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. 2024 May 9;4(5):2058–2066. doi: 10.1021/jacsau.4c00257

N-to-S Acyl Transfer as an Enabling Strategy in Asymmetric and Chemoenzymatic Synthesis

Woonkee S Jo †, Brian J Curtis ‡, Mohammad Rehan †, Maria L Adrover-Castellano ‡, David H Sherman ‡,§,*, Alan R Healy †,*
PMCID: PMC11134368  PMID: 38818054

Abstract

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The observation of thioester-mediated acyl transfer processes in nature has inspired the development of novel protein synthesis and functionalization methodologies. The chemoselective transfer of an acyl group from S-to-N is the basis of several powerful ligation strategies. In this work, we sought to apply the reverse process, the transfer of an acyl group from N-to-S, as a method to convert stable chiral amides into more reactive thioesters. To this end, we developed a novel cysteine-derived oxazolidinone that serves as both a chiral imide auxiliary and an acyl transfer agent. This auxiliary combines the desirable features of rigid chiral imides as templates for asymmetric transformations with the synthetic applicability of thioesters. We demonstrate that the auxiliary can be applied in a range of highly selective asymmetric transformations. Subsequent intramolecular N-to-S acyl transfer of the chiral product and in situ trapping of the resulting thioester provides access to diverse carboxylic acid derivatives under mild conditions. The oxazolidinone thioester products can also be isolated and used in Pd-mediated transformations to furnish highly valuable chiral scaffolds, such as noncanonical amino acids, cyclic ketones, tetrahydropyrones, and dihydroquinolinones. Finally, we demonstrate that the oxazolidinone thioesters can also serve as a surrogate for SNAC-thioesters, enabling their seamless use as non-native substrates in biocatalytic transformations.

Keywords: Chiral auxiliary; N-to-S acyl transfer; thioester; chemoenzymatic; native chemical ligation, noncanonical amino acids; SNAC

Introduction

Thioester-mediated reactions are abundant in nature. In biosynthesis, thioesters serve as acyl donors in the thiotemplated synthesis of fatty acids, polyketides, and nonribosomal peptides.1 They also play a vital role as intermediates in several critical biological processes, such as intein-mediated protein splicing, protein ubiquitination, and transglutamination.2 In these processes, an acyl group undergoes an S-to-N transfer, enabling the efficient and chemoselective synthesis of amide bonds in a complex biological environment. New ligation methodologies that harness this selective S-to-N acyl transfer step have been developed and applied in protein synthesis and modification, and in the development of chemical probes and molecular machines (Figure 1A).2 The most notable of these methodologies is native chemical ligation (NCL), a process involving the coupling of a peptide containing a C-terminal thioester and a peptide containing an N-terminal cysteine.3 The reaction is initiated by an intermolecular transthioesterification to link the two peptide fragments together followed by a spontaneous intramolecular S-to-N acyl transfer to generate the peptide bond. The attractiveness of NCL lies in its ability to chemoselectively condense large peptide fragments under mild conditions.

Figure 1.

Figure 1

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(A) Novel methodologies inspired by the S-to-N acyl transfer reaction. (B) The application of imide auxiliaries in asymmetric synthesis. (C) The application of N-to-S acyl transfer in the synthesis of peptide thioesters. (D) A cysteine-derived chiral auxiliary that unites the desirable features of an imide auxiliary with the downstream functionality of a thioester.

Thioesters are also versatile precursors in the field of synthetic organic chemistry as they can be chemoselectively converted to diverse carboxylic acid derivatives under mild conditions.4 Moreover, they can participate in Pd-mediated reactions to generate ketones and aldehydes in one step under neutral conditions.5 Beyond traditional synthetic chemistry, thioesters have also been extensively used as substrates in enzymatic transformations.6 However, despite these attractive features, thioesters are not widely used as substrates in asymmetric synthesis. Although there have been some notable successes in the application of thioesters in asymmetric catalysis,7 particularly as substrates in the asymmetric aldol reaction,8 their lack of rigidity and higher reactivity has limited their potential as a general template for asymmetric reactions. In contrast, amides, and in particular imides, have been widely employed in asymmetric synthesis, as they provide a rigid template that can be activated through Lewis acid coordination, leading to high reactivity and excellent asymmetric induction. Chiral-nonracemic imides (such as oxazolidinones and imidazolidinones) have proven to be powerful mediators of asymmetric transformations, including α-functionalization of a carbonyl group, aldol addition, Michael addition, and cycloadditions (Figure 1B).9 Many of these methods have evolved from stoichiometric to catalytic using achiral imides in the presence of chiral catalysts.10 Although these auxiliaries have had tremendous success as templates in asymmetric catalysis, difficulties often arise when cleaving the chiral product from the auxiliary.11,12 A mild, chemoselective, and general method to convert the amide product to the respective chiral aldehyde, ketone, or carboxylic acid derivative remains elusive. These transformations often require harsh or nonstrategic synthetic steps and can be accompanied by unwanted side reactions or loss of stereochemical integrity.13 As a consequence, significant efforts have been dedicated to the identification of more readily functionalizable ester equivalents as substrates for asymmetric transformations.14

In this work, we sought to combine the attractive features of the imide auxiliaries for asymmetric transformations, with the downstream synthetic utility of a thioester group by employing an intramolecular N-to-S acyl transfer reaction. Similar to the S-to-N acyl transfer, the reverse reaction, the transfer of an acyl group from N-to-S to generate a thioester, is an important transformation in many biological processes, including the first step in intein-mediated protein splicing.15 However, this rearrangement is thermodynamically unfavorable and requires the scissile amide bond to be in a high-energy twisted conformation.16 While less common than S-to-N acyl transfer, a variety of N-to-S acyl transfer auxiliaries have been developed that mimic this process and are used in the formation of peptide thioesters (Figure 1C).17 These acyl transfer auxiliaries consist of a tertiary amide to aid distortion of the amide bond (ground-state destabilization), and a pendant thiol to enable an intramolecular proximity-driven N-to-S acyl transfer (Figure S1).18 The N-to-S acyl transfer reaction is typically reversible and, therefore, the transient thioester is either used in situ in a ligation reaction, or transthioesterified with excess thiol to form a stable C-terminal peptide thioester.19

We reasoned that an intramolecular N-to-S acyl transfer could provide a mild and chemoselective strategy to convert the chiral imide product to the more reactive and synthetically tractable thioesters. We chose to investigate this hypothesis using a cysteine-derived oxazolidinone chiral auxiliary (Figure 1D). Oxazolidinones have been extensively used as chiral auxiliaries in asymmetric transformation,20 and also have previously been shown to be suitable auxiliaries for the N-to-S acyl transfer reaction.21 The exocyclic amide bond of N-acyloxazolidinone derivatives is twisted out of planarity, resulting in ground-state destabilization.22 We hypothesized that on completion of the chiral auxiliary-mediated stereoselective transformation, deprotection of the proximal thiol group would result in an N-to-S acyl transfer to generate a chiral thioester product that could be further derivatized by synthetic or chemoenzymatic methods.

Results and Discussion

Auxiliary Development

We chose the readily accessible cysteine-derived oxazolidinone 1 to test our proposed strategy. The trityl protecting group was selected due to its facile and efficient removal under mildly acidic conditions. Additionally, we expected that upon coordination of a Lewis acid by oxazolidinone 1, the sterically hindered trityl group would create a well-defined chiral environment, leading to enhanced selectivity. An efficient and scalable 3-step synthesis of S-trityl oxazolidinone 1 was achieved from commercially available l-cysteine (Scheme S1). This sequence only requires one column purification and has provided >200 g of 1 to date. We opted for the boron-mediated propionate aldol as a model reaction to investigate the efficiency of our thiol-based oxazolidinone auxiliary. N-Acylation of auxiliary 1 with propionyl chloride yielded N-acyloxazolidinone 2. Subsequent condensation of 2 with hydrocinnamaldehyde under standard boron aldol conditions provided the desired Evans syn-aldol product 3 in high yield and stereoselectivity (Figure 2A).23 Exposure of 3 to 10% trifluoroacetic acid (TFA) in dichloromethane rapidly removed (30 min) the S-trityl group to quantitatively provide the free thiol 4.24 Solvent removal and subsequent subjection of the crude thiol 4 to a mildly basic n-propanol solution smoothly effected the desired N-to-S acyl transfer to afford the thioester 5 in 83% isolated yield (Figure 2B). The acyl transfer reaction could be readily monitored by LC-MS, showing the complete conversion within 5 h.

Figure 2.

Figure 2

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(A) Synthesis of syn-aldol product 3. (B) Mass-selective (m/z = 346.11) LC-MS analysis of the conversion of 4 to 5 at 0 (top), 1 (middle), and 5 h (bottom).

Chemoselective Auxiliary Cleavage

In addition to the Evans syn-aldol product 3, we also accessed the non-Evans anti-aldol product 7 in high yield and selectivity using a magnesium-halide-catalyzed aldol (Scheme 1).25 A notable feature of this example is the use of the methyl-3-formylbenzoate 6 as the electrophile. The most common methods to cleave oxazolidinone auxiliaries are LiBH4-mediated reduction to the corresponding alcohol,26 or hydrolysis to the carboxylic acid using LiOOH.27 The resulting carboxylic acid can be converted to carboxylic acid derivatives using stochiometric coupling reagents. Alternatively, the alcohol can be oxidized to the aldehyde for subsequent carbon–carbon bond-forming transformations. A limitation of this approach is that substrates containing electrophilic functional groups (such as the ester in 6) are typically not compatible with the conditions used to cleave the oxazolidinone auxiliary. This limitation can be overcome using the cysteine-derived auxiliary 1, as the N-to-S transfer generates a more electrophilic thioester that can be chemoselectively functionalized in the presence of the ester (Scheme 1). To demonstrate this, we subjected the anti-aldol product 7 to the N-to-S acyl transfer conditions to form the corresponding oxazolidinone thioester. Subsequent Fukuyama reduction chemoselectively converted the thioester to the aldehyde 8.28 We next investigated if it was possible to directly trap the thioester in situ with a range of nucleophiles. Indeed, changing the solvent to tetrahydrofuran (THF) and heating the acyl transfer step at 60 °C resulted in hydrolysis of the thioester intermediate to directly afford the carboxylic acid 9 in 79% yield. Changing the solvent to ethanol and heating at 60 °C effected the N-to-S transfer and subsequent esterification to yield the diester 10. The thioester could also be trapped in situ with cysteine methyl ester in a native chemical ligation reaction to furnish 11 in 82% yield.

Scheme 1. Synthesis and Derivatization of the anti-Aldol Product 7.

Scheme 1

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Reagents and conditions: (a) MgCl2, trimethylsilyl chloride (TMSCl), Et3N, EtOAc, 23 °C; then TFA, MeOH, 23 °C, 88%; (b) (i) TFA, Et3SiH, CH2Cl2, thennPrOH-NaHCO3, 23 °C, 93%; (ii) Pd(OAc)2, Et3SiH, MgSO4, acetone, 23 °C, 72%; (c) TFA, Et3SiH, CH2Cl2, then THF-NaHCO3, 60 °C, 79%; (d) TFA, Et3SiH, CH2Cl2, then EtOH-NaHCO3, 60 °C, 80%; (e) TFA, Et3SiH, CH2Cl2, then DMF-NaHCO3, l-cysteine methyl ester, DL-dithiothreitol (DTT), 23 °C, 82%; (f) TFA, Et3SiH, CH2Cl2, then Et2O-Et3N, benzylamine, silver trifluoroacetate (AgTFA), 23 °C, 83%.

Finally, we sought to directly form an amide from the intermediate thioester using silver trifluoroacetate (AgTFA) as a thiophilic Lewis acid.29 To achieve this, nonaqueous conditions for the N-to-S acyl transfer were required. Initial screening revealed that the saturated aqueous sodium bicarbonate solution could be replaced with excess triethylamine (5–10 equiv). We subsequently discovered that complete N-to-S transfer is observed in 4 h in a wide variety of solvents (Table S1). Undertaking the acyl transfer reaction in diethyl ether–triethylamine generated the thioester intermediate that was trapped in situ by the addition of benzylamine and AgTFA to afford amide 12 in 83% yield. Importantly, all these transformations proved to be chemoselective with no cleavage of the methyl ester observed. Furthermore, this approach provided direct access to the corresponding chiral aldehyde, ester, and amide without the need for additional redox/protecting group manipulations or coupling synthetic steps.

Noncanonical Amino Acid Synthesis

Outside of the 20 proteinogenic l-amino acids that serve as the primary protein building blocks are countless noncanonical amino acids (ncAAs), which contain atypical side chains, backbone connectivity, or stereochemistry (d). The distinct chemical and biological properties that ncAAs impart to natural products, peptide therapeutics, and unnatural proteins has elicited considerable interest.30 As a result, a general and efficient method for the synthesis and subsequent utilization of ncAAs would be desirable within both synthetic chemistry and biology.

β-Hydroxy, homo-, and d-amino acids are among the most common ncAAs in biologically active natural products and pharmaceuticals. Incorporation of these ncAAs into peptides can confer resistance to enzymatic degradation or alter the stability or activity of the peptide.31 However, these unnatural amino acids are typically expensive and only available in small quantities. A general method to access natural and unnatural α-amino acids was previously reported using Evans oxazolidinone.32 Using this strategy, we sought to synthesize l- and d-homophenylalanine (HPA), an unnatural isomer of phenylalanine containing an extra methylene at the α-position. Both isomers of homophenylalanine are essential building blocks of many bioactive small molecules and drugs, including angiotensin converting enzyme (ACE) inhibitors, proteasome inhibitors, acetylcholinesterase inhibitors, and caspase inhibitors.33,34

The N-acyloxazolidinone 13 was synthesized from readily available and inexpensive 4-phenylbutyric acid (see Supporting Information). A direct azide transfer to the enolate of carboxamide 13 was used to access the (S)-α-azidocarboximide 14 (Scheme 2). This process involved the treatment of the potassium enolate of 13 with trisyl azide at −78 °C followed by quenching with glacial acetic acid to yield (S)-14 in 59% yield. The (R)-α-azidocarboximide 14 was synthesized by a two-step α-bromination/azidation sequence. Reaction of N-bromosuccinimide (NBS) with the dibutylboryl enolate derived from 13 afforded the corresponding α-brominated product. Treatment with tetramethylguanidinium azide (TMGA) provided the diastereomerically pure (R)-14 in 68% isolated yield over the two steps.

Scheme 2. Synthesis and Derivatization of l- and d-Homophenylalanine; See the Supplementary Materials for Experimental Details.

Scheme 2

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The α-azidocarboximides are versatile intermediates as both the N- and C- termini can be orthogonally derivatized. Ligation of the azide with a thioacid provides direct access to amides without requiring prior reduction to the amine, or the need for activating or coupling agents. Stirring either (S)- or (R)-14 in thioacetic acid at room temperature afforded the respective N-acetyl derivatives 15.35N-to-S acyl transfer of (S)-15 and in situ hydrolysis provided N-acetyl-l-homophenylalanine 16 (Scheme 2). Alternatively, N-to-S acyl transfer and in situ trapping with cysteine methyl ester provided the N-protected dipeptide 17. This sequence involves the sequential application of three unique acyl transfer reactions, an N-to-S transfer to form the thioester of 15, an S-to-S reaction to link the two amino acids, and an S-to-N transfer to yield the dipeptide.

In addition to their application in peptide synthesis, the HPA-auxiliary adducts provide a powerful entry point to chiral α-amino ketones. α-Amino ketones are present in numerous important natural products and pharmaceutical agents, and also serve as versatile building blocks for the synthesis of polyfunctional amino derivatives.36N-to-S acyl transfer of (R)-15, followed by Fukuyama coupling of the resulting thioester with ethylzinc iodide yielded the α-amino ketone 18 in 77% yield.37

Synthesis of Chiral Scaffolds

Chiral auxiliary mediated synthesis has empowered the modern synthetic chemist with a rich arsenal of methods to rapidly assemble stereodefined acyclic molecules. However, the conversion of these linear precursors to complex cyclic motifs still poses many challenges. A notable advantage of using thioesters as carboxylic acid equivalents is their participation in mild Pd-mediated transformations with diverse coupling partners.5 We sought to investigate if the thioester intermediate formed after N-to-S acyl transfer could provide an expedient entry to a number of stereodefined cyclic scaffolds common in natural products and pharmaceutical agents. N-to-S acyl transfer of the syn-aldol product 19 and subsequent coupling with phenylacetylene yielded the chiral ynone 21.38 A silver-mediated intramolecular oxy-Michael reaction directly afforded tetrahydropyrone 22 (Scheme 3A).39 To demonstrate the utility of the auxiliary beyond the aldol reaction, we subjected the unsaturated imide 23 to Michael addition with an allyl Grignard.40 The β-allyl product 24 was obtained as a single diastereomer in 77% yield. N-to-S transfer followed by intramolecular Pd-mediated carbocyclization provided the chiral enone 26 (Scheme 3B).41 Finally, alkylation of 2 with 2-nitrobenzyl bromide provided 27 in 81% yield.42 The thioester obtained after N-to-S transfer was treated with Fe/AcOH to effect nitro reduction and intramolecular amidation to directly yield the dihydroquinolinone 29 in one step (Scheme 3C).43

Scheme 3. Synthesis of Dihydropyrone 22 (A), Cyclic Ketone 26 (B), and Dihydroquinolinone 29 (C); See the Supplementary Materials for Experimental Details; Red, Oxygen; Blue, Nitrogen; Gray, Carbon; Yellow, Sulfur; White, Hydrogen.

Scheme 3

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Application in Chemoenzymatic Synthesis

Biosynthetic pathways composed of polyketide synthases (PKSs), fatty acid synthases (FASs), and nonribosomal peptide synthetases (NRPSs) rely on thioester electrophiles as substrates for a range of chemical transformations.6 Typically, carboxylic acid building blocks are converted to activated acyl carrier protein (ACP) or acyl-coenzyme A (acyl-CoA) thioester substrates. Simpler thioester substrates, such as those containing the truncated CoA analogue, N-acetylcysteamine (SNAC), have found extensive use as model substrates to probe these biosynthetic pathways, which avoid the requirement for stoichiometric protein-bound substrates or expensive CoA-activated thioesters.44 A chiral auxiliary mediated synthetic approach remains the most common and reliable method to access polyketide intermediates, where the SNAC thioester is produced via coupling to the carboxylic acid that results from hydrolysis of the oxazolidinone-bound polyketide substrate.45 However, in many cases, this two-step strategy provides the desired SNAC thioester in low yield.6 We proposed that our auxiliary would provide facile access to SNAC thioester substrates by a one-pot N-to-S transfer and in situ transthioesterification with SNAC. Furthermore, due to the high structural similarity between the oxazolidinone thioester and SNAC-thioesters, we hypothesized it might be possible to directly use the oxazolidinone thioester as a substrate for enzymatic transformations. To test these hypotheses, we investigated the feasibility of non-native polyketide substrates (32 and 33) to be chain-extended and cyclized to a 6-membered triketide lactone by the last two PKS modules (PikAIII/PikAIV) from the pikromycin (Pik) biosynthetic pathway.46 Synthesis of the thioester substrates was initiated by α-methylation of 30 (Figure 3A).42 Removal of the trityl protecting group and subjecting the crude thiol 31 to a nPrOH-NaHCO3 solution yielded oxazolidinone thioester 32. Alternatively, in situ transthioesterification of the intermediate thiol 31 with SNAC directly furnished the SNAC-thioester 33 in 86% yield without the need for stoichiometric coupling reagents. Applying previously developed conditions involving purified PikAIII/PikAIV modules and methylmalonyl (MM)-SNAC as an extender unit,44a,44b both substrates were evaluated for conversion to triketide lactone 34 (Figure 3B). Reactions involving 10 mg of both thioester substrates required 72–96 h for full substrate consumption as determined by LC-MS (Figure 3C). The formation of triketide lactone 34 was observed in comparable amounts for both substrates, where 34 was isolated in 29% yield from SNAC thioester 33 and 27% yield from oxazolidinone thioester 32. Throughout the reaction course, we observed transthioesterification of oxazolidinone thioester 32 to SNAC-thioester 33, where excess SNAC is derived from the MM-SNAC extender unit (Figure S2).47

Figure 3.

Figure 3

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Chemoenzymatic synthesis of triketide lactone 34. (A) Synthesis of acyl-thioester feeding substrates (32 and 33); see the Supporting Information for experimental details. (B) Formation of triketide lactone 34 catalyzed by PKS modules (PikAIII/PikAIV) from the pikromycin (Pik) biosynthetic pathway; see the Supporting Information for experimental details. (C) LC/MS traces (ESI+) showing the production of 34 from all three feeding substrates (31–33).

Having demonstrated that the oxazolidinone thioester 32 was a viable thioester surrogate for biocatalysis, we sought to investigate if thiol 31 could also be processed by PikAIII/PikAIV. An initial investigation demonstrated that thiol 31 completely rearranged to the oxazolidinone thioester 32 in reaction phosphate buffer (pH 7.2, Scheme S2).21,48 Indeed, subjecting crude or purified thiol 31 to the enzymatic transformations produced lactone 34 in 25% and 27% yield, respectively, equal to that from oxazolidinone thioester 32. In addition to exploring the feasibility of utilizing oxazolidinone thioesters as substrates in PKS biocatalysis, we wanted to investigate if the cyclization to form triketide lactone 34 is an enzyme-mediated or spontaneous process. Earlier studies have shown similar 6-membered ring lactones being formed spontaneously in the presence or absence of a thioesterase (TE).45c,46b,46c,49 We found that efficient formation of 34 requires the Pik TE terminal domain in PikAIV for cyclization,50,51 as the PikAIII/PikAIV bearing an inactive TE (S148A) variant produces only small amounts of 34 (Figure S3). Our chemoenzymatic approach illustrates the viability of employing non-native oxazolidinone thioester-containing substrates for biocatalytic transformations. The utilization of these short-chain substrates will facilitate future enzymatic explorations involving additional functional groups, as well as varying chain lengths, to produce a range of diverse products with varied architectures and ring sizes.52,53

Conclusions

Numerous powerful ligation methodologies have been developed that employ a chemoselective S-to-N acyl transfer reaction. In contrast, the antipodal N-to-S acyl transfer reaction has been underutilized. In this work, we demonstrate that an intramolecular N-to-S acyl transfer can provide a powerful method to convert amide derivatives to versatile thioesters.

We report the application of a cysteine-derived oxazolidinone chiral auxiliary in a wide range of asymmetric transformations: the aldol reaction, Michael addition, α-alkylation, bromination, and azidation.54 The high yields and selectivity observed in the auxiliary 1-mediated transformations and the relative ease of synthesis of the auxiliary make it an attractive alternative to traditional oxazolidinone auxiliaries. The mild conditions for both the acyl transfer reaction and subsequent transformation of the thioester products are compatible with a range of reactive functional groups. The thioester products were either converted in situ to diverse carboxylic acid derivatives or subjected to Pd-mediated cross-coupling reactions to provide efficient access to several biologically relevant chiral motifs and cyclic scaffolds. Importantly, these transformations did not require the use of protecting groups, coupling reagents, or nonstrategic functional group manipulation steps. Finally, we demonstrated that this strategy provided ready access to competent thioester probes for enzymatic transformations. Thiol 31, obtained after a facile trityl deprotection, was converted to the 6-membered triketide lactone 34 by the action of two PKS modules from the pikromycin biosynthetic pathway, thereby seamlessly linking traditional polyketide synthetic strategies to emerging biocatalytic processes.

Beyond the potential broad application of this auxiliary in asymmetric and chemoenzymatic synthesis, we propose that the acyl transfer strategy outlined herein could provide a powerful method to couple the benefits of amides in asymmetric transformations with the downstream utility of thioesters. This strategy could also be extended to include the development of other thiol-functionalized chiral auxiliaries, and achiral N-to-S, or N-to-O acyl transfer agents for the development of catalytic methods.55

Acknowledgments

Dedicated to the memory of Professor David A. Evans. We thank Dr. Yao He for X-ray crystallographic analysis.

Glossary

ABBREVIATIONS

NCL

native chemical ligation

PKS

polyketide synthase

SNAC

N-acetylcysteamine

TE

thioesterase

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.4c00257.

  • Schemes, figures, and tables; detailed experimental procedures; characterization data for all new compounds (PDF)

Accession Codes

X-ray data for compounds 22, 25, 27, 29, and S5 are freely available at the Cambridge Crystallographic Data Centre under deposition numbers 2287271, 2286532, 2286531, 2286539, and 2286538, respectively. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Author Contributions

CRediT: Woonkee Jo data curation, investigation, methodology, writing-review & editing; Brian J Curtis data curation, investigation, writing-original draft, writing-review & editing; Mohammad Rehan data curation, investigation; Maria L. Adrover-Castellano data curation, investigation, writing-review & editing; David H. Sherman funding acquisition, methodology, resources, supervision, writing-review & editing; Alan R. Healy conceptualization, funding acquisition, methodology, project administration, supervision, writing-original draft, writing-review & editing.

A.R.H thanks New York University Abu Dhabi (NYUAD) and the Core Technology Platform for its generous support of this research program. Support from NIH grant R35 GM118101, a Diversity Supplement to R35 GM118101S, F31 Fellowship GM143769 (to M.L.A.C.), a Michigan Pioneer Fellowship (to B.J.C.), and the Hans W. Vahlteich Professorship (to D.H.S.) are gratefully acknowledged.

The authors declare no competing financial interest.

Supplementary Material

au4c00257_si_001.pdf (10.3MB, pdf)

References

  1. Mercer A. C.; Burkart M. D. The Ubiquitous Carrier Protein—a Window to Metabolitebiosynthesis. Nat. Prod. Rep. 2007, 24 (4), 750–773. 10.1039/b603921a. [DOI] [PubMed] [Google Scholar]
  2. Burke H. M.; McSweeney L.; Scanlan E. M. Exploring Chemoselective S-to-N Acyl Transfer Reactions in Synthesis and Chemical Biology. Nat. Commun. 2017, 8 (1), 15655. 10.1038/ncomms15655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Dawson P. E.; Muir T. W.; Clark-Lewis I.; Kent S. B. H. Synthesis of Proteins by Native Chemical Ligation. Science 1994, 266 (5186), 776–779. 10.1126/science.7973629. [DOI] [PubMed] [Google Scholar]
  4. Cellnik T.; Healy A. R. Sulfonyl Chlorides as Thiol Surrogates for Carbon–Sulfur Bond Formation: One-Pot Synthesis of Thioethers and Thioesters. J. Org. Chem. 2022, 87 (9), 6454–6458. 10.1021/acs.joc.2c00330. [DOI] [PubMed] [Google Scholar]
  5. For reviews, see:; a Hirschbeck V.; Gehrtz P. H.; Fleischer I. Metal-Catalyzed Synthesis and Use of Thioesters: Recent Developments. Chem. – Eur. J. 2018, 24 (28), 7092–7107. 10.1002/chem.201705025. [DOI] [PubMed] [Google Scholar]; b Cheng H.; Chen H.; Liu Y.; Zhou Q. The Liebeskind–Srogl Cross-Coupling Reaction and Its Synthetic Applications. Asian J. Org. Chem. 2018, 7 (3), 490–508. 10.1002/ajoc.201700651. [DOI] [Google Scholar]; c Sikandar S.; Zahoor A. F.; Naheed S.; Parveen B.; Ali K. G.; Akhtar R. Fukuyama Reduction, Fukuyama Coupling and Fukuyama–Mitsunobu Alkylation: Recent Developments and Synthetic Applications. Mol. Divers. 2022, 26, 589–628. 10.1007/s11030-021-10194-7. [DOI] [PubMed] [Google Scholar]
  6. Franke J.; Hertweck C. Biomimetic Thioesters as Probes for Enzymatic Assembly Lines: Synthesis, Applications, and Challenges. Cell Chem. Biol. 2016, 23 (10), 1179–1192. 10.1016/j.chembiol.2016.08.014. [DOI] [PubMed] [Google Scholar]
  7. For select examples, see:; a Des Mazery R.; Pullez M.; López F.; Harutyunyan S. R.; Minnaard A. J.; Feringa B. L. An Iterative Catalytic Route to Enantiopure Deoxypropionate Subunits: Asymmetric Conjugate Addition of Grignard Reagents to α,β-Unsaturated Thioesters. J. Am. Chem. Soc. 2005, 127 (28), 9966–9967. 10.1021/ja053020f. [DOI] [PubMed] [Google Scholar]; b Bahlinger A.; Fritz S. P.; Wennemers H. Stereoselective Metal-Free Synthesis of β-Amino Thioesters with Tertiary and Quaternary Stereogenic Centers. Angew. Chem., Int. Ed. 2014, 53 (33), 8779–8783. 10.1002/anie.201310532. [DOI] [PubMed] [Google Scholar]
  8. a Magdziak D.; Lalic G.; Lee H. M.; Fortner K. C.; Aloise A. D.; Shair M. D. Catalytic Enantioselective Thioester Aldol Reactions That Are Compatible with Protic Functional Groups. J. Am. Chem. Soc. 2005, 127 (20), 7284–7285. 10.1021/ja051759j. [DOI] [PubMed] [Google Scholar]; b Bae H. Y.; Sim J. H.; Lee J.; List B.; Song C. E. Organocatalytic Enantioselective Decarboxylative Aldol Reaction of Malonic Acid Half Thioesters with Aldehydes. Angew. Chem., Int. Ed. 2013, 52 (46), 12143–12147. 10.1002/anie.201306297. [DOI] [PubMed] [Google Scholar]; c Saadi J.; Wennemers H. Enantioselective Aldol Reactions with Masked Fluoroacetates. Nat. Chem. 2016, 8 (3), 276–280. 10.1038/nchem.2437. [DOI] [PubMed] [Google Scholar]; d Rahman Md. A.; Cellnik T.; Ahuja B. B.; Li L.; Healy A. R. A Catalytic Enantioselective Stereodivergent Aldol Reaction. Sci. Adv. 2023, 9 (11), eadg8776 10.1126/sciadv.adg8776. [DOI] [PMC free article] [PubMed] [Google Scholar]; e Kobayashi S.; Uchiro H.; Fujishita Y.; Shiina I.; Mukaiyama T. Asymmetric Aldol Reaction between Achiral Silyl Enol Ethers and Achiral Aldehydes by Use of a Chiral Promoter System. J. Am. Chem. Soc. 1991, 113 (11), 4247–4252. 10.1021/ja00011a030. [DOI] [Google Scholar]
  9. Shamszad M.; Crimmins M. T.. 3.2 Amino Acid Derived Heterocyclic Chiral Auxiliaries: The Use of Oxazolidinones, Oxazolidinethiones, Thiazolidinethiones, and Imidazolidinones. In Comprehensive Chirality; Carreira E. M., Yamamoto H., Eds.; Elsevier: Amsterdam, 2012; pp 19–41. 10.1016/B978-0-08-095167-6.00302-5. [DOI] [Google Scholar]
  10. Monge D.; Jiang H.; Alvarez-Casao Y. Masked Unsaturated Esters/Amides in Asymmetric Organocatalysis. Chem. - Eur. J. 2015, 21 (12), 4494–4504. 10.1002/chem.201405552. [DOI] [PubMed] [Google Scholar]
  11. Evans D. A.; Britton T. C.; Ellman J. A. Contrasteric Carboximide Hydrolysis with Lithium Hydroperoxide. Tetrahedron Lett. 1987, 28 (49), 6141–6144. 10.1016/S0040-4039(00)61830-0. [DOI] [Google Scholar]
  12. Kanomata N.; Maruyama S.; Tomono K.; Anada S. A Simple Method Removing 2-Oxazolidinone and 2-Hydroxyethylamine Auxiliaries in Methoxide–Carbonate Systems for Synthesis of Planar-Chiral Nicotinate. Tetrahedron Lett. 2003, 44 (18), 3599–3603. 10.1016/S0040-4039(03)00698-1. [DOI] [Google Scholar]
  13. For select examples, see:; a Wu Y.; Shen X.; Yang Y.-Q.; Hu Q.; Huang J.-H. Enantioselective Total Synthesis of (+)-Brefeldin A and 7-Epi-Brefeldin A. J. Org. Chem. 2004, 69 (11), 3857–3865. 10.1021/jo049971d. [DOI] [PubMed] [Google Scholar]; b Morimoto Y.; Iwahashi M.; Kinoshita T.; Nishida K. Stereocontrolled Total Synthesis of the Stemona Alkaloid (−)-Stenine. Chem. – Eur. J. 2001, 7 (19), 4107–4116. . [DOI] [PubMed] [Google Scholar]; c Morimoto Y.; Iwahashi M.; Nishida K.; Hayashi Y.; Shirahama H. Studies on the Asymmetric Synthesis of Stemona Alkaloids: Total Synthesis of (−)-Stenine. Angew. Chem., Int. Ed. Engl. 1996, 35 (8), 904–906. 10.1002/anie.199609041. [DOI] [Google Scholar]; d Evans D. A.; Mathre D. J.; Scott W. L. Asymmetric Synthesis of the Enkephalinase Inhibitor Thiorphan. J. Org. Chem. 1985, 50 (11), 1830–1835. 10.1021/jo00211a008. [DOI] [Google Scholar]; e Lamont R. B.; Allen D. G.; Clemens I. R.; Newall C. E.; Ramsay M. V. J.; Rose M.; Fortt S.; Gallagher T. Synthetic Studies Directed towards the Vancomycin Carboxylate Binding Pocket. J. Chem. Soc. Chem. Commun. 1992, 0 (22), 1693–1695. 10.1039/c39920001693. [DOI] [Google Scholar]; f Mohri T.; Ogura Y.; Towada R.; Kuwahara S. Enantioselective Total Synthesis of Sacrolide A. Tetrahedron Lett. 2017, 58 (42), 4011–4013. 10.1016/j.tetlet.2017.09.017. [DOI] [Google Scholar]
  14. For select examples, see:; a Fanjul S.; Hulme A. N.; White J. W. Achieving High Selectivity and Facile Displacement with a New Thiol Auxiliary for Boron-Mediated Aldol Reactions. Org. Lett. 2006, 8 (19), 4219–4222. 10.1021/ol0614774. [DOI] [PubMed] [Google Scholar]; b Davies S. G.; Fletcher A. M.; Roberts P. M.; Thomson J. E. SuperQuat Chiral Auxiliaries: Design, Synthesis, and Utility. Org. Biomol. Chem. 2019, 17 (6), 1322–1335. 10.1039/C8OB02819B. [DOI] [PubMed] [Google Scholar]; c Fanjul S.; Hulme A. N. Anti and Syn Glycolate Aldol Reactions with a Readily Displaced Thiol Auxiliary. J. Org. Chem. 2008, 73 (24), 9788–9791. 10.1021/jo801720v. [DOI] [PubMed] [Google Scholar]; d Jiang H.; Paixão M. W.; Monge D.; Jørgensen K. A. Acyl Phosphonates: Good Hydrogen Bond Acceptors and Ester/Amide Equivalents in Asymmetric Organocatalysis. J. Am. Chem. Soc. 2010, 132 (8), 2775–2783. 10.1021/ja9097803. [DOI] [PubMed] [Google Scholar]; e Gao P.; Rahman Md. M.; Zamalloa A.; Feliciano J.; Szostak M. Classes of Amides That Undergo Selective N–C Amide Bond Activation: The Emergence of Ground-State Destabilization. J. Org. Chem. 2023, 88, 13371. 10.1021/acs.joc.2c01094. [DOI] [PubMed] [Google Scholar]; f Mellado-Hidalgo M.; Romero-Cavagnaro E. A.; Nageswaran S.; Puddu S.; Kennington S. C. D.; Costa A. M.; Romea P.; Urpí F.; Aullón G.; Font-Bardia M. Protected Syn-Aldol Compounds from Direct, Catalytic, and Enantioselective Reactions of N-Acyl-1,3-Oxazinane-2-Thiones with Aromatic Acetals. Org. Lett. 2023, 25 (4), 659–664. 10.1021/acs.orglett.2c04254. [DOI] [PMC free article] [PubMed] [Google Scholar]; g Crimmins M. T.; King B. W.; Tabet E. A.; Chaudhary K. Asymmetric Aldol Additions: Use of Titanium Tetrachloride and (−)-Sparteine for the Soft Enolization of N- Acyl Oxazolidinones, Oxazolidinethiones, and Thiazolidinethiones. J. Org. Chem. 2001, 66 (3), 894–902. 10.1021/jo001387r. [DOI] [PubMed] [Google Scholar]; h Lauberteaux J.; Pichon D.; Baslé O.; Mauduit M.; Marcia de Figueiredo R.; Campagne J.-M. Acyl-Imidazoles: A Privileged Ester Surrogate for Enantioselective Synthesis. ChemCatChem. 2019, 11 (23), 5705–5722. 10.1002/cctc.201900754. [DOI] [Google Scholar]; i Meninno S.; Franco F.; Benaglia M.; Lattanzi A. Pyrazoleamides in Catalytic Asymmetric Reactions: Recent Advances. Adv. Synth. Catal. 2021, 363 (14), 3380–3410. 10.1002/adsc.202100006. [DOI] [Google Scholar]; j Kinoshita T.; Okada S.; Park S.-R.; Matsunaga S.; Shibasaki M. Sequential Wittig Olefination–Catalytic Asymmetric Epoxidation with Reuse of Waste Ph3P(O): Application of α,β-Unsaturated N-Acyl Pyrroles as Ester Surrogates. Angew. Chem., Int. Ed. 2003, 42 (38), 4680–4684. 10.1002/anie.200352509. [DOI] [PubMed] [Google Scholar]
  15. Shah N. H.; Muir T. W. Inteins: Nature’s Gift to Protein Chemists. Chem. Sci. 2014, 5 (2), 446–461. 10.1039/C3SC52951G. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Romanelli A.; Shekhtman A.; Cowburn D.; Muir T. W. Semisynthesis of a Segmental Isotopically Labeled Protein Splicing Precursor: NMR Evidence for an Unusual Peptide Bond at the N-Extein–Intein Junction. Proc. Natl. Acad. Sci. U. S. A. 2004, 101 (17), 6397–6402. 10.1073/pnas.0306616101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Tailhades J.; Patil N. A.; Hossain M. A.; Wade J. D. Intramolecular Acyl Transfer in Peptide and Protein Ligation and Synthesis. J. Pept. Sci. 2015, 21 (3), 139–147. 10.1002/psc.2749. [DOI] [PubMed] [Google Scholar]
  18. For select examples, see Supplementary Figure 1. For reviews, see:; a Kang J.; Macmillan D. Peptide and Protein Thioester Synthesis via N→S Acyl Transfer. Org. Biomol. Chem. 2010, 8 (9), 1993–2002. 10.1039/b925075a. [DOI] [PubMed] [Google Scholar]; b Macmillan D. Going Round in Circles with N→S Acyl Transfer. Synlett 2017, 28 (13), 1517–1529. 10.1055/s-0036-1588789. [DOI] [Google Scholar]
  19. Zheng J.-S.; Tang S.; Huang Y.-C.; Liu L. Development of New Thioester Equivalents for Protein Chemical Synthesis. Acc. Chem. Res. 2013, 46 (11), 2475–2484. 10.1021/ar400012w. [DOI] [PubMed] [Google Scholar]
  20. Evans D. A.; Shaw J. T. Recent Advances in Asymmetric Synthesis with Chiral Imide Auxiliaries. Actualite Chimique 2003, 34, 35–38. 10.1002/chin.200351251. [DOI] [Google Scholar]
  21. Ohta Y.; Itoh S.; Shigenaga A.; Shintaku S.; Fujii N.; Otaka A. Cysteine-Derived S-Protected Oxazolidinones: Potential Chemical Devices for the Preparation of Peptide Thioesters. Org. Lett. 2006, 8 (3), 467–470. 10.1021/ol052755m. [DOI] [PubMed] [Google Scholar]
  22. Evans D. A.; Anderson J. C.; Taylor M. K. Studies Directed toward the Design of Chiral Acylating Agents. The Utility of Chiral N-Benzoylimides in Enantioselective Alcohol Acylation. Tetrahedron Lett. 1993, 34 (35), 5563–5566. 10.1016/S0040-4039(00)73882-2. [DOI] [Google Scholar]
  23. Evans D. A.; Bartroli J.; Shih T. L. Enantioselective Aldol Condensations. 2. Erythro-Selective Chiral Aldol Condensations via Boron Enolates. J. Am. Chem. Soc. 1981, 103 (8), 2127–2129. 10.1021/ja00398a058. [DOI] [Google Scholar]
  24. Tsuda S.; Shigenaga A.; Bando K.; Otaka A. N→S Acyl-Transfer-Mediated Synthesis of Peptide Thioesters Using Anilide Derivatives. Org. Lett. 2009, 11 (4), 823–826. 10.1021/ol8028093. [DOI] [PubMed] [Google Scholar]
  25. Evans D. A.; Tedrow J. S.; Shaw J. T.; Downey C. W. Diastereoselective Magnesium Halide-Catalyzed Anti -Aldol Reactions of Chiral N -Acyloxazolidinones. J. Am. Chem. Soc. 2002, 124 (3), 392–393. 10.1021/ja0119548. [DOI] [PubMed] [Google Scholar]
  26. Evans D. A.; Sjogren E. B.; Bartroli J.; Dow R. L. Aldol Addition Reactions of Chiral Crotonate Imides. Tetrahedron Lett. 1986, 27 (41), 4957–4960. 10.1016/S0040-4039(00)85106-0. [DOI] [Google Scholar]
  27. Beutner G. L.; Cohen B. M.; DelMonte A. J.; Dixon D. D.; Fraunhoffer K. J.; Glace A. W.; Lo E.; Stevens J. M.; Vanyo D.; Wilbert C. Revisiting the Cleavage of Evans Oxazolidinones with LiOH/H2O2. Org. Process Res. Dev. 2019, 23 (7), 1378–1385. 10.1021/acs.oprd.9b00124. [DOI] [Google Scholar]
  28. Tokuyama H.; Yokoshima S.; Lin S. C.; Li L. P.; Fukuyama T. Reduction of Ethanethiol Esters to Aldehydes. Synth.-Stuttg. 2002, 2002, 1121–1123. 10.1055/s-2002-31969. [DOI] [Google Scholar]
  29. Kurosu M. Expeditious Amide-Forming Reactions Using Thiol Esters. Tetrahedron Lett. 2000, 41 (5), 591–594. 10.1016/S0040-4039(99)02132-2. [DOI] [Google Scholar]
  30. Hickey J. L.; Sindhikara D.; Zultanski S. L.; Schultz D. M. Beyond 20 in the 21st Century: Prospects and Challenges of Non-Canonical Amino Acids in Peptide Drug Discovery. ACS Med. Chem. Lett. 2023, 14 (5), 557–565. 10.1021/acsmedchemlett.3c00037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Almhjell P. J.; Boville C. E.; Arnold F. H. Engineering Enzymes for Noncanonical Amino Acid Synthesis. Chem. Soc. Rev. 2018, 47 (24), 8980–8997. 10.1039/C8CS00665B. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Evans D. A.; Britton T. C.; Ellman J. A.; Dorow R. L. The Asymmetric Synthesis of. Alpha.-Amino Acids. Electrophilic Azidation of Chiral Imide Enolates, a Practical Approach to the Synthesis of (R)- and (S)-.Alpha.-Azido Carboxylic Acids. J. Am. Chem. Soc. 1990, 112 (10), 4011–4030. 10.1021/ja00166a045. [DOI] [Google Scholar]
  33. Gao D.; Song W.; Wu J.; Guo L.; Gao C.; Liu J.; Chen X.; Liu L. Efficient Production of L-Homophenylalanine by Enzymatic-Chemical Cascade Catalysis. Angew. Chem., Int. Ed. 2022, 61 (36), e202207077 10.1002/anie.202207077. [DOI] [PubMed] [Google Scholar]
  34. Poreba M.; Kasperkiewicz P.; Snipas S. J.; Fasci D.; Salvesen G. S.; Drag M. Unnatural Amino Acids Increase Sensitivity and Provide for the Design of Highly Selective Caspase Substrates. Cell Death Differ. 2014, 21 (9), 1482–1492. 10.1038/cdd.2014.64. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Shangguan N.; Katukojvala S.; Greenberg R.; Williams L. J. The Reaction of Thio Acids with Azides: A New Mechanism and New Synthetic Applications. J. Am. Chem. Soc. 2003, 125 (26), 7754–7755. 10.1021/ja0294919. [DOI] [PubMed] [Google Scholar]
  36. Allen L. A. T.; Raclea R.-C.; Natho P.; Parsons P. J. Recent Advances in the Synthesis of α-Amino Ketones. Org. Biomol. Chem. 2021, 19 (3), 498–513. 10.1039/D0OB02098B. [DOI] [PubMed] [Google Scholar]
  37. Tokuyama H.; Yokoshima S.; Yamashita T.; Shao-Cheng L.; Leping L.; Fukuyama T. Facile Palladium-Mediated Conversion of Ethanethiol Esters to Aldehydes and Ketones. J. Braz. Chem. Soc. 1998, 9, 381–387. 10.1590/S0103-50531998000400011. [DOI] [Google Scholar]
  38. Tokuyama H.; Miyazaki T.; Yokoshima S.; Fukuyama T. A Novel Palladium-Catalyzed Coupling of Thiol Esters with 1-Alkynes. Synlett 2003, 2003 (10), 1512–1514. 10.1055/s-2003-40861. [DOI] [Google Scholar]
  39. Fuwa H.; Mizunuma K.; Matsukida S.; Sasaki M. A New Strategy for the Synthesis of Substituted Dihydropyrones and Tetrahydropyrones via Palladium-Catalyzed Coupling of Thioesters. Tetrahedron 2011, 67 (27–28), 4995–5010. 10.1016/j.tet.2011.03.114. [DOI] [Google Scholar]
  40. Schneider C.; Reese O. Diastereoselective Conjugate Additions to T-Leucine-Derived N-Enoyl 1,3-Oxazolidin-2-Ones. Synthesis 2000, 2000 (12), 1689–1694. 10.1055/s-2000-8199. [DOI] [Google Scholar]
  41. For further discussion of this reaction, see Supplementary Scheme 4.; Thottumkara A. P.; Kurokawa T.; Du Bois J. Carbocyclization of Unsaturated Thioesters under Palladium Catalysis. Chem. Sci. 2013, 4 (6), 2686–2689. 10.1039/c3sc50486g. [DOI] [Google Scholar]
  42. Evans D. A.; Ennis M. D.; Mathre D. J. Asymmetric Alkylation Reactions of Chiral Imide Enolates - a Practical Approach to the Enantioselective Synthesis of Alpha-Substituted Carboxylic-Acid Derivatives. J. Am. Chem. Soc. 1982, 104, 1737–1739. 10.1021/ja00370a050. [DOI] [Google Scholar]
  43. Nammalwar B.; Bunce R. A.; Hiett J. T. Ring Size and Substitution Effects in the Tandem Reduction-Lactamization of Ortho-Substituted Nitroarenes. Org. Prep. Proced. Int. 2015, 47 (5), 338–355. 10.1080/00304948.2015.1066643. [DOI] [Google Scholar]
  44. For select examples, see:; a Pohl N. L.; Gokhale R. S.; Cane D. E.; Khosla C. Synthesis and Incorporation of an N-Acetylcysteamine Analogue of Methylmalonyl-CoA by a Modular Polyketide Synthase. J. Am. Chem. Soc. 1998, 120 (43), 11206–11207. 10.1021/ja9830290. [DOI] [Google Scholar]; b Hansen D. A.; Rath C. M.; Eisman E. B.; Narayan A. R. H.; Kittendorf J. D.; Mortison J. D.; Yoon Y. J.; Sherman D. H. Biocatalytic Synthesis of Pikromycin, Methymycin, Neomethymycin, Novamethymycin, and Ketomethymycin. J. Am. Chem. Soc. 2013, 135 (30), 11232–11238. 10.1021/ja404134f. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Oguro S.; Akashi T.; Ayabe S.; Noguchi H.; Abe I. Probing Biosynthesis of Plant Polyketides with Synthetic N-Acetylcysteamine Thioesters. Biochem. Biophys. Res. Commun. 2004, 325 (2), 561–567. 10.1016/j.bbrc.2004.10.057. [DOI] [PubMed] [Google Scholar]; d Ho Y. T. C.; Leng D. J.; Ghiringhelli F.; Wilkening I.; Bushell D. P.; Köstner O.; Riva E.; Havemann J.; Passarella D.; Tosin M. Novel Chemical Probes for the Investigation of Nonribosomal Peptide Assembly. Chem. Commun. 2017, 53 (52), 7088–7091. 10.1039/C7CC02427D. [DOI] [PubMed] [Google Scholar]; e Ehmann D. E.; Trauger J. W.; Stachelhaus T.; Walsh C. T. Aminoacyl-SNACs as Small-Molecule Substrates for the Condensation Domains of Nonribosomal Peptide Synthetases. Chem. Biol. 2000, 7 (10), 765–772. 10.1016/S1074-5521(00)00022-3. [DOI] [PubMed] [Google Scholar]
  45. For select examples, see:; a Harvey C. J. B.; Puglisi J. D.; Pande V. S.; Cane D. E.; Khosla C. Precursor Directed Biosynthesis of an Orthogonally Functional Erythromycin Analogue: Selectivity in the Ribosome Macrolide Binding Pocket. J. Am. Chem. Soc. 2012, 134 (29), 12259–12265. 10.1021/ja304682q. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Berkhan G.; Hahn F. A Dehydratase Domain in Ambruticin Biosynthesis Displays Additional Activity as a Pyran-Forming Cyclase. Angew. Chem., Int. Ed. 2014, 53 (51), 14240–14244. 10.1002/anie.201407979. [DOI] [PubMed] [Google Scholar]; c Wu J.; Zaleski T. J.; Valenzano C.; Khosla C.; Cane D. E. Polyketide Double Bond Biosynthesis. Mechanistic Analysis of the Dehydratase-Containing Module 2 of the Picromycin/Methymycin Polyketide Synthase. J. Am. Chem. Soc. 2005, 127 (49), 17393–17404. 10.1021/ja055672+. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. a Wiesmann K. E. H.; Cortés J.; Brown M. J. B.; Cutter A. L.; Staunton J.; Leadlay P. F. Polyketide Synthesis in Vitro on a Modular Polyketide Synthase. Chem. Biol. 1995, 2 (9), 583–589. 10.1016/1074-5521(95)90122-1. [DOI] [PubMed] [Google Scholar]; b Beck B. J.; Aldrich C. C.; Fecik R. A.; Reynolds K. A.; Sherman D. H. Iterative Chain Elongation by a Pikromycin Monomodular Polyketide Synthase. J. Am. Chem. Soc. 2003, 125 (16), 4682–4683. 10.1021/ja029974c. [DOI] [PubMed] [Google Scholar]; c Beck B. J.; Aldrich C. C.; Fecik R. A.; Reynolds K. A.; Sherman D. H. Substrate Recognition and Channeling of Monomodules from the Pikromycin Polyketide Synthase. J. Am. Chem. Soc. 2003, 125 (41), 12551–12557. 10.1021/ja034841s. [DOI] [PubMed] [Google Scholar]; d Xue Y.; Zhao L.; Liu H.; Sherman D. H. A Gene Cluster for Macrolide Antibiotic Biosynthesis in Streptomyces Venezuelae: Architecture of Metabolic Diversity. Proc. Natl. Acad. Sci. U. S. A. 1998, 95 (21), 12111–12116. 10.1073/pnas.95.21.12111. [DOI] [PMC free article] [PubMed] [Google Scholar]; e Yin Y.; Lu H.; Khosla C.; Cane D. E. Expression and Kinetic Analysis of the Substrate Specificity of Modules 5 and 6 of the Picromycin/Methymycin Polyketide Synthase. J. Am. Chem. Soc. 2003, 125 (19), 5671–5676. 10.1021/ja034574q. [DOI] [PubMed] [Google Scholar]
  47. Ackenhusen S. E.; Wang Y.; Chun S. W.; Narayan A. R. H. Understanding and Circumventing the Requirement for Native Thioester Substrates for α-Oxoamine Synthase Reactions. ACS Chem. Biol. 2022, 17 (9), 2389–2395. 10.1021/acschembio.2c00365. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Shigenaga A. Theoretical Study on Reaction Mechanism of Phosphate-Catalysed N–S Acyl Transfer of N -Sulfanylethylanilide (SEAlide). Org. Biomol. Chem. 2020, 18 (47), 9706–9711. 10.1039/D0OB01968B. [DOI] [PubMed] [Google Scholar]
  49. Horsman M. E.; Hari T. P. A.; Boddy C. N. Polyketide Synthase and Non-Ribosomal Peptide Synthetase Thioesterase Selectivity: Logic Gate or a Victim of Fate?. Nat. Prod. Rep. 2016, 33 (2), 183–202. 10.1039/C4NP00148F. [DOI] [PubMed] [Google Scholar]
  50. Hansen D. A.; Koch A. A.; Sherman D. H. Identification of a Thioesterase Bottleneck in the Pikromycin Pathway through Full-Module Processing of Unnatural Pentaketides. J. Am. Chem. Soc. 2017, 139 (38), 13450–13455. 10.1021/jacs.7b06432. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Koch A. A.; Hansen D. A.; Shende V. V.; Furan L. R.; Houk K. N.; Jiménez-Osés G.; Sherman D. H. A Single Active Site Mutation in the Pikromycin Thioesterase Generates a More Effective Macrocyclization Catalyst. J. Am. Chem. Soc. 2017, 139 (38), 13456–13465. 10.1021/jacs.7b06436. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Hansen D. A.; Koch A. A.; Sherman D. H. Substrate Controlled Divergence in Polyketide Synthase Catalysis. J. Am. Chem. Soc. 2015, 137 (11), 3735–3738. 10.1021/ja511743n. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Mortison J. D.; Sherman D. H. Frontiers and Opportunities in Chemoenzymatic Synthesis. J. Org. Chem. 2010, 75 (21), 7041–7051. 10.1021/jo101124n. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. We have also demonstrated in our lab the application of the auxiliary in asymmetric acylation and amino-aldol reactions.
  55. See Figure S4 for a discussion of the proposed (and overlooked) role of N-to-O acyl transfer in the cleavage of several amide and imide auxiliaries.

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