Synthetic studies on sugar-fused erinacincs

Article abstract of DOI:10.1039/b503406j

The construction of the central 6-7-6 core ring system that exists in sugar-fused erinacines by an efficient samarium-mediated radial cyclization was investigated. It was observed that the samarium-mediated 7-endo-trig radial cyclization afforded excellen

Full text of DOI:10.1039/b503406j

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C O M M U N I C A T I O N
Synthetic studies on sugar-fused erinacines
Ayato Sato,a Tomoya Masuda,a Hirokazu Arimoto*a,b,c and Daisuke Uemuraa,b
a Department of Chemistry, Graduate School of Science, Nagoya University, Chikusa, Nagoya,
464-8602, Japan. E-mail: arimoto@biochem.tohoku.ac.jp; Fax: +81 52 789 5041;
Tel: +81 52 789 2479
b Institute for Advanced Research, Nagoya University, Chikusa, Nagoya, 464-8602, Japan
c PRESTO, JST, Chikusa, Nagoya, 464-8602, Japan
Received 8th March 2005, Accepted 20th April 2005
First published as an Advance Article on the web 4th May 2005
Samarium-mediated 7-endo-trig radical cyclization af-
forded excellent stereocontrol of the four contiguous asym-
metric centers present in the 6-7-6 tricyclic cores of the
(sugar-fused) erinacines E, F, and G.
7-membered ring, which possesses four contiguous asymmetric
centers.
Our synthetic plan is outlined in Scheme 1. Disconnection at
the C13–C14 bond of 4 gives the ald-enone 5, a key precursor in
our study. We chose samarium-mediated radical cyclization for
this transformation.7,8 Only a few examples of 7-endo-trig radical
cyclization have been reported,9 but we predicted that its mild
reaction conditions would be suitable for polyfunctionalized
target molecules.
Our synthesis commenced with chemoselective reduction of 6
(96% ee) (Scheme 2).10 Swern oxidation of the resulting primary
alcohol gave an aldehyde with a syn relative configuration. Treat-
ment of the syn-aldehyde with DBU afforded an equilibrium
mixture of aldehydes (syn : anti = 1 : 1). The desired anti-
isomer 7 was isolated, and the recovered syn-isomer was treated
again. After two cycles of these processes, 7 was obtained in 70%
yield. The anti-isomer 7 was then converted into homologated
aldehyde 8 by a Wittig reaction and hydrolysis of the resulting
enol ether without any epimerization at C-5. The installation of
2-cyclohexen-1-one with the Morita–Baylis–Hillman reaction11
proved to be more difficult than anticipated. Numerous reaction
The erinacines were isolated by Kawagishi from myceria of
the fungus Hericium erinaceum, as potent stimulators of nerve
growth factor (NGF) synthesis.1 Erinacines E 1, F 2, and G
32 share carbocyclic E-rings that are not seen in other cyathan
diterpenes,3 thus constituting a unique subgroup among the eri-
nacine family (Fig. 1). These E-rings are probably biosynthesized
by fusion of a sugar unit with a diterpenoid aglycon (cyathan
skeleton). In 1998, Saito et al. investigated erinacine E 1 from
the fermentation broth of a basidiomycete (Hericium ramosum
CL24240), and that it had j-opioid receptor agonist activity.4
Despite their intriguing structure and biological activities, no
synthetic studies have focused on the substructural family
containing erinacines E, F, and G.5,6 We report here the efficient
construction of the common 6-7-6 tricyclic core 4. A notable
challenge in this synthesis was the construction of the central
Scheme 2 Reagents and conditions: a) i) i-BuOCOCl, Et3N, Et2O; ii)
NaBH4, THF, 87% (2 steps); b) (COCl)2, DMSO; Et3N, CH2Cl2, 90%;
c) DBU, MeOH; d) separation of isomers, 70% of 7 after 2 cycles; e)
t-BuOK, MeOCH2PPh3Cl, toluene, 68%; f) TFA, THF–H2O (1 : 1),
94%; g) 2-cyclohexen-1-one, DBU, Et2O–MeOH (9 : 1), 47% for 9a and
47% for 9b; h) TBSOTf, 2,6-lutidine, CH2Cl2, 78% from 9a and 82%
˚
from 9b; i) DIBAL, toluene; j) TPAP, NMO, 4 A MS, CH2Cl2, 66% for
5a and 81% for 5b.
Fig. 1 Sugar-fused erinacines.
Scheme 1 Synthetic plan.
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
T h i s j o u r n a l i s
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 2 3 1 – 2 2 3 3
2 2 3 1
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systems were surveyed, and finally, aldehyde 8 and 2-cyclohexen-
1-one were treated with DBU in Et2O–MeOH, and the desired
product 9 was obtained in 94% yield. The use of MeOH as a
co-solvent was found to be essential, with 9 being obtained in
poor yield (<30%) in the absence of MeOH. Diastereomeric
secondary alcohols 9a and 9b12 were protected as their tert-
butyldimethylsilyl ethers. Reduction of the tert-butyl ester and
the enone moiety, followed by oxidation of the resulting diol
with TPAP, gave ald-enones 5a and 5b, respectively.
The stereochemical outcomes of the 7-endo-trig radical cy-
clization of 5b might be explained as follows (Scheme 5). The
cyclization from intermediate I leads to a cis arrangement be-
tween the newly formed hydroxy group at C-14 and the hydrogen
atom at C-13. This process is preferable to approach III, which
suffers from repulsion between Me-16, H-10, and H-13. The
resulting samarium enolate is protonated stereoselectively to
afford thermodynamically more stable 4 as a single isomer.
With the key precursor 5 in hand, we attempted the samarium-
mediated radical cyclization. With ald-enone 5b as a starting
material, the cyclization reaction proceeded smoothly to give
4 in 86% yield as a single diastereomer. Structural assignment
of cycloadduct 4 was initially obtained through 1H-NMR, 13C-
NMR, COSY, HMBC, and HOHAHA experiments, and these
spectra showed that 4 has the 6-7-6 tricyclic core as a platform.
The NOE correlations between H-12 and Me-16, and H-12 and
H-14 indicated that both H-12 and H-14 protons are oriented
in an a configuration. The 12, 13-trans stereochemistry was
assigned on the basis of the coupling constant (J12,13 = 12.8 Hz).
These experiments revealed that compound 4 has the correct
stereochemistry on four contiguous carbons, C-5, C-6, C-14, and
C-13.13 Finally, desilylation of 4 afforded a diol, and acetylation
and subsequent elimination of the resulting acetate afforded 10
with the same configuration of functional groups as in erinacines
E, F, and G (Scheme 3).
Scheme 5
In summary, we have succeeded in constructing the central
6-7-6 core ring system that exists in sugar-fused erinacines by an
efficient samarium-mediated radical cyclization. These synthetic
studies should constitute a firm basis for synthesis of the sugar-
fused erinacine subfamily. Further efforts toward the synthesis
of erinacine E will be reported in due course.
This research was supported in part by the Sasagawa Scientific
Research Grant, a Grant-in-Aid for Scientific Research, and the
21st century COE program (Establishment of COE on Material
Science) from the Ministry of Education, Science, Sports, and
Culture (MEXT), Japan.
Scheme 3 Reagents and conditions: l) SmI2 (20 eq.), THF–t-BuOH,
(100 : 1), 0 C, 2 h, 86%; m) TBAF, AcOH, THF, 67%; n) Ac2O, DBU,
CH2Cl2, 96%.
Unexpectedly, the radical cyclization with ald-enone 5a
failed under the conditions described above. The products
were inseparable mixtures of 13 and 14 (ca. 1 : 1). When
a Lewis-basic additive, HMPA, was added to increase the
reduction potential,14 the sole product was 14 in 76% yield. The
stereochemistry of the newly formed chiral centers at C-15 in 13
and 14 was not determined (Scheme 4).
Notes and references
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Scheme 4 Reagents and conditions: o) SmI2 (20 eq.), THF–t-BuOH
(100 : 1), 0 C, 3.5 h, 76%
2 2 3 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 2 3 1 – 2 2 3 3

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12 The configuration at C-11 in 9a and 9b was confirmed by converting
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13 Compound 4: 1H-NMR (600 MHz, CDCl3) d 5.56 (2H, m, H-8 and
H-9), 4.76 (1H, d, J = 10.8 Hz, OH), 4.69 (1H, d, J = 5.4 Hz, H-11),
3.20 (1H, d, J = 10.8 Hz, H-14), 2.70 (1H, dd, J = 3.0, 16.8 Hz, H-7),
2.49 (1H, d, J = 12.8 Hz, H-12), 2.36 (1H, ddd, J = 1.8, 3.6, 13.8 Hz,
H-4ꢀ), 2.22 (1H, ddd, J = 1.8, 12.8, 13.2 Hz, H-13), 2.20 (1H, m,
H-4ꢀ), 2.16 (1H, m, H-5), 2.05 (1H, dd, J = 3.0, 13.2 Hz, H-2ꢀ), 2.03
(1H, m, H-3ꢀ), 1.99 (1H, m, H-4), 1.86 (1H, m, H-10), 1.83 (1H, m,
H-2ꢀ), 1.69 (2H, m, H-4 and H-3ꢀ), 1.49 (1H, dd, J = 1.8, 16.8 Hz,
H-7), 1.30 (1H, ddd, J = 1.8, 12.6, 13.2 Hz, H-10), 0.94 (3H, s, H-16),
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40.7, 40.6, 39.5, 33.6, 31.7, 29.6, 25.9, 25.8, 18.2, 15.3, −4.80, −4.90;
IR (film, cm−1) 3396, 2929, 1712, 1209, 788, 670, 424; HRMS calcd.
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CHCl3).
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O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 2 3 1 – 2 2 3 3
2 2 3 3