Asymmetric synthesis of isohaliclorensin, a key intermediate of bisquinolinylpyrrole alkaloid halitulin

Article abstract of DOI:10.1016/S0957-4166(02)00007-1

A new enantioselective total synthesis of N-(3′-aminopropyl)-3-methylazacyclodecane, a partial structure of halitulin, has been achieved in eight steps with 14% overall yield. The key steps are the photochemical ring-expansion reaction of spirooxaziridine

Full text of DOI:10.1016/S0957-4166(02)00007-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 3293–3296
Asymmetric synthesis of isohaliclorensin, a key intermediate of
bisquinolinylpyrrole alkaloid halitulin
Yoshinosuke Usuki,* Hiroyuki Hirakawa, Kimihiko Goto and Hideo Iio
Department of Material Science, Graduate School of Science, Osaka City University, Sugimoto, Sumiyoshi-ku,
Osaka 558-8585, Japan
Received 4 December 2001; accepted 4 January 2002
Abstract—A new enantioselective total synthesis of N-(3%-aminopropyl)-3-methylazacyclodecane, a partial structure of halitulin,
has been achieved in eight steps with 14% overall yield. The key steps are the photochemical ring-expansion reaction of
spirooxaziridine to lactam for constructing the azacyclodecane moiety and 1,4-stereoinductive methylation of the resulting lactam.
© 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
A variety of structurally novel cytotoxic secondary
metabolites, which are of interest as potential lead
compounds for the development of new anti-cancer
drugs, have been isolated from marine sponges.1 Halit-
ulin 1, a novel bisquinolinylpyrrole, was isolated from
the South African sponges Haliclona tulearensis by
Kashman and co-workers, and found to be cytotoxic
against several tumor cells such as P-388, A-549, HT-29
and MEL-28 in concentrations of 12–25 ng/mL.2 The
structure of 1 was elucidated by analysis of spectral
data to have an N-(3%-aminopropyl)-3-methylazacyclo-
decane moiety 2 which is the proposed structure for
haliclorensin, another unique alkaloid isolated from the
same organism.3 Being interested in the novel structures
and biological activities of these compounds, several
groups have achieved the total synthesis of 2.4 How-
ever, the proposed structure for haliclorensin has been
the subject of much controversy. During the prepara-
tion of this manuscript, the structure of haliclorensin
was revised to 7-methyl-1,5-diazacyclo-tetradecane 3,
complex natural products and peptidomimetics. We
have been very interested in utilizing this methodology
to prepare medium-ring, nitrogen-containing com-
pounds. Described herein is a new enantioselective total
synthesis of 2 according to the following nitrogen inser-
tion strategy (Scheme 1). The 10-membered chiral lac-
tam thus obtained was 1,4-stereoselectively methylated
to afford 6.
and the synthetic isomer
2
was renamed
isohaliclorensin.55
2. Results and discussion
Only a few methods are available for constructing
macrocyclic amines.6,7 The photochemical rearrange-
ment reactions of oxaziridines afford lactams with high
regioselectivity8 and migration of the less substituted
carbon occurs preferentially. This ring-expansion reac-
tion has been applied to the synthesis of a number of
Our synthesis of isohaliclorensin commenced with the
imine formation between commercially available
cyclononanone
and
(R)-(−)-1-amino-1-phenyl-2-
methoxyethane,9 subsequent oxidation with m-CPBA
gave spirooxaziridine 4 as a single diastereomer in 86%
yield. Photolysis of 4 (254 nm, benzene, 6 h) followed
by chromatographic separation afforded ring-expanded
10-membered lactam 5 in 57% yield.
* Corresponding author. Fax: +81-6-6605-2522; e-mail: usuki@
sci.osaka-cu.ac.jp
0957-4166/01/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00007-1

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Y. Usuki et al. / Tetrahedron: Asymmetry 12 (2001) 3293–3296
Scheme 1. Reagents and conditions: (a) (R)-(−)-1-amino-1-phenyl-2-methoxyethane (1.5 equiv.), toluene, reflux; (b) m-CPBA (1.5
equiv.), CH2Cl2, −78°C; (c) hv (254 nm), degassed benzene; (d) sec-BuLi (2.5 equiv.), CH3I (3 equiv.), dry THF, −78°C; (e)
LiAlH4, dry THF, reflux; (f) Pd(OH)2, 6 MPa H2, aqueous MeOH, TFA, rt; (g) acrylonitrile (1.1 equiv.), dry MeOH, rt; (h)
Raney-Ni, 3.5 MPa H2, NH3 saturated MeOH, rt.
3. Experimental
1,4-Stereoinductive methylation of
5 was accom-
3.1. General
plished by treatment with sec-BuLi (2.5 equiv.) in
THF at−78°C followed by addition of iodomethane
to afford the product 6 as an inseparable 9:1 mixture
of diastereomers in 73% yield. The ratio of
All air and moisture sensitive reactions were carried
out in flame-dried, argon-flushed, two necked flasks
sealed with rubber septa, and the dry solvents and
1
diastereomers was determined from the H NMR sig-
reagents were introduced with
a syringe. Tetra-
nals of the methyne protons adjacent to the nitrogen
atom. Other chiral lactams corresponding to 5 were
prepared from (R)-a-phenylethylamine or the MOM
ether of (R)-2-phenylglycinol. The attempted increase
in diastereoselectivity of the methylation using these
lactams met with little success.
hydrofuran (THF) was fleshly distilled from sodium
benzophenone ketyl. Dichloromethane (CH2Cl2) was
fleshly distilled from phosphorus oxide. m-Chloroper-
benzoic acid (m-CPBA) was washed with phosphate
buffer (pH 7.4) and recrystallized from CH2Cl2. Ben-
zene in the photochemical reaction was degassed by
bubbling argon gas through it for 30 min under soni-
cation. UV lamp was used on Sterilaire Lamp (254
nm, 90 W). Flash column chromatography was car-
ried out on KANTO CHEMICAL silica gel 60 N
(spherical, neutral, 40–50 mm), and pre-coated Merck
silica gel plates (Art5715 Kiesel gel 60F254 0.25 mm)
Reduction of 6 with LiAlH4 in THF provided the
desired macrocyclic amine 7 in 76% yield. Subsequent
removal of the chiral auxiliary under hydrogenation
conditions with Pd(OH)2 in aqueous methanol in the
presence of TFA produced 3-methylazacyclodecane 8
in quantitative yield.
Table 1. 13C NMR data for natural halitulin 1 and syn-
thetic 2
Michael addition of amine 8 to acrylonitrile furnished
b-aminonitrile, which was immediately hydrogenated
over Raney-Ni in methanol saturated with NH3 to
afford 2 in 52% yield for two steps. Compound 2
thus prepared exhibits an [h]D value of +74.6 (c=
0.925, MeOH), which is in good agreement with the
[h]D value of +71 (c=0.6, MeOH) observed for the
(+)-(3R)-N-(3%-aminopropyl)-3-methylazacyclodecane.4a
The stereochemistry of synthetic 2 was thus assigned
as 3R.10
Carbon number Natural halitulin lC
Synthetic 2 lC (100
(125 MHz, CDCl3)
MHz, CDCl3)
2
3
4
5
6
7
8
9
10
11
1%
2%
3%
57.7
28.3
32.7
24.4
24.2
23.9
23.6
22.0
50.9
20.7
54.4
26.1
46.8
60.8
30.0
32.0
22.2
26.6
24.7
24.3
26.0
53.3
19.5
52.7
31.1
40.8
As summarized in Table 1, 13C NMR spectral data of
2 correspond with those reported for the macrocyclic
moiety of halitulin.1 This suggests that the structure
of halitulin has been correctly assigned. Synthetic
studies for halitulin are now underway in our labora-
tories and will be reported in due course.

Y. Usuki et al. / Tetrahedron: Asymmetry 12 (2001) 3293–3296
3295
were used for TLC. Unless otherwise mentioned 1H and
13C NMR spectra were recorded in CDCl3 on Bruker
DRX-600, JEOL JNM-LA400 or JEOL JNM-LA300
instruments. Coupling constants were determined directly
from 1H NMR spectra. Mass spectra (FAB) were
obtained on JEOL JMS-700T or JEOL JMS-AX500
spectrometers. Optical rotations were measured on a
JASCO P-1030 polarimeter with path length of 0.1 dm
at ambient temperature; the concentrations are reported
in g/dL.
was placed a solution of lactam 5 (2.03 g, 7.03 mmol) in
THF (60 mL). sec-BuLi (0.96 M solution in hexane, 18.3
mL, 17.6 mmol) was added at −78°C, and the mixture
was stirred for 0.5 h. Then CH3I (2.99 g, 21.1 mmol) was
added at −78°C, and the mixture was stirred for 3 h. The
reaction was quenched with saturated aqueous NH4Cl (40
mL), and the mixture was extracted with CH2Cl2 (3×15
mL). Thecombinedorganiclayerswerewashedwithbrine
(50 mL) and dried over Na2SO4. Purification of the crude
product by flash column chromatography (10% AcOEt
in hexane) afforded 6 (1.55 g, 73%). [h]D=−45.4 (c=
0.625, MeOH); 1H NMR (400 MHz, CDCl3) l 7.40–7.27
(m, 5H), 5.88 (t, J=7.1 Hz, 1H), 4.00–3.90 (m, 2H), 3.66
(ddd, J=16.0, 12.7, 4.4 Hz, 1H), 3.41 (s, 3H), 3.28–3.23
(m, 1H), 2.93 (ddd, J=16.0, 5.8, 1.7 Hz, 1H), 2.02–1.95
3.2. (1%R)-2-(2%-Methoxy-1%-phenylethyl)-1-oxa-2-aza-
spiro[2,8]undecane 4
In a round-bottomed flask equipped with a magnetic
stirring bar and a Dean–Stark apparatus were placed
cyclononanone (2.00 g, 14.3 mmol), (R)-(−)-1-amino-1-
phenyl-2-methoxyethane (3.24 g, 24.2 mmol), p-toluene-
sulfonic acid monohydrate (80 mg) in toluene (80 mL),
and the mixture was heated under reflux overnight. After
cooling to room temperature, the resultant mixture was
added to a solution of m-CPBA (3.76 g, 21.6 mmol) in
CH2Cl2 (68 mL) at −78°C under an argon atmosphere,
and stirred for 1.5 h. The reaction was quenched with 10%
aqueous Na2S2O3 (120 mL) and allowed to warm to room
temperature. The layers were separated and the aqueous
phase was extracted with CH2Cl2 (3×20 mL). The com-
bined organic layers were washed with saturated aqueous
NaHCO3 (100 mL) and brine (100 mL), and dried over
MgSO4. Purification of the crude product by flash column
chromatography (20% AcOEt in hexane) afforded 4 (3.56
(m, 1H), 1.69–1.25 (m, 9H), 1.11 (d, J=6.4 Hz, 3H); 13
C
NMR (100 MHz, CDCl3) l 178.5, 138.3, 128.5, 128.4,
127.5, 71.9, 58.7, 56.9, 42.8, 35.8, 34.8, 28.3, 28.2, 25.2,
22.1, 20.4, 18.8. HRMS calcd for C19H29NO2 304.2277,
found 304.2296 (M+); minor isomer (diagnostic peak
only): 1H NMR (400 MHz, CDCl3) l 5.23 (t, J=6.5 Hz,
1H), 3.37 (s, 3H), 1.08 (d, J=6.4 Hz, 1H).
3.5. (1%R,3R)-1-(2%-Methoxy-1%-phenylethyl)-3-methyl-
azacyclodecane 7
In a two-necked, round-bottomed flask equipped with an
argon inlet, rubber septum and a magnetic stirring bar
was placed a suspension of the LiAlH4 (0.402 g, 10.6
mmol) in THF (15 mL). A solution of lactam 6 (1.60 g,
5.29 mmol) in THF (10 mL) was added to the suspension
at 0°C and the resulting mixture was heated under reflux
overnight. After cooling to room temperature, excess
LiAlH4 was destroyed by cautious successive addition of
water (6 mL), 10% NaOH (6 mL) and water (18 mL) with
cooling in an ice bath. The mixture was filtered through
a pad of Celite® and the filtrate was extracted with CHCl3
(3×15 mL). The solid residue on Celite® was poured into
THF (20 mL) and heated under reflux for 2 h. The
resultant mixture was allowed to cool to room tempera-
ture and filtered through another pad of Celite®. The
filtrate thus obtained and organic extracts were combined,
and dried over MgSO4. The crude product was purified
by flash column chromatography (4% Et2O in hexane)
to afford 7 (1.16 g, 76%). [h]D=+43.8 (c=0.99, MeOH);
1H NMR (400 MHz, CDCl3) l 7.36–7.18 (m, 5H),
3.98–3.80 (m, 3H), 3.36 (s, 3H), 2.74–2.55 (m, 3H),
2.32–2.08 (m, 1H), 1.82–1.26 (m, 13H), 0.76 (d, J=6.8
Hz, 3H); 13C NMR (100 MHz, CDCl3) l 140.1, 128.9,
128.7, 127.9, 126.7, 71.3, 62.7, 58.8, 56.9, 49.5, 31.5, 31.3,
26.6, 24.7, 23.7, 23.3, 19.6. HRMS calcd for C19H31NO
290.2484, found 290.2483 (M+); minor isomer (diagnostic
peak only): 1H NMR (400 MHz, CDCl3) l 3.33 (s, 3H).
1
g, 86%). H NMR (600 MHz, CDCl3) l 7.43–7.26 (m,
5H), 3.86 (ddd, J=9.4, 5.8, 1.1 Hz, 1H), 3.71–3.69 (m,
1H), 3.66–3.64 (m, 1H), 3.35 (s, 3H), 1.89–1.78 (m, 3H),
1.72–1.42 (m, 13H); 13C NMR (150 MHz, CDCl3) l 138.0,
128.5, 127.8, 127.6, 85.8, 77.4, 66.4, 59.3, 37.1, 27.0, 26.5,
26.1, 25.8, 24.3, 23.5, 21.7. HRMS calcd for C18H27NO2
290.2120, found 290.2102 (M+).
3.3. (1%R)-1-(2%-Methoxy-1%-phenylethyl)azacyclodecan-
2-one 5
In a quartz schlenk flask equipped with rubber septum
was placed a solution of oxaziridine 4 (1.52 g, 5.26 mmol)
in degassed benzene (53 mL). Th e solution was irradiated
with a UV lamp (254 nm) at room temperature for 6 h.
The resultant mixture was concentrated. Purification of
the crude product by flash column chromatography (30%
AcOEt in hexane) afforded 5 (0.866 g, 57%). [h]D=−55.5
(c=1.25, MeOH); 1H NMR (400 MHz, DMSO-d6, 80°C)
l 7.37–7.23 (m, 5H), 5.43 (t, J=6.6 Hz, 1H), 3.98–3.89
(m, 2H), 3.46–3.44 (m, 2H), 3.29 (s, 3H), 2.56–2.44 (m,
2H), 1.75–1.74 (m, 2H), 1.44–1.26 (m, 10H); 13C NMR
(100 MHz, CDCl3) l 174.9, 138.6, 128.4, 128.3, 127.6,
72.6, 58.7, 57.7, 44.3, 31.1, 27.8, 27.5, 26.2, 25.1, 21.8, 18.9.
HRMS calcd for C18H27NO2 290.2120, found 290.2120
(M+).
3.6. (3R)-3-Methylazacyclodecane 8
In an autoclave was placed a solution of lactam 7 (0.587
g, 2.00 mmol) in MeOH (20 mL). Water (2 mL), TFA
(0.15 mL, 2.00 mmol), and palladium hydroxide (20%
on carbon, Pearlman’s catalyst) (0.86 g) were added
and hydrogenation was carried out at 6 MPa hydro-
gen pressure overnight. The resultant mixture was
filtered through a pad of Celite®. The filtrate was
3.4. (1%R,3R)-1-(2%-Methoxy-1%-phenylethyl)-3-methyl-
aza-cyclodecan-2-one 6
In a two-necked, round-bottomed flask equipped with an
argon inlet, rubber septum and a magnetic stirring bar

3296
Y. Usuki et al. / Tetrahedron: Asymmetry 12 (2001) 3293–3296
concentrated and partitioned between 3 M HCl (15
mL) and CH2Cl2 (15 mL). The aqueous layer was
washed with CH2Cl2 (2×15 mL) and basified with
NaOH pellets in small portions. The resulting mixture
was extracted with CH2Cl2 (3×15 mL). The combined
organic extracts were dried over Na2SO4 and concen-
trated (0.306 g, 98%). [h]D=+17.4 (c=0.205, MeOH);
1H NMR (400 MHz, CDCl3) l 2.85–2.72 (m, 3H), 2.44
(dd, J=12.6, 9.3 Hz, 1H), 1.93–1.25 (m, 14H), 0.84 (d,
J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) l 54.4,
48.4, 32.2, 31.4, 26.9, 26.0, 25.3, 24.4, 23.5, 20.2.
HRMS calcd for C10H21N 156.1752, found 156.1747
(M+).
26.6, 26.0, 24.7, 24.3, 22.2, 19.5. HRMS calcd for
C13H28N2 213.2331, found 213.2334 (M+).
Acknowledgements
Thanks are due to the Analytical Division at Osaka
City University for the measurements of mass spectra.
References
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Anderson, R. J. J. Org. Chem. 1998, 63, 4838–4841; (b)
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3.7. (3R)-1-(3%-Aminopropyl)-3-methylazacyclodecane 2
In a two-necked, round-bottomed flask equipped with
an argon inlet, rubber septum and a magnetic stirring
bar was placed a solution of amine 8 (0.155 g, 1.00
mmol) in MeOH (12 mL). At room temperature, acry-
lonitrile (0.0584 g, 1.10 mmol) was added to the solu-
tion, and the mixture was stirred overnight. The
resultant mixture was concentrated and dissolved in
MeOH (40 mL). The solution thus obtained was placed
in an autoclave. Raney-Ni (catalytic amount) was
added to the solution and hydrogenation was carried
out at 3.5 MPa hydrogen pressure overnight. The resul-
tant mixture was filtered through a pad of Celite®. The
filtrate was concentrated and partitioned between water
and CHCl3 (15 mL). The aqueous layer was extracted
with CHCl3 (2×15 mL), and the combined organic
layers were washed with water and 10% aqueous KOH
(30 mL). The extraction was dried over Na2SO4 and
concentrated to afford 2 (0.110 g, two steps 52%).
1
[h]D=+74.6 (c=0.925, MeOH); H NMR (600 MHz,
DMSO-d6) l 2.70 (ddd, J=13.1, 10.6, 4.0 Hz, 1H),
2.59–2.47 (m, 3H), 2.33 (dd, J=12.5, 11.9 Hz, 1H), 2.18
(ddd, J=13.0, 4.5, 4.0 Hz, 1H), 2.12–2.08 (m, 2H),
1.91–1.73 (m, 3H), 1.68–1.62 (m, 1H), 1.59–1.29 (m,
11H), 1.52 (q, J=7.3 Hz, 2H), 0.79 (d, J=6.8 Hz, 3H);
13C NMR (150 MHz, DMSO-d6) l 60.5 53.0, 52.6, 40.4,
31.8, 30.9, 29.6, 26.3, 25.6, 24.3, 24.1, 21.9, 19.5, (100
MHz, CDCl3) l 60.8, 53.3, 52.7, 40.8, 32.0, 31.1, 30.0,
9. Smith, A. B., III; Yager, K. M.; Taylor, C. M. J. Am.
Chem. Soc. 1995, 117, 10882–10888.
10. Though the enantiomeric excess of 2 has not been rigor-
ously determined, this apparent increase in enantiomeric
purity may be the result of separation of diastereomers
from their mixtures during the purification of 6 and 7.