Anti-selective

The second important group of configuralionally stable bis-protected a-amino aldehydes are the V-dibenzvl derivatives 5, easily prepared from amino acids in a three-step procedure65. These aldehydes react with various nucleophiles to normally provide the nonchelation-con-trolled adducts in high diastereoselectivity. This anti selectivity is observed when diethyl ether or telrahydrofuran is used as reaction solvent. Certain Lewis acidic nucleophiles or additives, such as tin(IV) chloride, in dichloromethane as solvent force chelation and therefore provide the. syn-adducts, once again with a high diastereoselectivity. 

The. s vn-diastereomer is formed exclusively, whereas the uncomplexed carbanion reacts anti selectively [d.r. (anti/syn) 74 26]11. 

For a-benzyloxycyclohexaneacelaldehyde and 2-butenylstannanes, good chelation control was observed using zinc iodide and titanium(IV) chloride, but only weak synjanti selectivity. Better syn/anti selectivity was found using boron trifluoride-diethyl ether complex, but weak chelation control. Magnesium bromide gave excellent chelation control and acceptable syn/anli selectivity90. 

There is evidence to suggest that the unexpected anti selectivity found in several cases of Lewis acid catalyzed carbonyl additions can be explained by transmetalation of 2-butenylstannanes by titanium(IV) chloride (Sections 1.3.3.3.8.2.3. and 1.3.3.3.6.1.3.) to form the reactive allyltri-chlorotitanium46-49. 

However, this is not true for the addition of carbonyl compounds to (Z)-2-alkenyltitanium, which also proceeds with moderate anti selectivity and requires a (twist) boat transition state16,51. 

Provided that the silanolate elimination proceeds with anti selectivity, it must be concluded, that the intermediate homoallylic alcohol has an anti configuration, and thus the reagent has an ( -configuration. Acidic hydrolysis of the enol ether leads to enones the overall sequence consists of a nucleophilic acroylation. This has also been applied in the total synthesis of the marine diterpene ( )-aplysin-2067. 

The addition of the 2-butenylchromium reagent to achiral aldehydes proceeds with excellent anti selectivity, irrespective of whether (E)- or (Z)-l-bromo-2-butene is used as precursor. 

When an enolate is forced to take the E configuration, e.g, the enolate derived from cyclohexanone, predominant formation of the anti-aldol might be expected. Surprisingly, early experiments gave more or less stereorandom results in that the reaction with benzaldehyde gave a ratio of. vvtt/ant/ -aldols of 48 521B 23, Contrarily, recent investigations24 reveal a substantial anti selectivity (16 84), which is lowered in a dramatic manner (50 50) by the presence of lithium salts. Thus, the low stereoselectivity in the early experiments may be attributed to impurities of lithium salts or lithium hydroxide. 

For acyclic systems, the anti diastereoselectivity of the (i )-enolates is lower than the syn diastereoselectivity of comparable (Z)-enolates. For example, carboxylic acid esters, which form predominantly ( )-enolates, react with aldehydes with high anti selectivity only in those cases where bulky aromatic substituents are in the alcoholic part of the ester22 25. 

High anti selectivity combined with induced diastereoselectivity is also provided by the prolinol derived siloxane 5 which reacts with benzaldehyde to give predominantly the adduct 6l06h. 

Enhanced anti selectivity is observed in reactions of lithiated 4.5-dihydrooxazoles bearing an additional substituent which facilitates the formation of rigid azaenolates by internal chelation of lithium13. Thus, reaction of 2-ethyl-4,5-dihydro-4,4-dimethyloxazole (10) with 2-methylpropanal gives a 56 44 mixture of adducts while (R)-2-ethyl-4,5-dihydro-4-(methoxymethyl)-oxazolc (12) reacts with the same aldehyde to yield a 90 10 mixture of adducts 1313. 

The addition of ( )-(3-trimcthylsilylallyl)boronate (10) to the racemic oxime 9 has been used in connection with a total synthesis of cannabisativine n. The results are congruent with the application of ( )-crotylboronatc as organometallic reagent9,, 0. The reaction is anti selective and generates the diastereomeric hydroxylamines 11 and 12, where 11 is converted to a tetrahydropyridine 13, a useful intermediate for the synthesis of cannabisativine11. 

To explain this extremely high anti selectivity, a cyclic transition state has been proposed in which the a-substituent of the inline and the methyl group of the allenic reagent are aligned in a less sterically congested anti relationship15. 

Enhancement of anti selectivity can be achieved by using more bulky alkyl groups (see table over, entries 1 -4) or phenoxy esters (entries 5 7)11. 

These results might be rationalized by assuming an aldol-like transition state induced by electrostatic forces as proposed by Seebach et al25,29 in order to explain the anti selectivity in the addition of titanium enolates to arylideniminium salts generated in situ (17-73% yield d.r. 66 34- >95 5 for related examples, see refs 30-32). 

The use of hydrazone or enamine derivatives of ketones or aldehydes offers the advantage of stcreocontrol via chelated azaenolates. Extremely useful synthetic methodology, with consistently high anti selectivity, has been developed using azaenolates based on (S)- or (R)-l-amino-2-(methoxymethyl)pyrrolidine (SAMP or RAMP)51 58 (Enders method, see Section 1.5.2.4.2.2.3.). An example which illustrates the efficiency of this type of Michael addition is the addition of the lithium azaenolate of (5 )-l-amino-2-(methoxymethyl)pyrrolidine (SAMP) hydrazone of propanal (R = II) to methyl (E )-2-butenoate to give the nub-isomer (an 1 adduct) in 80% yield with a diastereomeric ratio > 98 2,... 

Bulky amides show, however, anti selectivity, i.e., trawi-2,5-bis(methoxymethoxymethyl)-1-(1-oxopropyl)pyrrolidine gives a synjanti ratio of 9 91 in the same reaction. 

When the enolate of an ,) - or a /j,y-unsatunited amide is used, it can react in an a or in a y fashion with a,/i-unsaturated esters, however, in most cases only a-selectivity is observed. Using l-(l-oxo-2-butenyl)pyrrolidine and lithium diisopropylamide at — 78 °C in a THF/HM-I A mixture (1 1), high. syn-selective formation of 3-alkyl-5-oxo-5-(l-pyrrolidinyl)-4-vinylpen-tanoates is achieved78,381 382. Related syn- or anti-selective additions of a vinylogous urethane also are known79. 

This method is complementary to the anti-selective Michael route to 3-substituted glutamates using 2-azaallyl anions derived from alkylidene protected glycine (see Section 1.5.2.4.1.1.). 

When 2,2-dimethylpropanal is used to prepare the azomethine moiety, the corresponding azaallyl anion may be obtained when l,8-diazabicyclo[5.4.0]undec-7-ene/lithium bromide is used as base. The subsequent addition to various enones or methyl ( )-2-butenoate proceeds with anti selectivity, presumably via a chelated enolate. However, no reaction occurs when triethylamine is used as the base, whereas lithium diisopropylamide as the base leads to the formation of a cycloadduct, e.g., dimethyl 5-isopropyl-3-methyl-2,4-pyrrolidinedicarboxylate using methyl ( )-2-butenoate as the enone84 89,384. 

In contrast to the usual anti selectivity a remarkably high syn selectivity is observed in the addition of thioester enolates to 2-alkylidenealkanones297. The syn selectivity is probably due to a stereoselective internal autoprotonation of the resulting enolates by the dithioester a-pro-tons298 in these cases where the prostereogenic centers reside exclusively in the enone part (see also Section D.2.I.). 

A high degree of syn selectivity can be obtained from the addition of enamines to nitroalkenes. In this case, the syn selectivity is largely independent of the geometry of the acceptor, as well as the donor, double bond. Next in terms of selectivity, are the addition of enolates. However, whether one obtains syn or anti selectivity is dependent on both the geometry of the acceptor and the enolate double bond, whereas anti selectivity of a modest and unreliable level is obtained by reaction of enol silyl ethers with nitroalkenes under Lewis acid catalysis. 

Of perhaps greater use for organic synthesis was the observation that photo-driven reactions of alkoxycarbenes with unsubstituted optically active ene carbamates [65] produced aminocyclobutanones in fair yield with high dia-stereoselectivity (Table 12) [66]. In contrast, with a gem-disubstituted ene carbamate, the syn-anti selectivity was low but high asymmetric induction a to nitrogen was observed (Eq. 16). Trans-monosubstituted ene carbamates failed to react, as did a,/J-unsaturated chromium carbene complexes. 

We postulate that the attack on both sides is accelerated by positive SOI (89a), but an unfavorable orbital interaction along the syn attack trajectory (89b) cancels the acceleration at the syn face [151] as the diene approaches the anhydride moiety (preferentially in endo fashion), unfavorable out-of-phase interaction (SOI) of the n lobes at Cj and of the diene with the tt lobes of the aromatic moiety of the dienophile occurs (89). The unexpected anti-selectivity stems from nnfavorable SOI on the syn side. 

Ginsburg and coworkers found that the sulfoxide 94 and sulfone 95 reacted with iV-phenyltriazolinedione at the syn side of sulfoxide and sulfone moiety respectively [52] (Scheme 44). These results strongly contradict the anti selectivity observed in the reaction of the sulfide 39 (see Scheme 25). 

An unexpected result was obtained in the coupling of bis(3-alkoxypropyl)zincs with 152 [56] (Scheme 25). A substantial erosion in 1,3-anti selectivity was observed. The lower diastereoselectivity observed in these couplings may be a consequence of an equilibrium between the open-chain form (167) and the intramolecular chelated form (168) of the dialkylzinc, which increases the steric bulk about the C-Zn bond [57,58] (Fig. 6). As the steric bulk of the chelated form increases, addition from the less hindered equatorial trajectory begins to become competitive, and substantial amounts of the 5yn-l,3-diol synthon are generated. 

Dipole-dipole interactions may also be important in determining the stereoselectivity of Mukaiyama aldol reactions proceeding through an open TS. A BF3-catalyzed reaction was found to be 3,5-anti selective for several (3-substituted 5-phenylpentanals. This result can be rationalized by a TS that avoids an unfavorable alignment of the C=0 and C-X dipoles.97... 

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