Total synthesis of (-)-aplaminal

Article abstract of DOI:10.1021/ol801794f

(Chemical Equation Presented) The total synthesis and assignment of absolute configuration of (-)-aplaminal (1), a cytotoxic metabolite from a sea hare possessing a triazobicyclo[3.2.1]octane skeleton, has been achieved. The synthesis entailed condensatio

Full text of DOI:10.1021/ol801794f

Total Synthesis of (–)-Aplaminal
Amos B. Smith, III and Zhuqing Liu
Department of Chemistry, Monell Chemical Senses Center, and Laboratory for Research on the Structure of Matter, University of
Pennsylvania, Philadelphia, Pennsylvania 19104, U.S.A.
Supporting Information

Materials and Methods: All solvents were reagent grade. Dichloromethane, tetrahydrofuran (THF), and
toluene were filtered through activated alumina and copper purification system (Pure Solv. PS-400), while all
reagents were purchased from Aldrich or Acros and used as received unless otherwise mentioned. Reactions
were magnetically stirred under an argon atmosphere and monitored by thin layer chromatography (TLC)
with 0.25 mm E. Merck pre-coated silica gel plates. Flash chromatography was performed with silica gel 60
(particle size 0.040 - 0.062 mm) supplied by Silicycle and Sorbent Technologies. Yields refer to
chromatographically and spectroscopically pure compounds, unless otherwise stated. Infrared spectra were
recorded on a Jasco Model FT/IR-480 Plus spectrometer. NMR spectra were recorded on a Bruker AMX-500
spectrometer. Chemical shifts are reported relative to either chloroform (δ 7.26), methanol (δ 3.31) or
1
13
acetone (δ 2.05) for H NMR and either chloroform (δ 77.23), or methanol (49.15) for C NMR. Optical
rotations were measured on a Perkin-Elmer model 241 polarimeter. High resolution mass spectra were
measured at the University of Pennsylvania Mass Spectrometry Service Center.
Experimental Section.
O
BocHN
OMe
OBn
(-)-5
N-Boc-Serine methyl ester (–)-5. To a solution of amino acid (-)-SI 1 (2.95 g, 10 mmol) in CH2Cl2/MeOH
(35 mL, 7/1) was added trimethylsilyldiazomethane (5.05 mL, 2.0 M in diethyl ether, 10.1 mmol) and the
resultant solution was stirred for 0.5 h at room temperature. The mixtue was concentrated after the flask was
open to air for 5 min and the residue was purified by flash chromatography (5:1 to 1:1 = hex: EtOAc) to give
methyl ester (–)-5 (3.06 g, 99%). [α]D20 -15.0 (c 1.0, CHCl3); IR (thin film, CH2Cl2) 3362 (br, w), 2977 (w),
1752 (s), 1715 (s), 1693 (s), 1499 (m), 1365 (m), 1165 (s) cm-1; 1H NMR (500 MHz, CDCl3) δ 7.34-7.31 (m,
2H), 7.29-7.25 (m, 3H), 5.39 (d, J = 8.1 Hz, 1H), 4.50 (ABq, J = 12.2 Hz, ∆ν = 28.4 Hz, 2H), 4.44-4.42 (m,
1H), 3.86 (dd, J = 9.4, 3.1 Hz, 1H), 3.73 (s, 3H), 3.67 (dd, J = 9.4, 3.2 Hz, 1H), 1.44 (s, 9H); 13C NMR (125
MHz, CDCl3) δ 171.3, 155.6, 137.7, 128.5, 127.9, 127.7, 80.1, 73.3, 70.1, 54.1, 52.5, 28.4; high resolution
mass spectrum (ES+) m/z 332.1469 [(M+Na)+; calcd for C16H23NNaO5: 332.1474].
CO2Me
BocHN
N
H
OBn
(-)-3
Diamine (–)-3. To a solution of methyl ester (–)-5 (1.0 g, 3.24 mmol) in toluene (30 mL) was added DIBAL-
H (6.5 mL, 1.0 M in hexanes, 6.5 mmol) slowly at -78 °C, maintaining an internal temperature below -70 °C.
The mixture was stirred for additional 2 h at -78 °C before it was quenched by slowly adding MeOH (5 mL).
2

Then saturated Rochelle salt solution (30 mL) was added and the reaction was allowed to warm to room
temperature. The mixture was stirred vigorously until the two layers were cleanly separated. The organic
layer was separated and the aqueous layer was extracted with diethyl ether (2X 50 mL). The combined
organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated and the residue dried on the
vacuum. The crude aldehyde was taken forward without further purification. To a solution of the above
aldehyde in MeOH (15 mL) was added methyl 4-aminobenzoate (489 mg, 3.24 mmol) and a few drops of
acetic acid. The resultant mixture was stirred at room temperature for 24 h before the addition of NaCNBH3
(529 mg, 8.4 mmol). After 6 h, water (10 mL) was added and the aqueous layer was extracted with diethyl
ether (3X 30 mL). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was
concentrated and the residue was purified by flash chromatography (6:1 to 3:1 = hex: EtOAc) to provide
20
diamine (–)-3 (965 mg, 72% over two steps). [α]D –10.6 (c 0.2, CHCl3); IR (thin film, CH2Cl2) 3364 (br,
w), 1698 (s), 1605 (s), 1280 (s), 1175 (s) cm-1; 1H NMR (500 MHz, CDCl3) δ 7.84 (d, J = 8.8 Hz, 2H), 7.36-
7.28 (m, 5H), 6.53 (d, J = 8.8 Hz, 2H), 5.29 (br s, 1H), 4.90 (br s, 1H), 4.48 (ABq, J = 11.9 Hz, ∆ν = 20.4 Hz,
13
2H), 3.99 (br s, 1H), 3.81 (s, 3H), 3.59-3.53 (m, 2H), 3.32 (br s, 2H), 1.44 (s, 9H); C NMR (125 MHz,
CDCl3) δ 167.3, 156.0, 152.1, 137.7, 131.5, 128.4, 127.9, 127.7, 117.9, 111.2, 79.6, 73.2, 69.8, 51.4, 49.6,
45.2, 28.3; high resolution mass spectrum (ES+) m/z 415.2225 [(M+H)+; calcd for C23H31N2O5: 415.2233].
O
O
MeO
OMe
Ph
SI 2
Dimethyl 2-benzylidenemalonate SI 2. To a solution of benzaldehyde (6.6 mL, 60 mmol) in DMSO (20 mL)
was added proline (690 mg, 6.0 mmol) and the mixture was stirred for 5 min before the addition of dimethyl
manolate (13.7 mL, 120 mmol). After stirring at room temperature for 24 h, the reaction was diluted with
EtOAc (60 mL) and washed with water (2X 60 mL). The combined organic layer was dried over Na2SO4 and
the solvent was removed under vacuum. The residue was purified by column to give dimethyl 2-
benzylidenemalonate (12.9 g, 98%) as viscous oil, which is solidified standing in the refrigerator. Mp. 27-28
1
ºC. IR (thin film, CH2Cl2) 3002 (w), 2998 (m), 1731 (s), 1628 (m), 1436 (s), 1265 (s), 1221 (s) cm-1; H
NMR (500 MHz, CDCl3) δ 7.77 (s, 1H), 7.74-7.34 (m, 5H), 3.84 (s, 3H), 3.84 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ 167.3, 164.7, 143.1, 132.9, 130.9, 129.6, 129.1, 125.7, 52.9s; high resolution mass spectrum (ES+)
m/z 243.0667 [(M+H)+; calcd for C12H12O4: 243.0736].
O
MeO
OMe
O
O
4
Dimethyl 2-oxomalonate 4. To a solution of dimethyl 2-benzylidenemalonate (4.0 g, 4.54 mmol) in CH2Cl2
(15 mL) was bubbled ozone at -78 °C until a dark blue solution was obtained. Excess ozone was removed by
purging with argon for 10 min. Dimethyl sulfide (2 mL) was added to the mixture and the reaction was
3

warmed up slowly to room temperature. Then air was bubbled overnight and the mixture was concentrated
and distilled (90-100 °C at 20 mm pressure) as a yellow liquid. The yellow liquid was then passed through a
silica plug and eluted with diethyl ether. The solvent was removed and the residue was dehydrated by
azeotropic removal of water by heating for 12 h in a Soxhlet apparatus equipped with a thimble filled with
layers of basic alumina and phosphorous pentoxide. The solvent was finally removed and the residue was
distilled under vacuum to give dimethyl 2-oxomalonate 4 (1.67 g, 67%). 1H NMR (500 MHz, CDCl3) δ 3.95
(s, 6H); 13C NMR (125 MHz, CDCl3) δ 177.5, 160.5, 53.9.
CO2Me
N
OBn
HN
CO2Me
MeO2C
(+)-6
Imidazolidine (–)-6. To a solution of diamine (–)-3 (300 mg, 0.72 mmol) in CH2Cl2 (5 mL) was added TFA
(1 mL, 13.4 mmol). The mixture was stirred at room temperature for 6 h and concentrated. The residue was
dried over vacuum and the resulting amine was used directly in the next step. To the amine solution in
CH2Cl2 (4 mL) was added MgSO4 (300 mg) followed by the addition of dimethyl 2-oxomalonate 4 (118 mg,
0.72 mmol). The mixture was stirred at room temperature for 48 h and then concentrated. The residue was
purified by flash chromatography (5:1 = toluene: EtOAc) to afford imidiazolidine (+)-6 (224 mg, 70%) as a
20
white solid. Mp. 94-95 ºC; [α]D +35 (c 0.37, CHCl3); IR (thin film, CH2Cl2) 3335 (br, w), 2951 (w), 1739
(s), 1709 (s), 1606 (s), 1283 (s), 1190 (s) cm-1; 1H NMR (500 MHz, CDCl3) δ 7.88 (d, J = 8.9 Hz, 2H ), 7.36-
7.30 (m, 5H), 6.72 (d, J = 8.9 Hz, 2H), 4.57 (s, 2H), 3.85 (s, 3H), 3.81-3.74 (m, 1H), 3.79 (s, 3H), 3.73 (s,
3H), 3.67 (t, J = 7.8 Hz, 1H), 3.63 (dd, J = 9.5, 4.6 Hz, 1H), 3.58 (dd, J = 9.5, 5.3 Hz, 1H), 3.49 (t, J = 7.9
Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 169.9, 169.2, 167.3, 148.2, 137.9, 130.8, 128.7, 128.0, 127.9, 113.8,
83.0, 73.7, 70.3, 55.7, 53.5, 52.0, 51.8; high resolution mass spectrum (ES+) m/z 465.1628 [(M+Na)+; calcd
for C23H26N2NaO7: 465.1638]
CO2Me
NH
OH
HN
CO2Me
MeO2C
(-)-7
Amine (–)-7. To a solution of imidazolidine (+)-6 (5.0 mg, 0.011 mmol) in EtOAc (1 mL) was Pd(OH)2/C (2
mg) under H2 atmosphere (1 atm). The mixture was stirred at room temperature overnight and concentrated.
4

The residue was purified by flash chromatography (1:1 to 1:3 = hex: EtOAc) to afford amine (–)-7 (3.0 mg,
75%). [α]D20 -11.2 (c 0.2, CHCl3); IR (thin film, CH2Cl2) 3371 (br, w), 2922 (w), 1737 (m), 1710 (m), 1605
(s), 1281 (s), 1176 (s) cm-1; 1H NMR (500 MHz, CDCl3) δ 7.86 (d, J = 8.8 Hz, 2H ), 6.58 (d, J = 8.8 Hz, 2H ),
4.93 (br s, 1H), 4,20 (s, 1H), 3.85 (s, 3H), 3.80 (s, 3H), 3.77 (s, 3H), 3.68 (dd, J = 11.5, 1.0 Hz, 1H), 3.57 (dd,
J = 11.4, 4.5 Hz, 1H), 3.31-3.21 (m, 2H), 1.15 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ 169.7, 169.4, 167.5,
152.0, 131.7, 118.8, 111.9, 62.9, 62.8, 57.2, 53.4, 53.4, 51.8, 44.6; high resolution mass spectrum (ES+) m/z
355.1518[(M+H)+; calcd for C16H23N2O7: 355.1505].
O
BocHN
OMe
OTBDPS
(-)-9
N-Boc-(D)-Serine methyl ester tert-butyldiphenylsilyl ether (–)-9. To a solution of amino acid (–)-8 (1.5 g,
7.3 mmol) in CH2Cl2/MeOH (28 mL, 7/1) was added trimethylsilyldiazomethane (3.7 mL, 2.0 M in diethyl
ether, 7.4 mmol) and the resulting solution was stirred for 0.5 h at room temperature. The mixture was
concentrated and the resultant methyl ester was used for the next step without further purification. To a
solution of above methyl ester (1.6 g, 7.3 mmol) in DMF (12 mL) was added TBDPSCl (2.84 mL, 10.9
mmol) and imidazole (0.99 g, 14.6 mmol). The mixture was stirred at room temperature for 6 h before the
addition of saturated NH4Cl solution (30 mL). The mixture was extracted with diethyl ether (3 X 60 mL) and
the combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by flash
chromatography (30:1 to 10: 1 = hex: EtOAc) to provide tert-butyldiphenylsilyl ether (–)-9 (3.16 g, 95%
20
over two steps) as viscous oil. [α]D –14.3 (c 2.38, CHCl3); IR (thin film, CH2Cl2) 3448 (br, w), 2954 (m),
2932 (m), 1751 (m), 1718 (s), 1498 (m), 1166 (s), 1113 (s) cm-1; 1H NMR (500 MHz, CDCl3) δ 7.62-7.60 (m,
4H), 7.45-7.42 (m, 2H), 7.40-7.37 (m, 4H), 5.42 (d, J = 8.6 Hz, 1H), 4.41 (dd, J = 5.9, 2.9 Hz, 1H), 4.07 (dd,
J = 10.2, 2.8 Hz, 1H), 3.90 (dd, J = 10.1, 3.0 Hz, 1H), 3.75 (s, 3H), 1.47 (s, 9H), 1.04 (s, 9H); 13C NMR (125
MHz, CDCl3) δ 171.4, 155.6, 135.7, 135.7, 135.0, 133.2, 133.0, 130.1, 130.0, 130.0, 127.9, 80.1, 64.8, 55.7,
52.5, 28.5, 26.9, 26.8, 19.5; high resolution mass spectrum (ES+) m/z 480.2170 [(M+Na)+; calcd for
C25H35NNaO3Si+: 480.2182].
CO2Me
BocHN
N
H
OTBDPS
(-)-10
Diamine (–)-10. To a -78 ºC solution of methyl ester (–)-9 (2.0 g, 4.4 mmol) in toluene (50 mL) was slowly
added DIBAL-H (9.0 mL, 1.0 M in hexanes, 9.0 mmol), maintaining an internal temperature lower than -70
°C. The mixture was stirred for another 2 h at -78 °C after the completion of the addition before it was
quenched by slowly adding MeOH (10 mL). Then saturated Rochelle salt solution (50 mL) was added and
5

the reaction was allowed to warm to room temperature. The mixture was stirred vigorously until the two
layers were cleanly separated. The organic layer was separated and the aqueous layer was extracted with
diethyl ether (2X 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated.
The residue was dried on the vacuum and was used for the next step without further purification. To the
solution of the resulting aldehyde in MeOH (30 mL) was added methyl 4-aminobenzoate (660 mg, 4.4 mmol)
and a few drops of acetic acid. The resulting solution was stirred at room temperature for 24 h before the
addition of NaCNBH3 (892 mg, 13.1 mmol). After 6 h water (10 mL) was added and the mixture was
extracted with diethyl ether (3X 60 mL). The combined organic layer was dried over Na2SO4 and filtered.
The filtrate was concentrated and the residue was purified by flash chromatography (8:1 to 3:1 = hex: EtOAc)
20
to provide diamine (–)-10 (1.85 g, 75%) as a white solid. Mp. 49-50 ºC; [α]D –23 (c 0.9, CHCl3); IR (thin
1
film, CH2Cl2) 3370 (br, w), 2931 (w), 1706 (s), 1606 (s), 1280 (s), 1175 (s), 1113(s) cm-1; H NMR (500
MHz, CDCl3) δ 7.82 (d, J = 8.3 Hz, 2H), 7.67 (d, J = 7.1 Hz, 2H), 7.63 (d, J = 6.9 Hz, 2H), 7.51-7.39 (m,
6H), 6.45 (d, J = 8.1 Hz, 2H), 4.98 (d, J = 8.1 Hz, 1H), 4.37 (br s, 1H), 3.88 (br s, 1H), 3.84 (s, 3H), 3.80 (br
13
s, 2H), 3.28-3.23 (m, 2H), 1.46 (s, 9H), 1.15 (s, 9H); C NMR (125 MHz, CDCl3) δ 167.5, 156.2, 152.0,
135.8, 135.7, 133.0, 132.9, 131.7, 130.3, 130.2, 128.2, 128.1, 118.4, 111.4, 80.0, 64.0, 51.7, 50.9, 45.4, 28.5,
27.2, 19.5; high resolution mass spectrum (ES+) m/z 563.2924 [(M+H)+; calcd for C32H43N2O7Si: 563.2941].
CO2Me
N
OTBDPS
HN
CO2Me
MeO2C
(+)-11
Imidazolidine(+)-11. To a solution of diamine (–)-10 (400 mg, 0.71 mmol) in CH2Cl2 (8 mL) was added
TFA (2 mL mL, 26.8 mmol). The solution was stirred at room temperature for 6 h, and azeotropied with
toluene (3X 3 mL). The residue was dissolve in CH2Cl2 (5 mL) and Na2SO4 (400 mg) was added followed
by the addition dimethyl 2-oxamonate 4 (116 mg, 0.71 mmol). The mixture was stirred for 48 h and then
concentrated. The residue was purified by flash chromatography (6:1 to 3:1 = hex: EtOAc) to afford
imidazolidine (+)-11 (280 mg, 66%) as a white solid along with recovered dimethyl 2-oxamonate and amine.
Fractions containing of dimethyl 2-oxamonate and amine were concentrated and the procedure repeated to
give additional portion of imidazolidine (+)-11 (55 mg, 14%, total yield 80%). Mp. 138-139 ºC; [α]D20 +19.8
(c 0.71, CHCl3); (thin film, CH2Cl2) 3334 (br, w), 2952 (m), 1740 (s), 1711 (s), 1607 (s), 1283 (s), 1190 (s),
1113 (s) cm-1; 1H NMR (500 MHz, CDCl3) δ 7.89 (d, J = 8.9 Hz, 2H), 7.67-7.65 (m, 4H), 7.47-7.43 (m, 2H),
7.42-7.38 (m, 4H), 6.71 (d, J = 8.9 Hz, 2H), 3.90-3.86 (partially observed, m, 1H), 3.86 (s, 3H), 3.81 (s, 3H),
3.77 (dd, J = 10.5, 4.3 Hz, 1H), 3.73 (s, 3H), 3.66-3.62 (m, 1H), 3.59 (t, J = 7.2 Hz, 1H), 3.51 (t, J = 7.8 Hz,
13
1H), 1.08 (s, 9H); C NMR (125 MHz, CDCl3) δ 170.0, 169.0, 167.4, 148.3, 135.8, 135.8, 133.1, 133.0,
6

130.9, 130.2, 128.0, 119.8, 113.8, 83.2, 63.1, 57.4, 53.5, 51.9, 51.4, 27.0, 19.5; high resolution mass
spectrum (ES+) m/z 591.2507 [(M+H)+; calcd for C32H39N2O7Si: 591.2527].
CO2Me
N
OH
HN
CO2Me
MeO2C
(+)-2
Alcohol (+)-2. To a solution of imidazolidine (+)-11 (400 mg, 0.578 mmol) in THF (12 mL) was added
TBAF-HOAc (1 M in THF, 0.8l mL, 0.81 mmol). The resulting mixture was stirred at room temperature for
2 h and then concentrated. The residue was purified by flash chromatography (1:1 to 1:3 = hex: EtOAc) to
20
give alcohol (+)-2 (202 mg, 85%) as a colorless oil. [α]D +103.1 (c 0.64, CHCl3); IR (thin film, CH2Cl2)
1
3366 (br, w), 2952 (w), 1738 (s), 1707 (s), 1606 (s), 1520 (m), 1435 (m), 1284 (s),1191 (m) cm-1; H NMR
(500 MHz, CDCl3) δ 7.86 (d, J = 9.0 Hz, 2H), 6.71 (d, J = 9.0 Hz, 2H), 3.83 (s, 3H), 3.78 (s, 3H), 3.76-3.71
13
(partially observed, m, 2H), 3.72 (s, 3H), 3.68-3.62 (m, 2H), 3.52 (t, J = 7.0 Hz, 1H), 2.79 (br s, 1H); C
NMR (125 MHz, CDCl3) δ 169.9, 169.7, 167.4, 148.1, 130.8, 119.9, 113.8, 82.9, 63.3, 56.9, 53.5, 53.5, 51.8,
+
51.0; high resolution mass spectrum (ES+) m/z 353.1346 [(M+H)+; calcd for C16H21N2O7 : 353.1349].
CO2Me
N
N3
HN
CO2Me
(+)-12
MeO2C
Azide (+)-12. To a solution alcohol (+)-2 (120 mg, 0.34 mmol) in THF (10 mL) at 0 ºC was added PPh3 (267
mg, 1.022 mmol) and diisopropyl azodicarboxylate (0.20 mL, 1.022 mmol). After stirring for 5 min,
diphenylphosphoryl azide (0.22 mL, 1.022 mmol) was added. The mixture was slowly warmed up to room
temperature and stirred over for 12 h. The volatile solvent was removed and the residue was purified by flash
chromatography (8:1 to 2:1 = hex: EtOAc) to give azide (+)-12 (90 mg, 70%) as a viscous oil. [α]D20 +105.0
(c 0.48, CHCl3); IR (thin film, CH2Cl2) 3366 (br, w), 2953 (w), 2104 (s), 1739 (s), 1709 (s), 1606 (s), 1284 (s)
cm-1; 1H NMR (500 MHz, CDCl3) δ 7.89 (d, J = 9.0 Hz, 2H), 6.74 (d, J = 9.0 Hz, 2H), 3.86 (s, 3H), 3.80 (s,
3H), 3.78-3.75 (partially observed, m, 1H), 3.76 (s, 3H), 3.72 (dd, J = 8.2, 6.7 Hz, 1H), 3.67 (d, J = 6.3 Hz,
13
1H), 3.49 (d, J = 5.7 Hz, 1H), 3.46 (dd, J = 8.2, 6.9 Hz, 1H); C NMR (125 MHz, CDCl3) δ 169.7, 169.3,
167.2, 147.9, 130.8, 120.3, 114.0, 82.6, 55.3, 53.5, 53.5, 53.3, 52.3, 51.8; high resolution mass spectrum
+
(ES+) m/z 378.1420 [(M+H)+; calcd for C16H20N5O6 : 378.1414].
CO2Me
N
N3
MeN
CO2Me
(+)-13
MeO2C
7

Azide (+)-13. To a solution of azide (+)-12 (70 mg, 0.186 mmol) in CH2Cl2 (5.0 mL) was added K2CO3 (363
mg, 3.71 mmol) and MeOTf (0.12 mL, 1.10 mmol). The mixture was stirred at room temperature for 24 h
before the addition of water (5.0 mL). The aqueous layer was extracted with CH2Cl2 (3X 5.0 mL) and the
combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by flash
chromatography (6:1 to 3:1 = hex: EtOAc) to give azide (+)-13 (69 mg, 96%) as a viscous oil. [α]D20 +123.2
1
(c 0.46, CHCl3); IR (thin film, CH2Cl2) 2952 (w), 2102 (s), 1752 (s), 1709 (s), 1607 (s), 1283 (s) cm-1; H
NMR (500 MHz, CDCl3) δ 7.87 (d, J = 8.8 Hz, 2H), 6.57 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H), 3.80 (t, J = 7.6 Hz,
1H), 3.75 (s, 3H), 3.72 (s, 3H), 3.65 (t, J = 7.8 Hz, 1H), 3.59-3.56 (m, 1H), 3.53 (d, J = 5.2 Hz, 1H), 3.30 (dd,
J = 12.4, 2.7 Hz, 1H), 2.58 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 168.1, 167.3, 167.3, 147.5, 131.1, 119.8,
112.7, 84.5, 61.5, 53.1, 52.6, 51.9, 51.1, 50.8, 34.0; high resolution mass spectrum (ES+) m/z 392.1576
+
[(M+H)+; calcd for C17H22N5O6 : 392.1570].
CO2Me
N
NH2
MeN
CO2Me
(+)-14
MeO2C
Amine (+)-14. To a solution of azide (+)-13 (69 mg, 0.176 mmol) in EtOAc (5 mL) was added Pd(OH)2/C
(10%, 10 mg). The mixture was stirred at room temperature under H2 atmosphere (1 atm) for 3 hr and
filtrated through Celite. The filtrate was concentrated and the residue was purified by flash chromatography
(50: 1 to 20:1= CH2Cl2: MeOH) to give amine (+)-14 (58 mg, 90%) as an oil. [α]D20 +72.0 (c 0.075, CHCl3);
IR (thin film, CH2Cl2) 3389 (br, w), 2952 (w), 1750 (s), 1706 (s), 1606 (s), 1284 (s), 1190 (s) cm-1; 7.87 (d, J
= 8.7 Hz, 2H), 6.57 (d, J = 8.7 Hz, 2H), 3.84 (s, 3H), 3.80-3.77 (partially observed, m, 1H), 3.74 (s, 3H), 3.73
13
(s, 3H), 3.68 (t, J = 8.0 Hz, 1H), 3.44-3.40 (m, 1H), 2.95-2.88 (m, 2H), 2.51 (s, 3H), 2.41 (br s, 2H); C
NMR (125 MHz, CDCl3) δ 168.1, 167.7, 167.3, 147.7, 131.0, 119.5, 112.6, 84.8, 62.8, 53.0, 52.4, 51.8, 50.6,
+
40.8, 33.7; high resolution mass spectrum (ES+) m/z 366.1656 [(M+H)+; calcd for C17H24N3O6 : 366.1665].
CO2Me
N
NH
MeN
MeO2C
O
(-)-1
Aplaminal (-)-1. To a solution of amine (+)-14 (10 mg, 0.030 mmol) in toluene (3.0 mL) was added AlMe3
(1.8 M in hexane, 20 µL, 0.036 mmol). The resulting solution was heated at 100 ºC for 15 h and another
portion of AlMe3 (10 µL, 0.018 mmol) was added. The mixture was continued stirring for additional 6 h and
concentrated. The residue was purified on preparative TLC (20:1 = CH2Cl2: MeOH) to give aplaminal (6.0
20
mg, 66%) as a white solid. Mp. 233-235 ºC (decomposed) [α]D –132.7 (c 0.04, MeOH); IR (thin film,
1
CH2Cl2) 3389 (br, w), 1750 (s), 1684 (s), 1604 (s), 1277 (s), 1190 (s) cm-1; H NMR (500 MHz, CD3OD) δ
8

7.80 (dd, J = 9.1 Hz, 2H), 6.82 (d, J = 9.1 Hz, 2H), 4.24 (ddd, J = 9.2, 5.7, 1.5 Hz, 1H), 3.85 (s, 3H), 3.83 (s,
3H), 3.75 (t, J = 5.0 Hz, 1H), 3.64 (ddd, J = 12.0, 4.4, 1.5 Hz, 1H), 3.34 (d, J = 9.3 Hz, 1H), 3.17 (d, J = 11.3
Hz, 1H), 2.47 (s, 3H); 1H NMR (500 MHz, CD3COCD3) δ 7.77 (dd, J = 9.1 Hz, 2H), 6.86 (d, J = 9.1 Hz, 2H),
6.62 (br s, 1 H), 4.27 (ddd, J = 9.1, 5.7, 1.5 Hz, 1H), 3.86-3.76 (m, 1H), 3.80 (s, 3H), 3.79 (s, 3H), 3.67 (dd, J
= 11.2, 4.5 Hz, 1H), 3.37 (d, J = 9.2 Hz, 1H), 3.24 (ddd, J = 11.1, 11.1, 1.2 Hz, 1H), 2.47 (s, 3H); 13C NMR
(125 MHz, CD3OD) δ 169.1, 167.1, 167.0, 150.8, 131.3, 120.4, 116.4, 86.7, 59.1, 54.0, 53.4, 52.3, 47.6, 38.1;
+
high resolution mass spectrum (ES+) m/z 356.1205 [(M+Na)+; calcd for C16H19N3NaO5 : 356.1222].
Comparison of the 1H NMR spectra of the natural and synthesized (-)-Aplaminal
1H in d6-acetone
natural
Smith
∆δ (ppm)
0.01
0.01
0
10, 12
9,13
1N-H
4
5
5’
OMe
3
7.76 (d, J = 9.1 Hz, 2H)
6.85 (d, J = 9.1 Hz, 2H)
6.62 (br, s 1H)
7.77 (d, J = 9.1 Hz, 2H)
6.86 (d, J = 9.1 Hz, 2H)
6.62 (br, s 1H)
4.26 (ddd, J = 9.1, 5.7, 1.5 Hz, 1H) 4.27 (ddd, J = 9.1, 5.7, 1.5 Hz, 1H)
0.01
0.01
0.01
0.01
0.01
3.85-3.75 (m, 1H)
3.66 (m, 1H)
3.79 (s, 3H), 3.78 (s, 3H)
3.36 (d, J = 9.2 Hz, 1H)
3.23 (ddd, J = 11.1, 11.1, 1.2 Hz,
1H)
3.86-3.76 (m, 1H)
3.67 (dd, J = 11.2, 4.5 Hz, 1H)
3.80 (s, 3H), 3.79 (s, 3H)
3.37 (d, J = 9.2 Hz, 1H)
3.24 (ddd, J = 11.1, 11.1, 1.2 Hz,
1H)
3’
0.01
0.01
N-Me
2.46 (s, 3H)
2.47 (s, 3H)
Comparison of the 13C NMR spectra of the natural and synthesized (-)-Aplaminal
13C in CD3OD
natural
168.95
166.90
166.81
150.69
131.12
120.24
116.20
86.52
58.97
53.84
53.33
52.14
Smith
169.12
167.07
166.97
150.84
131.27
120.42
116.35
86.68
59.13
54.01
53.46
52.28
∆δ (ppm)
14
2
6
0.17
0.17
0.17
0.15
0.15
0.18
0.15
0.16
0.16
0.17
0.13
0.14
0.15
0.13
8
10,12
11
1,9
1
4
5
7
15
3
47.40
38.96
47.55
39.09
16
9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30