Memory of Chirality: Synthesis of enantiopure sultams derived from α-amino acids Cyclic sulfonamides (sultams), analogously to open chain sulfonamides, find important applications in human therapeutics. In particular, as a result of their biological activity and low toxicity, they have been recently employed in several fields of medicine, as drugs or as carriers of more complex molecules. Sultams, for example, are used in the design of potential thrombin inhibitors (1) or novel antiarthritic agents (2), showing a potent inhibitory effects on both cyclooxygenase (COX)-2 and 5-lipoxygenase (5-LO), proving to be effective in several animal arthritic models, without any ulcerogenic activities; β-lactam antibiotics, such as (3) that is an anti-MRSA (Methicillin-resistant Staphylococcus aureus) from a series of 1-β-methyl-2-(naphthosultamyl)methyl cationic carbapenems while 8-hydroxy-[1,6]naphthyridines (4) is an HIV-1 integrase inhibitors. Scheme 1 Moreover, since the introduction of Oppolzer’s sultam, camphorsultam and saccharin derived 3-alkyl benzosultams are relevant in asymmetric synthesis in many stereoselective transformations and have been wide-spreading used as chiral auxiliaries. Indeed, due to their importance in asymmetric synthesis and medicinal chemistry, many methodologies have been developed for the synthesis of sultams: intramolecular Diels-Alder reactions, sulphonamide dianion alkylations, radical cyclizations, ring closing metathesis, intramolecular Heck cyclizations, etc. Recently, our research group has reported a straightforward protocol for the preparation of racemic 3-aryl polyfluorobenzosultams, bearing a carboxylic function in the C-3 position. These compounds are obtained via an intramolecular nucleophilic substitution of a fluorine atom as leaving group . Scheme 2 Our know-how in the application of the concept of “non-racemic enolates” to the synthesis of non-natural quaternary α-amino acids made us focus our attentions on improving a stereoselective synthesis of benzosultams via chiral enolates. This reaction showed a significant bias toward the enantioselective non-catalized intramolecular cyclization. Given the results obtained in the application of the “Memory of chirality” (MOC) concept in the asymmetric transposition of 4-nitrobenzene sulfonamides, we turned our attention to the cyclization of (pentafluorobenzene)sulfonamido enolates, since these two reactions present a transition state/intermediate strictly related (Scheme 3). Scheme 3 Memory of chirality is an emerging strategy for enantioselective synthesis. In general, MOC methods involve destruction of the sole original stereogenic center of a starting material, enantioselective generation of conformationally chiral intermediate, and subsequent enantioselective transformation into a centrally chiral product. Successful MOC reactions must fulfill three conditions: • the enantiopure centrally chiral starting materials must be enantioselectively transformed into a conformationally chiral intermediate; • this chiral intermediate must not racemize during the timescale of the reaction.; • transformation of the conformationally chiral intermediate back to a centrally chiral product must occur with excellent enantioselectivity (Scheme 4). Scheme 4 The crucial point of our protocol was the stereoselective cyclization of sulfonamides to enantiopure benzosultams. Preliminary experiments performed on non-racemic L-phenylglycine derivatives showed that the cyclization with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) give the corresponding sultam in good yieds, but with lower ee. (Scheme 2). Therefore, we decided to evaluate the use of an additive in the system sulfonamide-DBU, looking for possible interactions additive-base-substrate capable to induce the formation of a chiral adduct, which can evolve enantioselectively toward the desired benzosultam. In particular good results were obtain by using a basic system 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG) and DBU (Scheme 5). Scheme 5 Very interesting results were also obtained by using BTMG as sole base: the target sultam was isolated in very high yields and ee and, as the most surprising and interesting feature, in the opposite configuration to that obtained with the other bases. With this strategy the absolute configuration of the final product can be modulated by simply changing the achiral base, thus influencing the different conformer equilibrium and, eventually, choosing the final absolute configuration starting from a unique sulphonamide enantiomer (Scheme 6). Scheme 6 Both the enantiomers have been prepared from a unique isomer of the starting sulfonamide. These compounds have been N-functionalized by alkylation under SL-PTC conditions giving the N-alkyl benzo[d]sultams in high yields. All these heterocycles gave, after one or more crystallization, the pure enantiomer allowing us to assign the configuration to the cyclization products by mean of single crystal X-ray analysis. The pure enantiomers of the non-N-alkylated sultams were obtained by deprotection of the recrystallized N-allyl derivative because they did not give preferentiale crystallization (Scheme 7). Scheme 7 In the way of improving the enantiodivergent course of this process, we applied the best reaction conditions previsioly found to a series of substituted N-(pentafluorobenzene)sulfonyl arylglycine esters. Results indicate that a substituent in the para- or ortho-position on the amino acid aromatic ring modulates the sulphonamide reactivity, depending on the type of the functional group used. In particular, the presence on the aromatic ring of a –M substituent was detrimental to the overall process, decreasing the reaction enantioselectivity: the para-nitro phenylglycine methyl ester, reacted rapidly, but gave the racemic sultam; the ortho-chlorine phenylglycine methyl ester, increasing the steric hindrance near the reactive centre, dramatically reduces the reaction rate. On the other hand, the presence of an EDG on the amino acid aromatic ring, such as methoxy, benzyloxy or phenyl, resulted in a quasi-complete enantioselectivity (Scheme 8). Even in this case, we obtained the corresponding benzosultams with retention of configuration by using the basic system (A=BTMG/DBU), and with inversion of configuration when we use the B=TBMG alone. Scheme 8 The behavior of NH sulfonamides shown in the presence of hindered organic bases, open the possibility to study the synthesis under MOC conditions of several amino acid derivatives, without the need of introducing two different N-activating groups, thus avoiding the cleavage step of one of them. We have also reported the synthesis of novel enantiopure chiral benzo[d]sultams bearing in the Cα position an alkyl chain, thus having a less acidic Hα than that of phenylglycine. N-Unsubstituted (polifluoro) benzenesulfonamides derived from these amino acids, differently from phenylglycine derivatives, did not react under the action of any base, but good results were obtained by using the corresponding N-alkyl sulfonamides and DBU as a base at low temperatures. Initially we investigate the synthesis of benzosultams derive from N-(pentafluorobenzene)sulfonyl phenylalanine. The cyclization reaction by using DBU gave, together with the desired sultam, relevant amounts of by-products derivated from nucleophilic attack of DBU on the fluorinated aromatic ring. To eliminate in the cyclization process any interference from the SNAr, which reduces the amount of the target sultam, we decided to synthesize new and more versatile sulfonamides bearing in the 4’ position a bromine or a hydrogen atom instead of the fluorine atom. The cyclization of this differently substituted sulfonamides, gave good yields and ee’s of the resulting benzosultams. In these cases the retention R sultam was the major enantiomer isolated (Scheme 9). Scheme 9 This strategy has been successfully applied to different optically pure α-amino acid derivatives (alanine, leucine, methionine, and tyrosine), thus performing the synthesis of enantioenriched polyfluorobenzo[d]sultams in few steps (Table 1). Table 1 R1 X t (h) (%) ee (%) a ArO-Phe Tyr Br 7 87 99 b ArO-Phe Tyr H 28 75 99 c Me Ala Br 24 83 35 d Me Ala H 5 day 75 27 e iPr Leu Br 5 day 42 95 f iPr Leu H 1 week 30 69 g MeS(CH2)2 Met Br 18 70 57 h MeS(CH2)2 Met H 24 52 37 In conclusion, in this thesis I have described the MOC stereodivergent synthesis of a series of enantiomerically enriched polyfluorobenzo[d]sultams, which were obtained in good to excellent yields, using very mild reaction conditions. The interest of this protocol resides in the possibility of making use of the chirality of a starting sulfonamide single enantiomer to synthesize the target sultams in both absolute configurations. The choice of the organic base system is the determining factor to direct the cyclization toward either enantiomer. In fact, the steric hindrance of the base regulates its access to the α-hydrogen, that can be approached alternatively through an inter- or an intramolecular attack. A further peculiarity of this protocol is the use, as starting compounds, of a α-amino acid derivatives bearing a mono-substituted sulfonamide NH function, in the case of phenylglycine derivatives, or N-alkylsulfonamides when the starting compound is an aliphatic derived α-amino acid.

MEMORY OF CHIRALITY: SYNTHESIS OF ENANTIOPURE SULTAMS DERIVED FROM ALFA-AMINO ACIDS / V. Mihali ; tutor: D. Albanese; co-tutor: M. Penso; coordinatore: D. Roberto. - : . UNIVERSITA' DEGLI STUDI DI MILANO, 2013 Jan 11. ((25. ciclo, Anno Accademico 2012. [10.13130/mihali-voichita_phd2013-01-11].

MEMORY OF CHIRALITY: SYNTHESIS OF ENANTIOPURE SULTAMS DERIVED FROM ALFA-AMINO ACIDS

V. Mihali
2013-01-11

Abstract

Memory of Chirality: Synthesis of enantiopure sultams derived from α-amino acids Cyclic sulfonamides (sultams), analogously to open chain sulfonamides, find important applications in human therapeutics. In particular, as a result of their biological activity and low toxicity, they have been recently employed in several fields of medicine, as drugs or as carriers of more complex molecules. Sultams, for example, are used in the design of potential thrombin inhibitors (1) or novel antiarthritic agents (2), showing a potent inhibitory effects on both cyclooxygenase (COX)-2 and 5-lipoxygenase (5-LO), proving to be effective in several animal arthritic models, without any ulcerogenic activities; β-lactam antibiotics, such as (3) that is an anti-MRSA (Methicillin-resistant Staphylococcus aureus) from a series of 1-β-methyl-2-(naphthosultamyl)methyl cationic carbapenems while 8-hydroxy-[1,6]naphthyridines (4) is an HIV-1 integrase inhibitors. Scheme 1 Moreover, since the introduction of Oppolzer’s sultam, camphorsultam and saccharin derived 3-alkyl benzosultams are relevant in asymmetric synthesis in many stereoselective transformations and have been wide-spreading used as chiral auxiliaries. Indeed, due to their importance in asymmetric synthesis and medicinal chemistry, many methodologies have been developed for the synthesis of sultams: intramolecular Diels-Alder reactions, sulphonamide dianion alkylations, radical cyclizations, ring closing metathesis, intramolecular Heck cyclizations, etc. Recently, our research group has reported a straightforward protocol for the preparation of racemic 3-aryl polyfluorobenzosultams, bearing a carboxylic function in the C-3 position. These compounds are obtained via an intramolecular nucleophilic substitution of a fluorine atom as leaving group . Scheme 2 Our know-how in the application of the concept of “non-racemic enolates” to the synthesis of non-natural quaternary α-amino acids made us focus our attentions on improving a stereoselective synthesis of benzosultams via chiral enolates. This reaction showed a significant bias toward the enantioselective non-catalized intramolecular cyclization. Given the results obtained in the application of the “Memory of chirality” (MOC) concept in the asymmetric transposition of 4-nitrobenzene sulfonamides, we turned our attention to the cyclization of (pentafluorobenzene)sulfonamido enolates, since these two reactions present a transition state/intermediate strictly related (Scheme 3). Scheme 3 Memory of chirality is an emerging strategy for enantioselective synthesis. In general, MOC methods involve destruction of the sole original stereogenic center of a starting material, enantioselective generation of conformationally chiral intermediate, and subsequent enantioselective transformation into a centrally chiral product. Successful MOC reactions must fulfill three conditions: • the enantiopure centrally chiral starting materials must be enantioselectively transformed into a conformationally chiral intermediate; • this chiral intermediate must not racemize during the timescale of the reaction.; • transformation of the conformationally chiral intermediate back to a centrally chiral product must occur with excellent enantioselectivity (Scheme 4). Scheme 4 The crucial point of our protocol was the stereoselective cyclization of sulfonamides to enantiopure benzosultams. Preliminary experiments performed on non-racemic L-phenylglycine derivatives showed that the cyclization with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) give the corresponding sultam in good yieds, but with lower ee. (Scheme 2). Therefore, we decided to evaluate the use of an additive in the system sulfonamide-DBU, looking for possible interactions additive-base-substrate capable to induce the formation of a chiral adduct, which can evolve enantioselectively toward the desired benzosultam. In particular good results were obtain by using a basic system 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG) and DBU (Scheme 5). Scheme 5 Very interesting results were also obtained by using BTMG as sole base: the target sultam was isolated in very high yields and ee and, as the most surprising and interesting feature, in the opposite configuration to that obtained with the other bases. With this strategy the absolute configuration of the final product can be modulated by simply changing the achiral base, thus influencing the different conformer equilibrium and, eventually, choosing the final absolute configuration starting from a unique sulphonamide enantiomer (Scheme 6). Scheme 6 Both the enantiomers have been prepared from a unique isomer of the starting sulfonamide. These compounds have been N-functionalized by alkylation under SL-PTC conditions giving the N-alkyl benzo[d]sultams in high yields. All these heterocycles gave, after one or more crystallization, the pure enantiomer allowing us to assign the configuration to the cyclization products by mean of single crystal X-ray analysis. The pure enantiomers of the non-N-alkylated sultams were obtained by deprotection of the recrystallized N-allyl derivative because they did not give preferentiale crystallization (Scheme 7). Scheme 7 In the way of improving the enantiodivergent course of this process, we applied the best reaction conditions previsioly found to a series of substituted N-(pentafluorobenzene)sulfonyl arylglycine esters. Results indicate that a substituent in the para- or ortho-position on the amino acid aromatic ring modulates the sulphonamide reactivity, depending on the type of the functional group used. In particular, the presence on the aromatic ring of a –M substituent was detrimental to the overall process, decreasing the reaction enantioselectivity: the para-nitro phenylglycine methyl ester, reacted rapidly, but gave the racemic sultam; the ortho-chlorine phenylglycine methyl ester, increasing the steric hindrance near the reactive centre, dramatically reduces the reaction rate. On the other hand, the presence of an EDG on the amino acid aromatic ring, such as methoxy, benzyloxy or phenyl, resulted in a quasi-complete enantioselectivity (Scheme 8). Even in this case, we obtained the corresponding benzosultams with retention of configuration by using the basic system (A=BTMG/DBU), and with inversion of configuration when we use the B=TBMG alone. Scheme 8 The behavior of NH sulfonamides shown in the presence of hindered organic bases, open the possibility to study the synthesis under MOC conditions of several amino acid derivatives, without the need of introducing two different N-activating groups, thus avoiding the cleavage step of one of them. We have also reported the synthesis of novel enantiopure chiral benzo[d]sultams bearing in the Cα position an alkyl chain, thus having a less acidic Hα than that of phenylglycine. N-Unsubstituted (polifluoro) benzenesulfonamides derived from these amino acids, differently from phenylglycine derivatives, did not react under the action of any base, but good results were obtained by using the corresponding N-alkyl sulfonamides and DBU as a base at low temperatures. Initially we investigate the synthesis of benzosultams derive from N-(pentafluorobenzene)sulfonyl phenylalanine. The cyclization reaction by using DBU gave, together with the desired sultam, relevant amounts of by-products derivated from nucleophilic attack of DBU on the fluorinated aromatic ring. To eliminate in the cyclization process any interference from the SNAr, which reduces the amount of the target sultam, we decided to synthesize new and more versatile sulfonamides bearing in the 4’ position a bromine or a hydrogen atom instead of the fluorine atom. The cyclization of this differently substituted sulfonamides, gave good yields and ee’s of the resulting benzosultams. In these cases the retention R sultam was the major enantiomer isolated (Scheme 9). Scheme 9 This strategy has been successfully applied to different optically pure α-amino acid derivatives (alanine, leucine, methionine, and tyrosine), thus performing the synthesis of enantioenriched polyfluorobenzo[d]sultams in few steps (Table 1). Table 1 R1 X t (h) (%) ee (%) a ArO-Phe Tyr Br 7 87 99 b ArO-Phe Tyr H 28 75 99 c Me Ala Br 24 83 35 d Me Ala H 5 day 75 27 e iPr Leu Br 5 day 42 95 f iPr Leu H 1 week 30 69 g MeS(CH2)2 Met Br 18 70 57 h MeS(CH2)2 Met H 24 52 37 In conclusion, in this thesis I have described the MOC stereodivergent synthesis of a series of enantiomerically enriched polyfluorobenzo[d]sultams, which were obtained in good to excellent yields, using very mild reaction conditions. The interest of this protocol resides in the possibility of making use of the chirality of a starting sulfonamide single enantiomer to synthesize the target sultams in both absolute configurations. The choice of the organic base system is the determining factor to direct the cyclization toward either enantiomer. In fact, the steric hindrance of the base regulates its access to the α-hydrogen, that can be approached alternatively through an inter- or an intramolecular attack. A further peculiarity of this protocol is the use, as starting compounds, of a α-amino acid derivatives bearing a mono-substituted sulfonamide NH function, in the case of phenylglycine derivatives, or N-alkylsulfonamides when the starting compound is an aliphatic derived α-amino acid.
ALBANESE, DOMENICO
ROBERTO, DOMINIQUE MARIE
benzosultams ; memory of chirality ; asymmetric synthesis ; polyfluorinated compounds ; α-amino acids
Settore CHIM/06 - Chimica Organica
MEMORY OF CHIRALITY: SYNTHESIS OF ENANTIOPURE SULTAMS DERIVED FROM ALFA-AMINO ACIDS / V. Mihali ; tutor: D. Albanese; co-tutor: M. Penso; coordinatore: D. Roberto. - : . UNIVERSITA' DEGLI STUDI DI MILANO, 2013 Jan 11. ((25. ciclo, Anno Accademico 2012. [10.13130/mihali-voichita_phd2013-01-11].
Doctoral Thesis
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