Preparation of 2-diazo-2-oxopiperidin-3-yl-3-oxopropanoates. Useful reagents for Rh(II)-catalyzed cyclization-cycloaddition chemistry

2-Diazo-2-oxopiperidin-3-yl-3-oxopropanoates containing a tethered indolyl group have been identified as useful intermediates for the Rh(II)-catalyzed cyclization-cycloaddition cascade for the synthesis of the core skeleton of various aspidosperma alkaloids. Several synthetic methods were developed to rapidly construct these important diazo imide substrates using cheap and readily available reagents.


Introduction
In recent years, a widespread upsurge of activity in the stereoselective preparation of highly substituted nitrogen heterocycles, especially structurally complex alkaloids has occurred. 1In particular, members of the Aspidosperma alkaloid family have occupied a central place in natural product chemistry because of their diverse biological activity. 2This family of indole alkaloids contains over 250 members that share in their molecular structure a common pentacyclic ABCDE framework, with the C-ring being of critical importance because all six stereocenters and most of the functionalities are located in this ring. 3Individual members differ mainly in functionality and stereochemistry.Over the years, efficient and elegant routes to this molecular framework have been developed. 4,5ur approach to the Aspidosperma skeleton was guided by a long-standing interest in developing new applications of the Rh(II) cyclization/cycloaddition cascade for the synthesis of complex natural products. 6The generation of onium ylides by a transition-metal promoted cyclization reaction has emerged in recent years as an important and efficient method for the assembly of ring systems that are difficult to prepare by other means. 7In earlier studies we described the formation of cyclic carbonyl ylide dipoles by a process involving cyclization of an electrophilic metallo-carbenoid onto an adjacent carbonyl group. 8N H Et MeO The general reaction investigated is illustrated in Scheme 1; variations in chain length (n = 0, 1, 2) and nature of the activating group (G) were explored. 9With limited exceptions, 10 alkyl and aryl ketones were employed and dipole 5 was generated by the rhodium(II)-catalyzed decomposition of the diazoalkanedione in benzene at 80 ºC. 11 Rh(II)

Scheme 1
More recently, we became interested in the formation of push-pull dipoles from the Rh(II)catalyzed reaction of α-diazo imides 12 and noted that a smooth intramolecular 1,3-dipolar cycloaddition occurred across both alkenyl and heteroaromatic π-bonds to provide novel pentacyclic compounds in good yield and in a stereocontrolled fashion. 13,14Our recent total synthesis of (±)-aspidophytine nicely demonstrates the utility of this cascade methodology for the construction of complex aspidosperma alkaloids. 15Thus, the Rh(II)-catalyzed reaction of diazo imido indole 7 produced cycloadduct 9 in 97% yield via the intermediacy of the carbonyl ylide dipole 8.The acid lability of cycloadduct 9 was exploited to provide the complete skeleton of aspidophytine in several additional steps (Scheme 2).

Results and Discussion
Several methods for preparing the diazo imides necessary for dipole formation have been explored.One option that we have used involves treating the commercially available 3carboethoxy-2-piperidone (11) with n-BuLi at -78 ºC followed by the addition of an indole acid chloride such as 12.This results in the joining of the two fragments to give imide 13 in 45% yield.A subsequent reaction of 13 with n-butylmagnesium chloride in THF at 0 ºC followed by the addition of ethyl 2-diazomalonyl chloride 16 afforded the indolyl substituted diazo imide 14 in 59% yield (Scheme 3).
Since the overall yield of diazo imide 14 obtained by this method was somewhat low, we opted to study some alternate procedures to prepare the starting diazo substrates.With this in mind, diazo imide 19 was synthesized in the manner outlined in Scheme 4. 3-Ethyl-2oxopiperidine-3-carboxylic acid 16 was first prepared in three steps from diethyl ethylmalonate (15).Treatment of 16 with 1,1-carbonyldiimidazole followed by reaction with the dianion of mono-methyl malonate furnished β-ketoester 17 in 60% yield.This compound was then converted to the indolyl-N-acylamide 18 (65%) by reaction with acid chloride 12 using 4Aº molecular sieves as a neutral acid scavenger.Finally, the requisite α-diazo imide 19 was easily obtained from 18 using standard Regitz diazo transfer conditions 17 and was isolated in 90% yield.Several other 3-substituted diazo-imides related to 19 could be prepared according to the reaction sequence outlined in Scheme 5. Deprotonation of the piperidone 11 with 1.1 equiv of nbutyllithium followed by reaction with 2-iodoethyl benzyl ether afforded lactam 20 in 70% yield.The ethyl ester portion of 20 was converted into the methyl 3-oxopropanoate group using a modified Masamune procedure 18 which furnished β-keto ester 21 in 82% yield.A related sequence of reactions was also used to prepare lactams 23 and 24.Thus, the anion derived from the piperidone 11 was allowed to react with t-butyl bromoacetate together with a catalytic amount of t-butyl ammonium iodide which lead to the formation of lactam 22 in 80% yield.Treatment of the resulting t-butyl ester 23, derived from heating 22 with (MeO) 3 CH/MeOH in the presence of p-TsOH gave the corresponding methyl ester 24 in almost quantitative yield (Scheme 5).When these lactams were allowed to react with the acid chloride derived from 2-(Ntosyl-1H-indol-3-yl)acetic acid, the expected imides were readily formed in high yield and were easily converted into the corresponding diazo substrates 25 and 26 using the Regitz diazotization procedure. 17

Scheme 5
Still another method that was used to prepare the key diazo-imide substrates needed for the Rh(II) cascade involved the initial preparation of a methyl 2-diazo-3-(3-alkyl-2-oxopiperidin-3yl)-3-oxopropanoate (i.e., 27 or 28) and then coupling it with an appropriate acid chloride (Scheme 6).By carrying out the synthesis of the indolyl substituted diazo imides in this manner, the Regitz diazo transfer reaction 17 can be avoided in the final step thereby simplifying the synthesis.Thus, piperidinones 21 and 23 were easily converted to the corresponding diazo lactams 27 and 28 in excellent yield.These compounds, in turn, were treated with indolyl acid chloride 12 which resulted in the formation of the desired diazo imides 29 and 30 in 82% and 73% yield, respectively.

Scheme 6
In conclusion, several synthetic methods have been developed to rapidly prepare various indolyl substituted 2-diazo-2-oxopiperidin-3-yl 3-oxopropanoates in high yield.Treatment of these substrates with Rh 2 (OAc) 4 generate push-pull 1,3-dipoles that undergo ready intramolecular dipolar cycloaddition across the indolyl π-bond.We are currently investigating the scope and limitations of the Rh(II) cyclization-cycloaddition cascade as a method for the synthesis of various aspidosperma alkaloids, the results of which will be disclosed in due course.

A general procedure for the synthesis of indolyl diazo imides 25 and 26
In a 200 mL round bottomed flask a sample of 2-(1-tosyl-1H-indol-3-yl) acetic acid (1.5 equiv) was taken up in CH 2 Cl 2 .After stirring for 5 min, (COCl) 2 (4.0 equiv) was added dropwise together with 2 drops of DMF.The solution was stirred at RT for 4 h and was then concentrated under reduced pressure.The resulting solid was dissolved in CH 2 Cl 2 and the solution was added dropwise to a solution of the appropriate lactam 24 (1.0 mmol) containing an excess of 4Å mesh molecular sieves in CH 2 Cl 2 .The reaction mixture was allowed to stir at RT for 12 h, filtered through a pad of Celite and concentrated under reduced pressure.The residue was subjected to flash silica gel chromatography.To the above keto ester (1.0 equiv) in 140 mL of CH 3 CN at 0 ºC was added 2.3 mL (1.0 equiv) of Et 3 N.The solution was allowed to stir for 20 min and then 1.9 g (2.0 equiv) of mesyl azide was added and the reaction mixture was allowed to stir for 1.5 h.The solution was concentrated under reduced pressure and the residue was subjected to flash chromatography on silica gel to give 25 as a pale yellow oil in 88%