Cycloaddition Reactions of Carbonyl Ylides Derived from Enones

Article abstract of DOI:10.1055/s-0034-1379926

The formation of unsaturated carbonyl ylides via rhodium-catalyzed carbene cyclization with enones and their subsequent inter- and intramolecular cycloadditions to construct functionalized oxapolycyclic rings have been realized.

Full text of DOI:10.1055/s-0034-1379926

SYNLETT
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©
Georg Thieme Verlag Stuttgart · New York
2015, 26, A–D
A
letter
Synlett
Y. Yu et al.
Letter
Cycloaddition Reactions of Carbonyl Ylides Derived From Enones
Yang Yua
Loïc Cornelissena,b
Wing-Tak Wonga
Pauline Chiu*a
CO2Et
O
2
CO Et
–
H
cat. Rh2(OAc)4
CH2Cl2, 3 Å MS
O
N2
+
O
O
OEt
O
r.t., 4 h
O
O
72% yield
a
Department of Chemistry and the State Laboratory of Synthetic
a,b-unsaturated carbonyl ylide
Chemistry, The University of Hong Kong, Pokfulam Road, Hong
Kong, P. R. of China
pchiu@hku.hk
Department of Organic and Medicinal Chemistry, Université
b
Catholique de Louvain, Louvain-la-Neuve, Belgium
To Prof. Peter Vollhardt on the occasion of his 69th birthday,
and in appreciation of his contributions to Synlett
Received: 07.03.2015
Accepted after revision: 07.05.2015
Published online: 03.06.2015
(Scheme 1). The introduction of an additional, conjugated
olefin in the diazoketone substrate could conceivably derail
the intended cyclization to form carbonyl ylide for cycload-
dition to give 2 (Scheme 1, path A), as the carbene also ap-
pears to be well-poised to intramolecularly cyclopropanate
the carbon–carbon double bond (Scheme 1, path B). Herein
we report on our investigations to explore the feasibility of
the CCCC reaction in the context of the formation of unsatu-
rated carbonyl ylides for subsequent cycloadditions.
DOI: 10.1055/s-0034-1379926; Art ID: st-2015-b0164-l
Abstract The formation of unsaturated carbonyl ylides via rhodium-
catalyzed carbene cyclization with enones and their subsequent inter-
and intramolecular cycloadditions to construct functionalized oxapoly-
cyclic rings have been realized.
Key words carbenoids, ylides, cycloaddition, diazo compounds, dom-
ino reaction
Our work commenced with the synthesis of unsaturated
diazoketone 1a (Scheme 2). The treatment of 2-hexenal
with the Normant reagent8 at low temperature provided
the diol 4a in good yield. Byproducts arising from 1,4-addi-
tion were suppressed when the reaction was cooled suffi-
ciently. Bisoxidation of diol 4a was realized by a Swern oxi-
dation using DMSO–TFAA to give ketoaldehyde 5a. Alterna-
tively, the use of oxalyl chloride as activator resulted in a
much more complex product mixture, probably due to
Efficient generation of molecular complexity by the in-
stallation of new bonds, stereocenters, and functional
groups is a major goal of modern organic synthesis. The ap-
plications of such methodologies underwrite the concise
total syntheses of many complex natural products. To this
end, transition-metal-catalyzed cascade reactions have
contributed significantly to the repertoire of such efficient
1,2
9
transformations. Among these, the metal-catalyzed inter-
and intramolecular carbene cyclization cycloaddition cas-
cade (CCCC) reaction is one transformation that facilitates
the formation of three σ bonds and up to four stereocenters
in one operation and yield polycyclic skeletons with good
chlorination side reactions. A tin(II)-catalyzed Roskamp re-
action10 with ethyl diazoacetate (EDA) generated ester 6a
that was unstable on both silica gel or alumina. Thus with-
out further purification, 6a was subjected to diazo transfer
11
using p-acetamidobenzenesulfonyl azide (p-ABSA) to af-
ford diazoketone 1a.
3
stereochemical control. The CCCC reaction is a highly
atom-economic transformation, and numerous applica-
tions of this cascade have been demonstrated in the total
synthesis of natural products.
In typical CCCC reactions, dipolar cycloadditions occur
with carbonyl ylides that are generated from the cyclization
of the electrophilic metal carbene with the proximate car-
The results of the CCCC reactions of 1a are shown in
Scheme 3. Initial attempts to induce the rhodium-catalyzed
CCCC reaction of 1a in the presence of tetracyanoethylene
(TCE) or dimethyl acetylenedicarboxylate (DMAD) as dipol-
arophiles were uniformly unsuccessful.12 We wondered
whether the problem was that the putative cycloadducts 7a
and 7b were very unstable. Therefore, we also tried the
CCCC reaction of the saturated diazoketone 8, but this also
failed to react to yield any discernible products. Although it
4
3
3
5
bonyl group of a saturated ketone, amide, or ester. Car-
6
7
bene cyclization with aryl esters and ketones have also
yielded carbonyl ylides for subsequent cycloaddition. How-
ever, there have not yet been any examples in which the
carbonyl ylide is formed by cyclization with an enone such
as 1, and the outcome of such a process is unexplored
1
appeared that in each of the worked up reactions, the H
NMR and 13C NMR spectra of the crude product mixture
showed a set of predominant peaks which were consistent
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–D

B
Synlett
Y. Yu et al.
Letter
E
E
R2
R2
–
E
O
+
O
O
path A
O
E
O
N2
R1
2
cat. Rh(II)
R1
R1
R2
O
O
O
O
O
1
R1
R1
path B
R2
R2
3
Scheme 1 Possible reaction pathways of 1 (the metal associated with the carbonyl ylide and carbene is omitted for clarity)
with those of cycloadducts 7a, 7b, and 9, almost no major
compound could be isolated after chromatography on silica
gel or alumina, and none of the cycloadducts could be puri-
fied in order to be characterized fully. Fortunately, this
problem was partially solved by co-eluting with some ace-
tic acid, which decreased the rate of decomposition and al-
lowed us to isolate cycloadducts 7b and 9 in 78% and 52%
yields, respectively (Scheme 3). But unfortunately, even
with this protocol, cycloadduct 7a still could not be puri-
fied.
O
O
OH
(
a)
(b)
OH
4
a
O
(c)
OEt
CHO
5a
O
O
6a
O
N2
We then examined the outcome and selectivity of the
reaction of 1a with an unsymmetrical olefin as dipolaro-
phile, and whether the resultant cycloadduct may be less
prone to decomposition. In the event, diazoketone 1a un-
derwent diastereoselective CCCC with acrolein under rhodi-
um catalysis to give one regioisomer 10, as a 13:1 ratio of
exo/endo isomers (Scheme 4). The stereochemistry of exo-
10 was deduced by NOE analysis. The cycloadduct was ob-
tained in a yield of 40%, apparently also on account of the
decomposition of the cycloadduct during purification.
(
d)
OEt
O
O
1a
Scheme 2 Synthesis of diazoketone 1a. Reagents and conditions: (a)
ClMgCH CH CH OMgCl, THF, 4 h, –78 °C, 82%; (b) DMSO–TFAA, CH Cl ,
Et N, 0.5 h, –78 °C, 76%; (c) EDA, cat. SnCl , CH Cl , O/N, r.t.; (d) p-ABSA,
2
2
2
2
2
3
2
2
2
Et N, MeCN, O/N, r.t., 73% over 2 steps.
3
CN
NC
NC
NC
CO2Et
O
cat. Rh2(OAc)4
TCE
O
4
Å MS, CH2Cl2
O
N2
7a
OEt
cat. Rh2(OAc)4
DMAD
MeO2C
MeO2C
CO2Et
O
O
O
1a
3
Å MS, PhMe
0 °C
8% yield
O
7
7
7b
cat. Rh2(OAc)4
DMAD
MeO2C
MeO2C
CO2Et
O
O
N2
OEt
O
4
Å MS, CH2Cl2
r.t.
O
O
8
52% yield
9
Scheme 3 CCCC reactions of 1a and 8
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–D

C
Synlett
Y. Yu et al.
Letter
EtO2C
O
b O
H4
CHO
cat. Rh2(OAc)4
C3H7
O
N2
H3b
OEt
a
H7b
H4
H7a H3a
H6
3
Å MS, CH2Cl2, r.t. OHC
0% yield
exo/endo 13:1
O
O
4
1a
10
Scheme 4 CCCC reactions of 1a and acrolein
After demonstrating the viability of the intermolecular
CCCC reactions of diazoketones bearing an enone, we exam-
ined the intramolecular version of this reaction. For the in-
tramolecular CCCC reaction to be geometrically possible,
the enone must be cis. We designed substrate 11, which is a
precursor of an α,β-unsaturated carbonyl ylide tethered
with a simple terminal double bond as dipolarophile. To
avoid the complication of the possible isomerization of the
more labile cis-enone to the more stable trans-enone, we
planned to reveal this double bond in the last stages of the
synthetic route.
lactone furnished hydroxy ynone 13 in its acyclic and hemi-
acetal form. Oxidation provided ketoaldehyde 14, which
was homologated to β-ketoester 15 under the standard
Roskamp reaction conditions. With compound 15 in hand,
we attempted the reduction to chemoselectively and par-
tially reduce the ynone in the presence of the terminal ole-
fin. Using Lindlar catalyst, reduction for one hour produced
the undesired, fully hydrogenated product wherein both
the double and triple bonds were reduced. We screened ad-
ditives, as well as optimized the reaction concentration and
time. Finally, the Lindlar reduction of a dilute reaction mix-
ture (0.007 M) for ten minutes in the presence of quinolone
afforded the desired cis-enone 16 in 89% yield. Diazo trans-
fer then provided the required substrate 11. Gratifyingly,
the cycloaddition of 11 occurred smoothly under rhodium
catalysis to give exclusively cycloadduct 17 as a single dia-
stereomer and in good yield.13 The relative configuration of
cycloadduct 17 was deduced through NOE studies and fur-
(b)
(
a)
Cl
12
(c)
(d)
CHO
OH
ther confirmed by X-ray crystallographic analysis (Figure
O
13
O
14
14
1).
CO2Et
O
(e)
(f)
CO2Et
O
O
15
16
O
H
CO2Et
O
(g)
N2
CO2Et
O
O
Figure 1 X-ray crystal structure of cycloadduct 17
O
11
17
Scheme 5 Reagents and conditions: (a) allylmagnesium bromide, –20 °C
to r.t., 48%; (b) n-BuLi, –20 °C, 1 h, then γ-butyrolactone, –78 °C to –20 °C,
In conclusion, the rhodium-catalyzed carbene cycliza-
tion to form unsaturated carbonyl ylides from enones and
its subsequent cycloaddition could construct functionalized
oxapolycyclic rings efficiently. These results, in particular,
the generation of 17 from diazoketone 11, affirm that this
cascade reaction could be employed as a strategy toward
the total synthesis of anthecularin (Figure 2),15 an antima-
larial natural product. We will report our progress on its
synthesis in due course.
5
3%; (c) PDC, 4 Å MS, CH Cl , r.t., 65%; (d) EDA, SnCl , CH Cl , O/N, r.t.,
2 2 2 2 2
8
8%; (e) Lindlar cat. (2.5 mol%), H , quinoline, EtOAc–hexane, r.t. 10
2
min, 89%; (f) p-ABSA, Et N, MeCN, r.t., 89%; (g) cat. Rh (OAc) , 3 Ǻ MS,
3
2
4
CH Cl , r.t., 72%.
2
2
The overall synthesis is shown in Scheme 5. Enyne 12
was obtained by propargylation of allylmagnesium bro-
mide; the yield was low in part due to the volatility of 12.
The addition of the acetylide derived from 12 to γ-butyro-
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Y. Yu et al.
Letter
J.; Schmalz, H.-G. Org. Lett. 2005, 7, 4317. (f) Graening, T.;
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O
O
2
002, 41, 1524. (g) Geng, Z.; Chen, B.; Chiu, P. Angew. Chem. Int.
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O
9
(
Figure 2 Antimalarial natural product, anthecularin
1
2
Acknowledgment
The University of Hong Kong Seed Funding for Basic Research, The Re-
search Grants Council of Hong Kong General Research Fund (HKU
015/13P), and the State Key Laboratory of Synthetic Chemistry are
7
(7) Padwa, A.; Zhang, Z. J.; Zhi, L. J. Org. Chem. 2000, 65, 5223.
thanked for financial support.
(8) Cahiez, G.; Alexakis, A.; Normant, J. F. Tetrahedron Lett. 1978, 33,
3
013.
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Commun. 1987, 17, 1709.
(
Supporting Information
(
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379926.
(
(
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
(
12) Cycloaddition with electron-rich dipolarophiles such as 2-
butyne, (Z)-1,4-diacetoxybut-2-ene, and ethoxyethene, also
met with failure.
References and Notes
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(13) Experimental for the Reaction of Diazoketone 11
Y. J. Am. Chem. Soc. 1993, 115, 12491. (c) van der Baan, J. L.; van
der Heide, T. A. J.; van der Louw, J.; Klumpp, G. W. Synlett 1995,
To a solution of Rh (OAc) (25.2 mg, 0.0570 mmol) in dry CH Cl
2
4
2
2
(30 mL) was added predried 3 Å MS (0.48 g). After stirring for 10
1. (d) Snider, B. B.; Vo, N. H.; Foxman, B. M. J. Org. Chem. 1993,
min, diazoketoester 11 (61.2 mg, 0.220 mmol) in dry CH Cl (10
58, 7228. (e) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew.
2
2
mL) was added via cannula. The reaction was stirred at r.t. and
monitored by TLC. When the reaction was complete (4 h), the
mixture was filtered through a pad of Celite, and the plug was
washed successively with several volumes of EtOAc. The filtrate
was removed of volatiles in vacuo, and the residue was purified
by flash chromatography using 5% EtOAc in hexane to afford 17
Chem. Int. Ed. 2006, 45, 7134.
2) (a) Recent reviews about palladium-, ruthenium-, and gold-cat-
alyzed domino reactions: Pellissier, H. Chem. Rev. 2013, 113,
(
4
42. (b) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127.
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005, 105, 1001.
3) Reviews on CCCC reactions: (a) Padwa, A. Acc. Chem. Res. 1991,
(
2
(
39.6 mg, 72% yield) as a white solid. R = 0.15 (10% EtOAc in
(
f
1
hexane). H NMR (600 MHz, C D ): δ = 5.71–5.68 (m, 1 H), 5.63
24, 22. (b) Padwa, A.; Weingarten, M. D. Chem. Rev. 1996, 96,
6
6
(dd, J = 2.4, 10.0 Hz, 1 H), 4.16–4.03 (m, 2 H), 2.24–2.01 (m, 4 H),
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1
1
.82–1.77 (m, 1 H), 1.64 (d, J = 17.3 Hz, 1 H), 1.47–1.40 (m, 2 H),
.36–1.30 (m, 3 H), 1.14–1.07 (m, 2 H), 0.99 (t, J = 7.2 Hz, 3 H)
(
(
d) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98, 863.
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13
ppm. C NMR (150 MHz, C D ): δ = 202.0, 168.0, 132.0, 128.9,
1
(
. (f) Mehta, G.; Muthusamy, S. Tetrahedron 2002, 58, 9477.
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6
6
8
8.9, 79.6, 61.5, 40.5, 39.6, 38.3, 33.0, 29.3, 25.1, 14.2 ppm. IR
–1
(CH Cl ): 3065, 2931, 1747, 1726, 1606, 1316, 1079, 947 cm .
2 2
+
LRMS (EI): m/z (rel) = 250.1 (2) [M ], 92.1 (100), 91.1 (51), 93.1
3
(
50), 117.1 (30), 134.1 (27), 106.1 (27), 79.0 (24). HRMS (EI):
M.; Labande, A. H.; Muthusamy, S. Org. React. 2013, 80, 133.
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Kikuchi, F.; Hashimoto, S. Angew. Chem. Int. Ed. 2006, 45, 6532.
+
m/z calcd for C14H18O [M ]: 250.1205; found: 250.1195.
(
4
(
14) Full crystallographic data for 17 (CCDC 1051518) can be
obtained from the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK.
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(
(
1
c) Hodgson, D. M.; Stupple, P. A.; Johnstone, C. Chem. Commun.
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©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, A–D