Selectivity in reactions of allyl diazoacetates as a function of catalyst and ring size from γ-lactones to macrocyclic lactones

Article abstract of DOI:10.1021/jo005589z

Catalytic reactions of diazoacetates tethered through zero, one, two, and three ethylene glycol units to an allyl group have been investigated for chemoselectivity, diastereoselectivity, and enantioselectivity. Results from cyclopropanation, carbon-hydrogen insertion, and oxonium ylide generation are compared from reactions of achiral and chiral catalysts of copper(I) and dirhodium(II) carboxylates and carboxamidates. Relative to results from intermolecular reactions of ethyl diazoacetate with allyl ethyl ether, intermolecular reactions show a diversity of selectivities including preference for the opposite configurational arrangement from the one preferred in corresponding intermolecular cyclopropanation reactions. Enantioselectivities for cyclopropanation are dependent on the catalyst ligands in a manner that reflects divergent trajectories of the carbon-carbon double bond to the reacting carbene center. Enantioselectivity increases as a function of ring size with chiral copper catalysts, but the reverse occurs with chiral dirhodium(II) carboxamidates. Mechanistic implications, including those related to the conformation of the reacting metal carbene, offer a new dimension to understanding of enantioselectivity in catalytic asymmetric cyclopropanation reactions.

Full text of DOI:10.1021/jo005589z

J . Org. Chem. 2000, 65, 8839-8847
8839
Selectivity in Rea ction s of Allyl Dia zoa ceta tes a s a F u n ction of
Ca ta lyst a n d Rin g Size fr om γ-La cton es to Ma cr ocyclic La cton es
Michael P. Doyle* and Wenhao Hu
Department of Chemistry, University of Arizona, Tucson, Arizona 85721
mdoyle@u.arizona.edu
Received J uly 25, 2000
Catalytic reactions of diazoacetates tethered through zero, one, two, and three ethylene glycol units
to an allyl group have been investigated for chemoselectivity, diastereoselectivity, and enantio-
selectivity. Results from cyclopropanation, carbon-hydrogen insertion, and oxonium ylide generation
are compared from reactions of achiral and chiral catalysts of copper(I) and dirhodium(II)
carboxylates and carboxamidates. Relative to results from intermolecular reactions of ethyl
diazoacetate with allyl ethyl ether, intermolecular reactions show a diversity of selectivities including
preference for the opposite configurational arrangement from the one preferred in corresponding
intermolecular cyclopropanation reactions. Enantioselectivities for cyclopropanation are dependent
on the catalyst ligands in a manner that reflects divergent trajectories of the carbon-carbon double
bond to the reacting carbene center. Enantioselectivity increases as a function of ring size with
chiral copper catalysts, but the reverse occurs with chiral dirhodium(II) carboxamidates. Mechanistic
implications, including those related to the conformation of the reacting metal carbene, offer a
new dimension to understanding of enantioselectivity in catalytic asymmetric cyclopropanation
reactions.
In recent years, we have reported the unprecedented
effectiveness of intramolecular cyclopropanation reac-
tions of diazo esters as an effective entry into macrocyclic
lactones.1,2 These reactions appear to have broad general-
ity and to occur with moderate to high levels of enantio-
control when selected chiral catalysts are employed.3
What is missing is an understanding of the influence of
ring size on selectivity as a function of catalyst.4,5 Can
one generalize the influence of specific catalysts or see
trends? For example, is there a trend toward selectivities
obtained in intermolecular reactions from intramolecular
cyclopropanation as ring size is increased, and can
mechanistic information be obtained from these selectivi-
ties?
We have investigated catalytic reactions of diazoac-
etates tethered through zero, one, two, and three ethylene
glycol units to an allyl group (1), and we compare these
results with those from intermolecular reactions of ethyl
diazoacetate with allyl ethyl ether. Both copper(I) and
dirhodium(II) catalysts have been employed, including
the highly reactive dirhodium(II) carboxamidate derived
from isobutyl 3,3-difluoro-2-oxaazetidine-(4R)-carboxylate
(2). We now report the chemoselectivity, diastereoselec-
tivity, and enantioselectivity of these reactions and
describe the generalities that can be drawn from the data.
Resu lts
That dirhodium(II) acetate-catalyzed reactions of ethyl
diazoacetate with allyl ethyl ether yields cyclopropane
products (3) predominantly together with a low yield of
the product from oxonium ylide generation followed by
[2,3]-sigmatropic rearrangement (4) has been previously
established.6 Data from this same reaction (eq 1) cata-
lyzed by chiral copper(I) and dirhodium(II) catalysts are
reported in Table 1. Note that cyclopropanation is
exclusive or virtually so with all of the dirhodium(II)
catalysts (5-9), but ylide formation is a competitive
process with copper(I) catalysts. The trans-disubstituted
cyclopropane product is favored with Cu(I) catalysts and
with dirhodium(II) carboxylates, but not carboxamidates.
The highest % ee value obtained for trans-3 came from
CuPF6/10, while 7 and 8 provided the highest % ee values
for cis-3. This latter observation is consistent with results
previously obtained with styrene and other monosubsti-
(1) Doyle, M. P.; Peterson, C. S.; Marnett, A. B.; Parker, D. L., J r.;
Ene, D. G.; Lynch, V. J . Am. Chem. Soc. 1997, 119, 8826.
(2) Doyle, M. P.; Peterson, C. S.; Parker, D. L., J r. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 1334.
(3) 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.
(4) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds: From Cyclopropanes
to Ylides; Wiley: New York, 1998.
(6) . (a) Doyle, M. P.; Griffin, J . H.; Chinn, M. S.; van Leusen, D. J .
Org. Chem. 1984, 49, 1917. (b) Doyle, M. P.; Bagheri, V.; Harn, N. K.
Tetrahedron Lett: 1988, 29, 5863.
(5) Doyle, M. P.; Forbes, D. C. Chem. Rev. 1998, 98, 911.
10.1021/jo005589z CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/29/2000

8840 J . Org. Chem., Vol. 65, No. 26, 2000
Doyle and Hu
Ta ble 1. Ch em oselectivity, Dia ster eoselectivity, a n d
En a n tioselectivity fr om Ca ta lytic Rea ca tion s of Eth yl
Dia zoa ceta te w ith Allyl Eth yl Eth er a
Ta ble 2. En a n tioselectivity fr om Ca ta lytic Rea ction s of
11a
11
% eed
yield,b
%
trans-3/
catalyst
CuPF6/10
Rh2(4S-IBAZ)4 (7)
Rh2(5S-MEPY)4 (8)
Rh2(4S-MEOX)4 (9)
yield,b %
% eec
catalyst
Rh2(OAc)4
Cu(MeCN)4PF6
CuPF6/10
Rh2(S-TBPRO)4 (5)
Rh2(4R-dFIBAZ)4
(ent-6)
3:4c
cis-3c trans-3 cis-3
4
61
92
75
95
20 (1R,5S)
80 (1R,5S)
95 (1R,5S)
94 (1R,5S)
74
87
61
50
34
95:5
62:38 70:30
73:27 81:19
100:0
97:3
62:38
75
4
43 60
5
84:16
52:48
a
Reactions performed by addition of 11 in CH2Cl2 to a refluxing
38
19 30
CH2Cl2 solution of catalyst (<1.0 mol %). b Isolated yield of 11 after
chromatographic separation from the catalyst and carbene dimers.
c Absolute configuration given in parentheses.
Rh2(4S-IBAZ)4 (7)
Rh2(5S-MEPY)4 (8)
Rh2(4R-MEOX)4 (9)
63
64
53
100:0
100:0
100:0
43:57
56:44
58:42
48
37
7
67
70
48
absolute configuration, we suggest that the dominant
enantiomer of trans-3 formed with Cu(I)/10, 5, and ent-6
has the (1R,2R)-configuration, while catalysts 7-9 pro-
duce trans-3 having the (1S,2S)-configuration predomi-
nantly. Similarly, for the cis isomer (1R,2S)-3 is favored
with Cu(I)/10, 5, and ent-6, but (1S,2R)-3 is favored with
7-9.
a
Reactions performed by addition of EDA in CH2Cl2 to a
refluxing CH2Cl2 solution containing allyl ethyl ether (10 equiv)
b
and catalyst (1.0 mol %). Isolated yield of 3 + 4 after chromato-
graphic separation. c Determined by GC on an SPB-5 column.
d
Determined by GC on a Chiraldex B-DM column.
Contrast these results with those from catalytic reac-
tions of allyl diazoacetate (eq 2)13-15 from which 12 is
formed as the sole product with enantiocontrol that is
exceptionally high (95% ee) with Rh2(MEPY)4 catalysts
and disappointingly low with CuPF6/10 (Table 2).14 The
absolute configuration of 12 formed in each of these
catalytic reactions has been established,13 and in this case
all of the catalysts in Table 2 give rise to (1R,5S)-12. The
effects of alkene substituents on enantiocontrol have been
determined, and they have formed the bases for current
mechanistic understanding of this intramolecular addi-
tion reaction.13 Note that the absolute configuration of
12 formed by all of dirhodium(II) carboxamidates listed
in Table 2 is opposite to that found in the intermolecular
cyclopropanation reaction (eq 1).
Consider now the case with the allyl group separated
from diazoacetate by one ethylene glycol unit. In catalytic
reactions cyclopropanation would form the disfavored
eight-membered ring; however, there are few examples
of medium ring formation in all of the catalytic cyclopro-
panation literature.4,15-18 A favorable competing trans-
formation is intramolecular carbon-hydrogen insertion
into the ether-oxygen-activated position (five-membered
ring formation),4,19,20 as also might be intramolecular
tuted alkenes.12 The predominant enantiomer for either
trans-3 or cis-3, as well as for ylide product 4, formed
via catalysis with Cu(I)/10, 5, or ent-6 is opposite of that
formed via catalysis with 7-9.
The absolute configurations of products formed by
asymmetric catalytic intermolecular cyclopropanation
have been established in many cases,4,5 although not from
reactions with allyl ethyl ether. With styrene and ethyl
diazoacetate, for example, the predominant enantiomers
formed with Cu(I)/10 as the catalyst are (1R,2R) for the
trans isomer and (1R,2S) for the cis isomer.4 The opposite
preference is obtained with Rh2(5S-MEPY)4,4,12 and S-
configured dirhodium(II) carboxamidates in the sense of
7-9 direct product formation to those having the same
absolute configuration. On the basis of these consider-
ations and the similarity of 3 to products of known
(7) (a) Kennedy, M.; McKervey, M. A.; Maguire, A. R.; Roos, G. H.
P. J . Chem. Soc., Chem. Commun. 1990, 361. (b) Davies, H. M. L.;
Bruzinski, P. R.; Lake, D. H.; Kong, N.; Fall, M. J . J . Am. Chem. Soc.
1996, 118, 6897.
(8) Doyle, M. P.; Zhou, Q.-L.; Simonsen, S. H.; Lynch, V. Synlett
1996, 697.
(13) 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.
(9) Doyle, M. P.; Winchester, W. R.; Hoorn, J . A. A.; Lynch, V.;
Simonsen, S. H.; Ghosh, R. J . Am. Chem. Soc. 1993, 115, 9968.
(10) Doyle, M. P.; Dyatkin, A. B.; Protopopova, M. N.; Yang, C. I.;
Miertschin, C. S.; Winchester, W. R.; Simonsen, S. H.; Lynch, V.;
Ghosh, R. Recl. Trav. Chem. Pays-Bas 1995, 114, 163.
(11) Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul, M. M. J .
Am. Chem. Soc. 1991, 113, 726.
(12) Mu¨ller, P.; Baud, C.; Ene, D.; Motallebi, S.; Doyle, M. P.;
Brandes, B. D.; Dyatkin, A. B.; See, M. M. Helv. Chim. Acta 1995, 78,
459.
(14) Doyle, M. P.; Peterson, C. S.; Zhou, Q.-L.; Nishiyama, H. J .
Chem. Soc., Chem. Commun. 1997, 211.
(15) Doyle, M. P.; Protopopova, M. N. Tetrahedron 1998, 54, 7919.
(16) Burke, S. D.; Grieco, P. A. Org. React. (N. Y.) 1979, 26, 361.
(17) Nefedov, O. M.; Shapiro, E. A.; Dyatkin, A. B. In Supplement
B: The Chemistry of Acid Derivatives; Patai, S., Ed.; Wiley: New York,
1992; Chapter 25.
(18) (a) Padwa, A.; Krumpe, K. E. Tetrahedron 1992, 48, 5385. (b)
Padwa, A.; Austin, D. J . Angew. Chem., Int. Ed. Engl. 1994, 33, 1797.
(19) Adams, J .; Spero, D. M. Tetrahedron 1991, 47, 1765.

Selectivity in Reactions of Allyl Diazoacetates
J . Org. Chem., Vol. 65, No. 26, 2000 8841
Ta ble 3. Ch em oselectivity a n d En a n tioselectivity fr om
Ca ta lytic Rea ction s of 13a
Sch em e 1
% ee
yield,b 14-16/
catalyst
Rh2(OAc)4
%
dimerc 14:15:16c 14d 15e 16d
93
87
61
61
50
34
91:9
77:17:6
26:0:74
14:30:56 67 22
7:12:81 71 27
88:5:7
Cu(MeCN)4PF6
CuPF6/10
34:66
12:88
74:26
96:4
6
8
CuPF6/10e
Rh2(S-TBPRO)4 (5)
Rh2(4R-dFIBAZ)4
(ent-6)
28 19 18
42:58
29:32:39 19 62 88
Ta ble 4. Ch em oselectivity, Dia ster eoselectivity, a n d
En a n tioselectivity fr om Ca ta lytic Rea ction s of 17a
Rh2(4S-IBAZ)4 (7)
Rh2(5S-MEPY)4 (8)
Rh2(4R-MEOX)4 (9)
63
64
78
81:19
98:2
99:1
5:95:0
0:100:0
0:98:2
49 91
91
% eed
yield,b
%
96 94
catalyst
Rh2(OAc)4
Cu(MeCN)4PF6
CuPF6/10
Rh2(S-TBPRO)4 (5)
Rh2(4R-dFIBAZ)4
(ent-6)
18:19c Z-18:E-18c Z-18 E-18 19
a
Reactions performed by addition of 13 in CH2Cl2 to a refluxing
b
CH2Cl2 solution of catalyst (1.0 mol %). Isolated yield of 14-16
83
64
58
80
67
96:4
100:0
100:0
98:2
87:13
91:9
86:14
87:13
84:16
+ dimer after chromatography. c Determined by GC on a SPB-5
d
column. Determined by GC on
a Chiraldex B-DM column.
79
11
33
85
12 14
67 75
e Determined by GC on a Chiraldex G--TA column. e Catalyst was
diluted 20X-greater than in other reported runs.
85:15
oxonium ylide formation followed by [2,3]-sigmatropic
rearrangement (six-membered ring formation).21 In fact,
the products from each of these intramolecular trans-
formationsscyclopropanation, C-H insertion, and oxo-
nium ylide formation/[2,3]-sigmatropic rearrangements
are observed (eq 3). Results from this investigation as a
Rh2(4S-IBAZ)4 (7)
Rh2(5S-MEPY)4 (8)
Rh2(4R-MEOX)4 (9)
69
77
73
42:58
5:95
1:99
88:12
88:12
88:12
56
53
48
64 90
65 92
67 92
a
Reactions performed by addition of 17 in CH2Cl2 to a refluxing
b
CH2Cl2 solution of catalyst (1.0 mol %). Isolated yield of 18 + 19
after chromatography. c Determined by GC on a SPB-5 column.
d
Determined by GC on a Chiraldex B-TA column.
dirhodium(II) carboxylates. Dirhodium(II) carboxami-
dates favored C-H insertion, and 15 was formed with
the high enantiocontrol anticipated from earlier studies.23
The major enantiomer of C-H insertion product 15
formed with catalysts 7-9 is assigned (4S)sthe same as
that reported previously from reactions of a wide variety
of diazo substrates.4,5,23,24 In contrast, with copper(I)
catalysts oxonium ylide formation leading to 16 was
dominant. The high enantiocontrol for 16 that was
observed with dirhodium(II) carboxamidate catalysts
ent-6 and 9 reflected results from previously reported
systems,25 and signaled once again the importance of
metal-associated ylides as reaction intermediates,25-27 as
well as the role of ligands on the metal for a high level of
asymmetric induction in the product-forming step.
The outcome of these intramolecular reactions changes
once again when the allyl group is separated from
diazoacetate by two ethylene glycol units. In this case
intramolecular cyclopropanation would form an eleven-
membered ring (18), whereas oxonium ylide formation
that could lead to product via [2,3]-sigmatropic rear-
rangement would require the intervention of a nine-
membered ring (20). The results from diazo decomposi-
tion of 17 (eq 4) reflect these considerations (Table 4).
With this system, copper(I) catalysts and dirhodium(II)
carboxylates form macrocyclic lactone 18 almost exclu-
sively whereas dirhodium(II) carboxamidates Rh2(5R-
MEPY)4 and Rh2(4S-MEOX)4 give the product from
intramolecular C-H insertion (19) almost exclusively.
function of catalyst are reported in Table 3. The pre-
dominant enantiomer of 14 formed with CuPF6/10 and
with 5 and ent-6 is opposite to that formed with 7-9. By
analogy with the preferred configuration of 12 and
through rotational (same sign) and chromatographic
(same order of elution) correlations, the dominant enan-
tiomer of 14 formed by catalysis with 7 is assigned
(1R,8S); that from catalysis with CuPF6/10, 5, and ent-6
is assigned (1S,8R). The dimer that is reported in eq 1
and Table 3 is that of “carbene dimer” formation, an
intermolecular reaction product that serves as a kinetic
monitor of the ease or difficulty of intramolecular reac-
tions. Since reaction conditions for each catalyzed diazo
decomposition were identical, the extent of dimer forma-
tion is a direct measure of the sum of the relative rates
for intramolecular reactions (Scheme 1). Accordingly, use
of the more reactive catalysts22sthose of copper(I) and
of ent-6sresulted in the formation of carbene dimers as
the predominant reaction process. Note that, consistent
with Scheme 1, a 20-fold dilution of the catalyst solution
with CuPF6/10 caused a more than 3-fold decrease in the
amount of carbene dimer.
(23) (a) Doyle, M. P.; Kalinin, A. V.; Ene, D. G. J . Am. Chem. Soc.
1996, 118, 8837. (b) Bode, J . W.; Doyle, M. P.; Protopopova, M. N.;
Zhou, Q.-L. J . Org. Chem. 1996, 61, 9146.
(24) Doyle, M. P.; Tedrow, J . S.; Dyatkin, A. B.; Spaans, C. J .; Ene,
D. G. J . Org. Chem. 1999, 64, 8907.
(25) Doyle, M. P.; Forbes, D. C.; Vasbinder, M. M.; Peterson, C. S.
J . Am. Chem. Soc. 1998, 120, 7653.
(26) McCarthy, N.; McKervey, M. A.; Ye, T.; McCann, M.; Murphy,
E.; Doyle, M. P. Tetrahedron Lett. 1992, 33, 5983. (b) Pierson, N.;
Fernandez-Garcia, C.; McKervey, M. A. Tetrahedron Lett. 1997, 38,
4705.
Because of the strain imparted into the ring upon its
formation, 14 was a major product only with the use of
(20) Doyle, M. P.; van Oeveren, A.; Westrum, L. J .; Protopopova,
M. N.; Clayton, T. W., J r. J . Am. Chem. Soc. 1991, 113, 8982.
(21) Padwa, A.; Hornbuckle, S. F. Chem. Rev. 1991, 91, 263.
(22) Doyle, M. P.; Davies, S. B.; Hu, W. Org. Lett. 2000, 2, 1145.
(27) Kitagaki, S.; Anada, M.; Kataoka, O.; Matsuno, K.; Umeda, C.;
Watanabe, N.; Hashimoto, S. J . Am. Chem. Soc. 1999, 121, 1417.

8842 J . Org. Chem., Vol. 65, No. 26, 2000
Doyle and Hu
Ta ble 5. Ch em oselectivity, Dia ster eoselectivity, a n d
En a n tioselectivity fr om Ca ta lytic Rea ction s of 21a
% eed
yield,b
%
Z-22:
catalyst
Rh2(OAc)4
Cu(MeCN)4PF6
Cu(PhCOCHCOCH3)2
CuPF6/10
22:23:24c E-22c Z-22 E-22 24
65
65
82
73
56
97:3:0
86:0:14 56:44
90:0:10 47:53
83:13:4 40:60 88
83:13:0 65:35 37
64:36
80 27
26
Rh2(4R-dFIBAZ)4
(ent-6)
Rh2(4S-IBAZ)4 (7)
Rh2(5S-MEPY)4 (8)
Rh2(4R-MEOX)4 (9)
70
61
67
53:47:0 65:35 59
13:87:0 63:37 49
7:93:0 64:36 47
44
44
33
The azetidinone-ligated dirhodium(II) catalysts, whose
reactivities fall between those of the carboxylates and
carboxamidates 8 and 9 yield both 18 and 19. Here again,
the dominant enantiomer of Z-18 formed by catalysis
with dirhodium(II) carboxamidates 7-9 is assigned the
(1R,11S) configuration; catalysis by CuPF6/10, 5, and
ent-6 gave the enantiomer of opposite configuration
predominantly. Both the cis and trans fused rings of 18
were observed in this case, but their ratio was invariant
with the catalyst. Although absolute configuration is not
assigned for E-18, we can report that the dominant
enantiomer formed by catalysis with 7-9 is opposite to
that formed by catalysis with CuPF6/10, 5, and ent-6.
Enantioselectivities for intramolecular cyclopropanation
by the dirhodium(II) carboxamidates varied from catalyst
to catalyst by only a small degree, and they were
moderately less than those from CuPF6/10. The predomi-
nant enantiomer in CuPF6/10-catalyzed reactions was
opposite to that found from reactions catalyzed by chiral
dirhodium(II) carboxamidates. Ylide-derived 20 was not
detected except perhaps as a minor constituent in CuPF6-
catalyzed reactions.
a
Reactions performed by addition of 21 in CH2Cl2 to a refluxing
b
CH2Cl2 solution of catalyst (1.0 mol %). Isolated yield of 22-24
after chromatography. c Determined by GC on a SPB-5 column.
d
Determined by GC on a Chiraldex B-PH column.
F igu r e 1. Ring size versus % ee for reactions of 11, 27, 13,
28, 17, and 21 with catalysts CuPF6/10 (2) and Rh2(4S-IBAZ)4
(7) (9).
Finally, with three interlinked ethylene glycol spacers
between allyl and diazoacetate, the three intramolecular
processes that we have been reportingscyclopropanation,
C-H insertion, and oxonium ylide generation/[2,3]-sig-
matropic rearrangementswere all observed (eq 5). The
molecular reaction (eq 1) as a function of catalyst.
Enantiomers of C-H insertion product 23 could not be
separated, but selectivity could be assumed to be ap-
proximately that found for 19 (Table 4).
Discu ssion
A plot of % ee versus ring size (Figure 1) for cyclopro-
panation (Z-only) reveals a pattern that reflects the
geometrical differences between Cu(I)/10 (trans array, 25)
and dirhodium(II) carboxamates (cis array, 26) and their
influences on olefin trajectories to the carbene center.3
results from diazo decomposition of 21 with copper(I) and
dirhodium(II) catalysts are reported in Table 5. Here
again, macrocyclic cyclopropanation dominates with Rh2-
(OAc)4 and with copper catalysts, and intramolecular
C-H insertion leading to γ-lactone 23 is preferred with
the less reactive dirhodium(II) carboxamidates, Rh2(5S-
MEPY)4 and Rh2(4R-MEOX)4. Ylide formation is a minor
process with copper catalysts but is not observed with
dirhodium(II) catalysts. Enantioselectivity and enanti-
omer preferences in cyclopropanation with 21 match
those found with 17 and with 14, and preference for the
(1R,nS)- or (1S,nR)-configuration of these cyclopropana-
tion products is opposite to that found in the inter-
Notice that as ring size increases, % ee for the Z-isomer
decreases with chiral dirhodium(II) catalysts 7-9, whereas
% ee increases significantly through the formation of 14
and 18 to 22 for chiral CuPF6/10. Confirmation of these
trends can be seen in results from intramolecular cyclo-
propanation of homoallylic diazoacetate 2713 and of allylic
diazoacetate 28,3 the results for which are also found in
Figure 1.

Selectivity in Reactions of Allyl Diazoacetates
J . Org. Chem., Vol. 65, No. 26, 2000 8843
Sch em e 2
Furthermore, in a series of benzenedimethanol-linked
methallyl diazoacetates, % ee for the Z-isomer was found
to increase with increasing ring size for chiral dirhodium-
(II) carboxamidates but remain virtually unchanged with
chiral CuPF6/10. These quite different results reflect
divergent trajectories of the carbon-carbon double bond
toward the carbene center for copper(I) and rhodium(II)
catalysts.
In the formation of the cyclopropane E-isomers, % ee
values for E-18 and E-22 appear to be moving toward
limiting values from the intermolecular cyclopropanation
product trans-3. The same cannot be said for Z-isomers
from 18 and 22 which do not appear to be moving toward
limiting values of cis-3. However, diastereoselectivities
from intramolecular cyclopropanation reactions do ap-
proach those from intermolecular cyclopropanation as
ring size is increased.
Sch em e 3
As seen by the results from intermolecular cyclopro-
panation of allyl ethyl ether (Table 1), copper catalysts
and rhodium(II) carboxylates show a marked preference
for the trans-cyclopropane isomer whereas rhodium(II)
carboxamidates are more amenable to the formation of
the thermodynamically less stable cis-cyclopropane iso-
mer. However, where ring strain is not appreciable, the
cis-cyclopropane isomer is preferred in intramolecular
cyclopropanation for all catalysts to a ring size of
fourteen. There is a dramatic difference in % ee values
between trans (E) and cis (Z) cyclopropane isomers
formed by intermolecular cyclopropanation (Table 1) but
not by intramolecular cyclopropanation (Tables 4 and 5).
When the cis-cyclopropane isomer is formed in in-
tramolecular cyclopropanation reactions, enantiocontrol
can be represented as being dependent upon trajectories
29 and 30 (Scheme 2, L ) linker), previously described
with reference to the limiting conformations available for
product formation,3,14 as well as the mirror image rep-
resentations of 29 and 30. Trajectories 29 and 30 are the
configurations preferred for the S-configured dirhodium-
(II) carboxamidates.9 Results obtained for intramolecular
cyclopropanation with dirhodium(II) carboxamidates in
this study, and in prior investigations of the influence of
alkene substituents on enantiocontrol,13,14 are consistent
with reactions occurring through trajectory 29 and its
mirror image, and influences from 30 are consistent with
the dominant stereochemistry for Cu(I)/10-catalyzed
reactions.
cated as a preferred energy minimum through compu-
tational analyses.9 In this depiction, looking down the
carbon-rhodium bond, the direction of the ligand car-
boxylate esters (E), is counterclockwise, but the motion
of the alkene to the carbene center is clockwise.
These trajectories are based on the alignment of the
carbene carbonyl oxygen anti to the transition metal. Syn
alignments are also possible and, as depicted in Scheme
3, can be used with the same mode of clockwise or
counterclockwise rotation to designate the observed
products. Application of these conformations actually
leads to the prediction of preference for the correct
enantiomer in intramolecular cyclopropanation reactions,
but because the alkene is placed even farther from the
influence of the metal (32A) than in 29A, and as a result
of the preference for the carbonyl syn to the metal
through computational analysis,9 we prefer to use 29 and
30.
The rotational preference of the alkene about the
carbene center is clockwise in 29 and 30, an example for
which is depicted in 29A for the reactions that occur on
an S-configured dirhodium(II) carboxamidate (E ) ester).
When the trans-cyclopropane isomer is formed, enan-
tiocontrol can be considered to be a function of trajectories
33-36 (Scheme 4, L ) linker).3 Although the absolute
stereochemistries of E-18 and E-22 have not been deter-
mined, results from intermolecular cyclopropanation,
which suggest that Cu(I)/10 yields (1R,2R)-3 and that
chiral rhodium(II) carboxamidates 7-9 produce 3 in the
The conformation identified here was previously indi-

8844 J . Org. Chem., Vol. 65, No. 26, 2000
Doyle and Hu
Sch em e 4
Sch em e 6
away from the metal and from OR. Notice that increasing
the size of LnM favors 37 over 38 and should lead to
increased cis-selectivity, and this is what has been
observed.29 Increasing the size of R should lead to a
modest increase in trans-selectivity, and this is also what
has been observed.4,15
The alternative alignment is that depicted in Scheme
6 for reactions catalyzed by Cu(I)/10. Here the alkene
substituent lies close to or far away from R, so that
increasing the size of R should have a dramatic influence
on the diastereomer ratio. As predicted, increasing the
size of R increases trans-selectivity directly and substan-
tially.11
This mechanistic treatment provides a new level of
understanding for considerations of enantiocontrol in
cyclopropanation reactions. First of all, that dirhodium-
(II) carboxamidates 7-9 react primarily through 29, and
that Cu(I)/10 operates primarily through 30, in intra-
molecular cyclopropanation reactions offers a predictive
interpretation of the outcome of a vast array of intra-
molecular reactions already reported as well as those not
yet performed. That the preference for 30 is not solely a
function of C2-symmetric ligands such as 10 can be seen
in that (pybox)RuCl2(ethene) (41) appears to operate via
29,30 and with such a late transition state that methallyl
diazoacetate does not undergo intramolecular cyclopro-
panation.14 Furthermore, the design of Rh2(4S-MPPIM)4
(42) as a catalyst makes possible mechanistic preference
for 30 in reactions with 2-substituted allyl diazoacetates31
not possible with 7-9.
Sch em e 5
predominant (1S,2S)-configuration,4,12,28 implicate either
33 and 34 or 35 and 36. If the anti-alignment of metal
and carbonyl is preferred for the intermolecular reaction,
then chiral dirhodium(II) carboxamidate catalysts prefer
33 and Cu(I)/10, 5, and ent-6 prefer 34. The positioning
of the carbon-carbon double bond on a specific trajectory
to the metal carbene center is obviously a function of the
chiral ligands on the metal and conformational prefer-
ences in the reacting substrate.
Why then does intermolecular cyclopropanation give
configurational preference that is opposite to that from
intramolecular cyclopropanation? The answer, we believe,
lies in the trajectories of the alkene with respect to the
carbene. Consider first the alignment depicted in Scheme
5 for reactions catalyzed by chiral dirhodium carboxa-
midates 7-9. Here the alkene substituent is oriented
A second consideration made possible by this mecha-
nistic treatment is the recognition that the preferred
configuration for the cis(Z)-isomer formed by intermo-
lecular cyclopropanation may be opposite of that formed
by intramolecular cyclopropanation. This is, in fact, the
case for Cu(I)/10, 5, ent-6, and 7-9, and this observation
explains why, in the limit as ring size increases, enan-
tiomeric excess for the cis(Z)-isomer does not approach
(29) Doyle, M. P.; Davies, S. B.; Hu, W. J . Chem. Soc., Chem.
Commun. 2000, 867.
(30) Nishiyama, H.; Itoh, Y.; Sugaware, Y.; Matsumoto, H.; Aoki,
K.; Itoh, K. Bull. Chem. Soc. J pn. 1995, 68, 1247.
(31) Doyle, M. P.; Zhou, Q.-L.; Dyatkin, A. B.; Ruppar, D. A.
Tetrahedron Lett. 1995, 36, 7579.
(28) Doyle, M. P.; Brandes, B. D.; Kazala, A. P.; Pieters, R. J .;
J arstfer, M. B.; Watkins, L. M.; Eagle, C. T. Tetrahedron Lett. 1990,
31, 6613.

Selectivity in Reactions of Allyl Diazoacetates
J . Org. Chem., Vol. 65, No. 26, 2000 8845
(comp, 2H); 13C NMR (CDCl3, 125 MHz) δ 172.4, 68.2, 65.9,
60.3, 20.8, 17.5, 15.2, 14.2, 11.7; GC on a 30-m SPB-5 column:
tR 8.22 min (flow rate: 1 mL/min, oven temp: 100 °C for 2
min then 10 °C/min to 275 °C), GC on a 30-m Chiraldex B-DM
column: tR 51.7 and 54.1 min (flow rate: 1 mL/min, oven
temp: 70 °C for 30 min then 0.5 °C/min to 80 °C). 3E: 1H
NMR (CDCl3, 500 MHz) δ 4.18-4.08 (comp, 2H), 3.49 (q, J )
7.0 Hz, 2H), 3.37 (dd, J ) 10.4, 7.1 Hz, 1H), 3.34 (dd, J ) 10.4,
6.5 Hz, 1H), 1.72 (ddddd, J ) 8.3, 7.1, 6.5, 4.8, 4.0 Hz, 1H),
1.53 (ddd, J ) 8.8, 6.3, 4.0 Hz, 1H), 1.26 (t, J ) 7.1 Hz, 3 H),
1.20 (t, J ) 7.1 Hz, 3 H), 1.19 (ddd, J ) 8.8, 4.8, 4.3 Hz, 1H),
0.85 (ddd, J ) 8.3, 6.3, 4.3 Hz, 1H); 13C NMR (CDCl3, 125 MHz)
δ 173.7, 72.0, 66.0, 60.4, 21.6, 18.5, 15.1, 14.1, 12.9; GC on a
30-m SPB-5 column: tR 8.57 min (flow rate: 1 mL/min, oven
temp: 100 °C for 2 min then 10 °C/min to 275 °C), GC on a
30-m Chiraldex B-DM column: tR 57.9 and 59.5 min (flow
rate: 1 mL/min, oven temp: 70 °C for 30 min then 0.5 °C/min
to 80 °C). 4: 1H NMR (CDCl3, 300 MHz) δ 5.83 (ddt, J ) 13.9,
10.3, 7.1 Hz, 1H), 5.12 (dd, J ) 17.9, 1.7 Hz, 1H), 5.07 (dd, J
) 10.5, 1.7 Hz, 1H), 4.25-4.18 (comp, 2H), 3.89 (t, J ) 6.6
Hz, 1H), 3.64 (dt, J ) 9.3, 7.1 Hz, 1H), 3.44 (dt, J ) 9.3, 7.1
Hz, 1H), 2.48 (dd, J ) 7.1, 6.6 Hz, 2H), 1.29 (t, J ) 7.1 Hz,
3H), 1.23 (t, J ) 7.1 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ
172.3, 133.5, 117.7, 78.5, 65.9, 60.7, 37.3, 15.0, 14.2; MS (EI):
that of cis-3. However, with use of 41 cyclopropane
products having the same absolute configuration are
obtained whether intermolecular or (from a limited data
set) intramolecular cyclopropanation occurs.30
Last, consideration of the trajectories of Schemes 5 and
6 begins to suggest the trans(E)-preference from the vast
array of copper(I) cyclopropanation catalysts,4,5,15 espe-
cially from 40, and the cis(Z)-preference of dirhodium-
(II) carboxamidates29 (from 37 where the substituent of
the alkene (A) is located away from the ligated metal;
compare with 38). However, the determination of whether
absolute configuration is maintained in the trans(E)-
substituted cyclopropane series from catalytic inter-
molecular to intramolecular cyclopropanation awaits
discovery, as does the question of whether the carbonyl
group of the intermediate carbene lies syn or anti to the
ligated metal. So also will be the determination of
configurational preference in intramolecular cyclopropa-
nation reactions from the recently reported metal-salen
catalysts.32
m/z 173 (M + 1); IR (CDCl3) 1742 (CdO), 1645 (CdC) cm-1
;
Exp er im en ta l Section
GC on a 30-m SPB-5 column: tR 6.35 min (flow rate: 1 mL/
min, oven temp: 100 °C for 2 min then 10 °C/min to 275 °C),
GC on a 30-m Chiraldex B-DM column: tR 21.5 and 23.4 min
(flow rate: 1 mL/min, oven temp: 70 °C for 30 min then 0.5
°C/min to 80 °C). For cyclopropanes 3E and 3Z the major
enantiomers eluted second from Chiraldex B-DM columns for
catalysis by 7-9 and first for catalysis Cu(I)/10, 5, and ent-6.
For 4 the major enantiomer eluted second with Cu(I)/10 and
ent-6. The racemates of 3 and 4 have been reported.37
Gen er a l Meth od s. 1H NMR (250, 300 or 500 MHz) and
13C NMR (62.5, 75 or 125 MHz) spectra were obtained from
solutions in CDCl3, and chemical shifts are reported in parts
per million (ppm, δ) downfield from the internal standard, Me4-
Si (TMS). Mass spectra were obtained using electron ionization
on a quadrupole instrument. Infrared spectra were recorded
as indicated, either as a thin film on sodium chloride plates
or as solutions; absorptions are reported in wavenumbers
(cm-1). Anhydrous THF was distilled over sodium/benzophe-
none ketyl, and dichloromethane was distilled over calcium
hydride. Methanesulfonyl azide was prepared by reaction of
methanesulfonyl chloride with sodium azide and was not
2-Allyloxyeth yl Dia zoa ceta te (13) was prepared by the
same procedure as described for the preparation of diazo
compound 21 by using 2-allyloxyethanol as the starting
material (65% yield): 1H NMR (CDCl3, 250 MHz) δ 5.91 (ddt,
J ) 17.4, 10.5, 5.7 Hz, 1H), 5.28 (ddt, J ) 17.4, 1.8, 1.2 Hz,
1H), 5.19 (ddt, J ) 10.5, 10.3, 5.7 Hz, 1H), 4.81 (br s, 1H),
4.40-4.25 (comp, 2H), 4.03 (dt, J ) 5.7, 1.2 Hz, 2H), 3.72-
3.61 (comp, 2H); 13C (CDCl3, 62.5 MHz) δ (CdO not observed),
134.3, 117.3, 72.0, 67.8, 63.9; HRMS calcd for C7H11N2O3
171.0770, found 171.0773; IR (CDCl3) 2117 (CdN2), 1700
distilled.33 Cu(MeCN)4PF6 and Rh2(4S-IBAZ)4,8 Rh2(5S-
34
MEPY)4,9 Rh2(4R-MEOX)4 were prepared as previously
10
described. The preparation of 2 and Rh2(4R-dFIBAZ)4 is being
reported separately from this contribution.35 The preparation
of bis-oxazoline 10 followed the literature description.36
Gen er a l P r oced u r e for th e Rea ction of Eth yl Dia zo-
a ceta te w ith Allyl Eth yl Eth er . A solution of ethyl diaz-
oacetate (0.165 g, 1.50 mmol) in 10 mL of CH2Cl2 was added
via a syringe pump (5.0 mL/h) over 2 h to a refluxing solution
of Cu(MeCN)4PF6 (5.6 mg, 0.015 mmol) and allyl ethyl ether
(1.29 g, 15.0 mmol) in 10 mL of CH2Cl2. After complete addition
the reaction mixture was stirred at reflux for an additional 1
h to ensure complete reaction. The reaction mixture was cooled
to room temperature, then passed through a short silica plug,
which was subsequently washed with CH2Cl2 (20 mL). The
solvent was removed under reduced pressure to produce 0.225
g of products (87% yield) consisting a mixture of 3 and 4. The
crude products were subjected to GC on a 30-m SPB-5 column
for the determination of the relative ratio of 3Z, 3E and 4.
Enantioselectivites of the products were determined by GC on
a 30-m Chiraldex B-DM column. Column chromatography on
silica gel (hexanes/ethyl acetate ) 20:1) yielded 92 mg of Z/E
mixture 3 (37% yield) and 38 mg of 4 (15% yield). 3Z: 1H NMR
(CDCl3, 500 MHz) δ 4.18-4.08 (comp, 2H), 3.73 (dd, J ) 10.3,
6.0 Hz, 1H), 3.49 (q, J ) 7.0 Hz, 2H), 3.45 (dd, J ) 10.3, 9.6
Hz, 1H), 1.80 (ddd, J ) 8.6, 7.8, 5.8 Hz, 1H), 1.58 (comp, 1H),
1.27 (t, J ) 7.2 Hz, 3H), 1.17 (t, J ) 7.0 Hz, 3H), 1.11-1.05
(CdO) cm-1
.
Dia zo Decom p osition of 13. To a refluxing solution of Rh2-
(OAc)4 (1.8 mg, 0.0040 mmol) in CH2Cl2 (2.0 mL) was added
diazoacetate 13 (68.0 mg, 0.40 mmol) in 2 mL of CH2Cl2 over
2 h via a syringe pump. The reaction mixture was refluxed
for an additional half hour to complete the reaction. After
cooling to room temperature, the reaction mixture was filtered
through a short plug of silica gel, and the solvent was removed
under reduced pressure to provide 53 mg (93% yield) of crude
product as a colorless oil which contained 14-16 and dimer.
Relative yield of the crude product was determined by GC on
a 30-m SPB-5 column. The Rh2(S-TBPRO)4-catalyst catalyzed
reaction of 13 gave 54 mg crude product (95% crude yield),
from which 33 mg authentic cyclopropane product 14 was
isolated (58% yield) after column chromatography (hexanes/
ethyl acetate ) 10:1). Using the same procedure, the C-H
insertion product 15 (46 mg, 81% yield) was isolated from the
reaction catalyzed by Rh2(4R-MEOX)4, and the ylide product
16 (42 mg, 74% yield) was obtained from the CuPF6/10-
catalyzed reaction. 3,6-Dioxa b icyclo[6.1.0]n on a n -2-on e
(14): [R]26 ) -0.6 for 33% ee (c ) 1.0, CH2Cl2) from reaction
D
of 13 with Rh2(S-DOSP)4;38 1H NMR (CDCl3, 500 MHz) δ 5.02
(ddd, J ) 13.5, 8.6, 1.0 Hz, 1H), 4.39 (dd, J ) 13.2, 3.8 Hz,
1H), 4.21 (ddd, J ) 13.5, 4.2, 1.0 Hz, 1H), 4.03 (ddd, J ) 14.2,
(32) (a) Uchida, T.; Irie, R.; Katsuki, T. Tetrahedron 2000, 56, 3501.
(b) Niimi, T.; Uchida, T.; Irie, R.; Katsuki, T. Tetrahedron Lett. 2000,
41, 3647.
(33) Boyer, J . H.; Mack, C. H.; Goebel, W.; Morgan, L. R. J . Org.
Chem. 1959, 24, 1051.
(34) Kubas, G. J . Inorg. Synth. 1979, 19, 90.
(37) Ando, W.; Kondo, S.; Nakayama, K.; Yamato, H.; Nakaido, S.;
Migita, T. J . Org. Chem. 1971, 36, 1732.
(35) Doyle, M. P.; Hu, W.; Phillips, I. M.; Moody, C. J .; Pepper, A.
G. Adv. Synth. Cat. 2000, in press.
(36) Evans, D. A.; Peterson, G. S.; J ohnson, J . S.; Barnes, D. M.;
Campos, K. R.; Woerpel, K. A. J . Org. Chem. 1998, 63, 4541.
(38) Reaction gave results nearly identical with those reported in
Table 3 (14: 15: 16 ) 86:10:4) with 33% ee for 14, 26% ee for 15, and
18% ee for 16. For details of Rh2(S-DOSP)4 reactions see: Davies, H.
M. L. Eur. J . Chem. 1999, 7919.

8846 J . Org. Chem., Vol. 65, No. 26, 2000
Doyle and Hu
1
4.2, 1.0 Hz, 1H), 3.73 (ddd, J ) 14.2, 8.6, 1.0 Hz, 1H), 2.81
(dd, J ) 13.2, 10.0 Hz, 1H), 1.89 (td, J ) 8.7, 5.6 Hz, 1H), 1.67
(dtdd, J ) 10.0, 8.7, 5.6, 3.8 Hz, 1H), 1.14 (td, J ) 8.7, 5.6 Hz,
1H), 0.88 (td, J ) 5.8, 5.6 Hz, 1H); 13C NMR (CDCl3, 125 MHz)
δ (CdO not observed), 72.4, 71.3, 70.1, 20.2, 18.9, 8.3; HRMS
calcd for C7H13O3 143.0708, found 143.0702; IR (CDCl3) 1727
(CdO) cm-1; GC on a 30-m SPB-5 column: tR 10.03 min (flow
rate: 1 mL/min, oven temp: 100 °C for 2 min then 10 °C/min
to 275 °C); GC on a 30-m Chiraldex B-DM column: tR 74.3
and 76.9 min (flow rate: 1 mL/min, oven temp: 90 °C for 40
min then 1 °C/min to 140 °C). The predominant enantiomer
from reactions catalyzed by Cu(I)/10, 5, and ent-6 eluted first
on a Chiraldex G-TA column, opposite to that for 14 from the
reaction catalyzed by 7. 4-Allyloxyd ih yd r ofu r a n -2-on e
[R]28 ) +11.7 for 59% ee (c ) 1.3, CH2Cl2); H NMR (CDCl3,
D
500 MHz) δ 4.67 (ddd, J ) 10.0, 7.0, 2.5 Hz, 1H), 4.11 (dd, J
) 10.0, 5.0 Hz, 1H), 4.03 (ddd, J ) 8.0, 5.5, 2.5 Hz, 1H), 3.97
(ddd, J ) 8.0, 5.5, 2.5 Hz, 1H), 3.73-3.66 (comp, 2H), 3.58-
3.50 (comp, 2H), 3.38-3.29 (comp, 1H), 3.17 (t, J ) 10.0 Hz,
1H), 1.93 (ddd, J ) 9.0, 7.5, 6.0 Hz, 1H), 1.71-1.61 (comp,
1H), 1.20 (dt, J ) 6.0, 5.5 Hz, 1H), 1.04 (ddd, J ) 8.0, 7.5, 5.5
Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 172.2, 71.7, 70.8, 69.6,
69.5, 63.3, 20.7, 18.4, 10.8; GC/MS (EI): m/z 187 (M + 1) (19),
158 (6), 143 (9), 99 (100); GC on a 30-m SPB-5 column: tR 12.81
min (flow rate: 1.0 mL/min, oven temp: 100 °C for 2 min then
10 °C/min to 275 °C), GC on a 30-m Chiraldex B-TA column:
t
R 31.6 (major isomer with 7-9; minor isomer with CuC(I)/10,
5, and ent-6) and 32.4 min (flow rate: 1 mL/min, oven temp:
120 °C); E-18 from the reaction of 17 catalyzed by 5: 1H NMR
(CDCl3, 500 MHz) δ 5.02 (ddd, J ) 12.0, 10.5, 3.0 Hz, 1H),
4.41-4.30 (comp, 2H), 4.03 (dd, J ) 12.5, 4.0, 1H), 3.88 (ddd,
J ) 12.5, 3.5, 1.5 Hz 1H), 3.78-3.72 (comp, 2H), 3.56-3.50
(comp, 2H), 2.88 (dd, J ) 12.5, 11.0 Hz, 1H), 1.81 (ddd, J )
7.5, 5.5, 4.5 Hz, 1H), 1.64-1.50 (comp, 2H), 0.91 (ddd, J )
7.5, 6.0, 4.5 Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 172.2, 73.1,
72.6, 71.5, 68.2, 64.7, 27.0, 20.7, 12.4; GC/MS (EI): m/z 187
(M + 1) (3), 158 (5), 143 (20), 99 (100); GC on a 30-m SPB-5
column: tR 12.97 min (flow rate: 1 mL/min, oven temp: 100
°C for 2 min then 10 °C/min to 275 °C), GC on a 30-m
Chiraldex B-TA column: tR 38.9 (minor isomer with 7-9;
major isomer with Cu(I)/10, 5, and ent-6) and 42.0 min (flow
rate: 1.0 mL/min, oven temp: 120 °C). 4-(2-Allyloxy)eth oxy-
d ih yd r ofu r a n -2-on e (19): 1H NMR (CDCl3, 250 MHz) δ 5.93
(ddt, J ) 17.2, 11.7, 5.7 Hz, 1H), 5.28 (dq, J ) 17.2, 1.5 Hz,
1H), 5.20 (dq, J ) 11.7, 1.5 Hz, 1H), 4.41-4.35 (comp, 3H),
4.03 (dt, J ) 5.7, 1.5 Hz, 2H), 3.68-3.55 (comp, 4H), 2.69, 2.61
(AB system, J AB ) 14.8 Hz, 2H); 13C NMR (CDCl3, 62.5 MHz)
δ 175.5, 134.4, 117.3, 75.0, 73.2, 72.3, 69.4, 68.8, 35.0; IR (CH2-
Cl2) 1783 (CdO) cm-1; HRMS calcd for C9H15O4 187.0970,
found 187.0978; GC on a 30-m SPB-5 column: tR 13.8 min (flow
rate: 1 mL/min, oven temp: 100 °C for 2 min then 10 °C/min
to 275 °C), GC on a 30-m Chiraldex B-TA column: tR 40.5
(major isomer with Cu(I)/10, 5, and ent-6) and 44.0 min (flow
rate: 1.0 mL/min, oven temp: 150 °C).
(15): [R]26 ) +45.1 for 96% ee (c ) 2.0, CH2Cl2); 1H NMR
D
(CDCl3, 500 MHz) δ 5.89 (ddt, J ) 17.1, 10.4, 5.5 Hz, 1H), 5.31
(ddt, J ) 17.1, 1.5, 1.4 Hz, 1H), 5.23 (ddt, J ) 10.4, 1.5, 1.4
Hz, 1H), 4.39 (dd, J ) 10.2, 4.5 Hz, 1H), 4.37 (dd, J ) 10.2,
1.2 Hz, 1H), 4.35 (comp, 1H), 4.02 (ddt, J ) 12.7, 5.5, 1.4 Hz,
1H), 3.99 (ddt, J ) 12.7, 5.5, 1.4 Hz, 1H), 2.70 (dd, J ) 17.9,
6.2 Hz, 1H), 2.60 (dd, J ) 17.9, 2.4 Hz, 1H); 13C NMR (CDCl3,
125 MHz) δ 175.5, 133.6, 117.8, 73.8, 73.1, 69.9, 34.9; HRMS
calcd for C7H13O3 143.0708, found 143.0710; IR (CDCl3): 1782
(CdO) cm-1; GC on a 30-m SPB-5 column: tR 9.29 min (flow
rate: 1 mL/min, oven temp: 100 °C for 2 min then 10 °C/min
to 275 °C), GC on a 30-m Chiraldex G-TA column: tR 39.5 and
41.2 min (flow rate: 1 mL/min, oven temp: 100 °C). The
predominant enantiomer from reactions catalyzed by Cu(I)/
10, 5, and ent-6 eluted first on the Chiraldex G-TA column,
opposite to that for 15 from the reactions catalyzed by 7-9.
3-Allyl-(1,4)-d ioxa n -2-on e (16): 1H NMR (CDCl3, 500 MHz)
δ 5.87 (ddt, J ) 17.1, 10.1, 6.8 Hz, 1H), 5.21 (dq, J ) 17.1, 1.4
Hz, 1H), 5.16 (dq, J ) 10.1, 1.4 Hz, 1H), 4.54 (ddd, J ) 12.7,
10.1, 3.4 Hz, 1H), 4.42 (ddd, J ) 12.7, 3.4, 2.5 Hz, 1H), 4.39
(dd, J ) 8.5, 3.8 Hz, 1 H), 4.00 (ddd, J ) 12.7, 2.7, 2.5 Hz, 1
H), 3.85 (ddd, J ) 12.7, 10.1, 2.7 Hz, 1H), 2.72 (comp, 1H),
2.66 (comp, 1H); 13C NMR (CDCl3, 125 MHz) δ 168.5, 132.8,
118.7, 76.4, 68.8, 62.4, 36.5; MS (EI): m/z 143 (M+1, 100), 99
(6), 73 (31); IR (CDCl3): 1742 (CdO), 1647 (CdC) cm-1; GC
on a 30-m SPB-5 column: tR 8.32 min (flow rate: 1 mL/min,
oven temp: 100 °C for 2 min then 10 °C/min to 275 °C), GC
on a 30-m Chiraldex B-DM column: tR 47.9 and 52.8 min (flow
rate: 1 mL/min, oven temp: 90 °C for 40 min then 1 °C/min
to 140 °C). The predominant enantiomer from reactions
catalyzed by Cu(I)/10, 5, and ent-6 eluted first on a Chiraldex
G-TA column, opposite to that for 16 from the reaction
catalyzed by 9. Compound 16 underwent decomposition on
standing; TOCSY analysis was consistent with the assigned
structure.
2-(2-Allyloxyeth oxy)eth a n ol was prepared by the same
procedure described for the preparation of [2-(2-allyloxy-
ethoxy)ethoxy]ethanol except using diethylene glycol instead
of triethylene glycol as starting material (70% yield): 1H NMR
(CDCl3, 250 MHz) δ 5.93 (ddt, J ) 17.2, 11.7, 5.7 Hz, 1H), 5.28
(dq, J ) 17.2, 1.5 Hz, 1H), 5.20 (dq, J ) 11.7, 1.5 Hz, 1H),
4.03 (dt, J ) 5.7, 1.5 Hz, 2H), 3.80-3.58 (comp, 8H); 13C NMR
(CDCl3, 62.5 MHz) δ 134.4, 117.2, 72.5, 72.1, 70.3, 69.3, 61.6.
2-(2-Allyloxyeth oxy)eth yl d ia zoa ceta te (17) was pre-
pared according to the same procedure described for the
preparation of diazo compound 21 (57% yield). 1H NMR
(CDCl3, 250 MHz) δ 5.93 (ddt, J ) 17.2, 11.7, 5.7 Hz, 1H), 5.28
(dq, J ) 17.2, 1.5 Hz, 1H), 5.20 (dq, J ) 11.7, 1.5 Hz, 1H),
4.80 (s, 1H), 4.35-4.30 (comp, 2H), 4.03 (dt, J ) 5.7, 1.5 Hz,
2H), 3.76-3.69 (comp, 2H), 3.69-3.54 (comp, 4H); 13C NMR
(CDCl3, 62.5 MHz) δ (CdO not observed), 134.6, 117.1, 72.2,
70.6, 69.4, 69.3, 63.9; IR (CDCl3) 2123 (CdN2), 1697 (CdO),
1455 (CdC) cm-1; HRMS calcd for C9H15O4N2 215.1032, found
215.1036.
Cyclopropane isomer Z-18 was produced from the corre-
sponding cyclopropene product formed by intramolecular cy-
clopropenation of 2-(2-propargyloxyethoxy)ethyl diazoacetate
using Rh2(4S-IBAZ)4 as the catalyst. Catalytic reduction with
H2 over 10% Pd/C in ethyl acetate formed only Z-18 which
was analyzed to have 59% ee. Since a very similar cyclopro-
penation process was demonstrated to produce the (1R)-
enantiomer with S-configured dirhodium(II) carboxamidate
catalysts,39 we assign Z-18 formed with catalyst 7 to have the
(1R,11S)-configuration since the predominant cyclopropane
enantiomer formed by hydrogenation of the cyclopropene
product: [R]28 ) -131.3 (c ) 1.0, CH2Cl2), and by cyclopro-
panation with Rh2(4S-IBAZ)4 were the same.
D
2-[2-(2-Allyloxyeth oxy)eth oxy]eth a n ol. To an anhydrous
THF (500 mL) solution of potassium tert-butoxide (2.3 g, 19.5
mmol) was added triethylene glycol (4.9 mL, 37.0 mmol) at
room temperature. The resulting mixture was stirred for half
an hour, after which was added allyl iodide (1.8 mL, 19.7
mmol) in 60 mL of THF over 1 h. After being stirred at room
temperature for 24 h, the reaction mixture was filtered though
a Celite plug (20 g), and the solvent was evaporated. The
residue was subjected to column chromatography, eluting with
ethyl acetate to give the title compound as a colorless oil (3.2
g, 86% yield): 1H NMR (CDCl3, 250 MHz) δ 5.86 (ddt, J )
17.2, 10.3, 5.7 Hz, 1H), 5.21 (ddt, J ) 17.2, 1.8, 1.2 Hz, 1H),
5.13 (ddt, J ) 10.3, 10.3, 5.7 Hz, 1H), 3.97 (dt, J ) 5.7, 1.2 Hz,
2H), 3.67-3.52 (comp, 13 H); 13C NMR (CDCl3, 62.5 MHz) δ
134.5, 117.1, 72.4, 72.1, 70.5, 70.4, 70.2, 69.2, 61.6; MS (FAB+)
Dia zo d ecom p osition of 17 proceeded via the same
procedure described for diazo decomposition of 13. Rh2(OAc)4
catalyst gave a Z/E mixture of 18 in a 73% isolated yield after
column chromatography on silica gel (hexanes/ethyl acetate
) 4:1) and C-H insertion product 19 was obtained by Rh2-
(4R-MEOX)4 catalysis in 70% yield. Tr ioxa bicyclo[9.1.0]-
d od eca n -2-on e (18): IR (CDCl3) 1720 (CdO) cm-1; for Z-18:
m/z 191.1 (M + 1); IR (neat) 3434 (OH), 1645 (CdC) cm-1
2-[2-(2-Allyloxyeth oxy)eth oxy]eth yl Dia zoa ceta te (21).
.
A solution of 2-[2-(2-allyloxyethoxy)ethoxy]ethanol (2.5 g, 13
(39) Doyle, M. P.; Ene, D. G.; Peterson, C. S.; Lynch, V. Angew.
Chem., Int. Ed. Engl. 1999, 38, 700.

Selectivity in Reactions of Allyl Diazoacetates
J . Org. Chem., Vol. 65, No. 26, 2000 8847
mmol) in 50 mL of THF was treated with triethylamine (0.36
mL, 2.6 mmol) and diketene (1.22 g, 14.5 mmol) at 0 °C. The
solution was allowed to warm to room temperature and stirred
for an additional 4 h. The solution was cooled to 0 °C again,
and triethylamine (1.82 mL, 13.2 mmol) was added, followed
by addition of methanesulfonyl azide (1.76 g, 14.5 mmol). The
reaction solution was allowed to warm to room temperature,
and stirring was continued for 15 h after which the solvent
was removed under reduced pressure. The residue was dis-
solved in 100 mL of ethyl acetate, then washed with H2O (50
mL) and brine (30 mL) and then the solvent was evaporated
under reduced pressure. The crude diazoacetoacetate was
purified by flash chromatography on silica gel (hexanes/ethyl
acetate ) 2:1) and then dissolved in THF (20 mL). The THF
solution was cooled to 0 °C and followed by addition of LiOH
(1.1 g, 46.2 mmol) in H2O (20 mL). The reaction mixture was
allowed to stir at room temperature for 1 h. The layers were
separated, and the aqueous layer was extracted with ethyl
acetate (3 × 50 mL). The combined organic layer was washed
with brine, and the solvent was evaporated under reduced
pressure. Purification by column chromatography (hexanes/
ethyl acetate ) 2:1) yielded product 21 as a yellow oil (1.7 g,
50% yield): 1H NMR (CDCl3, 300 MHz) δ 5.92 (ddt, J ) 17.4,
10.5, 5.7 Hz, 1H), 5.28 (ddt, J ) 17.4, 1.8, 1.2 Hz, 1H), 5.18
(ddt, J ) 10.5, 10.3, 5.7 Hz, 1H), 4.81 (br s, 1H), 4.32 (t, J )
4.8 Hz, 2H), 4.03 (dt, J ) 5.7, 1.2 Hz, 2H), 3.68-3.45 (comp,
10 H); 13C NMR (CDCl3, 75 MHz) δ 157.7, 134.7, 117.0, 72.2,
70.6, 70.5, 69.4, 69.2, 63.9, 46.3; MS (FAB+) m/z 259.1 (M +
1H), 4.02 (dd, J ) 12.6, 4.0 Hz, 1H), 4.00 (dt, J ) 12.0, 4.5 Hz,
1H), 3.76-3.44 (comp, 10H), 2.84 (dd, J ) 12.6, 10.4 Hz, 1H),
1.78 (comp, 1H), 1.76 (ddd, J ) 9.4, 6.3, 4.8 Hz, 1H), 1.35 (dt,
J ) 9.4, 4.8 Hz, 1H), 0.73 (ddd, J ) 8.0, 6.3, 4.8 Hz, 1H); 13C
NMR (CDCl3, 125 MHz) δ 173.9, 73.2, 71.0, 70.9, 70.1, 69.2,
68.7, 62.8, 23.3, 20.0, 11.8; GC on a 30-m SPB-5 column: tR
16.11 min (flow rate: 1 mL/min, oven temp: 100 °C for 2 min
then 10 °C/min to 275 °C), GC on a 30-m Chiraldex B-PH
column: tR 89.3 (minor isomer from reactions catalyzed by
7-9; major isomer from reactions catalyzed by Cu(I)/10, 5, and
ent-6) and 91.8 min (flow rate: 1 mL/min, oven temp: 150 °C).
4-[2-(2-Allyloxyeth oxy)-eth oxy]d ih yd r ofu r a n -2-on e (23):
1H NMR (CDCl3, 500 MHz) δ 5.92 (ddt, J ) 17.3, 10.4, 5.7 Hz,
1H), 5.29 (dq, J ) 17.3, 1.5 Hz, 1H), 5.20 (dq, J ) 10.4, 1.5
Hz, 1H), 4.40 (dd, J ) 8.5, 5.5 Hz, 1H), 4.38 (dd, J ) 8.5, 2.5
Hz, 1H), 4.03 (dt, J ) 5.7, 1.5 Hz, 2H), 3.75-3.59 (comp, 9H),
2.70 (dd, J ) 16.5, 5.5 Hz, 1H), 2.62 (dd, J ) 16.5, 2.2 Hz,
1H); 13C NMR (CDCl3, 125 MHz) δ 175.6, 134.5, 117.3, 75.0,
73.2, 72.2, 70.7, 70.6, 69.3, 68.7, 35.0; HRMS calcd for
C
11H19O5: 231.1232, found: 231.1239; IR (CDCl3): 1779 (Cd
O) cm-1; GC on a 30-m SPB-5 column: tR 16.56 min (flow
rate: 1 mL/min, oven temp: 100 °C for 2 min then 10 °C/min
to 275 °C). Enantiomer separation could not be achieved on
Chiraldex TA, PH, or DM chiral columns. 3-Allyl-1,4,7,10-
tetr a oxa cyclod eca n -2-on e (24). 1H NMR (CDCl3, 500 MHz)
δ 5.84 (ddt, J ) 17.0, 10.0, 6.8 Hz, 1H), 5.15 (ddt, J ) 17.0,
1.5, 1.2 Hz, 1H), 5.09 (ddt, J ) 10.1, 1.5, 1.2 Hz, 1H), 4.50
(ddd, J ) 12.0, 6.1, 2.7 Hz, 1H), 4.19 (ddd, J ) 11.8, 6.5, 2.7
Hz, 1H), 3.98 (t, J ) 6.8 Hz, 2H), 3.95-3.48 (comp, 9H), 2.48
(tt, J ) 6.5, 1.2 Hz, 2H); 13C NMR (CDCl3, 125 MHz) δ 173.2,
133.9, 118.5, 81.3, 72.1, 71.9, 71.7, 70.5, 69.3, 64.1, 38.3; GC
on a 30-m SPB-5 column: tR 14.72 min (flow rate: 1 mL/min,
oven temp: 100 °C for 2 min then 10 °C/min to 275 °C), GC
on a Chiraldex B-PH column: tR 36.6 (major isomer from the
reaction catalyzed by Cu(I)/10) and 38.5 min (flow rate: 1 mL/
min, oven temp: 150 °C).
1); IR (neat) 2114 (CdN2), 1682 (CdO) cm-1
.
Dia zo Decom p osition of 21. To a refluxing solution of
catalyst (1 mol %) in 4 mL of CH2Cl2 was added 21 (51.6 mg,
0.200 mmol) in 2 mL of CH2Cl2 over 2 h via a syringe pump.
The reaction mixture was refluxed for an additional half hour
to complete the reaction. After cooling to room temperature,
the reaction mixture was subjected to column chromatography
on silica gel (hexanes/ethyl acetate ) 1:2) to yield a colorless
oil. The product ratios and ee values were determined by GC
analysis on a 30-m Chiraldex B-PH column. The Rh2(OAc)4-
catalyzed reaction of 21 yielded cyclopropane product 22 (29
mg, 63% yield). The C-H insertion product 23 (25 mg, 54%
yield) was isolated from the product mixture catalyzed by Rh2-
(5S-MEPY)4, and the ylide product 24 (5 mg, 11% yield) was
obtained from the CuPF6 catalyzed reaction. 3,6,9,12-Tetr a -
oxa bicyclo[12.1.0]p en ta d eca n -2-on e (22): HRMS calcd for
Cyclopropane isomer Z-22 was produced from the corre-
sponding cyclopropene product formed by intramolecular cy-
clopropenation of 2-[2-(2-propargyloxyethoxy)ethoxy]ethyl di-
azoacetate using Rh2(4S-IBAZ)4 as the catalyst, and analyses
were performed as previously described for Z-18. The cyclo-
propene product, [R]28 ) -31.6 (c ) 2.1, CH2Cl2), was
D
subjected to catalytic hydrogenation with 10% Pd/C in ethyl
acetate to form only Z-22. The absolute configuration of the
major enantiomer of this product and that from 21 using Rh2-
(4S-IBAZ)4 were the same, prompting our assignment of (1R,-
14S)-22 to be the absolute configuration of the major enanti-
omer formed from catalysis by 7-9.
C
11H19O5 231.1232, found 231.1226; IR (CDCl3) 1720 (CdO)
cm-1. for Z-22: [R]28 ) +2.5 for 78% ee (c ) 2.2, CH2Cl2); 1H
D
NMR (CDCl3, 500 MHz) δ 4.76 (ddd, J ) 11.8, 8.3, 1.6 Hz,
1H), 3.89 (dd, J ) 10.2, 5.3 Hz, 1H), 3.87 (comp, 1H), 3.76-
3.44 (comp, 10H), 3.38 (t, J ) 10.2 Hz, 1H), 1.90 (ddd, J ) 8.2,
8.0, 5.6 Hz, 1H), 1.68 (dtdd, J ) 10.2, 8.2, 5.6, 5.3 Hz, 1H),
1.12 (ddd, J ) 5.6, 5.2, 4.8 Hz, 1H), 1.07 (ddd, J ) 8.2, 8.0, 4.8
Hz, 1H); 13C NMR (CDCl3, 125 MHz) δ 172.4, 70.8, 70.4, 69.9,
69.8, 69.3, 68.8, 63.5, 21.2, 17.7, 11.1; GC on a 30-m SPB-5
column: tR 16.11 min (flow rate: 1 mL/min, oven temp: 100
°C for 2 min then 10 °C/min to 275 °C), GC on a 30-m
Chiraldex B-PH column: tR 86.2 (minor isomer from reactions
catalyzed by 7-9; major isomer from reactions catalyzed by
Cu(I)/10, 5, and ent-6) and 88.3 min (flow rate: 1 mL/min, oven
temp: 150 °C); for E-22 from the reaction of 21 catalyzed by
9: 1H NMR (CDCl3, 500 MHz) δ 4.70 (dt, J ) 11.5, 4.5 Hz,
Ack n ow led gm en t. We are grateful to the National
Science Foundation and to the National Institutes of
Health (GM 46503) for their support of this research.
We wish to thank Andrew Wee for helpful mechanistic
discussions.
Su p p or tin g In for m a tion Ava ila ble: Carbon and proton
spectra for reaction products. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O005589Z