Divergent de novo synthesis of all eight stereoisomers of 2,3,6-trideoxyhexopyranosides and their oligomers

Article abstract of DOI:10.1039/c5cc07787g

All eight possible stereoisomers of 2,3,6-trideoxyhexopyranosides are prepared systematically from furan derivatives by a sequence of Achmatowicz rearrangement, Pd-catalysed glycosidation, and chiral catalyst-controlled tandem reductions. This sequence provides access to all possible stereoisomers of naturally occurring rhodinopyranosides, amicetopyranosides, disaccharide narbosine B, and other unnatural oligomeric 2,3,6-trideoxyhexopyranosides. It comprises a unique and systematic strategy for the de novo synthesis of deoxysugars.

Full text of DOI:10.1039/c5cc07787g

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Divergent De Novo Synthesis of All Eight Stereoisomers of 2,3,6-
Trideoxyhexopyranosides and Their Oligomers
Wangze Song,a Yu Zhao,*a,b John C. Lynch,a Hyunjin Kim,a and Weiping Tang*a,c
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
All eight possible stereoisomers of 2,3,6-trideoxyhexopyranosides power of this glycosidation method was elegantly demonstrated in
are prepared systematically from furan derivatives by a sequence the synthesis of several complex oligosaccharides recently.21
L-rhodinopyranoside
L-amicetopyranosides
of Achmatowicz rearrangement, Pd-catalysed glycosidation, and
chiral catalyst-controlled tandem reductions. This sequence
provides access to all possible stereoisomers of naturally occurring
rhodinopyranosides, amicetopyranosides, disaccharide narbosine
B, and other unnatural oligomeric 2,3,6-trideoxyhexopyranosides.
It comprises a unique and systematic strategy for the de novo
synthesis of deoxysugars.
Me
HO
O
OR Me
HO
O
OR
Me
HO
O
OR Me
HO
O
OR
2
3
1
4
Me
O
OMe
Me
O
O
OMe
Me
OH
Me
HO
O
O
Me
HO
O
Me
O
O
Carbohydrates play an important role in many biological processes.1
Being able to access any stereoisomers systematically will greatly
facilitate not only the study of the biological functions of
carbohydrates but also the development of carbohydrate analogues
as novel therapeutic agents. We herein report a divergent de novo
synthetic strategy that allows us to access any possible mono- and
oligomeric 2,3,6-trideoxyhexopyranosides at will.2
Deoxyhexopyranosides3 such as rhodinose and amicetose
(Figure 1) were found in numerous bioactive natural products.4-8
Two isomeric disaccharides, 5 and 6, were isolated from FH-S 1577
strain of Streptomyces from India and named as narbosine B.9
Congeners of narbosine B such as narbosine D 7 showed distinct
antiviral activity.9 As to oligosaccharides, there are 4096 possible
stereoisomers for the tetrameric 2,3,6-trideoxyhexopyranoside 8,
even though 2,3,6-trideoxyhexopyranose is one of the simplest
hexoses.
HO
5
7
6
OH
narbosine D
β−narbosine B
α−narbosine B
HO
Me
O
O
Me
O
O
OR
Me
O
O
Me
O
8 (4096 possible stereoisomers)
Figure 1. Natural and Unnatural 2,3,6-Trideoxyhexopyranosides
Dihydropyranones 12 and 13 were prepared as the precursors
of monomeric 2,3,6-trideoxy hexopyranosides according to the
strategy developed by O’Doherty (Scheme 1).17 Alcohol 10 was
obtained in nearly quantitative yield and 98% ee according to
known protocols.22 Achmatowicz rearrangement converts furan 10
to dihydropyranone 11.23 Following O’Doherty’s methods,24 benzyl
glycosides 12 and 13 are prepared efficiently from the
corresponding carbonates via Pd-π-allyl intermediates. Carbonate
intermediates 14 was isolated in 59% yield under condition c, while
carbonate intermediate 15 was isolated in 50% yield under
condition e.24 The enantiomers of 12 and 13 were synthesized
similarly by using (R,R)-ligand L2.
Among various strategies developed for de novo synthesis of
carbohydrates11,12 and O-glycosidation,13 particularly Pd-catalysed
Tsuji-Trost allylic alkylation14 employed by several research
groups,14-18 we are attracted by O’Doherty’s de novo synthetic
strategy because of its predictability, efficiency, and versatility
20
associated with the resulting enone functional group.12,
The
Previously, the enantiomer of α-L-amicetopyranoside 16
(Scheme 2) was prepared from ent-12 by a two-step sequence
including a highly diastereoselective reduction of the ketone by
NaBH4 at -78 oC and a diimide reduction of the alkene.25 The
diastereoselectivity for the reduction of enone ent-13 to the
corresponding allylic alcohols was about 1.5:1 under the condition
of Luche reduction.26 To the best our knowledge, there is no direct
one-step method that can provide access to 2,3,6-
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trideoxyhexopyranosides 16 to 19 from enones 12 or 13 chiral catalyst regardless the absolute or relative stereochemistry of
stereoselectively. We envisioned that a chiral catalyst-controlled the enone precursors.
tandem reduction could provide divergent products with high
Table 1. Preparation of All Eight Stereoisomers of 2,3,6-Trideoxyhexopyranosides by
predictability.27 To achieve high stereoselectivity for each product,
low intrinsic diastereoselectivity is highly desirable.28 Given the high
efficiency and selectivity of RhIII-catalysed transfer hydrogenation of
ketone 9, we investigated the reduction of enones 12 and 13 using
achiral ligands. Both ketone and alkene groups were reduced and
the diastereomeric ratios were less than 2:1 for the two pairs of
alcohol products (Scheme 2).
Chiral Catalyst-Controlled Reductiona
Substrate
Product
Ligand
Yield (%)b
12
16
L2
89
86
71
73
79
84
79
83
12
17
L1
L2
L1
L2
L1
L2
L1
13
18
13
19
ent-12
ent-12
ent-13
ent-13
ent-17
ent-16
ent-19
ent-18
O
OH
Me
O
O
OH
b)
O
a)
O
Me
Me
73%
>99%
10
9
11
a. Conditions: [Cp*RhCl2]2 (0.5 mol%), ligand (1.2 mol%), HCO2Na, 40 oC; b.
Isolated yield, dr > 20:1.
98% ee
Me
O
O
OBn
Me
O
O
OBn
c) 59%
d) 84%
e) 50%
d) 87%
We further examined the scope of this chiral catalyst-controlled
divergent synthesis in more complex settings (Schemes 3 and 4).
Naturally occurring disaccharides β-narbosine B 5 was synthesized
for the first time from building blocks 15 and 14 derived from
Achmatowicz rearrangement product 11 (Scheme 3). Natural
product α-narbosine B 6 was prepared similarly. The spectral data
and optical rotation of our synthetic 6 are in accordance with those
reported by Trost.10 The (S,S)- ligand (L1) was employed to install all
the hydroxyl groups with (S)-configuration in intermediates and
products 5/6.
11
12
13
Me
O
OBoc
Me
O
O
OBoc
O
14
15
under condition c):
under condition e):
14/15 = 3.1 : 1
15/14 = 1.3 : 1
(S,S)-Ts-DPEN L1
(R,R)-Ts-DPEN L2
Disaccharide 23, trisaccharide 24, and tetrasaccharide 25 were
synthesized efficiently and stereoselectively from α-L-
amicetopyranoside 18 in a few steps (Scheme 4). The (R,R)-ligand
(L2) was employed to install all the hydroxyl groups with R-
configuration in these oligosaccharides. The high fidelity of Pd-
catalysed glycosidation and chiral catalyst-controlled reduction
allows the preparation of any one of the 4096 possible
stereoisomeric tetrasaccharides, which complements to the
approach developed by Rhee recently.19
Ph
Ph
Ph
Ph
TsHN
NH2
TsHN
NH2
a) [Cp*RhCl2]2 (0.05 mol%), (S,S)-Ts-DPEN L1 (0.12 mol%),
HCO2Na, 40 oC; b) NBS, NaOAc, NaHCO3; c) Boc2O, DMAP, -78oC;
d) Pd2(dba)3 (0.5 mol%), PPh3 (2 mol%), BnOH; e) Boc2O, NaOAc,
80oC.
Scheme 1. Preparation of Precursors of Monomeric Hexopyranosides by O’Doherty’s
De Novo Synthetic Strategy
Scheme 2. Reduction of Enone Using Achiral Ligand
When we switched to chiral ligands, we were pleased to find
that a single stereoisomer was observed for products 16, 17, 18,
and 19 depending on the choice of substrate and chiral ligand
(Table 1). Similarly, products ent-16, ent-17, ent-18, and ent-19
were prepared selectively from ent-12 and ent-13. In all cases, the
(S,S)-ligand always yielded hydroxyl groups with S-configuration,
while the (R,R)-ligand afforded R-configured secondary alcohols.
The stereochemistry of the product is completely controlled by the
Scheme 3. Preparation of Naturally Occurring Disaccharides Narbosine B
2 | J. Name., 2012, 00, 1-3
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HO
1.
2.
For selected reviews, see: a) B. Ernst and J. L. Magnani,
Nat. Rev. Drug Discovery, 2009, 8, 661; b) P. Stallforth, B.
Lepenies, A. Adibekian and P. H. Seeberger, J. Med. Chem.,
2009, 52, 5561; c) J. J. Reina and A. Bernardi, Mini-Rev.
Med. Chem., 2012, 12, 1434; d) C.-H. Wong,
Me
HO
O
OBn
Me
a) 15, 90%;
O
Me
O
b), 89%
O
OBn
23
18
a) 15, 90%;
b), 73%
Carbohydrate-based Drug Discovery, WILEY-VCH Verlag
GmbH & Co. KGaA,, Weinheim, 2003.
Me
HO
O
24
O
Me
For selected examples of deoxysugar synthesis, see: a) K.
C. Nicolaou, T. Ladduwahetty, J. L. Randall and A.
Chucholowski, J. Am. Chem. Soc., 1986, 108, 2466; b) J.
Gervay and S. Danishefsky, J. Org. Chem., 1991, 56, 5448;
c) W. R. Roush and X. F. Lin, J. Am. Chem. Soc., 1995, 117,
2236; d) W. R. Roush, D. P. Sebesta and C. E. Bennett,
Tetrahedron, 1997, 53, 8825; e) W. R. Roush, D. P.
Sebesta and R. A. James, Tetrahedron, 1997, 53, 8837; f)
W. R. Roush and C. E. Bennett, J. Am. Chem. Soc., 1999,
121, 3541; g) W. R. Roush, B. W. Gung and C. E. Bennett,
Org. Lett., 1999, 1, 891; h) B. Yu and Z. Y. Yang, Org. Lett.,
2001, 3, 377; i) B. Yu and P. Wang, Org. Lett., 2002, 4,
1919; j) A. F. G. Bongat, M. N. Kamat and A. V.
O
Me
O
OBn
O
a) ent-14, 82%;
b), 82%
OH
Me
O
Me
O
O
25
a) Pd2(dba)3 (2.5 mol%), PPh3 (10 mol%);
O
Me
O
Me
O
OBn
O
b) [Cp*RhCl2]2 (0.5 mol%), (R,R)-Ts-DPEN L2 (1.2 mol%), HCO2Na, 40 oC.
Scheme 4. Preparation of Tetrasaccharide by the Sequence of Pd-Catalysed Allylic
Alkylation and Chiral Catalyst-Controlled Reduction
Demchenko, J. Org. Chem., 2007, 72, 1480; k) E. I.
Balmond, D. M. Coe, M. C. Galan and E. M. McGarrigle,
Angew. Chem. Int. Ed., 2012, 51, 9152; l) J. P. Issa, D.
Lloyd, E. Steliotes and C. S. Bennett, Org. Lett., 2013, 15,
4170; m) K. N. Baryal, D. Zhu, X. Li and J. Zhu, Angew.
Chem. Int. Ed., 2013, 52, 8012; n) E. I. Balmond, D.
Benito-Alifonso, D. M. Coe, R. W. Alder, E. M. McGarrigle
and M. C. Galan, Angew. Chem. Int. Ed., 2014, 53, 8190;
o) J. P. Issa and C. S. Bennett, J. Am. Chem. Soc., 2014, 136,
5740; p) D. Zhu, K. N. Baryal, S. Adhikari and J. Zhu, J. Am.
Chem. Soc., 2014, 136, 3172; q) M. Kaneko and S. B.
Herzon, Org. Lett., 2014, 16, 2776; r) T. K. Pradhan, C. C.
Lin and K. K. T. Mong, Synlett, 2013, 24, 219; s) T. K.
Pradhan, C. C. Lin and K.-K. T. Mong, Org. Lett., 2014, 16,
1474; t) J.-H. Chen, J.-H. Ruei and K.-K. T. Mong, Eur. J.
Org. Chem., 2014, 1827.
To understand the mechanism of the tandem reduction in more
details, we studied the distribution of products using limited
amount of sodium formate reducing agent (Scheme 5). A mixture of
ketone 26, alcohol 18, and starting material 13 was obtained in 10%,
40%, and 50% yields, respectively, based on NMR of the crude
product. No allylic alcohol 27 was observed by NMR. This suggests
that the 1,4-reduction is much faster than the 1,2-reduction of
enone 13. The ratio of 26/18 also indicates that the reduction of
ketone 26 is faster than the 1,4-reduction of enone 13.
3.
For selected reviews, see: a) A. Kirschning, M. Jesberger
and K. U. Schoning, Synthesis, 2001, 507; b) W. Chen, G.
Zhang, L. Zhu, L. Fang, X. Cao, J. Kedenburg, J. Shen, D.
Sun and P. G. Wang, in Frontiers in Modern Carbohydrate
Chemistry, ed. A. V. Demchenko, 2007, vol. 960, pp. 15; c)
R. M. De Lederkremer and C. Marino, in Advances in
Carbohydrate Chemistry and Biochemistry, Vol 61, ed. D.
Horton, 2008, vol. 61, pp. 143; d) A. Borovika and P.
Nagorny, J. Carbohydr. Chem., 2012, 31, 255; e) M.
Emmadi and S. S. Kulkarni, Nat. Prod. Rep., 2014, 31, 870.
Y. Hayakawa, T. Iwakiri, K. Imamura, H. Seto and N. Otake,
J. Antibiot., 1985, 38, 960.
a) T. Henkel, J. Rohr, J. M. Beale and L. Schwenen, J.
Antibiot., 1990, 43, 492; b) S. Weber, C. Zolke, J. Rohr and
J. M. Beale, J. Org. Chem., 1994, 59, 4211.
L. M. Canedo, J. L. F. Puentes, J. P. Baz, X. H. Huang and K.
L. Rinehart, J. Antibiot., 2000, 53, 479.
a) S. Kunimoto, T. Someno, Y. Yamazaki, J. Lu, H. Esumi
and H. Naganawa, J. Antibiot., 2003, 56, 1012; b) T.
Someno, S. Kunimoto, H. Nakamura, H. Naganawa and D.
Ikeda, J. Antibiot., 2005, 58, 56.
A. Luzhetskyy, J. Hoffmann, S. Pelzer, S.-E. Wohlert, A.
Vente and A. Bechthold, Appl. Microbiol. Biotechnol.,
2008, 80, 15.
Scheme 5. Reduction with Limited Amount of Reducing Agent
In summary, we realized a divergent synthesis of all eight
stereoisomers 2,3,6-trideoxyhexopyranosides. The sequence
of Pd-catalysed glycosidation and chiral catalyst-controlled
tandem reduction can lead to a systematic de novo synthesis
of
all
stereoisomers
of
any
oligomeric
2,3,6-
trideoxyhexopyranosides. We expect that the chiral catalyst-
directed divergent synthesis strategy can be extended to the
divergent synthesis of other oligosaccharides and their
analogues.
4.
5.
We thank University of Wisconsin (UW) for funding. Y. Zhao
thanks Jiangsu Overseas Research and Training Program for
financial support of the visiting scholar position at UW-
Madison. We thank Professor George O’Doherty (Northeastern
University) for reading the manuscript and offering insightful
comments. This study made use of the Medicinal Chemistry
Center at UW-Madison instrumentation, funded by the
Wisconsin Alumni Research Foundation (WARF) and the UW
School of Pharmacy
6.
7.
8.
Notes and references
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9.
T. Henkel, S. Breidingmack, A. Zeeck, S. Grabley, P. E.
Hammann, K. Hutter, G. Till, R. Thiericke and J. Wink,
Liebigs Ann. Chem., 1991, 575.
B. M. Trost and Y. H. Rhee, J. Am. Chem. Soc., 2002, 124,
2528.
21.
22.
R. S. Babu, Q. Chen, S.-W. Kang, M. Zhou and G. A.
O'Doherty, J. Am. Chem. Soc., 2012, 134, 11952.
a) X. Wu, X. Li, A. Zanotti-Gerosa, A. Pettman, J. Liu, A. J.
Mills and J. Xiao, Chem. Eur. J., 2008, 14, 2209; b) M. P.
Croatt and E. M. Carreira, Org. Lett., 2011, 13, 1390.
O. Achmatowicz, P. Bukowski, B. Szechner, Z. Zwierzch
and A. Zamojski, Tetrahedron, 1971, 27, 1973.
M. Zhou and G. A. O'Doherty, Org. Lett., 2006, 8, 4339.
M. Shan, Y. Xing and G. A. O'Doherty, J. Org. Chem., 2009,
74, 5961.
10.
11.
For selected examples on de novo synthesis of
carbohydrates, see: a) S. Y. Ko, A. W. M. Lee, S.
Masamune, L. A. Reed, K. B. Sharpless and F. J. Walker,
Science, 1983, 220, 949; b) M. Takeuchi, T. Taniguchi and
K. Ogasawara, Synthesis, 1999, 341; c) J. M. Harris, M. D.
Keranen and G. A. O'Doherty, J. Org. Chem., 1999, 64,
2982; d) J. M. Harris, M. D. Keranen, H. Nguyen, V. G.
Young and G. A. O'Doherty, Carbohydr. Res., 2000, 328,
17; e) A. B. Northrup and D. W. C. MacMillan, Science,
2004, 305, 1752; f) M. M. Ahmed, B. P. Berry, T. J. Hunter,
D. J. Tomcik and G. A. O'Doherty, Org. Lett., 2005, 7, 745;
g) D. Enders and C. Grondal, Angew. Chem. Int. Ed., 2005,
44, 1210; h) D. J. Covell, N. A. Vermeulen, N. A. Labenz
and M. C. White, Angew. Chem. Int. Ed., 2006, 45, 8217; i)
23.
24.
25.
26.
27.
M. Zhou and G. A. O'Doherty, J. Org. Chem., 2007, 72,
2485.
For selected examples of chiral catalyst controlled
divergent synthesis, see: a) N. Minami, S. S. Ko and Y. Kishi,
J. Am. Chem. Soc., 1982, 104, 1109; b) S. Kobayashi, A.
Ohtsubo and T. Mukaiyama, Chem. Lett., 1991, DOI:
10.1246/cl.1991.831, 831; c) M. P. Doyle, A. V. Kalinin
and D. G. Ene, J. Am. Chem. Soc., 1996, 118, 8837. Also
see referenece 11.
S. B. Han, J. R. Kong and M. J. Krische, Org. Lett., 2008, 10, 28.
4133.
For a recent example of enantio- and diastereodivergent
catalysis, see: S. Krautwald, D. Sarlah, M. A. Schafroth and
E. M. Carreira, Science, 2013, 340, 1065.
12.
For recent reviews on de novo synthesis of carbohydrates,
see: a) A. Z. Aljahdali, P. Shi, Y. Zhong and G. A. O'Doherty,
in Advances in Carbohydrate Chemistry and Biochemistry,
Vol 69, ed. D. Horton, 2013, vol. 69, pp. 55; b) M. F.
Cuccarese, J. J. Li and G. A. O’Doherty, in Modern
Synthetic Methods in Carbohydrate Chemistry: From
Monosaccharides to Complex Glycoconjugates, eds. D. B.
Werz and S. Vidal, 2014 Wiley-VCH Verlag GmbH & Co.
KGaA, Weinheim, 2014, ch. 1, pp. 1.
13.
For selected reviews, see: a) A. V. Demchenko, Handbook
of Chemical Glycosylation: Advances in Stereoselectivity
and Therapeutic Relevance, WILEY-VCH Verlag GmbH &
Co. KGaA, Weinheim, 2008; b) X. Zhu and R. R. Schmidt,
Angew. Chem. Int. Ed., 2009, 48, 1900; c) X. Li and J. Zhu,
J. Carbohydr. Chem., 2012, 31, 284; d) M. J. McKay and H.
M. Nguyen, Acs Catalysis, 2012, 2, 1563; e) D. B. Werz
and S. Vidal, Modern Synthetic Methods in Carbohydrate
Chemistry: From Monosaccharides to Complex
Glycoconjugates, Wiley-VCH Verlag GmbH & Co. KGaA,
Weinheim, 2014; f) T. Nokami, J. Synth. Org. Chem. Jpn.,
2014, 72, 797.
14.
For selected reviews, see: a) J. Tsuji, Acc. Chem. Res., 1969,
2, 144; b) B. M. Trost, Acc. Chem. Res., 1980, 13, 385; c) J.
Tsuji, Tetrahedron, 1986, 42, 4361; d) J. Tsuji and I.
Minami, Acc. Chem. Res., 1987, 20, 140; e) B. M. Trost
and M. L. Crawley, Chem. Rev., 2003, 103, 2921.
a) H. Kim and C. Lee, Org. Lett., 2002, 4, 4369; b) H. Kim,
H. Men and C. Lee, J. Am. Chem. Soc., 2004, 126, 1336.
A. C. Comely, R. Eelkema, A. J. Minnaard and B. L. Feringa,
J. Am. Chem. Soc., 2003, 125, 8714.
15.
16.
17.
a) R. S. Babu and G. A. O'Doherty, J. Am. Chem. Soc., 2003,
125, 12406; b) R. S. Babu, M. Zhou and G. A. O'Doherty, J.
Am. Chem. Soc., 2004, 126, 3428.
18.
a) S. Xiang, Z. Lu, J. He, K. L. M. Hoang, J. Zeng and X.-W.
Liu, Chem. Eur. J., 2013, 19, 14047; b) S. Xiang, J. He, Y. J.
Tan and X.-W. Liu, J. Org. Chem., 2014, 79, 11473; c) S.
Xiang, K. L. M. Hoang, J. He, Y. J. Tan and X.-W. Liu, Angew.
Chem. Int. Ed., 2015, 54, 604.
19.
20.
W. Lim, J. Kim and Y. H. Rhee, J. Am. Chem. Soc., 2014,
136, 13618.
N. L. Holder, Chem. Rev., 1982, 82, 287.
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