Synthesis of pyrinodemins A and B. Assignment of the double bond position of pyrinodemin A

Article abstract of DOI:10.1016/S0040-4039(01)00003-X

Condensation of aldehyde 3a with hydroxylamine 4b afforded nitrone 2, which underwent an intramolecular cycloaddition to give 1b, the proposed structure of pyrinodemin A. A similar condensation of aldehyde 3a and hydroxylamine 4a provided pyrinodemin A (1a), which has the double bond one carbon further away from the isoxazolidine. An analogous sequence gave pyrinodemin B (21).

Full text of DOI:10.1016/S0040-4039(01)00003-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1639–1642
Synthesis of pyrinodemins A and B. Assignment of the double
bond position of pyrinodemin A
Barry B. Snider* and Bo Shi
Department of Chemistry, MS 015, Brandeis University, Waltham, MA 02454-9110, USA
Received 8 November 2000; accepted 29 December 2000
Abstract—Condensation of aldehyde 3a with hydroxylamine 4b afforded nitrone 2, which underwent an intramolecular
cycloaddition to give 1b, the proposed structure of pyrinodemin A. A similar condensation of aldehyde 3a and hydroxylamine 4a
provided pyrinodemin A (1a), which has the double bond one carbon further away from the isoxazolidine. An analogous sequence
gave pyrinodemin B (21). © 2001 Elsevier Science Ltd. All rights reserved.
Kobayashi and co-workers reported the isolation of the
novel bis 3-alkylpyridine substituted cis-
prepared by condensation of aldehyde 3a and hydroxyl-
amine 4b, which can be formed from aldehyde 3b, not
3a. It seemed unlikely that both aldehydes 3a and 3b
are intermediates in the biosynthesis of pyrinodemin A.
This analysis suggested that the double bond of
pyrinodemin A is not between carbons 16% and 17% as in
1b, but rather between carbons 15% and 16% as in 1a.
Retrosynthetically, and biosynthetically, 1a is a dimer
that can be prepared by the condensation of aldehyde
3a and hydroxylamine 4a, which can be formed from
3a. Analysis of the chemical shifts of the allylic carbons
cyclopent[c]isoxazolidine alkaloid pyrinodemin A (1b)
from the marine sponge Amphimedon sp. that shows
potent cytoxicity to murine leukemia L1210 (IC50 0.058
mg/mL) and KB epidermoid carcinoma cells (IC 0.5
5
0
1
,2
mg/mL) in vitro. The structure of pyrinodemin A was
1
13
assigned by analysis of the H, C, and 2D NMR and
mass spectra. The position of the double bond was
tentatively assigned based on the fragmentation pattern
in the mass spectrum.
17
19
4'
6'
H
H
4
7
9
11
13 15
N
N
O
H
20'
18'
15'
13'
11'
9'
7'
2'
6
2
N
1b (proposed strcture for pyrodemin A)
(
CH2)8
(CH )
2 3
CHO
3a
N
(
CH2)
8
N
N
N
O
(CH2)
3
(CH2)9
R(CH2)2
(CH )
2 9
N
2
4
b, R = CH NHOH
2
3b, R = CHO
provides further support for this analysis. Both allylic
Retrosynthetically, and presumably biosynthetically as
1
carbons of pyrinodemin A absorb at l 27.1, as
well, 1b can be prepared by the well-known intramolec-
3
expected for 1a. Analysis of the expected substituent
effects suggests that the g-nitrogen should shield C-18%
of 1b, which should therefore absorb at l 25. The
potent cytotoxicity of pyrinodemin A prompted us to
undertake the syntheses of both 1a and 1b to provide
material for further biological evaluation and to deter-
mine the double bond position unambiguously.
ular [3+2] dipolar cycloaddition of 2. Nitrone 2 can be
*
0
Corresponding author. Fax: 781-736-2516; e-mail: snider@
brandeis.edu
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00003-X

1
640
B. B. Snider, B. Shi / Tetrahedron Letters 42 (2001) 1639–1642
17
19
H
H
4'
6'
4
7
9
11
13 15
17'
14'
13'
N
N
O
H
20'
18'
15'
11'
9'
7'
2'
6
2
N
1a (revised strcture for pyrodemin A)
(
CH )
2 3
(
CH2)8
(CH )
(CH )
2 8
2 3
HOHNCH2
CHO
4a
3a
N
N
Isomerization of 3-octyn-1-ol (5a) with NaH in 1,3-
A similar five-step sequence starting with the conver-
sion of 3-nonyn-1-ol (5b) to 8-nonyn-1-ol (6b) and
4
15
diaminopropane at 80°C overnight afforded 7-octyn-1-
5
6
16
ol (6a), which was coupled with 3-bromopyridine using
concluding with alkylation of LiCꢀC(CH ) OTHP
2
3
10
(
Ph P) PdCl and CuCl to give 7a. Hydrogenation of 7a
with 9b in DMPU and THF provided 10b in 47%
overall yield from 5b. Hydrogenation, hydrolysis and
Swern oxidation afforded 84% of 3b, which was con-
verted to hydroxylamine 4b as described above for 4a.
Condensation of 3a and 4b in toluene containing
3
2
2
7
over PtO afforded saturated alcohol 8a, which was
2
8
converted to bromide 9a in conc. hydrobromic acid at
9
reflux. Alkylation of LiCꢀC(CH ) OTHP with 9a in
2
4
1
0
DMPU and THF provided 10a in 45% overall yield
from 5a. Hydrogenation of 10a over lead-poisoned Pd on
Na SO4 at 0°C to form the nitrone and heating at
2
14
CaCO and quinoline in the presence of 1-hexene to
reflux for 1 h to effect cycloaddition gave 1b in 79%
yield from 3a and 4b. This sequence provides 1b in 11
steps from 3-octyn-1-ol and 3-nonyn-1-ol in 30% over-
all yield.
3
1
1
prevent over reduction afforded 96% of cis alkene 11a,
which was hydrolyzed with 6 M hydrochloric acid in
MeOH to give 12a. Swern oxidation afforded aldehyde
a in 91% yield from 11a. Oxime 12a was prepared by
reaction with NH OH·HCl and NaOAc in MeOH.
3
12,13
Spectral comparison indicates that pyrinodemin A is
not 1b, and is probably 1a. The EI mass spectra of 1a
and 1b are quite similar. Significant differences are: 1a
m/z 258 (4), 231 (15), 124 (17); 1b m/z 258 (26), 231 (0),
2
Reduction of 12a with NaBH CN in MeOH at pH 3–4
3
1
2,13
at −40 to −20°C afforded hydroxylamine 4a.
Conden-
4
sation of 3a and 4a in toluene containing Na SO at 0°C
2
to form the nitrone and heating at reflux for 1 h to effect
124 (0). The EI mass spectrum of natural pyrinodemin
1
4
17
cycloaddition gave 1a in 75% yield from 3a and 4a. The
stereochemistry of 1a was confirmed by NOEs between
H-15, H-16, and H-20. This sequence provides 1a in 11
steps from 3-octyn-1-ol in 29% overall yield.
A
is similar to that of 1a with significant peaks at m/z
1
231 and 124, but not 258. The H NMR spectra of 1a
and 1b are again very similar except for the allylic
methylene groups, which absorb at l 2.07–1.96 (m, 4)
2.5 eq NaH
Br
(CH ) OH
2 n
H N(CH ) NH
2
2 3
2
N
CH (CH )
(CH2)2OH
HC C (CH ) OH
2 n
3
2 n
o
8
0 C, 2h
5
5
a, n = 3
b, n = 4
6a, n = 6
b, n = 7
1% (PPh ) PdCl
2,
0.5% CuI, CH Cl
N
7a, n = 6
7b, n = 7
3
2
6
2
2
reflux, overnight
(
CH ) X
2
n
(
CH )
(CH ) CH OTHP
2 m 2
(
1) H , 1 atm, rt, 2 d
2 n
2
HC C (CH ) CH OTHP
2
m
2
2
% PtO , EtOH
2
N
DMPU, THF, n-BuLi
N
(
2) 48% HBr
reflux, 6 h
8a, n = 8, X = OH
8b, n = 9, X = OH
o
0 C to rt, overnight
1
1
0a, m = 3, n = 8 (45% from 5a)
0b, m = 2, n = 9 (47% from 5a)
9a, n = 8, X = Br
b, n = 9, X = Br
9
(
1) H NOH•HCl
NaOAc, MeOH
2
(
CH )
2 m
(
1) Pb-poisoned Pd/CaCO3
quinoline
(CH )
2 n
(
CH2)
(CH )
2 m
n
R
R
1
atm H , 1-hexene
(2) NaBH CN, MeOH
2
3
N
N
pH 3-4, -40 to -20 °C
(
(
2) 6 M aq HCl, MeOH
3) Swern
11a, m = 3, n = 8, R = CH2OTHP (96%)
11b, m = 2, n = 9, R = CH2OTHP
13a, m = 3, n = 8, R = CH=NOH
13b, m = 2, n = 9, R = CH=NOH
4a, m = 3, n = 8, R = CH2NHOH
4b, m = 2, n = 9, R = CH2NHOH
1
1
3
3
2a, m = 3, n = 8, R = CH OH
2
2b, m = 2, n = 9, R = CH OH
2
a, m = 3, n = 8, R = CHO (91% from 11a)
b, m = 2, n = 9, R = CHO (84% from 10b)
toluene, 0 °C 0.5 h
reflux, 1 h
toluene, 0 °C 0.5 h
reflux, 1 h
3a
+
4a
1a (75%)
3a
+
4b
1b (79%)

B. B. Snider, B. Shi / Tetrahedron Letters 42 (2001) 1639–1642
1641
in 1a and natural pyrinodemin A and at l 2.17–2.04
m, 2) and 2.01 (dt, 2, J=6, 6) in 1b. The allylic
carbons absorb at l 27.1 and 27.2 in 1a, while they
both absorb at l 27.1 in the natural product. In 1b,
they absorb at l 27.0 for C-14% and l 24.9 for C-18%, as
calculated, due to greater shielding by the g-nitrogen
than by a g-carbon.
Pyrinodemins 1a and 1b are moderately toxic to DU
145 prostate cancer cells (IC 8 mM) and HT-29 colon
(
50
21
cancer cells (IC50 8 mM).
In conclusion, we have developed efficient syntheses of
pyrinodemins A (1a) and B (21) that proceed in 26–30%
overall yield. Analysis of the spectral data indicates that
pyrinodemin A is definitely not 1b and is probably 1a.
1
3
However, neither the C NMR spectra of 1a or 1b
match well with the published data for pyrinodemin A.
For instance, the alkene carbons absorb at l 129.6 and
Acknowledgements
129.9 in 1a, at l 129.3 and 130.3 in 1b, and at l 129.3
and 129.3 in the natural product. For 1a, there are five
absorptions between l 27.0 and 28.5: C-13, 27.0; C-14%
and C-17%, 27.1 and 27.2; C-18%, 27.5; C-19%, 27.8. In the
published data for pyrinodemin A there are only three
absorptions in this region: l 27.9, 27.1, and 27.1.
However, examination of the C NMR spectrum of
the natural product shows peaks in this region that are
smaller than expected, but do correspond well to those
of 1a, suggesting that this is the structure of the natural
product.
We are grateful to the National Institute of General
Medical Sciences, National Institutes of Health for
financial support. We thank Professor Kobayashi for
copies of the spectral data of pyrinodemin A and
helpful discussions and Dr. Bruce Littlefield, Eisai
Research Institute for evaluating the cytotoxicity of 1a
and 1b.
1
7
13
Kobayashi and co-workers recently reported the isola-
tion of additional cytotoxic pyridine natural products
References
18
from Amphimedon sp including oxime 13a
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1a) by the absence of a double bond and a one-carbon
and
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(
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160.
shorter side chain. Coupling of aldehyde 3a with
hydroxylamine 20 should provide an expeditious route
1
9
to pyrinodemin B (21). Alkylation of the lithium
acetylide ethylenediamine complex with 13-bromo-1-
20
tridecanol (14) in DMSO containing NaI afforded 15,
which underwent Pd-catalyzed coupling to give 48% of
1
6 from bromo alcohol 14. Hydrogenation afforded
9
0% of saturated alcohol 17, which was oxidized to
aldehyde 18. Reaction with NH OH·HCl and NaOAc
2
provided 85% of oxime 19 from 17. Low temperature
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mun. 1995, 25, 4035–5043.
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3
gave 92% of hydroxylamine 20, which was condensed
with aldehyde 3a in toluene at 0°C to reflux to give 81%
6. Guthrie, R. W.; Kaplan, G. L.; Mennona, F. A.; Tilley,
J. W.; Kierstead, R. W.; Mullin, J. G.; LeMahieu, R. A.;
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1993, 58, 5925–5930.
14
of pyrinodemin B (21) in 26% overall yield from 14.
1
The H NMR spectrum of 21 is identical to that
13
reported for the natural product. The C NMR spec-
trum is similar, except for the presence of peaks at l
27.0, 27.3, and 28.1 in synthetic 21, but only l 27.9 in
the natural product as with synthetic and natural
pyrinodemin A.
8. Rama Rao, A. V.; Reddy, G. R. Tetrahedron Lett. 1993,
34, 8329–8332.

1
642
B. B. Snider, B. Shi / Tetrahedron Letters 42 (2001) 1639–1642
29.27, 29.24, 29.10, 29.06, 28.7, 28.0, 27.2, 27.0, 26.4,
9. Adams, T. C.; Dupont, A. C.; Carter, J. P.; Kachur, J.
F.; Guzewska, M. E.; Rzeszotarski, W. J.; Farmer, S. G.;
Noronha-Blob, L.; Kaiser, C. J. Med. Chem. 1991, 34,
26.3, 24.9; IR (neat) 1654, 1574, 1464, 1422;; MS m/z 575
(14), 574 (32), 365 (22), 355 (16), 327 (5), 301 (7), 299 (4),
289 (21), 288 (11), 287 (24), 286 (41), 285 (36), 270 (9),
258 (26), 244 (15), 231 (0), 220 (19), 204 (4), 190 (22), 176
1
585–1593.
1
1
1
0. Bengtsson, M.; Liljefors, T. Synthesis 1988, 250–252.
1. Ho, T.-L.; Liu, S.-H. Synth. Commun. 1987, 17, 969–973.
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Petrzilka, M. Tetrahedron 1985, 41, 3497–3509.
(
1
30), 162 (12), 148 (15), 146 (6), 136 (13), 134 (9), 124 (0),
20 (21), 106 (100), 93 (82); HRMS (DEI) calcd for
+
1
C H N O (MH ) 574.4736; found 574.4761. 21:
H
38
60
3
1
3. LeBel, N. A.; Balasubramanian, N. J. Am. Chem. Soc.
NMR 8.46–8.41 (m, 4), 7.49 (br d, 2, J=7.9), 7.20 (dd, 2,
J=7.9, 4.9), 4.06 (ddd, 1, J=6, 6, 6), 3.50–3.42 (br, 1),
1
989, 111, 3363–3368.
1
1
4. 1a: H NMR 8.46–8.41 (m, 4), 7.48 (br d, 2, J=7.9), 7.20
dd, 2, J=7.9, 4.9), 5.39–5.30 (m, 2), 4.05 (ddd, 1, J=6,
2
1
.88–2.79 (m, 2), 2.64–2.60 (m, 1), 2.59 (t, 4, J=7.6),
(
13
.83–1.72 (br, 1), 1.71–1.38 (m, 13), 1.36–1.22 (m, 28);
C
6
2
1
, 6), 3.50–3.42 (br, 1), 2.89–2.78 (m, 2), 2.64–2.60 (m, 1),
NMR 149.9 (2 C), 147.1 (2 C), 137.89, 137.85, 135.7 (2
C), 123.1 (2 C), 77.7 (br), 72.6 (br), 57.1 (br), 49.9, 34.2
.60 (t, 4, J=7.6), 2.07–1.96 (m, 4), 1.82–1.72 (br, 1),
13
.71–1.50 (m, 9), 1.50–1.36 (m, 6), 1.36–1.24 (m, 20);
C
(
br), 32.9 (2 C), 31.1 (2 C), 29.7, 29.5–29.6 (5 C), 29.48,
NMR 150.0 (2 C), 147.2 (2 C), 137.9 (2 C), 135.7 (2 C),
2
2
5
9.35 (2 C), 29.27, 29.09, 29.05, 28.7, 28.1, 27.3, 27.0,
1
4
30.0, 129.6, 123.2 (2 C), 77.8 (br), 72.6 (br), 57.2 (br),
9.9, 34.2 (br), 33.0 (2 C), 31.1 (2 C), 29.7 (2 C), 29.4 (2
+
6.4, 26.3; HRMS (DEI) calcd for C H N O (M )
37
59
3
61.4658; found 561.4645.
C), 29.33, 29.30, 29.2, 29.11, 29.08, 28.8, 27.8, 27.5, 27.18,
7.12, 27.0, 26.4, 26.3; IR (neat) 1574, 1464, 1422; MS
m/z 575 (20), 574 (49), 365 (29), 355 (18), 327 (12), 301
1
5. Tellier, F.; Hammoud, A.; Ratovelomanama, V.; Lin-
2
strumelle, G.; Descoins, C. Bull. Soc. Chim. Fr. 1993, 130,
2
81–286.
6. Pflieger, D.; Muckensturm, B. Tetrahedron 1989, 45,
031–2040.
7. We thank Professor Kobayashi for helpful discussions
(
(
(
(
10), 299 (9), 289 (11), 288 (9), 287 (19), 286 (24), 285
30), 270 (11), 258 (4), 244 (22), 231 (15), 220 (31), 204
3), 190 (13), 176 (17), 162 (12), 148 (15), 146 (11), 136
1
1
2
10), 134 (13), 124 (17), 120 (22), 106 (100), 93 (94);
1
13
+
and copies of the H and C NMR and mass spectra of
pyrinodemin A.
HRMS (DEI) calcd for C H N O (MH ) 574.4736;
found 574.4753. 1b: H NMR 8.46–8.41 (m, 4), 7.49 (br
d, 2, J=7.9), 7.20 (dd, 2, J=7.9, 4.9), 5.41–5.30 (m, 2),
38
60
3
1
1
8. The spectral data for 13a are identical to those reported
for the natural product.
9. Singh, A.; Schnur, J. M. Synth. Commun. 1986, 16,
847–852.
20. Singh, A.; Markowitz, M. A. New. J. Chem. 1994, 18,
477–485.
4
2
2
1
.05 (ddd, 1, J=6, 6, 6), 3.50–3.42 (br, 1), 2.89–2.79 (m,
), 2.64–2.60 (m, 1), 2.60 (t, 4, J=7.6), 2.17–2.04 (m, 2),
.01 (dt, 2, J=6, 6), 1.80–1.72 (br, 1), 1.71–1.52 (m, 10),
1
13
.50–1.38 (m, 3), 1.36–1.24 (m, 22); C NMR 149.9 (2
C), 147.1 (2 C), 137.91, 137.89, 135.7 (2 C), 130.3, 129.3,
1
3
23.2 (2 C), 77.8 (br), 72.6 (br), 56.8 (br), 49.9, 34.2 (br),
3.0 (2 C), 31.1 (2 C), 29.7 (2 C), 29.5 (2 C), 29.36, 29.35,
21. We thank Dr. Bruce Littlefield, Eisai Research Institute
for evaluating the cytotoxicity of 1a and 1b.
.
.