Synthesis of a New Stable Conformationally Constrained 2,7-Anhydrosialic Acid Derivative

Article abstract of DOI:10.1021/jo034679b

A stereoseletive synthesis of 2,7-anhydrosialic acid derivative 18 was achieved from D-glucono-δ-lactone. A highly syn-selective addition of Grignard reagent to the N-benzylimine 8 served as a key step.

Full text of DOI:10.1021/jo034679b

CHART 1
Syn th esis of a New Sta ble
Con for m a tion a lly Con str a in ed
2,7-An h yd r osia lic Acid Der iva tive
Ke-Gang Liu, Hai-Bin Zhou, Yu-Lin Wu, and
Zhu-J un Yao*
State Key Laboratory of Bioorganic and Natural Products
Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenlin Road, Shanghai
200032, China
(1) by Ogura and co-workers.9,10 Due to the existence of
an intramolecular acetal moiety in 2, it offers an unusual
rigid core that provides conformational constraint (Chart
1). Undoubtedly, the design and synthesis of additional
sialic acid derivatives with stable and rigid conformations
would provide valuable tools for the investigation of
related biological questions. As mentioned above, the
previously reported syntheses9,10 of 2 are all from the
sialic acid Neu5Ac, and therefore, most of the functional
groups and their stereochemistries are fixed. To make
more structurally diverse molecules, we are developing
new stereoselective syntheses of these sialic acid deriva-
tives from common sugars.6k,11 Our considerations were
based on a biomimetic [6 + 3] strategy (Scheme 1), which
is commonly accepted as a biosynthetic route to sialic
acids. The key point of our synthesis is that a three-
carbon allylic bromide or propargyl bromide unit could
be regarded as a synthetic precursor of pyruvate in the
corresponding biosynthesis. One of the major advantages
of such a strategy is that because lower carbon sugars
are used as the starting materials, more diverse sialic
acids can be generated via these new intermediates
through various chemical reactions used during the
synthesis. Herein, we present our recent results on the
synthesis of a new sialic acid 3, which contains an
intramolecular glycoside prepared by the above-men-
tioned strategy. By comparison of 3 with 2, the positional
changes of functional groups on C-4 and C-5 are evident,
as are their reversed stereochemistries which act as
equatorial substitutions in 3. Physically, the structure
of 3 is kept rigid by the intramolecular glycoside,
although a lower energy of 3 is theoretically possible
determined by MM2 calculations12 (see the Supporting
Information). All of these structural characteristics were
successfully established through a highly syn-selective
addition of allylmagnesium bromide to the N-ben-
zylimine, as well as further chemical transformations.
The synthesis of 3 was accomplished as shown in
Scheme 2, Scheme 3, and Scheme 4. First, treatment of
D-gluocono-δ-lactone with 2,2-dimethoxypropane in ac-
etone and methanol in the presence of a catalytic amount
of pTsOH hydrate afforded the methyl ester 413 in high
yield (83%) after simple distillation. Protection of the
second alcohol with benzyl bromide in CH2Cl2 using silver
yaoz@mail.sioc.ac.cn
Received May 21, 2003
Abstr a ct: A stereoseletive synthesis of 2,7-anhydrosialic
acid derivative 18 was achieved from D-glucono-δ-lactone.
A highly syn-selective addition of Grignard reagent to the
N-benzylimine 8 served as a key step.
Sialic acids (e.g., N-acetylneuraminic acid, Neu5Ac, 1)
play significant biological roles in normal physiological
processes and in disease states and microbial infections.1-4
Due to the importance of sialic acids in biological
investigations, many chemists have developed a number
of efficient synthetic approaches5,6 to these valuable
compounds and their derivatives. Cornforth7 completed
the first synthesis of Neu5Ac in 1958. However, reports
of sialic acids containing intramolecular glycosides are
few. The first natural example, 2,7-anhydro-N-acetyl-
neuraminic acid 2, was isolated in a free form, cerumen
of the wet type, by Suzuk8 and synthesized from Neu5Ac
* To whom correspondence should be addressed. Fax: +86 21
64166128.
(1) Schauer, R.; Kamerling, J . P. Chemistry, biochemistry and
biology of sialic acids. In Glycoproteins II; Montreuil, J ., Vliegenthart,
J . F. G., Schachter, H., Eds.; Elsevier Science: Amsterdam, 1997; p
243.
(2) Biology of the Sialic Acids; Rosenberg, A., Ed.; Plenun Press:
New York, 1995.
(3) Reuter, G.; Gabius, H.-J . Bio. Chem. Hoppe-Seyler 1996, 377,
325.
(4) Varki, A. FASEB J . 1997, 248.
(5) For a recent review, see: (a) Kiefel, M. J .; von Itzstein, M. Chem.
Rev. 2002, 102, 471. (b) Boons, G.; Demchenko, A. V. Chem. Rev. 2000,
100, 4539.
(6) Recent examples: (a) Kim, M.-J .; Hennen, W. J .; Sweers, H. M.;
Wong, C.-H. J . Am. Chem. Soc. 1988, 110, 6481. (b) Simon, E. S.;
Bednarski, M. D.; Whitesides, G. M. J . Am. Chem. Soc. 1988, 110, 7159.
(c) Kragl, U.; Gygax, D.; Ghisalba, O., Wandrey, C. Angew. Chem., Int.
Ed. Engl. 1991, 30, 827. (d) Sugai, T.; Kuboki, A.; Hiramatsu, S.;
Okazaki, H.; Ohta, H. Bull. Chem. Soc. J pn. 1995, 3581. (e) Danishef-
sky, S. J .; DeNinno, M. P.; Chen, S.-H. J . Am. Chem. Soc. 1988, 110,
3929. (f) Gordon, D. M.; Whitesides, G. M. J . Org. Chem. 1993, 58,
7937. (g) Chan, T.-H.; Lee, M.-C. J . Org. Chem. 1995, 60, 4228. (h)
Takahashi, T.; Tsukamoto, H.; Kurosaki, M.; Yamada, H. Synlett 1997,
1065. (i) Banwell, M.; DeSavi, C.; Watson, K. J . Chem. Soc., Perkin
Trans. 1 1998, 2251. (j) Kang, S. H.; Choi, H.-W.; Kim, J . S.; Youn,
J .-H. Chem. Commun. 2000, 227-8. (k) Liu, K.-G.; Yan, S.; Wu, Y.-L.;
Yao, Z.-J . J . Org. Chem. 2002, 67, 6758. (l) Voight, E. A.; Ren, C.;
Burke, S. D. J . Org. Chem. 2002, 67, 8489. Recent review: (m) Li,
L.-S.; Wu, Y.-L. Current Org. Chem. 2003, 7, 447.
(7) Cornforth, J . W.; Firth, M. E.; Gottschalk, A. J . Biol. Chem. 1958,
68, 57.
(9) Furuhata, K.; Takeda, K.; Ogura, H. Chem. Pharm. Bull. 1991,
39, 817.
(10) Furuhata, K.; Ogura, H. Chem. Pharm. Bull. 1992, 40, 3197.
(11) Liu, K.-G.; Hu, S.-G.; Yao, Z.-J .; Wu, Y.-L. J . Chem. Soc., Perkin
Trans. 1 2002, 1890.
(12) MM2 calculations were carried out by ChemBats3D 7.01 of
Cambridge Soft Corp. The lowest energy of 2 is 24.5348 kcal/mol and
that of 3 is 15.4993 kcal/mol.
(8) Suzuki, M.; Suzuki, A.; Yamakawa, T.; Matsunaga, E. J . Bio-
chem. 1985, 97, 509.
(13) J arosz, S.; Ciunik, Z. Pol. J . Chem. 1998, 72, 1182.
10.1021/jo034679b CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/06/2003
9528
J . Org. Chem. 2003, 68, 9528-9531

SCHEME 1
SCHEME 2 a
a
Reagents and conditions: (a) pTsOH, acetone, DMOP, MeOH, 83%; (b) Ag2O, BnBr, CH2Cl2, 74%; (c) LAH, THF, 87%; (d) Dess-
Martin periodinane, CH2Cl2, 83%; (e) Mg2SO4, 4 Å molecular sieves, BnNH2, THF, 100%.
SCHEME 3 a
a
Reagents and conditions: (a) C3H5MgBr, Et2O, 0-25 °C, two steps 56%; (b) Ac2O, Et3N, CH2Cl2, 88%; (c) OsO4, NMO, acetone, H2O,
76-83%; (d) Bu2SnO, TBAB, BnBr, toluene, 98%; (e) Dess-Martin periodinane, CH2Cl2, 90%.
oxide as a base gave 5 in 74% yield.14 The corresponding
alcohol 6 was obtained by reduction of ester 5 with LiAlH4
(87%). Treatment of alcohol 6 with Dess-Martin perio-
dinane in CH2Cl2 gave the aldehyde 7 (83%), which was
further converted into the imine 8 in quantitative yield.
The highly syn-selective addition of Grignard reagent
to N-benzylimine 8 served as a key step in our synthesis
(Scheme 3). The N-benzylimine 8 was treated with 3
equiv of allylmagnesium bromide in ether at room
temperature to afford the syn adduct 9 (two steps in 56%
yield) and minor anti adduct (syn/anti > 10:1 as mea-
yield. Dihydroxylation of alkene 10 with NMO and
catalytic OsO4 (2.5 wt % in BuOH) in acetone and H2O
n
afforded diol 11 in 76% yield (as a mixture of two
diastereomers). Selective protection of the primary hy-
droxyl group with Bu2SnO and benzyl bromide yielded
12 in 98% yield. Subsequent oxidation of the free hy-
droxyl group with Dess-Martin periodinane gave ketone
13 (90%) as a single enantiomer.
Removal of the two acetonide protecting groups in 13
was carried out with hydrogen chloride in methanol
(Scheme 4), and the 6,8-dioxabicyclo[3.2.1]octane core
was formed in situ to provide the 2,7-anhydro sugar
derivative 14 in 80% yield. The facile formation of acetal
could be explained by the spatial proximity of the
2-hydroxyl and 7-hydroxyl groups during the reaction,
allowing additional free space for the three benzyl groups
in the same molecule. The remaining two hydroxyls of
14 were then protected with 2,2-dimethoxylproprane to
afford 15 (82%), which was further treated with lithium
in liquid ammonia to give diol 16 in 90% yield. The
1
sured by the H NMR of crude product). The syn selectiv-
ity was finally confirmed by an X-ray study of a related
derivative after five-step transformation from the major
adduct 9 (unpublished results; see the Supporting Infor-
mation), and the stereochemistry of addition could be
explained well by Cram’s rule.15-19 The amine 9 was
directly treated with Ac2O and triethylamine in CH2Cl2
using DMAP as catalyst to give acetamide 10 in 88%
(14) Satyamurthi, N.; Singh, J .; Singh, I. Synthesis 2000, 3, 375.
(15) Eliel, E. L.; Frye, S. V.; Hortelano, E. R.; Chen, X.; Bai, X. Pure
Appl. Chem. 1991, 63, 1591.
(16) Chen, X.; Hortelano, E. R.; Eilel, E. L.; Frye, S. V. J . Am. Chem.
Soc. 1990, 112, 6130.
(17) Chen, X.; Hortelano, E. R.; Eilel, E. L.; Frye, S. V. J . Am. Chem.
Soc. 1992, 114, 1778.
(18) (a) Franz, T.; Hein, M.; Veith, U.; J a¨ger, V.; Peters, E.-M.;
Peters, K.; von Schnering, H. G. Angew. Chem., Int. Ed. Engl. 1994.
33, 1298. (b) Veith, U.; Leurs, S.; J a¨ger, V.; Chem. Commun. 1996,
329. (c) Meunier, N.; Veith, U.; J a¨ger, V.; Chem. Commun. 1996, 331.
(19) Schwardt, O.; Veith, U.; Leurs, S.; Gaspard, C.; J a¨ger, V.
Synthesis 1999, 1473.
J . Org. Chem, Vol. 68, No. 24, 2003 9529

SCHEME 4 a
a
Reagents and conditions: (a) HCl, MeOH, 80%; (b) DMOP, pTsOH (cat.), 82%; (c) Li, liquid NH3, 90%; (d) (1) KBr, TEMPO, TBAB,
Ca(ClO)2, (2) MeI, K2CO3, DMF, 60% in two steps; (e) HCl, MeOH, 89%.
Hz), 3.65 (dd, 1H, J ) 4.8, 3.3 Hz), 2.94 (m, 1H), 2.51 (m, 1H),
2.30 (m, 1H), 1.42 (s, 3H), 1.38 (s, 3H), 1.37 (s, 3H), 1.32 (s, 3H).
EI-MS (m/z): 481 (M+, 0.08), 466 (M+ - Me, 3.08), 440 (10.76),
161 (12.59), 160 (100.0). IR (film): 3030, 2987, 2935, 1639, 1455,
1371, 1069 cm-1. Anal. Calcd for C29H39NO5: C, 72.32; H, 8.16;
N, 2.91. Found: C, 72.82; H, 8.41; N, 2.91.
primary alcohol of 16 was selectively oxidized by TEMPO
and aqueous calcium hypochlorite to yield the corre-
sponding acid, which was immediately trapped as its
methyl ester by MeI in DMF to afford 17 (60% yield in
two steps). Treatment of 17 with hydrogen chloride in
methanol gave the final product 18 as a white solid in
89% yield. The structure of 18 was unambiguously
confirmed by its physical data.
In summary, a new conformationally constrained 2,7-
anhydrosialic acid derivative 18 was synthesized for the
first time from readily available D-glucono-δ-lactone. The
stereoselectivity, regioselectivity, and selective protection
of free hydroxyls were controlled well in our synthesis.
A highly syn-selective addition of allylmagnesium bro-
mide to an R-alkoxyl imine served as a key step to
introduce an essential three-carbon unit flowing a bio-
mimetic [6 + 3] strategy. The strategy and methods
described in this paper could be useful tools to obtain
more diverse sialic acid derivatives for potential biological
investigations.
(4R,5S,6R,7R,8R)-N4-Ben zyl-N4-a cet yl-5-b en zyloxy-6,7:
8,9-d i-O-isop r op ylid en e-1-n on en e (10). To a solution of 9
(1.31 g, 2.7 mmol) in dry CH2Cl2 (20 mL) were added Et3N (1.1
mL, 8.2 mmol), DMAP (cat.), and acetic anhydride (0.55 mL,
5.46 mmol) at 0 °C. After the mixture was stirred for 8 h at room
temperature, the reaction was quenched by water and the
mixture was extracted with ether. The combined organic layers
was washed with brine, dried over MgSO4, concentrated, and
purified by flash chromatography (hexane/EtOAc ) 5:1) to give
compound 10 (1.25 g, 88%) as a yellowish oil. [R]D ) +0.2 (c 1.50,
CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.43-7.19 (m, 10H), 5.58
(m, 1H), 5.04-4.94 (m, 2H), 4.70 (AB, 2H, J AB ) 11.4 Hz), 4.47
(m, 1.14H), 4.27-4.11 (m, 2.86H), 4.04-3.83 (m, 4.58H), 3.60
(m, 0.42H), 2.43 (m, 2H), 2.21 (s, 1.19H), 2.00 (s, 1.81H), 1.43-
1.25 (m, 12H). ESI-MS (m/z): 524 (M+ + 1, 100), 546 (M+ + Na,
10). IR (film): 3032, 2987, 2935, 1652, 1455, 1381, 1215, 1068
cm-1. HRESIMS: calcd for C31H41NO6 + Na 546.2826, found
546.2808.
(2RS,4R,5S,6R,7R,8R)-N4-Ben zyl-N4-a cetyl-5-ben zyloxy-
6,7:8,9-d i-O-isop r op ylid en en on a n e-1,2-d iol (11). To a solu-
tion of 10 (0.52 g, 1 mmol) in acetone (5 mL) and water (1 mL)
were added NMO monohydrate (202 mg, 1.5 mmol) and OsO4
solution in n-BuOH (2.5 wt %, 508 mg, 0.05 mmol) at rt. After
being stirred for 19 h at this temperature, the reaction was
quenched by adding saturated aq Na2SO3. The mixture was
filtered through a Celite pad and washed with ethyl acetate. The
aqueous phase was extracted with ethyl acetate. The combined
organic layers were washed with brine, dried over MgSO4,
concentrated, and purified by flash chromatography (hexane/
EtOAc ) 1:4) to afford 11 (0.38 g, 76%) as a yellowish oil. [R]D
) +22.9 (c 1. 0, CHCl3). 1H NMR (300 MHz, CDCl3): δ 7.31-
7.18 (m, 10H), 5.29-4.30 (m, 4.50H), 4.17-3.80 m, 6.0H), 3.70-
2.90 (m, 4.40H), 2.67-1.92 (m, 4.50H), 1.82-1.56 (m, 1.60H),
1.43-1.34 (m, 12H). ESI-MS (m/z): 580 (M+ + Na, 100). IR
(film): 3420, 3032, 2988, 2936, 1624, 1454, 1372, 1215, 1070
Exp er im en ta l Section
(4R,5S,6R,7R,8R)-N4-Ben zyl-5-ben zyloxy-6,7:8,9-d i-O-iso-
p r op ylid en e-1-n on en e (9). To a stirred solution of Dess-
Martin periodinane (0.72 g, 1.7 mmol) in dry CH2Cl2 (8 mL) was
added 614 (0.53 g, 1.5 mmol) in dry CH2Cl2 (13 mL) over 15 min.
After 30 min, the homogeneous mixture was diluted with ether
and poured into cooled saturated aq NaHCO3 (15 mL) containing
Na2S2O3 (1.87 g). The combined organic layers were washed with
saturated aq NaHCO3 and brine and dried over MgSO4. The
solvents were evaporated to give compound 7 (0.44 g, 83%). The
resultant yellow residue was used directly for the next step
without further purification.
A mixture of 7 (1.73 g, 4.91 mmol), MgSO4 (1.95 g), 4 Å MS
(1.95 g), and benzylamine (0.67 mL) in dry THF (10 mL) was
stirred at rt for 2 h. The solid was filtered and washed with dry
THF (2 mL), and the filtrate was carried to the next step without
cm-1
.
further purification.
To the above THF solution of imine 8 was added allylmag-
nesium bromide (1 M in ether, 15 mL) at 0 °C. The reaction
mixture was then stirred at room temperature for 2 h until it
was quenched with saturated aq NH4Cl at 0 °C. The mixture
was extracted with ether, and the combined organic layers were
washed with saturated aq NaHCO3, brine, dried over MgSO4,
concentrated, and purified by flash chromatography (hexane/
ethyl acetate ) 20:1) to give compound 9 (1.31 g, 56% yield based
on crude 7) as a yellowish oil. [R]D ) +4.4 (c 1.30, CHCl3). 1H
NMR (300 MHz, CDCl3): δ 7.32-7.19 (m, 10H), 5.75 (m, 1H),
5.15-5.10 (m, 2H), 4.67 (AB, 2H, J AB ) 11.4 Hz), 4.29 (dd, 1H,
J ) 7.5, 3.3 Hz), 4.15-4.03 (m, 2H), 3.96 (dd, 1H, J ) 7.5, 6.9
Hz), 3.88 (dd, 1H, J ) 7.5, 5.7 Hz), 3.76 (AB, 2H, J AB ) 12.8
(2RS,4R,5S,6R,7R,8R )-N4-Ben zyl-N4-a cet yl-1,5-b is(b en -
zyloxy)-6,7:8,9,-d i-O-isop r op ylid en en on a n -2-ol (12) A mix-
ture of compound 11 (403 mg, 0.7 mmol) and Bu2SnO (200 mg,
0.8 mmol) in toluene (15 mL) and methanol (0.73 mL) was
heated at 85 °C for 2 h. The solvents were evaporated under
reduced pressure. TBAB (258 mg, 0.8 mmol), BnBr (0.26 mL),
and toluene (11 mL) were then added. The mixture was heated
at 80 °C for 10 h, and then the solvents were evaporated again
under vacuum. The residue was directly purified by flash
chromatography (hexane/EtOAc ) 2:1) to give 12 (0.46 g, 98%)
as a yellowish oil. [R]D ) +24.9 (c 1.25, CHCl3). 1HNMR (300
MHz, CDCl3): δ 7.40-7.23 (m, 15H), 5.10-5.02 (m, 0.4H), 4.77-
4.64 (m, 2.10H), 4.51-4.33 (m, 3.40H), 4.32-4.03 (m, 2.50H),
9530 J . Org. Chem., Vol. 68, No. 24, 2003

4.07-3.60 (m, 5.60H), 3.36-3.25 (m, 2H), 2.46 (d, 1H, J ) 4.5
Hz), 2.13 (s, 1H), 1.98 (s, 2H), 1.92-1.78 (m, 2H), 1.43-1.25 (m,
12H). ESI-MS (m/z): 648 (M+ + 1, 100), 670 (M+ + Na, 25). IR
(film): 3376, 3032, 2987, 2934, 1645, 1619, 1455, 1217, 1072
cm-1. HRESIMS: calcd for C38H49NO8 + Na 670.3350, found
670.3326.
1H, J ) 12.8, 6.3 Hz), 1.94 (s, 3H), 1.53 (dd, 1H, J ) 12.8, 11.4
Hz), 1.39 (s, 3H), 1.29 (s, 3H). ESI-MS (m/z): 318 (M+ + 1,
100.00). IR (KBr): 3396, 3324, 2986, 2935, 1656, 1542, 1372,
1050, 850 cm-1. HR-ESIMS: calcd for C14H23NO7 + Na 340.1357,
found 340.1367.
(2S,3R,5S,7R)-Meth yl 3-Aceta m id o-2-h yd r oxy-7-((R)-2,2-
d im eth yl-1,3-d ioxoxla n -4-yl)-6,8-d ioxa bicyclo[3.2.1]octa n e-
5-ca r boxyla te (17). To a stirred mixture of alcohol 16 (62 mg,
0.2 mmol), KBr (4 mg), and TBAB (4 mg) in saturated aq
NaHCO3 (2 mL) was added solid Ca(ClO)2 (140 mg) at 15-18
°C. After 5 min, TEMPO (2 mg) was added in portions, and the
mixture was vigorously stirred at 16-20 °C. After completion
of the reaction monitored by TLC, solid NaHSO3 was added to
remove the excess Ca(ClO)2. The solution was lyophilized, and
the solid residue was suspended in DMF (2 mL) and treated with
MeI (0.05 mL) for 4 h at rt. Water was added, and the mixture
was extracted with chloroform. The combined extracts were
washed with brine, dried over MgSO4, and concentrated. The
residue was purified by flash chromatography (chloroform/
methanol ) 20:1) to give 17 (38 mg, 60%) as a white solid. [R]D
(4R,5S,6R,7R,8R)-N4-Ben zyl-N4-acetyl-1,5-bis(ben zyloxy)-
6,7:8,9-d i-O-isop r op ylid en e-2-oxon on a n e (13). To a stirred
solution of Dess-Martin periodinane (341 mg, 0.8 mmol) in dry
CH2Cl2 (2 mL) was added 12 (461 mg, 0.7 mmol) in CH2Cl2 (4
mL) over 2 min. After 2 h, the homogeneous mixture was diluted
with ether and poured into cooled saturated NaHCO3 (7 mL)
containing Na2S2O3‚5H2O (1.39 g). The combined organic layers
were washed with brine, dried over MgSO4, and concentrated.
The residue was purified by flash chromatography (hexane/
EtOAc ) 2:1) to give 13 (416 mg, 90%) as a yellowish oil. [R]D
)
1
+42.3 (c 1.80, CHCl3). HNMR (300 MHz, CDCl3): δ 7.36-7.11
(m, 15H), 5.39-5.24 (m, 0.96H), 4.87-4.82 (m, 0.67H), 4.60-
4.45 (m, 2.68H), 4.36-4.16 (m, 2.69H), 4.09-3.68 (m, 6.96H),
3.13 (d, 0.50H, J ) 17.4 Hz), 3.01 (d, 0.54H, J ) 16.8 Hz), 2.86
(m, 1.29H), 2.60 (dd, 0.71H, J ) 16.9, 3.0 Hz), 2.38 (s, 2H), 2.02
(s, 1H), 1.45-1.32 (m, 12H). ESI-MS (m/z): 668 (M+ + Na,
100.00). IR (film): 3065, 3032, 2988, 2935, 1728, 1646, 1619,
1454, 1372, 1215, 1069 cm-1. HRESIMS: calcd for C38H47NO8
+ Na 668.3194, found 668.3187.
1
) +72.0 (c 0.50, CHCl3). H NMR (300 MHz, CDCl3): δ 5.57 (d,
1H, J ) 5.7 Hz), 5.06 (s, 1H), 4.60 (d, 1H, J ) 4.5 Hz), 4.38 (d,
1H, J ) 8.4 Hz), 4.11-3.96 (m, 4H), 3.83 (s, 3H), 3.77 (dd, 1H,
J ) 9.0, 4.5 Hz), 2.42 (dd, 1H, J ) 13.2, 6.6 Hz), 2.06 (s, 3H),
1.78 (dd, 1H, J ) 13.2, 11.4 Hz), 1.44(s, 3H), 1.33(s, 3H). EI-MS
(m/z): 330 (M+ - Me, 59.09), 202(30.81), 193 (16.01), 173 (22.90),
142 (3.73), 101 (100.00). IR (KBr): 3438, 3323, 2988, 2957, 2881,
N-Ben zyl-N-((2S,3R,5S,7R)-2-(ben zyloxy)-5-((ben zyloxy)-
m eth yl)-7-((R)-2,2-d im eth yl-1,3-d ioxoxla n -4-yl)-6,8-d ioxa -
bicyclo[3.2.1]octa n -3-yl)a ceta m id e (15). To a solution of 13
(130 mg, 0.2 mmol) in methanol (1 mL) was added HCl in
methanol (1M, 4 mL). The mixture was stirred at room temper-
ature for 14 h and then concentrated under reduced pressure.
The residue was purified by flash chromatography (chloroform/
methanol ) 4:1) to give 14 (92 mg, 80%) as a syrup. The
resultant diol 14 (85 mg) was then dissolved in 2,2-dimethoxy-
lpropane (2 mL), and p-toluenesulfonic acid (cat.) was added.
The reaction mixture was stirred at rt for 10 min and extracted
with CH2Cl2. The combined organic layers were washed with
brine, dried over MgSO4, and concentrated. The residue was
purified by flash chromatography (hexane/EtOAc ) 4:1-2:1) to
give 15 (75 mg, 82% yield based on crude 14) as a yellowish oil.
[R]D ) -36.0 (c 0.80, CHCl3). 1H NMR (300 MHz, CDCl3): δ
7.39-7.16 (m, 15H), 4.70-4.18 (m, 8.3H), 4.07-3.88 (m, 4.10H),
3.63 (m, 0.6H), 3.48 (m, 2H), 2.37 (s, 1.8H), 2.0 (s, 1.2H), 1.95
(m, 2H), 1.47-1.29 (m, 6H). ESI-MS (m/z): 588 (M+ + 1, 100.00),
610 (M+ + Na, 38). IR (film): 3032, 2986, 2935, 1653, 1619, 1454,
1371, 1216, 1076 cm-1. HRESIMS: calcd for C35H41NO7 + Na
610.2775, found 610.2788.
1756, 1636, 1562, 1293, 1084 cm-1. HREIMS: calcd for C14H20
-
NO8 (M+ - Me) 330.1189, found 330.1181.
(2S,3R,5S,7R)-Meth yl 3-Aceta m id o-2-h yd r oxy-7-((R)-1,2-
d ih yd r oxyeth yl)-6,8-d ioxa bicyclo[3.2.1]octa n e-5-ca r boxy-
la te (18). To a solution of 17 (38 mg, 0.11 mmol) in methanol (1
mL) was added HCl in methanol (1 M, 1 mL). The mixture was
stirred at room temperature for 6 h and then concentrated under
vacuum. The residue was purified by flash chromatography
(chloroform/methanol ) 6:1) to give 18 (30 mg, 89%) as a white
solid. [R]D ) -4.5 (c 1.15, MeOH). 1H NMR (300 MHz, CD3OD):
δ 4.56 (d, 1H, J ) 3.9 Hz), 4.32 (d, 1H, J ) 8.4 Hz), 4.13 (m,
1H), 3.79 (s, 3H), 3.78-3.72 (m, 2H), 3.65 (dd, 1H, J ) 11.4, 4.5
Hz), 3.54 (m, H), 2.30 (dd, 1H, J ) 13.2, 6.0 Hz), 1.98 (s, 3H),
1.53 (dd, 1H, J ) 13.2, 11.1 Hz). 13C NMR (75 MHz, CDCl3):
173.8, 169.1, 105.5, 79.9, 78.0, 72.3, 70.5, 63.4, 53.7, 49.2, 38.9,
22.9. ESI-MS (m/z): 306 (M+ + 1, 100.00). IR (KBr): 3381, 2960,
1752, 1620, 1561, 1375, 1087, 992 cm-1. HRESIMS: calcd for
C
12H19NO8 + Na 328.1003, found 328.0999.
Ack n ow led gm en t. This work is supported by the
Major State Basic Research and Development Program
(G2000077500), the Chinese Academy of Sciences and
Shanghai Municipal Commission of Science and Tech-
nology. We thank Dr. Terrence R. Burke, J r., at NCI
for English corrections.
N-((2S,3R,5S,7R)-2-H yd r oxy-5-(h yd r oxym et h yl)-7-((R)-
2,2-d im et h yl-1,3-d ioxoxla n -4-yl)-6,8-d ioxa b icyclo[3.2.1]-
octa n -3-yl)a ceta m id e (16). To the precooled liquid ammonia
(30 mL) was added lithium metal (189 mg, 27 mmol) until a
dark blue color persisted, followed by the addition of a solution
of 15 (1.6 g, 2.7 mmol) in anhydrous THF (15 mL). The mixture
was stirred at the reflux temperature for 30 min, and solid NH4-
Cl was added to quench the reaction. The temperature was
allowed to warm naturally, and ammonia was evaporated. The
solid residue was purified by flash chromatography (chloroform/
methanol ) 20:1) to give 16 (0.778 g, 90%) as a white solid. [R]D
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 9, 13, and 15-18 and the 13C NMR spectrum of
18, configuration confirmation of 9 by X-ray crystallography,
and colored molecular presentations of 2 and 3 with lowest
energies calculated by MM2. This material is available free
of charge via the Internet at http://pubs.acs.org.
1
) +15.8 (c 0.50, CH3OH). H NMR (300 MHz, CD3OD): δ 4.34
(d, 1H, J ) 3.9 Hz), 4.15 (d, 1H, J ) 8.7 Hz), 4.06 (m, 2H), 3.94
(m, 2H), 3.68 (dd, 1H, J ) 9.9, 4.2 Hz), 3.54 (s, 2H), 2.03 (dd,
J O034679B
J . Org. Chem, Vol. 68, No. 24, 2003 9531