Synthesis and Synthetic Applications of Stannylated Amino Acids and Peptides

Abstract

Amino acids and peptides with stannylated vinyl or aryl side chains are interesting synthetic building blocks that can be easily modified by cross-couplings and metal–halogen exchange reactions, whether for the synthesis of complex natural products and active ingredients or for radiolabeling. The article provides an overview of the new methods and applications.

 

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Keywords

Amino acids - Cross-couplings - Hydrostannylations - Peptides - Stannanes

1

Introduction

Amino acids and peptides play a key role in biological processes in many ways and are involved in many biochemical signaling pathways. Peptide natural products, which are often produced by microorganisms and plants as secondary metabolites, are therefore often important lead structures for the development of active ingredients and drugs.[1] These small peptides differ significantly from larger proteins in that they often contain complex noncanonical amino acids.[2] However, highly active and therefore interesting natural products in particular are often only formed and/or isolated in tiny quantities, and therefore total synthesis is usually the only way to produce sufficient quantities for biological studies. In addition, total synthesis also allows the modification of natural products for studies of the structure–activity relationship (SAR) or for their transformation into tool compounds for chemical biology.[3] Methods are therefore particularly designed for modifying amino acids and peptides and are carried out under the mildest possible conditions, under which, for example, no epimerization of the stereogenic centers of a peptide occurs.[4] In this respect, the Stille coupling[5] is clearly superior to the Suzuki coupling,[6] although organotin compounds are more toxic than the corresponding boronic acids. Nevertheless, aryl and vinyl stannanes are extremely useful synthetic intermediates that can be coupled with a variety of electrophiles often under neutral reaction conditions.[5] In addition, stannylated aromatic amino acids are often used for the synthesis of fluorinated and radiolabeled amino acids and peptides, which find applications as drugs[7] or in medicine, e.g., in positron emission tomography (PET).[8]

This article summarizes the synthesis and applications of stannylated amino acids and peptides and gives an overview of current methods and procedures.

 

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2

Syntheses and Reactions of Amino Acids with Stannylated Aromatic Side Chains

Stannylated aromatic amino acids are often used in the synthesis of fluorinated amino acid derivatives. The incorporation of fluorine often improves the properties of functional molecules. For example, fluorine substituents can increase metabolic stability as well as the speed and extent of penetration of the blood–brain barrier by drugs.[7] Fluorinated aromatic compounds are also used as agrochemicals, materials, and tracers for PET.[8] The latter method, in particular, is an important diagnostic imaging method used to capture essential clinical information.[9] 6-^[18F]Fluoro-L-dopa (6-FDOPA) is used, for example, as a probe for central dopamine metabolism in vivo in humans.[10]

The radiofluorodemetallation method is one of the most efficient protocols for the synthesis of radiofluorinated aromatic amino acid probes.[11] Namavari et al. described the regioselective radiofluorodestannylation of 6-trimethylstannyl-L-m-tyrosine and dopa derivatives with F₂, ^[18F]F_2, and ^[18F]acetylhypofluorite.[12] The synthesis of the required stannylated amino acids started from the corresponding aryl iodides such as 1 and their Pd-catalyzed reaction with hexamethyldistannane ([Scheme 1]).[13] With this method, the desired aryltin compounds 2 can be produced regioselectively, while other methods, such as hydrostannylations of in situ generated arines, lead to regioisomeric mixtures.[14] For further conversion, the corresponding fluorinating agent (1%) was passed in a helium stream through a solution of arylstannane 2 in CFCl₃ (Freon-11). When [¹⁸F]F₂ and [¹⁸F]acetylhypofluorite were used, the radiochemical yield (RCY) was 23% and 17%, respectively. Acid hydrolysis provided the free fluorinated amino acids. Similar results have also been reported by other groups.[15]

Scheme 1 Synthesis of stannylated and fluorinated m-tyrosine.

In 2010, the Ritter group described a very efficient method for the late-stage fluorination of complex molecules such as carbohydrates, polyketides, alkaloids, and amino acids.[16] Based on previous work on the electrophilic fluorination of aryl silver compounds,[17] they developed a silver-catalyzed fluorination of aryl stannanes using Selectfluor as a fluorinating agent, which is easier to handle than elemental F₂. However, initial trials with AgOTf resulted primarily in protodestannylation products, probably due to the intermediate formation of triflic acid. However, this problem could be solved to a large extent using basic Ag₂O. The addition of methanol (5 equiv) also had a positive effect on the yield. In all cases, the degree of protodestannylation could be reduced to less than 10%. The method is suitable for both electron-rich and electron-poor aromatic rings and not only for amino acids, but also for larger peptides such as the enkephalin derivative 4 ([Scheme 2]).

Scheme 2 Late-stage modification of peptides with Selectfluor.

A similar approach was taken by Gouverneur’s group for the synthesis of ¹⁸F-labeled dopa by using ¹⁸F-selectfluor ditriflat.[18] But again, protodestannylation was the main observed side reaction. However, ¹⁸F-labeled dopa could be obtained by this protocol in RCY of about 12% ([Scheme 3]).

Scheme 3 Silver-catalyzed radiofluorination of Dopa-derivatives using ¹⁸F-Selectfluor ditriflate.

Sanford’s group was able to achieve better RCY under Cu-catalyzed conditions.[19] The decisive factor here was the switch to an amide solvent such as DMF or dimethylacetamide and the addition of 15 equiv of pyridine. With [¹⁸F]KF, an RCY of around 56% could be achieved in the radiofluorination of a Boc-protected dopa derivative ([Scheme 4]). This method has been applied to the synthesis of a variety of clinically relevant radiotracers and could also be automated.

Scheme 4 Copper-catalyzed radiofluorination of Dopa-derivatives using [¹⁸F]KF.

Further radiofluorinations were described, in which the stannylated amino acids were first converted into the corresponding diaryliodonium salts with Koser reagent,[20] which were then converted with ¹⁸F reagents.[21] However, these methods did not result in any improvement in the RCY.

In addition to the production of fluorinated amino acids, stannylated amino acids are also suitable for the generation of complex peptide structures by Stille couplings. An impressive example of this is the synthesis of the biaryl bridge of the right half (blue) of the complestatin molecule ([Fig. 1]).[22] Complestatin was derived from Streptomyces sp. WK-3419 and WK-3490 and is an inhibitor of the gp120-CD4 receptor.[23]

Fig. 1 Complestatin.

The key steps in the synthesis include the C–C linkage between the central phenylglycine building block and the tryptophan ([Scheme 5]). For this purpose, the diiodinated amino acid 5 was selectively monostannylated, whereby the best results were obtained using (o-tolyl₃P)₂PdCl₂ in the presence of iPr₂NEt, although even under these conditions, the yield of 6 was only moderate. iPr₂NEt was used to stabilize the resulting Bu₃Sn group and to accelerate transmetallation. The iPr₂NEt increases the electron-donating property of palladium without disturbing the catalysis cycle.[24] The nevertheless moderate yield is due to the formation of by-products and the acid-lability of the Bu₃Sn group. Stille coupling between 6 and the 6-iodotryptophan derivative 7 yielded the desired biaryl compound 8 in 41% yield.

Scheme 5 Stille coupling of stannylated phenylglycine 6.

 

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3

Syntheses and Reactions of Amino Acids with Vinylstannane Side Chains

3.1

Syntheses of Amino Acids with Vinylstannane Side Chains

3.1.1

Syntheses of Amino Acids via Hydrostannylations

In 1992, Crisp and Clink reported on the synthesis of protected stannylated allylglycines via hydrostannylation of propargylglycine 9 ([Scheme 6]).[25] Both radical and catalytic processes were investigated,[26] whereby three differently stannylated amino acid derivatives (E/Z)-10 and 11 became accessible. Under radical conditions, as expected, the terminal products 10 were preferentially obtained, whereby the product distribution depended decisively on the reaction conditions ([Table 1]).[25] Under relatively mild conditions (entry 1), a mixture of (E)-10 and (Z)-10 was obtained with a slight preference for the thermodynamically more stable (E)-product. In thermally induced hydrostannylation (entry 2), on the other hand, only the more stable (E)-product was formed in moderate yield, whether by isomerization or decomposition of (Z)-10. Interestingly, photochemical reaction conditions yielded only traces of 10. As expected, the palladium-catalyzed version (entry 3) provided the products (E)-10 and 11 in a stereospecific syn-addition, which could be separated by chromatography. Unfortunately, this was not possible with (E)-10 and (Z)-10.

Scheme 6 Hydrostannylation of propargylglycine 9.

Table 1 Hydrostannylation of propargylglycine 9

Entry	Reaction conditions	Equiv Bu3SnH	Isolated yields (%)
			(Z)-10	(E)-10	11
1	Bu3B/O2, toluene, 25 °C, 2 d	1.1	27	37	--
2	AIBN, dioxane, 100 °C, 100 min	2.1	Trace	32	--
3	Pd(PPh3)4, benzene, 25 °C, 5 min	1.1	--	15	58

In addition to these reactions, the bistannylation of the propargylglycine derivative 9 was also investigated ([Scheme 7]).[25] Reaction of 1 with hexamethylditin in the presence of Pd(PPh₃)₄ [27] yielded the cis-bis(trimethylstannyl)allylglycine derivative 12 in acceptable yield.

Scheme 7 Bistannylation of propargylglycine 9.

Although the catalytic hydrostannylation processes provide the corresponding syn-addition products in a mechanism-controlled stereospecific manner, the regioselectivity usually leaves much to be desired. Crisp and Gebauer investigated the hydrostannylation of the progargyl glycine derivative 13 with a total of 19 different transition metal complexes, but without achieving a regioselective product formation ([Scheme 8]).[28]

Scheme 8 Hydrostannylation of propargylglycine 13.

This hydrostannylation process is not limited to terminal alkynes but can also be used with internal alkynes. For example, Isaac et al. reported stereoselective hydrostannylation of aryl-substituted propargylglycines such as 14 but did not address the regioselectivity of the reaction ([Scheme 9]).[29] The products 15 were usually obtained only in moderate yields and were converted directly into the corresponding vinyl iodides.

Scheme 9 Hydrostannylation of substituted propargylglycine 14.

In connection with the synthesis of photoswitchable glutamate analogues, Isacoff and Trauner et al. used the hydrostannylation of the propargylated pyroglutamic acid derivative 16 for the synthesis of the terminal vinyl stannane 17 ([Scheme 10]), which was subsequently converted into a corresponding azobenzene derivative by Stille coupling.[30] Here, too, the yield in the hydrostannylation step was only moderate; unfortunately, no further information on the regioselectivity was given.

Scheme 10 Hydrostannylation of pyroglutamic acid derivates 16.

In 2006, Chena and Williams investigated the hydrostannylation of polarized triple bonds as in 18 ([Scheme 11]).[31] Hydride preferentially adds to the β position of the unsaturated ester, causing the tin residue to stand in the α position (19). Attempts to increase the ratio in favor of the β-stannylated product 20 by using sterically more demanding esters were unsuccessful. The corresponding t-butyl ester could no longer be hydrostannylated under the same conditions. However, the corresponding β-stannylated product could selectively be obtained by stannylcupration in the presence of alcohol (see [Scheme 22]).

Scheme 11 Hydrostannylation and stannylcupration of acetylenic esters.

In contrast to the transition metal–catalyzed hydrostannylations, the corresponding radical reactions provide three possible regioisomers, whereby in terminal alkynes the attack usually takes place preferably at the sterically less hindered position, whereby the more stable vinyl radical is formed. In the case of polyunsaturated compounds, the intermediately formed vinyl radical can be intercepted in cyclization reactions.

For example, Alcaide et al. reported on the synthesis of vinylstannyl-carbapenem 22 by regio- and stereo-controlled intramolecular cyclization of enyne β-lactame 21 ([Scheme 12]).[32] The cyclization process was completely regioselective in all cases. The products were formed by a 5-exo-trig radical process, which is known to be preferred when the radical acceptor has a radical-stabilizing substituent at the β position.[33]

Scheme 12 Radical cyclization of β-lactam 23.

In the context of syntheses of inhibitors of angiotensin converting enzymes, Clivea et al. investigated the radical cyclization of propargylated enamide 23, which was used as a diastereomer mixture of unknown ratios ([Scheme 13]).[34] The cyclization took place without any problems and again yielded only two diastereomers of 24 in a ratio of 3:1, the configuration of which has also not been elucidated. The cyclization was obviously highly stereoselective, as otherwise the formation of further stereoisomers would have been observed. The configuration of the vinyl stannane was also not determined, but rather this group was converted into an exocyclic methylene group by protodestannylation (>90% yield).

Scheme 13 Radical cyclization of enamide 25.

 

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3.1.2

Syntheses of Amino Acids by Introduction of Stannylated Side Chains

An alternative approach to the synthesis of γ,δ-unsaturated amino acids uses the highly stereoselective Claisen rearrangement.[35] For example, the deprotonation of N-protected amino acid allyl esters 25 with LDA at −78 °C with the addition of a metal salt such as ZnCl₂ presumably leads to the formation of a chelated metal enolate 26, which undergoes a Claisen rearrangement when heated to room temperature, forming γ.δ-unsaturated amino acids 27 ([Scheme 14]).[36] Due to the fixed enolate geometry as a result of chelation and a strong preference for the chair-like transition state, the rearrangement is highly diastereoselective. The use of esters of chiral allylic alcohols allows the highly stereoselective formation of optically active amino acids.[37] Another possibility for asymmetric reaction control is the rearrangement in the presence of chiral ligands.[38] During the rearrangement of peptide allyl esters, the chiral information of the peptide chain can also be used to control the stereochemical outcome of the rearrangement.[39]

Scheme 14 Synthesis of γ,δ-unsaturated amino acids via ester enolate-Claisen rearrangement.

To be able to use these protocols for the synthesis of amino acids with a vinylstannane side chain, a regioselective hydrostannylation of allyl alcohol derivatives is required, which preferentially yields the α-stannylated products (R¹ = SnR₃). The corresponding β-stannylated allyl alcohols (R² = SnR₃) provide allyl stannanes during rearrangement that can no longer be used in Stille couplings. Thus, radical hydrostannylations are ruled out, as they preferentially provide β-products, as well as (E/Z) mixtures.

Chong and coworkers investigated in detail the influence of ligands on the regioselectivity of Pd-catalyzed hydrostannylation of propargyl alcohol derivatives 28 ([Table 2]).[40] When using sterically demanding phosphine ligands such as Cy₃P or tBu₃P, the β-stannylated product 30 could be obtained with regioselectivities of up to 99:1, but a preferred formation of the α-stannylated allyl alcohol derivatives 29 was not possible. In addition to palladium, however, a number of other transition metals can be used as catalysts.[41] Among other things, Guibe et al. described the application of a molybdenum catalyst.[42] For example, MoBr(allyl)(CO)₂(CH₃CN)₂ is suitable for the hydrostannylation of propargylic alcohol derivatives, but without significant regioselectivity ([Table 2], entries 1–4).

Table 2 Catalytic hydrostannylation of propargylic alcohol derivatives 30

Entry	R	Catalyst	Yield [%]	Ratio 29:30
1	H	PdCl2(PPh3)2	41	55:45
2	THP	PdCl2(PPh3)2	68	67:33
3	H	MoBr(allyl)(CO)2(MeCN)2	n.r.	67:33
4	THP	MoBr(allyl)(CO)2(MeCN)2	n.r.	64:36
5	THP	Mo(CO)6	64	68:32
6	H	Mo(CO)3(CNt-Bu)3	94	89:11
7	THP	Mo(CO)3(CNt-Bu)3	98	>95:<5

n.r.: not reported.

The catalytically active species in these processes are probably Pd(0) and Mo(0) complexes formed in situ by reduction with tin hydride. Kazmaier et al. therefore also investigated the use of Mo(CO)₆ as a catalyst for hydrostannylations. Mo(CO)₆ proved to be suitable for this reaction in principle, although the reaction was slow and provided comparatively moderate yields ([Table 2], entry 5).[43] The observed regioselectivities were comparable to the results of Guibe’s catalyst (entries 3 and 4). However, replacing some CO ligands with suitable isonitriles[44] led to a dramatic increase in both yield and selectivity.[45] The best result was achieved with Mo(CO)₃(CNt-Bu)₃ (MoBI₃)[46] (entries 6 and 7); an additional isonitrile ligand had no further positive influence on the reaction.[47]

In general, high α-selectivities are achieved with terminal alkynes with this catalyst, even with secondary propargylic alcohols with sterically demanding protective groups. Interestingly, hydrostannylation works not only with allyl alcohols or allyl ethers but also with allyl carboxylates and carbonates. Although MoBI₃ has previously been used as a catalyst for allyl alkylations with allyl acetates and carbonates,[48] hydrostannylation seems to take place under such mild conditions that decomposition of the stannylated allyl substrate does not matter.[43] [49] [50] Of particular interest for the synthesis of stannylated amino acids is the direct regioselective hydrostannylation of glycine propargyl esters 31 to the corresponding stannylated allyl esters 32, which can then be rearranged to the stannylated γ,δ-unsaturated amino acids in a chelate enolate-Claisen rearrangement ([Scheme 15]).[51] [52]

Scheme 15 Synthesis and chelate enolate-Claisen rearrangement of stannylated allylic esters 34.

The stannylated allyl acetates and carbonates, which are also accessible by hydrostannylation, form another interesting approach to stannylated unsaturated amino acids via palladium-catalyzed allylic alkylation. The chelate enolates already presented during the enolate-Claisen rearrangement are excellently suited as nucleophiles in palladium-catalyzed allylations.[53] These reactions usually only succeed with stabilized enolates, such as malonates, as unstabilized enolates normally coordinate toward the palladium and thus deactivate the catalyst. The few exceptions include tin and zinc ketone enolates and these chelate enolates.[54] Here, the enolate forms a stable chelate complex that does not transmetallate to palladium. At the same time, chelate enolates are highly reactive enolates, which react with π-allyl complexes already at −78 °C. This makes it possible to eliminate even typical side reactions such as the π-σ-π isomerization of the allyl–palladium complexes.[53c] [55] With stannylated allyl acetates and carbonates 33, stannylated amino acid derivatives 34 ([Scheme 16]) can also be obtained under these very mild conditions.[52]

Scheme 16 Synthesis of stannylated amino acid derivatives 36 via allylic alkylation using stannylated allyl carbonates 35.

Of course, the “classic” allylation nucleophiles such as amines can also be reacted with these allyl substrates.[56] If, for example, amino acid ester 35 is used as nucleophiles, stannylated N-allylated amino acid derivatives 36 are obtained, which can be further converted directly via Stille couplings in a one-pot process ([Scheme 17]).[57]

Scheme 17 N-Allylation of amino acid esters.

In addition to amino acid esters, larger peptide fragments as nucleophiles are also suitable for allylic alkyations.[58] Their deprotonation in the presence of zinc chloride also leads to highly reactive nucleophiles that can be palladium-catalyzed allylated. Excellent diastereoselectivities are achieved almost independently of the allylic substrate used. The stereochemical outcome of the reaction is controlled exclusively by the peptide chain. It is likely that the deprotonated peptide chain coordinates several times to the chelated metal ion. In such metal peptide complexes, one side of the generated enolate is shielded by the side chain of the adjacent amino acid, directing the electrophilic attack to the opposite face of the enolate. This explains that an (S)-amino acid always generates an (R)-amino acid (and vice versa). The method is not limited to C-terminal peptide esters but also works with peptides that contain proline or N-methylated amino acids in the peptide chain. During deprotonation, amide enolates are formed, which are also suitable for palladium-catalyzed allylation.[59] Also functionalized side chains can be installed in a highly stereoselective manner.[60] With stannylated allyl acetates and carbonates such as 33, stannylated peptides 37 are obtained, which allow a variety of further modifications onto the existing peptide framework ([Scheme 18]).[61]

Scheme 18 Synthesis of stannylated peptides via allylic alkylation.

In addition to classic peptides, N-(α-hydroxyacyl)-glycine esters 38 can also be used as nucleophiles.[62] Optimal results are obtained by using ClTi(OiPr)₃ as a chelating agent, whereby both diastereomers 39a and 39b can be specifically built up by varying the reaction conditions ([Scheme 19]). Thus, when LDA is used as a base, the (S)/(R) product 39a is preferentially obtained, as with peptides, while LHMDS yields the diastereomeric (S)/(S) product 39b in a highly stereoselective fashion.

Scheme 19 Allylic alkylation of N-(α-Hydroxyacyl)-glycine esters.

 

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3.1.3

Miscellaneous Further Methods

An interesting approach to α-alkylated amino acids with stannylated vinyl side chains was described by Berkowitz et al. ([Scheme 20]).[63] Starting from N-benzoyl-protected (S)-vinylglycine 40, the diastereomeric oxazolines 41a and 41b were obtained by 5-exo-trig-selenocyclization, which could be easily separated chromatographically.[64] Deprotonation of the pure enantiomers and anti-α-alkylation yielded more or less enantiomerically pure oxazolines 42.

Scheme 20 Synthesis α-alkylated β,γ-unsaturated amino acid derivatives.

The original β,γ-unsaturation was regenerated by base-mediated oxazoline ring opening, whereby this reaction also yielded the corresponding (E)-configured product 43 stereoselectively. By heating with HSnBu₃ and AIBN, the corresponding vinyl stannane 44 was obtained, which could be used in different cross-coupling reactions. Protodestannylation yields, for example, the unsubstituted α-alkylated amino acid derivatives 45.

From these, fluorinated stannylated quaternary vinyl amino acids could also be obtained by subjecting 45 to ozonolysis ([Scheme 21]).[65] The formylamino acids 46 formed could be reacted with McCarthy's phosphonate 47,[66] [67] whereby almost exclusively the (E)-fluorovinyl sulfone 48 was formed. This high degree of diastereoselectivity is unusual for condensation reactions of 47 and is probably due to the high steric demand of the quaternary α center. The subsequent sulfone–tin exchange to 49 went smoothly under the mediation of Bu₃SnH, usually with very high yields.

Scheme 21 Synthesis of α-alkylated fluorinated vinylstannane amino acids.

Chena and Williams described syntheses of highly functionalized γ,δ-unsaturated amino acids based on a regioselective stannylation of propargylglycine derivatives.[29] Starting from iodoalanine 50, which can be easily obtained from (S)-serine,[68] the corresponding zinc cuprate 51 was generated via halogen–metal exchange, which was then coupled with 3-bromopropiolate ([Scheme 22]).[69] Among the various stannylation methods tested, the addition of [(Me₃Sn)CuCN]Li proved to be the method of choice. When 54 was added to [(Me₃Sn)CuCN]Li in dry THF at −78 °C, the expected vinyl stannane was obtained as a 1:1 (E/Z) mixture, which unfortunately could not be separated chromatographically. However, if [(Me₃Sn)CuCN]Li was treated with EtOH before the addition of 52, only the desired (E)-isomer 20 was formed. The regioisomeric vinylstannane 19 was obtained by hydrostannylation of 52 ([Scheme 11]).

Scheme 22 Synthesis of stannylated (E)-γ,δ-unsaturated amino acids.

As part of their domoic acid syntheses, the Clayden group investigated the stereoselective formation of trisubstituted double bonds starting from alkinylpyrrolidine 53.[70] Syn-Stannylcupration with [(Bu₃Sn)Cu(Bu)CN]Li₂ according to the Lipshutz protocol[71] intermediately yielded a vinyl cuprate that was directly methylated ([Scheme 23]). The desired product 54 was the only regio- and stereoisomer obtained. Subsequent Stille couplings provided the desired domoic acids.

Scheme 23 Synthesis of stannylated proline derivatives via stannylcupration.

As part of their total synthesis of runanins, Kim et al. investigated cross-couplings of the exocyclic bromoalkene group of 55.[72] After all coupling reactions had failed, they converted 55 into vinylstannane 56, which could then be reacted, e.g., with acyl chlorides ([Scheme 24]).

Scheme 24 Synthesis of stannylated proline derivatives via halogen–metal exchange.

 

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3.2

Reactions of Amino Acids with Vinylstannane Side Chains

Crisp and Clink were the first to investigate the conversion of stannylated amino acids more intensively ([Scheme 25]).[25] For example, copper(II) nitrate–mediated homocoupling reactions[73] of racemic vinylstannanes 11 and (E)-10 gave access to the symmetrically substituted dienes 57 and (E,E)-58 as diastereomer mixtures. Treatment of 11 with a slight excess (1.1 equiv) of iodine yielded the corresponding γ-iodoallylglycine derivative 59, albeit in moderate yield.[74] Interestingly, the corresponding terminal stannane (E)-10 provided not only the expected vinyl iodide (E)-60 but also small amounts (about 6%) of the corresponding (Z)-isomer.

Scheme 25 Reactions of stannylated allylglycines.

The authors also investigated the modification of stannylated amino acids via Stille couplings.[75] The reaction of 11 with iodobenzene served as a model reaction ([Scheme 26]). Interestingly, the reaction with Pd(PPh₃)₄ and other palladium catalysts resulted not only in the desired product 61 but also in the unexpected δ-isomers (E)-62 and (Z)-62 resulting from cine substitution. When using more electron-rich ligands such as AsPh₃ or P(2-furyl)₃, the coupling ran under milder conditions but also delivered more cine product. The cine substitution of vinyl stannanes is usually found only in sterically hindered organostannanes, in which transmetallation occurs only slowly.[76] It is probably the result of a Heck reaction between the terminal alkene position of 11 and the organic electrophile, followed by a palladium-catalyzed elimination of Bu₃SnI. For example, no cine substitution product was obtained with the linear vinyl stannane (E)-10, even when the activating ligand AsPh₃ was used.

Scheme 26 Stille couplings with aryl iodides of stannylated allylglycines.

Interestingly, the problem of cine substitution seems to be limited to aryl and hetaryl iodides as well as vinyl halides; with a variety of other electrophiles such as vinyl triflates and allyl and acyl halides, this side reaction has not been observed, even during the use of the activating ligand AsPh₃.[51] [52] [75] No isomerization of double bonds was observed in cases where isolated double bonds were formed ([Scheme 27]).

Scheme 27 Cross-couplings of stannylated allylglycines.

Kazmaier et al. also used the coupling with α,β-unsaturated acid chlorides to build amino acids with heterocyclic side chains by double 1,4-addition of amines ([Scheme 28]).[77]

Scheme 28 Synthesis of amino acids with heterocyclic side chains.

Stille couplings between vinyl stannanes and vinyl halides or triflates represent an interesting approach to 1,3-dienes, as these couplings occur under neutral conditions and often even at room temperature.[78] These mild conditions allow for the production of delicate dienes that are difficult to obtain by alternative means.[79] Therefore, the formation of the cine product when using vinyl halides is a significant limitation.[75]

Crisp and Gebauer therefore investigated in detail the influence of the N-protection group on the product distribution of the Stille coupling with vinyl bromide.[80] By palladium-catalyzed hydrostannylation of imine-protected propargylglycine ester 13 ([Scheme 8]), the vinyl stannanes 63 and 64 were obtained in a 1:1 ratio, and as such reacted with vinyl bromide in the presence of various catalysts ([Scheme 29]). The relative reactivity of the two isomers was to be investigated. When PdCI₂(CH₃CN)₂ was used as a catalyst with an excess of vinyl bromide, the two coupling products 65 and 66 were formed in a ratio of 5:1, whereby unreacted 64 could be partially recovered. Apparently, the sterically more hindered vinyl stannane reacted more quickly than the terminal one, which may be due to a coordination of the Pd catalyst toward the imine and a chelated-controlled transmetallation. Interestingly, Pd(AsPh₃)₄ provided the opposite product distribution in a similar ratio. In this case, 63 could be recovered and the reaction was significantly slower. Presumably, the AsPh₃ ligand reduces or prevents the coordination of palladium toward the imine nitrogen. The same applies to the acetylated glycine derivative 11, which also preferentially supplied the linear cine substitution product.

Scheme 29 Synthesis of dienes via cross-coupling.

For the modification of peptides, Deska and Kazmaier investigated reactions of stannylated peptides such as 37 ([Scheme 30]), which are very easily accessible by palladium-catalyzed allylic alkylation ([Scheme 18]).[61] Very good yields were obtained throughout, with the reaction with some acid chlorides and iodine being approximately quantitative. The vinyl iodide 67 formed in this process could then be further converted in a variety of cross-coupling reactions. Thus, the reaction with vinylstannane also resulted in conjugated diene 68, whereby the problem of cine substitution could be circumvented by this protocol. Carbonylation reactions are suitable for the synthesis of α.β-unsaturated esters and amides (69).[81] Analogous conversions were also achieved with N-(α-hydroxyacyl)-glycine esters.[79]

Scheme 30 Cross-coupling reactions of stannylated dipeptides.

Junk and Kazmaier also developed a new synthetic route for modified tryptophans based on stannylated amino acids and peptides ([Scheme 31]).[82] Stille couplings of 37 with arbitrarily substituted o-iodanilines yielded styrene derivatives such as 70. Conversion of the free amino functionality into an azide and subsequent irradiation resulted in a C–H insertion of the intermediately formed nitrene and the formation of tryptophans 71. This method was used in the synthesis of several cyclopeptide natural products such as Keramamide A[83] and Mozamide A.[84]

Scheme 31 Synthesis of tryptophans from stannylated peptides.

Berkowitz et al. intensively investigated the conversion of α-quaternary stannylated vinylglycine 44 as building blocks for potential applications in de novo peptide design and engineering.[63] The corresponding vinyl stannanes can be produced by radical substitution from the corresponding vinyl selenium compounds ([Scheme 20]), whereby only (E)-configured vinyl stannanes are formed. These can be easily reacted with a large number of electrophiles ([Scheme 32]).[85] Protodestannylation yields the corresponding vinyl amino acids, while when reacted with D₂O, the corresponding (E)-configured deuterated amino acids 72 are formed. The reaction with iodine yields the corresponding vinyl iodide 73, which in turn can be converted back into dienes with vinyl stannanes. While ¹²³I-labeled NaI is used to obtain the corresponding radioiodinated amino acids,[86] [87] the analogous radiobrominated derivatives result from the use of NH₄ [79]Br.[88]

Scheme 32 Conversions of α-quaternary stannylated vinyl glycine.

Starting from γ-fluorinated vinyl stannanes 74, a whole range of fluorinated unsaturated amino acids was obtained in an analogous way, whereby the fluorinated vinyl iodide 75 can in turn be further converted in a series of cross-couplings ([Scheme 33]).[65]

Scheme 33 Reactions of fluorinated α-quaternary stannylated vinylglycines.

Chena and Williams reported the synthesis of a series of highly functionalized γ,δ-unsaturated amino acids by Stille couplings of stannylated amino acids 19 and 20 ([Scheme 34]).[31] The catalytic system Pd₂dba₃/CuI/AsPh₃ performed quite well for the studied Stille coupling reactions.

Scheme 34 Silver-catalyzed radiofluorination of Dopa-derivatives using¹⁸F-Selectfluor ditriflate.

The Akiyama group developed an extremely elegant asymmetric one-pot synthesis of dehydroproline esters, based on a formal [3+2] cycloaddition of α-imino esters 76 and allenylstannane 77 ([Scheme 35]).[89] The reaction probably proceeds stepwise via a copper(I)-catalyzed nucleophilic addition of allenylstannane 77 to the α-imino ester 76, forming a vinylic carbenium ion, which ultimately leads to a migration of the tin residue and cyclization. The intermediately formed 4-stannylated dehydroprolinester 78 yielded optically active 4-iodine and 4-aryldehydroproline esters in good yields and high ee’s via iodine oxidation and Stille coupling reactions. Depending on the reaction partner and coupling conditions, the dehydroproline derivative 79, formed by protodestannylation, was found as a by-product, also with good ee’s.

Scheme 35 One-pot synthesis of dehydroproline esters via [3+2]-cycloaddition.

The stannylated pyroglutamic acid derivative 17 was used in the synthesis of photoswitchable glutamate analogues, which are potent and selective iGluR5 and 6-kainate receptor (KAR) agonists ([Scheme 36]). For example, palladium-catalyzed Stille coupling with iodoazobenzene yielded the N-Boc-protected azobenzene pyroglutamate 80.[30] Azobenzenes are the most studied photoswitches and have become popular optical probes for biological systems. The trans-configuration is the thermodynamically preferred form. The cis-configuration is usually metastable, but it can be fixed when an o-bridged azobenzene such as 81 is used.[90]

Scheme 36 Synthesis of photoswitchable glutamate analogues.

The Clayden group used vinylstannane 54 as a central building block during the synthesis of kainic acid 82 and various isodomoic acids ([Scheme 37]).[70] Stannane 54 was obtained via stannylcupration and subsequent palladium-catalyzed methylation ([Scheme 23]). Treatment of 54 with TFA resulted in protodestannylation and global deprotection giving rise to 82. The different isodomoic acids were obtained by coupling 54 with different halogenated unsaturated carboxylic acid derivatives and subsequent deprotection.

Scheme 37 Synthesis of kainic and isodomoic acids.

In the context of the synthesis of Hasubanan alkaloids, Kim et al. described cross-couplings of vinyl stannane 56 with methoxyacetyl chloride, providing exocyclic enone 83 in an acceptable yield ([Scheme 38]).[72]

Scheme 38 Cross-coupling of sterically hindered vinylstannane 58.

 

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Conclusion

Amino acids and peptides with stannylated vinyl or aryl side chains are interesting synthesis building blocks that can be easily modified by cross-couplings and metal–halogen exchange reactions. Stannylated aromatic amino acids are mainly used for the synthesis of fluorinated and radiolabeled amino acids and peptides, while amino acids with stannylated unsaturated side chains are mainly used in cross-coupling reactions. This allows the synthesis of unusual amino acids and complex natural products. The major advantages of these organotin compounds are the mild and neutral reaction conditions used in their coupling reactions, avoiding epimerization of configurationally labile substrates. The major disadvantage results from the toxicity of many organotin compounds, which is why the cross-coupling reactions should not be carried out at the end of a synthesis, as also the catalysts used often have toxic properties. Recent developments should therefore aim to use more environmentally friendly and nontoxic metals that can be implemented under similarly mild conditions.

 

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Uli Kazmaier

Uli Kazmaier, born in 1960, studied chemistry at the University of Stuttgart where he obtained his diploma (1985) and his PhD (1989). Afterward, he joined as a postdoc in the research groups of M.T. Reetz (Marburg) and B.M. Trost (Stanford). In 1992, he moved to Heidelberg starting his own scientific work as a habilitand at the Institute of Organic Chemistry. In 2000, he received a Novartis Chemistry Lectureship and an offer of a full professorship at the University Bayreuth. In 2001, he also obtained an offer of a full professorship at the University des Saarlandes, which he accepted. His current research interest extends to new organometallic reagents and reactions especially for amino acid and peptide synthesis. Besides the development of new synthetic protocols, the application of these new reactions toward the synthesis of natural products and other pharmaceutical relevant structures plays a central role.

Conflict of Interest

The authors declare that they have no conflict of interest.

Acknowledgment

I thank Saarland University and Deutsche Forschungsgemeinschaft (DFG) for continuous support of our work and all the highly engaged coworkers for their outstanding contributions.

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Publikationsverlauf

Eingereicht: 17. Mai 2025

Angenommen nach Revision: 03. Juli 2025

Accepted Manuscript online:
07. Juli 2025

Artikel online veröffentlicht:
20. August 2025