Letter pubs.acs.org/OrgLett
Regio- and Stereospecific Construction of 3a-(1H‑Indol-3yl)pyrrolidinoindolines and Application to the Formal Syntheses of Gliocladins B and C Honghui Lei,# Lushun Wang,# Zhengshuang Xu,* and Tao Ye* Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Xili, Nanshan District, Shenzhen 518055, China S Supporting Information *
ABSTRACT: A one-pot regio- and stereospecific strategy for the construction of 3a(3-indolyl)-hexahydropyrrolo[2,3-b]indoles based on the condensation of an indole and an in situ generated cyclopropylazetoindoline has been developed. This unified strategy works with a variety of substituted indoles to produce 3a-(3-indolyl)hexahydropyrrolo[2,3-b]indole products in high yields. The utility of this transformation was highlighted in the formal total syntheses of gliocladins B and C.
T
improvement. In order to maximize convergency in the access to an entire class of nondimeric C3−C3′ bisindole alkaloids, we set out to develop a one-pot process that would rely upon the direct condensation of unprotected indoles with bromopyrroloindolines to establish the C3−C3′ bisindole core. In 2008, Rainier reported that the anionic condensation of a 3-bromocyclotryptophan derivative with indoles, under basic conditions, led to N-alkylation products.19 As shown in Scheme 1, the base admirably served its dual purpose in this process,
he 3a-(3-indolyl)hexahydropyrrolo[2,3-b]indole ring system is a common structural motif found in several nondimeric C3−C3′ bisindole alkaloids. The core skeleton is present in gliocladins A−C,1 bionectins A−C,2 T988 A−C,3 gliocladines C−E,4 leptosins D−F,5 glioclatine,6 and luteoalbusins A and B7 (Figure 1), which exhibit a broad range of potent
Scheme 1. Strategy for the Synthesis of Pyrrolidinoindoline
Figure 1. Nondimeric C3−C3′ bisindole alkaloids.
biological activities.1−7 Not surprisingly, considerable effort has been devoted to the development of novel strategies for the construction of the nondimeric C3−C3′ bisindole core skeleton bearing a C3 all-carbon quaternary center. These included indirect methods to make accessible nondimeric C3− C3′ bisindoles from 3-(3′-indolyl)oxindoles8−16 and the direct condensation of orthogonally protected indole derivatives.17,18 Although the aforementioned approaches to prepare nondimeric C3−C3′ bisindoles had been reported, these strategies were either lengthy or less selective. Consequently, the overall efficiency of these processes left considerable room for © 2017 American Chemical Society
including the deprotonation of indole and promoting the formation of a transient cyclopropane intermediate from a 3bromocyclotryptophan derivative. These results suggested that alkylation at the indole nitrogen is usually predominant when ionic bases and strongly ionizing solvents were employed;20 however, more covalently coordinated metals promoted Calkylation.21−25For example, N-indolyltriethylborate was found Received: August 6, 2017 Published: September 18, 2017 5134
DOI: 10.1021/acs.orglett.7b02425 Org. Lett. 2017, 19, 5134−5137
Letter
Organic Letters
improved the yield of 7a up to 95% (entry 5). The improved yield is likely a result of the lower degree of dissociation of the nitrogen−zinc bond in a nonpolar medium, and TMEDA could alter its attendant nucleophilicity. The formation of a sterically demanding TMEDA−zinc complex prevented not only the competing N-alkylation but also the C2-alkylation pathway, leading to 7a as the only isolated product.27 Furthermore, when the quantity of potassium tert-butoxide was increased from 3.5 to 5 equiv and TMEDA was added to the reaction mixture, neither magnesium triflate nor copper triflate promoted the formation of the desired C3−C3′ bisindole (entries 6 and 7). Switching the Lewis acid from metal triflate to trisubstituted boranes in the Friedel−Crafts alkylation under identical conditions also provided the desired product (entries 8−11). The C3−C3′ bisindole (7a) was only isolated in 38% yield when triphenylborane was employed in the reaction (entry 8). Changing the Lewis acid from triphenylborane to the sterically bulky n-hexyl-9-borabicyclo[3.3.1]nonane (entry 9) dramatically improved the conversion, with the yield now being 83%. Subsequent efforts with triethylborane led to a significant improvement in the reaction yield (entries 10 and 11). As illustrated in Table 1, there is a strong solvent effect; THF or Et2O proved to be the most effective medium for this reaction to proceed with significant conversion. When the solvent was switched to dioxane (entry 12), CH3CN (entry 13), or DMF (entry 14), the reaction produced either trace amounts or none of the desired product. Furthermore, both NaHMDS (entry 15) and KHMDS (entry 16) provided either none or a low yield of the desired product. Two optimal one-pot procedures were established for the Friedel−Crafts alkylation of indoles. Method A consisted of the employment of t-BuOK as the base and Et3B as the Lewis acid. Method B comprised the selection of t-BuOK as the base, Zn(OTf)2 as the Lewis acid, and TMEDA as an additive. After the optimized conditions were established, we sought to examine the generality of this chemistry with respect to other πnucleophiles. Figure 2 demonstrates the substrate scope and limitation of the one-pot Friedel−Crafts alkylation reaction. Indole acts as a suitable π-nucleophile, and the desired product (7a) could be obtained in high yield by either method A or B. Furthermore, multigram quantities of 7a can be obtained by a
to be a useful reagent for dearomatizing C3-alkylation of 3substituted indole,22 and zinc triflate has been employed as an effective catalyst for regioselective synthesis of 3-alkylindoles.25 These observations also indicated that enhancement of the πnucleophilicity of N-deprotonated indoles might serve to further improve the regioselectivity in the Friedel−Crafts alkylation of indoles with a C3-bromopyrrolidinoindoline. In line with our interest in improving the regioselectivity of the Friedel−Crafts alkylation mentioned above, we envisaged that the π-nucleophilicity of N-deprotonated indoles could be modulated through the addition of Lewis acids/additives to the reaction system (Scheme 1). With this as our starting point, we screened a range of conditions to effect the Friedel−Crafts alkylation of the indole with C3-bromopyrrolidinoindoline (ent4), which could be easily obtained from D-tryptophan.26 As expected, the coupling of the nucleophile with a transient cyclopropane resulted in the formation of an endo isomer after kinetic protonation,19 the results of which are summarized in Table 1. Thus, treatment of a mixture of indole and C3Table 1. Optimization Studies
entries
basea
Lewis acid(1.5 equiv)
solvent
yield (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
t-BuOK t-BuOK t-BuOK t-BuOK (5.0) t-BuOK (5.0) t-BuOK (5.0) t-BuOK (5.0) t-BuOK t-BuOK t-BuOK t-BuOK t-BuOK t-BuOK t-BuOK NaHMDS KHMDS
Zn(OTf)2 Mg(OTf)2 Cu(OTf)2 Zn(OTf)2 Zn(OTf)2TMEDAc Mg(OTf)2TMEDAc Cu(OTf)2TMEDAc BPh3 hexyl-9-BBN BEt3 BEt3 BEt3 BEt3 BEt3 BEt3 BEt3
THF THF THF THF THF THF THF THF THF THF Et2O dioxane MeCN DMF THF THF
39 NDb ND 79 95 ND ND 38 83 98 96 trace trace ND ND 38
a
3.5 equiv of base was used unless specified. bND: desired product was not detected, while starting material was decomposed. cTMEDA (1.5 equiv) was used as an additive.
bromopyrrolidinoindoline (ent-4) with 3.5 equiv of potassium tert-butoxide and 1.5 equiv of zinc triflate in THF at 0 °C provided the desired C3−C3′ bisindole (7a) at low conversion (39% yield) along with substantial recovery of starting materials (entry 1). Under the same conditions, neither magnesium triflate nor copper triflate proved effective for the construction of the desired product (entries 2 and 3). Since zinc triflate is capable of effecting alkylation, it was selected for further optimization of reaction conditions. The recovery of starting materials described in entry 1 might indicate more base is required to drive the reaction to high conversions. To our delight, increasing the quantity of potassium tert-butoxide from 3.5 to 5 equiv increased the yield to 79% (entry 4). The addition of TMEDA at the beginning of the reaction further
Figure 2. Substrate scope of pyrroloindoline formation. 5135
DOI: 10.1021/acs.orglett.7b02425 Org. Lett. 2017, 19, 5134−5137
Letter
Organic Letters
been carried on to 1 and 2 by Boyer and Movassaghi.18 In addition, the synthesis of diketopiperazine 8 also constitutes a significant improvement over the previous route to the same intermediate.28 Most importantly, the regio- and stereospecific method described above represents a viable approach toward synthesizing natural products containing 3a-(1H-indol-3-yl)pyrrolidinoindoline. In summary, two one-pot procedures involving the regio- and stereospecific Friedel−Crafts alkylation of indoles with a C3bromopyrrolidinoindoline have been developed. These mild and practical conditions exhibit greater substrate scope than those previously employed and provide direct access to the multigram quantity of 3a-(3-indolyl)hexahydropyrrolo[2,3-b]indole core (7a). The synthetic utility of this method was demonstrated by the concise, formal syntheses of gliocladin B and gliocladin C.
chromatography-free procedure (see the Supporting Information). A large variety of functionalities at the four positions of the indoles are tolerated. In general, the efficiency of the reactions appears to correlate well with the relative nucleophilicity of indole derivatives. The reactions of 2methylindole, 7-methylindole, and 6-methoxyindole proceeded smoothly under the conditions described for methods A and B to afford the corresponding products 7b, 7c, and 7d in excellent yield. Indoles bearing some electron-withdrawing groups were also tolerated in the reaction. High yields were obtained with 5chloroindole and 5-bromoindole under the conditions described for both methods A and B. Interestingly, when 6chloroindole was employed as the substrate, the corresponding product 7f was obtained in 98% yield when method A was adopted. However, a significant decrease in yield for the same reaction was observed with method B. The inductive effect of the chlorine atom and the relatively stable zinc−N bond may contribute to the observed low reactivity. Under the reaction conditions of methods A and B, none of the desired bisindole (7g) was observed, likely reflecting a sterically demanding transition state in the formation of the C3−C3′ carbon−carbon bond. As anticipated, a moderate decrease in yield was observed with more electron-poor substrates. Bisindole 7i was obtained in 86% and 50% yield under the conditions of methods A and B, respectively. When 7-azaindole and pyrrole were subjected to the reaction conditions described in method A, the desired products 7j and 7k were obtained in 83% and 91% yield, respectively. Surprisingly, attempts to carry out the same reactions under the conditions described in method B were not successful, presumably because the corresponding zinc indolides are only moderately nucleophilic, and the relatively stable zinc-N bond prevents the N-alkylation pathway. Furthermore, when benzenesulfonyl was switched to the tertbutyl carbamate of compound ent-4, the corresponding bisindole 7l was obtained in 94% and 62% yield under the conditions of methods A and B, respectively. In short, method A usually displayed a wider substrate scope and should be of great utility. Although method B was also successful for the synthesis of bisindoles with various substrates, the efficiency of this method seems more sensitive to the nucleophilicity of indole derivatives. In order to showcase the new method in the milieu of total synthesis, we decided to carry out the formal total syntheses of gliocladins B and C. Thus, 7a was transformed into the known diketopiperazine 8 in 94% yield by a four-step sequence involving (1) cleavage of the Boc group with trifluoroacetic acid to furnish the corresponding amine, (2) condensation of the resultant amine with N-Boc-N(Me)-Gly-OH via the mixed anhydride formed with ethyl chloroformate, (3) removal of the Boc group with TFA, and (4) intramolecular lactamization with the terminal ester promoted by NH4OH in methanol (Scheme 2). The formation of diketopiperazine 8 represents formal syntheses of gliocladins B (1)9,10,17,18 and C (2)18 since 8 had
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02425. Experimental details and data (PDF)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Tao Ye: 0000-0002-2780-9761 Author Contributions #
H.L. and L.W. contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We acknowledge financial support from the Shenzhen Peacock Plan (KQTD2015071714043444), NSFC (21272011, 21572007), SZSTDF (JCYJ20140419131807793, JCYJ20130329175740481, JCYJ20160527100424909, ZDSYS201504301539161), and GDNSF (2014A030312004, 2014B030301003).
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REFERENCES
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Scheme 2. Formal Syntheses of Gliocladins Band C
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DOI: 10.1021/acs.orglett.7b02425 Org. Lett. 2017, 19, 5134−5137
