Total synthesis of (-)-dihydrocorynantheol using bicyclo[3.2.1]octenone chiral building block

Article abstract of DOI:10.3987/com-06-s(w)49

The diastereocontrolled synthesis of (-)-dihydrocorynantheol from a bicyclo[3.2.l]octane chiral building block has been achieved by employing a tandem retro-aldol-Pictet-Spengler reaction-C-3 epimerization sequence as the key step.

Full text of DOI:10.3987/com-06-s(w)49

HETEROCYCLES, Vol. 70, 2006
153
HETEROCYCLES, Vol. 70, 2006, pp. 153 - 159. © The Japan Institute of Heterocyclic Chemistry
Received, 25th September, 2006, Accepted, 17th November, 2006, Published online, 21st November, 2006. COM-06-S(W)49
TOTAL SYNTHESIS OF (–)-DIHYDROCORYNANTHEOL USING
BICYCLO[3.2.1]OCTENONE CHIRAL BUILDING BLOCK†
Ayako Tosaka, Shinichiro Ito, Norio Miyazawa, Masatoshi Shibuya,
Kunio Ogasawara,* and Yoshiharu Iwabuchi*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences,
Tohoku University, 6-3 Aobayama, Sendai 980-8578, Japan. E-mail:
konol@mail.tains.tohoku.ac.jp
iwabuchi@mail.pharm.tohoku.ac.jp
Abstract – The diastereocontrolled synthesis of (–)-dihydrocorynantheol from a
bicyclo[3.2.1]octane chiral building block has been achieved by employing a
tandem retro-aldol-Pictet-Spengler reaction-C-3 epimerization sequence as the
key step.
The topological placement of functional groups endows molecules with substantial reactivity. In
endeavors aimed at developing versatile chiral building blocks, we have realized that certain
bicyclo[3.n.1]alkanes harboring an aldol functionality straddled at the bridgehead are exclusively obliged,
because of Bredt’s rule, 1 to give rise to a retro-aldol reaction on acidic treatment2,3 (Scheme 1), and have
been exploiting its use in organic synthesis.4,5 We previously reported a facile construction of
18-keto-pseudoyohimbane ketal (4) from the bicyclo[3.2.1]octenone chiral building block (–)-(1) by
employing a novel cascade sequence consisting of a Brønsted-acid-promoted retro-aldol reaction of 3 and
the subsequent stereocontrolled Pictet-Spengler reaction.4c We also disclosed that 4 gradually
isomerizes6 to the 18-keto-yohimbane ketal (5) on treatment with p-TsOH in boiling toluene,4c indicating
its potential use as a common intermediate of both yohimbine- and corynanthe-type indole alkaloids,7
which are useful antiparasitic, antiviral, and analgesic agents.8 On the basis of these findings, we
embarked on the total synthesis of (–)-dihydrocorynantheol (2), a representative of corynanthe-type
indole alkaloids first isolated from the bark of Aspidosperma marcgravianum Woodson
(Apocynaceae).9,10 We report here the stereocontrolled total synthesis of (–)-dihydrocorynantheol (2)
from the chiral bicyclo[3.2.1]octenone (1), featuring a tandem retro-aldol-Pictet-Spengler reaction-C-3
epimerization sequence to allow a facile construction of the 18-keto-yohimbane skeleton.

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HETEROCYCLES, Vol. 70, 2006
H+
m
m
(m = 1 or 2)
O
O
OH
HO
Scheme 1
ref. 4c
O
ref. 4c
3
N
N
O
HN
N
H
N
H
N
H
H
H
H
O
H
O
ref. 4c
H
H
O
3
OMOM
O
O
(+)-18-keto pseudoyohimbane ketal 4
(–)-1
(+)-18-keto-yohimbane ketal 5
OMOM
this study
O
O
N
this study
this study
N
H
N
O
HN
H
H
N
H
N
H
H
O
H
O
H
H
O
OMOM
8
OH
(–)-dihidrocorynantheol (2)
Scheme 2
In our initial effort employing 4 as the key intermediate, we encountered a serious problem: insufficient
material throughput in the C-3 epimerization6 of 4 to 5. In light of the experimental result that 5 does
not isomerize to 4 under an acidic condition causing the epimerization of 4 to 5,4c and calculations
indicating that 4 is more stable than 5 by 6.8 kcal/mol,11 it was assumed that the incomplete epimerization
is not due to maturation in equilibrium but to the protonation of the amine moiety giving the
corresponding ammonium ion, in which a positive charge prevents the crucial protonation on the indole
moiety that will trigger the subsequent epimerization. Our desire to improve the productivity of
epimerization prompted us to explore an amide (8) as the substrate of the key reaction. By employing a
previously established procedure, 8,12 mp 65–67 °C, [α]D –20.1° (c 1.0, CHCl3), was prepared in 62%
27
overall yield from the bicyclo[3.2.1]octenone chiral building block (–)-(1)2,4c in a four-step sequence
involving the regioselective and convex-face-selective introduction of a nitromethyl group, ketalization
using ethylene glycol bis-trimethylsilyl ether under Noyori’s conditions,13 the reduction of the nitro group
to a primary amino group, and condensation with indole-3-acetic acid.

HETEROCYCLES, Vol. 70, 2006
155
O
O
O
H2N
O2N
a, b
c
O
d
O
HN
O
O
N
H
O
OMOM
OMOM
OMOM
OMOM
8
(–)-1
6
7
Scheme 3. Reagents and conditions: a) MeNO2, DBU, MeCN (86%); b) (CH2OTMS)2, TMSOTf (cat.),
CH2Cl2, –30 °C (77%); c) LiAlH4, THF; d) indole-3-acetic acid, WSCD, THF, rt (94%, two steps).
Although 8 showed a slightly low reactivity in the Pictet-Spengler reaction, the resulting
18-keto-pseudoyohimbane ketal (12) was found to elicit an improved reactivity in the acid-promoted C-3
epimerization to give 16. Thus, on exposure to p-TsOH and ethylene glycol, in refluxing MeCN, which
enables the stereoselective construction of pseudoyohimbane ketal (4) from 3 in 82% yield,4c 8 afforded
12 and 16 in 21% and 22% yields, respectively. After considerable experimentation, we found effective
conditions using methanesulfonic acid in boiling dioxane for 12 h that allowed us to obtain the desired 16,
30 29
[α]D –44.5° (c 1.0, CHCl3), in 52% yield together with pseudoyohimbane (12), [α]D +72.3° (c 1.0,
CHCl3), in 23% yield as a readily separable mixture.
OH
O
O
O
N
HN
O
HN
N
H
N
H
N
H
a
H
O
H
O
8
H
H
O
OH
9
O
O
10
11
HO
O
O
H
H
N
3
O
N
H
N
H
H
H
O
H
O
H
O
12
H
N
O
NH
H
13
O
H
NH
b
14
O
H
3 N
H
O
N
H
O
O
N
H
O
H
H
O
H
H
NH
16
15
Scheme 4. Reagents and conditions: a) MsOH, (CH2OH)2, 1,4-dioxane, Dean-Stark, reflux, 12 h, 52% of
16 with 23% of 12; b) MsOH, (CH2OH)2, 1,4-dioxane, reflux, 6 h, 59% of 16 with 29% of 12.

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HETEROCYCLES, Vol. 70, 2006
The prolongation of the reaction time led to the complete consumption of 12, as determined by TLC;
however, it also diminished the yield of 16 to 40% because of concomitant decompositions. We
therefore separated these isomers and the recovered 12 was again subjected to the above-mentioned acidic
conditions to obtain 16 in 59% yield and unreacted 12 in 29% yield.14 As a result of this sequence, 16
was obtained in 66% yield from 8. Note that 16 did not afford 12 under the same acidic conditions and
that 12 isomerized to 16, indicating that no equilibrium exists between 16 and 12 by epimerization at the
C3 stereogenic center in which two indolenium intermediates (13 and 15)15 via 1,2-diamine (14) exist, as
in the case of the amine substrate (5).4c
Having established an acceptable method for obtaining 16, we next examined the conversion of 16 into
(–)-dihydrocorynantheol (2). Thus, to realize the transformation of the E-ring moiety to the seco form as
expressed in 2, ketal was deprotected and the resulting ketone was treated with pyrrolidine to form an
enamine, which was immediately treated with trimethylene dithiotosylate16,17 to generate 17,18-diketone
mono-17-thioketal (17), mp 198 °C, [α]D24 –139.1° (c 1.0, DMSO), as brown needles. Upon exposure to
potassium hydroxide in boiling tert-butyl alcohol, the dithioketone moiety was cleaved to obtain
27
seco-acid thioketal having a corynanthe framework, which was isolated as a methyl ester (18), [α]D
+24.3° (c 1.0, CHCl3), as brown amorphous powder, after esterification using TMSCl in MeOH.18
O
O
N
N
N
H
d, e
N
H
c
H
a, b
H
H
S
H
16
H
H
CO2Me
S
O
S
S
18
17
O
O
N
N
N
H
N
N
H
H
H
f, g, h
i
N
H
H
H
H
H
H
OMs
H
H
CO2Me
OH
(-)-dihydrocorynantheol (2)
OTBS
OH
20
19
Scheme 5. Reagents and conditions: a) p-TsOH, aq. acetone (98%); b) (i) pyrrolidine, benzene,
Dean-Stark; (ii) TsS(CH2)3STs, Et3N, MeCN (85%, two steps); c) (i) KOH, t-BuOH, reflux; (ii) TMSCl,
MeOH (58%); d) MeI, aq. MeCN; e) NaBH4, MeOH (79%, two steps); f) TBSCl, DMAP, imidazole
(cat.), DMF (72%); g) LiAlH4, THF, 0 °C (94%); h) MsCl, imidazole, CH2Cl2; i) LiAlH4, dioxane, reflux
(65%, two steps).

HETEROCYCLES, Vol. 70, 2006
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The treatment of 18 with iodomethane in aqueous acetonitrile followed by the reduction of the resulting
29
aldehyde with sodium borohydride yielded 19, [α]D –20.0° (c 1.01, CHCl3), as yellow amorphous
powder. The primary alcohol (19) was first protected as TBS ether, which was then treated with lithium
aluminum hydride in THF to convert the ester functionality into a primary hydroxy group. After
mesylation, the resulting mesylate (20) was subjected to reduction using lithium aluminum hydride in
boiling dioxane to furnish, with the concomitant reduction of the amide functionality to amine as well as
24
the deprotection of the TBS group, (–)-dihydrocorynantheol (2), mp 176–179 °C, [α]D –16.3° (c 0.3,
pyridine),19 [lit.,9d mp 178–180 °C, [α]D24 –30±2° (c 0.68, pyridine).
In conclusion, we have accomplished the total synthesis of (–)-dihydrocorynantheol starting from the
bicyclo[3.2.1]octenone chiral building block we developed by exploiting a practical method that enables
the relay of the tandem retro-aldol-Pictet-Spengler reaction giving 18-keto-pseudoyohimbane with its
epimerization at C-3 to give the 18-keto-yohimbane skeleton and have extended the versatility of such a
chiral building block.
REFERENCES (AND NOTES)
† This paper is dedicated to Professor Steven M. Weinreb on the occasion of his 65th birthday.
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(e) K. Hanada, N. Miyazawa, and K. Ogasawara, Chem. Pharm. Bull., 2003, 51, 104.
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6. For pioneering work on C-3 epimerization of corynanthe-type indole alkaloids, see (a) R. B.
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HETEROCYCLES, Vol. 70, 2006
'Alkaloids: Chemical and Biological Perspectives,' Vol. 8, ed. by S. W. Pelletier, Springer Verlag,
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and T. Kametani, Heterocycles, 1985, 23, 835.
11. Calculations were performed on Chem 3D (Cambridge Soft) using the MM2 force field.
12. All new compounds were fully characterized by spectroscopic means [1H-NMR (400 MHz in
13
CDCl3), C-NMR (100 MHz in CDCl3), IR] and gave satisfactory HREIMS. Yields referred to
homogeneous samples obtained by chromatographic purification on silica gel.
13. T. Tsunoda, R. Suzuki, and R. Noyori, Tetrahedron Lett., 1980, 21, 1357.
14. Calculations indicated that 16 is more stable than 12 by 3.5 kcal/mol.11
15. On treatment with MsOD and (CH2OD)2 in boiling 1,4-dioxane, 12 afforded C3-deuterated 16,
supporting the validity of the mechanism shown in Scheme 4.
O
O
3 N
N
3
N
MsOD
N
H
H
O
D
H
H
O
H
Dn
O
(CH2OD)2
1,4-dioxane
reflux
H
H
O
(n = 0, 1 !r 2)
16-d
12
Dn
16. R. B. Woodward, I. J. Pachter, and M. L. Scheinbaum, Org. Synth., 1974, 54, 33.
17. (a) S. Takano, K. Hiroya, and K. Ogasawara, Chem. Lett., 1983, 255; (b) M. Kawamura and K.

HETEROCYCLES, Vol. 70, 2006
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Ogasawara, Tetrahedron Lett., 1995, 36, 3369.
18. M. A. Brook and T. H. Chan, Synthesis, 1983, 201.
1
19. H-NMR (400 MHz in CDCl3), 13C-NMR (100 MHz in CDCl3), and IR data of synthetic
(–)-dihydrocorynantheol (2) were in good agreement with those reported for the natural product.
We unexpectedly observed the yellowing of 2 during the measurement of specific rotation in
pyridine. The TLC results indicate the partial decomposition of 2, which we attribute the decrease
in the absolute value of the specific rotation.