Total synthesis of (±)-lepadiformine a via radical translocation-cyclization reaction

Article abstract of DOI:10.1055/s-0029-1219389

A total synthesis of (±)-lepadiformine A was accomplished through construction of the 1-azaspiro[4.5]decane skeleton by a sequential radical translocation-cyclization reaction.

Full text of DOI:10.1055/s-0029-1219389

822
LETTER
Total Synthesis of ( )-Lepadiformine A via Radical Translocation–Cyclization
Reaction
Total
Synthesis of
(
)-
a
Lepadiform
n
ine
A
abu Fujitani, Masami Tsuchiya, Kentaro Okano, Kiyosei Takasu,1 Masataka Ihara,2 Hidetoshi Tokuyama*
Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki, Aoba-ku, 980-8578 Sendai, Japan
Fax +81(22)7956877; E-mail: tokuyama@mail.pharm.tohoku.ac.jp
Received 19 November 2009
precursor under neutral conditions. During the studies of
Abstract: A total synthesis of ( )-lepadiformine A was accom-
plished through construction of the 1-azaspiro[4.5]decane skeleton
by a sequential radical translocation–cyclization reaction.
this process, we then investigated the feasibility of the
construction of a 1-azaspiro[4.5]decane framework,
which is the core skeleton of lepadiformines. Herein, we
report the total synthesis of ( )-lepadiformine A (1) fea-
Key words: radical reaction, cyclization, domino reaction, natural
products, total synthesis
O
CO2Me
n-Bu3SnH
AIBN
A variety of structurally unique alkaloids are found in ma-
rine sources. Among them, lepadiformines (A–C, 1–3)
isolated from the tunicate Clavelina lepadiformis and
Clavelina moluccensis by Biard and co-workers
(Figure 1),3 exhibit modest cytotoxic activity towards var-
ious cardiovascular effects in vitro and in vivo.3b,4 In
2000, Kibayashi and co-workers revised the originally
proposed structure of lepadiformine (4) to structure 1 by
their first total synthesis.5a Because of the unique azaspi-
rocyclic skeleton with four asymmetric stereocenters,
these compounds have been attractive targets for the syn-
thetic community. To date, a number of synthetic ap-
proaches have been reported.5
BnN
Br
benzene
reflux
N
MeO2C
88%
(dr = 78:22)
O
6
5
generation of
5-exo
cyclization
sp2-radical species
CO2Me
radical
translocation
H
•
•
N
O
CO2Me
N
Bn
O
7
8
Scheme 1 Stereoselective construction of 6-azaspiro[4.5]decane
skeleton of ( )-halichlorine
R1
R2
N
N
N
H
H
R1
R2
n-Hex
O
lepadiformine A (1) R1 = CH2OH, R2 = n-Hex
B (2) R1 = CH2OH, R2 = n-Bu
putative lepadiformine (
4)
1
C (3) R1 = H, R2 = n-Bu
NBoc
N
CHO
BnO
BnO
Figure 1 The family of lepadiformines A–C (1–3) and the putative
structure of lepadiformine (4)
R2
9
10
Recently, we have developed a diastereoselective cascade
radical translocation–cyclization reaction6 to construct the
6-azaspiro[4.5]decane skeleton of ( )-halichlorine
(Scheme 1).7 The reaction is initiated by the 1,5-radical
translocation from sp2-radical 7 to generate the more sta-
ble nitrogen-substituted sp3-radical 8. Then 5-exo cycliza-
tion proceeds to construct the azaspiro compound 6. This
reaction was proven to be quite effective for stereoselec-
tive construction of the consecutive quaternary and tertia-
ry stereogenic centers from a readily available lactam
SO2Ph
SO2Ph
NPMB
NBoc
R1
O
11
12
radical
translocation–
cyclization
reaction
SO2Ph
O
( )4
N
O
O
N
H
MeO
I
13
14
SYNLETT 2010, No. 5, pp 0822–0826
1
6.
3
.2
0
1
0
Advanced online publication: 10.02.2010
DOI: 10.1055/s-0029-1219389; Art ID: U11109ST
Scheme 2 Retrosynthetic analysis
© Georg Thieme Verlag Stuttgart · New York

LETTER
Total Synthesis of ( )-Lepadiformine A
823
philic addition to the iminium ion 9. Compound 10 could
be prepared from lactam 12 by introduction of a hy-
droxymethyl group followed by alkylation at the a-posi-
tion of sulfone.
Cl
MeO
I
15
1) NaBH , MeOH
O
O
4
N
KOH, TBAI
–10 °C
O
N
O
DMF
2) PhSO2H, CaCl2
CH2Cl2, r.t.
88% (2 steps)
For the crucial construction of the azaspirocyclic frame-
work, we applied the radical translocation–cyclization re-
action to alkenyl sulfone 13, which is readily prepared
from succinimide (14).
r.t. to 60 °C
63%
H
MeO
I
14
16
( )4
BrMg
The synthesis of the precursor for the key radical reaction
commenced with alkylation of succinimide (14) with
known benzyl chloride 15 according to the reported pro-
cedure (Scheme 3).8 The imide 16 thus obtained was
transformed to the corresponding sulfone 17 by partial re-
duction of imide and subsequent sulfonylation. The alkyl
side chain was then introduced by addition of a Grignard
reagent in the presence of ZnCl2 to provide 18,9 which was
subjected to cross metathesis with vinyl sulfone to give
the radical reaction precursor 13.10
O
O
( )4
SO2Ph
N
N
ZnCl2
CH2Cl2–Et2O
0 °C
MeO
I
MeO
I
85%
17
18
SO2Ph
Grubbs II
(3 mol%)
SO2Ph
O
( )4
N
CH2Cl2
reflux
We were delighted to find that the key radical transloca-
tion–cyclization reaction took place smoothly to furnish
the desired azaspirocyclic compound 12 in good yield as
a single diastereomer (Table 1). Among reaction condi-
tions tested, combination of AIBN (0.50 equiv) and n-
Bu3SnH (2.0 equiv) was found to effective to reduce the
amount of deiodinated 13 and give the desired 12 in 60%
yield with excellent diastereoselectivity (entries 1 and
2).11,12 The radical reaction also proceeded with a sub-
strate 19 comprising an a,b-unsaturated ester moiety to
provide the corresponding azaspirocyclic compound 20 in
a moderate yield (entry 3). Deprotection of the PMB
group13 provided crystalline lactam 23, which allowed us
MeO
I
55%
(25% SM recovery)
13
Scheme 3 Synthesis of the precursor for the radical translocation–
cyclization reaction
turing a diastereoselective radical translocation–cycliza-
tion reaction.
We planned to introduce two alkyl chains (R1 and R2) at
the later stage of the synthesis, which would provide facile
access to a variety of derivatives (Scheme 2). According
to several synthetic studies,5b,d,m lepadiformine A (1) is
derived from aldehyde 10 via diastereoselective nucleo-
Scheme 4 Radical translocation–cyclization reaction and determination of the relative stereochemistry by X-ray crystallography
Synlett 2010, No. 5, 822–826 © Thieme Stuttgart · New York

824
M. Fujitani et al.
LETTER
24 by Boc protection, partial reduction of imide, and sul-
fonylation for introduction of the side chain at C-1 posi-
tion. Unexpectedly, however, it was quite difficult to
carry out direct introduction of hydroxymethyl group.15
Thus, we turned our attention to the construction of the
hydroxymethyl group in a stepwise manner.
Table 1 Radical Translocation–Cyclization Reaction
R
O
AIBN (0.50 equiv)
n-Bu3SnH
( )4
N
R
NPMB
benzene
reflux, 4 h
O
MeO
I
After survey of various nucleophiles, we found that vinyl
Grignard reagents, which are synthetic equivalents of the
hydroxymethyl anion, served as appropriate reagents for
the additional reaction. Furthermore, the more sterically
demanding reagent provided the desired diastereomer in
higher selectivity. For instance, while poor facial selectiv-
ity was observed with vinyl magnesium bromide giving
the diastereomeric mixtures 25a and 25b in a ratio of ca.
2:1, a bulky Grignard reagent, such as prenyl Grignard re-
agent, dramatically improved selectivity up to the ratio of
4.7:1. We anticipated that the stereochemical course of
this addition reaction would be governed by the sulfonyl
methyl group by blocking the b-face of the acyl iminium
ion (Scheme 5).
13 R = SO2Ph
19 R = CO2Me
12 R = SO2Ph
20 R = CO2Me
Entry
R
n-Bu3SnH Additive
Yield
(%)a
(equiv)
0.50
2.0
(equiv)
1
2
3
SO2Ph
SO2Ph
CO2Me
NaBH3CN (3.0)
none
51b
60c (67d)
63e
2.0
none
a Isolated yield.
b De-iodinated 13 was isolated in 26% yield.
c De-iodinated 13 was isolated in 11% yield.
d The reaction was carried out for 6 h in a gram scale.
e De-iodinated 19 was isolated in 18% yield.
The prenyl group was converted into a hydroxymethyl
group by ozonolysis followed by reductive workup, which
was then protected as a benzyl ether (Scheme 6). Elonga-
tion of sulfone 27 was executed by allylation at the a-
position of sulfone and subsequent reductive removal
of sulfone. Then, the terminal olefin was cleaved by
Lemieux–Johnson oxidation to provide the known ad-
•
•
H
H
O
N
O
N
W
W
Ar
Ar
disfavored TS
(W = SO2Ph)
favored TS
Figure 2 Conformational preference
1) Boc2O, DMAP
CH3CN, 40 °C, 86%
2) DIBAL-H, THF
–78 °C
n-BuLi;
1) O3, MeOH–CH2Cl2
SO2Ph
allyl iodide
–78 °C; NaBH4
SO2Ph
RMgBr, ZnCl2
26a
THF–HMPA
–78 °C
23
2) NaH, BnBr, TBAI
DMF
0–60 °C
94% (2 steps)
NBoc
NBoc
CH2Cl2–Et2O–THF
–78 °C to r.t.
3) PhSO2H, CaCl2
CH2Cl2, r.t.
BnO
SO2Ph
96% (dr = 4:1)
27
24
1) Na/Hg
H
MeOH, r.t.
SO2Ph
NBoc
SO2Ph
+
SO2Ph
SO2Ph
N
2) OsO4, NaIO4
2,6-lutidine
1,4-dioxane–H2O
30 °C
77% (2 steps)
NBoc
NBoc
NBoc
R
CHO
R
Boc
BnO
BnO
R
R
10
28
25a (39%)
26a (52%)
25b (20%)
26b (11%)
R = vinyl
1) p-TsOH
acetone–H2O
reflux
2) KCN, 1 M HCl
acetone–H2O, r.t.
R = prenyl
the yields in parenthese are based on a three-step conversion
+
Scheme 5 Stereoselective introduction of the hydroxymethyl group
N
N
3) n-HexMgBr
BF3⋅OEt2, THF
–20 °C to r.t.
37% (3 steps)
BnO
BnO
n-Hex
29a
n-Hex
to determine its relative stereochemistry by X-ray crystal-
lography (Scheme 4).14 The excellent stereochemical con-
trol is explained by taking TS in the 6-exo cyclization due
to decreased 1,3-diaxial steric repulsion between the vinyl
sulfonyl group and benzylic methylene hydrogens
(Figure 2).
29b
(10%)
(27%)
Na, NH3
1 M HCl
Et2O
29a
⋅ HCl
THF
–78 °C
N
N
Having successfully constructed the requisite azaspiro cy-
clic system, our efforts were then focused on stereoselec-
tive introduction of side chains toward ( )-lepadiformine
A (Scheme 5). First, lactam 23 was converted into sulfone
HO
HO
n-Hex
n-Hex
57%
( )-lepadiformine A • HCl (30)
( )-lepadiformine A (1)
Scheme 6 Total synthesis of ( )-lepadiformine A
Synlett 2010, No. 5, 822–826 © Thieme Stuttgart · New York

LETTER
Total Synthesis of ( )-Lepadiformine A
825
vanced synthetic intermediate 10,16 which was converted
into ( )-lepadiformine A (1) according to Weinreb’s pro-
cedure.5b,d Finally, treatment of ( )-lepadiformine A (1)
with 1 M HCl in Et2O gave the hydrochloride salt 30,
whose physical properties were identical in all aspects to
those reported for the natural product.3
A.; Ohshima, T.; Shibasaki, M. Chem. Asian J. 2007, 2, 794.
For reviews, see: (p) Weinreb, S. M. Acc. Chem. Res. 2003,
36, 59. (q) Weinreb, S. M. Chem. Rev. 2006, 106, 2531.
(r) Schär, P.; Cren, S.; Renaud, P. Chimia 2006, 60, 131 .
For synthetic studies, see: (s) Pearson, W. H.; Barta, N. S.;
Kampf, J. W. Tetrahedron Lett. 1997, 38, 3369. (t)Pearson,
W. H.; Ren, Y. J. Org. Chem. 1999, 64, 688. For total
syntheses of putative lepadiformine, see: (u) Werner, K. M.;
de los Santos, J. M.; Weinreb, S. M.; Shang, M. J. Org.
Chem. 1999, 64, 686. (v) Werner, K. M.; de los Santos,
J. M.; Weinreb, S. M.; Shang, M. J. Org. Chem. 1999, 64,
4865. (w) Abe, H.; Aoyagi, S.; Kibayashi, C. Tetrahedron
Lett. 2000, 41, 1205. (x) Wang, J.; Swidorski, J. J.;
In conclusion, we have achieved a total synthesis of ( )-
lepadiformine A (1) featuring a highly diastereoselective
radical translocation–cyclization reaction. The cascade
radical process enabled us to carry out diastereocontrolled
construction of 1-azaspiro[4.5]decane skeleton. Due to
the mild and neutral reaction conditions, this strategy is a
powerful tool for the synthesis of a variety of azaspiro-
cyclic compounds, which are often involved in bioactive
natural products and important medicines.
Sydorenko, N.; Hsung, R. P.; Coverdale, H. A.; Kuyava,
J. M.; Liu, J. Heterocycles 2006, 70, 423.
(6) (a) Curran, D. P.; Kim, D.; Liu, H. T.; Shen, W. J. Am. Chem.
Soc. 1988, 110, 5900. (b) For a review on a radical
translocation–cyclization reaction, see: Robertson, J.; Pillai,
J.; Lush, R. K. Chem. Soc. Rev. 2001, 30, 94.
(7) Takasu, K.; Ohsato, H.; Ihara, M. Org. Lett. 2003, 5, 3017.
(8) (a) Steffen, S.; Andreas, K. WO 0127122, 2001.
(b) Chloromethylation of m-iodoanisole gave some
inseparable regioisomers, which were used for the next step
without isolation of 2-iodo-4-methoxybenzyl chloride. After
benzylation with succinimide, the desired isomer 12 could
be separated by recrystallization.
(9) (a) Brown, D. S.; Charreau, P.; Ley, S. V. Synlett 1990, 749.
(b) Brown, D. S.; Charreau, P.; Hansson, T.; Ley, S. V.
Tetrahedron 1991, 47, 1311.
(10) Grela, K.; Bieniek, M. Tetrahedron Lett. 2001, 42, 6425.
(11) (a) n-Bu3SnH (97% purity) was purchased from Aldrich
Chemical Company and was used as supplied. AIBN was
purchased from Wako Pure Chemical Industries, Ltd. and
was used as supplied. Anhydrous benzene was purchased
from Kanto Chemical Co., Inc. and was degassed by
bubbling with argon gas for 30 min before use.
Acknowledgment
We are indebted to Professor J. F. Biard, Université de Nantes, for
providing spectral data (1H and 13C NMR, and IR) for lepadiform-
ines. We thank Dr. C. Kabuto for her technical assistance and hel-
pful discussions for X-ray crystallographic analysis. This work was
financially supported by the Ministry of Education, Culture, Sports,
Science, and Technology, Japan, the KAKENHI, a Grant-in-Aid for
Scientific Research (B) (20390003), Tohoku University Global
COE program ‘International Center of Research and Education for
Molecular Complex Chemistry’, Kato Memorial Bioscience Foun-
dation, and Takeda Science Foundation.
References and Notes
(1) Current address: Graduate School of Pharmaceutical
Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-
8501, Japan.
General Procedure
A three-necked 1000 mL round-bottomed flask fitted with a
reflux condenser, an inlet adapter with three-way stopcock,
and a septum was charged with starting material 13 (4.8 g,
8.7 mmol). The flask was evacuated and backfilled with
argon gas. To the flask was added degassed benzene (300
mL), and the resulting solution was heated at reflux. A
benzene solution (20 mL) of AIBN (0.71 g, 4.4 mmol, 0.50
equiv) and n-Bu3SnH (4.7 mL, 17 mmol, 2.0 equiv) was
added to the refluxing benzene solution of 13 (0.03 M) over
3 h via a syringe pump, and the reaction mixture was stirred
for an additional three hours, after which time TLC (EtOAc)
indicated complete consumption of starting material 13. The
solvent was removed under reduced pressure to give a crude
material, which was purified by silica gel–KF (10:1) column
chromatography11b (EtOAc) to afford the desired product 12
(2.5 g, 5.8 mmol, 67%) as a white solid. In the smaller scale
reaction, 12 (63.3 mg, 0.152 mmol) was obtained from 13
(139 mg, 0.251 mmol), n-Bu3SnH (135 mL, 0.52 mmol), and
AIBN (20.6 mg, 0.126 mmol) in the same way as described
in the general procedure; mp 178–179 °C. IR (KBr): 2937,
1682, 1512, 1447, 1408, 1308, 1244, 1148 cm–1. 1H NMR
(500 MHz, CDCl3): d = 7.85 (dd, 2 H, J = 7.5, 1.0 Hz), 7.71–
7.65 (m, 1 H), 7.60 (dd, 2 H, J = 7.5, 7.5 Hz), 7.17 (d, 2 H,
J = 8.5 Hz), 6.81 (d, 2 H, J = 8.5 Hz), 4.70 (d, 1 H, J = 16.0
Hz), 3.80 (s, 3 H), 3.67 (d, 1 H, J = 16.0 Hz), 2.88 (dd, 1 H,
J = 14.0, 1.5 Hz), 2.78 (dd, 1 H, J = 14.0, 11.0 Hz), 2.54–
2.40 (m, 3 H), 2.32–2.22 (m, 1 H), 1.92–1.83 (m, 1 H), 1.75–
(2) Current address: Hoshi University, Ebara, Shinagawa-ku,
Tokyo 142-8501, Japan.
(3) (a) Biard, J. F.; Guyot, S.; Roussakis, C.; Verbist, J. F.;
Vercauteren, J.; Weber, J. F.; Boukef, K. Tetrahedron Lett.
1994, 35, 2691. (b) Sauviat, M.-P.; Vercauteren, J.;
Grimaud, N.; Jugé, M.; Nabil, M.; Petit, J.-Y.; Biard, J. F.
J. Nat. Prod. 2006, 69, 558.
(4) Jugé, M.; Grimaud, N.; Biard, J. F.; Sauviat, M.-P.; Nabil,
M.; Verbist, J.-F.; Petit, J.-Y. Toxicon 2001, 39, 1231.
(5) For total syntheses, see: (a) Abe, H.; Aoyagi, S.; Kibayashi,
C. J. Am. Chem. Soc. 2000, 122, 4583. (b) Sun, P.; Sun, C.;
Weinreb, S. M. Org. Lett. 2001, 3, 3507. (c) Greshock, T.
J.; Funk, R. L. Org. Lett. 2001, 3, 3511. (d) Sun, P.; Sun,
C.; Weinreb, S. M. J. Org. Chem. 2002, 67, 4337. (e) Abe,
H.; Aoyagi, S.; Kibayashi, C. Angew. Chem. Int. Ed. 2002,
41, 3017. (f) Kibayashi, C.; Aoyagi, S.; Abe, H. Bull. Chem.
Soc. Jpn. 2003, 76, 2059. (g) Liu, J.; Hsung, R. P.; Peters,
S. D. Org. Lett. 2004, 6, 3989. (h) Abe, H.; Aoyagi, S.;
Kibayashi, C. J. Am. Chem. Soc. 2005, 127, 1473. (i)Schär,
P.; Renaud, P. Org. Lett. 2006, 8, 1569. (j) Caldwell, J. J.;
Craig, D. Angew. Chem. Int. Ed. 2007, 46, 2631.
(k) Kibayashi, C.; Aoyagi, S.; Abe, H. J. Synth. Org. Chem.
Jpn. 2007, 65, 805. (l) Lygo, B.; Kirton, E. H. M.; Lumley,
C. Org. Biomol. Chem. 2008, 6, 3085. For formal syntheses,
see: (m) Lee, M.; Lee, T.; Kim, E.-Y.; Ko, H.; Kim, D.; Kim,
S. Org. Lett. 2006, 8, 745. (n) Mihara, H.; Shibuguchi, T.;
Kuramochi, A.; Ohshima, T.; Shibasaki, M. Heterocycles
2007, 72, 421. (o) Shibuguchi, T.; Mihara, H.; Kuramochi,
1.52 (m, 2 H), 1.61–1.51 (m, 1 H), 1.34–1.18 (m, 5 H). 13
C
NMR (125 MHz, CDCl3): d = 174.9, 158.6, 139.9, 133.8,
130.6, 129.4, 129.0, 127.8, 113.8, 66.9, 56.4, 55.2, 41.8,
Synlett 2010, No. 5, 822–826 © Thieme Stuttgart · New York

826
M. Fujitani et al.
LETTER
37.8, 37.5, 29.3, 29.1, 25.1, 24.4, 22.9; HRMS (EI+): m/z
calcd for C24H29NO4S [M+]: 427.1817; found: 427.1828
(b) Harrowven, D. C.; Guy, I. L. Chem. Commun. 2004,
1968.
(14) CCDC 754968 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(15) Bussolo, V. D.; Fiasella, A.; Romano, M. R.; Favero, L.;
Pineschi, M.; Crotti, P. Org. Lett. 2007, 9, 4479.
(16) Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004,
6, 3217.
(12) A careful inspection of the 1H NMR spectra of the crude
material indicated that the trace amount (<5%) of the
diastereomer of 12 was observed: however, we could not
isolate and identify the diastereomer.
(13) (a) Georg, G. I.; Mashava, P. M.; Akgün, E.; Milstead,
M. W. Tetrahedron Lett. 1991, 32, 3151. (b) Wang, Y.;
Babirad, S. A.; Kishi, Y. J. Org. Chem. 1992, 57, 468.
Synlett 2010, No. 5, 822–826 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.