Catalyst Choice for Highly Enantioselective [3 + 3]-Cycloaddition of Enoldiazocarbonyl Compounds

Abstract

Chiral copper(I) catalysts are preferred over chiral dirhodium(II) catalysts for [3 + 3]-cycloaddition reactions of enoldiazocarbonyl compounds with nitrones and acyliminopyridinium ylides, forming chiral oxazines and pyrazines in very high yield and enantioselectivity. Yields and stereoselectivities from reactions of enoldiazoketones are virtually the same as those from the corresponding esters and amides, but products from enoldiazoketones are precursors to chiral 1,3-dicarbonyl derivatives that provide additional opportunities in heterocyclic synthesis through the formation of pyrazoles and isoxazoles.

Catalytic asymmetric cycloaddition reactions of enoldiazo compounds

“…The copper(I)-catalyzed [3+3]-cycloaddition of nitrones 10 using silyl-protected enoldiazoacetates, 39 -acetamides, 39,40 -ketones 39 and -sulfones 41 (9) (Scheme 5) illustrates the exceptional selectivity that can be achieved in these transformations as well as their inherent complexity. Because of their inherent stability, nitrones are popular for catalytic dipolar cycloaddition transformations.…”

“…4b, [10][11][12][13]42 In previous investigations of nitrone cycloaddition reactions with enoldiazoacetates, copper(I) catalysis was not as effective or selective as catalysis by chiral rhodium(II) carboxylates 43 or silver(I)/t-BuBOX. 44 However, reinvestigation of this process revealed that enoldiazocarbonyl compounds and enoldiazosulfones offered consistently higher yields and enantioselectivities under copper(I) catalysis [39][40][41] than did the corresponding enoldiazoacetates under rhodium(II) catalysis. 43 The key factor in this discovery was the modification of the chiral box ligands on copper, and the greater electrophilic reactivity of these copper catalysts over chiral dirhodium carboxylate catalysts.…”

“…43 Sterically encumbered sabox ligand 21 was the most effective in reactions of enoldiazo-ketones 17 (Scheme 6C), as well as -acetates 15, andacetamides 16. 39 However, the use of sabox ligand 22 also provides very high yields and enantioselectivities in the formation of oxazines 19 from reactions with enoldiazoacetamides 16 (Scheme 6B). 40 There are very few reports on the cycloaddition reactions of diazosulfones.…”

“…In the absence of stabilizing ligands on, for example, copper(I) activates the nitrone for electrophilic addition to the vinylogous center of the vinyldiazo compound, causing subsequent TBS transfer and formation of the Mannich product 14 (Scheme 5). [39][40][41] Formal asymmetric [3+3]-cycloaddition of nitrones 10 with D-A cyclopropene 29 has been reported using Ag(I)-catalysis (Scheme 8). 44 The parent γ-phenyl-enoldiazoacetate 1b does not undergo dirhodium(II) catalyzed cycloaddition with nitrones, but chiral AgSbF 6 /(S)-tBuBOX (30) catalysis facilitated formal [3+3]-cycloaddition of 29 at low temperature (−78 °C); and a one-pot TBS removal afforded cis-diarylsubstituted 3,6-dihydro-1,2Hoxazines 31, which exist exclusively in the enol form, in high yields and with exceptional stereocontrol.…”

“…12,48 Variations between Rh 2 (S-PTTL) 4 or Rh 2 (S-PTAD) 4 chiral catalysts, and toluene or fluorobenzene as solvents provided high yields and enantioselectivities of bicyclic diazines 33 in [3+3]-cycloaddition reactions performed at 0 °C. Recent studies of this reaction using copper(I) catalysis 39 Products of [3+2]-cycloaddition were obtained in moderate yields via direct catalyst-free treatment of a D-A cyclopropene with a methylide. The experimental data was consistent with a recent theoretical study 50 that confirmed the [3+3]-cycloaddition as the major reaction pathway with Rh 2 (S-PTIL) 4 catalyst, and that preferential [3+2]-cycloaddition occurred in reactions catalyzed by electron-deficient Rh 2 (CF 3 COO) 4 and the chiral rhodium(II) catalyst Rh 2 (S-TCPTTL) 4 which has greater steric repulsions from its ligands compared to Rh 2 (S-PTIL) 4 .…”