Direct-type aldol reactions of fluorenylidene-protected/activated glycine esters with aldehydes for the synthesis of β-hydroxy-α-amino acid derivatives

Article abstract of DOI:10.1002/asia.201200081

Two birds with one stone: Magnesium-base-catalyzed highly diastereoselective direct-type aldol reaction of glycine Schiff base bearing a fluorenylidene moiety as a protecting and activating group was developed. The desired reactions proceeded smoothly at low temperature, and the aldol products were obtained in high yield with high diastereoselectivity. Copyright

Full text of DOI:10.1002/asia.201200081

DOI: 10.1002/asia.201200081
Direct-Type Aldol Reactions of Fluorenylidene-Protected/Activated Glycine
Esters with Aldehydes for the Synthesis of b-Hydroxy-a-amino Acid
Derivatives
Raphaꢀl Rahmani, Masatoshi Matsumoto, Yasuhiro Yamashita, and Shu Kobayashi*[a]
¯
Celebrating 150 years of German–Japanese relations
The synthesis of b-hydroxy-a-amino acid has been widely
documented in the literature.[1] Indeed, this moiety can be
found in numerous natural products such as vancomycin[2]
and lactacystin.[3] One of the most rapid routes to these
products involves an aldol condensation between an N-pro-
tected glycine and an aldehyde. Miller and co-workers[4] re-
ported aldol condensation of a glycine Schiff base with alde-
hydes using a chiral phase-transfer catalyst. More recently,
Shibasaki and co-workers[5] reported the successful direct
asymmetric aldol reaction[6] between a glycine Schiff base
and several aliphatic aldehydes with moderate diastereo-
and enantioselectivities. In the same year, Maruoka and co-
workers[7] described the same reaction using a phase-transfer
catalyst giving the corresponding aldol adduct with high dia-
stereo- and enantioselectivities. Other groups also reported
similar aldol condensations using glycine Schiff bases.[8] As
alternative nucleophilic species, 5-alkoxyoxazole,[9] a-isocya-
no acetates,[10] and a-isothiocyanatoimides[11] were used for
this type of reaction.[12] Moreover, enzymatic accesses have
been found but show some substrate limitations.[13]
We started our investigation by using fluorenylidene gly-
cine methyl ester (1a)[16] and a typical aliphatic aldehyde,
cyclohexanecarboxyaldehyde (2a) in THF in the presence of
10 mol% base catalyst (Scheme 1). The results are summar-
Scheme 1. Catalytic aldol reaction of Flu-protected glycine ester 1a.
Recently, our group showed that aminoalkanes could be
protected and activated at the same time by using a 9-fluo-
renylidene group.[14] This group allows a strong activation of
the a-position of the nitrogen atom via stabilization of the
14 p electron system.[15] Based on that idea, we have devel-
oped an efficient synthesis of diamine compounds by Man-
nich-type reactions of N-protected imines, such as N-tert-bu-
toxycarbonyl (Boc) or N-diphenylphosphinoyl (Dpp) imines.
Those results encouraged us to investigate the direct-type
aldol reactions of fluorenylidene-protected glycine Schiff
bases. Herein, we describe the development of highly stereo-
selective aldol reactions using a catalytic amount of func-
tionalized base.
ized in Table 1. In this reaction system, the reaction at lower
temperature was found to be quite effective, and an interest-
ing diastereoselectivity was observed when sodium 2,6-di-
methylphenoxide was used as a base catalyst (Table 1,
Table 1. Optimization of reaction conditions.[a]
Entry
Base 4
anti/syn[b]
Yield [%][c]
1
2
3
4
5
6
4a
4b
4c
4d
4e
4 f
4 f
4 f
4 f
4 f
78/22
79/21
87/13
90/10
n.d.
96/4
96/4
96/4
96/4
–
45
69
82
85
5
95
72
96
96
NR
7[d]
8[e]
9[f]
10[g]
[a] Dr. R. Rahmani, M. Matsumoto, Dr. Y. Yamashita,
Prof. Dr. S. Kobayashi
Department of Chemistry, School of Science
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo, 113-0033 (Japan)
Fax : (+81)3-5684-0634
[a] The reaction was performed using 1a and cyclohexanecarboxyalde-
hyde (2a, 1.1 equiv) in THF at À788C for 15 h in the presence of base 4
(10 mol%). [b] Determined by 1H NMR analysis of the crude mixture.
n.d.=not determined. [c] Yield of isolated product. [d] The reaction was
performed in Et2O. [e] Catalyst loading of 5 mol% was used. [f] Catalyst
loading of 2 mol% was used. [g] The reaction was performed using the
glycine Schiff base 1b instead of 1a.
E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201200081.
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COMMUNICATION
entry 1). In the reaction, the choice of the base appears to
be crucial for the reactivity and the selectivity, and sodium
N-aryltosylamide gave promising results (entries 2–4).
Among them, the amides bearing naphthalene ring systems
performed best, and sodium N-5,6,7,8-tetrahydro-1-naph-
thyltosylamide showed the high diastereomeric ratio of anti/
syn=90:10. We then investigated the effect of the metal
moiety in the amide catalyst and found that magnesium salts
showed the best stereoselectivity (entry 6). It was confirmed
that Et2O also worked as an acceptable solvent, but the
yield was a little lower (entry 7). Further, reduction of the
catalyst amount was conducted, and just 2 mol% Mg cata-
lyst gave the desired product in high yield without any loss
of diastereoselectivity (entry 9). The effect of the fluorenyli-
dene group is very important, and the typical glycine Schiff
base 1b derived from benzophenone did not work at all
under the reaction conditions (entry 10). It should be noted
that the use of fluorenylidene group enhanced the reactivity
of the glycine ester dramatically in the aldol reaction.
Scheme 2. Modification of the product.
dene group and hydrolysis of the ester (Scheme 2). Acid hy-
drolysis of the aldol adduct 3a gave the corresponding b-hy-
droxy-a-amino ester HCl salt 5 in 94% yield, and following
basic hydrolysis, the desired b-hydroxy-a-amino acid 6[17]
was obtained. This sequence could also be performed with-
out any purification of the intermediates.
With optimum reaction conditions in hand, we next inves-
tigated the scope of aldehydes (Table 2). Typical aliphatic al-
During the investigations of this aldol reaction, we could
easily observe the retro-aldol process. When we carried out
the reaction at room temperature, the desired aldol product
3a was obtained in moderate yield with very low diastereo-
selectivity (Scheme 3). When we put the product 3a with
Table 2. Aldehyde scope.[a]
Entry
R
anti/syn
Yield [%]
1
2
n-C5H11 (2b)
iPr (2c)
89/11
94/6
92/8
95/5
95/5
94/6
55/45
54/46
–
91
88
90
85
87
74
35
79
NR
53
3
ACHTUNGTRENNUNG(CH3)2CHCH2 (2d)
4
PhCH2 (2e)
5
6
PhCH2CH2 (2 f)
Ph2CH (2g)
7
Ph (2h)
8
9
10
o-O2NC6H4 (2i)
(E)-PhCH=CH (2j)
(E)-CH3CH=CH (2k)
52/48
[a] The reaction was performed using 1a and 2 (1.1 equiv) in THF at
À788C for 15 h in the presence of 4 f (2 mol%). [b] Determined by
1H NMR analysis of the crude mixture. [c] Yield of isolated product.
dehydes, n-hexanylaldehyde (2b), isobutylaldehyde (2c),
and isopentylaldehyde (2d), worked well, similarly to 2a,
and high yields and high diastereoselectivities were obtained
(entries 1–3). The reaction was not sensitive to substitutions
at the a-position of the aldehyde. Aliphatic aldehydes bear-
ing an aromatic ring were also found to be effective, and
good to high yields and high selectivities were observed (en-
tries 4–6). Interestingly, easily enolizable aldehydes, phenyl-
acetoaldehyde (2e) and diphenylacetoaldehyde (2g), gave
the desired products in good yields without significant side
reactions. However, use of aromatic and a,b-unsaturated al-
dehydes was not fruitful, and the desired aldol products
were obtained in low to good yields with quite disappointing
selectivities (entries 7–10). That is presumably because
a retro-aldol process from the aldol product in the reaction
system seemed to be significant when conjugated aldehydes
were employed.
Scheme 3. Consideration of the reaction process.
low diastereomeric ratio under the reaction conditions at
À788C, no change in the diastereomeric ratio was observed.
On the other hand, when we put 3a with high diastereo-
meric ratio under the reaction conditions at room tempera-
ture, the ratio dramatically decreased, with some loss of the
product. These results indicate that the aldol reaction pro-
ceeded at À788C under kinetic control to afford the desired
product in high diastereoselectivity, and the diastereomeric
ratio of the product decreased at high reaction temperature
to lead to a low diastereomeric ratio under thermodynamic
control via the retro-aldol process.
The products could be easily converted to the correspond-
ing b-hydroxy-a-amino acid by removal of the fluorenyli-
Finally, the structure of 4 f was investigated by NMR stud-
ies. In THF-d8, the tosyl amide and 4 f showed very different
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Aldol Reactions of Glycine Ester with Aldehydes
Acknowledgements
This work was partially supported by a Grant-in-Aid for Science Re-
search from the Japan Society for the Promotion of Science (JSPS) and
Global COE Program (Chemistry Innovation through Cooperation of
Science and Engineering), the University of Tokyo, MEXT, Japan.
Keywords: aldol reaction · amino acids · base catalyst ·
fluorenylidene · magnesium
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In summary, we have developed highly diastereoselective
direct-type aldol reactions of glycine Schiff bases bearing
a fluorenylidene moiety as a protecting/activating group of
the amino group using only a catalytic amount of base. The
desired reactions proceeded smoothly at low temperature
using the Mg catalyst, and the aldol products were obtained
in high yields with high diastereoselectivities when aliphatic
aldehydes were employed. The activating group was easily
removed to give the corresponding free amino acid. It was
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In
a well-dried 10 mL reaction tube, the tosyl amide (2.4 mg,
0.0080 mmol, 0.040 equiv) was dissolved in anhydrous THF (1.0 mL) and
cooled to À788C. nBu2Mg in heptane (0.0040 mmol, 0.020 equiv) was
then added dropwise to the mixture, and the mixture was stirred at room
temperature. After 30 min stirring, the reaction tube was cooled again to
À788C, and a solution of N-fluorenylidene glycine ester 1a (50 mg,
0.20 mmol, 1.0 equiv) and aldehyde 2 (0.22 mmol, 1.1 equiv) in dry THF
(1.0 mL) were introduced. After 15 h, the reaction was quenched by addi-
tion of sat. NH4Cl (1.0 mL) and extracted with Et2O (5.0 mLꢁ3). The
combined organic layers were then dried over Na2SO4 and concentrated
under vacuum. Finally the crude material was purified by column chro-
matography (deactivated silica gel (10% of water)) using a mixture of
Et2O/hexane to give the corresponding aldol product.
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Received: January 24, 2012
Published online: && &&, 0000
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ÝÝ These are not the final page numbers!

COMMUNICATION
Aldol Reactions
Raphaꢀl Rahmani,
Masatoshi Matsumoto,
Yasuhiro Yamashita,
Shu¯ Kobayashi*
&&&& — &&&&
Direct-Type Aldol Reactions of Fluo-
renylidene-Protected/Activated
Glycine Esters with Aldehydes for the
Synthesis of b-Hydroxy-a-amino Acid
Derivatives
Two birds with one stone: Magnesium-
base-catalyzed highly diastereoselec-
tive direct-type aldol reaction of gly-
cine Schiff base bearing a fluorenyli-
dene moiety as a protecting and acti-
vating group was developed. The
desired reactions proceeded smoothly
at low temperature, and the aldol
products were obtained in high yield
with high diastereoselectivity.
Chem. Asian J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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These are not the final page numbers! ÞÞ