Deprotonations chiral auxiliaries

In an extensive investigation, Seebach has developed a deprotonative chiral auxiliary approach with an oxazolidinone to provide a reagent for enantioselec-tive formylation of aldehydes and ketones [ 14-16]. Lithiation-substitution of 20 gives a diasteromeric mixture of 21, as representative examples, with the major diastereoisomer formed in drs greater than 70 30, and up to 95 5 in most cases. The separated diastereoisomers were converted to highly enantioenriched products via the hemiaminal and hydrolysis, as shown in the representative examples in Scheme 6. Additions to imine derivatives were also foimd to be possible in this approach [14-16]. 

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. 

R)- and (,S )-1.1,2-Triphenyl-l,2-ethancdiol which are reliable and useful chiral auxiliary groups (see Section 1.3.4.2.2.3.) also perform ami-sclcctive aldol additions with remarkable induced stereoselectivity72. The (/7)-diastercomer, readily available from (7 )-methyl mandelate (2-hy-droxy-2-phcnylaeetate) and phenylmagnesium bromide in a 71 % yield, is esterified to give the chiral propanoate which is converted into the O-silyl protected ester by deprotonation, silylation, and subsequent hydrolysis. When the protected ester is deprotonated with lithium cyclohexyliso-propylamide, transmetalated by the addition of dichloro(dicyclopentadienyl)zirconium, and finally reacted with aldehydes, predominantly twm -diastereomers 15 result. For different aldehydes, the ratio of 15 to the total amount of the syn-diastereomers is between 88 12 and 98 2 while the chemical yields are 71 -90%. Furthermore, high induced stereoselectivity is obtained the diastereomeric ratios of ami-15/anti-16 arc between 95 5 and >98 2. 

An excellent synthetic method for asymmetric C—C-bond formation which gives consistently high enantioselectivity has been developed using azaenolates based on chiral hydrazones. (S)-or (/ )-2-(methoxymethyl)-1 -pyrrolidinamine (SAMP or RAMP) are chiral hydrazines, easily prepared from proline, which on reaction with various aldehydes and ketones yield optically active hydrazones. After the asymmetric 1,4-addition to a Michael acceptor, the chiral auxiliary is removed by ozonolysis to restore the ketone or aldehyde functionality. The enolates are normally prepared by deprotonation with lithium diisopropylamide. 

Analogous rearrangement occurs under much milder conditions when the reactant is a zwitterion generated by deprotonation of an acylammonium ion. Substituted pyrrolidines were used as the chiral auxiliary, with the highest enantioselectivity being achieved with a 2-TBDMS derivative.267... 

The addition of doubly deprotonated HYTRA to achiral4 5 as well as to enantiomerically pure aldehydes enables one to obtain non-racemic (3-hydroxycarboxylic acids. Thus, the method provides a practical solution for the stereoselective aldoi addition of a-unsubstituted enolates, a long-standing synthetic problem.7 As opposed to some other chiral acetate reagents,7 both enantiomers of HYTRA are readily available. Furthermore, the chiral auxiliary reagent, 1,1,2-triphenyl-1,2-ethanediol, can be recovered easily. Aldol additions of HYTRA have been used in syntheses of natural products and biological active compounds, and some of those applications are given in Table I. (The chiral center, introduced by a stereoselective aldol addition with HYTRA, is marked by an asterisk.)... 

The mechanism of this sequence is enlightening when contrasted with the mechanism of the formamidine auxiliary (Scheme 56). Scheme 59a illustrates the results of some deprotonation-alkylation experiments on deuteriated diastereomers. ° ° Two features of the product of these experiments were examined the diastereomer ratio and the percent deuterium incorporation. The deuterium incorporation in the product reveals that there is a preference for removal of the -proton. When deuterium is in the -position, this selectivity is opposed by the isotope effect, and the product has about half the original deuterium remaining. When deuterium is in the a-position, the selectivity for the -proton (imposed by the chiral auxiliary) and the isotope effect act in concert, and virtually all the... 

How ever, deprotonation/alkylation of enantiomerically pure 1-iminomethyl-substituted 1,2,3,4-tetrahydro-1-methylisoquinoline bearing an achiral auxiliary similar to the chiral auxiliary of c led to racemic product only21. Therefore, the lithiated intermediate 8 turned out to be configurationally unstable and stereoselectivity in the alkylation of 4 relies on the higher thermodynamic stability of 5 versus its benzyelic epimer (Model B). 

When the tertiary center in 6 containing the chiral auxiliary is subjected to deprotonation/ benzylation the stereoselective formation of l-benzyl-l,2,3,4-tetrahydro-l-methylisoquinoline (97-98% ee) was reported which interestingly had the R configuration. Hence, the monoalky-lated intermediate related to 8 is alkylated from the bottom face, opposite to that found with unsubstituted 5. Obviously the existence of two diastereomeric lithiocompounds accounts for these results. Now the strong temperature dependence of the selectivity, which usually hints that an equilibrium is involved, can also be easily understood. 

Asymmetric alkylation of benzylamine via the imine 6A, with ( + )-D-camphor (5 A) as chiral auxiliary is possible. Deprotonation with butyllithium and subsequent alkylation with haloalkanes, (R X) afforded the alkylated imines 7 A with reasonable yield but variable diastereo-selectivity. The diastereoselectivity depends strongly on the haloalkane with methoxy-substi-tuted halomethylbenzenes moderate to good diastereoselectivity (d.r. 80 20-90 10) is obtained, however, with haloalkanes or 3-halopropenes only low optical purities (< 50%) were observed. 

Following the same procedure, formation of the imine 6D and subsequent deprotonation with two equivalents of butyllithium followed by alkylation, either enantiomer of the a-substituted benzylamines could he obtained with nearly complete stereocontrol. Unfortunately only poor yields are obtained51,52,53. The (-)-(15,25, 55)-2-hydroxy-3-pinanone derived from ( + )-a-pinene resulted in the formation of the R-configurated benzylamines, conversely the ( + )-2-hy-droxy-3-pinanone derivative led to the (S )-benzylamine product. It has been shown that the high stereocontrol occurs within the alkylation step. The chiral auxiliary can be recovered without racemization from the oxime with aqueous titanium(III) chloride. 

In a complementary approach23, aryl ethers with the chiral auxiliary attached to the oxygen atom were reduced to give the enol ethers, subsequent deprotonation with. vcc-butyllithium in THF generated a 2-alkoxy-l,4-cyclohexadienyl carbanion. 

The allylically activated chiral methanimidamides are more reactive and can be prepared from 2,5-dihydro-l//-pyrrole or 1,2,5,6-tetrahydropyridine by heating with a chiral auxiliary substituted methanimidamide in toluene. Deprotonation of the more acidic 1 -iminomethy 1-2,5-dihydro-1//-pyrrole with butyllithium was complete after a few minutes, even at — 100 °C41. Alkylation afforded a mixture of regioisomers, 2-alkylated 2,5-dihydro-l //-pyrrole 1 (n = 1) and 3-alkylated 2,3-dihydro-l//-pyrrole 2 (n = 1), the former strongly predominating (about 92 8). During hydrazinolysis of the 2-substituted 2,5-dihydro-1 //-pyrrole 1 (n = 1) the minor product decomposed, thus separation of the regioisomers was unnecessary. About 80-85% of the chiral auxiliary (S)-l- m-butoxy-3-methyl-2-butanamine was recovered after hydrazinolysis. 

Deprotonation of either the (4S.5R)- or (4/ ,5S)-enantiomer of 3-acyl-1,5-dimelhyl-4-phenyl-2-imidazolidinones 4 by lithium cyclohexylisopropylamide (LICA)1 or diisopropylamide2 furnishes chiral, supposedly chelated enolates, very similar to those enolates obtained from 2-oxazolidi-nones (see Section 1.1.1.3.3.4.2.1.). With LICA the. yyn-enolate is formed exclusively, as shown by O-silylation of the enolate with /ert-butylchlorodimethylsilane1. Attack of an electrophile, such as a haloalkane, from the less hindered side furnishes products (usually crystalline) with a moderate to high degree of diastereoselectivity (see Tabled)1 2. The diastereoselectivities observed in comparable alkylation reactions of the 3-acyl-4-cyclohexyl-l,5-dimethylimidazo-lidinone 3b are superior to those obtained with the 4-phenyl derivative 3a2,7. Thus, as also observed in similar alkylations with oxazolidinones10 (see Section 1.1.1.3.3.4.2.1), a phenyl substituent on the chiral auxiliary seems to be relatively inefficient as a steric control element. 

Depending on the nature of the imine, deprotonation and alkylation occurs either at the amine residue or at the carbonyl part of the molecule. Deprotonation of the amine residue (chiral auxiliary), as observed in the reaction of valine derived imines, can be excluded by choosing optimized metalation conditions3. 

To circumvent side reactions and racemization of the chiral auxiliary in metalation reactions of cyclohexanone imines derived from the tert-butyl esters of valine and tm-leucine, deprotonation is performed using LDA at low temperatures (— 78 °C, THF, 0.5 h). 

The disadvantage in using such symmetrical bislactim ethers is that half the chiral auxiliary ends up as part of the product molecule thus only half of the auxiliary can be recovered and reused. This drawback is avoided in the mixed bislactim ether prepared from a chiral auxiliary (L-valine) and a racemic amino acid (e.g., DL-alanine). Regiospecific deprotonation followed by diastereoselective alkylation leads to the required a-methyl amino acid ester (193) (83T2085) the de is >95%. In this method, the chiral auxiliary (L-valine) is recovered intact. (Scheme 59). 

Taddol has been widely used as a chiral auxiliary or chiral ligand in asymmetric catalysis [17], and in 1997 Belokon first showed that it could also function as an effective solid-liquid phase-transfer catalyst [18]. The initial reaction studied by Belokon was the asymmetric Michael addition of nickel complex 11a to methyl methacrylate to give y-methyl glutamate precursors 12 and 13 (Scheme 8.7). It was found that only the disodium salt of Taddol 14 acted as a catalyst, and both the enantio- and diastereos-electivity were modest [20% ee and 65% diastereomeric excess (de) in favor of 12 when 10 mol % of Taddol was used]. The enantioselectivity could be increased (to 28%) by using a stoichiometric amount of Taddol, but the diastereoselectivity decreased (to 40%) under these conditions due to deprotonation of the remaining acidic proton in products 12 and 13. Nevertheless, diastereomers 12 and 13 could be separated and the ee-value of complex 12 increased to >85% by recrystallization, thus providing enantiomerically enriched (2S, 4i )-y-methyl glutamic add 15. 

Atorvastin (Lipitor, 13.40) is a cholesterol-lowering drug that has been synthesized as a single enantiomer through use of a chiral auxiliary (Scheme 13.6).16 Ester 13.36 contains the auxiliary, a chiral alcohol. Deprotonation of the ester forms an enolate (13.37). The enolate then attacks an aldehyde. The asymmetry of the stereocenter on the auxiliary causes the reaction to favor stereoisomer 13.38 over 13.39. Several recrystallizations are required to obtain 13.38 in high enantiomeric excess. Cleavage of the auxiliary from 13.38 and further manipulations of the side-chain afford atorvastin. 

Iron acyl complexes are among the most widely studied of the organometallic iron species, especially as applied to organic synthesis. As previonsly mentioned they are prepared to provide access to iron alkyls (via decarbonylation), and because iron acyls can be deprotonated to form enolates much like any carbonyl they have been utilized as chiral auxiliaries in asymmetric synthesis. Also, iron acyls are an important entry point for the preparation of iron carbenes. 

Bicyclic oxazolidinones derived from carbohydrates have been used as chiral auxiliaries in conjugate addition reactions [147]. After deprotonation with MeMgBr, the D-galacto-oxazolidin-2-one 178 and the D-g/wc6>-oxazolidin-2-one 179 (Figure 10.17) were A-acylated with... 

Matsumura and his coworkers [38] have employed the 2-pyrrolidone anion, in DMF solution, to deprotonate arylacetic acid esters with subsequent oxidative dimerization of the corresponding carbanions. This study includes a useful comparison between the electrochemical and chemical generation of the 2-pyrrolidone anion (by fluoride anion displacement in A-trimethylsilyl-2-pyrrolidone). The advantage lies with the electrochemical route, which gave yields of final product of 80%, compared with the 30% obtained with the chemically generated base (Scheme 10). The overall process, formation of dimethyl 2,3-diphenylsuccinates, is not only efficient and convenient but also operates with high diastereoselectivity when under the control of an oxazolidinone chiral auxiliary (Scheme 10). 

The synthesis of (-)-Cio-desmethyl arteannuin B, a structural analog of the antimalarial artemisinin, was developed by D. Little et a. In their approach, the absolute stereochemistry was introduced early in the synthesis utilizing the Enders SAMP/RAMP hydrazone alkylation method. The sequence begins with the conversion of 3-methylcyclohexenone to the corresponding (S)-(-)-1-amino-2-(methoxymethyl)pyrrolidine (SAMP) hydrazone. Deprotonation with lithium diisopropylamide, followed by alkylation in the presence of lithium chloride at -95 °C afforded the product as a single diastereomer. The SAMP chiral auxiliary was removed by ozonolysis. 

Application of the Enders SAMP/RAMP hydrazone alkylation method on 1,3-dioxan-5-one derivatives leads to versatile C3 building blocks. To demonstrate the usefulness of the above method, the research group of D. Enders applied it during the first asymmetric total synthesis of both enantiomers of streptenol A. " To obtain the natural isomer, the RAMP hydrazone of 2,2-dimethyl-1,3-dioxan-5-one was used as starting material. This compound was deprotonated with f-butyllithium and alkylated with 2-bromo-1-fert-butyldimethylsilyloxyethane. The chiral auxiliary could be hydrolyzed under mildly acidic conditions to provide the ketone in excellent yield and enantioselectivity. 

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