Synthesis of 3,4-substituted cyclopentenones via an intramolecular Pauson-Khand reaction of N-O linked enynes

Article abstract of DOI:10.1016/S0040-4039(00)01495-7

Differentially 3,4-disubstituted cyclopentenones are constructed via a novel Pauson-Khand cyclization/cleavage strategy of N-O linked enynes. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01495-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9393–9396
Synthesis of 3,4-substituted cyclopentenones via an
intramolecular Pauson–Khand reaction of NꢀO linked
enynes
Stefan G. Koenig, Kristi A. Leonard, Ralf S. Lo¨we and David J. Austin*
Department of Chemistry, Yale University, New Haven, CT 06520, USA
Received 30 August 2000; accepted 7 September 2000
Abstract
Differentially 3,4-disubstituted cyclopentenones are constructed via a novel Pauson–Khand cyclization/
cleavage strategy of NꢀO linked enynes. © 2000 Published by Elsevier Science Ltd.
The Pauson–Khand cycloaddition has recently emerged as a premier method for the construc-
tion of cyclopentenones and cyclopentane containing natural products.1 Intermolecular exam-
ples of this formal [2+2+1] cycloaddition generally provide a mixture of regioisomers.2
Intramolecular reactions generally overcome this regioselectivity issue, however, not all synthetic
targets are amenable to an intramolecular approach.3 In these instances, a cleavable and
sometimes ‘traceless’ tether can provide an intramolecular cyclization that can be subsequently
cleaved. In an attempt to apply this approach to a general methodology for natural product
synthesis, we utilized a cleavable tether strategy that provides additional functionality for further
synthetic modification.
The use of cleavable tethers was first applied to the radical-mediated synthesis of C-
glycosides4 (silyloxy tether) and palladium-catalyzed cycloadditions5 (ester tether). Since these
first examples, both tethered and cleavable functional groups have been recognized for their
entropic benefits and have become more widespread in synthetic endeavors.6 Many natural
products contain cyclopentane rings with adjacent heteroatom functionality. Examples include
palau’amine7,8 styloguanidines,9 axinellamines,10 and agelastatin.11 Utilization of a cyclization/
cleavage strategy for the construction of a five-membered ring 2 through an intramolecular
Pauson–Khand reaction with a novel tethered enyne 3 was envisioned (Scheme 1). This
nitrogenꢀoxygen linkage, in addition to controlling the regiochemistry of the transformation,
can allow for cleavage to give the monocyclic compound 1 that contains discriminant function-
alities, in this case an amino and hydroxyl group.
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01495-7

9394
X
Y
X
Y
X
Y
O
O
R
R
R
1
2
3
X = N, Y = O.
Scheme 1. Retrosynthesis of the NꢀO linked cyclization/cleavage strategy
Construction of the benzyl-protected NꢀO linked enyne 7 was initiated from benzaldehyde
oxime 4. Treatment of 4 with NaH and propargyl bromide at 0°C furnished the oxime ether 5
in 84% yield (Scheme 2). Reductive amination under acidic conditions, followed by allylation of
the hydroxylamine 6, furnished the Pauson–Khand precursor 7 in moderate yield. Cycloaddition
of 7 mediated by dicobalt octacarbonyl and trimethylamine N-oxide furnished the Pauson–
Khand product 8 in 51% yield.12 This transformation validated the feasibility of an intramolec-
ular Pauson–Khand reaction using a novel NꢀO linkage.
Br
NaCNBH3
H
N
N
N
NaH, nBu4NI,
THF, 0oC, 84%
O
MeOH, pH 3
59%
OH
O
4
5
6
1. Co2(CO)8,
DCM, rt
Br
K2CO3, nBu4NI,
18-crown-6, DMF, rt
69%
N
N
O
O
O
2. TMANO,
51%
7
8
Scheme 2. Synthesis of benzyl protected enyne 7 and cyclopentenone 8
O
NH2
Boc2O, Na2CO3
1. TMS
O
Br
DBU, DMF, 82%
2. H2NNH2, DCM, 95%
N OH
TMS
dioxane
79%
O
9
NBoc
2h, 63%
11
O
TMS
Br
NHBoc
O
TMS
NaH, DMF,
50oC
NBoc
12
O
10
12h, 97%
H
Scheme 3. Synthesis of t-butoxycarbonyl-protected enynes 11 and 12

9395
An analogous t-butoxycarbonyl-protected enyne would further expand the scope of this NꢀO
cleavable tether approach. Alkylation of N-hydroxy phthalimide with TMS–propargyl bromide,
followed by treatment with hydrazine gave TMS–propargyl hydroxylamine 9 in 78% yield over
two steps. Hydroxylamine 9 could be protected as its Boc-carbamate 10 by treatment with
Boc-anhydride in the presence of Na2CO3 (79%). Further alkylation with allyl bromide in the
presence of NaH in DMF at 50°C for 2 h led to the formation of 11 in 63% yield, while allowing
the reaction to proceed for 12 h yielded 12 in 97% yield (Scheme 3).
Pauson–Khand cycloadditions of 11 and 12 to cyclopentenones 13 and 1413 (Scheme 4) were
accomplished under identical conditions as those for the benzyl-protected enyne 7. It is
interesting to note that comparable yields were observed for the cycloaddition of substrates 7
and 12 (51 and 59%, respectively), while the silyl-protected alkyne substrate 11 gave the highest
yield overall (76%).
1. Co2(CO)8, DCM, rt
2. TMANO
NBoc
O
NBoc
O
O
R
R
11: R = TMS
12: R = H
13: R = TMS, 76%
14: R = H, 59%
Scheme 4. Pauson–Khand reaction of t-butoxycarbonyl-protected enynes 11 and 12
General utility of this methodology will require mild and efficient cleavage of the NꢀO bond.
Treatment of both 13 and 14 with activated Zn/AcOH, nickel boride (NiB2), and hydrogenation
with various catalysts afforded none of the desired products (15 and 16). However, treatment
with SmI2 in THF/EtOH facilitated smooth cleavage of the backbone to give differentially
3,4-substituted cyclopentenones 15 and 16 in 83% and 76% yields, respectively (Scheme 5). These
and other cyclopentenones could prove to be valuable intermediates in the synthesis of complex
natural products.
NHBoc
SmI2 under N2
NBoc
O
O
O
THF, EtOH, rt
R
R
OH
13: R = TMS
14: R = H
15: R = TMS, 83%
16: R = H, 76%
Scheme 5. Cleavage of NꢀO tether of cyclopentenones 13 and 14
In conclusion, we have designed a new NꢀO tethered enyne approach, compatible with
existing Pauson–Khand reaction conditions, to provide novel cyclopentenones. Selective cleav-
age of the NꢀO backbone produces differentially 3,4-substituted cyclopentenones. Further work
expanding the application and scope of this methodology is currently underway and will be
reported shortly.

9396
Acknowledgements
The authors gratefully acknowledge financial support from Yale Corporation and The
Johnson & Johnson Focus Giving Program.
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mL of anhydrous dichloromethane. After stirring for 1 h at rt and verification of the reddish-brown cobalt–
alkyne complex by TLC, 8.4 equivalents of anhydrous trimethylamine N-oxide are added in portions to the dark
solution. We have found that cooling the solution below 0°C prior to addition of the N-oxide helps to control
the exothermic character of the reaction and facilitates greater yields of product. Further stirring (2 h) followed
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SiO2 (Hex/EtOAc, 4:1 gradient to 1:1) furnishes UV active cyclopentenone 2.
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;
NMR (300 MHz, CDCl3) l 6.06 (s, 1H), 4.73 (d, 1H, J=13.3 Hz), 4.66 (d, 1H, J=13.3 Hz), 4.41 (m, 1H), 3.11
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154.3, 128.8, 82.5, 70.1, 52.9, 38.2, 37.8, 28.2; HRMS (FAB) calcd for C12H17NO4 239.1158, found 239.1156.
.