Synthesis of the 11-membered ring of the marine alkaloids, madangamines

Article abstract of DOI:10.1016/j.tetlet.2006.02.160

The first successful attempt at synthesizing the 11-membered ring of madangamine alkaloids is described. The synthesis involves intramolecular N,O-acetalization of a cyclohexanone derivative, cross-coupling reaction with (Z)-vinylstannane, and intramolecu

Full text of DOI:10.1016/j.tetlet.2006.02.160

Tetrahedron Letters 47 (2006) 3489–3492
Synthesis of the 11-membered ring of the marine alkaloids,
madangamines
Yuta Yoshimura, Junji Inoue, Naoki Yamazaki,* Sakae Aoyagi and Chihiro Kibayashi
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 19 January 2006; revised 20 February 2006; accepted 21 February 2006
Abstract—The first successful attempt at synthesizing the 11-membered ring of madangamine alkaloids is described. The synthesis
involves intramolecular N,O-acetalization of a cyclohexanone derivative, cross-coupling reaction with (Z)-vinylstannane, and intra-
molecular reductive amination for elaboration of the 11-membered macrocycle.
Ó 2006 Elsevier Ltd. All rights reserved.
Madangamine A (1) is a novel pentacyclic alkaloid that
was isolated from the marine sponge Xestospongia
ingens by Andersen in 1994.1 Soon after, new constitu-
ents of this alkaloid type, madangamines B–E (2–5),
were isolated from the same organism.2 Madangamine
A exhibits cytotoxic activities against P388, A549,
U373, and MCF-7 tumor cell lines. The unprecedented
structure, including a diamond-lattice core (ABC-ring)
and two macrocyclic rings (D- and E-rings), has
attracted much attention in the fields of organic and
medicinal chemistry.
To date, there have been reports on tricyclic ABC-ring
synthesis.3,4 By adopting the Diels–Alder reaction fol-
lowed by intramolecular aminomercuration as key steps,
construction of the diazatricyclic ring has been
achieved3 and, more recently, one-step construction of
the tricyclic core of madangamines via condensation of
dihydropyridinium salt with the sodium salt of diethyl
acetonedicarboxylate has been reported.4 In connection
with our investigations, devoted to the use of N,O-ace-
tals in alkaloid synthesis,5 we succeeded in synthesizing
the tricyclic ring system (ABC ring) of madangamines
by adopting intramolecular N,O-acetalization of the
corresponding keto-aminophenol for the AC-ring con-
struction and then intramolecular cyclization for the
B-ring construction.6 To date, contrary to the case of
the ABC-ring formation, there have been no reports
of the synthesis of macrocyclic ring(s) (D- and/or
E-ring(s)). In this context, we set out to develop a proto-
col for the elaboration of the 11-membered ring (E-ring)
in madangamine alkaloids as a common architecture.
The strategy for the construction of the E-ring, which
is fused to the AC-ring, involves intramolecular reduc-
tive amination of 7 and intramolecular N,O-acetaliza-
tion of 9 as shown in Scheme 1.
1
X
9
D
N
A
B
7N
E
C
3
Madangamines
A (1): NX =
B (2): NX =
C (3): NX =
D (4): NX =
E (5): NX =
N
N
N
N
N
The Michael addition of ethyl cyanoacetate to 10 was car-
ried out in the standard manner to give the adduct 117 as a
1:1 diastereomeric mixture in an 80% yield. Protection of
the keto group of 11 with 1,2-bis(hydroxymethyl)benzene
Keywords: Alkaloid; Madangamine; N,O-Acetalization; Macro-
cyclization.
*
Corresponding author. E-mail: yamazaki@ps.toyaku.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.160

3490
Y. Yoshimura et al. / Tetrahedron Letters 47 (2006) 3489–3492
OR1
OR1
NH
Sequential treatment of 16 with ethylene glycol and
CHO
trimethylsilylchloride followed by TBDMSOTf in the
presence of 2,6-lutidine gave 17 in an 81% yield as a
3:1 diastereomeric mixture over two steps.9 After reduc-
tion of nitrile 17 with DIBAL-H, the resulting primary
amine was treated with salicylaldehyde and sodium
borohydride to give the reductive amination product
18 in a 96% yield (Scheme 2).
R1O
R1O
N
A
A
E
C
C
7
6
OR1
R1O
The cyclic ketal 18 was treated with hydrochloric acid in
methanol to give the tetracyclic N,O-acetal 19 as a single
diastereomer10 in a 51% yield with the accompanying
uncyclized 20 in a 42% yield. The uncyclized product
20 was converted to 19 under the same acidic conditions
(3 M HCl–MeOH) in a 65% yield. Reductive cleavage of
the N,O-acetal 19 with alane in ether provided the 2-aza-
bicyclo[3.3.1]nonane (morphan) derivative 21 in an 84%
yield. Removal of the (2-hydroxyphenyl)methyl group
of 21 was accomplished by hydrogenation using palla-
dium hydroxide as a catalyst to give 22 in a 50% yield
along with a 49% recovery of 21 (Scheme 3).11
OR1 NH OH
N
O
R1O
O
OH
8
OR
9
Scheme 1. Retrosynthetic analysis of the 11-membered ring in the
madangamine alkaloids.
yielded the seven-membered cyclic acetal 12. Potassium-
carbonate mediated hydroxymethylation followed by
TBDMS protection led to ester 13 having a quaternary
carbon center in a 98% yield over two steps. Conversion
of the diastereomeric mixture of 13 to the bis(hydroxy-
methyl)nitrile 14 was carried out in the standard manner
by lithium borohydride reduction in an ether–ethanol
solution, and subsequent desilylation with TBAF. After
the protection of the two hydroxy groups of 14 as their
benzyl ethers, the cyclic acetal was cleaved with pyridi-
nium p-toluenesulfonate in a mixture of acetone and
water at reflux to give the 3-substituted cyclohexanone
15 in excellent yields.
The next stage of our synthesis involved macrocycliza-
tion between the secondary amine and the carbinol car-
bon via the retrosynthesis (Scheme 1). After protection
of the secondary amine of 22 as a tert-butyl carbamate,
treatment of Dess–Martin periodinane gave ketone 23
in a 99% yield in two steps. The application of Still’s
Z-selective Wittig–Horner olefination12 to 23 employing
KHMDS as a base in the presence of 18-crown-6 yielded
the (Z)-exo-olefin 24 as a major product with the accom-
panying undesired (E)-isomer in a ratio of 11:1. This
inseparable geometrical mixture (11:1) was treated with
DIBAL-H in dichloromethane at À78 °C to give (Z)-
allylic alcohol 25 in an 85% yield after chromatographic
removal of a small amount of the (E)-isomer. Methoxy-
carbonylation of the allylic alcohol 25 with methyl
chloroformate in the presence of pyridine at 0 °C gave
26 in an 88% yield. Palladium-catalyzed coupling of 26
with the (Z)-vinylstannane, (1,1-dimethylethyl)(dimeth-
yl){[(5Z)-6-(tributylstannanyl)hex-5-enyl]oxy}silane, in
Application of the modified Rubottom oxidation proto-
col to 15 with tert-butyldimethylchlorosilane in the pres-
ence of NHMDS followed by osmium tetroxide in the
presence of a stoichiometric amount of N-methylmorpho-
line oxide gave the secondary a-alcohol 16 in a 65% yield
as a single diastereomer.8
With a-hydroxylated cyclohexanone in hand, we next
examined its conversion to the tetracyclic N,O-acetal.
O
O
O
a
b
c
d
e
OBn
OBn
O
O
H
O
O
H
O
O
CO2Et
CN
11
OTBDMS
CO2Et
OH
OH
H
CO2Et
CN
CN
10
15
CN
CN
14
12
13
HO
O
O
O
O
O
H
H
TBDMSO
HO
TBDMSO
N
f
g
h
OBn
OBn
OBn
OBn
OBn
OBn
H
H
CN
CN
17
16
18
Scheme 2. Reagents and conditions: (a) CH2(CN)CO2Et, NaOEt, EtOH, rt, 80%; (b) o-C6H4(CH2OH)2, p-TsOH, benzene, reflux, 99%; (c) (i)
HCHO, K2CO3, THF, rt, 99%; (ii) TBDMSCl, imidazole, DMF, rt, 99%; (d) (i) LiBH4, Et2O–EtOH, reflux, 95%; (ii) TBAF, THF, rt, 99%; (e) (i)
BnBr, NaH, DMF, rt, 95%; (ii) PPTS, acetone–H2O, reflux, 98%; (f) (i) TBDMSCl, NHMDS, THF, rt 96%; (ii) OsO4, NMO, MeCN–H2O, rt, 65%;
(g) (i) HO(CH2)2OH, TMSCl, CH2Cl2, rt, 83%; (ii) TBDMSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 99%; (h) (i) DIBAL-H, CH2Cl2, 0 °C, 82%; (ii)
o-(OH)C6H4CHO, NaBH4, MeOH, rt, 96%.

Y. Yoshimura et al. / Tetrahedron Letters 47 (2006) 3489–3492
3491
18
already established the ABC-ring construction starting
from 4-hydroxycyclohex-2-en-1-one, our future studies
will be focused on the construction of a 15-membered
macrocycle (D-ring) for the total synthesis of madang-
amine A.
a
O
HO
OBn
H
HO
BnO
N
N
+
O
OBn
OBn
Acknowledgements
OH
19
20
This work was partly supported by a Grant-in-Aid for
Science Research from the Japan Society for the Promo-
tion of Sciences.
a
b
OBn
NH
OBn
BnO
BnO
c
N
References and notes
OH
OH
OH
22
21
1. Kong, F.; Andersen, R. J.; Allen, T. M. J. Am. Chem. Soc.
1994, 116, 6007–6008.
2. Kong, F.; Graziani, E. I.; Andersen, R. J. J. Nat. Prod.
1998, 61, 267–271.
3. Matzanke, N.; Gregg, R. J.; Weinreb, S. M.; Parvez, M.
J. Org. Chem. 1997, 62, 1920–1921.
Scheme 3. Reagents and conditions: (a) 3 M HCl, MeOH, reflux, 51%
for 19 from 18, 42% for 20 from 18, 65% for 19 from 20; (b) LiAlH4–
AlCl3, Et2O, rt, 84%; (c) H2, Pd(OH)2, MeOH–THF, rt, 50%, 98%
based on recovered 21.
´ ´
4. Tong, H.-M.; Martin, M.-T.; Chiaroni, A.; Benechle, M.;
the presence of lithium chloride in DMF led to the
skipped diene 27 as a single stereoisomer.13 It is note-
worthy that the (Z)-geometry of the starting material
was clearly retained in the product as (Z)-exo olefin
Marazano, C. Org. Lett. 2005, 7, 2437–2440.
5. Yamazaki, N.; Suzuki, H.; Kibayashi, C. J. Org. Chem.
1997, 62, 8280–8281; Suzuki, H.; Yamazaki, N.; Kiba-
yashi, C. Tetrahedron Lett. 2001, 42, 3013–3015.
6. Yamazaki, N.; Kusanagi, T.; Kibayashi, C. Tetrahedron
Lett. 2004, 45, 6509–6512.
7. For other methods of synthesis of 11 see: Macquarrie, D.
J. Tetrahedron Lett. 1998, 39, 4125–4128; Subba Rao, Y.
V.; De Vos, D. E.; Jacobs, P. A. Angew. Chem., Int. Ed.
1997, 36, 2661–2663; Manickam, G.; Sundararajan, G.
Tetrahedron 1999, 55, 2721–2736; Ranu, B. C.; Saha, M.;
Bhar, S. Synth. Commun. 1997, 27, 621–626.
3
via the g-allylpalladium intermediate.13 Deprotection
of the TBDPS group from 27 by treatment of TBAF
gave the primary alcohol 28 in a 97% yield. Finally,
the 11-membered ring was constructed by a sequential
reaction involving oxidation of 28 with Dess–Martin
periodinane followed by deprotection of the Boc group
with trifluoroacetic acid and intramolecular reductive
amination giving rise to the expected tricyclic product
29 in a 35% yield over three steps. The product thus
obtained exhibited the satisfactory spectral data
(Scheme 4).14
8. The configuration and conformation of 16 were deter-
mined by the coupling constants and NOESY spectra as
shown below:
NOE
In summary, an efficient construction of the madang-
amine tricyclic ring, 4-azatricyclo[11.2.2.04,14]heptadec-
12-ene, including an 11-membered macrocycle has been
accomplished via construction of the morphan skeleton
by N,O-acetalization of a cyclohexanone derivative,
geometry-retained cross-coupling reaction, and intra-
molecular reductive amination. Because we have
H
H
11.8 Hz
NOE
H
H
H
OH
O
R
H
H
H
NOE
CN
OBn
OBn
R =
16
OBn
OBn
OBn
OBn
Boc
Boc
Boc
Boc
BnO
BnO
BnO
BnO
d
N
a
N
b
c
N
N
22
CO2Me
CO2Me
24 (Z/E = 11:1)
O
O
OH
23
25
26
OH
OTBDPS
OBn
N4
OBn
OBn
BnO
Boc
e
Boc
f
g
BnO
BnO
N
N
1
14
29
28
27
Scheme 4. Reagents and conditions: (a) (i) (Boc)2O, 1 M NaOH, dioxane, rt, quant; (ii) Dess–Martin periodinane, CH2Cl2, rt, 99%; (b)
(CF3CH2O)2P(@O)CH2CO2Me, KHMDS, 18-crown-6, THF, rt, 83%, Z/E = 11:1; (c) DIBAL-H, CH2Cl2, À78 °C, 85%; (d) ClCO2Me, pyridine,
CH2Cl2, 0 °C, 88%; (e) (Z)-Bu3SnCH@CH(CH2)4OTBDPS, Pd(dba)2, LiCl, DMF, rt, 92%; (f) TBAF, THF, rt, 97%; (g) (i) Dess–Martin
periodinane, CH2Cl2, rt; (ii) TFA, CH2Cl2, rt; (iii) NaBH(OAc)3, MeOH–THF, rt; 35% from 28.

3492
Y. Yoshimura et al. / Tetrahedron Letters 47 (2006) 3489–3492
9. During acetalization by acidic treatment (TMSCl–ethyl-
J = 12.4 Hz), 3.52 (2H, s), 3.68 (1H, 1/2ABq, J =
15.4 Hz), 3.77 (1H, 1/2ABq, J = 15.4 Hz), 3.765 (1H, s),
3.773 (1H, s), 4.14 (1H, s), 4.43–4.58 (4H, m), 6.85–6.92
(2H, m), 6.98 (1H, t, J = 7.1 Hz), 7.13 (1H, t, J = 7.4 Hz),
7.24–7.33 (10H, m); 13C NMR (100.6 MHz, CDCl3) d 21.4
(CH2), 28.1 (CH2), 30.0 (CH2), 32.1 (CH), 41.4 (C), 48.8
(CH2), 56.4 (CH2), 64.4 (CH2), 71.1 (CH2), 72.1 (CH2),
73.2 (CH2), 73.4 (CH2), 88.2 (C), 117.0 (CH), 120.6 (C),
120.8 (CH), 126.6 (CH), 127.4 (five carbons, CH), 127.5
(CH), 128.0 (CH), 128.25 (two carbons, CH), 128.30 (two
carbons, CH), 150.6 (C). Compound 22: 1H NMR
(400 MHz, CDCl3) d 1.65–1.92 (9H, m), 2.01–2.12 (1H,
m), 2.82–2.92 (3H, m), 3.38 (1H, 1/2ABq, J = 8.8 Hz),
3.41 (1H, 1/2ABq, J = 8.8 Hz), 3.62 (1H, 1/2ABq,
J = 8.9 Hz), 3.71 (1H, 1/2ABq, J = 8.9 Hz), 3.91 (1H, s),
4.48 (2H, s), 4.51 (1H, 1/2ABq, J = 12.2 Hz), 4.55 (1H,
1/2ABq, J = 12.2 Hz), 7.24–7.33 (10H, m); 13C NMR
(100.6 MHz, CDCl3) d 22.9 (CH2), 25.1 (CH2), 28.7 (CH),
30.2 (CH3), 40.6 (C), 45.4 (CH2), 52.1 (CH), 70.8 (CH2),
70.9 (CH2), 72.5 (CH2), 73.2 (CH2), 73.3 (CH2), 127.36
(two carbons, CH), 127.39 (CH), 127.41 (CH), 127.5 (two
carbons, CH), 128.28 (two carbons, CH), 128.31 (two
carbons, CH), 138.8 (C), 138.9 (C). Compound 29: 1H
NMR (400 MHz, CDCl3) d 1.30–1.52 (7H, m), 1.95–2.17
(8H, m), 2.22–2.29 (1H, m), 2.54–2.58 (1H, m), 2.75 (1H,
d, J = 12.1 Hz), 2.82 (1H, quint, J = 6.8 Hz), 3.00 (1H, s),
3.44 (1H, 1/2ABq, J = 8.0 Hz), 3.48 (1H, 1/2ABq,
J = 8.0 Hz), 3.70 (1H, 1/2ABq, J = 10.0 Hz), 3.80 (1H,
1/2ABq, J = 10.0 Hz), 4.47–4.53 (4H, m), 4.95 (1H, m),
5.32–5.43 (2H, m), 7.23–7.33 (10H, m); 13C NMR
(100.6 MHz, CDCl3) d 25.2 (CH2), 26.3 (CH2), 26.5
(CH2), 26.8 (CH2), 27.0 (CH2), 27.4 (CH2), 28.8 (CH),
32.3 (CH2), 41.8 (C), 53.4 (CH2), 54.9 (CH2), 60.7 (CH),
71.4 (CH2), 72.5 (CH2), 73.1 (CH2), 73.3 (CH2), 125.5
(CH), 127.17 (two carbons, CH), 127.25 (two carbons,
CH), 127.29 (two carbons, CH), 127.9 (CH), 128.16 (two
carbons, CH), 128.19 (two carbons, CH), 134.4 (C), 138.9
(C), 139.2 (C).
ene glycol), no regioisomerization of the a-hydroxy ketone
was observed, but epimerization of carbinol carbon at C-2
occurred to result in a diastereomeric mixture of 17.
10. The configuration of 19 was determined by NOESY
spectra as shown below:
OBn
H
BnO
N
O
H
OH
NOE
H
Selected NOE correlation for 19.
11. An extended reaction time resulted in the cleavage of the
O-benzyl groups.
12. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405–
4408.
13. Valle, L. D.; Stille, J. K.; Hegedus, L. S. J. Org. Chem.
1990, 55, 3019–3023.
14. NMR data for selected compounds: Compound 16: 1H
NMR (500 MHz, CDCl3) d 1.43 (1H, qd, J = 12.9,
3.5 Hz), 1.75 (1H, qd, J = 13.1, 3.3 Hz), 1.91–1.97 (1H,
m), 2.21 (1H, tt, J = 12.7, 3.7 Hz), 2.41–2.47 (2H, m),
2.61–2.67 (1H, m), 3.53 (1H, br s), 3.58 (1H, 1/2ABq,
J = 9.2 Hz), 3.63 (1/2ABq, J = 9.2 Hz), 3.69 (1H, 1/2ABq,
J = 9.2 Hz), 3.74 (1H, 1/2ABq, J = 9.2 Hz), 4.12 (1H, dd,
J = 11.8, 7.1 Hz), 4.49–4.59 (4H, m), 7.27–7.38 (10H, m);
13C NMR (125 MHz, CDCl3) d 24.9 (CH2), 33.9 (CH2),
39.7 (CH), 40.9 (CH2), 47.0 (C), 67.9 (CH2), 68.0 (CH2),
73.6 (CH2), 73.7 (CH2), 74.8 (CH), 119.3 (C), 127.7 (two
carbons, CH), 127.8 (two carbons, CH), 128.1 (two
carbons, CH), 128.6 (four carbons, CH), 137.0 (C),
137.1 (C), 209.0 (C). Compound 19: 1H NMR
(400 MHz, CDCl3) d 1.48–1.92 (5H, m), 2.21–2.32 (2H,
m), 2.65 (1H, 1/2 ABq, J = 12.4 Hz), 3.16 (1H, 1/2ABq,