Organic Letters
Letter
a
Scheme 3. Late-Stage Functionalization of Pharmaceutical Molecules
a
Reaction conditions (0.15 mmol): 1 (1.5 equiv), 2 (1.0 equiv), H2O (10.0 equiv), and n-Bu4NPF6 (0.25 M) in DCE (1.5 mL), BDD electrodes,
b
25 °C, 4.0 V, undivided cell. Using norfloxacin-derived DHP 1z (1.0 equiv; for the structure, see the Supporting Information) and 2a (3.0 equiv)
c
in DCE/TFE (14/1, 1.5 mL), at 6.0 V, 50 °C for 10 h. Using fluoxetine-derived DHP 1aa (1.0 equiv; for the structure, see the Supporting
Information) and 2a (3.0 equiv) at 5.0 V, 50 °C for 10 h.
Peptides are important therapeutics, and the modification of
the peptide N-terminus is crucial for the improvement of their
bioavailability and stability. This transformation can be
employed in peptide chemistry. The DHP scaffold can be
readily introduced into the N-terminus of peptides. (See
Subsequently, peptidyl acyl-DHPs gave the corresponding
peptides 23−26 in decent yields. DHPs bearing carboxylic
acids (18, 25), esters (17, 23, 26), amides (25, 26), amine
of this transformation. Amino acids, such as histidine with an
imidazole, serine, and tyrosine, moderately suppressed this
details.) Recent seminal works in this field using photoredox
catalysis can provide ynones and ynamides under mild
conditions. Furthermore, functional groups like halogen,
carboxylic acid, and amino acid residues25 (Trp,26 Met27)
were proven to be excellent substrates for photoinduced
transformations, whereas electrochemistry enabled the selec-
tive activation of the DHP moiety under proper potential, with
these photosensitive functional groups remaining intact. As a
result, our reaction showed a different range in comparison
with the existing strategies with regard to functional group
tolerance. As demonstrated by the late-stage functionalization
of these complex molecules, a unique advantage of electro-
chemistry was the selectivity and tunability of the reaction
based on the redox potentials of the functional groups present
in the molecule.
Next, we proceeded to investigate the mechanism of this
electrochemical transformation. No desired product was
isolated in the presence of TEMPO (3.0 equiv), and the
reaction was inhibited with the addition of 1,1-diphenyl-
ethylene (2.0 equiv). Furthermore, the corresponding coupling
products 50 and 51 were isolated, and these results indicated
that an acyl radical was generated under electrochemical
conditions (Scheme 4a). Subsequently, cyclic voltammetry
(CV) experiments were conducted. As shown in Scheme 4b,
the redox behavior of substrate 1a (+1.31 V) was recorded. An
obvious peak current increase was observed with the addition
of 0.2% water, whereas no new peaks were detected by CV
analysis. 2a did not show any obvious redox signal. (See page
of these substrates showed no obvious change (Scheme 4c),
suggesting no interaction between both partners (further
confirmed using UV−vis spectrophotometer analysis; see page
t
(22), alcohol (24), and Bu-protected Tyr (26) were well
tolerated in this transformation. Unfortunately, we failed to
demonstrate the reaction efficiency with acyl DHPs bearing
linear alkyl chains because of the lack of synthetic methods to
obtain the corresponding DHPs. In addition, the reactions
employing acyl DHPs featuring an α-tBu moiety or free
phenols were unsuccessful.
To explore the universality of the reaction further, we
investigated a wide range of various alkynyl benziodoxolones
(BI-alkynes) under electrochemical conditions. The HIR with
various electron-rich or electron-deficient aryl substitutions
reacted well to provide ynones 27−36 in good yields. TIPS-
ynones are important scaffolds involved in synthesis. The
corresponding product 37 was successfully achieved in good
yield. Next, the coupling of DHP 1a with the alkyl-substituted
HIR provided ynones 38−42 in good yields. It is noteworthy
that the formation of ynones bearing alkyl chloride (41) and
bromide (42) by radical and metal-catalyzed chemistry was
challenging due to the high reactivity of halogens. These
examples demonstrated that the tunability of electrochemistry
established on the proper applied potential enabled the
selective activation of substrate functional groups.
This strategy was next demonstrated via its application to
the late-stage functionalization of complex pharmaceutical
molecules (Scheme 3). Galactose (43), pregnenolone (44),
testosterone (45), and cinchonine (46) derivatives were
obtained in moderate to good yields. 4-Acyl DHPs bearing
cortisone, norfloxacin, and fluoxetine were selectively alkyny-
lated to smoothly provide products 47−49. A broad range of
functional groups (esters, olefins, ketones, and ketenes) can be
employed in this reaction. To further explore the functional
tolerance and robustness of this transformation, we inves-
tigated the impact of additives in this transformation. (See
addition of alcohol, alkene, alkyne, alkyl halogens (Cl, Br, I),
and carboxylic acids had no negative impact on the efficiency
Compound 2a was not redox-active within this potential
range, and only 1a exhibited an oxidation peak at +1.31 V. This
provided evidence that the reaction was initiated by the anodic
oxidation of DHP reagents. Importantly, the addition of 0.2%
water increased the conductivity of the reaction system and
thus significantly accelerated the reaction. CV analysis
demonstrated no obvious change after the addition of water.
On the basis of these experimental studies, a possible
mechanism for this transformation is proposed in Scheme
4962
Org. Lett. 2021, 23, 4960−4965