FELKIN Cyclization

Cram s open-chain model 229 Cram s rule 229, 233 Cram chelate model 229 Cram cyclic model 229 Cram-Felkin-Anh model 191,207, 236 f 246 cubane 12,318 cyanoacetic acid 636 f. cyanohydrin, protected 145, 150 f. cyclic carbonate protection 541 f., 657, 659 f., 666, 670 cyclization -,6-endo 734 -, 5-exo 733 f. 

The asymmetric synthesis of (—)-denticulatin A (30) shows an interesting application of the boron aldol chemistry (Scheme 6) [23]. In a group-selective aldol reaction between the weso-aldehyde 27 and (5)-28, the hydroxyalde-hyde 29 was formed with > 90 % de, which spontaneously cyclized to the lactol 31. The configuration at the stereocenters of C-2 and C-3 in 29 is in accordance with the induction through the sultam auxiliary as well as with preference of an a-chiral aldehyde to react to the ant/-Felkin diastereomer in an aldol reaction which is controlled by the Zimmermann-Traxler model [24, 25]. 

Felkin product (69% ds, 2-anti). A (Z)-titanium enolate usually favours the anti-Felkin adduct, and the subsequent Oppolzer synthesis of denticulatins A (see Scheme 9-69) highlights this behaviour (see also Scheme 9-30) however, exceptions can be found (Scheme 9-45). Oxidation of the C3 and Cn hydroxyls of 258, and cyclization, under carefully controlled conditions to preserve the configuration of the Cio stereocenter, then allowed the selective synthesis of denticulatin B. 

Another application of this high pressure cyclization technique to ste-reochemically more complex aldehydes has recently been described (Scheme 4-VII).34b For example, aldehyde 15 reacts with ( )-l-methoxy-butadiene to give exclusively adduct 16, which can be epimerized to 17. A Felkin model for cycloaddition can again be used to rationalize these results (cf. 18). It is the greater rigidity and steric bulk of this system that imparts the high facial selectivity relative to the glyceraldehyde derivative in Scheme 4-VI. 

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]. 

Here, the initially formed endo adducts 4.50 and 4.51 spontaneously cyclize to the lactols 4.52 and 4.53. No exo adducts were obtained in this Diels-Alder reaction. While the observed diastereoselection is only modest in this case, it is better than that obtained in organic solvents and is consistent with a Felkin-Anh type of transition-state conformation. 

Next the benzimidazole was introduced. Thus, cleavage of the olefin liberated Cio as an aldehyde. The HWE reaction proceeded without incident. The Cl5 ketone was protected and the Cis acetal hydrolyzed to give aldehyde 103. An aldol condensation then provided the Felkin-Ahn (or Cram) product 104, in good overall yield. The key cyclization occurred as anticipated using sodium methoxide as a catalyst to trigger the process (104 to 105). The Troc protecting group was removed and the methyl ester was converted to the acid to provide calcimycin (1). 

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... 

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