Ligand-Controlled Regiodivergent Enantioselective Rhodium-Catalyzed Alkene Hydroboration

Article abstract of DOI:10.1002/anie.201903308

Regiocontrol in the rhodium-catalyzed boration of vinyl arenes is typically dominated by the presence of the conjugated aryl substituent. However, small differences in TADDOL-derived chiral monophosphite ligands can override this effect and direct rhodium-catalyzed hydroboration of β-aryl and β-heteroaryl methylidenes by pinacolborane to selectively produce either chiral primary or tertiary borated products. The regiodivergent behavior is coupled with enantiodivergent addition of the borane. The nature of the TADDOL backbone substituents and that of the phosphite moiety function synergistically to direct the sense and extent of regioselectivity and enantioinduction. Twenty substrates are shown to undergo each reaction mode with regioselectivity values reaching greater than 20:1 and enantiomer ratios reaching up to 98:2. A variety of subsequent transformations illustrate the potential utility of each product.

Full text of DOI:10.1002/anie.201903308

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Accepted Article
Title: Ligand-Controlled Regiodivergent Enantioselective Rhodium-
Catalyzed Alkene Hydroboration
Authors: Andrew J. Bochat, Veronika M. Shoba, and James M Takacs
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201903308
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10.1002/anie.201903308
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Ligand-Controlled Regiodivergent Enantioselective Rhodium-
Catalyzed Alkene Hydroboration
Andrew J. Bochat, Veronika M. Shoba, and James M. Takacs*
Dedicated to Professor David A. Evans
Abstract: Regiocontrol in the rhodium-catalyzed boration of vinyl
arenes is typically dominated by the presence of the conjugated aryl
substituent. However, small differences in TADDOL-derived chiral
monophosphite ligands can override this effect and direct rhodium-
catalyzed hydroboration of -aryl and -heteroaryl methylidenes by
pinacolborane to produce either chiral primary or tertiary borated
products selectively. The regiodivergent behavior is coupled with
enantiodivergent addition of the borane. The nature of the TADDOL
backbone substituents and that of the phosphite moiety function
synergistically to direct the sense and extent of regioselectivity and
enantioinduction. Twenty substrates undergo each reaction mode
with regioselectivities reaching greater than 20:1 and enantiomer
ratios reaching up to 98:2. A variety of subsequent transformations
illustrate the potential utility of each product.
The enantioselective preparation of chiral boronic esters is
of current interest due to their synthetic utility through a diverse
set of stereospecific transformations[1] and the growing
appreciation that boronic acid derivatives may hold significant
potential in medicinal chemistry.[2] Considerable progress has
been realized in the development of regioselective asymmetric
hydroboration[3],[4] and asymmetric borometallation[5] reactions,
most exploiting substrate control through use of activated alkenes
or directing groups. Catalysts that override inherent substrate bias
to selectively produce either of two regioisomers offer greater
synthetic utility. In addition to several recent examples of non-
Figure 1. Regiodivergent hydroboration of alkenes.
stereocontrolled borylative difunctionalizations via regiodivergent
borocupration,[6] the ligand-controlled regiodivergent palladium-
catalyzed hydroboration of terminal alkynes serves to illustrate
substrates
3 by pinacolborane (pinBH). This methodology
the potential. Prabhu[7] reported a bulky N-heterocyclic carbene
ligand promotes regioselective boropalladation to deliver boron to
the terminus; protonolysis leads to 1 (Figure 1). In contrast,
tricyclohexylphosphine effects delivery of boron to the internal
position leading to the regioisomeric product 2.
provides access to either rhodium-catalyzed -boration at the
unsubstituted terminus leading to the primary organoboronic ester
4 (si-face addition favored)[10] or -boration leading to the tertiary
organoboronic ester 5 (re-face addition favored)[11] using ligands
(R,R)-T1a or (R,R)-T2b, respectively.
Examples of chiral catalyst-controlled regiodivergent and
enantioselective reactions are less common.[8],[9] Herein, we
report that relatively modest structural changes to a chiral
TADDOL-monophosphite ligand results in a switch in both
regioselectivity and the sense of enantioselectivity in the catalytic
asymmetric hydroboration (CAHB) of -aryl methylidene
To probe the influence of structural changes in the ligand on
the - to -boration ratio (i.e., 4:5) and the levels of asymmetric
induction (i.e., re:si face addition), a series of TADDOL-derived
phosphite ligands were evaluated under a standard set of
screening conditions for the CAHB of 3a (Figure 2). The selected
TADDOL-derived ligands varied in the substituents at two
positions. The T1-T6 series of phosphites differ with respect to the
aryl appendages on the TADDOL backbone; for example, the aryl
appendages are 3,5-dimethylphenyl groups in the T1 series, 4-
methylphenyl groups in T2, etc. Next, each TADDOL backbone
was evaluated as its phenyl phosphite (i.e., T1a-T6a, R = C6H5)
and as its pentafluorophenyl phosphite (i.e., T1b-T6b, R = C6F5);
for example, T1a is the TADDOL-phenylphosphite bearing 3,5-
dimethylphenyl appendages and T1b is the corresponding
pentafluorophenyl phosphite.
[*]
Andrew J. Bochat, Dr. Veronika M. Shoba, Dr. James M. Takacs
Department of Chemistry and Nebraska Center for Integrated
Biomolecular Communication, University of Nebraska-Lincoln
807 Hamilton Hall, Lincoln, NE, 68588-0304 (USA)
E-mail: jtakacs1@unl.edu
Supporting information and the ORCHID identification number(s) for
the author(s) of this article can be found under:
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summarizes the results obtained using each ligand for
CAHB/oxidation of 4-substituted aryl methylidene derivatives 3b-
j. Halogenated derivatives generally work well affording
predominantly 4b-d using T1a and predominantly 5b-d using T2b.
Yields are in the range of 64-76% after oxidation with enantiomer
ratios (er) up to 98:2. The methyl benzoate derivative 3e, 4-
trifluoromethylphenyl derivative 3f, and 4-methylphenyl derivative
3g undergo -boration using the Rh-T1a catalyst to afford 4e (70%,
94:6 er), 4f (76%, 94:6 er), and 4g (63%, 98:2 er), respectively.
The more electron rich aromatic derivatives, 4-methoxyphenyl 3h
and 4-(dimethylamino)phenyl 3i, afford their respective -
borylated products 4h (57%, 95:5 er) and 4i (57%, 94:6 er) albeit
with lower regiocontrol. The Boc-protected 4-aminophenyl
derivative 3j exhibits good regioselectivity, but the yield of 4j (52%,
93:7 er) is again moderate.
The -boration results obtained using the T2b catalyst for
substrates 3b-f are like those described above for the T1a -
boration catalyst; yields for 5b-f range from 64-78% with
enantiomer ratios from 96:4 to 98:2 er. The two catalyst systems
differ to a greater extent with substrates bearing electron donating
substituents. In contrast to the moderate yields but good
enantioselectivity using the T1a catalyst, 3g-i (especially the 4-
methoxyphenyl and 4-(dimethylamino)phenyl derivatives 3h and
3i) give somewhat higher yields but exhibit attenuated
enantioselectivity for -borated 5g (66%, 91:9 er), 5h (76%, 86:14
er) and 5i (60%, 80:20 er) using T2b.
Figure 3B illustrates the results obtained with several more
highly functionalized aryl derivatives including several
methylidenes bearing heteroaryl substituents. Using the T1a-
catalyst, the 3-methoxyphenyl (3k), 3-chlorotolyl (3l), 3,4-
methylenedioxyphenyl (3m), and indole derivative (3n) afford 4k-
n in 60-75% yield and up to 97:3 er. The thienyl and benzofuran
derivatives 3o-q give -borylated products in more moderate
yields (50-59%) due to higher levels of -boration for 4o and 4q,
and higher levels of the reduction product for 4p. The
enantioselectivity is also lower for these substrates, ranging from
90:10 er for 4o to 65:35 er for 4q. In contrast, the 3- and 2-thienyl
derivatives are efficient substrates in the T2b-catalyzed reaction
affording 5o (85%, 98:2 er) and 5p (71%, 96:4 er), respectively.
The benzofuran derivative 3q provides good regio- and
enantioselectivity for 5q (40%, 94:6 er); the moderate yield
reflects competing reduction in this case.[4a, 14] The yields, regio-
and enantioselectivities obtained for 5k (60%, 94:6) and 5l (65%,
95:5) are similar to those observed for the corresponding -
borated products. However, substrates bearing multiple donor
groups can give surprising results; 5k and 5l, for example, form
with the opposite sense of stereoinduction (see SI).
Several other limitations are found (Figure 3C). Substrates
bearing ortho-substituted aryl groups (e.g., 3r and 3s) do not
exhibit regio- or enantioswitching. Both catalyst systems provide
almost exclusively -borated products with little asymmetric
induction. Unlike aryl substituted methylidenes 3a-s, the alkyl-
substituted methylidene 3t undergoes -boration using the T1a-
catalyst to give 5t (85%, 95:5 er);[4a] less than 5% of the -
borylated product is formed. -Boration of 3t giving 5t (58%, 92:8
er) remains the major pathway using ligand T2b, although the
percentage of -boration increases to 32%.
Figure 2. Comparison of phenyl and pentafluorophenyl phosphites for a series
of TADDOL backbone derivatives. Notes: the structures shown correlate to the
major enantiomer from HPLC, except the product from T5b which arises from
the opposite sense of -facial selectivity.
Phenylphosphite T1a (Ar
= 3,5-Me2C6H3) displays a
significant preference for enantioselective -boration giving
predominantly 4a (6:1 :); the major product reflects addition of
pinBH to the si-face of the substrate (96:4 er). In contrast, the
reaction run using phenylphosphite T2a (Ar = 4-MeC6H4) shows
a slight preference for -boration (1:1.1 :), and the major
regioisomer 5a arises via predominant addition of pinBH to the re-
face (93:7 er). The results show that the aryl substituents
appended to the TADDOL backbone have a significant effect on
the sense of enantioinduction and regioselectivity. The nature of
the phosphite substituent also plays a significant role. Compared
to the phenylphosphites T1a-T3a, the corresponding
pentafluorophenyl phosphites T1b-T3b give enhanced levels of
-boration. Among the latter, T2b (Ar = 4-MeC6H4) gives the
highest level (1:10 :) and enantioselectivity favoring re-face
addition (97:3 er).[12] Ligands T4-T6 generally are less selective
than the other structural analogs examined. The 4-tBuC6H4-
TADDOL derivative T5b is a curious case. It affords the -boration
product 5a with moderate regioselectivity (1:4 :), but in contrast
to other -selective ligands (e.g., T2b), pinBH adds to the si-face
of the alkene (96:4 er).
Having identified the , si-face selective ligand T1a and ,
re-face selective ligand T2b, a series of methylidenes were
examined to probe the substrate scope of each.[13] Figure 3A
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Figure 3A
a
X =
F
Cla
Bra
CO2Meb
CF3
CH3
OMe
NMe2
N(H)Boc
4b 74%,
97:3 er
4c 65%
98:2 er
(<5% )
4d 75%
97:3 er
(<5% )
4e 70%
94:6 er
(<5% )
4f 76%
94:6 er
(<5% )
4g 63%
98:2 er
(8% )
4h 57%
95:5 er
4i 57%
94:6 er
(14% )
4j 52%
93:7 er
(5% )
(<5% )
(19% )
5b 73%,
96:4 er
(13% )
5c 64%
98:2 er
(<5% )
5d 76%
96:4 er
(8% )
5e 78%
96:4 er
(<5% )
5f 75%
98:2 er
(7% )
5g 66%
91:9 er
(18% )
5h 76%
86:14 er
(5% )
5ic 60%
80:20 er
(5% )
5j 65%
94:6 er
(5% )
Figure 3B
Figure 3C
Figure 3A-C. Substrate scope: A. 4-Substituted phenyl derivatives; B. 3-Substituted phenyl and heteroaromatic derivatives; C. ortho-Substituted aryl and alkyl
b
derivatives. Reported yields and enantiomer ratios are for the isolated alcohol after oxidation. DG = (Me2C=N-O). Notes: a used 1:1 Rh:L ratio; yield of boronic
ester before oxidation with NaBO3-H2O; c Compounds 5i, 5k, and 5l exhibited an opposite sign of optical rotation and order of elution on chiral HPLC; see SI.
The synthetic versatility of enantioselective, regiodivergent
CAHB is demonstrated by the selected conversions of 4a and 5a
to 6-21 (Figure 4).[15] Both the primary and tertiary pinacol boronic
esters are converted to the corresponding cesium[16] or
potassium[17] trifluoroborate salts, 6a and 7a respectively, in 97-
98% yield. Similarly, boronic acids 6b and 7b and the
corresponding N-methyliminodiacetic acid (MIDA) esters[18] 6c
and 7c are readily accessible (62-72%). The one-carbon
homologated boronic esters 8 (75%) and 9 (55%) are obtained
via the Matteson protocol.[19] In the case of the tertiary boronic
ester 5a, the reaction proceeds with stereoretention to afford (R)-
9 (98:2 er). Hydrolysis of the primary boronic ester 4a to the
boronic acid, followed by Raney Nickel cleavage of N-O bond
affords chiral oxaborolane 10 (71%). Reduction of the oxime C-N
double bond in 5a with NaCNBH3 affords 11 (77%); the reduction
works equally as well for 4a (results not shown, see SI).
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In addition to forming boron derivatives 6–11, other
transformations highlight the flexible and diverse ways in which
4a and 5a can be elaborated. Using Aggarwal’s modification of
the Zweifel olefination,[20] the primary boronic ester 4a is
converted to ketone 12 (57%). For the tertiary boronic ester 5a,
rhodium-catalyzed 1,2-addition to 4-nitrobenzaldehyde followed
by DMP oxidation affords ketone 13 (59%, 96:4 er).[21] Ketones 12
and 13 undergo acid-catalyzed cyclizations to the chiral
dihydrooxazine 14 (39%) and chiral isoxazoline 15 (53%, 96:4 er),
respectively.
The transition-metal-free sp2-sp3 cross-couplings of
electron-rich aromatic systems convert 4a and 5a to the thienyl
derivatives 16 (70%) and 17 (84%), respectively.[22] Treatment of
the primary boronic ester 4a with bromobenzene under typical
palladium-catalyzed Suzuki cross-coupling conditions[5c] affords
18, a product that is not readily accessible using the transition-
metal-free
procedure
employed
for
thienylation.
Protodeboronation of the tertiary boronic ester 5a affords 19 (90%,
98:2 er).[23] In our hands, the common amination procedure[24] is
only successful for the primary boronic ester 4a; a moderate yield
of the chiral 1,3-aminoalcohol derivative 20 (43%) is obtained.
Oxidation of C-B bond in the tertiary boronic ester 5a followed by
N-O bond cleavage gives chiral 1,2-diol 21 (86%, 99:1 er).
In summary, the CAHB of styrene and related vinyl arenes
(e.g., -methylstyrene or indene derivatives) often leads to
formation of the chiral secondary benzylic borated products. The
observed regioselectivity is usually attributed to the formation of
an intermediate 3-complex with the aryl substituent.[25] However,
aryl methylidenes (e.g., -methylstyrene) generally give the
primary boronic ester. The chiral, tertiary benzylic regioisomer is
not formed, presumably due to hindrance in forming the
corresponding 3-complexed intermediate. We find that rhodium-
catalyzed hydroboration of -aryl methylidenes affords either the
chiral primary or tertiary boronic ester depending on the TADDOL-
derived phosphite ligand employed. Twenty substrates are shown
to undergo regioselective reaction using each catalyst system.
Regioselectivities reach levels greater than 20:1 and enantiomer
ratios up to 98:2 are obtained. Conversions of 3a to 6-21 illustrate
the potential synthetic utility of regiodivergent CAHB.
In terms of the mechanism, the aryl substituents appended
to the TADDOL backbone as well as the nature of the
arylphosphite moiety act synergistically to affect the sense of
regioselectivity and enantioinduction. This appears to be due, at
least in part, to an electronic effect because the pentafluorophenyl
substituent is not unique in promoting -boration. For example,
Reaction Conditions: (a) CsF or KF, MeCN/H2O; (b) BCl3, DCM; (c) BCl3, DCM;
MIDA, DMSO; (d) LiCH2Cl, -78 oC Et2O; (e) BCl3, DCM; Raney Ni, H2,
MeOH/THF; (f) NaBH3CN, MeOH/HCl; (g) LiC(OEt)=CH2, THF, -78 oC; I2;
NaOMe, MeOH; (h) KF, MeCN/H2O; O2NC6H4CHO, 5 mol% [Rh(cod)Cl]2,
the corresponding T2 ligand bearing either
a
(4-
dioxane, 80 ̊
C; DMP, DCM; (i) 12 or 13, HCl/H2O/MeOH, 40 oC; (j) thiophene,
nBuLi, THF, -78 oC; NBS; (k) PhBr, 15 mol% Pd(OAc)2, 15 mol% BINAP, KOH,
THF/H2O, 100 oC; (l) TBAF, toluene; (m) MeON(H)Li, THF, 60
̊C; Boc2O; (n)
H2O2, NaOH, MeOH/H2O; Raney Ni, H2
trifluoromethyl)phenyl or a 4-cyanophenyl phosphite substituent
also exhibit regioswitching, although the levels of regio- and
enantioselectivity are not as high. Deuterium labeling experiments
with T1a and T2b show that addition of H (D) is rapid and
reversible, leading to competitive H/D-exchange in the substrate
using either regiodivergent catalyst.[26] Several hypotheses that
might account for the coupled regio- and enantiodivergent CAHB,
effected by ostensibly similar catalyst systems, are currently
under investigation.
Figure 4. Versatility of the primary and tertiary boronic esters 4a and 5a [DG =
(Me2C=N-O)].
Acknowledgements
Funding from the NIH National Institutes of General Medical
Sciences (R01-GM100101) is gratefully acknowledged.
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Keywords: regiodivergent
catalyzed hydroboration • catalysis
•
enantiodivergent
•
rhodium-
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10.1002/anie.201903308
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Andrew J. Bochat, Veronika M. Shoba,
James M. Takacs*
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Ligand-Controlled Regiodivergent
Enantioselective Rhodium-Catalysed
Alkene Hydroboration
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Regiodivergent with enantioselectivity included! Small changes in the structure of the
TADDOL-derived chiral monophosphite ligand direct the rhodium-catalyzed
hydroboration of methylidenes to give either primary or tertiary chiral boronic esters.
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