Felkin-Ahn controlled

High yields and enantiopurity have been realized by a highly diastereoselective MPV reduction of protected a-amino aromatic ketones using catalytic amounts of aluminium isopropoxide. The high anti selectivity resulted from the chelation of the (g) nitrogen anion to the aluminium. In contrast, high syn selectivity was obtained with a-alkoxy ketones and other compounds via Felkin-Ahn control.354... 

A convergent total synthesis of 15-membered macrolactone, (-)-amphidinolide P was reported by D.R. Williams and coworkers.In their approach, they utilized the Sakurai aiiyiation to introduce the C7 hydroxyl group and the homoallylic side chain. The transformation was effected by BF3-OEt2 at -78 °C to provide the homoallylic alcohol as a 2 1 mixture of diastereomers. The desired alcohol proved to be the major diastereomer, as it resulted from the Felkin-Ahn controlled addition of the allylsilane to the aldehyde. The minor diastereomer was converted into the desired stereoisomer via a Mitsunobu reaction. 

The Kishi synthesis ot monensin teatures allylic conformational analysis to predict stereochemistry of hydroboratlon-oxidations in acyclic systems. The Still synthesis features acyclic diastereoselection in carbonyl addition reactions (chelation control and Felkin-Ahn control). 

Sir Robert Robinson played an early central role in the development of the electronic theoiy of organic chemistry (5S). For example, he was the first to use the now commonplace curly arrow to imply the reorganization of electron density during the course of a chemical reaction (59). The constract of stereoelectronic control (which, in its most literal sense, explains all chemical reactions) underpins many concepts now in the lexicon of mechanistic and synthetic organic chemistry. These include the Hammond postulate, the Curtin-Hammett Principle, the Markovnikov rule (for additions to alkenes), the Thorpe-lngold effect (on rates of cyclization), the Btirgi-Dunitz approach trajectory, Cram/Comforth/Felkin-Ahn controlled additions (to chiral ketones... 

Substrate control This refers to the addition of an achiral enolate (or allyl metal reagent) to a chiral aldehyde (generally bearing a chiral center at the a-position). In this case, diastereoselectivity is determined by transition state preference according to Cram-Felkin-Ahn considerations.2... 

Murakami and Taguchi utilized a diastereoselective Grignard addition to a substituted-chiral oxazoline aldehyde 524 (Scheme 8.170) in an improved stereoselective synthesis of D-n7 o-phytosphingosine. The good stereoselectivity observed for 525 can be rationalized by a Felkin-Ahn transition state model although a chelation control mechanism could not be mled out. 

The addition of acetate-derived, achiral lithium enolates to monoprotected a-amino aldehydes is controlled by chelation, and leads to a modest stereochemical preference in favor of the 3,4-syn configuration (Table 1, entry a). 18 The formation of the 3, A-syn-product is enhanced by the use of acetate-derived silyl ketene acetals and the addition of titanium(IV) chloride or tin(IV) chloride to the reaction mixture (Table 1, entries b and c). 22-23 The same enolates add stereoselectively to A2 A-dibenzyl a-amino aldehydes but with diastereomeric ratios in favor of the Felkin-Ahn 3,4-anti-product (Table 1, compare entries a and d, and b and f). 22-24 Reverse stereocontrol is observed in the presence of a Lewis acid such as tita-nium(IV) chloride, but the yield is low (Table 1, entry e). 24 ... 

Chiral centres within the nucleophile or the conjugated double bond will control the stereochemistry of the chiral centres that are formed. For example, the Felkin-Ahn model has been applied to nucleophilic 1,4-addition to an ,/3-unsaturatcd carbonyl bearing a... 

Coordination with heteroatoms is not an absolute prerequisite for efficacy in directional control. Thus, the stereochemistry observed in the epoxidation of alkoxy-substituted cyclohexenyl ketones 21 has been explained on the basis of a Felkin-Ahn transition... 

Additions of allyltributyltin to an a-oxygenated aldehyde are also influenced by the choice of Lewis acid (Table 7) [16]. The relative stereochemistry of the adduct is a result of the facial preference for attack on the aldehyde-Lewis acid complex by the stannane. The reaction involving BF3 OEta is subject to Felkin-Ahn/Comforth control whereas MgBr2 and TiCU in CH2CI2 proceed by chelation control. In THF the... 

These results can be understood on the basis of a Felkin-Ahn transition state arrangement for the BF3 experiments and a chelation transition state arrangement with MgBt2 as the promoter. The matched transition states are pictured in Fig. 12. The latter additions are strongly substrate-controlled, which accounts for the formation of (Z) products as the minor adducts. Evidently the methyl substituent is an efficient facially directing group in the chelated aldehyde substrate. 

Additions of the presumed /3-oxygenated allylic trichlorostannane to a-methyl, a-benzyloxy and /3-benzyloxy aldehydes are characterized by high reagent-controlled diastereoselectivity (Eq. 48) [70]. In the several examples examined aldehyde facial attack is little influenced by the resident chirality of the aldehyde. The result is particularly striking with the a-methyl aldehyde where the syn, syn adduct is the product of Felkin-Ahn addition and the anti, syn adduct is the anh-Felkin-Ahn or chelation-controlled adduct. 

The foregoing addition reaction is strongly reagent-directed. Both (S)- and (R)-2-benzyloxypropanal afford adducts with high diastereoselectivity (Eq. 51). With the former the product might arise by Felkin-Ahn addition whereas a chelation controlled transition state could account for the latter. 

Further evidence for the racemization premise was obtained from experiments employing (R)-a-methyl-/3-ODPS propanal (Eq, 85) [93]. Addition of the allenylin-dium chloride derived from an enantioenriched (P)-allenyl stannane yielded a 60 40 mixture of anti, anti and anti, syn adducts, not unlike that obtained when racemic alle-nylstannane was used to generate the transient allenylindium chloride. When the (5) aldehyde was employed for this addition a 40 60 mixture of anti, anti and anti, syn adducts was formed. Thus it can be concluded that substrate control (Felkin-Ahn or chelation) is, at best, only modest in these reactions, and that the rate of racemization is only slightly less than the rate of addition. The use of -benzyloxy-a-methyl propa-... 

Threo diastereoselectivity is consistent with a chelation-controlled (Cram cyclic model) organolithium addition (Figure 8a). Since five-membered chelation of lithium is tenuous, an alternative six-membered chelate involving the dimethylamino nitrogen atom of the thermodynamically less stable (Z)-hydrazone (in equilibrium with the ( )-isomer) cannot be discounted. The trityl ether (entry 4, Table 9) eliminates the chelation effect of the oxygen atom such that the erythro diastereomer predominates (via normal Felkin-Ahn addition) (Figure 8b). 

Stereochemical control in the addition of Grignard reagents to chiral racemic iV-(2-phenylpropyl-idene)alkylamine (V-oxides (215) has been observed (equation 27). Diastereoselectivity is modest (216 217 = 2 1-5 1). The formation of hydroxylamines (216) as the major products is consistent with Felkin-Ahn Grignard addition (Figure 11). 

In the asymmetric alkylation of a-chiral aldehydes using dialkylzinc reagents, the stereochemistry is controlled by the configuration of the chiral catalyst, not by the stereochemistry in the a-position. It is different from the diastereoselec-tive alkylation using other organometallic reagents where the stereochemistry follows from Cram s rule or the Felkin-Ahn model. Each diastereomer with high ee was obtained by the choice of the appropriate enantiomer of chiral catalyst [(IS, 2R)- or (li ,2S)-DBNE 1] (Scheme 6) [18]. 

The most intensely studied aldol addition mechanisms are those beUeved to proceed through closed transition structures, which are best understood within the Zimmerman-Traxler paradigm (Fig. 5) [Id]. Superposition of this construct on the Felkin-Ahn model for carbonyl addition reactions allows for the construction of transition-state models impressive in their abiUty to account for many of the stereochemical features of aldol additions [50a, 50b, 50c, 51]. Moreover, consideration of dipole effects along with remote non-bonding interactions in the transition-state have imparted additional sophistication to the analysis of this reaction and provide a bedrock of information that may be integrated into the further development and refinement of the corresponding catalytic processes [52a, 52b]. One of the most powerful features of the Zimmerman-Traxler model in its application to diastereoselective additions of chiral enolates to aldehydes is the correlation of enolate geometry (Z- versus E-) with simple di-astereoselectivity in the products syn versus anti). Consequently, the analyses of catalytic, enantioselective variants that display such stereospecificity often invoke closed, cyclic structures. Further studies of these systems are warranted, since it is not clear to what extent such models, which have evolved in the context of diastereoselective aldol additions via chiral auxiliary control, are applicable in the Lewis acid-catalyzed addition of enol silanes and aldehydes. 

The Cram selectivity is consistent with Felkin-Ahn addition, as shown in Figure 8a, with the large phenyl substituent controlling the organometallic approach. In addition, Yamamoto et a/. have proposed more detailed chair-like transition state models shown in Figures 8b and 8c to account for the un-... 

One broad generalization is that when steric interactions are dominant the Felkin-Ahn model is predictive. Thus steric approach control, the idea that the approaching nucleophile will approach the carbonyl group from the least hindered direction, is the first guiding principle. ... 

A -(a-Carboxyalkyl)tryptamines can be prepared by alkylation of a-amino acid ester by tryptophyl bromide. The chirality of the amino acid unit directs diastereo-selectivity in the range of 70-98% for cyclization with a variety of aromatic aldehydes. The best selectivity is obtained with relatively bulky amino acid substituents, as for valine and isoleucine. The reactions appear to occur under kinetic control and the stereoselectivity is consistent with the sterically preferred Felkin-Ahn transition state [336]. 

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