Flexible synthesis, structural determination, and synthetic application of a new C1-symmetric chiral ammonium betaine

Article abstract of DOI:10.1039/b916627k

A C₁-symmetric chiral ammonium betaine has been developed, and its intramolecular ion-pairing structure in solid state and its catalytic performance to achieve the highly stereoselective Mannich-type reaction of 2-alkoxythiazol-5(4H)-ones are r

Full text of DOI:10.1039/b916627k

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Flexible synthesis, structural determination, and synthetic application
of a new C1-symmetric chiral ammonium betainew
Daisuke Uraguchi, Kyohei Koshimoto and Takashi Ooi*
Received (in College Park, MD, USA) 13th August 2009, Accepted 9th November 2009
First published as an Advance Article on the web 25th November 2009
DOI: 10.1039/b916627k
A C1-symmetric chiral ammonium betaine has been developed,
and its intramolecular ion-pairing structure in solid state and its
catalytic performance to achieve the highly stereoselective Mannich-
type reaction of 2-alkoxythiazol-5(4H)-ones are revealed.
Chiral ammonium betaine had been a previously unexplored
structural motif in asymmetric catalysis despite its inherent
potential as a bifunctional onium salt catalyst.1 Recently, our
Fig. 1 Design concept for C1-symmetric ammonium betaine 1.
group uncovered its capability to function as a chiral organic
base catalyst by the development of pseudo C2-symmetric
As shown in Scheme 1, we initially prepared 2 from
commercially available (R)-1,10-bi-2-naphthol in the usual
manner, and methoxycarbonylation of the triflate moiety
yielded 3. Then, selective ortho-metallation and subsequent
chlorination were realized, giving rise to 4 in 51% yield.
After simple reduction of the ester, the primary alcohol was
brominated to 5. The generated benzylic bromide was used
for the alkylation of dimethylamine, and the sequential
MOM-directed lithiation–bromination resulted in the formation
of the key intermediate 7 (83%) for the introduction of
different substituents to the 3 and 30 positions. Indeed, when
7 was subjected to the Suzuki–Miyaura coupling conditions,
only the aryl bromide functionality participated in the reaction
and thus various aromatic substituents (Ar1) could be
selectively installed. In the consecutive cross-coupling of 8
with another boric acid [Ar2B(OH)2], employment of
2-dicyclohexylphosphino-20,60-dimethoxybiphenyl (S-phos) as
a ligand turned out to be essential to achieve a synthetically
satisfactory chemical yield.5 Quaternization of the tertiary
amine moiety of 9 with MeI and deprotection of the MOM
group gave ammonium salt, which was treated with 0.1 M
NaHCO3 aqueous solution to afford the requisite chiral
chiral quaternary ammonium aryloxides; these betaines can
be applied to the catalytic, highly enantioselective direct
Mannich-type reaction of a-nitrocarboxylates.2 Although the
C2-symmetric nature of the catalyst played a crucial role in
inducing a high level of stereocontrol, it made it difficult to
verify the three-dimensional structure and to pursue rational
yet flexible manipulations of the catalyst. This situation
prompted us to devise structurally simplified C1-symmetric
chiral quaternary ammonium aryloxides in order to create a
basis for further investigating the potential applicability of
betaines as a chiral organic base catalyst. Here we describe the
synthesis and an unequivocal structural determination of a
chiral C1-symmetric ammonium betaine 1 and its successful
application to the highly stereoselective direct Mannich-type
reaction of 2-alkoxythiazol-5(4H)-ones (Fig. 1 and Table 1).3,4
Our prime concern for consolidating the structural features
of the pseudo C2-symmetric chiral ammonium betaine into
a single binaphthyl unit leads to the design concept for
the differently 3,30-substituted 1, which has the following
characteristics: (1) the ortho-substituent of aryloxide (Ar1)
would create an effective chiral environment around the reaction
sphere; (2) the aromatic group at the ortho-position of the
alkylammonium moiety (Ar2) could restrict the free rotation
of the pendant cation; (3) the intramolecular electrostatic
interaction regulates the direction of the cationic site, which
would eventually affect the position of a nucleophilic anion
(Fig. 1). To prove the validity of this approach toward
developing the C1-symmetric betaine, establishment of a
reliable and flexible synthetic route to 1 was required.
Department of Applied Chemistry, Graduate School of Engineering,
Nagoya University, Furo-cho B2-3(611), Chikusa, Nagoya 464-8603,
Japan. E-mail: tooi@apchem.nagoya-u.ac.jp;
Fax: +81-(0)52-789-3338; Tel: +81-(0)52-789-4501
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data of 1–14, and details of X-ray crystallo-
graphic analysis of 1a and anti-13. CCDC 744059 & 744058. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/b916627k
Fig. 2 ORTEP diagrams of 1a: (a) top view (b) front view. All
hydrogen atoms, and solvent molecules are omitted for clarity. The
thermal ellipsoids of non-hydrogen atoms are shown at the 50%
probability level.
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i
Scheme 1 Flexible synthetic route to 1. (a) CO (1 atm), Pd(OAc)2, dppp, Pr2NEt, MeOH, DMSO, 80 1C, 71%; (b) LTMP, B(OiPr)3, THF,
ꢁ78 1C-rt; (c) CuCl2, KFꢂ2H2O, THF, H2O, rt, 51% (2 steps); (d) LiAlH4, Et2O, 0 1C; (e) NBS, Me2S, 0 1C, 92% (2 steps); (f) Me2NH aq., MeCN, rt;
(g) nBuLi, THF, then (BrF2C)2, ꢁ78 1C-rt, 83% (2 steps); (h) Pd(OAc)2, PPh3, Ar1B(OH)2, K3PO4, THF, 65 1C, 73–79%; (i) Pd2dba3, S-phos,
Ar2B(OH)2, K3PO4, DMF, 100 1C, 44–98% (except 8b); (j) MeI, rt; (k) HCl, MeOH, 40 1C, (l) NaHCO3 aq., rt, 71–82% (3 steps). dppp:
1,3-diphenylphosphinopropane, LTMP: lithium 2,2,6,6-tetramethylpiperidide, NBS: N-bromosuccinimde, dba: dibenzylideneacetone, S-phos:
2-dicyclohexylphosphino-20,60-dimethoxybiphenyl, Mes = 2,4,6-trimethylphenyl, Tip = 2,4,6-triisopropylphenyl.
Table 1 Optimization of catalyst structurea
was found to be 99% ee (entry 1 in Table 1). Here, replace-
ment of the phenyl group (Ar2, cation side) with smaller chloro
functionality (1b) or hindered p-tert-butylphenyl moiety (1c)
led to decrease in the diastereoselectivity (entries 2 and 3). On
the other hand, as the steric demand of Ar1 (aryloxide side)
was increased,
a substantial improvement in diastereo-
selectivity was observed without any detrimental effect on the
reactivity and enantioselectivity (entries 4 and 5). Consequently,
chiral ammonium betaine 1f possessing a phenyl group as Ar2
and p-(2,4,6-triisopropylphenyl)phenyl group as Ar1 was
identified as an optimal catalyst for achieving high levels of
relative and absolute stereocontrol (entry 6).
Yield dr
ee
Yield dr
ee
Entry 1 (%)b (anti/syn)c (%)d Entry 1 (%)b (anti/syn)c (%)d
1
2
3
1a 97
1b 95
1c 91
4.7 : 1
2.1 : 1
4.5 : 1
99
99
99
4
5
6
1d 96
1e 94
1f 97
5.7 : 1
6.4 : 1
10 : 1
99
99
99
a
b
c
See ESIw for details. Isolated yield. Diastereomeric ratio was
The results of further experiments to probe the substrate
scope by using 1f are summarized in Table 2. Generally,
1 mol% of the catalyst was sufficient for rapid bond-formation
under mild conditions, giving 11 in high yield. The stereo-
chemical outcome was scarcely affected by the electronic
properties of the substituents of aromatic N-Boc imines
(entries 1–5), and hetero- and fused-aromatic imines were also
tolerated (entries 6 and 7). Since the a-aryl substituent of the
determined by 1H NMR of crude mixture. Enantiomeric excess of
major anti isomer was indicated and it was analyzed by chiral HPLC.
d
ammonium betaine 1. Single crystal X-ray diffraction analysis
of 1a revealed its three-dimensional molecular appearance
(Fig. 2).6 Importantly, the tetraalkylammonium cation moiety
turns in the same direction as the oxygen of the aryloxide
anion, thereby revealing the intramolecular ion-pairing structure.
With the flexible synthetic scheme and precise structural
information in hand, we set out to evaluate the structure–
activity relationship of these C1-symmetric ammonium betaines
as a chiral organic base catalyst in order to demonstrate the
effectiveness of the present molecular design. For this purpose,
we chose 2-benzyloxythiazol-5(4H)-ones (10, scheme shown in
Table 1) as a new class of amino acid-derived nucleophiles for
the Mannich-type reaction because the following notable
advantages were expected: (1) the enolate generated from the
sulfur-containing heterocycle could exert prominent nucleo-
philicity, and its beneficial consequence would be the accom-
modation of a-aryl substituents; (2) the reaction products
could be readily derivatized into the corresponding differently
protected a-tetrasubstituted a,b-diamino acids2,7 through mild
oxidative cleavage of the thiazolone moiety.
Table 2 Substrate scopea
Yield dr
ee
Entry R1
R2
10
(%)b (anti/syn)c (%)d 11
1
2
3
4
p-F–C6H4
Ph
Ph
Ph
Ph
10a 92
10a 90
10a 92
10a 95
10a 93
10a 97
10a 96
15 : 1
11 : 1
10 : 1
12 : 1
10 : 1
11 : 1
10 : 1
11 : 1
2.7 : 1
99
98
99
99
99
97
97
99
92
11b
11c
11d
11e
11f
11g
11h
11i
p-Br–C6H4
p-Me–C6H4
m-Br–C6H4
5
m-MeO–C6H4 Ph
6e
7
3-furyl
b-Naph
Ph
Ph
Ph
8
p-Cl–C6H4 10b 96
PhCH2
An initial attempt was made by treating phenylglycine-
derived 10a with benzaldehyde N-Boc imine in the presence
of 1a (1 mol%) in Et2O at ꢁ40 1C. As assumed, the reaction
was completed within 15 min to furnish the desired 11a in a
near quantitative yield with an anti/syn ratio of 4.7 : 1.8
Fortunately, the enantiomeric excess of the major anti isomer
9f
Ph
10c 88
11j
a
b
c
See ESIw for details. Isolated yield. Diastereomeric ratio was
determined by 1H NMR of crude mixture. Enantiomeric excess of
major anti isomer was indicated and it was analyzed by chiral HPLC.
d
e
f
Reaction was performed at ꢁ60 1C for 1 h. 0 1C, 14 h.
ꢀc
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In conclusion, we have presented a reliable yet flexible
synthesis and a complete structural determination of a new
C1-symmetric chiral ammonium betaine, and its ability as an
organic base catalyst has been demonstrated by successfully
applying it to the development of the highly stereoselective
direct Mannich-type reaction of 2-alkoxythiazol-5(4H)-ones.
The synthetic value of the Mannich adducts has been revealed
by simple derivatization processes that offer a facile and
stereoselective way to the differently protected a-tetrasubstituted
a,b-diamino acids and their derivatives bearing a,b-diaryl side
chains. We believe that the structural features of C1-symmetric
chiral quaternary ammonium aryloxides provide a new
platform for cultivating the potential functions of the
betaines as a bifunctional chiral organic molecular catalyst
through taking full advantage of the intramolecular ion-
pairing structure.
Scheme 2 Derivatization of 11a to a-aryl-a,b-diamino acid ester 12
and amide 14. [*1 A mixture of diastereomers (anti/syn = 10 : 1) and
99% ee for major anti isomer.]
This work has been supported by Astellas Foundation for
Research on Metabolic Disorders, the Global COE program
in Chemistry of Nagoya University, and the Tatematsu
Fundation.
nucleophilic component (10) could be variable with similar
degree of stereocontrol (entry 8), this direct Mannich-
type protocol provided a reliable entry to optically active
a-tetrasubstituted a,b-diamino acids bearing a,b-diaryl side
chains, a potentially useful chiral building block not accessible
so far in a catalytic enantioselective manner.9 Moreover,
a-alkyl-substituted thiazol-5(4H)-ones such as 10c were
employable, although a decrease in the diastereoselectivity
seemed to be inevitable (entry 9).
Notes and references
1 M. Shibasaki and M. Kanai, in New Frontiers in
Asymmetric Catalysis, ed. K. Mikami and M. Lautens, John Wiley
& Sons, Inc., Hoboken, 2007, p. 383.
2 D. Uraguchi, K. Koshimoto and T. Ooi, J. Am. Chem. Soc., 2008,
130, 10878.
The product derivatizations illustrated in Scheme 2 clearly
demonstrates the synthetic utility of the present system.
As expected, the thiazolone ring of 11a was readily cleaved
with in situ generated LiOOH under mild conditions,
directly producing the corresponding, differently protected
a-tetrasubstituted a,b-diamino acid. Subsequent esterification
followed by chromatographic separation of diastereomers
gave the stereochemically homogeneous ester anti-12
(66% in 2 steps). It should be noted that this process involves
the one-pot conversion of the intermediary benzyloxy
thiocarbonyl moiety into the common carbobenzyloxy (Cbz)
group, highlighting the unique property of 2-alkoxythiazol-
5(4H)-ones.10 Meanwhile, treatment of 11a with 1 M hydrochloric
acid in methanol afforded N-carboxythio anhydride 13 and its
single crystal X-ray diffraction analysis enabled the assignment
of the absolute configuration of the major anti-isomer
(Fig. 3).11 Further, simple exposure of 13 to methylamine in
acetonitrile furnished a,b-diamino acid amide 14 without loss
of stereochemical integrity.
3 For reviews on organocatalyzed Mannich-type reactions, see:
(a) A. Ting and S. E. Schaus, Eur. J. Org. Chem., 2007, 5797;
(b) J. M. M. Verkade, L. J. C. van Hemert, P. J. L. M. Quaedflieg
and F. P. J. T. Rutjes, Chem. Soc. Rev., 2008, 37, 29.
4 Y. Lin and K. K. Andersen, Eur. J. Org. Chem., 2002, 557.
5 S. D. Walker, T. E. Barder, J. R. Martinelli and S. L. Buchwald,
Angew. Chem., Int. Ed., 2004, 43, 1871.
6 Crystal data for 1aꢂ2MeOHꢂH2O (CCDC 744059): C36H31NOꢂ
2CH4OꢂH2O (MW 575.72), monoclinic, P21, a = 11.552(5), b =
9.827(5), c = 14.569(7) A, b = 109.875(11)1, V = 1555.4(13) A3,
Z = 2, T = 153(2) K, Independent reflections 6478 [Rint
=
0.0329], R1(Rw) = 0.0496 (0.1157) (I 4 2s(I)), GOF = 1.032.
7 Catalytic asymmetric synthesis of a-substituted a,b-diamino acids:
(a) K. R. Knudsen and K. A. Jørgensen, Org. Biomol. Chem., 2005,
3, 1362; (b) Z. Chen, H. Morimoto, S. Matsunaga and
M. Shibasaki, J. Am. Chem. Soc., 2008, 130, 2170; (c) A. Singh
and J. N. Johnston, J. Am. Chem. Soc., 2008, 130, 5866;
(d) B. Han, Q.-P. Liu, R. Li, X. Tian, X.-F. Xiong, J.-G. Deng
and Y.-C. Chen, Chem.–Eur. J., 2008, 14, 8094; (e) D. Uraguchi,
Y. Ueki and T. Ooi, J. Am. Chem. Soc., 2008, 130, 14088;
(f) J. Hernandez-Toribio, R. G. Arrayas and J. C. Carretero,
J. Am. Chem. Soc., 2008, 130, 16150. See also: R. G. Arrayas
and J. C. Carretero, Chem. Soc. Rev., 2009, 38, 1940.
8 The reaction with the betaine precursor 1aꢂHCl was very sluggish
under the identical conditions.
9 For non-enantioselective examples, see: (a) Y. Wang, Y. Zhu,
Z. Chen, A. Mi, W. Hu and M. P. Doyle, Org. Lett., 2003, 5,
3923; (b) J. S. Dickstein, M. W. Fennie, A. L. Norman,
B. J. Paulose and M. C. Kozlowski, J. Am. Chem. Soc., 2008,
130, 15794.
10 It is known that the deprotection of a,a-disubstituted oxazol-5-one
requires harsh conditions due to the high stability of amide
protective group in the ring-opening product. For examples, see:
(a) ref. 7e; (b) D. Uraguchi, Y. Asai, Y. Seto and T. Ooi, Synlett,
2009, 658.
11 Crystal data for anti-13 (CCDC 744058): C21H22N2O4S
(MW 398.47), Orthorhombic, P212121,
a = 11.7097(16),
b = 16.840(2), c = 21.042(3) A, V = 4149.2(10) A3, Z = 8,
T = 153(2) K, Independent reflections 10322 [Rint = 0.0696],
Flack parameter 0.01(7), R1(Rw) = 0.0627 (0.1196) (I 4 2s(I)),
GOF = 1.084.
Fig.
3 ORTEP diagram of anti-13. The thermal ellipsoids of
non-hydrogen atoms are shown at the 50% probability level.
ꢀc
This journal is The Royal Society of Chemistry 2010
302 | Chem. Commun., 2010, 46, 300–302