A highly enantioselective intramolecular heck reaction with a monodentate ligand

Article abstract of DOI:10.1021/ja017200a

An efficient enantioselective intramolecular Heck reaction of cyclohexadienones, using readily available and modular TADDOL-based mono- and bidentate phosphoramidites as chiral ligands and not requiring any additives, has been developed. Excellent enantio

Full text of DOI:10.1021/ja017200a

Published on Web 12/18/2001
A Highly Enantioselective Intramolecular Heck Reaction with a Monodentate
Ligand
Rosalinde Imbos, Adriaan J. Minnaard, and Ben L. Feringa*
Stratingh Institute, Department of Organic Chemistry, UniVersity of Groningen,
Nijenborgh 4, 9747 AG Groningen, The Netherlands
Received October 1, 2001
Since the first reports in the late 1980s1 the asymmetric Heck
reaction (AHR) has received considerable attention.2-4 High
selectivities have been reached by using bidentate ligands, usually
phosphines (predominantly BINAP) or phosphine-oxazolines. A
number of intermolecular AHR’s with ee’s >96% have been
reported.2,3 For the intramolecular AHR, however, the ee values
are typically around 80% with notable exceptions leading to g90%
ee.5 The intramolecular AHR has featured a prominent role in the
synthesis of complex natural products.2,3,5
Figure 1. General asymmetric Heck reaction.
We have shown that phosphoramidites are versatile ligands for
a variety of catalytic asymmetric transformations.6 Despite the fact
that the classic Heck reaction was shown to occur in the presence
of phosphoramidites,7 the use of phosphoramidites as chiral ligands
in an AHR resulted in very low enantioselectivity.8
Figure 2. Chiral ligands used for the AHR.
We designed prochiral cyclohexadienone 1 as a new substrate
for the intramolecular AHR (see Figure 1).9 Upon AHR, the
Scheme 1. Synthesis of Dienone 1
stereogenic center is not created at the site of C-C bond formation,
but instead the cyclohexadienone is desymmetrized. We expected
the chiral catalyst to show high face-selectivity (based on the
excellent face-selectivity already observed in asymmetric 1,4-
additions to cyclohexadienones10) leading to 4a-methoxy-4aH-
benzo[c]chromen-2(6H)-one, which could act as a model compound
for, e.g., the synthesis of the anticancer Amaryllidaceae alkaloid
pancratistatin.11
Herein we report cyclohexadienones as new substrates for the
intramolecular AHR and the remarkable finding that monodentate
phosphoramidites are effective ligands for this highly enantiose-
lective AHR with ee’s up to 96%.
Cyclohexadienone 1 is efficiently synthesized in two steps from
commercially available 2-iodobenzyl chloride 3. Formation of the
monoether of hydroquinone in 91%, using benzyl chloride 3, is
followed by phenolic oxidation with phenyliododiacetate (PIDA)
in MeOH12 to provide 1 in 83% yield. (Scheme 1)
best results were obtained with iPr2EtN and especially Cy2MeN
(based on recent reports of the effectiveness of this bulky tertiairy
amine15), both with full conversion and high enantioselectivities
of 89% and 90%, respectively. Additives such as nBu4NX (X ) I,
OTf) or iPr2EtN‚HCl did not result in improvement of the reaction,
whereas with silver salts no conversion was obtained. This AHR
turned out not to be very sensitive to air and water and it could
even be performed with nondistilled solvents.
Since, to the best of our knowledge, all successful ligands used
so far for the AHR were bidentate, we focused our initial studies
on the use of bidentate TADDOL-based phosphoramidite L*-1 as
chiral ligand.13 Employing an in situ prepared catalyst from
Pd(OAc)2, and L*-1 (1:2 ratio) in the presence of K2CO3 as a base
in THF we indeed obtained with full conversion of the starting
material product 2 in 68% ee14 (Table 1). Changing the solvent to
CHCl3 resulted in full conversion and 86% ee. For NMP and DMA,
commonly used solvents in Heck couplings, the stereoselectivities
were much lower (ee <60%), whereas for acetonitrile and DMSO
racemic product was obtained due to a very fast background reaction
(not involving L*).
Recent developments in asymmetric catalysis show that high
enantioselectivities can be induced by monodentate chiral ligands,6,16,17
and that monodentate BINOL based phosphoramidites are excellent
ligands for rhodium-catalyzed asymmetric hydrogenations.18 Al-
though monodentate ligands were never very successful in inter-
as well as intramolecular AHR’s, we examined the monodentate
analogue L*-219 of bidentate ligand L*-1 in the Heck coupling of
1.
Much to our delight the use of monodentate ligand L*-2 resulted
in a more selective conversion of 1 to 2 compared to the Heck
coupling of 1 employing bidentate ligand L*-2 (entries 15,16).
Again Cy2MeN is the base of choice. With use of Pd(OAc)2 in the
presence of L*-2 and Cy2MeN, full conversion was reached,
providing 2 in 71% isolated yield with an excellent ee of 96%,20,21
without the use of expensive silver or toxic thallium salts.
As is commonly seen in AHR’s, the nature of the base has a
dramatic effect on the reaction (entries 6-10). The use of Et3N
resulted in a slower reaction but with enhanced selectivity. The
9
184 VOL. 124, NO. 2, 2002 J. AM. CHEM. SOC.
10.1021/ja017200a CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Table 1. AHR of 1 to 2, Using Phosphoramidites as Liganda
ligands and not requiring any additives, has been developed.
Excellent enantioselectivities up to 96% ee are reached for the first
time in a Heck reaction with monodentate ligands. Extension of
the scope of this reaction and detailed mechanistic studies are
currently in progress.
entry
L*
solvent
base
additive
conv. (%)b ee (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
L*-1 THF
L*-1 CH2Cl2
L*-1 CHCl3
K2CO3
K2CO3
K2CO3
100
100
100
100
<10
60
68
35
100
100
80
95
90
<2
100
100
68
84
86
80
L*-1 Toluene K2CO3
L*-1 CHCl3
L*-1 CHCl3
L*-1 CHCl3
L*-1 CHCl3
L*-1 CHCl3
L*-1 CHCl3
L*-1 CHCl3
L*-1 CHCl3
L*-1 CHCl3
L*-1 CHCl3
L*-2 CHCl3
L*-2 CHCl3
PSd
K3PO4
PMP
Acknowledgment. We thank Mr. M. B. van Gelder for carrying
out the HPLC measurements. Financial support from the Dutch
Foundation for Scientific Research (NWO-CW) is gratefully
acknowledged.
86
87
92
89
90
83
75
78
Et3N
iPr2EtN
Cy2MeN
iPr2EtN
iPr2EtN
iPr2EtN
iPr2EtN
iPr2EtN
Cy2MeN
Supporting Information Available: Experimental and chromato-
graphic details (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
iPr2EtN‚HCl
e
f
Ag3PO4
93
96
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Scheme 2. Proposed Catalytic Cycle
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conditions, and product 2 was obtained after 48 h in 0-50% yield
and 0-5% ee.
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of dienone 1 results in Pd(II) complex B. Subsequent C-C bond
formation (association and insertion into Pd-C) leads to complex
C, which does not have a syn â-hydride. To reach the final product
2 epimerization of the C-2 center leading to D followed by syn
â-hydride elimination to complex E needs to take place. The net
trans elimination can be explained via a mechanism involving oxo-
π-allylpalladium intermediates, similar to enolization in normal
ketones,11 which have found precedence in the Pd-catalyzed
dehydrosilylation of silyl enolethers.24 It should be noted that several
examples of apparent trans â-hydride elimination have appeared
in the literature.25 Finally, reductive elimination of HI with base
leads to the starting complex A. Preliminary mechanistic studies
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(20) This is the average of 8 experiments with ee’s ranging from 94.0 to 96.5%.
(21) The results of the AHR of two other examples of dienones, resulting in
93% and 75% ee, respectively, are given in the Supporting Information.
(22) Sato, Y.; Honda, T.; Shibasaki, M. Tetrahedron Lett. 1992, 33, 2593.
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In conclusion, an efficient enantioselective intramolecular Heck
reaction of cyclohexadienones, using readily available and modular
TADDOL-based mono- and bidentate phosphoramidites as chiral
(27) The ligand-to-palladium ratio in the actual catalytically active complex
is at present unclear.
JA017200A
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J. AM. CHEM. SOC. VOL. 124, NO. 2, 2002 185