Desymmetrization of meso-glycerol derivatives induced by L -histidine-derived acylation catalysts

Article abstract of DOI:10.1002/adsc.201100252

The desymmetrization of meso-glycerol derivatives bearing a 3-pyrroline-1-carbonyl (Pyroc) directing group is demonstrated through an enantioselective acylation reaction promoted by L-histidine-derived bifunctional catalysts. The desired monoacylated products are obtained in good yields (up to 74%) with high enantioselectivities (up to 99% ee). Copyright

Full text of DOI:10.1002/adsc.201100252

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DOI: 10.1002/adsc.201100252
Desymmetrization of meso-Glycerol Derivatives Induced by
l-Histidine-Derived Acylation Catalysts
Akira Sakakura,a Shuhei Umemura,b and Kazuaki Ishiharab,c,*
a
EcoTopia Science Institute, Nagoya University, Chikusa, Nagoya 464-8603, Japan
Graduate School of Engineering, Nagoya University, Chikusa, Nagoya 464-8603, Japan
b
Fax : (+81)-52-789-3222; phone: (+81)-52-789-3331; e-mail: ishihara@cc.nagoya-u.ac.jp
JST, CREST, Nagoya University, Chikusa, Nagoya 464-8603, Japan
c
Received: April 4, 2011; Published online: August 10, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100252.
Abstract: The desymmetrization of meso-glycerol
derivatives bearing a 3-pyrroline-1-carbonyl (Pyroc)
directing group is demonstrated through an enan-
tioselective acylation reaction promoted by l-histi-
dine-derived bifunctional catalysts. The desired
monoacylated products are obtained in good yields
(up to 74%) with high enantioselectivities (up to
99% ee).
We previously reported the kinetic resolution of
racemic secondary alcohols and carboxylic acids
through asymmetric acylation promoted by l-histi-
dine-derived bifunctional catalysts 1 (Figure 1).[7,8]
Keywords: asymmetric acylation; desymmetriza-
tion; glycerol; l-histidine; Pyroc (3-pyrroline-1-car-
bonyl) group
Figure 1. l-Histidine-derived bifunctional acylation catalysts
1.
Enantioselective transformations of C2-symmetrical
molecules are among the most useful reactions in
asymmetric synthesis. In particular, optically active Catalysts 1 contain an N-methylimidazole moiety as a
glycerol derivatives are valuable chiral building nucleophilic base and a sulfonamidyl proton as a
blocks for the synthesis of natural products and bioac- Brønsted acid, and induce high-level kinetic resolu-
tive compounds. For the synthesis of these chiral tion through hydrogen bonding between the sulfona-
building blocks, various methods have been devel- midyl proton and a Brønsted basic site of the sub-
oped for the desymmetrization of meso-diols through strates. The 3-pyrroline-1-carbonyl (Pyroc) group is a
enantioselective acylation.[1] Although some methods useful directing group of substrates in 1-catalyzed ki-
have been reported for the desymmetrization of acy- netic resolutions.[7d] The strong Brønsted basicity of
clic meso-1,3-diols with good yields and enantioselec- Pyroc plays a key role in high-level asymmetric induc-
tivities,[2–5] there are only a few examples of the de- tion through the formation of strong hydrogen bond-
symmetrization of meso-glycerol derivatives through ing with the sulfonamidyl proton of 1. In addition,
enantioselective acylation.[2] In 2005, Miller and col- Pyroc can be selectively removed via DDQ oxida-
leagues reported peptide-based catalysts[6] for the de- tion[9] followed by hydrolysis through the use of
symmetrization of glycerol derivatives.[2a] Although NaOH[10] without any loss of stereochemical integrity.
Millerꢀs reaction was highly enantioselective (>90% We report here the desymmetrization of meso-glycer-
ee), the desired monoesters were obtained in moder- ol derivatives bearing a Pyroc group by a 1-catalyzed
ate yields along with significant amounts of undesired asymmetric acylation reaction.
diesters. The non-enzymatic organocatalyzed desym-
First, the desymmetrization of 2-O-Pyroc-glycerol 2
metrization of meso-glycerol derivatives is still a chal- with a carboxylic anhydride (1.0 equiv.) was examined
lenging issue in organic chemistry.
in the presence of 1 (5 mol%) and (i-Pr)2NEt
(1.0 equiv.) (Table 1). Although the use of a less polar
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Desymmetrization of meso-Glycerol Derivatives Induced by l-Histidine-Derived Acylation Catalysts
Table 1. Desymmetrization of 2-O-Pyroc-glycerol 2.
Entry
1
R
T [8C], t [h]
Yield of 3 [%]
ee of 3 [%]
Yield of 4 [%]
Ratio 3/4
1
1a
1a
1a
1a
1a
1b
1b
1b
1b
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Cy
ꢀ20, 3
ꢀ20, 3
ꢀ20, 3
ꢀ20, 12
r.t., 3
r.t., 3
r.t., 15
r.t., 2
37
24
17
55
61
61
74
63
71
98
58
99
98
81
91
93
94
86
16
10
28
6
13
15
13
12
12
2.3
2.4
0.61
9.2
4.7
4.1
5.7
5.3
5.9
2[a]
3[b]
4[c]
5
6
7
8
9
Et
t-Bu
r.t., 48
[a]
2-O-Benzoylglycerol 5 was used as a substrate.
The reaction was conducted in the presence of 6 (0.7 equiv., 98% ee).
3 equiv. of (i-Pr)2NEt were used.
[b]
[c]
solvent such as CCl4 is the most suitable for obtaining creased to 81% ee (entry 5). These reaction conditions
high enantioselectivity, the reaction of 2 was carried might successfully prevent the interaction between 1a
out in CCl4-CHCl3 (3:1 v/v) due to the poor solubility and 3. The use of bulkier catalyst 1b gave improved
of 2 in CCl4. When the reaction with isobutyric anhy- enantioselectivity without any loss of reactivity (61%
dride (R=i-Pr) was conducted in the presence of 1a yield, 91% ee, entry 6).
at ꢀ208C, the corresponding monoester (R)-3 (R=i-
The reactivity and enantioselectivity of the 1-cata-
Pr) was obtained in 37% yield with 98% ee along lyzed asymmetric acylations depended on the carbox-
with diester 4 (16%) (entry 1). On the other hand, 2- ylic anhydrides.[7] For the present 1b-catalyzed desym-
O-benzoylglycerol 5 showed poor reactivity and enan- metrization of 2, the use of cyclohexanecarboxylic an-
tioselectivity under the same reaction conditions hydride (R=Cy) gave the best results (74% yield,
(24% yield, 58% ee, entry 2). These results indicated 93% ee, 3/4=5.7, entry 7). Under the present reaction
that the Pyroc group successfully acted as a directing conditions, racemization of these monoesters through
group in the 1a-catalyzed desymmetrization of 2.
acyl migration was not observed. Less bulky carboxyl-
Despite the high enantioselectivity of the 1a-cata- ic anhydride (R=Et) gave the corresponding ester
lyzed desymmetrization of 2, the yield of 3 did not in- with high enantioselectivity in rather lower yield
crease further even when the reaction time was pro- (63% yield, 94% ee) (entry 8). More bulky pivalic an-
longed. The catalysis of 1a might be inhibited by the hydride (R=t-Bu) showed poor reactivity (entry 9).
interaction of generated 3, since the reaction was sig-
We next examined the desymmetrization of the sec-
nificantly prevented by the addition of optically ondary meso-1,3-diol 7a (Table 2). The solubility of 7a
active (R)-6 (0.7 equiv., 98% ee) (entry 3). To over- in less polar solvents was good enough for the reac-
come this problem, the reaction conditions were in- tion to proceed in CCl4-CHCl3 (9:1 v/v). The reactivi-
vestigated. We found that the use of 3 equivalents of ty of 7a was lower than that of 2, and the reaction re-
(i-Pr)2NEt significantly improved the yield of 3 to quired a prolonged reaction time to give the corre-
55% and suppressed the generation of 4 to 6% sponding monoester 8a in an appreciable yield. When
(entry 4). Alternatively, when the reaction was con- the reaction of 7a with (CyCO)2O (1.0 equiv.) was
ducted at ambient temperature, the yield of 3 in- conducted at ambient temperature for 24 h, 8a was
creased to 61%, while the enantioselectivity de- obtained in 59% yield with 89% ee (entry 1). The use
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1939

Akira Sakakura et al.
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Table 2. Desymmetrization of 3-O-Pyroc-2,3,4-pentanetriol 7a.
Entry
R (equiv.)
X
T [8C], t [h]
Yield of 8a [%]
ee of 8a [%]
Ratio 8a/9a
1
2
3
4
5
Cy (1.0)
i-Pr (1.0)
Cy (1.3)
Cy (1.3)
Cy (1.3)
2
2
3
3
3
r.t., 24
r.t., 12
r.t., 4
10, 12
0, 24
59
34
71
70
64
89
92
94
89
94
3.1
1.5
3.1
2.5
2.4
of (i-PrCO)2O significantly decreased the yield of 8a
and the ratio of 8a to diester 9a, although the enantio-
selectivity was high (entry 2). To improve the yield of
8a, the reaction of 7a was conducted with 1.3 equiva-
lents of (CyCO)2O and 3 equivalents of (i-Pr)2NEt.
As a result, the reaction at ambient temperature gave
an increased yield and enantioselectivity of 8a (71%
yield, 94% ee, entry 3). However, the reaction at
lower temperature (0–108C) did not improve the
enantioselectivity (89–94% ee) and the ratio of 8a to
9a (2.4–2.5) (entries 4 and 5). On the other hand, the
desymmetrization of diastereomeric secondary meso-
1,3-diol 7b showed poor reactivity and enantioselec-
tivity (Scheme 1).
Figure 2. Plausible transition-state assemblies 10 and 11.
the Pyroc group would direct the pro-(R) hydroxy
In the 1-catalyzed kinetic resolution of racemic sec- group outside in the transition-state assembly 11b,
ondary alcohols, intermolecular hydrogen bonding be- which might cause poor reactivity and enantioselectiv-
tween the sulfonamidyl proton in 1 and the carbamoyl ity.
oxygen of the substrates has been proposed to pro-
The obtained optically active monoester 3 is a
mote the acylation by a proximity effect with high useful chiral building block for the synthesis of vari-
enantioselectivity.[7] Based on this intermolecular hy- ous bioactive natural products. Chlorination of the
drogen bonding, plausible transition-state assemblies primary hydroxy group of (R)-3 with SOCl2 gave the
10 and 11a were proposed for the present desymmet- corresponding chroride quantitatively. Subsequent se-
rization of 2 and 7a (Figure 2). In these transition- lective removal[7d] of the cyclohexanecarbonyl group
state assemblies, pro-(R) hydroxy groups of 2 and 7a with aqueous HCl gave 12 in 91% yield (2 steps)
would be placed close to the acylammonium moiety (Scheme 2). On the other hand, alkaline hydrolysis of
and acylated selectively. In addition, the pro-(S) hy- cyclohexanecarboxylate gave 13 (88%, 2 steps from
droxy proton might be interact with the sulfonyl 3) via the migration of Pyroc group to the primary hy-
oxygen to stabilize the conformation of the transition droxy group.[11] Compounds 12 and 13 were obtained
state. In contrast, for the desymmetrization of 7b, without any loss of stereochemical integrity. In addi-
steric repulsion between the methyl group (Rb) and tion, Mitsunobu reaction of 8a using PhCO2H, DIAD
and PPh3 gave the corresponding benzoate 14 in 77%
yield with inversion of the stereochemistry of the sec-
ondary hydroxy group.
For further application of the present method, we
investigated the desymmetrization of meso-2-amino-
1,3-propanediols[4] bearing a Pyroc group at the 2-po-
sition (Table 3). First, the desymmetrization of N-
Pyroc-2-amino-1,3-propanediol 15a (R=H) was ex-
amined in CHCl3 due to the poor solubility of 15a.
The reaction with (CyCO)2O (1.2 equiv.) gave the cor-
Scheme 1. Desymmetrization of 7b.
responding monoester 16a in 64% yield with 59% ee
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Adv. Synth. Catal. 2011, 353, 1938 – 1942

Desymmetrization of meso-Glycerol Derivatives Induced by l-Histidine-Derived Acylation Catalysts
Experimental Section
Representative Procedure for the Desymmetrization
of meso-1,3-Diols
To
a
solution of meso-1,3-diol (0.24 mmol) and
1
(0.012 mmol) in CHCl3 (1.2 mL) and CCl4 (3.6 mL) were
added (i-Pr)2NEt (41.8 mL, 0.24 mmol) and carboxylic anhy-
dride (0.24 mmol) at ambient temperature or ꢀ208C (for
each reaction temperature). After being stirred at ambient
temperature or ꢀ208C (for each reaction temperature), the
reaction mixture was treated with aqueous 0.1M HCl solu-
tion and extracted with EtOAc. The organic layer was
washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified by flash
column chromatography on silica gel (hexane-EtOAc 2:1!
1:2) to give the desired monoester. The ee value was deter-
mined by HPLC analysis.
Scheme 2. Transformations of optically cctive 3 and 8a.
(R)-1-Hydroxy-3-(isobutyryloxy)propan-2-yl 2,5-Dihydro-
1H-pyrrole-1-carboxylate (3, R=i-Pr): [a]2D4: ꢀ13.7 (c 1.0,
CHCl3) for 96% ee; HPLC (Daicel Chiralcel AS-H, hexane-
2-propanol 19:1, flow rate 1.0 mLminꢀ1): tR =47.4 (major
enantiomer), 52.0 (minor enantiomer) min; IR (KBr): n=
Table 3. Desymmetrization of N-Pyroc-2-amino-1,3-propane-
diols 14.
3443, 1737, 1710, 1688, 1429, 1327, 1192, 1159, 1124 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d=1.18 (d, J=6.9 Hz, 6H),
2.59 (septet, J=6.9 Hz, 1H), 2.76 (br s, 1H), 3.77 (br s, 2H),
4.09–4.24 (m, 4H), 4.31 (d, J=5.0 Hz, 2H), 5.01 (tt, J=5.0,
5.5 Hz, 1H), 5.75–5.86 (m, 2H); 13C NMR (100 MHz,
CDCl3): d=18.8, 33.8, 52.8, 53.2, 61.7, 62.4, 73.6, 125.4,
125.5, 154.2, 176.8; HR-MS (FAB): m/z=258.1339, calcd.
for C12H20NO5 [(M+H)+]: 258.1341.
Entry 15 (R)
Yield of 16 [%] ee of 16 [%] Ratio 16/17
1[a]
2
15a (H) 64
15b (Me) 60
15c (Bn) 15
59
55
11
2.4
2.7
0.45
3
[a]
Acknowledgements
The reaction was conducted in CHCl3.
Financial support for this project was provided by JSPS.KA-
KENHI (20245022and 23350039), NEDO, the Global COE
Program of MEXT, and JSPS Research Fellowships for
Young Scientists (S.U.).
(entry 1). The moderate enantioselectivity was proba-
bly due to the high polarity of the reaction solvent.
Therefore, we next examined the desymmetrization of
N-methyl and N-benzyl derivatives 15b and 15c, both
of which could be dissolved in CCl4-CHCl3 (3:1 v/v).
Disappointingly, the yield and enantioselectivity of 16
decreased with an increase in the steric bulkiness of
the substituent on the nitrogen (entries 1–3). Further-
more, the desymmetrization of 15c predominantly
gave the corresponding diester 17c (16c/17c=0.45,
entry 3). Steric hindrance of the substituents on the
nitrogen, which would be directed to the catalyst in
the transition-state, might prevent interaction with
the catalyst.
In conclusion, we have demonstrated the desym-
metrization of acyclic meso-1,3-diols by asymmetric
acylation induced by bifunctional catalyst 1b. A Pyroc
group successfully acted as a directing group through
intermolecular hydrogen bonding for high-level asym-
metric induction.
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Adv. Synth. Catal. 2011, 353, 1938 – 1942