Synthesis of 2,6-dideoxysugars via ring-closing olefinic metathesis.

Article abstract of DOI:10.1021/ol026710m

[formula: see text] Grubbs' RuCl2 (=CHPh)(PCy3)2 (catalyst 1) and RuCl2(=CHPh)(PCy3)(IMess) (catalyst 2) complexes have been successfully utilized in the construction of beta,gamma-unsaturated delta-lactones containing various substitution patterns of methyl groups. Asymmetric dihydroxylation followed by reduction leads to 3,4-cis-dihydroxy-2,6-dideoxypyranoses, which have proven to play very important biological roles as key components of natural products.

Full text of DOI:10.1021/ol026710m

ORGANIC
LETTERS
2002
Vol. 4, No. 22
3875-3878
Synthesis of 2,6-Dideoxysugars via
Ring-Closing Olefinic Metathesis
Peter R. Andreana, Jason S. McLellan, Yongchen Chen, and Peng George Wang*
Department of Chemistry, Wayne State UniVersity, Detroit, Michigan
pwang@chem.wayne.edu
Received August 9, 2002
ABSTRACT
Grubbs’ RuCl2(dCHPh)(PCy3)2 (catalyst 1) and RuCl2(dCHPh)(PCy3)(IMess) (catalyst 2) complexes have been successfully utilized in the
construction of â,γ-unsaturated δ-lactones containing various substitution patterns of methyl groups. Asymmetric dihydroxylation followed
by reduction leads to 3,4-cis-dihydroxy-2,6-dideoxypyranoses, which have proven to play very important biological roles as key components
of natural products.
The ring-closing metathesis (RCM) reaction continues to play
a powerful role in the construction of complex organic
molecules.1 The development of ruthenium carbene com-
plexes (1 and 2 Figure 1) by Grubbs and co-workers is
availability.2 Although used extensively to form large-
membered macrocycles and nitrogen-containing heterocylces,
only a few examples are found in the literature for the
formation of R,â-unsaturated γ- and δ-lactones.3 To the best
of our knowledge, there is no precedence for the RCM
production of â,γ-unsaturated δ-lactones.
Deoxysugars and deoxysugar oligosaccharides are impor-
tant integrated components in biological systems.4 Because
of the high density of stereogenic centers in these com-
pounds, their synthesis from nonchiral compounds represents
a challenge for synthetic chemists. All diastereomers of the
2,6-dideoxypyranoses have been previously synthesized
and are all found in nature in medicinally interesting
glycosides.5 Our strategy for the synthesis of 2,6-dideoxy-
pyranosides was to utilize the RCM reaction for the forma-
Figure 1. Grubbs first (1) and second (2) generation catalysts.
(2) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953-956. (b) Fu, G. C.; Nguyen, S. B. T.; Grubbs, R. H. J. Am. Chem.
Soc. 1993, 115, 9856-9857. (c) Nyguyen S. B. T.; Grubbs, R. H.; Ziller,
J. W. J. Am. Chem. Soc. 1993, 115, 9858-9859.
particularly notable because of the remarkable functional
group tolerance, operational simplicity, high stability, and
(1) For recent reviews see: (a) Trnka, T. M.; Grubbs, R. H. Acc. Chem.
Res. 2001, 34, 18-29. (b) Maier, M. E. Angew. Chem., Int. Ed. 2000, 39,
2073-2077. (c) Furstner, A. Angew. Chem., Int. Ed. 2000, 39, 3013-
3043. (d) Jorgensen, M.; Hadwiger, P.; Madsen, R.; Stutz, A. E.; Wrodnigg,
T. M. Curr. Org. Chem. 2000, 4, 565-588. (e) Wright, D. L. Curr. Org.
Chem. 1999, 3, 211-240. (f) Grubbs, R. H.; Chang, S. Tetrahedron 1998,
54, 4413-4450. (g) Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998,
371-388. (h) Blechert, S.; Schuster, M. Angew. Chem., Int. Ed. Engl. 1997,
36, 2036-2056.
(3) For R,â-unsaturated γ-lactones see: (a) Furstner, A.; Dierkes, T. Org.
Lett. 2000, 2, 2463-2465. For R,â-unsaturated γ- and δ-lactones see: (b)
Cossy, J.; Bauer, D.; Bellosta, V. Tetrahedron Lett. 1999, 40, 4187-4188.
(c) Ghosh, A. K.; Liu, C. Chem. Commun. 1999, 17, 1743-1744. (d)
Nicolaou, K. C.; Rodriguez, R. M.; Mitchell, H. J.; van Delft, F. L. Angew.
Chem., Int. Ed. 1998, 37, 1874-1876. (e) Ghosh, A. K.; Cappiello, J.; Shin,
D. Tetrahedron Lett. 1998, 39, 4651-4654.
(4) Kirschning, A.; Bechtholdt, A. F. W.; Rohr, J. Top. Curr. Chem.
1997, 188, 1-84.
10.1021/ol026710m CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/01/2002

tion of â,γ-unsaturated δ-lactones. Asymmetric dihydroxy-
lation (AD) of these highly functionalized compounds
followed by borohydride reduction would result in the
desired compounds. The dihydroxylation of these â,γ-
unsaturated cyclic systems introduces cis-hydroxyl groups
in the C(4)- and C(5)-positions of the δ-lactone. Our route,
which starts from simple precursors, is amenable to variations
at several positions and proves valuable in the diastereose-
lective synthesis of an array of highly functionalized δ-lac-
tones, which can be easily converted to 2,6-dideoxypyrano-
sides.
Scheme 2. Preparation of Stereodefined Olefinic Esters
Our reaction sequence takes advantage of the formation
of simple homoallylic esters. First, acids 4a-c were prepared
via a Grignard reaction (Scheme 1).6 By introducing readily
Esterification followed by reduction with Lindlar’s catalyst
proved to be the method of choice for producing both the
(R)- [corresponding to (D)] and (S)- [corresponding to (L)]
enantiomers for the construction of pyranosides.
Scheme 1. Grignard Syntheses of Homoallylic Acids
The ring-closing metathesis of compounds 6a-j proceeded
in high yields. Grubbs’ RuCl2(dCHPh)(PCy3)2 catalyst 1
proved to be efficient for compounds 6a,c,d,g-j, producing
yields similar to those obtained with the use of RuCl2-
(dCHPh)(PCy3)(IMes) catalyst 2, as illustrated in Table 2.
Reaction conditions were optimized to run in either dichlo-
romethane or chloroform under refluxing conditions in the
0.01 M range. It was observed that under increased concen-
tration conditions (i.e., >0.01 M), a cross-metathesis product
would arise with the use of both 1 and 2.9
available homoallylic alcohols 5a and 5b, compounds 6a-f
were prepared via a Fisher esterification by employing an
inverse Dean-Stark trap utilizing chloroform as the azeotro-
ping solvent (Table 1).7 It is important to note that esterifi-
The major difference between the two catalysts is their
relative reactivity. Catalyst 1 worked best at 5 mol %,
whereas catalyst 2 worked on a 1 mol % scale. Also entry
6 in Table 2 illustrates the formation of a tetrasubstituted
olefin in which catalyst 1 gave no evidence of the δ-lactone.
This reactivity difference can be reasoned that due to the
lack of carbene stabilization provided by the absence of
π-interactions, the imidazole ligand is more basic than the
tricyclohexylphosphine analogue. The higher basicity trans-
lates into an increased activity of RuCl2(dCHPh)(PCy3)-
(IMes) (catalyst 2).2a In an attempt to optimize the reaction
conditions, various amounts of Ti(OiPr)4 were added.3a-c,e,10
The rationale for its addition has to do with alleviating the
formation of a seven-membered stable metal complex in
which the Ru chelates to the carbonyl oxygen of the ester,
which can potentially slow the conversion rate. GC monitor-
Table 1. Utilizing an Inverse Dean-Stark Trap for the
Formation of Terminal Substituted Olefinic Esters
(5) (a) Ulven, T.; Carlsen, P. H. J. Eur. J. Org. Chem. 2001, 3367-
3374 (and references therein). (b) Shafer, C. M.; Molinski, T. F. Carbohydr.
Res. 1998, 310, 223-228. (c) Roush, W. R.; Straub, J. A. Tetrahedron
Lett. 1986, 27, 3349-3352. (d) Bock, K.; Lundt, I.; Pedersen, C.; Refn, S.
Acta Chem. Scand. 1986, B40, 740-744. (e) Roush, W. R.; Brown, J. R.
J. Org. Chem. 1983, 48, 5093-5101. (f) Chmielewski, M. Tetrahedron
1979, 35, 2067-2070.
(6) Oppolzer, W.; Kuendig, E. P.; Bishop, P. M.; Perret, C. Tetrahedron
Lett. 1982, 23, 3901-3904.
(7) Harcken, C.; Bruckner, R.; Rank, E. Chem. Eur. J. 1998, 4, 2342-
2352.
(8) DCC coupling provided the desired ester in high yield but the
unwanted dicyclohexylurea byproduct proved difficult to remove.
(9) (a) Toste, D. F.; Chatterjee, A. K.; Grubbs, R. H. Pure Appl. Chem.
2002, 74, 7-10. (b) Goldberg, S. D.; Grubbs, R. H. Angew. Chem., Int.
Ed. 2002, 41, 807-810 (and references therein). (c) Sukkari, H. E.; Gesson,
J.-P.; Renoux, B. Tetrahedron Lett. 1998, 39, 4043-4046.
(10) Furstner, A.; Langemann, K. J. Am. Chem. Soc. 1997, 119, 9130-
9136.
cation did not work efficiently under Fisher conditions with
azeotroping solvents toluene or benzene.8 Ester precursors
for D- and L-pyranosides were prepared from readily available
chiral propargylic alcohols (-)-(S)-7a and (+)-(R)-7b (Scheme
2).
3876
Org. Lett., Vol. 4, No. 22, 2002

The use of methanesulfonamide in the reaction led to product
degredation. Commercially available AD-mixes consist of
0.4 mol % K2[OsO2(OH)4], 1 mol % (DHQD)2PHAL (AD-
mix â) or (DHQ)2PHAL (AD-mix R), 3 equiv of K3[Fe-
(CN)6], and 3 equiv of K2CO3.13 In the case of internal
olefins, the addition of at least a stoichiometric amount of
a hydrolysis aid such as Et4NOAc or MeSO2NH2 is
required to obtain reasonable reaction rates due to hydrolysis
problems or sterically hindered intermediate osmate esters.
It was found that the optimal reaction conditions were
met when the substrates were subjected to mild basic
conditions such as 1.5 M KH2PO4 at pH 10.1, 4 mol % K2-
OsO2(OH)4, 3 equiv of K3Fe(CN)6, and 5 mol % ligand. It
is known that internal olefins react best at pH values between
11.2 and 12 due to an enhanced hydrolysis of the intermedi-
ate osmate esters under strong basic conditions.14 It was
observed that the diastereoselectivity of the reaction was
lower when the reaction was run with high pH values (ca.
pH 12.0).
Table 2. Synthesis of Methyl-Substituted δ-Lactones via
Ring-Closing Metathesis
With achiral substrates, the chiral ligand induces the
expected configuration according to the Sharpless mnemonic
(Scheme 3). However, when the methodology was applied
Scheme 3. Asymmetric Dihydroxylation for the Synthesis of
2-Deoxyribolactone
a Reaction concentration was 0.01 M. b Isolated yield from column
chromatography. N/A ) no attempt; NR ) no reaction.
a Key: (a) Na(CN)BH3, 1.0 M AcOH/AcONa pH 5.2.
ing provided direct evidence for complete conversion.
Column chromatography ensued after each â,γ-unsaturated
δ-lactone formed for the purposes of removing the cross-
metathesis product (<1% w/w) and Ru catalyst.11 Com-
pounds 8b and 8e (entries 2 and 5, Table 2) proved to
be relatively unstable at room temperature and quickly
decomposed into the more highly stable conjugated com-
pounds.
to those compounds of preset chirality (entries 1-8, Table
3), the desired dihydroxylated compound had a tendency to
arise as a mixture of diastereomers in the “mismatched”
cases. These diastereomers were purified by column chro-
matography. The diastereomeric ratios were calculated from
data obtained by NMR and confirmed by utilizing a
Chiraldex B-PH 30 m × 0.32 mm capillary GC column (â-
cyclodextrin permethylated hydroxypropyl) by first convert-
ing the free hydroxyls to the trifluoroacetates. Attempts
to invoke the dihydroxylation in the absence of the chiral
ligand gave an 80:20 mix with compounds 9c, 9e, 9g, and
9j.
The asymmetric dihydroxylation was attempted utilizing
a number of procedural protocols.12 The readily available
AD-mix (both R and â) gave both poor yields and low d.r.
(11) For the removal of ruthenium byproducts see: (a) Ahn, Y. M.; Yang,
K. L.; Georg, G. I. Org. Lett. 2001, 3, 1411-1413. (b) Paquette, L. A.;
Schloss, J. D.; Efremov, I.; Fabris, F.; Gallou, F.; Mendez-Andino, J.; Yang,
J. Org. Lett. 2000, 2, 1259-1261. (c) Maynard, H. D.; Grubbs, R. H.
Tetrahedron Lett. 1999, 40, 4137-4140.
(12) Reviews: (a) Kolb, H. C.; Van Nieuwenhze, M. S.; Sharpless, K.
B. Chem. ReV. 1994, 94, 2483-2547. (b) Johnson, R. A.; Sharpless, K. B.
Asymmetric Catalysis in Organic Synthesis; Ojima, I., Ed.; VCH: New
York, 1993; pp 227-272. (c) Lohray, B. B. Tetrahedron: Asymmetry 1992,
3, 1317-1349.
(13) Preparation of AD mixes: Sharpless, K. B.; Amberg, W.; Bennani,
Y. L.; Crispino, G. A.; Hartung, J.; Jeong, K.-S.; Kwong, H. L.; Morikawa,
K.; Wang, Z. M.; Xu, D.; Zhang, X. L. J. Org. Chem. 1992, 57, 2768-
2771.
(14) Mehltretter, G. M.; Dobler, C.; Sundermeier, U.; Beller, M.
Tetrahedron Lett. 2000, 41, 8083-8087.
Org. Lett., Vol. 4, No. 22, 2002
3877

Table 3. Conversion of â,γ-Unsaturated δ-Lactones to 2,6-Dideoxysugars
a Overall yield after chromatography based on the starting â,γ-unsaturated δ-lactones. b c ) 1.0, D2O.
Reduction of the lactone to the lactol was accomplished
with aqueous Na(CN)BH3 to give the final 2,6-dideoxysugar.
In conclusion, we have demonstrated a feasible route into
2,6-dideoxysugars employing a RCM and an AD strategy.
This chemistry provides an avenue into a number of â,γ-
unsaturated δ-lactones that can be easily converted into an
array of deoxygenated sugar derivatives. We have found that
the use of Ti(OiPr)4 as a chelating agent was not required in
the RCM reaction, but did serve to expedite the overall
reaction (16 h to 6 h). Asymmetric dihydroxylation of
chirally biased molecules provided access into the cis-
hydroxyl diastereomers.
Acknowledgment. We thank the Herman Frasch Foun-
dation, grant no. 449-HF97, administered by the American
Chemical Society, as well as the Dryfus Foundation for a
Jean Dreyfus Boissevain Undergraduate Scholarship for
J.S.M. P.R.A. gratefully recognizes important discussions
with Dr. M. S. Van Nieuwenhze.
Supporting Information Available: Detailed descrip-
tions of experimental procedures, as well as a listing of all
spectroscopic data. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL026710M
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Org. Lett., Vol. 4, No. 22, 2002