Allenes as dipolarophiles in the intramolecular carbene cyclization-cycloaddition cascade reaction

Article abstract of DOI:10.1055/s-2006-939080

Intramolecular carbene cyclization-cycloaddition cascade reactions with allenes occur efficiently in the presence of dirhodium catalysts to afford oxatricyclic products as single diastereomers. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-939080

LETTER
1197
Allenes as Dipolarophiles in the Intramolecular Carbene Cyclization–
Cycloaddition Cascade Reaction
I
ntramolecular Car
i
bene
C
n
yclizationC
g
ycloaddition
x
with
A
llenesian Zhang,1 Rebecca Y. Y. Ko, Shuoliang Li, Ru Miao, Pauline Chiu*
Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and
Synthesis, The University of Hong Kong, Pokfulam Road, Hong Kong, P. R. of China
Fax +85228571586; E-mail: pchiu@hku.hk
Received 5 December 2005
allene to form perhydroazulene 4, or with the distal olefin
Abstract: Intramolecular carbene cyclization–cycloaddition cas-
of the allene to give polycyclic 5 with a fused cyclohexene
(Scheme 2). The outcome would have a significant
bearing on the viability of our retrosynthetic plan for
isocurcumenol.
cade reactions with allenes occur efficiently in the presence of
dirhodium catalysts to afford oxatricyclic products as single dia-
stereomers.
Key words: allenes, carbenoids, cyclization, cycloadditions, domi-
no reactions
R
H
O
O
R
O
O
R
RhLn
In our studies toward the total synthesis of the vasorelax-
ing and hepatoprotective sesquiterpenoid (+)-iso-
curcumenol (1),2 our retrosynthesis envisioned the
perhydroazulene nucleus to arise from a metal carbene
cyclization–cycloaddition cascade (CCCC) reaction, a
highly efficient chemical transformation that is finding
increasing utility in synthesis.3–5 Using this metal-cata-
lyzed domino reaction as the key step, the carboskeleton
of isocurcumenol retroanalyzes most straightforwardly to
diazoketone 2 (Scheme 1), because intramolecular dipolar
cycloaddition with the tethered allene in the final step of
the cascade would directly provide the perhydroazule-
none bearing the exocyclic methylene moiety, a structural
feature that has been associated with the bioactivity of this
natural product.
cat.
Rh2+
N2C
O
O
O
O
4
5
R
2
3
Scheme 2 Carbene cyclization–cycloaddition cascade reaction of 2.
According to competitive intermolecular cycloaddition
experiments by Padwa and co-workers, the intramolecular
carbene cyclization cycloaddition to concomitantly con-
struct a five-membered ring occurs more rapidly than
forming a six-membered ring.9 However, in the present
system, it is not certain to what degree the increased con-
straints of the sp2-hybridized carbon atoms in the tether
would affect the relative rates of five- versus six-mem-
bered ring formation. The course of the reaction is also
made ambiguous by the lack of strongly directing, elec-
tron-donating or electron-withdrawing substituents on the
allene.10 In the absence of overwhelming stereoelectronic
factors or limitations imposed by the length of the tether,
the related intramolecular [4+2] cycloaddition with furan
engaged the terminus of the allenic dienophile.11 In both
the intermolecular carbonyl ylide cycloaddition,8b and the
intermolecular [5+2] oxidopyrilium cycloaddition with
allenes,12 reactions also proceeded at the terminal double
bond of the allene. Herein we describe our studies to de-
lineate the outcome of the intramolecular carbene cycliza-
tion–cycloaddition with an allene as the dipolarophile.
H
N2
H
OH
O
O
O
R
O
O
R'
R'
(+)-isocurcumenol (1)
2
Scheme 1 Synthetic plan toward (+)-isocurcumenol (1).
While the cycloaddition of a variety of dipolarophiles
with carbonyl ylides generated from metal carbenes are
known, the corresponding cycloaddition with allenes had
not been reported in the literature at the time when this
work was started.6–8 The intramolecular cycloaddition
concomitantly creates a ring fused to the cycloadduct, the
size of which is dictated by the length of the tether to the
dipolarophile. Interestingly, diazoketone 2 reacts to
generate a carbonyl ylide 3 that could conceivably under-
go cycloaddition with the proximal olefin of the tethered
The synthesis of the requisite allene-tethered diazoke-
tones 2 is shown in Scheme 3. The transformation of
alkynols 6a and 10b,c to allenols was achieved by the pro-
tocol described by Crabbé.13 Homologation by three me-
thylene units was achieved using Normant’s Grignard
reagent [ClMg(CH2)3OMgCl].14 Oxidation of aldehydes
to acids was best achieved using the Lindgren oxidation
under mild and neutral conditions.15 Diazoketones 2aa,
SYNLETT 2006, No. 8, pp 1197–1200
1
5.
0
5.
2
0
0
6
Advanced online publication: 05.05.2006
DOI: 10.1055/s-2006-939080; Art ID: W32605ST
© Georg Thieme Verlag Stuttgart · New York

1198
X. Zhang et al.
LETTER
O
HO
( )n
Table 1 Carbene Cyclization–Cycloaddition Cascade Reactions of
Diazoketones 2a
HO
( )n
b, c, d
a
( )n
8a n = 3
e, f
NMe
Entry Diazoketone 2
Cycloadduct
Yield
(%)b
OMe
7a n = 3
6a n = 3
6b n = 4
6c n = 2
1
74
H
b, e
O
O
CHN2
O
O
( )3
( )n
CHO
OH
HO
c, g
CHN2
O
9a n = 3
4aa
( )n
O
2aa
( )n
10b n = 4
10c n = 2
h, i
2
50
71
79
73
O
2aa n = 3
2ba n = 4
2c n = 2
CO2Et
O
H
O
CO2Et
N2
c,g
a, b
O
OEt
N2
O
( )3
O
O
O
O
O
O
CHO
O
h, i
4ab
2ab
( )n
( )n
11b n = 4
11c n = 2
2ab n = 3
2bb n = 4
3
H
O
CHN2
O
Scheme 3 Synthesis of diazoketones 2. Reactions and conditions:
(a) (CH2O)n, CuBr, i-Pr2NH, 28–87% yields; (b) (COCl)2, DMSO,
Et3N; (c) NaClO2, NaH2PO4, t-BuOH–H2O, Me2C=CHMe, 80–84%
yields; (d) MeONHMe·HCl, EDCI, HOBt, CH2Cl2, 92% yield; (e)
ClMg(CH2)3OMgCl, 73–99% yields; (f) Dess–Martin periodinane;
(g) (i) i-BuCOCl, Et3N; (ii) CH2N2, 62–78% (h) EDA, SnCl2·2H2O,
85–86% yields; (i) AcNHC6H4SO2N3, MeCN, 86–93% yields.
O
( )4
4ba
2ba
4
CO2Et
O
H
O
CO2Et
N2
O
( )4
2ba and 2c were synthesized from their respective acid
precursors via the mixed carbonic anhydrides and diazo-
methane.16 The synthesis of b-ketoesters from aldehydes
was accomplished using ethyl diazoacetate (EDA) in the
presence of Lewis acid.17 The stabilized diazoketones 2ab
and 2bb were synthesized by diazo transfer.18
4bb
2bb
5
O
O
O
CHN2
( )2
5c
The results of the metal-catalyzed carbene cyclization–cy-
cloaddition cascade reactions are shown in Table 1. When
2aa with a three-carbon tether was treated with a catalytic
amount of Rh2(OAc)4 in CH2Cl2, we were gratified to find
that five-membered ring formation was preferred, and the
sole cycloadduct was the perhydroazulenone 4aa bearing
the requisite exocyclic methylene moiety in the trans-
fused [5.3.0] carbobicyclic system, as required for the car-
boskeleton of isocurcumenol. The stabilized diazoketone
2ab also underwent cyclization–cycloaddition, under
slightly more vigorous conditions, to afford the perhy-
droazulenone 4ab also as the sole diastereomeric product.
2c
a Reaction conditions: see text.
b Isolated yields.
the exclusive formation of five-membered rings was
found in the intramolecular oxidopyrilium–allene cyclo-
addition, while no cycloaddition was observed for the
substrate which would react to form six- or seven-mem-
bered rings.12 The divergence of the results of the CCCC
reaction compared to the oxidopyrilium cycloaddition
could be due to the higher reactivity of carbonyl ylides
over oxidopyrilium ions.
To further explore the parameters of the CCCC reaction,
diazoketones 2ba and 2bb bearing tethers of n = 4 were
also prepared. The CCCC reactions of these substrates
with the proximal or distal allenic double bonds would
form fused cyclohexane or cycloheptene rings, respec-
tively. When 2ba was treated with a catalytic amount of
Rh2(OAc)4, cycloaddition proceeded smoothly, and the
sole cycloadduct was 4ba fused with a cyclohexane ring
from reaction with the proximal allene double bond. Sim-
ilarly, 2bb also underwent rhodium-induced CCCC reac-
tion to form the analogous cycloadduct 4bb. These results
stand in contrast to related studies by Lee et al. in which
Diazoketone 2c bearing a two-carbon tether could under-
go CCCC reaction to form an intervening four- or five-
membered ring depending on cycloaddition with the prox-
imal or distal olefin of the allene. As four-membered ring
formation was expected to be quite strained, this scenario
was conducive for directing the course of the cycloaddi-
tion to engage the terminal rather than the internal double
bond of the allene. Indeed this was the case, and the sole
cycloadduct was 5c bearing an endocyclic olefin, isolated
in 73% yield.
Synlett 2006, No. 8, 1197–1200 © Thieme Stuttgart · New York

LETTER
Intramolecular Carbene Cyclization–Cycloaddition with Allenes
1199
2.21–2.06 (m, 2 H), 1.79–1.68 (m, 3 H), 1.57–1.50 (m, 3 H), 1.32 (t,
J = 7.1 Hz, 3 H), 1.24–1.14 (m, 2 H). 13C NMR (75 MHz, CDCl3):
d = 200.8, 165.6, 150.7, 110.8, 89.1, 80.6, 62.2, 48.5, 37.6, 34.1,
34.0, 31.8, 24.4, 21.7, 14.5. LRMS (EI): m/z (%) = 264 (26) [M+],
236 (20), 191 (26), 163 (100), 135 (53), 93 (29). HRMS (EI): m/z
calcd for C15H20O4: 264.1362; found: 264.1358.
In summary, the intramolecular rhodium carbene cycliza-
tion–cycloaddition reactions with allenes as dipolaro-
philes proceed in good yields, predominantly under
control by the length of tethers. Intramolecular cycloaddi-
tion to concomitantly construct five- or six-membered
rings have been observed. Thus, the synthesis of bicyc-
lo[5.3.0]decanone and bicyclo[5.4.0]undecanone systems
can be readily acccomplished by this methodology. In
particular, the CCCC reaction of 2aa provides in excellent
selectivity the requisite carboskeleton of isocurcumenol
and other Curcuma sesquiterpenes bearing an exocyclic
methylene group. The application of these results to the
total syntheses of these natural products will be reported
in due course.
11-Oxatricyclo[5.3.1.01,5]undec-5-en-8-one (5c)
Rf = 0.26 (10% EtOAc in hexane). IR (CH2Cl2): 3061, 2992, 1732
(ketone C=O), 1650 (C=C), 1423, 1261 cm–1. 1H NMR (300 MHz,
CDCl3): d = 5.57–5.54 (m, 1 H), 4.61 (d, J = 7.7 Hz, 1 H), 2.84–2.79
(m, 2 H), 2.68–2.58 (m, 1 H), 2.47–2.43 (m, 2 H), 2.37–2.15 (m, 4
H), 1.96 (dd, J = 12.8, 6.1 Hz, 1 H). 13C NMR (75 MHz, CDCl3):
d = 206.8, 147.1, 122.6, 94.8, 87.3, 37.2, 36.6, 32.7, 32.5, 28.8.
LRMS (EI): m/z (%) = 164 (42) [M+], 149 (50), 136 (28), 122 (100),
109 (39). HRMS (EI): m/z calcd for C10H12O2: 164.0837; found:
164.0834.
Typical Experimental Procedure
Acknowledgment
6-Methylene-11-oxatricyclo[5.3.1.01,5]undecan-8-one (4aa)
To a solution of compound 2aa (34 mg, 0.16 mmol) in CH2Cl2 (1.0
mL) at 0 °C was added 3 mol% Rh2(OAc)4 under an atmosphere of
argon. The reaction mixture was stirred at 0 °C for 50 min and the
solvent was removed. The residue was purified by silica gel column
flash chromatography, eluting with hexane–EtOAc (20:1) to give
compound 4aa (19 mg, 74% yield) as a colorless oil: Rf = 0.64 (20%
EtOAc in hexane). IR (CH2Cl2): 2962, 2871, 1725 (ketone C=O),
1448, 1413, 1047, 1025, 909 cm–1. 1H NMR (400 MHz, CDCl3):
d = 5.17–5.16 (m, 1 H), 5.07–5.06 (m, 1 H), 4.56 (s, 1 H), 2.91 (dd,
J = 10.1, 2.0 Hz, 1 H), 2.54–2.33 (m, 3 H), 2.11–2.05 (m, 1 H),
2.03–1.96 (m, 1 H), 1.94–1.84 (m, 2 H), 1.77–1.57 (m, 3 H). 13C
NMR (100 MHz, CDCl3): d = 205.0, 152.6, 108.8, 93.4, 88.3, 50.1,
37.0, 33.8, 33.6, 33.0, 25.3. LRMS (EI): m/z (%) = 178 (96) [M+],
150 (100), 135 (55), 121 (43). HRMS (EI): m/z calcd for C11H14O2:
178.0994; found: 178.1003.
This work was supported by the University of Hong Kong. The
Research Grants Council of Hong Kong (Project HKU 7081/ 01P),
and the Areas of Excellence Scheme established under the Univer-
sity Grants Committee of the Hong Kong Special Administrative
Region, China (Project No. AoE/P-10/01). RYYK thanks the
University of Hong Kong for a conference travel grant.
References and Notes
(1) Present address: Xingxian Zhang, College of
Pharmaceutical Science, Zhejiang University, P. R. of
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1,6-Methylene-8-oxo-11-oxatricyclo[5.3.1.01,5]undecan-7-car-
boxylic Acid Ethyl Ester (4ab)
Rf = 0.55 (25% EtOAc in hexane). IR (CH2Cl2): 2962, 2873, 1749
(ester C=O), 1732 (ketone C=O), 1656 (C=CH2), 1466, 1447, 1245,
1046, 910 cm–1. 1H NMR (400 MHz, CDCl3): d = 5.76 (d, J = 1.8
Hz, 1 H), 5.24 (d, J = 1.8 Hz, 1 H), 4.26–4.40 (m, 2 H), 3.07–3.03
(m, 1 H), 2.68–2.61 (m, 1 H), 2.52–2.43 (m, 2 H), 2.20–2.12 (m,
2 H), 2.08–1.94 (m, 2 H), 1.74–1.64 (m, 3 H), 1.33 (t, J = 7.1 Hz,
3 H). 13C NMR (100 MHz, CDCl3): d = 199.1, 165.5, 150.2, 111.6,
92.3, 91.5, 61.9, 52.1, 36.7, 34.4, 34.3, 34.2, 25.4, 14.3. LRMS (EI):
m/z (%) = 250 (15) [M+], 222 (60), 194 (24), 177 (30), 149 (100),
131 (38), 121 (39), 93 (49). HRMS (EI): m/z calcd for C14H18O4:
250.1205; found: 250.1200.
7-Methylene-12-oxatricyclo[6.3.1.01,6]dodecan-9-one (4ba)
Rf = 0.70 (25% EtOAc in hexane). IR (CH2Cl2): 2940, 2858, 1730
1
(ketone C=O), 1662 (C=CH2), 1449, 1412, 1032 cm–1. H NMR
(300 MHz, CDCl3): d = 1.16–1.28 (m, 2 H), 1.42–1.56 (m, 3 H),
1.63–1.79 (m, 3 H), 1.95–2.06 (m, 2 H), 2.31–2.38 (m, 1 H), 2.40–
2.50 (m, 2 H), 4.55 (s, 1 H), 5.07–5.09 (m, 2 H). 13C NMR (75 MHz,
CDCl3): d = 206.2, 152.4, 107.4, 84.5, 80.6, 47.4, 36.2, 34.1, 33.0,
31.4, 24.1, 21.5. LRMS (EI): m/z = 192 (100) [M+], 164 (23), 149
(34), 135 (75), 120 (52). HRMS (EI): m/z calcd for C12H16O2:
192.1150; found: 192.1150.
7-Methylene-9-oxotricyclo[6.3.1.01,6]dodecane-8-carboxylic
Acid Ethyl Ester (4bb)
(9) Padwa, A.; Hornbuckle, S. F.; Fryxell, G. E.; Zhang, Z. J. J.
Org. Chem. 1992, 57, 5747.
Rf = 0.56 (25% EtOAc in hexane). IR (CH2Cl2): 2940, 2853, 1751
(ester C=O), 1730 (ketone C=O), 1654 (C=CH2), 1449, 1085, 914
cm–1. 1H NMR (300 MHz, CDCl3): d = 5.56 (s, 1 H), 5.24 (s, 1 H),
4.32 (q, J = 7.1 Hz, 2 H), 2.62–2.50 (m, 1 H), 2.53–2.42 (m, 2 H),
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Synlett 2006, No. 8, 1197–1200 © Thieme Stuttgart · New York

1200
X. Zhang et al.
LETTER
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Synlett 2006, No. 8, 1197–1200 © Thieme Stuttgart · New York