Enantioselective Synthesis of Polycyclic Indole Derivatives Based on

Oct 1, 2015 - Using 2b, 2c, and 2d as Michael acceptors did not improve the reaction .... 4 in good yields with the retained ee values (Table 3, entri...
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Enantioselective Synthesis of Polycyclic Indole Derivatives Based on aza-Morita-Baylis-Hillman Reaction Yuning Gao, Qin Xu, and Min Shi ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.5b01579 • Publication Date (Web): 01 Oct 2015 Downloaded from http://pubs.acs.org on October 3, 2015

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Enantioselective Synthesis of Polycyclic Indole Derivatives Based on aza-Morita-Baylis-Hillman Reaction Yuning Gao,a Qin Xu,*a and Min Shi*a,b a

Laboratory for Advanced Materials & Institute of Fine Chemicals, School of Chemistry & Molecular Engineering, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, P. R. China b Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R.China

ABSTRACT: A chiral phosphine-catalyzed asymmetric aza-Morita-Baylis-Hillman reaction between indole-derived sulfonyl imines and bis(3-chlorophenyl)methyl acrylate has been developed, giving the desired adducts in good yields and ee values along with the further transformations to polycyclic indoles such as dihydropyrido[1,2-a]indole and dihydropyrazino[1,2-a]indole skeleton.

KEYWORDS: chiral phosphine catalysis, asymmetric aza-MBH reaction, polycyclic indole, ring-closing-metathesis, gold catalysis.

as a key step in the synthesis of complex natural products.9 In 2012, Kwon and co-workers reported the enantioselective total synthesis of (+)-ibophyllidine containing a polycyclic indole skeleton, in which a chiral phosphine-catalyzed [3+2] annulation plays a key role in this synthesis.10 Among the phosphine-mediated/catalyzed carbon-carbon bond forming reactions, the Morita-Baylis-Hillman (MBH) reaction is well equipped with large varieties of parameters, providing a huge reservoir of diverse classes of densely functionalized compounds.11 In recent decades, the MBH reaction and its applications have received remarkable growing progress, which are evidenced by large numbers of papers.12 The MBH reaction provides different products with several adjacent function groups which play specific roles in the subsequent transformations. Complex molecular structures can be constructed through fine tuning of these groups either individually or two together in a branched manner.13 Therefore the MBH reaction is the unified strategy to increase the structural diversity we have been searching. Besides, it has been well known that the C-3 position of an indole molecule is the most reactive site compared to N1 and C2 positions since it has stronger nucleophilicity. This is quite meaningful for us to achieve diversity-oriented synthesis (DOS) in polycyclic indole derivatives with this additional reactive site.

INTRODUCTION Enantiomerically pure polycyclic indole frameworks are ubiquitous in a variety of natural products,1 which have multiform biological activities and vital medicinal value (Figure S1 in the Supporting Information).2 They are also key building blocks in organic synthesis of diverse natural products possessing a range of potential biological properties, such as insecticidal, anti-bacterial, -inflammatory, -cancer, and -malarial activity. Thus far, it has always been challenging and interesting to develop novel methodologies for enantioselectively constructing polycyclic indole derivatives. The concept of diversity-oriented synthesis (DOS) around privileged structures, defined as rational DOS or privileged-substructure-based DOS (pDOS), has been identified as an efficient strategy to establish high-quality compound libraries.3 Inspired by the concept of DOS, we have been exploring a unified strategy to construct various polycyclic indole nucleus through divergent synthetic approaches. During the past decade, nucleophilic phosphine catalyses have been widely used in synthetic organic chemistry in producing carbo- and heterocycles4 as well as in the construction of core structures of natural products or analogues5 via [3+2] and [4+2] annulations on imines or electron-deficient alkenes and alkynes.6,7,8 For example, phosphine-catalyzed Rauhut-Currier reaction has been used

RESULTS AND DISCUSSION

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Using 2f and 2g as Michael acceptors, which are more sterically bulky than 2e, did not give better reaction outcomes (Table 1, entries 2 and 3). These results led us to believe that a sterically demanding Michael acceptor is more significant than a sterically bulky one for this reaction. Changing phosphine catalyst CP1 to CP6, CP7 and CP8, we found that the use of CP1 was still the best choice (Table 1, entries 4-6). Considering the significant solvent effects for distinct substrates, we screened the solvent effect again and found that THF was the suitable one for Michael acceptor 2e (Table 1, entries 7-13). In order to further modify the steric hindrance of 2e, we introduced

Encouraged by the reports mentioned above, we wish to report the first phosphine-catalyzed enantioselective synthesis of dihydropyrido[1,2-a]indole and dihydropyrazino[1,2-a]indole derivatives from the asymmetric aza-MBH reaction of 2-indolyl sulfonated imines with electron-deficient olefins as well as the construction of polycyclic indole compounds through the use of C-3 position of indole. On the basis of previous work on asymmetric MBH reactions with chiral phosphines,14 we initiated our study by utilizing N-((1-allyl-1H-indol-2-yl)methylene)-4-methylbenzenesulf onamide 1a and benzyl acrylate 2a as the substrates and multifunctional chiral phosphine CP1 as the catalyst in THF at room temperature for 12 hours. We found that the desired product 3aa could be obtained in 82% yield and 59% ee value (see entry 1 of Table S1 in the Supporting Information, for more details, see Table S1). The examination of solvents revealed that MeCN is the suitable one under this condition, affording 3aa in 94% yield along with 69% ee value (Scheme 1) and the use of several new chiral phosphine catalysts such as CP2, CP3, CP4 and CP5 in this reaction did not give superior results (Scheme 1, MBH adduct 3aa). Next, we decided to change our strategy by using sterically bulky Michael acceptors 2b, 2c or 2d shown in Scheme 1 and 2e shown in Table 1. Using 2b, 2c and 2d as Michael acceptors did not improve the reaction outcomes in the presence of CP1 (Scheme 1, MBH adducts 3ab, 3ac and 3ad). To our delight, the use of benzhydryl acrylate 2e as a Michael acceptor produced the desired product 3ae in 88% yield and 84% ee value (Table 1, entry 1).

Table 1. Optimization of the reaction conditions for asymmetric aza-MBH reaction

substituent into the phenyl ring and prepared bis(4-chlorophenyl)methyl acrylate 2h as the Michael acceptor. The corresponding product 3ah was obtained in 92% yield along with 89% ee value (Table 1, entry 14). This gratifying result also suggested that a sterically appropriate Michael acceptor 2 is vital. Thus we went a step further to change the location of substituent on the phenyl ring and synthesized bis(3-chlorophenyl)methyl acrylate 2i. As expected, the corresponding product 3ai was obtained in 93% yield and 91% ee value (Table 1, entry 15). This is a sterically suitable Michael acceptor for this type of asymmetric aza-MBH reaction in the presence of CP1. Having established the optimal reaction condition, we turned our attention to the scope and limitations by using a variety of indole-derived imines 1 and bis(3-chlorophenyl)methyl acrylate 2i in the presence of CP1, and the results are summarized in Table 2. All

Scheme 1. Chiral phosphine catalysts and substrates 2 applied in this aza-MBH reactiona

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reactions proceeded smoothly to give the corresponding products 3 in excellent yields (86-95%) and good to high ee values (76-97%) (Table 2, entries 1-13). As can be seen in Table 2, regardless of whether electron-donating or electron-withdrawing R2 groups were introduced at the indole ring of 1, all of the substrates were well-tolerated, indicating no significant electronic impact on the reaction outcomes. Substrate 1f (R3 = Me) afforded the corresponding product 3fi in 76% ee value (Table 2, entry 5). Substrate 1o bearing a phenyl group at the 3-position gave the desired product in trace (Table 2, entry 14), presumably due to the steric effect compared to substrate 1a. The absolute configuration of 3 has been identified as R configuration on the basis of crystal structure of 3ah (see Supporting Information).15 Table 2. Substrate scope of asymmetric aza-MBH reaction Cl

4

5

3 2

R2 N

6 7

1

O

NTs +

CP1 (20 mol%) O

THF, 12 h, rt

1

R3

2i

Cl NHTs

3

5 4

2

R2 6

1

7

O

N R3

O

3 Cl Cl

a

R2

R

yield (%)

ee (%)c

1

1b, 5-Cl

allyl

3bi, 93

90

2

1c, 5-Br

allyl

3ci, 92

91

3 4

1d, 5-NO2 1e, 6-Cl

allyl allyl

3di, 90 3ei, 92

82 88 76

entry

3

b

5

1f, H

methyl

6

1g, H

1-(but-3-en-1-yl)

3fi, 93 3gi, 88

7

1h, H

propargyl

3hi, 86

90

8

1i, 5-OMe

allyl

3ii, 90

90

9 10

1j, 5-Me 1k, 5-F 1l, 4-OMe 1m, 5-OBn 1n, 3-I 1o, 3-Ph

allyl allyl allyl allyl allyl allyl

3ji, 91 3ki, 91

90 85

3li, 92 3mi, 95 3ni, 93 3oi, trace

91 91

11 12 13 14

90

Figure 1. X-ray crystal structure of 4p (N-methyl protected 4ai).

97 -

a

Unless otherwise indicated, all reactions were carried out with 1 (0.3 mmol), 2 (0.6 mmol), and CP1 (0.06 mmol) in THF (3 mL) at room temperature. b Yields of isolated products. c Determined by HPLC using a chiral stationary phase.

The synthetic utility of this asymmetric MBH reaction was certified by a gram-scale reaction of 1a and 2i in the presence of 3 mol% of CP1, affording 3ai in 82% yield and 89% ee value (Scheme 2). Using 1b as substrate, a satisfactory result was also obtained, affording 3bi in 84% yield and 89% ee.

We next explored the asymmetric synthesis of dihydropyrido[1,2-a]indole derivatives 4 from 3 using ring-closing-metathesis (RCM) of the tethered allyl group and the newly generated alkene.16 The reaction was carried out using Zhan catalyst 1B as the catalyst in DCM under reflux and the results are summarized in Table 3. As can be seen in Table 3, the RCM reactions proceeded efficiently to afford the desired compounds 4 in good yields with the retained ee values (Table 3, entries 1-6). Their structures have been also determined by X-ray diffraction of 4p (N-methyl protected 4ai) (see Supporting Information) and its ORTEP drawing is shown in Figure 1.15

Scheme 2. A gram-scale synthesis of 3ai and 3bi in the presence of 3 mol% CP1

Table 3. Substrate scope of RCM reaction of 3

The construction of enantiomerically enriched polycyclic indole nucleus has been first explored using 4ai as starting materials (Scheme 3). Hydrogenation of 4ai with

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Pd(OH)2/C (10 mol%) stereoselectively afforded cis-6,7,8,9-tetrahydropyrido[1,2-a]indole derivative 5 in 69% yield, which produced the corresponding amino alcohol 6 in 65% yield upon treatment with diisobutyl aluminum hydride (DIBAL-H) (4.0 eq). Its structure has been determined by X-ray crystallographic analysis.15 Treatment of 6 with allyl bromide (2.4 eq) in DMF gave allyl-protected amino alcohol 7 in 80% yield, which was again applied in RCM strategy with Grubbs II catalyst (5 mol%) to construct chiral polycyclic indole derivative 8 in 77% yield with 92% ee, which was determined by NMR spectroscopic data including COSY, HSQC, HMBC and NOESY (see Supporting Information). As for propargyl-protected MBH adduct 3hi, we utilized another method to construct 1,2-dihydropyrazino[1,2-a]indole derivative 12 (Scheme 4). Under gold catalysis, dihydropyrazino[1,2-a]indole derivative 9 could be obtained in 80% yield, which subsequently gave 10 in 72% yield upon treatment with

Scheme 3. Synthetic manipulations dihydropyrido[1,2-a]indole derivative

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Figure 2. X-ray crystal structure of 9. Furthermore, during our further investigation, we found that treating racemic MBH adduct 3ai with EtOH and base at 90 oC in toluene delivered transesterification and indole migration product 13 in 78% yield (Scheme 5). Its structure has been determined by X-ray diffraction.15 Our control experiment identified that the presence of 0.1 eq of NH2Ts which may be generated from the decomposition of 3ai under the base condition, could indeed produce 13 in 84% yield. Therefore, a plausible mechanism for the generation of 13 has been presented in Scheme 6. First, intermediate I is produced through the aza-Michael addition reaction of TsNH- to 3ai. Then another TsNH- is eliminated to form intermediate II, which undergoes interesterification to give the final product 13. Using 13 as starting materials, 1H-pyrrolo[1,2-a]indole 14 was obtained in 81% yield through RCM reaction and 1,2,3,6-tetrahydroazepino[4,3-b]indole derivative 15 was afforded in 73% yield through Pictet-Spengler reaction. The structure of 15 has been also identified by NMR spectroscopic data.

of

DIBAL-H (4.0 eq) in DCM at -78 oC. The ORTEP drawing of 9 is shown in Figure 2. The Mitsunobu reaction of 10 with tosylated propargylic amine afforded 11 in 84% yield, which could produce 12 in 68% yield along with 98% ee value through the cyclization between C-3 position of indole and the remaining alkyne moiety under gold catalysis. The structure of 12 has been also confirmed by NMR spectroscopic data including COSY, HSQC, HMBC and NOESY (see Supporting Information).

Scheme 5. Synthetic manipulations 1H-pyrrolo[1,2-a]indole tetrahydroazepino[4,3-b]indole derivative

Scheme 4. Synthetic manipulations dihydropyrazino[1,2-a]indole derivative

of

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Cl NHTs O

2858, 1723, 1596, 1574, 1476, 1462, 1409, 1335, 1258, 1160, 1093, 1080, 1059, 1019, 925, 812, 788, 736, 705, 677 cm-1; HRMS (ESI) Calcd. For C35H30Cl3N2O4S+1 (M+H)+ requires 645.1376, Found: 645.1377; Enantiomeric excess was determined by HPLC with a Chiralcel PC-4 column [λ = 230 nm; eluent: Hexane/Isopropanol = 60/40; Flow rate: 0.70 mL/min; tminor = 10.22 min, tmajor = 18.43 min; ee% = 91%; [α]20D = +60.8 (c 1.00, CH2Cl2)].

Cl

N

NHTs Cs2CO3

O

NHTs O N O NHTs

3ai

Cl

I Cl

NHTs NHTs OEt O

Cl Cs2CO3 EtOH

N

General Procedure for 4: To a flame-dried round bottle were added MBH adducts 3 (0.2 mmol) and Zhan Catalyst-1B (0.01 mmol), followed by the addition of dry DCM (15 mL) under argon atmosphere. The reaction mixture was heated to reflux for 8 h. Solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 2:1) to afford 4. 4ai: A yellow solid, 112 mg, 91% yield; m. p. 110-111 oC; 1 H NMR (400 MHz, CDCl3, TMS) δ 7.42-7.41 (m, 1H), 7.37-7.24 (m, 11H), 7.18-7.17 (m, 2H), 7.09-7.05 (m, 1H), 6.83 (s, 1H), 6.81 (s, 1H), 6.78 (s, 1H), 6.07 (s, 1H), 5.64 (d, J = 6.4 Hz, 1H), 5.55 (d, J = 6.4 Hz, 1H), 4.77-4.60 (m, 2H), 2.21 (s, 3H); 13C NMR (100 MHz, CDCl3, TMS) δ 163.4, 142.9, 141.2, 141.0, 138.0, 136.9, 135.2, 134.60, 134.56, 131.2, 130.10, 130.07, 128.8, 128.6, 128.5, 127.9, 127.7, 127.2, 126.9, 126.7, 125.4, 125.0, 121.8, 120.9, 120.3, 108.9, 100.9, 76.6, 45.5, 42.2, 21.3; IR (CH2Cl2): ν 3251, 2915, 1723, 1596, 1575, 1470, 1445, 1363, 1325, 1265, 1229, 1185, 1156, 1092, 1079, 1012, 789, 745, 704, 669 cm-1; HRMS (ESI) Calcd. For C33H27Cl2N2O4S+1 (M+H)+ requires 617.1063, Found: 617.1070; Enantiomeric excess was determined by HPLC with a Chiralcel PC-2 column [λ = 214 nm; eluent: Hexane/Isopropanol = 60/40; Flow rate: 0.60 mL/min; tminor = 26.70 min, tmajor = 35.63 min; ee% = 90%; [α]20D = -1.5 (c 0.50, CH2Cl2)].

O N O NHTs II

Cl

Scheme 6. A possible pathway for the generation of 13 from 3ai In conclusion, the asymmetric MBH reaction of indole-derived sulfonyl imines and bis(3-chlorophenyl)methyl acrylate using thiourea-phosphine catalyst CP1 has been developed, giving the desired adducts in good yields and ee values. These multifunctional MBH adducts have been applied to synthesize enantiomerically enriched dihydropyrido[1,2-a]indole and dihydropyrazino[1,2-a]indole derivatives. Chiral polycyclic indole derivatives have been synthesized upon further transformation on the basis of these two indole derivatives. Further efforts to apply this strategy to synthesize more complex biologically active compounds are ongoing. EXPERIMENTAL SECTION General Procedure for 3: To a flame-dried Schlenk tube were added indole-derived sulfonyl imide 1 (0.3 mmol), bis(3-chlorophenyl)methyl acrylate 2 (0.6 mmol) and chiral phosphine catalyst CP1 (0.03 mmol), followed by the addition of dry THF (3 mL) under argon atmosphere. The reaction mixture was stirred at room temperature for 12 h. Solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 6:1) to afford 3. 3ai: A light yellow solid, 180 mg, 93% yield; m. p. 117-119 oC; 1H NMR (400 MHz, CDCl3, TMS) δ 7.57 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.0 Hz, 1H), 7.29-7.18 (m, 6H), 7.08-7.04 (m, 5H), 6.99 (t, J = 8.0 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.69 (s, 1H), 6.27 (s, 1H), 6.10 (s, 1H), 5.81-5.71 (m, 3H), 5.54 (d, J = 8.8 Hz, 1H), 5.00 (d, J = 10.0 Hz, 1H), 4.84 (d, J = 17.6 Hz, 1H), 4.78-4.64 (m, 2H), 2.30 (s, 3H); 13C NMR (100 MHz, CDCl3, TMS) δ 164.1, 143.7, 140.8, 137.6, 137.2, 137.1, 135.7, 134.6, 134.4, 133.2, 130.0, 129.9, 129.5, 128.6, 128.4, 127.9, 127.1, 127.0, 126.8, 125.3, 125.0, 122.5, 121.0, 119.9, 116.7, 109.9, 102.5, 76.1, 50.8, 45.3, 21.4; IR (CH2Cl2): ν 3286, 2923,

ASSOCIATED CONTENT Supporting Information: Experimental procedures, characterization data, and 1H and 13C NMR spectra for new compounds are included. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author *E-mail for Q.X.: [email protected]. *E-mail for M.S.: [email protected]. Notes The authors declare no competing financial interest. ACKNOWLEDGMENT We are grateful for the financial support from the National Basic Research Program of China (973)-2015CB856603, and the National Natural Science Foundation of China (20472096, 21372241, 21361140350, 20672127,

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21421091, 21372250, 21121062, 21302203, 20732008 and 21572052).

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