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Subscriber access provided by Brought to you by ST ANDREWS UNIVERSITY LIBRARY Review Catalytic Stereoselective [2,3]-Rearrangement Reactions Thomas H. West, Stéphanie S.M. Spoehrle, Kevin Kasten, James E Taylor, and Andrew D. Smith ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.5b02070 • Publication Date (Web): 29 Oct 2015 Downloaded from http://pubs.acs.org on November 3, 2015
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ACS Catalysis is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties. Page 1 of 88 ACS Catalysis
1 2 3 Catalytic Stereoselective [2,3]-Rearrangement Reactions 4 5 6 7 Thomas H. West, Stéphanie S. M. Spoehrle, Kevin Kasten, James E. Taylor, 8 9 and Andrew D. Smith* 10 11 12 EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 13 14 9ST, U.K. 15 16 17 18 ABSTRACT 19 20 21 22 23 24 25 26 27 28 29 30 [2,3] Sigmatropic rearrangement processes of allylic ylides or their equivalents can be 31 32 applied to a variety of different substrates and generate products of wide interest / 33 34 applicability to organic synthesis. This review describes the development and applications of 35 36 stereoselective [2,3] rearrangement reactions in which a sub stoichiometric amount of a 37 38 catalyst is used in either the formation of the reactive intermediate or the [2,3] rearrangement 39 40 41 step itself. 42 43 44 45 46 47 Keywords: Stereoselective catalysis, [2,3] rearrangement, allylic oxonium ylides, allylic 48 49 ammonium ylides, allylic sulfonium ylides, O propargylic oximes, allylic sulfoxides, allylic 50 51 N oxides 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 1 ACS Catalysis Page 2 of 88
1 2 3 1. INTRODUCTION 4 5 Stereoselective [2,3] sigmatropic rearrangements have great utility in organic synthesis. 1,2 In 6 7 8 particular, the ability to form carbon carbon bonds with high diastereo and enantioselectivity 9 10 through well defined and predictable transition states under often mild reaction conditions 11 12 makes [2,3] sigmatropic rearrangements attractive for the synthesis of complex targets. [2,3] 13 14 Sigmatropic processes can be broadly categorized into two main types: a) neutral 15 16 17 rearrangements involving ylides and b) anionic rearrangements (Scheme 1). These reactions 18 19 almost always involve at least one heteroatom and allow a number of different products 20 21 containing various functional groups to be accessed. 22 23 24 25 26 27 28 29 30 Scheme 1. General classifications of [2,3] sigmatropic rearrangements 31 32 33 Many stereoselective [2,3] rearrangements developed for organic synthesis utilize either 34 35 existing stereocenters within the starting materials, chiral auxiliaries, or stoichiometric chiral 36 37 ligands to control the configuration of the newly formed σ bond. Advances in the 38 39 40 development and applications of catalytic, stereoselective [2,3] rearrangement reactions are 41 42 less prevalent. This review surveys stereoselective [2,3] rearrangement processes where a 43 44 sub stoichiometric amount of a catalyst is used in either the formation of the reactive ylide / 45 46 anion or to promote the [2,3] rearrangement itself (Scheme 2). The most widely explored 47 48 49 processes within this remit are transition metal catalyzed formations of allylic onium ylides 50 51 from diazo compounds, followed by a facile in situ [2,3] rearrangement (Section 2). More 52 53 recently, alternative methods for the catalytic [2,3] rearrangement of allylic ammonium 54 55 ylides derived from quaternary ammonium salts have been developed (Section 3). The 56 57 transition metal promoted rearrangement of O propargylic oximes generates highly reactive 58 59 60 ACS Paragon Plus Environment 2 Page 3 of 88 ACS Catalysis
1 2 3 allenyl nitrone intermediates that can participate in a number of different reaction cascades 4 5 (Scheme 4). Catalytic variants of commonly used [2,3] rearrangements of allylic sulfoxides 6 7 (Mislow Evans), selenoxides (Riley oxidation), sulfimides, and N oxides (Meisenheimer) 8 9 10 have also been explored (Section 5). Finally, a limited number of catalytic, stereoselective 11 12 anionic [2,3] Wittig rearrangements have been reported (Section 6). 13 14 15 2. Onium ylides from metal carbenoids 16 R R 17 R [2,3] 18 + X X N2 X 19 20 X = R2N, RO, RS, halogen 21 22 3. Ammonium ylides from quaternary ammonium salts 23 R 24 R R R 25 Base N + X 26 N N N [2,3] 27 28 4. O-Propargylic oximes 29 30 O 31 N N 32 O [2,3] • 33 34 N 35 5. Sulfoxides, selenoxides, sulfimides, and -oxides 36 Y Y X 37 ZY + X 38 X [2,3] 39 X = RS, RSe, R2N 40 Y = O, RN 41 42 6. [2,3]-Wittig rearrangements 43 R 44 R R 45 O 46 O Base O [2,3] 47 48 Scheme 2. Overview of catalytic [2,3] rearrangements discussed 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 3 ACS Catalysis Page 4 of 88
1 2 3 1.1 General mechanism and stereochemical control 4 5 [2,3] Sigmatropic rearrangements are symmetry allowed concerted processes that proceed 6 7 through a five membered, six electron transition state with an envelope conformation. The 8 9 presence of a heteroatom within the reaction framework lowers the energy of these processes 10 11 12 and can provide additional stabilization of the transition state through resonance 13 14 contributions. Generally, [2,3] rearrangements of allylic ammonium ylides are favorable 15 16 processes, but competing [1,2] or [1,4] rearrangements (where possible) are observed in 17 18 some cases. 19 20 21 Stereocontrolled [2,3] rearrangement processes can generate up to two new stereogenic 22 23 24 centers around the newly formed σ bond and allow (E) or (Z) selectivity within the new π 25 26 bond. The greater conformational flexibility of five membered transition states compared 27 28 with six membered transition states of [3,3] sigmatropic rearrangements make them more 29 30 susceptible to substituent effects and complete stereocontrol can be difficult to attain. 3 31 32 33 The observed diastereoselectivity of [2,3] rearrangement of generic substrates such as ( E) 1 34 35 36 is dependent on the relative energies of the exo 2 and endo 3 transition states as outlined by
37 4 38 Houk and Marshall for the [2,3] Wittig rearrangement (Scheme 3a). The stereochemical 39 40 preference for a given process is dependent on both steric and stereoelectronic properties of 41 42 the two substituents (R 1 and R 2) as well as the heteroatom present. [2,3] Sigmatropic 43 44 rearrangements are often stereospecific, with ( E) 1 and (Z) 6 isomers leading to the formation 45 46 47 of the opposite product diastereoisomers (Scheme 3b). For example, rearrangement of ( E) 1 48 49 through exo type transition state 2 leads to the formation of (±) anti 4, whereas 50 51 rearrangement of the corresponding ( Z) 6 through exo type transition 7 state gives (±) syn 5. 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 4 Page 5 of 88 ACS Catalysis
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Scheme 3. Generic pre transition state assemblies for diastereoselective [2,3] rearrangements 31 32 33 The geometry of the newly formed π bond after [2,3] rearrangement is also subject to 34 35 stereocontrol by the substituents. As a result, the (E) alkene geometry is often favored over 36 37 38 the corresponding ( Z) alkene due to minimization of allylic 1,3 strain in transition state 10 39 3,5 40 compared with 11 (Scheme 4). 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 Scheme 4. Control of ( E)/(Z) alkene geometry in [2,3] rearrangements 58 59 60 ACS Paragon Plus Environment 5 ACS Catalysis Page 6 of 88
1 2 3 While these general stereochemical considerations can often be used to account for the 4 5 observed diastereoselectivity, the precise origin of any enantioselectivity is poorly understood 6 7 in many cases. There are relatively few detailed mechanistic studies regarding catalytic 8 9 10 stereoselective [2,3] rearrangements as these processes are often highly complex and difficult 11 12 to probe experimentally and computationally. 13 14 15 16 2. METAL-CATALYZED ONIUM YLIDE FORMATION AND [2,3]- 17 18 19 REARRANGEMENTS VIA METAL CARBENOIDS 20 21 The use of diazo compounds as allylic onium ylide precursors in [2,3] rearrangements has 22 23 been widely studied. 6 The metal catalyzed decomposition of diazo compounds proceeds 24 25 readily to form metal carbenoids with concomitant loss of nitrogen. A wide range of 26 27 28 transition metal complexes can be used for this purpose with catalysts based upon rhodium 29 30 and copper by far the most common, although iron, cobalt, ruthenium, silver, platinum, and 31 32 gold based complexes have been used. The metal carbenoid species can react in situ with 33 34 allylic ethers, amines, sulfides, and allyl halides to form the corresponding allylic onium 35 36 ylides that can undergo the desired [2,3] rearrangement. (Scheme 5) However, metal 37 38 39 carbenoids are often highly reactive intermediates that can participate in a variety of 40 41 competing processes including cyclopropanation reactions alongside C H, O H and Si H 42 43 insertions. It is therefore often necessary to tune the metal ligand combination used in order 44 45 to bias the desired chemoselectivity for [2,3] rearrangement over any competing processes. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 6 Page 7 of 88 ACS Catalysis
1 2 3 O [ML n] 4 3 R2 R 5 R1 6 X 7 O O 17 O R3 [ML ] 8 R2 n R2 R1 R1 3 R1 * * 9 N2 X R [ML ] 16 n 2 10 N2 [ML n] X R 11 14 15 O 19 2 3 12 1 R R 13 R 14 X 15 18 16 17 Scheme 5. Onium ylides generated from metal carbenoids 15 and subsequent [2,3] rearrangement. X = R 2N, 18 RO, RS, RSe, Br, or I 19 20 21 There has been extensive work on developing diastereo and/or enantioselective onium ylide 22 23 [2,3] rearrangements originating from the catalytic decomposition of diazo compounds. A 24 25 successful strategy in diastereoselective processes makes use of achiral transition metal 26 27 complexes reacting with diazo compounds bearing chiral auxiliaries and/or existing 28 29 stereogenic centers. The development of [2,3] rearrangements via metal carbenoids in which 30 31 32 control of the product configuration is derived catalytically from a chiral metal complex has 33 34 been more challenging. One of the key factors in determining the success of an 35 36 enantioselective variant is the degree of association between the chiral metal complex and the 37 38 ylide during the [2,3] rearrangement step. 6b If the metal complex dissociates prior to 39 40 41 rearrangement then any enantiocontrol must arise from a configurationally restricted ylide, 42 43 otherwise a racemic product will be observed. The number of potential reaction pathways and 44 45 complexity of these processes makes detailed elucidation of the reaction mechanism 46 47 challenging. As a result, many catalytic asymmetric [2,3] rearrangements from metal 48 49 50 carbenoid species are optimized through traditional ligand screening approaches. 51 52
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1 2 3 2.1 Oxonium ylides. 4 5 2.1.1 Intermolecular oxonium ylide formation and [2,3]-rearrangement. The [2,3] 6 7 rearrangement of allylic oxonium ylides generated from the intermolecular reaction between 8 9 metal carbenoids and allyl ethers is challenging, with side reactions including 10 11 12 cyclopropanation and [1,2] insertion reactions potentially problematic. Doyle and co workers 13 14 were the first to report the diastereoselective [2,3] rearrangement of oxonium ylides from the 15 16 reaction of catalytically generated rhodium carbenoids and allylic ethers. 7 For example, the 17 18 dropwise addition of ethyl diazoacetate 20 to a solution of Rh (OAc) (1 mol%) and allylic 19 2 4 20 21 ether 21 led to the selective formation of [2,3] rearrangement product 22 in 92% yield and 22 23 83:17 dr (syn :anti ), although competitive cyclopropanation to generate 23 was also observed 24 25 (Scheme 6a). The reaction was applicable to both diazoacetates and diazoacetophenones, 26 27 alongside a small range of substituted allylic ethers, with [2,3] rearrangement favored over 28 29 cyclopropanation in all cases. Doyle subsequently reported a highly enantioselective version 30 31 32 of this process utilizing a rhodium complex bearing enantiomerically pure oxazolidin 2 one 33 34 ligand 24 (Scheme 6b). 8 Under these conditions [2,3] rearrangement is again favored over 35 36 cyclopropanation, with the major product 25 isolated in 36% yield, 85:15 dr (anti :syn ), and 37 38 an impressive 98% ee. In this case the major diastereoisomer formed is opposite to that 39 40 41 preferentially formed using the achiral rhodium catalyst. The catalyst dependent 42 43 diastereoselectivity observed suggests a metal associated ylide is involved in the product 44 45 forming step of these reactions. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 8 Page 9 of 88 ACS Catalysis
1 2 3 a) O 4 O Rh 2(OAc) 4 O Ph 5 (1 mol%) Ph Ph 6 EtO + MeO Ph EtO + CH 2Cl 2, rt 7 N2 21 OMe 8 20 (2 eq) 22 73:27 MeO 9 92% 22 :23 23 10 83:17 dr syn :anti 11 b) 12 Rh (4 S-MEOX) O 13 O 2 4 O Ph (1 mol%) 14 EtO + MeO Ph EtO + Ph Ph 15 CH 2Cl 2, rt N OMe 16 2 21 O MeO 17 20 (2 eq) 25 89:11 18 O NH 36% 25 :23 23 19 85:15 dr anti :syn 20 CO 2Me 98% ee 21 4S-MEOX-H (24 ) 22 Scheme 6. a) Diastereoselective intermolecular oxonium ylide formation and [2,3] rearrangement. b) 23 Enantioselective version using oxazolidin 2 one 24 as a ligand 24 25 26 Quinn and co workers reported the copper catalyzed reaction of diazoacetate 26 with C 2 27 28 29 symmetric vinyl epoxide 27 to give the ring expanded cis dihydropyran 28 in good yield as a 30 9 31 single diastereoisomer (Scheme 7). However, the process was limited to symmetric epoxide 32 33 27 , with other substituted vinyl epoxides giving low yields and poor selectivity towards the 34 35 desired [2,3] rearrangement pathway. 36 37 38 39 40 41 42 43 44 45 46 Scheme 7. Copper catalyzed ring expansion of vinyl epoxide 27 47 48 49 Njardarson and co workers showed that copper carbenoids generated from the decomposition 50 51 of diazoacetophenone 29 undergo oxonium ylide formation and [2,3] rearrangement with a 52 53 10 54 variety of substituted allylic ethers. For example, reaction with symmetrical allylic ether 30 55 56 forms product 31 in good yield and high diastereoselectivity, with subsequent ring closing 57 58 metathesis of 31 using Grubbs II catalyst giving pyran 32 in high yield (Scheme 8a). The 59 60 ACS Paragon Plus Environment 9 ACS Catalysis Page 10 of 88
1 2 3 reaction of 29 with unsymmetrical allylic ether (E) 33 followed by deprotection of the [2,3] 4 5 rearrangement product 34 with BF 3·Et 2O gave α hydroxy ketone 35 with high levels of 6 7 diastereoselectivity (Scheme 8b). This process is stereospecific, with ( Z) allylic ether 36 8 9 10 reacting to give the corresponding syn product 37 with reasonable levels of 11 12 diastereoselectivity (Scheme 8c). 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 Scheme 8. Diastereoselective reaction of diazoacetophenone 29 with functionalized allylic ethers 42 43 44 In 2009, Davies and co workers reported a highly enantioselective oxonium ylide generation 45 46 47 [2,3] rearrangement of racemic allylic alcohols with donor acceptor diazo compounds using a
48 11 49 chiral rhodium catalyst. The substitution pattern of the allylic alcohol is key to determining 50 51 the chemoselectivity of the reaction. For example, reacting diazo compound 38 with primary 52 53 allylic alcohol 39 exclusively formed O H insertion product 43 , whereas the reaction with 54 55 secondary allylic alcohol 40 selectively gave [2,3] rearrangement product 42 in good yield 56 57 58 and excellent enantioselectivity (Scheme 9a). This trend was general for a range of substrates, 59 60 ACS Paragon Plus Environment 10 Page 11 of 88 ACS Catalysis
1 2 3 with various substituted secondary and tertiary allylic alcohols reacting to give [2,3] 4 5 rearrangement products with high levels of chemo and enantioselectivity. The 6 7 enantioselectivity of the process is derived purely from the chiral ligand 41 as racemic, ( R) 8 9 10 and ( S) allylic alcohol 40 all react with methyl 2 diazo 2 phenyl acetate 44 to give the same 11 12 absolute configuration of the corresponding [2,3] rearrangement product 45 (Scheme 9b). 13 14 15 a) Rh (S-DOSP) 16 OH 2 4 (1 mol%) 17 MeO 2C Ph + MeO 2C + MeO 2C Ph R pentane, 0 °C R 18 OH 19 N2 39 , R = H O 20 38 (1.1 eq) 40 , R = Me Ph O 42 43 R 21 N 22 a S OH R Yield (%) 42 :43 ee (%) 23 O H 74 >5:95 <5 24 O Me 66 94:6 98 25 C12 H25 26 (S)-DOSP (41 ) 27 28 b) Rh (S-DOSP) 29 OH 2 4 (1 mol%) 30 MeO 2C Ph + MeO 2C pentane, 0 °C 31 Ph OH 32 N2 40 45 33 44 (1.1 eq) 34 Yield (%) ee (%) a 35 ( )- 40 69 88 36 (S)- 40 (84% ee) 61 85 37 (R)- 40 (83% ee) 59 94 38 39 Scheme 9. Enantioselective [2,3] rearrangement reactions using racemic allylic alcohols. aee of major product 40 41 42 This methodology was extended to the enantioselective synthesis of products containing two 43 44 vicinal stereocenters. 12 The reaction is stereospecific with respect to the geometry of the 45 46 allylic alcohol, with ( E) 46 reacting with diazo compound 38 to give product 47 and ( Z) 48 47 48 49 reacting under the same conditions to give the opposite diastereoisomer 49 (Scheme 10). The 50 51 matched/mismatched effect between the allylic alcohol configuration and chiral catalyst was 52 53 much more significant for ( Z) allylic alcohol 48 with the reaction using ( S) DOSP 41 as the 54 55 ligand leading to reduced yields and diastereoselectivity. Through judicious choice of alcohol 56 57 58 configuration, alkene geometry and chiral ligand used, all four possible stereoisomers of the 59 60 ACS Paragon Plus Environment 11 ACS Catalysis Page 12 of 88
1 2 3 [2,3] rearrangement products were accessible. The scope of the reaction has been fully 4 5 explored, with a number of α aryl and α alkenyl diazoacetates reacting with a wide variety of 6 7 substituted allylic alcohols to give the rearranged products in uniformly high yields and 8 9 10 excellent diastereo and enantioselectivity. The same catalytic system has been utilized in the 11 12 reaction of α aryl and α alkenyl diazoacetates with tertiary propargylic alcohols to form 13 14 substituted allenes in high enantioselectivity. 13 When racemic tertiary propargylic alcohols 15 16 were used, kinetic resolution was observed with the allene rearrangement products formed in 17 18 19 good dr and high ee and the unreacted propargylic alcohols recovered enantioenriched. A 20 21 silica supported version of Rh 2(S DOSP) 4 can also be used for the catalytic oxonium ylide 22 23 formation and [2,3] rearrangement reactions using both allylic alcohols and propargylic 24 25 alcohols, forming the corresponding products in good yields with enantioselectivity 26 27 comparable with those obtained in the homogeneous reactions. 14 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 Scheme 10 . Stereospecific [2,3] rearrangement of allylic alcohols 50 51 52 Davies and co workers have applied their methodology to the synthesis of highly 53 54 15 55 functionalized cyclopentanes through a complex domino reaction sequence. As previously, 56 57 reacting α alkenyl diazo compounds such as 38 with allylic alcohol 46 in the presence of a 58 59 60 ACS Paragon Plus Environment 12 Page 13 of 88 ACS Catalysis
1 2 3 chiral rhodium catalyst promotes oxonium ylide formation followed by enantioselective 4 5 [2,3] rearrangement. Heating product 47 in a sealed tube promotes an oxy Cope 6 7 rearrangement followed by tautomerization, and an intramolecular ene cyclization to form 8 9 10 substituted cyclopentane 51 containing four contiguous stereocenters in high diastereo and 11 12 enantioselectivity (Scheme 11a). Although racemic allylic alcohols can be utilized in this 13 14 reaction, higher enantioselectivity was obtained using enantiomerically pure allylic alcohols 15 16 and a matched chiral rhodium catalyst. 15b The process was applicable to a variety of 17 18 19 substituted allylic alcohols, forming functionalized cyclopentanes in high yields and excellent 20 21 diastereo and enantioselectivity in all cases. Introducing a C(3) methyl substituent onto the 22 23 allylic alcohol alters the reaction pathway, with a type II ene cyclization favored to form 24 25 cyclohexane products containing an exocyclic alkene substituent and four stereogenic 26 27 centres. 16 For example, the rhodium catalyzed reaction of 38 with allylic alcohol 52 followed 28 29 30 by heating in heptane results in the formation of substituted cyclohexane 53 in 67% yield as a 31 32 single diastereoisomer in 99% ee (Scheme 11b). This domino reaction sequence was 33 34 applicable to a range of α alkenyl diazo compounds and substituted allylic alcohols, forming 35 36 the products in excellent diastereo and enantioselectivity. Cyclic allylic alcohols, including a 37 38 39 monoterpenoid derived substrate, could also be utilized to generate a series of structurally 40 41 complex fused bicyclic products with high diastereoselectivity. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 13 ACS Catalysis Page 14 of 88
1 2 3 a) Rh (R-DOSP) (0.1 mol%) 4 OH 2 4 HO CaCl (2 eq) 5 MeO 2C Ph 2 + MeO 2C 6 heptane, 0 °C 7 N2 46 Oxonium ylide formation, 8 38 (1.2 eq) [2,3]-rearrangement Ph 9 47 10 125 °C [3,3] oxy-Cope, 11 tautomerisation 12 13 14 HO MeO C O MeO C 2 15 2 Ene cyclisation 16 17 Ph 18 Ph 50 19 51 20 71% 21 88:12 dr 22 91% ee 23 b) i) Rh (R-DOSP) (0.1 mol%) HO 24 OH 2 4 25 CaCl 2 (3 eq) MeO 2C MeO 2C Ph + 26 heptane, 0 °C N 27 2 ii) 120 °C Ph 28 38 (1.2 eq) 52 53 29 67% 30 31 >95:5 dr 32 99% ee 33 Scheme 11 . Domino reaction sequence for the synthesis of a) cyclopentanes and b) cyclohexanes 34 35 36 2.1.2 Diastereoselective intramolecular oxonium ylide formation and [2,3]- 37 38 rearrangement. The intramolecular generation and [2,3] rearrangement of oxonium ylides 39 40 41 from diazo compounds offers an efficient and potentially stereoselective route towards a 42 43 variety of highly functionalized oxocyclic products. The synthetic utility of these [2,3] 44 45 rearrangement products has been widely demonstrated through the synthesis of a variety of 46 47 complex natural products. 48 49 50 In 1986 Johnson 17 and Pirrung 18 independently reported the first examples of 51 52 diastereoselective catalytic generation and [2,3] rearrangement of oxonium ylides. For 53 54 55 example, treating allyloxy substituted diazoketone 54 with Rh 2(OAc) 4 (1 mol%) generates 56 57 oxonium ylide 55 in situ , which undergoes intramolecular [2,3] rearrangement to form 58 59 60 ACS Paragon Plus Environment 14 Page 15 of 88 ACS Catalysis
1 2 3 furanone 56 in 65% yield and excellent 93:7 dr (anti :syn ) (Scheme 12). Importantly, this class 4 5 of allyloxy diazoketones exhibited excellent chemoselectivity for [2,3] rearrangement over 6 7 potential [1,2] rearrangement under the reaction conditions. 8 9 10 11 O O O 12 N2 Rh 2(OAc) 4 (1 mol%) [2,3] 13 O C6H6, rt 14 O O 15 (±)- 54 56 16 55 65% 17 93:7 dr 18 19 Scheme 12. Rearrangement of oxonium ylide 55 generated from alkoxy substituted diazoketone 54 20 21 22 Pirrung and co workers subsequently utilized the catalytic oxonium ylide generation and 23 24 [2,3] rearrangement methodology in the first enantioselective total synthesis of the antifungal 25 26 agent (+) griseofulvin 59 .19 The key step within this sequence involves the diastereoselective 27 28 29 [2,3] rearrangement of the oxonium ylide generated from enantiomerically pure diazoketone 30 31 57 using Rh 2(piv) 4 (5 mol%) to form advanced intermediate 58 in 62% yield as a single 32 33 stereoisomer (Scheme 13). The reaction is also completely chemoselective, with no products 34 35 from potential competing o methoxy ylide formation or [1,2] rearrangement observed. 36 37 38 39 40 41 42 43 44 45 46 47 48 Scheme 13. Enantioselective synthesis of (+) griseofulvin 59 49 50 51 The concept of catalytic oxonium ylide formation and [2,3] rearrangement was further 52 53 54 explored by Clark in 1992 with the demonstration of an intramolecular Cu(acac) 2 catalyzed 55 56 tandem carbenoid insertion and [2,3] rearrangement process to form anti tetrahydrofuran 3 57 58 59 60 ACS Paragon Plus Environment 15 ACS Catalysis Page 16 of 88
1 2 3 ones in good yields with excellent levels of diastereoselectivity (Scheme 14). 20 In this case 4 5 catalytic Rh 2(OAc) 4 was ineffective, giving the products in modest yields with lower levels of 6 7 diastereoselectivity. 8 9 10 11 12 13 14 15 16 17 18 19 Scheme 14. Copper catalyzed generation and [2,3] rearrangement of oxonium ylides 20 21 22 Clark and co workers have subsequently used this synthetic procedure as a key step towards 23 24 the total synthesis of a wide variety of natural products. For example, the divergent synthesis 25 26 of three of the family of amphidinolide macrolide natural products utilizes the copper 27 28 catalyzed decomposition of diazoketone 63 and diastereoselective rearrangement of the 29 30 21 31 resulting oxonium ylide as a key step. Commercially available alcohol 62 is readily 32 33 converted in three steps into diazoketone 63 , which upon treatment with Cu(acac) 2 (10 mol%) 34 35 in THF at reflux undergoes a diastereoselective oxonium ylide formation and [2,3] 36 37 rearrangement to give dihydrofuranone 64 in 91% yield as a single diastereoisomer (Scheme 38 39 15a). Dihydrofuranone 64 serves as a common intermediate in the divergent total synthesis of 40 41 42 amphidinolides T1, T3 and T4 ( 65 67 ) (Scheme 15b). Analogous methodology has also been 43 44 used as the key step in the preparation of fragments of large natural products including the 45 22 23 24 46 amphidinolides, gambieric acid A, and cinatrin C 1. 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 16 Page 17 of 88 ACS Catalysis
1 2 3 a) 4 O OH O O 5 N 2 Cu(acac) 2 (10 mol%) OTBDPS 6 MeO THF, O 7 OTBDPS O 8 64 62 OTBDPS 9 63 91% 10 >98:2 dr 11 b) 12 OH OH O R2 13 1 14 R 15 H H 16 O O 17 H H 18 O O 19 20 O O 21 amphidinolide T1 65 amphidinolide T3 66 (R 1 = OH, R2 = H) 22 amphidinolide T4 67 (R1 = H, R2 = OH) 23 24 Scheme 15. Divergent total syntheses of amphidinolides T1, T3, and T4 (65 67 ) 25 26 27 Mechanistically, Clark found that the equilibrium between metal bound and free ylides in a 28 29 non stereoselective intramolecular oxonium ylide [2,3] rearrangement process is highly 30 31 dependent on both the catalyst and substrate. 25 For example, treating 13 C labelled α diazo β 32 33 34 keto ester 68 with various transition metal catalysts resulted in a variable mixture of [2,3] 35 36 rearrangement product 69 and formal [1,2] rearrangement product 70 (Scheme 16). The 37 38 catalyst dependent reaction outcome suggests this reaction may proceed via either a metal 39 40 bound ylide species or alternative non ylide pathways to give the formally rearranged 41 42 products. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 Scheme 16. Isotopic substitution suggests metal bound non ylide mechanistic pathways 58 59 60 ACS Paragon Plus Environment 17 ACS Catalysis Page 18 of 88
1 2 3 In 2008, Hodgson and co workers reported a tandem cross metathesis oxonium ylide 4 5 formation [2,3] rearrangement protocol for the diastereoselective synthesis of 6 7 dihydrofuranones, which was applied to the synthesis of anti HIV agent hyperolactone C. 26 8 9 10 Diazoketone 71 was treated with Grubbs II catalyst and methacrolein 72 to form 73 in situ , 11 12 catalytic Rh 2(OAc) 4 (4 mol%) was then added to promote diastereoselective oxonium ylide 13 14 formation and [2,3] rearrangement (Scheme 17). The resulting dihydrofuranone 74 was 15 16 immediately reduced with NaBH 3CN to form fused hemiketal 75 in 26% yield over the three 17 18 19 steps with good diastereocontrol. A further two steps finished the synthesis of the spirocyclic 20 21 hyperolactone C 76 . Hodgson subsequently reported an enantioselective synthesis of (−) 22 23 hyperolactone C 76 starting form enantiomerically pure diazoketone 71 .27 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 Scheme 17. Diastereoselective synthesis of (±) hyperolactone C 76 46 47 48 In 2014 Hodgson reported a new route to a small number of hyperolactone C analogues 49 50 through intramolecular oxonium ylide formation and [2,3] rearrangement of diazoacetals. For 51
52 example, treating diazoacetal 77 with Rh 2(tfa) 4 (1 mol%) forms bicyclic acetal 78 in 43% 53 54 yield as a single diastereoisomer (Scheme 18). 28 Acid catalyzed elimination of acetal 78 and 55 56 57 subsequent lactonization led to the formation of spirofuranone 79 in high yield. 58 59 60 ACS Paragon Plus Environment 18 Page 19 of 88 ACS Catalysis
1 2 3 4 5 6 7 8 9 10 11 12 13 Scheme 18 . Synthesis of (±) hyperolactone C analogue from diazoacetal 77 14 15 16 Clark and co workers have extended this methodology to the synthesis of tetrahydropyran 3 17 18 29 19 ones. Building on an earlier diastereoselective synthesis, the enantioselective synthesis of 20 21 the fungal metabolite (+) decarestrictine L 83 was reported starting from ethyl ( R) 3 22 30 23 hydroxybutyrate 80 . Treatment of enantiomerically pure diazoketone 81 with Cu(tfacac) 2 (2 24 25 mol%) gave tetrahydropyran 3 one 82 in 60% yield and 91:9 dr (Scheme 19). Four further 26 27 steps converted 82 into (+) decarestrictine L 83 in an overall 9% yield over ten steps. 28 29 30 31 32 33 34 35 36 37 38 Scheme 19. Enantioselective synthesis of (+) decarestrictine L 83 . tfacac = trifluoroacetylacetonate 39 40 41 A similar approach has been employed to synthesize a large number of structurally complex 42 43 44 diterpene marine natural products through formation of bicyclic allylic oxonium ylides 45 46 followed by diastereoselective [2,3] rearrangement. For example, the first total synthesis of 47 48 (±) vigulariol 87 , a member of the Cladiellin family possessing in vitro cytotoxic activity 49 50 against human lung cancer cells, utilized the copper catalyzed decomposition of diazo 51 52 31 53 intermediate 84 and [2,3] rearrangement of the resulting oxonium ylide (Scheme 20). The 54 55 bicyclic products (Z) 85 and (E) 86 were formed in 96% yield as an 83:17 mixture, with the 56 57 undesired ( E) 86 subsequently isomerized into ( Z) 85 using AIBN and ethanethiol. Related 58 59 60 ACS Paragon Plus Environment 19 ACS Catalysis Page 20 of 88
1 2 3 strategies using bicyclic oxonium ylides generated in the same way have been utilized in the 4 5 synthesis of a number of other natural products including other members of the Cladiellin 6 7 family of diterpenes, 32 sclerophytin F, 33 the tricyclic core of labiatin A and Australin A 34 , and 8 9 10 neoliacinic acid. 11 12 13 14 15 16 17 18 19 20 21 22 Scheme 20 . Synthesis of (±) vigulariol 87 23 24 25 26 In 2001 West and co workers reported a diastereoselective iterative synthesis of polypyran 27 35 28 scaffolds, which are common cores in polyether marine natural products. Treatment of 29 30 diazoketone 88 with Cu(tfacac) 2 (5 mol%) induced a diastereoselective oxonium ylide 31 32 formation [2,3] rearrangement process to give bicyclic ether 89 in good yield and high 33 34 diastereoselectivity (Scheme 21). Further manipulation of 89 into diazoketone 90 set up a 35 36 37 second copper catalyzed [2,3] rearrangement step to form polypyran fragment 91 in 80% 38 39 yield as a single diastereoisomer. 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 20 Page 21 of 88 ACS Catalysis
1 2 3 Scheme 21. Diastereoselective synthesis of polypyran motifs 4 5 6 Doyle and co workers found that competing [1,2] and [2,3] rearrangements were observed 7 8 when diazoacetate substituted tetrahydropyran 4 ones such as 92 undergo rhodium catalyzed 9 10 intramolecular oxonium ylide formation and rearrangement (Scheme 22). 36 The poor 11 12 13 selectivity observed for both rearrangement products 93 and 94 was independent of the 14 15 catalyst structure, suggesting these reactions proceed through a metal free ylide species. 16 17 Moreover the modest diastereoselectivity observed in each case reflects the axial equatorial 18 19 conformational isomer distribution of the reacting diazoacetate. 20 21 22 23 24 25 26 27 28 29 30 31 32 Scheme 22 . Competing [1,2] and [2,3] rearrangements 33 34 35 Tae and co workers have reported the use of alkynes as gold carbenoid precursors in 36 37 37 38 intramolecular oxonium ylide formations. Treating propargylic ethers 95 with a gold (I) 39 40 catalyst in the presence of stoichiometric oxidant 97 generates gold carbenoids 98 , which can 41 42 undergo intramolecular oxonium ylide formation and subsequent [2,3] rearrangement into 43 44 dihydrofuranone derivatives 99 in modest yields (Scheme 23). The diastereoselectivity of the 45 46 process was dependent on the nature of the propargylic substituent. Electron rich aryl (R = 4 47 48 49 MeOC 6H4) or heteroaryl (R = 2 furyl) groups gave the anti product exclusively, whereas 50 51 various alkyl substituents gave lower levels of diastereoselectivity (61:39 to 80:20 dr). Tang 52 53 and co workers have reported a related gold catalyzed rearrangement of benzannulated 54 55 propargylic ethers to form dihydrobenzofuranones under similar oxidative conditions. 38 56 57 58 Additionally, two diastereoselective examples utilizing carbocyclic aliphatic tethers were 59 60 ACS Paragon Plus Environment 21 ACS Catalysis Page 22 of 88
1 2 3 investigated, with the resulting fused bicyclic tetrahydrofuranones formed in good yields as 4 5 single diastereoisomers. 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Scheme 23. Alkynes as gold carbenoid precursors 23 24 25 Boyer has utilized N tosyl triazoles as alternatives to diazo compounds for the generation of 26 39 27 rhodium carbenoids. For example, treating 100 with catalytic Rh 2(OAc) 4 results in 28 29 decomposition of the triazole ring with release of nitrogen to form intermediate rhodium 30 31 carbenoid 101 . Subsequent in situ oxonium ylide formation and diastereoselective [2,3] 32 33 34 rearrangement followed by hydrolysis over basic alumina of the resultant N tosyl 35 36 dihydrofuran imine allowed isolation of dihydrofuranone ent 64 in 78% yield and >95:5 dr 37 38 (Scheme 24a). A range of C(5) alkyl substituents was tolerated in this process giving 39 40 dihydrofuranones in high yields and excellent dr, however incorporation of a C(5) phenyl 41 42 43 substituent gave the product in a reduced 83:17 dr. A small number of 2,2 disubstituted 44 45 dihydrofuran 3 ones could also be synthesized using an increased catalyst loading of 15 46 47 mol% Rh 2(OAc) 4, with the products formed in reasonable yields with high levels of 48 49 diastereoselectivity. This methodology was subsequently applied to the total synthesis of the 50 51 acetogenin (+) petromyroxol 104 .40 Treatment of enantiomerically pure triazole 102 under 52 53 54 the previously optimized conditions gave anti tetrahydrofuranone 103 as a single 55 56 57 58 59 60 ACS Paragon Plus Environment 22 Page 23 of 88 ACS Catalysis
1 2 3 diastereoisomer, which was converted into (+) petromyroxol 104 in four further steps 4 5 (Scheme 24b). 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 Scheme 24. a) Diastereoselective synthesis of dihydrofuran 3 imines from N tosyl 1,2,3 triazoles. b) 28 Application in natural product synthesis 29 30 31 A series of C(2) tetrasubstituted tetrahydrofurans was accessible through the rhodium 32 33 catalyzed decomposition of triazoles such as 105 (Scheme 25).41 As previously, the 34 35 intermediate N tosyl imine 106 was unstable to purification but was readily hydrolyzed into 36 37 38 aldehyde 107 in an overall 88% yield as a single diastereoisomer. The reaction tolerates a 39 40 range of functionalized C(5) alkyl substituents, forming the synthetically useful products in 41 42 high yields and excellent diastereoselectivity. The catalytic rearrangement of an O 43 44 propargylic triazole was also possible, with the corresponding allenyl tetrahydrofuran formed 45 46 47 in excellent yield but with a slightly reduced dr (6:1). 48 49 50 51 52 53 54 55 56 57 58 Scheme 25. Diastereoselective synthesis of C(2) tetrasubstituted saturated heterocycles 59 60 ACS Paragon Plus Environment 23 ACS Catalysis Page 24 of 88
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 24 Page 25 of 88 ACS Catalysis
1 2 3 2.1.3 Enantioselective intramolecular oxonium ylide formation and [2,3]- 4 5 rearrangement. In 1992 McKervey and McCann reported the first enantioselective 6 7 intramolecular [2,3] rearrangement of allylic oxonium ylides in which the stereochemistry is 8 9 42 10 derived from the catalyst. The catalytic decomposition of diazo compound 108 (R = Me) 11 12 using rhodium complexed with ( S) BNP 110 followed by oxonium ylide formation and [2,3] 13 14 rearrangement gave substituted benzofuranone 109 in 92% yield and 30% ee (Scheme 26). 15 16 Hodgson subsequently showed that alkyl substituted phosphate ligand 111 gave higher levels 17 18 43 19 of enantioselectivity, albeit in lower yield. Moody and co workers tested a range of pyrrole 20 21 2 carboxylate ligands with chiral N substituents in the same reaction, but only low levels of 22 23 enantioselectivity were observed. 44 An extensive study by McKervey and co workers 24 25 assessed a range of different chiral ligands in this process with ( S) PTTL 112 , derived from 26 27 (S) tert leucine, giving product 109 (R = H) in 96% yield and 60% ee. 45 Hashimoto and co 28 29 30 workers found that the enantioselectivity of the reaction using 112 could be improved by 31 32 performing the reaction in toluene at low temperature (–10 °C), although the product yield 33 34 was reduced (Scheme 26). 46 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 Scheme 26 . Enantioselective [2,3] rearrangement of oxonium ylides using chiral rhodium complexes 59 60 ACS Paragon Plus Environment 25 ACS Catalysis Page 26 of 88
1 2 3 Calter and Sugathapla reported that diazoacetal 113 reacted with the rhodium complex of 4 5 ligand 115 to give bicyclic tetrahydrofuran derivative 114 in 47% yield and 34% ee (Scheme 6 7 27). 47 Hashimoto and co workers later reported an improved variant of this reaction through 8 9 48 10 screening of a wide range of chiral carboxylate Rh(II) complexes. The optimal catalytic 11 12 system used fluorinated ligand 116 to form rearranged product 114 in 72% yield and an 13 14 impressive 93% ee. 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 Scheme 27 . Enantioselective synthesis of bicyclic tetrahydrofuran derivatives 35 36 37 Clark and co workers screened a number of C symmetric chiral diimines in the copper 38 2 39 40 catalyzed reaction of diazoketone 117 , with ligand 118 giving dihydrofuranone product 119 41 49 42 in 62% yield and reasonable 57% ee (Scheme 28). The substitution pattern around the 43 44 diazoketone had a large impact on the enantioselectivity observed. For example, introduction 45 46 of an α methyl substituent adjacent to the carbonyl had little effect, whereas placing a methyl 47 48 49 group in either the β position or the 2 position of the allyl group led to a dramatic drop in 50 51 enantioselectivity. Benzannulation of the substrate also led to reduced levels of 52 53 enantioselectivity in the resulting benzofuranone products. 54 55 56 57 58 59 60 ACS Paragon Plus Environment 26 Page 27 of 88 ACS Catalysis
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Scheme 28 . Copper catalyzed enantioselective intramolecular [2,3] rearrangement of 112 16 17 18 Doyle and co workers reported the enantioselective [2,3] rearrangement of a 13 membered 19 20 21 ring oxonium ylide formed from decomposition of diazo compound 120 in the presence of a 22 8,50 23 copper catalyst and BOX ligand 121 (Scheme 29). The reaction was selective for [2,3] 24 25 rearrangement over competing cyclopropanation (89:11 123 :122 ), allowing macrocyclic ether 26 27 123 to be isolated as a single diastereoisomer in 35% yield and 65% ee. The relative 28 29 stereochemistry was determined by analysis of γ lactone 124 , which was formed in excellent 30 31 32 yield upon hydrogenation of macrocycle 123 . 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 Scheme 29 . Enantioselective macrocyclic ether synthesis 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 27 ACS Catalysis Page 28 of 88
1 2 3 2.2 Ammonium ylides. 4 5 The [2,3] rearrangement of allylic ammonium ylides leads to the formation of substituted α 6 7 amino acid derivatives. Despite the huge synthetic potential of this process, the development 8 9 10 of a catalytic enantioselective variant using intermediate metal carbenoids has remained 11 12 elusive, with only diastereoselective examples reported to date. 13 14 15 2.2.1 Intermolecular ammonium ylide formation and [2,3]-rearrangement. In 1981 16 17 Doyle and co workers reported the first diastereoselective intermolecular ammonium ylide 18 19 formation and [2,3] rearrangement from the catalytic decomposition of a diazo compound. 51 20 21 22 Reacting ethyl diazoacetate 20 with Rh 2(OAc) 4 (0.5 mol%) and an excess of tertiary allylic 23 24 amine 125 gave rearranged α amino acid derivative 126 in 59% yield as a 75:25 mixture of 25 26 anti :syn diastereoisomers (Scheme 30). Che and co workers have performed a similar 27 28 reaction using a ruthenium porphyrin based catalyst, with the rearranged product being 29 30 obtained with same level of diastereoselectivity. 52 31 32 33 34 35 36 37 38 39 40 41 42 Scheme 30 . Intermolecular diastereoselective allylic ammonium ylide generation and [2,3] rearrangement 43 44 45 In 2003 Sweeney and co workers investigated the [2,3] rearrangement of ammonium ylides 46 47 128 generated from the reaction of tetrahydropyridine 127 and ethyl diazoacetate 20 (Scheme 48 53 49 31a). In this case, using Rh 2(OAc) 4 as the catalyst gave low yields and a complex mixture 50 51 of products. Copper catalysts were more selective, with Cu(acac) 2 (20 mol%) promoting 52 53 54 ammonium ylide formation and subsequent endo selective [2,3] rearrangement to give syn 55 56 pyrrolidine 129 in 59% yield as a single diastereoisomer. The use of α keto diazoacetates 57 58 such as 130 was also investigated in this process, forming functionalized pyrrolidine 131 59 60 ACS Paragon Plus Environment 28 Page 29 of 88 ACS Catalysis
1 2 3 containing a quaternary stereocenter in good yields with reasonable levels of 4 5 diastereoselectivity (Scheme 31b). 54 The use of a bicyclic tetrahydropyridine was also trialed, 6 7 but the desired bicyclic rearrangement product was only formed in low yields and the 8 9 10 stoichiometric base mediated rearrangement of the pre formed ammonium ylide was more 11 55 12 efficient in this case. 13 14 15 a) O 16 Cu(acac) 2 (20 mol%) + 17 EtO PhMe, N N N CO 2Et 18 N2 19 20 127 129 20 CO 2Et 59% 21 128 >95:5 dr 22 23 b) O O 24 Cu(acac) 2 (5 mol%) CO Et + 2 25 EtO i- Pr PhMe, i-Pr 26 N N N2 27 O 130 127 28 131 29 56% 30 75:25 dr 31 Scheme 31. Copper catalyzed synthesis of substituted pyrrolidines 32 33 34 2.2.2. Intramolecular ammonium ylide formation and [2,3]-rearrangement. In 1994 35 36 Clark and co workers reported the first diastereoselective [2,3] rearrangement of an 37 38 39 ammonium ylide generated from the intramolecular reaction of a metal carbenoid and an 40 56 41 cyclic allylic amine. Treating diazoketone 132 with Cu(acac) 2 (2 mol%) generated syn 42 43 ammonium ylide 133 , which underwent [2,3] rearrangement to give indolizidine 134 as a 44 45 single diastereoisomer. Upon treatment with silica gel indolizidine 134 underwent complete 46 47 48 epimerization into the opposite diastereoisomer 135 , which was isolated in 72% yield 49 50 (Scheme 32). This methodology was subsequently applied to the diastereoselective synthesis 51 52 of a small range of pyrrolizidine, indolizidine and quinolizidine motifs. 57 Acyclic substrates 53 54 containing a stereogenic center on the tether connecting the allylic amine and diazoketone 55 56 57 58 59 60 ACS Paragon Plus Environment 29 ACS Catalysis Page 30 of 88
1 2 3 also undergo metal catalyzed ylide formation and [2,3] rearrangement to form cyclic amine 4 5 products in good yields but with little diastereoselectivity. 58 6 7 8 9 10 11 12 13 14 15 16 17 Scheme 32 . Diastereoselective synthesis of indolizidines via intramolecular ylide generation and[2,3] 18 rearrangement 19 20 21 Clark and co workers applied intramolecular ammonium ylide formation and [2,3] 22 23 24 rearrangement to the asymmetric synthesis of the CE ring system of the manzamine and 25 57,59 26 ircinal families of marine alkaloids. Diazoketone 136 , prepared in four steps from ( S) 27 28 prolinol, was treated with Cu(acac) 2 (2 mol%) to form the bicyclic rearrangement product 29 ® 30 137 in 56% yield (Scheme 33). Diastereoselective reduction of ketone 137 with L Selectride 31 32 gave alcohol 138 in 75% yield and >98% ee, confirming essentially complete transfer of 33 34 35 stereochemistry during the [2,3] rearrangement of the intermediate spiro fused ammonium 36 37 ylide. 38 39 40 41 42 43 44 45 46 47 48 49 50 Scheme 33. Asymmetric synthesis of the CE ring system of the manzamine and ircianl alkaloids 51 52 53 McMills and co workers reported an analogous method for the synthesis of medium sized 54 55 azacane rings. 60 L Proline derived diazoketone 139 also undergoes ylide formation and [2,3] 56
57 rearrangement with transfer of stereochemistry in the presence of Cu(hfacac) 2 (15 mol%) to 58 59 60 ACS Paragon Plus Environment 30 Page 31 of 88 ACS Catalysis
1 2 3 form azacane 140 in 70% yield and 98% ee (Scheme 34). However, in this case competing 4 5 [1,2] Stevens rearrangement into bicycle 141 was also observed (70:30 140 :141 ), which is 6 7 attributed to the increased tether length of diazoketone 139 compared with 136 . 8 9 10 11 12 13 14 15 16 17 18 19 Scheme 34 . Catalytic asymmetric synthesis of medium sized azacane rings 20 21 22 Rowlands and Barnes have investigated the copper catalyzed aziridinium ylide generation 23 24 61 25 and [2,3] rearrangement of diazo compound 142 (Scheme 35). Treating 142 with catalytic 26 27 Cu(acac) 2 allowed indolizine 145 to be isolated in only 21% yield but as a single 28 29 diastereoisomer. The low yield is proposed to be partially due to the slow rate of inversion of 30 31 configuration at nitrogen in aziridines. Starting material 142 exists as a mixture of nitrogen 32 33 invertomers (43:57) that react to give intermediate aziridinium ylides 143 and 144 . In this 34 35 36 case, only ylide 143 derived from the minor N invertomer of 142 has the correct geometry to 37 38 undergo [2,3] rearrangement. 39 40 41 O Ph CO 2Et 42 CO 2Et 43 O 44 N N EtO 2C 45 Ph N2 Ph Ph 46 O 143 145 Ph Cu(acac) 2 (cat.) 47 + 21% MeCN, 48 N Ph >95:5 dr 49 50 Ph N 51 142 52 43:57 mixture Ph O CO Et 53 of N-invertomers 2 144 54 55 Scheme 35 . Copper catalyzed generation and rearrangement of aziridinium ylides 56 57 58 59 60 ACS Paragon Plus Environment 31 ACS Catalysis Page 32 of 88
1 2 3 2.3 Sulfonium ylides 4 5 The [2,3] rearrangement of sulfonium ylides, sometimes referred to as the Doyle Kirmse 6 7 reaction, generated from the reaction of a metal carbenoid with an allylic sulfide has been 8 9 widely studied. While high diastereo and/or ( E)/( Z) selectivity is attainable, the development 10 11 12 of catalytic enantioselective variants of this reaction is particularly challenging. This is due to 13 14 the fact that the catalyst must first distinguish between the heterotopic lone pairs of the sulfur 15 16 atom and then promote a selective [2,3] rearrangement reaction in which the stereochemical 17 18 information is efficiently transferred from sulfur to carbon. 62 19 20 21 2.3.1 Diastereoselective intermolecular sulfonium ylide formation and [2,3]- 22 23 24 rearrangement. One of the early examples of a stereoselective [2,3] rearrangement utilizing 25 63 26 the catalytic in situ formation of sulfonium ylides was reported by Grieco et al. in 1973. 27 28 Treating sulfide 147 with dimethyl diazomalonate 146 and catalytic CuSO 4 gave product 148 29 30 in 70% yield and an 90:10 E:Z isomeric ratio (Scheme 36). 31 32 33 34 35 36 37 38 39 40 Scheme 36. Copper catalyzed [2,3] rearrangement using diazomalonate 146 41 42 43 Yoshimoto and co workers demonstrated that cephalosporin derivatives such as 149 undergo 44 45 completely diastereoselective ring contraction into penicillin derivatives through the copper 46 47 catalyzed reaction with ethyl diazoacetate followed by [2,3] rearrangement (Scheme 37a). 64 48 49 50 Thomas and co workers subsequently utilized the diastereoselective [2,3] rearrangement of 51 52 sulfonium ylides to form a series of functionalized penicillanates. 65 For example, treating 53
54 diazopenicillanate 151 with allylic sulfide 152 and Cu(acac) 2 (11 mol%) resulted in formation 55 56 of 6,6 disubstituted penicillanate 153 in 65% yield and 87:13 dr (Scheme 37b). However, the 57 58 59 60 ACS Paragon Plus Environment 32 Page 33 of 88 ACS Catalysis
1 2 3 reaction using the corresponding allylic selenide under the same conditions resulted in 4 5 formation of the product with no diastereoselectivity. 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 Scheme 37 . a) Ring contraction of cephalosporin core into a penicillin derivative; b) Functionalization of 30 diazopenicillanates 151 31 32 33 Early attempts to utilize [2,3] rearrangements in ring expansion reactions, for example 34 35 copper bronze promoted decomposition of diazomalonate 146 followed by reaction with 36 37 cyclic sulfide 154 and subsequent [2,3] rearrangement, gave ring expanded product 155 in 38 39 66 40 53% yield (Scheme 38). However, subsequent attempts to explore the scope and utility of 41 42 such ring expansion processes have met with difficulties due to competing [1,2] 43 44 rearrangements and elimination reactions leading to mixtures of products. 67,68,69,70,71 45 46 47 48 49 50 51 52 53 54 55 56 Scheme 38. Ring expansion of cyclic sulfide 154 57 58 59 60 ACS Paragon Plus Environment 33 ACS Catalysis Page 34 of 88
1 2 3 Xu and co workers demonstrated that sulfonium ylides derived from the rhodium catalyzed 4 5 reaction between ethyl 2 diazo 3,3,3 trifluoropropanoate 156 and a wide range of allylic 6 7 sulfides undergo moderately diastereoselective [2,3] rearrangements to form synthetically 8 9 72 10 useful α trifluoromethyl esters in high yields (Scheme 39a). The scope of this process was 11 12 explored through the use of a wide range of functionalized allylic, propargyl, and allenyl 13 14 sulfides, forming the corresponding products in high yields in all cases, although only modest 15 16 levels of diastereoselectivity were obtained in most cases. The synthetic utility of the 17 18 19 products was demonstrated through conversion into trifluoromethyl substituted conjugated 20 21 dienes via oxidation of the sulfide with m CPBA followed by thermal elimination of the 22 23 resulting sulfoxide. This reaction sequence was successfully applied to a range of the 24 25 rearranged sulfide products and was further utilized in the synthesis of trifluoromethyl epoxy 26 27 retinal derivative 162 (Scheme 39b). Subsequent attempts to render this process 28 29 30 enantioselective by Müller and co workers through use of a chiral rhodium catalyst were 31 73 32 unsuccessful, with only low levels of enantioselectivity obtained for a range of catalysts. 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 34 Page 35 of 88 ACS Catalysis
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 Scheme 39 . [2,3] Rearrangement of sulfonium ylides generated from rhodium catalyzed decomposition of 156 . 34 Configuration of the major diastereoisomer is unreported 35 36 37 In 2009, Davies and co workers reported the first silver catalyzed reaction between ethyl 2 38 74 39 diazo 2 phenylacetate and various allylic and propargylic sulfides. A wide range of 40 41 rearranged products was obtained in good yields, although when a substituted cinnamyl 42 43 phenyl sulfide was used only low levels of diastereoselectivity were observed. 44 45 46 In 1999, Aggarwal and Van Vranken independently investigated the use of trimethylsilyl 47 48 75 49 diazomethane 163 as a sulfonium ylide precursor. Aggarwal and co workers used 50 51 Rh 2(OAc) 4 (1 mol%) to catalyze the reaction of trimethylsilyl diazomethane 163 with allylic 52 53 sulfide 164 with [2,3] rearrangement of the resulting sulfonium ylide forming syn product 54 55 165 in 90% yield and 90:10 dr (Scheme 40). 75a In this case an excess of 163 could be used 56 57 and, unlike with alternative carbonyl stabilized diazo compounds, slow addition was not 58 59 60 ACS Paragon Plus Environment 35 ACS Catalysis Page 36 of 88
1 2 3 required. The scope of the process was examined using a small range of differentially 4 5 substituted allylic sulfides, with the rearranged products formed in high yields with good 6 7 levels of diastereoselectivity in each case. The use of a variety of chiral rhodium or copper 8 9 10 catalysts in this process led to a decrease in diastereoselectivity and only low levels of 11 12 enantioselectivity were obtained in all cases (up to 18% ee). 13 14 15 16 17 18 19 20 21 22 23 Scheme 40 . Use of trimethylsilyl diazomethane 163 as a sulfonium ylide precursor 24 25 26 Van Vranken and co workers also investigated the use of both Rh 2(OAc) 4 and CuOTf as 27 28 catalysts for generation of sulfonium ylides through the decomposition of trimethylsilyl 29 75b 30 diazomethane 163 . In 2000, dppeFeCl 2 (5 mol%) was reported to effectively catalyze the 31 32 reaction between 163 and various allylic sulfides. For example, the reaction between 163 and 33 34 75c 35 cinnamyl phenyl sulfide 157 gave the rearranged product in 94% yield and 87:13 dr. This 36 37 methodology has been applied to the synthesis of the meroterpene natural product (±) 3 38 39 hydroxybakuchiol 168 (Scheme 41). 75d The iron catalyzed reaction of 163 with allylic sulfide 40 41 166 was performed on a multi gram scale to afford product 167 in 89% yield and 67:33, with 42 43 subsequent manipulation of the α silyl thioether functionality resulting in the first reported 44 45 46 synthesis of 168 . The use of various palladium catalysts has also been studied for the reaction 47 48 between trimethylsilyl diazomethane 163 and allylic sulfides, however the yields and 49 50 diastereoselectivity obtained are lower than those reported for the corresponding rhodium or 51 52 iron catalyzed processes. 76 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 36 Page 37 of 88 ACS Catalysis
1 2 3 4 5 6 7 8 9 10 11 12 Scheme 41 . Synthesis of (±) 3 hydroxybakuchiol 168 . The relative configuration of the major diastereoisomer 13 is unreported 14 15 16 A number of alternatives to highly reactive diazo compounds have been investigated as metal 17 18 19 carbenoid precursors for the formation of allylic sulfonium ylides. For example, triazoles act 20 21 as masked diazo compounds and react with allylic sulfides in the presence of a rhodium 22 23 catalyst. 77 The resulting sulfonium ylides undergo efficient [2,3] rearrangement to form 24 25 products in good yields, however the diastereoselectivity obtained with substituted allylic 26 27 28 sulfides is low. In 2015, Wang and co workers reported the use of highly strained 29 30 cyclopropenes 169 as rhodium carbenoid precursors that could be trapped with allylic 31 32 sulfides, with [2,3] rearrangement of the resulting sulfonium ylides leading to the isolated 33 34 products. 78 The reaction was demonstrated for a wide range of allyl sulfide substituents 35 36 including S aryl, heteroaryl, alkyl and allyl forming the rearranged products in excellent 37 38 39 yields. Unfortunately, when substituted allylic sulfides such as 157 were used, low levels of 40 41 diastereoselectivity were obtained although the yields remained high (Scheme 42). A range of 42 43 alternative substituted cyclopropenes was also explored as well as the use of propargylic 44 45 sulfides, but only modest levels of E:Z selectivity of the resulting allylic sulfides was 46 47 obtained in either case. Furthermore, attempts to perform the reaction enantioselectively 48 49 50 using a number of different chiral rhodium catalysts gave the rearranged products with only 51 52 moderate levels of enantioselectivity (up to 53% ee). 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 37 ACS Catalysis Page 38 of 88
1 2 3 Ph 4 Ph Rh 2(OAc) 4 (0.5 mol%) Ph + 5 Ph PhS Ph THF, 50 °C, 18 h 6 169 157 Ph SPh 7 (3 eq) 170 8 95% 9 68:32 dr 10 11 Scheme 42 . Use of cyclopropenes as rhodium carbenoid precursors. Configuration of the major diastereoisomer is unreported 12 13 14 Substituted alkynes have also been utilized as metal carbenoid precursors in catalytic [2,3] 15 16 17 rearrangements. Uemura and co workers have developed the rhodium catalyzed formation of 18 19 sulfonium ylides and subsequent [2,3] rearrangement starting from (2 furyl) carbenoid 20 21 precursors such as 171 and allylic sulfide 157 (Scheme 43). 79 The resulting substituted furan 22 23 172 is obtained in excellent yield as a single diastereoisomer, although the scope of this 24 25 26 process was only explored for two examples. 27 28 29 30 31 32 33 34 35 36 37 38 Scheme 43 . Use of substituted alkynes as rhodium carbenoid precursors. The relative configuration of the major diastereoisomer is unreported 39 40 41 Davies and co workers have reported the use of propargylic carboxylates as gold carbenoid 42 43 80 44 precursors. Treating propargylic acetate 173 with AuCl (5 mol%) in the presence of allylic 45 46 sulfide 152 led to the unexpected formation of ( Z) 175 in 82% yield, with none of the 47 48 expected [2,3] rearrangement product 174 observed (Scheme 44). It is proposed that [2,3] 49 50 rearrangement product 174 undergoes a Cope rearrangement into 175 , although an alternative 51 52 53 mechanistic pathway involving an oxygen assisted 1,4 shift followed by elimination of AuCl 54 55 could not be ruled out. The process is general for a range of aryl substituted propargyl 56 57 58 59 60 ACS Paragon Plus Environment 38 Page 39 of 88 ACS Catalysis
1 2 3 carbonates and aryl allylic sulfides, forming the (Z) isomers of the rearranged products in 4 5 high yields. 6 7 8 9 10 11 12 13 14 15 16 Scheme 44 . Gold catalyzed rearrangement of propargylic carboxylates 17 18 19 Building upon the initial work of Davies and co workers for a related intermolecular process 20 21 (vide infra ), 81 Zhang and co workers used a gold complex bearing sterically demanding 22 23 24 ligand 177 to form [2,3] rearrangement products such as 179 from the reaction of alkynes 25 82 26 with allyl sulfides in the presence of stoichiometric oxidant 178 (Scheme 45a). The process 27 28 works for a range of different substituted alkynes and allyl sulfides, forming the rearranged 29 30 products in high yields albeit with moderate diastereoselectivity when substituted allylic 31 32 33 sulfides were used. The proposed general mechanism for this process involves in situ 34 35 oxidation of allylic sulfide 157 with 178 to form allylic sulfoxide 181 , which can attack gold 36 37 activated alkyne 180 (Scheme 45b). The resulting intermediate 182 can decompose into gold 38 39 carbene 183 , which can recombine with released allylic sulfide 157 to form sulfonium ylide 40 41 184 that readily undergoes [2,3] rearrangement into the observed products. 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 39 ACS Catalysis Page 40 of 88
1 2 3 a) (177 )-AuCl (2 mol%) 4 O Ph NaB(3,5-(CF 3)2C6H3)4 (3 mol%) 5 + Ph PhS Ph 178 (1.3 eq) Ph 6 176 157 7 1,2-DCE, 60 °C, 10 h SPh (1.5 eq) 8 179 9 P(Ad) 2 84% 10 67:33 dr t-Bu 11 S N O 12 177 13 178 14 b) O 15 Ph 16 Ph 179 17 S Ph 176 18 Ph [Au] 184 19 20 21 [Au] [Au] 22 183 Ph 23 Ph O Ph 180 Ph 24 O 178 25 S S 157 26 Ph Ph 157 181 27 [Au] 28 Ph 29 Ph O 30 S Ph 31 182 32 33 Scheme 45 . Alkynes as metal carbenoid precursors 34 35 36 At the same time, Davies and co workers reported a similar process using substituted 37 38 ynamides as gold carbene precursors. 83 In this case pyridine N oxide 187 was utilized as the 39 40 stoichiometric oxidant alongside gold complexed with ligand 186 as the catalyst. The 41 42 43 reaction proceeds under mild conditions to form the rearranged products is reasonable yields 44 45 and importantly, unlike in many of the previously described cases, the reaction with 46 47 substituted allylic sulfide 157 was highly diastereoselective (Scheme 46). 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 40 Page 41 of 88 ACS Catalysis
1 2 3 4 5 6 7 8 9 10 11 12 13 14 Scheme 46 . Diastereoselective [2,3] rearrangement using ynamide 185 as a gold carbene precursor 15 16 17 2.3.2 Enantioselective intermolecular sulfonium ylide formation and [2,3]- 18 19 20 rearrangement. The first attempted enantioselective [2,3] rearrangement of a sulfonium 21 84 22 ylide was reported in 1995 by Uemura and co workers. The reaction between cinnamyl 23 24 phenyl sulfide 157 and ethyl diazoacetate 20 was trialed using both CuBOX complexes and 25 26 chiral rhodium catalysts, but in each case the rearranged product was formed with low levels 27 28 of diastereo and enantioselectivity. The effect of the sulfide substituent on the 29 30 31 enantioselectivity of this process was subsequently investigated by McMillen and co 32 33 workers. 85 The reaction between methyl diazoacetate 189 and various S substituted allylic 34 35 sulfides were studied using CuOTf (2 mol%) and BOX ligand 121 (2.1 mol%) as the catalytic 36 37 system (Scheme 47a). Increasing the steric demand of the S substituent increased the 38 39 40 enantioselectivity of the process. For example, small sulfide substituents such as methyl gave 41 42 no enantioselectivity whereas more sterically demanding 2,6 xylyl sulfide gave product 191 43 44 in 62% yield and 52% ee. The use of a (+) menthyl sulfide substituent as a chiral auxiliary in 45 46 combination with the chiral catalyst only gave a marginal increase in the enantioselectivity of 47 48 49 the process. Wang and co workers have also investigated the influence of the allylic S 50 51 substituent alongside various aryl substituted diazoacetates using the same CuBOX complex 52 53 as the catalyst (Scheme 47b). 86 In this case the best enantioselectivities were obtained using 54 55 2 tolyl allyl sulfide 193 , with the rearranged products formed in good yields and reasonable 56 57 enantioselectivity for a range of α aryl diazoacetates 192 . The highest enantioselectivity was 58 59 60 ACS Paragon Plus Environment 41 ACS Catalysis Page 42 of 88
1 2 3 obtained using methyl 1 naphthyldiazoacetate, forming the corresponding product in 66% 4 5 yield and 78% ee. 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Scheme 47 . Investigation of sulfide and diazoacetate substitution in enantioselective [2,3] rearrangements of 31 sulfonium ylides formed using BOX ligand 121 32 33 34 The scope of the reaction has been further extended to the rearrangement of sulfonium ylides 35 36 α 37 generated in situ from propargyl sulfides and aryl diazoacetates, with the products formed 38 39 with levels of selectivity comparable with the allylic substrates. 87 The rearrangement of 40 41 allenyl sulfides with a range of chiral rhodium and copper catalysts has also been studied, 42 43 with the products formed in generally good yields but with moderate levels of 44 45 88 46 enantioselectivity. These reactions have also been performed using water as the solvent 47 89 48 using chiral rhodium catalysts, although the enantioselectivities obtained were lower. 49 50 51 Rhodium and cobalt based catalysts have also been utilized in the enantioselective [2,3] 52 53 rearrangement of sulfonium ylides. Hashimoto and co workers used rhodium complexed with 54 55 ligand 196 as a catalyst for the rearrangement of sulfonium ylides generated from the reaction 56 57 90 58 of diazoacetates with allyl sulfides. Increasing the steric demand of the diazoester led to 59 60 ACS Paragon Plus Environment 42 Page 43 of 88 ACS Catalysis
1 2 3 higher levels of diastereo and enantioselectivity, for example reaction of 195 with cinnamyl 4 5 phenyl sulfide 157 gave product 197 in excellent 94:6 dr and 53% ee (Scheme 48a). Katsuki 6 7 and co workers used cobalt and salen ligand 198 to catalyze the reaction between t butyl 8 9 10 diazoacetate 26 and allylic sulfide 157 , forming product 199 in 85:15 dr and 64% ee for the 11 91 12 major anti diastereoisomer (Scheme 48b). Comparable levels of diastereo and 13 14 enantioselectivity were obtained in the reaction with a small range of substituted allylic 15 16 sulfides. The use of (–) menthyl diazoacetate to act as a chiral auxiliary alongside the cobalt 17 18 19 salen catalyst gave the rearranged products with increased diastereo and enantioselectivity. 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 Scheme 48 . a) rhodium and b) cobalt catalysts for the enantioselective rearrangement of sulfonium ylides 47 48 49 Wang and co workers have reported the most enantioselective variant of this reaction to date 50 51 92 52 using a series of diazo compounds bearing Oppolzer’s camphor sultam chiral auxiliary. The 53 54 reaction between the diazo compounds and an allylic sulfide is efficiently catalyzed by 55 56 copper bearing salen ligand 202 , with the resulting chiral sulfonium ylides undergoing highly 57 58 59 60 ACS Paragon Plus Environment 43 ACS Catalysis Page 44 of 88
1 2 3 stereoselective [2,3] rearrangements. For example, reaction of diazo compound 200 with 4 5 allylic sulfide 201 followed by reduction of rearranged product 203 with LiAlH 4 to remove 6 7 the chiral auxiliary gave alcohol 204 in 72% yield and 92% ee (Scheme 49a). The reaction 8 9 10 was applicable to α alkyl, alkenyl and aryl substituted diazo compounds with the 11 12 corresponding alcohol products formed in high yields with good levels of enantioselectivity. 13 14 Attempts to improve the process through double asymmetric induction using a chiral salen 15 16 ligand in conjunction with the auxiliary did not offer any appreciable advantages in terms of 17 18 19 either yield or enantioselectivity. Moreover, using either enantiomer of a chiral salen ligand 20 21 in the reaction between 200 and 201 gave the same major enantiomer of alcohol 204 in 80% 22 23 ee in both cases, suggesting that the asymmetry of the process is induced solely by the chiral 24 25 auxiliary and that a ligand bound catalyst is not involved in the rearrangement step. The 26 27 28 scope of this process was further extended to the reaction of a range of chiral sultam 29 30 containing diazo compounds with propargyl sulfides, forming allenyl alcohols such as 206 in 31 32 good yields with high levels of enantioselectivity (Scheme 49b). 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 44 Page 45 of 88 ACS Catalysis
1 2 3 a) 4 O O Cl O O 5 O Cu(MeCN) 4PF 6 (20 mol%) O S Ph S 6 N 202 (22 mol%) N + S Ph S 7 N2 CH 2Cl 2, 0 °C, 10 h 8 201 9 200 (1.1 eq) Cl N N Cl Cl 10 203 11 Cl Cl LiAlH 12 4 202 13 THF 14 0 °C to rt 15 16 HO 17 Ph S 18 19 Cl 20 204 21 72% 22 92% ee 23 b) 24 O O Cl 25 O i) Cu(MeCN) 4PF 6 (20 mol%) S 26 N 202 (22 mol%) + S HO 27 N2 CH 2Cl 2, 0 °C, 15 min 28 S 205 ii) LiAlH 4, THF, 0 °C to rt 29 200 (1.1 eq) 30 Cl 31 206 32 88% 33 92% ee 34 Scheme 49 . Auxiliary controlled reactions of a) allylic and b) propargyl sulfides 35 36 37 Wee and co workers investigated the ability of remote stereocenters within the allylic sulfide 38 39 40 to influence the stereoselectivity in the rhodium catalyzed reaction with diazoacetates. 41 42 However, this approach proved to be challenging and only modest levels of enantioselectivity 43 44 were achieved. 93 45 46 47 2.3.3 Diastereoselective intramolecular sulfonium ylide formation and [2,3]- 48 49 rearrangement. Kido and co workers have extensively studied the intramolecular reaction of 50 51 52 allylic sulfides containing tethered stabilized diazo functionality for the diastereoselective 53 54 synthesis of substituted cyclic systems. Early examples made use of allylic sulfides such as 55 56 207 , which was synthesized by acylation of the corresponding alcohol with mono ethyl 57 58 59 60 ACS Paragon Plus Environment 45 ACS Catalysis Page 46 of 88
1 2 94 3 malonate followed by diazotization. Treating allylic sulfide 207 with Rh 2(OAc) 4 (1 mol%) 4 5 resulted in the intramolecular formation of eight membered cyclic sulfonium ylide 208 , 6 7 which then undergoes [2,3] rearrangement to form γ butyrolactone 209 in 70% yield as a 8 9 10 single diastereoisomer (Scheme 50). The same methodology was also applied to the synthesis 11 95,96 12 of related δ valerolactones, but the yields and diastereoselectivity were reduced. 13 14 However, further investigation found that increasing the complexity and substitution of the 15 16 substrates helped to improve the diastereoselectivity of δ lactone formation. For example, a 17 18 19 series of structurally complex polycyclic bridged δ lactones such as steroid derivative 211 20 97 21 were synthesized in high yields as single diastereoisomers (Scheme 51). Altering the tether 22 23 length in the system also allowed a small number of fused bicyclic seven membered lactones 24 25 to be synthesized with good levels of diastereoselectivity. 98 26 27 28 29 30 31 32 33 34 35 36 37 38 Scheme 50 . Intramolecular [2,3] rearrangement to form γ butyrolactones 39 40 41 OAc OAc 42 43 H H 44 O Rh (OAc) (1 mol%) 45 H H 2 4 H H EtO 2C C H , 46 O 6 6 47 N2 O SPh SPh 48 CO 2Et 210 49 O 50 211 51 78% 52 >95:5 dr 53 Scheme 51 . Synthesis of complex bicyclic δ lactones 54 55 56 57 58 59 60 ACS Paragon Plus Environment 46 Page 47 of 88 ACS Catalysis
1 2 3 The intramolecular [2,3] rearrangement of cyclic sulfonium ylides can also be used to 4 5 synthesize substituted cyclohexanone rings with high levels of diastereoselectivity. 99 The 6 7 method has been demonstrated for the synthesis of functionalized cyclohexanones such as 8 9 10 215 that may be of use for the synthesis of sesquiterpene natural products. They key diazo 11 12 tethered allylic sulfide 213 was synthesized through a multi step linear sequence starting 13 14 from ( R) (+) limonene 212 .99b Catalytic sulfonium ylide formation and [2,3] rearrangement 15 16 gave product 214 in 61% yield as a single diastereoisomer (Scheme 52). The phenyl sulfide 17 18 19 substituent within 214 could be removed using zinc powder in acetic acid and subsequent 20 21 decarboxylation gave substituted cyclohexanone 215 in 54% over the two steps. 22 23 Incorporation of a ring system within the tethered diazoallyl sulfide allows synthetically 24 25 useful cis fused bicyclic systems such as 217 to be synthesized in high yields with excellent 26 27 levels of diastereoselectivity (Scheme 52). 100 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 Scheme 52 . a) Synthesis of substituted cyclohexanone 215 staring from ( R) (+) limonene 212 . b) Synthesis of 53 cis fused bicyclic ring systems 54 55 56 57 58 59 60 ACS Paragon Plus Environment 47 ACS Catalysis Page 48 of 88
1 2 3 McMills and co workers have studied the intramolecular [2,3] rearrangements of sulfonium 4 5 ylides to form substituted pyrrolizine cores. 101 The reaction of ( Z) allylic sulfide 218 is 6 7 sensitive to both catalyst and solvent, with the direct cyclopropanation of the allylic system to 8 9 10 give 220 observed in many cases. However, treating (Z) 218 with catalytic rhodium 11 12 caprolactamate in fluorobenzene resulted in the highly chemo and diastereoselective 13 14 formation of syn pyrrolizine 219 in 60% yield (Scheme 53a). The reaction is stereospecific, 15 16 with ( E) allylic sulfide 221 undergoing catalytic sulfonium ylide formation followed by 17 18 19 rearrangement in benzene to give anti pyrrolizine 222 in 71% yield as a single 20 21 diastereoisomer (Scheme 53b). 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 Scheme 53 . Stereospecific synthesis of substituted pyrrolizine cores. Cap = caprolactamate 44 45 46 Kido and co workers showed that by altering the position of the allylic sulfide a 47 48 102 49 diastereoselective [2,3] rearrangement to form spirocyclic products is possible. This 50 51 method has been exemplified through the synthesis of the enantiomer of sesquiterpene natural 52 53 product (–) acorenone B ( ent 227 ). Starting from commercially available ( S) (–) 54 55 perillaldehyde 224 , key tethered diazoallylic sulfide 225 was synthesized over 15 steps. 56 57 Catalytic cyclic sulfonium ylide formation using Rh (OAc) (1 mol%) and [2,3] 58 2 4 59 60 ACS Paragon Plus Environment 48 Page 49 of 88 ACS Catalysis
1 2 3 rearrangement gave advanced intermediate 226 in 72% yield as a single diastereoisomer, with 4 5 only four further steps required to convert 226 into (+) acorenone B 227 (Scheme 54). 102b 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Scheme 54 . Synthesis of spirocyclic sesquiterpene (+) acorenone B 227 20 21 22 Davies and co workers have reported the use of tethered sulfoxides and alkynes as sulfonium 23 24 ylide precursors in the presence of either gold or platinum catalysts. 81 For example, allylic 25 26 27 sulfoxide 228 undergoes an internal redox reaction in the presence of PtCl 2 (10 mol%) to 28 29 form a sulfonium ylide, with subsequent [2,3] rearrangement forming product 229 in 60% 30 31 yield and 83:17 dr (Scheme 55). The scope of the reaction was demonstrated for a range of 32 33 substituted allylic sulfoxides, with the cyclic products generally formed in good yields under 34 35 36 either gold or platinum catalysis. The diastereoselectivity of the reaction was better with 37 38 terminal alkynes, with only moderate levels of diastereoselectivity obtained when substituted 39 40 alkynes were used. 41 42 43 44 45 46 47 48 49 50 51 Scheme 55 . Tethered sulfoxides and alkynes as sulfonium ylide precursors. The relative configuration of the 52 major diastereoisomer is unreported 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 49 ACS Catalysis Page 50 of 88
1 2 3 2.4 Halonium ylides 4 5 The reaction of metal carbenes with allyl halides and subsequent [2,3] rearrangement of the 6 7 resulting halonium ylides has been less widely studied and there are only a few reports of 8 9 stereoselective variants of this reaction. An early diastereoselective example of such a 10 11 12 process was reported in 1980 by Thomas and co workers. Catalytic decomposition of 13 14 diazopenicillanate 151 with Cu(acac) 2 (11 mol%) in the presence of excess allyl bromide 230 15 16 gave rearranged product 231 in 48% yield as a single diastereoisomer (Scheme 56), however 17 18 product 231 was unstable and more readily characterized after dehalogenation using tributyl 19 20 65 21 tin hydride. 22 23 24 25 26 27 28 29 30 31 32 33 34 35 Scheme 56 . Catalytic halonium ylide formation from diazopenicillanate 151 36 37 38 Doyle and co workers investigated the reaction of ethyl diazoacetate 20 with allyl halides
39 51 40 using rhodium based catalysts. The major reaction product obtained was dependent on the 41 42 allyl halide used. For example both allyl chloride and allyl bromide predominantly gave 43 44 cyclopropanation in the reaction with Rh 2(OAc) 4, whereas allyl iodide led to halonium ylide 45 46 formation and [2,3] rearrangement into 233 (Scheme 57). The reaction of ethyl diazoacetate 47 48 49 20 with crotyl bromide using either copper or rhodium catalysis led to a mixture of products 50 51 from [2,3] rearrangement, [1,2] rearrangement, and cyclopropanation and in all cases 52 53 essentially no diastereoselectivity was observed for the [2,3] rearrangement product. 54 55 56 57 58 59 60 ACS Paragon Plus Environment 50 Page 51 of 88 ACS Catalysis
1 2 3 4 5 6 7 8 9 10 11 12 13 Scheme 57 . Effect of the allyl halide on product selectivity in the reaction with ethyl diazoacetate 20 14 15 16 The reaction of ethyl diazoacetate 20 with substituted allyl bromide and chlorides has 17 18 103 19 subsequently been investigated using catalytic silver (I) complexes and ruthenium 20 104 21 porphyrin complexes. In these cases the desired [2,3] rearranged products were obtained in 22 23 high yields, but unfortunately the products were formed as a 50:50 mixture of 24 25 diastereoisomers in all cases. 26 27 28 In 1998, Doyle and co workers reported the first enantioselective halonium ylide 29 30 8 31 rearrangement. The reaction of ethyl diazoacetate 20 with allyl iodide 235 catalyzed by a 32 33 variety of chiral dirhodium carboxamides gave [2,3] rearrangement product 236 in low yields 34 35 and poor enantioselectivity, with products of carbene dimerization also observed in many 36 37 cases. However, use of catalytic copper complexed with BOX ligand 121 led to selective 38 39 [2,3] rearrangement, forming product 236 in 62% yield and a promising 69% ee (Scheme 40 41 42 58). 43 44 45 O Cu(MeCN) 4PF 6 (1 mol%) O 46 121 (1.2 mol%) + I 47 EtO CH 2Cl 2, EtO 48 N2 235 (4 eq) I 49 20 O O 236 50 62% 51 NN 69% ee 52 t-Bu t-Bu 53 121 54 Scheme 58 . First example of an enantioselective halonium rearrangement. The absolute configuration of the 55 product is unreported 56 57 58 59 60 ACS Paragon Plus Environment 51 ACS Catalysis Page 52 of 88
1 2 3 The use of dirhodium complexes with fluorinated chiral carboxamide ligands has also been 4 5 investigated in this process. 105 In this case, competing cyclopropanation was observed and the 6 7 [2,3] rearrangement product 236 was only obtained in modest yields with low levels of 8 9 10 enantioselectivity. 11 12 13 14 3. [2,3]-REARRANGEMENTS OF AMMONIUM YLIDES FROM ALLYLIC 15 16 QUATERNARY AMMONIUM SALTS 17 18 19 In 2011, Tambar and co workers reported an alternative strategy to avoid the use of diazo 20 106 21 compounds in catalytic [2,3] rearrangements of allylic ammonium ylides. The 22 23 methodology makes use of the palladium catalyzed allylic substitution of allylic carbonates 24 25 237 with tertiary amino esters 239 (Scheme 59a). The resulting quaternary ammonium salt 26 27 28 240 undergoes rapid deprotonation into ammonium ylides 241 and subsequent [2,3] 29 30 rearrangement to generate α amino ester products 242 . Optimization of the catalyst system 31 32 revealed that Pd 2dba 3·CHCl 3 in combination with electron deficient P(2 furyl) 3 ligand gave 33 34 the desired products in high yields with good levels of diastereoselectivity (Scheme 59b). The 35 36 reaction was applicable to a range of aryl, heteroaryl and alkyl substituted allylic carbonates 37 38 39 244 alongside various substituted α amino esters or α amino ketones to form the 40 41 corresponding anti [2,3] rearrangement products 245 in uniformly good yield and high 42 43 diastereoselectivity in most cases. The observed anti diastereoselectivity is proposed to be 44 45 due to an exo transition state during the [2,3] rearrangement step. α Amino sulfonimide 246 46 47 48 bearing Oppolzer’s camphor sultam auxiliary could also be utilized in this process, forming 49 50 enantiomerically enriched α amino acid derivatives such as 248 in excellent yield and high dr 51 52 (Scheme 59c). 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 52 Page 53 of 88 ACS Catalysis
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 Scheme 59. Palladium catalyzed allylic amination to form [2,3] rearrangement precursors 36 37 38 This methodology was subsequently applied to the formal total synthesis of the marine 39 40 107 41 alkaloid (±) amathaspiramide F ( 253 ). Reacting proline derivative 249 under the 42 43 previously optimized conditions with the allylic carbonate bearing the functionalized aryl 44 45 ring found within amathaspiramide F ( 253 ) unexpectedly led to the preferential formation of 46 47 undesired diastereoisomer 252 in 75% yield (Scheme 60). Further investigation on a 48 49 50 simplified system revealed that the presence of an ortho substituent within the aryl allylic 51 52 carbonate led to a significant reduction in previously observed anti diastereoselectivity. In 53 54 light of this, the synthetic route was modified and the key ammonium salt formation [2,3] 55 56 rearrangement step was performed using MOM protected aryl carbonate, resulting in 57 58 59 60 ACS Paragon Plus Environment 53 ACS Catalysis Page 54 of 88
1 2 3 preferential formation of the desired diastereoisomer 251 in 70% yield. Further manipulation 4 5 of 251 gave an advanced intermediate in the formal total synthesis of (±) amathaspiramide F 6 7 (253 ). Although proline ester 249 was enantiomerically pure, the resulting [2,3] 8 9 10 rearrangement products 251 and 252 were racemic showing that the stereochemical 11 12 information within 249 is lost during the allylic amination. 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 Scheme 60 . Switch in diastereoselectivity observed en route to the formal synthesis of (±) amathaspiramide F 35 (253 ) 36 37 38 Tambar and co workers reported the diastereoselective synthesis of cyclic α amino acid 39 40 derivatives through a tandem allylic amination [2,3] rearrangement followed by ring closing 41 42 metathesis. 108 For example, reacting homoallyl amino ester 254 with allylic carbonate 255 43 44 under the previously optimized conditions followed by ring closing metathesis of the 45 46 47 intermediate [2,3] rearrangement product using Hoveyda Grubbs II gave cyclic α amino acid 48 49 256 in 85% yield and 89:11 dr (Scheme 61). The methodology was applied to a range of aryl 50 51 and alkyl substituted allylic carbonates, forming the cyclic products in generally good yields 52 53 and high diastereoselectivity over the two steps. An enantiomerically pure cyclic α amino 54 55 56 acid was also accessible using a homoallyl α amino acid derivative bearing Oppolzer’s 57 58 camphorsultam auxiliary as the starting material. 59 60 ACS Paragon Plus Environment 54 Page 55 of 88 ACS Catalysis
1 2 3 4 5 6 7 8 9 10 11 12 Scheme 61 . Diastereoselective cyclic α amino ester synthesis. aCatalyst added in two portions 13 14 15 In 2014, Smith and co workers reported the first organocatalytic stereoselective [2,3] 16 17 rearrangement of allylic ammonium salts 259 , which were either isolated or made in situ 18 19 109 20 from p nitrophenyl bromoacetate 257 and an allylic amine 258 . Reacting allylic 21 22 ammonium salts 259 with the isothiourea catalyst ( R) BTM 260 (20 mol%) and HOBt (20 23 24 mol%) as a co catalyst in the presence of a mild base promoted a stereoselective [2,3] 25 26 rearrangement, with a nucleophilic quench giving syn α amino acid derivatives 261 in high 27 28 yield and excellent stereocontrol (Scheme 62a). The reaction scope was demonstrated for a 29 30 31 range of amine substituents and vinylic aryl groups alongside a number of different amine 32 33 and alcohol nucleophiles for the quench, giving access to functionalized α amino acid 34 35 derivatives with excellent diastereo and enantioselectivity. The proposed mechanism 36 37 involves N acylation of ( R) BTM 260 with allylic ammonium salt 259 to form dicationic 38 39 40 species 262 , with deprotonation forming ammonium ylide 263 (Scheme 62b). Stereoselective 41 42 [2,3] rearrangement of 263 generates acyl ammonium 264 , which can be intercepted by either 43 44 the HOBt 265 co catalyst to form 266 or directly by p nitrophenoxide to form ester 267 . 45 46 Nucleophilic quench of 267 displaces p nitrophenol to give readily isolable α amino acid 47 48 derivatives 261 . The high levels of stereocontrol observed can be rationalized by endo type 49 50 51 pre transition state assembly TS-263 (Scheme 62c). Stabilizing interactions between the lone 52 53 pair of the oxygen atom n o and the σ* C S help to lock the conformation of N acyl ammonium 54 55 263 , while the stereodirecting phenyl substituent adopts a pseudoaxial position to minimize 56 57 1,2 steric interactions. Rearrangement occurs preferentially opposite to the stereodirecting 58 59 60 ACS Paragon Plus Environment 55 ACS Catalysis Page 56 of 88
1 2 3 group, with a favorable π cation interaction been the allylic C(3) aryl substituent and the acyl 4 5 ammonium thought to be a requirement for high stereocontrol. 6 7 8 a) 9 O N 10 Ph Br 11 PNPO N S 12 257 O Br i) (R)-BTM 260 (20 mol%) O Ar 13 PNP = 4-NO C H Ar 2 6 4 MeCN PNPO HOBt (20 mol%) 14 + Nuc rt 1 N i- Pr 2NH (1.4 eq) 15 1 Ar R N R MeCN, –20 °C 16 R2 R1 R2 17 N ii) Nuc-H (excess) R2 259 261 18 258 (1.05 eq) up to 89% 19 up to >95:5 dr 20 up to >99% ee 21 22 b) 259 261 23 24 PNPO Nuc-H N 25 Ph LB 26 N O Ar N S Ar 27 N 260 (LB) O 28 N PNPO R1 N 29 OH N 265 R2 Br 262 30 R1 R2 31 267 32 PNPO N N Base 33 LB X N 34 O Ar X Ar 35 LB Ar O O N 36 R1 37 N O 2 1 2 R 38 R R N 263 39 266 R1 R2 40 264 c) Ar 41 H 42 N 43 N S 44 Ph O H 45 N R2 46 R1 47 TS-263 48 49 Scheme 62 . Organocatalytic stereoselective [2,3] rearrangement of allylic ammonium salts 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 56 Page 57 of 88 ACS Catalysis
1 2 3 4. [2,3]-REARRANGEMENT OF O-PROPARGYLIC OXIMES 4 5 Nakamura and co workers have extensively studied the transition metal catalyzed [2,3] 6 7 8 rearrangement of O propargylic oximes 268 (Scheme 63). The resulting N allenyl nitrones 9 10 269 undergo a variety of further transformations into different products depending on the 11 12 specific substrate utilized and the reaction conditions. N Allenyl nitrones had received little 13 14 attention previously due to their inherent instability, therefore in situ generation through 15 16 17 [2,3] rearrangement provides an effective method of investigating the reactivity of these 18 19 intermediates in a variety of cascade processes. Although the N allenyl nitrone intermediates 20 21 are formal [2,3] rearrangement products, it is possible that in many cases their formation 22 23 proceeds through alternative metal mediated pathways and therefore the reactions may not be 24 25 true pericyclic processes. 26 27 28 29 30 31 32 33 34 35 36 37 Scheme 63 . [2,3] Rearrangement of O propargylic oximes 38 39 4.1 Synthesis of pyridine N-oxides and four-membered cyclic nitrones 40 41 42 Nakamura and co workers first reported the copper catalyzed [2,3] rearrangement of ( E) O 43 44 propargylic α,β–unsaturated aldoximes such as 270 for the synthesis of pyridine N oxides 45 46 (Scheme 64a). 110 The initially formed [2,3] rearrangement product 271 undergoes a 6π 47 48 electrocylization followed by tautomerization to form pyridine N oxide 272 in 70% yield. 49 50 However, the reaction of ( Z) 273 gave cyclic nitrone 275 in 84% yield and excellent E:Z 51 52 53 selectivity, with intermediate 274 undergoing preferential 4π electrocyclization followed by 54 55 isomerization via an allyl cation into the observed product (Scheme 64b). Nitrone 275 could 56 57 58 59 60 ACS Paragon Plus Environment 57 ACS Catalysis Page 58 of 88
1 2 3 also be thermally isomerized into a 2,3,6 trisubstituted pyridine N oxide by heating in DMF 4 5 at 180 °C. 111 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 Scheme 64 . Differential reactivity of ( E) 270 and ( Z) 273 30 31 32 The stereoselective formation of cyclic nitrones was subsequently studied in more detail 33 34 using aryl aldoximes. 112 Reacting oxime 276 with [CuCl(cod)] (5 mol%) in MeCN at 70 °C 35 2 36 37 led to the regioselective formation of nitrone 277 in 86% yield as a 73:27 E:Z mixture 38 39 (Scheme 65). In this case the E:Z geometry of the aldoxime was not important, with both 40 41 reacting to give nitrone 277 with similar levels of selectivity. The reaction was applicable to a 42 43 range of propargylic aryl and alkyl substituents, forming the corresponding nitrones in high 44 45 46 yields and with reasonable E:Z selectivity obtained in most cases. Mechanistically, the copper 47 48 is thought to activate the alkyne towards [2,3] rearrangement, with the resulting N allenyl 49 50 nitrone undergoing a 4π electrocyclization into the observed product. At high temperature, 51 52 the minor ( Z) isomer of 277 can undergo thermal isomerization into both ( E) 277 and 53 54 regioisomer 278 whereas ( E) 277 is stable at high temperature. 55 56 57 58 59 60 ACS Paragon Plus Environment 58 Page 59 of 88 ACS Catalysis
1 2 3 4 5 6 7 8 9 10 11 12 13 14 Scheme 65 . Copper catalyzed rearrangement of O propargylic aryl aldoximes 15 16 17 Subsequently it was reported that the outcome of the reaction using alkyl propargylic 18 19 substituents is highly dependent on the electronic nature of the aryl oxime substituent 20 21 113 22 (Scheme 66). For example, reacting ( E) oxime 279 bearing an electron deficient 3,5 23 24 Br 2C6H3 substituent with CuCl (10 mol%) led to exclusive formation of cyclic nitrone 280 . 25 26 However, 4 ClC 6H3 substituted oxime 279 gave a 60:30 mixture of nitrone 280 and 27 28 amidodiene 281 and introduction of a strongly electron donating 4 Me 2NC 6H4 group led to 29 30 selective formation of the corresponding amidodiene 281 in 87% yield. This process was 31 32 33 general for electron rich aryl oxime substituents and could tolerate various propargylic alkyl 34 35 groups, forming amidodiene products with high levels of selectivity in good yield. It is 36 37 postulated that the presence of an electron rich aryl oxime substituent alters the mechanism 38 39 of the reaction after the copper catalyzed rearrangement of the O propargylic oxime. In this 40 41 42 case, the N allenyl nitrone intermediate is thought to undergo selective oxaziridine formation 43 44 instead of 4π electrocyclization. A 1,2 hydrogen shift followed by copper catalyzed 45 46 isomerization of the allene leads to the observed amidodiene products. 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 59 ACS Catalysis Page 60 of 88
1 2 3 H Ar O 4 5 N Ar O O CuCl (10 mol%) N HN Ar 6 + Ph MeCN, 100 °C Ph 7 8 Ph 9 OMe 280 281 10 OMe OMe 11 (E)- 279 12 Ar 280 (%) 281 (%) 13 3,5-Br 2C6H3 68 <1 14 4-ClC 6H4 60 30 15 4-Me 2NC 6H4 <1 87 16 17 Scheme 66 . Effect of the aryl oxime substituent on the rearrangement 18 19 20 4.2 Synthesis of seven- and eight-membered rings 21 22 Nakamura and co workers further explored the utility of O propargylic oximes in tandem 23 24 rhodium catalyzed [2,3] rearrangement heterocyclization processes to form azepine and 25 26 azocine N oxide derivatives. For example, treating ( Z) O propargylic 27 28 cyclopropylcarbaldoxime 282 with [RhCl(cod)] (2.5 mol%) and sodium 29 2 30 31 diphenylphosphinobenzene 3 sulfonate (tppms, 18 mol%) gave ( Z) azepine N oxide 283 in 32 114 33 92% yield (Scheme 67a). Water soluble tppms was used as the ligand to avoid difficulties 34 35 encountered in separating 283 from triphenylphosphine oxide. The reaction works well for a 36 37 range of aryl substituents, but the presence of alkyl substituents on either the propargylic 38 39 40 carbon or the alkyne led to longer reaction times and lower yields. The rhodium catalyzed 41 42 rearrangement of the corresponding ( E) O propargylic cyclopropylcarbaldoximes exclusively 43 44 gave the ( Z) azepine N oxide products. However, the reactions using ( E) oximes were much 45 46 more sensitive to the amount of ligand used and generally gave lower yields than the reaction 47 48 using the corresponding ( Z) oxime. 49 50 51 This methodology was extended to the synthesis of azocine N oxides using ( E) O propargylic 52 53 115 54 cyclobutylcarbaldoxime as substrates. For example, the rhodium catalyzed reaction of ( E) 55 56 284 gave ( Z) azocine N oxide 285 in 93% yield with complete control of the alkene geometry 57 58 59 60 ACS Paragon Plus Environment 60 Page 61 of 88 ACS Catalysis
1 2 3 (Scheme 67b). A number of aryl substituents was tolerated in this process, but propargylic 4 5 alkyl substituents gave the products in lower yields and the use of a terminal alkyne gave a 6 7 complex mixture. The tandem [2,3] rearrangement metallacyclization of enantiomerically 8 9 10 pure ( E) oxime 286 gave ( Z) azocine N oxide 287 in 87% yield and 74% ee, showing 11 12 reasonably high levels of chirality transfer through the axially chiral N allenyl nitrone 13 14 intermediate (Scheme 67c). 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 Scheme 67 . [2.3] Rearrangement of a) O propargylic cyclopropyl and b) cyclobutylcarbaldoximes. c) Chirality 49 transfer in the [2,3] rearrangement of cyclobutylcarbaldoximes. The absolute configuration of the major 50 enantiomer of 287 was unreported. tppms = sodium diphenylphosphinobenzene 3 sulfonate 51 52 53 A simplified mechanistic proposal for the tandem [2,3] rearrangement heterocyclization 54 55 reaction is shown in Scheme 68.114 115 Coordination of the rhodium catalyst to ( Z) O 56 57 propargylic oxime 282 promotes rearrangement into η 4 coordinated N allenyl nitrone 289 . 58 59 60 ACS Paragon Plus Environment 61 ACS Catalysis Page 62 of 88
1 2 3 While this step represents a formal [2,3] rearrangement, it may proceed stepwise via a cyclic 4 5 vinyl rhodium species. Metallacyclization of 289 gives aza rhodacycle 290 , which undergoes 6 7 ring expansion through cleavage of the least hindered cyclopropane bond to form eight 8 9 10 membered aza rhodacyclic 291 , with subsequent reductive elimination of the rhodium giving 11 12 product 283 . 13 14 15 283 16 282 Rh I 17 H O Ph 18 Ph N N 19 O 20 288 Rh III 21 Ph 22 291 Ph 23 Ring Rh I 24 expansion 25 [2,3] 26 27 O 28 N Rh III O 29 I N 30 Ph Rh 31 290 • Ph Ph 32 Metalla- Ph 289 33 cyclization 34 35 Scheme 68 . Proposed mechanism for the tandem [2,3] rearrangement and heterocyclization of 282 36 37 38 Alternative cascade processes using the N allenyl nitrone intermediates generated from [2,3] 39 40 rearrangement of O propargylic aldoxmines as a 1,3 dipolar reagents have also been 41 42 investigated. 116 Treating ( Z) O propargylic aldoxime 292 and N phenylmaleimide 293 with 43 44 [CuCl(cod)] 2 (5 mol%) promotes a cascade sequence involving [2,3] rearrangement, [3+2] 45 46 cycloaddition, and [1,3] oxygen migration to form oxazepine derivative 294 in 71% yield as 47 48 49 a single diastereoisomer (Scheme 69). The [3+2] cycloaddition between the intermediate 50 51 nitrone and N phenylmaleimide 293 is thought to be highly exo selective, accounting for the 52 53 high levels of diastereoselectivity. The reaction scope was demonstrated for various aryl and 54 55 alkyl substituted O propargylic formaldoximes, giving the oxazepine products in good yields. 56 57 58 59 60 ACS Paragon Plus Environment 62 Page 63 of 88 ACS Catalysis
1 2 3 Alternative dipolarophiles including various N substituted maleimides and fumaric acid 4 5 esters were also tolerated. 6 7 8 F3C 9 10 F3C 11 H 12 O O H 13 N N [CuCl(cod)] 2 (5 mol%) 14 O + NPh PhN Ph MeCN, 50 °C 15 Ph O 16 O O H Ph 17 Ph (Z)- 292 293 (5 eq) 294 18 71% 19 >95:5 dr 20 21 Scheme 69 . Copper catalyzed cascade to form substituted oxazepines 22 23 24 5. [2,3]-REARRANGEMENT OF ALLYLIC SULFOXIDES, SELENOXIDES, 25 26 SULFIMIDES, AND N-OXIDES 27 28 29 5.1 Catalytic [2,3]-Rearrangement of Allylic Sulfoxides and Selenoxides 30 31 The [2,3] rearrangement of allylic sulfoxides (Mislow Evans rearrangement) into allylic 32 33 alcohols has found a number of uses in organic synthesis. The reaction is stereospecific as 34 35 any stereochemistry on sulfur can be transferred onto carbon during the rearrangement. 3 36 37 38 Given the potential synthetic utility of this reaction, it is perhaps surprising that relatively few 39 40 stereoselective catalytic procedures have been developed. 41 42 43 Hilvert and co workers reported one of the first stereoselective catalytic [2,3] rearrangements 44 45 of a single allylic sulfoxide using catalytic antibodies. Although significant rate enhancement 46 47 over the background rearrangement was observed, the resulting allylic alcohol was only 48 49 obtained in modest enantioselectivity (40% ee). 117 50 51 52 Hagiwara and co workers reported a tandem Knovenagel condensation [2,3] rearrangement 53 54 118 55 reaction catalyzed by silica supported nitrogen base 297 (50 mol%). The catalytic 56 57 Knovenagel reaction between a range of substituted aldehydes and aryl sulfinylacetonitrile 58 59 60 ACS Paragon Plus Environment 63 ACS Catalysis Page 64 of 88
1 2 3 296 gave intermediate 298 , which underwent isomerization into an allylic sulfoxide followed 4 5 by [2,3] rearrangement under the reaction conditions. Addition of diethylamine promoted 6 7 hydrolysis of the resulting sulfinate ester into allylic alcohol 299 (Scheme 70). A range of 8 9 10 substituted aldehydes could be used, selectively forming the ( E) allylic alcohol products in 11 12 reasonable yields with excellent E:Z selectivity. When ( R) (+) citronellal was used the 13 14 resulting allylic alcohol was formed in 50:50 dr, with the stereocenter within the aldehyde 15 16 having no influence on the diastereoselectivity of the [2,3] rearrangement. 17 18 19 20 21 22 23 24 25 26 27 28 29 Scheme 70 . Tandem Knovenagel condensation [2,3] rearrangement promoted by silica supported base 297 30 31 32 Miura and co workers have reported a stereoselective organocatalytic [2,3] rearrangement of 33 34 119 35 α sulfinyl enones. Treating enantiomerically pure enone 300 with catalytic DBU (10 36 37 mol%) in the presence of an excess of triphenyl phosphine promotes isomerization into an 38 39 allylic sulfoxide, which spontaneously undergoes a stereoselective [2,3] rearrangement. 40 41 Quenching the reaction with aqueous hydrogen peroxide to hydrolyze the initially formed 42 43 44 sulfinyl ester was optimal, forming allylic alcohol 301 in 77% yield and 99% ee (Scheme 71). 45 46 The reaction was applicable to a range of alkyl and aryl substituted enones, with the allylic 47 48 alcohol products formed in good yield. In the majority of cases the configuration of the 49 50 enantiomerically enriched α sulfinyl enone was efficiently transferred into the corresponding 51 52 53 allylic alcohol. 54 55 56 57 58 59 60 ACS Paragon Plus Environment 64 Page 65 of 88 ACS Catalysis
1 2 3 4 5 6 7 8 9 10 11 Scheme 71 . Organocatalytic [2,3] rearrangement of α sulfinyl enones. DBU = 1,8 diazabicyclo[5.4.0] undec 7 12 ene 13 14 15 Diastereoselective allylic oxidation reactions using selenium dioxide (Riley oxidation) have 16 17 also been utilized in organic synthesis, for example in one of the final steps in Corey’s first 18 19 120 20 total synthesis of Miroestrol. The oxidation can be rendered catalytic in SeO 2 by using an 21 22 excess of a suitable oxidant, such as hydrogen peroxide. The reaction is thought to proceed 23 24 through an ene reaction between the allylic system and SeO 2, followed by [2,3] 25 26 rearrangement of the intermediate seleninic acid 303 (Scheme 72). 27 28 29 30 31 32 33 34 35 Scheme 72 . Allylic oxidation using selenium dioxide 36 37 38 Paquette and Lobben used a catalytic diastereoselective Riley oxidation in the synthesis of 39 40 cyclohexanone 308 , which was used as a substrate for investigating the facial selectivity of 41 42 indium promoted allylations of various 2 hydroxycyclohexanone (Scheme 73).121 Treating 43 44 45 exo methylenecyclohexane 306 with catalytic SeO 2 (5 mol%) and an equivalent of t butyl 46 47 hydroperoxide gave allylic alcohol 307 in 75% yield as a single diastereoisomer. 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 65 ACS Catalysis Page 66 of 88
1 2 3 Scheme 73 . Catalytic diastereoselective Riley oxidation 4 5 6 Carter and co workers reported the first catalytic oxidation of prochiral allylic selenides and 7 8 tandem [2,3] rearrangement. 122 Vanadyl acetylacetonate (10 mol%) in the presence of 9 10 cumene hydroperoxide 310 promoted the tandem oxidation and [2,3] rearrangement of a 11 12 13 small range of allylic selenides. Addition of tributyl phosphine efficiently cleaved the initially 14 15 formed selenate to give a range of allylic alcohols in good yield. However, initial attempts to 16 17 perform the reaction stereoselectivity by introducing a remote stereocenter were 18 19 unsuccessful, with allylic selenide 309 reacting to give allylic alcohol 311 as a mixture of 20 21 diastereoisomers (Scheme 74a). Further attempts to induce stereochemical control over this 22 23 123 24 tandem process using chiral ligands for the vanadium were also unsuccessful. However, 25 26 introduction of an oxazole based auxiliary onto allylic selenide 312 resulted in a more 27 28 diastereoselective rearrangement, with allylic alcohol 313 obtained in good enantioselectivity 29 30 after cleavage of the selenate (Scheme 74b). 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 Scheme 74 . Vanadium catalyzed tandem oxidation and [2,3] rearrangement 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 66 Page 67 of 88 ACS Catalysis
1 2 3 5.2 Catalytic [2,3]-Rearrangement of Allylic Sulfimides 4 5 Sharpless first reported that sulfur diimide species react with alkenes in a similar way to 6 7 selenium dioxide, undergoing an ene reaction into an intermediate sulfimide (the nitrogen 8 9 analogue of a sulfoxide) followed by [2,3] rearrangement into an allylic amine. 124 For many 10 11 12 years this process was thought to be incompatible with enantioselective catalysis due to the 13 14 facile nature of the thermal [2,3] rearrangement of sulfimides without a catalyst. 3 15 16 17 However, in 1996 Uemura and co workers reported the first enantioselective copper 18 19 catalyzed sulfimidation using N tosyliminobenzyliodinane 314 as a nitrene source. 125 20 21 Applying these conditions to allylic sulfides resulted in sulfimidation followed by [2,3] 22 23 24 rearrangement to afford sulfonamides, with no competing aziridination observed. For 25 26 example, treating allylic sulfide 315 with 314 in the presence of CuOTf (5 mol%) and BOX 27 28 ligand 316 (6 mol%) gave sulfonamide 317 in 80% yield and 58% ee (Scheme 75). This 29 30 methodology was applied to a small range of substituted allylic sulfides, with the 31 32 corresponding sulfonamides formed in only moderate yields and low enantioselectivity. The 33 34 35 same conditions were also applied to the catalytic [2,3] rearrangement of allylic selenides, 36 37 but lower levels of enantioselectivity were obtained. 126 38 39 40 41 42 43 44 45 46 47 48 49 50 Scheme 75 . Enantioselective sulfimidation followed by [2,3] rearrangement. Configuration of the major 51 enantiomer is unreported 52 53 54 Bolm and co workers subsequently reported an iron(III) PyBOX catalyst system for highly 55 56 enantioselective sulfimidation reactions. 127 A single example of enantioselective 57 58 59 60 ACS Paragon Plus Environment 67 ACS Catalysis Page 68 of 88
1 2 3 sulfimidation and subsequent [2,3] rearrangement was reported using allylic sulfide 318 4 5 (82:18 E:Z) and nitrene precursor 314 , forming sulfonamide 320 in 73% yield and 80% ee 6 7 (Scheme 76). 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Scheme 76 . Iron catalyzed sulfimidation and subsequent [2,3] rearrangement. Configuration of the major 24 enantiomer is unreported. dmhdCl = 4 chloro 2,6 dimethyl 3,5 heptanedionate 25 26 27 Katsuki and co workers reported the ruthenium catalyzed tandem sulfimidation and [2,3] 28 29 rearrangement of allylic sulfides with tosyl azide 321 .128 The initially formed sulfonamides 30 31 were conveniently hydrolyzed into N Ts allyl amines using potassium hydroxide. For 32 33 34 example, reacting allylic sulfide 318 with tosyl azide 321 in the presence of ruthenium salen 35 36 complex 322 (2 mol%) gave sulfonamide 323 , which was immediately hydrolyzed to give 37 38 324 in an overall 82% yield and 78% ee (Scheme 77). The reaction was applicable to a range 39 40 of substituted S aryl allylic sulfides to give the corresponding N tosyl allylic amines in good 41 42 yield with comparable enantioselectivity obtained in each case. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 68 Page 69 of 88 ACS Catalysis
1 2 3 4 Ph 322 (2 mol%) Ts KOH 5 Ts N + N Ts 3 S 4Å MS, CH Cl , 15 °C MeOH N 6 2 2 S H 321 (1.2 eq) 318 Ph 7 81:19 E:Z 324 8 323 82% 9 78% ee 10 N CO N 11 Ru 12 O O 13 Ph Ph 14 15 16 17 322 18 Scheme 77 . Tandem sulfimidation and [2,3] rearrangement using tosyl azide 321 19 20 21 Tambar and co workers have developed a two step method for the conversion of unactivated 22 23 24 terminal alkenes into sulfonamides though a sequential hetero ene reaction and 25 129 26 enantioselective palladium catalyzed formal [2,3] rearrangement protocol. Reacting 27 28 terminal alkenes 326 with benzenesulfonyl sulfurdiimide 325 forms stable sulfimides 327 29 30 through a hetero ene reaction. Sulfimides such as 327 could be purified by filtration and did 31 32 not undergo un catalyzed background [2,3] rearrangement at low temperatures. Treating 33 34 35 sulfimide 327 with Pd(TFA) 2 (10 mol%) and BOX ligand 316 (12 mol%) promoted a highly 36 37 enantioselective [2,3] rearrangement to form allylic sulfonamides 328 (Scheme 78a). This 38 39 reaction sequence was applicable to substrates possessing an impressive range of aliphatic 40 41 substituents at the homoallylic position, including those containing benzyl ether, phthalimide, 42 43 44 nitrile, aldehyde, or alkyl chloride functional groups. In all cases the corresponding 45 46 sulfonamide products were obtained in high yields with excellent enantioselectivity. 47 48 Interestingly, this catalytic system was not suitable for substrates containing aryl substituents 49 50 in the homoallylic position, giving sulfonamide products 331 with essentially no 51 52 enantioselectivity. 130 However, using alternative BOX ligand 330 and 1,2 DCE as the 53 54 55 reaction solvent a range of aryl substituents was tolerated, including those bearing both 56 57 electron withdrawing and electron donating substituents, forming sulfonamides 331 in high 58 59 60 ACS Paragon Plus Environment 69 ACS Catalysis Page 70 of 88
1 2 3 yields with excellent enantioselectivity (Scheme 78b). The synthetic utility of these 4 5 methodologies was exemplified through the synthesis of the antiepileptic drug vigabatric 332 6 7 and the enantiomer of peptidase inhibitor sitagliptin ent 333 , approved for the treatment of 8 9 129 130 10 Type II diabetes (Scheme 78c). Mechanistically, the palladium BOX complex is 11 12 proposed to bind to π system of intermediate sulfimide 327 to promote aminopalladation, 13 14 with subsequent fragmentation of the five membered cyclic intermediate giving the formal 15 16 [2,3] rearranged sulfonamide 328 . 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 Scheme 78 . Tandem homo ene reaction and palladium catalyzed [2,3] rearrangement of terminal alkenes 49 bearing a) aliphatic homoallylic substituents and b) aryl homoallylic substituents. c) Pharmaceutically active 50 compounds synthesized using this methodology 51 52 N 53 5.3 Catalytic [2,3]-Rearrangement of Allylic -Oxides 54 55 The [2,3] rearrangement of allylic N oxides into hydroxylamine derivatives was first reported 56 131 57 by Meisenheimer in 1919 and the reaction often bears his name. Although there has been 58 59 60 ACS Paragon Plus Environment 70 Page 71 of 88 ACS Catalysis
1 2 3 some limited success in developing stoichiometric stereoselective versions of the 4 5 Meisenheimer rearrangement, a catalytic version remained elusive for many years. 131 In 6 7 2011, Tambar and co workers reported the first such catalytic enantioselective [2,3] 8 9 132 10 rearrangement of amine N oxides. Allylic amines 334 were first oxidized into isolable 11 12 allylic N oxides 335 using m CPBA. Treating allylic N oxides 335 with Pd(OAc) 2 (10 mol%) 13 14 and phosphoramidite ligand 336 (24 mol%) promoted the highly enantioselective [2,3] 15 16 rearrangement into allylic hydroxylamines 337 (Scheme 79). The addition of catalytic 17 18 19 amounts of MeOH and m CPBA gave a slight increase in the enantioselectivity, although the 20 21 exact role of these additives is currently unknown. The reaction was applicable to a variety of 22 23 aliphatic allylic N oxides 335 including those bearing pendent alcohol, ether, aldehyde, and 24 25 phosphate ester functional groups, forming hydroxylamines 337 in good yields and excellent 26 27 enantioselectivity. The palladium(II) phosphoramidite catalyst is proposed to activate the 28 29 30 allylic N oxide to enantioselective oxypalladation, with fragmentation of the resulting 31 32 heterocyclic intermediate giving the formal [2,3] rearranged products. This presence of a 33 34 heterocyclic intermediate is supported by the fact that C2 substituted substrates do not 35 36 undergo rearrangement, while crossover experiments suggest that an allylpalladium 37 38 39 intermediate is unlikely. 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 Scheme 79 . Palladium catalyzed [2,3] rearrangement of allyic N oxides to form hydroxylamines 337 58 59 60 ACS Paragon Plus Environment 71 ACS Catalysis Page 72 of 88
1 2 3 6. CATALYTIC [2,3]-WITTIG REARRANGEMENTS 4 5 The base promoted anionic [2,3] Wittig rearrangement of allylic ethers into homoallylic 6 7 1a 8 alcohols has been widely used in organic synthesis. These reactions can be highly 9 10 stereoselective depending upon the nature of any substituents, with the transition state models 11 12 calculated by Houk and Marshall often used to rationalize any diastereoselectivity observed. 4 13 14 However, catalytic asymmetric [2,3] Wittig rearrangements remain an underdeveloped area, 15 16 17 probably due to the typical requirement for a strong base to promote anionic [2,3] 18 19 rearrangements. 20 21 22 6.1 Base-Catalyzed [2,3]-Wittig Rearrangements 23 24 One strategy for rendering base mediated [2,3] Wittig rearrangements asymmetric is the use 25 26 of stoichiometric amounts of chiral ligands. Kimachi and co workers first reported the use of 27 28 a catalytic amount of chiral ligand for the [2,3] rearrangement of allylic ether 338 (Scheme 29 30 80a). 133 Treating 338 with an excess of n BuLi and catalytic (−) sparteine 339 (20 mol%) at 31 32 33 low temperature gave homoallylic alcohol 340 in 44% yield and 48% ee, compared with 83% 34 35 yield and 60% ee when an excess of ( −) sparteine 339 (2.2 eq) was used. Building upon 36 37 earlier reports of chiral BOX ligands in [2,3] rearrangements, 134 Maezaki and co workers 38 39 reported catalytic [2,3] Wittig rearrangement of allylic ether using ligand 121 (50 mol%) and 40 41 42 a large excess of t BuLi to form homoallylic alcohol 342 in 52% yield as a single 43 44 diastereoisomer in excellent 98% ee (Scheme 80b). Lower amounts of ligand (10 mol%) 45 46 could be used, but although the high stereoselectivity was retained a decrease in yield (23%, 47 48 >95:5 dr, 98% ee) was observed.135 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 72 Page 73 of 88 ACS Catalysis
1 2 3 a) 4 H 5 N 6 N 7 OH 8 339 (20 mol%) 9 O n-BuLi (2.2 eq) 10 NEt 2 pentane, 95 °C NEt 2 11 12 O O 13 338 340 14 44% 15 48% ee 16 b) 17 O O 18 N N 19 20 t-Bu t-Bu 21 121 (50 mol%) t-BuLi (10 eq) Ph 22 Ph O 23 hexane, 78 °C OH 24 TIPSO TIPSO 25 341 342 26 52% 27 >95:5 dr 28 98% ee 29 Scheme 80 . Asymmetric base mediated [2,3] Wittig rearrangements using catalytic chiral ligands 30 31 32 Terada and Kondoh reported the first [2,3] Wittig rearrangement that was catalytic in 33 34 136 35 Brønsted base by utilizing a tandem phospha Brook rearrangement. Treating 36 37 allyloxyphosphonate 343 with catalytic KO t Bu (10 mol%) resulted in deprotonation 38 39 followed by [2,3] rearrangement into alkoxide 344 (Scheme 81). Subsequent phospha Brook 40 41 rearrangement of 344 followed by protonation to regenerate the catalyst gave product 345 in 42 43 44 85% yield and 68:32 dr. The reaction was applicable to a range of substituted 45 46 allyloxyphosphonates forming the products in generally high yield but modest 47 48 diastereoselectivity. Cyclic allyloxyphosphonates underwent the tandem reaction sequence to 49 50 form ring contracted lactone products with slightly higher levels of diastereoselectivity. 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 73 ACS Catalysis Page 74 of 88
1 2 3 4 5 6 7 8 9 10 11 12 Scheme 81 . Catalytic tandem [2,3] Wittig rearrangement and phospha Brook rearrangement. Configuration of 13 the major diastereoisomer is unreported 14 15 16 Gaunt and co workers reported a conceptually new method of performing stereoselective 17 18 [2,3] Wittig rearrangements using organocatalysts under mild conditions without the use of a 19 20 strong base. 137 Using pyrrolidine 347 as a catalyst, α allyloxy ketone 346 reacts to form an 21 22 enamine that can undergo highly diastereoselective [2,3] rearrangement into homoallylic 23 24 25 alcohol 348 in good yield (Scheme 82a). The syn diastereoselectivity could be further 26 27 improved to 91:9 dr by lowering the reaction temperature to –25 °C, although a significantly 28 29 longer reaction time was needed to achieve complete conversion. The use of methanol as 30 31 solvent was essential for obtaining diastereoselectivity, suggesting that the protic solvent is 32 33 involved in hydrogen bonding to the substrate during the rearrangement. The reaction of an 34 35 36 enantiomerically enriched allylic ether resulted in complete chirality transfer into the product, 37 38 suggesting a concerted mechanism is in operation. The reaction was applicable to a range of 39 40 aliphatic ketones as well as allylic ethers bearing alkyl, aryl, alkynyl, and alkenyl functional 41 42 groups, forming the homoallylic alcohol products in high yields with mostly good 43 44 45 diastereoselectivity. In a single example, chiral proline derivative 350 was investigated as an 46 47 enantioselective catalyst for this process, promoting the rearrangement of α allyloxy ketone 48 49 349 into alcohol 351 in 75% yield with moderate diastereoselectivity but promising 60% ee 50 51 (Scheme 82b). 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 74 Page 75 of 88 ACS Catalysis
1 2 3 a) 4 5 N O H O Ph 6 347 (20 mol%) O Ph 7 MeOH, 5°C 8 346 OH 9 348 10 84% 11 87:13 dr 12 13 b) CF 3 14 15 N 16 CF 3 N O H O 17 350 (20 mol%) O 18 Ph MeOH, rt, 5 d Ph 19 349 OH 20 351 21 75% yield 22 67:33 dr 23 60% ee 24 25 Scheme 82 . Stereoselective organocatalytic [2,3] Wittig rearrangements 26 27 28 6.2 Non-Base-Catalyzed [2,3]-Wittig Rearrangements 29 30 While [2,3] Wittig rearrangements are traditionally performed using strong inorganic bases, a 31 32 few examples of non base catalyzed [2,3] rearrangements of allyloxy ethers have been 33 34 reported. In 1986, Nakai and co workers found that silyl ketene acetals such as 352 undergo 35 36 37 highly diastereoselective [2,3] rearrangements in the presence of catalytic trimethylsilyl 38 138 39 triflate (20 mol%) at low temperature. It is proposed that trimethylsilyl triflate reacts with 40 41 the ether oxygen of 352 to form a silyloxonium salt, with subsequent reaction of the triflate 42 43 anion with the silyl ketene acetal forming silyloxonium ylide 353 and regenerating the 44 45 46 catalyst. Ylide 353 can then undergo a diastereoselective [2,3] rearrangement via an endo 47 48 transition state to form α hydroxy ester 354 in high yield and >95:5 dr (Scheme 83). 49 50 51 52 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 75 ACS Catalysis Page 76 of 88
1 2 3 Scheme 83 . Diastereoselective [2,3] Wittig rearrangement catalyzed by trimethylsilyl triflate 4 5 6 More recently, Porco and co workers synthesized a range of enantiomerically enriched 3,4 7 8 chromanedione derivatives through the scandium catalyzed rearrangement of 3 9 10 139 allyloxyflavones. For example, treating 355 with Sc(OTf) 3 (30 mol%) and PyBOX ligand 11 12 13 319 (30 mol%) gave rearranged 3,4 chromanedione 357 , which was immediately reacted 14 15 with 1,2 ethylenediamine to allow dihydropyrazine 358 to be isolated in 98% yield and 94% 16 17 ee (Scheme 84). Various 2 aryl and benzenoid substituents were tolerated and a few different 18 19 diamines were utilized to form substituted dihydropyrazines in excellent yield and 20 21 enantioselectivity. Preliminary mechanistic studies using both fluorescence and 13 C NMR 22 23 24 spectroscopy favor an enantioselective scandium catalyzed [2,3] rearrangement into 25 26 benzopyrylium 356 followed by a stereospecific [1,2] allyl shift into 357 over a direct [3,3] 27 28 sigmatropic rearrangement of the allyl vinyl ether. 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 Scheme 84 . Enantioselective synthesis of 3,4 chromanedione derivatives 51 52 53 More complex cascade processes utilizing [2,3] Wittig rearrangements for the synthesis of 54 55 nitrogen heterocycles using metallonitrene intermediates have been investigated by Blakey 56 57 and co workers. 140 For example, sulfamate ester 359 and enantiomerically pure allylic ether 58 59 60 ACS Paragon Plus Environment 76 Page 77 of 88 ACS Catalysis
1 2 3 360 react under oxidative rhodium catalysis to selectively give 361 in 64% yield as a 73:27 4 5 E:Z mixture in 80% ee (Scheme 85a). 140b Product 361 was subsequently derivatized into the 6 7 core AB ring system of the Securinega alkaloid family of natural products. The cascade 8 9 10 reaction was applicable to a range of terminal allylic ethers, but only modest 11 12 diastereoselectivity was obtained with substituted allylic ethers. The proposed mechanism 13 14 involves a metallonitrene initiated alkyne oxidation, with nucleophilic attack of benzyl ether 15 16 360 onto intermediate 363 leading oxonium 364 (Scheme 85b). Stereospecific [2,3] 17 18 19 rearrangement of 364 forms product 361 and releases the catalyst. 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 Scheme 85 . Rhodium catalyzed cascade process to form nitrogen heterocycles. tfacam = trifluoroacetamide 51 52 53 7. CONCLUSION AND OUTLOOK 54 55 Catalytic stereoselective [2,3] rearrangements are powerful methods in asymmetric synthesis. 56 57 Many efficient catalytic protocols have been developed for a diverse range of [2,3] 58 59 60 ACS Paragon Plus Environment 77 ACS Catalysis Page 78 of 88
1 2 3 rearrangements, allowing new carbon carbon and/or carbon heteroatom bonds to be formed 4 5 with high levels of diastereo and enantioselectivity. The synthetic utility of a number of 6 7 these methodologies have also been demonstrated through the synthesis of target molecules. 8 9 10 The [2,3] rearrangement of onium ylides generated catalytically through reaction of a metal 11 12 13 carbenoid remains the most widely explored methodology in the area. However, there is an 14 15 increasing number of alternative catalytic strategies available using different methods of 16 17 accessing reactive intermediates capable of undergoing stereoselective [2,3] rearrangements. 18 19 The incorporation of stereoselective [2,3] rearrangements within tandem catalytic processes 20 21 22 is an expanding area of research that is likely to increase further in the future. 23 24 25 Although the number of catalytic asymmetric [2,3] rearrangements has increased 26 27 dramatically over the last 20 years, there is still room for improvement in many areas. While 28 29 highly diastereoselective reactions are more readily attained, the development of highly 30 31 enantioselective variants remains a significant challenge in many cases. The ability to 32 33 rationally design effective enantioselective protocols is often hampered by the limited 34 35 36 detailed mechanistic understanding of many of these processes. Therefore an increased 37 38 understanding of how catalysts interact and participate in [2,3] rearrangements is likely to be 39 40 hugely beneficial for the further development of highly stereoselective reactions. 41 42 43 Given the demonstrated synthetic utility of [2,3] rearrangements, the further development of 44 45 highly stereoselective catalytic variants will remain an active and worthwhile area of 46 47 48 research. The design of new substrates capable of undergoing [2,3] rearrangement processes 49 50 as well as incorporation of known [2,3] rearrangements within complex cascade reactions are 51 52 also likely to lead to further advances in this field. 53 54 55 56 57 58 59 60 ACS Paragon Plus Environment 78 Page 79 of 88 ACS Catalysis
1 2 3 AUTHOR INFORMATION 4 5 Corresponding Author 6 7 8 E mail: ads10@st andrews.ac.uk 9 10 11 Notes 12 13 The authors declare no competing financial interest. 14 15 16 17 ACKNOWLEDGEMENTS 18 19 We thank the Royal Society for a University Research Fellowship (A.D.S.), the European 20 21 Research Council under the European Union’s Seventh Framework Programme (FP7/2007 22 23 24 20013) ERC Grant Agreement No. 279850 (J.E.T., T.H.W., K.K.), and the European Union 25 26 (Marie Curie ITN ‘SuBiCat’ PITN GA 2013 607044) (S.S.M.S.) for financial support. 27 28 29 30 REFERENCES 31 32 (1) (a) Nakai, T.; Mikami, K. Chem. Rev. 1986 , 86 , 885 902. (b) Mikami, K.; Nakai, T. 33 34 35 Synthesis 1991 , 1991 , 594 604. (c) Nitrogen, Oxygen, and Sulfur Ylide Chemistry: A 36 37 Practical Approach in Chemistry ; Clark, J. S. Ed.; Oxford University Press: New York, 2002; 38 39 p 1 308. (d) Sweeney, J. B. Chem. Soc. Rev. 2009 , 38 , 1027 1038. (e) Murphy, G. K.; 40 41 Stewart, C.; West, F. G. Tetrahedron 2013 , 69 , 2667 2686. 42 43 44 (2) Jones, A. C.; May, J. A.; Sarpong, R.; Stoltz, B. M. Angew. Chem. Int. Ed. 2014 , 53 , 45 46 2556 2591. 47 48 (3) Hoffmann, R. W. Angew. Chem. Int. Ed. 1979 , 18 , 563 572. 49 50 (4) Wu, Y. D.; Houk, K. N.; Marshall, J. A. J. Org. Chem. 1990 , 55 , 1421 1423. 51 52 (5) Hoffmann, R. W. Chem. Rev. 1989 , 89 , 1841 1860. 53 54 55 (6) (a) Doyle, M. P. Chem. Rev. 1986 , 86 , 919 939. (b) Doyle, M. P.; Forbes, D. C. Chem. 56 57 Rev. 1998 , 98 , 911 936. (c) Doyle, M. P. Russ Chem Bull 1999 , 48 , 16 20. 58 59 60 ACS Paragon Plus Environment 79 ACS Catalysis Page 80 of 88
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