2024 年 72 巻 8 号 p. 731-746
Nitrones are widely used as 1,3-dipoles in organic synthesis, but control of their reactions is not always easy. This review outlines our efforts to make the reactions of nitrones more predictable and easier to use. These efforts can be categorized into (1) 1,3-nucleophilic addition reaction of ketene silyl acetals to nitrones, (2) geometry-controlled cycloaddition of C-alkoxycarbonyl nitrones, (3) stereo-controlled cycloaddition using double asymmetric induction, and (4) generation of nitrones by N-selective modification of oximes.
Nitrones, which contain a C–N double bond and an oxygen atom in a compact structure, are attractive synthetic starting materials for many nitrogen-containing biologically active compounds, such as amino acids, alkaloids, β-lactam antibiotics, and other clinically important compounds. Nitrones have several important characteristics: (A) imine character, (B) E,Z-isomerism, and (C) a 4π-electron system that undergoes 1,3-dipolar cycloaddition1–3) (Chart 1). Taking advantage these characteristics, we have advanced nitrone chemistry in the following fields: (1) 1,3-nucleophilic addition reaction of ketene silyl acetals to nitrones, (2) geometry-controlled cycloaddition of C-alkoxycarbonyl nitrones, (3) stereo-controlled cycloaddition using double asymmetric induction, and (4) generation of nitrones by N-selective modification of oximes.
In the 1980s, the synthesis of anthracycline antitumor antibiotics was a hot topic4,5) (Chart 2A). In this context,6) an efficient method for the synthesis of daunosamine, a sugar constituent of the anthracyclines was required. To solve this problem, 1,3-nucleophilic addition of ketene silyl acetals to chiral nitrones was employed. Thus, on treatment of chiral nitrone 1 with ketene silyl acetal 2a in the presence of a catalytic amount of ZnI2 in acetonitrile, O-silylation occurred, affording O-silylated iminium ion A, which underwent stereoselective Mannich-type nucleophilic addition to afford exclusively the 3,4-anti 1,3-adduct 3. Adduct 3 was readily transformed to N-benzoyl daunosamine (4) in a few additional steps7,8) (Chart 2B).
In the case of nitrones 5, the stereoselectivity was greatly affected by the bulkiness of both the substituent R1 of 5 and the substituent R2 of the ketene silyl acetal 2 (Chart 3). Thus, treatment of nitrone 5 having a less bulky substituent (R1 = CH2Ph) with 2a (R2 = Me) in a similar manner to that described for nitrones 1 afforded the 3,4-syn major adduct 6, whereas the combination of nitrone 5 (R1 = CHPh2) and bulky ketene silyl acetal 2b (R2 = tert-butyl) gave the 3,4-anti adduct 7 with high selectivity.9,10)
The vinylogous nucleophilic 1,3-addition of nitrones was also useful. Nitrone 8 having a sugar auxiliary (L-gulosyl group) reacted stereoselectively with 2-siloxyfuran 9 in the presence of a catalytic amount of Me3SiOTf to give 1,3-addition product B, which, without isolation, was desilylated, resulting in intramolecular conjugate addition to butenolide to give bicyclic lactone 10 (Chart 4). The stereochemistry of 10 was suitable for the synthesis of uracyl polyoxin C (12), the N-terminal amino acid of nikkomycin Bz (11). In fact, bicyclic lactone 10 was readily transformed to known synthetic intermediate 1311) through a short synthetic sequence.12) In addition, lactone 10 has the appropriate four contiguous stereogenic centers for dysiherbaine, a non-N-methyl-D-aspartic acid (NMDA) glutamate receptor agonist. Indeed, lactone 10 was led to Hatakeyama’s lactone 14,13) the key synthetic intermediate of dysiherbaine.14)
C-Alkyl or -aryl nitrones exist in (Z)-form, because (E)-nitrones have severe steric repulsion between R1 and R2 (Chart 5A).15) However, C-alkoxycalbonyl nitrones are geometrical mixtures of (E)-form and (Z)-form in solution.16) Although the (E)-form has severe steric repulsion, the (Z)-form exhibits dipole-dipole repulsion, so the energy difference between them is not large17,18) (Chart 5B). Moreover, the bond order of the C–N bond of C-alkoxy nitrones is less than two, because the nitrone moiety and ester group are well conjugated, resulting in facile E,Z-isomerization (Chart 5C). This is the reason why cycloaddition of C-alkoxycarbonyl nitrones always affords a mixture of trans- and cis-isomers19–24) (Chart 5D).
To overcome this problem, we used three methods: (1) (Z)-selective activation by chelation of Eu(III); (2) cycloaddition from the (Z)-form by employing intramolecular reaction; and (3) use of (E)-geometry-fixed nitrones.
2.1. (Z)-Selective Activation by Chelation of Eu(III)25,26)Since C-alkoxycarbonyl nitrone 15 exhibits a resonance effect between the nitrone moiety and the carbonyl group similar to that of a β-diketone anion, it can be regarded as isoelectronic to β-diketone anion 16 (Chart 6). Since the NMR shift reagent Eu(fod)3 has β-diketone anions as ligands, we expected that Eu(fod)3 would selectively activate (Z)-15 in an equilibrium mixture of (Z)-15 and (E)-15 by forming 17 [(Z)-15–Eu(fod)3 complex], which would undergo stereoselective 1,3-dipolar cycloaddition. A Lewis acid should lower the lowest unoccupied molecular orbital (LUMO) energy of (Z)-15, so the use of dipolarophiles having a high highest occupied molecular orbital (HOMO) energy, such as vinyl ethers, would be reasonable.
The effect of Eu(fod)3 was examined in the cycloaddition of nitrone 15a with vinyl ethers 18 (Table 1). Treatment of nitrone 15a (1 equivalent (equiv.)) with vinyl ether 18a (20 equiv.) at room temperature for 36 h gave a 72 : 28 mixture of cycloadducts trans-19a and cis-19a (entry 1). The use of 1 equiv. of Eu(fod)3 shortened the reaction time (5 h) and improved the selectivity (>98 : 2) (entry 2). Similarly, while the reactions of 15a with 18b–d in the absence of Eu(fod)3 gave mixtures of trans- and cis-cycloadducts (trans-19b–d and cis-19b–d) (entries 3, 6, 8), the reactions of 15a with 18b–d in the presence of equimolar Eu(fod)3 afforded trans-19b–d with high selectivity (entries 4, 7, 9). It is worth noting that the use of only 0.3 equiv. of Eu(fod)3 with 3 equiv. of vinyl ether improved the stereoselectivity (entry 5).
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The reaction is considered to involve 17 [(Z)-15a-Eu(for)3 complex]. Thus, Eu(fod)3 selectively activates (Z)-15a by forming 17, which reacts with the vinyl ether 18 via transition state endo-C to give the cycloadduct trans-19, because exo-C would have a severe steric interaction between the substituent (OR) and bulky Eu(fod)3 (Chart 7).
Efficient transesterification might enable tandem transformation of nitrones 15 to cycloadducts 22. Thus, transesterification of readily available C-methoxycarbonyl nitrone (15) with allylic alcohol 20 would provide C-allyloxylcarbonyl nitrones (E)-21 and (Z)-21, which could undergo intramolecular cycloaddition to give 22 via (Z)-transition state D in the reaction system (Chart 8).
The crucial transesterification was accomplished by using Ti(IV) catalyst. Thus, when nitrone 15a was treated with allylic alcohol 20 in the presence of 1 equiv. of Ti(OiPr)4 or 0.1 equiv. of TiCl4 and molecular sieves 4A (MS 4A), transesterification proceeded smoothly followed by intramolecular cycloaddition via (Z)-nitrone transition state D to afford stereo-controlled cycloadduct 2227,28) (Charts 8 and 9). Since the cycloadducts have a bicyclic [3.3.0] ring system, the stereochemistry at the bridgehead position is always cis (22a). The use of simple allylic alcohol 20a gave cycloadduct 22a in 74% yield. When cyclic allylic alcohol 20b was used, cycloadduct 22b having four cis-stereogenic centers was formed via transition state D. Reaction of trans-cinnamyl alcohol 20c gave 3,3a-trans cycloadduct 22c whereas cis-cinnamyl alcohol 20d furnished 3,3a-cis cycloadduct 22d.
C-Diethyloxycarbonyl nitrone 23 underwent similar tandem transesterification and intramolecular cycloaddition with allylic alcohols 20a–d to give bicyclic cycloadducts 24a–d29) (Chart 10). It should be noted that this cycloaddition affords cycloadducts 24a–d featuring tetra-substituted carbon atoms.
Our tandem ester-formation and intramolecular cycloaddition concept was applied to synthesize a large library of compounds. Schreiber used esterification in place of transesterification, and reported construction of a huge chemical library by employing combinatorial chemistry based on split-pool synthesis (Chart 11). Thus, solid-supported allylic alcohol 25 derived from shikimic acid underwent condensation reaction with C-carboxylic acid nitrones 26 to provide intramolecular cycloadducts 27 having several functional groups that provide diversity. This method yielded as many as 2.18 million compounds.30,31)
Utilization of cyclic allylic alcohols such as 20b or 25 enabled complete asymmetric induction to provide cycloadduct 24b or 27 bearing multiple stereogenic centers (Charts 10, 11). Next, we examined the stereoselectivity of cycloaddition using linear secondary allylic alcohols (Z)-28 and (E)-2832,33) (Charts 12, 13). Nitrone (S)-15b having an (S)-2-phenylethyl group on the nitrogen atom reacted with allylic alcohol (Z)-28 in the presence of TiCl4 and MS4A to give a 92 : 8 mixture of (S)-29 and (S)-30. When the antipodal nitrone (R)-15b was used, the diastereofacial selectivity of the reaction with (Z)-28 did not change, and a 93 : 7 mixture of (R)-29 and (R)-30 was obtained. The stereoselectivities can be rationalized by considering transition models E and F for the cycloaddition step of (Z)-nitrones. Transition state F suffers severe allylic 1,3-strain34,35) whereas transition state E does not. Accordingly, the reactions give cycloadducts (S)-29 and (R)-29 as the major isomers, respectively (Chart 12).
When (E)-28 was employed, the reaction exhibited different stereoselectivities. Reaction of (S)-15b with (E)-28 gave (S)-31 and (S)-32 as an 8 : 92 mixture of diastereomers. On the other hand, (R)-15b exhibited the opposite stereoselectivity, affording a 63 : 37 mixture of (R)-31 and (R)-32 (Chart 13). These selectivities can be rationalized in terms of transition models G and H. Little allylic 1,3-strain is involved in transition state H because the (E)-alkene moiety has only a hydrogen atom in the inside of the allyl system. On the other hand, the chirality of the R1 group can greatly affect the adjacent R2 group. Accordingly, the antipodal nitrones (S)-15b and (R)-15b exhibited opposite diastereofacial selection.
The above stereoselectivities can be explained by considering the (Z)-nitrone transition state model. Transition state model I in Chart 14 shows the factors affecting stereoselection in the present intramolecular cycloaddition. When the allylic alcohol has (Z)-geometry (R2 = H, R3 ≠ H), allylic 1,3-strain is the most important factor, but when an (E)-allylic alcohol is used (R2 ≠ H, R3 = H), the chirality of R1, a substituent on the nitrogen atom, affects the stereoselection.
A protected gulosyl group36–38) was a better chiral N-substituent than an N-2-phenylethyl group.39,40) Oxime 33 derived from L-gulose was condensed with aldehyde 34 in refluxing toluene to generate nitrone 35, which was treated with (E)-cinnamyl alcohol (36), a catalytic amount of TiCl4, and MS 4A, giving rise to intramolecular cycloadduct 38a as a single isomer via transition state J. In contrast, the reaction using (Z)-cinnamyl alcohol (37) was much less selective and gave a 3 : 2 mixture of diastereomers 39a and 39b due to the weak steric interaction between the L-gulosyl group and hydrogen atom compared to the L-gulosyl group and phenyl group (Chart 15).
This method was directly applied for the synthesis of the N-terminal amino acid 42 of the dipeptide antibiotic nikkomycin Bz (43).41–44) Nitrone 35 derived from protected L-gulose oxime 33 and aldehyde 34 was exposed to allylic alcohol 40 in the presence of a catalytic amount of TiCl4 and MS 4A at 100 °C, resulting in transesterification and intramolecular cycloaddition to afford cycloadduct 41 as a single stereoisomer in 73% yield. The cycloadduct 41 was led to 42 via several steps, including (a) reductive cleavage of the N–O bond, (b) acidic removal of the N-substituent, and (c) cleavage of the C–O bond39) (Chart 15).
Stereoselective intramolecular cycloaddition of an L-gulosyl-derived nitrone was utilized for syntheses of (−)-funebral (50)45) and (−)-funebrine (51)46) (Chart 16). Condensation of propylidene-protected L-gulose oxime 44 with aldehyde 34 generated nitrone 45, which was treated with allylic alcohol 46 in the presence of a catalytic amount of Ti(OiPr)4 and MS 4A to afford cycloadduct 47 as a major isomer. Cycloadduct 47, on treatment with Mo(CO)6 in MeCN-H2O followed by diluted hydrochloric acid, underwent reductive cleavage of the N–O bond, removal of the N-substituent, and translactonization. In-situ protection of the primary amino group gave lactone 48. Removal of the hydroxyl group by a three-step sequence (mesylation of the primary hydroxyl group, displacement with iodine, and treatment with Bu3SnH) and subsequent removal of the tert-butoxycarbonyl (Boc) group by hydrogen chloride in methanol afforded hydrochloride 49·HCl, the key intermediate of (−)-funebral and (−)-funebrine. Three further steps, including Knorr pyrrole synthesis, gave (−)-funebral (50). Finally, the first synthesis of (−)-funebrine (51) was accomplished by condensation of amine 49 and aldehyde 50.47)
As described above, C-alkoxycarbonyl nitrone 15 exists as an equilibrium mixture of (Z)-15 and (E)-15. Connection of the R1 group on the nitrogen atom with the R2 group on the ester group of (E)-15 led to cyclic nitrone 52, as shown in Chart 17.48,49)
Typical examples of cycloaddition of (R)-52 are shown in Chart 18. The major products were produced via transition state K that features exo addition from the less-hindered face (Chart 18). Nitrone (R)-52 reacted with cyclopentene (53a) at room temperature to give cycloadduct 54a as a sole product in 90% yield. Mild heating of nitrone (R)-52 with isobutene (53b) afforded cycloadduct 54b in 95% yield. In contrast, the reaction of (R)-52 with terminal alkene 53c was less selective, and gave an 83 : 8 : 9 mixture of cycloadducts, although the major product was 54c generated via transition state K.
Cycloaddition of nitrone 52 was utilized in syntheses of maremycin A (58)50) and maremycin D1 (59)51) (Chart 19). Cycloaddition of (S)-52 with 3-ethylidene indolinone 55 gave cycloadduct 56 and its regio-isomer. Cycloadduct 56 possessing three continuous stereogenic centers underwent hydrogenolysis with cleavage of the N–O bond and N-benzyl bond, and hydrolysis of the ester group afforded amino acid 57. Three additional steps, including peptide bond formation and cyclization, gave maremycin A (58), whose sulfide group was oxidized to sulfoxide. Syn-elimination occurred on heating to afford maremycin D1 (59).52,53) This was the first synthesis of 58 and 59, and served to establish the absolute stereochemistry of the methyl group on the asymmetric carbon atom.
As mentioned above, the reaction of nitrone 52 with a mono-substituted alkene such as 1-hexene (53c) was less stereoselective (Chart 18). The use of allylic alcohol with MgBr254) overcame this problem (Chart 20). Nitrone (R)-52 reacted with allylic alcohols 60a–c in the presence of MgBr2·OEt2 at room temperature to 50 °C, giving the corresponding 61a–c as the sole products, probably via transition state L.55) Reaction of the simple allylic alcohol 60a proceeded at room temperature to give cycloadduct 61a in high yield (89%), whereas cycloaddition of the sterically hindered tert-alcohol 60b required heating to 50 °C and afforded only a low yield of cycloadduct 61b (30%). It should be noted that allylic alcohol having an R1 substituent, 60c, also smoothly reacted with nitrone (R)-52 to furnish cycloadduct 61c as a single isomer.
The 4-hydroxy-4-substituted glutamic acid moiety 62 is a common structural feature of several unusual, naturally occurring, biologically important amino acids such as monatin (63)56) (a high intensity sweetener), lycoperdic acid (64),57) and neodysiherbaine A (65)58) (an agonist of non-NMDA-type glutamate receptor) (Chart 21). Although there have been intensive studies on the syntheses of these natural products,58–78) the stereogenic centers at the 2- and 4-positions were constructed independently in all previous studies. Therefore, it seemed useful to explore methodology for the construction of both stereocenters in a single operation. We applied MgBr2-promoted cycloaddition of nitrone (S)-52 with allylic alcohols such as 61c to the synthesis of these compounds.
Synthesis of monatin (63) was first examined.79,80) Cycloaddition of nitrone (S)-52 with allylic alcohol 66 in the presence of MgBr2 was conducted to give cycloadduct 67 as a sole product in 98% yield via transition state M (Chart 22). Cycloadduct 67 possesses all the carbon atom and stereogenic centers required for the synthesis of 63. The indole nitrogen of 67 was protected in three steps, giving compound 68, which was subjected to hydrogenolysis to induce reductive cleavage of the N–O bond and benzylic N–C bond and lactonization. The nitrogen atom of the N-free lactone was protected with a Boc group to give lactone 69, in which primary hydroxyl group was oxidized with PDC to afford carboxylic acid 70 in three steps in 56% yield. Finally, synthesis of monatin (63) was accomplished by removal of the two Boc groups and hydrolysis of the lactone.79,80)
MgBr2-promoted cycloaddition of (S)-52 with allylic alcohol 71 again took place stereoselectively to provide a 91 : 9 mixture of cycloadduct 73 and its diastereomer in 94% yield. Hydrogenolysis of compound 73 followed by protection of the amino group afforded lactone 74. Oxidation of the primary alcohol of 74 with PDC, alkaline hydrolysis of both the lactone and ethyl ester group, and removal of the Boc group by acid treatment furnished lycoperdic acid (64)80) (Chart 23).
Nitrone (S)-52 reacted with L-xylose-derived allylic alcohol 75 in the presence of an excess of MgBr2 and isopropanol to afford cycloadduct 76 as a sole product in 80% yield (Chart 24). Hydrogenolysis of 76 in the presence of Boc2O induced reductive cleavage of the N–O bond, O-benzyl bond and N-benzyl bond, then protection of the primary alcohol with tert-butyldimethylsilyl (TBS) group followed by chloromethanesulfonylation of the secondary alcohol afforded protected γ-lactone 77 in 66% yield. Treatment of 77 with LiOH at room temperature then at 70 °C caused ring opening of the γ-lactone followed by tetrahydrofuran ring formation via intramolecular SN2 reaction. Extraction of the reaction mixture after adjustment of the pH to 2 gave the crude acid 78, which was treated with O-tert-butyl-N,N′-diisopropylisourea to afford tert-butyl ester 79 in 95% yield from 77. The TBS group of 79 was removed and the resulting primary alcohol was oxidized with tetra-n-propylammonium perruthenate (TPAP) to give lactam 80 in 68% yield (two steps). Finally, removal of all protective groups and hydrolysis of the lactam by acid treatment afforded neodysiherbaine A (65) in 98% yield.81)
We required hydroxycotinine O-glucuronide (81) for studies of the metabolism of nicotine (Chart 25). For this purpose, we adopted a strategy of double asymmetric induction. Heating nitrone 82 having L-gulosyl auxiliary with dipolarophile 83 bearing camphor sultam XS in refluxing 1,2-dichloroethane caused stereoselective cycloaddition to give predominantly (3S,5S)-isoxazolidine 84 (84 : others = 9.4 : 1). Removal of the L-gulosyl group, N-methylation, and reductive cleavage of the N–O bond in cycloadduct 84 afforded lactam 85 via transcyclization. Transformation of lactam 85 to hydroxycotinine (86) was conducted by Mitsunobu reaction.82) Finally, glucuronylation of 86 afforded hydroxycotinine O-glucuronide (81). This material was used for studies of the metabolism of nicotine in human body.83)
Tubulysins are naturally occurring linear tetrapeptides that contain three non-proteogenic amino acids, N-methyl-D-pipecolic acid, tubuvaline, and tubuphenylalanine. The tubulysins display potent antitumor activity by inhibiting tubulin polymerization and have antiangiogenic activity (Chart 26). Thus, they have attracted considerable attention as synthetic target molecules as well as leads for the development of new anticancer agents.84–88)
A similar approach to that used for the synthesis of hydroxycotinine was applied to tubulysins. Nitrone 90 having a D-gulosyl group as an auxiliary reacted with dipolarophile ent-83, the antipode of 83, to afford predominantly 91. This process could be conducted on a 60 g scale. Removal of the D-gulosyl group and thiazole formation afforded 92, which underwent reductive N–O bond cleavage to give tubuvaline methyl ester (93). Tubulysin D was synthesized from 93 by standard methodology.89,90) Use of ent-90 and 83 gave the enantiomer of 91. The combination of Mitsunobu reaction and the above reaction enabled synthesis of all four stereoisomers of 93. These stereoisomers were used to synthesize tubulysin D derivatives, and their bioactivities were examined. As a result, it was found that the stereochemistry of the isopropyl group is important for the anti-tumor activity.91) When isoxazolidine 92 was used for the synthesis of tubulysins U and V, the isoxazolidine ring served as a protective group for the amino and hydroxyl groups until the final stage of the synthesis. Removal of the N-protective group of 92 followed by peptide extension in the N-terminal direction gave tripeptide 94. The methyl ester of 94 was hydrolyzed, and the resulting carboxylic acid was condensed with tubuphenylalanine to afford tetraeptide 95. Finally, reductive cleavage of the N–O bond in the isoxazolidine ring gave tubulysin V, whose hydroxyl group was acetylated to afford tubulysin U.90)
The most frequently used method for the synthesis of nitrones is condensation of N-alkylhydroxylamines and carbonyl compounds (Chart 27A). We considered that efficient N-modification of the nitrogen atom of O-silylated oximes would also produce nitrones (Chart 27B).
We found an efficient method to transform cyclic hemiacetals, such as sugar derivatives, to highly functionalized cyclic nitrones.92) Thus, treatment of hemiacetal 96 with O-silylhydroxylamine followed by mesylation of the hydroxyl group gave 97. Exposure of ω-mesyloxy oxime 97 to TBAT induced desilylative cylization to give cyclic nitrones 98 (Chart 28). This three-step sequence enabled efficient transformation from 96a to five-membered cyclic nitrone 98a. In the case of 96b, nitrone 98b having opposite stereochemistry was obtained because of the SN2 cyclization step. Six-membered cyclic nitrone 98c was also produced without difficulty from 96c.
Synthesized cyclic nitrones 98 also underwent 1,3-dipolar cycloaddition with alkenes (Chart 29). For example, heating nitrones 98a with styrene in refluxing toluene gave cycloadduct 99 in a stereoselective manner. The intramolecular reaction also worked well. Three-step treatment of hemiacetal 100 in situ generated cyclic nitrone 101, which simultaneously underwent intramolecular cycloaddition to afford cycloadduct 102 in high yield from 100.
L-Xylose-derived hemiacetal 103 was transformed to nitrone 104 in three steps. Nitrone 104 underwent 1,3-dipolar cycloaddition with 105 to give cycloadduct 106, which was led to lactam 107, a synthetic intermediate for hyathinthacine A2 (108) (Chart 30). On the other hand, nucleophilic addition of Grignard reagent 109 to nitrone 104 afforded 110 exclusively in 95% yield. Adduct 110 is a direct intermediate for codonopsinine (111).93)
Considering the strong affinities of nitrogen-borane and silicon-fluorine, we hypothesized that an O-silyl oxime containing an olefin moiety 112 would react with BF3·OEt2 to generate an N-boranonitrone N, which in turn would undergo intramolecular cycloaddition to give a cycloadduct O coordinated with BF3 in the reaction system. Then, aqueous work-up should afford an N-H cycloadduct 11394,95) (Table 2). Despite the requirement of 2 equiv. of BF3·OEt2, this reaction proceeded well. Thus, trans-substrate 112a gave trans-cycloadduct 113a in excellent yield (entry 1) and cis-substrate 112b afforded cis-cycloadduct 113b in high yield (entry 2). Oxime 112c having dimethyl alkene and N-tethered oxime 112d also yielded the corresponding cycloadducts 113c and 113d, respectively (entries 3, 4).
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In general, an oxime 114 having an olefin moiety undergoes isomerization on heating to generate a small amount of NH-nitrone P, which causes 1,3-dipolar cycloaddition to furnish a cycloadduct 113 (Chart 31). This reaction, intramolecular oxime-olefin cycloaddition (so-called IOOC), is operationally very simple, but its success is strongly dependent on the structure of the starting oxime 114. The present BF3-mediated cycloaddition of O-silyl oxime offers advantages over IOOC. Thus, IOOC of oxime 112e (R = H) required heating in refluxing toluene for 1 week to give cycloadduct 113e in 54% yield, accompanied with recovery of the starting 112e (R = H) in 27% yield. In contrast, cycloaddition of 112e (R = TBS) in the presence of BF3·OEt2 proceeded at room temperature to afford 113e in 73% yield.
Changing the substitution pattern of the olefin moiety provided access to different ring systems (Chart 32). Oxime 112f containing a dimethyl-substituted olefin afforded only the bicyclo[3.3.0] ring system 113f in 68% yield. Oxime 112g containing a non-substituted olefin moiety afforded the bicyclo[3.3.0] ring system 113g and bicyclo[3.2.1] ring system 115a. Oxime 112h gave only the bicyclo[3.2.1] ring system 115b in 58% yield.
The regiochemistry may be rationalized by considering the electrophilicity of the intermediate N-boranonitrones (Chart 33). Adducts 113f and 113g may be formed via transition state Q, whereas 115a and 115b may be obtained via R. This consideration suggests that the carbon atom of N-boranonitrones should exhibit highly electrophilic character because of double activation by boron fluoride, and hence, the more electron-rich carbon atom in the olefin would attack the electrophilic nitrone-carbon.
When oxime 116 containing an acetylene moiety was treated with BF3·OEt2, the reaction afforded not the expected cycloadduct 118, but dimer 11796) (Chart 34). Single crystal X-ray diffraction of 117 revealed the ladder-shaped structure depicted as 117′.
The formation of dimer 117 is considered to involve strain-induced protonation of the initial product 118 (Chart 35). Oxime 116 reacts with BF3·OEt2 to generate N-boranonitrone 119, which undergoes cycloaddition, affording BF3-coodinated cycloadduct 120, in which the lone pair of electron is trapped by coordination with BF3. After work-up, the liberated lone pair in 118 participates in protonation at the 3a-position to release the high strain, generating oxonium cation S. The cation S undergoes addition reaction with ent-T to yield U, which induces cyclization via V to afford 117.
In general, intermolecular cycloaddition is less efficient than the intramolecular counterpart. Indeed, intermolecular cycloaddition of N-boranonitrone required incorporation of an electron-withdrawing group as a C-substituent for activation. O-Silyloxime 121 having ethyl ester as an electron-withdrawing group, on treatment with BF3·OEt2, underwent cycloaddition with alkenes 122 to give 3,5-trans cycloadducts 123 as the major isomers97,98) (Chart 36). Terminal alkenes 122a–c and cyclic alkenes 122d,e predominantly afforded trans-cycloadducts 123a–c and 123d,e.
3,5-Trans-cycloadducts 123a–c were readily transformed to 1,3-aminoalcohols 125a–c (Chart 37). Reduction of the ester group in 123a–c followed by protection of nitrogen gave 124a–c in good yields. Then, reductive cleavage of the N–O bond of 124a–c afforded 125a–c.
In contrast to ester-substituted oxime 121, cycloaddition of amide-substituted oxime 126 was found to require warming to 60 °C and was 3,5-cis-selective (Chart 38). Treatment of oxime 126 with alkenes 127a–e in the presence of 2.2 equiv. of BF3·OEt2 followed by aqueous work-up predominantly gave 3,5-cis cycloadducts 128a–e. Since the 1H-NMR spectra of NH-cycloadducts 128a–e exhibited broadened signals, cycloadducts 128a–e were isolated as their Boc derivatives 129a–e. All reactions afforded 3,5-cis cycloadducts 129a–e in the range of 3 : 1 to cis only.99)
When oxime 126 was treated with 1 equiv. of BF3·OEt2, crystalline material precipitated from the solution (Chart 39). X-ray diffraction analysis revealed that this material was boracycle 130. Although 130 did not react with alkene 127b, it did react with 127b in the presence of another 1 equiv. of BF3·OEt2 to give cycloadduct 127b after work-up and treatment with Boc2O. Thus, the reactive species in the present reaction would be 130-BF3.
One of the products was applied to the synthesis of HPA-12, an inhibitor of ceramide transport protein CERT100–108) (Chart 40). Removal of the Boc group of 129a followed by acylation under Schotten–Baumann conditions gave amide 131, whose N–O bond was reductively cleaved to afford amino alcohol 132, which underwent lactonization to afford 133. Remaining 132 was converted to 133 by simple heating. Finally, lactone 133 was reduced with NaBH4 to afford HPA-12 (134).99)
We found three types of methods to generate nitrones from free oximes by N-selective modification.109–111) These reactions have been recently reviewed by one of our ex-colleagues,112) so here they are just shown as equations (1)–(3) in Chart 41.
This review outlines our work on nitrone chemistry. Although nitrone is a simple structure, it has not been easy to control the reactivity, regiochemistry and stereochemistry of its reactions. We have explored and developed various aspects of nitrone chemistry for use in the synthesis of a variety of biologically important nitrogen-containing compounds. We hope the chemistry described here will be helpful for further synthetic work in this area.
These studies were carried out at the Graduate School, School of Pharmaceutical Sciences, Osaka University; Meiji Pharmaceutical University (MPU); Graduate School, Division of Pharmaceutical Sciences, Kanazawa University; Showa Pharmaceutical University (SPU). I would like to thank the staff and students of these laboratories, particularly Drs. Nobuyoshi Morita, Yoshimitsu Hashimoto, Kosaku Tanaka, III, and Prof. Iwao Okamoto (SPU). I would also like to express my great appreciation to Prof. Yasumitsu Tamura (Osaka Univ.), Prof. Yasuyuki Kita (Osaka Univ.), Prof. Masanori Sakamoto (MPU), and Prof. Hiroyuki Ishibashi (Kanazawa Univ.) for their supervision and kind encouragement. I would also like to thank the students who worked so hard on the experiments described here.
The author declares no conflict of interest.
This review of the author’s work was written by the author upon receiving the 2022 Pharmaceutical Society of Japan Award for Divisional Scientific Contribution.
