Catalytic enantioselective formation of chiral-bridged dienes which are themselves ligands for enantioselective catalysis

Article abstract of DOI:10.1021/ol9025793

"Chemical Equation Presented" This paper reports a method for highly enantioselective Diels-Alder reaction with an acetylene equivalent to produce chiral-bridged dienes. These dienes, by coordination to Rh(I), can serve as catalysts for the enantioselective addition of vinyl or aryl groups to (aryl-unsaturated ketones

Full text of DOI:10.1021/ol9025793

ORGANIC
LETTERS
2010
Vol. 12, No. 1
172-175
Catalytic Enantioselective Formation of
Chiral-Bridged Dienes Which Are
Themselves Ligands for
Enantioselective Catalysis
M. Kevin Brown and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVeristy,
Cambdrige, Massachusetts 02138
corey@chemistry.harVard.edu
Received November 6, 2009
ABSTRACT
This paper reports a method for highly enantioselective Diels-Alder reaction with an acetylene equivalent to produce chiral-bridged dienes.
These dienes, by coordination to Rh(I), can serve as catalysts for the enantioselective addition of vinyl or aryl groups to r,ꢀ-unsaturated
ketones.
Reaction sequences in which a catalytic enantioselective
process produces a catalyst for another enantioselective
transformation are synthetically advantageous. In addition,
along with template-directed molecular reproduction, such
catalytic cascades are fundamental to life.
lectivity, and (3) predictable absolute configuration of product. Their
use has enabled the conversion of some of the most important
multistep syntheses of racemic natural products to catalytic enan-
tioselective versions. This letter describes the use of I toward two
objectives: first, the development of a method for the enantiose-
lective synthesis of Diels-Alder adducts of acetylenic dieneo-
philes;2 and second, the development of methodology for the
catalytic enantioselective synthesis of catalysts (e.g., [M]-II), which
can function enantioselectively. The advent of cascades of processes
for the generation of enantioselective catalysts would allow
significant improvement in the power of chemical synthesis. One
can envisage that there will eventually be a large collection of
The N-protonated oxazaborolidine I and its N+-AlBr3 and N+-
CH3 coordinated analogues represent a new class of chiral and
strong Lewis acids that have proved to be remarkably useful for
the synthesis of chiral organic molecules from simple, achiral
precursors.1 These catalysts offer numerous advantages in enan-
tioselective Diels-Alder reactions, including: (1) broad applicabil-
ity, even with less reactive substrates, (2) 20:1 or better enantiose-
(1) (a) Corey, E. J. Angew. Chem., Int. Ed. 2002, 41, 1650–1667. (b)
Corey, E. J. Angew. Chem., Int. Ed. 2009, 48, 2100–2117.
(2) (a) Corey, E. J.; Lee, T. W. Tetrahedron Lett. 1997, 38, 5755–5758.
(b) Ishihara, K.; Kondo, S.; Kurihara, H.; Yamamoto, H. J. Org. Chem.
1997, 62, 3026–3027. (c) Evans, D. A.; Miller, S. J.; Lectka, T.; Matt, P. V.
J. Am. Chem. Soc. 1999, 121, 7559–7573. (d) Ishihara, K.; Fushimi, M.
J. Am. Chem. Soc. 2008, 130, 7532–7533. (e) Payette, J. N.; Yamamoto,
H. Angew. Chem., Int. Ed. 2009, 48, 8060–8062.
10.1021/ol9025793  2010 American Chemical Society
Published on Web 11/30/2009

molecules produced by enantioselective catalysts that constitutes
a “catalytic pool” analogous to the “chiral pool” of naturally
produced organic molecules.
The utility of dienes 4-6 as chiral ligands was examined in the
context of Rh-catalyzed enantioselective conjugate additions of
ArB(OH)2 to R,ꢀ-unsaturated ketones (Table 1).3,5,6 Initial studies
Chiral, nonracemic, bridged dienes have proven to be
exceptionally useful ligands for several classes of catalytic
enantioselective C-C bond forming reactions.3 Nearly all
of the known bicyclic diene ligands are prepared in enan-
tiomerically pure form from either chiral pool starting
materials or by the use of resolution techniques (fractional
crystallization or HPLC with a chiral column).
Table 1. Initial Survey of Norbornadiene-Based Chiral Ligands
As illustrated in Scheme 1, we have established a catalytic
enantioselective route to norbornadiene-based ligands (4-6).4,6a
Scheme 1. Preparation of Norbornadiene-Based Ligands
established that while use of ligands 4-6 all lead to highly
enantioselective reactions (96-98% ee), the BOM-ether 6 gives
the highest conversion of starting material (Table 1, entry 3).
As illustrated in Table 2, highly enantioselective (86-97%
ee) conjugate additions of PhB(OH)2 to various R,ꢀ-
Table 2. Rh-Catalyzed Enantioselective Conjugate Addition of
PhB(OH)2 to Various Enones Promoted by Rh-6a
The route hinges on the use of a catalytic enantioselective
Diels-Alder cycloaddition of ꢀ-chloroacrylate 1 (a relatively
unreactive dieneophile) with cyclopentadiene promoted by
protonated oxazaborolidine 2, which proceeds with high
enantioselectivity and in good yield. From there, the dienes
are prepared in enantiomerically pure form in two to three
straightforward, high-yielding transformations (Scheme 1).
a Reactions carried out under N2, in dioxane/H2O (5/2) with 1.0 equiv
of KOH (aq), 2 h reaction time, 24 °C, 1.1:1 (6:Rh). b Yield of isolated
product after silica gel column chromatography. c Determined by HPLC
analysis with a chiral column.
(3) For reviews regarding diene-based ligands, see: (a) Johnson, J. B.; Rovis,
T. Angew. Chem., Int. Ed. 2008, 47, 840–871. (b) Defieber, C.; Grutzmacher,
H.; Carreira, E. M. Angew. Chem., Int. Ed. 2008, 47, 4482–4502.
(4) Initial studies on the synthesis of the diene framework by Diels-Alder
cycloaddition of dienes to alkyne-based dieneophiles were discontinued
because only moderate enantioselectivities were observed.
(5) (a) Hayashi, T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829–2844.
(b) Hayashi, T. Bull. Chem. Soc. Jpn. 2004, 77, 13–21. (c) Christoffers, J.;
Koripelly, G.; Rosiak, A.; Ro¨ssle, M. Synthesis 2007, 1279–1300.
(6) For early reports regarding catalytic enantioselective reactions with
diene-based ligands, see: (a) Hayashi, T.; Ueyama, K.; Tokunaga, N.; Yoshida,
K. J. Am. Chem. Soc. 2003, 125, 11508–11509. (b) Fischer, C.; Defieber,
C.; Suzuki, T.; Carreira, E. M. J. Am. Chem. Soc. 2004, 126, 1628–1629.
(c) Defieber, C.; Paquin, J.-F.; Serna, S.; Carreira, E. M. Org. Lett. 2004, 6,
3873–3876. For selected recent reports on Rh-catalyzed conjugate addition
with diene-based ligands, see: (d) Okamoto, K.; Hayashi, T.; Rawal, V. H.
Org. Lett. 2008, 10, 4387–4389. (e) Gendrineau, T.; Chuzel, O.; Eijsberg,
H.; Genet, J.-P.; Darses, S. Angew. Chem., Int. Ed. 2008, 47, 7669–7672.
(f) Grendrineay, T.; Genet, J.-P.; Darses, S. Org. Lett. 2009, 11, 3486–
3489. (g) Okamoto, K.; Hayashi, T.; Rawal, V. H. Chem. Commun. 2009,
4815–4817. (h) Shintani, R.; Tsutsumi, Y.; Nagaosa, M.; Nishimura, T.;
Hayashi, T. J. Am. Chem. Soc. 2009, 131, 13588–13589. (i) Hu, X.; Zhuang,
M.; Cao, Z.; Du, H. Org. Lett. 2009, 11, 4744–4747. (j) Mahoney, S. J.;
Dumas, A. M.; Fillion, E. Org. Lett. 2009, 11, 5346–5349. (k) Shintani,
R.; Ichikawa, Y.; Takatsu, K.; Chen, F.-X.; Hayashi, T. J. Org. Chem. 2009,
74, 869–873. For mechanistic studies on Rh-catalyzed conjugate addition,
see: (l) Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am.
Chem. Soc. 2002, 124, 5052–5058. (m) Kina, A.; Yasuhara, Y.; Nishimura,
T.; Iwamura, H.; Hayashi, Y. Chem. Asian J. 2006, 1, 707–711.
unsaturated carbonyls promoted by Rh-6 can be carried out.
With five- and six-membered-ring R,ꢀ-unsaturated ketones
(Table 2, entries 1 and 2), only 0.5 mol % catalyst is
adequate, but somewhat more (3 mol %) is appropriate for
less reactive substrates, such as cycloheptenone (Table 2,
entry 3) or an acyclic enone (Table 2, entry 4).7
During the course of our studies, we discovered that
the efficiency of the reaction depends on the order of
addition of reagents as outlined in Figure 1. One explana-
tion for this observation is that the ligand (6) is trans-
formed into a catalytically incompetent product under the
conditions of the conjugate addition. This possibility was
tested by allowing the diene 6 to react with stoichiometric
amounts of PhB(OH)2 and [RhCl(CH2CH2)2]2 in
dioxane-KOH-H2O for 10 min at 24 °C. Under these
standard reaction conditions, rapid phenylation of the
Org. Lett., Vol. 12, No. 1, 2010
173

illustrated in Scheme 3, bicyclooctadienes 11 and 12 are
prepared efficiently in three steps. Diels-Alder reaction of
trifluoroethylacrylate (7) and 1,3-cyclohexadiene gives 8 in 90%
yield and 99% ee with 2 as catalyst.9 Oxidation of 8 with the
Mukaiyama reagent 910 followed by reaction with an alkyl-
lithium reagent provides the diene ligands 11 and 12.11 Although
it is not necessary to prepare and isolate Rh-12 for efficient
conjugate addition, we have established its structure by X-ray
crystallography (Scheme 3).
The hydroxy bicyclooctadienes 11 and 12 are excellent
ligands for the Rh-catalyzed enantioselective conjugate
addition of PhB(OH)2 to cyclohexenone (Table 3) and Rh-
Figure 1. Investigations into order of addition.
Table 3. Initial Survey of Bicyclooctadiene-Based Chiral
Ligands
disubstituted olefinic linkage of 6 occurred to form the
product shown in Scheme 2 (stereochemistry assumed).
Scheme 2. Arylation of Diene 6
12 is especially effective with only 0.25 mol % catalyst
(Table 4, entry 2).12
Catalytic arylation of norbornenes has been observed
previously.8
To overcome the issues associated with such strained ligands,
we turned to the less strained bicyclooctadiene systems. As
Table 4. Rh-Catalyzed Enantioselective Conjugate Addition of
PhB(OH)2 to Various Enones Promoted by Rh-12a
Scheme 3. Preparation of Bicyclooctadiene-Based Ligands
a Reactions carried out under N2, in MeOH/H2O (5/2) with 0.5 equiv
of KOH (aq), 1 h reaction time, 1.1:1 (12:Rh). b Reaction carried out in
dioxane/H2O (5/2). c Yield of isolated product after silica gel column
chromatography. d Determined by HPLC analysis with a chiral column.
Several points regarding reactions promoted by Rh-12
merit mention:13 (1) Lower catalyst loading of Rh-12 can
be employed as compared to Rh-6 (0.5 mol % vs. 3.0 mol
%, Table 4). (2) Addition of a vinylboronic acid or a
174
Org. Lett., Vol. 12, No. 1, 2010

sterically hindered arylboronic acid to cyclohexenone (1 mol
% Rh-12, dioxane, 50 °C, 2 h) provides 14 or 15 (respec-
tively) in high yield and enantiomeric excess. (3) Rhodium-
catalyzed conjugate addition of boronic acid 17 to R,ꢀ-
unsaturated ketone 16 provides 18, a key intermediate for
the enantioselective synthesis of 9-isocyanopupukeanane via
the bicyclic ketone 20 (Scheme 4).14
a catalyst is used for the enantioselective synthesis of another
chiral catalyst.
Acknowledgement. We thank the National Institutes of
Health for a Postdoctoral Fellowship to M.K.B., the Jacobsen
lab (Harvard University) for assistance in acquiring HPLC
and IR data, and Dr. Shao-Liang Zheng (Harvard University)
for X-ray diffraction analysis.
Supporting Information Available: Experimental pro-
cedures and spectral and analytical data for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Scheme 4. Enantioselective Synthesis of
9-Isocyanopupukeanane Intermediate 20
OL9025793
(7) Use of 1.0 equiv of KOH is optimal for reactions promoted by
Rh-6.
(8) Oguma, K.; Miura, M.; Satoh, T.; Nomura, M. J. Am. Chem. Soc.
2000, 122, 10464–10465.
(9) Diels-Alder cycloaddition promoted by 2 between ꢀ-chloroacrylate
1 and 1,3-cyclohexadiene (24 °C) results in <2% conversion.
(10) Mukaiyama, T.; Matsuo, J.-I.; Kitagawa, H. Chem. Lett. 2000,
1250–1251.
(11) 13 was prepared from 11 in 87% yield (BOMCl, i-Pr2NEt, CH2Cl2,
24 °C).
(12) In select cases, Rh-12 is significantly more selective than Rh-11.
For example, the reaction presented in Table 4, entry 4 promoted by Rh-11
furnishes the product with 75% ee.
(13) For reactions promoted by Rh-12, in general, use of MeOH leads
to slightly higher levels of enantioselectivity versus dioxane. For
reactions presented in Table 2, MeOH was found to provide similar
results as dioxane.
(14) Corey, E. J.; Behforouz, M.; Ishiguro, M. J. Am. Chem. Soc. 1979,
101, 1608–1609.
The results above effectively address the longstanding
problem of catalytic enantioselective synthesis of adducts
of 1,3-dienes and acetylenic dieneophiles. The application
of this advance leads to a useful catalytic cascade in which
Org. Lett., Vol. 12, No. 1, 2010
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