De novo approach to 2-deoxy-β-glycosides: Asymmetric syntheses of digoxose and digitoxin

Article abstract of DOI:10.1021/jo062534+

A highly enantioselective and straightforward route to trisaccharide natural products digoxose and digitoxin has been developed. Key to this approach is the iterative application of the palladium-catalyzed glycosylation reaction, reductive 1,3-transposition, diastereoselective dihydroxylation, and regioselective protection. The first total synthesis of natural product digoxose was accomplished in 19 total steps from achiral 2-acylfuran, and digitoxin was fashioned in 15 steps starting from digitoxigenin 2 and pyranone 8β. This flexible synthetic strategy also allows for the preparation of mono- and disaccharide analogues of digoxose and digitoxin.

Full text of DOI:10.1021/jo062534+

De Novo Approach to 2-Deoxy-â-glycosides: Asymmetric Syntheses
of Digoxose and Digitoxin1
Maoquan Zhou and George A. O’Doherty*
Department of Chemistry, West Virginia UniVersity, Morgantown, West Virginia 26506
george.odoherty@mail.wVu.edu
ReceiVed December 12, 2006
A highly enantioselective and straightforward route to trisaccharide natural products digoxose and digitoxin
has been developed. Key to this approach is the iterative application of the palladium-catalyzed
glycosylation reaction, reductive 1,3-transposition, diastereoselective dihydroxylation, and regioselective
protection. The first total synthesis of natural product digoxose was accomplished in 19 total steps from
achiral 2-acylfuran, and digitoxin was fashioned in 15 steps starting from digitoxigenin 2 and pyranone
8â. This flexible synthetic strategy also allows for the preparation of mono- and disaccharide analogues
of digoxose and digitoxin.
Introduction
The cardiac glycoside digitoxin (1) (Figure 1), an extract from
the leaves of Digitalis purpurea (purple foxglove), has long been
used to slow the heart rate while increasing the contractility of
the heart muscle (inotropic activity). It has been widely
prescribed for congestive heart failure and cardiac arrhythmia
for over 200 years. However, extensive care must be taken when
treating patients with digitoxin, because the typical therapeutic
dose (14-26 ng mL-1) is dangerously close to the toxic dose
(>35 ng mL-1).2 Digitoxin has also been shown to possess
potential anticancer activities.3 Structurally, digitoxin is the
combination of two natural products, the aglycon digitoxigenin
(2)4 and the trisaccharide digoxose (3).5 Oligosaccharides are
known to play important roles in many pharmacologically
FIGURE 1. Digitoxin, digoxose, and digitoxigenin.
important antibiotics, vaccines, and antitumor agents.6 For
instance, while the digitoxigenin is considered to be the
(4) For the synthesis of digitoxigenin, see: (a) Danieli, N.; Mazur, Y.;
Sondheimer, F. J. Am. Chem. Soc. 1962, 84, 875-876. (b) Donovan,
Stephen, F.; Avery, Mitchell, A.; McMurry, John, E. Tetrahedron Lett. 1979,
35, 3287-3290. (c) Tsai, T. Y.R.; Minta, A.; Wiesner, K. Heterocycles
1979, 12, 1397-1402. (d) Marini-Bettolo, R.; Flecker, P.; Tsai, T. Y.R.;
Wiesner, K. Can. J. Chem. 1981, 59, 1403-1410. (e) Kabat, M. M. J. Org.
Chem. 1995, 60, 1823-1827. (f) Stork, G.; West, F.; Lee, H. Y.; Isaacs, R.
C. A.; Manabe, S. J. Am. Chem. Soc. 1996, 118, 10660-10661. (g)
Almirante, N.; Cerri, A. J. Org. Chem. 1997, 62, 3402-3404. (f) Bocknack,
B. M.; Wang, L.-C.; Krische, M. J. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5421-5424.
(1) This paper is dedicated to a dear friend and former colleague,
Professor Wayland Noland, on the occasion of his 80th birthday.
(2) Greeff, K. Cardiac Glycosides, Part 1: Experimental Pharmacology.
In Handbook of Experimental Pharmacology; Springer-Verlag: Berlin, New
York, 1981; Vol. 56.
(3) (a) Haux; J. Med. Hypotheses 1999, 53, 543-548. (b) Kometiani,
P.; Liu, L.; Askari, A. Mol. Pharmacol. 2005, 67, 929-936. (c) Lopez-
Lazaro, M.; Pastor, N.; Azrak, S. S.; Ayuso, M. J.; Austin, C. A.; Cortes,
F. J. Nat. Prod. 2005, 68, 1642-1645. (d) Winnicka, K. Bielawski, K.;
Bielawska, A. Acta Pol. Pharm. 2006, 63, 109-115.
10.1021/jo062534+ CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/06/2007
J. Org. Chem. 2007, 72, 2485-2493
2485

Zhou and O’Doherty
SCHEME 1. Digitoxin/Digoxose Retrosynthesis
pharmacophore portion of digitoxin 1, the aglycon 2 is inactive
without the attachment of digoxose trisaccharide 3. Thus, it is
reasonable to assume that by manipulating the sugar portion,
the resulting analogues may have improved activities. An
excellent example of the interplay between carbohydrate
structure and biological activity can be seen in the digitoxin
neoglycoside library constructed by Thorson and co-workers.7
Several of these digitoxigenin monosaccharide analogues showed
improved anticancer activity yet lower cardiotoxicity.7 In an
effort to differentiate the effects of carbohydrate substitution
versus neoglycoside substitution on activity, we desired access
to digitoxin and its bis- and monosaccharide analogues as well
as the free sugar digoxose and its mono- and disaccharide.
OAc,17 and NHCHO18) to control the anomeric stereochemistry,
which after glycosylation need to be reductively removed using
radical tin-hydride chemistry. Similarly the Barton-type deoxy-
genation of C-2 hydroxyl groups has been used in combination
with nucleophilic opening of anomeric epoxides.19 This chal-
lenge of stereocontrolled synthesis of 2-deoxy â-glycosides is
evident in the two previous syntheses of the tris-1,4-linked 2,6-
dideoxy-â-D-allose portion of digitoxin. While there has been
no synthesis of the natural product digoxose (3), there have been
two syntheses of digitoxin (1), a carbohydrate approach by
Wiesner and co-workers and a de novo approach by McDonald
and co-workers.20,21 Herein we describe the full account of our
successful de novo approach to 2-deoxy-â-allo-glycosides and
its application to syntheses of â-linked 1,4-oligosaccharide
natural products digoxose (3) and digitoxin (1).22 This de novo
methodology (Scheme 1) features the iterative use of a â-selec-
tive palladium-catalyzed glycosylation reaction23 and subsequent
chemo- and stereoselective transformations for the diastereo-
selective installation of the C-3/C-4 hydroxy groups and
regioselective C-3 protection, which we believe resulted in a
more efficient and flexible route in terms of number of steps
and stereocontrol compared with the previous approaches.24
The stereocontrolled synthesis of 2-deoxy-â-glycosides is
difficult as a result of the missing control element at the C-2
position.8,9 The use of the participation of an attached C-3 group
to control the anomeric stereochemistry had been shown to be
unreliable.10 To date, the most direct method involved an SN2
substitution of an R-D-glycopyranosyl donor and alcohol ac-
ceptor.11 The selectivity of this method, however, is highly
dependent on the protecting-group manipulation (activation) of
the pyranose donor and the reactivity of the acceptor.12 Their
use is also limited by the low availability of corresponding
monosaccharides in nature. Other strategies utilized equatorial
C-2 heteroatom neighboring groups (Br,13 I,14 SAr,15 SePh,16
(5) The attempts at the selective hydrolysis of digitoxin to form digoxose
(3) has been futile, only the monosaccharide digitoxose was isolated.
Surprisingly, 3 can be isolated from the dried twigs of Orthenthera Viminea,
see: Tiwari, K. N.; Khare, N. K.; Khare, A.; Khare, M. P. Carbohydr.
Res. 1984, 129, 179-187.
(6) (a) Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503-1531. (b)
Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed. Engl. 1996, 35,
1380-1419. (c) Kirschning, A.; Bechthold, A. F.-W.; Rohr, J. Top. Curr.
Chem. 1997, 188, 1-84. (d) Marzabadi, C. H.; Frank, R. W. Tetrahedron
2000, 56, 8385-8417. (e) Kirschning, A.; Jesberger, M.; Schoning, K. U.
Synthesis 2001, 507-540. (f) Nicolaou, K. C.; Mitchell, H. J. Angew. Chem.,
Int. Ed. 2001, 40, 1576-1624. (g) Sears, P.; Wong, C.-H. Science 2001,
291, 2344-2350. (h) He, X.; Liu, H.-W. Annu. ReV. Biochem. 2002, 71,
701-754.
Results and Discussion
Approach to â-Pyranones. Previously, we have shown that
R-glycosyl donors, such as R-Boc-pyranones 8R and 15R, can
be oligomerized and subsequently transformed into R-linked
oligosaccharides.23d Because these oligosaccharides are prepared
from achiral acylfurans, such as 9 and 10, we call this a de
(7) Langenhan, J. M.; Peters, N. R.; Guzei, I. A.; Hoffmann, F. M.;
Thorson, J. S. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 12305-12310.
(8) (a) Roush, W. R.; Bennett, C. E. J. Am. Chem. Soc. 1999, 121, 3541-
3542. (b) Sherry, B. D.; Loy, R. N.; Toste, F. D. J. Am. Chem. Soc. 2004,
126, 4510-4511.
(9) Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503-1531.
(10) (a) Binkley, R. W.; Koholic, D. J. J. Carbohydr. Chem. 1988, 7,
487-499. (b) Hashimoto, S.; Sano, A.; Sakamoto, H.; Nakajima, M.;
Yanagiya, Y.; Ikegami, S. Synlett 1995, 1271-1273. (c) Guo, Y.; Su-
likowski, G. A. J. Am. Chem. Soc. 1998, 120, 1392-1397. (d) Pongdee,
R.; Wu, B.; Sulikowski, G. A. Org. Lett. 2001, 3, 3523-3525.
(11) (a) Paulsen, H.; Kutschker, W.; Lockhoff, O. Chem. Ber. 1981, 114,
3233-3241. (b) Paulsen, H.; Lockhoff, O. Chem. Ber. 1981, 114, 3102-
3214.
(17) (a) Trumtel, M.; Veyribres, A.; Sinay, P. Tetrahedron Lett. 1989,
30, 2529-2532. (b) Trumtel, M.; Tavecchia, P.; Veyribres, A.; Sinay, P.
Carbohydr. Res. 1989, 191, 29-52.
(18) Tavecchia, P.; Trumtel, M.; VeyriBres, A.; Sinay, P. Tetrahedron
Lett. 1989, 30, 2533-2536.
(19) Gervay, J.; Danishefsky, S. J. Org. Chem. 1991, 56, 5448-5451.
(20) (a) Wiesner, K.; Tsai, T. Y. R.; Jin, H. HelV. Chim. Acta 1985, 68,
300-314. (b) Wiesner, K.; Tsai, T. Y. R. Pure Appl. Chem. 1986, 58, 799-
810. and (c) McDonald, F. E.; Reddy, K. S.; Diaz, Y. J. Am. Chem. Soc.
2000, 122, 4304-4309. (d) McDonald, F. E.; Reddy, K. S. Angew. Chem.,
Int. Ed. 2001, 40, 3653-3655.
(12) (a) van Boeckel, C. A. A.; Beetz, T.; van Aelst, S. F. Tetrahedron
1984, 40, 4097-4107. (b) van Boeckel, C. A. A.; Beetz, T. Recl. TraV.
Chim. Pays-Bas 1985, 104, 171-173.
(13) (a) Thiem, J.; Karl, H. Chem. Ber. 1980, 113, 3039-3048. (b)
Thiem, J.; Gerken, M. J. Carbohydr. Chem. 1982/3, 1, 229-249. (c) Thiem,
J.; Gerken, M.; Bock, K. Liebigs Ann. Chem. 1983, 462-470. (d) Bock,
K.; Lundt, I.; Pedersen, C. Carbohydr. Res. 1984, 130, 125-134. (e) Lundt,
I.; Thiem, J.; Prahst, A. J. Org. Chem. 1984, 49, 3063-3069. (f) Thiem,
J.; Gerken, M. J. Org. Chem. 1985, 50, 954-958.
(21) In contrast, McDonald and coworkers are able to use his methodol-
ogy to prepare an all-alpha analogue of digitoxin with high stereocontrol,
see: McDonald, F. E.; Wu, M. Org. Lett. 2002, 4, 3979-3981.
(22) For the communication of our initial approach to 1 see: Zhou, M.;
O’Doherty, G. A. Org. Lett. 2006, 8, 4339-4342.
(23) (a) Babu, R. S.; O’Doherty, G. A. J. Am. Chem. Soc. 2003, 125,
12406-12407. (b) Comely, A. C.; Eelkema, R.; Minnaard, A. J.; Feringa,
B. L. J. Am. Chem. Soc. 2003, 125, 8714-8715. (c) Kim, H.; Men, H.;
Lee, C. J. Am. Chem. Soc. 2004, 126, 1336-1337. For its application in
the de novo synthesis of a-linked 1,4- and 1,6-oligosaccharides, see: (d)
Babu, R. S.; Zhou, M.; O’Doherty, G. A. J. Am. Chem. Soc. 2004, 126,
3428-3429.
(24) In both the Wiesner and McDonald syntheses of digitoxin at least
one of the three glycosidic bonds was assembled with poor stereoselectivity;
see ref 20.
(14) Roush, W. R.; Lin, X.-F. J. Am. Chem. Soc. 1995, 117, 2236-
2250.
(15) (a) Ramesh, S.; Kaila, N.; Grewal, G.; Franck, R. W. J. Org. Chem.
1990, 55, 5-7. (b) Nicolaou, K. C.; Ladduwahetty, T.; Randall, J. L.;
Chucholowski, A. J. Am. Chem. Soc. 1986, 108, 2466-2467. (c) Ito, Y.;
Ogawa, T. Tetrahedron Lett. 1987, 28, 2723-2726. (d) Preuss, R.; Schmidt,
R. R. Synthesis 1988, 694-697. (e) Hashimoto, S.; Yanagiya, Y.; Honda,
T.; Ikegami, S. Chem. Lett. 1992, 1511-1514.
(16) Perez, M.; Beau, J.-M. Tetrahedron Lett. 1989, 30, 75-78.
2486 J. Org. Chem., Vol. 72, No. 7, 2007

Asymmetric Syntheses of Digoxose and Digitoxin
SCHEME 2. De Novo Pyranone Synthesis
SCHEME 4. Pd(0)-Catalyzed Glycosylation of
2-Deoxy-L-allose 19
toward the preparation of 2-deoxy-â-L-allose, which started with
the palladium-catalyzed glycosylation (5 mol % Pd(0)/10%
PPh3) of BnOH with the â-pyranone 15â27 to form the
â-benzyloxy pyranone 16 in 84% yield as a single diastereomer
28
(Scheme 3). Ketone reduction of pyranone 16 with NaBH4
gave a mixture of allylic alcohols 17a and 17b in 88% yield
with the diastereomeric ratio of ca. 1.5:1, respectively. Fortu-
nately, both diastereomers 17a/b could be used in the next
reaction. The diastereomeric ratio of alcohols could be improved
with the use of DibalH (dr ) 6:1); however, because of the
slightly lower yields, we preferred to use the operationally
simpler Luche procedure (NaBH4/CeCl3, -78 °C; 88% 1.5:1).
Applying the Myers’ reductive rearrangement conditions29
(NBSH, PPh3/DEAD, NMM, -30 °C to rt) to the mixture of
allylic alcohols 17 cleanly provided olefin 18 in 71% yield.
Finally, exposing olefin 18 to the Upjohn conditions30 (OsO4/
NMO) gave exclusively the diol 19 in 91% yield.31
With the successful synthesis of 2-deoxy-L-allose 19, we next
investigated the synthesis of allo-disaccharides using the same
strategy (Scheme 4). Our attempts at the regioselective glyco-
sylation of diol 19 using pyranones 15â were not promising,
giving a mixture of C-3 and C-4 glycosylated product 20 and
21 in a ratio of ca. 1.3:1. The regiochemistry of glycosylation
was assigned by coupling constant analysis of the benzoate 22
from the major isomer 20. Because of the inability of our
palladium glycosylation methodology to differentiate the equa-
torial alcohol from the axial alcohol in 19, we decided to
incorporate a selective protection step and applied this meth-
odology toward oligosaccharides (vide infra).
novo approach. By employing an enantioselective Noyori
reduction,25,26 an Achmatowicz oxidation, and diastereoselective
acylation, the acylfurans can be converted into R-Boc-pyranones
8R and 15R (Scheme 2).27 Alternatively, the Boc protection can
be preformed at an elevated temperature ((Boc)2O/NaOAc in
benzene at 80 °C) such that â-pyranones 8â and 15â can be
isolated in ∼50% yields from Achmatowicz products 13 and
14, and the ratio of â-pyranones to R-pyranones at these higher
temperatures can be as high as 1.3:1 (Scheme 2). As with
R-pyranones 8R and 15R, â-pyranones 8â and 15â can be
converted via palladium(0) catalysis into their corresponding
mixed acetal pyranones with complete retention of stereochem-
istry (i.e., 8 to 7 and 15â to 16, Scheme 1 and 3).
SCHEME 3. Synthesis of 2-Deoxy-L-allose 19
Synthesis of Digoxose and Digitoxin. Encouraged by these
promising results toward the synthesis of 2-deoxy-L-allose 19,
we next investigated the use of this approach for the synthesis
of digitoxose 25a. Thus, palladium-catalyzed glycosylation of
pyranone (D)-8â with benzyl alcohol provided the pyranone
7a in 85% yield as a single diastereomer (Scheme 5). The Luche
reduction of pyranone 7a gave a mixture of allylic alcohols 23a
in 85% yield. Reductive rearrangement of allylic alcohols 23a
provided olefin 24a in 84% yield. Dihydroxylation of 24a using
the Upjohn conditions (OsO4/NMO)30 gave exclusively the diol
25a in 92% yield.31 Using the same strategy starting from the
digitoxigenin and â-pyranone (D)-8â, the digitoxigenin mono-
(28) For reduction of â-pyanones, the CeCl3 is necessary to avoid 1,4-
reduction products. For Luche reduction, see: (a) Luche, J. L. J. Am. Chem.
Soc. 1978, 100, 2226-2227. (b) Haukaas, M. H.; O’Doherty, G. A. Org.
Lett. 2001, 3, 401-404.
(29) (a) Myers, A. G.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492-
4493. (b) Myers, A. G.; Zheng, B. Tetrahedron Lett. 1996, 37, 4841-
4844. (c) Myers, A. G.; Zheng, B.; Movassaghi, M. J. Org. Chem. 1997,
62, 7507. (d) Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2002, 4, 1771-
1774.
Approach to 2-Deoxy-â-glycosides. With a practical route
to the â-pyranones glycosyl donors, we next turned our attention
(25) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1996, 118, 2521-2522.
(26) (a) Li, M.; Scott, J. G.; O’Doherty, G. A. Tetrahedron Lett. 2004,
45, 1005-1009. (b) Li, M.; O’Doherty, G. A. Tetrahedron Lett. 2004, 45,
6407-6411.
(27) For the preparation of Boc-protected pyranones, see ref 26. (a) Babu,
R. S.; O’Doherty, G. A. J. Carb. Chem. 2005, 24, 169-177. (b) Guo, H.;
O’Doherty, G. A. Org. Lett. 2005, 7, 3921-3924.
(30) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
17, 1973-1976.
1
(31) No minor diastereomer was detected by H NMR.
J. Org. Chem, Vol. 72, No. 7, 2007 2487

Zhou and O’Doherty
SCHEME 7. Synthesis of Digitoxin and Digitoxose
SCHEME 5. Synthesis of Digitoxose and Digitoxin
Monosaccharides 25a/b
Disaccharides
digitoxoside 25b was prepared with similar efficiency.32,33 It is
worth noting that both the tertiary alcohol and the butenolide
ring of the aglycon were left untouched and thus compatible to
the palladium-catalyzed glycosylation and subsequent transfor-
mation.
SCHEME 6. Regioselective Protection of Diol 25
accharide 31a/b were fashioned by deprotection of the acetate-
protecting groups in 30a/b in 93% and 82% yield, respectively.
Gratifyingly, the preparation of trisaccharide occurred with
the same efficiency and high degree of stereocontrol as with
the disaccharides 31a/b (Scheme 7). Thus, regioselective
protection of the C-3 axial alcohol in diol 30a/b provided the
equatorial alcohol 32a/b which were subjected to the pyranone
(D)-8â under Pd(0) catalyst to fashion the 1,4-linked trisaccha-
rides 33a/b in 79% and 90% yield, respectively (Scheme 8).
When enone 33a/b were subjected to Luche reduction, a mixture
To prepare the digitoxose disaccharide, a regioselective
protection of diols 25a/b was needed. This was achieved by
the formation of an orthoester and regioselective ring opening
(Scheme 6).34 Specifically, the diol 25a was treated with
trimethyl orthoacetate and catalytic p-toluenesulfonic acid to
form an orthoester intermediate, which upon regiospecific acid
hydrolysis (TsOH/H2O) opened to the kinetically preferred axial
acetate 26a in excellent yield (95%). In the case of digitoxigenin
monodigitoxoside 25b, the reaction works as well as when using
25a. The tertiary alcohol, the butenolide ring of the aglycon,
and glycosidic bond were compatible with the acidic condition.
The remaining equatorial alcohol was then ready to serve as a
glycosyl acceptor for a second Pd(0)-catalyzed glycosylation.
We next explored the potential for the synthesis of â-linked
1,4-oligosaccharides via glycosylation of the C-4 secondary
alcohol in 26a/b.35 Applying the same palladium-catalyzed
glycosylation conditions to 26a/b (2 equiv of pyranone (D)-
8â, with 5% Pd(0)/10% PPh3) afforded the C-4 disaccharides
27a/b with complete stereocontrol at the anomeric center in 78%
and 80% yields, respectively (Scheme 7). Once again, the 1,2-
reduction of the keto-group in pyranone 27a/b under Luche
conditions provided a mixture of allylic alcohols 28a/b (∼1:1),
which when exposed to the Myers’ reductive 1,3-allylic
transposition conditions provided olefin 29a/b in 82% yield.
Finally, applying the Upjohn conditions to 29a/b gave exclu-
sively the dihydroxylated products 30a/b in 90% and 91% yield,
respectively.31 The digitoxose disaccharide and digitoxin dis-
SCHEME 8. Synthesis of Digitoxin and Digitoxose
Trisaccharides 1 and 4
(32) Mono- and bisdigtoxosides have been prepared by gradual degrada-
tion of digitoxin; see: (a) Satoh, D., Aoyama, K. Chem. Pharm. Bull. 1970,
18, 94-98. (b) Templeton, F. J.; Setiloane, P.; Kumar, V. P. S.; Yan, Y.;
Zeglam, H. T.; LaBella, F. S. J. Med. Chem. 1991, 34, 2778-2782. Our
synthetic material 25b and 31b have physical and spectral data identical
1
with those of the degraded products in the terms of H NMR, 13C NMR,
optical rotation, and melting point.
(33) The nomenclature of compounds 25b and 31b was used according
to ref 32.
(34) (a) King, J. F.; Allbutt, A. D. Can. J. Chem. 1970, 48, 1754-1769.
(b) Lowary, T. L.; Hindsgaul, O. Carbohydr. Res. 1994, 251, 33-67.
(35) For glycosylation at the C-4 position, we found that the best yields
were obtained when a 2:1 ratio of glycosyl donor to acceptor was used.
2488 J. Org. Chem., Vol. 72, No. 7, 2007

Asymmetric Syntheses of Digoxose and Digitoxin
SCHEME 9. Synthesis of Digoxose Bisdigitoxoside 37 and
Digoxose 3
0 °C. The reaction mixture was stirred at 0 °C for 2 h, quenched
with 10 mL of saturated aqueous NaHCO3, extracted (3 × 10 mL)
with Et2O, dried (Na2SO4), and concentrated under reduced pressure.
The crude product was purified by silica gel flash chromatography
eluting with 8% EtOAc/hexanes to give 7a (582 mg, 2.67 mmol,
85%) as a viscous oil: Rf (15% EtOAc/hexanes) ) 0.23; [R]21
D
-41.8 (c 1.20, CHCl3); IR (thin film, cm-1) 2933, 1698, 1453,
1373, 1163, 1057, 1023, 903, 800, 733, 697; 1H NMR (270 MHz,
CDCl3) δ 7.37 (m, 5H), 6.92 (dd, J ) 10.3, 2.0 Hz, 1H), 6.14 (dd,
J ) 10.3, 1.6 Hz, 1H), 5.40 (m, 1H), 4.95 (d, J ) 11.7 Hz, 1H),
4.69 (d, J ) 11.7 Hz, 1H), 4.24 (q, J ) 6.9 Hz, 1H), 1.53 (d, J )
6.9 Hz, 3H); 13C NMR (67.5 MHz, CDCl3) δ 196.8, 146.4, 136.8,
128.5 (2C), 128.1(3C), 128.0, 94.3, 75.2, 70.1, 17.2; HRCIMS calcd
for [C13H14O3Na+] 241.0835, found 241.0843.
of allylic alcohols 34a/b was obtained in 93% and 98% yields,
respectively. The alcohols 34a/b were then reductively rear-
ranged to corresponding olefin 35a/b in 81% and 89% yield,
respectively. The trisaccharides 4 and 1 were prepared with high
yield and complete stereocontrol by dihydroxylation of olefins
in 35a/b followed by deprotection of acetate groups in 36a/b.
The synthetic material 1 has physical and spectral data identical
to those of the commercially available natural product 136,37 (1H
NMR, 13C NMR, optical rotation, and melting point).
Finally the digoxose bisdigitoxoside 37 and natural product
digoxose 3 were prepared by hydrogenolysis of the anomeric
benzyl group (H2, Pd/C), which gave synthetic material with
physical and spectral data identical to those of the isolated
natural product 3 (1H NMR, 13C NMR, optical rotation, and
melting point).37,38
(2R,6R)-3,6-Dihydro-2-methyl-6-(phenylmethoxy)-2H-pyran-
3-ol (23a). A CH2Cl2 (2 mL) solution of enone 7a (435 mg, 2.0
mmol) and CeCl3 in MeOH solution (1.7 mL) was cooled to -78
°C. NaBH4 (75 mg, 2.0 mmol) was added, and the reaction mixture
was stirred at -78 °C for 3 h. The reaction mixture was diluted
with Et2O (5 mL), quenched with 5 mL of saturated aqueous
NaHCO3, extracted (3 × 5 mL) with Et2O, dried (Na2SO4), and
concentrated under reduced pressure. The crude product was
purified by silica gel flash chromatography eluting with 20%
EtOAc/hexanes to give allylic alcohols 23a (374 mg, 1.70 mmol,
85%) as a viscous oil (diastereomeric ratio I:II ) 1.5:1, inseparable
by silica gel chromatography): Rf (40% EtOAc/hexanes) ) 0.30;
IR (thin film, cm-1) 3397, 2978, 2933, 2869, 1498, 1455, 1378,
1
1053, 1010, 808, 738, 698; H NMR (600 MHz, CDCl3) (isomer
I) δ 7.35 (m, 5H), 6.16 (ddd, J ) 10.2, 5.4, 1.2 Hz, 1H), 5.86 (d,
J ) 10.2 Hz, 1H), 5.14 (ddd, J ) 1.8, 1.8, 1.2 Hz, 1H), 4.92 (d, J
) 12.0 Hz, 1H), 4.66 (d, J ) 12.0 Hz, 1H), 3.75 (qd, J ) 6.0, 2.4
Hz, 1H), 3.68 (m, 1H), 2.0 (d, J ) 10.2 Hz, 1H), 1.34 (d, J ) 6.0
Hz, 3H); (isomer II) δ 7.30 (m, 5H), 5.95 (ddd, J ) 10.2, 2.4, 1.8
Hz, 1H), 5.79 (ddd, J ) 10.2, 1.8, 1.2 Hz, 1H), 5.18 (ddd, J ) 1.8,
1.8, 1.2 Hz, 1H), 4.86 (d, J ) 12.0 Hz, 1H), 4.61 (d, J ) 12.0 Hz,
1H), 3.90 (m, 1H), 3.64 (dq, J ) 6.6, 6.0 Hz, 1H), 2.10 (d, J ) 6.6
Hz, 1H), 1.38 (d, J ) 6.0 Hz, 3H); 13C NMR (150 MHz, CDCl3)
(isomer I) δ 137.5, 131.3, 130.6, 128.4 (2C), 127.9 (2C), 127.7,
97.0, 71.4, 69.9, 64.7, 16.6; (isomer II) δ 137.7, 132.1, 128.7, 128.3
(2C), 127.9 (2C), 127.6, 95.5, 74.4, 69.2, 68.3, 17.8; HRCIMS calcd
for [C13H16O3Na+] 243.0992, found 243.0983.
cis-3,6-Dihydro-6-methyl-2-(phenylmethoxy)-2H-pyran (24a).
A flask was charged with dry N-methyl morpholine (NMM) 3.0
mL and triphenyl phosphine (1.45 g, 5.54 mmol) and was cooled
to -30 °C under Ar atmosphere. Diethylazodicarboxylate (0.8 mL,
5.05 mmol) was added and the reaction was stirred for 5 min.
Allylic alcohol 23a (370 mg, 1.68 mmol) was added in a 1 M
solution of NMM and the reaction mixture was stirred for 10 min,
followed by addition of o-nitrobenzenesulfonyl hydrazide (NBSH)
(1.02 g, 5.05 mmol). The reaction was stirred at -30 °C for 2 h
and was monitored by TLC. Upon consumption of starting material,
the mixture was warmed to room temperature and stirred for another
2 h. The reaction mixture was diluted with Et2O (10 mL), quenched
with 5 mL of saturated aqueous NaHCO3, extracted (3 × 5 mL)
with Et2O, dried (Na2SO4), and concentrated under reduced pressure.
The crude product was purified using silica gel flash chromatog-
raphy eluting with 2% Et2O/hexanes to give product 24a (293 mg,
1.44 mmol, 84%) as a viscous oil: Rf (15% EtOAc/hexanes) )
0.48; [R]2D1 -128.5 (c 1.80, CHCl3); IR (thin film, cm-1) 2973,
2927, 1453, 1366, 1158, 1080, 1028, 880, 777, 733. 1H NMR (600
MHz, CDCl3) δ 7.35 (m, 5H), 5.69 (ddd, J ) 10.2, 4.8, 2.4 Hz,
1H), 5.60 (ddd, J ) 10.2, 1.2, 1.2 Hz, 1H), 4.95 (d, J ) 12.0 Hz,
1H), 4.75 (dd, J ) 9.0, 3.0 Hz, 1H), 4.63 (d, J ) 12.0 Hz, 1H),
4.35 (m, 1H), 2.27 (dddd, J ) 17.4, 8.4, 3.6, 2.4 Hz, 1H), 2.19
(dddd, J ) 17.4, 6.6, 2.4, 1.2 Hz, 1H), 1.33 (d, J ) 6.6 Hz, 3H);
13C NMR (150 MHz, CDCl3) δ137.9, 130.9, 128.3 (2C), 127.9 (2C),
127.6, 122.5, 97.7, 70.6, 69.8, 30.9, 21.1; HRCIMS calcd for
[C13H16O2Na+] 227.1042, found 227.1045.
Conclusions
In conclusion, a highly enantioselective route to digitoxin (1)
and digoxose (3) as well as corresponding mono- and disac-
charides (25a, 25b and 31b, 37) has been developed. Key to
the success of this approach is the iterative use of the palladium-
catalyzed glycosylation reaction, Myers’ reductive rearrange-
ment, diastereoselective dihydroxylation, and regioselective
protection. Digoxose (3) was enantioselectively prepared in 16
steps and 12% overall yield from pyranone 8â (19 steps from
achiral 2-acylfuran), which constitutes the first total synthesis
of 3. The digitoxin (1) was achieved in 15 steps from
digitoxigenin 2 and â-pyranone 8, which is not only the shortest
but also the most stereocontrolled synthesis so far.39 This
approach is equally amenable for the synthesis of the diaster-
eomeric L-sugar digitoxin analogues. The uses of this strategy
for the synthesis of these various analogues are ongoing and
will be reported in due course.
Experimental Section40
(2R,6R)-2-Methyl-6-(phenylmethoxy)-2H-pyran-3(6H)-one (7a).
A CH2Cl2 (3 mL) solution of Boc pyranone 8â (716 mg, 3.14 mmol)
and benzyl alcohol (678 mg, 6.28 mmol) was cooled to 0 °C. A
CH2Cl2 (2 mL) solution of Pd2(DBA)3‚CHCl3 (81 mg, 2.5 mol %)
and PPh3 (82 mg, 10 mol %) was added to the reaction mixture at
(36) Digitoxin purchased from Acros was used to do the comparison.
(37) Stereochemical assignments were made by coupling constant
analysis and verified by the synthesis of known natural products 1 and 3.
(38) We found our synthetic digoxose had higher optical rotation and
melting points ([R]2D1 ) +40.0 (c 0.35, MeOH), mp 210-212 °C) than the
literature values ([R]2D1 ) +36.25 (c 0.70, MeOH); mp 171-174 °C),
which is probably just an indication of purity.
(39) The synthesis by McDonald and co-workers prepares digitoxin in
18 steps and experiences poor stereocontrol in the installation of the final
glycosidic bond; see ref 20d.
(40) Presented in this experimental section are the procedures and spectral
data for all new compounds. Complete experimental procedures and spectral
data for all compounds are presented in Supporting Information.
J. Org. Chem, Vol. 72, No. 7, 2007 2489

Zhou and O’Doherty
Phenylmethyl 2,6-Dideoxy-â-D-ribo-hexopyranoside (25a). To
a CH2Cl2 (3 mL) solution of olefin 24a (291 mg, 1.43 mmol) at 0
°C was added a solution of 50% (w/v) of N-methyl morpholine
N-oxide/water (0.67 mL). Crystalline OsO4 (3.6 mg, 1 mol %) was
added and the reaction was stirred for 3 h. The reaction was
quenched by adding EtOAc and saturated NaHCO3. The organic
layer was separated and concentrated. It was purified by a silica
gel column using 35% EtOAc/hexanes. Pure fractions were
combined and concentrated to afford diol 25a as a viscous oil (313
Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 196.2, 170.1, 146.3, 137.6,
128.8, 128.4 (2C), 127.8 (2C), 127.7, 97.1, 97.0, 79.4, 75.2, 70.5,
69.4, 69.3, 35.6, 21.2, 18.3, 16.3; HRCIMS calcd for [C21H26O7-
Na+] 413.1571, found 413.1558.
Phenylmethyl 3-O-Acetyl-2,6-dideoxy-4-O-[(2R,6R)-5,6-dihy-
dro-5-hydroxy-6-methyl-2H-pyran-2-yl]-â-D-ribo-hexopyrano-
side (28a). A CH2Cl2 (0.6 mL) solution of enone 27a (228 mg,
0.584 mmol) and CeCl3 in MeOH solution (0.6 mL) was cooled to
-78 °C. NaBH4 (22 mg, 0.585 mmol) was added and the reaction
mixture was stirred at -78 °C for 3 h. The reaction mixture was
diluted with Et2O (5 mL), quenched with 5 mL of saturated aqueous
NaHCO3, extracted (3 × 5 mL) with Et2O, dried (Na2SO4), and
concentrated under reduced pressure. The crude product was
purified using silica gel flash chromatography eluting with 35%
EtOAc/hexanes to give allylic alcohols 28a (211 mg, 0.538 mmol,
92%) as a viscous oil (diastereometric ratio I:II ) 1.6:1, inseparable
by silica gel chromatography): Rf (40% EtOAc/hexanes) ) 0.15;
IR (thin film, cm-1) 3471, 2980, 2934, 2875, 1740, 1498, 1455,
mg, 1.31 mmol, 92%): Rf (50% EtOAc/hexanes) ) 0.23; [R]21
D
-85.9 (c 1.30, CHCl3); IR (thin film, cm-1) 3426, 2883, 1496,
1454, 1364, 1164, 1137, 1072, 1007, 867, 731, 698; 1H NMR (600
MHz, CDCl3) δ 7.34 (m, 5H), 4.90 (dd, J ) 9.0, 1.8 Hz, 1H), 4.88
(d, J ) 11.4 Hz, 1H), 4.57 (d, J ) 12.0 Hz, 1H), 4.09 (m, 1H),
3.74 (dq, J ) 9.0, 6.0 Hz, 1H), 3.32 (m, 1H), 2.51(s, 1H), 2.35 (s,
1H), 2.12 (ddd, J ) 13.8, 3.6, 2.4 Hz, 1H), 1.78 (ddd, J ) 13.8,
9.0, 3.0 Hz, 1H), 1.33(d, J ) 6.0 Hz, 3H); 13C NMR (150 MHz,
CDCl3) δ 137.7, 128.4 (2C), 127.9 (2C), 127.7, 96.9, 73.0, 70.5,
69.5, 67.9, 37.7, 18.1; HRCIMS calcd for [C13H18O4Na+] 261.1097,
found 261.1087.
1
1372, 1243, 1154, 1057, 1009, 736, 698; H NMR (600 MHz,
CDCl3) (isomer I) δ 7.28 (m, 5H), 6.17 (dd, J ) 10.2, 5.4 Hz,
1H), 5.75 (d, J ) 10.2 Hz, 1H), 5.57 (ddd, J ) 3.0, 3.0, 3.0 Hz,
1H), 5.15 (m, 1H), 4.91 (d, J ) 12.0 Hz, 1H), 4.84 (dd, J ) 9.0,
1.8 Hz, 1H), 4.57 (d, J ) 12.0 Hz, 1H), 3.91 (dq, J ) 9.0, 6.0 Hz,
1H), 3.70 (dq, J ) 1.8, 6.0 Hz, 1H), 3.60 (dd, J ) 11.4, 6.0 Hz,
1H), 3.47 (dd, J ) 10.2, 3.6 Hz, 1H), 2.27 (d, J ) 14.4 Hz, 1H),
2.10 (ddd, J ) 14.4, 4.8, 2.4 Hz, 1H), 2.05 (s, 3H), 1.87 (ddd, J )
14.4, 9.6, 2.4 Hz, 1H), 1.32 (d, J ) 6.0 Hz, 3H), 1.27 (d, J ) 6.6
Hz, 3H); (isomer II) δ 7.34 (m, 5H), 5.96 (d, J ) 10.2 Hz, 1H),
5.78 (d, J ) 10.2 Hz, 1H), 5.42 (ddd, J ) 3.0, 3.0, 3.0 Hz, 1H),
5.18 (m, 1H), 4.90 (d, J ) 12.0 Hz, 1H), 4.80 (dd, J ) 9.0, 1.8 Hz,
1H), 4.56 (d, J ) 12.0 Hz, 1H), 3.86 (m, 2H), 3.64 (dq, J ) 6.6,
6.0 Hz, 1H), 3.45 (dd, J ) 9.6, 3.0 Hz, 1H), 2.16 (ddd, J ) 14.4,
3.6, 2.4 Hz, 1H), 2.06 (s, 3H), 1.83 (ddd, J ) 14.4, 9.0, 3.0 Hz,
1H), 1.63 (d, J ) 7.8 Hz, 1H), 1.34 (d, J ) 6.6 Hz, 3H), 1.29 (d,
J ) 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3) (isomer I) δ 170.3,
137.67, 131.8, 128.4, 128.2 (2C), 127.7 (3C), 98.3, 97.21, 78.2,
71.5, 70.51, 70.1, 69.3, 64.4, 35.9, 21.28, 18.1, 16.7; (isomer II)
δ 170.2, 137.65, 132.9, 129.3, 128.37 (2C), 127.8 (3C), 97.5, 97.16,
78.1, 74.5, 70.49, 69.8, 69.4, 68.5, 35.8, 21.25, 18.3, 18.2; HRCIMS
calcd for [C21H28O7Na+] 415.1727, found 415.1726.
Phenylmethyl 3-O-Acetyl-2,6-dideoxy-â-D-ribo-hexopyrano-
side (26a). A round-bottom flask containing a 0.5 M solution of
diol 25a (300 mg, 1.26 mmol) in benzene (2.5 mL) was stirring at
room temperature. To this solution were added trimethylorthoacetate
(0.8 mL, 6.29 mmol) and a catalytic amount of p-toluenesulfonic
acid (12 mg, 63 µmol). The reaction was allowed to stir until starting
material is gone. The solvent was removed under reduced pressure
and the residue was dissolved in 3 mL of THF/H2O (1:1,v/v)
solution. Then p-toluenesulfonic acid (600 mg, 3.15 mmol) was
added. Stirring was continued until hydrolysis was complete as seen
by TLC. The reaction was quenched by adding EtOAc and saturated
NaHCO3. The organic layer was separated and concentrated. It was
purified by a silica gel column using 30% EtOAc/hexanes. Pure
fractions were combined and concentrated to afford compound 26a
(335 mg, 1.20 mmol, 95%): Rf (50% EtOAc/hexanes) ) 0.38;
[R]2D1 -52.4 (c 1.40, CHCl3); IR (thin film, cm-1) 3471, 2975,
1
2934, 1740, 1498, 1455, 1372, 1242, 1164, 1075, 1006, 698; H
NMR (600 MHz, CDCl3) δ 7.34 (m, 5H), 5.29 (ddd, J ) 3.6, 3.0,
3.0 Hz, 1H), 4.91 (d, J ) 12.0 Hz ,1H), 4.83 (dd, J ) 9.0, 2.4 Hz,
1H), 4.57 (d, J ) 12.0 Hz, 1H), 3.73 (dq, J ) 9.0, 6.0 Hz, 1H),
3.46 (dd, J ) 9.0, 3.0 Hz, 1H), 2.14 (ddd, J ) 14.4, 3.6, 2.4 Hz,
1H), 2.10 (s, 3H), 1.87 (ddd, J ) 14.4, 9.0, 3.0 Hz, 1H), 1.36 (d,
J ) 6.0 Hz, 3H); 13C NMR (67.5 MHz, CDCl3) δ 171.2, 137.5,
128.3(2C), 127.8 (2C), 127.7, 97.0, 72.2, 71.0, 70.4, 70.3, 35.6,
21.1, 18.0; HRCIMS calcd for [C15H20O5Na+] 303.1203, found
303.1201.
Phenylmethyl 3-O-Acetyl-2,6-dideoxy-4-O-[(2S,6R)-3,6-di-
hydro-6-methyl-2H-pyran-2-yl]-â-D-ribo-hexopyranoside (29a).
A flask was charged with dry NMM 0.9 mL and triphenyl
phosphine (465 mg, 1.78 mmol) and was cooled to -30 °C under
Ar atmosphere. Diethylazodicarboxylate (0.25 mL, 1.61 mmol) was
added and the reaction was stirred for 5 min. Allylic alcohol 28a
(195 mg, 0.50 mmol) was added in a 1 M solution of NMM and
the reaction mixture was stirred for 10 min, followed by addition
of o-nitrobenzenesulfonyl hydrazide (NBSH) (328 mg, 1.61 mmol).
The reaction was stirred at -30 °C for 2 h and was monitored by
TLC. Upon consumption of starting material, the reaction was
warmed to room temperature and stirred for another 2 h. The
reaction mixture was diluted with Et2O (10 mL), quenched with 5
mL of saturated aqueous NaHCO3, extracted (3 × 5 mL) with Et2O,
dried (Na2SO4), and concentrated under reduced pressure. The crude
product was purified by silica gel flash chromatography eluting
with 8% EtOAc/hexanes to give product 29a (156 mg, 0.41 mmol,
Phenylmethyl 3-O-Acetyl-2,6-dideoxy-4-O-[(2R,6R)-5,6-dihy-
dro-6-methyl-5-oxo-2H-pyran-2-yl]-â-D-ribo-hexopyranoside (27a).
A CH2Cl2 (0.8 mL) solution of Boc pyranone 8â (337 mg, 1.48
mmol) and alcohol 26a (207 mg, 0.74 mmol) was cooled to 0 °C.
A CH2Cl2 (0.4 mL) solution of Pd2(DBA)3‚CHCl3 (19 mg, 2.5 mol
%) and PPh3 (20 mg, 10 mol %) was added to the reaction mixture
at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The
reaction mixture was quenched with 5 mL of saturated aqueous
NaHCO3, extracted (3 × 5 mL) with Et2O, dried (Na2SO4), and
concentrated under reduced pressure. The crude product was
purified using silica gel flash chromatography eluting with 22%
EtOAc/hexanes to give enone 27a (228 mg, 0.58 mmol, 78%) as
82%) as a viscous oil: Rf (15% EtOAc/hexanes) ) 0.31; [R]21
D
+4.0 (c 0.5, CHCl3); IR (thin film, cm-1) 2974, 2927, 1742, 1453,
1367, 1243, 1156, 1090, 1065, 1044, 781, 698. 1H NMR (600 MHz,
CDCl3) δ 7.34 (m, 5H), 5.63 (dddd, J ) 9.6, 4.8, 2.4, 2.4 Hz, 1H),
5.55 (ddd, J ) 10.2, 2.4, 1.2 Hz, 1H), 5.55 (ddd, J ) 3.6, 3.0, 3.0
Hz, 1H), 4.90 (d, J ) 12.0 Hz, 1H), 4.81 (dd, J ) 9.6, 1.8 Hz,
1H), 4.69 (dd, J ) 8.4, 3.0 Hz, 1H), 4.56 (d, J ) 12.0 Hz, 1H),
4.28 (m, 1H), 3.93 (dq, J ) 9.0, 6.0 Hz, 1H), 3.38 (dd, J ) 9.0,
3.0 Hz, 1H), 2.20 (ddd, J ) 14.4, 3.6, 2.4 Hz, 1H), 2.18 (ddd, J )
17.4, 7.2, 4.2 Hz, 1H), 2.13 (ddd, J ) 17.4, 6.6, 3.0 Hz, 1H), 2.07-
(s, 3H), 1.84 (ddd, J ) 14.4, 9.0, 3.0 Hz, 1H), 1.33 (d, J ) 6.0 Hz,
3H), 1.21 (d, J ) 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ170.3,
a viscous oil: Rf (30% EtOAc/hexanes) ) 0.23; [R]21 +20.0 (c
D
0.55, CHCl3); IR (thin film, cm-1) 2931, 1739, 1698, 1454, 1373,
1
1256, 1242, 1155, 1050, 1004, 787, 698; H NMR (600 MHz,
CDCl3) δ 7.34 (m, 5H), 6.89 (dd, J ) 10.2, 1.2 Hz, 1H), 6.13 (dd,
J ) 10.2, 1.2 Hz, 1H), 5.44 (ddd, J ) 3.6, 3.0, 3.0 Hz, 1H), 5.42
(d, J ) 1.2 Hz, 1H), 4.90 (d, J ) 11.4 Hz, 1H), 4.83 (dd, J ) 9.0,
2.4 Hz, 1H), 4.57 (d, J ) 11.4 Hz, 1H), 4.16 (q, J ) 6.6 Hz, 1H),
3.96 (dq, J ) 9.0, 6.6 Hz, 1H), 3.55 (dd, J ) 9.0, 3.0 Hz, 1H),
2.19 (ddd, J ) 14.4, 3.6, 2.4 Hz, 1H), 2.06 (s, 3H), 1.85 (ddd, J )
14.4, 9.0, 3.0 Hz, 1H), 1.40 (d, J ) 6.6 Hz, 3H), 1.37 (d, J ) 6.6
2490 J. Org. Chem., Vol. 72, No. 7, 2007

Asymmetric Syntheses of Digoxose and Digitoxin
(80% EtOAc/hexanes) ) 0.48; mp 105-106 °C; [R]2D1 +14.8 (c
1.15, CHCl3); IR (thin film, cm-1) 3475, 2972, 2932, 2879, 1741,
1370, 1243, 1165, 1068, 1009, 947, 870, 704; 1H NMR (600 MHz,
CDCl3) δ 7.33 (m, 5H), 5.39 (ddd, J ) 3.6, 3.0, 3.0 Hz, 1H), 5.25
(ddd, J ) 3.6, 3.0, 2.4 Hz, 1H), 4.89 (d, J ) 12.0 Hz ,1H), 4.79
(dd, J ) 9.6, 1.8 Hz, 1H), 4.74 (dd, J ) 9.6, 1.8 Hz, 1H), 4.55 (d,
J ) 12.0 Hz, 1H), 3.88 (dq, J ) 9.0, 6.0 Hz, 1H), 3.65 (dq, J )
9.0, 6.0 Hz, 1H), 3.36 (dd, J ) 9.0, 3.0 Hz, 1H), 3.35 (ddd, J )
9.0, 3.0, 3.0 Hz, 1H), 2.17 (ddd, J ) 14.4, 3.6, 1.8 Hz, 1H), 2.13
(s, 3H), 2.08 (ddd, J ) 14.4, 3.6, 2.4 Hz, 1H), 2.05 (s, 3H), 1.81
(ddd, J ) 14.4, 9.6, 3.0 Hz, 1H), 1.78 (ddd, J ) 14.4, 9.6, 3.0 Hz,
1H), 1.30 (d, J ) 6.0 Hz, 3H), 1.24 (d, J ) 6.0 Hz, 3H); 13C NMR
(150 MHz, CDCl3) δ 171.5, 170.4, 137.8, 128.6 (2C), 128.2 (2C),
127.9, 98.8, 97.4, 79.8, 72.2, 71.3, 70.7, 70.4, 69.7, 69.5, 36.1, 35.8,
21.5, 21.4, 18.4, 18.1; HRCIMS calcd for [C23H32O9Na+] 475.1938,
found 475.1926.
137.7, 131.2, 128.4 (2C), 127.8 (2C), 127.7, 122.2, 100.3, 97.2,
79.2, 70.9, 70.5, 69.9, 69.4, 35.7, 30.9, 21.3, 20.8, 18.2; HRCIMS
calcd for [C21H28O6Na+] 399.1778, found 399.1773.
Phenylmethyl 3-O-Acetyl-4-O-[2,6-dideoxy-â-D-ribo-hexopy-
ranosyl]-2,6-dideoxy-â-D-ribo-hexopyranoside (30a). To a CH2-
Cl2 (3 mL) solution of olefin 29a (148 mg, 0.39 mmol) at 0 °C
was added a solution of 50% (w/v) N-methyl morpholine N-oxide/
water (0.11 mL). Crystalline OsO4 (1.2 mg, 1 mol %) was added
and the reaction was stirred for 3 h. The reaction was quenched by
adding EtOAc and saturated aqueous NaHCO3. The organic layer
was separated and concentrated. It was purified by a silica gel
column using 60% EtOAc/hexanes. Pure fractions were combined
and concentrated to afford diol 30a (145 mg, 0.35 mmol, 90%):
Rf (70% EtOAc/hexanes) ) 0.18; [R]21 +1.6 (c 1.35, CHCl3); IR
D
(thin film, cm-1) 3436, 2972, 2932, 2879, 1741, 1370, 1247, 1165,
1
1066, 1012, 868, 740, 698; H NMR (600 MHz, CDCl3) δ 7.33
(m, 5H), 5.38 (ddd, J ) 3.6, 3.0, 3.0 Hz, 1H), 4.89 (d, J ) 12.0
Hz, 1H), 4.84 (dd, J ) 9.6, 2.4 Hz, 1H), 4.79 (dd, J ) 9.6, 2.4 Hz,
1H), 4.55 (d, J ) 12.0 Hz, 1H), 4.05 (m, 1H), 3.88 (dq, J ) 9.0,
6.0 Hz, 1H), 3.67 (dq, J ) 9.0, 6.0 Hz, 1H), 3.35 (dd, J ) 9.6, 3.0
Hz, 1H), 3.24 (ddd, J ) 9.0, 6.6, 3.6 Hz, 1H), 2.54 (s, 1H), 2.33(d,
J ) 5.4 Hz, 1H), 2.16 (ddd, J ) 14.4, 3.6, 2.4 Hz, 1H), 2.08 (ddd,
J ) 14.4, 3.0, 2.4 Hz, 1H), 2.06 (s, 3H), 1.82 (ddd, J ) 14.4, 9.6,
3.0 Hz, 1H), 1.68 (ddd, J ) 14.4, 9.6, 3.0 Hz, 1H), 1.31(d, J ) 6.0
Hz, 3H), 1.22(d, J ) 6.0 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ
170.3, 137.6, 128.3 (2C), 127.8 (2C), 127.7, 98.6, 97.2, 79.4, 72.7,
70.5, 69.7, 69.3, 69.2, 68.0, 37.6, 35.6, 21.3, 18.2, 17.9; HRCIMS
calcd for [C21H30O8Na+] 433.1833, found 433.1826.
Phenylmethyl 2,6-Dideoxy-4-O-[2,6-dideoxy-â-D-ribo-hexopy-
ranosyl]-â-D-ribo-hexopyranoside (31a). To a MeOH/H2O (0.1
mL, 1:1, 1 M) solution of diol 30a (6 mg, 14.6 µmol) at room
temperature was added LiOH (0.35 mg, 14.6 µmol) and the reaction
was stirred for 3 h. The reaction was quenched by adding EtOAc
and saturated aquous NaHCO3. The organic layer was separated
and concentrated. It was purified by a silica gel column using 65%
EtOAc/hexanes. Pure fractions were combined and concentrated
to afford triol 31a (5 mg, 13.6 µmol, 93%) as a white solid: Rf
(80% EtOAc/hexanes) ) 0.28; mp 145-145.5 °C; [R]2D1 -44.0 (c
0.20, CHCl3); IR (thin film, cm-1) 3437, 2962, 2931, 2886, 1454,
1405, 1368, 1164, 1068, 1011, 868, 735, 698; 1H NMR (600 MHz,
CDCl3) δ 7.32 (m, 5H), 4.92 (m, 1H), 4.91 (m, 1H), 4.88 (d, J )
12.0 Hz, 1H), 4.56 (d, J ) 12.0 Hz, 1H), 4.26 (dddd, J ) 6.6, 3.6,
3.6, 1.8 Hz, 1H), 4.12 (dddd, J ) 5.4, 4.2, 3.0, 2.4 Hz, 1H), 3.82
(dq, J ) 9.0, 6.0 Hz, 1H), 3.67 (dq, J ) 9.6, 6.0 Hz, 1H), 3.30
(ddd, J ) 9.6, 6.6, 3.0 Hz, 1H), 3.26 (dd, J ) 9.6, 3.0 Hz, 1H),
2.96 (m, J ) 2.4, 1.8, 1.2 Hz, 1H), 2.28 (d, J ) 1.2 Hz, 1H), 2.17
(ddd, J ) 14.4, 4.2, 2.4 Hz, 1H), 2.13 (ddd, J ) 14.4, 3.0, 2.4 Hz,
1H), 1.96 (d, J ) 6.6 Hz, 1H), 1.79 (m, 1H), 1.75 (m, 1H), 1.29
(d, J ) 6.0 Hz, 3H), 1.28(d, J ) 6.0 Hz, 3H); 13C NMR (150 MHz,
CDCl3) δ 137.8, 128.4 (2C), 127.9 (2C), 127.6, 98.3, 97.1, 82.7,
72.8, 70.6, 69.5, 68.3, 68.2, 66.3, 37.9, 36.6, 18.2, 18.1; HRCIMS
calcd for [C19H28O7Na+] 391.1727, found 391.1726.
Phenylmethyl 3-O-Acetyl-4-O-[3-O-acetyl-2,6-dideoxy-â-D-
ribo-hexopyranosyl]-2,6-dideoxy-â-D-ribo-hexopyranoside (32a).
A round-bottom flask containing a 0.5 M solution of diol 30a (140
mg, 0.34 mmol) in benzene (0.6 mL) was stirred at room
temperature. To this solution were added trimethylorthoacetate (0.13
mL, 1.02 mmol) and a catalytic amount of p-toluenesulfonic acid
(3.2 mg, 17 µmol). The reaction was allowed to stir until starting
material was gone. The solvent was removed under reduced pressure
and the residue was dissolved in 0.8 mL of THF/H2O (1:1,v/v)
solution. Then p-toluenesulfonic acid (97 mg, 0.51 mmol) was
added. Stirring was continued until hydrolysis was complete as seen
by TLC. The reaction was quenched by adding EtOAc and saturated
aqueous NaHCO3. The organic layer was separated and concen-
trated. It was purified by a silica gel column using 45% EtOAc/
hexanes. Pure fractions were combined and concentrated to afford
compound 32a (143 mg, 0.32 mmol, 93%) as a white solid: Rf
Phenylmethyl 3-O-Acetyl-2,6-dideoxy-4-O-[[3-O-acetyl-2,6-
dideoxy-4-O-[(2R,6R)-5,6-dihydro-6-methyl-5-oxo-2H-pyran-2-
yl]-â-D-ribo-hexopyranosyl]-â-D-ribo-hexopyranoside (33a). A
CH2Cl2 (0.3 mL) solution of Boc pyranone 8â (228 mg, 0.62 mmol)
and alcohol 32a (141 mg, 0.31 mmol) was cooled to 0 °C. A CH2-
Cl2 (0.2 mL) solution of Pd2(DBA)3‚CHCl3 (16 mg, 2.5 mol %)
and PPh3 (16 mg, 10 mol %) was added to the reaction mixture at
0 °C. The reaction mixture was stirred at 0 °C for 2 h, quenched
with 5 mL of saturated aqueous NaHCO3, extracted (3 × 5 mL)
with Et2O, dried (Na2SO4), and concentrated under reduced pressure.
The crude product was purified by silica gel flash chromatography
eluting with 33% EtOAc/hexanes to give enone 33a (138 mg, 0.25
mmol, 79%) as a white solid: Rf (40% EtOAc/hexanes) ) 0.18;
mp 95-96 °C; [R]2D1 +43.0 (c 0.3, CHCl3); IR (thin film,
1
cm-1)2980, 1740, 1702, 1454, 1372, 1243, 1158, 1055, 1006; H
NMR (600 MHz, CDCl3) δ 7.33 (m, 5H), 6.87 (dd, J ) 10.2, 1.2
Hz, 1H), 6.11 (dd, J ) 10.2, 1.8 Hz, 1H), 5.40 (ddd, J ) 3.6, 3.0,
3.0 Hz, 1H), 5.39 (m, 2H), 4.89 (d, J ) 12.0 Hz, 1H), 4.79 (dd, J
) 9.6, 1.8 Hz, 1H), 4.74 (dd, J ) 9.6, 1.8 Hz, 1H), 4.55 (d, J )
12.0 Hz, 1H), 4.14 (q, J ) 6.0 Hz, 1H), 3.88 (dq, J ) 9.0, 6.0 Hz,
1H), 3.86 (dq, J ) 9.0, 6.0 Hz, 1H), 3. 45 (dd, J ) 9.6, 3.0 Hz,
1H), 3. 34 (dd, J ) 9.6, 3.0 Hz, 1H), 2.15 (ddd, J ) 14.4, 3.6, 2.4
Hz, 1H), 2.11 (ddd, J ) 14.4, 3.6, 2.4 Hz, 1H), 2.09 (s, 3H), 2.06
(s, 3H), 1.81 (ddd, J ) 14.4, 9.0, 3.0 Hz, 1H), 1.76 (ddd, J ) 14.4,
9.0, 3.0 Hz, 1H), 1.38 (d, J ) 6.6 Hz, 3H), 1.30 (d, J ) 6.6 Hz,
3H), 1.26 (d, J ) 6.0 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ
196.1, 170.1, 170.07, 146.2, 137.6, 128.7, 128.3 (2C), 127.8 (2C),
127.7, 98.7, 97.1, 97.07, 79.6, 79.2, 75.1, 70.5, 69.64, 69.60, 69.2,
69.0, 35.9, 35.7, 21.24, 21.20, 18.2, 18.0, 16.3; HRCIMS calcd for
[C29H38O11Na+] 585.2306, found 585.2299.
Phenylmethyl 3-O-Acetyl-2,6-dideoxy-4-O-[[3-O-acetyl-2,6-
dideoxy-4-O-[(2R,6R)-5,6-dihydro-5-hydroxy-6-methyl-2H-py-
ran-2-yl]-â-D-ribo-hexopyranosyl]-â-D-ribo-hexopyranoside (34a).
A CH2Cl2 (0.3 mL) solution of enone 33a (138 mg, 0.245 mmol)
and CeCl3 in MeOH solution (0.3 mL) was cooled to -78 °C.
NaBH4 (10 mg, 0.25 mmol) was added and the reaction mixture
was stirred at -78 °C for 3 h. The reaction mixture was diluted
with Et2O (5 mL), quenched with 5 mL of saturated aqueous
NaHCO3, extracted (3 × 5 mL) with Et2O, dried (Na2SO4), and
concentrated under reduced pressure. The crude product was
purified using silica gel flash chromatography eluting with 50%
EtOAc/hexanes to give allylic alcohols 34a (374 mg, 1.70 mmol,
85%) as a viscous oil (diastereometric ratio I:II ) 1.4:1, inseparable
in chromatography): Rf (60% EtOAc/hexanes) ) 0.25; IR (thin
film, cm-1) 3478, 2972, 2932, 2874, 1742, 1371, 1243, 1156, 1059,
1
1010; H NMR (600 MHz, CDCl3) (isomer I) δ 7.33 (m, 5H),
6.15 (dd, J ) 10.2, 6.0, Hz, 1H), 5.72 (d, J ) 9.6 Hz, 1H), 5.54
(ddd, J ) 3.0, 3.0, 3.0 Hz, 1H), 5.40 (ddd, J ) 3.6, 3.0, 3.0 Hz,
1H), 5.12 (m, 1H), 4.89 (d, J ) 12.0 Hz, 1H), 4.788 (dd, J ) 9.6,
2.4 Hz, 1H), 4.75 (dd, J ) 9.6, 1.8 Hz, 1H), 4.551 (d, J ) 12.0
Hz, 1H), 3.88 (dq, J ) 9.6, 6.0 Hz, 1H), 3.87 (m, 1H), 3.77 (dq, J
) 9.6, 6.0 Hz, 1H), 3.68 (qd, J ) 6.0, 1.8 Hz, 1H), 3.58 (dd, J )
J. Org. Chem, Vol. 72, No. 7, 2007 2491

Zhou and O’Doherty
11.4, 5.4 Hz, 1H), 3.39 (dd, J ) 9.6, 3.0 Hz, 1H), 3.34 (dd, J )
9.6, 3.6 Hz, 1H), 2.16 (ddd, J ) 14.4, 3.6, 2.4 Hz, 1H), 2.08 (s,
3H), 2.069 (s, 3H), 2.02 (ddd, J ) 14.4, 3.0, 2.4 Hz, 1H), 1.79
(ddd, J ) 14.4, 9.0, 3.0 Hz, 1H), 1.72 (ddd, J ) 14.4, 9.0, 3.0 Hz,
1H), 1.70 (s, 1H), 1.31 (d, J ) 6.6 Hz, 3H), 1.25 (d, J ) 6.6 Hz,
3H), 1.21 (d, J ) 6.6 Hz, 3H); (isomer II) δ 7.33 (m, 5H), 5.94
(ddd, J ) 10.8, 1.8, 1.8 Hz, 1H), 5.86 (d, J ) 10.2 Hz, 1H), 5.75
(ddd, J ) 10.2, 1.8, 1.2 Hz, 1H), 5.39 (ddd, J ) 3.6, 3.0, 3.0 Hz,
1H), 5.38 (ddd, J ) 3.0, 3.0, 2.4 Hz, 1H), 5.13 (m, 1H), 4.88 (d,
J ) 12.0 Hz, 1H), 4.783 (dd, J ) 9.6, 2.4 Hz, 1H), 4.71 (dd, J )
9.6, 1.8 Hz, 1H), 4.548 (d, J ) 12.0 Hz, 1H), 3.87 (m, 1H), 3.83
(dq, J ) 9.6, 6.0 Hz, 1H), 3.54 (dq, J ) 6.6, 6.0 Hz, 1H), 3.35 (m,
2H), 2.32 (d, J ) 11.4 Hz, 1H), 2.16 (ddd, J ) 14.4, 3.6, 2.4 Hz,
1H), 2.09 (s, 3H), 2.056 (s, 3H), 2.02 (ddd, J ) 14.4, 3.0, 2.4 Hz,
1H), 1.81 (ddd, J ) 14.4, 9.0, 3.0 Hz, 1H), 1.76 (ddd, J ) 14.4,
9.0, 3.0 Hz, 1H), 1.29 (d, J ) 6.6 Hz, 3H), 1.27 (d, J ) 6.6 Hz,
3H), 1.23 (d, J ) 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3)
(isomer I) δ 170.1 (2C), 133.0 (2C), 131.7, 128.1 (2C), 127.7 (3C),
98.75 (2C), 98.24, 98.22, 79.5, 77.8, 71.4, 69.9, 69.7, 69.2, 69.1,
64.4, 36.0, 35.7, 21.30, 21.28, 18.18, 18.03, 17.9; (isomer II) δ
170.3 (2C), 137.6 (2C), 129.2, 128.3 (2C), 127.8 (3C), 98.72, 97.6,
97.2 (2C), 79.6, 78.0, 74.5, 70.5, 70.2, 69.6, 69.3, 68.4, 35.9, 35.6,
21.28, 21.26, 18.17, 18.16, 16.7; HRCIMS calcd for [C29H40O11-
Na+] 587.2463, found 587.2453.
EtOAc/hexanes. Pure fractions were combined and concentrated
to afford alcohol 36a (92 mg, 0.16 mmol, 92%) as a white solid:
Rf (80% EtOAc/hexanes) ) 0.25; mp 167-167.5 °C; [R]21+35.0
(c 1.45, CHCl3); IR (thin film, cm-1) 3455, 2972, 2932, 288D0, 1741,
1
1370, 1244, 1162, 1065, 1011, 869, 704; H NMR (600 MHz,
CDCl3) δ 7.33 (m, 5H), 5.39 (ddd, J ) 3.6, 3.0, 3.0 Hz, 1H), 5.34
(ddd, J ) 3.0, 3.0, 3.0 Hz, 1H), 4.88 (d, J ) 12.0 Hz, 1H), 4.81
(dd, J ) 9.6, 1.8 Hz, 1H), 4.78 (dd, J ) 9.6, 1.8 Hz, 1H), 4.70 (dd,
J ) 9.6, 1.8 Hz, 1H), 4.54 (d, J ) 12.0 Hz, 1H), 4.05 (m, 1H),
3.86 (dq, J ) 9.0, 6.0 Hz, 1H), 3.80 (dq, J ) 9.0, 6.0 Hz, 1H),
3.65 (dq, J ) 9.0, 6.0 Hz, 1H), 3.33 (dd, J ) 9.6, 3.0 Hz, 1H),
3.27 (dd, J ) 9.6, 3.6 Hz, 1H), 3.23 (ddd, J ) 9.6, 6.0, 3.6 Hz,
1H), 2.47 (s, 1H), 2.25 (d, J ) 6.6 Hz, 1H), 2.15 (ddd, J ) 14.4,
3.6, 1.8 Hz, 1H), 2.09 (s, 3H), 2.08 (ddd, J ) 14.4, 3.0, 1.8 Hz,
1H), 2.06 (ddd, J ) 14.4, 3.0, 1.8 Hz, 1H), 2.05 (s, 3H), 1.80 (ddd,
J ) 14.4, 9.6, 2.4 Hz, 1H), 1.72 (ddd, J ) 14.4, 9.6, 3.0 Hz, 1H),
1.66 (ddd, J ) 13.8, 9.6, 3.0 Hz, 1H), 1.29 (d, J ) 6.6 Hz, 3H),
1.22 (d, J ) 6.0 Hz, 3H), 1.20 (d, J ) 6.0 Hz, 3H); 13C NMR (150
MHz, CDCl3) δ 170.3, 170.2, 137.6, 128.3(2C), 127.8 (2C), 127.7,
98.8, 98.7, 97.2, 79.5, 79.2, 72.7, 70.5, 69.9, 69.7, 69.3 (2C), 69.1,
68.0, 37.6, 35.9, 35.6, 21.3, 21.2, 18.2, 17.9 (2C); HRCIMS calcd
for [C29H42O12Na+] 605.2568, found 605.2580.
Phenylmethyl 2,6-Dideoxy-4-O-[[2,6-dideoxy-â-D-ribo-hex-
opyranosyl]-2,6-dideoxy-â-D-ribo-hexopyranosyl]-â-D-ribo-hex-
opyranoside (4). To a MeOH/H2O (0.3 mL, 1:1, 1 M) solution of
alcohol 36a (14 mg, 24 µmol) at room temperature was added LiOH
(2.5 mg, 60 µmol) and the reaction was stirred for 3 h. The reaction
was quenched by adding EtOAc and saturated aqueous NaHCO3.
The organic layer was separated and concentrated. It was purified
by a silica gel column using 75% EtOAc/hexanes. Pure fractions
were combined and concentrated to afford 4 (11.5 mg, 23 µmol,
96%) as a white solid: Rf (80% EtOAc/hexanes) ) 0.18; mp 120-
121 °C; [R]2D1 -13.3 (c 0.60, CHCl3); IR (thin film, cm-1) 3424,
2927, 2886, 1455, 1369, 1318, 1163, 1130, 1068, 1012, 869, 733,
Phenylmethyl 3-O-Acetyl-2,6-dideoxy-4-O-[[3-O-acetyl-2,6-
dideoxy-4-O-[(2S,6R)-3,6-dihydro-6-methyl-2H-pyran-2-yl]-â-D-
ribo-hexopyranosyl]-â-D-ribo-hexopyranoside (35a). A flask was
charged with dry NMM 0.4 mL and triphenyl phosphine (191 mg,
0.73 mmol) and was cooled to -30 °C under Ar atmosphere.
Diethylazodicarboxylate (0.1 mL, 0.66 mmol) was added, the
reaction was stirred for 5 min, allylic alcohols 34a (125 mg, 0.22
mmol) was added in a 1 M solution of NMM, and the reaction
mixture was stirred for 10 min, followed by addition of o-
nitrobenzenesulfonyl hydrazide (NBSH) (135 mg, 0.66 mmol). The
reaction was stirred at -30 °C for 4 h and was monitored by TLC.
Upon consumption of starting material, the reaction was warmed
up to room temperature and stirred for another 2 h. The reaction
mixture was diluted with Et2O (10 mL), quenched with 5 mL of
saturated aqueous NaHCO3, extracted (3 × 5 mL) with Et2O, dried
(Na2SO4), and concentrated under reduced pressure. The crude
product was purified using silica gel flash chromatography eluting
with 20% EtOAc/hexanes to give product 35a (97 mg, 0.18 mmol,
81%) as a white solid: Rf (50% EtOAc/hexanes) ) 0.44; mp 101-
101.5 °C; [R]2D1 +38.0 (c 0.9, CHCl3); IR (thin film, cm-1) 2981,
1
699; H NMR (600 MHz, CDCl3) δ 7.33 (m, 5H), 4.91 (dd, J )
9.6, 3.0 Hz, 1H), 4.90 (m, 2H), 4.88 (d, J ) 12.0 Hz, 1H), 4.56 (d,
J ) 12.0 Hz, 1H), 4.25 (m, 2H), 4.12 (ddd, J ) 3.6, 3.6, 2.4 Hz,
1H), 3.83 (dq, J ) 9.6, 6.0 Hz, 1H), 3.81(dq, J ) 9.0, 6.0 Hz, 1H),
3.76 (dq, J ) 9.6, 6.0 Hz, 1H), 3.30 (m, 1H), 3.26 (dd, J ) 9.6,
3.0 Hz, 1H), 3.20 (dd, J ) 9.6, 3.0 Hz, 1H), 2.99 (s, 1H), 2.95 (s,
1H), 2.33 (s, 1H), 2.16 (ddd, J ) 13.8, 3.6, 2.4 Hz, 1H), 2.14 (ddd,
J ) 14.4, 3.0, 2.4 Hz, 1H), 2.11 (ddd, J ) 13.8, 3.0, 2.4 Hz, 1H),
2.03 (s, 1H), 1.78 (ddd, J ) 14.4, 9.0, 3.0 Hz, 1H), 1.74 (m, 2H),
1.28 (d, J ) 6.6 Hz, 6H), 1.22 (d, J ) 6.0 Hz, 3H); 13C NMR (150
MHz, CDCl3) δ 137.8, 128.3 (2C), 127.9 (2C), 127.6, 98.30, 98.26,
97.1, 82.6, 82.2, 72.7, 70.6, 69.5, 68.32, 68.26, 68.1, 66.4, 66.2,
37.8, 36.7, 36.6, 18.2 (2C), 18.1; HRCIMS calcd for [C25H38O10-
Na+] 521.2357, found 521.2360.
1
2932, 2871, 1742, 1368, 1243, 1157, 1090, 1067, 1008, 704; H
NMR (600 MHz, CDCl3) δ 7.33 (m, 5H), 5.62 (dddd, J ) 10.2,
4.8, 2.4, 2.4 Hz, 1H), 5.53 (ddd, J ) 9.6, 1.2, 1.2 Hz, 1H), 5.41
(ddd, J ) 3.6, 3.0, 3.0 Hz, 1H), 5.37 (ddd, J ) 3.6, 3.0, 3.0 Hz,
1H), 4.89 (d, J ) 12.0 Hz, 1H), 4.78 (dd, J ) 9.6, 1.8 Hz, 1H),
4.71 (dd, J ) 9.6, 1.8 Hz, 1H), 4.65 (dd, J ) 8.4, 3.6 Hz, 1H),
4.55 (d, J ) 12.0 Hz, 1H), 4.25 (m, 1H), 3.87 (dq, J ) 9.0, 6.0 Hz,
1H), 3.84 (dq, J ) 9.6, 6.0 Hz, 1H), 3.34 (dd, J ) 9.6, 3.6 Hz,
1H), 3.28 (dd, J ) 9.6, 3.6 Hz, 1H), 2.14 (m, 4H), 2.11 (s, 3H),
2.06 (s, 3H), 1.81 (dddd, J ) 14.4, 9.0, 3.0 Hz, 1H), 1.74 (dddd,
J ) 14.4, 9.6, 3.0 Hz, 1H), 1.30 (d, J ) 6.0 Hz, 3H), 1.23 (d, J )
6.6 Hz, 3H), 1.20 (d, J ) 6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3)
δ170.3, 170.1, 137.6, 131.1, 128.3 (2C), 127.8 (2C), 127.7, 122.2,
100.3, 98.8, 97.2, 79.5, 78.9, 70.9, 70.5, 70.1, 69.7, 69.3, 69.2, 35.9,
35.7, 30.9, 21.33, 21.26, 20.8, 18.2, 18.0; HRCIMS calcd for
[C29H40O10Na+] 571.2514, found 571.2525.
Phenylmethyl 3-O-Acetyl-2,6-dideoxy-4-O-[[3-O-acetyl-4-O-
[2,6-dideoxy-â-D-ribo-hexopyranosyl]-2,6-dideoxy-â-D-ribo-hex-
opyranosyl]-â-D-ribo-hexopyranoside (36a). To a CH2Cl2 (0.6
mL) solution of olefin 35a (94 mg, 0.17 mmol) at 0 °C was added
a solution of 50% (w/v) N-methyl morpholine N-oxide/water (80
µL). Crystalline OsO4 (0.4 mg, 1 mol %) was added and the reaction
was stirred for 3 h. The reaction was quenched by adding EtOAc
and saturated NaHCO3. The organic layer was separated and
concentrated. It was purified by a silica gel column using 60%
O-2,6-Dideoxy-â-D-ribo-hexopyranosyl-(1f4)-2,6-dideoxy-D-
ribo-hexose (37). To an EtOH (2 mL) solution of 31a (15.6 mg,
42 µmol) under H2 atmosphere at room temperature was added
Pd/C (8 mg) and the reaction was stirred for 6 h. The reaction
mixture was filtered through a pad of Celite using MeOH. The
filtrate was concentrated and purified by a silica gel column using
1% MeOH/EtOAc. Pure fractions were combined and concentrated
to afford digoxose bisdigitoxide 37 (11 mg, 39.5 µmol, 94%) as a
white solid: Rf (10% MeOH/EtOAc) ) 0.18; mp 132-135 °C;
[R]2D1 +56.7 (c 0.80, MeOH); IR (thin film, cm-1) 3426, 2930,
1376, 1319, 1165, 1132, 1068, 1014, 992, 869, 729; 1H NMR (600
MHz, CD3OD/CDCl3) (â) δ 5.03 (dd, J ) 9.6, 1.8 Hz, 1H), 4.84
(dd, J ) 9.6, 2.4 Hz, 1H), 4.17 (ddd, J ) 3.6, 3.0, 2.4 Hz, 1H),
3.98 (m, 1H), 3.78 (dq, J ) 9.0, 6.0 Hz, 1H), 3.69 (dq, J ) 9.0,
6.0 Hz, 1H), 3.15 (dd, J ) 9.0, 3.0 Hz, 1H), 3.13 (dd, J ) 9.0, 3.0
Hz, 1H), 2.04 (m, 2H), 1.61 (ddd, J ) 13.8, 9.6, 3.0 Hz, 1H), 1.67
(m, 1H), 1.20 (d, J ) 6.0 Hz, 3H), 1.17 (d, J ) 6.6 Hz, 3H); (R)
5.01 (d, J ) 3.0 Hz, 1H), 4.87 (dd, J ) 9.6, 1.8 Hz, 1H), 4.26
(ddd, J ) 3.6, 3.0, 3.0 Hz, 1H), 4.07 (dq, J ) 9.6, 6.0 Hz, 1H),
3.97 (m, 1H), 3.68 (dq, J ) 9.6, 6.0 Hz, 1H), 3.18 (dd, J ) 9.0,
2492 J. Org. Chem., Vol. 72, No. 7, 2007

Asymmetric Syntheses of Digoxose and Digitoxin
3.0 Hz, 1H), 3.14 (dd, J ) 9.0, 3.0 Hz, 1H), 2.06 (m, 2H), 1.80
(ddd, J ) 14.4, 3.0, 3.0 Hz, 1H), 1.68 (m, 1H), 1.19 (d, J ) 6.0
Hz, 3H), 1.16 (d, J ) 6.0 Hz, 3H); 13C NMR (150 MHz, CD3OD/
CDCl3) (â) δ 98.56, 91.4, 82.4, 72.46, 69.59, 68.0, 67.62, 66.3,
37.76, 37.69, 17.92, 17.86; (R) δ98.58, 91.5, 82.2, 72.44, 69.60,
67.6, 66.9, 61.6, 37.74, 34.3, 17.93, 17.7; HRCIMS calcd for
[C12H22O7Na+] 301.1263, found 301.1255.
9.6, 3.0 Hz, 1H), 2.16 (m, 3H), 1.65 (m, 3H), 1.213 (d, J ) 6.6
Hz, 3H), 1.175 (d, J ) 6.6 Hz, 3H), 1.165 (d, J ) 6.6 Hz, 3H); (R)
5.01 (d, J ) 3.0 Hz, 1H), 4.87 (dd, J ) 10.2, 2.4 Hz, 1H), 4.848
(dd, J ) 9.6, 2.4 Hz, 1H), 4.26 (ddd, J ) 3.6, 3.0, 3.0 Hz, 1H),
4.06 (m, 2H), 3.77 (m, 2H), 3.70 (dq, J ) 9.0, 6.0 Hz, 1H), 3.19
(dd, J ) 9.6, 3.0 Hz, 1H), 3.137 (dd, J ) 9.6, 3.0 Hz, 1H), 3.140
(m, 1H), 2.06 (m, 3H), 1.64 (m, 3H), 1.216 (d, J ) 6.6 Hz, 3H),
1.19 (d, J ) 6.6 Hz, 3H), 1.160 (d, J ) 6.6 Hz, 3H); 13C NMR
(150 MHz, CD3OD/CDCl3) (â) δ 98.6, 98.5, 91.4, 82.4, 82.19,
82.17, 72.5, 69.64, 68.2, 67.6, 66.9, 66.15, 37.75 (2C), 36.61, 17.95
(2C), 17.75; (R) δ 98.6, 98.5, 91.5, 82.21, 82.19, 82.17, 69.63, 68.0,
66.4, 66.18, 66.16, 61.50, 37.71, 36.62, 34.3, 17.95, 17.93, 17.90;
HRCIMS calcd for [C18H32O10Na+] 431.1889, found 431.1888.
O-2,6-Dideoxy-â-D-ribo-hexopyranosyl-(1f4)-O-2,6-dideoxy-
â-D-ribo-hexopyranosyl-(1f4)-2,6-dideoxy-D-ribo-hexose (3). To
an EtOH (0.3 mL) solution of 4 (11 mg, 22 µmol) under H2
atmosphere at room temperature was added Pd/C (6 mg) and the
reaction was stirred for 6 h. The reaction mixture was filtered
through a pad of Celite using MeOH. The eluent was concentrated
and purified by a silica gel column using 2% MeOH/EtOAc. Pure
fractions were combined and concentrated to afford digoxose 3 (8
mg, 20 µmol, 92%) as a white solid: Rf (10% MeOH/EtOAc) )
0.29; mp 210-212 °C; [R]2D1 +40.0 (c 0.35, MeOH); IR (thin film,
cm-1) 3425, 2929, 1376, 1319, 1231, 1165, 1133, 1067, 1013, 992,
Acknowledgment. We are grateful to the WVU Arts
Foundation, NIH (GM63150) and NSF (CHE-0415469) for the
support of our research program and NSF-EPSCoR (0314742)
for a 600 MHz NMR at WVU.
1
869, 729; H NMR (600 MHz, CD3OD/CDCl3) (â) δ 5.04 (dd, J
) 9.6, 2.4 Hz, 1H), 4.845 (dd, J ) 9.6, 1.8 Hz, 1H), 4.841 (dd, J
) 9.6, 1.8 Hz, 1H), 4.18 (ddd, J ) 3.6, 3.0, 3.0 Hz, 1H), 4.17
(ddd, J ) 3.6, 3.0, 3.0 Hz, 1H), 3.98 (ddd, J ) 3.6, 3.0, 3.0 Hz,
1H), 3.78 (m, 2H), 3.69 (dq, J ) 9.0, 6.0 Hz, 1H), 3.16 (dd, J )
9.6, 3.0 Hz, 1H), 3.147 (dd, J ) 9.6, 3.0 Hz, 1H), 3.144 (dd, J )
Supporting Information Available: Complete experimental
procedures and spectral data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO062534+
J. Org. Chem, Vol. 72, No. 7, 2007 2493