Expeditious synthesis of nitrogenated spongianes: 4-methyldecarboxyspongolactams

Article abstract of DOI:10.1016/j.tet.2010.01.091

Herein, the synthesis of 4-methyldecarboxyhaumanamide (9) and 4-methyldecarboxyspongolactams A?(11) and C (13) is presented. (-)-Sclareol is the starting material and the chloroderivative 7 is the common intermediate. Moreover, this synthesis represents a new strategy for the preparation of pyrrolinones.

Full text of DOI:10.1016/j.tet.2010.01.091

Tetrahedron 66 (2010) 2422–2426
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Expeditious synthesis of nitrogenated spongianes: 4-methyldecarboxy-
spongolactams
,
a
a
a
a
a
b
a
P. Basabe a , A. Blanco , O. Bodero , M. Martın , I.S. Marcos , D. Dıez , F. Mollinedo , J.G. Urones
*
´
´
a
´
´
´
Departamento de Qu´ımica Organica, Facultad de Ciencias Quımicas, Universidad de Salamanca. Plaza de los Caıdos 1-5, 37008 Salamanca, Spain
Centro de investigacio´n del Cancer, CSIC-Universidad de Salamanca, Campus Miguel de Unamuno, 37007 Salamanca, Spain
b
´
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein, the synthesis of 4-methyldecarboxyhaumanamide (9) and 4-methyldecarboxyspongolactams
A (11) and C (13) is presented. (ꢀ)-Sclareol is the starting material and the chloroderivative 7 is the
common intermediate. Moreover, this synthesis represents a new strategy for the preparation of
pyrrolinones.
Received 17 December 2009
Received in revised form 22 January 2010
Accepted 26 January 2010
Available online 1 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Diterpenes
Sclareol
Spongolactams
Pyrrolinones
Haumanamide
Spongianes
16
13
1. Introduction
21
20
25
27
17
N
1
9
Spongianes are a group of tetracyclic diterpenes isolated from
marine organisms,1 some of which display an interesting range of
biological activities.2
23
22
15 O
H
16
13
C 17
COOH
11
9
18
1
20
19
O
D
1
Haumanamide
14
Structurally, haumanamide is a terpenoid with two clearly dis-
tinguished parts: a phenylethylamine part and a terpenic moiety,
which belong to the nitrospongiane family. This compound is the
first one of this class to be isolated.
15
B
A
7
5
18
19
Spongiane skeleton
Recently,4 novel nitrogenous diterpenoids, spongolactams A–C
(2–4) were isolated as trace compounds from an Okinawan marine
sponge, Spongia sp. They showed Farnesyl Transferase Inhibition
activity.
Haumanamide3 1 is a nitrogenous derivative isolated from
a Pohnpei Spongia sp. It is active in the KB (MIC 5 g/mL) and LoVO
(MIC 10 g/mL) bioassays.
X
m
m
H
N
N
N
COOH
Y
O
N
H
H
COOH
COOH
2 X=H2, Y=O, Spongolactam A
3 X=O, Y=H2, Spongolactam B
* Corresponding author. Tel.: þ34 923 294474; fax: þ34 923294574.
E-mail address: pbb@usal.es (P. Basabe).
4 Spongolactam C
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.091

P. Basabe et al. / Tetrahedron 66 (2010) 2422–2426
2423
Spongolactams have a pyrrolinone core in common.
N
N
Pyrrolinones are the predominant tautomeric form of the
d
a
-hydroxypyrroles. Traditionally,5 they have be synthesized either
H
O
O
directly by oxidation of the corresponding pyrroles or by ring
synthesis. Those latter include the reduction and cyclization of
cyanohydrins derived from b-keto-esters, the cyclization of acyl-
H
H
9
8
4-Methyldecarboxyhaumanamide
a
succinic esters with ammonia or primary amines, or the Michael
addition of nucleophiles to acetylenic carbonyls.
Cl
Recently, new strategies have been reported. Many synthetic
routes to these compounds introduce the nitrogen heteroatom into
a carbon framework via azide, cyanide or ammonia substitution
reactions,6 via reduction of imine derivatives, or they are based on
a coupling promoted by a metal catalyst.7 Ring expansion of
cyclobutanones8 and biomimetic studies have also been reported.9
The synthetic route that we present offers an alternative method
of preparation of this moiety by condensation of the allylic halide/
ester with an amine followed by isomerisation of the olefin.
Besides, it is a useful way of achieving a series of spongolactams
depending on the amine chosen.
In this work, the synthesis of 4-methyldecarboxyhaumanamide,
9, and 4-methyldecarboxyspongolactams A, 11, and C, 13, is
described.
The synthesis of this kind of molecules is interesting in order to
build an even wider portfolio of spongianes on which the oxygen in
ring D has been replaced by a nitrogen atom.
COOMe
b
H
c
7
H
N
N
N
COOMe
H
H
O
O
N
H
H
10
12
d
d
H
N
N
N
COOH
O
O
N
H
H
13
4-Methyldecarboxyspongolactam C
11
4-Methyldecarboxyspongolactam A
Scheme 2. Reagents and conditions: (a)
b
-phenylethylamine, NaCN, 45 ꢁC, 24 h (81%);
On the other hand the synthesis of 4-methyldecarboxy-
compounds will help to establish the influence of carboxylic group
in the biological activity.
(b) Histamine, MeOH, 80 ꢁC, 24 h (42%); (c) Glycine methyl ester hydrochloride, MeOH,
Et3N, 80 ꢁC, 24 h (38%); (d) 10% KOH/MeOH, rt (82% 9, 91% 11, 93% 13).
Treatment of 7 with b
–phenylethylamine in presence of NaCN14
affords the lactamic ring of 8. The reaction of 7 with histamine in
MeOH at 80 ꢁC leads to 10. When the same conditions are applied
to 7 and glycine methyl ester hydrochloride, the desired compound
2. Results and discussion
The key intermediate in the synthesis of the targeted spongo-
lactams is the halogenated compound 7. This compound is obtained
throughout the reaction sequence shown in Scheme 1, using methyl
isoanticopalate as the starting material. Methyl isoanticopalate,
obtained from sclareol,10 is an excellent precursor for the synthesis
of bioactive natural compounds.11
Treatment of methyl isoanticopalate with mCPBA gives the
expected epoxide 5. Reaction of 5 with Al(iPrO)312 leads to alcohol
6. From 6, an allylic rearrangement13 of the double bond and
nucleophilic substitution of the hydroxyl group by a chlorine atom
yields the desired chloroderivative 7. With the key intermediate 7
in hand, the synthesis of the 4-metyldecarboxyspongolactams is
carried out following the reaction sequence described in Scheme 2.
12 is obtained. Double bond isomerization from D12 D13 tested
–
with LDA and t-BuOK gave no satisfactory results. However,
treatment of 8, 10 and 12 with KOH/MeOH, respectively yielded 9,
11 and 13.
Compounds 9, 11 and 13 did not inhibit tumour cell growth of
a number of established human tumour cell lines, including HeLa
(epitheloid cervix carcinoma), MCF-7 (breast adenocarcinoma),
NCI-H460 (non-small lung carcinoma), and SF-268 (glioblastoma),
when used in a molar range of 10ꢀ5–10ꢀ9 M, as assessed by Alamar
Blue assay.15 This fact indicates that the IC50 (50% inhibitory
concentration, drug concentration causing 50% inhibition in cell
proliferation) values for these compounds were higher than
HO
O
Ref. 10
a
COOMe
COOMe
OH
H
H
5
H
(-)-sclareol
methyl isoanticopalate
b
OH
Cl
COOMe
c
COOMe
H
H
7
6
Scheme 1. Reagents and conditions: (a) mCPBA, DCM, 0 ꢁC, 2 h (78%); (b) (iPrO)3Al, toluene, 110 ꢁC, 12 h (86%); (c) SOCl2, C6H6, 0 ꢁC, 15 min (52%).

2424
P. Basabe et al. / Tetrahedron 66 (2010) 2422–2426
1ꢂ10ꢀ5 M, whereas Taxol, used as a positive control, rendered IC50
values of 3.8ꢃ0.5ꢂ10ꢀ9 M (HeLa), 8.4ꢃ0.7ꢂ10ꢀ9 M (MCF-7),
3.9ꢃ0.2ꢂ10ꢀ9 M (NCI-H460), and 4.9ꢃ0.2ꢂ10ꢀ9 M (SF-268) (data
are mean valuesꢃSD of three independent determinations).
All these results seem to show that the presence of the
carboxylic group in C-4, as in 1, 2 and 4, is essential for the activity
of these compounds.
vacuo. Silica gel chromatography gave 6 as a colourless oil (457 mg,
1.37 mmol, 86% yield).
22
4.3.1. Methyl 12-a-hydroxy-isoanticopal-13-(16)-en-15-oate (6). [a]
D
ꢀ32.2 (c 0.82, CHCl3); IR (film): 3424, 2936, 1737, 1435, 1387, 1194,
1163, 1043, 1005, 911 cmꢀ1; 1H NMR (200 MHz)
d: 5.03 (1H, s), 4.84
(1H, s), 4.38 (1H, s), 3.64 (3H, s), 3.34 (1H, s), 1.88–0.87 (14H, m), 1.02
(3H, s), 0.86 (3H, s), 0.84 (3H, s), 0.80 (3H, s), OH not observed; 13C
3. Conclusions
NMR (50 MHz) d: 172.2, 145.3, 111.5, 73.1, 57.6, 56.9, 51.9, 51.2, 42.2,
40.4, 40.3, 39.9, 37.5, 33.5, 33.3, 29.3, 21.7, 18.9, 18.7, 16.3, 14.4;
The synthesis of three 4-methyldecarboxyspongolactams 9, 11
and 13 has been accomplished. The chloroderivative 7 is the key
intermediate to get to this kind of compounds. This synthesis offers
a novel, rapid, and metal-free strategy for the construction of
pyrrolinones. The presence of a carbonyl group in C-4 is essential
for the activity of these compounds.
EIHRMS: calcd for C21H34O3Na (MþNa): 357.2400, found 357.2393.
4.4. Rearrangement of 6 with SOCl2 to yield 7
A solution of 6 (145 mg, 0.43 mmol) in C6H6 (1.1 mL) was cooled
to 0 ꢁC and SOCl2 (2.2 mL, 30 mmol) was added. The mixture was
stirred for 15 min at this temperature. Then, it was quenched with
ice and extracted with EtOAc. The organics were washed with
NaHCO3 and brine, dried over Na2SO4 and concentrated under
reduced pressure. The residue purified by chromatography on silica
gel afforded the yellowish oil 7 (80 mg, 0.23 mmol, 52% yield).
4. Experimental
4.1. General
Unless otherwise stated, all chemicals were purchased as the
highest purity commercially available and were used without fur-
ther purification. IR spectra were recorded on a BOMEM 100 FTIR or
an AVATAR 370 FTIR Thermo Nicolet spectrophotometers. 1H and
13C NMR spectra were performed in CDCl3 and referenced to the
4.4.1. Methyl 16-chloro-isoanticopal-12-en-15-oate (7). IR (film):
1730, 1450, 1430, 1390, 1190, 1160 cmꢀ1; 1H NMR (200 MHz)
d: 5.93
(1H, br s), 4.32 (1H, d, J¼11.1 Hz), 3.99 (1H, d, J¼11.1 Hz), 3.71 (3H,
s), 3.22 (1H, br s), 2.10–0.90 (14H, m), 0.91 (3H, s), 0.88 (3H, s) 0.87
residual peak of CHCl3 at
respectively, using Varian 200 VX and Bruker DRX 400 instruments.
Chemical shifts are reported in ppm and coupling constants (J) are
d 7.26 ppm and d
77.0 ppm, for 1H and 13C,
(3H, s), 0.82 (3H, s); 13C NMR (50 MHz)
d: 172.7, 131.1, 129.8, 58.6,
57.5, 56.9, 51.3, 49.1, 42.1, 41.8, 40.1, 37.7, 36.8, 33.3, 33.3, 23.2, 21.8,
18.9, 18.6, 15.8, 15.8; EIHRMS: calcd for C21H33O2NaCl (MþNa):
375.2061, found 375.2076.
d
given in hertz. MS were performed at a VG-TS 250 spectrometer at
70 eV ionising voltage. Mass spectra are presented as m/z (% rel
int.). HRMS were recorded on a VG Platform (Fisons) spectrometer
using chemical ionisation (ammonia as gas) or Fast Atom
Bombardment (FAB) technique. For some of the samples, QSTAR XL
spectrometer was employed for electrospray ionization (ESI).
Optical rotations were determined on a Perkin–Elmer 241 polar-
imeter in 1 dm cells. Diethyl ether and THF were distilled from
sodium, and dichloromethane was distilled from calcium hydride
under argon atmosphere.
4.5. Reaction of 7 to yield 8
Compound 7 (30 mg, 0.08 mmol) was dissolved in phenyl-
ethylamine (2.8 mL, 22 mmol) and 0.42 mg (0.008 mmol) of NaCN
were added to the reaction mixture. It was stirred at 45 ꢁC under
argon atmosphere for 24 h. Then, ether was added and the solution
was washed with 2 N HCl, NaHCO3 10% and brine. The combined
organic extracts were dried over Na2SO4 and the solvent removed
under reduced pressure. The crude was purified by chromatogra-
phy on silica gel affording 8 as a yellowish oil (28 mg, 0.07 mmol,
81% yield).
4.2. Epoxidation of methyl isoanticopalate to yield 5
To a solution of methyl isoanticopalate (960 mg, 3.0 mmol) in
CH2Cl2 (33 mL), cooled at 0 ꢁC, mCPBA (938 mg, 5.4 mmol) was
added. The reaction was controlled by TLC. After stirring for 2 h the
solution was diluted with ether, washed with NaHSO3 10%, NaHCO3
10% and brine. It was dried with Na2SO4 and concentrated under
reduced pressure. The crude was purified by chromatography on
silica gel to give the colourless oil 5 (789 mg, 2.36 mmol, 78% yield).
22
4.5.1. 13-iso-4-Methyldecarboxyhaumanamide (8). [
a
]
ꢀ23.0 (c
D
0.84, CHCl3); IR (film): 1690, 1560, 1450, 1390, 1270 cmꢀ1; 1H NMR
(200 MHz) : 7.30–7.20 (5H, m, C6H5), 5.55 (1H, br s), 3.80–3.35 (3H,
m), 2.82 (2H, t, J¼7.4 Hz), 2.61 (2H, br s), 2.10–0.90 (14H, m), 0.88
(6H, s), 0.83 (3H, s), 0.75 (3H, s); 13C NMR (50 MHz)
: 173.5, 139.0,
d
d
128.9, 128.7, 128.7, 128.7, 128.7, 128.6, 120.5, 57.4, 56.9, 54.5, 51.2,
43.8, 42.1, 40.6, 40.0, 37.8, 34.8, 34.0, 33.7, 33.2, 23.0, 21.9, 18.7, 18.7,
15.4, 14.9; EIHRMS: calcd for C28H40NO (MþH): 406.3104, found
406.3106.
22
4.2.1. Methyl 12,13-
a
-epoxy-isoanticopal-15-oate (5). [
a
]
ꢀ23.0 (c
D
0.85, CHCl3); IR (film): 1737, 1443, 1329, 1268, 1163, 1103,
1007 cmꢀ1; 1H NMR (200 MHz)
: 3.64 (3H, s), 3.02 (1H, br s), 2.45
(1H, s), 2.1–0.92 (14H, m), 1.26 (3H, s), 1.05 (3H, s), 0.87 (3H, s), 0.81
(3H, s), 0.77 (3H, s); 13C NMR (50 MHz)
: 172.6, 62.1, 60.3, 57.0,
d
d
4.6. Reaction of 8 with KOH/MeOH to yield 9
56.5, 51.2, 50.3, 41.9, 40.4, 39.5, 37.4, 36.2, 33.6, 33.3, 22.6, 21.9, 21.9,
18.5, 18.5, 15.9, 15.2; EIHRMS: calcd for C21H34O3Na (MþNa):
357.2400, found 357.2401.
To a solution of 8 (18 mg, 0.04 mmol) in MeOH (0.3 mL), 0.1 mL
of 10% KOH in MeOH were added. The reaction mixture was stirred
at room temperature for 3 h. Then the solvent was removed under
reduced pressure. The residue was diluted with ether and washed
with water. The organics were dried over Na2SO4 and concentrated.
Purification by chromatography on silica gel afforded the desired
4-methyldecarboxyhaumanamide 9 (15 mg, 0.04 mmol, 82% yield).
4.3. Reaction of 5 with (iPrO)3Al to yield 6
To a solution of 5 (530 mg, 1.59 mmol) in toluene (52 mL),
(iPrO)3Al (312 mg, 1.53 mmol) was added. The mixture was
refluxed for 12 h. Then, it was allowed to reach room temperature.
After dilution with ether, it was washed with NaHCO3 and brine.
The organic phase was dried with Na2SO4 and concentrated in
22
4.6.1. 4-Methyldecarboxyhaumanamide (9). [
a
]
ꢀ30.5 (c 0.41,
D
CHCl3); IR (film): 1670, 1455, 1410, 1380 cmꢀ1; 1H NMR (200 MHz)

P. Basabe et al. / Tetrahedron 66 (2010) 2422–2426
2425
d
: 7.30–7.20 (5H, m, C6H5), 3.75–3.40 (3H, m), 3.58 (1H, d, J¼5.9 Hz),
3.50 (1H, d, J¼5.9 Hz), 2.90 (3H, m), 2.25–1.10 (14H,m), 1.16 (3H, s),
0.88 (3H, s), 0.85 (3H, s), 0.83 (3H, s); 13C NMR (50 MHz)
: 170.8,
1209 cmꢀ1
;
1H NMR (200 MHz)
d
: 5.65 (1H, br s), 4.14 (1H, d,
J¼17.6 Hz), 3.99 (1H, d, J¼17.6 Hz), 3.89 (1H, s), 3.72 (3H, s), 2.61
d
(1H, s), 2.70 (1H, s), 2.20–1.05 (14H, m), 0.89 (3H, s), 0.88 (3H,s),
147.2, 141.5, 139.3, 128.7, 128.7, 128.5, 128.5, 126.3, 57.0, 57.0, 52.7,
43.6, 42.2, 40.0, 37.6, 36.6, 36.0, 35.2, 33.3, 33.3, 21.3, 21.3, 21.3, 18.6,
18.3, 17.5, 16.5; EIHRMS: calcd for C28H40NO (MþNa): 406.3104,
found 406.3106.
0.83 (3H,s), 0.81 (3H, s); 13C NMR (50 MHz)
d: 174.5, 169.4, 128.5,
121.0, 56.9, 56.8, 54.5, 52.4, 51.4, 43.8, 42.1, 40.5, 40.0, 37.8, 35.0,
33.7, 33.4, 23.0, 21.9, 18.7, 18.6, 15.4, 15.0; EIHRMS: calcd for
C23H35NO3Na (MþNa): 396.2509, found 396.2522.
4.10. Reaction of 12 with KOH/MeOH to yield 13
4.7. Reaction of 7 to yield 10
Compound 12 (8 mg, 0.02 mmol) was dissolved in 0.8 mL of 10%
KOH/MeOH. The reaction mixture was stirred at room temperature
for 8 h. Then methanol was removed and water was added. It was
extracted with EtOAc, and the organic phase was washed with
brine. It was dried over Na2SO4 and concentrated under reduced
pressure. The residue was purified by chromatography on silica gel
to give 6 mg of the 4-methyldecarboxyspongolactam C, 13
(0.02 mmol, 93% yield).
Compound 7 (64 mg, 0.18 mmol) was dissolved in MeOH (6 mL)
and histamine (300 mg, 2.7 mmol) was added. The reaction
mixture was stirred at 80 ꢁC under argon atmosphere for 24 h. Then
it was allowed to reach room temperature, and the MeOH was re-
moved under reduced pressure. After addition of water the solution
was extracted with EtOAc. The combined organic extracts were
washed with brine and dried over Na2SO4. The solvent was evap-
orated and the residue was purified by chromatography on silica gel
affording 10 as a yellowish oil (22 mg, 0.06 mmol, 42% yield).
22
4.10.1. 4-Methyldecarboxyspongolactam C (13). [
a]
ꢀ56.0 (c 0.05,
D
22
CHCl3); IR (film): 2922, 2850, 1737, 1632, 1441, 1383, 1177,
4.7.1. 13-iso-4-Methyldecarboxyspongolactam A (10). [
a]
ꢀ29.4 (c
D
1014 cmꢀ1 1H NMR (400 MHz)
;
d
: 4.18 (2H, s), 3.86 (1H, d,
0.16, CHCl3); IR (film): 2998, 2929, 1669, 1478, 1270, 1091 cmꢀ1; 1H
NMR (400 MHz) : 7.54 (1H, br s), 6.81 (1H, br s), 5.60 (1H, br s),
J¼14.4 Hz), 3.80 (1H, d, J¼14.4 Hz), 2.72 (1H, dt, J¼12.8, 1.5 Hz), 2.33
(1H, dd, J¼18.0, 4.8 Hz), 2.25 (1H, ddd, J¼18.0, 11.5, 6.5 Hz), 2.10–
1.20 (13H, m), 1.15 (3H , s), 0.87 (3H, s), 0.85 (3H, s), 0.82 (3H, s),
d
3.90–3.55 (3H, m), 2.88 (2H, t, J¼6.8 Hz), 2.65–2.55 (2H, m),
2.05–1.05 (14H, m), 0.87 (6H, s), 0.82 (3H, s), 0.71 (3H, s), NH not
COOH signal not observed; 13C NMR (100 MHz)
d: 172.1, 165.7,
observed; 13C NMR (100 MHz)
d: 174.4, 134.6, 132.6, 129.0, 120.7,
150.0, 140.6, 56.8, 56.7, 53.3, 42.1, 39.8, 38.7, 37.5, 36.4, 35.9, 33.3,
29.7, 26.5, 21.3, 21.2, 18.5, 18.2, 17.2, 16.4; EIHRMS: calcd for
C22H33NO3Na (MþNa): 382.2353, found 382.2345.
118.9, 57.2, 56.6, 54.1, 50.7, 41.8, 41.1, 40.4, 39.7, 37.5, 34.7, 33.4, 33.1,
24.6, 22.7, 21.6, 18.4, 18.3, 15.1, 14.7; EIHRMS: calcd for C25H38N3O
(MþH): 396.3009, found 396.3020.
Acknowledgements
4.8. Reaction of 10 with KOH/MeOH to yield 11
´
The authors thank the Junta de Castilla y Leon for financial
Compound 10 (22 mg, 0.06 mmol) was dissolved in 2.2 mL of
10% KOH/MeOH. The reaction mixture was stirred at room tem-
perature for 6 h. Then the solvent was removed and water was
added. After extraction with EtOAc, the organics were washed with
brine. The combined extracts were dried over Na2SO4 and con-
centrated under reduced pressure. Purification by chromatography
on silica gel afforded 20 mg of 4-methyldecarboxyspongolactam A,
11 (0.05 mmol, 91% yield).
support (GR178 and SA063A07), MICINN (CTQ2009-11557) and for
the doctoral fellowships awarded to A.B. and O.B.
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S. P.; Duraiswami, C.; Tran, T. B.; Steward, E. L.; Grygielko, E. T.; Glace, L. E.;
Trizna, W.; Nagila, R.; Bray, J. D.; Thompson, S. K. Bioorg. Med. Chem. Lett. 2009,
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7. (a) Rehak, J.; Fisera, L.; Podolan, G.; Kozisek, J.; Perasınova, L. Synlett 2008, 1260;
(b) Yeh, C. H.; Korivi, R. P.; Cheng, C. H. Angew. Chem., Int. Ed. 2008, 47, 4892.
8. Verniest, G.; Boterberg, S.; Bombeke, F.; Stevens, C. V.; De Kimpe, N. Synlett
2004, 1059.
22
4.8.1. 4-Methyldecarboxyspongolactam A (11). [
a]
ꢀ41.4 (c 0.07,
D
CHCl3); IR (film): 2905, 2850, 1663, 1458, 1408, 1224 cmꢀ1; 1H NMR
(400 MHz)
d
: 7.58 (1H, br s), 6.83 (1H, br s), 3.71 (2H, t, J¼6.4 Hz),
3.64 (2H, d, J¼2.6 Hz), 2.93 (2H, t, J¼6.4 Hz), 2.76 (2H, d, J¼12.9 Hz),
2.7–1.4 (14H, m), 1.13 (3H, s), 0.88 (3H, s), 0.85 (3H, s), 0.83 (3H, s),
NH not observed; 13C NMR (100 MHz)
d: 171.6, 148.3, 141.0, 134.6,
132.6, 118.9, 56.8, 56.8, 52.5, 42.1, 40.7, 39.8, 37.5, 36.5, 35.9, 33.3,
33.3, 26.4, 25.9, 21.3, 21.2, 18.5, 18.2, 17.3, 16.4; EIHRMS: calcd for
C25H38N3O (MþH): 396.3009, found 396.3004.
4.9. Reaction of 7 to yield 12
Glycine methyl ester hydrochloride (105 mg, 0.84 mmol) was
dissolved in 0.5 mL of MeOH and Et3N (0.12 mL, 0.84 mmol) was
added. To this mixture a solution of 7 (27 mg, 0.08 mmol) in MeOH
was added. The reaction mixture was stirred overnight at 80 ꢁC
under argon atmosphere. Then it was allowed to reach room
temperature and water was added. After extraction with EtOAc the
organic phase was washed with 2 N HCl, NaHCO310 % and brine. It
was dried over Na2SO4 and the solvent evaporated. The crude was
purified by chromatography to yield 12 as a yellowish oil (9 mg,
0.03 mmol, 38%).
´
´
´
9. Smith, A. B.; Wang, W.; Sprengeler, P. A.; Hirschmann, R. J. Am. Chem. Soc. 2000,
122, 11037.
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1995, 6, 285.
11. (a) Basabe, P.; Diego, A.; Dı´ez, D.; Marcos, I. S.; Urones, J. G. Synlett 2000, 1807;
(b) Basabe, P.; Diego, A.; Delgado, S.; Dı´ez, D.; Marcos, I. S.; Urones, J. G. Tetra-
22
4.9.1. 13-iso-4-Methyldecarboxyspongolactam C (12). [
a
]
D
ꢀ21.4 (c
´
hedron 2003, 59, 9173; (c) Basabe, P.; Delgado, S.; Marcos, I. S.; Dıez, D.; Diego,
A.; de Roma´n, M.; Urones, J. G. J. Org. Chem. 2005, 70, 9480; (d) Basabe, P.;
0.27, CHCl3); IR (film): 2923, 2847, 1752, 1688, 1434, 1273,

2426
P. Basabe et al. / Tetrahedron 66 (2010) 2422–2426
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Bodero, O.; Marcos, I. S.; Dı´ez, D.; de Roman, M.; Blanco, A.; Urones, J. G.
´
´
Tetrahedron 2007, 63, 11838; (e) Basabe, P.; de Roman, M.; Dıez, D.; Marcos, I.
S.; Bodero, O.; Blanco, A.; Mollinedo, F.; Urones, J. G. Synlett 2008, 1149; (f)
13. Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1984, 25, 3055.
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1997, 204, 205.
´
´
Basabe, P.; Bodero, O.; Marcos, I. S.; Dıez, D.; Blanco, A.; de Roman, M.; Urones,
J. G. J. Org. Chem. 2009, 74, 7750.