Total Synthesis of (-)-Lepadiformine A Utilizing Hg(OTf)2-Catalyzed Cycloisomerization Reaction

Article abstract of DOI:10.1021/acs.orglett.5b02867

A cytotoxic marine alkaloid (-)-lepadiformine A (1) possesses a unique structure characterized by the trans-1-azadecalin AB ring system fused with the AC spiro-cyclic ring. In this research, we found that a cycloisomerization reaction from amino ynone 2 t

Full text of DOI:10.1021/acs.orglett.5b02867

Letter
pubs.acs.org/OrgLett
Total Synthesis of (−)-Lepadiformine A Utilizing Hg(OTf) ‑Catalyzed
2
Cycloisomerization Reaction
Keisuke Nishikawa, Seiho Kikuchi, Shinnosuke Ezaki, Tomoyuki Koyama, Haruka Nokubo,
Takeshi Kodama, Yoshimitsu Tachi, and Yoshiki Morimoto*
Department of Chemistry, Graduate School of Science, Osaka City University, Sumiyoshi-ku, Osaka 558-8585, Japan
*
S Supporting Information
ABSTRACT: A cytotoxic marine alkaloid (−)-lepadiformine A
1) possesses a unique structure characterized by the trans-1-
(
azadecalin AB ring system fused with the AC spiro-cyclic ring. In
this research, we found that a cycloisomerization reaction from
amino ynone 2 to a 1-azaspiro[4.5]decane skeleton 3,
corresponding to the AC ring system of 1, is promoted by
Hg(OTf) . Thus, we have accomplished the efficient total
2
synthesis of (−)-lepadiformine A in 28% overall yield by
featuring the novel Hg(OTf) -catalyzed cycloisomerization.
2
1
,4
5
6
n azatricyclic alkaloid (−)-lepadiformine A (1) was
alkaloids such as lepadiformines, cylindricines, polycitorols,
7
8
A
isolated from the marine tunicate Clavelina lepadiformis
FR901483, and Kopsia alkaloids. It was envisioned that the
desired azaspiro compound 3 could be obtained from an acyclic
amino ynone 2 in one step if 6-exo-dig oxymetalation and
aminoketalization for the substrate 2 with metal catalysis and
Mu
̈
ller in the Mediterranean near Tunisia by Biard and co-
1
workers in 1994 (Figure 1). Compound 1 exhibits
9
subsequent Ferrier-type cyclization consecutively proceeded as
shown in Scheme 1. It was investigated using substrate 4
whether or not such a cycloisomerization reaction takes place
(
Table 1).
Scheme 1. Metal-Catalyzed Cycloisomerization Reaction
Figure 1. Structure of (−)-lepadiformine A (1).
cytotoxicities against various tumor cells [IC50 = 9.20 μg/mL
(
(
KB), 0.75 μg/mL (HT29), 3.10 μg/mL (P388), 6.30 μg/mL
P388 doxorubicin-resistant), and 6.10 μg/mL (NSCLS-N6)]
and also possesses antiarrhythmic and antihypertensive proper-
ties. Although the structure different from 1 was first proposed
based on spectroscopic and chemical methods, the original
structure was finally revised to 1 through total synthesis by the
2
Kibayashi and Weinreb groups. The complex skeleton
structure is characterized by the trans-1-azadecalin AB ring
system fused with the AC spiro-cyclic ring, four asymmetric
centers including a nitrogen-containing stereogenic tetrasub-
stituted carbon, and the B ring as a boat form. Although the
specific skeleton structure and the interesting biological
activities have prompted many synthetic organic chemists to
promote the total synthesis so far, we intended to carry out
the efficient total synthesis of (−)-1 based on our original
synthetic methodology. In this contribution, we report the total
1
0
First, gold catalysts known as a good ynophile were
examined. Although AuCl and AuCl showed little reactivity,
recovering only starting material 4 (entries 1 and 2), it was
found that Ph PAuOTf and Ph PAuBF brought about the
cycloisomerization to afford desired spiro product 5 albeit in
modest yields (entries 3 and 4). Only AgOTf required for
preparation of Ph PAuOTf resulted in no reaction (entry 5).
Platinum catalysts (entries 6 and 7) afforded compound 5 in
low yields along with alkyne hydration byproduct 6, which was
3
3
3
4
12
2
,3
3
synthesis of (−)-lepadiformine A (1) utilizing a Hg(OTf) -
2
catalyzed cycloisomerization reaction as a key step.
We focused on construction of a 1-azaspiro[4.5]decane
skeleton corresponding to the AC spiro-cyclic ring system of 1,
because the skeleton is embedded in a number of complex
Received: October 3, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02867
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Conditions for the Cycloisomerization Reaction
to functionalized amino ynone precursor 8 bearing all carbon
numbers required for the synthesis of 1. The product 7 could
be converted into (−)-lepadiformine A (1) via deoxygenation
and the B ring formation according to Kibayashi’s and Zhao’s
3c,i
precedents. The precursor 8 would be prepared by acylation
of sulfone 10, which should be assembled from the known
14
15
hemiacetal 11 and alkyne 12, with the known pyrrolidinone
a
yield (%)
16
9
.
entry
catalyst
AuCl
solvent
time
14 h
5
4
6
The synthesis of the cyclization precursor 8 began with
1
2
3
4
5
6
7
8
9
MeCN
MeCN
CH Cl
65
57
Wittig olefination of the hemiacetal 11 with pentylidene-
triphenylphosphorane to provide Z-selective alkene 13
(Scheme 3). After hydrogenation of the alkene 13 and
subsequent iodination of the alcohol, alkylation of the lithium
AuCl3
22 h
b
Ph PAuOTf
3
30 min
30 h
53
47
2
2
b
Ph PAuBF4
3
MeCN
17
AgOTf
PtCl2
MeCN
CH Cl
23 h
73
11
acetylide of 12 with iodide 14 and selective deprotection of
the DPS group afforded alcohol 15. Conversion of the alcohol
15 to sulfone 10 was carried out via iodination and
sulfonylation, and acylation of an α-anion of sulfone 10 with
42 h
21
22
40
23
12
16
2
2
c
PtCl4
CH Cl
5 h
2
2
Pd(TFA)2
Hg(OTf)2
Hg(OTf)2
Hg(OTf)2
MeCN
CH Cl
13 h
21
10
18
40 min
40 min
1 h
71
74
64
61
pyrrolidinone 9 followed by desulfonylation prepared the
functionalized cyclization substrate 8 in high overall yield. After
optimization of the reaction conditions, ynone 8 was treated
2
2
10
11
12
MeCN
toluene
MeCN
33
d
Hg(OTf)2
25 min
with 0.2 equiv of Hg(OTf) in MeCN at −20 to 0 °C for 5 min
2
a
b
Isolated yield. These catalysts were prepared in situ from Ph PAuCl
and AgOTf or AgBF (ref 11). 10 mol %. MS4A (100 wt %) was
added.
to give the desired AC spiro-cyclic ring system 7 in 78% yield
3
c
d
19
4
and good diastereoselectivity (dr = 13:1).
The reaction mechanism and the diastereoselectivity of the
cycloisomerization that we propose at present are shown in
Scheme 3. As predicted in Scheme 1, a 6-exo-dig intramolecular
also generated in a palladium-catalyzed reaction (entry 8).
13
oxymercuration initiated by coordination of Hg(OTf) to the
2
Next, mercury(II) triflate, as a good ynophile as a gold(I)
catalyst, was tested. To our delight, it was found that Hg(OTf)2
effected the cycloisomerization reaction in better yields than
gold(I) catalysts (entries 9−11). As the alkyne hydration
byproduct 6 was observed, the reaction was conducted in the
presence of molecular sieves (MS); however, the yield of 5
could not be improved (entry 12). Thus, we could develop the
alkyne π-electron and nucleophilic addition of the nitrogen
function to the carbonyl carbon would produce aminoketal a.
The aminoketal could be cleaved by protonation of the enol
ether with TfOH generated to afford iminium ion intermediate
20
b. Although an α-mercury carbonyl in b would be in
equilibrium with the enolate form c, we think that the α-
mercury carbonyl would predominate due to the stability of a
Hg(OTf) -catalyzed cycloisomerization reaction from acyclic
2
21
C−Hg bond. The spiro-cyclic products could be obtained by
amino ynone 2 to spiro compound 3, a 1-azaspiro[4.5]decane
skeleton frequently occurring in the aforementhioned complex
alkaloids. With this method in hand, we embarked on the total
synthesis of (−)-lepadiformine A (1).
The retrosynthetic analysis of 1 was outlined in Scheme 2.
We planned to construct the AC spiro-cyclic ring system 7 by
reforming a carbocycle via Ferrier-type cyclization with
regeneration of a Hg(OTf) catalyst, yielding diastereoselec-
2
tively 7 along with a minor product 16. Considering chairlike
transition states d−h in the cyclization, d−f could be more
stable than g and h because in g and h a bulky NBoc iminium
moiety is disposed in an axial position. In transition states d−f,
f with a bulky TBSO-containing alkyl group in an axial
applying the Hg(OTf) -catalyzed cycloisomerization reaction
2
22
position and e with steric repulsion between benzyloxymethyl
Scheme 2. Retrosynthetic Analysis of (−)-Lepadiformine A
1)
and the TBSO-containing alkyl groups would be less stable
(
3c
than d without such steric repulsion. Thus, 7 would be
selectively produced by way of the transition state d.
The residual tasks toward the total synthesis are deoxyge-
nation in the A ring and formation of the B ring.
Deoxygenation of 7 was performed according to Barton’s
23
24
method after diastereoselective reduction to axial alcohol 17
to furnish 19 in good yield (Scheme 4). After removal of both
the Boc and TBS protective groups in 19 with TFA, the
resulting amino alcohol was subjected to Kibayashi’s and Zhao’s
3c,i
procedure to provide azatricyclic ring system 20 via the B
ring formation accompanied by inversion of configuration.
Finally, deprotection of a Bn group in 20 gave synthetic
1
13
(
−)-lepadiformine A (1), the spectral data ( H and C NMR)
30
and the optical rotation of which, [α]D −14.6 (c 0.38,
MeOH), were consistent with those reported for the previous
2c
20
synthetic one, lit. [α] −15 (c 0.45, MeOH). We confirmed
D
that the spectral data and the optical rotation of the
hydrochloride salt 21, [α]D30 +2.2 (c 0.70, CHCl ), are also
3
B
DOI: 10.1021/acs.orglett.5b02867
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Synthesis of the AC Spiro-cyclic Ring System 7
Scheme 4. Total Synthesis of (−)-Lepadiformine A (1)
utilizing the cycloisomerization of 8 to 7 as a key step. The
synthesis has been efficiently achieved in 28% overall yield and
14
1
6 steps based on the known hemiacetal 11. This novel
Hg(OTf) -catalyzed cycloisomerization reaction could be
2
useful for the construction of complex polycyclic alkaloids. A
detailed reaction mechanism of the cycloisomerization and its
application to other natural products are under investigation.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02867.
Experimental procedures, spectroscopic data, copies of
1
13
H and C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
E-mail: morimoto@sci.osaka-cu.ac.jp.
■
*
Notes
2c
20
The authors declare no competing financial interest.
comparable to those reported for the authentic one, lit. [α]
D
+
2.5 (c 0.51, CHCl3).
In conclusion, we have developed the novel construction
ACKNOWLEDGMENTS
This work was financially supported by the Astellas Foundation.
■
method of a 1-azaspiro[4.5]decane skeleton, frequently
occurring in many complex polycyclic alkaloids, by using a
Hg(OTf) -catalyzed cycloisomerization reaction from an
acyclic amino ynone substrate and accomplished the total
synthesis of an azatricyclic alkaloid (−)-lepadiformine A (1)
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(
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D
DOI: 10.1021/acs.orglett.5b02867
Org. Lett. XXXX, XXX, XXX−XXX