Stereoselective synthesis of β-L-rhamnopyranosides

Article abstract of DOI:10.1021/ja801574q

Stereoselective construction of 1,2-cis-β-l-rhamnopyranoside was achieved by our effective methodology using naphthylmethyl (NAP) ether-mediated intramolecular aglycon delivery (IAD). The complete stereoselective synthesis of the bacterial extracellular p

Full text of DOI:10.1021/ja801574q

Published on Web 04/24/2008
Stereoselective Synthesis of ꢀ-L-Rhamnopyranosides
Yong Joo Lee, Akihiro Ishiwata, and Yukishige Ito*
RIKEN (The Institute of Physical and Chemical Research),
2-1 Hirosawa, Wako, Saitama 351-0198, Japan
Received March 3, 2008; E-mail: yukito@riken.jp
Table 1. Results of ꢀ-L-Rhamnopyranosylations (Protocol C)a
In spite of remarkable progress in O-glycoside bond forming
reactions, the stereoselective synthesis of ꢀ-L-rhamnopyranosides
(ꢀ-L-Rha) remains challenging. Although its difficulty derives from
structural features similar to ꢀ-D-mannopyranosides (ꢀ-D-Man) (i.e.,
equatorial, 1,2-cis),1 the formation of ꢀ-L-Rha is by far more
difficult. The direct glycosylation strategy employed for ꢀ-D-Man
is not effective for ꢀ-L-Rha because the 6-deoxy structure of Rha
excludes the use of a donor with 4,6-O-cyclic (e.g., benzylidene)
protection,2 which is essential for the stereoselective ꢀ-D-Man
formation. Although ꢀ-D-Rha may be formed from ꢀ-D-Man through
deoxygenation,3 this strategy is not suitable for ꢀ-L-Rha because
of the limited availability of L-Man. In spite of various attempts
using structurally modified donors, such as 2,3-O-carbonate,4 2,3-
O-alkylidene,5 3,4-O-carbonate,6 2-ulosyl7 or 2-O-sulfonate,8 1,2-
O-stanylene acetal,9 and allyl-mediated IAD,10 there was limited
selectivity. We report herein the unprecedented stereoselective
synthesis of ꢀ-L-Rha through intramolecular aglycon delivery (IAD).
Our strategy exploits 2-naphthylmethyl (NAP) ether11,12 to make
a temporary linkage between donor and acceptor as a mixed acetal.
We recently found that NAP ether is highly favorable as a tether
for IAD. NAP-mediated IAD was found to be versatile, providing
ꢀ-D-mannopyranosides, ꢀ-D-arabinofuranosides, and R-D-glucopy-
ranosides in high yields and complete selectivity.13 ꢀ-L-Rha has
been discovered in various bacterial polysaccharides, such as
Sphaerotilus natans,14 Azotobacter beijerinckii TNM1,15 Salmonella
serogroup,16 Shigella boydii type 18,17 and Vibrio cholerae
NRT36S.18 These polysaccharides have (1f3)-ꢀ-L-Rhap substruc-
tures that are linked to GlcO-4, GlcO-3, ManO-2, RhaO-4, and
GlcNAcO-4, respectively. From examination of these structures, the
corresponding derivatives 9, 16, 17, 18, and 19 were chosen as
acceptors for this study (Table 1). As rhamnosyl donors, 2-O-NAP
equipped thioglycosides 4, 5, and 8 were designed, which were all
synthesized from thiorhamnoside 1.
a Conditions: (a) DDQ, MS 4Å, CH2Cl2, 0 °C, 4 h; (b) MeOTf,
DTBMP, MS 4Å (CH2Cl)2, 48 h. b Determined by 1H NMR after
isolation.
Scheme 1. Synthesis of Rhamnosyl Donors 4, 5, and 8a
Thus, compounds 4 and 5 were prepared through 3,4-O-diacetal
2 and 2-O-NAP ether 3, while preparation of compound 8 was
conducted via monobenzyl ether 6, which was regioselectively
alkylated to give compound 7 (Scheme 1). The capacity of these
donors was compared using the glucose derivative 9 as an acceptor.
The formation of mixed acetals (MAs) with 2,3-dichloro-5,6-
dicyanobenzoquinone (DDQ) under anhydrous conditions afforded
10 (89%, diastereomeric ratio 12:1), 11 (75%, diastereomeric ratio
7:1), and 12 (93%, diastereomeric ratio 25:1). To our delight,
subsequent IAD under standard conditions with MeOTf and 2,6-
di-tert-butyl-4-methylpyridine (DTBMP) proceeded smoothly. From
10 and 11, ꢀ-L-rhamnosides 13 (72%, JC1-H ) 162 Hz)20 and 14
(56%, JC1-H ) 164 Hz)20 were obtained as single isomers, after
acidic treatment and acetylation (Protocol A).
a Conditions: (a) (i) 2,3-butanedione, CH(OMe)3, CSA, MeOH, 86%,
(ii) NAPBr, NaH, DMF, 96%; (b) TFA, H2O, CH2Cl2, 97%; (c) for 4, BnBr,
NaH, DMF, 88%; (d) for 5, BzCl, DMAP, CH2Cl2, Et3N, 92%; (e) see ref
19; (f) NAPBr, NaH, DMF, 71%; (g) TMSCl, imidazole, DMF, 93%.
naphthylidene cyclic acetal 15,21 which was obtained in 83% yield
(JC1-H ) 164 Hz)20 (Scheme 2).
The operationally simple IAD of crude 12 was attempted
(Protocol C, Table 1), which gave 15 in a satisfactory yield of 68%
based on 9. The stereochemistry of the acetal carbon was assigned
as endo, based on a 1H NMR NOE experiment. Namely, NOE
correlations were observed between the naphthylidene acetal proton
A more favorable result was obtained with 3-O-TMS protected
MA 12 (Protocol B). In this case, the TMS ether intramolecularly
trapped the transiently generated benzylic cation to give the
9
6330 J. AM. CHEM. SOC. 2008, 130, 6330–6331
10.1021/ja801574q CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. NAP-Mediated IAD (Protocols A, B)a
under standard conditions to achieve the synthesis of 27, corre-
sponding to the substructure of S. natans polysaccharide14 (Scheme
4).
In conclusion, application of the novel naphthylmethyl ether-
mediated IAD toward the stereoselective construction of ꢀ-L-Rhap
was achieved with various acceptors in good yield. The complete
stereoselective synthesis of a trisaccharide, R-L-Rhap-(1f3)-ꢀ-L-
Rhap-(1f4)Glcp from S. natans, was successfully accomplished,
clearly suggesting the utility of NAP-IAD for ꢀ-L-rhamnopyrano-
sylation.
Acknowledgment. We thank Professor D. Crich (Wayne State
University) for directing our interest to ꢀ-rhamnosylation. This work
was partly supported by the Korea Research Foundation Grant
founded by the Korean Government (MOEHRD) (KRF-2006-352-
C00048), “Ecomolecular Science” and “Chemical Biology” pro-
grams in RIKEN, and a Grant-in-Aid for Encouragement of Young
Scientists from the Ministry of Education, Culture, Sports, Science,
and Technology (No. 18710196). We thank Dr. T. Chihara and his
staff for elementary analyses, and Ms. A. Takahashi for technical
assistance.
a Conditions: (a) DDQ, MS 4Å, CH2Cl2; (b) Protocol A for MA 10 and
11, (i) MeOTf, DTBMP, MS 4Å, (CH2Cl)2; (ii) TFA, CH2Cl2, then Ac2O,
DMAP, pyridine; Protocol B for MA 12, only (i). b Determined by 1H NMR
after isolation.
Scheme 3. Determination of Stereochemistry for 15 as endo
Supporting Information Available: Experimental procedures and
spectroscopic data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
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Scheme 4. Complete Stereoselective Synthesis of a Trisaccharide
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and the ring protons at C-2 and C-3 in the rhamnopyranoside
(Scheme 3).22
Having achieved the stereoselective synthesis of ꢀ-L-
Rhap(1f4)Glc (15), acceptors that correspond to Glc3-OH (16),
Man2-OH (17), Rha4-OH (18), and GlcNAc4-OH (19) were examined.
As expected, reactions with 8 gave desired products 20 [ꢀ-L-
Rhap(1f3)Glc],
21
[ꢀ-L-Rhap(1f2)Man],
22
[ꢀ-L-
Rhap(1f4)Rha], and 23 [ꢀ-L-Rhap(1f4)GlcN] in 64-71% yields
(Table 1).
With the aim of synthesizing bacterial glycans, regioselective
opening of the naphthylidene acetal was conducted to liberate the
3-OH of ꢀ-L-Rhap. DIBAL-H was suitable for this purpose, solely
giving 2-O-NAP ether 24 from 15. Subsequent R-L-rhamnopyra-
nosylation of 24 with trichloroacetimidate 2523 cleanly afforded
the desired trisaccharide 26 in high yield, which was deprotected
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3.98 (2.3%, H-2Rha) and δ 4.10 (1.0%, H-3Rha).
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2283–2290.
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