Concise asymmetric synthesis of (-)-deoxoprosophylline

Article abstract of DOI:10.1016/j.tetasy.2008.12.014

An efficient asymmetric synthesis of the 2-hydroxymethyl 3,6-disubstituted piperidine alkaloid, (-)-deoxoprosophylline, is described. The key step of this route is the SmI₂-mediated cross-coupling of chiral N-tert-butanesulfinyl imine 9 with al

Full text of DOI:10.1016/j.tetasy.2008.12.014

Tetrahedron: Asymmetry 19 (2008) 2731–2734
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Concise asymmetric synthesis of (ꢀ)-deoxoprosophylline
a,b,
Ru-Cheng Liu a, Jin-Hu Wei b, Bang-Guo Wei a, , Guo-Qiang Lin
*
*
a Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, PR China
b Institutes of Biomedical Sciences, Fudan University, 138 Yixueyuan Road, Shanghai 200032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient asymmetric synthesis of the 2-hydroxymethyl 3,6-disubstituted piperidine alkaloid, (ꢀ)-deo-
xoprosophylline, is described. The key step of this route is the SmI2-mediated cross-coupling of chiral
N-tert-butanesulfinyl imine 9 with aldehyde 11 to construct hydroxymethyl-b-amino alcohol 12b in
83% yield and high diastereoselectivity (>99%, de).
Received 13 November 2008
Accepted 10 December 2008
Available online 10 January 2009
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
thesized by the reaction of N-tert-butanesulfinyl imine 9 with alde-
hyde 11.
Alkaloids containing multifunctionalized piperidine rings exist
abundantly in Nature.1 Several 2,3,6-trisubstituted piperidines
such as prosophyllines 2 and 6, and prosopinines 4 and 8 have been
isolated from the leaves of the West African savanna tree Prosopis
Africana Taub2 and the leaves of Microcos philippinenis (Perk) Bur-
rentt (Tiliaceae).3 These trisubstituted piperidine alkaloids and
their deoxygenated analogues, especially 2-hydroxymethyl-6-
alkylated 3-hydroxypiperidines and their deoxygenated deriva-
tives (Fig. 1), have shown anesthetic, analgesic, antibiotic, and
CNS stimulating biological properties, and are of considerable
pharmacological interest.4 Structurally, these compounds possess
a polar head group and a hydrophobic aliphatic tail, and can be
considered as cyclic analogues of the lipid sphingosine membrane.5
These interesting structural features and therapeutic potential
make them attractive synthetic targets. For example, various syn-
thetic strategies for deoxoprosophylline 1 have been reported.6–8
Although it could be conveniently synthesized based on chiral
building blocks from natural amino acids6 and carbohydrates,7
there is still a need to develop a general strategy for the asymmet-
ric preparation with desired stereochemistry.8
In recent years, chiral N-tert-butanesulfinamide, as pioneered
by Ellman and Davis, is undoubtedly one of the most efficient aux-
iliaries developed.9 It enables the preparation of various enantio-
pure amines, which are ubiquitous in natural products and
biologically active substances. Our laboratory has documented
the use of N-tert-butanesulfinyl imines for the synthesis of unsym-
metrical vicinal b-amino alcohols,10a and applied this method to
synthesize several natural products.10 As a result of our ongoing ef-
forts on developing a method to prepare hydroxymethyl b-amino
alcohols, we herein report a novel route to (ꢀ)-deoxoprosophylline
1 based on hydroxymethyl b-amino alcohol 12b, which was syn-
2. Results and discussion
As illustrated in Scheme 1, we envisioned that the stereochem-
istry of C-2 and C-3 could be constructed by a cross-coupling of
aldehydes 10 and 11 with chiral N-tert-butanesulfinyl imine 9 to
form protected hydroxymethyl-b-amino alcohols 12. To make this
synthesis more convergent, we selected methyl 4-oxobutanoate 10
as a starting material.
The SmI2-induced cross-coupling of 10 with (S)-N-tert-butane-
sulfinyl imine 9, which was easily prepared from chiral N-tert-
butanesulfinamide,11 gave hydroxymethyl b-amino alcohol 12a
with high diastereoselectivity (>99%, de) in 89% yield. After re-
moval of the chiral auxiliary, the resulting amino alcohol was eas-
ily cyclized in one pot under TEA conditions to produce 13 in 80%
HO
HO
HO
HO
N
8
N
H
X
H
8
X
(-)-deoxoprosopinine 3 X=H2
(-)-prosopinine 4 X=O
(-)-deoxoprosophylline 1 X = H2
(-)-prosophylline 2 X=O
HO
HO
HO
N
HO
N
8
H
8
H
X
X
(+)-deoxoprosophylline 5 X=H2
(+)-prosophylline 6 X=O
(+)-deoxoprosopinine 7 X=H2
(+)-prosopinine 8 X=O
* Corresponding authors. Tel./fax: +86 21 54237757 (B.-G.W.).
E-mail address: bgwei1974@fudan.edu.cn (B.-G. Wei).
Figure 1. Structures of some prosopis alkaloids and synthetic analogues.
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.12.014

2732
R.-C. Liu et al. / Tetrahedron: Asymmetry 19 (2008) 2731–2734
O
OH
H
a
b
S
BnO
BnO
OH
OH
O
HN
C12H25
O
17
11
18
R
O
S
C12H25
N
H
OH OBn
O
O
HN
c
O
1
(-)-deoxoprosophylline
O
12a R=OMe; 12b R=C12H25
C12H25
C12H25
OH OBn
12b
S
O
R1
N
+
d
BnO
(-)-deoxoprosophylline 1
10 R1 = COOMe
11 R1 = COC12H25
9
Scheme 3. Reagents and conditions: (a) C12H25MgBr, THF, 88%; (b) (i) Pd/C, H2,
MeOH, rt, 12 h; (ii) PCC, CH2Cl2, 5 h, two steps 81%; (c) 9, SmI2, t-BuOH, THF, 83%;
(d) (i) HCl/MeOH, MeOH; (ii) Pd(OH)2/C, H2, EtOH, 4 h, then concd HCl, 33 h, two
steps 58%.
Scheme 1. Retrosynthetic analysis of (ꢀ)-deoxoprosophylline 1.
yield. Protection of alcohol 13 (TBSCl, imidazole) and amide 14
(Boc2O, n-BuLi) gave 15 in 66% overall yield. The next step for syn-
thesis of (ꢀ)-deoxoprosophylline 1 was to introduce a dodecyl side
chain in a cis-diastereoselective manner with an organometallic
ring-opening method developed by Savoia,12 which was used by
Huang et al.13 in the total synthesis of 2-epi-deoxoprosopinine.
N-Deprotection of 16 with TFA, followed by treatment with satu-
rated aqueous NaHCO3 solution led to the cyclic imine, which,
without further purification, was hydrogenated under acidic condi-
tions [20% Pd(OH)2, H2, EtOH and 10% concd HCl, 36 h] and alkal-
ized with an aqueous solution of 1 M sodium hydroxide to afford
(ꢀ)-deoxoprosophylline 1 as a white solid (Scheme 2).
diumhydroxidetogive(ꢀ)-deoxoprosophylline1asawhitesolid(mp
87–88 °C (lit.6h 89.5–90 °C); ½a 2D5
ꢁ
¼ ꢀ15:1 (c 0.12, CHCl3) {lit.6d
½
a 2D5
ꢁ
¼ ꢀ14:7 (c 0.55, CHCl3)}). The spectroscopic and physical data
of the synthetic (ꢀ)-deoxoprosophylline 1 were identical with those
described in the literature.6 Thus, a concise method for the synthesis
of (ꢀ)-deoxoprosophylline was established with an overall yield of
34% from starting material 17 (Scheme 3).
3. Conclusion
In conclusion, hydroxymethyl b-amino alcohol 12b was pre-
pared by SmI2-induced cross-coupling of N-tert-butanesulfinyl
imine 9 with 4-oxohexadecanal 11, in 83% yield and high diastere-
oselectivity (>99%, de). This is a convenient approach for preparing
(ꢀ)-deoxoprosophylline 1. Moreover, the key step might be gener-
ally applicable in the synthesis of various 2-hydroxymethyl-6-
alkylated 3-hydroxy piperidine alkaloids and their deoxygenated
derivatives with structural and biological importance.
Although (ꢀ)-deoxoprosophylline 1 was synthesized, the method
forinducing thechainwas a known one, andthe overallyieldwas low.
As a result, we turned our attention to study the cross-coupling of 4-
oxohexadecanal 11 with chiral N-tert-butanesulfinyl imine 9. 4-Ben-
zyloxyl butanal 17, which was easily prepared from
c-butyrolac-
tone,14 was treated with dodecylmagnesium bromide to afford the
secondary alcohol 18 in 88% yield. Hydrogenation (Pd/C, H2) of 18
was followed by oxidation (PCC, CH2Cl2) to give the aldehyde 11 in
81% overall yield. The SmI2-induced cross-coupling of 11 with 9 affor-
ded hydroxymethylb-amino alcohol 12b with high diastereoselectiv-
ity (>99%, de) in 83% yield. Removal of the chiral auxiliary of 12b with
HCl/MeOH, followed by treatment with saturated aqueous NaHCO3
solution led to the cyclic imine, which, without further purification,
was hydrogenated under acidic conditions [20% Pd(OH)2, H2 , EtOH
and concd HCl, 33 h] and basified with an aqueous solution of 1 M so-
4. Experimental
4.1. General methods
Melting points were recorded on a Mel-Temp apparatus and
uncorrected. Optical rotations were measured on a P-1020 polar-
imeter manufactured by JASCO Corporation. IR spectra were re-
O
OR
OH
S
a
d
b
O
O
NH
O
O
N
H
O
OBn
O
BnO
12a
13 R=H
10
c
14 R=TBS
O
NHBoc
OH
OH
OTBS
OBn
OBn
e
f
C12H25
C12H25
N
H
O
N
OTBS
Boc
1
15
16
Scheme 2. Reagents and conditions: (a) 9, SmI2, t-BuOH, THF, 89%; (b) (i) HCl/MeOH, MeOH; (ii) TEA, MeOH, two steps 80%; (c) TBSCl, imidazole, DMAP, DMF, 90%; (d) n-BuLi,
Boc2O, THF, 73%; (e) C12H25MgBr, THF, 66%; (f) (i) TFA; (ii) Pd(OH)2/C, H2, EtOH–HCl, two steps 47%.

R.-C. Liu et al. / Tetrahedron: Asymmetry 19 (2008) 2731–2734
2733
corded using KBr disks or film, on a Fourier Transform Infrared
Spectrometer, Type: Avatar 360 E.S.P, manufactured by Thermo
Nicolet Corporation, USA. NMR spectra were recorded on Bruker
av 400 spectrometer in CDCl3 and chemical shifts were expressed
in parts per million relative to internal Me4Si. Silica gel (300–400
mesh) was used for chromatography, eluting (unless otherwise
stated) with an ethyl acetate/petroleum ether mixture. Dichloro-
methane, DMF, and diisopropylamine were distilled over calcium
hydride under N2. Ether and THF were distilled over sodium benzo-
phenone ketyl under N2.
2953, 2928, 2856, 1671, 1471, 1098 cmꢀ1; 1HNMR(400 MHz, CDCl3)
d: 7.35–7.26(m, 5H), 6.13 (brs, 1H), 4.52(d, J = 11.84 Hz, 1H), 4.48 (d,
J = 11.84 Hz, 1H), 3.73 (ddd, J = 3.72, 6.66, 9.78 Hz, 1H), 3.59 (dd,
J = 3.91, 9.00 Hz, 1H), 3.55–3.43 (m, 1H), 3.31 (dd, J = 8.21, 9.00 Hz,
1H), 2.43 (ddd, J = 5.27, 6.07, 17.80 Hz, 1H), 2.29 (ddd, J = 6.26,
9.39, 17.80 Hz, 1H), 1.91–1.75 (m, 2H), 0.84 (s, 9H), 0.05 (s, 3H),
0.02 (s, 3H); 13C NMR (100 MHz, CDCl3) d: 171.2, 137.4, 128.5 (2C),
127.9 (2C), 127.7, 73.4, 71.3, 66.5, 58.7, 28.4, 28.3, 25.6 (3C), 17.9,
ꢀ4.4, ꢀ5.0; MS (ESI): 372.2 (M+Na+); HRESIMS calcd for (C19H31NO3-
Si+Na+): 372.1972, found: 372.1971.
4.1.1. (4R,5S)-Methyl-6-(benzyloxy)-4-hydroxy-5-(2-methyl-
propane-2-ylsulfinamido)hexanoate 12a
4.1.4. (2S,3R)-tert-Butyl 2-(benzyloxymethyl)-3-(tert-butyl-
dimethylsilyloxy)-6-oxopiperidine-1-carboxylate 15
To a mixture of 2-benzoxyl ethyl (S)-N-tert-butanesulfinyl imine
9 (1.52 g, 6 mmol), methyl 4-oxobutanoate 10 (2.79 g, 24 mmol),
and t-BuOH (4.5 mL, 48 mmol) in THF (250 mL) was added a solution
of freshly prepared SmI2 (48 mmol) in THF (250 mL) at ꢀ78 °C under
an argon atmosphere. After being stirred vigorously for 4 h at the
same temperature, the reaction mixture was quenched with satu-
rated Na2S2O3 aqueous solution (40 mL). The organic layer was sep-
arated, and aqueous layer was extracted with ethyl acetate
(200 mL ꢂ 3). The combined organic layers were washed with brine,
dried over anhydrous Na2SO4, filtered, and concentrated under re-
duced pressure. The residue was purified by chromatography on sil-
ica gel (EtOAc/PE) to give 12a (1.95 g, yield 89%) as a colorless oil.
To a solution of 14 (800 mg, 2.29 mmol) and Boc2O (750 mg,
3.44 mmol) in anhydrous THF (25 mL) was slowly dropped a solution
of 1.6 M n-BuLi (1.36 mL) in hexane at ꢀ78 °C under an argon atmo-
sphere. After being stirred for 40 min at the same temperature, the
mixture was quenched with saturated NH4Cl aqueous solution
(5 mL) and extracted with ethyl acetate (30 mL ꢂ 3). The combined
organic layers were washed with brine (15 mL ꢂ 3), dried over anhy-
drous Na2SO4, filtered, and concentrated. The residue was purified by
chromatography on silica gel (EtOAc/PE) to give 15 (714 mg, yield
73%) as a colorless oil. ½a D25
ꢁ
¼ ꢀ25:2 (c 0.97, CHCl3); IR (film)
m:
2954, 2929, 1722, 1717, 1367, 1296, 1253, 1154 cmꢀ1
;
1H NMR
(400 MHz, CDCl3) d: 7.36–7.26 (m, 5H), 4.53 (d, J = 12.13 Hz, 1H),
4.48 (d, J = 12.13 Hz, 1H), 4.31–4.29 (m, 1H), 4.23–4.21 (m, 1H), 3.55
(dd, J = 3.92, 9.98 Hz, 1H), 3.45 (dd, J = 8.02, 9.98 Hz, 1H), 2.71 (ddd,
J = 7.24, 10.95, 17.90 Hz, 1H), 2.37 (ddd, J = 2.94, 6.65, 17.90 Hz, 1H),
2.07–1.98 (m, 1H), 1.77–1.72 (m, 1H), 1.48 (s, 9H), 0.89 (s, 9H), 0.08
(s, 3H), 0.06 (s, 3H); 13C NMR (100 MHz, CDCl3) d: 171.5, 152.7,
137.7, 128.4 (2C), 127.8 (2C), 127.6, 82.8, 73.3, 69.9, 65.4, 61.7, 29.9,
27.9 (3C), 25.7 (3C), 25.6, 17.9, ꢀ4.8, ꢀ5.0; MS (ESI): 472.2 (M+Na+);
HRESIMS calcd for (C24H39NO5Si+Na+): 472.2497, found: 472.2490.
½
a 2D5
ꢁ
¼ ꢀ25:5 (c 1.33, CHCl3); IR (film)
m: 3386, 2953, 2919, 1736,
1454, 1364, 1047 cmꢀ1 1H NMR (400 MHz, CDCl3) d: 7.36–7.26
;
(m, 5H), 4.58 (d, J = 11.74 Hz, 1H), 4.53 (d, J = 11.74 Hz, 1H), 3.97–
3.90 (m, 2H), 3.78–3.72 (m, 1H), 3.65 (s, 3H), 3.33–3.26 (m, 1H),
2.86 (m, 1H), 2.53–2.42 (m, 2H), 1.96–1.88 (m, 2H), 1.84–1.78 (m,
1H), 1.24 (s, 9H); 13C NMR (100 MHz, CDCl3) d: 174.4, 137.5, 128.5
(2C), 127.9 (3C), 73.6, 72.4, 70.3, 59.7, 56.1, 51.7, 30.5, 28.8, 22.6
(3C); MS (ESI): 394.2 (M+Na+); HRESIMS calcd for (C18H29NO5S +
Na+): 394.1666, found: 394.1659.
4.1.5. tert-Butyl (2S,3R)-1-(benzyloxy)-3-(tert-butyldimethyl-
silyloxy)-6-oxooctadec-2-ylcarbamate 16
4.1.2. (5R,6S)-6-(Benzyloxymethyl)-5-hydroxypiperidin-2-one
13
To a solution of 15 (600 mg, 1.34 mmol) in anhydrous THF
(60 mL) was slowly dropped a solution of 0.3 M n-C12H25MgBr
in THF (5.8 mL, 1.74 mmol) at ꢀ78 °C under an argon atmo-
sphere. After being stirred for 3 h at this temperature, the mix-
ture was slowly warmed to ꢀ40 °C and stirred for another
40 min. Then, the reaction mixture was quenched with saturated
NH4Cl aqueous solution (2 mL) and diluted with EtOAc (10 mL).
The organic layer was separated and the aqueous phase ex-
tracted with EtOAc (10 mL ꢂ 3). The combined organic layers
were dried over anhydrous Na2SO4, filtered, and concentrated.
The residue was purified by chromatography on silica gel
(EtOAc/PE) to give 16 (322 mg) in 66 % yield based on recovered
To a solution of 12a (1.80 g, 4.85 mmol) in MeOH (25 mL) was
added a solution of HCl/MeOH (2 M, 13 mL) at room temperature.
After stirring for 4 h, the mixture was concentrated under reduced
pressure to afford crude intermediate product without further
purification, which was dissolved in MeOH (30 mL). Next, TEA
(0.68 mL) was added at room temperature. After stirring for 36 h,
the mixture was concentrated under reduced pressure. The residue
was purified by chromatography on silica gel (EtOAc/PE) to give 13
(915 mg, yield 80% two steps) as a colorless oil. ½a D25
ꢁ
¼ ꢀ18:5 (c
0.14, CHCl3); IR (film) m ;
: 3385, 2920, 1649, 1078 cmꢀ1 1H NMR
(400 MHz, CDCl3) d: 7.35–7.26 (m, 5H), 6.39 (br s, 1H), 3.73–3.65
(m, 2H), 3.50–3.44 (m, 1H), 3.40–3.36 (m, 1H), 2.45 (ddd, J = 4.88,
5.68, 17.42 Hz, 1H), 2.28 (ddd, J = 6.26, 9.39, 17.42 Hz, 1H), 1.97–
1.93 (m, 2H), 1.86–1.78 (m, 1H); 13C NMR (100 MHz, CDCl3) d:
171.8, 137.3, 128.5 (2C), 128.0 (2C), 127.7, 73.5, 71.9, 70.7, 63.6,
56.2, 28.4; MS (ESI): 258.1 (M+Na+). HRESIMS calcd for
(C13H17NO3+Na+): 258.1106, found: 258.1095.
starting material 15 (245 mg). ½a D25
ꢁ
¼ ꢀ11:0 (c 1.64, CHCl3); IR
(film)
m
: 3450, 2926, 2855, 1715, 1498, 1365 cmꢀ1 1H NMR
;
(400 MHz, CDCl3) d: 7.36–7.26 (m, 5H), 4.82 (d, J = 8.80 Hz,
1H), 4.51 (d, J = 11.74 Hz, 1H), 4.45 (d, J = 11.74 Hz, 1H), 3.90–
3.85 (m, 1H), 3.78–3.67 (m, 2H), 3.51 (dd, J = 3.72, 9.00 Hz,
1H), 2.64–2.60 (m, 1H), 2.52–2.50 (m, 1H), 2.49–2.35 (m, 2H),
1.82–1.71 (m, 2H), 1.57–1.54 (m, 2H), 1.42 (s, 9H), 1.34–1.25
(m, 19H), 0.88 (s, 9H), 0.89–0.86 (m, 3H), 0.08 (s, 3H), 0.04 (s,
3H); 13C NMR (100 MHz, CDCl3) d: 211.5, 155.5, 138.0, 128.4
(2C), 127.7 (3C), 79.3, 73.1, 70.5, 68.7, 52.8, 43.0, 37.1, 31.9,
29.6, 29.6, 29.5, 29.4(3C), 29.2, 28.3(3C), 26.8, 25.8 (3C), 24.0,
22.7, 18.0, 14.1, ꢀ4.4, ꢀ5.0; MS (ESI): 620.3 (M+H+); HRESIMS
calcd for (C36H65NO5Si+H+): 620.4710, found: 620.4718.
4.1.3. (5R,6S)-6-(Benzyloxymethyl)-5-(tert-butyldimethyl-
silyloxy)piperidin-2-one 14
To a mixture of 13 (823 mg, 3.5 mmol) and imidazole (1.70 g,
25.0 mmol) in DMF (30 mL) was added a solution of tert-butyldim-
ethylchlorosilane (2.108 g, 14 mmol) in DMF (10 mL). After being
stirred for 15 h, the reaction mixture was quenched with water
(50 mL) and extracted with ethyl acetate (60 mL ꢂ 3). The combined
organic layerswere washed with brine (30 mL ꢂ 3), driedover anhy-
drous Na2SO4, filtered, and concentrated. The residue was purified
by chromatography on silica gel (EtOAc/PE) to give 14 (1.10 g, yield
4.1.6. 1-(Benzyloxy) hexadecan-4-ol 18
To a solution of 4-(benzyloxy)butanal 17 (4.26 g, 24 mmol) in dry
THF(30 mL)wasslowlydroppedasolutionoffreshlyprepareddode-
90%) as a colorless oil. ½a D25
ꢁ
¼ ꢀ39:7 (c 0.6, CHCl3); IR (film)
m: 3211,

2734
R.-C. Liu et al. / Tetrahedron: Asymmetry 19 (2008) 2731–2734
cylmagnesium bromide in THF (1.3 M, 30 mL) at 0 °C under an argon
atmosphere. After being stirred for 2 h, the reaction mixture was
quenched with a solution of 1M HCl and extracted with ethyl acetate
(50 mL ꢂ 3). The combined organic layers were washed with brine
(20 mL ꢂ 3), dried over anhydrous Na2SO4, filtered, and concen-
trated. The residue was purified by chromatography on silica gel
(EtOAc/PE) to afford 18 (7.35 g, yield 88%) as a colorless oil. IR (film)
tracted thoroughly with CHCl3 (40 mL ꢂ 5). The combined organic
layers were dried over anhydrous Na2SO4, filtered, and concen-
trated. The residue was purified by chromatography on silica gel
(CHCl3/MeOH/NH3ꢃH2O = 100:10:2, V/V/V) to afford a light yellow
solid (ꢀ)-deoxoprosophylline 1 (125 mg, 58%), which was recrys-
tallized from acetone to give a white solid 1. Mp 87–88 °C (lit.6h
89.5–90 °C); ½a 2D5
ꢁ
¼ ꢀ15:9 (c 0.62, CHCl3) {lit.6d
½
a 2D5
ꢁ
¼ ꢀ14:7 (c
m
: 3405, 2924, 2852, 1454, 1362, 1099 cmꢀ1
;
1H NMR (400 MHz,
0.55, CHCl3)}; IR (film) m ;
: 3343, 3266, 2921, 2851, 1466 cmꢀ1 1H
CDCl3) d: 7.37–7.26 (m, 5H), 4.52 (s, 2H), 3.66 (br s, 1H), 3.60–3.49
(m, 2H), 1.76–1.60 (m, 4H), 1.56–1.42 (m, 2H), 1.26–1.21 (m, 20H),
0.88 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) d: 138.1, 128.4
(2C), 127.7 (3C), 73.0, 71.6, 70.5, 37.5, 34.7, 31.9 (2C), 29.7 (4C),
29.6, 29.3, 26.2, 25.7, 22.7, 14.1; MS (ESI): 371.2 (M+Na+); HRESIMS
calcd for (C23H40O2 + Na+) : 371.2926, found: 371.2927.
NMR (400 MHz, CDCl3) d: 3.86 (dd, J = 4.89, 11.06 Hz, 1H), 3.71
(dd, J = 5.28, 10.76 Hz, 1H), 3.47 (ddd, J = 4.89, 10.36, 13.29 Hz,
1H), 2. 60–2.52 (m, 2H), 2.07–2.03 (ddd, J = 3.91, 7.82, 11.53 Hz,
1H), 1.76–1.36 (m, 3H, 2H exchangeable with D2O), 1.31–1.25
(m, 24H), 0.88 (t, J = 6.65 Hz, 3H); 13C NMR (100 MHz, CDCl3) d:
70.9, 64.9, 63.1, 55.9, 36.6, 33.9, 31.9, 31.1, 29.8, 29.7, 29.6 (4C),
29.3, 26.2, 22.7, 14.1 ppm; MS (ESI): 300.2 (M+H+), HRESIMS calcd
for (C18H37NO2+H+): 300.2903, found: 300.2927.
4.1.7. (R)-N-((2S,3R)-1-(Benzyloxy)-3-hydroxy-6-oxooctadec-2-
yl)-2-methylpropane-2-sulfinamide 12b
To a suspension of 10% Pd/C (500 mg) in methanol (60 mL) was
added a solution of 18 (3.636 g, 10.45 mmol) in methanol (20 mL)
under a H2 atmosphere. After being stirred for 12 h, the mixture
was filtered and concentrated to give crude hexadecane-1,4-diol,
which was dissolved in CH2Cl2 (40 mL) at room temperature, then
PCC (5.72 g, 26.12 mmol) was added. After stirring for 5 h, the mix-
ture was filtered and concentrated to afford crude 11 (2.15 g, yield
81%, two steps) without further purification. To a mixture of 2-benz-
oxyl ethyl (S)-N-tert-butanesulfinyl imine 9 (536 mg, 2.13 mmol), 4-
oxohexadecanal 11 (2.15 g, 8.47 mmol), and t-BuOH (2.0 mL,
21 mmol) in THF (105 mL) was dropped a solution of freshly pre-
pared SmI2 (21 mmol) in THF (42 mL) at ꢀ78 °C under an argon
atmosphere. After being stirred vigorously for 4 h at the same tem-
perature, the reaction mixture was quenched with saturated
Na2S2O3 aqueous solution (20 mL). The organic layer was separated,
and aqueous layer was extracted with ethyl acetate (100 mL ꢂ 3).
The combined organic layers were washed with brine, dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pres-
sure. The residue was purified by chromatography on silica gel
(EtOAc/PE) to give 12b (895 mg, yield 83%) as a colorless oil.
Acknowledgments
The authors are grateful to the National Natural Science Foun-
dation of China (20702007, 20832005) and Fudan University for
financial support.
References
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½
a 2D5
ꢁ
¼ ꢀ13:0 (c 0.64, CHCl3); IR (film)
m: 3441, 2924, 2853, 1635,
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4.61–4.63 (m, 2H), 3.95–3.91 (m, 2H), 3.79–3.64 (m, 2H), 3.33–
3.30 (m, 1H), 2.89 (d, J = 6.62 Hz, 1H), 2.63–2.57 (m, 2H), 2.41 (t,
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4.1.8. (ꢀ)-Deoxoprosophylline 1
To a solution of 12b (368 mg, 0.72 mmol) in MeOH (15 mL) was
added a saturated HCl/MeOH solution (5 mL) at room temperature.
After being stirred for 4 h, the reaction mixture was concentrated
and dissolved in CH2Cl2 (100 mL). The resulting solution was
washed with saturated NaHCO3 aqueous solution and brine, dried,
and concentrated to give a yellow oil, which, without further puri-
fication, was stirred in EtOH (20 mL) at room temperature under an
argon atmosphere. Next 20% Pd(OH)2/C (60 mg) was added in one
portion, then the argon atmosphere was exchanged with a H2
atmosphere three times. After stirring for 4 h under a H2 atmo-
sphere, a solution of concd HCl (2.5 mL) was added dropwise and
the mixture was stirred for another 33 h. The reaction mixture
was filtered and concentrated. The residue was dissolved in water
(20 mL) and extracted with ether (20 mL). Then, the aqueous layer
was basified by the addition of 1 M NaOH aqueous solution and ex-
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4215.