Construction of the CDE-ring framework of erinacine E through a Pummerer-type cyclization

Article abstract of DOI:10.1055/s-2008-1042922

The CDE-ring framework of erinacine E, a potent stimulator against nerve growth factor (NGF) synthesis, was constructed using stereocontrolled Grignard addition, silicon-promoted Pummerer-type cyclization, and ring-closing metathesis as key transformations. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1042922

1086
LETTER
Construction of the CDE-Ring Framework of Erinacine E through a
Pummerer-Type Cyclization
C
onstructiono
h
f
the CDE-R
o
ingFramew
j
orkof
E
i
rinacine
E
Kobayashi,* Akiko Ishii, Masahiro Toyota
Department of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai 599-8531, Japan
Fax +81(72)2549695; E-mail: koba@c.s.osakafu-u.ac.jp
Received 23 January 2008
H
H
Abstract: The CDE-ring framework of erinacine E, a potent stimu-
O
O
O
D
O
lator against nerve growth factor (NGF) synthesis, was constructed
using stereocontrolled Grignard addition, silicon-promoted Pum-
merer-type cyclization, and ring-closing metathesis as key transfor-
mations.
OH
OH
B
H
OH
OH
H
C
H
A
H
H
F
E
H
OH
OH
Key words: erinacine, Pummerer reaction, ring-closing metathesis,
HO
HO
stereoselective addition, cyathane diterpene
erinacine E (1)
erinacine F (2)
(unknown stereochemistry)
H
O
O
Cyathane diterpenes have attracted immense attention
among chemists and biologists alike because of their
unique chemical structures and fascinating biological ac-
tivities involving stimulation of nerve growth factor
(NGF) synthesis.1 Erinacine E (1), erinacine F (2), and er-
inacine G (3) isolated from the cultured myceria of Heri-
cium erinaceum are representative of this family
(Figure 1).2,3 The attractive features of these molecules lie
not only within the complicated chemical structure that in-
volves a five- to seven-membered ring-fused multicyclic
skeleton with ten chiral centers, but also in that erinacine
E exerts selective k-opioid receptor agonistic activity.4
Despite the numerous synthetic endeavors in this area,5–8
only two successful total syntheses have been reported for
the sugar-containing erinacines.5 Total synthesis of penta-
cyclic or hexacyclic cyathanes such as 1, 2, or 3 has never
been achieved.9 We report herein a strategy to form the
central CDE-ring system of erinacine E (1) featuring the
intramolecular Pummerer-type reaction as a key transfor-
mation.
OH
OH
H
O
H
O
H
OH
HO
erinacine G (3)
(unknown stereochemistry)
Figure 1 Structures of erinacine E (1), erinacine F (2), and erinacine
G (3)
intramolecular
acetalization
H
SPh
O
O
D
O
OH
OBn
OMPM
OH
H
C
H
F
H
H
E
OH
O
HO
RCM
HO
O
4
5
intramolecular
Pummerer-type reaction
From a retrosynthetic point of view, the chemically stable
tricyclic O,S-acetal 5 was considered to be a suitable pre-
cursor of the CDEF-ring moiety (4) of 1 and selected as a
prime synthetic target (Scheme 1). We planned to apply
ring-closing metathesis (RCM) for the formation of the C
ring due to its mildness and high chemoselectivity within
polyfunctionalized molecules.10 The requisite O,S-acetal
6 can be prepared through the intramolecular Pummerer-
type reaction,11 although the analogous cyclization to
achieve polysubstituted hydroisobenzofurans has not
been reported. The highly oxygenated nature and demand-
ing stereochemistry of several of the proposed intermedi-
ates required an elaborate protecting group strategy as
well as many stereoselective transformations. Thus, the
SPh
O
O
OEt
OBn
O
OMPM
E
H
O
H
O
O
O
O
O
O
6
7
Scheme 1 Strategy for constructing the CDEF ring moiety (4) of er-
inacine E (1). MPM = p-methoxybenzyl
optically active acetonide-protected methylenecyclohexyl
ethyl carbonate 7,12 which was prepared from D-mannose
via radical cyclization in a stereoselective manner, was
chosen as the starting material.
Sequential protecting group manipulation involving (a)
selective cleavage of the 1,3-acetonide, (b) selective pro-
tection of the primary alcohol as a TBDPS ether, (c)
SYNLETT 2008, No. 7, pp 1086–1090
Advanced online publication: 17.03.2008
DOI: 10.1055/s-2008-1042922; Art ID: U00708ST
x
x.
x
x.
2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

LETTER
Construction of the CDE-Ring Framework of Erinacine E
1087
MOM protection of the secondary alcohol, and (d) meth- The silyl-protected aldehydes 15a and 15b were prepared
anolysis of ethyl carbonate, provided allylic alcohol 8 in a similar manner as above, except that a pivaloyl group
(Scheme 2). Diastereoselective epoxidation of 8 under was used for the protection of the primary alcohol
Sharpless conditions13 afforded the requisite b-epoxide 9 (Scheme 3).18 In sharp contrast to our observation with the
in a 9:1 ratio. MPM protection of the secondary alcohol 9 C6-MOM ether 11, addition of homoallylmagnesium bro-
followed by thiol-assisted epoxide opening gave phenyl mide to the TBS-protected aldehyde 15a proceeded in the
sulfide 10 in high yield. Strong NOE correlations between desired fashion to give a mixture of 8R- (17a) and 8S-al-
H1 and H3, and H1 and H8, confirmed the relative stereo- cohols in a 4:1 ratio.14 The use of the more bulky TIPS
chemistry of 10. The remaining tertiary alcohol of 10 was ether 15b improved diastereoselectivity up to 10:1. It
protected as a benzyl ether, and desilylation and oxidation should be noted that the high stereoselection established
afforded the suitably functionalized aldehyde 11. Addi- here could be extended to another nucleophile involving
tion of homoallylmagnesium bromide, which corresponds oxygen-containing cyclohexenyllithium, which corre-
to the C-ring chain, to 11 occurred in an undesired manner sponds to the B ring of 1, and the reaction generated the
to give 8S-alcohol 13a exclusively.14 A similar tendency 8R-alcohol 17c in 99% yield with a diastereomeric ratio of
was observed when the cyclohexyllithium derivative15 4.8:1. It is likely that the nucleophiles approached from
was employed, leading to a mixture of 8S- (13b) and 8R- the re face of the aldehyde to avoid the steric hindrance of
alcohols in a 3.8:1 ratio. This unfavorable selectivity can the bulky silyl ethers 16.
be explained by the chelation transition state 12, which
causes the nucleophiles to approach from the si face of the
O
SPh
OBn
aldehyde. Since neither inversion of the C8-alcohol of 13a
under a variety of Mitsunobu conditions16 nor an oxida-
tion–reduction sequence were effective,17 we resorted to
changing the C6-protective group from a MOM ether to
bulky silyl ethers to reduce this unfavorable chelation.
PivO
RO
H
6 steps
a–d
6
6
OH
OMPM
7
RO
42% (for 15a)
57% (for 15b)
O
O
O
O
14a: R = TBS
14b: R = TIPS
15a: R = TBS
15b: R = TIPS
TBDPSO
MOMO
TBDPSO
MOMO
O
e
a–d
SPh
OH
OH
OH
PhS
BnO
7
OBn
8R
R
MPMO
OMPM
O
O
O
O
e or f or g
O
H
E
6
8
9
O
H
H
R'O
O
O
O
SPh
OBn
H
1
H
O
O
H
SiR3
SPh
H
17a: R = CH2CH2CH=CH2
R' = TBS
17b: R = CH2CH2CH=CH2
R' = TIPS
TBDPSO
f, g
16
8
h–j
OH
H
OMPM
MOMO
3
MOMO
NOE
17c: R =
OMPM
O
O
O
O
O
10
11
O
B
R' = TIPS
SPh
PhS
OH
8S
Scheme 3 Reagents and conditions: (a) CSA, MeOH, 0 °C, 55% (3
cycles); (b) PivCl, pyridine, 0 °C; (c) TBSOTf or TIPSOTf, 2,6-luti-
dine, CH2Cl2; (d) K2CO3, MeOH, 59% (for 14a, 3 steps), 64% (for
14b, 3 steps); (e) homoallylmagnesium bromide, THF, 0 °C, 17a:
55% (dr = 4:1); (f) homoallylmagnesium bromide, THF, –50 °C, 17b:
78% (dr = 10:1); (g) 2-iodocyclohexen-1-one ethylene ketal, t-BuLi,
Et2O, –78 °C, 17c: 99% (dr = 4.8:1).
OBn
OMPM
BnO
R
MPMO
O
H
O
H
E
k or l
6
H
MOMO
O
O
H
O
O
M
12
13a: R = CH2CH2CH=CH2
13b: R =
MeO
O
Having realized the stereoselective installation of the ho-
moallyl moiety into the E ring, we then focused our atten-
tion on the formation of the D ring. We first attempted
direct cyclization of 17b by activating the phenyl sulfide
moiety with NCS.19 However, no cyclization products
were detected even if the uncharacterized reaction prod-
uct, which can be thought as an a-chlorosulfide, was treat-
O
B
Scheme 2 Reagents and conditions: (a) CSA, MeOH, 0 °C, 65% (3
cycles); (b) TBDPSCl, imidazole, DMF, 0 °C to r.t., 93%; (c) MOM-
Cl, i-Pr2NEt, CH2Cl2, 94%; (d) K2CO3, MeOH, 99%; (e) VO(acac)2,
t-BuOOH, CH2Cl2, reflux, 96% (dr = 9:1); (f) MPMBr, NaH, TBAI,
THF, 92%; (g) PhSH, K2CO3, DMF, 92%; (h) BnBr, NaH, TBAI,
THF, reflux, 97%; (i) TBAF, THF, 100%; (j) (COCl)2, DMSO, Et3N, ed with AgOTf in the presence of 2,6-di-tert-butyl-4-
CH2Cl2, –70 to –20 °C, 84%; (k) homoallylmagnesium bromide,
THF, 0 °C, 13a: 90% (single diastereomer); (l) 2-iodocyclohexen-1-
one ethylene ketal, t-BuLi, Et2O, –78 °C, 13b: 91% (dr = 3.8:1).
methylpyridine (DTBMP) without purification.20 There-
fore, indirect methods via phenyl sulfoxide were investi-
gated.11 The standard conditions of the Pummerer
reaction, including the use of trifluoroacetic anhydride or
Synlett 2008, No. 7, 1086–1090 © Thieme Stuttgart · New York

1088
S. Kobayashi et al.
LETTER
+
H
H
SPh
SPh
O
O
1
8
OBn
3
OBn
D
1. MCPBA, CH2Cl2
OMPM
H
H
OMPM
–70 to –50 °C
H
H
H
17b
4
60% (2 steps)
2. TBDPSCl
imidazole, DMF
80 °C
RO
TIPSO
O
O
O
O
18
NOE
TBAF, THF
19: R = TIPS
20: R = H
94%
Ph
S+
SPh
OBn
O
O
H
OBn
OMPM
OMPM
H
H
B
30% (2 steps)
TIPSO
TIPSO
O
O
O
O
21
22
Scheme 4 Intramolecular Pummerer-type reaction
triflic anhydride in the presence of pyridine, 2,6-lutidine, less hindered a face to give tertiary alcohol 25, whose ste-
DTBMP, or i-Pr2NEt, gave disappointing results, most reochemistry was determined by NOE experiments. Irra-
likely due to competition with acylation or sulfonation of diation at H7 caused enhancement of the OH signal. RCM
the secondary alcohol. Treatment with TBDPSCl11b or of 25 with Grubbs’ second generation catalyst proceeded
TIPSCl, however, in the presence of imidazole at high smoothly at room temperature to furnish the tricyclic
temperature gave rise to the cyclized product 19 in 60% compound 5 in good yield.23 Further investigations direct-
yield (Scheme 4). It is likely that the bulky silyl chlorides ed toward the CDEF ring as well as assembly of the AB
are less reactive toward the secondary alcohol and hence ring are currently underway.
the hydroxyl group could attack the thionium cation 18
without any loss of its nucleophilicity. We also isolated
SPh
O
ketone 22 as a minor product, which presumably arose
OBn
through the six-membered oxathianium intermediate 21.21
OMPM
H
a
b
H
O
20
The NOE correlations between H1 and H3, and H1 and
H8, in connection with the singlet signal at d = 5.10 cor-
responding to H1 confirmed the structure of 19. More-
over, for the desilylated product 20, strong positive NOEs
at H4 and H5 upon irradiation at H1 and H8, respectively,
indicated that the E ring was in the boat conformation
(Figure 2).22 In order to obtain more detailed stereochem-
ical information, the acetonide group of 19 was removed
by p-TsOH in MeOH, leading to diol 23 (53% yield)
(Figure 2). The intensive NOEs between H8 and H3, and
H8 and H5, in addition to indicated coupling constants,
confirmed the C8-stereochemistry and the chair confor-
mation of the E ring.
O
O
24
SPh
OBn
SPh
O
O
OBn
OMPM
D
7
OMPM
c
H
H
C
H
H
E
O
O
OH
HO
O
O
5
25
NOE
Scheme 5 Reagents and conditions: (a) (COCl)2, DMSO, Et3N,
CH2Cl2, –70 to –50 °C, 100%; (b) tetravinyltin, MeLi, THF, –78 °C,
80%; (c) Grubbs’ 2nd generation catalyst (5 mol%), CH2Cl2, 84%.
OMPM
OBn
OH
O
OMPM
H
6
H
In conclusion, we have developed an efficient route to the
CDE ring system 5 of erinacine E (1) via substrate-con-
trolled stereoselective Grignard addition, Pummerer-type
cyclization, and RCM. The latter cyclization sequence
will serve as a powerful tool for the synthesis of valuable
multicyclic hydroisobenzofurans.24
H
4
O
5
BnO
H
6
3
5
H 7
OH
7
H
H
PhS
H
H
HO
8
H
TIPSO
PhS
O
1 O
H
H
8
H
JH5-H6 = 7.6 Hz
20 JH7-H8 = 6.4 Hz
JH5-H6 = 9.6 Hz
23JH7-H8 = 10.0 Hz
NOE
Figure 2 Conformational analyses of the cyclized products
Acknowledgment
With the DE ring 20 in hand, construction of the C ring
was undertaken. The secondary alcohol 20 was oxidized
to ketone 24 under Swern conditions (Scheme 5). Addi-
tion of vinyllithium, which was prepared in situ from tet-
ravinyltin and MeLi at –78 °C, to 24 took place from the
This work was supported by a Grant-in-Aid for Scientific Research
(Wakate B) from the Japan Society for the Promotion of Science
(JSPS), the Shorai Foundation for Science and Technology, the Su-
mitomo Foundation, and the Protein Research Foundation.
Synlett 2008, No. 7, 1086–1090 © Thieme Stuttgart · New York

LETTER
Construction of the CDE-Ring Framework of Erinacine E
1089
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(14) The C8-stereochemistry of each product was confirmed by
NOE experiments after the Pummerer-type cyclization.
(15) 2-Iodocyclohexen-1-one ethylene ketal was synthesized
from 2-cyclohexen-1-one as follows: (i) I2, pyridine, THF,
r.t., 12 h, 80%; (ii) 1,2-bis(trimethylsilyloxy)ethane,
TMSOTf, CH2Cl2, –20 °C, 72 h, 86%.
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C8-ketone of 13a with LiAlH4 in THF at 0 °C (98% yield).
Other reductants including Zn(BH4)2, NaBH4, L-Selectride,
or Red-Al gave inferior yields and selectivity.
(18) Pivaloate was cleaved with DIBAL in CH2Cl2 at –78 °C.
(19) Dilworth, B. M.; McKervey, M. A. Tetrahedron 1986, 42,
3731.
(20) For leading examples of intermolecular AgOTf-mediated
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(22) To a solution of 17b (108 mg, 0.139 mmol) in CH2Cl2 (2
mL) was added MCPBA (65%, 111 mg, 0.417 mmol) at –78
°C. The mixture was stirred at –78 °C to –50 °C for 1 h,
followed by addition of sat. Na2S2O3 solution, Et2O, and sat.
NaHCO3 solution. The resulting mixture was stirred at r.t.
for 30 min and extracted with Et2O. The combined organic
phase was washed with sat. NaHCO3 solution, brine, and
dried over anhyd MgSO4. Concentration of the solution gave
the corresponding sulfoxide (117 mg), which was used
without further purification. To a solution of sulfoxide (117
mg) and imidazole (94.6 mg, 1.39 mmol) in DMF (1.4 mL)
was added TBDPSCl (107 mL, 0.417 mmol). The mixture
was stirred at 80 °C for 3 h, and diluted with Et2O and sat.
NaHCO3 solution. After separation of the organic phase, the
aqueous phase was extracted with Et2O and the combined
organic phase was washed with sat. NH4Cl solution, brine,
and dried over anhyd MgSO4. After concentration, the
residue was purified by flash column chromatography (silica
gel; hexane–EtOAc, 40:1 → 25:1 → 10:1) to give O,S-acetal
19 (64.7 mg, 0.0835 mmol, 60%) and ketone 22 (32.3 mg,
0.0417 mmol, 30%). To a solution of 19 (33.3 mg, 0.0430
mmol) in THF (1.4 mL) was added TBAF (1.0 M solution in
Synlett 2008, No. 7, 1086–1090 © Thieme Stuttgart · New York

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S. Kobayashi et al.
LETTER
mg, 1.6 mmol). The mixture was stirred at r.t. for 9 h and
THF, 64.4 mL, 0.0644 mmol). The mixture was stirred at r.t.
for 1.5 h. After concentration, the residue was purified by
flash column chromatography (silica gel; hexane–EtOAc,
10:1 → 5:1 → 3:1 → 1:1) to give alcohol 20 (24.9 mg,
0.0403 mmol, 94%). Compound 20: [a]D29 –2.4° (c = 0.822,
CHCl3). 1H NMR (400 MHz, CDCl3): d = 1.34 (s, 3 H, Me),
1.51 (s, 3 H, Me), 1.93 (q, J = 7.6 Hz, 2 H, H9), 2.15–2.25
(m, 1 H, H10), 2.28–2.38 (m, 1 H, H10), 2.77 (dd, J = 6.4,
6.8 Hz, 1 H, H7), 3.80 (s, 3 H, MPM), 4.00 (q, J = 6.4 Hz, 1
H, H8), 4.10 (d, J = 3.6 Hz, 1 H, H3), 4.25 (dd, J = 7.6, 8.0
Hz, 1 H, H5), 4.40 (dd, J = 3.6, 8.0 Hz, 1 H, H4), 4.57 (br dd,
J = 6.8, 7.6 Hz, 1 H, H6), 4.60 (d, J = 11.0 Hz, 1 H, MPM),
4.83 (d, J = 11.0 Hz, 1 H, MPM), 4.89 (d, J = 12.0 Hz, 1 H,
Bn), 4.95 (d, J = 12.0 Hz, 1 H, Bn), 4.97 (br dd, J = 1.0, 10.0
Hz, 1 H, H12), 5.05 (br dd, J = 1.6, 17.0 Hz, 1 H, H12), 5.05
(s, 1 H, H1), 5.78–5.89 (m, 1 H, H11), 6.81 (d, J = 8.8 Hz, 2
quenched with Et3N (1 mL). After concentration, the residue
was purified by flash column chromatography (silica gel;
hexane–EtOAc, 5:1 → 3:1) to give the tricyclic product 5
(22.4 mg, 0.0363 mmol, 84%); [a]D29 +21.8° (c = 1.24,
CHCl3). 1H NMR (400 MHz, CDCl3): d = 1.35 (s, 3 H), 1.58
(s, 3 H), 1.79–1.88 (m, 1 H), 2.08–2.23 (m, 1 H), 2.29–2.43
(m, 2 H), 3.02 (d, J = 10.0 Hz, 1 H), 3.53 (dt, J = 3.0, 10.0
Hz, 1 H), 3.78 (s, 3 H), 4.10 (d, J = 4.0 Hz, 1 H), 4.18 (d,
J = 8.4 Hz, 1 H), 4.41 (dd, J = 4.0, 8.4 Hz, 1 H), 4.73 (d, J =
10.0 Hz, 1 H), 4.78 (d, J = 10.0 Hz, 1 H), 4.91 (br s, 1 H),
4.94 (d, J = 12.0 Hz, 1 H), 5.02 (d, J = 12.0 Hz, 1 H), 5.29
(br s, 1 H), 5.66 (ddd, J = 4.0, 6.8, 13.0 Hz, 1 H), 5.77 (br d,
J = 13.0 Hz, 1 H), 6.77 (d, J = 8.8 Hz, 2 H), 7.18 (d, J = 8.8
Hz, 2 H), 7.24–7.35 (m, 5 H), 7.45 (br d, J = 7.6 Hz, 2 H),
7.54 (br d, J = 7.6 Hz, 2 H). 13C NMR (100 MHz, CDCl3):
d = 24.4, 24.9, 26.2, 31.7, 55.4, 68.2, 71.0, 74.2, 76.3, 76.8,
78.5, 79.7, 88.7, 94.4, 110.4, 113.9, 127.0, 127.3, 127.4,
128.3, 129.2, 129.4, 130.1, 131.1, 135.3, 135.6, 139.0,
159.5. FT-IR (KBr): 3398, 3060, 2984, 2933, 2871, 2837,
1612, 1585, 1514, 1481, 1457, 1439, 1379, 1303, 1250,
1211, 1173, 1136, 1118, 1075, 1026, 970, 881, 845, 822,
738, 694 cm–1. HRMS (FAB): m/z [M + Na]+ calcd for
C36H40NaO7S: 639.2392; found: 639.2413.
H, MPM), 7.21–7.40 (m, 10 H), 7.53–7.56 (m, 2 H). 13
C
NMR (100 MHz, CDCl3): d = 24.7, 26.6, 30.8, 35.5, 48.8,
55.4, 68.3, 70.7, 74.4, 75.2, 77.3, 78.1, 80.2, 88.8, 94.6,
110.0, 113.7, 114.9, 127.06, 127.13, 127.2, 128.3, 129.1,
129.3, 130.9, 131.0, 136.1, 138.3, 139.4, 159.1. FT-IR
(film): 3465, 3062, 3031, 2978, 2932, 2913, 2875, 2837,
1640, 1613, 1585, 1514, 1497, 1481, 1463, 1454, 1440,
1381, 1351, 1302, 1248, 1209, 1173, 1161, 1121, 1064,
1029, 913, 880, 822, 777, 739, 695 cm–1. HRMS (FAB):
m/z [M + Na]+ calcd for C36H42NaO7S: 641.2549; found:
641.2563.
(24) (a) Bernadelli, P.; Paquette, L. A. Heterocycles 1998, 49,
531. (b) Chai, Y.; Mcintosh, M. C. Tetrahedron Lett. 2004,
45, 3269; and references cited therein.
(23) To a solution of diene 25 (27.9 mg, 0.0433 mmol) in CH2Cl2
(4.3 mL) was added second generation Grubbs’ catalyst (1.4
Synlett 2008, No. 7, 1086–1090 © Thieme Stuttgart · New York

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