Gold(I)-Catalyzed enantioselective synthesis of pyrazolidines, isoxazolidines, and tetrahydrooxazines

Article abstract of DOI:10.1002/anie.200905000

(Figure Presented) (Figure Presented) Au-ff on a trip: Chiral ligands (L) and chiral anions [(S)-TriPAg] are employed in the gold(I)-catalyzed enantioselective intramolecular additions of hydrazines and hydroxylamines to allenes. These complementary methods allow access to chiral vinyl isoxazolidines, oxazines, and differentially protected pyrazolidines. PNB = para-nitrobenzoyl.

Full text of DOI:10.1002/anie.200905000

Communications
DOI: 10.1002/anie.200905000
Gold Catalysis
Gold(I)-Catalyzed Enantioselective Synthesis of Pyrazolidines,
Isoxazolidines, and Tetrahydrooxazines**
R. L. LaLonde, Z. J. Wang, M. Mba, A. D. Lackner, and F. Dean Toste*
The field of gold(I)-catalyzed addition of heteroatom nucle-
ophiles to allenes[1] has recently expanded to include enan-
tioselective synthesis of heterocyclic products.[2,3] Despite the
growth in this area of research and the biological relevance of
heterocycles containing multiple heteroatoms, the asymmet-
ric addition of hydrazine and hydroxylamine nucleophiles to
allenes has not yet been reported.[4] In 2007, our group
reported the enantioselective hydroamination of allenes
catalyzed by gold(I)/bis(p-nitrobenzoate) complexes.[2a] We
hypothesized that in addition to tosyl amines, gold(I)/bis(p-
nitrobenzoate) complexes would perform as efficient cata-
lysts for the enantioselective addition of hydroxylamines and
hydrazines to allenes. The heterocycles formed from these
reactions, vinyl isoxazolidines[5] and pyrazolidines,[6] appear
frequently in biologically important molecules.[7] In addition,
these heterocycles serve as precursors to unnatural amino
acid derivatives such as 5-oxaproline[7,8] as well as chiral allylic
alcohols and 1,3-diamines [Eq. (1)].
(AuOPNB)2] (I) in nitromethane at 508C the desired product
2a was formed, although in modest yield and low enantiose-
lectivity (Table 1, entry 1). By simply adding a second
Table 1: Hydroamination optimization.
Entry
1; X
R
Cond.[a]
2; Yield[b] [%]
ee[c] [%]
1
2
3
4
5
6
7
1a; NBoc
1b; NBoc
1c; NBoc
1c; NBoc
1d; O
H
A
A
A
2a; 46
5
70
80
97
10
–
Boc
Mts
Mts
H
Cbz
Boc
2b;>98[d]
2c;>98[d]
2c; 78
A[e]
B[f]
B
2d; 92
1e; O
1 f; O
2e; 8[d]
2 f; 93
B
93
[a] Reaction Conditions: A=Catalyst I (5 mol%), 0.3m in MeNO2, 508C,
15 h; B=Catalyst I (3 mol%), 0.1m in CH2Cl2, 238C, 24 h; [b] Yield of
product isolated after column chromatography. [c] Determined by HPLC
methods. [d] Conversion determined by 1H NMR analysis. [e] Catalyst II.
[f] 18 h. Boc=tert-butoxycarbonyl, Cbz=benzyloxycarbonyl, Mts=
2-mesitylsulfonyl, binap=2,2-bis(diphenylphosphanyl)-1,1-binaphthyl,
DTBM-Segphos=5,5’-bis{di(3,5-di-tert-butyl-4-methoxyphenyl)phos-
phino}-4,4’-bi-1,3-benzodioxole.
We began our studies with a mono-Boc-protected homo-
allenic hydrazine, easily synthesized in four steps from the
homoallenic alcohol. Whereas unprotected amines are usu-
ally considered incompatible with cationic gold complexes, we
hypothesized that the reduced Lewis basicity of the hydrazine
would allow the use of an unprotected terminal amine.
Indeed, upon treatment of 1a with [(R)-xylyl-binap-
protecting group, both the yield and enantiomeric excess of
2b were improved (Table 1, entry 2). This result led us to
theorize that sterically differentiating the protecting groups
would be necessary to additionally improve the enantiose-
lectivity. Indeed, utilizing a mesitylenesulfonyl protecting
group on the terminal nitrogen atom raised the observed
enantioselectivity to 80% ee (Table 1, entry 3). A brief
examination of chiral ligands revealed that (R)-DTBM-
Segphos was optimal, yielding pyrazolidine 2c in 97% ee
(Table 1, entry 4). Similar to hydroamination with hydrazines,
we found that although unprotected hydroxylamines were
transformed into the isoxazolidines in excellent conversion
(>92%), low enantioselectivity (10% ee) was observed
(Table 1, entry 5). Upon treating N-Boc-protected hydroxyl-
amine 1 f with catalyst I the isoxazolidine 2 f was formed in
93% yield and 93% ee (Table 1, entry 7). Other protecting
[*] R. L. LaLonde, Z. J. Wang, Dr. M. Mba, A. D. Lackner,
Prof. F. D. Toste
Department of Chemistry
University of California
Berkeley, CA 94720 (USA)
Fax: (+1)510-643-9480
E-mail: fdtoste@berkeley.edu
[**] We gratefully acknowledge NIHGMS (R01 GM073932-04S1), Bris-
tol-Myers Squibb, and Novartis for funding. R.L.L. thanks Novartis
and Eli Lilly and Z.J.W. thanks the Hertz Foundation for graduate
fellowships. We thank Dr. Francesco Santoro for preliminary studies
on the synthesis of silver biarylsulfonates. We are grateful Johnson
Mathey for a generous donation of AuCl3 and to Takasago and
Solvias for providing Segphos and MeOBiPhep ligands, respec-
tively.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200905000.
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Table 2: Hydroalkoxylation optimization.
groups, such as Cbz, significantly reduced the conversion to
8% (Table 1, entry 6). Additionally, a polar, noncoordinating
solvent such as nitromethane was effective, producing 2 f in
98% conversion and 87% ee. However, nonpolar solvents
(benzene) and coordinating solvents (dioxane) completely
eliminated catalyst activity.
Entry
Catalyst[a]
Yield [%][b]
ee [%][c]
1
2
I
0
–
65
Whereas gold(I)/bis(p-nitrobenzoate) complexes proved
to be ineffective catalysts for the hydroalkoxylation of allenes
(Table 2, entry 1), we hypothesized that employing a more
noncoordinating counterion with a lower pKa value would
improve catalysis. Chiral silver sulfonate (S)-(5)Ag (IV) was
synthesized in seven steps from (S)-binol (binol = 2,2-dihy-
droxy-1,1-binaphthyl).[9] Gratifyingly, upon treatment with
3 mol% [dppm(AuCl)2] and 3 mol% IV, isoxazolidine 4 was
formed in quantitative conversion and 65% ee (Table 2,
entry 2). However, attempts to improve the enantioselectvity
by matching the chiral counterion with chiral gold/binap
complexes were unsuccessful (Table 2, entries 3 and 4). Both
the matched and mismatched mixtures produced 4 with lower
enantioselectivity (42% and 8% ee, respectively). Chiral
silver phosphate (S)-TriPAg (III) proved to be the key to
enhancing the enantioselectivity to 97% ee (Table 2, entry 5).
We next sought to test the substrate scope of our
optimized hydroamination conditions (Table 3). Linear and
cyclic alkyl substitutions were tolerated at the allene terminus
in both the hydrazine and hydroxylamine hydroamination.
For instance, methyl-substituted substrates cyclized with
excellent enantioselectivity (Table 3, entries 1 and 4). Cyclo-
hexyl-substituted allenes also reacted with high enantioselec-
tivity (Table 3, entries 3 and 6). Cyclopentyl-substituted
substrates 8 and 12 also provided pyrazolidine 9 and
isoxazolidine 13 in good yield and slightly lower enantiose-
lectivity (Table 3, entries 2 and 5). Furthermore, sterically
challenging backbone substitutions were accommodated by
heating gently (508C) in a polar, noncoordinating solvent
(nitromethane). Whereas substitution at the allenic position
(Table 3, entry 8) gave enhanced
3 mol% [dppm(AuCl)2]
3 mol% IV
98[d]
3
4
5
3 mol% [(R)-binap(AuCl)2]
3 mol% IV
3 mol% [(S)-binap(AuCl)2]
3 mol% IV
3 mol% [dppm(AuCl)2]
6 mol% III
98[d]
98
8
42
98
98
[a] Reaction Conditions: 0.1m in toluene, 238C, 15 h; [b] Yield of product
isolated after column chromatography. [c] Determined by HPLC meth-
ods. [d] Conversion determined by 1H NMR analysis. dppm=bis(diphe-
nylphosphanyl)methane.
The advantage of the increased nucleophilicity of hydrox-
ylamines was demonstrated in the cyclization onto tetrasub-
stituted allenes. Nucleophilic additions to tetrasubstituted
allenes is challenging; only a handful of substrates have been
reported.[4a,10] Whereas the use of a protecting group is
normally beneficial to enantioselectivity (vide supra), in the
case of addition to sterically encumbered substrates such
protecting groups are detrimental to both the observed
enantioselectivity and conversion [Eq. (2)]. Unprotected
hydroxylamines, however, when treated with the same
enantioselectivity
(99%)
with
modest yield (73%), the homoal-
lenic position showed the reverse
trend: modest enantioselectivity
(63%) and excellent yield (94%).
We also applied our hydroami-
nation conditions to the formation
of six-membered ring tetrahydroox-
azine heterocycles. Gentle heating
in a polar noncoordinating solvent
was required to produce tetrahy-
drooxazines in good yield (63–
85%). Substrates with backbone
substitutions (Table 3, entries 10
and 11) have higher yield than
those without substitutions, pre-
sumably the result of a Thorpe–
Ingold effect. Also, both linear and
cyclic alkyl substitutions were tol-
erated at the allene terminus, pro-
viding the heterocycles with 89% ee
in all cases.
Table 3: Hydrazine and hydroxylamine hydroamination scope.
Entry Substrate
R1
R2
Cond.[a] Product
Yield ee
[%][b] [%][c]
1
2
3
6
8
Me
-(CH2)4-
–
–
–
A
A
A
7
9
98
90
2c 75
99
83
97
1c -(CH2)5-
4
5
6
10
12
1 f
Me
-(CH2)4-
-(CH2)5-
–
–
–
B
B
B
11
13
2 f
91
98
93
98
91
93
7
8
14
16
Me
H
H
Me
C
C
15
17
94
73
63
99
9
10
11
18
20
22
-(CH2)5-
-(CH2)5- Me
Me Me
H
D[d]
D
D
19
21
23
63
85
79
89
89
89
[a] Reaction Conditions: A=[(R)-DTBM-Segphos(AuOPNB)2] (5 mol%), 0.3m in MeNO2, 508C, 15 h;
B=I (3 mol%), 0.1m in CH2Cl2, 238C, 24 h; C=[(R)-DM-MeOBiPhep(AuOPNB)2] (5 mol%), 0.1m in
MeNO2, 508C, 24 h; D=I (5 mol%), 0.3m in MeNO2, 508C, 24 h. [b] Yield of the product isolated after
column chromatography. [c] Determined by HPLC methods. [d] 36 h, 658C. DM-MeOBiPhep=2,2’-
bis[di(3,5-xylyl)phosphino]-6,6’-dimethoxy-1,1’-biphenyl.
Angew. Chem. Int. Ed. 2010, 49, 598 –601
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Communications
oxazines, and differentially protected pyrazolidines.[13,14]
Studies on the mechanism of enantioinduction in these
transformations are ongoing in our laboratories.
Received: September 7, 2009
Published online: December 15, 2009
Keywords: asymmetric catalysis · gold · heterocycles ·
.
hydroamination · pyrazolidines
catalyst produce the desired product in quantitative conver-
[1] For examples of gold-catalyzed hydroamination of allenes, see:
a) N. Krause, N. Morita, Org. Lett. 2004, 6, 4121 – 4123; b) N.
Nishina, Y. Yamamoto, Angew. Chem. 2006, 118, 3392 – 3395;
Angew. Chem. Int. Ed. 2006, 45, 3314 – 3317; c) N. T. Patil, L. M.
Lutet, N. Nishina, Y. Yamamoto, Tetrahedron Lett. 2006, 47,
4749 – 4751; d) Z. Zhang, C. Liu, R. E. Kinder, X. Han, H. Qian,
R. A. Widenhoefer, J. Am. Chem. Soc. 2006, 128, 9066 – 9073;
e) N. Morita, N. Krause, Eur. J. Org. Chem. 2006, 4634 – 4641;
For a recent review of gold(I)-catalyzed heterocyclic synthesis,
see: H. C. Shen, Tetrahedron 2008, 64, 3885 – 3903.
[2] a) R. L. LaLonde, B. D. Sherry, E. J. Kang, F. D. Toste, J. Am.
Chem. Soc. 2007, 129, 2452 – 2453; b) Z. Zhang, C. F. Bender,
R. A. Widenhoefer, Org. Lett. 2007, 9, 2887 – 2889; c) For a
dynamic kinetic resolution, see: Z. Zhang, C. F. Bender, R. A.
Widenhoefer, J. Am. Chem. Soc. 2007, 129, 14148 – 14149; For a
previous report of asymmetric hydroamination of allenes
(maximum ee value was 16%), see: d) J. M. Hoover, J. R.
Peterson, J. H. Pikul, A. R. Johnson, Organometallics 2004, 23,
4614 – 4620; e) For an gold(I)-catalyzed asymmetric hydroalkox-
ylation of allenes, see: Z. Zhang, R. A. Widenhoefer, Angew.
Chem. 2007, 119, 287 – 289; Angew. Chem. Int. Ed. 2007, 46, 283 –
285; f) G. L. Hamilton, E. J. Kang, M. Mba, F. D. Toste, Science
2007, 317, 496 – 499.
[3] For a review of recent developments in enantioselective gold
catalysis, see: a) R. A. Widenhoefer, Chem. Eur. J. 2008, 14,
5382 – 5391; For reviews of enantioselective hydroamination,
see: b) K. C. Hultzsch, Org. Biomol. Chem. 2005, 3, 1819 – 1824;
c) K. C. Hultzsch, Adv. Synth. Catal. 2005, 347, 367 – 391.
[4] For a racemic gold-catalyzed synthesis of N-hydroxypyrrolines,
dihydroisoxazoles, and dihydro-1,2-oxazines, see: a) C. Winter,
N. Krause, Angew. Chem. 2009, 121, 6457 – 6460; Angew. Chem.
Int. Ed. 2009, 48, 6339 – 6342; For a gold(I)-catalyzed addition of
hydroxylamines to alkynes, see: b) H.-S. Yeom, E.-S. Lee, S.
Shin, Synlett 2007, 2292 – 2294; For a silver-catalyzed addition of
hydroxylamines to allenes, see: c) R. Bates, J. Nemeth, R. Snell,
Synthesis 2008, 1033 – 1038.
sion and 32% ee. Modifying the catalyst ligand to (R)-
MeOBiPhep additionally improved the enantioselectivity to
49%.
We were pleased to find that chiral silver salts used with
gold(I) complexes catalyze the hydroalkoxylation of N-linked
hydroxylamines with good to excellent enantioselectivity.
Both cyclic and linear alkyl substitutions at the allene
terminus were well tolerated, yielding the corresponding
isomeric vinyl-isoxazolidines in good yield and high enantio-
meric excess (Table 4, entries 1 and 2). Formation of oxazines
Table 4: Hydroxylamine hydroalkoxylation scope.
Entry Substr.
n
R1; R2
Cond.[a] Prod. Yield [%][b] ee [%][c]
1
2
3
4
5
6
26
3
28
30
30
30
1
1
1
2
2
2
Me; H
A
A
A
27
4
29
31
31
31
98
98
99
40/97
50
87
-(CH2)5-; H
Me; Me
Me; H
Me; H
Me; H
75
99[d]
66
A[e]
B
94
36
C
45
[a] Reaction Conditions: A=[dppm(AuCl)2] (3 mol%), III (6 mol%),
0.1m in toluene, 238C, 18 h; B=[(S,S)-dipamp(AuCl)2] (3 mol%), III
(6 mol%), 0.1m in toluene, 238C, 18 h; C=[(S,S)-dipamp(AuCl)2]
(3 mol%), (R)-AgTriP (6 mol%), 0.1m in toluene, 238C, 18 h. [b] Yield
of product isolated after column chromatography. [c] Determined by
HPLC methods. [d] 5:1 d.r. [e] 60 h. dipamp=1.
proved to be more challenging, with the gold(I)-catalyzed
reaction affording 31 in modest yield and 50% ee (Table 4,
entry 4).[11] However, both the yield and enantioselectivity
were greatly improved by combining a chiral ligand with the
chiral silver salt (Table 4, entry 5). Additionally, whereas
good diasteroselectivity was observed for substituted sub-
strates (Table 4, entry 3), the corresponding enantioselectiv-
ities favor the minor diasteromer.
In conclusion, we have developed a series of enantiose-
lective gold(I)-catalyzed hydroaminations and hydroalkoxy-
lations of allenes with hydroxylamines and hydrazines.
Whereas chiral biarylphosphinegold(I) complexes[12] are
suitable catalysts for the enantioselective addition of nitrogen
nucleophiles to allenes, the addition of oxygen nucleophiles
requires the use of chiral anions. These complementary
methods allow rapid access to chiral vinyl isoxolidines,
[5] For selected enantioselective syntheses of isoxazolidines, see:
a) R. Rios, I. Ibrahem, J. Wesely, G.-L. Zhao, A. Cordova,
Tetrahedron Lett. 2007, 48, 5701 – 5705; b) L. Troisi, S. De Lor-
enzis, M. Fabio, F. Rosato, C. Granito, Tetrahedron: Asymmetry
2008, 19, 2246 – 2251; c) M. Tokizane, K. Sato, T. Ohta, Y. Ito,
Tetrahedron: Asymmetry 2008, 19, 2519 – 2528.
[6] For selected methods to synthesize pyrazolines and pyrazoli-
dines, see: a) G. A. Whitlock, E. M. Carreira, J. Org. Chem.
1997, 62, 7916 – 7917; b) Y. Yamashita, S. Kobayashi, J. Am.
Chem. Soc. 2004, 126, 11279 – 11282; c) R. Shintani, G. C. Fu, J.
Am. Chem. Soc. 2003, 125, 10778 – 10779; d) Q. Yang, X. Jiang, S.
Ma, Chem. Eur. J. 2007, 13, 9310 – 9316; e) N. C. Giampietro, J. P.
Wolfe, J. Am. Chem. Soc. 2008, 130, 12907 – 12911.
[7] For an isoxazoline artifical transcription activator, see: a) S. J.
Buhrlage, B. B. Brennan, A. R. Minter, A. K. Mapp, J. Am.
Chem. Soc. 2005, 127, 12456 – 12457.
[8] A. Vasella, R. Voeffray, J. Chem. Soc. Chem. Commun. 1981,
97 – 98.
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[9] a) M. Hatano, T, Maki, K. Moriyama, M. Arinobe, K. Ishihara,
J. Am. Chem. Soc. 2008, 130, 16858 – 16860; b) P. Garcꢀa-Garcꢀa,
F. Lay, P. Garcꢀa-Garcꢀa, C. Rabalakos, B. List, Angew. Chem.
2009, 121, 4427 – 4430; Angew. Chem. Int. Ed. 2009, 48, 4363 –
4366.
[10] For a single example of an intermolecular gold(I)-catalyzed
addition of methyl carbamate to tetramethyl allene (61% yield),
see: a) R. E. Kinder, Z. Zhang, R. A. Widenhoefer, Org. Lett.
2008, 10, 3157 – 3159; For a single example of an intermolecular
gold(I)-catalyzed addition of indole to tetramethyl allene (56%
yield), see: b) K. Toups, G. Liu, R. A. Widenhoefer, J. Organo-
met. Chem. 2009, 694, 571 – 575.
Soc. 2009, 131, 5372 – 5373; c) M. Uemura, I. D. G. Watson, M.
Katsukawa, F. D. Toste, J. Am. Chem. Soc. 2009, 131, 3464 –
3465; d) I. D. G. Watson, S. Ritter, F. D. Toste, J. Am. Chem.
Soc. 2009, 131, 2056 – 2057; e) C.-M. Chao, M. R. Vitale, P. Y.
Toullec, J.-P. GenÞt, V. Michelet, Chem. Eur. J. 2009, 15, 1319 –
1323.
[13] The absolute configuration of 11 was assigned by oxidative
cleavage, Boc removal, and Cbz protection to (S)-methyl-2-
benzyloxycarbonyl-3-isoxazolidinecarboxylate (see the Support-
ing Information). The absolute configurations of the remaining
hydroamination products were assigned by analogy to 11.
À
[14] For a representative procedure to cleave the N O bond, see: A.
[11] Use of 3 mol% [dppm(AuCl)2], 6 mol% (S)-Ag(5), 0.1m in
toluene, 238C, 18 h gave oxazine 27 in 60% yield and 34% ee.
[12] a) F. Kleinbeck, F. D. Toste, J. Am. Chem. Soc. 2009, 131, 9178 –
9179; b) Z. Zhang, S. D. Lee, R. A. Widenhoefer, J. Am. Chem.
Vasella, R. Voeffray, J. Pless, R. Hugenin, Helv. Chim. Acta 1983,
66, 1241 – 1252.
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