De novo asymmetric synthesis of an α-6-deoxyaltropyranoside as well as its 2-/3-deoxy and 2,3-dideoxy congeners

Article abstract of DOI:10.1021/jo9009722

(Chemical Equation Presented) A highly divergent de novo asymmetric synthesis of benzyl α-6-deoxyaltropyranoside, benzyl Rascarylopyranoside, benzyl α-amicetopyranoside, and benzyl α-digitoxopyranoside has been achieved via a common pyranone intermediate. The routes rely upon a palladium(0)-catalyzed glycosylation reaction and corresponding post-glycosylation transformations. The control of the absolute and relative stereochemical configuration came from a Noyori reduction of 2-acylfuran and subsequent diastereoselective introduction of other stereogenic centers.

Full text of DOI:10.1021/jo9009722

pubs.acs.org/joc
De Novo Asymmetric Synthesis of an r-6-Deoxyaltropyranoside as Well
as its 2-/3-Deoxy and 2,3-Dideoxy Congeners
Mingde Shan, Yalan Xing, and George A. O’Doherty*
Department of Chemistry, West Virginia University, Morgantown, West Virginia 26506
george.odoherty@mail.wvu.edu
Received May 9, 2009
A highly divergent de novo asymmetric synthesis of benzyl R-6-deoxyaltropyranoside, benzyl R-
ascarylopyranoside, benzyl R-amicetopyranoside, and benzyl R-digitoxopyranoside has been
achieved via a common pyranone intermediate. The routes rely upon a palladium(0)-catalyzed
glycosylation reaction and corresponding post-glycosylation transformations. The control of the
absolute and relative stereochemical configuration came from a Noyori reduction of 2-acylfuran and
subsequent diastereoselective introduction of other stereogenic centers.
Introduction
Over the last 10 years, there has been considerable effort
made toward the synthesis of monosaccharides from achiral
starting materials.6 In this regard, we have reported a de
novo asymmetric synthesis of carbohydrates using achiral
acylfurans 1 (Scheme 1).7 Our approach used a Noyori
reduction, an Achmatowicz reaction, and a Pd(0)-catalyzed
glycosylation (2 to 3) to prepare pyranone intermediate 3,7-9
which via post-glycosylation transformations were con-
verted into the corresponding carbohydrates (e.g., 3 to 4, 5
and 6).7,9 This method has allowed for the stereoselective
synthesis of a variety of sugars, including rare sugars,
aminosugars, and even unnatural sugars.10
Deoxysugars are a common structural motif in biologi-
cally active natural products.1 Among the deoxysugars, the
6-deoxysugars are the most prevalent followed by sugars
with deoxygenation at the C-2 and C-3 positions. The
removal of the hydroxyl groups in sugars along with the
use of unusual stereochemistry imparts resistance to most
glycosidases and thus conveys improved metabolic stability.1
Examples of nature’s reliance of these structural motifs are
seen in the use of R-6-deoxyaltrose as the main constituent of
some bacterial lipopolysaccharides,2 as well as the use of R-
2,6- and R-3,6-dideoxyaltrose (i.e., R-digitoxose and R-
ascarylose) in biologically active natural products such as
jadomycin B3 and daumone,4 respectively.5
(6) (a) Zamoiski, A.; Banaszek, A.; Grynkiewicz, G. Adv. Carbohydr.
Chem. Biochem. 1982, 40, 1. (b) Ernst, B., Hart, G. W., Sinay, P., Eds.
Carbohydrates in Chemistry and Biology; Wiley-VCH: New York, 2000.
(c) Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Reed, L. A.; Sharpless, K. B. Science
1983, 220, 949–951. (d) Northrup, A. B.; MacMillan, D. W. C. Science 2004, 305,
1752–1755.
(7) (a) Harris, J. M.; Keranen, M. D.; O’Doherty, G. A. J. Org. Chem.
1999, 64, 2982–2983. (b) Harris, J. M.; Keranen, M. D.; Nguyen, H.; Young,
V. G.; O’Doherty, G. A. Carbohydr. Res. 2000, 328, 17–36. For its use in
oligosaccharide synthesis, see: (c) Babu, R. S.; Zhou, M.; O’Doherty, G. A.
J. Am. Chem. Soc. 2004, 126, 3428–3429. (d) Ahmed, Md. M.; O’Doherty, G.
A. Tetrahedron Lett. 2005, 46, 3015–3019. (e) Ahmed, Md. M.; Berry, B. P.;
Hunter, T. J.; Tomcik, D. J.; O’Doherty, G. A. Org. Lett. 2005, 7, 745–748.
(f) Guo, H.; O’Doherty, G. A. Angew. Chem., Int. Ed. 2007, 46, 5206–5208.
(g) Zhou, M.; O’Doherty, G. A. Org. Lett. 2008, 10, 2283–2286.
(1) (a) Johnson, D. A.; Liu, H.-w. Comprehensive Natural Products
Chemistry; Elsevier: Amsterdam, NY, 1999; Vol. 3, pp 311-365. (b) Thibodeaux,
C.; Melanc€uon, C. E. III; Liu, H.-w. Nature 2007, 446, 1008–1016. (c) Kren, V.;
Martinkova, L. Curr. Med. Chem. 2001, 8, 1303–1328.
(2) Gorshkova, R. P.; Kalmykova, E. N.; Isakov, V. V.; Ovodov, Y. S.
Eur. J. Biochem. 1985, 150, 527–531.
(3) (a) Doull, J. L.; Singh, A. K.; Hoare, M.; Ayer, S. W. J. Ind. Microbiol.
1994, 13, 120–125. (b) Jakeman, D. L.; Borissow, C. N.; Graham, C. L.;
Timmons, S. C.; Reid, T. R.; Syvitski, R. T. Chem. Commun. 2006, 3738–
3740.
(4) (a) Jeong, P.-Y.; Jung, M.; Yim, Y.-H.; Kim, H.; Kim, K.; Paik, Y.-K.
Nature 2005, 433, 541–545. (b) Guo, H.; O’Doherty, G. A. Org. Lett. 2005, 7,
3921–3924. (c) Baiga, T. J.; Guo, H.; Xing, Y.; O’Doherty, G. A.; Parrish, A.;
Dillin, A.; Austin, M. B.; Noel, J. P.; La Clair, J. J. ACS Chem. Biol. 2008, 3,
294–304.
(5) For a recent approach to 2,6-dideoxysugars, see: (a) Hou, D.; Lowary,
T. L. J. Org. Chem. 2009, 74, 2278–2289. For approaches to 3,6-dideoxy-
sugars, see: (b) Weigel, T. M.; Liu, H.-w. Tetrahedron Lett. 1988, 29, 4221–
4224 and ref 4b.
(8) Jones, R. A.; Krische, M. J. Org. Lett. 2009, 11, 1849–1851.
(9) (a) Babu, R. S.; Guppi, S. R.; O’Doherty, G. A. Org. Lett. 2006, 8,
1605–1608. (b) Shan, M.; O’Doherty, G. A. Org. Lett. 2006, 8, 5149–5152.
(c) Guppi, S. R.; O’Doherty, G. A. J. Org. Chem. 2007, 72, 4966–4969.
(10) (a) Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2001, 3, 3899–3992.
(b) Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2002, 4, 1771–1774.
(c) Ahmed, Md. M.; O’Doherty, G. A. Tetrahedron Lett. 2005, 46, 4151–4155.
DOI: 10.1021/jo9009722
r
Published on Web 07/16/2009
J. Org. Chem. 2009, 74, 5961–5966 5961
2009 American Chemical Society

Shan et al.
JOCArticle
SCHEME 1. De Novo Approach to Carbohydrate
SCHEME 2. Retrosynthetic Analysis
produced either enantiomer of furfuryl alcohol 14 in 96% yield
with high enantiomeric excess (>96% ee).13 An Achmatowicz
rearrangement transformed the furfuryl alcohol to pyranone
in 91% yield. The hemiacetal was then protected as tert-butyl
carbonate 15 at low temperature in 78% yield with 3:1 ratio of
R- and β-diastereomers (Scheme 3).
These approaches primarily rely on the osmium-catalyzed
dihydroxylation reaction for the syn-addition of two hydro-
xyl groups across the C-2/C-3 pyran double bond, which has
been used to prepare D- or L-sugars with manno-, gulo-, and
talo-stereochemistry.9,10 A related dihydroxylation on the C-
3/C-4 pyran double bond provided the sugars with
galacto- and allo-stereochemistry.10,11 By combining this
approach with protection/inversion reactions, this route
has also been used to access to the gluco-stereoisomers.12
As part of our efforts to expand upon this methodology,
we have been investigating epoxidation/nucleophilic ring-
opening reactions for the net anti-addition of hydroxyl
groups across the C-2/C-3 pyran double bond. Herein we
describe our successful application of this new post-glycosy-
lation transformation for the de novo synthesis of four
deoxysugar targets (i.e., benzyl pyranosides with R-altro-
stereochemistry as well as its 2-deoxy (R-digitoxose), 3-deoxy
(R-ascarylose), and 2,3-dideoxy (R-amicetose) congeners)
(Figure 1).
SCHEME 3. De Novo Synthesis of R-Boc-pyranone
Our proposed synthesis of a R-6-deoxyaltropyranoside
started with the attempted epoxidation of pyran 11. Unfor-
tunately, our efforts to epoxidize allylic alcohol 11 were not
satisfactory. So, we decided to reverse the reduction/oxida-
tion sequence. These efforts began with our Pd(0)-catalyzed
glycosylation reaction to diastereoselectively install the
anomeric benzyloxy group with complete R-selectivity
(Scheme 4). Similarly, treating pyranone 12 with hydrogen
peroxide in the presence of a catalytic amount of base (10 mol
% of NaOH/H2O2) diastereoselectively installed the epoxide
16 in 88% yield.4b In an equally diastereoselective fashion,
the ketone 16 was reduced with NaBH4 (-78 to -20 °C) to
form the equatorial alcohol 8 in 85% yield.
FIGURE 1. Targeted rare sugar pyranosides.
Results and Discussion
Retrosynthetically, we envisioned both R-6-deoxyaltro-
pyranoside and R-3,6-dideoxyaltropyranoside 7 as being
derived from the trans-diaxial opening of epoxide 8 with
either a formal hydroxy or hydride nucleophile, respectively
(Scheme 2). Epoxide 8 could be prepared by epoxidation of
pyran 11, which in turn could be prepared by a ketone
reduction of pyranone 12. The regioisomeric 2-deoxysugars
could be prepared by switching the order of trans-diaxial
addition of oxygen and halogen across pyran 11. Thus, the R-
digitoxose 9 should come from the radical reduction of
iodocarbonate 10, which in turn could be prepared from
pyran 11 (Scheme 2). Because our route began with the
Noyori reduction of acylfuran, it is amenable to the synthesis
of either D- or L-enantiomer of these sugars.13
SCHEME 4. Synthesis of R-6-Deoxyaltropyranoside
As we have previously reported,13b the Noyori reduction of
acylfuran 13, with formic acid/triethylamine as hydride source,
(11) (a) Zhou, M.; O’Doherty, G. A. Org. Lett. 2006, 8, 4339–4342. (b)
Zhou, M.; O’Doherty, G. A. J. Org. Chem. 2007, 72, 2485–2493.
(12) Balachari, D.; O’Doherty, G. A. Org. Lett. 2000, 2, 4033–4036.
(13) (a) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1996, 118, 2521–2522. (b) Li, M.; O’Doherty, G. A.
Tetrahedron Lett. 2004, 45, 6407–6411.
With the alcohol in hand, we turned our attention to the
epoxide ring opening with acetic acid. After investigating the
use of a variety of Lewis acids, we found Sc(OTf)3 gave the
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best results. In practice, treatment of epoxide 8 with Sc(OTf)3
in HOAc afforded an inseparable mixture of acetates which
presumably resulted from acid-catalyzed ester migration of
the initial epoxide ring-opening product. This mixture was
directly hydrolyzed with LiOH in aqueous THF to produce
R-6-deoxyaltrose 17 in 69% yield. The stereochemistry of the
ring opening was confirmed by analysis of the corresponding
proton/proton coupling constants at C-2, C-3, and C-4
positions of 17 (see the Supporting Information).
SCHEME 6. Synthesis of 2,3,6-Trideoxy- and 2,6-Dideoxy-D-
sugars
SCHEME 5. Synthesis of R-Ascarylopyranoside
As we previously reported,4b epoxide 8 was converted into
the R-ascarylose sugar 18 in 85% yield using LiAlH4
(Scheme 5). This same regioselective Lewis acid promoted
ring-opening reaction can also be used for 3-deoxysugars to
provide a less basic alternative to our previously reported
LiAlH4 method.4b Simply switching the Lewis acid to
(TTMSS) under radical condition in 45% yield. Finally, the
cyclic carbonate was hydrolyzed with NaOH in aqueous THF
afforded desired R-digitoxose (ent)-9 in 84% yield.
MgBr2 Et2O promoted a regioselective opening to form
3
bromide 19. The axial bromide in 19 was cleanly removed
to give 18 in 76% yield, using an AIBN-promoted tris-
(trimethylsilyl)silane (TTMSS) radical reduction.
In summary, a highly enantio- and diastereoselective
procedure for the preparation of various C-2, C-3, and C-6
deoxypyranosides has been developed. Our approach to
these sugars provides rapid and practical access to these rare
and naturally occurring sugars, which should be of use for
further natural product synthesis. Critical to the success of
this synthesis was the use of the Pd(0)-catalyzed glycosyla-
tion and corresponding post-glycosylation transformations.
It is also worth noting that our method is structurally
divergent in that it produces four different sugar congeners
from the same advanced intermediate. We believe that this
approach will be particularly useful for medicinal chemistry.
Finally, by selecting either enantiomeric form of the Noyori
catalyst (R,R) or (S,S), our strategy is also amenable to the
synthesis of both D- or L-forms of these sugars. Our efforts to
apply these postglycosylation reactions in oligosaccharide
settings will be reported in due course.
Using our previously reported NBSH diimide procedure
(o-NO2PhSO2NHNH2/Et3N),10a,10b the D-amicetose 20 was
prepared from pyran (ent)-11, which was easily prepared by a
reduction of pyranone (ent)-12 (Scheme 6). A related regio-
isomeric halohydrin could be used to prepare the 2-deox-
ypyranoside, R-digitoxose 9. This was accomplished by
replacing the epoxide opening with a trans-diaxial iodocar-
bonate formation. This has been most commonly accom-
plished using I(collidine)2ClO4 as the electrophilic reagent.14
We believed a more economical method would employ the
cheaper NIS. These efforts began with the conversion of the
allylic alcohol (ent)-11 into the Cbz- and Boc-allylic carbo-
nates 21 and 22, respectively.
Because of the electron-deficient nature of the pyran
double bonds in the carbonates 21 and 22, it was not
surprising that they did not react with NIS in CH2Cl2. This
changed upon the addition of Lewis acids, such as 1 equiv of
Experimental Section16
(1R,2R,4S,6S)-2-(Benzyloxy)-4-methyl-3,7-dioxabicyclo[4.1.0]-
heptan-5-one (16). To the solution of pyranone 12 (220 mg, 1.0
mmol) in methanol (3 mL) at 0 °C was added dropwise 30%
aqueous hydrogen peroxide (0.26 mL, 2.5 mmol), followed by
aqueous sodium hydroxide (0.1 mL, 0.5 M). The reaction mixture
was stirred at rt for 4 h, and then the reaction mixture was extracted
with diethyl ether. The extracts were washed with saturated
aqueous NaHCO3, dried over Na2SO4, and concentrated under
reduced pressure. The crude product was purified using silica gel
flash chromatography to give epoxide 16 (207 mg, 0.88 mmol,
88%) as a colorless oil: Rf (20% EtOAc/hexane) 0.47; [R]20D -59.3
(c 1.0, MeOH); IR (thin film, cm-1) ν 3034, 2937, 1726, 1455, 1369,
MgBr2 Et2O (26% yield) and 30 mol % of LiClO4 (<10%
3
yield), albeit in low yields. An even more efficient conversion
occurred when the solvent was changed from CH2Cl2 to
AcOH. Thus, simply exposing the Boc-carbonate 22 to 2.5
equiv of NIS in acetic acid without any Lewis acid, provided
an excellent yield of the desired iodocarbonate (ent)-10
(96%).15 This improved reactivity was also found for the
Cbz-carbonate 21, although it gave the iodo-carbonate (ent)-
10 in significantly lower yield (51%). The iodine in iodo-
carbonate (ent)-10 was reduced by tris(trimethylsilyl)silane
(14) (a) Pauls, H. W.; Fraser-Reid, B. J. Carbohydr. Chem. 1985, 4, 1–14.
(b) Martin, S. F.; Zinke, P. W. J. Org. Chem. 1991, 56, 6600–6606.
(15) To the best of our knowledge, this is the first successful use of NIS to
convert allyl carbonate to an iodo-cyclic carbonate.
(16) Experimental procedures for the synthesis of all new compounds are
presented in the Experimental Section. Complete experimental procedures
and spectral data for the remaining compounds are presented in the
Supporting Information.
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1
1256, 1146, 1060, 996, 859, 699; H NMR (270 MHz, CDCl3) δ
7.36 (m, 5H), 5.30 (d, J=1.2 Hz, 1H), 4.80 (d, J=11.6 Hz, 1H), 4.64
(d, J=11.6 Hz, 1H), 4.17 (q, J=6.9 Hz, 1H), 3.59 (dd, J=3.9, 1.2
Hz, 1H), 3.46 (d, J=4.0 Hz, 1H), 1.38 (d, J=6.9 Hz, 3H); 13C
NMR (67.5 MHz, CDCl3) δ 203.1, 136.6, 128.7, 128.4, 128.2, 93.3,
93.2, 72.0, 70.8, 53.8, 53.1; HRMS calcd for [C13H14O4 + Na]+
257.0784, found 257.0784.
68.5, 56.0, 16.9; HRMS calcd for [C13H17BrO4 + Na]+ 339.0202,
found 339.0204.
(2R,3R,5R,6S)-2-(Benzyloxy)-6-methyltetrahydro-2H-pyran-
3,5-diol (18). To a solution of bromide 19 (17 mg, 0.05 mmol) in
dry toluene (0.5 mL) were added tris(trimethylsilyl)silane
(TTMSS) (0.033 mL, 0.1 mmol) and AIBN (4 mg, 0.025 mmol)
at 0 °C. At this stage, the reaction mixture was degassed using a
freeze-pump-thaw technique three times. The reaction mix-
ture was then stirred at 80 °C for 4 h under Ar. The mixture was
directly loaded onto silica gel column for purification to give
R-ascarylose 18 (10 mg, 0.038 mmol, 76%) as a colorless oil.
Alternative Procedure for 18. To a round-bottom flask were
added epoxide 8 (23 mg, 0.094 mmol), THF (0.5 mL), and
LiAlH4 (7.1 mg, 0.19 mmol) at 0 °C. The reaction solution was
stirred for 30 min at 0 °C. Water was added dropwise to quench
the reaction, and then the mixture was extracted with EtOAc.
The organic layer was washed with saturated brine, dried over
Na2SO4, and concentrated under reduced pressure. The crude
product was purified using silica gel flash chromatography to
give R-ascarylose 18 (19 mg, 0.08 mmol, 85%) as a colorless oil:
Rf (60% EtOAc/hexane) 0.17; [R]20D -90.8 (c 1.0, MeOH); IR
(thin film, cm-1) ν 3405, 2935, 1718, 1686, 1256, 1123, 1080, 995;
1H NMR (600 MHz, CDCl3) δ 7.34 (m, 5H), 4.74 (d, J=12.0 Hz,
1H), 4.68 (s, 1H), 4.53 (d, J=12.0 Hz, 1H), 3.91 (dd, J=4.8, 3.0
Hz, 1H), 3.70 (dq, J=9.6, 6.0 Hz, 1H), 3.61 (ddd, J=10.8, 9.0,
4.2 Hz, 1H), 2.09 (ddd, J=13.2, 3.6, 3.6 Hz, 1H), 1.89 (ddd, J=
13.2, 11.4, 3.0 Hz, 1H), 1.30 (d, J=6.6 Hz, 3H); 13C NMR (150
MHz, CDCl3) δ 137.4, 128.5, 127.9, 127.8, 98.2, 69.8, 69.0, 68.8,
68.1, 35.2, 17.7; HRMS calcd for [C13H18O4 + H]+ 239.0202,
found 239.0204.
(2R,3S,6S)-6-(Benzyloxy)-2-methyltetrahydro-2H-pyran-3-ol
(20). To a solution of allylic alcohol (ent)-11 (40 mg, 0.18 mmol)
in N-methylmorpholine (NMM) (0.5 mL) was added o-nitro-
benzenesulfonyl hydrazide (NBSH) (118 mg, 0.54 mmol) fol-
lowed by addition of Et3N (100 μL). The mixture was stirred at
rt for 1 day, and then more NBSH (60 mg, 0.27 mmol) was added
and the mixture stirred at rt overnight. At 0 °C, the reaction
mixture was diluted with ethyl acetate and washed with 1 M HCl
(aq). The aqueous layer was extracted twice with ethyl acetate.
The combined organic layer was subsequently washed with
saturated aqueous NaHCO3 and saturated brine and dried over
Na2SO4. The solvent was removed under reduced pressure, and
the residue was subjected to silica gel column chromatography.
Elution with hexane/EtOAc (3.5:1, v/v) afforded the dideoxy-
sugar 20 (26 mg, 64%) as a clear oil: Rf (hexanes/EtOAc, 2:1 v/v)
0.24; [R]20D +133.2 (c 1.26, CHCl3); IR (thin film, cm-1) ν 3419
(broad), 3071, 3037, 2936, 2891, 1501, 1453, 1350, 1227, 1123,
(1R,2R,4S,5S,6R)-2-(Benzyloxy)-4-methyl-3,7-dioxabicyclo-
[4.1.0]heptan-5-ol (8). To a solution of epoxide 16 (672 mg, 2.87
mmol) in CH2Cl2 (3 mL) was added a solution of CeCl3/MeOH (3
mL, 0.4 M). The mixture was cooled to -78 °C. NaBH4
(130 mg, 3.4 mmol) was added, and the reaction mixture was
stirred at -78 to -20 °C for 4 h. The reaction was quenched with
saturated aqueous NaHCO3. The mixture was extracted with
Et2O, and the organic layer was washed with saturated brine,
dried over Na2SO4, and concentrated under reduced pressure. The
crude product was purified using silica gel flash chromatography
to give epoxide 8 (576 mg, 2.44 mmol, 85%) as a colorless oil: Rf
(80% EtOAc/hexane) 0.47; [R]20D -62.8 (c 1.0, MeOH); IR (thin
film, cm-1) ν 3430, 2911, 1454, 1370, 1241, 1114, 1054, 980, 848,
805, 738, 698; 1H NMR (600 MHz, CDCl3) δ 7.34 (m, 5H), 5.03 (s,
1H), 4.75 (d, J=11.4 Hz, 1H), 4.57 (d, J=11.4 Hz, 1H), 3.58 (dq,
J=9.0, 6.0 Hz, 1H), 3.45 (d, J=9.0 Hz, 1H), 3.23 (d, J=3.6 Hz,
1H), 3.12 (d, J=3.6 Hz, 1H), 1.21 (d, J=6.0 Hz, 3H); 13C NMR
(150 MHz, CDCl3) δ 137.5, 128.8, 128.4, 128.3, 94.5, 70.3, 68.0,
65.8, 56.1, 50.5, 18.5; HRMS calcd for [C13H16O4 + H]+
237.1121, found 237.1121.
(2R,3R,4S,5R,6S)-2-(Benzyloxy)-6-methyltetrahydro-2H-pyr-
an-3,4,5-triol (17). To a round-bottom flask were added epoxide
8 (13 mg, 0.055 mmol), HOAc (0.5 mL), and Sc(OTf)3 (5 mg,
0.01 mmol). The reaction solution was stirred for 1 h at rt. The
reaction mixture was diluted with EtOAc, and saturated aque-
ous NaHCO3 was added at 0 °C. The mixture was extracted
with EtOAc, and the EtOAc layer was washed with saturated
brine, dried over Na2SO4, and concentrated under reduced
pressure. The crude product was dissolved in THF/H2O
(0.4 mL, 3:1) at rt, and lithium hydroxide monohydrate (5 mg,
0.13 mmol) was added to the solution. The reaction mixture
was stirred at rt for 5 h, and then the reaction mixture was directly
loaded onto a silica gel column to give R-6-deoxyaltrose 17
(9.6 mg, 0.038 mmol, 69%) as a colorless oil: Rf (EtOAc) 0.49;
[R]20 -73.3 (c 1.0, MeOH); IR (thin film, cm-1) ν 3384, 2930,
D
1455, 1375, 1259, 1127, 1061, 1014, 970, 852, 737, 698; 1H NMR
(600 MHz, CDCl3) δ 7.35 (m, 5H), 4.81 (s, 1H), 4.75 (d, J=12 Hz,
1H), 4.55 (d, J=12 Hz, 1H), 3.98 (dd, J=3.6, 1.8Hz, 1H), 3.89(dd,
J=3.6, 3.6 Hz, 1H), 3.79 (dq, J=9.0, 6.0 Hz, 1H), 3.51 (dd, J=9.6,
3.6Hz, 1H), 1.21(d, J=6.0Hz, 3H); 13C NMR (150 MHz, CDCl3)
δ 136.5, 128.9, 128.6, 128.4, 99.0, 70.9, 70.1, 69.8, 69.6, 65.8,
17.8; HRMS calcd for [C13H18O5 + Na]+ 277.1046, found
277.1047.
1
1045, 982; H NMR (CDCl3, 600 MHz) δ 7.38-7.33 (m, 4H),
7.29 (m, 1H), 4.84 (dd, J=3.0, 1.2 Hz, 1 H), 4.71 (d, J=12.0 Hz, 1
H), 4.48 (d, J=12.0 Hz, 1H), 3.66 (dq, J=9.0, 6.0 Hz, 1H), 3.29
(dddd, J=9.6, 9.0, 5.4, 4.8 Hz, 1 H), 1.88 (m, 2H), 1.80 (m, 2H),
1.45 (d, J=4.8 Hz, OH), 1.27 (d, J=6.6 Hz, 3 H); 13C NMR
(CDCl3, 150 MHz) δ 138.1, 128.4, 127.8, 127.6, 95.5, 72.2, 69.6,
68.6, 29.6, 27.7, 17.9; HRMS calcd for [C13H18O3 + Na]+
245.1148, found 245.1148.
(2R,3S,4S,5S,6S)-2-(Benzyloxy)-4-bromo-6-methyltetrahy-
dro-2H-pyran-3,5-diol (19). To a round-bottom flask were
added epoxide 8 (96 mg, 0.41 mmol), HOAc (0.5 mL), and
MgBr2 Et2O (106 mg, 0.41 mmol). The reaction mixture was
3
stirred at rt for 1 h. The reaction mixture was diluted with
EtOAc, and saturated aqueous NaHCO3 was added at 0 °C.
The mixture was extracted with EtOAc, and the organic layer was
washed with saturated brine, dried over Na2SO4, and concen-
trated under reduced pressure. The crude product was purified
using silica gel flash chromatography to give bromide 19 (137 mg,
0.4 mmol, 98%) as a colorless oil: Rf (50% EtOAc/hexane)
Benzyl (2R,3S,6S)-6-(Benzyloxy)-2-methyl-3,6-dihydro-2H-
pyran-3-ylcarbonate (21). A solution of allylic alcohol (ent)-11
(224 mg, 1.03 mmol) in CH2Cl2 (4 mL) at rt was added 60%
NaH (220 mg, 5.5 mmol) in CH2Cl2 (4 mL), which was washed
with hexane before use. Then n-Bu4NI (369 mg, 1 mmol) was
added to the mixture followed by the addition of DMAP (61 mg,
0.5 mmol). The reaction mixture was stirred at rt for 2 h. It was
then diluted with Et2O and washed with saturated aqueous
NH4Cl, and the aqueous layer was extracted with Et2O twice.
The combined organic layer was then washed with saturated
aqueous NaHCO3 and saturated brine and dried over Na2SO4.
After removal of the solvent under reduced pressure, the residue
was subjected to silica gel flash column chromatography, and
0.28; [R]20 -57.2 (c 1.0, MeOH); IR (thin film, cm-1) ν 3402,
D
1
2919, 1718, 1454, 1245, 1055, 994, 739; H NMR (600 MHz,
CDCl3) δ 7.34 (m, 5H), 4.80 (d, J=12.0 Hz, 1H), 4.72 (d, J=3.6
Hz, 1H), 4.54 (d, J=12.0 Hz, 1H), 4.35 (dd, J=6.0, 3.6 Hz, 1H),
4.12 (dd, J=6.0, 3.6 Hz, 1H), 4.08 (qd, J=6.6, 6.6 Hz, 1H), 3.67
(dd, J=6.0, 3.6 Hz, 1H), 1.27 (d, J=6.6 Hz, 3H); 13C NMR (150
MHz, CDCl3) δ 137.2, 128.4, 127.8, 127.7, 99.0, 71.8, 70.4, 69.8,
5964 J. Org. Chem. Vol. 74, No. 16, 2009

Shan et al.
JOCArticle
elution with hexane/EtOAc (15:1, v/v) afforded the carbonate
21 (270 mg, 74%) as a colorless viscous oil: Rf (hexanes/EtOAc,
0.1 mmol) was added, and the mixture was stirred at rt for
another 24 h. The reaction mixture was diluted with EtOAc,
cooled to 0 °C, and quenched by addition of saturated aqueous
NaHCO3. The mixture was extracted with EtOAc, and the
organic layer was washed subsequently with saturated aqueous
Na2S2O3 and saturated brine and dried over Na2SO4. After
removal of the solvent under reduced pressure, a crude 1H NMR
experiment showed that the ratio of product and remaining
starting material is 2:1. Then the residue was subjected to silica
gel column chromatography, and elution with hexane/EtOAc
(7:1, v/v) afforded iodocarbonate (ent)-10 (10.1 mg, 26%).
Second Alternative Procedure for (ent)-10. A solution of allyl
carbonate 21 (35.4 mg, 0.10 mmol) in HOAc (3 mL) was added
NIS (33.8 mg, 0.15 mmol) at rt. It was stirred at rt for 12 h, then
more NIS (22.5 mg, 0.1 mmol) was added, and the mixture was
stirred at rt for another 24 h. Once again, more NIS (22.5 mg,
0.1 mmol) was added, and the mixture was stirred at rt for an
additional 24 h. The reaction mixture was diluted with EtOAc,
and cooled to 0 °C, and quenched by addition of saturated
aqueous NaHCO3. The mixture was extracted with EtOAc, and
the organic layer was washed subsequently with saturated
aqueous Na2S2O3 and saturated brine, and dried over Na2SO4.
After removal of the solvent under reduced pressure, the residue
was subjected to silica gel column chromatography. Elution
with hexane/EtOAc (7:1, v/v) afforded the iodocarbonate (ent)-
10 (20 mg, 51%).
(3aR,4R,6S,7aS)-6-(Benzyloxy)-4-methyltetrahydro-3aH-[1,3]-
dioxolo[4,5-c]pyran-2-one (23). To a solution of iodocarbonate
(ent)-10 (59 mg, 0.15 mmol) in toluene (2 mL) was added
tris(trimethylsilyl)silane (TTMSS) (70 μL, 0.22 mmol) and then
solid AIBN (5 mg, 0.03 mmol) was quickly added in one portion
at 0 °C. The system was then cooled to approximately -50 °C,
degassed with vacuum, and refilled with Ar. This procedure was
repeated three times, and then the mixture was heated to 75 °C
for 40 min. The reaction mixture was cooled to rt and then
directly loaded onto silica gel column. Elution with hexane/
EtOAc (3:1, v/v) afforded carbonate 23 (17.8 mg, 45%) as a
3:1 v/v) 0.44; [R]20D +96.1 (c 4.48, CHCl3); IR (thin film, cm-1
)
ν 3032, 2979, 2936, 1747, 1497, 1456, 1382, 1250, 1049, 1020,
962; 1H NMR (CDCl3, 600 MHz) δ 7.41-7.34 (m, 9H), 7.31(m,
1H), 5.96 (d, J=10.2 Hz, 1 H), 5.85 (ddd, J=9.6, 2.4, 1.8 Hz, 1
H), 5.21 (d, J=12.6 Hz, 1H), 5.18 (d, J=12.0 Hz, 1H), 5.08 (brs,
1H), 4.94 (ddd, J=9.0, 3.0, 1.8 Hz, 1H), 4.79 (d, J=12.0 Hz, 1H),
4.62 (d, J=12.0 Hz, 1H), 4.05 (dq, J=9.6, 6.6 Hz, 1H), 1.24 (d,
J=6.0 Hz, 3 H); 13C NMR (CDCl3, 150 MHz) δ 154.7, 137.9,
135.0, 129.1, 128.6, 128.5, 128.4, 128.2, 128.1, 127.9, 127.6, 93.6,
74.7, 70.1, 69.8, 64.7, 17.8; HRMS calcd for [C21H22O5 + Na]+
377.1359, found 377.1362.
tert-Butyl (2R,3S,6S)-6-(Benzyloxy)-2-methyl-3,6-dihydro-
2H-pyran-3-ylcarbonate (22). A solution of allylic alcohol
(ent)-11 (519 mg, 2.38 mmol) and DMAP (14.5 mg, 0.119 mmol)
in CH2Cl2 (8 mL) at 0 °C was added a solution of Boc2O (778
mg, 3.57 mmol) in CH2Cl2 (2.5 mL). The reaction mixture was
then stirred at rt for 1 h. It was diluted with Et2O and quenched
with saturated aqueous NaHCO3 at 0 °C. The mixture was
stirred at 0 °C for 20 min and then was extracted with Et2O, and
the aqueous layer was extracted again with Et2O. The pooled
organic layer was subsequently washed with saturated aqueous
NH4Cl, saturated aqueous NaHCO3, and saturated brine and
dried over Na2SO4. After removal of the solvent under reduced
pressure, the residue was subjected to silica gel flash column
chromatography, and elution with hexane/EtOAc (20:1, v/v)
afforded the carbonate 22 (663 mg, 87%) as a white solid: mp
60-62 °C; Rf (hexanes/EtOAc, 3:1 v/v) 0.60; [R]20 +88.6 (c
D
2.99, CHCl3); IR (thin film, cm-1) ν 2982, 2935, 1732, 1455,
1370, 1336, 1317, 1286, 1269, 1254, 1154, 1094, 1049, 1028, 969;
1H NMR (CDCl3, 600 MHz) δ 7.38-7.32 (m, 4H), 7.29 (m, 1H),
5.93 (d, J=10.2 Hz, 1 H), 5.82 (ddd, J=10.8, 2.4, 1.8 Hz, 1 H),
5.06 (brs, 1H), 4.86 (ddd, J=9.0, 3.0, 1.8 Hz, 1H), 4.77 (d, J=
12.0 Hz, 1H), 4.60 (d, J=12.0 Hz, 1H), 4.01 (dq, J=9.0, 6.0 Hz,
1H), 1.50 (s, 9H), 1.22 (d, J=6.0 Hz, 3 H); 13C NMR (CDCl3,
150 MHz) δ 153.1, 138.1, 129.7, 128.4, 127.9, 127.8, 127.6, 93.7,
82.6, 73.5, 70.1, 64.9, 27.7, 17.8; HRMS calcd for [C18H24O5 +
Na]+ 343.1516, found 343.1517.
colorless viscous oil: Rf (hexanes/EtOAc, 2:1 v/v) 0.29; [R]20
D
+129.5 (c 0.93, CHCl3); IR (thin film, cm-1) ν 3035, 2975, 2940,
1798, 1454, 1356, 1175, 1152, 1066, 1036, 1023, 919; 1H NMR
(CDCl3, 600 MHz) δ 7.36-7.27 (m, 5H), 4.92 (dd, J=5.4, 4.8
Hz, 1 H), 4.78 (ddd, J=7.2, 7.2, 6.0 Hz, 1 H), 4.71 (d, J=12.6 Hz,
1H), 4.52 (d, J=12.0 Hz, 1H), 4.26 (dd, J=9.0, 7.8 Hz, 1H), 4.01
(dq, J=9.0, 6.0 Hz, 1H), 2.31 (ddd, J=15.0, 5.4, 5.4 Hz, 1H),
(3aR,4R,6S,7S,7aR)-6-(Benzyloxy)-7-iodo-4-methyltetrahy-
dro-3aH-[1,3]dioxolo[4,5-c]pyran-2-one ((ent)-10). To a solution
of allyl carbonate 22 (285 mg, 0.90 mmol) in HOAc (3 mL) was
added NIS (320 mg, 1.42 mmol) at rt. It was stirred at rt for 12 h,
more NIS (230 mg, 1.0 mmol) was added, and the mixture was
stirred at rt for another 12 h. The reaction mixture was diluted
with EtOAc, cooled to 0 °C, and quenched by addition of
saturated aqueous NaHCO3. The mixture was extracted with
EtOAc, and the organic layer was washed subsequently with
saturated aqueous Na2S2O3 and saturated brine and dried over
Na2SO4. After removal of the solvent under reduced pressure,
the residue was subjected to silica gel column chromatography,
and elution with hexane/EtOAc (5:1, v/v) afforded the iodocar-
bonate (ent)-10 (335 mg, 95%) as a white solid: mp 80.5-82.5 °C;
Rf (hexanes/EtOAc, 3:1 v/v) 0.38; [R]20D +52.0 (c 2.65, CHCl3);
IR (thin film, cm-1) ν 3030, 2980, 2935, 1839, 1806, 1497, 1454,
1347, 1331, 1147, 1087, 1053, 1021, 970; 1H NMR (CDCl3, 600
2.19 (ddd, J=15.0, 7.2, 4.8 Hz, 1 H), 1.31 (d, J=6.6 Hz, 3H); 13
C
NMR (CDCl3, 150 MHz) δ 154.3, 137.2, 128.5, 127.8, 127.7,
94.2, 77.0, 72.5, 69.3, 63.3, 30.7, 18.5; HRMS calcd for
[C14H16O5 + Na]+ 287.0890, found 287.0890.
(2R,3S,4S,6S)-6-(Benzyloxy)-2-methyltetrahydro-2H-pyran-
3,4-diol ((ent)-9)17. To a solution of carbonate 23 (16 mg, 0.06
mmol) in THF (2 mL) was added 2 M NaOH (1 mL). The
mixture was stirred at rt for 1 h. It was then diluted with EtOAc
and passed through a pad of Celite, eluting with EtOAc/MeOH
(3:1, v/v). The eluent was dried over Na2SO4. After removal of
the solvent under reduced pressure, the residue was subjected to
silica gel column chromatography, and elution with hexane/
EtOAc (1.5:1, v/v) afforded the R-digitoxose (ent)-9 (12 mg,
MHz)
δ 7.39-7.34 (m, 4H), 7.32 (m, 1H), 5.16 (d,
84%) as a colorless oil: Rf (hexanes/EtOAc, 1:1 v/v) 0.25; [R]20
J=5.4 Hz, 1 H), 4.96 (dd, J=8.4, 7.8 Hz, 1 H), 4.76 (d, J=
12.0 Hz, 1H), 4.59 (d, J=12.0 Hz, 1H), 4.40 (dd, J=9.0, 7.8 Hz,
1H), 4.21 (dd, J=8.4, 6.0 Hz, 1H), 4.05 (dq, J=9.0, 6.6 Hz, 1H),
1.35 (d, J=6.0 Hz, 3 H); 13C NMR (CDCl3, 150 MHz) δ 152.9,
136.6, 128.5, 128.1, 127.9, 101.0, 78.7, 77.1, 70.2, 64.0, 21.0,
18.6; HRMS calcd for [C14H15IO5 + Na]+ 412.9856, found
412.9859.
D
+107.5 (c 1.2, CHCl3); IR (thin film, cm-1) ν 3461 (broad),
3090, 3065, 3033, 2975, 2918, 1497, 1454, 1407, 1235, 1148, 1120,
1101, 1054, 1010, 970; 1H NMR (CDCl3, 600 MHz) δ 7.39-7.35
(m, 2H), 7.34-7.30 (m, 3H), 4.97 (d, J=3.6 Hz, 1 H), 4.72 (d, J=
12.0 Hz, 1 H), 4.50 (d, J=11.4 Hz, 1H), 3.96 (brs, 1 H), 3.77 (dq,
J=9.6, 6.0 Hz, 1H), 3.45 (brs, OH), 3.16 (dd, J=10.2, 3.6 Hz,
1H), 2.48 (brs, OH), 2.22 (ddd, J=15.0, 3.0, 1.2 Hz, 1H), 1.94
Alternative Procedure for (ent)-10. To a solution of allyl
carbonate 22 (31.8 mg, 0.1 mmol) and NIS (33.8 mg, 0.15 mmol)
in CH2Cl2 (0.8 mL) was added MgBr2 Et2O (25.8 mg, 0.1 mmol)
(17) (a) Current, S.; Sharpless, K. B. Tetrahedron Lett. 1978, 19, 5075–
5078. (b) Koepper, S.; Thiem, J. J. Carbohydr. Chem. 1987, 6, 57–85.
3
at rt. It was stirred at rt for 12 h, then more NIS (22.5 mg,
J. Org. Chem. Vol. 74, No. 16, 2009 5965

Shan et al.
JOCArticle
(ddd, J=15.0, 3.6, 3.6 Hz, 1H), 1.33 (d, J=6.6 Hz, 3 H); 13C
NMR (CDCl3, 150 MHz) δ 136.9, 128.6, 128.1, 127.9, 96.4, 72.6,
69.5, 67.3, 64.7, 35.1, 17.8.
600 MHz NMR at WVU. A dissertation fellowship to M.S.
from WVU’s Office of Graduate Study and Life is greatly
appreciated.
Acknowledgment. We are grateful to the NSF (CHE-
0749451) and the ACS-PRF (47094-AC1) for the support
of our research program and NSF-EPSCoR (0314742) for a
Supporting Information Available: Experimental proce-
dures, characterization data, and NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
5966 J. Org. Chem. Vol. 74, No. 16, 2009