Biomedical subjects
Publications and source records attributed to E J Corey.
[reaction: see text] Nine examples are reported of enantioselective [4 + 2] cycloaddition reactions of achiral, acyclic substrates to form chiral bicyclo[4.3.0]nonane or bicyclo[4.4.0]decane derivatives.
[structure: see text] The catalytic asymmetric dihydroxylation of olefins has been accomplished with high enantioselectivities using a proline-based catalyst. The pre-transition-state assembly for styrene is shown.
[reaction: see text] The Diels-Alder reaction of cyclopentadiene and 2-methacrolein is catalyzed by a chiral Lewis acid to form the exo adduct in 96% yield and 96% ee.
[reaction: see text] The scope and generality of a new reaction of indoles with MTAD is discussed. In most cases the ene-type reaction proceeds within seconds or minutes at 0 degrees C to provide the urazole adducts in high yield. This reaction provides the first method for protecting the indole 2,3-double bond since the urazole adducts can be reconverted to the starting indole (retro-ene) simply by heating.
The strong acid triflimide ((CF3SO2)2NH) protonates chiral oxazaborolidines to form superactive, stable, chiral Lewis acids which are highly effective catalysts for a wide variety of enantioselective Diels-Alder reactions, documented herein by more than 20 examples.
The first enantioselective total synthesis of a member of the okaramine family of bis-indole alkaloids, okaramine N (1), has been accomplished via intermediates 2-7, as outlined. The N-prenylated derivative of (S)-tryptophan methyl ester (2) was coupled with Fmoc-protected N-tert-prenylated tryptophan (3) to form the amide 4 in 70% yield. Pd(II)-mediated cyclization/rearrangement, a key step in the synthesis, transformed 4 into the indoloazacine 5 (44%), which was deprotected and cyclized in a single step to give the hexacyclic diketopiperazine 6 (95%). In the following novel and key sequence, 6 was transformed into 1: (1) selective ene reaction with N-methyltriazolinedione, (2) photooxidation of the remaining tert-prenylated indole subunit to provide 7, and (3) thermal retroene reaction of 7 to afford okaramine N (70% from 6).
An efficient and practical synthesis of alpha-methylomuralide (3), a selective inhibitor of proteasomes, has been developed as outlined in Scheme 1. Among the advantages of this route of synthesis over previously described approaches are (1) ease of scale-up and (2) high yields (28% overall yield of alpha-methylomuralide from 6) and stereocontrol (including high enantiocontrol). The synthesis is well suited to the production of 3 in the quantities needed for material-intensive in vivo investigations.
A new and simple method is described for the one-step oxidation of alpha,beta-enones to 1,4-enediones in good yields (generally 80-90%) using t-butylhydroperoxide as stoichiometric oxidant and 20% Pd(OH)2 on carbon (5 mol %) as catalyst in CH2Cl2 solution. The same reagents have been used to convert ethylene ketals of alpha,beta-enones to the corresponding monoethylene ketals of 1,4-enediones. Seven representative examples are presented in Table 1. All of the available evidence on these oxidations points to a radical-chain mechanism initiated by the tert-butylperoxy radical (see Scheme 1). gamma-tert-Butylperoxy ethers are formed as major products in the oxidation of alpha,beta-enones possessing only a single gamma-hydrogen.
All-E or E,Z,E-oligoprenols may be synthesized from allylic stannanes by reaction with prenyl aldehydes. [reaction: see text]
A remarkably short (four steps, 31% overall yield) enantioselective synthesis of the structurally unique C2-symmetric tetracyclic triterpene (+)-alpha-onocerin (1) has been developed. The brevity of this mechanism depends on the assembly of four fragments (two molecules of a chiral epoxy ketone and two molecules of vinyllithium) to generate the chiral bis-epoxide 4 in one step, and on the efficient formation of all four carbocyclic rings in one step by cation-olefin tetracyclization. New and general methodology for the conversion of vinyl tert-butyldimethylsilyl ethers to vinyl triflates with retention of E or Z olefinic geometry also was utilized in the synthesis of 1. A short enantioselective synthesis of a non-C2-symmetric diastereomer of 1 is also described which uses the new methodology.
The cationic chiral Lewis acids 1 and 2, generated by triflic acid protonation of the corresponding neutral oxazaborolidines, serve as excellent catalysts for Diels-Alder addition of cyclopentadiene to a wide variety of dienophiles. Adducts have been obtained in excellent yield and enantioselectivity from alpha,beta-unsaturated esters, lactones, and cyclic ketones. The absolute facial selectivity for each of these substrates follows a common pattern which differs from that observed with alpha,beta-enals. The different reaction channels can be understood in terms of pathways via complexes 3 (for alpha,beta-enals) and 4 (for alpha,beta-enones and esters).
[reaction: see text] New procedures are described for the palladium-catalyzed oxidation of olefins by tert-butylhydroperoxide under slightly basic conditions in CH(2)Cl(2) solution at 0-25 degrees C.
[reaction: see text] The four components shown are assembled in two steps, and the product is converted to araneosene by a short sequence.
The first synthesis of (+)-austamide (1), (+)-deoxyisoaustamide (2), and (+)-hydratoaustamide (10) by a very direct route is described (Scheme 1). Starting from tryptophan methyl ester (3) intermediate 5 is generated in two steps in >98% overall yield. The key step in the synthesis is a novel cyclization of 5 involving organopalladium intermediates which gives the dihydroazocine 6. From this key intermediate the target structures are accessible in just a few steps as shown in Scheme 1. The remarkable conversion of 5 --> 6 can be rationalized by the mechanistic pathway shown in Scheme 2 that involves a multistep sequence which includes palladation, cyclization, and rearrangement.
This paper reports a new method for the generation of chiral Lewis superacids by protonation of a non-Lewis acidic oxazaborolidine (1) with triflic acid. The resulting cationic species (3) are powerful and highly enantioselective catalysts for the Diels-Alder reaction of various 1,3-dienes with alpha,beta-enals. An optimization study (see Table 1) led to the selection of reaction conditions and catalysts (6A and 6B) which are very effective. The reactions are simple to conduct, reproducible, and economical, since only ca. 6 mol % of catalyst is required. In addition, the chiral catalyst precursor is readily recovered for reuse (>95% efficiency) and is commercially available. The broad scope of the process is documented by the 14 examples listed in Table 2. The absolute stereochemical course of the Diels-Alder reactions catalyzed by 6A and 6B was successfully predicted on the basis of the mechanistic principles which have recently been formulated for this type of catalytic enantioselective reaction involving re-face attack by the diene on complex 7. The mode of generation of Lewis superacids 6A and 6B allows an approximate comparison (or scale) connecting the catalytic power Lewis and protic acids.
A solution is reported to the classic unsolved problem of stereoselective synthesis of all-E oligoprenols, such as E-farnesylfarnesol, by a cationic coupling analogous to the biosynthetic pathway. The simplicity and efficacy of the method, which is outlined in Scheme 1, are demonstrated by the synthesis of a series of all-E oligoprenols from C(20) to C(35) in uniformly excellent overall yield. The success of the approach is due not only to the highly E-stereoselective C-C coupling that forms the oligoprenyl chain but also to the development of efficient syntheses of allylic secondary silanes and E-oligoprenal acetals, and to a selective allylic demethoxylation reaction.
[reaction: see text]. Ultraviolet irradiation of a series of polyunsaturated allylic benzoates results in highly selective E/Z interconversion of the allylic double bond.
[structure: see text]. The new silyllithium reagent 1 and the corresponding cyanocuprate 3 are readily generated under optimal conditions and are useful for the formation of C-Si bonds. Tamao-Fleming oxidation of such C-Si bonds can be effected under very mild conditions.