Iridium-catalyzed regioselective and enantioselective allylation of trimethylsiloxyfuran

Article abstract of DOI:10.1021/ja306850b

We report the regio- and enantioselective allylation of an ester enolate, trimethylsiloxyfuran. This enolate reacts at the 3-position with linear aromatic allylic carbonates or aliphatic allylic benzoates to form the branched substitution products in the presence of a metallacyclic iridium catalyst. This process provides access to synthetically important 3-substituted butenolides in enantioenriched form. Stoichiometric reactions of the allyliridium intermediate suggest that the trimethylsiloxyfuran is activated by the carboxylate leaving group.

Full text of DOI:10.1021/ja306850b

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Communication
Iridium-Catalyzed Regioselective and
Enantioselective Allylation of Trimethylsiloxyfuran
Wenyong Chen, and John F. Hartwig
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja306850b • Publication Date (Web): 06 Sep 2012
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Iridium-Catalyzed Regioselective and Enantioselective Allylation of
Trimethylsiloxyfuran
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Wenyong Chen and John F. Hartwig*
Department of Chemistry, University of California, Berkeley, California, 94720, United States
Supporting Information Placeholder
namyl carbonates. The process furnishes 3-substituted bu-
ABSTRACT: We report the regioselective and enantioselec-
tenolides containing an easily functionalized terminal double
tive allylation of an ester enolate, trimethylsiloxyfuran. This
bond and various aryl and alkyl groups at the stereogenic cen-
enolate reacts in the 3-position with linear aromatic allylic
ter. In addition to providing useful butenolides, this process
carbonates or aliphatic allylic benzoates to form the branched
begins to address the challenge of conducting allylic substitu-
tion with ester enolates.
substitution products in the presence of a metallacyclic iridium
catalyst. This process provides access to synthetically im-
portant 3-substituted butenolides in enantioenriched form.
Stoichiometric reactions of the allyliridium intermediate imply
that the trimethylsiloxyfuran is activated by the carboxylate
leaving group.
SCHEME 1. Palladium and iridium catalyzed allylic sub-
stitution with trimethylsiloxyfuran
Me
O
[Pd]
OAc
O
*
OTMS +
(a)
ref. 7
kinetic resolution
O
R'
Me
R'
R' = aryl, conjugation control
R' = alkyl, steric control
Asymmetric allylic substitution catalyzed by metallacyclic
iridium phosphoramidite complexes 1 and 21 forms enantioen-
riched materials from readily available allylic esters and a
variety of heteroatom2 and carbon3 nucleophiles. However, the
carbon nucleophiles that undergo this process are mainly stabi-
lized enolates.3a-h Reactions of unstabilized enolates3i-k have
been limited to those derived from methyl ketones. Enolates of
esters that undergo iridium catalyzed allylic substitutions pos-
sess a second electron-withdrawing group (EWG) to stabilize
the enolate.
R'
O
[Ir]
O
*
OTMS +
R'
LG
(b)
O
this work
100% conversion
R
R
R = H, Me, R' = alkyl, aryl
LG = OCO2Me or OBz
deconjugative
product
Ar
O
O
O
Ir
P
N
O
O
= (R)-Binol
P
N
O
Ar
Ar Ar
1: Ar = Ph
Trimethylsiloxyfuran 3a is an important ester enolate be-
cause it can be used to construct butenolides, a motif found in
over 13,000 natural products.4 High diastereo- and enantiose-
lectivity has been achieved from the addition of 3a to carbonyl
acceptors with Lewis-acid or organic catalysts.4a, 5 These reac-
tions occurred at C-5 of 3a. Regioselective reactions at C-3 of
3a to form enantioenriched, 3-substituted butenolides are rare.6
(Ra, Rc, Rc)-L1: Ar = Ph
2: Ar = 2-MeO-C6H4
(Ra, Rc, Rc)-L2: Ar = 2-MeO-C6H4
TABLE 1. Effect of catalyst and fluoride source on the Ir-
catalyzed allylic substitution of trimethylsiloxyfurana
One set of palladium-catalyzed kinetic resolutions of methyl
substituted allylic acetate with trimethylsiloxyfuran does occur
at C-3 of the nucleophile 3a (a of Scheme 1).7 In this case, the
regioselectivity at the electrophile was controlled by the prop-
erties of the substrate. The attack at the less hindered end of
the allyl unit led to the conjugated product.8, 9 This origin of
regioselectivity restricts the scope of electrophiles that give
one major product. Moreover, the reactions occurred with only
unsubstituted trimethylsiloxyfuran. Asymmetric reactions
with catalysts based on other metals could provide comple-
mentary selectivities to these palladium–catalyzed reactions.
However, asymmetric allylic substitutions catalyzed by com-
plexes of other metals with ester enolates lacking a second
EWG have not been reported.
Entry
Cat.b
Fluoride
CsF
Yield(%)c
13
5a:6ad
-
ee(%)e
1
2
3
4f
5
6
-
1
2
2
2
2
2
2
CsF
32
20:1
20:1
-
99
99
-
ZnF2
87(85)
trace
trace
40
TBAF
TBAT
None
None
-
-
20:1
20:1
99
99
7g
89
We report an iridium catalyzed allylic substitution between
trimethylsiloxyfuran and prochiral electrophiles to form enan-
tioenriched 3-substituted butenolides with high regioselectivi-
ty for the more hindered product (b of Scheme 1), including
formation of the deconjugated product from reactions of cin-
a
See supporting information for experimental details. b 1 mol %
c
Ir catalyst was used unless otherwise noted. The yield was de-
termined by 1H NMR analysis with mesitylene as the internal
standard. The value in parentheses corresponds to the isolated
d
1
yield. The ratio was determined by H NMR analysis of crude
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f
reaction mixtures. e The ee was determined by chiral HPLC. 1-
5f with a 10:1 ratio of 5f to linear product 6f (entry 5). How-
phenylallylalcohol was formed in 69% yield. g 2 mol % Ir catalyst
was used.
1
2
3
4
5
6
7
8
ever, the reaction of the corresponding aliphatic allylic benzo-
ate 4g gave the branched allylation product 5f in good yield
and regioselectivity (10:1) with high enantioselectivity (entry
6) in the presence of 3 mol % catalyst 2 at 50 °C.
Our initial studies focused on the reaction of trime-
thylsiloxyfuran 3a with cinnamyl carbonate 4a. Table 1 sum-
marizes the effect of several parameters on this reaction. Reac-
tions catalyzed by complexes 1 and 2 with CsF to activate the
silyl enolate formed the 3-allylated product 5a regioselective-
ly.10, 11 The reaction with catalyst 2 occurred in higher yield
than the reaction with catalyst 1 (entries 1 and 2). Further as-
sessment of fluoride activators showed that reactions conduct-
ed with ZnF2 gave the desired product 5a in a high 85% isolat-
ed yield with 99% ee (entry 3). The reaction with soluble fluo-
ride salts, such as TBAF and TBAT, gave only trace amounts
of the desired product (entries 4 and 5). To our surprise, this
reaction also proceeded to completion without any additives,
although higher catalyst loadings were needed in this case
(entries 6 and 7). This final observation is consistent with
studies on stoichiometric reactions of catalytic intermediates
in the absence of additives described later in this paper.
These conditions were suitable for a range of aliphatic ben-
zoates. For example, crotyl substrate 4h reacted to give the
substitution product in 71% yield with excellent enantioselec-
tivity (entry 7). Furthermore, the branched product formed
selectively, even when the aliphatic substituent was branched
at the carbon adjacent to the allyl unit (entry 8). The allylic
substitution of dienyl benzoate 4j with catalyst 2 yielded the
product as a 1:1 mixture of constitutional isomers (entry 9),
but occurred with moderate regioselectivity and high enanti-
oselec-tivity when dibenzo[a,e]cyclooctatetraene (DBCOT)
was used as a supporting ligand instead of cyclooctadiene
(COD).2
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The reactions of 3, 4, and 5-methyl trimethylsiloxyfurans
(3b-d) revealed the effect of furanyl substituents on the cata-
lytic process. The reaction of 3-methyl trimethylsiloxyfuran
3b gave two products (Scheme 2). The 5-substituted linear
product 6j was isolated in 28% yield and 94% ee. The 3-
substituted product was obtained as inseparable diastereomers
5j and 5j’. Heating the mixture of diastereomers in dichloro-
methane at 40 °C for 1 h led to a single diastereomer 5j con-
taining adjacent quaternary and tertiary stereogenic centers
and linear product 6j. Product 6j formed by a Cope rear-
rangement of one of the diastereomers.12 Thus, the 3-
substituted product 5j was ultimately isolated as a single dia-
stereomer in 97% ee by a one-pot process involving asymmet-
ric allylation and Cope rearrangement (Scheme 2, bottom).13
TABLE 2. Iridium-catalyzed allylic substitution of trime-
thylsiloxyfuran 3aa
Entry
1
R (4)
4-MeO-C6H4 (4b)
4-F- C6H4 (4c)
4-Cl- C6H4 (4d)
3-F- C6H4 (4e)
n-Propyl (4f)
LG
Yield(%)b 5/6c eed (%)
OCO2Me
OCO2Me
OCO2Me
OCO2Me
OCO2Me
OBz
5b, 70 20:1
5c, 83 20:1
5d, 78 20:1
5e, 91 20:1
5f, 18 10:1
5f, 80 10:1
5g, 71 10:1
5h, 60 8:1
5i, 90 1:1
5i, 83 3:1
98
95
97
97
99
96
97
94
-
2
SCHEME 2. Iridium-catalyzed allylic substitution with 3-
methyl substituted trimethylsiloxyfuransa
3
4e
5f
6f,g
7 f,g
8 g
9
n-Propyl (4g)
Methyl (4h)
OBz
Cyclohexyl (4i)
1-propenyl (4j)
1-propenyl (4j)
OBz
OCO2Me
OCO2Me
10h
99
a See supporting information for experimental details. b Isolated
c
1
yield Ratio was determined by H NMR analysis of the crude
reaction mixtures. d ee was determined by chiral HPLC analysis. e
2 mol % Ir catalyst 2 was used. f The products 6 are 3-substituted
linear products. g The reaction was conducted with 3 mol % Ir
catalyst 2 at 50 °C. h 2 mol % [(dbcot)IrCl]2 was used.
The scope of the Ir-catalyzed asymmetric allylation of tri-
methylsiloxyfuran in the presence of ZnF2 is summarized in
Table 2. The reaction of the electron-rich, 4-methoxy cinnam-
yl carbonate 4b afforded the desired substitution product in
good yield with exceptional enantioselectivity and high regi-
oselectivity. The reactions of electron-poor substrates 4c-e
furnished the corresponding products in high yield with excel-
lent regio- and enantioselectivities, although 3-substituted
cinnamyl carbonate 4e required 2 mol % catalyst loading for
full conversion.
a
o
(a) 2 mol % (S, S, S)-2, ZnF2, CH2Cl2, 12 h; (b) 40 C,
CH2Cl2, 1 h
The reaction of 4-methyl trimethylsiloxyfuran 3c with cin-
namyl carbonate 4a in the presence of the catalyst (S, S, S)-2
also gave products from allylic substitution (Scheme 3). The
reaction of 3c produced the 3-substituted product in 47%
yield, which consisted of double bond isomers 5k and 5k’, and
the undesired 5-substituted product in 38% yield. We were
able to convert isomer 5k’ to isomer 5k with a catalytic
amount of O-desmethyl quinine under mild conditions.14 Thus,
Reactions of aliphatic allylic electrophiles occurred with
some changes to the reaction conditions. Propyl-substituted
allylic carbonate 4f gave only 18% yield of branched product
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the overall process furnished the 3-substituted product 5k in Stoichiometric reactions were conducted with the Ir-
allylcomplex19 to gain insight into the mode of addition and
effect of additives on this addition step. The isolated Ir-allyl
complex did not react with 1.5 equiv of trimethylsiloxyfuran
in the presence of ZnF2 alone (a of Scheme 5).20 However, the
iridium complex reacted immediately in the presence of 1.0
equiv of NBu4OAc with or without ZnF2 to form the product
5a in 92% yield and 99% ee with the same absolute configura-
tion as the product of the catalytic reaction (b of Scheme 5).
This observation implies that the carbonate or benzoate gener-
ated in situ in the catalytic reaction activates the siloxyfuran.
The R absolute configuration of the product of this stoichio-
metric reaction suggests that nucleophilic attack occurs at the
face anti to the iridium fragment.
1
2
3
4
5
6
7
8
45% yield with 93% ee. Likewise, the reaction of 5-methyl
trimethylsiloxyfuran 3d gave disubstituted butenolides 5l in an
overall 88% yield with 6:1 diastereoselectivity in 99% ee after
isomerization of the diastereomeric mixture of 5l’ to isomer 5l
in the presence of O-desmethyl quinine.14
SCHEME 3. Iridium-catalyzed allylic substitution with 4-
and 5-methyl substituted trimethylsiloxyfuransa
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SCHEME 5. Stoichiometric reactions of the cinnamyl irid-
ium intermediate with trimethylsiloxyfuran
a (a) 2 mol % (S, S, S)-2, ZnF2, CH2Cl2, 12 h; (b) 20 mol % O-
desmethyl quinine, CH2Cl2, 12 h
SCHEME 4. Derivatization of the butenolide producta
To determine if the acetate anion activated the trime-
thylsiloxyfuran directly or if it reacted with Ir-allyl complex to
release an allylic acetate that reacted in a subsequent catalytic
process, the reaction of the allyliridium complex with trime-
thylsiloxyfuran 3a was conducted in the presence of 5.0 equiv
of p-tolyl allylic acetate (c of Scheme 5). If the acetate anion
led to the release of the free allylic acetate, little product from
the allyl group on iridium would be observed in the presence
of excess of the tolyl-substituted allylic acetate. In the event,
the reaction of the Ir-allyl complex in the presence of excess
of tolyl-substituted acetate formed phenyl-substituted product
5a in 92% yield. (The p-tolyl product formed in only 37%
yield based on p-tolyl allylic acetate.) This yield of phenyl-
substituted product 5a was the same as that formed in the ab-
sence of p-tolyl allylic acetate, and the yield of 5a was much
higher than that of p-tolyl-substituted product. These observa-
tions imply that the trimethylsiloxyfuran reacts directly with
the Ir-allyl complex when activated by a carboxylate, not by
initial release of an allylic ester.
a
See supporting information for experimental details. All yields
reported here are isolated yields. Diastereomeric ratio was deter-
mined from H NMR spectra of the crude reaction mixtures. ee
was determined by chiral HPLC analysis.
1
The products of these substitutions contained two double
bonds that underwent further functionalizations (Scheme 4).
For example, the terminal double bond of 5a underwent cross
metathesis with vinyl boronate15 in the presence of the
Grubbs-Hoveyda 2nd generation catalyst.16 The resulting vinyl
boro-nate 7a underwent Suzuki-Miyaura coupling with bro-
moben-zene or 5-bromo-2-methylpyridine to yield 7b or 7c in
the presence of Pd(Qphos)(crotyl)Cl. Compound 5g was con-
verted to 7d by a cross metathesis with styrene catalyzed by
Schrock’s catalyst.17 In addition, the electron deficient double
bond in 5l served as a site for conjugate additions.18 Me2CuLi
reacted with 5l to furnish product 7e containing four contigu-
ous stereogenic centers.
In summary, we report an iridium-catalyzed asymmetric
allylic substitution reaction with a silyl ketene acetal. The re-
action between a variety of aromatic and aliphatic allylic car-
bonates or benzoates and trimethylsiloxyfuran proceeded
smoothly to furnish 3-substituted butenolides in excellent re-
gio- and enantioselectivity. Moreover, methyl substituted tri-
methylsiloxyfurans react regioselectively to form enantioen-
riched products. These allylation products can be converted to
an array of organic building blocks by reactions at one or the
other of the alkene units of the product. Stoichiometric reac-
tions of the allyliridium intermediate imply that the reaction
proceeds by anti attack on the coordinated allyl ligand, as re-
ported previously for iridium catalyzed allylic substitution
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with carbon and heteroatom nucleophiles,19a but that the si-
loxyfuran is activated by coordination of the carboxylate leav-
ing group. Further studies to expand the scope of the reaction
to encompass additional silyl ketene acetals are underway in
this laboratory.
(5) (a) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem.
Rev. 2000, 100, 1929; (b) Singh, R. P.; Foxman, B. M.; Deng, L. J.
Am. Chem. Soc. 2010, 132, 9558; (c) Jiang, Y.-Q.; Shi, Y.-L.; Shi, M.
J. Am. Chem. Soc. 2008, 130, 7202; (d) Szlosek, M.; Figadère, B.
Angew. Chem. Int. Ed. 2000, 39, 1799.
(6) For a substrate controlled example, see: (a) Fujioka, H.;
Matsunaga, N.; Kitagawa, H.; Nagatomi, Y.; Kondo, M.; Kita, Y.
Tetrahedron: Asymmetry 1995, 6, 2117; for a racemic example, see:
(b) Boukouvalas, J.; Loach, R. P. J. Org. Chem. 2008, 73, 8109.
(7) Mao, B.; Ji, Y.; Fañanás-Mastral, M.; Caroli, G.; Meetsma, A.;
Feringa, B. L. Angew. Chem. Int. Ed. 2012, 51, 3168.
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ASSOCIATED CONTENT
Experimental procedures and characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
9
(8) (a) Hayashi, T.; Yamamoto, A.; Hagihara, T. J. Org. Chem.
1986, 51, 723; (b) Branchadell, V.; Moreno-Mañas, M.; Pajuelo, F.;
Pleixats, R. Organometallics 1999, 18, 4934.
AUTHOR INFORMATION
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Corresponding Author
(9) Consistent with this origin of regioselectivity, we found that the
palladium catalyzed reaction of cinnamyl acetate with 3a failed to
deliver the desired product 5a. Instead, a mixture of 3-cinnamyl-2-
furanone and 6a formed in a combined 30% yield. See supporting
information for details.
*jhartwig@berkeley.edu
Notes
The authors declare no competing financial interest.
(10) The regioselectivity for reaction at the butenolide is distinct
from several processes forming products from attack at C-5.
Selectivities from reactions at C-5 have been rationalized by initial
[4+2] cycloadditions with an alkene or carbonyl group. In our case,
the siloxyfuran activated by an anionic group is more likely reacting
as an enolate, which tends to react with electrophiles at the C-3.
(11) For proposed [4+2] mechanism to rationalize C-5
selectivity, see: (a) Cho, C.-W.; Krische, M. J. Angew. Chem. Int. Ed.
2004, 43, 6689; (b) Brown, D. W.; Campbell, M. M.; Taylor, A. P.;
Zhang, X.-a. Tetrahedron Lett. 1987, 28, 985; for a computational
study, see: (c) López, C. S.; Álvarez, R.; Vaz, B.; Faza, O. N.; de
Lera, Á. R. J. Org. Chem. 2005, 70, 3654. For a C-3 Aldol reaction of
lithium enolate, see 11b.
(12) For a similar aza-Cope rearrangement, see: Kawatsura, M.;
Tsuji, H.; Uchida, K.; Itoh, T. Tetrahedron 2011, 67, 7686.
(13) The stereochemistry of 5j and 6j was tentatively assigned
by analogy to the aza-Cope analogue in ref 12.
(14) Wu, Y.; Singh, R. P.; Deng, L. J. Am. Chem. Soc. 2011,
133, 12458.
(15) (a) Nicolaou, K. C.; Li, A.; Edmonds, D. J.; Tria, G. S.;
Ellery, S. P. J. Am. Chem. Soc. 2009, 131, 16905; (b) Njardarson, J.
T.; Biswas, K.; Danishefsky, S. J. Chem. Commun. 2002, 2759.
(16) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A.
H. J. Am. Chem. Soc. 2000, 122, 8168.
(17) Compound 7d was determined to have an S configuration
by comparing the optical rotation of this material to a literature value
in reference 7.
(18) (a) Perlmutter, P. Conjugate Addition Reactions in Organic
Synthesis. Pergamon: Oxford, UK: 1992; (b) Rosso, G. B.; Pilli, R. A.
Tetrahedron Lett. 2006, 47, 185.
(19) (a) Madrahimov, S. T.; Markovic, D.; Hartwig, J. F. J. Am.
Chem. Soc. 2009, 131, 7228; (b) Raskatov, J. A.; Spiess, S.; Gnamm,
C.; Broedner, K.; Rominger, F.; Helmchen, G. Chem.--Eur. J. 2010,
16, 6601.
ACKNOWLEDGMENT
We thank the NIH (GM-58108) for support of this work, Johnson-
Matthey for gifts of [Ir(COD)Cl]2, and Dr. Klaus Ditrich and
BASF for gifts of chiral amines. We thank Dr. Phong V. Pham
and Dr. Tyler W. Wilson for helpful discussions.
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Bartels, B.; Garcia-Yebra, C.; Helmchen, G. Eur. J. Org. Chem. 2003,
1097; (h) Janssen, J. P.; Helmchen, G. Tetrahedron Lett. 1997, 38,
8025; (i) Weix, D. J.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129,
7720; (j) He, H.; Zheng, X.-J.; Li, Y.; Dai, L.-X.; You, S.-L. Org.
Lett. 2007, 9, 4339; (k) Graening, T.; Hartwig, J. F. J. Am. Chem. Soc.
2005, 127, 17192; (l) Polet, D.; Rathgeb, X.; Falciola, C. A.;
Langlois, J.-B.; El, H. S.; Alexakis, A. Chem.--Eur. J. 2009, 15, 1205;
(m) Liu, W.-B.; Zheng, C.; Zhuo, C.-X.; Dai, L.-X.; You, S.-L. J. Am.
Chem. Soc. 2012, 134, 4812; (n) Zhuo, C.-X.; Liu, W.-B.; Wu, Q.-F.;
You, S.-L. Chem. Sci. 2012, 3, 205; (o) Wu, Q.-F.; He, H.; Liu, W.-
B.; You, S.-L. J. Am. Chem. Soc. 2010, 132, 11418.
(20) To understand the effect of ZnF2, 19F NMR experiments
were conducted. The 19F NMR spectrum of the catalytic reaction
(Table 1, entry 3) contained a peak at -156.9 ppm, which matches the
19F NMR resonance of TMSF. The same species was found in the
mixture of ZnF2 and TMSOAc, but not in the mixture of ZnF2 and
trimethylsiloxyfuran. These observations suggest that ZnF2 promotes
the allylic substitution reaction by reacting with the trimethylsilylcar-
bonate formed in the reaction to release the carbonate, which then
activates the trimethylsiloxyfuran.
(4) (a) Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2003, 125, 1192; (b) Carmen Zafra-Polo, M.; Figadère,
B.; Gallardo, T.; Tormo, J.; Cortes, D. Phytochemistry 1998, 48,
1087; (c) Kitson, R. R. A.; Millemaggi, A.; Taylor, R. J. K. Angew.
Chem. Int. Ed. 2009, 48, 9426.
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R'
O
[Ir]
O
O
O
a
Ir
*
P
N
OTMS
ZnF2, CH2Cl2
LG
O
+
R'
g
R
R
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Ar Ar
= (R)-Binol
Yield: 60-91%
92-99% ee
a /g up to 20/1
O
O
R = H, Me
R' = Aryl, alkyl
LG = Leaving group
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Ar = 2-MeO-C6H4
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