Stereoselective Cobalt-Catalyzed Cross-Coupling Reactions of Arylzinc Chlorides with α-Bromolactones and Related Derivatives

Article abstract of DOI:10.1021/acs.orglett.9b04564

α-Bromolactones bearing a substituent in the β-position undergo a highly trans-diastereoselective arylation with arylzinc chlorides in the presence of 10-20% CoCl₂ and 10-20% PPh₃ in THF under mild conditions (25 °C, 16 h) leading to

Full text of DOI:10.1021/acs.orglett.9b04564

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Letter
Stereoselective Cobalt-Catalyzed Cross-Coupling Reactions of
Arylzinc Chlorides with α‑Bromolactones and Related Derivatives
†
†
̈
Maximilian S. Hofmayer, Alisa Sunagatullina, Daniel Brosamlen, Philipp Mauker, and Paul Knochel*
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ABSTRACT: α-Bromolactones bearing a substituent in the β-position undergo a highly trans-diastereoselective arylation with
arylzinc chlorides in the presence of 10−20% CoCl2 and 10−20% PPh3 in THF under mild conditions (25 °C, 16 h) leading to
optically enriched α-arylated lactones and protected aldol products (99% ee) in 52−96% yield. The synthetic utility of this arylation
was demonstrated by the stereoselective preparation of an artificial rotenoid MOM-protected munduserol derivative.
asymmetric carbon−carbon bond forming reactions have been
reported.2 These transition-metal-catalyzed asymmetric cross-
couplings involve expensive3 or toxic4 Ni- or Pd-catalysts. Also,
reactions involving alkyl-palladium intermediates are often of
limited scope due to β-hydrogen elimination side reactions.5 It
was shown that relatively inexpensive and less toxic CoCl2 does
efficiently catalyze cross-couplings.6 Also, organozinc com-
pounds are excellent nucleophilic reagents for various Co-
catalyzed cross-coupling reactions, as a broad range of sensitive
functional groups are tolerated in these organometallics.7 1,2-
Substituted alkyl halides were used as electrophiles for trans-
diastereoselective cobalt-catalyzed cross-coupling reac-
he preparation of chiral agrochemicals and pharmaceut-
1
Ticals requires general and efficient asymmetric syntheses.
Recently, several advances involving Pd- and Ni-catalyzed
Table 1. Reaction Conditions Optimization for the Cross-
Coupling of p-Anisylzinc Chloride (2a) with α-
Bromolactone (1)
tions.6h,m,7a,8In preliminary experiments, the readily available
́
α-bromolactone 1, which was prepared from D-isoascorbic acid
in 99% ee,9 was submitted to an arylation using 4-anisylzinc
chloride (2a). The formation of product 3a was optimized
using various metallic salts (Table 1). Whereas CuCl2, CrCl2,
MnCl2, and FeCl2 were not effective catalysts (entries 1−5),
CoCl2 gave excellent results compared to CoBr2 or Co(acac)2
(entries 6−8). The addition of a ligand, such as PPh3, allowed
further yield improvement (entries 9−12). NiCl2/PPh3 was
equally efficient (entry 13).
Received: December 19, 2019
a
b
Calibrated GC-yield using undecane as internal standard. 99.99%
c
CoCl2 was used. Isolated yield of analytically pure 3a (dr = 99:1, 99%
ee).
https://dx.doi.org/10.1021/acs.orglett.9b04564
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
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Table 2. Stereoselective Cobalt-Catalyzed Cross-Couplings
of Arylzinc Reagents of Type 2 with α-Bromolactone 1
Table 3. Stereoselective Cobalt-Catalyzed Cross-Couplings
of Arylzinc Reagents of Type 2 with α-Bromolactone 4
Leading to Protected β-Hydroxy Esters of Type 5
a
Isolated yield of analytically pure lactones of type 3.
These optimized conditions were then applied to the
arylation of α-bromolactone 1 using various arylzinc reagents
of type 2 (Table 2).
a
b
Isolated yield of analytically pure products of type 5. dr = 50:50.
Thus, p-trifluoromethoxyphenylzinc chloride (2b) was
cross-coupled with 1, leading to the desired α-arylated lactone
3b in 63% yield (dr = 99:1, 99% ee, entry 1). Similarly, the
electron-poor organozinc reagent 2c furnished the 4-
trifluorotolyl substituted lactone 3c in 62% yield (dr = 99:1,
99% ee, entry 2). Also, the meta-substituted arylzinc reagents
2d and 2e, bearing a MeS- and a TBSO-group in the meta-
position are satisfactory coupling partners. They afforded the
optically pure products 3d and 3e in 63−77% yield (dr = 99:1,
99% ee, entries 3−4). The arylation of 1 with (6-
methoxynaphthalen-2-yl)zinc chloride (2f) and the benzodiox-
olylzinc reagent 2g gave the lactone derivatives 3f and 3g in
61−84% yield (dr = 99:1, 99% ee, entries 5−6). Interestingly,
the sterically hindered organozinc chloride 2h, having a
benzyloxy substituent in the ortho-position, was efficiently
coupled with α-bromolactone 1. The arylated lactone 3h was
obtained in 94% yield; dr = 99:1; 99% ee (entry 7).
various arylzinc reagents of type 2 was performed (Table 3).
Thus, p-anisylzinc chloride 2a led to the desired product 5a in
81% yield (dr = 99:1, 99% ee). Similarly, p-trifluoromethoxy-
phenylzinc chloride 2b and the electron-poor trifluoromethyl-
substituted arylzinc reagent 2c underwent the coupling
reaction affording the protected β-hydroxy ester derivatives
5b and 5c (dr = 99:1, 99% ee) in 61−63% yield (entries 2−3).
This arylation also proceeded well with meta-substituted zinc
organometallics, such as the TBS-protected phenol (2e) and
thioanisylzinc chloride (2d). The corresponding arylated esters
5d and 5e were obtained in 61−69% yield (dr = 99:1, 99% ee,
entries 4−5). Methoxynaphthylzinc chloride 2f and benzodiox-
olylzinc chloride 2g stereoselectively arylated the α-bromo-
lactone 4, leading to the protected β-hydroxy esters 5f and 5g
in 73−82% yield (dr = 99:1, 99% ee, entries 6−7).
Also, the zinc organometallics 2i and 2j bearing an ester
function in the meta- and para-position were satisfactory
coupling partners, leading to 5h and 5i in 52−76% yield
(entries 8−9). The meta-carbethoxyphenylzinc chloride 2j
Starting from L-threonine and pivalaldehyde, the chiral α-
bromolactone 4 was prepared, bearing a smaller methyl
substituent in the β-position.8 The cross-coupling of 4 with
B
https://dx.doi.org/10.1021/acs.orglett.9b04564
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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Letter
Scheme 1. Total Synthesis of the Artificial Rotenoid
Derivative MOM-Protected Munduserol (6)
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04564.
Full experimental details, 1H and 13C NMR spectra
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
Paul Knochel − Department of Chemistry, Ludwig-Maximilians-
̈
̈
Universitat 81377 Munchen, Germany; orcid.org/0000-
0001-7913-4332; Email: paul.knochel@cup.uni-
muenchen.de
Authors
Maximilian S. Hofmayer − Department of Chemistry, Ludwig-
̈
̈
Maximilians-Universitat 81377 Munchen, Germany
Alisa Sunagatullina − Department of Chemistry, Ludwig-
̈
̈
Maximilians-Universitat 81377 Munchen, Germany
̈
Daniel Brosamlen − Department of Chemistry, Ludwig-
̈
̈
Maximilians-Universitat 81377 Munchen, Germany
Philipp Mauker − Department of Chemistry, Ludwig-
Maximilians-Universitat 81377 Munchen, Germany
̈
̈
gave the product in excellent diastereomeric ratio (dr = 99:1).
However, an ester substituent in the para-position resulted in
epimerization in the course of the reaction (dr = 50:50). This
can be explained by a subsequent base-catalyzed epimerization
of the very acidic proton in the α-position to the aryl
substituent in 5h.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.9b04564
Author Contributions
†M.S.H. and A.S. contributed equally to this work.
Many naturally occurring rotenoids and their structurally
closely related unnatural derivatives show considerable
antiplasmodial or cytotoxic activities.10 These bioactive
compounds were the target of several total syntheses.11
Using this new Co-catalyzed arylation, we have prepared
MOM-protected munduserol 6, an artificial rotenoid derivative
starting from the α-arylated lactone 3h (Scheme 1). Thus, 3h
was reduced to the lactol with DIBAL-H and trapped with 2-
fluoro-4-methoxyphenylmagnesium chloride (7). Interestingly,
the diol 8 was obtained as a single diastereomer in 86% yield
over two steps (dr = 99:1).12 Next, the benzyl protecting group
of 8 was removed via a palladium-catalyzed hydrogenolysis.13
A selective Mitsunobu reaction allowed the first ring closure,
affording the desired product 9 in 74% yield over two steps (dr
= 99:1). Protection of 9 with MOMCl and deprotection of the
silyl group with TBAF furnished 10 in 53% yield over two
steps (dr = 99:1). Deprotonation of the secondary alcohol
under forcing reaction conditions allowed the second ring
closure via an intramolecular nucleophilic aromatic substitu-
tion. The MOM-protected munduserol 6 was obtained in 28%
yield (dr = 99:1).
In conclusion, a highly trans-diastereoselective cobalt-
catalyzed cross-coupling of arylzinc reagents with α-bromo-
lactones bearing a substituent in the β-position was developed.
α-Arylated butyrolactones and α-arylated protected β-hydroxy
esters were obtained in the presence of 10−20% CoCl2 and
10−20% PPh3 in THF under mild conditions (25 °C, 16 h) in
52−96% yield (dr = 99:1, 99% ee). A stereoselective synthesis
of an artificial rotenoid derivative MOM-protected munduserol
(6) was performed.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the DFG and the LMU Munich for financial support.
We also thank Albemarle for the generous gift of chemicals.
■
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