Amphiphilic π-Allyliridium C,O-Benzoates Enable Regio- and Enantioselective Amination of Branched Allylic Acetates Bearing Linear Alkyl Groups

Article abstract of DOI:10.1021/jacs.7b13482

The first examples of amphiphilic reactivity in the context of enantioselective catalysis are described. Commercially available π-allyliridium C,O-benzoates, which are stable to air, water and SiO₂ chromatography, and are well-known to catalyze

Full text of DOI:10.1021/jacs.7b13482

Communication
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Amphiphilic π‑Allyliridium C,O‑Benzoates Enable Regio- and
Enantioselective Amination of Branched Allylic Acetates Bearing
Linear Alkyl Groups
Arismel Tena Meza,§,‡ Thomas Wurm,†,‡ Lewis Smith,§ Seung Wook Kim,† Jason R. Zbieg,*,§
Craig E. Stivala,*,§ and Michael J. Krische*,†
§Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States
†Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, United States
S
* Supporting Information
ABSTRACT: The first examples of amphiphilic reactivity
in the context of enantioselective catalysis are described.
Commercially available π-allyliridium C,O-benzoates,
which are stable to air, water and SiO2 chromatography,
and are well-known to catalyze allyl acetate-mediated
carbonyl allylation, are now shown to catalyze highly
chemo-, regio- and enantioselective substitutions of
branched allylic acetates bearing linear alkyl groups with
primary amines.
ince the discovery of the Tsuji−Trost reaction,1 diverse
Scatalytic systems for metal catalyzed allylic substitution have
emerged.2 Among the many useful transformations based on this
pattern of reactivity, enantioselective iridium catalyzed amina-
tions figure prominently.3−11 Largely due to the pioneering work
of Takeuchi,3,4 Helmchen,5,6 Hartwig,7,8 Carreira9 and You,10,11
a broad range of amine nucleophiles can now be accommodated
in highly regio- and enantioselective reactions of linear or
branched allylic acetates (and in certain cases allylic alco-
hols).3−11 Two classes of iridium catalysts may be distinguished
on the basis of their ability to promote regio- and enantioselective
reactions of either linear or branched allylic acetates (Figure 1).
For type I catalysts, linear allyl proelectrophiles are used under
Figure 1. Phosphoramidite modified iridium complexes and amphi-
philic π-allyliridium C,O-benzoates for regio- and enantioselective allylic
amination.
basic conditions. For type II catalysts, branched allyl proelec-
trophiles are used under acidic conditions. Whereas type I
catalysts are modified by one phosphoramidite and one external
diene ligand, type II catalysts incorporate an internal mono-olefin
allylation is often accompanied by small quantities of O-
allylation, suggesting amphiphilic character of these π-allyl
complexes. Pursuant to an accumulation of similar observations
by coauthors at Genentech, a systematic attempt to evoke
electrophilic behavior was undertaken in the context of allylic
amination. Here, we show that the commercially available π-
allyliridium C,O-benzoate modified by SEGPHOS catalyzes
asymmetric allylic amination. This catalyst overcomes a
significant limitation in scope across all known catalytic systems,
the ability to engage branched allylic acetates bearing linear alkyl
groups with uniformly high levels of regio- and enantio-
selectivity.3−11,17−18
ligand and two π-acidic phosphoramidites, which may account
for their exceptional electrophilicity. The internal olefin of type II
catalysts may enhance enantioselectivity in reactions of branched
allyl proelectrophiles by displacing the π-bond of (σ+π)-allyl
(enyl) iridium intermediates,12 thus enabling rapid π-facial
interconversion in otherwise stereospecific substitutions.13
Both type I and II catalysts bear π-acidic ligands and a formal
positive charge at the metal center. These features enforce
electrophilic properties of the allyliridium intermediate. In
contrast, we have developed π-allyliridium C,O-benzoates,
which are neutral and incorporate relatively strong σ-donor
ligands (Figure 1).14,15 As demonstrated by their ability to
promote diverse allylative carbonyl additions, the supporting
ligands of this catalyst confer nucleophilic character onto the allyl
moiety.16 However, as observed in our initial studies,14b carbonyl
Received: December 20, 2017
© XXXX American Chemical Society
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DOI: 10.1021/jacs.7b13482
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Journal of the American Chemical Society
Communication
(5 mol%) in THF (1 M) at 40 °C (Table 1). In the absence of
base, products of amination were not observed. However, after
screening various heterogeneous bases, it was found that
reactions conducted in the presence of Cs2CO3 (120 mol%)
provided the desired product of allylic amination 3a exclusively
as the branched regioisomer with high levels of enantiomeric
enrichment. After further optimization, the allylic amine 3a could
be obtained in 90% isolated yield as a single regioisomer in 90%
enantiomeric excess. Wet THF solvent is required, perhaps to
partially solubilize Cs2CO3. Using distilled THF under otherwise
optimal conditions, 3a was obtained in only 61% yield. Optimal
yields were restored using distilled THF in combination with
water (250 mol%). The absolute stereochemistry of 3a was
determined by comparison of its optical rotation to that of an
authentic sample reported in the literature (and X-ray analysis of
3j′).20
Table 1. Influence of Base in the Amination of α-Methyl Allyl
Acetate 1a To Form Allylic Amine 3a
a
a
All reactions were performed on a 0.44 mmol scale. Enantio-
selectivities were determined by chiral stationary phase HPLC analysis.
See Supporting Information for further experimental details.
b
c
Conversion was determined by 1H NMR. Cs2CO3 (200 mol%).
d
Yield of material isolated by silica gel chromatography.
Under these optimized conditions, primary benzylic, allylic
and aliphatic amines serve as nucleophilic partners in aminations
of diverse branched allylic acetates (Table 2). Complete
branched-regioselectivity was accompanied by high levels of
In an initial set of experiments, α-methyl allyl acetate 1a (100
mol%) was exposed to benzyl amine 2a (200 mol%) in the
presence of the SEGPHOS modified π-allyliridium C,O-benzoate
a
Table 2. Regio- and Enantioselective Iridium-Catalyzed Amination of Branched Allylic Carboxylates
a
Yields of material isolated by silica gel chromatography. Standard conditions: (R)-IrLn (5 mol%), amine (200 mol%), Cs2CO3 (200 mol%), “wet”
THF (1 M), 50 °C. Enantioselectivities were determined by chiral stationary phase HPLC analysis. See Supporting Information for further
b
c
experimental details. H2NCH2CH2NHBn (400 mol%), ee% determined at the stage of 4l (eq 1). The cyclometalated iridium catalyst modified by
the Roche ligand was used.19
B
DOI: 10.1021/jacs.7b13482
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Journal of the American Chemical Society
Communication
Scheme 1. Identical π-Allyliridium C,O-Benzoate Complexes
a
Promote Both Nucleophilic and Electrophilic Allylation
a
See Supporting Information for further experimental details.
enantioselectively (1H NMR and HPLC). Additionally, the levels
of chemoselectivity in favor of primary amine allylation were
sufficiently high that N-benzyl ethylene diamine and tryptamine
could be converted to the respective amination products 3l and
3a′ without competing allylation of the secondary amine. As
demonstrated by the formation of 3z, 3g′, 3h′, 3i′, primary
amines that are branched at the α-position are effective
nucleophilic partners. Further, as illustrated by the formation
of 3b vs 3c, 3e vs 3f and 3h vs 3i, excellent levels of catalyst-
directed stereoinduction are observed. Perhaps the most notable
feature of this catalytic system, however, resides in the ability to
engage branched allylic acetates bearing linear alkyl groups in
highly regio- and enantioselective aminations, a capability that
complements the scope of previously reported iridium catalysts
for allylic amination.3−11,17,18
To illustrate the utility of the reaction products a series of
transformations were performed. The N-benzyl ethylene
diamine adduct 3l was subjected to reductive amination with
glyoxal to form the piperazine 4l (eq 1).21 Adducts 3x and 3j′
were converted to 1-(N-benzyl-amino)-2-cyclohexene 4x (eq
2)22 and the cyclopropyl substituted lactam 4j′ through ring-
closing metathesis (eq 3).5g
Figure 2. Stereochemical models accounting for equivalent π-facial
selectivity in crotylation and amination.
In summary, highly tractable and commercially available π-
allyliridium C,O-benzoates, which are well-known to catalyze
nucleophilic carbonyl allylation, are now shown to catalyze
chemo-, regio- and enantioselective electrophilic aminations of
branched allylic acetates bearing linear alkyl groups. These
processes broaden access to chiral N-containing building
blocks25 and establish unique amphiphilic properties of π-
allyliridium C,O-benzoates, which should inform the design of
new catalytic processes. More broadly, this work demonstrates
how academic-industrial collaboration accelerates the discovery
of robust, innovative methods for chemical synthesis.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b13482.
Although numerous reports of “umpoled allylations” exist,23
the amphiphilic properties displayed by π-allyliridium C,O-
benzoates appear quite unique.24 The same catalyst, (R)-IrLn (5
mol%), will promote both nucleophilic and electrophilic
allylation under very similar conditions. For example, under
standard amination conditions, 4-aminomethyl-benzyl alcohol
and α-methyl allyl acetate are directly converted to compound 7
in 36% yield. Alternatively, compound 5 can be converted to
compound 7 in a stepwise manner with higher levels of
stereoselectivity using the same iridium catalyst (Scheme 1).
The nature of the C−N bond forming event merits discussion.
For related enantioselective iridium catalyzed allylic aminations,
an outer-sphere mechanism is postulated.3−11 Though it is likely
such pathways are also operative in aminations catalyzed by π-
allyliridium C,O-benzoates, an inner-sphere mechanism cannot
be excluded. The more stringent steric constraints of an inner-
sphere mechanism may account for the fact that primary amines
engage in allylation while secondary amines do not. Furthermore,
enantiofacial selectivity for amination through an inner sphere
mechanism matches that observed in nucleophilic allylations of
α-substituted allylic acetates (Figure 2). Computational studies
are underway to evaluate outer vs inner sphere pathways.
■
S
Experimental procedures and spectral data. HPLC traces
of racemic and enantiomerically enriched products (PDF)
Crystallographic data for 3j′ (CIF)
AUTHOR INFORMATION
■
Corresponding Authors
*zbieg.jason@gene.com
*stivala.craig@gene.com
*mkrische@mail.utexas.edu
ORCID
Jason R. Zbieg: 0000-0002-2897-8911
Craig E. Stivala: 0000-0002-5024-6346
Michael J. Krische: 0000-0001-8418-9709
Author Contributions
‡A.T.M. and T.W. contributed equally.
Notes
The authors declare no competing financial interest.
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Communication
Ed. 2012, 51, 5183. (c) Ye, K.-Y.; Zhao, Z.-A.; Lai, Z.-W.; Dai, L.-X.; You,
S.-L. Synthesis 2013, 45, 2109. (d) Ye, K.-Y.; Dai, L.-X.; You, S.-L. Chem. -
Eur. J. 2014, 20, 3040. (e) Yang, Z.-P.; Wu, Q.-F.; You, S.-L. Angew.
Chem., Int. Ed. 2014, 53, 6986. (f) Zhang, X.; Yang, Z.-P.; Huang, L.;
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F.; Shao, W.; You, S.-L. J. Am. Chem. Soc. 2015, 137, 15899. (h) Ye, K.-Y.;
Cheng, Q.; Zhuo, C.-X.; Dai, L.-X.; You, S.-L. Angew. Chem., Int. Ed.
2016, 55, 8113. (i) Zhang, X.; Liu, W.-B.; Cheng, Q.; You, S.-L.
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ACKNOWLEDGMENTS
■
The Robert A. Welch Foundation (F-0038), the NIH-NIGMS
(RO1-GM069445), and the Alexander von Humboldt Founda-
tion Feodor-Lynen postdoctoral fellowship program (T.W.) are
acknowledged for partial support of this research. Steven T.
Staben is thanked for helpful discussions and Baiwei Lin, Kewei
Xu and Yanzhou Liu for analytical data.
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