Catalytic Asymmetric Carbohydroxylation of Alkenes by a Tandem Diboration/Suzuki Cross-Coupling/Oxidation Reaction

Article abstract of DOI:10.1021/ol036219a

(Equation presented) Chiral nonsymmetric 1,2-diboron adducts are generated by catalytic enantioselective diboration. Oxidation of these adducts provides 1,2-diols in good yield. Alternatively, 1,2-diboron compounds may be reacted, in situ, with aryl halides wherein the less hindered C-B bond participates in cross-coupling. The remaining C-B bond is then oxidized in the reaction workup thereby allowing for net asymmetric carbohydroxylation of alkenes in a tandem one-pot diboration/Suzuki coupling/oxidation sequence.

Full text of DOI:10.1021/ol036219a

ORGANIC
LETTERS
2004
Vol. 6, No. 1
131-133
Catalytic Asymmetric
Carbohydroxylation of Alkenes by a
Tandem Diboration/Suzuki
Cross-Coupling/Oxidation Reaction
Steven P. Miller, Jeremy B. Morgan, Felix J. Nepveux V, and James P. Morken*
Department of Chemistry, The UniVersity of North Carolina at Chapel Hill,
Chapel Hill, North Carolina 27599-3290
morken@unc.edu
Received November 12, 2003
ABSTRACT
Chiral nonsymmetric 1,2-diboron adducts are generated by catalytic enantioselective diboration. Oxidation of these adducts provides 1,2-diols
in good yield. Alternatively, 1,2-diboron compounds may be reacted, in situ, with aryl halides wherein the less hindered C−B bond participates
in cross-coupling. The remaining C−B bond is then oxidized in the reaction workup thereby allowing for net asymmetric carbohydroxylation
of alkenes in a tandem one-pot diboration/Suzuki coupling/oxidation sequence.
Catalytic asymmetric complexity-generating reactions are
valuable tools for enantioselective synthesis of natural
products and basic organic building blocks. In an effort to
expand the number of complexity-generating reactions which
are available to simple alkenes, we recently began developing
the asymmetric diboration reaction as a platform for intro-
ducing new asymmetric alkene transformations.1,2 The asym-
metric diboration of olefins provides versatile reactive 1,2-
diboron intermediates in a catalytic enantioselective fashion
from commercially available reagents and catalyst. While
these intermediates are readily converted to the corresponding
diols by oxidative workup, it appeared tenable that interme-
diate diboron adducts might also engage in cross-coupling
reactions. This transformation would allow catalytic conver-
sion of alkenes to optically active compounds which are not
readily accessible by other means. These efforts are described
in this letter where the net catalytic enantioselective carbo-
hydroxylation of alkenes by a tandem single-pot diboration/
Suzuki cross-coupling/oxidation process is described.3
The rhodium-catalyzed asymmetric diboration reaction
provides aliphatic boronic esters which are not as well-
studied in cross-coupling reactions as their aryl and vinyl
counterparts.4 Available evidence indicates that primary
(1) Morgan, J. B.; Miller, S. P.; Morken, J. P. J. Am. Chem. Soc. 2003,
125, 8702.
(2) For nonenantioselective alkene diboration with Rh, see: (a) Baker,
R. T.; Nguyen, P.; Marder, T. B.; Westcott, S. A. Angew. Chem., Int. Ed.
Engl. 1995, 34, 1336. (b) Dai, C.; Robins, E. G.; Scott, A. J.; Clegg, W.;
Yufit, D. S.; Howard, J. A. K.; Marder, T. B. Chem. Commun. 1998, 1983.
(c) Nguyen, P.; Coapes, R. B.; Woodward, A. D.; Taylor, N. J.; Burke, J.
M.; Howard, J. A. K.; Marder, T. B. J. Organomet. Chem. 2002, 652, 77.
With Pt, see: (d) Iverson, C. N.; Smith, M. R., III Organometallics 1997,
16, 2757. (e) Ishiyama, T.; Yamamoto, M.; Miyaura, N. Chem. Commun.
1997, 689. (f) Marder, T. B.; Norman, N. C.; Rice, C. R. Tetrahedron Lett.
1998, 39, 155. (g) Ishiyama, T.; Momota, S.; Miyaura, N. Synlett 1999,
1790.
(3) Asymmetric carbometalation/oxidation also accomplishes net carbo-
hydroxylation albeit usually providing the primary alcohol. For a review
see: Marek, I. J. Chem. Soc., Perkin Trans. 1 1999, 545.
10.1021/ol036219a CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/27/2003

alkylboronic esters and their derivatives can participate in
Pd-catalyzed Suzuki coupling reactions, but that secondary
boronates are reluctant to react.5 This fact suggests that
unsymmetrical 1,2-bis(boronates), such as those derived from
terminal alkenes, might engage in selective cross-coupling
reactions. In this process, the more accessible C-B bond
would react faster leaving the secondary C-B bond available
for further transformation. Since there are no reports of
Suzuki couplings involving aliphatic 1,2-diboron adducts,
the stereochemical integrity of the nonreacting C-B bond
was uncertain. A recent report by Hartwig suggests the
potential for isomerization during Suzuki couplings of
alkylboronic acids, presumably by â-hydride elimination/
hydrometalation.6 In the context of 1,2-diboron reagents, this
complication might racemize the remaining C-B bond and
was cause for concern.
4-bromopyridine hydrochloride were added.8 The reaction
was stirred at 80 °C for 18 h, cooled to room temperature,
and treated with alkaline H2O2. Upon purification, the
carbohydroxylation adduct was isolated in 58% yield and in
an identical level of selectivity as the simple oxidation
adduct. That is, the configuration of secondary C-B was
unaltered during the cross-coupling process.
To explore the potential generality of the tandem dibora-
tion/Suzuki coupling reaction, diboration of other 1-alkene
substrates was examined. As shown in Table 1, encumbered
Table 1. Enantioselective Diboration/Oxidation of 1-Alkenesa
Prior to exploring the tandem diboration/Suzuki sequence,
access to an enantioselective diboration of sterically non-
symmetric alkenes was required. Preliminary studies indi-
cated that diboration of both styrene (33% ee) and R-meth-
ylstyrene (46% ee) is nonselective.1 Noting that regioselection
during alkene insertion into rhodium hydrides is dependent
on alkene electronics,7 it was reasoned that aliphatic 1-alk-
enes might exhibit different enantioselectivity patterns
compared to aromatic olefins and these substrates were
therefore examined. As shown in Scheme 1, aliphatic alkenes
Scheme 1
a Conditions: 5 mol % of (S)-Quinap, 5 mol % of (nbd)Rh(acac), 1.5
equiv of B2(cat)2, THF, rt, 6 h. Oxidative workup with NaOH/H2O2.
b Isolated yield of purified material. c This number was determined based
on the enantiopurity of the corresponding diboration/cross-coupling adduct.
R-olefins generally provide excellent levels of enantioselec-
tion although the level of induction tends to decrease with
diminished steric bulk adjacent to the reacting site. It also
appears that while both aromatic and aliphatic alkenes react
to form diols of the same configuration, aliphatic alkenes
react with higher selectivity than similarly sized aromatic
olefins (cf. entries 5 and 7).
Having established the level of enantioselection in the
diboration of 1-alkenes and therefore the level of selectivity
one can expect in carbohydroxylation adducts, the scope of
the single-pot cross-coupling process was examined. As
shown in Table 2, both aryl halides and aryl triflates can
provide acceptable yields of tandem reaction product.
can undergo efficient diboration in a highly selective fashion
and provide, after oxidative workup, the derived 1,2-diol in
high enantiopurity. To explore the Suzuki cross-coupling
reaction, the same 1,2-diboron intermediate was subjected
to in situ cross-coupling. In this experiment, the diboration
reaction mixture was diluted with THF/H2O and then 10 mol
% of (dppf)PdCl2, 4 equiv of Cs2CO3, and 2 equiv of
(4) For recent reviews of the Suzuki coupling reaction, see: (a) Suzuki,
A. J. Organomet. Chem. 1999, 576, 147. (b) Kohta, S.; Lahirir, K.;
Kashinath, D. Tetrahedron 2002, 58, 9633.
(5) (a) Kirchhoff, J. H.; Dai, C.; Fu, G. C. Angew. Chem., Int. Ed. 2002,
41, 1945. (b) Netherton, N. R.; Dai, C.; Neuschu¨tz, K.; Fu, G. C. J. Am.
Chem. Soc. 2001, 123, 10099. (c) Zou, G.; Falck, J. R. Tetrahedron Lett.
2001, 42, 5817.
(6) Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem.
2002, 67, 5553.
(7) (a) Hayashi, T.; Matsumoto, Y.; Ito, Y. J. Am. Chem. Soc. 1989,
111, 3426. (b) Evans, D. A.; Fu, G. C.; Anderson, B. A. J. Am. Chem. Soc.
1992, 114, 6679.
(8) (a) Gray, M.; Andrews, I. P.; Hook, D. F.; Kitteringham, J.; Voyle,
M. Tetrahedron Lett. 2000, 41, 6237. (b) Molander, G. A.; Ito, T. Org.
Lett. 2001, 3, 393. (c) Molander, G. A.; Yun, C. S. Tetrahedron 2002, 58,
1465. For other Suzuki reactions with alkylboronic acids, see: Ag(I)
acceleration: (d) Occhiato, E. G.; Trabocchi, A.; Guarna, A. J. Org. Chem.
2001, 66, 2459. (e) Zou, G.; Reddy, Y. K.; Falck, J. R. Tetrahedron Lett.
2001, 42, 7213. Fluoride acceleration: (f) Wright, S. W.; Hageman, D. L.;
McClure, L. D. J. Org. Chem. 1994, 59, 6095. Palladacycle catalysts: (g)
Botella, L.; Na´jera, C. J. Organomet. Chem. 2003, 663, 46.
132
Org. Lett., Vol. 6, No. 1, 2004

°C for 1 h. Oxidation provided the carbohydroxylation adduct
in 70% yield and 93% ee demonstrating that microwave
irradiation accelerates the alkyl boronic acid Suzuki coupling
without racemization of the adjacent C-B bond.
Table 2. Single-Pot Asymmetric Diboration/Suzuki Couplinga
The example in Scheme 3 demonstrates that the tandem
diboration/cross-coupling/oxidation sequence can be used to
Scheme 3 a
a Reagents and conditions: (a) 5 mol % of (S)-Quinap, 5 mol %
of (nbd)Rh(acac), 1.5 equiv of B2(cat)2, THF, rt, 6 h; then 3 equiv
of Cs2CO3, 2 equiv of bromochlorobenzene, 10 mol % of (dppf)-
PdCl2, THF/H2O, 80 °C, 18 h; oxidative workup with H2O2/NaOH,
6 h. (b) 10 mol % of Pd(OAc)2, 12 mol % of (t-Bu)2P(2-biphenyl),
1.5 equiv of Cs2CO3, 80 °C, 28 h.
prepare versatile intermediates in a concise fashion. Engaging
bromochlorobenzene in the tandem reaction sequence pro-
vides intermediate 1 in 50% isolated yield. Catalytic in-
tramolecular etherification11 using the Buchwald ligand
preserves substrate configuration11c provides benzofuran 2
in 87% ee and 90% yield. This sequence makes the optically
active heterocycle available from the simple alkene in a
concise two-pot reaction sequence.
In summary, we have described an operationally simple,
single-pot carbohydroxylation of olefin substrates. Current
research efforts are directed toward expanding the range of
synthetic transformations of chiral 1,2-diboron reagents.
a Conditions: 5 mol % of (S)-Quinap, 5 mol % of (nbd)Rh(acac), 1.5
equiv of B2(cat)2, THF, rt, 6 h; then 3 equiv of Cs2CO3, 2 equiv of aryl
halide, 10 mol % of (dppf)PdCl2, THF/H2O, 80 °C, 18 h. Oxidative workup
with H2O2/NaOH, 6 h. b Suzuki coupling at 50 °C for 24 h.
Heterocycles are accommodated in the reaction and, notably,
pyridines and aldehydes are unaltered during the oxidation.
Many organic transformations are accelerated by micro-
wave reaction conditions9 and the Suzuki coupling of
arylboronic acids is no exception.10 To determine whether
the diboration/cross-coupling/oxidation reaction sequence
could be accelerated by microwave irradiation during the
alkyl Suzuki coupling step, this transformation was examined
in further detail (Scheme 2). After diboration for 6 h, the
Acknowledgment. J.B.M. thanks the Wellcome Trust for
a fellowship. This work was supported by the NIH (GM
59417-03). J.P.M. thanks AstraZeneca, Bristol-Myers Squib,
DuPont, GlaxoSmithKline, and the Packard Foundation for
support.
Scheme 2
Supporting Information Available: Characterization
data and experimental procedures. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL036219A
(10) (a) Larhed, M.; Hallberg, A. J. Org. Chem. 1996, 61, 9582. (b)
Leadbeater, N. E.; Marco, M. Org. Lett. 2002, 17, 2973. (c) Leadbeater, N.
E.; Marco, M. J. Org. Chem. 2003, 68, 888.
(11) (a) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc.
1996, 118, 10333. (b) Mann, G.; Harwig, J. F. J. Am. Chem. Soc. 1996,
118, 13109. (c) Kuwabe, S.; Torraca, K. E.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 12202.
abovementioned cross-coupling reagents were added and the
reaction subject to microwave irradiation at 50 W and 80
(9) For a review on the utility of microwave heating see: L¨ındstrom,
P.; Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225.
Org. Lett., Vol. 6, No. 1, 2004
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