2018 Volume 66 Issue 2 Pages 105-115
The divergent total syntheses of three types of heteropolycyclic natural products, namely gelsedine-type alkaloids, amathaspiramide alkaloids, and erythrina alkaloids, are outlined. A strategy involving a late-stage pluripotent common synthetic intermediate prepared via original and innovative transformations was employed. A brief description of the philosophy and criteria for choosing the synthetic targets and common synthetic precursors, as well as details regarding the development of the overall synthetic schemes from a common intermediate are discussed.
The analogy between mountain climbing and natural product total synthesis is well established. Just as one might find an unexpected precious flower when seeking an alternative path on a mountain, one may stumble upon serendipitous discoveries regarding methodology or strategy during the evolution of an artificial synthetic route for a complex natural product. Similarly, the purpose of climbing is not restricted to reaching the single summit of a steep mountain, as the “joy” of climbing is obtained by walking through the ridges of adjoining mountain peaks, and the syntheses of an array of structurally similar compounds have their own charm that would not be obtained through a target-oriented or single-shot total synthesis.1–5) It is thus desirable that one approach towards the total synthesis of a natural product is easily applied to biosynthetically and structurally related targets. Approaches that fall into this category include “diversity-oriented synthesis,”6,7) “diverted total synthesis,”8) “divergent total synthesis,”9) and “collective total synthesis”10) with small fluctuations among the definitions. While planning the synthetic route for these divergent strategies, it is necessary to design a pluripotent late-stage common synthetic intermediate that can be transformed into an array of target family molecules. In most cases, the targets comprise one biosynthetic family that share the same biosynthetic precursors that can be employed as candidates for common synthetic precursors. However, it is not often easy to employ naturally occurring molecules as synthetic intermediates for divergent syntheses, particularly because of their high polarity or instability, as well as the difficulty in the biomimetic transformations that are often incompatible with most laboratory organic synthesis techniques. Therefore, a versatile synthetic intermediate with an understanding of the mutual relationship among the target compounds, especially their recurrent structures, different appendages, and stereochemical or skeletal diversity is required. In other words, it is necessary to extract the common structural features from all targets, and to design a precursor to synthetically realize the peripheral alterations. This task demands both simplicity and diversity, which are opposing requirements that limits the possible strategies. Paradoxically, this restriction clarifies the challenges in devising the appropriate design of the desired intermediate.
The strategy for diversification employed in the reviewed studies does not mimic natural biosynthetic transformations, but applies ideas inspired by natural processes. With the original strategy for diversification in mind, the syntheses of heteropolycyclic complex natural products were examined by designing a late-stage common synthetic intermediate that could be used to synthesize the target molecules.11) Towards that end, three syntheses of natural products will be reviewed, with an emphasis on how the common synthetic intermediates were designed, synthesized, and derivatized.
To illustrate the above-mentioned divergent strategy, the unified synthesis of gelsedine-type gelsemium alkaloids15–18) is reviewed. These compounds share a common core structure with a spiro-N-methoxy indolinone moiety, an oxabicyclo[3.2.2]nonane core skeleton, and a variably functionalized pyrrolidine or azetidine moiety. Their prominent cytotoxic activity against A431 epidermoid carcinoma cells19,20) is noteworthy.
Synthetic studies on these gelsedine-type alkaloids have been conducted by many laboratories21–23) and have culminated in the total syntheses of gelsedine,24,25) gelsenicine,26) and gelsemoxonine.12,13,27,28) A comprehensive approach to these gelsedine-type alkaloids has been demonstrated in the pioneering semisynthesis based on the biogenetic pathway as reported by Takayama and Sakai.29–36) Thus, the development of an original and flexible divergent synthetic route was envisioned for gelsedine-type alkaloids in the current synthetic campaign. The target compounds were selected so that the biosynthesis or other potential chemical conversions could connect each of the molecules within one or two transformations. As such, the targets were set as gelsenicine37–39) (1), gelsedine40–42) (2), gelsedilam33) (3), 14-hydroxygelsenicine (humantenidine)43,44) (4), 14,15-dihydroxygelsenicine45) (5), and gelsemoxonine45,46) (6) (Chart 1). Since these alkaloids were found in a single species, Gelsemium elegans BENTH, the compounds are closely related within the integrated biosynthetic pathway proposed by Takayama and Sakai.44) The parent intermediate gelselegine (7) was proposed to oxidatively lose the C21 unit to furnish the cyclic imine metabolite gelsenicine (1), which would then be selectively reduced to give gelsedine (2). Oxidation of gelsenicine (1) to gelseziridine (8) and removal of a two-carbon unit47) would afford the lactam derivative, gelsedilam (3). Oxygenation at C14 would give 14-hydroxygelsenicine (4), and repeated oxygenation at C14 and C15 would give 14,15-dihydroxygelsenicine (5), which would in turn afford gelsemoxonine (6) upon opening of the cyclic imine and formation of the azetidine moiety.45) Synthetic transformations that emulate this entire biosynthesis, especially C–H oxidations of C14 and C15, do not seem to be synthetically practical. Accordingly, a customized biomimetic strategy, and the design of a single artificial intermediate bearing a core structure that could access all targets were envisioned (Chart 2).11) Structural differences among the target molecules primarily relate to the C14 and C15 functional groups with the hydrogen or oxygen atoms in different positions, and the substituents on the pyrrolidine/azetidine functionality. Hence, key intermediate 10 came into focus. Intermediate 10 bears the common spiro-N-methoxyindolinone moiety and a nitrogen functionality on the oxabicyclo[3.2.2]nonane structure, which is also equipped with a versatile enal functionality. The presence/absence of the two-carbon unit, as well as the hydrogen/oxygen atoms on the C14–C15 double bond of the enal moiety and subsequent cyclizations of the nitrogen functionality were expected to afford the target gelsedine-type alkaloids.
Synthesis of projected intermediate 10 began with the m-chloroperoxybenzoic acid (m-CPBA)-mediated Achmatowicz reaction48,49) of the furfuryl alcohol (11) to afford enone 12 (Chart 3). Chiral 13 was prepared on over a 10 g scale by the sequential dynamic kinetic resolution with lipase AK50) (74% enantiomeric excess (ee)) and solvolytic removal of undesired R isomer with lipase CR in n-BuOH/n-hexane (>99% ee). 13 was treated with diethyl bromomalonate (14) in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to deliver cyclopropane 15 with a quaternary stereocenter. The acetoxy group was then removed by Et3SiH and trimethysilyl trifluoromethanesulfonate (TMSOTf) in CH3CN to facilitate the reduction of 15 to 16. Following the conversion of keto-diester 16 to triol 17 for the subsequent chemoselective transformations, the high chelating ability and water-solubility of 17 were troublesome. After extensive experimentation, the reduction was achieved by a modified Soai reduction upon treatment with NaBH4 in refluxing tetrahydrofuran (THF) with the slow addition of methanol.51) Quenching of the reaction with acetic acid and repeated evaporation–addition cycles from methanol mediated the formation of the B(OCH3)3, which was volatile enough to be removed. The residual mixture of sodium acetate and triol 17 was purified by silica gel chromatography to give pure 17. The introduction of a pivalate on the less hindered primary alcohol and the oxidation of the resulting diol with 2-iodoxybenzoic acid (IBX) afforded keto-aldehyde 18 in 93% yield.
The coupling of 18 with the N-methoxy indolinone moiety was conducted via a two-step aldol condensation using boron enolate 1923) followed by methanesulfonyl chloride (MsCl) and N,N,N′,N′-tetramethylethylenediamine (TMEDA)52) at −78°C, which successfully afforded 20 as a single diastereomer. Subsequent treatment with lithium hexamethyldisilazide (LHMDS) in the presence of trimethylsilyl chloride (TMSCl) selectively furnished divinylcyclopropane 21, the substrate for the crucial divinylcyclopropane–cycloheptadiene rearrangement.53–55) As expected, silyl enol ether 21 rearranged smoothly upon heating at 70°C for 30 min via transition state model 22 to afford silyl enol ether 23. Removal of the TMS group with tetrabutylammonium fluoride (TBAF) in the presence of acetic acid furnished bicyclic ketone 24 in 89% yield from 21. The stereochemistry of the cyclopropane moiety and C–C double bond in 21 was successfully transferred to the quaternary spirocyclic stereocenter in 24.
The introduction of a nitrogen functionality to the seven-membered carbon skeleton was examined. As is often the case with highly functionalized and rigid molecules, manipulation of the C5–C6 double bond of the bicyclic structure of 24 proved extremely difficult, retarding the direct approach of any reagents. After extensive studies, redox-neutral isomerization of unsaturated aldehyde 25 was revealed as the appropriate transformation.56–59) Thus, solvolysis of 24 followed by 2,2,6,6-tetramethylpiperidinyloxy (TEMPO) oxidation were conducted to provide α,β-unsaturated aldehyde 25. Because protocols employing N-heterocyclic carbene (NHC) catalyst did not work in this specific case, other conditions were examined, which finally led to the combination of trimethylsilyl cyanide (TMSCN)–DBU.60,61) Under these conditions, 25 was initially converted into cyanohydrin trimethylsilyl ether 26, followed by the DBU-mediated isomerization to generate α,β-unsaturated nitrile 27.62,63) Interestingly, ensuing treatment of the reaction mixture with an allyl alcohol resulted in the kinetic protonation of the silyl enol ether 27 to afford acyl cyanide (5S)-28, which was further transformed into the corresponding allyl ester (5S)-29 in one pot64–67) as a 4 : 1 diastereomeric mixture with the thermodynamically more stable (5R)-29. After purification, (5S)-29 was isolated in 78% yield. Ester 29 could be transformed into the benzyloxycarbonyl (Cbz)-protected amine 30 in a three-step sequence involving deallylation, a Curtius rearrangement, and treatment with benzyl alcohol. Stereoselective introduction of the nitrogen atom on the bicyclic skeleton was achieved. Ketone 30 was treated with Bredereck’s reagent68,69) (31) to give vinylogous amide 32 and then converted into β-chloro unsaturated aldehyde 33 under Vilsmeier’s conditions.70,71) Dechlorination was subsequently achieved upon treatment with Pd(PPh3)4 and Et3SiH72,73) to furnish aldehyde 10. This aldehyde represents the common core structure for all of the targeted gelsedine-type alkaloids via the programmed introduction of the two carbon unit, hydrogen atom, and oxygen atom on the enal moiety.
Chart 4 represents the divergent transformations to gelsedine-type alkaloids from common intermediate 10. For the synthesis of gelsedilam 3, it was necessary to introduce two hydrogen atoms onto the C14–C15 double bond and to oxidize the aldehyde moiety. A one-step conversion that might fulfill this requirement was the redox-neutral isomerization reaction using the above-mentioned conditions with TMSCN–DBU.60,61) Treatment of 10 initially formed a TMS cyanohydrin in situ, which subsequently underwent a double bond migration to form 34. To expedite the stereoselective Si-face protonation of intermediate 34 and solvolysis of acyl cyanide 35, methanol was employed to yield 36. This gave an acceptable ratio of the products (15R : 15S=2.6 : 1), and (15R)-36 was isolated in 57% yield. Removal of the Cbz group by TMS iodide and subsequent cyclization under basic conditions completed the synthesis of (−)-gelsedilam (3).33) The intriguing stereochemical outcomes obtained on this specific structural motif could be explained by the fact that the Re-face of the enolate was blocked by the indolinone moiety.
Other targeted gelsedine-type alkaloids contain two additional carbon atoms on the side chain. Thus, enal 10 was converted to ethyl ketone intermediate 37 in two steps. The synthesis of gelsenicine (1) requires the reduction of the C14–C15 double bond of 37 and deprotection of the amine. When 37 was treated with Et3SiH in the presence of Pd(OAc)2,74,75) hydrosilylation of the enone and hydrogenolysis of the Cbz group proceeded simultaneously to give silyl enol ether/silyl carbamate intermediate 38. Subsequent treatment with TBAF liberated the amine and facilitated the Si-face protonation to smoothly form the cyclic imine, (−)-gelsenicine (1).31,76) Catalytic hydrogenation of 1 with Adams’ catalyst following the procedure rerpoted by Takayama and Sakai furnished (−)-gelsedine (2).31) The next target transformation involved the introduction of two oxygen atoms onto the C14–C15 double bond. Dihydroxylation of 37 was performed using catalytic OsO4 and N-methylmorpholine N-oxide (NMO), which occurred smoothly at the desired face to afford diol 39. Removal of the Cbz group and subsequent desilylation caused the spontaneous dehydrative cyclization of the imine, leading to the first total synthesis of (−)-14,15-dihydroxygelsenicine (5).45) 14-Hydroxygelsenicine (4) bears one oxygen atom and one hydrogen atom at C14–C15. This pattern was realized via the partial reduction of the C14–C15 epoxide. Diastereoselective introduction of the epoxide functionality upon treatment with tert-butyl hydroperoxide (TBHP) and Triton B was followed by the removal of the Cbz group with TMS iodide,77,78) which afforded amino epoxide 40. The reductive transformation was conducted with SmI2, which mediated the reduction of the carbon–oxygen bond adjacent to the carbonyl group79) while the N–O bond on the indolinone was maintained. Samarium enolate 41 generated in situ was protonated at C15 from the less hindered Re-face, resulting in the formation of a cyclic imine. The formal cis hydration of the C14–C15 double bond eventually afforded (−)-14-hydroxygelsenicine (4).80) The last target, gelsemoxonine (6), was equipped with an oxygen functionality at C14 and a nitrogen functionality on the azetidine moiety at C15. The opening of the epoxide from the amine functionality of 40 was accordingly envisaged. Protic acids or Lewis acids or bases in a variety of solvents did not facilitate the formation of the azetidine moiety. It was, therefore, surprising to find that the ring-opening reaction of 40 proceeded by simply heating in boiling ethanol81–83) to afford gelsemoxonine (6).45)
The divergent strategy with the use of the newly designed versatile intermediate with an enal moiety enabled the streamlined syntheses of six gelsedine-type alkaloids. This synthesis underscores the importance of scrutinizing and understanding the chemical relationship among the synthetic targets, with inspiration attained from the biosynthesis. This would partly pave the road towards a general strategy for the design of a versatile common intermediate for the divergent natural product synthesis. The established synthetic route to a broad range of gelsedine-type alkaloids sets the stage for the synthesis of structurally similar, unnatural analogs that could potentially stimulate medicinal research based on these alkaloids.
A divergent strategy was also applied to synthesize amathaspiramides A (42)–F (47) equipped with diverse substructures with a uniform core skeleton. Morris and Prinsep isolated these natural products in 1999 from a collection of marine bryozoan Amathia wilsoni from New Zealand.86) These compounds are characterized by the highly functionalized diazaspiro[3.3]nonane framework equipped with an intriguingly stable C-8 N-acyl hemiaminal, a C-9 benzylic center of dibromomethoxyphenyl group, and variable pyrrolidine moiety connected through a C-5 tetrasubstituted spiro center. The molecules have garnered considerable attention from the synthetic community, with amathaspiramide F, an 8S member, as the primary target.87–89) It was envisioned to establish a novel and versatile synthetic route to all amathaspiramides whose pyrrolidine moieties exhibit various oxidation states from secondary (44, 47) or tertiary amines (42), cyclic imines (46), to unsubstituted (45) or N-methyl γ-lactams (43). Therefore, systematic access from a common intermediate was required for the C-8 stereochemistry and the variable oxidation states of the spiro pyrrolidine units.
The synthetic approach is based on the idea that each member of the amathaspiramide family can be derived from oxidized common intermediate 48 via sequential reductions (Chart 5). This “abiotic” idea required the most oxidized intermediate as a common precursor, thus cyclic imide 48 was set as the first target. Chart 6 shows an outline of the synthesis. The synthesis of cyclic imide 55 commenced with the copper-catalyzed asymmetric reduction of butenolide 4990) to give chiral lactone 50 with 98% ee on a 20 g scale in 72% yield,91) thereby establishing the latent C-9 stereochemistry. To introduce the quaternary center in the α-position of the carbonyl group, lithium enolate of 50 was reacted with CbzCl followed by a Michael addition with methyl acrylate (51) in the presence of a catalytic amount of K2CO3 to selectively afford 52. Construction of the crucial tetrasubstituted spiro center was subsequently realized via a Curtius rearrangement. Hydrogenolysis, formation of acyl azide, and the Curtius rearrangement performed in 1,4-dioxane at 100°C gave the intermediate isocyanate, which was successfully hydrolyzed in aqueous media to afford γ-lactam 53. Introduction of two bromine atoms on the aromatic ring at the ortho and para positions could not be accomplished under conventional conditions, but could be performed under forced conditions using bromine in the presence of ZnCl2 and HCO2H92) to afford 54. Cyclic imide 48 was synthesized in one pot from 54 in 44% yield via aminolysis of the lactone with methylamine in methanol followed by oxidation with pyridinium dichlomate (PDC). The cyclic imide was envisioned to serve as a versatile common intermediate for the synthesis of all amathaspiramide alkaloids. Cyclic imide 48 was first examined for the regio- and stereoselective partial reduction on the imide to construct the (8R)-N-acyl hemiaminal moiety. Extensive examination of various reductive conditions revealed that diisobutylaluminum hydride (DIBAL) facilitated the desired regio- and stereoselective transformation at C-8, while other reductive conditions (NaBH4, Luche reduction, L-selectride, or LiAlH4) only mediated the undesired C-6 reduction. Accordingly, the desired 8R hemiaminal was successfully obtained in 52% yield without formation of the 8S isomer. The regioselectivity of the reduction could be reasoned in terms of the reduced inductive effect and increased steric bulk of the γ-lactam as a result of the formation of the nitrogen–aluminum bond caused by DIBAL. The 8R-hemiaminal showed surprising stability, which allowed conventional handling and even purification on silica gel. Amathaspiramide D (45) was thus synthesized from 48 in 52% yield on a 5 g scale. After protection of the hydroxy group of the hemiaminal in 45 leading to 55, methylation was performed by treatment with CH3I and Cs2CO3 to give amathaspiramide B (43) in 75% yield, after the workup with aqueous HCl for the deprotection.
It was next envisioned to reduce the γ-lactam moiety without affecting the other functional groups in the molecule. Consequently, amathaspiramide D (45) was subjected to reduction with Schwartz’s reagent (Cp2Zr(H)Cl); the secondary lactam was directly reduced to the cyclic imine93–95) without affecting the C-6 tertiary amide or C-8 N-acyl hemiaminal, affording amathaspiramide E (46) in 67% yield (Chart 6). The imine moiety in 46 could be selectively reduced under reductive methylation conditions, which furnished amathaspiramide A (42) in 78% yield. Similarly, 46 could be reduced to a secondary amine upon treatment with NaBH3CN and AcOH in methanol to afford amathaspiramide C (44) in 65% yield. Since amathaspiramide F (47) differs from amathaspiramide C (44) only in the stereochemistry of the C-8 N-acyl hemiaminal, epimerization of the C-8 center was attempted. Epimerization was not observed under the conventional acidic conditions; therefore, it was conducted under basic conditions with a catalytic amount of Cs2CO3 in CH3CN, resulting in the formation of the thermodynamic mixture of the products (47 : 44=13 : 1). From this mixture, 8S-isomer amathaspiramide F (47) was isolated in 82% yield. These transformations eventually completed the syntheses of all the amathaspiramide alkaloids.
The antiproliferative activity of the synthesized amathaspiramide alkaloids and synthetic intermediates was assessed in vitro using a panel of four human cancer cell lines (HCT116, PC-3, MiaPaCa-2, and MV4-11). Amathaspiramide A (42), C (44), E (46) exhibited moderate antiproliferative activities against all four cell lines. The structure activity relationship among active amathaspiramides A (42), C (44), E (46) and less active B (43), D (45), as well as inactive 48, 52, 53, 54, and amathaspiramide F (47) indicated that the amathaspiramide core structure with the cyclic amine/imine substructure and the 8R N-acyl hemiaminal moiety were indispensable for the antiproliferative activity.
By designing the most oxidized common synthetic intermediate for the targeted amathaspiramide alkaloids, abiotic and reductive sequential transformations were employed for the comprehensive syntheses. By exploiting reductive transformations, six alkaloids were schematically synthesized and subjected to antiproliferative activity assays, leading to interesting results on the structure–activity relationship.
Among the over one hundred erythrina alkaloids that have been identified to date, representative members are 56–63,97–102) which share a central common core structure with A–D rings (Fig. 1). Notably, dihydro-β-erythroidine97,103–105) (DHβE, 63) is an antagonist of the nicotinic acetylcholine receptor (nAChR).106) Recently the X-ray structure of the complex comprised of 63 and acetylcholine binding protein (AChBP) was reported.107) Combined with the fact that other erythrina alkaloids also exhibit nAChR antagonist activity,108,109) the flexible synthesis of erythrina alkaloid analogues with a variety of peripheral functional groups is expected to enable the development of novel subtype-selective nAChR antagonists.110,111)
Early pioneering synthetic studies of erythrina alkaloids were reported by Belleau,112–114) Mondon,115) and Prelog.116,117) Numerous groups were subsequently involved in the synthesis of these alkaloids,118–130) with asymmetric syntheses comprising only a small percentage.131–139) To design an original synthetic intermediate as part of a divergent strategy to access as many natural congeners as possible within a short time frame, the biosynthetic relationship was expected to serve as a map and compass for the best synthetic pathway. The biosynthetic scheme of erythrina alkaloids, first proposed by Barton et al.99,140,141) and later revised by Zenk and colleagues,142) involves 9-membered dibenz[d.f]azonine intermediate 64, wherein the phenol moiety is oxidized by a two-step single electron transfer (SET) mechanism (Chart 7a). Transannulation of the amine on resulting planar cationic intermediate 65 gives 66 equipped with a tetrasubstituted C5 center. Subsequent adjustment of the oxidation state would give multiple erythrina alkaloids. Inspired by this biosynthetic sequence, a novel asymmetric synthetic approach was envisioned using a synthetically more practical 9-membered lactam intermediate, which was rarely employed in the syntheses of erythrina alkaloids.143–145) Oxidative transformation of 67 to dienone 68 would be followed by an intramolecular attack from the amide, which would form the C5 tetrasubstituted chiral carbon center in 69 (Chart 7b). A variety of erythrina alkaloids with a common core ABCD ring structure featuring diverse peripheral variations could be synthetically derived from oxidized intermediate 69 through a combination of eliminations or reductions of the oxygen functionalities. This two-stage synthetic strategy involving the initial biosynthesis-inspired construction of a common core structure and further abiotic transformations of the late-stage synthetic intermediate would facilitate the divergent syntheses of natural and artificial derivatives of erythrina alkaloids.
The synthesis commenced with the conversion of chiral nitroaldol (11R)-70146) to bromoaryl 71 in a three-pot transformation (Chart 8). Commercially available carboxylic acid 72 was transformed into aryl boronate 73 in four steps and was subjected to the Suzuki–Miyaura cross-coupling with 71. Coupled biaryl 74 was fully deprotected to give the amino acid intermediate 75 and formation of the 9-membered lactam was successfully achieved using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM)147) as the condensation reagent in methanol. Interestingly, the 9-membered lactam was obtained as a mixture of two diastereomers consisting of stable biaryl atropisomers (M)-76 and (P)-77 in a 2 : 1 ratio. Mislow’s pioneering work on the stereochemical fixation of the medium-membered biaryl148) revealed the origin of the inversion barrier could be ascribed to the steric repulsion between the protons on C7 and C11. These two diastereomers were interconvertible at high temperatures; 40 h of heating in 2-butanol at 90°C mediated the successful reversal of the ratio of 76 to 77, favoring the thermodynamically more stable 77 as the major isomer (76 : 77=1 : 7). The mixture was subjected to silylation selectively on 77 and the hydrolysis of the mesyl group selectively afforded 78. The stereochemical configuration of the C11 benzylic hydroxy group was thus transferred to the atropisomeric stereochemistry of the biaryl moiety.
The X-ray structure of 78 indicated that the silyloxy group was pointing towards the phenol moiety to shield one of the faces. Incoming reagents were thus expected to approach selectively from one direction. Oxidative transformation of the phenol moiety of 78 using singlet oxygen149) gave a single diastereomer via the transition state depicted in 79, without forming the undesired orthoquinone derivatives. The amide nitrogen of the intermediate spontaneously attacked the C5 position of dienone 80 to create the crucial C5 tetrasubstituted carbon center. Reduction of the hydroperoxide in situ by PPh3 yielded tertiary alcohol 81 bearing the C11 oxygen functionality with the desired configuration. The biaryl atropisomeric stereochemistry was successfully transferred to the tetrasubstituted point chirality at C5. Intermediate 81 was equipped with the common core helical architecture with functional groups on the A–C rings, which fulfilled the requirements for the intermediate for the divergent synthesis. The potential versatility of intermediate 81 was showcased by the facile transformations to four erythrina alkaloids. Elimination of the tertiary hydroxy group by thionyl chloride gave 82. Diastereoselective Luche reduction of the enone moiety150,151) led to 83, which was converted to 8-oxo-erythrinine101,129) (57) upon methylation and deprotection of the secondary hydroxy group. Subsequent elimination of the hydroxy group under acidic conditions provided crystamidine (56).102) A series of compounds without a benzylic hydroxy group was synthesized by first treating 82 under reductive conditions to afford 84. Luche reduction and methylation provided 8-oxo-erythraline129) (59) and reduction of the lactam moiety using LiAlH4 and AlCl3150,151) afforded erythraline152,153) (58).
The first asymmetric total syntheses of four erythrina alkaloids were accomplished via the divergent strategy, with the most oxidized intermediate bearing the common core structure of these alkaloids as the common intermediate. Subsequent reductive or redox neutral transformations were applied to realize an efficient route that could also facilitate the synthesis of a broad range of erythrina alkaloids.
This review provides an overview of the divergent syntheses of three families of natural products that have been successfully accomplished. The key to the syntheses is the development of a strategy for certain groups of naturally occurring molecules by designing a late-stage pluripotent common synthetic intermediate that is suitable for diversification. The strategy for the appropriate design of the common intermediate consists of four steps: 1) selection of target molecules that share a common core structure, 2) drawing a map to reveal the structural relationship among the molecules to ensure that all targets could be linked to each other by potential chemical transformations, 3) combining the mapping information with state-of-the-art synthetic transformations to designate where the branching of the synthetic scheme should start, and 4) inspection of the first target intermediate and its detailed synthetic planning. By following these guidelines, the total syntheses of three natural product families were accomplished.
Application of the divergent strategy to gelsedine-type alkaloids revealed that these molecules consist of a common core structure with peripheral structures with various oxidation states. This notion simplified the design of late-stage common synthetic intermediate 1, which could be used to introduce various functionalities on the reactive enal moiety. With intermediate 10 synthesized via innovative transformations including the divinylcyclopropane–cycloheptadiene rearrangement and TMSCN–DBU-mediated redox neutral isomerization, comprehensive asymmetric syntheses of the targeted gelsedine-type alkaloids were achieved from this single intermediate.
As the pyrrolidine moiety on amathaspiramide alkaloids has different oxidation states, a sequential reductive strategy was chosen for the comprehensive synthesis. The most oxidized intermediate was thus designed, and appropriate reductive conditions successfully streamlined the first asymmetric syntheses of all six amathaspiramide alkaloids.
A versatile strategy for the synthesis of erythrina alkaloids was also developed based on the most oxidized common synthetic intermediate. The use of the medium-membered lactam intermediate with biaryl atropisomeric stereochemistry controlled the point chirality at the central tetrasubstituted stereocenter in the singlet oxygen-mediated transformation. Reductive manipulation of the functionalities on the peripheral moieties of the core A–C rings enabled the first syntheses of four chiral erythrina alkaloids that could potentially give rise to a divergent synthetic strategy for this class of alkaloids.
Collectively, endeavors toward these three families of natural products helped develop the synthetic pathways derivatized from each of the late-stage common synthetic intermediates that were designed through the divergent synthetic strategy.
The author thanks Prof. Tohru Fukuyama (Nagoya University), Prof. Masato Kitamura (Nagoya University), and Prof. Satoshi Yokoshima for fruitful discussions and helpful support. The following collaborators are appreciated for their invaluable efforts: Dr. Takaaki Harada, Ms. Hiromi Kaise, Dr. Koji Chiyoda, Dr. Hirotatsu Umihara, and Ms. Tomomi Yoshino. Dr. Yosuke Kaburagi (Eisai Co., Ltd.) is acknowledged for his support on the growth inhibition assay. This work was supported by the Kato Memorial Bioscience Foundation, a Mitsubishi Tanabe Pharma Award in Synthetic Organic Chemistry Japan, Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Numbers 21790009, 20002004, 23590003, 25221301, 15H05641, 12J10846, the Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and the Advanced Catalytic Transformation Program for Carbon Utilization (ACT-C) from the Japan Science and Technology Agency (JST).
The author declares no conflict of interest.
This review of the author’s work was written by the author upon receiving the 2017 Pharmaceutical Society of Japan Award for Young Scientists.
