Radical homologation of D-gluconic acid: Highly diastereoselective synthesis of D-gluco-KDO derivatives

Article abstract of DOI:10.1016/S0040-4020(01)00865-1

D-glucono 1,5-lactone was converted to O-protected D-gluconic acids. The latter were transformed to gluco-KDO derivatives using Barton ester-based radical chemistry with high diastereoselectivity.

Full text of DOI:10.1016/S0040-4020(01)00865-1

TETRAHEDRON
Pergamon
Tetrahedron 57 62001) 8767±8771
Radical homologation of d-gluconic acid: highly diastereoselective
synthesis of d-gluco-KDO derivatives
Derek H. R. Barton,a Mauro V. De Almeida,b,p Wansheng Liu,a Tetsuro Shinada,a
a
Joseph Cs. Jaszberenyi, Helio F. Dos Santos and Mireille Le Hyaric
b
b
Â
aDepartment of Chemistry, Texas A&M University, College Station, Texas, TX 77843, USA
b
Â
Departamento de Quõmica, I.C.E., U.F.J.F., 36036-330, Juiz de Fora, MG, Brazil
Received 28 June 2001; accepted 23 August 2001
AbstractÐd-glucono 1,5-lactone was converted to O-protected d-gluconic acids. The latter were transformed to gluco-KDO derivatives
using Barton ester-based radical chemistry with high diastereoselectivity. q 2001 Elsevier Science Ltd. All rights reserved.
3-Deoxy-d-manno-2-octulosonic acid 6KDO) 1 6Fig. 1) is
known as a vital sugar component of lipopolysaccharides
6LPS) of the outer membrane of Gram-negative bacteria.1±3
The rate-limiting enzyme for the incorporation of KDO into
these LPS is CMP-KDO synthetase 63-deoxy-d-manno-
octulosonate cytidylyl transferase).4 Chemical synthesis
of KDO and analogs has been intensively studied5 in view
to obtain effective inhibitors of this enzyme and
potential anti-infective agents speci®c against Gram-
negative bacteria.
the synthesis of KDO derivatives starting from penta-
acetyl-d-gluconic acid.7 As another part of this work, we
found that using different protecting groups on the
d-gluconic acid, addition of the arabinosyl radical to an
ole®n, namely ethyl a-6tri¯uoroacetoxy)acrylate,8 resulted
in the formation of the products with very high diastereo-
selectivity. Herein we wish to report the results of this
highly diastereoselective radical reaction in the synthesis
of phenylhydrazone and oxime derivatives of d-gluco-
KDO starting from inexpensive commercial d-glucono-
1,5-lactone.
The common strategies for the synthesis of KDO and its
analogs involve homologation of lower monosaccharides
d-mannose or d-arabinose with two and three carbons
atoms, respectively. These also include radical carbon±
carbon bond formation reactions, and the latter have proven
to be an important tool in carbohydrate chemistry.6 We
previously reported the successful application of O-acyl
derivatives of N-hydroxy-2-thiopyridone 6Barton ester) to
By a literature procedure,9 d-glucono-1,5-lactone 2 was
converted to the d-gluconate ester 3 in 70% yield through
reaction with 2,2-dimethoxypropane in acetone/methanol in
the presence of a catalytic amount of p-toluenesulphonic
acid 6Scheme 1). In a similar manner, the ester 4 was also
prepared in 70% yield by reaction with 1,1-dimethoxy-
cyclohexane in cyclohexanone/methanol.
Protection of 3 and 4 with tert-butyldiphenylchlorosilane
and imidazole in N,N-dimethylformamide led to 5 695%
yield) and 6 692% yield), respectively. Treatment of 5 and
6 with 0.1 M of lithium hydroxide solution in tetrahydro-
furan gave acids 7 and 8 in 70% yields. Acid 7 and 8 reacted
with N-hydroxy-2-thiopyridone in the presence of dicyclo-
hexylcarbodiimide 6DCC) in anhydrous dichloromethane
in the absence of light to give the corresponding Barton
esters 6Scheme 2). Irradiation of the Barton esters in situ
with a tungsten lamp in the presence of ethyl a-6tri¯uoro-
acetoxy)acrylate, followed by work up with aqueous
K2CO3, afforded the protected d-gluco-KDO ester deriva-
tives 9 and 10 6both in 53% yield) as single isomers, veri®ed
by NMR of the crude product 6Scheme 1). This modest
yield could be explained by cleavage of the acetal groups
of the compounds involved in the three steps reactions. The
Figure 1.
Keywords: KDO; radicalar reaction; diastereoselectivity.
Corresponding author. Fax: 155-32-3229-3314;
e-mail: mvieira@quimica.ufjf.br
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020601)00865-1

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D. H. R. Barton et al. / Tetrahedron 57 92001) 8767±8771
Scheme 1. 6a) 2,2-dimethoxypropane 6or 1,1-dimethoxycyclohexane), acetone 6or cyclohexanone), MeOH, TsOH, rt, 18 h; 6b) TBDPSCl, imidazole, DMF,
608C, 12 h; 6c) LiOH 0.1 M, THF, rt, 40 h; 6d) i. N-hydroxy-2-thiopyridone, DCC, CH2Cl2, 08C, 1 h; ii. H2CvC6OCOCF3)6COOEt), hn, 2308C, 1 h; iii.
PhNHNH2´HCl, Py, 2208C±rt, 12 h; 6e) TBAF, THF, rt, 12 h; 6f) HCl, EtOH, rt, 12 h; 6g) i. N-hydroxy-2-thiopyridone, DCC, CH2Cl2, 08C, 1 h; ii.
H2CvC6OCOCF3)6COOEt), hn, 2308C, 1 h; iii. saturated aqueous K2CO3/acetone 1:1, 2208C±rt, 12 h; 6h) HONH2´HCl, Py, 08C, rt, 12 h.
corresponding 4-epimers were not obtained from the above
reactions.
Starting from acid 7 or 8, work-up of the radical reaction
intermediates with phenylhydrazine in pyridine gave
phenylhydrazone derivatives 13 and 14, both in 55%
yields 6proportion E/Zˆ6:1). Removal of the C-4 protect-
ing group of these compounds with TBAF in tetrahydro-
furan yielded 15 and 16 in 90 and 92% yields,
respectively. gluco-KDO lactone 17 was obtained in
85% yield by the treatment of 15 or 16 with hydrochloric
acid in ethanol.
The oxime 11 6proportion E/Zˆ6:1) was then obtained in
90% yield by treatment of 10 with hydroxylamine hydro-
chloride in pyridine. Removal of TBDPS group was
achieved by reaction with tetra6n-butyl)ammonium ¯uoride
6TBAF) in tetrahydrofuran to give the g-lactone 12 in 90%
yield.
Scheme 2.

D. H. R. Barton et al. / Tetrahedron 57 92001) 8767±8771
8769
were determined with TMS internal reference on Varian
Gemini 200 or Varian UNITY NMR spectrometers.
Chemical shifts are reported 6d) relative to TMS. Column
chromatography was carried out on silica gel 60 60.040±
0.063). Elemental analyses were performed by Atlantic
Microlab Inc. N-hydroxy-2-thiopyridone was isolated
from its sodium salt 6Omadine), which was a gift of the
Olin Corporation, Cheshire, CT. All reagents were
purchased from the Aldrich Co. Inc. or Fluka Chemika-
BioChemica and were used without further puri®cation.
Compound 3 was synthesized according to the literature
method.9
1.1.1. Methyl 3,4:5,6-di-O-cyclohexylidene-d-gluconate
4. A mixture of d-gluconolactone 2 617.8 g, 0.1 mol),
methanol 65 mL), 1.1 dimethoxycyclohexane 650 mL),
cyclohexanone 620 mL) and p-toluenesulphonic acid
6300 mg) was stirred at room temperature for 48 h. The
mixture was then neutralized by addition of sodium hydro-
gen carbonate, ®ltered and the ®ltrate concentrated. The
resulting syrup was dissolved in dichloromethane
6100 mL) and the solution was washed with water
62£50 mL). Concentration of the extract, followed by
¯ash chromatography of the residue gave the ester 4
625.5 g, 70%). mp 99±1008C ; a[ ]Dˆ168 6c 1.4, CHCl3);
1H NMR 6200 MHz, CDCl3): d 1.20±1.80 6m, 20H,
cyclohex.); 3.00 6d, 1H, OH); 3.80 6s, 3H, OCH3); 4.00
6m, 4H, H3, H5, H6, H60); 4.20 6dd, 1H, H4); 4.30
6dd, 1H, H2); 13C NMR 650 MHz, CDCl3): d 24.1±37.2
6cyclohex.); 53.0 6OCH3); 68.0; 70.0; 76.6; 77.6; 81.1
6C2, C3, C4, C5, C6); 110.8 [C6OR)2]; 173.4 6CO); Anal.
Calcd for C19H30O7: C, 61.60; H, 8.16. Found: C, 61.75; H,
8.20.
Figure 2.
In summary, the O-protected d-gluco-KDO was synthesized
as the only diastereoisomer in good yields from d-glucono-
1,5-lactone through the Barton ester mediated radical
carbon±carbon bond formation reaction and the correspond-
ing oxime and phenylhydrazone derivatives were also
readily synthesized in good overall yields. The high dia-
stereoselectivity of this radical reaction should help for a
better understanding of the stereochemistry of other related
radical reactions.
1.1.2. Methyl 3,4:5,6-di-O-isopropylidene-2-O-tert-butyl-
diphenylsilyl-d-gluconate 5 and methyl 3,4:5,6-di-O-
cyclohexylidene-2-O-tert-butyldiphenylsilyl-d-gluconate
6. A mixture of 3 614.5 g, 0.05 mol) or 4 618.5 g, 0.05 mol),
tert-butyldiphenylsilyl chloride 615.6 g, 0.06 mol) and
imidazole 68.12 g, 0.12 mol) in DMF 620 mL) was stirred
at 608Cfor 12 h. The mixture was cooled, diluted with
dichloromethane 6100 mL) and washed with water
62£50 mL). Concentration of the dried extract followed by
¯ash chromatography gave the desired compounds 5
625.08 g, 95% from 3) and 6 627.9 g, 92% from 4). 5: Mp
Aiming to understand the diastereoselectivity at molecular
level, the reaction step involving the conversion of 7 to 9
was investigated theoretically using the semiempirical
method PM3 6Parametric Method 3)10. The radical inter-
mediate and the gluco and manno epimers were analyzed.
From the thermodynamic data calculated in gas phase at
298 K and 1.0 atm, both products are equally probable
with the gluco isomer being less stable by only 3.8 Kcal/
mol. This energy difference is within the con®dence limit
of the calculation method used. It suggests that the
stereoselectivities of the process g 6Scheme 1) might be
kinetically controlled. The fully optimized geometry for
the radical intermediate is depicted in Fig. 2, where it can
be seen that the attack through the side A, leading to the
manno epimer, should be more dif®cult due the steric
hindrance. A more detailed theoretical study is in progress
and should be reported in a near future paper.
1
73±758C ; [a]Dˆ16486c 0.9, CHCl3); H NMR 6200 MHz,
CDCl3): d 1.12 6s, 9H, tButyl); 1.35±1.48 63s, 12H,
isoprop.); 3.37 6s, 3H, OCH3); 3.85 6m, 1H, H6); 4.00±
4.44 6m, 4H, H3, H4, H5, H60); 4.45 6d, 1H, H2);
7.30±7.80 6m, 10H, Ph); 13C NMR 650 MHz, CDCl3): d
19.7±27.5 [tButyl, C6CH3)2]; 51.5 6OCH3); 67.6 6C6);
73.1; 77.0; 81.6 6C2, C3, C4, C5); 109.6; 110.4
[C6CH3)2]; 127.0±136.0 6ph); 171.0 6CO); Anal. Calcd for
C29H40O7Si: C, 65.88; H, 7.63. Found: C, 65.78; H, 7.68. 6:
Mp 86±878C ; [a]Dˆ155 6c 1, CHCl3);1H NMR 6200 MHz,
CDCl3): d 1.10 6s, 9H, tButyl); 1.50 6m, 20H, cyclohex.);
3.30 6s, 3H, OCH3); 3.80±4.30 6m, 4H, H3, H5, H6, H60);
4.35 6dd, 1H, H4); 4.45 6d, 1H, H2); 7.30±7.80 6m, 10H,
Ph); 13CNMR 650 MHz, CDCl 3): d 20.2±37.7 6tButyl,
cyclohex.); 51.9 6OCH3); 67.9 6C6); 73.9; 77.3; 77.5; 81.9
6C2, C3, C4, C5); 110.6; 111.4 [C6OR)2]; 127.7±136.6 6ph);
171.5 6CO); Anal. Calcd for C35H48O7Si: C, 69.05; H, 7.95
Found: C, 69.22; H, 8.01.
1. Experimental
1.1. General methods and starting materials
Melting points were determined with a Ko¯er hot-stage
melting point apparatus and are uncorrected. IR spectra
were recorded on a Perkin±Elmer 881 infrared spectro-
photometer. Speci®c rotations were determined on a Jasco
1
DIP±360 digital polarimeter. H- and 13CNMR spectra

8770
D. H. R. Barton et al. / Tetrahedron 57 92001) 8767±8771
1.1.3. 3,4:5,6-Di-O-isopropylidene-2-O-tert-butyldiphe-
nylsilyl-d-gluconic acid 7 and 3,4:5,6-di-O-cyclohexyl-
idene-2-O-tert-butyldiphenylsilyl-d-gluconic acid 8. A
solution of the ester 5 62.11 g, 4 mmol) or 6 62.43 g,
4 mmol) in THF 6100 mL) was treated with 0.1 M lithium
hydroxide solution 650 mL) and then stirred at room
temperature for 40 h. The mixture was cooled to 08C,
adjusted to pH 2 with ice-cold 0.5 M hydrochloric acid
and extracted immediately with dichloromethane
63£50 mL). The combined extracts were dried, concentrated
in vacuum and the residue was submitted to ¯ash chromato-
graphy to furnish the acids 7 61.44 g, 70% from 5) and 8
61.66 g, 70% from 6). 7: Mp 141±1438C ; [a]Dˆ16386c 1,
CHCl3); 1H NMR 6200 MHz, CDCl3): d 1.10 6s, 9H,
tButyl); 1.24±1.45 64s, 12H, isoprop.); 3.70 6dd, 1H, H6);
4.00 6m, 3H, H3, H5, H60); 4.20 6dd, 1H, H4); 4.40 6d, 1H,
H2); 7.30±7.70 6m, 10H, Ph); 13C NMR 650 MHz, CDCl3):
d 19.7±27.4 [tButyl, C6CH3)2]; 67.6; 72.6; 76.8; 81.3 6C2,
C3, C4, C5, C6); 109.7; 110.5 [C6CH3)2]; 127.0±136.0 6ph);
173.8 6CO); Anal. Calcd for C28H38O7Si: C, 65.34; H, 7.44.
Found: C, 65.40; H, 7.46. 8: Mp 113±1158C ; [a]Dˆ1308 6c
62.2 6CH2CH3); 67.3; 69.0; 77.0; 77.4; 82.1 6C4, C5, C6,
C7, C8); 109.5; 109.6 [C6CH3)2]; 127.0±136.0 6ph); 160.0
6COOEt); 191.0 6COCH2); Anal. Calcd for C32H44O8Si: C,
65.72; H, 7.58. Found: C, 65.68; H, 7.63. 10: oil; 1H NMR
6200 MHz, CDCl3): d 1.05 6s, 9H, tButyl); 1.25 6t, 3H,
CH3CH2); 1.30±1.70 6m, 20H, cyclohex); 3.10 6m, 2H,
H3, H30); 3.80 6m, 1H, H8); 3.90±4.10 6m, 4H, H4, H5,
H7, H80); 4.20 6q, 2H, CH2CH3); 4.50 6m, 1H, H6); 7.40±
7.70 6m, 10H, Ph); 13C NMR 650 MHz, CDCl3): d 13.9
6CH3CH2), 19.4±36.7 6tButyl, cyclohex.); 43.5 6C3); 62.2
6CH2CH3); 67.4; 69.4; 77.1; 77.4; 82.1 6C4, C5, C6, C7,
C8); 110.1; 110.3 [C6OR)2]; 127.5±135.9 6ph); 160.2
6COOEt); 191.1 6COCH2); Anal. Calcd for C38H52O8Si: C,
68.64; H, 7.88. Found: C, 68.68; H, 7.73. 13E: oil;
[a]Dˆ21338 6c 0.6, CHCl3); 1H NMR 6200 MHz,
CDCl3): d 1.10 6m, 12H, CH3CH2, tButyl); 1.15±1.40 64s,
12H, isoprop.); 2.80 6m, 2H, H3, H30); 3.70 6m, 2H, H8,
H80); 3.80±4.40 6m, 6H, CH2CH3, H4, H5, H6, H7); 6.90±
7.50 6m, 11H, ph); 7.80 6m, 4H, ph); 9.10 6sl, 1H, NH); 13C
NMR 650 MHz, CDCl3): d 14.2 6CH3CH2); 19.5±27.5
6tButyl, isoprop.); 31.6 6C3); 60.6 6CH2CH3); 67.7; 69.2;
76.8; 77.2; 81.4 6C4, C5, C6, C7, C8); 109.5; 110.0
[C6CH3)2]; 113.0±136.0 6ph); 143.3 6CvN); 164.5
6CvO); Anal. Calcd for C38H50N2O7Si.H2O: C, 65.87; H,
7.56; N, 4.04. Found: C, 66.06; H, 7.55; N, 3.78. 14E: Oil;
1H NMR 6200 MHz, CDCl3): d 1.10 6s, 9H, tButyl); 1.20 6t,
3H, CH3CH2); 1.25±2.00 6m, 20H, cyclohex.); 2.90 6m, 2H,
H3, H30); 3.70±4.40 6m, 8H, CH2CH3, H4, H5, H6, H7, H8,
H80); 6.90±7.50 6m, 11H, ph); 7.80 6m, 4H, ph); 9.00 6sl,
1H, NH); 13C NMR 650 MHz, CDCl3): d 14.3 6CH3CH2);
19.5±37.2 6C3, tButyl, cyclohex.); 60.7 6CH2CH3); 67.7;
69.6; 76.3; 77.0; 81.3 6C4, C5, C6, C7, C8); 110.0; 110.9
[C6OR)2]; 113.9±136.0 6ph); 143.4 6CvN); 164.5 6CvO).
1
0.8, CHCl3); H NMR 6200 MHz, CDCl3): d 1.10 6s, 9H,
tButyl); 1.50 6m, 20H, cyclohex.); 3.80 6m, 1H, H5); 4.10
6m, 3H, H3, H6, H60); 4.30 6dd, 1H, H4); 4.40 6d, 1H, H2);
7.30±7.80 6m, 10H, Ph); 13C NMR 650 MHz, CDCl3): d
20.2±37.5 6tButyl, cyclohex.); 67.9 6C6); 73.4; 77.3; 77.4;
81.6 6C2, C3, C4, C5); 110.7; 111.6 [C6OR)2]; 127.9±136.5
6ph); 174.5 6CO); Anal. Calcd for C34H46O7Si: C, 68.65; H,
7.80. Found: C, 68.76; H, 7.86.
1.1.4. General procedure to obtain compounds ethyl 3-
deoxy-5,6:7,8-di-O-isopropylidene-4-O-tert-butyldiphenyl-
silyl-d-gluco-oct-2-ulosonate 9, ethyl 3-deoxy-5,6:7,8-di-O-
cyclohexylidene-4-O-tert-butyldiphenylsilyl-d-gluco-oct-2-
ulosonate 10, ethyl 3-deoxy-5,6:7,8-di-O-isopropylidene-4-
1.1.5. Preparation of ethyl 3-deoxy-5,6:7,8-di-O-cyclo-
hexylidene-4-O-tert-butyldiphenylsilyl-d-gluco-oct-2-uloso-
nate .EZ)-oxime 11. To a solution of ketone 10 6664 mg,
1 mmol) in pyridine 610 mL) at 08Cwas added hydroxyl-
amine hydrochloride 6105 mg, 1.5 mmol). The mixture was
stirred at room temperature for 4 h and diluted with CH2Cl2
650 mL). The solution was washed with water, dried,
concentrated in vacuum and the residue was puri®ed by
silicagel chromatography 6hexane/EtOAc) to afforded the
desired compounds 11E and 11Z 6611 mg, 90%; proportion
E/Zˆ6:1).
O-tert-butyldiphenylsilyl-d-gluco-oct-2-ulosonate
.EZ)-
phenylhydrazone 13 and ethyl 3-deoxy-5,6:7,8-di-O-cyclo-
hexylidene-4-O-tert-butyldiphenylsilyl-d-gluco-oct-2-uloso-
nate .EZ)-phenylhydrazone 14. To a mixture of N-
hydroxy-2-thiopyridone 6127 mg, 1 mmol), DCC 6216 mg,
1.05 mmol), and anhydrous dichloromethane in a round
¯ask covered with aluminum foil was added acids 7
6514 mg, 1 mmol) or 8 6594 mg, 1 mmol) at 08Cunder
argon with stirring. After 1 h, the solution was cooled at
2608Cand transferred dropwise into the ole®n [CH vC6O-
2
COCF3)6COOEt)] 61.06 g, 5 mmol) which was placed in a
¯ask under argon at 2308Cand irradiated with a Q-Beam
lamp. After the transfer, the photoreaction was continued for
1 h at 2308C. A solution of aqueous satured K2CO3±
acetone 610 mL, 1:1) or pyridine 610 mL)/phenylhydrazine
hydrochloride 62.2 g, 15 mmol) was added and the solution
was stirred at 2208Cto room temperature overnight. The
mixture was diluted with CH2Cl2, washed with water, dried,
concentrated in vacuum and puri®ed by silica gel chromato-
graphy 6hexane/EtOAc) to give ketones 9 and 10 653%) or
phenylhydrazone 13 and 14 655%).
1
11E: Oil; H NMR 6200 MHz, CDCl3): d 1.00 6s, 9H,
tButyl); 1.25 6t, 3H, CH3CH2); 1.25±1.70 6m, 20H, cyclo-
hex.); 2.70 6dd, 1H, H3); 3.20 6dd, 1H, H30); 3.75±4.30 6m,
7H, CH2CH3, H4, H5, H7, H8, H80); 4.50 6m, 1H, H6);
7.10±7.50 6m, 6H, ph); 7.75 6m, 4H, ph); 8.60 6sl, 1H,
NH); 13CNMR 650 MHz, CDCl
3): d 14.0 6CH3CH2);
19.5±36.4 6C3, tButyl, cyclohex.); 61.4 6CH2CH3); 67.2;
69.7; 76.3; 77.0; 81.4 6C4, C5, C6, C7, C8); 110.0
[C6OR)2]; 124.0±136.8 6ph); 149.5 6CvN); 163.3 6CvO).
1.1.6. Cleavage of TBDPS protective group: synthesis of
ethyl 3-deoxy-5,6:7,8-di-O-cyclohexylidene-d-gluco-oct-
2-ulosonate .E)-oxime 12, ethyl 3-deoxy-5,6:7,8-di-O-
isopropylidene-d-gluco-oct-2-ulosonate .E)-phenylhydra-
zone 15 and Ethyl 3-deoxy-5,6:7,8-di-O-cyclohexyl-
idene-d-gluco-oct-2-ulosonate .E)-phenylhydrazone 16.
To a solution of oxime 11E or hydrazone 13E or 14E
9: Oil; 1H NMR 6200 MHz, CDCl3): d 1.05 6m, 12H,
CH3CH2, tButyl); 1.20±1.40 63s, 12H, isoprop.); 3.10 6m,
2H, H3, H3'); 3.75 6m, 1H, H8); 4.00 6m, 3H, H5, H7, H8');
4.15 6q, 2H, CH2CH3); 4.30 6dd, 1H, H6); 4.50 6d, 1H, H4);
7.40±7.70 6m, 10H, Ph); 13C NMR 650 MHz, CDCl3): d
13.9 6CH3CH2), 19.4±27.1 [tButyl, C6CH3)2]; 43.5 6C3);

D. H. R. Barton et al. / Tetrahedron 57 92001) 8767±8771
8771
61 mmol) in THF 610 mL) was added TBAF 6523 mg,
2 mmol). The mixture was stirred at room temperature for
6±12 h and was then diluted with CH2Cl2 650 mL). The
solution was washed with water, dried, concentrated in
vacuum and the residue was puri®ed by silicagel chromato-
graphy 6hexane/EtOAc) to give the desired compounds 12,
15 or 16 in 90±92% yield.
Anal. Calcd for C14H18N2O6: C, 54.19; H, 5.85; N, 9.03.
Found: C, 54.13; H, 5.81; N, 9.07.
Acknowledgements
We thank the N.I.H., the Schering-Plough-Corporation and
the Robert A. Welch Foundation for ®nancial support of this
work.
1
12: Mp 157±1598C; H NMR 6200 MHz, CDCl3): d 1.20±
1.70 6m, 20H, cyclohex.); 3.10 6m, 2H, H3, H30); 3.90±4.20
6m, 5H, H5, H6, H7, H8, H80); 4.90 6dd. 1H, H-4); 13CNMR
650 MHz, CDCl3): d 22.0±39.0 6C3, cyclohex.); 67.6; 74.8;
76.0; 77.0; 81.6 6C4, C5, C6, C7, C8); 110.6±110.9
[C6OR)2]; 148.0 6CvN); 166.2 6CO); 15: Mp 104±1058C;
References
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2. Inouye, M. Bacterial Outer Membranes; Biogenesis and
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1
[a]Dˆ1408 6c 1, CHCl3); H NMR 6200 MHz, CDCl3): d
1.20±1.50 6m, 15H, CH3CH2, isoprop.); 2.90 6ddd, 2H, H3,
H30); 4.00 6m, 6H, H4, H5, H6, H7, H8, H80); 4.30 6q, 2H,
CH2CH3); 6.90±7.40 6m, 5H, Ph); 9.30 6s, 1H, NH); 13C
NMR 650 MHz, CDCl3): d 14.5 6CH2CH3); 22.0±31.0
6tButyl, C3); 61.5 6CH2CH3); 68.2; 70.0; 77.3; 82.7 6C4,
C5, C6, C7, C8); 110.4±110.5 [C6CH3)2]; 114.4; 122.4;
129.8; 133.3 6Ph); 144.2 6CvN); 166.0 6CO); Anal. Calcd
for C22H32N2O7: C, 60.53; H, 7.39; N, 6.42. Found: C,
60.62; H, 7.37; N, 6.42. 16: oil; 1H NMR 6200 MHz,
CDCl3): d 1.30 6t, 3H, CH3CH2); 1.30±1.70 6m, 20H, cyclo-
hex.); 2.90 6m, 2H, H3, H30); 3.80±4.20 6m, 6H, H4, H5,
H6, H7, H8, H80); 4.30 6q, 2H, CH2CH3); 6.90±7.40 6m, 5H,
Ph); 9.35 6s, 1H, NH); 13C NMR 650 MHz, CDCl3): d 14.3
6CH2CH3); 23.7±37.0 6C3, cyclohex.); 61.1 6CH2CH3);
67.5; 70.0; 76.8; 77.5; 82.1 6C4, C5, C6, C7, C8); 110.5±
110.6 [C6OR)2]; 114.0; 121.7; 129.2; 133.2 6Ph); 143.6
6CvN); 165.4 6CO).
3. Anderson, L.; Unger, F. M. Bacterial Lipopolysaccharides:
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1.1.7. Synthesis of 3-deoxy-d-gluco-oct-2-ulosono-1,4-
lactone .E)-phenylhydrazone 17. A solution of hydrazone
15 6218 mg, 0.5 mmol) in ethanol 65 mL) was treated with
1 M hydrochloric acid solution 65 mL) and stirred at room
temperature for 12 h. The solution was concentrated in
vacuum to give the lactone 17 6130 mg, 85%) which was
recrystallized in ethanol. 17 was also prepared from 16 by
this same procedure in 80% yield. 17: Mp 225±2278C;
[a]Dˆ11108 6c 0.5, DMSO); 1H NMR 6200 MHz,
DMSO-d6): d 2.90 6ddd, 2H, H3, H30); 3.50 6m, 5H, 4OH,
H5); 4.40 6t, 1H, H7); 4.55 6m, 2H, H8, H80); 4.80 6m, 1H,
H6); 5.00 6d, 1H, H4); 13CNMR 650 MHz, DMSO d6): d
27.9 6C3); 63.1; 70.2; 71.2; 71.8; 77.4 6C4, C5, C6, C7, C8);
113.5; 121.1; 129.0; 131.2 6Ph); 144.1 6CvN); 167.1 6CO);
7. Barton, D. H. R.; Jaszberenyi, J. Cs.; Liu, W.; Shinada, T.
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