Cu-Catalyzed Diastereo- and Enantioselective Reactions of γ,γ-Disubstituted Allyldiboron Compounds with Ketones

Article abstract of DOI:10.1002/anie.202000675

A catalytic diastereo- and enantioselective method for the preparation of complex tertiary homoallylic alcohols containing a vicinal quaternary carbon stereogenic center and a versatile alkenylboronic ester is disclosed. Transformations are promoted by 5 mol % of a readily available copper catalyst bearing a bulky monodentate phosphoramidite ligand, which is essential for attaining both high dr and er. Reactions proceed with a wide variety of ketones and allylic 1,1-diboronate reagents, which enables the efficient preparation of diverse array of molecular scaffolds.

Full text of DOI:10.1002/anie.202000675

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Cu-Catalyzed Diastereo- and Enantioselective Reactions of γ,γ-
Disubstituted Allyldiborons with Ketones
Authors: Joseph M Zanghi and Simon John Meek
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202000675
Angew. Chem. 10.1002/ange.202000675
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10.1002/anie.202000675
Angewandte Chemie International Edition
COMMUNICATION
Cu-Catalyzed Diastereo- and Enantioselective Reactions of γ,γ-
Disubstituted Allyldiborons with Ketones
Joseph M. Zanghi and Simon J. Meek*[a]
A. Diastereo- and Enantioselective Allyl Addition to Ketones with Boronic Acids:
Abstract: Catalytic diastereo- and enantioselective preparation of
HO
Me
Me
O
complex tertiary homoallylic alcohols containing a vicinal quaternary
carbon stereogenic center and a versatile alkenylboronic ester is
disclosed. Transformations are promoted by 5 mol % of a readily
BINOL-derived cat.
toluene, 0 °C, 24 h
+
R1
G
B(OH)2
G
Me
R1
Me
R1 = Me, geranyl,
or neryl
B. Diastereo- and Enantioselective Synthesis of Tertiary Alcohols: (single example)
available copper catalyst bearing
a
bulky monodentate
O
Me
Me OH
phosphoramidite ligand, which is essential for attaining both high dr
and er. Reactions proceed with a wide variety of ketones and allylic
1,1-diboronate reagents that allows for the efficient preparation of
diverse array of molecular scaffolds.
15 mol % (L)Cu(OAc)
B2(pin)2
+
Ph
Me
Ph
Me
OH
Me
H2O2/NaOH
Me
80%
57:43 dr, 90:10 er
C. This Work: Diastero- and Enantioselective Syntheis of Tertiary Alcohols/Quaternary
Carbon Stereogenic Centers
n Principal Strategy for Reaction Development:
Quaternary carbon stereogenic centers and tertiary alcohols are
common motifs found in many bioactive molecules, and their
enantioselective preparation, particularly in acyclic systems, are
essential transformations in organic synthesis.[1,2] Nonetheless,
catalytic enantioselective C–C bond forming reactions that
establish both of these critical functional groups remain a
significant challenge. To this end, the enantio- and
R3
O
B(pin)
B(pin)
HO
RS
cat. (L)Cu–OR
MeOH
B(pin)
R2
RL
RS
+
RL
R3 R2
1
2
anti–3
(L)Cu–OR
a. Enantioselective Transmetalation
R3
MeOH
R2
Cu(L)
(L)CuO RS
(pin)B
minimize
sterics
B(pin)
diastereoselective addition of
a suitably substituted allyl
A
RL
O
R3 R2
nucleophile to ketones provides a concise strategy for assembling
these key chemical structures.[3] Significant efforts have been
directed towards catalytic enantioselective synthesis of tertiary
homoallylic alcohols that contain a vicinal tertiary carbon
stereocenter.[4] Conversely, the diminished reactivity of ketones
and the closer parity in size of the carbonyl substituents serve to
hamper development of quaternary carbon equivalents.[5]
However, a few examples of enantioselective allylic nucleophile
additions to ketones that form quaternary carbon stereocenters
have been reported. Enantiospecific reactions of chiral allylboron
compounds with ketones proceed efficiently and with excellent
levels of diastereoselectivity.[6] In addition, Szabó reported the first
catalytic enantio- and diastereoselective synthesis of homoallylic
alcohols bearing quaternary carbon stereocenters (Scheme
1A).[7,8] Reactions employ stereodefined γ,γ-disubstituted
allylboronic acids and are catalyzed by chiral binaphthyl-based
diols. Recent notable advances that circumvent the initial
preparation of the organometallic by coupling a diene to a ketone
via a tandem Cu-catalyzed borylation/1,2-addition sequence have
been disclosed (Scheme 1B).[9] Nevertheless, shortcomings
related to the use of unstable boronic acids or the need for
sparteine-mediated generation of the allylboronates detract from
the implementation of these methods.
B(pin)
D
RS
RL
RS
Cu(L)
1
R3
H
R2
O
(pin)B
(L)Cu
RL
R3
b. Site- and
diastereoselective allylic
Cu addition to ketone
R2
B
C
n Diastereoselectivity: Increase size of ligand ꢀ Increase dr?
(minimize (L)Cu⟷RL; RL pseudoequatorial)
Scheme 1. Catalytic Diastereo- and Enantioselective γ,γ-Disubstituted Allylic
Nucleophile Additions to Ketones. B(pin) = (pinacolato)boron.
the stereoselective formation of quaternary carbon centers vicinal
to tertiary alcohols (Scheme 1C). Our approach centers on the
development of
a catalyst controlled 1,2-addition of γ,γ-
disubstituted allyldiboronate esters to ketones.[10] 1,1-Diboron
reagents represent a nascent class of functional reagents for the
enantioselective synthesis of alcohols and amines.[11] In this
regard, we envisioned a catalytic reaction that begins with an
enantioselective SE2’ transmetalation between in situ-generated
(L)-Cu–OMe and a stereodefined allyldiboron (e.g., 2).[12,13]
Quaternary allylic Cu A can undergo rapid suprafacial shift to the
sterically less congested and energetically more favorable tertiary
a-boryl–Cu species B, which can add diastereoselectively to a
ketone via C. Notably, with γ,γ-disubstitution, A(1,3)-strain likely
limits σ-bond rotation and migration of (L)-Cu, preventing
scrambling of alkene geometry.[14] Finally, the sequence (C®D)
furnishes tertiary alcohols, following (L)-Cu–OMe regeneration by
MeOH, bearing a vicinal quaternary center appended with a
versatile alkenylboron. To address the challenge of dr, we
postulated that increasing the size of the ligand would lead to
allyl-Cu addition that places RL of the ketone in the pseudo-
equatorial position in the chair-like transition state of C.[15]
Moreover, the reactive allylic Cu species would also counter lower
reactivity caused by steric congestion present during C–C bond
formation.
In light of the aforementioned limitations, we sought to
develop a general catalytic allylic nucleophile addition protocol for
[a]
J. M. Zanghi, Prof. S. J. Meek
Department of Chemistry
The University of North Carolina at Chapel Hill
Chapel Hill, NC 27599 (USA)
E-mail: sjmeek@unc.edu
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.202000675
Angewandte Chemie International Edition
COMMUNICATION
O
Me B(pin)
HO
CH3
5 mol % CuOtBu
10 mol % Ligand
the reaction with L5 to -60 °C affords 6a in 10:1 dr and 97:3 er, an
observation noted with other substrates.
B(pin)
CH3 n-Bu
B(pin)
Me n-Bu
6a
MeOH (1.05 equiv)
THF, -40 °C, 16 h
4
5
(1.2 equiv)
As illustrated in Scheme 3A, a wide variety of aryl-, and
heteroaryl-substituted ketones were examined. For example, aryl
ketones bearing electron-donating (6b–e) as well as electron-
withdrawing (6f–k) groups can be used, including those
containing meta- (6l–o) and ortho (6p) substitution. In addition,
aryl ketone product 6q is formed in good yield and excellent
selectivity, indicating the protocol is tolerant of primary alkyl
chlorides. Heteroaryl and polyaromatic ketones are also effective
substrates (6r–t); unprotected parent indole was not effective.
While the aryl ketone scope is tolerant of substituent electronics,
the reaction is sensitive to sterics; most ortho-substituents (such
as o-Me) or diaryl ketones such as benzophenone (e.g., 6u) do
not participate due to steric congestion. Ketone diversity also
extends to enones (7a–b),[16] ynones (7c), and cyclic (7d) and
acyclic alkyl ketones (7e–g) (Scheme 3B). The formation of 7d–
f demonstrates that transformations in the presence of NBoc
amides and silyl ethers proceed in good yield and stereoselectivity.
As illustrated by the synthesis of 7h–i, the catalytic protocol
extends to symmetrical dialkyl ketones such as acetone (95:5 er)
and cyclohexanone (97:3 er) that form enantiomerically enriched
tertiary alcohols, without a stereogenic carbinol. Such examples
provide support for the highly enantioselective transmetalation
that occurs in the initial step (2®A®B, Scheme 1C). Reactions
with chiral ketones also proceed with high levels of
diastereoselectivity. For example, catalytic addition to (S)-Hajos-
Parrish diketone under standard conditions affords 7j as a single
diastereomer (>50:1 dr), with exclusive chemoselectivity for the
enone over the aliphatic ketone.
F
OMe
R
F
F
O
P
R =
NMe2
OMe
O
L1
L2
L3
79% NMR yield
86% NMR yield 96% NMR yield
R
4:1 dr
83:17 er
3:1 dr
74:26 er
4:1 dr
94:6 er
L1–L6
OMe
Me
t-Bu
OMe
OMe
L6 (-60 °C)
>98% NMR yield
15:1 dr
Me
t-Bu
L4
90% NMR yield
L5
72% NMR yield
7:1 dr
96.5:3.5 er
L6
94% NMR yield
10:1 dr
93.5:6.5 er
97:3 er
4:1 dr
96.5:3.5 er
Scheme 2. Investigation of Chiral Cu Complexes. Reactions performed under
N2 atmosphere. Yield and diastereomeric ratios (dr) determined by analysis of
1H NMR spectra of crude reactions with hexamethyldisiloxane as internal
standard. Enantiomeric ratios (er) determined by HPLC analysis. See SI for
details.
Our studies began by examining the ability of in situ-
generated phosphoramidite–Cu complexes, which had previously
emerged as optimal in promoting reactions with aryl aldimines,[10e]
in the reaction of 4 and 5 to afford 6a (Scheme 2). We found that
treatment of acetophenone 4 and allyldiboron 5, with 5.0 mol %
CuOtBu, 10 mol % H8-binaphthyl-derived L1, and 1.05 equiv
MeOH in THF at -40 °C for 16 h furnished 6a as a single
regioisomer, favoring generation of the quaternary carbon center
(i.e., γ-allylation) in 86% NMR yield, 4:1 dr, and 83:17 er.
Switching to ligands L2–L5, which contain increasingly larger aryl
groups at the 3,3’-positions, result in an increase in dr (4:1®7:1)
and er (83:17®96.5:3.5) at -40 °C. Further improvement in
diastereoselectivity to 10:1 dr was observed by the application of
phosphoramidite L6 containing 3,5-t-BuC6H3 substituents.
Importantly, the slight diminution in enantioselectivity (93.5:6.5 er)
could be restored by cooling the reaction of (L6)-Cu to -60 °C,
affording 6a in >98% NMR yield, 15:1 dr, and 97:3 er, and
represented optimal reaction conditions. In comparison, cooling
The range of allyldiboron reagents also displays broad scope
with regard to varying the substituents of the quaternary carbon
stereogenic center (Scheme 4). The requisite stereodefined
allyldiboron reagents are readily prepared from the corresponding
alkenyl halides (see the SI). The stereospecific nature of the
catalytic reaction is exemplified by the enantio- and
diastereoselective formation of tertiary alcohols 8a (47:1 dr, 91:9
er) and 8b (32:1 dr, 96.5:3.5 er) bearing Me/Et quaternary
R2
O
Me B(pin)
5 mol % CuOtBu
10 mol % L6
HO
R1
B(pin)
+
R1 R2
n-Bu
B(pin)
MeOH (1.05 equiv)
THF, -60 °C, 16 h
Me n-Bu
(1.2 equiv)
5
6a–u, 7a–j
A. Aryl–Alkyl Ketones:
6a: G=H, 85% yield, 17:1 dr, 97:3 er
HO
F
HO
Me
Me
6b: G=Me, 85% yield, 20:1 dr, 98:2 er
6c: G=SMe, 80% yield, 46:1 dr, 97.5:2.5 er
6d: G =OMe, 80% yield, 28:1 dr, 97.5:2.5 er
6e: G= NMe2, 54% yield, 17:1 dr, 93.5:6.5 er
6f: G=Br, 85% yield, >50:1 dr, 97.5:2.5 er
6g: G=I, 85% yield, >50:1 dr, 97.5:2.5 er
6h: G=CF3, 89% yield, 39:1 dr, 98:2 er
6i: G=CO2Me, 92% yield, 23:1 dr, 97.5:2.5 er
6j: G=CN, 88% yield, 13:1 dr, 97:3 er
6k: G=NO2, 92% yield, 15:1 dr, >99:1 er
B(pin)
B(pin)
HO
Me
Me n-Bu
Me n-Bu
B(pin)
G
6l–o
Me n-Bu
6p
G
85% yield
18:1 dr, 94.5:5.5 er
6l: G=Me, 86% yield, >50:1 dr, 96:4 er
6m: G=F, 87% yield, 15:1 dr, 97.5:2.5 er
6n: G=Cl, 76% yield, 21:1 dr, 96.5:3.5 er
6o: G=CO2Me, 92% yield, 20:1 dr, 97:3 er
6a–k
Cl
HO
HO
HO
HO
Me
HO
Me
Me
B(pin)
B(pin)
B(pin)
B(pin)
B(pin)
Me n-Bu
Me n-Bu
Me n-Bu
Me n-Bu
Me n-Bu
O
TsN
6q
6r
6s
6t
6u
84% yield
63% yield
86% yield
80% yield
< 5% yield
18:1 dr, >99:1 er
>50:1 dr, 98:2 er
8:1 dr, 97:3 er
>50:1 dr, 97.5:2.5 er
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10.1002/anie.202000675
Angewandte Chemie International Edition
COMMUNICATION
B. Alkenyl, Alkynyl, and Alkyl Ketones:
HO
HO
Me Me
Me
HO
HO
Me
Me
OH
Me
Boc
N
B(pin)
B(pin)
B(pin)
BocN
B(pin)
B(pin)
B(pin)
Ph
Me n-Bu
Me n-Bu
Me n-Bu
Me n-Bu
Me n-Bu
Ph
Me
7a
86% yield
8:1 dr, 97:3 er
7b
87% yield
8:1 dr, 97.5:2.5 er
7c
80% yield
17:1 dr, 97:3 er
7d[a]
69% yield
14:1 dr, 96.5:3.5 er
7e[a]
68% yield
20:1 dr, 95:5 er
OH
HO
Me
HO
Me
OH
HO
B(pin)
B(pin)
B(pin)
B(pin)
Me
Me
TBSO
n-Bu
Me
n-Bu
Me n-Bu
Me n-Bu
Me n-Bu
Me
Me
7f[a]
57% yield
8:1 dr, 94:6 er
7g[a,b]
60% yield
13:1 dr, 92:8 er
7j
66% yield
>50:1 dr
7h[a,b]
90% yield
95:5 er
7i[a,b]
82% yield
97:3 er
O
Scheme 3. Diastereo- and Enantioselective Cu-Catalyzed Synthesis of Homoallyl Alcohols and Quaternary Carbon Stereocenters by Allylic Nucleophile Additions
to Aryl, Heteroaryl, Alkenyl, Alkynyl, and Alkyl Ketones. Reactions performed under N2 atmosphere on 0.05 mmol scale with 1.0 equiv of ketone, 1.2 equiv. of 5, in
0.350 ml of THF. Yields of purified products after SiO2 chromatography. Experiments were run in duplicate. Diastereomeric ratios (dr) determined by analysis of
1H NMR spectra of purified products. Enantiomeric ratios (er) determined by HPLC or SFC analysis. [a] Reactions run at -50 °C. [b] 2.0 equivalents of CD3OD used
in place of CH3OH. See SI for details.
0.350 ml of THF. Yields of purified products after SiO2 chromatography.
Experiments were run in duplicate. Diastereomeric ratios (dr) determined by
analysis of 1H NMR spectra of purified products. Enantiomeric ratios (er)
carbon stereogenic centers arising for the reaction of both E- and
Z-allyldiboron isomers. Additionally, a variety of quaternary
carbon stereogenic centers can be prepared, including those
determined by HPLC or SFC analysis. See the SI for details.
containing cyclopropyl (8c), N-heteroaryl (8d), silylether (8e), and
homobenzyl (8f) groups. In all cases, yield (>71%), dr (>7:1), and
er (>95.5:4.5) remain high. Similar to non-prochiral ketone
examples 7h–i (Scheme 3), symmetrically γ,γ-disubstituted allylic
diboronates also undergo efficient C–C bond formation to
The relative and absolute stereochemistry of the product, as
well as confirmation of the proposed stereochemical model in
Scheme 1C, was assigned by single crystal X-ray diffraction of 6q
generate chiral tertiary alcohols with
a
non-stereogenic
(Scheme 5). As expected, an anti-relationship between the
hydroxyl and n-butyl (E-) substituent is observed, corresponding
to positioning of the large ketone substituent in the pseudo-
equatorial position. In addition, the diastereoselectivity for alkyl
ketone-derived 7g was also determined as anti, consistent with
the proposed stereochemical model (see SI for details). This is in
contrast to the Cu-catalyzed reactions of γ,γ-disubstituted
allyldiborons with NPMB-imines, which afford the syn
stereoisomer.[10e]
quaternary carbon center; for example, the tertiary alcohols
containing gem-dimethyl (8g), cyclohexane (8h), and cyclobutane
(8i) substituents shown in Scheme 4, formed in >75% yield and
88:12–97.5:2.5 er, are representative.
5 mol % CuOtBu
10 mol % L6
MeOH (1.05 equiv)
R4
R2
O
(pin)B
(pin)B
HO
R1
B(pin)
B(pin)
+
R1 R2
R3
(1.2 equiv)
2
R4 R3
8a–i
THF, -60 °C, 16 h
(1.0 equiv)
HO Me
HO Me
HO Me
B(pin)
B(pin)
Cl
Ph
Ph
Me
Ph
O
B
HO
Me
Me
Me
Me
O
Me n-Bu
8a (from E isomer)
97% yield
47:1 dr, 91:9 er
8b (from Z isomer)
81% yield
32:1 dr, 96.5:3.5 er
8c
72% yield
>50:1 dr, 98.5:1.5 er
6q
X-ray of 6q
HO Me
B(pin)
HO Me
HO Me
Scheme 5. X-Ray Structure of 6q. See SI for details.
B(pin)
B(pin)
Ph
Ph
Me
Me
Me
O
OTBS
Ph
The variety of functional group rich products synthesized
through the catalytic protocol can be transformed in a number of
ways to furnish useful enantio- and diastereomerically enriched
compounds; five examples are depicted in Scheme 6. Firstly,
treatment of 6f and 6g with NaBO3•4H2O results in C–B oxidation
and conversion of the vinyl boronic esters to corresponding
hemiacetals (9) (Scheme 6A), which can be can be used crude in
subsequent reactions. For example, 9 can be deoxygenated with
trifluoroacetic acid and triethylsilane to generate tetrahydrofuran
10 in 82% yield,[17] or oxidized with PCC to afford lactone 11
isolated in 51% yield over two steps. Second, both aryl and alkyl
N
Me
8d
75% yield
8e
75% yield
7:1 dr, 95.5:4.5 er
8f
91% yield
13:1 dr, 98:2 er
32:1 dr, 99:1 er
HO Me
HO Me
HO Me
Ph
B(pin)
B(pin)
B(pin)
Ph
Me Me
I
8g
75% yield
94:6 er
8h
86% yield
97.5:2.5 er
8i
86% yield
88:12 er
Scheme 4. Variation of Allyl 1,1-Diboronate Scope. Reactions performed under
N2 atmosphere on 0.05 mmol scale with 1.0 equiv of ketone, 1.2 equiv. of 2, in
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10.1002/anie.202000675
Angewandte Chemie International Edition
COMMUNICATION
ketone-derived alkenylboron products undergo efficient Pd-
catalyzed Suzuki-Miyaura cross coupling (Scheme 6B); the
Acknowledgements
Financial support was provided by the United States National
Institutes of Health, Institute of General Medical Sciences
(R01GM116987). Mass spectrometry facilities in the Department
of Chemistry at University of North Carolina are supported by the
National Science Foundation (CHE1726291). We thank Tia
Cervarich of UNC for X-ray structure elucidation of 6q.
A. Tetrahydrofuran and γ-Lactone Synthesis:
O
Me
Et3Si–H (3 equiv), CF3CO2H
CH2Cl2, -78 to 22 °C, 2 h
n-Bu
Me
I
10
OH
HO Me
82% yield, >50:1 dr
(over 2 steps)
O
B(pin)
NaBO3
Me
O
Me n-Bu
THF/H2O
0 to 22 °C
6 h
n-Bu
Me
G
O
G
Me
Keywords: 1,1-Allyldiboron • Ketones • Quaternary carbon •
6f: G = Br, (>50:1 dr)
6g: G = I, (>50:1 dr)
9
Enantioselective • Copper
n-Bu
Me
Br
11
PCC (5 equiv)
CH2Cl2, 22 °C, 1.5 h
[1]
For recent reviews on the enantioselective synthesis of quaternary
carbon stereogenic centers, see: (a) J. P. Das, I. Marek, Chem. Commun.
2011, 47, 4593–4623. (b) Y. Minko, I. Marek, Chem. Commun. 2014, 50,
12597–12611. (c) I. Marek, Y. Minko, M. Pasco, T. Mejuch, N. Gilboa, H.
Chechik, J. P. Das, J. Am. Chem. Soc. 2014, 136, 2682–2694. (d) K. W.
Quasdorf, L. E. Overman, Nature 2014, 516, 181–191. (e) Y. Liu, S.-J.
Han, W.-B. Liu, B. M. Stoltz, Acc. Chem. Res. 2015, 48, 740–751. (f) X.-
P. Zeng, Z.-Y. Cao, Y.-H. Wang, F. Zhou, J. Zhou, Chem. Rev. 2016,
116, 7330–7396. (g) J. Feng, M. Holmes, M. J. Krische, Chem. Rev.
2017, 117, 12564–12580.
51% yield, >50:1 dr
(over 2 steps)
B. Suzuki-Miyaura Cross Coupling
HO Me
B(pin)
HO Me
N
Me n-Bu
Me n-Bu
5 mol % Pd(PPh3)4
Ar–Br (1.5 equiv)
MeS
MeS
6c
12
Na2CO3 (3 equiv)
(46:1 dr)
55% yield, >50:1 dr
H2O, MeOH, C6H6
80 °C, 20 h
HO
HO
Me
Me
B(pin)
TBSO
TBSO
N
[2]
[3]
For recent reviews on the enantioselective synthesis of tertiary alcohols,
see: (a) O. Riant, J. Hannedouche, Org. Biomol. Chem. 2007, 5, 873–
888. (b) M. Hatano, K. Ishihara, Synthesis 2008, 1647–1675. (c) M.
Shibasaki, M. Kanai, Chem. Rev. 2008, 108, 2853–2873. (d) Y.-L. Liu,
X.-T. Lin, Adv. Synth. Catal. 2019, 361, 876–918.
Me n-Bu
7f
Me n-Bu
13
84% yield, 7:1 dr
(8:1 dr)
C. γ-Hydroxy Aldehdye Synthesis:
TMSOTf, 2,6-lutidine
THF, 22 °C, 2 h;
HO Me
TMSO Me
For a recent reviews of catalytic allyl additions to ketones, see: (a) S. E.
Denmark, J. Fu, Chem. Rev. 2003, 103, 2763–2794. (b) M. Shibasaki,
M. Kanai, Chem. Rev. 2008, 108, 2853–2873. (c) M. Yus, González- J.
C. Gómez, F. Foubelo, Chem. Rev. 2011, 111, 7774–7854. (d) H.-X. Huo,
J. R. Duvall, M.-Y. Huang, R. Hong, Org. Chem. Front. 2014, 1, 303–320.
(e) See also ref. 1g.
O
Cl
B(pin)
Cl
NaBO3, THF/H2O
0 to 22 °C, 4 h
Me n-Bu
Me n-Bu
6n
(21:1 dr)
14
61% yield, >50:1 dr
(over 2 steps)
[4]
For representative catalytic enantioselective examples of crotyl additions
to ketones, see: (a) R. Wada, K. Oisaki, M. Kanai, M. Shibasaki, J. Am.
Chem. Soc. 2004, 126, 8910–8911. (b) M. Wadamoto, H. Yamamoto, J.
Am. Chem. Soc. 2005, 127, 14556–14557. (c) J. J. Miller, M. S. Sigman,
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Scheme 6. Synthetic Utility of Alkenyl Boronate Products. See SI for details.
conversion of 6c and 7f to N-heteroarene-containing 12 and 13,
generated in 55% and 84% yield, are representative. In addition,
preparation of the aliphatic aldehyde, without cyclization, can be
accomplished by
a two-step sequence that first requires
protection of the tertiary alcohol (Scheme 6C). In this regard,
treatment of 6n with TMSOTf and 2,6-lutidine followed by C–B
bond oxidation with NaBO3•4H2O affords b-quaternary carbon
aldehyde 14, isolated in 61% yield over two steps.
In conclusion, we have developed a practical, efficient
diastereo- and enantioselective Cu-catalyzed allyl addition to
ketones that generates vicinal stereogenic centers – a tertiary
alcohol and quaternary carbon. The reaction tolerates a wide
variety of aryl, heteroaryl, alkenyl, alkynyl, and alkyl ketones, as
well as a diverse array of allyldiboron reagents. In addition, both
non-prochiral ketones and symmetrically γ,γ-disubstituted
nucleophiles can be employed with high stereoselectivity. The
synthetically versatile alkenyl boron products can be elaborated
by a number of chemical transformations to useful chiral
molecules. Further catalytic stereoselective methods utilizing
allylic 1,1-bis-boronates are in progress.
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Entry for the Table of Contents (Please choose one layout)
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A
catalytic diastereo- and
Joseph M. Zanghi, Simon J. Meek
enantioselective method for the
preparation of complex tertiary
homoallylic alcohols containing a
R4
O
B(pin)
B(pin)
HO
R2
R4
Page No. – Page No.
cat.
(L)Cu–OR
B(pin)
R3
+
R1
R2
R1
R3
Cu-Catalyzed Diastereo- and
Enantioselective Reactions of
γ,γ-Disubstituted Allyldiborons
with Ketones
vicinal
quaternary
carbon
R1, R2 = aryl,
alkenyl, alkynyl,
alkyl
B(pin)
Cu(L)
R3
stereogenic
center and
a
versatile alkenylboronic ester is
disclosed. Reactions proceed in
the presence of chiral Cu
complex with a wide variety of
ketones and γ,γ-disubstituted
allylic diboronates to afford
products in both high dr and er.
R4
H
l Up to 97% yield, >50:1 dr. >99:1 er l Tertiary alcohol and
quaternary carbon stereogenic center l Including aliphatic
ketones l 10 Allyldiboron reagents
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Author(s), Corresponding Author(s)*
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Title
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