Asymmetric total synthesis of glycinoeclepin A: Generation of a novel bridgehead anion species

Article abstract of DOI:10.1246/cl.2010.835

The asymmetric total synthesis of glycinoeclepin A, a hatchstimulating agent of the soybean, cyst nematode, was accomplished on the basis of a cyclopentene annulation for constructing the CD ring moiety having contiguous quaternary carbon atoms. Introduction of the A ring moiety was achieved by an alkylation reaction using a 7-oxabicyclo[2.2.1]hex-l-yl anion species.

Full text of DOI:10.1246/cl.2010.835

doi:10.1246/cl.2010.835
Published on the web June 29, 2010
835
Asymmetric Total Synthesis of Glycinoeclepin A: Generation of a Novel Bridgehead Anion Species
Yasuhiro Shiina,1 Yoshihide Tomata,1 Masaaki Miyashita,2 and Keiji Tanino*1
1Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo, Hokkaido 060-0810
2Department of Applied Chemistry, Faculty of Engineering, Kogakuin University, Hachioji, Tokyo 192-0015
(Received June 18, 2010; CL-100570; E-mail: ktanino@sci.hokudai.ac.jp)
The asymmetric total synthesis of glycinoeclepin A, a hatch-
HO
stimulating agent of the soybean cyst nematode, was accomplished
on the basis of a cyclopentene annulation for constructing the CD
ring moiety having contiguous quaternary carbon atoms. Intro-
duction of the A ring moiety was achieved by an alkylation
reaction using a 7-oxabicyclo[2.2.1]hex-1-yl anion species.
2C3 O2H
12
17
20
13
D
C
19
10
1
9
14
8
A
O
CO2H
3
7
5
O
Figure 1. Structure of glycinoeclepin A (1).
The soybean cyst nematode (SCN) is a devastating pest of a
small group of host plants including soybean, kidney bean, and
adzuki. They have a limited host range and the specificity arises
from response to specific stimuli secreted by the host plant.1
Glycinoeclepin A (1) (Figure 1) was isolated from dried root
of the kidney bean by Masamune et al. as a potent hatch-
stimulating agent (10¹12-10¹11 g mL¹1) of the SCN.2 From a
synthetic point of view, the structural features of 1, namely, the
contiguous quaternary carbon atoms on the CD ring system and
the A ring with an oxygen bridge have attracted considerable
attention from organic chemists, and three groups have reported
the asymmetric total synthesis of 1.3
CN
R
CN
3
KHMDS
O
R
OMe
THF
−78 °C
OMe
then Ac2O
2a: R = H
2b: R = Me
OAc
4
CN
R
HCl
THF−H2O
5a: R = H, 78% from 3 (dr 87:13)
5b: R = Me, 71% from 3 (dr 91: 9)
O
Recently, we developed a stereoselective cyclopentene
annulation method for preparing a CD ring segment of steroids
from enone 3 on the basis of a conjugate addition reaction using
nitrile 2a (Scheme 1).4
Scheme 1. Cyclopentene annulation for stereoselective synthesis of
bicyclic enones.
PO
PO
−
20
Thus, the reaction of enone 3 with a carbanion species,
which was generated from nitrile 2a and potassium bis(tri-
methylsilyl)amide (KHMDS), followed by acetic anhydride
afforded enol acetate 4 stereoselectively. Treatment of the adduct
with aqueous hydrochloric acid resulted in formation of enone
5a via hydrolysis of the enol ether moiety and intramolecular
aldol condensation. Since the method was also effective for the
stereoselective synthesis of enone 5b with contiguous quaternary
carbon atoms, we planned to develop a concise route for the
asymmetric total synthesis of glycinoeclepin A (1) as shown in
Scheme 2.
12
O
+
1
X
O
OTf
O
I
II
PO
PO
TBSO
TBSO
CN
12
III
6
7
O
O
Scheme 2. Retrosynthetic analysis of glycinoeclepin A (1).
We chose optically active £-silyloxy enone 75 as the
substrate of the cyclopentene annulation. Thus, bicyclic enone
6, a monooxygenated analog of enone 5b, would be obtained
through attack of the anion species of nitrile 2b on enone 7 from
the opposite face of the TBSO group. The cyano group of 6 would
be utilized for the stereoselective construction of the side chain
through a hydroboration reaction of diene III followed by the
Suzuki-Miyaura coupling. With a view to introducing the A
ring moiety in a straightforward manner, we planned to develop
a coupling reaction of anionic species I with the CD ring
segment II.
The CD ring segment was synthesized as shown in
Scheme 3. Enone 75 was treated with the anion generated from
nitrile 86 followed by acetic anhydride to afford enol acetate 9
with high stereoselectivity (96:4). In order to avoid removal of
the TBS group by hydrochloric acid, the cyclization reaction was
performed by heating the crude product in aqueous acetic acid,
and enone 6 was obtained in 62% yield after recrystallization.
The trans relationship between the two methyl groups of enone
6 was established by NOE experiments. After reduction and
protection of the ketone moiety, nitrile 10 was converted to
diene 11 through an addition reaction with MeLi followed by a
Wittig reaction. The stereocontrolled construction of the side
chain was achieved through hydroboration of diene 11 using 9-
borabicyclo[3.3.1]nonane (9-BBN) followed by palladium-cata-
lyzed coupling with vinyl bromide,7 while the configuration of
the C20 position was not confirmed until the completion of the
total synthesis.
Since the bicyclic compounds derived from optically active
enone 7 have S-configuration at the C12 position, which is
opposite to that of glycinoeclepin A, inversion of the chiral
Chem. Lett. 2010, 39, 835-837
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

836
TBSO
TBSO
AcO
TBSO
O
a
b
c
CN
CN
CN OBn
a
b
O
O
O
OTIPS
21 90%
HO
O
OTIPS
+
22
BnO
8
20
59% (95% ee)
O
6
9 (dr 96:4)
7
62% from 7
I
d
e
O
TBSO
NMe2
N
CN
HO
O
O
20
g
c,d
e,f
25
23 (dr 91: 9)
24
60% from 22
12
TIPSO
HO
11 89%
10 95%
97% (dr 94:6)
Scheme 4. Synthesis of the
A ring segment. Reagents and
conditions: (a) KHMDS (1.05 equiv), TIPSOTf (1.05 equiv),
THF, ¹78-0 °C, 30 min; (b) (¹)-DIPCl (1.1 equiv), rt, 24 h; (c)
NIS (1.2 equiv), CH2Cl2, ¹40 °C-rt, 40 min; (d) AgOTf (1.5 equiv),
2,6-lutidine (1.1 equiv), CH2Cl2, 40 °C, 2 h; (e) Me2NNH2 (4.5
equiv), AcOH (0.3 equiv), ethanol, 70 °C, 12 h.
O
HO
12
8
12
12
8
h,i
j
k
TIPSO
TIPSO
TIPSO
13 97%
14 90%
15 88%
AcO
AcO
77:23 by using LiEt3BH, a bulky reducing agent. Since the
reaction with Li(sec-Bu)3BH resulted in recovery of the substrate,
we optimized the conditions of the LiEt3BH reduction. Fortu-
nately, the stereoselectivity was improved to 92:8 by performing
the reaction in toluene, and alcohol 15 was obtained in 88% yield
after silica gel column chromatography. Then alcohol 15 was
converted to ketone 16 through acetylation, desilylation, and the
Swern oxidation. With the CD ring segment having the four
contiguous stereogenic centers in hand, the stage was set for
introduction of the A ring moiety. To this end, ketone 16 was
converted to allyl tosylate 19 in four steps: (1) condensation with
Bredereck’s reagent,10 (2) sulfonylation of aminovinyl ketone 17
with triflic anhydride followed by hydrolysis, (3) the Luche re-
duction of aldehyde 18, and (4) tosylation of the allylic alcohol.11
On the other hand, the optically active A ring segment was
synthesized as shown in Scheme 4. Diketone 2012 was treated
with KHMDS followed by TIPSOTf to afford ketone 21 which
was subjected to asymmetric reduction by Brown’s protocol.13
Thus, the reaction with (¹)-B-chlorodiisopinocampheylborane
(DIPCl) gave rise to optically active alcohol 22 in 95% ee.14
Formation of the oxygen bridge was achieved through stereo-
selective iodination of enol silyl ether 22 with N-iodosuccin-
imide (NIS) and intramolecular cyclization of ketone 23
mediated by AgOTf.15 The resulting ketone 24 was then
converted to the corresponding hydrazone 25 which was
obtained as a mixture of geometric isomers.16
Prior to the coupling with the CD ring segment, experiments
to generate an anion species from the A ring segment were
carried out (Scheme 5). It should be noted that ketone 24 with a
bridged bicyclic framework cannot form a stable enolate anion
because of Bredt’s rule.17 Indeed, treatment of 24 with LDA in
THF resulted in formation of dimer 26 even at ¹78 °C. This
indicates that the hydrogen atom at the bridgehead position is
acidic enough to be abstracted with LDA, but the resulting anion
immediately attacks the remaining ketone. We therefore decided
to protect the carbonyl group of ketone 24, and promising results
were obtained by using hydrazone 25.16 Thus, treatment of 25
with n-BuLi at 0 °C afforded a stable bridgehead anion species
that underwent an addition reaction with benzaldehyde giving
rise to 27.18 While the alkylation reaction with benzyl bromide
suffered from formation of 1,2-diphenylethane through a Br-Li
exchange pathway, the corresponding cuprate was found to give
ketone 28 in high yield.
o
p
l,m,n
Me2N
O
O
16 88%
17
AcO
AcO
TfO
q,r
19
TsO
OHC
TfO 18
89% from 16
19 93%
Scheme 3. Synthesis of the CD ring segment. Reagents and
conditions: (a) nitrile 8 (1.5 equiv), KHMDS (1.3 equiv), THF,
¹78 °C, 1 h, then enone 7 (1 equiv), ¹78 °C, 1 h, then Ac2O (2
equiv), ¹78- ¹50 °C; (b) AcOH-water (3:1), 100 °C, 9 h; (c)
NaBH4 (2.5 equiv), CeCl3¢7H2O (2.5 equiv), MeOH, ¹78 °C-rt,
1 h; (d) TIPSOTf (1.3 equiv), 2,6-lutidine (2.6 equiv), CH2Cl2, 0 °C,
10 min; (e) MeLi (2 equiv), ether, rt, 6.5 h, then AcOH-water-THF
(1:1:2), 40 °C, 1 h; (f) Ph3PCH3¢Br (3.3 equiv), t-BuOK (3 equiv),
toluene-t-BuOH (1:1), 80 °C, 3 h; (g) 9-BBN (2 equiv), THF, 0 °C-
rt, 7 h, then Pd(PPh3)4 (0.03 equiv), BrCH=CH2 (excess), aq.
NaOH, rt, 1.5 h; (h) TBAF (5 equiv), DMF, 80 °C, 6 h; (i) TIPSOTf
(1.2 equiv), 2,6-lutidine (2.4 equiv), CH2Cl2, 0 °C, 20 min; (j) TPAP
(0.05 equiv), NMO (2 equiv), MS 4A, CH2Cl2, rt, 1.5 h; (k)
LiEt3BH (2 equiv), toluene, ¹78- ¹15 °C, 4 h; (l) Ac2O (2 equiv),
DMAP (0.2 equiv), pyridine, rt, 3 h; (m) TBAF (5 equiv), THF, rt,
1.5 h; (n) Swern oxidation; (o) t-BuOCH(NMe2)2 (3.5 equiv),
benzene, 50 °C, 5.5 h; (p) Tf2O (1.1 equiv), 2,6-di-tert-butylpyridine
(2.2 equiv), CH2Cl2 ¹78 °C, 15 min, then aq. NaHCO3, rt; (q)
NaBH4 (1.5 equiv), CeCl3¢7H2O (1.5 equiv), MeOH, 0 °C-rt,
15 min; (r) p-TsCl (2 equiv), Et3N (4 equiv), Me3N¢HCl (1 equiv),
toluene, 0 °C, 2 h.
center was needed. To this end, compound 12 was transformed
into alcohol 13 through removal of the two silyl groups by
tetrabutylammonium fluoride (TBAF) followed by selective
silylation of the less hindered C8 hydroxy group. Initial attempts
to invert alcohol 13 under the Mitsunobu conditions8 were not
successful probably due to steric hindrance, which prompted us
to explore stereoselective reduction of the corresponding ketone.
Alcohol 13 was treated with N-methylmorpholine N-oxide
(NMO) and tetrapropylammonium perruthenate (TPAP)9 to give
ketone 14. The reaction of the ketone with LiAlH4 in THF at
¹78 °C afforded a 7:93 mixture of diastereomers 15 and 13, but
the ratio of the desired product 15 was dramatically increased to
Chem. Lett. 2010, 39, 835-837
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

837
This work was partially supported by the Global COE
Program (Project No. B01: Catalysis as the Basis for Innovation
in Materials Science) and a Grant-in-Aid for Scientific Research
(B) (No. 21350021) from the Ministry of Education, Culture,
Sports, Science and Technology, Japan. Y. S. thanks JSPS for a
pre-doctoral fellowship.
O
O
LDA
24
25
O
OH
THF, −78 °C
Li
O
O
O
26
OTBS
Ph
PhCHO
then
TBSOTf
n-BuLi
References and Notes
O
NMe2
1
M. Tsutsumi, K. Sakurai, Jpn. J. Appl. Entomol. Zool. 1966, 10,
129.
−78 ~ 0 °C
N
THF, 0 °C
Li
NMe2
N
27
2
a) T. Masamune, M. Anetai, M. Takasugi, N. Katsui, Nature
1982, 297, 495. b) A. Fukuzawa, A. Furusaki, M. Ikura, T.
Masamune, L. D. Hall, V. Rajanayagam, J. Chem. Soc., Chem.
Commun. 1985, 748.
75% (dr 76:24)
CuBr·SMe2
then PhCH2Br
Ph
O
NMe2
N
3
a) A. Murai, N. Tanimoto, N. Sakamoto, T. Masamune, J. Am.
Chem. Soc. 1988, 110, 1985. b) K. Mori, H. Watanabe, Pure
Appl. Chem. 1989, 61, 543. c) E. J. Corey, I. N. Houpis, J. Am.
Chem. Soc. 1990, 112, 8997. d) H. Watanabe, K. Mori, J. Chem.
Soc., Perkin Trans. 1 1991, 2919.
−50 °C
28 93%
Scheme 5. Generation and reactions of the bridgehead anion
species.
4
5
6
K. Tanino, Y. Tomata, Y. Shiina, M. Miyashita, Eur. J. Org.
Chem. 2006, 328.
J.-P. Uttaro, G. Audran, H. Monti, J. Org. Chem. 2005, 70, 3484,
and references cited therein.
Since nitrile 2b proved to be unsuitable for large scale synthesis
due to its high volatility, nitrile 8 was used for the cyclopentene
annulation method instead of 2b. Nitrile 8 was prepared from
glycerol monobenzyl ether as shown bellow.
AcO
AcO
c
a,b
19
O
OTf
CO2Me
30 87%
O
29 65%
NaH
O
HO
OBn
AcO
OBn
CO2H
CHO
e,f
CN
OBn
NaIO4
(EtO)2PCH2CN
HO
HO
OHC
OBn
ether-H2O
THF
d
0 °C ~ rt
O
CO2H
1 95%
CN
CO2Me
t-BuOK
LDA then MeI
THF, −78 °C
69% for 3 steps
O
8 89%
31 81%
t-BuOH-THF
0 °C ~ rt
Scheme 6. Total synthesis of glycinoeclepin A. Reagents and
conditions: (a) hydrazone 25 (4.8 equiv), n-BuLi (4 equiv), THF,
0 °C, 1 h, then CuBr¢SMe2 (2.1 equiv), ¹40 °C, 30 min, then
tosylate 19 (1 equiv), ¹40 °C, 5 h; (b) AcOH-H2O (3:1), 130 °C,
5 h; (c) CO (1 atm), Pd(OAc)2 (0.1 equiv), 1,1¤-bis(diphenylphos-
phino)ferrocene (0.11 equiv), Bu3N (1.5 equiv), DMF-MeOH (2:1),
80 °C, 45 min; (d) OsO4 (0.1 equiv), NMO (3 equiv), t-BuOH-H2O-
THF (2:2:1), 0 °C, 1.5 h, then NaIO4 (5 equiv), rt, 2 h; (e) NaClO2 (2
equiv), NaH2PO4 (3 equiv), 2-methyl-2-butene (6 equiv), t-BuOH-
H2O (3:1), 0 °C, 1 h; (f) LiI (5 equiv), 2,4,6-collidine, 120 °C, 2 h,
then LiOH (20 equiv), THF-H2O (1:1), 60 °C, 2 h, then dil. H2SO4.
7
A similar transformation for the stereoselective synthesis of a
steroid was reported: N. Miyaura, T. Ishiyama, H. Sasaki, M.
Ishikawa, M. Satoh, A. Suzuki, J. Am. Chem. Soc. 1989, 111,
314.
For a review: D. L. Hughes, Org. React. 1992, 42, 335.
S. V. Ley, J. Norman, W. P. Griffith, S. P. Marsden, Synthesis
1994, 639.
8
9
10 H. Bredereck, G. Simchen, S. Rebsdat, W. Kantlehner, P. Horn,
R. Wahl, H. Hoffman, P. Grieshaber, Chem. Ber. 1968, 101, 41;
See also: B. Trost, M. Preckel, J. Am. Chem. Soc. 1973, 95,
7862.
11 Y. Yoshida, Y. Sakakura, N. Aso, S. Okada, Y. Tanabe,
Tetrahedron 1999, 55, 2183.
12 Y. Lu, G. Barth, K. Kieslich, P. D. Strong, W. L. Duax, C.
Djerassi, J. Org. Chem. 1983, 48, 4549.
13 H. C. Brown, J. Chandrasekharan, P. V. Ramachandran, J. Am.
Chem. Soc. 1988, 110, 1539.
14 Alcohol 22 was converted to the corresponding (R)- and (S)-
MTPA esters, which enabled us to estimate the enantiomeric
purity and the absolute configuration of 22 by Kusumi’s
protocol: I. Ohtani, T. Kusumi, Y. Kashman, H. Kakisawa,
J. Am. Chem. Soc. 1991, 113, 4092.
15 The minor diastereomer of iodo ketone 23 remained unchanged,
suggesting that the major isomer of 23 has a trans relationship of
the hydroxy and iodo groups.
16 E. J. Corey, H. L. Pearce, J. Am. Chem. Soc. 1979, 101, 5841.
17 C. J. Hayes, N. S. Simpkins, D. T. Kirk, L. Mitchell, J. Baudoux,
A. J. Blake, C. Wilson, J. Am. Chem. Soc. 2009, 131, 8196, and
references cited therein.
18 Since it was difficult to separate the adduct from hydrazone 25, it
was converted to the corresponding silyl ether 27.
The reaction conditions were applied to the coupling
reaction with allyl tosylate 19, and ketone 29 was obtained
after hydrolysis of the hydrazone moiety (Scheme 6). The
palladium-catalyzed carbonylation reaction3a of enol triflate 29
afforded ester 30, and glycinoeclepin A (1) was obtained
through oxidative cleavage of the terminal olefin followed by
deprotection of the ester groups. The synthetic 1 gave spectral
and physical data in full agreement with those reported by
29
24
Mori3d (½¡ꢀD ¹11.5 (c = 0.67, MeOH), lit. ½¡ꢀD ¹10.2 (c =
0.63, MeOH), mp 120-123 °C (lit. 120-121.5 °C)).
In conclusion, the asymmetric total synthesis of glycinoe-
clepin A (1) was accomplished on the basis of a cyclopentene
annulation for constructing the CD ring moiety with contiguous
quaternary carbon atoms. The A ring moiety was introduced by
an alkylation reaction using a novel bridgehead anion. Appli-
cation of these methods to total synthesis of related compounds
are under investigation.
Chem. Lett. 2010, 39, 835-837
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/