Total synthesis of aspidophytine

Article abstract of DOI:10.1016/j.tetlet.2006.08.115

A total synthesis of aspidophytine was accomplished by employing a newly developed strategy for the enantiospecific syntheses of aspidosperma alkaloids. The key steps involve a novel ketene-lactonization reaction of a chiral vinyl sulfoxide (Marino annula

Full text of DOI:10.1016/j.tetlet.2006.08.115

Tetrahedron Letters 47 (2006) 7711–7713
Total synthesis of aspidophytine
Joseph P. Marino* and Ganfeng Cao
Department of Chemistry, The University of Michigan, Ann Arbor, MI 48109, United States
Received 4 August 2006; revised 23 August 2006; accepted 25 August 2006
Available online 18 September 2006
Abstract—A total synthesis of aspidophytine was accomplished by employing a newly developed strategy for the enantiospecific syn-
theses of aspidosperma alkaloids. The key steps involve a novel ketene-lactonization reaction of a chiral vinyl sulfoxide (Marino
annulation reaction) to set up the chiral quaternary carbon center, and a tandem Michael addition-alkylation reaction sequence
to form the polycyclic core structure.
Ó 2006 Elsevier Ltd. All rights reserved.
Recently, we reported a total synthesis of (+)-aspido-
spermidine 1 via the Marino annulation reaction, and
demonstrated a new, efficient and highly enantiospecific
synthetic strategy for the syntheses of aspidosperma
alkaloids.1,2 In order to further evaluate this new syn-
thetic strategy and exploit the power of Marino annula-
tion reaction for the formation of chiral quaternary
carbon centers, we initiated the research toward the con-
struction of a more complex structure aspidophytine 2.3
Here, we describe a completed total synthesis of aspido-
phytine 2, a potential synthetic precursor for haplo-
phytine 3 (Fig. 1).
N
N
H
O
MeO
N
O
N
H
H
MeO
Me
H
Aspidospermidine (1)
Aspidophytine (2)
Me
N
O
N
N
HO
O
O
MeO
N
O
H
MeO
Me
Haplophytine 3 is one of the active chemical compo-
nents of ‘La hierba de la cucaracha’, an anticockroach/
insecticidal powder extracted from the dried leaves of
the plant Haplophyton Cimicidium. The degradative
product aspidophytine 2 was isolated after haplophytine
3 was subjected to strong proteolytic conditions. Two
asymmetric syntheses of aspidophytine 2 were com-
pleted by Corey’s group in 1999 and by Fukuyama’
group in 2003, respectively.4 Most recently, Padwa’s
group also successfully synthesized aspidophytine 2 in
its racemic form5.
Haplophytine (3)
Figure 1.
Our synthesis started with the preparation of a chiral
alkynylsulfoxide 9. A process of dianion alkylation6
with benzyl 2-iodoethyl ether 47 converted b-ketoester
5 to an exclusively c-alkylated product 6. Compound 6
was then b-alkylated with propargyl bromide, followed
by decarboxylation, ketal formation to give alkyne 8
in 63% yield over three steps. Treatment of 8 with
n-BuLi and then MgBr2 formed an alkynyl Grignard
reagent, which was added to Evans’ chiral N-sul-
finyloxazolidinone A8 to form chiral alkynyl sulfoxide
9 in 78% yield (Scheme 1).
Keywords: Aspidophytine; Haplophytine; Aspidosperma alkaloids;
Quaternary carbon center; Chiral vinyl sulfoxide; Ketene-lactoniza-
tion; Marino annulation reaction; Enantiospecific; Tandem.
Once the chiral alkynyl 9 was in hand, it was coupled
with an N-protected dimethoxy aniline 109 by being
added to the cuprate reagent formed from transmetalla-
tion of the ortholithiated intermediate derived from 10
*
Corresponding author at present address: Department of Chemistry
and Biochemistry, University of Notre Dame, Notre Dame, IN
46556, United States. Tel.: +1 574 631 6456; e-mail:
Joseph.P.Marino.12@nd.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.115

7712
J. P. Marino, G. Cao / Tetrahedron Letters 47 (2006) 7711–7713
O
O
hydrolyzed. By employing the mixed anhydride proto-
col, the so formed carboxylic acid was linked to 3-chlo-
ropropylamine to give amide 15 in 64% over two steps.
A tandem conjugate addition-intramolecular alkylation
reaction sequence was triggered once amide 15 came
into contact with NaH, forming what will become the
C- and D-rings of aspidophytine. The product was fur-
ther oxidized through a modified Saegusa reaction to
furnish tricyclic enone 16. When enone 16 was stirred
in formic acid overnight, multiple events occurred and
a rather advanced intermediate, pentacyclic structure
17 was obtained in 90% yield. These events included
the removal of two Boc groups, N-formylation and an
intramolecular Michael addition reaction to form the
B-ring. A Stille reduction reaction4,10 was then applied
to transform the ketone functionality in compound 17
to a double bond, and carboxylic acid 18 was secured
after the side chain primary alcohol was deprotected
and oxidized11 (Scheme 2).
O
O
a
BnO
BnO
BnO
+
I
Ot-Bu
Ot-Bu
4
5
6
O
b,c
O
O
d
BnO
7
8
O
O
O
e
O
S
BnO
p
-Tol
N
O
O
S
Me
A
Ph
p-Tol
9
Scheme 1. Reagents and conditions: (a) THF, NaH, 0 °C, n-BuLi,
À78 °C, 83%. (b) NaOEt/EtOH, 3 equiv proparagyl bromide; (c)
TsOH, benzene, reflux; (d) ethylene glycol, TsOH, benzene, reflux, 63%
over three steps; (e) THF, n-BuLi, À78 °C then MgBr2, 0 °C, then A,
(4R, 5S)-4-methyl-5-phenyl-3-[(R)-p-tolysulfinyl]-2-isoxazolidinone,
À78 °C, 78%.
with CuBrÆMe2S. To the adduct, a second Boc group
was introduced and a stereodefined chiral vinyl sulfoxide
11 was obtained. Subsequently, the reaction of this vinyl
sulfoxide with the in situ formed dichloroketene from
trichloroacetyl chloride and a zinc-copper reagent (Mar-
ino annulation reaction), delivered lactone 12 with a
chiral quaternary carbon center in 84% yield. After
dechlorination with Et3B/n-Bu3SnH and the deprotec-
tion of the ketal, lactone 13 was generated. The lactone
13 was then opened by pyrrolidine to afford aldehyde 14
in 86% yield. A subsequent intramolecular aldol conden-
sation process set up the nascent C-ring of aspido-
phytine, concurrently the pyrrolidine amide was
Finally, the two amide groups in structure 18 were
reduced by the combination of Meerwein’s salt with
NaBH4,12 and the product was further treated sequen-
tially by K3Fe(CN)6 and NaHCO3 (oxidative lactone
formation conditions invented by Corey) to give aspido-
phytine 2 in 40% yield over two steps. The spectroscopic
data and optical rotation of 2 were consistent with those
reported.4,5
In summary, we completed an enantiospecific total
synthesis of aspidophytine 2. The synthetic success with
both aspidospermidine 1 and aspidophytine 2 further
O
p-Tol
OMe
S S
O
O
OMe
BnO
NBoc2
O
O
NBoc2
OMe
a,b
c
BnO
Cl
MeO
MeO
NHBoc
Cl
MeO
10
O
p-Tol
S
O
OMe
11
12
d,e
OMe
OMe
OMe
OMe
O
MeO
Boc2N
O
N
H
Cl
O
NBoc2
NBoc2
N
g,h
f
BnO
BnO
OBn
H
O
p-Tol
S
13
O
O
15
O
O
14
i,j
O
O
O
N
N
N
C
D
H
H
H
CO2H o,p
l,m,n
k
A
B
E
OBn
OBn
2
MeO
MeO
MeO
N
O
MeO
N
O
H
NBoc2
H
MeO
MeO
O
H
18
O
H
17
16
Scheme 2. Reagents and conditions: (a) 2 equiv t-BuLi, 1 equiv CuBrÆMe2S, then 9, THF, À78 °C, 75%; (b) MeLi, Boc2O, THF, À78 °C, 85%. (c)
Zn(Cu), Cl3CCOCl, THF, À45 °C, 84%; (d) n-Bu3SnH, cat. Et3B, benzene, reflux, 87%; (e) Acetone, cat. p-TsOH, rt, 85%; (f) Pyrrolidine, benzene,
rt, 80%; (g) Pyrrolidine, i-PrOH, 33% aq AcOH; (h) i-BuOCOCl, Et3N, 3-chloropropylamine hydrochloride, THF, 0 °C, 67%, (two steps); (i) NaH,
DMF, 0 °C, 88%; (j) KHMDS, TMSCl, THF, À78 °C, then Pd(OAc)2/O2, DMSO, 60 °C, 85%; (k) HCO2H, rt, 90%; (l) THF, À78 °C, KHMDS,
PhN(Tf)2, 85%; Pd(PPh3)4, (Bu)3SnH, 85%; (m) Pd/C, H2, CH3OH, 92%; (n) PDC, wet DMF, 75%; (o) Et3OBF4, CH2Cl2 then NaBH4, EtOH; (p)
K3Fe(CN)6, t-BuOH/H2O then NaHCO3, 40% (two steps).

J. P. Marino, G. Cao / Tetrahedron Letters 47 (2006) 7711–7713
7713
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Acknowledgments
The research on the syntheses of aspidosperma alkaloids
was originally supported by NIH (CA22237). G.C.
thanks Chemistry Department, University of Michigan,
for the financial support.
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