Construction of a fully substituted cyclopentenone as the core skeleton of stemonamide via a Nazarov cyclization

Article abstract of DOI:10.1016/j.tetlet.2010.08.032

A synthetic study of the Stemona alkaloid stemonamide is described. The FeCl₃-promoted fast Nazarov reaction of β-alkoxy divinyl ketones in the presence of t-BuOH afforded an α-methylene cyclopentenone, which was subsequently subjected to the R

Full text of DOI:10.1016/j.tetlet.2010.08.032

Tetrahedron Letters 51 (2010) 5469–5472
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Tetrahedron Letters
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Construction of a fully substituted cyclopentenone as the core skeleton
of stemonamide via a Nazarov cyclization
Kentaro Yaji a, Mitsuru Shindo b,
*
a Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, 6-1 Kasugako-en, Kasuga 816-8580, Japan
b Institute for Materials Chemistry and Engineering, Kyushu University, 6-1 Kasugako-en, Kasuga 816-8580, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthetic study of the Stemona alkaloid stemonamide is described. The FeCl3-promoted fast Nazarov
Received 8 July 2010
Revised 31 July 2010
Accepted 10 August 2010
Available online 14 August 2010
reaction of b-alkoxy divinyl ketones in the presence of t-BuOH afforded an
which was subsequently subjected to the Rh-catalyzed C–H amination to provide a fully appropriately
substituted -methylene cyclopentenone as the core skeleton of stemonamide.
a-methylene cyclopentenone,
a
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Natural product
Stemona alkaloid
Nazarov reaction
C–H amination
Synthetic study
The Stemona alkaloids are a class of polycyclic alkaloids contain-
ing the pyrrolo[1,2-a]azepine nucleus. Derived from Stemonaceae
plants, they have long been used in traditional Chinese and Japa-
nese folk medicine for cough relief medication and in anthelmin-
tics.1 Although numerous analogs have been isolated from these
plants,2 difficulty in purifying the crude extracts has prevented a
more extensive study of the compounds’ individual bioactivities.
Stemonamide (1) is one example of this class of alkaloids isolated
from the roots of the Stemona japonica by Xu in 1994.3 It has a tet-
racyclic structure with a fully substituted core cyclopentenone
bearing two spiro five-membered heterocycles (Fig. 1). While sev-
eral groups have succeeded in achieving the total synthesis of race-
mic stemonamide (1) using an N-acyliminium approach4 and a
radical cascade reaction5 as the key steps, respectively, much lar-
ger amounts of these alkaloids in pure form are required for use
in medicinal chemistry and drug development. Therefore a more
efficient synthetic methodology would be highly desirable.
O
O
OMe
O
O
N
1
Figure 1. Stemonamide (1).
acid catalyst
(0.001 mol%
O
O
RO
to 10 mol%)
OR rt, < 3 min
64-96% yield
Recently, we developed the acid-catalyzed fast Nazarov cycliza-
tion using b-alkoxy divinyl ketones derived from torquoselective
olefination via ynolates (Scheme 1)6,7 and have also achieved the
enantioselective Nazarov reaction catalyzed by a chiral Lewis acid.8
It was anticipated that the cyclization products of this reaction, the
Scheme 1. Acid-catalyzed fast Nazarov reaction of b-alkoxy divinyl ketones.
regarded as the core structure of stemonamide (1), via a modified
Nazarov reaction.
a-alkoxy cyclopentenones, would lead to the cyclopentenone core
structure in stemonamide (1). Herein, we report the synthesis of a
As shown in our synthetic strategy (Scheme 2), the target core
fully appropriately substituted cyclopentenone, which can be
structure 2 is the fully substituted a-exo-methylene cyclopentenone
bearing a quaternary center at C-9a. We envisioned making the car-
bon–nitrogen bond at the C-9a position (stemonamide numbering)
via the intramolecular C–H bond amination of the carbamate 3.
The fully substituted cyclopentenone 3 would be constructed by
* Corresponding author. Fax: +81 92 583 7875.
E-mail address: shindo@cm.kyushu-u.ac.jp (M. Shindo).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.032

5470
K. Yaji, M. Shindo / Tetrahedron Letters 51 (2010) 5469–5472
our modified Nazarov reaction.9 The precursor, the b-alkoxy divinyl
ketone4, wouldbeprepared bythetorquoselective olefinationofthe
ester 7.
tive would lead to route b (elimination) rather than route a
(addition).
Based on this concept, the Nazarov reaction of 4e was at-
tempted using Sc(OTf)3 and t-BuOH as additives (Table 1). As ex-
The divinyl ketones 4 were prepared as shown in Scheme 3. The
ester 7a,10 protected by a TBDPS group at the terminal alcohol, re-
pected, the
a-exo-methylene product 13e was generated in the
acted with the ynolate 611 prepared from the
a,a-dibromo ester
presence of 1.0 equiv of t-BuOH and 0.1 equiv of Sc(OTf)3 albeit
in low yield (entry 1). While increasing the equivalents of t-BuOH
enhanced the yield of 13e, up to 70%, the catalyst also had to be in-
creased to complete the reaction (entries 2 and 3).
For a more selective formation of 13e, the ethoxy group at the b-po-
sition in4e shouldbe lessnucleophilic;forpreparationonalargerscale,
a less expensive Lewis acid should be used. Screening results revealed
that a combination of the b-isopropoxy divinyl ketone 18e and the
inexpensive FeCl3 afforded the completely selective formation of 13e
in good yield. As shown in Scheme 5, the isopropyl ester 15a was olef-
inated via the ynolate 6 to give a carboxylate, which was subsequently
esterificated to give 16a in good yield.15 After conversion to the Wein-
and s-BuLi, at room temperature to give the tetrasubstituted olefin
5a with excellent E-selectivity.12 The carboxylic acid in 5a was con-
verted into the Weinreb amide 8a (R = TBDPS),13 and the amides 8b–
e (R = TBS, TMS, MOM, and Me) were prepared from 8a. The next alk-
enylation was found to be highly dependent on the steric hindrance
of the terminal-protecting group, even though it is far from the reac-
tion center. The alkenyllithium 9,14 prepared from the correspond-
ing bromide and t-BuLi, reacted with 8a and 8b to afford the
divinyl ketones 4a and 4b in low yield. Although 8c gave 4c in better
yield, 8ddidnotworkwell, possiblyduetothesterichindranceofthe
MOM–lithium complex. The methyl ether 8e (R = Me) provided the
corresponding divinyl ketone 4e in satisfactory yield.
With the divinyl ketones 4e and 4c in hand, we next examined
the Nazarov reaction with Sc(OTf)3 as the catalyst. Previously, we
have shown that the Nazarov reaction generates a small amount
O
RO
OR
route a
b
H
a
O
Sc(OTf)2
OR
of
a
-exo-methylene products (12) along with the major
a
-alkoxy
Sc(OTf)3
OR
11
O
O
product (11).6,8 In the present case, however, since the
a-exo-
methylene compounds (e.g., 12) are the desired products, an alkox-
b
route
ide (ROÀ) must act as a base, deprotonating the b-proton (route b
in Scheme 4), rather than as a nucleophile, attacking the
(route a) in the cyclopentadienyl cation intermediates 10. For the
selective synthesis of the -exo-methylene compounds, the nucle-
a-cation
10
12
Scheme 4. Two kinds of products via the Nazarov reaction.
a
ophilicity of the alkoxide should be diminished by steric hindrance.
Since the intermolecular migration of the alkoxide has been proven
by our previous studies,6 a sterically hindered alcohol as an addi-
Table 1
Nazarov cyclization of the b-alkoxy divinyl ketone (4e)
OTBS
OEt
OTBS
O
O
O
Sc(OTf)3
O
O
O
O
O
OTBS
OMe
t-BuOH
9a
O
1
N
+
NH2
H
CH2Cl2
rt, 3 min
OMe
EtO
4e
P
O
P
O
2
3
OR
13e
P: Protecting group
14
Me
Me
OR'
Yielda (%)
O
Entry
Equivalents
OR
OLi
O
HO2C
6
Sc(OTf)3
t-BuOH
13e
14
RO
1
2
3
0.1
0.5
1.0
1.0
3.0
10
23
48
70
37
22
6
RO
PO
PO
5
P
O
4
7
a
The ratios were determined by the 1H NMR of the mixture of 13e and 14.
Scheme 2. Synthetic strategy of the core structure of stemonamide (2).
s-BuLi
Me CO2Et
Br Br
THF
-78 ºC; 0 ºC
Me
Me(MeO)NH•HCl
TBTU, Et3N
Me
Li
OTBS
O
OEt
OLi
6
O
OEt
9
HO2C
N
EtO
OTBDPS
MeO
CH3CN, rt, 24 h
77%
Me
OR
THF
-78 ºC, 20 min
THF, rt, 3 h
58%
TBDPSO
7a
5a
(E:Z=>99:1)
8a (R = TBDPS)
8b (R = TBS)
8c (R = TMS)
8d (R = MOM)
8e (R = Me)
1) TBAF, THF
rt, 2 h, quant.
2) base, RX
4a (R = TBDPS)
4b (R = TBS)
4c (R = TMS)
4d (R = MOM)
4e (R = Me)
<30%
<30%
60%
OTBS
O
<30%
71%
EtO
OR
Scheme 3. Preparation of the b-alkoxy divinyl ketones 4.

K. Yaji, M. Shindo / Tetrahedron Letters 51 (2010) 5469–5472
5471
Me
1) PhSH, Et3N
SPh
OH
O
O
CH2Cl2, rt
O
O
OMe
OLi
30 min, 95%
6
13e
i-PrO
H
H
2) 6 M HCl, THF
rt, 4 h, quant.
THF, rt, 3 h;
MeI, HMPA
TBDPSO
i-PrO
OTBDPS
OMe
15a
16a (E:Z = >99:1)
1) Cl3CC(O)NCO
CH2Cl2, 0 ºC
then SiO2, MeOH
rt, 12 h, quant.
2) Oxone®, MeOH,H2O
then Al2O3, rt, 2 h
quant.
86%
Me
O
O
1) TBAF, THF
rt, 2 h, 89%
Me(MeO)NH•HCl
O
N
NH2
OMe
i-PrMgCl
OMe
2) NaH, MeI
rt, 30 min
quant
THF, rt, 1 h
77%
OTBDPS
i-PrO
3e
17a
Me
Rh2(OAc)4
OTBS
Li
OTBS
O
O
N
O
(5 mol%)
MgO
O
O
O
OMe
9
O
O
N
N
H
PhI(OAc)2
THF,-78 ºC
20 min, 80%
H
i-PrO
OMe
OMe
i-PrO
toluene, 6 h
98%
OMe
OH
17e
18e
2e
2f
O
OTBS
OMe
FeCl3 (1.0 equiv.)
Scheme 6. Preparation of the spirocyclic carbamate 2 via C–H amination.
CH2Cl2-t-BuOH (1:1)
rt, 3 min, 71%
13e
cyclic compound 2e in excellent yield. However, demethylation at
the terminal methoxy moiety was unsuccessful (Scheme 6).
Since it was found that the deprotection of the methoxy moiety
must be carried out at an earlier stage, the TBS and methoxy
groups were successively deprotected in good yield by 6 M HCl
and then AlCl3/Bu4NI (TBAI),19 in which the product 19, iodinated
at the exo-b-position, was isolated. This primary diol 19 was selec-
tively protected with TIPSCl at the less-hindered site to give the
alcohol 20 after elimination of iodide with basic alumina. The alco-
hol 20 was converted into the carbamate 3g (R = TIPS), which was
submitted to the rhodium(II) acetate-catalyzed C–H amination;
however, it did not work at all, probably due to ‘remote’ steric hin-
drance. Therefore, we prepared the substrates bearing several
kinds of different protecting groups at the terminal position
(Scheme 7).
Scheme 5. Preparation of the cyclopentenone 13e via the Nazarov cyclization of
the b-isopropoxy divinyl ketone 18e.
reb amide 17a16 and replacement of the TBDPS group with a methyl
group at the terminal position, alkenylation provided the divinyl ke-
tone 18e, which was subjected to the Nazarov reaction in the presence
of 1.0 equiv of FeCl3 in CH2Cl2/t-BuOH (1:1) to furnish the
a-exo-meth-
ylene compound 13e with excellent selectivity.17
Next, we examined the C–H amination by a carbamate to form
the fully substituted cyclopentenone. The -exo-methylene moiety
was protected by a phenylthio group, before the removal of the TBS
a
group by 6 M HCl. Formation of the carbamate with trichloroacetyl
isocyanate afforded the precursor 3e after deprotection at the
a-
exo-methylene moiety with OxoneÒ. The carbamate 3e, when sub-
jected to rhodium(II) acetate-catalyzed C–H amination18 at the b-
methine position, proceeded smoothly to afford the desired spiro-
The results of the C–H amination are summarized in Table 2.
Although the TMS- and Ms-protected substrates (3i, 3j) did not
give 2 (entries 3 and 4), the amination reactions of 3f (R = H) and
Scheme 7. Preparation of 3.

5472
K. Yaji, M. Shindo / Tetrahedron Letters 51 (2010) 5469–5472
5. (a) Taniguchi, T.; Tanabe, G.; Muraoka, O.; Ishibashi, H. Org. Lett. 2008, 10, 197;
Table 2
(b) Taniguchi, T.; Ishibashi, H. Tetrahedron 2008, 64, 8773.
6. Shindo, M.; Yaji, K.; Kita, T.; Shishido, K. Synlett 2007, 1096.
7. For a review on torquoselective olefination, see: Shindo, M.; Mori, S. Synlett
2008, 2231.
8. Yaji, K.; Shindo, M. Synlett 2009, 2524.
9. For construction of a-exo-methylene cyclopentenones via Nazarov cyclization,
Synthesis of the A-ring of stemonamide (1) via C–H amination
O
O
O
Rh2(OAc)4 (5mol%)
MgO, PhI(OAc)2
O
O
O
H
N
NH2
OR
H
toluene
see: (a) Tius, M. A.; Astrab, D. P. Tetrahedron Lett. 1984, 25, 1539; (b) Tius, M. A.
Acc. Chem. Res. 2003, 36, 284; (c) de los Santos, D. B.; Banaag, A. R.; Tius, M. A.
Org. Lett. 2006, 8, 2579; For the total synthesis of natural products via cationic
cyclopentannelation of allenyl ether, see: (d) Drake, D. J.; Tius, M. A.
Tetrahedron Lett. 1996, 52, 14651; (e) Wan, L.; Tius, M. A. Org. Lett. 2007, 9,
647; (f) Berger, G. O.; Tius, M. A. J. Org. Chem. 2007, 72, 6473.
OR
3
2
Entry
R
3
Temp (°C)
Time (h)
Yield (%)
1
2
3
4
5
TIPS
H
TMS
Ms
Ac
3g
3f
3i
3j
3h
125
80
25
125
125
6
3
1
1
0
80
0
<5
80
10. The ester 7a was prepared from 1,5-pentanediol by a four-step sequence: (a)
NaH, TBDPSCl; THF, room temperature; (b) (COCl)2, DMSO, Et3N; CH2Cl2,
À78 °C to room temperature; (c) NaClO2, NaH2PO4; t-BuOH/THF/2-methyl-2-
butene (3:1:1), H2O, room temperature; (d) EtBr, K2CO3; DMF, room
temperature (78% yield).
0.6
11. For a review on ynolates, see: Shindo, M. Tetrahedron 2007, 63, 10.
12. Shindo, M.; Kita, T.; Kumagai, T.; Matsumoto, K.; Shishido, K. J. Am. Chem. Soc.
2006, 128, 1062.
13. Mannekens, E.; Tourwé, D.; Lubell, W. D. Synthesis 2000, 1214.
14. The alkenyl bromide 9 was prepared from 2-butyn-1-ol in two steps, as
follows: (1) Cp2TiCl2 (cat.), i-BuMgCl; Et2O, room temperature; then (BrCF2)2;
THF, room temperature; (2) TBSCl, imidazole, DMAP; CH2Cl2, room
temperature (57% yield).
15. An ester having a methoxy group at the terminal position in place of TBDPSO
gave the olefinated product in low yield. The reason for this is not clear.
16. Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.; Dolling, U.-H.;
Grabowski, E. J. J. Tetrahedron Lett. 1995, 36, 5461.
17. Procedure for the synthesis of 13e: To a solution of 18e (986 mg, 2.47 mmol) in
14 mL of CH2Cl2/t-BuOH (1:1), under argon, was added anhydrous FeCl3
(401 mg, 2.47 mmol). After 3 min at room temperature, the mixture was
quenched by saturated aqueous NaHCO3 and extracted with CH2Cl2. The
organic extracts were washed with saturated aqueous NaHCO3 and brine and
dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified
by column chromatography over silica gel (5–7% EtOAc/hexane) to give 13e
(593.9 mg, 71%) as a yellow oil. 1H NMR (400 MHz, CDCl3) d 0.01 (s, 3H), 0.02 (s,
3H), 0.85 (s, 9H), 1.52–1.68 (m, 4H), 1.79 (d, J = 1.6 Hz, 3H), 2.40–2.49 (m, 1H),
2.52–2.61 (m, 1H), 3.30–3.37 (m, 1H), 3.30 (s, 3H), 3.39 (t, J = 6.4 Hz, 2H), 3.70–
3.74 (m, 1H), 3.78–3.82 (m, 1H), 5.42 (s, 1H), 6.06 (t, J = 1.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d À5.88, À5.84, 8.10, 17.8, 23.8, 25.5, 28.3, 29.4, 46.6, 58.3,
63.8, 72.0, 114.8, 138.8, 144.0, 168.1, 195.7; IR (neat) 2930, 1697, 1119,
484.2 cmÀ1; MS (FAB) m/z 339 (M++H); HRMS (FAB) m/z calcd for C19H35O3Si
(M++H): 339.2355, found: 339.2360.
3h (R = Ac) successfully afforded the spirocyclic products 2f and
2h20 in high yields, respectively (entries 2 and 5).
In conclusion, we have synthesized the core skeleton of stemo-
namide (1) via the Nazarov reaction, in which a new method for
the selective synthesis of the
a-exo-methylene cyclopentenones
from b-alkoxy divinyl ketones has been developed. The spirocyclic
products 2 have a fully substituted cyclopentenone bearing appro-
priate functionality for stemonamide (1) and thus would be a po-
tential precursor for its total synthesis. Furthermore, this study
demonstrates the synthetic utility of the torquoselective olefin-
ation via ynolates as well as the Nazarov reaction.
Acknowledgments
This research was partially supported by a Grant-in-Aid for Sci-
entific Research (B) (22390002) and the Program for the Promotion
of Basic and Applied Research for Innovations in the Bio-oriented
Industry (BRAIN). One of the authors (K.Y.) also acknowledges
the support of the JSPS.
18. (a) Fiori, K. W.; Espino, C. G.; Brodsky, B. H.; Du Bois, J. Tetrahedron 2009, 65,
3042; For reviews on C–H amination, see: (b) Espino, C. G.; Du Bois, J. In Modern
Rhodium-Catalyzed Organic Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim,
2005; pp 379–416; (c) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417.
19. Akiyama, T.; Shima, H.; Ozaki, S. Tetrahedron Lett. 1991, 32, 5593.
20. Compound 2h: 1H NMR (600 MHz, CDCl3) d 1.60–1.77 (m, 4H), 1.87 (s, 3H),
2.06 (s, 3H), 2.40–2.47 (m, 1H), 2.48–2.62 (m, 1H), 4.06–4.15 (m, 2H), 4.37 (dd,
J = 13.8 Hz, 9.0 Hz, 2H), 5.71 (bs, 1H), 5.72 (s, 1H), 6.25 (s, 1H); 13C NMR
(150 MHz, CDCl3) d 8.74, 20.9, 24.9, 25.7, 28.9, 63.5, 64.6, 73.5, 117.5, 142.4,
146.2, 158.6, 163.2, 171.2, 192.4; IR (neat) 3306, 2956, 2926, 1770, 1732, 1715,
1248, 1038, 468.7 cmÀ1; MS (ESI) m/z 316 (M++Na); HRMS (FAB) m/z calcd for
References and notes
1. For reviews on stemona alkaloids, see: (a) Pilli, R. A.; Ferreira de Oliveira, M. C.
Nat. Prod. Rep. 2000, 17, 117; (b) Alibes, R.; Figueredo, M. Eur. J. Org. Chem. 2009,
2421.
2. Greger, H. Planta Med. 2006, 72, 99.
3. Ye, Y.; Qin, G.-W.; Xu, R.-S. J. Nat. Prod. 1994, 57, 655.
4. (a) Kende, A. S.; Martin Hernando, J. I.; Milbank, J. B. J. Org. Lett. 2001, 3, 2505;
(b) Kende, A. S.; Martin Hernando, J. I.; Milbank, J. B. J. Tetrahedron 2002, 58, 61.
C
15H20O5N (M++H): 294.1341, found: 294.1343.