A short synthesis of (-)-deoxoprosophylline

Article abstract of DOI:10.3987/COM-04-S(P)21

Syntheses of (-)-deoxoprosophylline from chiral L-N,N-dibenzylserine (TBDMS) aldehyde is reported. A highly diastereoselective nucleophilic addition of Buechi's Grignard reagent to chiral serinal followed by an intramolecular reductive amination of ω-oxo

Full text of DOI:10.3987/COM-04-S(P)21

HETEROCYCLES, Vol. 64, 2004
249
HETEROCYCLES, Vol. 64, 2004, pp. 249 - 259
Received, 20th July, 2004, Accepted, 18th October, 2004, Published online, 19th October, 2004
A SHORT SYNTHESIS OF (-)-DEOXOPROSOPHYLLINE
Angélique Jourdant and Jieping Zhu*
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette
Cedex, France
Abstract – Syntheses of (-)-deoxoprosophylline from chiral L-N,N-dibenzylserine
(TBDMS) aldehyde is reported. A highly diastereoselective nucleophilic addition
of Büchi’s Grignard reagent to chiral serinal followed by an intramolecular
reductive amination of ω-oxo amino diol are two key steps of the present
synthesis.
This paper is dedicated to Professor Pierre Potier on the occasion of his 70th
birthday
INTRODUCTION
2,6-Dialkylated piperidine alkaloids have been found abundantly in nature and are key structural units in
many medicinally important compounds.1 Prosopis alkaloids, isolated from Prosopis africana, forms a
subgroup possessing a characteristic 3- hydroxy function.2 Structurally, these compounds, possessing a
polar head group and a hydrophobic aliphatic tail, can be considered as cyclic analogues of membrane
lipid sphingosine (5).3 Indeed, interesting bioactivities including analgesic, anaesthetic and antibiotic have
been reported for prosophylline, prosopinine and their deoxygenated derivatives (1-4, Figure 1). Many
elegant syntheses of piperidine alkaloids have been developed,4 including asymmetric syntheses of
optically pure prosopis alkaloids.5 Our approach to deoxoprosophylline (1) from
L-(N,N-dibenzylamino)serine (TBDMS) aldehyde (L-6),6,7,8 was depicted retrosynthetically in Scheme 1.
Key steps are a highly diastereoselective nucleophilic addition of Büchi’s Grignard reagent (7) to chiral
serinal L-6 leading to amino diol (8) and an intramolecular reductive amination of ω-oxo amino diol (9).
We detail herein successful implementation of this strategy leading to a short synthesis of 1.9 The
observation that diastereoselectivity in the reduction of iminium intermediate (10) is irrelevant of the
N-protective group (P) is documented.

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HETEROCYCLES, Vol. 64, 2004
X
X
H
H
H2N
N
N
OH
OH
OH
OH
OH
OH
8
8
12
1 X = H, H, (-)-deoxoprosophylline
2 X = O, (-)-prosophylline
3 X = H, H, (-)-deoxoprosopinine
4 X = O, (-)-prosopinine
5 sphingosine
Figure 1
Bn2N
H
P2P1N
OTBDMS
OH
OH
OH
N
OH
O
10
OH
10
O
O
1
9
8
P
N
OTBDMS
+
MgBr
O
O
OH
O
H
10
+
Bn2N
L-6
OH
7
10
Scheme 1. Retrosynthesis of deoxoprosophylline
RESULTS AND DISCUSSION
Synthesis of (-)-deoxoprosophylline was accomplished as depicted in Scheme 2. Addition of Büchi's
Grignard reagent,10 prepared in situ from the corresponding bromide (11), to the aldehyde (L-6) gave the
amino diol (8) in excellent yield and diastereoselectivity (anti/syn = 15/1). The major stereomer was
assumed to be anti according to Felkin-Anh model11 and this is corroborated by the synthesis of final
compound. Protection of the secondary hydroxy group as benzyl ether followed by acidic hydrolysis of
dioxolane and reprotection of the primary hydroxyl group gave the aldehyde (13). Reaction of aldehyde
(13) with an excess of dodecylmagnesium bromide afforded alcohol (14) as a mixture of two
diastereomers. This lack of diastereoselectivity was nevertheless of no consequence since the chiral centre
in question was anyway thought to be introduced at the end of the synthesis via reduction of a cyclic
iminium.
Swern oxidation of alcohol (14) afforded ketone (15) in 84% yield. Catalytic hydrogenation of 15 under
acidic conditions (3N HCl, MeOH, Pd/C, H ) furnished directly the (-)-deoxoprosophylline (1). However,
2
this process is found to be non-reproducible and an alternative two-step process was developed. Thus,
under catalytic transfer hydrogenolysis conditions developed by Bajwa and co-workers [Pd(OH)2,
cyclohexene, EtOH, HOAc reflux],12 a chemoselective N-debenzylation followed by a reductive
amination occurred to provide O-benzyldeoxoprosophylline (16) which, without purification, was
O-debenzylated (Pd(OH)2, EtOH, cyclohexene, reflux)13 to afford (-)-deoxoprosophylline (1) in 73%
yield. The deoxoprosopinine was not detectable from the 1H NMR spectrum of the crude reaction mixture

HETEROCYCLES, Vol. 64, 2004
251
indicating the high diastereoselectivity in the reduction step. The physical and spectroscopic data of our
synthetic material are identical with those described in the literature.5d Thus from the serine aldehyde
(L-6), we were able to synthesize the (-)-deoxoprosophylline (1) in 7 steps with a 32% overall yield.
Bn2N
Bn2N
OTBDMS
OBn
OTBDMS
Br
O
a
b
c
O
O
OH
O
O
O
11
Bn2N
8
12
Bn2N
Bn2N
OTBDMS
OTBDMS
OTBDMS
d
e
C12H25
C12H25
H
OBn
OBn
OBn
O
O
OH
13
14
15
H
N
f
g
1
OH
OBn
8
16
Scheme 2. Reagents and conditions: a) Mg, THF, rt, then L-6, 86%; b) NaH, BnBr, Bu4NI, THF, 0°C, then rt, 85%; c) (i) 3N
HCl-THF, (ii) TBDMSCl, imidazole, DMF, 90%; d) C12H25Br, Mg, dibromoethane, THF, then 13, 70°C, 80%; e) DMSO,
(COCl)2, then Et3N, 84%; f) Pd(OH)2, cyclohexene, EtOH, AcOH, reflux, 90%; g) Pd(OH)2, cyclohexene, EtOH, reflux, 81%.
The diastereoselectivity observed in the addition of nucleophiles to substituted iminium is determined by
both the conformational preference of the 6-membered iminium intermediate and the reactivity of each
conformer as mandated by Curtin-Hammett principle.14 To probe the influence of the N-protective group
on the selectivity of the reductive amination process, the N-acylated derivative (20) was prepared from 15
according to Scheme 3. Protection of the carbonyl function of ketone (15) provided the dioxolane (17)
which was selectively N-debenzylated under controlled conditions to afford primary amine (18).
N-Benzyloxycarbonylation followed by hydrolysis of the acetal furnished the cyclization precursor (20).
Reductive cyclization of 20 was carried out under a variety of conditions varying the reductant, the acid,
and the solvent. Under optimal conditions found [NaBH3CN (2 equiv.), TFA (2 equiv.), CH2Cl2,
molecular sieve, rt], the desired piperidine (21) was obtained in 58% yield. Simultaneous removal of
N-CBZ and O-benzyl groups under transfer hydrogenolysis conditions provided the
(-)-deoxoprosophylline (1) in 80% yield. Once again, only the 2,6-cis derivative (1), hence 21, was
obtained from 20 by intramolecular reductive amination process.

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HETEROCYCLES, Vol. 64, 2004
H2N
O
Bn2N
OH
b
OBn
O
OH
OBn
a
C12H25
O
C12H25
O
15
17
18
CbzHN
CbzHN
c
OH
OBn
OH
OBn
d
C12H25
C12H25
O
O
O
19
20
Cbz
N
e
f
C12H25
1
OH
OBn
21
Scheme 3. Reagents and conditions: a) ethylene glycol, TMSCl, rt, 12h, 95%; b) Pd(OH)2, cyclohexene, EtOH, 85°C, 4h,
78%; c) CbzOSu, NaHCO3, dioxane-H2O, 94%; d) 3N HCl, THF, rt, 5h, 85%; e) TFA (2 equiv.), CH Cl , 4Å molecular sieve,
2
2
then NaBH CN (2 equiv.), rt, 24 h, 58%; f) Pd(OH)2, cyclohexene, EtOH, reflux, 4 h, 80%.
3
The cyclic imminium intermediate (10, Scheme 1) can exist in either of the two conformations shown in
Scheme 4. In the case of reductive amination of 15, we speculated that the bis N-debenzylation preceded
the reduction of iminium. Under this circumstance, conformer B would be predominant over conformer A
since the allylic strain A1,2 was minimized when P = H and the developing 1,3-diaxial interaction was
avoided.15 Axial attack of nucleophile from the bottom face of the iminium B gave the observed
lower-energy chair product (16) (P = H).
H-
HO
BnO
C12H25
HO
N
N
P
C12H25
P
OBn
A
B
H-
P = H and Cbz
HO
BnO
HO
N
C12H25
P
N
P
C12H25
OBn
Scheme 4. Conformational biases in the formation of 2,6-cis-piperidine (16).
The formation of 2,6-cis-piperidine (21) from amino ketone (20) (P = Cbz) on the other hand was
intriguing. Both allylic strain and electrostatic stabilization between OBn group and the iminium cation16
should favor the conformer A in case P = Cbz (Scheme 4). This consideration would predict that the

HETEROCYCLES, Vol. 64, 2004
253
2,6-trans isomer would be produced predominantly resulting from the hydride attack from the top face of
the iminium if the reaction involved earlier transition states. This was, however, not the case and we
hypothesized that the reduction of iminium intermediate under the present reaction conditions may
involve a product-like transition state.17 Hydride attack along the axial trajectory from the bottom face of
the less stable iminium B (R = Cbz) is favored leading to the all-equatorial substituted piperidine (21).
In summary, we have developed a short synthesis of (-)-deoxoprosophylline from chiral
L-N,N-dibenzylserine (TBDMS) aldehyde. A highly diastereoselective nucleophilic addition of Büchi’s
Grignard reagent to chiral serinal followed by an intramolecular reductive amination of ω-oxo amino diol
are two key steps of the present synthesis.
ACKNOWLEDGEMENT
A doctoral fellowship from the “Ministère de l’Enseignement Supérieur et de la Recherche” to A.
Jourdant is gratefully acknowledged.
EXPERIMENTAL
(2S,3R)-1-(tert-Butyldimethylsilanyloxy)-2-dibenzylamino-5-[1,3]dioxolan-2-yl-pentan-3-ol (8). To
the suspension of Mg (221.6 mg, 9.12 mmol) in THF (5 mL) was added 2-(2-bromoethyl)-1,3-dioxolane
(1.07 mL, 9,12 mmol) dropwise at 0°C. After being stirred at rt for 1 h, the serinal (L-6) (1.17 g, 3.03
mmol) was introduced at 0°C. The resulting reaction mixture was stirred at rt for 1 h and quenched with
saturated aqueous NH Cl. The aqueous phase was extracted with ethyl acetate and the combined organic
4
extracts were washed with brine, dried over Na SO and concentrated. The crude mixture was purified by
2
4
flash chromatograph (SiO2, eluent: heptane/AcOEt = 8/1) to provide 8 as colorless oil (1.03 g, 86%). [α]
D
-1
+ 35° (c 1.0, CHCl ,); IR (CHCl ) ν 3660, 3066, 2931, 2890, 2859, 1494, 1454, 1259, 1099, 1071 cm ;
3
3
1
H NMR (CDCl , 300 MHz) δ 0.09 (s, 3H), 0.10 (s, 3H), 0.81 (s, 9H), 1.34 (m, 1H), 1.60 (m, 2H), 1.85
3
(m, 1H), 2.55 (td, J = 5.4, 7.2, 1H), 3.08 (s, 1H, OH), 3.52 (d, J = 13.7, 2H), 3.70-3.90 (m, 7H), 3.73 (d, J
13
= 13,7, 2H), 4.75 (t, J = 4.6, 1H), 7.18 (m, 10H); C NMR (CDCl , 62,5 MHz) δ -5.3, 18.1, 25.9, 29.0,
3
+
29.9, 55.4, 61.3, 61.7, 64.8, 64.9, 71.7, 104.8, 126.9, 128.3, 128.9, 140.1; MS (IC) m/z 486 (M+H) ; Anal.
Calcd for C H NO Si: C, 69.24; H, 8.92; N, 2.88; Found: C, 69.15; H; 8.99; N, 2.92.
28 43
4
(2S,3R)-1-(tert-Butyldimethylsilanyloxy)-2-dibenzylamino-3-benzyloxy-5-[1,3]dioxolan-2-ylpentane
(12). To a suspension of NaH (175.6 mg, 75% w/w, 5.48 mmol) in THF (1.6 mL) was added at 0°C a
solution of alcohol (8, 2,42 g, 4.99 mmol) in THF (5 mL). The reaction mixture was stirred at the same

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HETEROCYCLES, Vol. 64, 2004
temperature for 30 min. Bu NI (368.6 mg; 0.99 mmol) and BnBr (772.0 µL, 6.49 mmol) were added.
4
After being stirred at rt for 12 h, the reaction was quenched with saturated aqueous NH Cl. The aqueous
4
phase was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried
over Na SO and concentrated. The crude mixture was purified by flash chromatograph (SiO2, eluent:
2
4
heptane/AcOEt = 15/1) to provide 12 (2.50 g, 85%) as colorless oil: [α] + 2° (c 1.0, CHCl ); IR
D
3
-1 1
(CHCl ) ν 2955, 2858, 1454, 1389, 1361, 939, 838 cm ; H NMR (CDCl , 300 MHz) δ 0.09 (s, 3H),
3
3
0.10 (s, 3H), 0.98 (s, 9H), 1.50 (m, 2H), 1.88 (m, 1H), 2.01 (m, 1H), 2.76 (m, 1H), 3.75 (d, J = 13.4, 2H),
3.85 (m, 5H), 3.94 (d, J = 13.4, 2H), 4.12 (dd, J = 3.0, 10.6, 1H), 4.45 (d, J = 11.1, 1H), 4.55 (d, J = 11.1,
13
1H), 4.85 (t, J = 7.0 1H), 7.31 (m, 15H); C NMR (CDCl , 75 MHz) δ -4.8, 19.8, 25.0, 26.7, 28.8, 56.2,
3
60.2, 60.7, 65.5, 65.5, 72.6, 78.0, 105.5, 127.4, 128.0, 128.3, 128.8, 128.9, 129.7, 141.1; MS (IE) m/z 575
+.
(M) ; Anal. Calcd for C H NO Si: C, 73.00; H, 8.58; N, 2.43; Found: C, 72.68; H, 8,26; N, 2.45.
35 49
4
(4R,5S)-6-(tert-Butyldimethylsilanyloxy)-4-benzyloxy-5-dibenzylaminohexanal (13). A solution of
acetal (12, 2.15 g, 3.73 mmol) in a mixture of solvent HCl (3N, 10 mL)) / THF (10 mL) was stirred at rt
for 4 h. The reaction mixture was neutralized by addition of aqueous NaOH (1N) and was extracted with
EtOAc. The combined organic extracts were washed with brine, dried over Na SO and concentrated to
2
4
give the analytical pure aldehyde which was re-silylated under classic conditions (TBDMSCl, imidazole,
DMF, 0.3M, rt) to provide 13 as colorless oil (1.78 g, 90%): [α] + 8° (c 1.3, CHCl ); IR (CHCl ) ν 3016,
D
3
3
-1 1
2830, 2726, 1952, 1883, 1813, 1720, 1454, 1214, 526 cm ; H NMR (CDCl , 250 MHz) δ 0.09 (s, 3H),
3
0.10 (s, 3H), 0.85 (s, 9H), 1.54 (m, 1H), 1.92 (m, 3H), 2.60 (ddd, J = 2.8, 6.5, 8.2, 1H), 3.56 (d, J = 13.4,
2H), 3.64 (m, 1H), 3.75 (d, J = 13.4, 2H), 3.82 (dd, J = 6.5, 11.1, 1H), 4.04 (dd, J = 2.8, 11.1, 1H), 4.29 (d,
13
J = 11.4, 1H), 4.31 (d, J = 11.4, 1H), 7.28 (m, 15H), 9.46 (s, 1H); C NMR (CDCl , 62.5 MHz) δ -5.5,
3
18.1, 21.8, 26.0, 37.7, 55.4, 58.9, 59.6, 71.9, 76.1, 126.7, 126.9, 127.1, 127.6, 128.2, 129.2, 140.2, 202.8;
+
MS ( IE ) m/z 531 (M) .
(2S,3R)-1-(tert-Butyldimethylsilanyloxy)-3-benzyloxy-2-dibenzylaminooctadecane-1,6-diol (14). To
the suspension of Mg (696.6 mg, 28.9 mmol) in THF (6 mL) were added bromoundecane (8.04 mL, 28.9
mmol) and dibromethane (159.0 µL, 1.61 mmol) dropwise. After being stirred at 70°C for 1 h, a solution
of aldehyde (13, 1.71 g, 3.22 mmol) in THF (12 mL) was introduced at rt. The resulting reaction mixture
was stirred at rt for 3 h and quenched with saturated aqueous NH Cl. The aqueous phase was extracted
4
with ethyl acetate and the combined organic extracts were washed with brine, dried over Na SO and
2
4
concentrated. The crude mixture was purified by flash chromatograph (SiO2, eluent: heptane/ Et2O = 9/ 1)
to provide 14 as a mixture of two diastereomers in a ratio of 7/3 (1.82 g, 80%): IR (CHCl ) ν 3630, 2928,
3
-1 1
2855, 1718, 1684, 1653, 1360, 1253, 1089 cm ; H NMR (CDCl , 250 MHz) δ 0.09 (s, 3H), 0.10 (s, 3H),
3
0.75 (t, J = 7.1, 3H), 0.79 (s, 9H), 1.15 (m, 20H), 1.50-1.80 (m, 6H), 2.72 (m, 1H), 3.21 (m, 1H), 3.61 (d,

HETEROCYCLES, Vol. 64, 2004
255
J = 13.6, 2H), 3.75 (d, J = 13.6, 2H), 3.76 (m, 2H), 3.98 (dd, J = 2.3, 10.6, 1H), 4.26 (d, J = 11.1, 1H),
13
4.28, 4.35 (d, J = 11.1), 7.32 (m, 15H); C NMR (CDCl , 62.5 MHz) δ -5.4, 14.1, 18.1, 22.7, 25.7, 26.0,
3
29.4, 29.7, 31.9, 37.3, 37.5, 55.4, 59.5, 59.7, 71.8, 72.1, 77.7, 126.8, 127.5, 127.8, 128.2, 129.2, 138.2,
+
+
140.4; MS ( ES ) m/z 702 (M+H) .
(2S,3R)-1-(tert-Butyldimethylsilanyloxy)-3-benzyloxy-2-dibenzylamino-6-oxooctadecan-6-one (15).
To a solution of oxalyl chloride (277.9 µL, 3.20 mmol) in CH Cl , cooled at –78°C, was added DMSO
2
2
(2.94 mL, 2.4 M in CH Cl , 7.06 mmol). After 5 min, a solution of alcohol (14, 1.5 g, 2.14 mmol) in
2
2
CH Cl (3 mL) was introduced. The reaction mixture was stirred at –78°C for 30 min followed by
2
2
addition of triethylmine (2.02 mL, 14.5 mmol). The reaction temperature was raised gradually to rt and
stirring was continued for 45 min. The reaction mixture was diluted with saturated aqueous NaHCO and
3
extracted with CH Cl . The combined organic extracts were washed with brine, dried over Na SO and
2
2
2
4
concentrated. The crude mixture was purified by flash chromatograph (SiO2, eluent: heptane/AcOEt =
11/1) to provide 15 as colorless oil (1.26 g, 84%): [α] + 6° (c 1.25, CHCl ); IR (CHCl ) ν 2929, 2856,
D
3
3
-1 1
1707, 1373, 1361, 1256, 724 cm ; H NMR (CDCl , 250 MHz) δ 0.09 (s, 3H), 0.10 (s, 3H), 0.72 (t, J =
3
7.2, 3H), 0.85 (s, 9H), 1.12 (m, 20H), 1.52 (m, 2H), 1.89 (m, 4H), 2.55 (ddd, J = 2.3, 6.0, 8.1, 1H), 3.55
(d, J = 13.4, 2H), 3.62 (m, 1H), 3.75 (d, J = 13.4, 2H), 3.83 (dd, J = 6.0, 11.1, 1H), 4.02 (dd, J = 2.3, 11.1,
13
1H), 4.25 (d, J = 11.6, 1H), 4.43 (d, J = 11.6, 1H), 7.32 (m, 15H); C NMR (CDCl , 62.5 MHz) δ -5.4,
3
14.1, 18.1, 22.6, 22.8, 23.7, 26.0, 29.3, 29.4, 29.6, 31.9, 35.8, 42.8, 55.3, 58.9, 59.6, 71.7, 77.4, 126.8,
+
+
127.4, 127.7, 128.2, 129.2, 138.5, 140.3, 211.4; MS ( ES ) m/z 700 (M+H) ; Anal. Calcd for
C H NO Si: C, 77.20; H, 9.93; N, 2.00; Found: C, 76.91; H, 10.05; N, 1.91.
45 69
3
(2S, 3R, 6S)-(3-Benzyloxy-6-dodecylpiperidin-2-yl)methanol (16). A suspension of amino ketone (15,
483.0 mg, 0.69 mmol) and Pd(OH) (10% on charcon, 102.2 mg) in ethanol (5.3 mL), cyclohexene (2.9
2
mL) and acetic acid (1.6 mL) were stirred at 85°C for 12 h. The reaction mixture was diluted with
saturated aqueous NaHCO and filtered through a short pad of celite. The filtrate was extracted with
3
EtOAc. The combined organic extracts were washed with brine, dried over Na SO and concentrated.
2
4
The crude mixture was purified by flash chromatograph (SiO2, eluent: CH Cl /MeOH = 15/1) to provide
2
2
piperidine (16) as colorless oil (242.0 mg, 90%): [α] -20° (c 0.56, CHCl ); IR (CHCl ) ν 2928, 2855,
D
3
3
-1 1
1661, 1456, 1074 cm ; H NMR (CDCl , 250 MHz) δ 0.75 (t, J = 7.2, 3H), 1.15 (m, 22H), 1.45 (m, 2H),
3
1.55 (m, 2H), 2.02 (m, 1H), 2.45 (dt, J = 5.2, 9.0, 1H), 3.45 (ddd, J = 4.6, 9.1, 10.9, 1H), 3.56 (dd, J = 5.2,
13
10.7, 1H), 3.82 (dd, J = 4.1, 10.7, 1H), 4.45 (d, J = 11.8, 1H), 4.60 (d, J = 11.8, 1H), 7.32 (m, 5H);
C
NMR (CDCl , 62.5 MHz) δ 14.1, 22.6, 24.0, 26.1, 29.2, 29.3, 29.6, 29.8, 31.0, 31.9, 36.6, 40.2, 55.9, 62.0,
3
+.
64.2, 70.6, 73.3, 127.7, 128.4, 138.4; MS (IE) m/z 389 (M) ; HRMS: calcd for C H NO 390.3372
25 43
2:

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HETEROCYCLES, Vol. 64, 2004
(M+H), found: 390.3364.
(-)-Deoxoprosophylline (1). A suspension of piperidine (16, 50.1 mg, 0.12 mmol) and Pd(OH) (10%,
2
10.0 mg) in ethanol (1.1 mL), cyclohexene (0.5 mL) was stirred at 85°C for 12 h. The reaction mixture
was filtered through a short pad of celite and washed thoroughly with ethyl acetate. The filtrate was
concentrated and the crude mixture was purified by flash chromatograph (SiO2, eluent: CH Cl /MeOH =
2
2
15/1) to provide (-)-deoxoprosophylline (1) as a white solid (31.2 mg, 81%): mp 85°C; [α] -13° (c 0.3,
D
CHCl ) {lit., 5d [α]
-14° (c 0.24, CHCl3)}; IR (CHCl ): ν 3414, 3024, 2927, 2854, 1466, 1221, 1060
3
23
3
D
-1 1
cm ; H NMR (CDCl , 250 MHz) δ 0.88 (t, J = 6.7, 3H), 1.00-1.41 (m, 22H), 1.65-1.80 (m, 2H),
3
1.96-2.04 (m, 2H), 2.41-2.65 (m, 5H), 3.46 (ddd, J = 4.3, 9.7, 10.0), 3.70 (dd, J = 5.5. 10.7, 1H), 3.84 (dd,
13
J = 4.7, 10.7, 1H); C NMR (CDCl , 62.5 MHz) δ 14.1, 22.7, 26.2, 29.4, 29.7, 29.8, 31.1, 31.9, 33.9,
3
+
36.6, 56.1, 63.3, 64.6, 70.6; MS (IE) m/z 299 (M) ; HRMS calcd for C H NO 300.2902 (M+H),
18 37
2:
found: 300.2909.
(2S, 3R)-3-Benzyloxy-2-dibenzylamino[1,3]dioxolan-6-yl-octadecan-1-ol (17). To a solution of amino
ketone (15, 887.5 mg, 1.27 mmol) in ethylene glycol (6.0 mL) was added TMSCl (0.65 mL, 5.1 mmol).
After being stirred at rt for 12 h, the reaction mixture was diluted with saturated aqueous NaHCO and
3
was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over
Na SO and concentrated. The crude mixture was purified by flash chromatograph (SiO2, eluent:
2
4
heptane/ether = 9/1) to provide dioxolane (17, 755.0 mg, 95%) as colorless oil: [α] -43° (c 0.7, CHCl );
D
3
-1 1
IR (CHCl ) ν 3512, 2930, 2858, 1495, 1454, 1364, 1073, 909, 749, 723 cm ; H NMR (CDCl , 250
3
3
MHz) δ 0.78 (t, J = 7.3, 3H), 1.21 (m, 20H), 1.48 (m, 2H), 1.65 (m, 2H), 2.68 (q, J = 5.9, 1H), 3.49 (d, J
= 13.2, 2H), 3.75 (d, J = 13.2, 2H), 3.80 (m, 7H), 4.35 (d, J = 11.0, 1H), 4.55 (d, J = 11.0, 1H), 6.55 (m,
13
15H); C NMR (CDCl , 75 MHz) δ 14.1, 22.6, 23.9, 24.6, 29.3, 29.6, 29.9, 31.4, 31.9, 37.4, 54.3, 58.8,
3
+
60.7, 64.9, 71.0, 78.3, 111.6, 127.1, 127.7, 128.3, 128.4, 128.9, 138.0, 139.5; MS (IC) m/z 630 (M+H) ;
Anal. Calcd for C H NO : C, 78.18; H, 9.44; N, 2.22; Found: C, 77.94; H, 9.65; N, 2.14.
41 59
4
(2S,3R)-2-Amino-3-benzyloxy[1,3]dioxolan-6-yl-octadecan-1-ol (18). A suspension of dioxolane (17,
1.05 g, 1.67 mmol) and Pd(OH) (10%, 181.2 mg) in ethanol (13.0 mL), cyclohexene (6.7 mL) was
2
stirred at 85°C for 4 h. The reaction mixture was filtered through a short pad of celite and washed
thoroughly with ethyl acetate. The filtrate was concentrated and the crude mixture was purified by flash
chromatograph (SiO2, eluent: toluene/CH Cl /EtOH = 4/5/1) to provide amino alcohol (18) as a white
2
2
solid (580.0 mg, 78%): mp 50°C; [α] -15° (c 1, CHCl ); IR (CHCl ) ν 3467, 3020, 2957, 2854, 1601,
D
3
3
-1 1
1455, 1207, 1072, 948 cm ; H NMR (CDCl , 250 MHz) δ 0.92 (t, J = 7.2, 3H), 1.23 (m, 20H), 1.62 (m,
3
6H), 3.00 (m, 1H), 3.10 (m, 3H), 3.46 (q, J = 4.8, 1H), 3.52 (dd, J = 6.6, 10.9, 1H), 3.62 (dd, J = 3.5, 10.5,

HETEROCYCLES, Vol. 64, 2004
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13
1H), 3.95 (s, 4H), 4.46 (d, J = 11.4, 1H), 4.52 (d, J = 11.4, 1H), 7.35 (m, 5H); C NMR (CDCl , 75
3
MHz) δ 14.0, 22.7, 23.9, 24.0, 29.3, 29.6, 32.9, 37.3, 54.2, 63.2, 64.9, 72.0, 81.3, 111.6, 127.8, 128.4,
+
+
138.2; MS (ES ) m/z 450 (M+H) ; Anal. Calcd for C H NO : C, 72.12; H, 10.54; N, 3.11; Found: C,
27 47
4
71.97; H, 10.64; N, 3.11.
N-Benzyloxycarbamate (19). A solution of amino alcohol (18, 516.7 mg, 1.15 mmol) and CbzOSu (2.07
mmol) in a mixture of solvent (saturated aqueous NaHCO /1,4 dioxane = 1/ 1, 5 mL each) was stirred at
3
rt for 14 h. The reaction mixture was diluted with saturated aqueous NH4Cl and was extracted with ethyl
acetate. The combined organic extracts were washed with brine, dried over Na SO and concentrated.
2
4
The crude mixture was purified by flash chromatograph (SiO2, eluent: heptane/AcOEt = 4/1) to provide
carbamate (19) as white solid (630.9 mg, 94%): mp 42°C; [α] -17° (c 0.4, CHCl ); IR (CHCl ) ν 3642,
D
3
3
-1 1
3436, 2928, 2855, 1717, 1505, 1261, 1069, 948 cm ; H NMR (CDCl , 250 MHz) δ 0.85 (t, J = 7.2, 3H),
3
1.25 (m, 20H), 1.52 (m, 4H), 1.70 (m, 2H), 2.75 (s, 1H), 3.53 (m, 3H), 3.80 (s, 4H), 3.95 (dd, J = 3.5,
10.9, 1H), 4.45 (d, J = 10.9, 1H), 4.55 (d, J = 10.9, 1H), 5.02 (s, 2H), 5.50 (d, J = 7.7, 1H), 7.27 (m, 10H);
13
C NMR (CDCl , 75 MHz) δ 13.9, 22.5, 23.6, 24.8, 25.2, 27.0, 29.1, 29.5, 29.7, 31.7, 32.2, 53.8, 61.6,
3
+
64.7, 66.5, 72.3, 80.4, 111.3, 127.6, 127.9, 128.3, 128.6, 129.0, 136.3, 137.8, 156.8; MS ( ES ) m/z 606
+
(M+Na) ; Anal. Calcd for C H NO : C, 72.01; H, 9.14; N, 2.40; Found: C, 71.98; H, 9.05; N, 2.24.
35 53
6
Ketone (20). A solution of compound (19, 597.2 mg, 1.02 mmol) in a mixture of solvent: HCl (3N)/THF
= 1/1 (5 mL) was stirred at rt for 24 h. The reaction mixture was basified with saturated aqueous NaHCO3
and was extracted with EtOAc. The combined organic extracts were washed with brine, dried over
Na SO and concentrated. The crude mixture was purified by flash chromatograph (SiO2, eluent:
2
4
heptane/AcOEt = 9/1) to provide ketone (20) as white solid (469.3 mg, 85%): mp 58°C; [α] -13° (c 1.0,
D
-1 1
CHCl ); IR (CHCl ) ν 3637, 3436, 2928, 2855, 1713, 1507, 1455, 1064, 729 cm ; H NMR (CDCl ,
3
3
3
250 MHz) δ 0.82 (t, J = 7.4, 3H), 1.22 (m, 18H), 1.45 (m, 2H), 1.81 (q, J = 7.1, 2H), 2.26 (t, J = 7.3, 2H),
2.41 (q, J = 6.7, 2H), 2.62 (br s, 1H, OH), 3.60 (m, 3H), 3.82 (dd, J = 2.7, 10.9, 1H), 4.41 (d, J = 11.6,
13
1H), 4.50 (d, J = 11.6, 1H), 5.00 (s, 2H), 5.41 (d, J = 7.9, 1H), 7.30 (m, 10H); C NMR (CDCl , 75
3
MHz) δ 14.2, 22.8, 23.9, 24.1, 29.6, 29.3, 29.4, 29.5, 29.7, 32.0, 37.9, 43.1, 53.7, 62.1, 66.9, 72.4, 79.6,
+
+
128.1, 128.2, 128.3, 128.5, 128.7, 128.9, 136.5, 137.8, 156.5, 210.8; MS ( ES ) m/z 540 (M+H) , 562
+
(M+Na) ; Anal. Calcd for C H NO : C, 73.43; H, 9.15; N, 2.59; Found: C, 73.12; H, 9.05, N, 2.67.
33 49
5
Piperidine (21). To a solution of ketone (20, 20.0 mg, 0,037 mmol) in CH Cl (1 mL) were added TFA
2
2
(6.0 µL, 0,074 mmol), 4 Å molecular sieve and NaBH CN (4.66 mg, 0.074 mmol). After being stirred at
3
rt for 1 h, the reaction mixture was diluted with saturated aqueous NaHCO3 and was extracted with ethyl
acetate. The combined organic extracts were washed with brine, dried over Na SO and concentrated.
2
4

258
HETEROCYCLES, Vol. 64, 2004
The crude mixture was purified by flash chromatograph (SiO2, eluent: heptane/AcOEt = 4/1) to provide
piperidine (21) as colorless oil (11.2 mg, 58%): [α] -33° (c 0,7, CHCl ); IR (CHCl ) ν 2927, 2854,
D
3
3
-1 1
1745, 1264, 1220, 778 cm ; H NMR (CDCl , 250 MHz) δ 0.82 (t, J = 7.3, 3H), 1.22 (m, 22H), 1.75 (m,
3
4H), 2.11 (m, 1H), 2.48 (br s, 1H, OH), 2.82 (td, J = 2.4, 9.4, 1H), 3.12 (td, J = 4.3, 10.5, 1H), 4.02 (dd, J
= 7.6, 10.5, 1H), 4.32 (d, J = 11.4, 1H), 4.49 (dd, J = 2.4, 10.5, 1H), 4.52 (d, J = 11.4, 1H), 5.11 (s, 2H),
13
7.30 (m, 10H); C NMR (CDCl , 75 MHz) δ 14.1, 22.7, 26.2, 29.0, 29.4, 29.6, 29.8, 30.9, 31.9, 36.6,
3
+
55.9, 59.9, 69.7, 70.6, 75.7, 127.7, 127.8, 128.4, 128.6, 135.2, 138.3, 155.0; MS (IE) m/z 523 (M) ; Anal.
Calcd for C H NO : C, 75.68; H, 9.43; N, 2.67; Found: C, 75.42; H, 9.31; N, 2.77.
33 49
4
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