Synthesis of 6Z-pandanamine by regioselective cyclization reaction of 2-en-4-ynoic acid derivatives promoted by weak base

Article abstract of DOI:10.3987/COM-08-S(F)48

The stereoselective synthesis of 6Z-pandanamine by base-promoted 5-exo-dig-selective cyclization reaction of bis-2-en-4-ynoic acid derivative as a key step is described.

Full text of DOI:10.3987/COM-08-S(F)48

HETEROCYCLES, Vol. 77, No. 1, 2009
493
HETEROCYCLES, Vol. 77, No. 1, 2009, pp. 493 - 505. © The Japan Institute of Heterocyclic Chemistry
Received, 17th July, 2008, Accepted, 22nd August, 2008, Published online, 25th August, 2008.
DOI: 10.3987/COM-08-S(F)48
SYNTHESIS
OF
6Z-PANDANAMINE
BY
REGIOSELECTIVE
CYCLIZATION REACTION OF 2-EN-4-YNOIC ACID DERIVATIVES
PROMOTED BY WEAK BASE
Kou Hiroya,*,†,‡ Kazuya Takuma,† Kiyofumi Inamoto,† and Takao
Sakamoto†,‡
†
Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku,
Sendai 980-8578, Japan
‡
Tohoku University 21st Century COE Program “Comprehensive Research and
Education Center for Planning of Drug Development and Clinical Evaluation,”
Sendai 980-8578, Japan
* E-mail: hiroya@mail.tains.tohoku.ac.jp
This paper is dedicated to Professor Emeritus Keiichiro Fukumoto at Tohoku
University on the occasion of his 75th birthday.
Abstract – The stereoselective synthesis of 6Z-pandanamine by base-promoted
5-exo-dig−selective cyclization reaction of bis-2-en-4-ynoic acid derivative as a
key step is described
INTRODUCTION
The intramolecular cyclization reaction by nucleophilic addition to the carbon−carbon triple bond is a
useful methodology for constructing heterocyclic compounds, and significant efforts have been made to
develop reagents that promote such reactions.1 We have previously reported effective methods for the
synthesis of substituted heterocyclic compounds catalyzed by Cu(II) salts,2 Pd(PPh3)4-methyl propiolate
complex,3 or PtCl4 in ethanol.4
We have also reported regiocontrolled intramolecular annulation reactions between carbon−carbon triple
bonds and carboxylic acid, promoted by acid or base.5,6 Acid- and base-promoted cyclization gave
isocoumarin 2 and phthalide 3, respectively, from carboxylic acid 1 (Figure 1). This method was also
successfully applied to aliphatic (Z)-5-phenylpent-2-en-4-ynoic acid (4), which gave pyran-2(2H)-one 5

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HETEROCYCLES, Vol. 77, No. 1, 2009
and furan-2(2H)-one 6, respectively. In this paper, we present the total synthesis of 6Z-pandanamine (11)
using base-promoted cyclization as a key step.
Figure 1. Regio-controlled intramolecular annulation reactions of 1 and 4
H
"acid"
"base"
O
O
CO2H
O
O
2
1
3
H
"acid"
"base"
O
O
CO2H
O
O
5
4
6
In 2000, Takayama and co-workers reported the isolation of pandamarilactonine A (7) and B (8) (Figure
2) from the leaves of Pandanus amaryllifolius Roxb. from the Philippines, Thailand, and Indonesia,
where it is used as a traditional medicine for toothache, heart problems and other conditions.7
Subsequently, pandamarilactonine C (9) and D (10), isomers of 7 and 8, respectively, were isolated from
the plant,8 and the structure for the other congeners that contained 6E-pandanamine (12) were also
determined.9 The biomimetic total synthesis of racemic 7 and 8 was reported by Takayama’s research
group,7,8 and synthetic attempts at optically active forms were also reported.10 The first asymmetric total
synthesis and determination of absolute configuration of 7 was achieved by Takayama and co-workers in
2005.11
6Z-Pandanamine (11) was isolated from the same plant in 2001,12 although the secondary amine 11 was a
nameless precursor molecule for the total synthesis of 7 and 8 in 2000.7 Takayama reported that the
optical purity of the isolated 7 was low (26% e.e.), and 8 was isolated as racemate. Later, Craik and
co-workers suggested that both 7 and 8, which were not isolated using a solvent partitioned method, were
artifacts formed during the acid-base extraction.9 Meanwhile, Takayama concluded that 7 was formed
enzymatically with high optical purity and racemized during the isolation process, and that 8 was an
artifact from 11, which were demonstrated by NMR experiments using 7 synthesized as an optically
active form.11

HETEROCYCLES, Vol. 77, No. 1, 2009
495
Figure 2. The Pandanus alkaloids
Me
Me
O
O
O
O
O
Me
Me
6
6
6
O
O
HN
O
O
N
N
O
O
Me
Me
O
H
H
H
H
6Z-pandamarilactonine-A (7) 6Z-pandamarilactonine-B (8)
6E-pandamarilactonine-C (9) 6E-pandamarilactonine-D (10)
6Z-pandanamine (11)
6E-pandanamine (12)
RESULTS AND DISCUSSION
The synthetic strategy for 11 is shown in Figure 3. Briefly, the enol-lactone moieties of 11 are constructed
from the symmetrical bis-carboxylic acid 13 by the base-promoted cyclization reaction. The
stereochemistry of the enol moiety can be expected as “Z” from our previous results.5 Since 14, which is
the precursor of the target natural product(s), has a symmetrical structure, it can be synthesized from the
amide 15 and the iodide 16. Both 15 and 16 will be synthesized from the common intermediate 17, which
will be synthesized by Pd-catalyzed coupling reaction between 4-hexyn-1-ol (18) and the vinyl iodide 19.
Figure 3. Synthetic strategy for 6Z-pandanamine (11) and/or 6E-pandanamine (12)
OH
HO2C
Me
Me
Me
Me
6Z-pandanamine (11)
6E-pandanamine (12)
R2
N
R2
N
HO2C
13
14
OH
R1O
R2
N
HO
H
Me
18
R1O
15
16
HO
R1O
I
17
Me
R1O
I
Me
Me
19

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HETEROCYCLES, Vol. 77, No. 1, 2009
Along with the strategy shown above, we started synthesizing the common intermediate 17. The vinyl
iodide 21 was selectively synthesized from propargyl alcohol (20) according to the literature,13 and it was
converted to the TBDMS ether 22 by standard reaction conditions (Scheme 1). The Sonogashira coupling
reaction between 22 and 18 was carried out in the presence of Pd(PPh3)4 and CuI in piperidine, which
afforded the desired alcohol 23 in good yield. Treatment of 23 with N-tert-butoxycarbonyl-2-
nitorobenzensulfonamide (24) under Mitsunobu reaction condition gave 25 in 95% yield.14 Attempts at
selective removal of the Boc group of 25 using either Lewis acid or protonic acid were unsuccessful.
However, the amide 26 was successfully obtained under thermal condition (diphenyl ether at 180 ˚C,
85%).15 On the other hand, the iodide 27 was synthesized from 23 by standard reaction conditions (I2,
PPh3, imidazole, 92%).
Scheme 1. Synthesis of the fragments 26 and 27
CuI, THF, 0 °C, 1 h
then MeMgBr, Et2O, 0 °C, 1.5 h
then I2, 0 °C to rt 1.5 h
82%
TBDMSCl, imid.
DMAP, DMF
rt, 25 min, 98%
OH
Me
OTBDMS
Me
OH
I
I
20
21
Ns
22
H
N
HO
18
Boc
24
TBDMSO
TBDMSO
Pd(PPh3)2, CuI, piperidine
rt to 70 °C, 13 h, 77%
Ns
Ns
PPh3, DEAD, THF
0°C to rt, 6 h
95%
HO
N
Me
Boc
Me
23
25
I2, PPh3, imid., CH2Cl2
0 °C to reflux, 30 min, 92%
Ph2O, 180 °C
20 min, 85%
TBDMSO
TBDMSO
N
H
I
Me
Me
27
26
As we could establish an efficient pathway to synthesize both fragments 26 and 27, the next task was the
coupling reaction of them. The sodium salt of 26, which was prepared from 26 with NaH, was reacted
with the iodide 27 in DMF at 80 ˚C, affording the desired alkylated product 28 in 90% yield. Next, 28
was converted to the bis-carboxylic acid 29, which is the substrate for the key reaction, by removal of the
TBDMS group (TBAF) and oxidation of the allylic alcohol (Dess-Martin periodinane; DMP), followed
by oxidation of the formyl group with NaClO2 in the presence of NaH2PO4･H2O (Pinnick oxidation). The
cyclization reaction of the bis-carboxylic acid 29 was carried out by refluxing with the excess amount of
DMAP in toluene to afford the expected bis-lactone 30 as a sole product, in 9% overall yield from 28.

HETEROCYCLES, Vol. 77, No. 1, 2009
497
The stereochemistry of the cyclized product was determined as “Z” by comparing the chemical shift of
the olefinic protons with those of 11 and 129,12 (Table 1). Consequently, 5-exo-dig reaction was far
superior to 6-endo-dig mode in base-promoted cyclization reaction for this substrate, which is identical to
our previous observation (Figure 1).5 We encountered trouble with the last stage, removal of the
2-nitorobenzensulfonamide (Ns) group. The lactone moiety decomposed before elimination of the Ns
group due to instability of the vinylogous lactone, even under mild reaction condition [(A) PhSH, Cs2CO3,
DMF, rt or (B) 2-mercaptoethanol, DBU, MeCN, rt] (Scheme 2).14
Scheme 2. Synthesis of the bis-lactone 30
OTBDMS
Me
TBDMSO
NaH, DMF-THF, 0 °C
Ns
Ns
N
N
H
then
TBDMSO
Me
Me
26
I
27
28
Me
OTBDMS
80 °C, 90%
HO2C
1) TBAF, THF, rt, 20 min
2) DMP, CH2Cl2, rt, 11 h
Me
Me
DMAP (10 equiv.)
Ns
N
toluene, 90 °C, 3.5 h
9% from 28 (4 steps)
3) NaClO2, NaHPO4, 2-methyl-2-butene
tert-BuOH-H2O (4:1), rt, 30 min
HO2C
29
O
O
Me
Ns
N
6Z-pandanamine (11)
Me
O
30
O
Table 1. Comparison of the chemical shifts of the olefinic protons
Me
O
Hd
O
O
Me
Compound
O
Hb
Ha
Hc
6Z-pandanamine (11)
Ha = 5.14
6E-pandanamine (12)
Hc = 5.51
Hd = 7.43
Natural product
Synthesized 30
Synthesized 33
Hb = 7.03
Ha = 5.15
Hb = 7.00
Ha = 5.16
−
−
−
−
Hb = 6.99

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Having learned that the Ns group has to be removed before cyclization reaction, we decided to replace the
protecting group before cyclization. Removal of the Ns group was carried out with ethanethiol and DBU
in MeCN at room temperature, and the resulting secondary amine was treated with (Boc)2O in the
presence of pyridine to afford the carbamate 31. The following three-step sequence was carried out as
described above. Desilylation of 31 with TBAF, DMP oxidation, and Pinnick oxidation gave
bis-2-en-4-ynoic acid derivative 32. Et3N was a much better base than DMAP for the stereoselective
cyclization reaction of 32, and 33 was obtained as a single isomer in 37% overall yield from 28. The
stereochemistry of 33 was confirmed as “Z” by comparing with 11 and 30 as described before (Table 1).
The synthesis was completed by removal of the Boc group with formic acid in THF, which provided 11
(Scheme 3).
Scheme 3. Synthesis of 6Z-pandanamine (11)
OTBDMS
1) EtSH, DBU, MeCN, rt, 1 h
2) (Boc)2O, pyridine, MeOH, rt, 3 h
3) TBAF, THF, rt, 30 min
Me
Me
R N
4) DMP, CH2Cl2, rt, 7 h
5) NaClO2, NaHPO4, 2-methyl-2-butene
tert-BuOH-H2O (4:1), rt, 3.5 h
OTBDMS
28: R = Ns
31: R = Boc
O
O
HO2C
HO2C
Me
Me
1) Et3N, toluene, 90 °C, 4.5 h
Me
Me
37% from 28
R
N
Boc N
2) HCO2H, THF, rt, 12 h
~ 20%
O
32
O
N-Boc-6Z-pandanamine (33): R = Boc
6Z-pandanamine (11): R = H
In summary, we demonstrated the application of base-promoted 5-exo-dig–selective cyclization reaction
of bis-2-en-4-ynoic acid derivatives 29 and 32 to the enol-lactones 30 and 33. Although the bis-lactone 30
could not be converted to the target natural product, the synthesis of 6Z-pandanamine (11) was achieved
from 33.
EXPERIMENTAL
(Z)-3-Iodo-2-methylprop-2-en-1-ol (21).13 Under Ar atmosphere, propargyl alcohol (20) (2.66 mL, 45.0
mmol) was added to a suspension of CuI (857 mg, 4.5 mmol) in anhydrous THF (50 mL) at 0 °C and

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499
stirred for 1 h, then a solution of MeMgBr (3.0 M solution in Et2O, 30 mL, 90 mmol) was added to a
reaction mixture over 10 min and the stirring was continued for 90 min at the same temperature. A
solution of I2 (17.1 g, 67.5 mmol) in anhydrous Et2O (80 mL) was added to a reaction mixture over 10
min, then stirred at rt for 90 min. The reaction mixture was treated with saturated aqueous NH4Cl solution
and the aqueous solution was extracted with Et2O (40 mL x 3). The combined organic solution was
washed with saturated aqueous NaCl solution, dried over anhydrous MgSO4, and the solvent was
removed under reduced pressure. The residue was purified by silica gel column chromatography
[hexane-AcOEt (3:1)] to afford 21 (7.27 g, 82%) as a yellow oil: IR (neat) cm-1 3329, 3053, 1435, 1013;
1H-NMR (400 MHz, CDCl3) δ 1.96 (3H, s), 3.40 (1H, br), 4.21 (2H, s), 5.96 (1H, s); 13C-NMR (100 MHz,
CDCl3) δ 21.6, 67.8, 74.6, 145.9; MS m/z (relative intensity) 198 (100, M+), 149 (84), 71 (86); HRMS
Calcd for C4H7IO: 197.9542. Found: 197.9536.
tert-Butyl-[(Z)-3-iodo-2-methylallyloxy]dimethylsilane (22). Imidazole (210 mg, 3.1 mmol), DMAP
(12 mg, 0.15 mmol), and TBDMSCl (465 mg, 3.1 mmol) were added to a solution of
(Z)-3-iodo-2-methylprop-2-en-1-ol (21) (309 mg, 1.5 mmol) in DMF (10 mL) and the mixture was
allowed to react at rt for 25 min. The reaction mixture was extracted with Et2O (10 mL x 3). The
combined organic solution was washed with saturated aqueous NaCl solution, dried over anhydrous
MgSO4, and the solvent was removed under reduced pressure. The residue was purified by silica gel
column chromatography [hexane-AcOEt (1:1)] to afford 22 (472 mg, 98%) as a colorless oil: IR (neat)
1
cm-1 2955, 2930, 2856, 1472, 1097, 839; H-NMR (400 MHz, CDCl3) δ 0.10 (6H, s), 0.91 (9H, s), 1.91
(3H, s), 4.24 (2H, s), 5.85 (1H, s); 13C-NMR (100 MHz, CDCl3) δ −5.1, 18.3, 21.5, 25.9, 68.7, 72.4,
146.6; FAB-MS m/z 311 (M+). Anal. Calcd for C10H21IOSi: C, 38.46; H, 6.78. Found: C, 38.30; H, 6.60.
(Z)-8-(tert-Butyldimethylsilanyloxy)-7-methyloct-6-en-4-yn-1-ol (23). Under Ar atmosphere, CuI (10
mg, 0.05 mmol) and Pd(PPh3)4 (58 mg, 0.05 mmol) were added to a solution of
tert-butyl-[(Z)-3-iodo-2-methylallyloxy]dimethylsilane (22) (312 mg, 1.0 mmol) in anhydrous piperidine
(5 mL) and the mixture was stirred at 80 °C. After being stirred for 1 h, pentyn-1-ol (18) (138 mg, 1.5
mmol) was added to a reaction mixture and stirring was continued for 13 h. The reaction mixture was
extracted with AcOEt (5 mL x 3). The combined organic solution was washed with saturated aqueous
NaCl solution, dried over anhydrous MgSO4, and the solvent was removed under reduced pressure. The
residue was subjected to silica gel column chromatography [hexane-AcOEt (9:1)] to afford 23 (207 mg,
77%) as a brown oil: IR (neat) cm-1 3354, 2953, 2930, 2856, 2361, 1251, 1074, 837; 1H-NMR (600 MHz,
CDCl3) δ 0.09 (6H, s), 0.91 (9H, s), 1.79 (2H, quint, J = 6.6 Hz), 1.82 (3H, s), 2.46 (2H, td, J = 6.6, 2.2
Hz), 3.77 (2H, t, J = 6.6 Hz), 4.36 (2H, s), 5.28 (1H, brs); 13C-NMR (100 MHz, CDCl3) δ −5.2, 16.1, 18.3,

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19.7, 25.9, 31.6, 61.6, 63.9, 77.6, 92.6, 105.5, 149.2; MS m/z: (relative intensity) 268 (4, M+), 211 (68),
183 (64), 75 (100); HRMS Calcd for C15H28O2Si: 268.1859. Found: 268.1844.
N-[(Z)-8-(tert-Butyldimethylsilanyloxy)-7-methyloct-6-en-4-ynyl]-N-(tert-butoxycarbonyl)-2-nitro-
benzenesulfonamide (25). Under Ar atmosphere, a solution of (Z)-8-(tert-butyldimethylsilanyloxy)-
7-methyloct-6-en-4-yn-1-ol (23) (1.34 g, 5.0 mmol) in anhydrous THF (5 mL) was added to a mixture of
PPh3 (1.44 g, 5.5 mmol) and N-tert-butoxycarbonyl-2-nitrobenzenesulfonamide (24) (2.27 g, 7.5 mmol)
in anhydrous THF (10 mL). Diethyl azodicarboxylate (40 w/v% toluene solution, 2.42 mL, 5.5 mmol)
was added to a reaction mixture at 0 °C. After being stirred for 6 h, the reaction mixture was extracted
with AcOEt (10 mL x 3). The combined organic solution was washed with saturated aqueous NaCl
solution, dried over anhydrous MgSO4, and the solvent was removed under reduced pressure. The residue
was purified by silica gel column chromatography [hexane-AcOEt (5:1)] to afford 25 (2.62 g, 95%) as a
yellow oil: IR (neat) cm-1 2928, 2856, 2361, 1732, 1545, 1367, 1153; 1H-NMR (600 MHz, CDCl3) δ 0.09
(6H, s), 0.91 (9H, s), 1.37 (9H, s), 1.82 (3H, s), 1.99 (2H, quint, J = 7.2 Hz), 2.44 (2H, td, J = 7.2, 1.8 Hz),
13
3.86 (2H, t, J = 7.2 Hz), 4.38 (2H, s), 5.29 (1H, brs), 7.73-7.76 (3H, m), 8.30-8.32 (1H, m); C-NMR
(100 MHz, CDCl3) δ −5.2, 17.2, 18.4, 19.8, 26.0, 27.4, 27.9, 29.5, 30.9, 47.4, 63.9, 77.7, 85.0, 91.9, 105.4,
124.2, 131.6, 133.2, 134.0, 149.4, 150.2; MS m/z (relative intensity) 552 (0.5, M+), 439 (24), 395 (46),
253 (64), 209 (100); HRMS Calcd for C26H40N2O7SSi: 552.2326. Found: 552.2323.
N-[(Z)-8-(tert-Butyldimethylsilanyloxy)-7-methyloct-6-en-4-ynyl]-2-nitrobenzenesulfonamide (26).
A solution of N-[(Z)-8-(tert-butyldimethylsilanyloxy)-7-methyloct-6-en-4-ynyl]-N-(tert-butoxycarbonyl)-
2-nitrobenzenesulfonamide (25) (1.35 g, 2.45 mmol) in diphenyl ether (5 mL) was stirred at 180 °C for 20
min. The reaction mixture was subjected to silica gel column chromatography [hexane-AcOEt (3:1)] to
afford 26 (937 mg, 85%) as a yellow oil: IR (neat) cm-1 3344, 2930, 2856, 2359, 1541, 1361, 1167, 1084;
1H-NMR (600 MHz, CDCl3) δ 0.06 (6H, s), 0.90 (9H, s), 1.77 (2H, quint, J = 6.6 Hz), 1.81 (3H, s), 2.40
(2H, td, J = 6.6, 2.0 Hz), 3.23 (2H, q, J = 6.6 Hz), 4.32 (2H, s), 5.24 (1H, brs), 5.40 (1H, t, J = 6.6 Hz),
7.73-7.76 (2H, m), 7.86-7.88 (1H, m), 8.14-8.15 (1H, m); 13C-NMR (100 MHz, CDCl3) δ −5.2, 16.8, 18.4,
19.8, 25.9, 28.8, 42.8, 63.9, 78.3, 91.2, 105.2, 125.3, 131.0, 132.7, 133.5, 133.6, 147.9, 149.7; MS m/z
(relative intensity) 452 (0.7, M+), 395 (69), 209 (100); HRMS Calcd for C21H32N2O5SSi: 452.1801.
Found: 452.1807.
tert-Butyl-[(Z)-8-iodo-2-methyloct-2-en-4-ynyloxy]dimethylsilane (27). Imidazole (544 mg, 8.0 mmol),
PPh3 (1.57 g, 6.0 mmol), and I2 (1.52 g, 6.0 mmol) were successively added to a solution of
(Z)-8-(tert-butyldimethylsilanyloxy)-7-methyloct-6-en-4-yn-1-ol (23) (1.08 g, 4.0 mmol) in CH2Cl2 (10

HETEROCYCLES, Vol. 77, No. 1, 2009
501
mL) at 0 °C. The reaction mixture was refluxed for 30 min and extracted with CHCl3 (10 mL x 3). The
combined organic solution was washed with saturated aqueous NaCl solution, dried over anhydrous
MgSO4, and the solvent was removed under reduced pressure. The residue was purified by silica gel
column chromatography [hexane-AcOEt (9:1)] to afford 27 (1.39 g, 92%) as a yellow oil: IR (neat) cm-1
2955, 2928, 2856, 2360, 1252, 1086, 837; 1H-NMR (600 MHz, CDCl3) δ 0.09 (6H, s), 0.91 (9H, s), 1.82
(3H, s), 2.00 (2H, quint, J = 6.5 Hz), 2.48 (2H, td, J = 6.5, 2.2 Hz), 3.31 (2H, t, J = 6.5 Hz), 4.34 (2H, s),
13
5.28 (1H, brs); C-NMR (100 MHz, CDCl3) δ −5.1, 5.5, 18.4, 19.8, 20.6, 26.0, 32.3, 63.9, 78.3, 91.0,
105.3, 149.7; FAB-MS m/z 377 (M+−1).
N,N-Bis-[(Z)-8-(tert-butyldimethylsilanyloxy)-7-methyloct-6-en-4-ynyl]-2-nitrobenzenesulfonamide
(28). Under Ar atmosphere, a solution of N-[(Z)-8-(tert-butyldimethylsilanyloxy)-7-methyloct-6-en-4-
ynyl]-2-nitrobenzenesulfonamide (26) (804 mg, 1.77 mmol) in anhydrous DMF (6 mL) was added to a
suspension of NaH (85 mg, 2.12 mmol) in anhydrous THF (5 mL) at 0 °C. After being stirred for 1 h, a
solution of tert-butyl-[(Z)-8-iodo-2-methyloct-2-en-4-ynyloxy]dimethylsilane (27) (1.34 g, 3.54 mmol) in
anhydrous DMF (6 mL) was added to the reaction mixture. After being stirred for another 3 h at 80 °C,
the reaction mixture was extracted with Et2O (30 mL x 3). The combined organic solution was washed
with saturated aqueous NaCl solution, dried over anhydrous MgSO4, and the solvent was removed under
reduced pressure. The residue was purified by silica gel column chromatography [hexane-AcOEt (9:1)] to
afford 28 (1.12 g, 90%) as a brown oil: IR (neat) cm-1 2930, 2856, 1547, 1360, 1252, 1163, 1084, 837,
1
775; H-NMR (600 MHz, CDCl3) δ 0.07 (12H, s), 0.90 (18H, s), 1.79 (4H, quint, J = 7.2 Hz), 1.82 (6H,
s), 2.33 (4H, td, J = 7.2, 1.8 Hz), 4.00 (4H, t, J = 7.2 Hz), 4.33 (4H, s), 5.25 (2H, s), 7.62 (1H, dd, J = 7.7,
13
1.8 Hz), 7.64-7.72 (2H, m), 8.03 (1H, dd, J = 7.7, 1.8 Hz); C-NMR (150 MHz, CDCl3) δ −5.2, 16.9,
18.3, 19.8, 25.9, 27.6, 46.8, 63.8, 78.0, 91.6, 105.3, 124.1, 130.9, 131.5, 133.2, 133.3, 147.9, 150.0; MS
m/z (relative intensity) 702 (3, M+), 645 (68), 459 (100); HRMS Calcd for C36H58N2O6SSi2: 702.3554.
Found: 702.3562.
N-Ns-Pandanamine (30). TBAF (1.0 M solution in THF, 11.4 mL, 11.4 mmol) was added to a solution
of
N,N-bis-[(Z)-8-(tert-butyldimethylsilanyloxy)-7-methyloct-6-en-4-ynyl]-2-nitrobenzenesulfonamide
(28) (1.0 g, 1.43 mmol) in THF (5 mL) at rt. After being stirred for 20 min, the reaction mixture was
extracted with AcOEt (10 mL x 3). The combined organic solution was washed with saturated aqueous
NaCl solution, dried over anhydrous MgSO4, and the solvent was removed under reduced pressure to
afford the crude alcohol, which was used to the next reaction without further purification.
Dess-Martin periodinane (DMP) (705 mg, 1.66 mmol) was added to a solution of the crude alcohol in
CH2Cl2 (7 mL) at rt. After being stirred for 11 h, the reaction mixture was neutralized with saturated

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aqueous NaHCO3 solution and the aqueous solution was extracted with AcOEt (10 mL x 3). The
combined organic solution was washed with saturated aqueous NaCl solution, dried over anhydrous
MgSO4, and the solvent was removed under reduced pressure to afford the crude α,β-unsaturated
aldehyde, which was used to the next reaction without further purification.
NaClO2 (360 mg, 3.32 mmol), NaH2PO4･H2O (518 mg, 3.32 mmol), and 2-methyl-2-butene (2 M
solution in THF, 3.3 mL, 6.64 mmol) were added to a solution of the crude α,β-unsaturated aldehyde
(156 mg) in a mixture of tert-BuOH-H2O (4:1, 5 mL) at rt. After being stirred for 30 min, 3N HCl was
added and the aqueous solution was extracted with AcOEt (10 mL x 3) and the combined organic solution
was washed with saturated aqueous NaCl solution, dried over anhydrous MgSO4, and the solvent was
removed under reduced pressure to afford the crude carboxylic acid (29), which was used to the next
reaction with out further purification.
DMAP (41 mg, 0.33 mmol) was added to a solution of the crude carboxylic acid (29) in toluene (5 mL) at
90 °C. After being stirred for 3.5 h, the reaction mixture was extracted with AcOEt (5 mL x 3). The
combined organic solution was washed with saturated aqueous NaCl solution, dried over anhydrous
MgSO4, and the solvent was removed under reduced pressure. The residue was purified by silica gel
column chromatography [hexane-AcOEt (3:1)] to afford N-Ns-pandanamine (30) (65 mg, 9% overall
yield from 28) as a brown oil: IR (neat) cm-1: 2926, 2855, 1767, 1543, 1346, 1161; 1H-NMR (600 MHz,
CDCl3) δ 1.75 (4H, quint, J = 7.5 Hz), 2.00 (6H, s), 2.34 (4H, td, J = 7.8, 7.5 Hz), 3.31 (4H, t, J = 7.5 Hz),
5.15 (2H, t, J = 7.8 Hz), 7.00 (2H, s), 7.61 (1H, m), 7.69-7.70 (2H, m), 7.97-7.99 (1H, m); 13C-NMR (150
MHz, CDCl3) δ −0.02, 10.5, 23.3, 28.0, 29.7, 47.4, 112.2, 124.2, 129.5, 130.6, 131.7, 133.6, 137.7, 149.0,
170.9; MS m/z (relative intensity) 502 (29, M+), 180 (100); HRMS Calcd for C24H26N2O8S: 502.1410,
Found: 502.1415.
N-Boc-Pandanamine (33). DBU (0.55 mL, 3.65 mmol) and EtSH (0.27 mL, 3.65 mmol) were added to a
solution of N,N-bis[(Z)-8-(tert-butyldimethylsilanyloxy)-7-methyloct-6-en-4-ynyl]-2-nitrobenzenesulfon-
amide (28) (512 mg, 0.73 mmol) in MeCN (5 mL) at rt. After being stirred for 1 h, the solvent was
removed under reduced pressure to afford the crude amine, which was used to the next reaction without
further purification.
Pyridine (0.29 mL, 3.65 mmol) and (Boc)2O (0.8 mg, 3.65 mmol) were added to a solution of the crude
amine in MeOH (5 mL) at rt. After being stirred for 3 h, the reaction mixture was extracted with AcOEt
(10 mL x 3). The combined organic solution was washed with saturated aqueous NaCl solution, dried
over anhydrous MgSO4, and the solvent was removed under reduced pressure to afford the crude 31,
which was used to the next reaction without further purification.
TBAF (1 M solution in THF, 3.65 mL, 3.65 mmol) was added to a solution of the crude 31 in THF (5

HETEROCYCLES, Vol. 77, No. 1, 2009
503
mL) at rt. After being stirred for 30 min, the reaction mixture was extracted with AcOEt (10 mL x 3). The
combined organic solution was washed with saturated aqueous NaCl solution, dried over anhydrous
MgSO4, and the solvent was removed under reduced pressure to afford the crude alcohol, which was used
to the next reaction without further purification.
DMP (2.5 g, 5.84 mmol) was added to a solution of the crude alcohol in CH2Cl2 (8 mL) at rt. After being
stirred for 7 h, the reaction mixture was neutralized with saturated aqueous NaHCO3 solution and the
aqueous solution was extracted with AcOEt (10 mL x 3). The combined organic solution was washed
with saturated aqueous NaCl solution, dried over anhydrous MgSO4, and the solvent was removed under
reduced pressure to afford the crude α,β-unsaturated aldehyde, which was used to the next reaction
without further purification.
NaClO2 (528 mg, 5.84 mmol), NaH2PO4･H2O (911 mg, 5.84 mmol), and 2-methyl-2-butene (2 M
solution in THF, 5.8 mL, 11.7 mmol) were added to a solution of the crude α,β-unsaturated aldehyde in
tert-BuOH-H2O (4:1, 5 mL) at rt. After being stirred for 3.5 h, 3N HCl was added and the aqueous
solution was extracted with AcOEt (10 mL x 3). The combined organic solution was washed with
saturated aqueous NaCl solution, dried over anhydrous MgSO4, and the solvent was removed under
reduced pressure to afford the crude carboxylic acid 32, which was used to the next reaction without
further purification.
Et3N (1.0 mL, 7.3 mmol) was added to a solution of the crude carboxylic acid 32 in toluene (5 mL) at
90 °C. After being stirred for 4.5 h, the reaction mixture was extracted with AcOEt (5 mL x 3). The
combined organic solution was washed with saturated aqueous NaCl solution, dried over anhydrous
MgSO4, and the solvent was removed under reduced pressure. The residue was chromatographed on silica
gel [hexane-AcOEt (3:1)] to give N-Boc-pandanamine (33) (109 mg, 37% overall yield from 28) as a
brown oil. Since 33 was decomposed on standing, the product was immediately used to the next reaction;
1H-NMR (400 MHz, CDCl3) δ 1.46 (9H, s), 1.70 (4H, t, J = 7.2 Hz), 2.00 (6H, s), 2.37 (4H, td, J = 7.5,
7.2 Hz), 3.20 (4H, brs), 5.16 (2H, brs), 6.99 (2H, s); MS m/z 317 (100).
6Z-Pandanamine (11). Formic acid (0.9 mL) was added to a solution of N-Boc-pandanamine (33) (2.4
mg, 0.06 mmol) in THF (0.3 mL) and stirred at rt for 12 h. The reaction mixture was neutralized with
saturated aqueous NaHCO3 solution and the aqueous solution was extracted with CHCl3 (5 mL x 3). The
combined organic solution was washed with saturated aqueous NaCl solution, dried over anhydrous
1
MgSO4, and the solvent was removed under reduced pressure to afford 6Z-Pandanamine (11); H-NMR
(600 MHz, CDCl3) δ 2.00 (6H, s), 2.00-2.06 (4H, m), 2.45 (4H, m), 2.85 (4H, m), 5.14 (2H, t, J = 7.8 Hz),
7.01 (2H, d, J = 1.8 Hz).

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HETEROCYCLES, Vol. 77, No. 1, 2009
ACKNOWLEDGEMENTS
This work was partly supported by a Grant-in-Aid for Scientific Research (B) from Japan Society for the
Promotion of Science (JSPS).
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