Formal Synthesis of 3-Deoxy-D-manno-2-Octulosonic Acid (KDO) via a Highly Double-Stereoselective Hetero Diels-Alder Reaction Directed by a (Salen)CoII Catalyst and Chiral Diene

Article abstract of DOI:10.1021/jo971186w

This paper presents a formal total synthesis of 3-deoxy-D-manno-2-octulosonic acid (KDO) based on a highly double-stereoselective hetero Diels-Alder reaction between an electron-rich diene and ethyl glyoxylate catalyzed by (Salen)Co^II complex, a new catalyst for Diels-Alder reactions. A facial specific hydrofaoration followed by oxidative workup leads to a diol system with the trans-diequatorial arrangement of hydroxyl groups at the C-4 and C-5. Inversion of the configuration of the C-5 hydroxyl group in 12 and then ketal formation afford the desired target diisopropylidene-2-deoxy-KDO methyl ester (18), which can be converted to KDO according to the literature procedure.

Full text of DOI:10.1021/jo971186w

2456
J . Org. Chem. 1998, 63, 2456-2461
F or m a l Syn th esis of 3-Deoxy-D-m a n n o-2-Octu loson ic Acid (KDO)
via a High ly Dou ble-Ster eoselective Heter o Diels-Ald er Rea ction
Dir ected by a (Sa len )CoII Ca ta lyst a n d Ch ir a l Dien e
Yun-J in Hu, Xiao-Dong Huang, Zhu-J un Yao, and Yu-Lin Wu*
State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai, 200032, China
Received J uly 1, 1997
This paper presents a formal total synthesis of 3-deoxy-D-manno-2-octulosonic acid (KDO) based
on a highly double-stereoselective hetero Diels-Alder reaction between an electron-rich diene and
ethyl glyoxylate catalyzed by (Salen)CoII complex, a new catalyst for Diels-Alder reactions. A
facial specific hydroboration followed by oxidative workup leads to a diol system with the trans-
diequatorial arrangement of hydroxyl groups at the C-4 and C-5. Inversion of the configuration of
the C-5 hydroxyl group in 12 and then ketal formation afford the desired target diisopropylidene-
2-deoxy-KDO methyl ester (18), which can be converted to KDO according to the literature
procedure.
The monosaccharide 3-deoxy-D-manno-2-octulosonic
the value of Lubineau’s original protocol (as well as the
modified one) as a novel methodology for construction of
highly substituted tetra- or dihydropyrans is unequivocal,
the low (endo/exo, re/si) selectivities5,6 and the poor yields
of the cycloaddition reaction obviously thwart any pos-
sible synthetic applications. This prompted us to initiate
the work disclosed below.
We began our explorations with examining electron-
deficient dienes. The initial experiments with a 2-phen-
ylsulfonyl 1,3-diene were rather disappointing, for (with
or without Lewis acid catalysts) no reactions occurred at
all at room temperature. Later, it was found that the
expected reaction could take place at higher tempera-
tures. However, the low selectivities suggested that the
phenylsulfonyl was not a good activating group.7 This
result turned our attention to the electron-rich 2-silyloxy
dienes.
acid (KDO) is an essential constituent of the outer
membrane lipopolysaccharide (LPS) of Gram-negative
bacteria. It has been shown1 that the incorporation of
KDO is highly likely to be a vital step in the growth of
Gram-negative bacteria. For this reason KDO is chosen
by many workers as a lead in developing rationally
designed inhibitors for the cell-wall assembly process. As
a consequence of this trend, work toward the synthesis
of KDO and its analogues has accelerated, and several
such endeavors, including enzymatic syntheses,2 semi-
syntheses starting from carbohydrates,3a-c and de novo
syntheses,4 have already appeared in the literature.
We were attracted to this area by the work of
Lubineau3b et al., in which a hetero cycloaddition of chiral
dienes to glyoxylate was employed as the key step for
the construction of both 2-deoxy KDO and KDO. While
The needed silyloxy diene (6,8a Scheme 1) was prepared
from enones 3 and 48b (obtained as a 1:3 mixture from
the Wittig reaction between O-isopropylidene-D-glycer-
aldehyde8c and acetonylidenetriphenylphosphorane) and
tert-butyldimethylsilyl trifluoromethanesulfonate (tri-
flate).9 The TMS (trimethylsilyl) counterpart of 6 could
also be used, although it was less stable and much less
reactive than 6. The diene 6 was then treated with ethyl
glyoxylate (freshly distilled). After 4 hours of reaction
at 40 °C, all four possible adducts (8a -d ) were produced
(1) Levin, D. H.; Racker, E. J . Biol. Chem. 1959, 234, 2532. (b)
Unger, F. M. Adv. Carbohydr. Chem. Biochem. 1981, 38, 323. (c) York,
W. S.; Darvill, A. G.; McNeil, M.; Albersheim, P. Carbohydr. Res. 1985,
138, 109. (d) Claesson, A.; Luthman, K.; Gustafsson, K. Biochem.
Biophys. Res. Commun. 1987, 143, 1063. (e) Goldman, R.; Kohlbrenner,
W.; Lartey, P.; Pernet, A. Nature, 1987, 329, 162.
(2) For enzymatic syntheses of KDO (a) Bendnarski, M. D.; DiCo-
simo, R.; Simon, E. S.; Stein, P. D.; Whitesides, G. M. Tetrahedron
Lett. 1988, 29, 427. (b) Auge´, C.; Bouxom, B.; Cavaye´, B.; Gautheron,
C. Tetrahedron Lett. 1989, 30, 2217.
(3) For chemical synthesis see: (a) Lo´pez-Herrera, F. J .; Sarabia-
Garc´ıa, F. Tetrahedron 1997, 53, 3325. (b) Lubineau, A.; Auge J .; Lubin,
N. Tetrahedron 1993, 49, 4639 and references therein. (c) Shing, K.
M. Tetraheron 1992, 48, 6777 and ref 5 cited therein. Several other
methods for hetero Diels-Alder reactions have also been developed.
See (d) Boger, D. L.; Weinreb, S. M. Hetro Diels-Alder Methodology
in Organic Synthesis; Academic Press: San Diego, 1987. (e) J ohannsen,
M.; J ørgensen K. A. J . Org. Chem. 1995, 60, 5757. (f) McGinnis, M.
B.; Vagle K.; Green, J . F.; Tan, L. C.; Palmer, R.; Siler J .; Pagni, R.
M.; Kabalka, G. J . Org. Chem. 1996, 61, 3496. (g) Organ, M. G.; Winkle,
D. D. J . Org. Chem. 1997, 62, 1881. (h) Evans, D. A.; J ohnson, J . S. J .
Org. Chem. 1997, 62, 786. (i) Evans, P. A.; Nelson, J . D. J . Org. Chem.
1996, 61, 7600. For reviews on the hetero Diels-Alder reactions. See:
(j) Danishefsky, S. Aldrichimica Acta 1986, 19, 59. (k) Schmidt, R. R.
Acc. Chem. Res. 1986, 19, 250. (l) Danishefsky, S. J . Chemtracts: Org.
Chem. 1989, 273. (m) Bednarski, M. D.; Lyssikatos, J . P. In Compre-
hensive Organic Synthethsis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: New York, 1991; Vol. 2, p 661.
(5) Li, C. J . Chem. Rev. 1993, 93, 2023. (b) Blokzijl, W.; Engberts,
J . B. F. N. Angew. Chem., Int. Ed. Engl. 1993, 32, 1545. (c) Auge´, J .;
Queneau, Y. Synthesis, 1994, 741.
(6) Lubineau, A.; Arcostanzo H.; and Queneau Y.; J . Carbohydr.
Chem. 1995, 14, 1307. (b) Lubineau, A.; Queneau, Y.; J . Carbohydr.
Chem. 1995, 14, 1295.
(7) See: (a) Andell, O. S.; Ba¨ckvall, J .-E. Tetrahedron Lett. 1985,
26, 4555. (b) Ba¨ckvall, J .-E. Bull. Soc. Chim. Fr. 2 1987, 665. (c)
Ba¨ckvall, J .-E.; J untunen, S. K. J . Am. Chem. Soc. 1987, 109, 6396.
(8) Galley, G.; Pa¨tzel, M. J . Chem. Soc., Perkin Trans. 1 1996, 2297.
(b) Enone 4 has been reported before (but it was likely to be a mixture
of 3 and 4): Ronnenberg, H.; Borch, G.; Buchecker, R.; Arpin, N.;
Liaaen-J enson, S. Phytochemistry 1982, 21, 2087. (c) J urczak, J .; Pikul,
S.; Bauer, T. Tetrahedron 1986, 42, 447.
(4) For de novo syntheses, see: (a) Martin, S. F.; Zinke, P. W. J .
Org. Chem. 1991, 56, 6600. (b) Smith, D. B.; Wang, Z.; Schreiber, S.
L. Tetrahedron 1990, 46, 4793. (c) Danishefsky, S. J .; DeNino, M. P.;
Chen, S.-H. J . Am. Chem. Soc. 1988, 110, 3929.
(9) Emde, H.; Gotz, A.; Hofmann, K.; Simchen, G. Liebigs Ann.
Chem. 1981, 1643. (b) Corey, E. J .; Cho, H.; Hua, D. H. Tetrahedron
Lett. 1981, 22, 3455. (c) Kozikowski, A. P.; Thaddeus, R. N.; Springer,
J . P. Tetrahedron 1986, 27, 819.
S0022-3263(97)01186-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/24/1998

Synthesis of 3-Deoxy-D-manno-2-Octulosonic Acid
J . Org. Chem., Vol. 63, No. 8, 1998 2457
Sch em e 1
Sch em e 3
Sch em e 2
Ta ble 1. Resu lts of Cycloa d d ition of Dien e 6 to Eth yl
Glyoxyla te in CH2Cl2
temp yield
entry catalyst
(°C)
(%) 8a :8b:8c:8d endo/exo si/re
1
2
3
4
5
6
7
8
9
none
none
none
ZnCl2
60
20
0
90
50
30
60
65
75
90
85
50b
35:20:21:24
40:16:23:21
56:11:20:13
45:15:23:17
45:15:26:14
22:11:44:23
65:12:21:2
80:5:13:2
56/44
63/37
76/24
68/32
71/29
66/34
86/14
93/7
55/45
56/44
67/33
60/40
60/40
33/67
77/23
85/15
81/19
-78
Et2AlCla -78
10
11
11
11
-78
40
20
0
77:4:14:5
91/9
a
Strong Lewis acids such as AlCl3 and BF3‚OEt2 decompose 6
b
and therefore cannot be used here. When the reaction temper-
ature was below -30 °C, lower yields were obtained even after
prolonged reaction.
were 6.7 and 3.8 Hz, respectively, the absolute configura-
tions at the C6 were assigned to S for 9a (and conse-
quently 8a ) and R for 9c (and consequently 8c). Further
evidence for the stereochemistries of the major isomers
9a and 9c was obtained from the phase-sensitive NOESY
experiments, which showed significant cross-peaks cor-
relating the H2, H5, and H6.10 With the stereochemis-
tries of 8a and 8c established, the remaining two isomers
(8b and 8d ) were also easily assigned by analogy.
Having found a satisfactory diene and established the
essential means to identify the product isomers, we were
now in a position to deal with the selectivity problem.
We first examined the temperature effect. It appeared
(Table 1) that with the increase of the reaction temper-
ature, the yield increased significantly but the selectivi-
ties became even poorer, implying the necessity of using
a catalyst. We then tested a few common Lewis acids.
The strong acids such as BF3‚OEt2 and AlCl3 led to
decomposition of 6 and therefore were not suitable for
our purpose. ZnCl2 and Et2AlCl speeded up the reaction
dramatically. However, the selectivities were still rather
poor. It seemed to us at this point that only the chiral
induction from the substrate was not enough. Therefore
we tried next the chiral vanadium catalyst 1011 (Scheme
4). The result was somewhat to our surprise; besides the
expected rate acceleration, the re/si selectivity was
reversed. This was later attributed to the mismatched
chiral induction effect of the catalyst (which worked
against that of the substrate, see below), so that the
(Scheme 2) in 90% total yield. These isomers were then
separated on silica gel and characterized separately
(except 8d , which could not be obtained in high purity).
To facilitate the assignment of the stereochemistries
of C2 and C6, the major components 8a and 8c were
converted to corresponding diacetates 9a and 9c (Scheme
1
3) and subjected to intensive H NMR analyses. The 3J 2,3
values for both 9a and 9c were found to be 2.4 and 12.3
Hz, which were consistent with the known rule that in
3
cyclohexane systems J a,e should be significantly smaller
3
than J a,a (If the H were in an equatorial position, the
3
3
two J ’s would be the same because J e,e ≈ J a,e). There-
fore, the orientation of the H at C2 is assigned to axial
(which means that these adducts were formed through
an endo transition state).
The stereochemistry of C6 was established according
to the empirical rules in the literature,10 i.e., the KDO
type of configuration has a “large” 3J 6,7 (6-7 Hz) whereas
the KDN or sialic acid type of configuration has a “small”
(10) Brandstetter, H. H.; Zbiral, E. Liebigs Ann. Chem. 1983, 2055.
(b) Zbiral, E.; Brandstetter, H. H. Monatsh. Chem. 1985, 116, 87. (c)
Salunkhe, M.; Hartmann, M.; Schmid, W.; Zbiral, E. Liebigs Ann.
Chem. 1988, 187. (d) Zbiral, E.; Schreiner, E,; Salunkhe, M.; Schulz,
G.; Kleineidam, R. G.; Schauer, R. Liebigs Ann. Chem. 1989, 519.
3
3J 6,7 (0-3.5 Hz). Since the observed J 6,7’s for 9a and 9c

2458 J . Org. Chem., Vol. 63, No. 8, 1998
Hu et al.
Sch em e 4
matched with that of the substrate so that one of the
isomers, 8a , predominated over others. This compound
has the same stereochemistry at C6 as KDO’s and
therefore could be very useful as a precursor to KDO type
of compounds.
In the present work, further elaboration of 8a was done
as shown in Scheme 5, starting with introducing a
hydroxyl group at the C5 by hydroboration. Due to the
steric hindrance15 caused by the substituent at C6, the
OH “entered” from the wrong direction. An inversion of
configuration at C5 thus became unavoidable. We first
tried Mitsunobu reaction. Unfortunately, this did not
work out. So we had to take a round-about way to
oxidize16 12 into 14, followed by reducing it to 13 with a
proper reducing agent. To our delight, after failure with
BH3 (with which no reactions occurred, even under
forcing conditions) and L-Selectride (giving rather com-
plicated products) the desired 13 could be obtained as
the sole product by reduction at -15 °C with NaBH4/
CeCl3 in ethanol. At higher temperature (0 °C), the ester
group was also reduced.
Exposure of the intermediate 13 to acidic ion-exchange
resin Amberlyst 15 in methanol at 40 °C removed both
the TBS and isopropylidene protecting groups in 13. After
masking the diols as diacetonides with 2,2-dimethoxy-
propane, 17 and 1817 (formed via ester exchange) were
obtained, which could be converted to KDO by the
literature procedure.3,18
attack of the dienophile occurred mainly on the re face
of the diene, giving 8c and 8d .
Salen-derived compounds12,13 have found wide applica-
tions in many types of asymmetric reactions (but not
Diels-Alder reactions) in recent years. Enlightened by
these successful cases, we tested the (Salen)CoII complex
(11)14 in our reaction. We were pleased to find that with
this compound as catalyst the cycloaddition reaction
underwent easily and exhibited good double diastereo-
selectivity. At 40 °C, the total yield was as high as 90%
although the endo/exo and si/re selectivities were only 86/
14 and 77/23, respectively (Table 1). The selectivities
were remarkably improved (endo/exo ) 93/7, si/re ) 85/
15) when the reaction temperature was lowered to 20 °C.
Further decreasing the temperature, however, was not
rewarding; the yield was significantly reduced but the
selectivities were not getting any better.
In contrast to the situation with catalyst 10, the
asymmetric induction effect of the 11 seems to be
Su m m a r y
(11) Togni A. Organometallics 1990, 9, 3106.
(12) Groves, J . T.; Viski, P. J . Org. Chem. 1990, 55, 3628. (b) Zhang,
W.; Loebach, J . L.; Wilson, S. R. (b) J acobsen, E. N. J . Am. Chem. Soc.
1990, 112, 2801. (c) J acobsen, E. N.; Zhang W.; Muci, A. R.; Ecker, J .
R.; Deng L. J . Am. Chem. Soc. 1991, 113, 7063. (d) Lee, N. H.; Chang,
S.; Lee, N. H.; J acobsen, E. N. J . Org. Chem. 1993, 58, 6939. (e)
Collman, J . P.; Lee, V. J .; Zhang, X.; Ibers, J . A.; Brauman, J . I. J .
Am. Chem. Soc. 1993, 115, 3834. (f) J acobsen, E. N.; Deng, L.;
Furukawa, Y.; Mart´ınez, L. E. Tetrahedron 1994, 50, 4323. (g) Chang,
S.; Heid, R. M.; J acobsen, E. N. Tetrahedron Lett. 1994, 35, 669. (h)
Brandes, B. D.; J acobsen, E. N. J . Org. Chem. 1994, 59, 4378.
(13) Mart´ınez, L. E.; Leighton, J . L.; Carsten, D. H.; J acobsen, E.
N. J . Am. Chem. Soc. 1995, 117, 5897 and references therein. For
leading references on Cr(Salen) complexes see: (b) Larkworthy, L. F.;
Nolan, K. B.; O′Brien, P. In Comprehensive Coordination Chemistry;
Wilkinson, G., Ed.; Pergamon: Oxford, 1987; Vol. 3, Chapter 35.4.8.
(c) Samsel, E. G.; Srinivasan, K.; Kochi, J . K. J . Am. Chem. Soc. 1985,
107, 7606.
In the preceding paragraphs we present a successful
hetero Diels-Alder reaction between an electron-rich
diene and ethyl glyoxylate, where with the (Salen)CoII
complex 11 as catalyst (which has not been tested for
Diels-Alder and hetero Diels-Alder reactions before)
good selectivities (endo/exo ) 93/7, si/re ) 85/15) were
achieved. The major product 8a was further elaborated
into diisopropylidene-2-deoxy-KDO methyl ester 18 and
thus completed a formal total synthesis of KDO.
Exp er im en ta l Section
Gen er a l. Melting points (mp) were uncorrected. IR spectra
were recorded on a Shimadzu IR-440 spectrometer. 1H and
13C NMR were recorded on EM-360A, FX 90q, AMX-300, or
AMX-600 spectrometers with TMS as an internal standard.
Mass spectra were taken on VG Quattro MS/MS, HP5989A,
Finnigan Mat 8430 instruments. Optical rotations were
measured on a Perkin-Elmer 241 MC polarimeter. Flash
column chromatography was performed on silica gel H (10-
40 µm) and with petroleum ether-ethyl acetate system as
eluant. Microanalyses were carried out in the Microanalytical
Laboratory at Shanghai Institute of Organic Chemistry.
(4S)-(Z)-4,5-(Isop r op ylid en ed ioxy)h exa -3-en -2-on e (3)
a n d (4S)-(E)-4,5-(Isop r op ylid en ed ioxy)h exa -3-en -2-on e
(4).8b To a solution of O-isopropylidene-D-glyceraldehyde (1.3
g, 10 mmol, freshly prepared from 1,2:5,6-di-O-isopropylidene-
D-mannitol) in 150 mL of THF was added 3.82 g (12 mmol) of
acetonylidenetriphenylphosphorane. This solution was re-
fluxed for 2 h. After cooling, the reaction mixture was passed
(14) [(R,R)-N,N′-Bis(3,5-di-tert-butylsalicyclidene)-1,2-cyclohexane-
diaminato(2-)]cobalt (11) was prepared as follows: NaOH (95%, 421
mg) in anhydrous EtOH (25 mL) was added to a mixture of the ligand
(2.73 g, 5 mmol, 1.0 equiv) in ethanol (25 mL). After completion of the
addition, the mixture was heated to reflux with stirring for ca. 30 min
until the suspension became a solution. CoCl2‚6H2O (1.20 g, 5 mmol,
1 equiv) in anhydrous ethanol (25 mL) was then added over 45 min.
The addition funnel was rinsed with ethanol (3 mL), and the stirring
was continued at reflux for 4 h. The reaction was monitored by TLC
(EtOAc/petroleum ether 1:4; free ligand Rf ) 0.95; 11 Rf ) 0.10. EtOAc/
hexane 1:2; 11 Rf ) 0.50) until no free ligand was left. The mixture (a
dark yellow solution over a thick, medium brown oily layer) was
allowed to cool to room temperature. The precipitated brown solid was
collected by suction filtration and then dried under high vacuum at
50-60 °C for 1 h to yield the desired catalyst 11 (a brown, water-soluble
powder, 2.76 g, 92%) as an orange crystal: mp >330 °C. [R]20 -1100
D
(c, 0.01, CH2Cl2). IR (neat): 2951, 1610, 1595, 1527, 1360, 1254, 1176,
787, 758, 543 cm-1. EIMS (m/z): 603 (M+, 100.00), 588 (63.66), 516
(5.17), 286 (36.86), 276 (5.92), 260 (5.08), 258 (6.52), 242 (2.42), 57
(3.88). HREIMS calcd for C36H52N2O2Co 603.3361. Found 603.3354.
Preparative scale isolation of 11 was most conveniently achieved by
crystallization from ethanol. We finished the above preparation two
years ago. After we had sent in the first version of this manuscript,
we noticed Leung’s report on the X-ray crystal structure of (R,R)-
Salen(Co): Leung, W.-H.; Chan, E. Y.; Chow, E. K. F.; Williams, I. D.;
Peng, S.-M. J . Chem. Soc., Dalton Trans. 1996, 1229. More recently,
J acobsen also reported on the use of (S,S)-Salen(Co), the enantiomer
of 11, in enantioselective catalytic ring-opening of epoxides by car-
boxylic acids: J acobsen, E. J .; Kakiuchi, F.; Konsler, R.; Larrow, J .
F.; Tokunaga, M. Tetrahedron Lett. 1997, 38, 773.
(15) Larrow, J . F.; J acobsen, E. N.; Gao, Y.; Hong, Y.; Nie, X.; Zepp,
C. M., J . Org. Chem. 1994, 59, 1939.
(16) J onnson, F. Chem. Rev. 1968, 68, 375. (b) Vereshchagin A. N.
Russ. Chem. Rev. 1983, 52, 1081.
(17) Luthman, K.; Orbe, M.; Waglund, T.; Claesson, A. J . Org. Chem.
1987, 52, 3777.
(18) Adinolfi, M.; Barone, G.; Corsaro, M. M.; Lanzetta, R.; Mangoni
L.; Monaco, P. J . Carbohydrate. Chem. 1995, 14, 913.

Synthesis of 3-Deoxy-D-manno-2-Octulosonic Acid
J . Org. Chem., Vol. 63, No. 8, 1998 2459
Sch em e 5
through a short pad of silica gel (10% ethyl acetate-petroleum
as eluant) to remove the triphenylphosphine oxide. The
filtrate was concentrated and subjected to flash chromatog-
raphy eluted with 10% ethyl acetate-petroleum ether to give
1.21 g (7.1 mmol, 71%) of 4 and 0.40 g (2.4 mmol, 24%) of 3 as
1.6 Hz, H-5), 4.28 (1 H, dd, J ) 10.9, 3.8 Hz, H-2), 4.19 (2 H,
q, J ) 7.1 Hz, OCH2CH3), 4.16 (1 H, m, H-7), 4.02 (1 H, dd, J
) 8.1, 6.1 Hz, H-8), 3.94 (1 H, dd, J ) 8.1, 5.2 Hz, H-8), 3.92
(1 H, m, H-6), 2.35 (1 H, m), 2.21 (1 H, m), 1.38 (3 H, s), 1.29
(3 H, s), 1.26 (3 H, t, J ) 7.1 Hz, OCH2CH3), 0.94 (9 H, s), 0.20
(6 H, s). ESIMS (m/z): 409 (M+ + Na) 387 (M+ + 1), 369,
329, 311, 255, 237, 197, 179, 149, 73. Anal. Calcd for
a clear oil. Compound 3: TLC: Rf ) 0.32. [R]20 +188.3 (c,
D
3.7, CHCl3). IR (neat): 2988, 2939, 1695, 1616, 1406, 1381,
1258, 1215, 1162, 1057, 858 cm-1
.
1H NMR (90 MHz, CDCl3):
C19H34O6Si: C, 59.04; H, 8.87. Found: C, 59.06; H, 9.01.
δ 6.27 (1 H, d, J ) 2.1 Hz), 6.38 (1 H, dt, J ) 6.9, 2.1 Hz), 4.46
(1 H, t, J ) 7.8 Hz), 4.10 (1 H, m), 3.60 (1 H, t, J ) 7.8 Hz),
2.26 (3 H, s), 1.49 (3 H, s), 1.42 (3 H, s).
Compound 8b: Rf ) 0.29. [R]20 +20.0 (c, 1.93, CHCl3). IR
D
(neat): 2960, 1745, 1372, 1226, 1195, 1149, 1102, 1050, 813,
602 cm-1 1H NMR (600 MHz, CD3COCD3): δ 4.81 (1 H, m,
.
Compound 4: Rf ) 0.30. [R]20D +42.7 (c, 3.8, CHCl3). (lit.8b
H-5), 4.63 (1 H, dd, J ) 6.0, 3.9 Hz, H-2), 4.56 (1 H, m, H-6),
4.17 (2 H, q, J ) 7.1 Hz), 4.13-4.19 (1 H, m, H-7) 3.94 (1 H,
dd, J ) 8.2, 6.7 Hz, H-8), 3.75 (1 H, dd, J ) 8.2, 6.5 Hz, H-8),
2.44 (1 H, m, H-3), 2.35 (1 H, m, H-3), 1.34 (3 H, s), 1.29 (3 H,
s), 1.23 (3 H, t, J ) 7.1 Hz), 0.92 (9 H, s), 0.172 (3 H, s), 0.168
(3 H, s). EIMS (m/z): 317 (37.4), 299 (7.2), 2.89 (13.3), 257
(18.2), 225 (19.9), 203 (43.3), 197 (49.8), 183 (26.1), 175 (43.6),
165 (89.2), 143 (31.1), 117 (100.0), 43 (97.7). Anal. Calcd for
[R]25 +49.5). IR (neat): 2988, 1687, 1373, 1258, 1221, 1178,
D
1061, 939, 660 cm-1
.
1H NMR (90 MHz, CDCl3): δ 6.82 (1 H,
dd, J ) 16.8, 5.7 Hz), 6.26 (1 H, d, J ) 16.8 Hz), 6.64 (1 H, m),
4.16 (1 H, t, J ) 7.5 Hz), 3.68 (1 H, t, J ) 7.5 Hz), 2.24 (3 H,
s), 1.44 (3 H, s), 1.42 (3 H, s).
(1′E,4S)-4-[3′-(ter t-Bu tyld im eth ylsilyloxy)bu ta -1′,3′-d i-
en yl]-2,2-d im eth yl-1,3-d ioxola n e (6).8a To an ice-cooled
solution of 4 (1.10 g, 6.5 mmol) in ether (20 mL) were added
dropwise 1.41 g (10.2 mmol) of triethylamine and 2.23 g (8.44
mmol) of tert-butyldimethylsilyl triflate. After stirring for 5
min, the cooling bath was removed, and the two-phase mixture
was stirred at 0 °C for 15 min and then at 20 °C for 1 h. The
mixture was concentrated and passed through a pad of silica
gel (petroleum ether as the eluant) to give 1.85 g (6.5 mmol,
C
19H34O6Si: C, 59.04; H, 8.87. Found: C, 59.03; H, 9.00.
Compound 8c: Rf ) 0.28. [R]20 -21.1 (c, 1.33, CHCl3). IR
D
(neat): 2961, 1745, 1437, 1121, 1195, 1102, 947, 775 cm-1. 1H
NMR (600 MHz, CD3COCD3): δ 4.86 (1 H, t, J ) 1.7 Hz, H-5),
4.38 (1 H, m, H-7), 4.26 (1 H, dd, J ) 11.0, 3.7 Hz, H-2), 4.22
(1 H, dd, J ) 11.6, 5.7 Hz, H-6), 4.17 (2 H, q, J ) 7.1 Hz), 3.95
(1 H, dd, J ) 8.4, 7.0 Hz, H-8), 3.73 (1 H, dd, J ) 8.4, 5.9 Hz,
H-8), 2.33 (1 H, m, H-3), 2.19 (1 H, m, H-3), 1.38 (3 H, s), 1.28
(3 H, s), 1.23 (3 H, t, J ) 7.1 Hz), 0.92 (9 H, s), 0.19 (3 H, s),
0.18 (3 H, s). EIMS (m/z): 317 (14.3), 289 (7.9), 257 (9.1), 225
(8.4), 213 (8.5), 203 (42.8), 197 (30.5), 175 (37.4), 165 (63.9),
143 (27.5), 117 (100.0), 83 (15.7), 55 (12.7). Anal. Calcd for
100%) of 68a as a thick, yellow oil: Rf ) 0.20. [R]20 +17.0 (c,
D
1.2, CH2Cl2). 1H NMR (90 MHz, CDCl3): δ 6.12 (1 H, d, J )
15.2 Hz), 5.92 (1 H, dd, J ) 15.2, 7.1 Hz), 4.56 (1 H, q, J ) 7.1
Hz), 4.31 (2 H, s), 4.09 (1 H, dd, J ) 8.5, 6.3 Hz), 3.58 (1 H, t,
J ) 8.0 Hz), 1.42 (3 H, s), 1.38 (3 H, s).
Eth yl 2,5-Did eoxy-4-O-(ter t-bu tyld im eth ylsilyl)-6,7-O-
isop r op ylid en -4-en e-D-r ibo- a n d -D-a r a bin o-octon a te (8a
a n d 8c). Th er m a l Diels-Ald er Rea ction s. A mixture of
diene 6 (2.84 mg, 1.0 mmol) and ethyl glyoxylate (112 mg, 1.1
mmol) was heated at 60 °C in an autoclave for 4 h. The
reaction mixture was cooled and passed through a silica gel
column by using 5% ethyl acetate-petroleum as the eluant to
give 8a , 8b, and 8c in 90% yield as colorless oil (pure 8d could
C
19H34O6Si: C, 59.04; H, 8.87. Found: C, 59.36; H, 9.11.
Ca ta lyzed Diels-Ald er Rea ction s. A solution of the
catalyst (0.1 mmol) was added to ethyl glyoxylate (1.1 mmol,
112 mg) in toluene (2 mL). The mixture was stirred at a
particular temperature (see Table 1) for 10 min. Then diene
6 (1.0 mmol, 284 mg) was added, and the resulting solution
was stirred until TLC showed the completion of the reaction.
Water (2 drops) was added to destroy the Lewis acid, and the
mixture was then diluted with dichloromethane. The solution
was filtered with suction through Celite, and the filter cake
was washed several times with dichloromethane. The filtrate
not be obtained). Compound 8a : Rf ) 0.30. [R]20 +42.0 (c,
D
1.58, CHCl3). IR (neat) 2980, 1743, 1374, 1194, 1103, 815, 640
cm-1
.
1H NMR (600 MHz, CD3COCD3): δ 5.12 (1 H, t, J )

2460 J . Org. Chem., Vol. 63, No. 8, 1998
Hu et al.
was dried over MgSO4 and concentrated under reduced pres-
sure before being subjected to column chromatography.
Eth yl 2,5-Did eoxy-4,4-d im eth yl-6,7-O-d ia cetyl-D-r ibo-
octon a te (9a ). Compound 8a (300 mg, 1.06 mmol) and
Amberlyst 15 ion-exchange resin (100 mg) in 10 mL of
methanol was stirred and heated at 60 °C for 3 h. (Longer
reaction time led to ester exchange; the ethyl ester was
converted to the methyl ester). After being cooled and filtered,
the reaction mixture was then diluted with dichloromethane
and washed with water (2 × 2 mL). After evaporation of the
solvent, acetylation of the residue with a mixture of acetic
anhydride and pyridine (1:1.1, 2 mL) produced compound 9a
(345 mg, 0.95 mmol) in 90% yield. Compound 8c was subjected
to the same conditions as above, giving 9c in 91% yield.
1.72 (1 H, q, J ) 12 Hz, H-3), 1.39 (3 H, s), 1.32 (3 H, s), 1.22
(3 H, t, J ) 7.1 Hz), 0.90 (9 H, s), 0.15 (3 H, s), 0.14 (3 H, s).
EIMS (m/z): 387 (M+ - 15, 1.0), 343 (8.8), 311 (7.1), 285
(100.0), 243 (36.8), 211 (11.0), 197 (17.9), 185 (4.4), 171 (13.2),
149 (23.6), 129 (12.4), 101 (85.9), 73 (55.8). HR EIMS calcd
for C18H31O7Si (M+ - CH3) 387.1839. Found 387.1849.
Eth yl 2,5-Did eoxy-4-O-(ter t-bu tyld im eth ylsilyl)-5-h y-
d r oxy-6,7-O-isop r op ylid en e-D-glycer o-octon a te (13). To
a
mixture of sodium borohydride (76 mg, 2 mmol) and
CeCl3‚7H2O (75 mg, 0.2 mmol) in ethanol (15 mL) stirred at
-15 °C was added dropwise ketone 14 (402 mg, 1 mmol,
dissolved in 10 mL of EtOH). The addition funnel was rinsed
with ethanol (3 mL), and the mixture was stirred at -15 °C
for 3 h before 10 mL of water was added to quench the reaction.
The mixture was extracted with several portions of ether. The
combined ether layers were washed with water and dried over
anhydrous sodium sulfate. Flash chromatography (petroleum
ether/EtOAc, 1:1, v/v) gave compound 13 as an oil (280 mg,
Compound 9a : Rf ) 0.30 (petroleum ether-EtOAc 2:1). [R]20
D
+25.3 (c, 0.23, CHCl3). IR (neat): 2966, 1743, 1317, 1244,
1197, 1050, 669 cm-1 1H NMR (300 MHz, CDCl3): δ 5.09 (1
.
H, dt, J ) 6.4, 3.0 Hz, H-7), 4.48 (1 H, dd, J ) 12.1, 3.0 Hz,
H-8), 4.22 (1 H, dd, J ) 12.1, 3.0 Hz, H-8), 4.21 (2 H, q, J )
7.2 Hz), 4.12 (1 H, dd, J ) 12.2, 2.4 Hz, H-2), 3.70 (1 H, ddd,
J ) 11.9, 6.4, 2.4 Hz, H-6), 3.22 (3 H, s), 3.21 (3 H, s), 2.28 (1
H, m), 2.13 (1 H, m), 2.08 (3 H, s), 2.05 (3 H, s), 1.50 (2 H, m),
1.28 (3 H, t, J ) 7.2 Hz). EIMS (m/z): 317 (M+ - OEt, 1.0),
285 (3.2), 201 (26.9), 183 (8.9), 171 (58.2), 141 (11.8), 123 (49.2),
101 (15.4), 71 (15.8), 43 (100.0). HR EIMS calcd for C14H21O8
(M+ - OEt) 317.1236. Found: 317.1236.
70% yield): Rf ) 0.33. [R]20
:
-12.2 (c, 0.26, CHCl3). IR
(neat): 3300, 2978, 1750, 1384, 1371, 1226, 1210, 1196, 1150,
1106, 1063, 881, 846, 514 cm-1 1H NMR (300 MHz, CD3-
D
.
COCD3): δ 4.29 (1 H, q, J ) 6.7 Hz, H-7), 4.14 (2 H, q, J ) 7.1
Hz, OCH2CH3), 4.13-4.02 (2 H, m), 4.01 (1 H, dd, J ) 8.5, 6.2
Hz, H-8), 3.93 (1 H, dd, J ) 8.5, 5.5 Hz, H-8), 3.80 (1 H, dd, J
) 0.5, 3.0 Hz), 3.40 (1 H, dd, J ) 7.5, 1.2 Hz), 1.90 (2 H, m),
1.32 (3 H, s), 1.27 (3 H, s), 1.22 (3 H, t, J ) 7.1 Hz, OCH2CH3),
0.90 (9 H, s), 0.12 (3 H, s), 0.11 (3 H, s). EIMS (m/z): 404(M+,
0.5), 389 (M+ - 15, 3.1), 345 (2.1), 309 (3.2), 257 (7.2), 243
Compound 9c: Rf ) 0.31 (petroleum ether-EtOAc, 2:1).
[R]20 -22.4 (c, 0.34, CHCl3). IR (neat): 2840, 1745, 1373,
D
1250, 1166, 1080, 99 cm-1
.
1H NMR (300 MHz, CDCl3): δ 5.16
(6.6), 197 (8.4), 169 (9.9), 101 (100.0). HR EIMS calcd for C19
H36O7Si: 404.2230. Found: 404.2184.
-
(1 H, m, H-7), 4.38 (1 H, dd, J ) 12.0, 3.8 Hz, H-8), 4.21 (1 H,
dd, J ) 12.0, 7.4 Hz, H-8), 4.10 (2 H, q, J ) 7.1 Hz), 4.09 (1 H,
dd, J ) 12.2, 2.4 Hz, H-2), 3.78 (1 H, ddd, J ) 12.0, 3.8, 2.1
Hz, H-6), 3.20 (3 H, s), 3.17 (3 H, s), 2.28 (1 H, dd, J ) 13.5,
2.4 Hz, H-3), 2.10 (3 H, s), 2.02 (3 H, s), 1.89 (1 H, dd, J )
13.5, 2.1 Hz, H-5), 1.55 (1 H, dd, J ) 13.3, 12.2 Hz, H-3), 1.41
(1 H, dd, J ) 13.5, 12.0 Hz, H-5), 1.24 (3 H, t, J ) 7.1 Hz).
EIMS (m/z): 317(M+ - OEt, 6.0), 257 (4.0), 243 (22.6), 199
(2.6), 183 (34.2), 165 (49.3), 157 (40.5), 123 (25.9), 113 (13.5),
97 (14.8). HR EIMS calcd for C14H21O8 (M+ - OEt) 317.1236.
Found: 317.1200.
Eth yl a n d Meth yl 2,6-An h yd r o-3-d eoxy-4,5:7,8-d i-O-iso-
p r op ylid en e-D-glycer o-D-ga la cer o-D-ga la cto-octon a te (17
a n d 18).17 Compound 13 (404 mg, 1.0 mmol) and Amberlyst
15 ion-exchange resin (200 mg) in 100 mL of methanol was
heated at 60 °C for 3 h. The mixture was then cooled, diluted
with CH2Cl2, and washed with water (2 × 2 mL). After
evaporation of the solvent, the residue was dissolved in a
mixture of freshly distilled 2,2-dimethoxypropane (0.5 mL),
and anhydrous acetone (3 mL), p-toluenesulfonic acid (1 mg),
and MgSO4 (1.0 g) were added. After stirring at room
temperature for 3 h, the mixture was concentrated, and the
residue was chromatographed on silica gel with ethyl acetate/
petroleum (1:3) as eluant, affording 17 (15.8 mg) and 18 (271.8
Eth yl 2,5-Did eoxy-4-O-(ter t-bu tyld im eth ylsilyl)-5-h y-
d r oxy-6,7-O-isop r op ylid en e-D-glycer o-octon a te (12). To
0.518 mL of 2.0 N borane in tetrahydrofuran at 0 °C under
nitrogen was added 200 mg (0.518 mmol) of 8a in 7 mL of
anhydrous tetrahydrofuran. The reaction mixture was stirred
at 0 °C for 30 min, before 2 mL of water, 1.5 mL of 20% sodium
hydroxide solution, and finally 1.2 mL of 30% hydrogen
peroxide were introduced in turn. The reaction mixture was
then extracted with several portions of ether. The combined
ethereal phases were washed with water and dried over
anhydrous sodium sulfate. Flash chromatography (petroleum
ether/EtOAc, 1:1, v/v) gave compound 12 as an oil (188 mg,
90%, yield): Rf ) 0.30. IR (neat): 3600-3850, 2950, 2880,
mg) as an oil in 95% yield. Compound 17: Rf ) 0.33. [R]20
D
+29.8 (c, 1.5, CHCl3). IR (neat): 2978, 1750, 1384, 1371, 1226,
1063 cm-1 1H NMR (300 MHz, CD3COCD3): δ 4.43 (1 H, dt,
.
J ) 8.3, 5.9 Hz, H-7), 4.27 (1 H, dt, J ) 7.4, 5.7 Hz, H-4), 4.19
(1 H, dd, J ) 5.7, 2.1 Hz, H-5), 4.17 (2 H, m, OCH2CH3), 4.13
(1 H, m, H-2), 4.03 (2 H, m, H-8), 3.71 (1 H, dd, J ) 7.4, 2.1
Hz, H-6), 2.14 (1 H, ddd, J ) 13.6, 6.0, 3.7 Hz, H-3), 1.80 (1 H,
ddd, J ) 13.6, 9.7, 8.4 Hz, H-3), 1.42 (3 H, s), 1.35 (3 H, s),
1.29 (3 H, s), 1.28 (3 H, s), 1.23 (3 H, t, J ) 7.1 Hz). EIMS
(m/z): 363 (M+ + 1, 0.5), 347 (M+ - 15, 15.0), 305 (6.1), 269
(2.8), 247 (9.6), 229 (13.5), 211 (12.4), 203 (26.6), 75 (100.0).
1744, 1371, 1244, 1223, 1145, 1049, 700 cm-1 1H NMR (300
.
MHz, CD3COCD3): δ 4.14 (2 H, q, J ) 7.1 Hz), 4.10-3.80 (6
H, m), 3.54 (1 H, dd, J ) 11.5, 6.0 Hz), 1.33 (3 H, s), 1.24 (3 H,
s), 1.22 (3 H, t, J ) 7.14 Hz), 0.86 (9 H, s), 0.08 (3 H, s), 0.07
(3 H, s). EIMS (m/z): 357 (M+ - OEt, 19.2), 283 (19.8), 243
(29.7), 225 (47.6), 181 (58.3), 151 (64.4), 135 (44.4), 119 (37.2),
109 (33.1), 101 (37.9), 81 (83.9), 73 (100.0), 55 (57.6), 43 (87.6).
HR EIMS calcd for C18H33O7Si 389.1996. Found 389.2025.
Eth yl 2,5-Did eoxy-4-O-(ter t-bu tyld im eth ylsilyl)-6,7-O-
isop r op ylid en e-5-on e-D-glycer o-octon a te (14). Compound
12 (100 mg, 0.25 mmol), pyridinium chlorochromate (320 mg),
and activated molecular sieves (200 mg) in dry benzene (8 mL)
were heated under refluxed for 1 h. The reaction mixture was
filtered through a short silica gel column (benzene) to give
compound 14 as an oil (79 mg, 80%): Rf ) 0.33. [R]20D: +18.9
(c, 1.78, CHCl3). IR (neat): 2082, 2056.5, 1761, 1740, 1474,
1464, 1361, 1371, 1257, 1222, 1176, 1140, 1065, 1032, 655, 616
Compound 18: Rf ) 0.30. [R]20 +28.8 (c, 1.5, CHCl3). (lit.18
D
+30.4 (c, 1.5, CHCl3)). IR (neat): 2940, 1765, 1369, 1240, 1213,
1050 cm-1 1H NMR (300 MHz, CD3COCD3): δ 4.43 (1 H, dt,
.
J ) 8.1, 5.8 Hz, H-7), 4.26 (1 H, ddd, J ) 7.5, 6.0, 5.4 Hz,
H-4), 4.20 (1 H, dd, J ) 5.8, 2.1 Hz, H-5), 4.17 (1 H, dd, J )
9.5, 3.8 Hz, H-2), 4.05 (1 H, dd, J ) 8.6, 6.0 Hz, H-8), 4.03 (1
H, dd, J ) 8.6, 5.3 Hz, H-8), 3.70 (1 H, dd, J ) 5.8, 2.1, H-6),
3.69 (3 H, s, OCH3), 2.19 (1 H, ddd, J ) 13.6, 5.8, 3.8 Hz, H-3),
1.81 (1 H, ddd, J ) 13.6, 9.5, 8.2 Hz, H-3), 1.41 (3 H, s), 1.37
(3 H, s), 1.29 (3 H, s), 1.27 (s, 3 H). 13C NMR (75 MHz,
CD3COCD3): δ 171.74, 109.60, 109.55, 76.57, 75.25, 73,13,
72.36, 72.06, 67.37, 52.10, 31.73, 27.92, 27.05, 26.30, 25.74.
MS (m/z): 301 (M - 1, 64.5), 243 (20.7), 199 (4.6), 183 (100.0),
155 (12.5), 149 (13.2), 123 (27.8), 113 (16.9), 101 (76.8).
cm-1
.
1H NMR (300 MHz, CD3COCD3): δ 4.53 (1 H, q, J )
Ack n ow led gm en t. We are grateful to the Chinese
Academy of Sciences (KJ 952-S1-503, KJ 95-A1-504),
Chinese Natural Science Foundation, and State Com-
mittee of Science and Technology for generous financial
6.3 Hz, H-7), 4.22 (1 H, dd, J ) 12.2, 2.2 Hz, H-2), 4.15 (2 H,
q, J ) 7.1 Hz, OCH2CH3), 4.07 (1 H, dd, J ) 8.7, 6.4 Hz, H-8),
4.00 (1 H, dd, J ) 8.7, 5.9 Hz, H-8), 3.92 (1 H, dd, J ) 11.3,
5.3 Hz, H-4), 3.39 (1 H, d, J ) 6.6 Hz, H-6), 2.01 (1 H, m, H-3),

Synthesis of 3-Deoxy-D-manno-2-Octulosonic Acid
J . Org. Chem., Vol. 63, No. 8, 1998 2461
17, 18 (16 pages). This material is contained in libraries on
microfiche, immediately follows this article in microfilm ver-
sion of the journal, and can be ordered from the ACS; see any
current masthead page for ordering information.
support. We also express our appreciation to Dr. Yi-
Kang Wu for his helpful discussion.
Su p p or tin g In for m a tion Ava ila ble: Reproductions of 1H
NMR for compounds 8a , 8b, 8c, 9a , 9c, 12, 13, 15, 16, 17, 18;
2D NMR for compounds 8a , 8b, 8c, 9c; 13C NMR for compound
J O971186W