R E V I E W
`
`Modern synthetic efforts toward biologically
`active terpenes
`
`
`
`Thomas J Maimone & Phil S BaranThomas J Maimone & Phil S Baran
`
`
`Terpenes represent one of the largest and most diverse classes of secondary metabolites, with over 55,000 members isolated to Terpenes represent one of the largest and most diverse classes of secondary metabolites, with over 55,000 members isolated to
`date. The terpene cyclase enzymes used in nature convert simple, linear hydrocarbon phosphates into an exotic array of chiral,
`date. The terpene cyclase enzymes used in nature convert simple, linear hydrocarbon phosphates into an exotic array of chiral,
`carbocyclic skeletons. Further oxidation and rearrangement results in an almost endless number of conceivable structures. The
`carbocyclic skeletons. Further oxidation and rearrangement results in an almost endless number of conceivable structures. The
`enormous structural diversity presented by this class of natural products ensures a broad range of biological properties—ranging
`enormous structural diversity presented by this class of natural products ensures a broad range of biological properties—ranging
`from anti-cancer and anti-malarial activities to tumor promotion and ion-channel binding. The marked structural differences of
`from anti-cancer and anti-malarial activities to tumor promotion and ion-channel binding. The marked structural differences of
`terpenes also largely thwart the development of any truly general strategies for their synthetic construction. This review focuses on
`terpenes also largely thwart the development of any truly general strategies for their synthetic construction. This review focuses on
`synthetic strategies directed toward some of the most complex, biologically relevant terpenes prepared by total synthesis within the
`synthetic strategies directed toward some of the most complex, biologically relevant terpenes prepared by total synthesis within the
`past decade. Of crucial importance are both the obstacles that modern synthetic chemists must confront when trying to construct
`past decade. Of crucial importance are both the obstacles that modern synthetic chemists must confront when trying to construct
`such natural products and the key chemical transformations and strategies that have been developed to meet these challenges.
`such natural products and the key chemical transformations and strategies that have been developed to meet these challenges.
`
`With their usage dating as far back as ancient Egypt, terpenes hold a
`With their usage dating as far back as ancient Egypt, terpenes hold a
`special place in both chemical and world history. Scientists and non-
`special place in both chemical and world history. Scientists and non-
`scientists alike can appreciate these truly functional molecules, whose
`scientists alike can appreciate these truly functional molecules, whose
`applications range from flavor and fragrance to hormones, medicine
`applications range from flavor and fragrance to hormones, medicine
`and even rubber1. Synthetic chemists were drawn to terpenes before
`and even rubber1. Synthetic chemists were drawn to terpenes before
`their polymeric origins were even clearly delineated (via the “biogenetic
`their polymeric origins were even clearly delineated (via the “biogenetic
`isoprene rule”) by Ruzicka in 1953 (refs. 2,3 and references therein). The
`isoprene rule”) by Ruzicka in 1953 (refs. 2,3 and references therein). The
`arrival of spectroscopic and chromatographic techniques brought about
`arrival of spectroscopic and chromatographic techniques brought about
`an explosion in the chemical aspects of terpene research that continues
`an explosion in the chemical aspects of terpene research that continues
`to this day. As a consequence, many highly complex terpenes have been
`to this day. As a consequence, many highly complex terpenes have been
`
`prepared by total synthesis (Fig. 1)4–6. Although terpenes formally are prepared by total synthesis (Fig. 1)4–6. Although terpenes formally are
`made from only one biosynthetic unit, in contrast to the 20 proteogenic
`made from only one biosynthetic unit, in contrast to the 20 proteogenic
`amino acids that make up proteins, the fact that they can be rearranged
`amino acids that make up proteins, the fact that they can be rearranged
`and highly oxidized means that the synthetic challenge of construct-
`and highly oxidized means that the synthetic challenge of construct-
`ing them rivals that of many other secondary metabolites in terms of
`ing them rivals that of many other secondary metabolites in terms of
`difficulty. In addition, their ubiquity in nature often results in natural
`difficulty. In addition, their ubiquity in nature often results in natural
`products of ‘mixed’ biosynthetic origins, such as terpene alkaloids and
`products of ‘mixed’ biosynthetic origins, such as terpene alkaloids and
`terpene polyketides7.
`terpene polyketides7.
`
`Introduction to the synthesis of terpenes
`Introduction to the synthesis of terpenes
`Because the carbon skeleton of a terpene is often its defining structural
`Because the carbon skeleton of a terpene is often its defining structural
`feature, it is there that synthetic chemists usually begin their planning.
`feature, it is there that synthetic chemists usually begin their planning.
`Indeed, a plethora of approaches for accessing terpene ring systems are
`Indeed, a plethora of approaches for accessing terpene ring systems are
`often published before an actual total synthesis. Unfortunately, signifi-
`often published before an actual total synthesis. Unfortunately, signifi-
`cant difficulties are often encountered in attempting to translate the
`cant difficulties are often encountered in attempting to translate the
`results of a model system to one laden with more functionality; in some
`results of a model system to one laden with more functionality; in some
`cases an entirely new strategy must be devised to access the natural
`cases an entirely new strategy must be devised to access the natural
`product8. This highlights the fact that subtle steric and electronic factors,
`product8. This highlights the fact that subtle steric and electronic factors,
`
`
`Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines
`Road, La Jolla, California 92037, USA. Correspondence should be addressed to
`Road, La Jolla, California 92037, USA. Correspondence should be addressed to
`P.S.B. (pbaran@scripps.edu).
`P.S.B. (pbaran@scripps.edu).
`
`Published online 18 June 2007; doi:10.1038/nchembio2007.1
`Published online 18 June 2007; doi:10.1038/nchembio2007.1
`
`as well as functional-group incompatibilities, are often difficult—or
`as well as functional-group incompatibilities, are often difficult—or
`impossible—to predict at the beginning of a total synthesis endeavor9.
`impossible—to predict at the beginning of a total synthesis endeavor9.
`So where does one start when trying to access a complex terpene skel-
`So where does one start when trying to access a complex terpene skel-
`eton? Although there are many useful guidelines that can be followed
`eton? Although there are many useful guidelines that can be followed
`during the planning stage, there are simply no general rules to apply
`during the planning stage, there are simply no general rules to apply
`when synthesizing a terpene. Indeed, successful syntheses of complex
`when synthesizing a terpene. Indeed, successful syntheses of complex
`terpenes often rely on a mixture of imaginative planning and extensive
`terpenes often rely on a mixture of imaginative planning and extensive
`empirical testing. Part of the charm and appeal of such molecules to syn-
`empirical testing. Part of the charm and appeal of such molecules to syn-
`thetic organic chemists is the unpredictable nature that results from their
`thetic organic chemists is the unpredictable nature that results from their
`highly rearranged and unprecedented carbon skeletons. Three different
`highly rearranged and unprecedented carbon skeletons. Three different
`approaches can often aid chemists in their synthetic studies, all rely-
`approaches can often aid chemists in their synthetic studies, all rely-
`ing on the principles of retrosynthetic analysis10. In the first approach,
`ing on the principles of retrosynthetic analysis10. In the first approach,
`the standard logic of synthetic planning can be applied, whereby one
`the standard logic of synthetic planning can be applied, whereby one
`looks for strategic bond disconnections within the target molecule. This
`looks for strategic bond disconnections within the target molecule. This
`approach largely rests on the available toolbox of known transforma-
`approach largely rests on the available toolbox of known transforma-
`tions, resulting, after multiple iterations, in the identification of a suit-
`tions, resulting, after multiple iterations, in the identification of a suit-
`able starting material. A second approach identifies a specific structural
`able starting material. A second approach identifies a specific structural
`motif contained within the terpene skeleton that could be made via a
`motif contained within the terpene skeleton that could be made via a
`certain synthetic methodology that is either known or newly invented.
`certain synthetic methodology that is either known or newly invented.
`As a third option, one can try to find a structural match between the
`As a third option, one can try to find a structural match between the
`target and a smaller, commercially available terpene. The large number
`target and a smaller, commercially available terpene. The large number
`of commercially available terpenes (often in either enantiomer) coupled
`of commercially available terpenes (often in either enantiomer) coupled
`with the abundance of modern asymmetric transformations make the
`with the abundance of modern asymmetric transformations make the
`
`last two methods particularly attractive for asymmetric synthesis11,12. last two methods particularly attractive for asymmetric synthesis11,12.
`As we will see, modern terpene syntheses are an amalgam of classical
`As we will see, modern terpene syntheses are an amalgam of classical
`organic transformations, modern catalytic asymmetric reactions and
`organic transformations, modern catalytic asymmetric reactions and
`efficient use of the pool of available chiral terpenes.
`efficient use of the pool of available chiral terpenes.
`The importance of natural products as sources of new drugs has been
`The importance of natural products as sources of new drugs has been
`
`recently reviewed13,14. Although many terpenes do not resemble ‘typi-recently reviewed13,14. Although many terpenes do not resemble ‘typi-
`cal’ therapeutics (heteroatom-laden aromatics), their structures have
`cal’ therapeutics (heteroatom-laden aromatics), their structures have
`presumably been selected to interact with biological targets. In addi-
`presumably been selected to interact with biological targets. In addi-
`tion, the presence of multiple stereocenters, molecular rings and diverse
`tion, the presence of multiple stereocenters, molecular rings and diverse
`oxygenation patterns also bodes well for sampling chemical space15.
`oxygenation patterns also bodes well for sampling chemical space15.
`
`396
`396
`
`VOLUME 3 NUMBER 7 JULY 2007 NATURE CHEMICAL BIOLOGY
`VOLUME 3 NUMBER 7 JULY 2007 NATURE CHEMICAL BIOLOGY
`
`LCY Biotechnology Holding, Inc.
`Ex. 1009
`Page 1 of 13
`
`

`

`R E V I E W
`R E V I E W
`
`a
`a
`
`NHBz
`NHBz
`
`O
`O
`
`O
`O
`
`OH
`OH
`
`AcO
`AcO
`
`O
`O
`
`OH
`OH
`
`HO
`HO
`
`BzO
`BzO
`
`H
`H
`AcO
`AcO
`
`O
`O
`
`Taxol
`Taxol
`
`HO
`HO
`
`O
`O
`
`O
`O
`
`H
`H
`
`O
`O
`
`Longifolene
`Longifolene
`
`
`
`PleuromutilinPleuromutilin
`
`H
`H
`
`H
`H
`
`O
`O
`
`O
`O
`
`HO
`HO
`
`H
`H
`
`H
`H
`
`HO
`HO
`HO
`HO
`
`HO
`HO
`
`OH
`OH
`
`HO
`HO
`
`O
`O
`
`OH
`OH
`
`OH
`OH
`
`Ryanodol
`Ryanodol
`
`OH
`OH
`
`OH
`OH
`
`OH
`OH
`
`H
`H
`
`OH
`OH
`
`H
`H
`
`H
`H
`
`O HO
`O HO
`
`OH
`OH
`
`Phorbol
`Phorbol
`
`H
`H
`
`HO2C
`HO2C
`
`H
`H
`
`O
`O
`
`OH
`OH
`
`H
`H
`t-Bu
`t-Bu
`
`O
`O
`
`HO
`HO
`
`O
`O
`
`H
`H
`
`H
`H
`
`
`
`CO2HCO2H
`
`Gibberellic acid
`Gibberellic acid
`
`O
`O
`
`O
`O
`
`HO
`HO
`HO
`HO
`
`O
`O
`
`O
`O
`
`H
`H
`HO
`HO
`
`O
`O
`
`O
`O
`
`H
`H
`
`O
`O
`
`Ginkgolide B
`Ginkgolide B
`
`O
`O
`
`H
`H
`
`H
`H
`
`H
`H
`
`the most potent tumor promoters ever isolated.
`the most potent tumor promoters ever isolated.
`Accordingly, these molecules have received
`Accordingly, these molecules have received
`considerable attention from the biological and
`considerable attention from the biological and
`medical communities. More recently ingenol
`medical communities. More recently ingenol
`has also been shown to possess anti-tumor,
`has also been shown to possess anti-tumor,
`anti-leukemic and anti-HIV properties (ref.
`anti-leukemic and anti-HIV properties (ref.
`19 and references therein). Its structural fea-
`19 and references therein). Its structural fea-
`tures have also fascinated synthetic chemists
`tures have also fascinated synthetic chemists
`for the past 25 years, owing in large part to a
`for the past 25 years, owing in large part to a
`rare form of isomerism displayed in its B and C
`rare form of isomerism displayed in its B and C
`rings (Scheme 1a). ‘In-out’ isomerism, wherein
`rings (Scheme 1a). ‘In-out’ isomerism, wherein
`a bridgehead hydrogen is formally ‘inside’ the
`a bridgehead hydrogen is formally ‘inside’ the
`bicycle, provides ingenol with a thermody-
`bicycle, provides ingenol with a thermody-
`
`namically disfavored configuration20,21. Many namically disfavored configuration20,21. Many
`early synthetic investigations failed to address
`early synthetic investigations failed to address
`this feature, although some provided evi-
`this feature, although some provided evi-
`dence that this isomeric form is required for
`dence that this isomeric form is required for
`
`biological activity22. The first synthetic strat-biological activity22. The first synthetic strat-
`egy to address this challenging aspect of the
`egy to address this challenging aspect of the
`molecule was described in 1987 by Winkler
`molecule was described in 1987 by Winkler
`and colleagues23 and later by several other
`and colleagues23 and later by several other
`
`groups21,24,25; however—as a true testament to groups21,24,25; however—as a true testament to
`the difficulty ingenol poses—it was not until
`the difficulty ingenol poses—it was not until
`2002 that Winkler’s group could claim a total
`2002 that Winkler’s group could claim a total
`synthesis of 1 (Scheme 1b)26. After Winkler’s
`synthesis of 1 (Scheme 1b)26. After Winkler’s
`synthesis, total syntheses were reported by the
`synthesis, total syntheses were reported by the
`Kuwajima group in 2003 (Scheme 1c) and by
`Kuwajima group in 2003 (Scheme 1c) and by
`
`the Wood group in 2004 (Scheme 1d)27,28. the Wood group in 2004 (Scheme 1d)27,28.
`In addition, one formal synthesis and many
`In addition, one formal synthesis and many
`
`approaches have been published19,29,30.approaches have been published19,29,30.
`
`N
`N
`
`N
`N
`
`OH
`OH
`
`OH
`OH
`
`Lupeol
`Lupeol
`
`Periplanone
`Periplanone
`
`Retigeranic acid
`Retigeranic acid
`
`Progesterone
`Progesterone
`
`b
`b
`
`O
`O
`
`HO
`HO
`
`HO
`HO
`HO
`HO
`
`H
`H
`
`OH
`OH
`
`O
`O
`
`H
`H
`
`H
`H
`
`OH
`OH
`
`HO
`HO
`
`CHO
`CHO
`
`O
`O
`
`OAc
`OAc
`
`H
`H
`
`O
`O
`
`H
`H
`
`H
`H
`
`Ingenol (1)
`Ingenol (1)
`
`Guanacastepene (3)
`Guanacastepene (3)
`
`Neotripterifordin (5)
`Neotripterifordin (5)
`
`Eleutherobin (7)
`Eleutherobin (7)
`
`O
`O
`
`O
`O
`
`O
`O
`
`OMe
`OMe
`
`O
`O
`
`OAc
`OAc
`
`O
`O
`
`O
`O
`
`HO
`HO
`
`O
`O
`
`HO
`HO
`
`OH
`OH
`
`Terpestacin (8)
`Terpestacin (8)
`
`OH
`OH
`
`OH
`OH
`
`O
`O
`
`H
`H
`
`O
`O
`
`O
`O
`
`O
`O
`
`O
`O
`
`H
`H
`
`O
`O
`
`O
`O
`
`O
`O
`
`Phomactin A (4)
`Phomactin A (4)
`
`Saudin (6)
`Saudin (6)
`
`OMe
`OMe
`
`OH
`OH
`
`O
`O
`
`O
`O
`
`OO H
`OO H
`
`H
`H
`
`O
`O
`
`OH
`OH
`
`O
`O
`
`Resiniferatoxin (2)
`Resiniferatoxin (2)
`
`Use of the De Mayo reaction en route to the
`Use of the De Mayo reaction en route to the
`first total synthesis of (±)-1 (Winkler). The
`first total synthesis of (±)-1 (Winkler). The
`Winkler group sought to assemble the in-out
`Winkler group sought to assemble the in-out
`system by an intramolecular variant of the ven-
`system by an intramolecular variant of the ven-
`erable De Mayo reaction wherein a vinylygous
`erable De Mayo reaction wherein a vinylygous
`
`ester engages an olefin in a 2+2 cycloaddition26,31,32. The intermedi-ester engages an olefin in a 2+2 cycloaddition26,31,32. The intermedi-
`ate cyclobutane then undergoes base-mediated retro-aldol fragmenta-
`ate cyclobutane then undergoes base-mediated retro-aldol fragmenta-
`tion (Scheme 1b). To give the desired strained bicycle, they began by
`tion (Scheme 1b). To give the desired strained bicycle, they began by
`elaborating enone 9 into key compound 10 by an 11-step procedure.
`elaborating enone 9 into key compound 10 by an 11-step procedure.
`Irradiation of 10 in acetonitrile provided the desired cyclobutane 11.
`Irradiation of 10 in acetonitrile provided the desired cyclobutane 11.
`It is worth noting that the hydrogen atom in the cyclobutane ring will
`It is worth noting that the hydrogen atom in the cyclobutane ring will
`become the ‘in’ hydrogen in the in-out bicycle, and thus its position in
`become the ‘in’ hydrogen in the in-out bicycle, and thus its position in
`the cycloaddition is critical to its position in the C–B-ring junction.
`the cycloaddition is critical to its position in the C–B-ring junction.
`Treatment of 11 with potassium carbonate in methanol led to 13 after
`Treatment of 11 with potassium carbonate in methanol led to 13 after
`loss of acetone and retro-aldol fragmentation. The conversion of 13 into
`loss of acetone and retro-aldol fragmentation. The conversion of 13 into
`ingenol required 33 steps owing to both the unfunctionalized nature
`ingenol required 33 steps owing to both the unfunctionalized nature
`of 13 and the synthetic difficulty associated with the three contiguous
`of 13 and the synthetic difficulty associated with the three contiguous
`asymmetric hydroxyl groups. Capable of being performed in a com-
`asymmetric hydroxyl groups. Capable of being performed in a com-
`plex molecular setting, the De Mayo reaction—as demonstrated by
`plex molecular setting, the De Mayo reaction—as demonstrated by
`Winkler—is an extremely powerful tool for the synthesis of complex
`Winkler—is an extremely powerful tool for the synthesis of complex
`ring systems. Another elegant application of this strategy, in the synthesis
`ring systems. Another elegant application of this strategy, in the synthesis
`of saudin, is discussed below.
`of saudin, is discussed below.
`
`Figure 1 Highly complex terpenes that have been prepared by total synthesis. (a) Classic terpene
`Figure 1 Highly complex terpenes that have been prepared by total synthesis. (a) Classic terpene
`targets of the twentieth century. (b) Selected complex, biologically active terpenoids synthesized in the
`targets of the twentieth century. (b) Selected complex, biologically active terpenoids synthesized in the
`past decade (1997–2007). Ac, acetyl; Bz, benzoyl.
`past decade (1997–2007). Ac, acetyl; Bz, benzoyl.
`
`
`While most of the terpenes discussed in this review may never arrive in While most of the terpenes discussed in this review may never arrive in
`your neighborhood pharmacy (although some have), the motifs pres-
`your neighborhood pharmacy (although some have), the motifs pres-
`ent in these natural products could very well find their way into future
`ent in these natural products could very well find their way into future
`pharmaceuticals. Indeed, terpenes often provide the impetus for the
`pharmaceuticals. Indeed, terpenes often provide the impetus for the
`discovery and development of new ring-forming reactions in synthesis.
`discovery and development of new ring-forming reactions in synthesis.
`In addition, the synthesis of terpenes can lead to a greater understand-
`In addition, the synthesis of terpenes can lead to a greater understand-
`ing of fundamental chemical reactivity, as well as proving or disproving
`ing of fundamental chemical reactivity, as well as proving or disproving
`a structural assignment16. Diversification of strategy is also important
`a structural assignment16. Diversification of strategy is also important
`in modern day chemists’ pursuit of efficiency, selectivity and flexibility.
`in modern day chemists’ pursuit of efficiency, selectivity and flexibility.
`Molecules discussed in this review were chosen on the basis of following
`Molecules discussed in this review were chosen on the basis of following
`criteria: (i) their primary carbon skeletons are solely of terpene origin (or
`criteria: (i) their primary carbon skeletons are solely of terpene origin (or
`believed to be), (ii) they possessed interesting biological profiles at the
`believed to be), (ii) they possessed interesting biological profiles at the
`time of their isolation, (iii) they possess interesting, unusual or unprece-
`time of their isolation, (iii) they possess interesting, unusual or unprece-
`dented structures and (iv) solutions to their total chemical synthesis
`dented structures and (iv) solutions to their total chemical synthesis
`have been reported only within the past decade (1997–2007). Because
`have been reported only within the past decade (1997–2007). Because
`of space limitations, only the key chemical transformations leading to
`of space limitations, only the key chemical transformations leading to
`successful total syntheses can be illustrated. In many cases, the interested
`successful total syntheses can be illustrated. In many cases, the interested
`reader can find a more comprehensive survey on the approaches to these
`reader can find a more comprehensive survey on the approaches to these
`natural products elsewhere.
`natural products elsewhere.
`
`Ingenol (1)
`Ingenol (1)
`In 1968 Hecker and co-workers isolated the highly oxygenated diterpene
`In 1968 Hecker and co-workers isolated the highly oxygenated diterpene
`
`ingenol (1) from the roots of Euphorbia ingens17,18. Though the terpenes ingenol (1) from the roots of Euphorbia ingens17,18. Though the terpenes
`are not carcinogenic themselves, esters of several diterpenes derived
`are not carcinogenic themselves, esters of several diterpenes derived
`from this genus—including ingenol and phorbol (Fig. 1)—are some of
`from this genus—including ingenol and phorbol (Fig. 1)—are some of
`
`A total synthesis of (±)-1 featuring Nicholas and pinacol-type chem-
`A total synthesis of (±)-1 featuring Nicholas and pinacol-type chem-
`istry (Kuwajima). The Kuwajima group took a markedly different
`istry (Kuwajima). The Kuwajima group took a markedly different
`approach to constructing the ingenane skeleton, in which they envi-
`approach to constructing the ingenane skeleton, in which they envi-
`sioned that that C ring could be formed via a Nicholas-type reaction
`sioned that that C ring could be formed via a Nicholas-type reaction
`(16 → 18) (Scheme 1c)19,27,33. In this reaction, the presence of the
`(16 → 18) (Scheme 1c)19,27,33. In this reaction, the presence of the
`cobalt-carbonyl complex makes the neighboring acetate highly prone
`cobalt-carbonyl complex makes the neighboring acetate highly prone
`to ionization and displacement due to the bridging ability of cobalt.
`to ionization and displacement due to the bridging ability of cobalt.
`
`NATURE CHEMICAL BIOLOGY VOLUME 3 NUMBER 7 JULY 2007
`NATURE CHEMICAL BIOLOGY VOLUME 3 NUMBER 7 JULY 2007
`
`
`
`397397
`
`LCY Biotechnology Holding, Inc.
`Ex. 1009
`Page 2 of 13
`
`

`

`R E V I E W
`R E V I E W
`
`
`The A and B rings would originate from a pinacol-type rearrangement The A and B rings would originate from a pinacol-type rearrangement
`converting the 6-6 fused ring system into the desired 7-5 system. The
`converting the 6-6 fused ring system into the desired 7-5 system. The
`synthesis of 16 required 15 steps, and upon treatment with Lewis acid 17,
`synthesis of 16 required 15 steps, and upon treatment with Lewis acid 17,
`Kuwajima and colleagues were able to produce tricyclic compound 18. In
`Kuwajima and colleagues were able to produce tricyclic compound 18. In
`a short (five-step) sequence, 18 could be converted into 19. Treatment of
`a short (five-step) sequence, 18 could be converted into 19. Treatment of
`19 with trimethylaluminum induced the desired bond reorganization to
`19 with trimethylaluminum induced the desired bond reorganization to
`give 20, which contains the complete ingenane skeleton. Ingenol could
`give 20, which contains the complete ingenane skeleton. Ingenol could
`then be prepared in 18 steps from compound 20. This synthesis served
`then be prepared in 18 steps from compound 20. This synthesis served
`to demonstrate how a complex ring system can be prepared by a careful
`to demonstrate how a complex ring system can be prepared by a careful
`orchestration of favorable known reactions.
`orchestration of favorable known reactions.
`
`A ring-opening and ring-closing metathesis strategy to construct
`A ring-opening and ring-closing metathesis strategy to construct
`ingenol (Wood). Wood and co-workers began their journey to the syn-
`ingenol (Wood). Wood and co-workers began their journey to the syn-
`thesis of ingenol with a functionalized C ring possessing the requisite
`thesis of ingenol with a functionalized C ring possessing the requisite
`asymmetric methyl and dimethylcyclopropyl groups (Scheme 1d)28.
`asymmetric methyl and dimethylcyclopropyl groups (Scheme 1d)28.
`This key compound (enone 21) could be constructed from a commer-
`This key compound (enone 21) could be constructed from a commer-
`cially available terpene in ten steps, closely following a route described
`cially available terpene in ten steps, closely following a route described
`
`by Funk21. Enone 21 was then coaxed into participating in a Lewis by Funk21. Enone 21 was then coaxed into participating in a Lewis
`acid–catalyzed Diels-Alder cycloaddition with cyclopentadiene to pro-
`acid–catalyzed Diels-Alder cycloaddition with cyclopentadiene to pro-
`duce spirocycle 22, thus delivering all of the carbons needed for the
`duce spirocycle 22, thus delivering all of the carbons needed for the
`five-membered A ring. Treatment of ketone 22 with Grubb’s catalyst
`five-membered A ring. Treatment of ketone 22 with Grubb’s catalyst
`in refluxing toluene opened the bicyclo [2.2.1] ring system (ring-open-
`in refluxing toluene opened the bicyclo [2.2.1] ring system (ring-open-
`ing metathesis) to spiro-ketone 23, which in turn could be elaborated
`ing metathesis) to spiro-ketone 23, which in turn could be elaborated
`into 24 via a four-step procedure. Using Grubbs-Hoveyda catalyst 25,
`into 24 via a four-step procedure. Using Grubbs-Hoveyda catalyst 25,
`the Wood group was able to carry out the transformation 24 → 26
`the Wood group was able to carry out the transformation 24 → 26
`
`(ring-closing metathesis), thus forming the coveted in-out system.
`(ring-closing metathesis), thus forming the coveted in-out system.
`Compound 26 could be transformed into ingenol in an additional 17
`Compound 26 could be transformed into ingenol in an additional 17
`steps. The olefin metathesis reaction (whose pioneers were awarded the
`steps. The olefin metathesis reaction (whose pioneers were awarded the
`2005 Nobel Prize in chemistry) has proven to be one of the most reli-
`2005 Nobel Prize in chemistry) has proven to be one of the most reli-
`able and powerful reactions in modern chemistry for the construction
`able and powerful reactions in modern chemistry for the construction
`of carbocyclic rings34.
`of carbocyclic rings34.
`
`Resiniferatoxin (2)
`Resiniferatoxin (2)
`Isolated from Euphorbia resinifera, resiniferatoxin is a powerful analge-
`Isolated from Euphorbia resinifera, resiniferatoxin is a powerful analge-
`sic that has been used to treat pain for almost 2,000 years6. It belongs
`sic that has been used to treat pain for almost 2,000 years6. It belongs
`to the daphnane family of diterpenes, and its molecular skeleton is
`to the daphnane family of diterpenes, and its molecular skeleton is
`biosynthetically related to both the tigliane (phorbol) and ingenane
`biosynthetically related to both the tigliane (phorbol) and ingenane
`(ingenol) classes (Scheme 2a). Although it lacks the in-out ring system
`(ingenol) classes (Scheme 2a). Although it lacks the in-out ring system
`of its chemical cousin, it is still an extremely challenging synthetic target
`of its chemical cousin, it is still an extremely challenging synthetic target
`owing to its dense, highly oxygenated skeleton. Indeed, Wender’s 1997
`owing to its dense, highly oxygenated skeleton. Indeed, Wender’s 1997
`total synthesis remains the only synthetic route to 2 (ref. 35), although
`total synthesis remains the only synthetic route to 2 (ref. 35), although
`various approaches toward obtaining the A-B-C ring system have been
`various approaches toward obtaining the A-B-C ring system have been
`reported (refs. 36,37 and references therein).
`reported (refs. 36,37 and references therein).
`
`Total synthesis of (+)-2 featuring an oxidopyrylium 1,3-dipolar
`Total synthesis of (+)-2 featuring an oxidopyrylium 1,3-dipolar
`cycloaddition (Wender). As an efficient synthetic entry into both the
`cycloaddition (Wender). As an efficient synthetic entry into both the
`tigliane and daphnane terpene classes, the Wender group developed
`tigliane and daphnane terpene classes, the Wender group developed
`an intramolecular variant of the oxidopyrylium 1,3-dipolar cyclo-
`an intramolecular variant of the oxidopyrylium 1,3-dipolar cyclo-
`addition (Schemes 2b,c) (ref. 38 and references therein). This powerful
`addition (Schemes 2b,c) (ref. 38 and references therein). This powerful
`reaction allows for the rapid, stereoselective construction of bridged
`reaction allows for the rapid, stereoselective construction of bridged
`
`O
`O
`
`11 steps
`11 steps
`
`9
`9
`
`H
`H
`10
`10
`
`Cl
`Cl
`
`O
`O
`
` hν,
`hν,
`
` MeCN
` MeCN
`
`O
`O
`
`O
`O
`
`[2+2]
`
`[2+2][2+2]
` Photo-
` Photo-
`cycloaddition
`cycloaddition
`
`Cl
`Cl
`
`O
`O
`
`O
`O
`
`O
`O
`
`
` K2CO3 K2CO3
`
`MeOHMeOH
`(–Me2CO)
`(–Me2CO)
`
`H
`H
`
`H
`H
`11
`11
`
`a
`a
`
`O
`O
`
`C
`C
`
`A
`A
`
`B
`B
`
`HO
`HO
`
`HO
`HO
`HO
`HO
`Ingenol (1)
`Ingenol (1)
`
`H
`H
`
`OH
`OH
`
`H
`H
`
`H
`H
`
`H
`H
`
`vs.
`vs.
`
`H
`H
`
`Out-out
`Out-out
`bicycle
`bicycle
`0
`0
`
`ΔErel
`ΔErelEE
`(kcal mol–1)
`(kcal mol–1)
`
`In-out
`In-out
`bicycle
`bicycle
`6.3
`6.3
`
`b
`b
`
`c
`c
`
`(±)-1
`(±)-1
`
`27 steps
`27 steps
`
`O
`O
`
`H
`H
`
`14
`14
`
`17
`17
`
`
`
`AcOAcO
`
`O
`O
`
`Br
`Br
`
`Cl
`Cl
`
`O
`O
`
`O
`O
`
`OMe
`OMe
`
`12
`12
`
` Retro-aldol
` Retro-aldol
`fragmentation
`fragmentation
`
`Cl
`Cl
`
`H
`H
`
`H
`H
`
`H
`H
`
`O
`O
`
`CO2Me
`CO2Me
`
`H
`H
`
`6 steps
`6 steps
`
`O
`O
`
`Cl
`Cl
`
`H
`H
`
`OTBS
`OTBS
`
`Co(CO)3
`Co(CO)3
`Co(CO)3
`Co(CO)3
`
`H
`H
`
`
`
`(17)(17)
`
`CO2Me
`CO2Me
`
`H
`H
`
`13
`13
`
`Co(CO)3
`Co(CO)3
`Co(CO)3
`Co(CO)3
`H
`H
`
`OH
`OH
`
`O
`O
`
`O
`O
`
`OTES
`OTES
`
`OMe
`OMe
`
`H
`H
`
`OH
`OH
`
`15
`15
`Prepared in
`Prepared in
` 4 steps
` 4 steps
`
`11 steps
`11 steps
`
`H
`H
`
`MeAl(OAr)2
`MeAl(OAr)2
`CH2Cl2
`CH2Cl2
`(–HOAc)
`(–HOAc)
`
`NicholasNicholas
`reaction
`reaction
`
`OTIPS
`OTIPS
`
`OMe
`OMe
`16
`16
`
`
`
`5 steps5 steps
`
`OTIPS
`OTIPS
`
`OMe
`OMe
`
`
`
`1818
`
`H
`H
`
`vs.
`vs.
`
`HO
`HO
`
`HO
`HO
`HO
`HO
`Iso-1
`Iso-1
`0
`0
`
`HO
`HO
`HO
`HO
`
`HO
`HO
`
`OH
`OH
`
`ΔErel
`ΔErelEE
`
`(kcal mol–1)(kcal mol–1)
`
`1
`1
`5.9
`5.9
`
`d
`d
`
`
`BF3• OEt2BF3• OEt2
`Diels-Alder
`Diels-Alder
` reaction
` reaction
`
`O
`O
`
`22
`22
`
`O
`O
`21
`21
`Prepared in 10 steps
`Prepared in 10 steps
`from a chiral terpene
`from a chiral terpene
`
`Ar =
`Ar =
`
`NO2
`NO2
`
`18 steps
`18 steps
`
`1
`1
`
`HO
`HO
`
`O
`O
`
`MeO
`MeO
`
`H
`H
`
` Me3Al
` Me3Al
`
`CH2Cl2CH2Cl2
`Pinacol
`Pinacol
`rearrangement
`rearrangement
`
`OTIPS
`OTIPS
`
`20
`20
`
`CH2=CH2
`CH2=CH2
`(PCy3)2Cl2RuCHPh
`(PCy3)2Cl2RuCHPh
`PhH, Δ
`PhH, Δ
`
`Ring– openingRing– opening
` metathesis
` metathesis
`
`4 steps
`4 steps
`
`O
`O
`
`O
`O
`
`O
`O
`
`23
`23
`
`25
`25
`PhH, Δ
`PhH, Δ
`Ring-closing
`Ring-closing
` metathesis
` metathesis
`
`OPMB
`OPMB
`
`O
`O
`
`24
`24
`
`Ru cat.
`Ru cat.
`Ring-closing
`Ring-closing
`metathesis
`metathesis
`
`Ru cat.
`Ru cat.
`Ring-opening
`Ring-opening
`metathesis
`metathesis
`
`Mes
`Mes
`Cl
`Cl
`Cl
`Cl
`
`N
`N
`
`N
`N
`
`Mes
`Mes
`
`Ru
`Ru
`
`i-PrO
`i-PrOii
`25
`25
`
`Me3Al
`Me3Al
`
`O
`O
`
`OH
`OH
`
`H
`H
`
`OTIPS
`OTIPS
`
`
`OMeOMe
`19
`19
`
`O
`O
`
`H
`H
`
`H
`H
`
`26
`26
`
`OPMB
`OPMB
`
` 17
` 17
`steps
`steps
`
`O
`O
`
`O
`O
`
`1
`1
`
`Scheme 1 The total synthesis of ingenol. (a) ‘In-out’ isomerism of the C-B rings as a key synthetic challenge posed by ingenol. (b) Winkler’s approach
`Scheme 1 The total synthesis of ingenol. (a) ‘In-out’ isomerism of the C-B rings as a key synthetic challenge posed by ingenol. (b) Winkler’s approach
`featuring an intramolecular variant of the De Mayo reaction. (c) Kuwajima and Tanino’s approach using a Nicholas-type cyclization and pinacol rearrangement
`featuring an intramolecular variant of the De Mayo reaction. (c) Kuwajima and Tanino’s approach using a Nicholas-type cyclization and pinacol rearrangement
`to form the in-out system. (d) Wood’s approach using a ring-opening and ring-closing metathesis strategy. Cy, cyclohexyl; Mes, 2,4,6-trimethylphenyl; PMB,
`to for