Tandem RCM-isomerization approach to glycals of desoxyheptoses from a common precursor

Article abstract of DOI:10.1021/ol702586b

Ring closing metathesis and tandem RCM-isomerization have been applied to the synthesis of six- to eight-membered oxacycles, starting from a common precursor. The products of the tandem RCM-isomerization sequence are glycals of 3-deoxyheptoses of varying

Full text of DOI:10.1021/ol702586b

ORGANIC
LETTERS
2008
Vol. 10, No. 1
105-108
Tandem RCM−Isomerization Approach
to Glycals of Desoxyheptoses from a
Common Precursor
Bernd Schmidt* and Anne Biernat
Institut fuer Chemie, Organische Chemie II, UniVersitaet Potsdam,
Karl-Liebknecht-Strasse 24-25, D-14476 Golm, Germany
bernd.schmidt@uni-potsdam.de
Received October 25, 2007
ABSTRACT
Ring closing metathesis and tandem RCM
−isomerization have been applied to the synthesis of six- to eight-membered oxacycles, starting
from a common precursor. The products of the tandem RCM−isomerization sequence are glycals of 3-deoxyheptoses of varying ring size.
Glycals,1 cyclic enol ethers derived from or related to
carbohydrates, have found numerous applications in the total
synthesis of natural products2 or in the construction of
oligosaccharide chains.3 While the reduction of glycosyl
bromides, first introduced by Fischer and Zach,4 remains a
reliable, well-established and improved5 synthesis for many
derivatives, several other methods have been developed
which are especially suited for non-natural derivatives or for
glycals which are derived from less common sugars. Among
these, the hetero-Diels-Alder reaction is particularly im-
portant,6 but several transition-metal-mediated reactions have
also attracted considerable attention recently. Examples are
the catalyzed endo-cyclization of alkynols7 or ring closing
olefin metathesis8 of enol ethers. Although a significant
number of successful enol ether metathesis reactions have
been reported,9 the method is often associated with some
drawbacks as high dilution and, in most cases, the more
active but less conveniently available molybdenum10 or
second generation ruthenium catalysts11 are required. Fur-
thermore, undesired non-metathesis side reactions such as
isomerization12 may occur if a metathesis catalyst reacts with
electron-rich olefins such as vinyl ethers.13 These issues have
recently been addressed by the development of a tandem14
RCM-isomerization sequence by Snapper et al.15 and by
us,16 where a metathesis catalyst is converted to a selective
olefin isomerization catalyst after completion of the metath-
esis reaction.
(1) Tolstikov, A. G.; Tolstikov, G. A. Russ. Chem. ReV. 1993, 62, 579-
601.
(2) Denmark, S. E.; Regens, C. S.; Kobayashi, T. J. Am. Chem. Soc.
2007, 129, 2774-2776.
(3) (a) Seeberger, P. H.; Haase, W. C. Chem. ReV. 2000, 100, 4349-
4394. (b) Kunst, E.; Kirschning, A. Synthesis 2006, 2397-2403.
(4) Fischer, E.; Zach, K. Sitz. Ber. Kgl. Preuss. Akad. Wiss. 1913, 27,
311-317.
(5) (a) Spencer, R. P.; Schwartz, J. Tetrahedron 2000, 56, 2103-2112.
(b) Shull, B. K.; Wu, Z.; Koreeda, M. J. Carbohydr. Chem. 1996, 15, 955-
964.
(7) (a) McDonald, F. E. Chem.sEur. J. 1999, 5, 3103-3106. (b)
McDonald, F. E.; Reddy, K. S.; D´ıaz, Y. J. Am. Chem. Soc. 2000, 122,
4304-4309. (c) Alca´zar, E.; Pletcher, J. M.; McDonald, F. E. Org. Lett.
2004, 6, 3877-3880. (d) Koo, B.; McDonald, F. E. Org. Lett. 2005, 7,
3621-3624. (e) Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 2003, 125,
7482-7483. (f) Wipf, P.; Graham, T. H. J. Org. Chem. 2003, 68, 8798-
8807. (g) Weyershausen, B.; Do¨tz, K. H. Eur. J. Inorg. Chem. 1999, 1057-
1066.
(8) Recent reviews on olefin metathesis: (a) Deshmukh, P. H.; Blechert,
S. Dalton Trans. 2007, 2479-2491. (b) Conrad, J. C.; Fogg, D. E. Curr.
Org. Chem. 2006, 10, 185-202. (c) Nicolaou, K. C.; Bulger, P. G.; Sarlah,
D. Angew. Chem., Int. Ed. 2005, 44, 4490-4527. (d) Schmidt, B.;
Hermanns, J. Top. Organomet. Chem. 2004, 13, 223-267. (e) Deiters, A.;
Martin, S. F. Chem. ReV. 2004, 104, 2199-2238.
(6) (a) Schmidt, R. R. Acc. Chem. Res. 1986, 19, 250-259. (b) For a
recent application in total synthesis, see: Krauss, I. J.; Mandal, M.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 2007, 46, 5576-5579.
10.1021/ol702586b CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/08/2007

In this contribution, we describe the application of the
tandem RCM-isomerization method to the synthesis of
heptose glycals. Certain heptopyranoses are found as con-
stituents in lipopolysaccharides,17 and recently, a route to
KDO starting from a heptopyranose glycal has been de-
scribed.18 The seven-membered ring sugars, septanoses,19 are
not found in Nature but have recently attracted considerable
attention because they may serve as building blocks for non-
carbohydrate natural products or non-natural homologues of
hexoses, with significantly different conformational proper-
ties.20,21
The starting point of the current investigation was epoxide
2. We have previously obtained 2 from 122 by vanadium-
catalyzed epoxidation; however, only a poor diastereoselec-
tivity was observed.23 Enantio- and diastereomerically pure
2 was obtained in good yield by subjecting 1 to the conditions
of a Sharpless epoxidation using (+)-DET as a ligand.24 With
a view toward accessing 3-deoxyheptopyranoses, 2 was
allylated to give 3, which underwent ring closure to dihy-
dropyran 4 in the presence of ruthenium catalyst [Cl2(PCy3)2-
RudCHPh] (A) in 94% yield. Under RCM-isomerization
conditions, 3 was cleanly converted to enol ether 5 using
the isopropanol/NaOH protocol.16b,c NMR spectroscopy of
the crude reaction mixture revealed that 5 was the only
product of the reaction, and that the presence of a base and
a nucleophilic cosolvent did not affect the epoxide moiety.
However, 5 was found to be rather sensitive toward chro-
matography on silica, resulting in a significantly reduced
yield. This problem was overcome by cleaving the epoxide
and protecting the resulting diol 6 as an acetonide 7 prior to
RCM and RCM-isomerization. For both reactions, dihy-
dropyrans 8 and 9, respectively, were obtained in high yields
and selectivities. An alternative route to a monoprotected
Vic-diol side chain was investigated by selectively cleaving
the epoxide moiety in 3 with benzylic alcohol. The resulting
precursor 10 undergoes RCM in a fair yield of 67% of 11.
A significantly reduced yield was obtained for 12 under the
conditions mentioned above for the tandem RCM-isomer-
ization. Thus, tandem RCM-isomerization of partially
unprotected metathesis precursors is, in principle, possible
but does not appear to be the method of choice (Scheme 1).
Next, an approach to septanose structures starting from
epoxide 2 was investigated. To this end, the alcohol
functionality in 2 was protected as a benzyl ether 13, which
was subsequently cleaved with benzylic alcohol to give 14.25
Allylation of 14 yields allyl ether 15, which undergoes RCM
smoothly to give the oxepine 16.26 Under tandem RCM-
isomerization conditions, the glycal 17 is obtained in
comparable yield (Scheme 2).27
Finally, application of the concept to the synthesis of eight-
membered heptose derivatives was investigated (Scheme 3).
The sequence started with epoxide 13, which undergoes
chemo- and regioselective ring opening with allyl alcohol
in the presence of substoichiometric amounts of sodium
methoxide to give 18.28 Lewis acid catalysis using BF3OEt2
results only in poor yields of impure epoxide cleavage
product. In light of previous reports in the literature where
the first generation catalyst A was used for the synthesis of
medium-ring heterocycles,29 we first tested A for the RCM
of 18, however, only the dimer 19 was isolated in low yield
as a single isomer, which is presumably E-configured, along
with unreacted starting material 18. Attempts to convert 19
into the desired oxocene 20 via a backbite mechanism were
unsuccessful with the first generation catalyst A. However,
with B (5 mol %), 20 was quantitatively obtained from 19.
Compound 20 was of course more conveniently obtained
from 18 by treatment with B at elevated temperature. There
have been reports that B, in contrast to A, undergoes a
defined thermal decomposition to a Ru-hydride complex
which does not require any additives.30 Although it has been
(9) (a) Sturino, C. F.; Wong, J. C. Y. Tetrahedron Lett. 1998, 39, 9623-
9626. (b) Rainier, J. D.; Allwein, S. P.; Cox, J. M. J. Org. Chem. 2001, 66,
1380-1386. (c) Peczuh, M. W.; Snyder, N. L. Tetrahedron Lett. 2003, 44,
4057-4061. (d) Postema, M. H. D.; Piper, J. L.; Liu, L.; Shen, J.; Faust,
M.; Andreana, P. J. Org. Chem. 2003, 68, 4748-4754. (e) Zhang, S.; Reith,
M. E. A.; Dutta, A. K. Bioorg. Med. Chem. Lett. 2003, 13, 1591-1595. (f)
Postema, M. H. D.; Piper, J. L.; Komanduri, V.; Liu, L. Angew. Chem.
2004, 116, 2975-2978. (g) Chaulagain, M. R.; Postema, M. H. D.;
Valeriote, F.; Pietraszkewicz, H. Tetrahedron Lett. 2004, 45, 7791-7794.
(h) Peczuh, M. W.; Snyder, N. L.; Fyvie, W. S. Carbohydr. Res. 2004,
339, 1163-1171. (i) van Otterlo, W. A. L.; Morgans, G. L.; Madeley, L.
G.; Kuzvidza, S.; Moleele, S. S.; Thornton, N.; de Koning, C. B.
Tetrahedron 2005, 61, 7746-7755. (j) Majumder, U.; Cox, J. M.; Johnson,
H. W. B.; Rainier, J. D. Chem.sEur. J. 2006, 12, 1736-1746. (k) Lee,
A.-L.; Malcolmson, S. J.; Puglisi, A.; Schrock, R. R.; Hoveyda, A. H. J.
Am. Chem. Soc. 2006, 128, 5153-5157. (l) Roberts, S. W.; Rainier, J. D.
Org. Lett. 2007, 9, 2227-2230.
(10) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; DiMare,
M.; O’Regan, M. J. Am. Chem. Soc. 1990, 112, 3875-3886.
(11) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
(12) (a) Alcaide, B.; Almendros, P. Chem.sEur. J. 2003, 9, 1259-1262.
(b) Schmidt, B. Eur. J. Org. Chem. 2004, 1865-1880. (c) Schmidt, B. J.
Mol. Catal. A 2006, 254, 53-57.
(13) Louie, J.; Grubbs, R. H. Organometallics 2002, 21, 2153-2164.
(14) Fogg, D. E.; dos Santos, E. N. Coord. Chem. ReV. 2004, 248, 2365-
2379.
(15) Sutton, A. E.; Seigal, B. A.; Finnegan, D. F.; Snapper, M. L. J.
Am. Chem. Soc. 2002, 124, 13390-13391.
(16) (a) Schmidt, B. Eur. J. Org. Chem. 2003, 816-819. (b) Schmidt,
B. Chem. Commun. 2004, 742-743. (c) Schmidt, B. J. Org. Chem. 2004,
69, 7672-7687.
(17) (a) Tanaka, H.; Takahashi, D.; Takahashi, T. Angew. Chem., Int.
Ed. 2006, 45, 770-773. (b) Yoshizaki, H.; Fukuda, N.; Sato, K.; Oikawa,
M.; Fukase, K.; Suda, Y.; Kusumoto, S. Angew. Chem., Int. Ed. 2001, 40,
1475-1480.
(18) Wardrop, D. J.; Zhang, W. Tetrahedron Lett. 2002, 43, 5389-5391.
(19) Pakulski, Z. Pol. J. Chem. 1996, 70, 667-707.
(25) Compound 14 has previously been obtained by Wittig reaction of
arabinose derivatives: (a) Hekking, K. F. W.; Moelands, M. A. H.; van
Delft, F. L.; Rutjes, F. P. J. T. J. Org. Chem. 2006, 71, 6444-6450. (b)
Postema, M. H. D.; Calimente, D.; Liu, L.; Behrmann, T. L. J. Org. Chem.
2000, 65, 6061-6068.
(26) Ovaa, H.; Leeuwenburgh, M. A.; Overkleeft, H. S.; van der Marel,
G. A.; van Boom, J. H. Tetrahedron Lett. 1998, 39, 3025-3028.
(27) For a synthesis of 17 via elimination of a glycoside, see: Castro,
S.; Peczuh, M. W. J. Org. Chem. 2005, 70, 3312-3315.
(28) Lecollinet, G.; Auzely-Velty, R.; Danel, M.; Benvegnu, T.; Mack-
enzie, G.; Goodby, J. W.; Plusquellec, D. J. Org. Chem. 1999, 64, 3139-
3150.
(20) (a) Peczuh, M. W.; Snyder, N. L.; Fyvie, W. S. Carbohydr. Res.
2004, 339, 1163-1171. (b) Ganesh, N. V.; Jayaraman, N. J. Org. Chem.
2007, 72, 5500-5504.
(21) Review: Snyder, N. L.; Haines, H. M.; Peczuh, M. W. Tetrahedron
2006, 62, 9301-9320.
(22) Quinn, K. J.; Isaacs, A. K.; Arvary, R. A. Org. Lett. 2004, 6, 4143-
4145.
(23) Schmidt, B.; Nave, S. AdV. Synth. Catal. 2006, 345, 531-537.
(24) (a) Katsuki, T.; Martin, V. S. Org. React. 1996, 48, 1-299. (b) 2
has previously been obtained from rac-1 in significantly lower yield by
kinetic resolution under Sharpless conditions: Ku¨fner, U.; Schmidt, R. R.
Liebigs Ann. Chem. 1986, 1600-1609.
(29) Review: Chattopadhyay, S. K.; Karmakar, S.; Biswas, T.; Majum-
dar, K. C.; Rahaman, H.; Roy, B. Tetrahedron 2007, 63, 3919-3952.
106
Org. Lett., Vol. 10, No. 1, 2008

Scheme 1. 3-Desoxyheptopyranose Glycals
Scheme 2. Septanose Glycal
Scheme 3. Extension to Eight-Membered Oxacycles
reported that the use of B at elevated temperatures might
result in the formation of isomerized products,31 we only
observed the initial metathesis product 20 under our condi-
tions. A possible explanation might be that the formation of
a Ru-hydride upon thermolysis of B is a bimolecular
process30 which will most likely proceed efficiently only at
catalyst loadings significantly higher than those used in our
experiments.31 In order to access the cyclic enol ether 21
via our tandem process, the standard protocol was tested.
However, 2-propanol and NaOH as additive combination did
not give any isomerized product. Gratifyingly, the use of
NaBH416a,c was successful, and 21 was obtained in good yield
as a single isomer. The conversion of 18 to 21 represents
the first application of the tandem RCM-isomerization
concept to an eight-membered ring.
In conclusion, we have shown that the combination of
RCM and tandem RCM-isomerization opens up promising
opportunities for the synthesis of unsaturated six- to eight-
membered oxacycles related to heptoses. Remarkably, just
one precursor is required to access a considerable number
of structurally diverse carbohydrate-related products.
(30) Hong, S. H.; Day, M. W.; Grubbs, R. H. J. Am. Chem. Soc. 2004,
126, 7414-7415.
(31) Fustero, S.; Sa´nchez-Rosello´, M.; Jime´nez, D.; Sanz-Cervera, J. F.;
del Pozo, C.; Acen˜a, J. L. J. Org. Chem. 2006, 71, 2706-2714.
Org. Lett., Vol. 10, No. 1, 2008
107

Acknowledgment. Generous financial support of this
work by the Deutsche Forschungsgemeinschaft and generous
donations of chemicals and solvents by LANXESS and
Evonik-Oxeno are gratefully acknowledged. We thank Dr.
Stefan Nave (University of Bristol, UK) for advice and
support in the early stages of the project.
Supporting Information Available: Experimental pro-
1
cedures, analytical data, and copies of H and 13C NMR
spectra of all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL702586B
108
Org. Lett., Vol. 10, No. 1, 2008