Flexible access to monoterpenoid indole alkaloids using a cyclopentanoid chiral building block

Article abstract of DOI:10.3987/COM-08-S(F)120

Expedient, diasterocontrolled transformations of 1 to the key synthetic intermediate of corynanthe, iboga, and aspidosperma-class of monoterpenoid indole alkaloids which led up to a formal synthesis of (+)-20R- dihydrocleavamine, (-)-eburnamonine, and a total synthesis of (+)-aspidospermidine (2) have been demonstrated.

Full text of DOI:10.3987/COM-08-S(F)120

HETEROCYCLES, Vol. 77, No. 2, 2009
855
HETEROCYCLES, Vol. 77, No. 2, 2009, pp. 855 - 863. © The Japan Institute of Heterocyclic Chemistry
Received, 9th October, 2008, Accepted, 10th November, 2008, Published online, 11th November, 2008
DOI: 10.3987/COM-08-S(F)120
FLEXIBLE ACCESS TO MONOTERPENOID INDOLE ALKALOIDS
USING A CYCLOPENTANOID CHIRAL BUILDING BLOCK
Masato Hayashi, Keiichi Motosawa, Atsushi Satoh, Masatoshi Shibuya,
Kunio Ogasawara, and Yoshiharu Iwabuchi*
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aobayama,
Sendai 980-8578, Japan
E-mail: iwabuchi@mail.pharm.tohoku.ac.jp
Abstract – Expedient, diasterocontrolled transformations of 1 to the key synthetic
intermediate of corynanthe, iboga, and aspidosperma-class of monoterpenoid
indole alkaloids which led up to a formal synthesis of (+)-20R-dihydrocleavamine,
(–)-eburnamonine, and a total synthesis of (+)-aspidospermidine (2) have been
demonstrated.
Molecules capable of dictating regio- and diastereoselective modifications thereof offer versatile use in
organic synthesis. We previously reported an efficient chemoenzymatic preparation of the
2,3,4-trioxycyclopentanol 1 having a dioxabicyclo[3.3.0]octane framework in both enantiomeric forms1
and demonstrated its use in the efficient stereocontrolled synthesis of α-cuparenone,2a (+)-estrone,2b
Calabar bean alkaloids,2c and Sceletium alkaloids.2d Highlighting its flexible features, we have now
explored its potential as a chiral building block for the representative class of monoterpenoid indole
alkaloids derived from secologanin:3 the facts that the overwhelming structural diversity of
monoterpenoid indole alkaloids is originated from the common intermediate, secologanin via the
adoption of multiple set of biochemical transformations and that secologanin is produced by the oxidative
scission of the cyclopentane-ring of loganin (Scheme 1) stimulated our challenge to exploit the further
versatility of 1. We report here the diastereocontrolled transformation of 1 to the key intermediates for
the synthesis of corynanthe, iboga, and aspidosperma-class of monoterpenoid indole alkaloids which led
up to a formal synthesis of (+)-20R-dihydrocleavamine (4),4 (–)-eburnamonine (6),5 and a total synthesis
of (+)-aspidospermidine (5).3b,6,7,8 (Scheme 2).
This paper is dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday.

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HETEROCYCLES, Vol. 77, No. 2, 2009
HO
CHO
H
H
O
OGlc
OGlc
H
MeO2C
H
O
MeO2C
iboga
aspidosperma
corynanthe
loganin
secologanin
Scheme 1
O
O
OH
O
Ph
N
N
N
H
N
H
present study
H
H
H
O
OPiv
H
H
H
O
OH
HO
OH
(+)-1
corynanthe
(–)-dihydrocorynantheol (2)
(–)-antirhine (3)
OH
OH
N
H
H
present study
ref. 4b
O
O
O
H
H
Ph
O
N
H
O
(–)-1
iboga
(+)-20R-dihydrocleavamine (4)
present study
HO
O
N
O
present study
N
present study
O
N
H
H
O
N
H
O
O
H
aspidosperma
(–)-eburnamonine (6)
(+)-aspidospermidine (5)
Scheme 2
The strategic point of this synthetic venture is to exploit expedient methods addressing issues on how and
when to install the requisite side chains selectively at the right positions on the periphery of the
cyclopentane ring and to cleave the exact bond by taking a full advantage of functionalities in 1.
Our effort to transform (+)-1 to a key synthetic intermediate of the corynanthe-class of indole alkaloids,
featuring the 1,2-vicinal stereogenic centers consisting of secondary alkyl carbons, was commenced with
the oxidative activation of the chiral building block (+)-1 to place the base for installation of the two alkyl
branches (Scheme 3). Thus, the oxidation of the alcohol (+)-1 was first carried out using IBX9 in DMSO
at 60 °C to give the enone 8 in 75% via the ketone 710 with the concomitant β-elimination of a cumyl
alcohol. Upon treatment with sodium borohydride in the presence of cerium(III) chloride, the enone 8
afforded the cyclopentenol 9 having the all-cis oxygen stereochemistry as a sole product via the

HETEROCYCLES, Vol. 77, No. 2, 2009
857
diasterocontrolled delivery of a hydride from the convex-face.11 The installation of the first C2 branch
was then conducted by the Eschenmoser reaction of 9 with dimethylacetamide dimethyl acetal in
diphenyl ether at 280 °C to give the single cyclopentene 10 having the acetamide moiety cis to the
acetonide moiety.1,12,13 Due to the given stereochemical arrangement, the amide 10 allowed consecutive
facile deacetonization and lactonization under acidic condition to give the δ-hydroxy-γ-lactone 11, which
on treatment with MnO2 gave the enone 12 with a biased platform suitable for the stereocontrolled
installation of the second branch intrinsic the corynanthe-family. As expected, reaction of 12 with
allyltributylstannane in CH2Cl2 at –78 °C in the presence of TBSOTf furnished the silyl enol ether 13 in
74% yield by concurrent diastereoselective 1,4-addition and O-silylation.14
O
O
O
Ph
O
Ph
c
a
b
O
O
O
O
O
O
OH
O
O
OH
O
8
(-)-1
9
7
TBSO
O
O
O
O
HO
O
O
g
d
e
f
O
O
CONMe2
13
11
12
10
HO
OTBS
O
O
OH
O
O
OTBS
N
h, i, j
N
H
k
H
H
OPiv
OH
OPiv
H
OH
16
15
14
(–)-dihydrocorynantheol (2)
k, l, m
O
CHO
N
H
H
H
H
H
N
O
O
ref. 16b
ref. 16b
SePh
H
H
O
O
O
H
OPiv
HO
H
19
17
18
H
(–)-antirhine (3)
Scheme 3. Reagents and conditions: (a) IBX, DMSO, 60 °C, 15 h (75%); (b) NaBH4, CeCl3·7H2O,
MeOH, -20 C (98%); (c) Me2NC(OMe)2Me, Ph2O, reflux, 2 h (98%); (d) 10% HCl, THF (97%); (e)
o
o
MnO2, CH2Cl2 (quant.); (f) allyltributyltin, TBSOTf, CH2Cl2, -78 C (74%); (g) NaBH4, EtOH, reflux
(77%); (h) PivCl, Et3N, DMAP, CH2Cl2 (75%); (i) PCC, MS 4Å, CH2Cl2 (89%); (j) mCPBA, NaHCO3,
CH2Cl2 (83%); (k) aq. HF, MeCN, (l) NaBH4, MeOH, 0 °C; (m) PPTS, toluene (64%, 3 steps).

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HETEROCYCLES, Vol. 77, No. 2, 2009
The task for a regioselective cleavage of the cyclopentane ring of 13 suitable for the corynanthe-class of
indole alkaloid could be facilitated with an unexpected side reaction provoked by a protecting group.
Thus, on treatment with sodium borohydride in boiling EtOH, 13 gave the diol 14 in 77% yield via the
concomitant migration of a TBS group to the possible secondary oxyanion generated right after the partial
reduction of the γ-lactone 13. The selective protection of the primary hydroxy group of 14 as the
pivalate and PCC oxidation of the remaining secondary hydroxy group and the following Baeyer-Villiger
oxidation using mCPBA afforded the lactone 15. On HF-mediated deprotection of TBS group, 15 gave
16, which on sequential sodium borohydride treatment in MeOH, and PPTS-catalyzed lactonization with
azeotropic removal of water afforded the δ-lactone 17, [α]D +9.23o (c 0.86, CHCl3). In light of the
28
close topological correlations and the functionalities of 16 and 17 with the non-tryptamine moieties of 2
and 3, respectively, 16 should be a potential synthon of (–)-dihydrocorynantheol (2)15 and (–)-antirhine
(3).16b,g
The synthetic effort directed toward iboga-type indole alkaloid was put into practice by setting the exact
target to (+)-20R-dihydrocleavamine (4), where the construction of the characterictic 1,3-vicinal tertiary
alkyl centers was accomplished by applying the Stork radical cyclization protocol17 to the allyl alcohol
ent-11 as the key step (Scheme 4). Thus, treament of ent-11, prepared from (–)-1 by employing the
same sequence as shown in Scheme 3, with NBS in CH2Cl2 in the presence of ethyl vinyl ether and
sodium bicarbonate gave quantitatively the bromoethyl acetal 20, which on treatment with AIBN in
boiling toluene in the presence of Bu3SnH furnished the tricyclic lactone 21 in 77% yield.
EtO
O
EtO
O
Br
S
S
HO
O
HO
O
c, d
b
a
f
e
ent-11
O
O
O
O
O
O
23
22
21
20
OH
N
H
HO
HO
HO
HO
g
ref. 4b
H
H
N
H
O
H
CONHMe
CONHMe
24
26
25
(+)-20R-dihydrocleavamine (4)
O
Scheme 4. Reagents and conditions: (a) ethyl vinyl ether, NBS, NaHCO3, CH2Cl2 (98%); (b) Bu3SnH,
AIBN, toluene, reflux (77%); (c) PPTS, MeCN, H2O, reflux (92%); (d) HS(CH2)2SH, BF3·OEt2, (quant.);
(e) Raney Ni, EtOH (78%); (f) MeNH2, AlMe3, THF, reflux (74%); (g) NaIO4, THF, H2O then NaBH4,
then 10% HCl (64%).

HETEROCYCLES, Vol. 77, No. 2, 2009
859
After acidic hydrolysis of the acetal moiety of 21, the resulting lactol was converted to the dithiane 22 on
treatment with ethanedithiol and BF3·OEt2. Upon exposure to Raney-Nickel in EtOH, 22 furnished the
hydroxy-lactone 23 with the requisite 20R-ethyl group being arranged in 78% yield. Then, the
hydroxy-lactone 23 was exposed to the complex generated from methylamine hydrochloride and
trimethylaluminum in THF at reflux to give the dihydroxy-amide 24.18 On sequential periodate cleavage
and borohydride reduction in the same flask, 24 afforded the lactone 26, [α]D31 -0.47 (c 0.11, CHCl3) {lit.,
[α]D -0.5 (c 1.0, CHCl3)4b}, via diol 25 through a conccurent cyclization during the acidic work up.
26
Since 26 has been transformed into (+)-20R-dihydrocleavamine (4), this constitutes the development of
new formal route to this alkaloid.4b
Exploration of a route to aspidosperma-type indole alkaloid was carried out targeting
(+)-aspidospermidine (5) with the intention of adopting the Harley-Mason’s protocol. 8
The synthesis was commenced with the formal substitution of the vinylic hydrogen of ent-8 with an ethyl
group to prepare for the construction of the quarternary carbon characteristic to aspidosperma-family
(Scheme 5). The task was executed via a sequence involving the conjugate addition of a cuprate
generated from ethylmagnesium bromide in THF containing HMPA in the presence of copper(I) iodide
and triethysilyl chloride at –40 °C, followed by the in situ trapping of the enolate with triethysilyl chloride,
and the subsequent oxidation of the resulting silyl enol ether 27 by the palladium-catalyzed protocol
developed by Ito and Saegusa19 to furnish the β-ethyl enone 28 in 89%. The reduction of 28 with
sodium borohydride in MeOH at –40 °C in the presence of cerium(III) chloride gave the endo-allyl
alcohol 29 as the only product by convex-face selective 1,2-reduction. The Eschenmoser rearrangement
reaction1,12,13 of 29 was carried in boiling diphenyl ether (~ 280 °C) to give the acetamide 30 having the
desired quarternary center in 86% yield as the single product. The acetamide moiety thus arranged was
transformed into the hydroxylethyl handle, which is essential for the Harley-Mason reaction, by treating
30 with LiEt3BH20 in THF.
Having served its dual purpose as a stereocontrolling element and a protecting group, the
dioxabicyclo[3.3.0]octane moiety of 31 was converted into the two side chains of the secologanin-derived
C9 unit suitable for merger with a tryptamine.
Thus, posterior to the hydrogenation of 31, the
treatment of the resulting product with HIO4 in 1,4-dioxane-H2O afforded the dioxabicyclo[4.3.0]nonane
lactol 32, via the sequential hydrolysis of the acetonide moiety, the oxidative cleavage of the resulting
1,2-glycol, and further spontaneous cyclization, which on oxidation with cat. TPAP and NMO21 yielded
the dioxabicyclo[4.3.0]nonane lactone 33, as an armed form of the key C9 unit. The projected merger
was then conducted by treating 33 with tryptamine in boiling toluene to give the known secondary amide
34, hereby establishing the formal synthesis6a,c of aspidospermidine. As a result of our serious attack to

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HETEROCYCLES, Vol. 77, No. 2, 2009
accomplish the synthesis, we found efficient conditions for the promotion of the Pictet-Spengler
cyclization of 34. Thus, on warming in phenol22 with a catalytic amount of H2SO4 at 50 °C for 1 h, 34
induced diasteroselective cyclization to give 36 in 70% yield as a 10:1 mixture with C(3) β-epimer as the
major product.23
OH
O
O
OTES
O
O
O
O
O
O
O
O
a
b
c
27
28
29
ent-8
O
O
O
O
O
d
e
OH
OH
f, g
O
O
NMe2
30
31
OH
O
HN
O
N
O
O
O
N
H
h
i
N
H
j
H
H
O
O
HO
HO
34
O
33
32
35
O
N
H
H
N
N
O
N
H
l
k
H
N
H
N
H
HO
36
37
(+)-aspidospermidine (5)
H
H
N
ref. 5c, 6a
N
ref. 5c, 6a
N
H
N
8
ent-36
O
HO
(–)-eburnamonine (6)
38
Scheme 5. Reagents and conditions: (a) EtMgBr, CuI, HMPA, TESCl, THF, -78 to -40 °C; (b) Pd(OAc)2,
O2, DMSO, 50 °C, 9 h (89%, 2 steps); (c) NaBH4, CeCl3·7H2O, MeOH, -40 °C (90%); (d)
Me2NC(OMe)2Me, Ph2O, reflux, 2 h (86%); (e) LiEt3BH, THF, 0 °C (quant.); (f) H2, 10% Pd-C, AcOEt
(quant.); (g) HIO4·2H2O, dioxane-H2O (1:1), rt; (h) TPAP, NMO, CH2Cl2, rt (94%, 2 steps); (i) tryptamine,
toluene, reflux, 2 h; (j) cat. H2SO4, phenol, 50 °C, 1 h (70%, 2 steps); (k) 40% aq. H2SO4, 110 °C, 1.5 h;
(l) LiAlH4, THF, reflux, 2 h (51%, 2 steps).

HETEROCYCLES, Vol. 77, No. 2, 2009
861
Note that the well-precedent protocol required 48 h refluxing in acetic acid for the Pictet-Spengler
reaction to give a 1:1 mixture of the C(3)α, and β-epimers as their acetate in moderate (up to 50%) yield,
which required the subsequent alkaline hydrolysis to detach the acetate moiety. The conversion of the
alcohol 36 to (+)-aspidospermidine (5) was carried out as described by Harley-Mason and Kaplan:
treatment7 in 40% H2SO4 at 100-110 °C for 1.5 h to give 37, and immediate reduction of 37 with LiAlH4
in refluxing THF to give (+)-aspidospermidine (5) in 51% yield. The spectral data (1H and 13C NMR, IR,
23
MS), mp (115-118 °C) and specific rotation of synthetic aspidospermidine [α]D +16.4° (c 1.01 EtOH)
were consistent with reported values22 (mp 120-121 °C, [α]D +17.0 (c 0.60, EtOH)). The present
23
synthesis implies development of a new diastero- and enantiocontrolled synthesis of ebrunamonine, the
medicinally important eburnane-class of indole alkaloid, since the starting ketone 1 is available in both
enantiomeric form and the transformation of 36 to eburnamonine (6) via 385c,6a has been established.
In conclusion, we have demonstrated the transformation of 1 to the key synthetic intermediates of
corynanthe, iboga, and aspidosperma-class of monoterpenoid indole alkaloids which led up to a formal
synthesis of (+)-20R-dihydrocleavamine, (–)-eburnamonine, and a total synthesis of (+)-aspidospermidine
(2), thereby extending the utility of 1 as a chiral building block.
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