Anti-diastereo-and enantioselective carbonyl crotylation from the alcohol or aldehyde oxidation level employing a cyclometallated iridium catalyst: α-methyl allyl acetate as a surrogate to preformed crotylmetal reagents

Article abstract of DOI:10.1021/ja808857w

Under the conditions of transfer hydrogenation employing an ortho-cyclometallated iridium catalyst generated in situ from [Ir(cod)Cl] ₂, 4-cyano-3-nitrobenzoic acid and the chiral phosphine ligand (S)-SEGPHOS, α-methyl allyl acetate couples to

Full text of DOI:10.1021/ja808857w

Published on Web 02/03/2009
anti-Diastereo- and Enantioselective Carbonyl Crotylation
from the Alcohol or Aldehyde Oxidation Level Employing a
Cyclometallated Iridium Catalyst: r-Methyl Allyl Acetate as a
Surrogate to Preformed Crotylmetal Reagents
In Su Kim, Soo Bong Han, and Michael J. Krische*
Department of Chemistry and Biochemistry, UniVersity of Texas at Austin, Austin, Texas 78712
Received November 11, 2008; E-mail: mkrische@mail.utexas.edu
Abstract: Under the conditions of transfer hydrogenation employing an ortho-cyclometallated iridium catalyst
generated in situ from [Ir(cod)Cl]2, 4-cyano-3-nitrobenzoic acid and the chiral phosphine ligand (S)-
SEGPHOS, R-methyl allyl acetate couples to alcohols 1a-1j with complete levels of branched regioselectivity
to furnish products of carbonyl crotylation 3a-3j, which are formed with good levels of anti-diastereo-
selectivity and exceptional levels of enantioselectivity. An identical set of optically enriched carbonyl
crotylation products 3a-3j is accessible from the corresponding aldehydes 2a-2j under the same conditions,
but employing isopropanol as the terminal reductant. Experiments aimed at probing the origins of
stereoselection establish a matched mode of ionization for the (R)-acetate and the iridium catalyst modified
by (S)-SEGPHOS, as well as reversible ionization of the allylic acetate with rapid π-facial interconversion
of the resulting π-crotyl intermediate in advance of C-C bond formation. Additionally, rapid alcohol-aldehyde
redox equilibration in advance of carbonyl addition is demonstrated. Thus, anti-diastereo- and enantio-
selective carbonyl crotylation from the alcohol or aldehyde oxidation level is achieved in the absence of
any stoichiometric metallic reagents or stoichiometric metallic byproducts.
Introduction
catalyzed additions of crotylmetal reagents are reported by
Yamamoto (1991),3a-c Mikami (1993),3d Nishiyama (2001),3e
Carbonyl crotylation ranks among the foremost methods
used for the construction of polypropionate natural products.1
The majority of enantioselective crotylation protocols exploit
chirally modified crotylmetal reagents, such as the B-crotyl
reagents developed by Hoffmann (1979),2a Brown (1986),2b,c
Roush (1986),2d,e Masamune (1987),2f and Soderquist
(2005),2g the Ti-crotyl reagents developed by Duthaler
(1989),2h,i and the Si-crotyl reagents developed by Panek
(1991)2j,k and Leighton (2004).2l Enantioselective Lewis acid
Evans (2006)3f and Hall (2006).3g,h Additionally, enantiose-
lective Lewis base catalyzed carbonyl crotylations employing
crotylmetal reagents are reported by Denmark (1994),4a,b Iseki
(1997),4c Nakajima (1998),4d and Kocˇovsky (2003).4e Finally,
a chiral diol catalyzed allylboration of ketones is reported
by Schaus (2006).5
In these cases, the crotylating agent is a metal or metalloid
that is itself prepared from a metallic precursor. For example,
the crotylating agent developed by Brown2b,c is prepared
(1) For selected reviews on enantioselective carbonyl allylation and
crotylation, see: (a) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl.
1982, 21, 555. (b) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93,
2207. (c) Ramachandran, P. V. Aldrichim. Acta 2002, 35, 23. (d)
Kennedy, J. W. J.; Hall, D. G. Angew. Chem., Int. Ed. 2003, 42, 4732.
(e) Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103, 2763. (f) Yu, C.-
M.; Youn, J.; Jung, H.-K. Bull. Kor. Chem. Soc. 2006, 27, 463. (g)
Marek, I.; Sklute, G. Chem. Commun. 2007, 1683. (h) Hall, D. G.
Synlett 2007, 1644.
(3) For enantioselective Lewis acid catalyzed carbonyl additions of
crotylmetal reagents, see: (a) Furuta, K.; Mouri, M.; Yamamoto, H.
Synlett 1991, 561. (b) Yanagasawa, A.; Ishiba, A.; Nakashima, H.;
Yamamoto, H. Synlett 1997, 88. (c) Yanagasawa, A.; Kageyama, H.;
Nakatsuka, Y.; Asakawa, K.; Matsumoto, Y.; Yamamoto, H. Angew.
Chem., Int. Ed. 1999, 38, 3701. (d) Aoki, S.; Mikami, K.; Terada,
M.; Nakai, T. Tetrahedron 1993, 49, 1783. (e) Motoyama, Y.; Okano,
M.; Narusawa, H.; Makihara, N.; Aoki, K.; Nishiyama, H. Organo-
metallics 2001, 20, 1580. (f) Evans, D. A.; Aye, Y.; Wu, J. Org. Lett.
2006, 8, 2071. (g) Rauniyar, V.; Hall, D. G. Angew. Chem., Int. Ed.
2006, 45, 2426. (h) Rauniyar, V.; Zhai, H.; Hall, D. G. J. Am. Chem.
Soc. 2008, 130, 8481.
(2) For enantioselective carbonyl additions of chirally modified crotylmetal
reagents, see: (a) Hoffmann, R. W.; Ladner, W. Tetrahedron Lett.
1979, 20, 4653. (b) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc.
1986, 108, 293. (c) Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc.
1986, 108, 5919. (d) Roush, W. R.; Halterman, R. L. J. Am. Chem.
Soc. 1986, 108, 294. (e) Roush, W. R.; Ando, K.; Powers, D. B.;
Palkowitz, A. D.; Halterman, R. L. J. Am. Chem. Soc. 1990, 112,
6339. (f) Garcia, J.; Kim, B.-M.; Masamune, S. J. Org. Chem. 1987,
52, 4831. (g) Burgos, C. H.; Canales, E.; Matos, K.; Soderquist, J. A.
J. Am. Chem. Soc. 2005, 127, 8044. (h) Riediker, M.; Duthaler, R. O.
Angew. Chem., Int. Ed. Engl. 1989, 28, 494. (i) Hafner, A.; Duthaler,
R. O.; Marti, R.; Rihs, G.; Rothe-Streit, P.; Schwarzenbach, F. J. Am.
Chem. Soc. 1992, 114, 2321. (j) Panek, J. S.; Yang, M. J. Am. Chem.
Soc. 1991, 113, 6594. (k) Hu, T.; Takenaka, N.; Panek, J. S. J. Am.
Chem. Soc. 2002, 124, 12806. (l) Hackman, B. M.; Lombardi, P. J.;
Leighton, J. L. Org. Lett. 2004, 6, 4375.
(4) For enantioselective Lewis base catalyzed carbonyl additions of
crotylmetal reagents, see: (a) Denmark, S. E.; Coe, D. M.; Pratt, N. E.;
Griedel, B. D. J. Org. Chem. 1994, 59, 6161. (b) Denmark, S. E.; Fu,
J. J. Am. Chem. Soc. 2001, 123, 9488. (c) Iseki, K.; Kuroki, Y.;
Takahashi, M.; Kishimoto, S.; Kobayashi, Y. Tetrahedron 1997, 53,
3513. (d) Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S.-I. J. Am.
Chem. Soc. 1998, 120, 6419. (e) Malkov, A. V.; Dufkova´, L.; Farrugia,
L.; Kocˇovsky, P. Angew. Chem., Int. Ed. 2003, 42, 3674.
(5) For enantioselective chiral diol catalyzed carbonyl additions of
crotylmetal reagents, see: Lou, S.; Moquist, P. N.; Schaus, S. E. J. Am.
Chem. Soc. 2006, 128, 12660.
9
2514 J. AM. CHEM. SOC. 2009, 131, 2514–2520
10.1021/ja808857w CCC: $40.75
2009 American Chemical Society

Carbonyl Crotylation
A R T I C L E S
through potassiation of butene employing Schlosser’s base6
followed by transmetalation to boron. Here, multiple ma-
nipulations and multiple preformed organometallics (n-BuLi,
KC4H7, Ipc2BOMe) are required to prepare the desired
crotylborane, which contributes to cost and waste generation.
An alternate approach to enantioselective carbonyl crotylation
involves reductive generation of crotylmetal reagents from the
corresponding halides, as in catalytic enantioselective variants
of the Nozaki-Hiyama reaction.7,8 Here, metallic reductants
are required for catalytic turnover and modest diastereoselec-
tivities are typically observed. Related reductive couplings of
allylic alcohols, acetates, and carboxylates, which constitute an
umpolung of π-allyl chemistry, also have been disclosed.9-13
However, catalytic enantioselective crotylations based on this
approach are absent and, with one exception,12 metallic terminal
reductants are again required.
Scheme 1. Carbonyl Crotylation from the Alcohol or Aldehyde
Oxidation Level via Transfer Hydrogenative C-C Coupling
increasing range of CdX (X ) O, NR) addition processes.14
A
powerful manifestation of these concepts resides in the coupling
of unsaturates to carbonyl partners to furnish homoallylic
alcohols,15-17 wherein allenes,15 dienes,16 or allyl acetate17 serve
as surrogates to preformed allylmetal reagents. The iridium
catalyzed transfer hydrogenative couplings of allyl acetate17
represent an especially significant advance over established
carbonyl allylation protocols,1 as highly enantioselectiVe car-
bonyl allylation is achieVed from the alcohol or aldehyde
oxidation leVel in the absence of any stoichiometric metallic
reagents. Inspired by these results, stereoselective carbonyl
crotylations employing R-methyl allyl acetate as the crotyl donor
were sought. Here, we report a second generation ortho-
cyclometallated iridium catalyst modified by 4-cyano-3-ni-
trobenzoic acid and (S)-SEGPHOS that promotes highly regio-
and enantioselective carbonyl crotylation from the alcohol or
aldehyde oxidation level with good levels of anti-diastereo-
selectivity (Scheme 1).
Metal catalyzed reductive C-C coupling under the conditions
of hydrogenation or transfer hydrogenation provides an alterna-
tive to the use of preformed organometallic reagents in an ever-
(6) (a) Schlosser, M.; Rauchschwalbe, G. J. Am. Chem. Soc. 1978, 100,
3258. (b) Schlosser, M.; Sta¨hle, M. Angew. Chem., Int. Ed. 1980, 19,
487.
(7) For catalytic enantioselective carbonyl crotylation via Nozaki-Hiyama
coupling, see: (a) Bandini, M.; Cozzi, P. G.; Umani-Ronchi, A.
Polyhedron 2000, 19, 537. (b) Bandini, M.; Cozzi, P. G.; Umani-
Ronchi, A. Tetrahedron 2001, 57, 835. (c) Bandini, M.; Cozzi, P. G.;
Umani-Ronchi, A. Angew. Chem., Int. Ed. 2000, 39, 2327. (d) Inoue,
M.; Suzuki, T.; Nakada, M. J. Am. Chem. Soc. 2003, 125, 1140. (e)
Lee, J.-Y.; Miller, J. J.; Hamilton, S. S.; SIgman, M. S. Org. Lett.
2005, 7, 1837. (f) McManus, H. A.; Cozzi, P. G.; Guiry, P. J. AdV.
Synth. Catal. 2006, 348, 551. (g) Xia, G.; Yamamoto, H. J. Am. Chem.
Soc. 2006, 128, 2554.
(8) For recent reviews of catalytic Nozaki-Hiyama coupling, see: (a)
Avalos, M.; Babiano, R.; Cintas, P.; Jime´nez, J. L.; Palacios, J. C.
Chem. Soc. ReV. 1999, 28, 169. (b) Bandini, M.; Cozzi, P. G.; Umani-
Ronchi, A. Chem. Commun. 2002, 919. (c) Hargaden, G. C.; Guiry,
P. J. AdV. Synth. Catal. 2007, 349, 2407.
Results and Discussion
(9) For catalytic carbonyl allylation Via reductive coupling of π-allyls
based on palladium, see: (a) Tabuchi, T.; Inanaga, J.; Yamaguchi, M.
Tetrahedron Lett. 1986, 27, 1195. (b) Takahara, J. P.; Masuyama, Y.;
Kurusu, Y. J. Am. Chem. Soc. 1992, 114, 2577. (c) Kimura, M.;
Ogawa, Y.; Shimizu, M.; Sueishi, M.; Tanaka, S.; Tamaru, Y.
Tetrahedron Lett. 1998, 39, 6903. (d) Kimura, M.; Tomizawa, T.;
Horino, Y.; Tanaka, S.; Tamaru, Y. Tetrahedron Lett. 2000, 41, 3627.
(e) Kimura, M.; Shimizu, M.; Shibata, K.; Tazoe, M.; Tamaru, Y.
Angew. Chem., Int. Ed. 2003, 42, 3392. (f) Zanoni, G.; Gladiali, S.;
Marchetti, A.; Piccinini, P.; Tredici, I.; Vidari, G. Angew. Chem., Int.
Ed. 2004, 43, 846. (g) Kimura, M.; Shimizu, M.; Tanaka, S.; Tamaru,
Y. Tetrahedron 2005, 61, 3709. (h) Howell, G. P.; Minnaard, A. J.;
Feringa, B. L. Org. Biomol. Chem. 2006, 4, 1278. (i) Barczak, N. T.;
Grote, R. E.; Jarvo, E. R. Organometallics 2007, 26, 4863.
(10) For catalytic carbonyl allylation via reductive coupling of π-allyls based
on rhodium, see: Masuyama, Y.; Kaneko, Y.; Kurusu, Y. Tetrahedron
Lett. 2004, 45, 8969.
Using our first-generation catalytic system,17a which employs
an iridium complex generated in situ from [Ir(cod)Cl]2, m-
nitrobenzoic acid and chelating chiral phosphine ligand, carbonyl
couplings employing R-methyl allyl acetate occur with complete
branch regioselectivity. However, poor anti-diastereoselectivities
were observed and the level of diastereoselection was insensitive
to changes in the character of the phosphine ligand. Our
subsequent discovery that the active catalyst is an ortho-
cyclometallated iridium C,O-benzoate17b unveiled new op-
portunities to direct diastereoselectivity involving modification
of the cyclometallating agent.
(11) For catalytic carbonyl allylation via reductive coupling of π-allyls based
on iridium, see: (a) Masuyama, Y.; Chiyo, T.; Kurusu, Y. Synlett 2005,
2251. (b) Banerjee, M.; Roy, S. J. Mol. Catal. A 2006, 246, 231. (c)
Masuyama, Y.; Marukawa, M. Tetrahedron Lett. 2007, 48, 5963.
(12) For catalytic carbonyl allylation via reductive coupling of π-allyls based
on ruthenium, see: (a) Tsuji, Y.; Mukai, T.; Kondo, T.; Watanabe, Y.
J. Organomet. Chem. 1989, 369, C51. (b) Kondo, T.; Ono, H.; Satake,
N.; Mitsudo, T.-a.; Watanabe, Y. Organometallics 1995, 14, 1945.
(c) Denmark, S. E.; Nguyen, S. T. Org. Lett. 2009, 11, ASAP,
ol8028725.
(14) For selected reviews of hydrogenative C-C coupling, see: (a) Ngai,
M.-Y.; Kong, J.-R.; Krische, M. J. J. Org. Chem. 2007, 72, 1063. (b)
Iida, H.; Krische, M. J. Top. Curr. Chem. 2007, 279, 77. (c) Skucas,
E.; Ngai, M.-Y.; Komanduri, V.; Krische, M. J. Acc. Chem. Res. 2007,
40, 1394. (d) Shibahara, F.; Krische, M. J. Chem. Lett. 2008, 37, 1102.
(e) Bower, J. F.; Kim, I. S.; Patman, R. L.; Krische, M. J. Angew.
Chem., Int. Ed. 2009, 48, 34.
(15) For hydrogenative and transfer hydrogenative carbonyl allylations
employing allenes as allyl donors, see: (a) Skucas, E.; Bower, J. F.;
Krische, M. J. J. Am. Chem. Soc. 2007, 129, 12678. (b) Bower, J. F.;
Skucas, E.; Patman, R. L.; Krische, M. J. J. Am. Chem. Soc. 2007,
129, 15134. (c) Ngai, M.-Y.; Skucas, E.; Krische, M. J. Org. Lett.
2008, 10, 2705.
(13) For selected reviews covering carbonyl allylation via umpolung of
π-allyls, see: (a) Masuyama, Y. In AdVances in Metal-Organic
Chemistry; Liebeskind, L. S., Ed.; JAI Press: Greenwich, CT, 1994;
Vol. 3, p 255. (b) Tamaru, Y. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E.-i., de Meijere, A., Eds.;
Wiley: New York, 2002; Vol. 2, p 1917. (c) Tamaru, Y. In
PerspectiVes in Organopalladium Chemistry for the XXI Century;
Tsuji, J., Ed.; Elsevier: Amsterdam, 1999; p 215. (d) Kondo, T.;
Mitsudo, T.-a. Curr. Org. Chem. 2002, 6, 1163. (e) Tamaru, Y. Eur.
J. Org. Chem. 2005, 2647. (f) Zanoni, G.; Pontiroli, A.; Marchetti,
A.; Vidari, G. Eur. J. Org. Chem. 2007, 3599.
(16) For hydrogenative carbonyl allylations employing dienes as allyl
donors, see: (a) Bower, J. F.; Patman, R. L.; Krische, M. J. Org. Lett.
2008, 10, 1033. (b) Shibahara, F.; Bower, J. F.; Krische, M. J. J. Am.
Chem. Soc. 2008, 130, 6338.
(17) For hydrogenative carbonyl allylations employing allyl acetate as allyl
donor, see: (a) Kim, I. S.; Ngai, M.-Y.; Krische, M. J. J. Am. Chem.
Soc. 2008, 130, 6340. (b) Kim, I. S.; Ngai, M.-Y.; Krische, M. J.
J. Am. Chem. Soc. 2008, 130, 14891.
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A R T I C L E S
Kim et al.
Table 1. Optimizing Relative and Absolute Stereocontrol in
Transfer Hydrogenative Carbonyl Crotylation from the Alcohol
Oxidation Levela
Scheme 2. Experiments Aimed at Probing the Origins of
Stereoselection in Ir-Catalyzed Transfer Hydrogenative Crotylation
(Ar ) (4-(CO2Me)Ph)a
a Reactions were performed in 13 × 100 mm2 pressure tubes. Cited
yields are of material isolated by silica gel chromatography. Enantiomeric
excess was determined by chiral stationary phase HPLC analysis via
comparison to racemic diastereomeric mixtures. See Experimental
Section for further details.
10). Alternative cyclometallating agents, as represented by
compounds L-M, were ineffective.
Using the catalyst modified by 4-cyano-3-nitrobenzoic acid
I, it was found that the level of diastereoselection was dependent
upon the loading of R-methyl allyl acetate. Specifically, a
reduction in the loading of R-methyl allyl acetate from 1000 to
500 to 200 mol % was found to increase the level of
anti-diastereoselection from 3.0:1 to 3.7:1 to 4.3:1, respectively
(Table 1, entries 9, 15 and 16). Remarkably, at 200 mol %
loadings of R-methyl allyl acetate, both diastereoselectivity and
isolated yield were found to improve substantially with increas-
ing concentration. At 0.2, 0.5, and 1.0 M concentrations, anti-
diastereoselectivities increased from 4.3:1 to 4.8:1 to 7.1:1,
respectively (Table 1, entries 16-18). Finally, by decreasing
reaction temperature from 100 to 90 °C, homoallyl alcohol 3e
was formed in 78% yield with 7.5:1 anti-diastereoselectivity
(Table 1, entry 19). Notably, the catalyst modified by 3,4-
dinitrobenzoic acid J was highly sensitive to reaction temper-
ature, and under identical conditions at 90 °C, homoallyl alcohol
3e was produced in only 42% yield with 7.6:1 anti-diastereo-
selectivity (Table 1, entry 20).
a All reactions were performed in 13 × 100 mm2 pressure tubes. The
cited yields are of material isolated by silica gel chromatography.
Enantiomeric excess was determined by chiral stationary phase HPLC
analysis via comparison to racemic diastereomeric mixtures. For entries
1-18, the reaction was allowed to run for 20 h. For entries 19-27, the
reaction was allowed to run for 48 h. See Experimental Section for
further details.
Accordingly, a range of substituted m-nitrobenzoic acids were
assayed in the transfer hydrogenative coupling of R-methyl allyl
acetate and alcohol 1e to furnish homoallyl alcohol 3e (Table
1). This assay focused primarily on 4-substituted-3-nitrobenzoic
acids, as substitution at the 5- and 6-positions substantially
diminished the reactivity of the resulting catalytic complex.
Iridium catalysts modified by 4-cyano-3-nitrobenzoic acid I and
3,4-dinitrobenzoic acid J displayed the highest levels of
diastereocontrol, providing the homoallyl alcohol 3e in 3.0:1
and 3.5:1 anti/syn ratios, respectively (Table 1, entries 9 and
At this point, chirally modified catalysts were assayed.
Although catalysts incorporating the ligands (S)-BINAP, (S)-
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Carbonyl Crotylation
A R T I C L E S
Table 2. Ir-Catalyzed Transfer Hydrogenative Crotylation of
Alcohols 1a-1ja
Table 3. Ir-Catalyzed Transfer Hydrogenative Crotylation of
Aldehydes 2a-2ja
a Reactions were performed in 13 × 100 mm2 pressure tubes. Cited yields
are of material isolated by silica gel chromatography. Enantiomeric excess was
determined by chiral stationary phase HPLC analysis via comparison to racemic
diastereomeric mixtures. See Experimental Section for further details. b 80 °C,
72 h. c (S)-C3-TUNEPHOS was used as ligand.
a Reactions were performed in 13 × 100 mm2 pressure tubes.
Cited yields are of material isolated by silica gel chromatography.
Enantiomeric excess was determined by chiral stationary phase
HPLC analysis via comparison to racemic diastereomeric mixtures.
See Experimental Section for further details. b 80 °C, 72 h.
c (S)-C3-TUNEPHOS was used as ligand.
diastereoselectivity was observed (Table 1, entries 21-23).
Using a catalyst modified by (S)-SEGPHOS, the carbonyl
crotylation product 3e is formed in 70% isolated yield with 7.4:1
MeO-BIPHEP, and (S)-Cl,MeO-BIPHEP were found to enforce
high levels of absolute stereocontrol, significant erosion of
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J. AM. CHEM. SOC. VOL. 131, NO. 7, 2009 2517

A R T I C L E S
Kim et al.
Scheme 3. Stereochemical Features Associated with Formation and Isomerization of the Purported Crotyl Iridium Intermediates (*Ln )
(S)-SEGPHOS and C,O-Benzoate of 4-Cyano-3-nitrobenzoic Acid I)
anti-diastereoselectivity and 95% enantiomeric excess (Table
Scheme 4. Experiments Establishing Rapid Redox Equilibration in
1, entries 24). The TUNEPHOS ligands of Zhang18 also were
assayed (Table 1, entries 25-27). Here, (S)-C3-TUNEPHOS
was found to provide the carbonyl crotylation product 3e in
77% isolated yield with 8:1 anti-diastereoselectivity and 97%
enantiomeric excess (Table 1, entry 26).
Advance of Carbonyl Addition (Ar ) (4-(CO2Me)Ph)a
Using the aforementioned coupling conditions employing
(S)-SEGPHOS and (S)-C3-TUNEPHOS, a range of alcohols
were subjected to carbonyl crotylation (Table 2). In most
cases, the catalyst modified by (S)-SEGPHOS gave superior
results. In terms of scope, diverse substituted benzylic
alcohols 1a-1f are converted to the corresponding carbonyl
crotylation products 3a-3f in good to excellent yield, very
good levels of anti-diastereoselectivity and with exceptional
levels of absolute stereocontrol (Table 2, entries 1-6). As
demonstrated by the conversion of cinnamyl alcohol 1g to
homoallyl alcohol 3g, allylic alcohols participate in the
coupling (Table 2, entry 7). Finally, unactivated aliphatic
alcohols 1h-1j are transformed to the corresponding carbonyl
crotylation products 3h-3j in good yield with equally high
levels of relative and absolute stereocontrol (Table 2, entries
8-10).
Carbonyl crotylation from the aldehyde oxidation level
employing isopropanol as the terminal reductant also was
explored (Table 3). To our delight, under conditions identical
to those cited in Table 2, but in the presence of isopropanol
(200 mol%), aryl aldehydes 2a-2f, cinnamaldehyde 2g, and
unactivated aliphatic aldehydes 2h-2j are converted to the
corresponding carbonyl crotylation products 3a-3f with
complete levels of regioselectivity, very good levels of anti-
diastereoselectivity and with exceptional levels of enantio-
selectivity. Thus, carbonyl crotylation is achieved from the
aldehyde or alcohol oxidation level in the absence of
preformed crotylmetal reagents.
a Reactions were performed in 13 × 100 mm2 pressure tubes. Cited
yields are of material isolated by silica gel chromatography. See
Experimental Section for further details.
To further probe the origins of stereoselection, optically
enriched allylic acetate 4 (98% ee) was coupled to alcohol
1e under standard conditions employing iridium catalysts
modified by (S)-SEGPHOS and (R)-SEGPHOS (Scheme 2,
eqs 3 and 4, respectively). In the former case, excellent levels
of relative and absolute stereocontrol are observed. In the
later case, diminished efficiencies and reduced levels of
diastereo- and enantioselectivity are evident. In both cases,
recovered allylic acetate 4 exhibits significant erosion of
optical purity. These experiments suggest that ionization of
the (R)-allylic acetate 4 by the (S)-SEGPHOS modified
iridium catalyst represents the lower energy diastereomeric
pathway, that is, a stereochemically matched ionization mode.
Partial racemization of recovered allylic acetate 4 suggests
that ionization occurs reversibly with incomplete kinetic
stereoselectivity.
Finally, in reactions employing racemic allylic acetate 4
and the iridium catalyst modified by (S)-SEGPHOS, recov-
ered 4 exhibits a substantial degree of optical enrichment
favoring the (S)-enantiomer (Scheme 2, eq 5). This result is
consistent with the notion that consumption of the (R)-allylic
acetate 4 by the (S)-SEGPHOS modified iridium catalyst
represents a more rapid stereochemically matched reaction
In prior studies of the parent allylation reaction,17b interven-
tion of symmetric iridium π-allyl intermediates or rapid inter-
conversion of σ-allyl haptomers through the agency of a
symmetric π-allyl was inferred on the basis of isotopic labeling
studies. To evaluate the nature of the purported π-crotyl iridium
intermediate, optically enriched allylic acetate 4 (98% ee) was
coupled to alcohol 1e under standard conditions employing the
achiral ligand BIPHEP. The product, homoallyl alcohol 5, is
produced in 48% isolated yield with 9:1 anti-diastereoselectivity
and 14% enantiomeric excess (Scheme 2, eq 2). These data
suggest racemization via π-facial interconversion of the kinetic
π-crotyl iridium complex occurs at a rate only marginally slower
than the rate of carbonyl addition.
(18) (a) Zhang, X. U.S, Patent 6521769, 2003 (filed 1999). (b) Zhang, Z.;
Qian, H.; Longmire, J.; Zhang, X. J. Org. Chem. 2000, 65, 6223. (c)
Sun, X.; Zhou, L.; Li, W.; Zhang, X. J. Org. Chem. 2008, 73, 1143.
(19) The designation of “cis” is made in reference to the substituent of the
central carbon atom of the π-allyl complex.
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Carbonyl Crotylation
A R T I C L E S
Scheme 5. (Left) Simplified Catalytic Mechanism Proposed for the Iridium Catalyzed Transfer Hydrogenative Crotylation and (Right) Model
Accounting for the Observed Sense of Relative and Absolute Stereocontrol
pathway. Notably, the degree of optical enrichment of
recovered (S)-4 does not increase as a function of conversion
due to erosion of the optical purity of unreacted allylic acetate
4 via reversible ionization, as established in a preceding
experiment (Scheme 2, eq 2).
acetate delivers the iridium π-crotyl complex III. The parent
BINAP-ligated iridium π-allyl C,O-benzoate complex has
been characterized by single-crystal X-ray diffraction and
has been demonstrated to be catalytically relevant.17b Alde-
hyde addition by way of the (E)-σ-crotyliridium complex IV
through a closed chairlike transition structure delivers the
anti-homoallyl iridium alkoxide V. This intermediate is stable
with respect to ꢀ-hydride elimination of the carbinol C-H
due to occupation of the remaining coordination site at
iridium(III) by the olefin moiety of the homoallylic alcohol.
Exchange of the homoallyl alcohol for isopropanol or a
reactant alcohol provides VI, which has an open coordination
site and, consequently, ꢀ-hydride eliminates to regenerate
the ortho-cyclometallated complex I. A stereochemical model
accounting for the observed stereochemistry is analogous to
that previously proposed (Scheme 5, right).
The observed anti-diastereoselectivity presumably arises
via kinetic formation of the cis-π-crotyl complex,19 which
engages the carbonyl partner by way of an (E)-crotyl iridium
intermediate (Scheme 3). Erosion of diastereoselectivity may
result via isomerization to the trans-π-crotyl complex, which
engages the carbonyl partner by way of the (Z)-crotyl iridium
complex to form the syn-diastereomer. This interpretation
may account for the fact that couplings to aldehydes exhibit
uniformly higher levels of diastereoselectivity. For the
aldehyde couplings, carbonyl addition is anticipated to be
faster as higher concentrations of aldehyde are present
throughout the course of the reaction, promoting rapid capture
of the kinetic allyliridium intermediate. The observation that
diastereoselectivity increases with increasing concentration
in couplings of alcohols further supports the veracity of this
interpretation (Table 1, entries 16-18). The favorable
influence of the 4-cyano-3-nitro-C,O-benzoate moiety on anti-
diastereoselection is the subject of computational study.
Exposure of R-methyl allyl acetate to equimolar quantities
of 1a and 2e under standard conditions employing BIPHEP
as ligand provides 3a and 3e in 83% yield in a 1:2.3 ratio,
respectively. Exposure of R-methyl allyl acetate to equimolar
quantities of 2a and 1e under otherwise identical conditions
provides 3a and 3e in 74% yield in a 1:1.1 ratio, respectively.
These experiments demonstrate rapid redox equilibration in
advance of carbonyl addition, which is relevant to crotylations
conducted from the alcohol oxidation level (Scheme 4).
A simplified catalytic mechanism consistent with our
collective results is depicted in Scheme 5. The ortho-
cyclometallated iridium hydride I undergoes deprotonation
in the presence of Cs2CO3 to furnish the anionic iridium(I)
C,O-benzoate II.20 Oxidative addition to R-methyl allyl
Summary
We report a protocol for anti-diastereo- and enantioselec-
tive carbonyl crotylation from the alcohol or aldehyde
oxidation level under the conditions of iridium-catalyzed
transfer hydrogenation. This method circumvents the use of
chirally modified crotylmetal reagents or metallic terminal
reductants and, consequently, avoids generation of stoichio-
metric metallic byproducts. Furthermore, the ability to
conduct carbonyl crotylation directly from the alcohol
oxidation level allows one to bypass the oxidation chemistry
typically required to convert alcohols to aldehydes.
Mechanistic studies establish a matched mode of ionization
for the (R)-acetate and the iridium catalyst modified by (S)-
SEGPHOS, as well as reversible ionization of the allylic
acetate with rapid π-facial interconversion of the resulting
π-crotyl intermediate in advance of C-C bond formation.
Additionally, rapid alcohol-aldehyde redox equilibration in
advance of carbonyl addition is demonstrated. The 4-cyano-
3-nitro-C,O-benzoate moiety appears to facilitate partitioning
of the (E)- and (Z)-σ-crotyliridium intermediates and, hence,
anti- and syn-diastereoselectivity. However, the specific
interactions that mediate partitioning remain unclear and are
currently the subject of computational analysis.
(20) As described in ref 17b, we report a crystal structure of the BINAP-
ligated iridium C,O-benzoate derived from m-nitrobenzoic acid. Such
ortho-cyclometallation onto m-nitrobenzoate was described previously
for C5Me5-iridium complexes: Kisenyi, J. M.; Sunley, G. J.; Cabeza,
J. A.; Smith, A. J.; Adams, H.; Salt, N. J.; Maitlis, P. M. J. Chem.
Soc., Dalton Trans. 1987, 2459.
Our collective studies on C-C bond forming hydrogena-
tion and transfer hydrogenation define a departure from the
use of preformed organometallic reagents in carbonyl addition
9
J. AM. CHEM. SOC. VOL. 131, NO. 7, 2009 2519

A R T I C L E S
Kim et al.
for the generous donation of (S)-C2-TUNEPHOS, (S)-C3-
TUNEPHOS, and (S)-C4-TUNEPHOS.
chemistry. Future studies will focus on the development of
related transformations, including imine additions from the
amine oxidation level.
Supporting Information Available: Experimental details and
1
Acknowledgment. Acknowledgment is made to Merck, the
Robert A. Welch Foundation, the ACS-GCI Pharmaceutical
Roundtable, the NIH-NIGMS (RO1-GM069445), and the Korea
Research Foundation (KRF-2007-356-E00037) for partial support
of this research. Dr. Oliver Briel of Umicore is thanked for the
generous donation of [Ir(cod)Cl]2. Dr. Hideo Shimizu and Dr.
Wataru Kuriyama of Takasago are thanked for the generous
donation of (S)-SEGPHOS. Professor Xumu Zhang is thanked
spectroscopic data. For unknown compounds (3f and 5), H
NMR, 13C NMR, IR, HRMS, and HPLC data are provided. For
1
known compounds (3a-3e and 3g-3j), H NMR, 13C NMR,
and HPLC data are provided. This material is available free of
charge via the Internet at http://pubs.acs.org.
JA808857W
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2520 J. AM. CHEM. SOC. VOL. 131, NO. 7, 2009