Diastereoselective Copper-Mediated Cross-Couplings between Stereodefined Secondary Alkylcoppers with Bromoalkynes

Article abstract of DOI:10.1021/acs.orglett.8b00699

A copper(I)-mediated cross-coupling of stereodefined secondary alkyllithiums with bromoalkynes provided stereodefined alkynes with high diastereoselectivity (dr up to 98:2). This cross-coupling was extended to various secondary alkyllithiums bearing a remote oxygen functionality, and the alkyne synthesis was also performed with optically enriched alkyl iodides (up to 99% ee) providing, after cross-coupling, alkynes bearing two stereocenters (dr = 93:7; up to 99% ee).

Full text of DOI:10.1021/acs.orglett.8b00699

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Diastereoselective Copper-Mediated Cross-Couplings between
Stereodefined Secondary Alkylcoppers with Bromoalkynes
Juri Skotnitzki, Varvara Morozova, and Paul Knochel*
Department of Chemistry, Ludwig-Maximilians-Universitat, Butenandtstrasse 5-13, 81377 Munchen, Germany
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̈
S
* Supporting Information
ABSTRACT: A copper(I)-mediated cross-coupling of stereo-
defined secondary alkyllithiums with bromoalkynes provided
stereodefined alkynes with high diastereoselectivity (dr up to
98:2). This cross-coupling was extended to various secondary
alkyllithiums bearing a remote oxygen functionality, and the
alkyne synthesis was also performed with optically enriched alkyl iodides (up to 99% ee) providing, after cross-coupling, alkynes
bearing two stereocenters (dr = 93:7; up to 99% ee).
ross-coupling reactions have been successfully used to
prepare polyfunctional alkynes. Thus, the Sonogashira1
Scheme 1. Enantioselective Synthesis of Stereodefined
Alkynes Starting from Optically Enriched Iodides via I/Li-
Exchange, Transmetalation to Copper Reagents, and
Quench with 1-Bromoalkynes
C
and Negishi2 cross-couplings allow linking alkynyl moieties
3
2
with Csp -unsaturated halides in the presence of copper or
palladium4 catalysts. The alkyne acts as a nucleophile in these
reactions. Alternatively, 1-halogenoalkynes react with zinc
organometallics or mixed copper−zinc reagents,5 providing
alkylated alkynes. The use of catalytic amounts of copper salts6
or palladium catalysts7 in such cross-couplings has been
reported. However, the preparation of alkynes bearing chiral
centers in the α-position is still a challenge.8
Recently, we have reported that secondary alkyl iodides such
as 1 undergo an I/Li exchange, leading to the corresponding
secondary alkyllithium reagents of type 2 with retention of
configuration using t-BuLi (2.5 equiv, inverse addition).9 We
have shown that these secondary alkyllithium reagents undergo
a stereoretentive transmetalation to the corresponding
Table 1. Effect of Temperature and Time on the Stability of
Secondary Alkylcopper Reagent anti-3a
10
alkylcopper reagents of type 3. The use of CuBr·P(OEt)3
as a soluble copper salt was essential for achieving high
stereoselectivity.11 These secondary alkylcopper reagents react
with activated alkynes, allylic halides, and epoxides with
retention of configuration.9d,11
Herein, we report a successful cross-coupling reaction of
stereodefined secondary alkylcopper reagents of type 3 with 1-
bromoalkynes (4), leading to alkylated alkynes of type 5
bearing a chiral side chain with high retention of configuration
(up to 98:2; Scheme 1).
In preliminary experiments, we have studied the thermal and
configurational stability of such alkylcopper species 3. Thus, we
have treated the diastereomerically enriched secondary alkyl
iodide (anti-1a; dr = 1:99) with t-BuLi (hexane−ether, −100
°C, 1 min) followed by the addition of CuBr·P(OEt)3 (2 equiv,
−100 °C), leading to the corresponding alkylcopper reagent
anti-3a (Table 1). After stirring the solution at −70 °C for 10
min or for 1 h, benzoyl chloride (3.0 equiv)12 was added at −70
°C, leading to the desired ketone anti-6 in 59% yield (dr =
3:97; entry 1) and 38% yield (dr = 6:94; entry 2), respectively.
This result indicated the high configurational stability of anti-3a
at −70 °C.
a
a
entry
temp (°C)
time (min)
yield (%)
dr
1
2
3
4
5
6
−70
−70
−50
−50
−30
−30
10
60
10
60
10
60
59
38
50
37
41
26
3:97
6:94
5:95
7:93
6:94
50:50
a
The diastereoselectivity (dr; syn/anti ratio) and yield were
determined by capillary GC using undecane as internal standard.
Stirring the copper intermediate (anti-3a) at −50 °C (for 10
min or 1 h, entries 3 and 4) or at −30 °C for 10 min (entry 5)
led, after benzoylation, to a yield decrease of anti-6, but only to
a marginal loss of diastereoselectivity. However, stirring anti-3a
Received: March 1, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00699
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
type 4, leading to the corresponding syn- and anti-alkynes of
type 5.
Table 2. Stereoselective Preparation of Secondary syn- and
anti-Alkylated Alkynes (5) Obtained by the Cross-Coupling
of syn- and anti-Alkylcopper (3a) with 1-Bromoalkynes of
Type 4
Typically, the secondary alkylcopper reagent (syn- or anti-3a)
was generated as described above and treated with a
bromoalkyne of type 4 (3.0 equiv) at −100 °C. The reaction
mixture was allowed to warm to −50 °C within 10 min and was
stirred at this temperature for 1.5 h to ensure complete
conversion. After workup, the alkynes 5a−f were isolated in
29−66% yields (Table 2). In most cases, a high retention of
configuration between the two adjacent centers was observed,
and only the cross-coupling of 4f with syn-3a led to more than
10% epimerization (entry 11).
This cross-coupling was extended to a range of secondary
alkylcopper reagents of type 3 prepared by an I/Li-exchange
reaction of the secondary alkyl iodides 1. Thus, the reaction of
the syn- and anti-alkyl iodides (syn-1b and anti-1b) with t-BuLi
(2.5 equiv, −100 °C), followed by the addition of CuBr·
P(OEt)3 (2.0 equiv, −100 °C, 5 min), provided the
intermediate alkylcopper reagents (syn- and anti-3b), which
underwent a smooth cross-coupling with 1-bromo-2-(trimethyl-
silyl)ethyne (4a), leading to the expected alkynes syn- and anti-
7a in 48−53% yield with a dr of 89:11 and 9:91, respectively
(entries 1 and 2, Table 3). Similarly, the syn- and anti-alkyl
Table 3. Scope of Diastereoconvergent Quenching of
Secondary syn- and anti-Alkylcoppers (3) with 1-
Bromoalkyne (4a) Leading to Alkylated Alkynes of Type 7
a
b
1
Isolated yield. dr (syn/anti ratio) was determined by H and 13C
NMR analysis.
a
b
1
Isolated yield. dr (syn/anti ratio) was determined by H and 13C
NMR analysis.
iodides (syn- and anti-1c) were converted to the corresponding
copper reagents and gave, after cross-coupling with 4a, the
diastereomerically enriched alkynes syn-7b (58% yield; dr =
87:13; entry 3) and anti-7b (51% yield; dr = 15:85; entry 4).
The use of a more bulky silyl protecting group such as TBDPS
(1d) improved the diastereoselectivity and yield of the cross-
coupling reaction with 4a, leading to the syn-product syn-7c in
67% yield (dr = 91:9, entry 5).
at −30 °C for 1 h led to a complete epimerization, as well as to
a significant yield decrease (entry 6). This indicated that
secondary alkylcoppers of type 3 are configurationally stable at
−30 °C for only a short time.
After having determined the configurational stability of the
alkylcopper reagents 3, we have performed a cross-coupling of
the diastereomerically defined syn- and anti-secondary
alkylcopper reagents (3a) with a range of alkynyl bromides of
We have also performed such a cross-coupling with an
optically enriched alkyl iodide syn-10 (see Scheme 2). Starting
from the commercially available (+)-R-hydroxybutyrate 8 (99%
B
DOI: 10.1021/acs.orglett.8b00699
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Preparation of the Chiral Alkyne syn-12 Starting
from Optically Enriched Alcohol anti-9
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: paul.knochel@cup.uni-muenchen.de.
ORCID
Paul Knochel: 0000-0001-7913-4332
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the DFG (SFB749) and the LMU Munich for
financial support. We also thank Albemarle (Hoechst,
Germany) for the generous gift of chemicals. J.S. thanks the
FCI Foundation for a fellowship.
ee), we have prepared the alcohol anti-9 (dr = 2:98) in 5 steps
and 42% overall yield.9e This alcohol was converted to the
corresponding iodide (syn-10) with complete inversion of
configuration (dr = 97:3) using an Appel reaction.9 An I/Li
exchange, followed by a transmetalation with CuBr·P(OEt)3,
furnished the intermediate copper reagent syn-11, which was
converted, after a cross-coupling with 4a, to the syn-alkyne syn-
12 in 56% yield and dr = 93:7 (97% ee13).
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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.8b00699.
Full experimental details; 1H and 13C NMR spectra
(PDF)
C
DOI: 10.1021/acs.orglett.8b00699
Org. Lett. XXXX, XXX, XXX−XXX

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Skotnitzki, J.; Moriya, K.; Karaghiosoff, K.; Knochel, P. Angew. Chem.,
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(11) Moriya, K.; Schwarzer, K.; Karaghiosoff, K.; Knochel, P.
̈
Synthesis 2016, 48, 3141−3154.
(12) Benzoyl chloride was used as an electrophile, because the anti/
syn ratio of the ketone 6 could be determined by GC analysis.
(13) The enantiomeric excess (ee) was determined by chiral GC
analysis. For details, see Suporting Information.
D
DOI: 10.1021/acs.orglett.8b00699
Org. Lett. XXXX, XXX, XXX−XXX