Diazo lactone

A versatile stereoselective synthesis of endo,exo-furofuranones was accomplished by R.C.D. Brown and coworkers. One of the key steps was a Rh(ll)-catalyzed C-H insertion reaction and the required diazo lactone was prepared via the Regitz diazo transfer reaction. The 2-acetyl substituted lactone substrate proved to be recalcitrant toward the deacylative diazo transfer under standard conditions. Eventually the authors decided to use the very reactive triflyl azide (TfNs), which was generated in situ under phase-transfer conditions to afford the desired a-diazo lactone. The C-H insertion product was then converted to (+)-methylxanthoxylol. 

Making use of the same reaction principle, disubstituted ketenes 66 have been reacted with aldehydes 80 to form p-lactones 81 [100], with diazo-compounds 82 to form 1,2-diazetidin-3-ones 83 [101] and with nitroso-compounds 84 to form 1,2-oxazetidin-3-ones 85 as precursors of a-hydroxy carboxylic acids (Fig. 42) [102],... 

In recent years, the variety of useful diazo substrates for asymmetric intramolecular cyclopropanation processes has really expanded. As another example, Charette and Wurz have reported the first example of an intramolecular cyclopropanation involving a-nitro-a-diazo carbonyl compounds.This reaction, catalysed by Rh2[(S)-DOSP]4, led to the formation of nine-membered nitrocyclopropyl lactones in good yields and enantioselectivities with extremely high diastereoselectivities (Scheme 6.17). This novel methodology constituted an efficient entry into chiral functionalised macrocyclic-fused cyclopropane oc-amino acids. 

The insertion reaction can be used to form lactones from -diazo-(J-keto esters. 

Decarboxylation, Masamune reaction, and diazotransfer Diazo 25 was prepared under optimized conditions, as summarized in Scheme 2.9. Decarboxylation of the malonate could be done under either acidic or basic conditions. Reaction of 17 under acidic conditions provided the desired mono-carboxylic acid 18 but lactone 35 was simultaneously formed (Figure 2.2). Under basic conditions,... 

Metal catalysed or photochemically promoted reactions of diazo compounds with diketene gave cyclopropanespiro-P-lactones 25 and 26 <00JCS(P1)2109>. 

Because of the special structural requirements of the resin-bound substrate, this type of cleavage reaction lacks general applicability. Some of the few examples that have been reported are listed in Table 3.19. Lactones have also been obtained by acid-catalyzed lactonization of resin-bound 4-hydroxy or 3-oxiranyl carboxylic acids [399]. Treatment of polystyrene-bound cyclic acetals with Jones reagent also leads to the release of lactones into solution (Entry 5, Table 3.19). Resin-bound benzylic aryl or alkyl carbonates have been converted into esters by treatment with acyl halides and Lewis acids (Entry 6, Table 3.19). Similarly, alcohols bound to insoluble supports as benzyl ethers can be cleaved from the support and simultaneously converted into esters by treatment with acyl halides [400]. Esters have also been prepared by treatment of carboxylic acids with an excess of polystyrene-bound triazenes here, diazo-nium salts are released into solution, which serve to O-alkylate the acid (Entry 7, Table 3.19). This strategy can also be used to prepare sulfonates [401]. 

A few natural products which contain the cyclopropyl ring have been synthesized through metal catalysed cyclopropanation using dicarbonyl diazomethanes. ( )-Cycloeudesmol 63, isolated from marine alga Chondria oppositiclada, was synthesized via a sequence involving a copper catalysed cyclopropanation of a-diazo-/8-ketoester 61 to give the key intermediate 62 (equation 73)1 7,108. Similarly, the bicyclo[3.1.0]hexane derivative 65 was synthesized from the corresponding a-diazo-/8-ketoester 64 via the catalytic method and was converted into ( )-trinoranastreptene 66 (equation 74)109. Intramolecular cyclopropanation of -diazo-/i-ketoesters 67 results in lactones 68 which are precursors to 1-aminocyclopropane-l-carboxylic acids 69 (equation 75)110. 

Cyclization to a morpholinolactone (59) occurs in the hydrolysis reaction of the di-A-hydroxylethylated compound (60). Compound (59) is rapidly hydrolysed by water to (61) but in file presence of equimolar amounts of amines (RNH2) or ammo acid derivatives (62) forms.56 A novel reaction of cyclic 2-diazo-l,3-dicarbonyl compounds (63) with lactones (64) affords the products (65) in the presence of rhodium acetate, Rh2(OAc)4.57 Lewis acid-promoted intramolecular additions of allylsilanes to lilac tones gave substituted cyclopentanes.58 A proposed transition state guided efforts to improve the stereoselectivity of the reaction. The reaction of a series of /1-lactone derivatives, such as (66)-(68), has been studied and they have been ling cleaved the reaction outcome is both Lewis acid and structure dependent.59... 

Intramolecular Carbon-Hydrogen Insertion. The advantages of rhodium(II) catalysts for carbenoid transformations are nowhere more evident than with carbon-hydrogen insertion reactions. Exceptional regio- and diastereocontrol has been observed for Rh2(OAc)4 catalyzed transformations of a broad selection of diazoketones, a-diazo-p-ketoesters, a-diazo-P-keto-sulfones and -phosphonates which yield cyclopentanone derivatives in moderate to good yields (57-54). In contrast, poor yields and low regioselectivities characterize the corresponding copper catalyzed reactions. Applications of dirhodium(II) catalysts for C-H insertion reactions have even been extended to the synthesis of y-lactones (55), 3(2//)-furanones (56,57), P-laetones (58), and P-lactams (59,60). 

Applications with diazo esters that undergo insertion into a C-H bond vicinal to the incipient chiral center demonstrated further advantages of this catalytic methodology for asymmetric synthesis. 2,3,4-Trimethyl-2-pentyl diazoacetate formed lactone 19 exclusively (eq 7) in 60% ee (77% isolated yield) with Rh2(5S-MEPY)4 and Rh2(5/ -MEPY)4 and in 70% ee with the neopentyl ester analog, Rh2(5S-NEPY)4 (82% isolated yield). Cumyl diazoacetate underwent insertion into the normally disfavored 1° C-H bond (eq 8) to yield lactone 20 in 76% ee (30% isolated yield) with... 

The high degree of enantiocontrol in C-H insertion reactions with such a diversity of diazoacetates suggests unique advantages for chiral dirhodium(II) catalysts derived from pyrrolidone-5-carboxylates. Both lactone enantiomers are accessible from a single diazo ester, and the absence of by-products of similar composition allows convenient product isolation. 

Cyclopropyl lactones. Copper-catalyzed decomposition of unsaturated esters of dia-zoacetic acid can provide eyclopropyl lactones >2, 83). The soluble copper chelate 1 is superior for this purpose to copper powder or copper oxide. In a typical example, the lactone 3 is obtained from the diazo ester 2 in 92% yield. 

Enantioselective Intramolecular Carbon-Hydrogen Insertion Reactions. The suitability of Rh2(55-MEPY)4 and Rh2(5R-MEPY)4 for enantioselective intramolecular C-H insertion reactions is evident in results with 2-alkoxyethyl diazoacetates (eq 4). Both lactone enantiomers are available from a single diazo ester. Other examples have also been reported, especially those with highly branched diazo substrate structures. ... 

The rhodium (II) catalysed thermolysis of e-trimethylsilyloxy-a-diazo-P-ketophosphonates (249) is reported to give rise to a-phosphono- -lactones (250) in moderate to good yields. Diels-Alder reactions of enone phosphonates (251) with different 1,3-dienes give adducts, which are complex phosphonate-contain-ing polycycles with keto function (252) e.g.. Scheme 65). These -keto phosphon-ate systems found interesting synthetic applications. ... 

Now when phthalophenone is hydrolyzed with alkalies it yields mono-carboxy tri-phenyl carbinol which on reduction yields mono-carbozy tri-phenyl methane and this by loss of carbon dioxide yields tri-phenyl methane. This means that phthalophenone is a lactone inner anhydride of mono-carboxy tri-phenyl carbinol and a true tri-phenyl methane derivative as shown in the reactions below. Now, also, phthalophenone by nitrating yields a di-nitro compound which by reduction yields a di-amino derivative and this by the diazo reaction has the two amino groups replaced by hydroxyls. The result is phenol phthalein, which is therefore also a lactone inner anhydride of mono-carboxy di-hydroxy tri-phenyl carbinol. All of these relationships may be represented by the following ... 

The use of chiral additives with a rhodium complex also leads to cyclopropanes enantioselectively. An important chiral rhodium species is Rh2(5-DOSP)4, which leads to cyclopropanes with excellent enantioselectivity in carbene cyclopro-panation reactions. Asymmetric, intramolecular cyclopropanation reactions have been reported. The copper catalyzed diazoester cyclopropanation was reported in an ionic liquid. ° It is noted that the reaction of a diazoester with a chiral dirhodium catalyst leads to p-lactones with modest enantioselectivity Phosphonate esters have been incorporated into the diazo compound... 

The same method was applied to the synthesis of biologically active nucleosides ( )-2 -deoxy-2 -(carboxymethylene)-5 -0-trityluridine-3, 2 -)/-lactone 158 (O Scheme 42). Exposure of 2, 5 -cyclouridine derivative to the House-Blankey protocol afforded the corresponding diazo compound 156, which could be converted to the y-butyrolactone of uridine 157 in 65% yield via [1,5]-C,// insertion. Lactone 158 could be smoothly obtained by an elimination reaction with sodium hydride in 85% yield. 

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