A new approach to macrocyclization via alkene formation in catalytic diazo decomposition. Synthesis of patulolides A and B.

Article abstract of DOI:10.1021/ol005983j

[reaction: see text] Effective synthetic uses of bisdiazocarbonyl compounds for the selective construction of diverse macrocycles, including the synthesis of patulolides A and B, by catalytic "carbene dimer" formation are reported. Control of stereochemistry and efficient methods for product isomerization or kinetic isomer differentiation have been achieved.

Full text of DOI:10.1021/ol005983j

ORGANIC
LETTERS
2
000
Vol. 2, No. 12
777-1779
A New Approach to Macrocyclization via
Alkene Formation in Catalytic Diazo
Decomposition. Synthesis of Patulolides
A and B
1
Michael P. Doyle,* Wenhao Hu, and Iain M. Phillips
Department of Chemistry, UniVersity of Arizona, Tucson, Arizona 85721
Andrew G. H. Wee*,†
Department of Chemistry, UniVersity of Regina,
Regina, Saskatchewan, Canada S4S 0A2
mdoyle@u.arizona.edu
Received April 25, 2000
ABSTRACT
Effective synthetic uses of bisdiazocarbonyl compounds for the selective construction of diverse macrocycles, including the synthesis of
patulolides A and B, by catalytic “carbene dimer” formation are reported. Control of stereochemistry and efficient methods for product
isomerization or kinetic isomer differentiation have been achieved.
The formation of alkenes from diazocarbonyl compounds
by so-called “carbene dimer” formation is a well-known
process that has been overlooked as a viable synthetic
transformation.1,2 Its potential in intermolecular coupling
formation of cycloalkenediones from R,ω-bisdiazoketones
with up to a 20-carbon ring in modest yields. Convinced
8
from prior investigations of addition reactions (cyclopropa-
nation, cyclopropenation, aromatic cycloaddition) with the
high potential of catalytic metal carbene processes for
3,4
from diazo ketones has been reported with copper catalysts,
9
-11
and the stereochemical outcome of these reactions as a
function of catalyst and substrate substituent effects has been
reported.5 Only two publications have described intramo-
lecular applications,7 although one of them reported the
macrocyclic ring formation,
we set out to demonstrate
the suitability of the so-called “carbene dimer” formation
1
2
,6
process for macrocycle syntheses. We now report that
,8
(
7) Font, J.; Serratosa, F.; Valls, J. J. Chem. Soc., Chem. Commun. 1970,
21.
(8) Kulkowit, S.; McKervey, M. A. J. Chem. Soc., Chem. Commun. 1978,
1069.
(9) Doyle, M. P.; Chapman, B. J.; Hu, W.; Peterson, C. S.; McKervey,
7
†
E-mail: andrew.wee@uregina.ca.
(1) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds: From Cyclopropanes to
Ylides; Wiley: New York, 1998.
M. A.; Garcia, C. F. Org. Lett. 1999, 1, 1327.
(
(
(
2) Doyle, M. P.; Forbes, D. C. Chem. ReV. 1998, 98, 911.
3) Grundman, C. J. Liebigs Ann. Chem. 1938, 536, 2936.
4) (a) Ernest, I.; Stanek, J. Collect. Czech. Chem. Commun. 1959, 24,
(10) (a) Doyle, M. P.; Peterson, C. S.; Protopopova, M. N.; Marnett, A.
B.; Parker, Jr., D. L.; Ene, D. G.; Lynch, V. J. Am. Chem. Soc. 1997, 119,
8826. (b) Doyle, M. P.; Protopopova, M. N.; Peterson, C. S.; Vitale, J. P.
J. Am. Chem. Soc. 1996, 118, 7865.
(11) (a) Doyle, M. P.; Peterson, C. S.; Parker, Jr., D. L. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 1334. (b) Doyle, M. P.; Ene, D. G.; Peterson, C.
S.; Lynch, V. Angew. Chem., Int. Ed. 1999, 38, 700.
5
1
30. (b) Palmisano, G.; Danieli, B.; Lesma, G.; Riva, R. J. Org. Chem.
985, 50, 3322.
(
5) Oshima, T.; Hagar, T. Tetrahedron Lett. 1980, 21, 1251.
(6) Shankar, B. K. R.; Shechter, H. Tetrahedron Lett. 1982, 23, 2277.
1
0.1021/ol005983j CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/16/2000

stereochemical control in macrocyclic formation can be
achieved by specific catalyst selection and that this meth-
odology can be effectively employed for the synthesis of
patulolide A and patulolide B.
cause predominant formation of the Z-isomer, presumably
due to steric effects during dinitrogen loss from the coupled
6
intermediate.
The bisdiazoacetate of hexaethylene glycol (1) was
prepared from hexaethylene glycol by conventional methods
in 58% overall yield. Addition of this diazo ester to a
refluxing dichloromethane solution of catalyst produced
macrocycle 2 (eq 1) in amounts and stereochemistry that
Treatment of a 25:75 mixture of 2Z:2E with 2,3-dimethyl-
1
,3-butadiene (10 molar equiv) in carbon tetrachloride at
reflux gave, after 48 h, complete consumption of 2E without
any observable reaction of 2Z (eq 2). This outcome was
were dependent on the catalyst employed (Table 1). The
major competing process was intermolecular oligomerization;
intramolecular insertion into an ether oxygen-activated
carbon-hydrogen bond, a highly favorable process with
dirhodium(II) catalysis,13 was not visibly productive. What
is perhaps most surprising about the data in Table 1 is the
surprising since relative reactivities of geometrical isomers
were not anticipated to differ to such a level in Diels-Alder
chemistry. For comparison, we reacted a mixture of dimethyl
maleate and fumarate under the same conditions and found
that the fumarate ester was also at least 50 times more
reactive than the maleate ester toward 2,3-dimethyl-1,3-
butadiene. The overall outcome is an effective kinetic isomer
differentiation, with the trans isomer reacting first followed
by a very slow cycloaddition of the cis dienophile. The
implications of these constructions for the design and
applications of crown ethers are under investigation.
Table 1. Catalyst Dependence for Yield and Z/E Ratio of 2a
catalyst
yield, %b
2Z:2E
Cu(MeCN)4PF6
Cu(PhCOCHCOCH3)2
Rh2(OAc)4
73
40
43
35
62
75
18:82
32:68
39:61
46:54
73:27
74:26
Rh2(pfb)4c
Rh2(4S-MEAZ)4
Rh2(5R-MEPY)4
A broad selection of bisdiazoacetates, including those from
diethylene glycol and tetraethylene glycol, have been treated
with dirhodium(II) catalysts, and the coupling products are
the only ones observed (from 96:4 to 88:12 Z:E ratios). Other
systems capable of addition, insertion, or ylide reactions,
namely bidsiazoacetates from cis-2-butene-1,4-diol, isoman-
nide, and 1,4-butanediol, give coupling product (Z only)
exclusively. Thus, as previously suggested by data from
a
Reaction performed in refluxing dichloromethane; diazo ester was added
b
to the catalyst (1.0 mol %) solution via a syringe pump. Yield (unopti-
mized) of 2 after chromatography on silica gel. Rhodium(II) perfluorobu-
c
tyrate.
extent of stereocontrol that could be achieved. With Cu-
8
(MeCN)
4
PF
6
as the catalyst, 2 was obtained with a greater
McKervey for bisdiazoketones, this coupling reaction is
than 4:1 E:Z ratio. The use of rhodium acetate changes this
stereoisomer ratio but not enough to be synthetically relevant.
general for the formation of medium rings to macrocycles
and occurs exclusively even when alternative addition,
insertion, or ylide transformations might also be favorable.
2
In contrast, chiral dirhodium(II) carboxamidates, either Rh -
14
15
(
4 2 4
4S-MEAZ) (3) or, preferably, Rh (5R-MEPY) (4),
Patulolides A and B (6 and 7) are macrocyclic lactones
that, since their isolation from Penicillium urticae mutant
(
12) Recent reviews: (a) Roxburgh, C. J. Tetrahedron 1995, 51, 9767.
b) Stach, H.; Hesse, M. Tetrahedron 1988, 44, 1573. (c) Tius, M. A. Chem.
ReV. 1988, 88, 719. (d) Paterson, I.; Mansuri, M. M. Tetrahedron 1985,
1, 3569.
16
S11R59, have been shown to have antifungal, antibacterial,
(
1
6,17
and antiinflammatory activities.
Multistep syntheses of
4
(
(
(
13) Wang, P.; Adams, J. J. Am. Chem. Soc. 1994, 116, 3296.
14) Doyle, M. P.; Davies, S. B.; Hu, W. Org. Lett. 2000, 2, 1145.
15) (a) Doyle, M. P.; Winchester, W. R.; Hoorn, J. A. A.; Lynch, V.;
(17) Makita, A.; Yamada, Y.; Okada, H. J. Antibiot. 1986, 39, 1259.
(18) Kalita, D.; Khan, A. T.; Barua, N. C.; Bez, G. Tetrahedron 1999,
55, 5177.
(19) Bestmann, H. J.; Kellermann, W.; Pecher, B. Synthesis 1993, 149.
(20) Solladi e´ , G.; Gerber, C. Synlett 1992, 449.
Simonsen, S. H.; Ghosh, R. J. Am. Chem. Soc. 1993, 115, 9968. (b) Doyle,
M. P.; Winchester, W. R.; Protopopova, M. N.; Kazala, A. P.; Westrum,
L. J. Org. Synth. 1996, 73, 13.
(
16) (a) Sekiguchi, J.; Kuruda, H.; Yamada, Y.; Okada, H. Tetrahedron
Lett. 1985, 26, 2341. (b) Rodphya, D.; Sekiguchi, J.; Yamada, Y. J. Antibiot.
986, 39, 629.
(21) Mori, K.; Sakai, T. Liebigs Ann. Chem. 1988, 13.
(22) Corey, E. J.; Myers, A. G. Tetrahedron Lett. 1984, 25, 3559.
(23) Ye, T.; McKervey, M. A. Tetrahedron 1992, 48, 8007.
1
1778
Org. Lett., Vol. 2, No. 12, 2000

Scheme 1
these lactones have been reported,18-21 most of which having
employed esterification as the ring-closing step.
iodine quantitatively converted 6 to 7. This observation, and
the probable thermodynamic stability of 7 relative to 6, also
explains the serendipitous discovery by Mori and Sakai of
double bond isomerization during pyridinium chlorochromate
oxidation of patulolide C, the γ-hydroxyenoate analogue of
21
6
. The simple isomerization of patulolides A to B renders
all previous syntheses of patulolide A as de facto syntheses
of patulolide B. Overall, the synthesis presented in Scheme
1
is the most efficient and economical yet designed for the
construction of patulolide B.
Further optimizations of these processes are possible, both
in the synthesis of bisdiazocarbonyl compounds and in yields
and selectivities from coupling reactions. However, the
present results demonstrate a synthetically viable approach
to a broad range of macrocycles.
In the synthetic approach to 6 and 7 that we now report
Scheme 1), two previously unexplored processessthe
(
sequential construction of a diazo ester and a diazo ketone
and the coupling of this mixed diazo compoundswere
employed. Accordingly, because of the known relative
1
reactivities of diazo ketones and diazo esters, bisdiazocar-
Acknowledgment. We are grateful to the National
Institutes of Health (GM 46503), to the National Science
Foundation, and to the donors of the Petroleum Research
Fund, administered by the American Chemical Society, for
their support of this research. A. G. H. Wee thanks the
Natural Science and Engineering Research Council, Canada,
and the University of Regina for financial support.
bonyl compound 11 was constructed by initially preparing
2
2
23
diazo ester 10 and then preparing diazo ketone 11.
Treatment of 11 with a catalytic amount of Rh (OAc)
2
4
produced a 1:1 mixture of 6 and 7, each of which was
isolated in chromatographically pure form (15% 6 + 15%
). With Cu(MeCN) PF as the catalyst, a 1:2 ratio of 6:7
4 6
7
was formed but in only 11% isolated yield.
Copper catalysts normally exhibit a preference for forma-
Supporting Information Available: Experimental and
spectral data that include the synthesis and reactions of diazo
compounds and characterization of reaction products. This
information is available free of charge via the Internet at
http://pubs.acs.org.
3
-5,8
tion of the E-isomer in these coupling transformations,
so the reverse preference from the CuPF -catalyzed reaction
6
was surprising. Furthermore, computational analysis (SPAR-
TAN SGI version 5.1.1) suggested that 6 was more stable
than 7. However, treatment of 6 with a catalytic amount of
OL005983J
Org. Lett., Vol. 2, No. 12, 2000
1779