Letter pubs.acs.org/OrgLett
AgNTf2‑Mediated Allylation with Allylsilanes at C3a‑Position of Hexahydropyrroloindoles: Application to Total Syntheses of Amauromine Alkaloids Hiroyuki Hakamata, Soichiro Sato, Hirofumi Ueda, and Hidetoshi Tokuyama* Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba 6-3, Aramaki, Aoba-ku, Sendai 980-8578, Japan S Supporting Information *
ABSTRACT: A protocol for the allylation at the C3a-position of hexahydropyrroloindole using allylsilanes is developed. AgNTf2 proved to be an efficient activator of halopyrroloindoline substrates. This method is applicable to the introduction of various allyl groups including the reverse prenyl group. The utility of this reaction is demonstrated by total synthesis of amauromine alkaloids. Stepwise bromocyclizations of the bis-indolylmethyl diketopiperazine derivative and subsequent double reverse prenylation furnished (+)-novoamauromine and (−)-epiamauromine.
S
the C3a.4 Qin’s protocol required prenylstannane and the potentially explosive AgClO4 to activate halopyrroloindoline.5 An example of allylation using nontoxic allylsilane was reported by Movassaghi and co-workers in their investigation on functionalization of the C3a of pyrroloindole. However, the product yield was low and the generality and scope of allylsilanes have not been fully explored.3j Recently, it has been discovered that AgNTf2 is a highly effective activating agent of haloindolenines and halopyrroloindolines to promote their Friedel−Crafts type arylation with electron-rich aromatic compounds.6 Its efficiency and utility were demonstrated by our total syntheses of dimeric indole alkaloids, (+)-haplophytine6a and (+)-T988B.6b Focusing on the high efficiency of AgNTf2, AgNTf2-mediated allylation using allylsilanes was investigated. Herein we report a protocol for allylation of halopyrroloindolines using a combination of AgNTf2 and allylsilanes. In addition, through the application of the newly developed protocol, the facile total synthesis of amauromine alkaloids is accomplished. Initially, bromopyrroloindoline 1a and allyltrimethylsilane were selected and examined to determine if silver salts promoted allylation (Table 1). As expected, when a mixture of 1a and allyltrimethylsilane was treated with 1.2 equiv of AgNTf2 in dichloromethane at 0 °C, the desired allylation proceeded smoothly and produced the desired allylated product 2 in 93% yield (Table 1, entry 1). A series of experiments using other silver salts revealed the superiority of AgNTf2 (Table 1, entries 2−6).7 The reaction with AgF did not produce 2, but instead produced fluorinated compound 1b in 81% yield (Table 1, entry 2). The salts AgSbF6, AgPF6, AgBF4, and AgOTf produced allylated product 2 in unsatisfactory yields (Table 1, entries 3−6).8,9 It was found that the amount of AgNTf2 could be reduced to 1.2 equiv without loss of the yield (Table 1, entry
ince a number of hexahydropyrrolo[2,3-b]indole alkaloids possessing a potent and wide range of biological activity have been isolated from nature, these alkaloids have attracted considerable attention as potential drug candidates (Figure 1).1
Figure 1. Hexahydropyrroloindole alkaloids.
In addition to their fascinating bioactivity, the structural diversity of these compounds has made them attractive synthetic targets. In particular, this class of alkaloids has various substituents at the C3a-position including alkyl, aryl, and reverse prenyl groups. Introduction of these substituents at the sterically hindered position with formation of the quaternary carbon center has been one of the major synthetic challenges of these compounds. Among the various substituents, the reverse prenyl group is particularly important with respect to the biosynthetic background.2 However, due to the difficulty in constructing the two contiguous quaternary carbon centers at the hindered position, few methodologies are currently available.3 The seminal work by Danishefsky and co-workers required prenylstannane to react with a hazardous selenylated pyrroloindole substrate at © 2017 American Chemical Society
Received: August 22, 2017 Published: September 19, 2017 5308
DOI: 10.1021/acs.orglett.7b02602 Org. Lett. 2017, 19, 5308−5311
Letter
Organic Letters
The installation of a reverse prenyl group was then examined (Table 3). The initial trial using prenyltrimethylsilane afforded
Table 1. Silver-Mediated Allylation of Halopyrroloindolines
Table 3. Effect of Silyl Groups on Reverse Prenylation
entry
X
substrate
Ag salt (equiv)
temp (°C)
time (min)
yield (%)a
1 2b 3 4 5 6 7 8 9
Br Br Br Br Br Br Br Cl F
1a 1a 1a 1a 1a 1a 1a 1c 1b
AgNTf2 (1.5) AgF (1.5) AgSbF6 (1.5) AgPF6 (1.5) AgBF4 (1.5) AgOTf (1.5) AgNTf2 (1.2) AgNTf2 (1.2) AgNTf2 (1.2)
0 0 0 0 0 0 0 0 to rt 0 to reflux
30 90 30 40 30 30 30 180 540
93 0c 22 23 53 62 96 76 0
yield (%)a
Isolated yield. bThe reaction was performed at 0 °C to rt. Compound 1b was obtained in yield of 81%.
a c
a
entry
Si
8
9a−gb
1 2 3 4 5 6 7
SiMe3 SiEt3 SiMe2(t-Bu) Si(n-hex)3 Si(i-Pr)3 SiMe2Ph Si(Oi-Pr)3
49 59 55 65 74 41 36
51 36 41 24 18 53 16
Isolated yield. eomixture.
7). In respect to the leaving group of the substrate, the reaction of C3a-chloro substrate 1c required a prolonged reaction time even at room temperature to give 2 in a diminished yield (Table 2, entry 8). Fluoropyrroloindoline 1b was unreactive, and no product was obtained under the heating conditions (Table 2, entry 9).
b
9a−g were obtained as an inseparable diaster-
the desired reverse prenyl product 8 in only 49% yield along with methallyl product 9a; this is due to competing reactions at the β position of prenylsilane and subsequent deprotonation. After extensive investigation, it was found that steric bulkiness and electronic features of the substituents on the silicon atom affected the regioselectivity of the prenylation. Therefore, the ratio of the desired reverse prenyl compound to the undesired methallyl product improved with the increase in steric bulk (Table 3, entries 2−5). Prenyltriisopropylsilane, in particular, was found to be the most suitable for this reaction, and the desired product was obtained in 74% yield (Table 3, entry 5). By comparison, prenyldimethylphenylsilane and triisopropoxysilane gave 8 in low to modest yields (Table 3, entries 6 and 7). The established reverse prenylation conditions were found to be feasible for the more functionalized bromopyrroindoline 11 derived from tryptophan (Scheme 1). Therefore, treatment of 11 under optimal conditions using prenyltriisopropylsilane furnished the corresponding product in 83% yield.
Table 2. Scope of Allylsilanes
Scheme 1. Reverse Prenylation of the Substrate Derived from Tryptophan
a c
Isolated yield. bDiastereomeric ratio was determined by 1H NMR. The reaction was carried out on a 1 mmol scale.
Due to the successful establishment of reverse prenylation, synthetic studies on amauromine alkaloids were then conducted (Figure 2). Amauromine isolated from Amauroascus sp. No. 6237 by Takase and co-workers exhibits vasodilator activity as a CB1 antagonist. These compounds could therefore hold potential to be a leading compound of vasodilator drug.11 Structural features of these compounds include the following: (1) Two vicinal quaternary carbon atoms including a reverse prenyl group at the C3a-position of the pyrroloindole nucleus; (2) a C2-symmetrical heptacyclic diketopiperazine core in conjunction with two pyrroloindole skeletons. To date, the
Having established the optimal conditions, the scope of allylsilanes was then investigated (Table 2). A 1-butenyl unit was installed by either using trans- or cis-crotylsilane to give 3 as a 2:1 or 1:1.4 mixture of diastereomers, respectively (Table 2, entries 1 and 2). Reaction of 5- or 6-membered cyclic allylsilanes also took place smoothly to afford high yields of the corresponding products (Table 2, entries 3 and 4).10 When dienylsilane was used, the linear diene 6 was obtained in 92% yield with high regioselectivity (Table 2, entry 5). This method was also applicable for the introduction of a propargyl group through the use of allenylsilane (Table 2, entry 6). 5309
DOI: 10.1021/acs.orglett.7b02602 Org. Lett. 2017, 19, 5308−5311
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Organic Letters total synthesis of amauromine alkaloids has been accomplished by three groups, Takase, Danishefsky, and Stark.4,12
Table 4. Optimization of Double Reverse Prenylation
entry
R
Ag salt
additive
1 2
Si(i-Pr)3 Si(i-Pr)3
AgNTf2 AgNTf2
3
SnBu3
AgNTf2
SnBu3 SnBu3
AgClO4 AgClO4
− DTBP MS 5 Å DTBP MS 5 Å Cs2CO3 Cs2CO3
ref5
4 5
temp (°C)
time (h)
yield (%)a
0 to rt 0 to rt
0.5 0.5
trace 42
0 to rt
0.5
11
−78 0 to rt
30 0.5
0b trace
a
The reactions were conducted using nucleophiles (3.0 equiv) or silver salt (4.0 equiv), and isolated yields of products were noted above. b Monoalkylated product was detected. DTBP = 2,6-di-tert-butylpyridine.
Figure 2. Amauromine and related compounds.
The synthesis of amauromines was initiated with double bromocyclization of bisindolylmethyldiketopiperazine 15, which was readily prepared according to the modified procedure reported by Evano13 (Scheme 1). Initially, sequential bromocyclizations using an excess amount (2.5 equiv) of brominating agents was examined. However, all trials using various bromonium sources resulted in complex mixtures. Bromocyclization was then tested in a stepwise manner. Treatment of 15 with 1.1 equiv of NBS in CH2Cl2 at −20 °C provided the monocyclic compound 16 in 87% yield, albeit with poor diastereoselectivity (Scheme 2). In the second
butylpyridine and MS 5 Å to give a moderate yield of the desired product 19 (Table 4, entry 2). Contrary to expectation, the reaction using prenylstannane, which generally possesses higher nucleophilicity than prenylsilanes, only produced an 11% yield of 19 (Table 4, entry 3). Moreover, the reaction using a combination of silver perchlorate and prenyltributyltin5 did not give the desired product 19 but afforded a trace amount of the mono-reverse prenylated product (Table 4, entries 4 and 5). The endgame sequence of the total synthesis of (−)-epiamauromine (13) and the total synthesis of (+)-novoamauromine (14) are described in Scheme 3. The total synthesis of
Scheme 2. Preparation of Bis-bromopyrroloindolines
Scheme 3. Total Syntheses of (−)-Epiamauromine and (+)-Novoamauromine
bromocyclization, the generation of three diastereomers was anticipated; this corresponds to amauromine (12), epiamauromine (13), and novoamauromine (14). However, the second bromocyclization provided two products 17 and 18 in good yields. A compound possessing stereochemistry for (−)-amauromine (12) was not detected.14 With the heptacyclic bis-bromopyrroloindoles 17 and 18 in hand, the crucial reverse prenylation was then examined (Table 4). However, only a trace amount of the desired product 19 was obtained, along with other associated side products. This is due to the removal of the Boc group and hydroxylation of the bromo group (Table 4, entry 1). After extensive investigations, these side reactions were suppressed by addition of 2,6-di-tert-
(−)-epiamauromine (13) was completed by cleavage of two Boc groups under thermolysis. The modified reverse prenylation conditions were then applied to 18 to obtain the doubly prenylated product 20 in 35% yield. Finally, two Boc groups were removed to furnish (+)-novoamauromine (14). In summary, we developed an efficient and environmentally benign allylation of the C3a-position of pyrroloindolines using 5310
DOI: 10.1021/acs.orglett.7b02602 Org. Lett. 2017, 19, 5308−5311
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Fenton, O. S.; Movassaghi, M. J. Am. Chem. Soc. 2016, 138, 1057. (n) Adhikari, A. A.; Chisholm, J. D. Org. Lett. 2016, 18, 4100. (4) (a) Marsden, S. P.; Depew, K. M.; Danishefsky, S. J. J. Am. Chem. Soc. 1994, 116, 11143. (b) Depew, K. M.; Marsden, S. P.; Zatorska, D.; Zatorski, A.; Bornmann, W. G.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 11953. (5) Wang, Y.; Kong, C.; Du, Y.; Song, H.; Zhang, D.; Qin, Y. Org. Biomol. Chem. 2012, 10, 2793. (6) (a) Satoh, H.; Ojima, K.; Ueda, H.; Tokuyama, H. Angew. Chem., Int. Ed. 2016, 55, 15157. (b) Sato, S.; Hirayama, A.; Ueda, H.; Tokuyama, H. Asian J. Org. Chem. 2017, 6, 54. (c) Sato, S.; Hirayama, A.; Adachi, T.; Kawauchi, D.; Ueda, H.; Tokuyama, H. Heterocycles (DOI: 10.3987/COM-17-13777). (7) For a review on metal triflimidate, see: Antoniotti, S.; Dalla, V.; Duñach, E. Angew. Chem., Int. Ed. 2010, 49, 7860. (8) For determination of Lewis acidity, see: (a) Childs, R. F.; Mulholland, D. L.; Nixon, A. Can. J. Chem. 1982, 60, 801. (b) Laszlo, P.; Teston, M. J. Am. Chem. Soc. 1990, 112, 8750. (c) Mathieu, B.; Ghosez, L. Tetrahedron 2002, 58, 8219. (9) The preliminary NMR experiments indicated that the advantage of AgNTf2 over other silver salts would be due to its high efficiency to activate bromo group of bromopyrroloindoline 1a to generate the corresponding cationic intermediate. Time-dependent 1H NMR spectra were determined after addition of 1.2 equiv of silver salt (AgNTf2 or AgOTf) to a CDCl3 solution (0.1 M) of bromopyrroloindoline 1a in the absence of a nucleophile. In case of AgNTf2, the proton signal of 1a disappeared approximately after 10 min. On the other hand, in the case of AgOTf, complete consumption of 1a required about 1 day. For 1H NMR of time-dependent experiments and observed NTf2 adduct, see the Supporting Information. (10) The stereochemistry of a mixture of diastereomers was not determined. (11) (a) For the isolation, see: Takase, S.; Iwami, M.; Ando, T.; Okamoto, M.; Yoshida, K.; Horiai, H.; Kohsaka, M.; Aoki, H.; Imanaka, H. J. Antibiot. 1984, 37, 1320. (b) For the structure, see: Takase, S.; Kawai, Y.; Uchida, I.; Tanaka, H.; Aoki, H. Tetrahedron 1985, 41, 3037. (c) For the biological activity, see: Elsebai, M. F.; Rempel, V.; Schnakenburg, G.; Kehraus, S.; Müller, C. E.; König, G. M. ACS Med. Chem. Lett. 2011, 2, 866. (12) (a) Takase, S.; Itoh, Y.; Uchida, I.; Tanaka, H.; Aoki, H. Tetrahedron 1986, 42, 5887. (b) Müller, J. M.; Stark, C. B. W. Angew. Chem., Int. Ed. 2016, 55, 4798. (13) Coste, A.; Toumi, M.; Wright, K.; Razafimahaléo, V.; Couty, F.; Marrot, J.; Evano, G. Org. Lett. 2008, 10, 3841. (14) This result indicates that bromocyclization of 16β provided 17 as the sole product. This selectivity would be controlled by either the bromination or cyclization step. The reason for the excellent selectivity is currently unclear.
a combination of AgNTf2 and allylsilanes. These reaction conditions are advantageous compared with conventional methodologies which employ highly toxic tin compounds and an explosive and/or toxic activativing agent. The synthetic utility of this newly developed protocol was demonstrated by the total synthesis of (−)-epiamauromine (13) and (+)-novoamauromine (14).
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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.7b02602. Experimental details and procedures, compound characterization data, and copies of 1H and 13C NMR spectra for all new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Hidetoshi Tokuyama: 0000-0002-6519-7727 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was financially supported by JSPS KAKENHI Grant Numbers JP16H01127 in Middle Molecular Strategy and JP16H00999 in Precisely Designed Catalysts with Customized Scaffolding, a Grant-in aid for Scientific Research (A) (26253001) and (C) (17K08204), and the Platform Project for Supporting Drug Discovery and Life Science Research funded by Japan Agency for Medical Research and Development (AMED).
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REFERENCES
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DOI: 10.1021/acs.orglett.7b02602 Org. Lett. 2017, 19, 5308−5311
