Polyether macrocycles from intramolecular cyclopropanation and ylide formation. Effect of catalyst and coordination

Article abstract of DOI:10.1021/jo0614902

The use of catalytic metal carbene methodology with diazoacetates for the construction in high yield of polyether macrocycles having ring sizes greater than 25 has been achieved by preventing access to γ-C-H positions for intramolecular insertion. Cyclopr

Full text of DOI:10.1021/jo0614902

Polyether Macrocycles from Intramolecular Cyclopropanation
and Ylide Formation. Effect of Catalyst and Coordination
Thomas M. Weathers, Jr., Yuanhua Wang, and Michael P. Doyle*
Department of Chemistry and Biochemistry, UniVersity of Maryland, College Park, Maryland 20742
mdoyle3@umd.edu
ReceiVed July 18, 2006
The use of catalytic metal carbene methodology with diazoacetates for the construction in high yield of
polyether macrocycles having ring sizes greater than 25 has been achieved by preventing access to γ-C-H
positions for intramolecular insertion. Cyclopropanation is the exclusive outcome of reactions performed
with dirhodium(II) catalysts, and product yields of greater than 70% are obtained without resorting to
high dilution with solvents. With copper(I) catalysts having multiple sites for polyether coordination,
intramolecular oxonium ylide formation occurs at the terminal oxygen, followed by [2,3]-sigmatropic
rearrangement of the pendant allyl group, in competition with cyclopropanation. Sodium ion coordination
with the reactant diazo compound inhibits oxonium ylide formation in copper-catalyzed reactions. The
composite results are consistent with copper serving as a template for the substrate as well as the site in
the ether complex for diazo decomposition and subsequent metal carbene reactions.
Introduction
Since the initial report of macrocyclization in catalytic metal
carbene addition reactions in 1995,7 these ring-closing reactions
with diazoesters have been demonstrated to be surprisingly
effective.8 Intramolecular ring closure by addition to a carbon-
carbon double bond,9 carbon-carbon triple bond,10 and aryl
group11 or furan12 (aromatic cycloaddition) has been reported
to occur in good yields for selected examples up to ring sizes
of 20,9 and high enantiocontrol, matching those for intermo-
lecular reactions of diazoacetates with alkenes using chiral
The formation of macrocycles has been a difficult challenge
in organic synthesis.1 As the internal distance between reacting
centers increases, the energy difference between intramolecular
and intermolecular reactions decreases to zero. Few reactions
have been successful in effecting macrocyclization in moderate-
to-high yields,2,3 and, despite improvements in ring-closing
methodologies, the need exists for procedures that provide
reliable and selective access to macrocycles4,5 without having
to approach infinite dilution in the process.6
(4) (a) Raymo, F. M.; Stoddart, J. F. Chem. ReV. 1999, 99, 1643. (b)
Fyfe, M. C. T.; Stoddart, J. F. Acc. Chem. Res. 1997, 30, 393.
(5) Adams, R. D. Acc. Chem. Res. 2000, 33, 171.
(6) Namba, K.; Kishi, Y. J. Am. Chem. Soc. 2005, 127, 15382.
(7) Doyle, M. P.; Hu, W. Synlett 2001, 1364.
(8) Doyle, M. P.; Protopopova, M. N.; Poulter, C. D.; Rogers, D. H. J.
Am. Chem. Soc. 1995, 117, 7281.
(9) Doyle, M. P.; Peterson, C. S.; Protopopova, M. N.; Marnett, A. B.;
Parker, D. L., Jr.; Ene, D. G.; Lynch, V. J. Am. Chem. Soc. 1997, 119,
8826.
(10) Doyle, M. P.; Peterson, C. S.; Parker, D. L., Jr. Angew. Chem., Int.
Ed. Engl. 1996, 35, 1334.
(11) 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.
(12) Doyle, M. P.; Chapman, B. J.; Hu, W.; Peterson, C. S.; McKervey,
M. A.; Garcia, C. F. Org. Lett. 1999, 1, 1327.
(1) (a) Meng, Q.; Hesse, M. In Topics in Current Chemistry: Macro-
cycles; Dewar, M. J. S., Dunitz, J. D., Hafner, K., Ito, S., Lehn, J.-M.,
Niedenzu, K., Raymond, K. N., Rees, C. W., Vo¨gtle, F., Eds.; Springer-
Verlag: New York, 1992; Vol. 161, pp 107-176. (b) Macrocycle
Synthesis: A Practical Approach; Parker, D., Ed.; Oxford University
Press: Oxford, New York, 1996.
(2) For reviews, see: (a) Roxburgh, C. J. Tetrahedron 1995, 36, 9767.
(b) Griesbeck, A. G.; Henz, A.; Hirt, J. Synthesis 1996, 1261.
(3) For recent examples, see: (a) Molander, G. A.; Dehmel, F. J. Am.
Chem. Soc. 2004, 126, 10313. (b) Lee, C. W.; Choi, T. L.; Grubbs, R. H.
J. Am. Chem. Soc. 2002, 124, 3224. (c) Lee, X. H.; Upton, T. G.; Gibb, C.
L. D.; Gibb, B. C. J. Am. Chem. Soc. 2003, 125, 650. (d) Hodgson, D. M.;
Angrish, D. Chem. Commun. 2005, 4902. (e) Li, G.-Y.; Che, C.-M. Org.
Lett. 2004, 6, 1621.
10.1021/jo0614902 CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/21/2006
J. Org. Chem. 2006, 71, 8183-8189
8183

Weathers et al.
SCHEME 1
SCHEME 2
catalysts, often accompanies these reactions.13-17 The major
limitation of macrocycle formation by metal carbene addition
from diazoacetates has been competitive carbon-hydrogen
insertion to form γ-butyrolactones,18 and this competition has
prevented further development of this methodology. To control
competing C-H insertion, we have designed a polyether
framework that not only allows cyclopropanation reactions to
ring sizes of 28 in high yield, but we have also discovered
preferential macrocyclic ylide formation over cyclopropanation
with the use of weakly ligated copper(I) catalysts, exemplifying
a templating effect around the metal ion to control product
formation.
Results and Discussion
In prior studies, dirhodium(II) carboxylates and active copper
catalysts were found to be suitable for intramolecular cyclo-
propanation of the triglyme-linked allyl diazoacetate 1,14 but
competition from intramolecular carbon-hydrogen insertion
forming γ-butyrolactone 4 reduced the macrocyclization path-
way to the point of exclusion when dirhodium(II) carboxami-
dates such as Rh2(MEOX)4 were used, prohibiting the use of
these highly enantioselective catalysts for asymmetric macro-
cyclic cyclopropanation (Scheme 1). Modest amounts of the
product from [2,3]-sigmatropic rearrangement (3) were observed
with copper catalysts, but not with dirhodium catalysts. Similar
outcomes were obtained with homologues of 1 and dirhodium
catalysts.14 Since the major limitation to further development
of this macrocyclization process for the production of polyethers
is intramolecular C-H insertion, we designed a system blocking
γ-lactone formation with the goal of enhancing macrocyclic
cyclopropanation in dirhodium(II)-catalyzed reactions and inves-
tigating the alternative ylide pathway for copper carbenes.
Since the 1,2-benzenedimethanol linker was shown in earlier
studies to inhibit C-H insertion,10,13,15 the placement of this
linker at the diazoacetate terminus was expected to prevent
γ-butyrolactone formation. We sought a procedure that would
allow allyl group placements at various distances from the
diazoacetate terminus, thus allowing access to increasingly
larger ring sizes. Synthesis of diazoacetate 8 was accomplished
linearly, starting from the olefin terminus (Scheme 2) to allow
modification of the length of the ethylene glycol linker. The
Corey-Myers diazoacetate transfer protocol19 was used in
preference to other diazo transfer methods20 because it is a
single-step process in organic solvent, avoiding exposure of 7
TABLE 1. Diazo Decompositiona of 8 with Selected Dirhodium(II)
Catalysts
catalyst
Rh2(pfb)4
11:12b
E:Z (11)a
yield (11 + 12)c
94:6
100:0
100:0
100:0
100:0
52:48
36:64
44:56
40:60
75:25
41
71
70
62
41
Rh2(OAc)4
d
Rh2(oct)4
Rh2(4S-DOSP)4
Rh2(4S-MEOX)4
a Reactions were performed by 2 h addition of 8 to refluxing solution of
1 mol % catalyst in 10 mL of dichloromethane. Average of two or more
reactions. b Ratios of products obtained by 1H NMR spectroscopy. c Yields
were obtained from the mass of the composite isolated products and the
1
integrated H NMR signals of 11 and 12. d oct ) octanoate.
to water and the inherent difficulties in product isolation
associated with the removal of water from 8. The syntheses of
9 and 10 were accomplished in a similar manner with the
modifications of using allyl bromide in place of 2-allyloxyethyl
methanesulfonate (for 9) or penta(ethylene glycol) in place of
tetra(ethylene glycol) (for 10) (Scheme 2).
Dirhodium(II) catalysts with a known range of reactivity were
selected for the diazo decomposition of 8 (eq 1). Chemoselec-
tivity and diastereoselectivity realized from the employment of
each catalyst are summarized in Table 1. Only the 25-membered
macrocycles (11) from cyclopropanation were isolated from
diazo decomposition of 8 catalyzed by dirhodium(II) tetraacetate,
and they were obtained in relatively high yield. Macrocycle 11
was formed as a composite of two HPLC-separable geometrical
1
isomers that were structurally characterized by their H NMR
(13) Doyle, M. P.; Hu, W.; Chapman, B.; Marnett, A. B.; Peterson, C.
S.; Vitale, J. P.; Stanley, S. A. J. Am. Chem. Soc. 2000, 122, 5718.
(14) Doyle, M. P.; Hu, W. J. Org. Chem. 2000, 65, 8839.
(15) Doyle, M. P.; Ene, D. G.; Forbes, D. C.; Pillow, T. H. Chem.
Commun. 1999, 1691.
chemical shifts, with coupling constants for the cyclopropane
hydrogen alpha to the carbonyl group [E (δ 1.69; J ) 8.3, 4.6,
and 4.3 Hz) and Z (δ 1.89; J ) 8.5, 7.7, and 5.9 Hz)] consistent
(16) Doyle, M. P.; Davies, S. B.; Hu, W. Chem. Commun. 2000, 867.
(17) Doyle, M. P.; Hu, W. Tetrahedron Lett. 2000, 41, 6265.
(18) Doyle, M. P.; Phillips, I. M. Tetrahedron Lett. 2001, 42, 3155.
(19) Corey, E. J.; Myers, A. G. Tetrahedron Lett. 1984, 25, 3359.
(20) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds: From Cyclopropanes to
Ylides; Wiley-Interscience: New York, 1998.
8184 J. Org. Chem., Vol. 71, No. 21, 2006

Polyether Macrocycles from Cyclopropanation and Ylides
with those seen for E and Z isomers of previously characterized
cyclopropanes.13,14 Products were analyzed for geometrical
preference on the cyclopropane ring by integration of the char-
acteristic signals observed at 0.89 and 1.10 ppm in the 1H NMR
spectrum of the reaction mixture; these isolated signals cor-
respond to the E and Z isomers of 11, respectively. Integration
of the UV absorbance from HPLC separation of the isomers of
11 agreed with the E and Z isomer ratios obtained by 1H NMR
signal integration.
effectively promote C-H insertion reactions in competition
with cyclopropanation.22,23 The formation of macrocyclic cyclo-
propane 11 as the exclusive product with both of these catalysts,
demonstrates that blocking of the γ position prevents C-H
insertion, providing access to a much larger range of dirhodium-
(II) catalysts for this important ring-forming methodology.
However, with Nishiyama’s RuCl2(S,S)iPr-pyBOX catalyst
(13),24 [RuCl2(p-cymene)]2 (14), and silver(I) triflate, catalytic
diazo decomposition of 8 showed no macrocycle formation.
Copper catalysts also effect good conversion of 8 to macro-
cyclic products, but oxonium ylide formation, previously found
to be a minor process in Cu(CH3CN)4PF6-catalyzed reactions
of diazoacetates linked to an allyl group through 1,2-benzene-
dimethanol9 or naphthalene-1,8-dimethanol,15 is substantially
competitive with cyclopropanation. As seen by the results in
Table 2, counterions associated with the copper catalyst had
TABLE 2. Diazo Decomposition of 8 with Selected Copper
Catalystsa
catalyst
11:12b
E:Z (11)b
yield (11 + 12), %c
[Cu(OTf)]2C6H6
Cu(CH3CN)4PF6
Cu(hfacac)2
62:38
51:49
52:48
57:43
57:43
60:40
76
82
75
Cyclopropanation products 11 were also obtained with other
dirhodium(II) catalysts (Table 1), showing modest variation in
the diastereomer ratio (11E:11Z). The chiral carboxamidate
catalyst Rh2(4S-MEOX)4 formed 11 in moderate yield, but,
despite extensive efforts, the enantioselectivities of the products
formed from this reaction could not be obtained due to the
lack of enantiomer separation. Dirhodium(II) caprolactamate
[Rh2(cap)4] was used for comparison with results from the use
of Rh2(4S-MEOX)4, but with Rh2(cap)4 only trace amounts of
11 were formed, and the only additional products that could be
identified (20% of total) were those resulting from carbene
dimerization (singlets at 6.3 and 6.9 ppm for maleate and
fumarate esters, respectively). With use of the highly reactive
Rh2(pfb)4, a new product (12), consistent with that from
intramolecular oxonium ylide formation and subsequent [2,3]-
sigmatropic rearrangement, was observed in minor amounts (eq
1). Overall, the high yields of product obtained in this catalytic
procedure that uses regulated addition of the diazo compound,
but not high dilution, are quite distinctive.
d
a Reactions were performed by 2 h addition of 8 to refluxing solution of
10 mol % catalyst in 10 mL of dichloromethane. Average of two or more
reactions. b Ratios of products obtained by 1H NMR spectroscopy. c Yields
were obtained from the mass of the isolated products and the integrated 1H
NMR ratios for 11 and 12. d hfacac ) hexafluoroacetoacetonate.
minimal influence on reaction chemoselectivity or diastereo-
selectivity. However, adding the (S,S)-tBu-BOX ligand25 to
Cu(CH3CN)4PF6 resulted in no identifiable products even
though complete diazo decomposition was observed. Diazo
decomposition was also attempted using copper(II) acetyl-
acetonate [Cu(acac)2], but reaction only occurred in refluxing
dichloroethane (DCE) without formation of macrocycles 11 or
12. These results suggest that coordination of polyether reactant
and/or product with the copper catalyst is occurring; complex-
(21) Davies, H. M. L.; Bruzinski, P. R.; Hutcheson, D. K.; Kong, N.;
Fall, M. J. J. Am. Chem. Soc. 1996, 118, 6897.
(22) Davies, H. M. L.; Beckwith, R. E. J. Chem. ReV. 2003, 103, 2861.
(23) Timmons, D.; Doyle, M. P. In Multiple Bonds Between Metal Atoms,
3rd ed.; Cotton, F. A., Murillo, C. A., Walton, R. A., Eds.; Springer: New
York, 2005; Chapter 13.
(24) Nishiyama, H.; Itoh, Y.; Matsumoto, H.; Park, S.-B.; Itoh, K. J.
Am. Chem. Soc. 1994, 116, 2223.
(25) Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M. M. J. Am.
Chem. Soc. 1991, 113, 726.
The results found in Table 1 demonstrate that large rings can
be formed exclusively through cyclopropanation in moderate-
to-good yields and that inhibition of C-H insertion at the γ
position enhances the effectiveness for macrocycle formation
of dirhodium(II) catalysts, especially Rh2(4S-DOSP)421 and the
chiral carboxamidate Rh2(4S-MEOX)4,20 which are known to
J. Org. Chem, Vol. 71, No. 21, 2006 8185

Weathers et al.
TABLE 4. Selectivity in Diazo Decomposition of 8 with a Na+
TABLE 3. Catalyst Loading and Product Selectivity in Diazo
Decomposition of 8a
Templatea
catalyst (mol %)
11:12b
E:Z (11)b
yield (11 + 12), %c
NaBPh4
(mol %)
yield (11 + 12),
c
catalyst
11:12b
E:Z (11)b
%
110
80
10d
1
62:38
63:37
51:49
61:39
66:34
63:37
57:43
48:52
62
54
82
76
Rh2(OAc)4
(1.0 mol %)
110
80
10
0
110
80
10
0
100:0
100:0
100:0
100:0
100:0
100:0
63:37
51:49
35:65
38:62
35:65
36:64
d
80:20
72:38
57:43
45
47
61
71
49
55
73
82
a Reactions were performed by 2 h addition of 8 to refluxing solution of
10 mol % copper(I) hexafluorophosphate in 10 mL of dichloromethane.
b Ratios of products obtained by 1H NMR spectroscopy. c Yields were
obtained from the mass of the isolated products and the integrated 1H NMR
ratios for 11 and 12. d Reaction repeated three times with same outcome.
Cu(CH3CN)4PF6
(10 mol %)
a Decomposition carried out as 2 h addition of catalyst in dichloromethane
to a refluxing dichloromethane solution of 8 and sodium tetraphenylborate.
b Ratios of products obtained by 1H NMR. Variability ( 3%. c Yields
obtained are based on proton NMR data and assume complete mass recovery
after filtration. d Not determined.
ation between copper(I) hexafluorophosphate and the acetate
of 8, wherein acetate replaces the diazoacetate functionality,
was verified by H NMR and IR spectroscopy.26
1
The effect of catalyst loading on chemoselectivity and
diastereoselectivity (Table 3) was modest, suggesting that the
copper species that is the active catalyst does not change signif-
icantly either during the course of the reaction or as a result of
different molar ratios of 8 to copper. If 8 or one of the reaction
products formed a complex with copper that underwent reaction
with a “free” diazoacetate (eq 2), one should expect differences
in diastereoselectivity and/or chemoselectivity with changing
ratios of reactant to catalyst.
diazo decomposition and subsequent carbene reactions of the
copper-templated reactant can be said to be occurring. Note that
intramolecular cyclopropanation and ylide reactions of the metal
carbene are inhibited if 16 is the reactive form that undergoes
diazo decomposition.
8 + LCu f (11 + 12) + LCu
(2)
That only modest differences are observed, and the absence of
macrocyclization from reactions in which copper is coordinated
with a ligand that does not undergo exchange with 8, suggests
that the major reaction pathway is the one through which the
copper-complexed 8 is undergoing internal diazo decomposition
and subsequent carbene reactions (eqs 3 and 4).
(8)Cu f (11/12)Cu
(3)
(4)
Mixtures of 8 with variable amounts of sodium tetraphen-
ylborate, dissolved in refluxing dichloromethane, were allowed
to equilibrate for 30 minutes and then subjected to diazo decom-
position by controlled addition of the 8/NaBPh4 complex to
catalyst in dichloromethane, and the results are shown in Table
4. Reactions containing 110 or 80 mol % of sodium tetraphen-
ylborate had 15-30% lower yields of 11 (and 12) than did
those with 10 mol % or no sodium tetraphenylborate, consistent
with the involvement of 16. The E:Z ratio of diastereoisomers
of 11 did not change with the change in mol % of NaBPh4 for
dirhodium(II) tetraacetate-catalyzed reactions, but they were
substantially different in the copper(I) hexafluorophosphate-
catalyzed reactions. Formation of oxonium ylide-derived product
(11/12)Cu + 8 f (8)Cu + (11 + 12)
The use of the tetrahedral copper(I) geometry to hold ligands
in an orientation suitable for subsequent macrocyclization is well
established;27 the unique role of copper(I) in this study is that
the templated copper is the site on which metal carbene reactions
occur, a depiction for which is given in eq 5. In the orientation
depicted in eq 5, the bound carbene has access to both the
carbon-carbon double bond and to the allyl ether oxygen; an
alternative orientation that afforded coordination with the allylic
ether oxygen would prevent oxonium ylide formation, but not
cyclopropanation.
1
12 was not observed in the H NMR spectrum of the crude
reaction mixtures using 110 or 80 mol % of sodium tetraphe-
nylborate, and even 10 mol % of sodium tetraphenylborate
(26) Although there is evident broadening of lines with the use of an
equivalent amount of copper(I) hexafluorophosphate, the chemical shift of
allylic, phenyl, acetyl, and benzylic hydrogens change less than 0.05 ppm.
However, the ether ethylene hydrogens, originally compacted in the region
3.60-3.72 ppm, are spread from 3.6 to 4.20 ppm. In contrast, the complex
with sodium tetraphenylborate produces a decrease in the chemical shift
for ether hydrogens to 3.18-3.70; the allylic methylene group shifted from
4.05 to 3.95 ppm; and phenyl, acetyl, and benzylic hydrogens were only
modestly affected.
(27) For recent examples, see: (a) Perret-Aebi, L.-E.; von Zelewsky,
A.; Dietrich-Buchecker, K.; Sauvage, J.-P. Angew. Chem., Int. Ed. 2004,
43, 4482. (b) Jime´nez, M. C.; Dietrich-Buchecker, K.; Sauvage, J.-P. Angew.
Chem., Int. Ed. 2000, 39, 3284. (c) Kwan, H. P.; Swager, T. M. J. Am.
Chem. Soc. 2005, 127, 5902. (d) Weber, N.; Hamann, C.; Kern, J.-M.;
Sauvage, J.-P. Inorg. Chem. 2003, 42, 6780.
Sodium tetraphenylborate effectively coordinates Na+ with
8 as a 1:1 complex (15 and 16 are proposed structures). If
reaction selectivity from diazo decomposition is independent
of NaBPh4 and its molar ratio with 8, then carbene addition/
ylide formation can be attributed to dynamic factors that are
independent of copper coordination with 8. If, on the other hand,
sodium ion coordination of 8 influences product selectivity, then
8186 J. Org. Chem., Vol. 71, No. 21, 2006

Polyether Macrocycles from Cyclopropanation and Ylides
TABLE 5. Effect of Catalyst and Length of Linker on Product
Distributiona
SCHEME 3
catalyst
substrate
∆:ylide
E:Zb
% yieldc
Rh2(OAc)4
(1.0 mol %)
9
8
10
9
8
10
9
8
10
9
8
10
100:0
100:0
100:0
100:0
100:0
100:0
56:44
51:49
55:45
47:53
52:48
51:49
40:60
36:64
35:65
44:56
65:35
n.d.
61:39
57:43
47:53
54:46
60:40
54:46
69
71
68
39
46
<5
84
82
76
63
75
66
Rh2(4S-MEOX)4
(1.0 mol %)
Cu(CH3CN)4PF6
(10 mol %)
impacted chemoselectivity, lowering the amount of 12. Sodium
ion coordination with 8 effectively blocks ylide formation by
association with the allyl ether oxygen so that one can conclude
that the template of copper(I) with 8 is responsible for the
production of ylide-derived 12. That there is also a change in
diastereoselectivity from addition of sodium tetraphenylborate
also suggests that the cyclopropanation pathway occurs with
copper coordination (eqs 2 and 3).
Cu(hfacac)2
(10 mol %)
a Reactions were performed by 2 h addition of the diazoacetate to a
refluxing solution of the catalyst in 10 mL of dichloromethane. Outcome
from duplicate or triplicate reactions. b Ratios of products obtained by
1
integration of characteristic H NMR absorbances. c Yields were obtained
from the mass of the composite isolated products and the integrated 1H
NMR signals of cyclopropane and ylide products.
Sodium tetraphenylborate also forms a 1:1 complex with
macrocycles E-11 and Z-11. These complexes were recovered
after reverse-phase chromatography of the product mixture
resulting from diazo decomposition of the 11/NaBPh4 complex
by dirhodium(II) tetraacetate. Evidence for a complex between
8 and either potassium tetraphenylborate or cesium tetraphen-
ylborate was not obtained. Although the solubility of these salts
in methylene chloride was lower than that of sodium tetraphe-
nylborate, extensive mixing and greater dilution of the reaction
solution did not increase solubility or provide spectral evidence
indicative of coordination.
however, chemoselectivity and diastereoselectivity in the diazo
decomposition of 8-10 do not significantly differ from that
observed when using copper(I) hexafluorophosphate, strongly
suggesting that the hfacac ligand is not bound to copper during
the product-forming steps and challenging assumptions made
in the uses of this catalyst.29 The cyclopropanes formed from
8-10 using dirhodium(II) tetraacetate exhibit anticipated dia-
stereoselectivity, with E-to-Z ratios consistent with those seen
in intermolecular cyclopropanation using ethyl diazoacetate.14,20
Similar diastereoselectivities are also seen in the decompositions
of 8-10 using copper catalysts, but with a discernible trend as
a function of ring size. Once again, use of copper hexafluoro-
phosphate with the (S,S)-tBu-BOX ligand25 inhibited diazo
decomposition, and only with 9 was a low amount of 15
produced (13% yield, 50:50 E:Z, no 17). Each reaction was run
at 0.25 M in diazoacetate compound, yet the preference for
intramolecular reaction over intermolecular reaction was not
affected by the length of the linker between the diazoacetate
and the allyl group at this concentration.
Given the virtually constant ratio products of cyclopropanation
to ylide formation/rearrangement in copper ion catalysis for the
series of diazoacetates 8-10 where n ) 4-6, compared with
those diazoacetates (Scheme 1) that are incapable of this degree
of association, the templating ability of copper(I) in metal
carbene reactions is clear. Even the smallest member of the
series (9) can form a carbene complex (21) that will facilitate
both oxonium ylide formation and cyclopropanation with the
same constraints between copper and either the ether oxygen
or carbon-carbon double bond as either 8 or 10. The ratio of
the two products reflects this.
The effect of the length of the linker between the diazoacetate
and the allyl group on chemoselectivity and yield was inves-
tigated using diazoacetates 8-10 (Scheme 2). These compounds
have five (9), six (8), and seven (10) ether oxygen atoms. The
difference in available oxygen atoms could produce a difference
in chemoselectivity from diazo decomposition, should copper
be acting as a template and assuming that coordination is rapid
and equilibration between ligated copper species is slow on the
reaction time scale. Substrate coordination in a tetrahedral
geometry by copper(I) will involve all but one of the ether
oxygen atoms of 9, while coordination with 10 will leave three
oxygen atoms uncoordinated, allowing more conformational
freedom in the substrate. In addition, coordination to the allyl
oxygen atom would inhibit ylide formation, and, if copper(I)
coordination occurs, the difference in selectivity between cyclo-
propanation and ylide formation with [2,3]-sigmatropic rear-
rangement should be evident from diazo decomposition of 8-10.
Decomposition of these compounds with dirhodium(II) tetra-
acetate or copper(I) hexafluorophosphate led to cyclopropanes
11, 17, and 18 from carbene addition to the allyl double bond,
as well as 12, 19, and 20, resulting from oxonium ylide forma-
tion followed by [2,3]-sigmatropic rearrangement (Scheme 3).
Diazo decomposition of 10 with Rh2(4S-MEOX)4 did not
yield cyclopropanation products in signification quantities
Substrate design inhibiting γ-lactone formation from C-H
insertion opens new possibilities for the use of carbene insertion
reactions in macrocycle formation. This inhibition further
increases the chemoselectivity of dirhodium(II) catalysts and
permits the use of carboxamidate-ligated catalysts not previously
viable for macrocycle formation. The good-to-excellent yields
observed and diastereoselectivities consistent with intermolecular
1
despite several attempts (Table 5); H NMR spectral analysis
of the reaction mixture showed only trace amounts of macro-
cyclic compounds resulting from cyclopropanation. Though
Rh2(4S-MEOX)4-catalyzed diazo decomposition of 10 was com-
plete, no additional products could be identified in the 1H NMR
spectrum. Copper(II) hexafluoroacetoacetonate [Cu(hfacac)2]
was employed because Clark et al. had described the favorable
chemoselectivity of this catalyst in oxonium ylide formation
followed by [2,3]-sigmatropic rearrangement relative to that
from dirhodium(II) tetraacetate and other copper catalysts;28
(28) Clark, J. S.; Krowiak, S. A.; Street, L. J. Tetrahedron Lett. 1993,
34, 4385.
(29) (a) Roskamp, E. J.; Johnson, C. R. J. Am. Chem. Soc. 1986, 108,
6062. (b) Brogan, J. B.; Bauer, C. B.; Rogers, R. D.; Zercher, C. K.
Tetrahedron Lett. 1996, 37, 5053. (c) Wright, D. L.; Weekly, R. M.; Groff,
R.; McMills, M. C. Tetrahedron Lett. 1996, 37, 2165.
J. Org. Chem, Vol. 71, No. 21, 2006 8187

Weathers et al.
remove the catalyst. The filtrate was concentrated under reduced
pressure to yield a clear oil (82 mg, 91%), and an 1H NMR spectrum
1
was obtained immediately. H NMR spectra of the crude decom-
position mixtures did not reveal any signals between 2.5 and 3.3
ppm that would correlate with an intramolecular C-H insertion
product, and no other monomeric product from 8, including those
from aromatic cycloaddition or formal aromatic substitution, could
be identified. Other materials were observed, but their origins were
not determined.
reactions demonstrate that a high degree of reaction control is
occurring during the process leading even to 28-membered rings,
and further development of this chemistry is possible. In the
now well-established applications of copper catalysts in metal
carbene transformations, there has been an implicit assumption
that the coordination sphere of copper does not change with
copper carbene formation.20,22,23,30 However, the recent structural
characterization of N-heterocyclic carbene complexes of cop-
per31 suggests structural flexibility that could account for the
unique role of ligand-exchangeable copper catalysts in reactions
of 8-10.
Example Procedure for Diazo Decomposition of 8, 9, and 10
with Copper(I) Catalysts. An oven-dried flask was charged with
copper(I) hexafluorophosphate (7.8 mg, 22 µmol, 0.10 equiv) and
DCM (5 mL) and brought to reflux. To the refluxing solution was
added a solution of 10 (120 mg, 0.22 mmol, 1.0 equiv) dissolved
in anhydrous DCM (5 mL) over 2 h using a Kazel syringe pump.
The resultant yellow solution was allowed to reflux for an additional
2 h, and products were isolated as previously described to yield a
1
clear oil (88 mg, 84%), and an H NMR spectrum was obtained
immediately.
Z-3,9,12,15,18,21,24-Heptaoxatricyclo[24.4.0.05,7]triaconta-
1
1(26),27,29-trien-4-one (Z-11). H NMR (400 MHz) δ 7.46 (dd,
Experimental Section
J ) 9.0, 3.7 Hz, 1 H), 7.42 (dd, J ) 9.0, 3.7 Hz, 1 H), 7.33 (dd,
J ) 9.0, 3.7 Hz, 2 H), 5.32 (d, J ) 12.7 Hz, 1 H), 5.25 (d, J )
12.7 Hz, 1 H), 4.72 (d, J ) 12.0, 1 H), 4.68 (d, J ) 12.0 Hz, 1 H),
3.87 (dd, J ) 10.6, 5.1 Hz, 1 H), 3.75-3.48 (comp, 21 H), 1.89
(ddd, J ) 8.5, 7.7, 5.9 Hz, 1 H), 1.65 (dddt, J ) 8.5, 8.4, 7.0, 5.1,
1 H), 1.14-1.08 (comp, 2 H); 13C NMR (100 MHz) δ 172.3, 136.7,
134.8, 129.6, 129.3, 128.2, 128.0, 71.1, 70.7, 70.5, 70.0, 69.8, 68.6,
63.9, 21.2, 17.6, 11.5; HRMS (FAB+) calcd for C23H34O8:
439.2332; found: 439.2338.
(2-(2-(2-(2-(2-(2-Allyloxyethoxy)-ethoxy)-ethoxy)-ethoxy)-
ethoxymethyl)-phenyl)methyl Diazoacetate (8). The title com-
pound was synthesized using the Corey-Myers procedure with
modifications to the molar ratio of glyoxylic acid chloride p-
toluenesulfonylhydrazone and N,N-dimethylaniline to alcohol, reac-
tion time, and purification.32 To a flame-dried round-bottom flask
was added (2-(2-(2-(2-(2-(2-allyloxyethoxy)-ethoxy)-ethoxy)-ethoxy)-
ethoxymethyl)-phenyl)-methanol (1.00 g, 2.51 mmol, 1.00 equiv)
and DCM (5.0 mL). The stirred solution was cooled to 0 °C, and
glyoxylic acid chloride p-toluenesulfonylhydrazone (1.18 g, 4.52
mmol, 1.80 equiv) was added in one portion followed by addition
of N,N-dimethylaniline (0.570 mL, 4.52 mmol, 1.80 equiv) as one
aliquot, producing a clear, yellow solution. After being stirred for
1 h, during which time the solution changed to a deep green color,
triethylamine (1.76 mL, 12.6 mmol, 5.00 equiv) was added as one
aliquot, instantly changing the solution color to deep red, and the
reaction mixture was stirred for an additional hour, then concen-
trated under reduced pressure. Concentration produced a hetero-
geneous mixture that was dissolved in a minimal amount of
methanol and subjected to flash chromatography on silica gel (Et2O/
petroleum ether/MeOH 50:50:0 to 48:48:4) to afford diazoacetate
8 as a viscous yellow oil (0.895 g, 1.91 mmol, 76%): TLC Rf )
0.25 (Et2O/petroleum ether/MeOH, 48:48:4): 1H NMR (400 MHz)
δ 7.40-7.29 (comp, 4 H), 5.91 (ddt, J ) 17.3, 10.4, 5.7 Hz, 1 H),
5.31 (s, 2 H), 5.26 (ddd, J ) 17.3, 3.1, 1.3 Hz, 1 H), 5.17 (ddd, J
) 10.4, 3.1, 1.3 Hz, 1 H), 4.81 (s, broad, 1 H), 4.62 (s, 2 H), 4.02
(dt, J ) 1.3, 5.7 Hz, 2 H), 3.67-3.58 (comp, 20 H); 13C NMR
(100 MHz) δ 136.5, 134.7, 134.3, 129.2, 129.1, 128.4, 128.0, 117.0,
72.2, 70.9, 70.6, 70.5, 69.6, 69.4, 64.0, 46.2; IR (neat oil): 2111
cm-1 (CdN2), 1692 cm-1 (CdO); HRMS (FAB+) calcd for
C23H34O8N2Li: 473.2475; found: 473.2481.
E-3,9,12,15,18,21,24-Heptaoxatricyclo[24.4.0.05,7]triaconta-
1(26),27,29-trien-4-one (E-11). 1H NMR (400 MHz) δ 7.43-7.36
(comp, 2 H), 7.33 (dt, J ) 6.0, 2.7 Hz, 2 H), 5.29 (d, J ) 12.5 Hz,
1 H), 5.25 (d, J ) 12.5 Hz, 1 H), 4.71 (d, J ) 12.5 Hz, 1 H), 4.68
(d, J ) 12.5 Hz, 1 H), 3.74-3.61 (comp, 21 H), 3.23 (dd, J )
10.6, 7.5 Hz, 1 H), 1.76 (ddddd, J ) 8.5, 7.5, 6.9, 4.6, 4.3 Hz, 1
H), 1.69 (dt, J ) 8.3, 4.3 Hz, 1 H), 1.25 (ddd, J ) 9.1, 4.6, 4.6 Hz,
1 H), 0.89 (ddd, J ) 8.3, 6.3, 4.3 Hz, 1 H); 13C NMR (100 MHz)
δ 173.6, 137.0, 134.6, 129.7, 129.2, 128.4, 128.0, 72.5, 71.2, 70.93,
70.85, 70.81, 70.78, 70.75, 70.72, 70.67, 70.1, 69.8, 64.3, 22.0,
18.9, 12.6; HRMS (FAB+) calcd for C23H34O8: 439.2332; found:
439.2338.
Purification of the crude reaction mixture containing Z-11 and
E-11 was achieved using semipreparative reverse-phase chroma-
tography at a flow rate of 3.0 mL/min with water/acetonitrile (60:
40) for 18 min, ramped at 2.4%/min to water/acetonitrile (0:100)
and maintained for 15 min. Z-11 was eluted at 23.1 min, and E-11
was eluted at 24.7 min. The collected fractions were concentrated
under reduced pressure to remove acetonitrile and were frozen.
Residual water was sublimed under reduced pressure.
Example Procedure for Diazo Decomposition of 8, 9, and 10
with NaBPh4. To a 1.5-dram vial with a Teflon cap liner were
added 8 (0.101 g, 0.214 mmol, 1.00 equiv), then DCM (1.0 mL),
and finally NaBPh4 (81.8 mg, 0.235 mmol, 1.10 equiv). The solution
was shaken for 1 min and allowed to stand for 30 min. Next, an
oven-dried flask was charged with the appropriate catalyst, and
DCM (5 mL) and brought to reflux. To the refluxing solution was
added the solution of 8 and NaBPh4 diluted with DCM to a total
volume of 5 mL over 2 h using a Kazel syringe pump. The resultant
yellow/brown solution was allowed to reflux for an additional 2 h,
and products were isolated as previously described to yield a cloudy
heterogeneous mixture; integration of 1H NMR spectra of the crude
reaction mixture was used to determine relative yields. Purification
of the crude reaction mixture was achieved using semipreparative
reverse-phase HPLC at a flow rate of 3.0 mL/min with water/
acetonitrile (60:40) for 28 min, ramped at 2.7%/min to water/
acetonitrile (0:100) and maintained for 15 min. Z-11 and E-11 were
eluted as a mixture at 20.5-22.8 min along with their NaBPh4 salts.
The collected fractions were concentrated under reduced pressure
Example Procedure for Diazo Decomposition of 8, 9, and 10
with Dirhodium(II) Catalysts. An oven-dried flask was charged
with Rh2(OAc)4 (1.7 mg, 2.1 µmol, 0.010 equiv) and DCM (5 mL)
and brought to reflux. To the refluxing solution was added a solution
of 8 (100 mg, 0.21 mmol, 1.0 equiv) dissolved in anhydrous DCM
(5 mL) over 2 h using a Kazel syringe pump. The resultant yellow
solution was allowed to reflux for an additional 2 h, cooled to room
temperature, and concentrated under reduced pressure. The crude
reaction mixture was filtered through a glass pipet loaded with 2
in. of silica gel with a solution of EtOAc/Et2O (3:1, 15 mL) to
(30) Fraile, J. M.; Garc´ıa, J. I.; Mart´ınez-Merino, V.; Mayoral, J. A.;
Salvatella, L. J. Am. Chem. Soc. 2001, 123, 7616.
(31) Hu, X.; Castro-Rodriguez, I.; Meyer, K. J. Am. Chem. Soc. 2003,
125, 12237.
(32) Corey, E. J.; Myers, A. G. Tetrahedron Lett. 1984, 25, 3359.
8188 J. Org. Chem., Vol. 71, No. 21, 2006

Polyether Macrocycles from Cyclopropanation and Ylides
to remove acetonitrile and were frozen. Residual water was sub-
limed under reduced pressure.
Supporting Information Available: Additional experimental
1
details, H and 13C NMR spectra, and other spectral details for
reactants and products. This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. The financial support of the National
Institutes of Health (GM 46503) and the National Science
Foundation is gratefully acknowledged.
JO0614902
J. Org. Chem, Vol. 71, No. 21, 2006 8189