Total synthesis of the marine alkaloid halitulin

Article abstract of DOI:10.1016/j.tet.2003.02.005

The structure of the strongly cytotoxic marine alkaloid halitulin (1) has been confirmed by total synthesis and its absolute configuration determined as (15S). The synthesis follows a strategy previously reported by one of us and uses an efficient prepara

Full text of DOI:10.1016/j.tet.2003.02.005

Tetrahedron 59 (2003) 9239–9247
Total synthesis of the marine alkaloid halitulin
b
c
Markus R. Heinrich,a Wolfgang Steglich,a Martin G. Banwell and Yoel Kashman
,
*
a
¨
¨
¨
Department Chemie, Ludwig-Maximilians-Universitat Munchen, Butenandtstr. 5-13, D-81377 Munchen, Germany
bResearch School of Chemistry, Australian National University, Canberra, ACT 0200, Australia
cSchool of Chemistry, Tel Aviv University, Tel Aviv 69978, Israel
Received 8 January 2003; revised 28 February 2003; accepted 28 February 2003
Dedicated to Professor Dieter Seebach on the occasion of his 65th birthday
Abstract—The structure of the strongly cytotoxic marine alkaloid halitulin (1) has been confirmed by total synthesis and its absolute
configuration determined as (15S). The synthesis follows a strategy previously reported by one of us and uses an efficient preparation of the
quinoline-7,8-diol unit by modified Baeyer–Villiger and Skraup reactions. The O-benzyl protecting groups were removed in the last step of
the synthesis by transfer hydrogenolysis without concomitant reduction of the quinoline ring. The method can be applied for the synthesis of
halitulin analogues.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
moiety, have stimulated several synthetic efforts. Syntheses of
isohaliclorensin (3)3–5 and the diquinolinylpyrrole unit of
halitulin6 have been reported, and one of us7 has recently
accomplished the synthesis of racemic halitulin tetra-O-
methyl ether. In this publication we describe the first total
synthesis of halitulin (1) which proves the proposed structure1
and defines the absolute configuration of this unique marine
alkaloid. Our synthesis combines the convergent strategy
(Scheme 1) developed in Canberra7 with efficient syntheses of
subunits 4 and 7 devised in Mu¨nchen.3,8
Halitulin (1) was isolated by Kashman et al.1 from the South
African marine sponge Haliclona tulearensis. It is
accompanied by the 1,5-diazacyclotetradecane derivative
haliclorensin (2),2 which is closely related to isohali-
clorensin (3),3 the hypothetical precursor to halitulin.
Whereas haliclorensin was shown to consist of a 3:1
mixture of the (S)- and (R)-enantiomers2b the absolute
configuration of halitulin has not been determined to date.
Compound 1 exhibits strong cytotoxic activity against
several human tumor cell lines with IC50 values in the
0.012–0.025 mg range.1 This and the unique structure of 1,
including two quinoline-7,8-diol residues and an azecane
2. Results and discussion
The synthesis of building block 4 commences with
Keywords: natural product synthesis; marine metabolites; halitulin; quinoline-7,8-diols; Baeyer–Villiger oxidation; Suzuki reaction.
*
Corresponding author. Tel.: þ49-89-2180-77757; fax: þ49-89-2180-77756; e-mail: wos@cup.uni-muenchen.de
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.02.005

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Scheme 1. Retrosynthetic analysis of halitulin (1).
Scheme 2. Construction of the 10-membered ring. Reagents and conditions: (a) (2S)-2-methylhex-5-en-1-ol (9, 1.2 equiv.), PPh3 (1.3 equiv.), DEAD
(1.3 equiv.), dry THF, rt, 24 h, 84%. (b) Grubbs’ catalyst (0.1 equiv.), CH2Cl2, reflux, 18 h, 56%. (c) PhSH, (1.2 equiv.), K2CO3 (3 equiv.), dry DMF, rt, 1.5 h.
(d) 3-bromopropan-1-ol (1.1 equiv.), K2CO3 (1.0 equiv.), CH3CN, 708C, 2 h. (e) H2 (25 atm), Pd/C (10%), 0.25 M HCl in dry MeOH, rt, 12 h, 90% (from 11).
(f) TsCl (1.2 equiv), NEt3 (2.5 equiv.), DMAP (0.2 equiv.), CH2Cl2, 08C!rt, 2 h, 78% DMAP¼4-(dimethylamino)pyridine.
sulfonamide 8,9,10 which was converted into the protected
secondary amine 10 by reaction with (2S)-2-methylhex-5-en-
1-ol (9) under Mitsunobu conditions11 (Scheme 2). Alcohol 9
was obtained in optically pure form in five steps from
commercially available methyl (2R)-3-hydroxy-2-methyl-
propanoate and in 73% overall yield.12 The ring-closing
metathesis of diene 10 to the azacyclodecene 11 was carried
out under standard conditions using the Grubbs’ catalyst in
dry dichloromethane.13 We observed that the formation of
dimers and oligomers is the predominant reaction, which
can, however, be minimized by using concentrations lower
than 0.5 mmol/L. The removal of the protecting group from
11 with PhSH and K2CO3 according to Fukuyama10
furnished (S)-3-methyl-6-azacyclodecene (12) that was
converted to alcohol 13 by treatment with 3-bromo-1-
propanol without formation of by-products. Hydrogenation
of 13 in dry MeOH under acidic conditions yielded the
saturated alcohol 14 that was converted into the desired
tosylate 4. The latter could be easily purified by chroma-
tography, in contrast to the corresponding triflate.7
Scheme 3. Synthesis of analogue 17. Reagents and conditions: (a) 3-bromopropan-1-ol (1.0 equiv.), K2CO3 (1.0 equiv.), dioxane, 958C, 18 h, 45%. (b) TsCl
(1.2 equiv), NEt3 (2.5 equiv), DMAP (0.2 equiv.), CH2Cl2, 08C!rt, 2 h, 80%.

M. R. Heinrich et al. / Tetrahedron 59 (2003) 9239–9247
9241
Scheme 4. Synthesis of the quinoline building block. Reagents and conditions: (a) 100% HNO3 (1.2 equiv.), AcOH, 108C!rt, 1 h, 81%. (b) peracetic acid
(35% in AcOH, 2.0 equiv), 2.6 M NH3 in MeOH (5.5 equiv), CH2Cl2, rt, 3 h, .95%. (c) H2 (1 atm), Pd/C (10%), 1.5 M HCl in MeOH, rt, 3–6 h, ca. 80%. (d)
acrolein (7.5 equiv.) air, 1.3 M HCl in dry MeOH, 08C!rt, 4–6 d. (e) BnBr (4.0 equiv.), K2CO3 (5 equiv.), dry DMF, 08C!rt, 24 h, 40% (2 steps). Bn¼benzyl.
In the same manner as described for tosylate 4, the lower
homologue 17 was prepared from azonane (15) (Scheme 3).
Interestingly, the alkylation of the saturated amine 15 with
3-bromopropan-1-ol required more drastic conditions than
that of the cyclic alkene 12 (958C, 18 h vs. 708C, 2 h). The
pronounced nucleophilicity of 12 was also observed in the
reaction with acrylonitrile, which was completed within
12 h at rt,3 whereas saturated cyclic amines require more
drastic reaction conditions.4
We have recently discovered that quinoline-7,8-diols can be
prepared under mild conditions by treatment of 3-amino-
catechols with acrolein in 1 M methanolic HCl at rt.8
Applying this method to the present problem allowed the
synthesis of doubly benzyl-protected 5-bromoquinoline-
7,8-diol (7) in five steps from commercially available
5-bromosalicylaldehyde (18) (Scheme 4). Nitration of 18 in
acetic acid yielded nitroaldehyde 19, which was then treated
with peracetic acid. As in similar cases,15 the Baeyer–
Villiger rearrangement of this electron-poor system failed,
so we were pleased to discover that the desired nitrocatechol
20 was formed quantitatively after adding anhydrous
ammonia in methanol to the reaction mixture.8 The
reduction of 5-bromo-3-nitrocatechol (20) to amine 21 is
Achieving a synthesis of halitulin required surmounting two
obstacles: the lack of an efficient synthesis of the quinoline-
7,8-diol unit14 and the problem of selecting a suitable
O-protecting group.
Scheme 5. Reagents and conditions: (a) 7 (2.0 equiv.), Na2CO3 (10 equiv.), Pd(PPh3)4 (0.1 equiv.), toluene/MeOH/H2O (deoxygenated by argon), 708C, 24 h.
(b) nBu4NþF2 (1.2 equiv.), THF, rt, 10 min, 24% (2 steps). (c) 1,4-cyclohexadiene (50 equiv.), cat. Pd/C (10%), EtOH–TFA (10:1), reflux, 45 min, .95%. (d)
6, KHMDS (0.5 M in toluene, 1.3 equiv.), DMF–THF (4:1), cat. DMPU, rt, 10 min, then 4 (1.0 equiv.), rt, 3 h, ca. 90% (isolated as the TFA salt). (e) Same
conditions as for (d) but with tosylate 17 instead of 4. TIPS¼triisopropylsilyl, Bn¼benzyl, DMPU¼N,N0-dimethylpropyleneurea, KHMDS¼potassium
hexamethyldisilazide, TFA¼trifluoroacetic acid.

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M. R. Heinrich et al. / Tetrahedron 59 (2003) 9239–9247
critically dependent on the presence of mineral acid which
suppresses the loss of the bromo-substituent. Interestingly,
higher hydrogen pressure leads cleanly to 3-aminocatechol,
which has, hitherto, only been accessible by more
complicated16a or uneconomic16b routes.
pyrrole-3,4-diboronate 57 (Scheme 5). After treatment of the
primary coupling product with n-tetrabutylammonium
fluoride, the bisquinolinylpyrrole 6 was obtained, which
can be converted into the free tetrahydroxy compound 22 by
hydrogen transfer hydrogenolysis (see below). The syn-
thesis of halitulin was completed by alkylation of the
potassium salt derived from pyrrole 6 with tosylate 4.18 The
reaction can be easily followed by TLC and gives tetra-O-
benzylhalitulin (23) in excellent yield. Not unexpectedly,
removal of the benzyl groups by catalytic hydrogenation
over Pd–C yielded octahydrohalitulin. However, reduction
of the pyridine rings could be avoided by transfer
hydrogenolysis with Pd–C/1,4-cyclohexadiene in ethanol19
in the presence of trifluoroacetic acid. Under these
conditions, the trifluoroacetate of (S)-halitulin (1) was
obtained in quantitative yield. All spectral data derived
from the compound (1H, 13C NMR, UV, MS) matched those
obtained from the natural product (see also Table 1. As
expected, a direct HPLC comparison of synthetic and
natural halitulin proved their identity. Interestingly, salts of
halitulin and the alcohol corresponding to tosylate 4 show a
double set of signals in the NMR spectra, due to the
formation of two diastereomers resulting from protonation
of the chiral azecane moiety either syn or anti to the methyl
group.
The conversion of amine 21 into 5-bromoquinoline-7,8-diol
proceeds under surprisingly mild conditions with acrolein in
1.3 M methanolic HCl at rt. In this Skraup-type reaction, air
serves as oxidant for the dihydroquinoline intermediate. The
dehydrogenation is meditated by the catechol unit which
forms a redox system with the corresponding ortho-
quinone. Compared to the classical Skraup synthesis the
reaction is no longer dependent on the presence of an added
oxidizing agent. When the reaction is applied to the
corresponding catechol dimethyl ether, the yield is far
lower, and a mixture of the quinoline and the tetrahydro-
quinoline is obtained.17 Since previous experience7 dis-
favored the use of O-protecting groups like methyl, which
require strong Lewis acids or acids for removal, we selected
benzyl for O-protection despite the prospect that reduction
of the pyridine ring might accompany the final hydro-
genolysis. The desired dibenzyl ether 7 was prepared from
the crude 5-bromoquinoline-7,8-diol using benzyl bromide
and K2CO3 in anhydrous DMF.
The synthesis of the core unit 6 was achieved by Pd-
catalyzed Suzuki–Miyaura coupling of quinoline 7 with the
The synthetic product exhibited an optical rotation of
[a]2D2¼23.5. Different samples of the natural product varied
Table 1. Comparison of the 13C and 1H NMR data for synthetic and natural halitulin (1)
Synthetic 1£3TFAa
Natural 1£3TFAa
C
dC
dH (mult, J in Hz)
HMBC (H!C)
dC
144.0
dH
2
3
4
4a
5
6
7
8
8a
9
144.0
8.79 (dd, J¼5.5, 1.3)
7.58 (dd, J¼8.6, 5.5)
9.00 (d, J¼8.6)
3, 4, 8a
2, 4a
2, 5, 8a
8.78
7.57
9.00
118.8
146.8
124.8
128.5
124.3
150.1
133.6
132.3
120.9
124.6
48.3
118.8
146.8
124.8
128.5
124.3
150.1
133.6
132.3
120.9
124.6
48.3
7.28 (s)
4a, 5, 7, 8, 9
7.27
10
11
12
7.32 (s)
4.31 (m)
2.48 (m)
[2.48 (m)]
5, 9
12
11
7.32
4.32
27.8 [27.9]
27.8
13
14
55.9 [56.5]
59.7
3.35 (m) [3.35 (m)]
3.03 (dd, J¼14.4, 5.3)
3.46 (dd, J¼14.4, 5.7)
[3.21 (m), 3.28 (m)]
2.28 (m)
11, 12
13, 22, 23
55.9 [56.5]
59.7
[59.4]
30.3
[59.4]
30.3
15
[28.9]
34.3 [32.1]
25.8b
2.32 (m)
1.57 (m), 1.63 (m)
1.70 (m)
1.55 (m), 1.70 (m)
1.71 (m), 1.80 (m)
1.62 (m), 1.68 (m)
[28.9]
34.3 [32.1]
25.8
25.6
25.2
23.7
21.9
[27.0]
[20.0]
53.2
16
14, 23
17b
18b
19b
20b
21b
25.6b
25.2b
23.7b
21.9b
[27.0b]
[26.0b]
53.2
22
23
3.34 (m), 3.54 (m)
[3.33 (m), 3.60 (m)]
1.13 (d, J¼6.7)
[52.3]
21.3
[20.7]
[52.3]
21.3
[20.7]
14, 16
[1.10 (d, J¼6.3)]
a
4:1-Mixture of diastereomers. Values in brackets relate to the minor diastereomer.
Assignments may be interchanged.
b

M. R. Heinrich et al. / Tetrahedron 59 (2003) 9239–9247
9243
from [a]2D2¼21 to 23.0. Since the intense colour of
halitulin trifluoroacetate made an exact comparison of the
optical rotations unreliable, we compared the only lightly
yellow tetraacetates.1,20 The synthetic sample exhibited
[a]2D2¼221, whereas the average of several measurements
of the tetraacetate from natural halitulin was [a]2D2¼222 (in
both cases c¼0.15). Since our synthesis commenced from
the octahydroazecin derivative (S)-12,3 halitulin has the
(15S)-configuration. This supports the idea that both,
halitulin and haliclorensin (2), are derived from a common
precursor.2b
calcd C, 48.88; H, 5.22; N, 10.36; S, 11.86; found C, 49.41;
H, 5.46; N, 10.50; S, 11.78.
3.2.2. N-[(2S)-2-Methylhex-5-enyl]-N-pent-4-enyl-2-
nitrobenzenesulfonamide (10). A solution of 8 (1.69 g,
6.25 mmol) and (2S)-2-methylhex-5-en-1-ol (9)12 (1.07 g,
9.38 mmol) in dry THF (30 mL) was treated with PPh3
(1.64 g, 6.25 mmol) and diethyl azodicarboxylate (DEAD)
(1.09 g, 6.25 mmol) under an argon atmosphere. After being
stirred for 8 h at rt, additional PPh3 (0.55 g, 2.08 mmol) and
DEAD (0.36 g, 2.08 mmol) were added to the solution, and
the stirring was continued for additional 16 h. The reaction
mixture was then concentrated under reduced pressure and
the residue purified by silica gel flash chromatography
(EtOAc–hexanes, 1:1, v/v) to yield, after removal of traces
of 2-methylhex-5-en-1-ol under reduced pressure, 10
(1.92 g, 84%) as a light yellow oil: Rf¼0.45 (EtOAc–
Our convergent synthesis is flexible and allows easy access
to simplified halitulin analogues in which the ‘northern half’
is exchanged by other residues. Thus, the achiral azonane
derivative 25 was obtained from tosylate 17 and the
potassium salt of 6, followed by transfer hydrogenolysis
of the resulting tetrabenzyl derivative 24 (Scheme 5). The
biological evaluation of these compounds is now underway.
1
hexanes, 1:1, v/v); [a]D¼215 (c 1.3, CHCl3); H NMR
(300 MHz, CDCl3) d 0.83 (d, J¼6.6 Hz, 3H), 1.04–1.17 (m,
1H), 1.18–1.28 (m, 1H), 1.36–1.48 (m, 1H), 1.50–1.62 (m,
1H), 1.66–1.78 (m, 1H), 1.90–2.16 (m, 4H), 3.05–3.29 (m,
4H), 4.87–4.99 (m, 4H), 5.60–5.78 (m, 2H), 7.55–7.68 (m,
3H), 7.94–7.98 (m, 1H); 13C NMR (75.5 MHz, CDCl3) d
16.8 (CH3), 26.7 (CH2), 30.3 (CH), 30.5 (CH2), 30.8 (CH2),
32.9 (CH2), 46.7 (CH2), 53.4 (CH2), 114.6 (CH2), 115.2
(CH2), 124.0 (CH), 130.6 (CH), 131.5 (CH), 133.3 (CH),
133.4 (Cq), 137.0 (CH), 138.2 (CH), 147.8 (Cq); MS (EI) m/
z (rel. int.): 366 (4, Mþ), 311 (4), 284 (7), 283 (52,
Mþ2C6H11), 268 (11, Mþ2C7H14), 229 (16), 215 (19), 186
(100, C6H4NO4S); HRMS (EI) calcd for C18H26N2O4S [Mþ]
366.1613, found 366.1586. Anal. calcd C, 58.99; H, 7.15; N,
7.64; S, 8.75; found C, 59.21; H, 7.45; N, 7.72; S, 8.66.
3. Experimental
3.1. General
Silica gel 60 (230–400 mesh, Merck) was used for flash
chromatography. Rf values were determined on silica gel 60
1
F-254 TLC plates (Merck). H and 13C NMR spectra were
recorded on Bruker ARX 300, Varian VXR 400S and/or
Bruker AMX 600 instruments. Chemical shifts are reported
1
in ppm d units relative to chloroform (7.26 ppm for H
NMR and 77.0 ppm for decoupled 13C NMR). IR spectra
were measured on a Perkin–Elmer FT 1000 instrument.
Mass spectra were recorded with a Finnigan MAT 90 sector
field mass spectrometer operating at 70 eV. HPLC was
carried out on a Nucleosil 100 C-18 column (5 mm,
250£4.0 mm). Optical rotations were determined on a
Perkin–Elmer 241 polarimeter. C, H, N and S analyses were
performed by the microanalytical laboratory of the Chem-
istry Department, LMU, Mu¨nchen.
3.2.3. (3S)-3-Methyl-1-(2-nitrobenzenesulfonyl)-
1,2,3,4,5,8,9,10-octahydroazecine (11). To a refluxing
solution of Grubbs’ catalyst13a (74 mg, 0.09 mmol) in dry
CH2Cl2 (1500 mL) maintained under argon was added a
solution of 10 (330 mg, 0.9 mmol) in dry CH2Cl2 (10 mL)
and refluxing was continued for 18 h. The reaction was
monitored by TLC [Rf(10)¼0.45, Rf(11)¼0.3, Rf(Polymer)¼
,0.1; EtOAc–hexanes 1:3, v/v] and, depending on the
conversion and formation of undesired polymers, additional
catalyst was added and the reaction time prolonged. The
cooled reaction mixture was filtered through a plug of Celite
and the filtrate concentrated under reduced pressure. After
silica gel flash chromatography (EtOAc–hexanes, 1:3, v/v)
pure 11 (171 mg, 56%) was obtained as a colorless solid: mp
101–1038C; [a]D¼288 (c 0.9, MeOH); 1H NMR
(600 MHz, CDCl3) d 0.82 (d, J¼6.7 Hz, 3H), 1.43–1.49
(m, 1H), 1.54–1.58 (m, 2H), 1.88–1.95 (m, 2H), 1.97–2.03
(m, 1H), 2.14–2.20 (m, 1H), 2.53 (dd, J¼13.0, 3.6 Hz, 1H),
2.73–2.80 (m, 1H), 2.95–2.99 (m, 1H), 3.02 (dd J¼13.0,
4.7 Hz, 1H), 3.11 (ddd, J¼14.4, 5.0, 1.7 Hz, 1H), 3.42 (dd,
J¼13.1, 9.7 Hz, 1H), 5.44–5.46 (m, 2H), 7.54 (dd, J¼7.2,
1.9 Hz, 1H), 7.67–7.72 (m, 2H), 7.89 (dd, J¼7.2, 1.9 Hz,
1H); 13C NMR (75.5 MHz, CDCl3) d 20.7, 23.2, 24.7, 26.7,
27.2, 35.0, 45.5, 57.9, 123.8, 128.5, 129.9, 131.0, 131.1,
131.9, 133.5, 149.0; MS (EI) m/z (rel. int.): 338 (1, Mþ), 309
(1), 281 (9), 229 (3), 186 (32, C6H4NO4S), 152 (100,
C10H18N); HRMS (EI) calcd for C16H22N2O4S [Mþ]
338.1300, found 338.1300. Anal. calcd C, 56.78; H,
6.55; N, 8.28; S, 9.48; found C, 56.73; H, 6.51; N, 8.01;
S, 9.02.
3.2. Syntheses of the tosylates 4 and 17
3.2.1. N-Pent-4-enyl-2-nitrobenzenesulfonamide (8). 2-
Nitrobenzenesulfonyl chloride (2.55 g, 11.5 mmol), K2CO3
(3.17 g, 23.0 mmol) and pent-4-enylamine (0.98 g,
11.5 mmol) were heated at reflux in dry THF (40 mL) for
24 h. The resulting reaction mixture was acidified with 2N
HCl and extracted with CHCl3 (3£). The combined organic
phases were dried (Na2SO4), filtered and concentrated under
reduced pressure. The residue was purified by silica gel flash
chromatography (CHCl3) to provide 8 (2.48 g, 80%) as a
yellow oil: Rf¼0.5 (CHCl3); 1H NMR (300 MHz, CDCl3) d
1.64 (tt, J¼7.2, 7.1 Hz, 2H), 2.09 (td, J¼7.2, 6.8 Hz, 2H),
3.12 (m, 2H), 4.95–5.02 (m, 2H), 5.28 (m, 1H), 5.72 (ddt,
J¼17.0, 10.3, 6.8 Hz, 1H), 7.74 (m, 2H), 7.86 (m, 1H), 8.14
(m, 1H); 13C NMR (75.5 MHz, CDCl3) d 28.7, 30.5, 43.2,
115.8, 125.4, 131.1, 132.8, 133.5, 133.8, 136.9, 148.1; MS
(EI) m/z (rel. int.): 270 (0.3, Mþ), 269 (2, Mþ2H), 255 (2),
215 (6), 187 (8), 186 (100, C6H4NO4S), 170 (3), 123 (3), 92
(7), 84 (17) (C5H10N), 70 (17); HRMS (EI) calcd for
C11H15N2O4S [MþþH] 271.0752, found 271.0776. Anal.

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M. R. Heinrich et al. / Tetrahedron 59 (2003) 9239–9247
3.2.4. (3S)-3-Methyl-1,2,3,4,5,8,9,10-octahydroazecine
(12). To a solution of 11 (52 mg, 0.15 mmol) in dry DMF
(5 mL) was added thiophenol (18 mL, 20 mg, 0.185 mmol)
and K2CO3 (62 mg, 0.45 mmol). The mixture was stirred at
rt for 2 h, then diluted with brine (15 mL) and extracted with
Et2O (3£10 mL). From the combined organic phases the
amine was extracted with 1N hydrochloric acid (3£5 mL).
On addition of 2N sodium hydroxide, the free amine
separated as a white precipitate which was taken up in
Et2O. After drying (Na2SO4), the solvent was carefully
removed under reduced pressure to yield 12 as a colorless
oil containing traces of DMF: Rf¼0.1 (EtOAc–hexanes,
1:1, v/v), Rf¼0.2 (CHCl3–MeOH, 5:1, v/v); [a]D¼224 (c
0.5, MeOH); 1H NMR (400 MHz, CDCl3) d 0.77 (d,
J¼7.0 Hz, 3H), 1.34–1.49 (m, 2H), 1.50–1.67 (m, 3H),
1.85–1.97 (m, 3H), 2.50–2.66 (m, 5H), 3.12 (m, 1H), 5.34
(dddd, J¼11.0, 11.0, 5.8, 1.8 Hz, 1H), 5.47 (ddd, J¼11.0,
11.0, 4.2 Hz, 1H); 13C NMR (100.7 MHz, CDCl3) d 21.3,
23.1, 26.0, 26.3, 26.7, 37.3, 43.0, 57.4, 127.5, 132.5; MS
(EI) m/z (rel. int.): 153 (20, Mþ), 152 (29, Mþ2H), 138 (8),
124 (17), 111 (11), 110 (60), 98 (13), 97 (30), 96 (100), 84
(34), 82 (29), 70 (21), 56 (19), 44 (60); HRMS (EI) calcd for
C10H19N [Mþ] 153.1518, found 153.1494.
(CH), 30.3 (CH), 31.9 (CH2), 32.2 (CH2), 53.6 (CH2), 54.7
(CH2), 58.6 (CH2), 59.5 (CH2), 59.6 (CH2), 60.1 (CH2), 61.6
(CH2), 62.2 (CH2) [double set of signals due to formation of
diastereomers after protonation]; MS (EI) m/z (rel. int.): 213
(14, Mþ), 212 (4, Mþ2H), 169 (12), 168 (100), 154 (10),
140 (4), 128 (4), 126 (24), 114 (7), 102 (15), 88 (44); HRMS
(EI) calcd for C13H27NO [Mþ] 213.2093, found 213.2101.
3.2.7. 3-(Azonan-1-yl)propan-1-ol (16). A mixture of
azonane21 (15) (0.50 g, 3.94 mmol), 3-bromopropan-1-ol
(0.34 mL, 0.55 g, 3.94 mmol) and K2CO3 (1.63 g,
11.82 mmol) in dry dioxane (8 mL) was heated at 958C
for 18 h under an argon atmosphere. The cooled reaction
mixture was filtered and concentrated under reduced
pressure. Purification of the residue by silica gel flash
chromatography (CHCl3–MeOH, 4:1, v/v) afforded 16
(0.33 g, 45%) as a colorless oil: Rf¼0.35 (CHCl3–MeOH,
4:1, v/v); 1H NMR (300 MHz, CDCl3) d 1.48 (m, 4H), 1.55
(m, 8H), 1.71 (tt, J¼6.0, 5.8 Hz, 2H), 2.54 (m, 4H), 2.67 (t,
J¼6.0 Hz, 2H), 3.76 (t, J¼5.8 Hz, 2H), 4.15 (s, 1H); 13C
NMR (75.5 MHz, CDCl3) d 22.9 (2£CH2), 25.2 (2£CH2),
25.9 (2£CH2), 28.7 (CH2), 53.1 (2£CH2), 57.9 (CH2), 63.2
(CH2); MS (EI) m/z (rel. int.): 185 (20, Mþ), 144 (4), 141
(10), 140 (100), 126 (8), 114 (9), 112 (33), 100 (5), 88 (16), 84
(13), 70(10), 58(20), 57(17), 55(13), 44(21), 41(22); HRMS
(EI) calcd for C11H23NO [Mþ] 185.1780, found 185.1786.
3.2.5. 3-[(3S)-3-Methyl-3,4,5,8,9,10-hexahydro-2H-
azecin-1-yl]propan-1-ol (13). A mixture of crude amine
12 (50 mg, 0.33 mmol), 3-bromopropan-1-ol (30 mL,
45 mg, 0.33 mmol) and K2CO3 (45 mg, 0.33 mmol) in dry
CH3CN (5 mL) maintained under argon was stirred for 2 h
at 708C. The cooled reaction mixture was filtered and
concentrated under reduced pressure to remove traces of
3-bromo-1-propanol. Compound 13 (65 mg, 94%; ,80%
from 12) was thus obtained as a light yellow oil: Rf¼0.5
3.3. General procedure for the tosylation of alcohols 14
and 16
A solution of the alcohol (1.0 mmol) in dry CH2Cl2 (5 mL)
under argon, maintained at 08C, was treated with triethyl-
amine (208 mL, 152 mg, 1.5 mmol; in case of hydrochloride
14 2.5 mmol), DMAP (24 mg, 0.2 mmol) and tosyl chloride
(229 mg, 1.2 mmol). The resulting mixture was stirred for
5 min, then, the ice-bath was removed and the reaction
mixture warmed over 2 h to rt. The solution was diluted with
CH2Cl2, washed several times with water and dried over
Na2SO4. Purification of the crude product by silica gel flash
chromatography (EtOAc–hexanes, 2:3, v/v) afforded the
tosylates 4 or 17 as colorless oils, which decompose in
solution at rt, but are stable in pure form over several weeks
at 08C.
1
(CHCl3–MeOH, 4:1, v/v); H NMR (600 MHz, CD2Cl2) d
0.85 (d, J¼6.7 Hz, 3H), 1.32 (m, 1H, 9b-H), 1.40 (m, 1H,
4b-H), 1.59 (m, 1H, 40a-H), 1.72 (m, 1H, 20b-H), 1.77–1.78
(m, 4H, 20a-H, 5b-H, 8b-H, 9a-H), 1.95 (m, 2H, 3-H,
10b-H), 2.08–2.16 (m, 2H, 10b-H, 2b-H), 2.50 (m, 1H,
8a-H), 2.58 (m, 1H, 2a-H), 2.75 (m, 1H, 10a-H), 2.83 (m, 1H,
10a-H), 3.10 (m, 1H, 5a-H), 3.70 (t, J¼6.4 Hz, 2H, 30-H),
5.33 (m, 1H, 6/7-H), 5.45 (ddd, J¼11.4, 11.3, 3.8 Hz, 1H,
6/7-H); 13C NMR (151 MHz, CD2Cl2) d 21.4 (C-11), 23.5
(C-8), 24.4 (C-9), 25.6 (C-5), 27.0 (C-3), 29.7 (C-20), 37.5
(C-4), 49.5 (C-10), 52.0 (C-10), 62.1 (C-30), 63.5 (C-2),
127.9 (C-6/7), 132.7 (C-6/7); MS (EI) m/z (rel. int.): 211
(0.5, Mþ), 210 (1, Mþ2H), 168 (9), 167 (6), 166 (41), 154
(25), 153 (28), 152 (19), 142 (12), 138 (7), 125 (10), 124
(100), 111 (6), 110 (7), 96 (8); HRMS (EI) calcd for
C13H24NO [Mþ2H] 210.1858, found 210.1846.
3.3.1. 3-[(3S)-3-Methyl-azecan-1-yl]propyl toluene-4-sul-
fonate (4). Yield: 287 mg (78%); Rf¼0.75 (EtOAc–
hexanes, 1:3, v/v); Rf¼0.20 (CH2Cl2); 1H NMR
(300 MHz, CDCl3) d 0.77 (d, J¼6.2 Hz, 3H), 1.22–1.39
(m, 5H), 1.41–1.53 (m, 2H), 1.54–1.73 (m, 5H), 1.75–1.82
(m, 2H), 2.04 (m, 1H), 2.10–2.17 (m, 2H), 2.22–2.26 (m,
1H), 2.42–2.50 (m, 2H), 2.44 (s, 3H), 2.57–2.62 (m, 1H),
4.11 (t, J¼6.3 Hz, 2H), 7.34 (d, J¼7.7 Hz, 2H), 7.89 (d,
J¼7.7 Hz, 2H); 13C NMR (75.5 MHz, CDCl3) d 19.4, 21.6,
22.2, 24.3, 24.7, 25.9, 26.5, 30.0, 30.3, 31.8, 51.1, 53.2, 60.6,
69.7, 127.9 (2C), 129.8 (2C), 133.3, 144.6; MS (EI) m/z (rel.
int.): 368 (4, MþþH), 367 (5, Mþ), 324 (3), 312 (5), 282 (6),
256 (10), 243 (8), 242 (62), 169 (12), 168 (100), 155 (8), 154
(11), 126 (27), 106 (9), 98 (11), 91 (10), 70 (15), 58 (11);
HRMS (EI) calcd for C20H33NO3S [Mþ] 367.2181, found
367.2202.
3.2.6. 3-[(3S)-3-Methyl-azecan-1-yl]propan-1-ol hydro-
chloride (14). To a solution of 13 (65 mg, 0.31 mmol) in dry
MeOH (5 mL) were added HCl (1.25 M in MeOH, 1 mL)
and palladium on charcoal (30 mg, 10% Pd). The hydro-
genation was carried out at 10–20 atm H2-pressure for 16 h.
After removal of the catalyst by filtration through Celite, the
solution was concentrated and the residue dried under
reduced pressure to afford hydrochloride 14 (75 mg, 90%)
as a colorless oil: Rf¼0.35 (CHCl3–MeOH, 4:1, v/v);
[a]D23¼212 (c 2.0, MeOH); 13C NMR (75.5 MHz, CD3OD)
d 19.8 (CH3), 20.4 (CH3), 22.5 (CH2), 22.6 (CH2), 24.3
(CH2), 24.4 (CH2), 25.1 (CH2), 25.3 (CH2), 25.6 (CH2), 25.8
(CH2), 26.2 (CH2), 26.3 (CH2), 26.7 (CH2), 27.1 (CH2), 28.6
3.3.2. 3-(Azonan-1-yl)prop-1-yl toluene-4-sulfonate (17).
Yield: 272 mg (80%); Rf¼0.75 (EtOAc–hexanes, 1:3, v/v);

M. R. Heinrich et al. / Tetrahedron 59 (2003) 9239–9247
9245
1H NMR (300 MHz, CDCl3) d 1.32–1.48 (m, 12H), 1.77 (tt,
J¼6.7, 6.5 Hz, 2H), 2.37 (m, 4H), 2.42 (s, 3H), 2.44 (t,
J¼6.7 Hz, 2H), 4.10 (t, J¼6.5 Hz, 2H), 7.32 (dd, J¼8.5,
0.6 Hz, 2H), 7.77 (d, J¼8.5 Hz, 2H); 13C NMR (75.5 MHz,
CDCl3) d 21.5 (CH3), 23.4 (2£CH2), 25.4 (2£CH2), 26.4
(2£CH2), 27.3 (CH2), 53.3 (2£CH2), 53.9 (CH2), 69.3
(CH2), 127.8 (2£CH), 129.7 (2£CH), 133.0 (Cq), 144.6
(Cq); MS (EI) m/z (rel. int.): 339 (13, Mþ), 298 (7), 282 (7),
268 (9), 242 (32), 184 (4), 155 (5), 141 (10), 140 (100), 138
(9), 126 (12), 124 (7), 112 (28), 91 (22), 84 (12), 70 (15), 58
(11), 55 (13); HRMS (EI) calcd for C18H29NO3S [Mþ]
339.1868, found 339.1861.
1H NMR (300 MHz, CD3OD) d 7.04 (d, J¼2.2 Hz, 1H),
7.07 (d, J¼2.2 Hz, 1H); 13C NMR (75.5 MHz, CD3OD) d
111.6, 118.3, 120.1, 121.1, 141.3, 149.0; MS (EI) m/z (rel.
int.): 206 (49, MþþH, C6H781BrNO2), 205 (100, Mþ,
C6H861BrNO2), 204 (48, MþþH, C6H779BrNO2), 203 (84,
Mþ, C6H769BrNO2), 187 (39), 185 (33), 160 (23), 159 (52),
158 (21), 157 (45), 125 (27), 107 (19), 82 (21), 80 (21), 79
(63), 51 (39), 44 (43), 36 (95); HRMS (EI) calcd for
C6H769BrNO2 [Mþ] 202.9582, found 202.9602.
3.4.4. 5-Bromo-7,8-dibenzyloxyquinoline (7). A solution
of 21 (2.3 g, 9.6 mmol) in MeOH (120 mL), maintained at
08C, was treated with HCl (5–6 M in isopropanol, 30 mL)
and acrolein (4.8 mL, 4.0 g, 72 mmol). Then, the ice-bath
was removed and the mixture stirred for at least 5 d at rt in a
flask equipped with a drying tube. After completion of the
quinoline formation (1H NMR monitoring!), the solution
was carefully concentrated under reduced pressure and the
residue dried in vacuo. The crude 5-bromoquinoline-7,8-
diol hydrochloride (4.95 g) was obtained as a brown foam
3.4. Synthesis of quinolinediol 7
3.4.1. 5-Bromo-3-nitrosalicylaldehyde (19). A solution of
5-bromosalicylaldehyde (18, 10.0 g, 49.7 mmol) in acetic
acid (50 mL), maintained at 108C, was treated with 100%
nitric acid (2.70 mL, 4.10 g, 64.6 mmol). The resulting
mixture was warmed to rt over 1 h, then, the reaction
mixture was quenched with water and extracted several
times with EtOAc. The combined organic phases were
washed with water and brine then dried over Na2SO4.
Removal of the solvents and drying under reduced pressure
gave 19 (11.9 g, 97%) as a yellow solid: mp 108–1098C;
1
that was used directly for the next reaction step: H NMR
(200 MHz, CD3OD) d 7.86 (s, 1H), 7.92 (dd, J¼8.6, 5.5 Hz,
1H), 8.99 (dd, J¼5.5, 1.4 Hz, 1H), 9.14 (dd, J¼8.6, 1.4 Hz,
1H); 13C NMR (75.5 MHz, CD3OD) d 119.9 (CH), 120.2
(CH), 126.0 (Cq), 129.8 (Cq), 132.2 (Cq), 135.6 (Cq), 143.6
(CH), 145.5 (Cq), 147.7 (CH).
1
Rf¼0.7 (CHCl3–MeOH, 20:1, v/v); H NMR (300 MHz,
CDCl3) d 8.19 (d, J¼2.5 Hz, 1H), 8.46 (d, J¼2.5 Hz, 1H),
10.37 (s, 1H), 11.24 (s, 1H); 13C NMR (75.5 MHz, CDCl3) d
111.8, 126.8, 133.3, 135.7, 139.4, 155.3, 187.5; MS (EI) m/z
(rel. int.): 247 (37, Mþ, C7H481BrNO4), 245 (37, Mþ,
C7H749BrNO4), 230 (11), 229 (100), 228 (11), 227 (100), 217
(16), 215 (17), 200 (26), 199 (34), 198 (25), 197 (27), 172
(14), 171 (22), 170 (15), 169 (21), 143 (19), 141 (10), 120
(10), 91 (13), 64 (11), 63 (39), 62 (19); HRMS (EI) calcd for
C7H749BrNO4 [Mþ] 244.9324, found 244.9294.
A solution of the crude quinolinediol (4.95 g, diol content
,50–55% besides polymerisation products of acrolein,
,9.0 mmol) in dry DMF maintained under argon at 08C,
was treated with K2CO3 (6.22 g, 45 mmol) and benzyl
bromide (4.28 mL, 6.16 g, 36 mmol). The resulting mixture
was stirred for 24 h at rt, then diluted with water and
extracted several times with CH2Cl2. The combined organic
phases were dried over Na2SO4 and concentrated under
reduced pressure. Purification by flash chromatography on
silica gel (CH2Cl2–acetone, 20:1, v/v) yielded 7 (1.61 g,
40% from 21) as a light brown solid: mp 67–698C; Rf¼0.7
(CH2Cl2–acetone, 20:1, v/v); 1H NMR (300 MHz, CD3OD)
d 5.30 (s, 2H), 5.31 (s, 2H), 7.26–7.30 (m, 3H), 7.37–7.46
(m, 3H), 7.47–7.53 (m, 4H), 7.54 (dd, J¼8.5, 4.3 Hz, 1H),
7.92 (s, 1H), 8.53 (dd, J¼8.5, 1.6 Hz, 1H), 8.90 (dd, J¼4.3,
1.6 Hz, 1H); 13C NMR (75.5 MHz, CD3OD) d 72.5, 76.1,
115.8, 120.4, 121.8, 123.8, 127.4, 127.8, 128.1, 128.1,
3.4.2. 5-Bromo-3-nitrocatechol (20). A solution of 19
(17.8 g, 72.4 mmol) in CH2Cl2 (500 mL) was treated with
peracetic acid (39% in AcOH, 20.5 mL, 120 mmol) and
stirred at 208C for 1 h. After the addition of ammonia (2.5 M
in MeOH, 144 mL, 360 mmol), the mixture was stirred for
another hour. The solution was then diluted with CH2Cl2,
washed with 2N HCl (2£250 mL) and dried (Na2SO4).
Removal of the solvents and drying under reduced pressure
afforded 20 (15.8 g, 93%) as a red solid: mp 82–848C;
128.5, 128.5, 135.7, 136.3, 137.5, 142.8, 144.0, 150.5,
81
18
1
Rf¼0.55 (CHCl3–MeOH, 10:1, v/v); H NMR (300 MHz,
150.9; MS (EI) m/z (rel. int.): 421 (0.5, Mþ, C23H BrNO2),
79
18
CDCl3) d 6.03 (s, 1H), 7.35 (d, J¼2.3 Hz, 1H), 7.79 (d,
J¼2.3 Hz, 1H), 10.54 (s, 1H); 13C NMR (75.5 MHz,
CDCl3) d 111.6, 118.0, 124.6, 133.8, 142.1, 147.3; MS
(EI) m/z (rel. int.): 236 (6), 235 (93, Mþ, C6H481BrNO4), 234
(7) 233 (94, Mþ, C6H479BrNO4), 205 (12), 203 (12), 189
(14), 188 (14), 187 (100), 186 (8), 185 (89), 173 (10), 171
(10), 159 (24), 157 (17), 79 (24); HRMS (EI) calcd for
C6H749BrNO4 [Mþ] 232.9324, found 232.9326.
419 (0.5, Mþ, C23H BrNO2), 331 (4), 330 (25), 329 (5),
79
18
328 (25), 91 (100); HRMS (EI) calcd for C23H BrNO2
[Mþ] 419.0521, found 419.0485.
3.5. Syntheses of halitulin and bisnorhalitulin
3.5.1. Bis-3,4-(3,3,4,4-tetramethyl-2,5-dioxaborolan-1-
yl)-1-(triisopropylsilyl)pyrrole (5).7 The successful syn-
thesis of 5 depends critically on dry solvents. To a stirred
solution of 3,4-diiodo-1-(triisopropylsilyl)pyrrole7 (0.57 g,
1.20 mmol) in dry dioxane (14 mL) under argon were added
at 15–208C triethylamine (1.66 mL, 1.22 g, 12.0 mmol) and
PdCl2(dppf)£CH2Cl2 (69 mg, 0.08 mmol). After the
addition of pinacolborane (0.78 mL, 335 mg, 2.62 mmol),
the mixture was heated at reflux for 24 h. The reaction
mixture was then cooled to rt and after the addition of water,
the solution was extracted several times with CHCl3. The
3.4.3. 3-Amino-5-bromocatechol hydrochloride (21). A
mixture of catechol 20 (2.35 g, 10.0 mmol) and 10% Pd on
charcoal (0.20 g) in MeOH (90 mL) and HCl (5–6 M in
isopropanol, 20 mL) was stirred under H2 (1 atm). After
1
completion of the hydrogenation, as indicated by H NMR
and TLC analysis, the mixture was filtered through a small
pad of Celite and the filtrate concentrated under reduced
pressure to yield 21 (2.16 g, 90%) as a greenish brown foam:

9246
M. R. Heinrich et al. / Tetrahedron 59 (2003) 9239–9247
combined organic phases were dried (Na2SO4) and
concentrated under reduced pressure. The residue was
dissolved in a mixture of hexanes and EtOAc (10:1, v/v,
33 mL), filtered and dried under reduced pressure to give
3.6. General procedure for the N-alkylation of pyrrole 6
A stirred solution of pyrrole 6 (0.031 mmol) in dry DMF
(2 mLþcat. DMPU) maintained under argon at 08C, was
treated with potassium hexamethyldisilazide (0.5 M in
toluene, 80 mL, 0.04 mmol). After 10 min, a solution of
the relevant tosylate (0.032 mmol) in dry THF (0.5 mL) was
added dropwise. The resulting mixture was stirred for 24 h
at rt, quenched with aqueous NaHCO3 and extracted several
times with CH2Cl2. The combined organic extracts were
dried (Na2SO4) and concentrated under reduced pressure.
Purification by HPLC [solvent A: H2O–CH3CN
(9:1)þ0.05% TFA, solvent B: CH3CN; gradient: start:
100% A, 40–60 min: 45% A, 70 min: 100% B, flow: 3 mL/
min] provided 23 or 24 as yellow oils.
1
crude 5 (0.38 g) as a light brown oil: H NMR (200 MHz,
CDCl3) d 1.05 (d, J¼7.3 Hz, 18H), 1.28 (s, 24H), 1.40 (sept,
J¼7.3 Hz, 3H), 7.11 (s, 2H).
3.5.2. Bis-3,4-(7,8-dibenzyloxyquinolin-5-yl)pyrrole (6).
To a stirred solution of crude 5 (0.36 g, 0.76 mmol), 7
(0.63 g, 1.50 mmol) and Pd(PPh3)4 (88 mg) in a mixture of
toluene (15 mL) and MeOH (20 mL) under argon was added
Na2CO3 (0.80 g in 4 mL H2O). Then, the flask and the reflux
condenser were evacuated and flashed several times with
argon to remove oxygen. The mixture was then heated for
24–30 h to 65–758C, cooled to rt, diluted with water and
extracted with CHCl3 (3£30 mL). The combined organic
phases were dried (Na2SO4) and concentrated under
reduced pressure. The residue was purified by silica gel
flash chromatography (toluene–CHCl3–MeOH, 15:10:1,
v/v/v) to afford bis-3,4-(7,8-dibenzyloxyquinolin-5-yl)-1-
(triisopropylsilyl)pyrrole as a brown oil, which, according to
3.6.1. (S)-Tetra-O-benzylhalitulin tris-trifluoroacetate
(23). Yield: 80–95%; TLC Rf¼0.2 (EtOAc–hexanes, 3:1,
v/v); HPLC Rt¼58.5 min; UV lmax(qual.): 263 nm (1.00),
1
341 (0.10), 412 (0.15); H NMR (400 MHz, CD3OD) d
1.10p/1.13p (2£d, J¼6.7/6.6 Hz, 3H), 1.52–1.78 (m, 10H),
1.87–2.10 (m, 2H), 2.29–2.36 (m, 1H), 2.44–2.54 (m, 2H),
3.14 (m, 1H), 3.20–3.59 (m, 5H), 4.30 (t, J¼6.8 Hz, 2H),
5.21 (s, 4H), 5.44 (s, 4H), 7.21–7.42 (m, 22H), 7.49 (s, 2H),
7.61 (dd, J¼8.4, 5.4 Hz, 2H), 8.91 (dd, J¼5.4, 1.3 Hz, 2H),
8.98 (dd, J¼8.4, 1.3 Hz, 2H) [2 diastereomers due to
protonation]; 13C NMR (100.7 MHz, CD3OD) d 21.4 (CH3),
21.9 (CH2), 23.7 (CH2), 25.2 (CH2), 25.6 (CH2), 25.8 (CH2),
27.7 (CH2), 30.2 (CH), 34.4 (CH2), 48.6 (CH2), 53.1 (CH2),
55.8 (CH2), 59.7 (CH2), 73.1 (2£CH2), 76.8 (2£CH2), 120.4
(2£CH), 120.6 (2£Cq), 121.7 (2£CH), 125.2 (2£Cq), 125.3
(2£CH), 128.7 (4£CH), 129.7 (4£CH), 129.9 (2£CH),
130.1 (4£CHþ2£CH), 130.4 (4£CH), 133.0 (2£Cq), 135.3
(2£Cq), 136.1 (2£Cq), 137.2 (2£Cq), 137.6 (2£Cq), 146.0
(2£CH), 146.9 (2£CH), 155.1 (2£Cq) [only signals of the
major diastereomer are given]; MS (FAB) m/z 941
[MþþH]; HRMS (FAB) calcd for C63H64N4O4 [Mþ]
940.4928, found: 940.4930.
1
the H NMR spectrum, still contained traces of triphenyl-
1
phosphine: Rf¼0.45 (CHCl3–MeOH, 10:1, v/v); H NMR
(300 MHz, CDCl3) d 1.22 (d, J¼7.5 Hz, 18H), 1.56 (sept,
J¼7.5 Hz, 3H), 4.82 (s, 4H), 5.31 (s, 4H), 6.95 (s, 2H), 7.02
(dd, J¼8.5, 4.3 Hz, 2H), 7.03 (s, 2H), 7.22–7.25 (m, 16H),
7.47–7.50 (m, 4H), 8.19 (dd, J¼8.5, 1.6 Hz, 2H), 8.85 (dd,
J¼4.3, 1.6 Hz, 2H); 13C NMR (75.5 MHz, CDCl3) d 11.7
(3£CH), 17.9 (6£CH3), 72.1 (2£CH2), 76.0 (2£CH2), 118.8
(2£CH), 119.3 (2£CH), 123.3 (2£Cq), 123.7 (2£Cq), 125.1
(2£CH), 127.3 (4£CH), 127.7 (2£CH), 127.9 (2£CH),
128.1 (4£CH), 128.4 (4£CH), 128.6 (4£CH), 129.7 (2£Cq),
132.0 (2£Cq), 132.1 (2£Cq), 136.7 (2£Cq), 137.8 (2£Cq),
149.3 (2£CH), 150.6 (2£Cq) [only 22 of the expected 23
signals were visible]; MS (EI) m/z (rel. int.): 902 (0.2,
MþþH), 901 (0.3, Mþ), 811 (2), 810 (4), 720 (1), 704 (1),
655 (2), 654 (3), 628 (2), 472 (2), 262 (48), 250 (18), 183
(32), 108 (19), 91 (100).
3.6.2. Tetra-O-benzylbisnorhalitulin tris-trifluoroacetate
(24). Yield: 80–95%; TLC Rf¼0.2 (EtOAc–hexanes, 3:1,
v/v); HPLC Rt¼58 min; UV lmax(qual.): 263 nm (1.00),
The deprotection of the TIPS derivative (0.53 g, 0.59 mmol)
was carried out in THF (5 mL) with a solution of tetra-n-
butyl ammonium fluoride in THF (1 M, 0.7 mL). After
stirring for 10 min at 208C, the solution was diluted with
water and extracted with CH2Cl2. Drying over Na2SO4 and
purification by silica gel flash chromatography (EtOAc–
hexanes, 1:1, v/v) gave 6 (0.38 g, 86%; 25% from 3,4-
diiodo-1-TIPS-pyrrole) as an orange solid: mp 54–558C;
1
341 (0.10), 412 (0.15); H NMR (600 MHz, CD3OD): d
1.67–1.80 (m, 8H), 1.93–2.07 (m, 4H), 2.41–2.54 (m, 2H),
3.32–3.38 (m, 2H), 3.39–3.52 (m, 4H), 4.29 (t, J¼7.0 Hz,
2H), 5.18 (s, 4H), 5.42 (s, 4H), 7.20–7.40 (m, 22H), 7.47 (s,
2H), 7.57 (dd, J¼8.5, 5.4 Hz, 2H), 8.89 (dd, J¼5.4, 1.4 Hz,
2H), 8.93 (dd, J¼8.5, 1.4 Hz, 2H); 13C NMR (151 MHz,
CD3OD): d 23.2 (2£CH2), 24.9 (2£CH2), 25.5 (2£CH2),
27.8 (CH2), 48.4 (CH2), 52.7 (2£CH2), 55.5 (CH2), 73.1
(2£CH2), 76.8 (2£CH2), 120.4 (2£CH), 120.8 (2£Cq),
121.6 (2£CH), 125.1 (2£Cq), 125.2 (2£CH), 128.7 (4£CH),
129.7 (4£CH), 129.9 (2£CH), 130.0 (2£CH), 130.1
(4£CH), 130.3 (4£CH), 132.9 (2£Cq), 135.7 (2£Cq),
136.7 (2£Cq), 137.2 (2£Cq), 137.7 (2£Cq), 146.2 (2£CH),
146.4 (2£CH), 154.9 (2£Cq); MS (ESI) m/z 913 [MþþH];
HRMS (ESI) calcd for C61H61N4O4 [MþþH] 913.4693,
found 913.4708.
1
Rf¼0.4 (EtOAc–hexanes 1:1, v/v); H NMR (600 MHz,
CDCl3) d 4.79 (s, 4H, 80-benzyl-H), 5.28 (s, 4H, 70-benzyl-
H), 6.95 (d, J¼2.8 Hz, 2H, 2-H), 6.98 (dd, J¼8.3, 4.1 Hz,
2H, 30-H), 7.03 (s, 2H, 60-H), 7.17–7.23 (m, 16H, benzyl-
H), 7.43–7.44 (m, 4H, benzyl-H), 8.22 (dd, J¼8.3, 1.7 Hz,
2H, 40-H), 8.80 (dd, J¼4.1, 1.7 Hz, 2H, 20-H), 10.52 (s, 1H,
1-H). 13C NMR (151 MHz, CDCl3) d 71.8, 76.0, 118.7,
119.0, 119.3, 120.4, 123.6, 127.2, 127.7, 127.9, 128.0,
128.4, 128.5, 130.2, 135.8, 136.5, 137.6, 140.4, 143.0,
149.1, 150.6; MS (EI) m/z (rel. int.): 746 (3, MþþH), 745
(5, Mþ), 655 (14), 654 (25), 564 (7), 549 (13), 548 (29),
472 (17), 458 (5), 382 (4), 347 (4), 262 (8), 108 (25), 107 (21),
106 (35), 105 (35), 92 (18), 91 (100), 79 (16), 77 (28);
HRMS (EI) calcd for C50H39N3O4 [Mþ] 745.9241, found
745.9206.
3.7. General procedure for benzyl deprotection by
transfer hydrogenolysis
A solution of the relevant tetrabenzyl ether (10 mg,

M. R. Heinrich et al. / Tetrahedron 59 (2003) 9239–9247
9247
0.01 mmol) in dry ethanol (5 mL) and TFA (0.1 mL)
References
maintained under argon was treated with palladium on
charcoal (5 mg, 10% Pd) and 1,4-cyclohexadiene (0.1 mL,
85 mg, 1.1 mmol). The resulting mixture was heated at
reflux for 45 min then cooled to rt over 1 h. Filtration and
removal of the solvents under reduced pressure gave the free
quinolinediols as red oils and in good purity. Further
purification was achieved by HPLC [solvent A: H2O–
CH3CN (9:1)þ0.05% TFA, solvent B: CH3CN; gradient:
start-10 min: 100% A, 50 min: 100% B, flow: 3 mL/min].
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Yield: 87%, red oil; UV lmax(qual.): 205 nm (1.00), 252
(0.85), 360 (0.15); 1H NMR (600 MHz, CD3OD) d 7.16 (s,
2H), 7.18 (s, 2H), 7.27 (dd, J¼8.4, 4.8 Hz, 3-H, 2H), 8.59 (d,
J¼8.4 Hz, 4-H, 2H), 8.65 (d, J¼4.8 Hz, 2-H, 2H); 13C NMR
(151 MHz, CD3OD) d 118.8 (2£CH), 120.8 (2£CH), 121.2
(2£Cq), 123.1 (2£CH), 124.3 (2£Cq), 128.3 (2£Cq), 135.3
(2£Cq), 136.3 (2£Cq), 142.0 (2£CH), 146.3 (2£CH), 147.0
(2£Cq); MS (EI) m/z (rel. int.): 386 (27, MþþH), 385 (100,
Mþ), 356 (12), 193 (3), 178 (5).
5. Usuki, Y.; Hirakawa, H.; Goto, K.; Iio, H. Tetrahedron:
Asymmetry 2001, 12, 3293–3296.
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1922–1930.
3.7.2. (S)-Halitulin tris-trifluoroacetate (1). Yield: .90%;
orange–red oil, [a]D¼23.5 (c 0.25, MeOH); HPLC
Rt¼37 min; UV lmax(1): 266 nm (67310), 351 (5070), 434
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14. Syntheses of quinoline-7.8-diol: (a) Ohta, T.; Okuda, O.
J. Pharm. Soc., Jpn 1951, 71, 784–786. (b) Ried, W.; Berg,
A.; Schmidt, G. Chem. Ber. 1952, 85, 204–216. (c) Ohta, T.;
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1
(7320); H and 13C NMR: see Table 1; MS (EI) m/z (rel.
int.): 581 (12, MþþH), 580 (46, Mþ), 424 (3), 399 (100),
398 (23), 385 (2), 235 (5), 169 (6), 168 (40), 152 (11), 126
(14), 124 (12), 110 (22), 98 (15), 91 (13), 86 (12), 82 (11),
70 (25), 58 (23), 55 (23); HRMS (EI) calcd for C35H40N4O4
[Mþ] 580.3050, found 580.3052.
3.7.3. Bisnorhalitulin tris-trifluoroacetate (25). Yield:
.90%, orange–red oil; HPLC Rt¼37 min; UV lmax(qual.):
264 nm (1.00), 336 (0.05), 423 (0.15); 1H NMR (400 MHz,
CD3OD) d 1.66–1.87 (m, 8H), 1.90–2.10 (m, 4H), 2.47–
2.51 (m, 2H), 3.33–3.37 (m, 4H), 3.44–3.49 (m, 2H), 4.31
(t, J¼7.0 Hz, 2H), 7.27 (s, 2H), 7.32 (s, 2H), 7.58 (dd,
J¼8.5, 5.6 Hz, 2H), 8.79 (dd, J¼5.6, 1.5 Hz, 2H), 9.01 (dd,
J¼8.5, 1.5 Hz, 2H); 13C NMR (151 MHz, CD3OD): d 23.2,
24.9, 25.5 (each 2£CH2), 27.9, 48.3 (CH2), 52.7 (2£CH2),
55.6 (CH2), 118.8 (2£CH), 120.9 (2£Cq), 124.3, 124.6
(each 2£CH), 124.8, 128.5, 132.3, 133.6 (each 2£Cq), 144.0
(2£CH), 146.8 (2£CH), 150.0 (2£Cq); MS (EI) m/z (rel.
int.): 553 (19, MþþH), 552 (57, Mþ), 400 (21), 399 (100),
398 (30), 371 (5), 276 (4), 140 (21); HRMS (EI) calcd for
C33H36N4O4 [Mþ] 552.2737, found 552.2719.
´
Queguiner, G. Synthesis 1995, 1159–1162.
15. See, for example Dakin, H. D. Am. Chem. J. 1909, 42, 495.
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K. Liebigs Ann. Chem. 1957, 608, 128–139, and references
cited therein.
17. Ogata, Y.; Kawasaki, A.; Suyama, S. Tetrahedron 1969, 25,
1361–1366.
18. With the corresponding triflate no coupling product could be
obtained (see however Ref. 7).
19. Nakano, Y.; Imai, D. Synthesis 1997, 1425–1428.
20. The tetraacetates were prepared by treatment of synthetic and
natural halitulin, respectively, with Ac2O, NEt3 and cat.
DMAP in dichloromethane. The resulting solutions were used
directly for the [a]D measurements.
Acknowledgements
The authors are grateful to the Fonds der Chemischen
Industrie and the Alexander von Humboldt foundation for
financial support and to Mrs Sabine Voss and Ms Kathrin
Hohnholt for skillful technical assistance.
21. Williams, D. E.; Craig, K. S.; Patrick, B.; Mc Hardy, L. M.;
van Soest, R.; Roberge, M.; Andersen, R. J. J. Org. Chem.
2002, 67, 245–258.