New concise asymmetric total synthesis of (+)-desoxoprosophylline and prosophylline

Article abstract of DOI:10.1016/S0957-4166(99)00239-6

Asymmetric total syntheses of (+)-desoxoprosophylline 1 and prosophylline 2 from 1-(α-furyl)-2-phenylmethoxy-N-tosylethylamine 3 were accomplished in 10 steps with an overall yield of 4% and in nine steps with an overall yield of 11%, respectively. The oxidation of 3 to dihydropyridone was used as the key step.

Full text of DOI:10.1016/S0957-4166(99)00239-6

Pergamon
Tetrahedron: Asymmetry 10 (1999) 2311–2318
New concise asymmetric total synthesis of
(+)-desoxoprosophylline and prosophylline
Cuifen Yang,b Lixin Liao,a Yiming Xu,a Hongxing Zhang,b Peng Xia b and Weishan Zhou a,∗
aShanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
bDepartment of Organic Chemistry, Pharmacy School, Shanghai Medical University, Shanghai 200032, China
Received 26 April 1999; accepted 7 June 1999
Abstract
Asymmetric total syntheses of (+)-desoxoprosophylline 1 and prosophylline 2 from 1-(α-furyl)-2-
phenylmethoxy-N-tosylethylamine 3 were accomplished in 10 steps with an overall yield of 4% and in
nine steps with an overall yield of 11%, respectively. The oxidation of 3 to dihydropyridone was used as the key
step. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
(+)-Desoxoprosophylline 1, prosophylline 2 and their related compounds are naturally occurring
alkaloids isolated from the African mimosa Prosopis africana Taub.1 These polysubstituted piperidine
alkaloids exhibit a variety of pharmacological properties such as anesthetic, analgesic and antibiotic
activities.2 Compounds 1 and 2 are particularly intriguing because of their dual physiologically important
structural features. The polar head group consists of a piperidine ring similar to the alkaloid deoxyno-
jirimycin, an inhibitor of glucosidase from a variety of sources3 and potentially valuable therapeutic
agent for diabetes mellitus, hyperlipoproteinemia, cancer and arthritis.4 The lipophilic tail portion, which
resembles sphingosine of the membrane sphingolipid, serves to facilitate transfer across membranes. So
these alkaloids have become important synthetic targets.5
During the past several years we have been interested in the preparation of chiral α-furfuryl amine
derivatives and the application of these chiral building blocks to the total synthesis of natural products.
∗
Corresponding author. Tel: 86-21-64163300; fax: 86-21-64166128; e-mail: zhws@pub.sioc.ac.cn
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00239-6

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We have developed two methods to prepare these chiral α-furfuryl amine derivatives, one is the
kinetic resolution of racemic α-furfuryl amine derivatives using the modified Sharpless asymmetric
epoxidation reagent,6 the other is the diastereoselective addition of organometallic reagents to α-
furfuryl imine derivatives.7 Several natural products and their analogs, such as α-amino acids,8 δ-
hydroxy-α-aminolactones,9 (+)-azimic acid,10 dihydropinidine,11 polyhydroxylated indolizidines12,13
and 1-deoxyazasugars14 have been successfully synthesized from the chiral α-furfuryl amine derivatives
we have prepared. Very recently, we developed a more convenient method to prepare this chiral α-
furfuryl amine derivative 3 from α-furyl ethylene in five steps using Sharpless dihydroxylation as the
key step (Scheme 1).15 This new method could provide a large quantity of 3, which is a very useful
building block for the stereocontrolled synthesis of the polysubstituted piperidines present in a wide
variety of natural products. Here we report a full account of the experimental details of the synthesis of
(+)-desoxoprosophylline 116 and of prosophylline 2 starting from this building block.
Scheme 1.
2. Results and discussion
Scheme 2 delineates the synthetic sequence required for the preparation of 1. Treatment of 3 with
m-CPBA afforded the dihydropyridone 4,17 in which the hydroxyl group was protected with triethyl
orthoformate in the presence of BF3·Et2O to give 5. Reduction of 5 with sodium borohydride in methanol
gave the α-hydroxyl product 6, in which the configuration of C3 had been proved in our previous report.11
After protection of 6 with a benzyl group, we initially attempted to introduce the side chain at C6 directly
by reaction of 7 with a Grignard reagent (C12H25MgBr), but this reaction gave low stereoselectivity
and yield. However treatment of 7 with allyltrimethylsilane in the presence of 0.5 equiv. of titanium
tetrachloride at −75°C gave 8 exclusively, this reaction produced 9 as major product when 1.0 equiv. of
titanium tetrachloride was present. The stereochemistry of the allyl group was assigned by analogy with
the results obtained in allylation of structurally related compounds.11,18 Hydroboration and oxidation
of 8 with a borane–dimethyl sulfide complex, followed by tosylation of the hydroxyl group with tosyl
imidazole produced 11, which was coupled with a Grignard reagent (C9H19MgBr) to afford 12. Removal
of the benzyl group of 12 with Pd–C, H2 resulted in 13, the configuration of which was confirmed by
2D-NOESY analysis since there was no NOE correlation between H2 and H3. Finally, deprotection of the
amino group produced (+)-desoxoprosophylline 1. Thus the first total synthesis of (+)-1 was achieved.
In connection with the synthesis of (+)-desoxoprosophylline 1 using this new chiral building block,
1-(α-furyl)-2-phenylmethoxy-N-tosylethylamine (3),15 we continued to use this building block for
synthesis of a related alkaloid prosophylline 2 as depicted in Scheme 3.
The side chain was introduced by the following procedures: ozonolysis of 8 in CH2Cl2:MeOH (9:1)
followed by immediate reduction with sodium borohydride in methanol gave the alcohol 14. Protection
of the hydroxyl group of 14 with tosyl imidazole gave the tosylate 15, which was used to couple with
Grignard reagent formed from protected propionylheptyl bromide 175b and magnesium to afford 16.
Initially, chain extension of the aldehyde through the Wittig method with the ylide formed from 17
afforded very low yield. An attempt to remove simultaneously both the benzyl and tosyl groups of 16

C. Yang et al. / Tetrahedron: Asymmetry 10 (1999) 2311–2318
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Scheme 2. (a) m-CPBA, CH2Cl2, rt, 82%; (b) HC(OEt)3, BF3·OEt2, 4 Å molecular sieves, THF, 0°C, 97%; (c) NaBH4, MeOH,
0°C, 88%; (d) BnBr, NaH, THF, rt, 85%; (e) allyltrimethylsilane, TiCl4, CH2Cl2, −78°C, 67%; (f) (i) BH3·SMe2, THF; (ii)
NaOH, H2O2, 45%; (g) Ts–Im, NaH, THF, 0°C, 87%; (h) C9H19MgBr, Li2CuCl4, THF, 0°C, 68%; (i) 10% Pd–C, H2, EtOH,
84%; (j) liq. NH3/Na, −78°C, 46%
Scheme 3. (a) (i) O3, CH2Cl2:MeOH (9:1), −78°C; (ii) NaBH4, MeOH, 0°C, 83% from 8; (b) Ts–Im, NaH, THF, 0°C, 94%; (c)
7-(2-ethyl-1,3-dioxol-2-yl)heptyl bromide 17/Mg, Li2CuCl4, THF, 0°C, 81%; (d) (i) 10% Pd–C, H2, EtOH; (ii) liq. NH3/Na,
−78°C; (iii) 10% HCl, THF, 75% from 16
with liq. NH3 and sodium19 resulted in a poor yield of 2, while debenzylation and detosylation proceeded
smoothly by separately using Pd–C catalytic hydrogenation and liq. NH3/Na to give 2.
In summary, (+)-desoxoprosophylline 1 and prosophylline 2 have been synthesized using a new chiral
α-furfuryl amine derivative 3 as a building block, respectively. This chiral building block 3 is very useful
for the stereoselective synthesis of the polysubstituted piperidine alkaloids and aza-sugars.
3. Experimental
3.1. General
Melting points were determined with a Büchi 535 melting point apparatus and were uncorrected. All
additions were made by syringe. Reactions were monitored by using thin layer chromatography (TLC).
The silica gel used in flash chromatography was silica gel H (10 µ) which was produced by the Qingdao
1
Chemical Plant, China. IR spectra were measured on a Shimadzu IR 400 spectrometer. H NMR spectra
were recorded on a Bruker AM-300 (300 MHz) with CDCl3 as solvent and values were reported in
ppm using TMS or residual CHCl3 as internal standard. Mass spectra were obtained on a Finnigan
4021 GC–MS instrument and JMS-01U spectrometer. The optical rotations, [α]20, were measured on
D
a Perkin–Elmer 241 MC automatic polarimeter in a 1 dm cell and recorded in units of 10−1 deg cm2 g−1.
Element analyses were performed by the Analytical Department of this institute. Dichloromethane was
distilled from calcium hydride. Tetrahydrofuran was freshly distilled from Na–benzophenone.

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3.2. (2R,6S)-1,6-Dihydro-1-tosyl-6-hydroxy-2-phenylmethoxymethyl-3(2H)-pyridinone 4
To a solution of 3 (1.0 g, 2.69 mmol) in 15 ml of dichloromethane was added m-CPBA (1.0 g, 3.23
mmol). After being stirred for 16 h at rt, the solvent was evaporated under reduced pressure to give a
solid which was purified by flash column chromatography on silica gel [petroleum ether:ethyl acetate
(40:10)] to afford a solid 4 (0.86 g, 82%). M.p. 102–104°C; [α]20=+3.5 (c=0.8, EtOH); 1H NMR δ: 2.42
D
(s, 3H, Ts-CH3), 3.55 (dd, 1H, J=2.6, 9.3 Hz, CHaHbOBn), 3.79 (dd, 1H, J=2.2, 9.6 Hz, CHaHbOBn),
4.30, 4.42 (ab, 2H, J=11.5 Hz, PhCH2), 4.58 (dd, 1H, J=2.5, 2.2 Hz, 2-H), 4.69 (d, 1H, J=11.8 Hz, OH),
5.94 (dd, 1H, J=4.9, 11.6 Hz, 6-H), 6.10 (d, 1H, J=10.3 Hz, 4-H), 6.92 (dd, 1H, J=5.0, 10.3 Hz, 5-H),
7.10 (m, 2H, Ts), 7.31–7.26 (m, 5H, Ph), 7.77 (d, 2H, J=8.3 Hz, Ts); IR: 3335, 1683 cm−1; MS m/z:
370 (M++1−H2O), 263 (M++1−H2O−BnO), 155 (Ts), 91 (Bn). HRMS (M+) calcd for C20H21NO5S:
387.1141. Found: 387.1156.
3.3. (2R,6S)-1,6-Dihydro-1-tosyl-6-ethoxy-2-phenylmethoxymethyl-3(2H)-pyridinone 5
To 4 Å molecular sieves (0.273 g, 66 mmol) in 15 ml of THF was sequentially added 4 (1.60 g, 4.13
mmol), triethylorthoformate (1.72 ml, 10.3 mmol) and BF3·Et2O (57.3 µl) at 0°C. After being stirred
for 4 h at 0°C, 5 ml of water was added. The water layer was extracted with ethyl acetate (3×5 ml). The
combined organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure
to give an oil which was purified by flash column chromatography on silica gel [petroleum ether:ethyl
20
1
acetate (40:10)] to afford a solid 5 (1.67 g, 97%). M.p. 106–108°C; [α] =−62.6 (c=1.0, EtOH); H
D
NMR (600 Hz) δ: 1.197 (t, 3H, J=7.02 Hz, CH3CH2), 2.378 (s, 3H, Ts-CH3), 3.655 (qd, 1H, J=7.02,
9.26 Hz, CH3CHaHb), 3.795 (dd, 1H, J=6.71, 10.22 Hz, CHaHbOBn), 3.915 (dd, 1H, J=7.66, 10.22 Hz,
CHaCHbOBn), 3.992 (qd, 1H, J=7.02, 9.42 Hz, CH3CHaHb), 4.525, 4.589 (ab, 2H, J=11.8 Hz, PhCH2),
4.632 (dd, 1H, J=6.71, 7.66 Hz, 2-H), 5.641 (d, 1H, J=4.48 Hz, 6-H), 5.826 (d, 1H, J=10.21 Hz, 4-H),
6.754 (dd, 1H, J=4.47, 10.22 Hz, 5-H), 7.221 (d, 2H, J=7.99 Hz, Ts), 7.326 (m, 5H, Ph), 7.587 (d, 2H,
J=8.30 Hz, Ts); IR: 1698 cm−1; MS m/z: 415 (M+), 370 (M+−EtO), 155 (Ts), 91 (Bn). Anal. calcd for
C22H25NO5S: C, 63.59; H, 6.06; N, 3.37. Found: C, 63.52; H, 5.88; N, 3.05.
3.4. (2R,3S,6S)-1-Tosyl-3-hydroxy-6-ethyloxy-2-phenylmethoxymethylpiperidine 6
To a solution of 5 (1.67 g, 4.02 mmol) in 30 ml of absolute methanol was added NaBH4 (2.14 g,
28 mmol) at 0°C. After being stirred for 3 h, 8 ml of water was added. Work up as usual afforded a
crude oil which was purified by flash column chromatography on silica gel [petroleum ether:ethyl acetate
(40:10)] to afford an oil 6 (1.48 g, 88%). [α]20=−21.0 (c=0.4, EtOH); 1H NMR δ: 1.23 (t, 3H, J=7.0 Hz,
D
CH3CH2O), 1.51–2.00 (m, 4H), 2.43 (s, 3H, Ts-CH3), 2.69 (m, 1H), 3.72 (q, 2H, J=7.0 Hz, CH3CH2O),
3.78–3.86 (m, 2H), 4.23 (m, 1H), 4.55 (dd, 2H, J=11.8, 16.2 Hz, PhCH2), 5.65 (m, 1H), 7.26–7.38 (m,
7H, Ph), 7.73 (d, 2H, J=8.2 Hz, Ts); IR: 3400, 1600 cm−1; MS m/z: 420 (M++1), 374 (M+−OEt), 155
(Ts), 91 (Bn). Anal. calcd for C22H29NO5S: C, 62.98; H, 6.97; N, 3.34. Found: C, 63.45; H, 7.36; N,
2.88.
3.5. (2R,3S,6S)-1-Tosyl-3-phenylmethoxy-6-ethyloxy-2-phenylmethoxymethylpiperidine 7
To sodium hydride (0.166 g, 6.9 mmol) in 20 ml of DMF at 0°C was added 6 (1.45 g, 3.45 mmol) for
0.5 h, then benzyl bromide (0.49 ml, 4.43 mmol) was added slowly for another 0.5 h. After being stirred
for 2 h, 20 ml of aqueous NH4Cl and 10 ml of water were added sequentially. The mixture was extracted

C. Yang et al. / Tetrahedron: Asymmetry 10 (1999) 2311–2318
2315
with ethyl acetate and the combined organic layer was washed with water, dried (Na2SO4), evaporated
under reduced pressure to afford a crude oil which was purified by flash column chromatography on
silica gel [petroleum ether:ethyl acetate (90:10)] to afford an oil 7 (1.48 g, 88%). [α]20=−27.8 (c=1.5,
D
EtOH); 1H NMR δ: 1.25 (t, 3H, J=7.1 Hz, CH3CH2O), 1.74–1.96 (m, 4H), 2.38 (s, 3H, Ts-CH3), 3.09
(m, 1H), 3.54 (dd, 1H, J=7.8, 10.5 Hz), 3.68–3.76 (m, 2H, CH3CH2O), 4.37 (m, 1H), 4.45–4.57 (m, 4H),
4.94 (m, 1H), 6.55 (d, 1H, J=7.7 Hz), 7.11–7.38 (m, 12H, Ph), 7.66 (d, 2H, J=8.4 Hz, Ts); IR: 3050,
1600 cm−1; MS m/z: 464 (M+−EtO), 402 (M+−BnO), 308 (M++1−Ts−EtO), 155 (Ts), 91 (Bn). HRMS
(M++1−Ts−EtO) calcd for C20H22NO2: 308.1650. Found: 308.1629.
3.6. (2R,3S,6R)-1-Tosyl-3-phenylmethoxy-2-phenylmethoxymethyl-6-(2-propenyl)piperidine 8
To a solution of 7 (0.112 g, 1.0 mmol) in 10 ml of dichloromethane was added allyltrimethylsilane
(144 µl, 4 mmol). Then TiCl4 (12 µl, 0.5 mmol) was added at −78°C. After being stirred for 45 min, 5
ml of aqueous NaHCO3 was added, then warmed up to rt. The mixture was diluted with 5 ml of Et2O
and 2 ml of 20% KF was added. Work up as usual afforded a crude oil which was purified by flash
column chromatography on silica gel [petroleum ether:ethyl acetate (15:1)] to afford an oil 8 (0.12 g,
67%). [α]20=+6.1 (c=2.0, EtOH); 1H NMR δ: 1.67 (m, 4H), 2.27 (m, 2H), 2.39 (s, 3H, Ts-CH3), 3.37
D
(m, 1H), 3.68 (dd, 1H, J=7.0, 10.1 Hz), 3.90 (m, 2H), 4.45–4.65 (m, 4H, PhCH2), 4.73 (m, 1H), 4.96 (m,
2H), 5.64 (m, 1H), 7.15 (d, 2H, J=8.2 Hz, Ts), 7.23 (m, 10H, Ph), 7.71 (d, 2H, J=8.2 Hz, Ts); IR: 3100,
2850 cm−1; MS m/z: 506 (M++1), 464 (M+−allyl), 398 (M+−BnO), 155 (Ts+), 91 (Bn+). Anal. calcd for
C30H35NO4S: C, 71.26; H, 6.98; N, 2.77. Found: C, 71.21; H, 6.96; N, 3.07.
3.7. (2R,3S,6S)-1-Tosyl-3-phenylmethoxy-2-phenylmethoxymethyl-6-(1-hydroxy-3-propyl)piperidine 10
To a solution of 8 (0.309 g, 0.61 mmol) in 15 ml of THF was added BH3·SMe2 (36 µl, 10 M) at 0°C.
After being stirred for 5 h, aqueous sodium hydroxide (105 µl, 3 M) and 30% of H2O2 (105 µl) were
added. Work up as usual afforded a crude oil which was purified by flash column chromatography on
silica gel [petroleum ether:ethyl acetate (70:30)] to afford an oil 10 (0.18 g, 45%). [α]20=−16.4 (c=2.2,
D
EtOH); 1H NMR δ: 1.26–1.79 (m, 8H), 2.38 (s, 3H, Ts-CH3), 3.21 (m, 1H), 3.53 (t, 2H, J=6.0 Hz), 3.73
(dd, 1H, J=7.6, 10.4 Hz), 3.83 (dd, 1H, J=5.1, 10.5 Hz), 3.87 (m, 1H), 4.50 (m, 4H, Bn-CH2), 4.65 (m,
1H), 7.15 (d, 2H, J=8.1 Hz, Ts), 7.32 (m, 10H, Ph), 7.66 (d, 2H, J=8.1 Hz, Ts); IR: 3450, 3100 cm−1; MS
m/z: 524 (M++1), 506 (M++1−H2O), 368 (M+−Ts), 155 (Ts), 91 (Bn). Anal. calcd for C30H37NO5S: C,
68.81; H, 7.12; N, 2.67. Found: C, 68.89; H, 7.21; N, 2.92.
3.8. (2R,3S,6S)-[1-Tosyl-3-phenylmethoxy-2-phenylmethoxymethyl-6-piperidyl]propyl tosylate 11
To NaH (25 mg, 1 mmol) in 5 ml of THF was added 10 (0.16 g, 0.306 mmol) (dissolved in 4 ml of
THF) at 0°C. Then Ts–Im (0.102 g, 0.459 mmol, dissolved in 0.5 ml of THF) was added for 10 min. After
being stirred for 2 h, 2 ml of aqueous NH4Cl was added. Work up as usual afforded a crude oil which was
purified by flash column chromatography on silica gel [petroleum ether:ethyl acetate (50:10)] to afford an
oil 11 (0.18 g, 87%). [α]20=−11.4 (c=1.0, EtOH); 1H NMR δ: 1.26–1.78 (m, 8H), 2.38 (s, 3H, Ts-CH3),
D
2.43 (s, 3H, Ts-CH3), 3.15 (m, 1H), 3.64 (dd, 1H, J=7.6, 10.3 Hz), 3.84 (m, 3H), 4.00 (m, 1H), 4.39–4.61
(m, 5H), 7.14 (d, 2H, J=8.2 Hz, Ts), 7.29 (m, 12H, Ph), 7.61 (d, 2H, J=8.2 Hz, Ts), 7.75 (d, 2H, J=8.2
Hz, Ts); IR: 3050, 2900 cm−1; MS m/z: 678 (M++1), 572 (M++2−BnO), 465 (M++2−2BnO), 155 (Ts),
91 (Bn). Anal. calcd for C37H43NO7S2: C, 65.56; H, 6.39; N, 2.07. Found: C, 65.80; H, 6.44; N, 2.20.

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C. Yang et al. / Tetrahedron: Asymmetry 10 (1999) 2311–2318
3.9. (2R,3S,6S)-1-Tosyl-3-phenylmethoxy-2-phenylmethoxymethyl-6-dodecylpiperidine 12
To a solution of 11 (0.22 g, 0.325 mmol) in 5 ml of THF and Li2CuCl4 (1.63 ml, 0.1 M in THF) was
added at 0°C nonyl magnesium bromide (C9H19MgBr) (1 ml) prepared from nonyl bromide (0.1 ml) and
magnesium (47 mg) in THF (1.5 ml). After being stirred for 1 h, 4 ml of aqueous NH4Cl was added.
Work up as usual afforded a crude oil which was purified by flash column chromatography on silica gel
[petroleum ether:ethyl acetate (20:1)] to afford an oil 12 (0.14 g, 68%). [α]20=−7.2 (c=0.67, EtOH); 1H
D
NMR δ: 0.88 (t, 3H, J=6.9 Hz, CH3CH2), 1.26–1.74 (m, 26H), 2.37 (s, 3H, Ts-CH3), 3.33 (m, 1H, 6-H),
3.65 (dd, 1H, J=7.2, 10.1 Hz, CHaHbOBn), 3.84 (m, 2H), 4.46–4.60 (m, 4H, CH2Ph), 4.71 (m, 1H, 2-H),
7.13 (d, 2H, J=8.2 Hz, Ts), 7.33 (m, 10H, Ph), 7.70 (d, 2H, J=8.2 Hz, Ts); IR: 3050, 1600 cm−1; MS m/z:
633 (M+), 477 (M+−1−Ts), 419 (M+−2BnO), 155 (Ts), 91 (Bn). Anal. calcd for C39H55NO4S: C, 73.89;
H, 8.74; N, 2.21. Found: C, 74.31; H, 9.19; N, 2.42.
3.10. (2R,3S,6S)-1-Tosyl-3-hydroxy-2-hydroxymethyl-6-dodecylpiperidine 13
To a solution of 12 (0.120 g, 0.190 mmol) in 5 ml of ethanol was added a catalytic amount of 10%
Pd/C (12 mg). After the mixture was stirred under H2 atmosphere (1 atm) at rt for 7.5 h, work up as
usual afforded a crude oil which was purified by flash column chromatography on silica gel [petroleum
20
1
ether:ethyl acetate (30:10)] to afford an oil 13 (72 mg, 84%). [α] =−4.5 (c=1.0, EtOH); H NMR δ:
D
0.88 (t, 3H, J=6.5 Hz, CH3CH2), 1.26–1.75 (m, 26H), 2.42 (s, 3H, Ts-CH3), 3.55 (m, 1H), 3.71 (m,
1H), 3.91 (dd, 1H, J=6.7, 13.3 Hz), 4.13 (dd, 1H, J=6.7, 13.3 Hz), 4.22 (m, 1H), 7.29 (d, 2H, J=8.0 Hz,
Ts), 7.73 (d, 2H, J=8.0 Hz, Ts); IR: 3400, 2900 cm−1; MS m/z: 454 (M++1), 436 (M++1−H2O), 422
(M+−CH2OH), 155 (Ts). HRMS (M+−CH2OH) calcd for C24H40NO3S: 422.2729. Found: 422.2729.
3.11. (+)-Desoxoprosophylline 1
To the liquid ammonia (10 ml) was added 13 (50 mg, 0.011 mmol) (dissolved in 2 ml of THF) and
sodium to keep the solution a blue color. After being stirred for 5 h, the solid NH4Cl was added. Warming
up to rt under N2, liquid ammonia was evaporated. HCl (2 M, 2 ml) was added. The water was extracted
with dichloromethane and 8 ml of saturated NaHCO3 was added to the water layer, then 5 ml of 3 M
NaOH was added to make pH=11. Work up as usual afforded a crude oil which was purified by flash
column chromatography on silica gel (first, toluene:ethanol=5:1, then toluene:ethanol=1:5 with 5% of
20
1
Et3N) to afford a colorless solid 1 (15 mg, 46%). M.p. 89.5–90°C; [α] =+14.4 (c=0.32, CHCl3); H
D
NMR δ: 0.89 (t, 3H, J=6.1 Hz, CH3), 1.24–1.88 (m, 26H), 1.92–2.00 (m, 1H, N-H), 2.58 (m, 1H), 3.47
(m, 2H), 3.78 (m, 1H), 3.86 (m, 1H); IR: 3338, 3238 cm−1; MS m/z: 300 (M++1), 282 (M++1−H2O),
268 (M+−CH2OH), 130 (M+−C12H25). HRMS (M+) calcd for C18H37NO2: 299.2824. Found: 299.2843.
The enantiomer of 1 had m.p. 90.5, [α]21=−14.4 (c=0.24, CHCl3). The 1H NMR and the mass spectrum
D
of 1 were identical with the literature data.5d
3.12. (2R,3S,6R)-1-Tosyl-3-phenylmethoxy-2-phenylmethoxymethyl-6-(1-hydroxy-2-ethyl)piperidine 14
A solution of 8 (93 mg, 0.18 mmol) in 5 ml of CH2Cl2:CH3OH (9:1) was bubbled with ozone at −78°C
for 5 min until a light blue color appeared. The excess of ozone was removed by passing through N2 and
1 ml of Me2S was added. The reaction mixture was stirred at rt for 1 h and evaporated under reduced
pressure to give a residue. To a solution of the residue in 5 ml of MeOH was added NaBH4 (46 mg, 1.2
mmol) in portions at 0°C. The reaction mixture was stirred at 0°C for 1 h, 2 ml of aqueous NH4Cl was

C. Yang et al. / Tetrahedron: Asymmetry 10 (1999) 2311–2318
2317
added. Work up as usual afforded a crude oil which was purified by flash column chromatography on
silica gel [petroleum ether:ethyl acetate (30:10)] to afford an oil 14 (78 mg, 83%). [α]20=−37.7 (c=3.8,
D
1
CHCl3); H NMR δ: 1.26–1.66 (m, 6H), 2.39 (s, 3H, Ts-CH3), 3.11 (m, 1H), 3.58 (m, 1H), 3.70 (dd,
1H, J=7.5, 10.4 Hz, BnOCHaHb), 3.81 (dd, 1H, J=5.0, 10.5 Hz, C6H5OCHaHb), 3.91 (m, 1H), 4.10 (m,
1H), 4.53 (m, 5H, 2-H and PhCH2), 7.17 (d, 2H, J=8.0 Hz, Ts), 7.31 (m, 10H, Ph), 7.62 (d, 2H, J=8.2
Hz, Ts); IR: 3537, 1598 cm−1; MS m/z: 510 (M++1), 492 (M++1−H2O), 294 (M+−1−2BnO), 155 (Ts).
HRMS (M+) calcd for C29H35NO5S: 509.2208. Found: 509.2236.
3.13. (2R,3S,6R)-[1-Tosyl-3-phenylmethoxy-2-phenylmethoxymethyl-6-piperidyl]ethyl tosylate 15
To a solution of 14 (130 mg, 0.257 mmol) in 3 ml of THF was added sodium hydride (21 mg, 60%
purity, 0.525 mmol) at 0°C. After the reaction mixture was stirred at 0°C for 10 min, Ts–Im (85 mg,
0.383 mmol) was added. The reaction mixture was stirred at 0°C for 3 h and aq. NH4Cl solution was
added. Work up as usual afforded a crude oil which was purified by flash column chromatography on
silica gel [petroleum ether:ethyl acetate (50:10)] to afford an oil 15 (161 mg, 94%). [α]20=−8.2 (c=5.4,
D
CHCl3); 1H NMR δ: 1.26 (m, 6H), 2.38 (s, 3H, Ts-CH3), 2.44 (s, 3H, Ts-CH3), 3.23 (m, 1H), 3.70 (m,
2H, CH2OBn), 4.00 (m, 3H), 4.41∼4.56 (m, 4H, PhCH2), 4.60 (m, 1H, 2-H), 7.13 (d, 2H, J=8.0 Hz, Ts),
7.30 (m, 12H, Ph), 7.60 (d, 2H, J=8.2 Hz, Ts), 7.75 (d, 2H, J=8.3 Hz, Ts); IR: 3064, 1598 cm−1; MS
m/z: 665 (M++2), 542 (M+−CH2OBn), 508 (M+−Ts), 401 (M+−BnO−Ts), 246 (M+−OBn−2Ts). HRMS
(M+−OBn−2Ts) calcd for C15H20NO2: 246.1494. Found: 246.1503.
3.14. (2R,3S,6S)-1-Tosyl-3-phenylmethoxy-2-phenylmethoxymethyl-6-[9-(2-ethyl-1,3-dioxol-2-yl)-
nonyl]piperidine 16
To a solution of 15 (72 mg, 0.108 mmol) in 1 ml of THF at 0°C was added Li2CuCl4 (0.048 ml, 0.114
M in THF) and 7-(2-ethyl-1,3-dioxol-2-yl)heptyl magnesium bromide (0.5 ml) prepared from 20 (0.18
ml) and magnesium (31 mg) in THF (1.5 ml). The reaction mixture was stirred at 0°C for 1 h and aq.
NH4Cl solution was added. Work up as usual afforded a crude oil which was purified by flash column
chromatography on silica gel [petroleum ether:ethyl acetate (12:1)] to afford an oil 13 (67 mg, 89%).
20
1
[α] =−5.3 (c=4.1, EtOH); H NMR δ: 0.91 (t, 3H, J=7.4 Hz, CH2CH3), 1.21–1.65 (m, 24H), 2.39
D
(s, 3H, Ts-CH3), 3.31 (m, 1H), 3.66 (m, 1H), 3.84 (m, 2H, CH2OBn), 3.93 (s, 4H, OCH2CH2O), 4.46
(m, 2H, PhCH2), 4.60 (m, 2H, PhCH2), 4.71 (m, 1H, 2-H), 7.12 (d, 2H, J=8.0 Hz, Ts), 7.29 (m, 10H,
Ph), 7.69 (d, 2H, J=8.2 Hz, Ts); IR: 3064, 1599 cm−1; MS m/z: 693 (M++2), 663 (M+−CH2CH2), 536
(M+−Ts) and 155 (Ts+). Anal. calcd for C41H57NO6S: C, 71.17; H, 8.30; N, 2.02. Found: C, 71.42; H,
8.67; N, 1.93.
3.15. Prosophylline 2
To a solution of 16 (70 mg, 0.102 mmol) in 4 ml of ethanol was added 10% Pd/C (17 mg), and the
solution was stirred under H2 atmosphere (1 atm) for 10 h. The mixture was filtered and concentrated
under reduced pressure. The residue was purified by chromatography to give an oil (50 mg) which was
added to liquid ammonia and sodium was added. The mixture was kept blue by replenishing sodium.
After the reaction mixture was stirred at −55°C for 4 h, NH4Cl (200 mg) was added. The mixture was
warmed up to rt, and ammonia was evaporated. NH4Cl solution was added. The mixture was extracted
with CH2Cl2, dried over Na2SO4 and concentrated to afford a residue, which was purified by silica gel
column chromatography to give an oil (24 mg). To a solution of the oil in THF (2 ml) was added 10% HCl

2318
C. Yang et al. / Tetrahedron: Asymmetry 10 (1999) 2311–2318
(0.6 ml). The mixture was stirred at rt for 2 h, neutralized with saturated NaHCO3 (2 ml) and extracted
with CHCl3. The combined organic layers were dried over Na2SO4 and concentrated under reduced
pressure to give a solid which was purified by flash column chromatography on silica gel [toluene:EtOH
(4:1)] to afford crystals (11 mg, 75%). M.p. 79.5–81°C; [α]20=0 (c=0.5, CHCl3); [lit.1: m.p. 79°C; [α]D
D
1
0]; H NMR δ: 1.06 (t, 3H, J=7.3 Hz, CH3CH2), 1.29–1.61 (m, 20H), 1.90–1.94 (m, 1H, N-H), 2.43
(m, 4H, CH2COCH2), 2.56 (m, 1H), 2.75 (m, 1H), 3.74–3.83 (m, 3H); IR: 3350 cm−1; MS m/z: 314
(M++1), 282 (M+−CH2OH), 130 (M+−CH3CH2CO(CH2)9), 57 (CH3CH2CO+). The H NMR and the
1
mass spectra of 2 were identical with the literature data.1
Acknowledgements
Project (29872046) supported by the National Natural Science Foundation of China. We thank Mr.
Jian Chen for valuable discussions.
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