Exploiting self-assembly for ligand-scaffold optimization: Substrate-tailored ligands for efficient catalytic asymmetric hydroboration

Article abstract of DOI:10.1002/anie.200703127

(Chemical Equation Presented) Mix and match: A self-assembled ligand library (SAL XY) affords a wide range of R/S ratios in Rh-catalyzed asymmetric hydroboration (see scheme; nbd = 2,5-norbornadiene, R* is a chiral substituent). Ligand-scaffold optimization reveals "substrate- tailored" ligands that afford high regio- and enantioselectivity for a variety of ortho-substituted styrene derivatives.

Full text of DOI:10.1002/anie.200703127

Communications
DOI: 10.1002/anie.200703127
Self-Assembled Ligands
Exploiting Self-Assembly for Ligand-Scaffold Optimization: Substrate-
Tailored Ligands for Efficient Catalytic Asymmetric Hydroboration**
Shin A. Moteki and James M. Takacs*
Table 1: TADDOL-derived subunits (S,S)- and (R,R)-1A–P are used to
form (SS,RR)-SAL XY by chirality-directed self-assembly.
Rhodium-catalyzed hydroboration has attracted much inter-
est, in part owing to the complementary regio- and diaste-
reoselectivity obtained with certain substrates compared to
the uncatalyzed process.[1,2] The novel regiocontrol is exem-
plified in the rhodium-catalyzed hydroborations of vinyl
arenes, which, in contrast to the uncatalyzed reaction,
introduce boron at the benzylic position. For example, styrene
affords 1-phenylethanol after hydroboration and oxidation.
Several catalyst systems exhibit both high regio- and enan-
X=O
X=CH2O
Ar2
1,3-Ar1
1,4-Ar1
Ar2
1,3-Ar1
1,4-Ar1
tioselectivity for the catalytic asymmetric hydroboration of
[3]
styrene and some ofits substituted derivatives.
However,
–
A
C
E
B
D
F
–
I
J
the reaction is sensitive to both steric and electronic factors,
and for the reactions of ortho-substituted styrene derivatives,
an important subclass ofthese substrates, high levels of
enantioselection have proved elusive.[4] Herein, we report the
use of self-assembled ligands (SALs) for the catalytic
asymmetric hydroboration ofa afmily of ortho-substituted
styrene derivatives varying in steric and electronic character.
Several strategies for preparing novel ligands by self-
assembly have emerged as promising approaches to unsolved
problems in catalysis.[5,6] We reported a novel method for the
in situ preparation ofchiral ligand libraries by chirality-
directed self-assembly, a strategy by which the topography at
the catalytic site is varied over a wide range by subtle changes
in the ligand scaffold.[7]
1,2-
1,3-
1,4-
1,2-
1.3-
1,4-
K
M
O
L
N
P
G
H
A mixture of( S,S)- and (R,R)-1A–P readily undergoes
chirality-directed self-assembly upon addition of zinc(II) to
yield the heterodimeric (SS,RR)-SALs.[9] In the present study,
we found it convenient to first prepare the (S,S)- and (R,R)-
homodimers from 1A–P, which upon mixing rapidly equili-
brate to the (SS,RR)-heterodimer. For example, mixing
[{(S,S)-1D}2Zn] with [{(R,R)-1C}2Zn] affords (SS,RR)-
SAL DC (Scheme 1). The latter can be isolated; however,
Bifunctional subunits (S,S)- and (R,R)-1A–P exploit a
chiral bisoxazoline to direct the self-assembly, substituted
with a series ofphenylmethyl or biphenylmethyl tethers
terminating in a phosphite ligating group derived from
TADDOL[8] ((4R,5R)-a,a,a’,a’-tetraphenyl-2,2-dimethyl-1,3-
dioxolan-4,5-dimethanol, TDL). The subunits differ with
respect to the tether substitution pattern (Table 1).
[*] S. A. Moteki, Prof. J. M. Takacs
Department ofChemistry
University ofNebraska-Lincoln
Lincoln, NE 68588-0304 (USA)
Fax: (+1)402-472-9402
Scheme 1. Heterodimer (SS,RR)-SAL DC is readily prepared by ligand
exchange ofthe appropriate homodimers.
E-mail: jtakacs1@unl.edu
Homepage: http://www.chem.unl.edu/index.shtml
[**] Financial support for this research from the Nebraska Research
Initiative, ONR (05PR07809-00) and NSF (CHE-0316825) is grate-
fully acknowledged. We thank T. A. George (UNL Chemistry) for the
loan ofequipment, N.C. Thacker and X. Zhang (UNL Chemistry) for
preparing some ligands, and the NSF (CHE-0091975, MRI-0079750)
and NIH (SIG-1-510-RR-06307) for the NMR spectrometers used in
these studies carried out in facilities renovated under NIH
RR016544.
the SALs and their derived catalyst systems are typically
generated in situ and used without isolation.[10] Combining
various pairs of( S,S)- and (R,R)-1A–P quickly affords a
library ofunique ( SS,RR)-SAL XY differing only in scaffold
structure.
The hydroboration of2-methoxystyrene ( 2a) with pina-
colborane (PBH) was screened using [{Rh(nbd)Cl}2] (nbd =
2,5-norbornadiene) in combination with 162 in situ prepared
SAL XY [Eq. (1), DME = dimethoxyethane].[11] Remarka-
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
894
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 894 –897

Angewandte
Chemie
Table 2: {RhICl} and {RhIBF4} catalyst precursors require different ligand
scaffolds for the hydroboration of 2-methoxystyrene (2a).[a]
Ligand
[{Rh(nbd)Cl}2]
[Rh(nbd)2BF4]
SAL DC
SAL HC
SAL CC
SAL CD
SAL CH
SAL DD
SAL HH
96 (98)
86 (94)
75 (88)
92 (94)
–
78 (96)
95 (98)
84 (97)
–
86 (97)
–
79 (90)
–
93 (94)
[a] Conditions: see Equation (1). The results listed indicate % ee (% a-
isomer).
bly, this readily accessible, focused ligand library affords R:S
enantiomeric ratios ranging from 98:2 to 35:65 (Figure 1).[12]
Analysis ofthese data reveals that with efw exceptions the
most efficient catalysts combine SALs containing only phenyl
phosphite subunits 1A–H (65 to 96% ee (R)). The SALs
containing only benzyl phosphite subunits (1I–P) afford
lower levels ofenantioselectivity (30% ee (S) to 40% ee (R)).
Mixed phenyl/benzyl combinations tend to fall in between.
steric and electronic factors in the substrate.[14] The avail-
ability of a range of different SAL scaffolds proves useful for
the rapid optimization of different catalysts for individual
substrates. High regio- and enantioselectivity can be obtained
for each substrate within the series of ortho-substituted
styrene derivatives 2a–e using in situ generated
[(SAL XY)Rh(nbd)BF4] catalysts derived from the subunits
1A–H.[15] The best results for each substrate are highlighted in
Table 3 (entries in boldface); these results are for preparative
reactions run on a 1-mmol or greater scale. The regio- and
enantioselectivities found in preparative reactions are similar
to those obtained under the screening conditions (Æ 1–2%);
the yields ofisolated product range rfom 82–98%. For
comparison, Table 3 also gives the results achieved using two
equivalents of(TDL)POPh (53–81% ee), the monodentate
Table 3: Different ligand scaffolds are used to achieve optimal results for
substrates 2a–e with [(SAL XY)Rh(nbd)BF4] catalysts.[a]
Figure 1. Wide variation in enantioselectivity is observed for the SAL/
[{Rh(nbd)Cl}2]-catalyzed asymmetric hydroboration of2-methoxy-
styrene (2a) as a function of ligand scaffold.
Varying the catalyst precursor reveals other remarkable
features of the role of scaffold structure in catalyst optimi-
I
zation. The nature ofthe Rh catalyst precursor can be an
important factor in catalytic asymmetric hydroboration.[13]
Having obtained data using [{Rh(nbd)Cl}2], the reaction of
2-methoxystyrene (2a) was carried out using [Rh(nbd)2BF4]
in combination with each ofthe 64 possible SALs rfom
derived from subunits 1A–H. As summarized in Table 2,
different optimal ligand scaffolds were found for each catalyst
precursor. SAL DC (96% ee) was best for [{Rh(nbd)Cl}2]
while SAL HC (95% ee) proved best for [Rh(nbd)2BF4]. It is
interesting to note that while subunit (R,R)-1C is present in
both optimal SALs, the SAL combination containing only 1C
(i.e., the pseudo-C2-symmetric SAL CC) is less effective with
either catalyst precursor. In addition, SAL DC is more
selective than its closely related diastereomer SAL CD, and
SAL HC is more selective than its corresponding diastereo-
mer SAL CH.
Ligand
3a
3b
3c
3d
3e
(R=OMe) (R=Me) (R=CF3) (R=Cl) (R=F)
SAL HC
SAL EE
SAL ED
SAL HG
94 (99)[b]
66 (93)
75 (96)
91 (95)
87 (86)
91 (95)[b]
85 (93)
87 (81)
73 (78)
92 (93)
66 (66)
76 (49)
91 (95)[b]
53 (72)
69 (73)
83 (97)
78 (96)
73 (87)
68 (67)
76 (88)
91 (92)[b]
68 (78)
93 (92)[b] 77 (73)
(TDL)POPh 81 (91)
77 (83)
69 (93)
53 (76)
72 (92)
literature[c] 82 (99)
[a] Conditions: see Equation (1). The results indicate % ee (% a-isomer).
[b] Reaction run on a 1-mmol scale. [c] The best results previously
reported for each substrate; see reference [7] for details.
Prior studies have shown that the efficiency of rhodium-
catalyzed asymmetric hydroboration is quite sensitive to
Angew. Chem. Int. Ed. 2008, 47, 894 –897
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
895

Communications
and then filtered. The filtrate was extracted with diethyl ether (3 ”
15 mL) and the combined organics were dried (anhydrous Na2SO4),
filtered, and concentrated. Chromatography on silica (10% 1:9
EtOAc/Hex) gives 1-(2-methoxyphenyl)ethanol (3a, 194 mg, 98%)
as a clear oil: capillary GC analysis (J&W Scientific 30 m ” 0.25 mm
ID Cyclosil b, 1208C (1 min hold) to 1308 at 18minÀ1 then to 1658 at
28minÀ1) found peaks at 21.19 (97.2%, (R)-3a) and 23.55 (2.8%, (S)-
chiral phosphite moiety present in each SAL, as well as the
best results previously reported for each substrate. For
substrates 2a (R = OMe) and 2c–e (R = CF3, Cl, F), the
SAL identified is the most selective catalyst reported to date.
For 2b (R = Me), the best SAL and literature results are
nearly equivalent.
The importance ofthe heterodimeric zinc complex as a
structural element for the SALs is further illustrated by
comparing three diastereomeric ligands derived from (S,S)-
and (R,R)-1E. Even though the ligating groups and tethers
are identical in all three zinc complexes, the results obtained
in the hydroboration of2-methylstyrene ( 2b) vary signifi-
cantly. In contrast to the (SS,RR)-heterodimer, SAL EE
(91% ee, 95% a-3b), the diastereomeric (SS,SS)- and
(RR,RR)-homodimers, that is, [{(S,S)-1E}2Zn] and [{(R,R)-
1E}2Zn], exhibit low reactivity and lower selectivity: 87% ee
(84% a-3b) and 79% ee (82% a-3b), respectively.
In summary, a series ofTADDOL phosphite-bearing
SALs, readily prepared in combinatorial arrays by chirality-
directed self-assembly, provides a focused ligand library for
RhI-catalyzed hydroboration. These SALs exhibit the unique
feature of achieving high enantioselectivity through the subtle
manipulation ofthe chiral catalytic pocket by small system-
atic changes in the ligand scaffold, an approach not available
with classic ligand designs. The ligands differ only in scaffold
structure, yet the enantioselectivity obtained in catalytic
asymmetric hydroboration of2-methoxystyrene varies rfom
96% ee favoring the R-configuration to 30% ee favoring S.
{RhICl} and {RhIBF4} catalyst precursors and different sub-
strates require different ligand scaffolds to achieve success.
Nevertheless, {(SAL XY)RhI} catalysts afford high regiose-
lectivity (92–99% a3) and enantioselectivity (91–96% ee)
across a series of ortho-substituted styrenes varying in
electronic character and steric demand. Thus, a facile
method of self-assembly is exploited to fine tune catalysts
by ligand scaffold optimization, improving substrate general-
ity in a reaction that has thus far exhibited rather limited
substrate scope. Studies directed toward understanding the
structural basis for the wide variation in selectivity as a
function of ligand scaffold (i.e. the structure–activity relation-
ship ofthese ligands) are in progress.
1
3a); H NMR (400 MHz, CDCl3): d = 7.39 (1H, dd, J = 7.5, 1.4 Hz),
7.37–7.26 (1H, dt, J = 8.2, 1.6 Hz), 7.00 (1H, t, J = 7.5 Hz), 6.90 (1H,
d, J = 8.2 Hz), 5.15–5.11 (1H, q, J = 13.0, 6.5 Hz), 3.88 (3H, s)
1.53 ppm (3H, d, J = 6.5 Hz); 13C NMR (100 MHz, CDCl3): d = 156.5,
133.6, 128.2, 126.1, 120.8, 110.4, 66.4, 55.3, 23.0 ppm; [a]2D5 = + 25.88
(c = 1.4 g(100mL)À1, CHCl3).
Received: July 13, 2007
Revised: September 13, 2007
Published online: December 21, 2007
Keywords: asymmetric synthesis · combinatorial chemistry ·
.
hydroboration · self-assembly · stereoselective catalysis
[1] D. Männig, H. Nöth, Angew. Chem. 1985, 97, 854 – 855; Angew.
Chem. Int. Ed. Engl. 1985, 24, 878 – 879.
[2] Recent reviews: a) A.-M. Carroll, T. P. OꢀSullivan, P. J. Guiry,
Adv. Synth. Catal. 2005, 347, 609 – 631; b) C. M. Vogels, S. A.
Westcott, Curr. Org. Chem. 2005, 9, 687 – 699; c) P. J. Guiry, C. P.
Saunders, Adv. Synth. Catal. 2004, 346, 497 – 537; d) C. M.
Crudden, D. Edwards, Eur. J. Org. Chem. 2003, 4695 – 4712.
[3] a) S. A. Moteki, D. Wu, K. L. Chandra, D. S. Reddy, J. M.
Takacs, Org. Lett. 2006, 8, 3097 – 3100; b) F. Y. Kwong, Q. Yang,
T. C. W. Mak, A. S. C. Chan, K. S. Chan, J. Org. Chem. 2002, 67,
2769 – 2777; c) C. Köllner, A. Togni, Can. J. Chem. 2001, 79,
1762 – 1774; d) A. Schnyder, L. Hintermann, A. Togni, Angew.
Chem. 1995, 107, 996 – 998; Angew. Chem. Int. Ed. Engl. 1995,
34, 931 – 933; e) A. Togni, C. Breutel, A. Schnyder, F. Spindler,
H. Landert, A. Tijani, J. Am. Chem. Soc. 1994, 116, 4062 – 4066.
[4] a) H. Doucet, E. Fernandez, T. P. Layzell, J. M. Brown, Chem.
Eur. J. 1999, 5, 1320 – 1330; b) T. Hayashi, Y. Matsumoto, Y. Ito,
J. Am. Chem. Soc. 1989, 111, 3426 – 3428; c) T. Hayashi, Y.
Matsumoto, Y. Ito, Tetrahedron: Asymmetry 1991, 2, 601 – 612.
[5] For reviews highlighting recent strategies, see: a) S. J. Reyes, K.
Burgess, Chem. Soc. Rev. 2006, 35, 416 – 423; b) A. J. Sandee,
J. N. H. Reek, Dalton Trans. 2006, 3385 – 3391; c) B. Breit,
Angew. Chem. 2005, 117, 6976 – 6986; Angew. Chem. Int. Ed.
2005, 44, 6816 – 6825; d) M. J. Wilkinson, P. W. N. M. van Leeu-
wen, J. N. H. Reek, Org. Biomol. Chem. 2005, 3, 2371 – 2383.
[6] For more recent examples, see: a) C. Machut, J. Patrigeon, S.
Tilloy, H. Bricout, F. Hapiot, E. Monflier, Angew. Chem. 2007,
119, 3100 – 3102; Angew. Chem. Int. Ed. 2007, 46, 3040 – 3042;
b) S. Chikkali, D. Gudat, M. Niemeyer, Chem. Commun. 2007,
981 – 983; c) A. J. Sandee, A. M. Van der Burg, J. N. H. Reek,
Chem. Commun. 2007, 864 – 866; d) M. L. Clarke, J. A. Fuentes,
Angew. Chem. 2007, 119, 948 – 951; Angew. Chem. Int. Ed. 2007,
46, 930 – 933; e) M. Kuil, P. E. Goudriaan, P. W. N. M. Van Leeu-
wen, J. N. H. Reek, Chem. Commun. 2006, 4679 – 4681; f) Y. Liu,
C. A. Sandoval, Y. Yamaguchi, X. Zhang, Z. Wang, K. Kato, K.
Ding, J. Am. Chem. Soc. 2006, 128, 14212 – 14213; g) S. Jonsson,
F. G. J. Odille, P.-O. Norrby, K. Wärnmark, Org. Biomol. Chem.
2006, 4, 1927 – 1948; h) F. Chevallier, B. Breit, Angew. Chem.
2006, 118, 1629 – 1632; Angew. Chem. Int. Ed. 2006, 45, 1599 –
1602; i) M. Weis, C. Waloch, W. Seiche, B. Breit, J. Am. Chem.
Soc. 2006, 128, 4188 – 4189; j) X.-B. Jiang, L. Lefort, P. E.
Goudriaan, A. H. M. de Vries, P. W. N. M. van Leeuwen, J. G.
de Vries, J. N. H. Reek, Angew. Chem. 2006, 118, 1245 – 1249;
Angew. Chem. Int. Ed. 2006, 45, 1223 – 1227.
Experimental Section
[(SAL HC)Rh(nbd)BF4]-catalyzed asymmetric hydroboration of2-
methoxystyrene:
A solution of[{( S,S)-1H}2Zn] (10.0 mg, 1.4 ”
10À2 mmol) and [{(R,R)-1C}2Zn] (10.0 mg, 1.4 ” 10À2 mmol) in
CH2Cl2 (10 mL) was stirred at ambient temperature (10 min), and
then a solution of[Rh(nbd) 2BF4] (9.7 mg, 2.6 ” 10À2 mmol) in CH2Cl2
(5 mL) was added. The resulting mixture was stirred at ambient
temperature (0.5 h), after which the volatile solvent was removed
under vacuum. The residue was dissolved in DME (10 mL), stirred
(0.5 h), and then a solution of2-methoxystyrene ( 2a, 174.0 mg,
1.30 mmol) in DME (2.0 mL) and powdered 4-Š molecular sieves (ca.
0.5 g) were added. The resulting mixture was cooled (08C) and a
solution ofpinacolborane (199.0 mg, 1.56 mmol) in DME (4.0 mL)
added dropwise. The reaction mixture was gradually warmed to room
temperature and stirred (12 h). Afterwards, the mixture was again
cooled (08C) and quenched by the addition ofMeOH (10 mL),
NaOH(aq) (3.0m, 15 mL), and H2O2(aq) (1 mL ofa 30% solution).
The ice bath was removed, and the resulting mixture stirred (3 h, RT)
896
www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 894 –897

Angewandte
Chemie
[7] a) J. M. Takacs, D. S. Reddy, S. A. Moteki, D. Wu, H. Palencia, J.
Am. Chem. Soc. 2004, 126, 4494 – 4495; b) J. M. Takacs, K.
Chaiseeda, S. A. Moteki, D. S. Reddy, D. Wu, K. Chandra, Pure
Appl. Chem. 2006, 78, 501 – 509.
[8] J. Sakaki, W. B. Schweizer, D. Seebach, Helv. Chim. Acta 1993,
76, 2654 – 2665.
[9] a) J. M. Takacs, P. M. Hrvatin, J. M. Atkins, D. S. Reddy, J. L.
Clark, New J. Chem. 2005, 29, 263 – 265; b) J. M. Atkins, S. A.
Moteki, S. G. DiMagno, J. M. Takacs, Org. Lett. 2006, 8, 2759 –
2762.
catalysts generally affording higher regioselectivity. We find no
strong correlation between regio- and enantioselectivity, how-
ever, there seems to be a loose correlation between enantiose-
lectivity and conversion/yield under the conditions examined.
[13] A. M. Segarra, E. Daura-Oller, C. Claver, J. M. Poblet, C. Bo, E.
Fernandez, Chem. Eur. J. 2004, 10, 6456 – 6467, and references
therein.
[14] E. Daura-Oller, A. M. Segarra, J. M. Poblet, C. Claver, E.
Fernandez, C. Bo, J. Org. Chem. 2004, 69, 2669 – 2680, and
references therein.
[10] (SS,RR)-SAL DC was combined with [{Rh(nbd)Cl}2] to gener-
ate the heterobimetallic complex [(SAL DC)Rh(nbd)Cl]. Its
31P NMR spectrum, obtained after addition of a stoichiometric
amount of1,10-phenanthroline (see reefrence [2i]), shows a
doublet at d = 112.8 ppm (JP, Rh = 250 Hz).
[11] In contrast to the results found using pinacol borane, the use of
catechol borane gave low levels ofasymmetric induction.
[12] The regioselectivity also varies as a function of SAL scaffold
structure, but to a lesser extent (70–99% a-3), with {RhIBF4}
[15] While [Rh(nbd)2BF4] is an effective catalyst precursor, other
complexes can give comparable or superior results for some
substrates in Table 3. For example, slightly higher enantioselec-
tivity can be obtained for 2-methoxystryene (96% ee, 98% a-
3a) using [{Rh(nbd)Cl}2] and SAL (SS,RR)-SAL DC and for 2-
(trifluoromethyl)styrene (94% ee, 92% a-3c) using [Rh-
(cod)2OTf] using (SS,RR)-SAL CH.
Angew. Chem. Int. Ed. 2008, 47, 894 –897
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
897