Highly α-selective synthesis of sialyl spirohydantoins by regiospecific domino condensation/O→N acyl migration/N-sialylation of carbodiimides with peracetylated sialic acid

Article abstract of DOI:10.1021/jo100016k

Figure presented A novel and efficient process for the synthesis of α-sialyl spirohydantoin analogues via one-pot sequential reaction involving various carbodiimides and peracetylated Neu5Ac is reported. BF ₃·Et₂O mediating intramolecular N-sialylation with excellent α-selectivity is first demonstrated.

Full text of DOI:10.1021/jo100016k

pubs.acs.org/joc
Highly r-Selective Synthesis of Sialyl Spirohydantoins by Regiospecific
Domino Condensation/OfN Acyl Migration/N-Sialylation
of Carbodiimides with Peracetylated Sialic Acid
Dengyou Zhang, Deju Ye, Enguang Feng, Jinfang Wang, Jianmei Shi, Hualiang Jiang, and
Hong Liu*
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for
Biological Sciences, Chinese Academy of Sciences, Shanghai, 201203, People’s Republic of China
hliu@mail.shcnc.ac.cn
Received January 6, 2010
A novel and efficient process for the synthesis of R-sialyl spirohydantoin analogues via one-pot
sequential reaction involving various carbodiimides and peracetylated Neu5Ac is reported. BF3 Et2O
mediating intramolecular N-sialylation with excellent R-selectivity is first demonstrated.
3
Introduction
Hydantoins (1, Figure 1) are an important class of hetero-
cyclic compounds with numerous pharmaceutical applica-
tions that have been widely used in biological screenings.
These compounds have been used as anticonvulsants,1
antimuscarinics,2 anticancers,3 antivirals,4 antidiabetics,5
antiulcers, and antiarrythmics.6
FIGURE 1. The structures of hydantoins and spirohydantoins.
The spirohydantoin nucleus incorporated at the anome-
ric position of the carbohydrates has been reported to
show important biological activities. (þ)-Hydantocidin (2,
Figure 1), which includes 1-deoxy-L-ribofuranose with
hydantoin scaffold, has potent herbicidal activity and is
nontoxic in microorganisms and animals.7 Glucopyrano-
sylidene-spiro-hydantoin (3, Figure 1) was found to be one
of the most potent inhibitors of glycogen phosphorylase
known to date.8
Sialic acids are a family of 9-carbon carboxylated sacchar-
ides often found at the nonreducing terminus of glycans and
play significant roles in a number of biological processes,
including cell-cell recognition, cell-adhesion, and tumor
metastasis.9 N-Acetylneuraminic acid (Neu5Ac), a predomi-
nant sialic acid, is typically linked R-(2,3) or R-(2,6) to
galactoside residues, or polymerized in the form of R-(2,8)
or R-(2,9) linkages. Over the years, considerable attention
has been paid to the development of methodologies and
strategies for the synthesis of sialyl analogues, including
O-sialosides,10 C-sialosides,11 and N-sialosides.12 Furthermore,
some studies have shown that sialyl nucleotides serve as
inhibitors of sialyltransferase.13 To our knowledge, synthesis
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3552 J. Org. Chem. 2010, 75, 3552–3557
Published on Web 05/12/2010
DOI: 10.1021/jo100016k
r
2010 American Chemical Society

Zhang et al.
JOCArticle
SCHEME 1. Proposed One-Pot Sequential Synthesis of Sialyl Hydantoins
of spirohydantoins based on the sialic acid scaffold has not
been reported yet.
carbodiimides with peracetylated sialic acid 4. An attractive
feature of this protocol is that high R-selectivity can be
achieved via intramolecular N-sialylation of the urea group
We had previously reported an efficient approach for
the dehydrative sialylation of various substrates with C-4-
aminated sialyl-hemiketal donors based on the reaction of
simultaneous stereoselective 2-O-deacetylation and 4-ami-
nation of peracetylated Neu5Ac.14 In this study, we report
the synthesis of spirohydantoins based on the sialic acid
scaffold (sialyl spirohydantoins) by regiospecific one-pot
domino condensation/OfN acyl migration/N-sialylation of
mediated by BF3 Et2O. To the best of our knowledge, this
3
is the first report on the synthesis of sialyl spirohydantoins
using readily available 4 and carbodiimides as starting
materials.
We hypothesized that peracetylated sialic acid 4, which
can be easily synthesized from Neu5Ac, may undergo the
following process (Scheme 1), leading to the formation of a
wide range of sialyl spirohydantoins. Initially, carbodiimides
1015 rapidly react with the peracetylated sialic acid 4 to form
O-acyl isourea intermediate 5, which may undergo OfN
acyl migration16 to give N-acyl urea 6 in the absence of a
nucleophile. Subsequently, the N-acyl urea 6 activated by an
appropriate Lewis acid in situ would undergo intramolecular
N-sialylation to afford the sialyl spirohydantoin. Under
Lewis acid mediation, the N-acyl urea 6 may generate
intermediate 7, which is likely to be stabilized by the carbonyl
group of the urea,17 followed by the generation of inter-
mediates 8a and 8b. In comparison with 8b, 8a may proceed
smoothly from O- to N- acyl migration16 due to less steric
hindrance of the Rface, which would furnish the desired R-sialyl
spirohydantoins.
(10) (a) Ye, D. J.; Liu, W. F.; Zhang, D. Y.; Feng, E. G.; Jiang, H. L.; Liu,
H. J. Org. Chem. 2009, 74, 1733–1735. (b) Liu, Y. P.; Ruan, X. H.; Li, X. P.;
Li, Y. X. J. Org. Chem. 2008, 73, 4287–4290. (c) Crich, D.; Li, W. J. J. Org.
Chem. 2007, 72, 2387–2391. (d) Okamoto, R.; Souma, S.; Kajihara, Y.
J. Org. Chem. 2008, 73, 3460–3466. (e) Crich, D.; Li, W. J. J. Org. Chem.
2007, 72, 7794–7797. (f) Cow, D.; Li, W. J. Org. Lett. 2006, 8, 959–962.
(g) Tanaka, H.; Nishiura, Y.; Takahashi, T. J. Am. Chem. Soc. 2006, 128,
7124–7125. (h) Abdu-Allah, H. H.; Tamanaka, T.; Yu, J.; Zhuoyuan, L.;
Sadagopan, M.; Adachi, T.; Tsubata, T.; Kelm, S.; Ishida, H.; Kiso, M.
J. Med. Chem. 2008, 51, 6665–6681. (i) Crich, D.; Wu, B. Org. Lett. 2008, 10,
4033–4035. (j) Tanaka, H.; Adachi, M.; Takahashi, T. Chem. Eur. J. 2005,
11, 849–862.
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Angew. Chem., Int. Ed. 2003, 42, 2073–2075. (b) Abdallah, Z.; Doisneau, G.;
Beau, J. M. Angew. Chem., Int. Ed. 2003, 42, 5209–5212. (c) Malapelle, A.;
Abdallah, Z.; Doisneau, G.; Beau, J. M. Angew. Chem., Int. Ed. 2006, 45,
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J. Org. Chem. 2007, 72, 3085–3088.
(12) (a) Llinares, M.; Roy, R. Chem. Commun. 1997, 21, 2119–2120.
(b) Sabesan, S. Tetrahedron Lett. 1997, 38, 3127–3130. (c) Ogura, H.; Fujita, H.;
Furuhata, K.; Itoh, M.; Shitori, Y. Chem. Pharm. Bull. 1986, 34, 1479–1484.
(13) Kleineidam, R. G.; Schmelter, T.; Schwarz, R. T.; Schauer, R.
Glycoconjugate J. 1997, 14, 57–66.
(15) Carbodiimides can be efficiently prepared according to the follow-
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TABLE 1. Optimization of One-Pot Reaction Conditions
entry
solvent
T (°C)
t (h)
10a (equiv)
BF3 Et2O (equiv)
3
9a: % yielda (R)b
1
2
3
4
5
6
7
8
9
dioxane
dioxane
dioxane
CH3CN
DMF
CH2Cl2
dioxane
dioxane
dioxane
rt
rt
rt
rt
rt
rt
rt
40
rt
12
24
48
24
24
24
24
24
24
1.1
1.1
1.1
1.1
1.1
1.1
1.5
1.1
1.1
3
3
3
3
3
3
3
3
2
53
66
66
16
trace
29
46
60
55
aIsolated yields. bDetermined by LC-MS on the crude reaction mixture and 1H NMR analysis.
SCHEME 2. Proposed Mechanism for the Reaction of Asym-
metric N-Alkyl-N0-arylcarbodiimides with Acid
Results and Discussion
Initially, we chose N,N0-dicyclohexylcarbodiimide (DCC)
as a model carbodiimide to test the reaction conditions.
The critical point in this reaction is the effective formation
of intermediate, N-acyl urea 6, as well as the Lewis acid-
mediatedintramolecularcyclization.AsdiscussedinScheme1,
direct reaction of 4 with DCC produced N-acyl urea 6a, which
was isolated in 85% yield and confirmed by LC-MS and
NMR analysis. We observed that the BF3 Et2O, an inexpen-
3
sive and easily available Lewis acid, could effectively catalyze
the intramolecular N-sialylation of 6a to afford the desired
product 9a in 78% yield. To avoid isolation of 6a, we per-
formed the reaction in a one-pot sequential fashion. We
started by treating 4 (0.1 mmol) with DCC (0.11 mmol) in
dioxane (2 mL) at room temperature for 12 h, followed by
revealed a doublet C-1 signal with a coupling constant of
5.24 Hz, indicative of a (5R)-configuration.
After determining the optimal conditions, we proceeded
to examine the generality of the process. As illustrated in
Table 2, we first demonstrated that a wide range of sym-
metric N,N0-dialkyl- and N,N0-diarylcarbodiimides can
provide the corresponding sialyl spirohydantoins 9b-f in
moderate to good yields and with excellent R-selectivity
(entries 1-5, Table 2). The reaction with N,N0-diisopro-
pylcarbodiimide (DIC) was slower than that with DCC,
furnishing the corresponding product 9b in 35% yield. It is
worth noting that a good yield was obtained when the
reaction temperature of 4 with DIC was increased to 40 °C
(entry 1, Table 2). Compared to symmetric N,N0-dialkyl-
carbodiimides, the symmetric N,N0-diarylcarbodiimides
10c-e with electron-rich and electron-neutral groups
(entries 2-4, Table 2) proceeded smoothly (84-85%),
presumably due to the efficient OfN acyl migration of
electron-rich and electron-neutral N,N0-diarylcarbodii-
mides. However, the reaction of N,N0-diarylcarbodiimide
10f incorporating an electron-withdrawing group (entry 5,
Table 2) was not very satisfactory and the yield was only
40%. It is well-known that the reaction of asymmetric
N-alkyl-N0-arylcarbodiimides with acid will exclusively
form the regioisomer of CdN bond migration conjugated
with the aromatic π-system (Scheme 2).16b Finally, we
investigated the sterically congested strongly asymmetric
N-cyclohexyl-N0-arylcarbodiimide 10g-i (entries 6-8,
Table 2). As anticipated, compound 4 reacted smoothly with
the addition of BF3 Et2O (0.3 mmol). After overnight
3
incubation, 53% yield of the desired product 9a was ob-
tained (entry 1, Table 1). When the reaction time of 4 with
DCC was prolonged to 24 h, the yield increased to 66%
(entry 2, Table 1). However, the yield did not increase when
the reaction time of 4 with DCC was prolonged to 48 h
(entry 3, Table 1). It did not work very well when perform-
ing the reaction in other solvents, such as CH2Cl2, DMF,
and CH3CN, due to inefficient formation of N-acyl urea 6a
monitored by thin-layer chromatography (TLC) analysis
(entries 4-6, Table 1). The yields were also reduced when
the amount of DCC was increased (entry 7, Table 1), or
when the reaction temperature of 4 with DCC was increased
to 40 °C (entry 8, Table 1). Finally, we found that reducing
the amount of BF3 Et2O reduced the yield slightly (55%,
3
entry 9). The anomeric configuration of the R-sialyl hydantoin
9a was determined by the long-range JC-5,H-9ax coupling con-
stant of its hydrolyzed product 11 (see the Supporting
Information).18 By selective gated proton-decoupled 13C
NMR experiment, the coupling pattern of C-1 of the Ranomer
(18) (a) Hori, H.; Nakajima, T.; Nishida, Y.; Ohrui, H.; Meguro, H.
Tetrahedron Lett. 1988, 29, 6317–6320. (b) Lu, K. C.; Tseng, S. Y.; Lin, C. C.
Carbohydr. Res. 2002, 337, 755–760. (c) Lin, C. C.; Huang, K. T. Org. Lett.
2005, 7, 4169–4172.
3554 J. Org. Chem. Vol. 75, No. 11, 2010

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JOCArticle
TABLE 2. Synthesis of Various Sialyl Spirohydantoin Analogues
aIsolated yields. bDetermined by LC-MS on the crude reaction mixture and 1H NMR analysis. cReaction at 40 °C.
J. Org. Chem. Vol. 75, No. 11, 2010 3555

Zhang et al.
JOCArticle
10g-i affording sialyl spirohydantoins 9g-i as the single
products with good yields (70-78%). It was found that the N-
acyl urea intermediates while undergoing intramolecular cy-
(m, 1H), 4.74 (dd, J = 2.0, 12.0 Hz, 1H), 4.19-4.06 (m, 2H), 4.00
(dd, J = 2.0, 10.8 Hz, 1H), 3.90 (dd, J = 7.2, 12.0 Hz, 1H),
3.72-3.66 (m,1H), 2.72 (dd, J =10.8, 13.2 Hz, 1H), 2.36 (dd, J =
5.2, 13.2 Hz, 1H), 2.24-2.20 (m, 1H), 2.17-2.16 (m, 4H), 2.13 (s,
3H), 2.07 (s, 3H), 2.05 (s, 3H), 2.01 (s, 3H), 1.87 (s, 3H), 1.82-
1.75 (m, 6H), 1.65-1.49 (m, 4H), 1.33-1.10 (m, 8H); 13C NMR
(100 MHz, CDCl3) δ 171.5, 171.1, 170.8, 170.2, 170.0, 168.3,
167.3, 153.5, 100.5, 73.4, 71.9, 69.0, 67.4, 63.0, 57.2, 50.6, 48.8,
36.39, 32.2, 31.8, 31.6, 29.6, 26.2, 26.1, 25.5, 25.4, 24.9, 24.5, 23.1,
21.0, 20.8, 20.7, 20.6. MS (ESI, m/z) 747.9 [M þ Na]þ. HRMS
(ESI) calcd for C34H51N3O14Na ([M þ Na]þ) 748.3269, found
748.3267.
clization via BF3 Et2O mediation decomposed to other
3
byproducts.19
Conclusion
In conclusion, we have developed a novel and efficient
process for the synthesis of sialyl spirohydantoin analogues
via one-pot sequential reaction involving carbodiimides and
peracetylated Neu5Ac. We have demonstrated that BF3
3
(5R,7R,8R,9S)-8-Acetamido-9-acetoxy-7-[((1S,2R)-1,2,3-tri-
acetoxy)propyl]-1,3-dicyclohexyl-6-oxa-1,3-diazaspiro[4.5]decane-
2,4-dione, 9a. Method A: To a stirred solution of 6a (100 mg, 0.14
mmol) in dioxane (3 mL) was added BF3.Et2O (53 μL, 0.42 mmol).
The solution was stirred overnight, and then water (1 mL) was
added. The crude was extracted with EA; the combined organic
layers were dried over anhydrous Na2SO4, filtered, and concen-
trated under vacuum; and the crude was purified by silica gel
column chromatography (chloroform/acetone, from 12/1 to10/1)
to afford 9a in 77% yield . Method B: 9a was prepared according
to the general experimental procedure. [R]18D þ9 (c 0.055, MeOH).
1H NMR (400 MHz, CDCl3) δ 5.58 (m, 1H), 5.48 (dt, J = 5.2,
11.6 Hz, 1H), 5.28 (dd, J = 2.0, 8.4 Hz, 1H), 5.26-5.24 (m, 1H),
4.51 (dd, J = 2.0, 10.8 Hz, 1H), 4.24-4.14 (m, 2H), 4.03 (dd, J =
6.0, 12.8 Hz, 1H), 3.85 (m, 1H), 3.59 (m, 1H), 2.30 (dd, J = 5.2,
13.2 Hz, 1H), 2.18-2.10 (m, 6H), 2.02 (m, 6H), 2.00 (s, 3H), 1.90
(s, 3H), 1.81-1.55 (m, 10H), 1.34-1.10 (m, 8H); 13C NMR
(100 MHz, CDCl3) δ 170.8, 170.5, 170.3, 170.0, 169.3, 168.9,
141.6, 97.1, 72.3, 68.7, 68.6, 66.9, 62.3, 53.7, 52.9, 48.9, 35.5, 34.0,
33.8, 28.5, 28.2, 25.8, 25.7, 25.1, 24.4, 24.3, 23.1, 20.8, 20.8, 20.7.
LC/MS (75% MeOH/25% H2O), tR = 10.787 min, MS (ESI,
m/z) 666.3 [M þ H]þ. HRMS (ESI) calcd for C32H47N3O12Na
([M þ Na]þ) 688.3057, found 688.3063.
Et2O mediates intramolecular N-sialylation with excellent
R-selectivity. This new synthetic strategy would be a useful
tool for the preparation of a variety of biologically important
modified Neu5Ac derivatives.
Experiment Section
General Methods. The reagents (chemicals) were purchased
from commercial sources, and used without further purification.
Carbodiimides (10c, 10e, 10g, 10h, 10i) were prepared according
to ref 15. Analytical thin layer chromatography (TLC) was
HSGF 254 (0.15-0.2 mm thickness). Compound spots were
visualized by UV light (254 nm) and/or by staining with iodine.
Column chromatography was performed on silica gel FCP
200-300. Optical rotations were measured on a polarimeter.
NMR spectra were run on 300 or 400 MHz instrument. Chemical
shifts were reported in parts per million (ppm, δ) downfield from
tetramethylsilane. Proton coupling patterns are described as
singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and
broad (br). Low- and high-resolution mass spectra (LRMS and
HRMS) were measured on a spectrometer.
General Experimental Procedure for the Carbodiimides Reacted
with Peracetylated Sialic Acid 4. To a stirred solution of peracety-
lated sialic acid 4 (0.19 mmol) in dioxane (3 mL) was added
carbodiimide (1.1 equiv), then the mixture was stirred at room
(5R,7R,8R,9S)-8-Acetamido-9-acetoxy-7-[((1S,2R)-1,2,3-tri-
acetoxy)propyl]-1,3-diisopropyl-6-oxa-1,3-diazaspiro[4.5]decane-
1
2,4-dione, 9b. [R]18 þ7 (c 0.18, MeOH). H NMR (400 MHz,
temperature, followed by the addition of BF3 Et2O (3.0 equiv).
D
3
CDCl3) δ 5.52-5.45 (m, 2H), 5.30-5.25 (m, 2H), 4.52 (dd, J =
2.0, 10.8 Hz, 1H), 4.30 (quint, J = 6.8 Hz, 1H), 4.24-4.17 (m,
2H), 4.04 (dd, J = 5.2, 12.8 Hz, 1H), 3.94 (quint, J = 6.0 Hz,
1H), 2.32 (dd, J = 5.2, 13.2 Hz, 1H), 2.18-2.12 (m, 4H),
2.04-2.03 (m, 6H), 2.01 (s, 3H), 1.91 (s, 3H), 1.42-1.38 (m,
6H), 1.14 (d, J = 6.4 Hz, 3H), 1.08 (d, J = 6.4 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 170.8, 170.5, 170.3, 170.0, 169.3,
168.9, 141.9, 97.2, 72.3, 68.6, 68.5, 67.0, 66.9, 62.3, 48.9, 46.3,
45.3, 35.5, 24.1, 23.8, 23.2, 20.8, 20.8, 20.7, 18.9, 18.7. LC/MS
(65% MeOH/35% H2O), tR = 5.787 min, MS (ESI, m/z) 586.2
[M þ H]þ. HRMS (ESI) calcd for C26H39N3O12Na ([M þ Na]þ)
608.2431, found 608.2416.
The resulting solution was stirred overnight and then the satu-
rated sodium bicarbonate solution or water (1 mL) was added.
The mixture was extracted with ethyl acetate (EA); the combined
organic layers were dried over anhydrous Na2SO4, filtered, and
concentrated under vacuum; and the crude was purified by silica
gel column chromatography (chloroform/acetone, from 15/1 to
10/1) to afford the product.
Typical Procedure for Deprotection of Sialyl Spirohydantoin
9a. To a solution of 9a (100 mg, 0.15 mmol) in methanol (2 mL)
was added a catalytic amount of sodium methoxide. The solution
was stirred for 0.5 h at room temperature and then quenched with
Dowex 50WX2, 100-200 mesh, ion-exchange resin. The mixture
was filtered through Celite and concentrated under reduced
pressure to give 11.
(2R,3S)-3-(Acetyloxy)-3-[(3R,4R,6R)-4,6-bis(acetyloxy)-6-{[1-
cyclohexyl(cyclohexylcarbamoyl)amino]carbonyl}-3-acetamidooxan-
2-yl]-2-(prop-1-en-2-yloxy)propyl Acetate, 6a. To a stirred solu-
tion of peracetylated sialic acid 4 (100 mg, 0.19 mmol) in dioxane
(3 mL) was added N,N0-dicyclohexylcarbodiimide (43.7 mg, 0.21
mmol). The solution was stirred for 24 h at room temperature,
then concentrated under vacuum. The crude was extracted with EA;
the combined organic layers were dried over anhydrous Na2SO4,
filtered, and concentrated under vacuum; and the crude was
purified by silica gel column chromatography (chloroform/acetone,
from 8/1 to 6/1) to afford 6a in yield 85%. 1H NMR (400 MHz,
CDCl3) δ 6.38 (d, J = 6 Hz 1H), 5.42 (dd, J = 2.0, 4.8 Hz, 1H),
5.55-5.31 (m, 1H), 5.26 (dt, J = 5.2, 10.8 Hz, 1H), 4.92-4.89
(5R,7R,8R,9S)-8-Acetamido-9-acetoxy-7-[((1S,2R)-1,2,3-tri-
acetoxy)propyl]-1,3-diphenyl-6-oxa-1,3-diazaspiro[4.5]decane-
1
2,4-dione, 9c. [R]18 -5 (c 0.12, MeOH). H NMR (400 MHz,
D
CDCl3) δ 7.58-7.42 (m, 5H), 7.34-7.30 (m, 2H), 7.13-7.09 (m,
3H), 5.57-5.51 (m, 2H), 5.40-5.35 (m, 1H), 5.29 (dd, J = 2.0,
8.8 Hz, 1H), 4.49 (dd, J = 2.0, 10.4 Hz, 1H), 4.29-4.21 (m, 2H),
4.03 (dd, J = 6.0, 12.4 Hz, 1H), 2.57 (dd, J = 5.2, 13.2 Hz, 1H),
2.30 (dd, J = 11.6, 13.2 Hz, 1H), 2.15 (s, 3H), 2.04 (s, 3H), 2.02 (s,
3H), 1.90 (s, 3H), 1.78 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
170.8, 170.5, 170.3, 170.0, 169.4, 167.8, 143.8, 143.1, 131.0, 129.1,
128.7, 127.0, 124.5, 123.3, 98.6, 72.4, 68.4, 68.1, 66.6, 62.4, 48.7,
35.1, 23.1, 20.8, 20.7, 20.6. LC/MS (61% MeOH/39% H2O),
tR = 8.151 min, MS (ESI, m/z) 654.2 [M þ H]þ. HRMS (ESI)
calcd for C32H35N3O12Na ([Mþ Na]þ) 676.2118, found 676.2117.
(5R,7R,8R,9S)-8-Acetamido-9-acetoxy-7-[((1S,2R)-1,2,3-tri-
acetoxy)propyl]-1,3-di-p-tolyl-6-oxa-1,3-diazaspiro[4.5]decane-
2,4-dione, 9d. [R]18D -14 (c 0.11, MeOH). 1H NMR (300 MHz,
CDCl3) δ 7.43 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H),
(19) See analysis ofthe crude spectrumsection intheSupporting Information.
3556 J. Org. Chem. Vol. 75, No. 11, 2010

Zhang et al.
JOCArticle
(5R,7R,8R,9S)-8-Acetamido-9-acetoxy-7-[((1S,2R)-1,2,3-tri-
acetoxy)propyl]-1-cyclohexyl-3-phenyl-6-oxa-1,3-diazaspiro[4.5]-
7.12 (d, J = 8.1 Hz, 2H), 7.01 (d, J = 8.1 Hz, 2H), 5.54 (dt, J =
5.1, 11.4 Hz, 1H), 5.39-5.27 (m, 2H), 5.29 (dd, J = 1.8, 8.7 Hz,
1H), 4.49 (dd, J = 1.8, 10.5 Hz, 1H), 4.29-4.18 (m, 2H), 4.03
(dd, J = 6.1, 12.8 Hz, 1H), 2.55 (dd, J = 4.8, 13.2 Hz, 1H), 2.40
(s, 3H), 2.33-2.25 (m, 4H), 2.14 (s, 3H), 2.04 (s, 3H), 2.03 (s,
3H), 1.91 (s, 3H), 1.80 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
170.9, 170.5, 170.3, 170.0, 169.4, 167.9, 143.7, 140.5, 139.1,
134.0, 129.7, 129.2, 128.4, 126.7, 123.2, 98.6, 72.4, 68.5, 68.2,
66.6, 62.4, 48.7, 35.1, 23.1, 21.2, 20.9, 20.8, 20.7, 20.6. LC/MS
(60% MeOH/40% H2O), tR = 15.706 min, MS (ESI, m/z) 682.2
[M þ H]þ. HRMS (ESI) calcd for C34H39N3O12Na ([M þ Na]þ)
704.2431, found 704.2430.
(5R,7R,8R,9S)-8-Acetamido-9-acetoxy-7-[((1S,2R)-1,2,3-tri-
acetoxy)-propyl]-1,3-bis(4-methoxyphenyl)-6-oxa-1,3-diazaspiro-
[4.5]decane-2,4-dione, 9e. [R]18D -15 (c 0.15, MeOH). 1H NMR
(400 MHz, CDCl3) δ7.44 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.8Hz,
2H), 7.00 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 5.55-5.52
(m, 2H), 5.39-5.35 (m, 1H), 5.28 (dd, J = 2.0, 9.6 Hz, 1H), 4.49
(dd, J = 2.0, 10.4 Hz, 1H), 4.29-4.20 (m, 2H), 4.02 (dd, J = 6.0,
12.4 Hz, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 2.56 (dd, J = 5.2, 13.2 Hz,
1H), 2.31 (t, J = 12.4 Hz, 1H), 2.15 (s, 3H), 2.05 (s, 3H), 2.02
(s, 3H), 1.90 (s, 3H), 1.80 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
170.9, 170.5, 170.3, 170.0, 169.4, 167.9, 159.7, 156.6, 143.4, 136.0,
128.3, 124.8, 123.6, 114.3, 113.8, 98.6, 72.4, 68.6, 68.0, 66.6, 62.4,
55.4, 48.7, 35.2, 23.1, 20.9, 20.8, 20.7, 20.6. LC/MS (65% MeOH/
35% H2O), tR = 14.219 min, MS (ESI, m/z) 714.1 [M þ H]þ.
HRMS (ESI) calcd for C34H39N3O14Na ([M þ Na]þ) 736.2330,
found 736.2328.
(5R,7R,8R,9S)-8-Acetamido-9-acetoxy-7-[((1S,2R)-1,2,3-tri-
acetoxy)propyl]-1,3-bis(4-nitrophenyl)-6-oxa-1,3-diazaspiro-
[4.5]decane-2,4-dione, 9f. [R]18D -32 (c 0.14, MeOH). 1H NMR
(400 MHz, CDCl3) δ8.42 (d, J = 9.2 Hz, 2H), 8.23 (d, J = 8.8Hz,
2H), 7.88 (d, J = 9.2 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 5.51 (dt,
J = 5.2, 11.2 Hz, 1H), 5.41-5.37 (m, 1H), 5.33-5.26 (m, 2H),
4.43 (dd, J = 2.0, 10.4 Hz, 1H), 4.31-4.21 (m, 2H), 4.00 (dd, J =
6.4, 12.4 Hz, 1H), 2.63 (dd, J = 5.2, 13.2 Hz, 1H), 2.33 (dd, J =
11.6, 13.2 Hz, 1H), 2.18 (s, 3H), 2.06 (s, 3H), 2.03 (s, 3H), 1.94 (s,
3H), 1.80 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.0, 170.7,
170.6, 170.0, 169.7, 167.0, 149.0, 147.5, 144.6, 144.5, 136.1, 127.8,
124.7, 124.4, 123.8, 99.1, 72.7, 68.4, 68.0, 66.6, 62.5, 48.7, 34.8,
23.0, 20.7. LC/MS (65% MeOH/35% H2O), tR = 7.397 min, MS
(ESI, m/z) 684.0 [M þ H]þ. HRMS (ESI) calcd for C32H33N5O16-
Na ([M þ Na]þ) 766.1820, found 766.1805.
1
decane-2,4-dione, 9h. [R]18 þ14 (c 0.085, MeOH). H NMR
D
(400 MHz, CDCl3) δ 7.48-7.42 (m, 4H), 7.38-7.34 (m, 1H),
5.59-5.52 (m, 2H), 5.36-5.29 (m, 2H), 4.50 (dd, J = 2.0, 10.4 Hz,
1H), 4.29 (q, J = 10.0, 1H), 4.20 (dd, J = 2.0, 12.4 Hz, 1H), 4.02
(dd, J = 5.2, 12.4 Hz, 1H), 3.69 (m, 1H), 2.52 (dd, J = 5.2, 13.2
Hz, 1H), 2.28 (dd, J = 11.6, 13.2 Hz, 1H), 2.17 (s, 3H), 2.05 (s,
3H), 2.01 (s, 3H), 1.89 (s, 3H), 1.83-1.57 (m, 8H), 1.37-1.15 (m,
5H); 13C NMR (100 MHz, CDCl3) δ 170.9, 170.5, 170.3, 170.0,
169.2, 167.9, 142.1, 131.4, 128.7, 128.4, 126.5, 97.7, 72.3, 68.7,
68.0, 66.6, 62.4, 54.2, 48.8, 35.4, 33.9, 33.6, 25.6, 24.6, 24.5, 23.1,
20.8, 20.7, 20.4. LC/MS (65% MeOH/35% H2O), tR = 11.158
min, MS (ESI, m/z) 660.3 [M þ H]þ. HRMS (ESI) calcd for
C32H41N3O12Na ([M þ Na]þ) 682.2588, found 682.2600.
(5R,7R,8R,9S)-8-Acetamido-9-acetoxy-7-[((1S,2R)-1,2,3-tri-
acetoxy)propyl]-1-cyclohexyl-3-(4-(trifluoromethyl)phenyl)-6-oxa-
1,3-diazaspiro[4.5]decane-2,4-dione, 9i. [R]18D þ30 (c0.08, MeOH).
1H NMR (400 MHz, CDCl3) δ 7.74-7.69 (m, 4H), 5.53 (dt, J =
5.2, 10.4 Hz, 1H), 5.39-5.34 (m, 2H), 5.29 (dd, J = 2.0, 9.2 Hz,
1H), 4.45 (dd, J = 2.0, 10.4 Hz, 1H), 4.30 (q, J = 10.4 Hz, 1H),
4.19 (dd, J = 2.4, 12.4 Hz, 1H), 4.02 (dd, J = 6.0, 12.4 Hz, 1H),
3.71 (m, 1H), 2.53 (dd, J = 5.2, 13.2 Hz, 1H), 2.31 (dd, J = 11.6,
13.2 Hz, 1H), 2.18 (s, 3H), 2.06 (s, 3H), 2.01 (s, 3H), 1.93 (s, 3H),
1.85-1.58 (m, 8H), 1.41-1.17 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ 170.8, 170.5, 170.3, 170.0, 169.2, 167.6, 141.5, 134.6,
130.3, 130.0, 126.7, 125.8, 125.0, 122.2, 97.8, 72.4, 68.6, 68.0,
66.6, 62.4, 54.3, 48.7, 35.2, 33.8, 33.5, 25.5, 24.5, 23.1, 20.8, 20.7,
20.4. LC/MS (70% MeOH/30% H2O), tR = 17.959 min, MS (ESI,
m/z) 728.2 [M þ H]þ. HRMS (ESI) calcd for C33H40N3O12NaF3-
([M þ Na]þ) 750.2462, found 750.2469.
(5R,7R,8R,9S)-8-Acetamido-9-hydroxy-7-((1S,2R)-1,2,3-hydroxy-
propyl)-1,3-dicyclohexyl-6-oxa-1,3-diazaspiro[4.5]decane-2,4-dione,
11. [R]22D -29.2 (c 0.13, MeOH). 1H NMR (400 MHz, CD3OD) δ
4.37 (dt, J = 5.2, 11.2 Hz, 1H), 4.27 (dd, J = 1.6, 10.4 Hz, 1H),
3.92-3.84 (m, 2H), 3.76-3.70 (m, 1H), 3.64-3.56 (m, 3H), 3.47 (d,
J = 9.2 Hz, 1H), 2.34 (dd, J = 5.2, 13.2 Hz, 1H), 2.12-2.13 (m,
2H), 2.02 (s, 3H), 1.92 (dd, J = 11.6, 13.2 Hz, 1H), 1.84-1.60 (m,
10H), 1.33-1.16 (m, 8H); 13C NMR (100 MHz, CDCl3) δ 175.8,
171.1 (C-1, JC-1,H-3ax = 5.24 Hz), 146.4, 99.8, 75.2, 71.7, 70.3, 67.8,
65.6, 55.8, 54.7, 54.2, 50.1, 39.7, 35.8, 35.7, 30.1, 29.9, 27.4, 26.8,
26.3, 23.1. MS (ESI, m/z) 496.0 [M þ H]þ. HRMS (ESI) calcd for
C24H39N3O8Na ([M þ Na]þ) 520.2635, found 520.2646.
(5R,7R,8R,9S)-8-Acetamido-9-acetoxy-7-[((1S,2R)-1,2,3-tri-
acetoxy)propyl]-1-cyclohexyl-3-(4-methoxyphenyl)-6-oxa-1,3-
diazaspiro[4.5]decane-2,4-dione, 9g. [R]18D þ7 (c 0.12, MeOH). 1H
NMR (300 MHz, CDCl3) δ 7.37 (d, J = 8.9 Hz, 2H), 6.95 (d,
J = 8.9 Hz, 2H), 5.55-5.52 (m, 2H), 5.38-5.28 (m, 2H), 4.51 (dd,
J = 1.8, 10.5 Hz, 1H), 4.33-4.18 (m, 2H), 4.03 (dd, J = 5.4,
12.6 Hz, 1H), 3.82 (s, 3H), 3.68 (br, 1H), 2.50 (dd, J = 4.8,
13.2 Hz, 1H), 2.28 (dd, J = 11.4, 13.2 Hz, 1H), 2.17 (s, 3H), 2.05
(s, 3H), 2.01 (s, 3H), 1.90 (s, 3H), 1.78-1.56 (m, 8H), 1.37-1.14
(m, 5H); 13C NMR (100 MHz, CDCl3) δ 170.9, 170.5, 170.3,
170.0, 169.2, 168.1, 159.2, 127.9, 124.0, 114.0, 97.8, 72.3, 68.8,
68.0, 66.6, 62.4, 55.4, 54.2, 48.7, 35.4, 33.9, 33.6, 25.6, 24.7, 24.6,
Acknowledgment. We gratefully acknowledge financial
support from the National Natural Science Foundation of
China (Grants 20721003 and 20872153), International Col-
laboration Projects (Grant 20720102040), the 863 Hi-Tech
Program of China (Grant 2006AA020602), and National
S&T Major Projects (2009ZX09301-001, 2009ZX09501-001,
and 2009ZX09501-010).
Supporting Information Available: Detailed experimental
procedures, general method for LC/MS, characterization data,
and copies of 1H NMR and 13C NMR spectra and LC/MS
spectra for all products. This material is available free of charge
via the Internet at http://pubs.acs.org.
23.1, 20.8, 20.7, 20.5. LC/MS (65% MeOH/35% H2O), tR =
11.381 min, MS (ESI, m/z) 690.0 [M þ H]þ. HRMS (ESI) calcd
for C33H43N3O13Na ([M þ Na]þ) 712.2694, found 712.2692.
J. Org. Chem. Vol. 75, No. 11, 2010 3557