Nonenzymatic enantioselective monoacetylation of prochiral 2-protectedamino-2-alkyl-1,3-propanediols utilizing a chiral sulfonamide-Zn complex catalyst

Article abstract of DOI:10.1021/ol063063g

Treatment of a chiral sulfonamide with Et₂Zn gave quantitatively its Zn complex and then the structure was determined by X-ray crystallographic analysis. Reaction of prochiral W-Boc-2-amino-2-alkyl-1,3-propanediols with Ac₂O in the presence of 5 mol% of chiral sulfonamide - Zn complex catalyst afforded the corresponding chiral monoacetyl products in 70-92% yields with 70-88% ee values. The proposed mechanism for the catalytic monoacetylation of a prochiral 1,3-propanediol was presented on the basis of CSI-MS analysis.

Full text of DOI:10.1021/ol063063g

ORGANIC
LETTERS
2007
Vol. 9, No. 3
509-512
Nonenzymatic Enantioselective
Monoacetylation of Prochiral
2-Protectedamino-2-alkyl-1,3-propanediols
Utilizing a Chiral Sulfonamide
−Zn
Complex Catalyst
Takashi Honjo,† Michiyasu Nakao,† Shigeki Sano,† Motoo Shiro,‡
Kentaro Yamaguchi,§ Yoshihisa Sei,§ and Yoshimitsu Nagao*,†
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokushima,
Sho-machi, Tokushima 770-8505, Japan, Rigaku Corporation, 3-9-12 Matsubara-cho,
Akishima, Tokyo 196-8666, Japan, and Faculty of Pharmaceutical Sciences at
Kagawa Campus, Tokushima Bunri UniVersity, 1314-1 Shido, Sanuki-city,
Kagawa 769-2193, Japan
ynagao@ph.tokushima-u.ac.jp
Received December 19, 2006
ABSTRACT
Treatment of a chiral sulfonamide with Et2Zn gave quantitatively its Zn complex and then the structure was determined by X-ray crystallographic
analysis. Reaction of prochiral N-Boc-2-amino-2-alkyl-1,3-propanediols with Ac2O in the presence of 5 mol % of chiral sulfonamide Zn complex
catalyst afforded the corresponding chiral monoacetyl products in 70 92% yields with 70 88% ee values. The proposed mechanism for the
catalytic monoacetylation of a prochiral 1,3-propanediol was presented on the basis of CSI-MS analysis.
−
−
−
In recent years, numerous nonenzymetic catalytic kinetic
resolution methods for racemic alcohols have been disclosed
by utilizing chiral analogues of trialkylphosphine,1 diamine,2
4-(dimethylamino)pyridine,3 peptide-based catalyst,4 1-alkyl-
imidazole,5 and dihydroimidazopyridine.6 On the other hand,
catalytic asymmetric desymmetrization procedures for prochiral
and meso diols have been less investigated. Catalytic
asymmetric desymmetrization methods for meso 1,2-diols
have been reported with good yields and enantioselectivities.7
However, similar desymmetrization methods for prochiral
1,3-diols are rare.8,9 To obtain the high ee products in
asymmetric acylation of prochiral 1,3-diols, the monoacylated
product was subjected to further kinetic resolution forming
† The University of Tokushima.
‡ Rigaku Corporation.
§ Tokushima Bunri University.
(1) Vedejs, E.; Daugulis, O. J. Am. Chem. Soc. 2003, 125, 4166 and
references cited therein.
(2) Sano, T.; Imai, K.; Ohashi, K.; Oriyama, T. Chem. Lett. 1999, 265.
(3) For a review, see: Fu, G. C. Acc. Chem. Res. 2004, 37, 542.
(4) For a review, see: Miller, S. J. Acc. Chem. Res. 2004, 37, 601.
(5) Ishihara, K.; Kosugi, Y.; Akakura, M. J. Am. Chem. Soc. 2004, 126,
12212.
(6) Birman, V. B.; Uffman, E. W.; Jiang, H.; Li, X.; Kilbane, C. J. J.
Am. Chem. Soc. 2004, 126, 12226.
(7) (a) Oriyama, T.; Imai, K.; Sano, T.; Hosoya, T. Tetrahedron Lett.
1998, 39, 3529. (b) Matsumura, Y.; Maki, T.; Murakami, S.; Onomura, O.
J. Am. Chem. Soc. 2003, 125, 2052. (c) Mizuta, S.; Sadamori, M.; Fujimoto,
T.; Yamamoto, I. Angew. Chem., Int. Ed. 2003, 42, 3383.
10.1021/ol063063g CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/12/2007

the diester. Thereby, the utility should be limited from a
viewpoint of their chemical yields.8a,b Recently, Trost and
Mino reported a new fascinating method for catalytic and
direct asymmetric monobenzoylation of prochiral 1,3-diols
having a tertiary prochiral center by the use of a dinuclear
zinc catalyst.9 However, our target substrates, prochiral
2-protectedamino-2-alkyl-1,3-propanediols (PAAPs), having
a quaternary-like prochiral center seemed to be very difficult
compounds for asymmetric monoacylation. Although some
enzymatic acylation methods for prochiral PAAPs (useful
prochiral precursors for chiral R-substituted serines) have
been described,10 there has been no report of the nonenzy-
matic catalytic procedure to the best of our knowledge.11
Herein, we describe a nonenzymatic enantioselective
monoacetylation of prochiral 2-protectedamino-2-alkyl-1,3-
propanediols in the presence of a novel chiral sulfonamide-
Zn complex catalyst.
Scheme 1. Synthesis and X-ray Structure of 1
We tentatively carried out monobenzoylation of N-Z-2-
amino-2-methyl-1,3-propanediol using the Trost’s catalyst.9
The benzoylation proceeded slightly to give a chiral monoben-
zoyl derivative in 12% yield with 10% ee. Thus, we designed
a simple chiral Zn-bridging bis-sulfonamide catalyst 1. Very
recently, we developed catalytic enantioselective thiolysis
of various prochiral dicarboxylic anhydrides using a chiral
sulfonamide 2 based on our concerns about cysteine pro-
tease.11,12 The key function of the Zn2+ cation in the reactive
site of Zn peptidase involves the OH- ion generated by
abstraction of H+ from H2O with the neighboring basic
group.13 Hence, a chiral Zn catalyst seemed to exhibit Lewis
acidic activity to the OH and carbonyl groups. A diuretic
drug acetazolamide bearing the sulfonamide moiety coor-
dinates to the Zn2+ cation in the molecule of carbonic
anhydraze I or II.14 Then, we tried to synthesize a Zn-
contained catalyst using 2. A new chiral sulfonamide-Zn
complex 1 was quantitatively obtained by the reaction of
sulfonamide 2 with Et2Zn (0.55 equiv) in CHCl3 at room
temperature within 1 min (Scheme 1). The structure of
crystalline compound 1 was determined by X-ray crystal-
lographic analysis. Fortunately, compound 1 is remarkably
stable and can be stored at room temperature for several
months without any decomposition.
yield with 63% ee (Table 1, entry 1). Diacetate compound
of 3a was formed in only 3% yield. The ee of 4a should not
be due to a kinetic resolution of the initial monoacetyl
compound because of the very low yield of diacetate.
Table 1. Investigation of the Reaction Conditions for the
Catalytic Enantioselective Monoacetylation of Prochiral
2-Protectedamino-2-methyl-1,3-propanediols
catalyst
temp yield,a ee,b
entry 1,3-diol (mol %)
solvent
THF
CH2Cl2
toluene
MeCN
Et2O
Et2O
i-Pr2O
CPME
t-AmylOMe
t-BuOMe
t-BuOMe
t-BuOMe
t-BuOMe
t-BuOMe
t-BuOMe
(°C)
%
%
1
2
3a
3a
3a
3a
3a
3b
3b
3b
3b
3b
3b
3b
3b
3b
3b
1 (2.5)
1 (2.5)
1 (2.5)
1 (2.5)
1 (2.5)
1 (2.5)
1 (2.5)
1 (2.5)
1 (2.5)
1 (2.5)
1 (2.5)
1 (2.5)
1 (5)
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
4
0
0
-5
-15
82c
51c
31c
60c
82c
90d
91d
87d
92d
94d
77d
74d
92d
80d
65d
63
57
59
32
70
77
77
80
83
83
87
88
88
86
86
3
4
5
6
7
8
9
First, we examined enantioselective acetylation of 3a with
Ac2O (1.5 equiv) in the presence of 2.5 mol % of 1 in THF
at room temperature for 20 h. The reaction smoothly
proceeded to afford the monoacetylated product 4a in 82%
10
11
12
13
14
15
(8) (a) Oriyama, T.; Taguchi, H.; Terakado, D.; Sano, T. Chem. Lett.
2002, 26. (b) Lewis, C. A.; Sculimbrene, B. R.; Xu, Y.; Miller, S. J. Org.
Lett. 2005, 7, 3021. (c) Mizuta, S.; Tsuzuki, T.; Fujimoto, T.; Yamamoto,
I. Org. Lett. 2005, 7, 3633.
(9) Trost, B. M.; Mino, T. J. Am. Chem. Soc. 2003, 125, 2410.
(10) Wang, Y.-F.; Lalonde, J. J.; Momongan, M.; Bergbreiter, D. E.;
Wong, C.-H. J. Am. Chem. Soc. 1988, 110, 7200.
(11) (a) Honjo, T.; Sano, S.; Nagao, Y. Abstracts of Papers, 31th
Synposium on Progress in Organic Reactions and Syntheses, Kobe, Japan,
Nov. 8, 2005, pp 286. (b) Honjo, T.; Sano, S.; Shiro, M.; Nagao, Y. Angew.
Chem., Int. Ed. 2005, 44, 5838.
1 (5)
1 (5)
a Isolated yield. b Determined by HPLC analysis. c Yield of diacetate is
less than 4%. d No production of diacetate. Z ) benzyloxycarbonyl, Boc
) tert-butoxycarbonyl, CPME ) cyclopentyl methyl ether.
(12) Musil, D.; Zucic, D.; Turk, D.; Engh, R. A.; Mayr, I.; Huber, R.;
Popovic, T.; Turk, V.; Towatari, T.; Katunuma, N.; Bode, W. EMBO J.
1991, 10, 2321.
(13) Lipscomb, W. N.; Stra¨ter, N. Chem. ReV. 1996, 96, 2375.
(14) (a) Chakravarty, S.; Kannan, K. K. J. Mol. Biol. 1994, 243, 298.
(b) Nair, S. K.; Krebs, J. F.; Christianson, D. W.; Fierke, C. A. Biochemistry
1995, 34, 3981.
We investigated the similar catalytic enantioselective
acetylation of 3a employing several solvents such as CH2-
Cl2, toluene, MeCN, and Et2O but the yield and the ee were
510
Org. Lett., Vol. 9, No. 3, 2007

Figure 1. Proposed mechanism for catalytic monoacetylation of prochiral N-Boc-2-amino-2-methyl-1,3-propanediol 3b with chiral
sulfonamide-Zn complex catalyst 1.
not remarkably improved (Table 1, entries 2-5). Subse-
quently, enantioselective acetylation of N-Boc-2-amino-2-
methyl-1,3-propanediol 3b was attempted as follows. Treat-
ment of 3b with Ac2O (1.5 equiv) in the presence of 2.5
mol % of the Zn complex catalyst 1 in Et2O at room
temperature for 20 h afforded only monoacetylated product
4b in 90% yield with 77% ee (Table 1, entry 6). This
outcome prompted us to investigate the influence of the
solvent and the possibility of increasing the enantioselectivity
by lowering the reaction temperature for the catalytic
enantioselective acetylation of 3b (Table 1, entries 7-15).
The best result was obtained when t-BuOMe was used as a
solvent in the presence of 5 mol % of chiral catalyst 1 at 0
°C, thus giving 4b in 92% yield with 88% ee (Table 1, entry
13). Tentative catalytic enantioselective acylation of 3a or
3b with 1.5 equiv of benzoic anhydride [(PhCO)2O] in the
presence of 2.5 mol % of the Zn complex catalyst 1 in Et2O
at room temperature gave the corresponding monobenzo-
ylated N-Z-product (60% ee) or N-Boc-product (71% ee) in
60% or 66% yield, respectively.15
Finally, we determined cold-spray ionization mass spec-
trometry (CSI-MS),16 which allows facile and precise
characterization of labile organic species bearing noncovalent
bonding interactions in a solution. The CSI-MS spectrum
for a 1:1 mixture of the Zn complex catalyst 1 [0.1 mM]
and 1,3-diol 3b [0.1 mM] in THF at room temperature
showed the prominent ion peak of 1:1 complex [1-3b-Na]+
at m/z 1322.3.15 Thus, we consider that coordination of 1,3-
propanediol 3b to the Zn complex catalyst 1 may first
generate an activated form A of the 1,3-diol. Then, enantio-
selective hydrogen abstraction of one of two enantiotopic
hydroxy groups with one of two dimethylamino groups in
A (i.e., the Zn complex catalyst 1) would give an anionic
intermediate B. Acetylation of B with Ac2O would furnish
a monoacetate C releasing an acetate ion. The desirable chiral
monoacetate 4b can be obtained by coordination of the 1,3-
Table 2. Catalytic Enantioselective Monoacetylation of
Various Prochiral N-Boc-2-amino-2-alkyl-1,3-propanediols
On the basis of the best reaction conditions (Table 1, entry
13), the catalytic enantioselective acetylation of various
prochiral 1,3-propanediols 3b and 5-8 were performed. The
corresponding chiral monoacetyl products 4b and 9-12 were
obtained in 70-92% yields with 70-88% ee values (Table
2).
yield,a
%
ee,b
%
entry
1,3-diol
product
The absolute configuration of the newly formed chiral
carbon atom in the monoacetyl product 4b, 10, 11, and 12
was determined to be S by their chemical conversion into
the corresponding known R-alkyl serine derivatives.15 Ster-
eochemistry of another monoacetyl product 9 seems to be S
based on a similar reaction.
1
2
3
4
5
3b (R ) Me)
5 (R ) Et)
6 (R ) allyl)
7 (R ) n-hexyl)
8 (R ) Bn)
4b (R ) Me)
9 (R ) Et)
10 (R ) allyl)
11 (R ) n-hexyl)
12 (R ) Bn)
92
87
70
84
70
88
86
82
83c
70
a Isolated yield. b Determined by HPLC analysis. c Determined by HPLC
analysis after quantitative conversion of 11 to its (+)-MTPA ester.
(15) See the Supporting Information.
Org. Lett., Vol. 9, No. 3, 2007
511

propanediol 3b to monool zincate C regenerating the 1,3-
propanediol-Zn complex A, which would be utilized for
further similar reactions in a catalytic cycle manner, as shown
in Figure 1.
Acknowledgment. This work was supported by Grant-
in-Aid for Scientific Research (B) (2) from the Japan Society
for the Promotion of Science.
In conclusion, we have demonstrated, for the first time,
nonenzymatic, catalytic, and enantioselective monoacetyla-
tion of prochiral 2-protectedamino-2-alkyl-1,3-propanediols
utilizing the novel chiral sulfonamide-Zn complex catalyst
1.
Supporting Information Available: Experimental pro-
cedures, compound characterization, X-ray data (CIF), and
CSI mass spectral chart. This material is available free of
charge via the Internet at http://pubs.acs.org.
(16) Yamaguchi, K. J. Mass Spectrom. 2003, 38, 473.
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Org. Lett., Vol. 9, No. 3, 2007