Diastereo- and enantioselective iridium-catalyzed carbonyl propargylation from the alcohol or aldehyde oxidation level: 1,3-enynes as allenylmetal equivalents

Article abstract of DOI:10.1002/anie.201200239

Axial to axial to point chirality transfer: Exposure of conjugated enynes to alcohols in the presence of an iridium catalyst modified by a segphos ligand results in the generation of aldehyde-allenyliridium pairs and formation of enantiomerically enriched products of carbonyl anti-(α-methyl) propargylation (see scheme). An identical set of products are obtained from aldehydes under related transfer hydrogenation conditions by employing formic acid as a reductant. Copyright

Full text of DOI:10.1002/anie.201200239

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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
under http://dx.doi.org/10.1002/anie.201200239.
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Chemie
(Table 1, Entries 3–5). Whereas (R)-segphos provides homo-
propargylic alcohol 4b-TBS in 93% enantiomeric excess, the
yield and diastereoselectivity were poor (Table 1, Entry 3).
Using (R)-DM-segphos, homopropargylic alcohol 4b was
isolated in 75% yield with a promising 6:1 anti-diastereo-
selectivity and 80% enantiomeric excess (Table 1, Entry 4).
Increased anti-diastereoselectivity upon use of xylyl-substi-
tuted ligands also was observed in the binap and p-phos ligand
classes, although segphos ligands[17] consistently provided
higher diastereo- and enantioselectivity. It was postulated that
an even more sterically demanding ligand, (R)-DTBM-
segphos, might promote higher stereoselectivities, however,
this catalytic system did not pro-
alcohols 4a–4k were formed with uniformly high levels of
anti-diastereo- and enantioselectivity, whether the reaction
was performed in pressure tubes or round-bottomed flasks.[20]
While reactions of benzylic and allylic alcohols 2a–2h require
(R)-DM-segphos to enforce stereoselectivity, reactions of
aliphatic alcohols 2i–k were highly stereoselective by using
(R)-segphos as ligand. Reactions with alcohols 2g–k were
higher yielding in the presence of either isopropanol or formic
acid, although the reason for this observation remains
unclear. Aliphatic alcohols branched at the a position are
converted to homopropargylic alcohols with exceptional
levels of stereoselectivity, however, diminished yields of
duce 4b-TBS (Table 1, Entry 5).
Table 2: anti-Diastereo- and enantioselective carbonyl propargylation from the alcohol or aldehyde
Given these trends, it was postu-
lated that increased steric demand
of the enyne might enhance anti-
diastereoselectivity. Indeed, use of
the enyne 1c, which incorporates
a TIPS ether, and the (R)-segphos
modified catalyst provided homo-
propargylic alcohol 4b-TIPS in
81% yield, 3:1 anti-diastereoselec-
tivity, and 94% enantiomeric excess
(Table 1, Entry 6). Furthermore, by
using the TIPS ether enyne 1c in
combination with (R)-DM-segphos,
homopropargylic alcohol 4b-TIPS
was obtained in 80% yield, 8:1 anti-
diastereoselectivity, and 87% enan-
tiomeric excess (Table 1, Entry 7).
Upon use of THF as solvent, 12:1
anti-diastereoselectivity and 90%
enantiomeric excess were observed
(Table 1, Entry 8). Use of acetoni-
trile as solvent enhanced stereose-
lectivity (93% ee, 13:1 d.r.), but
diminished the yield of isolated
product (Table 1, Entry 9). Use of
acetonitrile as an additive in THF
proved optimal, allowing the homo-
propargylic alcohol 4b-TIPS to be
generated in 75% yield, 12:1 anti-
diastereoselectivity, and 92% enan-
tiomeric excess (Table 1, Entry 10).
The effect of solvent on stereose-
lectivity is more pronounced when
the reaction is performed from the
aldehyde oxidation level.[19] The
oxidation level.[a]
Entry
Oxidation
level
Lig.
Solv.
Product
Yield
[%]
d.r.
ee
[%]
alcohol
aldehyde
A
A
THF
THF
85
79
19:1
12:1
91[b]
86[b]
1
2
alcohol
aldehyde
A
A
THF
THF
75
86
12:1
10:1
92[b]
90[b]
alcohol
aldehyde
A
A
THF
THF
87
89
12:1
11:1
89[b]
87[b]
3
4
alcohol
aldehyde
A
A
THF
THF
77
82
18:1
20:1
92[b]
89[b]
alcohol
aldehyde
A
A
THF
THF
82
89
22:1
12:1
94[b]
90[b]
5
alcohol
aldehyde
A
A
THF
THF
81
78
29:1
12:1
95[b]
95[b]
6
alcohol
aldehyde
A
A
PhMe
THF
38
67
ꢀ40:1
99[c]
94
22:1
7
alcohol
aldehyde
A
A
PhCF3
THF
62
82
32:1
24:1
90[d]
89[f]
8
alcohol
aldehyde
B
B
PhCF3
THF
53
89
40:1
17:1
99[d,e]
99[f]
9
observed
correlation
between
alcohol
aldehyde
B
B
PhCF3
THF
54
68
ꢀ50:1
ꢀ50:1
99[d,e]
99[f]
increased ability of the solvent to
coordinate to the metal with selec-
tivity may be consistent with a slow-
ing of the overall reaction rate (see
below).
10
11
alcohol
aldehyde
B
B
PhCF3
THF
48
68
ꢀ50:1
ꢀ50:1
96[d,e]
96[f]
With these optimized conditions
in hand, enyne 1c was coupled to
a diverse range of alcohols 2a–2k
(Table 2). The homopropargylic
[a] Reaction conditions as described in Table 1. HCO2H (1.5 equiv) added to reactions with aldehydes.
[b] MeCN (2 equiv). [c] iso-Propanol (1 equiv). [d] HCO2H (0.5 equiv). [e] [{Ir(cod)Cl}2] (5 mol%),
(R)-segphos (10 mol%). [f] Na2SO4 (1 equiv).
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isolated products were observed for this substrate class. Using
formic acid as terminal reductant, enyne 1c participates in
reductive couplings to aldehydes 3a–3i to furnish an equiv-
alent set of homoallylic alcohols 4a–4i in good to excellent
yield with outstanding levels of anti-diastereo- and enantio-
selectivity (Table 2). As observed in the coupling of benzylic
and allylic alcohols, (R)-DM-segphos was required to enforce
stereoselectivity in the propargylation of (hetero)aryl and
a,b-unsaturated aldehydes 3a–3h, whereas aliphatic alde-
hydes 3i–3k undergo stereoselective propargylation using
(R)-segphos as ligand. For aldehydes 3i–3k, higher yields
were obtained upon use of Na2SO4 (1 equiv) as additive.[21]
Propargylation products 4c, 4g, and 4i are directly converted
to the corresponding terminal alkynes 5c, 5g, and 5i upon
exposure to TBAF and NaOH in refluxing toluene
(Scheme 1). As terminal alkynes 5c and ent-5i are known
compounds of established relative and absolute stereochem-
istry, their preparation served to confirm the stereochemical
assignment of adducts 4a–4k.
Scheme 2. General catalytic mechanism and stereochemical model
accounting for the observed anti-diastereo- and enantioselectivity.
1
= =
(III) complex [IrCl(PPh3)2(NHSO2Ph)(CO)(h -CH C CH2)]
has been isolated, and characterized by single crystal X-ray
diffraction.[22b] The stereochemical outcome of the trans-
formation is predicted on the basis of the indicated model,
which involves carbonyl addition through the closed six-
centered transition state A (Scheme 2). Regarding the con-
formation of such square-planar allenyliridium species A–D,
Scheme 1. Deprotection of homopropargyl alcohols 4c, 4g, and 4i to
generate terminal alkynes 5c, 5g, and 5i. Yields of isolated materials
are given. See the Supporting Information for details. TBAF=tetra-n-
butylammonium fluoride.
it is shown in a related h1-allenylplatinum(II) complex, trans-
1
= =
[Pt(PPh3)2(Br)(h -CH C CH2)], that the allenyl moiety lies
roughly perpendicular to the square coordination plane.[22c]
As the allenyliridium substructures of transition states A
and B exhibit enantiomeric axial chirality, enantioselective
enyne-mediated propargylation requires high kinetic stereo-
selectivity in the enyne hydrometalation event to form
a single diastereomeric allenyliridium intermediate, or rever-
sible enyne hydrometalation to correct for incomplete
stereoselectivity, should the less stable allenyliridium species
be formed. To probe this issue, the coupling of enyne 1c and
[D2]-benzyl alcohol 2a was performed under standard con-
ditions (Scheme 3). The distribution of deuterium in deuter-
ated 4a suggests that the enyne hydrometalation is reversible
and that the carbonyl addition occurs by way of a single
diastereomeric allenyliridium intermediate, even if the kinetic
stereoselectivity of the hydrometalation is incomplete.
A plausible catalytic mechanism is as follows. The
combination of [{Ir(cod)Cl}2], ligand, and reactant alcohol
provides the iridium(I) alkoxide I, which dehydrogenates to
form an aldehyde and generate iridium(I) hydride II. For
reactions conducted from the aldehyde oxidation level, the
formate complex Ib is converted to iridium(I) hydride II.
Enyne hydrometallation provides the s-propargyl- and alle-
nyliridium species III and IV, respectively. Coordination of
the aldehyde by the latter provides V, which engages in
carbonyl addition through a closed transition structure to
furnish the homopropargylic iridium(I) alkoxide VI. Alk-
oxide exchange with a reactant alcohol delivers the product
and regenerates the iridium(I) alkoxide
I
(Scheme 2).
In summary, we report highly anti-diastereo- and enan-
tioselective iridium-catalyzed enyne-mediated carbonyl prop-
argylations from the alcohol or aldehyde oxidation level. This
methodology provides an alternative to stoichiometric (or-
gano)metallic reagents in enantioselective carbonyl propar-
Although undescribed for iridium, the stoichiometric reaction
of 1,3-enynes and [RuHCl(CO)(PPh3)3] to form s-allenyl
complexes that have been characterized by single crystal X-
ray diffraction is known.[22a] Additionally, the allenyliridium-
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À
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1
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alcohol oxidation level bypass redox manipulations otherwise
required for discrete aldehyde generation. Future studies will
À
focus on the development of related C C bond forming
À
transfer hydrogenations, including the catalytic C C coupling
of propargyl chlorides and alcohols.
Received: January 10, 2012
Published online: February 15, 2012
Keywords: enantioselectivity · homogeneous catalysis · iridium ·
.
propargylation · transfer hydrogenation
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e) Allenylzinc Reagents: J. A. Marshall, N. D. Adams, J. Org.
Chem. 1998, 63, 3812 – 3813; f) J. A. Marshall, N. D. Adams, J.
Org. Chem. 1999, 64, 5201 – 5204; g) J. P. Marino, M. S. McClure,
[15] For related nickel-catalyzed reductive coupling of 1,3-enynes to
carbonyl compounds, see: a) K. M. Miller, T. Luanphaisarnnont,
C. Molinaro, T. F. Jamison, J. Am. Chem. Soc. 2004, 126, 4130 –
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4131; b) K. M. Miller, T. F. Jamison, Org. Lett. 2005, 7, 3077 –
3080; c) K. M. Miller, E. A. Colby, K. S. Woodin, T. F. Jamison,
Adv. Synth. Catal. 2005, 347, 1533 – 1536.
[20] Experiments reported in Tables 1 and 2 were made in pressure
tubes. However, the reaction of enyne 1c and alcohol 2c
conducted in a round-bottomed flask fitted with a reflux
condenser gave 4c in similar yields and selectivities. See the
Supporting Information for details.
[21] The propargylation of aldehyde 3h gave adduct 4h in 58% yield
in the absence of Na2SO4 and 77% yield in the presence of
Na2SO4 (1 equiv) under otherwise identical conditions. It is
possible that Na2SO4 is acting as a desiccant, as the deliberate
introduction of water (2 equiv) to the reaction mixture dramat-
ically reduces the reaction rate.
[22] a) Y. Wakatsuki, H. Yamazaki, Y. Maruyama, I. Shimizu, J.
Chem. Soc. Chem. Commun. 1991, 261 – 263; b) J.-T. Chen, Y.-K.
Chen, J.-B. Chu, G.-H. Lee, Y. Wang, Organometallics 1997, 16,
1476 – 1483; c) T.-M. Huang, R.-H. Hsu, C.-S. Yang, J.-T. Chen,
G.-H. Lee, Organometallics 1994, 13, 3657 – 3663.
[16] R. L. Patman, V. M. Williams, J. F. Bower, M. J. Krische, Angew.
Chem. 2008, 120, 5298 – 5301; Angew. Chem. Int. Ed. 2008, 47,
5220 – 5223.
[17] T. Saito, T. Yokozawa, T. Ishizaki, T. Moroi, N. Sayo, T. Miura, H.
Kumobayashi, Adv. Synth. Catal. 2001, 343, 264 – 267.
[18] 2-Methyl-3-butyn-2-ol may be purchased from City Chemical for
$47.17 per kg (October 20, 2011).
[19] The analogous reactions between enyne 1c and aldehyde 4b also
gave adduct 4b in 76% yield, 4:1 anti-diastereoselectivity, and
76% enantiomeric excess in toluene as solvent. When the
reaction was conducted in THF, a 6:1 anti-diastereoselectivity
and 86% enantiomeric excess were observed. When the reaction
was conducted in THF using CH3CN (2 equiv) as an additive, 4b
was obtained in 86% yield with 10:1 anti-diastereoselectivity
and 90% enantiomeric excess.
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