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Cite This: J. Org. Chem. 2018, 83, 11510−11518
Diastereoselective Synthesis of Unnatural Amino Acids by Alkylation of α-tert-Butanesulfinamide Auxiliary-Bound Enolates Natalie C. Dwulet, Tina A. Zolfaghari, Molly L. Brown, and Jeffrey S. Cannon* Department of Chemistry, Occidental College, 1600 Campus Road M-5, Los Angeles, California 90041, United States
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ABSTRACT: A new chiral auxiliary for the diastereoselective alkylation of amino ester enolates that takes advantage of chiral information stored on the enolate side of the amino ester substrate has been developed. Chiral α-sulfinamido esters were alkylated under basic conditions in good yields (up to 90%) and good to high diastereoselectivities (generally >6:1) to provide unnatural mono- and α,α-disubstituted amino acid derivatives. This auxiliary allowed for the ready conversion of ester functionality without the need for esoteric reagents. Furthermore, the auxiliary is easily removed to provide enantiopure amino acids. Computational studies revealed that a chelated transition state governs electrophile addition from the convex face of a transient bicyclic intermediate. This method allows ready access to enantioenriched natural and unnatural amino acids.
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INTRODUCTION Amino acids are one of the most important and prevailing structural motifs in chemistry.1 Besides their role as the key building blocks for proteins and many other biomolecules, amino acids are widely used in the construction of small molecules, both by nature and by synthetic chemists. Unnatural amino acids, especially those that are α,αdisubstituted, are significant in their ability to expand the applications of amino acids in chemistry.2−5 Furthermore, recent advances in ribosomal protein synthesis have enabled the ready incorporation of many unnatural amino acids into functional cellular machinery.6−8 For instance, peptides that incorporate α,α-disubstituted amino acids can improve stability by resisting chemical and enzymatic degradation pathways.9−11 There currently exist only a few enantioselective methods for the synthesis of α,α-disubstituted amino acids.12−16 As a result, new methods for the construction of enantiopure, unnatural amino acids remain an important avenue of study in organic synthesis. Chiral auxiliaries are a proven strategy for the synthesis of new bonds to enolates (Figure 1).17−19 Although catalytic, enantioselective methods for the synthesis of amino acids have been developed,16 the Evans,20,21 Myers,22−24 and related auxiliaries25,26 remain the primary methods for stereoselective reactions of enolate intermediates. These auxiliaries, however, are limited by storing chiral information on the amide side of the carbonyl. It was anticipated that an enolate-side auxiliary, where chiral information is stored on the other side of the reactive intermediate, would provide additional flexibility in the functionalization of carbonyl derivatives. Such a strategy would enable the direct alkylations of esters and amides without the need for further transformations. Seminal work has shown that chiral Schiff bases of amino esters can provide stereochemically enriched amino acid derivatives,27,28 but selectivities and scope were variable. Recently, Uang has also © 2018 American Chemical Society
Figure 1. Strategy for enolate-side auxiliaries.
demonstrated that ketopinic glycine imines can undergo diastereoselective conjugate addition reactions with high diastereoselectivities.29 Key considerations in the design of selective reactions of enolates include the control of the geometry (E vs Z enolates) and facial control of electrophile approach. tert-Butanesulfinamides were chosen as the ideal auxiliary to address these issues. The installation of this auxiliary in the α-position of an ester would satisfy three key design criteria for enolate auxiliaries: (1) the acidified N−H bond would enforce the Z-enolate geometry by intramolecular coordination to the counterion of the base;30−35 (2) the nearby stereogenic sulfur atom would preferentially block one face of the enolate nucleophile;36,37 and (3) the sulfinamide is readily removed under mild conditions.38,39 Previous reports of sulfoxide coordination to Received: June 1, 2018 Published: September 7, 2018 11510
DOI: 10.1021/acs.joc.8b01379 J. Org. Chem. 2018, 83, 11510−11518
Article
The Journal of Organic Chemistry
diastereoselectivities.47 Later, Lu reported similar reactivity with palladium catalysis, with comparably high diastereoselectivities.48 Reddy also prepared alkylglycine derivatives in good yields and high diastereoselectivities by the reduction of a broad scope of aryl and alkyl oxalate-derived sulfinimines.49 The use of the tert-butanesulfinamide auxiliary has been rare in the synthesis of α,α-disubstituted amino acids. Ellman employed a creative strategy utilizing the addition of 2methylfuryllithium as a carboxylate surrogate, which allowed the use of ketimine electrophiles to provide protected carboxylic acids in high yields and modest to high diastereoselectivities.41 These substituted furans were then readily converted to the carboxylic acid by ruthenium-catalyzed oxidation. Addition of allylindium species has also been reported by Foubelo and Yus to provide α,α-disubstituted amino acid derivatives in modest to high yields and high diastereoselectivities.50 Although there are several reported syntheses of amino acids utilizing the tert-butanesulfinamide auxiliary, all of them direct the diastereoselective approach of nucleophiles to a chiral electrophile (Figure 2). We believed that this auxiliary could also be used to direct the addition of electrophiles to a chiral nucleophilic species, with the considerations noted above as the key controlling elements. Such a strategy would therefore be complementary to the existing methods for amino acid synthesis with the tert-butanesulfinamide auxiliary. Herein we report the development and use of this auxiliary to synthesize stereochemically enriched mono- and α,α-disubstituted amino acid derivatives in modest to high yields and good to high diastereoselectivities. Any mixtures of diastereomers produced were readily separated, and the resulting alkylated sulfinamidebound esters were converted to useful amino acid building blocks without the need for esoteric reagents.
Lewis acids indicate that these auxiliaries may have highly organized, stereocontrolling enolate intermediates.36 Furthermore, sulfinamides were attractive because of their ease of synthesis40 and the existing precedent for their use in diastereoselective reactions.38,41,42 A number of methods have been developed for the synthesis of amino acids using the tert-butanesulfinamide auxiliary (Figure 2). The most common approach has been the
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RESULTS AND DISCUSSION The synthesis of sulfinamide auxiliary-bound amino esters from tert-butanesulfinamide (2) was straightforward (Scheme 1). Sulfinamide 2 was condensed with ethyl glyoxylate (3) to provide sulfinimine 1 in quantitative yield. This imine could be functionalized by nucleophilic addition to the C−N π-bond. For these studies, two amino esters were selected as model substrates. Glycine derivative 4a was prepared by L-selectride reduction of 1.51 Alanine derivative 4b could be accessed by addition of methylmagnesium bromide to 1. Both derivatives were readily available on multigram quantities by these methods. It should also be noted that in our hands the
Figure 2. Reported uses of tert-butanesulfinamides in the synthesis of amino acid derivatives and comparison to this study.
Scheme 1. Synthesis of α-tert-Butanesulfinamido Esters
diastereoselective 1,2-addition of nucleophiles to glyoxylatederived sulfinimine (1). Davis originally discovered that Grignard reagents could be added to sulfinimine 1 in good yields and diastereoselectivities with the assistance of added Lewis acids.43,44 Grigg discovered that indium reagents, prepared by transmetalation from palladium π-allyl species, could synthesize allylglycine derivatives when reacted with sulfinimine 1.45,46 This cascade reaction was accomplished with good yields and excellent diastereoselectivities with a wide variety of aromatic iodides. Transition metal catalysis has also proved useful for the diastereoselective addition of boronic acids to sulfinimine 1 in the synthesis of amino acid derivatives. Ellman described a rhodium-catalyzed method for this addition, which demonstrated consistently high yields and 11511
DOI: 10.1021/acs.joc.8b01379 J. Org. Chem. 2018, 83, 11510−11518
Article
The Journal of Organic Chemistry
Table 2. Scope of Diastereoselective Enolate Alkylationa
diastereoselectivity for Grignard addition, although unoptimized and inconsequential, was low (ca. 2:1). Optimization studies began by investigating the most appropriate base for enolate alkylation (Table 1). Although Table 1. Optimization of Enolate Alkylationa
entry
R
4
5
base
t (°C)
yield (%)b
drc
1 2 3 4 5 6 7 8d 9e
H H H Me Me Me Me Me H
4a 4a 4a 4b 4b 4b 4b 4b 4a
5a 5a 5a 5b 5b 5b 5b 5b 5a
LDA NaHMDS LTMP LDA NaHMDS LTMP LTMP LTMP NaHMDS
−78 −78 −78 −78 −78 −78 −78−0 −78 −78−rt
