Catalytic enantioselective amination of enolsilanes using C2-symmetric copper(II) complexes as chiral lewis acids

Article abstract of DOI:10.1021/ol990113r

(Matrix presented) [Cu(S,S)-t-Bu-box](OTf)₂ (1) catalyzes the enantioselective amination of enolsilanes with azodicarboxylate derivatives. Isomerically pure enolsilanes of aryl ketones, acylpyrroles, and thioesters added to the azo-imide in gre

Full text of DOI:10.1021/ol990113r

ORGANIC
LETTERS
1999
Vol. 1, No. 4
595-598
Catalytic Enantioselective Amination of
Enolsilanes Using C -Symmetric
2
Copper(II) Complexes as Chiral Lewis
Acids
David A. Evans* and Douglas S. Johnson
Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts, 02138
eVans@chemistry.harVard.edu
Received June 1, 1999
ABSTRACT
[Cu(S,S)-t-Bu-box](OTf)2 (1) catalyzes the enantioselective amination of enolsilanes with azodicarboxylate derivatives. Isomerically pure enolsilanes
of aryl ketones, acylpyrroles, and thioesters added to the azo-imide in greater than 95% ee. The use of an alcohol additive was critical to
achieving catalyst turnover.
Recent reports from this laboratory have documented the
utility of chiral Cu(II) Lewis acids such as 1 in the
enantioselective catalysis of a range of carbon-carbon bond
forming reactions, including carbo- and heterocyclic Diels-
Alder, aldol, Michael, and ene reactions.1 Herein, we report
the use of these catalysts in the enantioselective amination
of enolsilanes with azodicarboxylate derivatives (Scheme
1).2-4 This methodology provides an enantioselective cata-
lytic route to differentially protected R-hydrazino carbonyl
compounds.5
(Scheme 1) in direct analogy to previously reported Diels-
Alder reactions.1d While a number of azodicarboxylate
derivatives were prepared, 3a (mp 86 °C) was selected over
3b (mp 99 °C) and 3c (mp 105 °C) for the present study on
the basis of its favorable solubility properties and reactivity
profile. A survey of Cu(II) complexes revealed that [Cu-
Scheme 1
It was envisioned that azo-imides such as 3,6 upon
coordination with the chiral Cu(II) complex 1 to give adduct
2, might participate in enantioselective enol amination
(1) (a) Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.;
Connell, B. J. Am. Chem. Soc. 1999, 121, 669-685 and references therein.
(b) Evans, D. A.; Johnson, J. S. J. Am. Chem. Soc. 1998, 120, 4895-4896.
(c) Evans, D. A.; Olhava, E. J.; Johnson, J. S.; Janey, J. M. Angew. Chem.,
Int. Ed. Engl. 1998, 37, 3372-3375. (d) Evans, D. A.; Miller, S. J.; Lectka,
T. C. J. Am. Chem. Soc. 1993, 115, 7027-7030.
(2) For reviews on electrophilic amination, see: (a) Boche, G. In
StereoselectiVe Synthesis; Helmchen, G., Hoffmann, R. W., Mulzer, J.,
Schaumann, E., Eds.; Thieme: Stuttgart, 1996; Vol. 9, pp 5133-5157. (b)
Greck, C.; Genet, J. P. Synlett 1997, 741-748. For diastereoselective
aminations of chiral enolates or chiral silylketene acetals, see: (c) Evans,
D. A.; Britton, T. C.; Dorow, R. L.; Dellaria, J. F. J. Am. Chem. Soc. 1986,
108, 6395-6397. (d) Evans, D. A.; Britton, T. C.; Dorow, R. L.; Dellaria,
J. F. Tetrahedron 1988, 44, 5525-5540. (e) Trimble, L. A.; Vederas, J. C.
J. Am. Chem. Soc. 1986, 108, 6397-6399. (f) Gennari, C.; Colombo, L.;
Bertolini, G. J. Am. Chem. Soc. 1986, 108, 6394-6395.
10.1021/ol990113r CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/23/1999

(S,S)-t-Bu-box](OTf)2 (1)7 was the catalyst of choice for the
addition of propiophenone enolsilane (4a) to azo-imide 3a,
affording the (R) hydrazino adduct 5a in 99% ee and 96%
yield (Table 1).8 The reaction is completely regioselective
erosion in reaction stereoselection (Table 2). A range of aryl
ketone enolsilanes were aminated in excellent enantioselec-
tivity and yield. The reaction of 4a-c provided the adducts
5a-c in 99% ee and 95% yield even at -20 °C (entries
1-3). Reaction times increased as the R group of the
enolsilane became larger.
Table 1. Survey of Reaction Conditions for Amination of 4a
Table 2. Amination of Aryl Ketone Enolsilanes (4)
a Z:E g 99:1. b 40 mol %. c 48 mol %. d Isolated yield. e Enantiomeric
excess determined by HPLC (Chiralcel AD). (Troc: O2CCH2CCl3.)
on the azo component, suggesting that 3a is being activated
through the anticipated chelate 2. Complete conversion was
observed when a catalyst loading of 25 mol % was employed;
however, reduction of the catalyst loading resulted in lower
product yield and enantiomeric excess (entries 1 and 2).
Presumably, the adduct was competitively binding to the
copper catalyst thus sequestering it from the catalytic cycle.
It was found that when the reaction was conducted with
excess Cu(OTf)2 (50 mol %) relative to ligand (2-10 mol
%), the reaction proceeded to completion without a signifi-
cant decrease in enantioselectivity (entries 3 and 4), high-
lighting the importance of ligand acceleration in this
reaction.9 However, more reactive enolsilanes (4b and 4c)
were susceptible to Cu(OTf)2-catalyzed additions under these
conditions resulting in diminished enantioselectivities (80%
and 90% ee, respectively).
The amination of 4a was complete within 5 min at -78
°C when a stoichiometric amount of 1 was used (versus 12-
24 h for entries 1-4), indicating that the initial addition is
very fast and catalyst turnover is rate-limiting. Therefore,
additives to promote catalyst turnover were evaluated. It was
observed that the reaction proceeded to completion in 3 h at
-78 °C in the presence of 1 equiv of trifluoroethanol (Table
1, entry 5).10 Ethanol, 2-propanol, and hexafluoro-2-propanol
also worked in a similar manner, but reaction times were
slightly longer.
a Enolsilane of 6′-methoxy-2′-propiononaphthone. b Z:E g 99:1. c Isolated
yield. d Enantiomeric excess determined by HPLC (Chiralcel AD). e Re-
action progress was monitored by in situ IR spectroscopy using a ReactIR
1000 from ASI Applied Systems except entries 8 and 10-12. f A total of
1.2 equiv of 3 was used; yield is based on enolsilane. (Troc: O2CCH2CCl3.)
Several cyclic enolsilanes were also examined in the
amination reaction (Table 3). The enolsilane of indanone (6a)
was aminated in only 21% ee (entry 1), whereas the
2-methyl-substituted variant 6b provided the adduct 7b,
containing a tetrasubstituted stereogenic center, in 96% ee
(entry 3). In contrast to the low selectivity observed with
6a, increasing the ring size to the six- and seven-membered
homologues 6c and 6d resulted in products with high
enantioselectivities (entries 4 and 5).
This methodology was extended to thioester silylketene
acetals, providing access to R-hydrazino esters and acids
Table 3. Amination of Cyclic Enolsilanes (6)
This reaction may also be carried out at higher tempera-
tures (-20 °C)11 and with lower catalyst loadings (5 mol %
1) in the presence of alcoholic additives without significant
(3) For diastereoselective aminations of enolates with chiral aminating
reagents, see: (a) Oppolzer, W.; Tamura, O.; Sundarababu, G.; Signer, M.
J. Am. Chem. Soc. 1992, 114, 5900-5902. (b) Harris, J. M.; McDonald,
R.; Vederas, J. C. J. Chem. Soc., Perkin Trans. 1, 1996, 2669-2674.
(4) For a merged enolization enantioselective amination, see: Evans, D.
A.; Nelson, S. G. J. Am. Chem. Soc. 1997, 119, 6452-6453.
(5) This functionality is present in a number of biologically important
natural products: (a) Ciufolini, M. A.; Xi, N. Chem. Soc. ReV. 1998, 27,
437-445. (b) Schmidt, U.; Braun, C.; Sutoris, H. Synthesis 1996, 223-
229. For a ribosome-mediated incorporation of hydrazinophenylalanine into
a protein, see: (c) Killian, J. A.; Van Cleve, M. D.; Shayo, Y. F.; Hecht,
S. M. J. Am. Chem. Soc. 1998, 120, 3032-3042.
a Isolated yields. b Enantiomeric excess determined by HPLC (Chiralcel
AD or OJ). c The corresponding TES enolsilane was aminated in 53% yield
and 93% ee (-20 °C, 30 min). d The reduced yield is a result of competitive
reduction of the azo compound with concomitant production of 1-naphthol.
596
Org. Lett., Vol. 1, No. 4, 1999

(Scheme 2). Addition of (E)-8 to 3a provided the (R) adduct
9 in 96% ee (-20 or -78 °C). However, a 93:7 (E)/(Z)
mixture of 8 afforded (R)-9 in only 83% ee. In fact, the pure
(Z) isomer afforded the opposite enantiomer (S)-9 in 84%
ee at -78 °C (64% ee, -20 °C).12 Therefore, it is critical to
use geometrically pure enolsilanes to achieve high enantio-
selection in these additions.
the pyrrole ring to give 12d (entry 8). Despite their limitation
in the present study, acylpyrrole-derived enolsilanes should
find widespread use as nucleophiles in Mukaiyama-type
addition reactions.
Mechanistic Considerations. The stoichiometric [Cu-
((S,S)-t-Bu-box)](OTf)2 (1)-catalyzed reaction between enol-
silane 4 and azo-imide 3 in the absence of trifluoroethanol
results in the rapid formation of an intermediate with an IR
frequency at 1687 cm-1, characteristic of the CdN stretch
in 5,6-dihydrooxadiazenes,15 as evidenced by in situ IR
spectroscopy (Supporting Information). We propose that this
intermediate is the formal hetero-Diels-Alder adduct A as
its derived Cu(II) complex A-1 (Scheme 3).16 In the absence
Scheme 2
Scheme 3
The preceding conclusion led us to investigate silylketene
aminals of acylpyrroles,13 which can more easily be obtained
as the (Z) isomer in high geometrical purity (g98:2)
(NaHMDS, THF/DMPU, TMSCl, -78 °C). Enolsilane 10a
proved to be a highly effective nucleophile in the amination
reaction, affording (R) 11a in 99% ee and 96% yield in less
than 30 min at -78 °C (Table 4, entry 1). The reaction was
Table 4. Amination of Acylpyrrole Enolsilanes (10)
a Z:E g 98:2. b The hydrate catalyst of 1 was used. c Isolated yields.
d Isolated yield of 12 after protodesilylation with 10% HCl (see Supporting
Information). e Enantiomeric excess determined by HPLC (Chiralcel AD).
of the alcohol additive, this intermediate sequesters the chiral
catalyst 1 suppressing catalyst turnover. Upon the addition
of trifluoroethanol, this intermediate is rapidly transformed
into product hydrazide 5 along with silylated alcohol.
Alternatively, when the catalytic process (5 mol % 1, THF,
-78 °C) is carried out in the presence of trifluoroethanol,
the buildup of this intermediate is not observed. It is
instantaneous at -20 °C (entry 2). The enhanced nucleo-
philicity of 10a allowed the catalyst loading to be lowered
to 1 mol %, and the reaction was still complete in less than
5 min (entry 3). Unfortunately, increasing the size of the R
group (10b and 10c) slowed the reaction enough to allow
for a competing amination of the pyrrole ring (entries 4-7).
Nonetheless, the hydrazino adducts 11b and 11c are obtained
in >96% ee even when the reactions are conducted at 25
°C.14 The t-Bu-substituted enolsilane 10d proved to be too
sterically demanding and amination occurred exclusively on
(6) Details on the preparation of the azo compounds 3a-c and an X-ray
crystal structure of 3c may be found in the Supporting Information.
(7) Evans, D. A.; Peterson, G. S.; Johnson, J. S.; Barnes, D. M.; Campos,
K. R.; Woerpel, K. A. J. Org. Chem. 1998, 63, 4541-4544.
(8) The absolute configuration was proven by X-ray crystallography as
well as chemical correlation by conversion to the known oxazolidinone 16
(vide infra).
Org. Lett., Vol. 1, No. 4, 1999
597

significant that the sense of asymmetric induction in these
reactions is coupled to enolsilane geometry (Scheme 2). We
propose that the strong endo bias for the OR substituent on
the electron-rich olefin reaction component,17 documented
for related hetero cycloadditions,1b,c provides the organization
for the 2π reaction component while face selectivity for the
4π reaction component is controlled by the azo-imide catalyst
complex as illustrated in Scheme 3.
AcOH, acetone) to give oxazolidinone 16.21 Comparison of
the specific rotation of 16 ([R]D ) -17.9 (c 1.15, CHCl3))
with the literature value22 confirmed the absolute stereo-
chemistry of 5a to be the (R) configuration.
The acylpyrrole and thioester hydrazino adducts were
converted to the corresponding esters or carboxylic acids
(Scheme 5).23 Treatment of the thioester 9 with NBS in THF/
Product Modification. The keto hydrazides may be
transformed into synthetically useful building blocks. Fol-
lowing Boc protection of adduct 5a,18 the imide was
hydrolyzed with LiO2H to give orthogonally protected
hydrazine 13 (Scheme 4).19 Alternatively, these adducts may
Scheme 5a
Scheme 4a
a Key: [X ) StBu (9)] (a) NBS, THF, H2O; CH2N2, 72%; (b)
LiOOH, THF, H2O, 0 °C; CH2N2, 60%; [X ) pyrrole (11a)] (c)
MeOH, Et3N, 90%; (d) H2SO4, H2O, dioxane, reflux; CH2N2, 74%
(yields are unoptimized). (Troc: O2CCH2CCl3.)
H2O provided the carboxylic acid which was converted to
ester 18 with CH2N2. Acylpyrrole 11a could be hydrolyzed
to the carboxylic acid (H2SO4, H2O, dioxane) or converted
directly to ester 18 (MeOH, Et3N).24
Acknowledgment. Financial support was provided by the
NIH (GM33328). A postdoctoral fellowship (D.S.J.) from
the NIH (GM18595-02) is gratefully acknowledged. Jason
Tedrow is acknowledged for the solution of X-ray structures.
a Key: (a) Boc2O, cat. DMAP, THF; (b) LiOOH, THF, H2O, 0
°C; (c) L-Selectride, THF, -78 °C to room temperature; (d) Et3SiH,
TFA, 0 °C; (e) 4 M HCl in dioxane; (f) Zn, HOAc, acetone.
Supporting Information Available: Experimental pro-
cedures and characterization of compounds and figure
detailing in situ IR experiments. This material is available
free of charge via the Internet at http://pubs.acs.org.
be stereoselectively reduced to provide the derived syn or
anti hydrazino alcohols, respectively.20 For example, the
Et3SiH reduction of 5a affords the anti product 17 with good
stereoselectivity. Alternatively, during the related L-Selec-
tride reduction of 13 to the diastereomeric syn-hydrazino
alcohol, facile cyclization to the derived N-amino oxazoli-
dinone 14 is observed. Removal of the Boc group (4 M HCl,
dioxane, 25 °C) provided the potentially useful N-amino-
oxazolidinone 15. The N-N bond was readily cleaved (Zn,
OL990113R
(15) (a) Hall, J. H.; Wojciechowska, M. J. Org. Chem. 1978, 43, 3348-
3353. (b) Hall, J. H.; Wojciechowska, M. J. Org. Chem. 1979, 44, 4, 38-
41. (c) Leblanc, Y.; Fitzsimmons, B. J.; Springer, J. P.; Rokach, J. J. Am.
Chem. Soc. 1989, 111, 2995-3000.
(16) An intermediate such as A-1 (L ) OTf, THF) was detected by
electrospray MS (m/z ) 807 with correct Cu and Cl isotope pattern).
(17) (a) For a summary, see: Boger, D. L. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
Vol. 5, pp 451-512. (b) Liu, J.; Niwayama, S.; You, Y.; Houk, K. N. J.
Org. Chem. 1998, 63, 1064-1073.
(18) Burk, M. J.; Allen, J. G. J. Org. Chem. 1997, 62, 7054-7057.
(19) These unsymmetrical hydrazines could serve as templates for
diversity chemistry since each nitrogen can be selectively deprotected and
then alkylated or acylated. Selective deprotection is crucial because the free
R-hydrazino acid derivatives are sensitive to oxidation and loss of N2 (see
ref 5a). Grehn, L.; Ragnarsson, U. Synthesis 1998, 1817-1821.
(20) (a) Paleo, M. R.; Calaza, M. I.; Sardina, F. J. J. Org. Chem. 1997,
62, 6862-6869. (b) Kano, S.; Yokomatsu, T.; Iwasawa, H.; Shibuya, S.
Tetrahedron Lett. 1987, 28, 6331-6334. (c) Fujita, M.; Hiyama, T. J. Org.
Chem. 1988, 53, 5415-5421.
(21) (a) Leblanc, Y.; Fitzsimmons, B. J. Tetrahedron Lett. 1989, 30,
2889-2892. (b) McClure, C. K.; Mishra, P. K.; Grote, C. W. J. Org. Chem.
1997, 62, 2437-2441.
(22) Jephcote, V. J.; Pratt, A. J.; Thomas, E. J. J. Chem. Soc., Perkin
Trans. 1, 1989, 1529-1535. Compound (4R, 5R)-16: [R]D ) -15.9 (c
0.38, CHCl3).
(23) (a) Minato, H.; Takeda, K.; Miura, T.; Kobayashi, M. Chem. Lett.
1977, 1095-1098. (b) Arai, E.; Tokuyama, H.; Linsell, M. S.; Fukuyama,
T. Tetrahedron Lett. 1998, 39, 71-74. (c) Myers, A. G.; Gleason, J. L.;
Yoon, T.; Kung, D. W. J. Am. Chem. Soc. 1997, 119, 656-673.
(24) The methyl ester derived from (R)-9 was identical to the methyl
ester prepared from 11a (HPLC, Chiracel AD) confirming the (R) absolute
stereochemisty for 11a.
(9) The complex between 1 and 3 is cationic because at least one of the
triflates is displaced upon binding of the imide moiety. However, Cu(OTf)2
has two open coordination sites so its complex with 3 remains neutral. For
a review on ligand accelerated catalysis, see: Berrisford, D. J.; Bolm, C.;
Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1995, 34, 1059-1070.
(10) This observation aided the development of two Mukaiyama-
Michael reactions: Evans, D. A.; Rovis, T.; Kozlowski, M. C.; Tedrow, J.
S. J. Am. Chem. Soc. 1999, 121, 1994-1995.
(11) The azo compound decomposes in the presence of catalyst 1 at
temperatures above -10 °C.
(12) Compound (S)-9 was recrystallized (96% ee) and its absolute
configuration was proven by X-ray crystallography.
(13) N-Acylpyrroles have been used as acylating agents and, as such,
can be regarded as activated carboxylic acid equivalents: (a) Brandange,
S.; Rodriguez, B. Acta Chem. Scand. 1987, B41, 740-744. (b) Brandange,
S.; Holmgren, E.; Leijonmarck, H.; Rodriguez, B. Acta Chem. Scand. 1995,
49, 922-928. (c) Lee, S. D.; Brook, M. A.; Chan, T. H. Tetrahedron Lett.
1983, 24, 1569-1572. To the best of our knowledge only the silylketene
aminal of acetylpyrrole has been previously described: (d) Frick, U.;
Simchen, G. Liebigs Ann. Chem. 1987, 839-845.
(14) It is best to use the hydrate catalyst of 1 when conducting the reaction
at room temperature. Compound 3 appears to be stable in the presence of
the hydrate catalyst for about 1 h (THF, 25 °C). Notably, the use of sieves
is not required, see: ref 1c.
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