Preparation of C-1 glycals via olefin metathesis. A convergent and flexible approach to C-glycoside synthesis

Full text of DOI:10.1021/jo982331o

1770
J . Org. Chem. 1999, 64, 1770-1771
Initial work by Grubbs10 established the viability of this
ring closure with simple substrates. Later work by Nico-
laou11 focused on the one-pot preparation of cyclic enol ethers
directly from esters using stoichiometric titanium reagents.12
More recently, the preparation of cyclic enol ethers from
olefinic acyclic enol ethers using a two-step protocol was re-
ported.13,14 While this work was underway, Rainier15 re-
ported an olefin-enolether metathesis-based method of fus-
ing glycals onto existing carbohydrates. In addition, scien-
tists at Merck Frosst16 found that some carbohydrate-derived
unsubstituted (on the enol ether olefin) enol ethers can
undergo ring-closing metathesis with the use of 2b to give
glycals.
In this paper, we outline our preliminary results for the
synthesis of C-1 glycals by an olefin-enol ether metathetical
coupling approach. To have the structural diversity needed
to prepare a variety of C-glycoside compounds, we needed a
general approach to the sugar-based coupling partner 3.
Accordingly, treatment of 3,4,6-tri-O-benzyl-D-glucal (10)
with ozone in dichloromethane at low temperature followed
by reductive workup and deprotection of the formyl group
gave lactol 12 as a mixture of inseparable anomers (91%).
Wittig reaction, along ample literature precedent,8 furnished
olefins 13 as a 1:1 mixture (73%, 1H NMR, 500 MHz) of
partially separable isomers. Acetylation then provided 15
in quantitative yield demonstrating that diversity in the
sugar portion is possible.17 We employ commercially avail-
able 2,3,5-tri-O-benzyl-â-D-arabinofuranoside (12â)18 as our
starting material for the Wittig olefination19 reaction to
prepare hydroxy-olefin 14.
P r ep a r a tion of C-1 Glyca ls via Olefin
Meta th esis. A Con ver gen t a n d F lexible
Ap p r oa ch to C-Glycosid e Syn th esis1
Daniel Calimente and Maarten H. D. Postema*
Department of Chemistry, Wayne State University,
Detroit, Michigan 48202
Received November 25, 1998
The recent interest in olefin metathesis is attested by the
abundance of work that has appeared dealing with this new2
and exciting approach to carbon-carbon bond formation.3
This is largely due to the availability of effective catalyst
systems such as 14 and 25 used to carry out this mild6 and
selective transformation.
Metathesis chemistry has been applied to many types of
systems,3 and its use has started to find application in the
carbohydrate field.7 C-Glycosides,8 compounds in which the
glycosidic oxygen atom has been replaced by a carbon-based
group,9 are biologically relevant compounds that have
potential as enzyme inhibitors and stable sugar mimics.
Conceptually, we felt that olefin metathesis and C-glycoside
chemistry would mesh together quite well to provide a
convergent and flexible route to a wide variety of C-1 glycals
(eq 2). The sequence begins with a dehydrative coupling of
The ester precursors, except for 16a (Ac2O, 4-DMAP), were
prepared by DCC-mediated coupling of 14 with the ap-
an appropriate olefin alcohol 3 with the requisite acid 4 to
give ester 5. Ring-closing metathesis, either via a one- or
two-pot method, is then expected to give the C-1 glycal 7.
Compound 7 will then serve as an intermediate to both the
â-C-glycosides with the general structures 8 and 9 available
from 7 by hydroboration (followed by oxidative workup) or
stereoselective reduction, respectively.
(5) (a) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H. J . Am. Chem. Soc. 1993,
115, 9856-9857. (b) Nguyen, S. T.; J ohnson, L. K.; Grubbs, R. H.; Ziller, J .
W. J . Am. Chem. Soc. 1992, 114, 3974-3975. (c) Nguyen, S. T.; Grubbs, R.
H.; Ziller, J . W. J . Am. Chem. Soc. 1993, 115, 9858-9859. (d) Schwab, P.;
France, M. B.; Ziller, J . W.; Grubbs, R. H. Angew. Chem., Int. Ed. Engl.
1995, 34, 2039-2041.
(6) For newly developed ruthenium-based metathesis catalysts, see: (a)
Weskamp, T.; Schattenmann, W. C.; Spiegler, M.; Herrmann, W. A. Angew.
Chem., Int. Ed. Engl. 1998, 37, 2490-2493. (b) Wolf, J .; Stu¨er, W.;
Gru¨nwald, C.; Werner, H.; Schwab, P.; Schulz, M. Angew. Chem., Int. Ed.
Engl. 1998, 37, 1124-1126.
(7) For some recent examples of the application of the olefin metathesis
reaction to carbohydrates, see: (a) Sturino, C. F.; Wong, J . C. Y. Tetrahedron
Lett. 1998 39, 9623-9626. (b) El Sukkari, H.; Gesson, J . P.; Renoux, B.
Tetrahedron Lett. 1998, 39, 4043-4046. (c) O’Leary, D. J .; Blackwell, H.
E.; Washenfelder, R. A.; Grubbs, R. H. Tetrahedron Lett. 1998, 39, 7427-
7430.
(1) Dedicated to the memory of Professor Michael G. Hogben, Concordia
University, Montreal.
(2) (a) Evans, P. A.; Murthy, V. S. J . Org. Chem. 1998, 63, 6768-6769.
(b) Limanto, J .; Snapper, M. L. J . Org. Chem. 1998, 63, 6440-6441. (c) La,
D. S.; Alexander, J . B.; Cefalo, D. R.; Graf, D. D.; Hoveyda, A. H.; Schrock,
R. R. J . Am. Chem. Soc. 1998, 120, 9720-9721. (d) Renaud, J .; Ouellet, S.
G. J . Am. Chem. Soc. 1998, 120, 7995-7996. (e) Zuercher, W. J .; Scholl,
M.; Grubbs, R. H. J . Org. Chem. 1998, 63, 4291-4298.
(3) For recent reviews on olefin metathesis chemistry, see: (a) Grubbs,
R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450. (b) Ivin, K. J . J . Mol.
Catal. A-Chem. 1998, 133, 1-16. (c) Randall, M. L.; Snapper, M. L. J . Mol.
Catal. A-Chem. 1998, 133, 29-40. (d) Armstrong, S. K. J . Chem. Soc.,
Perkin Trans. 1 1998, 371-388. (e) Schuster, M.; Blechert, S. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 2036-2056. (f) Fu¨rstner, A. Top. Catal. 1997, 4,
285-299.
(8) For reviews on C-glycoside synthesis, see: (a) Du, Y.; Lindhart, R. J .
Tetrahedron 1998, 54, 9913-9959. (b) Togo, H.; He, W.; Waki, Y.; Yokoyama,
M. Synlett 1998, 700-717. (c) Postema, M. H. D.C-Glycoside Synthesis, 1st
ed.; CRC Press: Boca Raton, 1995. (d) Levy, D. E.; Tang, C. The Chemistry
of C-Glycosides, 1st ed.; Elsevier Science: Oxford, 1995; Vol. 13.
(9) For some recent examples of C-glycoside synthesis see: (a) Wamhoff,
H.; Warnecke, H.; Sohar, P.; Csampai, A. Synlett 1998, 1193-1194. (b) Polat,
T.; Du, Y.; Linhardt, R. J . Synlett 1998, 1195-1196. (c) Buffet, M. F.; Dixon,
D. J .; Ley, S. V.; Tate, E. W. Synlett 1998, 1091-1092. (d) Belica, P. S.;
Franck, R. W. Tetrahedron Lett. 1998, 39, 8225-8228.
(4) (a) Schrock, R. R.; Murdzek, J . S.; Bazan, G. C.; Robbins, J .; DiMare,
M.; O’Regan, M. J . Am. Chem. Soc. 1990, 112, 3875-3886. (b) Feldman, J .;
Murdzek, J . S.; Davis, W. M.; Schrock, R. R. Organometallics 1989, 8, 2260-
2265.
(10) Fujimura, O.; Fu, G. C.; Grubbs, R. H. J . Org. Chem. 1994, 59, 4029-
4031.
10.1021/jo982331o CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/20/1999

Communications
J . Org. Chem., Vol. 64, No. 6, 1999 1771
Ta ble 1. P r ep a r a tion of C-1 Glyca ls fr om Olefin Ester s
recovered starting material 17a (∼20%) as well as some of
alcohol 14 (∼15%), the latter product arising from hydrolysis
of the acyclic enol ether 17a .
Operationally, the reagents were weighed out in a glove-
box, and the reaction was then heated under argon on the
bench. If the reagents and substrate were weighed in the
box and the reaction then heated in the box the yield of the
ring closure (17a f 18a ) increased to 72%. Similar observa-
tions, with regard to catalyst handling,22 have been re-
ported.23 Table 1 shows some of the substrates that were
examined.
Both alkyl (entries 1-2) and cycloalkyl (entry 4) substit-
uents posed no problem for the ring-closing metathesis
(RCM) reaction when 25 mol % of 1 was employed. The
presence of the benzyloxy substituent adjacent to the olefin
did not seem to impede the metathesis reaction. No acyclic
enol ether was formed when 16c (entry 3) was subjected to
an excess of the the standard reagent. The cinnamyl deriva-
tive 16e (entry 5) was readily methylenated (62%) to 17e,
but in our hands, attempted ring-closing metathesis with 1
gave only recovered 17e (95%). Several aromatic substrates
were also examined (16f-h ) and gave acceptable yields of
products, but required the use of 50 mol % of 1 in order to
obtain the results shown. Naphthyl ester 16i (entry 9) gave
a good yield of the methylenation product 17i, but we have
not yet been able to improve the yield for the RCM step.
This is due to competitive formation24 of a second as of yet
unidentified product. The less sterically encumbered â-naph-
thyl derivative 17j (entry 10) underwent smooth RCM to give
18j (68%).
In summary, we have demonstrated that a variety of C-1
glycals can be prepared via a highly convergent and efficient
esterification-metathesis protocol.
a
Yields refer to chromatographically homogeneous (1H NMR,
b
400 MHz) material. Reaction was carried out on 40-70 mg scale
Ack n ow led gm en t. We are grateful to Wayne State
University for financial support. This work was also
partially supported by the PRF (No. 33075-G1).
at 0.01-0.02 M in substrate using 25 mol % 1 for entries 1-4 and
50 mol % 1 for entries 6-10. c Reaction was carried out using Ac2O,
4-DMAP. Reaction was carried out in the glove box. e Reaction
d
was carried out under argon (rubber septum) on the benchtop.
f Reaction was not carried out. Only starting material was
g
Su p p or tin g In for m a tion Ava ila ble: Copies of experimental
procedures for the preparation of 11-13 and 16-18 and spectral
data listings for 11-13, 16a,b,d, 16f-j, 17a,b,d,f-j and 18a,b,d,f-j.
h
recovered (∼95%). 28% recovered starting material was isolated
i
along with an unidentified second product (∼30%). Product
contained
a
small amount of catalyst-derived impurity (2,6-
diisopropylaniline) following chromatography.
J O982331O
propriate acids. These couplings proceeded in 67-92% yield
(Table 1) with unreacted starting material accounting for
the remainder of the mass balance. The preparations of the
labile acyclic enol ethers 17 were carried out using the
modified Takai procedures20,21 and were purified to about
95% purity by flash chromatography. Exposure of the formed
acyclic enol ether (derived from 15) to the Schrock catalyst
14 under the prescribed conditions for this type of ring
closure failed to produce any of the desired cyclized material.
We then employed the monosubstituted olefin 17a (Table
1, entry 1) as the substrate for metathesis and exposure to
1 produced cyclized product 18a in 53% yield along with
(13) (a) Clark, J . S.; Kettle, J . G. Tetrahedron Lett. 1997, 38, 123-126.
(b) Clark, J . S.; Kettle, J . G. Tetrahedron Lett. 1997, 38, 127-130.
(14) Clark, J . S.; Trevitt, G. P.; Boyall, D.; Stammen, B. J . Chem. Soc.,
Chem. Commun. 1998, 2629-2630.
(15) Rainier, J . D.; Allwein, S. P. J . Org. Chem. 1998, 63, 5310-5311.
(16) Sturino, C. F.; Wong, J . C. Y. Tetrahedron Lett. 1998, 39, 9623-
9626.
(17) For example, application of this sequence to 3,4,5-tri-O-benzyl-D-
galactal should allow access to the corresponding C-1-galactals, although
we have not yet carried this out.
(18) Commercially available from Sigma.
(19) Freeman, F.; Robarge, K. D. Carbohydr. Res. 1986, 154, 270-274.
(20) Takai, K.; Kakiuchi, T.; Kataoka, Y.; Utimoto, K. J . Org. Chem. 1994,
59, 2668-2670.
(21) Rainier and Allwein (ref 15) have postulated that an excess of
reagent is required to compensate for the unfavorable chelation of the active
reagent with the ethereal oxygen atoms of the substrate.
(22) Armstrong, S. K.; Christie, B. A. Tetrahedron Lett. 1996, 37, 9373-
9376.
(11) (a) Nicolaou, K. C.; Postema, M. H. D.; Yue, E. W.; Nadin, A. J . Am.
Chem. Soc. 1996, 118, 10335-10336. (b) Nicolaou, K. C.; Postema, M. H.
D.; Claiborne, C. F. J . Am. Chem. Soc. 1996, 118, 1565-1566.
(12) Stille, J . R.; Santarsiero, B. D.; Grubbs, R. H. J . Org. Chem. 1990,
55, 843-862.
(23) Martin, S. F.; Chen, H.-J .; Courtney, A. K.; Liao, Y.; Pa¨tzel, M.;
Ramser, M. N.; Wagman, A. S. Tetrahedron 1996, 52, 7251-7264.
(24) This second product is not the expected dimer.