Asymmetric synthesis of sphinganine and clavaminol H

Article abstract of DOI:10.1021/jo1003899

(Figure presented) An efficient enantioselective synthesis of sphinganine and clavaminol H is reported. These sphingoid-type bases were obtained from commercially available fatty acids using highly enantioselective Ru-catalyzed hydrogenation and organocatalytic electrophilic amination reactions to create the stereogenic centers.

Full text of DOI:10.1021/jo1003899

pubs.acs.org/joc
Asymmetric Synthesis of Sphinganine and
Clavaminol H
Ramzi Ait-Youcef, Xavier Moreau, and Christine Greck*
ꢀ
Institut Lavoisier de Versailles, UMR CNRS 8180, Universite
de Versailles-St-Quentin-en Yvelines, 45 Avenue des
Etats-Unis, 78035 Versailles Cedex, France
FIGURE 1. Structure of sphinganine and clavaminol H.
SCHEME 1. Proposed Retrosynthesis of Sphingoids
greck@chimie.uvsq.fr
Received March 2, 2010
An efficient enantioselective synthesis of sphinganine and
clavaminol H is reported. These sphingoid-type bases
were obtained from commercially available fatty acids
using highly enantioselective Ru-catalyzed hydrogena-
tion and organocatalytic electrophilic amination reac-
tions to create the stereogenic centers.
In 2007 and 2009, a new family of sphingoid-type bases, called
clavaminols, have been extracted from the Mediterranean asci-
dian Clavelina phlegraea. Some of these news compounds
possess cytotoxic properties against lung, breast, and gastric
carcinoma cell lines by activating the apoptic machinery.5
Among these molecules, clavaminol H (Figure 1) presents a
structure similar to sphinganine and differs only by the length
of the alkyl chain. This product did not exhibit significant
biological activity, but the corresponding hydrolysis has
showed cytotoxic activities against gastric carcinoma cell
lines.5b To our knowledge, only onesynthesis of the hydrolysis
product of clavaminol H was recently described in the
literature.4a
In this paper, we report a general approach to the long-chain
2-amino 1,3-diol. In our ongoing program toward electrophilic
amination,6 we recently reported an efficient access to the enantio-
enriched 2-amino 1,3-diol moiety based on asymmetric R-
amination of chiral β-hydroxy aldehydes catalyzed by proline.7
We envisioned applying this strategy to the synthesis of two
sphingoid-type bases, sphinganine and clavaminol H.
Sphingoid bases or related long-chain amino alcohols are
common subunits present in a large class of biologically active
natural products.1 Among these sphingoids, sphinganine is
known to be an important precursor in the biosynthesis of
ceramides or sphingolipids (for example, sphingomyelin, cere-
brosides, or gangliosides) which play important roles in cell
regulation, cell growth modulation, and signal transmission.2
Sphinganine itself found to be an inhibitor of protein kinase C.3
As a consequence, several methods for the synthesis of sphin-
ganine were reported in the literature.4
(1) Pruett, S. T.; Bushnev, A.; Hagedorn, K.; Adiga, M.; Haynes, C. A.;
Sullards, M. C.; Liotta, D. C.; Merrill, H. M., Jr. J. Lipids Res. 2008, 49,
1621.
(2) (a) Hannun, Y. A.; Bell, R. M. Science 1989, 243, 500. (b) Kolter, T.;
Sandhoff, K. Angew. Chem., Int. Ed. 1999, 38, 1532. (c) Brodesser, S.;
Sawatzki, P.; Kolter, T. Eur. J. Org. Chem. 2003, 2021. (d) Liao, J.; Tao,
J.; Lin, G.; Liu, D. Tetrahedron 2005, 61, 4715.
We proposed that 2-aminoalkane-1,3-diols A could be ob-
tained from the intermediates B. anti-R-Hydrazino β-hydroxy
aldehydes B could be synthesized stereoselectively by organo-
catalytic electrophilic amination of β-hydroxy esters C. Inter-
mediates C could be prepared enantioselectively by Ru-
catalyzed asymmetric hydrogenation of β-keto esters D followed
by the reduction of the ester moiety (Scheme 1).
(3) Schwartz, G. K.; Jiang, J.; Kelsen, D.; Albino, A. P. J. Nat. Cancer
Inst. 1993, 85, 402.
(4) For recent references on the synthesis of sphinganine derivatives, see: (a)
Seguin, C.; Ferreira, F.; Botuha, B.; Chemla, F.; Perez-Luna, A. J. Org. Chem.
2009, 74, 6986. (b) Cai, Y.; Ling, C. C.; Bundle, D. R. Org. Biomol. Chem. 2006,
4, 1140. (c) Zhong, Y.-W.; Dong, Y.-Z.; Fang, K.; Izumi, K.; Xu, M.-H.; Lin,
G.-Q. J. Am. Chem. Soc. 2005, 127, 11956. (d) Howell, A. R.; So, R. S.;
Richardson, S. K. Tetrahedron 2004, 60, 11327. (e) Torssell, S.; Somfai, P. J.
Org. Chem. 2005, 70, 10260. (f) Kokatla, H. P.; Sagar, R.; Vankar, Y. D.
Tetrahedron Lett. 2008, 49, 4728. (g) Mun., J.; Onorato., A.; Nichols., F. C.;
Morton., M. D.; Saleh., A. I.; Welzel., M.; Smith, M. B. Org. Biomol. Chem.
2007, 5, 3826. (h) So, R. C.; Douglas, R. N.; Izmirian, P.; Richardson, S. K.;
Guerrera, R. L.; Howell, A. R. J. Org. Chem. 2004, 69, 3233. (i) Enders, D.;
(5) (a) Aiello, A.; Fattorusso, E.; Giordano, A.; Menna, M.; Navarrete,
~
C.; Munoz, E. Bioorg. Med. Chem. 2007, 15, 2920. (b) Aiello, A.; Fattorusso,
E .; Giordano, A.; Menna, M.; Navarrete, C.; Munoz, E. Tetrahedron 2009,
~
65, 4384.
(6) (a) Kalch, D.; De Rycke, N.; Moreau, X.; Greck, C. Tetrahedron Lett.
2009, 50, 492. (b) Ait-Youcef, R.; Kalch, D.; Moreau, X.; Thomassigny, C.;
Greck, C. Lett. Org. Chem. 2009, 6, 377. (c) For either diastereoselective or
organocatalylic electrophilic R-amination, see: Greck, C.; Drouillat, B.;
Thomassigny, C. Eur. J. Org. Chem. 2004, 1377. Thomassigny, C; Prim, D;
Greck, C. Tetrahedron Lett. 2006, 1117.
€
€
Muller-Huwen, A. Eur. J. Org. Chem. 2004, 1732. (j) Abraham, E.; Davies,
S. G.; Millican, N. L.; Nicholson, R. L.; Roberts, P. M.; Smith, A. D. Org.
Biomol. Chem. 2008, 6, 1655.(k) Tian, Y.-S.; Joo, J.-E.; Pham, V.-T.;Lee, K.-Y.;
Ham, W.-H. Arch. Pharmacal Res. 2007, 30, 167.
(7) Ait-Youcef, R.; Sbargoud, K.; Moreau, X.; Greck, C. Synlett 2009,
18, 3007.
5312 J. Org. Chem. 2010, 75, 5312–5315
Published on Web 06/28/2010
DOI: 10.1021/jo1003899
r
2010 American Chemical Society

Ait-Youcef et al.
JOCNote
SCHEME 2. Syntheses of Sphinganine and the Hydrolysis Product of Clavaminol H Hydrochloride Salts
SCHEME 3. Completion of Clavaminol H Synthesis
Starting from commercially available decanoic and palmitic
acids and employing a procedure described by Masamune,8 we
first synthesized the long-chain β-keto esters 3 and 4 with good
yields of 80%. Asymmetric Ru-catalyzed hydrogenation of
these intermediates was achieved in the presence of 2 mol % of
[(R)-BinapRu]Br2 under mild conditions: under 6 atm of hydro-
gen and at 50 °C. The β-hydroxy esters 59 and 610 were isolated
in high yields of 89% and 90%, respectively, and excellent
enantioselectivities (ee >95%).11 They were converted to their
tert-butyldimethylsilyl ethers under classical conditions, and the
corresponding O-protected β-hydroxy esters 7 and 8 were
obtained in good yields (Scheme 2).
Following our recent report dealing with organocatalytic
R-amination of protected β-hydroxy aldehydes,7 the reduc-
tion of the ester moieties of compounds 7 and 8 was per-
formed at -78 °C using diisobutylaluminium hydride to pro-
duce the corresponding O-protected β-hydroxy aldehydes
which were engaged directly in this transformation. The reac-
tion was conducted in the presence of L-proline (20 mol %) and
dibenzyl azodicarboxylate (1.5 equiv) as a source of electrophilic
nitrogen in CH3CN at room temperature. After completion of
the reaction (2 h), NaBH4 and EtOH were added to reduce the
aldehyde functionality. Monoprotected R-hydrazino 1,3-diols 9
and 10 were isolated in good yields of 75% and 76%, respec-
tively, for the three steps. At this stage, the diastereomeric
excesses could not be determinated precisely by NMR
analysis.12 They have been measured unambiguously on the
O,O-diprotected amino diols 13 and 14.
to cleave the hydrazine bond failed, and the protection of the
primary alcohol of 9 and 10 as the tert-butyldimethylsilyl
ether was necessary. The silylation step was quantitative; the
compounds 11 and 12 were isolated in 96% yield after flash
chromatography. They were then submitted to hydrogeno-
lysis using Raney-Ni in MeOH at room temperature. Under
these conditions, the free amines 13 and 14 were obtained in
77% and 76% yields, respectively, and excellent levels of
diastereoselectivities anti/syn > 95:5.13
Finally, acidic removal of the silyl ether afforded quantita-
tively the hydrolysis product of clavaminol H and sphinganine as
their hydrochloride salts 15 and 1 HCl, respectively. The phy-
3
sical and spectroscopic data of 15 and 1 HCl were in agreement
3
with those described in the literature for the same products.4a
To complete the synthesis of clavaminol H, the amine of
the compound 13 was acetylated to give the compound 16 in
86% yield. In the last step, the silyl ethers were deprotected
using tetrabutylammonium fluoride (1 M in hexanes) to
regenerate the 1,3-diol. After flash chromatography, clava-
minol H (2) was isolated in 90% yield (Scheme 3).
In conclusion, we have developed an efficient method for
the asymmetric synthesis of sphingoid-type bases involving
enantioselective catalytic hydrogenation of β-keto ester in
presence of chiral ruthenium complex and organocatalytic
electrophilic R-amination of aldehyde as key steps. Sphinga-
nine and the hydrolysis product of clavaminol H as their
The regeneration of the amine and alcohol functionalities
would afford the target molecules. Unfortunately, hetero-
geneous hydrogenation to remove the benzyl carbamate and
(8) Brooks, D. W.; Lu, L. D. L.; Masamune., S. Angew. Chem., Int. Ed.
Engl. 1979, 18, 72.
(9) Utaka, M.; Watabu, H.; Higashi, H.; Sakai, T.; Tsuboi, S.; Torii., S. J.
Org. Chem. 1990, 55, 3917.
(10) Ratovelomanana-Vidal, V.; Girard, C; Touati, R.; Tranchier, J. P.;
hydrochloride salts, 1 HCl and 15, were prepared efficiently
3
in eight steps with overall yields of 43% and 44%, respec-
tively, from the corresponding long-chain β-keto esters 3 and
4. We described the first synthetic access to clavaminol H (2)
in nine steps with an overall yield of 34%.
^
Ben Hassine, B.; Genet, J. P. Adv. Synth. Catal. 2003, 345, 261.
(11) The enantiomeric excesses were determined by 1H NMR analysis of
the crude product using (þ)-Eu(tfc)3.
(12) HPLC analysis was also uneffective because the diastereomers of
compounds 9 and 10 were unseparable.
(13) The diastereoisomeric excess was determined by 1H NMR analysis.
J. Org. Chem. Vol. 75, No. 15, 2010 5313

Ait-Youcef et al.
JOCNote
Experimental Section
colorless oil; [R]25D = -5.9 (c 0.5, CHCl3); IR (ATR, cm-1) 2944,
2922, 2855, 2161, 2013, 1974, 1704, 1471, 1255, 1218, 1082, 834; 1H
NMR (300 MHz, CDCl3) δ -0.07-0.10 (m, 12H), 0.84-0.90 (m,
21H), 1.09-1.31 (m, 28H), 3.46-4.01 (m, 3H), 4.12-4.40 (m, 1H),
5.04-5.29 (m, 4H), 6.19-6.52 (s, 1H), 7.20-7.46 (m, 10H);
13C NMR (300 MHz, CDCl3) δ 157.7, 156.9, 156.6, 156.1, 135.9,
135.7, 135.5, 128.6, 128.5, 128.4, 128.4, 128.2, 128.2, 128.0, 127.6,
127.6, 71.0, 70.7, 68.4, 67.9, 67.6, 67.4, 61.2, 61.2, 33.6, 33.4, 31.9,
30.0, 29.6, 29.6, 29.5, 29.3, 22.6, 17.9, 14.1, 14.0, -4.0, -4.1, -4.9,
-5.0, -5.5, -5.6. Anal. Calcd for C46H80N2O6Si2: C, 67.93; H,
9.91; N, 3.44. Found: C, 68.21; H, 10.14; N, 3.61.
General Procedure for Hydrogenation Reaction at Atmo-
spheric Pressure. A solution of the β-keto ester 3 (500 mg,
2.18 mmol) or 4 (500 mg, 1.60 mmol) was diluted in degassed
methanol (4 mL). This solution was canulated into a Schlenk
tube and degassed by three cycles of vacuum/argon. The mixture
was added to the in situ generated catalyst (2 mol % [(R)-
10
BinapRu]Br2 in a glass vessel and placed under argon. The
argon atmosphere was replaced with 6 atm of hydrogen, and the
mixture was heated to 50 °C. The solvent was evaporated under
vacuum, and the β-hydroxy esters were purified on a short pad
of silica using a pentane/Et2O = 8/2 mixture.
General Procedure for the Organocatalytic r-Amination. To a
solution of 7 or 8 (1.72 mmol) in CH2Cl2 (10 mL) was added
DIBAL-H (1.80 mmol, 1 M in hexane) at -78 °C. The mixture
was stirred for 30 min, and then MeOH (1 mL) and HCl (1 N)
(3 mL) were added, and the solution was stirred during 30 min
at rt. The layers were separated, and the aqueous layer was ex-
tracted with CH2Cl2. The combined organic layers were washed
with water and then brine, dried over MgSO4, and concentrated
in vacuo. The crude aldehyde was immediately dissolved in
MeCN (10 mL). To this solution were added dibenzyl azodi-
carboxylate (1.14 mmol) and L-proline (0.22 mmol) at rt. The
reaction mixture was stirred during 2 h at this temperature. The
mixture was thentreated withEtOH (10mL) andNaBH4 (40mg)
and was stirred for 5 min at 0 °C. The reaction was worked up
with aq NH4Cl solution and EtOAc. The organic layers were
dried (MgSO4), filtered, and concentrated. The resulting crude
product 9 or 10 was purified by flash chromatography on silica
(pentane/Et2O = 8/2).
Methyl (R)-3-hydroxydodecanoate (5): yield 445 mg (89%);
white solid; mp 28-29 °C (lit.9 mp 26-28 °C); [R]25D=-21.4
(c 0.9, CHCl3) [lit.9 [R]25D =-21.1 (c 1.5, CHCl3)]; H NMR
1
(CDCl3) δ 0.86 (t, J = 6.9 Hz, 3H), 1.25 (s, 14H), 1.46 (m, 2H),
2.43 (m, 2H), 3.69 (s, 3H), 3.98 (m, 1H); 13C NMR (300 MHz,
CDCl3) δ 173.4, 67.9, 51.6, 41.0, 36.4, 31.8, 29.5, 29.4, 29.4, 29.2,
25.4, 22.6, 14.0.
Methyl (R)-3-hydroxyoctadecanoate (6): yield 450 mg (90%);
white solid; mp 57-58 °C (lit.10 mp 55-56 °C); [R]25D=-15.9
(c 0.9, CHCl3) [lit.10 [R]25D=-15.5 (c 1.0, CHCl3)]; H NMR
1
(CDCl3) δ 0.86 (t, J=6.9 Hz, 3H), 1.25 (s, 28H), 1.47 (m, 2H),
2.46 (m, 2H), 3.71 (s, 3H), 3.99 (m, 1H); 13C NMR (300 MHz,
CDCl3) δ 173.4, 67.9, 51.6, 41.0, 36.5, 31.9, 29.6, 29.6, 29.6, 29.5,
29.5, 29.4, 29.3, 25.4, 22.6, 14.0.
General Procedure for Formation of Silyl Ethers. To a stirred
solution of alcohol (2 mmol) in dry CH2Cl2 (10 mL) cooled to
-78 °C were added 2,6-lutidine (4 mmol) and tert-butyldi-
methylsilyl triflate (3 mmol). After 2 h of stirring at -78 °C,
MeOH (3 mL) was added, and the solution was warmed to room
temperature. The organic layers were evaporated under va-
cuum, and the residue was purified by flash chromatography
on silica (pentane/ether =9/1).
(2S,3R)-2-(N,N0-Bis(benzyloxycarbonyl)hydrazino)-3-(tert-
butyldimethylsilyloxy)dodecanol (9): yield 803 mg (76%); color-
less oil; [R]25D = -12.2 (c 0.4, CHCl3); IR (ATR, cm-1) 3482,
1
3282, 2915, 2848, 1726, 1679, 1526, 1429, 1259, 1055, 836; H
NMR (300 MHz, CDCl3) δ 0.004-0.04 (m, 6H), 0.87 (s, 12H),
1.12-1.44 (m, 16H), 3.50-4.12 (m, 4H), 4.31-4.47 (m, 1H),
5.15-5.31 (m, 4H), 6.54 (s, 1H), 7.24-7.38 (m, 10H); 13C NMR
(300 MHz, CDCl3) δ 158.8, 158.1, 156.8, 155.6, 135.7, 135.4,
134.9, 128.6, 128.5, 128.4, 128.2, 128.1, 127.7, 71.1, 70.5, 68.7,
68.1, 67.8, 63.2, 59.8, 34.4, 34.1, 31.8, 30.3, 29.6, 29.5, 29.3, 25.7,
23.1, 22.6, 17.9, 14.1, -4.1, -4.8. Anal. Calcd for C34H54N2O6-
Si: C, 66.41; H, 8.85; N, 4.56. Found: C, 66.31; H, 8.81; N, 4.47.
(2S,3R)-2-(N,N0-Bis(benzyloxycarbonyl)hydrazino)-3-(tert-
butyldimethylsilyloxy)octadecanol (10): yield 925 mg (77%);
Methyl (R)-3-(tert-butyldimethylsilyloxy)dodecanoate (7): yield
406 mg (89%); colorless oil; [R]25D =-13.2 (c 1.0, CHCl3); IR
(ATR, cm-1) 2953, 2926, 2850, 1734, 1469, 1250, 1069, 834; H
1
NMR (300 MHz, CDCl3) δ0.03 (s, 3H), 0.05 (s, 3H), 0.86 (s, 12H),
1.26 (s, 14H), 1.43-1.52 (m, 2H), 2.42 (d br., J = 6.9 Hz, 2H), 3.66
(s, 3H), 4.12 (m, 1H); 13C NMR (300 MHz, CDCl3) δ 172.3, 69.4,
51.3, 42.5, 37.6, 31.8, 29.6, 29.5, 29.5, 29.2, 25.7, 25.6, 24.9, 22.6,
17.9, 14.0, -2.9, -4.5, -4.8. Anal. Calcd for C19H40O3Si: C, 66.22;
H, 11.70. Found: C, 65.92; H, 11.88.
colorless oil; [R]25 = -5.6 (c 0.3, CHCl3); IR (ATR, cm-1
)
D
Methyl (R)-3-(tert-butyldimethylsilyloxy)octadecanoate (8):
3509, 3278, 2919, 2857, 1723, 1684, 1530, 1418, 1321, 1259, 1066,
835; 1H NMR (300 MHz, CDCl3) δ 0.006-0.05 (m, 6H), 0.87 (s,
12H), 1.02-1.53 (m, 28H), 3.47-4.21 (m, 4H), 4.22-4.56 (m,
yield 556 mg (89%); colorless oil; [R]25D=-16.9 (c 1.0, CHCl3);
IR (ATR, cm-1) 2923, 2846, 1742, 1452, 1252, 1078, 843; H
1
1H), 5.08-5.34 (m, 4H), 6.57 (s, 1H), 7.23-7.46 (m, 10H); 13
C
NMR (300 MHz, CDCl3) δ 0.03 (s, 3H), 0.06 (s, 3H), 0.86 (s,
12H), 1.25 (s, 26H), 1.43-1.50 (m, 2H), 2.44 (d br, J = 6.9 Hz,
2H), 3.66 (s, 3H), 4.12 (m, 1H); 13C NMR (300 MHz, CDCl3) δ
172.3, 69.5, 51.3, 42.5, 37.6, 31.9, 29.7, 29.6, 29.5, 29.3, 25.7, 25.7,
25.6, 24.9, 22.6, 18.0, 17.9, 14.1, -2.9, -4.5, -4.8. Anal. Calcd for
C25H52O3Si: C, 70.03; H, 12.22. Found: C, 70.03; H, 12.41.
(2S,3R)-2-(N,N0-Bis(benzyloxycarbonyl)hydrazino)-1,3-bis-
(tert-butyldimethylsilyloxy)dodecane (11): yield 1179 mg (96%);
NMR (300 MHz, CDCl3) δ 158.7, 158.3, 156.8, 155.5, 135.7,
135.6, 134.9, 134.9, 128.6, 128.5, 128.4, 128.3, 128.1, 127.7,
127.6, 71.2, 70.5, 68.6, 68.5, 68.4, 68.1, 67.8, 63.2, 60.1, 34.3,
34.0, 31.9, 31.8, 29.8, 29.6, 29.6, 29.3, 25.7, 25.6, 23.2, 22.6, 17.8,
14.0, -4.1, -4.8. Anal. Calcd for C40H66N2O6Si: C, 68.73; H,
9.52; N, 4.01. Found: C, 68.71; H, 9.62; N, 3.96.
General Procedure for the Conversion of Hydrazino Diols into
the Corresponding Amino Diols. To a stirred solution of hydra-
zino diols 11 or 12 (0.30 mmol) in anhydrous MeOH (5.0 mL)
were added AcOH (5 drops) and Raney-Ni (ca. 200 mg,
prewashed with anhydrous MeOH). The reaction mixture was
degassed under vacuum and saturated with hydrogen (by an H2-
filled balloon) three times. The suspension was stirred at room
temperature for 20 h under a slightly positive pressure of
hydrogen and then filtered off through a pad of Celite. The
solvent were evaporated under vacuum, and the residue was
purified by flash chromatography on silica (pentane/ether =8/2)
to give 13 or 14 as an oil.
colorless oil; [R]25 = -4.9 (c 0.9, CHCl3); IR (ATR, cm-1
)
2947, 2924, 2858, 2165, 2017, 1978, 1710, 1476, 1254, 1216, 1083,
D
1
830; H NMR (300 MHz, CDCl3) δ -0.01 (s, 12H), 0.84 (s,
21H), 1.02-1.63 (m, 16H), 3.37-4.00 (m, 3H), 4.11-4.39 (m,
1H), 5.16-5.54 (m, 4H), 6.16-6.59 (s, 1H), 7.21-7.48 (m, 10H);
13C NMR (300 MHz, CDCl3) δ 157.6, 156.9, 156.6, 156.1, 135.9,
135.7, 135.5, 128.6, 128.5, 128.3, 128.2, 128.1, 127.9, 127.6, 71.1,
70.7, 68.4, 67.6, 67.6, 67.4, 67.3, 62.0, 61.2, 33.6, 33.4, 31.8, 29.9,
29.5, 29.1, 22.6, 17.8, 14.1, -4.1, -5.1, -5.6, -5.7. Anal. Calcd
for C40H68N2O6Si2: C, 65.89; H, 9.40; N, 3.84. Found: C, 66.09;
H, 9.64; N, 3.99.
(2S,3R)-2-(N,N0-Bis(benzyloxycarbonyl)hydrazino)-1,3-bis-
(tert-butyldimethylsilyloxy)octadecane (12): yield 1341 mg (96%);
(2S,3R)-2-Amino-1,3-(di-tert-butyldimethylsilyloxy)dodecane
(13): yield 102 mg (77%); colorless oil; [R]25 = -0.6 (c 1.0,
D
5314 J. Org. Chem. Vol. 75, No. 15, 2010

Ait-Youcef et al.
JOCNote
CHCl3); IR (ATR, cm-1) 2955, 2924, 2851, 2126, 1758, 1721,
1478, 1246, 1080, 846; H NMR (300 MHz, CDCl3) δ 0.00 (s,
12H), 0.84 (s, 21H), 1.20 (s, 14H), 1.37 (m, 2H), 2.82 (m, 1H,),
3.38 (ABX system, J = 10.0 and 7.7 Hz, 1H), 3.56-3.70 (m, 2H);
13C NMR (300 MHz, CDCl3) δ 73.6, 64.8, 56.5, 32.3, 31.8, 29.8,
29.6, 29.5, 29.2, 25.9, 25.8, 25.0, 22.6, 18.4, 18.0, 14.1, -4.3,
-4.5, -5.3, -5.4. Anal. Calcd for C24H55NO2Si2: C, 64.65; H,
12.43; N, 3.14. Found: C, 65.04; H, 12.25; N, 3.11.
Hz, 1H), 3.73-3.82 (m, 1H), 3.84 (ABX system, J = 11.5 and 4.2
Hz, 1H); 13C NMR (300 MHz, CD3OD) δ 71.3, 59.6, 59.5, 35.2,
34.1, 31.9, 31.8, 31.6, 31.5, 31.5, 31.4, 28.1, 24.8, 15.5; HRMS
(ESI) calcd for C18H40NO2 [M þ H]þ 302.3059, found 302.3058.
N-((2S,3R)-1,3-Bis(tert-butyldimethylsilyloxy)dodecan-2-yl)-
acetamide (16). To a solution of 13 (33 mg, 0.074 mmol) in
pyridine (0.3 mL) was added Ac2O (0.15 mL), and the reaction
mixture was stirred at rt for 18 h. The solvent was removed by
evaporation under vacuum, and the residue was purified by
flash chromatography on silica (pentane/EtOAc = 9/1) to give
16 (31 mg, 86%) as a colorless oil: [R]25D = þ2.2 (c 0.5, CDCl3);
1
(2S,3R)-2-Amino-1,3-bis(tert-butyldimethylsilyloxy)octadecane
(14): yield 120 mg (76%); colorless oil; [R]25D=-5.7 (c 1.0, CH-
Cl3); IR (ATR, cm-1) 2954, 2927, 2853, 2124, 1757, 1719, 1476,
1248, 1082, 844; 1H NMR(300 MHz, CDCl3) δ 0.00 (s, 12H), 0.84
(s, s21H), 1.19 (s, 26H), 1.45 (m, 2H), 2.89 (m, 1H,), 3.45 (ABX
system, J = 10.0 and 7.3 Hz, 1H), 3.56-3.70 (m, 2H); 13C NMR
(300 MHz, CDCl3) δ 73.6, 64.8, 56.4, 32.3, 31.9, 29.9, 29.8,
29.8, 29.6, 29.6, 29.6, 29.7, 29.6, 29.3, 25.8, 25.8, 25.7, 24.9, 22.6,
18.2, 18.0, 14.1, -4.3, -4.5, -5.3, -5.4. Anal. Calcd for C30H67NO2-
Si2: C, 67.98; H, 12.74; N, 2.64. Found: C, 67.88; H, 12.78; N, 2.63.
(1S,2R)-2-Aminododecane-1,3-diol Hydrochloride (15). Un-
der an argon atmosphere, a stirred solution of 13 (15 mg,
0.033 mmol) in absolute MeOH (2 mL) was prepared. HCl
(4 M in solution in 1,4-dioxane, 0.171 mmol) was then added
dropwise. After 2 h of stirring at 65 °C, the solvents were
removed in vacuo to give 15 (8 mg, 99%) as a colorless oil:
[R]25D =-5.8 (c 0.9, MeOH) [lit.4a [R]20D = -6.0 (c 0.1, Me-
OH)]; IR (ATR, cm-1) 3340, 2907, 2842, 1499, 1055; 1H NMR
(300 MHz, CD3OD) δ 0.84 (t, J = 6.9 Hz, 3H), 1.24-1.42 (m,
13H), 1.44-1.59 (m, 3H), 3.19 (dt, J = 8.4 and 4.1 Hz, 1H), 3.70
(ABX system, J = 11.5 and 8.4 Hz, 1H), 3.73-3.82 (m, 1H), 3.84
(ABX system, J = 11.5 and 4.2 Hz, 1H); 13C NMR (300 MHz,
CD3OD) δ 71.1, 59.6, 59.2, 35.0, 33.9, 31.5, 31.4, 31.3, 27.8, 24.5,
15.2; HRMS (ESI) calcd for C12H28NO2 [M þ H]þ 218.2120,
found 218.2117.
1
IR (ATR, cm-1) 2954, 2926, 2855, 1644, 1097, 833; H NMR
(300 MHz, CDCl3) δ 0.00-0.11 (m, 12H), 0.89 (s, 21H),
1.16-1.57 (m, 16H), 1.97 (s, 3H), 3.64 (ABX system, J=10.4
and 5.0 Hz, 1H), 3.75 (ABX system, J = 10.4 and 5.4 Hz, 1H),
3.83 (q, J = 6.6 Hz, 1H), 3.96-4.06 (m, 1H), 5.56 (d, J = 8.4 Hz,
1H); 13C NMR (300 MHz, CDCl3) δ 169.3, 71.7, 60.9, 53.7, 33.7,
31.8, 29.8, 29.5, 29.2, 25.8, 25.8, 25.7, 24.8, 23.5, 22.6, 18.2, 18.0,
14.1, -4.2, -4.6, -5.3, -5.5. Anal. Calcd for C26H57NO3Si2: C,
64.00; H, 11.78; N, 2.87. Found: C, 64.28; H, 11.94; N, 3.02.
Clavaminol H (2). To a solution of 16 (18 mg, 0.036 mmol) in
THF (0.5 mL) at 0 °C was added TBAF (0.05 mL), and the
reaction mixture was stirred at rt for 1 h. The solvent was
removed by evaporation under vacuum, and the residue was
purified by flash chromatography on silica (EtOAc/MeOH =
95/5) to give 2 (9 mg, 90%) as a colorless oil: [R]25D = þ3.0 (c
0.6, CHCl3) [lit.5b [R]25D = þ3.19 (c 0.0013, MeOH)]; IR (ATR,
cm-1) 3274, 2907, 2849, 1715, 1364, 1221; 1H NMR (300 MHz,
CDCl3) δ 0.88 (t, J = 6.9 Hz, 3H), 1.26 (s, 13H), 1.47-1.58 (m,
3H), 2.05 (s, 3H), 2.73 (s br., 2H), 3.70-3.90 (m, 3H), 4.03 (dq,
J = 8.3 and 2.7 Hz, 1H), 6.45 (d, J = 7.0 Hz, 1H); 13C NMR
(300 MHz, CDCl3) δ 170.6, 74.3, 62.4, 53.8, 34.6, 32.0, 29.6,
29.4, 29.3, 26.1, 23.5, 22.8, 22.7, 14.2; HRMS (ESI) calcd for
C14H29NO3Na [M þ Na]þ 282.2045, found 282.2050.
(þ)-(2S,3R)-2-Aminoctadecane-1,3-diol Hydrochloride(1 HCl).
3
The same procedure as for 15 was followed from 14 (25 mg,
0.047 mmol) to give 1 HCl (16 mg, 100%) as a white solid: mp
Acknowledgment. We thank the ANR CP2D program for
its financial support.
3
90-91 °C (lit.4a mp 89-90 °C); [R]25D =þ9.8 (c 0.4, MeOH)
[lit.4a [R]20D =þ10.0 (c 0.06, MeOH)]; IR (ATR, cm-1) 3340,
2911, 2842, 1468, 1055; 1H NMR (300 MHz, CD3OD) δ 0.84 (t,
J=6.9 Hz, 3H), 1.24-1.42 (m, 25H), 1.44-1.59 (m, 3H), 3.19
(dt, J = 8.4 and 4.1 Hz, 1H), 3.70 (ABX system, J = 11.5 and 8.4
Supporting Information Available: General experimental
methods and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 15, 2010 5315