Total synthesis of the putative structure of the marine alkaloid haliclorensin

Article abstract of DOI:10.1039/b105045c

Compound 1, the structure of which has been assigned to the marine natural product haliclorensin, was prepared by an unambiguous synthetic pathway and subjected to spectroscopic analysis. The derived data do not match those reported for the natural produc

Full text of DOI:10.1039/b105045c

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Total synthesis of the putative structure of the marine alkaloid
haliclorensin
Martin G. Banwell,*a Andrew M. Bray,b Alison J. Edwardsa and David J. Wonga
a Research School of Chemistry, Institute of Advanced Studies, T he Australian National
University, Canberra, ACT 0200, Australia. E-mail: mgb=rsc.anu.edu.au
L e t t e r
b Mimotopes Pty L td, 11 Duerdin Street, Clayton South, Melbourne, V ictoria 3169, Australia
Received (in Montpellier, France) 8th June 2001, Accepted 21st August 2001
First published as an Advance Article on the web 9th October 2001
Compound 1, the structure of which has been assigned to the
marine natural product haliclorensin, was prepared by an unam-
biguous synthetic pathway and subjected to spectroscopic
analysis. The derived data do not match those reported for the
natural product.
The natural products haliclorensin1 and halitulin2 were iso-
lated by Kashman and co-workers from the marine sponge
Haliclona tulearensis, collected in Sodwana Bay, Durban,
South Africa. The structures of these compounds were assign-
ed as 1 and 2, respectively, using a combination of spectro-
scopic studies and biosynthetic considerations. The absolute
stereochemistry associated with the single stereogenic centre
incorporated in these structures was not assigned. While no
signiÐcant biological activity has been ascribed to halicloren-
sin, halitulin was found to be cytotoxic against several tumour
means and report that it does not correspond to the natural
product haliclorensin.7
The synthesis of compound 1 is shown in Scheme 1. The
key step involves a ring-closing metathesis (RCM) step for
construction of the azacyclodecane ring,8 a protocol that has
been applied to the preparation of a number of other promi-
nent and structurally related marine alkaloids, including
manzamine C.9 Thus, condensation of the commercially avail-
able acid 3 with benzylamine using DMTMM10 a†orded
amide 4 (100%), which was reduced to the N-benzylamine 5
(100%) with lithium aluminium hydride. DMTMM-mediated
condensation of the latter compound with 5-hexenoic acid
then gave the doubly unsaturated amide 6 (40%), which was
obtained as a ca. 1 : 1 and chromatographically distinguish-
able mixture of rotamers. In keeping with the studies of Weiler
et al.,11 compound 6 participated in a RCM reaction when
treated with 15 mol% of (Cy P) Cl Ru2CHPh (GrubbsÏ
cell lines (e.g., P-388, A-549, HT-29 and MEL-28) with IC
50
values in the 12È25 ng ml~1 range. Such properties, coupled
with the novel structure assigned to halitulin, prompted a
patent Ðling3 (jointly with PharmaMar S. A., Madrid) claim-
ing 3,4-bis(7,8-dihydroxyquinolin-5-yl)pyrroles as antitumour
agents.
Our continued interest in developing total syntheses of
biologically active, pyrrole-containing marine natural
products4h6 prompted us to undertake the preparation of the
racemic modiÐcation of compound 1 as a prelude to the
assembly of the structurally more challenging congener 2.
Herein, we detail the synthesis of target 1 by unambiguous
3
2 2
Scheme 1 Reagents and conditions: (i) benzylamine (1.2 mol equiv.), DMTMM (1 mol equiv.), THF, 18 ¡C, 16 h; (ii) LiAlH (2 mol equiv.), THF,
4
0È18 ¡C, 16 h; (iii) 5-hexenoic acid (1 mol equiv.), DMTMM (1.5 mol equiv.), THF, 18 ¡C, 16 h; (iv) (Cy P) Cl Ru2CHPh (ca. 15 mol%), CH Cl ,
3
2
2
2 2
reÑux, 48 h; (v) H (1 atm.), 10% Pd on C (50% by wt.), MeOH, 18 ¡C, 24 h; (vi) LiAlH (2 mol equiv.), THF, 18 ¡C, 16 h; (vii) H (1 atm.), 20%
Pd(OH) on C, CH Cl , 18 ¡C, 24 h; (viii) acrylonitrile (excess), AcOH (2 mol equiv.), reÑux, 16 h; (ix) NaBH (25 mol equiv.), CoCl É 6H O (2.5
2
4
2
2
2
2
4
2
2
mol equiv.), MeOH, 18 ¡C, 2 h. DMTMM \ 4-M4,6-dimethoxy[1,3,5]triazin-2-ylN-4-methylmorpholinium chloride.
DOI: 10.1039/b105045c
New J. Chem., 2001, 25, 1347È1350
1347
This journal is ( The Royal Society of Chemistry and the Centre National de la Recherche ScientiÐque 2001

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catalyst)12 in reÑuxing dichloromethane, although it was clear
that one rotameric form reacted more rapidly than the other
in this process. The resulting ca. 3 : 1 mixture of E- and Z-
alkenes (76%) was immediately subjected to hydrogenation
with dihydrogen in the presence of 10% palladium on carbon
and, in this manner, the corresponding saturated lactam 7
(100%) was obtained and the structure determined by single-
crystal X-ray analysis (Fig. 1 and Experimental).
On the basis of the foregoing, we conclude that the struc-
ture for haliclorensin has been incorrectly assigned. These
observations also call into question the structure assigned to
halitulin. Synthetic and spectroscopic studies designed to
establish the structures of haliclorensin and halitulin are now
underway in our laboratories and results will be reported in
due course.
Lithium aluminum hydride-promoted reduction of the
latter compound then a†orded the N-benzylated amine 8
(100%), which was reacted with hydrogen in the presence of
Experimental
Unless otherwise speciÐed, 1H and 13C NMR spectra were
recorded on a Varian Gemini 300 spectrometer using deutero-
chloroform as solvent. The 500 MHz 1H NMR spectra and
the 150 MHz 13C NMR spectrum were obtained on the corre-
sponding Varian Inova spectrometers. Infrared spectra were
recorded on either a PerkinÈElmer 683 or 1800 FTIR instru-
ment. Unless otherwise speciÐed, mass spectral analyses were
carried out in electron-impact mode and on a VG Micromass
7070F double-focussing spectrometer. Thin layer chromato-
graphic analyses were carried out on aluminium-backed 0.2
20% Pd(OH) on carbon to give 3-methylazadodecane (9).
2
This latter compound was not characterized but immediately
subjected to treatment with excess acrylonitrile in the presence
of acetic acid and, in this manner, the expected Michael addi-
tion product 10 (36% from 8) was obtained. Treatment of
compound 10 with sodium borohydride in the presence of
cobalt(II) chloride hexahydrate13 then gave the target diamine
1 in 90% yield. NMR spectroscopic and mass spectrometric
analysis of this material gave data completely consistent with
structure 1 but these did not match those reported1 for the
natural product (Table 1 and Experimental). Our data do,
however, match those reported7 by Heinrich and Steglich for
their synthetically-derived samples of compound 1.
mm thick silica gel 60 GF
plates supplied by Merck while
254
Ñash chromatographic puriÐcations were conducted according
to the method of Still et al.14 and using Merck silica gel 60
(230È400 mesh) as adsorbent. All solvents and common
reagents were puriÐed by established procedures.15
Syntheses
(»)-2-Methylpent-4-enoic acid benzylamide (4). DMTMM
(9.09 g, 32.96 mmol) was added in portions to a magnetically
stirred solution of benzylamine (2.94 g, 27.46 mmol) and 2-
methylpent-4-enoic acid (3.14 g, 27.46 mmol) in THF (125 ml)
maintained at 0 ¡C under
a nitrogen atmosphere. The
resulting mixture was allowed to warm to 18 ¡C over ca. 1 h,
stirred at this temperature for a further 15 h, then poured into
water (150 ml) and extracted with diethyl ether (3 ] 200 ml).
The combined ethereal extracts were washed with HCl
(2 ] 400 ml of a 2 M aq. solution), NaHCO (2 ] 400 ml of a
3
saturated aq. solution) and brine (1 ] 400 ml) before being
dried (Na SO ), Ðltered and concentrated under reduced pres-
2
4
sure to a†ord a dark yellow oil. Subjection of this material to
Ñash chromatography (silica gel, 2 : 3 v/v ethyl acetateÈhexane
elution) and concentration of the appropriate fractions (R 0.6)
f
a†orded amide 416 (4.95 g, 89%) as a pale yellow oil. HRMS:
m/z 203.1316 (M~`); C
3076, 3030, 2971, 2931, 1643, 1548, 1454, 1250, 993, 914, 730,
H
NO requires 203.1310; l
3286,
13 17
max
697 cm~1; d 7.34È7.26 (m, 5H), 5.83È5.69 (complex m, 2H),
Fig. 1 Diagram derived from single-crystal X-ray analysis of com-
pound 7.
H
5.11È5.01 (complex m, 2H), 4.48 (dd, J 14.7 and 5.6 Hz, 1H),
4.42 (dd, J 14.7 and 5.6 Hz, 1H), 2.44 (m, 1H), 2.25 (m, 1H),
2.18 (m, 1H), 1.18 (d, J 6.2 Hz, 3H); d 175.8 (CO), 138.4 (C),
C
Table 1 Comparison of 13C NMR spectral data derived from com-
pound 1 with those reported1 for haliclorensina
135.7 (CH), 128.3 (2 ] CH), 127.4 (2 ] CH), 127.1 (CH), 116.5
(CH ), 43.0 (CH ), 40.7 (CH), 38.2 (CH ), 17.2 (CH ); m/z 203
2
2
2
3
(M~`, 47%), 188 [(M [ CH )`, 22], 162 [(M [ C H )`, 33],
Compound 1
3
3 5
91 (100).
Carbon no.
(at 125 MHz)
Haliclorensin
Calc.b
2
3
4
5
6
7
8
9
10
11
1@
2@
3@
60.3(CH )
2
48.5(t)
26.5(d)
30.3(t)
22.6(t)
24.3(t)
24.1(t)
22.3(t)
21.5(t)
42.4(t)
17.7(q)
41.3(t)
19.2(t)
41.2(t)
61.1
31.7
34.7
27.5
30.6
30.0
28.0
30.0
54.5
17.8
51.6
34.1
40.0
(»)-Benzyl(2º-methylpent-4º-enyl)amine (5). Lithium alu-
minium hydride (13.7 ml of a 1.0 M solution in THF, 13.7
mmol) was added, dropwise, to a magnetically stirred solution
of amide 4 (1.39 g, 6.86 mmol) in THF (50 ml) maintained at
0 ¡C under a nitrogen atmosphere. The resulting mixture was
allowed to warm to 18 ¡C over ca. 1 h, stirred at this tem-
perature for a further 15 h then quenched with ethyl acetate
(20 mL). The resulting mixture was treated with sodium
hydroxide (20 ml of a 2 M aq. solution) and the ensuing pre-
cipitate Ðltered through CeliteTM. The Ðltrate was treated with
water (100 ml) and ethyl acetate (100 ml) and the separated
aqueous phase extracted with ethyl acetate (3 ] 100 ml). The
combined organic extracts were then dried (Na SO ), Ðltered
29.4(CH)
31.6(CH )
2
21.7(CH )
2
26.1(CH )
2
24.2(CH )
2
24.0(CH )
2
25.4(CH )
2
52.8(CH )
2
19.4(CH )
3
52.4(CH )
2
30.0(CH )
2
40.3(CH )
2
a Both spectra recorded in DMSO-d . b Generated using the NMR
chemical shift calculation package associated with ChemDraw
UltraTM 6.0 (PC Version).
6
2
4
and concentrated under reduced pressure to a†ord the title
amine 517 (1.33 g, 99%) as a pale yellow oil. HRMS: m/z
1348
New J. Chem., 2001, 25, 1347È1350

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174.1283 (M [ CH )`; C
H
N
requires 174.1283; l
pressure to a†ord a light yellow oil. Subjection of this material
to Ñash chromatography (silica gel, 1 : 5 v/v ethyl acetateÈ
hexane elution) and concentration of the appropriate fractions
3
12 16
max
3063, 3026, 2954, 2905, 2813, 1639, 1494, 1453, 1118, 993, 910,
734, 697 cm~1; d 7.33È7.21 (complex m, 5H), 5.78 (m, 1H),
H
5.05È4.96 (complex m, 2H), 3.78 (s, 2H), 2.56 (dd, J 11.6 and
(R 0.5) gave the saturated lactam 7 (325 mg, 99%) as crys-
f
6.3 Hz, 1H), 2.43 (dd, J 11.6 and 6.9 Hz, 1H), 2.16 (m, 1H), 1.91
talline masses, m.p. 46È49 ¡C. HRMS: m/z 259.1934 (M~`);
(m, 1H), 1.73 (m, 1H), 1.37 (br s, 1H), 0.91 (d, J 6.7 Hz, 3H); d
C
H
NO requires 259.1936; l
2930, 1632, 1450, 1144,
C
17 25
max
140.5 (C), 137.0 (CH), 128.1 (2 ] CH), 127.8 (2 ] CH), 126.6
740, 700 cm~1; d 7.30È7.10 (complex m, 5H), 5.37 (br d, J
14.2 Hz, 1H), 3.80 (br d, J 14.2 Hz, 1H), 3.40 (t, J 13.5 Hz, 1H),
2.90 (m, 2H), 2.20È1.96 (complex m, 3H), 1.60È1.10 (complex
H
(CH), 115.7 (CH ), 55.2 (CH ), 53.9 (CH ), 39.2 (CH ), 33.0
2
2
2
2
(CH), 17.8 (CH ); m/z 189 (M~`, 58%), 188 [(M [ H)`, 67],
3
174 [(M [ CH )`, 22], 120 [(M [ C H )`, 92], 91 (100). This
material was used without further puriÐcation in the next step
of the reaction sequence.
m, 9H), 0.76 (d, J 6.9 Hz, 3H); d 173.9 (C), 137.6 (C), 128.4
3
5
9
C
(2 ] CH), 128.2 (2 ] CH), 127.1 (CH), 50.7 (CH ), 46.8 (CH ),
2
2
30.0 (CH ), 29.0 (CH), 27.4 (CH ), 26.0 (CH ), 23.9 (CH ), 21.0
2
2
2
2
(CH ), 20.3 (CH ), 15.8 (CH ); m/z 259 (M~`, 35%), 140 (35),
120 (100), 91 (100).
2
2
3
(»)-Hex-5-enoic acid benzyl(2º-methylpent-4º-enyl)amide
(6). DMTMM (2.77 g, 10.02 mmol) was added, in portions, to
a magnetically stirred solution of amine 5 (1.26 g, 6.68 mmol)
and 5-hexenoic acid (0.76 g, 6.68 mmol) in THF (60 ml) main-
tained at 0 ¡C under a nitrogen atmosphere. The reaction
mixture was allowed to warm to 18 ¡C over ca. 1 h, stirred at
this temperature for a further 15 h then poured into water (60
ml) and extracted with diethyl ether (3 ] 100 ml). The com-
bined ethereal extracts were washed with HCl (2 ] 200 ml of a
(»)-1-Benzyl-3-methylazacyclodecane (8). Lithium alumin-
um hydride (690 ll of a 1.0 M solution in THF, 0.69 mmol)
was added dropwise to a magnetically stirred solution of the
lactam 7 (89 mg, 0.34 mmol) in THF (5 ml) maintained at
18 ¡C under a nitrogen atmosphere. After the addition was
complete stirring was continued for a further 16 h, then the
reaction mixture was quenched with ethyl acetate (3 ml) and
2 M aq. solution), NaHCO (2 ] 200 ml of a saturated aq.
then diluted with water (40 ml) and CHCl (40 ml). The
3
3
solution) and brine (1 ] 200 ml), then dried (Na SO ), Ðltered
separated aqueous phase was extracted with CHCl (3 ] 40
2
4
3
ml) and the combined organic extracts dried (MgSO ), Ðltered
4
and concentrated under reduced pressure to a†ord a dark
yellow oil. Subjection of this material to Ñash chromatog-
raphy (silica gel, 1 : 4 v/v ethyl acetateÈhexane elution) and
and concentrated under reduced pressure to give a light
yellow oil. Subjection of this material to Ñash chromatog-
concentration of the appropriate fractions (R 0.4) a†orded
amide 6 (800 mg, 42%) as a pale yellow oil and a ca. 1 : 1
mixture of rotamers (as judged by 13C NMR analysis).
raphy (silica gel, 1 : 5 v/v ethyl acetateÈhexane elution) and
f
concentration of the appropriate fractions (R 0.5) gave the
f
title amine 8 (84 mg, 99%) as a clear colourless oil. HRMS:
HRMS: m/z 285.2093 (M~`); C
H
NO requires 285.2093;
m/z 245.2140 (M~`); C
1477, 1451, 734, 697 cm~1; d 7.40È7.20 (complex m, 5H), 3.84
(d, J 13.5 Hz, 1H), 3.10 (d, J 13.5 Hz, 1H), 2.77 (m, 1H), 2.40 (t,
H
N requires 245.2144; l
2922,
19 27
17 27
max
l
2957, 2925, 1642, 1451, 1421, 911, 698 cm~1; d 7.38È7.12
max
H
H
(complex m, 5H), 5.82È5.67 (complex m, 2H), 5.06È4.91
(complex m, 4H), 4.71È4.54 (complex m, 2H), 3.56È2.94
(complex m, 2H), 2.35 (dt, J 19.3 and 7.5 Hz, 2H), 2.18È2.00
(complex m, 3H), 2.00È1.70 (m, 4H), 0.89 (apparent t, J 6 Hz,
J 12.1 Hz, 1H), 2.20 (dt, J 12.1 and 5.0 Hz, 1H), 2.10 (dd, J
12.1 and 5.0 Hz, 1H), 2.02È1.56 (complex m, 6H), 1.54È1.30
(complex m, 7H), 0.80 (d, J 6.0 Hz, 3H); d 139.9 (C), 129.2
C
3H); d 173.5 (C), 173.2 (C), 138.0 (CH), 137.7 (C), 137.0 (C),
(CH), 128.0 (CH), 126.5 (CH), 60.1(5) (CH ), 60.0(8) (CH ), 52.7
C
2
2
136.6 (CH), 135.8 (CH), 128.8 (2 ] CH), 128.4 (2 ] CH), 127.8
(CH ), 31.8 (CH ), 29.5 (CH), 26.1 (CH ), 25.6 (CH ), 25.1
(CH ), 24.3 (CH ), 22.5 (CH ), 19.4 (CH ); m/z 245 (M~`,
2
2
2
2
2
2
(2 ] CH), 127.3 (CH), 127.1 (CH), 126.0 (2 ] CH), 116.8
2
3
(CH ), 116.1 (CH ), 115.1 (CH ), 115.0 (CH ), 52.3 (CH ), 51.6
35%), 244 [(M [ H)`, 30], 154 [(M [ C H )`, 72], 120 (77),
2
2
2
2
2
7 7
(CH ), 51.5 (CH ), 48.3 (CH ), 38.8 (CH ), 38.6 (CH ), 33.2
91 (100).
2
2
2
2
2
(CH ), 33.1 (CH ), 32.4 (CH ), 32.3 (CH ), 32.1 (CH), 31.5
2
2
2
2
(CH), 24.9 (CH ), 17.2(9) (CH ), 17.2(6) (CH ) (one signal due
2
3
3
to CH and one due to CH carbon are overlapping or
obscured); m/z 285 (M~`, 26%), 244 [(M [ C H )`, 26], 216
(27), 188 (28), 120 (100), 91 (94).
(»)-3-(3º-Methylazacyclodecan-1º-yl)propionitrile (10). Pal-
ladium hydroxide (120 mg of 20 wt% on carbon) was added
to a solution of amine 8 (120 mg, 0.49 mmol) in CH Cl (10
2
3
5
2
2
ml) maintained under an atmosphere of hydrogen (1 atm) and
the resulting suspension stirred at 18 ¡C for 24 h. The reaction
mixture was then Ðltered through a pad of CeliteTM and the
residue washed with a solution of CH Cl [pretreated with
(»)-1-Benzyl-9-methylazacyclodecan-2-one (7). A solution
of GrubbsÏ catalyst [(Cy P) Cl Ru2CHPh] (205 mg, 0.25
3
2
2
2 2
mmol) in CH Cl (5 ml) was added dropwise (in two aliquots
aqueous NH OH then dried (Na SO )] (3 ] 30 ml). The Ðl-
2
2
4
2
4
over 24 h) to a magnetically stirred solution of diene 6 (475
mg, 1.66 mmol) in CH Cl (600 ml) maintained under a nitro-
trate was concentrated under reduced pressure to a†ord (^)-
3-methylazecane (9) as a dark green oil. This material was
immediately dissolved in acrylonitrile (10 ml) containing acetic
acid (50 ll) and the resulting mixture heated at reÑux for 16 h.
The cooled reaction mixture was concentrated under a stream
of nitrogen and the residue subjected to Ñash chromatography
(silica gel, 1 : 19 v/v ethyl acetateÈhexane elution). Concentra-
2
2
gen atmosphere at 18 ¡C. The resulting mixture was heated at
reÑux for 48 h, then cooled and concentrated under reduced
pressure to give a light orange oil. This material was subjected
to Ñash chromatography (silica gel, 1 : 5 v/v ethyl acetateÈ
hexane elution) and concentration of the appropriate fractions
(R 0.3) gave an inseparable and ca. 3 : 1 mixture (as judged by
NMR analysis) of the E and Z isomers of the expected unsatu-
rated lactam (325 mg, 76%) as a pale yellow oil. This material
was used immediately in the next step of the reaction
sequence.
tion of the appropriate fractions (R 0.4) a†orded nitrile 10 (37
f
f
mg, 36% from 8) as a pale yellow oil. HRMS: m/z 208.1938
(M~`); C
H
N
requires 208.1939; l
2924, 2850, 2804,
13 24
2
max
2246, 1457, 1377, 1124, 1079 cm~1; d 2.89 (dt, J 13.2 and 7.6
H
Hz, 1H), 2.78È2.59 (complex m, 2H), 2.46 (m, 2H), 2.40È2.24
A magnetically solution of the above-mentioned lactam
(325 mg, 1.26 mmol) in methanol (20 ml) containing 10% Pd
on C (160 mg) was maintained under a hydrogen atmosphere
at 18 ¡C for 24 h. The resulting mixture was Ðltered through a
short pad of CeliteTM which was washed with methanol (150
ml). The combined Ðltrates were concentrated under reduced
(complex m, 3H), 1.96È1.30 (complex m, 13H), 0.82 (d, J 6.7
Hz, 3H); d 119.4 (C), 59.9 (CH ), 52.5 (CH ), 50.2 (CH ), 31.8
C
2
2
2
(CH ), 30.0 (CH), 26.6 (CH ), 25.8 (CH ), 24.4 (CH ), 24.2
2
2
2
2
(CH ), 22.0 (CH ), 19.3 (CH ), 14.7 (CH ); m/z 208 (M~`,
2
2
3
2
18%), 168 [(M [ C H N)`, 100], 149 (30), 126 (30), 97 (49), 83
2
2
(67).
New J. Chem., 2001, 25, 1347È1350
1349

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(»)-3-(3º-Methylazacyclodecan-1º-yl)propylamine
(1).
determined positions riding on the carbon of attachment. The
Ðnal cycle of full-matrix least squares reÐnement20 was based
on 1892 observed reÑections [I [ 3.0p(I)] and 173 variable
parameters.
CCDC reference number 170402. See http://www.rsc.org/
suppdata/nj/b1/b105045c/ for crystallographic data in CIF or
other electronic format.
Sodium borohydride (38 mg, 1.00 mmol) was added in por-
tions to a magnetically stirred solution of nitrile 10 (8 mg, 0.04
mmol) and cobalt(II) chloride hexahydrate (23 mg, 0.10 mmol)
in methanol (2 ml) maintained at 18 ¡C under a nitrogen
atmosphere. After 2 h HCl (5 ml of a 2 M aq. solution) was
added and the resultant mixture concentrated under reduced
pressure. The residue thus obtained was then dissolved in
NH OH (20 ml of a concentrated aq. solution) and CHCl (20
Acknowledgements
4
3
ml) and the separated aqueous phase extracted with CHCl
3
(3 ] 20 ml). The combined organic extracts were dried
We thank the Institute of Advanced Studies for Ðnancial
support and the Australian Research Council for providing an
APA(I) (to D. J. W.). Professor Wolfgang Steglich (Ludwig-
Maximilians-Universitat, Munchen) is thanked for providing
a preprint of his paper on the synthesis of compounds (])-
and ([)-1.
(Na SO ), Ðltered and concentrated under reduced pressure to
2
4
a†ord a tan oil. Subjection of this material to Ñash chroma-
tography (silica gel, 3 : 2 v/v methanolÈchloroform elution)
and concentration of the appropriate fractions (R 0.4) a†ord-
f
ed the title amine 17 (6 mg, 90%) as a pale yellow oil. HRMS:
m/z 212.2253 (M~`); C
2923, 2867, 2849, 2792, 1578, 1473, 1455 cm~1; d 2.90 (br s,
2H), 2.69 (ddd, J 12.8, 10.6 and 4.0 Hz, 1H), 2.58 (br s 2H),
H
N
requires 212.2252; l
2947,
13 28
2
max
Notes and references
H
1
2
3
G. Koren-Goldshlager, Y. Kashman and M. Schleyer, J. Nat.
Prod., 1998, 61, 282.
2.52È2.44 (complex m, 1H), 2.32 (dd, J 13.0 and 11.5 Hz, 1H),
2.15 (dt, J 13.0 and 4.5 Hz, 1H), 2.10È2.05 (complex m, 2H),
1.90È1.70 (complex m, 3H), 1.68È1.26 (complex m, 12 H), 0.78
Y. Kashman, G. Koren-Goldshlager, M. D. Garcia Gravalos and
M. Schleyer, T etrahedron L ett., 1999, 40, 997.
(d, J 7.0 Hz, 3H); d see Table 1; m/z 212 (M~`, 7%), 182
Y. Kashman, G. Koren-Goldshlager and M. D. Garcia Gravalos,
W orld Pat. WO 00/20411, 2000; Y. Kashman, G. Koren-
Goldshlager and M. D. Garcia Gravalos, Chem. Abstr., 2000, 132,
260678.
C
[(M [ CH NH )`, 13], 168 [(M [ C H NH )`, 100], 154
2
2
2
4
2
(23), 126 (31).
4
5
6
7
M. G. Banwell, B. L. Flynn and D. C. R. Hockless, Chem.
Crystal data and reÐnement details for lactam 7
Commun., 1997, 2259.
M. G. Banwell, B. L. Flynn, E. Hamel and D. C. R. Hockless,
Chem. Commun., 1997, 207.
M. G. Banwell, A. M. Bray, A. C. Willis and D. J. Wong, New J.
Chem., 1999, 23, 687.
Heinrich and Steglich (M. R. Heinrich and W. Steglich, T etra-
hedron L ett., 2001, 42, 3287) have recently achieved, via a related
ring closing metathesis strategy, total syntheses of both enantio-
mers of compound 1. These workers concluded that this com-
pound di†ers in its NMR data and optical rotation from
haliclorensin.
Data collection and reduction. Crystallographic data for the
title compound are given in Table 2. Intensity data were col-
lected (from a plate only 0.017 mm thick) on a Nonius Kappa
CCD di†ractometer using graphite monochromated Mo-Ka
radiation (j \ 0.71073 A) to a maximum 2h value of 55¡. Data
were extracted from di†raction images via the DENZO18
package and an analytical absorption correction was applied.
8
9
A. J. Phillips and A. D. Abell, Aldrichimica Acta, 1999, 32, 75.
See, for example: (a) S. F. Martin, Y. Liao, Y. Wong and T. Rein,
T etrahedron L ett., 1994, 35, 691; (b) J. D. Winkler, J. E. Stelmach
and J. Axten, T etrahedron L ett., 1996, 37, 4317; (c) U. K. Pandit,
B. C. Borere and H. Bieraugel, Pure Appl. Chem., 1996, 68, 659;
(d) E. Magnier and Y. Langlois, T etrahedron L ett., 1998, 39, 837;
(e) W. P. D. Golding and L. Weiler, Org. L ett., 1999, 1, 1471.
Table 2 Crystallographic data for lactam 7
Formula
FW
Crystal system
Space group
C
H
NO
17 25
259.393
Monoclinic
P2 /a
8.6690(2)
15.7588(3)
11.4462(2)
102.0894(11)
1529.02(5)
4
10 A. Falchi, G. Giacomelli, A. Porcheddu and M. Taddei, Synlett,
2000, 275.
11 W. P. D. Goldring, A. S. Hodder and L. Weiler, T etrahedron
1
a/A
b/A
c/A
b/¡
L ett., 1998, 39, 4955.
12 T. M. Trnka and R. H. Grubbs, Acc. Chem. Res., 2001, 34, 18.
13 T. Satoh, S. Suzuki, Y. Suzuki, Y. Miyaji and Z. Imai, T etra-
hedron L ett., 1969, 4555.
14 W. C. Still, M. Kahn and A. Mitra, J. Org. Chem., 1978, 43, 2923.
15 D. D. Perrin and W. L. F. Amarego, PuriÐcation of L aboratory
Chemicals, Pergamon Press, Oxford, 3rd edn., 1988.
16 O. Kitagawa, T. Hanano, T. Hirata, T. Inoue and T. Taguchi,
T etrahedron L ett., 1992, 33, 1299.
17 E. Lorthiois, I. Marek and J. F. Normant, J. Org. Chem., 1998,
63, 566.
18 A. Altomare, M. Cascarano, C. Giacovazzo and A. Guagliardi, J.
Appl. Crystallogr., 1993, 26, 343.
U/A
Ž
3
Z
T /K
200(^1)
k/mm~1
0.069
No. of reÑections
Unique reÑections
R
26911
3513 (R \ 0.072)
int
0.0372
R
0.0395
w
19 Z. Otwinowski and W. Minor, in Methods in Enzymology, ed. C.
W. Carter, Jr. and R. M. Sweet, Academic Press, London, 1997,
vol. 276, pp. 307È326.
20 D. J. Watkin, C. K. Prout, J. R. Carruthers and P. W. Betteridge,
Crystals, Issue 10, Chemical Crystallography Laboratory,
Oxford, UK, 2000.
Structure solution and reÐnement. The structure was solved
by direct methods19 and expanded using Fourier tech-
niques.20 The non-hydrogen atoms were reÐned anisotropi-
cally. Hydrogen atoms were included at geometrically
1350
New J. Chem., 2001, 25, 1347È1350