An alternative synthesis of some carbohydrate α-amino acids

Article abstract of DOI:10.1071/CH03214

Several carbohydrate ketones have been converted into their trichloromethyl-branched tertiary alcohols. A subsequent treatment of these alcohols under Corey-Link conditions (base, sodium azide, methanol) has given rise to α-azido esters, transformable int

Full text of DOI:10.1071/CH03214

Rapid Communication
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2004, 57, 25–28
An Alternative Synthesis of Some Carbohydrate α-Amino Acids
Grant S. Forman,A Adrian Scaffidi,A and Robert V. StickA,B
A Chemistry, School of Biomedical and Chemical Sciences, University of Western Australia,
Perth WA 6009, Australia.
B Author to whom correspondence should be addressed (e-mail: rvs@chem.uwa.edu.au).
Several carbohydrate ketones have been converted into their trichloromethyl-branched tertiary alcohols. A sub-
sequent treatment of these alcohols under Corey–Link conditions (base, sodium azide, methanol) has given rise to
α-azido esters, transformable into azido acids, amino esters, and amino acids. An amino ester and an azido acid
have been coupled to form a dipeptide.
Manuscript received: 27 August 2003.
Final version: 28 October 2003.
The Corey–Link reaction provides a ready access to α-azido
esters, which are direct precursors of α-amino acids
(Scheme 1).[1–3] We were interested in applying such a
sequence to some carbohydrate substrates, in the hope
of synthesizing some carbohydrate α-amino acids, rare
examples within a general class of carbohydrate containing
both amine and carboxylic acid functional groups.[4,5]
The Strecker synthesis converts the aldehyde 1 into the
amino nitrile 2 (Scheme 2);[6] a similar procedure applied
to the ketone 3 gives only the cyanohydrin 4—titanium(iv)
isopropoxide must be employed to ensure intermediate imine
formation and, subsequently, the addition of trimethylsilyl
cyanide provides the amino nitrile 5.[7] Although 2 is formed
as a mixture of diastereoisomers, the amino nitrile 5 confers
the (R)-configuration on the α-carbon of the derived amino
acid 6.
amino ester 10, the azido acid 11, and the α-amino acid 7.
The configuration of 11, and hence 9, 10, and 7 by deduction,
was again determined from a single-crystal X-ray structure
determination. It is noteworthy that the stereoselectivity of
the initial nucleophilic addition to 3 (to form 8) is guided by
its well-established stereochemical bias, and that the sub-
sequent Corey–Link reaction proceeded with inversion of
configuration at C3 (Scheme 1).
With such an excellent result in hand for the ketone 3,
we expanded our horizons to the even more stereochemi-
cally biased ketone 12, easily obtained from the alcohol 13[9]
(Scheme4).Theadditionof chloroformto 12 gave the alcohol
14 and the subsequent Corey–Link reaction gave the azido
ester 15. Further transformations of 15 then provided 16–18,
with the stereochemistry determined by X-ray analysis for 14
and 17.
The dual appeal of the Corey–Link reaction was that it
would not only offer some new chemistry as applied to car-
bohydrates but also probably provide amino acids with the
oppositeconfigurationattheα-carbon(tothenormalStrecker
product), namely of (S)-configuration in 7 (Scheme 3).
In our initial investigation, the ketone 3[8] (Scheme 3)
was converted into the alcohol 8 [the use of lithium
bis(trimethylsilyl)amide was essential to achieve a good
yield[3]], with the configuration of the newly formed stereo-
genic centre established by a single-crystal X-ray structure
determination. The subsequent Corey–Link reaction pro-
vided the azido ester 9 and this could be converted into the
For pyranose examples, we prepared the alcohols 19, 20
(utilizing an improved procedure recently described[10]), and
21[11] (Scheme 5).These three alcohols were easily converted
into their corresponding ketones, and then subsequently into
the alcohols 22–24. The Corey–Link reaction on the alcohols
22 and 23 provided the azido esters 25 and 26, respectively,
and the subsequent general transformations on 25 and
26 provided the suites of compounds 27–29 and 30–32,
respectively. X-ray analysis of 22 and 26 confirmed the
configuration of the new stereogenic centre in these two com-
pounds, and strongly supports the assignments of 23, 25,
27–29, and 30–32.
+
CCl3
NH3
N3
Corey–Link
Cl2C
base, NaN3
ROH
CO2–
OH
CO2R
O
Scheme 1. Overview of the Corey–Link reaction.
© CSIRO 2004
10.1071/CH03214
0004-9425/04/010025

26
G. S. Forman, A. Scaffidi and R. V. Stick
NH2
O
O
CN
CHO
O
O
O
(a)
O
O
O
O
O
1
2
O
O
O
O
O
CN
(b)
O
O
O
O
O
OH
O
3
4
(c)
O
O
O
O
O
O
O
O
CO2–
CN
O
(d )
hydrolysis
O
O
+ O
O
NH2
O
NH3
HN
O
5
6
Scheme 2. (a) KCN, NH3, THF, H2O. (b) KCN, (NH4)2CO3, MeOH, H2O. (c) Ti(OPri)4, NH3, MeOH. (d) Me3SiCN.
O
O
O
O
O
O
(a)
O
CCl3
(b)
O
(d)
O
NH2
3
N3
O
O
O
O
O
O
OH
MeO2C
MeO2C
8
9
10
(c)
O
O
O
O
O
O
(d)
NH3+
N3
HO2C
O
O
O
O
CO2–
11
7
Scheme 3. (a) CHCl3, (Me3Si)2NLi, THF. (b) DBU, NaN3, [18]crown-6, MeOH. (c) KOH, MeOH. (d) H2, Pd/C, MeOH.
The configuration of C4 in the alcohol 24 is not con-
gave the dipeptide 33 in excellent yield (Scheme 6). This
result bodes well for the synthesis of oligomers, in both
acyclic and cyclic forms.
firmed, but suggested. Somewhat perplexingly, treatment of
24 under Corey–Link conditions gave no recognizable car-
bohydrate product—only amounts of benzyl alcohol were
isolated! Further investigation is obviously warranted.
Finally, we report a very preliminary result in our plans for
these carbohydrate amino acids. Treatment of the amine 10
andtheacid 11inpyridinewith4-toluenesulfonylchloride[12]
Experimental
General experimental procedures have been given previously.[13]
Typical procedures are described below for the series beginning with
the ketone 3.

Alternative Synthesis of Carbohydrate α-Amino Acids
27
O
CCl3
O
O
OH
(b)
(a)
O
O
O
O
OH
O
O
O
O
O
O
O
O
O
13
12
14
(c)
O
R
+
–
O
R
N3
N3
NH2
NH3
CO2
18
RЈ
O
RЈ
CO2Me CO2H CO2Me
15 16 17
O
O
Scheme 4. (a) Pyridinium dichromate, Ac2O, CH2Cl2. (b) CHCl3, (Me3Si)2NLi, THF. (c) Corey–Link sequence (Scheme 3).
OBn
Ph
Ph
O
O
O
O
O
HO
BnO
O
O
BnO
HO
BnO
HO
BnO
OMe
OMe
OMe
19
20
21
OBn
OH
Ph
O
Ph
O
R
O
O
O
O
Cl3C
BnO
O
R
BnO
BnO
BnO
RЈ
RЈ
OMe
OMe
OMe
24
22
25
27
28
29
R ϭ CCI3
N3
23 RЈ ϭ OH
26
30
31
32
CO2Me
CO2H
N3
NH2
NH3+
CO2Me
–
CO2
Scheme 5. Compounds 19–32.
14 mmol) and CHCl3 (7.0 mL, 85 mmol) in THF (80 mL) at −78◦C.
The resulting solution was stirred at −78◦C (1 h) before being diluted
with saturated NaHCO3 solution. Usual workup (CH2Cl2) followed by
flash chromatography (EtOAc/petrol, 1 : 4) afforded the alcohol 8 as
prisms (4.4 g, 83%), mp 137–139◦C (Et2O), [α]D+34.7◦ (Found: C 41.0,
H 5.0. C13H19Cl3O6 requires C 41.3, H 5.1%). δH (300 MHz) 1.36, 1.43,
1.45, 1.63 (12H, s × 4, CH3), 3.85 (s, OH), 3.90 (dd, J6,6 8.6, J5,6 7.0,
H6), 4.13 (d, J4,5 8.3, H4), 4.14 (dd, J5,6 5.8, H6), 4.78 (m, H5), 4.79,
5.90 (ABq, J1,2 4.4, H1, H2). δC (75.5 MHz) 25.5, 26.4, 26.6, 26.9 (4C,
CH3), 67.9 (C6), 71.9, 82.0, 85.0 (C2, C4, C5), 87.6 (C3), 100.9 (CCl3),
104.0 (C1), 109.9, 113.3 (2C, C(CH3)2). HR-MS m/z (FAB) 377.0307;
O
O
O
N3
O
O
O
O
O
O
CO
O
NH
MeO2C
•
[M+H]+ requires 377.0325.
33
(3S)-3-C-Azido-3-deoxy-1,2:5,6-di-O-isopropylidene-
3-C-methoxycarbonyl-α-D-ribo-hexose 9
Scheme 6. Compound 33.
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU; 5.7 mL, 38 mmol) was
added to the alcohol 8 (2.9 g, 7.7 mmol), NaN3 (1.5 g, 23 mmol) and
[18]crown-6 (12 mg, 0.04 mmol) in MeOH (60 mL). The resulting solu-
tion was stirred at 50◦C (1 h) before being diluted with saturated NH4Cl
1,2:5,6-Di-O-isopropylidene-3-C-trichloromethyl-α-D-allose 8
Lithium bis(trimethylsilyl)amide (LiHMDS; 1.0 M) in tetrahydrofuran
(THF; 20 mL, 20 mmol) was added dropwise to the ketone 3 (3.7 g,

28
G. S. Forman, A. Scaffidi and R. V. Stick
solution. Usualworkup(EtOAc)gaveayellowresiduethatwassubjected
to flash chromatography (EtOAc/petrol, 1 : 4) to furnish the azide 9 as a
colourless oil (2.4 g, 91%), [α]D +80.7◦, vmax (film)/cm−1 2120 (N3),
1740 (C=O). δH (300 MHz) 1.32, 1.38, 1.53 (12H, s × 3, CH3), 3.82 (s,
OCH3), 4.02 (dd, J6,6 8.8, J5,6 4.4, H6), 4.10 (dd, J5,6 4.2, H6), 4.20
(m, H5), 4.62 (d, J4,5 7.3, H4), 4.64, 5.98 (ABq, J1,2 3.6, H1, H2). δC
(75.5 MHz) 24.9, 26.1, 26.4, 26.8 (4C, CH3), 52.9 (OCH3), 66.9 (C6),
73.1, 81.3, 85.1 (C2, C4, C5), 74.4 (C3), 105.0 (C1), 109.6, 113.5 (2C,
(3S)-3-C-Azido-3-deoxy-3-C-hydroxycarbonyl-
1,2:5,6-di-O-isopropylidene-α-D-ribo-hexose 11,
Amide with (3S)-3-C-Amino-3-deoxy-1,2:5,6-di-O-isopropylidene-
3-C-methoxycarbonyl-α-D-ribo-hexose 10 (33)
Tosyl chloride (116 mg, 0.60 mmol) was added to the acid 11 (100 mg,
0.30 mmol) and the amine 10 (96 mg, 0.30 mmol) in pyridine (2 mL)
at 0◦C. The resulting solution was stirred at 25◦C (12 h) before being
diluted with saturated NaHCO3 solution. Usual workup (CH2Cl2) fol-
lowed by flash chromatography (EtOAc/petrol, 2 : 3) furnished the
dipeptide 33 as cubes (147 mg, 77%), mp 183–185◦C (EtOAc/pentane),
[α]D +65.1◦, vmax (KBr)/cm−1 3270 (NH), 2120 (N3), 1740 (OC=O),
1680 (NHC=O). δH (300 MHz) 1.23, 1.27, 1.29, 1.33, 1.34, 1.42, 1.48,
1.53 (24H, s × 8, CH3), 3.77 (s, OCH3), 3.95 (dd, J6,6 8.9, J5,6 6.2,
H6),[14] 4.03–4.37 (6H, m, H4–H6, H5ꢀ, H6ꢀ), 4.76, 5.81 (ABq, J1,2 3.5,
•
C(CH3)2), 166.7 (CO2CH3). HR-MS m/z (FAB) 344.1478; [M+H]+
requires 344.1458.
(3S)-3-C-Amino-3-deoxy-1,2:5,6-di-O-isopropylidene-
3-C-methoxycarbonyl-α-D-ribo-hexose 10
10% Pd/C (54 mg) was added to the azide 9 (540 mg) in MeOH
(10 mL) and the mixture stirred under a hydrogen atmosphere at room
temperature (16 h). Removal of the solvent gave a black residue that
was subjected to flash chromatography (Et3N/EtOAc/petrol, 1 : 8 : 12)
to yield the amine 10 as a colourless gum (490 mg, 98%), [α]D +3.8◦,
vmax (film)/cm−1 1740 (C=O). δH (300 MHz) 1.23, 1.24, 1.31, 1.42
(12H, s × 4, CH3), 1.82 (bs, NH2), 3.70 (s, OCH3), 3.92 (m, H6), 4.05–
4.13 (2H, m, H5, H6), 4.23, 5.90 (ABq, J1,2 3.8, H1, H2), 4.62 (d, J4,5
8.3, H4). δC (75.5 MHz) 24.9, 25.9, 26.6, 26.7 (4C, CH3), 52.1 (OCH3),
67.8 (C6), 68.0 (C3), 73.2, 81.8, 88.4 (C2, C4, C5), 105.5 (C1), 109.5,
112.7 (2C, C(CH3)2), 171.9 (CO2CH3). HR-MS m/z (FAB) 318.1551;
H1, H2), 4.82 (d, J4 ,5 8.6, H4ꢀ), 5.27, 6.23 (ABq, J1 ,2 4.0, H1ꢀ, H2ꢀ),
8.02 (bs, NH). δC (75.5 MHz) 25.2–26.6 (8C, CH3), 52.7 (OCH3), 67.2,
67.8 (C6, C6ꢀ), 71.5, 73.8, 80.6, 83.1, 84.9, 86.0 (C2, C2ꢀ, C4, C4ꢀ, C5,
C5ꢀ), 72.5, 75.4 (C3, C3ꢀ), 103.5, 106.9 (C1, C1ꢀ), 109.3, 110.8, 112.0,
113.3 (4C, C(CH3)2), 164.2, 168.0 (2C, C=O). HR-MS m/z (FAB)
ꢀ
ꢀ
ꢀ
ꢀ
•
629.2694; [M + H]+ requires 629.2670.
Acknowledgements
We thank Professor Allan H. White and Dr Brian W. Skelton
for the X-ray investigations, and the University of Western
Australia for financial assistance.
•
[M + H]+ requires 318.1553.
(3S)-3-C-Azido-3-deoxy-3-C-hydroxycarbonyl-
1,2:5,6-di-O-isopropylidene-α-D-ribo-hexose 11
References
KOH (400 mg, 7.1 mmol) in MeOH (20 mL) was added to the azide 9
(1.0 g, 2.9 mmol) and the solution stirred at 25◦C (1 h).Water was added,
followed by evaporation of the MeOH and addition of 1 M HCl until pH
4. Usual workup (EtOAc) afforded the acid 11 as prisms (896 mg, 92%),
mp 128–130◦C (Et2O), [α]D +86.9◦, vmax (KBr)/cm−1 2120 (N3), 1730
(C=O) (Found: C 47.5, H 5.9, N 12.4. C13H19N3O7 requires C 47.4,
H 5.8, N 12.8%). δH (300 MHz) 1.32, 1.33, 1.39, 1.53 (12 H, s × 4,
CH3), 4.03 (dd, J6,6 8.9, J5,6 4.5, H6), 4.12 (dd, J5,6 6.2, H6), 4.24 (m,
H5), 4.60 (d, J4,5 7.5, H4), 4.68, 5.95 (ABq, J1,2 3.7, H1, H2), 9.14
(bs, OH). δC (75.5 MHz) 24.9, 25.8, 26.4, 26.7 (4C, CH3), 66.8 (C6),
73.0, 81.2, 85.0 (C2, C4, C5), 74.2 (C3), 105.0 (C1), 109.9, 113.7 (2C,
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de Souza Filho, Synth. Commun. 1996, 26, 1015.
•
C(CH3)2), 170.8 (CO2H). HR-MS m/z (FAB) 330.1306; [M + H]+
requires 330.1301.
[7] D. Postel, A. N. Van Nhien, P. Villa, G. Ronco, Tetrahedron
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6214.
(3S)-3-C-Amino-3-deoxy-3-C-hydroxycarbonyl-
1,2:5,6-di-O-isopropylidene-α-D-ribo-hexose, zwitterion 7
10% Pd/C (10 mg) was added to the acid 11 (100 mg) in MeOH
(15 mL) and the mixture stirred under a hydrogen atmosphere at room
temperature (16 h). Filtration through Celite, evaporation of the fil-
trate, and flash chromatography (EtOAc/MeOH, 1 : 1) of the residue
yielded the amino acid 7 as needles (89 mg, 97%), mp 140–142◦C (dec.)
(EtOAc/pentane), [α]D +71.5◦. δH (300 MHz, CD3OD)1.28, 1.30, 1.40,
1.52 (12H, s × 4, CH3), 3.97 (dd, J6,6 8.3, J5,6 5.8, H6), 4.10 (dd, J5,6
6.4, H6), 4.22 (ddd, J4,5 6.0, H5), 4.45, 5.90 (ABq, J1,2 3.8, H1, H2),
4.81 (d, H4). δC (75.5 MHz, CD3OD) 25.5, 26.5, 27.0, 27.2 (4C, CH3),
67.9 (C3), 70.2 (C6), 75.2, 82.7, 88.3 (C2, C4, C5), 106.1 (C1), 110.6,
113.8 (2C, C(CH3)2), 173.2 (CO2H). HR-MS m/z (FAB) 304.1412;
[13] J. C. McAuliffe, R. V. Stick, Aust. J. Chem. 1997, 50, 193.
[14] It was not possible to assign unambiguously any of the ring
hydrogen atoms to the amine or the acid portion of the molecule.
•
[M + H]+ requires 304.1396.