An in-depth study on ring-closing metathesis of carbohydrate-derived α-alkoxyacrylates: Efficient syntheses of DAH, KDO, and 2-deoxy-β-KDO

Article abstract of DOI:10.1021/jo060913x

Novel, efficient synthetic pathways to DAH, KDO, and 2-deoxy-β-KDO are described. Ring-closing metathesis (RCM) of highly functionalized α-alkoxyacrylate fragments resulted in a series of synthetically versatile oxygen heterocyclic intermediates. Further

Full text of DOI:10.1021/jo060913x

An In-Depth Study on Ring-Closing Metathesis of
Carbohydrate-Derived r-Alkoxyacrylates: Efficient Syntheses of
DAH, KDO, and 2-Deoxy-â-KDO
Koen F. W. Hekking, Marcel A. H. Moelands, Floris L. van Delft, and
Floris P. J. T. Rutjes*
Institute for Molecules and Materials, Radboud UniVersity Nijmegen, ToernooiVeld 1, NL-6525 ED
Nijmegen, The Netherlands
F.Rutjes@science.ru.nl
ReceiVed May 3, 2006
Novel, efficient synthetic pathways to DAH, KDO, and 2-deoxy-â-KDO are described. Ring-closing
metathesis (RCM) of highly functionalized R-alkoxyacrylate fragments resulted in a series of synthetically
versatile oxygen heterocyclic intermediates. Further functionalization of the resulting enol ether double
bond and subsequent deprotection provided the natural products in high overall yields, starting from
commercially available protected sugars.
CHART 1. Structures of DAH, KDO, and 2-Deoxy-KDO
Introduction
The 3-deoxy-2-ulosonic acids constitute a family of carbo-
hydrates that are encountered in a wide variety of biological
systems (Chart 1). For instance, 3-deoxy-D-arabino-2-heptu-
losonic acid (DAH, 1) is a key intermediate in the biosynthesis
of aromatic metabolites in plants and microorganisms (Shikimate
pathway). It is formed through stereoselective condensation of
phosphoenolpyruvate with D-erythrose by DAHP synthase and
transformed in a series of steps to dehydroquinate by the enzyme
dehydroquinate synthase.1 Furthermore, 3-deoxy-D-manno-2-
octulosonic acid (KDO, 2) is an essential component of the cell
wall lipopolysaccharides (LPS) of gram-negative bacteria.2
Activation of KDO by the enzyme CMP-KDO synthase (CKS)
is believed to be the rate-determining step in the biosynthesis
of LPS,3 thereby rendering it an interesting target in the
development of antibiotics. For example, 2-deoxy-â-KDO (3)
has been reported as a potent inhibitor of CKS.4
The rapid increase in drug-resistant bacteria clearly empha-
sizes the need for development of new classes of antibiotics.
Therefore, it is not surprising that the development of efficient
synthetic routes to 3-deoxy-2-ulosonic acids and derivatives is
of broad interest.5-8
(3) (a) Ray, P. H.; Benedict, C. D.; Grasmuk, H. J. Bacteriol. 1981, 145,
1283. (b) Goldman, R. C.; Bolling, T. J.; Kohlbrenner, W. E.; Kim, Y.;
Fox, J. L. J. Biol. Chem. 1986, 261, 15831.
(4) (a) Hammond, S. M.; Claesson, A.; Jansson, A. M.; Larsson, L.-G.;
Pring, B. G.; Town, C. M.; Ekstro¨m, B. Nature 1987, 327, 730. (b) Claesson,
A.; Luthman, K.; Gustafsson, K.; Bondesson, G. Biochem. Biophys. Res.
Commun. 1987, 143, 1063.
(1) (a) Haslam, E. Shikimic Acid: Metabolism and Metabolites; Wiley:
New York, 1993. (b) Bentley, R. Crit. ReV. Biochem. Mol. Biol. 1990, 25,
307. (c) Coggins, J. R.; Abell, C.; Evan, L. B.; Frederickson, M.; Robinson,
D. A.; Roszak, A. W.; Lapthorn, A. P. Biochem. Soc. Trans. 2003, 31, 548.
(2) Unger, F. M. AdV. Carbohydr. Chem. Biochem. 1981, 38, 323 and
references therein.
10.1021/jo060913x CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/26/2006
6444
J. Org. Chem. 2006, 71, 6444-6450

Ring-Closing Metathesis of R-Alkoxyacrylates
SCHEME 1. Retrosynthetic Route to 3-Deoxy-2-ulosonic
Acids
SCHEME 2. Formation of Functionalized Acrylates
SCHEME 3. RCM of Alkoxyacrylates
Ring-closing metathesis (RCM) of highly functionalized
carbohydrate-derived olefins has received broad attention over
the past years, often leading to biologically relevant oxygen
heterocycles.9,10 In this contribution, we report short and efficient
total syntheses of KDO and DAH via an RCM-mediated
pathway, starting from natural sugars (IV, Scheme 1). Key steps
in the synthetic route include ring-closing metathesis (RCM)
of R-alkoxyacrylates IIIsrecently developed in our group10s
and functionalization of the resulting unsaturated heterocycles
II via the corresponding iodohydrins.
Results and Discussion
Preparation of the metathesis precursors, more specifically
the required R-alkoxyacrylate fragments, appeared not to be
straightforward. At the time that this research was initiated, only
one suitable pathway had been reported. This method involves
a laborious three-step procedure, based on a carbene insertion
using dimethyl diazomalonate, followed by alkylation with
Eschenmoser’s salt and subsequent elimination/decarboxylation,
with typical overall yields of 25-40%.11 During our search for
shorter and more efficient pathways to these fragments, we
developed a synthetic method based on bromides 4a and b,
which are readily available from the corresponding 2,3-
dibromides. A single preliminary example of this synthetic route
was previously described.10 To optimize the conditions and to
investigate the scope of this methodology, we decided to apply
this sequence to phenol (5) and thiophenol (6, Scheme 2).
Gratifyingly, the reaction of 5 and 6 with 4a or b followed by
N-methylation and subsequent base-induced elimination pro-
ceeded well, resulting in R-alkoxyacrylate 9 and R-alkylthio-
acrylate 10 in overall yields of 55% and 53%, respectively. In
addition to our earlier findings, we found isolation of intermedi-
ates 7 and 8 to be unnecessary. Instead, a single extraction
between the substitution and the methylation/elimination steps
was sufficient for the overall reaction sequence to proceed
efficiently.
As expected, applying these conditions to ortho-substituted
phenols 11 and 12 resulted in the formation of RCM-precursors
13 and 14 in satisfactory yields of 61 and 78%, respectively
(Scheme 3). Subsequent ring-closing metathesis proceeded
rapidly within 30 min, using the second generation Grubbs
catalyst (A) in toluene at 70 °C. The resulting benzofuran
carboxylate (15) and benzopyran carboxylate (16) were isolated
in excellent yields of 89 and 92%. Interestingly, no olefin
isomerization was observed prior to the cyclization of 14. This
is somewhat surprising, since previously reported comparable
model systems were found to be prone to isomerization under
metathesis conditions.10,12
(5) For a recent review on syntheses of 3-deoxy-2-ulosonic acids, see
Li, L.-S.; Wu, Y.-L. Curr. Org. Chem. 2003, 7, 447.
(6) For recent syntheses of DAH, see the following: (a) Crestia, D.;
Demuynck, C.; Bolte, J. Tetrahedron 2004, 60, 2417. (b) Liu, K.-G.; Hu,
S.-G.; Wu, Y.; Yao, Z.-J.; Wu, Y.-L. J. Chem. Soc., Perkin Trans. 1 2002,
1890. (c) Wardrop, D., J.; Zhang, W. Tetrahedron Lett. 2002, 43, 5389.
(d) Reiner, M.; Stolz, F.; Schmidt, R. R. Eur. J. Org. Chem. 2002, 57. (e)
Li, L.-S.; Wu, Y.; Wu, Y.-L. J. Carbohydr. Chem. 1999, 18, 1067. (f)
Dondoni, A.; Marra, A.; Merino, P. J. Am. Chem. Soc. 1994, 116, 3324.
(7) Recent syntheses of KDO can be found in the following: (a) Kikelj,
V.; Plantier-Royon, R.; Portella, C. Synthesis 2006, 1200. (b) Kim, B. G.;
Schilde, U.; Linker, T. Synthesis 2005, 1507. (c) Hartmann, K.; Kim, B.
G.; Linker, T. Synlett 2004, 2728. (d) Kuboki, A.; Tajimi, T.; Tokuda, Y.;
Kato, D.; Sugai, T.; Ohira, S. Tetrahedron Lett. 2004, 45, 4545. (e) ref 6a.
(f) Li, L.-S.; Wu, Y.-L. Tetrahedron 2002, 58, 9049. (g) ref 6c. (h) Barco,
A.; Bassetti, L.; Benetti, S.; Bertolasi, V.; De Risi, C.; Marchetti, P.; Pollini,
G. P. Tetrahedron 2002, 58, 8553.
(8) Recent syntheses of 2-deoxy-â-KDO can be found in the following:
(a) Kumaran, G.; Mootoo, D. R. Tetrahedron Lett. 2001, 42, 3783. (b)
Mlynarski, J.; Banaszek, A. Org. Lett. 1999, 1, 1709. (c) Burke, S. D.;
Sametz, G. M. Org. Lett. 1999, 1, 71.
(9) (a) Roy, R.; Das, S. K. Chem. Commun. 2000, 519 and references
therein (b) Jørgensen, M.; Hadwiger, P.; Madsen, R.; Stu¨tz, A. E.; Wrodnigg,
T. M. Curr. Org. Chem. 2000, 4, 565 and references therein. (c) Postema,
M. H. D.; Piper, J. L.; Betts, R. L.; Valeriote, F. A.; Pietraszkewicz, H. J.
Org. Chem. 2005, 70, 829. (d) Postema, M. H. D.; Piper, J. L.; Komanduri,
V.; Liu, L. Angew. Chem., Int. Ed. 2004, 43, 2915. (e) Ovaa, H.;
Leeuwenburgh, M. A.; Overkleeft, H. S.; van der Marel, G. A.; van Boom,
J. H. Tetrahedron Lett. 1998, 39, 3025.
With the availability of a suitable procedure for the synthesis
of R-alkoxyacrylate functionalities, the stage was set for
(10) Hekking, K. F. W.; van Delft, F. L.; Rutjes, F. P. J. T. Tetrahedron
2003, 59, 6751.
(11) Gajewski, J. J.; Jurayj, J.; Kimbrough, D. R.; Gande, M. E.; Ganem,
B.; Carpenter, B. K. J. Am. Chem. Soc. 1987, 109, 1170.
J. Org. Chem, Vol. 71, No. 17, 2006 6445

Hekking et al.
TABLE 1. Ring-Closing Metathesis and Homologation of 28a
SCHEME 4. Preparation of Functionalized Heterocycles via
RCM
catalyst
(mol %)
concn
(M)
entry
32 (%)
33 (%)
32/33
28 (%)
1
2
3
4
5b
6
7
A (20)
A (20)
A (100)
A (100)
A (100)
B (20)
0.05
0.02
0.05
0.02
0.02
0.02
0.02
39
52
31
47
56
15c
18c
15
19
24
40
36
11c
13c
2.6:1
2.7:1
1.3:1
1.2:1
1.5:1
1.4:1
1.4:1
43
25
n.d.d
n.d.
n.d.
74c
69c
C (20)
a Conditions: solution in toluene, inert atmosphere, 80 °C, 18 h. b At
1
60 °C. c Based on H NMR. d n.d. ) not determined.
significant amount (43%) of unreacted starting material behind.
Although the side product could not be separated from the major
product 32 by silica gel chromatography, both compounds were
eventually obtained in analytically pure form through preparative
HPLC. After extensive investigation of the analytical data, the
side-product was identified as the seven-membered ring 33
(Table 1).
b
a Reaction time was 20 h; the catalyst was added portionwise. 20 mol
% of catalyst was used and added portionwise.
This observation implies that a methylene group is introduced
during the RCM process, which to the best of our knowledge,
is unprecedented in ring-closing olefin metathesis. The observa-
tion of such an “insertion mechanism” sharply contrasts with
the frequently observed “deletion mechanism” where ethylene
is lost, caused by olefin isomerization prior to cyclization.15
Interestingly, when a mixture of the two products was resub-
jected to the metathesis conditions, the ratio did not change.
This suggests that the one-carbon homologation takes place in
the starting compound 28 prior to cyclization. Carrying out the
reaction at different temperatures and/or concentrations did not
significantly influence the ratio between 32 and 33, although
lower concentrations clearly resulted in higher conversion of
the starting material (Table 1, entries 1 and 2). On the other
hand, in case 1 equiv of A was used, the ratio 32/33 changed
from 2.6:1 to 1.2-1.5:1 (entries 3 to 5). Finally, the first
generation catalysts B and C also produced 33 as a side product,
albeit with low conversions (entries 6 and 7).
application of this methodology in the synthesis of DAH (1)
and derivatives. Scheme 4 shows the preparation of the
functionalized precursors for 1, as well as analogues with a ribo-,
lyxo-, and xylo-configuration. Alcohols 21-24 were prepared
from the protected sugars 17-2013 under standard Wittig
conditions, following known procedures.14 Next, the alcohol
groups were converted into R-alkoxyacrylate moieties to gener-
ate the RCM-precursors 25-28 in isolated yields of 49-67%.
This transformation was carried out using the two-step procedure
described above, involving bromides 4a,b.
Gratifyingly, RCM of 25a,b and 26 proceeded readily using
the second generation Grubbs catalyst (A) in toluene at 80 °C.
Considering the highly functionalized nature of the olefins, the
heterocycles 29a,b and 30 were isolated in remarkably good
yields of 82%, 80%, and 85%, respectively. On the other hand,
olefin 27 reacted significantly slower under these conditions.
After portionwise addition of the catalyst and a prolonged
reaction time, 31 could be isolated in a yield of 51%.
Interestingly, an unexpected side reaction was observed in the
cyclization of xylo-derivative 28. Moreover, the reaction ap-
peared to come to an end at a certain conversion, leaving a
A tentative mechanism for this transformation has recently
been foreseen by others on the basis of DFT calculations on
ruthenacyclobutane intermediates.16 This mechanistic pathway
involves â-hydrogen elimination from the known metathesis
(12) Recently, Grubbs and co-workers reported that the addition of metal
hydride scavengers can prevent isomerization during olefin metathesis:
Hong, S. H.; Sanders, D. P.; Lee C. W.; Grubbs, R. H. J. Am. Chem. Soc.
2005, 127, 17160.
(13) Protected sugar 17 was commericially available; 18-20 were
prepared using known protection procedures: Barker, R.; Fletcher, H. G.
J. Org. Chem. 1961, 26, 4605.
(15) (a) Schmidt, B. Eur. J. Org. Chem. 2004, 1865. (b) Bourgeois, D.;
Pancrazi, A.; Nolan, S. P.; Prunet, J. J. Organomet. Chem. 2002, 643-
644, 247. (c) Kinderman, S. S.; van Maarseveen, J. H.; Schoemaker, H. E.;
Hiemstra, H.; Rutjes, F. P. J. T. Org. Lett. 2001 3, 2045. (d) Fu¨rstner, A.;
Thiel, O. R.; Ackermann, L.; Schanz, H.-J.; Nolan, S. P. J. Org. Chem.
2000, 65, 2204.
(14) (a) Postema, M. H. D.; Calimente, D.; Liu, L.; Behrmann, T. L. J.
Org. Chem. 2000, 65, 6061. (b) Pearson, W. H.; Hines, J. V. J. Org. Chem.
2000, 65, 5785. (c) Freeman, F.; Robarge, K. D. Carbohydr. Res. 1986,
154, 270.
(16) DFT calculations suggested the feasability of this pathway, which
was supported experimentally by the generation of propene from ethene:
Janse van Rensburg, W.; Steynberg, P. J.; Meyer, W. H.; Kirk, M. M.;
Forman, G. S. J. Am. Chem. Soc. 2004, 126, 14332.
6446 J. Org. Chem., Vol. 71, No. 17, 2006

Ring-Closing Metathesis of R-Alkoxyacrylates
SCHEME 5. Tentative Homologation Mechanism
SCHEME 7. Cross-Metathesis Instead of Homologation
SCHEME 6. Possible Formation of 32 and 33 from 34
SCHEME 8. Potential Approaches from 29a to DAH (1)
intermediate II, resulting in π-allylruthenium(IV) complex III
(Scheme 5). Reductive elimination to complex IV and subse-
quent dissociation of the olefin from the metal center would
then generate the homologated product.
such as its substrate-dependent behavior, are currently under
investigation.19
In our case, this would imply that subjection of 28 to this
pathway would lead to the homologated RCM-precursor 34,
which gives 33 upon cyclization (Scheme 6). Since a ruthenium
carbene species is not regenerated through this sequence, it also
represents a decomposition pathway for olefin metathesis
catalysts. This is in agreement with (a) the observation of lower
total conversions in cases of catalytic amounts of A and (b) the
fact that the yield of homologated product never exceeds the
amount of catalyst used (Table 1).
Unfortunately, we have not been able to observe compound
34 by NMR, presumably because of the high reactivity of the
relatively unhindered monosubstituted double bond. In addition,
we cannot exclude the occurrence of olefin isomerization in 34
under metathesis conditions, eventually resulting in formation
of 32 (Scheme 6). Thus, the homologation might in fact be more
efficient than the ratio between 32 and 33 initially suggests. To
further investigate this assumption, we decided to synthesize
compound 3517 and subject it to the previously discussed
conditions to see whether it would be possible to isolate the
homologated product. The lack of a second double bond in 35
eliminates the possibility of cyclization, and we anticipated that
the presence of an allylic benzyloxy substituent would inhibit
formation of a homodimeric cross-metathesis product,18 thereby
preventing these two reactions to compete with the homologa-
tion.
Initial attempts to complete the synthesis of DAH were based
on modification of a glycal intermediate in earlier reported
syntheses of KDO (Scheme 8).8c This involved hydrogenation
of 29a to the saturated counterpart 37. Next, the lithium enolate
could be formed (LDA, THF, -78 °C), but did not exhibit any
reactivity toward several electrophilic reagents including MoO5‚
Py‚HMPA (MoOOPH)8c,20 and PhSSPh.21 The lack of further
literature precedent inspired us to actually take advantage of
the reactivity of the double bond in 29a. Initially however,
attempts to hydrate 29a under acidic conditions in water led to
decomposition. When carried out in methanol, the reaction
proceeded extremely slowly and produced only moderate yields
of the desired acetal. In addition, hydrolysis of the resulting
acetal was found to be problematic, forcing us to abandon this
route.
Finally, we were pleased to find that by applying the
electrophilic reagent N-iodosuccinimide (NIS) in acetonitrile/
water,22 enol ether 29a was efficiently converted into iodohydrin
38, which was isolated as a 1:1 mixture of diastereoisomers
(Scheme 9). Subsequent removal of the iodide under hydrogena-
tion conditions in the presence of triethylamine gave protected
DAH (39) in a yield of 83% from 29a.
Deprotection of 39 proved to be somewhat less trivial than
expected. Despite literature precedent,6c in our hands removal
of the benzyl protective groups did not occur under regular
hydrogenation conditions using Pd/C or Pd(OH)2/C, in combi-
nation with different solvents and pressures up to 40 bar.
Reaction of 39 with BCl3 did result in debenzylation, but the
isolated yields never exceeded 60%. However, when carrying
out the hydrogenation procedure with Degussa type Pd/C (H2O
Indeed, no homodimerization took place, but instead, cross-
metathesis (CM) of 35 was observed with styrene that presum-
ably originates from catalyst A (Scheme 7). The efficient nature
of this reaction prevented us from detecting any homologated
products. Nevertheless, this outcome is somewhat surprising,
especially since this side-reaction is generally not observed in
olefin metathesis. Further aspects of the homologation reaction,
(19) For other nonmetathetic behavior of Grubbs catalyst, see the
following: (a) Alcaide, B.; Almendros, P. Chem. Eur. J. 2003, 9, 1259.
(b) Trost, B. M.; Toste, F. D.; Pinkerton, A. B. Chem. ReV. 2001, 101,
2067.
(17) Compound 35 was synthesized by reacting 28 with NaH and MeI
in DMF.
(18) The inhibition of cross-metathesis by allylic ether substituents has
been previously reported: (a) Nolen, E. G.; Kurish, A. J.; Potter, J. M.;
Donahue, L. A.; Orlando, M. D. Org. Lett. 2005, 7, 3383. (b) Maishal, T.
K.; Sinha-Mahapatra, D. K.; Paranjape, K.; Sarkar, A. Tetrahedron Lett.
2002, 43, 2263 and references therein.
(20) (a) Vedejs, E.; Engler, D. A.; Telschow, J. E. J. Org. Chem. 1978,
43, 3, 188. (b) Vedejs, E.; Larsen, S. Org. Synth. 1986, 64, 127.
(21) Lubineau, A.; Auge, J.; Lubin, N. Tetrahedron 1993, 49, 4639.
(22) Kok, G. B.; van Phan, T.; von Itzstein, M. J. Carbohydr. Chem.
2001, 20, 359.
J. Org. Chem, Vol. 71, No. 17, 2006 6447

Hekking et al.
SCHEME 9. Completion of the Synthesis of DAH (1)
substitution of the iodide by methanol as well. Switching to a
mixture of isopropyl alcohol and ethyl acetate solved this
problem so that protected KDO (41) could be isolated in a yield
of 75% from 40. This NIS-based conversion now represents a
significantly more efficient alternative to the known methods,
which rely on enolate formation of the hydrogenated form of
40, followed by introduction of an oxygen or sulfur electro-
phile.8c,21 Perhaps more importantly, this mild method might
even be applicable to complex oligosaccharides, in which such
a glycal unit is incorporated. Finally, general deprotection
conditions converted 41 into KDO (2), which was isolated and
analyzed as its ammonium salt.25 The overall yield of KDO (2)
was 44% over eight steps, starting from commercially available
protected D-mannose.
SCHEME 10. Synthesis of KDO (2) and 2-Deoxy-â-KDO
(3)
Conclusions
In conclusion, we have shown that ring-closing metathesis
of highly substituted R-alkoxyacrylates and subsequent novel
functionalization via the iodohydrin represent a short and
efficient synthetic pathway to 3-deoxy-2-ulosonic acids. Fur-
thermore, this route includes a high-yielding four-step procedure
from protected natural sugars to substituted glycals, which can
serve as versatile building blocks for biologically relevant
derivatives. The viability of the route was proven by syntheses
of the natural products DAH and KDO, as well as that of
2-deoxy-â-KDO, a potent inhibitor of CMP-KDO synthase.
In addition, we have reported the first example of one-carbon
homologation in a ring-closing metathesis reaction. This ob-
servation provides important new insight into catalyst decom-
position during ruthenium-based olefin metathesis. Furthermore,
it might open up new possibilities for versatile tandem reaction
sequences. Additional aspects of this novel Ru-mediated reaction
are currently under investigation.
content 50%), complete deprotection took place within 1 h at
room temperature and under atmospheric pressure. Saponifica-
tion of the ester then gave DAH (1)23 in an overall yield of
39% over eight steps, starting from commercially available 17.
Encouraged by these results, more specifically the straight-
forward preparation of the glycals and their efficient function-
alization, we decided to apply this approach in a total synthesis
of KDO (2, Scheme 10). The heterocyclic intermediate 40 was
prepared in 64% over four steps from protected D-mannose,
under similar conditions as 29-32, following our previous
report.10,24
The potential of these types of glycal intermediates was
further demonstrated by quantitative hydrogenation of the double
bond in 40, selectively yielding protected 2-deoxy-R-KDO. This
can then be epimerized and deprotected via a reported procedure8c
to give 2-deoxy-â-KDO (3).
Moreover, reaction of glycal 40 with NIS appeared to proceed
as anticipated at 60 °C giving rise to the corresponding
iodohydrin, although substantial product decomposition was
observed when the reaction was left stirring for longer than 4
h. Removal of the iodide demanded certain optimization as well.
Triethylamine was required in the hydrogenation to scavenge
the liberated HI, but these mildly basic conditions led to partial
Experimental Section
General. General experimental details are described in the
Supporting Information.
General Procedure A for the Preparation of R-Alkoxyacry-
lates. To a cooled (0 °C) solution of the alcohol (1 equiv) in diethyl
ether/DMF (1:1, 0.05 M) was added NaH (60% in mineral oil; 2.5
equiv), and the mixture was stirred at 40 °C for 1 h. After cooling
to room temperature, freshly prepared 4a or b (3.5 equiv) was
added, and the reaction was stirred for 18 h. Next, H2O was added,
the mixture was extracted with diethyl ether (3×), and the combined
organic layers were concentrated in vacuo. The residue was
dissolved in (m)ethanol (0.1 M). MeI (10 equiv) and Na2CO3 (5
equiv) were added, and the reaction mixture was allowed to stir at
reflux temperature for 48 h. Next, H2O was added, and the mixture
was extracted with CH2Cl2 (3×). The combined organic layers were
dried with MgSO4 and concentrated, and the product was isolated
by column chromatography (EtOAc/heptane, 1:6).
Methyl 2-((2R,3S,4R)-1,3,4-Tris(benzyloxy)hex-5-en-2-yloxy)-
acrylate (25a). This compound was synthesized from 21, following
general procedure A. The yield was 708 mg (69%). 1H NMR
(CDCl3, 300 MHz): δ 7.32-7.24 (m, 15H), 5.89 (m, 1H), 5.38 (d,
J ) 2.5 Hz, 1H), 5.32 (m, 2H), 4.72 (d, J ) 2.5 Hz, 1H), 4.67 (s,
2H), 4.50 (s, 2H), 4.46 (m, 1H), 4.43 (dAB, J ) 11.7 Hz, 2H), 4.04
(m, 1H), 3.91-3.72 (m, 3H), 3.77 (s, 3H). 13C NMR (CDCl3, 75
MHz): δ 163.7, 149.8, 138.3, 138.2, 138.1, 135.4, 128.3, 128.2,
(23) Spectroscopic data agreed with those previously reported: (a) ref
6d. (b) Barton, D. H. R.; Liu, W. S. Tetrahedron 1997, 53, 12067.
(24) Using the optimized procedures described here, we are now able to
prepare 40 from protected D-mannose more efficiently (64% compared to
45%), than we initially reported (ref 10). In addition, we found that the use
of first-generation catalysts B and C for the ring-closing metathesis also
resulted in cyclization, albeit under more harsh conditions (100 °C) and
with lower yields (50-62%).
(25) Spectroscopic data agreed with those of an authentic commercial
sample and with those previously reported: (a) Schlessinger, R. H.; Pettus,
L. H. J. Org. Chem. 1998, 63, 9089. (b) Sugai, T.; Shen, G.-J.; Ichikawa,
Y.; Wong, C.-H. J. Am. Chem. Soc. 1993, 115, 413.
6448 J. Org. Chem., Vol. 71, No. 17, 2006

Ring-Closing Metathesis of R-Alkoxyacrylates
128.1 (2), 127.7, 127.6, 127.5 (2), 127.4, 119.0, 96.3, 80.1, 80.0,
77.3, 74.9, 73.3, 70.6, 67.9, 52.2. IR (CH2Cl2): ν 3029, 2948, 2865,
1734, 1621 cm-1. [R]22D -8.6 (c 1.3, CH2Cl2). HRMS (CI+): calcd
for C31H35O6 [M + H]+, 503.2434; found, 503.2434.
3.1 Hz, 1H), 4.82-4.53 (m, 6H), 4.28 (dd, J ) 3.1, 6.2 Hz, 1H),
4.19 (m, 1H), 3.95 (dd, J ) 6.2, 8.6 Hz, 1H), 3.84 (d, J ) 3.8 Hz,
2H), 3.81 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ 162.6, 144.3,
138.0, 137.9, 137.8, 128.5, 128.4, 128.3, 127.9, 127.8 (3), 127.6,
Ethyl 2-((2R,3S,4R)-1,3,4-Tris(benzyloxy)hex-5-en-2-yloxy)-
acrylate (25b). This compound was synthesized from 21, following
general procedure A. The yield was 380 mg (68%). 1H NMR
(CDCl3, 300 MHz): δ 7.31-7.24 (m, 15H), 5.89 (m, 1H), 5.38 (d,
J ) 2.6 Hz, 1H), 5.31 (m, 2H), 4.72 (d, J ) 2.6 Hz, 1H), 4.69 (s,
2H), 4.51 (s, 2H), 4.45 (m, 1H), 4.44 (dAB, J ) 11.8 Hz, 2H), 4.22
(q, J ) 7.2 Hz, 2H), 4.04 (m, 1H), 3.88 (m, 2H), 3.75 (dd, J ) 5.1,
10.9 Hz), 1.29 (t, J ) 7.2 Hz, 3H). 13C NMR (CDCl3, 75 MHz):
δ 162.9, 149.9, 138.1 (2), 138.0, 135.2, 128.1, 128.0, 127.9, 127.8,
127.4, 127.3, 127.2, 118.8, 96.0, 80.3, 80.2, 77.4, 75.0, 73.3, 70.7,
68.1, 61.3, 14.4. IR (CH2Cl2): ν 3030, 2927, 2869, 1727, 1620
108.3, 77.8, 75.4, 73.8, 73.5 (2), 70.9, 67.7, 52.4. [R]22 -9.6 (c
D
0.5, CH2Cl2).
(4R,5S,6R)-Ethyl 4,5-Bis(benzyloxy)-6-(benzyloxymethyl)-5,6-
dihydro-4H-pyran-2-carboxylate (29b). This compound was
synthesized from 25b, following general procedure B. The yield
was 77 mg (80%). 1H NMR (CDCl3, 300 MHz): δ 7.34-7.24 (m,
15H), 6.08 (d, J ) 3.1 Hz, 1H), 4.82-4.55 (m, 6H), 4.30-4.16
(m, 2H), 4.26 (q, J ) 7.2 Hz, 2H), 3.94 (dd, J ) 6.1, 8.4 Hz, 1H),
3.84 (d, J ) 3.8 Hz, 2H), 1.32 (t, J ) 7.2 Hz, 3H). 13C NMR
(CDCl3, 75 MHz): δ 161.8, 144.2, 137.8, 137.7, 137.6, 128.2 (2),
128.1, 127.7, 127.6 (2), 127.5, 127.4, 107.8, 77.7, 75.5, 73.8, 73.5,
73.4, 71.0, 67.7, 61.5, 14.4. IR (CH2Cl2): ν 3029, 2866, 1733, 1652
cm-1. [R]22 -6.2 (c 0.5, CH2Cl2). HRMS (CI+): calcd for
D
C32H37O6 [M + H]+, 517.2590; found, 517.2597.
cm-1. [R]22 -5.9 (c 0.5, CH2Cl2). HRMS (CI+): calcd for
D
Ethyl 2-((2R,3S,4S)-1,3,4-Tris(benzyloxy)hex-5-en-2-yloxy)-
acrylate (26). This compound was synthesized from 22, following
general procedure A. The yield was 27 mg (49%). 1H NMR (CDCl3,
300 MHz): δ 7.30-7.15 (m, 15H), 5.89-5.75 (m, 1H), 5.40 (d, J
) 2.7 Hz, 1H), 5.37-5.21 (m, 2H), 4.80 (d, J ) 2.1 Hz, 1H), 4.69
(s, 2H), 4.49 (s, 2H), 4.47-4.45 (m, 1H), 4.48 (dAB, J ) 11.6 Hz,
2H), 4.24 (q, J ) 6.9 Hz, 2H), 4.00 (dd, J ) 6.0, 7.5 Hz, 1H), 3.93
(dd, J ) 4.5, 6.0 Hz, 1H), 3.83-3.70 (m, 2H), 1.29 (t, J ) 7.2 Hz,
3H). 13C NMR (CDCl3, 75 MHz): δ 163.0, 150.0, 138.2, 138.1,
135.3, 128.1 (2), 128.0, 127.4 (3), 127.3 (2), 119.5, 96.3, 80.7, 79.6,
78.1, 74.4, 73.3, 70.5, 68.5, 61.3, 14.4. IR (CH2Cl2): ν 3023, 2920,
1722, 1623 cm-1. [R]25D +20.3 (c 0.2, CH2Cl2). HRMS (CI+): calcd
for C32H37O6 [M + H]+, 517.2590; found, 517.2593.
C30H33O6 [M + H]+, 489.2277; found, 489.2277.
(4S,5S,6R)-Ethyl 4,5-Bis(benzyloxy)-6-(benzyloxymethyl)-5,6-
dihydro-4H-pyran-2-carboxylate (30). This compound was syn-
thesized from 26, following the general procedure. The yield was
17 mg (85%). 1H NMR (CDCl3, 300 MHz): δ 7.34-7.24(m, 15H),
6.05 (d, J ) 5.5 Hz, 1H), 4.72-4.50 (m, 6H), 4.35 (dt, J ) 2.9,
10.0 Hz, 1H), 4.24 (q, J ) 7.1 Hz, 2H), 4.03 (dd, J ) 3.8, 5.7 Hz,
1H), 3.88 (d, J ) 3.1 Hz, 2H), 3.83 (dd, J ) 3.8, 10.0 Hz, 1H),
1.31 (t, J ) 7.1 Hz, 3H). 13C NMR (CDCl3, 75 MHz): δ 161.9,
145.5, 138.0, 137.9, 137.5, 128.2, 127.8 (2), 127.5, 106.0, 74.4,
73.5, 72.9, 71.8, 71.2, 68.2, 65.9, 61.5, 14.4. IR (CH2Cl2): ν 3020,
2872, 1732, 1645 cm-1. [R]25 +200.5 (c 0.2, CH2Cl2). HRMS
D
(CI+): calcd for C30H32O6 [M]+, 488.2199; found, 488.2198.
(4R,5R,6R)-Ethyl 4,5-Bis(benzyloxy)-6-(benzyloxymethyl)-5,6-
dihydro-4H-pyran-2-carboxylate (31) This compound was syn-
thesized from 27, following general procedure B. The catalyst was
added portionwise over 4 h, and the total reaction time was 20 h.
The yield was 48 mg (51%), and 37 mg (42%) of starting material
Ethyl 2-((2R,3R,4R)-1,3,4-Tris(benzyloxy)hex-5-en-2-yloxy)-
acrylate (27). This compound was synthesized from 23, following
1
the general procedure. The yield was 272 mg (55%). H NMR
(CDCl3, 300 MHz): δ 7.32-7.17 (m, 15H), 6.01-5.90 (m, 1H),
5.45-5.37 (m, 2H), 5.24 (d, J ) 2.4 Hz, 1H), 4.71-4.44 (m, 6H),
4.38 (d, J ) 2.7 Hz, 1H), 4.26-4.11 (m, 4H), 3.76-3.68 (m, 3H),
1.30 (t, J ) 7.2 Hz, 3H). 13C NMR (CDCl3, 75 MHz): δ 162.6,
150.9, 138.3, 138.1, 137.9, 136.0, 128.3, 128.1 (2), 128.0 (2), 127.5
(2), 127.4, 127.3, 127.0, 119.4, 94.0, 80.7, 80.0, 76.4, 74.3, 73.6,
1
was recovered. H NMR (CDCl3, 300 MHz): δ 7.30-7.18 (m,
15H), 6.25 (d, J ) Hz, 1H), 4.59-4.43 (m, 6H), 4.24 (q, J ) 7.1
Hz, 2H),4.42 (m, 2H), 4.15 (m, 1H), 3.85 (m, 2H), 1.30 (t, J ) 7.1
Hz, 3H). [R]25 -58.9 (c 0.1, CH2Cl2). HRMS (CI+): calcd for
D
70.2, 69.2, 61.3, 14.4. IR (CH2Cl2): ν 3022, 2868, 1723, 1619 cm-1
.
C30H33O6 [M + H]+, 489.2277; found, 489.2275.27
[R]25 -17.7 (c 1.5, CH2Cl2). HRMS (CI+): calcd for C32H37O6
(4S,5R,6R)-Ethyl 4,5-Bis(benzyloxy)-6-(benzyloxymethyl)-5,6-
dihydro-4H-pyran-2-carboxylate (32) and (5S,6R,7R)-Ethyl 5,6-
Bis(benzyloxy)-7-(benzyloxymethyl)-4,5,6,7-tetrahydrooxepine-
2-carboxylate (33). The reaction was carried out according to
general procedure B, using 28 and 20 mol % of catalyst, which
was added portionwise. 1H NMR showed a mixture of two products
in a ratio of 1:0.45, which could not be separated by column
chromatography. After separation by preparative HPLC, the isolated
products were identified as 32 (major) and 33 (minor). The
combined yield was 54%.
D
[M + H]+, 517.2590; found, 517.2607.
Ethyl 2-((2R,3R,4S)-1,3,4-Tris(benzyloxy)hex-5-en-2-yloxy)-
acrylate (28). This compound was synthesized from 24, following
general procedure A. The yield was 33 mg (49%). 1H NMR (CDCl3,
300 MHz): δ 7.35-7.19 (m, 15H), 5.92-5.77 (m, 1H), 5.33 (d, J
) 2.5 Hz, 1H), 5.24 (m, 2H), 4.73 (m, 2H), 4.71 (d, J ) 2.7 Hz,
1H), 4.40 (dab, J ) 11.7 Hz, 2H), 4.41-4.13 (m, 5H), 4.08 (dd, J
) 5.3, 7.7 Hz, 1H), 3.78 (t, J ) 5.1 Hz, 1H), 3.69-3.43 (m, 2H),
1.28 (t, J ) 7.1 Hz, 3H). 13C NMR (CDCl3, 75 MHz): δ 163.0,
150.6, 138.4, 138.0, 137.8, 135.1, 128.1(2), 128.0, 127.9, 127.5-
(2), 127.3(2), 118.9, 96.1, 80.9, 80.4, 78.7, 75.0, 73.3, 70.6, 67.7,
Compound 32. 1H NMR (CDCl3, 300 MHz): δ 7.36-7.21 (m,
15H), 6.12 (dd, J ) 1.5, 5.1 Hz, 1H), 4.59-4.43 (m, 6H), 4.23 (q,
J ) 7.2 Hz, 2H), 4.17 (m, 1H), 3.84 (m, 2H), 3.75 (m, 2H), 1.30
(t, J ) 7.2 Hz, 3H). 13C NMR (CDCl3, 75 MHz): δ 162.3, 145.8,
138.0, 137.9, 137.6, 128.5, 128.4 (2), 128.2, 128.0, 127.9, 127.7
(2), 106.5, 73.9, 73.4, 72.5, 71.8, 70.5, 67.8, 67.7, 61.4, 14.1. IR
61.3, 14.4. IR (CH2Cl2): ν 3023, 2863, 1722, 1619 cm-1. [R]25
D
+1.3 (c 0.8, CH2Cl2). HRMS (CI+): calcd for C32H37O6 [M + H]+,
517.2590; found, 517.2588.
General Procedure B for Ring-Closing Metathesis. To a
solution of the R-alkoxy acrylate in toluene (0.05 M) was added
10 mol % of (IMes)(PCy3)Cl2RudCHPh (A), and the mixture was
stirred under an inert atmosphere at 80 °C for 4 h. The reaction
was ended by exposure to air and removal of the solvent in vacuo.
The product was purified by column chromatography (EtOAc/
heptane, 1:6).
(4R,5S,6R)-Methyl 4,5-Bis(benzyloxy)-6-(benzyloxymethyl)-
5,6-dihydro-4H-pyran-2-carboxylate (29a). This compound was
synthesized from 25a, following general procedure B. The yield
was 529 mg (82%). The analytical data agreed with literature data.26
1H NMR (CDCl3, 300 MHz): δ 7.34-7.25 (m, 15H), 6.11 (d, J )
(CH2Cl2): ν 3022, 2930, 1726, 1637 cm-1. [R]22 +61.2 (c 0.24,
D
CH2Cl2). HRMS (EI+): calcd for C30H32O6 [M]+, 488.2199; found,
488.2190.
Compound 33. 1H NMR (CDCl3, 400 MHz): δ 7.32-7.25 (m,
15H), 6.17 (dd, J ) 5.0, 7.0 Hz, 1H), 4.75-4.47 (m, 6H), 4.30 (dt,
J ) 1.9, 6.6 Hz, 1H), 4.18 (q, J ) 7.2 Hz, 2H), 3.89 (m, 2H), 3.79
(dd, J ) 5.5, 10.0 Hz, 1H), 3.71 (dd, J ) 6.6, 10.0 Hz, 1H), 2.60
(ddd, J ) 2.3, 7.0, 17.1 Hz, 1H), 2.48 (ddd, J ) 5.0, 8.9, 17.1 Hz),
1.25 (t, J ) 7.2 Hz, 3H). 13C NMR (CDCl3, 75 MHz): δ 163.4,
149.3, 138.3, 138.2, 138.0, 128.4, 128.3 (2), 128.0, 127.8, 127.7
(27) Rapid deterioration of the product during or immediately after
column chromatography prevented further characterization.
(26) Crich, D.; Ritchie, T. J. J. Chem. Soc., Perking Trans. 1 1990, 945.
J. Org. Chem, Vol. 71, No. 17, 2006 6449

Hekking et al.
(2), 127.6 (2), 115.8, 81.1, 80.1, 78.4, 73.9, 73.5, 71.6, 69.1, 61.1,
and N-iodosuccinimide (63 mg, 0.282 mmol) in MeCN (6 mL) and
H2O (1.5 mL) was stirred for 2 h at 60 °C. Next, the solvent was
removed in vacuo, and the product was purified by column
chromatography (EtOAc/heptane, 1:6), yielding 53 mg (91%) of
the iodohydrin. The product was a single isomer, the absolute
configuration of which was not determined. 1H NMR (CDCl3, 300
MHz): δ 4.56 (dd, J ) 5.0, 9.5 Hz, 1H), 4.35 (m, 2H), 4.26-4.15
(m, 3H), 4.04-3.88 (m, 2H), 3.88 (s, 3H), 1.55 (s, 3H), 1.20 (s,
3H), 1.39 (s, 3H), 1.34 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ
163.1, 109.4 (2), 95.9, 78.2, 73.8, 73.2, 70.0, 66.8, 54.2, 30.4, 28.6,
27.1, 26.4, 25.6. HRMS (CI+): calcd for C15H24O8I [M + H]+,
459.0516; found, 459.0501. A solution of the iodohydrin (53 mg,
0.116 mmol) and Et3N (18 µL, 0.127 mmol) in EtOAc (5 mL) and
i-PrOH (5 mL) was treated with 10% Pd/C (7 mg) and H2 (1 atm)
for 18 h. After the reaction, the mixture was filtered over Celite
and concentrated, and the product was purified by column chro-
matography (EtOAc/heptane, 1:4). The yield was 32 mg (75% from
40). The analytical data agreed with those reported in the literature.28
1H NMR (CDCl3, 300 MHz): δ 4.49 (m, 1H), 4.34 (ddd, J ) 4.5,
6.2, 8.3 Hz, 1H), 4.25 (dd, J ) 2.4, 6.4 Hz, 1H), 4.07 (dd, J ) 6.2,
8.8 Hz, 1H), 3.97 (dd, J ) 4.5, 8.8 Hz, 1H), 3.88 (dd, J ) 2.4, 8.3
Hz, 1H), 3.80 (s, 3H), 3.50 (br, 1H), 2.49 (dd, J ) 6.6, 14.5 Hz,
1H), 1.89 (dd, J ) 5.0, 14.5 Hz, 1H), 1.45 (s, 3H), 1.41 (s, 3H),
1.36 (s, 3H), 1.35 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ 169.8,
109.3, 109.1, 94.4, 73.8, 71.3, 70.8, 69.8, 67.0, 53.3, 32.6, 27.2,
27.1, 25.9, 25.5. IR (CH2Cl2): ν 3520, 3002, 2977, 1751, 1450
27.0, 14.2. IR (CH2Cl2): ν 3052, 2985, 1717, 1649 cm-1. [R]22
D
+4.5 (c 0.11, CH2Cl2). HRMS (EI+): calcd for C31H35O6 [M+H]+,
503.2434; found, 503.2427.
(4S,5S,6R)-Methyl 4,5-Bis(benzyloxy)-6-(benzyloxymethyl)-
2-hydroxy-3-iodo-tetrahydro-2H-pyran-2-carboxylate (38). A
solution of 29a (425 mg, 0.896 mmol) and N-iodosuccinimide (301
mg, 1.34 mmol) in MeCN (25 mL) and H2O (10 mL) was stirred
for 4 h at 40 °C. Next, the solvent was removed in vacuo, and the
products were purified by column chromatography (EtOAc/heptane,
1:6). The product was isolated as a mixture (∼1:1) of two
diastereoisomers. A small portion of the mixture was separated for
analytical purposes. The combined yield of both isomers was 514
mg (93%).
First Diastereoisomer. 1H NMR (CDCl3, 300 MHz): δ 7.43-
7.15 (m, 15H), 4.99-4.79 (m, 3H), 4.59-4.35 (m, 4H), 4.12 (m,
1H), 4.02 (dd, J ) 9.0, 11.5 Hz, 1H), 3.89 (s, 3H), 3.73 (m, 2H),
3.62 (dd, J ) 2.0, 11.3 Hz, 1H). 13C NMR (CDCl3, 75 MHz): δ
168.9, 138.0, 137.8 (2), 128.4 (2), 128.3, 128.0, 127.9, 127.8, 127.7
(2), 127.6, 96.1, 82.2, 79.3, 75.5, 75.0, 74.2, 73.4, 68.2, 54.0, 30.8.
[R]22 +3.9 (c 0.9, CH2Cl2).
D
Second diastereoisomer. 1H NMR (CDCl3, 300 MHz): δ 7.41-
7.14 (m, 15H), 4.88-4.48 (m, 7H), 4.09 (m, 2H), 3.88-3.72 (m,
3H), 3.84 (s, 3H), 3.46 (dd, J ) 4.1, 8.7 Hz, 1H). 13C NMR (CDCl3,
75 MHz): δ 168.9, 138.2, 138.0, 137.5, 128.4, 128.3 (2), 128.1,
128.0, 127.9 (2), 127.7, 127.5, 96.9, 76.7, 75.7, 75.2, 74.0, 73.4,
70.8, 68.7, 53.1, 35.0. [R]22 -10.1 (c 0.9, CH2Cl2).
cm-1. [R]22 +20.1 (c 0.25, CH2Cl2). HRMS (EI+): calcd for
D
D
Mixture. IR (CH2Cl2): ν 3030, 2981, 2870, 1725, 1264, 1186
cm-1. HRMS (ESI+): calcd for C29H31O7INa [M+Na]+, 641.1012;
found, 641.1000.
C15H24O8 [M]+, 332.1471; found, 332.1473.
3-Deoxy-D-manno-2-octulosonic Acid (KDO), Ammonium
Salt (2.NH3). A solution of 41 (5.9 mg) in 90% aqueous acetic
acid (5 mL) was heated to 90 °C for 45 min. Next, the mixture
was concentrated in vacuo, and the residue was dissolved 0.1 M
aqueous NaOH. The reaction was stirred at room temperature for
1 h, followed by the addition of Amberlyte IR-120+. After the
mixture was stirred for 30 min, the ion-exchange resin was filtered
off, and concentrated ammonia was added to obtain a pH of 11.
The mixture was again stirred for 30 min, after which the solvent
was evaporated, yielding the ammonium salt of 2 (4.2 mg, 99%).
(4R,5S,6R)-Methyl 4,5-Bis(benzyloxy)-6-(benzyloxymethyl)-
2-hydroxy-tetrahydro-2H-pyran-2-carboxylate (39). A solution
of 38 (49.5 mg, 80.0 µmol) and Et3N (35 µL, 0.25 mmol) in MeOH
(8 mL) was treated with 10% Pd/C (9 mg) and H2 (1 atm) for 18
h. After the reaction, the mixture was filtered over Celite and
concentrated, and the product was purified by column chromatog-
raphy (EtOAc/heptane, 1:4). The yield was 35 mg (89%). 1H NMR
(CDCl3, 300 MHz): δ 7.33-7.17 (m, 15H), 4.92-4.48 (m, 6H),
4.03 (m, 2H), 3.83 (s, 3H), 3.78-3.64 (m, 3H), 3.60 (dd, J ) 9.0,
9.8 Hz, 1H), 2.28 (dd, J ) 5.0, 12.6 Hz, 1H), 2.09 (t, J ) 12.2 Hz,
1H). 13C NMR (CDCl3, 75 MHz): δ 170.0, 138.2 (2), 138.0, 128.2,
128.1, 127.7, 127.6, 127.5, 127.4 (2), 94.9, 78.0, 77.6, 75.0, 73.4,
1
As expected,2,25 the H NMR spectrum in D2O showed a compli-
cated mixture of the R- and â-furanose and -pyranose forms, as
well as traces of lactone forms. The spectrum and the optical
rotation agreed with those of a purchased sample and with literature
data: [R]22 +38.8 (c 0.4, H2O) [purchased sample [R]22 +38.0
73.1, 71.9, 69.0, 53.4, 36.3. IR (CH2Cl2): ν 3052, 2987, 1754 cm-1
.
D
D
[R]22 +46.0 (c 0.2, CH2Cl2). HRMS (CI+): calcd for C29H32O7
(c 0.5, H2O); lit.25a [R]21 +39.5 (c 1.2, H2O)].
D
D
[M + H]+, 493.2226; found, 493.2228.
Acknowledgment. This research has been financially sup-
ported (in part) by the Council for Chemical Sciences of The
Netherlands Organization for Scientific Research (CW-NWO).
Irmgard Henning is acknowledged for kindly performing several
reactions. Christien A. Schortinghuis (Chiralix B.V., Nijmegen,
The Netherlands) is acknowledged for kindly providing the
preparative HPLC separations.
3-Deoxy-D-arabino-2-heptulopyranosonic Acid (DAH, 1). A
solution of 39 (6.2 mg, 12.6 µmol) in MeOH (1.5 mL) was treated
with 10% Pd/C (Degussa type E101 NE/W, H2O content 50%; 3
mg) and H2 (1 atm) for 1 h. 1H NMR of the reaction mixture showed
a quantitative conversion, and the mixture was filtered over Celite
and concentrated. The resulting DAH methyl ester was dissolved
in 1 N NaOH (4 mL) and stirred at room temperature for 1 h. The
mixture was neutralized with Amberlyte IR-120+, filtered, and
concentrated. The resulting solid was washed with EtOAc and dried,
giving 1 in a yield of 2.6 mg (99%). The analytical data were in
agreement with reported data.23 1H NMR (D2O, 400 MHz): δ
3.92-3.98 (m, 1H), 3.84-3.74 (m, 3H), 3.45 (t, J ) 9.3 Hz, 1H,
5-H), 2.20 (dd, J ) 5.1, 13.0 Hz, 1H, 3-H), 1.79 (t, J ) 12.5 Hz,
Supporting Information Available: Experimental procedures
and/or spectroscopic and analytical data including NMR spectra
for compounds 1, 2, 4, 9, 10, 13-16, 21-33, 36-39, 41. This
material is available free of charge via the Internet at http://
pubs.acs.org.
1H, 3-H). [R]22 +41.5 (c 0.25, D2O).
D
JO060913X
(3aR,4R,7aR)-Methyl 4-((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-
6-hydroxy-2,2-dimethyl-tetrahydro-3aH-[1,3]dioxolo[4,5-c]py-
ran-6-carboxylate (41). A solution of 40 (40 mg, 0.128 mmol)
(28) Norbeck, D. W.; Kramer, J. B.; Lartey, P. A. J. Org. Chem. 1987,
52, 2174.
6450 J. Org. Chem., Vol. 71, No. 17, 2006