Hydroxy Group Directed Catalytic Hydrosilylation of Amides

Article abstract of DOI:10.1021/acs.orglett.8b03014

Chemo- and site-selective hydrosilylation of α- or β-hydroxy amides using organocatalyst B(C₆F₅)₃ and commercially available hydrosilanes is described. This transformation is operative under mild conditions and tolerates a wide range of functional groups. The reaction was applied for selective reduction of a specific amide group of the therapeutically important cyclic peptide cyclosporin A, demonstrating the potential usefulness of this catalytic method in late-stage structural transformations of drug lead molecules.

Full text of DOI:10.1021/acs.orglett.8b03014

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Hydroxy Group Directed Catalytic Hydrosilylation of Amides
Jizhi Ni,† Tsubasa Oguro,† Taka Sawazaki, Youhei Sohma,* and Motomu Kanai*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
S
* Supporting Information
ABSTRACT: Chemo- and site-selective hydrosilylation of α-
or β-hydroxy amides using organocatalyst B(C6F5)3 and
commercially available hydrosilanes is described. This trans-
formation is operative under mild conditions and tolerates a
wide range of functional groups. The reaction was applied for
selective reduction of a specific amide group of the
therapeutically important cyclic peptide cyclosporin A,
demonstrating the potential usefulness of this catalytic
method in late-stage structural transformations of drug lead molecules.
ydroxy amines are important structural motifs in various
biologically active compounds, including drugs (Figure
Herein, we describe a new strategy for chemo- and site-
selective reduction of α- or β-hydroxy amides using
commercially available organocatalyst B(C6F5)3 and hydro-
silanes (Scheme 1). This hydrosilylation method efficiently
reduces both tertiary and secondary amide (peptide) bonds
with high functional group tolerance under very mild
conditions.
H
1).1 Due to the ready availability of amides, reduction of
Scheme 1. Strategy for OH-Directed Selective
Hydrosilylation of Hydroxy Amides
Figure 1. Selected examples of pharmaceuticals containing β- or γ-
hydroxy amine motifs.
amides constitutes an important transformation for amine
synthesis. Traditional methods using aluminum hydrides and
borohydrides, however, often exhibit poor tolerance toward
other more reducible functional groups.2 In an effort to
improve the chemoselectivity, catalytic hydrosilylation of
amides has been intensively investigated.3 Various metal-
based catalytic systems, such as Ru,4 Pt,5 Rh,6 Ir,7 Fe,8 Zn,9
Cu,10 Au,11 Co,12 Mg,13 and In,14 are effective for this purpose.
Alternatively, a few organocatalysts, such as tris-
(pentafluorophenyl)borane (B(C6F5)3),15 boronic acids,16
and triphenylborane (BPh3),17 have emerged for “metal-free”
protocols that allow for novel reactivity and chemoselectivity.
Most of these catalysts, however, are only suitable for the
reduction of tertiary amides, which are more reactive than
secondary amides. Furthermore, very few methods are available
in terms of site-selective reduction of a specific amide group
among many others when the substrates contain multiple
amide groups.18 Hence, the development of a method for
amide reduction, especially secondary amides, at a specific site
with broad functional group tolerance is highly desirable.
For the synthesis of hydroxy amines from hydroxy amides
through catalytic chemo- and regioselective hydrosilylation, we
were particularly interested in use of organocatalyst B(C6F5)3,
which exhibits unique reactivity for both silylation of alcohols19
and hydrosilylation of amides15 (Scheme 1). We envisioned
that the hydroxy group of a hydroxy amide substrate could first
react with a hydrosilane to form silyl ether A in a
dehydrogenative manner.19 Another hydride atom of the
Received: September 20, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03014
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
hydrosilane could be abstracted by B(C6F5)3 to form ion pair B
comprising a cationic silicon atom and a hydroborate anion.
The amide carbonyl group of this ion-pair intermediate would
be activated by coordination to the Lewis acidic silicon atom,20
allowing for subsequent reduction by the hydroborate to give
the O-silyl hemiaminal species C.15b Further reaction of C with
hydrosilane and B(C6F5)3 would then lead to silyl ether E.21
Finally, the hydroxy amine product could be released after
desilylation.
To test our hypothesis, we initially investigated the directing
effect of a hydroxy group in the B(C6F5)3-catalyzed hydro-
silylation of a mixture of amides 1a and 1a′ in the presence of
different hydrosilanes (Table 1). With trihydride silane
temperature (entries 8 and 9). Therefore, at least two hydride
atoms on a silicon atom are necessary for the amide reduction
to proceed. Among the solvents examined, 1,4-dioxane and
toluene produced the best results (entries 3 and 10). The
observed reactivity and selectivity in the two-substrate system
shown in Table 1 supported the reaction design shown in
Scheme 1. In sharp contrast to entry 10, hydrosilylation of 1a
did not proceed at all when B(C6F5)3 was replaced by other
boron catalysts, such as Ph3B,17 and boronic acids 3,16b 4,16b
and 5.16a
We next investigated the substrate scope of hydroxy amides
under the optimized conditions (Scheme 2). In previously
Scheme 2. Scope of Hydroxy-Directed Reduction of
Amides
a
Table 1. Structural Effect of Hydrosilanes for Selective
Reduction of Hydroxy Amide
a
a
The reactions were carried out with 1a (0.1 mmol), 1a′ (0.1 mmol),
B(C6F5)3 (0.01 mmol), and hydrosilane (hydride atoms = 4.0 equiv)
in 1,4-dioxane (1.0 mL) at 40 °C for 24 h. NMR yield. PhMe was
used as the solvent instead of 1,4-dioxane.
b
c
a
All reactions were run on a 0.2 mmol scale of amides. Isolated yields
PhSiH3, β-hydroxy amide 1a was selectively reduced, affording
2a in moderate yield (33%, entry 1). Amine product 2a′,
derived from simple amide 1a′, was produced in only trace
amounts. Screening dihydride silanes (entries 2−7) revealed
that the selective hydrosilylation proceeded best with
PhMeSiH2, affording 2a in nearly quantitative yield (96%,
entry 3). Poor selectivity was realized with tetramethyldisilox-
ane and octamethyltetrasiloxane (entries 6 and 7), suggesting
that the selectivity of the reduction might be sensitive to the
distance between the two Si−H groups. Monohydride silanes
were only reactive for the first silylation step of the hydroxy
group, leaving the amide bonds intact under a mild
are given. Yields based on converted starting material are indicated in
parentheses.
reported B(C6F5)3-catalyzed hydrosilylations, the reduction of
tertiary amides proceeded at elevated temperatures (50−130
°C), while N-alkyl-substituted secondary amides were
unreactive.15 In the present case, however, the secondary
amines were obtained from α- or β-hydroxy amides in high
yields under mild conditions (rt to 60 °C) (2a−n). It is
noteworthy that the highly challenging secondary amide in 1o
derived from phenylalanine was selectively reduced with good
B
DOI: 10.1021/acs.orglett.8b03014
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 2. (a) Site-selective hydrosilylation of cyclosporin A. 2v was isolated in 25% yield (89% yield based on converted 1v). (b) HPLC
chromatogram of the reaction mixture. After quenching with TBAF, the less polar silanes in the mixture were washed out through silica gel flash
column chromatography. The remaining organic components were combined for HPLC analysis (detected at 214 nm).
yield (42%). The phenolic hydroxy group also worked as the
directing site for the hydrosilane, which allowed for hydro-
silylation under mild conditions (50−60 °C, 2q−u). In
diamide substrates 1p (tertiary amide) and 1u (secondary
amide), the amides proximal to hydroxy groups were site-
selectively reduced in good yields.22 Functional groups that are
sensitive to reduction conditions, such as ester (1o and 1r),
nitro (1s), and halo (1g−i, and 1t) groups, were tolerated.
Moreover, we synthesized 0.6 g of 2a from 1a (53%), which
illustrated the potential utility of this method in a large-scale
synthesis (see the Supporting Information).
Finally, to demonstrate adaptability to complex substrates,
we applied the current hydrosilylation conditions to the site-
selective reduction of a pharmaceutically important cyclic
peptide, cyclosporin A (1v), which comprises 11 amino acids
with four secondary and seven tertiary amide bonds.
Cyclosporin A was gradually consumed in the presence of
B(C6F5)3 (20 mol %) and PhMeSiH2 (2.0 equiv) at 50 °C,
providing the reduced form 2v in 25% isolated yield after 48 h,
with 72% 1v recovered (Figure 2a). HPLC analysis of the
crude mixture revealed that the reaction was rather clean
(Figure 2b).
bond worked as the directing group for the silanes. This
method was applicable to the reduction of N-alkyl-substituted
secondary amides, which were difficult to reduce using the
previously available methods, with high functional group
tolerance. The present reaction was successfully applied to
chemo- and site-selective reduction of a specific amide bond of
cyclosporin A possessing 11 amide bonds. This catalytic
method will be applicable for complex molecule synthesis and
drug discovery.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03014.
General experimental procedures and characterization of
the products (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: kanai@mol.f.u-tokyo.ac.jp.
*E-mail: ysohma@mol.f.u-tokyo.ac.jp
ORCID
The HRMS spectrum of the isolated product 2v showed
signals at m/z = 1188.8699 for [M + H]+ (calcd m/z =
1188.8694) and 1210.8514 for [M + Na]+ (calcd m/z =
1
Motomu Kanai: 0000-0003-1977-7648
Author Contributions
†J.N. and T.O. contributed equally.
1210.8513). The structure of 2v was further confirmed by H
and 13C NMR spectroscopy. Four proton signals were
observed for the amide NH groups in cyclosporin A, while
only three signals were found for 2v, indicating the reduction
of only one amide group. Furthermore, signals for the newly
Notes
1
The authors declare no competing financial interest.
formed CH2 group were observed in both the H (2.42−2.18
ppm) and 13C NMR (46.28 ppm) spectra of 2v. The position
1
of this CH2 group was also confirmed by the H−1H COSY
ACKNOWLEDGMENTS
■
1
and H−13C HMQC correlations. The signals for the CC
This work was supported in part by JSPS KAKENHI Grant
Nos. JP17H06442 (M.K.) (Hybrid Catalysis), 17H01522
(M.K.), 17K19479 (M.K.), and 16H06216 (Y.S.).
bond remained intact in 13C NMR (129.90 and 125.99 ppm),
indicating that the alkene functionality was not affected. Unlike
the reported reduction using a Rh complex, in which the most
reactive tertiary amide site was selectively reduced,6 the
chemo- and site-selectivity of the B(C6F5)3−PhMeSiH2 system
developed here relied on the adjacent hydroxy group. This
result clearly demonstrates that the present method is reliable
even when using a complex peptide substrate.
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