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. Author manuscript; available in PMC: 2018 Oct 4.
Published in final edited form as: J Am Chem Soc. 2017 Sep 25;139(39):13944–13949. doi: 10.1021/jacs.7b08496

Sequential Ruthenium Catalysis for Olefin Isomerization and Oxidation: Application to the Synthesis of Unusual Amino Acids

Marc Liniger 1,†, Yiyang Liu 1, Brian M Stoltz 1,*
PMCID: PMC5628162  NIHMSID: NIHMS906975  PMID: 28918631

Abstract

How can you use a ruthenium isomerization catalyst twice? A ruthenium-catalyzed sequence for the formal two-carbon scission of allyl groups to carboxylic acids has been developed. The reaction includes an initial isomerization step using commercially available ruthenium catalysts followed by in situ transformation of the complex to a metal-oxo species, which is capable of catalyzing subsequent oxidation reactions. The method enables enantioselective syntheses of challenging α-tri- and tetrasubstituted α-amino acids including an expedient total synthesis of the antiepileptic drug levetiracetam.

SYNOPSIS TOC

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INTRODUCTION

The use of a single metal catalyst for several chemical transformations in a one-pot and/or a sequential manner1 is highly desirable due to high material cost and limited resources of transition metals.2 Moreover, new tools for modifying prevalent functional groups, which are easily installed in a chemo- and stereoselective fashion, are needed to expand the application of novel methodology in both academic and industrial settings.3 In this context, allyl groups are ubiquitous and their introduction is very well established including asymmetric additions.4 In general, three modes for their installation can be distinguished (Figure 1): As a nucleophile5,6 (e.g. Grignard addition7), as an electrophile8 (e.g. Tsuji-Trost allylation9) or as a formally neutral species10 (e.g. Keck radical allylation11).

Figure 1.

Figure 1

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General modes for the introduction of allyl groups.

Most of these methods not only find widespread use in organic synthesis, but also allow for the installation of allyl groups in a highly stereoselective fashion, even to build challenging chiral quaternary stereocenters.12 However, tools for the formal scission of two carbons of an allyl group leading to a truncated carboxylic acid using a single transition metal catalyst have, to our knowledge, not been described (Scheme 1A, M1=M2). The use of only one catalyst is in strong contrast to the field of one-pot catalysis, where for instance two transition metal catalysts are used for isomerization/metathesis reactions. 13

Scheme 1.

Scheme 1

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Sequences and methods for the introduction of chiral carboxylic acid groups.

Although a sequence involving vinylation followed by oxidative cleavage of the double bond would in theory lead to the same carboxylic acid product, asymmetric vinylation reactions are far less established than allylations (Scheme 1B).4 In particular, catalytic enantioselective vinylation of carbonyl enolates is still highly challenging and limited in substrate scope and, moreover, methods for the construction of quaternary stereocenters are very rare.12,14 Even more scarce and far less established are catalytic enantioselective carboxylations (Scheme 1C).15

As a result, we focused our attention on the catalytic oxidative scission of two carbons from the tail of an allyl unit in order to render such groups as carboxylic acid synthesis equivalents (Scheme 2). Herein, we present the results of that study and provide illustrative examples of this new method in the context of high value and unusual amino acid synthesis.

Scheme 2.

Scheme 2

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Ruthenium-catalyzed two-carbon truncation of allyl groups to carboxylic acids.

RESULTS AND DISCUSSION

After exploring a variety of transition metal catalysts known for alkene isomerization (iridium, rhodium, palladium, ruthenium; for details see the Supporting Information), we found that ruthenium catalysts performed best and were amenable to further oxidative catalysis (Scheme 2).

In particular, the commercially available Grubbs second generation catalyst 1a (Figure 2) under Nishida’s conditions16 was highly chemoselective for alkene isomerization and displayed good conversion (>90%) without noticeable side reactions. Moreover, we discovered that the in situ formed Ru–H complex17 1b, after solvent exchange, can be oxidized with NaIO4 to an oxidized ruthenium species,18 which is capable of catalyzing subsequent oxidation reactions (e.g. oxidative cleavage of alkenes, Scheme 2).19 It has to be reinforced at this point that we do not add a new external ruthenium source for the second step. Instead, the crude transition metal catalyst from the previous isomerization step is modified in situ and reused for the catalytic oxidation reactions. Moreover, the only operation between the two steps is evaporation of the solvent from the isomerization reaction (toluene for 1a, acetone for 2) followed by dissolution of the crude reaction mixture in the solvent mixture used for oxidation (CCl4, MeCN, H2O).

Figure 2.

Figure 2

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Identified ruthenium catalysts for olefin isomerization/ oxidation sequences – An in situ formed ruthenium-hydride complex 1b derived from Grubbs second generation catalyst (1a) and Grotjahn’s catalyst (2).

Even though NaIO4 mediated oxidations of ruthenium alkylidene complexes and their use in sequential and tandem catalysis19b,20 have been described previously (e.g. RCM/dihydroxylation),21 the modification and multiple use13 of a ruthenium-hydride complex17 1b (derived from precatalyst 1a) or a ruthenium phosphine-imidazole complex22 2 in an isomerization/oxidation sequence was not known, until now (Figure 2).

Hence, chiral homoallylic amine 3, which was readily synthesized via diastereoselective allylation of Ellman’s sulfinimine, 5e was subjected to the optimized conditions using Grubbs catalyst 1a giving the isomerized alkene in 98% conversion (Scheme 3A). After oxidation of the crude catalyst, an alkene cleavage/sulfinamide oxidation duet23 took place furnishing Bus-protected24 D-tert-leucine (4) in 72% yield over 2 steps, notably without racemization (99% ee). The Bus protected amino acid 4 can be employed directly for a peptide coupling as reported by Hanessian,24 or the Bus group is readily cleaved under acidic conditions to afford D-tert-leucine (5) in 96% yield (98% ee) after ion exchange chromatography.

Scheme 3.

Scheme 3

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a) 1. Grubbs 1a (5 mol%), VTMS, toluene, reflux, 21 h, 98% conv., E/Z 4.4:1; 2. NaIO4, CCl4, MeCN, H2O, 23°C, 2.5 d, 72% yield over 2 steps, 99% ee; b) 1. TfOH, CH2Cl2, 0°C, 2.5 h; 2. IEC, 96% yield, 98% ee; c) RuCl3•H2O (5 mol%), NaIO4, CCl4, MeCN, H2O, 23°C, 16 h, 93% yield; d) 1. TfOH, CH2Cl2, 0°C→23°C, 2 d; 2) IEC, 91% yield, 98% ee; e) 1. Grubbs 1a (5 mol%), VTMS, toluene, 128°C, 16 h, 97% conv., E/Z 4:1; 2. NaIO4, CCl4, MeCN, H2O, 23°C, 22 h, 88% yield over 2 steps; f) 1. 4 M aq. HCl, MeOH, reflux, 24 h; 2. IEC, 57% yield; g) 1. Grubbs 1a (5 mol%), VTMS, toluene, 128°C, 18 h, 92% conv., E/Z 4.5:1; 2. NaIO4, CCl4, MeCN, H2O, 23°C, 24 h, 62% yield over 2 steps; h) ClCO2Et, NEt3, THF, then NH4OH, 0°C→23°C, 19 h, 67% yield, >98% ee. IEC=ion exchange chromatography, VTMS=vinyloxy trimethylsilane.

Alternatively, by leaving out the olefin isomerization, sulfinamide 3 was subjected to a similar alkene cleavage/ sulfinamide oxidation sequence with a catalytic amount of RuCl3 hydrate giving Bus-protected β-amino acid 6 in 93% yield (Scheme 3B). After deprotection and ion exchange chromatography, (S)-β-neopentylglycine (7) was obtained in 91% yield and 98% ee. Benzoyl protected amine 8, which is accessible in enantiopure form using Schaus’ allylboration,25 performed equally well in our sequential ruthenium catalysis, affording carboxylic acid 9 in 88% yield over 2 steps (Scheme 3C). Benzoyl deprotection with aqueous HCl in methanol provided racemic tert-leucine (5) in 57% yield.

The sequential ruthenium catalysis was then used for an enantioselective total synthesis of levetiracetam (12), the active pharmaceutical ingredient of the antiepileptic medicine Keppra ® (Scheme 3D).26 The synthesis commenced from homoallylic amide 10, which was prepared in four steps from commercially available propionaldehyde and Ellman’s auxiliary5e (see the Supporting Information for details). Sequential ruthenium catalysis of alkene 10 with Grubbs catalyst 1a provided access to carboxylic acid 11 in 62% yield over two steps. Amidation of 11 was achieved via the corresponding mixed anhydride and reaction with ammonium hydroxide as described previously by Sánchez.27 Levetiracetam (12) was isolated in 67% yield (>98% ee) and, after one recrystallization, was enriched to excellent enantiopurity (>99.9% ee).

We next applied our sequential ruthenium catalysis conditions to α-quaternary lactams (Scheme 4), which were readily available in enantiopure form using palladium-catalyzed decarboxylative allylic alkylation.8a,28 The unprotected methyl- and ethyl-substituted lactams 13 and 14 were treated with a catalytic amount of Grubbs catalyst 1a and the internal alkene was subsequently cleaved to give the crude carboxylic acids. A Curtius rearrangement29 then furnished isocyanates 15 and 16 in 27% and 47% yield over 3 steps, respectively.30 Likewise, we found that 2 mol% of Grotjahn’s catalyst22 (2, Figure 2) worked equally well31 for the ruthenium-catalyzed isomerization/oxidation sequence of lactam 14 to give, after Curtius rearrangement, isocyanate 16 in a comparable 52% yield over 3 steps.32 Hydrolysis of the isocyanate and the amide bond of 15 and 16 were achieved under acidic conditions to give access to enantiopure (R)-α-methylornithine33 (17) and (R)-α-ethylornithine34 (18) in 61% and 95% yield, respectively. The latter has been synthesized for the first time as a single enantiomer. 34 Biologically, both α-alkyl ornithine analogs are known to be ornithine decarboxylase inhibitors.33a,34

Scheme 4.

Scheme 4

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a) 15: 1. Grubbs 1a (5 mol%), VTMS, toluene, 130°C, 18 h, 88% conv.; 2. NaIO4, CCl4, MeCN, H2O, 23°C; 3. DPPA, NEt3, MeCN, 0°C→65°C, 3 h, 27% yield over 3 steps; 16: 1. Grubbs 1a (5 mol%), VTMS, toluene, 125°C, 16 h, 96% conv. or Grotjahn 2 (2 mol%), acetone-d6, 70°C, 63 h, 95% conv.; 2. NaIO4, CCl4, MeCN, H2O, 23°C, 3. DPPA, NEt3, MeCN, 0°C→65°C, 47% yield over 3 steps (with 1a) and 52% yield over 3 steps (with 2); b) 17: 1. 4 M aq. HCl, 1,4-dioxane, 120°C, 12 h; 2. IEC, 61% yield; 18: 1. 2 M aq. HCl, THF, reflux, 24 h; 2. IEC, 95% yield; c) 1. Grubbs 1a (5 mol%), VTMS, toluene, 129°C, 21 h, 96% conv., 2. NaIO4, CCl4, MeCN, H2O, 23°C, 24 h; 3. DPPA, NEt3, MeCN, 0°C→65°C, 3 h, 65% yield over 3 steps; d) 1. 4 M aq. HCl, dioxane, reflux, 18 h; 2. IEC, 92% yield; e) 1. Grubbs 1a (5 mol%), VTMS, toluene, 129°C, 21 h, 93% conv.; 2. NaIO4, CCl4, MeCN, H2O, 23°C, 25 h; 3. DPPA, NEt3, MeCN, 0°C→65°C, 3 h, 34% yield over 3 steps; f) 1. 4 M aq. HCl, dioxane, reflux, 18 h; 2. IEC, 99% yield. DPPA=diphenyl phosphoryl azide, IEC=ion exchange chromatography, VTMS=vinyloxy trimethylsilane.

Treatment of caprolactam 19 and glutarimide 22 with catalyst 1a under our optimized conditions gave, after Curtius rearrangement, hydantoin 20 and isocyanate 23 in 65% and 34% yield over 3 steps, respectively. Anti-Bredt bicycle35–37 20 results from an intramolecular cyclization of the lactam NH to the isocyanate. Its structure was unambiguously confirmed by X-ray crystallography (see the Supporting Information). Subsequent hydrolysis of 20 and 23 with aqueous HCl furnished (R)-α-methyllysine33d (21) and (R)-α-methylglutamic acid33c,38 (24), respectively, in excellent yields (92% and 99%). Given the recent availability of α-quaternary lactams and imides,28 it is possible to envision the synthesis of a wide range of α-substituted amino acid derivatives for a multitude of applications.

The enantioenriched carboxylic acid 25, obtained by our Ru-catalyzed isomerization oxidation method on lactam 14 (Scheme 4), is not only an intermediate in Padwa’s racemic synthesis of desacetoxy-4-oxo-6,7-dihydrovindoro-sine39 (29), but can also be used for the synthesis of Cbz-protected α-amino lactam 26 (98% ee) by trapping the intermediate isocyanate 16 with benzyl alcohol following the Curtius rearrangement (Scheme 5). Hydrogenolysis of the Cbz group gave amino lactam 27 in quantitative yield, which renders Knabe’s racemic synthesis of 3-ethyl thalidomide40 (30) enantioselective. Reduction of lactam 27 with LiAlH4, followed by precipitation as the bishydrochloride salt furnished chiral diamine 28 in 89% yield. The racemic, mono-Boc protected version of 28 was used recently by Nishio et al.41 for the synthesis of dipeptidyl peptidase IV (DPP-4) inhibitors.

Scheme 5.

Scheme 5

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a) DPPA, NEt3, DCE, 23°C→reflux, 5 h, then BnOH, reflux, 38 h, 29% yield, 98% ee; b) H2, Pd/C, MeOH, 23°C, 4 h, >99% yield; c) LiAlH4, THF, 0°C→reflux, 24 h, then HCl/dioxane, 89% yield. DCE=1,2-dichloroethane, DPPA= diphenyl phosphoryl azide.

CONCLUSIONS

In summary, we have developed a highly efficient ruthenium catalyzed isomerization/oxidation sequence, which enabled the syntheses of challenging unnatural amino acids such as D-tert-leucine (5), (S)-β-neopentylglycine (7), (R)-α-methyl- and ethylornithine (17 and 18), (R)-α-methyllysine (21) and (R)-α-methylglutamic acid (24). The reaction sequence performs well with not only ruthenium-hydride complex 1b (derived from Grubbs catalyst 1a), but also with the less common Grotjahn catalyst 2. We found that both isomerization catalysts 1b and 2 can be used to perform one or several subsequent oxidation steps after NaIO4 treatment of the crude reaction mixtures. To demonstrate the utility of our method, we have completed an enantioselective total synthesis of the antiepileptic drug levetiracetam (12) and enantioselective formal syntheses of a vindorosine derivative 29 and of (R)-3-ethyl thalidomide (30). Given the importance and ubiquity of the amino acid subunit in organic chemistry, we believe that our method will inspire many creative permutations and applications. Further usages of the method are currently under investigation.

Supplementary Material

Supplemental

Acknowledgments

Dedicated to Professor Albert Padwa on the occasion of his 80th birthday. The authors wish to thank NIH-NIGMS (R01GM080269), Amgen, the Gordon and Betty Moore Foundation and Caltech for financial support. M.L. thanks the Swiss National Science Foundation (SNSF) for a postdoctoral fellowship (P2EZP2_148751). Dr. Scott Virgil and the Caltech Center for Catalysis and Chemical Synthesis are acknowledged for the generous donation of catalyst 2 and Materia Inc. for the donation of catalyst 1a. The authors thank Dr. Michael Takase and Larry Henling for X-ray structural determinations. The Hsieh-Wilson group is acknowledged for nanopure water and the Dougherty group for using their freeze-drying equipment. Lukas Hilpert, Kyle Virgil and Katerina Korch are thanked for experimental assistance. Beau P. Pritchett is gratefully acknowledged for recording analytical data and for proofreading this manuscript.

Footnotes

ASSOCIATED CONTENT

Experimental procedures, characterization data, and crystallographic information files. This material is available free of charge via the Internet at http://pubs.acs.org.

Notes

The authors declare no competing financial interest.

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