Rhodium-Catalyzed Asymmetric Ring Opening of Oxabicyclic Alkenes with Organoboronic Acids

Article abstract of DOI:10.1021/ol0256062

(Equation Presented) The first rhodium(I)-catalyzed asymmetric addition of organoboronic acids to oxabicyclic alkenes is reported. This asymmetric ring-opening (ARO) reaction can proceed in high yield under very mild conditions with electronically diverse

Full text of DOI:10.1021/ol0256062

ORGANIC
LETTERS
2002
Vol. 4, No. 8
1311-1314
Rhodium-Catalyzed Asymmetric Ring
Opening of Oxabicyclic Alkenes with
Organoboronic Acids
Mark Lautens,* Chris Dockendorff, Keith Fagnou, and Adrianna Malicki
DaVenport Laboratories, Department of Chemistry, UniVersity of Toronto,
Toronto, Ontario, Canada M5H 3H6
mlautens@chem.utoronto.ca
Received January 22, 2002
ABSTRACT
The first rhodium(I)-catalyzed asymmetric addition of organoboronic acids to oxabicyclic alkenes is reported. This asymmetric ring-opening
(ARO) reaction can proceed in high yield under very mild conditions with electronically diverse organoboronic acids, in a highly diastereoselective
and enantioselective manner.
Significant advances have been made in the area of rhodium-
catalyzed additions of aryl-1 and alkenylboronic acids to
activated olefins since the first report by Miyaura.2 Highly
enantioselective conjugate additions of boronic acids to
olefins have been reported by Hayashi.3 A common step in
these reactions is the carborhodation of the carbon-carbon
double bond followed by hydrolysis of the organorhodium
intermediate. We imagined a system whereby after carbo-
rhodation, a â-elimination instead of hydrolysis would occur
(Scheme 1). Where two enantiotopic leaving groups are
Herein, we present the realization of this concept by the
development of a rhodium-catalyzed asymmetric ring open-
ing (ARO)4 reaction of oxabicyclic alkenes with organo-
boronic acids. The reaction proceeds under very mild
conditions and generates multiple stereocenters in high yield
with excellent diastereoselectivity5 and enantioselectivity.
Our early efforts focused on the enantioselective addition
of arylboronate esters to activated oxabicyclic alkenes. It was
found that oxabenzonorbornadiene 1 undergoes rapid ring-
opening addition of various phenylboron species to give 2,
using catalytic [Rh(COD)Cl]2 and various phosphine ligands.
PPF-PtBu2 3 was identified as the ligand giving the best
reactivity and enantioselectivity for the addition of phenyl-
boronate (activated by MeLi)6 to 1 (Scheme 2).7
Scheme 1
(1) Review of asymmetric arylations: Bolm, C.; Hildebrand, J. P.; Mun˜iz,
K.; Hermanns, N. Ang. Chem., Int. Ed. 2001, 40, 3284.
(2) Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997, 16, 4229.
(3) (a) Hayashi, T. Synlett 2001, 879. (b) Senda, T.; Ogasawara, M.;
Hayashi, T. J. Org. Chem. 2001, 66, 6852 and references therein.
(4) For other examples of ARO reactions, see, for example: (a) Lautens,
M.; Hiebert, S.; Renaud, J.-L. J. Am. Chem. Soc. 2001, 123, 6834. (b)
Lautens, M.; Fagnou, K.; Taylor, M.; Rovis, T. J. Organomet. Chem. 2001,
624, 259. (c) Lautens, M.; Rovis, T. J. Am. Chem. Soc. 1997, 119, 11090.
(5) Only a single diastereomer has ever been detected for any of the
ring-opened products in this Letter.
available, an asymmetric carborhodation/â-elimination path-
way would result in the enantioselective formation of a new
carbon-carbon bond and regeneration of the olefin.
10.1021/ol0256062 CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/20/2002

catalytic turnover,9 and at room temperature it appears to
work best with 5-10 equiv relative to the oxabicycle. We
also found that complete reaction occurs with only 1.2 equiv
of ArB(OH)2 in THF at both room temperature and reflux,
indicating that catalytic deboronation of the arylboronic acid
does not occur to any appreciable extent, as has been
observed with Rh(I)-catalyzed reactions at higher tempera-
tures.10
Scheme 2
On the basis of these findings, we used as our standard
conditions 5 mol % of catalyst, 1.2 equiv of organoboronic
acid, and 0.5 equiv of Cs2CO3 (5 M in H2O) in THF at
room temperature and stirring for ∼15 h. The ARO reaction
of oxabicycle 4a works equally well with both electron-rich
and electron-poor arylboronic acids (Table 2). However, it
Shortly after these early experiments, it was found that
the ARO of other oxabicyclic substrates with a [Rh(COD)-
Cl]2/PPF-PtBu2 catalyst system can occur in high yield with
excellent enantioselectivity using arylboronic acids as the
nucleophillic partner, plus added water and base. The ARO
of [2.2.1] oxabicycle 4a with 4-methylphenylboronic acid
was adopted as the prototype reaction. Initial optimization
studies examined the effect of temperature on enantio-
selectivity (Table 1).
11
Table 2. ARO of Oxabicycle 4a with Arylboronic Acidsa
Table 1. Enantioselectivity vs Temperature Studiesa
phenyl
entry
substituent
productb
yield (%)c
ee (%)d
1
2
3
4
5
6
7e
8
9
4-Me
none
2-Me
4-Cl
3-Cl
2-Cl
5a
5b
5c
5d
5e
5f
5g
5h
5i
88
91
n.r.
95
73
n.r.
85
71
87
91
95
95
entryb
solvent
THF
THF
THF
THF
1,4-dioxane
THF/H2Oe
temp (°C)
ee (%)c
95
99
1
2
3
4
5
6d
65
55
40
25
25
88
90
94
95
93
99
3-I
95
94
96
95
4-Ac
4-OMe
3-OMe
10
5j
-20
a Reactions performed with 50 mg (0.271 mmol) of 4a. b Products are
diastereomerically pure. c Isolated yield after column chromatography. d As
determined by chiral HPLC (Chiracel OD or AD columns). e Required 5
mol % of [Rh(COD)Cl]2 to proceed to completion.
a Conditions (unoptimized): oxabicycle 4a (50 mg, 1 equiv) and Cs2CO3
(2 M in H2O, 50 mL, 0.4 equiv) is added to a stirred solution of
[Rh(COD)Cl]2 (3.3 mg, 0.025 equiv), (R)-(S)-PPF-P(tBu)2 (7.4 mg, 0.05
equiv), and 4-methylphenylboronic acid (0.111 g, 3 equiv) in the solvent
of choice (3 mL), at the stated reaction temperature, under a nitrogen
atmosphere. b All reactions gave complete conversion of starting material
to product as observed by TLC. Isolated yield for entry 4 ) 92%. c As
determined by chiral HPLC (Chiracel OD column). d With 0.1 equiv of
[Rh(COD)Cl]2, 0.2 equiv of PPF-P(t-Bu)2, and 20 equiv of Cs2CO3 (2 M
in H2O) solution. e Reaction was biphasic.
appears to be intolerant of substituents on the phenyl ring
ortho to boron (entries 3 and 6). Even under harsher
conditions (refluxing 1,4-dioxane with 10 mol % of Rh
catalyst), no measurable amount of ring-opened product was
observed. 3-Iodophenylboronic acid is compatible with the
catalyst, indicating that insertion into the Ar-I bond is not
competitive with insertion of the alkene (although higher
catalyst loadings were necessary for the reaction to proceed
to completion), permitting subsequent functionalization of
the product (entry 7).
The enantioselectivity of the ARO reaction increases with
decreasing temperature, within the studied range. This result
is in contrast to other known Rh(I)-catalyzed conjugate
additions, where enantioselectivities are improved at elevated
temperatures.3,4b The reaction is very sluggish at -20 °C,
though it was discovered that it is much faster at this
temperature when an excess of base solution is used (entry
6).8 The reaction requires a minimum amount of water for
(8) It is hypothesized that the use of base accelerates the transmetalation
of the boronic acid to rhodium. This has been proposed in the Pd-catalyzed
Suzuki reaction. See, for example: (a) Suzuki, A.; Miyaura, N. Chem. ReV.
1995, 95, 2457. (b) Wright, S. W.; Hageman, D. L.; McClure, L. D. J.
Org. Chem. 1994, 59, 6095.
(9) No reaction was observed in the presence of 4 Å molecular sieves
and no added water.
(10) Lautens, M.; Roy, A.; Fukuoka, K.; Fagnou, K.; Mart´ın-Matute, B.
J. Am. Chem. Soc. 2001, 123, 5358.
(11) ARO of 4 with 4-methylphenylboronic acid works equally well
(same yield and enantioselectivity) with CsF instead of Cs2CO3.
(6) Our initial efforts were inspired by a report by Kobayashi where
boronates were found to show enhanced reactivity relative to the analagous
boronic esters and acids: Kobayashi, Y.; Mizojiri, E.; Ikeda, E. J. Org.
Chem. 1996, 61, 5391.
(7) Other ligands giving worse reactivity and/or enantioselectivity were
BINAP, tol-BINAP, and i-Pr-POX. See the Supporting Information for more
details.
1312
Org. Lett., Vol. 4, No. 8, 2002

Alkenylboronic acids are also compatible in the reaction.
ARO of 1 and 4b with trans-1-hexen-1-ylboronic acid using
the standard conditions occurs in high yield with good
enantioselectivity (Scheme 3). Application of these conditions
phenylboron species are under investigation. The boronic
ester method was applied to oxabicycles 9a and 9b to
investigate the electronic effects of the substrate (Scheme
4). Preliminary results indicate a comparable yield and
Scheme 3
Scheme 4
enantioselectivity with the difluoro compound 9a, but
reaction with 9b led to a complex mixture of products.14
to the ARO of 1 with PhB(OH)2 gave a complex mixture of
products (Table 3, entry 1).12 At first it was hypothesized
The proposed mechanism for the ARO of oxabicyclic
alkenes is given in Scheme 5.15 The first step involves a
Table 3. ARO of Oxabicycle 1 with Ph Nucleophile 8a or 8ba
Scheme 5
entry
Ph source
yield (%)b
ee (%)c
methodd
1
2
3
8a
8a
8b
20
28
78
93
92
92
A
B
C
a All reactions performed with 50 mg (0.347 mmol) of 1. Reactions were
stirred for ∼15 h. b Isolated yield after column chromatography. c As
determined by chiral HPLC (Chiracel OD column). d Method A: Rh, ligand,
1, and 8a were added to a flask and placed under nitrogen. THF (1 mL)
and Cs2CO3 solution were then added. Method B: Rh, ligand, and 8a were
added to a flask and placed under nitrogen. THF (1.5 mL) and Cs2CO3
solution were then added. 1 (0.35 M THF solution) was added by syringe
pump to the reaction over 3.5 h. Method C: Rh, ligand, and 1 were added
to a flask and placed under nitrogen. 8b was added with THF (3 mL),
followed by Cs2CO3 solution.
transmetalation of the arylboronic acid to a rhodium(I)
chloride or hydroxide. This species will then undergo an exo-
selective asymmetric carborhodation at the oxabicycle olefin
to generate intermediate 11. Chelation of the olefin and the
oxygen atom of the oxabicycle may help to contribute to
the high exo selectivity with 1. â-Elimination of oxygen16
to give ring-opened intermediate 12 occurs, followed by
hydrolysis to liberate the ring-opened product and rhodium(I)
hydroxide.
that the product 2 may not be stable under the reaction
conditions, but this was disproven by resubmitting pure 2 to
the reaction conditions. While the slow addition of 1 resulted
in a cleaner reaction, the yield was still low (entry 2).
Surprisingly, much better results were obtained with the
ethylene glycol ester of PhB(OH)2 using the standard reaction
conditions (entry 3). The absolute configuration of 2 was
determined by an X-ray crystal structure of the hydrogenated
(tetrahydronaphthalene) 4-bromobenzoate derivative.13 The
reasons for the difference in reactivity between the two
In conclusion, we have developed a novel asymmetric ring-
opening reaction of oxabicyclic alkenes with addition of
alkenyl or aryl groups. The reactions can proceed in high
yield under very mild conditions with a variety of boronic
acids, with excellent enantio- and diastereoselectivities using
the [Rh(COD)Cl]2/PPF-PtBu2 catalyst system.
Acknowledgment. We thank AstraZeneca (Montreal),
NSERC, the ORDCF, and the University of Toronto for the
(12) (a) A racemic version of this reaction using Rh(I)/P(OEt)3 was
recently reported: Murakami, M.; Igawa, H. Chem. Commun. 2002, 390.
(b) Pd-catalyzed asymmetric arylation reactions of 1 have been reported:
Fiaud, J.-C.; Moinet, C. Tetrahedron Lett. 1995, 36, 2051.
(13) See the Supporting Information for details. Absolute configurations
of the other compounds in this Letter have been tentatively assigned by
analogy.
(14) Additional catalyst and phenylboronic ester were added to both
reactions (performed with 50 mg of oxabicycle) to push reactions to
completion.
(15) Studies to support this mechanism are underway.
(16) See ref 4a for a discussion of this step in a Pd-catalyzed ARO.
Org. Lett., Vol. 4, No. 8, 2002
1313

funding of this research. We also thank Solvias for providing
the PPF-PtBu2 ligand used in these studies and Dr. Alan
Lough for X-ray structure determination. K.F. thanks NSERC
for a postgraduate scholarship (Ph.D.). K.F. and C.D. thank
AstraZeneca and NSERC for industrial postgraduate scholar-
ships. A.M. thanks NSERC for a summer scholarship.
Supporting Information Available: Experimental details
and characterization data including 1H and 13C NMR, X-ray
crystal data, IR, HR-MS, and HPLC conditions. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL0256062
1314
Org. Lett., Vol. 4, No. 8, 2002