Amide-directed catalytic asymmetric hydroboration of trisubstituted alkenes

Article abstract of DOI:10.1021/ja908257x

(Chemical Equation Presented) Rhodium-catalyzed hydroborations of trisubstituted alkenes are generally slow and often suffer from competing alkene isomerization. In contrast, the trisubstituted alkene moieties contained within the framework of a β,γ-unsat

Full text of DOI:10.1021/ja908257x

Published on Web 01/21/2010
Amide-Directed Catalytic Asymmetric Hydroboration of Trisubstituted
Alkenes
Sean M. Smith and James M. Takacs*
Department of Chemistry, UniVersity of NebraskasLincoln, Lincoln, Nebraska 68588-0304
Received September 28, 2009; E-mail: jtakacs1@unl.edu
Rhodium-catalyzed hydroboration1 often exhibits interesting
chemo-, regio-, and diastereoselectivity, at times nicely comple-
menting that obtained via the noncatalyzed reaction. Chiral orga-
noboranes are useful intermediates for a variety of subsequent
transformations.2 Some efficient chiral catalysts have been devel-
oped for the catalytic asymmetric reaction, but they are largely
limited to vinyl arene substrates.3,4 Furthermore, catalyzed hy-
droboration of trisubstituted alkenes is usually slow or suffers from
competing rhodium-catalyzed alkene isomerization.5,6 Thus, the
utility of catalytic asymmetric hydroboration is significantly
compromised by the present lack of substrate scope.
syn/anti-diastereoselectivity is also a relevant concern. The rhodium-
catalyzed asymmetric hydroboration of (E)-1 using ligand 3c affords
the anti-diastereomer of 2 in good yield (79%) after oxidative
workup (Figure 1). The level of diastereoselectivity is high; we
see none of the corresponding syn-diastereomer which is easily
recognized by 1H NMR analysis. The level of enantioselectivity is
also excellent; anti-diastereomer (3R,4S)-2 is obtained in 98% ee
as determined by chiral HPLC analysis. Using the same chiral ligand
(i.e., 3c), (Z)-1 affords the syn-diastereomer (3R,4R)-2, again with
high diastereo- and enantioselectivity (80% yield, 96% ee).13
Building on the Evans5c,d and Gevorgyan7 reports of carbonyl-
directed hydroboration, we found that the amide-directed asym-
metric hydroborations of (E)- and (Z)-disubstituted ꢀ,γ-unsat-
urated amides proceed with high regio- and enantioselectivity
using (BINOL)PN(Me)Ph in conjunction with Rh(nbd)2BF4.8
However, this catalyst proves somewhat less applicable to similar
trisubstituted alkene substrates, for example, (E)- and (Z)-1.
Although the level of enantioselectivity obtained is good
(89-90% ee), the reaction is slow and the yield rather modest
(Table 1, entry 1). The results obtained using (TADDOL)POPh
(3a) are more encouraging (entry 2).9
Table 1. Catalyzed Hydroborations of (E)- and (Z)-1 as a Function
of Ligand 3a-da
(E)-1
ee
(Z)-1
ee
Entry
Ligand
yield
yield
Figure 1. Selective formation of either Felkin or anti-Felkin acetate-aldol
products via stereospecific rhodium-catalyzed asymmetric hydroboration.
1
2
3
4
(BINOL)PN(Me)Ph
90
89
91
98
91
87
5
55
65
72
79
76
66
35
89
90
87
96
95
50
81
76
80
80
3a
3b
3c
3d
3a
3a
While the reactions of (E)- and (Z)-1 are quite efficient, it was
initially disappointing to find that other trisubstituted substrates gave
slightly lower levels of enantioselectivity under similar conditions.
Monitoring the course of the reaction of (E)-5 proved insightful.
The blue data points in Figure 2 show the yield (0) and
enantiomeric excess (b) of anti-6 as formed over time. In the initial
stages of the reaction, the anti-6 produced is near racemic; only
10-15% ee in the first hour. However, the enantiomeric purity
increases dramatically over time, and upon complete consumption
of starting materials, anti-6 is obtained in good, but obviously not
optimal, enantiopurity (80% yield, 92% ee). The improvement in
enantioselectivity over time suggests that a transient rhodium
complex is an active but poorly stereoselective catalyst at the early
stages of the reaction. Once replaced by the more highly selective
catalyst, the reaction proceeds with high levels of asymmetric
induction.14
5
6b
7c
a Unless otherwise specified, the reaction was run as follows: 1.0%
Rh(nbd)2BF4, 2.1% of the indicated ligand, 2.0 PinBH, 40 °C, 12-24 h.
b Uses 1.0% Rh(cod)2BF4. c Uses 0.5% [Rh(cod)Cl]2.
Seebach showed that adding substituents to the four phenyl
groups appended to the TADDOL core (e.g., structures 3a-d)
subtly changes the topography defined by this versatile chiral
scaffold.10 Screening a series of such ligands reveals that the tert-
butyl-substituted derivative 3c affords both a good yield of product
and high levels of enantioselectivity of the (E)- and (Z)-isomers of
substrate 1 (Table 1, entry 4, 96-98% ee).11,12 Substituting
[Rh(cod)Cl]2 as the source of the rhodium catalyst leads to markedly
lower reactivity and poor asymmetric induction (entry 7). A
trisubstituted alkene lacking the amide directing group, (E)-4, reacts
only sluggishly under these conditions (<20% conversion) high-
lighting the role of the carbonyl directing group and apparent two-
point binding of the unsaturated amide substrate to the catalyst.
Trisubstituted alkenes bearing nonidentical alkenyl substituents
generate two new stereocenters upon hydroboration, and therefore,
Switching from Rh(nbd)2BF4 to Rh(cod)2BF4 or increasing the
time for complexation with the chiral ligand (in this case, 3b) did
not significantly improve the results. Several “sacrificial” alkene
addends were screened based on the premise that a more reactive
alkene might be preferentially consumed by the nonselective catalyst
leaving the ꢀ,γ-unsaturated amide to react with the later formed
9
1740 J. AM. CHEM. SOC. 2010, 132, 1740–1741
10.1021/ja908257x  2010 American Chemical Society

C O M M U N I C A T I O N S
perhaps facilitated by carbonyl directing effects and two-point
binding of the substrate to the rhodium catalyst. The reactions of
stereoisomer substrates, for example, (E)- and (Z)-3, cleanly give
rise to diastereomeric anti- and syn-products; thus the rhodium-
catalyzed reaction is stereospecific. In addition, simple TADDOL-
derived phenyl monophosphite ligands in combination with
Rh(nbd)2BF4 afford highly enantioselective catalysts. These catalysts
provide an alternative methodology to prepare Felkin or anti-Felkin
acetate-aldol products and related derivatives that are obtainable
from the intermediate organoboranes. Further studies are in progress.
Acknowledgment. Financial support for this research from the
NSF (CHE-0809637) and Nebraska Research Initiative is gratefully
acknowledged. We thank T. A. George (UNL Chemistry) for the
loan of equipment, N. C. Thacker (UNL Chemistry) for some
preliminary experiments, and the NSF (CHE-0091975, MRI-
0079750) and NIH (SIG-1-510-RR-06307) for the NMR spectrom-
eters used in these studies carried out in facilities renovated under
NIH RR016544.
Figure 2. Comparing the yield of anti-6 (0) and its enantiomeric excess
(b) over time with (red) and without (blue) added norbornene.
selective catalyst. The red data points in Figure 2 show the yield
for the formation of anti-6 (0) and its enantiomeric excess (b) for
the reaction run in the presence of norbornene, a more reactive
alkene under the conditions employed. In its presence (10 mol
percent with respect to (E)-5), anti-6 is formed in a similar yield
but somewhat higher enantiopurity (80%, 95% ee) than the reaction
lacking norbornene.15
Supporting Information Available: Experimental procedures and
selected spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
References
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3160–3161. (b) Sim, H.-S.; Feng, X.; Yun, J. Chem.sEur. J. 2009, 15,
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(5) (a) Hadebe, S. W.; Robinson, R. S. Tetrahedron Lett. 2006, 47, 1299–
1302. (b) Edwards, D. R.; Crudden, C. M.; Yam, K. AdV. Synth. Catal.
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While more work is needed to understand the role of the addend,
these modified reaction conditions prove useful for a number of
substrates (Table 2). For example, both (E)-5 and its stereoisomer
(Z)-5 (entries 1-2) undergo hydroboration/oxidation with a high
degree of stereocontrol to afford anti-6 and syn-6 respectively, each
in 95% ee. It is interesting to note that, while the end results are
essentially identical, these stereoisomeric substrates each require a
different ligand for optimal results.16 Additionally, (Z)-5 requires
a higher catalyst load, 2% versus 1%, to effect complete conversion
within 24 h. Other (E)-substrates also give the anti-product with
good enantioselectivity (entries 3-4, 93 and 96% ee, respectively).
Other (Z)-substrates, including ones bearing somewhat more
sterically encumbering branched substituents, afford the syn-product
in good yield and high enantioselectivity (entries 5-7, 80-82%
yield, 91-95% ee).
Table 2. Other Trisubstituted Alkene Substrates Undergo Efficient
Catalytic Asymmetric Hydroborationa
(6) For example, reaction in fluorous media, see: Juliette, J. J. J.; Rutherford,
D.; Horvth, I. T.; Gladysz, J. A. J. Am. Chem. Soc. 1999, 121, 2696–2704.
(7) Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2003, 125, 7198–
7199.
(8) Smith, S. M.; Thacker, N. C.; Takacs, J. M. J. Am. Chem. Soc. 2008, 130,
3734–3735.
(9) Chiral monophosphites and monophosphoramidites are useful for the
asymmetric hydroboration of styrenes: Moteki, S. A.; Wu, D.; Chandra,
K. L.; Reddy, D. S.; Takacs, J. M. Org. Lett. 2006, 8, 3097–3100.
(10) Seebach, D.; Dahinden, R.; Marti, R. E.; Beck, A. K.; Plattner, D. A.;
Kuhnle, F. N. M. J. Org. Chem. 1995, 60, 1788–1799.
Entry
Ligand
RE
RZ
Yield (%)
ee (%)
1
3b
3d
3b
3c
3b
3c
3c
(CH2)3Ph
CH3
(CH2)4Ph
(CH2)2CH3
CH3
CH3
81
83
79
80
81
80
82
95
95
93
96
91
95
93
(11) A 2.1:1.0 P/Rh ratio is employed. At a 1:1 P/Rh ratio, the enantioselectivity
is diminished while, at a 4:1 P/Rh ratio, the yield suffers.
2b
3
(CH2)3Ph
CH3
(12) 11B NMR experiments carried out on a related substrate indicate that
rhodium-catalyzed decomposition of PinBH necessitates its use in excess,
consistent with a report by Robinson; see: Hadebe, S. W.; Robinson, R. S.
Eur. J. Org. Chem. 2006, 4898–4904.
(13) The enantiomeric syn- and anti-products are easily obtained using the
enantiomeric TADDOL-derived ligand. For example, using (3aS,8aS)-3c
(E)-1 gives the anti-diastereomer (3S,4R)-2 (80%, 98% ee) while (Z)-1
affords the syn-diastereomer (3S,4S)-2 (81%, 96% ee).
(14) The extent to which the poorly selective reaction competes is both a function
of substrate and ligand. Substrate (E)-5 is particularly problematic.
(15) Using 20 mol% norbornene does not further improve enantioselectivity,
but 5 mol% gives slightly lower ee (93%). The reaction of norbornene
itself (1.0% Rh(nbd)2BF4, 2.1% 3a, 2 equiv of PinBH) is complete within
1 h giving exo-norborneol quantitatively but only 20% ee.
(16) For example, the reaction of (E)-5 in combination with 3d afforded anti-6
in only 84% ee; (Z)-5 in combination with 3b afforded syn-6 in only 91%
ee.
4c
5b
6
CH3
CH2CH(CH3)2
CH(CH3)2
c-C6H11
CH3
CH3
7
a Unless otherwise specified the reaction conditions are as shown
above the table. b Carried out using 2% Rh(nbd)2BF4, 4.1% ligand 3,
and 10% norbornene. c Carried out in the absence of norbornene using
0.5% Rh(nbd)2BF4, 1.1% 3c, 40 °C.
In summary, the rhodium-catalyzed hydroborations of trisubsti-
tuted alkenes are generally slow or suffer competing isomerization.
In contrast, the trisubstituted alkene moieties contained within the
framework of a ꢀ,γ-unsaturated amide undergo facile reaction,
JA908257X
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J. AM. CHEM. SOC. VOL. 132, NO. 6, 2010 1741