Enantioselective desymmetrization via carbonyl-directed catalytic asymmetric hydroboration and Suzuki-Miyaura cross-coupling

Article abstract of DOI:10.1021/ol503764d

The rhodium-catalyzed enantioselective desymmetrization of symmetric γ,δ-unsaturated amides via carbonyl-directed catalytic asymmetric hydroboration (directed CAHB) affords chiral secondary organoboronates with up to 98% ee. The chiral γ-borylated products undergo palladium-catalyzed Suzuki-Miyaura cross-coupling via the trifluoroborate salt with stereoretention.

Full text of DOI:10.1021/ol503764d

Letter
pubs.acs.org/OrgLett
Enantioselective Desymmetrization via Carbonyl-Directed Catalytic
Asymmetric Hydroboration and Suzuki−Miyaura Cross-Coupling
Gia L. Hoang,† Zhao-Di Yang,‡,† Sean M. Smith,† Rhitankar Pal,§ Judy L. Miska,† Damaris E. Perez,†
́
Libbie S. W. Pelter,∥ Xiao Cheng Zeng,† and James M. Takacs*,†
†Department of Chemistry, University of NebraskaLincoln, Lincoln, Nebraska 68588, United States
‡Key Laboratory of Green Chemical Engineering and Technology, College of Heilongjiang Province, College of Chemical and
Environmental Engineering, Harbin University of Science and Technology, Harbin 150040, P. R. China
§Department of Chemistry, Yale University, New Haven, Connecticut 06518, United States
∥Department of Chemistry and Physics, Purdue University Calumet, Hammond, Indiana 46323-2094, United States
S
* Supporting Information
ABSTRACT: The rhodium-catalyzed enantioselective desym-
metrization of symmetric γ,δ-unsaturated amides via carbonyl-
directed catalytic asymmetric hydroboration (directed CAHB)
affords chiral secondary organoboronates with up to 98% ee.
The chiral γ-borylated products undergo palladium-catalyzed
Suzuki−Miyaura cross-coupling via the trifluoroborate salt
with stereoretention.
with tmdBH; the products obtained are near racemic for most
combinations of L2−5 possessing substituents b−e.
hiral organoboronates are useful intermediates in organic
1,2
Csynthesis,
and consequently, a number of research
groups are developing enantioselective methods for their
preparation.3−10 We reported the rhodium-catalyzed carbonyl-
directed catalytic asymmetric hydroborations (directed CAHBs)
of certain (E)- and (Z)-disubstituted and -trisubstituted β,γ-
unsaturated amides 1 and 1,1-disubstituted (i.e., methylidene)
β,γ-unsaturated amides and tert-butyl esters 3.11 Simple chiral
catalyst systems have been identified to give chiral β- and γ-
borylated carbonyl compounds with high regio- and π-facial
selectivity (Figure 1). We now report the efficient CAHB of
symmetric γ,δ-unsaturated amides 5. For example, 5a undergoes
carbonyl-directed CAHB with 4,4,6-trimethyl-1,3,2-dioxabor-
inane (tmdBH, ( )-B1) using Rh(nbd)2BF4 in conjunction with
(BINOL)PN(Bn)Ph (L1b) to give the cis-γ-borylated amide
(1R,3S)-6a in 80% yield and 94% ee (determined after oxidation)
via enantioselective desymmetrization.12 Asymmetric desym-
metrization is a widely used method for generating chiral
substances;13 however, few examples employ CAHB.14
The enantioselectivity obtained for CAHB by pinBH (B2)
with catalysts derived from BINOL-derived phosphoramidites
L1a and b and the series of phenyl phosphites L2a−L5a is
significantly lower (55−81% ee) than obtained with tmdBH
(Figure 2). However, pinBH generally affords higher levels of
enantioselectivity with TADDOL-derived phosphoramidites
L2−5b−e. Furthermore, these phosphoramidites generally give
the enantiomeric product compared to that obtained with the
corresponding phenyl phosphite; an enantioselectivity as high as
78% ee for (1S,3R)-6a is found using L3c. The results are in
qualitative agreement with our previous report of exceptionally
high levels of enantioswitching15 with the acyclic substrate 1.11d
Using the most promising catalyst system identified in our
brief ligand/borane survey (i.e., [(L1b)2Rh(nbd)BF4] with
tmdBH), a series of γ,δ-unsaturated amides 5a−l varying in
their amide- and α-substituents are converted via the γ-borylated
intermediate to their chiral cyclopentanols 7a−l (Table 1 and
Figure 3). Phenyl amides 5a−d, a series of substrates bearing α-
H, -alkyl, -aryl, and −CF3 substituents, gave the respective γ-
alcohol in good yield and high enantiomeric excess (i.e., 7a−d,
96:4 to 97:3 er) (entries 1−4). Substituting benzyl for phenyl as
the amide substituent gave 7e−h in comparable yields but
slightly lower enantioselectivity; enantiomer ratios ranged from
92:8 to 96:4 (entries 5−8). Chiral substrates 5i and 5j bear a
chiral phenethyl substituent on the amide nitrogen and were
included in the screening to confirm structural assignments (vide
infra). These chiral substrates undergo CAHB with somewhat
Varying the nature of the ligand used (i.e., L1−L5) for
rhodium-catalyzed CAHB of 5a by tmdBH (B1) reveals a
number of interesting effects on the sense and degree of
enantioselectivity (Figure 2). BINOL-derived phosphoramidites
L1a−b in combination with tmdBH (B1) give the most selective
catalysts for the formation of (1R,3S)-6a (93−94% ee). Catalysts
formed from TADDOL phenyl phosphites L2a−L5a are also
quite selective (83−92% ee); small changes in the TADDOL
backbone only incrementally affect enantioselectivity. In contrast
to the TADDOL-derived phenyl phosphites L2a−L5a and
BINOL-derived phosphoramidites L1a/b, TADDOL-derived
phosphoramidites afford catalysts that are much less selective
Received: January 6, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/ol503764d
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Letter
Table 1. Enantioselective Desymmetrization via CAHB
a
b
entry
5
R1
R2
yield
er/dr
1
2
3
4
5
6
7
8
a
b
c
d
e
f
H
Ph
Ph
Ph
Ph
Bn
Bn
Bn
Bn
80
65
72
78
69
62
70
71
76
74
97:3
96:4
96:4
97:3
94:6
92:8
93:7
96:4
Me
Ph
CF3
H
Me
Ph
g
h
i
CF3
Ph
c
9
(R)-CH(Me)Ph
(S)-CH(Me)Ph
88:12
20:80
c
10
j
Ph
a
Isolated yields, an average of three experiments generally exhibiting a
b
spread of 2%. Enantiomer ratio (er) determined by chiral HPLC
c
analysis or diastereomer ratio (dr) determined by 1H NMR. 2%
catalyst loading.
Figure 1. Carbonyl-directed CAHB exploits π-facial selectivity for β,γ-
unsaturated substrates 1 and 3 and re/si-site selectivity for the
enantioselective desymmetrization of γ,δ-substrate 5a.
Figure 3. Group-selective enantioselective desymmetrization.
organoboronate generated upon CAHB was converted to the
cesium17 or potassium18 trifluoroborate by the reported
methods. The latter gave crystals of the major diastereomer
suitable for X-ray crystallographic analysis; the structure of
(1R,3S)-8i (M = K) is shown in Figure 4.
Figure 2. Varying the boranes and ligands employed strikingly affects
the enantioselectivity for the CAHB of 5a.16
lower stereoselectivity compared to the corresponding phenyl
and benzyl amides and exhibit a modest matched/mismatched
diastereomer effect (entries 9 and 10).
Two derivatives shown in Figure 3 highlight unusual group
selectivity in the CAHB. Substrates 5k and 5l each contain two
alkene moieties ostensibly positioned equidistant from the
carbonyl directing group, one endocyclic double bond, and an
unsaturated side chain substituent on the ring. The side-chain
alkene is trans-disubstituted in the case of 5k and a methylidene
derivative in the case of 5l. Both substrates undergo CAHB
selectively with the endocyclic double bond to give the
monounsaturated γ-alcohol [i.e., (1S,3S)-7k and 7l, respectively]
in good yield (75−80%) and high enantioselectivity (99:1 and
97:3 er, respectively). We speculate that the preferred orientation
of the carbonyl oxygen and/or somewhat greater reactivity for
the endocyclic double bond might account for the observed
product.
Figure 4. Preparation and crystal structure of 8i (M = K).
The cross-coupling reactions of chiral, secondary organo-
boronates have recently attracted a great deal attention.19 Several
examples illustrating successful Suzuki−Miyaura cross-coupling
of the benzyl and chiral phenethyl amide derivatives of (1R,3S)-
8i (M = Cs) using Buchwald’s palladium-precatalyst 1020 are
summarized in Table 2.21
Understanding the stereochemical course of the Suzuki−
Miyaura reaction has recently attracted considerable attention.19
Spectral data obtained for products 9a and b indicate that the
The CAHB of chiral amide 5i proved useful in unambiguously
assigning the absolute configuration of the product and thereby
the stereochemical course of the reaction. The intermediate
B
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Letter
Table 2. Palladium-Catalyzed Cross-Coupling of Cesium
Trifluoroborate Salt 8i
a
entry
8
R1
R2
aryl halide
9
yield
b
1
8g
8h
8i
8i
8i
8i
8i
8i
Ph
CF3
Ph
Ph
Ph
Ph
Ph
Ph
Bn
Bn
11
11
11
12
13
14
15
16
a
b
c
d
e
f
69
63
86
66
66
71
b
2
3
4
5
6
7
8
(R)-CH(Me)Ph
(R)-CH(Me)Ph
(R)-CH(Me)Ph
(R)-CH(Me)Ph
(R)-CH(Me)Ph
(R)-CH(Me)Ph
c
g
h
75
Figure 5. In contrast to recent examples of β-borylated amides,
palladium-catalyzed cross-coupling of γ-borylated amide (1R,3S)-8i
proceeds with stereoretention.
70
a
Isolated yields based on limiting aryl halide, an average ( 2%) of two
b
runs. Cross-coupling proceeds with high diastereoselectivity (ca. 94:6
dr). CsOH (5 equiv) replaces Cs2CO3.
c
cross-coupling is highly diastereoselective. For example, the 19
F
NMR spectrum of 9b shows a single major resonance with no
minor peak integrating for more than 6% abundance. As first
demonstrated by Crudden,1g,2 Suzuki−Miyaura cross-couplings
of α-chiral alkylboron compounds possessing adjacent π-systems
proceed with stereoretention. However, substrates similar to
those used here by Molander22 and Suginome,23 as well as other
substrates reported by Biscoe,1a Morken,4b and Hall,24 proceed
with stereoinversion. For example, the borylated amides 17 and
19 undergo palladium-catalyzed cross-coupling with near
complete stereoinversion (Figure 5). The intermediate γ-borylated
amide (1R,3S)-8i was coupled with 2-methoxy-5-chloropyridine
(15); product 9g was isolated and subsequently converted to its
tetrafluoroborate salt 21 (66% overall). The latter gives crystals
suitable for X-ray analysis which confirms the structure as
(1R,3S)-21 and establishes that palladium-catalyzed cross-
coupling proceeds with stereoretention.
Figure 6. Unexpected influence of the amide substituent on the facility
of palladium-catalyzed cross-coupling.
Substrate reactivity is another aspect of the cross-coupling
chemistry that has attracted recent attention.25 For example,
Molander19 proposed that intramolecular hemilabile π-complex-
ation of palladium by a suitably disposed benzyl substituent was a
key element facilitating cross-coupling with stereoretention. In
contrast to the corresponding benzyl and phenethyl amides,
phenyl amide 22 (M = K or Cs) gives little or no cross-coupling
product under the conditions used in Table 2. For example, the
attempted cross-coupling of phenyl amide 22 with 1-bromo-
naphthalene gives only 20% (based on limiting aryl bromide) of
the cross-coupled product 23; in addition, 7c is isolated in 85%
yield (based on the amount of 22) from the reaction mixture after
oxidation with Oxone (Figure 6). The reproducible, low yield of
cross-coupled product initially suggested that the greater
rotational freedom and reach available to benzyl amides was a
necessary feature for efficient cross-coupling. However, the direct
competition of equal amounts of phenyl amide 22 and 8i (R1 =
Ph, R2 = (R)−CH(Me)Ph) for a limiting amount of 1-
bromonaphthalene 11 gave surprising results and raise doubt
about that explanation (Figure 6). The total yield of cross-
coupled products is high (90% based on the limiting aryl
bromide), and a near 1:1 mixture of 23 (48%) and 9c (42%) is
obtained along with commensurate amounts of the respective
alcohols 7c and 7i resulting from oxidation of the two residual
starting materials.
In summary, carbonyl-directed CAHB of γ,δ-unsaturated
substrate 5 proceeds with efficient π-facial discrimination to
introduce boron cis with respect to the amide functional group
consistent with two-point binding of the substrate as described in
a prior computational study;12 efficient re/si-site selectivity by the
chiral catalyst controls enantioselectivity. The ligand and the
borane employed have striking effects on the level and sense of
enantioinduction including in some cases enantioswitching.
C
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Letter
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Unusual group selectivity is seen in the CAHBs of the doubly γ,δ-
unsaturated substrates 5k and 5l for which the endocyclic alkene
preferentially undergoes reaction. The chiral γ-trifluoroborates
produced via CAHB undergo palladium-catalyzed Suzuki−
Miyaura cross-coupling with stereoretention. The amide
substituent influences the efficiency of the cross-coupling
reaction under the conditions examined, although the reasons
are not clear. Further studies are in progress.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jtakacs1@unl.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support for these studies
from the NIH (GM100101). The crystal structures reported
herein were determined by V. W. Day at the KU Small-Molecule
X-ray Crystallography Lab using instrumentation purchased with
funds from the NSF (CHE-0923449) and the University of
Kansas.
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D
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