Biomimetic total synthesis of (-)-erinacine E

Article abstract of DOI:10.1021/ja7102795

Biomimetic total synthesis of (-)-erinacine E (1) has been achieved starting from the enantiopure key intermediate, which was prepared via the convergent approach developed by us. The crucial step in this synthesis is an intramolecular aldol reaction driven by the 1,2-migration of a benzoyl group within a compound that was rationally designed to prevent the retro-aldol reaction, thereby successfully providing the strained skeleton of 1. Considering the structure of a putative biosynthetic intermediate, striatal A, the intramolecular aldol reaction driven by the C4′ acetyl group could be involved in the biosynthesis of 1. This acyl group migratory ring-closing reaction could be applied to the synthesis of other strained molecules. Copyright

Full text of DOI:10.1021/ja7102795

Published on Web 01/09/2008
Biomimetic Total Synthesis of (-)-Erinacine E
Hideaki Watanabe and Masahisa Nakada*
Department of Chemistry and Biochemistry, AdVanced School of Science and Engineering, Waseda UniVersity,
3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan
Received November 13, 2007; E-mail: mnakada@waseda.jp
In 1996, (-)-erinacine E (1) (Figure 1) was reported to be a
strong stimulator of nerve growth factor (NGF) synthesis from the
mycelia of Hericium erinaceum whose fruiting bodies have been
known as Chinese medicine or food.1 Two years later, a Pfizer
research group isolated 1 from a different source, the fermentation
broth of Hericium ramosum CL24240, and disclosed that 1 was a
potent, highly selective κ-opioid receptor agonist.2
Single-crystal X-ray crystallographic analysis unambiguously
elucidated the absolute structure of 1.1 Its unique hexacyclic ring
system includes ten stereogenic centers as well as a 5-6-7 tricyclic
cyathane skeleton, which is fused with a highly oxygenated tricyclic
2,9-dioxatricyclo[5.2.2.04,10]undecane system. These structural fea-
tures make 1 a strained and largely different compound compared
with other cyathane diterpenoids and erinacines.3
Since striatals, exemplified as striatal A (2) and striatal D (3),
and (-)-erinacine P (4) (Figure 1) have been isolated,4 it was
proposed that the C-C bond-forming reaction a (Scheme 1)
between the C2′ and C13 positions of keto aldehyde 6, which could
be derived from 4, could provide striatals, and subsequent intramo-
(-)-erinacine P (4), and (-)-erinacine B (5).
lecular aldol reaction b (Scheme 1) between the C4′ and C15
Figure 1. Structures of (-)-erinacine E (1), striatal A (2), striatal D (3),
Scheme 1. Proposed Biosynthesis of Erinacines and Striatals
positions could yield erinacines. However, to the best of our
knowledge, none of these transformations have been reported.5
The complex structure, significant biological activity, and
biogenesis of 1 are features that make it a fascinating target.
Nevertheless, although enantioselective total syntheses of (+)-
erinacine A,6 (-)-erinacine B (5),7 and some cyathane diterpenoids8
have been published, the total synthesis of 1 has not been reported.
Since we had already achieved the enantioselective total synthesis
of 5 via enantiopure alcohol 7 (Scheme 2),7 we investigated the
provide the initial aldol product 19, in which the benzoyl group
enantioselective total synthesis of 1 via alcohol 7 and report herein
the biomimetic total synthesis of 1.
could migrate to the secondary C15 hydroxyl to provide stable
ketone 20, which would not revert to ketone 17.
We first examined the glycosylation of alcohol 7 with thiogly-
coside 89 (Scheme 2). The glycosylation with MeOTf7,10 success-
fully provided glycoside 9 in 84% overall yield with high selectivity
(R/â ) 1/14) using the recycling technique.11,12 Deprotection of
glycoside 9 afforded diol 10 and subsequent Swern oxidation
provided keto aldehyde 11, which was found to be gradually
converted in situ to ketone 12 as the sole product, probably due to
the catalysis by Et3N.12
We anticipated that the aldol reaction of ketone 12 would be
difficult to achieve because the product was energetically unfavor-
able owing to its strained structure and would easily undergo a
retro-aldol reaction. Indeed, despite extensive studies, the aldol
reaction of ketone 12 under any conditions resulted in no reaction
or in decomposition,13 suggesting that this process needed an
exceptional procedure to provide the product.
Deprotection of ketone 12 caused decomposition under any
conditions, hence, ketone 17 was prepared from diol 10 (Scheme
3). Deprotection of diol 10 provided tetraol 13, which was
monoprotected with a TES group to provide a separable mixture
of TES ethers 14 and 15. Recycling TES ether 15 to tetraol 13 was
successfully achieved. Selective benzoylation of TES ether 14,
subsequent deprotection of the C15 TES group, and Swern oxidation
of the resultant diol to keto aldehyde 16, followed by in situ
cyclization/elimination gave ketone 17 directly.
Initial attempts of the intramolecular aldol reaction of ketone
17 using bases containing a metal cation (t-BuOK, LiBr/Et3N,
CsCO3)13 resulted in no reaction or decomposition. However, DBU
effectively provided a product in 85% yield, and the detailed NMR
studies12 of the product confirmed its structure as ketone 20, proving
that the aldol reaction of ketone 17 proceeded as expected with
concomitant 1,2-migration of the benzoyl group.
Considering the structure of 2, a proposed biosynthetic inter-
mediate of 1, we were inspired by the acetyl group at the C4′
position and we decided to examine the aldol reaction of ketone
17 possessing a benzoate at the C4′ position (Scheme 3).14 Thus,
we conceived that the enolate 18 generated from ketone 17 would
Reduction of ketone 20 with NaBH4 occurred as anticipated at
the less hindered side to provide alcohol 21,12 which was depro-
tected to afford diol 22. Mitsunobu reaction of alcohol 22 did not
proceed; hence, the oxidation and stereoselective reduction sequence
9
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J. AM. CHEM. SOC. 2008, 130, 1150-1151
10.1021/ja7102795 CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Enantioselective Synthesis of 12a
16
several attempts, the reduction with Me4NBH(OAc)3 was found
to provide the desired 1,2-reduction product as a single isomer,
which was identical to the natural product 1 in all respects (1H
NMR, IR, MS, [R]D, and 13C NMR).1
In summary, highly stereoselective total synthesis of 1 has been
achieved in 12 steps from the enantiopure alcohol 7. The intramo-
lecular aldol reaction of ketone 17, driven by the rationally designed
1,2-migration of a benzoyl group, is the crucial step in this synthesis
that effectively prevented the retro-aldol reaction and permitted the
successful construction of the strained skeleton of 1. Considering
the structure of a putative biosynthetic intermediate 2, striatal A,
the intramolecular aldol reaction driven by the C4′ acetyl group
could be involved in the biosynthesis of 1. This acyl group
migratory ring-closing reaction would be applicable to the synthesis
of other strained molecules.
Acknowledgment. This work is dedicated to Emeritus Professor
Masaji Ohno (University of Tokyo, Japan) on the occasion of his
77th birthday. We thank Professor Yoshikazu Kawagishi (Shizuoka
a
Conditions: (a) MeOTf, Et2O, MS 4 Å, room temp, 1 d, 84% (one
recycling), (R/â ) 1/14); (b) TBAF, NH4Cl, room temp, 12 h; (c) DMSO,
(COCl)2, CH2Cl2, -78 °C, 2 h, then Et3N, room temp, 12 h, 80% (two
steps).
University, Japan) for kindly giving us copies of 1H NMR and 13
C
NMR of (-)-erinacine E. This work was financially supported in
part by a Waseda University Grant for Special Research Projects,
a Grant-in-Aid for Scientific Research on Priority Areas (No.
17035082), Young Scientists (No. 18850023), and the Global COE
program “Center for Practical Chemical Wisdom” by MEXT.
Scheme 3. Biomimetic Total Synthesis of 1a
Supporting Information Available: Complete ref 2. Experimental
and characterization details. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(1) Kawagishi, H.; Shimada, A.; Hosokawa, S.; Mori, H.; Sakamoto, H.;
Ishiguro, Y.; Sakemi, S.; Bordner, J.; Kojima, N.; Furukawa, S. Tetra-
hedron Lett. 1996, 37, 7399-7402.
(2) IC50 values of 1 in the binding experiments of [3H] CI-977, [3H] DAGO,
and [3H] DPDPE (1 nM) to guinea pig brain membrane were 0.8 µM,
>200 µM, and >200 µM, respectively. For the details, see: Saito, T.; et
al. J. Antibiot. 1998, 51, 983-990.
(3) Recently isolated erinacines: Kawagishi, H.; Masui, A.; Tokuyama, S.;
Nakamura, T. Tetrahedron 2006, 62, 8463-8466. For examples of
erinacines isolated before this report, see ref. 7.
(4) (a) Anke, T.; Oberwinkler, F. J. Antibiot. 1977, 30, 221-225. (b) Hecht,
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(6) (+)-Erinacine A: (a) Snider, B. B.; Vo, N. H.; O’Neil, S. V.; Foxman,
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(8) Enantioselective total synthesis of cyathane diterpenoids. (+)-Allocyathin
B2: (a) Takano, M.; Umino, A.; Nakada, M. Org. Lett. 2004, 6, 4897-
4900. (b) Trost, B. M.; Dong, L.; Schroeder, G. M. J. Am. Chem. Soc.
2005, 127, 2844-2845. (c) Trost, B. M.; Dong, L.; Schroeder, G. M. J.
Am. Chem. Soc. 2005, 127, 10259-10268. (+)-Cyanthiwigin U: (d)
Pfeiffer, M. W. B.; Phillips, A. J. J. Am. Chem. Soc. 2005, 127, 5334-
5335. (-)-Scabronine G: (e) Waters, S. P.; Tian, Y.; Li, Y.-M.;
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(9) For preparation of thioglycoside 8, see Supporting Information.
(10) Lo¨nn, H. J. Carbohydr. Chem. 1987, 6, 301-306.
a
Conditions: (a) TFA, CH2Cl2, -20 °C, 2 h, 93% from 9; (b) TESCl,
Et3N, CH2Cl2, 0 °C, 2 h, 14 (44%), 15 (44%); (c) HF‚Py, 0 °C to room
temp, 1 h, 98%; (d) Bz2O, Et3N, DMAP (catalyst), CH2Cl2, 0 °C, 5 h,
92%; (e) 10% citric acid, saturated NH4Cl, THF, room temp, 1.5 h, 91%;
(f) DMSO, (COCl)2, CH2Cl2, -78 °C, 2 h, then Et3N, room temp, 12 h,
93%; (g) DBU, C6H6, room temp, 2 h, 85%; (h) NaBH4, MeOH, -78 °C
to 0 °C, 1 h; (i) K2CO3, MeOH, room temp, 2 h, 96% (two steps); (j) IBX,
CH2Cl2, DMSO, room temp, 2 h; (k) Me4NBH(OAc)3, AcOH, CH3CN,
0 °C, 30 min, 70% (two steps).
(11) The glycosylation for 2 days afforded glycoside 9 in 73% yield (R/â )
1/7), but the reaction after 1 day gave glycoside 9 in 55% yield (R/â )
1/14) and recycling a recovered mixture of alcohol 7 and thioglycoside 8
provided glycoside 9 in 29% yield (R/â ) 1/14).
(12) See Supporting Information for the detail.
(13) Stabilizing the product with a metal chelate was very effective in the total
syntheses of (-)-erinacine B7 and (+)-allocyathin B2,8a but this method
was fruitless in this synthesis.
(14) A benzoyl group was used because of its stability.
was investigated. o-Iodoxybenzoic acid (IBX) oxidation15 of alcohol
22 provided the desired enone, but reduction of the enone with
most reducing reagents resulted in decomposition or only provided
the 1,4-reduction product, probably due to its s-cis structure. After
(15) Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019-8022.
(16) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc. 1988,
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