Letter pubs.acs.org/acscatalysis
Design and Enantioselective Synthesis of β‑Vinyl Tryptamine Building Blocks for Construction of Privileged Chiral Indole Scaffolds Tao-Yan Lin, Hai-Hong Wu, Jian-Jun Feng,* and Junliang Zhang* Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Chemistry and Molecular Engineering, East China Normal University, 3663 N. Zhongshan Road, Shanghai 200062, People’s Republic of China S Supporting Information *
ABSTRACT: The highly efficient and stereo-specific synthesis of the enantioenriched versatile building blocksnamely, β-vinyltryptaminesby rhodium-catalyzed allylic substitutions of vinylaziridines and indoles is presented. Besides indoles, pyrroles can also serve as competent carbon nucleophiles in the current reaction, which is different from the previous works. To demonstrate the synthetic utility of our method, up to 11 natural product and pharmaceutically relevant chiral indole scaffolds were synthesized in highly efficient reaction sequences. Notably, asymmetric formal synthesis of a potent constrained analogue of MS-245 and a nNOS and 5-HT1B/1D receptor inhibitor are also reported. KEYWORDS: rhodium, vinylaziridines, tryptamines, chirality transfer, diversity-oriented synthesis, allylic substitution reaction
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INTRODUCTION Methodologies that provide stereo-defined “privileged scaffolds” in natural products and drugs will underpin future advances in library design and drug discovery.1 In this context, the design and synthesis of new versatile building blocks from simple starting materials in minimum steps to prepare the “privileged scaffolds” have gained growing interest among the synthetic community. Among the “privileged scaffolds” in a great many natural bioactive products and pharmaceuticals, the indole scaffolds2a (such as substituted tryptamine skeletons,2b pyrroloindolines,2c carbazoles,2d tetrahydrocarbolines,2e and azepinoindoles2f) represent highly important structural subunits for the discovery of new drug candidates (see Figure 1). Therefore, considerable effort has been devoted to the development of efficient methods for the synthesis of these privileged indole scaffolds.3 Nonetheless, the widely applied approaches for the construction of the indole backbones involve preparing the corresponding key building blocks one by one. An ideal way to build the privileged indole scaffolds would be to construct entire classes of indole skeletons from one versatile building block.3f,i A careful inspection of an array of indole-containing drugs reveals the tryptamine moiety as a common recognizable motif. In addition, tryptamine is a direct precursor to many alkaloid natural products, including ∼3000 monoterpene indole alkaloids.4 Thus, exploration of chiral tryptamine building blocks may have more opportunity to access to chiral privileged indole scaffolds. Consistent with our interest in developing asymmetric syntheses of polycyclic indole subunits5a−c and stereo-specific ring-opening of vinylaziridines,5d−f herein, we envisaged that a facile access to enantioenriched β-vinyltryptamines might be realized by rhodium-catalyzed intermolecular © XXXX American Chemical Society
Figure 1. Biologically active privileged indole scaffolds.
stereo-specific allylic substitution reaction of vinylaziridine and indole through chirality transfer strategy via the enyl (σ+π) rhodium intermediate.6,7 The additional olefin moiety installed to the tryptamine skeleton would increase the structural flexibility in view of a tremendous number of reactions associated with olefins. Of note, You and co-workers have developed an elegant iridium-catalyzed intramolecular dearomatization/retro-Mannich/hydrolysis cascade reaction of an indole derivative, providing efficient access to chiral βReceived: March 18, 2017 Revised: May 8, 2017
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DOI: 10.1021/acscatal.7b00870 ACS Catal. 2017, 7, 4047−4052
Letter
ACS Catalysis
used Lewis acid, including Mg(OTf)2, Cu(OTf)2, Cu(CH3CN)4BF4, Yb(OTf)3, and Eu(OTf)3 were also tested, but leading to low conversions and ee values (see entries 5−10 in Table 1). Of note, treatment of rac-1a and 2a with 10 mol % Cu(CH3CN)4BF4/12 mol % (R)-Segphos in toluene for 18 h at 25 °C gave (S)-3aa in 57% NMR yield and 21% ee (entry 8 in Table 1). Catalysts such as Mn(OTf)2, Sm(OTf)3, and Pd(PhCN)2Cl29c showed almost no catalytic activity (see entries 11−13 in Table 1). Gratifyingly, we found that [Rh(NBD)2]BF4 affords the desired β-vinyltryptamine 3aa in >99% NMR yield and 98% ee within 15 min, with a net inversion of absolute configuration (see entry 16 in Table 1). By contrast, the use of [Rh(CO)2Cl]2 and [Rh(COD)2]BF4 was inferior for this reaction (see entries 14 and 15 in Table 1). Different silver salts were also investigated. Similar results were obtained with [Rh(NBD)Cl] 2 /AgOTf, [Rh(NBD)Cl] 2 / AgSbF6, and [Rh(NBD)Cl]2/AgClO4 catalysts (entries 17−19 in Table 1). By contrast, use silver catalysts alone gave the desired product in lower conversions and ee values (see entries 20 and 21 in Table 1). Given that the catalyst [Rh(NBD)2]BF4 is commercially available, the final reaction conditions are described as follows: 1 (1.0 equiv), 2 (1.5 equiv), 5 mol % [Rh(NBD)2]BF4, 1,2-dichloroethane (DCE), RT, and 15 min. Having the optimal reaction conditions in hand, we first investigated the generality of the vinylaziridines 1. As depicted in Table 2, the substituents on nitrogen of the aziridines can be the tosyl, nosyl, and mesyl groups. When the mesyl-protected vinylaziridine (R)-1d was used instead of tosylated (R)-1b or nosylated (R)-1c, the reaction could proceed smoothly but gave the corresponding product with lower ee values. The substituents on olefin moiety of vinylaziridine can be either H (1b), isopropyl (1e) n-butyl (1f) or phenyl (1g) groups, without a notable negative effect on the reactions. Moreover, the vinylaziridine (S)-1h could also successfully deliver the βvinyltryptamine product (S)-3ha bearing a chiral quaternary allcarbon stereocenter. Notably, vinylaziridine (R)-1i and (R)-1j were compatible to afford the corresponding products (R)-3ia and (R)-3jb, respectively, in good yield and with highly efficient chirality transfer, which is complementary to Jia’s method (Scheme 1d).11a Next, the reactions of various substituted indoles or pyrroles with vinyl aziridines (R)-1a (98% ee) or (R)-1c (93% ee) were examined (Table 3). Generally, the chirality of the (R)-1 can be completely transferred to the chiral β-vinyltryptamines (3). The substituents on nitrogen of indoles could be a H, allyl, Boc, and methyl group (3aa−3ad). Alkyl, H, vinyl, allyl, conjugated enones, hydroxyl and ester group at the C2 position of indoles were also compatible and the corresponding products were isolated in good yield, with 90%−98% ee (3ae−3al, 3cl). A variety of functional groupsespecially the hydroxyl group at the C4 position of indoleswere also tolerant under the current reaction conditions (3am−3ao, 3ct). Besides these, indoles-bearing substituents at the C5, C6, or C7 position yielded the corresponding β-vinyltryptamines successfully (3ap−3as). Notably, the reaction remained efficient when the nucleophiles were changed from indoles to pyrroles (3au− 3aw). Reactions that result in the generation of functional and structural diversity are highly attractive for the synthesis of entire classes of privileged scaffolds.13 As depicted in Tables 2 and 3, the current allylic substitution reaction delivered a class of chiral functionalized tryptamine building blocks. To showcase the synthetic applications, the diversity-oriented
vinyltryptamine. However, the reaction was limited to 2arylindole substrates (Scheme 1a).4b Thus, the development of the current allylic substitution reaction of vinylaziridine with general indole is highly desirable.8 Scheme 1. Reactions of Vinylaziridines with Indoles
However, this hypothesis may face considerable challenges, such as the following: (1) Reactions of vinyl aziridines with indoles usually result in [3 + 2] cycloadducts (Scheme 1b).9 (2) In Trost’s pioneering work, indole was utilized as hard Nnucleophile, rather than C-nucleophile, to afford the chiral 1,2-diamine product (Scheme 1c).10 (3) Although Friedel−Crafts alkylation of indole with alkylor aryl-aziridine is well documented,11,12 the stereospecific allylic substitution reaction of vinylaziridine and indole has not been well explored. For example, Jia’s recent elegant work on Cu(I)-catalyzed enantioselective Friedel−Crafts alkylation of indole with arylaziridine could not be extended to vinylaziridine (Scheme 1d)11a). (4) Complete chirality transfer is difficult in the ring-opening reaction of chiral monosubstituted aziridine with nucleophile.11c Herein, we report our efforts to address these issues and realize the diversity-oriented synthesis of diverse indole scaffolds starting from β-vinyltryptamine building block.13
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RESULTS AND DISCUSSION We initiated our investigation with the optimization of the reaction of vinylaziridine (R)-1a (98% ee, where ee denotes enantiometric excess) and 1H-indole 2a. As shown in Table 1, (R)-1a decomposed quickly when Sc(OTf)3, Ga(OTf)2, FeCl3, or In(OTf)3 was used as the catalyst, even though these are commonly used in Friedel−Crafts alkylation of indole with alkyl- or aryl-aziridine (entries 1−4).11,12 Notably, these reactions gave exclusively the β-vinyltryptamine product, rather than the branched N-alkylated product.10 Other commonly 4048
DOI: 10.1021/acscatal.7b00870 ACS Catal. 2017, 7, 4047−4052
Letter
ACS Catalysis Table 1. Optimization of Reaction Conditionsa
entry
catalyst
time (h)
conversionb (%)
yieldb (ee)c (%)
1 2 3 4 5 6 7 8d 9 10 11 12 13f 14 15 16 17g 18g 19g 20h 21h
Sc(OTf)3 Ga(OTf)2 FeCl3 In(OTf)3 Mg(OTf)2 Cu(OTf)2 Cu(CH3CN)4BF4 Cu(CH3CN)4BF4/(R)-Segphos Yb(OTf)3 Eu(OTf)3 Mn(OTf)2 Sm(OTf)3 Pd(PhCN)2Cl2 [Rh(CO)2Cl]2 [Rh(COD)2]BF4 [Rh(NBD)2]BF4 [Rh(NBD)Cl]2/AgOTf [Rh(NBD)Cl]2/AgSbF6 [Rh(NBD)Cl]2/AgClO4 AgSbF6 AgClO4
1 1 1 14 14 14 14 18 14 14 14 14 14 14 3.5 0.25 0.25 0.25 0.25 1.5 1.5
100 100 100 100 52 70 70 100 39 60 20 15 10 72 100 100 100 100 100 100 100
20 (83) 25 (79) 21 (87) 26 (81) 18 (86) 29 (68) 40 (88) 57 (−21) 16 (91) 23 (93)
