A double ring-closing metathesis approach for the synthesis of β-C-trisaccharides

Article abstract of DOI:10.1002/anie.200353478

Good things come in threes: A variety of β-C-trisaccharides have been successfully synthesized by double ring-closing metathesis, which provides the products in excellent overall yield after functionalization of the newly formed double bonds (see scheme).

Full text of DOI:10.1002/anie.200353478

Angewandte
Chemie
Carbohydrate Synthesis
A Double Ring-Closing Metathesis Approach for
the Synthesis of b-C-Trisaccharides**
Maarten H. D. Postema,* Jared L. Piper,
Venu Komanduri, and Lei Liu
The synthesis of C-glycosides, compounds in which the
interglycosidic oxygen atom has been replaced by a carbon
atom, has received considerable attention from both the
synthetic[1] and biological[2] point of view. They comprise an
important class of stable carbohydrate mimics and the debate
regarding their validity as conformational mimics of the
parent O-glycosides is ongoing.[3]
Scheme 1. Double RCM approach to C-trisaccharides. L=ligand,
M=metal.
Although there have been many interesting and unique
approaches to the synthesis of C-glycosides,[4] the preparation
of C-saccharides,[5] whether they are C-disaccharides or
higher homologues, has been considerably more challenging.
The first C-trisaccharide synthesis by Kishi and co-workers[6]
clearly showed that these compounds could be prepared and,
since that time, several other research groups[7] have targeted
these carbohydrate-based compounds for synthesis. There are
two main challenges associated with the synthesis of C-
saccharides. The first challenge is the difficulty associated in
functionalizing one carbohydrate ring (or open chain) fol-
lowed by its subsequent attachment to the anomeric center of
a second (or more) monosaccharide unit(s). To address this,
several approaches to the synthesis of a variety of differ-
entially linked C-saccharides[5] have been developed and we
have recently published a unified and versatile strategy for a
convergent and efficient synthesis of (1!6)-b-C-disacchar-
ides[8] and a variety of differentially linked b-C-disacchar-
ides.[9] Our ring-closing-metathesis (RCM)[10] approach is
flexible enough to deliver a wide variety of C-glycoside-type
structures.[11] We now report that our metathesis-based
approach can be used to efficiently synthesize a variety of
b-C-trisaccharides through a highly efficient double enol
ether–olefin RCM cyclization[12] that provides the products in
excellent overall yield after functionalization of the newly
formed double bonds.
followed by a double RCM reaction to give bis-C-glycal 5.
Functionalization of the bis-glycal double bonds then delivers
the b-C-trisaccharide 6.
In our previous C-disaccharide work[8,9] the installation of
only one acetyl group onto the pyranose ring was needed,
whereas in this case the preparation of a diacetyl derivative
was required. We permitted the nature of the diacid to dictate
the type of chemistry that would be used for its preparation.
Scheme 2 shows the use of both Wittig- and Keck-type
The general approach begins with dehydrative coupling of
olefin alcohol 1 with a suitable carbohydrate-based diacid
such as 2 to give diester 3 (Scheme 1). Methylenation of 3 is
Scheme 2. Preparation of diacid 2a. Bn=benzyl, NHS=N-hydroxysuc-
cinimide, AIBN=azobisisobutyronitrile.
[*] Prof. M. H. D. Postema, J. L. Piper, V. Komanduri, L. Liu
Department of Chemistry
allylation chemistry for the synthesis of diacid 2a. The
primary alcohol on 7[13] was oxidized, olefinated, and hydro-
genated, which served to reduce the double bond and cleave
the benzyl group, to furnish 8. The Robins-based[14] radical
precursor was then installed by using the N-hydroxysuccini-
mide method[15] and Keck allylation[16] then delivered com-
pound 9 as the sole isomer. Two-step oxidative cleavage of the
olefin in 9 to an intermediate monoacid was followed by
saponification to give diacid 2a.
Wayne State University
Detroit, MI 48202 (USA)
Fax: (+1)313-577-2554
E-mail: mpostema@chem.wayne.edu
[**] We gratefully acknowledge the National Science Foundation (Grant:
CHE-0132770) for support of this research. J.L.P. held a Willard R.
Lenz Fellowship and a David H. Green Fellowship. We thank Dr.
M. K. Ksebati (Wayne State University) for assistance with NMR
spectra collection and Prof. J. Santa Lucia and L. Clos II for
1
We relied upon a slightly different set of reactions to
prepare acid 2b (Scheme 3). Diol 10 was selectively esterified
to provide the stable keto-monophosphonate 11, after Swern
obtaining 700 MHz HNMR spectra.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200353478
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The stereochemistry of all the diacids, esters, and/or
allylated derivatives was rigorously established by NOE,
proton-decoupling and two-dimensional NMR spectroscopy
experiments. In theory, the esters could be differentiated and
distinctive olefin alcohols installed sequentially[20] but, in the
present work, we chose to install the same olefin alcohol on
each acid function. DCC-mediated coupling of diacid 2a with
two equivalents of alcohol 1a gave diester 3a in good yield
(Scheme 5). Methylenation[21] of 3a with an excess of the
Takai reagent and subsequent RCM with the second-gener-
ation Grubbs catalyst 17[22] (35 mol%) gave the intermediate
Scheme 3. Preparation of diacid 2b. DCC=N,N’-dicyclohexylcarbodi-
imide.
oxidation of the remaining secondary alcohol. Masa-
mune–Roush olefination[17] gave an intermediate
unsaturated lactone that, under a variety of different
reduction conditions, gave exclusively lactone 12
possessing the galacto configuration at the C4 posi-
tion. Methanolysis of 12, according to the conditions
of Corey et al.,[18] was followed by oxidation and
Wittig reaction to form 13. Reduction of the olefin
was followed by bis-saponification to deliver the 4,6-
diacid 2b in good overall yield (Scheme 3).
Diacid 2c was prepared by a slightly different
strategy, as shown in Scheme 4. Known olefin 14[9]
was converted into a,b-unsaturated ester 15 in three
steps, and conjugate reduction[19] was followed by
oxidative cleavage of the remaining double bond to
afford 16. Oxidation and saponification of 16 then
delivered the target diacid 2c in good overall yield
(Scheme 4).
Scheme 5. Double RCM synthesis of b-C-trisaccharides. 4-DMAP=4-dimethylami-
nopyridine, TMEDA=N,N,N’,N’-tetramethylethylenediamine, Mes=b-morpholi-
noethanesulfonic acid, Cy=cyclohexyl, THF=tetrahydrofuran.
bis-C-glycal 5a. The bis-C-glycal was not isolated but instead
was directly subjected to hydroboration by BH3·THF.[23]
Subsequent oxidative workup then afforded the C-trisacchar-
ide 6a in 49% yield over three steps.[24]
Table 1 shows the examples that have been prepared thus
far. Ester formation (1 + 2!3), mediated by DCC and 4-
DMAP, proved to be routine, except for the case shown in
entry 5 (Table 1). Alarge excess of the methylenating reagent
was required for the methylenation (3!4) reactions to be
driven to completion. In all the cases, 35–40 mol% of the
RCM catalyst 17 was needed to achieve a complete reaction.
It is noteworthy that the three-step protocol works quite well
even when both groups to be cyclized are on the same side of
the pyranose ring, as in 3b (entry 2, Table 1). No evidence of
other cyclized products was noted by thin-layer chromatog-
raphy (TLC) or crude NMR spectroscopy of the crude
reaction mixtures. In one case (entry 8), we isolated the bis-
glycal 5h, since hydroboration gave a mixture of two
inseparable products.
Scheme 4. Preparation of diacid 2c.
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Table 1: Synthesis of b-C-trisaccharides by double RCM.[a]
The above results show that our double
Entry
Diester 3
C-Trisaccharide 6[b]
RCM approach for C-trisaccharide synthesis is
viable and efficient. Application of this meth-
odology to other congeners is currently under-
way and will be reported in due course.
1
Received: December 8, 2003
Revised: March 8, 2004 [Z53478]
3a: 89%
6a: 49%
Keywords: carbohydrates · cyclization ·
.
ring-closing metathesis · synthesis design ·
trisaccharides
2
[1] For reviews on C-glycoside synthesis, see: a) Y.
Du, R. J. Linhardt, I. R. Vlahov, Tetrahedron
1998, 54, 9913 – 9959; b) J.-M. Beau, T. Gal-
lagher, Top. Curr. Chem. 1997, 187, 1 – 54; c) F.
Nicotra, Top. Curr. Chem. 1997, 187, 55 – 83.
[2] C. Bertozzi, M. Bednarski in Modern Methods
in Carbohydrate Synthesis (Eds.: S. H. Khan,
R. A. O. O'Neil), Harwood Academic Publish-
ers, Amsterdam, 1996, pp. 316 – 351.
[3] a) A. Wei, A. Haudrechy, C. Audin, H.-S. Jun,
N. Haudrechy-Bretel, Y. Kishi, J. Org. Chem.
1995, 60, 2160 – 2169; b) J. L. Asensio, J. F.
Espinosa, H. Dietrich, F. J. Caæada, R. R.
Schmidt, M. Martín-Lomas, S. AndrØ, H.-J.
Gabius, J. JimØnez-Barbero, J. Am. Chem. Soc.
1999, 121, 8995 – 9000; c) G. Rubinstenn, P.
Sinay¨, P. Berthault, J. Phys. Chem. A 1997,
101, 2536 – 2540, and references therein.
3b: 84%
6b: 55%
3
4
5
3c: 74%
6c: 57%
3d: 88%
6d: 59%
[4] a) M. H. D. Postema, C-Glycoside Synthesis,
CRC Press, Boca Raton, 1995; b) D. E. Levy,
C. Tang, The Chemistry of C-Glycosides,
Vol. 13, Elsevier Science, Oxford, 1995.
[5] For a review of C-saccharide synthesis, see: M.
McKee, L. Liu, M. H. D. Postema, Curr. Org.
Chem. 2001, 5, 1133 – 1167.
3e: 48%[c]
6e: 33%[d]
[6] T. Haneda, P. G. Goekjian, S. H. Kim, Y. Kishi,
J. Org. Chem. 1992, 57, 490 – 498.
6
7
[7] For some recent synthetic approaches to C-
trisaccharides, see: a) A. Dondoni, A. Marra,
Tetrahedron Lett. 2003, 44, 4067 – 4071; b) L. M.
Mikkelsen, S. L. Krintel, J. JimØnez-Barbero, T.
Skrydstrup, J. Org. Chem. 2002, 67, 6297 – 6308;
c) D. P. Sutherlin, R. W. Armstrong, J. Org.
Chem. 1997, 62, 5267 – 5283; d) D. P. Sutherlin,
R. W. Armstrong, J. Am. Chem. Soc. 1996, 118,
9802 – 9803.
[8] M. H. D. Postema, D. Calimente, L. Liu, T. L.
Behrmann, J. Org. Chem. 2000, 65, 6061 – 6068.
[9] M. H. D. Postema, J. L. Piper, L. Liu, J. Shen, M.
Faust, P. Andreana, J. Org. Chem. 2003, 68,
4748 – 4754.
3 f: 88%
6 f: 50%
3g: 87%
6g: 53%
8
[10] For a review on the use of olefin metathesis in
carbohydrate chemistry, see: M. Jørgensen, P.
Hadwiger, R. Madsen, A. E. Stütz, T. M. Wrod-
nigg, Curr. Org. Chem. 2000, 4, 565 – 588.
3h: 76%
6h: 57%[e]
[a] Yields refer to chromatographically homogeneous material. Yields are for three steps:
methylenation, RCM (35–40 mol% of 17), and hydroboration/oxidative workup. [b] Stereo- [11] M. H. D. Postema, J. L. Piper, Org. Lett. 2003, 5,
chemistry at the C1 and C2 positions was determined by acetylation and analysis of the H2
coupling constant in the HNMR spectra. [c] A fair amount of recovered mono-1,6-ester
was isolated from the reaction mixture. [d] In this case, the RCM reaction was stopped early
and the bis-C-glycal was isolated, purified (48%, unoptimized), and then subjected to
hydroboration (66%, unoptimized). [e] In this case, the yield is for two steps (methylen-
ation and RCM) since hydroboration gave an inseparable mixture of two isomers.
1721 – 1723.
1
[12] For examples of double RCM reactions, see:
a) R. H. Grubbs, G. C. Fu, J. Am. Chem. Soc.
1992, 114, 7324 – 7325; b) D. J. Wallace, P. G.
Bulger, D. J. Kennedy, M. S. Ashwood, I. F.
Cottrell, U.-H. Dolling, Synlett 2001, 3, 357 –
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Communications
360; c) D. J. Wallace, C. J. Cowden, D. J. Kennedy, M. S. Ash-
wood, I. F. Cottrell, U.-H. Dolling, Tetrahedron Lett. 2000, 41,
2027 – 2029; d) B. Schmidt, H. Wildemann, J. Chem. Soc. Perkin
Trans. 1 2000, 2916 – 2925; e) J. S. Clark, O. Hamelin, Angew.
Chem. 2000, 112, 380 – 382; Angew. Chem. Int. Ed. 2000, 39, 372 –
374, and references therein.
[13] The corresponding a anomer is known: S. Knapp, P. J. Kukkola,
J. Org. Chem. 1990, 55, 1632 – 1636.
[14] M. J. Robins, J. S. Wilson, J. Am. Chem. Soc. 1981, 103, 932 – 933.
[15] D. H. R. Barton, J. C. Jaszberenyi, Tetrahedron Lett. 1989, 30,
2619 – 2622.
[16] G. E. Keck, E. J. Enholm, J. B. Yates, M. R. Wiley, Tetrahedron
1985, 41, 4079 – 4094.
[17] M. A. Blanchette, W. Choy, J. T. Davis, A. P. Essenfeld, S.
Masamune, W. R. Roush, T. Sakai, Tetrahedron Lett. 1984, 25,
2183 – 2186.
[18] E. J. Corey, W.-g. Su, M. B. Cleaver, Tetrahedron Lett. 1989, 30,
4181 – 4184.
[19] M. Narisada, I. Horibe, F. Watanabe, K. Takeda, J. Org. Chem.
1989, 54, 5308 – 5313.
[20] For example, by preparing a tert-butyl ester and an ethyl ester.
[21] K. Takai, T. Kakiuchi, Y. Kataoka, K. Utimoto, J. Org. Chem.
1994, 59, 2668 – 2670.
[22] M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett. 1999, 1,
953 – 956.
[23] a) S. Hanessian, M. Martin, R. C. Desai, J. Chem. Soc. Chem.
Commun. 1986, 926 – 927; b) R. R. Schmidt, R. Preuss, R. Betz,
Tetrahedron Lett. 1987, 28, 6591 – 6594.
[24] All new compounds were fully characterized by 1H, 13C, DEPT,
GCOSY, and GHMQC NMR spectroscopy, IR spectroscopy,
exact mass spectrometry, and optical rotation measurements.
See the Supporting Information for further details.
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