Configuration cyclic imines

While enantiomerically pure a-substituted isocyanoacetates have been used in Passerini condensation without significant racemization [4-6], the same class of compounds is believed to be configurationally unstable under the conditions of U-4CRs [7]. However, one notable exception is the reaction shown in Scheme 1.1, where L-isoleucine-derived isocyanide 2 has been condensed without such problems with pyrroline 1 [8]. The bulkiness of this isocyanide or the use of a preformed cyclic imine, thus avoiding the presence of free amine in solution, may be the reasons for the absence of racemization. 

Stereoselective addition of a chiral cyclic phosphite to a cyclic imine was applied to the synthesis of phosphonic analogs of d- and L-penicillamine41. Enantiomerically pure dioxaphospholane oxide 6 underwent addition to 2,5-dihydro-2,2,5,5-tetramethylthiazole in the presence of boron trifluoride as a catalyst. The diastereomeric adducts 7, obtained in a 2 1 ratio, were easily separated on silica gel and their configuration assigned by X-ray analysis the (4/ )-isomer was shown to be the major diastereomer. Hydrolysis of each diastereomer gave pure enantiomers of phosphopenicillamine 841. 

Under the same conditions, the [2 + 2] cycloaddition of 36 to cyclic imine 39 gave trans- -lactam 40 as the only detectable isomer [31] (Scheme 10.10). Unfortunately, the authors did not assign the absolute configuration of the p-lactam 40. 

The mode of action of cyclic imine toxins is still vague. Why are they so acutely lethal and so fast-acting in mammalian bioassays It is not clear if they aU share a conunon mode of action that is modulated merely by configurational differences among various derivatives and toxin types. 

Substrate control is another approach for synthesis of anti-Mannich products. The proline-catalyzed Mannich reaction between aldehydes and pre-formed N-Boc-imines affords the syn-Mannich product with exceptionally high diastereoselectivi-ties and enantioselectivities [44]. In contrast, the reaction of aldehyde 83 with N-Boc-imines, generated in situ from the stable a-amido sulfone 84, catalyzed by the commercially available chiral secondary amine 85 provides antt-Mannich product 86 with 96% ee (Scheme 28.7a) [45]. Cyclic iminoglyoxylate 88, readily prepared from commercially available starting materials, is a useful alternative imine electrophile its configuration is locked in the (Z)-form. Because of the (Z)-configuration of imine 88, the anti-selective Mannich reaction proceeds (Scheme 28.7b) [46]. 

Lithium and zinc tert-butyl phenylmethyl sulfoxide (1) and A-phenyl imines 2, in which the substituent R is alkenyl or aryl, react at —78 °C over 2 hours with high anti diastereoselection (d.r. >98.5 1.5)6. Shorter reaction times result in poorer yields, due to incomplete reaction. In contrast, the reaction of the sulfoxide anion with benzaldehyde is complete after 5 seconds, but shows poor diastereoselection. When the substituent R1 or R2 of the imine 2 is aliphatic, the substrates exhibit poor chemical reactivity and diastereoselection. The high anti diastereoselection suggests that if a chelated cyclic transition state is involved (E configuration of the imine), then the boat transition state 4 is favored over its chair counterpart 5. 

In addition, the /erf-butyl esters of valine and tert-leucine are excellent chiral auxiliaries in asymmetric alkylation of their imines. These chiral auxiliaries are preferentially used in the alkylation of cyclic ketones (73 to >99% ee)17 and /i-oxo esters (44 to >99% ee)18,, 9 and the absolute configuration of the products can be safely predicted. 

Complexity is added to the study of this system by the ready functionalization of the sulfur atom by alkylation, oxidation and imination. 5-Alkylation to produce a compound such as (9) <76T1873) affords a system in which either of two possible chair conformers possesses an axial t-butyl group, and this system therefore exists preferentially in a twist conformation (10). Where no such conflicts occur the sulfur substituent adopts the equatorial position in a chair form. Inversion of configuration at sulfur in cyclic sulfides has been investigated in the system (11) (12) and the corresponding ylides (13) (14) (77JA2337). 

Asymmetric Alkylations. The use of nitrogen derivatives of carbonyl compounds (imines, imides, amides, sultams, oxazo-lines) is often the most efficient procedure for achieving a-alkylations. Chiral auxiliaries bearing heteroatoms in a 1,2-relationship appear to work best, as they have chelation sites for the metal cation. High levels of asymmetric induction can thus be achieved due to the system rigidity. Cyclic ketones have been alkylated via the lithiated enamine formed from L-f-leucine f-butyl ester (eq 1). High enantiomeric excesses and predictability of absolute configuration make this method attractive. 

The absolute configuration of the structurally unique fungal metabolite mycosporins was determined in the laboratory of J.D. White by means of enantioselective total synthesis." In the endgame of the synthetic effort, the Staudinger reaction was used to elaborate the side chain. The cyclic vinyl azide was first converted to a stable vinyl iminophosphorane, which was subsequently reacted with benzyl glyoxylate to afford the corresponding Schiff base. Reduction of the imine was achieved with sodium cyanoborohydride. 

Chirality also has been introduced on the inline. After treatment with Na/NHg, 3-amino-2-azetidinones are obtained from reactions of (R)- or (5)-l-phe-nethylamine imines and zinc enolates of ethyl bis-silylaminoacetate 6.109 (R = Et) [131,1289]. In Et20, trans isomers are formed, while in THF-HMPA, cis isomers predominate. The facial selectivity depends upon the (R)- or ( configuration of the imine W-substituent (Figure 6.91). If the inline C-substituent R is h CsC, then the selectivity is lower. Cyclic transition-state models account for the observed selectivities. From the titanium enolate of 2-pyridylthioester Me2CHCOS-2-Py and benzaldehyde (S)-1 -phenethylimines 6.111, Cinquini, Cozzi and cowork-... 

Nagasawa and co-workers [108] were the first to introduce chiral thiourea catalyst to the BH reaction. They synthesized a tra 5-(li ,2i )-l,2-diaminocy-clohexane-derived bisthiourea 57 as catalyst to promote the BH reaction of cyclohexanone and aldehydes in the presence of DMAP co-catalyst (Scheme 9.31). The dual activations of both substrates were proposed to account for excellent enantioselectivites (for aliphatic aldehydes) and reactivity enhancement. Later on, chiral bisthiourea 58 was prepared and applied as catalyst under solvent-free conditions [109]. Around at the same time, Raheem and Jacobsen [110] demonstrated that chiral thiourea 59 was an efficient catalyst for the DABCO promoted aza-BH reaction of IV-nosyl imines and methyl acrylate. Chiral Hg-binaphthyl bisthiourea 60 was then prepared by Shi and Liu [111] and used as the co-catalyst of DABCO in the reaction of cyclic enones with aldehydes, providing the products in high enantioselectivities. The application of chiral bisthiourea 61 as catalyst resulted in the formation of S configurational products in good to excellent enantioselectivities (Scheme 9.31) [112]. Moreover, thiourea 62 turned out to be an efficient catalyst in the reaction of cyclohex-2-enone with aldehydes co-catalyzed by triethylamine under solvent-free conditions [113]. 

---