WO2010008727A1

WO2010008727A1 - Asymmetric synthesis of allyl or allene oxindoles

Info

Publication number: WO2010008727A1
Application number: PCT/US2009/047453
Authority: WO
Inventors: Marisa C. Kozlowski; Elizabeth Carol Linton
Original assignee: The Trustees Of The University Of Pennsylvania
Priority date: 2008-06-16
Filing date: 2009-06-16
Publication date: 2010-01-21

Abstract

The invention concerns processes for the preparation of a compound of the formula I comprising contacting a compound of formula II with a catalyst, said catalyst comprises (i) at least one of Pd and Cu and (ii) one or more of diamine, diphosphine and aminophosphine ligands; wherein Z is -C(R⁵)(R⁶)-C(R²)=C(R³)(R⁴) and Y is -C(R³)(R⁴)-C(R²)=C(R⁵)(R⁶) or Z is -C(R⁵)(R⁶)-C≡C-R³; Y is or -C(R³)=C=C(R⁵)(R⁶); X is NH, NR¹⁵, O or S; a is O or an integer from 1 to 4 and R¹ -R⁷ and R¹⁵ are as defined in the specification.

Description

ASYMMETRIC SYNTHESIS OF ALLYL OR ALLENE OXINDOLES

RELATED APPLICATIONS

[0001] This application claims benefit of U.S. Patent Application No. 61/061,706, filed June 16, 2008, the disclosure of which is incorporated herein in its entirety.

TECHNICAL FIELD

[0002] The present invention relates to the asymmetric synthesis of allyl or allene oxindole compositions.

BACKGROUND

[0003] The [3,3'] sigmatropic rearrangements of allyl vinyl ethers (Claisen rearrangement) and their derivatives have enjoyed a long and rich history due to the utility of the products. Though first discovered almost 100 years ago, only one substrate class has proven amenable to asymmetric catalysis. The 2-ester substituted allyl vinyl ethers undergo highly enantioselective rearrangement with both Lewis acid and hydrogen bonding catalysts. A key barrier to development of this transformation is identification of systems that turn over readily with catalysts.

[0004] There are a host of natural products with diverse biological activities that incorporate a chiral oxindole moiety. A small selection includes physostigmine, flustramine B, pseudophrynaminol, and mollenine. In addition, the oxindole core has been used in the development of pharmaceutical agents. See, Ding, et al, J. Am. Chem. Soc. 2005, 127, 10130-10131, Ding, et al, J. Med. Chem. 2006, 49, 3432-3435 and Franz, et al, J. Am. Chem. Soc. 2007, 129, 1020-1021.

[0005] Trost and coworkers (J. Am. Chem. Soc. 2007, 129(47), 14548- 14549) have generated oxindoles with quaternary stereocenters in high yields and good levels of selectivity . All of these substrates, however, have an aryl substituent at the 3 -position. In addition, the nitrogen on the indole is always protected, and is never the free NH.

[0006] When Trost, et al. (Org. Lett., 2006, 8(10), 2027-2030) attempted asymmetric allylic alkylation with substrates bearing an ester group, lower enantioselectivities were observed, and a recrystallization was needed to increase the selectivity to 98% ee. Again, the nitrogen was protected. In both cases, it took three steps to generate the starting materials for the allylation. This is the only report for the allyl/ester substitution; the disclosed method provides superior selectivity, access to more analogs, and shorter routes.

[0007] Fu and coworkers (Angew. Chemie. Int. Ed., 2003, 42(33), 3921- 3924) have developed an asymmetric rearrangement of O-acylated oxindoles, to generate their C-acylated isomers. Again, all substrates bore an aryl group at the 3-position of the indole ring. When the aryl ring was replaced with a methyl, higher loadings were needed and the selectivity dropped to 72% ee. In addition, a bulky trichloro-tert-butyl ester was needed to achieve high enantioselectivity. In all cases, the nitrogen was protected as the TV-methyl, and the starting material for the rearrangement was made in three steps.

[0008] Overman and coworkers (J. Am. Chem. Soc, 2004, 126(43), 14043-14053) have developed an asymmetric intramolecular Heck cyclization to generate oxindoles bearing a quaternary stereocenter. The substrate scope is limited to only having a methyl substituent at the 3-position, as well as having the nitrogen protected. In addition only moderate yields were seen, and it took three steps to generate the starting material for the cyclization.

[0009] There is a need in the art for improved methods of synthesis of chiral allyl or allene oxindole for use in asymmetric synthesis of pharmaceutical and other intermediates.

SUMMARY

[0010] In some aspects, the invention concerns processes for the preparation of a compound of the formula I

comprising contacting a compound of formula II

with a catalyst, said catalyst comprises (i) at least one of Pd and Cu and (ii) one or more of diamine, diphosphine and aminophosphine ligands; wherein

Z is -C(R⁵)(R⁶)-C(R²)=C(R³)(R⁴) and Y is -C(R³)(R⁴)-C(R²)=C(R⁵)(R⁶) or Z is

-C(R⁵)(R⁶)-C≡C-R³; Y is or -C(R³)=C=C(R⁵)(R⁶);

X is NH, NR¹⁵, O or S;

R¹ is alkyl, aryl, O-alkyl, O-aryl, or NR⁹R¹⁰;

R² is hydrogen, alkyl, aryl, halogen, silyl, or stannyl;

R³ and R⁴ are, independently, hydrogen, alkyl or aryl, or R² and R³ together are

(CH₂)₄;

R⁵ and R⁶ are each, independently, hydrogen, alkyl or aryl;

R⁷ is alkyl, alkenyl, alkynyl, aryl, halogen, OR⁸, NR⁹NR¹⁰, CN, or COR¹¹ _;

R⁸, R⁹, R¹⁰, and R¹¹ are each, independently, alkyl or aryl;

R¹⁵ is alkyl, aryl, CO₂R¹⁶, CONR¹⁶;

R¹⁶ is alkyl or aryl; and a is 0 or an integer from 1 to 4.

[0011] In some processed, the compound of the formula I is of the formula:

and the compound of formula II is of the formula:

[0012] In other processes, the compound of the formula I is of the formula:

and the compound of formula II is of the formula:

[0013] In certain embodiments, the contacting is performed at a temperature of 0 to 25 ⁰C. Certain processes perform the in the presence of a solvent that comprises CH₂Cl₂. In some embodiments, the contacting is performed for 5 minutes to 24 hours.

[0014] Some preferred process are such that X is NH. In certain processes a is 1 or 2. In certain embodiments R¹ is alkyl or aryl and R² is alkyl, aryl, or halogen. In some preferred embodiments, X is NH; R¹ is alkyl or aryl; R² is alkyl, aryl, or halogen; and a is 1 or 2. In other preferred embodiments, R³ is alkyl, aryl, halogen, OR⁹, NR⁷NR⁸, CN, or COR¹⁰. In some embodiments, one or more of R -R is other than H.

[0015] Other aspects of the invention concern processes for the preparation of a compound of the formula

comprising:

— contacting a compound of the formula

with a compound of the formula

to produce a compound of the formula

— contacting a compound of formula IV with a catalyst to produce a compound of formula III, said catalyst comprises (i) at least one of Pd and Cu and (ii) one or more of diamine, diphosphine and aminophosphine ligands; wherein

X is NH, NR¹⁵, O or S; R¹ is alkyl, aryl, O-alkyl, O-aryl, or NR⁹R¹⁰; R² is hydrogen, alkyl, aryl, halogen, silyl, or stannyl;

R³ and R⁴ are, independently, hydrogen, alkyl or aryl, or R² and R³ together are be (CH₂)₄;

R⁵ and R⁶ are each, independently, hydrogen, alkyl or aryl; R⁷ is alkyl, alkenyl, alkynyl, aryl, halogen, OR⁸, NR⁹NR¹⁰, CN, or COR¹¹ _; R⁸, R⁹, R¹⁰, and R¹¹ are each, independently, alkyl or aryl; R¹⁵ is alkyl, aryl, CO₂R¹⁶, CONR¹⁶; R¹⁶ is alkyl or aryl; and a is 0 or an integer from 1 to 4; wherein R² and R⁴, optionally, together form a carbon-carbon bond. DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0016] The methods of the present invention provide a novel and efficient access to enantiopure oxindoles containing quaternary centers. These materials are useful small molecule organic building blocks and have been employed in the synthesis of medicinal agents and natural products. In one aspect, the method centers on a metal catalysts to effect asymmetric Eschenmoser Claisen rearrangements.

[0017] The processes of the instant invention allow access to oxindoles with two functional groups that can be readily manipulated. These functional groups can be, for example, an allyl group as well as an ester. This allows generation molecules with important biological activity. As is the case for the methods described above, an aryl or a methyl group limits the molecules that can be accessed. In addition, the disclosed chemistry is compatible with an unprotected indole nitrogen, eliminating two steps from any synthesis. We are also able to generate our substrates in a two-step, one-pot method, providing quick entry to the oxindoles.

[0018] The conversion of the compound of formula II to the oxindole products of formula I can be accomplished using Lewis Acid catalysts. In general, the reaction utilizes a Lewis Acid and a metal complexed with a nitrogen and/or phosphorous ligand. Any suitable Lewis Acid can be utilized in the invention. One example of a Lewis Acid catalyst is L*(SbFe)₂ where L* is a chiral diamine, phosphine or aminophosphine.

[0019] In some embodiments, it is preferred that a copper and/or palladium complex with one or more of diamine, diphosphine, and aminophosphine ligands catalyze the reaction. Suitable ligands include diamine (bisimine and bisoxazoline) ligands with the copper, and diphosphine (BINAP, BIPHEP, difluorophos) and amino phosphine (PHOX) ligands with the palladium. The palladium catalysts provide complete conversion to product within minutes and with high enantioselectivity (>85% ee). Copper catalysts also give high selectivities and fast rates but with lower turnover numbers (i.e., higher catalyst loading). The enantiomeric catalysts generate the enantiomeric products. [0020] Suitable ligands include the following compounds.

[0021] The reactions can be performed at any suitable temperature. In some embodiments the reaction temperature is from about -78 ⁰C to about 40 ⁰C. In some preferred embodiments, the reactions are preformed at about 0 ⁰C to about 25 ⁰C.

[0022] The reaction can be performed in a variety of solvents so long as the solvent provides sufficient solubility of the reactants and does not negatively impact the reaction. Suitable solvents include dichloromethane; tetrahydrofuran, diethyl ether, ethyl acetate, toluene, benzene, nitromethane, chloroform, benzotrifluoride, heptane/dichloromethane, and acetone. In some preferred embodiments, the solvent is dichloromethane.

[0023] In regard to time, the reaction is run until a desired conversion is achieved. In some embodiments, reaction times are from about 5 minutes to about 24 hours. In certain embodiments, the reaction time is from about 20 to about 30 minutes.

[0024] Any concentrations of reactants and catalyst that produces acceptable product may be utilized. In some embodiments, the reactant are used at a concentrations of about 0.05 M to about 1.0 M. In certain embodiments, the catalyst is used at a concentration of about 0.002 M to about 0.01 M. [0025] The number of commercially available allyl alcohols and indoles allows entry to a broad substrate scope. Catalytic methods have been devised for various substitution pattern son the allylic alcohol and on the indole.

[0026] In some embodiments, the compound of formula IV is made by contacting a compound of the formula VII

with a compound of the formula IV

[0027] In some embodiments, the reaction of the compound of formula VII with the compound of formula VIII is performed in the presence of N- chlorosuccinimide (NCS), a compound of formula IX and CI3CO2H.

[0028] In certain embodiments, the invention relates to the reaction shown below.

[0029] The term "alkyl", as used herein, refers to a substituted or unsubstituted aliphatic hydrocarbon chain and includes, but is not limited to, straight and branched chains. In some embodiments, the alkyl group contains from 1 to 12 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, i-butyl and t-butyl are encompassed by the term "alkyl." Specifically included within the definition of "alkyl" are those aliphatic hydrocarbon chains that are optionally substituted.

[0030] The term "alkenyl", as used herein, refers to a substituted or unsubstituted aliphatic hydrocarbon chain and includes, but is not limited to, straight and branched chains having 2 to 8 carbon atoms and containing at least one double bond. Preferably, the alkenyl moiety has 1 or 2 double bonds. Such alkenyl moieties may exist in the E or Z conformations and the compounds of this invention include both conformations. Specifically included within the definition of "alkenyl" are those aliphatic hydrocarbon chains that are optionally substituted.

[0031] As used herein, the term "aryl' refers to an aromatic carbocyclic moiety of up to 20 carbon atoms, which can be a single ring (monocyclic) or multiple rings (bicyclic, up to three rings) fused together or linked covalently. Any suitable ring position of the aryl moiety can be covalently linked to the defined chemical structure. Examples of aryl moieties include, but are not limited to, chemical groups such as phenyl, 1-naphthyl, 2-naphthyl, dihydronaphthyl, tetrahydronaphthyl, biphenyl, anthryl, phenanthryl, fluorenyl, indanyl, biphenylenyl, acenaphthenyl, acenaphthylenyl, and the like. Specifically included with the term "aryl" are those aryl groups that are optionally substituted. Preferred aryl groups contain from 6 to 14 carbon atoms. One particularly preferred aryl group is an optionally substituted phenyl group. [0032] Optionally substituted alkyl, alkenyl, and aryl may be substituted with one or more substituents. Suitable optionally substituents may be selected independently from nitro, cyano, -N(R²¹)(R²²), halogen, hydroxy, carboxy, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, heteroaryloxy, alkylalkoxy, alkoxycarbonyl, alkoxyalkoxy, perfluoroalkyl, perfluoroalkoxy, arylalkyl, alkylaryl, hydroxyalkyl, alkoxyalkyl, alkylthio, -S(O)₂-N(R²¹)(R²²), - C(=O)-N(R²¹)(R²²), (R²¹)(R²²)N-alkyl, (R²¹)(R²²)N-alkoxyalkyl, (R²¹)(R²²)N- alkylaryloxyalkyl, -S(O)_s-aryl (where s=0-2) or -S(O)_s-heteroaryl (where s=0-2). In certain embodiments of the invention, preferred substitutents for alkyl, alkenyl,

01 00 and alkynyl include nitro, cyano, -N(R )(R ), halogen, hydroxyl, aryl, heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl. In certain embodiments of the invention, preferred substituents for aryl include -N(R²¹)(R²²), alkyl, halogen, perfluoroalkyl, perfluoroalkoxy, arylalkyl and alkylaryl. R²¹ and R²² are each, independently, alkyl or aryl, or R²¹ and R²² together, along with the nitrogen to which they are attached, can form a ring.

[0033] The term halogen includes bromine, chlorine, fluorine, and iodine.

[0034] As used herein, the term "silyl" refers to a silyl of the formula -Si(R)₃ where each R is, independently, an alkyl or aryl.

[0035] The term "stannyl" refers to groups of the formula -Sn(R')3 where R' is typically alkyl. Examples of such compounds include trimethylstannyl and tributylstannyl.

[0036] The carbon number used in these definition refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like.

[0037] The invention is illustrated by the following examples that are intended to be illustrative and not limiting.

Example 1

[0038] This example illustrates the conversion of compound 3a to 4a under various reaction conditions. Scheme I

[0039] As used herein, "M" is metal, "L*" is ligand, "ee" is entantiomeric excess, "t" is time, "Conv." is conversion, and "rt" is room temperature.

Example 2

[0040] This example shows the conversion of compound 3 to compound 4 under various reaction conditions.

Table 2. Substrate Scope in the Oxindole Claisen Rearrangement (Eq l).^a

Example 3

[0041] This example shows the conversion of compound 3 to compound 4 under various reaction conditions.

Table 3. Additional examples of the conversion of compound 3 to compound 4.

Example 4

General Considerations.

[0042] Unless otherwise noted, all non-aqueous reactions were carried out under an atmosphere of dry N₂ in dried glassware. When necessary, solvents and reagents were dried prior to use. THF was distilled from sodium benzophenone ketyl. CH₃CN, CH₂Cl₂, TMEDA, and hexanes were distilled from CaH₂. Benzene was distilled from sodium.

[0043] Analytical thin layer chromatography (TLC) was performed on EM Reagents 0.25 mm silica-gel 254-F plates. Visualization was accomplished with UV light. Chromatography was performed using a forced flow of the indicated solvent system on EM Reagents Silica Gel 60 (230-400 mesh). See, Still, W. C; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923-2925. Enantiomeric excesses were determined using analytical high performance liquid chromatography (HPLC), performed on a Waters 600 HPLC with UV detection at 254 nm. An analytical Chiralpak OD, AS and AD column (0.46 cm x 25 cm) from Daicel was used. ¹H NMR spectra were recorded on Bruker AM-500 (500 MHz), AM-360 (360 MHz), or AM-300 (300 MHz) spectrometers. Chemical shifts are reported in ppm from tetramethylsilane (0 ppm) or from the solvent resonance (CDCl₃ 7.27 ppm). Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants, and number of protons. Decoupled ¹³C NMR spectra were recorded on a Bruker AM- 500 (125 MHz) spectrometer. IR spectra were taken on a Perkin-Elmer FT-IR spectrometer using a thin film on NaCl plates or a CHCI₃ solution. Mass spectra were obtained on a low resonance Micromass Platform LC in electrospray mode and high resonance VG autospec with an ionization mode of either CI or ES. Melting points were obtained on Thomas Scientific Unimelt apparatus and are uncorrected. Optical rotations were measured on a Perkin-Elmer Polarimeter 341 with a sodium lamp and are reported as follows M^*ϋ (c g/100 mL, solvent).

Catalyst Screening:

Catalyst Loadings with Coppei7Indanol(bisoxazoline) Complex:

Metal Screening with BINAP and Indanol(bisoxazoline) Ligands:

Screening of Hydrogen-Bonding Catalysts:

Preparation of Claisen Substrate Precursors Ia-Ij:

[0044] 3-Bromo-l-(triisopropylsilyl)-lH-indole (S6). A solution of indole (2.0 g, 17.1 mmol) in TΗF (100 mL) was cooled to 0 ⁰C, at which time NaH (60% in oil, 3.4 g, 85.5 mmol) was added. The mixture was stirred together for 5 min, followed by addition of TIPSCl (10 rnL, 46.7 mmol). After 1 h stirring at room temperature, the mixture was cooled to 0 ⁰C, then H₂O was added. The organic layer was washed with 1 M HCl and brine, dried over Na2SO4, and concentrated under vacuum. A solution of the TIPS-indole (4.67 g, 17.1 mmol) in THF was cooled to -78 ⁰C, then recrystallized iVbromosuccinimide (3.0 g, 17.1 mmol) was added. After stirring for 3 h, another aliquot of iV-bromosuccinimide (1.5 g, 8.6 mmol) was added and stirring was continued for another 2 h. After warming to room temperature, pyridine (170 μL) and hexanes (30.7 mL) were added and the mixture was concentrated. The precipitate was washed thoroughly with hexanes and the combined filtrate was concentrated. The residue was chromatographed (SiO₂, 100% hexanes) to afford S6 (4.5 g) in 75% yield over the 2 steps as a white solid: mp 56-58 ⁰C; ¹H NMR (500 MHz, CDCl₃) δ 7.58- 7.57 (m, IH), 7.50-7.48 (m, IH), 7.25 (s, IH), 7.22-7.19 (m, 2H), 1.72-1.65 (m, 3H), 1.17 (d, J= 7.5 Hz, 18H); ¹³C NMR (500 MHz, CDC13) δ 140.1, 130.0, 129.7, 122.5, 121.6, 119.1, 114.1, 93.6, 18.0, 12.8; IR (film) 2949, 2868, 1463, 1285 cm^"1; HRMS (CI) m/z = 352.1109 calcd for C₁₇H₂₇BrNSi [MH]+, found 352.1018.

[0045] Isopropyl lH-indole-3-carboxylate (Ie). Indole S6 (0.50 g, 1.42 mmol) was dissolved in Et₂O (14 mL) and cooled to -78 ⁰C. A solution of t- BuLi (1.5 M in pentane, 2.1 mL, 3.12 mmol)) was added dropwise, allowed to stir for 15 minutes, and then isopropyl chloroformate (1 M in PhCH₃, 1.71 mL, 1.71 mmol) was added. The reaction mixture stirred for 30 min at -78 ⁰C, and then warmed to room temperature over 30 min. The reaction mixture was quenched with NaHCO₃, washed with H₂O and brine, dried over Na2SO4, and concentrated under vacuum. To a solution of the resultant carboxylate-indole (0.511 g, 1.42 mmol) in THF (14 mL) was added TBAF (1 M in THF, 1.4 mL, 1.42 mmol). After stirring 15 min, the mixture was quenched with NH4C1, washed with brine, dried over Na₂S(M, and concentrated under vacuum. The oil was chromatographed (SiO₂, 25% EtOAc/hexanes) to give Ie (0.26 g) in 90% yield over 2 steps. The ¹H NMR spectrum matches that of the reported compound. See, Stanovnik, B.; Tisler, M.; Carlock, J. T. "Heterocycles 159. Novel Synthesis of Alkyl Indole-3-Carboxylates" Synthesis- Stuttgart 1976, 754- 755.

[0046] Benzyl lH-indole-3-carboxylate (Id). Using the procedure from compound Ie with benzylchloroformate, Id (0.35 g, 1.41 mmol) was obtained in 62% yield as a white solid: mp 142-145°C; ¹H NMR (300 MHz, CDCl₃) δ 8.63 (bs, IH), 8.23-8.18 (m, IH), 7.96 (d, J= 3.0 Hz, IH), 7.55-7.26 (m, 8H), 5.49 (s, 2H); ¹³C NMR (300 MHz, CDCl₃) δ 165.1, 136.7, 136.1, 131.4, 128.5, 128.0 (2), 127.0, 123.2, 122.1, 121.4, 111.6, 108.5, 65.6; IR (film) 3398, 3298, 3128, 3066, 2958, 2881, 1676, 1529, 1429, 1328, 1244 cm^"1; HRMS (ES) m/z = 252.0946 calcd for C₁₆H₁₄NO₂ [MH]⁺, found 252.1071.

[0047] tert-Buty\ lH-indole-3-carboxylate (If) Oxalyl chloride (320 μL, 3.72 mmol) was added to a suspension of indole-3-carboxylic acid (0.20 g, 1.24 mmol) in anhydrous CH₂Cl₂ (10 mL), followed by a catalytic amount of anhydrous DMF (2 drops). The suspension was stirred at rt for 3 h. Removal of the solvent in vacuo gave the crude acid chloride as a yellow oil. To this material was added slightly warmed t-BuOH (1.7 mL), followed by KOt-Bu (0.226 g, 2.02 mmol). The resulting mixture was stirred for 90 min, diluted with Et₂O and washed with sat. aq. NH₄Cl and brine. The organic layer was dried over Na₂SO4 and concentrated under vacuum. The oil was purified by chromatography (SiO₂, 40% EtOAc/Hexanes) to yield If (0.27 g, 1.24 mmol) in 100% yield as a white solid. The ¹H NMR spectrum matches that of the reported compound. See, Janosik, T.; Shirani, H.; Wahlstrom, N.; Malky, L; Stensland, B.; Bergman, J. Tetrahedron 2006, 62, 1699-1707.

[0048] Methyl S-methoxy-lH-indole-S-carboxylate (Ih). Pyridine (0.30 mL, 3.54 mmol) was added to a suspension of 5-methoxy-lH-indole (0.40 g, 2.72 mmol) in anhydrous TΗF (6 mL) at 0 ⁰C. A solution of trichloroacetyl chloride (0.40 mL, 3.54 mmol) in TΗF (6 mL) was added dropwise via an addition funnel over Ih. The reaction mixture was then allowed to warm to room temperature to stir for 16 h. The reaction mixture was quenched in 1 M HCl, dried over Na₂SO₄, and concentrated under vacuum. The resulting solid was then dissolved in MeOH (54 mL), and aq. KOΗ (50 % by wt., 0.20 mL) was added. The reaction mixture was heated to reflux for 5 h, then stirred at ambient temperature for 1 h, followed by concentration under vacuum. The solid was purified by chromatography (SiO₂, 25% EtOAc/Hexanes) to yield Ih (0.50 g, 2.45 mmol) in 90% yield as a off-white solid: mp 141-142°C; ¹H NMR (500 MHz, CDCl₃) δ 8.87 (bs, IH), 7.86 (d, J = 2.9 Hz, IH), 7.68 (d, J = 2.3 Hz, IH), 7.29 (d, J= 8.8 Hz, IH), 6.91 (dd, J= 2.3 Hz, 8.8 Hz, IH), 3.93 (s, 3H), 3.89 (s, 3H); ¹³C NMR (500) MHz, CDC13) δ 165.9, 155.8, 131.3, 131.0, 126.7, 113.7, 112.4, 108.2, 102.8, 55.7, 51.0; IR (film) 3236, 2950, 2835, 1661, 1529, 1444, 1367, 1282 cm^"1; HRMS (ES) m/z = 206.0739 calcd for C₁₁H₁₂NO₃ [MH]+, found 206.0850.

[0049] Methyl 5-bromo-lH-indole-3-carboxylate (Ii). Using the procedure from Ih with 5-bromo-lHindole, Ii (0.65 g, 2.57 mmol) was obtained in 50% yield as an off-white solid: mp 212-214 ⁰C; ¹H NMR (500 MHz, CDCl₃) δ 8.60 (bs, IH), 8.34 (d, J= 1.3 Hz, IH), 7.92 (d, J= 2.9 Hz, IH), 7.38 (dd, J = 1.8 Hz, 8.6 Hz, IH), 7.29 (d, J= 8.6 Hz, IH), 3.94 (s, 3H); 13C NMR (500) MHz, CDCl₃) δ 165.0, 134.7, 131.7, 127.4, 126.3, 124.3, 115.7, 112.9, 108.8, 51.2; IR (film) 3290, 2943, 1684, 1529, 1452, 1359, 1189 cm^"1; HRMS (CI) m/z = 253.1323 calcd for Ci₀H₉BrNO₂ [MH]⁺, found 253.9817.

[0050] Methyl T-methoxy-lH-indole-S-carboxylate (Ij). Using the procedure from Ih with 7-methoxy-lH-indole, Ij (0.56 g, 2.72 mmol) was obtained in 100% yield as a white solid. ¹H NMR spectrum matches that of the reported compound. See, Prashad, M.; Vecchia, L. L.; Prasad, K.; Repic, O., Synthetic Comm. 1995, 25, 95-100.

Representative Procedure (A) for Installation of an Allyl Alcohol to Indole Substrates:

[0051] Methyl 2-(2-methylallyloxy)-lH-indole-3-carboxylate (3a).

To a flame-dried round-bottom flask was added Ia (3.0 g, 17.13 mmol). CH₂Cl₂ (15 mL) was added and upon cooling to 0 ⁰C, distilled 1 ,4-dimethylpiperazine (1.29 mL, 9.60 mmol) and recrystallized TV-chlorosuccinimide (2.52 g, 19.02 mmol) were added. The resulting solution was stirred at 0 ⁰C for 2 h. In a separate flame-dried round bottom flask, the allyl alcohol 2a (2.9 mL, 34.26 mmol) and trichloroacetic acid (0.67 g, 4.11 mmol) were dissolved in CH₂Cl₂ (15 mL). The solution was cooled to 0 ⁰C, and transferred via cannula to the indole solution. This mixture was stirred for 2 h at 0 ⁰C, at which time the reaction mixture was concentrated under vacuum. It was then loaded onto a basewashed SiO₂ column (1% Et₃N, 24% EtOAc, 75% Hexanes) and eluted with 25% EtOAc/Hexanes to afford 3a (2.5 g) in 60% yield as a white solid: mp 92-94 ⁰C; ¹H NMR (500 MHz, CDCl₃) δ 8.63 (bs, IH), 8.03 (d, J= 7.7 Hz, IH), 7.23-7.14 (m, 3H), 5.18 (s, IH), 5.05 (s, IH), 4.81 (s, 2H), 3.93 (s, 3H), 1.86 (s, 3H); ¹³C NMR (360 MHz, THF-dg) δ 164.5, 156.9, 141.4, 131.0, 127.2, 121.5, 121.4, 121.1, 113.1, 110.6, 89.9, 76.8, 49.9, 19.0; IR (film) 3231, 2949, 1660, 1552, 1475 cm^"1; HRMS (ES) m/z = 268.0950 calcd for C₁₄Hi₅NO₃Na [MNa]+, found 268.0950. This material rearranges at ambient temperature, but could be stored for up to one year at -20 ⁰C. Since rearrangement would occur during the timeframe of the ¹³C NMR experiment even in d8-THF which slows the rearrangement, purity was typically assessed by ¹H NMR spectroscopy.

Representative Procedure (B) for Installation of an Allyl Alcohol to Indole Substrates:

[0052] Isopropyl 2-(allyloxy)-lH-indole-3-carboxylate (3e). To a flame-dried round-bottom flask was added Ie (0.15 g, 0.74 mmol). After dissolving in CH₂Cl₂ (3 niL) and cooling to 0 ⁰C, l,4-diazobicyclo[2.2.0]octane (DABCO) (0.046 g, 0.41 mmol) was added followed by recrystallized N- chlorosuccinimide (0.11 g, 0.82 mmol) were added. The resultant solution was stirred at 0 ⁰C for 30 min, followed by addition of allyl alcohol (0.10 mL, 1.48 mmol) and methanesulfonic acid (0.007 mL, 0.10 mmol). This mixture was stirred for 30 min at 0 ⁰C, at which time the reaction mixture was concentrated under vacuum and chromatographed on a base-washed SiO₂ column (1% Et₃N, 24% EtOAc, 75% Hexanes) using 25% EtOAc/Hexanes as the eluent to afford 3e (0.15 g, 0.59 mmol) in 80% yield as an off-white oil: ¹H NMR (300 MHz, CDCl₃) δ 8.22 (bs, IH), 8.05 (d, J= 7.0 Hz, IH), 7.25-7.19 (m, 3H), 6.18-6.05 (m, IH), 5.49 (ddd, J= 1.4, 2.9, 17.2 Hz, IH), 5.36 (ddd, 1.4, 2.9, 10.4 Hz, IH), 5.35 (septet, J= 6.3 Hz, IH), 4.96 (ddd, J= 1.3, 2.7, 5.7 Hz, 2H); 1.42 (d, J= 6.3 Hz, 6H); ¹³C NMR (360 MHz, THF-d8) δ 163.9, 156.9, 133.8, 131.5, 127.4, 121.5 (2), 121.3, 117.7, 110.7, 90.9, 74.4, 66.2, 22.3; IR (film) 3229, 2981, 2935, 1738, 1661, 1552, 1468, 1375, 1244, 1097 cm-1; HRMS (ES) m/z = 260.12084 calcd for C₁₅H₁₈NO₃ [MH]+, found 260.1281. This material rearranges at ambient temperature, but could be stored for up to one year at -20 ⁰C. Rearrangement would occur during the timeframe of the NMR experiment even in d₈-THF which slows the rearrangement. As a consequence, purity was typically assessed by the more rapid ¹H NMR experiment.

[0053] Methyl 2-(allyloxy)-lH-indole-3-carboxylate (3b). Following the general procedure (B) 3b (0.224 g, 0.97 mmol) was obtained in 57% yield as a white solid: mp 80-82 ⁰C; ¹H NMR (300 MHz, CDCl₃) δ 8.21 (bs, IH), 8.05 (m, IH), 7.22-7.18 (m, 3H), 6.13-6.05 (m, IH), 5.49 (d, J= 17.2 Hz, IH), 5.36 (d, J= 10.4 Hz, IH), 4.95 (d, J= 5.7 Hz, 2H), 3.94 (s, 3H); ¹³C NMR (360 MHz, THF-d₈) δ 164.7, 157.0, 133.7, 131.0, 127.3, 121.6, 121.5, 121.2, 117.8, 110.7, 90.3, 74.4, 50.0; IR (film) 3229, 2997, 2950, 1668, 1552, 1468, 1328, 1251, 1213 cm^"1; HRMS (ES) m/z = 254.0793 calcd for C₁₃Hi₃NO₃Na [MNa]⁺, found 254.0797. This material rearranges at ambient temperature, but could be stored for up to one year at -20 ⁰C. Rearrangement would occur during the timeframe of the NMR experiment even in ds-THF which slows the rearrangement. As a consequence, purity was typically assessed by the more rapid ¹H NMR experiment.

[0054] Methyl 2-(2-methylenebutoxy)-lH-indole-3-carboxylate (3c).

Following the general procedure (A) 3c (0.257 g, 0.99 mmol) was obtained in 43% yield as a yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 8.30 (bs, IH), 8.04 (d, J = 7.4 Hz, IH), 7.26-7.15 (m, 3H), 5.23 (s, IH), 5.09 (s, IH), 4.89 (s, 2H), 3.93 (s, 3H), 2.23 (q, J= 7.0 Hz, 2H), 1.13 (t, J= 7.4 Hz, 3H); ¹³C NMR (360 MHz, THF-dg) δ 165.1, 157.5, 147.4, 131.5, 127.7, 122.0, 121.9, 121.6, 111.8, 111.1, 90.4, 76.4, 50.4, 26.6, 12.5; IR (film) 3229, 2966, 2881, 1668, 1552, 1468, 1352, 1267 cm^"1; HRMS (ES, negative ion) m/z = 258.12084 calcd for C15H16NO3 [M-Hf, found 258.1123.

[0055] Methyl 2-(l-deutero-2-methylenebutoxy)-lH-indole-3- carboxylate (d-3c). Following the general procedure (A) d-3c (0.036 g, 0.14 mmol) was obtained in 17% yield as a yellow resin: ¹H NMR (300 MHz, CDCl₃) δ 8.22 (bs, IH), 8.04 (d, J= 7.2 Hz, IH), 7.26-7.16 (m, 3H), 5.23 (t, J= 1.1 Hz, IH), 5.09 (s, IH), 4.86 (s, IH), 3.91 (s, 3H), 2.23 (q, J= 7.4 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H); ¹³C NMR (360 MHz, THF-dg) δ 164.5, 157.0, 147.0, 131.1, 127.3, 121.5, 121.4, 121.2, 111.5, 110.6, 90.0, 75.8 (t, J= 22.3 Hz), 49.9, 26.2, 12.3; IR (film) 3229, 3090, 2935, 2881, 1668, 1552, 1468, 1328, 1244 cm^"1; HRMS (ES) m/z = 283.1169 calcd for C₁₅Hi₆DNO₃Na [MNa]⁺, found 283.1165.

[0056] Benzyl 2-(allyloxy)-lH-indole-3-carboxylate (3d). Following the general procedure (B) 3d (0.121 g, 0.39 mmol) was obtained in 66% yield as a yellow oil: ¹H NMR (360 MHz, THFd₈) δ 10.87 (bs, IH), 8.07 (m, IH), 7.53 (d, J= 7.3 Hz, 2H), 7.37-7.20 (m, 4H), 7.11-7.06 (m, 2H), 6.14-6.04 (m, IH), 5.45 (dd, J= 1.6, 17.2 Hz, IH), 5.39 (s, 2H), 5.24 (dd, J= 1.3, 10.5 Hz), 4.92 (m, 2H); ¹³C NMR (360 MHz, THF-d₈) δ 164.1, 157.2, 138.4, 133.5, 131.2, 128.7, 128.2, 128.0, 127.3, 121.7, 121.6, 121.2, 118.0, 110.8, 90.1, 74.2, 64.9; IR (film) 3229, 3090, 3035, 2950, 2881, 1661, 1552, 1460, 1352, 1259, 1213 cm^"1; HRMS (ES) m/z = 308.12084 calcd for Ci₉Hi₈NO₃ [MH]+, found 308.1285. This material rearranges at ambient temperature, but could be stored for up to one year at -20 ⁰C. Rearrangement would occur during the timeframe of the NMR experiment even in d₈-THF which slows the rearrangement. As a consequence, purity was typically assessed by the more rapid ¹H NMR experiment.

[0057] tert-Butyl 2-(allyloxy)-lH-indole-3-carboxylate (3f).

Following the general procedure (A) 3f (0.53 g, 1.94 mmol) was obtained in 77% yield as a white solid: mp 124-126 ⁰C; ¹H NMR (300 MHz, CDCl₃) δ 8.36 (bs, IH), 8.01 (d, J= 7.0 Hz, IH), 7.25-7.13 (m, 3H), 6.15-6.02 (m, IH), 5.46 (dd, J = 17.2, 1.4 Hz, IH), 5.33 (dd, J= 10.4, 1.2 Hz, IH), 4.92 (m, 2H), 1.66 (s, 9H); ¹³C NMR (360 MHz, THF-d8) δ 163.9, 156.7, 134.0, 130.9, 127.4, 121.4 (2), 121.3, 117.7, 110.6, 92.1, 81.6, 74.6, 28.6; IR (film) 3229, 2981, 2881, 1661, 1552, 1468, 1367, 1251, 1174, 1097; HRMS (ES) m/z = 274.1365 calcd for C₁₆H₂₀NO₃ [MH]⁺, found 274.1435. This material rearranges at ambient temperature, but could be stored for up to one year at -20 ⁰C. Rearrangement would occur during the timeframe of the NMR experiment even in ds-THF which slows the rearrangement. As a consequence, purity was typically assessed by the more rapid ¹H NMR experiment.

[0058] tørt-Butyl 2-(2-methylallyloxy)-lH-indole-3-carboxylate (3g).

Following the general procedure (A) 3g (0.12 g, 0.418 mmol) was obtained in 34% yield as a pale yellow solid: mp 105-107 ⁰C; ¹H NMR (500 MHz, CDCl₃) δ 8.20 (bs, IH), 7.96 (d, J= 8.7 Hz, IH), 7.15-7.08 (m, 3H), 5.13 (s, IH), 5.01 (s, IH), 4.77 (s, 2H), 1.82 (s, 3H), 1.60 (s, 9H); ¹³C NMR (360 MHz, THF-d₈) δ 163.8, 156.6, 141.0, 129.9, 127.4, 121.2 (2), 121.1, 113.1, 110.4, 91.6, 78.6, 76.8, 28.6, 19.1; IR (film) 3237, 2976, 1656, 1552, 1459, 1366 cm^"1; HRMS (ES) calcd for C₁₇H_2INO₃Na (MNa⁺) 310.1419, found 310.1611.

[0059] Methyl 2-(2-methylallyloxy)-5-methoxy-lH-indole-3- carboxylate (3h). Following the general procedure (B) 3h (0.03 g, 0.11 mmol) was obtained in 22% yield as an off-white oil: ¹H NMR (300 MHz, CDCl₃) δ 8.44 (bs, IH), 7.59 (m, IH), 7.10 (d, J= 8.6 Hz, IH), 6.78 (d, J= 8.6 Hz, IH), 5.19 (s, IH), 5.06 (s, IH), 4.79 (s, 2H), 3.90 (s, 3H), 3.83 (s, 3H), 1.89 (s, 3H); ¹³C NMR (360 MHz, THF-dg) δ 164.6, 157.1, 156.3, 141.5, 128.2, 125.6, 113.1, 111.2, 110.1, 104.2, 90.2, 76.8, 55.4, 49.9, 19.1; IR (film) 3244, 2950, 1668, 1591, 1552, 1468, 1352, 1274, 1205 cm^"1; HRMS (ES) m/z = 298.1056 calcd for C₁₅H_nNO₄Na [MNa]⁺, found 298.1066.

[0060] Methyl 2-(2-methylallyloxy)-5-bromo-lH-indole-3- carboxylate (3i). Following the general procedure (B) 3i (0.07 g, 0.22 mmol) was obtained in 55% yield as an off-white oil: ¹H NMR (300 MHz, CDCl₃) δ 8.23 (bs, IH), 8.17 (d, J= 2.0 Hz, IH), 7.26 (m, IH), 7.09 (d, J= 8.5 Hz, IH), 5.20 (s, IH), 5.10 (s, IH), 4.85 (s, 2H), 3.93 (s, 3H), 1.90 (s, 3H); ¹³C NMR (360 MHz, THF-dg) δ 164.2, 157.6, 141.1, 134.6, 129.1, 124.3, 123.5, 115.1, 113.4, 112.4, 89.7, 76.8, 50.7, 19.1; IR (film) 3221, 2950, 1668, 1552, 1483, 1352, 1251, 1213 cm^"1; HRMS (ES) m/z = 346.0055 calcd for C₁₄Hi₄BrNO₃Na [MNa]⁺, found 346.0045.

[0061] Methyl 2-(2-methylallyloxy)-7-methoxy-lH-indole-3- carboxylate) (3j). Following general procedure (B), 3j (0.086 g, 0.31 mmol) was obtained in 43% yield as a white resin: ¹H NMR (500 MHz, CDCl₃) δ 8.45 (bs, IH), 7.63 (d, J= 8.1 Hz, IH), 7.13 (t, J= 8.0 Hz, IH), 6.66 (d, J= 7.9 Hz, IH), 5.21 (s, IH), 5.08 (s, IH), 4.83 (s, 2H), 3.94 (s, 3H), 3.90 (s, 3H), 1.90 (s, 3H); ¹³C NMR (360 MHz, THF-dg) δ 164.0, 156.0, 145.4, 141.1, 127.5, 121.9, 121.3, 113.5, 112.6, 101.9, 90.5, 77.0, 54.6, 49.3, 18.6; IR (film) 3221, 1950, 2842, 1668, 1552, 1475, 1367, 1282, 1220 cm^"1; HRMS (ES) m/z = 298.1056 calcd for Ci₅H_nNOaNa [MNa]⁺, found 298.1057.

[0062] Pd(7d)Cl₂. To a round-bottom flask was added PdCl₂(MeCN)₂ (0.20 g, 0.52 mmol) and 7d (0.133 g, 0.51 mmol), followed by addition of CH₂Cl₂ (12 rnL). The resulting solution was allowed to stir at room temperature for 24 h, then concentrated under vacuum to give Pd(7d)Cl₂ (0.29 g, 0.51 mmol) in 100% yield as a yellow solid.

[0063] Pd(Sa)Cl₂. To a round-bottom flask was added PdCl₂(MeCN)₂ (0.124 g, 0.48 mmol) and iϊBINAP (5a, 0.300 g, 0.48 mmol), followed by addition Of CH₂Cl₂ (15 mL). The resulting solution was allowed to stir at room temperature for 24 h, then concentrated under vacuum to give Pd(Sa)Cl₂ (0.384 g, 0.48 mmol) in 100% yield as a yellow solid.

General Procedure for the Asymmetric Meerwein-Eschenmoser Claisen Rearrangement:

[0064] (S)-Methyl 3-(2-methylallyl)-2-oxoindoline-3-carboxylate (4a). To a solution of the Pd(7d)Cl₂ complex (0.004 g, 0.008 mmol, 20 mol%) in CH₂Cl₂ (0.5 mL) was added via cannula a solution OfAgSbF₆ (0.005 g, 0.014 mmol, 40 mol%) in CH₂Cl₂ (0.50 mL). The resulting solution was stirred in the absence of light for 3 h, and filtered through a PTFE filter to remove the precipitated AgCl. The resulting clear yellow solution was cooled to 0 ⁰C, followed by addition of 3a (0.009 g, 0.038 mmol) in CH₂Cl₂ (1.0 niL) via cannula. The reaction mixture was stirred at 0 ⁰C until the starting material was completely consumed, as determined by TLC. Filtration through a plug of SiO₂ (5 mm x 2 cm) with 25% EtOAc/Hexanes and concentration of the solution under vacuum 4a (0.008 g, 0.033 mmol) in 89% yield as a white resin: M^ +79.25 (c 0.40, 89% ee, CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃) δ 8.84 (bs, IH), 7.27-7.26 (m, 2H), 7.05 (t, J= 7.9, IH), 6.94 (d, J= 7.7 Hz, IH), 4.65 (s, IH), 4.63 (s, IH), 3.69 (s, 3H), 3.06 (s, 2H), 1.41 (s, 3H); ¹³C NMR (500 MHz, CDCl₃) δ 176.1, 169.6, 141.3, 139.4, 129.1, 128.3, 124.4, 122.6, 115.7, 110.1, 59.9, 53.1, 41.2, 23.6; IR (film) 3250, 2953, 1741, 1702, 1621, 1475 cm^"1; HRMS (CI) m/z = 245.1052 calcd for C₁₄Hi₆NO₃ [MH]⁺, found 246.1136; CSP HPLC (Chiralpak OD, 1.0 niL/min, 96.5:3.5 hexanes:z-PrOH): tR(R) = 16.5 min, tR(5) = 20.3 min. The reaction was also conducted with 5 mol% catalyst (5 mol% Pd(7d)Cl₂ and 10 mol% AgSbF₆) following the same procedure to yield 4a in 100% yield and 88% ee.

[0065] (5)-Methyl S-allyM-oxoindoline-S-carboxylate (4b).

Following the general procedure, 4b (0.10 g, 0.043 mmol) was obtained in 100% yield as a white resin: fc«] D +51.30 (c 0.50, 83% ee, CH2C12); ¹H NMR (500 MHz, CDCl₃) δ 8.20 (bs, IH), 7.28-7.25 (m, 2H), 7.07 (t, J= 7.6 Hz, IH), 6.92 (d, J= 7.9 Hz, IH), 5.49-5.41 (m, IH), 5.08 (dd, J= 1.2, 17.0 Hz, IH), 4.97 (d, J = 10.1 Hz, IH), 3.71 (s, 3H), 3.04 (dd, J= 6.7, 13.8 Hz, IH), 2.97 (dd, J= 7.9, 13.8 Hz, IH); ¹³C NMR (500 MHz, CDCl₃) δ 175.6, 169.3, 141.1, 130.8, 129.1, 128.0, 124.0, 122.8, 120.0, 110.0, 59.6, 53.1, 38.4; IR (film) 3252, 3090, 2958, 2858, 1715, 1622, 1475, 1437, 1336, 1236 cm^"1; HRMS (ES) m/z = 254.0793 calcd for C₁₃Hi₃NO₃Na [MNa]+, found 254.0791; CSP HPLC (Chiralpak AD, 1.0 mL/min, 95.5 hexanes:z-PrOH): tR(S) = 18.4 min, tR(R) = 20.6 min.

[0066] (SVMethyl S-Cl-methylenebutylJ-l-oxoindoline-S-carboxylate (4c). Following the general procedure, 4c (0.009 g, 0.03 mmol) was obtained in

82% yield as a white resin: Mϊ +59.00 (c 0.45, 92% ee, CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃) δ 8.12 (bs, IH), 7.28-7.23 (m, 2H), 7.05 (t, J= 7.5 Hz, IH), 6.88 (d, J= 7.7 Hz, IH), 4.66 (t, J= 1.4 Hz, IH), 4.64 (s, IH), 3.69 (s, 3H), 3.08 (d, J = 16.7 Hz, IH), 3.05 (d, J= 16.8 Hz, IH), 1.68 (q, J= 7.4 Hz, 2H), 0.84 (t, J = 7.4 Hz, 3H); ¹³C NMR (500 MHz, CDCl₃) δ 176.0, 169.7, 145.0, 141.3, 129.1, 128.3, 124.4, 122.6, 113.2, 110.0, 60.0, 53.1, 39.5, 29.7, 12.3; IR (film) 3275, 2927, 2858, 1715, 1622, 1444, 1236 cm^"1; HRMS (CI) m/z = 260.1287 calcd for Ci₅Hi₈NO₃ [MH]⁺, found 259.1208; CSP HPLC (Chiralpak OD, 1.0 mL/min, 96.5:3.5 hexanes :z -PrOH): tR(R) = 13.6 min, tR(5) = 15.8 min.

[0067] (5)-Methyl 3-(2-(deuteromethylene)butyl)-2-oxoindoline-3- carboxylate (d-4c). Following the general procedure, d-4c (0.008 g, 0.03 mmol) was obtained in 80% yield as a white resin: Wr +43.13 (c 0.40, 92% ee, CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃) δ8.04 (bs, IH), 7.32-7.24 (m, 2H), 7.05 (t, J= 7.6 Hz, IH), 6.88 (d, J= 7.6 Hz, IH), 4.63 (s, 0.5 H, Z-deutero), 4.62 (s, 0.5 H, E-deutero), 3.70 (s, 3H), 3.07 (d, J= 16.3 Hz, IH), 3.04 (d, J= 16.2 Hz, IH), 1.68 (q, J= 7.3 Hz, 2H), 0.84 (t, J= 7.4 Hz, 3H); ¹³C NMR (500 MHz, CDCl₃) δ 175.8, 169.9, 145.1, 141.4, 129.3,

128.6, 124.7, 122.8, 113.1 (t, Jl CD = 23.6 Hz), 110.1, 60.2, 53.4, 39.7, 29.9, 12.5; IR (film) 3252, 3090, 2981, 2935, 1715, 1622, 1475, 1375, 1251, 1159 cm^" ¹J HRMS (ES) m/z = 283.1169 calcd for C₁₅Hi₆DNO₃Na [MNa]⁺, found 283.1173; CSP HPLC (Chiralpak OD, 1.0 niL/min, 96.5:3.5 hexanes :z -PrOH): IR(R) = 13.6 min, IR(S) = 15.8 min.

[0068] (S)-Benzyl 3-allyl-2-oxoindoline-3-carboxylate (4d).

Following the general procedure except that Pd(5a)C12 was employed, 4d (0.008 g, 0.03 mmol) was obtained in 74% yield as a white resin: MB +51.38 (c 0.40, 72% ee, CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃) δ 8.28 (bs, IH), 7.28- 7.22 (m, 5H), 7.17-7.16 (m, 2H), 7.05 (td, J= 7.5, 0.9 Hz, IH), 6.90 (d, J= 7.8 Hz, IH), 5.50- 5.41 (m, IH), 5.16 (d, J= 15.5 Hz, IH), 5.14 (d, J= 15.6 Hz, IH), 5.08 (dd, J= 1.4, 16.9 Hz, IH), 4.96 (dd, J= 1.7, 10.1 Hz, IH), 3.05 (dd, J= 6.7, 13.9 Hz, IH), 2.99 (dd, J= 7.9, 13.9 Hz, IH); ¹³C NMR (500 MHz, CDCl₃) δ 175.3, 168.6, 141.2, 135.3, 130.8, 129.1, 128.4, 128.1, 128.0, 127.4, 124.0, 122.7, 120.0, 110.0, 67.3, 59.7, 38.2; IR (film) 3259, 3066, 2927, 1715, 1622, 1468, 1336 cm^"1; HRMS (ES) m/z = 308.12084 calcd for Ci₉Hi₈NO₃ [MH]⁺, found 308.1273; CSP HPLC (Chiralpak OD, 1.0 niL/min, 96.5:3.5 hexanes :z -PrOH): IR(R) = 20.7 min, tR(5) = 29.7 min.

[0069] (S)-Isopropyl S-allyl-l-oxoindoline-S-carboxylate (4e).

Following the general procedure except that Pd(5a)C12 was employed, 4e (0.01 g, 0.04 mmol) was obtained in 91% yield as a white resin: Mt +44.20 (c 0.50, 74% ee, CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃) δ 8.04 (bs, IH), 7.25-7.23 (m, 2H), 7.05 (t, .7=7.6 Hz, IH), 6.90 (d, J= 7.8 Hz, IH), 5.50-5.41 (m, IH), 5.07 (d, J= 17.0 Hz, IH), 5.02 (m, IH), 5.00 (d, J= 10.1 Hz, IH), 3.01 (dd, J= 6.7, 13.8 Hz, IH), 2.95 (dd, J= 7.8, 13.8, IH), 1.23 (d, J= 6.3 Hz, 3H), 1.13 (d, J= 6.3 Hz, 3H); ¹³C NMR (500) MHz, CDCl₃) δ 175.5, 168.3, 141.1, 131.0, 128.9, 128.4, 123.9, 122.7, 119.8, 109.8, 69.7, 59.8, 38.3, 21.5, 21.3; IR (film) 3252, 3090, 2981, 2927, 2858, 1722, 1622, 1468, 1236 cm^"1; HRMS (ES) m/z = 282.1208 calcd for C₁₅H₁₇NO₃Na [MNa]⁺, found 282.1092; CSP HPLC (Chiralpak OD, 1.0 niL/min, 96.5:3.5 hexanes :z -PrOH): tR(R) = 11.8 min, tR(5) = 14.9 min.

[0070] (S)-tert-Butyl S-allyM-oxoindoline-S-carboxylate (4f).

Following the general procedure except that Pd(5a)C12 was employed, 4f (0.006 g, 0.02 mmol) was obtained in 60% yield as a white resin: Mt +106.5 (c 0.30, 92% ee, CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃) δ8.95 (bs, IH), 7.26-7.23 (m, 2H), 7.05 (t, J= 7.6 Hz, IH), 6.89 (d, J= 7.8 Hz, IH), 5.50 (m, IH), 5.06 (d, J= 17.0 Hz, IH), 4.94 (d, J= 10.1 Hz, IH), 2.98-2.90 (m, 2H), 1.31 (s, 9H); 13C NMR (500 MHz, CDCl₃) 5175.9, 167.7, 141.2, 131.2, 128.8, 128.7, 123.7, 122.6, 119.5, 109.7, 82.5, 60.5, 38.2, 27.7; IR (film) 3252, 3090, 2981, 2927, 1722, 1622, 1475, 1251, 1159 cm^"1; HRMS (CI) m/z = 274.1459 calcd for C₁₆H₂₀NO₃ [MH]⁺, found 274.1362; CSP HPLC (Chiralpak OD, 1.0 mL/min, 96.5:3.5 hexanes :z -PrOH): tR(R) = 7.2 min, tR(5) = 8.8 min.

[0071] (SVfc^Butyl S-^-methylallyl^-oxoindoline-S-carboxylate (4g). Following the general procedure except that Pd(5a)C12 was employed, 4g

(0.018 g, 0.063 mmol) was obtained in 82% yield as a white resin: E^»] c +66.89 (c 0.90, 82% ee, CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃) 69.09 (bs, IH), 7.23 (m, 2H), 7.02 (t, J= 7.6 Hz, IH), 6.90 (d, J= 7.7 Hz, IH), 4.61 (s, 2H), 3.04 (d, J = 13.9 Hz, IH), 2.97 (d, J= 13.9 Hz, IH), 1.38 (s, 3H), 1.36 (s, 9H); ¹³C NMR (500 MHz, CDCl₃) 6175.6, 167.9, 141.1, 139.9, 129.0, 128.8, 124.1, 122.4, 115.3, 109.6, 82.5, 60.7, 40.8, 27.7, 23.7; IR (film) 3262, 2980, 2930, 1733, 1621, 1475 cm^"1; HRMS (ES) m/z = 310.1419 calcd for C₁₇H₂₁NO₃Na [MNa]⁺, found 310.1416; CSP HPLC (Chiralpak OD, 1.0 niL/min, 96.5:3.5 hexanes :z -PrOH): tR(R) = 6.1 min, tR(5) = 9.2 min.

[0072] (5)-Methyl 5-methoxy-3-(2-methylallyl)-2-oxoindoline-3- carboxylate (4h). Following the general procedure, 4h (0.006 g, 0.02 mmol) was obtained in 60% yield as a white resin: Mϊ +40.83 (c 0.30, 91% ee, CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃) 67.55 (bs, IH), 6.88 (s, IH), 6.80 (m, 2H), 4.70 (s, IH), 4.65 (s, IH), 3.79 (s, 3H), 3.70 (s, 3H), 3.05 (d, J= 19.5 Hz, IH), 3.02 (d, J = 19.4 Hz, IH), 1.42 (s, 3H); ¹³C NMR (500) MHz, CDCl₃) 6 175.6, 169.6, 155.9, 139.4, 134.5, 129.5, 115.7, 113.9, 111.3, 110.3, 60.2, 55.8, 53.2, 41.2, 23.7; IR (film) 3259, 2927, 2858, 1715, 1607, 1491, 1444, 1236 cm^"1; HRMS (ES) m/z = 276.1158 calcd for C₁₅Hi₈NO₄ [MH]⁺, found 276.1248; CSP HPLC (Chiralpak OD, 1.0 niL/min, 96.5:3.5 hexanes :z-PrOH): tR(R) = 20.7 min, tR(5) = 23.8 min.

[0073] (S)-Methyl 5-bromo-3-(2-methylallyl)-2-oxoindoline-3- carboxylate (4i). Following the general procedure, 4i (0.009 g, 0.03 mmol) was obtained in 82% yield as a white resin: E⁰O D +38.67 (c 0.45, 87% ee, CH₂Cl₂); IH NMR (500 MHz, CDCl₃) δ 8.34 (bs, IH), 7.40 (m, 2H), 6.80 (d, J = 8.7 Hz, IH), 4.70 (s, IH), 4.63 (s, IH), 3.72 (s, 3H), 3.05 (d, J = 19.8 Hz, IH), 3.02 (d, J = 19.8 Hz, IH), 1.46 (s, 3H); ¹³C NMR (500) MHz, CDCl₃) δ 175.3, 168.9, 140.2, 139.0, 132.0, 130.2, 127.7, 116.1, 115.2, 111.4, 59.9, 53.4, 41.2, 23.7; IR (film) 3252, 2958, 2858, 1738, 1614, 1475, 1228 cm^"1; HRMS (ES) m/z = 324.0157 calcd for C₁₄Hi₅BrNO₃ [MH]⁺, found 324.0240; CSP HPLC (Chiralpak AS, 1.0 niL/min, 92.5:7.5 hexanes:i-PrOH): tR(R) = 15.1 min, tR(S) = 25.5 min.

[0074] (S)-Methyl 7-methoxy-3-(2-methylallyl)-2-oxoindoline-3- carboxylate (4j). Following the general procedure, 4j (0.009 g, 0.03 mmol) was obtained in 95% yield as a white resin: E-Ii= +82.78 (c 0.450, 85% ee, CH₂Cl₂); ¹H NMR (500 MHz, CDCl₃) δ 8.65 (bs, IH), 7.01 (t, J = 8.0 Hz, IH), 6.89 (d, J = 7.5 Hz, IH), 6.84 (d, J = 8.1 Hz, IH), 4.67 (s, IH), 4.64 (s, IH), 3.88 (s, 3H), 3.69 (s, 3H), 3.04 (m, 2H), 1.43 (s, 3H); ¹³C NMR (500) MHz, CDCl₃) δ 174.7, 169.6, 143.8, 139.5, 130.1, 128.9, 123.1, 116.6, 115.6, 111.3, 60.5, 55.6, 53.1, 41.0, 23.7; IR (film) 3229, 3090, 2958, 2850, 1715, 1622, 1498, 1228 cm^"1; HRMS (ES) m/z = 298.1056 calcd for Ci₅H_nNO₄Na [MNa]⁺, found 298.1057; CSP HPLC (Chiralpak AS, 1.0 niL/min, 96.5:3.5 hexanes:i-PrOH): tR(R) = 21.3 min, tR(S) = 27.0 min.

[0075] 7V-Camphorsulfonyl derivative of 4b (S7). To a solution of 60% NaH in oil (0.003 g, 0.13 mmol) in THF (2 niL) at 0 ⁰C was added 4f (0.018 g, 0.07 mmol). After stirring 5 min, camphorsulfonyl chloride (0.0180 g, 0.07 mmol) was added and the mixture was warmed to rt. After 2 h, H₂O was added, and the aqueous layer was extracted with CH₂Cl₂, dried over Na2SO₄, and concentrated under vacuum to give the camphorsulfonyl derivative in 47% yield as a white solid (0.015 g, 0.03 mmol) which was used without further purification. The camphorsulfonyl derivative (0.015 g, 0.03 mmol) was treated with a solution of 2,4- dinitrophenylhydrazine (0.26 mL, 0.12 M) in 1 :1 H₂SO₄/MeOH. The resulting solution was allowed to stir for 10 min, then cooled to 0 ⁰C, where upon formation of crystals were observed after 24 h. Instead of obtaining the expected hydrazone, the transesterified methyl ester product was observed. The configuration obtained from the crystal structure was used to establish the absolute stereochemistry of 4b. The remaining compounds, 4a and 4c-4j were assigned by analogy. ¹H NMR (500 MHz, CDCl₃) δ 7.82 (d, J= 8.3 Hz, IH), 7.39-7.32 (m, 2H), 7.23 (t, J= 7.5 Hz, IH), 5.46-5.36 (m, IH), 5.12 (d, J= 17.0 Hz, IH), 5.03 (d, J= 10.2 Hz, IH), 3.86 (d, J= 15.0 Hz, IH), 3.72 (s, 3H), 3.54 (d, J= 14.9 Hz, IH), 3.06 (m, 2H), 2.50-2.38 (m, 2H), 2.16-2.14 (m, IH), 2.11-2.04 (m, IH), 1.98-1.94 (m, IH), 1.82-1.76 (m, IH), 1.50-1.44 (m, IH), 1.16 (s, 3H), 0.91 (s, 3H).

Example 5

[0076] A series of metal catalyzed rearrangements were preformed and reported in the following paragraphs. While zinc, nickel, and silver catalysts were ineffective, palladium catalysts possessed the necessary combination of substrate/product affinity and effective chiral environment. The optimal ligand sets for turnover were found to be the bisphosphines and phosphinooxazolines (PHOX) (Table 1). See, Allen, J. V.; Dawson, G. J.; Frost, C. G.; Williams, J. M. J. Tetrahedron 1994, 50, 799-808. For substrate 3a, the t-BuPHOX (7d) palladium catalyst was superior providing 4a with excellent yield and high enantioselectivity (entry 11, 89% ee). The counterion was crucial in line with catalyst coordination to the substrate /?-amidoester array; the SbF₆ and BF₄ complexes provided faster rates and greater turnover than the corresponding perchlorates, triflates, and halides.

[0077] Good to excellent enantioselectivities were obtained in the rearrangement of a range of substrates (Table 2). The reactions were very fast, occurring within 5-30 min at 0 ⁰C (Surprisingly, lowering the temperature to improve enantioselectivity caused a disproportionate change in the rate (>12 h at- 20 ⁰C).) Optimal rates and enantioselectivities were observed in CH₂Cl₂ and no catalysis was observed in ethereal solvents such as Et₂O or THF.

[0078] For the bisphosphine (5, 6) derived catalysts, the enantioselectivity steadily increased as the size of the C3 ester group increased (Table 2, entries 2, 4-7) with the tert-butyl ester providing 89% ee with BINAP and 92% ee with a smaller dihedral angle ligand, difluoroPHOS. See, Jeulin, S.; Duprat de Paule, S.; Ratovelomanana-Vidal, V.; Genet, J. -P.; Champion, N.; Dellis, P. Angew. Chem., Int. Ed. 2004, 43, 320-325. On the other hand, sterically larger groups at the allyl C2' position eroded selectivity (Table 2, entries 1, 3, 8). The PHOX series proved complementary providing the best selectivity with the smaller C3 methyl ester and the larger C2' groups (Table 2, entries 10-14). Notably, reactions conducted on a larger scale proceeded with slightly improved enantioselectivity (entry 10). Furthermore, high enantioselection was retained with either electron donating or electron withdrawing substitution on the aromatic ring (Table 2, entries 15-17). It was found that catalyst loadings could be lowered to 5 mol % with no loss in enantioselectivity (Table 2, entries 9, 11).

[0079] Because palladium(II) catalysts are employed here, the possibility of π-allyl cation chemistry (i.e., 8) needed to be considered. On the basis of the results with other Lewis acids such as copper and zinc complexes (good to excellent enantioselectivity, but poor turnover), our preliminary hypothesis centers on a Lewis acid-catalyzed mechanism. Further support for this pathway was found in the lack of any deuterium scrambling with labeled substrate d-3c (Scheme 2).

Scheme I. Meerwein-Eschenmoser Claisen Rearrangement

Table 1. Metal-Catalyzed Rearrangement (Scheme 1 , 3a to 4a).

[0080] The absolute configuration of the products was established through crystal structures of derivatives.

Claims

What is Claimed:

1. A process for the preparation of a compound of the formula I

comprising contacting a compound of formula II

-C(R⁵)(R⁶)-C≡C-R³; Y is or -C(R³)=C=C(R⁵)(R⁶);

X is NH, NR¹⁵, O or S;

R¹ is alkyl, aryl, O-alkyl, O-aryl, or NR⁹R¹⁰;

R² is hydrogen, alkyl, aryl, halogen, silyl, or stannyl;

(CH₂)₄;

R⁵ and R⁶ are each, independently, hydrogen, alkyl or aryl;

R⁸, R⁹, R¹⁰, and R¹¹ are each, independently, alkyl or aryl;

R¹⁵ is alkyl, aryl, CO₂R¹⁶, CONR¹⁶;

R¹⁶ is alkyl or aryl; and a is 0 or an integer from 1 to 4.

2. The process of claim 1 wherein the compound of the formula I is of the formula:

and the compound of formula II is of the formula:

3. The process of claim 1, wherein the compound of the formula I is of the formula:

and the compound of formula II is of the formula:

4. The process of claim 1, wherein said contacting is performed at a temperature of 0 to 25 ⁰C.

5. The process of claim 1 , wherein X is NH.

6. The process of claim 1 , wherein said contacting is performed in the presence of a solvent that comprises CH₂Cl₂.

7. The process of claim 1, wherein a is 1 or 2.

8. The process of claim 1 , wherein a is 1.

9. The process of claim 1, wherein R¹ is alkyl or aryl and R² is alkyl, aryl, or halogen.

10. The process of claim 1, wherein X is NH;

R¹ is alkyl or aryl;

R² is alkyl, aryl, or halogen; and a is 1 or 2.

11. The process of claim 10, wherein R³ is alkyl, aryl, halogen, OR⁹,

NR⁷NR⁸, CN, or COR 10

12. The process of claim 1, wherein said contacting is performed for 5 minutes to 24 hours.

13. A process for the preparation of a compound of the formula

comprising:

— contacting a compound of the formula

with a compound of the formula

to produce a compound of the formula

R⁵ and R⁶ are each, independently, hydrogen, alkyl or aryl; R⁷ is alkyl, alkenyl, alkynyl, aryl, halogen, OR⁸, NR⁹NR¹⁰, CN, or COR¹ *_; R⁸, R⁹, R¹⁰, and R¹¹ are each, independently, alkyl or aryl; R¹⁵ is alkyl, aryl, CO₂R¹⁶, CONR¹⁶; R¹⁶ is alkyl or aryl; and a is 0 or an integer from 1 to 4; wherein wherein R² and R⁴, optionally, together form a carbon-carbon bond.

14. The process of claim 13, wherein X is NH.

15. The process of claim 13, wherein a is 1 or 2.

16. The process of claim 13, wherein a is 1.

17. The process of claim 13, wherein R¹ is alkyl or aryl and R² is alkyl, aryl, or halogen.

18. The process of claim 13 , wherein

X is NH;

R¹ is alkyl or aryl;

R² is alkyl, aryl, or halogen; and a is 1 or 2.

19. The process of claim 18, wherein R³ is alkyl, aryl, halogen, OR⁹, NR⁷NR⁸, CN, or COR¹⁰.