Revision of the structure of haliclorensin to (S)-7-methyl-1,5-diazacyclotetradecane and confirmation of the new structure by synthesis

Article abstract of DOI:10.1016/S0040-4020(01)01020-1

A reinvestigation of the marine alkaloid haliclorensin led to a revision of the proposed structure to 7-methyl-1,5-diazacyclotetradecane. The new structure was confirmed by total synthesis of both optical forms. According to chiroptical measurements and G

Full text of DOI:10.1016/S0040-4020(01)01020-1

TETRAHEDRON
Pergamon
Tetrahedron 57 62001) 9973±9978
Revision of the structure of haliclorensin to
ꢀS)-7-methyl-1,5-diazacyclotetradecane and con®rmation of the
new structure by synthesis
Markus R. Heinrich,a Yoel Kashman,b Peter Spitellera and Wolfgang Steglicha,p
a
È È È È
Department Chemie, Institut fur Organische Chemie, Ludwig±Maximilians-Universitat, Universitat Munchen, Haus F, Butenandtstr. 5-13,
È
D-81377 Munchen, Germany
bSchool of Chemistry, Tel-Aviv University, Tel-Aviv 69978, Israel
Received 16August 2001; revised 12 October 2001; accepted 19 October 2001
AbstractÐA reinvestigation of the marine alkaloid haliclorensin led to a revision of the proposed structure to 7-methyl-1,5-diazacyclo-
tetradecane. The new structure was con®rmed by total synthesis of both optical forms. According to chiroptical measurements and GC±MS
investigations, natural haliclorensin consists of a 3:1 mixture of the 6S)- and 6R)-enantiomers. q 2001 Published by Elsevier Science Ltd.
1. Introduction
communication we report on the revision of the structure
of haliclorensin to that of the isomeric diamine 3.
Recently, Kashman et al. reported the isolation of two
unique marine alkaloids from the South African sponge
Haliclona tulearensis. For haliclorensin the diamine
structure 1 was proposed,1 which also forms part of the
more complex pyrrole alkaloid halitulin 62).2 In this
Recent syntheses of 6R)- and 6S)-1 by Heinrich and Steglich3
and of 6^)-1 by Banwell et al.4 raised doubts about the
proposed structure. Major discrepancies include the presence
of an intense M12CH2CH2NH2 ion in the mass spectrum of
synthetic 1 as well as strong deviations in the 13C NMR data
and the optical rotation from those of natural haliclorensin.
2. Results and discussion
Re-isolation of haliclorensin and a careful re-investigation
of its HMBC spectrum led to the H±C correlations shown in
Fig. 1 and Table 1. As a result, the structure of haliclorensin
has to be revised to 7-methyl-1,5-diazacyclotetradecane 63).
Structure 3 explains the pronounced solvent and pH
dependency of the 13C NMR data of this alkaloid1 by the
formation of 6bridged) mono- and di-cations. Furthermore,
on treatment with acetic anhydride, haliclorensin yields a
diacetyl derivative, in accordance with structure 3.
Structure 3 was con®rmed by syntheses of the optically pure
enantiomers as shown in Scheme 1. In this synthesis, a
similar strategy was applied as for isomer 1,3 for which
the name isohaliclorensin is proposed.
The synthesis of 3 starts with bis-sulfonamide 4 that was
obtained in 82% yield by reaction of 1,3-diaminopropane
with o-nitrobenzenesulfonyl chloride. Two successive
Keywords: haliclorensin; alkaloids; marine metabolites; metathesis; stereo-
chemistry.
Corresponding author. Tel.: 149-89-2180-7757; fax: 149-89-2180-
7756; e-mail: wos@cup.uni-muenchen.de
couplings of
4
under Mitsunobu conditions5 with
p
4-penten-1-ol and 6S)-2-methyl-5-hexen-1-ol afforded the
protected secondary diamines 5 and 6, respectively.
0040±4020/01/$ - see front matter q 2001 Published by Elsevier Science Ltd.
PII: S0040-4020601)01020-1

9974
M. R. Heinrich et al. / Tetrahedron 57 32001) 9973±9978
Figure 1. HMBC correlations of haliclorensin 63).
Table 1. NMR data of natural and synthetic haliclorensin 6600 MHz, 10 mg 3 in CD3OD120 mL CF3CO2D, 286K)
d
C 6natural)
dH
3.23
2.08
2.24
Multiplicity
J 6Hz)
HMBC correlations
dC 6synthetic)
2
3
42.03
20.64
dd
6.6, 6.6
14.4, 7.0
14.4, 7.2
C-3, C-4, C-14
C-2, C-4
C-2, C-4
C-2, C-3, C-642.6
50.36
C-4, C-7, C-8, 7-Me
C-6, C-8, 7-Me
C-6, C-7, C-9, C-10, 7-Me
42.02
20.82
ddm
ddm
m
4
650.16 2.87
42.54
3.20±3.25
2
dd
13.0, 7.8
C-4, C-7, C-8, 7-Me
13.0, 5.5
6.6
3.13
2.04
1.31
dd
qm
ddm
7
8
28.13
31.96
28.35
32.26
13.5, 6.8
1.52±1.56m
1.46±1.49
1.45±1.55
1.45±1.55
1.45±1.55
1.67
, C-7, CC-9-6, C-10, 7-Me
C-7, C-8, C-10, C-11
9
24.15
25.37
25.78
23.64
22.70
m
m
m
m
ddm
ddm
m
m
d
24.48
25.61
26.09
23.88
22.88
10
11
12
13
Assignment not possible
Assignment not possible
Assignment not possible
C-11, C-12, C-14
C-11, C-12, C-14
C-2, C-13, C-12
13.3, 6.6
13.3, 6.7
1.83
14
44.35
18.12
3.08±3.12
3.17±3.20
1.05
44.54
18.35
C-2, C-13, C-12
C-6, C-7, C-8
7-Me
6.5
6S)-2-Methyl-5-hexen-1-ol was synthesized by established
methods6 in ®ve steps from commercially available methyl
6R)-3-hydroxy-2-methylpropanoate 673% overall yield).
were observed during the azacyclodecene ring formation asso-
ciated with the synthesis of 1.3 Analysis of the NMR integrals
of 7 revealed a 7:3 ratio of the E/Z-isomers. Deprotection with
PhSH and K2CO3 according to Fukuyama7 afforded the E/Z-
mixture of diazacyclotetradecene 8. The stereochemistry of
the diastereomers was determined from the 1H NMR signals
of the ole®nic protons 6J6E)ˆ15 Hz, J6Z)ˆ10 Hz).
Ring closing metathesis of diene 6 with Grubbs' catalyst
afforded diazacyclotetradecene 7 without signi®cant forma-
tion of dimers and oligomers. In contrast, such by-products
Scheme 1. Reagents and conditions: 6a) 4-penten-1-ol 61 equiv.), PPh3 6110.33 equiv.), DEAD 6110.33 equiv.), dry THF, 08C!rt, 24 h; 6b) 6S)-2-methyl-5-
hexen-1-ol 61.5 equiv.), PPh3 6110.33 equiv.), DEAD 6110.33 equiv.), dry THF, 08C!rt, 48 h; 6c) Grubbs' catalyst 60.1 equiv.), CH2Cl2, re¯ux, 24 h;
6d) PhSH 62.5 equiv.), K2CO3 67.5 equiv.), dry DMF, rt, 48 h; 6e) Pd/C 610% Pd), 40 bar 6580 psi) H2, dry MeOH, rt, 18 h.

M. R. Heinrich et al. / Tetrahedron 57 32001) 9973±9978
9975
Figure 2. EIMS spectra of natural and synthetic haliclorensin 63).
Catalytic hydrogenation of ole®n 8 over Pd/C yielded
6S)-haliclorensin 63), identical with the natural product.
The 6R)-enantiomer of 3 was synthesized in the same
manner from 6R)-2-methyl-5-hexen-1-ol. The comparison
of the EI-MS spectra of natural and synthetic haliclorensin
63) is shown in Fig. 2.
spectrum of the derivative derived from natural halicloren-
sin with that of 6R)-10 prepared from synthetic 6R)-3
supported the predominant 6S)-con®guration of the natural
product 6Fig. 3).
The optical rotation of haliclorensin depends strongly on the
pH value. Thus, synthetic 6S)-haliclorensin exhibits an [a]D-
value of 218.5 6c 0.5, in MeOH), the 6R)-compound 120 6c
2.0, in MeOH). For the natural compound a much lower
rotation of 28.5 was observed. Nevertheless, this com-
parison indicates that the natural product has the 6S)-con-
®guration. In 1 M HCl the optical rotation of synthetically
derived 6S)-haliclorensin changes to 17.0. Because of
the lower rotation of the natural product, additional
investigations were carried out.
In order to determine the optical purity, natural haliclorensin
was treated with formaldehyde to yield the methylene
derivative 9.8 In contrast to diamine 3, the enantiomers of
9 can be separated by GC±MS on a chiral b-cyclodextrin
column. The comparison with optically pure samples of 6S)-
and 6R)-9 obtained from the synthetic haliclorensins,
revealed the presence of a 3:1-mixture of the 6S)- and
6R)-enantiomers. This result is in good agreement with the
lower [a]D-value of 28.5 observed for the natural product.
Figure 3. CD spectra of 6R)-10 6- - -) and the same derivative derived from
natural 3 6Ð) 6in acetonitrile).
Haliclorensin 63) can be easily converted to its bis-dinitro-
phenyl derivative 10 by treatment with an excess of 2,4-
dinitro¯uorobenzene 6Sanger's reagent).9 The CD-spectrum
of the resulting yellow oil shows an exciton coupling
between the two chromophores. A comparison of the CD-

9976
M. R. Heinrich et al. / Tetrahedron 57 32001) 9973±9978
Scheme 2. Proposed common intermediate 11 for the biosynthesis of 1 and 3.
Haliclorensin 63) and its synthetic isomer 1 6isohali-
clorensin) can be derived hypothetically from the same
intermediate 11, which might explain the common occur-
rence of 3 and halitulin 62) in H. tulearensis 6Scheme 2).
The synthesis of 11 is under active investigation.
tion of the solvent and trituration of the resulting crude oil
with Et2O yielded pure 4 63.40 g, 82%) as a colorless solid:
mp 117±1198C; Rf 0.3 6EtOAc±petroleum ether, 1:1 v/v);
1H NMR 6300 MHz, [D6]acetone): d 1.83 6tt, Jˆ6.7, 6.7 Hz,
2H), 3.21 6dt, Jˆ6.7, 6.7 Hz, 4H), 6.66 6t, Jˆ6.7 Hz, 2NH),
7.86±7.98 6m, 6H), 8.08±8.14 6m, 2H); 13C NMR
675.5 MHz, [D6]acetone): d 30.3 6CH2), 41.0 62£CH2),
125.3 62£CH), 130.8 62£CH), 133.0 62£CH), 133.8
62£Cq), 134.3 62£CH), 148.662 £Cq); MS 6ESI) m/z:
445.1 [M1H]1; HRMS 6ESI) calcd for C15H16N4O8S21Na
[M11Na] 467.0307, found 467.0333; Anal. calcd C, 40.54;
H, 3.63; N, 12.61; S, 14.43; found C, 40.44; H, 3.63; N,
12.54; S, 14.50.
3. Experimental
3.1. General
Silica gel 60 230±400 mesh 6Merck) and Sephadex LH-20
6Pharmacia) were used for chromatography. Rf values were
determined on silica gel 60 F254 TLC plates 6Merck).
Petroleum ether refers to the fractions with bp 40±608C.
1H and 13C NMR spectra were recorded on Bruker ARX
300 and Bruker AMX 600 instruments. 1H and 13C chemical
shifts are given with respect to the solvent as internal
standard. IR spectra were measured on a Perkin±Elmer
FT 1000. C, H, N and S analyses were performed by the
microanalytical laboratory of the Chemistry Department,
LMU, MuÈnchen. Mass spectra were recorded with a
Finnigan MAT 90 sector ®eld mass spectrometer at 70 eV.
For GC±MS a Varian GC 3400 gas chromatograph with a
fused silica DB-5ms 6Macherey±Nagel) capillary column
630 m£0.25 mm, coated with a 0.25 mm layer of liquid
phase) or a b-DEX 120 6Supelco) capillary column
625 m£ 0.25 mm, coated with a 0.25 mm layer of liquid
phase) and helium as carrier gas was used for sample separa-
tion. The injector temperature was kept at 3008C 6column
DB-5ms) 2208C 6column b-DEX 120), respectively, injec-
tion volumes were 0.1±0.2 mL of a 1±2% 6m/v) solution.
Temperature programmes: Column DB-5ms: 2 min iso-
thermal at 508C, then 10 K/min up to 3008C, ®nally 10 min
isothermal at 3008C; Column b-DEX 120: 2 min isothermal
at 1508C, then 2 K/min up to 2008C, ®nally 10 min iso-
thermal at 2008C. Retention indices10 Ri were determined
by co-injection of a 0.2 mL sample of a standard mixture of
saturated straight chain alkanes 6C10±C36). Optical rotations
were determined on a Perkin±Elmer 241 polarimeter. For
removal of oxygen, nitrogen was bubbled through the
dichloromethane prior to its use in the RCM reaction.
3.1.2. N-{3-[ꢀ2-Nitrobenzenesulfonyl)pent-4-enylamino]-
propyl}-2-nitrobenzenesulfonamide ꢀ5). A solution of
4-penten-1-ol
60.78 mL,
7.65 mmol),
4
63.40 g,
7.65 mmol), and triphenylphosphine 62.01 g, 7.65 mmol)
in dry THF 660 mL) was cooled to 08C under an argon
atmosphere. After the dropwise addition of diethyl azodi-
carboxylate 61.19 mL, 7.65 mmol), the ice-bath was
removed and the mixture stirred at room temperature.
After 8 h, additional triphenylphosphine 60.67 g,
2.55 mmol) and diethyl azodicarboxylate 60.44 g,
2.55 mmol) were added, and the stirring was continued for
16h. The solvent was removed under reduced pressure and
the residue chromatographed on silica gel with CH2Cl2±
acetone, 20:1 v/v, to yield 5 62.43 g, 62%) as a clear yellow
oil: Rf 0.7 6CH2Cl2±acetone, 20:1 v/v); 1H NMR 6300 MHz,
CDCl3): d 1.57 6tt, Jˆ7.4, 7.4 Hz, 2H), 1.81 6tt, Jˆ6.7,
6.7 Hz, 2H), 1.97 6dt, Jˆ7.4, 7.4 Hz, 2H), 3.14 6dt, Jˆ6.7,
6.7 Hz, 2H), 3.23 6t, Jˆ7.4 Hz, 2H), 3.366t, Jˆ6.7 Hz, 2H),
4.91±4.99 6m, 2H), 5.61±5.75 6m, 1H); 5.68±5.73 6m, NH),
7.58±7.62 6m, 1H), 7.66±7.74 6m, 4H), 7.81±7.85 6m, 1H),
7.95±7.99 6m, 1H), 8.06±8.10 6m, 1H); 13C NMR
675.5 MHz, CDCl3): 27.3 6CH2), 28.8 6CH2), 30.5 6CH2),
40.66CH ), 44.8 6CH2), 47.3 6CH2), 115.5 6CH2), 124.2
2
6CH), 125.3 6CH), 130.7 6CH), 130.8 6CH), 131.8 6CH),
132.8 6CH), 133.0 6Cq), 133.5 6Cq), 133.59 6CH), 133.64
6CH), 136.9 6CH), 147.9 62£Cq); MS 6EI) m/z 6rel. int.):
457 62, M12C4H7), 326637, M 12C6H4NO4S), 1866100,
C6H4NO4S1); MS 6FAB) m/z: 513 [M11H]; HRMS 6ESI)
calcd for C20H24N4O8S21H [M11H] 513.1114, found
513.1108; Anal. calcd C, 46.87; H, 4.72; N, 10.93; S,
12.51; found C, 47.36; H, 5.06; N, 10.59; S, 12,05.
3.1.1.
N-[3-ꢀ2-Nitrobenzenesulfonyl)amino-propyl]-2-
nitrobenzenesulfonamide ꢀ4). To a stirred suspension of
2-nitrobenzenesulfonyl chloride 64.16g, 18.7 mmol) and
potassium carbonate 62.59 g, 18.7 mmol) in dry THF
640 mL) was added, dropwise at 08C, 1,3-diaminopropane
60.78 mL, 9.35 mmol). The resultant mixture was heated
under re¯ux for 24 h, and after evaporation of the solvent,
the residue was partitioned between CH2Cl2 650 mL) and
2 M HCl 650 mL). The organic phase was washed with
saturated aqueous sodium bicarbonate and water. Evapora-
3.1.3. ꢀS)-N-{3-[ꢀ2-Nitrobenzenesulfonyl)-ꢀ2-methylhex-
5-enyl)amino]propyl}-N-ꢀpent-4-enyl)-2-nitrobenzene-
sulfonamide ꢀ6). A solution of 6S)-2-methylhex-5-en-1-ol6
6115 mg, 1.01 mmol), 5 6345 mg, 0.67 mmol) and triphenyl-
phosphine 6177 mg, 0.67 mmol) in dry THF 610 mL)
was cooled to 08C. After the dropwise addition of diethyl
azodicarboxylate 6105 mL, 0.67 mmol) the ice-bath was

M. R. Heinrich et al. / Tetrahedron 57 32001) 9973±9978
9977
removed and the mixture stirred at room temperature for
48 h. After ca. 24 h, additional triphenylphosphine 660 mg,
0.23 mmol) and diethyl azodicarboxylate 640 mg,
0.23 mmol) were added. The solvent was then removed
under reduced pressure and the residue chromatographed
on silica gel 6EtOAc±petroleum ether, 1:1 v/v) to afford 6
6280 mg, 69%) as a light yellow foam: Rf 0.8 6EtOAc±
of 7 6150 mg, 0.26mmol) in dry DMF 65 mL), maintained
under argon, was treated with potassium carbonate 6270 mg,
1.96mmol) and thiophenol 666 mL, 0.65 mmol). The result-
ing reaction mixture was stirred at room temperature for
48 h. After addition of water 615 mL) and 2 M NaOH
65 mL), the aqueous phase was extracted with CHCl3
63£15 mL). The combined organic layers were extracted
with 2 M HCl 63£5 mL) and the aqueous phase adjusted
to alkaline pH by adding 2 M NaOH which resulted in
partial precipitation of the product. It was extracted with
CHCl3, washed with 2 M NaOH 62£10 mL) and dried
over sodium sulfate. Evaporation of the solvent yielded
pure 8 640 mg, 73%) as a 7:3 mixture of E/Z isomers as
judged by NMR analysis: colorless oil; 1H NMR
6600 MHz, CDCl3): d 0.85E and 0.87Z 62£d, Jˆ6.7,
6.9 Hz, 3H), 1.16±1.55 6m, 3H), 1.56±1.71 6m, 4H),
1.72±1.94 6m, 3H), 1.94±2.166m, 3H), 2.22±2.75 6m,
8H), 5.23Z 6dt, br., Jˆ10, 8 Hz, 0.3H), 5.40E 6dt, Jˆ15,
7 Hz, 0.7H), 5.47Z 6dt, br., Jˆ10, 8 Hz, 0.3H), 5.52E 6dt,
Jˆ15, 7 Hz, 0.7H); 13C NMR 6151 MHz, CDCl3): 18.3Z
6CH3), 18.5E 6CH3), 22.1Z 6CH2), 23.2Z 6CH2), 27.87E
6CH2), 27.88E 6CH2), 28.3Z 6CH2), 28.9E 6CH2), 29.1Z
6CH2), 29.2E 6CH), 30.4E 6CH2), 30.8Z 6CH), 33.1Z 6CH2),
33.4E 6CH2), 45.1E 6CH2), 47.25Z 6CH2), 47.31E 6CH2), 47.4E
6CH2), 48.7Z 6CH2) 49.3Z 6CH2), 53.7Z 6CH2), 54.5E 6CH2),
129.0Z 6CH), 130.4E 6CH) 130.8Z 6CH) 131.7E 6CH); GC±
MS 6EI) m/z 6rel. int.): 211 616, M11H), 210 65, M1), 181
612), 167 625), 152 633), 139 632), 124 624), 112 626), 110
633), 99 638), 84 640), 70 669), 58 643), 44 6100); HRMS 6EI)
calcd for C13H26N2 [M1] 210.2096, found 210.2092.
1
petroleum ether, 1:1 v/v); [a]Dˆ25.66 c 0.8, MeOH); H
NMR 6300 MHz, CDCl3): d 0.82 6d, Jˆ6.6 Hz, 3H), 1.05±
1.17 6m, 1H), 1.35±1.47 6m, 1H), 1.57 6tt, Jˆ7.6, 7.6 Hz,
2H), 1.64±1.75 6m, 1H), 1.76±1.86 6m, 2H), 1.93±2.02 6m,
3H), 2.05±2.15 6m, 1H), 3.05±3.18 6m, 2H), 3.20±3.27 6m,
6H), 4.89±5.01 6m, 4H), 5.62±5.78 6m, 2H), 7.57±7.61 6m,
2H), 7.65±7.71 6m, 4H), 7.95±7.99 6m, 2H); 13C NMR
675.5 MHz, CDCl3): 16.8 6CH3), 27.0 6CH2), 27.1 6CH2),
30.47 6CH2), 30.49 6CH), 30.8 6CH2), 32.9 6CH2), 44.9
62£CH2), 47.1 6CH2), 53.8 6CH2), 114.8 6CH2), 115.5
6CH2), 124.1 62£CH), 130.7 6CH), 130.8 6CH), 131.69
6CH), 131.72 6CH), 133.0 62£Cq), 133.51 6CH), 133.55
6CH), 137.0 6CH), 138.2 6CH), 147.9 62£Cq); MS 6EI) m/z
6rel. int.): 608 60.3, M1), 525 632, M12C6H11), 422 637,
M12C6H4NO4S), 229 672), 1866100, C 6H4NO4S1); HRMS
6ESI) calcd for C27H36N4O8S2 [M1] 608.1974, found
608.1964; Anal. calcd C, 53.27; H, 5.96; N, 9.20; S,
10.54; found C, 53.07; H, 6.03; N, 9.06; S, 10.43.
3.1.4. ꢀS)-1,5-Bisꢀ2-nitrobenzenesulfonyl)-13-methyl-1,5-
diazacyclotetradec-9-ene ꢀ7) ꢀmixture of E/Z-isomers).
To dry re¯uxing CH2Cl2 6500 mL) under argon were
added Grubbs' catalyst 624 mg, 0.029 mmol) and a solution
of 6 6175 mg, 0.29 mmol) in dry CH2Cl2 65 mL). The result-
ing mixture was re¯uxed for 24 h, then cooled to room
temperature and ®ltered over Celite. After evaporation of
the solvent, the residue was puri®ed by chromatography
6EtOAc±petroleum ether, 1:1 v/v) to afford 7 634 mg,
80%) as a 7:3 mixture of the E/Z isomers 6NMR analysis):
colorless oil, Rf 0.65 6EtOAc±petroleum ether, 1:1 v/v); 1H
NMR 6300 MHz, CDCl3): d 0.77E and 0.87Z 62£d, Jˆ6.5,
6.6 Hz, 3H), 1.32±1.57 6m, 4H), 1.57±1.97 6m, 3H), 2.00±
2.15 6m, 4H), 2.80±3.566m, 8H), 5.34±5.38 and 5.42±5.47 E
62£m, 2H), 7.56±7.60 and 7.65±7.70 62 £m, 6H), 7.86±7.92
and 7.96±8.00 62£m, 2H); 13C NMR 675.5 MHz, CDCl3):
17.2E 6CH3), 18.2Z 6CH3), 24.0Z 6CH2), 24.8E 6CH2), 24.9E
6CH), 25.1Z 6CH2), 28.0E 6CH), 28.6E 6CH2), 28.9E 6CH2),
29.1Z 6CH2), 29.5Z 6CH2), 31.6Z 6CH), 33.0E 6CH2), 33.9Z
6CH2), 42.6E 6CH2), 43.4E 6CH2), 44.3E 6CH2), 46.5Z 6CH2),
46.7Z 6CH2), 49.5Z 6CH2), 53.2E 6CH2), 56.0Z 6CH2), 124.02Z
6CH), 124.06E 6CH), 124.10Z 6CH), 124.15E 6CH), 128.9Z
6CH), 130.18Z 6CH), 130.22E 6CH), 130.50E 6CH), 130.63Z
6CH), 130.67E 6CH), 130.7Z 6CH), 131.57Z 6CH), 131.61Z
6CH), 131.66E 6CH), 131.73Z 6CH), 131.78E 6CH), 131.85Z
6Cq), 132.3Z 6Cq), 132.4E 6CH), 132.8E 6Cq), 132.9E 6Cq),
133.5E 6CH), 133.6Z 6CH), 133.7E 6CH), 147.7E 6Cq),
147.9E 6Cq), 148.2Z 6Cq), 148.3Z 6Cq); MS 6EI) m/z 6rel.
int.): 580 60.02, M1), 563 64), 395 622), 394 6100,
M12C6H4NO4S), 209 631), 208 65, M122£C6H4NO4S),
3.1.6. ꢀS)-7-Methyl-1,5-diazacyclotetradecane, ꢀS)-ꢀ2)-
haliclorensin ꢀ3). Palladium on activated charcoal 620 mg,
10% Pd) was added to a solution of 8 625 mg, 0.12 mmol) in
dry MeOH 65 mL). Hydrogenation was carried out at 40 bar
6580 psi) hydrogen pressure for 18 h. The catalyst was
removed by ®ltration and the solvent evaporated under
reduced pressure to yield pure 62)-haliclorensin [62)-3]
623 mg, 90%) as a colorless oil: [a]Dˆ218.5 6c 0.6,
MeOH), after removal of traces of acids by washing the
probe with 2 M NaOH; IR 6®lm): 3306w, 2927s, 2860m,
2804m, 1678w, 1460m, 1129w; 1H NMR 6600 MHz,
CD3OD): d 0.94 6d, Jˆ7.0 Hz, 3H), 1.25±1.31 6m, 1H),
1.32±1.55 6m, 9H), 1.56±1.63 6m, 2H), 1.71±1.80 6m,
3H), 2.42 6dd, Jˆ11.8, 9.7 Hz, 1H), 2.57 6dd, Jˆ11.8,
3.8 Hz, 1H), 2.64 6ddd, Jˆ11.1, 7.6, 3.5 Hz, 1H), 2.66±
2.70 6m, 2H), 2.72±2.75 6m, 2H), 2.84 6ddd, Jˆ11.1, 7.0,
3.5 Hz, 1H); 13C NMR 6100 MHz, CD3OD): 19.1 6CH3),
22.3 6CH2), 23.5 6CH2), 24.9 6CH2), 27.66CH 2), 28.0
6CH2), 29.66CH ), 30.8 6CH2), 33.0 6CH), 47.8 6CH2),
2
50.1 6CH2), 50.8 6CH2), 55.9 6CH2); GC±MS 6column
DB-5ms): Ri 1711; 6EI) m/z 6rel. int.): see Fig. 1. HRMS
6EI) calcd for C13H28N2 [M1] 212.2253, found 212.2245.
3.1.7. ꢀR)-7-Methyl-1,5-diazacyclotetradecane, ꢀR)-ꢀ1)-
haliclorensin ꢀ3). The compound was prepared by the
same synthetic steps by using 6R)-2-methylhex-5-en-1-ol6
instead of the 6S)-isomer: [a]Dˆ120.0 6c 2.0, MeOH).
207 623), 186623, C H4NO4S1); HRMS 6EI) calcd for
6
C25H33N4O8S2 [M11H] 581.1739, found 581.1785; Anal.
calcd 6C25H32N4O8S2£H2O) C, 50.15; H, 5.72; N, 9.36; S,
10.71; found C, 50.01; H, 5.45; N, 9.19; S, 10.43.
3.1.8. Natural haliclorensin ꢀ3). NMR, see data for 6S)-
62)-haliclorensin 63); GC±MS 6column DB-5ms): Ri
1711; 6EI) m/z 6rel. int.): see Fig. 1; HRMS 6EI) calcd for
C13H28N2 [M1] 212.2253, found 212.2248.
3.1.5. ꢀS)-13-Methyl-1,5-diazacyclotetradec-9-ene ꢀ8)
ꢀmixture of E/Z isomers). A magnetically stirred solution

9978
M. R. Heinrich et al. / Tetrahedron 57 32001) 9973±9978
3.2. Determination of the ꢀR)/ꢀS)-ratio of natural
haliclorensin after conversion into the 3-methyl-1,11-
diazabicyclo[9.3.1]pentadecane derivative ꢀ9)
6CH2), 49.9 6CH2), 51.1 6CH2), 56.2 6CH2), 119.2 6CH),
120.0 6CH), 123.5 6CH), 123.8 6CH), 127.7 6CH), 127.9
6CH), 137.7 6Cq), 137.9 6Cq), 138.2 6Cq), 138.3 6Cq), 148.7
6Cq), 150.2 6Cq); MS 6EI) m/z 6rel. int.): 544 68, M1), 527
69), 497 68), 288 629), 210 657), 184 630), 180 6100), 164
638), 149 662), 55 648); HRMS 6EI) calcd for C25H32N6O8
[M1] 544.2282, found 544.2273.
Formaldehyde 620 mL of a 37% aq. solution) was added to a
solution of natural 3 6100 mg) in CHCl3 6100 mL) and
incubated for 30 min at 258C before injection 60.1 mL) of
this solution in the GC±MS. GC±MS 6column: b-DEX
120): 6S)-9: Ri 1800 6rel. int.: 75%); 6R)-9: Ri 1803 6rel
int.: 25%); 6EI) m/z 6rel. int.): 224 642), 223 6100), 209
65), 182 65), 180 614), 168 67), 166 610), 139 67), 138 67),
124 67), 112 67), 110 67), 99 613), 98 69), 9665), 84 66), 82
65), 70 615), 58 68), 5665), 44 624).
Acknowledgements
We thank Professor Martin Banwell, Australian National
University, Research School of Chemistry, Canberra, for
helpful discussions and Mrs Sabine Voss for skillful
technical assistance.
3.2.1. ꢀR)-1,5-Bisꢀ2,4-dinitrophenyl)-7-methyl-1,5-diaza-
cyclotetradecane ꢀ10). To a solution of 6R)-3 610 mg,
0.047 mmol) in dry CH2Cl2 62 mL) under argon were
added 2,4-dinitro¯uorobenzene 615 mL, 22 mg, 0.12
mmol) and triethylamine 620 mL, 0.14 mmol). After the
resulting mixture had been stirred at room temperature for
18 h, the solvent was evaporated. The residue was puri®ed
by chromatography 6EtOAc±petroleum ether, 1:3 v/v) to
yield 10 620 mg, 0.037 mmol, 78%) as a clear yellow oil.
Rf 0.3 6EtOAc±petroleum ether, 1:3 v/v); UV lmax
6CH3CN) nm 6log 1): 363 64.31), 389 64.28); CD l
6CH3CN) nm 6D1): 2866 24.68), 304 60.00), 326 66.01),
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