Modular monodentate oxaphospholane ligands: Utility in highly efficient and enantioselective 1,4-diboration of 1,3-dienes

Article abstract of DOI:10.1002/anie.201102404

Tune it up! Tunable, chiral, monodentate oxaphospholane ligands (termed OxaPhos) are highly effective in the Pt-catalyzed title reaction, providing the 1,4-addition products in enantiomer ratios approaching 99:1 (see scheme). In the presence of enantiomerically pure cis-iBu-OxaPhos, a catalyst loading of only 0.02 mol% [Pt(dba)₃] was sufficient for effective reaction. pin=pinacolato, dba=dibenzylideneacetone.

Full text of DOI:10.1002/anie.201102404

Communications
DOI: 10.1002/anie.201102404
Phosphorus Ligands
Modular Monodentate Oxaphospholane Ligands: Utility in Highly
Efficient and Enantioselective 1,4-Diboration of 1,3-Dienes**
Christopher H. Schuster, Bo Li, and James P. Morken*
Chiral monodentate ligands are important tools for the
control of enantioselectivity in catalytic reactions. These
compounds are particularly important when transition-metal
catalysts lack sufficient coordination sites to bind a bidentate
ligand and still retain activity. Along these lines, modular,
tunable chiral carbenes[1] and phosphoramidites[2] have found
particular prominence in the field of asymmetric catalysis.
Aside from these compound classes, however, there is a
relative paucity of effective, tunable monodentate chiral
ligands that have found widespread utility. In recent studies
on the platinum-catalyzed enantioselective diboration of
dienes, we achieved limited success when optimizing chiral
phosphoramidite and phosphonite ligands for certain sub-
strates.[3,4] Because catalytic diboration benefits from the
presence of electron-rich monodentate phosphines,[5] we
considered that solutions to problematic substrates might
arise from the availability of a readily preparable, tunable,
chiral, Lewis basic phosphine ligand.[6] Herein, we describe
the synthesis and properties of enantiomerically enriched
modular 1,3-oxaphospholanes (termed OxaPhos ligands,
Scheme 1). These ligands are readily available from the
Scheme 2. Synthesis of Et-OxaPhos ligands.
phide to furnish ring-opened secondary phosphine 2. Without
purification, phosphine 2 was subjected to transketalization
with the dimethyl ketal of the reacting ketone. This synthesis
sequence delivered a 1:1 mixture of tertiary phosphines that
were directly oxidized with hydrogen peroxide. The stable
phosphine oxides were easily separated by silica gel chroma-
tography and subsequent stereoretentive reduction with
phenylsilane[8] cleanly delivered the isomerically pure tertiary
phosphines in good yield.
The crystal structures of the phosphine oxide derivates of
both cis- and trans-Et-OxaPhos ligands are depicted in
Figure 1.[9] A notable feature of these structures is the
invariant nature of the five-membered ring with the tert-
butyl substituent adopting an equatorial position in each.
Assuming similar conformations predominate in the reduced
phosphine derivatives, one can anticipate that the phosphorus
Scheme 1. Modular assembly of OxaPhos ligands.
combination of an enantiopure epoxide, a primary phosphine,
and a ketone or the derived ketal.[7] In addition to describing
their synthesis and properties, we also describe their use in the
catalytic 1,4-diboration of challenging diene substrates.
The OxaPhos ligands possess two stereocenters, one at
carbon and one at phosphorus, and are therefore available in
two epimeric forms. The preparation of both epimers of the
Et-OxaPhos ligand is described in Scheme 2 and is represent-
ative of the synthesis of this ligand class. Enantiomerically
enriched terminal epoxide 1 was treated with phenylphos-
[*] C. H. Schuster, Dr. B. Li, Prof. Dr. J. P. Morken
Department of Chemistry, Boston College
Chestnut Hill, MA 02467 (USA)
E-mail: morken@bc.edu
[**] We are grateful to the NIH (NIGMS GM-59417) for support of this
work and to AllyChem for a gift of B2(pin)2.
Figure 1. ORTEP representation of cis (a) and trans (b) Et-OxaPhos
phosphine oxides (ellipsoids at the 60% probability level). C gray,
O red, P yellow.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201102404.
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lone pair in the cis-OxaPhos ligand is better aligned with the
To survey the utility of cis-iBu-OxaPhos in the diboration
of other dienes, the collection of substrates in Table 2 was
examined. As shown by the data, cis-iBu-OxaPhos is useful
À
adjacent C O s* orbital (OPCO dihedral angle = 1518)
compared to the trans-OxaPhos ligand (OPCO dihedral =
998). However, this alignment appears to have little conse-
quence on the ligand electronic properties; after reduction,
the derived trans-[L2Rh(CO)Cl] complexes exhibit nearly
identical CO stretching frequencies (1961 cmÀ1 for the cis
ligand and 1962 cmÀ1 for the trans).[10] Of note, the CO
stretching frequencies also suggest that the phosphorus atom
in the OxaPhos ligands is relatively basic, comparable to
Table 2: Pt-catalyzed enantioselective diboration/oxidation in the pres-
ence of (R,R)-iBu-OxaPhos.[a]
PhPCy2
(CO
stretching
frequency
for
trans-
[(PhPCy2)2Rh(CO)Cl] = 1964 cmÀ1).[10b]
Entry Substrate
Product
Yield [%][b]
e.r.[c]
To study the utility of oxaphospholanes in catalytic
diboration, diene 3 was chosen for analysis (Table 1). Previous
studies from our laboratory documented the efficacy of chiral
1
2
3
4
86
65
97.0:3.0
96.1:3.9
98.2:1.8
Table 1: Pt-catalyzed enantioselective diboration/oxidation of trans-
piperylene in the presence of OxaPhos ligands.[a]
>95
>95(>95)[d] 97.5:2.5
5
6
7
8
82
99.0:1.0
98.8:1.2
98.1:1.9
82.5:17.5
Ligand
Yield [%][b]
e.r.[c]
>95
cis-Me-OxaPhos
trans-Me-OxaPhos
cis-Et-OxaPhos
trans-Et-OxaPhos
cis-iBu-OxaPhos
trans-iBu-OxaPhos
83
62
85
86
86
88
85.5:14.5
20.2:79.8
94.5:5.5
22.8:77.2
97.0:3.0
61[e]
82
38.9:61.1
[a] Reactions employed 1.05 equivalents of B2(pin)2 and were carried out
at 608C for 12 h. [b] Yield of isolated purified product; value is an average
of two experiments. [c] Determined by GC with a chiral stationary phase;
error ꢀÆ0.2%. pin=pinacolato, dba=dibenzylideneacetone.
[a] Reactions employed 1.05 equivalents of B2(pin)2 and were carried out
at 608C for 12 h. [b] Yield of isolated purified product; value is an average
of two experiments. [c] Determined by GC, HPLC, or SFC analysis on a
chiral stationary phase; error ꢀÆ0.2%. With (xylyl)TADDOL-PPh, the
enantioselectivities of the reactions corresponding to entries 1–5 are 70,
84, 91, 84, and 45% ee, respectively. [d] Yield in parentheses is for the
purified 1,4-bis(boronate) intermediate. [e] 2:1 ratio of 1,4-/1,2-dibora-
tion products obtained; yield is for the purified 1,4 product. Cy=cyclo-
hexyl.
a,a,a’,a’-tetraaryl-1,3-dioxolane-4,5-dimethanol (TADDOL)
derived phosphonite ligands in diene diboration reactions,
and with the most optimal ligand (xylyl-TADDOL-derived
phenyl phosphonite) this substrate underwent diboration in
only 70% ee.[3] As shown in Table 1 and discussed in the
following, diboration under the influence of oxaphospholane
ligands can be much more selective, and reactivity is out-
standing. While diborations with propylene oxide derived
ligands and ligands derived from aldehydes were not highly
selective (data not shown), when the tert-butyl-substituted
ligands were employed, elevated levels of enantiomeric
enrichment were obtained. As depicted in Table 1, the cis
and trans isomers of the OxaPhos ligands favor opposite
product enantiomers. Significantly, the enantioselectivity with
the cis ligand isomer is markedly enhanced as the size of the
ketal substituents is increased, (substituents larger than
isobutyl could not be incorporated with the current synthesis
route), whereas the opposite trend occurs with the trans
epimer. Importantly, with the cis-iBu-OxaPhos ligand, the
selectivity in the diboration of trans-1,3-pentadiene (Table 1)
far surpasses that obtained with (xylyl)TADDOL-derived
phosphonite ligand (97:3 e.r. versus 85:15 e.r.).
for a range of aromatic and aliphatic terminal dienes,
affording the derived 1,4-diol in excellent yield and enantio-
selectivity upon oxidative workup. The selective diboration
reaction could be extended to 3,4-disubstituted dienes
(Table 2, entries 5–7). The diboration of these substrates
occurs in low selectivity with TADDOL-derived ligands, but
with cis-iBu-OxaPhos, enantiomeric purities of 96–98% ee
were observed. A particularly noteworthy feature is that these
substrates deliver difficult-to-access trisubstituted alkene
products in a highly diastereo- and enantioselective fashion.
The result in entry 8 suggests that the diboration strategy with
cis-iBu-OxaPhos can deliver chiral, tetrasubstituted alkene
products with synthetically useful levels of selectivity. Lastly,
it was demonstrated that the intermediate 1,4-bis(boronate)
could be isolated in excellent yield and fully characterized
(Table 2, entry 4).
The cis-butene-1,4-diols obtained by diene diboration can
be readily oxidized[11] to butenolides and therefore represent
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Communications
valuable synthetic intermediates.[12] However, if these struc-
which proceed in < 5% conversion at 0.02 mol% loading
and in 23% conversion at the 0.1% loading level.
tures are to be accessed on large scale using Pt catalysis, the
amount of catalyst employed in the reaction can be a concern.
To address this issue, the effects of catalyst composition and
loading were examined (Table 3). Similar to the reactions
The remarkable diboration activity of Pt catalysts derived
from cis-iBu-OxaPhos raises the concern that the presence of
trace amounts of stereoisomeric catalysts (i.e. from incom-
plete chromatographic resolution during synthesis) might
erode selectivity. To study this feature, we examined catalysts
of varying diastereomeric purity in the diboration of 1,3-
pentadiene. As depicted in Figure 2, these experiments
Table 3: Effect of catalyst loading and composition.[a]
Entry
L [mol%]
M [mol%]
Yield [%][b]
ton[c]
e.r.[d]
1[e]
2[f]
3[e]
4[e]
5[e]
6
2.0
2.0
1.95
1.1
0.5
0.2
1.0
1.0
1.0
1.0
1.0
0.1
0.05
0.02
<5
90
97
98
71
98
95
95
–
90
97
98
–
96.4:3.6
97.4:2.6
97.3:2.7
95.4:4.6
97.3:2.7
97.2:2.8
97.1:2.9
71
980
1900
4750
7
8
0.1
0.04
[a] Reactions were conducted under Ar atmosphere with anhydrous
deoxygenated solvent and 1.05 equivalents of B2(pin)2 and were carried
out at 608C for 12 h. [b] Yield of isolated purified product. [c] Turnover
number=yield [%]/Pt [mol%]. [d] Determined by GC on a chiral sta-
tionary phase; error ꢀÆ0.2%. [e] Substrate was degassed. [f] Substrate
was degassed substrate and the reaction mixture was briefly exposed to
air (<5 s) after a reaction time of 4 h.
described above, these reactions were carried out with
rigorously dried and deoxygenated solvents and were con-
ducted under argon. However, in contrast to the previous
studies, the substrate for these experiments was also rigor-
ously deoxygenated. As indicated in entry 1 (Table 3), very
little reaction occurred when a ligand(L)/metal(M) ratio of
2:1 was employed. Suspecting that PtL2 complexes might be
inactive and that trace oxygen in the substrate might serve to
oxidize a portion of the ligand and provide an active ML1
complex, we repeated the experiment (Table 3, entry 2).
After 4 h (no reaction, TLC analysis) the mixture was briefly
exposed (< 5 s) to air, sealed, and allowed to react for 2 more
hours. This experiment provided diol 6 in excellent yield and
enantiomeric purity. Also consistent with the hypothesis that
the active species may be an ML1 complex is the fact that with
1.95:1 L/M and degassed substrate (Table 3, entry 3), the
reaction proceeds normally. Notably, L/M ratios of 1.1:1 and
0.5:1 (Table 3, entries 4 and 5) provide reasonable yields and
selectivity in the diboration of 5, with the latter experiment
indicating that a significant level of ligand-accelerated
catalysis occurs. Expecting that at lower catalyst loading
trace oxygen may be more problematic, we employed an L/M
ratio of 2:1 when the amount of catalyst used in experiments
was decreased to 0.1 mol% and 0.02 mol% (Table 3,
entries 6–8). These reactions used nondegassed substrate
and even at a 0.02 mol% loading of Pt0, the diene diboration
proceeds in excellent yields and enantioselectivity (Table 3,
entry 8). This level of reactivity is in marked contrast to
diborations with TADDOL-derived phosphonite ligands
Figure 2. Correlation between catalyst diastereomer ratio and product
enantiomer ratio.
revealed a substantial nonlinear effect that favors the more
selective cis diastereomer of the iBu-OxaPhos ligand.[13]
Remarkably, even a 1:1 mixture of cis and trans iBu-OxaPhos
ligands delivers the product with synthetically useful levels of
selectivity. Furthermore, the more selective cis ligand, even
when contaminated with the less selective trans isomer
(25%), provides the product in levels of selectivity nearly
indistinguishable from that derived from a ligand sample that
is > 97% pure cis isomer. Thus, not only is trace contami-
nation by the trans stereoisomer of catalyst of little conse-
quence, it is also not necessarily important to achieve
substantial resolution during the synthesis outlined in
Scheme 1.
In conclusion, OxaPhos ligands are tunable, chiral,
monodentate phosphines that can offer very high enantiose-
lectivity in catalytic diboration. Of particular note is that at
the 0.02 mol% level of catalyst loading with which these
catalysts can be effective, the cost of the catalyst becomes
meaningless relative to the substrates and reagents in the
diboration reaction.[14] Considering the impact that phosphor-
amidite ligands have had on asymmetric catalysis and the
observation that OxaPhos ligands can offer advantages, it is
anticipated that the latter ligand class may find significant use
in catalysis.
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Angew. Chem. Int. Ed. 2011, 50, 7906 –7909

Received: April 6, 2011
Published online: July 12, 2011
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Keywords: asymmetric catalysis · boron · ligand design ·
.
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[14] [Pt(dba)3] can be prepared from K2PtCl4 in one step (85%
yield). At a price of roughly US$20000 per mole for K2PtCl4, a
1-mol-scale diboration reaction at
a catalyst loading of
0.02 mol% Pt requires about $4 worth of catalyst. The current
price of B2(pin)2 from AllyChemUSA, Inc. is approximately
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