ENDOCRINE, PHYSIOLOGICAL AND HISTOPATHOLOGICAL RESPONSES OF FISH AND THEIR LARVAE TO STRESS WITH EMPHASIS ON EXPOSURE TO CRUDE Science and Technology, Special Review (2000) 73-113 ©2000 Sultan Qaboos University 73 Dirhodium(II) Carbenes : The Chiral Product Cascade *Gregory H. P. Roos, **Conrad E. Raab and *Said Al-Hatmi * Chemistry Department, College of Science, Sultan Qaboos University, P.O. Box 36, Al-Khod 123, Muscat, Sultanate of Oman ** Department of Drug Metabolism , Merck and Co., Inc., RY80R -104, P. O. Box 2000, Rahway, New Jersey 07065, USA. نسج الناتج الكايرالي) . ٢(كاربينات دايروديم راب ، وسعيد الحاتمي. روس ، و كونراد أ. جريجوري هـ أحد الطرق . شهدت العشر سنوات الماضية توسعاً كبيراً في طرق تحضير المركبات الكايرالية :خالصة استنباط طرق . ات الديازو المحضرة من مركب ) ٢(الهامة في هذا المجال هو استعمال كاربينات دايروديم جديدة باستعمال العوامل المساعدة الموجهة أدت إلى تحضير عدد من المركبات الغير راسمية عبر قنوات هذه . واإلضافة األروماتية الحلقية وخالفه C-Xمختلفة مثل إضافة البروبان الحلقي واإلدخال من نوع دة التي تؤدي إلى تحضير مركبات عالية النقاء لمتماكب النبذة القصيرة تتعرض بإختصار للعوامل المساع .ضوئي ABSTRACT: The last decade has witnessed enormous growth in the spectrum of highly efficient asymmetric synthetic transformations. One prominent example of this progress is the application of dirhodium (II) carbenes generated from diazo- precursors. Innovative construction of ‘designer’ catalysts has played a integral role in extending the breadth of the synthetic cascade of non-racemic products now available through the range of cyclopropanation, C-X insertion, aromatic cycloaddition-rearrangement, and ylide-based reaction types. This review deals briefly with an overview of the important catalytic systems and maintains as its primary focus the cascade of diverse optically enriched products that flow from their applications. ROOS, RAAB, and AL-HATMI 74 CONTENTS 1. Introduction 74 1.1 The Need for Asymmetric Synthesis 74 1.2 Carbene Reactions 74 2. Generation of Dirhodium(II) Carbenes 75 2.1 Diazo Compounds 75 2.2 Metal-Catalysed Diazo Decomposition 76 2.3 Dirhodium(II) Catalysts 76 3. Reaction Products From Dirhodium(II) Carbenes 80 3.1 Cyclopropanes and Cyclopropenes 80 3.2 Intermolecular Processes 81 3.3 Intramolecular Processes 87 3.4 Insertion Products 92 3.4.1 Carbon-Hydrogen Insettion Products 94 3.4.2 Heteroatom-Hydrogen Insertion Products 100 3.5 Aromatic Cycloaddition and Substitution Products 101 3.6 Ylide Cascade Products 104 4. Conclusion 105 5. References 106 1. Introduction 1.1 The Need for Asymmetric Synthesis The world around us is chiral. Most organic compounds are chiral. The chemistry of perfumes, nutrients, pesticides, and pharmaceuticals involves chiral compounds whose physiological or pharmacological properties depend upon their recognition by chiral receptors. Public opinion and associated legislation surrounding the pharmaceutical industry demands, especially since the thalidomide disaster (Figure 1), the preparation and testing of enantiopure compounds. This has, in part, caused asymmetric synthesis to become the single greatest “growth industry” within organic chemistry over the past 25 years. Once the important factors that control reaction stereoselectivity were recognized, development has exploded throughout the arena of organic synthesis (Ager and East, 1996; Gawley and Aubé, 1996; Seyden-Penne, 1995). Of the handful of approaches to asymmetric synthesis, catalysis has the advantage over stoichiometric synthesis with chirons (enantiomerically pure substrate fragments) or chiral auxiliaries (temporary enantiomerically pure attachments), particularly in terms of large-scale or industrial processes. Catalytic asymmetric reactions have been the subject of research investigations for many years and, particularly over the last decade, the number of catalytic asymmetric processes (some giving enantioselectivities of greater than 99%) has burgeoned (Brünner and Zettlmeier, 1993; Jacobsen et al, 1999). Whilst broad scope and high enantioselectivity are important for any catalytic asymmetric transformation, they alone are not necessarily sufficient to ensure that a process will become widely used, especially on industrial scale. To reach this goal, the process additionally needs to be economical and easy to perform. For this reason, many of the new wave of catalysts are either already commercially available, or are designed for easy or in situ preparation. 1.2 Carbene Reactions The general group of transformations referred to as “carbene reactions” forms a versatile class of transition metal catalysed processes. These reactions are characterised by the involvement of a transition DIRHODIUM(II) CARBENES: THE CHIRAL PRODUCT CASCADE metal stabilized carbene that is formed from the decomposition of a diazo compound in the presence of the transition metal catalyst. Further reaction of the carbene may follow a number of pathways including insertion and addition reactions, as well as ylide generation. Recent investigations have focussed on the development of catalysts that control the selectivity of what had traditionally been thought of as non- selective reactions of “free carbenes”. Of these, dirhodium catalysts have emerged as arguably the most versatile for a wide range of stereoselective transformations (Doyle et al, 1993a, 1994a, 1996a, 1997a, 1998a, 1998b, 1998c, 1999; Ene and Doyle, 1998; Ye and McKervey, 1994; Roos and Raab, 1997). Given the rapid growth within this area of endeavor, this review seeks to place these developments in context via the published literature through mid-1999. The specific focus is on homochiral catalysts and therefore excludes chiron-based syntheses, and only pertinent examples of diastereoselectivty via chiral auxiliaries are covered. Previous reviews have tended to focus on details of catalyst development or of subsequent reaction type that the carbene undergoes. Outside of essential introductory material, this review seeks primarily to highlight the wealth of diverse enantiomerically enriched chiral products that are available via the numerous highly chemoselective, regioselective, and stereoselective transformations brought about by dirhodium(II) catalyst systems. Some of these have a high potential for commercial adaptation. Readers seeking further details on access to diazo compounds, catalyst design and preparation, as well as mechanistic aspects are referred to the alternative specialist reviews cited throughout. 75 N N O O OO H N N O O OO H (R)-Thalidomide Sedative (S)-Thalidomide Teratogenic Figure 1. Thalidomide enantiomers 2. Generation of Dirhodium(II) Carbenes 2.1 Diazo Compounds Diazo compounds are derivatives of diazomethane, and as such have stabilities and reactivities that reflect their substituents. Generally, the stabilities of diazo compounds towards diazo decomposition are increased by electron withdrawing substituents, and decreased by electron donating substituents (Figure 2). For this reason, the most widely employed diazo compounds for metal catalysed reactions are diazocarbonyl compounds. Numerous synthetic methodologies are now available for the synthesis of diazo compounds and these have been reviewed by Regitz and Maas (1986) and Doyle et al (1998a). ROOS, RAAB, and AL-HATMI 2.2 Metal-Catalysed Diazo Decomposition Since diazo decomposition is an acid promoted process, transition metal complexes that are effective catalysts for diazo decomposition are of necessity Lewis acids (Doyle, 1986). Their catalytic activity depends on the metal centre being coordinatively unsaturated, which allows them to react as electrophiles with diazo compounds. Z Y O N2 O Z O N2 R R N2 R Increasing Stability Increasing Reactivity Z, Y = R, OR, NR2 R = alkyl, aryl, H Figure 2. Relative stability/reactivity of diazo substrates In the generally accepted mechanism for catalytic diazo decomposition, electrophilic addition of the catalyst to the diazo compound causes the loss of dinitrogen from a diazonium ion adduct 1 to produce a metal-stabilized carbene 2 (Scheme 1). The electrophilic carbene is transferred to an electron-rich substrate (S:) to form the product of the carbene reaction (SCR2), with release of the transition metal catalyst to complete the catalytic cycle. 2.3 Dirhodium(II) Catalysts A wide range of other metals such as copper, cobalt, palladium, ruthenium, osmium, iron, nickel, and zinc have been employed with varying success in catalytic systems (Roos and Raab, 1997; Doyle et al, 1998a). Rhodium, and more specifically dirhodium(II) complexes have proven to be the most effective and versatile catalysts for diazo decomposition (Maas, 1987; Padwa and Krumpe, 1992; Davies, 1993a; Padwa and Austin, 1994; Ye and McKervey, 1994; Doyle, 1995a). Generally, rhodium-mediated carbene reactions proceed under much milder conditions than is common for classical synthetic methodology with copper(II) catalysts (Padwa and Austin, 1994). 76 LnM LnM CR2 N2 LnM CR2 SCR2 N2 R2C N2 2 1 S: Scheme 1. Cycle for transition-metal catalyzed diazo decomposition DIRHODIUM(II) CARBENES: THE CHIRAL PRODUCT CASCADE Their versatility arises from the large variety of bridging ligands that can be coordinated to the dirhodium(II) skeleton, and in their marked influence on reactivity and selectivity. Dirhodium(II) catalyst complexes are divided into two major groups, those bridged with carboxylate ligands and those bridged with carboxamidate ligands. It is through the tuning of these ligands that particular catalysts are able to provide appropriate chemical properties as well as specific reactivity and selectivity profiles for desired transformations. The dirhodium(II) catalysts are based on the parent dirhodium(II) tetraacetate, Rh2(OAc)4 3, first introduced by Paulissenen et al (1973). Since that time, this has been the single most widely used catalyst for metal carbene transformations. Rh2(OAc)4 3 possesses four bridging acetate ligands and has D4h symmetry, leaving one vacant axial coordination site on each metal for carbene attachment (Boyar and Robinson, 1983). A multitude of dirhodium(II) catalysts is available by replacement of the acetate ligands with other carboxylate or carboxamidate ligands. Many of these catalysts have unique properties or synthetic uses (Doyle et al, 1998a, 1998b). 77 Rh2(acam)4 5Rh2(pfb)4 4Rh2(OAc)4 3 O Rh Rh CH3 OO O O CH3 O O O CH3 CH3 O Rh Rh CH3 ON O N CH3 N N O CH3 CH3 H HH H O Rh Rh C3F7 OO O O C3F7 O O O F7C3 C3F7 Rh Rh O O R3 R2 R1 6 Rh Rh O O N S O O H Z 7 8 Rh Rh O O NH R O O R = PhCH2, tBuZ = H, NO2, OMe, Me tBu [Rh2(TBSP)4], nC12H25 [Rh2(DOSP)4] Dirhodium(II) perfluorobutyrate, Rh2(pfb)4 4, is the most reactive dirhodium(II) catalyst, and its selectivity in diazo decomposition reactions is often correspondingly poor (Doyle et al, 1993b). In contrast, dirhodium(II) carboxamidates such as Rh2(acam)4 5, which have two nitrogen and two oxygen donor atoms at each rhodium, with the two nitrogens arranged cis to each other (a [2,2-cis] configuration) ROOS, RAAB, and AL-HATMI (Ahsan et al, 1986) are less reactive than the dirhodium(II) carboxylates in diazo decomposition, but are often more selective in the subsequent carbene reactions (Doyle et al, 1989a,b; Doyle et al, 1991a). Homochiral dirhodium(II) carboxylate catalysts 6 for asymmetric carbene reactions were simultaneously developed in three laboratories (Brunner et al, 1989; Kennedy et al, 1990; Hashimoto et al, 1990; Roos and McKervey, 1992) from enantiomerically pure carboxylic acids. More recent refinements have demonstrated highly successful prolinate 7 (McKervey and Ye, 1992; Davies et al, 1993b, 1996; Doyle et al, 1996b) and phthalimide 8 derivatives (Hashimoto et al, 1994; Watanabe et al, 1995, 1996a). A recent report (Buck et al, 1998) has employed parallel array techniques to screen rapidly for novel carboxylate catalysts. In contrast to the dirhodium(II) carboxylates, the rhodium(II) carboxamidates allow placement of an inducing chiral centre adjacent to nitrogen in closer proximity to the axial carbene centre. A series of more than twenty structurally varied homochiral dirhodium(II) carboxamidates derived from chiral cyclic amide ligands has been developed by Doyle and co-workers (Doyle, 1994b, 1996a). In general, dirhodium(II) carboxamidate catalysts based on chiral 2-oxopyrrolidine 9 (Doyle et al, 1993c, 1994c) 2- oxazolidinone 10 (Doyle et al, 1993d, 1995b), N-acylimidazolidinone 11 (Doyle, 1995c, 1996c, 1997b; Roos et al, 1998), and 2-azetidinone 12 (Doyle et al, 1996d) ligands, especially those bearing pendant carboxylate groups, afford the highest levels of enantioselectivity. Dirhodium(II) complexes 13 bearing chiral phosphate ligands derived from binaphthol have been reported to provide moderate enantioselectivities in a number of carbene reactions (McCarthy et al, 1992; Pirrung and Zhang, 1992). In addition, Estevan et al (1995) prepared a novel set of C2-symmetric catalysts 14 bearing two cis carboxylate ligands along with two orthometallated phosphine ligands. X H Z COORH Z Z COORH ZH ROOCCH N2 + Rh2L4 X H Z X ROOCCH2X Ylide generation Insertion Cyclopropanation Cyclopropenation Z X = sulphides, amines, halides, ethers = C-H, N-H, O-H, Si-H, S-H Z = alkyl, aryl, vinyl, OR' Z = alkyl, vinyl Z X CHCOOR CO2R Aromatic cycloaddition Scheme 2. Diversity of metal carbene reactions 78 DIRHODIUM(II) CARBENES: THE CHIRAL PRODUCT CASCADE 9 a A = CO2CH2Ph; Rh2(4S-BNAZ)4 b A = CO2CH2CHMe2; Rh2(4S-IBAZ)4 O Rh Rh ON O N N N O A H a A = CO2Me, R = CH3; Rh2(4S-MACIM)4 b A = CO2Me, R = Ph; Rh2(4S-MBOIM)4 c A = CO2Me, R = PhCH2; Rh2(4S-MPAIM)4 d A = CO2Me, R = PhCH2CH2; Rh2(4S-MPPIM)4 e A = CO2Me, R = c-C6H11CH2; Rh2(4S-MCHIM)4 O Rh Rh ON O N N N O N A H O R a A = CO2Me, R = H; Rh2(4S-MEOX)4 b A = CO2Me, R = CH3; Rh2(4S-THREOX)4 c A = CH2Ph, R = H; Rh2(4R-BNOX)4 d A = iPr, R = H; Rh2(4R-IPOX)4 e A = Ph, R = H; Rh2(4R-PHOX)4 a A = CO2Me; Rh2(5S-MEPY)4 b A = CO2CH2CMe3; Rh2(5S-NEPY)4 c A = CO2(CH2)17Me; Rh2(5S-ODPY)4 d A = CONMe2; Rh2(5S-DMAP)4 10 O Rh Rh ON O N N N O A H O Rh Rh ON O N N N O O A H H R 11 12 P RhRh O PArC O O O R1 R2 X 14 X = H, F, CH 3, CF3 O O P OO Rh Rh 13 a. Rh2(S-BNHP)2(HCO3)2 b. Rh2(R-BNHP)4 79 ROOS, RAAB, and AL-HATMI 80 -R* -R* R*O O N2 MLn X R*O O X * (a) RO O N2 MLn* X RO O X * (b) R*O O N2 MLn* X R*O O X * (c) Scheme 3. Approaches to asymmetric synthesis with metal carbene 3. Reaction Products From Dirhodium(II) Carbenes The metal-carbenes resulting from the diazo decomposition of α-diazocarbonyl compounds by a transition metal catalyst, are versatile electrophilic reagents. Dirhodium(II) catalysed diazo decompositions provide the greatest versatility in subsequent carbene reactions, and provide many synthetically useful transformations. This includes inter- and intramolecular reactions as diverse as cyclopropanation, cyclopropenation, insertion, aromatic cycloaddition, and ylide generation (Scheme 2). As a result, the range of stereoselectively generated product types is large. Researchers in this area have tested a variety of fundamental approaches to the asymmetric production of chiral compounds via dirhodium(II)-catalysed reactions (Scheme 3). Thus, (a) diastereoselective reaction of achiral catalysts with diazo substrates containing chiral auxiliaries, (b) enantioselective reaction between chiral catalysts and achiral substrates, and in a few instances (c) a double diastereoselective approach with both chiral catalyst and substrate have been used. For the purpose of orderly classification, the range of product molecules has been grouped according to the reaction type via which they are generated. 3.1 Cyclopropanes and Cyclopropenes Due to their biological significance and synthetic utility, cyclopropanes and cyclopropenes are extremely important target molecules (Rappoport, 1987; Binger and Büch, 1987; Baird, 1988; Salaün, 1989). They are often present as structural sub-units in natural and non-natural products (Rappoport, 1987; Burke and Grieco, 1979; Hudlicky et al, 1985; Ho, 1988; Burgess and Ho, 1994), are frequently used as mechanistic probes to elucidate reaction pathways (Suckling, 1988; Silverman et al, 1993; Newcomb and Chestney, 1994; Caldwell and Zhou, 1994; Husbands et al, 1994), and are increasingly valuable as synthetic intermediates (Wong et al, 1989; Davies, 1991; Reissig, 1995). DIRHODIUM(II) CARBENES: THE CHIRAL PRODUCT CASCADE cistrans + Rh2L4 + Z COORZ COOR N2CHCOOR Z (1) Since the availability of enantiomerically pure cyclopropanes is critical to many applications, a number of useful methods for their enantioselective synthesis have been developed. These include the cyclopropanation of chiral bicyclic lactams to give optically pure di- and trisubstituted cyclopropanes; highly diastereoselective Simmons-Smith cyclopropanation of chiral auxiliary-derivatised allylic ethers; enantioselective Simmons-Smith cyclopropanation of allylic alcohols using diethylzinc that is coordinated with chiral ligands; and enzymatic resolutions of meso-cyclopropanes. In the field of asymmetric synthesis, cyclopropanation of electron-rich olefins by catalytic diazo decomposition of α-diazocarbonyl compounds with chiral catalysts equation 1, particularly copper and rhodium, has become an attractive and important route to optically active cyclopropanes (Maas, 1987; Doyle, 1993a, 1998a, 1998d; Ye and McKervey, 1994, Singh et al, 1997). Cyclopropanation may either be performed intermolecularly or intramolecularly. A successful example of the former is the commercial synthesis (by the “Sumitomo process”) of optically pure cilastatin 15, an in vivo stabiliser of the antibiotic imipenem (Doyle, 1995a). Generally it has been found that copper-based systems are the better catalysts for intermolecular cyclopropanation with traditional diazoacetates, whilst dirhodium catalysts provide the better results in intramolecular variants (Roos and Raab, 1997; Doyle et al, 1998a). 81 S COOH NH2 HOOC NH O H3C H3C 15 1716 O N O CHN2 O O N Ph CH3 O CHN2 O 3.2 Intermolecular Processes Initial attempts at asymmetric intermolecular cyclopropanations by means of chiral auxiliaries bonded to diazoacetates were largely unsuccessful (equation 1, Z = chiral auxiliary). Chiral N- (diazoacetyl)oxazolidinones 16 and 17 underwent Rh2(OAc)4 catalysed cyclopropanation of styrene in ROOS, RAAB, and AL-HATMI good yield but with low diastereoselectivity (Doyle et al, 1990). High diastereoselectivities in the catalytic cyclopropanation of diazo compounds bearing chiral auxiliaries have only been achieved in select cases (Davies et al, 1993c; Doyle et al, 1993e). These reports now include diastereomeric excesses of up to 97% in the dirhodium(II) octanoate catalysed cyclopropanation of styrenes and vinyl ethers with (R)- pantolactone- and (S)-lactate-substituted vinyldiazomethane 18 with (Table 1) (Davies et al, 1993c, 1997a) These workers (Davies et al, 1998a) have shown that appropriate choice of vinyldiazo substituent allows facile subsequent transformation of the cyclopropyl products to 2,3-dihydrofurans with high asymmetric induction. Table 1. Diastereoselective intermolecular cyclopropanation with vinyldiazoacetates containing chiral auxiliaries. R + Ph N2 CO2X Rh2(OOct)4 CH2Cl2 42-92% CO2X R Ph 18 a X = O O b X = CO2Et CH3 19 R Diazo de, % Abs. config. Ph Ph pClC6H4 pMeOC6H4 AcO EtO Ph 18a 18a 18a 18a 18a 18a 18b 89 97 >95 >95 90 92 67 (1R,2R) (1R,2R) (1R,2R) (1R,2R) - - (1S,2S) This methodology has been extended to diene systems, furans (Davies et al, 1996b) to give 8- oxabicyclo[3.2.1]octan-3-ones and pyrroles (Davies et al, 1997b) to give tropanes (Scheme 4).The fundamental reaction sequence has allowed the preparation of the oxabicycles 20-22 and a series of 2β- acyl-3β-aryltropanes 23 (Davies et al, 1994a, 1996c), which are important building blocks in further synthesis. 82 DIRHODIUM(II) CARBENES: THE CHIRAL PRODUCT CASCADE X = chiral auxiliary O R3 R2 + N2 CO2X OTBS R1 Rh2(OOct)4 R3 CO2X OTBS R1 R2 O 75-95% de N R1 BOC + N2 CO2X R2 Rh2(OOct)4 CO2X R2 R1 N BOC 53-80% de O Me O H O Me O H Me CO2Me H O H O 20 21 22 COEt R1 N R X 23 Scheme 4. Diastereoselective synthesis of oxabicyclooctanones and tropanes Enantioselective approaches have surveyed two distinct types of homochiral dirhodium(II) carboxylates. Brünner et al (1989) used carboxylate ligands of the type R1R2R3CCOO, as in catalysts 6 (substituents varied from H, Me, and Ph; to OH, NHAc, and CF3) and Kennedy et al (1990) persued the chiral prolinate derivatives 7 (Z = H). They found that enantioselectivities in the cyclopropanation of styrene with ethyl diazoacetate were less than 12% ee and 30% ee respectively. More recently, Davies et al (1993b, 1996b, 1997) have used modified prolinate catalysts with vinyldiazoacetates to achieve enantioselectivities of ≥90%, with correspondingly high diastereoselectivities (Table 2). It has further been shown that with suitably fuctionalised vinyldiazoacetates, the cyclopropyl products can afford cyclopentenes with high stereoselectivity (Davies et al, 1998b). A recent catalyst, based on an axially 83 ROOS, RAAB, and AL-HATMI Table 2. Dirhodium(II) prolinate catalyzed intermolecular cyclopropanation with vinyldiazoacetates R + Ph N2 CO2Me catalyst pentane 40-90% CO2Me R Ph R ee, % with Rh2(TBSP)4 ee, % with Rh2(DOSP)4 Ph pClC6H4 pMeOC6H4 AcO EtO nBu Et iPr 90 89 83 76 59 >90 >95 95 98 >97 90 95 93 - - - dissymmetric biphenyl, does as yet not appear to offer any significant advantages over existing examples (Ishitani and Achiwa, 1997). 84 CO2Me Ph Ph CO2Me Ph CO2H CO2Me Ph NH2.HCl CO2Me Ph CO2Me CO2H Ph CO2Me NH2.HCl Ph CO2Me 72% 43% 94% 78% 66% a d b c d a: RuCl3/NaIO4 b: K2CO3, Me2SO4 c: LiOH, MeOH d: NEt3, DPPA, tBuOH; [(CH3)3COCO]2O; NaOH/H2O/THF; HCl/EtOAc Scheme 5. Stereoselective synthesis of cyclopropaneamino acids DIRHODIUM(II) CARBENES: THE CHIRAL PRODUCT CASCADE 85 Ph + Ph N2 CO2Me Rh2L4* 7 (Z = C12H25) 79% CO2Me Ph Ph H 94% ee CO2Me CO2MePh H H NHCH3 H Cl Cl Sertraline Scheme 6. Enantioselective synthesis of the antidepressant Sertraline The vinyl functionality that exists in the cyclopropane offers a number of opportunities for further transformations. One generally useful application is for the stereoselective synthesis of cyclopropaneamino acids (Scheme 5) (Davies et al, 1993b, 1996b). This approach has been utilised in a recent synthesis of the antidepressant sertraline (Scheme 6) (Corey and Grant, 1994). (2) EWG R3 R4 R5 R2 X R6 R1R3 X R2 R1 EWG R4 R6R5 EWG = electron-withdrawing group R1 R6 R5 R4 R3 R2 + EWG N2 X The extension of asymmetric vinylcarbenoid cyclopropanation to dienes affords a good general entry into seven-membered rings equation 2 (Davies et al, 1994b). The stereoselectivity that occurs results in a strong preference for the formation of cis-divinylcyclopropanes, and the subsequent Cope rearrangement follows with a predictable stereochemical outcome. ROOS, RAAB, and AL-HATMI 86 Me Me CO2Me N2 Ph Me CO2Me Ph Me CO2Me Ph 90% ee [Rh2(S-TBSP)4] 96% ee [Rh2(S-DOSP)4] 90% ee [Rh2(S-TBSP)4] 98% ee [Rh2(S-DOSP)4] Scheme 7. Enantioselective cycloheptatriene synthesis This methodology, which represents a formal [3 + 4]-cycloaddition, has been well exploited by Davies et al (1994b) (Scheme 7) (Table 3). Table 3. Enantioselective synthesis of bicyclo[3.2.1]octadienes CO2Me N2 R2 R1 + catalyst 66-98% CO2Me R2 R1 R1 R2 ee % with Rh2(S-TBSP)4 ee % with Rh2(S-DOSP)4 Ph Me CH=CH2 H CO2Et H H H H H H H Me OTBS 75 83 91 63 10 64 42 93 92 93 - - - - Although the dirhodium(II) carboxamidate catalysts 9-12 are able to provide substituted cyclopropanes with reasonable levels of enantioselectivity, they suffer the drawback of poor DIRHODIUM(II) CARBENES: THE CHIRAL PRODUCT CASCADE diastereoselective when diazoacetates are employed, with mixtures of trans- and cis-adducts being formed (Table 4) (Doyle et al, 1993d; Müller et al, 1995; Watanabe et al, 1996b). Diastereoselectivity can only be effectively induced when sterically demanding diazo esters can be employed. The most noteworthy recent examples have been reported with the catalysts Rh2(4S-IBAZ)4 12b (Doyle et al, 1996d) and Rh2(S-PTPI)4 (Kitagaki et al, 1997) where enantioselectivities of up to 95% have been achieved in selected systems. The situation has been somewhat improved by the discovery that methyl phenyldiazoacetate 24 is an excellent substrate for intermolecular cyclopropanation (Table 5) (Davies et al, 1996d; Doyle et al, 1996b). Homochiral dirhodium(II) carboxamidates, in particular 9a, have proven to be exceptional catalysts for highly enantioselective intermolecular cyclopropenation (Table 6) (Doyle et al, 1994d). Since the cyclopropene products can be quantitatively reduced to cis-cyclopropanes, this provides an alternative route to these products in high enantiomeric purity. Table 4. Dirhodium(II) carboxamidate catalyzed intermolecular cyclopropanation N 87 CPh Tr Ci 2CHCO2R Rh2L*4 9-12 Ph H CO2R H H Ph O2R H ans s + R Catalyst Trans yield % (de %) Cis yield % (de %) d-menthyl Et l-menthyl Et d-menthyl Et cyc-(C6H11)2CH Et Et Rh2(5S-MEPY)4 Rh2(5S-MEPY)4 Rh2(4S-PHOX)4 Rh2(4S-PHOX)4 Rh2(4R-BNOX)4 Rh2(4R-BNOX)4 Rh2(4S-IBAZ)4 Rh2(4S-IBAZ)4 Rh2(4S-MACIM)4 57 (31) 56 (58) 27 (40) 34 (24) 67 (34) 46 (8) 34 (77) 36 (47) 43 (30) 43 (88) 44 (33) 73 (72) 66 (57) 33 (62) 54 (13) 66 (95) 64 (73) 57 (37) 3.3 Intramolecular Processes Because of geometric constraints, intramolecular cyclopropanations of unsaturated diazocarbonyl compounds can produce only one fused bicyclic cyclopropane (the cis isomer). Tanimori et al (1997) have reported a chiral auxiliary approach to intramolecular cyclopropanation of a diazoacetate in their synthetic route to the carbocyclic moiety of the anti-HIV agent carbovir equation 3. This is, however, a rare diastereoselective approach, since the dirhodium(II) carboxamidate catalysts 9-12 have proven to be ROOS, RAAB, and AL-HATMI most efficient and selective for reactions of diazoacetates and diazoacetamides (Doyle et al, 1995c, 1997c, 1998d). Table 5. Enantioselective intermolecular cyclopropanation with phenyldiazoacetate R Ph cat R PhR1 2 + N2 CO2Me alyst 1 R2 CO2Me 24 R1 R2 Catalyst ee of Z, % Ph pClC6H4 pMePC6H4 EtO nBuO nBu Ph Ph H H H H H H Ph Me Rh2(S-TBSP)4 Rh2(S-TBSP)4 Rh2(S-TBSP)4 Rh2(S-DOSP)4 Rh2(S-DOSP)4 Rh2(S-DOSP)4 Rh2(S-TBSP)4 Rh2(S-TBSP)4 87 85 88 66 64 77 97 85(E), 81(Z) Table 6. Enantioselective intermolecular cyclopropenation COXH R CH2Cl2 Rh2L4*, 9aN2CHCOX+R R X Yield % ee % CH(OEt)2 CH2OMe CH2OMe tBu CH2OMe tBu OMe OtBu OEt OEt NMe2 NMe2 42 52 73 85 22 47 ≥ 98 78 69 57 ≥ 94 89 88 DIRHODIUM(II) CARBENES: THE CHIRAL PRODUCT CASCADE (3) O CO2R* N2 Rh2(OAc)4 HO N N N N OH NH2 CO2R* O major isomer (de 72%) carbovirR* = ( R)-pantolactone ( )n (4) 26: n = 1,2 Z = O, N-tBu 25: n = 1,2 Z = O, N-tBu Rh2L4*, (S)- or (R)-9a CH2Cl2 Z O R1 R2 n( ) Z O CHN2 R1 R2 Excellent enantioselectivities have been reported in a series of allylic diazoacetates 25 (n = 1, Z = O) catalysed by Rh2(5S-MEPY)4 (S-9a), and Rh2(5R-MEPY)4 (R-9a) to give fused cyclopropyl lactones 26 (n = 1, Z = O) equation 4 (Doyle et al, 1991b, 1995c, 1996e). Cyclopropanation of homoallylic diazoesters 25 (n = 2, Z = O) (Martin et al, 1992a) and N-tert-butyldiazoacetamides 25 (n = 2, Z = N-tBu) equation 4 (Doyle et al, 1994e) proceeded with moderate to high enantioselectivities with the same catalysts. It has further been shown that enantioselectivities obtained in the catalysed cyclopropanation of allylic diazoacetates 27a-g to give the cyclopropyl γ-lactones 28a-g, were largely dependant on the position of vinylic substitution (Table 7) (Doyle et al, 1995c). As is shown in Table 7, careful selection of the catalyst becomes necessary in order to optimise the enantioselectivity (Doyle et al, 1995d, 1997c). Application of the enantiomeric catalysts to the cyclopropanation of these allylic diazoacetates provide the cyclopropyl lactone products with the same enantiomeric excesses, but with the opposite absolute configurations. A recent contribution to the area by Martin and Hillier (1998) has investigated the complimentarity of chiral diazoacetates and chiral catalysts in a form of double diastereodifferention- cyclopropanation. Several pharmacologically important molecules have been synthesized through the use of the above methodology, using either of the enantiomeric catalysts 9a. As outlined in Scheme 8, Martin et al (1992b, 1993) synthesized trisubstituted cyclopropanes as conformationally restricted peptide isosteres for renin 29 and collagenase inhibitors, and Rogers et al (1995) have synthesizes presqualene alcohol 30. In addition, the products of these cyclopropanation reactions may serve as synthetic precursors to cis- chrysanthemic acid (Mukaiyama et al, 1983) and the pheromone R-(-)-dictyopterene C (Schotten et al, 1986). With homoallylic diazoacetates 31 (n = 2, R4 = H) (Martin et al, 1992a; Doyle et al, 1995c) and allylic diazopropionates 31 (n = 1, R4 = Me) (Doyle and Zhou, 1995e), there is a moderate reduction in the enantioselectivity with a similar selection of dirhodium catalysts (Table 8). 89 ROOS, RAAB, and AL-HATMI Table 7. Enantioselective intramolecular cyclopropanation of allylic diazoacetates R Rh R O H 90 O CH O refluxCH2Cl2 2 R1 N2 3 27a-g 28a-g O R2 R3 R1 2L4* 27 R1 R2 R3 Catalyst Yield % (ee %) Config. a b c c d e e f f g H Me H H H Ph Ph Pr Pr H H Me H H Ph H H H H iPr H H Me Me H H H H H H 9a 9a 9a 11d 9a 9a 11d 9a 11d 9a 75 (95) 89 (98) 72 (7) 75 (89) 70 (≥94) 78 (68) 61 (96) 93 (85) 83 (95) 85 (≥94) (1R,5S) (1S,5R) (1R,5S) (1S,5R) (1R,5S) (1R,5S) (1R,5S) (1R,5S) (1R,5S) (1R,5S) Analogous intramolecular cyclopropanation of N-allyl diazoacetamides 32 (n = 1) (Doyle et al, 1995c, 1996f) and N-tert-butyl-N-homoallylic diazoacetamides 32 (n = 2) (Doyle et al, 1994e) to give the cyclopropyl lactams have progressively been refined to high yielding, highly enantioselective processes (Table 9). O N2 O Me H O Me O H H H O Me H H HO (5) Rh2L4* 7 (Z = C12H25) 93% ee heat Although diazoacetates and diazoacetamides generally undergo dirhodium(II)-catalysed intramolecular cyclopropanation with high enantiocontrol, the same is not true for diazoketones. Here the best results were obtained from copper-based catalysts (Doyle et al, 1997d). The Davies group has demonstrated the applicability of their formal [3 + 4]-cycloaddition in an intramolecular example as part of a synthesis of 5-epitremulenolide equation 5 (Davies and Doan, 1996e). DIRHODIUM(II) CARBENES: THE CHIRAL PRODUCT CASCADE Outside of two very recent preliminary reports from the Doyle group (Doyle et al, 1999b, 1999c), no widespread success with intramolecular cyclopropenation has been developed. These reactions often produce unstable fused cyclopropenes that undergo ring opening to vinylcarbenes that can react by a number of pathways, often giving rise to multiple products (Padwa et al, 1991, 1993). N2CH O O R2 R1 N2CH O O Rh2(5S-MEPY)4 9a O O H H R1 R2 >94% ee>94% ee O O H H Me O N O H R1 R2 O N H O H N OH OH SN HMe OH H 29 renin inhibitor 30 presqualene alcohol Scheme 8. Applications of enantioselective intramolecular cyclopropanation 91 ROOS, RAAB, and AL-HATMI Table 8. Enantioselective intramolecular cyclopropanation of homoallylic diazoacetates and allylic diazopropionates R 92 RR Rh2L4* O O 2 3 R4 R1 31 O O R4 N2 R1 R2 3 ( )n ( )n CH2Cl2 n R1 R2 R3 R4 Cat. Yield % (ee %) 2 2 2 2 2 2 1 1 1 H Me H Ph H H Me H H H Me Ph H Et H Me nPr Ph H H H H H Me H H H H H H H H H Me Me Me 9a 9a 9a 9a 9a 9a 10a 10a 10a 80 (71) 74 (77) 73 (88) 55 (73) 80 (90) 76 (83) 81 (71) 62 (85) 65 (78) 3.4 Insertion Products Catalytically generated metal carbenes have been shown to be capable of highly versatile insertion into carbon-hydrogen and heteroatom-hydrogen bonds equation 6. X H LnM CR2 R2C H X + + MLn (6) Although generally indiscriminate, the advent of dirhodium(II) catalysts provided the required element of control to make these highly attractive C-C bond-forming processes (Maas, 1987; Doyle, 1986, 1995a; Ye and McKervey, 1994; Nefedov et al, 1992; Padwa and Krumpe, 1992). Although the DIRHODIUM(II) CARBENES: THE CHIRAL PRODUCT CASCADE mechanism of the transition metal catalysed C-H insertion reactions has been the subject of considerable speculation (Taber, 1991; Doyle, 1992), there is general agreement that insertion occurs through a metal carbene intermediate. Doyle and co-workers have suggested the mechanism depicted below as a suitable model for the C-H insertion process (Scheme 9) (Doyle et al, 1993b). Table 9. Enantioselective intramolecular cyclopropanation of N-allyl and N-homoallylic diazoacetamides R RR R Rh2L4* N R4 O 2 3 1 32 N R4 O N2 1 R2 R3 ( )n ( )n CH2Cl2 n R1 R2 R3 R4 Cat. Yield % (ee %) 1 1 1 1 1 2 2 2 2 2 H Me H Pr H H Me H Et H H Me Pr H H H Me Et H H H H H H Me H H H H Me H Me Me Me Me tBu tBu tBu tBu tBu 10a 10a 11d 11d 11d 9a 9a 9a 9a 9a 40 (98) 91 (94) 88 (95) 93 (92) 84 (44) 60 (60) 75 (75) 94 (90) 62 (67) 87 (78) 93 C HB C HB A H A D Rh2L4 H E + A C Rh2L4 H E D CB H ED Scheme 9. Proposed mechanism of C-H insertion ROOS, RAAB, and AL-HATMI 3.4.1 Carbon-Hydrogen Insertion Products Although examples of dirhodium(II) catalysed intermolecular C-H insertion reactions are known, they generally lead to multiple products and require highly electrophilic catalysts in order to minimise competitive reactions such as formal carbene dimer formation. The yields and regioselectivities of these reactions are highly dependant on the catalyst employed (Demonceau et al, 1981, 1984). 94 34 N2 OO OR* OH 33 R* = Rh2(OAc)4 O CO2R* MeO O Scheme 10. Diastereoselective route to (+)-estrone methyl ether Intramolecular C-H insertion reactions of diazocarbonyl compounds are more effective and selective, and they have become synthetically relevant, with the dirhodium(II) carboxylates and carboxamidates 7-12 as the catalysts of choice (Doyle 1994a, Watanabe et al, 1995; Doyle and McKervey, 1997a, Anada and Hashimoto, 1998a). Two diastereoselective approaches are worthy of note. Both groups have used 1-naphthylborneol 33 esters as the chiral auxiliary for asymmetric induction in C- H insertion reactions (Taber et al, 1987, 1998; Wee and Liu, 1996). Taber and co-workers achieved diastereoselectivities of 83:17-92:8, which corresponds to enantiomeric excesses for the hydrolysed ester of 66 to 84%. This procedure was extended to a synthesis of (+)-estrone methyl ether 34 (Scheme 10). Wee and Liu (1996) used this auxiliary in the C-H insertion reactions of diazomalonamides equation 7. Enantioselective adaptations have been a more recent development. The McKervey group (McKervey an Ye, 1992; Kennedy et al, 1990; Doyle and McKervey, 1997a) and others (Hashimoto et al, 1990, 1994; Anada and Hashimoto, 1998a, 1998b) have utilised dirhodium(II) carboxylates derived from N-protected amino acids (catalysts 7 and 8 respectively) to catalyse the enantioselective C-H insertion of diazoketone derivatives. Enantioselectivities in the C-H insertion reactions of α-diazo-β-ketosulphones catalysed by 7 (Z = H) were low (~12% ee), although yields were high Kennedy et al, 1990). With a series of methyl diazo ketones 35, the same catalyst yielded the corresponding chromanones with enantioselectivities (for the major cis isomers) of 62-82% ee equation 8 (McKervey an Ye, 1992). Taber and co-workers have very recently published a preliminary report on the preparation of a new type of chiral catalyst 36 (enantiomeric M and P) that has backbone chirality. Whilst this design strategy may DIRHODIUM(II) CARBENES: THE CHIRAL PRODUCT CASCADE have potential, the initial intramolecular C-H insertions with a diazoketone only afforded an enantioselectivity of 36% (Taber et al, 1999). 95 R R*O O N2 O N PMP PMP = pMeOC6H4 R* = 33 N RR*O2C O PMP Rh2(OAc)4 N R O PMP R = nHex 45% ee (R) R = cHex 98% ee (S) R = Ph 79% ee (S) (7) R = CH3, Ph, CH=CH2 O N2 CH3 O R O O CH3 R (8) 35 Major cis 62-82% ee Rh2L4* 7 (Z = H) CH2Cl2 Hashimoto and co-workers obtained enantiomeric excesses of 24-76% ee in the intramolecular C-H insertion reactions of α-diazo-β-keto esters 37 catalysed by catalysts of type 8, to yield β-keto esters 38 equation 9 (Hashimoto et al, 1990). More recent results with this catalyst line have afforded good enantioselective routes to azetidinones (Anada and Hashimoto, 1998b) and 2-pyrrolidones (Anada and Hashimoto, 1998a). These successes are exemplified by their syntheses of intermediates for trinem β- lactam antibiotics 39 and a typical GABAB receptor agonist (R)-(-)-baclofen 40 (Scheme 11). P Rh Rh Ph PhP Ph Ph O O CF3 O O CF3 (M)-36 P RhRh Ph Ph P Ph Ph OO CF3 OO CF3 (P)-36 ROOS, RAAB, and AL-HATMI 96 N N ON 2 O MeO2C ON O MeO2C H H NH RO H H O O N2MeO2C O R NO2 Rh2L4* 8 N MeO2C O NO2 R 82% ee HO2C NH2.HCl RH 40 84% ee R = pClC 6H4 N HO H H O OMe CO2R 39 trinem antibiotics (R)-(-)-baclofen Rh2L4* 8 Scheme 11. Applications of enantioselective intramolecular C-H insertion DIRHODIUM(II) CARBENES: THE CHIRAL PRODUCT CASCADE Doyle and co-workers have applied the homochiral dirhodium(II) carboxamidate catalysts to the enantioselective carbon-hydrogen insertion reactions of diazoesters and diazoamides (Doyle et al, 1993c, 1995b, 1996c). An early application of Rh2(5S-MEPY)4 9a was in the diazo decomposition of alkyl diazoacetates such as 41 to give the corresponding γ-lactones 42 in high yield, since insertion into a C-H bond α to an ether oxygen is a facile process equation 10 (Doyle et al, 1991c). With primary alkyl diazoacetates other than 41, C-H insertion reactions catalysed by Rh2(MEPY)4 proceed with enantioselectivities that are < 70% ee. However, the introduction of 2-oxoimidazolidine catalyst variants 11 has led to enhanced enantioselectivities and excellent regiocontrol (Doyle et al, 1994f, 1995f-h; Müller and Polleux, 1994; Bode et al, 1996). For example, use of Rh2(4S-MPPIM)4 11d provided γ-lactones 44 from diazoacetates 43 derived from primary alcohols equation 11. This methodology provided facile access to a series of naturally occuring lignans, for example (-) enterolactone 45, (+)-arctigenin 46 and (+)-isodeoxypodophyllotoxin 47 (Bode et al, 1996). A = Me, Ph, C5H11, CH=CH2 38 24-76% ee37 (9) O COOR A Rh2L4* 8 CH2Cl2 A COOR N2 O (10) 91% ee 89% ee 87% ee R = Me Et Bn 62-73% CH2Cl2 Rh2L4* 9a 4241 O O RO O O RO N2 (11) 96% ee 95% ee 89% ee 92% ee 94% ee R = Et iBu Bn mMeOBn 3,4-(MeO)2Bn 62-73% CH2Cl2 Rh2L4* 11d 4443 O O R O O R N2 97 ROOS, RAAB, and AL-HATMI O O 98 47 O O OMe OMeMeO O 46 HO OMe O OMe OMe O O HO HO 45 This methodology has been applied to the C-H insertion reactions of secondary cycloalkyl diazoacetates 48, where diastereoselectivity in the formation of cis- and trans-fused bicyclic lactones 49 and 50 is a critical control feature (Table 10) (Doyle et al, 1994f). Use of Rh2(5S-MEPY)4 9a or Rh2(4S- MEOX)4 10a produced insertion products with a high degree of enantiocontrol, but levels of diastereocontrol were far lower. In the formation of the more strained fused cyclopentyl lactone, only the cis diastereomer is formed, but the levels of enantioselectivity are lower than those obtained with the larger ring-sizes. However, both high enantiocontrol and almost complete stereocontrol were achieved in the latter with the catalyst Rh2(4S-MACIM)4 11a (Table 10) (Doyle et al, 1994f). Investigation of the enantioselective C-H insertion reactions of tertiary cycloalkyl diazoacetates 51a,b catalysed by Rh2(5S-MEPY)4 9a and Rh2(4S-BNOX)4 10c have been carried out equation 12 (Müller and Polleux, 1994). In contrast to the secondary cycloalkyl analogues above (Table 10), both enantioselectivities and yields obtained in the formation of the bicyclic lactones 52a,b were poor, although only cis products were observed. Again, Rh2(4S-MACIM)4 led to greatly improved results (Doyle et al, 1995f). High levels of enantio- and diastereocontrol have been achieved with cis- or trans-4- alkylcyclohexyldiazoacetates (Doyle et al, 1994f; Müller and Polleux, 1994), and with 2-adamantyl diazoacetate (Doyle et al, 1995b) in the formation of lactones 53-55 respectively. CH3 O O CHN2 Rh2L4* 9a CH2Cl2 O O CH3 H (12) 51 a n = 1 b n = 2 52 a 85% ee b 90% ee Doyle and co-workers have described the use of Rh2(5R-MEPY)4 R-9a in the C-H insertion reactions of glycerol derived diazoacetates for the convenient synthesis of pure 2-deoxyxylolactone (Scheme 12) (Doyle et al, 1994g). The success of this reaction is probably based on the ether oxygen’s DIRHODIUM(II) CARBENES: THE CHIRAL PRODUCT CASCADE electronic activation of adjacent C-H bonds (Adams et al, 1989; Wang and Adams, 1994). In the absence of the ether oxygen, enantioselectivities in the C-H insertion reactions of alkyl diazoacetates remain high, but diastereocontrol with Rh2(MEPY)4 catalysts tends to be relatively low. 99 H O H3C O H H 54 95% ee O 3C O H H 53 98% ee 55 98% ee O O H Table 10. Diastereo- and enantioselective intramolecular synthesis of fused bicyclic lactones CH Rh O O O O N2 ( )n 2L4* CH2Cl2 O H H ( )n O H H ( )n 48 a n = 1 b n = 2 c n = 3 d n = 4 49 a-d 50 a-d 46 Cat 49:50 49 % ee 50 % ee a a b b b c d 11a 9a 11a 9a 10a 11a 11a 100:0 100:0 99:1 75:25 55:45 99:1 99:1 89 40 97 97 96 96 97 - - 65 91 95 61 59 Dirhodium(II) carboxamidate catalysed C-H insertion reactions of diazoacetamides derived from cyclic amines have been shown to afford β-lactam products preferentially, with a high degree of enantiocontrol equation 13 (Doyle and Kalinin, 1995i). ROOS, RAAB, and AL-HATMI Rh2L4* (R)-9a CH2Cl2 67% N H O N CHN2 O 97% ee (13) O C CH OR 100 RO RO HN2 O Rh2L4, (R)-9a 2Cl2 65-81% O O H H RO O O H H OR RO + R = Me, 97% ee R = Bn, 94% ee 93% 7% R =Bn H2 Pd(OH)2/C 83% O O H OH H HO 2-deoxyxylolactone Cl Cl OH Scheme 12. Enantioselective synthesis of 2-deoxyxylolactone 3.4.2 Heteroatom-Hydrogen Insertion Products The insertion of transition metal carbenes, particularly those derived from dirhodium(II) carboxylate catalysts, into a variety of nucleophilic heteroatom-H bonds have provided novel routes to the synthesis of many synthetically relevant compounds (Ye and McKervey, 1994; Doyle et al, 1998a). Of these, insertion into O-H, N-H and Si-H are the most prominent. Asymmetric variants of these reactions are, outside of those that are conducted on enantiomerically pure substrates, still in their infancy. Of the asymmetric variants reported, the diastereoselective chiral auxiliary approach has shown the most success. Recently, Moody and co-workers reported the Rh2(OAc)4 catalysed intermolecular O-H insertion reactions of chiral auxiliary-bearing diazoacetates with simple alcohols, with diastereomeric excesses of up to 53% being attained (Table 11) (Aller et al, 1995; Miller et al, 1999). To date the N-H insertion reactions reported have shown disappointing levels of asymmetric induction (< 50% ee), and much more research is required before this becomes a useful synthetic tool (Aller et al, 1996; Garcia et al, 1996). On the other hand, Si-H insertion has shown greater promise. The Landais group (Landais, 1997) has provided the most significant results via a chiral auxiliary approach (Landais et al, 1994a, 1994b; Bulugahapitiya et al, 1997) equations 14, 15. Three groups have independently reported initial successful results in an enantioselective approach with chiral dirhodium DIRHODIUM(II) CARBENES: THE CHIRAL PRODUCT CASCADE catalysts, Rh2(5S-MEPY) 9a (Buck et al, 1996; Bulugahapitiya et al, 1997) and Rh2(S-DOSP)4 7 (Davies et al, 1997c). The best results equation 16 were obtained with vinyldiazoacetates. 101 CH N2 O O menthyl Et3SiH Rh2(OAc)4 2Cl2 SiEt3 O O menthyl (14) dr = 72:28 Et N2 O O H O O PhMe2SiH Rh2(OAc)4 CH2Cl2 75% Et O O H O O PhMe2Si H (15) dr = 85:15 R1 R2 N2 CO2R3 Rh2L4* 7 PhMe2SiH R1 R2 CO2R3 SiMe2Ph L = (S-DOSP) ee 77-95% L = (5S-MEPY) ee 52-72% (16) 3.5 Aromatic Cycloaddition and Substitution Products Transition metal catalysed carbene addition to aromatic rings may be considered a special class of cyclopropanation reaction. The high-yielding dirhodium(II) catalysed intramolecular reactions of α- diazocarbonyl compounds form the fused bicyclic cycloheptatrienes such as 56 This was reduced to the bicyclodecanone 57 with a determined enantiomeric excess of 33% equation 17 (Kennedy et al, 1990). Asymmetric success has also been observed using chiral dirhodium(II) phosphates 13a and have yielded enantioselectivities of up to 60% ee equation 18 (McCarthy et al, 1992). 5756 (17) CH2Cl2 80% 93% 33% ee O N2 O O H Pd/C, H2Rh2L4* 7 (Z = H) ROOS, RAAB, and AL-HATMI Table 11. Diastereoselective intermolecular O-H insertion by chiral auxiliary-bearing diazoacetates Ph N2 O OR* ROH or H 2O Rh2(OAc)4 Ph O OR* H OR(H) R* ROH Yield % dr (major config) MeOH 95 52:48 H2O MeOH iPrOH 84 75 82 50:50 54:46 (S) 62:38 (S) H2O MeOH iPrOH tBuOH 79 63 85 40 66:34 (R) 72:28 (R) 68:32 (R) 76:24 (R) H2O IPrOH 85 71 75:25 (S) 71:29 (R) H2O iPrOH tBuOH 98 82 37 66:34 (R) 74:26 (R) 75:25 (R) 102 SO2N(cHex)2 iPr Ph Ph The only diastereoselective approach to aromatic cycloaddition involves the recent novel use of a chiral diol auxiliary as a tether between the aromatic substrate and the diazo reagent (Sugimura et al, 1998). This has provided entry into a series of potentially useful tropilidenes as chirons for further synthesis equation 19. DIRHODIUM(II) CARBENES: THE CHIRAL PRODUCT CASCADE O CH3 N2 CH3 O 60% ee 80% yield (18) catalyst 13a Rh2(OAc)4 CH2Cl2 O O R O (19)O O O R O O R N2 O Intramolecular aromatic substitution by metal carbenes represents a formal C-H insertion with tremendous potential for asymmetric synthesis via chiral catalysis. Although not many reports have appeared, there is evidence of early success. The Hashimoto group has exploited their amino acid phthalimide catalysts 8 to good effect in the synthesis of a range of indanones (Table 12) (Watanabe et al, 1995, 1996a). Table 12. Enantioselective intramolecular aromatic substitution 103 O N2 R2 R1 Rh2L4* 8 CH2Cl2 R1 O R2 58 R1 R2 58 yield % 58 % ee Me Et nPr allyl Me H H H H CO2Me 75 86 74 70 87 88 95 98 88 93 ROOS, RAAB, and AL-HATMI The same workers have exploited this protocol in the synthesis of the aspartate receptor antagonist FR 115427 (Scheme 13) (Watanabe et al, 1996a). 104 COMe O N2 CO2Me Me Me O CO2Me Rh2L4* 8 CH2Cl2 87%, 93% ee Me 2Me CO2Me NH.HCl 59 Scheme 13. Synthesis of antagonist FR 115427 via intramolecular aromatic substitution 3.6 Ylide Cascade Products Metal carbenes derived from α-diazocarbonyl compounds are electrophilic enough to add to heteroatoms and form ylides equation 20. These then may undergo a wide range of reactions including [2,3]-sigmatropic rearrangements, [1,2]-insertion (Stevens rearrangements), hydride elimination, and dipolar cycloaddition (Doyle and Forbes, 1998e; Doyle et al, 1998a). This diverse reactivity, along with their often-competitive initial formation, has contributed to the relatively barren landscape in terms of their dirhodium-catalysed asymmetric synthesis. Successful asymmetric adaptation is only a very recent achievement, and is so far restricted to oxonium ylide systems. R (20)+ R2 X R3 X R2O R1 R3 R R1 O Rh2L4 O O (21) CO2Me N2 O CH2Cl2 O CO2Me Rh2L4* 6, 8, 13a DIRHODIUM(II) CARBENES: THE CHIRAL PRODUCT CASCADE The initial examples were provided by the McKervey group who exploited a tandem ylide formation-[2,3]-sigmatropic rearrangement sequence to produce benzofuranone derivatives with up to 60% ee equation 21 (McCarthy et al, 1992; Pierson et al, 1997). Dirhodium(II) carboxamidate catalysts were used in initial studies of catalytic asymmetric tandem ylide formation-cycloaddition (Doyle and Forbes, 1998e; Suga et al, 1998). However, these only produced ee values of < 30%. Very recent developments have produced the first examples with ee values approaching synthetically useful levels. Thus diazo ketoesters were induced to give intramolecular cycloadducts with ee’s up to 53% equation 22 (Hodgson et al, 1997). The Hashimoto group has taken this development further with diazo ketones in the intermolecular cycloaddition to afford bridged bicyclic skeletons in good yield and high enantioselectivity equation 23 (Kitigaki et al, 1999). 105 N2 CO2R O O (CH2)n Rh2L4* 7 (Z = nC12H25) O O CO2R (CH2)n (22) The Doyle group has provided the best enantioselective (ee up to 88%) example of ylide formation- [1,2]-insertion in their report on the decomposition of 1,3-dioxane diazoacetates equation 24 (Doyle et al, 1997e). Ph O O Rh N2 CO2MeMeO2C 2L4* 8 O O Ph CO2MeMeO2C (23) 51-78% yield 70-92% ee O OMe Me O CHN2 O Me Rh2L4* 11d CH2Cl2 86%, 81% ee O O Me Me Me (24) 4. Conclusion Over the past decade, the reports of chiral dirhodium(II) catalyst systems and their applications to asymmetric synthesis have burgeoned. As this technology is applied to a greater diversity of reaction systems, it seems inevitable that the spectrum of dirhodium(II)-carbene chemistry will continue to ROOS, RAAB, and AL-HATMI 106 expand. Given the wide range of non-racemic products that can be targeted in this way, these developments auger well for asymmetric organic synthesis and the industries that depend thereon. Note added in proof The readers’ attention is drawn to the following noteworthy contributions which have appeared since original submission. Doyle et al (1999d) – intramolecular addition to remote furans; Davies and Panaro (1999) - improved D2-symmetric dirhodium(II) tetraprolinate cyclopropanation catalysts; Doyle et al (2000) – macrocycle formation via intramolecular cyclopropanation. 5. 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Use of Cyclopropanes and Their Derivatives in Organic Synthesis. Chem. Rev. 89: 165-198. YE, T. and McKERVEY, M. A. 1994. Organic Synthesis with α-Diazocarbonyl Compounds. Chem. Rev. 94: 1091- 1160. Received 29 January 2000 Accepted 28 August 2000 113 Dirhodium(II) Carbenes : The Chiral Product Cascade *Gregory H. P. Roos, **Conrad E. Raab and *Said Al-Hatmi Introduction74 1.1 The Need for Asymmetric Synthesis 74 Reaction Products From Dirhodium(II) Carbenes80 3.2 Intermolecular Processes81 3.3 Intramolecular Processes87 Introduction 1.1 The Need for Asymmetric Synthesis The world around us is chiral. Most organic compounds are chiral. The chemistry of perfumes, nutrients, pesticides, and pharmaceuticals involves chiral compounds whose physiological or pharmacological properties depend upon their recognition by chiral re Reaction Products From Dirhodium(II) Carbenes 3.2 Intermolecular Processes Initial attempts at asymmetric intermolecular cyclopropanations by means of chiral auxiliaries bonded to diazoacetates were largely unsuccessful (equation 1, Z = chiral auxiliary). Chiral N-(diazoacetyl)oxazolidinones 16 and 17 underwent Rh2(OAc)4 R R Ph R 3.3 Intramolecular Processes Because of geometric constraints, intramolecular cyclopropanations of unsaturated diazocarbonyl compounds can produce only one fused bicyclic cyclopropane (the cis isomer). Tanimori et al (1997) have reported a chiral auxiliary approach to intramolec Ph X Me Pr Heteroatom-Hydrogen Insertion Products The insertion of transition metal carbenes, particularly those derived from dirhodium(II) carboxylate catalysts, into a variety of nucleophilic heteroatom-H bonds have provided novel routes to the synthesis of many synthetically relevant compounds (Ye R* Conclusion Note added in proof