Iridium-catalyzed enantioselective polyene cyclization

Article abstract of DOI:10.1021/ja310386m

A highly enantioselective polycyclization method has been developed using the combination of Lewis acid activation with iridium-catalyzed allylic substitution. This strategy relies on direct use of branched, racemic allylic alcohols and furnishes a diverse and unique set of carbo- and heteropolycyclic ring systems in good yields and ≥99% ee.

Full text of DOI:10.1021/ja310386m

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Iridium-Catalyzed Enantioselective Polyene Cyclization
Michael Schafroth, David Sarlah, Simon Krautwald, and Erick M Carreira
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja310386m • Publication Date (Web): 29 Nov 2012
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IridiumꢀCatalyzed Enantioselective Polyene Cyclization
Michael A. Schafroth,† David Sarlah,† Simon Krautwald and Erick M. Carreira*
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Eidgenössische Technische Hochschule Zürich, HCI H335, 8093 Zürich – Switzerland
Supporting Information Placeholder
Our study of the Ir-catalyzed polycyclization began by
evaluating the reaction of 1a as a test substrate under condi-
tions we have employed for allylic substitution with hetero-
nucleophiles, such as amines, alcohols, and thiols, with add-
ed Brønsted acid activators (Table 1, entry 1). Exposure of 1a
to [{Ir(cod)Cl}2] and (R)-L in the presence of di-n-
butylphosphoric acid as promoter in dichloroethane afforded
tricyclic product 2a in 42% yield and 89% ee. Further screen-
ing of various conditions using a variety of Brønsted acids did
not significantly improve the reaction outcome (see Support-
ing Information, Table S2). Inspired by Shibasaki’s insightful
report that bismuth salts can efficiently catalyze allylic sub-
stitution of alcohols,13 we turned our attention towards Lewis
ABSTRACT:
A
highly enantioselective polycyclization
method has been developed using the combination of Lewis
acid activation with iridium-catalyzed allylic substitution.
This strategy relies on direct use of branched, racemic allylic
alcohols and furnishes a diverse and unique set of carbo- and
heteropolycyclic ring systems in good yields and ≥ 99% ee.
Almost six decades ago, Eschenmoser and Stork pointed
out that the stereochemical course of the biogenetic cycliza-
tions of polyenes could be rationalized on the basis of stereo-
electronic considerations.1 The hypothesis known as the
biogenic isoprene rule stimulated extensive non-enzymatic,
biomimetic studies and created one of the most powerful
methods for the rapid construction of polycyclic frame-
works.2 Despite substantial efforts in this field, only a limited
number of catalytic enantioselective cyclizations have been
developed to date. These include the use of Brønsted/Lewis
acid-catalysis by Yamamoto, Loh and Corey3 as well as or-
ganocatalysis by Ishihara, MacMillan, and Jacobsen.4 In con-
trast, transition metal-catalyzed enantioselective polycycliza-
tions have received significantly less attention. Gagné report-
ed a platinum-catalyzed cyclization of alkenes;5 and Toste
has developed a gold-catalyzed cyclization of alkynes.6 Fol-
lowing the seminal achievements of Takeuchi, Helmchen,
and Hartwig,7 iridium is now employed with a wide range of
nucleophiles in the allylic substitution reaction.8 We have
reported a number of substitution reactions9 characterized
by atom economy.10 Herein, we describe a new enantioselec-
tive polyene cyclization cascade from unactivated, branched
racemic allylic alcohols enabled by an Ir-(P,olefin) complex
(Scheme 1).11 As the first report of the use of allyl alcohols as
initiators in enantioselective polycyclizations,12 these results
serve as proof-of-principle for the use of allyl-metal species
in polyene cyclizations.
Table 1. Optimization of the Ir-Catalyzed Cyclization
Reactiona
ee
entry
promoter (mol %)
solvent
yieldb
(%)c
1
2
P(O)(OBu)2OH (50)
Bi(OTf)3 (10)
Sc(OTf)3 (10)
In(OTf)3 (10)
Yb(OTf)3 (10)
Zn(OTf)2 (10)
Zn(OTf)2 (10)
Zn(OTf)2 (10)
Zn(OTf)2 (20)
Zn(OTf)2 (50)
TfOH (20)
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
Dioxane
DMF
42
71
89
96
3
91
80
4
5
84
79
72
8
88
94
6
7
>99.5
>99.5
-
8
9
10
11
n.r.
90
83
12
Scheme 1. Ir-Catalyzed Enantioselective Cyclization
(CH2Cl)2
(CH2Cl)2
(CH2Cl)2
>99.5
99
81
aReaction conditions: 1a (0.25 mmol, 1.0 equiv), [{Ir(cod)Cl}2]
(4 mol %), (R)-L (16 mol %), promoter, solvent (1.5 mL), 25
b
°C, 24h. Yield of 2a after purification by chromatography.
cDetermined by SFC on a chiral stationary phase.
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acids as potential promoters.14 We observed that the use of 10
direct stereocontrol merely over the first cyclization event.21
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mol % Bi(OTf)3 drastically improved conversion, leading to
isolation of 2a in 71% yield and 96% ee after 24h at ambient
temperature (Table 1, entry 2). Further screening of the reac-
tion parameters, including metal triflates (Table 1, entries 3-
6) and solvents (Table 1, entries 7 and 8, see Supporting In-
formation Table S4), revealed that Zn(OTf)2 in dichloro-
ethane routinely afforded superb enantioselectivity, 2a
>99.5% ee (Table 1, entry 6).
The stereoselectivity of the subsequent ring closure is then
effectively encoded in the first ring, which proceeds selec-
tively in accordance with the Stork–Eschenmoser paradigm.
Table 2. Scope of Polyene Cyclizationa,b,c
The amount of Zn(OTf)2 influenced the reaction out-
come (Table 1, entries 6, 9 and 10): 20 mol % was found to be
optimal, in terms of both yield and reaction time. Thus,
under optimal conditions, tricyclic product 2a could be iso-
lated in 90% yield and >99.5% ee (Table 1, entry 9). It is im-
portant to note that the potential role of TfOH as promoter,
which could be generated from a triflate and adventitious
H2O, was excluded, because low yield of product 2a was
observed when using TfOH as an additive (Table 1, entry 11).
Additionally, reactions performed with Zn(OTf)2 and in the
absence of Ir/(R)-L provided none of the desired cyclized
product.
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With optimized conditions in hand, we evaluated the
scope of the cyclization. As shown in Table 2, the reaction
proceeded well with a range of substrates, encompassing
arenes as terminating nucleophiles and delivering a range of
carbo- and heterocyclic ring systems. Thus, a number of
alkoxy-substituted aromatics (2a–2c), pyrroles (2d, 2e), in-
doles (2f, 2g) and furan (2h) heterocycles all underwent
cyclization in high yield and excellent enantioselectivity (ee’s
≥ 99%). When the meta-methoxy substituted arene was
used, cyclization at the para-position (2c, relative to methoxy
group) was predominant, giving 1:2 ortho/para selectivity.
This result is consistent with the literature precedent for
cation-initiated cyclizations.15 In each case the cyclization
products were formed as single diastereoisomers, and no side
products resulting from potentially competitive intermolecu-
lar processes were observed.16 It is important to note that all
the reactions are conducted at ambient temperature with
commercial grade solvents and reagents, making this cycliza-
tion protocol convenient to perform. Lastly, this process can
be scaled up without any erosion in yield and selectivity, as
demonstrated in one example (1 mmol scale, 1a→2a, Table
2).
To further test the potential of this Ir-catalyzed cycliza-
tion reaction, we turned our attention towards expanding
beyond the bicyclization reactions discussed above and ex-
amining the corresponding tricyclization process. To this
end, Ir-catalyzed cyclization of 1i afforded tetracyclic product
2i in 43% isolated yield and >99.5% ee as a single diastere-
omer (Scheme 2).17 Careful separation of the reaction mixture
revealed additional byproducts of similar polarity, which
were identified as a mixture of isomeric 2i′.18 Although 2i’
could not be induced to undergo cyclization to 2i under the
reaction conditions,19 subsequent exposure of the latter to
trifluoroacetic acid gave fully cyclized tetracycle 2i in 75%
yield (combined yield of 65%) and with identical enantiose-
lectivity.20 The observations summarized in Scheme 2 pro-
vide insight concerning the stereochemical course of the
polycylization reaction 1i→2i. The facts that the formation of
2i’ from 1i proceeds with high stereoselectivity and that in
turn its cyclization under acidic conditions furnishes 2i with
complete stereoselectivity imply that the catalyst effects
aStandard procedure: substrate 1 (0.5 mmol, 1.0 equiv),
[{Ir(cod)Cl}2] (4 mol%), (R)-L (16 mol%), Zn(OTf)2 (20
mol%), DCE (3.0 mL), 25 °C, 24h. bIsolated yields after purifi-
cation by flash chromatography. cEnantiomeric excess de-
termined by SFC analysis on a chiral stationary phase, abso-
lute configuration determined by correlation. dRun on 1.0
e
mmol scale. Ortho/para mixture (1:2); 99% ee for the ortho
regioisomer (not shown).
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(3) (a) Ishihara, K.; Nakamura, S.; Yamamoto, H. J. Am. Chem. Soc.
Scheme 2. Ir-Catalyzed Tricyclization
1999, 121, 4906. (b) Ishihara, K.; Ishibashi, H.; Yamamoto, H. J. Am.
Chem. Soc. 2001, 123, 1505. (c) Ishibashi, H.; Ishihara, K.; Yamamoto,
H. J. Am. Chem. Soc. 2004, 126, 11122. (d) Zhao, Y.-J.; Li, B.; Tan, L.-J.
S.; Shen, Z.-L.; Loh, T.-P. J. Am. Chem. Soc. 2010, 132, 10242. (e)
Surendra, K.; Corey, E. J. J. Am. Chem. Soc. 2012, 134, 11992.
(4) (a) Sakakura, A.; Ukai, A.; Ishihara, K. Nature 2007, 445, 900.
(b) Rendeler, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132,
5027. (c) Knowles, R. R.; Lin, S.; Jacobsen, E. N. J. Am. Chem. Soc.
2010, 132, 5030.
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(5) Mullen, C. A.; Campbell, A. N.; Gagné, M. R. Angew. Chem.,
Int. Ed. 2008, 47, 6011.
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(6) Sethofer, S. G.; Mayer, T.; Toste, F. D. J. Am. Chem. Soc. 2010,
132, 8276.
(7) (a) Takeuchi, R.; Kashio, M. Angew. Chem., Int. Ed. 1997, 36,
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(c) Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 15164.
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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.; Nel-
son, A.; Marsden, S. P. Org. Biomol. Chem. 2012, 10, 3147.
(9) (a) Defieber, C.; Ariger, M. A.; Moriel, P.; Carreira, E. M. An-
gew. 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.
(10) (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.
(11) For recent enantioselective Ir-catalyzed intramolecular C–C
bond forming reactions, see: (a) Wu, Q.-F.; He, H.; Liu, W.-B.; You,
S.-L. J. Am. Chem. Soc. 2010, 132, 11418. (b) 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. (c) Zhuo, C.-X.; Liu, W.-B.; Wu, Q.-F.; You, S.-L.
Chem. Sci. 2012, 3, 205. (d) Xu, Q.-L.; Dai, L.-X.; You, S.-L. Org. Lett.
2012, 14, 2579.
(12) For early reports on the use of allylic alcohols as initiating
groups, see: (a) Johnson, W. S.; Semmelhack, M. F.; Sultanbawa, M.
U. S.; Dolak, L. A. J. Am. Chem. Soc. 1968, 90, 2994. (b) Carney, R. L;
Johnson, W.S. J. Am. Chem. Soc. 1974, 96, 2549.
(13) Qin, H.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Angew.
Chem., Int. Ed. 2007, 46, 409.
(14) For use of Lewis acids as activators of allylic alcohols in Ir-
catalyzed allylic substitution, see: Yamashita, Y.; Gopalarathnam, A.;
Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 7508.
(15) (a) Johnson, W. S. Bioorg. Chem. 1976, 5, 51. (b) See also Ref.
2c.
(16) In all cases, the only detectable byproduct is a linear ethyl ke-
tone, resulting from isomerization of the corresponding allylic alco-
hol.
(17) The relative stereochemistry of 2i was secured by X-ray crys-
tallography (see Supporting Information).
(18) In addition to monocyclized isomers, the mixture contained
also some bicyclized products, as determined by 1H-NMR.
(19) Heating the reaction (1i→2i) or exposing 2i′ to Zn(OTf)2 at
elevated temperatures (2i′→2i) did not induce any further cycliza-
tion.
(20) For selected examples on TFA-mediated polyene cyclizations,
see: (a) Schmid, R.; Huesmann, P. L.; Johnson, W. S. J. Am. Chem.
Soc. 1980, 102, 5122. (b) Johnson, W. S.; Lindell, S. D.; Steele, J. J. Am.
Chem. Soc. 1987, 109, 5852.
In conclusion, we have disclosed the first example of a
polyene cyclization reaction initiated by an Ir(P,olefin) cata-
lyst through the formation of an allyl-metal intermediate to
furnish polycyclization products in >99% ee. This Ir-
catalyzed, Zn(OTf)2-promoted direct activation of allylic
alcohols serves as an efficient, user-friendly and scalable
method for rapid and stereoselective construction of prod-
ucts, which are useful building blocks for terpenoids and
pharmaceuticals. Further applications of the [Ir]/Zn(OTf)2
system as well as mechanistic studies of the reaction are
under investigation and will be reported in due course.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and characterization data for all
1
reactions and products, including H and 13C NMR spectra
and crystallographic data (CIF) are available free of charge
via the Internet on http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: carreira@org.chem.ethz.ch
Author Contributions
†These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
S. K. thanks the Fonds der Chemischen Industrie for support
(Chemiefonds-Stipendium).
REFERENCES
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(21) Ir-complexes are known to catalyze intramolecular ene-type
reactions; however, to the best of our knowledge this is the first
known example where a π-allyl-Ir species initiates this process with
an isolated double bond.
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