Facile construction of novel polycyclic ring systems using a metallocarbenoid-induced cyclization of acetylenic diazo carbonyl compounds

Article abstract of DOI:10.1021/ol006004q

equation presented The Rh(II)-catalyzed reaction of diazo 2-propynyl maolonamic acid ester derivatives produce furo[3,4-c]furans in excellent yield. The methodology was applied to the synthesis of several polyheterocyclic systems by first generating a 2-a

Full text of DOI:10.1021/ol006004q

ORGANIC
LETTERS
2000
Vol. 2, No. 14
2093-2095
Facile Construction of Novel Polycyclic
Ring Systems Using a
Metallocarbenoid-Induced Cyclization of
Acetylenic Diazo Carbonyl Compounds
Albert Padwa* and Christopher S. Straub
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
Received May 1, 2000
ABSTRACT
The Rh(II)-catalyzed reaction of diazo 2-propynyl maolonamic acid ester derivatives produce furo[3,4-c]furans in excellent yield. The methodology
was applied to the synthesis of several polyheterocyclic systems by first generating a 2-alkoxy-substituted furan and then allowing it to
undergo a subsequent intramolecular Diels−Alder cycloaddition. Ring opening of the resulting cycloadduct is followed by deprotonation to
furnish a rearranged keto lactone.
Among the more recent catalytic strategies for the construc-
tion of common organic ring systems are the transition metal
mediated carbocyclizations of substrates containing two or
more elements of unsaturation.1-6
Another emerging area of synthesis involves the use of
transition metal complexes derived from R-diazo carbonyl
compounds to facilitate the fabrication of various polycyclic
rings.7-10 One of the approaches that we have found
particularly effective in the design of new processes for ring
assemblage is to employ diazoalkynyl-substituted carbonyl
compounds.11 The Rh(II)-catalyzed reaction of these systems
has been used by our group for the synthesis of both
carbocycles12 and heterocycles.13 In 1993 we reported on a
novel construction of bicyclic furans by coupling a metal
carbenoid cyclization onto a tethered alkyne with an elec-
trocyclization reaction (Scheme 1).13 The utility of this
tandem cyclization approach to ring construction would be
(1) Trost, B. M. Acc. Chem. Res. 1990, 23, 34. Trost, B. M.; Krische,
M. J. Synlett 1998, 1.
Scheme 1
(2) Wulff, W. D. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: New York, 1990; Vol. 5.
(3) Do¨tz, K. H. Tetrahedron Symposia in Print; Semmelhack, M. F.,
Ed.; Elsevier: New York, 1986; Vol. 42, p 5741.
(4) Harvey, D. F.; Sigano, D. M. Chem. ReV. 1996, 96, 271.
(5) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donavan, R. J. Chem. ReV.
1996, 96, 635.
(6) Mori, M.; Sakaibara, N.; Kinoshita, A. J. Org. Chem. 1998, 63, 6082.
Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2036.
(7) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds; Wiley and Sons: New York,
1998.
(8) Ye, T.; McKervey, A. Chem. ReV. 1994, 94, 1091.
(9) Taber, D. F. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: New York, 1991; Vol. IV, p 1046.
(10) Padwa, A.; Hornbuckle, S. F. Chem. ReV. 1991, 91, 263. Padwa,
A.; Weingarten, M. D. Chem. ReV. 1996, 96, 223.
10.1021/ol006004q CCC: $19.00 © 2000 American Chemical Society
Published on Web 06/16/2000

significantly expanded if the resulting furan was to undergo
a subsequent [4 + 2]-cycloaddition, since a cyclohexane
annulation would then result. The successful application of
this ring annulation approach for heterocyclic synthesis is
the subject of this communication.
To access synthetically more valuable targets, we focused
our attention on an intramolecular variation of the Rh(II)-
catalyzed cyclization-Diels-Alder cycloaddition cascade. In
this regard, we first investigated the IMDAF (intramolecular
Diels-Alder of furans) chemistry15 of furan 18, which was
readily formed by the Rh(II)-catalyzed reaction of 16
followed by protodesilylation with TBAF (Scheme 3).
Preparation of the propargyl diazo malonic ester system
was straightforward and high yielding. Silyl propargyl
alcohol was acylated with Meldrums acid and then allowed
to react with DCC in the presence of an appropriately
substituted alcohol to give the alkynyl ester derivative. Diazo
transfer to the activated methylene position was readily
accomplished using p-nitrobenzenesulfonyl azide and tri-
ethylamine.14 2-Diazo malonic acid methyl ester 6 was
efficiently converted to furan 9 in high yield (95%) by
treatment with a catalytic amount of rhodium acetate in
benzene at 80 °C. The Rh(II)-catalyzed cyclization reaction
was quite versatile with regard to the nature of the interacting
carbonyl group. Thus, when the cyclization reaction was
carried out with the closely related amides 7 and 8, there
was no notable difference in yield or reaction time required
for cyclization to the amino-substituted furo[3,4-c]furans 10
and 11 (Scheme 2). Exposure of the methoxy silyl substituted
Scheme 3
Scheme 2
Thermolysis of 18 afforded a 1:2-mixture of dihydrobenzo-
furan 20 and 1,7-dioxa-indacene dione 21 as the two major
products.16 In a similar manner, the related styryl-substituted
furo[3,4-c]furan 19 was easily prepared by the Rh(II)-
catalyzed reaction of diazo malonic ester 17. Heating a
sample of 19 afforded the related indacene dione 22, but
now as the minor component (36%) of the reaction mixture.
The major product (63%) corresponded to the dienol-
substituted lactam 23.
A reasonable mechanism for the formation of the IMDAF
products is outlined below. The initial step proceeds by the
expected [4 + 2]-cycloaddition of the furan across the
tethered π-bond to give cycloadduct 24. Following opening
of the oxybridge, proton loss is accompanied by dehydration
to give dihydrobenzofuran 20. When a phenyl group resides
at the bridgehead carbon (i.e., 25b), the deprotonation step
is now required to occur from the alternate γ-positions,
furan 9 to TBAF in THF afforded the desilylated furan 12
which could be induced to undergo Diels-Alder cycload-
dition at 145 °C with both N-phenylmaleimide and maleic
anhydride to furnish the expected anisole derivatives 13 and
14 in 88% and 65% yield, respectively. Interestingly, the [4
+ 2]-cycloaddition reaction of 12 with methyl vinyl ketone
in nitromethane containing an 1 equiv of methanol occurred
at room temperature and produced the ring-opened ketal 15
in quantitative yield.
(15) Kappe, C. O.; Murphree, S. S.; Padwa, A. Tetrahedron 1997, 53,
14179.
(11) Padwa, A.; Krumpe, K. E.; Zhi, L. Tetrahedron Lett. 1989, 30, 2623.
Padwa, A.; Chiacchio, U.; Gareau, Y.; Kassir, J. M.; Krumpe, K. E.;
Schoffstall, A. M. J. Org. Chem. 1990, 55, 414. Padwa, A.; Krumpe, K.
E.; Kassir, J. M. J. Org. Chem. 1992, 57, 4940.
(12) Padwa, A.; Straub, C. S. AdVances in Cycloaddition; Harmata, M.;
Ed.; JAI Press: Greenwich, CT, 1999; Vol. 6, p 55.
(13) Padwa, A.; Kinder, F. R. J. Org. Chem. 1993, 58, 21.
(14) Regitz, M. Chem. Ber. 1966, 99, 3128. Regitz, M.; Hocker, J.;
Liedhegener, A. Organic Syntheses; Wiley: New York, 1973; Collect Vol.
V, pp 179-183. Sundberg, R. J.; Pearce, B. C. J. Org. Chem. 1985, 50,
425.
(16) All new compounds in this study were fully characterized (IR, NMR,
elemental analysis, and/or HRMS). A combination of DQF-COSY, HMBC,
and HMQC NMR experiments were used to assign the stereochemistry of
the rearranged IMDAF products.
(17) An alternate possibility to rationalize the formation of 21 would
involve proton loss from the R-position of 25a followed by a rapid 1,5-
sigmatropic hydrogen shift of the resulting cyclohexadienol to give enol
26a.
(18) Woodward, R. B.; Cava, M. P.; Ollis, W. D.; Hunger, A.; Daeniker,
H. U.; Schennker, K. J. Am. Chem. Soc. 1954, 76, 4749.
(19) Kuehne, M. E.; Xu, F. J. Org. Chem. 1993, 58, 7490.
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Org. Lett., Vol. 2, No. 14, 2000

thereby resulting in the formation of compounds 22 and 23
as shown in Scheme 4. A related pathway seemingly occurs
amide 27 would constitute a formal synthesis of this
challenging alkaloid.
To evaluate this projected synthetic plan, model compound
31 (Scheme 6) was synthesized so as to probe the facility of
Scheme 4
Scheme 6
both the ring cyclization and [4 + 2]-cycloaddition across
the tethered five-ring π-bond. Easily prepared N-phenyl-N-
prop-2-ynyl-malonamic acid methyl ester was hydrolyzed
to the corresponding carboxylic acid which, in turn, was
subjected to a DCC coupling with the known 2-cyclopen-
tenylphenol.20 Diazo transfer to the activated methylene
group of the â-amido ester gave the R-diazo derivative 31,
possessing the necessary functionalities required for the
planned cascade sequence.21 Treatment of 31 with a catalytic
quantity of rhodium(II) perfluorobutyrate followed by ther-
molysis at 145 °C afforded the novel pentacyclic product
32 as a single stereoisomer in 44% overall yield.22 The
with oxonium ion 25a producing keto lactone 21 via enol
26a.17
To further illustrate the viability of our cascade sequence
as a practical strategy for the synthesis of complex hetero-
cycles, we have explored the feasibility of this approach in
the context of a total synthesis of strychnine (30).18 The key
step in our plan involves a sequential cyclization-IMDAF
cascade of diazo amide 27 to furnish the rearranged
1
structure and stereochemistry of 32 was confirmed by H
NMR and NOE experiments. Each of the bond-forming
events is assumed to occur by a pathway similar to that
outlined in Scheme 4.
In conclusion, the Rh(II)-catalyzed cyclization-IMDAF
cascade of diazo malonate esters affords structurally elabo-
rated polycyclic products with good to excellent efficiency.
The structural features of the resultant products present
numerous opportunities for post-cycloaddition manipulations
that could be exploited to synthetic advantage. Further efforts
to streamline this protocol and to utilize it to complete a
formal total synthesis of strychnine is in progress and will
be reported in due course.
Scheme 5
Acknowledgment. This research was supported by the
National Science Foundation (CHE-9806331).
Supporting Information Available: Experiment proce-
dures and characterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL006004Q
(20) Casiraghi, G.; Casnati, G.; Sartori, G.; Bolzoni, L. J. Chem. Soc.,
Perkin Trans. 1 1979, 2027.
(21) Diazo â-alkoxy esters such as 16 or 17 require the presence of a
trimethylsilyl group on the alkyne carbon for efficient cyclization to occur.
In contrast, diazo â-amido esters such as 31 undergo efficient reorganization
to 2-amino substituted furans using simple terminal alkynes.
(22) By carrying out the thermolysis of 31 at 80 °C, it was possible to
isolate the expected o-cyclopentenyl phenoxy substituted furan in 94% yield.
Further heating of this furan at 145 °C afforded 32 in 45% isolated yield.
cycloadduct 28 by a process similar to that outlined above.
Lactone 28 will eventually be transformed into compound
29 which had previously been converted into strychnine by
Kuehne and Feng.19 Thus, the formation of 29 from diazo
Org. Lett., Vol. 2, No. 14, 2000
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