Enantioselective organocatalysis of Strecker and Mannich reactions based on carbohydrates

Article abstract of DOI:10.1002/adsc.200600370

Efficient organocatalysts for enantioselective Strecker and Mannich reactions were constructed from glucosamine as a readily accessible chiral scaffold. A variety of aromatic aldimines were subjected to hydrocyanation with good to excellent yield (72-98%)

Full text of DOI:10.1002/adsc.200600370

FULL PAPERS
DOI: 10.1002/adsc.200600370
Enantioselective Organocatalysis of Strecker and Mannich
Reactions Based on Carbohydrates
Christian Becker,a Christine Hoben,a and Horst Kunza,*
a
Institut für Organische Chemie, Johannes Gutenberg-Universität, Duesbergweg 10-14, 55128 Mainz, Germany
Fax : (+49)-6131-392-4786; e-mail: hokunz@uni-mainz.de
Received: July 21, 2006
Dedicated to Professor Joachim Thiem on the occasion of his 65th birthday.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Efficient organocatalysts for enantioselec- the monosaccharidic backbone. In the asymmetric
tive Strecker and Mannich reactions were construct- Mannich reaction moderate yields (up to 76%) and
ed from glucosamine as a readily accessible chiral enantioselectivities (up to 58% ee) have been ach-
scaffold. A variety of aromatic aldimines were sub- ieved with the described catalyst.
jected to hydrocyanation with good to excellent yield
(72–98%) and, in part, high enantioselectivity (69–
95% ee). Influence of the catalyst architecture on Keywords: carbohydrate scaffolds; enantioselective
the enantioselectivity obviously arises from restric- organic catalysis; glucosamine derivatives; Mannich
tions imposed on the conformational flexibility of reaction; Strecker reaction
Introduction
Results and Discussion
During the past decade, a number of enantioselective Hydrocyanation of Imines (Strecker Reaction):
transformations of organic compounds promoted by Synthesis of the Catalyst
metal-free organocatalysts have been described.[1] Al-
though carbohydrates meet all requirements put on As was shown by Jacobsen et al.[2] 1,2-trans-diamino-
such an organocatalyst, no example of organocatalysis cyclohexane in combination with urea and thiourea
with a carbohydrate was reported so far. Carbohy- functions[2,3] as hydrogen bridge-forming groups can
drates, i.e., monosaccharides, are conformationally furnish efficient organocatalysts suitable for enantio-
stable, multifunctional, cheap and readily available. selective hydrogenation of imines (Strecker reaction).
Besides their high density of chiral information on Optimized catalysts[3b,e] contain a salicylaldimine and
one molecular unit, they offer a number of functional a urea side-chain linked to the diaminocyclohexane
groups useful for variation and optimization of the backbone. Enantiomerically pure 1,2-trans-diaminocy-
catalysts performance, e.g., by introducing additional clohexane is obtained from inexpensive mixtures of
stereodifferentiating groups or for immobilization on stereoisomeric 1,2-diaminocyclohexanes by resolution
a polymer support.
of their diastereomeric salts with tartaric acid. Never-
We herein report the synthesis of an efficient orga- theless, enantiomerically pure glucosamine 1 which is
nocatalyst based on a carbohydrate. It was obtained readily accessible from chitin is considered an attrac-
by structural modifications of d-glucosamine and ap- tive alternative backbone structure for the construc-
plied to the asymmetric hydrocyanation of imines and tion of this type of catalysts. Due to its polyfunction-
the Mannich reaction.
ality, the carbohydrate can easily be modified in order
to perform structure-efficiency relationship studies.
By introduction of a second amino function, 1 offers
four principal possibilities of arranging a Schiff base
and a urea-derived side-chain as the optimal combina-
tion reported in the literature[3b,e] for enantioselective
Strecker reactions (Figure 1).
Adv. Synth. Catal. 2007, 349, 417 – 424
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Christian Becker et al.
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Figure 1. Possible Jacobsen-type organocatalysts not derived from 1,2-trans-diaminocyclohexane, but from d-glucosamine.
Scheme 1. Synthesis of the glucosamine-derived catalyst 11.
In order to synthesize a type A+ catalyst, the with trimethylsilyl azide[6] to give glycosyl azide 6.
amino function of d-glucosamine 1 was protected as Formation of the urea linkage with the l-tert-leucine
the p-anisaldimine 2 which was acetylated to give benzylamide 7 was achieved by a Staudinger-aza-
compound 3 as the b-anomer. After acid-catalyzed Wittig-type reaction according to PintØr[7] and yielded
hydrolysis of the imine, the allyloxycarbonyl (Aloc)[4] N-glycosylurea derivative 8. Palladium(0)-catalyzed
group was introduced into amine 4 to furnish allyl car- removal of the Aloc group to give 9 and condensation
bamate 5.[5] Compound 5 is sufficiently stable to the with salicylaldehyde derivative 10[8] furnished the de-
conditions required for the SnCl4-catalyzed reaction sired catalyst 11 (Scheme 1).
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Enantioselective Organocatalysis of Strecker and Mannich Reactions
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Table 2. The results for the asymmetric Strecker reaction to
give 12r with different catalysts.
Entry Catalyst
T
Yield of 12r [%] ee [%][a,d]
1
2
3
4
5
6
7
8
9
11 (2 mol%) ꢀ708C 86
13 (5 mol%) ꢀ708C 100[b]
14 (4 mol%) ꢀ508C 64
15 (2 mol%) ꢀ508C 85
16 (8 mol%) ꢀ508C 35
17 (4 mol%) ꢀ508C 30
18 (2 mol%) ꢀ708C 45
19 (8 mol%) ꢀ508C 54
20 (2 mol%) ꢀ708C 18
95 (S)
15[c] (S)
30 (S)
23 (R)
12 (R)
15 (S)
36 (S)
4 (S)
10 (S)
Scheme 2. Strecker reaction of aldimines catalyzed with glu-
cosaminylurea derivative 11.
[a]
Determined by HPLC analysis using commercial chiral
columns.
[b]
[c]
1
Determined after 24 h by H NMR.
Glucosaminylurea derivative 11 proved to be an ef-
ficient catalyst for the asymmetric hydrocyanation of
a broad range of aldimines (Scheme 2 and Table 1).
As shown in Table 1, the Strecker reactions of ald-
imines of aromatic aldehydes (entries 1–14, 16, 18)
proceeded with high yield and enantiomeric excess up
Determined by optical rotation and comparison with the
literature.[3a)]
[d]
Assignment of the absolute configuration based on the
literature.[3a)]
to 84% at ꢀ508C (not at ꢀ708C as performed by Ja- was achieved with the glucosamine-derived catalyst
cobsen et al.[3a]). Aliphatic aldimines (entry 15) or ke- 11 (Table 2, entry 1)
timines (entry 17) only reacted with moderate enan-
tioselectivitiy. The electron-withdrawing p-nitro sub-
stituent (entry 11) gave rise to racemization of the Strecker Reaction: Structural Variations of the
formed nitrophenylglycinonitrile during the reaction. Catalyst
In the case of the reactive furfuryl derivative
(entry 12), the non-catalyzed transformation took Effects of structural variations of catalyst 11 on the
place to a perceptible extent resulting in a moderate enantioselectivity of the Strecker reaction were inves-
enantiomeric excess of only 50%.
tigated with nine representative compounds
In the Strecker reaction of benzaldimine 12r at (Figure 2). Structure modifications concerned the po-
ꢀ708C under conditions applied by Jacobsen et al.[3a] sition of the functional side-chains (Figure 2, 13, 14,
high yield and an excellent enantioselectivity of 95% 15) and alterations of the protecting group pattern of
Table 1. The results of the enantioselective Strecker reaction with various aldimines.
Entry
Product
R1
R2
R3
Yield [%]
ee [%][a]
1
2
3
4
5
6
7
8
12a
12b
12c
12d
12e
12f
12g
12h
12i
12j
12k
12l
12 m
12n
12o
12p
12q
12r
2-Me-C6H4
3-Me-C6H4
4-Me-C6H4
2-MeO-C6H4
3-MeO-C6H4
4-MeO-C6H4
2-Br-C6H4
allyl
allyl
allyl
allyl
allyl
allyl
allyl
allyl
allyl
allyl
allyl
allyl
allyl
allyl
benzyl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
81
93
83
98
96
79
69
83
77
82
67
87
78
73
60
97
63
72
69
78
75
64
66
82
72
74
84
84
0
50
80
76
47
86
50
84
3-Br-C6H4
4-Br-C6H4
9
10
11
12
13
14
15
16
17
18
4-t-Bu-C6H4
4-NO2-C6H4
2-furfuryl
1-naphthyl
2-naphthyl
cyclohexyl
6,7-dimethoxyisoquinoline
Ph
Ph
4-Br-C6H4CH2
allyl
[a]
Determined by HPLC analysis using commercial chiral columns.
Adv. Synth. Catal. 2007, 349, 417 – 424
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Christian Becker et al.
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Figure 2. Varied organocatalysts based on glucosamine.
the carbohydrate scaffold (Figure 2, 16, 17, 18, 20) as
well as immobilization of the catalyst on a solid sup-
port (Figure 2, 16, 17, 19).
Compound 13 was synthesized from 1 by forming
its p-nitrophenoxycarbonyl derivative prior to the in-
troduction of the anomeric azido group.[9] The 2,3-di-
aminoglucose derivatives 14 and 15 were formed from
the 3-azido precursor obtained by a double inversion
of configuration at position 3 of the corresponding
glucosamine derivative.[10] For the formation of the
compounds modified in the carbohydrate protecting
Scheme 3. Strecker synthesis of amino nitrile 12r catalyzed
by varied glucosamine-derived catalysts.
The anticipated inverse induction of the aminoni-
group pattern, compound 8 was deacetylated by Zem- trile configuration was not observed. This result gives
plØn transesterification. The product deblocked at the evidence that the carbohydrate is not just a cyclohex-
hydroxy functions was subjected to appropriate pro- ane surrogate. The exo-anomeric effect, that is, the
tecting group manipulations and immobilization reac- delocalization of p-electrons of the nitrogen substitu-
tions.[11] The results of enantioselective Strecker reac- ent in the anomeric position, in 11 enhances the NH-
tions catalyzed by 11 and its variants 13–20 are sum- acidity. In 13, however, it reduces the electron density
marized in Scheme 3 and Table 2.
of the imine nitrogen (Figure 3) and its ability to form
Reversal of the localization of the functional side- a hydrogen bond to the phenol hydroxy group which
chains in glucosaminylamine catalyst 11 leads to cata- spatially fixes the salen structure.
lyst 13. However, its use in the Strecker reaction
Moving the functional side chains from the 1,2 posi-
under identical conditions (Table 2, entries 1 and 2) tion (11) to the 2,3 position resulted in a catalyst 14
resulted in a tremendous decrease of enantioselectivi- which also induced prevailing formation of (S) amino-
ty.
nitrile 12r, however, with distinctly lower enantiose-
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Enantioselective Organocatalysis of Strecker and Mannich Reactions
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Figure 3. Effect of p-electron delocalization on the electron
density of the imine in catalyst 13.
lectivity. In compound 15 the urea-type and the salen
side-chains are in reversed positions. This catalyst in-
duced opposite enantioselectivity (entry 4), but again
with low efficiency. The moderate selectivity presuma-
bly also arises from the diminished flexibility of 14
and 15 due to the benzylidene acetal in position 4 and
Scheme 4. Mannich reaction catalyzed by glcosamine-de-
rived catalysts 11.
6 of the carbohydrate which constitutes a rigid hetero- interaction with HCN. In Jacobsenꢁs catalyst such an
decaline framework. interaction is restricted to the catalytic centre. The
The very subtle influence of substituents at the car- only improving effect by the carbohydrate may lie in
bohydrate even of those quite remote from the cata- the higher NH acidity provided the urea function is in
lytic centre on the enantiodifferentiating potency of anomeric position as given in 11.
the catalysts is illustrated in Strecker reactions cata-
lyzed by compounds 16–20 (Table 2, entries 5–9). The
use of catalysts with larger protecting groups and in- Enantioselective Catalysis of the Mannich Reaction
troduction of linkers (18, 20) instead of the O-acetyl
groups resulted in a dramatic decrease of enantiose- Like a-amino acids generated by the Strecker reac-
lectivity. Immobilization on polystyrene[12] either via tion, b-amino acid derivatives accessible, for example,
the carbohydrate (16, 17) or via the amino acid amide via Mannich reactions are important building blocks
(19) yielded catalysts which displayed low enantiose- for the construction of pharmaceutical products and
lectivity. Obviously, these modifications in the pro- natural compounds. Therefore, enantioselective syn-
tecting group pattern force the carbohydrate scaffold theses of these compounds are of interest.[3c,13] Jacob-
to adopt a less favorable conformation. None of these sen et al.[3c] successfully applied their 1,2-diaminocy-
modified catalysts 13–20 reached the high efficiency clohexane-derived catalyst to enantioselective Man-
of Jacobsenꢁs catalyst.[3a,b] or of the organocatalyst 11 nich reactions. Glucosaminylamine-derived catalyst 11
derived from the glucosaminyl azide. In compound proved also efficient in the enantioselective catalysis
11, an enhanced NH acidity may compensate the re- of the Mannich reaction between aldimine 21 and
stricted conformational flexibility compared to the di- silyl ketene acetal 22 (Scheme 4).
aminocyclohexane-derived catalyst. As
a
conse-
The reaction conditions were optimized with regard
quence, this compound is a potent enantioselective to temperature, solvent, equivalents of the enolate
catalyst of the Strecker reaction. Altogether, the ob- (22) and concentration of the reaction solution. At
tained results suggest that the polar functions within ꢀ208C, the yield of b-amino acid ester 23 was satisfy-
the carbohydrate interfere with the enantioselectivity ing (Table 3). The excess of enantiomer remained
of the reaction by offering too many basic centers for moderate (about 50%). In contrast to the results ob-
Table 3. Conditions and results of the enantioselective Mannich reaction with catalyst 11.
Entry
mol% of 11
T
Solvent
c [mol·Lꢀ1]
Equivs. of 22
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
9
5
5
5
5
2
10
5
5
5
ꢀ408C
ꢀ208C
ꢀ208C
ꢀ208C
ꢀ208C
ꢀ208C
ꢀ208C
ꢀ208C
ꢀ208C
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
0.15
0.15
0.40
0.004
0.15
0.15
0.15
0.15
0.15
2
2
2
2
2
2
1.1
1.1
1.1
12
59
53
49[c]
62
73
76
68
51
48
50
48
54
48
58
54
12
0
CH2Cl2
[a]
Yield after 48 h.
[b]
[c]
Determined by HPLC analysis using commercial chiral columns.
Yield after 96 h.
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Christian Becker et al.
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the reaction mixture is stirred for 24 h. After addition of tri-
fluoroacetic anhydride (0.15 mL, 1 mmol), the solution is
warmed to room temperature and stirred for additional 3 h.
After evaporation of the solvent under vacuum the remain-
ing oil is purified by flash chromatography on silica gel.
tained by Jacobsen, lowering the temperature below
ꢀ208C did not improve the enantioselectivity. Best
results were obtained in toluene. In more polar sol-
vents low or no enantioselectivity was observed. The
decreased enantioselectivity of the Mannich reaction
compared to the Strecker reaction may be traced
back to the reduced basicity of the N-acylimine 21
which reduces its affinity to the urea NH groups obvi-
1,3,4,6-Tetra-O-acetyl-b-d-glucosamine Hydrochloride
(Ac4GlcNH2·HCl) (4)
ously essential for binding the substrate to the cata- The product was obtained following a known procedure[14]
.
lyst. After all, the mode of action of the catalyst
which could explain the observed effects of structure
variation remains unclear.
1,3,4,6-Tera-O-acetyl-2-N-(allyloxycarbonyl)-2-amino-
2-deoxy-b-d-glucopyranose [Ac4GlcN(Aloc)] (5)
AHCTREUNG
1,3,4,6-Tetra-O-acetyl-b-d-glucosamine hydrochloride[14] (4)
(20.0 g, 52.1 mmol) is dissolved in water (200 mL) and
NaHCO3 (16.8 g, 200 mmol) is added. To this vigorously stir-
red mixture, a solution of allyl chloroformate (8.30 mL,
78.2 mmol) in chloroform (200 mL) is slowly added drop
wise under stirring. After 4 h the layers are separated and
the watery phase is extracted twice with chloroform (50 mL
each). The combined organic layers are washed with water
(100 mL) and with brine (100 mL). After drying over
MgSO4 the solvent is removed and the resulting viscous oil
is purified by column chromatography on silica gel (EtOAc/
cyclohexane, 1:5!5:1) affording the product as a colorless,
amorphous solid; yield: 18.5 g (82%); Rf =0.48 (CH2Cl2/
EtOAc, 5:1); a]2D0: 16.2 (c 1, CHCl3); 1H NMR (300 MHz,
CDCl3): d=5.89–5.80 (m, 1H, -CH2-CH=CH2), 5.67 (d, J=
8.8 Hz, 1H, H-1), 5.25–5.00 (m, 4H, -CH2-CH=CH2, H-3, H-
4), 4.52 (d, J=4.1 Hz, 2H, -CH2-CH=CH2), 4.25 (dd, J=
4.8 Hz, J=12.5 Hz, 1H, H-6), 4.08 (dd, J=1.8 Hz, J=
12.5 Hz, 1H, H-6’), 3.96–3.86 (m, 1H, H-2), 3.82–3.77 (m,
1H, H-5), 2.08, 2.05, 2.01, 2.00 (s, 3H, CH3); 13C NMR
(50.3 MHz, CDCl3): d=170.8, 170.6, 169.4 (COOCH3), 155.6
(OCONH), 132.5 (-CH2-CH=CH2), 117.7 (-CH2-CH=CH2),
93.2 (C-1), 73.3 (C-3), 73.0 (C-5), 72.8 (-CH2-CH=CH2), 68.1
(C-4), 61.9 (C-6), 54.9 (C-2), 20.8, 20.7, 20.6, 20.5 (CH3);
anal. calcd. for C14H20O8N4: C 50.10, H 5.84, N 3.25; found:
C 49.95, H 6.07, N 3.28.
Conclusions
Efficient organocatalysts for enantioselective Strecker
and Mannich reactions can by constructed from d-glu-
cosamine as a component of the natural chiral pool.
High enantioselectivity in Strecker reactions was only
achieved with the glucosaminylurea derivative 11 car-
rying the salen side-chain in the 2-position. With this
catalyst high yield and enantioselectivity up to 95%
were accomplished in hydrocyanation reactions of ar-
omatic aldimines. The glucosamine derivative 11
proved also able to enantioselectively catalyze the
Mannich reaction of N-Boc-aldimine 21 with silyl
ester enolate 22 to furnish b-amino acid ester 23 with
yields up to 76% and an enantiomeric excess up to
58%. Even slight modification of the carbohydrate-
derived catalyst’s architecture decreased the enantio-
selectivity of the investigated reactions giving evi-
dence of the fact that the polar nature of the carbohy-
drate backbone obviously does not favor enantiodif-
ferentiation in these addition reaction of nucleophiles
to imines.
3,4,6-Tetra-O-acetyl-2-N-(allyloxycarbonyl)-2-amino-
2-deoxy-b-d-glucopyranosyl Azide
[Ac3GlcN(Aloc)N3] (6)
Experimental Section
G
General Procedure for the Preparation of Substrate
Imines
1,3,4,6-Tera-O-acetyl-2-N-(allyloxycarbonyl)-2-amino-2-
deoxy-b-d-glucopyranose (5) (17.3 g, 40.1 mmol) is dissolved
in dry CH2Cl2 (300 mL). To this solution trimethylsilyl azide
(8.0 mL, 61.1 mmol) and tin(iv) chloride (0.87 mL,
6.4 mmol) are added via syringe at room temperature, and
the mixture is stirred for 4 h. The solution is poured into a
saturated NaHCO3 solution (300 mL) and shaken in a sepa-
ratory funnel until evolution of CO2 ceases. The organic
layer is separated, washed with brine (200 mL) and dried
over MgSO4. After removal of the solvent, the resulting vis-
cous oil is purified by column chromatography on silica gel
(CH2Cl2/EtOAc 5:1) affording a colorless, amorphous solid;
yield: 14.1 g (85%); Rf =0.52 (CH2Cl2/EtOAc 5:1); a]20:
ꢀ22.5 (c 1, CH2Cl2); FT-IR (CH2Cl2 thin film): n=3053 (s,Dn
CH), 2973 (s, n CH), 2117 (s, n N3), 1746 (s, n CO), 1520
To a suspension of 3 equivalents of MgSO4 in dry CH2Cl2
equimolar amounts of aldehyde and amine are added and
stirred at room temperature for 20 h. After filtering off the
MgSO4, the solvent is evaporated affording the desired
product in pure form and in quantitative yield.
General Procedure for the Preparation of N-
Substituted a-Aminonitriles 12
To dry toluene (4 mL) TMSCN (0.58 mL, 4.35 mmol) is
added and the solution is cooled to 08C. After addition of
dry methanol (0.86 mL), the solution is stirred at 08C for
1 h. The chosen amount of catalyst and the respective imine
(0.5 mmol) are dissolved in dry toluene (6 mL) and cooled
to the desired reaction temperature. The cyanide solution
(1.27 mL, 1 mmol TMSCN) is added slowly via syringe and
1
cmꢀ1 (m, n NCOO); H NMR (200 MHz, CDCl3): d=5.97–
5.77 (m, 1H, -CH2-CH=CH2), 5.30–5.17 (m, 3H, -CH2-CH=
CH2, NH), 5.10–4.99 (m, 2H, H-3, H-4), 4.77 (d, J=8.8 Hz,
422
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Enantioselective Organocatalysis of Strecker and Mannich Reactions
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1H, H-1), 4.55 (d, J=5.4 Hz, 2H, -CH-CH=CH2), 4.25 (dd,
J=4.6 Hz, J=12.2 Hz, 1H, H-6), 4.12 (dd, J=2.3 Hz, J=
12.2 Hz, 1H, H-6’), 3.81–3.72 (m, 1H, H-5), 3.58 (q, J=
9.8 Hz, 1H, H-2), 2.07, 2.01, 2.00 (s, 3H, CH3); 13C NMR
(50.3 MHz, CDCl3): d=170.6, 169.3 (COOCH3), 155.5
(OCONH), 132.3 (-CH2-CH=CH2), 118.0 (-CH2-CH=CH2),
88.7 (C-1), 74.0 (C-3), 72.0 (C-5), 68.2 (C-4), 66.1 (-CH2-
CH=CH2), 61.9 (C-6), 55.8 (C-2), 20.7, 20.6 (CH3); FD-MS:
m/z=415.9 (55%) [M+H]+, 414.9 (18%) [M]+, 372.8 (7%)
[MꢀN3]+.
other, glacial acetic acid (67 ml, 1.18 mmol) and tri-n-butyltin
hydride (0.15 mL, 543 mmol) are added and the mixture is
stirred at room temperature for 30 min. After evaporation
of the solvent, the residue is co-evaporated twice with tolu-
ene (10 mL each). The resulting oil is dissolved in isopropa-
nol (10 mL). To this solution MgSO4 (30 mg) and 5-tert-
butyl-3-pivaloyloxy-salicylaldehyde[8] (10) (152 mg, 543
mmol) are added. The suspension is heated to 808C for 2 h.
After filtering off the MgSO4 the solvent is removed under
vacuum. The resulting viscous oil is purified by column
chromatography on silica gel (CH2Cl2/EtOAc 4:1) affording
a yellow solid; yield: 366 mg (92%); Rf =0.29 (CH2Cl2/
EtOAc 4:1); a]D20: 19.1 (c 1, CH2Cl2); FT-IR (CH2Cl2 thin
film): n=3341 (br, n OH), 2986 (s, n CH), 1748 (s, n
OCOCH3), 1675 (br, n NHCONH), 1525 cmꢀ1 (br, n
NHCONH); 1H NMR (400 MHz, DMSO-d6): d=13.29 (s,
1H, OH), 8.52–8.49 (t+s, J=5.5 Hz, 2H, -CH=N-,
-NHCH2Ph), 7.17–7.13 (m, 5H, arom), 7.10 (d, J=2.8 Hz,
1H, arom), 6.96–6.94 (m, 2H, arom, -NH-CO-NH), 6.28 (d,
J=9.6 Hz, 1H, -NH-CO-NH), 5.48 (t, J=9.5 Hz, 1H, H-3),
5.36 (t, J=9.5 Hz, 1H, H-1), 4.92 (t, J=9.5 Hz, 1H, H-4),
4.27–4.20 (m, 2H, H-6, -NHCH2Ph), 4.11–4.10 (m, 1H, H-
N-[3,4,6-Tri-O-acetyl-2-N-(allyloxycarbonyl)-2-amino-
2-deoxy-b-d-glucopyranosyl]-carbamoyl-l-tert-
leucinyl-benzylamide (8)
l-tert-Leucine-N-benzylamide (7) (1.19 g, 5.42 mmol) is dis-
solved in dry DMF (30 mL) and the solution is saturated
with dry CO2. Under a constant stream of CO2 a solution of
3,4,6-tetra-O-acetyl-2-N-(allyloxycarbonyl)-2-amino-2-
deoxy-b-d-glucopyranosyl azide (6) (2.16 g, 5.21 mmol) in
dry DMF (5 mL) is added. After 2 min a solution of triphe-
nylphosphine (1.49 g, 5.68 mmol) in dry DMF (10 mL) is
slowly added while CO2 is constantly bubbled through the
solution. After 7 h the solvent is removed and the resulting
viscous oil is purified by column chromatography on silica
gel (CHCl3/acetone 10:1) affording a colorless, amorphous
solid; yield: 3.11 g (94%); Rf =0.29 (CHCl3/acetone 10:1);
5), 4.09–4.07 [m, 1H, -CHC
12.3 Hz, 1H, H-6’), 3.42 (t, J=9.5 Hz, 1H, H-2), 1.99, 1.97,
1.86 (s, 3H, -OCOCH3), 1.33 [s, 9H, -OCOC(CH3)3], 1.28 [s,
9H, -C(CH3)3], 0.83 [s, 9H, -CHC
(CH3)3]; 13C NMR (100.6
MHz, DMSO-d6): d=170.5, 169.9, 169.4, 169.1, 168.7
[-OCOCH3, -CONHCH2Ph, -OCOC(CH3)3], 157.1 (-CH=
N-), 156.0 (-NHCONH-), 141.7, 139.1, 137.7, 123.3, 122.2 [C-
(quart)], 128.0, 127.3, 126.6, 117.2 (C arom), 79.9 (C-1), 73.3
(C-3), 71.6 (C-5), 70.9 (C-2), 68.2 (C-4), 62.0 (C-6), 59.8[-
CHC(CH3)3], 42.0 (-NHCH2Ph), 38.4 [-OCOC(CH3)3], 34.5
(CH3)3], 26.4
A
AHCTREUNG
A
ACHTREUNG
1
a]2D0: 16.6 (c 2, CH2Cl2); H NMR (400 MHz, DMSO-d6): d=
AHCTREUNG
8.59 (t, J=5.8 Hz, 1H, -NH-CH2Ph), 7.44 (d, J=9.8 Hz, 1H,
-NH-COO-), 7.31–7.21 (m, 5H, arom), 6.88, 6.64 (d, J=
9.8 Hz, 1H, -NH-CO-NH-), 5.88–5.81 (m, 1H, -CH2-CH=
CH2), 5.20–5.11 (m, 2H, -CH2-CH=CH2), 5.05 (t, J=9.8 Hz,
1H, H-3), 4.96 (t, J=9.8 Hz, 1H, H-1), 4.80 (dd, J=9.8 Hz,
J=9.4 Hz, 1H, H-4), 4.51 (dd, J=5.0 Hz, J=14.1 Hz, 1H,
-CH2-CH=CH2), 4.40 (dd, J=4.9 Hz, J=14.1 Hz, 1H, -CH2-
CH=CH2), 4.32 (dd, J=6.2 Hz, J=14.9 Hz, 1H, H-6), 4.24–
4.13 (m, 2H, H-6’, -CH2-NHCH2Ph), 4.06 [d, J=9.7 Hz, 1H,
AHCTREUNG
ACHTREUNG
A
ACHTREUNG
[-CHC
G
(CH3)3], 26.7 [-OCOC
ACHTREUNG
[-CHC(CH3)3], 20.5, 20.4, 20.2 (-OCOCH3); FD-MS: m/z=
E
811.8 (91%) [M+H]+; anal. calcd. for C42H58O12N4: C 62.21,
H 7.21, N 6.91; found: C 61.85, H 7.23, N 6.72.
Typical Procedure for the Catalyzed Mannich
Reaction: 3-tert-Butyloxycarbonylamino-3-(2-
naphthyl)-isopropyl Propionate (23)
-CH
(m, 1H, H-5), 3.49 (q, J=9.9 Hz, 1H, H-2), 1.97, 1.94, 1.89
(s, 3H, -OCOCH3), 0.84 [s, 9H, -CHC
(CH3)3]; 13C NMR
(100.6 MHz, DMSO-d6): d=170.7, 169.9, 169.4, 169.2
(-OCOCH3, -CONH-), 156.3 (-NHCONH-), 155.8
(-NHCOO), 139.2 (C arom), 133.4 (-CH2-CH=CH2), 128.1,
127.4, 126.7 (C arom), 116.6 (-CH2-CH=CH2), 79.9 (C-1),
73.7 (C-3), 71.6 (C-5), 68.6 (C-4), 64.3 (-CH2-CH=CH2), 61.9
G
A solution of 21 (29 mg, 114 mmol) and catalyst 11 (e.g., 5
mol%: 4.6 mg, 5.7 mmol) in dry toluene (e.g., c=0.15
mol·Lꢀ1: 0.8 mL) is cooled to the desired reaction tempera-
ture. Over a period of 10 min, via syringe, 22 (e.g., 1.1
equivs., 27 mg, 125 mmol) is added, and the reaction mixture
is stirred for 48 h at the respective reaction temperature.
After evaporation of the solvent, the residue is purified by
column chromatography on silica gel (EtOAc/cyclohexane,
1:10); Rf =0.23 (EtOAc/cyclohexane 1:10) to give 23 (see
Table 3).
(C-6), 59.9 [-CHC
34.4 [-CHC
C
G
5-tert-Butyl-3-pivaloyloxy-salicylaldehyde (10)
The product was obtained following a known procedure.[8]
Acknowledgements
N-[3,4,6-Tri-O-acetyl-2-N-(3’-tert-butyl-2’-hydroxy-5’-
pivaloyloxybenzylidene)-2-amino-2-deoxy-b-d-
glucopyranosyl]-carbamoyl-l-tert-leucinyl-
benzylamide (11)
This work was supported by the Deutsche Forschungsgemein-
schaft and the Fonds der Chemischen Industrie.
To a solution of (8) (313 mg, 493 mmol) in CH2Cl2 (10 mL)
Pd(PPh3)4 (11 mg, 9.4 mmol) is added. Quickly one after the
A
Adv. Synth. Catal. 2007, 349, 417 – 424
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
423

Christian Becker et al.
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