Efficient macrocyclization by means of 2-nitrobenzenesulfonamide and total synthesis of lipogrammistin-A

Article abstract of DOI:10.1016/S0040-4020(02)00626-9

Synthesis of medium- and large-sized cyclic amines using alkylation with 2-nitrobenzenesulfonamides is described. Using either conventional alkylation procedures or Mitsunobu conditions, the cyclization reaction proceeded in a highly efficient manner. The usefulness of this methodology has been fully demonstrated in the total synthesis of lipogrammistin-A (9), an 18-membered cyclic polyamine.

Full text of DOI:10.1016/S0040-4020(02)00626-9

Tetrahedron 58 (2002) 6267–6276
Efficient macrocyclization by means of
2-nitrobenzenesulfonamide and total synthesis
of lipogrammistin-A
*
Toshiyuki Kan, Akiko Fujiwara, Hideki Kobayashi and Tohru Fukuyama
Graduate School of Pharmaceutical Sciences, Japan Science & Technology Corporation (JST), University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
Received 25 April 2002; accepted 10 June 2002
This paper is dedicated to Professor Yoshito Kishi of Harvard University on the occasion of his receiving the Tetrahedron Prize
Abstract—Synthesis of medium- and large-sized cyclic amines using alkylation with 2-nitrobenzenesulfonamides is described. Using either
conventional alkylation procedures or Mitsunobu conditions, the cyclization reaction proceeded in a highly efficient manner. The usefulness
of this methodology has been fully demonstrated in the total synthesis of lipogrammistin-A (9), an 18-membered cyclic polyamine. q 2002
Published by Elsevier Science Ltd.
1. Introduction
when an acetonitrile solution of 3a–c was slowly added
(2 h) by means of a syringe pump to a mixture of
tetrabutylammonium iodide and Cs2CO3 in acetonitrile at
608C, the cyclization proceeded smoothly to give the
desired products 4a–c in good yields.
Construction of medium- and large-sized cyclic amines is an
important subject in organic synthesis, since these structural
units are often found in the frameworks of a variety of
medicinally interesting natural products. While many
cyclization reactions have been reported, there seem to be
few direct alkylations with nitrogen nucleophiles.1,2 We
have recently developed a novel transformation of primary
amines to secondary amines using 2-nitrobenzenesulfona-
mides as an activating/protecting group (Ns-strategy).3–8
We envisioned that an intramolecular alkylation with a
Ns-amide would facilitate the construction of cyclic amines.
Herein we report an efficient macrocyclization with
2-nitrobenzenesulfonamides and its application to the total
synthesis of lipogrammistin-A (9).9
By contrast, the macrocyclization using N-tert-butoxycar-
bonyl-7-iodo-1-aminoheptane (5) did not give the desired
8-membered ring product (Scheme 1). While treatment of 5
with sodium hydride in DMF at room temperature resulted
in almost complete recovery of the starting material, heating
the mixture at 608C caused dehydroiodination to give 6 as
the major product.
In order to perform the cyclization under Mitsunobu
conditions, the precursors 8a–c were prepared from
Table 1. Synthesis of medium-sized ring via conventional alkylation
2. Results and discussion
Construction of medium-sized cyclic amines (8- to 10-
membered rings) was investigated first using non-branched,
simple substrates as shown in Table 1. Coupling between
sulfonamide 110 and v-bromoalcohol 2a–c was performed
under Mitsunobu conditions to give the predominantly
mono-alkylated products 3a–c. Preliminary studies on the
cyclization of 3a–c revealed that high-dilution conditions
(0.01 M) are preferred to achieve reasonable yields. Thus,
Ring size
Alcohol
Alkulationa (yield %)
Cyclizationb (yield %)
8
9
10
2a
2b
2c
3a (70)
3b (67)
3c (74)
4a (62)
4b (64)
4c (66)
Keywords: lipogrammistin-A; cyclization; Mitsunobu conditions.
*
a
Corresponding author. Tel.: þ81-3-3812-2111x4777; fax: þ81-3-5802-
Alkylation conditions: PPh3, DEAD, toluene–THF (10:1).
Cyclization conditions: Cs2CO3, CH3CN, n-Bu4Nl, 608C.
b
8694; e-mail: fukuyama@mol.f.u-tokyo.ac.jp
0040–4020/02/$ - see front matter q 2002 Published by Elsevier Science Ltd.
PII: S0040-4020(02)00626-9

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T. Kan et al. / Tetrahedron 58 (2002) 6267–6276
Scheme 1. Attempted cyclization of N-Boc-amide.
N-Boc-nitrobenzenesulfonamide 7 (Table 2). When the
mixture of 7 and bromide 2a–c was heated with K2CO3 in
DMF, the alkylation proceeded smoothly to give the N-Boc
protected precursors. Subsequent deprotection of the Boc
group with trifluoroacetic acid and methanolysis of the
trifluoroacetate formed during the deprotection provided the
cyclization precursors 8a–c. Upon treatment of 8a–c with
DEAD and PPh3 in 0.01 M solution of toluene–THF at
room temperature, the desired cyclization reaction pro-
ceeded smoothly to afford 4a–c in moderate yields.
In both ring closures (Tables 1 and 2), the cyclization
occurred successfully without the aid of the branching
effect.11 Thus, the Ns-strategy proved to be a powerful
protocol for the construction of medium-sized rings,
overriding the inherent entropic disadvantage of the ring
closure. With these successful results in hand, we turned our
attention to the construction of large-sized rings by means of
the Ns-strategy. Many macrocyclic polyamine alkaloids
(13- to 18-membered rings) have been isolated from plants
and marine sources and shown to exhibit interesting
biological activities.12 Although many synthetic efforts
have been made to date, only a few methodologies are
available for the macrocyclization.13 We anticipated that the
Ns-strategy would also be suitable for the construction of
large-sized rings. In order to demonstrate the utility of the
Ns-strategy, we attempted to synthesize lipogrammistin-A
(9) (Fig. 1).
Scheme 2. Construction of 18-membered ring. Reagents and conditions:
(a) 11 or 12 (1.0 equiv.), DEAD (1.1 equiv.), PPh3 (1.1 equiv.), benzene,
room temperature, 10 min. (b) Pd(PPh3)4 (0.05 equiv.), pyrrolidine
(1.2 equiv.), CH2Cl2, room temperature, 30 min. (c) 15 (1.2 equiv.),
EDCI (1.2 equiv.), CH2Cl2, room temperature, 30 min. (d) Cs2CO3
(3.0 equiv.), n-Bu4NI (2.0 equiv.), CH3CN, 608C, 2 h. (e) aq. HF (excess),
CH3CN, room temperature, 2 min. (f) DEAD (1.2 equiv.), PPh3
(1.2 equiv.), benzene/CH2Cl2 (2:1), room temperature, 10 min.
3-amino-n-butyric acid. The coupling reaction between
sulfonamide 10 and 11 was effected under Mitsunobu
conditions to give the diamine derivative 13. After the
palladium-mediated deprotection of the allyl group, the
resultant acid was condensed with diamine 158 to give the
cyclization precursor 16. Upon treatment of 16 with Cs2CO3
at 608C in acetonitrile, the desired cyclization proceeded
smoothly to give 19 in 79% yield. In order to perform the
similar macrocyclization under Mitsunobu conditions, the
precursor 18 was prepared from 10 and 12 by the similar
sequence described above. After removal of the TBS group,
the resultant alcohol 18 was subjected to the Mitsunobu
conditions to give the desired cyclization product 19 in 69%
yield. Both ring closures were successfully performed even
at 0.1 M concentration, obviating the need for high-dilution
conditions. As we hoped, the nosyl (Ns) group-mediated
cyclization proved to be an exceedingly effective method
for the construction of 18-membered ring.
Lipogrammistin-A (9) was isolated from the skin mucus of
grammistid fish by Fusetani and Tachibana.14 The structure
of lipogrammistin-A was determined on the basis of
extensive NMR studies, and the first total synthesis has
recently been reported by Tachibana.15 One of the key
structural features of 9 is the acylated polyamine lactam
ring. Firstly, construction of the 18-membered ring was
examined in the model compounds 16 and 18 (Scheme 2).
The cyclization precursors were synthesized from the
sulfonamide 10, which was readily available from
Our total synthesis of lipogrammistin-A (9) commenced
with carboxylic acid 2016 (Scheme 2). After a one-pot
exchange of the Cbz protecting group with a Boc group,17
the carboxylic acid was converted to the corresponding thiol
ester 21.18 Upon treatment with triethylsilane and 10% Pd
on C at room temperature, the thiol ester 21 underwent
Table 2. Synthesis of medium-sized ring by means of Mitsunobu reaction
Ring size
Bromide
Alkylationa (yield %)
Cyclizationb (yield %)
8
9
10
2a
2b
2c
8a (66)
8b (85)
8c (62)
4a (59)
4b (57)
4c (62)
a
Alkylation conditions: (1) K2CO3, n-Bu4Nl, DMF, 608C. (2) TFA,
CH2Cl2. (3) K2CO3, MeOH.
Cyclization conditions: PPh3, DEAD, toluene/THF (3:1).
b
Figure 1. Structure of lipogrammistin-A (9).

T. Kan et al. / Tetrahedron 58 (2002) 6267–6276
6269
smooth reduction to give aldehyde 22,19 which, without
purification, was subjected to the Wittig reaction to afford
the cis-alkene 23. The direct conversion of the thiol ester
into the aldehyde, which was developed in our laboratories,
is particularly valuable in the case where the intermediate
alcohol of the conventional acid-to-alcohol-to-aldehyde
protocol would have a chance to be captured by an internal
ester as a 5- or 6-membered lactone. At this stage, the Boc
group in 23 was deprotected under acidic conditions and the
resultant amine was converted to the 2-nitrobenzenesul-
fonamide 24 with NsCl and Et3N. Coupling between the
sulfonamide 24 and alcohol 11 was performed under the
standard Mitsunobu conditions to give 25 in excellent yield.
Since the undesired b-elimination of the alkylsulfonamide
in 25 occurred under alkaline hydrolysis conditions,
conversion of the methyl ester to the carboxylic acid 27
was performed in a two-step sequence via the corresponding
allyl ester 26. The carboxylic acid 27 thus obtained, was
condensed with amine 15 in a conventional manner to give
the amide 28. Upon heating a mixture of the sulfonamide
28, tetrabutylammonium iodide, and Cs2CO3 in acetonitrile
at 608C, the cyclization proceeded smoothly to give
predominantly the desired product 29 in 86% yield. After
removal of the three Ns groups in 29 with excess
mercaptoethanol and DBU in acetonitrile, the resultant
triamine was selectively diacylated with (S)-2-methyl-
butyric acid and BOPCl20 to give 9. All spectroscopic
data (1H and 13C NMR, IR, and MS) of synthetic
lipogrammistin-A (9) were identical with those of the
natural product. The total synthesis of lipogrammistin-A (9)
starting with carboxylic acid 20 has been achieved in a 13-
step sequence in 12% overall yield (Scheme 3).
3. Conclusion
In summary, the Ns-strategy proved to be a powerful
protocol for the construction of medium- and large-sized
rings. Considering the mildness of the alkylation and the
deprotection conditions, the Ns-strategy would be com-
patible with a variety of functional groups. Furthermore, the
fact that both alcohols and halides served as starting
materials would allow preparation of a wide range of
nitrogen heterocycles. Further applications of this method-
ology to the total syntheses of complex natural products are
currently under investigation in our laboratories.
4. Experimental
4.1. General methods
Unless otherwise noted, solvents and reagents were reagent
grade and used without purification. Dichloromethane
(CH2Cl2) and toluene were distilled from calcium hydride.
IR spectra were recorded on a JASCO FT/IR-410
1
spectrophotometer. H NMR and 13C NMR spectra were
obtained as solutions in CDCl3 unless otherwise indicated,
and chemical shifts are reported in parts per million (ppm,
d ) downfield from internal standard tetramethylsilane
(TMS), which were taken on a JEOL JNM-LA400.
Coupling constants are reported in Hertz (Hz). Spectra
splitting patterns are designated as s, singlet; br, broad; d,
doublet; t, triplet; m, multiplet. Mass spectra (MS) and high-
resolution mass spectra (HRMS) were measured with a
JEOL JMS-GCmate instrument.
4.1.1. N-(7-Bromoheptyl)-2-nitrobenzenesulfonamide
(3a). To a stirred solution of 2-nitrobenzenesulfonamide
(1) (3.20 g, 15.8 mmol), 2a (1.00 g, 5.13 mmol), and Ph3P
(1.80 g, 8.91 mmol) in toluene (9.00 mL) and THF
(1.20 mL) was added DEAD (40% in toluene, 4 mL,
8.80 mmol) dropwise at 08C under argon atmosphere. The
solution was stirred at 08C for 5 min, and room temperature
for 2.5 h. After removal of the solvent under reduced
pressure, the residue was purified by flash chromatography
(9:1 hexane/AcOEt) on a silica gel column, to give 3a
(1.36 g, 70%) as a white powder. Mp 69.5–71.08C. IR (film,
cm21): 3346, 3096, 2933, 2857, 1539, 1440, 1414, 1360,
Scheme 3. Total synthesis of lipogrammistin-A. Reagents and conditions:
(a) H2 (1 atm), Pd/C (0.1 equiv.), Boc2O (1.3 equiv.), MeOH, room
temperature, 1 h; Et3N (1.0 equiv.), room temperature, 30 min. (b) DCC
(1.1 equiv.), EtSH (2.0 equiv.), DMAP (0.1 equiv.), CH3CN, room
temperature, 1 h. (c) Et3SiH (2.2 equiv.), Pd/C (0.1 equiv.), acetone,
room temperature, 30 min. (d) C8H17CHvPPh3 (2.2 equiv.), THF,
2788C to room temperature, 30 min. (e) SOCl2 (excess), MeOH, room
temperature, 30 min. (f) NsCl (1.0 equiv.), Et3N (2.0 equiv.), CH2Cl2, 08C,
10 min. (g) 11 (1.5 equiv.), DEAD (2.0 equiv.), PPh3 (2.0 equiv.), benzene,
room temperature, 10 min. (h) Ti(OiPr)4 (1.5 equiv.), allyl alcohol, 958C,
15 h. (i) Pd(PPh3)4 (0.05 equiv.), pyrrolidine (1.2 equiv.), CH2Cl2, room
temperature, 30 min. (j) PivCl (1.2 equiv.), Et3N (1.1 equiv.), CH2Cl2,
room temperature, 30 min; 15 (1.2 equiv.), Et3N (1.1 equiv.), room
temperature, 30 min. (k) Cs2CO3 (3.0 equiv.), n-Bu4NI (2.0 equiv.),
CH3CN, 608C, 1 h. (l) HS(CH2)2OH (5.0 equiv.), DBU (5.0 equiv.),
CH3CN, room temperature, 2 h. (m) 30 (3.0 equiv.), BOPCl (4.0 equiv.),
Et3N (5.0 equiv.), CH2Cl2, room temperature, 15 h.
1
1341, 1166, 1125, 1060, 853, 782. H NMR (400 MHz,
CDCl3) d: 1.29 (4H, br), 1.33 (2H, br), 1.52 (2H, br), 1.81
(2H, m), 3.10 (2H, q, J¼6.8 Hz), 3.37 (2H, t, J¼6.8 Hz),
5.23 (1H, br), 7.76 (2H, m), 7.87 (1H, m), 8.14 (1H, m). 13C

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T. Kan et al. / Tetrahedron 58 (2002) 6267–6276
NMR (100 MHz, CDCl3) d: 26.2, 27.8, 28.1, 29.4, 32.5,
33.8, 43.7, 125.3, 131.0, 132.8, 133.5, 133.7, 148.0. FAB-
MS: 379 (MHþ). Anal. calcd for C13H20BrN2O4S: C, 41.17;
H, 5.05; N, 7.39. Found: C, 41.24; H, 5.04; N, 7.30.
313 (MHþ). Anal. calcd for C14H21N2O4S: C, 53.83; H,
6.45; N, 8.97. Found: C, 53.87; H, 6.29; N, 8.68.
4.1.6. 1-(2-Nitrobenzenesulfonyl)-azecane (4c). In a
manner similar to that used to prepare 4a, treatment of 3c
(200 mg, 0.49 mmol) gave 4c (105 mg, 66 %) as a white
powder. Mp 147.0–148.08C. IR (film, cm21): 2928, 2855,
4.1.2. N-(8-Bromooctyl)-2-nitrobenzenesulfonamide
(3b). In a manner similar to that used to prepare 3a,
treatment of 2b (1.05 g, 5.04 mmol) gave 3b (1.32 g, 67%)
as a white powder. Mp 61.5–62.58C. IR (film, cm21): 3346,
3099, 2930, 2856, 1592, 1539, 1440, 1414, 1360, 1342,
1165, 1125, 1061. 1H NMR (400 MHz, CDCl3) d: 1.26 (6H,
m), 1.39 (2H, m), 1.53 (2H, m), 1.83 (2H, m), 3.10 (2H, q,
J¼6.8 Hz), 3.39 (2H, t, J¼6.8 Hz), 5.23 (1H, m), 7.75 (2H,
m), 7.87 (1H, m), 8.15 (1H, m). 13C NMR (100 MHz,
CDCl3) d: 26.4, 28.0, 28.6, 28.9, 29.6, 32.7, 34.0, 43.9,
125.4, 131.2, 132.8, 133.6, 133.8, 148.2. FAB-MS: 393
(MHþ); HRMS (FAB): 393.0411 (C14H22BrN2O4S, MHþ).
Exact mass 393.0413 (MHþ).
1
1542, 1463, 1373, 1346, 1160, 851. H NMR (400 MHz,
CDCl3) d: 1.32 (10H, m), 1.57 (4H, m), 3.29 (4H, t,
J¼8.0 Hz), 7.59 (1H, m), 7.67 (2H, m), 7.97 (1H, m). 13C
NMR (100 MHz, CDCl3) d: 26.2, 27.9, 28.3, 28.5, 48.7,
124.0, 130.6, 131.4, 133.2, 133.3, 148.3. FAB-MS: 327
(MHþ); HRMS (FAB): 327.1311 (C15H23N2O4S, MHþ).
Exact mass 327.1308 (MHþ). Anal. calcd for C15H22N2O4S:
C, 54.96; H, 6.74; N, 8.30. Found: C, 55.19; H, 6.79; N,
8.58.
4.1.7. N-(7-Hydroxyheptyl)-2-nitrobenzenesulfonamide
(8a). To a stirred solution of N-Boc-2-nitrobenzenesul-
fonamide (7) (1.25 g, 4.14 mmol), K2CO3 (2.50 g,
18.1 mmol) and n-Bu4NI (40 mg, 0.11 mmol) in DMF
(7.00 mL) was added 2a (0.77 g, 3.98 mmol). The solution
was stirred at 608C for 10 h, and then poured into water. The
reaction mixture was extracted with AcOEt (3£20 mL).
The combined organic layer was washed with brine, dried
over MgSO4, filtered, and evaporated. The crude residue
was dissolved in CH2Cl2 (1.00 mL) and TFA (7.00 mL)
stirred for 1 h at room temperature, and then it was
concentrated. The residue was dissolved in MeOH
(20 mL), and stirred for 10 min with K2CO3, then poured
into water and extracted with CH2Cl2 (3£20 mL). The
combined organic layer was washed with brine, dried over
MgSO4, filtered, and evaporated. Purification was per-
formed by recrystallization with ether and hexane, to give
8a (1.00 g, 60%) as a white powder. Mp 57.5–59.58C. IR
(film, cm21): 3343, 2933, 2859, 1543, 1413, 1364, 1339,
1165, 1126, 1059, 853, 783, 741. 1H NMR (400 MHz,
CDCl3) d: 1.30 (4H, m), 1.50 (2H, m), 1.53 (4H, m), 3.09
(2H), 3.63 (2H), 5.25 (1H, m), 7.75 (2H, m), 7.87 (1H, m),
8.14 (1H, m). 13C NMR (100 MHz, CDCl3) d: 25.5, 26.4,
28.8, 29.5, 32.5, 43.8, 62.9, 125.4, 131.1, 132.8, 133.5,
133.8, 149.8. FAB-MS: 317 (MHþ); HRMS (FAB):
317.1180 (C13H21O2N5S, MHþ). Exact mass 317.1177
(MHþ).
4.1.3. N-(9-Bromononyl)-2-nitrobenzenesulfonamide
(3c). In a manner similar to that used to prepare 3a,
treatment of 2c (1.12 g, 5.02 mmol) gave 3c (1.52 g, 74%)
as a white powder. Mp 72.5–74.08C. IR (film, cm21): 3346,
3099, 2930, 2856, 1592, 1539, 1440, 1414, 1360, 1342,
1165, 1125, 1061. 1H NMR (400 MHz, CDCl3) d: 1.25 (8H,
m), 1.40 (2H, m), 1.54 (2H, m), 1.83 (2H, t, J¼4.0 Hz), 3.10
(2H, q, J¼3.4 Hz), 3.40 (2H, t, J¼3.4 Hz), 5.22 (1H, m),
7.75 (2H, m), 7.87 (1H, m), 8.15 (1H, m). 13C NMR
(100 MHz, CDCl3) d: 26.4, 28.0, 28.5, 28.8, 29.1, 29.5,
32.7, 34.0, 43.8, 125.3, 131.1, 132.7, 133.5, 133.8, 148.1.
FAB-MS: 407 (MHþ). Anal. calcd for C15H24BrN2O4S: C,
44.23; H, 5.69; N, 6.88. Found: C, 44.46; H, 5.71; N, 6.64.
4.1.4. 1-(2-Nitrobenzenesulfonyl)-azocane (4a). To a
stirred solution of Cs2CO3 (2.10 g, 6.45 mmol) and
n-Bu4NI (980 mg, 2.65 mmol) in CH3CN (3.00 mL) was
added 3a (500 mg, 1.32 mmol) in CH3CN (24.0 mL) via
syringe pump over 2 h at 608C. The reaction was stirred for
2 h at 608C after the addition was complete. The reaction
mixture was poured into water and extracted with AcOEt
(3£50 mL). The combined organic layer was washed with
brine, dried over MgSO4, filtered, and evaporated. The
residue was purified by flash chromatography (Et2O) on a
silica gel column, to give 4a (245 mg, 62%) as a white
powder. Mp 94.0–95.08C. IR (film, cm21): 2929, 2857,
1
1542, 1456, 1373, 1344, 1164, 993. H NMR (400 MHz,
4.1.8. N-(8-Hydroxyoctyl)-2-nitrobenzenesulfonamide
(8b). In a manner similar to that used to prepare 8a,
treatment of 2b (2.00 g, 9.60 mmol) gave 8b (2.69 g, 85%)
as a white powder. Mp 71.5–73.08C. IR (film, cm21): 3289,
2931, 2856, 1540, 1418, 1362, 1338, 1163, 1126, 1058. 1H
NMR (400 MHz, CDCl3) d: 1.27 (6H, m), 1.52 (6H, m),
3.09 (2H, m), 3.62 (2H, m), 5.28 (1H, m), 7.71 (2H, m), 7.87
(1H, m), 8.14 (1H, m). 13C NMR (100 MHz, CDCl3) d:
25.5, 26.3, 28.9, 29.1, 29.5, 32.6, 43.8, 62.9, 125.3, 131.1,
132.7, 133.5, 133.8, 148.1. FAB-MS: 331 (MHþ); HRMS
(FAB): 331.1327 (C14H23O2N5S, MHþ). Exact mass
331.1329 (MHþ).
CDCl3) d: 1.59 (6H, m), 1.69 (4H, m), 3.25 (4H, t,
J¼6.0 Hz), 7.52 (1H, m), 7.61 (2H, m), 7.84 (1H, m). 13C
NMR (100 MHz, CDCl3) d: 24.8, 26.5, 27.7, 49.3, 123.9,
130.4, 131.4, 132.5, 133.3, 148.4. FAB-MS: 299 (MHþ);
HRMS (FAB): 299.0981 (C13H19N2O4S, MHþ). Exact mass
299.0995 (MHþ). Anal. calcd for C13H18N2O4S: C, 52.33;
H, 6.08; N, 9.39. Found: C, 52.29; H, 5.99; N, 9.35.
4.1.5. 1-(2-Nitrobenzenesulfonyl)-azonane (4b). In a
manner similar to that used to prepare 4a, treatment of 3b
(200 mg, 0.51 mmol) gave 4b (102 mg, 64%) as a white
powder. Mp 133.5–135.08C. IR (film, cm21): 2931, 2859,
1725, 1546, 1463, 1373, 1347, 1290, 1161, 1125, 851, 777,
742. 1H NMR (400 MHz, CDCl3) d: 1.32 (8H, m), 1.57 (4H,
m), 3.25 (4H, t, J¼8.0 Hz), 7.61 (1H, m), 7.68 (2H, m), 7.98
(1H, m). 13C NMR (100 MHz, CDCl3) d: 25.9, 27.9, 28.1,
47.8, 124.4, 129.0, 130.9, 131.8, 133.6, 148.4. FAB-MS:
4.1.9. N-(9-Hydroxynonyl)-2-nitrobenzenesulfonamide
(8c). In a manner similar to that used to prepare 8a,
treatment of 2c (860 mg, 4.41 mmol) gave 8c (812 mg,
54%) as a white powder. Mp 68.5–70.08C. IR (film, cm21):
3287, 2926, 2853, 1541, 1360, 1333, 1163, 1126, 1062, 854,

T. Kan et al. / Tetrahedron 58 (2002) 6267–6276
6271
780, 728. 1H NMR (400 MHz, CDCl3) d: 1.25 (8H, m), 1.53
(6H, m), 3.09 (2H, q, J¼6.8 Hz), 3.63 (2H, t, J¼6.8 Hz),
5.27 (1H, m), 7.74 (2H, m), 7.87 (1H, m), 8.14 (1H, m).
13C NMR (100 MHz, CDCl3) d: 25.6, 26.4, 28.9, 29.2,
29.3, 29.5, 32.7, 43.8, 63.0, 125.3, 131.1, 132.7, 133.5,
133.8, 148.0. FAB-MS: 345 (MHþ); HRMS (FAB):
345.1407 (C15H25O2N5S, MHþ). Exact mass 345.1414
(MHþ).
nitrobenzenesulfonylamino)propan-1-ol8 (2.72 g, 10.5 mmol)
and dibromopentane (7.13 mL, 52.3 mmol) in acetonitrile
(50 mL) were added cesium carbonate (10.3 g, 31.5 mmol)
at room temperature. After stirring at 608C for 2 h, 3N
hydrochloric acid was added to the reaction mixture. The
mixture was extracted with dichloromethane. The organic
layer was washed with brine and dried over MgSO4. After
the solvent was concentrated in vacuo, the residue was
purified by column chromatography on silica gel (2:3
AcOEt/hexane) to give 11 (3.64 g, 85%) as a yellow oil. IR
(film, cm21) 3560, 3417, 3094, 2941, 2880, 1543, 1465,
1438, 1374, 1344, 1159, 1125, 1059, 913, 852, 779, 749. 1H
NMR (400 MHz, CDCl3) d: 1.39 (2H, tt, J¼8.0, 8.0 Hz),
1.58 (2H, tt, J¼8.0, 8.0 Hz), 1.76–1.88 (4H, m), 3.31 (2H,
t, J¼7.8 Hz), 3.35 (2H, t, J¼6.4 Hz), 3.46 (2H, t,
J¼6.8 Hz), 3.71 (2H, tt, J¼6.0, 6.0 Hz), 7.64 (1H, m),
7.67–7.73 (2H, m), 8.23 (1H, m). 13C NMR (100 MHz,
CDCl3) d: 25.1, 27.4, 30.8, 32.0, 33.4, 44.3, 47.4, 59.0,
124.2, 130.5, 131.7, 133.2, 133.6, 147.9.
4.1.10.
1-(2-Nitrobenzenesulfonyl)-azocane
(4a).
Mitsunobu conditions. To a stirred solution of Ph3P
(463 mg, 2.29 mmol) and 8a (200 mg, 0.63 mmol) in
toluene (48.0 mL) and THF (16.0 mL) was added DEAD
(40% in toluene, 1.05 mL, 2.31 mmol) dropwise, and the
mixture was stirred for 3 h. The reaction mixture was
concentrated and the residue was purified by flash
chromatography (1:4 AcOEt/hexane) on a silica gel column
to give 4a (112 mg, 59%) as white powder. All spectra data
were identical with 4a described above.
4.1.11.
1-(2-Nitrobenzenesulfonyl)-azonane
(4b).
4.1.15. 3-[{3-[(5-Bromopentyl)-(2-nitrobenzenesulfonyl)-
amino]-propyl}-(2-nitrobenzenesulfonyl)-amino]-buty-
ric acid allyl ester (13). To a solution of 10 (533 mg,
1.62 mmol), 11 (664 mg, 1.62 mmol) and PPh3 (468 mg,
1.79 mmol) in benzene (8.0 mL) was slowly added DEAD
(40% in toluene, 0.81 mL, 1.79 mmol) at room temperature.
After stirring for 10 min, the mixture was purified by flash
column chromatography on silica gel (3:7 AcOEt/hexane)
to give 13 (785 mg, 71%). IR (film, cm21) 3093, 2940,
1736, 1544, 1466, 1439, 1373, 1347, 1296, 1161, 1124,
Mitsunobu conditions. In a manner similar to that used to
prepare 4a using Mitsunobu conditions, treatment of 8b
(150 mg, 0.45 mmol) gave 4b (80 mg, 57%) as a white
powder. All spectra data were identical with 4b described
above.
4.1.12.
1-(2-Nitrobenzenesulfonyl)-azecane
(4c).
Mitsunobu conditions. In a manner similar to that used to
prepare 4a using Mitsunobu conditions, treatment of 8c
(300 mg, 0.87 mmol) gave 4c (200 mg, 62%) as a white
powder. All spectra data were identical with 4c described
above.
1
1059, 968, 852, 778, 743. H NMR (400 MHz, CDCl3) d:
1.20 (3H, d, J¼6.8 Hz), 1.40 (2H, tt, J¼8.0, 8.0 Hz), 1.60
(2H, m), 1.85 (2H, tt, J¼6.8, 6.8 Hz), 1.96 (2H, m), 2.46
(1H, dd, J¼8.8, 15.6 Hz), 2.59 (1H, dd, J¼6.0, 15.6 Hz),
3.25 (2H, t, J¼8.4 Hz), 3.31–3.52 (6H, m), 4.52 (2H, d,
J¼6.0 Hz), 5.23–5.32 (2H, m), 5.83–5.92 (1H, m), 7.59–
7.64 (2H, m), 7.69–7.71 (4H, m), 8.02–8.08 (2H, m). 13C
NMR (100 MHz, CDCl3) d: 19.2, 25.1, 27.1, 30.0, 32.1,
33.5, 40.6, 41.6, 44.9, 47.2, 51.2, 65.6, 118.8, 124.1, 124.2,
130.8, 131.4, 131.8, 131.9, 132.9, 133.2, 133.6, 133.8,
147.9, 148.0, 169.9.
4.1.13. 3-(2-Nitrobenzenesulfonylamino)-butyric acid
allyl ester (10). To a solution of 3-amino-butyric acid
(4.12 g, 40.0 mmol) in allyl alcohol (15 mL) was slowly
added thionyl chloride (8.26 mL, 120 mmol) at 08C. After
stirring at room temperature 15 h, the solvent was
evaporated. The residue was diluted with dichloromethane,
the organic layer was washed sequentially with saturated
NaHCO3 and brine, and dried over MgSO4. Evaporation of
the solvent gave the allyl ester (2.45 g, 43%). To a solution
of the allyl ester (2.45 g, 17.1 mmol) in dichloromethane
(50 mL) were added 2-nitrobenzenesulfonyl chloride
(2.65 g, 12.0 mmol) and triethylamine (3.57 mL,
25.6 mmol) at 08C. After stirring at room temperature for
30 min, 3N hydrochloric acid was added to the mixture. The
organic layer was washed with brine and dried over MgSO4.
Evaporation of the solvent gave residue, which was purified
by column chromatography on silica gel (1:4 AcOEt/hex-
ane) to give 10 (3.43 g, 87%) as a yellow solid. IR (film,
cm21) 3334, 3096, 2982, 1735, 1593, 1541, 1442, 1420,
1363, 1295, 1169, 1125, 1088, 989, 854, 784, 742, 731. 1H
NMR (400 MHz, CDCl3) d: 1.22 (3H, d, J¼5.6 Hz), 2.57
(2H, m), 3.56 (1H, m), 4.53 (2H, d, J¼5.6 Hz), 5.27 (2H,
m), 5.82–5.92 (2H, m), 7.72–7.78 (2H, m), 7.85 (1H, m),
8.17 (1H, m). 13C NMR (100 MHz, CDCl3) d: 21.0, 41.0,
47.6, 65.5, 118.9, 125.4, 130.7, 131.6, 132.9, 133.5, 134.7,
170.3.
4.1.16. 3-[{3-[(5-Bromopentyl)-(2-nitrobenzenesulfonyl)-
amino]-propyl}-(2-nitrobenzenesulfonyl)-amino]-buty-
ric acid. To a solution of 13 (1.19 g 1.62 mmol) in
dichloromethane (15 mL) were added Pd(PPh3)4 (93.8 mg,
0.081 mmol) and pyrrolidine (0.135 mL, 1.94 mmol) at
room temperature. After stirring for 30 min, 1N hydro-
chloric acid was added to the mixture. The phases were
separated and the organic layer was washed with brine and
dried over MgSO4. After evaporation of the solvent, the
residue was purified by column chromatography on silica
gel (3:2 AcOEt/hexane) to give the carboxylic acid
(784 mg) as a yellow powder. IR (film, cm21) 3095, 2941,
1712, 1544, 1466, 1439, 1373, 1346, 1297, 1219, 1161,
1124, 1059, 969, 852, 755; 1H NMR (400 MHz, CDCl3) d:
1.24 (3H, d, J¼6.8 Hz), 1.41 (2H, tt, J¼7.5, 7.5 Hz), 1.57
(2H, tt, J¼7.8, 7.8 Hz), 1.84 (2H, tt, J¼7.8, 7.8 Hz), 1.94–
1.99 (2H, m), 2.48 (1H, dd, J¼8.1, 16.1 Hz), 2.62 (1H, dd,
J¼6.1, 15.4 Hz), 3.25 (2H, t, J¼7.8 Hz), 3.32–3.38 (6H,
m), 4.34 (1H, m), 7.62–7.64 (2H, m), 7.69–7.73 (4H, m),
8.02–8.08 (2H, m); 13C NMR (100 MHz, CDCl3) d: 19.3,
25.0, 27.1, 29.8, 32.0, 33.6, 40.3, 41.5, 44.8, 47.2, 51.0,
4.1.14. N-(5-Bromopentyl)-N-(3-hydroxypropyl)-2-
nitrobenzenesulfonamide (11). To a solution of 3-(2-

6272
T. Kan et al. / Tetrahedron 58 (2002) 6267–6276
124.2, 130.5, 131.10, 131.9, 132.0, 132.1, 132.5, 132.9,
133.8, 134.0, 147.9, 147.9, 175.9.
(350 mg, 1.34 mmol) and 5-tert-butyldimethylsilyloxypent-
1-yl-bromide (420 mg, 1.49 mmol) in acetonitrile (7 mL)
was added cesium carbonate (1.46 g, 4.48 mmol) at room
temperature. After stirring at 608C for 15 h, 1N hydrochloric
acid was added to the mixture. The combined mixture
extracted with dichloromethane. The organic layer was
washed with brine and dried over MgSO4. Evaporation of
the solvent gave residue, which was purified by column
chromatography on silica gel (3:7 AcOEt/hexane) to give 12
(521 mg, 95%) as a yellow oil. IR (film, cm21) 3557, 3430,
2932, 2858, 1546, 1471, 1373, 1347, 1256, 1161, 1098, 851,
836, 777, 748. 1H NMR (400 MHz, CDCl3) d: 0.03 (6H, s),
0.88 (9H, s), 1.29 (2H, m), 1.43–1.60 (4H, m), 1.79 (2H, tt,
J¼6.1, 6.1 Hz), 1.91 (1H, t, J¼6.0 Hz), 3.29 (2H, t,
J¼7.8 Hz), 3.46 (2H, t, J¼6.8 Hz), 3.55 (2H, t, J¼6.4 Hz),
3.71 (2H, dt, J¼6.0, 6.0 Hz), 7.61–7.69 (3H, m), 8.01 (1H,
dd, J¼1.8, 7.2 Hz). 13C NMR (100 MHz, CDCl3) d: 25.3,
22.9, 25.9, 28.0, 30.9, 32.3, 44.3, 47.8, 59.0, 62.8, 124.2,
130.6, 131.6, 133.4.
4.1.17. 3-[{3-[(5-Bromopentyl)-(2-nitrobenzenesulfonyl)-
amino]-propyl}-(2-nitrobenzenesulfonyl)-amino]-N-[3-
(2-nitrobenzenesulfonylamino)-propyl]-butyramide
(16). To a solution of the carboxylic acid (784 mg,
1.15 mmol) in dichloromethane (12 mL) were added 158
(314 mg, 1.21 mmol) and EDCI (265 mg, 1.38 mmol) at
room temperature. After stirring for 30 min, 1N hydro-
chloric acid was added to the mixture. The phases were
separated and the organic layer was washed with brine and
dried over MgSO4. Evaporation of the solvent gave residue,
which was purified by column chromatography on silica gel
(4:1 AcOEt/hexane) to give 16 (760 mg, 51% from 13) as a
yellow powder. IR (film, cm21) 3403, 3095, 2941, 2874,
1661, 1591, 1543, 1440, 1372, 1343, 1266, 1163, 1124,
1
1060, 969, 852, 780, 740. H NMR (400 MHz, CDCl3) d:
1.16 (3H, d, J¼6.8 Hz), 1.38 (2H, tt, J¼7.5, 7.5 Hz), 1.68
(2H, tt, J¼6.0, 6.0 Hz), 1.83 (2H, tt, J¼7.1, 7.1 Hz), 1.90–
2.01 (2H, m), 2.37 (1H, dd, J¼7.1, 14.9 Hz), 2.54 (1H, dd,
J¼7.1, 14.9 Hz), 3.14 (2H, m), 3.25–3.39 (10H, m), 4.33
(1H, m), 6.02 (1H, t, J¼6.4 Hz), 6.18 (1H, t, J¼6.2 Hz),
7.60–7.65 (2H, m), 7.70–7.76 (6H, m), 7.83 (1H, dd,
J¼1.7, 8.6 Hz), 8.01 (1H, dd, J¼3.2, 6.0 Hz), 8.09–8.15
(2H, m). 13C NMR (100 MHz, CDCl3) d: 19.1, 25.1, 27.1,
29.7, 32.0, 33.6, 36.1, 40.7, 41.7, 42.4, 45.3, 47.6, 51.7,
124.0, 124.1, 125.2, 128.4, 128.6, 130.4, 130.7, 131.2,
132.0, 132.7, 132.8, 132.8, 133.5, 133.8, 133.9, 147.9,
147.9, 147.9, 170.2. FAB-MS: 920 (MHþ); HRMS (FAB):
920.1249 (C33H43BrN7O13S3, MHþ). Exact mass 920.1264
(MHþ).
4.1.20. 3-[{3-[[5-(tert-Butyldimethylsilanyloxy)-pentyl]-
(2-nitrobenzenesulfonyl)-amino]-propyl}-(2-nitrobenze-
nesulfonyl)-amino]-butyric acid allyl ester (14). To a
solution of 10 (262 mg, 0.799 mmol), 12 (327 mg,
0.799 mmol), and PPh3 (252 mg, 0.959 mmol) in toluene
(4.0 mL) were added DEAD in toluene (40%, 0.43 mL,
0.959 mmol) at room temperature. After stirring for 10 min,
the mixture was concentrated and the residue was purified
by flash column chromatography on silica gel (3:7
AcOEt/hexane) to give 14 (302 mg, 49%). IR (film, cm21
)
3095, 2934, 2857, 1735, 1546, 1472, 1438, 1374, 1349,
1295, 1256, 1162, 1124, 1059, 966, 852, 836, 777, 743. 1H
NMR (400 MHz, CDCl3) d: 0.03 (6H, s), 0.88 (9H, s), 1.20
(3H, d, J¼6.8 Hz), 1.28 (2H, m), 1.44–1.52 (4H, m), 1.94
(2H, m), 2.45 (1H, dd, J¼8.3, 15.5 Hz), 2.58 (1H, dd,
J¼5.8, 15.3 Hz), 3.22–3.36 (6H, m), 3.58 (2H, t,
J¼6.4 Hz), 4.33 (1H, m), 4.51 (2H, d, J¼5.6 Hz), 5.23–
5.32 (2H, m), 5.83–5.92 (1H, m), 7.59–7.62 (2H, m), 7.67–
7.71 (4H, m), 8.01–8.07 (2H, m). 13C NMR (100 MHz,
CDCl3) d: 25.3, 18.4, 19.3, 22.9, 25.9, 27.8, 30.0, 32.3,
40.6, 41.6, 44.8, 47.4, 51.2, 62.9, 65.6, 118.8, 124.1, 124.2,
130.8, 131.4, 131.8, 131.8, 133.0, 133.4, 133.5, 133.7,
148.1, 148.1, 169.9.
4.1.18. 8-Methyl-1,9,13-tris-(2-nitrobenzenesulfonyl)-
1,5,9,13-tetraazacyclooctadecan-6-one (19). Alkylation
conditions. To a solution of 16 (27.9 mg, 0.03 mmol) in
acetonitrile (0.76 mL) were added cesium carbonate
(29.6 mg, 0.09 mmol) and n-Bu4NI (22.4 mg, 0.06 mmol)
at room temperature. After stirring at 608C for 2 h, 1N
hydrochloric acid was added to the mixture. The mixture
was extracted with dichloromethane. The organic layer was
washed with brine and dried over MgSO4. Evaporation of
the solvent gave residue, which was purified by column
chromatography on silica gel (AcOEt) to give 19 (20.1 mg,
79%) as a yellow powder. Mp 88.0–90.08C. IR (film, cm21
)
4.1.21. 3-[{3-[[5-(tert-Butyldimethylsilanyloxy)-pentyl]-
(2-nitrobenzenesulfonyl)-amino]-propyl}-(2-nitrobenze-
nesulfonyl)-amino]-butyric acid. To a solution of 14
(174 mg 0.226 mmol) in dichloromethane (2.0 mL) were
added Pd(PPh3)4 (13.1 mg, 0.0113 mmol) and pyrrolidine
(22.6 mL, 0.271 mmol) at room temperature. After stirring
for 30 min, 1N hydrochloric acid was added to the mixture.
The phases were separated and the organic layer was
washed with brine and dried over MgSO4. Evaporation of
the solvent gave a residue that was purified by column
chromatography on silica gel (4:1 AcOEt/hexane) to give
the carboxylic acid (143 mg, 86%) as a yellow powder.
3409, 3092, 2940, 2874, 1670, 1590, 1543, 1466, 1439,
1374, 1345, 1267, 1162, 1125, 1060, 1032, 961, 852, 778,
737. 1H NMR (400 MHz, CDCl3) d: 1.15 (3H, d,
J¼6.6 Hz), 1.37 (2H, tt, J¼7.3, 7.3 Hz), 1.59–1.68 (4H,
m), 1.82 (2H, m), 1.97–2.05 (2H, m), 2.44 (1H, dd, J¼4.3,
16.1 Hz), 2.60 (1H, dd, J¼11.0, 16.1 Hz), 3.20–3.43 (12H,
m), 4.42 (1H, m), 6.30 (1H, t, J¼5.8 Hz), 7.56–7.77 (9H,
m), 7.90–7.96 (2H, m), 8.07–8.10 (1H, m). 13C NMR
(100 MHz, CDCl3) d: 18.7, 23.2, 27.5, 29.5, 28.4, 30.7,
37.3, 42.5, 42.8, 46.2, 46.4, 48.7, 49.1, 52.3, 123.9, 124.2,
130.1, 130.4, 131.0, 131.8, 131.9, 132.0, 132.4, 132.8,
133.1, 133.4, 133.8, 134.0, 148.1, 148.2, 148.3, 169.4. FAB-
MS:
840
(MHþ);
HRMS
(FAB):
840.1970
4.1.22. 3-[{3-[[5-(tert-Butyldimethylsilanyloxy)-pentyl]-
(2-nitrobenzenesulfonyl)-amino]-propyl}-(2-nitro-
benzenesulfonyl)-amino]-N-[3-(2-nitrobenzenesulfonyl-
amino)-propyl]-butyramide (17). To a solution of the
carboxylic acid (134 mg, 0.183 mmol) in acetonitrile
(2.0 mL) were added DCC (45.3 mg, 0.220 mmol) and 158
(C33H42N7O13S3, MHþ). Exact mass 840.2002 (MHþ).
4.1.19. N-[5-(tert-Butyl-dimethylsilanyloxy)-pentyl]-N-
(3-hydroxypropyl)-2-nitrobenzenesulfonamide (12). To
a solution of 3-(2-nitrobenzenesulfonylamino)propan-1-ol8

T. Kan et al. / Tetrahedron 58 (2002) 6267–6276
6273
(56.9 mg, 0.220 mmol) at room temperature. After stirring
for 20 min, the mixture was filtered through a Celite pad and
concentrated. The residue was purified by column chroma-
tography on silica gel (4:1 AcOEt/hexane) to give 17
(132 mg, 74%) as a yellow powder. IR (film, cm21) 3402,
3096, 293, 2858, 1659, 1591, 1544, 1471, 1440, 1372, 1344,
1256, 1164, 1124, 1095, 1060, 966, 852, 836, 778, 741. 1H
NMR (400 MHz, CDCl3) d: 0.03 (6H, s), 0.87 (9H, s), 1.17
(3H, d, J¼6.8 Hz), 1.24–1.29 (2H, m), 1.45–1.53 (4H, m),
1.65 (2H, tt, J¼6.2, 6.2 Hz), 1.86–2.03 (2H, m), 2.38 (1H,
dd, J¼7.6, 14.0 Hz), 2.55 (1H, dd, J¼7.1, 14.0 Hz), 3.14
(2H, dt, J¼6.8, 6.8 Hz), 3.28–3.32 (8H, m), 3.55 (2H, t,
J¼6.3 Hz), 6.00 (1H, m), 4.33 (1H, m), 6.15 (1H, t,
J¼6.0 Hz, NH), 7.59–7.64 (2H, m), 7.70–7.76 (6H, m),
7.83 (1H, dd, J¼1.7, 5.9 Hz), 7.98–8.01 (1H, m), 8.09–
8.15 (2H, m). 13C NMR (100 MHz, CDCl3) d: 25.4, 18.3,
19.1, 22.8, 25.9, 27.8, 29.7, 30.1, 32.2, 36.0, 40.7, 41.6,
42.4, 45.2, 47.9, 51.7, 62.8, 124.0, 124.1, 125.1, 130.4,
130.7, 131.3, 131.9, 131.9, 132.8, 132.8, 132.9, 133.4,
133.7, 133.8, 133.9, 147.9, 147.9, 147.9, 176.2.
(100 mL) was added 10% Pd on C (2.9 g, 3.07 mmol). After
stirring under hydrogen atmosphere at room temperature for
1 h, to the reaction mixture was added triethylamine
(3.8 mL, 27.3 mmol). After stirred for 10 min, the catalyst
was filtered through a Celite pad. The filtrate was
evaporated to give residue, which was purified by column
chromatography on silica gel (2:3 AcOEt/hexane) to give
the carboxylic acid as a colorless oil (7.7 g). [a]2D4¼21.368
(c¼0.746, CHCl3); IR (film, cm21) 3352, 2980, 1737, 1717,
1515, 1439, 1394, 1368, 1250, 1165, 1054, 1028, 850, 778.
1H NMR (400 MHz, CDCl3) d: 1.44 (9H, s), 2.57–2.75 (4H,
m), 3.69 (3H, s), 4.31 (1H, m), 5.40 (1H, m). 13C NMR
(100 MHz, CDCl3) d: 28.3, 37.9, 44.1, 51.8, 51.8, 79.8,
155.1, 171.6, 175.7.
4.1.26. (3R )-3-tert-Butoxycarbonylamino-4-ethylsul-
fanylcarbonyl-butyric acid methyl ester (21). To a
solution of the carboxylic acid (7.7 g) in acetonitrile
(100 mL) were added DCC (6.7 g, 2.95 mmol), ethanethiol
(4.4 mL, 59 mmol), and DMAP (360 mg, 0.295 mmol) at
08C. After stirring at room temperature for 1 h, the mixture
was filtrated through a Celite pad. The filtrate was
evaporated to give residue, which was purified by column
chromatography on silica gel (1:9 AcOEt/hexane) to give 21
(5.9 g, 70%, 2 steps) as a colorless solid. [a ]2D7¼þ1.568
(c¼0.810, CHCl3); IR (film, cm21) 3371, 2976, 2932, 1737,
1717, 1697, 1502, 1367, 1250, 1168, 1049, 1024, 874, 851,
780, 752. 1H NMR (400 MHz, CDCl3) d: 1.25 (3H, t,
J¼7.8 Hz), 1.43 (9H, s), 2.59–2.66 (2H, m), 2.81–2.96
(4H, m), 3.70 (3H, s), 4.30 (1H, m), 5.30 (1H, m). 13C NMR
(100 MHz, CDCl3) d: 14.6, 23.5, 28.4, 37.8, 45.0, 47.1,
79.6, 155.1, 171.6, 197.5.
4.1.23. 3-[{3-[(5-Hydroxypentyl)-(2-nitrobenzenesul-
fonyl)-amino]-propyl}-(2-nitrobenzenesulfonyl)-amino]-
N-[3-(2-nitrobenzenesulfonylamino)-propyl]-butyra-
mide (18). To a solution of 17 (56.1 mg, 0.058 mmol) in
acetonitrile (0.5 mL) was added 48% hydrofluoric acid
(100 mL) at 08C. After stirring for 2 min, the reaction was
quenched with saturated NaHCO3 and the mixture was
extracted with dichloromethane. The organic layer was
washed with brine and dried over Na2SO4. Evaporation of
the solvent gave a residue which was purified by column
chromatography on silica gel (4:1 AcOEt/hexane) to give 18
(50 mg, 30% from 14) as a yellow powder. IR (film, cm21
)
3567, 3402, 3096, 2939, 2874, 1653, 1591, 1543, 1440,
1373, 1341, 1267, 1163, 1124, 1060, 959, 852, 780, 740. 1H
NMR (400 MHz, CDCl3) d: 1.15 (3H, d, J¼6.8 Hz), 1.35–
1.39 (2H, m), 1.52–1.62 (4H, m), 1.68 (2H, tt, J¼6.1,
6.1 Hz), 1.85–2.10 (2H, m), 2.37 (1H, dd, J¼7.0, 14.3 Hz),
2.56 (1H, dd, J¼7.3, 14.6 Hz), 3.14 (2H, dt, J¼6.3,
6.3 Hz), 3.25–3.38 (8H, m), 3.62 (2H, t, J¼6.2 Hz), 4.33
(1H, m), 6.00 (1H, d, J¼6.2 Hz), 6.30 (1H, t, J¼6.2 Hz),
7.60–7.64 (2H, m), 7.68–7.76 (6H, m), 7.83 (1H, dd,
J¼2.4, 7.4 Hz), 7.98–8.00 (1H, m), 8.08–8.15 (2H, m). 13C
NMR (100 MHz, CDCl3) d: 19.0, 22.8, 27.8, 29.7, 30.3,
31.9, 36.1, 40.8, 41.8, 42.6, 45.6, 48.2, 51.7, 62.3, 124.0,
124.1, 125.2, 130.5, 130.8, 131.3, 131.9, 132.0, 132.8,
132.8, 133.5, 133.7, 133.9, 133.9, 140.1, 147.9, 148.1,
170.3. FAB-MS: 858 (MHþ); HRMS (FAB): 858.2099
(C33H44O14N7S3, MHþ). Exact mass 858.2108 (MHþ).
4.1.27. (3S,5Z )-3-(tert-Butoxycarbonylamino)-tetradec-
5-enoic acid methyl ester (23). To a solution of 21
(5.9 g, 19.3 mmol) and 10% Pd on C (2.05 g, 1.93 mmol) in
acetone (120 mL) was added triethylsilane (6.8 mL,
42.4 mmol) at room temperature. After stirring at room
temperature for 30 min, the catalyst was filtered off through
a Celite pad. The filtrate was concentrated to give 22, which
was used in the next reaction without further purification. To
a
solution of (1-nonyl)triphenylphosphonium iodide
(22.9 g, 44.4 mmol) in dry tetrahydrofuran (200 mL) was
added 1 M LHMDS in tetrahydrofuran (42.5 mL,
42.5 mmol). After stirring at 08C for 10 min and at room
temperature for 15 min, to this solution was added 22
(19.3 mmol) in dry tetrahydrofuran (15 mL) at 2788C. This
mixture was stirred at room temperature for 30 min and the
reaction was quenched with aqueous ammonium chloride.
The phases were separated and organic layer was washed
sequentially with saturated NaHCO3, saturated Na2S2O3
and brine, and dried over MgSO4. Evaporation of the
solvent gave residue, which was purified by column
chromatography on silica gel (1:4 Et2O/hexane) to give 23
as a colorless solid (5.08 g, 74%, 2 steps). [a ]2D7¼þ11.18
(c¼0.43, CHCl3). IR (film, cm21) 3371, 2955, 2926, 2855,
1741, 1717, 1501, 1437, 1391, 1366, 1247, 1171, 1048,
4.1.24. 8-Methyl-1,9,13-tris-(2-nitrobenzenesulfonyl)-
1,5,9,13-tetraazacyclooctadecan-6-one (19). Mitsunobu
conditions. To a solution of 18 (13.8 mg, 0.0161 mmol)
and PPh3 (5.1 mg, 0.0193 mmol) in dichloromethane
(0.22 mL) and benzene (0.1 mL) was added DEAD (40%
in toluene, 8.0 mL, 0.959 mmol) at room temperature. After
stirring for 10 min, the mixture was purified by preparative
TLC (AcOEt) to give 19 (9.4 mg, 69%). All spectra data
were identical with 19 described above.
1
1024, 856, 777, 721. H NMR (400 MHz, CDCl3) d: 0.88
(3H, t, J¼6.9 Hz), 1.26–1.30 (12H, m), 1.43 (9H, s), 1.99
(2H, dt, J¼7.1, 7.1 Hz), 2.31 (2H, m), 2.52 (2H, d,
J¼6.0 Hz), 3.68 (3H, s), 3.95 (1H, m), 4.94 (1H, m), 5.32
(1H, m), 5.50 (1H, m). 13C NMR (100 MHz, CDCl3) d:
14.2, 22.7, 27.5, 28.5, 29.4, 29.5, 29.5, 29.7, 32.0, 38.0,
4.1.25. (3R )-3-tert-Butoxycarbonylamino-4-methoxycar-
a
solution of 2016 (8.1 g,
bonyl-butyric acid. To
27.4 mmol) and Boc2O (7.7 g, 35.3 mmol) in methanol

6274
T. Kan et al. / Tetrahedron 58 (2002) 6267–6276
51.7, 79.9, 128.5, 133.6, 155.2, 171.2. FAB-MS: 356
(MHþ); HRMS (FAB): 356.2770 (C20H38NO4, MHþ).
Exact mass 356.2801 (MHþ).
44.9, 47.2, 51.9, 55.9, 123.7, 124.0, 124.2, 130.8, 131.6,
131.8, 132.9, 133.2, 133.5, 133.6, 133.7, 148.0, 170.9. FAB-
MS: 831 (MHþ); HRMS (FAB): 831.2297 (C35H51BrN4-
O10S2, MHþ). Exact mass 831.2308 (MHþ).
4.1.28. (3S,5Z )-3-(2-Nitrobenzenesulfonylamino)-tetra-
dec-5-enoic acid methyl ester (24). To a stirred solution
of 23 (5.08 g 14.3 mmol) in methanol (50 mL) was added
thionyl chloride (20 mL, 278 mmol) in methanol (50 mL) at
08C and stirred at room temperature for 30 min. After
evaporating the solvent, the residue was sequentially diluted
with dichloromethane. The organic layer washed sequen-
tially with saturated NaHCO3 and brine, and dried with
MgSO4. Evaporation of the solvent gave the primary amine,
which was used in the next reaction without purification. To
a solution of the primary amine in dichloromethane (50 mL)
were added 2-nitrobenzenesulfonyl chloride (3.17 g,
14.3 mmol) and triethylamine (3.98 mL, 28.6 mmol) at
room temperature. After stirring for 10 min, 1N hydro-
chloric acid was added to the mixture. The phases were
separated and organic layer was washed brine and dried
over MgSO4. Evaporation of the solvent gave residue,
which was purified by column chromatography on silica gel
(3:2 AcOEt/hexane) to give 24 (3.5 g, 56%, 2 steps) as a
yellow oil. [a ]2D7¼þ44.88 (c¼1.175, CHCl3); IR (film,
cm21) 3341, 3097, 2954, 2926, 2855, 1738, 1594, 1543,
1440, 1418, 1361, 1302, 1168, 1125, 1062, 972, 854, 783,
742, 731. 1H NMR (400 MHz, CDCl3) d: 0.88 (3H, t,
J¼7.0 Hz), 1.24–1.29 (12H, m), 1.90 (2H, dt, J¼7.1,
7.0 Hz), 2.31 (2H, dt, J¼7.6, 7.6 Hz), 2.53 (1H, dd, J¼5.9,
8.1 Hz), 2.61 (1H, dd, J¼5.4, 8.2 Hz), 3.61 (3H, s), 3.84
(1H, m), 5.13 (1H, dt, J¼7.6, 10.8 Hz), 5.62 (1H, dt, J¼7.5,
10.1 Hz), 5.86 (1H, d, J¼8.0 Hz), 7.70–7.78 (2H, m), 7.88
(1H, m), 8.16 (1H, m). 13C NMR (100 MHz, CDCl3) d:
14.0, 22.5, 27.2, 29.0, 29.1, 29.3, 29.3, 31.7, 32.4, 38.4,
51.6, 51.7, 123.0, 125.2, 128.5, 130.5, 132.8, 133.4, 134.4,
134.7, 147.6, 171.2. FAB-MS: 441 (MHþ); HRMS (FAB):
441.2030 (C21H33N2O6S3, MHþ). Exact mass 441.2059
(MHþ).
4.1.30. (3S,5Z)-3-[{3-[(5-Bromopentyl)-(2-nitrobenzene-
sulfonyl)-amino]-propyl}-(2-nitrobenzenesulfonyl)-
amino]-tetradec-5-enoic acid allyl ester (26). To a
solution of 25 (329 mg, 0.395 mmol) in allyl alcohol
(5.0 mL) was added Ti(OiPr)4 (0.175 g, 0.593 mmol) at
room temperature. After stirring at 958C for 15 h, to the
mixture was added 1N hydrochloric acid and extracted with
dichloromathane. The organic layer was washed with brine
and dried over MgSO4. Evaporation of the solvent gave
residue, which was purified by column chromatography on
silica gel (1:3 AcOEt/hexane) to give 26 (312 mg) as a
colorless oil. [a ]2D8¼þ6.138 (c¼0.53, CHCl3); IR (film,
cm21) 3092, 2926, 2855, 1736, 1546, 1466, 1439, 1372,
1350, 1264, 1161, 1125, 1059, 987, 852, 777, 743. 1H NMR
(400 MHz, CDCl3) d: 0.88 (3H, t, J¼6.8 Hz), 1.25–1.32
(12H, m), 1.40 (2H, tt, J¼7.6, 7.6 Hz), 1.57 (2H, tt, J¼8.0,
8.0 Hz), 1.84 (2H, tt, J¼6.8, 6.8 Hz), 1.93–2.00 (4H, m),
2.20 (1H, m), 2.37 (1H, m), 2.54 (2H, d, J¼6.8 Hz), 3.23–
3.80 (8H, m), 4.19 (1H, m), 4.50 (2H, d, J¼4.9 Hz), 5.09
(1H, m), 5.23–5.35 (3H, m), 7.58–7.63 (2H, m), 7.67–7.71
(4H, m), 8.03–8.07 (2H, m). 13C NMR (100 MHz, CDCl3)
d: 14.1, 22.6, 25.1, 27.4, 29.1, 29.2, 29.2, 29.3, 29.4, 29.5,
29.9, 31.8, 32.0, 33.4, 38.8, 42.0, 44.9, 47.1, 55.8, 65.5,
118.7, 123.7, 123.9, 123.9, 124.1, 130.7, 131.6, 131.6,
131.8, 132.9, 133.2, 133.6, 133.7, 147.9, 170.2. FAB-MS:
857 (MHþ); HRMS (FAB): 857.2460 (C37H54BrN4O10S2,
MHþ). Exact mass 857.2464 (MHþ).
4.1.31. (3S,5Z)-3-[{3-[(5-Bromopentyl)-(2-nitrobenzene-
sulfonyl)-amino]-propyl}-(2-nitrobenzenesulfonyl)-
amino]-tetradec-5-enoic acid (27). To a solution of 26
(312 mg, 0.364 mmol) in dichloromethane (4.0 mL) were
added Pd(PPh3)4 (21.1 mg, 0.0182 mmol) and pyrrolidine
(36.5 mL, 0.437 mmol) at room temperature. After stirring
for 30 min, 1N hydrochloric acid was added to the mixture.
The organic layer was washed with brine and dried over
MgSO4. Evaporation of the solvent gave residue, which was
purified by column chromatography on silica gel (3:2
AcOEt/hexane) to give 27 (0.277 g, 88%, 3 steps from 24)
as a yellow powder. [a]2D8¼þ8.808 (c¼0.41, CHCl3); IR
(film, cm21) 3095, 2927, 2855, 1711, 1591, 1545, 1466,
1438, 1373, 1349, 1161, 1125, 1059, 962, 852, 777, 742. 1H
NMR (400 MHz, CDCl3) d: 0.88 (3H, t, J¼6.8 Hz), 1.24–
1.28 (12H, m), 1.42 (2H, tt, J¼7.7, 7.7 Hz), 1.84 (2H, tt,
J¼7.6, 7.6 Hz), 1.97–2.00 (4H, m), 2.27 (1H, m), 2.40 (1H,
m), 2.58 (2H, d, J¼6.8 Hz), 3.27–3.39 (8H, m), 4.13 (1H,
m), 5.15 (1H, m), 5.35 (1H, m), 7.59–7.63 (2H, m), 7.68–
7.72 (4H, m), 8.02–8.07 (2H, m). 13C NMR (100 MHz,
CDCl3) d: 14.1, 22.6, 25.1, 27.1, 27.5, 29.1, 29.2, 29.2, 29.3,
29.4, 29.5, 31.8, 32.0, 33.5, 38.1, 42.0, 44.9, 47.1, 55.5,
123.6, 124.2, 130.7, 131.4, 131.7, 131.8, 132.6, 133.1,
133.7, 133.9, 134.0, 135.4, 147.9, 147.9, 176.4.
4.1.29. (3S,5Z)-3-[{3-[(5-Bromopentyl)-(2-nitrobenzene-
sulfonyl)-amino]-propyl}-(2-nitrobenzenesulfonyl)-
amino]-tetradec-5-enoic acid methyl ester (25). To a
solution of 24 (169 mg, 0.385 mmol), 11 (238 mg,
0.578 mmol), and PPh3 (202 mg, 0.770 mmol) in benzene
(2.5 mL) was added DEAD (40% in toluene, 0.35 mL,
0.770 mmol) at room temperature. After stirring for 10 min,
the mixture was concentrated and the residue was purified
by flash column chromatography on silica gel (1:3
AcOEt/hexane) to give 25 (329 mg, including 10% of
impurities from the reagent). Analytical sample was purified
preparative TLC (1:1 AcOEt/hexane) to give 25.
[a ]2D7¼þ3.748 (c¼0.587, CHCl3); IR (film, cm21) 3092,
2927, 2855, 1738, 1545, 1466, 1438, 1373, 1350, 1263,
1216, 1162, 1125, 1059, 962, 852, 777, 743. 1H NMR
(400 MHz, CDCl3) d: 0.88 (3H, t, J¼6.9 Hz), 1.26–1.32
(12H, m), 1.42 (2H, dt, J¼7.8, 7.8 Hz), 1.59 (2H, tt, J¼8.0,
8.0 Hz), 1.85 (2H, tt, J¼6.8, 6.8 Hz), 1.95–2.05 (4H, m),
2.20 (1H, m), 2.37 (1H, m), 2.52 (2H, d, J¼7.3 Hz), 3.25
(2H, t, J¼7.8 Hz), 3.29–3.39 (6H, m), 3.60 (3H, s), 4.18
(1H, m), 5.13 (1H, m), 5.33 (1H, m), 7.58–7.63 (2H, m),
7.66–7.72 (4H, m), 8.03–8.08 (2H, m). 13C NMR
(100 MHz, CDCl3) d: 14.1, 22.6, 25.1, 27.1, 27.4, 29.3,
29.3, 29.4, 29.5, 29.9, 31.4, 31.8, 32.1, 33.4, 38.6, 42.0,
4.1.32. (3S,5Z)-3-[{3-[(5-Bromopentyl)-(2-nitrobenzene-
sulfonyl)-amino]-propyl}-(2-nitrobenzenesulfonyl)-
amino]-tetradec-5-enoic acid [3-(2-nitrobenzenesulfonyl-
amino)-propyl]-amide (28). To a solution of 27 (266 mg,
0.325 mmol) in dichloromethane (4.0 mL) were added

T. Kan et al. / Tetrahedron 58 (2002) 6267–6276
6275
pivaloyl chloride (40 mL, 0.390 mmol) and triethylamine
(45.3 mL, 0.358 mmol) at 08C. After stirring for 30 min, 13
(101 mg, 0.390 mmol) and triethylamine (49.8 mL,
0.358 mmol) were added. After stirring for 30 min, 1N
hydrochloric acid was added to the mixture. The phases
were separated and organic layer was washed with brine and
dried over MgSO4. Evaporation of the solvent gave residue,
which was purified by column chromatography on silica gel
(3:7 AcOEt/hexane) to give 28 as a yellow powder (309 mg,
on silica gel (1:1:8 isopropylamine/MeOH/CH2Cl2) to give
triamine. To a solution triamine and this acid 30 (9.4 mg,
0.092 mmol) in dichloromethane (0.10 mL) were added
BOPCl (31.2 mg, 0.123 mmol) and triethylamine (21.4 mL,
0.154 mmol) at room temperature. After stirring at room
temperature overnight, the mixture was purified by column
chromatography on silica gel (methanol/dichloromethane
7:93) to give 7 (11.0 mg, 61%, 2 steps) as a oil.
[a ]2D5¼þ11.98 (c¼0.60, CHCl3); 1H NMR (500 MHz,
CD3OD containing 1% TFA-d ) d: 0.89 (6H, m), 0.90 (3H, t,
J¼7.0 Hz), 1.09 (m, 6H), 1.23–1.50 (m, 16H), 1.60–2.07
(m, 10H), 2.09 (2H, m), 2.64–2.81 (4H, m), 2.41–2.56 (4H,
m), 3.04–3.23 (3H, m), 3.25–3.55 (8H, m), 5.34 (1H, m),
5.69 (1H, m). 13C NMR, IR and MS (FAB) data were
identical to those of natural lipogrammistin-A.14
90%). [a]2D5¼þ6.938 (c¼0.407, CHCl3); IR (film, cm21
)
3402, 3095, 2927, 2855, 1661, 1591, 1544, 1440, 1372,
1345, 1163, 1125, 1060, 963, 852, 779, 741. 1H NMR
(400 MHz, CDCl3) d: 0.88 (3H, t, J¼6.8 Hz), 1.20–1.29
(12H, m), 1.38 (2H, tt, J¼7.9 Hz), 1.55–1.59 (2H, m), 1.67
(2H, tt, J¼6.1, 6.1), 1.82 (2H, tt, J¼6.8, 6.8 Hz), 2.19 (1H,
m), 1.90–2.01 (4H, m), 2.37 (1H, quintet, J¼7.6 Hz), 2.50
(2H, dd, J¼7.8, 7.8 Hz), 3.15 (2H, dt, J¼6.4, 6.4 Hz),
3.26–3.44 (10H, m), 4.17 (1H, tt, J¼7.1, 7.1 Hz), 5.07 (1H,
m), 5.30 (1H, dt, J¼7.3, 10.7 Hz), 6.03 (1H, t, J¼6.3 Hz),
6.16 (1H, t, J¼6.2 Hz, NH), 7.26–7.61 (1H, m), 7.63–7.65
(1H, m), 7.69–7.75 (6H, m), 7.81–7.84 (1H, m), 8.00–8.02
(1H, m), 8.09–8.14 (2H, m). 13C NMR (100 MHz, CDCl3)
d: 14.4, 22.9, 25.4, 27.5, 27.7, 29.5, 29.6, 29.6, 29.8, 30.1,
31.6, 32.1, 32.3, 32.8, 33.8, 36.4, 41.0, 42.5, 45.7, 48.0,
56.4, 124.2, 124.5, 125.5, 130.8, 132.0, 132.2, 132.2, 133.0,
133.1, 133.7, 133.8, 134.1, 134.4, 148.1, 148.3, 148.3,
170.8. FAB-MS: 1058 (MHþ); HRMS (FAB): 1058.2665
(C43H61BrN7O13S3, MHþ). Exact mass 1058.2673 (MHþ).
Acknowledgments
We thank Professor K. Tachibana and Dr Y. Kobayashi
(Department of Chemistry, School of Science, University of
1
Tokyo) for kindly measuring the H and 13C NMR spectra
of synthetic 9 and comparing them with those of the natural
product. The authors also thank Dr H. Naoki (Suntory
Institute for Bioorganic Research) for kindly measuring the
HRMS.
4.1.33. (8S,2Z )-1,9,13-Tris-(2-nitrobenzenesulfonyl)-8-
undec-2-enyl-1,5,9,13-tetraaza-cyclooctadecan-6-one
(29). To a solution of 28 (94.1 mg, 0.0889 mmol) in
acetonitrile (1.8 mL) were added cesium carbonate
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J¼6.9 Hz), 1.24–1.28 (12H, m), 1.59–1.67 (2H, tt, J¼7.2,
7.2 Hz), 1.81 (2H, tt, J¼6.8, 6.8 Hz), 1.94 (2H, m), 2.06
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m), 4.26 (1H, m), 5.23 (1H, m), 5.41 (1H, m), 6.26 (1H, t,
J¼6.0 Hz), 7.54–7.76 (9H, m), 7.90–7.96 (2H, m), 8.10–
8.13 (1H, m). 13C NMR (100 MHz, CDCl3) d: 14.1, 22.7,
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added mercaptoethanol (10.8 mL, 0.154 mmol) and DBU
(22.9 mL, 0.154 mmol) at room temperature. After stirring
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