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Cite this: Chem. Commun., 2014, 50, 13585 Received 25th August 2014, Accepted 15th September 2014
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A cation-directed two-component cascade approach to enantioenriched pyrroloindolines† Jamie R. Wolstenhulme, Alex Cavell, Matija Gredic ˇak, Russell W. Driver and Martin D. Smith*
DOI: 10.1039/c4cc06683a www.rsc.org/chemcomm
A cascade approach to complex pyrroloindolines bearing all-carbon quaternary stereocentres has been developed. This two-component process uses a chiral ammonium salt to control diastereo- and enantioselectivity in the addition of isocyanides to functionalized alkenes to afford pyrroloindolines with up to three stereocentres. A mechanistic proposal involving intramolecular hydrogen bond activation of the isocyanide is described.
New methods for the rapid and stereoselective construction of complex organic frameworks from simple starting materials are valuable for target-oriented synthesis and the discovery of bioactive entities. As part of an on-going programme into the development of new asymmetric phase transfer catalysed reactions, we recently reported the synthesis of indolenines using the intramolecular cyclization of a cyanocarbanion onto an isocyanide,1 and subsequently extended this method to encompass the cascade synthesis of pyrroloindolines bearing all-carbon quaternary stereocentres (Fig. 1).2,3
Fig. 1
Strategy for cascade assembly of pyrroloindolines.
Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK. E-mail: [email protected] † Electronic supplementary information (ESI) available: Full experimental details, 1 H and 13C NMR spectra and X-ray data. CCDC 1020472–1020476. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc06683a
This journal is © The Royal Society of Chemistry 2014
In both of these processes, a chiral ammonium salt controls the topicity of the cyclization, with concomitant activation of the isocyanide though hydrogen bonding (either via the substrate or the catalyst).4 This approach is complementary to existing methods such as C-3 arylation5 or synthesis from the chiral pool, which have been demonstrated to be effective in the synthesis of complex pyrroloindoline-containing natural products.6 Here we report an enantioselective two-component cascade to form pyrroloindolines containing three stereocentres, two of which are quaternary. We reasoned that an isocyanide component could be deprotonated under basic conditions in the presence of a chiral ammonium salt to form an ion pair, which could undergo an asymmetric Michael addition to an a,b-unsaturated ester.7 The enolate thus generated could subsequently cyclize onto the isocyanide to form an intermediate pyrroline that can then be trapped by the adjacent N-protected aniline to form a pyrroloindoline. This approach has the potential to assemble the entire pyrroloindoline ring system from simple and readily available precursors in a single operation. We began to explore the potential of this proposal by examining the 1,4-addition of disubstituted symmetrical isocyanides 2 (Table 1). Our preliminary investigations revealed that a,a-diaryl isocyanides readily underwent the cascade in the presence of tetra n-butyl ammonium bromide (TBAB) and potassium carbonate to afford a single cis-fused diastereoisomer (as exemplified by 3), presumably due to the ring strain associated with the alternative trans 5,5-ring junction. The poor reactivity observed in the formation of 5 (22% isolated yield and 30% conversion of isocyanide)8 confirmed our speculation that the acidity of the isocyanide component could be important in the reaction, with relatively electron-poor isocyanides delivering pyrroloindolines such as 4, 6 and 7 in reasonable to good isolated yields.9 The relationship between isocyanide acidity and overall conversion observed in these preliminary investigations indicated that ease of deprotonation could be a key consideration in the development of a cascade that involved non-symmetric isocyanide components. We were also interested to probe the effect of altering the aniline N-substituent and its ability to function as a hydrogen bond donor.
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Table 1 Preliminary cascade development. Conditions: 1 (1.0 eq.), 2 (1.0 eq.), TBAB (10 mol%), PhMe, K2CO3 (5.0 eq.), r.t., 16 h. Yields are for isolated material
a
Reaction time was 3 days.
Initially, we employed alkyl-substituted isocyanides derived from valine and phenylalanine (R = isopropyl and benzyl respectively) to evaluate their efficiency in our proposed cascade (Table 2). Table 2 Diastereoselective synthesis of pyrroloindolines. Conditions: Michael acceptor 8 (1.0 eq.), isocyanide 9 (1.0 eq.), TBAB (10 mol%), PhMe, K2CO3 (5.0 eq.), r.t., 2–24 h. d.r. determined by 1H NMR spectroscopy
a
KOH (25% w/w, aq.) was used as base.
13586 | Chem. Commun., 2014, 50, 13585--13588
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Treatment of a 1 : 1 mixture of isocyanide and a,b-unsaturated ester in the presence of TBAB and potassium carbonate in toluene afforded 11 and 12 in good yield, but in both cases as a 1 : 1 mixture of diastereoisomers. Gratifyingly, replacing the alkyl substituent with an aryl group was rewarded with a dramatic increase in diastereoselectivity. Pyrroloindolines 13 and 14, featuring 2-nitro-5-fluoro and 2-nitro-5-methyl aromatic substituents respectively were isolated in good yields as a single diastereoisomer (420 : 1 by 1H NMR spectroscopy). We were able to confirm the relative stereochemistry of 13 and 14 through X-ray crystallographic analysis,10 which demonstrated that the methyl ester group occupied the concave side of the pyrroloindoline scaffold, opposite to the isopropyl ester group.11 The selectivity observed for this substrate was consistent with other aryl-substituted isocyanides; this allowed the synthesis of pyrroloindolines 17–21 as a single diastereoisomer. Substitution on the Michael acceptor aryl ring was welltolerated, yielding 15 and 18 in 61% and 48% yields respectively and with the same diastereoselectivity as previously observed. Pleasingly, the nitro group in 16 could be replaced by a CF3 group (to afford 20) or an electron donating OMe group (to give 17). Changing the aniline N-substituent from a carbamate to an amide (as in 19) or a urea (as in 21) was also successful, generating pyrroloindoline products with three stereocentres as a single diastereoisomer. With conditions for the diastereoselective cascade in hand, we decided to
Table 3 Enantioselective reaction optimization. Conditions: 22 (1.0 eq.), 23 (1.1 eq.), catalyst (10 mol%), r.t., 24 h. d.r. determined by 1H NMR spectroscopy. e.r. determined by chiral stationary phase HPLC
Entry
Catalyst
Base (eq.)
Solvent
e.r.
1 2 3 4 5 6 7 8 9 10 11 12 13a
24 24 24 24 24 30 25 31 26 28 27 29 29
K2CO3 (5) K2CO3 (5) Na2CO3 (5) Cs2CO3 (5) K2CO3 (10) K2CO3 (5) K2CO3 (5) K2CO3 (5) K2CO3 (5) K2CO3 (5) K2CO3 (5) K2CO3 (5) K2CO3 (5)
Toluene m-Xylene m-Xylene m-Xylene m-Xylene Toluene Toluene Toluene Toluene Toluene Toluene Toluene Tol./CHCl3/H2Ob
80 : 20 82 : 18 n.r. 65 : 35 82 : 18 25 : 75 81 : 19 23 : 77 57 : 43 23 : 77 68 : 32 87 : 13 91 : 9
a
Reaction was performed at
20 1C.
b
Solvent ratio 15 : 4 : 1 respectively.
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examine the potential for an enantioselective catalytic transformation. Preliminary studies revealed that a urea was the most effective N-substituent for the cyclization and hence we used substrate 22 and isocyanide 23 in our search (Table 3). A survey of solvent and base combinations identified non-polar aromatic solvents and solid potassium carbonate as optimum (entry 1), together with cinchona-derived ammonium salts. Probing the effect of different catalyst N-alkyl groups (entries 6–13) demonstrated that electron-poor benzylic groups on a quinidinium scaffold were most enantioselective, yielding 21 in 91 : 9 e.r. The addition of chloroform as a co-solvent was advantageous, likely aiding solubility of the urea substrate. With optimum conditions for the preparation of 21 established, the scope of the enantioselective reaction was explored using a range of a-aryl substituted isocyanides (Table 4). In general the reaction is very effective, furnishing pyrroloindolines in good yield and generally good to excellent diastereoselectivity as well as high enantioselectivity. The reaction is tolerant of different ester groups on the isocyanide; changing from Me to Bn to iPr esters led to pyrroloindolines 21, 32 and 34 respectively, all as a single diastereoisomer and with high levels of enantiocontrol (e.r. up to 93 : 7). A limitation of the enantioselective transformation is that an ortho-nitro group is required for Table 4 Enantioselective pyrroloindoline formation. Conditions: Michael acceptor (1.0 eq.), isocyanide (1.1 eq.), catalyst 29 (10 mol%), PhMe : CHCl3 : H2O 15 : 4 : 1, K2CO3 (5.0 eq.), 20 1C, 48 h. d.r. determined by 1H NMR spectroscopy. e.r. determined by chiral stationary phase HPLC. e.r. reported for the major diastereoisomer
satisfactory results (as in 33). It may be that the extra acidity that an o-nitroaryl substituent imparts is necessary for reactions involving cinchona alkaloid derived ammonium salts; these are generally considered to exhibit poorer reactivity in base-mediated reactions than simple alkylammonium salts.12 The scalability of the reaction was demonstrated by the gram scale synthesis of 34, which was formed as a single diastereoisomer in 76% yield and 92 : 8 e.r. During these asymmetric cascade processes we also observed the formation of another compound in trace amounts, particularly with longer reaction times (Scheme 1). This was subsequently identified by X-ray crystallography as spirocyclic pyrroline 39. This material was isolated with the same d.r. and e.r. as the pyrroloindoline 21,13 and hence we speculated that it might arise from a subsequent transformation of the pyrroloindoline itself (Scheme 1). Consequently, we treated 21 with TBAB and observed smooth conversion to 39 over 48 h, once again without change in d.r. or e.r. With this information we are able to propose a plausible mechanism for the cascade reaction (Scheme 2). Initial enantiodetermining Michael addition of isocyanocarbanion 40 onto the a,b-unsaturated ester 41 is effectively irreversible when mediated with cinchona alkaloids. The resultant intermediate ester enolate 42 can then undergo a diastereoselective 5-endo-dig cyclization onto the isocyanide, which is activated through intramolecular hydrogen bonding from the acylated aniline as in 43. This preferentially orientates
Scheme 1 Unanticipated rearrangement. Conditions: TBAB (20 mol%), PhMe, K2CO3 (5.0 eq.), r.t., 48 h.
a Reaction was performed at 0 1C. 1 g scale.
b
Reaction was performed on a
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Scheme 2
Proposed mechanistic pathway.
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the smaller (ester) group on the more hindered concave face of the nascent bicycle rather than the larger aryl substituent. It is interesting to speculate whether the chiral cation is influential in the diastereoselective pyrroline-forming reaction or whether this is directed exclusively by the existing stereocentre. Once the pyrroline has been formed in 44, ring closure to form the pyrroloindoline skeleton inevitably leads to the cis-fused bicycle 45 due to the increased strain associated with the alternative trans-isomer. The spirocycle 46 is likely formed through reversible ring closing and ring opening of the indoline ring, with subsequent trapping of the aniline nitrogen onto the benzylic ester, giving rise to the amide as the thermodynamic product. In conclusion, we have developed an enantioselective twocomponent approach to the synthesis of pyrroloindolines. This cascade process, which exploits the remarkable reactivity profile of the isocyanide functional group, offers a rapid and stereoselective approach to highly functionalized scaffolds that may find application as natural product analogues and frameworks for the discovery of bioactive compounds. The European Research Council has provided financial support (FP7/2007-2013)/ERC grant agreement no. 259056. This work was supported by EPSRC and NSF (CHE-1026826), and the Croatian Science Foundation (to M.G., grant no. 02.03./158). We gratefully acknowledge the Diamond Light Source for an award of instrument time on I19 (MT7768). We are grateful to Keishi Kohara for helpful preliminary studies.
Notes and references 1 (a) E. E. Maciver, P. C. Knipe, A. P. Cridland, A. L. Thompson and M. D. Smith, Chem. Sci., 2012, 3, 537; (b) M. Li, P. A. Woods and M. D. Smith, Chem. Sci., 2013, 4, 2907. ˇak, A. Cernijenko, R. S. Paton and M. D. Smith, 2 P. C. Knipe, M. Gredic Chem. – Eur. J., 2014, 20, 3005. 3 For a review of catalytic methods for the synthesis of pyrroloindolines see: L. M. Repka and S. E. Reisman, J. Org. Chem., 2013, 78, 12314.
13588 | Chem. Commun., 2014, 50, 13585--13588
ChemComm 4 For phase transfer catalysts bearing Brønsted acidic groups see: ´ndez and J. M. Lassaletta, Chem. – Eur. J., 2010, (a) P. Bernal, R. Ferna 16, 7714; (b) K. M. Johnson, M. S. Rattley, F. Sladojevich, D. M. ˜ez, A. M. Goldys and D. J. Dixon, Org. Lett., 2012, Barber, M. G. Nun 14, 2492; (c) H.-Y. Wang, J.-X. Zhang, D.-D. Cao and G. Zhao, ACS Catal., 2013, 3, 2218; (d) J. Novacek and M. Waser, Eur. J. Org. Chem., 2014, 802; (e) S. Shirakawa, T. Tokuda, A. Kasai and K. Maruoka, Org. Lett., 2013, 15, 3350. 5 (a) S. Zhu and D. W. C. MacMillan, J. Am. Chem. Soc., 2012, 134, 10815; (b) A. Bigot, A. E. Williamson and M. J. Gaunt, J. Am. Chem. Soc., 2011, 133, 13778; (c) M. E. Kieffer, K. V. Chuang and S. E. Reisman, Chem. Sci., 2012, 3, 3170. 6 (a) N. Boyer and M. Movassaghi, Chem. Sci., 2012, 3, 1798; (b) W. Zi, W. Xie and D. Ma, J. Am. Chem. Soc., 2012, 134, 9126; (c) H. Mitsunuma, M. Shibasaki, M. Kanai and S. Matsunaga, Angew. Chem., Int. Ed., 2012, 51, 5217; (d) S. Y. Jabri and L. E. Overman, J. Am. Chem. Soc., 2013, 135, 4231. 7 For organocatalytic reactions involving 1,4 addition of isocyanides see: (a) C. Guo, M.-X. Xue, M.-K. Zhu and L.-Z. Gong, Angew. Chem., Int. Ed., 2008, 47, 3414; (b) M.-X. Xue, C. Guo and L.-Z. Gong, Synlett, 2009, 2191; (c) S. Nakamura, Y. Maeno, M. Ohara, A. Yamamura, Y. Funahashi and N. Shibata, Org. Lett., 2012, 14, 2960; (d) L.-L. Wang, J.-F. Bai, L. Peng, L.-W. Qi, L.-N. Jia, Y.-L. Guo, X.-Y. Luo, X.-Y. Xu and L.-X. Wang, Chem. Commun., 2012, 48, 5175. 8 Complete consumption of the Michael acceptor was observed in this reaction. 9 It is likely that the acidity of isonitriles affects the concentration of reactive isocyanocarbanion in the organic phase (which ultimately affects the rate of 1,4-addition). For the fluorenyl and di(chloroaryl) isocyanides, complete consumption of isocyanide was observed but a byproduct (likely carbene-derived) was also isolated in 34% and 25% yields respectively; see ESI† for full details. 10 X-ray crystal data for 13, 14 and 39 (CCDC 1020472, 1020473 and 1020474 respectively). Crystal data for two diastereoisomeric spirocycles analogous to 39 is also included (CCDC 1020475 and 1020476 respectively). 11 The relative stereochemistry of other examples was assigned by analogy to the X-ray structures of 13 and 14. We also observed a diagnostic chemical shift of the 5,5-ring junction proton in 1H NMR spectra which was used as further confirmation of stereochemical outcome. See ESI† for further details. 12 M. Rabinovitz, Y. Cohen and M. Halpern, Angew. Chem., Int. Ed. Engl., 1986, 25, 960. 13 In a control reaction we found that subjecting enantioenriched 21 (87 : 13 e.r.) to the reaction conditions using TBAB (r.t.) resulted in only a small erosion of e.r. (to 85 : 15) in recovered 21.
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COMMUNICATION
Cite this: Chem. Commun., 2014, 50, 13585 Received 25th August 2014, Accepted 15th September 2014
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A cation-directed two-component cascade approach to enantioenriched pyrroloindolines† Jamie R. Wolstenhulme, Alex Cavell, Matija Gredic ˇak, Russell W. Driver and Martin D. Smith*
DOI: 10.1039/c4cc06683a www.rsc.org/chemcomm
A cascade approach to complex pyrroloindolines bearing all-carbon quaternary stereocentres has been developed. This two-component process uses a chiral ammonium salt to control diastereo- and enantioselectivity in the addition of isocyanides to functionalized alkenes to afford pyrroloindolines with up to three stereocentres. A mechanistic proposal involving intramolecular hydrogen bond activation of the isocyanide is described.
New methods for the rapid and stereoselective construction of complex organic frameworks from simple starting materials are valuable for target-oriented synthesis and the discovery of bioactive entities. As part of an on-going programme into the development of new asymmetric phase transfer catalysed reactions, we recently reported the synthesis of indolenines using the intramolecular cyclization of a cyanocarbanion onto an isocyanide,1 and subsequently extended this method to encompass the cascade synthesis of pyrroloindolines bearing all-carbon quaternary stereocentres (Fig. 1).2,3
Fig. 1
Strategy for cascade assembly of pyrroloindolines.
Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK. E-mail: [email protected] † Electronic supplementary information (ESI) available: Full experimental details, 1 H and 13C NMR spectra and X-ray data. CCDC 1020472–1020476. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc06683a
This journal is © The Royal Society of Chemistry 2014
In both of these processes, a chiral ammonium salt controls the topicity of the cyclization, with concomitant activation of the isocyanide though hydrogen bonding (either via the substrate or the catalyst).4 This approach is complementary to existing methods such as C-3 arylation5 or synthesis from the chiral pool, which have been demonstrated to be effective in the synthesis of complex pyrroloindoline-containing natural products.6 Here we report an enantioselective two-component cascade to form pyrroloindolines containing three stereocentres, two of which are quaternary. We reasoned that an isocyanide component could be deprotonated under basic conditions in the presence of a chiral ammonium salt to form an ion pair, which could undergo an asymmetric Michael addition to an a,b-unsaturated ester.7 The enolate thus generated could subsequently cyclize onto the isocyanide to form an intermediate pyrroline that can then be trapped by the adjacent N-protected aniline to form a pyrroloindoline. This approach has the potential to assemble the entire pyrroloindoline ring system from simple and readily available precursors in a single operation. We began to explore the potential of this proposal by examining the 1,4-addition of disubstituted symmetrical isocyanides 2 (Table 1). Our preliminary investigations revealed that a,a-diaryl isocyanides readily underwent the cascade in the presence of tetra n-butyl ammonium bromide (TBAB) and potassium carbonate to afford a single cis-fused diastereoisomer (as exemplified by 3), presumably due to the ring strain associated with the alternative trans 5,5-ring junction. The poor reactivity observed in the formation of 5 (22% isolated yield and 30% conversion of isocyanide)8 confirmed our speculation that the acidity of the isocyanide component could be important in the reaction, with relatively electron-poor isocyanides delivering pyrroloindolines such as 4, 6 and 7 in reasonable to good isolated yields.9 The relationship between isocyanide acidity and overall conversion observed in these preliminary investigations indicated that ease of deprotonation could be a key consideration in the development of a cascade that involved non-symmetric isocyanide components. We were also interested to probe the effect of altering the aniline N-substituent and its ability to function as a hydrogen bond donor.
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Table 1 Preliminary cascade development. Conditions: 1 (1.0 eq.), 2 (1.0 eq.), TBAB (10 mol%), PhMe, K2CO3 (5.0 eq.), r.t., 16 h. Yields are for isolated material
a
Reaction time was 3 days.
Initially, we employed alkyl-substituted isocyanides derived from valine and phenylalanine (R = isopropyl and benzyl respectively) to evaluate their efficiency in our proposed cascade (Table 2). Table 2 Diastereoselective synthesis of pyrroloindolines. Conditions: Michael acceptor 8 (1.0 eq.), isocyanide 9 (1.0 eq.), TBAB (10 mol%), PhMe, K2CO3 (5.0 eq.), r.t., 2–24 h. d.r. determined by 1H NMR spectroscopy
a
KOH (25% w/w, aq.) was used as base.
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Treatment of a 1 : 1 mixture of isocyanide and a,b-unsaturated ester in the presence of TBAB and potassium carbonate in toluene afforded 11 and 12 in good yield, but in both cases as a 1 : 1 mixture of diastereoisomers. Gratifyingly, replacing the alkyl substituent with an aryl group was rewarded with a dramatic increase in diastereoselectivity. Pyrroloindolines 13 and 14, featuring 2-nitro-5-fluoro and 2-nitro-5-methyl aromatic substituents respectively were isolated in good yields as a single diastereoisomer (420 : 1 by 1H NMR spectroscopy). We were able to confirm the relative stereochemistry of 13 and 14 through X-ray crystallographic analysis,10 which demonstrated that the methyl ester group occupied the concave side of the pyrroloindoline scaffold, opposite to the isopropyl ester group.11 The selectivity observed for this substrate was consistent with other aryl-substituted isocyanides; this allowed the synthesis of pyrroloindolines 17–21 as a single diastereoisomer. Substitution on the Michael acceptor aryl ring was welltolerated, yielding 15 and 18 in 61% and 48% yields respectively and with the same diastereoselectivity as previously observed. Pleasingly, the nitro group in 16 could be replaced by a CF3 group (to afford 20) or an electron donating OMe group (to give 17). Changing the aniline N-substituent from a carbamate to an amide (as in 19) or a urea (as in 21) was also successful, generating pyrroloindoline products with three stereocentres as a single diastereoisomer. With conditions for the diastereoselective cascade in hand, we decided to
Table 3 Enantioselective reaction optimization. Conditions: 22 (1.0 eq.), 23 (1.1 eq.), catalyst (10 mol%), r.t., 24 h. d.r. determined by 1H NMR spectroscopy. e.r. determined by chiral stationary phase HPLC
Entry
Catalyst
Base (eq.)
Solvent
e.r.
1 2 3 4 5 6 7 8 9 10 11 12 13a
24 24 24 24 24 30 25 31 26 28 27 29 29
K2CO3 (5) K2CO3 (5) Na2CO3 (5) Cs2CO3 (5) K2CO3 (10) K2CO3 (5) K2CO3 (5) K2CO3 (5) K2CO3 (5) K2CO3 (5) K2CO3 (5) K2CO3 (5) K2CO3 (5)
Toluene m-Xylene m-Xylene m-Xylene m-Xylene Toluene Toluene Toluene Toluene Toluene Toluene Toluene Tol./CHCl3/H2Ob
80 : 20 82 : 18 n.r. 65 : 35 82 : 18 25 : 75 81 : 19 23 : 77 57 : 43 23 : 77 68 : 32 87 : 13 91 : 9
a
Reaction was performed at
20 1C.
b
Solvent ratio 15 : 4 : 1 respectively.
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examine the potential for an enantioselective catalytic transformation. Preliminary studies revealed that a urea was the most effective N-substituent for the cyclization and hence we used substrate 22 and isocyanide 23 in our search (Table 3). A survey of solvent and base combinations identified non-polar aromatic solvents and solid potassium carbonate as optimum (entry 1), together with cinchona-derived ammonium salts. Probing the effect of different catalyst N-alkyl groups (entries 6–13) demonstrated that electron-poor benzylic groups on a quinidinium scaffold were most enantioselective, yielding 21 in 91 : 9 e.r. The addition of chloroform as a co-solvent was advantageous, likely aiding solubility of the urea substrate. With optimum conditions for the preparation of 21 established, the scope of the enantioselective reaction was explored using a range of a-aryl substituted isocyanides (Table 4). In general the reaction is very effective, furnishing pyrroloindolines in good yield and generally good to excellent diastereoselectivity as well as high enantioselectivity. The reaction is tolerant of different ester groups on the isocyanide; changing from Me to Bn to iPr esters led to pyrroloindolines 21, 32 and 34 respectively, all as a single diastereoisomer and with high levels of enantiocontrol (e.r. up to 93 : 7). A limitation of the enantioselective transformation is that an ortho-nitro group is required for Table 4 Enantioselective pyrroloindoline formation. Conditions: Michael acceptor (1.0 eq.), isocyanide (1.1 eq.), catalyst 29 (10 mol%), PhMe : CHCl3 : H2O 15 : 4 : 1, K2CO3 (5.0 eq.), 20 1C, 48 h. d.r. determined by 1H NMR spectroscopy. e.r. determined by chiral stationary phase HPLC. e.r. reported for the major diastereoisomer
satisfactory results (as in 33). It may be that the extra acidity that an o-nitroaryl substituent imparts is necessary for reactions involving cinchona alkaloid derived ammonium salts; these are generally considered to exhibit poorer reactivity in base-mediated reactions than simple alkylammonium salts.12 The scalability of the reaction was demonstrated by the gram scale synthesis of 34, which was formed as a single diastereoisomer in 76% yield and 92 : 8 e.r. During these asymmetric cascade processes we also observed the formation of another compound in trace amounts, particularly with longer reaction times (Scheme 1). This was subsequently identified by X-ray crystallography as spirocyclic pyrroline 39. This material was isolated with the same d.r. and e.r. as the pyrroloindoline 21,13 and hence we speculated that it might arise from a subsequent transformation of the pyrroloindoline itself (Scheme 1). Consequently, we treated 21 with TBAB and observed smooth conversion to 39 over 48 h, once again without change in d.r. or e.r. With this information we are able to propose a plausible mechanism for the cascade reaction (Scheme 2). Initial enantiodetermining Michael addition of isocyanocarbanion 40 onto the a,b-unsaturated ester 41 is effectively irreversible when mediated with cinchona alkaloids. The resultant intermediate ester enolate 42 can then undergo a diastereoselective 5-endo-dig cyclization onto the isocyanide, which is activated through intramolecular hydrogen bonding from the acylated aniline as in 43. This preferentially orientates
Scheme 1 Unanticipated rearrangement. Conditions: TBAB (20 mol%), PhMe, K2CO3 (5.0 eq.), r.t., 48 h.
a Reaction was performed at 0 1C. 1 g scale.
b
Reaction was performed on a
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Scheme 2
Proposed mechanistic pathway.
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the smaller (ester) group on the more hindered concave face of the nascent bicycle rather than the larger aryl substituent. It is interesting to speculate whether the chiral cation is influential in the diastereoselective pyrroline-forming reaction or whether this is directed exclusively by the existing stereocentre. Once the pyrroline has been formed in 44, ring closure to form the pyrroloindoline skeleton inevitably leads to the cis-fused bicycle 45 due to the increased strain associated with the alternative trans-isomer. The spirocycle 46 is likely formed through reversible ring closing and ring opening of the indoline ring, with subsequent trapping of the aniline nitrogen onto the benzylic ester, giving rise to the amide as the thermodynamic product. In conclusion, we have developed an enantioselective twocomponent approach to the synthesis of pyrroloindolines. This cascade process, which exploits the remarkable reactivity profile of the isocyanide functional group, offers a rapid and stereoselective approach to highly functionalized scaffolds that may find application as natural product analogues and frameworks for the discovery of bioactive compounds. The European Research Council has provided financial support (FP7/2007-2013)/ERC grant agreement no. 259056. This work was supported by EPSRC and NSF (CHE-1026826), and the Croatian Science Foundation (to M.G., grant no. 02.03./158). We gratefully acknowledge the Diamond Light Source for an award of instrument time on I19 (MT7768). We are grateful to Keishi Kohara for helpful preliminary studies.
Notes and references 1 (a) E. E. Maciver, P. C. Knipe, A. P. Cridland, A. L. Thompson and M. D. Smith, Chem. Sci., 2012, 3, 537; (b) M. Li, P. A. Woods and M. D. Smith, Chem. Sci., 2013, 4, 2907. ˇak, A. Cernijenko, R. S. Paton and M. D. Smith, 2 P. C. Knipe, M. Gredic Chem. – Eur. J., 2014, 20, 3005. 3 For a review of catalytic methods for the synthesis of pyrroloindolines see: L. M. Repka and S. E. Reisman, J. Org. Chem., 2013, 78, 12314.
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ChemComm 4 For phase transfer catalysts bearing Brønsted acidic groups see: ´ndez and J. M. Lassaletta, Chem. – Eur. J., 2010, (a) P. Bernal, R. Ferna 16, 7714; (b) K. M. Johnson, M. S. Rattley, F. Sladojevich, D. M. ˜ez, A. M. Goldys and D. J. Dixon, Org. Lett., 2012, Barber, M. G. Nun 14, 2492; (c) H.-Y. Wang, J.-X. Zhang, D.-D. Cao and G. Zhao, ACS Catal., 2013, 3, 2218; (d) J. Novacek and M. Waser, Eur. J. Org. Chem., 2014, 802; (e) S. Shirakawa, T. Tokuda, A. Kasai and K. Maruoka, Org. Lett., 2013, 15, 3350. 5 (a) S. Zhu and D. W. C. MacMillan, J. Am. Chem. Soc., 2012, 134, 10815; (b) A. Bigot, A. E. Williamson and M. J. Gaunt, J. Am. Chem. Soc., 2011, 133, 13778; (c) M. E. Kieffer, K. V. Chuang and S. E. Reisman, Chem. Sci., 2012, 3, 3170. 6 (a) N. Boyer and M. Movassaghi, Chem. Sci., 2012, 3, 1798; (b) W. Zi, W. Xie and D. Ma, J. Am. Chem. Soc., 2012, 134, 9126; (c) H. Mitsunuma, M. Shibasaki, M. Kanai and S. Matsunaga, Angew. Chem., Int. Ed., 2012, 51, 5217; (d) S. Y. Jabri and L. E. Overman, J. Am. Chem. Soc., 2013, 135, 4231. 7 For organocatalytic reactions involving 1,4 addition of isocyanides see: (a) C. Guo, M.-X. Xue, M.-K. Zhu and L.-Z. Gong, Angew. Chem., Int. Ed., 2008, 47, 3414; (b) M.-X. Xue, C. Guo and L.-Z. Gong, Synlett, 2009, 2191; (c) S. Nakamura, Y. Maeno, M. Ohara, A. Yamamura, Y. Funahashi and N. Shibata, Org. Lett., 2012, 14, 2960; (d) L.-L. Wang, J.-F. Bai, L. Peng, L.-W. Qi, L.-N. Jia, Y.-L. Guo, X.-Y. Luo, X.-Y. Xu and L.-X. Wang, Chem. Commun., 2012, 48, 5175. 8 Complete consumption of the Michael acceptor was observed in this reaction. 9 It is likely that the acidity of isonitriles affects the concentration of reactive isocyanocarbanion in the organic phase (which ultimately affects the rate of 1,4-addition). For the fluorenyl and di(chloroaryl) isocyanides, complete consumption of isocyanide was observed but a byproduct (likely carbene-derived) was also isolated in 34% and 25% yields respectively; see ESI† for full details. 10 X-ray crystal data for 13, 14 and 39 (CCDC 1020472, 1020473 and 1020474 respectively). Crystal data for two diastereoisomeric spirocycles analogous to 39 is also included (CCDC 1020475 and 1020476 respectively). 11 The relative stereochemistry of other examples was assigned by analogy to the X-ray structures of 13 and 14. We also observed a diagnostic chemical shift of the 5,5-ring junction proton in 1H NMR spectra which was used as further confirmation of stereochemical outcome. See ESI† for further details. 12 M. Rabinovitz, Y. Cohen and M. Halpern, Angew. Chem., Int. Ed. Engl., 1986, 25, 960. 13 In a control reaction we found that subjecting enantioenriched 21 (87 : 13 e.r.) to the reaction conditions using TBAB (r.t.) resulted in only a small erosion of e.r. (to 85 : 15) in recovered 21.
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