DOI: 10.1002/chem.201500349
Communication
& Total Synthesis
Organocatalytic Highly Enantioselective Substitution of 3-(1Tosylalkyl)indoles with Oxindoles Enables the First Total Synthesis of (+)-Trigolutes B Jian-Zhou Huang,[a] Chen-Long Zhang,[a] Yi-Fan Zhu,[a] Lu-Lu Li,[a] Dian-Feng Chen,[a] Zhi-Yong Han,[a] and Liu-Zhu Gong*[a, b] Abstract: A highly enantioselective organocatalytic substitution of 3-(1-tosylalkyl)indoles with oxindoles has been established by using chiral bifunctional organocatalysts, providing an efficient entry to multiply functionalized 3,3’disubstituted oxindoles, and was exploited as the key step to enable the first asymmetric total synthesis of optically pure (+)-trigolutes B to be accomplished in a concise manner, within seven steps with an 18 % overall yield.
The spirooxindole core, a privileged nitrogen-containing heterocyclic ring system, is featured in a large number of natural products and pharmaceuticals, such as spirotryprostatins, horsfiline, gelsemine, gelseverine, rhynchophylline, and elacomine (Figure 1).[1] Given their diverse inherent bioactivities, the spirooxindole skeleton has drawn significant synthetic interest in the areas of both organic chemistry and pharmacology.[2] A variety of methodologies for the construction of the spirooxindole core, especially in an asymmetric fashion, have been well developed.[2d, 3] Williams and co-workers established chiral auxiliary-induced asymmetric cycloaddition strategies allowing for the asymmetric total synthesis of spirotryprostatin B and versicolamide B.[4] Our group accomplished a chiral phosphoric acid-catalyzed 1,3-dipolar cycloaddition to directly generate spriooxindoles in high enantioselectivities and structural diversity.[5] The groups of Trost,[6] Barbas,[7] and Antilla[8] have also developed spirooxindole-oriented enantioselective cycloaddition reactions for the syntheses of structurally diverse, optically active spirooxindoles. Other methods, including intramolecular Heck reaction,[9] cascade reaction,[10] and stepwise transforma-
Figure 1. Spirooxindole-containing natural products.
tion of 3,3’-disubstituted oxindoles,[11] have also greatly enriched the spectrum of spirooxindole skeletons. In 2013, two new types of spirooxindole alkaloids were isolated from the twigs of Trigonostemon lutescens and identified by Dai and co-workers.[12] These new spirooxindoles showed weak inhibitory activity and further biological studies indicated that they show good activity in the treatment of hemorrhagic fever with renal syndrome.[13] However, the total syntheses of these spirooxindole alkaloids have not been reported to date. Given our continuing interest in the asymmetric synthesis of bioactive heterocyclic compounds,[5, 14] we planned an asymmetric nucleophilic substitution for the total synthesis of trigolutes B. A retrosynthetic analysis (Scheme 1) implies that the spirooxindole skeleton could be prepared via dihydroxylation/ intramolecular esterification of the key intermediate 2, which was expected to be obtained directly from an enantioselective substitution reaction of 3-(1-tosylalkyl)indoles 4 with oxindole 3, presumably via an asymmetric conjugate addition pathway catalyzed by a bifunctional organocatalyst (TS-A, Scheme 1).[14a] The 3-allylideneindole intermediate A (in TS-A, Scheme 1), which could be readily generated by leaving group elimination of 4, turned out to be highly reactive toward various nucleophiles.[15] Although asymmetric conjugate addition to intermediate A has proven highly efficient in accessing optically active indole derivatives, the control of b and d-regioselectivity appears to be the most challenging issue in comparison with
[a] J.-Z. Huang, C.-L. Zhang, Y.-F. Zhu, L.-L. Li, D.-F. Chen, Z.-Y. Han, Prof. Dr. L.-Z. Gong Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and Technology of China Hefei, 230026 (P. R. China) Fax: (+ 86) 551-360-6266 E-mail: [email protected] Homepage: http://staff.ustc.edu.cn/ ~ gonglz/index.htm [b] Prof. Dr. L.-Z. Gong Collaborative Innovation Center of Chemical Science and Engineering (Tianjin) (P. R. China) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201500349. Chem. Eur. J. 2015, 21, 1 – 6
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Entry
Scheme 1. Retrosynthetic analysis for the synthesis of (+)-trigolutes B.
1 2 3 4 5 6 7 8 9[e] 10[f] 11[g] 12[h] 13[i]
previous conjugate addition reactions to 3-methyleneindole intermediates.[14b,c, 15–17] Herein, we report a highly enantioselective organocatalytic substitution of 3-(1-tosylalkyl)indoles 4 with oxindoles 3 and its application to the first and concise total synthesis of (+)-trigolutes B (Scheme 1). The initial investigations started with the evaluation of cinchona-derived bifunctional catalysts for the asymmetric substitution reaction of 3-(1-tosylalkyl)indole 4 a with oxindole 3 a in the presence of K3PO4 in toluene at room temperature (Table 1). To our delight, the reaction proceeded smoothly to specifically furnish b-selective addition product 2 aa and the thiourea-based bifunctional organocatalyst 5 b was able to give a much higher enantioselectivity than the urea 5 a (Table 1, entries 1 and 2). The N-protecting group of oxindoles also has considerable effect on the stereoselectivity (Table 1, entries 2–4). The N-Bz oxindole (3 c) provided comparably higher enantioselectivity than its counterparts (Table 1, entry 4 vs. entries 2 and 3). The screening of solvents indicated that Et2O enabled the diastereoselectivity to be slightly improved to 2.5:1 while maintaining excellent yield and enantioselectivity (Table 1, entries 5–8). Finally, the survey of inorganic bases found that the use of K2CO3 to replace K3PO4 as an acid scavenger led to the highest enantioselectivity (Table 1, entry 10 vs. entries 7, 9, and 11). Lowering the catalyst loading had no obvious effect on the enantioselectivity and led to a diminished yield (Table 1, entry 7 vs. entries 12 and 13). The optimized reaction conditions were then utilized for the asymmetric substitution reaction of a variety of substituted 3(1-tosylalkyl)indoles with substituted oxindoles (Scheme 2). Generally, this protocol tolerated a wide range of substituents on the oxindole moieties regardless of the electronic nature and thereby gave corresponding products in excellent yields and with excellent enantioselectivities (Scheme 2, 2 ca–2 ja). Interestingly, replacement of the ester in 3 with a cyano group was also permitted to undergo the transformation in excellent yield and with high stereoselectivity, as exemplified by 2 ka. In addition, the introduction of substituents at 3-(1-tosylalkyl)indoles was also allowed and participated in the asymmetric &
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3 5a 5b 5b 5b 5b 5b 5b 5b 5b 5b 5b 5b 5b
Solvent 3a 3a 3b 3c 3c 3c 3c 3c 3c 3c 3c 3c 3c
toluene toluene toluene toluene CH2Cl2 DCE Et2O THF Et2O Et2O Et2O Et2O Et2O
Yield [%][b] 85 85 99 98 97 98 93 88 82 95 98 68 36
d.r.[c] 1.9:1 1.5:1 1.3:1 1.3:1 1.7:1 1.7:1 2.5:1 1.9:1 1.7:1 2.5:1 2.0:1 2.5:1 2.5:1
ee [%][d] 36(68) 65(55) 92(64) 93(90) 96(90) 96(90) 97(90) 50(40) 97(90) 97(94) 94(85) 97(94) 97(94)
[a] Unless indicated otherwise, reaction conditions: 3 (0.10 mmol), 4 a (0.11 mmol), K3PO4(0.11 mmol), catalyst 5 (10 mol %), solvent (1.0 mL); [b] yield of isolated product; [c] diastereomeric ratio (d.r.) determined by 1 H NMR spectroscopy; [d] the ee values are those for the major diastereoisomer and those in parentheses are those for the minor diastereoisomer. The ee values were determined by HPLC analysis using a chiral stationary phase; [e] base = Na2CO3 ; [f] base = K2CO3 ; [g] base = KF; [h] 5 mol % of catalyst 5 b was used; [i] 2.5 mol % of catalyst 5 b was used.
substitution reaction to generate the desired products 2 cb and 2 cc in high yields and with excellent enantioselectivities. To understand the observed stereochemistry, a plausible mechanism of the asymmetric substitution reaction was proposed (Scheme 3). As indicated previously,[15] the vinylogous imine intermediate was generated from 4, as either a Z- or Eisomer (A-I or A-II), in the presence of inorganic base. The bifunctional catalyst 5 b activates A-I or A-II by a double hydrogen-bonding interaction with the nitrogen atom to thereby lower the LUMO of the carbon–carbon double bond.[17e] Simultaneously, the tertiary amine unit in 5 b promotes the tautomerization of oxindole 3 into a nucleophilic enol form. As such, a dual activation of both reaction components by bifunctional catalyst 5 b allowed the nucleophilic addition to proceed via either TS-A-I or TS-A-II, generating the experimentally observed products 2. Since A-I is more thermodynamically stable than A-II in consideration of the steric repulsion between benzene ring and R1, the transition state TS-A-I was more favorably formed than TS-A-II to give the experimentally observed major diastereoisomer. However, the low energy barrier be2
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Scheme 3. Proposed intermediates to account for the observed stereochemistry. Scheme 2. Asymmetric substitution of 3-(1-tosylalkyl)indoles with oxindoles. Reaction conditions: 3 (0.10 mmol), 4 (0.11 mmol), K2CO3 (0.11 mmol), catalyst 5 b (10 mol % ), Et2O (1.0 mL). The ee values in parentheses are those observed for the minor diastereoisomer of 2.
(Piv) protecting group under basic conditions. Finally, (+)-trigolutes B was obtained after removal of the methyl group in spirooxindole 9 with BBr3. All of the spectroscopic data of the thus-synthesized trigolutes B (see the Supporting Information) were in agreement with those reported previously.[12] In summary, we have established a highly enantioselective organocatalytic substitution of 3-(1-tosylalkyl)indoles with oxindoles by using chiral bifunctional organocatalysts, to generate 3,3’-disubstituted oxindoles in excellent yields and enantioselectivities. The concise first asymmetric total synthesis of optically pure (+)-trigolutes B has been accomplished within seven steps with an 18 % overall yield by exploiting the transformation as the key step.[20]
tween intermediates A-I and A-II led to the moderate diastereoselectivity. The asymmetric substitution reaction established was ultimately applied to the enantioselective total synthesis of (+)-trigolutes B (Scheme 4). The transformation of (S,S)-2 ja[18] into 3,3’-disubstituted oxindole 6 could be accomplished by protection with Boc followed by removal of the benzoyl group, in 98 % yield over two steps. The obtained oxindole 6 was dihydroxylated with OsO4 and oxidized with NaIO4 to give aldehyde 7, which could be further transformed into alcohol 8 by a diastereoselective addition reaction with Grignard reagent prepared according to Knochel’s method.[19] The alcohol 8 was then converted into spirooxindole 9 in 73 % yield by intramolecular esterification and subsequent removal of the pivaloyl Chem. Eur. J. 2015, 21, 1 – 6
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Scheme 4. Total synthesis of (+)-trigolutes B. Conditions: a) Boc2O, 4-(dimethylamino)pyridine, CH2Cl2, RT; b) EtOH, NaH, 0 8C to RT; 98 % yield, 97 % ee; c) OsO4, dioxane/py, RT, then NaHSO3 ; d) NaIO4, CH3OH, RT, 12 h, 79 % yield, 97 % ee; e) ICH2OPiv, iPrMgCl, TMSCl, THF/BNP, 78 8C, 8 h 92 % yield, 96 % ee with single diastereoisomer; f) NaOH aq, CH3OH, RT, 8 h, 73 % yield 96 % ee; g) BBr3, CH2Cl2, RT, 12 h, 34 % yield, 96 % ee.
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[8]
Experimental Section
[9]
A suspension of 3-(1-tosylalkyl)indoles 4 (0.10 mmol), catalyst 5 b (10.0 mol %, 6.00 mg) and K2CO3 (0.11 mmol, 15.20 mg) in Et2O (1.00 mL) was stirred at room temperature for 15 min before oxindoles 3 (0.10 mmol) were added. The resulted mixture was stirred at RT for 48 h. The mixture was diluted with EtOAc (15 mL) and washed with H2O (10 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure and the crude product was purified by flash chromatography (eluent = 3:1 petroleum ether/ethyl acetate) on silica gel to give the product 2.
[10]
[11]
Acknowledgements We are grateful for financial support from the NSFC (21232007). Keywords: asymmetric·synthesis · enantioselectivity organocatalysis · spirooxindoles · total synthesis
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ukawa, E. Tokunaga, T. Matsumoto, M. Shiro, N. Shibata, Org. Lett. 2013, 15, 3282 – 3285; e) L. Jing, J. Wei, L. Zhou, Z. Huang, Z. Li, D. Wu, H. Xiang, X. Zhou, Chem. Eur. J. 2010, 16, 10955 – 10958; f) C.-W. Cai, X.-L. Zhu, S. Wu, Z.-L. Zuo, L.-L. Yu, D.-B. Qin, Q.-Z. Liu, L.-H. Jing, Eur. J. Org. Chem. 2013, 456 – 459. [18] The absolute configurations of 2 ka were determined by X-ray diffraction and the absolute configurations of (S, S)-2 ja was assigned by analogy with compound 2 ka (major). See the Supporting Information for details. [19] S. Avolio, C. Malan, I. Marek, P. Knochel, Synlett 1999, 1820 – 1822. [20] Calculated from (S,S)-2 ja.
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COMMUNICATION & Total Synthesis J.-Z. Huang, C.-L. Zhang, Y.-F. Zhu, L.-L. Li, D.-F. Chen && – &&Z.-Y. Han, L.-Z. Gong* && – && Organocatalytic Highly Enantioselective Substitution of 3-(1Tosylalkyl)indoles with Oxindoles Enables the First Total Synthesis of (+)-Trigolutes B
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A highly enantioselective organocatalytic substitution of 3-(1-tosylalkyl)indoles with oxindoles has been developed, providing an efficient approach
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to access highly enantioenriched 3,3’disubstituted oxindoles, which are used as the key step in the total synthesis of (+)-trigolutes B.
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Organocatalytic Highly Enantioselective Substitution of 3-(1Tosylalkyl)indoles with Oxindoles Enables the First Total Synthesis of (+)-Trigolutes B Jian-Zhou Huang,[a] Chen-Long Zhang,[a] Yi-Fan Zhu,[a] Lu-Lu Li,[a] Dian-Feng Chen,[a] Zhi-Yong Han,[a] and Liu-Zhu Gong*[a, b] Abstract: A highly enantioselective organocatalytic substitution of 3-(1-tosylalkyl)indoles with oxindoles has been established by using chiral bifunctional organocatalysts, providing an efficient entry to multiply functionalized 3,3’disubstituted oxindoles, and was exploited as the key step to enable the first asymmetric total synthesis of optically pure (+)-trigolutes B to be accomplished in a concise manner, within seven steps with an 18 % overall yield.
The spirooxindole core, a privileged nitrogen-containing heterocyclic ring system, is featured in a large number of natural products and pharmaceuticals, such as spirotryprostatins, horsfiline, gelsemine, gelseverine, rhynchophylline, and elacomine (Figure 1).[1] Given their diverse inherent bioactivities, the spirooxindole skeleton has drawn significant synthetic interest in the areas of both organic chemistry and pharmacology.[2] A variety of methodologies for the construction of the spirooxindole core, especially in an asymmetric fashion, have been well developed.[2d, 3] Williams and co-workers established chiral auxiliary-induced asymmetric cycloaddition strategies allowing for the asymmetric total synthesis of spirotryprostatin B and versicolamide B.[4] Our group accomplished a chiral phosphoric acid-catalyzed 1,3-dipolar cycloaddition to directly generate spriooxindoles in high enantioselectivities and structural diversity.[5] The groups of Trost,[6] Barbas,[7] and Antilla[8] have also developed spirooxindole-oriented enantioselective cycloaddition reactions for the syntheses of structurally diverse, optically active spirooxindoles. Other methods, including intramolecular Heck reaction,[9] cascade reaction,[10] and stepwise transforma-
Figure 1. Spirooxindole-containing natural products.
tion of 3,3’-disubstituted oxindoles,[11] have also greatly enriched the spectrum of spirooxindole skeletons. In 2013, two new types of spirooxindole alkaloids were isolated from the twigs of Trigonostemon lutescens and identified by Dai and co-workers.[12] These new spirooxindoles showed weak inhibitory activity and further biological studies indicated that they show good activity in the treatment of hemorrhagic fever with renal syndrome.[13] However, the total syntheses of these spirooxindole alkaloids have not been reported to date. Given our continuing interest in the asymmetric synthesis of bioactive heterocyclic compounds,[5, 14] we planned an asymmetric nucleophilic substitution for the total synthesis of trigolutes B. A retrosynthetic analysis (Scheme 1) implies that the spirooxindole skeleton could be prepared via dihydroxylation/ intramolecular esterification of the key intermediate 2, which was expected to be obtained directly from an enantioselective substitution reaction of 3-(1-tosylalkyl)indoles 4 with oxindole 3, presumably via an asymmetric conjugate addition pathway catalyzed by a bifunctional organocatalyst (TS-A, Scheme 1).[14a] The 3-allylideneindole intermediate A (in TS-A, Scheme 1), which could be readily generated by leaving group elimination of 4, turned out to be highly reactive toward various nucleophiles.[15] Although asymmetric conjugate addition to intermediate A has proven highly efficient in accessing optically active indole derivatives, the control of b and d-regioselectivity appears to be the most challenging issue in comparison with
[a] J.-Z. Huang, C.-L. Zhang, Y.-F. Zhu, L.-L. Li, D.-F. Chen, Z.-Y. Han, Prof. Dr. L.-Z. Gong Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and Technology of China Hefei, 230026 (P. R. China) Fax: (+ 86) 551-360-6266 E-mail: [email protected] Homepage: http://staff.ustc.edu.cn/ ~ gonglz/index.htm [b] Prof. Dr. L.-Z. Gong Collaborative Innovation Center of Chemical Science and Engineering (Tianjin) (P. R. China) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201500349. Chem. Eur. J. 2015, 21, 1 – 6
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Entry
Scheme 1. Retrosynthetic analysis for the synthesis of (+)-trigolutes B.
1 2 3 4 5 6 7 8 9[e] 10[f] 11[g] 12[h] 13[i]
previous conjugate addition reactions to 3-methyleneindole intermediates.[14b,c, 15–17] Herein, we report a highly enantioselective organocatalytic substitution of 3-(1-tosylalkyl)indoles 4 with oxindoles 3 and its application to the first and concise total synthesis of (+)-trigolutes B (Scheme 1). The initial investigations started with the evaluation of cinchona-derived bifunctional catalysts for the asymmetric substitution reaction of 3-(1-tosylalkyl)indole 4 a with oxindole 3 a in the presence of K3PO4 in toluene at room temperature (Table 1). To our delight, the reaction proceeded smoothly to specifically furnish b-selective addition product 2 aa and the thiourea-based bifunctional organocatalyst 5 b was able to give a much higher enantioselectivity than the urea 5 a (Table 1, entries 1 and 2). The N-protecting group of oxindoles also has considerable effect on the stereoselectivity (Table 1, entries 2–4). The N-Bz oxindole (3 c) provided comparably higher enantioselectivity than its counterparts (Table 1, entry 4 vs. entries 2 and 3). The screening of solvents indicated that Et2O enabled the diastereoselectivity to be slightly improved to 2.5:1 while maintaining excellent yield and enantioselectivity (Table 1, entries 5–8). Finally, the survey of inorganic bases found that the use of K2CO3 to replace K3PO4 as an acid scavenger led to the highest enantioselectivity (Table 1, entry 10 vs. entries 7, 9, and 11). Lowering the catalyst loading had no obvious effect on the enantioselectivity and led to a diminished yield (Table 1, entry 7 vs. entries 12 and 13). The optimized reaction conditions were then utilized for the asymmetric substitution reaction of a variety of substituted 3(1-tosylalkyl)indoles with substituted oxindoles (Scheme 2). Generally, this protocol tolerated a wide range of substituents on the oxindole moieties regardless of the electronic nature and thereby gave corresponding products in excellent yields and with excellent enantioselectivities (Scheme 2, 2 ca–2 ja). Interestingly, replacement of the ester in 3 with a cyano group was also permitted to undergo the transformation in excellent yield and with high stereoselectivity, as exemplified by 2 ka. In addition, the introduction of substituents at 3-(1-tosylalkyl)indoles was also allowed and participated in the asymmetric &
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3 5a 5b 5b 5b 5b 5b 5b 5b 5b 5b 5b 5b 5b
Solvent 3a 3a 3b 3c 3c 3c 3c 3c 3c 3c 3c 3c 3c
toluene toluene toluene toluene CH2Cl2 DCE Et2O THF Et2O Et2O Et2O Et2O Et2O
Yield [%][b] 85 85 99 98 97 98 93 88 82 95 98 68 36
d.r.[c] 1.9:1 1.5:1 1.3:1 1.3:1 1.7:1 1.7:1 2.5:1 1.9:1 1.7:1 2.5:1 2.0:1 2.5:1 2.5:1
ee [%][d] 36(68) 65(55) 92(64) 93(90) 96(90) 96(90) 97(90) 50(40) 97(90) 97(94) 94(85) 97(94) 97(94)
[a] Unless indicated otherwise, reaction conditions: 3 (0.10 mmol), 4 a (0.11 mmol), K3PO4(0.11 mmol), catalyst 5 (10 mol %), solvent (1.0 mL); [b] yield of isolated product; [c] diastereomeric ratio (d.r.) determined by 1 H NMR spectroscopy; [d] the ee values are those for the major diastereoisomer and those in parentheses are those for the minor diastereoisomer. The ee values were determined by HPLC analysis using a chiral stationary phase; [e] base = Na2CO3 ; [f] base = K2CO3 ; [g] base = KF; [h] 5 mol % of catalyst 5 b was used; [i] 2.5 mol % of catalyst 5 b was used.
substitution reaction to generate the desired products 2 cb and 2 cc in high yields and with excellent enantioselectivities. To understand the observed stereochemistry, a plausible mechanism of the asymmetric substitution reaction was proposed (Scheme 3). As indicated previously,[15] the vinylogous imine intermediate was generated from 4, as either a Z- or Eisomer (A-I or A-II), in the presence of inorganic base. The bifunctional catalyst 5 b activates A-I or A-II by a double hydrogen-bonding interaction with the nitrogen atom to thereby lower the LUMO of the carbon–carbon double bond.[17e] Simultaneously, the tertiary amine unit in 5 b promotes the tautomerization of oxindole 3 into a nucleophilic enol form. As such, a dual activation of both reaction components by bifunctional catalyst 5 b allowed the nucleophilic addition to proceed via either TS-A-I or TS-A-II, generating the experimentally observed products 2. Since A-I is more thermodynamically stable than A-II in consideration of the steric repulsion between benzene ring and R1, the transition state TS-A-I was more favorably formed than TS-A-II to give the experimentally observed major diastereoisomer. However, the low energy barrier be2
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Scheme 3. Proposed intermediates to account for the observed stereochemistry. Scheme 2. Asymmetric substitution of 3-(1-tosylalkyl)indoles with oxindoles. Reaction conditions: 3 (0.10 mmol), 4 (0.11 mmol), K2CO3 (0.11 mmol), catalyst 5 b (10 mol % ), Et2O (1.0 mL). The ee values in parentheses are those observed for the minor diastereoisomer of 2.
(Piv) protecting group under basic conditions. Finally, (+)-trigolutes B was obtained after removal of the methyl group in spirooxindole 9 with BBr3. All of the spectroscopic data of the thus-synthesized trigolutes B (see the Supporting Information) were in agreement with those reported previously.[12] In summary, we have established a highly enantioselective organocatalytic substitution of 3-(1-tosylalkyl)indoles with oxindoles by using chiral bifunctional organocatalysts, to generate 3,3’-disubstituted oxindoles in excellent yields and enantioselectivities. The concise first asymmetric total synthesis of optically pure (+)-trigolutes B has been accomplished within seven steps with an 18 % overall yield by exploiting the transformation as the key step.[20]
tween intermediates A-I and A-II led to the moderate diastereoselectivity. The asymmetric substitution reaction established was ultimately applied to the enantioselective total synthesis of (+)-trigolutes B (Scheme 4). The transformation of (S,S)-2 ja[18] into 3,3’-disubstituted oxindole 6 could be accomplished by protection with Boc followed by removal of the benzoyl group, in 98 % yield over two steps. The obtained oxindole 6 was dihydroxylated with OsO4 and oxidized with NaIO4 to give aldehyde 7, which could be further transformed into alcohol 8 by a diastereoselective addition reaction with Grignard reagent prepared according to Knochel’s method.[19] The alcohol 8 was then converted into spirooxindole 9 in 73 % yield by intramolecular esterification and subsequent removal of the pivaloyl Chem. Eur. J. 2015, 21, 1 – 6
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[3] [4]
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Scheme 4. Total synthesis of (+)-trigolutes B. Conditions: a) Boc2O, 4-(dimethylamino)pyridine, CH2Cl2, RT; b) EtOH, NaH, 0 8C to RT; 98 % yield, 97 % ee; c) OsO4, dioxane/py, RT, then NaHSO3 ; d) NaIO4, CH3OH, RT, 12 h, 79 % yield, 97 % ee; e) ICH2OPiv, iPrMgCl, TMSCl, THF/BNP, 78 8C, 8 h 92 % yield, 96 % ee with single diastereoisomer; f) NaOH aq, CH3OH, RT, 8 h, 73 % yield 96 % ee; g) BBr3, CH2Cl2, RT, 12 h, 34 % yield, 96 % ee.
[7]
[8]
Experimental Section
[9]
A suspension of 3-(1-tosylalkyl)indoles 4 (0.10 mmol), catalyst 5 b (10.0 mol %, 6.00 mg) and K2CO3 (0.11 mmol, 15.20 mg) in Et2O (1.00 mL) was stirred at room temperature for 15 min before oxindoles 3 (0.10 mmol) were added. The resulted mixture was stirred at RT for 48 h. The mixture was diluted with EtOAc (15 mL) and washed with H2O (10 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure and the crude product was purified by flash chromatography (eluent = 3:1 petroleum ether/ethyl acetate) on silica gel to give the product 2.
[10]
[11]
Acknowledgements We are grateful for financial support from the NSFC (21232007). Keywords: asymmetric·synthesis · enantioselectivity organocatalysis · spirooxindoles · total synthesis
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ukawa, E. Tokunaga, T. Matsumoto, M. Shiro, N. Shibata, Org. Lett. 2013, 15, 3282 – 3285; e) L. Jing, J. Wei, L. Zhou, Z. Huang, Z. Li, D. Wu, H. Xiang, X. Zhou, Chem. Eur. J. 2010, 16, 10955 – 10958; f) C.-W. Cai, X.-L. Zhu, S. Wu, Z.-L. Zuo, L.-L. Yu, D.-B. Qin, Q.-Z. Liu, L.-H. Jing, Eur. J. Org. Chem. 2013, 456 – 459. [18] The absolute configurations of 2 ka were determined by X-ray diffraction and the absolute configurations of (S, S)-2 ja was assigned by analogy with compound 2 ka (major). See the Supporting Information for details. [19] S. Avolio, C. Malan, I. Marek, P. Knochel, Synlett 1999, 1820 – 1822. [20] Calculated from (S,S)-2 ja.
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COMMUNICATION & Total Synthesis J.-Z. Huang, C.-L. Zhang, Y.-F. Zhu, L.-L. Li, D.-F. Chen && – &&Z.-Y. Han, L.-Z. Gong* && – && Organocatalytic Highly Enantioselective Substitution of 3-(1Tosylalkyl)indoles with Oxindoles Enables the First Total Synthesis of (+)-Trigolutes B
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A highly enantioselective organocatalytic substitution of 3-(1-tosylalkyl)indoles with oxindoles has been developed, providing an efficient approach
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to access highly enantioenriched 3,3’disubstituted oxindoles, which are used as the key step in the total synthesis of (+)-trigolutes B.
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