Iridium-catalyzed enantioselective allylic vinylation

Article abstract of DOI:10.1021/ja311422z

The first example of Ir-catalyzed asymmetric substitution reaction with vinyl trifluoroborates is described. The direct reaction between branched, racemic allylic alcohols and potassium alkenyltrifluoroborates proceeded with high site selectivity and exce

Full text of DOI:10.1021/ja311422z

Communication
pubs.acs.org/JACS
Iridium-Catalyzed Enantioselective Allylic Vinylation
James Y. Hamilton, David Sarlah, and Erick M. Carreira*
Eidgenossische Technische Hochschule Zurich, HCI H335, 8093 Zurich, Switzerland
̈
̈
̈
S
* Supporting Information
alcohols with a variety of heteronucleophiles (amines, alcohols,
thiols) proceeded with excellent branched-to-linear ratio and
enantioselectivity in the presence of catalytic amounts of an Ir-
(P,olefin) complex and Brønsted acids as activators.6 Because
these transformations involve direct displacement of the allylic
alcohol, they display a high degree of atom economy.7
Consequently, we have been interested in extending the
scope of these Ir-catalyzed processes.
ABSTRACT: The first example of Ir-catalyzed asymmet-
ric substitution reaction with vinyl trifluoroborates is
described. The direct reaction between branched, racemic
allylic alcohols and potassium alkenyltrifluoroborates
proceeded with high site selectivity and excellent
enantioselectivity (up to 99%) mediated by an Ir-(P,olefin)
complex. This method allows rapid access to various 1,4-
dienes or trienes including the biologically active natural
products (−)-nyasol and (−)-hinokiresinol.
At the outset of our work, we focused on the identification of
a suitable vinylic nucleophile that would readily participate in
transfer to a putative allyl−Ir intermediate generated from the
starting allylic alcohol. Considering that we have demonstrated
that Brønsted acids can effect direct activation of allylic alcohols
in Ir-catalyzed allylation reactions, we began our investigation
by screening vinylboron reagents.8 A screen of various
styrylboron analogues with allylic alcohol 1a under a variety
of reaction conditions led to the identification of conditions
wherein vinylated product 3a is formed when potassium
triflouroborate 2a was used in combination with hydrofluoric
acid (Table 1, entry 1; for full screening details see Supporting
Information).9 Thus, the best early result was obtained in the
presence of di-n-butylphoshoric acid as promoter in acetone,
delivering branched vinylated product 3a in 24% yield and 99%
ee with a branched (3a) to linear (4a) ratio greater than 50:1.
Because of the low yields observed in the initial experiments,
which we attributed to the noticeably poor solubility of
potassium trifluoroborate 2a in organic solvents, we prepared
the corresponding tetra-n-butylammonium trifluoroborate
analogue of 2a.10 This modification proved beneficial, resulting
in an homogeneous reaction mixture and leading to a
pronounced increase in yield (40% and 98% ee, Table 1,
entry 2).
ridium-catalyzed allylic substitution constitutes a powerful
I
method for the enantioselective formation of both carbon−
heteroatom and carbon−carbon bonds.1−3 Despite extensive
studies and noteworthy advances in this field, several challenges
remain to be addressed. Among these is the development of a
method for enantioselective allylic vinylation. Herein we
describe our efforts that led to the discovery of a highly
enantioselective allylic substitution of unactivated allylic
alcohols with potassium alkenyltrifluoroborates (Scheme 1).
Scheme 1. Ir-Catalyzed Enantioselective Vinylation
These observations prompted us to examine the use of
potassium trifluoroborate 2a in the presence of a phase transfer
catalyst.11 Specifically, we hypothesized that nBu4NHSO4 could
play a dual role: first, as the phase transfer catalyst for
potassium alkenyltrifluoroborates; and second, as the Brønsted
acid activator for the allylic alcohols, since the pKa of HSO4− is
comparable to that of di-n-butylphoshoric acid (1.99 vs 1.72).
Indeed, exposure of allylic alcohol 1a to potassium styryltri-
fluoroborate 2a in the presence of 50 mol % of nBu4NHSO4 led
to formation of 2a in 53% yield and 98% ee after 24 h at
ambient temperature (Table 1, entry 3). The choice of solvent
markedly influenced both yield and site selectivity. The use of
MeCN, DME, or nitromethane as a solvent instead of acetone
resulted in poor yields (31%, 22% and 40%, respectively) and
lower branched/linear ratios (Table 1, entries 4−6). However,
The resulting process relies on an operationally simple protocol
that can be used to construct various dienes and polyenes with
control over olefin geometry. Furthermore, the utility of this
transformation is demonstrated by two-step enantioselective
syntheses of norlignans (−)-nyasol and (−)-hinokiresinol,
broad spectrum inhibitors of eicosanoid and nitric oxide
production.
Despite significant developments in the field of asymmetric
transition metal-catalyzed allylic substitution,4 there have been
only a few reports on vinylation. The recent pioneering work
from the Hoveyda and Hayashi groups showcased the use of
vinylaluminum and vinylboronic acid ester reagents in the
displacement reaction of allylic phosphates in a Cu-catalyzed
enantioselective substitution process.5 We previously reported
that direct allylic substitution of branched, racemic allylic
Received: November 21, 2012
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja311422z | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Table 1. Optimization of Ir-Catalyzed Allylic Vinylation
Table 2. Substrate Scope of the Enantioselective Allylic
Vinylation
a,b,c
cat.
2a
promoter
yield
c
ee
e
b
d
entry (mol %) (equiv) (equiv)
solvent
(%)
B:L
(%)
1
2
3
4
5
6
7
8
9
10
2
2
2
2
2
2
2
2
3
4
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
2.0
A (0.5)
A (0.5)
B (0.5)
B (0.5)
B (0.5)
B (0.5)
B (0.5)
B (0.1)
B (0.1)
B (0.1)
acetone
acetone
acetone
MeCN
DME
24
40
53
31
22
40
60
57
75
89
>50:1
>50:1
>50:1
0.7:1
99
98
98
97
97
97
98
99
99
99
f
20:1
MeNO2
dioxane
dioxane
dioxane
dioxane
0.6:1
>50:1
>50:1
>50:1
>50:1
a
Reaction conditions: 1a (0.25 mmol, 1.0 equiv), [{Ir(cod)Cl}2], [Ir]/
(S)-L = 1:2, HF (50% aq, equimolar to 2a), solvent (0.5 mL), 25 °C,
b
c
24 h. A: di-n-butylphosphoric acid, B: nBu4NHSO4. Determined by
d
1H NMR integration relative to the internal standard. Ratio of
branched (3a) to linear (4a) determined by H NMR integration.
Determined by SFC on a chiral stationary phase, absolute
1
e
stereochemistry was assigned by comparison with known compound.
f
Tetra-n-butylammonium styryltrifluoroborate was used instead of 2a.
a slightly better result was obtained in the case of 1,4-dioxane,
which delivered the product in 60% yield and 98% ee (Table 1,
entry 7). Importantly, reducing the amount of nBu4NHSO4
from 50 to 10 mol % had little effect on the reaction outcome
(Table 1, entry 8). Additionally, we found that the reaction
proceeded much more efficiently when the amounts of
potassium styryltrifluoroborate 2a and the Ir catalyst were
increased (Table 1, entries 8−10). Thus, under optimized
conditions, the reaction of allylic alcohol 1a with 2.0 equiv of 2a
and aqueous HF afforded vinylated product 3a in 89% yield
and 99% ee (Table 1, entry 10). Finally, we noted that under
these conditions the reaction was complete in 4 h.12
a
Standard procedure: substrate 1 (0.25 mmol, 1.0 equiv), potassium
styryltrifluoroborate 2a (0.50 mmol, 2.0 equiv), [{Ir(cod)Cl}2] (4 mol
%), (S)-L (16 mol %), nBu4NHSO4 (10 mol %), HF (50% aq, 2.0
b
equiv), 1,4-dioxane (0.5 mL), 25 °C, 4 h. Isolated yields after
purification by flash chromatography. Enantiomeric excess deter-
mined by SFC analysis on a chiral stationary phase, absolute
stereochemistry was assigned by comparison with known compound.
Ratio of branched to linear regioisomers in brackets. 1.1 equiv of 2a
and HF used.
c
d
Having identified optimized reaction conditions for the
enantioselective vinylation of allylic alcohols, we explored the
substrate scope of this process by using potassium styryltri-
fluoroborate 2a, as summarized in Table 2. Thus, a number of
alkoxy-substituted (3b and 3c) and halogenated (3d and 3e)
aromatics all furnished vinylated products in good yields and
excellent enantioselectivities. Electrophilic functional groups,
such as ester (3f) and aldehyde (3g), could be incorporated
into the products without greatly affecting the overall efficiency
of the allylic vinylation process. The tolerance of this reaction
toward more electronically demanding substrates is demon-
strated in the successful conversion of the p-NO2 or m-CF3-
substituted aryl allylic alcohols (3h and 3i), although a slight
decrease in yield was observed. Furthermore, other aromatic
and heteroaromatic systems could be successfully employed, as
showcased with the example of naphthalene, thiophene and
indole (3j−3l). Importantly, for vinylation of highly reactive
allylic alcohols (2b, 2k, 2l), using 1.1 equiv of 2a and HF was
sufficient to achieve the full conversion. At the current level of
development aliphatic allylic alcohols are not substrates for the
substitution reaction of vinylboron reagents we describe.13
We next investigated the scope of potassium alkenyltri-
fluoroborates by using allylic alcohol 1a, as depicted in Table 3.
In addition to the standard styrylation (3a), the corresponding
para-fluoro and para-methoxy substituted trifluoroborates
delivered styrylated products 3m−3o in comparable yields
and selectivities. It is important to note that under the reaction
conditions described, no potentially competitive olefin isomer-
ization processes were observed, especially in the case of 3o,
where the corresponding vinylation proceeded with exclusive cis
stereoselectivity. Gratifyingly, the Ir-catalyzed vinylation proto-
col is also suitable for enantioselective introduction of
conjugated dienes, efficiently delivering polyene products (3p
and 3q). Furthermore, vinylation using a cyclic vinyltrifluor-
oborate could readily be achieved (3r), albeit with reduced site
selectivity (3:1). Finally, the reaction proceeded as well with
monosubstituted vinyltrifluoroborates, giving vinylated prod-
ucts (3s−3u) in good yields and excellent selectivities.
To further highlight the synthetic utility of the method, we
applied this new catalytic vinylation reaction to the
enantioselective synthesis of (−)-nyasol (5)14 and (−)-hinokir-
esinol (6),15 biologically potent inhibitors of eicosanoid and
nitric oxide production. As illustrated in Scheme 2, exposure of
allylic alcohol 1m to either cis- or trans-para-methoxystyryltri-
fluoroborate (2o or 2n, 1.1 equiv) under optimized vinylation
conditions, followed by deprotection of the methoxy groups
B
dx.doi.org/10.1021/ja311422z | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
In summary, we have developed the first Ir-catalyzed
enantioselective allylic substitution of racemic secondary
alcohols, using a readily accessible potassium alkenyltrifluor-
oborates, to give optically active vinylated products. The
method delivers products via user-friendly, scalable, open-flask
conditions in high yields and excellent regio- and stereo-
selectivities. The synthetic value of this transformation has been
demonstrated through concise and divergent syntheses of
biologically active (−)-nyasol and (−)-hinokiresinol. It is
noteworthy that vinylation represents a very atom-economical
method that, unlike common alternatives, does not require any
separate prior activation of allylic alcohols. Further studies
regarding the development of related transformations and
applications of our new methodology are ongoing and will be
reported in due course.
Table 3. Potassium Alkenyltrifluoroborates Scope of the
Enantioselective Allylic Vinylation
a,b,c
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and characterization data for all
reactions and products, including H- and 13C NMR spectra.
1
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
carreira@org.chem.ethz.ch
Notes
The authors declare no competing financial interest.
a
ACKNOWLEDGMENTS
All reactions were carried out on 0.25 mmol scale under the standard
■
b
conditions (see Table 1 for details). Isolated yields after purification
by flash chromatography. Enantiomeric excess determined by SFC
analysis on a chiral stationary phase.
This research was supported by the ETH Zurich and the Swiss
National Science Foundation.
̈
c
REFERENCES
■
Scheme 2. Enantioselective Synthesis of (−)-Nyasol and
(−)-Hinokiresinol
(1) For seminal contributions, see: (a) Takeuchi, R.; Kashio, M.
Angew. Chem., Int. Ed. 1997, 36, 263. (b) Janssen, J. P.; Helmchen, G.
Tetrahedron Lett. 1997, 38, 8025. (c) Ohmura, T.; Hartwig, J. F. J. Am.
Chem. Soc. 2002, 124, 15164. For recent reviews on this topic, see:
(d) Hartwig, J. F.; Pouy, M. J. Top. Organomet. Chem. 2011, 34, 169.
(e) Liu, W.-B.; Xia, J.-B.; You, S.-L. Top. Organomet. Chem. 2012, 38,
155. (f) Tosatti, P.; Nelson, A.; Marsden, S. P. Org. Biomol. Chem.
2012, 10, 3147.
(2) For selected examples on formation of carbon−carbon bonds,
see: (a) Dubon, P.; Schelwies, M.; Helmchen, G. Chem.Eur. J. 2008,
̈
14, 6722. (b) Schelwies, M.; Dubon, P.; Helmchen, G. Angew. Chem.,
̈
Int. Ed. 2006, 45, 2466. (c) Forster, S.; Tverskoy, O.; Helmchen, G.
Synlett 2008, 2803. (d) Gnamm, C.; Forster, S.; Miller, N.; Brodner,
̈
̈
̈
K.; Helmchen, G. Synlett 2007, 790. (e) Dahnz, A.; Helmchen, G.
Synlett 2006, 697. (f) Kanayama, T.; Yoshida, K.; Miyabe, H.;
Takemoto, Y. Angew. Chem., Int. Ed. 2003, 42, 2054. (g) Bartels, B.;
Garcia-Yebra, C.; Helmchen, G. Eur. J. Org. Chem. 2003, 1097. (h) Ye,
K.-Y.; He, H.; Liu, W.-B.; Dai, L.-X.; Helmchen, G.; You, S.-L. J. Am.
Chem. Soc. 2011, 133, 19006. (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.; Hajjaji, S. E.; 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. (p) Wu, Q.-F.;
Liu, W.-B.; Zhuo, C.-X.; Rong, Z.-Q.; Ye, K.-Y.; You, S.-L. Angew.
Chem., Int. Ed. 2011, 50, 4455. (q) Chen, W.; Hartwig, J. F. J. Am.
Chem. Soc. 2012, 134, 15249.
with MeMgI, rapidly furnished both natural products. Addi-
tionally, the enantioselective vinylation reaction in the case of
(−)-nyasol (5) was also conducted on a larger scale (1.15 g, 7.0
mmol of 1m) by using a reduced amount of catalyst (3 mol %
of [{Ir(cod)Cl}2]), technical grade solvent and open to air. We
were pleased to observe only a slight decrease in yield,
rendering this process practical and robust on a larger scale.
C
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Journal of the American Chemical Society
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(3) For selected examples on formation of carbon−heteroatom
bonds, see: (a) Shu, C.; Leitner, A.; Hartwig, J. F. Angew. Chem., Int.
Ed. 2004, 43, 4797. (b) Weihofen, R.; Tverskoy, O.; Helmchen, G.
Angew. Chem., Int. Ed. 2006, 45, 5546. (c) Stanley, L. M.; Hartwig, J. F.
J. Am. Chem. Soc. 2009, 131, 8971. (d) Pouy, M. J.; Stanley, L. M.;
Hartwig, J. F. J. Am. Chem. Soc. 2009, 131, 11312. (e) Stanley, L. M.;
Hartwig, J. F. Angew. Chem., Int. Ed. 2009, 48, 7841. (f) Lopez, F.;
Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 3426. (g) Shu,
C.; Hartwig, J. F. Angew. Chem., Int. Ed. 2004, 43, 4794. (h) Ueda, M.;
Hartwig, J. F. Org. Lett. 2010, 12, 92.
see: (b) Bae, E.-A.; Park, E.-K.; Yang, H.-J.; Baek, N.-I.; Kim, D.-H.
Planta Med. 2006, 72, 1328.
(4) For a comprehensive collection of reviews on this subject, see:
Topics in Organometallic Chemistry: Transition Metal Catalyzed
Enantioselective Allylic Substitution in Organic Synthesis; Kazmaier, U.,
Ed.; Springer: Heidelberg, Germany, 2012; Vol. 38.
(5) (a) Akiyama, K.; Gao, F.; Hoveyda, A. H. Angew. Chem., Int. Ed.
2010, 49, 419. (b) Gao, F.; McGrath, K. P.; Lee, Y.; Hoveyda, A. H. J.
Am. Chem. Soc. 2010, 132, 14315. (c) Gao, F.; Carr, J. L.; Hoveyda, A.
H. Angew. Chem., Int. Ed. 2012, 51, 6613. (d) Shintani, R.; Takatsu, K.;
Takeda, M.; Hayashi, T. Angew. Chem., Int. Ed. 2011, 50, 8656.
(e) Jung, B.; Hoveyda, A. H. J. Am. Chem. Soc. 2012, 134, 1490.
(6) (a) Defieber, C.; Ariger, M. A.; Moriel, P.; Carreira, E. M. Angew.
Chem., Int. Ed. 2007, 46, 3139. (b) Lafrance, M.; Roggen, M.; Carreira,
E. M. Angew. Chem., Int. Ed. 2012, 51, 3470. (c) Roggen, M.; Carreira,
E. M. Angew. Chem. Int., Ed. 2011, 50, 5568. (d) Roggen, M.; Carreira,
E. M. Angew. Chem., Int. Ed. 2012, 51, 8652.
(7) (a) Trost, B. M. Science 1991, 254, 1471. (b) Trost, B. M. Angew.
Chem., Int. Ed. Engl. 1995, 34, 259. (c) Burns, N. Z.; Baran, P. S.;
Hoffmann, R. W. Angew. Chem., Int. Ed. 2009, 48, 2854.
(8) (a) Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34,
583. (b) Petasis, N. A.; Zavialov, I. A. Tetrahedron Lett. 1996, 37, 567.
(c) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445. (d)
For a recent review, see: Ramadhare, T. R.; Batey, R. A. In Boronic
Acids: Preparation and Applications in Organic Synthesis, Medicine and
Materials, 2nd ed.; Hall, D. G., Ed.; Wiley-VCH: Weinheim, Germany,
2011, pp 427−477.
(9) For selected seminal contributions in the field of organo-
trifluoroborates, see: (a) Vedejs, E.; Chapman, R. W.; Fields, S. C.;
Lin, S.; Schrimpf, M. R. J. Org. Chem. 1995, 60, 3020. (b) Vedejs, E.;
Fields, S. C.; Hayashi, R.; Hitchcock, S. R.; Powell, D. R.; Schrimpf, M.
R. J. Am. Chem. Soc. 1999, 121, 2460. (c) Darses, S.; Michaud, G.;
Genet, J.-P. Eur. J. Org. Chem. 1999, 1875. (d) Molander, G. A.; Ito, T.
Org. Lett. 2001, 3, 393. (e) Molander, G. A.; Fumagalli, T. J. Org.
Chem. 2006, 71, 5743. For reviews on synthetic application, see:
(f) Darses, S.; Genet, J.-P. Eur. J. Org. Chem. 2003, 4313. (g) Molander,
G. A.; Figueroa, R. Aldrichim. Acta 2005, 38, 49. (h) Stefani, H. A.;
Cella, R.; Vieira, A. S. Tetrahedron 2007, 63, 3623. (i) Darses, S.;
Genet, J.-P. Chem. Rev. 2008, 108, 288.
(10) Batey, R. A.; Quach, T. D. Tetrahedron Lett. 2001, 42, 9099.
(11) For applications of phase transfer catalysis in combination with
potassium organotrifluoroborates, see: (a) Thadani, A. N.; Batey, R.
A. Tetrahedron Lett. 2003, 44, 8051. (b) Thadani, A. N.; Batey, R. A.
Org. Lett. 2002, 4, 3827.
1
(12) The only side product observed by H-NMR was styrene. 19F-
NMR monitoring of the reaction mixture revealed complete
−
conversion of styryltrifluoroborate 2a and HF to BF4 . For similar
observation, see: Lee, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2007,
129, 15438.
(13) In addition, allylic alcohol substrates bearing substituents on the
vinyl group (at C2 and C3) were unreactive under these conditions.
Studies are ongoing to enable the use of these starting materials.
(14) For isolation, see: (a) Oketch-Rabah, H. A.; Dossaji, S. F.;
Christensen, S. B.; Frydenvang, K.; Lemmich, E.; Cornett, C.; Olsen,
C. E.; Chen, M.; Kharazmi, A.; Theander, T. J. Nat. Prod. 1997, 60,
1017. For biological activity, see: (b) Lim, H.; Nam, J. W.; Seo, E.-K.;
Kim, Y. S.; Kim, H. P. Arch. Pharm. Res. 2009, 32, 1509. (c) For
previous enantioselective synthesis of 5, see ref 3a.
(15) For isolation see: (a) Hirose, Y.; Oishi, N.; Nagaki, H.;
Nakatsuka, T. Tetrahedron Lett. 1965, 6, 3665. For biological activity,
D
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