First synthesis of Trans- and Cis-dendrochrysanines

Article abstract of DOI:10.3987/COM-06-10885

Trans- and cis-dendrochrysanines (1 and 2), isolated from t he stems of Dendrobium chrysanthum Wall., were first synthesized from l-proline. The absolute configuration of 1 and 2 was established to be S by the syntheses.{A figure is presented}. Dendrochry

Full text of DOI:10.3987/COM-06-10885

HETEROCYCLES, Vol. 68, No. 12, 2006
2579
HETEROCYCLES, Vol. 68, No. 12, 2006, pp. 2579 - 2585. © The Japan Institute of Heterocyclic Chemistry
Received, 12th September, 2006, Accepted, 23rd October, 2006, Published online, 27th October, 2006. COM-06-10885
FIRST SYNTHESIS OF TRANS- AND CIS-DENDROCHRYSANINES
Hiroyuki Konno*, Sayako Kusumoto, Sotaro Kanai, Yasuyuki Yamahana,
Kazuto Nosaka, and Kenichi Akaji
Department of Chemistry, Graduate School of Medical Science, Kyoto
Prefectural University of Medicine, Kita-ku, Kyoto 603-8334, Japan.
konno@koto.kpu-m.ac.jp
Abstract – Trans- and cis-dendrochrysanines (1 and 2), isolated from the stems
of Dendrobium chrysanthum Wall., were first synthesized from L-proline. The
absolute configuration of 1 and 2 was established to be S by the syntheses.
INTRODUCTION
Trans- and cis-dendrochrysanines (1 and 2)1 were isolated from the stems of Dendrobium chrysanthum
Wall.2 by Z. Wang and co-workers in 2005 and used in traditional Chinese medicine. These structures
were
identified
as
the
N-trans-cinnamoyl-2-oxopropyrrolidine
(1)
and
the
N-cis-cinnamoyl-2-oxopropyrrolidine (2), based on extensive 2D-NMR (1H-1H COSY, HMQC, and
HMBC) experiments. The absolute configuration of 1 and 2, however, has been estimated by comparing
their optical rotations and CD curve with those of known related compounds, N-cis-cinnamoly-L-proline
and N-cis-cinnamoyl-L-2-methyl pyrrolidine.3 In the course of studying cysteine protease inhibitors,4,5 we
have interested in these natural products, since their ꢀ,ꢁ-unsaturated carbonyl structure is known to be a
typical functional group for the thiol group of cysteine proteases. Here, we describe the first synthesis of
trans- and cis-dendrochrysanines (1 and 2) as well as the determination of their absolute configurations,
prior to medicinal studies of those natural products.
O
O
Me
N
Me
N
O
O
2
1
Figure Structure of trans-dendrochrysanine (1) and cis-dendrochrysanine (2)
ꢀ ꢀ ꢀ ꢀ ꢀ ꢀ ꢀ ꢀ ꢀ ꢀ ꢀ ꢀ ꢀ ꢀ ꢀ ꢀ ꢀ ꢀ ꢀ ꢀ ꢀ

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HETEROCYCLES, Vol. 68, No. 12, 2006
RESULTS AND DISCUSSION
Trans-dendrochrysanine (1) was synthesized according to the route shown in Scheme 1. Z-L-Proline
(Z-L-Pro-OH) was first transformed into Z-prolinal (3) through protection of the carboxyl group with
iodomethane, and aldehyde transformation via the alcohol in a overall yield of 30%.6 The optical purities
of 3 and the intermediate alcohol were determined to be >98%ee by HPLC using chiral column. A
subsequence Wittig reaction with (methoxymethyl)triphenylphosphonium chloride and potassium
tert-butoxide in THF gave a one-carbon extended methoxy olefin product, which was then treated with
1N HCl in THF to give the desired aldehyde (4) in 63% yield. Enantiomeric excess of aldehyde (4) was
determined to be 98%ee by HPLC using chiral column. A Grignard reaction of aldehyde (4) with
methylmagnesium iodide in ether afforded two diastereomeric alcohols (5) as a 1:1.5 mixture in 79%
yield. Deprotection of the Z group in the presence of 5% palladium on carbon in a hydrogen atmosphere
gave the pyrrolidine (6), which was coupled with trans-cinnamic acid (7) by a reaction with
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate
(HATU)9/
1-hydroxy-7-azabenzotriazole (HOAt)10/ N, N-diisopropylethylamine in CH2Cl2 to afford 8 as a
diastereoisomeric mixture in 85% yield. Finally, the alcohol (8) was oxidized with Jones’ reagent to give
trans-dendrochrysanine (1), [ꢀ]D20 -11.8° (c 0.15, CHCl3) [lit.; [ꢀ]D20 -19.2° (c 3.4, CHCl3)] in 95% yield.
The 1H- and 13C-NMR spectra of the synthetic 1 were in good agreement with those of natural 1.
Ph3PCH2OMeCl
OH
O
1) MeI, K2CO3
MeMgI, Et2O
tBuOK, THF
DMF
H
OH
Me
N
R
H
N
Z
N
Z
N
Z
2) LiAlH4, Et2O
3) SO3-py., Et3N, DMSO
then
1N HCl-THF
O
79%
O
63%
HCO2NH4
Pd-C, MeOH
R = Z: 5
R = H: 6
Z-L
-Pro-OH
4
3
30%
O
O
OH
Me
Me
OH
N
N
O
7
Jones' reagent
acetone
O
HATU, HOAt
iPr2NEt, CH2Cl2
95%
85%
8
trans-dendrochrysanine (1)
Scheme 1. Synthesis of trans-dendrochrysanine (1)
Similarly, cis-dendrochrysanine (2) was synthesized from pyrrolidine (6) in 2 steps (Scheme 2). The
pyrrolidine (6) was coupled with cis-cinnamic acid11 using HATU/ HOAt/ N, N-diisopropylethylamine in
CH2Cl2 as above. The condensation product, however, was obtained with only 5% yield probably deu to
the formation of stable adduct from the cis-cinnamic acid and HOAt. Desired alcohol (9) was obtained in
75% yield when benzotriazol-1-yl-oxy-tris–pyrrolidino-phosphonium hexafluorophosphate (PyBOP)12
was employed instead of HOAt. Finally, oxidation of 11 with Dess-Martin periodinane13 in CH2Cl2

HETEROCYCLES, Vol. 68, No. 12, 2006
2581
24
20
afforded cis-dendrochrysanine (2), [ꢀ]D -14.5° (c 0.04, CHCl3) [lit.; [ꢀ]D -17.7° (c 3.5, CHCl3)]. The
1H- and 13C-NMR spectra of the synthetic 2 were in good agreement with those of natural 2.
O
OH
Me
OH
Me
N
Dess-Martin
periodinane
OH
Me
N
O
O
O
N
H
PyBOP, iPr2NEt
CH2Cl2
CH2Cl2
73%
6
75%
9
cis-dendrochrysanine (2)
Scheme 2. Synthesis of cis-dendrochrysanine (2)
In conclusion, we have completed the first synthesis of trans- and cis-dendrochrysanines (1 and 2). The
absolute structure of these compounds has been established to be
(2S)-N-trans-cinnamoly-2-oxopropyrrolidine for 1 and (2R)-N-cis-cinnamoly-2-oxopropyrrolidine for 2.
EXPERIMENTAL
General Experimental Procedures. All manipulations were conducted under an inert atmosphere (N2).
All solvents were of reagent grade. THF was distilled from sodium and benzophenone ketyl. CH2Cl2 was
distilled from CaH2. All commercial reagents were of the highest purity available. Analytical TLC was
performed on silica gel (60 F-254, Plates 0.25 mm). Column chromatography was carried out on Wakogel
60 (particle size, 0.063-0.200 mm). 1H-, and 13C-NMR were recorded on a JEOL JNM-EX-400 or Bruker
AVANCEII-300. Chemical shifts are expressed in ppm relative to TMS (0 ppm) or CHCl3 (7.28 ppm for
13
1H and 77.1 ppm for C). IR were obtained on HORIBA FREEXACT-II FT-710 spectrometer. Optical
rotations were recorded on a HORIBA SEPA-200 or SEPA-300 polarimeter at the sodium D line.
Low-resolution mass spectra (LRMS) and High-resolution mass spectra (HRMS) were obtained on either
a JOEL JMS-DX-303 or a JMS-AX-500 (EI or FAB). Optical puries were determined on a Hitachi
LaChrom HPLC instrument equipped with the DAICEL chiral column.
(2S)-N-Benzyloxycarbonyl-prolinal (3): To a solution of Z-L-proline (43.4 g, 174 mmol) in DMF (200
mL) were added K2CO3 (121 g, 1.75 mmol) and MeI (16.2 mL, 260 mmol) at 0°C and the mixture was
stirred for 2 h. To the mixture were added H2O and Et2O. The organic layer was washed with brine, dried
over MgSO4, and evaporated in vacuo. To the residue in THF (300 mL) was added LiAlH4 (13.2 g, 348
mmol) at 0°C and the mixture was stirred for 1 h. H2O (15 mL) and 1N NaOH (30 mL) were added and
filtered. Evaporation of the solvent provided an oil, which was purified with silica gel column
chromatography (hexane:AcOEt = 4:1) to give Z-prolinol (24.2 g, 103 mmol, 59%) as a colorless oil: IR
1
(film) ꢁ = 3410, 3033, 2954, 1684, 1415, 1358, 1105, 769, 698 cm-1; H-NMR (300 MHz, CDCl3) ꢂ =

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HETEROCYCLES, Vol. 68, No. 12, 2006
1.50-2.10 (m, 4H), 3.30-3.70 (m, 4H), 4.01 (brs, 1H), 4.32 (brs, 1H), 5.15 (s, 2H), 7.36 (m, 5H). Optical
purity was determined to be 99%ee by HPLC using CHIRALCEL OD-H column (0.46 cmꢀ ꢁ 25 cm);
elution with 2% i-PrOH in hexane, tR = 8.11 min for S isomer, tR = 9.91 min for R isomer. To a solution of
Z-prolinol (2.45 g, 10.5 mmol) in DMSO (30 mL) were added sulfur trioxide pyridine complex (5.00 g,
31.4 mmol) and Et3N (13.9 mL, 98.8 mmol) and the mixture was stirred for 1 h. To the mixture were
added H2O, and Et2O, and the organic layer was washed with brine, dried over MgSO4, and evaporated in
vacuo. The product was purified with silica gel column chromatography (hexane:AcOEt = 6:1) to give
25
Z-prolinal (3) (1.22 g, 5.25 mmol, 51%) as a colorless oil: [ꢀ]D -211.5° (c 0.10, CHCl3); IR (film) ꢁ =
3033, 2956, 2702, 1732, 1695, 1413, 1357, 1101, 769, 698 cm-1; 1H-NMR (300 MHz, CDCl3) ꢂ = 1.89 (m,
2H), 2.06 (m, 2H), 3.58 (m, 2H), 4.22 (m, 0.5H), 4.33 (m, 0.5H), 5.12 (m, 2H), 7.35 (m, 5H), 9.51 (d,
0.5H, J = 2.4 Hz), 9.62 (d, 0.5H, J = 1.5 Hz); 13C-NMR (75 MHz, CDCl3) ꢂ = 23.9, 24.6, 26.7, 27.9, 46.8,
47.4, 65.0, 65.4, 67.4, 128.1, 128.2, 128.62, 136.6, 200.1; MS: m/z = 234 (MH+, 40%), 154 (70%), 91
(100%). HRMS Calcd. for C13H16NO3: 234.1130. Fonud: 234.1125. Optical purity was determined to be
98%ee by HPLC using CHIRALCEL OJ-H column (0.46 cmꢀ ꢁ 25 cm); elution with 0.5% i-PrOH in
hexane, tR = 22.95 min for S isomer, tR = 28.64 min for R isomer.
(2S)-N-Benzyloxycarbonyl-2-pyrrolidinylethanal
(4):
To
a
solution
of
(methoxymethyl)triphenylphosphonium chloride (2.92 g, 8.50 mmol) and potassium tert-butoxide (960
mg, 8.50 mmol) in THF (20 mL) was added Z-prolinal (1.00 g, 4.29 mmol), and the mixture was stirred
at room temperature for 30 min. To the mixture were added H2O and Et2O, and the organic layer was
washed with brine, and dried over MgSO4, and evaporated in vacuo. The product was stirred in 1N
HCl-THF (1:5 mixture, 10 mL) for 30 min. The mixture was extracted with Et2O, and the organic layer
was washed with brine, dried over MgSO4. The solvent was removed, and the product was purified with
silica gel column chromatography (hexane:AcOEt = 8:1) to give 4 (707 mg, 2.71 mmol, 63%) as a
colorless oil, [ꢀ]D25 +4.9° (c 1.22, CHCl3); IR (film) ꢁ = 3033, 2956, 2727, 1718, 1699, 1415, 1358, 1105,
769, 698 cm-1; 1H-NMR (300 MHz, CDCl3) ꢂ = 1.89 (m, 2H), 2.16 (m, 1H), 2.53 (m, 1H), 2.97 (m, 1H),
13
3.46 (m, 2H), 4.34 (m, 1H), 5.14 (s, 2H), 7.36 (m, 5H), 9.69 (brs, 0.4H), 9.82 (brs, 0.6H); C-NMR (75
MHz, CDCl3) ꢂ = 22.8, 23.6, 31.1, 31.9, 46.3, 46.6, 48.4, 49.1, 52.1, 52.9, 66.6, 127.7, 127.9, 128.0,
128.6, 128.8, 136.7, 154.7, 200.6; MS: m/z = 248 (MH+, 45%), 154 (45%), 91 (100%). HRMS Calcd. for
C14H18NO3: 248.1281. Fonud: 248.1288. Optical purity was determined to be 98%ee by HPLC using
chiral CHIRALCEL AD-H column (0.46 cmꢀ ꢁ 25 cm); elution with 2% i-PrOH in hexane, tR = 21.70
min for S isomer, tR = 26.26 min for R isomer.

HETEROCYCLES, Vol. 68, No. 12, 2006
2583
(2S)-N-Benzyloxycarbonyl-2-hydroxypropyrrolidine (5): To a solution of 4 (271 mg, 1.04 mmol) in
THF (5 mL) was added methylmagnesium iodide (2M in Et2O, 1.50 mL) at -20°C and mixture was stirred
for 20 min. To the mixture were added saturated aq. NH4Cl and Et2O, and the organic layer was washed
with brine, dried over MgSO4, and evaporated in vacuo. The product was purified with silica gel column
chromatography (hexane:AcOEt = 2:1) to give 5 (205 mg, 779 μmol, 75%) as a diastereomeric mixtures.
Low polar 5 as a colorless oil, [ꢀ]D25 -6.4° (c 0.94, CHCl3); IR (film) ꢁ = 3438, 3033, 2966, 1699, 1684,
1356, 1105, 769, 698 cm-1; 1H-NMR (300 MHz, CDCl3) ꢂ = 1.21 (d, 3H, J = 5.7 Hz), 1.48 (m, 1H), 1.72
(m 1H), 1.96 (m, 4H), 3.43 (t, 2H, J = 5.7 Hz), 3.88 (brs, 1H), 4.01 (m, 1H), 5.14 (s, 2H), 7.36 (m, 5H);
13C-NMR (75 MHz, CDCl3) ꢂ = 23.0, 23.8, 24.2, 31.1, 32.0, 45.2, 46.3, 54.6, 56.1, 66.4, 66.9, 127.9,
128.0, 128.5, 136.9, 155.6; MS: m/z = 264 (MH+, 95%), 154 (70%), 91 (100%). HRMS Calcd. for
25
C15H22NO3: 264.1600. Fonud: 264.1598. High polar 5 as a colorless oil, [ꢀ]D -4.2° (c 0.72, CHCl3); IR
(film) ꢁ = 3431, 3032, 2966, 1700, 1684, 1414, 1358, 1109, 769, 698 cm-1; 1H-NMR (300 MHz, CDCl3) ꢂ
= 1.19 (d, 3H, J = 6.0 Hz), 1.47 (m, 2H), 1.63 (brs, 1H), 1.93 (m, 3H), 3.43 (m, 2H), 3.76 (m, 1H), 4.23
13
(m, 1H), 5.16 (s, 2H), 7.38 (m, 5H); C-NMR (75 MHz, CDCl3) ꢂ = 22.7, 23.7, 31.2, 45.6, 46.4, 54.8,
63.8, 67.2, 127.9, 128.1, 128.6, 129.0, 136.8, 157.0; MS: m/z = 264 (MH+, 50%), 154 (100%), 91 (45%).
HRMS Calcd. for C15H22NO3: 264.1600. Fonud: 264.1600.
(2S)-N-trans-Cinnamoyl-2-hydroxypropyrrolidine (8): To a solution of 5 (27 mg, 102 μmol) in MeOH
(5 mL) were added HCO2NH4 (64 mg, 1.0 mmol) and Pd-C (20 mg). The mixture was stirred for 40 min
at 50°C and the solvent was removed in vacuo. The residue was added to H2O, extracted with AcOEt,
dried over MgSO4, and evaporated in vacuo. To the residue in CH2Cl2 (2 mL) were added trans-cinnamic
acid (20 mg, 134 μmol), HATU (58 mg, 204 μmol), HOAt (28 mg, 204 μmol), and iPr2NEt (50 μL, 703
μmol), and the mixture was stirred at room temperature for 10 h. To the mixture were added H2O and
CH2Cl2. The organic layer was washed with brine, dried over MgSO4, and evaporated in vacuo. The
product was purified with silica gel column chromatography (hexane:AcOEt = 1:1) to give 8 (20 mg, 77
μmol, 75%) as a colorless oil, IR (film) ꢁ = 3410, 2966, 1647, 1456, 1435, 1151, 843 cm-1; 1H-NMR (300
MHz, CDCl3) ꢂ = 1.18 (d, 2H, J = 6.1 Hz), 1.26 (d, 1H, J = 6.1 Hz), 1.55-2.10 (m, 6H), 3.62 (m, 2H),
3.80 (m, 1H), 4.40 (m, 1H), 6.72 (d, 1H, J = 15.4 Hz), 7.36 (m, 3H), 7.51 (m, 2H), 7.71 (d, 1H, J = 15.4
Hz); MS: m/z = 260 (MH+, 20%), 282 (M++Na, 100%). HRMS Calcd. for C16H22NO2: 260.1651. Fonud:
260.1653.
(2S)-N-trans-Cinnamoyl-2-oxoxypropyrrolidine (trans-dendrochrysanine; 1): To a solution of 8 (20
mg, 77 μmol) in acetone (2 mL) was added Jones’ reagent at 0°C and the mixture was stirred for 20 min.
To the mixture were added isopropanol and Et2O, and the organic layer was washed with brine, dried over

2584
HETEROCYCLES, Vol. 68, No. 12, 2006
MgSO4, and evaporated in vacuo. The product was purified with silica gel column chromatography
25
(hexane:AcOEt = 1:1) to give 1 (19 mg, 73 μmol, 95%) as a colorless oil, [ꢀ]D -11.8° (c 0.15, CHCl3);
1
IR (film) ꢁ = 2930, 1711, 1649, 1601, 1419, 1149, 980, 766 cm-1; H-NMR (400 MHz, CDCl3) ꢂ = 1.78
(m, 1H), 2.00 (m, 2H), 2.14 (m ,2H), 2.21 (s, 3H), 2.49 (dd, 1H, J = 16.6, 9.5 Hz), 3.28 (dd, 1H, J = 12.0,
7.8 Hz), 3.67 (m 2H), 4.54 (m, 1H), 6.73 (d, 1H, J = 15.6 Hz), 7.39 (m, 3H), 7.54 (m, 2H), 7.70 (d, 1H, J
= 15.4 Hz); 13C-NMR (100 MHz, CDCl3) ꢂ = 23.7, 29.9, 30.0, 46.7, 46.8, 53.6, 118.7, 127.6, 128.5, 129.4,
134.9, 141.7, 164.5; MS: m/z = 131 (100%), 257 (M+, 30%). HRMS Calcd. for C16H19NO2: 257.1416.
Fonud: 257.1414.
(2S)-N-cis-Cinnamoyl-2-hydroxypropyrrolidine (9): To a solution of 6 (15 mg, 116 μmol) in CH2Cl2 (1
mL) were added cis-cinnamic acid (18 mg, 121 μmol), PyBOP (60 mg, 115 μmol), and iPr2NEt (50 μL,
703 μmol). The mixture was stirred at room temperature for 10 h. To the mixture were added H2O and
CH2Cl2, and the organic layer was washed with brine, dried over MgSO4, and evaporated in vacuo. The
product was purified with silica gel column chromatography (hexane:AcOEt = 1:1) to give 11 (23 mg, 87
μmol, 75%) as a colorless oil, [ꢀ]D25 -20.0° (c 0.20, CHCl3); IR (film) ꢁ = 2923, 1712, 1612, 1434, 1371,
1153, 698 cm-1; 1H-NMR (300 MHz, CDCl3) ꢂ = 1.56 (m, 1H), 1.73 (m, 2H), 2.07 (m, 1H), 2.19 (s, 3H),
2.38 (dd, 1H, J = 16.5, 9.6 Hz), 3.12 (td, 1H, J = 10.8, 6.6 Hz), 3.31 (m, 2H), 4.43 (m, 1H), 6.03 (d, 1H, J
= 12.6 Hz), 6.65 (d, 1H, J = 12.6 Hz), 7.30 (m, 3H), 7.40 (m, 2H); 13C-NMR (75 MHz, CDCl3) ꢂ = 24.0,
30.2, 30.7, 46.6, 47.4, 53.3, 124.3, 128.38, 128.44, 128.6, 123.9, 135.7, 162.4, 207.0; MS: m/z = 260
(MH+, 20%), 282 (M++Na, 100%). HRMS Calcd. for C16H22NO2: 260.1651. Fonud: 260.1653.
(2S)-N-cis-Cinnamoyl-2-oxoxypropyrrolidine (cis-dendrochrysanine; 2): To a solution of 9 (11 mg,
42 mmol) in CH2Cl2 (1 mL) was added Dess-Martin periodinane (0.2 M in CH2Cl2, 200 ꢀL) at 0°C and
the mixture was stirred for 20 min at 0°C. To the mixture were added H2O and CH2Cl2, and the organic
layer was washed with brine, dried over MgSO4, and evaporated in vacuo. The product was purified with
silica gel column chromatography (hexane:AcOEt = 1:1) to give 2 (8 mg, 31 mmol, 73%) as a colorless
25
1
oil, [ꢀ]D -14.5° (c 0.04, CHCl3); IR (film) n = 2923, 1712, 1612, 1434, 1371, 1153, 698 cm-1; H-NMR
(300 MHz, CDCl3) d = 1.56 (m, 1H), 1.73 (m, 2H), 2.07 (m, 1H), 2.19 (s, 3H), 2.38 (dd, 1H, J = 16.5, 9.6
Hz), 3.12 (td, 1H, J = 10.8, 6.6 Hz), 3.31 (m, 2H), 4.43 (m, 1H), 6.03 (d, 1H, J = 12.6 Hz), 6.65 (d, 1H, J
= 12.6 Hz), 7.30 (m, 3H), 7.40 (m, 2H); 13C-NMR (75 MHz, CDCl3) d = 24.0, 30.2, 30.7, 46.6, 47.4, 53.3,
124.3, 128.38, 128.44, 128.6, 123.9, 135.7, 162.4, 207.0; FABMS: m/z = 258 (MH+, 45%), 69 (100%).
HRMS Calcd. for C16H20NO2: 258.1494. Fonud: 258.1498.
ACKNOWLEDGEMENTS

HETEROCYCLES, Vol. 68, No. 12, 2006
2585
We thank Prof. Nobutaka Fujii and Dr. Shinya Oishi of the Graduate School of Pharmaceutical Sciences,
Kyoto University for the measurements of NMR and MS spectra, and Prof. Shigefumi Kuwahara and Mr.
Takashi Nakahata of the Graduate School of Agriculture, Tohoku University for the measurements of
optical rotation and CD spectra.
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