Mariana
Crespo Monteiro
,
João Rafael
Vale
and
Filipa
Siopa
*
Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Professor Gama Pinto, 1649-003, Lisbon, Portugal. E-mail: filipasiopa@ff.ulisboa.pt
First published on 12th March 2024
2-Azabicyclo[3.2.1]octanes are nitrogen containing heterocycles with significant potential in the field of drug discovery. This core has been applied as key synthetic intermediate in several total synthesis, while their unique structure can make them a challenging scaffold to acquire. This Minireview summarizes the synthetic approaches to access this bicyclic architecture and highlights its presence in the total synthesis of several target molecules.
Interest in this core by the scientific community has spiked since 2014 after Massiot's group reported a series of structurally related cytisine-like alkaloids from the roots and stems of Ormosia hosier, a plant employed in traditional Chinese herbal medicine. These compounds, of the hosieine family (Fig. 2), exhibited high affinity for α4β2 neuronal nicotinic acetylcholine receptor. For instance, (−)-hosieine A, the most potent molecule in this class (IC50 = 0.96 nM, Ki = 0.32 nM), exhibits an activity five times stronger than nicotine.4 The remarkable high activity of (−)-hosieine A and its complex skeleton have already inspired its asymmetric total synthesis, as well as its enantiomer, which are discussed in this manuscript.
Other synthetic compounds containing the 2-azabicyclo[3.2.1]octane scaffold have also shown diverse biological activities. Ong and Anderson were pioneers in showcasing its medicinal potential as efficient analgesic agents. The most promising compounds 2a and 2b showed a combined agonist-antagonist effect with efficiency close to morphine (Fig. 2).5 In a similar line, Andreotti's group explored the effect of aryl substitution in the bridgehead carbon of the azabicyclo[3.2.1]octane. Compound 3, mimicking the 3D conformation of cocaine, proved to be a potent in vitro triple re-uptake inhibitor (TRUI).3b The introduction of a second nitrogen group attached to the bicyclic structure grants this class of molecules relevant biological activity. Agonist activity in κ-opioid receptors (KOR) was observed for compound 46 and cytotoxic activity on different tumor cell lines, such as glioblastoma (GBM), medulloblastoma (MB) and hepatocellular carcinoma (HCC) cell lines (Fig. 2) were reported for 5.7 Overall, the medicinal and biological effect of azabicyclo[3.2.1]octane derivatives appears to derive from its structural similarity with bioactive alkaloids such as nicotine, cocaine and morphine, while its bicyclic backbone provides additional rigidity to the molecular structure, which is an important feature in medicinal chemistry.8
2-Azabicyclo[3.2.1]octane system is chiral and, unless constructed from enantiomerically pure precursors, it is often present as a mixture of two enantiomers. In this review, we represent it in a consistent 3D configuration for the sake of clarity and consistency, adding (±) notation whenever a racemic mixture is present.
In this Minireview we discuss the reported methodologies for the synthesis of 2-azabicyclo[3.2.1]octanes, namely intramolecular cyclization and rearrangements, such as Beckmann rearrangement. Moreover, their application in total synthesis is also covered in this manuscript. We also include the synthesis of 2-azabicyclo[3.2.1]octan-3-ones, since they are common precursors to the 2-azabicyclo[3.2.1]octane core, typically accessed via reduction with LiAlH4.
One of the first examples in the literature comes from Gassman and co-workers that, in 1968, reported the preparation of 8-methoxy-2-methyl-2-azabicyclo[3.2.1]octane 8 (Scheme 1). Treatment of amine 6 with aqueous sodium hypochlorite resulted in 7. Reflux of a methanolic solution of 7 in the presence of silver nitrate resulted in product 8 in 55–65% yield.11
In 1977, Takeda and co-workers9c were the first to prepare 5-aryl substituted 2-azabicyclo[3.2.1]octane scaffolds (Scheme 2), inspired by the conventional synthesis of phenylmorphan.12 The azabicyclo-core was accessed through intramolecular cyclization using cyclopentanone 10 or cyclopentenone 13 (Scheme 2). The synthetic strategy commences with the α-alkylation of cyclopentanone 9 to afford 10. From there, two synthetic routes emerge: cyclopentanone 10 may be submitted to α-bromination, which is followed by ring closing. Demethylation of the resulting tetraalkyl ammonium is achieved under high temperatures to yield ketone 11 (Scheme 2). In a different approach, 10 may be turned to the corresponding carbamate and then oxidized to the enone 13. Carbamate deprotection leads to intramolecular 1,4-addition of the secondary amine to give bicyclic amino ketone 14 (Scheme 2). Compounds 11 and 14 underwent Wolff–Kishner reduction to yield the desired azabicycloalkane 12. In a convergent manner, ketone 14 could also be obtained via acid catalysed cyclization of 16 (Scheme 2).9c A year later, a similar procedure was described by Ong and co-workers, in which optimization of the reaction conditions applied to 10, 11 and 12 led to improvement of yields and the extension of the reaction scope.5
Fleming and coworkers10a reported the synthesis of 2-azabicyclo[3.2.1]octane 20 from urethane 19 (Scheme 3). Compound 17 was reacted with thionyl chloride and then sodium azide, resulting in the formation of azide 18 through C–C bond cleavage and ring opening. Compound 18 was then heated under reflux in methanol, resulting in 19. Finally, 19 was heated at 200 °C to produce lactam 20, in 87% yield.
Fourrey and co-workers10b reported in 1999 the preparation of 2-azabicyclo[3.2.1]octane core through Tsuji–Trost reaction followed by intramolecular cycloaddition. Palladium catalyzed intramolecular cyclization of hydrazine derivative 22 delivered the compound 23 in high yield. Bicyclic 23 was transformed into cyclopentane 24, a key intermediate in the synthesis of homocarbocyclic nucleosides (Scheme 4).
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Scheme 4 Synthesis of 2-azabicyclo[3.2.1]octan-3-one 23 by palladium catalyzed intramolecular cyclization. |
In the same year, the 2-azabicyclo[3.2.1]octan-3-one core was shown once more to be an important precursor to other carbocyclic nucleosides by Lundt's group.10c Bicyclic system 27 was accessed from 26via epoxide ring opening with ammonia followed by subsequent nucleophilic attack of the amine to the ester (Scheme 5). Amide cleavage and other operations led to the desired highly functionalized cyclopentane 28.
In a similar manner, 2-azabicyclo[3.2.1]octane core 32a–c, was prepared via intramolecular epoxide ring opening reaction of 31a–c with trifluoroacetamide (Scheme 6). Trifluoroacetamide removal led to bicyclic compound 33a–c, the precursor for the Aza-Cope-Mannich rearrangement, the key transformation in the total synthesis of Strychnos alkaloids: (±)-dehydrotubifoline 35, (±)-akuammicine 3613 and (−)-strychnine 41.14 The synthetic strategy to obtain (±)-dehydrotubifoline 35 and (±)-akuammicine 36 is very similar and commences from compound 29. While the synthesis of (−)-strychnine started with an enantioselective hydrolysis of cis-3,5 diacetoxycyclopentene to access compound 30. Epoxide 31a–c was synthesized by applying several standard manipulations, that include hydroxyl protection, Pd-catalyzed carbonylation, epoxide formation and Wittig methylenation towards compound 29 and 30. The desired azabicyclo[3.2.1]octane 33a–c, was accessed via epoxide ring opening with trifluoracetamide, followed by trifluoroacetamide removal. The Aza-Cope-Mannich rearrangement of 33a–c proceeds via the formation of an iminium intermediate A, that undergoes a [3,3] rearrangement to intermediate B. Cyclization leads exclusively to the formation of tricyclic compound 34a–c already containing three stereogenic centers present in the final molecules. Hydrolysis of 34a delivered the desired (±)-dehydrotubifoline 35. (±)-Akuammicine 36 was obtained after acylation, that furnished the correspondent β-keto ester, and acid catalyzed hydrolysis. (−)-Strychnine 41 was furnished after carbomethoxylation of 34c, that afforded the correspondent β-keto ester derivative mostly in the enol form, followed by tert-butyl and triazone removal. Selective reduction of vinylogous carbamate double bond provided a mixture of α-ester 38 and β-ester 39, that under basic conditions, efficiently converted to the desired β-ester 39. Finally, ester reduction with DIBALH led to Wieland-Gumlich aldehyde 40 that, upon treatment with malonic acid under Perkin condensation conditions, originated the desired (−)-strychnine 41.
In 2018, Wood and co-workers reported the total synthesis of (+)-hosieine A, an alkaloid containing the 2-azabicyclo[3.2.1]octane core, in just 7 steps with an overall yield of 16% (Scheme 7).15 The synthesis of (+)-hosieine A commences with N-alkylation of pyridinone 42 to provide (±)-43 by modification of Lee and Knochel's organozinc allylation reaction, nucleophilic alkynylation and sequential homologation, O-acylation and desilylation. The key step, a catalytic asymmetric Rautenstrauch reaction, was applied to (±)-43 and provided intermediate 45 with good enantiocontrol (90:
10 er). Sequential Michael-cyclization, reductive amination and lactamization delivered azabicyclo[3.2.1]octan-3-one core (+)-48 in moderate yield (42% from 45). Amide reduction with BH3/THF furnished (+)-hosieine A 49.
In 2010, Profeta and Andreotti3b employed cyclopentanone 50 for the synthesis of the 2-azabicyclo[3.2.1]octane system in a candidate molecule as TRUI (Scheme 8). The synthetic methodology involved the conversion of ketone 50 to 51 through Knoevenagel condensation. After a sequence of reactions involving cuprate 1,4-addition, Boc cleavage with TFA and basic treatment, a mixture of isomers 53 (anti/syn = 5/95) was obtained in 43% yield over three steps. Preparative HPLC separated both isomers which were subjected to amide and ester reduction and alcohol methylation (through amine protection/deprotection sequence), to give the desired cocaine analogue 3.
More recently, Wünsch and co-workers9b reported the synthesis of several 2-azabicyclo[3.2.1]octan-7-amines to study their KOR agonist activity. In this procedure, sulfonamide 55 afforded good yields of bicyclic compound 56 as a racemic mixture by intramolecular SN2 reaction upon deprotonation with NaH (Scheme 9). Then, tosylate 56 reacted with NaN3 to originate the corresponding azide, with unexpected retention of configuration, which after reduction yielded the primary amine 57. Alkylation of 57 afforded amines 58a and 58b. Tosyl removal and acylation provided the correspondent bicyclic compounds 59a and 59b.
The same group6 has also described the synthesis of 2-azabicyclo[3.2.1]octane core through Dieckmann cyclization of piperidine derivative 60 (Scheme 10). High temperatures were necessary to ensure that both ester substituents on 60 have an axial orientation and to prompt the inversion of configuration of trans-60. Compounds 61 were obtained in good yields, as a mixture of enantiomers (1S,5R) and (1R,5S) in a 3:
1 ratio. Deethoxycarbonylation using Krapcho conditions, followed by Boc removal with EtOH and H2O and subsequent acylation resulted in bicyclic amide 62. Compound 62 underwent reductive amination. NaBH(OAc)3 adds to the less hindered side of the iminium intermediate, resulting in 2-azabicyclo[3.2.1]octanes 4 and 63 with an endo-configuration.
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Scheme 10 Synthesis of 2-azabicyclo[3.2.1]octanes 4 and 63 by Dieckmann cyclization of a piperidine derivative. |
Dondas and co-workers synthesized bicyclic N-hydroxylamine 66a and amine 66b from compounds 64a and 64b, respectively (Scheme 11). Upon treatment with phenylselenyl bromide, aldoxime 64a was converted to bridged nitrone salt 65avia phenylselenyl induced cyclization, in a stereo- and regioselective manner. After reaction with NaBH4, compound 65a resulted in 2-azabicyclo[3.2.1]octane 66a in 69% yield. However, when the same conditions were applied to oxime 64b, only trace amounts of the desired product 66b were obtained. The authors attributed this lack of reaction to the steric inhibition of the gem-dimethyl group. The synthesis of azabicyclo[3.2.1]octane 69 was achieved in 34% yield, by using analogous conditions, starting from compound 67.9a
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Scheme 11 Synthesis of 2-azabicyclo[3.2.1]octanes 66a,b and 69via phenylselenyl induced cyclization. |
A unique way to access the azabicyclo[3.2.1]octane core was discovered by Namba and Tanino via construction of a N-acyl-N-tosylhydrazine 72 from an intramolecular palladium(II)-catalyzed cyclization reaction of 70 (Scheme 12). Treatment of 72 with trifluoracetic anhydride followed by epoxide formation provided access to 74. Then, samarium(II) iodide promoted the sequential N–N bond cleavage, epoxide ring opening/cyclization to furnish the azabicyclo[3.2.1]octane core.9d
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Scheme 12 Synthesis of azabicyclo[3.2.1]octane core taking profit of an intramolecular palladium(II)-catalyzed cyclization. |
In 2015, Hong and co-workers achieved the first asymmetric synthesis of (−)-hosieine A, an alkaloid containing the 2-azabicyclo[3.2.1]octane core (Scheme 13).3c The key transformation was the elegant nitroso-ene cyclization to form the 2-azabicyclo[3.2.1]octane core. The synthetic approach began with α-methyl aldehyde 76, that after several standard operations such as Horner–Wadsworth–Emmons olefination, 1,4-addition, and ring closing metathesis (RCM) provided hydroxamic acid 77. Hydroxamic acid oxidation delivered 78 that underwent retro-Diels–Alder to afford the unstable acylnitroso intermediate 79, that suffers intramolecular nitroso–ene cyclization. The major product 2-aza-bicyclo[3.2.1]octane 80, was obtained via 6-endo-type reaction, in 9:
1 ratio, and the minor 2-azabicyclo[3.3.0]octane 81, obtained via 5-endo-type. N-hydroxy acetylation and treatment with SmI2 resulted in the cleavage of N–O bond, followed by amide methylation to give compound 82. Bromohydrination, using an innovative methodology with NBS and phosphine, afforded the desired bicyclic ring 84, obtained in 84% combined yield (2
:
1) with a minor product 83. Radical debromination delivered compound 85. Hydroxyl activation and N-alkylation with 2-pyridone furnished 86. 1,6-Conjugate addition and subsequent protonation resulted in 87. Dehydrogenation with activated MnO2 and amide reduction in the presence of borane finally originated (−)-hosieine A 49.
In 2008, Gin and co-workers applied the Beckmann rearrangement towards the synthesis of chlorocyclopentane cores of the proposed original and revised structures of palau'amine 95a and 95b, respectively (Scheme 15).24 For that, ketone 97 and 103 were prepared in several steps from dihydroquinone 96. The corresponding oxime was formed, and thionyl-chloride mediated Beckmann rearrangement in a regioselective manner to 2-azabicyclo[3.2.1.]octan-3-one 98 (Scheme 15A), and 104, the last obtained after Boc protection (Scheme 15B). Regarding the proposed original structure of palau'amine (Scheme 15A), 98 suffers cyclopentene ozonolysis with subsequent reductive work up and diol acetylation to furnish 99. Lactam Boc protection gave 100. Lastly, acetal saponification, imide hydrolysis and subsequent acidic treatment resulted in lactone 102 in 96% yield, over the 2 steps. Compounds 101 and 102 represent the cyclopentane cores of the originally proposed structure of palau'amine, 95a. Concerning the revised chlorocyclopentane cores of palau'amine 95b (Scheme 15B), from compound 104 two synthetic routes emerge. Lemieux–Johnson oxidation of 104 and subjection to silica gel and Et3N provided di-aldehyde 105 with C12 epimerization. The bridged chlorocyclopentanes 105 and 100 are stereochemically distinct at C12 and C17. Cyclopentene ring of 104 also undergoes ozonolysis followed by reduction with NaBH4 and treatment with TsOH. This led to intramolecular alcoholysis of the imide and lactone formation. Hydroxy protection delivers 106 in 91% yield, over the 2 steps. Benzyl ether removal led to the formation of 107. Finally, lactone hydrolysis, methyl ester formation, and C12 oxidation/epimerization yielded aldehyde 108, that is the C12,C17 diastereomer of chlorocyclopentane 102 (Scheme 15A).
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Scheme 15 (A) Synthesis of chlorocyclopentane cores of the proposed original structure of palau'amine. (B) Synthesis of chlorocyclopentane cores of the revised structures of palau'amine. |
A way to access the bicyclic core from camphor is to initiate rearrangement with camphor hydrazone 109, as demonstrated by Tezuka and co-workers (Scheme 16). Treatment of 109 with m-chloroperbenzoic acid resulted in compounds 110 in high yield, as a 1:
1 mixture of endo (110a) and exo (110b) isomers. Upon reflux in ethanol in the presence of acid or base, lactam 112 was formed in 40% yield from 110a. This reaction proceeds via formation of the corresponding alcohol intermediate 111a (Scheme 16).16c The thermal decomposition reaction of α-azohydroperoxide 113 was also reported by the same group. When 113 was refluxed in benzene, a mixture of products were obtained, among them lactam 114 in 22% yield (Scheme 16B).16b
Entry | X | Y | Lactams yield | Ratio of lactams (2-aza![]() ![]() |
---|---|---|---|---|
Beckmann conditions (B) = hydroxylamine-O-sulfonic acid in acetic acid; Schmidt conditions (S) = sulfuric acid and sodium azide in chloroform. | ||||
1 | H | H | B = 37% | B = (90![]() ![]() |
S = 35% | S = (0![]() ![]() |
|||
2 | OMe | H | B = 27% | B = (100![]() ![]() |
S = 48% | S = (27![]() ![]() |
|||
3 | Cl | H | B = 49% | B = (100![]() ![]() |
S = 22% | S = (15![]() ![]() |
|||
4 | Br | H | B = 53% | B = (95![]() ![]() |
S = 34% | S = (19![]() ![]() |
|||
5 | OTs | H | B = 27% | B = (100![]() ![]() |
S = 52% | S = (65![]() ![]() |
|||
6 | H | COOMe | B = 29% | B = (100![]() ![]() |
S = 31% | S = (34![]() ![]() |
|||
7 | H | Cl | B = 23% | B = (100![]() ![]() |
S = 29% | S = (17![]() ![]() |
|||
8 | H | Br | B = 57% | B = (100![]() ![]() |
S = 41% | S = (0![]() ![]() |
|||
9 | H | OTs | B = 38% | B = (100![]() ![]() |
S = 40% | S = (64![]() ![]() |
|||
10 | H (exo-5-Br) | COOMe | B = 64% | B = (100![]() ![]() |
S = 52% | S = (48![]() ![]() |
In 2016, Aubé and co-workers18f implemented a new version of Schmidt reaction using triflic acid, in the presence of HFIP (Scheme 18). The reaction proceeds in two stages, first the ketone reacts with hydroxyalkyl azide and then is trapped intramolecularly by the hydroxyl to form the correspondent iminium ether. Finally, the iminium ether is hydrolyzed to deliver the amide. This new methodology was applied towards the synthesis of azabicyclo[3.2.1]octanes 116 and 117. While HFIP and the intramolecular hydroxyl group significantly improve the reaction yield, the poor selectivity in the C–C migration step continues to limit the applicability of the Schmidt rearrangement in the synthesis of azabicyclo[3.2.1]octanes as the resulting regioisomers are usually inseparable.
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Scheme 19 Proposed mechanistic pathway for the synthesis of N-tosyl-2-azabicyclo[3.2.1]octa-3,6-diene 123. |
Following the synthesis of 2-azabicyclo[3.2.1]octadiene 123 from norbornadiene 118, Young and co-workers17b obtained the desired 2-azabicyclo[3.2.1]octane 125 through a two-step sequence reduction, using LiAlH4 and hydrogenation. Direct hydrogenation of 2-azabicyclo[3.2.1]octadiene 126 with palladium catalyst results in 2-azabicyclo[3.2.1]octane 127 (Scheme 20).
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Scheme 20 Reduction of 2-azabicyclo[3.2.1]octadiene 123 and 126 to deliver 2-azabicyclo[3.2.1]octane 125 and 127, respectively. |
Another approach to prepare 2-azabicyclo[3.2.1]octane core from norbornadiene was reported by Bergmeier and co-workers.17d In this case, a dihydroxylation of the C6–C7 olefin of 128 was performed using either AD-mix α or β, achieving excellent yields in both cases. The resulting diol was protected to yield acetonide 129. This was followed by insertion of a hydroxyl group at C4, yielding 4-exo-hydroxy-6,7-exo-isopropylidenedioxy-N-tosyl-2-azabicyclo[3.2.1]octane 130a in 65% yield, together with the minor 4-endo isomer 130b (Scheme 21).
The same research group reported another example of the selective functionalization of the double bonds of compound 128.17e Selective reduction of the C6–C7 double bond of 128 resulted in bicyclic compound 131. 4-Arylated and alkenylated products 132 were obtained with good yields via Suzuki coupling. Finally, hydrogenation of the C3–C4 olefin afforded saturated azabicyclo 133 (Scheme 22).
2-Azabicyclo[3.2.1]octane can also be prepared taking profit of traditional Cope rearrangement, which allows an equilibrium between compounds 134 and 135, which are formed via epoxidation and rearrangement of norbornadiene. The mixture, when treated with excess methylamine, undergoes imine formation and 1,6-addition of methylamine, yielding 136 and 137 in equilibrium (Scheme 23). Only 137 reacts under hydrogenation conditions, resulting in 2-azabicyclo[3.2.1]octane 138 in 86% yield.18b
While some research groups have observed the formation of the 2-azabicyclo[3.2.1]octane system via rearrangement of oxaziridines of camphor27 and norcamphor,28 the low yields and poor selectivity have limited their applicability. Remarkably, Yamada and co-workers have tamed their reactivity through photochemical rearrangement of alkanenitronate anions like bicyclic nitro compounds 142a and 142b. After deprotonation and irradiation, isomerization of an oxaziridine intermediate gives access to the azabicyclo[3.2.1]octane hydroxamic acids 143a and 143b in good yields and selectivity. Then, reduction allowed the preparation of the corresponding azabicyclo[3.2.1]octane amides 144a and 144b (Scheme 25).18c,d
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Scheme 26 Synthesis of 2-azabicyclo[3.2.1]octane 147 through Mitsunobu reaction (A), and synthesis of derivatives (B). |
The correspondent rearranged products were obtained with inversion of configuration expected for SN2 aziridine ring-opening reaction. The minor endo-146 also undergoes the same aziridinium formation/regioselective ring opening isomer. The product derived from azide addition proved to be especially useful since after reduction to the amine 148, it provided the bicyclic core a synthetic handle to install further functionalities (Scheme 26B).
The same authors installed a 1,10-phenanthroline moiety via imine formation (149),30 and a proline via amide bond (150).29 These molecules were evaluated as catalysts for asymmetric aldol reactions, as the chiral and rigid core of the 2-azabicyclo[3.2.1]octane system could induce stereoselectivity. While a pioneer study in the utilization of the 2-azabicyclo[3.2.1]octane system in asymmetric organocatalysis, the des and ees obtained were not outstanding, and no other studies were performed in this topic. The free amine additionally proved useful for the synthesis of chiral thioureas (151)31 and sulfonamides (152), the latter displaying promising antiviral32 and antiproliferative activity,18g and also cytotoxicity to cancer cell lines.7
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