Synthesis of marine sponge alkaloid hachijodine B and a comment on the structure of ikimine B and on the absolute configuration of niphatesine D

Article abstract of DOI:10.1016/j.tetlet.2004.02.143

The syntheses of the proposed structures of hachijodine B 1, ikimine B 2 and niphatesine D 3 from S-citronellol are described. Our results suggest that the gross structures of hachijodine B and niphatesine D are correct, but that ikimine B was incorrectly

Full text of DOI:10.1016/j.tetlet.2004.02.143

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3273–3277
Synthesis of marine sponge alkaloid hachijodine B and a comment
on the structure of ikimine B and on the absolute configuration
of niphatesine D
Stuart P. Romeril, Victor Lee* and Jack E. Baldwin
The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QY, UK
Received 19 January 2004; revised 12 February 2004; accepted 20 February 2004
Abstract—The syntheses of the proposed structures of hachijodine B 1, ikimine B 2 and niphatesine D 3 from S-citronellol are
described. Our results suggest that the gross structures of hachijodine B and niphatesine D are correct, but that ikimine B was
incorrectly assigned. We have also established that the previous absolute stereochemical assignment for niphatesine D is unreliable.
Ó 2004Elsevier Ltd. All rights reserved.
Marine sponges have continued to fascinate chemists
due to the rich and diverse natural products they pro-
duce.1 3-Alkylpyridine alkaloids are a class of natural
products that occurs widely in marine sponges.2
Hachijodine B was recently isolated by Fusetani and
co-workers from a marine sponge of the genus Xesto-
spongia collected off Hachijo-jima Island in Japan, and
found to show cytotoxic activity towards P388 murine
leukaemia cells.3 The structure of hachijodine B was
proposed as 1 based on a combination of NMR spec-
troscopy and mass spectrometry. The presence of an
a-amino terminus with c-methyl substitution distin-
guishes hachijodine B from the majority of the mono-
meric 3-alkylpyridine alkaloids. Interestingly this
structural motif is also shared by two other marine
sponge alkaloids ikimine B and niphatesine D although
the oxidation state of the terminal nitrogen function
differs in the three alkaloids.
Ikimine B was isolated from an unidentified sponge
collected off Ant Atoll, Micronesia by Carroll and
Scheuer and showed cytotoxicity against KB cells.4 They
proposed that the structure of ikimine B was 2 based on
NMR and electron impact mass spectrometry studies.
The natural product was isolated as the E-oxime, but the
authors observed that it readily isomerised to an E/Z-
mixture in chloroform. The absolute stereochemistry of
ikimine B was not determined and its specific rotation
was not recorded.5
Niphatesine D was isolated by Kobayashi et al. from an
Okinawan sponge of the genus Niphates and it was
shown to be antineoplastic.6 The gross structure of
niphatesine D was established as 3 by NMR and elec-
tron impact mass spectrometry, and the specific rotation
25
D
MeOH). Subsequently Rao and Reddy completed the
of niphatesine D was reported to be ½aŠ þ4.4 (c 0.045,
H
N
R
N
OMe
N
N
ikimine B 2, stereochemistry unknown
hachijodine B 1, R = OMe, stereochemistry unknown
niphatesine D 3, R = H, stereochemistry assigned as S
Keywords: Sponge; Alkaloids.
* Corresponding author. Tel.: +44-1865-275693; fax: +44-1865-275632; e-mail: victor.lee@chem.ox.ac.uk
0040-4039/$ - see front matter Ó 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.143

3274
S. P. Romeril et al. / Tetrahedron Letters 45 (2004) 3273–3277
synthesis of niphatesine D and proposed that the abso-
lute configuration of natural product is S by comparison
of specific rotations.7
Retrosynthetically 1, 2 and 3 could be derived from 12,
which in turn was prepared from S-citronellol 4 (Scheme
2).
Although the specific rotations of hachijodine B 1 and
ikimine B 2 were not determined, it is likely that both
compounds are nonracemic. As the three alkaloids were
isolated from marine sponges it is possible that they
might be biosynthetically related. Thus, 2 could be
formed by the oxidation of 1, which in turn could be
produced from 3 by oxidation and methylation (Scheme
1). Hence we speculate that the configurations of the
methyl-bearing carbons of 1, 2 and 3 are identical. No
syntheses of 1 and 2 have been reported, and our con-
tinued interest in 3-alkylpyridine alkaloids8;9 prompted
us to develop an efficient and flexible synthetic route
that would provide access to all three alkaloids.
S-Citronellol 4 was converted into its tert-butyldiphen-
ylsilyl ether 5 in 93% yield using TBDPSCl and imid-
azole in THF.10 Silyl ether 5 was subjected to ozonolysis
followed by treatment with triphenylphosphine to give
aldehyde 6 in 91% yield,11 which was subsequently
converted into alkyne 8 in 96% yield using dimethyl (1-
diazo-2-oxopropyl)phosphonate 7 and potassium car-
bonate in methanol.12 Alkyne 8 was deprotonated by
n-butyllithium followed by addition of 1-iodo-4-chlo-
robutane in the presence of DMPU to deliver 9 in 86%
yield (based on recovered starting material).13 The pri-
mary chloride of 9 was displaced with lithiated 3-pico-
line in a mixture of DMPU and THF to deliver 10 in
H
N
N
Oxidation
OMe
OMe
N
N
hachijodine B 1
Proposed structure of E-ikimine B 2
Absolute configuration unknown
Absolute configuration unknown
Oxidation and methylation
NH2
niphatesine D 3
Absolute configuration proposed to be S
N
Scheme 1. Possible biogenetic relationship between 1, 2 and 3.
H
NOMe
N
OMe
2
N
N
1
3
NH2
OH
12
N
N
OH
4
Scheme 2.

S. P. Romeril et al. / Tetrahedron Letters 45 (2004) 3273–3277
3275
iii
OTBDPS
OTBDPS
ii
OR
O
O
O
P
OMe
OMe
6
8
N
N
4, R = H
7
i
5, R = TBDPS
iv
Cl
v
OTBDPS
10
OTBDPS
OTBDPS
9
N
vi
OH
vii
N
12
N
11
Scheme 3. Reagents and conditions: (i) TBDPSCl, imidazole, THF, 3 h, 93%; (ii) O3, CH2Cl2, À78 °C, 30 min, then PPh3, 91%; (iii) 7, K2CO3,
MeOH, 5 h, 96%; (iv) nBuLi, DMPU, Cl(CH2)4I, À78 °C to rt, 6 h, 86%; (v) 3-picoline, LDA, DMPU, THF, À78 °C to rt, 22 h, 85%; (vi) Pd(OH)2,
H2, MeOH, 24h, 95%; (vii) NH 4F, MeOH, 70 °C, 10 h, 98%.
85% yield.14 Saturation of the triple bond in 10 by
hydrogenation with Pearlman’s catalyst in methanol15
gave 11 in 95% yield, which was deprotected with
ammonium fluoride in methanol to afford the key
alcohol 12 in 98% yield16 (Scheme 3).
in 99% yield, which was deprotected using hydrazine
hydrate in ethanol to afford S-niphatesine D S-3 in 83%
yield20 (Scheme 4).
1
The H NMR spectroscopic data of 1 (in CDCl3 with
4equiv of trifluoroacetic acid added) was in good
agreement with the spectra of natural hachijodine B
hence the gross structure of hachijodine B is confirmed.
o-Iodoxybenzoic acid (IBX) oxidation17 of 12 afforded
aldehyde 13 in 83% yield and condensation with meth-
oxylamine hydrochloride in the presence of sodium
acetate in methanol gave the putative structure of iki-
mine B S-2 in 78% yield as a mixture of E/Z isomers.18
Reduction of 2 with sodium cyanoborohydride at pH 3
The spectra of synthetic 2 showed some discrepancies
with the published data for ikimine B. In the 13C NMR
spectrum of natural ikimine B, Carroll and Scheuer
assigned the signals between 26 and 33 ppm as the res-
onances of C-7 to C-17. They also specifically indicated
in methanol gave S-hachijodine B S–1 in 92% yield.19
A
Mitsunobu reaction of 12 with phthalimide delivered 14
O
O
N
iv
i
12
O
N
N
13
14
ii
v
7
9
11
13
15
17
NOMe
NH2
2
N
ikimine B proposed structure
3
N
iii
H
N
OMe
N
1
Scheme 4. Reagents and conditions: (i) IBX, THF, DMSO, 6 h, 83%; (ii) MeONH2ÆHCl, NaOAc, MeOH, 4h, 78%; (iii) NaCNBH 3, MeOH, pH 3,
0 °C, 4h, 92%; (iv) phthalimide, PPh 3, DIAD, THF, 18 h, 99%; (v) N2H4ÆH2O, MeOH, 60 °C, 2 h, 83%.

3276
S. P. Romeril et al. / Tetrahedron Letters 45 (2004) 3273–3277
Table 1. 13C Data of E-ikimine B and S-2 in CDCl3
that the alkaloid had been isolated as its bis-trifluoro-
acetate salt rather than as the free base. This observation
was not explicitly indicated in either of the previous
syntheses of niphatesine D.7;23
E-ikimine B4 75 MHz
S-2 (E/Z mixture) 125.8 MHz
155.31
149.41
146.85
138.31
136.17
124.73
61.11
150.9
150.1
149.8
147.0
137.8
135.6
123.1
61.3
61.0
36.6c
36.5c
36.3c
32.9
32.5
31.3
31.0
30.8
29.6
29.5
29.4
29.3
29.2
29.0
26.8
19.7
19.4
25
Our specific rotation measurements of S-3 f½aŠ À1.3 (c
D
25
D
1.0, MeOH) of S-3 as free base and ½aŠ À1.0 (c 1.0,
MeOH) of S-3 as its bis-trifluoroacetate saltg were dif-
ferent from the previously reported values. Rao and
Reddy published the first synthesis of S-niphatesine D
and reported the specific rotation of their synthetic
32.95
30.75
29.73
29.48a
29.35
sample as ½aŠ þ4.4 (c 0.5, MeOH), hence they con-
D
cluded that the absolute configuration of the natural
product was S.7 Bracher and Papke prepared both
enantiomers of the alkaloid and noted that their specific
29.10
29.02
26.89b
19.55
20
D
20
D
rotations were ½aŠ À1.9 (c 0.8, MeOH) for R-3 and ½aŠ
þ1.7 (c 0.5, MeOH) for S-3.23 Although their specific
rotation values differed in magnitude to Kobayashi’s,
Bracher and Papke did not raise any query about this
discrepancy. The three different specific rotations
observed by the three groups for synthetic S-niphatesine
D imply that in this case the sign of specific rotation is
not a reliable means to determine the absolute stereo-
chemistry and the original measurement may be incor-
rect.
It should be noted that the optical rotation of natural
niphatesine D was recorded at a very low concentration
and its absolute value was small. Assuming the optical
rotation measurement of a solution sample is performed
at a concentration of 0.045 g/100 mL using a 1 dm cell in
a polarimeter with a measurement accuracy of ꢀ0.002°
(angular reading),24 the inherent experimental error in
the specific rotation of this sample (assuming there is no
error in the sample weight) will be ꢀ4.4, that is, 100% of
Kobayashi’s observed value. This is further illustrated
a Reported as overlapping signals of four carbons.
b Assigned as C-17.
c Assigned as C-15 of E/Z-oximes and C-17 of E-oxime.
C-17 resonated at 26.89 ppm. In contrast, the 13C NMR
spectrum of synthetic 2 (as a mixture of E/Z isomers)
showed three peaks at ca. 36 ppm (two of these are
assigned as C-15 of the E and Z oximes, and the other as
C-17 of the E-oxime based on COSY and HMQC
analysis), which are absent from the tabulated data of
by our observation that the specific rotation of our
synthetic S-3 switched from negative to positive {½aŠ
25
D
E-ikimine B21 (Table 1). Close examination of the H
1
þ1.4( c 0.05, MeOH)} when measured at high dilution.
These results are summarised in Table 2.
NMR spectrum of synthetic S-2 revealed that one of the
diastereomeric pair of protons at H-15 resonates outside
the methylene envelope at 1.11–1.20 ppm as a distinct
peak, which is absent from the tabulated 1H NMR data
for ikimine B. Based on these differences, we conclude
that the structure proposed by Carroll and Scheuer is
incorrect.22
In conclusion, we have achieved the synthesis of 1, 2
and 3 using a highly efficient strategy. The synthesis of
2 has cast doubt upon the structure of natural
ikimine B. The gross structures of hachijodine B and
niphatesine D have been correctly assigned, however
we have demonstrated that the assignment of the
1
absolute stereochemistry of niphatesine
D based
The H NMR spectrum of 3 under acidic conditions
(4equiv of TFA were added to the NMR sample) mat-
ched the literature values for niphatesine D, suggesting
on optical rotation comparison is not reliable, and may
be incorrect.
Table 2. Various recorded specific rotations of niphatesine D
Entry
Group
Sample
½aŠ
Concentration
Temperature (°C)
D
1
2
3
Kobayashi
Rama Rao and Reddy
Bracher and Papke
3
S-3
þ4.4
0.045
0.5
0.5
0.8
1
25
––
20
20
25
þ4.4
S-3
R-3
þ1.7
4Bracher and Papke
À1.9
5
6
7
This work
This work
This work
S-3
S-3
À1.3
þ1.40.05
À1.0
25
S-3 þ TFA
1
25

S. P. Romeril et al. / Tetrahedron Letters 45 (2004) 3273–3277
3277
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Acknowledgements
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We thank the States of Jersey Education Committee for
a scholarship (to S.P.R.) and Professor Nobuhiro
Fusetani for providing us the spectra of natural
hachijodine B.
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D was
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particular model is no longer in production, however the
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