Short synthetic route toward the tricyclic core of schulzeines

Article abstract of DOI:10.1246/cl.2006.1008

The tricyclic core of marine natural products schulzeines was synthesized using N-acyliminium ion cyclization. The intermediate N-acyliminium ion was generated from treatment of α-hydroxy-δ-lactam with a Lewis acid. The tricyclic products were obtained as

Full text of DOI:10.1246/cl.2006.1008

1008
Chemistry Letters Vol.35, No.9 (2006)
Short Synthetic Route toward the Tricyclic Core of Schulzeines
Punlop Kuntiyong,ꢀ Sunisa Akkarasamiyo, and Gedsirin Eksinitkun
Department of Chemistry, Faculty of Science, Silpakorn University,
Rajamanka Nai Rd., Muang Nakhon Pathom 73000, Thailand
(Received May 16, 2006; CL-060576; E-mail: punlop@su.ac.th)
The tricyclic core of marine natural products schulzeines
8
7a
HO
OSO3Na
6
was synthesized using N-acyliminium ion cyclization. The inter-
mediate N-acyliminium ion was generated from treatment of ꢀ-
hydroxy-ꢁ-lactam with a Lewis acid. The tricyclic products were
obtained as a mixture of 2 diastereomers at the C-11b stereocen-
ter. The diastereomeric ratios were low and dependent on the
Lewis acid used in the reaction.
N
11b
O
R
O
NaO3SO
11
OH
1
N
H
3
OSO3Na
Figure 1. Schulzeines A (1) R = CH3, B (2) R = 11b-epi-
schulzeine C, C (3) R = H.
Schulzeines are a new class of marine natural products, iso-
lated from a marine sponge, Penares schulzei (Figure 1). They
exhibit potent ꢀ-glucosidase inhibitory effects making them
promising leads for drug development for diseases such as can-
cers, diabetes, and viral infections.1
The structure of schulzeines can be divided into two major
components, namely, the tricyclic core 4 containing tetrahydro
isoquinoline fused with ꢁ-lactam and the C28 fatty acid side
chain 5. The tricyclic core bears two stereogenic centers at
C-3 and C-11b. The stereocenter at C-3 is assigned as S in all
members of this family whereas schulzeines A and C have 11b
R, and schulzeine B has 11b S configuration. The C28 fatty acid
side chain of schulzeines bear three stereogenic centers at C-14,
C-17, and C-18 as sodium sulfate salts with the configurations
assigned as S, S, S. Schulzeine A has an extra stereogenic center
at C-20 bearing a methyl substituent.
and L-glutamic acid derivatives (Scheme 1).
2-(3,5-Dimethoxyphenyl)ethylamine (9) was prepared in a
straightforward fashion in 5 steps from 3,5-dihydroxybenzoic
acid. Amide formation of this amine with 5-benzyl-N,N-diben-
zyl-L-glutamate gave amide–ester 11. Initially, we planned to
reduce the benzyl ester to the corresponding primary alcohol.
We envisioned that oxidation of such alcohol would give an
ꢀ-hydroxy-ꢁ-lactam. Treatment of this intermediate with a
Lewis acid should give an N-acyliminium ion which should
promptly cyclize to give the tricyclic product with a certain
level of diastereoselectivity induced by the existing stereogenic
center. However, a reaction of this compound with lithium
aluminum hydride in THF at 0 ꢁC gave imide 12 in 53% yield.
This apparently resulted from abstraction of the amide’s N–H
proton by LAH and subsequent attack to the benzyl ester carbon-
yl. The corresponding alcohol from reduction of the benzyl ester
was not detected (Scheme 2).
Retrosynthetically, the tricyclic core of schulzeines can be
derived from cyclization of N-acyliminium ion 6.2 This in turn
can be synthesized from 2-(3,5-dihydroxyphenyl)ethylamine
However, there are several precedents where addition of a
nucleophile to an unsymmetrical imide delivers ꢀ-hydroxylac-
tam intermediate with good regiocontrol. Sodium borohydride
in ethanol gives a reduction product in which a more hindered
carbonyl group is reduced3 whereas DIBALH in toluene gives
the complimentary product.4 Thus treatment of imide 12 with
DIBALH in toluene at ꢂ78 ꢁC gave ꢀ-hydroxy-ꢁ-lactam 13 in
HO
OSO3Na
N
O
O
NaO3SO
OH
N
H
OSO3Na
.
3
a good yield. This compound was treated with BF3 OEt2 in di-
chloromethane to give tricyclic cores 14 and 15 of schulzeines as
MeO
NH2
MeO
OP
NBn2
PO
+
DCC, DMAP
HN
N
O
O
PO
*
9
OMe
+
O
OMe
CH2Cl2
63%
O
OP
11
HO
O
O
NH2
OBn
5
OP
4
LAH/THF
NBn2
53%
BnO
OH
NBn2
10
NRR'
PO
HO
NH2
O
O
PO
N
7
MeO
N
OP
O
O
O
OP
6
OMe
OH
12
NH2
8
Scheme 2. Amide 11 formation and subsequent reaction with
lithium aluminum hydride.
Scheme 1. Retrosynthetic analysis of schulzeines.
Copyright Ó 2006 The Chemical Society of Japan

Chemistry Letters Vol.35, No.9 (2006)
1009
chains of schulzeines is well underway in our laboratory. The
completion of these fatty acids and their union with the tricyclic
core to give the complete skeleton of schulzeines will be report-
ed in due course.
MeO
DIBALH , MeO
toluene
-78°C
O
N
O
HO
OMe
13
N
O
OMe
75%
NBn2
NBn2
12
PK would like to thank Prof. Boonsong Kongkathip, Prof.
Pittaya Tuntiwachwuttikul, and Prof. Surachai Nimgirawath
for helpful discussions and guidance. Dr. Somkiat Thadaniti is
acknowledged for assistance with NMR experiments. Mrs. Panit
Vedchakanchana is acknowledged for assistance with GC-MS
analysis. Financial supports are provided by the Thailand Re-
search Fund (TRF) and National Science and Technology Devel-
opment Agency (NSTDA) of Thailand.
Lewis acid CH2Cl2, 0°C
MeO
MeO
H
H
N
O
N
O
OMe
OMe
NBn2
NBn2
14
15
.
BF3 OEt2 84% dr = 1.7 : 1
TMSOTf 95% dr = 2.2: 1
Scheme 3. Reduction of imide 12 with DIBALH and subse-
quent treatment of the ꢀ-hydroxy-ꢁ-lactam with Lewis acids.
References and Notes
1
K. Takada, T. Uehara, Y. Nakao, S. Matsunaga, R. W. M.
van Soest, N. Fusetani, J. Am. Chem. Soc. 2004, 126, 187.
B. E. Maryanoff, H.-C. Zhang, J. H. Cohen, I. J. Turchi, C. A.
Maryanoff, Chem. Rev. 2004, 104, 1431.
MeO
2
MeO
H
H
N
O
H2, Pd/C
MeOH
N
O
3
4
5
N. S. Simpkins, C. D. Gill, Org. Lett. 2003, 5, 535.
W. N. Speckamp, H. Hiemstra, Tetrahedron 1985, 41, 4367.
NOESY experiment shows correlation between H-11b
and H-3 in 14. The 1D NOE difference experiments also
show signal enhancement of H-3 (ꢁ 3.55 ppm) when H-11b
(ꢁ 4.57 ppm) was irradiated.
OMe
14/15
OMe
PhCOCl,py,
NBn2
NH2
16
CH2Cl2, 0°C
94% (2 steps)
MeO
MeO
H
H
N
N
O
O
O
O
OMe
OMe
N
H
N
H
H
17
H
18
17:18 ca. 2 : 1 separable by flash chromatography
Scheme 4. Debenzylation of 14 and 15 and their conversion to
benzamide derivatives 17 and 18.
an inseparable mixture of two diastereomers at the C-11b. The
1
diastereomeric ratio was determined to be 1.7:1 from H NMR
data. The configuration at C-11b of the major diastereomer 14
is assigned as S according to the NOESY experiment of the prod-
uct mixture which shows correlation between the H-11b and H-3
indicating their cis relationship.5 This correlation is absent in the
minor diastereomer 15. The diastereomeric ratio of the products
showed some dependence on the nature of the Lewis acid used in
this reaction where TMSOTf gave slightly better selectivity of
2.2:1 (Scheme 3).6,7
Our initial hypothesis was that the aromatic moiety of the
molecule would approach the N-acyliminium ion from the oppo-
site face to the N,N-dibenzylamino substituent leading to the
product 15 with 11b R configuration as the major diastereomer.
However, the observed selectivity in favor of 14 does not support
this speculation. The two diastereomers at C-11b can be separat-
ed by flash column chromatography after conversion to their
benzamide derivatives 17 and 18 (Scheme 4).
6
7
Y. S. Lee, D. J. Cho, S. N. Kim, J. H. Choi, H. Park, J. Org.
Chem. 1999, 64, 9727.
Data for 14: H NMR (CDCl3, 300 MHz) ꢁ 7.20–7.50 (m,
1
Ph ꢃ 2), 6.34 (d, J ¼ 2:0, H-10), 6.29 (d, J ¼ 2:1, H-8),
4.85 (dd, J ¼ 10:3, 3.9, H-6ꢀ), 4.57 (dd, J ¼ 10:9, 3.2,
H-11b), 4.26 (d, J ¼ 14:6, N-CH2-Ph), 3.89 (d, J ¼ 14:6,
N-CH2-Ph), 3.81 (s, O-CH3), 3.79 (s, O-CH3), 3.55 (dd,
J ¼ 9:9, 9.1, H-3), 2.78 (m, H-6ꢂ), 2.72 (m, H-7), 2.35
(m, H-1ꢀ), 2.17 (m, H-2ꢂ), 1.90 (m, H-2ꢀ), 1.40 (m,
H-1ꢂ); 13C NMR (CDCl3, 75 MHz) ꢁ 172.5 (C-4), 159.2
(Ph), 157.5 (C-9), 157.0 (C-11), 141.2 (C-11a), 137.6
(C-7a), 128.4 (Ph), 128.1 (Ph), 126.6 (Ph), 104.3 (C-10),
96.9 (C-8), 56.7 (C-3), 55.3 (OCH3), 55.2 (OCH3), 49.6
(C-11b), 38.1 (C-6), 29.5 (C-7), 29.3 (C-1), 23.6 (C-2);
HRMS (ES) m/z 457.2487, calcd for C29H33N2O3 m/z
457.2491 (M + H)þ.
In summary, we have synthesized the tricyclic core of schul-
zeines. Albeit low diastereoselectivity was achieved, each dia-
stereomer can be proceeded to make the natural products. The
rationale for the selectivity is not clear to us at the moment
and is being investigated. The synthesis of C28 fatty acid side
8
Full experimental procedures and spectroscopic data of
compounds 11, 12, 13, 14, 15, 17, and 18 are provided.
This material is available free of charge at www.csj.jp/
journals/cl/.
Published on the web (Advance View) July 29, 2006; doi:10.1246/cl.2006.1008