H. G. Bazin et al. / Tetrahedron Letters 47 (2006) 2087–2092
2091
11. Boullanger, P.; Jouineau, M.; Bouammali, B.; Lafont, D.;
Descotes, G. Carbohydr. Res. 1990, 202, 151–164.
12. Keegan, D. S.; Hagen, S. R.; Johnson, D. A. Tetrahedron:
Asymmetry 1996, 7, 3559–3564.
13. Nakahata, K.; Imaida, M.; Ozaki, H.; Narada, T.; Tai, A.
Bull. Chem. Soc. Jpn. 1982, 55, 2186–2189.
A new method for preparing fatty acid starting materials
8 and 9 was also developed using in situ-generated
Ru(II)–Binap catalyst for asymmetric hydrogenation
of keto ester 5 in the key step and enhancing the enan-
tiopurity of scalemic PAc ester 7 by crystallization.
These methodologies are currently being applied to the
synthesis of other AGPs 2 and should find useful appli-
cation to the preparation of glucosamine-based lipid A
mimetics in general.
14. Labeeuw, O.; Phansavath, P.; Geneˆt, J.-P. Tetrahedron:
Asymmetry 2004, 15, 1899–1908.
15. General procedure for large-scale preparation of PAc ester
7: A degassed solution of RuCl3 (0.2 mol %), (R)-Binap
(0.2 mol %), and methyl 3-oxotetradecanoate (5) (200 g) in
MeOH (800 mL) was hydrogenated at 65 psig and 40–
50 °C for 20 h, and then filtered through silica gel. The
filtrate was concentrated and the hydroxy ester obtained
was hydrolyzed with LiOH (1.5 equiv) in 50% aq THF
(2.5 L). The resulting slurry was acidified and extracted
with MTBE (2 L). The organic layer was washed with
water, dried (Na2SO4), and concentrated. A solution of
the hydroxy acid 6 was obtained and triethylamine
(1.5 equiv) in EtOAc (5.5 L) was treated with 2,4-di-
bromoacetophenone (1 equiv) and the resulting mixture
was stirred overnight at room temperature. The suspen-
sion that formed was filtered and the filtrate concentrated
to give crude 7 (95.0% ee by chiral HPLC12), which was
crystallized twice from toluene to give 219 g (64% from 5)
of 7 as a white solid: mp 111–112.5 °C (lit.12 mp 109–
109.5 °C); 99.9% ee; [a]D ꢁ2.37 (c 2.40, CHCl3) (lit.12 [a]D
ꢁ2.4 (c 2.39, CHCl3)).
Acknowledgments
This work was funded in part by the Defense Advanced
Research Projects Agency (DARPA) under Contract
No. N66001-01-C-8007 and by the US Army Medical
Research Acquisition Activity (USAMRAA) under
Contract No. DAMD17-03-C-0089. Any opinions, find-
ings, and conclusions or recommendations expressed in
this article are those of the authors and do not necessar-
ily reflect the views of DARPA or USAMRAA.
References and notes
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18. General procedure for tri-acylation of 15 with acid 9: A
solution of 15 (4.87 g), EDC–MeI (3.2 equiv), and DMAP
(0.03 equiv) in CH2Cl2 (40 mL) at 0 °C was treated
dropwise with a solution of acid 9 (3.2 equiv) in CH2Cl2
(20 mL) and allowed to stir and warm to room temper-
ature over 2 h. Aqueous workup followed by flash
chromatography on silica gel (gradient elution, 10!40%
EtOAc–heptane containing 1% AcOH) gave 14.2 g (66%)
of 17 as an amorphous solid: [a]D ꢁ9.71 (c 2.10, CHCl3);
1H NMR (400 MHz, CDCl3) d 0.08 (s, 3H), 0.09 (s, 3H),
0.84–0.91 (m, 27H), 1.19–1.35 (m, 90H), 1.51–1.67 (m,
12H), 2.24–2.32 (m, 6H), 2.32–2.64 (m, 6H), 3.28–3.50 (m,
3H), 3.55 (s, 1H), 3.58–3.70 (m, 2H), 3.78–3.95 (m, 4H),
4.47 (d, 1H, J = 8.0 Hz), 4.94 (dd, 1H, J = 9.0, 11.0 Hz),
5.03–5.22 (m, 3H), 6.15 (d, 1H, J = 8.8 Hz), 6.50 (t, 1H,
J = 5 Hz); 13C NMR (100 MHz, CDCl3) d ꢁ5.43, ꢁ5.46,
14.11, 18.26, 22.68, 24.97, 25.01, 25.04, 25.16, 25.34, 25.83,
29.15, 29.20, 29.21, 29.29, 29.31, 29.36, 29.47, 29.49, 29.53,
29.58, 29.61, 29.64, 29.66, 29.70, 31.88, 31.91, 34.34, 34.41,
34.47, 34.57, 39.34, 40.00, 41.43, 41.98, 53.63, 64.08, 67.81,
70.73, 70.82, 71.15, 71.40, 74.70, 75.82, 77.21, 101.35,
169.86, 170.20, 171.63, 173.48, 173.53, 174.14. MALDI-
MS calcd for [MNa]+ 1500.1850, found 1500.1860.
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Johnson, D. A.; Lacy, M. J.; Clawson, V. G.; Yorgensen,
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21. Spectral data for compounds 3 and 4: Compound 3: H
1
NMR (400 MHz, CDCl3–CD3OD) d 0.88 (ꢀt, 18H), 1.19–
1.39 (m, 123H), 1.50–1.65 (m, 12H), 2.24–2.51 (m, 10H),
2.52–2.67 (m, AB type, 2H), 3.11 (q, 6H, J = 7.2 Hz),
3.22–3.30 (m, 1H), 3.36–3.45 (m, 2H), 3.58–3.66 (m, 1H),
3.73–3.83 (m, 3H), 3.92 (dd, 1H, J = 2.8, 12.8 Hz), 4.25
(ꢀq, 1H, J ꢀ 10 Hz), 4.53 (d, 1H, J = 8.4 Hz), 5.07–5.24
(m, 4H); 13C NMR (100 MHz, CDCl3) d 8.57, 14.10,
22.68, 25.05, 25.34, 29.21, 29.24, 29.29, 29.37, 29.40, 29.42,
29.44, 29.51, 29.55, 29.57, 29.62, 29.64, 29.67, 29.68, 29.73,
´
Program–Fondation Merieux, Annecy, France, 2002.