Stereoselective Synthesis and Biological Studies of ...

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b Lipid Science and Technology, Indian Institute of Chemical Technology, Hyderabad 500007, India. Received 11 August 2009; revised 25 August 2009.
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Stereoselective Synthesis and Biological Studies of the C2 and C3 Epimer and the Enantiomer of Pachastrissamine (Jaspine B) a StudiesofSter oisomersofPacJayachitra, G. hastris amine(JaspineB) N. Sudhakar,a Ravi Kumar Anchoori,a B. Venkateswara Rao,*a Sayantani Roy,b Rajkumar Banerjeeb a

Organic Division III, Indian Institute of Chemical Technology, Hyderabad 500007, India Fax +91(40)27193003; E-mail: [email protected] b Lipid Science and Technology, Indian Institute of Chemical Technology, Hyderabad 500007, India Received 11 August 2009; revised 25 August 2009

Key words: cytotoxicity, D-glucose, pachastrissamine, jaspine B, Mitsunobu inversion, Wittig olefination

H2N

C14H29

O

Due to their biological significance, as well as the complication of isolation from natural sources in homogeneous form, a great deal of effort has been devoted to the synthesis of this class of compounds.7,8 Our group reported the first total synthesis of jaspine B (1) and its C2 epimer 2.8a Jaspine B (1) has an erythro-amino alcohol moiety in the tetrahydrofuran ring, which may be a key structural feature for biological activity. The important biological activity and the novel structural features of jaspine B (1) prompted us to undertake the synthesis of some of its stereoisomers and to study their bioactivity in comparison to jaspine B. Therefore, we designed a new approach for making C2 and C3 epimer 3a8p of jaspine B and total antipode 4.8i Compounds 2 and 4 have erythro configuration for the amino alcohol moiety, like jaspine B, whereas 3a and 3b have threo configuration (Figure 1). The synthesis of 3a is illustrated in Scheme 1. D-Glucose was transformed into compound 6 using a reported procedure.9a Slightly modified conditions (i.e., using NaH, inSYNTHESIS 2010, No. 1, pp 0115–0119xx. 209 Advanced online publication: 03.11.2009 DOI: 10.1055/s-0029-1217096; Art ID: Z17109SS © Georg Thieme Verlag Stuttgart · New York

OH

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Pachastrissamine (jaspine B, 1), a natural anhydrophytosphingosine derivative with significant cytotoxicity, was first isolated by Higa and co-workers1 from the Okinawa marine sponge, Pachastrissa sp. (family calthropellidae) and found to possess cytotoxicity at a level of IC50 0.01 mg/mL against P388, A549, HT29, and Mel 28 cell lines. Later Debitus and co-workers2 isolated the same compound from a marine sponge, genus Jaspis, which is a main source of many cytotoxic compounds such as jaspamides,3 jaspisamides,4 isomalabaricane,5 toyocamycin, and 5-(methoxycarbonyl)tubercidine.6 Jaspine B displayed marked cytotoxicity (IC50 = 0.24 mM) against the A549 human lung carcinoma cell line using the ATPlite assay.

H2N

OH

3a 3b

C14H29 R=H R = Ac

TFA⋅H2N

OH

O

C14H29

4

Figure 1

stead of NaOMe) helped us to get better yields of compound 6 from 1,2-O-isopropylidene-D-glucofuranose 5. The alcohol functionality of compound 6 was converted into azide 8 via tosylate 7 using tosyl chloride/triethylamine and sodium azide in N,N-dimethylformamide. Compound 8 on hydrolysis with a catalytic amount of concentrated hydrochloric acid and 60% aqueous acetic acid furnished 1,2-diol 9. Oxidative cleavage of diol 9 with sodium periodate in methanol–water afforded aldehyde 10. Standard Wittig olefination of 10 with a C13 alkyl donor resulted in a single isomer 11 (determined on the basis of 1H NMR). Hydrogenation of the azido group and the side-chain double bond of 11 with hydrogen and palladium on carbon in methanol furnished target molecule 3a.10 Compound 3a was converted into diacetate 3b for the sake of complete characterization. Compound 4 was synthesized from D-glucose using the same strategy following the sequence of reactions described in Scheme 2. In this case, the hydroxy functionality of compound 6 underwent inversion using Mitsunobu conditions and subsequent hydrolysis of compound 12 with lithium hydroxide in tetrahydrofuran–water resulted in alcohol 13. The alcohol 13 was converted into azide 15 via mesylate 14 using mesyl chloride/triethylamine and sodium azide in N,N-dimethylformamide, albeit in two days; this may be because of the attack of the azide nucleophile from the sterically hindered side which retarded the reaction site. Acetonide deprotection in 15 gave diol 16. Oxidative cleavage of 16 gave aldehyde 17. Wittig olefination of 17 resulted olefin 18 and subsequent reduction afforded compound 4.

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Abstract: The synthesis of the C2 and C3 epimer and also the enantiomer of jaspine B from D-glucose is reported. The cytotoxicity of these isomers along with jaspine B and its C2 epimer on MCF7 cells has been correlated with commercially available anticancer drug Epirubicin.

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HO

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D-glucose

O

HO

O

O

6 N3

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O

OH

d O

O

N3

OCHO

e

OH

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N3

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b

O

O

5 TsO

O

a

9 H2N

OH

OH

g

f CHO

C11H23

O

O

11

10 AcHN

C14H29

O 3a

OAc

C14H29

O 3b

Scheme 1 Reagents and conditions: (a) 1. NaH, THF, 0 °C; 2. diethyl carbonate, reflux, 74%; (b) TsCl, Et3N, DMAP, CH2Cl2, 0 °C then r.t., 4 h, 84%; (c) NaN3, DMF, 90 °C, 12 h, 79%; (d) 60% aq AcOH, concd HCl, r.t., 12 h, 86%; (e) NaIO4, MeOH–H2O, 30 min; (f) [Me(CH2)12]Ph3P+Br–, t-BuOK, THF, –40 °C to r.t., 49%; (g) H2, Pd/C, MeOH, r.t., 2 h, 92%; (h) Ac2O, Et3N, DMAP, CH2Cl2, r.t., 4 h, 94%.

NO2 O O

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HO

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a 6

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CHO

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OH

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16 TFA⋅H2N

OH

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h C11H23

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C14H29

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Scheme 2 Reagents and conditions: (a) Ph3P, DIAD, 4-nitrobenzoic acid, THF, 0 °C to r.t., overnight, 89%; (b) LiOH·H2O, THF–H2O, 1 h, 75%; (c) MsCl, Et3N, CH2Cl2, 0 °C to r.t., 4 h, 86%; (d) NaN3, DMF, 120 °C, 2 d, 63%; (e) aq AcOH, concd HCl, r.t., 12 h, 85%; (f) NaIO4, MeOH–H2O, 30 min; (g) [Me(CH2)12]Ph3P+Br–, t-BuOK, THF, –40 °C to r.t., 51%; (h) H2, Pd/C, MeOH–TFA, 4 h, 92%.

Cytotoxic effects of compounds 1–4 on MCF7 cells were examined. Cytotoxicities of compounds 1–4 were evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay. Compounds 1,8a 2,8a 3a, 3b, and 4 were treated continuously for 72 hours on MCF7 (primary breast cancer cell). The commercially available anti-breast cancer drug Epirubicin was used for comparison. Following the termination of the experiment, cells were washed and promptly assayed Synthesis 2010, No. 1, 115–119

© Thieme Stuttgart · New York

for viability using MTT. The IC50 of the compounds are reported in Table 1. In conclusion, we have described a short, efficient, and stereoselective synthesis of stereoisomers of jaspine B, 3a and 4 starting from D-glucose. Compounds 1, 2, and 4 show promising results on MCF7 cells and compared with commercially available anti-breast cancer drug Epirubicin. From the above studies it is clear that compounds 1, 2, and 4 with a cis configuration of the amino and hydroxy

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h

PAPER Table 1

Studies of Stereoisomers of Pachastrissamine (Jaspine B) MCF7 Inhibitory Activities of Jaspine B and Its Isomers

Compound

IC50 (mM)

1

14

2

22.5

3a

–a

3b

–a

4

18.5

Epirubicin

5

a

No effect.

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C NMR (50 MHz, CDCl3): d = 21.2, 26.3, 26.8, 67.9, 76.0, 80.0, 84.3, 106.7, 112.4, 127.6, 129.5, 132.4, 144.9. MS (GC): m/z = 379 [M + Na]+.

3,6-Anhydro-5-azido-5-deoxy-1,2-O-isopropylidene-b-L-idofuranose (8) A mixture of 7 (1.25 g, 3.5 mmol) and NaN3 (1.5 g, 22.75 mmol) in DMF (10 mL) was heated at 90 °C for 12 h. The mixture was poured into H2O and extracted with EtOAc. The combined extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was column chromatographed (hexane–EtOAc, 24:1) to give 8 (0.625 g, 79%) as a syrup. [a]D28 +39.4 (c 0.0135, CHCl3) [Lit.9b [a]D20 +42.0 (c 0.5, CHCl3)]. IR: 2988, 2935, 2880, 2098, 1457, 1379, 1286, 1081 cm–1. 1

Reactions were performed in dried glassware, sealed with a rubber septum and stirred with a magnetic stirring bar, under N2 if required. THF was freshly distilled from Na/benzophenone ketyl and transferred with a syringe. CH2Cl2 was freshly distilled from CaH2. TLC was performed on Merck Kiesel gel 60, F254 plates (0.25 mm). Column chromatography was performed on silica gel (60–120 mesh) using EtOAc–hexane mixtures. Melting points were determined on a Fisher John melting point apparatus and are uncorrected. IR spectra were recorded on a Perkin-Elmer RX-1 FT-IR system. 1H NMR spectra were recorded using Varian Gemini-200 MHz or Bruker Avance-300 MHz spectrometers with TMS as reference. 13C NMR spectra were recorded using Varian Gemini-50 MHz or Bruker Avance-75 MHz spectrometers. Optical rotations were measured with a Horiba-SEPA-300 digital polarimeter. Accurate mass measurement was performed on a Q STAR mass spectrometer.

13

C NMR (75 MHz, CDCl3): d = 26.6, 27.2, 64.9, 71.7, 84.0, 85.5, 86.1, 106.4, 112.5. MS (LC): m/z = 227 [M]+.

(2R,3R,4S)-4-Azido-2-[(Z)-tetradec-1-enyl]tetrahydrofuran-3ol (11) To 8 (0.5 g, 2.2 mmol) was added 60% aq AcOH (10 mL) and concd HCl (catalytic amount) and the mixture was stirred at r.t. for 12 h. The mixture was neutralized with solid NaHCO3 until pH 7, filtered, and washed with EtOAc. The organic layers was dried (Na2SO4), concentrated in vacuo, and purified by column chromatography (hexane–EtOAc, 2:1) to give 9 (0.35 g, 86%) as a syrup as a mixture of anomers (~1:1). [a]D28 +79.9 (c 0.01, MeOH). To a soln of 9 (0.3 g, 1.6 mmol) in 80% aq MeOH (10 mL) was added NaIO4 (0.685 g, 3.2 mmol); the mixture was stirred for 30 min. Then the solvent was removed under reduced pressure and the residue was extracted with EtOAc and the combined extracts were dried (Na2SO4) and concentrated to afford crude 10.

3,6-Anhydro-1,2-O-isopropylidene-a-D-glucofuranose (6) To a precooled (0 °C) soln of 5 (2 g, 9.09 mmol) in THF (25 mL) was slowly added NaH (0.73 g, 18.18 mmol) under N2. After stirring for 30 min at this temperature, diethyl carbonate (1.65 mL, 13.63 mmol) was added dropwise and the mixture was refluxed for 12 h. The mixture was quenched with sat. NH4Cl at 0 °C, extracted with EtOAc, and concentrated in vacuo. The residue was purified by column chromatography (hexane–EtOAc, 4:1) to give 6 (1.35 g, 74%) as a syrup. Spectral data were in good agreement with reported values.9

To a precooled (–40 °C) soln of Wittig salt [Me(CH2)12]Ph3P+Br– (1.42 g, 2.7 mmol) in THF (25 mL) was slowly added t-BuOK (0.362 g, 3.24 mmol) under N2. The orange soln was stirred at this temperature for 1 h and then it was cannulated to a soln of 10 (0.2 g, 1.08 mmol) in anhyd THF (5 mL) at –40 °C under N2 and stirred at this temperature for 1 h, allowed to warm to r.t., and quenched with sat. NH4Cl. The mixture was diluted with H2O and extracted with EtOAc. The combined organic extracts were dried (anhyd Na2SO4) and concentrated to dryness. Purification of the residue by column chromatography (hexane–EtOAc, 15:1) gave 11 (0.17 mg, 49%) as a syrup.

3,6-Anhydro-1,2-O-isopropylidene-5-O-tosyl-a-D-glucofuranose (7) A soln of TsCl (1.13 g, 5.94 mmol) in CH2Cl2 (15 mL) was added to a mixture of 6 (1 g, 4.95 mmol), Et3N (2.06 mL, 14.85 mmol), and DMAP (catalytic amount) in CH2Cl2 (10 mL) at 0 °C. The mixture was stirred at r.t. for 4 h and then extracted with CH2Cl2, washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by column chromatography (hexane–EtOAc, 5:1) to give 7 (1.48 g, 84%) as a white solid; mp 133–135 °C.

[a]D28 –52.8 (c 0.005, CHCl3). IR: 3426, 2921, 2849, 2101, 1725, 1529, 1466, 1244, 1080 cm–1. 1 H NMR (300 MHz, CDCl3): d = 0.89 (t, J = 6.8 Hz, 3 H), 1.21–1.47 (m, 20 H), 1.99–2.21 (m, 2 H), 3.72 (dd, J = 2.6, 9.8 Hz, 1 H), 4.03– 4.08 (m, 2 H), 4.21 (dd, J = 4.5, 9.8 Hz, 1 H), 4.66 (dd, J = 2.3, 6.8 Hz, 1 H), 5.40 (m, 1 H), 5.73 (m, 1 H). 13

C NMR (75 MHz, CDCl3): d = 14.0, 22.6, 28.3, 29.2, 29.3, 29.4, 29.5, 29.6, 31.8, 67.3, 70.0, 77.2, 77.8, 123.2, 136.8.

[a]D28 +25.0 (c 0.034, CHCl3). IR: 2986, 2931, 2877, 1597, 1366, 1230, 1176, 1011, 849 cm–1. 1

H NMR (200 MHz, CDCl3): d = 1.29 (s, 3 H), 1.40 (s, 3 H), 2.46 (s, 3 H), 3.68 (t, J = 8.8 Hz, 1 H), 3.93 (t, J = 8.8 Hz, 1 H), 4.41 (d, J = 3.7 Hz, 1 H), 4.49 (d, J = 3.7 Hz, 1 H), 4.65 (t, J = 3.7 Hz, 1 H), 4.80 (m, 1 H), 5.85 (d, J = 3.7 Hz, 1 H), 7.34 (d, J = 8.0 Hz, 2 H), 7.82 (d, J = 8.0 Hz, 2 H).

(2R,3R,4S)-4-Amino-2-tetradecyltetrahydrofuran-3-ol (3a) A soln of 11 (50 mg, 0.154 mmol) in MeOH (5 mL) was hydrogenated over 10% Pd/C at r.t. for 2 h. The mixture was filtered through a short pad of Celite (CH2Cl2–MeOH, 1:1). The solvent was removed on a rotary evaporator to afford 3a (42 mg, 92%) as a white solid; mp 92–95 °C.

Synthesis 2010, No. 1, 115–119

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groups (erythro configuration) show better activity compared to trans compound 3a and its acetate 3b. Synthesis of some more jaspine B analogues and studies of their biological activity are in process.

H NMR (200 MHz, CDCl3): d = 1.30 (s, 3 H), 1.47 (s, 3 H), 3.91 (m, 1 H), 3.95 (d, J = 4.3 Hz, 1 H), 4.03 (m, 1 H), 4.52–4.58 (m, 2 H), 4.70 (d, J = 2.9 Hz, 1 H), 5.78 (d, J = 3.6 Hz, 1 H).

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[a]D28 +3.1 (c 0.005, CHCl3) [Lit.8p,10 [a]D25 –2.5 (c 0.71, CHCl3)].

[a]D22 +14.4 (c 0.008, CHCl3).

IR: 3341, 3291, 2918, 2853, 1461, 1376, 1042 cm–1.

IR: 3426, 2995, 2949, 1636, 1375, 1216, 1165, 1073 cm–1.

1

1

H NMR (300 MHz, CDCl3): d = 0.88 (t, J = 6.8 Hz, 3 H), 1.11–1.39 (m, 24 H), 1.5–1.64 (m, 2 H), 2.88 (br s, 3 H), 3.3–3.5 (m, 2 H), 3.78–3.91 (m, 2 H), 4.15 (m, 1 H). 13 C NMR (75 MHz, CDCl3): d = 14.0, 22.6, 26.4, 28.5, 29.3, 29.6, 29.8, 31.9, 59.8, 73.2, 79.2, 80.8.

H NMR (300 MHz, CDCl3): d = 1.31 (s, 3 H), 1.47 (s, 3 H), 1.74 (d, J = 4.5 Hz, 1 H), 3.77 (d, J = 9.8 Hz, 1 H), 3.96 (dd, J = 3.8, 9.8 Hz, 1 H), 4.33 (t, J = 3.8 Hz, 1 H), 4.56 (d, J = 3.8 Hz, 1 H), 4.58 (d, J = 3.0 Hz, 1 H), 4.64 (d, J = 3.0 Hz, 1 H), 5.78 (d, J = 3.0 Hz, 1 H). MS (LC): m/z = 225 [M + Na]+.

+

(2R,3R,4S)-4-Acetamido-2-tetradecyltetrahydrofuran-3-yl Acetate (3b) To an ice-cooled, stirred soln of 3a (20 mg, 0.07 mmol) in anhyd CH2Cl2 (5 mL) was added Et3N (0.05 mL, 0.16 mmol), Ac2O (0.016 mL, 0.33 mmol), and DMAP (catalytic amount). The temperature was allowed to reach r.t. and the mixture was stirred for 4 h. The mixture was diluted with CH2Cl2 and the organic layer was washed with sat. NH4Cl soln, H2O, and brine, and dried (anhyd Na2SO4). The solvent was removed on a rotary evaporator and the residue was purified by column chromatography (silica gel, hexane–EtOAc, 2:1) to afford 3b (24 mg, 94%) as an amorphous solid; mp 70–72 °C. [a]D28 +7.4 (c 0.002, CHCl3). IR: 3258, 2922, 2852, 1744, 1646, 1468, 1374, 1230, 1058 cm–1. 1 H NMR (300 MHz, CDCl3): d = 0.88 (t, J = 6.8 Hz, 3 H), 1.17–1.35 (m, 24 H), 1.35–1.55 (m, 2 H), 1.97 (s, 3 H), 2.10 (s, 3 H), 3.45 (dd, J = 4.5, 9.06 Hz, 1 H), 3.86 (m, 1 H), 4.15 (m, 1 H), 4.24 (dd, J = 6.0, 9.8 Hz, 1 H), 5.08 (dd, J = 3.0, 4.5 Hz, 1 H), 5.75 (d, J = 5.3 Hz, 1 H). 13 C NMR (75 MHz, CDCl3): d = 14.0, 20.8, 22.6, 23.1, 26.2, 28.7, 29.3, 29.5, 29.55, 31.9, 57.0, 71.0, 78.2, 80.1, 169.9, 170.3.

HRMS (ESI): m/z [M + Na]+ calcd for C22H41NNaO4: 406.2933; found: 406.2944. 3,6-Anhydro-1,2-O-isopropylidene-5-O-(4-nitrobenzoyl)-b-Lidofuranose (12) To a soln of 6 (2.0 g, 9.9 mmol) in THF (25 mL) was added Ph3P (9.9 g, 34.65 mmol), 4-nitrobenzoic acid (5.785 g, 34.65 mmol), and DIAD (6.82 mL, 34.65 mmol) under 0 °C. The mixture was brought up to r.t. and stirred overnight. The solvent was removed from the mixture under reduced pressure. The residue was column chromatographed (hexane–EtOAc, 7:1) to give 12 (3.09 g, 89%) as a yellow solid; mp 100–105 °C. [a]D29 +59.0 (c 0.007, CHCl3).

3,6-Anhydro-1,2-O-isopropylidene-5-O-mesyl-b-L-idofuranose (14) A soln of MsCl (0.574 mL, 7.42 mmol) in CH2Cl2 (5 mL) was added to a mixture of 13 (1 g, 4.95 mmol) and Et3N (3.44 mL, 24.75 mmol) in CH2Cl2 (15 mL) at 0 °C. The mixture was brought to r.t. and stirred for 4 h and then extracted with CH2Cl2 and the combined extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by column chromatography (hexane–EtOAc, 5:1) to give 14 (1.18 g, 86%) as a white solid; mp 102–104 °C. [a]D30 +20.7 (c 0.01, CHCl3). IR: 2986, 2935, 1627, 1350, 1169, 1078 cm–1. 1

H NMR (300 MHz, CDCl3): d = 1.31 (s, 3 H), 1.48 (s, 3 H), 3.04 (s, 3 H), 4.03–4.07 (m, 2 H), 4.58 (d, J = 3.6 Hz, 1 H), 4.61 (d, J = 3.2 Hz, 1 H), 4.85 (d, J = 3.2 Hz, 1 H), 5.09 (d, J = 3.0 Hz, 1 H), 5.80 (d, J = 3.4 Hz, 1 H).

MS (LC): m/z = 303 [M + Na]+. 3,6-Anhydro-5-azido-5-deoxy-1,2-O-isopropylidene-a-D-glucofuranose (15) A mixture of 14 (1 g, 3.57 mmol) and NaN3 (2.785 g, 42.85 mmol) in DMF (15 mL) was heated at 120 °C for 2 d. The mixture was poured into H2O and extracted with EtOAc. The combined extracts were washed with sat. brine, dried (Na2SO4), and concentrated in vacuo. The residue was column chromatography (hexane–EtOAc, 24:1) to give 15 (0.51 g, 63%) as a syrup. [a]D29 +32.5 (c 0.02, CHCl3). IR: 2987, 2108, 1378, 1285, 1227, 1073 cm–1. 1 H NMR (200 MHz, CDCl3): d = 1.32 (s, 3 H), 1.48 (s, 3 H), 3.66– 3.74 (m, 2 H), 3.98 (m, 1 H), 4.47 (d, J = 3.6 Hz, 1 H), 4.54 (d, J = 3.6 Hz, 1 H), 4.88 (t, J = 3.6 Hz, 1 H), 5.92 (d, J = 3.0 Hz, 1 H). 13

C NMR (75 MHz, CDCl3): d = 26.6, 27.3, 61.2, 68.6, 83.0, 84.8, 85.9, 107.0, 112.7. MS (LC): m/z = 227 [M]+.

C NMR (75 MHz, CDCl3): d = 26.5, 27.3, 29.6, 72.7, 78.1, 84.0, 85.4, 85.7, 106.5, 112.6, 134.6, 150.8, 163.5.

(2R,3R,4R)-4-Azido-2-[(Z)-tetradec-1-enyl]tetrahydrofuran-3ol (18) To 15 (0.4 g, 1.76 mmol) was added 60% aq AcOH (10 mL) and concd HCl (catalytic amount) and the mixture was stirred at r.t. for 12 h. The mixture was neutralized with solid NaHCO3 until pH 7, filtered, and washed with EtOAc. The organic layer was dried (Na2SO4), concentrated in vacuo, and purified by column chromatography (silica gel, hexane–EtOAc, 2:1) to give 16 (0.28 g, 85%) as a syrup as a mixture of anomers (~1:1).

MS (ESI): m/z = 352 [M + 1]+.

[a]D31 +107.3 (c 0.01, MeOH).

IR: 3111, 3082, 2995, 2942, 2884, 1752, 1607, 1529, 1285, 1081, 719 cm–1. 1

H NMR (200 MHz, CDCl3): d = 1.33 (s, 3 H), 1.48 (s, 3 H), 3.99 (d, J = 10.2 Hz, 1 H), 4.19 (dd, J = 3.7, 11.0 Hz, 1 H), 4.64 (m, 2 H), 4.87 (d, J = 3.7 Hz, 1 H), 5.45 (d, J = 3.7 Hz, 1 H), 5.86 (d, J = 3.7 Hz, 1 H), 8.16–8.34 (m, 4 H). 13

3,6-Anhydro-1,2-O-isopropylidene-b-L-idofuranose (13) A soln of 12 (2.8 g, 7.97 mmol) in THF–H2O (1:1, 30 mL) was added LiOH·H2O (0.67 g, 15.95 mmol) and the mixture was stirred for 1 h. Then it was extracted with EtOAc and the combined extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by column chromatography (hexane– EtOAc, 4:1) to give 13 (1.2 g, 75%) as a white solid; mp 125–130 °C. Synthesis 2010, No. 1, 115–119

© Thieme Stuttgart · New York

To a soln of 16 (0.2 g, 1.06 mmol) in 80% aq MeOH (10 mL) was added NaIO4 (0.46 g, 2.1 mmol); the mixture was stirred for 30 min. Then the solvent was removed under reduced pressure and the residue was extracted with EtOAc and the combined extracts were dried (Na2SO4) and concentrated to afford crude 17. To a precooled (–40 °C) soln of Wittig salt [Me(CH2)12]Ph3P+Br– (1.065 g, 2.4 mmol) in THF (25 mL) was slowly added t-BuOK (0.27 g, 2.43 mmol) under N2. The orange soln was stirred at this temperature for 1 h and then it was then cannulated to a soln of 17

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HRMS (ESI): m/z [M + H] calcd for C18H38NO2: 300.2902; found: 300.2894.

Studies of Stereoisomers of Pachastrissamine (Jaspine B)

(0.15 g, 0.81 mmol) in anhyd THF (5 mL) at –40 °C under N2 and stirred at this temperature for 1 h, allowed to warm to 25 °C, and quenched with sat. NH4Cl. The mixture was diluted with H2O and extracted with EtOAc. The combined organic extracts were dried (anhyd Na2SO4) and concentrated to dryness. Purification of the residue by column chromatography (hexane–EtOAc, 15:1) gave 18 (0.13 mg, 51%) as a syrup. [a]D23 +7.6 (c 0.001, CHCl3). IR: 3402, 3350, 2919, 2852, 2102, 1720, 1465, 1259, 1042 cm–1. 1

H NMR (300 MHz, CDCl3): d = 0.88 (t, J = 6.8 Hz, 3 H), 1.19–1.42 (m, 20 H), 1.99–2.13 (m, 2 H), 3.85–4.05 (m, 3 H), 4.26 (m, 1 H), 4.65 (m, 1 H), 5.45 (m, 1 H), 5.7 (m, 1 H). 13 C NMR (75 MHz, CDCl3): d = 14.0, 22.6, 28.9, 29.1, 29.3, 29.4, 29.6, 31.8, 32.7, 67.3, 70.2, 76.4, 81.5, 122.8, 137.2.

(2R,3R,4R)-4-Amino-2-tetradecyltetrahydrofuran-3-ol Trifluoroacetic Acid Salt (4) A mixture of 18 (50 mg, 0.15 mmol) and Pd/C (10%, 15 mg) in MeOH (15 mL, containing 1% TFA) was hydrogenated for 5 h. The Pd/C catalyst was filtered off and the filtrate was concentrated. The residue was purified by column chromatography (EtOAc–MeOH, 4:1) to furnish target 4 (42 mg, 92%); mp 121 °C. [a]D28 –15.5 (c 0.008, MeOH). IR: 3421, 2922, 2851, 1669, 1207, 1147 cm–1. 1 H NMR (300 MHz, CD3OD): d = 0.90 (t, J = 6.37 Hz, 3 H), 1.20– 1.50 (m, 24 H), 1.57–1.74 (m, 2 H), 3.72 (dt, J = 3.82, 7.64 Hz, 1 H), 3.80 (dd, J = 5.1, 8.91 Hz, 1 H), 3.83–3.96 (m, 2 H), 4.25 (dd, J = 3.8, 5.1 Hz, 1 H). 13 C NMR (75 MHz, CD3OD): d = 15.25, 24.55, 28.04, 30.55, 31.29, 31.60, 33.90, 55.24, 69.81, 71.76, 85.22.

HRMS (ESI): m/z [M + H]+ calcd for C18H38NO2: 300.2902; found: 300.2894.

Acknowledgment Authors thank the late Dr. A. K. Singh as well as Dr. J. S. Yadav, Dr. T. K. Chakraborty, and Dr. A. C. Kunwar for their support and encouragement. We also thank DST(SR/S1/OC-14/2007), New Delhi for financial support.

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