.
Angewandte
Communications
DOI: 10.1002/anie.201200239
Enantioselective Propargylation
Diastereo- and Enantioselective Iridium-Catalyzed Carbonyl
Propargylation from the Alcohol or Aldehyde Oxidation Level:
1,3-Enynes as Allenylmetal Equivalents**
Laina M. Geary, Sang Kook Woo, Joyce C. Leung, and Michael J. Krische*
Carbonyl propargylation has been the topic of intensive
investigation for over half a century.[1,2] An effective approach
to enantioselective carbonyl propargylation involves the
addition of chirally modified allenylmetal reagents,[3–7] includ-
ing axially chiral derivatives.[5] Contributions include allenyl-
boron reagents that are chirally modified at boron, as
reported by Yamamoto,[3a] Corey,[3b] and Soderquist,[3c,d]
allenylstannanes that are chirally modified at tin, as first
reported by Mukaiyama,[4] as well as axially chiral allenyl-
stannanes, allenylsilanes, allenylboron, and allenylzinc
reagents that engage aldehydes in enantioselective propargy-
lation, as described by Marshall,[5a,b,e,f] Hayashi,[5d] and
Panek,[5c] respectively. Increasingly effective protocols for
carbonyl propargylation, which involve stoichiometric chir-
ality transfer, continue to be developed.[6,7] Enantioselective
aldehyde propargylation using allenyltin[8] and allenylsilicon[9]
reagents may be catalyzed by chiral Lewis acids or chiral
Lewis bases, as first reported by Keck[8a] and Denmark,[8f]
respectively. Copper catalysts promote enantioselective car-
bonyl propargylation by employing allenylboron and prop-
argylboron reagents, as reported by Kanai and Shibasaki and
Boehringer–Ingelheim Pharmaceuticals Inc.[10] More recently,
Schaus, Antilla, and Reddy reported chiral H-bond donor and
Brønsted acid catalyzed propargylations using allenylboron
reagents.[11] Finally, catalytic enantioselective Nozaki–
Hiyama coupling of propargyl halides delivers products of
carbonyl propargylation.[12] Withstanding the Nozaki–
Hiyama protocol,[12] methods available for enantioselective
carbonyl propargylation have relied on stoichiometric allenyl-
or propargylmetal reagents. Moreover, while carbonyl prop-
argylations for the construction of non-methylated polyace-
tate subunits are common, catalytic diastereo- and enantio-
selective propargylations that convert achiral reactants to
polypropionate substructures remain undeveloped. We envi-
sioned an alternative strategy for carbonyl propargylation
based on the “transfer hydrogenative coupling”[13] of 1,3-
enynes and primary alcohols. Although related Rh- and Ni-
catalyzed reductive couplings occur at the acetylenic terminus
of the enyne,[14,15] ruthenium catalysts were found to promote
À
enyne–alcohol C C coupling to form the desired products of
propargylation as single regioisomers, but without stereocon-
trol.[16] Herein, we report that iridium catalysts modified by
(R)-segphos[17] or (R)-DM-segphos promote highly anti-
diastereo- and enantioselective enyne-mediated carbonyl
propargylation from the alcohol or aldehyde oxidation level
in the absence of stoichiometric allenyl- or propargylmetal
reagents.
À
Initial studies focused on the C C coupling of benzylic
alcohol 2b to enynes 1a and 1b, which are derived from 2-
methyl-3-butyn-2-ol (47 USD/Kg).[18] Whereas enyne 1a
À
failed to participate in C C coupling to benzylic alcohol 2b
under the conditions of iridium catalysis (Table 1, Entry 1),
the corresponding TBS ether 1b couples to benzylic alcohol
2b to form the desired propargylation product 4b-TBS in
69% yield as a 1:1 mixture of diastereomers upon exposure to
the catalyst generated from [{Ir(cod)Cl}2] and dppf (Table 1,
Entry 2). At this stage, a series of chiral ligands were assayed
Table 1: Structure–selectivity relationships between enynes 1 and
ligands.[a]
Entry 1, R
Ligand
Solvent Yield d.r.
[%]
ee
[%]
1
2
3
4
1a, H
dppf
dppf
PhMe
PhMe
PhMe
PhMe
0
69
35
75
0
–
1:1
1:1 93
6:1 80
–
–
–
1b, TBS
1b, TBS
1b, TBS
1b, TBS
(R)-segphos
(R)-DM-segphos
(R)-DTBM-segphos PhMe
5
–
6
7
8
1c, TIPS (R)-segphos
PhMe
PhMe
THF
CH3CN 50
THF 75
81
80
81
3:1 94
8:1 87
12:1 90
13:1 93
12:1 92
1c, TIPS (R)-DM-segphos
1c, TIPS (R)-DM-segphos
1c, TIPS (R)-DM-segphos
1c, TIPS (R)-DM-segphos
[*] Dr. L. M. Geary, Dr. S. K. Woo, J. C. Leung, Prof. M. J. Krische
University of Texas at Austin
9
Department of Chemistry and Biochemistry
1 University Station—A5300, Austin, TX 78712-1167 (USA)
E-mail: mkrische@mail.utexas.edu
10[b]
[a] Yields of isolated materials. Diastero- and enantioselectivities were
determined by HPLC or GC analysis on a chiral stationary phase. Entry in
bold highlights optimized reaction conditions. See the Supporting
Information for details. [b] CH3CN (2 equiv). cod=cycloocta-1,5-diene,
DM=3,5-dimethyl, dppf=diphenylphospinoferrocene, DTBM=3,5-di-
tert-butyl-4-methoxy, (R)-segphos=(R)-5,5’-bis(diphenylphosphino)-
4,4’-bi-1,3-benzodioxole, TBS=tert-butyldimethylsilyl, THF=tetrahydro-
furan, TIPS=triisopropylsilyl.
[**] Acknowledgements is made to the Robert A. Welch Foundation
(F-0038), the NSF (CHE-1008551), and the Government of Canada’s
Banting Postdoctoral Fellowship Program (L.M.G.) for financial
support. We thank Dr. Taichiro Touge of Takasago for the generous
donation of segphos ligands.
Supporting information for this article is available on the WWW
2972
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 2972 –2976