Remarkable levels of enantioswitching in catalytic asymmetric hydroboration

Article abstract of DOI:10.1021/ol101932q

TADDOL-derived phosphites and phosphoramidites are effective ligands for rhodium-catalyzed asymmetric hydroborations of β,γ-unsaturated amides, achieving up to 99% ee. However, the sense of stereoinduction, R or S, is surprisingly dependent on rather subt

Full text of DOI:10.1021/ol101932q

ORGANIC
LETTERS
2010
Vol. 12, No. 20
4612-4615
Remarkable Levels of Enantioswitching
in Catalytic Asymmetric Hydroboration
Sean M. Smith and James M. Takacs*
Department of Chemistry, UniVersity of Nebraska-Lincoln, Lincoln,
Nebraska 68588, United States
jtakacs1@unl.edu
Received August 16, 2010
ABSTRACT
TADDOL-derived phosphites and phosphoramidites are effective ligands for rhodium-catalyzed asymmetric hydroborations of ꢀ,γ-unsaturated
amides, achieving up to 99% ee. However, the sense of stereoinduction, R or S, is surprisingly dependent on rather subtle features of the
ligand. For example, catalysts employing a TADDOL phenylphosphite and those using the closely related N-methylaniline-derived phosphoramidite
of the same configuration give opposite enantiomers of the product. Those derived from optical antipodes give the same product with virtually
the same enantioselectivity as illustrated above. The different stereochemical outcomes may reflect fundamental differences in catalyst structure,
reactivity, or reaction mechanism.
Accessing either enantiomer of a chiral product via asym-
metric catalysis is typically achieved by preparing both
enantiomers of the catalyst. Occasionally, efficient enan-
tioswitching, that is, producing each enantiomer using similar
nonenantiomeric chiral catalysts, has been achieved by
changing substituents on a ligand while preserving its
absolute configuration.1,2 Although the structural changes
needed to effect enantioswitching are difficult to predict a
priori or even rationalize after the fact, such processes are
of special interest and hold the potential to yield fundamental
insight into the origin of enantioselectivity in asymmetric
catalysis. We now report striking examples of directed
rhodium-catalyzed asymmetric hydroboration for which
rather subtle changes in the structure of a TADDOL-derived
ligand, for example, comparing a phenylphosphite to an
N-methylaniline-derived phosphoramidite, lead to nearly
complete reversal of stereochemistry. Several factors influ-
encing the efficiency of enantioswitching and some surprising
characteristics of the catalysts are found.
The catalyzed hydroboration reaction, first reported in
1985,3 is of renewed interest.4 Building upon the work of
Evans5 and Gevorgyan,6 we reported that TADDOL-derived
monophosphites are excellent ligands for carbonyl-directed
(3) (a) Ma¨nnig, D.; No¨th, H. Angew. Chem., Int. Ed. Engl. 1985, 24,
878–879. (b) The first highly selective asymmetric version was reported
by Hayashi, T.; Matsumoto, Y.; Ito, Y. J. Am. Chem. Soc. 1989, 111, 3426–
3428.
(4) (a) Ely, R. J.; Morken, J. P. J. Am. Chem. Soc. 2010, 132, 2534–
2535. (b) Lata, C. J.; Crudden, C. M. J. Am. Chem. Soc. 2010, 132, 131–
137. (c) Wu, J. Y.; Morequ, B.; Ritter, T. J. Am. Chem. Soc. 2009, 131,
12915–12917. (d) Lee, K.; Zhugralin, A. R.; Hoveyda, A. H. J. Am. Chem.
Soc. 2009, 131, 7253–7255. (e) Lee, Y.; Hoveyda, A. H. J. Am. Chem.
Soc. 2009, 131, 3160–3161. (f) Crudden, C. M.; Glasspoole, B. W.; Lata,
C. J. Chem. Commun. 2009, 6704–6716. (g) Guiry, P. J. ChemCatChem
2009, 1, 233–235. (h) Carroll, A. M.; O’Sullivan, T. P.; Guiry, P. J. AdV.
Synth. Catal. 2005, 347, 609–631. (i) Vogels, C. M.; Westcott, S. A. Curr.
Org. Chem. 2005, 9, 687–699.
(1) Recent reviews: (a) Tanaka, T.; Hayashi, M. Synthesis 2008, 21,
3361–3376. (b) Bartok, M. Chem. ReV. 2010, 110, 1663–1705
.
(2) For several particularly impressive examples, see: (a) Wu, W.; Peng,
Q.; Dong, D.; Hou, X.; Wu, Y. J. Am. Chem. Soc. 2008, 130, 9717–9725.
(b) Zhang, W.; Shi, M. Tetrahedron: Asymmetry 2004, 15, 3467–3476. (c)
Hoarau, O.; Ait-Hadou, H.; Daran, J.; Cramailere, D.; Balavione, G. G. A.
Organometallics 1999, 18, 4718–4723
.
10.1021/ol101932q  2010 American Chemical Society
Published on Web 09/23/2010

rhodium-catalyzed asymmetric hydroborations of (E)- and
(Z)-trisubstituted-ꢀ,γ-unsaturated amides.7 BINOL-derived
phosphoramidites afford very selective catalysts for the
related disubstituted alkenes and certain vinyl arene sub-
strates.8-10
Several surprising observations were made while studying
a series of TADDOL derivatives, (TADDOL)PX (L1-L4),
in the reaction of amide 1.11 Small variations in the aryl
substituents give rise to subtle changes in the shape of the
phosphorus ligand.7,8a,12,13 A series of phosphites, including
phenylphosphites (i.e., L1A-L4A), and phosphoramidites
(i.e., L1-L4 with B-G) was used in conjunction with
Rh(nbd)2BF4 to effect asymmetric hydroboration of 1 with
pinacolborane (PinBH). The (3R)-2:(3S)-2 enantiomeric
ratios (er) determined after oxidative workup are summarized
in Figure 1.
is the most selective among the ligands examined. In contrast,
N-methylaniline-derived phosphoramidites L1B-L4B give
the enantiomeric product, (3S)-2 (77-92% ee); L1B and L2B
perform nearly equivalently. It is not simply a consequence
of phosphoramidite versus phosphite that determines the R/S
stereochemical course of the reaction. The N,N-dibenzy-
lamine-derived L3F affords (3R)-2 in 91% ee. Other phos-
phoramidites give only modest levels of asymmetric
induction. The N-benzylaniline-derived phosphoramidites
L1C-L4C favor (3S)-2 (4-40% ee). The indoline (i.e.,
L1D-L4D) and isoindoline (i.e., L1E-L4E) derivatives
give near racemic product in the L1 series and a modest
excess of the (3R)-2 for L2-L4 derivatives (i.e., 13-40%
ee). The N,N-dimethylamine derivative L1G affords (3S)-2
in 34% ee.
Although the extent of enantioreversal is very high for
(Z)-1 with monophosphoramidites L1B-L4B, the isolated
yields of 2 are significantly lower (35-45%) than those
obtained using monophosphites L1A-L4A (72-80%). A
side product, tentatively identified as an isomeric δ-hy-
droxyamide, is formed in substantial amounts (25-32%) but
low enantiomeric excess from 1. It presumably arises via
rhodium-catalyzed alkene isomerization followed by hy-
droboration. Although rhodium-catalyzed alkene isomeriza-
tion is well-known,14 it has not generally been problematic
with ꢀ,γ-unsaturated amides. For example, (Z)-3 affords
ꢀ-hydroxyamide 4 in 80% yield using either phosphite L3A
or phosphoramidite L4B; alkene isomerization is apparently
not a significant competing side reaction. Phenylphosphite
L3A gives (3R)-4 (96% ee). Phosphoramidite L4B exhibits
the expected enantioreversal; however, the level of enanti-
oselectivity favoring (3S)-4 is somewhat lower, 80% ee
(Figure 2). Other ꢀ,γ-unsaturated amides possessing trisub-
Figure 1. Enantiomeric ratio (er) for the formation of R/S-2 varies
as a function of the TADDOL subunit (i.e., L1-L4), while the
sense of asymmetric induction (3R or 3S) is a function of the
(TADDOL)PX substituent, X (X ) A-G).
Phenylphosphites L1A-L4A afford predominantly the
(3R)-ꢀ-hydroxyamide 2 (86-93% ee, 72-80% yield); L3A
Figure 2. Other trisubstituted substrates, for example, (Z)-3, exhibit
enantioreversal but to a somewhat lesser degree.
(5) (a) Evans, D. A.; Fu, G. C. J. Am. Chem. Soc. 1991, 113, 4042–
4043. (b) Evans, D. A.; Fu, G. C.; Hoveyda, A. H. J. Am. Chem. Soc. 1992,
114, 6671–6679. (c) Evans, D. A.; Fu, G. C.; Anderson, B. A. J. Am. Chem.
stituted alkenes bearing all alkyl substituents give similar
results.
Soc. 1992, 114, 6679–6685
(6) Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc. 2003,
125, 7198–7199
.
The disubstituted alkene, (E)-5 (R ) (CH2)2Ph), affords
(3S)-6 (90-99% ee) using monophosphites L1-4A; L3A
and L4A give the highest enantioselectivity (Table 1). In
contrast to the trisubstituted alkene substrates discussed
above, the N-methylaniline-derived phosphoramidite ligands
L1-4B afford poor to moderate levels of enantioselectivity
varying from 33% ee favoring (3S)-6 to 55% ee favoring
.
(7) Smith, S. M.; Takacs, J. M. J. Am. Chem. Soc. 2010, 132, 1740–
1741
.
(8) For disubstitued ꢀ,γ-unsaturated amides, see: (a) Smith, S. M.;
Thacker, N. C.; Takacs, J. M. J. Am. Chem. Soc. 2008, 130, 3734–3735.
(b) For vinylarenes, see: Moteki, S. A.; Wu, D.; Chandra, K. L.; Reddy,
D. S.; Takacs, J. M. Org. Lett. 2006, 8, 3097–3100
.
(9) Alexakis, A.; Polet, D.; Bournaud, C.; Bonin, M.; Micouin, L.
Tetrahedron: Asymmetry 2005, 16, 3672–3675
Org. Lett., Vol. 12, No. 20, 2010
.
4613

conditions employed.15b,16 It is, therefore, not feasible at this
time to develop a complete mechanistic rationale accounting
for the observed enantioreversal. Nonetheless, the (Z)- and
(E)-isomers of unsaturated amide 7 prove useful in identify-
ing several characteristics relevant to enantioswitching.
First, high levels of enantioselectivity and remarkably
efficient enantioswitching are observed for either alkene
geometry. Using phosphite L4A, (Z)- and (E)-7 each afford
(3S)-8 in excellent enantiopurity (96% and 94% ee, respec-
tively, Table 2, entries 1 and 2). Phosphoramidite L1D
Table 1. Enantiomeric Ratio and Sense of Enantioselectivity
(i.e., R or S) Vary Widely as a Function of the TADDOL
Scaffold (i.e., L1-L4) and the Nature of X (i.e., A-G) with
Unsaturated Amide 5
Table 2. (E)- and (Z)-7 Exhibit High Enantioswitchinga
a The ꢀ-hydroxyamide is favored over the γ-regioisomer in all cases
(2-15:1). The yield of 6 (R ) CH2CH2Ph) is ligand-dependent and varies
from 27% to 78%. The lowest yields generally reflect incomplete reaction
and are not corrected for recovered starting material; the reaction conditions
were not optimized. See Supporting Information for a complete summary
of conversions and yields.
(3R)-6. The indolinyl (D) and isoindolinyl (E) derivatives
are superior, giving (3R)-6 in up to 97% ee with L1D or
L2D. Furthermore, enantioswitching now strongly depends
upon the TADDOL scaffold. In contrast to L1D and L2D,
L3D and L4D give predominantly the enantiomeric product
(3S)-6. Using L4D the enantioselectivity reaches 90% ee.
a Reactions were run as follows: 1% Rh(nbd)2BF4, 2.1% ligand, 2.0
equiv of PinBH, rt, 24 h.
affords (3R)-8 in 97% and 96% ee from (Z)- and (E)-7,
respectively (entries 3 and 4). Using deuterated borane,
PinBD, the isomeric (Z)- and (E)-7 substrates afford dia-
stereomeric products using either ligand, indicating that the
catalyzed addition of boron and deuterium (hydrogen) across
the double bond is overall stereospecific and syn for either
ligand.17
Matched and mismatched combinations of L4A and L1D
were examined (Table 2, entries 5-8). Recognizing of course
that these heterocombinations could give rise to a mixture
of three distinct 2:1 L:Rh complexes,18 the “matched” pair
is a pseudoracemate consisting of 1 equiv of the indolinyl
phosphoramidite derived from the L or (4R,5R)-isomer of
tartaric acid (i.e., (4R,5R)-L1D) with 1 equiv of the phe-
While computational studies have addressed the mecha-
nism of rhodium-catalyzed hydroborations using rhodium
chloride catalysts, the conclusions are not directly applicable
-
to variants employing dissociable counterions (e.g., BF4 )
or two point binding substrates.15 Furthermore, prior studies
suggest that several reaction pathways are close in energy
and mechanistic details may vary depending on the exact
(10) Chiral monophosphoramidites are effective in rhodium-catalyzed
asymmetric hydrogenations; for example, see: Minnaard, A. J.; Feringa,
B. L.; Lefort, L.; De Vries, J. G. Acc. Chem. Res. 2007, 40, 1267–1277,
and references therein.
(11) Unless noted otherwise, the results reported are obtained using the
(4R,5R)-TADDOL derivative. See Supporting Information for complete
details.
(12) Seebach, D.; Dahinden, R.; Marti, R. E.; Beck, A. K.; Plattner,
D. A.; Kuhnle, F. N. M. J. Org. Chem. 1995, 60, 1788–1799.
(13) For reviews on the use of TADDOL-derived chiral catalysts, see:
(a) Seebach, D.; Beck, A. K.; Heckel, A. Angew. Chem., Int. Ed. 2001, 40,
92–138. (b) Pellisier, H. Tetrahedron 2008, 64, 10279–10317.
(14) (a) Edwards, D. R.; Crudden, C. M.; Yam, K. AdV. Synth. Catal.
2005, 347, 50–54. (b) Evans, D. A.; Fu, G. C.; Anderson, B. A. J. Am.
Chem. Soc. 1992, 114, 6679–6685. (c) Hadebe, S. W.; Robinson, R. S.
Tetrahedron Lett. 2006, 47, 1299–1302.
(16) (a) Edwards, D. R.; Hleba, Y. B.; Lata, C. J.; Calhoun, L. A.;
Crudden, C. M. Angew. Chem., Int. Ed. 2007, 46, 7799–7802. (b) Black,
A.; Brown, J. M.; Pichon, C. Chem. Commun. 2005, 5284–5286. (c) Segarra,
A. M.; Daura-Oller, E.; Claver, C.; Poblet, J. M.; Bo, C.; Fernandez, E.
Chem.-Eur. J. 2004, 10, 6456–6467. (d) Crudden, C. M.; Hleba, Y. B.;
Chen, A. C. J. Am. Chem. Soc. 2004, 126, 9200–9201. (e) Ramachandran,
P. V.; Jennings, M. P.; Brown, H. C. Org. Lett. 1999, 1, 1399–1402
(17) Approximately 70-76% γ-monodeuteration obtained in each
case.
.
(15) (a) Widauer, C.; Grutzmacher, H.; Ziegler, T. Organometallics 2000,
19, 2097–2107. (b) Dorigo, A. E.; Schleyer, P. v. R. Angew. Chem., Int.
Ed. Engl. 1995, 34, 115–118. (c) Musaev, D. G.; Mebel, A. M.; Morokuma,
K. J. Am. Chem. Soc. 1994, 116, 10693–10702.
(18) A 2:1 L:Rh ratio is required for efficient asymmetric hydroboration
using L4A or L1D. At lower L:Rh ratios, the level of enantioselectivity is
decreased using either ligand.
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nylphosphite derived from (4S,5S)-tartrate (i.e., (4S,5S)-
L4A). Surprisingly, the matched pseudoracemate combina-
tion is only moderately less selective than either enantiopure
ligand used separately. (3R)-8 is produced in 76-80% ee
(Table 2, entries 5 and 6), more selective than the homochiral
(i.e., mismatched) combination, (4R,5R)-L4A plus (4R,5R)-
L1D. The latter affords the opposite enantiomer, (3S)-8,
albeit in only 46-50% ee (entries 7 and 8).
The phenylphosphite L4A, indolinyl phosphoramidite
L1D, and the matched/mismatched combination catalysts
were evaluated for nonlinear effects19 in the catalyzed
reaction of (E)-7 with PinBH. The surprising results are
shown in Figure 3. Graph A shows the change in enantio-
meric purity of 8 as a function of the enantiomeric purity of
phenyl phosphite L4A. The dashed line serves as a reference
for a purely linear relationship. Viewing left-to-right, pure
(4R,5R)-L4A to pure (4S,5S)-L4A, the data show a negative
nonlinear effect for L4A. In contrast, indolinyl phosphora-
midite L1D (Graph B) exhibits a strong positive nonlinear
effect. Graph C shows two sets of data obtained by holding
one component of the matched/mismatched combination
catalysts constant while varying the enantiomeric purity of
the second component. The red data points are obtained
varying L4A; the blue data reflect varying L1D. The data
for each show little deviation from linearity, suggesting that
the mixed “(L4A)(L1D)Rh(I)” complex, rather than
“(L4A)2Rh(I)” or “(L1D)2Rh(I)”, dominates the reaction.
In summary, amide-directed rhodium catalyzed asym-
metric hydroboration exhibits remarkable levels of enan-
tioswitching. Relatively small changes in ligand substituents
result in complete enantioreversal without changing the
absolute stereochemistry of the ligand. Comparing nonlinear
effects for the phenylphosphite L4A, indolinyl phosphora-
midite L1D, and the apparent matched/mismatched combina-
tion catalysts suggests that although the ligands employed
are structurally quite similar, the reactivity of each catalyst
differs substantially from the others. The different stereo-
chemical outcomes therefore may reflect significant and
fundamental differences in catalyst structure, reactivity, and/
or perhaps reaction mechanism leading to enantioreversal.
Further work is in progress to gain a better understanding
of the mechanistic basis for enantioswitching.
Figure 3. Nonlinear effects in the catalyzed hydroboration of (E)-7
with PinBH. Negative and positive nonlinear effects for the catalysts
using phosphite L4A (graph A) and phosphoramidite L1D (graph
B), respectively, contrast with the largely linear effects found for
equimolar combinations of L4A and L1D (graph C). The dashed
lines are for reference only. (A) Negative nonlinear effect for L4A.
(B) Positive nonlinear effect for L1D. (C) A nearly linear effect
found for varying enantiomeric purity of L4A in combination with
(4R,5R)-L1D (red data) or varying L1D with (4R,5R)-L4A (blue
data).
Acknowledgment. Financial support for this research from
the NSF (CHE-0809637) is gratefully acknowledged. We
thank N. C. Thacker (UNL Chemistry) for some key
preliminary experiments 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.
Supporting Information Available: Experimental pro-
cedures and selected spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
(19) Recent reviews: (a) Satyanarayana, T.; Abaham, S.; Kagan, H. B.
Angew. Chem., Int. Ed. 2009, 48, 456–494. (b) Kagan, H. B. AdV. Synth.
Catal. 2001, 343, 227–233. (c) Girard, C.; Kagan, H. B. Angew. Chem.,
Int. Ed. 1998, 37, 2922–2959.
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