RSCPublishing ARTICLE An asymmetric pericyclic cascade approach to 3-alkyl-3-aryloxindoles; generality, applications Cite this: DOI: 10.1039/x0xx00000x and mechanistic investigations Edward Richmond,a Kenneth B. Ling,a Nicolas Duguet,a Lois B. Manton,a Nihan Received 00th January 2012, Çelebi-Ölçüm,b,c Yu-hong Lam,b Sezen Alsancak,c Alexandra M. Z. Slawin,a K. Accepted 00th January 2012 N. Houk*b and Andrew D. Smith*a DOI: 10.1039/x0xx00000x The reaction of L-serine derived N-arylnitrones with alkylarylketenes generates asymmetric 3- www.rsc.org/ alkyl-3-aryloxindoles in good to excellent yields (up to 93%) and excellent enantioselectivity (up to 98% ee) via a pericyclic cascade process. The optimization, scope and applications of this transformation are reported, alongside further synthetic and computational investigations. The preparation of the enantiomer of a Roche anti-cancer agent (RO4999200) 1 (96% ee) in three steps demonstrates the potential utility of this methodology. Introduction molecules with quaternary stereocentres,8 3,3-disubstituted oxindoles have emerged as ideal frameworks on which to Cascade reactions are highly desirable owing to the ability 9 develop new asymmetric methodologies. Typically, such to perform multiple sequential transformations without the approaches employ anilides, isatins or suitably substituted necessity for additional manipulation or introduction of further oxindole derivatives as starting materials (Fig 2), although reagents. Such approaches allow significant molecular numerous other standalone approaches have also been complexity to be rapidly assembled, provided each subsequent 9b,c,10-12 developed. Asymmetric intramolecular anilide transformation in the cascade unmasks a desirable, reactive 13 14 cyclizations or Heck reactions typically employ a palladium functionality.1 Pericyclic cascades are particularly attractive 2 catalyst in combination with chiral ligands (a), and have found given their predictable regio- and stereocontrol, coupled with 15 wide application in synthesis. In similar systems, direct the potential to readily generate multiple carbon-carbon bonds. coupling approaches, without the necessity for pre-activation Significant attention has focused on the expansion of this field 16 have been developed. However, these approaches have yet to toward both carbocyclic and heterocyclic frameworks.3 The be rendered enantioselective. O-to-C transfer reactions (b) have 3,3-disubstituted oxindole scaffold is an appealing target given 4 also been used to great effect including Trost’s asymmetric the prevalence of naturally occurring species and medicinal 17 5 6 allylic alkylation methodology, and Lewis base-catalyzed O- agents containing this core structure. Notably, alkaloids 2 and 18 to-C carboxyl transfer reactions. A plethora of catalytic 37 have both been prepared from 3,3-disubstituted oxindole methodologies has been developed over the past decade precursors (Fig 1). 19 employing isatins (c) as starting materials, giving access to 3- substituted-3-hydroxyoxindoles that serve as convenient Cl synthetic intermediates.20 Latterly, both stoichiometric and N O H catalytic asymmetric alkylation approaches (d) have been O O HN 21 MeO N reported to access 3,3-disubstituted oxindole species. This Me NMe manuscript details the asymmetric cycloaddition cascade N reaction between nitrones and ketenes (e), allowing direct O O Me O Cl N N N H access to the unprotected 3,3-disubstituted oxindole motif. This H H H O method contrasts the commonly employed approaches that 1, p53 inhibitor (Roche) 2, spirotryprostatin B 3, gliocladin C require protection of the amide functionality, thereby Fig. 1. Oxindole medicinal agent 1 and natural products 2 and 3 accessed synthetically from 3,3-disubstituted oxindoles. generating N-protected oxindoles. As a consequence of their wide-ranging biological properties, and given the synthetic community’s interest in developing novel approaches toward the preparation of This journal is © The Royal Society of Chemistry 2013 J. Name., 2013, 00, 1-3 | 1 ARTICLE Journal Name R X (X = Br/I/OTf/H) Ar R Ar O Ar OR' R R' O H O N cat. N R 3+2 Pd/Cu [3,3] R C=O O O PG R R' (b) PG Ph H O (a) N H N N O O H O H O O R N O N N N E Nu Boc Boc PG 4 5 Boc 6 O (d) (c) O N N PG PG Ar R O hydrolysis OH R This Work: O R' Ar R and Ph O cyclization N H O (e) N O O O N N N H Xc R R' Boc H H O 9 (S)-8 7 N Xc = stereodirecting group Boc Fig. 2. Typical approaches toward asymmetric 3,3-disubstituted oxindoles. Fig. 3. Proposed mechanism. Previous Studies and Mechanism The ability of this methodology to generate highly The hetero-Claisen approach to oxindoles using N- substituted quaternary stereocentres at the oxindole C(3)- phenylnitrones and diphenylketene was first reported by position with excellent enantiocontrol (up to 90% ee), coupled Staudinger22 and subsequently investigated by Lippman23 and with the inexpensive nature of the starting materials, warranted Taylor.24 Despite its synthetic potential, an asymmetric variant further development of this reaction manifold. To this end, this of this process was overlooked until we developed an manuscript describes our studies devoted to optimization of the asymmetric route to 3,3-disubstituted oxindoles (up to 90% ee) levels of enantioselectivity in this transformation, alongside using Garner’s aldehyde derived N-aryl nitrones and computational and experimental mechanistic studies of this disubstituted ketenes.25 Subsequent studies extended this process. The full scope and limitations of the optimized process methodology to the construction of asymmetric 3,3- are delineated, as well as its application to a target Roche anti- spirocarbocyclic oxindoles,26 and computational studies led to a cancer agent (RO4999200). revised mechanistic rationale for these processes.27 The mechanistic pathway is consistent with a 3+2 cycloaddition Results and Discussion across the ketene C=O bond, with preferential anti-addition with respect to the aryl portion of the ketene. Facial selectivity Stereodirecting Group Optimization in this cycloaddition is controlled by the preferred arrangement To explore the necessary structural requirements for of large and electronegative allylic groups, and 1,3-allylic generating high enantiocontrol in this reaction manifold, a 28 strain within the enantiopure nitrone chiral auxiliary 4, range of enantiopure N-aryl nitrones 11-16 was synthesized generating a stereodefined five-membered intermediate 5. from readily available chiral starting materials. These nitrones Subsequent [3,3]-sigmatropic rearrangement yields 6 that were then evaluated in the pericyclic cascade process with undergoes rearomatization and tautomerization to imino acid 7. ethylphenylketene (Fig 4).30 Initially, Naproxen-derived nitrone Each of these steps was established by computational studies of 11 was synthesized and evaluated, generating oxindole 10 in a 27 the reaction transition states. Acidic hydrolysis and poor 27% ee. Mannitol-derived nitrone 12 proved more concomitant cyclization generates the oxindole 8 with excellent successful, providing oxindole 10 in 78% yield and 70% ee 29 enantiocontrol and regenerates chiral aldehyde 9 (Fig 3). after treatment with ethylphenylketene. An α-oxygenated series of nitrones 13–16, derived from (S)-ethyl lactate, was also synthesized and tested. These nitrones proved difficult to isolate and were consequently prepared and evaluated in situ.31 A general trend of increasing enantioselectivity with increasing substituent size was observed, with O-TIPS-substituted nitrone 15 delivering 10 in 80% ee. 2 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 2012 Journal Name ARTICLE Ph Ph O Ph Et Et Ph O Ph Et N THF, N Ph Et THF, -78 °C, 3h -78 °C, 3h ∗ R O O H then H N O then N O 1M HCl (aq) H R' 10 N O 1M HCl (aq) H PG 10 Nitrones evaluated: Nitrones evaluated: Ph O OMe Ph O N N Ph O Ph O Ph O N N N H H O H Ph H H O Me 11 12 O O NBn2 N N Boc Bn Ph O Ph O Ph O Ph O 17 4 18 N N N N Ph Me Me Me H Ph O Ph O H H H N N OTBS OTBS OTIPS OTBDPS 13 14 15 16 H H O O O O N N O S O S Entry Nitrone Oxindole Oxindole i a b Pr Yield (%) ee (%) iPr 1 11 43 27 (ent) 2 12 78 70 (ent) 3 13 25 < 5 19 20 i 4 14 32 60 Me Pr 5 15 70 80 6 16 38 32 Entry Nitrone Oxindole Oxindole a b Fig. 4. Variation of the chiral nitrone. a Isolated yield of oxindole 10 after Yield (%) ee (%) purification by column chromatography. b Determined by chiral HPLC analysis. 1 17 21 70 2 4 83 84 3 18 60 20 Subsequent studies prepared and evaluated a series of chiral 4 19 75 91 nitrones bearing a protected nitrogen atom at the α-position. 5 20 86 96 The acyclic, α-dibenzylamino nitrone 17 provided the oxindole Fig. 5. Optimization of stereodirecting groups on the nitrone. a Isolated yield of b in 70% ee, but in poor yield. The N-Boc nitrone 4, derived from oxindole 10 after purification by column chromatography. Determined by chiral HPLC analysis. Garner’s aldehyde, gave oxindole 10 in good yield and 84% ee. This prompted us to evaluate a series of structural analogues of Computational Studies – Role of the N-Substituent in 4 in which the N-substituent is varied (Fig 5). Upon treatment Determining Enantioselectivity with ethylphenylketene, the N-benzyl nitrone 18 gave the desired oxindole with poor enantiocontrol, suggesting that In order to understand the origin of the effect of the size of structural rigidity or restricted rotation at this position may be the N-substituent on the enantioselectivity of the reaction, the crucial to engendering high levels of enantioselectivity.