REVIEWS K. C. Nicolaou et al confidence that synthetic chemists had in their designed structural chemists for a rather long time. Its gross structure strategies was soon to decrease as the complexity of newl as revealed in 1946 54l and was subsequently confirmed by discovered natural products increased, thus catalyzing the X-ray crystallographic analysis. 51 In 1952, Sir Robert Rob- development of novel strategies and new chemistry in inson commented that strychnine: For its molecular size it is bsequent years. In addition, advances in theoretical and the most complex substance known. "156 This estimation had mechanistic organic chemistry as well as new synthetic tools not, apparently, escaped R. B. Woodward's attention who had gere to allow much longer sequences to be planned with a already been fully engaged in strychnine's total synthesis. In heightened measure of confidence and considerable flexibility 1948 Woodward put forth the idea that oxidative cleavage of electron-rich aromatic rings might be relevant in the bio- genesis of the strychnos alkaloids. 57I This provocative idea was Strychnine(1954) implemented in his 1954 27 synthesis of strychnine, which established Woodward as the undisputed master of the art at As the most notorious poison 5) of the Strychnos plant the time. The total synthesis of (-)-strychnine by Woodward species, strychnine (1 in Scheme 4)occupied the minds of ( Scheme 4)ushered in a golden era of total synthesis and 0地 C-C bond CO Me lactan formation NHNH2 CoMe polyphosphoric acid(a oMe FIscher nidae G a, Hl, red 17 NaoMe, MeOH.A a pEsCI b NaSCH Ph, condensatioN C. Raney N 一 CO, H ACzo,py H, H2O. i af stereochemistry (14% overat司 c.LiAH4.△ ∥ 13% N Scheme 4. a) Strategic bond disconnections and retrosynthetic analysis of (-)-strychnine and b)total synthesis(woodward et al., 1954). 1271 Angew. Chem. Int. Ed. 2000. 39. 44-122
REVIEWS K. C. Nicolaou et al. confidence that synthetic chemists had in their designed strategies was soon to decrease as the complexity of newly discovered natural products increased, thus catalyzing the development of novel strategies and new chemistry in subsequent years. In addition, advances in theoretical and mechanistic organic chemistry as well as new synthetic tools were to allow much longer sequences to be planned with a heightened measure of confidence and considerable flexibility for redesign along the way. Strychnine (1954) As the most notorious poison[53] of the Strychnos plant species, strychnine (1 in Scheme 4) occupied the minds of structural chemists for a rather long time. Its gross structure was revealed in 1946[54] and was subsequently confirmed by X-ray crystallographic analysis. [55] In 1952, Sir Robert Robinson commented that strychnine: ªFor its molecular size it is the most complex substance known.º[56] This estimation had not, apparently, escaped R. B. Woodward s attention who had already been fully engaged in strychnine s total synthesis. In 1948 Woodward put forth the idea that oxidative cleavage of electron-rich aromatic rings might be relevant in the biogenesis of the strychnos alkaloids. [57] This provocative idea was implemented in his 1954[27] synthesis of strychnine, which established Woodward as the undisputed master of the art at the time. The total synthesis of (ÿ)-strychnine by Woodward (Scheme 4) ushered in a golden era of total synthesis and 54 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 Scheme 4. a) Strategic bond disconnections and retrosynthetic analysis of (ÿ)-strychnine and b) total synthesis (Woodward et al., 1954).[27]
Natural Products Synthesis REVIEWS installed unprecedented confidence in, and respect for, the introduced as a drug during World War II and saved countless science of organic synthesis. Although several of its steps were lives. Its molecular structure containing the unique and beautifully designed and executed, perhaps the most striking strained B-lactam ring was under the cloud of some contro- feature is its reliance on only the simplest of reagents to carry versy until Dorothy Crowfoot-Hodgkin confirmed it by X-ray out what seemed to be rather complex chemical transforma- crystallographic analysis. (641 tions. with its challenging molecular structure the molecule Not surprisingly, penicillin immediately became a highly of strychnine continued to occupy the minds of several priced synthetic target attracting the attention of major subsequent practitioners of the art and several other total players in total synthesis of the time. Finally, it was Sheehan theses have since appeared in the literature. 58, $91 and Henery-Loganl6sl at the Massachusetts Institute of Technology who delivered synthetic penicillin v by total Penicillin(1957) hesis of the enchanted" molecule. as sheehan late called it. lbb Their synthesis, reported in 1957 and summarized Few discoveries of the twentieth century can claim higher in Scheme 5, was accompanied by the development of the notoriety than that of penicillin(1 in Scheme 5) Discovered phthalimide and tert-butyl ester protecting groups and the in 1928 by Alexander Flemingl6ol in the secretion of the mold introduction of an aliphatic carbodiimide as a condensing Penicillium notatum, penicillin was later shown to possess agent to form amide bonds and-in the event--penicillin's remarkable antibacterial properties by Chain and Florey. 6l fragile B-lactam ring. With this milestone, another class of Following a massive development effort known as the natural products was now open to chemical manipulation and Anglo-American penicillin projectl62, 63) the substance was a new chapter in total synthesis had begun. Reserpine(1958) Amide formation Ring formation (1 in Scheme 6) snakeroot Rauwolfia serpentina BENTH., is an alkaloid sub- HCl-H,NCO stance with curative properties 671 for the treatment of hyper tension, as well as nervous and mental disorders. 6sI Reserpine was isolated in 1952 and yielded to structural elucidation CICH2cOC AczO, 60C 1955(Schlittler and co-workers )69I and to total synthesis in 1958(Woodward et al. ) I2 The first total synthesis of reser pine(Scheme 6), considered by some as one of Woodward greatest contributions to synthesis, inspires admiration and respect by the manner in which it exploits molecular conformation to arrive at certain desired synthetic objective During this synthesis, Woodward demonstrated brilliantly the power of the venerable Diels- Alder reaction to construct a highly functionalized 6-membered ring, to control stereo (75%)H2S, NaOMe/Michael addition/ chemistry around the periphery of such a ring, and most spci ome Mey M- owe He p s Mwe aH G HO M-5 e importantly, to induce a desired epimerization by constraining ℃oAMe(100% the molecule into an unfavorable conformation by molecular tethering. All in all, Woodward's total synthesis of HCOH reserpine remains as brilliant in strategy as admirable brucine (74) Ac o execution. It was to be followed by several others 70) a. BuoNa C HCL H The synthesis of reserpine appropriately represents Wood- ward's approach to total synthesis. Even though Woodward HCH-H.H 0=, co H did not talk about retrosynthetic analysis, he must have D-penicillamine practiced it subconsciously. In his mind, reserpine consisted of aOAc PhOCH2COCI three parts: the indole(the AB unit, see Scheme 6), the trimethoxybenzene system, and the highly substituted E-ring cOnexant simplicity of and their obvious attachment to fragment 3, Woodward concerned himself primarily with the stereoselective con- struction of 3 and the stereochemical problem encountered in b. py, acetone, Ho completing the architecture of the CD ring system. He a. KOH (1.0 equiv) brilliantly solved the first problem by employing the Diels y Alder reaction to generate a cycl lic template onto which he potassium salt of 1 eo loh installed the required functionality by taking advantage of the special effects of ring systems on the stereochemical outcomes Scheme 5. a)Strategic bond disconnections and retrosynthetic analysis of of reactions. He addressed the second issue, that of the last penicillin V and b)total synthesis(Sheehan et al, 1957). 166 stereocenter to be set at the junction of rings C and D, by Angew. Chem. Int Ed 2000, 39. 44-122
Natural Products Synthesis REVIEWS installed unprecedented confidence in, and respect for, the science of organic synthesis. Although several of its steps were beautifully designed and executed, perhaps the most striking feature is its reliance on only the simplest of reagents to carry out what seemed to be rather complex chemical transformations. With its challenging molecular structure, the molecule of strychnine continued to occupy the minds of several subsequent practitioners of the art and several other total syntheses have since appeared in the literature. [58, 59] Penicillin (1957) Few discoveries of the twentieth century can claim higher notoriety than that of penicillin (1 in Scheme 5). Discovered in 1928 by Alexander Fleming[60] in the secretion of the mold Penicillium notatum, penicillin was later shown to possess remarkable antibacterial properties by Chain and Florey. [61] Following a massive development effort known as the Anglo ± American penicillin project[62, 63] the substance was N S Me Me O H N PhO O H CO2H PhtN HCl•H2N CO2H Me HS Me HCl•H2N CO2H Me HS Me N O O CHO tBuO2C N O O tBuO2C HN S H Me Me CO2H HCl•H2N tBuO2C HN S H Me Me CO2H H N tBuO2C HN S H Me Me CO2H O PhO H N HO2C HN S H Me Me CO2H O PhO H N N S H Me Me CO2K O Me Me CO2H NH2 Me Me CO2H HN O Cl Me Me N O O Cl Me Me N O Me O Me N O O Me N H CO2Me Me HS Me Me O Me Me N O Cl O O O Me H Me Me N O O Cl HS N O O Me Me Me OMe HS N O O Me Me Me N H Me S Me Me Me CO2H N Me S Me Me Me O CO2H H N O O tBuO2C H O OH O a. HCl, H2O PhO O PhtN tBuO2C HN S H Me Me CO2H 2 [isomerization] NaOAc PhOCH2COCl, Et3N 1:penicillin V a) a. N2H4 b. HCl, H2O + b) Lactamization ClCH2COCl Ac2O, 60 °C H2S, NaOMe Amide formation 4: D-penicillamine hydrochloride 5: valine (72-80%) (75%) SH OAc (75%) HCO2H a. brucine Ac2O b. resolution c. HCl, H2O d. HCl a. tBuONa b. tBuOCHO + (82%) (70%) a. KOH (1.0 equiv) b. DCC, H2O, dioxane 4 [Michael addition] b. Me2CO (100%) (74%) a. HCl b. py, acetone, H2O (100%) (12%) 3a 6 7 11 10 9 8 12 13 14 18 OMe 3 15 17 16 2 19 [potassium salt of 1] 20 Ring formation H Scheme 5. a) Strategic bond disconnections and retrosynthetic analysis of penicillin V and b) total synthesis (Sheehan et al., 1957).[65] introduced as a drug during World War II and saved countless lives. Its molecular structure containing the unique and strained b-lactam ring was under the cloud of some controversy until Dorothy Crowfoot-Hodgkin confirmed it by X-ray crystallographic analysis. [64] Not surprisingly, penicillin immediately became a highly priced synthetic target attracting the attention of major players in total synthesis of the time. Finally, it was Sheehan and Henery-Logan[65] at the Massachusetts Institute of Technology who delivered synthetic penicillin V by total synthesis of the ªenchantedº molecule, as Sheehan later called it.[66] Their synthesis, reported in 1957 and summarized in Scheme 5, was accompanied by the development of the phthalimide and tert-butyl ester protecting groups and the introduction of an aliphatic carbodiimide as a condensing agent to form amide bonds andÐin the eventÐpenicillin s fragile b-lactam ring. With this milestone, another class of natural products was now open to chemical manipulation and a new chapter in total synthesis had begun. Reserpine (1958) Reserpine (1 in Scheme 6), a constituent of the Indian snakeroot Rauwolfia serpentina Benth., is an alkaloid substance with curative properties[67] for the treatment of hypertension, as well as nervous and mental disorders. [68] Reserpine was isolated in 1952 and yielded to structural elucidation in 1955 (Schlittler and co-workers)[69] and to total synthesis in 1958 (Woodward et al.).[28] The first total synthesis of reserpine (Scheme 6), considered by some as one of Woodward s greatest contributions to synthesis, inspires admiration and respect by the manner in which it exploits molecular conformation to arrive at certain desired synthetic objectives. During this synthesis, Woodward demonstrated brilliantly the power of the venerable Diels ± Alder reaction to construct a highly functionalized 6-membered ring, to control stereochemistry around the periphery of such a ring, and most importantly, to induce a desired epimerization by constraining the molecule into an unfavorable conformation by intramolecular tethering. All in all, Woodward s total synthesis of reserpine remains as brilliant in strategy as admirable in execution. It was to be followed by several others. [70] The synthesis of reserpine appropriately represents Woodward s approach to total synthesis. Even though Woodward did not talk about retrosynthetic analysis, he must have practiced it subconsciously. In his mind, reserpine consisted of three parts: the indole (the AB unit, see Scheme 6), the trimethoxybenzene system, and the highly substituted E-ring cyclohexane. Given the simplicity of the first two fragments and their obvious attachment to fragment 3, Woodward concerned himself primarily with the stereoselective construction of 3 and the stereochemical problem encountered in completing the architecture of the CD ring system. He brilliantly solved the first problem by employing the Diels ± Alder reaction to generate a cyclic template onto which he installed the required functionality by taking advantage of the special effects of ring systems on the stereochemical outcomes of reactions. He addressed the second issue, that of the last stereocenter to be set at the junction of rings C and D, by Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 55
REVIEWS K. C. Nicolaou et al cleverly coaxing his polycycle into an unfavorable conforma- Lactamization ion(through I* formatinn isomerization to give the desired stereochemistry. These maneuvers clearly constituted unprecedented so- phistication and rational thinking in chemical synthesis While this rational th advanced and formalized by Coreys concepts on retrosyn- thetic analysis, the stereocontrol strategies of this era were to Dleis-Alder← dominate synthetic planning for some time before being complemented and, to a large degree, eclipsed by acyclic Mec c stereoselection and asymmetric synthesis advances which emerged towards the end of the century (Meenweh-Pondorti-verley AK(OPr)3. Chlorophyll a(1960) Chlorophyll a(l in Scheme 7), the green pigment of plants fellminatian-conjugate addion MeoH lecule of photosynth from its cousin molecule haemin by the presence of two extra hydrogen atoms(and, therefore, two chiral centers )in one of its pyrrole rings, the presence of the phytyl side chain, and the encapsulation of a magnesium cation rather than an iron 8 OMe o H OMe cation. Its total synthesis by R. B. Woodward et al. in 1960/291 10 represents a beautiful example of bold planning and exquisite execution. This synthesis includes improvements over Fisch- er's routes to porphyrin building blocks and, most important- ly, a number of clever maneuvers for the installment of the Meo.c three stereocenters and the extra five-membered ring residing on the periphery of the chlorin system of chlorophyll a. The chemical synthesis of chlorophyll a is a significant advance reductive aminaton-lactamizationl over Fischer's total synthesis of haemin, 18I and must have given Woodward the confidence, and prepared the ground, for his daring venture towards vitamin B,2 in which he was to H HI D H NaBi joined by A Eschenmoser(see p 61). The publication of the total synthesis of longifolene(1 in Scheme 8)in 1961 by Corey et al. 34l is of historical signifi- R=COmE cance in that in it Corey laid out the foundation of his OMle BucozH, A oMe systematic approach to retrosynthetic analysis. Our thinking (isomerization/ about synthetic design has been profoundly affected and aped by the principles of retrosynthetic analysis ever since, nd the theory is sure to survive for a long time to come. Coreys longifolene synthesis 34l exemplifies the identification and mental disconnection of strategic bonds for the purposes of simplifying the target structure. The process of retrosyn thetic analysis unravels a retrosynthetic tree with possible pathways and intermediates from which the synthetic chemist can choose the most likely to succeed and/or most elegant C 1N NaOH strategies. The total synthesis of longifolene itself, shown in E Scheme 8, involves a Wittig reaction, an osmium tetroxide- mediated dihydroxylation of a double bond, a ring expansion, and an intramolecular Michael-type alkylation to construct Scheme 6. a) Strategic bond disconnections and retrosynthetic analysis of the longifolene skeleton. This synthesis remains a landmark in reserpine and b) total synthesis(Woodward et al., 1958) 2N the evolution of the art and science of total synthesis. Angew. Chem. Int. Ed. 2000. 39. 44-122
REVIEWS K. C. Nicolaou et al. O O O O MeO2C H H H OH H H H O O H H H H H O O H H O H Br H H H O O H H O H OMe H H H O O H H O H OMe Br HO H H H O O H H O H OMe Br O H H H O HO H O H OMe Br O H H OH OMe O HO2C H H H H OAc OMe MeO2C O MeO2C N H MeO NH2 N N H MeO OAc H H OMe MeO2C O N N H MeO OAc H H OMe MeO2C Cl N N H MeO OAc H H OMe MeO2C N N H MeO OAc H H OMe MeO2C H H N N H OMe H H OAc OMe N HN H H H O MeO OMe O N N H MeO O O H H OMe H OMe OMe OMe N N H MeO OH H H OMe MeO2C H MeO2C O OMe OMe OMe Cl N HN H H H O MeO OMe O N N H MeO O O H H OMe H OMe OMe OMe MeO2C N HN H H H OAc MeO R OMe N N H MeO O O H H OMe H OMe OMe OMe MeO2C OAc H H OMe MeO2C MeO2C O O O MeO2C H H H O O CO2Me N N H MeO OAc H H OMe MeO2C O CO2Me H [Meerwein-Pondorff-Verley reduction] [elimination-conjugate addition] [reductive amination-lactamization] ∆ Al(OiPr)3, iPrOH Br2 NaOMe MeOH NBS H2SO4 H2O Zn AcOH b) Zn AcOH Zn [Diels-Alder reaction] H2Cr2O7 a. CH2N2 b. Ac2O c. OsO4 d. HIO4 e. CH2N2 B B NaBH4, MeOH E A E D E A B D E POCl3 A E A B D E C C NaBH4 a. KOH, MeOH b. DCC, py B D 1: (–)-reserpine A B C D E 11 10 9 A B D E C py a. MeOH/CHCl3 (+)-CSA b. resolution c. 1 N NaOH tBuCO2H, ∆ [isomerization] NaOMe, MeOH, ∆ A B C E R = CO2Me A 4 7 8 17 5+6 12 13 2 15 17 19 3 14 18 20 21 23 D [esterification] 16 22 1: reserpine Esterification a) C-C bond formation Diels-Alder reaction A Imine formation B C D E E 6 2 3 5 4 + A B D E Lactamization R Scheme 6. a) Strategic bond disconnections and retrosynthetic analysis of reserpine and b) total synthesis (Woodward et al., 1958).[28] cleverly coaxing his polycycle into an unfavorable conformation (through intramolecular tethering), which forced an isomerization to give the desired stereochemistry. These maneuvers clearly constituted unprecedented sophistication and rational thinking in chemical synthesis design. While this rational thinking was to be further advanced and formalized by Corey s concepts on retrosynthetic analysis, the stereocontrol strategies of this era were to dominate synthetic planning for some time before being complemented and, to a large degree, eclipsed by acyclic stereoselection and asymmetric synthesis advances which emerged towards the end of the century. Chlorophyll a (1960) Chlorophyll a (1 in Scheme 7), the green pigment of plants and the essential molecule of photosynthesis, is distinguished from its cousin molecule haemin by the presence of two extra hydrogen atoms (and, therefore, two chiral centers) in one of its pyrrole rings, the presence of the phytyl side chain, and the encapsulation of a magnesium cation rather than an iron cation. Its total synthesis by R. B. Woodward et al. in 1960[29] represents a beautiful example of bold planning and exquisite execution. This synthesis includes improvements over Fischer s routes to porphyrin building blocks and, most importantly, a number of clever maneuvers for the installment of the three stereocenters and the extra five-membered ring residing on the periphery of the chlorin system of chlorophyll a. The chemical synthesis of chlorophyll a is a significant advance over Fischer s total synthesis of haemin,[18] and must have given Woodward the confidence, and prepared the ground, for his daring venture towards vitamin B12 in which he was to be joined by A. Eschenmoser (see p. 61). Longifolene (1961) The publication of the total synthesis of longifolene (1 in Scheme 8) in 1961 by Corey et al.[34] is of historical significance in that in it Corey laid out the foundation of his systematic approach to retrosynthetic analysis. Our thinking about synthetic design has been profoundly affected and shaped by the principles of retrosynthetic analysis ever since, and the theory is sure to survive for a long time to come. Corey s longifolene synthesis[34] exemplifies the identification and mental disconnection of strategic bonds for the purposes of simplifying the target structure. The process of retrosynthetic analysis unravels a retrosynthetic tree with possible pathways and intermediates from which the synthetic chemist can choose the most likely to succeed and/or most elegant strategies. The total synthesis of longifolene itself, shown in Scheme 8, involves a Wittig reaction, an osmium tetroxidemediated dihydroxylation of a double bond, a ring expansion, and an intramolecular Michael-type alkylation to construct the longifolene skeleton. This synthesis remains a landmark in the evolution of the art and science of total synthesis. 56 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122
Natural Products Synthesis REVIEWS COEt chlorophy ll a a EtNA MeO C 2 HN⊙ ak2 oxidation/ AcOH,△ cO Me piMe coMe ACOH/A m cyclopentadiene ningI cwna on (photooxygenation COMe Ho2C→ CN. EIN cyanohydrin lactone a NaOH, H2O Zn, ACOH NaoH, py heme 7. a) Strategic bond disconnections and retrosynthetic analysis of chlorophyll a and b)total synthesis( Woodward et al., 1960). 129 The locking of 2 and 9 together through formation of a schiff base forces the cyclization to proceed with the desired regioselectivity. Lycopodine(1968) features a unique"aza-annulation "strategy which utilizes the Lycopodine(1 in Scheme 9), first isolated in 1881, is the Stork enamine methodology 73(a generally useful strategy to most wildly distributed alkaloid from the genus lycopod- generate and trap enolates regiospecifically) to construct um. 71 In addition to the great challenge of synthesizing this quinolone systems, a stereospecific c cyclization to novel polycyclic framework in a stereocontrolled manner, one establish the C13 quaternary center, and a series of functional must effectively address the challenge posed by the C13 group manipulations to elaborate the resulting aromatic ring quaternary center, which is common to all four rings. Gilbert into ring D. Several syntheses of lycopodine have since Stork was one of the first to successfully complete the total appeared. 74l each featuring a unique strategy complementary ynthesis of lycopodine 72I This masterfully executed synthesis to Stork's beautiful synthesis Angew. Chem. Int Ed 2000, 39, 44-122
Natural Products Synthesis REVIEWS Lycopodine (1968) Lycopodine (1 in Scheme 9), first isolated in 1881, is the most wildly distributed alkaloid from the genus lycopodium. [71] In addition to the great challenge of synthesizing this novel polycyclic framework in a stereocontrolled manner, one must effectively address the challenge posed by the C13 quaternary center, which is common to all four rings. Gilbert Stork was one of the first to successfully complete the total synthesis of lycopodine. [72] This masterfully executed synthesis features a unique ªaza-annulationº strategy which utilizes the Stork enamine methodology[73] (a generally useful strategy to generate and trap enolates regiospecifically) to construct quinolone systems, a stereospecific cationic cyclization to establish the C13 quaternary center, and a series of functional group manipulations to elaborate the resulting aromatic ring into ring D. Several syntheses of lycopodine have since appeared,[74] each featuring a unique strategy complementary to Stork s beautiful synthesis. Angew. Chem. Int. Ed. 2000, 39, 44 ± 122 57 NH Me NH Me MeO2C H2N HN Me Me HN Me OHC CO2Et O CO2Me OH Me Me Me Me Me HN Me Me HN Me HN Me Me Cl NC CN HN Me CO2Et NC CN CO2Et HN Me Me HN Me OHC CO2Et O CO2Me NH Me NH NH Me H2N NH MeO2C OHC Me Me MeO2C H3N NH Me NH Me MeO2C H2N NH HN Me Me Me NH HN Me H3N H CO2Me CO CO2Me 2Me Me N NH Me Me Me NH N Me AcHN CO2Me CO2Me Me CO2Me NH HN Me Me Me NH HN Me AcHN H CO2Me CO CO2Me 2Me Me N NH Me Me Me NH N Me AcHN CO2Me CO2Me Me CO2Me NH HN Me Me Me NH HN Me CO2Me CO2Me Me N CO2Me O HN Me Me HN Me SHC CO2Et O CO2Me NH N Me Me Me N HN Me H Me H CO2Me MeO2C NH N Me Me Me N HN Me H Me H N N Me Me Me N N Me Mg O H CO2Me Me H H O O Me Me Me Me Me O H MeO2C NH N Me Me Me N HN Me AcHN CO2Me MeO2C MeO2C H Me NH N Me Me Me N HN Me CO2Me MeO2C MeO2C H Me NH N Me Me Me N HN Me H Me H CHO CO2Me NH N Me Me Me N HN Me H Me O O H NC NH N Me Me Me N HN Me CO2Me MeO2C MeO2C H Me O CHO NH N Me Me Me N HN Me HO2C H Me O O H HO CO2Me CO2Me CO2Me CO2Me MeO2C Cl O a. KOH, MeOH N N Me Me Me N N Me Mg O H CO2Me Me H H O O Me Me Me Me Me AcOH, ∆ air 2 HCl [thioaldehyde formation] 5 6 3 8 7 (50% overall) [oxidation] 9 10 11 12 13 14 [reduction] [methylation] [methanolysis] NaOH, py [ester exchangemagnesium insertion sequence] a. Zn, AcOH b. CH2N2 c. MeOH, HCl a. NaOH, H2O b. H , 4 [Dieckmann cyclization] 1: chlorophyll a 21 22 4: phytol AcOH/∆ a. HCl, MeOH b. Me2SO4, NaOH [hydrolysis] [Hofmann elimination] 16 15 [photooxygenation] + 1: chlorophyll a Dieckmann cyclization 2 3 a) Hofmann elimination reaction + HCl a. b. NaOH c. CH2N2 HBr Ester formation b) a. EtNH2, AcOH b. H2S a. resolution with quinine [cyanohydrin lactone formation] HCN, Et3N O2, hv [highly specific photochemical cleavage of the cyclopentadiene ring] 18 17 20 c. Mg(OEt)2 a. I2 [oxidation] b. Ac2O, py 19 b. CH2N2 NaBH4 b. NaOH, H2O Scheme 7. a) Strategic bond disconnections and retrosynthetic analysis of chlorophyll a and b) total synthesis (Woodward et al., 1960).[29] The locking of 2 and 9 together through formation of a schiff base forces the cyclization to proceed with the desired regioselectivity
REVIEWS K. C. Nicolaou et al 1: longifolene arrangement Miescher co日 (31% overal) rearrangementcacO3 CoEt a NaoEt,>any b K2 CO3, H2O (1020%) dCNa: Mel (60%) 「从「 NHzNHz,A b. LiAlHg,A b soCl, py heme 8. a)Strategic bond disconnections and retrosynthetic analysis of longifolene and b) total synthesis( Corey et al., 1961).4 O3 MeOH Cephalosporin C(1966) Cephalosporin C (1 in Scheme 10) was isolated from o Cephalosporium acremonium in the mid-1950s 75) and was cac 16 co Me L OaMe cycl M /overano-o structurally elucidated by X-ray crystallographic analysis in 1961.761 Reminiscent of the penicillins, the cephalosporins represent the second subclass of B-lactams, several of which became legendary antibiotics in the latter part of the twentieth century. Having missed the opportunity to deliver b. CrO3-H2SO4 penicillin, the Woodward group became at once interested in the synthesis of cephalosporin C and, by 1965, they completed 1: lycopodine the first total synthesis of the molecule. 301 This total synthesis of cephalosporin Cwas Woodwards 1965 Nobel lecture in Stockholm. Indeed, in a ()-lycopodine and b)total synthesis(G. Stork et al., 19/ analysis of Scheme 9. a)Strategic bond di move that broke tradition .r B. woodward described on that occasion for the first time, and in a breathtaking fashion the elegant synthesis of cephalosporin C. Highlights of this syn- Prostaglandins F2 and E,(1969) thesis, which is summarized in Scheme 10, include the The prostaglandins were discovered by von Euler in the development of the azodicarboxylate-mediated functional- 1930sIml and their structures became known in the mid-1960s ization of the methylene group adjacent to the sulfur atom of primarily as a result of the pioneering work of Bergstrom and L-cysteine, the aluminum-mediated closure of the aminoester his group. 78 With their potent and important biological to the B-lactam functionality, the brilliant formation of activities and their potential applications in medicine. 79Ithese cephalosporin's sulfur-containing ring, and the use of the scarce substances elicited intense efforts directed at their B.B. B-trichloroethyloxy moiety to protect the hydroxyl group. chemical synthesis. By 1969 Corey had devised and completed This total synthesis stands as a milestone accomplishment in his first total synthesis of prostaglandins Fza (l in Scheme 11) the field of natural product synthesi and E2. so These syntheses amplified brilliantly Corey's Angew. Chem. Int. Ed. 2000. 39. 44-122
REVIEWS K. C. Nicolaou et al. H Me Me Me O Me O Me H O Me O Me Me OTs O Me Me O O H Me Me O O H Me O Me OH H Me Me S S Me H O H Me Me Me H H Me Me Me HO OH HO OH HS SH H Me Me Me O H Me O O O O OMe OH Me OTs O Me O Me O O O O a. Na, NH2NH2, ∆ b. CrO3, AcOH H LiClO4, CaCO3 Me O O O 2 N HCl, ∆ a. OsO4, py b. pTsCl, py Ph3CNa; MeI (60%) a. BF3•Et2O b. LiAlH4, ∆ 1: longifolene a. MeLi, ∆ b. SOCl2, py b) a) 1: longifolene 5 a. pTsOH, ∆ b. Ph3P=CHMe Alkylation 3 6 4 Et3N , ∆ 8 3 7 9 10 Olefination 2 Michael addition 2 pinacol rearrangement [pinacol rearrangement] 5: Wieland-Miescher ketone 4 (31% overall) (10-20%) (49% overall) 3 O Me Me Scheme 8. a) Strategic bond disconnections and retrosynthetic analysis of longifolene and b) total synthesis (Corey et al., 1961).[34] Cephalosporin C (1966) Cephalosporin C (1 in Scheme 10) was isolated from Cephalosporium acremonium in the mid-1950s[75] and was structurally elucidated by X-ray crystallographic analysis in 1961. [76] Reminiscent of the penicillins, the cephalosporins represent the second subclass of b-lactams, several of which became legendary antibiotics in the latter part of the twentieth century. Having missed the opportunity to deliver penicillin, the Woodward group became at once interested in the synthesis of cephalosporin C and, by 1965, they completed the first total synthesis of the molecule. [30] This total synthesis of cephalosporin C was the sole topic of Woodward s 1965 Nobel lecture in Stockholm. Indeed, in a move that broke tradition, R. B. Woodward described on that occasion for the first time, and in a breathtaking fashion, the elegant synthesis of cephalosporin C. Highlights of this synthesis, which is summarized in Scheme 10, include the development of the azodicarboxylate-mediated functionalization of the methylene group adjacent to the sulfur atom of l-cysteine, the aluminum-mediated closure of the aminoester to the b-lactam functionality, the brilliant formation of cephalosporin s sulfur-containing ring, and the use of the b,b,b-trichloroethyloxy moiety to protect the hydroxyl group. This total synthesis stands as a milestone accomplishment in the field of natural product synthesis. N O H H Me H N CHO H Me H O O Cl3C CO2Me N H O Me OMe N CH3 OMe O OMe CO2Et MeO EtO2C O CO2Et MeO O OMe OH O Me OMe N Me H N O Ar H2N N Me Ar H2N O N H O Me OMe H N N H Me H O H OMe N H H Me H O OMe H H Me H OMe H N O O Cl3C Cl O O CCl3 N CHO H Me H O O Cl3C CO2Me N H Me H O O Cl3C CO2Me OH O O X N H Me H O O Cl3C CO2Me OH O N H Me H O O Cl3C CO2Me O O N O H H Me H O N O H H Me H N H H Me H O MeO O H Lactamization Allylic oxidation Ozonolysis Cationic Stork enamine cyclization Conjugate addition + [Isomerization; Michael addition] a. NaOEt, 7 b. K2CO3, H2O [decarboxylation] a. LiAlH4 b. MeMgBr, CuCl2 a) [conjugate addition] b) – H3PO4:HCO2H (1:1) [cationic cyclization] [Birch reduction] O3, MeOH SeO2 H2O2 c. KOtBu d. [Stork enamine] a. NaOMe [formate methanolysis] b. Zn, MeOH [deprotection of amine] a. LiAlH4 b. CrO3-H2SO4 (36%) (90%) (20-25% of desired isomer) (55%) (30% overall) 1: lycopodine 2 3 5 4 6 7 6 8 9 3 10 4 11 12 13 16 2 17 18 1: lycopodine a. LiAlH4 b. Li-NH3 15 14 Scheme 9. a) Strategic bond disconnections and retrosynthetic analysis of ()-lycopodine and b) total synthesis (G. Stork et al., 1968).[72] Prostaglandins F2a and E2 (1969) The prostaglandins were discovered by von Euler in the 1930s[77] and their structures became known in the mid-1960s primarily as a result of the pioneering work of Bergström and his group. [78] With their potent and important biological activities and their potential applications in medicine, [79] these scarce substances elicited intense efforts directed at their chemical synthesis. By 1969 Corey had devised and completed his first total synthesis of prostaglandins F2a (1 in Scheme 11) and E2 . [80] These syntheses amplified brilliantly Corey s 58 Angew. Chem. Int. Ed. 2000, 39, 44 ± 122