De novo synthesis of aceric acid and an aceric acid building block

Article abstract of DOI:10.1021/jo061607m

The de novo synthesis of an aceric acid thioglycoside building block and the total synthesis of the plant carbohydrate aceric acid are described via a highly convergent strategy. Aldol reaction of acetaldehyde and a protected tartaric acid derivative provided the open chain carbohydrate. Subsequent acid treatment yielded the aceric acid thioglycoside in 35% total yield over five steps. Oxidative cleavage of the thioketal in the open chain carbohydrate and basic hydrolysis of the methyl ester furnished fully deprotected aceric acid in 31% yield over six steps.

Full text of DOI:10.1021/jo061607m

De Novo Synthesis of Aceric Acid and an Aceric
Acid Building Block
Mattie S. M. Timmer, Bridget L. Stocker, and
Peter H. Seeberger*
Laboratory for Organic Chemistry, Swiss Federal Institute of
Technology (ETH) Z u¨ rich, Wolfgang-Pauli Strasse 10, 8093
Zurich, Switzerland
seeberger@org.chem.ethz.ch
ReceiVed August 2, 2006
The de novo synthesis of an aceric acid thioglycoside
building block and the total synthesis of the plant carbohy-
drate aceric acid are described via a highly convergent
strategy. Aldol reaction of acetaldehyde and a protected
tartaric acid derivative provided the open chain carbohydrate.
Subsequent acid treatment yielded the aceric acid thiogly-
coside in 35% total yield over five steps. Oxidative cleavage
of the thioketal in the open chain carbohydrate and basic
hydrolysis of the methyl ester furnished fully deprotected
aceric acid in 31% yield over six steps.
FIGURE 1. Structure of rhamnogalacturonan II.
For RG II, the incorporation of the unique sugar aceric acid
(
L-AcefA, RG II chain B, Figure 1) requires the synthesis of
such a building block. The C-3 branched acidic pentose (1,
Scheme 1) was first isolated from the sycamore maple Acer
7
pseudoplantanus. The monosaccharide was recently synthesized
by Jones et al., but thus far, no route to aceric acid building
blocks has been reported. Herein, we present a short and efficient
synthesis of an aceric acid building block.
Retrosynthetic analysis of aceric acid ethyl thioglycosides A
Rhamnogalacturonan-II (RG II) is a pectic polysaccharide1
found in the cell walls of all higher plants and is one of the
most complex carbohydrate structures found in nature. Al-
8
2
though only present in relatively small amounts, RG II is
believed to play a pivotal role in plant cell wall stabilization.
Defects in RG II production lead to growth inhibition and
dramatic changes in cell wall architecture. Furthermore, RG II
has been found in extracts used in traditional medicine and
(Scheme 1) reveals a ring formation that can take place in the
final stage of the synthesis via an intramolecular substitution
of an anomeric dithiane by the 4-hydroxyl. The dithiane can
function as a protecting group for the anomeric center during
the preceding reactions. Open chain carbohydrate B can in turn
be formed via an aldol reaction between acetaldehyde (C) and
3
fermentation products such as red wine. RG II consists of a (1
f 4)-linked galacturonic acid oligomeric backbone to which
four distinct side chains (A-D) are attached (Figure 1). The
side chains contain 12 different sugar monomers.
9
an appropriately protected ester D. The required stereocenters
for the chiral ester can be derived from D-arabinose (2).
The complexity of RG II represents an enormous synthetic
challenge despite significant advances in the field of oligosac-
(
4) For recent reviews on oligosaccharide synthesis, see: (a) Hanessian,
S. PreparatiVe Carbohydrate Chemistry; Marcel Dekker: New York, 1997.
b) Carbohydrates in Chemistry and Biology, Vol. 1; Ernst, B., Hart, G.
4
charide synthesis. Methodology has been developed for the
(
installation of even the most difficult glycosidic linkages and
5
W., Sina y¨ , P., Eds.; Wiley-VCH: Weinheim, Germany, 2000. (c) Davies,
B. J. Chem. Soc., Perkin Trans. 1 2000, 2137. (d) Garegg, P. J. AdV.
Carbohydr. Chem. Biochem. 2004, 59, 69.
for the rapid automated synthesis of oligosaccharides. As a
result, the bottleneck for the synthesis of complex carbohydrates
has shifted toward obtaining sufficient amounts of fully func-
(5) (a) Kanemitsu, T.; Kanie, O. Trends Glycosci. Glycotechnol. 1999,
11, 267. (b) Seeberger, P. H.; Haase, W. C. Chem. ReV. 2000, 100, 4349.
tionalized monosaccharide building blocks.6
(
c) Plante, O. J.; Palmacci, E. R.; Seeberger, P. H. Science 2001, 291, 1523.
d) Sears, P.; Wong, C.-H. Science 2001, 291, 2344. (e) Plante, O. J.;
(
(
1) For structural elucidation of RG II, see: (a) Darvill, A. G.; McNeil,
Palmacci, E. R.; Andrade, R. B.; Seeberger, P. H. J. Am. Chem. Soc. 2001,
123, 9545. (f) Seeberger, P. H. Solid Support Oligosaccharide Synthesis
and Combinatorial Carbohydrate Libraries; Wiley: New York, 2001. (g)
Kanemitsu, T.; Kanie, O. Comb. Chem. High Throughput Screening 2002,
5, 339. (h) Plante, O. J.; Seeberger, P. H. Curr. Opin. Drug DiscoVery DeV.
2003, 6, 521.
(6) Timmer, M. S. M.; Adibekian, A.; Seeberger, P. H. Angew. Chem.
Int. Ed. 2005, 44, 7605.
(7) Spellman, M. W.; McNeil, M.; Darvill, A. G.; Albersheim, P.
Carbohydr. Res. 1983, 122, 115.
M.; Albersheim, P. Plant Physiol. 1978, 62, 418. (b) Ishii, T.; Matsunaga,
T.; Pellerin, P.; O’Neill, M. A.; Darvill, A.; Albersheim, P. J. Biol. Chem.
1
999, 274, 13098. (c) Rodr ´ı guez-Carvajal, M. A.; Herv e´ du Penhoat, C.;
Mazeau, K.; Doco, T.; P e´ rez, S. Carbohydr. Res. 2003, 338, 651.
2) For a recent review, see: Paulsen, B. S.; Barsett, H. AdV. Polym.
Sci. 2005, 186, 69.
3) For biological functions, see: (a) H o¨ fte, H. Science 2001, 294, 795.
b) O’Neill, M.; Eberhard, S.; Albersheim, P.; Darvill, A. G. Science 2001,
(
(
(
2
2
94, 846. (c) Ridley, B. L.; O’Neill, M. A.; Mohnen, D. A. Phytochemistry
001, 57, 929. (d) O’Neill, M. A.; Ishii, T.; Albersheim, P.; Darvill, A. G.
Annu. ReV. Plant Biol. 2004, 55, 109.
(8) Jones, N. A.; Nepogodiev, S. A.; MacDonald, C. J.; Hughes, D. L.;
Field, R. A. J. Org. Chem. 2005, 70, 8556.
10.1021/jo061607m CCC: $33.50 © 2006 American Chemical Society
8
294
J. Org. Chem. 2006, 71, 8294-8297
Published on Web 09/19/2006

SCHEME 1. Retrosynthetic Analysis of Aceric Acid
Thioglycosides
SCHEME 3. Total Synthesis of Aceric Acida
SCHEME 2. Synthesis of Aceric Acid Thioglycosidesa
a
Reagents and conditions: (a) PhI(C(O)CF3)2, MeCN/H2O (85:15), 10
min, then TFA, 50 °C, 30 min, 52%. (b) PhI(C(O)CF3)2, MeCN/H2O (85:
15), then TFA/H2O (1:1), 50 °C, 30 min, 88%. (c) 1 M aq NaOH/MeOH
(1:4), 1 h, quant. (d) LiOH (2 equiv), MeOH/H2O (1:1), 0 °C to rt, 1.5 h,
quant. (e) TFA/H2O (1:1), rt, 2 h, quant.
agents leave thioethers unaffected, treatment of the crude
12
aldehyde with silver oxide, formed in situ by the combination
of aqueous sodium hydroxide and silver nitrate solutions,
resulted in the smooth formation of the acid. Moreover,
extraction and back-extraction of the acid resulted in homoge-
neous material that was used without further purification.
1
3
Finally, treatment of the acid with diazomethane gave methyl
ester 5 in an overall yield of 82%.
a
Reagents and conditions: (a) EtSH, concentrated aq HCl, 10 min, 77%.
Having established an efficient synthetic route for the ester,
the aldol reaction and cyclization were explored. Initial attempts
to combine ester 5 with acetaldehyde using lithium hexameth-
yldisilazane yielded only the starting material. Apparently, a
stonger base was required for effective enolization. Accordingly,
deprotonation of 5 with lithium diisopropylamide and subse-
quent reaction with acetaldehyde gave a 4:1 diastereomeric
mixture of â-hydroxy esters 6a and 6b in a combined yield of
(
7
b) (MeO)2CMe2, p-TsOH (cat.), 2 h, then MeOH/H2O (99:1), 50 °C, 3h,
5%. (c) 1: NaIO4, THF/H2O (9:1), 15 min, 0 °C to rt; 2: AgNO3/NaOH,
H2O/dioxane (1:1); 3: CH2N2, ether, 82%. (d) LDA, THF, -78 °C, then
CH3C(O)H, -78 to -20 °C, 3 h, 92% (4:1 mixture of diastereoisomers);
and (e) TFA/H2O (1:1), 50 °C, 30 min, then TFA, 50 °C, 30 min, 99%.
With this strategy in mind, our studies commenced with the
treatment of D-arabinose with concentrated hydrochloric acid
and ethane thiol (Scheme 2).10 The product crystallized from
the reaction mixture, and ethyl mercaptane 3 was isolated in
8
5%. Further optimization of the aldol reaction was ac-
complished by using the lithium salt of 2,2,4,4-tetramethylpi-
peridine (LTMP) as the base. This reaction resulted in a 92%
yield of esters 6, also as a 4:1 mixture of diastereoisomers.
Fortunately, the products were readily separable by column
chromatography, and the individual diastereoisomers 6a and 6b
were transformed into their respective thioglycosides. Subse-
quent treatment of 6a or 6b with 50% aqueous trifluoroacetic
acid (TFA), to affect acetonide deprotection, and with pure TFA,
to affect cyclization, gave the aceric acid ethyl thioglycosides
7
7% yield. Selective protection of the 2- and 3-hydroxyl groups
of 3 was accomplished via a two-step, one-pot, procedure.
Mercaptane 3 was first transformed into its 2,3:4,5-bisacetonide
by reaction with acetone in the presence of catalytic amounts
of para-toluenesulfonic acid (p-TsOH). Evaporation of the
solvent, redissolution in 99% aqueous methanol, and stirring at
5
0 °C led to the selective cleavage of the less stable 4,5-
1
1
isopropylidine to furnish monoacetonide 4 in 76% yield. At
this stage, the transformation of the diol into a methyl ester
was required, while avoiding oxidation of the mercaptane. First,
the diol was cleaved using sodium periodate in a water/THF
mixture to give the crude aldehyde. Although few oxidizing
7
a and 7b in near quantitative yields.
To determine the absolute configuration of the isomers, we
6
embarked upon the total synthesis of aceric acid (Scheme 3).
A two-step procedure was applied for the deprotection of the
dithioketal of 6a. Oxidation of the sulfide using PhI(C(O)CF3)2
(9) For aldol reactions of tartrates and derivatives, see: (a) Naef, R.;
14
led to a diastereomeric mixture of sulfoxides, but subsequent
Seebach, D. Angew. Chem., Int. Ed. Engl. 1981, 20, 1030. (b) Evans, D.
A.; Trotter, B. W.; Barrow, J. C. Tetrahedron 1997, 53, 8779. (c) Aggarwal,
V. K.; Masters, S. J.; Adams, H.; Spey, S. E.; Brown, G. R.; Foubister, A.
J. J. Chem. Soc., Perkin Trans. 1 1999, 155. (d) Ladner, W. Chem. Ber.
cleavage of both the thio and the isopropylidene ketals using
(12) Stepanova, L. G.; Keiko, N. A.; Malkova, T. N.; Leontyeva, A. G.;
Pushechkina, T. Y.; Voronkov, M. G. Pharm. Chem. J. 1988, 22, 477.
(13) De Boer, F. J.; Backer, H. J. Rec. TraV. Chim. Pays-Bas 1954, 73,
229.
1
983, 116, 3413.
(
10) Fischer, E. Ber. Dtsch. Chem. Ges. 1894, 27, 673.
(11) Procedure adapted from: Boz o´ , EÄ .; Boros, S.; Kuszmann, J.
Carbohydr. Res. 1997, 302, 149.
(14) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287.
J. Org. Chem, Vol. 71, No. 21, 2006 8295

SCHEME 4. Mechanism Aldol Reaction
FIGURE 2. Ortep representation of the crystal structures of aceric
acid dimer 8 and 4-epi-aceric acid diethyl dithio acetal 11.
TFA did not lead to the expected methyl ester 9. Instead, the
self-condensation product 8 was isolated in modest 52% yield.
X-ray crystallographic analysis of 8 (Figure 2) confirmed the
absolute configuration of L-aceric acid. Conversely, milder
deprotection of the sulfoxides using a 1:1 mixture of TFA and
H2O gave aceric acid methyl ester 9 in 88% yield. It is
interesting to note that subjecting thioglycoside 7a (Scheme 2)
to NIS in acetone/H2O (85:15) led to quantitative formation of
ester 9, but as depuration of the succinimide byproduct was
strenuous, the oxidative deprotection of 6a was preferred.
Surprisingly, saponification of the methyl ester of 9 using NaOH
in water/methanol did not lead to aceric acid but instead to
complete epimerization of the 2-position, and it was the
Experimental Section
,3-O-Isopropylidine-D-arabinose Diethyl Dithio Acetal (4).
2
2,2-Dimethoxypropane (40 mL, 325 mL, 2.25 equiv) and p-
toluenesulfonic acid (0.5 g, cat.) were added to a suspension of
15
6
diastereoisomer 2-epi-aceric acid 10 that was isolated. Depro-
tection under milder cleavage conditions (dilute LiOH at 0 °C)
quantitatively yielded acid 1, thereby completing the total
synthesis of L-aceric acid in a total of six steps and 31% overall
yield. All spectroscopic properties were in full accordance with
D-arabinose diethyl dithioacetal 3 (36.8 g, 144 mmol) in acetone
(500 mL). After obtaining a homogeneous solution and stirring for
an additional hour, the mixture was concentrated, and the residue
was dissolved in a mixture of MeOH (500 mL) and H
The solution was stirred for 2 h at 50 °C, saturated aqueous
NaHCO (100 mL) was added, and the mixture was concentrated
to 150 mL. The residue was extracted with ethyl acetate (3 × 100
mL) and dried (MgSO ) and concentrated. The resulting residue
2
O (5 mL).
7,8
3
the reported data for aceric acid, revealing that the major
isomer indeed had the desired 2S,3R,4S configuration.
The absolute configuration of the minor isomer 6b was
established from the crystal structure of the open chain triol 11
4
was triturated with dichloromethane and the solid D-arabinose
diethyl dithioacetal (4.5 g, 17.6 mmol, 12%) collected by filtration.
Concentration of the mother liquor and purification of the residue
by column chromatography (hexanes f ethyl acetate/hexanes, 1:3,
v/v) gave homogeneous diol 4 (32 g, 108 mmol, 75%) as a colorless
(Figure 2), synthesized in one step by treatment of the acetonide
with a 1:1 mixture of TFA and H2O. Here, it was found that
the minor aldol product had the 2S,3R,4R configuration, epimeric
to aceric acid at the 4-position.
2
0
oil. R
D
) 59 (c 1.0, CHCl
3 3
); IR (CHCl ): 3606, 3421, 2991, 2931,
-
1
2
873, 1602, 1455, 1385, 1374, 1248, 1161, 1052, 977, 881 cm
;
The stereochemical outcome of the aldol reaction and the
formation of the two diastereoisomers can be best explained
by assuming a mixture of enolates E and F, an observation
described earlier by Evans et al.,9 that react via closed
1
H NMR (300 MHz, CDCl
Hz), 4.08 (dd, 1H, J ) 6.9, J ) 7.0 Hz), 4.01 (d, 1H, J ) 3.8 Hz),
.81 (dd, 1H, J ) 2.8 Hz, J ) 10.5 Hz), 3.73 (ddd, J ) 2.8 Hz, J
5.4 Hz, J ) 7.0 Hz), 3.67 (dd, 1H, J ) 5.4 Hz, J ) 10.5 Hz),
.99 (bs, 2H), 2.77-2.65 (m, 4H), 1.43 (s, 3H), 1.36 (s, 3H), 1.25
3
): δ 4.31 (dd, 1H, J ) 3.8 Hz, J ) 6.9
3
)
2
16
Zimmerman-Traxler transition states G and H, respectively
(Scheme 4).
13
(
t, 1H, J ) 7.4 Hz), 1.24 (t, 1H, J ) 7.4 Hz); C NMR (75 MHz,
Assuming that the aldehyde approaches from the least
CDCl ): δ 110.0, 83.2, 79.1, 73.0, 63.9, 53.1, 27.4, 27.1, 25.5,
3
+
+
hindered side of the ester enolate, the methyl group of the
aldehyde adopts an equatorial position, leading to the two
isolated products. The product distribution can be explained by
the preferential formation of the trans-enolate E.
In conclusion, a short and efficient synthesis of an aceric acid
building block has been presented. Rapid access to large
amounts of this monosaccharide will greatly facilitate the
synthesis of larger oligosaccharides. Furthermore, this strategy
is an expeditious means to synthesize aceric acid and its
derivatives. Utilization of this methodology and the development
of convergent routes for the synthesis of other carbohydrate
building blocks are currently under investigation.
25.2, 14.4; ESI-MS (m/z): 319.2 [M + Na] , 615.2 [2M + Na] ,
-
+
341.0 [M + HCO
296.1111, obsd: 296.1109.
Methyl 2,3-O-Isopropylidine-D-threuronate Diethyl Dithio
Acetal (5). A solution of NaIO (6.34 g, 30 mmol, 1.4 equiv) in
O (25 mL) was added dropwise to a cooled (0 °C) and stirred
2 22 4 2
] ; HRMS(EI) m/z calcld for C12H O S :
4
H
2
solution of diol 4 (6.34 g, 21.4 mmol) in THF (75 mL). The ice
bath was removed, and the suspension was stirred for 10 min before
being quenched by the addition of concentrated aq sodium
bicarbonate (100 mL) and extracted with ethyl acetate (2 × 100
mL). The combined extracts were washed with brine (200 mL) and
dried (MgSO ), filtered, and concentrated. The resulting aldehyde
4
was dissolved in dioxane (100 mL), and the solution was added to
a stirred suspension of AgO, freshly made by the addition of a
solution of NaOH (2.56 g, 64.2 mmol, 3.0 equiv) in H
to a vigorously stirred solution of AgNO (7.28 g, 42.8 mmol, 2.0
equiv) in H O (50 mL). After 5 min, the reaction mixture was
filtered over Celite, and the filter washed with water. The aqueous
2
O (50 mL)
(
15) All spectroscopic properties were in full accordance with the reported
3
data (ref 8).
(16) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79,
2
1
920.
8
296 J. Org. Chem., Vol. 71, No. 21, 2006

solution was extracted with ether (2 × 100 mL), acidified with 1
M aq HCl to pH 2, and extracted with ethyl acetate (3 × 100 mL).
temperature, the solvents were evaporated in vacuo, and the residue
was taken up in pure TFA and stirred for an additional hour.
Concentration of the reaction mixture and purification of the residue
by column chromatography (ethyl acetate) gave thioglycoside 7a
4
The combined organic extracts were dried (MgSO ), filtered, and
concentrated. KOH (3.42 g, 56.1 mmol, 2.8 equiv) was dissolved
in a mixture of ether (15 mL), diethylene glycol monomethyl ether
20
(69 mg, 0.30 mmol, 99%) as a colorless oil. R
CHCl ); IR (CHCl ): 3520, 3007, 2931, 1732, 1602, 1439, 1380,
1264, 1147, 1063, 1012, 970, 909, 891 cm . R-anomer: 1H NMR
(300 MHz, CDCl ): δ 5.55 (d, 1H, J ) 5.0 Hz), 4.61 (q, 1H, J )
D
) 4.7 (c 1.0,
2
(30 mL), and H O (15 mL). This solution was placed in the distilling
3
3
-1
flask of a distillation setup equipped with a water bath at 70 °C, a
Claisen adapter, a dropping funnel, water cooled condenser, and
vacuum adapter for pressure relief, all without sharp edges or
ground-glass joints. The acid was dissolved in ether (90 mL) and
placed in the receiving flask. An ethereal solution of diazomethane17
was distilled by the dropwise addition of a solution of N-methyl-
N-(p-tolylsulfonyl)nitrosamide (11.9 g, 55.6 mmol, 2.6 equiv) in
ether (90 mL). After complete addition of the ethereal solution,
two additional portions of ether (10 mL) were added slowly, and
the distillation continued until the distillate was colorless. After 1
h, the reaction was quenched by the addition of acetic acid (2 × 1
mL) in both the receiving and the distillation flasks. After stirring
for an additional 16 h, the reaction mixture was concentrated, and
the residue was purified by column chromatography (hexanes f
3
6.3 Hz), 4.28 (dd, 1H, J ) 5.0 Hz, J ) 6.3 Hz), 3.87 (s, 3H), 3.18
(bs, 1H), 2.96 (bd, 1H, J ) 6.3 Hz), 2.77 (dq, 1H, J ) 12.7 Hz, J
) 7.4 Hz), 2.71 (dq, 1H, J ) 12.7 Hz, J ) 7.4 Hz), 1.32 (t, 3H, J
) 7.4 Hz), 1.24 (d, 3H, J ) 6.4 Hz); 13C NMR (75 MHz, CDCl
):
δ 171.8, 89.8, 83.4, 81.7, 77.3, 53.4, 25.8, 15.4, 12.8; â-anomer:
3
1
H NMR (300 MHz, CDCl ): δ 4.94 (d, 1H, J ) 5.3 Hz), 4.42 (q,
3
1H, J ) 6.4 Hz), 4.12 (dd, 1H, J ) 5.2 Hz, J ) 5.3 Hz), 3.88 (s,
3H), 3.35 (bs, 1H), 2.90 (bd, 1H, J ) 5.2 Hz), 2.70 (q, 2H, J ) 7.4
1
3
Hz), 1.32 (t, 3H, J ) 7.4 Hz), 1.29 (d, 3H, J ) 6.4 Hz); C NMR
(75 MHz, CDCl
3
): δ 172.3, 87.3, 84.3, 83.2, 79.5, 53.4, 25.3, 15.1,
-
14.9; ESI-MS (m/z): 281.0 [M + HCO
2
] ; HRMS(ESI) m/z calcld
9 16 5
for C H O SNa : 259.0611, obsd: 259.0613.
+
CH
5.16 g, 18 mmol, 82%) as a colorless oil. R
IR (CHCl ): 2993, 2931, 1750, 1439, 1376, 1263, 1163, 1109, 876,
2
Cl
2
/hexanes, 1:1, v/v) to yield homogeneous methyl ester 5
r,â-L-Aceric Acid Methyl Ester (9). Bis(trifluoroacetoxy)-
20
(
D
) 75 (c 1.0, CHCl
3
);
iodobenzene (66 mg) and sodium bicarbonate (34.7 mg) were added
3
1 1
2
to a mixture of acetonide 6a (32 mg, 0.11 mmol) in H O (1 mL)
and acetonitrile (4 mL). After stirring for 10 min, the reaction
mixture was concentrated, and the residue was dissolved in a
mixture of TFA (5 mL) and H O (5 mL). After stirring for 30 min
2
at 50 °C, the solvents were evaporated in vacuo, and the residue
was purified by column chromatography (hexanes f hexanes/ethyl
-
8
16 cm ; H NMR (300 MHz, CDCl
3
): δ 4.64 (d, 1H, J ) 6.8
Hz), 4.56 (dd, 1H, J ) 4.4 Hz, J ) 6.8 Hz), 3.98 (d, 1H, J ) 4.4
Hz), 3.79 (s, 3H), 2.77 (dq, 2H, J ) 12.4 Hz, J ) 7.4 Hz), 2.71
(
(
dq, 2H, J ) 12.3 Hz, J ) 7.4 Hz), 1.50 (s, 3H), 1.42 (s, 3H), 1.27
t, 3H, J ) 7.4 Hz), 1.26 (t, 3H, J ) 7.4 Hz); 13C NMR (75 MHz,
CDCl
3
): δ 170.9, 112.1, 82.2, 77.6, 52.8, 52.6, 52.6, 26.9, 25.9,
acetate, 1:2) to give methyl ester 9 (16 mg, 0.083 mmol, 88%) as
+
20
2
3
5.4, 25.0, 14.5, 14.4, 14.3; ESI-MS (m/z): 312.3 [M + NH
4
] ,
a colorless oil. R
D
3 3
) 54.6 (c 1.0, CHCl ); IR (CHCl ): 3600,
+
+
17.3 [M + Na] , 611.0 [2M + Na] ; HRMS(EI) m/z calcld for
3528, 3415, 3031, 2957, 2921, 2854, 1726, 1439, 1383, 1264, 1156,
1063, 1013, 970, 908 cm ; H NMR (300 MHz, MeOD):
+
-1
1
C
12
H
22
O
4
S
2
: 294.0955, obsd: 294.0962.
5
-Deoxy-3-C-methoxycarbonyl-2,3-O-isopropylidine-L-xy-
R-anomer: δ 5.42 (d, 1H, J ) 4.2 Hz), 4.64 (q, 1H, J ) 6.3 Hz),
4.05 (d, 1H, J ) 4.2 Hz), 3.77 (s, 3H), 1.16 (d, 3H, J ) 6.3 Hz);
â-anomer: δ 5.02 (d, 1H, J ) 2.1 Hz), 4.52 (q, 1H, J ) 6.4 Hz),
3.94 (d, 1H, J ) 2.1 Hz), 3.76 (s, 3H), 1.24 (d, 3H, J ) 6.4 Hz);
lose Diethyl Dithio Acetal (6a, Major) and 5-Deoxy-3-C-
methoxycarbonyl-2,3-O-isopropylidine-D-arabinose Diethyl Dithio
Acetal (6b, Minor). BuLi (10.1 mL 1.6 M in hexanes, 16.2 mmol,
.0 equiv) was added to a cooled (-50 °C), stirred solution of
tetramethyl piperidine (2.87 mL, 17.0 mmol, 2.1 equiv) in THF
100 mL). After 30 min, the reaction mixture was cooled further
-78 °C), and a solution of methyl ester 5 (2.38 g, 8.1 mmol) in
13
2
C NMR (75 MHz, MeOD): R-anomer: δ 172.2, 95.6, 82.4, 80.5,
76.9, 53.5, 13.6; â-anomer: δ 171.5, 102.8, 83.3, 81.8, 79.5, 53.6,
-
(
(
14.4; ESI-MS (m/z): 237.3 [M + HCO
2
] ; HRMS(ESI) m/z calcld
Na : 215.0526, obsd: 215.0523.
r,â-L-Aceric Acid (1). LiOH (0.125 mL 1 M in H
2 equiv) was added to a solution of methyl ester 9 (12 mg, 62
µmol) in H O (1 mL) and methanol (1 mL) at 0 °C. After stirring
+
7 12 6
for C H O
THF (20 mL) was added dropwise. After another 30 min,
acetaldehyde (2.26 mL, 40.4 mmol, 5.0 equiv) was added, and the
reaction mixture was stirred for 2 h, allowing the temperature to
rise to -20 °C. The reaction was quenched by the addition of
2
O, 125 µmol,
2
for 90 min, allowing the mixture to warm to room temperature,
the reaction was neutralized by the addition of Amberlite IR 120,
saturated aqueous NH
4
Cl (100 mL) and extracted with ethyl acetate
),
+
(
2 × 100 mL). The combined organic extracts were dried (MgSO
4
H -form. Filtration and concentration gave aceric acid 1 (11 mg,
2
0
filtered, and concentrated. Purification of the residue by column
chromatography (hexanes f 5% ethyl acetate in hexanes) gave
first 6b (0.50 g, 1.5 mmol, 18%) and then 6a (2.02 g, 6.0 mmol,
62 µmol, quant.) as a colorless oil. R
D
) -35.6 (c 1.0, CH
3
OH);
IR (neat): 3375, 2927, 2854, 1722, 1439, 1385, 1270, 1163, 1060,
1012, 895, 853 cm ; H NMR (300 MHz, D O): δ 5.49 (d, 1H,
-
1 1
2
20
7
2
9
4%). 6a: R
D
) 70 (c 1.0, CHCl
3
); IR (CHCl
3
): 3578, 2988,
J ) 4.4 Hz), 5.19 (d, 1H, J ) 2.8 Hz), 4.69 (q, 1H, J ) 6.4 Hz),
4.56 (q, 1H, J ) 6.5 Hz), 4.16 (d, 1H, J ) 4.4 Hz), 4.05 (d, 1H,
J ) 2.8 Hz), 1.26 (d, 1H, J ) 6.5 Hz), 1.19 (d, 1H, J ) 6.4 Hz););
931, 2873, 1750, 1720, 1455, 1435, 1382, 1259, 1143, 1101, 1034,
-
1 1
3
78, 894, 840 cm ; H NMR (300 MHz, CDCl ): δ 4.76 (d, 1H,
J ) 3.0 Hz), 4.13 (dq, 1H, J ) 9.9 Hz, J ) 6.4 Hz), 4.03 (d, 1H,
2
13C NMR (75 MHz, D O): δ 176.6, 176.6, 104.0, 98.4, 86.2, 85.4,
-
J ) 3.0 Hz), 3.74 (s, 1H), 2.74 (dq, 1H, J ) 12.4 Hz, J ) 7.5 Hz),
85.0, 80.9, 80.9, 79.6, 16.6, 15.3; ESI-MS (m/z): 177.0 [M - H] ,
-
-
2
.69 (dq, 1H, J ) 7.5 Hz, J ) 12.4 Hz), 2.69 (dq, 1H, J ) 7.4 Hz,
195.0 [M + OH] , 223.0 [M + HCO
2
] ; HRMS(ESI) m/z calcd
-
J ) 11.8 Hz), 2.60 (dq, 1H, J ) 7.4 Hz, J ) 11.8 Hz), 2.01 (d,
for C
6
H
9
O
6
: 177.0405, obsd: 177.0407.
1
H, J ) 9.9 Hz), 1.61 (d, 3H, J ) 0.5 Hz), 1.43 (d, 3H, J ) 0.5
Acknowledgment. This research was supported by the ETH
Z u¨ rich, the Niels Stensen Foundation (postdoctoral fellowship
for M.S.M.T.), and the Foundation for Research, Science and
Technology, New Zealand (postdoctoral fellowship for B.L.S.).
We wish to thank Paul Seiler for obtaining the crystallographic
data.
Hz), 1.26 (t, 3H, J ) 7.4 Hz), 1.21 (t, 3H, J ) 7.5 Hz), 1.20 (d,
3
8
H, J ) 6.4 Hz); 13C NMR (75 MHz, CDCl
7.9, 83.0, 68.1, 52.4, 50.9, 26.9, 26.7, 25.9, 25.0, 18.9, 14.4, 13.7;
3
): δ 171.7, 110.7,
+
ESI-MS (m/z): 699.0 [2M + Na] ; HRMS(EI) m/z calcld for
+
C
14
H
O S
26 5 2
: 338.1217, obsd: 338.1217.
-Deoxy-1-ethylthio-r,â-L-aceric Acid Methyl Ester (7a).
Acetonide 6a (100 mg, 0.30 mmol) was dissolved in a mixture of
TFA (2.5 mL) and H O (2.5 mL). After stirring for 2 h at room
1
Supporting Information Available: Full experimental details
and characterization data for all described compounds, including
2
7
b, 8, 10, and 11. This material is available free of charge via the
(
17) Caution: diazomethane is both explosive and carcinogenic and
Internet at http://pubs.acs.org.
should always be treated with care. For the preparation and use of
diazomethane, see ref 13.
JO061607M
J. Org. Chem, Vol. 71, No. 21, 2006 8297