Concatenated catalytic asymmetric allene diboration/allylation/ functionalization

Article abstract of DOI:10.1021/ol052312i

(Chemical Equation Presented) Palladium-catalyzed enantioselective diboration of prochiral allenes generates a reactive chiral allylboron intermediate which is a versatile reagent for the allylation of carbonyls. Experiments that improve the enantioselectivity of this process, examine the substrate scope, and are directed toward functionalization of the allylation intermediate are described.

Full text of DOI:10.1021/ol052312i

ORGANIC
LETTERS
2005
Vol. 7, No. 24
5505-5507
Concatenated Catalytic Asymmetric
Allene Diboration/Allylation/
Functionalization
Angela R. Woodward, Heather E. Burks, Louis M. Chan, and James P. Morken*
Department of Chemistry, Venable and Kenan Laboratories, The UniVersity of North
Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290
morken@unc.edu
Received September 23, 2005
ABSTRACT
Palladium-catalyzed enantioselective diboration of prochiral allenes generates a reactive chiral allylboron intermediate which is a versatile
reagent for the allylation of carbonyls. Experiments that improve the enantioselectivity of this process, examine the substrate scope, and are
directed toward functionalization of the allylation intermediate are described.
Methods for the stereoselective allylation of carbonyl
compounds have been aggressively developed by many
groups and are of substantial importance in synthetic organic
chemistry.1 The products that arise from these processes
contain versatile alkene functionality that renders the ho-
moallylic alcohol an important building block for asymmetric
synthesis. Recent advances in this area of investigation are
impressive; however, there are few stereoselective reactions
that result in homoallylic alcohols bearing functionalized
alkenes.2,3 Along these lines, we have recently developed
an asymmetric diboration of prochiral allenes4 with the
expectation that the resulting diboron compound (A, Scheme
1) might prove to be a versatile intermediate for allylation
reactions. It was expected that the in situ-generated chiral
type I allyl metal reagent would provide predictable and high
levels of chirality transfer in reactions with prochiral elec-
trophiles.5 Initial studies suggested that carbonyl allylation
reactions proceed through transition structure C to give vinyl
boronates B in an enantioenriched fashion. As depicted in
Scheme 1, the allylation product contains a malleable vinyl
boronic ester that might be used in concatenated reaction
sequences. While the precursor diboron reagents are rela-
tively inexpensive6 and allenes are readily available,7 our
initial report suggested that the level of chirality transfer in
the allylation is not perfect (i.e., 88% ee A f 82% ee B),
thereby diminishing the overall enantioselectivity, and the
(2) (a) Hoffmann, R. W.; Landmann, B. Chem. Ber. 1986, 119, 2013.
(b) Hoffmann, R. W.; Dresley, S. Chem. Ber. 1989, 122, 903. (c) Corey,
E. J.; Yu, C. M.; Kim, S. S. J. Am. Chem. Soc. 1989, 111, 5495. (d) Evans,
D. A.; Hu, E.; Burch, J. D.; Jaeschke, G. J. Am. Chem. Soc. 2002, 124,
5654. (e) Denmark, S. E.; Beutner, G. L. J. Am. Chem. Soc. 2003, 125,
7800. (f) Patterson, I.; Davies, R. D.; Marquez, R. Angew. Chem., Int. Ed.
2001, 40, 603.
(3) For allene-derived bis(stannanes) in synthesis, see: (a) Williams, D.
R.; Meyer, K. G. J. Am. Chem. Soc. 2001, 123, 765. (b) Williams, D. R.;
Fultz, M. W. J. Am. Chem. Soc. 2005, 127, 14550.
(1) (a) Yanagisawa, A. In ComprehensiVe Asymmetric Catalysis; Jacob-
sen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Berlin, 1999;
Vol. 2, pp 965-979. (b) Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103,
2763.
10.1021/ol052312i CCC: $30.25
© 2005 American Chemical Society
Published on Web 10/28/2005

corresponding synthetic utility, of the reaction sequence. To
address the shortcomings of this synthesis strategy, we have
undertaken a study of the catalytic diboration reaction and
have developed significantly improved catalysts that improve
the overall utility of the sequence depicted in Scheme 1.
Table 1. Effect of Ligand Modification on the Diboration of
Allenes
Scheme 1
ligand 1
ligand 2
% yield (ee)
ligand 3
% yield (ee)
% yielda (ee)b
R ) decylc
61 (91)
62 (89)
75 (87)
72 (98)
92 (93)
72 (97)
34 (63)
39 (66)
26 (51)
Cy
Ph
Described herein are studies that probe the potential of
tandem diboration/allylation/functionalization sequences for
the efficient preparation of enantiomerically enriched sub-
structures.
a Yield of diboration product isolated after silica gel chromatography.
Average of two experiments with <10% difference in yield and ee in each
case. b Enantiomeric excess determined by chiral GLC analysis of the diol
obtained from hydrogenation (dimide) of the vinylboronate followed by
oxidation (NaOH, H2O2). c Reaction time of 12 h.
Tunable TADDOL-derived phosphoramidite8 ligand 1
(Table 1) provides significant rate enhancement and good
enantioselectivity in the palladium-catalyzed diboration of
both aliphatic and aromatic monosubstituted allenes. In an
effort to improve the enantioselectivity of the allene dibo-
ration reaction, the components of the ligand structure were
systematically evaluated. Whereas variation of the nitrogen
substituents and the glycol protecting group was not reward-
ing (data not shown), modification of the aryl rings had a
significant positive impact on asymmetric induction (Table
1). The enantioselectivity of the reaction run in the presence
of xylyl-derived ligand 2 was substantially improved com-
pared to the selectivity obtained with the parent phenyl-
derived ligand 1. When the xylyl group was replaced by the
more sterically demanding 3,5-di-tert-butylphenyl group,
both the conversion and the enantioselectivity suffered.
The performance of ligand 2 in the single-pot diboration/
allylboration/oxidation cascade process renders the reaction
suitable for the consistent generation of â-hydroxyketones
with good levels of enantiocontrol (Table 2).9 Unless
Table 2. Sequential Diboration/Allylboration/Oxidation
Reaction
entry
R1
R2
% yielda
% eeb
1
2
Ph
Ph
n-Pr
i-Pr
i-Pr
i-Pr
Ph
n-Pr
i-Pr
i-Pr
Ph
85
89
70
80
81
88
96
68
96
89
83
83
94
95
91
92
93
91
91
88
87
86
87
84
3c
4d
5
Ph
Ph
Ph
6
decyl
(4) (a) Pelz, N. F.; Woodward, A. R.; Burks, H. E.; Sieber, J. D.; Morken,
J. P. J. Am. Chem. Soc. 2004, 16, 16328. For nonenantioselective processes,
see: (b) Ishiyama, T.; Kitano, T.; Miyaura, N. Tetrahedron Lett. 1998, 39,
2357. (c) Fang. F.-Y.; Cheng, C.-H. J. Am. Chem. Soc. 2001, 123, 761.
For borylsilation and borylstannation, see: (d) Suginome, M.; Ohmori, Y.;
Ito, Y. J. Organomet. Chem. 2000, 611, 403. (e) Onozawa, S.; Hatanaka,
Y.; Tanaka, M. Chem. Commun. 1999, 1863. For an asymmetric silylbora-
tion with a chiral silylboron, see: (f) Suginome, M.; Ohmura, T.; Miyake,
Y.; Mitani, S.; Ito, Y.; Murakami, M. J. Am. Chem. Soc. 2003, 125, 11174.
(5) Roush, W. R. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Ed.; Pergamon: Oxford, 1991; Vol. 2.
(6) Bis(pinacolato)diboron is commercially available for $1500/kg from
AllyChem, Co., Ltd (www.allychem.com).
(7) Allenes are conveniently prepared by copper-catalyzed addition of
Grignard reagents to propargyl tosylate or by rearrangement of propargylic
alcohols. See: (a) Vermeer, P.; Meijer, J.; Brandsma, L. Recl. TraV. Chim.
Pays-Bas 1975, 94, 112. (b) Myers, A. G.; Zheng, B. J. Am. Chem. Soc.
1996, 118, 4492.
7
decyl
8d
9
decyl
decyl
10
11
12
cyclohexyl
cyclohexyl
cyclohexyl
n-Pr
i-Pr
Ph
a Isolated yield of purified â-hydroxyketone product based on equivalents
of aldehyde. Average of two experiments with a difference in yield of
<10%. b Enantiomeric excess determined by chiral SFC analysis of
â-hydroxyketone or benzoate derivative. c Conditions: 4 mol % Pd2(dba)3,
10 mol % 2, 1.2 equiv of allene, 1.2 equiv of B2(pin)2, 1.0 equiv of aldehyde.
d Aldehyde and allene were added together, and the reaction was allowed
to stir for 14 h before oxidation.
otherwise noted, these experiments were performed by
executing a Pd-catalyzed allene diboration for 10 h at room
temperature prior to the introduction of the aldehyde
substrate. After allowing the allylation to proceed at room
temperature for 14 h, the mixture was subjected to oxidative
workup. Several observations are noteworthy. While an
(8) Review: (a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346.
Examples: (b) ven den Berg, M.; Minnard, A. J.; Schudde, E. P.; van Esch,
J.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc.
2000, 122, 11539. (c) Hydrosilation: Jensen, J. F.; Svendsen, B. Y.; la
Cour, T. V.; Pedersen, H. L.; Johannsen, M. J. Am. Chem. Soc. 2002, 124,
4558. (d) Hydroboration: Ma, M. F. P.; Li, K.; Zhou, Z.; Tang, C.; Chan.
A. S. C. Tetrahedron: Asymmetry 1999, 10, 3259.
5506
Org. Lett., Vol. 7, No. 24, 2005

excess of diboron intermediate was employed in these
reactions, near-stoichiometric amounts of organometallic
reagent are sufficient for acceptable, albeit slightly eroded,
yield and enantioselectivity (entry 3). Additionally, the
aldehyde may be added concomitantly with the allene (entries
4 and 8), reducing the overall reaction time and simplifying
the procedure. In this case as well, enantioselectivity and
yield are slightly diminished.
Scheme 3
With chiral substrates, high levels of asymmetric induction
can occur if a stereocenter is situated adjacent to a reacting
carbonyl. As such, it was of interest to ascertain whether
the stereoinduction arising from the chiral allylboron inter-
mediate would dominate Felkin selectivity that may arise
from the substrate stereocenter. Along these lines, glycer-
aldehyde derivative (R)-4 was examined with both enantio-
mers of allene diboration adduct (Scheme 2). Depending on
Scheme 2
plug of silica followed by treatment with aqueous NaOH
and I2.10 Alternatively, simply heating the crude diboration/
allylboration reaction mixture with acetic acid provided
access to the Z-olefin 8 in 80% yield and with no erosion of
enantiomeric excess as compared to entry 8 in Table 2.11
Finally, it was determined that a Suzuki-Miyaura coupling
reaction12 can also terminate a single-pot cascade reaction
sequence. In this particular case, simple addition of iodo-
benzene and KOH to the diboration/allylboration mixture,
without additional palladium catalyst, afforded the coupling
product 9 in 79% yield after heating to 95 °C for 6 h. That
is, the palladium catalyst that affects the allene diboration is
also competent for the Suzuki-Miyaura coupling and is not
destroyed during the allylation reaction.
the ligand enantiomer employed, either the syn or anti
product configuration could be obtained almost exclusively.
With (R,R)-2, the anti-Felkin product 5 was observed in 21:1
syn:anti selectivity whereas with the (S,S) enantiomer of 2,
the Felkin product 6 was the only observable product by 1H
NMR analysis.
As alluded to above, further transformations might be
achieved by alternate transformation of the vinylboronic ester
present in the allylation product. As depicted in Scheme 3,
E-configured vinyl iodide 7 is accessible in 48% yield by
filtration of the allylboration reaction mixture through a short
In summary, a strategy for the tandem allene diboration/
allylboration/functionalization reaction has been developed.
Future study will be devoted to the applicability of these
reactions to the synthesis of structurally and functionally
interesting natural products.
Acknowledgment. This work was supported by the NIH
(GM 59417). J.P.M. is a fellow of the Alfred P. Sloan
foundation.
(9) For contemporary catalytic enantioselective approaches to these
frameworks, see: (a) Palomo, C.; Oiarbide, M.; Garc´ıa, J. M. Chem. Soc.
ReV. 2004, 33, 65. (b) Alcaide, B.; Almendros, P. Eur. J. Org. Chem. 2002,
1595. (c) Nelson, S. G. Tetrahedron: Asymmetry 1998, 9, 357.
(10) Brown, H. C.; Hamaoka, T.; Ravindran, N. J. Am. Chem. Soc. 1973,
95, 5786.
(11) (a) Brown, H. C.; Gupta, S. K. J. Am. Chem. Soc. 1972, 94, 4370.
(b) Brown, H. C.; Zweifel, G. J. J. Am. Chem. Soc. 1961, 83, 3834.
(12) For recent reviews of the Suzuki-Miyaura coupling reaction, see:
(a) Suzuki, A. J. Organomet. Chem. 1999, 576, 147. (b) Kohta, S.; Lahirir,
K.; Kashinath, D. Tetrahedron 2002, 58, 9633.
Supporting Information Available: Complete experi-
mental procedures, characterization data (1H, 13C, and 31P
NMR, IR, and mass spectrometry), enantiomeric purity data
(chiral GC, SFC), and structure proofs (authentic syntheses).
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL052312I
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