Macrocycle formation by catalytic intramolecular cyclopropanation. A new general methodology for the synthesis of macrolides

Article abstract of DOI:10.1021/ja971687z

Catalytic intramolecular cyclopropanation by diazoacetates onto a remote carbon-carbon double bond resulting in the formation of 9- to 20-membered ring lactones is reported. When competition exists between proximal allylic and remote olefinic cyclopropanation, macrocyclization is favored by catalysts of increasing electrophilicity: Rh₂(pfb)₄ > Rh₂(OAc)₄, Cu(MeCN)₄PF₆ > Rh(cap)₄, and Cu(acac)₂. Terpene systems, cis-nerolidyl diazoacetate and related structures, malonic ester derivatives, and those with 1,2-benzenedimethanol, pentaerythritol, and cis-2-buten-1, 4-diol linkers undergo cyclopropanation onto the most remote carbon-carbon double bond in good yield. Generally, only one cyclopropane diastereoisomer is observed but increasing ring size allows stereochemistries in macrocyclization reactions that resemble those of their intermolecular cyclopropanation counterparts, In one system (25) macrocyclic addition is accompanied by ylide formation/[2,3]-sigmatropic rearrangement resulting in the formation of a 10-membered ring lactone. Overall, few limits to macrocycle formation are evident, and the methodology appears to have general applicability.

Full text of DOI:10.1021/ja971687z

8826
J. Am. Chem. Soc. 1997, 119, 8826-8837
Macrocycle Formation by Catalytic Intramolecular
Cyclopropanation. A New General Methodology for the
Synthesis of Macrolides
Michael P. Doyle,*,†,§ Chad S. Peterson,† Marina N. Protopopova,†
Alan B. Marnett,† Dann L. Parker, Jr.,† Doina G. Ene,† and Vincent Lynch*,‡
Contribution from the Department of Chemistry, Trinity UniVersity,
San Antonio, Texas 78212, and the Department of Chemistry and Biochemistry,
The UniVersity of Texas, Austin, Texas 78712
ReceiVed May 22, 1997X
Abstract: Catalytic intramolecular cyclopropanation by diazoacetates onto a remote carbon-carbon double bond
resulting in the formation of 9- to 20-membered ring lactones is reported. When competition exists between proximal
allylic and remote olefinic cyclopropanation, macrocyclization is favored by catalysts of increasing electrophilicity:
Rh2(pfb)4 > Rh2(OAc)4, Cu(MeCN)4PF6 > Rh(cap)4, and Cu(acac)2. Terpene systems, cis-nerolidyl diazoacetate
and related structures, malonic ester derivatives, and those with 1,2-benzenedimethanol, pentaerythritol, and cis-2-
buten-1,4-diol linkers all undergo cyclopropanation onto the most remote carbon-carbon double bond in good yield.
Generally, only one cyclopropane diastereoisomer is observed, but increasing ring size allows stereochemistries in
macrocyclization reactions that resemble those of their intermolecular cyclopropanation counterparts. In one system
(25) macrocyclic addition is accompanied by ylide formation/[2,3]-sigmatropic rearrangement resulting in the formation
of a 10-membered ring lactone. Overall, few limits to macrocycle formation are evident, and the methodology
appears to have general applicability.
The synthesis of macrocycles is rich in methodology and
Scheme 1
important for the construction of numerous biologically sig-
nificant compounds.1-4 Although macrocyclic systems can be
generated by cleavage of internal bonds in polycyclic systems
and by ring expansion,5 the methods of choice involve entropi-
cally disfavored end-to-end cyclization of open, long-chain
precursors, generally with the required use of high dilution
techniques.6 Rates for macrocyclization are intermediate be-
tween highly favored five- or six-membered ring formation and
the intermolecular transformation, and a variety of ingenious
processes have been devised to circumvent competition from
intermolecular reactions in large ring syntheses.
A recent communication has suggested catalytic cyclopro-
panation to be a new methodology for the construction of
macrocyclic lactones. Doyle, Poulter, and co-workers have
reported that whereas trans,trans-farnesyl diazoacetate (1)
underwent intramolecular cyclopropanation exclusively at the
allylic double bond to form 2 with the use of dirhodium(II)
carboxamidates, including dirhodium(II) caprolactamate [Rh2-
(cap)4] and those with chiral ligands, with the use of dirhodium-
(II) carboxylates addition took place solely at the terminal double
bond to produce a 13-membered cyclopropane-fused lactone
(Scheme 1).7 High dilution was not required, and macrocycle
3 was formed in relatively high yield and with diastereoselec-
tivity that was dependent on the catalyst ligands. With
consideration that the internal double bond could be responsible,
at least in part, for the macrocyclization, (-)-(7R)-6,7-dihydro-
farnesyl diazoacetate (4) was treated with the same selection
of catalysts only to find similar results: Rh2(cap)4 catalyzed
intramolecular allylic cyclopropanation exclusively, whereas
with Rh2(OAc)4 or dirhodium(II) perfluorobutyrate [Rh2(pfb)4]
macrolide formation was the major outcome. We now wish to
report investigations with diverse sets of molecular frameworks
possessing terminal alkene and diazoacetate units that demon-
strate the broad applicability of this catalytic intramolecular
cyclopropanation methodology for macrolide formation.
† Department of Chemistry, Trinity University.
‡ Department of Chemistry and Biochemistry, The University of Texas
at Austin.
§ Current address: Department of Chemistry, University of Arizona,
Tucson, AZ 85721.
Results
X Abstract published in AdVance ACS Abstracts, September 1, 1997.
(1) Nicolaou, K. C. Tetrahedron 1977, 33, 683-710.
(2) Paterson, I.; Mansuri, M. M. Tetrahedron 1985, 41, 3569-3624.
(3) Tius, M. A. Chem. ReV. 1988, 88, 719-732.
cis-Nerolidol and Related Systems. We have previously
reported that the diazoacetate formed from (+)-cis-nerolidol
underwent allylic cyclopropanation in reactions catalyzed by
Rh2(cap)4 but that Rh2(OAc)4 catalysis resulted in macrocy-
clization without significant competition from cyclopropanation
of the allylic double bond (Scheme 2). Only the cis-fused
cyclopropane stereoisomer of the 11-membered macrocycle 7
(4) Bradshaw, J. S.; Scott, P. E. Tetrahedron 1980, 36, 461-570.
(5) Stach, H.; Hesse, M. Tetrahedron 1988, 44, 1573-1590.
(6) Roxburgh, C. J. Tetrahedron 1995, 51, 9767-9822.
(7) Doyle, M. P.; Protopopova, M. N.; Poulter, C. D.; Rogers, D. H. J.
Am. Chem. Soc. 1995, 117, 7281-7282.
S0002-7863(97)01687-9 CCC: $14.00 © 1997 American Chemical Society

Catalytic Intramolecular Cyclopropanation
J. Am. Chem. Soc., Vol. 119, No. 38, 1997 8827
Scheme 2
Scheme 3a
a (a) NaH/THF, then cis-TBDMSOCH2CHdCHCH2OMs; (b) Bu4NF/
THF; (c) diketene/Et3N (catalyst)/THF; (d) MeSO2N3/Et3N; (e) LiOH,
THF/H2O, 0 °C.
was produced, but diastereocontrol at the methyl/vinyl-
substituted carbon was random (50:50). In addition, limited
diastereocontrol, anticipated from prior studies,8,9 was achieved
in the formation of 6. Structural modification of 5 resulting
from Grignard addition to nerylacetone followed by diazoacetate
formation gave 8a,b, which also underwent macrocyclization
in reactions catalyzed by Rh2(OAc)4 (eq 1). Once again, only
the cis-fused cyclopropane isomers were formed and, although
Table 1. Product Distributions from Diazo Decomposition of 10a
relative yield,c %
isolated
substrates, R )
catalyst
yield,b
13c
13t
14
H
Rh2(pfb)4
Rh2(OAc)4
Rh2(cap)4
CuPF6
Cu(acac)2
Rh2(pfb)4
Rh2(OAc)4
Rh2(cap)4
CuPF6
68
72
82
66
55
87
87
53
89
55
50
1
44
40
t
1
10
99
5
100
4
4
38
7
60
35
CH3
96
96
62
93
a Reactions performed in refluxing CH2Cl2 using 1.0 mol % of
catalyst. b Product yield after chromatography. c Determined by GC
analysis.
only a single isomer of 9a could be produced, diastereoselec-
tivity for 9b, like that for 7, was low (<60:40). With Rh2-
(pfb)4, a catalyst proven to be most suitable for macrocyclic
aromatic cycloaddition,10 complex product mixtures were
observed in which 9 was a minor product. The cis-cyclopropane
stereochemistry of 9 was evident from the coupling constant
between cyclopropane hydrogens (J ) 9.2-9.4 Hz).11,12
Malonic Ester Derivatives. The syntheses of 10a,b provided
the frame work for evaluation of competitive intramolecular
cyclopropanation of allylic and remote double bonds. The
preparation of 10a,b was accomplished in high yield by
sequential alkylation followed by diketene-derived diazoacetate
formation (Scheme 3). Catalytic diazo decomposition of 10a,b
produced the 10-membered ring macrocycle 13 and γ-lactone
14 in high yields and with regioselectivities that were dependent
on the catalyst and the substituent R (Table 1).
Stereochemistry at the cyclopropane ring was elucidated from
proton coupling constants (Jtrans ) 9.0 Hz, Jcis ) 13.5 Hz).
Pentaerythritol as Linker. The diazoacetate of pentaeryth-
ritol triallyl ether (15) is constructed to undergo competitive
ylide formation/[2,3]-sigmatropic rearrangement13,14 and in-
tramolecular cyclopropanation, but only intramolecular cyclo-
propanation resulting in the nine-membered ring lactone 16
having the cis-disubstituted cyclopropane geometry is observed
(eq 2). Oxonium ylide generation would have required the
Use of Rh2(cap)4 with 10a resulted in the allylic cyclopro-
panation product 14a virtually exclusively, but with the meth-
allyl derivative 10b the macrocyclic product 13c was the major
product even in reactions catalyzed by Rh2(cap)4. The copper
catalyst Cu(MeCN)4PF6 is similar to Rh2(OAc)4 in its reactivity
and selectivity, but Cu(acac)2 is comparable to Rh2(cap)4. Both
cis and trans-macrolide cyclopropanes were formed from 10a
with Rh2(pfb)4, Rh2(OAc)4, and Cu(MeCN)4PF6, but only the
cis isomer was produced from 10b. The cis/trans ratio (13ac/
13at) was relatively independent of the catalyst employed.
formation of a seven-membered ring which, although not
previously reported for allyl ether derivatives,13,14 has been
achieved in O-H insertion reactions15 and in sulfur ylide
chemistry even for the formation of eight- and nine-membered
rings.16 However, the product expected from sigmatropic
rearrangement was not observed, and, instead, cyclopropane-
fused lactone 16 was formed in good yield by reaction with a
spectrum of dirhodium(II) and copper catalysts: Rh2(pfb)4
(62%), Rh2(OAc)4 (71%), Rh2(cap)4 (33%), and Cu(MeCN)4-
PF6 (62%) with isolated yields of the purified product given in
(8) Martin, S. F.; Spaller, M. R.; Liras, S.; Hartmann, B. J. Am. Chem.
Soc. 1994, 116, 4493-4494.
(9) Doyle, M. P.; Dyatkin, A. B.; Kalinin, A. V.; Ruppar, D. A.; Martin,
S. F.; Spaller, M. R.; Liras, S. J. Am. Chem. Soc. 1995, 117, 11021-11022.
(10) 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-
7866.
(11) Doyle, M. P.; Dorow, R. L.; Buhro, W. E.; Griffin, J. H.; Tamblyn,
W. H.; Trudell, M. L. Organometal. 1984, 3, 44-52.
(12) Doyle, M. P.; Bagheri, V.; Wandless, T. J.; Harn, N. K.; Brinker,
D. A.; Eagle, C. T.; Loh, K.-L. J. Am. Chem. Soc. 1990, 112, 1906-1912.
(13) Doyle, M. P. In ComprehensiVe Organometallic Chemistry II;
Hegedus, L. S., Ed.; Pergamon Press: New York, 1995; Vol. 2, Chapter
5.2.
(14) Padwa, A.; Hornbuckle, S. F. Chem. ReV. 1991, 91, 263-309.
(15) Doyle, M. P.; Peterson, C. S.; Parker, D. L., Jr. Angew. Chem., Int.
Ed. Engl. 1996, 35, 1334-1336.
(16) (a) Kido, F.; Sinha, S. C.; Abiko, T.; Watanabe, M.; Yoshikoshi,
A. Tetrahedron 1990, 46, 4887-4906. (b) Kido, F.; Yamaji, K.; Sinha, S.
C.; Abiko, T.; Kato, M. Tetrahedron 1995, 51, 7697-7714.

8828 J. Am. Chem. Soc., Vol. 119, No. 38, 1997
Doyle et al.
parentheses; Cu(acac)2 did not cause cyclopropanation in
refluxing CH2Cl2, but 16 was isolated in 42% yield following
diazo decomposition of 15 using this catalyst in refluxing ClCH2-
CH2Cl. With catalysts of decreasing reactivity toward remote
double bonds, the amounts of carbene dimer and water insertion
byproducts increase.
1,2-Benzenedimethanol as Linker. Recently reported results
with diazoacetates derived from allyl-substituted 1,2-benzene-
dimethanol have shown that macrocyclization occurs in high
yields in reactions (eq 3) catalyzed by [Cu(MeCN)4](PF6)/bis-
oxazoline 19 and dirhodium(II) tetrakis[methyl 2-oxapyrrolidine-
5(S)-carboxylate], Rh2(5S-MEPY)4 (20).15 The extent of catalyst
effectiveness for this transformation is evident in the broad
spectrum of catalysts that produce 18 in high yield: Rh2(pfb)4,
Figure 1. Relative yield of intramolecular (O) and intermolecular (0)
reaction products from 17a catalyzed by Rh2(OAc)4 as a function of
alkene concentration.
Scheme 4a
72%; Rh2(OAc)4, 77%; Rh2(cap)4, 85%; Cu(MeCN)4PF6, 74%;
and Cu(acac)2, 86%. In contrast to reactions with 10, which in
cyclopropanation at the allylic position afforded an alternative
pathway to macrocyclization for Rh2(cap)4 and Cu(acac)2
catalysts (Table 1), all rhodium(II) and copper catalysts were
effective for macrocyclization with 17; product(s) from aromatic
cycloaddition onto the 1,2-benzenedimethyl linker were not
observed, nor were those from ylide formation. The allyl ether
analog 17b also underwent intramolecular cyclopropanation
catalyzed by Cu(MeCN)4PF6, and macrocycle 18b was isolated
in 63% yield. The cis stereochemistry for 18b was established
from the coupling constants for cyclopropane ring hydrogens.
The trans cyclopropane isomer of 18b was not detected.
To ascertain the degree to which intramolecular cyclopropa-
nation is favored over intermolecular cyclopropanation, com-
petition reactions with methallyl methyl ether were performed.
Methallyl methyl ether was selected, because it resembled the
methallyl ether of 17a most closely. Diazo compound 17a was
added to the reaction mixture containing methallyl methyl ether
and Rh2(OAc)4 by controlled addition so that at any one time
there was a large molar excess of external alkene, relative to
internal alkene, present throughout the addition. In addition to
intramolecular cyclopropanation product 18a, both E- and
Z-cyclopropane isomers from intermolecular cyclopropanation
(21) and the product from intermolecular ylide formation/[2,3]-
sigmatropic rearrangement (22) were formed (eq 4). Figure 1
a (a) NaH; (b) H2CdC(Me)CH2Br; (c) MsCl, Et3N, O °C; (d) 1,2-
benzene-dimethanol, NaH/THF; (e) diketene, Et3N/THF; (f) MsN3,
Et3N/THF; (g) LiOH (4 equiv), H2O/THF, 0 °C.
(21 f 29% relative yield of intermolecular reaction products)
over the range of olefin concentrations employed.
Further extension of the distance between the carbene center
and a site for intramolecular cyclization was achieved with the
use of cis-2-buten-1,4-diyl as an extender onto 1,2-benzene-
dimethanol (Scheme 4). With this system potential competition
exists not only between cyclopropanation, aromatic cycloaddi-
tion, and ylide formation/rearrangement but also in regioselec-
tivity (1 f 10 versus 1 f 15 addition) and diastereoselectivity
(cis- or trans-cyclopropane product). Catalytic diazo decom-
position of 25 resulted in the formation of products (eq 5) from
intramolecular cyclopropanation at the 15,16-double bond, solely
as the Z-cyclopropane stereoisomer (26), and from ylide
formation/[2,3]-sigmatropic rearrangement (27). The product
from intramolecular cyclopropanation at the 10,11-double bond
was not observed, nor were there products from intramolecular
aromatic cycloaddition. The influence of catalyst on selectivity
is seen in the results presented in Table 2. The production of
27, which arose from oxonium ylide formation with regiose-
lective and stereoselective [2,3]-sigmatropic rearrangement (eq
6) into the cis-2-buten-1,4-diyl linker rather than into the
methallyl ether, became more than marginally competitive with
reports relative yields of intramolecular (18a) and intermolecular
(21 + 22) reaction products as a function of alkene concentra-
tion. Isolated yields were 85 ( 2%, and the E-/Z-21 product
ratio was 1.0:1.0. The extent of ylide formation varied slightly

Catalytic Intramolecular Cyclopropanation
J. Am. Chem. Soc., Vol. 119, No. 38, 1997 8829
Table 2. Product Distributions from Diazo Decomposition of 25a
relative yield,c %
catalyst
isolated yield,b %
26
27
Rh2(pfb)4
Rh2(OAc)4
Rh2(cap)4
CuPF6
68
71
65
70
53
47
6
<1
16
94
>99
84
a Reactions performed in refluxing CH2Cl2 using 1.0 mol % of
catalyst. b Product yield after chromatography. c Determined by GC
analysis.
Figure 2. View of C18H22O4 (26). Thermal elipsoids are scaled to the
30% probability level. Hydrogen atoms are drawn to an arbitrary scale.
Scheme 5a
intramolecular cyclopropanation only with Rh2(pfb)4. Only the
cis-isomer 27 was observed based on NOE experiments on the
lactone formed by hydrogenolysis.
The structure of 26 was determined by X-ray diffraction
analysis of a crystal grown from hexanes/ethyl acetate (Figure
2) which established the Z-geometry of substituents on the
cyclopropane ring. In this structure the carbonyl oxygen is
directed inward and syn to the cyclopropane ring. Oxygens
are positioned so as to avoid dipolar repulsions.
Ylide formation does not occur in diazo decomposition of
the benzene dimethanol analog 29 whose formation follows the
sequence of steps outlined in Scheme 4. Instead, two products
(30Z and 30E), diastereoisomers of each other, are formed by
macrocyclic cyclopropanation (eq 7). Whereas only the Z-
cyclopropane isomer 26 was formed from 25, both Z- and
E-cyclopropane isomers were formed from 29, and the diaste-
reoisomer ratio varied with the catalyst employed. Higher Z:E
diastereomer ratios were obtained from Rh2(OAc)4 than from
Cu(MeCN)4PF6 catalyzed reactions. Product yields are for pure
30Z and pure 30E, obtained following chromatography, and
are not optimized.
a (a) MsCl, Et3N, 0 °C; (b) 1,2-benzenedimethanol/NaH in THF;
(c) diketene, Et3N/THF; (d) MsN3, Et3N/THF; (e) LiOH, H2O/THF, 0
°C.
Finally, in an effort to evaluate the potential of this methodol-
ogy in the formation of macrocycles even larger than 26 and
30, diazoacetate 32 was conveniently produced from the same
alcohol (28) employed in the formation of 29 (Scheme 5).
Diazoacetate 32 was formed in 39% overall yield from 28.
Treatment of 32 with Cu(MeCN)4PF6 formed products from
intramolecular cyclopropanation (eq 8) of which only the Z-
and E-cyclopropanes from addition to the remote carbon-carbon
double bond (33Z and 33E) were identifiable (in a 2:1 molar
ratio). Similar results were obtained using Rh2(OAc)4 but with
higher product yields (59% vs 42% with CuPF6) and a higher
Z:E diastereomer ratio. In fact, the crude product from reactions
catalyzed by Rh2(OAc)4 was >65% 33.
Discussion
As seen by the extent to which macrocylic cyclopropanation
can be achieved, there appears to be a global advantage of this
methodology for macrolide syntheses. The formation of rings
containing nine to 20 atoms is reported, and, with few
exceptions, product yields are generally greater than 50%. A
cis-2-buten-1,4-diyl or 1,2-benzenedimethyl linker, which brings
the remote reaction centers closer together, favors macrocy-
clization, but, as is the case with 1, 4, and 15, this geometrical
constraint is not a prerequisite.
Remote cyclopropanation is a function of the catalyst
employed. With dirhodium(II) compounds, macrocyclization

8830 J. Am. Chem. Soc., Vol. 119, No. 38, 1997
Doyle et al.
Scheme 6
conducive to cyclopropane formation. Proximal allylic double
bonds are sterically inhibited from π-complex formation with
the net effect that macrocyclization is favored over γ-lactone
production for those catalytic systems in which highly electro-
philic metal carbene formation can be achieved. In this respect,
π-complex formation effectively lowers the activation energy
for cyclopropanation and allows macrocyclization to compete
effectively with proximal allylic cyclopropanation, which is
favored entropically.
The competitive experiment whose results are presented in
Figure 1 suggests the extent to which entropic effects are
important for macrocyclization. Even at its lowest concentra-
tion, the external alkene is present initially in >100-fold greater
amount than the remote double bond of 17a. This signifies
that entropic effects, even from remote sites, are principal
determinates of reaction selectivity and, taken together with the
high yields achieved in the formation of the 20-membered ring
33, suggests the enormous potential of this methodology.
Experimental Section
is favored by ligands that increase the electrophilic character
of the dirhodium(II) core: Rh2(pfb)4 > Rh2(OAc)4 > Rh2-
(cap)4.17,18 With copper catalysts the same is true so that Cu-
(MeCN)4PF6 can be said to resemble Rh2(OAc)4, and Cu(acac)2
provides results that are comparable to those obtained with Rh2-
(cap)4. For systems in which alternative path ways for the
intermediate metal carbenes are not favorable (e.g., 15, 17, 29,
and 32), all catalysts form product(s) from cyclopropanation at
the remote double bond. In early investigations of intramo-
lecular cyclopropanation,19 the absence of reports of macrocy-
clization can be understood in terms of the catalyst that was
employedsthose like CuSO4 or Cu powder whose reactivity/
selectivity resembles that of Rh2(cap)4.
General Methods. 1H NMR (300 or 400 MHz) and 13C NMR (75
or 100 MHz) spectra were obtained as solutions in CDCl3, unless
indicated otherwise, and chemical shifts are reported in parts per million
(ppm, δ) downfield from internal Me4Si (TMS). Infrared spectra were
recorded as a thin film on sodium chloride plates or as KBr pellets,
and absorptions are reported in wave numbers (cm-1). Mass spectra
were obtained using electron ionization at 70 eV on a quadrupole
instrument. Elemental analyses were performed at Texas Analytical
Laboratories, Inc. Diketene was distilled under reduced pressure prior
to use. Methanesulfonyl azide was prepared from methanesulfonyl
chloride and sodium azide23 and was used without distillation. Rhod-
ium(II) acetate was obtained commercially and recrystallized prior to
use.24 The preparation of Rh2(pfb)4,25 Rh2(cap)4,17a and Cu(MeCN)4-
26
PF6 have been previously reported. Dichloromethane was distilled
Alkene reactivity plays a significant role in determining the
competitiveness of a reacting system for remote versus proximal
allylic cyclopropanation, and no where is this more evident than
in catalytic reactions of 10. Methallyl is more reactive than
allyl because of the stabilization provided by substituent groups
in the transition state for electrophilic cyclopropanation. As a
result, proximal intramolecular allylic cyclopropanation is
disfavored relative to addition to the remote methallyl group,
so that with Rh2(cap)4 and Cu(acac)2 only γ-lactone formation
occurs with 10a, but the γ-lactone is the minor product from
reactions with 10b. However, as seen in reactions of the
pentaerythrityl diazoacetate 15, addition to an unactivated allylic
double bond that is remote from the carbene center can be
favorable even with the least reactive catalytic systems.
Macrocyclization is consistent with the formation of an
intermediate π-complex between the carbon-carbon double
bond and the carbene carbon (Scheme 6), which is an explana-
tion initially advanced to explain stereoselectivity in intermo-
lecular reactions20 and substantiated by others.21,22 Rotation of
the alkene on the carbene center to maximize charge develop-
ment at the more substituted carbon of the carbon-carbon
double bond in the transition state provides the orientation
from CaH2 prior to use. Tetrahydrofuran was distilled from sodium
and benzophenone. Pentaerythritol triallyl ether (commercial, 70%
purity) was purified by column chromatography on silica gel (6:1
hexanes:EtOAc) prior to use.
cis-3,7,11-Trimethyl-1,6,10-undecatrien-3-yl diazoacetate (5) was
prepared from nerolidol, glyoxylic acid chloride p-toluenesulfonylhy-
drazone, and triethylamine according to the procedure of Corey and
Myers27 and isolated in 69% yield after column chromatography on
silica (20:1 hexanes:ethyl acetate): 1H NMR (C6D6, 300 MHz) δ 5.91
(dd, J ) 17.5, 11.0 Hz, 1 H), 5.30-5.18 (m, 1 H), 5.15 (d, J ) 7.0 Hz,
1 H), 5.07 (dd, J ) 17.5, 1.0 Hz, 1 H), 4.97 (dd, J ) 11.0, 1.0 Hz, 1
H), 3.97 (s, 1 H), 2.17-1.94 (m, 7 H), 1.83-1.71 (m, 1 H), 1.68 (s, 3
H), 1.67 (s, 3 H), 1.56 (s, 3 H), 1.51 (s, 3 H); 13C NMR (C6D6, 75
MHz) δ (CdO not detected), 142.2, 135.5, 131.4, 125.1, 124.8, 113.2,
83.7, 46.0, 40.4, 32.2, 27.0, 25.9, 24.3, 23.6, 22.6, 17.7; IR (film) 2112
(CdN2), 1700 (CdO), 1651 (CdC) cm-1
.
Anal. Calcd for
C17H26N2O2: C, 70.31; H, 9.03; N, 9.64. Found: C, 70.34; H, 9.08;
N, 9.61.
(1r,5r)-4-Methyl-4-(4,8-dimethyl-cis-3,7-nonadien-1-yl)-3-
oxabicyclo[3.1.0]hexan-2-one (6). To a refluxing solution of anhy-
drous CH2Cl2 (10 mL) containing 6.1 mg (92 µmol) of Rh2(cap)4 was
added via syringe pump over 8 h a 10 mL CH2Cl2 solution of 5 (0.280
g of 95% pure 5, 0.92 mmol). After addition was complete, the reaction
mixture was filtered through a 3-cm plug of silica to separate the
catalyst, and this plug was washed three times with 5-mL portions of
CH2Cl2. After evaporation of the solvent, GC and NMR analyses
showed the presence of only two products, exo-6 and endo-6 in a ratio
of 71:29. Chromatographic purification of the reaction mixture on silica
(10:1 hexanes:ethyl acetate) afforded 75 mg of exo-6, 34 mg of endo-
(17) (a) 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,
958-964. (b) Doyle, M. P.; Bagheri, V.; Wandless, T. J.; Harn, N. K.;
Brinker, D. A.; Eagle, C. T.; Loh, K.-L. J. Am. Chem. Soc. 1990, 112,
1906-1912.
(18) Padwa, A.; Austin, A. Angew. Chem. Int. Ed. Engl. 1994, 33, 1797.
(19) Burke, S. D.; Grieco, P. A. Org. React. (N.Y.) 1979, 26, 361-475.
(20) (a) Doyle, M. P.; Griffin, J. H.; Bagheri, V.; Dorow, R. L.
Organometal. 1984, 3, 53-61. (b) Doyle, M. P. Acc. Chem. Res. 1986, 19,
348-356.
(23) Boyer, J. H.; Mack, G. H.; Goebel, W.; Morgan, L. R. J. Org. Chem.
1959, 24, 1051-1053.
(24) Rampel, G. A.; Legzdins, P.; Smith, H.; Wilkinson, G. Inorg. Synth.
1972, 13, 90-91.
(21) Davies, H. M. L.; Clark, T. J.; Church, L. A. Tetrahedron Lett.
1989, 30, 5057-5060.
(25) Doyle, M. P.; Shanklin, M. S. Organometal. 1994, 13, 1081-1088.
(26) G. J. Kubas Inorg. Synth 1979, 19, 90-92.
(27) Corey, E. J.; Myers, A. G. Tetrahedron Lett. 1984, 25, 3359-3362.
(22) O’Bannon, P. E.; Dailey, W. P. Tetrahedron 1990, 46, 7341-7358.

Catalytic Intramolecular Cyclopropanation
J. Am. Chem. Soc., Vol. 119, No. 38, 1997 8831
6, and 110 mg of the mixture of isomers for a combined isolated yield
of 90%. Exo-6: 1H NMR (C6D6, 300 MHz) δ 5.24-5.17 (m, 1 H),
5.06 (t, J ) 7.0 Hz, 1 H), 2.18-2.00 (m, 6 H), 1.68 (d, J ) 1.3 Hz, 3
H), 1.67 (s, 3 H), 1.61-1.38 (m, 3 H), 1.58 (s, 3 H), 1.17 (ddd, J )
7.7, 5.7, 4.5 Hz, 1 H), 0.96 (s, 3 H), 0.37 (ddd, J ) 7.6, 4.7, 4.2 Hz,
1 H), 0.27 (ddd, J ) 8.8, 7.6, 4.9 Hz, 1 H); NOESY experiment showed
interaction between CH3 (0.96 ppm) and anti-H (0.37 ppm) of
cyclopropane; correlations also made by COSY, APT, and HETCOR
for structural identification. 1H NMR (CDCl3, 300 MHz) δ 5.15-
5.05 (m, 2 H), 2.22-2.00 (m, 8 H), 1.76 (dd, J ) 9.6, 3.2 Hz, 1 H),
1.74 (dd, J ) 9.6, 3.9 Hz, 1 H), 1.69 (s, 3 H), 1.69 (s, 3 H), 1.61 (s,
3 H), 1.35 (s, 3 H), 1.12 (ddd, J ) 8.8, 7.6, 5.1 Hz, 1 H), 0.94 (ddd,
J ) 5.1, 4.6, 3.2 Hz, 1 H); 13C NMR (CDCl3, 75 MHz) δ 175.8, 136.1,
131.7, 124.1, 123.8, 84.6, 42.4, 31.8, 26.4, 26.2, 25.7, 23.3, 22.6, 21.6,
19.3, 17.6, 10.5; IR (film) 1770 (CdO), 1670 (CdC) cm-1; mass
spectrum, m/z (relative abundance) 262 (M, 4), 219 (10), 206 (12),
147 (20), 136 (33), 135 (21), 123 (21), 122 (40), 121 (44), 119 (20),
111 (99), 107 (70), 105 (25), 93 (97), 81 (99), 69 (100), 68 (60), 67
(71), 55 (81). Endo-6: 1H NMR (CDCl3, 300 MHz) δ 5.15-5.05 (m,
2 H), 2.16-1.97 (m, 8 H), 1.79-1.51 (m, 2 H), 1.69 (s, 3 H), 1.69 (s,
3 H), 1.61 (s, 3 H), 1.47 (s, 3 H), 1.12 (ddd, J ) 8.8, 7.6, 5.1 Hz, 1 H),
0.96 (ddd, J ) 5.1, 4.8, 3.2 Hz, 1 H); 13C NMR (CDCl3, 75 MHz) δ
175.6, 136.1, 131.7, 124.1, 123.9, 84.9, 42.4, 37.7, 31.9, 26.8, 26.5,
26.3, 25.7, 23.3, 22.8, 18.8, 10.7; mass spectrum, m/z (relative
abundance) 262 (M, 2), 219 (7), 206 (3), 147 (13), 136 (19), 135 (12),
123 (16), 122 (29), 121 (25), 119 (13), 111 (73), 107 (45), 105 (17),
93 (59), 81 (94), 69 (100), 68 (46), 67 (42), 55 (48). Anal (exo/endo
mixture). Calcd for C17H26O2: C, 77.82; H, 9.99. Found: C, 77.76;
H, 10.05.
(m, 6 H), 1.78-1.71 (m, 2 H), 1.66 (br s, 6 H), 1.59 (s, 3 H), 1.45 (s,
6 H); 1H NMR (C6D6, 300 MHz) δ 5.36-5.25 (m, 1 H), 5.32 (dt, J )
7.1, 1.2 Hz, 1 H), 3.95 (s, 1 H), 2.18-2.04 (m, 6 H), 1.80-1.74 (m,
2 H), 1.70 (d, J ) 1.3 Hz, 3 H), 1.68 (s, 3 H), 1.57 (s, 3 H), 1.39 (s,
6 H); 13C NMR (CDCl3, 75 MHz) δ (CdO not detected), 135.5, 131.6,
124.6, 124.3, 83.4, 46.6, 41.5, 31.9, 26.6, 26.2, 25.7, 23.4, 22.4, 17.6;
. Anal. Calcd for
C16H26N2O2: C, 69.03; H, 9.41; N, 10.06. Found: C, 68.95; H, 9.44;
N, 10.12.
IR (film) 2106 (CdN2), 1693 (CdO) cm-1
cis-4,4,8,12,12-Pentamethyl-3-oxabicyclo[9.1.0]dodec-7-en-2-
one (9a). To a solution of anhydrous dichloromethane (6 mL)
containing 3.2 mg (7.2 mmol) of Rh2(OAc)4 at room temperature was
added a 10 mL solution of 8a (0.180 g, 0.647 mmol) in CH2Cl2 via
syringe pump over 4 h. After addition was complete, the reaction
mixture was filtered through a short plug of silica to remove the catalyst,
and this plug was rinsed with 15 mL of CH2Cl2. After evaporation of
the solvent, GC and NMR analyses showed the presence of one major
product. Purification by radial chromatography on silica (20:1 hexanes:
ethyl acetate) afforded 78 mg of the title compound (0.311 mmol, 48%
yield) as a colorless oil: 1H NMR (C6D6, 300 MHz) δ 5.19 (dd, J )
9.7, 6.2 Hz, 1 H), 2.43-2.28 (m, 2 H), 2.10-2.00 (m, 1 H), 1.92-
1.60 (m, 3 H), 1.68 (s, 3 H), 1.58-1.35 (m, 2 H), 1.41 (d, J ) 9.2 Hz,
1 H), 1.41 (s, 3 H), 1.33 (s, 3 H), 1.26 (s, 3 H), 0.84 (dt, J ) 9.2, 2.4
Hz, 1 H), 0.84 (s, 3 H); 13C NMR (C6D6, 75 MHz) δ 171.2, 135.6,
125.3, 81.2, 37.4, 35.1, 31.0, 30.3, 29.1, 27.8, 27.0, 24.3, 23.3, 22.2,
15.1. A COSY experiment shows correlation between absorptions at
δ 1.41 and 0.84, and the coupling constant (J ) 9.2 Hz) signifies the
cis geometry. Mass spectrum, m/z (relative abundance) 251 (0.4, M
+ 1), 250 (2.3, M), 195 (5), 181 (5), 152 (34), 123 (21), 109 (34), 107
(25), 95 (37), 93 (26), 82 (82), 81 (78), 79 (28), 69 (36), 68 (86), 67
(100), 55 (32). Anal. Calcd for C16H26O2: C, 76.75; H, 10.47.
Found: C, 76.65; H, 10.41.
(1r,11r)-4,8,12,12-Tetramethyl-4-vinyl-3-oxabicyclo[9.1.0]dodeca-
7-en-2-one (7). To a solution of anhydrous CH2Cl2 (10 mL) at room
temperature containing 4.3 mg (97 µmol) of Rh2(OAc)4 was added via
syringe pump over 7 h a 10 mL CH2Cl2 solution of 7 (0.280 g, 0.97
mmol). After addition was complete, the reaction mixture was filtered
through a 3-cm plug of silica to separate the catalyst, and this plug
was washed three times with 5-mL portions of CH2Cl2. After
evaporation of the solvent, GC and NMR analyses showed the presence
of two major products whose crude yield was 41%, subsequently
identified as two diastereoisomers (50:50 distribution of exo-7 and endo-
7). Other products identified in the crude mixture were 6 (9.5%) and
the product from water insertion into the carbene generated from 5
(<15%). Chromatographic purification of the reaction mixture on silica
(50:1 f 30:1 hexanes:ethyl acetate) afforded 50 mg of pure 7 (21%
yield). 1H NMR (C6D6, 300 MHz) of 50:50 exo:endo-7: δ 6.26 (dd,
J ) 11.0, 17.6 Hz, 0.5 H), 5.78 (dd, J ) 11.0, 17.4 Hz, 0.5 H), 5.26
(dd, J ) 17.4, 1.4 Hz, 0.5 H), 5.22-5.14 (m, 1 H), 5.03 (d, J ) 17.6
Hz, 0.5 H), 4.98 (dd, J ) 11.0, 0.5 Hz, 0.5 H), 4.92 (dd, J ) 11.0, 0.8
Hz, 0.5 H), 2.46-2.10 (m, 4 H), 1.93-1.70 (m, 4 H), 1.67 (s, 3 H),
1.52 (s, 1.5 H), 1.44 (d, J ) 9.3 Hz, 0.5 H), 1.42 (d, J ) 9.3 Hz, 0.5
H), 1.35 (s, 1.5 H), 1.35 (s, 1.5 H), 1.32 (s, 1.5 H), 0.89-0.81 (m, 1.0
H), 0.83 (s, 1.5 H), 0.82 (s, 1.5 H); 13C NMR (C6D6, 75 MHz) δ 170.7,
(144.0, 143.0), (135.8, 135.6), 125.1, (112.4, 112.3), (82.5, 82.3), (36.1,
35.9), (35.3, 35.2), (31.0, 30.0), (29.04, 29.00), 26.3, (25.1, 24.9), (24.3,
24.1), (23.4, 23.3), 22.1, (21.7, 21.5), 15.1. COSY, HETCOR, APT
correlations were made for structure identification; the cis geometry
for the cyclopropane was assigned from the coupling constants (J )
9.3 Hz) for doublet absorptions centered at δ 1.44 and 1.42 which were
correlated (COSY) with absorptions at δ 0.89-0.83. Mass spectrum,
m/z (relative abundance): first GC eluent, 262 (M, 2), 152 (22), 151
(19), 135 (12), 121 (18), 107 (24), 95 (30), 93 (43), 83 (26), 82 (45),
81 (36), 79 (29), 68 (77), 67 (100), 55 (40), 53 (35); second eluent,
262 (M, 2), 152 (20), 151 (17), 135 (12), 121 (18), 107 (25), 95 (30),
93 (47), 83 (23), 82 (47), 81 (35), 79 (31), 68 (75), 67 (100), 55 (42),
53 (35). Anal. Calcd for C17H26O2: C, 77.82; H, 9.99. Found: C,
77.80; H, 10.02.
(Z)-6,10-Dimethyl-2-phenyl-5,9-undecadien-2-yl diazoacetate (8b)
was prepared from (Z)-6,10-dimethyl-2-phenyl-5,9-undecadien-2-ol
(obtained from nerylacetone and phenylmagnesium bromide, 95% yield)
according to the procedure of Corey and Meyers27 and isolated in 33%
yield after column chromatography on silica (30:1 hexanes:ethyl
acetate): 1H NMR (CDCl3, 300 MHz) δ 7.34-7.17 (m, 5 H), 5.05-
5.00 (m, 2 H), 4.71 (br s, 1 H), 2.05-1.82 (m, 8 H), 1.87 (s, 3 H),
1
1.65 (s, 3 H), 1.62 (s, 3 H), 1.56 (s, 3 H); NMR (C6D6, 300 MHz) δ
7.27-7.01 (m, 5 H), 5.16 (t, J ) 5.5 Hz, 1 H), 5.09 (t, J ) 5.4 Hz, 1
H), 4.01 (br s, 1 H), 2.20-1.93 (m, 8 H), 1.83 (s, 3 H), 1.66 (s, 3 H),
1.65 (s, 3 H), 1.53 (s, 3 H); 13C NMR (C6D6, 300 MHz) δ (CdO not
detected), 145.4, 135.6, 131.4, 128.4, 127.1, 125.0, 124.9, 124.8, 84.9,
46.2, 43.1, 32.1, 27.0, 25.9, 25.7, 23.5, 22.8, 17.7; IR (film) 2108
(CdN2), 1699 (CdO) cm-1. Anal. Calcd for C21H28N2O2: C, 74.08;
H, 8.29; N, 8.23. Found: C, 73.92; H, 8.34; N, 8.20.
cis-4,8,12,12-Tetramethyl-4-phenyl-3-oxabicyclo[9.1.0]dodec-7-
en-2-one (9b). To a solution of anhydrous dichloromethane (5 mL)
containing 3.0 mg (6.8 mmol) of Rh2(OAc)4 at room temperature was
added a 10 mL solution of 8b (0.209 g, 0.615 mmol) in CH2Cl2 via
syringe pump over 4 h. After addition was complete, the reaction
mixture was filtered through a short plug of silica, and the plug was
rinsed with 15 mL of CH2Cl2. After evaporation of the solvent, GC
and NMR analyses showed the presence of four major products of
which 9b was dominant (45%). Carbene dimer formation was minimal,
and aromatic cycloaddition did not occur. Purification by radial
chromatography on silica (30:1 hexanes:ethyl acetate) afforded 35 mg
of a nearly equimolar mixture of the two diastereoisomers of the title
compound (0.111 mmol, 18% yield) as a colorless oil: 1H NMR (C6D6,
300 MHz) δ 7.45-7.00 (m, 5 H), 5.24 (dd, J ) 11.6, 5.2 Hz, 0.4 H),
5.16 (dd, J ) 9.7, 5.6 Hz, 0.6 H), 2.70-1.76 (m, 8 H), 1.75 (s, 1.8 H),
1.68 (s, 1.2 H), 1.65 (s, 1.8 H), 1.56 (d, J ) 9.2 Hz, 0.4 H), 1.53 (d,
J ) 9.4 Hz, 0.6 H), 1.45 (s, 3 H), 1.21 (s, 1.2 H), 0.93-0.85 (m, 1 H),
0.87 (s, 1.8 H), 0.80 (s, 1.2 H); 13C NMR (C6D6, 75 MHz, δ (171.6,
171.0), (148.1, 147.4), (136.8, 135.9), 128.7, (127.8, 127.7), (126.1,
125.6), (126.0, 125.9), (85.3, 83.6), (37.6, 36.7), (36.5, 35.6), 32.0,
31.9), (31.1, 30.7), (30.4, 30.0), (30.0, 29.9), (25.1, 24.9), (24.5, 24.4),
23.45, 22.51, (16.2, 15.9). The coupling constants for the hydrogens
at C1 (9.2 and 9.4 Hz for absorptions at δ 1.56 and 1.53, respectively)
are consistent with a cis-cyclopropane geometry for both diastereoi-
somers. Mass spectrum, m/e (relative abundance): first GC eluent,
(Z)-2,6,10-Trimethyl-5,9-undecadien-2-yl diazoacetate (8a) was
prepared from (Z)-2,6,10-trimethyl-5,9-undecadien-2-ol (obtained from
nerylacetone and methylmagnesium bromide, 87% yield), glyoxylic acid
chloride p-toluenesulfonylhydrazone, and triethylamine according to
the procedure of Corey and Meyers27 and isolated in 55% yield after
column chromatography on silica (10:1 hexanes:ethyl acetate): 1H NMR
(CDCl3, 300 MHz) δ 5.10-5.06 (m, 2 H), 4.58 (br s, 1 H), 2.07-1.96

8832 J. Am. Chem. Soc., Vol. 119, No. 38, 1997
Doyle et al.
313 (6, M + 1), 312 (24, M), 297 (7), 194 (14), 161 (23), 152 (39),
151 (28), 143 (95), 131 (21), 119 (30), 118 (100), 117 (69), 105 (65),
91 (62), 82 (78), 79 (38), 77 (46); second eluent, 313 (2, M + 1), 312
(8, M), 297 (13), 194 (10), 161 (9), 143 (37), 131 (56), 119 (20), 118
(100), 117 (38), 105 (59), 91 (46), 82 (22), 79 (25), 77 (32).
4.9 (ddd, J ) 15.1, 5.2, 0.9 Hz, 1 H), 4.62 (dddd, J ) 15.1, 3.1, 2.9,
2.0 Hz, 1 H), 4.30-4.13 (comp, 4 H), 3.28 (dd, J ) 14.4, 13.5 Hz, 1
H), 2.61 (dddd, J ) 14.4, 4.6, 3.1, 1.9 Hz, 1 H), 2.53 (dt, J ) 15.2, 1.7
Hz, 1 H), 1.96 (ddd, J ) 13.5, 7.8, 5.8 Hz, 1 H), 1.44 (dd, J ) 15.2,
11.4 Hz, 1 H), 1.26 (t, J ) 7.2 Hz, 3 H), 1.25 (t, J ) 7.2 Hz, 1 H),
1.01 (ddd, J ) 6.4, 5.8, 4.6 Hz, 1 H), 0.92 (ddd, J ) 8.6, 7.8, 4.6 Hz,
1 H), 0.91-0.82 (m, 1 H); 13C NMR (CDCl3, 400 MHz) δ 171.4, 171.1,
170.4, 128.4, 125.7, 62.7, 61.4, 61.3, 58.7, 31.0, 29.1, 20.2, 16.3, 14.1,
8.4; IR (neat) 1755 (CdO), 1654 (CdC) cm-1; mass spectrum, m/z
(relative abundance) 199 (3), 195 (25), 191 (16), 173 (17), 166 (22),
163 (12), 145 (18), 140 (12), 138 (35), 127 (15), 117 (27), 107 (21),
91 (38), 81 (54), 79 (42), 55 (100). Anal. Calcd for C16H22O6: C,
61.92; H, 7.15. Found: C, 61.78; H, 7.13.
8,8-Bis(carboethoxy)-3-oxa-trans-bicyclo[8.1.0]undec-cis-5-en-2-
one (13at): 1H NMR (CDCl3, 400 MHz) δ 5.66 (dddd, J ) 11.0, 10.2,
4.2, 1.3 Hz, 1 H), 5.57 (dd, J ) 11.0, 11.0, 5.5 Hz, 1 H), 5.20 (dd, J
) 12.9, 11.0 Hz, 1 H), 4.46 (dd, J ) 12.9, 4.2 Hz, 1 H), 4.35-4.11
(comp, 4 H), 2.95 (d, J ) 14.8 Hz, 1 H), 2.90-2.82 (m, 2 H), 1.67
(ddd, J ) 9.0, 7.5, 4.7 Hz, 1 H), 1.56 (ddd, J ) 9.0, 4.9, 4.7 Hz, 1 H),
1.50-1.41 (m, 1 H), 1.30 (t, J ) 7.2 Hz, 3 H), 1.24 (t, J ) 7.2 Hz, 3
H), 0.81 (dd, J ) 14.8, 10.7 Hz, 1 H), 0.61 (ddd, J ) 7.5, 5.8, 4.9 Hz,
1 H); 13C NMR (CDCl3, 100 MHz) δ 173.3, 171.6, 169.5, 129.9, 125.8,
62.4, 61.7, 61.3, 56.5, 40.9, 30.8, 21.7, 19.1, 13.9, 13.8, 11.7; IR (neat)
1755 (CdO), 1662 (CdC) cm-1; mass spectrum, m/e (relative
abundance) 199 (2), 195 (2), 191 (20), 173 (40), 166 (13), 163 (15),
145 (21), 140 (19), 138 (13), 127 (28), 117 (30), 107 (27), 91 (54), 81
(52), 79 (61), 55 (100). Anal. Calcd for C16H22O6: C, 61.92; H, 7.15.
Found: C, 61.78; H, 7.20.
5,5-Bis(carboethoxy)-cis-2,7-octadien-1-ol (12a). Diethyl allyl-
malonate (9.95 g, 50.2 mmol), dissolved in 20 mL of anhydrous THF,
was added via syringe to a stirred suspension of NaH (2.21 g, 55.2
mmol) in 150 mL of THF at 0 °C. Stirring was continued for an
additional 30 min, at which time the mesylate of 4-(tert-butyldimeth-
ylsiloxy)-cis-2-buten-1-ol, dissolved in 20 mL of THF, was added. The
solution was allowed to come to room temperature overnight, water
was added, the layers were separated, and the aqueous layer was
extracted with ether (3 × 50 mL). The organic layer was washed with
brine (40 mL) and dried over anhydrous MgSO4. The solvent was
removed under reduced pressure to yield the crude product, which was
dissolved in 50 mL of THF and treated with 70 mL of a 1.0 M solution
of tetrabutylammonium fluoride in THF. After stirring for 12 h, water
was added, the layers were separated, and the aqueous layer was
extracted with ether (3 × 40 mL). The organic layer was washed with
brine (30 mL) and dried over anhydrous MgSO4, and the solvent was
removed under reduced pressure to yield the crude alcohol. Purification
by column chromatography (7:1 hexanes:ethyl acetate) yielded 11.8 g
(92% yield) of product as a colorless oil: 1H NMR (400 MHz, CDCl3)
δ 5.78-5.60 (comp, 2 H), 5.44-5.37 (m, 1 H), 5.15-5.10 (comp, 2
H), 4.25-4.13 (comp, 6 H), 2.67-2.20 (comp, 4 H), 1.25 (t, J ) 7.1
Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 170.7, 132.3, 132.1, 125.3,
119.1, 61.3, 58.1, 57.2, 37.0, 30.2, 13.9; IR (neat) 3440, 1745, 1648
cm-1; mass spectrum, m/z (relative abundance) 196 (2), 183 (16), 179
(18), 165 (12), 151 (18), 137 (44), 125 (15), 108 (100), 91 (22), 79
(40), 67 (19). Anal. Calcd for C14H22O5: C, 62.20; H, 8.20. Found:
C, 62.07; H, 8.23.
syn-6-[1,1-Bis(carboethoxy)-3-buten-1-yl]-3-oxabicyclo[3.1.0]hexan-
1
2-one (14a): H NMR (CDCl3, 400 MHz) δ 5.65 (dddd, J ) 16.8,
10.2, 7.4, 7.2 Hz, 1 H), 5.13 (ddd, J ) 16.8, 3.3, 1.4 Hz, 1 H), 5.12
(ddd, J ) 10.2, 2.9, 1.0 Hz, 1 H), 4.39 (dd, J ) 10.1, 5.3 Hz, 1 H),
4.28-4.12 (comp, 5 H), 2.76 (dddd, J ) 14.4, 7.4, 1.2, 1.0 Hz, 1 H),
2.71 (dddd, J ) 14.4, 7.2, 1.3, 1.2 Hz, 1 H), 2.24 (dddd, J ) 6.2, 6.0,
5.3, 1.0 Hz, 1 H), 2.18 (ddd, J ) 8.9, 6.2, 1.2 Hz, 1 H), 2.01 (dd, J )
14.8, 6.1 Hz, 1 H), 1.89 (dd, J ) 14.8, 7.0 Hz, 1 H), 1.50 (dddd, J )
7.0, 6.2, 6.1, 6.0 Hz, 1 H), 1.27 (t, J ) 7.2 Hz, 3 H), 1.25 (t, J ) 7.2
Hz, 3 H); 13C NMR (CDCl3, 100 MHz) δ 174.1, 170.6 (2), 131.9, 119.5,
65.7, 61.53, 61.46, 56.9, 37.9, 26.4, 22.8, 22.4, 17.6, 13.98, 13.92; IR
(neat) 1755 (CdO), 1644 (CdC cm-1; mass spectrum, m/z (relative
abundance) 199 (51), 191 (34), 179 (37), 163 (20), 152 (79), 144 (31),
133 (40), 123 (67), 108 (48), 85 (81), 79 (100). Anal. Calcd for
C16H22O6: C, 61.92; H, 7.15. Found: C, 61.82; H, 7.09.
5,5-Bis(carboethoxy)-cis-2,7-octadien-1-yl Diazoacetate (10a).
Prepared by the one-pot modification of the three-step procedure of
Doyle28 using 9.00 g (33.5 mmol) of 5,5-bis(carboethoxy)-cis-2,7-
octadien-1-ol. The alcohol was dissolved in 100 mL of THF and treated
sequentially with diketene (4.23 g, 50.3 mmol) and a catalytic amount
of triethylamine at 0 °C for 12 h, methanesulfonyl azide (4.27 g, 35.2
mmol), triethylamine (4.07 g, 40.3 mmol) for 12 h, and then lithium
hydroxide (3.22 g, 134 mmol) in 100 mL of water at 0 °C for 4 h.
1
After the cleavage was complete (monitored by H NMR analysis),
100 mL of ether was added, the layers were separated, and the aqueous
layer was extracted with ether (3 × 30 mL). The organic layer was
washed with brine (50 mL) and dried over anhydrous MgSO4. Removal
of solvent under reduced pressure and purification by column chro-
matography (5:1 hexanes:ethyl acetate) yielded 7.60 g (67% yield) of
the title compound as an intensely yellow oil: 1H NMR (400 MHz,
CDCl3) δ 5.70-5.59 (comp, 2 H), 5.56-5.49 (m, 1 H), 5.14-5.09
(comp, 2 H), 4.75 (bs, 1 H), 4.70 (dt, J ) 7.1, 0.8 Hz, 2 H), 4.25-4.15
(comp, 4 H), 2.69 (dt, J ) 7.5, 0.8 Hz, 2 H), 2.64 (dt, J ) 7.5, 1.2 Hz,
2 H), 1.25 (t, J ) 7.1 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 170.4,
166.4, 132.0, 128.0, 127.0, 119.1, 76.6, 61.2, 60.3, 56.9, 45.9, 36.8,
13.9; IR (neat) 2110, 1731, 1643. Anal. Calcd for C16H22N2O6: C,
56.80; H, 6.55; N, 8.28. Found: C, 56.62; H, 6.48; N, 8.28.
General Procedure for Diazo Decomposition of 10a. The
procedure for diazo decomposition with Rh2(OAc)4 is representative.
Diazoacetate 10a (170 mg, 500 µmol) was dissolved in 5 mL of freshly
distilled CH2Cl2 and added via syringe pump over 5 h to a solution of
Rh2(OAc)4 (2.2 mg, 1.0 mol %) in 5 mL of refluxing CH2Cl2. After
the addition was complete, the solution was passed through a plug of
silica gel to remove the catalyst. The solvent was removed under
reduced pressure, and the crude reaction mixture was purified by column
chromatography (3:1 hexanes:ethyl acetate) to yield 58 mg (37% yield)
of 13ac, 45 mg (29% yield) of 13at, and 10 mg (6% yield) of the
γ-lactone 14a, all as colorless oils.
5,5-Bis(carboethoxy)-7-methyl-cis-2,7-octadien-1-ol (12b). Di-
ethyl (2-methyl-2-propen-1-yl)malonate (11b) was prepared from NaH
(0.76 g, 19 mmol) in 120 mL of freshly distilled THF to which was
added a 10-mL THF solution of diethyl malonate (3.07 g, 19.2 mmol)
and, after 30 min at room temperature, a 10-mL THF solution of
3-bromo-2-methylpropene (2.71 g, 20.2 mmol) dropwise over 10 min.
After the solution was stirred, for 24 h diethyl ether (250 mL) was
added, and the resulting solution was washed with 190 mL of water.
The aqueous phase was washed with ether (100 mL) and then with
ethyl acetate (100 mL). The combined organic solution was washed
with brine (150 mL) and then dried over anhydrous MgSO4. Removal
of the solvent under reduced pressure yielded a 4.5:1 mixture of mono-
to dialkylated malonate. Purification by chromatography on silica gel
(5:1 hexanes:EtOAc) furnished 2.90 g (70% yield) of diethyl (2-methyl-
2-propen-1-yl)malonate (11b) as a colorless oil: 1H NMR (CDCl3, 400
MHz) δ 4.79-4.78 (m, 1 H), 4.73-4.72 (m, 1 H), 4.19 (q, J ) 7.1
Hz, 4 H), 3.58 (t, J ) 7.8 Hz, 1 H), 2.62 (d, J ) 7.8 Hz, 2 H), 1.75 (t,
J ) 0.9 Hz, 3 H), 1.26 (t, J ) 7.1 Hz, 6 H).
To a gray suspension of NaH (0.55 g, 14 mmol) stirred at 0 °C in
120 mL of freshly distilled THF was added a 10-mL solution of diethyl
(2-methyl-2-propen-1-yl)malonate (2.80 g, 13.1 mmol). The reaction
mixture was stirred at 0 °C for 15 min, then warmed to room
temperature for 15 min, and cooled once again to 0 °C, at which time
a 10-mL solution of 4-(tert-butyldimethylsilyloxy)-cis-2-buten-1-yl
methanesulfonate (3.43 g, 13.7 mmol) was added dropwise over 10
min. The resulting mixture was warmed to room temperature, and
stirring was continued for an additional 24 h. Diethyl ether (150 mL)
was added, and the mixture was washed with water (120 mL). The
organic phase was then washed with brine (150 mL) and dried over
8,8-Bis(carboethoxy)-3-oxa-cis-bicyclo[8.1.0]undec-cis-5-en-2-
one (13ac): 1H NMR (CDCl3, 400 MHz) δ 5.57 (dddd, J ) 12.0, 5.2,
2.0, 1.9 Hz, 1 H), 4.99 (ddddd, J ) 12.4, 12.0, 4.6, 2.9, 0.9 Hz, 1 H),
(28) Doyle, M. P.; Austin, R. E.; Bailey, A. S.; Dwyer, M. P.; Dyatkin,
A. B.; Kalinin, A. V.; Kwan, M. M. Y.; Liras, S.; Oalmann, C. J.; Pieters,
R. J.; Protopopova, M. N.; Raab, C. E.; Roos, G. H. P.; Zhou, Q.-L.; Martin,
S. F. J. Am. Chem. Soc. 1995, 117, 5763-5775.

Catalytic Intramolecular Cyclopropanation
J. Am. Chem. Soc., Vol. 119, No. 38, 1997 8833
anhydrous MgSO4, and the solvent was removed under reduced pressure
to yield 4.64 g of the TBDMS derivative of 12b (90%) as a slightly
yellow oil. After dissolving in 125 mL of THF at 0 °C, 18 mL of a
1.0 M solution of tetrabutylammonium fluoride (TBAF) in THF (18
mmol, 1.5 equiv) was added with stirring over 5 min. The resulting
orange solution was warmed to room temperature, and stirring was
continued for 25 h. Purification by chromatography on silica gel (10:1
f 0:1 hexanes:EtOAc) afforded 2.03 g (61% yield) of 12b as a colorless
oil: 1H NMR (CDCl3, 400 MHz) δ 5.77-5.70 (m, 1 H), 5.49-5.42
(m, 1 H), 4.88-4.87 (m, 1 H), 4.76-4.75 (m, 1 H), 4.18 (q, J ) 7.1
Hz, 4 H), 4.15 (d, J ) 6.5 Hz, 2 H), 2.72 (d, J ) 0.7 Hz, 2 H), 2.69
(dt, J ) 7.6, 0.9 Hz, 2 H), 1.67 (dd, J ) 1.4, 0.8 Hz, 2 H), 1.57 (s, 1
H), 1.26 (t, J ) 7.1 Hz, 6 H); 13C NMR (CDCl3, 100 MHz) δ 171.3,
140.5, 132.0, 126.0, 115.6, 61.4, 58.3, 56.9, 40.5, 30.4, 23.1, 13.9; IR
(film) 3446, 1739, 1720, 1645 cm-1. Anal. Calcd for C15H24O5: C,
63.36; H, 8.51. Found: C, 63.17; H, 8.42.
syringe freshly distilled diketene (4.62 g, 55 mmol) over 5 min. The
resulting light orange-brown solution was stirred for 1 h at 0 °C and
then warmed to room temperature. After 18 h triethylamine (5.57 g,
55 mmol) and methanesulfonyl azide (6.679 g, 55.2 mmol) were added
via syringe, and the solution was stirred for 18 h at room temperature.
The diazoacetoacetate was isolated, after adding 25 mL of water, by
extraction with ether (3 × 50 mL). The organic phase was washed
with water (3 × 50 mL) and brine (3 × 50 mL), and then dried over
anhydrous MgSO4. After removal of the solvent under reduced
pressure, the crude dark orange diazoacetoacetate was generally used
without further purification in the subsequent acetyl cleavage step.
Purification by column chromatography over silica gel (4:1 hexanes:
EtOAc) afforded the diazoacetoacetate as a yellow oil: 1H NMR
(CDCl3, 300 MHz) 5.95-5.78 (comp, 3 H), 5.25 (dq, J ) 17.2, 2.2
Hz, 3 H), 5.20-5.12 (comp, 3 H), 4.26 (s, 2 H), 3.98-3.92 (comp, 6
H), 3.44 (s, 6 H), 2.47 (s, 3 H).
Acetyl cleavage of the diazoacetoacetate was performed in THF (8
mL) to which was added LiOH‚H2O (6.71 g, 159 mmol) in 10 mL of
water. The dark brown solution was stirred at room temperature for
15 min and then extracted with ether (3 × 25 mL). The organic phase
was washed with water (3 × 25 mL) and brine (3 × 25 mL) and then
dried over anhydrous MgSO4. After evaporation of the solvent under
reduced pressure 5.96 g of crude diazoacetate was obtained. Purifica-
tion by column chromatography on silica gel (2:1 hexanes:ethyl acetate)
afforded the title compound as a yellow liquid (5.44 g, 16.8 mmol,
73% yield from the alcohol): 1H NMR (CDCl3, 400 MHz) δ 5.86 (ddt,
J ) 17.2, 10.4, 5.4 Hz, 3 H), 5.25 (dq, J ) 17.2, 1.6 Hz, 3 H), 5.15
(dddd, J ) 10.4, 1.6, 1.6, 1.3 Hz, 1 H), 4.72 (s, 1 H), 4.26 (s, 2 H),
3.94 (ddd, J ) 5.3, 1.6, 1.3 Hz, 6 H), 3.43 (s, 6 H); 13C NMR (CDCl3,
100 MHz) δ 162.3 (s), 134.8 (d), 116.3 (t), 72.2 (t), 68.8 (t), 64.2 (t),
44.5 (d), 33.2 (s); IR (CHCl3) 2114 (CdN2), 1693 (CdO), 1647 (CdC)
5,5-Bis(carboethoxy)-7-methyl-cis-2,7-octadien-1-yl Diazoacetate
(10b). To alcohol 12b (1.60 g, 5.79 mmol) in 20 mL of THF at 0 °C
was added freshly distilled diketene (0.723 g, 8.60 mmol) and
triethylamine (6.8 mmol) followed by methanesulfonyl azide (0.726
g, 5.99 mmol). The resulting orange solution was warmed to room
temperature, and stirring was continued for 37 h. The reaction mixture
was then cooled with an ice bath, and LiOH‚H2O (0.546, 22.8 mmol)
was added. The resulting brown solution was stirred for 2.5 h, then
poured into ether (70 mL) and washed with water (30 mL). The
aqueous phase was washed with ether (2 × 20 mL) and then with
EtOAc (2 × 20 mL). The combined organic solution was washed with
brine (30 mL) and then dried over anhydrous MgSO4. After removal
of the solvent under reduced pressure, the resulting orange oil was
chromatographically purified on silica gel (hexanes:EtOAc 10:1 f 2:1)
to yield 1.16 g (57% yield from 12b) of a light yellow oil identified as
10b: 1H NMR (CDCl3, 400 MHz) δ 5.66-5.58 (m, 1 H), 5.56-5.48
(, 1 H), 4.86-4.85 (m, 1 H), 4.72-4.71 (m, 1 H), 4.68 (br s, 1 H),
4.67 (dd, J ) 6.7, 1.2 Hz, 2 H), 4.15 (q, J ) 7.1 Hz, 4 H), 2.71-2.69
(comp, 2 H), 2.69 (d, J ) 0.6 Hz, 2 H), 1.64 (dd, J) 1.4, 0.8 Hz, 2 H),
1.23 (t, J ) 7.1 Hz, 6 H); 13C NMR (CDCl3, 100 MHz) δ 171.0, 140.4,
128.4, 126.9, 115.8, 61.4, 60.6, 56.6, 46.1, 40.2, 30.3, 23.1, 14.0; IR
(film) 2112 (CdN2), 1733 (CdO), 1645 (CdC) cm-1. Anal. Calcd
for C17H24N2O6: C, 57.94; H, 6.87; N, 7.95. Found: C, 57.83; H,
6.78; N, 8.01.
cm-1
. Anal. Calcd for C16H24N2O5: C, 59.24; H, 7.46; N, 8.64.
Found: C, 59.18; H, 7.41; N, 8.57.
5,5-Di(2-propen-1-oxymethyl)-3,7-dioxabicyclo[9.1.0]decan-2-
one (16). To a refluxing solution of anhydrous CH2Cl2 (5.0 mL)
containing catalyst (10 µmol, 1.0 mol %) was added diazoacetate 15
(324 mg, 1.00 mmol) in 10 mL of CH2Cl2 at 1.0 mL/h. After addition
was complete, the reaction solution was refluxed for an additional hour,
then cooled to room temperature and filtered through a short plug of
silica gel to remove the catalyst. After removal of the solvent under
reduced pressure, the residue was analyzed directly by GC and 1H NMR
methods. Product isolation of the colorless liquid was achieved by
column chromatography on silica gel (4:1 hexanes:EtOAc): 1H NMR
(CDCl3, 400 MHz) δ 5.88 (ddt, J ) 17.4, 10.5, 5.4 Hz, 1 H), 5.86
(ddt, J ) 17.3, 10.4, 5.5 Hz, 1 H), 5.28-5.21 (comp, 2 H), 5.17-5.13
(comp, 2 H), 4.68 (d, J ) 11.4 Hz, 1 H), 4.27 (d, J ) 11.4 Hz, 1 H),
4.23 (dd, J ) 11.7, 5.1 Hz, 1 H), 3.97 (dt, J ) 5.5, 1.3 Hz, 2 H), 3.92
(dt, J ) 5.5, 1.3 Hz, 2 H), 3.74 (d, J ) 11.3 Hz, 1 H), 3.46 (d, J ) 9.4
Hz, 1 H), 3.41 (d, J ) 9.4 Hz, 1 H), 3.34 (d, J ) 9.3 Hz, 1 H), 3.30
(d, J ) 9.3 Hz, 1 H), 3.27 (dd, J ) 11.7, 7.9 Hz, 1 H), 1.84 (ddd, J )
13.6, 7.9, 5.8 Hz, 1 H), 1.58-1.48 (m, 1 H), 1.34 (q, J ) 5.8 Hz, 1 H),
1.06 (dt, J ) 5.0, 7.9 Hz, 1 H); 13C NMR (CDCl3, 75 MHz) δ 173.4
(s), 134.8 (d), 134.6 (d), 116.5 (t), 116.3 (t), 76.3 (t), 73.6 (t), 72.2 (t),
70.7 (t), 70.0 (t), 69.8 (t), 66.1 (t), 44.5 (s), 19.9 (d), 19.2 (d), 12.2 (t);
IR (CHCl3) 1723 (CdO), 1647 (CdC) cm-1; mass spectrum, m/z
(relative abundance) 199 (1), 197 (4), 157 (7), 139 (22), 127 (22), 99
(100), 97 (20), 83 (27), 82 (24), 81 (51), 71 (35), 55 (77). Anal. Calcd
for C16H24O5: C, 64.84; H, 8.16. Found: C, 64.61; H, 8.20.
Diazo decomposition of 10b followed the same procedure previously
described for 10a using 1.0 mol % of catalyst. Evaporation of the
solvent left a viscous oil that was subjected to GC analysis. Chro-
matographic purification on silica gel (10:1 f 2:1 hexanes:EtOAc)
provided a clear colorless oil.
8,8-Bis(carboethoxy)-10-methyl-3-oxa-cis-bicyclo[8.1.0]undec-cis-
5-en-2-one (13bc): 1H NMR (CDCl3, 400 MHz) δ 5.52 (dddd, J )
12.0, 5.0, 2.7, 1.8 Hz, 1 H), 4.94 (ddddd, J ) 12.8, 12.0, 4.6, 2.7, 1.1
Hz, 1 H), 4.80 (ddd, J ) 15.1, 5.0, 1.1 Hz, 1 H), 4.60 (dq, J ) 15.1,
2.7 Hz, 1 H), 4.28-4.04 (comp, 4 H), 3.10 (dd, J ) 14.5, 12.8 Hz, 1
H), 2.78 (dddd, J ) 14.5, 4.6, 2.7, 1.8 Hz, 1 H), 2.56 (dd, J ) 15.6,
1.1 Hz, 1 H), 1.72 (dd, J ) 7.5, 6.0 Hz, 1 H), 1.66 (d, J ) 15.6 Hz, 1
H), 1.24 (t, J ) 7.1 Hz, 3 H), 1.20 (t, J ) 7.1 Hz, 3 H), 1.08 (dd, J )
6.0, 5.0 Hz, 1 H), 1.00 (s, 3 H), 0.67 (dd, J ) 7.5, 5.0 Hz, 1 H); 13C
NMR (CDCl3, 100 MHz) δ 172.4, 170.9, 170.3, 127.6, 125.6, 62.7,
61.4, 61.3, 57.7, 34.5, 30.0, 28.6, 23.5, 23.1, 19.6, 14.0, 13.8; IR
(CDCl3) 1731, 1601 cm-1. Anal. Calcd for C17H24O6: C, 62.95; H,
7.46. Found: C, 62.78; H, 7.37.
1,2-Benzenedimethanol. To a stirring solution of phthalide (25.0
g, 186 mmol) in 350 mL of THF at 0 °C was added 225 mL of a 1.0
M solution of LAH in THF. This solution was allowed to warm to
room temperature overnight, and the reaction was quenched by the
sequential addition of 6.5 mL of water, 6.5 mL of 15% aqueous NaOH,
and 19.5 mL of water. The solid was removed by filtration and washed
with 300 mL of ethyl acetate. The solution was dried over anhydrous
MgSO4, and the solvent was removed under reduced pressure to yield
23.9 g (93% yield) of 1,2-benzenedimethanol as a pale yellow
crystalline solid, mp 63-64 °C (lit mp29 63-65 °C).
syn-6-[1,1-Bis(carboethoxy)-3-methyl-3-buten-1-yl]-3-oxabicyclo-
[3.1.0]hexan-2-one (14b): 1H NMR (CDCl3, 400 MHz) δ 4.88 (quin,
J ) 1.6 Hz, 1 H), 4.76-4.74 (m, 1 H), 4.38 (dd, J ) 10.0, 5.2 Hz, 1
H), 4.31-4.08 (comp, 5 H), 2.83 (d, J ) 15.2 Hz, 1 H), 2.78 (d, J )
15.2 Hz, 1 H), 2.26-2.13 (comp, 2 H), 2.01 (dd, J ) 14.9, 6.3 Hz, 1
H), 1.92 (dd, J ) 14.9, 6.6 Hz, 1 H), 1.67 (br s, 3 H), 1.59-1.48 (m,
1 H), 1.28 (t, J ) 6.9 Hz, 3 H), 1.26 (t, J ) 7.1 Hz, 3 H); 13C NMR
(CDCl3, 100 MHz) δ 174.1, 171.2, 171.1, 140.2, 115.9, 65.7, 61.7,
61.5, 56.3, 41.3, 26.4, 23.1, 22.8, 22.4, 17.7, 13.94, 13.87; IR (CDCl3)
. Anal. Calcd for C17H24O6: C, 62.95; H, 7.46.
Found: C, 62.80; H, 7.43.
O,O,O-Triallylpentaerythrityl Diazoacetate (15). To pentaeryth-
ritol triallyl ether (5.86 g, 22.9 mmol) and triethylamine (0.5 mL, 4
mmol) in 50 mL of HPLC-grade THF cooled at 0 °C was added via
1765, 1725 cm-1
2-(2-Methyl-2-propen-1-yloxymethyl)benzyl Alcohol. Sodium hy-
dride (2.67 g, 66.7 mmol, 60% dispersion in oil) was washed with
(29) Adkins, H.; Wojcik, B.; Covert, L. W. J. Am. Chem. Soc. 1933, 55,
1669.

8834 J. Am. Chem. Soc., Vol. 119, No. 38, 1997
Doyle et al.
hexanes and suspended in 250 mL of THF, and the suspension was
cooled to 0 °C. To this vigorously stirred suspension was added 1,2-
benzenedimethanol (21.5 g, 155 mmol) dissolved in 100 mL of THF.
After addition was complete, stirring was continued for an additional
15 min, whereupon methallyl bromide (6.00 g, 44.4 mmol) dissolved
in 10 mL of THF was added in one portion via syringe. The solution
was allowed to warm to room temperature overnight, and the reaction
was quenched by addition of 80 mL of 10% aqueous NH4Cl. The
layers were separated, and the aqueous layer was extracted with ethyl
acetate (3 × 150 mL). The combined organic layers were washed with
brine and dried over anhydrous MgSO4. Filtration, solvent removal,
and purification via column chromatography (2:1 hexanes:ethyl acetate)
yielded 8.28 g (97% yield) of the title compound as a colorless oil: 1H
NMR (CDCl3, 300 MHz) δ 7.41-7.29 (comp, 4H), 4.99 (d, J ) 1.0
Hz, 1H), 4.94 (d, J ) 1.6 Hz, 1H), 4.70 (s, 2H), 4.59 (s, 2H), 3.96 (s,
2H), 2.98 (bs, 1H), 1.76 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 142.5,
141.5, 137.0, 130.9, 129.8, 128.9, 114.0, 75.3, 71.9, 64.6, 20.6; IR
(CHCl3) 3450, 3109, 2882, 1658, 1484, 1082, 916 cm-1; mass spectrum,
m/z (relative abundance) 193 (M, 2), 174 (8), 163 (11), 135 (9), 119
(100), 104 (53), 91 (99), 77 (51), 65 (18), 55 (14). Anal. Calcd for
C12H16O2: C, 74.97; H, 8.39. Found: C, 74.82; H, 8.46. The column
was then flushed with 750 mL of 100% ethyl acetate to yield 14.43 g
(94% recovery) of pure 1,2-benzenedimethanol.
2-(2-Propen-1-yloxymethyl)benzyl Alcohol. Sodium hydride (2.48
g, 62.0 mmol, 60% dispersion in oil) was treated with 1,2-benzene-
dimethanol (20.0 g, 144 mmol) as in the previous procedure, and the
resulting anion was alkylated with allyl bromide (5.00 g, 41.3 mmol).
Workup and purification via column chromatography (2:1 hexanes:
ethyl acetate) yielded 7.01 g (95% yield) of the title compound as a
colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.43-7.29 (comp, 4H),
5.96 (ddt, J ) 17.2, 10.4, 5.8 Hz, 1H), 5.31 (ddd, J ) 17.2, 2.7, 1.5
Hz, 1H), 5.24 (ddd, J ) 10.4, 2.7, 1.3 Hz, 1H), 4.67 (s, 2 H), 4.63 (s,
2H), 4.08 (dt, J ) 5.8, 1.4 Hz, 2H), 2.58 (bs, 1H); 13C NMR (75 MHz,
CDCl3) δ 140.3, 135.7, 133.9, 129.8, 129.4, 128.7, 127.8, 117.8, 71.1,
71.0, 63.4; IR (CHCl3) 3458, 3082, 2864, 1746, 1466, 1422, 1072,
1012, 959 cm-1; mass spectrum, m/z (relative abundance) 160 (10),
120 (100), 91 (84), 77 (62), 65 (65). Anal. Calcd for C11H14O2: C,
74.13; H, 7.92. Found: C, 74.04; H, 7.68. The column was then
flushed with 750 mL of 100% ethyl acetate to yield 13.29 g (93%
recovery) of pure 1,2-benzenedimethanol.
) 17.2, 3.0, 1.6 Hz, 1H), 5.31 (s, 2H), 5.23 (ddd, J ) 10.4, 3.0, 1.0
Hz, 1H), 4.79 (bs, 1H), 4.59 (s, 2H), 4.02 (dt, J ) 5.6, 1.4 Hz, 2H);
13C NMR (75 MHz, CDCl3) δ 166.2, 136.4, 134.1, 129.1, 128.9, 127.9,
117.1, 69.6, 63.8, 46.1; IR (neat), 2104 (CdN2), 1693 (CdO) cm-1
.
Anal. Calcd for C13H14N2O3: C, 63.40; H, 5.73; N, 11.38. Found; C,
63.47; H, 5.71; N, 11.34.
General Procedure for Formation of Macrocyclic Lactones from
17. In a typical experiment, 1.00 mmol of diazoacetate was dissolved
in 10 mL of freshly distilled CH2C12 and added via syringe pump over
10 h to 3.7 mg (1.0 mol %) of Cu(MeCN)4PF6 in 10 mL of refluxing
CH2Cl2. Upon completion of addition, the solution was passed through
a short plug of silica gel to remove the catalyst. The plug was washed
with 100 mL of CH2Cl2, the solvent was removed, and the crude
reaction mixture was purified by flash chromatography in the solvent
system indicated.
5,6-Benzo-3,8-dioxa-10-methyl-cis-bicyclo[8.1.0]undecan-2-one
(18a): 6:1 hexanes:ethyl acetate; 74% yield with Cu(MeCN)4PF6; mp
69.0-69.5 °C. 1H NMR (300 MHz, CDCl3) δ 7.33-7.28 (comp, 4H),
5.36 (d, J ) 12.1 Hz, 1H), 5.8 (d, J ) 12.1 Hz, 1H), 4.68 (d, J ) 11.7
Hz, 1H), 4.28 (d, J ) 11.7 Hz, 1H), 3.74 (d, J ) 10.6 Hz, 1H), 3.28
(d, J ) 10.6 Hz, 1H), 1.61 (dd, J ) 7.9, 5.8 Hz, 1H), 1.35 (dd, J ) 5.4
Hz, 1H), 1.25 (s, 3H), 0.88 (dd, J ) 8.1, 4.8 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 172.5, 136.8, 135.8, 131.1, 130.7, 128.8, 128.4, 73.2,
72.2, 66.3, 27.6, 27.5, 23.8, 20.5; IR (CHCl3): 2969, 2882, 1719, 1283,
1117 cm-1; mass spectrum, m/z (relative abundance) 232 (M+, 3), 175
(8), 162 (11), 145 (13), 120 (63), 104 (100), 91 (52), 55 (94). Anal.
Calcd for C14H16O3: C, 72.39; H, 6.94. Found: C, 72.26; H, 6.90.
The cyclopropane moiety was determined to have the cis-configuration
due to the observation of an NOE interaction between the proton
adjacent to the carbonyl group and the methyl group.
5,6-Benzo-3,8-dioxa-cis-bicyclo[8.1.0]undecanan-2-one (18b): 6:1
hexanes:ethyl acetate; 63% yield with CuPF6; mp 64-65 °C. 1H NMR
(400 MHz, CDCl3) δ 7.36-7.22 (comp, 4H), 5.30 (d, J ) 12.1 Hz,
1H), 5.18 (d, J ) 12.1 Hz, 1H), 4.73 (d, J ) 11.6 Hz, 1H), 4.26 (d, J
) 11.6 Hz, 1H), 4.06 (dd, J ) 10.7, 6.0 Hz, 1H), 3.14 (dd, J ) 10.7,
9.2 Hz, 1H), 1.85 (ddd, J ) 9.1, 7.9, 5.8 Hz, 1H), 1.72-1.62 (m, 1H),
1.28 (ddd, J ) 6.1, 5.8, 4.9 Hz, 1H), 1.10 (ddd, J ) 8.1, 7.9, 4.9 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 172.8, 136.9, 135.8, 131.1, 129.0,
128.5, 72.7, 68.8, 66.5, 20.7, 19.9, 13.4; IR (CHCl3) 2882, 1728, 1291,
1108 cm-1; mass spectrum, m/z (relative abundance) 218 (M+, 4), 145
(12), 129 (28), 120 (100), 99 (43), 91 (39), 78 (15), 65 (11), 55 (17).
Anal. Calcd for C13H14O3: C, 71.54; H, 6.47. Found: C, 71.48; H,
6.43.
2-(2-Methyl-2-propen-1-yloxymethyl)benzyl diazoacetate (17a)
was prepared by a one-pot modification of the procedure of Doyle28 in
which 2-(2-methyl-2-propen-1-yloxymethyl)benzyl alcohol (4.57 g, 23.7
mmol), dissolved in 100 mL of THF, was treated with triethylamine
(240 mg) and diketene (2.48 g, 29.5 mmol) at 0 °C. The solution was
Intra- versus Intermolecular Cyclopropenation of 17a. Diazo-
acetate 17a (130 mg, 0.500 mmol) was dissolved in 5 mL of freshly
distilled CH2Cl2 and added via syringe pump at 1.0 mL/h to a solution
of Rh2(OAc)4 (2.2 mg, 1.0 mol %) and variable amounts of methyl
methallyl ether in 5 mL of refluxing CH2Cl2. After the addition was
complete, the reaction solution was passed through a short plug of silica
to remove the catalyst. The reaction mixture was directly analyzed by
GC and, following evaporation of the solvent and excess ether, by 1H
NMR. Chromatographic separation of the products on silica (5:1
hexanes:ethyl acetate) provided intermolecular cyclopropanation prod-
ucts 21 and ylide rearrangement product 22 in 83% isolated yield from
the reaction performed in methylmethallyl ether as the solvent.
2-(2-Methyl-2-propen-1-yloxymethyl)benzyl 2-Methyl-2-methoxy
methylcyclopropanecarboxylate (21). Colorless oil; identified from
1
allowed to come to room temperature overnight, at which point H
NMR analysis of the crude reaction mixture indicated complete
conversion of the starting alcohol to the desired acetoacetate. The
solution was cooled to 0 °C, triethylamine (2.88 g, 28.4 mmol) and
methanesulfonyl azide (3.15 g, 26.1 mmol) were added sequentially,
the solution was allowed to warm to room temperature, and stirring
was continued until 1H NMR analysis indicated that the diazo transfer
reaction was complete. The solution was again cooled to 0 °C, and
LiOH (2.28 g, 94.8 mmol), dissolved in 100 mL of water, was added.
The temperature of the solution was maintained at 0 °C until 1H NMR
analysis revealed the cleavage to be complete, at which time 100 mL
of ether was added, the layers were separated, and the aqueous layer
was extracted with ether (3 × 30 mL). The organic layer was washed
with brine (1 × 50 mL) and dried over MgSO4. Removal of solvent
under reduced pressure and purification by column chromatography
(6:1 hexanes:ethyl acetate) yielded 3.89 g (63% yield) of pure product
as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.43-7.30 (m, 4H),
5.31 (s, 2H), 4.99 (s, 1H), 4.92 (s, 2H), 4.78 (s, 1H), 3.94 (s, 2H), 1.77
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 167.4, 141.9, 136.7, 134.2, 129.2,
129.0, 128.4, 128.0, 112.4, 74.4, 69.5, 46.3, 19.5; IR (neat), 2121
(CdN2), 1702 (CdO) cm-1. Anal. Calcd for C14H16N2O3: C, 64.60;
H, 6.20; N, 10.76. Found: C, 64.50; H, 6.23; N, 10.63.
1
the mixture of E and Z isomers; 21E: H NMR (CDCl3, 400 MHz) δ
7.43-7.25 (comp, 4 H), 5.25 (d, J ) 12.8 Hz, 1 H), 5.19 (d, J ) 12.8
Hz, 1 H), 5.02-4.99 (m, 1 H), 4.94-4.91 (m, 1 H), 4.57 (s, 2 H), 3.94
(s, 2 H), 3.33 (s, 3 H), 3.24 (d, J ) 9.9 Hz, 1 H), 3.19 (d, J ) 9.9 Hz,
1 H), 1.77 (d, J ) 0.9 Hz, 3 H), 1.72 (dd, J ) 8.2, 5.6 Hz, 1 H), 1.25
(s, 3 H), 1.12 (dd, J ) 5.6, 4.6 Hz, 1 H), 1.01 (dd, J ) 8.2, 4.6 Hz, 1
H); 21Z: 1H NMR (CDCl3, 400 MHz) δ 7.43-7.24 (comp, 4 H), 5.25
(d, J ) 12.8 Hz, 1 H), 5.20 (d, J ) 12.8 Hz, 1 H), 4.81-4.79 (m, 1
H), 4.75-4.73 (m, 1 H), 4.58 (s, 2 H), 3.94 (s, 2 H), 3.53 (d, J ) 10.1
Hz, 1 H), 3.42 (d, J ) 10.1 Hz, 1 H), 3.22 (s, 3 H), 1.77 (s, 3 H), 1.64
(dd, J ) 7.9, 5.5 Hz, 1 H), 1.23 (s, 3 H), 1.22 (dd, J ) 5.5, 4.5 Hz, 1
H), 0.91 (dd, J ) 7.9, 4.5 Hz, 1 H). trans-3-(2-Methyl-2-propen-1-
oxy)-4-vinyl-8,9-benzo-1,6-dioxocyclodecan-2-one (22): colorless oil;
1H NMR (CDCl3, 400 MHz) δ 7.52-7.21 (comp, 4 H), 5.86 (ddd, J )
17.2, 10.4, 8.4 Hz, 1 H), 5.37 (s, 2 H), 5.20 (ddd, J ) 17.2, 1.6, 1.0
2-(2-Propen-1-yloxymethyl)benzyl diazoacetate (17b) was pre-
pared by the one-pot procedure described above and purified by column
chromatography (6:1 hexanes:ethyl acetate) to yield 2.23 g (65% yield)
of pure product as a yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.42-
7.26 (comp, 4H), 5.95 (ddt, J ) 17.2, 10.4, 5.6 Hz, 1H), 5.32 (ddd, J

Catalytic Intramolecular Cyclopropanation
J. Am. Chem. Soc., Vol. 119, No. 38, 1997 8835
Hz, 1 H), 5.16 (ddd, J ) 10.4, 1.6, 0.6 Hz, 1 H), 4.96-4.95 (m, 1 H),
4.88-4.87 (m, 1 H), 4.67 (d, J ) 9.8 Hz, 1 H), 4.48 (d, J ) 9.8 Hz,
1 H), 4.21 (d, J ) 12.4 Hz, 1 H), 3.95 (d, J ) 3.5 Hz, 1 H), 3.84 (d,
J ) 12.4 Hz, 1 H), 3.84 (t, J ) 10.3 Hz, 1 H), 3.51 (dd, J ) 10.3, 3.5
Hz, 1 H), 3.20-3.13 (m, 1 H), 1.54 (s, 3 H); 13C NMR (CDCl3, 100
MHz) δ 171.5, 141.6, 136.1, 134.9, 134.8, 131.6, 128.6, 128.1, 127.9,
117.7, 112.9, 77.8, 74.9, 72.2, 68.8, 66.8, 46.8, 19.6. Anal. Calcd for
C19H26O4: C, 71.67; H, 8.23. Found: C, 71.81; H, 8.18.
cis-4-(2-Methyl-2-propen-1-yloxy)-2-buten-1-ol (23). Sodium hy-
dride (887 mg, 22.2 mmol, 60% dispersion in oil) was treated with
cis-2-buten-1,4-diol (5.22 g, 59.2 mmol) according to the procedure
for preparation of 2-(2-methyl-2-propen-1-yloxymethyl)benzyl alcohol,
and the resulting anion was alkylated with methallyl bromide (2.00 g,
14.8 mmol) to yield, after workup and purification via column
chromatography (2:1 hexanes:ethyl acetate), 2.06 g (98% yield) of the
title compound as a colorless liquid: 1H NMR (300 MHz, CDCl3) δ
5.83-5.73 (comp, 2H), 4.97 (bs, 1H), 4.91 (bs, 1H), 4.20 (d, J ) 6.6
Hz, 2H), 4.03 (d, J ) 6.1 Hz, 2H), 3.90 (s, 2H), 2.00 (s, 1H), 1.75 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 141.2, 131.7, 127.3, 112.0, 73.7,
64.8, 57.8, 18.8; IR (neat) 3388, 2921, 2853, 1647, 1239, 1086, 1035
cm-1; mass spectrum, m/z (relative abundance) 142 (M, 8), 124 (63),
95 (55), 55 (75). Anal. Calcd for C8H14O2: C, 67.57; H, 9.92.
Found: C, 67.61; H, 9.87.
2.0 mL/h using a syringe pump. After addition was complete, the
reaction mixture was passed through a plug of silica gel to remove the
catalyst. The resulting solution was purified by flash chromatography
on silica (8.1 hexanes:ethyl acetate) to yield 176 mg (58% yield) of 26
and 34 mg (12% yield) of 27. For reactions involving dirhodium(II)
catalysts the same procedure was employed except that addition of 25
occurred at a rate of 1.0 mL/h.
(Z)-5,6-Benzo-3,8,13-trioxa-15-methylbicyclo[13.1.0]-cis-hexadec-
1
10-en-2-one (26): white solid, mp 96-97 °C; H NMR (300 CDCl3)
δ 7.45 (d, J ) 7.3 Hz, 1H), 7.39-7.28 (comp, 3H), 5.92-5.78 (comp,
2H), 5.64 (d, J ) 11.6 Hz, 1H), 4.64 (d, J ) 11.6 Hz, 1H), 4.52 (d, J
) 11.8 Hz, 1H), 4.43 (d, J ) 11.8 Hz, 1H), 4.24 (dd, J ) 11.9, 7.8
Hz, 1H), 4.16 (dd, J ) 11.9, 7.8 Hz, 1H), 4.05 (dd, J ) 11.6, 7.0 Hz,
1H), 3.87 (dd, J ) 11.6, 6.2 Hz, 1H), 3.66 (d, J ) 10.2 Hz, 1H), 3.53
(dd, J ) 10.2 Hz, 1H), 1.62 (dd, J ) 7.6, 5.7 Hz, 1H), 1.21 (dd, J )
5.7, 4.7 Hz, 1H), 1.22 (s, 3H), 0.89 (dd, J ) 7.6, 4.7 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 173.2, 139.2, 134.5, 132.1, 132.0, 130.3,
130.2, 129.6, 128.9, 73.0, 69.7, 66.8, 66.4, 66.1, 28.2, 26.8, 23.5, 20.1;
IR (CHCl3): 2873, 1728, 1466, 1414, 1169, 1090 cm-1; mass spectrum,
m/z (relative abundance) 302 (M+, 1), 233 (13), 215 (18), 183 (8), 175
(9), 169 (3), 162 (5), 143 (7), 129 (10), 121 (39), 113 (100), 104 (70)
91 (48), 78 (20), 55 (59). Anal. Calcd for C18H22O4: C, 71.50; H,
7.34. Found: C, 71.38; H, 7.36.
2-[cis-4-(2-Methyl-2-propen-1-yloxy)-2-buten-1-yloxymethyl]ben-
zyl Alcohol (24). cis-4-(2-Methyl-2-propen-1-yloxy)-2-buten-1-ol (2.06
g, 14.5 mmol) was dissolved in 50 mL of freshly distilled CH2Cl2,
triethylamine (1.69 g, 16.7 mmol) was added, and the solution was
cooled to 0 °C. Methanesulfonyl chloride (1.74 g, 15.2 mmol) was
added via syringe and the solution was stirred at 0 °C for 1 h. The
solution was diluted with 50 mL of CH2Cl2, water was added, and the
layers were separated. The organic layer was washed with brine (20
mL), dried over anhydrous MgSO4, and filtered, and the solvent was
removed to yield 2.94 g (92% yield) of product that was taken on
without further purification.
To a suspension of NaH (775 mg, 19.3 mmol, 60% dispersion in
oil) at 0 °C in 125 mL of THF was added 6.23 g (45.1 mmol) of 1,2-
benzenedimethanol dissolved in 40 mL of THF. The above mesylate
(2.84 g, 12.9 mmol) of the methallyl ether of 2-buten-1,4-diol was
dissolved in 20 mL of THF and added in one portion via syringe. The
solution was allowed to come to room temperature overnight, water
was added, the layers were separated, and the aqueous layer was
extracted with ethyl acetate (3 × 75 mL). The combined organic layer
was washed with brine (2 × 40 mL), dried over anhydrous MgSO4,
and filtered, and the solvent was removed under reduced pressure to
yield a pale yellow oil. Column chromatography (3:2 hexanes:ethyl
acetate) yielded 2.94 g (87% yield) of pure product as a colorless oil:
1H NMR (300 MHz, CDCl3) δ 7.42-7.29 (comp, 4H), 5.80-5.74
(comp, 2 H), 4.95 (bs, 1 H), 4.90 (bs, 1 H), 4.67 (s, 2 H), 4.62 (s, 2 H),
4.15 (d, J ) 5.0 Hz, 2 H), 4.00 (d, J ) 5.0 Hz, 2H), 3.99 (s, 2H), 2.68
(bs, 1H), 1.74 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 142.0, 140.4,
135.7, 130.2, 129.9, 129.5, 128.8, 128.4, 127.8, 112.4, 74.2, 71.1, 65.8,
65.4, 63.5, 19.5; IR (neat) 3440, 3083, 3032, 2930, 2857, 1650, and
1623 cm-1; mass spectrum, m/e (relative abundance) 172 (6), 135 (10),
121 (82), 104 (24), 91 (100), 77 (64), 69 (23), 55 (81). Anal. Calcd
for C16H22O3: C, 73.25; H, 8.45. Found: C, 73.16; H, 8.37. Washing
of the column with 100% ethyl acetate allowed recovery of 4.36 g
(98%) of excess 1,2-benzenedimethanol.
cis-3-(2-Methyl-2-propen-1-oxy)-4-vinyl-8,9-benzo-1,6-dioxocy-
clodecan-2-one (27): colorless oil; 1H NMR (CDCl3, 400 MHz) δ
7.52-7.21 (comp, 4 H), 5.86 (ddd, J ) 17.2, 10.4, 8.4 Hz, 1 H), 5.37
(s, 2 H), 5.20 (ddd, J ) 17.2, 1.6, 1.0 Hz, 1 H), 5.16 (ddd, J ) 10.4,
1.6, 0.6 Hz, 1 H), 4.96-4.95 (m, 1 H), 4.88-4.87 (m, 1 H), 4.67 (d,
J ) 9.8 Hz, 1 H), 4.48 (d, J ) 9.8 Hz, 1 H), 4.21 (d, J ) 12.4 Hz, 1
H), 3.95 (d, J ) 3.5 Hz, 1 H), 3.84 (d, J ) 12.4 Hz, 1 H), 3.84 (t, J
) 10.3 Hz, 1 H), 3.51 (dd, J ) 10.3, 3.5 Hz, 1 H), 3.20-3.13 (m, 1
H), 1.54 (s, 3 H); 13C NMR (CDCl3, 100 MHz) δ 171.5, 141.6, 136.1,
134.9, 134.8, 131.6, 128.6, 128.1, 127.9, 117.7, 112.9, 77.8, 74.9, 72.2,
68.8, 66.8, 46.8, 19.6. Anal. Calcd for C18H22O4: C, 71.50; H, 7.34.
Found: C, 71.48; H, 7.27. The cis geometry of 27 was established by
NOE experiments on the lactone formed by hydrogenolysis, which
conveniently removed the 1,2-benzenedimethyl linker.
X-ray Structure of 26.. Crystals grew as colorless prisms from
hexanes:ethyl acetate. The data crystal was cut from a larger crystal
and had approximate dimensions: 0.38 × 0.50 × 0.50 mm. Colorless
crystals of 26 (C18H22O4) were monoclinic, space group C2/c, with a
) 28.055(2), b ) 11.712(1), c ) 9.883(1)Å, b ) 98.425(5)°, V )
3
3211.3(3) Å , Z ) 8, Fcalc ) 1.25 g/cm-3. Data were collected out
to 2θ ) 60° by the ω-scan technique on a Siemens P4 diffractometer
at -95 °C using graphite monochromatized Mo KR radiation (λ )
0.71073Å). The 9983 reflections were measured of which 4690
reflections were unique [Rint(F2) ) 0.022]. The structure was solved
by direct methods and refined by full-matrix least-squares on F2 with
anisotropic displacement parameters for the non-hydrogen atoms. The
hydrogen atom positions were observed in a ∆F map and refined with
isotropic displacement parameters. The final Rw(F2) ) 0.109 with a
goodness of fit ) 1.022 for refining 288 parameters. The conventional
R(F) ) 0.0430 for 3495 reflections with Fo > 4(s(Fo)). Data reduction,
decay correction, structure solution, and refinement were done using
the SHELXTL/PC softwarepackage.30 Tables of positional and thermal
parameters, bond lengths, and angles and torsion angles and figures
are located in the Supporting Information.
2-[cis-4-(2-Methyl-2-propen-1-yloxy)-2-buten-1-yloxymethyl]ben-
zyl diazoacetate (25) was prepared by the one-pot procedure described
for 10a and purified by column chromatography (7:1 hexanes:ethyl
acetate) to yield 2.68 g (62%) of pure product as a yellow oil: 1H
NMR (300 MHz, CDCl3) δ 7.40-7.30 (m, 4H), 5.78-5.71 (m, 2H),
5.30 (s, 2H), 4.95 (bs, 1H), 4.89 (bs, 1H), 4.79 (bs, 1H), 4.57 (s, 2H),
4.11 (d, J ) 3.7 Hz, 2H), 4.01 (d, J ) 3.9 Hz, 2H), 3.87 (s, 2H), 1.73
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 166.3, 141.9, 136.3, 134.2, 129.6,
129.2, 129.0, 128.9, 128.3, 128.0, 112.1, 112.0, 74.0, 69.8, 65.9, 65.3,
63.8, 46.1, 19.3; IR (CHCl3) 2121 (CdN2), 1693 (CdO) cm-1. Anal.
Calcd for C18H22N2O4: C, 65.44; H, 6.71; N, 8.48. Found: C, 65.26;
H, 6.71; N, 8.41.
Preparation of Alcohol 28. To a continuously stirred solution of
NaH (0.71 g, 30 mmol, 60% dispersion in oil) in 150 mL of anhydrous
THF was added 1,2-benzenedimethanol (9.60 g, 69.5 mmol) in 50 mL
of THF. After cooling to 0 °C, 3-bromo-2-methylpropene (2.68 g, 19.9
mmol) was added by pipette, and the resulting solution was allowed to
warm to room temperature while stirring for 3 days. Water (50 mL)
was added, and the solution was extracted three times with 20-mL
portions of ethyl acetate. The combined extract was washed with 40
mL of brine and dried over anhydrous MgSO4. After removal of the
solvent under reduced pressure, the product mixture was refrigerated
overnight whereupon excess 1,2-benzenedimethanol crystallized and
was filtered (5.75 g, 41.6 mmol, 84% recovery). The residual oil (3.67
Diazo Decomposition of 25. To a solution of Cu(MeCN)4PF6 (3.7
mg, 1.0 mol %) in 10 mL of refluxing CH2Cl2 was added diazoacetate
25 (330 mg, 1.00 mmol) in 10 mL of anhydrous CH2Cl2 at a rate of
(30) Sheldrick, G. M. SHELXTL/PC (Version 5.03); Siemens Analytical
X-ray Instruments, Inc.: Madison, WI, U.S.A., 1994.

8836 J. Am. Chem. Soc., Vol. 119, No. 38, 1997
Doyle et al.
g, 19.1 mmol, 96% yield) was identified as 2-(2-methyl-2-propen-1-
yloxymethyl)benzyl alcohol. This alcohol was dissolved in 60 mL of
anhydrous CH2Cl2 to which was added, after cooling to 0 °C,
triethylamine (2.89 g, 28.5 mmol) followed by methanesulfonyl chloride
(2.30 g, 20.1 mmol). Stirring was continued at 0 °C for an additional
45 min, whereupon water (20 mL) was added and the organic layer
was separated. The organic layer was washed with H2O (30 mL) and
brine (30 mL) and dried over anhydrous MgSO4, and the solvent was
removed under reduced pressure to provide 5.02 g of mesylate ester
(18.6 mmol, 97% yield): 1H NMR (CDCl3, 400 MHz) δ 7.47-7.35
(comp, 4 H), 5.39 (s, 2H), 5.00-4.98 (m, 1 H), 4.95-4.93 (m, 1 H),
4.59, 3.95 (s, 2 H), 2.92 (s, H), 1.77 (s, 3 H).
To sodium hydride (0.66 g, 28 mmol, 60% dispersion in oil)
suspended in 65 mL of anhydrous THF at 0 °C was added 1,2-
benzenedimethanol (8.94 g, 64.7 mmol) slowly but continuously. After
stirring at room temperature for 15 min the previously prepared mesylate
ester (5.02 g, 18.6 mmol) was added neat, and the resultant mixture
was stirred for 20 h. Water (40 mL) was added, and the solution was
extracted with two 30-mL portions of ethyl acetate. The combined
organic extract was washed with brine (30 mL) and dried over
anhydrous MgSO4, and the solvent was evaporated under reduced
pressure to afford 4.33 g of colorless 28 (13.9 mmol, 79% yield)
following crystallization of unreacted 1,2-benzenedimethanol (5.91 g,
42.8 mmol, 91% recovery). Spectral data were consistent with assigned
structure 28: 1H NMR (CDCl3, 400 MHz) δ 7.43-7.27 (comp, 12 H),
4.99-4.97 (m, 1 H), 4.92-4.90 (m, 1 H), 4.68 (s, 2 H), 4.67 (s, 2 H),
4.66 (s, 2 H), 4.53 (s, 2 H), 3.89 (quin, J ) 0.5 Hz,), 2.95 (s, 1 H),
1.75 (dt, J ) 0.5, 0.9 Hz, 3 H); 13C NMR (CDCl3, 100 MHz) δ 142.1,
136.6, 135.9, 135.7, 130.1, 129.6, 129.0, 128.9, 128.8, 128.0, 127.94,
127.92, 113.1, 112.4, 74.2, 71.3, 69.8, 69.6, 63.7, 19.6; IR (film) 3462,
3075, 2870, 1070, 1008, 777, 759, 752 cm-1; mass spectrum, m/z
(relative abundance) 222 (14), 174 (22), 145 (12), 131 (15), 121 (32),
120 (21), 119 (80), 118 (25), 105 (39), 104 (83), 93 (49), 91 (100), 77
(47), 55 (21). Anal. Calcd for C20H24O3: C, 76.89; H, 7.74. Found:
C, 76.93; H, 7.68.
Preparation of diazoacetate 29 was accomplished by a modification
of the three-step reaction described by Doyle28 in which 28 (5.95 g,
19.1 mmol), dissolved in 65 mL of THF, was treated with triethylamine
(0.50 g, 4.9 mmol) and, after cooling to 0 °C, diketene (2.25 g, 26.7
mmol) with continued stirring for 20 h, then triethylamine (2.13 g,
21.0 mmol), and methanesulfonyl azide (2.78 g, 23.0 mmol) for 20 h
after which water (50 mL) was added, and the resulting mixture was
extracted with five 40-mL portions of ethyl acetate. The combined
extract was washed with brine (50 mL) and dried over anhydrous
MgSO4, and the solvent was evaporated under reduced pressure.
Column chromatographic purification on silica gel (3:1 hexanes:EtOAc)
provided the diazoacetoacetate (6.54 g, 15.4 mmol, 81% yield) as an
orange oil. This purified diazoacetoacetate was dissolved in THF (50
mL) and cooled to 0 °C. A solution of LiOH (1.48 g, 61.7 mmol) in
water (50 mL) was cooled to 0 °C and then added to the reaction
solution. After the solution was stirred for 6 h, ethyl acetate (40 mL)
was added, and the organic solution was washed twice with 30-mL
portions of water and with brine (40 mL). After drying over anhydrous
MgSO4, the solvent was evaporated under reduced pressure. Column
chromatographic purification on silica gel (3:1 hexanes:EtOAc) pro-
vided 3.89 g of a light yellow oil identified as 29 (10.2 mmol, 66%
overall yield): 1H NMR (CDCl3, 400 MHz) δ 7.43-7.25 (comp, 8
H), 5.29 (s, 2 H), 4.99-4.97 (m, 1 H), 4.92-4.89 (m, 1 H), 4.75 (br
s, 1 H), 4.65 (s, 2 H), 4.63 (s, 2 H), 4.54 (s, 2 H), 3.90 (br s, 2 H), 1.74
(br s, 3 H); 13C NMR (CDCl3, 100 MHz) δ 166.4, 142.0, 136.5, 136.1,
134.2, 129.2, 129.1, 128.6, 128.4, 128.0, 127.7, 127.7, 127.6, 112.4,
112.2, 74.1, 69.9, 69.8, 69.4, 63.8, 46.1, 19.4; IR (film) 2112 (CdN2),
1695 (CdO), 1640 (CdC) cm-1. Anal. Calcd for C22H24O4N2: C,
69.43; H, 6.36, N, 7.36. Found: C, 69.45; H, 6.32; N, 7.40.
30Z and 30E. These isomers were separated by column chromatog-
raphy on silica gel (9:1 hexanes:ethyl acetate) to give 156 mg (0.443
mmol, 44% yield) of pure 30Z and 69 mg (0.196 mmol, 20% yield) of
pure 30E. In Rh2(OAc)4 catalyzed reactions, these same products were
isolated in 57 and 7% yield, respectively. For 30Z: 1H NMR (CDCl3,
400 MHz) δ 7.48-7.25 (comp, 8 H), 5.69 (d, J ) 11.5 Hz, 1 H), 4.71
(d, J ) 11.5 Hz, 1 H), 4.70 (d, J ) 11.7 Hz, 1 H), 4.65 (d, J ) 11.7
Hz, 1 H), 4.61 (d, J ) 11.2 Hz, 1 H), 4.56 (d, J ) 11.0 Hz, 1 H), 4.49
(d, J ) 11.0 Hz, 1 H), 4.28 (d, J ) 11.2 Hz, 1 H), 3.84 (d, J ) 11.0
Hz, 1 H), 3.68 (d, J ) 11.0 Hz, 1 H), 1.69 (dd, J ) 7.7, 5.6 Hz, 1 H),
1.23 (s, 3 H), 1.19 (dd, J ) 5.6, 4.6 Hz, 1 H), 0.89 (dd, J ) 7.7, 4.6
Hz, 1 H); 13C NMR (CDCl3, 100 MHz) δ 172.2, 137.3, 136.7, 136.1,
134.3, 131.2, 130.4, 129.0, 128.9, 128.7, 128.3, 127.8, 127.7, 71.2,
70.9, 70.6, 69.2, 65.0, 26.9, 25.9, 22.2, 18.0; IR (CDCl3) 1716 (CdO),
1
1173, 1078 cm-1. For 30E: mp 110.5-112.0 °C; H NMR (CDCl3,
400 MHz) δ 7.54 (dd, J ) 7.6, 1.1 Hz, 1 H), 7.47 (dd, J ) 6.0, 2.9 Hz,
1 H), 7.40-7.25 (comp, 6 H), 5.51 (d, J ) 11.8 Hz, 1 H), 4.96 (d, J
) 10.7 Hz, 1 H), 4.86 (d, J ) 11.8 Hz, 1 H), 4.76 (d, J ) 11.0 Hz, 1
H), 4.73 (d, J ) 10.6 Hz, 1 H), 4.64 (d, J ) 10.6 Hz, 1 H), 4.56 (d, J
) 11.0 Hz, 1 H), 4.24 (d, J ) 10.7 Hz, 1 H), 4.13 (d, J ) 11.7 Hz, 1
H), 2.74 (d, J ) 11.7Hz, 1 H), 1.84 (dd, J ) 8.0, 5.7 Hz, 1 H), 1.22
(s, 3 H), 1.14 (dd, J ) 5.7, 5.1 Hz, 1 H), 0.77 (dd, J ) 8.0, 5.1 Hz, 1
H); 13C NMR (CDCl3, 100 MHz) δ 171.5, 137.8, 136.54, 136.49, 133.6,
131.1, 131.0, 129.44, 129.43, 129.3, 128.1, 128.08, 128.05, 78.4, 71.1,
70.2, 69.2, 65.5, 27.3, 25.6, 15.6, 14.5; IR (CDCl3) 1724, 1170, 1111
cm-1
. Anal. Calcd for C22H24O4 (30Z/E): C, 74.98,; H, 6.86.
Found: C, 74.91; H, 6.78.
Preparation of alcohol 31 followed the same procedure as that for
the formation of 28. Alcohol 28 (4.31 g, 13.8 mmol) dissolved in 75
mL of anhydrous CH2Cl2 was treated with Et3N (2.09 g, 20.6 mmol)
and then methanesulfonyl chloride (1.73 g, 15.1 mmol) to form the
methanesulfonate in 94% yield. The 1H NMR spectrum confirmed this
product assignment with an absorption at δ 5.35. Treatment of this
methanesulfonate ester with the sodium salt of 1,2-benzenedimethanol
gave, after a reaction time of 5 h and workup, 4.65 g of the desired
alcohol (10.8 mmol, 83% yield): 1H NMR (CDCl3, 400 MHz) δ 7.42-
7.23 (comp, 12 H), 4.98-4.96 (m, 1 H), 4.90-4.88 (m, 1 H), 4.60 (s,
2 H), 4.585 (s, 4 H), 4.576 (s, 2 H), 4.56 (s, 2 H), 4.51 (s, 2 H), 3.87
(br s, 2 H), 3.02 (br s, 1 H), 1.72 (br s, 3 H); 13C NMR (CDCl3, 75
MHz) δ 141.9, 140.2, 136.4, 136.3, 136.1, 135.7, 129.7, 129.1, 129.0,
128.9, 128.7, 128.6, 128.5, 127.94, 127.88, 127.7, 127.6, 112.3, 112.2,
74.1, 71.0, 69.73, 69.69, 69.66, 69.3, 63.2, 19.4; IR (film) 3392, 3068,
3032, 2915, 2868, 1070, 1008 cm-1. Anal. Calcd for C28H32O4: C,
77.75; H, 7.46. Found: C, 77.61; H, 7.42.
Preparation of diazoacetate 32 was accomplished by the same
procedure as that employed for the formation of 29. Diketene
condensation was performed with 29 (4.61 g, 10.7 mmol), diketene
(1.26 g, 15.0 mmol), and Et3N (0.5 g, 5 mmol), and stirring was
continued for 22 h. Diazo transfer utilized Et3N (1.19 g, 11.8 mmol)
and MsN3 (1.56 g, 12.8 mmol), and the reaction mixture was stirred
for 23 h. Deacylation was performed using pyrrolidine (4.30 g, 55.4
mmol), and column chromatography using silica gel (3:1 hexanes:ethyl
acetate) provided purification. Diazoacetate 32 (2.71 g, 5.41 mmol,
51% overall yield) was obtained as a yellow oil: 1H NMR (CDCl3,
400 MHz) δ 7.43-7.25 (comp, 12 H), 5.27 (s, 2 H), 4.98-4.96 (m, 1
H), 4.91-4.89 (m, 1 H), 4.73 (br s, 1 H), 4.62 (s, 2 H), 4.614 (s, 2 H),
4.608 (s, 2 H), 4.58 (s, 2 H), 4.53 (s, 2 H), 3.88 (quin, J ) 0.5 Hz, 2
H), 1.73 (dt, J ) 0.5, 1.0 Hz, 3 H); 13C NMR (CDCl3, 100 MHz) δ
166.3, 136.4, 136.22, 136.16, 136.08, 134.1, 129.2, 129.0, 128.8, 128.7,
128.6, 128.5, 128.3, 127.9, 127.7, 127.6, 127.5, 112.12, 112.10, 74.1,
69.83, 69.80, 69.70, 69.68, 69.3, 63.8, 46.1, 19.4; IR (film) 2112 (CdN2),
1695 (CdO), 1642 (CdC) cm-1. Anal. Calcd for C30H32O5N2: C,
71.96; H, 6.44; N, 5.59. Found: C, 72.03; H, 6.40; N, 5.54.
Diazo Decomposition of 32. To Rh2(OAc)4 (1.1 mg, 2.5 mmol)
dissolved in 2.5 mL of CH2Cl2 was added 32 (125 mg, 0.25 mmol) in
2.5 mL of CH2Cl2 via syringe pump according to the same procedure
as that used for diazo decomposition of 29. After the reaction was
complete, the reaction solution was filtered through a short plug of
silica gel, and the solvent was removed under reduced pressure to
provide 80 mg of crude product consisting of a mixture of 33Z and
33E. This mixture was chromatographed on silica gel (10:1 hexanes:
ethyl acetate) to provide 69.7 mg (0.15 mmol, 59% yield) of the purified
Diazo Decomposition of 29. To Cu(MeCN)4PF6 (3.7 mg, 1.0 mol
%) dissolved in 5.0 mL of refluxing anhydrous CH2Cl2, contained in
an oven-dried two-neck round bottom flask fitted with a condenser
and septum, was added diazoacetate 27 (0.380 g, 1.00 mmol) in 5.0
mL of CH2Cl2 via syringe pump at a rate of 1.0 mL/h. The reaction
solution was filtered through a plug of silica to remove the catalyst,
and solvent was evaporated under reduced pressure to produce 320
mg of product (0.909 mmol, 91% yield) consisting of a mixture of

Catalytic Intramolecular Cyclopropanation
J. Am. Chem. Soc., Vol. 119, No. 38, 1997 8837
product; we were not able to separate the individual isomers, so products
were analyzed from the two-component mixture. The Cu(MeCN)4PF6
catalyzed reaction of 32 was performed on a 1.00 mmol scale; crude
product yield was 78%, and 33 was isolated after chromatography in
42% yield. For 33Z: 1H NMR (CDCl3, 400 MHz) δ 7.49-7.23 (comp,
12 H), 5.32 (d, J ) 12.9 Hz, 1 H), 5.27 (d, J ) 12.9 Hz, 1 H), 4.71 (d,
J ) 12.2 Hz, 1 H), 4.70 (s, 2H), 4.67 (d, J ) 11.8 Hz, 1 H), 4.66 (d,
J ) 12.2 Hz, 1 H), 4.63 (s, 2 H), 4.63 (d, J ) 11.2 Hz, 1 H), 4.59 (d,
J ) 11.2 Hz, 1 H), 4.59 (d, J ) 11.2 Hz, 1 H), 4.38 (d, J ) 11.8 Hz,
1 H); 3.66 (d, J ) 10.0 Hz, 1 H), 3.59 (d, J ) 10.0 Hz, 1 H), 1.68 (dd,
J ) 7.8, 5.6 Hz, 1 H), 1.24 (s, 3 H), 1.21 (dd, J ) 5.6, 4.6 Hz, 1 H),
0.89 (dd, J ) 7.8, 4.6 Hz, 1 H); 13C NMR (CDCl3, 100 MHz) δ 172.3,
136.7, 136.6, 136.3, 136.2, 136.1, 135.0, 129.5, 129.4, 129.2, 129.02,
129.01, 128.6, 128.3, 128.2, 128.1, 128.0, 127.8, 127.6, 72.1, 71.2, 71.1,
70.9, 70.3, 70.1, 63.7, 27.5, 25.4, 22.7, 19.7. For 33E: 1H NMR
(CDCl3, 400 MHz) δ 7.50-7.25 (comp, 12 H), 5.22 (d, J ) 12.0 Hz,
1 H), 5.18 (d, J ) 12.0 Hz, 1 H), 4.77 (d, J ) 12.0 Hz, 1 H), 4.76 (d,
J ) 11.7 Hz, 1 H), 4.68 (d, J ) 12.0 Hz, 1 H), 4.67 (s, 2 H), 4.65 (d,
J ) 11.7 Hz, 1 H), 4.60 (d, J ) 11.8 Hz, 1 H), 4.53 (d, J ) 11.2 Hz,
1 H), 4.46 (d, J ) 11.8 Hz, 1 H), 4.28 (d, J ) 11.2 Hz, 1 H), 3.70 (d,
J ) 10.1 Hz, 1 H), 2.76 (d, J ) 10.1 Hz, 1 H), 1.72 (dd, J ) 8.2, 5.6
Hz, 1 H), 1.21 (s, 3 H), 1.06 (dd, J ) 5.6, 4.6 Hz, 1 H), 0.84 (dd, J )
8.2, 4.6 Hz, 1 H); 13C NMR (CDCl3, 100 MHz) δ 172.0, 137.6, 137.3,
136.8, 136.4, 135.5, 134.0, 131.3, 130.5, 129.4, 129.2, 129.1, 129.0,
128.8, 128.4, 128.2, 128.0, 127.9, 127.4, 77.2, 76.6, 71.3, 71.2, 70.7,
70.1, 64.7, 29.7, 26.4, 25.1, 17.3. IR (CDCl3) for 33Z + 33E: 3072,
3031, 2960, 2867, 1720, 1166, 1080 cm-1
.
Anal. Calcd for
C30H32O5: C, 76.25; H, 6.83. Found: C, 76.12; H, 6.74.
Acknowledgment. We are grateful to the Robert A. Welch
Foundation and the National Science Foundation for their
support of this research. We wish to thank Wietske Smid for
preliminary work in the synthesis of selected macrocycle
precursors. A Jean Dreyfus Boissevain Undergraduate Scholar-
ship for Excellence in Chemistry from the Camille and Henry
Dreyfus Foundation to A.B.M. is greatly appreciated.
Supporting Information Available: Tables of positional
and thermal parameters, bond lengths, angles, and torsional
angles and figures for the crystal structure of 26 (13 pages).
See any current masthead page for ordering and Internet access
instructions.
JA971687Z