Synthesis of (-)-noviose from 2,3-O-isopropylidene-D-erythronolactol

Article abstract of DOI:10.1021/jo048953t

Noviose is a key synthon for the construction of novobiocin, a clinically useful antitumor agent that has been shown to inhibit both type II topoisomerases and Hsp90. The synthesis of D-noviose from 2,3-O-isopropylidene- D-erythronolactol is described.

Full text of DOI:10.1021/jo048953t

Syn th esis of (-)-Noviose fr om
2,3-O-Isop r op ylid en e-D-er yth r on ola ctol
Xiao Ming Yu, Gang Shen, and Brian S. J . Blagg*
Department of Medicinal Chemistry and The Center for
Protein Structure and Function, The University of Kansas,
1251 Wescoe Hall Drive, Malott Hall 4070,
Lawrence, Kansas 66045-7564
bblagg@ku.edu
Received J une 21, 2004
Abstr a ct: Noviose is a key synthon for the construction of
novobiocin, a clinically useful antitumor agent that has been
shown to inhibit both type II topoisomerases and Hsp90. The
synthesis of D-noviose from 2,3-O-isopropylidene-D-erythro-
nolactol is described.
Novobiocin is an antitumor agent that has been used
clinically for the treatment of cancer for more than a
decade.1 Although originally identified as an inhibitor of
type II topoisomerases,2 novobiocin was recently shown
to be an inhibitor of the 90 kDa heat shock proteins,
Hsp90.3 Hsp90 is a molecular chaperone responsible for
the refolding of denatured proteins following cellular
stress as well as for the conformational maturation of
nascent polypeptides into biologically active three-
dimensional structures.4 In fact, proteins represented in
all six hallmarks of cancer are Hsp90 dependent.5
Consequently, Hsp90 has emerged as a promising target
for the development of cancer chemotherapeutics because
multiple oncogenic proteins can be simultaneously dis-
rupted by inhibition of the Hsp90 protein folding ma-
chinery.6
Unlike well-investigated inhibitors of the N-terminal
ATP binding site of Hsp90, novobiocin binds to and
inhibits a previously unrecognized C-terminal ATP bind-
ing pocket.3 Recently, cis-platinum was also shown to
bind to this region;7 however, the exact location of the
C-terminal nucleotide-binding pocket remains unknown.
New derivatives of novobiocin that have an increased
affinity for the C-terminal ATP binding site may prove
valuable toward the development of new Hsp90 inhibitors
and elucidation of the C-terminal nucleotide binding
domain.
F IGURE 1. Coumarin antibiotics.
Novobiocin is a coumarin antibiotic isolated from
Streptomyces species, which are also responsible for the
biosyntheses of related compounds, clorobiocin and
coumermycin A1 (Figure 1).8 All of these compounds
contain not only the coumarin ring system, but also a
carbamate-containing noviose moiety. Noviose is a unique
C8 sugar that has received considerable synthetic atten-
tion9 due to novobiocin’s role in the inhibition of type II
topoisomerases and more recently Hsp90.
Although noviose has been prepared by a variety of
methods, no single procedure capable of the synthesis of
both enantiomers has been reported. It was envisioned
that both L- and D-noviose could be synthesized from
readily available reagents to provide both enantiomers
in a minimal number of steps (Scheme 1). Commercially
available 2,3-O-isopropylidene-D-erythronolactol is a suit-
able reagent for the synthesis of D-noviose; however, 2,3-
O-isopropylidene-L-erythronolactol is also readily obtain-
able10,11 and provides an appropriate reagent for the
(8) (a) Hooper, D. C.; Wolfson, J . S.; McHugh, G. L.; Winters, M. B.;
Swartz, M. N. Antimicrob. Agents Chemother. 1982, 22, 662-671. (b)
Maxwell, A. Trends Microbiol. 1997, 5, 102-109. (c) Maxwell, A.
Biochem. Soc. Trans. 1999, 27, 48-53.
(1) Blagosklonny, M. V. Leukemia 2002, 16, 455-462.
(2) (a) Holdgate, G. A.; Tunnicliffe, A.; Ward, W. H. J .; Weston, S.
A.; Rosenbrock, G.; Barth, P. T.; Taylor, I. W. F.; Paupit, R. A.; Timms,
D. Biochemistry 1997, 36, 9663-9673. (b) Lewis, R. J .; Singh, O. M.
P.; Smith, C. V.; Skarzyknski, T.; Maxwell, A.; Wonacott, A. J .; Wigley,
D. B. EMBO J . 1996, 15, 1412-1420. (c) Freel Meyers, C. L.;
Oberthuer, M.; Xu, H.; Heide, L.; Kahne, D.; Walsh, C. T. Angew.
Chem., Int. Ed. 2004, 43, 67-70. (d) Albermann, C.; Soriano, A.; J iang,
J .; Vollmer, H.; Biggins, J . B.; Barton, W. A.; Lesniak, J .; Nikolov, D.
B.; Thorson, J . S. Org. Lett. 2003, 5, 933-936.
(9) (a) Kiss, J .; Spiegelberg, H. Helv. Chim. Acta 1964, 47, 398-
407. (b) Achmatowicz, O., J r.; Grynkiewicz, G.; Szechner, B. Tetrahe-
dron 1976, 32, 1051-1054. (c) Klemer, A.; Waldmann, M. Liebigs Ann.
Chem. 1986, 2, 221-225. (d) Pankau, W. M.; Kreiser, W. Tetrahedron
Lett. 1998, 39, 2089-2090. (e) Pankau, W. M.; Kreiser, W. Helv. Chim.
Acta 1998, 81, 1997-2004. (f) Periers, A.-M.; Laurin, P.; Benedetti,
Y.; Lachaud, S.; Ferroud, D.; Iltis, A.; Haesslein, J .-L.; Klich, M.;
L’Hermite, G.; Musicki, B. Tetrahedron Lett. 2000, 41, 867-871. (g)
Takeuchi, M.; Taniguchi, T.; Ogasawara, K. Tetrahedron Lett. 2000,
41, 2609-2611. (h) Gammon, D. W.; Hunter, R.; Wilson, S. Tetrahedron
Lett. 2002, 43, 3141-3144. (i) Musicki, B.; Periers, A.-M.; Piombo, L.;
Laurin, P.; Klich, M.; Dupuis-Hamelin, C.; Lassaigne, P.; Bonnefoy,
A. Tetrahedron Lett. 2003, 44, 9259-9262. (j) J eselnik, M.; Leban, I.;
Polanc, S.; Kocevar, M. Org. Lett. 2003, 5, 2651-2653.
(3) Marcu, M. G.; Chadli, A.; Bouhouche, I.; Catelli, M.; Neckers, L.
M. J . Biol. Chem. 2000, 276, 37181-37186.
(4) (a) Walter, S.; Buchner, J . Angew. Chem., Int. Ed. 2002, 41,
1098-1113. (b) Frydman, J . Annu. Rev. Biochem. 2001, 70, 603-649.
(c) Toft, D. O. Trends Endocrinol. Metab. 1998, 9, 238-243.
(5) Maloney, A.; Workman, P. Expert Opin. Biol. Ther. 2002, 2, 3-24.
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10.1021/jo048953t CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/14/2004
J . Org. Chem. 2004, 69, 7375-7378
7375

TABLE 1. Dih yd r oxyla tion of 4 a n d 5
preparation of L-noviose following the procedure de-
scribed herein.
SCHEME 1
entry
compd
oxidation
ratio (A:B)
yield (%)a
1
2
3
4
5
6
5
5
5
4
4
4
AD-Mix R
AD-Mix â
OsO4,NMO
AD-Mix R
AD-Mix â
OsO4,NMO
1:2
1:3
1.2:1
1:1
1:2
2:1
95
92
78
87
84
84
a
Isolated yields.
With this vision in mind, we set out to prepare
D-noviose from 2,3-O-isopropylidene-D-erythronolactol, 2.
Treatment of this hemiacetal with the ylide of isopropyl
triphenylphosphonium bromide12 provided the trisubsti-
tuted olefinic product 3 in good yield (Scheme 2). Protec-
tion of the primary alcohol was necessary to prevent
alkylation in subsequent steps. Therefore, the primary
alcohol was converted to benzyl ether 4 and the tert-
butyldimethylsilyl ether 5.
responding alcohol oxidized to provide lactone 10. Treat-
ment of 10 with diisobutylaluminum hydride, followed
by aqueous sulfuric acid gave (-)-noviose as a 3:1 mixture
1
of anomers. The H and 13C NMR spectra were identical
with those obtained by literature procedures;9e however,
the optical rotation was opposite to the reported value
and indicative of the successful completion of (-)-noviose.
SCHEME 3
SCHEME 2
Dihydroxylation13 of alkenes 4 and 5 proved to be
troublesome (Table 1). Initial attempts to oxidize this
double bond in the presence of the tert-butyldimethylsilyl
ether resulted in poor diastereoselectivity (entries 1-3).
Surprisingly, both AD-Mix R and â14 furnished primarily
the undesired products, B. When the silyl ether was
replaced with a benzyl ether, a higher yield of the desired
isomer was obtained; however, the major product re-
mained the undesired compound under asymmetric
conditions. Finally, the benzyl ether containing olefin was
treated with osmium tetraoxide and stoichiometric 4-
methylmorpholine N-oxide13 to provide a 2:1 mixture of
diastereomeric products (entry 6), which could be easily
separated by silica chromatography.
In conclusion, we have prepared (-)-noviose from 2,3-
O-isopropylidene-D-erythronolactol. The synthetic route
described in this note proceeds in 8 steps. To date, this
represents the shortest method for the preparation of (-)-
noviose from commercially available reagents. In addition
to the preparation of D-noviose, the L-enantiomer of 2,3-
O-isopropylidene erythronolactol is readily available and
provides a useful method for the synthesis of (+)-noviose.
Using the procedure described above, studies are now
underway to prepare new analogues of novobiocin for
identification of Hsp90 structure-activity relationships
and elucidation of the C-terminal ATP binding pocket.
Treatment of the desired diol (6A) with potassium tert-
butoxide, followed by addition of methyl iodide provided
the secondary methyl ether 8 in good yield (Scheme 3).
The benzyl-protecting group was removed and the cor-
Exp er im en ta l Section
((4R,5S)-2,2-Dim eth yl-5-(2-m eth ylp r op -1-en yl)-1,3-d iox-
ola n -4-yl)m eth a n ol (3). A solution of n-butyllithium in hexane
(1.6 M, 16 mL, 25.6 mmol) was added dropwise to a suspension
of isopropyltriphenylphosphonium bromide (10.0 g, 25 mmol) in
THF (120 mL) at -42 °C under argon. The mixture was stirred
at -42 °C until a red solution appeared (30 min). A solution of
2 (1.60 g, 10 mmol) in THF (20 mL) was added dropwise at -42
°C before the mixture was gradually warmed to 25 °C and stirred
for 20 h. Solid NH4Cl (5 g) was added, and the resulting
suspension filtered. The insoluble material was washed with
EtOAc (3 × 50 mL), the eluent concentrated, and the residue
(12) (a) Baker, W. R.; Condon, S. L. J . Org. Chem. 1993, 58, 3277-
3284. (b) Braverman, S.; Duar, Y. J . Am. Chem. Soc. 1990, 112, 5830-
5837. (c) Cane, D. E.; Prabhakaran, P. C.; Salaski, E. J .; Harrison, P.
H. M.; Noguchi, H.; Rawlings, B. J . J . Am. Chem. Soc. 1989, 111, 8914-
8916.
(13) J acobsen, E. N.; Marko´, I.; Mungall, W. S.; Schro¨eder, G.;
Sharpless, K. B. J . Am. Chem. Soc. 1988, 110, 1968-1970.
(14) Kolb, H. C.; VanHieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483-2547.
7376 J . Org. Chem., Vol. 69, No. 21, 2004

purified by chromatography (SiO2, 1:4, EtOAc in hexanes) to
0 °C. The resulting slurry was stirred at 0 °C for 36 h, before
Na2SO3 (1 g) was added. The mixture was stirred for 30 min,
and then extracted with ethyl acetate (3 × 5 mL). The combined
organic layers were washed with saturated aqueous NaCl (15
mL), dried (Na2SO4), filtered, and concentrated. The residue was
purified by chromatography (SiO2, 1:8 to 1:3, EtOAc in hexanes)
to afford 6A (26 mg, 26%) and 6B (58 mg, 58%).
afford 3 (1.69 g, 91%) as a colorless oil; [R]25 +46.3 (c 2.01,
D
CHCl3) {lit.12 [R]20D +43.1 (c 1.65, CHCl3)}; 1H NMR (CDCl3 400
MHz) δ 5.25 (d, J ) 8.9 Hz, 1H), 4.95 (dd, J ) 6.7, 8.8 Hz, 1H),
4.22 (dd, J ) 6.7, 12.1 Hz, 1H), 3.57 (m, 2H), 1.78 (s, 3H), 1.73
(s, 3H), 1.51 (s, 3H), 1.40 (s, 3H); 13C NMR (CDCl3 100 MHZ) δ
139.5, 119.5, 108.6, 78.5, 74.2, 62.7, 28.4, 26.4, 25.7, 18.8.
(4R,5S)-4-(Ben zyloxym eth yl)-2,2-d im eth yl-5-(2-m eth yl-
p r op -1-en yl)-1,3-d ioxola n e (4). Sodium hydride (60% in min-
eral oil, 80 mg, 2.0 mmol) was added to a solution of 3 (186 mg,
1.0 mmol) in THF (10 mL) at 25 °C. The suspension was stirred
at 25 °C for 20 min before benzyl bromide (300 mg, 1.75 mmol)
was added. The resulting mixture was stirred for 12 h before
the addition of water (20 mL). The heterogeneous solution was
extracted with EtOAc (3 × 20 mL) and the combined organic
layers were dried (Na2SO4), filtered, and concentrated. The
residue was purified by chromatography (SiO2, 1:20, EtOAc in
hexanes) to afford 4 (263 mg, 95%) as a colorless oil; [R]25D +34.5
(c 3.30, CH2Cl2); 1H NMR (CDCl3 400 MHz) δ 7.33 (m, 5H), 5.20
(d, J ) 9.2 Hz, 1H), 4.92 (dd, J ) 5.5, 9.2 Hz, 1H), 4.61 (d, J )
12.4 Hz, 1H), 4.53 (d, J ) 12.4 Hz, 1H), 4.35 (dd, J ) 6.1, 9.1
Hz, 1H), 3.50 (m, 2H), 1.76 (s, 3H), 1.70 (s, 3H), 1.50 (s, 3H),
1.40 (s, 3H); 13C NMR (CDCl3 100 MHZ) δ 138.6, 138.5, 128.7
(2C), 128.1 (2C), 128.0, 120.2, 108.7, 77.3, 74.4, 73.8, 70.1, 28.5,
26.5, 25.9, 18.6; IR (film) νmax 2980, 2929, 2909, 2852, 1454, 1372,
1244, 1214, 1070, 1050, 1024, 737 cm-1; HRMS (ESI+) m/z
294.2067 (M + NH4+, C17H28NO3 requires 294.2069).
(S)-1-((4R,5R)-5-(Ben zyloxym eth yl)-2,2-d im eth yl-1,3-d i-
oxola n -4-yl)-1-m eth oxy-2-m eth ylp r op a n -2-ol (8). Potassium
tert-butoxide (28 mg, 0.25 mmol) was added to a solution of 6A
(68 mg, 0.21 mmol) in anhydrous THF (4 mL) at 25 °C under
argon. The mixture was stirred for 20 min before addition of
iodomethane (15 µL, 35 mg, 0.25 mmol). The resulting mixture
was stirred for 10 h at 25 °C before water (10 mL) was added.
The heterogeneous solution was extracted with EtOAc (3 × 10
mL), and the combined organic layers were dried (Na2SO4),
filtered, and concentrated. The residue was purified by chro-
matography (SiO2, 1:4, EtOAc in hexanes) to afford 6A (9 mg)
and 8 (51 mg, 86%); [R]25 +15.1 (c 1.03, CH2Cl2); 1H NMR
D
(CDCl3 400 MHz) δ 7.35 (m, 5H), 4.61 (d, J ) 7.6 Hz, 1H), 4.53
(d, J ) 7.6 Hz, 1H), 4.37 (m, 2H), 3.66 (app t, J ) 8.5 Hz, 1H),
3.51 (s, 3H), 3.45 (dd, J ) 3.5, 9.3 Hz, 1H), 3.19 (m, 2H), 1.42 (s,
3H), 1.38 (s, 3H), 1.16 (s, 3H), 1.14 (s, 3H); 13C NMR (CDCl3
100 MHz) δ 137.1, 129.0 (2C), 128.7, 128.6 (2C), 107.6, 85.0, 78.0,
76.2, 74.2, 72.3, 69.4, 61.8, 29.3, 28.6, 25.9, 23.3; IR (film) νmax
3472, 2970, 2929, 2873, 2822, 1454, 1383, 1250, 1214, 1147,
1127, 1091, 1060, 737, 702 cm-1; HRMS (ESI+) m/z 342.2282
(M + NH4+, C18H32NO5 requires 342.2280).
(S)-1-((4S,5R)-5-(Ben zyloxym eth yl)-2,2-d im eth yl-1,3-d i-
oxola n -4-yl)-2-m eth ylp r op a n e-1,2-d iol (6A) a n d (R)-1-((4S,-
5R)-5-(Ben zyloxym eth yl)-2,2-d im eth yl-1,3-d ioxola n -4-yl)-
2-m eth ylp r op a n e-1,2-d iol (6B). Osmium tetraoxide (10 mg/
mL in toluene, 0.1 mL) was added to a solution of olefin 4 (62
mg, 0.22 mmol) in acetone (1 mL) and H2O (1 mL). The mixture
was stirred at 25 °C for 15 min before addition of 4-methylmor-
pholine N-oxide (59 mg, 0.9 mmol). The resulting solution was
stirred at 25 °C until TLC showed the consumption of 4 (∼8 h).
Water (10 mL) was added and the mixture was extracted with
EtOAc (3 × 10 mL). The combined organic layers were washed
with saturated aqueous NaCl (20 mL), dried (Na2SO4), filtered,
and concentrated. The residue was purified by chromatography
(SiO2, 1:8 to 1:3, EtOAc in hexanes) to afford 6B (20 mg) as a
higher Rf compound and 6A (38 mg) as a lower Rf compound
(S)-1-((4R,5R)-5-(Hyd r oxym eth yl)-2,2-d im eth yl-1,3-d iox-
ola n -4-yl)-1-m eth oxy-2-m eth ylp r op a n -2-ol (9). Palladium on
charcoal (10%, 20 mg) was added to a solution of 8 (173 mg,
0.53 mmol) in EtOAc (2 mL). The mixture was stirred under
hydrogen (1 atm) at 25 °C for 12 h, diluted with EtOAc (10 mL),
and filtered through a plug of Celite. The filtrate was concen-
trated and the residue purified by chromatography (SiO2, 1:1,
EtOAc in hexanes) to afford 9 (120 mg, 96%) as a colorless oil;
[R]25 +51.5 (c 2.12, CH2Cl2); 1H NMR (CDCl3 400 MHz) δ 4.36
D
(dd, J ) 5.3, 8.1 Hz, 1H), 4.21 (ap. q, J ) 5.2 Hz, 1H), 3.75 (dt,
J ) 4.8, 10.8 Hz, 1H), 3.62 (m, 1H), 3.59 (t, 3H), 3.24 (d, J ) 8.0
Hz, 1H), 3.20 (br t, J ) 5.0 Hz, 1H), 3.06 (s, 1H), 1.47 (s, 3H),
1.39 (s, 3H), 1.30 (s, 3H), 1.24 (s, 3H); 13C NMR (CDCl3 100 MHz)
δ 107.8, 84.5, 78.1, 77.6, 73.1, 62.1, 62.0, 28.9, 28.5, 25.9, 24.7;
IR (film) νmax 3390, 2980, 2924, 1460, 1372, 1244, 1214, 1157,
1122, 1091, 1045, 927, 876 cm-1; HRMS (ESI+) m/z 252.1811
(M + NH4+, C11H26NO5 requires 252.1811).
(84% total yield). 6B: [R]25 -0.1 (c 0.97, CH2Cl2); 1H NMR
D
(CDCl3 400 MHz) δ 7.36 (m, 5H), 4.59 (s, 2H), 4.40 (ddd, J )
3.5, 5.3, 9.3 Hz, 1H), 4.25 (dd, J ) 5.4, 9.6 Hz, 1H), 3.83 (d, J )
4.0 Hz, 1H), 3.72 (app t, J ) 9.6 Hz, 1H), 3.51 (m, 2H), 3.16 (s,
1H), 1.39 (s, 3H), 1.36 (s, 3H), 1.28 (s, 3H), 1.26 (s, 3H); 13C NMR
(CDCl3 100 MHz) δ 136.9, 129.1 (2C), 128.8, 128.5 (2C), 109.7,
78.1, 76.3, 74.4, 73.9, 72.8, 69.0, 28.4, 26.0, 25.7, 25.5; IR (film)
(3a S,7S,7a S)-7-Meth oxy-2,2,6,6-tetr am eth yldih ydr o-3a H-
[1,3]d ioxolo[4,5-c]p yr a n -4(6H)-on e (10). Pyridinium chloro-
chromate (151 mg, 0.7 mmol) was added to a solution of 9 (53
mg, 0.23 mmol) in CH2Cl2 (2 mL) at 25 °C. The mixture was
stirred at 25 °C for 8 h and filtered through a plug of silica gel
(3 × 0.5 cm) and eluted with CH2Cl2. The eluent was concen-
νmax 3462, 2980, 2929, 2868, 1455, 1373, 1219, 1163, 1075, 958,
+
850, 732, 691 cm-1; HRMS (ESI+) m/z 328.2097 (M + NH4
,
trated to afford 10 (43 mg, 82%) as white solid; [R]25 +40.3 (c
C
17H30NO5 requires 328.2124).
D
6A: [R]25 -38.5 (c 0.28, CH2Cl2); 1H NMR (CDCl3 400 MHz)
1
0.6, CH2Cl2); H NMR (CDCl3 400 MHz) δ 4.75 (d, J ) 8.4 Hz,
D
δ 7.33 (m, 5H), 4.63 (d, J ) 9.0 Hz, 1H), 4.57 (d, J ) 9.0 Hz,
1H), 4.42 (m, 2H), 3.80 (d, J ) 5.5 Hz, 2H), 3.40 (dd, J ) 1.3,
8.4 Hz, 1H), 2.83 (d, J ) 8.4 Hz, 1H), 2.71 (s, 1H), 1.51 (s, 3H),
1.39 (s, 3H), 1.24 (s, 3H), 1.12 (s, 3H); 13C NMR (CDCl3 100 MHz)
δ 138.0, 128.9 (2C), 128.4 (2C), 128.3, 109.0, 76.8, 76.0, 74.1,
74.0, 73.4, 69.5, 27.4, 27.3, 26.0, 25.1; IR (film) νmax 3482, 2986,
2934, 2868, 1454, 1373, 1219, 1091, 743, 697 cm-1; HRMS (ESI+)
m/z 328.2100 (M + NH4+, C17H30NO5 requires 328.2124).
Oxid a tion of 4 w ith AD-m ix-r. 4 (676 mg, 2.45 mmol) in
t-BuOH (24 mL) was added to a mixture of AD-mix R (4.2 g)
and methanesulfonamide (285 mg, 3 mmol) in H2O (24 mL) at
0 °C. The resulting slurry was stirred at 0 °C for 48 h, before
Na2SO3 (10 g) was added. The mixture was stirred for 15 min,
and then extracted with ethyl acetate (3 × 50 mL). The combined
organic layers were washed with saturated aqueous NaCl (100
mL), dried (Na2SO4), filtered, and concentrated. The residue was
purified by chromatography (SiO2, 1:8 to 1:3, EtOAc in hexanes)
to afford 6A (353 mg, 46%) and 6B (312 mg, 41%).
1H), 4.49 (dd, J ) 6.0, 8.4 Hz, 1H), 3.57 (s, 3H), 3.26 (d, J ) 6.0
Hz, 1H), 1.52 (s, 3H), 1.47 (s, 3H), 1.42 (s, 3H), 1.36 (s, 3H); 13
C
NMR (CDCl3 100 MHz) δ 169.3, 111.7, 84.9, 82.5, 77.8, 72.0,
59.4, 27.8, 27.0, 25.3, 22.5; IR (film) νmax 2991, 2939, 2914, 2873,
1741, 1465, 1383, 1352, 1260, 1214, 1137, 1065, 1060, 1024, 973,
876 cm-1; HRMS (ESI+) m/z 248.1497 (M + NH4+, C11H22NO5
requires 248.1498).
(3a S,7S,7a S)-7-Meth oxy-2,2,6,6-tetr a m eth yltetr a h yd r o-
3a H-[1,3]d ioxolo[4,5-c]p yr a n -4-ol (11). A solution of diisobu-
tylaluminum hydride (1 M in hexane, 180 µL, 0.18 mmol) was
added dropwise to a solution of 10 (35 mg, 0.15 mmol) in
anhydrous CH2Cl2 (2 mL) at -78 °C. The mixture was stirred
for 30 min at -78 °C before addition of saturated potassium
sodium tartrate aqueous solution (3 mL). The mixture was
warmed to 25 °C and stirred until layers separated (∼1 h). The
aqueous phase was extracted with CH2Cl2 (3 × 5 mL), and the
combined organic layers were dried (Na2SO4), filtered, and
concentrated. The residue was purified by chromatography
(SiO2, 1:1, EtOAc in hexane) to give 11 (31 mg, 89%) as a 3:1
mixture of anomers; [R]25D -1.6 (c 0.7, CH2Cl2); 1H NMR (CDCl3
400 MHz) δ 5.12 (d, J ) 4.0 Hz, major 1H), 5.11 (d, J ) 2.7 Hz,
Oxid a t ion of 4 w it h AD-m ix-â. 4 (90 mg, 0.32 mmol) in
t-BuOH (3 mL) was added to a mixture of AD-mix â (500 mg)
and methanesulfonamide (30 mg, 0.31 mmol) in H2O (3 mL) at
J . Org. Chem, Vol. 69, No. 21, 2004 7377

minor 1H), 4.37 (app t, J ) 6.8 Hz, major 1H), 4.30 (app t, J )
6.5 Hz, minor 1H), 4.23 (dd, J ) 2.7, 6.6 Hz, minor 1H), 4.16
(dd, J ) 4.0, 7.0 Hz, major 1H), 3.56 (s, major 3H), 3.53 (s, minor
3H), 3.28 (d, J ) 6.4 Hz, minor 1H), 3.20 (d, J ) 6.6 Hz, major
1H), 1.57 (s, minor 3H), 1.54 (s, major 3H), 1.39 (s, minor 3H),
1.37 (s, major 3H), 1.35 (s, minor 3H), 1.35 (s, major 3H), 1.27
(s, major 3H), 1.16 (s, minor 3H); 13C NMR (CDCl3 100 MHz) δ
110.2, 109.7, 92.9, 89.4, 89.3, 83.8, 83.7, 77.6, 75.9, 75.8, 74.7,
60.6, 60.5, 30.1, 29.0, 27.9, 27.7, 27.6, 26.2, 25.4, 25.0, 21.0; IR
8.2 Hz, minor 1H), 3.78 (dd, J ) 1.3, 3.3 Hz, major 1H), 3.72
(app t, J ) 3.4 Hz, minor 1H), 3.68 (dd, J ) 3.3, 9.9 Hz, major
1H), 3.58 (s, major 3H), 3.54 (s, minor 3H), 3.22 (d, J ) 8.2 Hz,
minor 1H), 3.18 (d, J ) 9.9 Hz, major 1H), 1.33 (s, minor 3H),
1.30 (s, major 3H), 1.28 (s, minor 3H), 1.15 (s, major 3H); 13C
NMR (CD3OD 100 MHz) 94.6, 89.9, 84.8, 84.2, 77.1, 74.7, 72.8,
72.2, 71.5, 68.7, 61.2, 60.5, 27.9, 27.5, 24.0, 17.6.
Ack n ow led gm en t. The authors gratefully acknowl-
edge support of this project by the NIH COBRE
RR017708, The University of Kansas Center for Re-
search, and The University of Kansas General Research
Fund. G.S. is the recipient of a Susan G. Komen Breast
Cancer Foundation Dissertation Award. The authors
would like to thank Professor J eff Aube for helpful
discussions and reading of the manuscript.
(film) νmax 3436, 2975, 2929, 1460, 1378, 1239, 1209, 1157, 1106,
+
1065, 871, 804 cm-1; HRMS (ESI+) m/z 250.1654 (M + NH4
,
C
11H24NO5 requires 250.1654).
(-)-Noviose, (-)-1. 11 (17 mg, 0.077 mmol) was dissolved
in aqueous sulfuric acid (0.1 N, 0.2 mL) and warmed to 75 °C
for 2 h. After the solution was cooled to 25 °C, solid Na2CO3
was added until pH 8. The mixture was evaporated to dryness
and washed with ethanol (3 × 2 mL). The extracts were
combined and concentrated to give a residue, which was purified
by chromatography (SiO2, 1:9, ethanol in CH2Cl2) to afford (-)-1
(12 mg, 80%) as a white solid representing a 3:1 ratio of anomers;
[R]25 -21.3 (c 0.1, EtOH/H2O 1:1) {lit.9e [R]20 -29.2 (c 1.0,
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectra
for all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
D
D
EtOH/H2O 1:1)}; 1H NMR (CD3OD 400 MHz) δ 5.01 (d, J ) 3.4
Hz, minor 1H), 4.88 (d, J ) 1.3 Hz, major 1H), 4.00 (dd, J ) 3.4,
J O048953T
7378 J . Org. Chem., Vol. 69, No. 21, 2004