Syntheses of guanidinoglycosides with the inventive use of Mitsunobu conditions and 1,8-diazabicyclo[5.4.0]undec-7-ene

Article abstract of DOI:10.1055/s-2003-36815

A series of novel guanidinoglycosides was successfully synthesized. This was accomplished with the use of Mitsunobu conditions as a strategy to convert the glycopyranose anomeric hydroxy group to give the corresponding substituted masked guanidines in high yields. Subsequent deprotection and coupling with Fmoc protected β-amino acid, afforded a series of N,N′-substituted-methyl-isothioureas. Cleavage of Fmoc followed by concomitant cyclization was achieved with a catalytic amount of DBU to give the guanidinoglycosides.

Full text of DOI:10.1055/s-2003-36815

PAPER
255
Syntheses of Guanidinoglycosides with the Inventive use of Mitsunobu
Conditions and 1,8-Diazabicyclo[5.4.0]undec-7-ene
G
uanidinoglyc
e
osides with
i
the
I
n
s
ventive us
h
e
of Mitsuno
a
bu Conditio
n
ns and
D
BU Lin, Sabrina Cher Hui Heng, Mui Mui Sim*1
Institute of Molecular and Cell Biology, 30 Medical Drive, Singapore 117609, Singapore
Fax +6567791117; E-mail: muimui@merlionpharma.com
Received 15 July 2002; revised 12 November 2002
in the presence of Et3N to yield the desired products.
However, with the former synthetic route, we were re-
stricted to the forming of guanidinoglycosides that were
di-substituted at the N-1 position. As such, we embarked
Abstract: A series of novel guanidinoglycosides was successfully
synthesized. This was accomplished with the use of Mitsunobu con-
ditions as a strategy to convert the glycopyranose anomeric hydroxy
group to give the corresponding substituted masked guanidines in
high yields. Subsequent deprotection and coupling with Fmoc pro- on the quest of designing an alternative route to enable the
tected β-amino acid, afforded a series of N,N′-substituted-methyl-
synthesis of guanidinoglycosides that are mono-substitut-
isothioureas. Cleavage of Fmoc followed by concomitant
ed at the N-3 position (the previously N-1 position). In
cyclization was achieved with a catalytic amount of DBU to give
this paper, we report the successful syntheses of these
the guanidinoglycosides.
guanidinoglycosides with the inventive use of the Mit-
sunobu reaction and DBU in guanidine formation.
Key words: guanidine, glycosides, Mitsunobu reaction, coupling,
cyclization
Classical Mitsunobu reactions entail the activation of an
alcohol entity with triphenylphosphine and diethyl azodi-
carboxylate so as to allow the ‘attack’ of a nucleophile
The significance of the guanidine moiety’s role in many
that results in an SN2-like reaction.10 Applying the theory,
biologically active compounds cannot be disputed. Dis-
we envisaged that, with a powerful guanidinylation re-
agent, the anomeric hydroxy group of a 2,3,4,6-O-acetyl-
ated glycopyranose should undergo Mitsunobu reaction to
covered in 1944, Streptomycin contains two essential
guanidine groups at C-1 and C-3 and is an important
member of the antibiotic family. It is active against gram-
yield the guanidinoglycosides. A search through the liter-
negative microbial infections and has beneficial effects in
ature revealed that diurethane-protected thiopseudourea,
the treatment of infections caused by intracellular patho-
diurethane- and triurethane-protected guanidines are ex-
gens.2 Over the years, numerous streptomycin analogs
cellent guanidinylaton reagents, which react with primary
have been prepared and analogs without both guanidino
or secondary alcohols under the Mitsunobu conditions to
groups were found to be inactive.3 Cotner and Smith per-
yield the (masked) guanidines.6b,11
formed extensive work on phosphotyrosine binding by
We have chosen 1,3-bis(tert-butoxycarbonyl)-2-methyl-
2-thiopseudourea as the guanidinylation reagent for two
reasons: it is commercially available and is relatively
cheap (US$39.10/5 g). As expected, the Mitsunobu reac-
tion with 2,3,4,6-O-acetylated galacto- and gluco-pyra-
nose proceeded with ease to yield 85 and 68% of 1a and
ammonium and guanidinium-modified cyclodextrins for
the inhibition of inappropriate mitogenic signaling.4
Meanwhile, Reitz et al. prepared a series of carbohydrate
biguanidines as potential hypoglycemic agents and suc-
ceeded in achieving activities equivalent to those of Phen-
formin and Metformin.5 More recently, Goodman and co-
workers synthesized a new class of guanidinylation re-
agents: N,N′-diBoc- and N,N′-diCBz-N′′-triflylguani-
dine,6 which efficiently guanidinylate aryl-, alkyl-amines
and amino acids to the corresponding guanidines in quan-
titative yields. The authors also used the reagents to con-
vert aminoglycosides to their corresponding guan-
idinoglycosides, and demonstrated that these were able to
inhibit replication of the HIV virus with good activities.7
1
1b, respectively (Scheme 1). H NMR spectra indicated
that both purified glycosyl substituted thiopesudoureas 1a
and 1b contained five (α1:α2:β1:β2:β3 = 1:1:0.5:0.9:0.5)
and four products (α1:α2:β1:β2 = 1:0.5:1:1.5), respective-
ly. The α and β anomers were assigned based on the J1–2
coupling constants. We suspected that these products
were mixtures of rotomers since HRMS gave only the de-
sired molecular peak. Boc-Deprotection with TFA (80%)
gave 2a (59%, α only) and 2b (75%, α:β = 19:1). The re-
action was completed within 15 min at 0 ºC. Since only
the desired deBoc product was obtained from compound
1, it indicates that the initial mixtures were indeed the ro-
tomers.12
Recently, our group reported the synthesis of novel
guanidinoglycosides8 via aza-Wittig type reaction of imi-
nophosphoranes.9 A series of β-glycosyl isothiocyanates
was used as starting materials for the formation of glyco-
syl carbodiimides, which in turn underwent addition and
spontaneous cyclization with β-amino acid methyl esters
Standard coupling conditions were employed during the
next step in the syntheses of disubstituted masked
guanidines 3a–e (Table 1). It is important to note that the
reaction, though it proceeded smoothly, did not reach
completion. The progress of the reaction was monitored
Synthesis 2003, No. 2, Print: 31 01 03.
Art Id.1437-210X,E;2003,0,02,0255,0261,ftx,en;F05902SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

256
P. Lin et al.
PAPER
R1
R1
OAc
OAc
a
b
O
O
R2
AcO
R2
AcO
SCH3
N NBoc
AcO
AcO
OH
Boc
2,3,4,6-Tetra-O-acetyl-
D-galactopyranose: R1 = OAc, R2 = H
1a: R1 = OAc, R2 = H, 85%
1b: R1 = H, R2 = OAc, 68%
2,3,4,6-Tetra-O-acetyl-
D-glucopyranose: R1 = H, R2 = OAc
R1
OAc
R1
OAc
O
R2
c
O
R2
AcO
AcO
AcO
AcO
H
N
HN
NH
N
NHFmoc
SCH3
CH3S
O
R3
2a: R1 = OAc, R2 = H, 59 %
2b: R1 = H, R2 = OAc, 75 %
3a-e, 39-68%
R1
OAc
O
R2
AcO
d
AcO
H
N
N
O
R3
HN
4a-e, 35-66%
Scheme 1 Reagents and Conditions: (a) N,N′-BocNHC(SMe)NBoc, Ph3P, DEAD, THF, 0 ºC to r.t., 18 h; (b) TFA, CH2Cl2, anisole, 15 min,
0 ºC; (c) Fmoc-protected β-amino acid, HOBt, DIC, DMA, i-Pr2NEt, CH2Cl2, 0 ºC to r.t., 24 h; (d) DBU, THF, r.t., 1 h.
by TLC and MS for 48 hours and observations indicated O-acetylated glycopyranoses (17, 15 and 4%, respective-
that the reaction typically reached a plateau after 24 hours. ly).
The pure isolated yields of 3a–e were in the range of 39–
68% (Table 1). The coupling reactions of α-2a,b and
Fmoc protected β-amino acids gave only the α-disubsti-
tuted masked guanidines 3a–e.
While performing HRMS, compounds 2–4 sometimes
gave peaks that corresponded to (M + 45)+. For example,
with 2a, on top of the desired molecular peak (HRMS
calcd for C16H25N2O9S: 421.1281; found: 421.1282), an
The next step was to unmask the guanidine by cleaving extra peak at 465.1176 (corresponding to C17H25N2O11S)
the Fmoc protecting group and cyclizing the free amine to was also observed. The extra peak was suspected to be a
yield the guanidinoglycoside. The classical way of cleav- result of CO2 trapped in the basic molecule. It was re-
ing Fmoc employs the use of large excess of secondary moved by bubbling argon gas through the sample solution
amine, such as piperidine in DMF. However, subsequent prior to HRMS analysis in neutral conditions. The 13C
experiments have been carried out to show the superiority NMR spectra of compounds 2–4 also gave an extra carbon
of DBU over other common reagents with Fmoc cleav- peak at δ = 158–159. The peak disappeared when fresh
ages.13 Although DBU is commonly employed as a base samples were prepared.
for cyclization reactions,14 none was found using DBU as
the reagent for the in situ cleavage of Fmoc and cycliza-
tion to form the guanidine moiety. We predicted that the
We have also isolated two cyclized products (4c-I, 4c-II
and 4d-I, 4d-II) from 4c and 4d, respectively. The more
1
polar products 4-II show very broad signals in their H
use of DBU should not only cleave the Fmoc protecting
NMR spectra and yet strong (M + H)+ HRMS signals. On
group but also cause the in situ intramolecular cyclization
the other hand, the less polar compounds 4-I gave a very
to guanidinoglycoside 4. Using a catalytic amount of
DBU (0.7% equiv), 3 was successfully converted to the
strong (M + H + CO2)+ HRMS signal. We suspected that
products 4-I are actually the trapped CO2 form of products
desired guanidinoglycoside 4 (35–66%) within an hour. In
4-II. An experiment was thus carried out by stirring 4c-II
some cases (4b–c,e), hydrolysis of the guanidine moiety
with dry ice in THF. Compound 4c-II was found to slowly
at the anomeric position was observed to yield the 2,3,4,6-
convert to 4c-I as monitored by TLC and 1H NMR.
Synthesis 2003, No. 2, 255–261 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Syntheses of Guanidinoglycosides with the Inventive use of Mitsunobu Conditions and DBU
257
Table 1 Isolated Yields of Methylisothioureas 3 and Guanidinoglycosides 4
R1
R2
R3
Isolated Yields (%)
3
4
a
b
c
OAc
OAc
H
H
CH2(4-CH3C6H4)
H
65
56
68
67
39
45
35
65
56
66
H
OAc
OAc
OAc
CH2(4-CH3C6H4)
CH2CH2Ph
d
e
H
H
CH2(4- NO2C6H4)
The chemical structures of compounds 3 and 4 were care- cal evaluation. More importantly, we have described two
1
fully studied using H, 13C and 2D NMR spectroscopy. novel uses of Mitsunobu conditions and DBU, both of
For example, the successful conversion of 3b to 4b was which are efficient and simple in application.
confirmed by the disappearance of the SCH3 group (δ =
14.93 and 174.07) as well as the appearance of the guani-
THF was distilled from sodium benzophenone ketyl prior to use.
CH2Cl2 was distilled from CaH2. Commercially available chemicals
were used without further purification. Analytical TLC was carried
dine group (δ = 161.24) from their 13C NMR spectra. Fur-
thermore, a 1H–13C HMBC experiment on 4b also showed
out on precoated glass plates (Merck silica gel 60, F254). Column
chromatography was performed with silica gel (420–630 mesh)
from Merck. All the NMR spectra were recorded with a Bruker
Avance DMX 400 MHz instrument in CDCl3 solutions and were
calibrated using TMS as an internal standard. HRMS were deter-
a correlation between the anomeric proton and the guani-
dine carbon (C-2) but not the carbonyl carbon (C-4), thus
indicating that the amide coupling occurred at the less hin-
dered amine (Figure 1).
1
Similarly, the H–13C HMBC correlation between the mined using a Marina Biospectrometry workstation via ESI+.
amide proton and carbonyl carbon confirmed the imino
position of 3d. However, unlike our previously reported
N-1 disubstituted guanidinoglycosides,8 we were unable
to determine the location of the imino-group on the guani-
Additional abbreviations: N-hydroxybenzotriazole (HOBt), N,N-
dimethylacetamide (DMA), and 1,3-diisopropylcarbodiimide
(DIC).
1
N-(2,3,4,6-Tetra-O-acetyl-D-galactopyranosyl)-N-N′-bis(tert-
butoxycarbonyl)methylisothiourea (1a)
dine moiety of guanidinoglycosides 4 using H–15N 2D
NMR experiments.
A mixture of Ph3P (450 mg, 1.72 mmol) and 1,3-bis(tert-butoxycar-
bonyl)-2-methyl-2-thiopseudourea (498 mg, 1.72 mmol) were dis-
solved in freshly distilled THF under argon. The mixture was
cooled to below 0 ºC with an ice/salt-bath, stirred for 10 min before
DEAD (271.7 µL, 1.72 mmol) was added dropwise. After another
In this report, we have described a synthetic route that not
only complements our previous work but also provided
another convenient and efficient way to synthesize novel
2-glycosylamino-dihydropyrimidinone for future biologi-
OAc
OAc
AcO
6'
AcO
6'
O
1'
O
1'
H
3'
3'
H
AcO
AcO
AcO
AcO
H
NHFmoc
N
N
N
4
N
H
6
2
N
O
CH3S
Ph
3d
4b
O
Figure 1 1H–13C HMBC correlations of methylisothiourea 3d and guanidinoglycoside 4b.
Synthesis 2003, No. 2, 255–261 ISSN 0039-7881 © Thieme Stuttgart · New York

258
P. Lin et al.
PAPER
10 min, a solution of 2,3,4,6-tetra-O-acetyl-D-galactopyranose (500
mg, 1.43 mmol) in distilled THF was transferred to it via a delivery
needle. The entire mixture was warmed up to r.t., stirred overnight
and concentrated. Triphenylphosphine oxide was removed by pre-
cipitating the crude mixture in Et2O. The filtrate was concentrated
and purified using flash chromatography (33% EtOAc in hexane) to
give pure 1a (750 mg, 85%, α1:α2:β1:β2:β3 = 1:1:0.5:0.9:0.5) as a
yellow, viscous syrup. Further separation of 1a into 1a-I and 1a-II
was achieved by developing the preparative TLC 3 times (25%
EtOAc in hexane).
N-(2,3,4,6-Tetra-O-acetyl-D-glucopyranosyl)-N-N′-bis(tert-bu-
toxycarbonyl)methylisothiourea (1b)
Compound 1b (602 mg, 68%, α1:α2:β1:β2 = 1:0.5:1:1.5) was pre-
pared as 1a from 2,3,4,6-tetra-O-acetyl-D-glucopyranose (500 mg,
1.43 mmol).
1 Anomer
1H NMR: δ = 6.29 (d, 1 H, J = 3.7 Hz, H-1), 5.54 (t, 1 H, J = 9.9 Hz,
H-3), 5.10 (t, 1 H, J = 9.9 Hz, H-4), 5.03 (dd, 1 H, J = 9.7, 3.8 Hz,
H-2), 4.22 (dd, 1 H, J = 12.4, 4.5 Hz, H-6a), 4.18–4.12 (m, 1 H, H-
5), 4.02 (dd, 1 H, J = 12.5, 2.1 Hz, H-6b), 2.39 (s, 3 H, SCH3), 2.03,
1.97 (9), 1.97 (7), 1.96 (4 s, 12 H, OAc), 1.44, 1.43 (2 s, 18 H, Boc).
From 1a-I (
1 Anomer
,
,
)
1
1
2
13C NMR: δ = 174.87, 170.57, 170.12, 169.92, 169.47, 161.91,
90.81, 69.80, 69.46, 68.18, 67.81, 61.29, 27.85, 20.65, 20.54, 14.76.
1H NMR: δ = 6.34 (d, 1 H, J = 3.5 Hz, H-1), 5.48 (dd, 1 H, J = 3.0,
1.0 Hz, H-4), 5.44–5.43 (overlapped with β1-H-4 and α2-H-3, 1 H,
H-3), 5.28 (dd, 1 H, J = 10.9, 3.4 Hz, H-2), 4.38 (t, 1 H, J = 6.7 Hz,
H-5), 4.11–4.01 (m, 2 H, H-6a, H-6b), 2.40 (s, 3 H, SCH3), 2.11,
2.00, 1.98, 1.96 (4 s, 12 H, OAc), 1.47, 1.45 (2 s, 18 H, Boc).
2 Anomer
1H NMR: δ = 6.11 (d, 1 H, J = 3.6 Hz, H-1), 5.45 (t, 1 H, J = 10.0
Hz, H-3), 5.09 (dd, 1 H, J = 9.5, 4.0 Hz, H-2), 5.05–5.00 (over-
lapped with other anomers, 1 H, H-4), 4.25–4.00 (overlapped with
other anomers, H-5, H-6a, H-6b), 2.34, (s, 3 H, SCH3), 2.03, 1.98
(3), 1.98 (0), 1.97 (4 s, 12 H, OAc), 1.45, 1.44 (2 s, 18 H, Boc).
13C NMR: δ = 174.79, 170.35, 170.27, 170.17, 170.10 159.07,
150.35, 91.50, 68.50, 67.50, 67.42, 66.79, 61.12, 27.91, 20.72,
14.80.
13C NMR: δ = 170.46, 169.91, 169.37, 169.32, 160.02, 153.13,
92.39, 69.75, 69.60, 69.14, 67.61, 61.23, 27.82, 20.70, 20.53, 14.03.
2 Anomer
1H NMR: δ = 6.18 (d, 1 H, J = 3.4 Hz, H-1), 5.47 (dd, J = 3.0, 1.3
Hz, H-4), 5.44–5.43 (overlapped with α1-H-3 and β1-H-4, 1 H, H-
3), 5.34 (dd, 1 H, J = 11.0, 3.1 Hz, H-2), 4.35 (t, 1 H, J = 6.6 Hz, H-
5), 4.11–4.01 (m, 2 H, H-6a, H-6b), 2.40 (s, 3 H, SCH3), 2.11, 2.00,
1.99, 1.95, (4 s, 12 H, OAc), 1.47, 1.45 (2 s, 18 H, Boc).
1 Anomer
1H NMR: δ = 5.75 (t, 1 H, J = 7.7 Hz, H-3), 5.70 (d, 1 H, J = 6.2 Hz,
H-1), 5.24 (dd, 1 H, J = 7.8, 6.2 Hz, H-2), 5.00 (dd, 1 H, J = 9.5, 7.3
Hz, H-4), 4.41 (ddd, 1 H, J = 9.4, 4.0, 2.9 Hz, H-5), 4.20 (dd, 1 H,
J = 12.2, 4.2 Hz, H-6a), 4.07 (dd, 1 H, J = 12.3, 2.6 Hz, H-6b), 2.34
(s, 3 H, SCH3), 2.01, 2.00, 1.97, 1.96 (4 s, 12 H, OAc), 1.44, 1.43 (2
s, 18 H, Boc).
13C NMR: δ = 170.77, 170.33, 170.09, 169.95, 153.36, 93.10,
68.81, 67.36, 67.18, 66.43, 61.12, 27.91, 20.72, 14.09.
1 Anomer
13C NMR: δ = 170.64, 169.66, 169.54, 169.48, 157.27, 151.86,
80.81, 71.55, 71,13, 68.62, 68.18, 61.95, 27.85, 20.70, 20.65, 15.78.
1H NMR: δ = 5.85 (d, 1 H, J = 6.2 Hz, H-1), 5.80 (dd, 1 H, J = 9.7,
3.5 Hz, H-3), 5.44–5.43 (overlapped with α1-H-3 and α2-H-3, 1 H,
H-4), 5.42 (dd, 1 H, J = 9.6, 6.2 Hz, H-2), 4.55 (dt, 1 H, J = 6.4, 1.9
Hz, H-5), 4.11–4.01 (m, 2 H, H-6a, H-6b), 2.38 (s, 3 H, SCH3), 2.07,
2.02, 1.99, 1.95 (4 s, 12 H, OAc), 1.46 (s, 18 H, Boc).
2 Anomer
1H NMR: δ = 5.70 (t, 1 H, J = 9.4 Hz, H-3), 5.13 (t, 1 H, J = 9.4 Hz,
H-2), 5.03 (t, 1 H, J = 9.8 Hz, H-4), 5.03 (d, 1 H, J = 9.5 Hz, H-1),
4.15 (dd, 1 H, J = 12.4, 4.8 Hz, H-6a), 4.09 (dd, 1 H, J = 12.3, 2.4
Hz, H-6b), 3.65 (ddd, 1 H, J = 9.9, 4.6, 2.5 Hz, H-5), 2.33 (s, 3 H,
SCH3), 2.01, 1.98, 1.96, 1.93 (4 s, 12 H, OAc), 1.45, 1.42 (2 s, 18
H, Boc).
13C NMR: δ = 170.39, 170.10, 169.96, 169.65, 161.79, 157.34,
151.97, 80.86, 71.20, 67.88, 67.09, 66.41, 61.63, 27.91, 20.72,
15.88.
HRMS: m/z calcd for C26H41N2O13S (M + H)+: 621.2328; found:
621.2323.
13C NMR: δ = 170.50, 170.14, 169.40, 169.34, 157.09, 150.42,
84.75, 74.08, 73.92, 68.20, 67.81, 61.83, 27.89, 20.66, 20.54, 15.62.
From 1a-II (
2 Anomer
,
)
3
HRMS: m/z calcd for C26H41N2O13S (M + H)+: 621.2328; found:
621.2327.
2
1H NMR: δ = 5.66 (d, 1 H, J = 8.3 Hz, H-1), 5.42–5.37 (m, 2 H, H-
2, H-4), 5.06 (dd, 1 H, J = 10.4, 3.4 Hz, H-3), 4.13–4.10 (m, 2 H, H-
6a, H-6b), 4.03 (t, 1 H, J = 6.5 Hz, H-5), 2.36 (s, 3 H, SCH3), 2.09,
1.98, 1.97, 1.94 (4 s, 12 H, OAc), 1.44, 1.43 (2 s, 18 H, Boc).
N-(2,3,4,6,-Tetra-O-acetyl- -D-galactopyranosyl)methyliso-
thiourea (2a)
To 1a (560 mg, 0.90 mmol) in distilled CH2Cl2 (1 mL) at 0 ºC was
added anisole (70 µL, 0.64 mmol) and TFA (7 mL, 90 mmol). The
solution was stirred for 15 min at 0 ºC. The solvent was removed in
vacuo, and the residue co-evaporated twice with hexane and then re-
dissolved in MeOH. Powdered NaHCO3 was added portionwise to
neutralize the solution. The solution was filtered, concentrated and
purified on a column (silica gel; 60% EtOAc in hexane) to afford
pure 2a.
13C NMR: δ = 175.19, 170.30, 170.14, 170.03, 169.19, 158.90,
150.24, 94.06, 71.54, 71.01, 67.07, 66.78, 61.07, 27.94, 20.64,
20.59, 20.53, 15.58.
3 Anomer
1H NMR: δ = 5.92 (t, 1 H, J = 9.7 Hz, H-2), 5.42–5.37 (overlapped
with β2 protons, 1 H, H-4), 4.99 (dd, 1 H, J = 10.0, 3.4 Hz, H-3),
4.94 (br d, 1 H, J = 9.5 Hz, H-1), 4.13–4.10 (m, 2 H, H-6a, H-6b),
3.94 (t, 1 H, J = 6.6 Hz, H-5), 2.33 (s, 3 H, SCH3), 2.07, 2.00, 1.97,
1.92 (4 s, 12 H, OAc), 1.47 (s, 18 H, Boc).
Yield: 223 mg (59%); colorless syrup.
1H NMR: δ = 6.39 (d, 1 H, J = 3.7 Hz, H-1), 5.52 (d, 1 H, J = 1.3
Hz, H-4), 5.50 (dd, 1 H, J = 13.5, 3.2 Hz, H-3), 5.31 (dd, 1 H,
J = 10.3, 3.7 Hz, H-2), 4.45 (t, 1 H, J = 6.7 Hz, H-5), 4.12 (dd, 1 H,
J = 11.3, 7.2 Hz, H-6a), 4.07 (dd, 1 H, J = 11.2, 6.6 Hz, H-6b), 2.49
(s, 3 H, SCH3), 2.15, 2.04, 2.02, 1.99 (4 s, 12 H, OAc).
13C NMR: δ = 175.60, 170.38, 170.21, 170.05, 91.01, 68.31, 67.63,
67.51, 66.89, 61.20, 20.75, 20.67, 13.68.
13C NMR: δ = 170.35, 170.19, 170.07, 169.48, 160.63, 157.24,
150.45, 85.64, 72.88, 72.35, 67.74, 66.08, 61.16, 27.91, 20.97,
20.71 (carbons overlapped with β2), 14.71.
HRMS: m/z calcd for C26H41N2O13S (M + H)+: 621.2328; found:
621.2327.
Synthesis 2003, No. 2, 255–261 ISSN 0039-7881 © Thieme Stuttgart · New York

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Syntheses of Guanidinoglycosides with the Inventive use of Mitsunobu Conditions and DBU
259
HRMS: calcd for C16H25N2O9S (M + H)+: 421.1281; found:
421.1282.
HRMS: m/z calcd for C42H48N3O12S (M + H)+: 818.2959; found:
818.2960.
N-(2,3,4,6-Tetra-O-acetyl-D-glucopyranosyl)methylisothiourea
(2b)
Compound 2b was prepared the same way as 2a from 1b (560 mg,
(S)-N-(2,3,4,6-Tetra-O-acetyl- -D-galactopyranosyl)-N′-[2-(9-
fluorenylmethylcarbonyl)aminoethylcarbonyl]methylisothio-
urea (3b)
0.90 mmol).
Compound 3b was prepared from 2a (95 mg, 0.23 mmol) and
Fmoc-β-alanine (77 mg, 0.25 mmol).
Yield: 284 mg (75%); α:β = 19:1; colorless syrup. The α- and β-
anomers were separated and characterized individually.
Yield: 90 mg (56%); white foam.
1H NMR: δ = 12.20 (br s, 1 H, NHCO), 7.69 (d, 2 H, J = 7.5 Hz,
Fmoc), 7.51 (d, 2 H, J = 7.3 Hz, Fmoc), 7.33 (t, 2 H, J = 7.5 Hz,
Fmoc), 7.24 (t, 2 H, J = 7.3 Hz, Fmoc), 6.32 (d, 1 H, J = 3.1 Hz, H-
1), 5.46 (br s, 1 H, H-4), 5.45–5.35 (m, 1 H, H-3), 5.29–5.23 (m, 2
H, NHFmoc, H-2), 4.33 (d, 2 H, J = 6.8 Hz, OCH2CH), 4.38–4.32
(hidden, 1 H, H-5), 4.18–4.10 (m, 1 H, OCH2CH), 4.08–4.01 (m, 2
H, H-6), 3.48–3.41 (m, 2 H, NCH2), 2.40 (br s, 2 H, CH2CO), 2.09
(s, 3 H, SCH3), 1.97, 1.95, 1.94 (3 s, 12 H, OAc).
Anomer
1H NMR: δ = 6.34 (d, 1 H, J = 3.7 Hz, H-1), 5.62 (t, 1 H, J = 9.9 Hz,
H-3), 5.15 (t, 1 H, J = 9.8 Hz, H-4), 5.07 (dd, 1 H, J = 10.3, 3.8 Hz,
H-2), 4.28 (dd, 1 H, J = 12.3, 3.7 Hz, H-6a), 4.25–4.21 (m, 1 H, H-
5), 4.07 (dd, 1 H, J = 12.3, 1.9, H-6b), 2.50 (s, 3 H, SCH3), 2.08,
2.02, 2.01(9), 2.01 (4 s, 12 H, OAc).
13C NMR: δ = 175.75, 170.73, 170.17, 170.10, 169.58, 90.36,
70.62, 69.61, 69.26, 68.00, 61.44, 20.70, 20.65, 20.62, 13.71.
HRMS: m/z calcd for C16H25N2O9S (M + H)+: 421.1281; found:
421.1282.
13C NMR: δ = 174.07, 170.32, 170.13, 156.29, 143.81, 141.28,
127.68, 127.01, 125.01, 119.96, 91.73, 68.59, 67.38, 67.32, 66.71,
61.01, 47.18, 36.97, 35.89, 20.64, 14.93.
HRMS: m/z calcd for C34H40N3O12S (M + H)+: 714.2332; found:
714.2333.
Anomer
1H NMR: δ = 5.29 (t, 1 H, J = 9.4 Hz, H-3), 5.08 (t, 1 H, J = 9.7 Hz,
H-4), 5.02–4.99 (m, 2 H, H-1, H-2), 4.24 (br d, 1 H, J = 11.8 Hz, H-
6a), 4.13 (br d, 1 H, J = 12.4, H-6b), 3.81 (ddd, 1 H, J = 10.1, 4.5,
2.5 Hz, H-5), 2.34 (s, 3 H, SCH3), 2.07, 2.04, 2.03, 2.01 (4 s, 12 H,
OAc).
(S)-N-(2,3,4,6-Tetra-O-acetyl- -D-glucopyranosyl)-N′-[2-(N-
fluorenylmethylcarbonyl)amino-3-(4-methylphenyl)propylcar-
bonyl]methylisothiourea (3c)
Compound 3c was prepared from 2b (100 mg, 0.24 mmol) and
Fmoc-(S)-3-amino-4-(4-methylphenyl)butyric acid (110 mg, 0.26
mmol).
13C NMR: δ = 170.68, 170.19, 169.50, 162.80, 83.20, 73.24, 72.97,
71.34, 68.31, 61.95, 20.74, 20.69, 20.62, 20.59, 13.0
HRMS: m/z calcd for C16H25N2O9S (M + H)+: 421.1281; found:
Yield: 133mg (68%); white foam.
421.1282.
1H NMR: δ = 12.12, (br s, 1 H, NH), 7.69 (d, 2 H, J = 7.6 Hz,
Fmoc), 7.49–7.47 (m, 2 H, Fmoc), 7.33 (t, 2 H, J = 7.4 Hz, Fmoc),
7.24 (t, 2 H, J = 7.4 Hz, Fmoc), 7.06–6.98 (m, 4 H, C6H4), 6.27 (d,
1 H, J = 2.6 Hz, H-1), 5.54 (t, 1 H, J = 9.8 Hz, H-3), 5.20 (d, 1 H,
J = 8.1 Hz, NH), 5.10 (t, 1 H, J = 9.9 Hz, H-4), 5.03 (dd, 1 H,
J = 10.3, 3.5 Hz, H-2), 4.29 (br s, 2 H, OCH2CH), 4.22 (dd, 1 H,
J = 12.6, 3.5 Hz, H-6a), 4.13–4.12 (m, 3 H, H-5, NCH, OCH2CH),
4.01 (br d, 1 H, J = 13.4 Hz, H-6b), 2.94–2.75 (m, 2 H, CH2C6H4),
2.65–2.46 (m, 2 H, CH2CO), 2.41 (s, 3 H, SCH3), 2.24 (s, 3 H,
C6H4CH3), 2.01, 1.98, 1.97, 1.96 (4 s, 12 H, OAc).
13C NMR: δ = 174.26, 170.62, 170.19, 169.95, 169.67, 169.47,
159.00, 155.62, 143.84, 141.29, 136.56, 133.91, 129.45, 129.05,
127.66, 127.02, 125.06, 119.94, 91.00, 69.82, 69.57, 69.41, 67.83,
66.65, 61.29, 49.41, 47.20, 40.00, 39.45, 21.02, 20.68, 20.58, 14.98.
Compounds 3; General Procedures
To a solution of Fmoc-protected β-amino acid (1.1 equiv) and
HOBt (1.1 equiv) in DMA (0.6 mL) and CH2Cl 2 (5 mL) was added
DIC (1.1 equiv). It was stirred for 10 min before being added to an
ice-cooled solution of 2 (1 equiv) and i-Pr2NEt (1.1 equiv) in
CH2Cl2 (5 mL). The resulting solution was allowed to stir at r.t. for
24 h. The mixture was concentrated and by-product urea was re-
moved by precipitation using hexane. Purification of the residue on
preparative TLC (50% EtOAc in hexane) afforded pure 3.
(S)-N-(2,3,4,6-Tetra-O-acetyl- -D-galactopyranosyl)-N′-[2-(9-
fluorenylmethylcarbonyl)amino-3-(4-methylphenyl)propylcar-
bonyl]methylisothiourea (3a)
Compound 3a was prepared from 2a (64 mg, 0.15 mmol) and
Fmoc-(S)-3-amino-4-(4-methylphenyl)butyric acid (70 mg, 0.17
mmol).
HRMS: m/z calcd for C42H48N3O12S (M + H)+: 818.2960; found:
818.2947.
(S)-N-(2,3,4,6-Tetra-O-acetyl- -D-glucopyranosyl)-N′-[2-(9-
fluorenylmethylcarbonyl)amino-4-phenylbutylcarbonyl]me-
thylisothiourea (3d)
Compound 3d was prepared from 2b (130 mg, 0.31 mmol) and
Fmoc-(S)-3-amino-5-phenylpentanoic acid (142 mg, 0.34 mmol).
Yield: 80 mg (65%); white foam.
1H NMR: δ = 12.12 (s, 1 H, NHCO), 7.69 (d, 2 H, J = 7.5 Hz,
Fmoc), 7.49–7.47 (m, 2 H, Fmoc), 7.33 (t, 2 H, J = 7.4 Hz, Fmoc),
7.23 (t, 2 H, J = 7.4 Hz, Fmoc), 7.09–6.92 (m, 4 H, C6H4), 6.31 (br
s, 1 H, H-1), 5.46 (br s, 1 H, H-4), 5.41 (br d, 1 H, J = 11.1 Hz, H-
3), 5.26 (dd, 1 H, J = 10.7, 3.2 Hz, H-2), 5.22 (d, 1 H, J = 10.2 Hz,
FmocNH), 4.35 (t, 1 H, J = 6.4 Hz, H-5), 4.35–4.24 (m, 2 H,
OCH2CH), 4.20–4.08 (m, 2 H, NCH, OCH2CH), 4.08–3.98 (m, 2 H,
H-6a. H-6b), 2.94–2.75 (m, 2 H, CH2C6H4), 2.65–2.45 (m, 2 H,
CH2CO), 2.39 (s, 3 H, SCH3), 2.24 (s, 3 H, CH3C6H4), 2.09, 1.96,
1.94 (3 s, 12 H, OAc).
13C NMR: δ = 174.04, 170.31, 170.11, 169.65, 155.60, 143.82,
141.27, 136.53, 133.90, 129.43, 129.04, 127.64, 127.00, 125.04,
119.93, 91.64, 68.55, 67.39, 67.33, 66.66, 61.02, 49.39, 47.18,
39.95, 39.44, 21.01, 20.68, 20.63, 14.93.
Yield: 169 mg (67%); white foam.
1H NMR: δ = 12.10 (s, 1 H, NHCO), 7.66 (d, 2 H, J = 7.4 Hz,
Fmoc), 7.50 (d, 2 H, J = 7.0 Hz, Fmoc), 7.29 (dd, 2 H, J = 10.9, 7.2
Hz, Ph), 7.21 (t, 2 H, J = 7.3 Hz, Fmoc), 7.18 (t, 2 H, J = 7.0 Hz,
Fmoc), 7.10–7.04 (m, 3 H, Ph), 6.26 (d, 1 H, J = 3.1 Hz, H-1), 5.53
(t, 1 H, J = 9.9 Hz, H-3), 5.28 (d, 1 H, J = 9.6 Hz, FmocNH), 5.09
(t, 1 H, J = 9.9 Hz, H-4), 5.01 (dd, 1 H, J = 10.0, 3.4 Hz, H-2), 4.33
(d, 2 H, J = 6.2 Hz, OCH2CH), 4.19 (dd, 1 H, J = 12.7, 3.5 Hz, H-
6a), 4.13–4.11 (m, 2 H, OCH2CH, H-5), 3.98 (br d, 1 H, J = 11.1
Hz, H-6b), 3.94–3.91 (m, 1 H, NHCH), 2.65–2.50 (m, 4 H, CH2CO,
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260
P. Lin et al.
PAPER
CH2Ph), 2.35 (s, 3 H, SCH3), 1.98, 1.95, 1.94, 1.93 (4 s, 12 H, OAc),
1.92–1.75 (m, 2 H, CH2CH2Ph).
1H NMR: δ = 6.22 (d, 1 H, J = 3.5 Hz, H-1′), 5.40 (dd, 1 H, J = 3.2,
1.3 Hz, H-4′), 5.36 (dd, 1 H, J = 10.9, 3.3 Hz, H-3′), 5.22 (dd, 1 H,
J = 10.9, 3.5 Hz, H-2′), 4.63 (t, 1 H, J = 6.7 Hz, H-5′), 4.05 (d, 2 H,
J = 6.7 Hz, H-6′a, H-6′b), 3.69 (ddd, 1 H, J = 13.2, 10.5, 5.4 Hz, H-
6a), 3.58 (dt, 1 H, J = 13.1, 6.4 Hz, H-6b), 2.75 (dt, 1 H, J = 16.9,
5.4 Hz, H-5a), 2.66 (ddd, J = 16.9, 10.4, 6.5 Hz, H-5b), 2.09, 1.98,
1.97, 1.90, (4 s, 12 H, OAc).
13C NMR: δ = 170.49, 170.25, 169.86, 168.62, 161.92, 90.70,
68.19, 68.11, 66.93, 61.36, 37.04, 30.42, 20.82, 20.75, 20.67, 20.63.
HRMS: m/z calcd for C18H26N3O10 (M + H)+: 444.1618; found:
13C NMR: δ = 174.02, 170.48, 170.05, 169.83, 169.41, 169.34,
155.68, 143.74, 143.65, 141.16, 140.76, 128.35, 128.20, 127.54,
126.89, 125.96, 124.89, 124.77, 119.82, 90.84, 69.69, 69.42, 69.27,
67.69, 66.38, 61.16, 47.85, 47.11, 41.57, 35.61, 32.35, 20.54, 20.45,
14.80
HRMS: m/z calcd for C42H48N3O12S (M + H)+: 818.2959; found:
818.2951.
(S)-N-(2,3,4,6-Tetra-O-acetyl- -D-glucopyranosyl)- N′-[2-(9-
fluorenylmethylcarbonyl)amino-3-(4-nitrophenyl)propylcar-
bonyl]methylisothiourea (3e)
Compound 3e was prepared from 2b (130 mg, 0.31 mmol) and
Fmoc-(S)-3-amino-4-(4-nitrophenyl)-butyric acid (152 mg, 0.34
mmol).
444.1614.
(S)-2-(2′,3′,4′,6′-Tetra-O- -acetyl- -D-glucopyranosyl)amino-6-
(4-methylbenzyl)-5,6-dihydro-4-pyrimidinone (4c)
Compound 4c-I (8.4 mg, 31%, colorless foam) and 4c-II (9 mg,
34%, colorless foam) were prepared from 3c (40 mg, 0.05 mmol).
Yield: 102 mg (39%); white foam.
Compound 4c-I
1H NMR: δ = 12.19 (s, 1 H, NHCO), 8.07 (d, 2 H, J = 7.6 Hz,
C6H4), 7.69 (d, 2 H, J = 7.5 Hz, Fmoc), 7.45 (br s, 2 H, Fmoc), 7.33
(t, 2 H, J = 7.5 Hz, Fmoc), 7.31–7.23 (m, 4 H, Fmoc, C6H4), 6.29
(br s, 1 H, H-1), 5.54 (t, 1 H, J = 9.4 Hz, H-3), 5.20 (br s, 1 H, Fmoc-
NH), 5.11 (t, 1 H, J = 9.9 Hz, H-4), 5.03 (br d, 1 H, J = 7.2 Hz, H-
2), 4.33 (br s, 2 H, OCH2CH), 4.23 (dd, 1 H, J = 12.5, 3.2 Hz, H-
6a), 4.15–4.12 (m, 3 H, H-5, CHC6H4, OCH2CH), 4.02 (br d, 1 H,
J = 12.1 Hz, H-6b), 3.07–2.90 (m, 2 H, CH2C6H4), 2.72–2.55 (m, 2
H, CH2CO), 2.42 (s, 3 H, SCH3), 2.02, 1.98, 1.97 (3 s, 12 H, OAc).
1H NMR: δ = 7.15 (d, 2 H, J = 7.8 Hz, C6H4), 7.06 (d, 2 H, J = 8.0
Hz, C6H4), 6.26 (d, 1 H, J = 3.8 Hz, H-1′), 5.56 (t, 1 H, J = 9.9 Hz,
H-3′), 5.14 (t, 1 H, J = 9.9 Hz, H-4′), 5.07 (dd, 1 H, J = 10.3, 3.8 Hz,
H-2′), 4.26 (dd, 1 H, J = 12.5, 3.5 Hz, H-6a′), 4.18 (dt, 1 H, J = 10.3,
2.7 Hz, H-5′), 4.05 (dd, 1 H, J = 12.5, 2.1 Hz, H-6b′), 3.97–3.91 (m,
1 H, H-6), 2.92 (dd, 1 H, J = 13.8, 6.1 Hz, CH2C6H4), 2.83 (dd, 1 H,
J = 13.8, 7.8 Hz, CH2C6H4), 2.76 (dd, 1 H, J = 16.8, 5.1 Hz, H-5a),
2.57 (dd, 1 H, J = 16.8, 9.6 Hz, H-5b), 2.33 (s, 3 H, C6H4CH3), 2.07,
2.03, 2.00, 1.99 (4 s, 12 H, OAc).
13C NMR: δ = 174.11, 170.62, 170.20, 169.94, 169.45, 169.19,
155.50, 146.95, 145.06, 143.63, 141.33, 130.00, 127.75, 127.02,
124.89, 123.88, 120.01, 91.06, 69.77, 69.60, 69.42, 67.78, 66.49,
61.23, 48.99, 47.14, 40.24, 39.50, 20.67, 20.57, 15.00.
HRMS: m/z calcd for C41H45N4O12S (M + H)+: 849.2653; found:
849.2659.
13C NMR: δ = 170.70, 170.03, 170.00, 169.59, 167.16, 161.59,
137.54, 131.47, 129.90, 128.98, 90.12, 69.96, 69.46, 69.24, 67.87,
61.35, 50.17, 40.46, 35.79, 21.07, 20.71, 20.67, 20.57.
HRMS: m/z calcd for C26H34N3O10 (M + H)+: 548.2246; found:
548.2243.
Compound 4c-II
1H NMR: δ = 7.09 (d, 2 H, J = 7.5 Hz, C6H4), 6.97 (d, 2 H, J = 7.8
Hz, C6H4), 5.61 (br s, 1 H, NH), 5.44 (br s, 1 H, H-3′), 5.23 (br s, 1
H, H-1′), 4.94 (t, 1 H, J = 9.7 Hz, H-4′), 4.87 (br d, 1 H, J = 6.5 Hz,
H-2′), 4.00 (br d, 1 H, J = 10.7 Hz, H-6a′), 3.82–3.72 (br m, 1 H, H-
5′), 3.75–3.65 (br m, 1 H, H-6), 3.38 (br d, 1 H, J = 11.8 Hz, H-6b′),
2.82 (br d, 1 H, J = 11.1 Hz, CH2C6H4), 2.65 (br d, 1 H, J = 15.6 Hz,
H-5a), 2.63–2.57 (m, 1 H, CH2C6H4), 2.40 (dd, 1 H, J = 16.7, 9.5
Hz, H-5b), 2.25 (s, 3 H, C6H4CH3), 2.02, 1.99, 1.95, 1.93 (4 s, 12 H,
OAc).
Compounds 4; General Procedures
To 3 (1 equiv) in freshly distilled THF (0.5 mL) was added DBU
(0.7% equiv). The mixture was stirred at r.t. for 1 h. The mixture
was concentrated and purified on preparative TLC (33% EtOAc in
hexane) to afford pure 4.
(S)-2-(2′,3′,4′,6′-Tetra-O-acetyl- -D-galactopyranosyl)amino-6-
(4-methylbenzyl)-5,6-dihydro-4-pyrimidinone (4a)
Compound 4a was prepared from 3a (20 mg, 0.025 mmol).
13C NMR: δ = 170.35, 170.13, 169.98, 169.60, 137.29, 132.60,
129.83, 128.88, 79.91, 70.65, 70.09, 68.38, 67.48, 61.86, 50.85,
41.04, 36.85, 20.97, 20.84, 20.68, 20.59.
HRMS: m/z calcd for C26H34N3O10 (M + H)+: 548.2246; found:
548.2247.
Yield: 6 mg (45%); white foam.
1H NMR: δ = 7.10 (d, 2 H, J = 7.8 Hz, C6H4), 7.00 (d, 2 H, J = 8.0
Hz, C6H4), 6.23 (d, 1 H, J = 3.7 Hz, H-1′), 5.42 (dd, 1 H, J = 3.2, 1.1
Hz, H-4′), 5.38 (dd, 1 H, J = 10.9, 3.3 Hz, H-3′), 5.24 (dd, 1 H,
J = 10.8, 3.7 H-2′), 4.37 (t, 1 H, J = 6.8 Hz, H-5′), 4.02 (d, 2 H,
J = 6.6 Hz, H-6a′, H-6b′), 3.92–3.86 (m, 1 H, H-6), 2.86 (dd, 1 H,
J = 13.8, 6.1 Hz, CH2C6H4), 2.78 (dd, 1 H, J = 13.8, 7.7 Hz,
CH2C6H4), 2.70 (dd, 1 H, J = 16.8, 5.1 Hz, H-5a), 2.52 (dd, 1 H,
J = 16.8, 9.6 Hz, H-5b), 2.27 (s, 3 H, C6H4CH3), 2.08, 1.98, 1.94,
1.91 (4 s, 12 H, OAc).
(S)-2-(2′,3′,4′,6′-Tetra-O-acetyl- -D-glucopyranosyl)amino-6-
ethylphenyl-5,6-dihydro-4-pyrimidinone (4d)
Compound 4d-1 (11.2 mg, 34%, white foam) and 4d-II (7.2 mg,
22%, white foam) were prepared from 3d (50 mg, 0.06 mmol).
13C NMR: δ = 170.36, 170.27, 170.18, 169.79, 167.27, 161.79,
137.49, 131.54, 129.89, 128.99, 90.76, 68.25, 67.63, 67.37, 66.76,
61.13, 50.16, 40.47, 35.78, 21.07, 20.78, 20.68, 20.63.
HRMS: m/z calcd for C26H34N3O10 (M + H)+: 548.2245; found:
548.2422.
Compound 4d-I
1H NMR: δ = 7.25 (t, 2 H, J = 7.3 Hz, Ph), 7.18 (t, 1 H, J = 7.4 Hz,
Ph), 7.11 (d, 2 H, J = 7.0 Hz, Ph), 6.23 (d, 1 H, J = 3.8 Hz, H-1′),
5.52 (t, 1 H, J = 9.9 Hz, H-3′), 5.10 (t, 1 H, J = 9.8 Hz, H-4′), 5.02
(dd, 1 H, J = 10.3, 3.8 Hz, H-2′), 4.23 (dd, 1 H, J = 12.3, 3.5 Hz, H-
6a′), 4.21–4.17 (m, 1 H, H-5′), 4.02 (dd, 1 H, J = 12.2, 1.7 Hz, H-
6b′), 3.68–3.61 (m, 1 H, H-6), 2.75 (dd, 1 H, J = 16.8, 5.4 Hz, H-
5a), 2.70–2.63 (m, 2 H, CH2Ph), 2.50 (dd, 1 H, J = 16.8, 8.4 Hz, H-
5b), 2.02, 1.97, 1.95, 1.94 (4 s, 12 H, OAc) 1.97–1.82 (m, 2 H,
CH2CH2Ph).
(S)-2-(2′,3′,4′,6′-Tetra-O-acetyl- -D-galactopyranosyl)amino-
5,6-dihydro-4-pyrimidinone (4b)
Compound 4b was prepared from 3b (50 mg, 0.07 mmol).
Yield: 11 mg (35%); colorless foam.
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Syntheses of Guanidinoglycosides with the Inventive use of Mitsunobu Conditions and DBU
261
13C NMR: δ = 170.71, 170.01, 169.92, 169.56, 167.32, 161.92,
139.19, 128.86, 128.19, 126.71, 90.18, 69.93, 69.47, 69.23, 67.86,
61.37, 47.78, 35.93, 35.83, 31.29, 20.73, 20.66, 20.58.
thank Miss Chor Yong Eng and Miss Wai See Yap for running the
2D-NMR experiments.
HRMS: m/z calcd for C26H34N3O10 (M + H)+: 548.2245; found:
548.2248.
References
(1) First and second authors contributed equally to this work.
(2) (a) Lemieux, R. U.; Wolfrom, M. L. Adv. Carbohydr. Chem.
1948, 3, 337. (b) Maurin, M.; Raoult, D. Antimicrob. Agents
Chemother. 2001, 45, 2977.
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Jr.; Bowden, C. R.; Maryanoff, B. E. J. Med. Chem. 1989,
32, 2110.
Compound 4d-II
1H NMR: δ = 7.24 (t, 2 H, J = 7.3 Hz, Ph), 7.16 (t, 1 H, J = 7.3 Hz,
Ph), 7.10 (d, 2 H, J = 7.3 Hz, Ph), 5.68 (br s, 1 H, NH), 5.48 (t, 1 H,
J = 9.8 Hz, H-3′), 5.22 (d, 1 H, J = 4.3 Hz, H-1′), 4.98 (t, 1 H,
J = 9.7 Hz, H-4′), 4.89 (dd, 1 H, J = 10.3, 4.0 Hz, H-2′), 4.08–4.03
(m, 2 H, H-6a′, H-6b′), 3.94–3.91 (m, 1 H, H-5′), 3.56–3.50 (m, 1
H, H-6), 2.66–2.62 (m, 3 H, CH2Ph, H-5a), 2.38 (dd, 1 H, J = 16.3,
7.6 Hz, H-5b), 2.11, 1.96, 1.95 (3 s, 12 H, OAc), 1.88–1.79 (m, 2 H,
CH2CH2Ph).
(6) (a) Feichtinger, K.; Zapf, C.; Sings, H. L.; Goodman, M. J.
Org. Chem. 1998, 63, 3804. (b) Feichtinger, K.; Sings, H.
L.; Baker, T. J.; Matthews, K.; Goodman, M. J. Org. Chem.
1998, 63, 8432.
(7) Baker, T. J.; Luedtke, N. W.; Tor, Y.; Goodman, M. J. Org.
Chem. 2000, 65, 9054.
13C NMR: δ = 170.43, 170.19, 169.99, 169.68, 139.82, 128.78,
128.21, 126.57, 79.46, 70.47, 70.13, 68.72, 67.70, 62.33, 48.46,
36.43, 36.28, 31.55, 20.83, 20.69, 20.64.
HRMS: m/z calcd for C26H34N3O10 (M + H)+: 548.2246; found:
548.2245.
(8) Lin, P.; Lee, C. L.; Sim, M. M. J. Org. Chem. 2001, 66,
8243.
(9) (a) Gololobov, Y. G.; Zhmurova, I. N.; Kasukhin, L. F.
Tetrahedron 1981, 37, 437. (b) Molina, P.; Vilaplana, M. J.
Synthesis 1994, 1197.
(S)-2-(2′,3′,4′,6′-Tetra-O-acetyl- -D-glucopyranosyl)amino-6-
(4-nitrobenzyl)-5,6-dihydro-4-pyrimidinone (4e)
Compound 4e was prepared from 3e (20 mg, 0.024 mmol).
Yield: 9 mg (66%); white foam.
(10) (a) Hughes, D. L. Org. Prep. Proced. Int. 1996, 28, 127.
(b) Mitsunobu, O. Synthesis 1981, 1.
(11) (a) Dodd, D. S.; Wallace, O. B. Tetrahedron Lett. 1998, 39,
5701. (b) Kim, H.; Mathew, F.; Ogbu, C. Synlett 1999, 2,
193. (c) Dodd, D. S.; Kozikowski, A. P. Tetrahedron Lett.
1994, 35, 977.
1H NMR: δ = 8.18 (d, 2 H, J = 8.6 Hz, C6H4), 7.23 (d, 2 H, J = 8.6
Hz, C6H4), 6.19 (d, 1 H, J = 3.7 Hz, H-1′), 5.51 (t, 1 H, J = 9.9 Hz,
H-3′), 5.09 (t, 1 H, J = 9.9 Hz, H-4′), 5.01 (dd, 1 H, J = 10.3, 3.8 Hz,
H-2′), 4.20 (dd, 1 H, J = 12.5, 3.4, H-6a′), 4.16–4.11 (m, 1 H, H-5′),
4.00 (dd, 1 H, J = 12.6, 2.1 Hz, H-6b′), 4.01–3.95 (m, 1 H, H-6),
3.00 (d, 2 H, J = 6.9 Hz, CH2C6H4), 2.76 (dd, 1 H, J = 16.7, 5.3, H-
5a), 2.54 (dd, 1 H, J = 16.7, 8.6 Hz, H-5b), 2.01, 1.97, 1.95, 1.94 (4
s, 12 H, OAc).
13C NMR: δ = 170.67, 169.97, 169.92, 169.51, 166.35, 157.65,
147.60, 142.13, 130.13, 124.42, 90.34, 69.87, 69.44, 69.34, 67.82,
61.31, 49.63, 40.59, 35.57, 20.71, 20.65, 20.58.
HRMS: m/z calcd for C25H31N4O12 (M + H)+: 579.1939; found:
579.1934.
(12) To further prove the existence of rotomers, Boc-protection
of 2 was carried out using Boc2O and DMAP in CH2Cl2.
Both 2a and 2b yielded only their respective α rotomers.
(13) (a) Bu, X.; Xie, G.; Law, C. W.; Guo, Z. Tetrahedron Lett.
2002, 43, 2419. (b) Sheppeck, J. E. II; Kar, H.; Hong, H.
Tetrahedron Lett. 2000, 41, 5329. (c) Metcalf, C. A. III; Vu,
C. B.; Sundaramoorthi, R.; Jacobsen, V. A.; Laborde, E. A.;
Green, J.; Green, Y.; Macek, K. J.; Merry, T. J.; Pradeepan,
S. G.; Uesugi, M.; Varkhedkar, V. M.; Holt, D. A.
Tetrahedron Lett. 1998, 39, 3435. (d) Wade, J. D.; Bedford,
J.; Sheppard, R. C.; Tregear, G. W. Pept. Res. 1991, 4, 194.
(14) (a) Ouyang, X.; Kiselyov, A. S. Tetrahedron 1999, 55,
8295. (b) Mori, Y.; Yaegashi, K.; Furukawa, H. Tetrahedron
Lett. 1999, 40, 7239. (c) Magri, N. F.; Kingston, D. G. I. J.
Nat. Prod. 1988, 51, 298. (d) Roush, W. R.; Follows, B. C.
Tetrahedron Lett. 1994, 28, 4935.
Acknowledgment
This project is funded by the Agency for Science, Technology and
Research of Singapore. We are grateful to Professor Murray Good-
man for his expert opinion in the guanidinlyation reaction. We
Synthesis 2003, No. 2, 255–261 ISSN 0039-7881 © Thieme Stuttgart · New York