Enantioselective Synthesis of α-Chiral Propargylic Silanes by Copper-Catalyzed 1,4-Selective Addition of Silicon Nucleophiles to Enyne-Type α,β,γ,δ-Unsaturated Acceptors

Article abstract of DOI:10.1021/acs.orglett.0c03046

A copper-catalyzed deconjugative addition of silicon nucleophiles to a broad range of enyne-type α,β,γ,δ-unsaturated acceptors with high enantiocontrol is reported. The method is 1,4-selective with hardly any formation of the 1,6-adduct. The double-bond geometry is shown to be critical for achieving this chemoselectivity: exclusive 1,4-addition for E and predominant 1,6-addition for Z. By this, E-configured enynoates, enynamides, and enynones have been converted to the corresponding α-chiral propargylic silanes with excellent enantiomeric excesses.

Full text of DOI:10.1021/acs.orglett.0c03046

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Letter
Enantioselective Synthesis of α‑Chiral Propargylic Silanes by
Copper-Catalyzed 1,4-Selective Addition of Silicon Nucleophiles to
Enyne-Type α,β,γ,δ-Unsaturated Acceptors
Wenbin Mao and Martin Oestreich*
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ABSTRACT: A copper-catalyzed deconjugative addition of silicon
nucleophiles to a broad range of enyne-type α,β,γ,δ-unsaturated
acceptors with high enantiocontrol is reported. The method is 1,4-
selective with hardly any formation of the 1,6-adduct. The double-
bond geometry is shown to be critical for achieving this
chemoselectivity: exclusive 1,4-addition for E and predominant
1,6-addition for Z. By this, E-configured enynoates, enynamides,
and enynones have been converted to the corresponding α-chiral
propargylic silanes with excellent enantiomeric excesses.
nlike numerous methods for the enantioselective syn-
The achieved 84% and 83% ee were further improved to 85%
1
Uthesis of α-chiral allylic silanes, there are essentially no yield and 91% ee by changing the solvent from tetrahydrofuran
(THF) to 2-MeTHF (Table 1, entry 6); other solvents were
less effective (Table 1, entries 7−9). Various attempts with
different combinations of base and alcohol additive revealed
that KOtBu/MeOH were optimal, affording 85% yield and
92% ee (Table 1, entries 10−14). Significantly lowering the
loadings of the catalyst, the ligand, and those of the additives
was not detrimental, and the enantiomeric excess remained
unchanged at high isolated yield (Table 1, entry 15).
Additional control experiments showed that the catalyst and
the additives employed in the reaction are needed (see Table
S5 in the Supporting Information), yet the reaction proceeded
without the chiral ligand L3 (Table 1, entry 16). Zinc-based
silicon nucleophiles15 Me2PhSiZnCl and (Me2PhSi)2Zn16 did
also give the 1,4-adduct regioselectively with good enantiocon-
trol, but the results were inferior to those obtained with the
silylboronic ester (Table 1, entries 17 and 18). Me2PhSiLi and
Me2PhSiMgHal17 (where Hal = Cl and Br) furnished only
trace amounts of the product.
general catalytic procedures to access α-chiral propargylic
silanes.2,3 One reason behind this could be that propargylic
substitution typically leads to the allene motif.4 Significant
advances in enantioselective Si−C(sp3) bond formation with
silicon nucleophiles have been made in recent years,5
particularly based on chiral copper catalysts,6 in conjunction
with Si−B reagents7 as silicon pronucleophiles.5 Hoveyda and
co-workers had developed 1,4-selective conjugate additions to
diene-type α,β,γ,δ-unsaturated acceptors (Scheme 1, top).8,9
Knowing that 1,4-selective addition to enyne-type α,β,γ,δ-
unsaturated acceptors is possible,10,11 we asked ourselves
whether this approach could be turned into an effective way to
make α-chiral propargylic silanes (Scheme 1, bottom).12
Interestingly, the same class of substrates had already been
investigated by Xu, Loh, and co-workers yet with exclusive 1,6-
selectivity (Scheme 1, bottom).13 We disclose here a mild and
general method for the rapid assembly of α-chiral propargylic
silanes by copper-catalyzed 1,4-selective conjugate addition of
silylboronic esters to enyne-type α,β,γ,δ-unsaturated acceptors.
We began our study with enynoate (E)-1a as the model
substrate and Me2PhSi−Bpin (2a) as the Si−B reagent (see
Table 1). From a ligand screening, (R,R)-QuinoxP* (L3)14
had emerged as a promising chiral ligand for this trans-
formation, especially with regard to 1,4- over 1,6-selectivity
(see Scheme S1 in the Supporting Information). 74% yield of
the 1,4-adduct 3aa with 70% ee, along with a small amount of
4aa, were obtained in the presence of 5.0 mol % CuCl, 7.5
mol % L3, 20 mol % NaOtBu, and 4.0 equiv MeOH in THF at
room temperature (Table 1, entry 1). (Ph3P)2CuBH4, as a
precatalyst, was superior to other typical copper salts, with
regard to yield and enantioinduction (Table 1, entries 1−5).
With the optimized conditions in hand, we set out to
evaluate the generality of this reaction (Scheme 2, top).
Various δ-aryl-substituted enynoates with an electron-donating
(1b−1e) or an electron-withdrawing group (1i−1k) on the
phenyl ring were suitable substrates, giving the corresponding
α-chiral propargylic silanes in good to excellent yields with
Received: September 11, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03046
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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high levels of enantioselectivity (up to 93% ee). A methyl
group in either the ortho-, meta-, or para-position of the phenyl
ring had only negligible influence (1b−1d → 3ba−3da). Good
functional-group compatibility was observed with tolerance of
halo (1f−1h → 3fa−3ha), cyano (1j → 3ja), ester (1k →
3ka), and boryl groups (1l → 3la), thereby allowing for
subsequent manipulations. Thienyl groups were also tolerated
(1m and 1n → 3ma and 3na). Enynoates with an alkyl group
or a silyl group in the δ position did participate equally well,
furnishing the corresponding 1,4-adducts in good yields with
slightly lower enantiomeric excesses (1o−1q → 3oa−3qa).
The absolute configuration of 3la was determined as R by X-
ray diffraction analysis (see the Supporting Information for
details), and all other products were assigned by analogy.
The 1,4-selectivity was excellent throughout for the above
acceptors. However, a methyl substituent at the β-C atom
completely steered the chemoselectivity toward the 1,6-adduct
to yield the allene in 50%, along with recovered starting
material with essentially no enantioinduction (1r → 4ra; see
the gray box in Scheme 2). Other silylboronic esters such as
MePh2Si−Bpin (2b) and Ph3Si−Bpin (2c) led to different
reaction outcomes (Scheme 2, bottom). While 2b reacted with
lower yield and enantioselectivity compared to 2a (48%, 78%
ee for 3ab versus 95%, 92% ee for 3aa), there was no reaction
for bulky 2c. The situation was even worse with Et3Si−Bpin
(2d) where both chemoselectivity (1,4:1,6 = 76:24) and
enantioinduction (58% ee) were eroded at good yield of 3ad.
This suggests that the substitution pattern of the silyl group
and its steric demand greatly influence this reaction.
Scheme 1. 1,4-Selectivity versus 1,6-Selectivity in Conjugate
Addition of Silicon Nucleophiles to α,β,γ,δ-Unsaturated
Acceptors
a
Table 1. Selected Examples of the Optimization
b
c
d
entry
copper salt
CuCl
CuBr
CuTC
CuBr·SMe2
base/alcohol
solvent
THF
THF
THF
THF
THF
2-MeTHF
Et2O
1,4:1,6 ratio
yield of 3aa (%)
ee of 3aa (%)
1
2
3
4
5
6
7
8
9
NaOtBu/MeOH
NaOtBu/MeOH
NaOtBu/MeOH
NaOtBu/MeOH
NaOtBu/MeOH
NaOtBu/MeOH
NaOtBu/MeOH
NaOtBu/MeOH
NaOtBu/MeOH
NaOtBu/EtOH
NaOtBu/H2O
KOtBu/MeOH
LiOtBu/MeOH
Et3N/MeOH
KOtBu/MeOH
KOtBu/MeOH

96:4
97:3
74
79
71
55
84
85
80
42
33
82
75
85
75
80
70
80
82
81
83
91
75
60
78
87
88
92
89
83
>98:2
>98:2
>98:2
>98:2
>98:2
92:8
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
93:7
(Ph3P)2CuBH4
(Ph3P)2CuBH4
(Ph3P)2CuBH4
(Ph3P)2CuBH4
(Ph3P)2CuBH4
(Ph3P)2CuBH4
(Ph3P)2CuBH4
(Ph3P)2CuBH4
(Ph3P)2CuBH4
(Ph3P)2CuBH4
(Ph3P)2CuBH4
(Ph3P)2CuBH4
(Ph3P)2CuBH4
(Ph3P)2CuBH4
toluene
AmylOH
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
10
11
12
13
14
e
f
f
15
95 (95)
92 (92)
g
16
17
89
45
80

90
80
h
>98:2
>98:2
i
18

a
b
c
All reactions were performed on a 0.10 mmol scale. Determined by 1H NMR spectroscopy. Isolated yield after flash chromatography on silica
d
e
gel. Determined by HPLC analysis on a chiral stationary phase. 0.50 mol % (Ph3P)2CuBH4, 0.75 mol % (R,R)-QuinoxP* (L3), 5.0 mol %
KOtBu, and 2.0 equiv MeOH were used. Values given in parentheses for reaction on a 1.2 mmol scale. Without ligand L3. Me2PhSiZnCl instead
of 2a. (Me2PhSi)2Zn instead of 2a. CuTC = copper(I) thiophene-2-carboxylate. 2-MeTHF = 2-methyltetrahydrofuran.
f
g
h
i
B
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Scheme 2. Enantioselective Deconjugative 1,4-Addition of
Silicon Nucleophiles to Enynoates
Scheme 3. Enantioselective Deconjugative 1,4-Addition of
Silicon Nucleophiles to Enynamides and Enynones
a
a
a
All reactions were performed on a 0.20 mmol scale. The ratio of 1,4-
1
b
versus 1,6-selectivity was determined by H NMR spectroscopy. 1.0
mol % (Ph3P)2CuBH4/1.5 mol % L3 for 12 h.
a
Scheme 4. Control Experiments
a
All reactions were performed on a 0.20 mmol scale. The ratio of 1,4-
1
b
versus 1,6-selectivity was determined by H NMR spectroscopy. 5.0
mol % (Ph3P)2CuBH4 and 7.5 mol % L3. 2.5 mol % (Ph3P)2CuBH4
and 3.8 mol % L3. 10 mol % (Ph3P)2CuBH4 and 15 mol % L3.
c
d
We next applied this procedure to enynamides and enynones
(see Scheme 3). A longer reaction time (60 h instead of 12 h)
was found to be necessary for the reaction of enynamides (E)-
5. Tertiary enynamides (E)-5a and (E)-5b reacted in good
yields and with ≥90% ee. Conversely, a free NH group as in
(E)-5c and (E)-5d was detrimental to the yield, and the
primary amide resulted in ∼95% ee, whereas the enantiomeric
excess for the secondary amide (E)-5c was moderate; we
cannot explain this difference. The yield was also high for
imide (E)-5e but the enantioinduction was poor. Enynone
(E)-6d proved to be a suitable substrate, delivering the 1,4-
adduct (R)-8aa in 61% yield and with 71% ee.
A deuteration experiment with CD3OD instead of MeOH
confirmed the alcohol additive as the proton source (Scheme
4, top). We also probed the other diastereomer (Z)-1a under
the standard protocol (Scheme 4, bottom). As expected on the
basis of Xu’s and Loh’s work (see Scheme 1, bottom),13 1,6-
adduct 4aa did form in 45% yield, albeit not selectively; the
1,4-adduct (R)-3aa was isolated in 34% yield. While there was
hardly any enantioinduction in the formation of the allene, the
α-chiral propargylic silane had an enantiomeric excess of 94%.
Interestingly, its absolute configuration was the same as
obtained from (E)-1a. The above stereochemical outcome
could be the result of in situ Z-to-E isomerization. However,
a
All reactions were performed on a 0.20 mmol scale. bDiastereomeric
ratio and deuteration grade were estimated using 1H NMR
spectroscopy.
we have not been able to detect (E)-1a during the reaction of
(Z)-1a by H NMR spectroscopy, even in the absence of the
1
silylboronic ester. Nevertheless, such a scenario is not
unprecedented. While an in-depth analysis of the mechanism
of copper-catalyzed conjugate silylation is missing, Minnaard,
Feringa, and co-workers explored the 1,4-addition of Grignard
reagents in great detail and made similar observations.18
In conclusion, a reliable and broadly applicable synthesis of
α-chiral propargylic silanes has been developed. The
enantioselective formation of the Si−C(sp3) bond is achieved
by a highly 1,4-selective copper-catalyzed conjugate addition of
silylboronic esters to enyne-type α,β,γ,δ-unsaturated acceptors.
The mild reaction conditions allow for very good functional-
group tolerance, and the substrate scope includes enynoates,
enynamides, and enynones.
C
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03046.
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General procedures, experimental details, character-
ization and spectral data for all new compounds, and
crystal data and structural refinement for compound
(R)-3la(PDF)
Accession Codes
CCDC 2025553 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,Cam-
bridge CB2 1EZ, UK; fax: + 44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
(4) (a) Ohmiya, H.; Ito, H.; Sawamura, M. General and Functional
Group-Tolerable Approach to Allenylsilanes by Rhodium-Catalyzed
Coupling between Propargylic Carbonates and a Silylboronate. Org.
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Nucleophiles. In Organosilicon Chemistry: Novel Approaches and
Reactions; Hiyama, T., Oestreich, M., Eds.; Wiley−VCH: Weinheim,
Germany, 2019; pp 1−31. (b) Hensel, A.; Oestreich, M. Asymmetric
Addition of Boron and Silicon Nucleophiles. Top. Organomet. Chem.
2015, 58, 135−167.
Martin Oestreich − Institut fur Chemie, Technische Universitat
̈
̈
Berlin, 10623 Berlin, Germany; orcid.org/0000-0002-
1487-9218; Email: martin.oestreich@tu-berlin.de
Author
Wenbin Mao − Institut fur Chemie, Technische Universitat
̈
̈
Berlin, 10623 Berlin, Germany; orcid.org/0000-0001-
8746-1616
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03046
(6) (a) Xue, W.; Oestreich, M. Beyond Carbon: Enantioselective
and Enantiospecific Reactions with Catalytically Generated Boryl- and
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(b) Wilkinson, J. R.; Nuyen, C. E.; Carpenter, T. S.; Harruff, S. R.;
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Oestreich, M., Ed.; Thieme: Stuttgart, Germany, 2017; pp 65−176.
(b) Oestreich, M.; Hartmann, E.; Mewald, M. Activation of the Si−B
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Silylboranes. Organometallics 2000, 19, 4647−4649.
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Catalyzed Silyl Conjugate Additions to Acyclic and Cyclic Dienones
and Dienoates. Efficient Site-, Diastereo- and Enantioselective
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Chem. Commun. 2013, 49, 5150−5152. (d) Pace, V.; Rae, J. P.;
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
W.M. thanks the China Scholarship Council for a predoctoral
fellowship (2017−2021), and M.O. is indebted to the Einstein
Foundation Berlin for an endowed professorship. We are
grateful to Dr. Elisabeth Irran (TU Berlin) for the X-ray
crystal-structure analysis.
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