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The enantioselective synthesis of stereochemically and structurally diverse spirocyclic oxindoles by [5+2]-annulation of chiral crotylsilanes bearing a primary alcohol is described. The annulation products were further elaborated to polycyclic oxindoles by Pd (0) catalysis.
Spirooxindoles are commonly occurring heterocyclic ring systems found in many natural products and pharmaceuticals.1 A range of biologically active compounds possessing the spiropyrrolidine framework is well documented.1a–c For instance, coerulescine (1), the simplest spirooxindole found in nature, displays a local anaesthetic effect.2a,b Polycyclic alkaloid pteropodine (2) has a long history for its medicinal applications.2c,d The recent discovery of small-molecule MDM2 inhibitors MI-219 (3) and its analogs has led to their advanced preclinical development as cancer therapeutics1d,e (Figure 1). Although azaspirooxindoles have been extensively studied, the corresponding oxaspirocyclic oxindoles remain underdeveloped.3 Recent approaches to oxaspirooxindoles include Lewis acid-promoted annulation,4a oxidative cycloaddition,4b RCM,4c photocycloaddition,4d base-catalyzed condensation4e and dipolar cycloaddition.4f However, very few examples demonstrate enantioselective preparation of these compounds. Herein, we describe an efficient protocol for accessing functionalized oxaspirooxindoles with high diastereo- and enantioselectivity by mild Lewis acid promoted [5+2]-annulation of chiral silylalcohols.5
As part of our ongoing investigations aimed at expanding the scope of organosilane reactivity, the [4+2]-annulations of crotylsilane 4 and its many structural and stereochemical counterparts have been previously documented.6 In that regard, we envisioned ring-expanded oxepene templates could be constructed via analogous [5+2]-annulations6d of silylalcohol (S)-5 (Scheme 1). Preliminary screening of electrophilic annulation partners identified N-methyl isatin dimethyl ketal 6a (Table 1) as a potential substrate for this ring-forming process.4a The stereoselective formation of a quaternary, spirocyclic center was especially intriguing and our efforts turned towards optimizing this transformation. It was eventually found that when treated with TMSOTf, silylalcohol (S)-5 cyclized with 6a to afford oxepenyl-spirooxindole 7a in 37% yield as a 15:1 mixture of trans- and cis-isomers (Table 1, entry 1).
Further experiments revealed that cis-7a could be preferentially prepared under appropriate conditions (Table 1, entry 2). After 10 minutes at 0 °C, the cis-isomer could be isolated in 70% yield (dr = 15:1). It was also observed that prolonged reaction time or increased polarity of solvents correlated with increased amounts of trans-7a (Table 1, entry 3 and 4).
The presence of trans-7a as a function of time suggested that the cis-product may be epimerizing to the trans-isomer, possibly through a spiro-ring opening mechanism involving intermediates I and II (Scheme 2).
In support of this hypothesis, polar solvents such as THF, CH3NO2, and CH3CN were found to yield preferentially trans-7a after 12 h at 0 °C as compared to the lower efficiency in CH2Cl2 (see Supporting Information). In fact, when reactions performed in dry CH3CN at low temperatures, indolenium ion I7 is sufficiently stable and upon aqueous quenching gave rise to isolatable amounts of diol 8 (inset). Fortunately, exposure to silica gel during purification does not influence the diastereomer ratio. Microwave irradiation of cis-7a in the presence of BF3•OEt2 provided the most efficient means of interconverting the stereoisomers (Scheme 2).
The structure and stereochemistry of cis- and trans-7a were established by X-ray crystallography (Figure 2). Analysis reveals the interatomic distance between the carbonyl oxygen and Ha in cis-7a (2.388 ) increases to 2.627 (O to Hb) in trans-7a. Orienting the isatin carbonyl away from the oxepene ring lowers ground-state energy of the trans-isomer by approximately 3.96 kcal/mol relative to the cis-product.8 This supports our observation that the cis-spirocycle is the kinetic product.
A plausible mechanistic rationale for the observed stereochemical outcome of the initial annulation reaction is illustrated in Scheme 3. Formation of the (Z)-oxonium intermediate is favored to avoid peri interaction associated with the corresponding (E)-oxonium intermediate. Designating the aryl ring as the larger steric contributor,9 orients the carbonyl pseudo-axial. Thus, transition state IV is preferred and leads to the formation of cis-7a as the major diastereomer under kinetic conditions.
At this juncture, we sought to expand this methodology to include additional isatin derivatives 6b–6e (Table 2). HPLC analyses of the spirooxindole products indicated complete chirality transfer from the starting silylalcohol (see Supporting Information). For all cases evaluated, both cis and trans diastereomers were readily obtained in useful yields and with exellent diastereoselectivities. 4-Bromoisatin 6b proved an exception affording only the kinetic product cis-7b (Table 2, entry 2).10 Thermal promoted epimerization failed perhaps as the result of the sterically bulky bromine, destabilizing transition state V en route to the trans-isomer. Isatin dimethylketal 6e also provided both kinetic and thermodynamic products, however, even prolonged reaction times afforded a 7:1 mixture of trans- and cis-7e (Table 2, entry 5).
In order to prepare more complex spirooxindoles, we prepared silylalcohols 9a–d using an established protocol.11 Because of the increased steric congestion the original annulation conditions described above were unable to afford useful amounts of desired product. Reoptimization led to the use of 1.0 equivalent of BF3•OEt2 in refluxing CH2Cl2 to provide the desired products as single diastereomers (Table 3).12 Unlike annulations with (S)-5, no products from spiro-ring opening and reclosure pathways were observed with these cases.
Additional skeletal complexity was achieved by diversification of the annulation products through intramolecular Heck cyclization. The cyclization of 10c under standard conditions (cat. Pd(OAc)2, Et3N, 120 °C) was highly regio- and stereoselective affording the pentacyclic oxindole 11 in 86% isolated yield as a single diastereomer (Scheme 4). Proton, COSY and n.O.e NMR experiments indicated syn-insertion of the aryl palladium occurred at the proximal olefin carbon. Subsequent elimination involved the only available syn-β-hydride (Hc) to form compound 11. The methyl bearing stereocenter was reintroduced through catalytic hydrogenation, and the stereochemistry of product 12 was determined by X-ray crystal analysis.
Cyclization of spirocycle cis-7b was also achieved with excellent regio- and stereocontrol (Scheme 5). Initially, cis-7b was treated with similar conditions as 10c, but the unexpected olefin isomer 14 was observed as the only product. However, by adding 1.0 equivalent of silver(I) nitrate,13 olefin isomerization was suppressed and compound 13 was isolated in 70% yield as a single diastereomer. The [4.2.1]-bicyclic structures of 13 and 14 were determined by 1D and 2D NMR experiments.14
In summary, we have developed a convenient approach for directly accessing spirooxindoles with excellent stereocontrol from enantiomerically enriched crotylsilanes. The complexity of the spirooxindoles can be enhanced by employing different combinations of functionalized silylalcohols or substituted isatin reaction partners. Products were further converted into fused polycyclic ring systems utilizing intramolecular Heck cyclization, thereby demonstrating skeletal variation. The [5+2]-annulation strategy nicely expands the scope of the Prins cyclization in the construction of highly functionalized spirocyclic oxindoles.15 Application of this methodology towards library synthesis and subsequent biological evaluation of its members are underway.
Financial support from the NIGMS CMLD initiative (GM-067041) is gratefully acknowledged. The authors thank Professors John A. Porco Jr., Aaron B. Beeler and Dr. Paola Castaldi (Boston University) for helpful discussions. The authors are endebted to Dr. Emil Lobkovsky (Cornell University) for X-ray crystal data.