Studies towards lipid A: a synthetic strategy for the enantioselective preparation of 3-hydroxy fatty acids

Article abstract of DOI:10.1016/j.tetasy.2006.10.023

A short and efficient enantioselective synthesis of (R)-3-hydroxydodecanoic acid is described, involving a Sharpless asymmetric dihydroxylation to produce the required (R)-stereochemistry.

Full text of DOI:10.1016/j.tetasy.2006.10.023

Tetrahedron: Asymmetry 17 (2006) 2839–2841
Studies towards lipid A: a synthetic strategy for the
enantioselective preparation of 3-hydroxy fatty acids
Annalisa Guaragna,* Mauro De Nisco, Silvana Pedatella and Giovanni Palumbo
`
Dipartimento di Chimica Organica e Biochimica, Universita di Napoli Federico II, Via Cynthia 4, Napoli I-80126, Italy
Received 5 October 2006; accepted 19 October 2006
Available online 16 November 2006
Abstract—A short and efficient enantioselective synthesis of (R)-3-hydroxydodecanoic acid is described, involving a Sharpless asymmet-
ric dihydroxylation to produce the required (R)-stereochemistry.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
OH
O
OH
OH
CN
OH
8
OH
8
8
8
Greater interest has been taken in 3-hydroxy fatty acids by
both synthetic chemists and glycobiochemists.1 In particu-
lar, the fatty acid chain length appears to be a significant
determinant of bioactivity in lipid A molecules, whose
(R)-3-hydroxytetradecanoic acid is the most common fatty
acid constituent. Recently published results have estab-
lished2 the unusual structure of the lipid A family (Fig. 1)
derived from LPS of Halomonas magadiensis, a bacterium
which is non-pathogenic in humans. This lipid A has been
shown to consist of a complex and heterogeneous mixture
of disaccharides variously acylated with primary (R)-3-
hydroxydodecanoic acid.
1
4
3
2
Scheme 1. Retrosynthetic path.
Since lipid A from H. magadiensis interferes with cytokine
induction in human cells,3 it would be very interesting to
observe the biological activity of each component of this
lipid A as a potential antagonist. We are currently develop-
ing a flexible procedure for the facile synthesis of its con-
stituents and, within this context, an efficient preparation
of lipidic moieties with high enantiomeric excess is also re-
quired. Herein, we report a new approach to the enantiose-
lective synthesis of (R)-3-hydroxydodecanoic acid 1 in high
yield and enantiomeric excess.
While many syntheses of (R)-3-hydroxytetradecanoic acid
derivatives have been achieved by both chemical and enzy-
matic methods,4 few procedures5 are reported for a large
scale preparation of (R)-3-hydroxydodecanoic acid 1. We
planned to start from the commercially available 1-unde-
cene 2 as outlined in the retrosynthetic path in Scheme 1.
OH
6'
O
P
4'
5'
6
O
O
HO
HO
O
4
O
5
2'
O
1'
3'
NH
HO
O
O
P
1
O
O
2
3
NH
OH
OH
O
R'O
O
O
R'O
R'O
7
R'O
7
2. Results and discussion
7
7
Our strategy involved homologation of the 1-undecene car-
bon chain through the displacement of the primary hydro-
xyl of chiral diol 3 with a cyano group. The chiral diol 3
was prepared in high yield (82%) by the Sharpless asym-
metric dihydroxylation reaction6 on alkene 2 using AD-
mix-b. This reagent produced the asymmetric carbon atom
R'= H or C16:0 or C14:0 or C18:1
Figure 1.
*
Corresponding author. Tel.: +39 081674118; fax: +39 081674119;
e-mail: guaragna@unina.it
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.10.023

2840
A. Guaragna et al. / Tetrahedron: Asymmetry 17 (2006) 2839–2841
with the required (R)-stereochemistry. The enantiomeric
excess (90%) was determined by H NMR spectroscopy
of the corresponding 1-methoxy derivative using the chiral
shift reagent Eu(hfc)3 in comparison with a racemic
mixture.7
od,5a which involves its conversion into the corresponding
N,N-dicyclohexylammonium salt. The enantiomerically
pure16 acid 1 (ee >99%) was obtained in 76% yield by three
successive recrystallizations from acetonitrile and acid
treatment of the salt.
1
Concerning the conversion of diol (R)-(ꢀ)-3 into the
cyanoalcohol (R)-(ꢀ)-4, we believed that it could be avail-
able through the regioselective opening of the chiral epox-
ide 5 that can be produced, as reported,8 by using a
betaine-like intermediate. In fact, activated phosphorus re-
agents such as DTPP, TPP–CCl4–K2CO3 and TPP–DEAD
promote cyclodehydration of unsymmetrical chiral diols to
afford epoxides with retention of stereochemistry at the chi-
ral carbon. Drawing on our previous9 experience with a
polystyryl diphenyl phosphine/iodine (PDP/I2) complex,
we chose to achieve the required chiral epoxide 5 using
TPP/I2 in the presence of potassium carbonate in anhy-
drous acetonitrile. However, under our conditions, the
yield of 5 was less than 50%. When the reported8 reagent
TPP–CCl4–K2CO3 was employed, similar results were ob-
tained. These findings prompted us to follow an alternative
synthetic procedure for the preparation of 5 (Scheme 2).
3. Conclusion
Herein, we reported a practical, highly enantioselective
synthesis of (R)-3-hydroxydodecanoic acid 1 with high
overall yield (39%) from a commercial starting product,
using a Sharpless AD reaction as source of chirality. The
synthetic strategy described here can be extended to other
b-hydroxy fatty acids and related analogues.
Acknowledgements
This research has been supported by MIUR Roma (Prog-
etto di Ricerca di Interesse Nazionale, 2004, Roma). H
1
and 13C NMR spectra were performed at Centro Interdi-
partimentale di Metodologie Chimico-Fisiche (CIMCF),
Universita’ di Napoli Federico II. Varian Inova 500 MHz
instrument is the property of Consorzio Interuniversitario
Nazionale La Chimica per l’Ambiente (INCA) and was
used in the frame of a project by INCA and MIUR
(L. 488/92, Cluster 11-A).
Firstly the primary alcohol was regioselectively converted10
in high yield (95%) into the monotosyl11 compound 6 by
treatment with dibutyltin oxide (0.02 equiv), followed by
the addition of p-toluenesulfonyl chloride (1.0 equiv) and
triethylamine (1.1 equiv) in anhydrous dichloromethane.
The treatment12 of (R)-(ꢀ)-6 in basic methanolic solution
afforded13 (R)-(+)-1,2-epoxyundecane 5 in 91% yield, with
complete retention of the C-2 configuration.
References
1. Alexander, C.; Rietschel, E. Th. J. Endotoxin Res. 2001, 7,
167–202.
2. Silipo, A.; Sturiale, L.; Garozzo, D.; de Castro, C.; Lanzetta,
R.; Parrilli, M.; Grant, W. D.; Molinaro, A. Eur. J. Org.
Chem. 2004, 10, 2263–2271.
3. Ialenti, A.; Di Meglio, P.; Grassia, G.; Maffia, P.; Di Rosa,
M.; Lanzetta, R.; Molinaro, A.; Silipo, A.; Grant, W. D.;
Ianaro, A. Eur. J. Immunol. 2006, 36, 354–360.
The regioselective ring opening using TBAF/TMSCN in
anhydrous tetrahydrofuran at room temperature gave
cyanoalcohol (R)-(ꢀ)-4 in 89% yield.14 Finally, the synthe-
sis was completed successfully by hydrolysis of intermedi-
ate 4, which was carried out15 through the action of
alkaline hydrogen peroxide in aqueous methanol to obtain
(R)-3-hydroxy acid 1 in 81% yield with an enantiomeric ex-
cess of 88%.
4. Ikunaka, M. Chem. Eur. J. 2003, 9, 379–388.
5. (a) Nakahata, M.; Imaida, M.; Ozaki, H.; Harada, T.; Tai, A.
Bull. Chem. Soc. Jpn. 1982, 55, 2186–2189; (b) Weil, K.;
Humpf, H.-U.; Schwab, W.; Schreier, P. Chirality 2002, 14,
51–58.
Since the synthesis of the components of lipid A needed
(R)-3-hydroxydodecanoic acid 1 with a high enantiomeric
excess, we purified crude 1 thus obtained, using Tai’s meth-
6. AD-mix-b (26.4 g) and MeSO2NH2 (1.8 g, 19.4 mmol) were
added to a stirring solution of 2 (3.0 g, 19.4 mmol) in tBuOH/
H2O (220 mL, 1:1) at room temperature. After the starting
product was completely consumed (TLC, 16 h), the mixture
was quenched by the addition of 0.4 equiv of Na2SO3, stirred
for 1 h and then concentrated under reduced pressure. Silica
gel column chromatography of crude product using CHCl3 as
eluent led to diol 3 as a white crystalline solid, after
recrystallization from hexane/acetone 9:1 (3.0 g, 82% yield).
OH
OH
ii
i
OH
OTs
O
8
8
8
2
3
6
iii
O
OH
OH
25
Mp 50.0–51.0; ½aꢁD ¼ ꢀ6:2 (c 2.9, CHCl3); 1H NMR
iv
v
CN
OH
(400 MHz, CDCl3): d 0.89 (t, J = 6.8 Hz, 3H), 1.23–1.29
(m, 14H), 1.41–1.53 (m, 2H), 1.77–2.12 (m, 2H), 3.45 (dd,
J = 7.6, 10.9 Hz, 1H), 3.68 (dd, J = 2.9, 10.9 Hz, 1H), 3.71–
3.77 (m, 1H); 13C NMR (100 MHz, CDCl3): d 14.5, 23.0,
25.9, 29.7, 29.9 (2 · C), 30.0, 32.2, 33.6, 67.2, 72.7. Anal.
Calcd for C11H24O2: C, 70.16; H, 12.85. Found: C, 70.37; H,
12.89.
8
8
8
1
4
5
Scheme 2. Reagents and conditions: (i) AD-mix-b, methanesulfonamide,
t-BuOH/H2O, rt, 16 h, 82%; (ii) dibutyltin oxide, p-TsCl, NEt3, CH2Cl2
anhydrous, rt, 50 min, 95%; (iii) NaOH, MeOH, 0 ꢁC, 30 min, 91%; (iv)
Me3SiCN, TBAF, THF, 50 ꢁC, 16 h, 89%; (v) a. NaOH/H2O2, MeOH,
reflux, overnight, 81%; b. 2 M aq HCl, rt; c. (c-C6H11)2NH, MeCN,
MeOH, reflux, 30 min; d. 10% aq HCl, 0 ꢁC, 10 min, 76%.
7. Ohta, H.; Tetsukawa, H. J. Chem. Soc., Chem. Commun.
1978, 849–850.

A. Guaragna et al. / Tetrahedron: Asymmetry 17 (2006) 2839–2841
2841
8. Robinson, P. L.; Barry, C. N.; Bass, S. W.; Jarvis, S. E.;
Evans, S. A., Jr. J. Org. Chem. 1983, 48, 5398–5400.
9. Pedatella, S.; Guaragna, A.; D’Alonzo, D.; De Nisco, M.;
Palumbo, G. Synthesis 2006, 2, 305–308.
20.5 mmol) and 1 M solution of TBAF in the same solvent
(5.9 mL) at 50 ꢁC. After 16 h (TLC; CHCl3/CH3OH = 95:5)
the reaction was concentrated and the mixture, diluted with
water (10 mL), was extracted with AcOEt (2 · 50 mL). The
organic layers were washed with brine, dried (Na2SO4) and
concentrated in vacuo. Silica gel column chromatography of
crude product (1:20, Etp/Et2O = 95:5) afforded the oily
10. Martinelli, M. J.; Vaidyanathan, R.; Pawlak, J. M.; Nayyar,
N. K.; Dhokte, U. P.; Doecke, C. W.; Zollars, L. M. H.;
Moher, E. D.; Khau, V. V.; Kosmrlj, B. J. Am. Chem. Soc.
2002, 124, 3578–3585.
25
compound 4 (2.3 g, 89% yield). ½aꢁD ¼ ꢀ4:3, (c 3.0, CHCl3);
25
11. Monotosylate 6: oil ½aꢁD ¼ ꢀ9:2 (c 2.3, CHCl3); 1H NMR
1H NMR (500 MHz, CDCl3): d 0.88 (t, J = 6.8 Hz, 3H),
1.20–1.38 (m, 14H), 1.52–1.68 (m, 2H), 2.48 (dd, J = 6.3,
16.6 Hz, 1H), 2.57 (dd, J = 4.8, 16.6 Hz, 1H), 3.80–4.00 (m,
1H); 13C NMR (100 MHz, CDCl3): d 13.9, 22.5, 25.3, 25.9,
26.0, 28.5, 29.2, 29.3, 31.7, 36.5, 67.7, 117.6. Anal. Calcd for
C12H23NO: C, 73.04; H, 11.75; N, 7.10. Found: C, 72.79; H,
11.71; N, 7.13.
(500 MHz, CDCl3): d 0.88 (t, J = 7.0 Hz, 3H), 1.10–1.34 (m,
14H), 1.35–1.50 (m, 2H), 2.46 (s, 3H), 3.80–3.86 (m, 1H), 3.88
(dd, J = 7.3, 9.8 Hz, 1H), 4.04 (dd, J = 2.4, 9.8 Hz, 1H), 7.36
(d, J = 8.0, 2H), 7.81 (d, J = 8.0, 2H); 13C NMR (125 MHz,
CDCl3): d 14.3, 22.8, 25.4, 29.5, 29.7, 29.9, 32.1, 32.9, 69.7,
74.2, 128.2, 130.2, 133.8, 145.3. Anal. Calcd for C18H30O4S:
C, 63.13; H, 8.83; S, 9.36. Found: C, 63.38; H, 8.80; S, 9.40.
12. Our attempts to obtain cyanoalcohol (R)-(ꢀ)-4 by the direct
nucleophilic displacement of tosylate 6 with tetraethylammo-
nium cyanide were unsuccessful.
15. Matsuyama, K.; Ikunaka, M. Tetrahedron: Asymmetry 1999,
10, 2945–2950.
16. Pure (R)-(ꢀ)-3-hydroxydodecanoic acid 1: white crystals.
25
Mp 57.5–58.0 ꢁC; ½aꢁD ¼ ꢀ17:8 (c 1.2, CHCl3) [lit.5a
25
20
13. ½aꢁD ¼ ꢀ9:7 (neat). The spectroscopic data were in full
½aꢁD ¼ ꢀ17:5 (c 1, CHCl3)]; 1H NMR (500 MHz, CDCl3):
agreement with the values of the racemic mixture reported
in the literature: Sato, K.; Aoki, M.; Ogawa, M.; Hashimoto,
T.; Panyella, D.; Notori, R. Bull. Chem. Soc. Jpn. 1997, 70,
905–915.
d 0.88 (t, J = 6.8 Hz, 3H), 1.22–1.59 (m, 16H), 2.47 (dd,
J = 9.3, 16.0 Hz, 1H), 2.57 (dd, J = 2.9, 16.6 Hz, 1H), 4.00–
4.07 (m, 1H); 13C NMR (125 MHz, CDCl3):
d 14.0,
22.6, 25.3, 29.2, 29.4, 31.7, 36.4, 41.0, 67.9, 177.5. Anal.
Calcd for C12H24O3: C, 66.63; H, 11.18. Found: C, 66.48;
H, 11.20.
14. A stirring solution of compound 5 (2.3 g, 13.7 mmol) in
anhydrous THF (68 mL) was treated with Me3SiCN (2.0 g,