Iridium-catalyzed allylation of chiral β-stereogenic alcohols: Bypassing discrete formation of epimerizable aldehydes

Article abstract of DOI:10.1021/ol3030692

The cyclometalated π-allyliridium 3,4-dinitro-C,O-benzoate complex modified by (R)- or (S)-Cl,MeO-BIPHEP promotes the transfer hydrogenative coupling of allyl acetate to β-stereogenic alcohols with good to excellent levels of catalyst-directed diastereose

Full text of DOI:10.1021/ol3030692

ORGANIC
LETTERS
2012
Vol. 14, No. 24
6302–6305
Iridium-Catalyzed Allylation of Chiral
β‑Stereogenic Alcohols: Bypassing
Discrete Formation of Epimerizable
Aldehydes
Daniel C. Schmitt, Anne-Marie R. Dechert-Schmitt, and Michael J. Krische*
University of Texas at Austin, Department of Chemistry and Biochemistry,
Austin, Texas 78712, United States
mkrische@mail.utexas.edu
Received November 7, 2012
ABSTRACT
The cyclometalated π-allyliridium 3,4-dinitro-C,O-benzoate complex modified by (R)- or (S)-Cl,MeO-BIPHEP promotes the transfer hydrogenative
coupling of allyl acetate to β-stereogenic alcohols with good to excellent levels of catalyst-directed diastereoselectivity to furnish homoallylic
alcohols. Remote electronic effects of the C,O-benzoate of the catalyst play a critical role in suppressing epimerization of the transient
R-stereogenic aldehyde.
Carbonyl allylation is one of the foremost methods
utilized for the construction of polyketide natural products.1
As established in pioneering work by Hoffmann,2a,b the vast
majority of methods for enantioselective carbonyl allyla-
tion rely upon the use of allylmetal reagents modified by
chiral auxiliaries.2 Subsequently, enantioselective carbonyl
allylations employing achiral allylmetal reagents in combi-
nation with chiral Lewis acidic and Lewis basic catalysts
were developed,3 as well as related processes catalyzed by
chiral H-bond donors and Brønsted acids.4 Other methods
for catalytic carbonyl allylation include reductive couplings
of allylic alcohols and their carboxylates to aldehydes,5
and asymmetric variants of the NozakiÀHiyama reaction.6
Without exception, the aforementioned enantioselective
methods employ either stoichiometric quantities of an allyl-
metal reagent or a stoichiometric (organo)metallic reductant.
In 2008, an alternate approach to enantioselective car-
bonyl allylation based on iridium catalyzed CÀC bond
(1) For selected reviews on enantioselective carbonyl allylation, see:
(a) Ramachandran, P. V. Aldrichimica Acta 2002, 35, 23. (b) Denmark,
S. E.; Fu, J. Chem. Rev. 2003, 103, 2763. (c) Yu, C.-M.; Youn, J.; Jung,
H.-K. Bull. Korean Chem. Soc. 2006, 27, 463. (d) Marek, I.; Sklute, G.
Chem. Commun. 2007, 1683. (e) Hall, D. G. Synlett 2007, 1644. (f)
Lachance, H.; Hall, D. G. Org. React. 2008, 73, 1. (g) Yus, M.; Gonzalez-
Gomez, J. C.; Foubelo, F. Chem. Rev. 2011, 111, 7774.
(2) For selected examples of chirally modified allylmetal reagents,
see: (a) Herold, T.; Hoffmann, R. W. Angew. Chem., Int. Ed. 1978, 17,
768. (b) Hoffmann, R. W.; Herold, T. Chem. Ber. 1981, 114, 375. (c)
Hayashi, T.; Konishi, M.; Kumada, M. J. Am. Chem. Soc. 1982, 104,
4963. (d) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105, 2092.
(e) Roush, W. R.; Walts, A. E.; Hoong, L. K. J. Am. Chem. Soc. 1985,
107, 8186. (f) Reetz, M. Pure Appl. Chem. 1988, 60, 1607. (g) Short, R. P.;
Masamune, S. J. Am. Chem. Soc. 1989, 111, 1892. (h) Brown, H. C.;
Bhat, K. S.; Randad, R. S. J. Org. Chem. 1989, 54, 1570. (i) Corey, E. J.;
Yu, C.-M.; Kim, S. S. J. Am. Chem. Soc. 1989, 111, 5495. (j) Seebach, D.;
Beck, A. K.; Imwinkeiried, R.; Roggo, S.; Wonnacott, A. Helv. Chim.
Acta 1987, 70, 954. (k) Riediker, M.; Duthaler, R. O. Angew. Chem., Int.
Ed. 1989, 28, 494. (l) Panek, J. S.; Yang, M. J. Am. Chem. Soc. 1991, 113,
6594. (m) Kinnaird, J.; Ng, P. Y.; Kubota, K.; Wang, X.; Leighton, J. L.
J. Am. Chem. Soc. 2002, 124, 7920. (n) Hackman, B. M.; Lombardi, P. J.;
Leighton, J. L. Org. Lett. 2004, 6, 4375. (o) Burgos, C. H.; Canales, E.;
Matos, K.; Soderquist, J. A. J. Am. Chem. Soc. 2005, 127, 8044.
(3) For selected examples of catalytic enantioselective carbonyl
allylation employing allylmetal reagents: (a) Furuta, K.; Mouri, M.;
Yamamoto, H. Synlett 1991, 561. (b) Costa, A. L.; Piazza, M. G.;
Tagliavini, E.; Trombini, C.; Umani-Ronchi, A. J. Am. Chem. Soc. 1993,
115, 7001. (c) Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. Soc.
1993, 115, 8467. (d) Denmark, S. E.; Coe, D. M.; Pratt, N. E.; Griedel,
B. D. J. Org. Chem. 1994, 59, 6161. (e) Denmark, S. E.; Fu, J. J. Am.
Chem. Soc. 2001, 123, 9488.
(4) For selected examples of enantioselective Brønsted acid or
H-bond donor catalyzed carbonyl allylations employing allylboron
reagents, see: (a) Rauniyar, V.; Hall, D. G. Angew. Chem., Int. Ed.
2006, 45, 2426. (b) Lou, S.; Moquist, P. N.; Schaus, S. E. J. Am. Chem.
Soc. 2006, 128, 12660. (c) Rauniyar, V.; Zhai, H.; Hall, D. G. J. Am.
Chem. Soc. 2008, 130, 8481. (d) Barnett, D. D.; Moquist, P. N.; Schaus,
S. E. Angew. Chem., Int. Ed. 2009, 48, 8679. (e) Jain, P.; Antilla, J. C.
J. Am. Chem. Soc. 2010, 132, 11884.
r
10.1021/ol3030692
Published on Web 12/11/2012
2012 American Chemical Society

forming transfer hydrogenation was developed in our
laboratory.7,8a,8b In these processes, primary alcohols
serve dually as reductants and aldehyde precursors, allow-
ing carbonyl addition to occur directly from the alcohol
oxidation level in the absence of stoichiometric organo-
metallic reagents. However, initial attempts to perform
stereoselective CÀH allylations of chiral β-stereogenic
primary alcohols under these conditions, which at the time
involved generation of the Ir catalyst in situ, were thwarted
by epimerization of the transient R-stereogenic aldehydes.
In subsequent work on anti-diastereo- and enantioselec-
tive carbonyl crotylations,8c it was found that para-sub-
stitution of the C,O-benzoate moiety of a cyclometalated
catalyst could favorably influence selectivity and reactivity
via remote electronic effects.9 Additionally, conventional
chromatographic isolation of the cyclometalated catalyst
was found to enhance the purity and, hence, performance
of the catalyst.8d
Table 1. Direct Allylation of the “Roche Alcohol” 1 with
Catalyst-Directed Diastereoselectivitya
The enhanced efficiency observed for the chromato-
graphically isolated catalyst, along with the ability to tune
catalyst performance via remote electronic effects, prompted
a reinvestigation of the transfer hydrogenative allylation
of β-stereogenic primary alcohols. Here, we report that
β-stereogenic primary alcohols participate in direct
a Cited yields are of diastereomeric mixtures isolated by silica gel
chromatography. Stereoisomeric ratios were determined by chiral sta-
tionary phase HPLC analysis using authentic samples of diastereomers
2aÀ2d. See Supporting Information for further experimental details.
(5) For selected examples of enantioselective carbonyl allylations
employing nucleophilic π-allyls derived from allylic alcohols and their
carboxylates, see: (a) Zanoni, G.; Gladiali, S.; Marchetti, A.; Piccinini,
P.; Tredici, I.; Vidari, G. Angew. Chem., Int. Ed. 2004, 43, 846. (b) Zhu,
S.-F.; Yang, Y.; Wang, L.-W.; Liu, B.; Zhou, Q.-L. Org. Lett. 2005, 7,
2333. (c) Howell, G. P.; Minnaard, A. J.; Feringa, B. L. Org. Biomol.
Chem. 2006, 4, 1278. (d) Zhang, T.-Z.; Dai, L.-X.; Hou, X.-L. Tetra-
hedron: Asymmetry 2007, 18, 251. (e) Wang, W.-F.; Zhang, T.; Shi, M.
Organometallics 2009, 28, 2640. (f) Jiang, J.-J.; Wang, D.; Wang, W.-F.;
Yuan, Z.-L.; Zhao, M.-X.; Wang, F.-J.; Shi, M. Tetrahedron: Asymme-
try 2010, 21, 2050. (g) Vogt, M.; Ceylan, S.; Kirschning, A. Tetrahedron
2010, 66, 6450. (h) Zhu, S.-F.; Qiao, X.-C.; Zhang, Y.-Z.; Wang, L.-X.;
Zhou, Q.-L. Chem. Sci. 2011, 2, 1135.
diastereoselective transfer hydrogenative allylation with
good to excellent levels of catalyst-directed stereoselectiv-
ity to furnish homoallylic alcohols. This protocol bypasses
discrete generation of configurationally unstable chiral
R-substituted aldehydes,10 which are used routinely in
polyketide construction, yet cannot be stored or chroma-
tographed without significant erosion of enantiomeric
purity.10a,11
In an initial experiment, the primary alcohol 1 derived
from the Roche ester12 was exposed to the cyclometalated
complex (S)-Ir-a-CN (5 mol %), which is modified by
(S)-SEGPHOS, in THF/H2O solvent at 60 °C using
Cs2CO3 (60 mol %) as the base and 4-CN-3-NO2BzOH
as the additive. The desired allylation product 2a was
generated stereoselectively in low isolated yield (Table 1,
entry 1). Elevating the reaction temperature enhanced the
isolated yield of 2a, but led to epimerization of the transient
R-substituted chiral aldehyde (entries 1À4). Remarkably,
increased loadings of Cs2CO3 (100 mol %) improved the
isolated yield of 2a while suppressing epimerization, and
(6) For catalytic enantioselective carbonyl allylation and crotylation
via NozakiÀHiyama coupling, see: (a) Bandini, M.; Cozzi, P. G.;
Umani-Ronchi, A. Angew. Chem., Int. Ed. 1999, 38, 3357. (b) Bandini,
M.; Cozzi, P. G.; Umani-Ronchi, A. Polyhedron 2000, 19, 537. (c)
Bandini, M.; Cozzi, P. G.; Umani-Ronchi, A. Tetrahedron 2001, 57,
835. (d) Inoue, M.; Suzuki, T.; Nakada, M. J. Am. Chem. Soc. 2003, 125,
€
1140. (e) Berkessel, A.; Mench, D.; Sklorz, C. A.; Schroder, M.;
Paterson, I. Angew. Chem., Int. Ed. 2003, 42, 1032. (f) Lee, J.-Y; Miller,
J. J.; Hamilton, S. S.; Sigman, M. S. Org. Lett. 2005, 7, 1837. (g)
McManus, H. A.; Cozzi, P. G.; Guiry, P. J. Adv. Synth. Catal. 2006,
348, 551. (h) Xia, G.; Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 2554.
€
(i) Hargaden, G. C.; Muller-Bunz, H.; Guiry, P. J. Eur. J. Org. Chem.
2007, 4235. (j) Hargaden, G. C.; O’Sullivan, T.; Guiry, P. J. Org. Biomol.
Chem. 2008, 6, 562. (k) Zhang, Z.; Huang, J.; Ma, B.; Kishi, Y. Org. Lett.
2008, 10, 3073. (l) White, J. D.; Shaw, S. Org. Lett. 2011, 13, 2488.
(7) For selected reviews on CÀC bond forming hydrogenation and
transfer hydrogenation, see: (a) Bower, J. F.; Kim, I. S.; Patman, R. L.;
Krische, M. J. Angew. Chem., Int. Ed. 2008, 48, 34. (b) Patman, R. L.;
Bower, J. F.; Kim, I. S.; Krische, M. J. Aldrichimica Acta 2008, 41, 95. (c)
Han, S. B.; Kim, I. S.; Krische, M. J. Chem. Commun. 2009, 7278. (d)
Bower, J. F.; Krische, M. J. Top. Organomet. Chem. 2011, 43, 107. (e)
Hassan, A.; Krische, M. J. Org. Process Res. Dev. 2011, 15, 1236.
(8) (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. (c) Kim, I. S.; Han, S. B.; Krische, M. J. J. Am. Chem.
Soc. 2009, 131, 2514. (d) Gao, X.; Townsend, I. A.; Krische, M. J. J. Org.
Chem. 2011, 76, 2350.
(10) For selected examples of problematic aldehyde epimerization,
see: (a) Roush, W. R.; Palkowitz, A. D.; Ando, K. J. Am. Chem. Soc.
1990, 112, 6348. (b) Nelson, S. G.; Bungard, C. J.; Wang, K. J. Am.
Chem. Soc. 2003, 125, 13000. (c) Haidle, A. M.; Myers, A. G. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 12048. (d) Lane, J. W.; Chen, Y.; Williams,
R. M. J. Am. Chem. Soc. 2005, 127, 12684. (e) Hara, A.; Morimoto, R.;
Ishikawa, Y.; Nishiyama, S. Org. Lett. 2011, 13, 4036.
(11) As stated in ref 10a, footnote 12, attempts to purify the Roche
aldehyde by silica gel chromatography resulted in 5À7% racemization.
(12) Cohen, N.; Eichel, W. F.; Lopresti, R. J.; Neukom, C.; Saucy, G.
J. Org. Chem. 1976, 41, 3505.
(9) For selected examples of remote electronic effects in enantiose-
€
lective catalysis, see: (a) Jacobsen, E. N.; Zhang, W.; Guller, M. L.
J. Am. Chem. Soc. 1991, 113, 6703. (b) RajanBabu, T. V.; Ayers, T. A.;
Casalnuovo, A. L. J. Am. Chem. Soc. 1994, 116, 4101. (c) Hamada, T.;
Fukuda, T.; Imanishi, H.; Katsuki, T. Tetrahedron 1996, 52, 515. (d)
Shiomi, T.; Ito, J.-I.; Yamamoto, Y.; Nishiyama, H. Eur. J. Org. Chem.
2006, 5594.
Org. Lett., Vol. 14, No. 24, 2012
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use of excess Cs2CO3 relative to alcohol 1 resulted in
diminished yield, but high diastereoselectivity was main-
tained (entries 5À8). Water suppresses competitive
transesterification between allyl acetate and alcohol 1 and
epimerization to form 2c (entry 9). As revealed in a com-
parison of 4-substituted C,O-benzoates (entries 7, 10,
12À14), an optimal balance in yield and selectivity is
obtained using the 3,4-dinitro-C,O-benzoate (entry 14).
Perhaps related to the observation that the cyclometalated
C,O-benzoate moiety of the catalyst is kinetically labile and
can exchange with exogenous benzoic acid, added benzoic
acid improves the isolated yield of 2a (entry 11). Finally,
by changing the ligand of the 3,4-dinitro-C,O-benzoate
to (S)-Cl,MeO-BIPHEP, and by increasing the loading of
water, alcohol 1 is converted to the product of allylation 2a
in optimal isolated yield and selectivity (entries 15, 16). This
catalyst, (R)-Ir-b-NO2, was characterized by single crystal
X-ray diffraction. Under these same conditions, the enan-
tiomeric catalyst (R)-Ir-b-NO2 delivers the diastereomeric
product 2b with optimal levels of stereoselectivity (entry 20).
Thus, diastereomeric products of carbonyl allylation 2a
(32:1 dr) or 2b (15:1 dr) are formed with good levels of
catalyst-directed diastereoselectivity13 and with exception-
ally little racemization of the transient aldehyde. Notably,
the “Roche aldehyde” is known to suffer significant race-
mization upon exposure to silica gel chromatography.10a,11
The formation of 2a represents the “matched case,” wherein
the diastereofacial bias of the catalyst is amplified by
FelkinÀAnh selectivity embodied by the transient alde-
hyde, and the formation of 2b represents the corresponding
mismatched cases.
Scheme 1. Catalyst-Directed Diastereoselective C-Allylation of
Chiral Alcohols syn-3, anti-3, 5, 7, and 9a
Using these optimal conditions, the catalyst-directed
diastereoselective allylation of higher chiral alcohols pos-
sessing embedded propionate substructures was explored
(Scheme 1). Upon exposure of alcohol syn-3 to the catalyst
(S)-Ir-b-NO2 under standard conditions, the desired product
of allylation 4a is obtained as a 17:1 mixture of diastereomers.
The enantiomeric catalyst (R)-Ir-b-NO2 delivers the diaster-
eomeric product 4b as a 9:1 mixture of diastereomers.
Similarly, exposure of alcohol anti-3, which is formed
via asymmetric anti-aldol addition of isobutyraldehyde, to
the catalysts (S)-Ir-b-NO2 and (R)-Ir-b-NO2 under standard
conditions provides diastereomers 4c (6:1 dr) and 4d (12:1
dr), respectively. Thus, all four diastereomers, 4aÀ4d, are
accessible via catalyst-directed diastereoselective C-allylation of
primary alcohols syn-3 and anti-3. In a similar fashion,
alcohols 5, 7, and 9 are converted to their respective diaster-
eomeric products 6a and 6b, 8a and 8b, and10a and 10b, with
good levels of catalyst-directed stereocontrol. In contrast
to the “Roche alcohol” 1, the minor diastereomer obtained
(13) For selected examples of catalyst-directed diastereoselectivity,
see: (a) Minami, N.; Ko, S. S.; Kishi, Y. J. Am. Chem. Soc. 1982, 104,
1109. (b) Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Reed, L. A.;
Sharpless, K. B.; Walker, F. J. Science 1983, 220, 949. (c) Kobayashi,
S.; Ohtsubo, A.; Mukaiyama, T. Chem. Lett. 1991, 831. (d) Hammadi,
A.; Nuzillard, J. M.; Poulin, J. C.; Kagan, H. B. Tetrahedron: Asym-
metry 1992, 3, 1247. (e) Doyle, M. P.; Kalinin, A. V.; Ene, D. G. J. Am.
Chem. Soc. 1996, 118, 8837. (f) Trost, B. M.; Calkins, T. L.; Oertelt, C.;
Zambrano, J. Tetrahedron Lett. 1998, 39, 1713. (g) Balskus, E. P.;
Jacobsen, E. N. Science 2007, 317, 1736. (h) Han, S. B.; Kong, J. R.;
Krische, M. J. Org. Lett. 2008, 10, 4133.
a Cited yields are of diastereomeric mixtures isolated by silica gel
chromatography. Stereoisomeric ratios were determined by 1H NMR
analysis of crude reaction mixtures (major diastereomer:sum of two
minor diastereomers). See Supporting Information for further experi-
mental details. b48 h.
from the allylation of β-substituted chiral alcohols syn-3,
anti-3, 5, 7, and 9 principally stems from epimerization of the
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Scheme 2. General Catalytic Mechanism
Figure 1. Survey of selected bond lengths from a series of
π-allyliridium C,O-benzoate complexes as determined by single
crystal x-ray diffraction analysis. See Supporting Information for
single crystal X-ray diffraction data of complexes (R)-Ir-a-OMe,
(R)-Ir-a-NO2, and (R)-Ir-b-NO2.
transient aldehydes. Here, it is likely that increased steric
demand of the aldehyde retards the rate of CÀC bond forma-
tion with respect to aldehyde epimerization. For the redox-
allylation of chiral β-stereogenic alcohols, the presence of an
electron-withdrawing group at the 4-position of the C,O-
benzoate moiety was found to favorably influence conver-
sion and stereoselectivity, minimizing epimerization of the
transient chiral R-stereogenic aldehyde.
To gain insight into how electronic characteristics of
the C,O-benzoate moiety manifest structurally, a series of
π-allyliridium C,O-benzoate complexes were analyzed via
single crystal X-ray diffraction and selected bond lengths
were surveyed (Figure 1). While the influence of crystal
packing forces on bond length cannotbe quantified, a clear
trend in the series (R)-Ir-a-OMe, (S)-Ir-a-H, (R)-Ir-a-NO2,
and (R)-Ir-b-NO2 is apparent: the more electron deficient
the C,O-benzoate moiety, the longer the CÀIr, OÀIr, and
PÀIr bonds. The elongation ofbonds toiridium, asevident
in (R)-Ir-b-NO2, naturally suggests greater Lewis acidity at
iridium. This interpretation is corroborated by the infrared
absorption of the iridium carboxylate moiety of (R)-Ir-a-
NO2 (1648 cmÀ1) and (R)-Ir-a-OMe (1633 cmÀ1).
The favorable influence of the 4-nitro-moiety of the
C,O-benzoate ligand on conversion and stereoselectivity
may be interpreted on the basis of the previously postulated
catalytic mechanism (Scheme 2).8b Enhanced Lewis acidity
at iridium may strengthen the agostic interaction between
the iridium center and the carbinol CÀH bond, thereby
facilitating alcohol dehydrogenation. Additionally, the
highly inductive nature of the 4-nitro-moiety may facilitate
deprotonation of the iridium(III) hydride obtained upon
alcohol dehydrogenation. Finally, both carbonyl addi-
tion and product-to-reactant alkoxide exchange may be
accelerated by enhanced Lewis acidity at iridium. An
acceleration of carbonyl addition with respect to aldehyde
epimerization in response to enhanced Lewis acidity would
account for how remote electron-withdrawing groups of
the catalyst serve to minimize racemization of the transient
chiral R-stereogenic aldehyde.
In summary, cyclometalated π-allyliridium 3,4-dinitro-
C,O-benzoate complexes modified by (R)- or (S)-Cl,MeO-
BIPHEP promote the direct CÀH allylation of diverse
β-substituted chiral primary alcohols to furnish homoallylic
alcohols with good to excellent levels of catalyst-directed
diastereoselectivity accompanied by minimal epimerization
of the transient R-stereogenic aldehyde intermediates. This
protocol avoids discrete generation of configurationally
and chemically labile chiral R-substituted aldehydes10a,11
in asymmetric carbonyl allylation.
Acknowledgment. Acknowledgment is made to the
Robert A. Welch Foundation (F-0038) and the NIH-
NIGMS (RO1-GM093905).
Supporting Information Available. Spectral data for
all new compounds (1H NMR, 13C NMR, IR, HRMS).
Single crystal X-ray diffraction data of complexes (R)-Ir-
a-OMe, (R)-Ir-a-NO2, and (R)-Ir-b-NO2. This material is
available free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
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