Control of diastereoselectivity for iridium-catalyzed allylation of a prochiral nucleophile with a phosphate counterion

Article abstract of DOI:10.1021/ja311363a

We report a highly diastereo- and enantioselective allylation of azlactones catalyzed by the combination of a metallacyclic iridium complex and an optically inactive phosphate anion. The process demonstrates an approach for conducting diastereoselective reactions with prochiral nucleophiles in the presence of metallacyclic allyliridium complexes. The reaction provides access to an array of enantioenriched allylated azlactones containing adjacent tertiary and quaternary carbon centers. Preliminary mechanistic studies suggest that the phosphate and methyl carbonate anions together induce the unusually high diastereoselectivity.

Full text of DOI:10.1021/ja311363a

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Communication
Control of Diastereoselectivity for Iridium-catalyzed Allylation
of a Prochiral Nucleophile with a Phosphate Counterion
Wenyong Chen, and John F. Hartwig
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja311363a • Publication Date (Web): 03 Jan 2013
Downloaded from http://pubs.acs.org on January 9, 2013
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Control of Diastereoselectivity for Iridium-catalyzed Allylation of a
Prochiral Nucleophile with a Phosphate Counterion
Wenyong Chen and John F. Hartwig*
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Department of Chemistry, University of California, Berkeley, California 94720, United States
Supporting Information Placeholder
Scheme 1. Envisioned Ir-Catalyzed Allylation Assisted by the
Counterion X-
ABSTRACT: We report a highly diastereo- and enantiose-
lective allylation of azlactones catalyzed by the combina-
tion of a metallayclic iridium complex and an optically
inactive phosphate anion. The process demonstrates an
approach to conduct diastereoselective reactions with
prochiral nucleophiles in the presence of metallacyclic
allyliridium complexes. The reaction provides access to an
array of enantioenriched allylated azlactones containing
adjacent tertiary and quaternary carbon centers. Prelimi-
nary mechanistic studies suggest that the phosphate and
methyl carbonate anions together induce the unusually
high diastereoselectivity.
Table 1. Evaluation of the Effects of Ligand and Coun-
terion on the Ir-Catalyzed Allylation of azlactone 3a
Asymmetric allylic substitution catalyzed by metallacyclic
iridium phosphoramidite complexes occurs with high regioselec-
tivity and enantioselectivity with a variety of heteroatom and car-
bon nucleophiles.1 However, none of these reactions with prochi-
ral nucleophiles occur with high diastereoselectivity.1b, 2 Careful
analysis of these reactions revealed that both diastereomers were
generally formed with high enantiopurity.3 Thus, the low diastere-
oselectivity originated from the lack of control of the configura-
tion at the prochiral nucleophiles. Therefore, a novel strategy is
needed to control the configuration at the nucleophilic carbon
atom for Ir-catalyzed allylic substitutions to be diastereoselective.
Entry
1e
ligand
AgX
AgBF4
2a
Yield(%)b
drc
7:1
ee(%)d
98
1
31
83
We considered that the configuration at the nucleophilic carbon
atom might be controlled by the counterion.4 Mechanistic studies
of Ir-catalyzed asymmetric allylation reactions have shown that
the counterion promoted nucleophilic attack by deprotonation of
an acidic pronucleophile5 or desilylation of a silyl enolate.6 How-
ever, a counterion effect on the diastereoselectivity of Ir-catalyzed
asymmetric allylation reactions has not been reported, presumably
due to the lack of appropriate methods to introduce different
counterions.7
1
2
8:1
98
1
2b
3
87
>20:1
>20:1
>20:1
20:1
>20:1
18:1
98
4f
5g
6
57
98
1
2b
1
2b
70
98
ent-1
2b
88
-98
98
1
1
2c
7
89(87)
81
Here, we report a highly diastereo- and enantioselective allyla-
tion of azlactones catalyzed by the combination of a metallacyclic
iridium complex and optically inactive phosphate cocatalysts.
These reactions reveal a new approach to control diastereoselec-
tivity with iridium catalysts for allylic substitutions.
2d
8
98
a1.00 equiv of cinnamyl carbonate, 2.20 equiv of 3. See the Sup-
porting Information (SI) for experimental details. Absolute con-
figuration of the allylation product was determined by chemical
correlation. Determined by H NMR analysis with mesitylene as
the internal standard. Numbers in parentheses correspond to iso-
b
1
Because silver salts, such as AgBF4, have been used in the syn-
thesis of metallacyclic allyliridium complexes,8 we envisioned
that counterions for control of diastereoselectivity could be intro-
duced into the catalytic system by generating the metallacyclic
iridium catalysts in situ from various silver salts (AgX). In this
case, the counterion X- would deprotonate the pronucleophile and
modulate the degree of stereocontrol at the new chiral center of
prochiral nucleophiles (Scheme 1). Because azlactones are valua-
ble pronucleophiles to access biologically important quaternary
c
1
lated yield. Determined by H NMR analysis of crude reaction
d
mixtures. Determined by chiral HPLC analysis of the major dia-
stereomer. 90% conversion of cinnamyl carbonate. f4 mol % 2b
e
g
was used. 64% conversion of cinnamyl carbonate. Without mo-
lecular sieves. 80% conversion of cinnamyl carbonate.
amino acids9 and have been used previously for allylic substitu-
tion,10 we chose to explore the counterion effect on diastereoselec-
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Table 2. Ir-Catalyzed Allylation of Azlactonesa, b
tivity in Ir-catalyzed allylic substitutions with this class of rea-
gents.
1
2
The reaction of cinnamyl methyl carbonate with azlactone 3
3
4
5
6
derived from alanine was first investigated to reveal potential
effects of the ligand and counterion on the Ir-catalyzed allylation
reaction (Table 1). Reactions catalyzed by the combination of
[Ir(COD)Cl]2, phosphoramidite
1 and AgBF4 formed the
branched allylation product in 31% yield with 7:1 dr and 98% ee
(entry 1).11 When AgBF4 was replaced with the silver phosphate
2a prepared from (R)-1,1’-bi-2-naphthol (BINOL), the yield of
the allylation reaction increased dramatically (83% yield, dr 8:1,
98% ee, entry 2). When 2b, a substituted analog of 2a, was used
as the silver salt, the reaction furnished the product with high
yield, enantioselectivity and diastereoselectivity (87% yield, dr
>20:1, 98% ee, entry 3). Variations of the conditions that gave
these high yields and selectivities showed that 8% silver phos-
phate and 3 Å molecular sieves were integral to obtaining com-
plete conversion of the carbonate (entries 4 and 5). An assessment
of the effect of the configuration of the ligand and counterion on
the product stereoisomer was conducted. In the presence of ent-1
and the same phosphate 2b, the reaction yielded the enantiomer of
the allylation product just described. Moreover, the reaction with
ent-1 occurred with only slightly lower diastereoselectivity (88%
yield, dr 20:1, -98% ee, entry 6). Therefore, the configuration of
the ligand dictated the absolute configuration of the product.
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Because the configuration of the phosphate in 2b had a negligi-
ble effect on the diastereoselectivity of the reaction, an easily
accessible silver phosphate 2c derived from an optically inactive
biphenol was examined as the source of the counterion.12 The
reaction provided the product with yield, diastereoselectivity and
enantioselectivity (89% yield, >20:1 dr, 98% ee, entry 7) that
were comparable to those of the reactions with the optically active
phosphate anions. Furthermore, the reactions conducted with the
phosphate containing two phenols in place of the biphenol,
AgO(O)P(OPh)2 (2d), furnished the substitution product with
only slightly lower yield and diastereoselectivity (entry 8). Be-
cause of the easy access to the biphenol12a in the silver phosphate
2c and the high solubility of the silver phosphate 2c in various
organic solvents, we conducted our further studies with this silver
salt.
The scope of the reaction under the conditions just described is
shown in Table 2. A broad range of para-substituted cinnamyl
carbonates possessing diverse electronic properties were exam-
ined. The reactions with cinnamyl carbonates containing a halo-
gen in the para position furnished the products in high yields with
excellent diastereo- and enantioselectivities (entries 1 and 2). The
substrate containing a MeO group in the para position afforded
the product in 68% yield with >20:1 dr and 98% ee (entry 3).
Although the substrates possessing strong electron-withdrawing
groups were less reactive, the reaction still yielded the product
with good enantioselectivity (82-83% yield, >20:1 dr, 84-94% ee,
entries 4 and 5). The substrate containing a meta-fluoro substitu-
ent reacted in high yield and selectivity (96% yield, dr >20:1,
>99% ee, entry 6). The lowest selectivities were observed with the
ortho-MeO substituted cinnamyl carbonate (81% yield, 7:1 dr and
80% ee; entry 7). Ortho-substituted cinnamyl carbonates typically
undergo Ir-catalyzed allylic substitution reactions with lower en-
antioselectivity than do the meta- and para-substituted isomers.13
aSee the SI for experimental details. bAbsolute configurations
were assigned by analogy. The diastereomeric ratios were deter-
1
mined by H NMR analysis of the crude reaction mixtures. The
ee’s were determined by chiral HPLC analysis. c8% linear product
was identified. d[Ir(dbcot)Cl]2 was used.
The reactions of various azlactones derived from natural
amino acids were also examined. Azlactones containing benzyl,
iso-butyl and thioether groups underwent the reaction smoothly
and with high stereoselectivity (entries 11-13). Even the reaction
of the azlactone containing a bulky iso-propyl group at the prochi-
ral center proceeded in acceptable yield and high stereoselectivity
14
when [Ir(dbcot)Cl]2 was used as the iridium source (69% yield,
>20:1 dr, 99% ee, entry 14). In contrast to the prior allylations of
10d
azlactones to give branched products,10b,
the current process
The reactions of electrophiles containing heteroaryl, alkenyl and
alkyl substituents were also examined. Carbonates containing
furyl and indoly groups reacted like the cinnamyl carbonates (81-
90% yield, 15:1 dr, 95-98% ee, entries 8 and 9). Dienyl car-
bonates also furnished the branched substitution product with high
yield (83%) and stereoselectivity (14:1 dr and 94% ee; entry 10).
Aliphatic allylic carbonates reacted with low diastereoselectivity.
occurs with allylic carbonates containing alkenyl groups and elec-
tron-deficient aryl groups in yields that are comparable to those of
the reactions of allylic carbonates containing electron-rich aryl
groups.
To gain insight into the mechanism of this reaction, we first
conducted experiments to test if the metallacyclic structure pre-
sent in prior systems is the active form of the catalyst generated
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with silver phosphates. Reactions conducted with catalytic
amounts of the preformed metallacyclic iridium phosphoramidite
1
complex were conducted (Scheme 2). In the absence of phosphor-
ic acid 2e, the product was obtained in 92% yield with 3:1 dr and
98% ee. However, in the presence of 4 mol% of phosphoric acid
2e the product was obtained with a high >20:1 dr and 98% ee.
These results imply that: (1) the reactions are catalyzed by a
metallacyclic iridium complex and (2) the phosphate anion, not
the silver cation is responsible for the high diastereoselectivity.
2
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Scheme 2. Allylation of 3 Catalyzed by the Preformed
Metallacyclic Iridium Catalyst with and without the Phos-
phoric Acid 2e
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To demonstrate the utility of this allylation chemistry, we ap-
plied the substitution process to prepare an enantioenriched pyr-
rolidine, which is a member of a family of compounds possessing
monoamine reuptake-blocking activity (Scheme 3).17 The reaction
of carbonate 6a with azlactone 3 provided the substitution product
6b in 93% yield with 15:1 dr under the standard conditions. The
enantiomeric excess of this product was determined to be 94%
after 6b was converted to the corresponding methyl ester 6c. Hy-
droboration and oxidation yielded the terminal alcohol, which was
converted to the corresponding tosylate 6d in 57% yield over
three steps. Cyclization in the presence of NaH delivered 6e in
95% yield.
Scheme 3. Synthesis of Pyrrolidine 6ea, b
Several experiments were conducted to reveal the origin of the
effect of the phosphate anion. First, the reaction of cinnamyl car-
bonate with azlactone 3 in the presence of 4 mol% diethyl phos-
phoric acid, along with the analogous reaction of the correspond-
ing allylic phosphate, were conducted. The reaction with added
phosphate formed the substitution product in 52% yield with 20:1
dr and 97% ee (eq 1). However, the reaction of cinnamyl phos-
phate formed the substitution product in only 35% yield, with just
4:1 dr, and 67% ee (eq 2). In contrast, the same reaction of methyl
cinnamyl carbonate in the presence of 4 mol% added cinnamyl
phosphate gave the product with 16:1 dr and 96% ee (eq 3), albeit
in only 25% yield. The difference in diastereomeric ratio between
the reaction of the cinnamyl phosphate alone and the reaction with
the two cinnamyl electrophiles together suggests that the diastere-
oselectivity results from the presence of the carbonate and phos-
phate anions together. This conclusion is consistent with a de-
pendence of the diastereoselectivity of the reaction of cinnamyl
electrophiles with azlactone 3 on the identity of the carbonate
leaving group (see Table 1 of the SI).
a(a) 2 mol % [Ir(cod)Cl]2, 4 mol % 1, 8 mol % 2c, toluene, 3Å MS;
(b) MeOH, K2CO3; (c) 9-BBN, THF; NaBO3·4H2O; (d) TsCl,
triethylamine, DCM; (e) NaH, DMF. bAbsolute configurations
were assigned by analogy.
In summary, we have revealed a strategy to achieve high dia-
stereoselectivity for allylic substitution reactions of a prochiral
nucleophile catalyzed by the phosphoramidite-derived metallacy-
clic iridium complex, which had catalyzed enantioselective, but
not diastereoselective, reactions previously. This stereoselectivity
is achieved by the addition of an optically inactive phosphate
anion. Preliminary mechanistic data suggest that the reaction pro-
ceeds by the generation of a metallacyclic iridium allylcomplex,
and both the carbonate and phosphate contribute to the high dia-
stereoselectivity observed. Considering the multitude of carbon
nucleophiles that react with allyliridium complexes and the avail-
ability of structurally diverse phosphates, this approach should be
widely applicable to the control of diastereoselectivity with iridi-
um catalysts. Studies to expand the scope of the prochiral nucleo-
philes that undergo similar diastereo- and enantioselective Ir-
catalyzed allylation reactions are ongoing.
The iridium complexes present in the catalytic system were
revealed by NMR spectroscopy. The 31P NMR spectrum of the
mixture of [Ir(cod)Cl]2, ligand 1, silver phosphate 2c and cinnam-
yl carbonate consisted of a major peak at 122.5 ppm. This spectral
feature was consistent with the 31P NMR chemical shift of al-
lyliridium complexes containing cyclometallated phospho-
ramidites characterized previously.8a, b A broad peak between -2.0
and 2.0 ppm in the 31P NMR spectrum was attributed to the phos-
phate. Therefore, we suggest that the reaction proceeded through a
metallacyclic allyliridium complex generated in situ and nucleo-
philic attack by the azlactones assisted by the phosphate and car-
bonate.15 The absolute configuration of the allylation product was
consistent with nucleophilic attack from the face opposite to iridi-
um moiety.16 Further studies on the details of the mechanism are
underway in this laboratory.
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7.
In transition metal catalyzed allylation reactions,
ASSOCIATED CONTENT
counterions were generally introduced by employing different leaving
groups, which restricted the scope of counterions.
8.
1
2
Experimental procedures and characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
For stoichiometric study on silver salt promoted formation
3
4
5
6
7
8
9
of metallacyclic iridium allylcomplex, see: (a) Madrahimov, S. T.;
Markovic, D.; Hartwig, J. F. J. Am. Chem. Soc. 2009, 131, 7228; (b)
Raskatov, J. A.; Spiess, S.; Gnamm, C.; Broedner, K.; Rominger, F.;
AUTHOR INFORMATION
Corresponding Author
Helmchen, G. Chem.--Eur. J. 2010, 16, 6601; For
a
*jhartwig@berkeley.edu
Notes
cycloisomerisation catalyzed by an iridium chiral phosphate complex,
see: (c) Barbazanges, M.; Augé, M.; Moussa, J.; Amouri, H.; Aubert,
C.; Desmarets, C.; Fensterbank, L.; Gandon, V.; Malacria, M.;
Ollivier, C. Chem.-Eur. J. 2011, 17, 13789.
The authors declare no competing financial interest.
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9.
10.
Tanaka, M. Chem. Pharm. Bull 2007, 55, 349.
For a review on azlactones in enantioselective reactions,
ACKNOWLEDGMENT
We thank the NIH (GM-58108) for support of this work, Johnson-
Matthey for gifts of [Ir(cod)Cl]2, and Dr. Klaus Ditrich and BASF
for gifts of chiral amines. W. C. thanks Dr. Ming Chen for helpful
discussions.
see: (a) Alba, A.-N. R.; Rios, R. Chem. -Asian J. 2011, 6, 720; For a
Mo-catalyzed asymmetric allylation of azlactones, see: (b) Trost, B.
M.; Dogra, K. J. Am. Chem. Soc. 2002, 124, 7256; For a Pd-catalyzed
asymmetric allylation of azlactones to form linear products, see: (c)
Trost, B. M.; Ariza, X. J. Am. Chem. Soc. 1999, 121, 10727. For an
[Ir(cod)Cl]2 catalyzed allylation/aza-Cope sequence with azlactones,
see: (d) Kawatsura, M.; Tsuji, H.; Uchida, K.; Itoh, T. Tetrahedron
2011, 67, 7686.
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11.
Unless otherwise noted, 2.20 equiv 3 was used because
methanol formed in the reaction reacted with 3 to form the methyl
ester.
12.
biphenol, see: (a) Wuennemann, S.; Froehlich, R.; Hoppe, D. Eur. J.
Org. Chem. 2008, 684; For an example of the phosphoric acid
catalyzed reaction, see: (b) Moreau, J.; Hubert, C.; Batany, J.; Toupet,
L.; Roisnel, T.; Hurvois, J.-P.; Renaud, J.-L. J. Org. Chem. 2009, 74,
8963.
See the SI for the synthesis of 2c. For the preparation of the
2.
For moderately diastereoselective allylations catalyzed by
13.
Liu, W.-B.; Zheng, C.; Zhuo, C.-X.; Dai, L.-X.; You, S.-L.
an iridium phosphite complex, see: (a) Kanayama, T.; Yoshida, K.;
Miyabe, H.; Takemoto, Y. Angew. Chem., Int. Ed. 2003, 42, 2054; (b)
Kanayama, T.; Yoshida, K.; Miyabe, H.; Kimachi, T.; Takemoto, Y.
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good diastereoselectivity, see: (c) Wu, Q.-F.; Liu, W.-B.; Zhuo, C.-X.;
Rong, Z.-Q.; Ye, K.-Y.; You, S.-L. Angew. Chem., Int. Ed. 2011, 50,
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14.
15.
See the SI for a new route to DBCOT.
The anion contains both components with an IR band at
3372 cm-1 that is consistent with the stretch of a hydrogen bonded O-
H group.
16.
The absolute configuration of the allylation product was
determined by comparison of the optical rotation and retention time to
a literature value in reference 10d.
17.
Compounds as Monoamine Reuptake Inhibitors. WO2010123006A1,
2010.
3.
Unpublished results. For two reported examples, see: (a)
Dahnz, A.; Helmchen, G. Synlett 2006, 697; (b) Polet, D.; Alexakis,
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G. Synlett 2007, 790.
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