Synthesis of the optically active bicyclo[4.2.1]nonane Segment of mediterraneols

Article abstract of DOI:10.1055/s-2002-19778

An efficient method was established for the synthesis of the optically active bicyclo[4.2.1]nonane segment of mediterraneols using diastereoselective sequential Michael reaction and then retro-aldol reaction.

Full text of DOI:10.1055/s-2002-19778

LETTER
227
Synthesis of the Optically Active Bicyclo[4.2.1]nonane Segment of
Mediterraneols
Synthesis of the
O
i
ptically
r
A
ctive
o
a
]nonane
S
k
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Fax +81(426)763069; E-mail: yamaday@ps.toyaku.ac.jp
Received 21 November 2001
method was used here for obtaining the bicy-
clo[4.2.1]nonane segment of mediterraneol. The synthetic
strategy involves diastereoselective formation of bicy-
clo[2.2.1]heptane derivative A by sequential Michael re-
action of lithium enolate C of the cyclopentenone
derivative and chiral , -unsaturated ester B and cleavage
of carbon-carbon bond in tricyclic compound 2 by retro-
aldol reaction to produce bicyclo[4.2.1]nonane derivative
1, a key intermediate in the synthesis of mediterraneol
(Figure 2).
Abstract: An efficient method was established for the synthesis of
the optically active bicyclo[4.2.1]nonane segment of mediterrane-
ols using diastereoselective sequential Michael reaction and then
retro-aldol reaction.
Key words: antitumor agents, marine natural products, sequential
Michael additions, bicyclic compounds, retro-aldol reactions
Mediterraneols, isolated in 1986 from the Mediterranean
brown alga, Cystoseira mediterranea, are structurally
unique marine diterpenoids.2 Mediterraneols A and B
(Figure 1) inhibit the mobility of sea urchin sperm and mi-
totic cell division in fertilized urchin eggs (ED50 2 g/
mL). These compounds express in vivo antitumor activity
toward P388 leukemia (T/C 128% at 32 mg/kg). Relative
configurations of mediterraneols, each possessing a high-
ly substituted bicyclo[4.2.1]nonane ring system, were de-
termined by NOE difference spectroscopy. However, the
absolute configurations of mediterraneols still remain un-
clear. The synthesis of racemic tetramethylated mediterra-
neol B3 and several synthetic studies on mediterraneol4,5
have been reported. The unique structural features and bi-
ological activity of these compounds prompted the au-
thors to establish a method for the synthesis of optically
active mediterraneol. This paper reports the synthesis of
the optically active bicyclo[4.2.1]nonane segment of
mediterraneol through application of the sequential
Michael reaction and retro-aldol reaction as key steps.
O
mediterraneols
O
O
O
H
Base-
O
O
O
1
O
2
O
O
R2
R1
R2
H
O
R1
O
O
H
+
OLi
RO
CO2R
CO2R
C
B
RO
O
A
Figure 2
The sequential Michael reaction of the enolate of cyclo-
pentenone 4 with chiral , -unsaturated ester 3, prepared
from D-mannitol, in THF at –78 °C was previously shown
to afford bicyclo[2.2.1]heptane 5a and 5b (5a:5b = 5.3:1)
in 82% yield (Scheme 1).6b To enhance diastereoselectiv-
ity in the sequential Michael reaction, examination was
made of the effects of C-5 substituent groups (R1 and R2)
of , -unsaturated ester. , -Unsaturated ester 67 (R1 = -
CH2OTBDMS, R2 = H) and 87 (R1 = -CH2OTBDPS,
R2 = H), possessing mono alkyl group at C-5, were react-
ed with lithium enolate of cyclopentene 4 to give bicyc-
lo[2.2.1]heptane 7 (7a:7b = 6.7:1) in 38% yield and 9
(9a:9b = 10:1) in 36% yield, respectively. The presence
of two methyl groups at C-5 of , -unsaturated ester gave
rise to high diastereoselectivity in the sequential Michael
reaction. , -Unsaturated ester 108 (R1 = R2 = Me) was
reacted with the enolate of 4 under similar reaction condi-
tions to provide predominantly bicyclo[2.2.1]heptane 11a
along with a small amount of 11b (11a:11b = 58:1) in
62% yield.9
OH
15
O
10
14
9
7
2
5
O
12
1
OH
O
mediterraneol A: 7β−Me
mediterraneol B: 7α−Me
Figure 1
Attention has been directed to the synthesis of natural
products using a bicyclic compound, prepared by sequen-
tial Michael reaction, as a chiral building block.6 This
Synlett 2002, No. 2, 01 02 2002. Article Identifier:
1437-2096,E;2002,0,02,0227,0230,ftx,en;Y21501ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
Stereoselectivity in the sequential Michael reaction of 4
with ester 10 may be explained based on transition state I

228
H. Miyaoka et al.
LETTER
LDA
O
O
R2
R1
O
R2
R1
O
O
CHO
O
R2
O
MOMO
A
C
H
H
B
H
R1
11a
4
O
O
15
+
5
OBn
OBn
MOMO
-78°C
THF
CO2Et
OBn
EtO2C
CO2Et
MOMO
MOMO
13
OBn
MOMO
H
O
O
12
5a
7a
9a
5b
7b
9b
3
6
8
R1=R2=H
CO2Me
R1=CH2OTBDMS, R2=H
R1=CH2OTBDPS, R2=H
LDA
then
10 R1=R2=Me
11a
11b
CO2Me
OBn
OBn
OBn
OBn
MOMO
MOMO
Scheme 1
MeI
14
15
Scheme 2 Reagents and conditions: A. i) DIBALH, THF, –78 °C,
99%, ii) Bn-Br, NaH, THF–DMF, r.t., 89%; B. i) HOAc–H2O (4:1),
60 °C, 92%, ii) NaIO4, MeOH–H2O, r.t., 77%, iii) MOM-Cl, i-
Pr2NEt, CH2Cl2, r.t., 99%; C. i) NaClO2, 2-methyl-2-butene, t-BuOH,
that leads to 11a and transition state II that leads to 11b,
as shown in Figure 3. The enolate of 4 approaches ester 10
from the re face, the hindered side, with coordination of
the lithium cation in the enolate of 4 with the carbonyl ox- r.t., ii) CH2N2, Et2O, 0 °C, 47% (2 steps).
ygen of 10. Transition state II is disfavored owing to the
steric hindrance between two methyl groups at the C-5 po-
alcohol 16, 2) thiophenylation with PhSSPh and Bu3P in
sition in ester 10 and enolate of 4.10
pyridine and 3) oxidation of sulfide with MCPBA
(Scheme 3). Sulfoxide 17 was heated in 1,2-dichloroben-
zene at 160 °C in the presence of i-Pr2NEt to give exo-ole-
fin 18. Treatment of exo-olefin 18 with CH2I2 and Et2Zn
could not be obtained desired cyclopropane 19. Alkyla-
tion at C-15 using intermolecure reaction was impossible
due to steric hindrance and therefore alkylation at C-15
using intramolecular reaction was conducted.
‡
OMOM
O
Li
O
H
H
11a
OEt
O
Me
O
Me
I
OH
S(O)Ph
‡
15
O
A
C
B
O
13
H
OBn
OBn
OEt
MOMO
MOMO
H
O
11b
OBn
OBn
Me Me
16
17
OMOM
O
II
Li
CH2I2
Et2Zn
OBn
OBn
Figure 3
MOMO
MOMO
OBn
OBn
18
19
Bicyclo[4.2.1]nonane segment of mediterraneol was syn-
thesized from bicyclo[2.2.1]heptane 11a via cleavage of
carbon-carbon bond in tricyclic compound by retro-aldol
reaction. Initially, construction of gem-dimethyl groups at
C-15 was carried out by intermolecular reaction.11 Bicy-
clo[2.2.1]heptane 11a was converted to aldehyde 13 via
benzyl ether 12 in the following five steps: 1) DIBALH
reduction of the ketone and ethoxy carbonyl to diol, 2)
protection of two hydroxyl groups as benzyl ether to give
benzyl ether 12, 3) hydrolysis of MOM ether and ace-
tonide, 4) NaIO4 oxidation of 1,2-diol, and 5) protection
of the tertiary hydroxyl group as MOM ether (Scheme 2).
Aldehyde 13 was oxidized with NaClO2 to give carboxy-
lic acid followed by esterification with CH2N2 to give me-
thyl ester 14. However, reaction of lithium enolate of ester
14, prepared from ester 14 and LDA, and MeI could not
give desired methylated compound 15.
Scheme 3 Reagents and conditions: A. NaBH4, MeOH, 0 °C, 98%;
B. i) PhSSPh, Bu3P, pyridine, r.t., 77%, ii) MCPBA, CH2Cl2, –78 °C,
83%; C. i-Pr2NEt, 1,2-dichlorobenzene, 160 °C, 87%.
Aldehyde 13 was treated with allyl tosylate in the pres-
ence of KH to give allyl enol ether 20 (Scheme 4). Enol
ether 20 in 1,2-dichlorobenzene was heated at 160 °C in
the presence of i-Pr2NEt in a sealed tube to give aldehyde
21 as the sole product via Claisen rearrangement. Formyl
group in 21 was reduced to methyl group by the Wolff–
Kishner reaction12 with isomerization of olefin to give a
mixture of exo-olefin 22a and endo-olefin 22b
(22a:22b = 4:1). This mixture was treated with potassium
3-aminopropylamide (KAPA)13 in THF to afford endo-
olefin 22b as the sole product. Olefin 22b was ozonolyzed
in the presence of pyridine14 followed by NaBH4 reduc-
tion to give alcohol 23. Hydroxyl group of 23 was con-
Therefore, cylopropanation of exo-olefin was examined. verted to phenylthio group followed by lithium reduction
Aldehyde 13 was converted to sulfoxide 17 via alcohol 16 in liquid NH3 to give diol 24, which has gem-dimethyl
in the following three steps: 1) NaBH4 reduction to give groups at C-15.
Synlett 2002, No. 2, 227–230 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of the Optically Active Bicyclo[4.2.1]nonane Segment
Tetrahedron Lett. 1985, 26, 2629. (b) Francisco, C.;
229
Synthesis of tricyclic compound and cleavage of carbon-
carbon bond in tricyclic compound by retro-aldol reaction
were carried out. Diol 24 was converted to keto aldehyde
25 in the following three steps: 1) PCC oxidation to give
keto aldehyde, 2) Wittig reaction to give methyl enol ether
and 3) hydrolysis of methyl enol ether. Keto aldehyde 25
was treated with 10% KOH aqueous solution at room tem-
perature to afford tricyclic compound 26 as the sole prod-
uct via intramolecular aldol reaction. MOM ether of 26
underwent hydrolysis to give diol followed by PDC oxi-
dation of secondary hydroxyl group to produce diketone
2, the substrate of the retro-aldol reaction. Treatment of
diketone 2 with DBU in benzene at room temperature pro-
vided bicyclo[4.2.1]nonane 115, [ ]D –54.6 (c 0.29,
CHCl3), which corresponds to the bicyclo[4.2.1]nonane
segment of mediterraneols. The total synthesis of mediter-
raneols from bicyclo[4.2.1]nonane 1 is now being carried
out.
Banaigs, B.; Teste, J.; Cave, A. J. Org. Chem. 1986, 51,
1115.
(3) Kakiuchi, K.; Nakamura, I.; Matsuo, F.; Nakata, M.; Ogura,
M.; Tobe, Y.; Kurosawa, H. J. Org. Chem. 1995, 60, 3318.
(4) Hadjiarapoglou, L.; Klein, I.; Spitzner, D.; de Meijere, A.
Synthesis 1996, 525.
(5) Mehta, G.; Acharyulu, P. V. R.; Reddy, K. S.; Umarye, J. D.
Synlett 1997, 1161.
(6) Recent examples: (a) Mitome, H.; Miyaoka, H.; Yamada, Y.
Tetrahedron Lett. 2000, 41, 8107. (b) Miyaoka, H.; Isaji,
Y.; Kajiwara, Y.; Kunimune, I.; Yamada, Y. Tetrahedron
Lett. 1998, 39, 6503. (c) Miyaoka, H.; Saka, Y.; Miura, S.;
Yamada, Y. Tetrahedron Lett. 1996, 37, 7107.
(7) , -Unsaturated esters 6 and 8 were prepared from diol a16
as shown in Scheme 5:
H
H
O
O
O
O
OH
OH
OR
OH
B
A
6 or 8
H
H
a
R= TBDMS or TBDPS
O
Scheme 5 Reagents and conditions: For 6: A. TBDMS-Cl,
Et3N, DMAP, CH2Cl2, r.t., 78% (based on SM recovered); B.
i) DMSO, (COCl)2, Et3N, CH2Cl2, –78 °C, ii)
Ph3P=C(CH3)CO2Et, benzene, r.t., 60% (2 steps). For 8: A.
TBDPS-Cl, Et3N, DMAP, CH2Cl2, r.t., 79% (based on SM re-
covered); B. i) DMSO, (COCl)2, Et3N, CH2Cl2, –78 °C, ii)
Ph3P=C(CH3)CO2Et, benzene, r.t., 63% (2 steps).
C
B
A
CHO
OBn
13
OBn
MOMO
MOMO
OBn
OBn
21
20
OH
+
E
OBn
OBn
OBn
MOMO
(8) , -Unsaturated ester 10 was obtained from p-
bromobenzoate b17 as shown in Scheme 6:
MOMO
OBn
22a
MOMO
OBn
OBn
22b
23
22a : 22b = 4 : 1
22b only
D
O
O
B
A
OBzNO2-p
10
15
O
OH
G
H
F
b
OH
MOMO
MOMO
OH
O
25
CHO
24
Scheme 6 Reagents and conditions: A. i) Acetone, H2SO4,
benzene, 0 °C to r.t., 97%, ii) K2CO3, EtOH, r.t., 81%; B. i)
DMSO,
(COCl)2,
Et3N,
CH2Cl2,
–78 °C,
ii)
I
J
2
1
MOMO
Ph3P=C(CH3)CO2Et, benzene, r.t., 54% (2 steps).
O
OH
(9) The stereochemistry of 11a was determined based on
26
chemical correlation with 5a, whose stereochemistry was
previously elucidated.6b Bicyclo[2.2.1]heptane derivative
11a was converted to aldehyde 13, [ ]D –52.4 (c 0.33,
CHCl3) (Scheme 2), whose spectral data and sign of optical
rotation were found identical to aldehyde 13, [ ]D –54.6 (c
0.29, CHCl3), which was converted from 5a as shown in
Scheme 7:
Scheme 4 Reagents and conditions: A. Allyl tosylate, KH, DME–
THF, –10 °C, 47%; B. i-Pr2NEt, 1,2-dichlorobenzene, 160 °C, sealed
tube, 96%; C. NH2NH2, t-BuOK, BuOH, 180 °C, sealed tube; D. KA-
PA, THF, r.t., 67% (2 steps); E. i) O3, pyridine, MeOH–CH2Cl2, –
78 °C, then Me2S, 85%, ii) NaBH4, MeOH, 0 °C, 99%; F. i) PhSSPh,
Bu3P, pyridine, 60 °C, 87%, ii) Li, liq. NH3, THF, reflux, 82%; G. i)
PCC, CH2Cl2, r.t., 87%, ii) Ph3P=CHOMe, THF, –78 °C, 83%, iii)
TsOH, benzene–acetone, r.t., 95%; H. 10% KOH, MeOH, r.t., quant.;
I. i) 1 N HCl, DME, 50 °C, 94%, ii) PDC, CH2Cl2, r.t., 93%; J. DBU,
benzene, r.t., 53%.
O
O
H
B
A
5a
13
References
OBn
OBn
MOMO
(1) Present address: Meiji Pharmaceutical University, 2-522-1
Noshio, Kiyose, Tokyo 204-8588, Japan,
Fax+81(424)958796; E-mail: nagaoka@my-pharm.ac.jp.
(2) (a) Francisco, C.; Banaigs, B.; Valls, R.; Codomier, L.
Scheme 7 Reagents and conditions: A. i) DIBALH, THF, –
78 °C, ii) Bn-Br, NaH, THF–DMF, r.t., 93% (2 steps); B. i)
HOAc–H2O (4:1), 60 °C, 91% (based on SM recovered), ii)
NaIO4, MeOH–H2O, r.t., 85%.
Synlett 2002, No. 2, 227–230 ISSN 0936-5214 © Thieme Stuttgart · New York

230
H. Miyaoka et al.
LETTER
(15) 1: Colorless solid: mp 142–145 °C. Anal. Calcd for
(10) The relative sequential Michael reaction has been reported:
(a) Nagaoka, H.; Shibuya, K.; Kobayashi, K.; Miura, I.;
Muramatsu, M.; Yamada, Y. Tetrahedron Lett. 1993, 34,
4039. (b) Nagaoka, H.; Kobayashi, K.; Okamura, T.;
Yamada, Y. Tetrahedron Lett. 1987, 28, 6641.
(11) Numbering of compounds is accordance with that of
mediterraneol.
(12) Van Middlesworth, F. L. J. Org. Chem. 1986, 51, 5019.
(13) Brown, C. A.; Yamashita, A. J. Am. Chem. Soc. 1975, 97,
891.
C12H16O3: C, 69.21; H, 7.74. Found: C, 69.25; H, 7.85. IR
(CHCl3): max 2950, 1745, 1720, 1695, 1618 cm–1. 1H NMR
(400 MHz, CDCl3): = 3.79 (1 H, d, J = 14.4 Hz), 3.44 (1 H,
dt, J = 14.4, 1.1 Hz), 2.96 (1 H, d, J = 8.6 Hz), 2.82 (1 H, dd,
J = 19.9, 8.6 Hz), 2.70 (1 H, d, J = 16.4 Hz), 2.64 (1 H, d,
J = 16.4 Hz), 2.58 (1 H, dd, J = 19.9, 0.9 Hz), 1.11 (3 H, s),
1.10 (3 H, s), 1.05 (3 H, s).
(16) Carmack, M.; Kelley, C. J. J. Org. Chem. 1968, 33, 2171.
(17) Smith, A. B. III.; Kingery-Wood, J.; Leenay, T. L.; Nolen, E.
G.; Sunazuka, T. J. Am. Chem. Soc. 1992, 114, 1438.
(14) Slomp, G. Jr.; Johnson, J. L. J. Am. Chem. Soc. 1958, 80,
915.
Synlett 2002, No. 2, 227–230 ISSN 0936-5214 © Thieme Stuttgart · New York