An asymmetric synthesis of (2S,3S)-safingol

Article abstract of DOI:10.1016/j.tetlet.2006.11.119

Two efficient asymmetric syntheses of (2S,3S)-safingol have been developed starting from easily available (R)-cyclohexylideneglyceraldehyde. The key steps in the syntheses were a diastereoselective addition of a suitable alkylmagnesium or lithium reagent,

Full text of DOI:10.1016/j.tetlet.2006.11.119

Tetrahedron Letters 48 (2007) 633–634
An asymmetric synthesis of (2S,3S)-safingol
Anubha Sharma, Sunita Gamre and Subrata Chattopadhyay*
Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai 400 085, India
Received 13 October 2006; revised 7 November 2006; accepted 17 November 2006
Abstract—Two efficient asymmetric syntheses of (2S,3S)-safingol have been developed starting from easily available (R)-cyclohexyl-
ideneglyceraldehyde. The key steps in the syntheses were a diastereoselective addition of a suitable alkylmagnesium or lithium
reagent, and simple organic transformations. Compared to earlier syntheses, the route involving alkyllithium addition is more viable
practically due to its excellent diastereoselectivity, use of inexpensive materials/reagents and operational simplicity.
Ó 2006 Elsevier Ltd. All rights reserved.
The amino alcohol, (2S,3S)-2-amino-1,3-octadecanediol
(safingol, 1) is valued as an antineoplastic and antipsori-
atic drug.1 The compound is being extensively investi-
gated for its role in cell regulation, signal
transduction,2 and inhibition of protein kinase C.3 Sev-
eral syntheses of 1 based on diastereoselective or enan-
tioselective methods4a–d and resolution5a–d have been
reported. These include methods based on enantioselec-
tive Henry reaction4a and ketone reduction,4b a multi-
step synthesis from (Z)-2-buten-1,4-diol,4c and a diaste-
reoselective synthesis using a suitable chiral oxazolidinyl
ester.4d In spite of their elegance, some of these meth-
ods4a,d use reagents that are either expensive or that
are prepared via several steps. Thus, the primary aim
of the present work was to develop a selective and effi-
cient synthesis for the medicinally important compound
(2S,3S)-1.
and 3b was confirmed by comparing the 1H NMR
resonances of the CH2O and CHO groups with those
reported in the literature.7a,b Protection of the hydroxyl
group of 3b by silylation gave 4 which following deace-
talization via a new neutral protocol (CuCl2ÆH2O/
MeOH) furnished diol 5. After regioselective monosilyl-
ation of the primary hydroxyl, the resultant compound 6
was converted to azide 7 with diphenylphosphoryl azide
in the presence of diethyl azodicarboxylate (DEAD)
and triphenylphosphine. The reduction of the azide
function of 7 with lithium aluminium hydride (LAH)
directly afforded the target compound 1 via concomitant
desilylation.
Having completed the above synthesis, we ventured
towards a more practicable synthesis of 1. For this, it
was essential to (i) develop a better enantioselective
route for 3b, and (ii) use inexpensive reagents for the
introduction of the required amine function, reagents
such as Ph3P, (PhO)2P(O)N3, TPSCl, TBSCl and
DEAD being deemed too expensive. Aldehyde 2 was re-
acted with freshly prepared n-pentadecyllithium in hex-
ane to give carbinols 3a and 3b with vastly improved
anti-selectivity (3a:3b, 6:94). Deacetalization with 2%
methanolic HCl furnished triol 8, which was converted
into acetal 9 under solvent-free conditions. Tosylation
followed by reaction with NaN3 furnished azide 10
along with a small amount (9%) of the elimination prod-
uct. Catalytic hydrogenation of 10 and subsequent
acidic hydrolysis afforded 1 (Scheme 2).8
Earlier, we showed6a that the addition of Grignard
reagents to cyclohexylideneglyceraldehyde 2 provides an
easy access to the C-3 epimers of alkanetriol derivatives,
which are useful chirons for the synthesis of various
classes of bioactive compounds.6b,c Consequently, we
explored a similar approach using aldehyde 2 for the
synthesis of 1 (Scheme 1). The reaction of pentadecyl-
magnesium bromide with 1 proceeded with a good
diastereoselectivity (syn:anti 22:78) to give the syn- and
anti-carbinols 3a and 3b in a good yield. The syn- and
anti-stereochemistry of easily isolated diastereomers 3a
Amongst the existing syntheses of 1, the recent multi-
gram scale synthesis5d appears most attractive.
However, as a resolution-based method, it has its own
*
Corresponding author. Tel.: +91 22 25593703; fax: +91 22
25505151; e-mail addresses: schatt@barc.gov.in; schatt@apsara.barc.
gov.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.119

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A. Sharma et al. / Tetrahedron Letters 48 (2007) 633–634
R
R
R
OH
R
R
R
O
O
O
i
iii
RO
iv
(CH2)14CH3
O
(CH2)14CH3
O
(CH2)14CH3
OR1
O
+
CHO
OTPS
OH
3a
2
5 R = H
3b R1 = H
ii
6 R = TBS
4 R1 = TPS
R,R = cyclohexylidene
N3
NH2
v
vi
TBSO
(CH2)14CH3
OTPS
HO
(CH2)14CH3
OH
1
7
Scheme 1. Reagents and conditions: (i) CH3(CH2)14MgBr, THF, rt (86%); (ii) tert-butyldiphenylsilyl chloride (TPSCl), imidazole, CH2Cl2, rt (93%);
(iii) CuCl2ÆH2O, MeOH, D (81%); (iv) tert-butyldimethylsilyl chloride (TBSCl), imidazole, CH2Cl2, rt (88%); (v) Ph3P, (PhO)2P(O)N3, DEAD, THF,
0 to rt (84%); (vi) LAH, diethyl ether, reflux (77%).
R
R
OH
R
R
O
iii
O
ii
i
HO
(CH2)14CH3
O
(CH2)14CH3
OH
O
CHO
OH
8
2
3b
R,R = cyclohexylidene
N3
OH
(CH2)14CH3
(CH2)14CH3
O
O
H
v
1
O
O
H
iv
10
MeO
9
MeO
Scheme 2. Reagents and conditions: (i) CH3(CH2)14Br, Li, hexane, À40 °C (89%); (ii) MeOH, HCl, rt (91%); (iii) p-anisaldehyde, HCl, rt (81%); (iv)
p-TsCl, pyridine, CH2Cl2, À5 °C, NaN3, DMF, D (75%); (v) H2, 10% Pd–C, EtOH, rt, aqueous HCl (72%).
(b) Masui, M.; Shioiri, T. Tetrahedron Lett. 1998, 39,
5199; (c) Shibuya, H.; Kawashima, K.; Narita, N.; Ikeda,
M.; Kitagawa, I. Chem. Pharm. Bull. 1992, 40, 1154; (d)
Villard, R.; Fotiadu, F.; Buono, G. Tetrahedron: Asym-
metry 1998, 9, 507.
limitations, especially for the generation of the enantio-
mer. Further, it required a laborious standardization of
the Henry reaction for the synthesis of the required dia-
stereomeric nitro carbinol, the precursor for 1. In com-
parison, the present method is operationally simple
and the reagents and starting material are readily avail-
able. The starting aldehyde 2 can be easily prepared in
appreciable amounts from the inexpensive (D)-mannitol.
We have standardized its synthesis on a 170 g scale and
used it for the syntheses of various bioactive com-
pounds.9a–c Both the Grignard or alkyllithium reaction
and azidation are amenable to scale-up. The second pro-
cedure involving five synthetic steps is reproducible and
provided 1 in ꢀ35–37% overall yield starting from 2.
Given that (S)-2 is also available easily from vitamin C,10
the flexibility of our method would allow the prepara-
tion of any desired isomer of 1 with an equal efficiency.
5. (a) Grob, C. A.; Jenny, E. F.; Utzinger, H. Helv. Chim.
Acta 1951, 34, 2249; (b) Egerton, M. J.; Gregory, G. I.;
Malkin, T. J. Chem. Soc. 1952, 2272; (c) Grob, C. A.;
Jenny, E. F. Helv. Chim. Acta 1952, 35, 2106; (d) Zhang,
L. H.; Oniciu, D. C.; Mueller, R.; McCosar, B. H.; Popa,
E. ARKIVOC 2005, 285.
6. (a) Chattopadhyay, A.; Mamdapur, V. R. J. Org. Chem.
1995, 60, 585; (b) Sharma, A.; Chattopadhyay, S. Tetra-
hedron: Asymmetry 1999, 10, 883; (c) Sharma, A.;
Chattopadhyay, S. Enantiomer 2000, 5, 175.
7. (a) Bastian, G.; Bessodes, M.; Panzica, R. P.; Abushanab,
E.; Chen, S. F.; Stoeckler, J. D.; Parks, R. E., Jr. J. Med.
Chem. 1981, 24, 1385; (b) Baker, D. C.; Hawkins, L. D.
J. Org. Chem. 1982, 47, 2179.
8. All the compounds were characterized by their optical
rotation, spectral (IR and 1H, 13C NMR) and micro-
analytical data.
References and notes
9. (a) Salaskar, A.; Sharma, A.; Chattopadhyay, S. Tetra-
hedron: Asymmetry 2006, 17, 325; (b) Salaskar, A. A.;
Mayekar, N. V.; Sharma, A.; Nayak, S. K.; Chattopad-
hyay, A.; Chattopadhyay, S. Synthesis 2005, 2777; (c)
Roy, S.; Sharma, A.; Chattopadhyay, N.; Chattopadhyay,
S. Tetrahedron Lett. 2006, 47, 7067.
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