One-step formation of fused tetracyclic skeletons from cyclohexene-diynes and carbon monoxide through Rh(i)-catalyzed [2 + 2 + 2 + 1] cycloaddition reaction

Article abstract of DOI:10.1039/b909781c

Rapid construction of 5-7-6-5 fused tetracyclic carbocycles and heterocycles from cyclohexene-diynes and CO has been achieved in one step through a Rh(i)-catalyzed [2 + 2 + 2 + 1] cycloaddition process. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b909781c

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One-step formation of fused tetracyclic skeletons from
cyclohexene-diynes and carbon monoxide through Rh(I)-catalyzed
[2 + 2 + 2 + 1] cycloaddition reactionwz
Joseph J. Kaloko, Yu-Han Gary Teng and Iwao Ojima*
Received (in Cambridge, UK) 18th May 2009, Accepted 15th June 2009
First published as an Advance Article on the web 29th June 2009
DOI: 10.1039/b909781c
Rapid construction of 5-7-6-5 fused tetracyclic carbocycles and
heterocycles from cyclohexene-diynes and CO has been achieved
in one step through a Rh(I)-catalyzed [2 + 2 + 2 + 1]
cycloaddition process.
Transition metal-catalyzed carbocyclization and cycloaddition
reactions have proven to be among the most efficient methods
for constructing complex polycyclic systems.1 A variety of higher
order processes have been reported including [2 + 2 + 2 + 1],2
[4 + 2 + 2],3 [5 + 1 + 2 + 1],4 [3 + 3 + 1]5 and
[5 + 2 + 1]6 cycloadditions. In addition, transition metal-
catalyzed cycloaddition reactions are frequently utilized in the
syntheses of complex molecules and natural products.6,7
Intrigued by naturally occurring 5-7-6-5 fused tetracyclic
compounds such as recently discovered Caribenol A,8 we set
out to develop a highly efficient synthetic route to the 5-7-6-5
tetracyclic skeleton via a single step process from enediynes. If
successful, such a catalytic process will provide rapid access to
a library of drug-like carbocycles and heterocycles.
Scheme 2 [2 + 2 + 2 + 1] cycloaddition of cyclohexene-diyne 4h
with CO.
indeed gives the desired 5-7-6-5 fused tetracyclic products in
good to excellent yields and as single diastereomers.
The reaction of 4h was carried out in the presence of
[Rh(COD)Cl]2 (5 mol%); treatment with CO (1 atm) in
dichloroethane at 60 1C2b for 50 h gave the desired fused
tetracyclic product 5h along with a small amount of the
[2 + 2 + 2] cycloadduct 6h (ca. 11.5 : 1) in 89% isolated
yield (Scheme 2, Table 1, entry 1).
However, we found that these conditions were not generally
applicable to other substrates 4 to achieve high selectivity.
Thus, the reaction conditions were optimized to improve
product selectivity as well as the rate of the reaction
(Table 1). The use of [Rh(CO)2Cl]2 (5 mol%) as the catalyst
substantially increased the rate of the reaction (i.e., completion
in 20 h) but resulted in somewhat decreased selectivity
(Table 1, entry 2). Increase in the CO pressure resulted in
lower conversion in 20 h, but with better selectivity (entries 3
and 4). Using trifluoroethanol (TFE) as the solvent10 under
2 atm of CO, 5h was obtained exclusively with complete
conversion in 20 h, but in 70% yield. The optimal conditions
found to date are with [Rh(CO)2Cl]2 (5 mol%) under 2 atm of
CO in DCE–TFE (10 : 1) at 60 1C for 20 h, which gave
5h exclusively in 92% isolated yield (Table 1, entry 6).
Our first attempt at constructing this skeleton by Rh-catalyzed
carbonylative silicon-initiated carbotricyclization (CO-SiCaT)9 of
enediyne 1 bearing a cyclohexenyl group as the olefin moiety
resulted in the formation of tricyclic product 3 via a facile
b-hydride elimination in the key intermediate 2 (Scheme 1).2a
In the present work, we have applied our previously
developed [2 + 2 + 2 + 1] cycloaddition process2a,b to similar
cyclohexene-diyne substrates 4, and found that the reaction
Table 1 Optimization of [2 + 2 + 2 + 1] cycloaddition of 4h
with CO
Scheme 1 CO-SiCaT of cyclohexene-diyne.
Conv.
Yield
Entry Solvent
[Rh] (5 mol%) CO/atm (%)a 5h : 6ha (%)b
1
2
3
4
5
6
DCE
DCE
DCE
DCE
TFE
[Rh(COD)Cl]2
[Rh(CO)2Cl]2
[Rh(CO)2Cl]2
[Rh(CO)2Cl]2
[Rh(CO)2Cl]2
1
1
2
3
2
2
100b
100
75
92 : 8 89
90 : 10 86
Department of Chemistry, State University of New York at
Stony Brook, Stony Brook, New York 11794-3400, USA.
E-mail: iojima@notes.cc.sunysb.edu; Fax: +1-631-632-7942;
Tel: +1-631-632-1339
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-theme issue showcasing high quality research in organic chemistry.
Please see our website (http://www.rsc.org/chemcomm/organic
webtheme2009) to access the other papers in this issue.
z Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b909781c
93 : 7 NDc
93 : 7 NDc
100 : 0 70
100 : 0 92
90d
100
100
DCE–TFE [Rh(CO)2Cl]2
(10 : 1)
a
Determined by reverse phase HPLC analysis (Phenomenex, Jupiter
b
c
10 m Proteo 90A) for 20 h reaction. Isolated yield. Not determined.
At 50 h.
d
ꢀc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 4569–4571 | 4569

Table 2 [2 + 2 + 2 + 1] cycloaddition of 4a–g with COa
(Table 2, entries 5 and 6). The reaction of 4g, bearing a phenyl
group at the terminal ethynyl moiety, also gave 5g-1, but an
equal amount of 6g was formed. Thus, further optimization of
reaction conditions is underway for this substrate.
Entry Substrate
5-1 (Yield %)b
6 (Yield %)b
As described above (Scheme 2, Table 1, entry 6), the
reaction of 4h proceeded exclusively to give 5h in excellent
yield. However, 1H and 13C NMR spectra as well as LC-MS of
5h obtained after flash chromatography indicated that 5h was
a ca. 1 : 1 mixture of two isomers, which were isolated by
preparative HPLC. Further analysis revealed that one of the
isomers was the anticipated product 5h-1, while the other was
its diene-shifted regioisomer 5h-2 (Table 3, entry 1). It should
be noted that both 5h-1 and 5h-2 were single diastereomers.
Similar results were obtained for the reactions of 4i–k bearing
a PhMe2Si or Me3Si group at the terminal ethynyl moiety,
affording 5i–k as a ca. 1 : 1 mixture of regioisomers (Table 3,
entries 2–4).
1
—
2
3
4
5
6
—
—
—
Molecular modeling studies (Gaussian; AM1) on 5(h–k)-1
and 5(h–k)-2 indicated that 5(h–k)-2 should be energetically
favorable. However, attempted diene isomerization with
extended reaction time did not result in any appreciable
change in product ratios. Further investigation into the mecha-
nism and suppression of this isomerization is in progress.
The key to the successful rapid construction of the 5-7-6-5
fused tetracyclic skeleton in one step from enediynes 4 and CO
lies in the mechanism of the [2 + 2 + 2 + 1] cycloaddition
process. As illustrated in Scheme 3, the reaction proceeds
through (i) selective coordination of the diyne moiety of
enediyne 4 to the active Rh-catalyst species to give metalla-
cycle A ([2 + 2 + M]); (ii) insertion of the olefin moiety of 4
into the Rh–C bond to yield 5-7-6-5 fused-tetracyclic rhoda-
cycle B ([2 + 2 + 2 + M]); (iii) coordination of CO to the [Rh]
metal followed by migratory insertion of CO into the Rh–C
bond to form 5-8-6-5 rhodacycle C or C0 ([2 + 2 + 2 + 1 + M]);
and (iv) reductive elimination to give [2 + 2 + 2 + 1]
cycloadduct 5-1 and regenerate the active Rh-catalyst species.
Reductive elimination from rhodacycle B prior to CO
insertion gives [2 + 2 + 2] cycloadduct 6.2a,c The observed
exclusive formation of 5-1 and 6 as a single diastereomer is
ascribed to the exclusive endo insertion of the olefin moiety of
the cyclohexene group into the Rh–C bond to form rhodacycle
B, which is energetically the only feasible pathway.
7
It should be noted that intermediate B has already installed
the Rh–C bond with the sp2 carbon, which was originally the
terminal ethynyl group. This metallacycle structure prevents
the b-hydride elimination which took place in 2 (Scheme 1)
as the most facile pathway. This newly found feature has
significantly expanded the scope of the [2 + 2 + 2 + 1]
cycloaddition process.
a
Reactions were run with [Rh(CO)2Cl]2 (5 mol%) at 60 1C and 2 atm
of CO and in DCE–TFE (10 : 1) for 20 h. Averaged isolated yield of
b
analytically pure products based on at least two runs using 50–100 mg
of substrates.
It is clear that this novel [2 + 2 + 2 + 1] cycloaddition
process has opened an avenue for possible rapid construction
of a library of fused tetracyclic compounds using unsaturated
carbocycles and heterocycles as the ene component. Further
studies on the scope and application of this unique process are
actively underway in these laboratories.
Under the optimized conditions, [2 + 2 + 2 + 1] cycloaddition
of various cyclohexene-diynes 4 afforded the corresponding
5-7-6-5 fused tetracyclic cycloadducts in good to excellent yields.
The reactions of 4a–d, bearing a methyl group at the terminal
ethynyl moiety, gave 5(a–d)-1 exclusively in 74–91% yields
(Table 2, entries 1–4).
This work was supported by a grant from the National
Science Foundation. A Fellowship to JJK from The W.
Burghardt Turner Fellowship at the State University of
New York at Stony Brook is gratefully acknowledged.
The reactions of 4(e,f) also gave 5(e,f)-1 in high yields, but
accompanied by small amounts of 6(e,f) as side products
ꢀc
This journal is The Royal Society of Chemistry 2009
4570 | Chem. Commun., 2009, 4569–4571

Table 3 [2 + 2 + 2 + 1] cycloaddition of 4h–k with COa
Entry
Substrate
5-1
5-2
Yield (%)b
1
92
2
3
77
92
4
87c
a
b
c
See footnote a of Table 2. Isolated yield. Isomers were isolated by preparative HPLC (Phenomenex, Jupiter 10m Proteo 90A). 6k was formed
in 6% yield.
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ꢀc
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Chem. Commun., 2009, 4569–4571 | 4571