Catalytic intramolecular addition of metal carbenes to remote furans

Article abstract of DOI:10.1021/ol990168t

(formula presented) Diazo esters and diazo ketones linked to a furan undergo catalytic intramolecular addition of an intermediate metal carbene to the remote furan to form diendiones with ring sizes up to 17. Regioselectivity is catalyst dependent with addition to either the more or less substituted double bond. The high product yields and absence of need for high dilution suggest that this methodology is general for macrocycle preparations.

Full text of DOI:10.1021/ol990168t

ORGANIC
LETTERS
1999
Vol. 1, No. 9
1327-1329
Catalytic Intramolecular Addition of
Metal Carbenes to Remote Furans
Michael P. Doyle,* Brant J. Chapman, Wenhao Hu, and Chad S. Peterson
Department of Chemistry, UniVersity of Arizona, Tucson, Arizona 85721
M. Anthony McKervey† and Concepcio´n F. Garcia
School of Chemistry, The Queen’s UniVersity of Belfast, Belfast BT9 5AG,
North Ireland
mdoyle@u.arizona.edu
Received July 16, 1999
ABSTRACT
Diazo esters and diazo ketones linked to a furan undergo catalytic intramolecular addition of an intermediate metal carbene to the remote
furan to form diendiones with ring sizes up to 17. Regioselectivity is catalyst dependent with addition to either the more or less substituted
double bond. The high product yields and absence of need for high dilution suggest that this methodology is general for macrocycle preparations.
Transition metal catalyzed addition of carbene intermediates
to furans via diazocarbonyl compounds is now well estab-
lished.1 In intermolecular reactions with diazo esters, addition
occurs onto the less substituted double bond to produce a
labile, but generally detectable, cyclopropane intermediate
which rearranges to ring-opened products in which a diene
is located between two carbonyl groups (Scheme 1).2 An
possible, and probably operative, with select diazocarbonyl
compounds;1 the outcome is the same, but the framework
for stereocontrolled ring opening is absent. In any case, the
net result is a four-carbon homologation of a carbene
intermediate to a highly functionalized product.
Similar addition occurs with diazo ketones,3 but in these
cases the intermediate addition product has not been detected.
There have been a few examples of intramolecular addition4
but here also, ring opening of the presumed initially formed
addition product directs the formation of the observed
product. Dirhodium(II) acetate has been the catalyst of choice
for these reactions.
Scheme 1
(1) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds: From Cyclopropanes to
Ylides; Wiley: New York, 1998; Chapter 6.
(2) (a) Monn, J. A.; Valli, M. J.; Massey, S. M.; Hansen, M. M.; Kress,
T. J.; Wepsiec, J. P.; Harkness, A. R.; Grutsch, Jr., J. L.; Wright, R. A.;
Hohnson, B. G.; Andis, S. L.; Kingston, A.; Tomlinson, R.; Lewis, R.;
Griffey, K. R.; Tizzano, J. P.; Schoepp, D. D. J. Med. Chem. 1999, 42,
1027. (b) Wenkert, E.; Guo, M.; Lavilla, R.; Porter, B.; Ramachandran,
K.; Sheu, J.-H. J. Org. Chem. 1990, 55, 6203.
(3) (a) Adams, J.; Leblanc, Y.; Rokach, J. Tetrahedron Lett. 1984, 25,
1227. (b) Shew, J.-H.; Yen, C.-F.; Huang, H.-C.; Hong, Y.-L. V. J. Org.
Chem. 1989, 54, 5126.
(4) (a) Wenkert, E.; Decorzant, R.; Na¨f, F. HelV. Chim. Acta 1989, 72,
756. (b) Padwa, A.; Wisnieff, T. J.; Walsh, E. J. J. Org. Chem. 1989, 54,
299. (c) Davies, H. M. L.; Smith, H. D.; Korkor, O. Tetrahedron Lett. 1989,
28, 1853.
alternative mechanism involving electrophilic aromatic ad-
dition to the furan to form a zwitterionic intermediate is also
† tmckervey@quchem.com.
10.1021/ol990168t CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/06/1999

Scheme 2
We have previously reported investigations of intramo-
graphically pure material and fully characterized.
lecular addition reactions of diazocarbonyl compounds to
alkenes,5,6 alkynes,7 and benzene derivatives8 that have
resulted in the formation of macrocyclic esters and ketones.
We now report results from addition to tethered furans that
document their facility as well as their catalyst-dependent
regio- and stereocontrol and that suggest this process as an
exceptional methodology for macrocyclization.
We have used the benzenedimethanol tether to link the
diazocarbonyl carbene source to the reacting functional
group,5-8 and we did so this time. The synthesis of these
compounds involved leaving group displacement on the
monoprotected benzenedimethyl mesylate by the sodium salt
of furfuryl alcohol and subsequent preparation of the
diazocarbonyl compound, withthese steps occuring in moder-
ate to high yield. Diazo decomposition of 1 with Rh2(OAc)4
produced three products (2 and Z-4/E-4, Table 1), two of
The influence of catalyst on regioselectivity and diastereo-
selectivity was determined, and as can be seen from the data
in Table 1, changing the ligand on Rh2(OAc)4 to caprolac-
tamate (cap)9 allowed exclusively the production of 4.
Use of Cu(MeCN)4PF68 gave virtually the same results as
Rh2(pfb)4 (pfb ) perfluorobutyrate).10 In one case the
reaction mixture was worked up immediately after addition,
and syn-3 was detected in the reaction mixture; as expected
in a symmetry-controlled process, syn-3 formed Z-4 exclu-
sively. Treatment of the mixture of Z-4 and E-4 with 1 mol
% of I2 caused the immediate conversion of Z-4 to 5 and a
much slower isomerization of E-4, first to Z-4, and then to
5 quantitatively. Addition product 2 was stable to ring
opening even in the presence of a stoichiometric amount of
I2 at room temperature (16 h). Computational analysis11
showed E-4 to be less stable than Z-4 and that 5 was more
stable than either isomer of 4.
Dienes Z-4 and E-4 are consistent with the formation of
syn-3 and anti-3, respectively, with syn-3 favored over anti-3
by at least 70:30 (Table 1). However, the exclusive formation
of 7 suggests that only syn addition occurs with 6.
In a like manner, diazo ketone 6 was treated with Rh2-
(pfb)4 at room temperature, and following chromatographic
purification, only 7 (eq 1) was formed (40% yield).
Table 1. Products from Catalytic Diazo Decomposition of 1a
rel yield, %
catalyst
isolated yield, %b
2
4
4 (Z/E)c
Rh2(OAc)4
Rh2(cap)4
Rh2(pfb)4
62
40
67
73
19
0
48
45
81
100
52
86/14
70/30
72/28
87/13
Cu(MeCN)4PF6
55
a Reactions performed in refluxing dichloromethane; diazo ester was
added to catalyst (1.0 mol %) solution via a syringe pump. b Yield of purified
product after chromatographic purification. c Refers to the olefin geometry
at the R,â-position.
which were formally derived from the syn and anti isomers
of 3 (Scheme 2). Each product was isolated as a chromato-
The presumed cyclopropane precursor was not observed,
nor was the product, like 2, from addition to the 2,3-position
of the furan ring. Their absence is consistent with results
from intermolecular reactions with diazo ketones.3 Although
these results were not optimized, they demonstrate, as did
comparable aromatic cycloaddition reactions,8 inherent se-
lectivity differences between diazoacetates and diazo ketones.
(5) Doyle, M. P.; Peterson, C. S.; Parker, D. L., Jr. Angew. Chem., Int.
Ed. Engl. 1996, 35, 1334.
(6) Doyle, M. P.; Peterson, C. S.; Protopopova, M. N.; Marnett, A. B.;
Parker, Jr., D. L.; Ene, D. G.; Lynch, V. J. Am. Chem. Soc. 1997, 119,
8826.
(7) Doyle, M. P.; Ene, D. G.; Peterson, C. S.; Lynch, V. Angew. Chem.
Int. Ed. Engl. 1999, 38, 700.
1328
Org. Lett., Vol. 1, No. 9, 1999

The extent to which this macrocyclization process can be
used for the preparation of large-ring esters can be seen in
results from diazo decomposition of the diazoacetate 8
derived from triethylene glycol (Scheme 3).
quantitatively, but in this case conversion of E-11 to 13
occurred through the trans,trans-isomer 14 rather than via
Z-11.
Scheme 3
That Rh2(cap)4 promoted exclusive formation of 9 is
consistent with its overall reduced electrophilic character of
dirhodium(II) carboxamidates compared to carboxylates.12
However, the disparity in product formation between dirhod-
ium(II) and copper(I) was unexpected, especially in view of
results from diazo decomposition of 1 (Table 1). Preliminary
results with the next higher glycol homologue of 8sthe one
that would form the 21-membered homologue of 11 and the
17-membered homologue of 12sshow similar selectivity
with dirhodium(II) and copper(I) catalysts, suggesting a
generality that may be related to copper(I) coordination with
the ether framework.
In summary, catalytic metal carbene addition to remote
furans appears to be a general and highly versatile methodol-
ogy for the synthesis of macrocyclic lactones and ketones.
These reactions occur in high yield without the need for high
dilution methods. Further extensions and applications are
under active investigation.
Catalysis by Rh2(cap)4 gave only the product from C-H
insertion (9) whereas use of Cu(MeCN)4PF6 gave mainly
10 and dirhodium(II) octanoate, Rh2(oct)4, and Rh2(OAc)4
gave mainly ring-opened products 11 (Table 2).
Acknowledgment. We are grateful to the donors of the
Petroleum Research Fund, administered by the American
Chemical Society, and to the National Science Foundation
for support of this research.
Table 2. Products from Catalytic Diazo Decomposition of 8a
rel yield, %
Supporting Information Available: Experimental and
spectral data that include the synthesis and reactions of diazo
compounds and characterization of reaction products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
catalyst
Rh2(cap)4
Rh2(oct)4
Rh2(OAc)4
Rh2(pfb)4
isolated yield,%b
9
10 11 11 (Z/E)
100
0
0
16
20
32
0
84
80
68
58
50
33
65
36/64b
18/82b
18/82
17/83
0
0
0
Cu(CH3CN)4PF6
82c 18
OL990168T
a Reactions performed in refluxing dichloromethane; diazo ester was
added to catalyst (1.0 mol %) solution via syringe pump. b Product E-11
was isolated in 30% yield. c Product 10 was isolated in 55% yield.
(8) Doyle, M. P.; Protopopova, M. N.; Peterson, C. S.; Vitale, J. P.;
McKervey, M. A.; Garcia, C. F. J. Am. Chem. Soc. 1996, 118, 7865.
(9) Doyle, M. P.; Westrum, L. J.; Wolthuis, W. N. E.; See, M. M.; Boone,
W. P.; Bagheri, V.; Pearson, M. M. J. Am. Chem. Soc. 1993, 115, 958.
(10) Doyle, M. P.; Shanklin, M. S. Organometallics 1994, 13, 1081.
(11) Osawa conformational analysis in Spartan 4.0.5, then geometry
optimization using semiempirical PM3: Stewart, J. J. P. J. Comput. Chem.
1990, 11, 543 and 569.
The product from anti addition, E-11, was favored over
the product from syn addition, Z-11, in this case. Further-
more, 10 was converted to 12 by treatment with 1 mol % of
I2 in chloroform (4 h), and 11 was isomerized to 13
(12) Padwa, A.; Austin, D. J.; Price, A. T.; Semones, M. A.; Doyle, M.
P.; Protopopova, M. N.; Winchester, W. R.; Tran, A. J. Am. Chem. Soc.
1993, 115, 8669.
Org. Lett., Vol. 1, No. 9, 1999
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