Chemistry and catalysis advances in organometallic chemistry and catalysis
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Figure 23.4 Generalization of Pd-catalyzed, Cu-mediated desulfitative catalysis. The thiolate residue must be fully scavenged by an equivalent of the Cu(I) and, as dictated by a balanced reaction, the presence of a full equivalent of a strongly bonding third valence for the –B(OH) 2 fragment is required, in this case, the carboxylate. The mechanistic requirement of a stoichiometric quantity of a Cu(I) carboxylate for pH-neutral desulfitative cross-coupling will be incompatible with any desulfitative bioconjugative transformations of biomolecules, such as proteins, that must be carried out in water.
298 TOWARD CHEMOSELECTIVE BIOCONJUGATIVE DESULFITATIVE CATALYSIS stoich. Cu(I)OCOR + R 1 SR R 2 B(OH)
2 S R Cu + + RC(O) O B
(OH) 2 + Cat. Pd R 1 R 2
Stoichiometry of the Pd-catalyzed, Cu(I) carboxylate-mediated desulfitative coupling.
Bioconjugative processes require reasonably fast reactions that can take place at ambient temperature, usually in water. Therefore, any anticipated bioconjugative desulfitative cross-coupling with boronic acids will involve reactions that can occur rapidly in water and use only catalytic quantities of palladium and/or copper. The challenge then is clear: in order to transform the first generation of desulfitative cross-couplings, which require stoichiometric amounts of a Cu carboxylate to reach completion, into a reaction system that is catalytic in Cu, the Cu–SR reaction product must be converted back into a Cu-oxygenate during the catalytic cycle (Scheme 23.4). Therefore, a catalytic variant of desulfitative cross-coupling with boronic acids that proceeds through a Cu-thiolate intermediate will necessitate (i) breaking of the strong Cu–S bond, (ii) trapping of the thiolate ligand producing a weakly coordinating derivative, and (iii) regeneration of a Cu-oxygenate in order to continue the catalytic cycle. 23.3.1 Cu-Desulfitative Catalysis under Aerobic Conditions How might a copper thiolate be transformed into a copper oxygenate a neutral pH? Taniguchi [43, 44] disclosed results suggesting that copper thiolates, Cu(I)–SR, react with boronic acids, R B(OH) 2 , when exposed to air (oxygen) to generate thioethers, R–S–R . This observation implies that a desulfitative cross-coupling using only catalytic quantities of the Cu source could be achieved if the reaction were carried out open to air, but with a second (sacrificial) equivalent of the boronic acid present to scavenge the thiolate as a thioether. This logical analysis proved fruitful and led to the discovery of a novel aerobic coupling of thiol esters and boronic acids that uses only catalytic quantities of Cu to effect the reaction (Scheme 23.5) [45]. Interesting attributes of this new reaction are (i) the use of only Cu, and not Pd, to catalyze the desulfitative carbon– carbon bond formation, (ii) the strict requirement for a Cu-coordinating functional group on the sulfur-pendant, and (iii) the very mild (room temperature, neutral pH) reaction conditions. S-acylthiosalicylamides proved to be particularly effective substrates for this chemistry. A study of peptidic S-acylthiosalicylamides was used to demonstrate broad functional group compatibility and high stereoretention (Scheme 23.6) [46]. The mechanism of this new aerobic, Cu-catalyzed desulfitative coupling is thought to proceed through a three-stage process (Fig. 23.5) [41] commencing with oxidation of a Cu(I) S-acylthiosalicylamide complex A to generate the dimeric species B, L Cu II/III
-(O 2 )-Cu II/III L , for which the side-on μ-η 2
η 2 -peroxo, bis-( μ-O), and trans end-on μ-η 1 : η 1 -superoxo are known to be dominant bonding motifs [47–50]. A subsequent transmetalation from the boronic acid to the higher oxidation state Cu center generates an intermediate C in which a nucleophilic organocopper, R 2 -Cu is positioned in close proximity to the electrophilic thiol ester. An internal transfer produces the anticipated ketone product, R 1 -CO-R 2 , and a
cat. Cu ? oxygenate + R 1 SR R 2 B(OH) 2 + + oxygenate B(OH) 2
R 1 R 2 Cat. Cu-SR Cat. Trap
RS -trap
How? Scheme 23.4 The catalytic challenge. 5 − 20 mol% Cu(I) or Cu(II) rt, air 30 min to 18 h DMF or DMF/H 2 O S R 1 O 2 R
2 B(OH)
2 R 1 R 2 O + + S R 2 CONHR ′ CONHR
′ Scheme 23.5 Cu-catalyzed aerobic desulfitative catalysis of S-acylthiosalicylamides. CU-CATALYZED DESULFITATIVE COUPLING 299 O S CbzHN HN O NHi Pr + 20 mol % CuMeSal DMF, air rt O CbzHN
HN F F B(OH) 2 F F 99% ee
97% yield >15 other examples Trp 1 equiv
2.5 equiv Scheme 23.6 Aerobic, room temperature coupling of peptidic S-acylthiosalicylamides. R 1
2 O Cu II/III S O NHR ′ R 1 O O 2 S O NHR ′ R 2 S O NHR ′ R 1 CO Cu II/III S O NHR ′ R 1 O O O [O 2 ] R 2 B(OH) 2 Cu I S O NHR ′ R 1 O X Cu II/III
S O R 2 O NHR ′ R 1 O Cu II/III S O O NHR ′ Cu II/III S O R 2 NHR ′ R 2 B(OH) 2
B C D E Figure 23.5 Mechanism of the aerobic, Cu-catalyzed desulfitative coupling. higher oxidation state copper thiolate D. The catalytic cycle is completed in stage 3 when the second (sacrificial) equivalent of the boronic acid reacts via transmetalation-reductive elimination with the higher oxidation state copper thiolate D to generate E, which undergoes reductive elimination to scavenge the thiolate as a thioether and to regenerate a Cu I -oxygenate (A, X = oxygenate), which continues the cycle. In contrast to the first generation of Pd-catalyzed, Cu-mediated desulfitative couplings, it should be noted that the aerobic, Cu-catalyzed process does not require the presence of Pd to cleave (and activate) a C–S bond through an oxidative addition. The thiol ester is a native electrophile and possesses sufficient inherent electrophilic reactivity when activated by coordination to copper to capture an in situ generated organocopper intermediate. It is therefore likely that the aerobic, Cu-catalyzed desulfitative coupling system will not be broadly extensible to other thioorganics (that require activation by oxidation addition to low valent Pd), although it could prove highly useful for the molecular engineering of complex thiol esters such as those derived from proteins and complex peptides.
The mechanistic requirement of 2 equiv of boronic acid to drive the aerobic, Cu-catalyzed coupling with S- acylthiosalicylamides to completion will not be problematic in those cases where the thiol ester partner is far more precious than the boronic acid. However, there are many systems where sacrificing an equivalent of the boronic acid is not appropriate—in those cases where the boronic acid is precious, or where the boronic acid is used as a linker that is structurally integrated to the coupling partner for the thiol esters (i.e., coupling to surfaces via boronic acid linkers or ligations using boronic acid-modified proteins). For these systems, if they are to be used in bioconjugative applications, it is essential to develop mild, pH-neutral Cu (or Pd) catalytic systems that require only 1 equiv of the boronic acid partner. In order to render Cu(I) catalytically viable in a desulfitative chemical transformation without sacrificing a second equivalent of the boronic acid coupling agent, a small molecule analog of the metallothionein (MT) protein system was designed [36]. MTs are small proteins capable of binding up to 7 equiv of mono and divalent metals such as Cu(I) and Zn(II) [51]. Although positioned within a tightly binding thiol/thiolate-rich ligand environment, a thiophilic metal is rapidly released from MT binding when a MT is exposed to an exogenous disulfide (Scheme 23.7) [52, 53]. An “MT mimic” was constructed in which the exogenous S–S reactant of the biological system was replaced with an N–O moiety of an oxime integrated into thiolate pendant residue (Scheme 23.8).
300 TOWARD CHEMOSELECTIVE BIOCONJUGATIVE DESULFITATIVE CATALYSIS S Cu
Metallothionein inspiration -SR trapped S Cu
S R ′ S R ′ S R ′ “liberated” Cu S R ′ S R ′ S R +
Cu-thiolate activation by exogenous disulfide in metallothioneins. S R 1 O N Me OR ′ R 1 R 2 O + S N R 2 B(OH)
2 1 equiv
Me + CuOR Cu-oxygenate regeneration Templating ligand Thiolate
scavenged S Cu N Me OR internal thiolate trap Cu X
′OB(OH) 2 + Scheme 23.8 Cu-catalyzed desulfitative catalysis using metallothionein mimics. R 2
2 + CuMeSal (20 mol%) 90 −150 °C, DMF, 1 h nitrogen R 1 O R 2 yields: 60 −95%
>20 examples 1 equiv
S N Me OMe R 1 O S N Me MeO-B(OH) 2 +
Cu-catalyzed anaerobic desulfitative ketone synthesis. Through its oxime N–O bond the MT mimic internally provides a mild S-centered oxidation of a Cu(I) thiolate thereby converting the strongly bonding thiolate to a weakly bonding disulfide equivalent (in this case the S–N bond of the benzoisothiazole shown). This mild oxidative trapping of thiolate was also intended to continuously regenerate a catalytically viable “oxygenate” form of Cu(I) (and a stoichiometric oxygenate residue to pair with –B(OH) 2 ) so that a useful Cu(I)- catalyzed desulfitative carbon– carbon bond-forming reaction with boronic acids can ensue. Using only 1 equiv of the boronic acid (or an organostannane) the MT mimic provides an effective vehicle for the production of ketones using only catalytic quantities of Cu (Scheme 23.9).
As described above, two new Cu-catalyzed desulfitative transformations have been discovered that can be used for the construction of peptidyl ketones from peptidic thiol esters and boronic acids. Under aerobic reaction conditions,
(Scheme 23.6). In comparison, S-acyl-2-mercaptoaryloximes function as MT mimics and can produce peptidyl ketones under anaerobic reaction conditions from only a single equivalent of boronic acid. The latter reaction is also efficient and general, but in its current design, it is only catalytically effective at elevated temperatures ( >90 ◦
Control experiments using stoichiometric quantities of Cu demonstrate that the carbon– carbon bond-forming step of both the aerobic and anaerobic reaction systems proceeds at room temperature (Fig. 23.6). However, the two systems differ in the Cu-recycle step. The aerobic system recycles Cu for catalysis at room temperature, while Cu-recycle by internal trapping of the Cu-thiolate by the N–O bond of the MT mimic in the current anaerobic reaction system is not effective until the reaction temperature reaches 90 ◦ C. It is this latter step of the anaerobic MT mimic system that will need to be accomplished near room temperature if a biologically relevant variant of the chemistry is to be achieved. To accomplish this task logic suggests that use of a MT mimic substrate with a weaker N–O bond [54]. CONCLUSION: APPROACHING AQUEOUS DESULFITATIVE REACTION CONDITIONS FOR BIOLOGICAL APPLICATIONS 301 S O NHR ′ Cu III S N Me OMe
Cu I Cu OR Air Cu-oxygenate regenerated Thiolate
trapped Thiolate
trapped O S Peptide FG / FG R Peptide O R S O NHR
′ S N Me O O R-B(OH) 2 Aerobic, FG = amide Cu-centered oxidation room temperature reaction for all steps Anaerobic, FG = oxime S-centered oxidation C Cu recycle step: >90 °C Cu X Second equiv RB(OH) 2 This step requires >90 °C N 2 Figure 23.6 Mechanisms of (a) the aerobic and (b) the anaerobic desulfitative catalysis. Water-solubilizing sites are in gray. O SR
H 2 N O H 2 N R (HO) 2 R-B
Catalyst in water at room temp Scheme 23.10 Proteo-ketones via bioconjugative desulfitative catalysis. The next phase of development of desulfitative catalysis will focus on its use in the synthetic manipulation of proteins and complex peptides (Scheme 23.10). To achieve this goal, the following hurdles must be overcome: (i) the anaerobic catalysis using MT mimics must be modified for effective catalysis at room temperature and (ii) both the aerobic S-acylthiosalicylamide substrates and the anaerobic MT mimic substrates must be modified for effective reaction in water at room temperature. For biological applications the metal-catalyzed desulfitative transformations must be made effective in pure water or in aqueous biological buffers as the reaction solvent. This will require the development of substrates that are not only water soluble, but that also retain their effectiveness in desulfitative reactions with boronic acids in both the aerobic and anaerobic reaction systems (Fig. 23.7) [54]. Finally, current efforts in defining water-soluble reactants for both the aerobic and anaerobic reaction systems will guide the use of the new catalytic desulfitative transformations in advanced “ketobioconjugations” as represented in Fig. 23.8 [54]. O NH
′ S X O Protein
R S X N R ′ O O Protein R Reacted with: 2 RB(OH) 2 catalyst in water air
Reacted with: 1 RB(OH)
2 catalyst
in water N 2 (a) (b)
Figure 23.7 Potential water-soluble substrates for desulfitative catalysis. 302 TOWARD CHEMOSELECTIVE BIOCONJUGATIVE DESULFITATIVE CATALYSIS S O
Expressed chemical ligation technology Solid-phase peptide synthesis R thiol
cleavage site
HN O Intein HS Chitin
solid support Target protein N H
S Resin
O Peptide
Kent, Org. Lett. 2006, 8, 1049. SH R Finding the right water-soluble thiol R O NH 2 cat. Cu in H 2 O Air R -B(OH)
2 cat. Pd in H 2 O
2 R -B(OH) 2 R O NH 2 FG / FG FG / FG Aerobic Anaerobic Protein/peptide Chitin-binding domain
Figure 23.8 Proposed “ketobioconjugation” of protein and peptide thiol esters. REFERENCES 1. Song, C. Catal. Today 2003, 86 , 211. 2. Smith, B. M. Chem. Soc. Rev. 2008, 37 , 470 3. Melnvchuk, S. A.; Neverov, A. A.; Brown, R. S. Angew. Chem. Int. Ed. 2006, 45 , 1767. 4. Garnier-Amblard, E. C.; Liebeskind, L. S. In Boronic Acids. Preparation and Applications in Organic Synthesis, Medicine and
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