Natural Products Synthesis REVIEWS wittig olefination CH,OAe iodolactonization Dc a acetone Meo,C cove MeO. c b. BuOCocI H NaH: MeOCH-CI KOH coMe Die's-Alder relayed s a (80%) CO Me 10-OMe (99%) BUOCON S BoCON、 s COMe BBuOC()N S CO2Me (>63%lb. CrO3'2py BLOC(O)N major product a. KCO3 Aco, MeOH DHP, PTSOH Meog H a Meso Cl Meo C N, /reduction of azide o DIBAL-H BUoNO)N lactamization no"aeop。0、a CocH,cCk HO C H Scheme 11. a) Strategic bond disconnections and retrosynthetic analysis of (+)-PGF and b) the total synthesis( Corey et al., 1969). M BUOCION synthetic work s1-83I followed the initial Corey synthesis and CClCH2OH, myriad prostaglandin analogues have since been synthesized a. BH3 /neutral reducing agent) aiding both biology and medicine tremendously Coreys original strategy evolved alongside the impressive CHOAc developments in the field of asymmetric catalysis, many which he instigated, which culminated by the 1990s, in a refined, highly efficient and stereocontrolled synthesis of the CO:CH2CCls prostaglandins. I 84) Thus, in its original version, the Corey synthesis of prostaglandins F2a and E2 was nonstereoselective Scheme 10. a)Strategic bond disconnections and retrosynthetic analysis of and delivered the racemate and as a mixture of C15 epimers. cephalosporin C and b) total synthesis (Woodward et al., 1966). 3o1 Then, in 1975, came a major advance in the use of a chiral auxiliary to control the stereochemical outcome of the crucial Diels-Alder reaction to form the bicyclo[2. 2. 1 heptane trosynthetic analysis concepts and demonstrated the uti- system in its optically active form. ls) The theme of chiral lization of the bicycloheptane system derived from a Diels- auxiliaries to control stereochemistry played a major role Alder reaction as a versatile key intermediate for the syn- the development of organic and natural products synthesis in hesis of several of the prostaglandins. A large body of the latter part of the century. In addition to the contributions Angew. Chem. Int Ed 2000, 39, 44-122
Natural Products Synthesis REVIEWS N S O H H CO2H CH2OAc NH CO2H O H H2N NH O tBuOC(O)N S Me Me H H tBuOC(O)N S Me Me H H MeO2C N3 H2N SH H HO2C H2N SH H HO2C tBuOC(O)N S Me Me H MeO2C N N CO2Me MeO2C tBuOC(O)N S Me Me H MeO2C H N N CO2Me CO2Me tBuOC(O)N S Me Me H MeO2C N NH CO2Me CO2Me tBuOC(O)N S Me Me H MeO2C H N NH CO2Me CO2Me tBuOC(O)N S Me Me H MeO2C H N N CO2Me CO2Me tBuOC(O)N S Me Me H MeO2C H N N CO2Me tBuOC(O)N S Me Me H MeO2C N N CO2Me tBuOC(O)N S Me Me H MeO2C N N CO2Me OAc tBuOC(O)N S Me Me H MeO2C OAc tBuOC(O)N S Me Me H MeO2C OAc tBuOC(O)N S Me Me H MeO2C OAc H H tBuOC(O)N S Me Me H MeO2C OH H tBuOC(O)N S Me Me H MeO2C N3 H tBuOC(O)N S Me Me H H NH O CO2H HO2C H OH HO H CHO O O CCl3 O H O HO H CO2CH2CCl3 H O O CO2CH2CCl3 H H tBuOC(O)N S Me Me H H N O O H O H N O S CHO CO2CH2CCl3 H2N H H N O S CHO CO2CH2CCl3 N H H CO2CH2CCl3 H NHCO2CH2CCl3 O H N O S CH2OAc CO2CH2CCl3 N H H CO2CH2CCl3 H NHCO2CH2CCl3 O H N O S CH2OAc CO2CH2CCl3 N H H CO2CH2CCl3 H NHCO2CH2CCl3 O H N O S CH2OAc CO2H N H H CO2H H NH2 O NaO CHO CO2H CO2H H NHCO2CH2CCl3 [-N2] O CHO CO2CH2CCl3 H tBuOC(O)N S Me Me H MeO2C OAc H CO2CH2CCl3 [equilibration] 6 a. acetone b. tBuOCOCl c. CH2N2 OAc 1: cephalosporin C OAc OAc b) a) Conjugate addition Cyclization Amide bond formation 1: cephalosporin C Pd(OAc)4 OAc + AcO, MeOH a. MeSO2Cl b. NaN3 a. Al/Hg/MeOH b. iBu3Al a. CCl3CH2OH, pTsOH b. NaIO4 ∆ TFA a. DCC b. CCl3CH2OH, DCC a. BH3 b. Ac2O, py py Zn, AcOH [oxidation] [SN2 with inversion of configuration] [reduction of azide] [lactamization] 19: tartaric acid [neutral reducing agent] [reductive removal of the protecting groups] 2 4 7 9 8 12 11 10 13 14 15 17: minor product 16 5 4 2 20 21 18 22 3 27 24 28 25 6: L-(+)-cysteine 23 + 3 26 5: major product Scheme 10. a) Strategic bond disconnections and retrosynthetic analysis of cephalosporin C and b) total synthesis (Woodward et al., 1966).[30] retrosynthetic analysis concepts and demonstrated the utilization of the bicycloheptane system derived from a Diels ± Alder reaction as a versatile key intermediate for the synthesis of several of the prostaglandins. A large body of Scheme 11. a) Strategic bond disconnections and retrosynthetic analysis of ()-PGF2a and b) the total synthesis (Corey et al., 1969).[80] synthetic work[81±83] followed the initial Corey synthesis and myriad prostaglandin analogues have since been synthesized, aiding both biology and medicine tremendously. Corey s original strategy evolved alongside the impressive developments in the field of asymmetric catalysis, many of which he instigated, which culminated by the 1990s, in a refined, highly efficient and stereocontrolled synthesis of the prostaglandins. [84] Thus, in its original version, the Corey synthesis of prostaglandins F2a and E2 was nonstereoselective and delivered the racemate and as a mixture of C15 epimers. Then, in 1975, came a major advance in the use of a chiral auxiliary to control the stereochemical outcome of the crucial Diels ± Alder reaction to form the bicyclo[2.2.1]heptane system in its optically active form.[85] The theme of chiral auxiliaries to control stereochemistry played a major role in the development of organic and natural products synthesis in the latter part of the century. In addition to the contributions Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 59
REVIEWS K. C. Nicolaou et al of Corey, those of A I Myers, 86 D. A. Evans, s7 W.Oppolz- er,/sSI and H. C. Brown! I as well as many others helped shape the field t-cyclization Finally came the era of catalyst design and here again the prostaglandins played a major role in providing both a driving force and a test. In a series of papers, Corey disclosed a set of 1: progesterone chiral aluminum- and boron-based 9o, 91 catalysts for the a/dowdehydration Diels-Alder reaction (and several other reactions) that facilitated the synthesis of an enantiomerically enriched intermediate along the route to prostaglandins And, finally, e problem of stereoselectivity at C15 was solved by the introduction of the oxazaborolidine catalyst(CBS) by Corey 6 in 1987. 192 These catalysts not only refined the industrial process for the production of prostaglandins, but also found b) uses in many other instances both in small scale laborator perations and manufacturing processes of drug candidates and pharmaceuticals. For a more in-depth analysis of the Corey syntheses of prostaglandins Fza and E2 and other advances on asymmetric catalysis, the reader is referred to b, CrO,2 py ref [4] and other appropriate literature sources. a PIsON b Nal, Mgo (cat. Progesterone(1971) Progesterone (1 in Scheme 12), a hormone that prepares b.-70→30 the lining of the uterus for implantation of an ovum, is a member of the steroid class of compounds that is found ubiquitously in nature. Its linearly fused polycyclic carbon 29 NaOHEtOH framework is characteristic of numerous natural products of C steroidal or triterpenoid structures. A daring approach to progesterone's skeleton by W S Johnson(93 was inspired by the elucidated enzyme ed conversion! of squalene oxide into lanosterol or to the closely related plant triterpen ML(99% oid dammaradienol. This biomimetic strategy was also encoura ged by the Stork-Eschenmoser hypothesis, whicl was proposed in 19551351 to rationalize the stereochemical o steroid. According to this postulate it was predicted that polyunsaturated molecules with trans C-C bonds, such as qualene oxide, should cyclize in a stereospecific manner, to furnish polycyclic systems with trans, anti, trans stereochemis- try at the ring fusion This brilliant proposition was confirmed by w.S. Johnson and his group through the biomimetic total synthesis of progesterone (Scheme 12). A tertiary alcohol serves as the initiator of the polyolefinic ring-closing cascade, in this Scheme 12. a)Strategic bond disconnections and retrosynthetic analysis of nstance, but other groups have also been successfully progesterone and b)total synthesis (Johnson et al., 1971) employed in this regard(for example, acetal, epoxide). The methylacetylenic group performed well as a terminator of the cascade in the original work. A number of new terminating Woodward in 1965. 96 By 1972 Kishi and his group had systems have since been successfully employed(for example, challenging saved at the time with great enthusiasm and Johnson was complemented by that of van Tamelen() and Japan was rece others 4 who also explored such biomimetic cascades. remains to this day as a classic in total synthesis. The target molecule was reached through a series of maneuvers which included a Diels- Alder reaction of a quinone with butadiene, Tetrodotoxin(1972) Beckman rearrangement to install the first nitrogen atom, stereoselective reductions, strategic oxidations, unusual func- of the Japanese puffer fish and its structure was elucidated by guanidinium system. As a highly condensed and polytuin Tetrodotoxin(1 in Scheme 13)is the poisonous compo tional group manipulations, and, finally, construction of Angew. Chem. Int. Ed. 2000. 39. 44-122
REVIEWS K. C. Nicolaou et al. of Corey, those of A. I. Myers, [86] D. A. Evans, [87] W. Oppolzer,[88] and H. C. Brown[89] as well as many others helped shape the field. Finally came the era of catalyst design and here again the prostaglandins played a major role in providing both a driving force and a test. In a series of papers, Corey disclosed a set of chiral aluminum- and boron-based[90, 91] catalysts for the Diels ± Alder reaction (and several other reactions) that facilitated the synthesis of an enantiomerically enriched intermediate along the route to prostaglandins. And, finally, the problem of stereoselectivity at C15 was solved by the introduction of the oxazaborolidine catalyst (CBS) by Corey in 1987. [92] These catalysts not only refined the industrial process for the production of prostaglandins, but also found uses in many other instances both in small scale laboratory operations and manufacturing processes of drug candidates and pharmaceuticals. For a more in-depth analysis of the Corey syntheses of prostaglandins F2a and E2 and other advances on asymmetric catalysis, the reader is referred to ref. [4] and other appropriate literature sources. Progesterone (1971) Progesterone (1 in Scheme 12), a hormone that prepares the lining of the uterus for implantation of an ovum, is a member of the steroid class of compounds that is found ubiquitously in nature. Its linearly fused polycyclic carbon framework is characteristic of numerous natural products of steroidal or triterpenoid structures. A daring approach to progesterone s skeleton by W. S. Johnson[93] was inspired by the elucidated enzyme-catalyzed conversion[94] of squalene oxide into lanosterol or to the closely related plant triterpenoid dammaradienol. This biomimetic strategy was also encouraged by the Stork ± Eschenmoser hypothesis, which was proposed in 1955[35] to rationalize the stereochemical outcome of the biosynthetic transformation of squalene oxide to steroid. According to this postulate it was predicted that polyunsaturated molecules with trans CC bonds, such as squalene oxide, should cyclize in a stereospecific manner, to furnish polycyclic systems with trans,anti,trans stereochemistry at the ring fusion. This brilliant proposition was confirmed by W. S. Johnson and his group through the biomimetic total synthesis of progesterone (Scheme 12). A tertiary alcohol serves as the initiator of the polyolefinic ring-closing cascade, in this instance, but other groups have also been successfully employed in this regard (for example, acetal, epoxide). The methylacetylenic group performed well as a terminator of the cascade in the original work. A number of new terminating systems have since been successfully employed (for example, allyl or propargyl silanes, vinyl fluoride). The work of W. S. Johnson was complemented by that of van Tamelen[95] and others[3, 4] who also explored such biomimetic cascades. Tetrodotoxin (1972) Tetrodotoxin (1 in Scheme 13) is the poisonous compound of the Japanese puffer fish and its structure was elucidated by Scheme 12. a) Strategic bond disconnections and retrosynthetic analysis of progesterone and b) total synthesis (Johnson et al., 1971).[93] Woodward in 1965.[96] By 1972 Kishi and his group had published the total synthesis[97] of this highly unusual and challenging structure. This outstanding achievement from Japan was received at the time with great enthusiasm and remains to this day as a classic in total synthesis. The target molecule was reached through a series of maneuvers which included a Diels ± Alder reaction of a quinone with butadiene, a Beckman rearrangement to install the first nitrogen atom, stereoselective reductions, strategic oxidations, unusual functional group manipulations, and, finally, construction of the guanidinium system. As a highly condensed and polyfunc- 60 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122
Natural Products Synthesis REVIEWS Rarely before has a synthetic project yielded so much CH-OH knowledge, including: novel bond-forming reactions and strategies, ingenious solutions to formidable synthetic prob- lems, biogenetic considerations and hypotheses, and the seeds 1: tetrodotoxin(%o epoxide opening of the principles of orbital imetry conservation known as he woodward and hoffmann rules [ss the structure of Epoxide opening vitamin B1 was revealed in 1956 through the elegant X-ray crystallographic work of Dorothy Crowfoot-Hodgkin I99 The escalation of molecular complexity from haemin to chloro phyll a to vitamin B1 is interesting not only from a structural point of view, but also in that the total molecule reflects the limits of the power of the art and science Sncl4 of organic synthesis at the time of the accomplishment. One of the most notable of the many elegant maneuvers of the Woodward-Eschenmoser synthesis of vitamin B1 is the reaction photoinduced ring closure of the corrin ring from a pre- Regio- and stereoselective reduction/ a. NaBH4, MeoH(%) organized linear system wrapped around a metal template lepaxide-mediated etherification/b. mCPBA CSA which was an exclusive achievement of the eschenmoser group. The convergent approach defined cobyric acid(2 in b BFr,O. Scheme 14)as a landmark key intermediate, which had (100%) I previously been converted into vitamin Bu by Bernhausen C. AMOIPr)3, IPrOH, et al. ool The synthesis of vitamin Bu defined the frontier of research in organic natural product synthesis at that time. For d(Etoj3CH, CSA; Aczo. py dimethylketal formation/ an in depth discussion of this f. mCPBA, K2CO oxidation/ reader is referred to ref [4] g. AcO lepard opening and acetylation) Erythronolide B(1978) The macrolide antibiotics, of which erythromycin is perhaps minato the most celebrated, stood for a long time as seemingly unapproachable by chemical synthesis. The origin of the initial barriers and difficulties was encapsulated in the following statement made by Woodward in 1956, "Erythro- EIo.. Na-c9pLA-cHionc complex, particularly in view of its plethora of asymmetric centers lol In addition to the daunting stereochemical a BrCN, NaHcO3 roblems of erythromycin and its relatives, also pending was the issue of forming the macrocyclic ring. These challenges gave impetus to the development of new synthetic technol- ogies and strategies to address the stereocontrol and macro- cyclization problems. The brilliant total synthesis of erythronolide Bloz(1 overall) Scheme 15), the aglycon of erythromycin B, by Corey et al. HOA YOH published in 1979, symbolizes the fall of this class of natural products in the face of the newly acquired power of organic thesis. additionally, it provides further illustration of the Scheme 13. a)Strategic bond disconnections and retrosynthetic analysis of classical strategy for the setting of stereocenters on cyclic trodotoxin and b)total synthesis(Kishi et al. 1972). 971 templates. The synthesis began with a symmetrical aromatic system that was molded into a fully substituted cyclohexane tional molecule, tetrodotoxin was certainly a great conquest ring through a short sequence of reactions in which two and elevated the status of both the art and the practitioner, bromolactonizations played important roles. A crucial Baey- and at the same time was quite prophetic of things to come er-Villiger reaction then completed the oxygenated stereo- center at C6 and rendered the cyclic system cleavable to an vitamin Bn(973) open chain for further elaboration As was the case in many of Coreys syntheses, the total The total synthesis of vitamin B1(1 in Scheme 14), synthesis of erythronolide B was preceded by the invention of accomplished in 1973 by a collaboration between the groups a new method, namely the double activation procedure for the of Woodward and Eschenmoser, B,32l stands as a monumental formation of macrocyclic lactones employing 2-pyridinethiol achievement in the annals of synthetic organic chemistry. esters. 03 This landmark invention allowed the synthesis of Angew. Chem. Int Ed 2000, 39, 44-122
Natural Products Synthesis REVIEWS HN N H H2N HO H O HO O O OH CH2OH OH O O Me N Me HO Me O O H Me N HO Me O O H AcNH Me O H AcNH HO O H HO OH Me H AcNH O O O OAc H AcNH O O O OAc OH O O AcO OAc O H O AcNH H AcNH O OAc OAc O AcO O O O OAc CH2OAc H O H AcO AcHN OAc O O H H OAc CH2OAc H H O H AcO H2N OAc O O O O H H OAc CH2OAc H H O H AcO OAc O O N H HN N H H2N HO H O H HO O H O OH CH2OH OH H NH2 AcHN N H O H AcO O OHOAc CH2OAc OAc O O O AcO OAc O H CH2OAc O Me O H HO O H H S H2N O O H H OAc CH2OAc H H O H AcO OAc O O N AcHN AcHN O O H H OAc CH2OAc H O H AcO OAc HO HO N H2N AcHN OAc AcO- , SnCl4 a. MsCl, Et3N b. H2O, ∆ 1: tetrodotoxin [Beckmann rearrangement] [Lewis acid catalyzed Diels-Alder reaction] (83%) (61%) a. NaBH4, MeOH b. mCPBA, CSA (72%) b. Ac2O, CSA, ∆ (80%) a. OsO4, py b. (MeO)2CMe2, CSA c. Et3O BF4 , Na2CO3; AcOH (65%) a. BrCN, NaHCO3 b. H2S (100%) a. H5IO6 b. NH4OH 1: tetrodotoxin (9% overall) Orthoester formation C-N Bond formation trans-Esterification/ epoxide opening AcNH Baeyer-Villiger oxidation AcNH Epoxide opening/ cyclization Diels-Alder reaction [regio- and stereoselective reduction] [epoxide-mediated etherification] [diethylketal formation] [ethyl enol ether formation] [epoxidation] [epoxide opening and acetylation] a. Et3O BF4 ; Ac2O, py b. acetamide a. CrO3, py b. BF3•Et2O, c. Al(OiPr)3, iPrOH, ∆ d. Ac2O, py (86% overall) a. SeO2 b. NaBH4 (100%) d. (EtO)3CH, CSA; Ac2O, py e. ∆ f. mCPBA, K2CO3 g. AcOH a. mCPBA b. Ac2O, py c. TFA, H2O; Ac2O, py (53% overall) [Baeyer-Villiger oxidation] mCPBA (100%) a) b) a. (50%) BF3, TFA b. TFA, H2O 2 4 3 4 3 5 6 7 9 8 10 11 14 13 12 15 a. KOAc, AcOH c. vacuum, 300 °C [acetate elimination] Scheme 13. a) Strategic bond disconnections and retrosynthetic analysis of tetrodotoxin and b) total synthesis (Kishi et al., 1972).[97] tional molecule, tetrodotoxin was certainly a great conquest and elevated the status of both the art and the practitioner, and at the same time was quite prophetic of things to come. Vitamin B12 (1973) The total synthesis of vitamin B12 (1 in Scheme 14), accomplished in 1973 by a collaboration between the groups of Woodward and Eschenmoser,[3, 32] stands as a monumental achievement in the annals of synthetic organic chemistry. Rarely before has a synthetic project yielded so much knowledge, including: novel bond-forming reactions and strategies, ingenious solutions to formidable synthetic problems, biogenetic considerations and hypotheses, and the seeds of the principles of orbital symmetry conservation known as the Woodward and Hoffmann rules. [98] The structure of vitamin B12 was revealed in 1956 through the elegant X-ray crystallographic work of Dorothy Crowfoot-Hodgkin.[99] The escalation of molecular complexity from haemin to chlorophyll a to vitamin B12 is interesting not only from a structural point of view, but also in that the total synthesis of each molecule reflects the limits of the power of the art and science of organic synthesis at the time of the accomplishment. One of the most notable of the many elegant maneuvers of the Woodward ± Eschenmoser synthesis of vitamin B12 is the photoinduced ring closure of the corrin ring from a preorganized linear system wrapped around a metal template, which was an exclusive achievement of the Eschenmoser group. The convergent approach defined cobyric acid (2 in Scheme 14) as a landmark key intermediate, which had previously been converted into vitamin B12 by Bernhauser et al.[100] The synthesis of vitamin B12 defined the frontier of research in organic natural product synthesis at that time. For an in depth discussion of this mammoth accomplishment, the reader is referred to ref. [4]. Erythronolide B (1978) The macrolide antibiotics, of which erythromycin is perhaps the most celebrated, stood for a long time as seemingly unapproachable by chemical synthesis. The origin of the initial barriers and difficulties was encapsulated in the following statement made by Woodward in 1956, ªErythromycin, with all our advantages, looks at present hopelessly complex, particularly in view of its plethora of asymmetric centers.º[101] In addition to the daunting stereochemical problems of erythromycin and its relatives, also pending was the issue of forming the macrocyclic ring. These challenges gave impetus to the development of new synthetic technologies and strategies to address the stereocontrol and macrocyclization problems. The brilliant total synthesis of erythronolide B[102] (1 in Scheme 15), the aglycon of erythromycin B, by Corey et al. published in 1979, symbolizes the fall of this class of natural products in the face of the newly acquired power of organic synthesis. Additionally, it provides further illustration of the classical strategy for the setting of stereocenters on cyclic templates. The synthesis began with a symmetrical aromatic system that was molded into a fully substituted cyclohexane ring through a short sequence of reactions in which two bromolactonizations played important roles. A crucial Baeyer ± Villiger reaction then completed the oxygenated stereocenter at C6 and rendered the cyclic system cleavable to an open chain for further elaboration. As was the case in many of Corey s syntheses, the total synthesis of erythronolide B was preceded by the invention of a new method, namely the double activation procedure for the formation of macrocyclic lactones employing 2-pyridinethiol esters. [103] This landmark invention allowed the synthesis of Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 61
REVIEWS K. C. Nicolaou et al eo.c Meon EeOC COoMe 、m0pmnm COMe The A-B variant HOC CO Me oNA Moc The A-D variant 6-sgmatropic H-shilt 1: vitam PeSt, P-picoline MeOyC CoNvea MeDoc Me0-c Medic C-C bond 9 10 cO-Me b) The Eschenmoser sulfide contraction Meo.c X=OO N The Eschenmoser amide hydrolysis H2N.o HNO CN 16 CO2e MeO CMs CO Me M a N-O, CCl or 17 CONH AgBF4. 18 Eschenmoser's electrocyclic ring closure mode/ study based on the Woodward-Hoffmann transfornation 1: vitamin B12 2: cobyric acld heme 14. a)Strategic bond disconnections and retrosynthetic analysis of (-)-vitamin Bu. b)key synthetic methodologies developed in the course of the total synthesis, c)and final synthetic steps in the Woodward-Eschenmoser total synthesis of vitamin Bu(Woodward-Eschenmoser, 1973). P2 Angew. Chem. Int. Ed. 2000. 39, 44-122
REVIEWS K. C. Nicolaou et al. 62 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Scheme 14. a) Strategic bond disconnections and retrosynthetic analysis of (ÿ)-vitamin B12 , b) key synthetic methodologies developed in the course of the total synthesis, c) and final synthetic steps in the Woodward-Eschenmoser total synthesis of vitamin B12 (Woodward ± Eschenmoser, 1973).[32]
Natural Products Synthesis REVIEWS several macrolides including erythronolide b and,most significantly, catalyzed the development of several improve ments and other new methods for addressing the macro- cyclization problem. no4 Soon to follow Corey's synthesis of DH Functionalization erythronolide B was Woodward's total synthesis of erythro- Monensin(1979, 1980) Monensinllo!(1 in Scheme 16), isolated from a strain of Streptomyces cinamonensis, is perhaps the most prominent member of the polyether class of antibiotics. Also known as 5 ionophores, these naturally occurring substances have the ability to complex and transport metals across membranes, thus exerting potent antibacterial action. 106, 107 These struc- (96%) tures are characterized by varying numbers of tetrahydropyr an, tetrahydrofuran, and/or spiroketals. Kishi's total synthesis of monensin, s! which followed his synthesis of the simpler of complex molecules and is one of the first examples of and elegantly marked the application of the Cram rules within a. IOH the context of natural-product synthesis By unraveling the (70%)B20 spiroketal moiety of the molecule Kishi was able to adopt aldol-based strategy to couple monensin's two segments. A epoxidations)on acyclic systems with pre-existing stereo- a H2O2, Na2 WO4 b. Ambertyst IRC-50 centers allowed the construction of the two heavily substi C. Arso2CL py C CICO Et tuted fragments of the molecule which were then successfully coupled and allowed to fold into the desired spiroketal upon deprotection. Kishi's beautiful synthesis of monensin also HO,C 6% overal)o、OMeg provided a demonstration of the importance of 1, 3-allylic Buti, MgBr2Me strain in acyclic conformational preferences, which in turn can [ (s0%) be exploited for the purposes of stereocontrolled reactions (for example, epoxidation) Zn(BH4)2 A second total synthesis of monensin was accomplished in Bs 1980 by W C Still and his group(Scheme 17). 110 Just elegant as Kishi's synthesis, the Still total synthesis monensin demonstrates a masterful application of chelation controlled additions to the carbonyl function. A judicious choice of optically active starting materials as well as a highly convergent strategy that utilized the same aldol-spiroketali- zation sequence as in Kishi's synthesis allowed rapid access to 23。 monensin rather complex structure PhMe,△ Endiandric Acids(1982) The endiandric acids(Scheme 18)are a fascinating group of b HO2 NaoH natural products discovered in the early 1980s in the Australian plant Endiandra intros(Lauraceae) by Black epimerization at C-101 et al. un Their intriguing structures and racemic nature gave rise to the so called "Black hypothesis for their plant origin Me. >mq Me which involved a series of non-enzymatic electrocyclization from acyclic polyunsaturated precursors(see Scheme 18) Intrigued by these novel structures and Black's hypothesis for cheme 15. a)Strategic bond disconnections and retrosynthetic analysis of their"biogenetic"origin, we directed our attention towards thronolide B and b)total synthesis(Corey et al., 1978). a their total synthesis. Two Angew. Chem. Int Ed 2000, 39. 44-122
Natural Products Synthesis REVIEWS O Me OH Me OH Me Me OH OH Me Me O O O Me O Me CO2H Me O O Me Me O O Me Br OBz Me Me O O Me BzO OBz Me CO2H Me Me BzO Me O O S O N Me Me Me Me O OBz BzO O CO2H Me Me Me Me O OBz BzO N S S N O Me Me Me Me O OBz BzO O Me OTBS Me Me O Me Me Me HO OBz Me OTBS Me Me OBz Me O OH Me OH Me Me O O Me Me OH Me Me Me Me Me HO O O Me Me OH Me Me O O Me Me O O Me O Me Me OH Me Me O O Me Me O OH Me Me Me N N S S N N tBu tBu iPr iPr Me Me O OH Me Me Me Br O Me Me Me Me O Me CO2H Me O Me Me O O Me Br O O Me Me O O Me O Me Me O O Me HO OBz Me Me O O Me BzO Me Me HO2C OMe O OMe Me Me Me O Li Me I Me Me OTBS OH Me OH Me Me OBz OBz Me Me OH Me Me HO O O Me OH Me OH Me Me OH OH Me Me O O Me Me I Me OTBS O S O N Me Me Me Me O OBz BzO O Me Me OTBS Me O Me OBz Me HO OBz Me Me O OBz Me Me BzOMe O O Me Br Me O O O Me O Me Me O O Me Br OH Me Me Me OMe 13 15 11 14 (70%) (65%) a. H2O2, Na2WO4 b. resolution c. ClCO2Et d. NaBH4 e. POCl3, (76% overall) (90%) (98% ) a. H2, Pd/C [epoxide reduction] b. K2CO3, MeOH [epimerization at C-10] c. HCl Br2, KBr (50% ) 1: erythronolide B Ph3P CH3CO3H tBuLi, MgBr2 a. AcOH Zn(BH4)2 b. LiOH Ph3P; PhMe, ∆ a. MnO2 b. H2O2, NaOH b) NaOMe a. BH3•THF; H2O2, NaOH b. CrO3, H2SO4 (72%) Br2, KBr (96%) (91%) a. KOH, H2O (98%) b. resolution nBu3SnH AIBN (93%) Al/Hg a. H2, Raney-Ni b. BzCl 9 a. LDA b. MeI (75% overall) (80%) a. b. Amberlyst IRC-50 c. ArSO2Cl, py d. Me2CuLi e. TBSCl, imid. f. LDA; MeI g. [Cp2ZrHCl] h. I2, CCl4 d. Amberlyst IRC-50 e. KOH (61% overall) 8 7 6 5 3 4 (76%) 10 12 16 17 18 19 21 20 24 22 23 25 H2O2 2 a. LiOH b. CrO3, H2SO4 10 1: erythronolide B a) C-C bond formation Functionalization Lactonization Alkylation Baeyer-Villiger oxidation Bromolactonization Bromolactonization 2 3 4 8 7 6 5 a. KOH b. CH2N2 c. HBr, [bromolactonization] [bromolactonization] [Baeyer-Villiger oxidation] Me Scheme 15. a) Strategic bond disconnections and retrosynthetic analysis of erythronolide B and b) total synthesis (Corey et al., 1978).[102] several macrolides including erythronolide B and, most significantly, catalyzed the development of several improvements and other new methods for addressing the macrocyclization problem.[104] Soon to follow Corey s synthesis of erythronolide B was Woodward s total synthesis of erythromycin A.[33] Monensin (1979, 1980) Monensin[105] (1 in Scheme 16), isolated from a strain of Streptomyces cinamonensis, is perhaps the most prominent member of the polyether class of antibiotics. Also known as ionophores, these naturally occurring substances have the ability to complex and transport metals across membranes, thus exerting potent antibacterial action.[106, 107] These structures are characterized by varying numbers of tetrahydropyran, tetrahydrofuran, and/or spiroketals. Kishi s total synthesis of monensin,[108] which followed his synthesis of the simpler ionophore lasalocid, [109] represents a milestone achievement in organic synthesis (Scheme 16). This accomplishment demonstrates the importance of convergency in the total synthesis of complex molecules and is one of the first examples of stereoselective total synthesis through acyclic stereocontrol, and elegantly marked the application of the Cram rules within the context of natural-product synthesis. By unraveling the spiroketal moiety of the molecule Kishi was able to adopt an aldol-based strategy to couple monensin s two segments. A series of daring reactions (for example, hydroborations, epoxidations) on acyclic systems with pre-existing stereocenters allowed the construction of the two heavily substituted fragments of the molecule which were then successfully coupled and allowed to fold into the desired spiroketal upon deprotection. Kishi s beautiful synthesis of monensin also provided a demonstration of the importance of 1,3-allylic strain in acyclic conformational preferences, which in turn can be exploited for the purposes of stereocontrolled reactions (for example, epoxidation). A second total synthesis of monensin was accomplished in 1980 by W. C. Still and his group (Scheme 17).[110] Just as elegant as Kishi s synthesis, the Still total synthesis of monensin demonstrates a masterful application of chelationcontrolled additions to the carbonyl function. A judicious choice of optically active starting materials as well as a highly convergent strategy that utilized the same aldol ± spiroketalization sequence as in Kishi s synthesis allowed rapid access to monensin s rather complex structure. Endiandric Acids (1982) The endiandric acids (Scheme 18) are a fascinating group of natural products discovered in the early 1980s in the Australian plant Endiandra introsa (Lauraceae) by Black et al.[111] Their intriguing structures and racemic nature gave rise to the so called ªBlack hypothesisº for their plant origin, which involved a series of non-enzymatic electrocyclizations from acyclic polyunsaturated precursors (see Scheme 18). Intrigued by these novel structures and Black s hypothesis for their ªbiogeneticº origin, we directed our attention towards their total synthesis. Two approaches were followed, a Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 63