Chiral Catalyst-Directed Dynamic Kinetic Diastereoselective Acylation of Lactols for de Novo Synthesis of Carbohydrate

Article abstract of DOI:10.1021/acs.orglett.5b02641

The control of the stereochemistry at the anomeric position is still one of the major challenges of synthetic carbohydrate chemistry. We have developed a new strategy consisting of a chiral catalyst-directed acylation followed by a palladium-catalyzed gly

Full text of DOI:10.1021/acs.orglett.5b02641

Letter
pubs.acs.org/OrgLett
Chiral Catalyst-Directed Dynamic Kinetic Diastereoselective
Acylation of Lactols for De Novo Synthesis of Carbohydrate
†
†
†
†
‡
,†,‡
Hao-Yuan Wang, Ka Yang, Dan Yin, Can Liu, Daniel A. Glazier, and Weiping Tang*
†
School of Pharmacy, University of WisconsinMadison, Madison, Wisconsin 53705, United States
‡
Department of Chemistry, University of WisconsinMadison, Madison, Wisconsin 53706, United States
*
S Supporting Information
ABSTRACT: The control of the stereochemistry at the anomeric
position is still one of the major challenges of synthetic carbohydrate
chemistry. We have developed a new strategy consisting of a chiral
catalyst-directed acylation followed by a palladium-catalyzed glyco-
sidation to achieve high α- and β-stereoselectivity on the anomeric
position. The former process involves a dynamic kinetic diaster-
eoselective acylation of lactols derived from Achmatowicz rearrange-
ment, while the latter is a stereospecific palladium-catalyzed allylic
alkylation.
arbohydrate, one of the four basic macromolecules of life,
Scheme 1. De Novo Synthesis of Carbohydrates
C
plays an essential role in numerous important biological
processes such as immunological responses, cancer metastasis,
and bacterial or viral infections. Efficient and stereoselective
1
synthetic methods, especially de novo synthetic methods that do
not rely on naturally occurring sugars, may greatly facilitate the
study of the biological functions of carbohydrate. It will also
enable the development of carbohydrate analogues as novel
therapeutic agents.
Since the seminal work by Sharpless and Masamune on de
2
novo synthesis of hexopyranoses, a number of new strategies
have been developed for the de novo synthesis of carbohy-
3
drates. However, the stereochemistry at the anomeric position
or stereoselective glycosidation remained largely unaddressed in
4
these de novo synthesis. Among various O-glycosidation
5
6
methods, Pd-catalyzed Tsuji−Trost allylic alkylation has
7
8
9
10
been recognized by Lee, Feringa, O’Doherty, Liu, and
Rhee as a powerful way to link monosaccharides. The de novo
synthesis of carbohydrate developed by Feringa and
O’Doherty relies on Achmatowicz rearrangement and
stereoselective Pd-catalyzed glycosidation (Scheme 1). The
former converts the biogenic feedstock furan 1 to dihydropyr-
anone 2, which has been extensively applied in the de novo
synthesis of carbohydrates since its initial discovery in the
1
1
8
9
12
stereoselective because of the low selectivity of the acylation
of the lactol.
Although trans-3b could be prepared exclusively from the
corresponding Achmatowicz rearrangement product 2b
3a,13
1
970s (Scheme 1A).
In the latter process, esters or
9
carbonates 3a−c undergo Pd-catalyzed Tsuji−Trost allylic
(Scheme 2A), the best diastereomeric ratio favoring cis-3b
6
was only 1:1. The ratios for the closely related carbonates trans-
c and cis-3c ranged from 3:1 to 1:1.3.
alkylation to afford product 4 with retention of stereo-
9
,16
3
Chromatographic
chemistry (Scheme 1B). Feringa and co-workers primarily
separation of these isomers is required with the exception of
trans-3b. We recently became interested in the dynamic kinetic
diastereoselective transformations of lactol 2 and discovered an
Ir-catalyzed dynamic kinetic diastereoselective redox isomer-
focused on the glycosidation of ester 3a, which was derived
8
,14
from lipase mediated resolution.
In the past decade,
O’Doherty and co-workers have applied the Pd-catalyzed
glycosidation of 3b and 3c to the synthesis of numerous mono-
and oligosaccharides, such as mannose derivatives and
4
,15
cleistriosides shown in Scheme 1.
However, the overall
Received: September 11, 2015
transformation from lactol 2 to product 4 is often not
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02641
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. DKDA of Lactols
using more hindered anhydrides 7c and 7d. A similar trend was
also observed by Birman and co-workers for the acylation of
20
alcohols.
Since only one enantiomeric isomer was commercially
available for catalyst 6, we prepared substrate D-2c to explore
the mismatched acylation. The dr dropped from 8:1 to 1:1
when D-2c was employed as the substrate using acetic
anhydride as the acylation reagent. Under the conditions of
entry 7 in Table 1, a dr of 8:1 favoring the mismatched cis-
isomer with a β-D configuration was observed, and this cis-
isomer could be isolated in 76% yield. We then tried to acylate
mismatched substrate D-2b with a silyloxymethylene group on
the 5-position under the conditions of entry 4 in Table 1.
Unfortunately, low conversions and low dr’s were observed. No
improvement was obtained by changing the TBS group to
benzyl or benzoyl protecting groups.
While we were optimizing conditions for these challenging
mismatched substrates, Ortiz and co-workers reported the
dynamic kinetic asymmetric transformation (DYKAT) of lactol
2
a (R = H) and four related lactols with either two hydrogen or
1
7
ization of lactol 2 to its lactone. We envisioned that chiral
catalysts could either reinforce or override the intrinsic
diastereoselectivity for the acylation of lactol 2 and provide a
general solution for the synthesis of either trans-5 or cis-5 via
chiral catalyst-directed dynamic kinetic diastereoselective
acylation (DKDA) (Scheme 2B).
two methyl substituents on the 5-position to the corresponding
esters with up to 88% ee.
2
5
Commercially available
(
−)-levamisole was also employed as the chiral organocatalyst.
The method was then applied to an elegant synthesis of anti-
HIV drug BMS-986001. Although the DYKAT of lactol 2a was
nicely demonstrated by Ortiz and co-workers, it was not
obvious that the DKDA of substrates 2b and 2c could be easily
achieved. In fact, our results have indicated that it is challenging
to override the intrinsic diastereoselectivity for mismatched
substrates.
After we analyzed chiral organocatalysts that are known to
1
8
mediate enantioselective acylation of alcohols, commercially
available levamisole 6 with an (S)-configuration became
attractive to us because of its broad utility in many different
1
9
reactions (Table 1). This type of tetramisole-based catalyst
We also tried to acylate substrates L-2c and D-2c under the
conditions in entry 4 of Table 1 using benzotetramisole (BTM)
catalyst 9 (Table 2), which was first introduced by Birman for
the kinetic resolution of alcohols. We obtained products with
dr’s ranging from 8:1 to 1:7 for matched and mismatched
substrates. We were then attracted by Shiino’s mixed anhydride
conditions for the kinetic resolution of alcohols because a wide
a
Table 1. Screening of Anhydride for DKDA
20
26
b
b
variety of carboxylic acids are readily available. We explored
different carboxylic acids for the acylation of matched substrate
entry
anhydride 7
conversion (%)
product (dr)
1
2
3
4
5
6
7a, Boc O
0
>99
>99
>99
70
2
7b, Ac O
α-L-8b (8:1)
α-L-8c (11:1)
α-L-8d (15:1)
α-L-8e (1:1)
a
2
Table 2. Screening of Mixed Anhydride for DKDA
7c, (EtCO) O
2
7d, (i-PrCO) O
2
7e, Bz O
2
7f, Piv O
<10
2
c
d
7
7d
92
α-L-8d (15:1)
a
Conditions: CDCl , L-2c (1.0 equiv), 6 (5 mol %) 7 (2.0 equiv), i-
b
b
3
b
entry
acid 10
AcOH
EtCO H
conversion (%)
product (dr)
Pr NEt (2.0 equiv), Na SO , rt, unless noted otherwise. The
conversion of 2c and dr of 8 were determined by H NMR of the
crude product using CH Br as the internal standard. The reaction
was carried out in CHCl . Isolated yield of 8d.
2
2
4
1
1
2
3
4
5
6
85
>99
>99
<10
>99
>99
80
α-D-8b (13:1)
α-D-8c (18:1)
α-D-8d (9:1)
c
2
2
2
d
i-PrCO H
2
3
PhCO H
2
Ph CHCO H
2
α-D-8f (14:1)
α-D-8g (>20:1)
α-D-8g (16:1)
α-D-8g (>20:1)
α-D-8g (>20:1)
2
has been extensively used by Birman and co-workers for the
kinetic resolution of secondary alcohols, azlactones, and α-
thiolcarboxylic acids. Wiskur and co-workers also applied
them to the asymmetric silylation of alcohols.
20
21
PhCH CO H
2 2
c
22
7
PhCH CO H
2 2
d
23
8
PhCH CO H
>99
2
2
d
e
9
PhCH CO H
76
2
2
Chiral lactol L-2c was prepared enantioselectively in two
steps from 2-acetylfuran via catalytic asymmetric hydrogenation
a
Conditions: D-2c (1.0 equiv), 9 (10 mol %), Piv O (1.3 equiv), 10
2
(
98% ee) and Achmatowicz rearrangement according to known
(
1.3 equiv), i-Pr NEt (2.5 equiv), Et O, rt, unless noted otherwise.
17,24
2 2
The conversion of 2c and dr of 8 were determined by H NMR of
protocols.
Using 6 as the catalyst, no reaction was observed
b
1
c
when (Boc )O was employed. We were pleased to find that
2
crude product using CH Br as the internal standard. The reaction
2
2
d
simple acetic anhydride provided product 8b with a dr of 8:1
favoring the trans-α-isomer. Higher selectivity was observed by
was carried out in CH Cl . The reaction was carried out in CHCl .
2
2
3
e
Isolated yield of 8g.
B
DOI: 10.1021/acs.orglett.5b02641
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
D-2c using catalyst 9 as shown in Table 2. The diastereose-
lectivity for product 8b was improved from 8:1 (entry 2, Table
Scheme 4. Pd-Catalyzed Stereospecific Glycosidation
1) to 13:1 (entry 1, Table 2) under these new conditions. We
quickly found that simple phenylacetic acid yielded α-isomer 8g
exclusively (entry 6). The reaction also worked well in CHCl3
(
entries 8 and 9), and it became the choice of solvent since the
catalyst is more soluble in CHCl than ether.
3
With these new conditions in hand, we examined the
acylation of substrate D-2c using catalyst 11; the more
challenging mismatched scenario (Scheme 3). Product β-D-8g
Scheme 3. Catalyst-Directed DKDA of Different Lactols
was prepared in high yield and diastereoselectivity. We were
also pleased to find that both α- and β-isomeric products 12
could be prepared in high diastereoselectivity using catalyst 9 or
ASSOCIATED CONTENT
Supporting Information
1
1, though the reaction was much slower for the mismatched
■
*
S
case in CHCl . Faster reaction and higher yield were observed
3
in toluene for products α-D-12 and β-D-12. Both enantiomers of
substrates 2b were prepared highly enantioselectively (98% ee)
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02641.
17
according to our previous protocols. All diastereoisomers of 8
and 12 could be easily separated by SiO column chromatog-
2
Detailed experimental procedures, characterization data,
raphy, and the yield refers to the isolated yield of a single
isomer. All of these isomers are basic chiral building blocks for
the synthesis of various oligosaccharides via Pd-catalyzed
1
13
and spectra ( H, C NMR, IR, and HRMS) (PDF)
4
,15
AUTHOR INFORMATION
Corresponding Author
glycosidation.
■
16
Following O’Doherty’s conditions, glycosides 13 and 14
were prepared efficiently and stereospecifically from the
corresponding esters via Pd−π-allyl intermediates (Scheme
*E-mail: weiping.tang@wisc.edu.
Notes
4). All of the ester substrates (8d, 8g, and 12) employed here
The authors declare no competing financial interest.
are single stereoisomers (drs >20:1). The standard conditions
worked well for most substrates, including α-L-8d, β-D-8d, α-D-
ACKNOWLEDGMENTS
■
8g, and α-D-12. However, the dr of the product dropped to 6:1
We thank the University of WisconsinMadison for funding.
C.L. thanks Guangzhou Medical University for financial
support of her visiting scholarship.
for cis-substrate β-D-8g. The addition of organic base
significantly improved the dr. Similarly, the addition of base
is required for the preparation of β-D-14. Various postglyco-
sidation modification methods have been developed by
O’Doherty and co-workers for the conversion of products in
Scheme 4 to diverse range of mono- and oligomeric
REFERENCES
■
(
1) For selected reviews, see: (a) Ernst, B.; Magnani, J. L. Nat. Rev.
4
,15
Drug Discovery 2009, 8, 661. (b) Stallforth, P.; Lepenies, B.; Adibekian,
A.; Seeberger, P. H. J. Med. Chem. 2009, 52, 5561. (c) Reina, J. J.;
Bernardi, A. Mini-Rev. Med. Chem. 2012, 12, 1434. (d) Wong, C.-H.
Carbohydrate-based Drug Discovery; Wiley−VCH Verla: Weinheim,
saccharides.
In summary, the combination of chiral organocatalyst-
directed DKDA and Pd-catalyzed glycosidation allows the
complete stereochemical control of the anomeric center and
paves the way for highly stereoselective de novo synthesis of
many natural and non-natural carbohydrates.
2
003.
(2) Ko, S. Y.; Lee, A. W. M.; Masamune, S.; Reed, L. A.; Sharpless, K.
B.; Walker, F. J. Science 1983, 220, 949.
C
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Organic Letters
Letter
(
3) (a) Takeuchi, M.; Taniguchi, T.; Ogasawara, K. Synthesis 1999,
(24) (a) Wu, X.; Li, X.; Zanotti-Gerosa, A.; Pettman, A.; Liu, J.; Mills,
A. J.; Xiao, J. Chem. - Eur. J. 2008, 14, 2209. (b) Croatt, M. P.; Carreira,
E. M. Org. Lett. 2011, 13, 1390.
(25) Ortiz, A.; Benkovics, T.; Beutner, G. L.; Shi, Z.; Bultman, M.;
Nye, J.; Sfouggatakis, C.; Kronenthal, D. R. Angew. Chem., Int. Ed.
1999, 341. (b) Harris, J. M.; Keranen, M. D.; O’Doherty, G. A. J. Org.
Chem. 1999, 64, 2982. (c) Harris, J. M.; Keranen, M. D.; Nguyen, H.;
Young, V. G.; O’Doherty, G. A. Carbohydr. Res. 2000, 328, 17.
d) Northrup, A. B.; MacMillan, D. W. C. Science 2004, 305, 1752.
(
(
2
(
(
015, 54, 7185.
26) (a) Shiina, I.; Nakata, K. Tetrahedron Lett. 2007, 48, 8314.
b) Shiina, I.; Nakata, K.; Ono, K.; Onda, Y.-s.; Itagak, M. J. Am. Chem.
e) Ahmed, M. M.; Berry, B. P.; Hunter, T. J.; Tomcik, D. J.;
O’Doherty, G. A. Org. Lett. 2005, 7, 745. (f) Enders, D.; Grondal, C.
Angew. Chem., Int. Ed. 2005, 44, 1210. (g) Covell, D. J.; Vermeulen, N.
A.; Labenz, N. A.; White, M. C. Angew. Chem., Int. Ed. 2006, 45, 8217.
Soc. 2010, 132, 11629. (c) Nakata, K.; Gotoh, K.; Ono, K.; Futami, K.;
Shiina, I. Org. Lett. 2013, 15, 1170.
(
h) Han, S. B.; Kong, J. R.; Krische, M. J. Org. Lett. 2008, 10, 4133.
4) (a) Aljahdali, A. Z.; Shi, P.; Zhong, Y.; O’Doherty, G. A. In
(
Advances in Carbohydrate Chemistry and Biochemistry, Vol 69; Horton,
D., Ed.; Elsevier: New York, 2013; Vol. 69, p 55. (b) Cuccarese, M. F.;
Li, J. J.; O’Doherty, G. A. In Modern Synthetic Methods in Carbohydrate
Chemistry: From Monosaccharides to Complex Glycoconjugates; Werz, D.
B., Vidal, S., Eds.; Wiley−VCH: Weinheim, 2014; p 1.
(
5) For selected reviews, see: (a) Demchenko, A. V. Handbook of
Chemical Glycosylation: Advances in Stereoselectivity and Therapeutic
Relevance; Wiley−VCH: Weinheim, 2008. (b) Zhu, X.; Schmidt, R. R.
Angew. Chem., Int. Ed. 2009, 48, 1900. (c) Li, X.; Zhu, J. J. Carbohydr.
Chem. 2012, 31, 284. (d) McKay, M. J.; Nguyen, H. M. ACS Catal.
2
012, 2, 1563. (e) Werz, D. B.; Vidal, S. Modern Synthetic Methods in
Carbohydrate Chemistry: From Monosaccharides to Complex Glycoconju-
gates; Wiley−VCH: Weinheim, 2014. (f) Nokami, T. Yuki Gosei
Kagaku Kyokaishi 2014, 72, 797.
(
6) (a) Tsuji, J. Acc. Chem. Res. 1969, 2, 144. (b) Trost, B. M. Acc.
Chem. Res. 1980, 13, 385. (c) Tsuji, J. Tetrahedron 1986, 42, 4361.
d) Tsuji, J.; Minami, I. Acc. Chem. Res. 1987, 20, 140. (e) Trost, B.
M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921.
7) (a) Kim, H.; Lee, C. Org. Lett. 2002, 4, 4369. (b) Kim, H.; Men,
H.; Lee, C. J. Am. Chem. Soc. 2004, 126, 1336.
8) Comely, A. C.; Eelkema, R.; Minnaard, A. J.; Feringa, B. L. J. Am.
Chem. Soc. 2003, 125, 8714.
9) (a) Babu, R. S.; O’Doherty, G. A. J. Am. Chem. Soc. 2003, 125,
(
(
(
(
12406. (b) Babu, R. S.; Zhou, M.; O’Doherty, G. A. J. Am. Chem. Soc.
2
004, 126, 3428.
(
10) (a) Xiang, S.; Lu, Z.; He, J.; Hoang, K. L. M.; Zeng, J.; Liu, X.-
W. Chem. - Eur. J. 2013, 19, 14047. (b) Xiang, S.; He, J.; Tan, Y. J.; Liu,
X.-W. J. Org. Chem. 2014, 79, 11473. (c) Xiang, S.; Hoang, K. L. M.;
He, J.; Tan, Y. J.; Liu, X.-W. Angew. Chem., Int. Ed. 2014, 54, 604.
(
11) Lim, W.; Kim, J.; Rhee, Y. H. J. Am. Chem. Soc. 2014, 136,
3618.
12) Achmatowicz, O.; Bukowski, P.; Szechner, B.; Zwierzchowska,
Z.; Zamojski, A. Tetrahedron 1971, 27, 1973.
13) (a) Achmatowicz, O., Jr.; Bukowski, P. Can. J. Chem. 1975, 53,
524. (b) Achmatowicz, O.; Szechner, B. Carbohydr. Res. 1976, 50, 23.
c) Bognar, R.; Herczegh, P. Carbohydr. Res. 1976, 52, 11. (d) Holder,
N. L. Chem. Rev. 1982, 82, 287.
14) van den Heuvel, M.; Cuiper, A. D.; van der Deen, H.; Kellogg,
R. M.; Feringa, B. L. Tetrahedron Lett. 1997, 38, 1655.
15) (a) Guo, H.; O’Doherty, G. A. Angew. Chem., Int. Ed. 2007, 46,
206. (b) Babu, R. S.; Chen, Q.; Kang, S.-W.; Zhou, M.; O’Doherty, G.
A. J. Am. Chem. Soc. 2012, 134, 11952.
1
(
(
2
(
(
(
5
(
(
16) Zhou, M.; O’Doherty, G. A. Org. Lett. 2006, 8, 4339.
17) Wang, H.-y.; Yang, K.; Bennett, S. R.; Guo, S.-r.; Tang, W.
Angew. Chem., Int. Ed. 2015, 54, 8756.
18) (a) Fu, G. C. Acc. Chem. Res. 2004, 37, 542. (b) Mueller, C. E.;
Schreiner, P. R. Angew. Chem., Int. Ed. 2011, 50, 6012.
19) Taylor, J. E.; Bull, S. D.; Williams, J. M. J. Chem. Soc. Rev. 2012,
1, 2109.
20) (a) Birman, V. B.; Li, X. M. Org. Lett. 2006, 8, 1351. (b) Li, X.;
(
(
4
(
Jiang, H.; Uffman, E. W.; Guo, L.; Zhang, Y.; Yang, X.; Birman, V. B. J.
Org. Chem. 2012, 77, 1722.
(
(
(
21) Yang, X.; Lu, G.; Birman, V. B. Org. Lett. 2010, 12, 892.
22) Lu, G.; Birman, V. B. Org. Lett. 2011, 13, 356.
23) (a) Sheppard, C. I.; Taylor, J. L.; Wiskur, S. L. Org. Lett. 2011,
1
1
3, 3794. (b) Wang, L.; Akhani, R. K.; Wiskur, S. L. Org. Lett. 2015,
7, 2408.
D
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Org. Lett. XXXX, XXX, XXX−XXX