Enantioselective synthesis of α-aminosilanes by copper-catalyzed hydroamination of vinylsilanes

Article abstract of DOI:10.1002/anie.201410326

The synthesis of α-aminosilanes by a highly enantio- and regioselective copper-catalyzed hydroamination of vinylsilanes is reported. The system employs Cu-DTBM-SEGPHOS as the catalyst, diethoxymethylsilane as the stoichiometric reductant, and O-benzoylhyd

Full text of DOI:10.1002/anie.201410326

Angewandte
Chemie
DOI: 10.1002/anie.201410326
Asymmetric Synthesis
Enantioselective Synthesis of a-Aminosilanes by Copper-Catalyzed
Hydroamination of Vinylsilanes**
Nootaree Niljianskul, Shaolin Zhu, and Stephen L. Buchwald*
Abstract: The synthesis of a-aminosilanes by a highly enantio-
and regioselective copper-catalyzed hydroamination of vinyl-
silanes is reported. The system employs Cu-DTBM-SEG-
PHOS as the catalyst, diethoxymethylsilane as the stoichio-
metric reductant, and O-benzoylhydroxylamines as the elec-
trophilic nitrogen source. This hydroamination reaction is
compatible with differentially substituted vinylsilanes, thus
providing access to amino acid mimics and other valuable
chiral organosilicon compounds.
O
rganosilicon compounds have recently gained promi-
nence within the field of medicinal chemistry. Silicon is often
used as an isostere for carbon due to its similar valency and
tetrahedral bonding pattern.[1] In addition, because of its
larger covalent radius, electropositive/lipophilic nature, and
low intrinsic toxicity, silicon is complementary to carbon and
is valuable in pharmaceutical research.[2] Among the many
subclasses of organosilicon compounds, chiral a-aminosilanes
in particular have demonstrated significant bioactivities.[2,3]
Several potent inhibitors of proteolytic enzymes possess the
a-aminosilane motif, and a-aminosilanes have been incorpo-
rated into peptide isosteres (Scheme 1).[2–4] Thus, the devel-
opment of robust methods for the construction of chiral a-
aminosilanes is an important area of research.
Scheme 1. Examples of silicon-containing peptidomimetics and amino
acids. Boc=tert-butoxycarbonyl.
Although there has been progress in the synthesis of
racemic a-aminosilanes,[5,6] enantioselective approaches
remain limited. Previous methods include asymmetric depro-
tonation followed by reverse aza-Brook rearrangement
[Scheme 2, Eq. (1)].[7] Other approaches have utilized the
chiral auxiliary bearing aldimines developed by Davis or
Ellman in conjunction with silyllithium reagents [Eq. (2)].[3,8]
Recently, Oestreich and co-workers reported an elegant
process catalyzed by a chiral N-heterocyclic carbene/copper
complex using Suginomeꢀs Ph(Me)2SiBpin reagent
[Eq. (3)].[8i] However, these methods have limitations with
Scheme 2. Previous approaches towards the synthesis of chiral a-
aminosilanes and the development of our strategy. Bpin=pinacolbor-
ane, Bz=benzoyl, Tol=tolyl.
[*] N. Niljianskul, Dr. S. Zhu, Prof. Dr. S. L. Buchwald
Department of Chemistry, Massachusetts Institute of Technology
77 Massachusetts Avenue, Cambridge, MA 02139 (USA)
E-mail: sbuchwal@mit.edu
respect to the scope of the amine, and, with the exception of
the report by Oestreich and co-workers, require the use of
a stoichiometric chiral auxiliary or reagent.
[**] Research reported in this publication was supported by the National
Institutes of Health under award number GM58160. The content is
solely the responsibility of the authors and does not necessarily
represent the official views of the National Institutes of Health. We
are grateful to Dr. Yiming Wang and Dr. Daniel T. Cohen for
insightful discussions, and Phillip J. Milner and Dr. Michael Pirnot
for help with the preparation of this manuscript. We thank Dr.
Christopher Welch and Dr. Erik Regalado (Merck), and Christina
Kraml (Lotus Separations) for SFC analysis.
Recently, we, as well as Hirano, Miura, and co-workers,
reported the CuH-catalyzed asymmetric Markovnikov hydro-
amination of styrenes.[9] We felt that this method, when
applied to vinylsilane substrates, would allow the generation
of a broad range of chiral a-aminosilanes [Eq. (4)]. As
vinylsilanes are readily prepared and bench-stable, they are
attractive as starting materials for the synthesis of a-amino-
silanes.[10] The intermolecular hydroamination of vinylsilanes
would likely, based on literature precedent, proceed regiose-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201410326.
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Scheme 3. Regioselectivity in the hydroamination of b-vinylsilanes.
lectively to give chiral a-aminosilanes (III), via the a-silyl-
alkylcopper intermediate II (Scheme 3),[11] on reaction with
the O-benzoylhydroxylamine electrophile 2.[9]
We began our investigation by examining the hydro-
amination of (E)-vinylsilane 1a using conditions previously
developed for the hydroamination of styrene (Table 1).[9] The
Table 1: Reaction optimization.[a]
Scheme 4. Influence of the silyl group and olefin geometry on yield
and enantioselectivity. Reaction conditions: 1a–1d (1 mmol), 2a
(1.2 mmol), Cu(OAc)2 (0.02 mmol), (R)-DTBM-SEGPHOS
(0.022 mmol), THF (1 mL), 408C, 36 h. Yields are of isolated products
(average of two runs). [a] Cu(OAc)2 (0.04 mmol), (R)-DTBM-SEGPHOS
(0.044 mmol). [b] 8 h. [c] Cu(OAc)2 (0.04 mmol), (R)-DTBM-SEGPHOS
(0.044 mmol), THF (0.5 mL, 2m). Bn=benzyl.
Entry
Solvent
L
Yield 3a [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
THF
cyclohexane
Et2O
toluene
CH2Cl2
THF
L1
L1
L1
L1
L1
L2
L3
L4
>99
>99
>99
>99
0[e,f,g]
37[f]
>99
>99
>99
>99
–
95
98
–
meric product, and 2) E substrates invariably reacted faster
and with a higher level of enantioselectivity than the
corresponding Z substrates.
THF
THF
92[d]
0[e,f,h]
Thus, we chose to examine the scope of the hydroamina-
tion of (E)-vinylsilanes. This method accommodates a broad
range of functional groups (Scheme 5). Vinylsilanes contain-
ing a nitrile (5a), an alkyl chloride (5b), an ester (5c),
a sulfonamide (5d), a tert-butyldimethylsilyl ether (5e), and
an allylic ether moiety (5 f) were readily handled. No
competitive elimination of alkoxide was observed with an
ether (5 f).[19] Additionally, we applied our method to the
synthesis of a-amino acid mimics by hydroamination of
a secondary benzylamine (5i), a b,b-disubstituted vinylsilane
(5j), and a b-isopropyl-substituted vinylsilane (5k), to
provide mimics of lysine, valine, and leucine, respectively.
The compatibility of this reaction with a variety of O-
benzoylhydroxylamine electrophiles was then examined
(Scheme 6). Acyclic dialkyl (6a), cyclic dialkyl (6b), and
alkylbenzylamine-based electrophiles (6c) were all suitable
partners, delivering the hydroaminated products with high
yields and enantioselectivities. In addition, a heterocycle-
containing electrophile was tolerated (6d). Hydroamination
to install a bis(p-methoxybenzyl)amino group was also
successful (6e).
As previously mentioned (Scheme 4), the E and Z sub-
strates provide the same enantiomer of the product. However,
E substrates react faster and afford a higher level of
enantioselectivity than the corresponding Z substrates. We
thus wondered whether, in the case of (Z)-alkenes, most of
the hydroamination product was formed by isomerization of
the slower reacting Z isomer, followed by transformation of
the nascent E isomer. We investigated this possibility through
the use of a deuterated silane reagent. In this case, L*Cu-D
[a] Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), Cu(OAc)2
(0.02 mmol), ligand (0.022 mmol), solvent (1 mL). [b] Yields of isolated
products. [c] Determined by HPLC analysis on a chiral stationary phase.
[d] 16 h. [e] Yield determined by GC (dodecane as internal standard).
[f] 36 h. [g] 77% of 1a remained. [h] 96% of 1a remained.
reaction furnished a-aminosilane 3a regioselectively in quan-
titative yield with > 99% ee after 8 h (entry 1). Switching the
solvent to cyclohexane, diethyl ether, or toluene (entries 2–4)
had no effect, but no conversion was seen in dichloromethane
(entry 5). We also examined other chiral ligands that were
previously shown to be effective in reactions catalyzed by
a copper(I) hydride complex (entries 6–8).[9b,17] However, the
use of (R)-DTBM-SEGPHOS was found to give the highest
reactivity and selectivity.
We next investigated the influence of the nature of the
silyl group and olefin geometry on the reactivity and
enantioselectivity (Scheme 4). The reaction was compatible
with vinylsilanes containing triethylsilyl (3a), trimethylsilyl
(3b), dimethylphenylsilyl (3c), and methyldiphenylsilyl
groups (3d).[18] In all cases, the reactions proceeded regiose-
lectively to give a-aminosilane products. Interestingly, we
found: 1) both E and Z isomers provided the same enantio-
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Scheme 7. Possible reaction pathways.
Scheme 5. Hydroamination of (E)-vinylsilanes. Reaction conditions:
4a–4k (1 mmol), 2a (1.2 mmol), Cu(OAc)2 (0.02 mmol), (R)-DTBM-
SEGPHOS (0.022 mmol), THF (1 mL), 408C, 36 h. Yields are of
isolated products (average of two runs). [a] 16 h reaction time. [b] Cu-
(OAc)2 (0.04 mmol), (R)-DTBM-SEGPHOS (0.044 mmol), THF (1 mL,
1m). [c] From (Z)-4g. TBS=tert-butyldimethylsilyl, Ts=p-toluenesul-
fonyl.
Scheme 8. Deuterium-labeling experiments.
R,S product. However, if the Z substrate undergoes Cu-
catalyzed isomerization to the E alkene prior to reaction
with O-benzoylhydroxylamine, the major product would
contain approximately two deuterium atoms.
Deuterium-labeling experiments (Scheme 8) revealed
that the hydroamination of (E)-4g was completely diastereo-
selective with about 99% deuterium incorporation[20] to give
the monodeuterated R,R isomer 5g’ [Eq. (5)]. The reaction
was also diastereoselective for (Z)-4g, and gave the mono-
deuterated R,S isomer 5gꢀ with about 96% deuterium
incorporation [Eq. (6)].[20] The stereochemical result and the
presence of the monodeuterated product from the Z substrate
indicates that most of the product does not form by isomer-
ization of the substrate to the E isomer.
Lastly, to demonstrate the scalability of this transforma-
tion, we carried out the hydroamination of 1a with Bn2N-OBz
(2a) on a 10 mmol scale (Scheme 9). Full conversion of the
vinylsilane was achieved with a catalyst loading of only
0.5 mol%. The yield and the enantioselectivity was the same
as for the 1 mmol scale reaction (Table 1).
Scheme 6. Scope of O-benzoylhydroxylamine electrophiles. Reaction
conditions: 1 (1 mmol), 2a (1.2 mmol), Cu(OAc)2 (0.02 mmol), (R)-
DTBM-SEGPHOS (0.022 mmol), THF (1 mL), 408C, 36 h. Yields are of
isolated products (average of two runs).
would form and the olefin would insert into it through a syn-
addition process (Scheme 7). For the more reactive E sub-
strate, subsequent reaction with the O-benzoylhydroxylamine
would generate the R,R product. For the Z substrate, if no
isomerization occurs, the reaction should generate the
Scheme 9. Large-scale hydroamination reaction of (E)-triethylsilylvinyl-
silane.
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In summary, we have developed an enantioselective Cu-
catalyzed hydroamination of vinylsilanes. The reaction pro-
ceeds in a regioselective manner to provide enantioenriched
a-aminosilanes in high yield with outstanding levels of
enantioselectivity. The method is applicable to a variety of
substrates, and provides rapid access to a family of valuable
chiral organosilicon building blocks and bioactive molecules.
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[11] For vinylsilanes, the partial positive charge is more pronounced
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Refs. [12] and [13]). The partial negative charge that develops at
the a-position is stabilized by the silyl group (see Refs. [14] and
[15]). Furthermore, intermediate II (Scheme 3) is thermody-
namically stabilized by hyperconjugation of the s-orbital of the
Cu-alkyl bond with a s*-orbital on the silicon–carbon bond (see
Ref. [16]).
Received: October 21, 2014
Published online: && &&, &&&&
Keywords: asymmetric synthesis · copper · hydroamination ·
.
silicon
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analysis.
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Chemie
Communications
Asymmetric Synthesis
N. Niljianskul, S. Zhu,
S. L. Buchwald*
&&&& — &&&&
Enantioselective Synthesis of a-
Aminosilanes by Copper-Catalyzed
Hydroamination of Vinylsilanes
Versatile vinylsilanes: The use of a Cu
catalyst, diethoxymethylsilane as a stoi-
chiometric reductant, and O-benzoylhy-
droxylamines as the electrophilic nitrogen
source allows the synthesis of a-amino-
silanes. This highly enantio- and regiose-
lective hydroamination reaction is com-
patible with differentially substituted
vinylsilanes, thereby providing access to
amino acid mimics and other valuable
chiral organosilicon compounds.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!