synthesis of a-hydroxyketones and vicinal diols using the (S)-proline derivative (S)-l-formyl-2-methoxymethyl-pyrrolidine as chiral auxiliary. However, the a-hydroxyketones and vicinal diols, respectively, were only obtained with low stereoselectivity. 

Not surprinsingly, the aldol addition of the lithium enolates derived from these systems proved to be unsatisfactory. However, the derived zirkonium enolates in these and related systems have proven to be exceptional 176). The amides (171) and (172), each of which is readily derived from (S)-proline and (S)-valine respectively, exhibit good stereoselectivity with a range of aldehydes. The optical purity of the P-hydroxy amides (173) was very good (>95% e.e.). However, this method has a limitation which has been associated with the acidic conditions that are required to hydrolize these chiral amides (173) to their derived carboxylic acids (174). While... 

S)-proline. The lithium amides of />o/> -(imino-1 -isobutylethylene) and its corresponding low-molecular-weight model compound, derived from (S)-leucine, were similarly used in order to examine the polymer effects with regard to the stereoselectivity. After acetylation, N-acetyl-a-methylphenylalanine was obtained in max. 31 % optical yield 195). 

---