Communication pubs.acs.org/JACS
Facile Net Cycloaddition Approach to Optically Active 1,5‑Benzothiazepines Yukihiro Fukata, Keisuke Asano,* and Seijiro Matsubara* Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyotodaigaku-Katsura, Nishikyo, Kyoto 615-8510, Japan S Supporting Information *
evaluation. To date, a few asymmetric syntheses have been reported through a multistep construction of the ring structure.2 In this context, an asymmetric cycloaddition approach is proposed for the diversity-oriented synthesis of 1,5-benzothiazepines. Recently, the use of α,β-unsaturated acylammonium species in organocatalyzed transformations was reported, where they were employed as components bearing two electrophilic sites to allow annulations through sequential nucleophilic attacks by carbon and heteroatom, or two carbon nucleophiles, to take place.3 The α,β-unsaturated acylammonium species can therefore be considered a promising candidate as the intermediate of a reaction with a molecule bearing two nucleophilic heteroatoms. However, despite the clear advantages in this type of transformation, a number of alternative pathways are possible when these reactants are employed. As shown in Scheme 1, besides the
ABSTRACT: The 1,5-benzothiazepine moiety is wellknown as a versatile pharmacophore, and its derivatives are expected to have antagonism against numerous diseases. Thus, it is desirable to develop a synthetic route that enables facile enantioselective preparation of a wide range of such derivatives. Although the cycloaddition approach could be considered a possible route to these compounds, to date, there has been no precedent of such a protocol. We therefore present the first example of a highly enantioselective net [4 + 3] cycloaddition to afford 1,5benzothiazepines by utilizing α,β-unsaturated acylammonium intermediates generated by chiral isothiourea catalysts, which undergo two sequential chemoselective nucleophilic attacks by 2-aminothiophenols. This protocol provided cycloadducts in extremely high regioselectivity, with a good-to-excellent stereoselectivity being achieved regardless of the steric and electronic properties of the substrates. This method therefore offers promising synthetic routes for the construction of a library of optically active 1,5-benzothiazepines for assay evaluation.
1
Scheme 1. Net Cycloaddition between α,β-Unsaturated Acylammonium Ion and Nucleophilic Counterpart Bearing Two Heteroatoms
,5-Benzothiazepines are well-known as representative molecules in the field of pharmaceutical science (Figure 1)
desired pathway via intermediate A, alternative pathways through undesired intermediates B−D could also take place to lower the enantioselectivity or generate the undesired regioisomer. Therefore, to achieve a highly enantio- and regioselective net cycloaddition, pathways B−D must be suppressed. In our previous study, we reported an organocascade reaction via two nucleophilic attacks by different heteroatoms to α,βunsaturated acylammonium species.4 In the course of this study, we noted the high chemoselectivity of the described intermediates, which exclusively captures a sulfur-centered nucleophile at the β-position via a sulfa-Michael addition. Thus, we proposed a net cycloaddition reaction of an α,βunsaturated acylammonium salt, with a reagent containing both
Figure 1. Representative pharmaceutical compounds containing the 1,5-benzothiazepine moiety.
and are expected to exhibit antagonism against various diseases.1 Indeed, 1,5-benzothiazepins, such as thiazesim, originally attracted a great amount of attention as antidepressant agents. Later, thanks to a random screening program in a Japanese pharmaceutical company, calcium antagonism was unexpectedly observed, and diltiazem (Herbesser) was developed as an effective medication for the treatment of hypertension and angina and is currently used in more than 100 countries. These successful examples of the use of 1,5-benzothiazepines stress their great potential for application as pharmaceutical products. Thus, there exists a high demand for methods that allow rapid and divergent syntheses of such derivatives to support assay © XXXX American Chemical Society
Received: March 10, 2015
A
DOI: 10.1021/jacs.5b02537 J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Communication
Journal of the American Chemical Society Table 1. Optimization of Conditionsa
entry
catalyst (mol %)
R1, R2
solvent
yield of 3 (%)b
yield of 4 (%)b
ee of 3a (%)
1 2 3 4 5 6 7 8 9 10 11c 12c 13c 14c,d
6a (10) 6b (10) 6c (10) 6a (10) 6a (10) 6a (10) 6a (10) 6a (10) 6a (10) 6a (10) 6a (10) 6a (10) 6a (5) 6a (0.5)
i-Pr (1a), Ts (2a) i-Pr (1a), Ts (2a) i-Pr (1a), Ts (2a) i-Pr (1a), Ts (2a) i-Pr (1a), Ts (2a) i-Pr (1a), Ts (2a) i-Pr (1a), Ts (2a) i-Pr (1a), Ts (2a) Et (1b), Ts (2a) Bn (1c), Ts (2a) i-Pr (1a), Ts (2a) i-Pr (1a), Boc (2b) i-Pr (1a), Ts (2a) i-Pr (1a), Ts (2a)
toluene toluene toluene benzene EtOAc THF CH2Cl2 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 CHCl3 toluene
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