Diazoacetoacetate enones for the synthesis of diverse natural product-like scaffolds

Article abstract of DOI:10.1021/ol4015199

Diazoacetoacetate enones are a new class of Michael acceptors that enable the efficient construction of natural product-like scaffolds. Through their Michael addition reactions, including those with silyl enol ethers, indoles, pyrroles, and amines, δ-functionalized diazoacetoacetates are formed in high yield and with overall operational efficiency. Subsequent catalytic dinitrogen extrusion reactions provide access to a diverse series of natural product-like carbo- and heterocyclic ring systems in only three steps from commercial materials.

Full text of DOI:10.1021/ol4015199

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Diazoacetoacetate Enones for the Synthesis
of Diverse Natural Product-like Scaffolds
Charles S. Shanahan, Phong Truong, Savannah M. Mason, John S. Leszczynski, and
Michael P. Doyle*
Department of Chemistry and Biochemistry, University of Maryland, College Park,
Maryland 20742, United States
mdoyle3@umd.edu
Received May 29, 2013
ABSTRACT
Diazoacetoacetate enones are a new class of Michael acceptors that enable the efficient construction of natural product-like scaffolds. Through
their Michael addition reactions, including those with silyl enol ethers, indoles, pyrroles, and amines, δ-functionalized diazoacetoacetates are
formed in high yield and with overall operational efficiency. Subsequent catalytic dinitrogen extrusion reactions provide access to a diverse series
of natural product-like carbo- and heterocyclic ring systems in only three steps from commercial materials.
Complex diazoacetoacetate compounds 2 (Scheme 1)
have been of particular interest in organic synthesis due to
their high stability and unique reactivity relative to other
classes of diazo compounds;1 as such, they have been applied
with great success in natural product total sytheses.2 More-
over, the unique reactivity of the diazoacetoacetate func-
tional group often compliments the conventional reactivity
of comparable 1,3-dicarbonyl compounds and has resulted
in the development of a variety of novel synthetic methods to
construct more elaborate organodiazo compounds.3 Most
applications of the diazoacetoacetate group in targeted
oriented synthesis, however, have traditionally been executed
by installation of the diazo group at an advanced stage of the
synthesis using an already complex carboxylic acid deriva-
tive, and reaction at the diazo functional group usually
occurs in the steps immediately following its installation.2
Recently our group has begun exploring ways to construct
similarly complex diazo compounds in a more convergent
way by building complexity around the readily available
diazoacetoacetate subunit.3 In an effort to broaden access to
δ-substituted diazoacetoacetates 2, whose metal-catalyzed
carbene transformations provide convenient access to carbo-
and heterocyclic ring systems, we devised a synthetic strategy
(1) (a) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds: From Cyclopro-
panes to Ylides; John Wiley & Sons: New York, 1998. Reviews: (b) Doyle,
M. P.; Duffy, R.; Ratnikov, M. O.; Zhou, L. Chem. Rev. 2010, 110, 704–724.
(c) Merlic, C. A.; Zechman, A. L. Synthesis 2003, 1137–1156. (d) Davies,
H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861–2904. (e)
Davies, H. M. L.; Antoulinakis, E. G. Org. React. 2001, 57, 1–326. (f)
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(2) (a) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417–424.
(b) Doyle, M. P.; Ratnikov, M.; Liu, Y. Org. Biomol. Chem. 2011, 9,
4007–4016. (c) Fang, C.; Shanahan, C. S.; Paull, D. H.; Martin, S. F.
Angew. Chem., Int. Ed. 2012, 45, 10596–10599. (d) Nicolaou, K. C.;
Ding, H.; Richard, J.; Chen, D. Y. J. Am. Chem. Soc. 2010, 7, 1227–1229.
(3) (a) Doyle, M. P.; Kundu, K.; Russell, A. E. Org. Lett. 2005, 7,
5171–5174. (b) Liu, Y.; Zhang, Y.; Jee, N.; Doyle, M. P. Org. Lett. 2008,
10, 1605–1608. (c) Truong, P.; Xu, X.; Doyle, M. P. Tetrahedron Lett.
2011, 52, 2093–2096. (d) Xu, X.; Ratnikov, M. O.; Zavalij, P. Y.; Doyle,
M. P. Org. Lett. 2011, 13, 6122–6125. (e) Zhou, L.; Doyle, M. P. Org.
Lett. 2010, 12, 796–799. (f) Xu, X.; Hu, W.; Doyle, M. P. Angew. Chem.,
Int. Ed. 2011, 50, 6392–6395. (g) Mo, F.; Li, F.; Qiu, D.; Wang, J.
Tetrahedron 2010, 66, 1274–1279. (h) Dong, C.; Mo, F.; Wang, J. J. Org.
Chem. 2008, 73, 1971–1974. (i) Deng, G.; Tian, X.; Wang, J. Tetrahedron
Lett. 2003, 44, 587–589.
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10.1021/ol4015199
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involving the general 1,4-addition of nucleophiles into dia-
zoacetoacetate enones 1(DAAEs,Scheme1).Inthisway, the
bulk of the organic framework can be conveniently installed
to access 1 via a Wittig olefination reaction, and 1,4-addition
reactions of a variety of nucleophiles would facilitate con-
struction of CꢀC and CꢀN bonds at C(5) using 1 as a
modular synthetic platform.
Related tetralin natural products, exemplified by trihy-
droxycalamenene 4, constitute a broad class of biologically
active natural products.4,5 On the other hand, if indoles or
pyrroles are added, the electron-rich heterocycle present in
2 is expected to react preferentially to allow access to
dihydrocarbazoles 5 and dihydroindoles 7. These hetero-
cycles are present in a variety of biologically active sub-
stances including the natural products angustilodine (6)6
and stenine (8).7 Finally, the reactions of 2 with amines
would allow expedient access to pyrrolidinones 9 of which
a large number of biologically active substances belong
and in this case is exemplified by the natural product
condonopsinol (10).8 The proposed route to these natural
product-like scaffolds represents an efficient and atom-
economical approach in that both steps are catalyst con-
trolled; exceptfor dinitrogen, all of the atoms present in the
starting materials are maintained through the sequence.
Only a few examples of diazoacetoacetate enones 1 in
dinitrogen extrusion reactions have been reported;9 how-
ever, their reactivity as electrophiles has not been explored.
Since a general method for synthesizing DAAEs 1 was not
available, we set out to develop a convenient one-pot
protocol for the general prepartion of 1 (Table 1). Com-
mercially available Wittig reagent 11 was chosen as the
starting material,10 and treatment of 11 with a variety of
aldehydes in the presence of NaH effected olefination to
provide enones that were not isolated. Rather, upon
completion of the olefination reaction, buffered NEt3
(3:1 withAcOH) and the diazo transfer agent p-acetamido-
benzenesulfonyl azide (p-ABSA)11 were added to the reac-
tion mixture to afford DAAE 1 as mixtures (1:1 to 3:1) of
(E) and (Z)-isomers. Isomerization of the (Z)-enones to the
more thermodyamically favored (E)-enones was promoted
by the addition of DABCO in catalytic amounts to the
initial olefination reaction. This two-step/one-pot proce-
dure cleanly provided (E)-diazoacetoacetate enones 1 in
64ꢀ75% yield for a series of nine different derivatives of 1
ranging in group electronegativities and subsitution.
Scheme 1. Natural Product-like Scaffolds Derived from
Nucleophilic Additions to Diazoacetoacetate Enones (DAAEs)
We envisioned DAAE 1 as being a general template for
the construction of a variety of important, biologically
relevant carbo- and heterocyclic ring systems byemploying
selective rhodium-catalyzed ring forming reactions on the
1,4-addition products 2 (Scheme 1). Therefore, the fate of
adduct 2 in catalytic dinitrogen extrusion reactions would
depend solely on the nucleophile that is chosen to function-
alize 1, since the intermediate metal carbene formed from
diazo decomposition of 2 would be expected to react with
the newly installed RZ functionality or the aromatic ring
native to 1 (R = Ar) depending on which is more electron
rich. For example, the adduct resulting from reactions with
silyl enol ethers (RZ = CH2COR0), when exposed to a
rhodium catalyst, would give β-tetralone derivatives 3 by
Buchner-type reactions onto the appended aromatic ring.
The electrophilic behavior displayed by the library of
DAAEs 1 as novel Michael acceptors (Scheme 2) was
explored. Mukaiyama-Michael additions of enone 1a with
silyl enol ethers 12aꢀc were first chosen to test the pro-
posed electrophilic behavior of DAAE 1. A variety of
metal triflate salts was screened, and Sc(OTf)3 was found
to provide the highest reactivity and overall yields in
CH2Cl2 as the solvent. For the Mukaiyama-type reactions,
˚
theuseof4 A molecularsievesallowed thesereactionstobe
performed in a moisture-free environment that was
(6) Kam, T.; Choo, Y. Helv. Chim. Acta 2004, 87, 366–369.
(7) Uyeo, S.; Irie, H.; Harada, H. Chem. Pharm. Bull. 1967, 15, 768–
770.
(8) Ishida, S.; Okasaka, M.; Ramos, F.; Kashiwada, Y.; Takaishi, Y.;
Kodzhimatov, O. K.; Ashurmetov, O. J. Nat. Med. 2008, 62, 236–238.
(9) (a) Collomb, D.; Doutheau, A. Tetrahedron Lett. 1997, 38, 1397–
1398. (b) Taylor, E. C.; Davies, H. M. L. Tetrahedron Lett. 1983, 24,
5453–5456. (c) Deng, G.; Xu, B.; Wang, J. Tetrahedron 2005, 61, 10811–
10817.
(10) Pietrusiewicz, K. M.; Monkiewicz, J.; Bodalski, R. J. Org. Chem.
1983, 48, 788–790.
(11) Baum, J. S.; Shook, D. A.; Davies, H. M. L. Synth. Commun.
(4) Silva, G. H.; Teles, H. L.; Zanardi, L. M.; Young, M. C. M.;
Eberlin, M. N.; Hadad, R.; Pfenning, L. H.; Costa-Neto, C. M.; Castro-
ꢀ
Gamboa, I.; Bolzani, V. S.; Araujo, A. R. Phytochemistry 2006, 67,
1964–1969.
(5) (a) Bianco, G. G.; Ferraz, H. M. C.; Costa, A. M.; Costa-Lotufo,
L. V.; PesCsoa, C.; de Moraes, M. O.; Schrems, M. G.; Pfaltz, A.; Silva,
L. F. J. Org. Chem. 2009, 74, 2561–2566. (b) Silva, L. F.; Siqueira, F. A.;
Pedrozo, E. C.; Vieira, F. Y. M.; Doriguetto, A. C. Org. Lett. 2007, 9,
1433–1436.
1987, 17, 1709–1716.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. General One-pot Synthesis of DAAEs 1a
Scheme 2. Nucleophilic Additions of Diazoacetoacetate Enonesa
1
X
Y
Z
yield (%)b
a
b
c
d
e
f
H
H
H
65
67
71
72
69
68
71
64
61
H
H
OMe
Br
F
H
H
H
H
H
OMe
OMe
Br
H
OMe
H
H
g
h
i
H
H
Me
Cl
H
H
H
a Wittig/diazo transfer was performed reproducibly in one-pot by
addition of NaH to a solution of the aldehyde and Wittig reagent on
decagram scales. Upon completion of the olefination AcOH, NEt3, and
p-ABSA were sequentially added. Reactions were performed with the
Wittig reagent as the limiting reagent; however, the aldehyde can also be
the limiting reagent (see Supporting Information for procedural details).
b Isolated yield following purification via column chromatography.
essential for high conversions. In this way, silyl ketene
acetal 12a provided carboxylate derivative 13a in virtually
quantitative yield. The use of silyl enol ether 12b similarly
gave ketone derivative 13b in 58% yield in CH2Cl2; how-
ever, when this reaction was run with MeCN as the solvent
with a slight increase in catalyst loading (5 mol %), the
yield was improved to 65%. Lastly, siloxyfuran 12c pro-
vided the butenolide derivative 13c in 92% yield, and
notably, the product was isolated as a single diastereomer.
The catalyst induced FriedelꢀCrafts-type additions of
the electrophilic enone to indole (12d) and N-methyl-
pyrrole (12e) were investigated as a way to prepare nitrogen
containing heterocycles (Scheme 2). These reactions did
not require special handling as did the Mukaiyama-type
reactions; however, the use of MeCN as the solvent was
crucial. Additions in CH2Cl2 or in refluxing toluene gave
low conversions (<50%), whereas those performed in
MeCN were complete in 24 h at room temperature. The
reactions of indole and N-methylpyrrole could also be
accelerated by increasing the reaction temperature, and
at 50 °C, optimal conditions provided the indole adduct
13d and pyrrole adduct 13e in 88 and 58% yields,
respectively.12
a
˚
Reaction performed with Sc(OTf)3 (3 mol %) and 4 A mol. sieves in
CH2Cl2 at rt. bReaction performed with Sc(OTf)3 (5 mol %) in MeCN at
rt. cReaction performed with Sc(OTf)3 (2 mol %) in MeCN at rt.
dReaction performed with Sc(OTf)3 (5 mol %) in toluene at 50 °C.
eReaction performed with Sc(OTf)3 (3 mol %) in CH2Cl2 at 40 °C.
fPMP = p-methoxyphenyl.
upon reaction with 1a under standard Sc(OTf)3 catalyzed
conditions afforded 13f in 60% yield (Scheme 2).
The influence of substituents on the aromatic ring of 1
on reactivity toweards 1,4-addition was assesed through
reactions of silyl ketene acetal 12a (Scheme 2). Gratifyingly,
the addition reactions of silyl ketene acetal 9a proceeded
in >90% yield regardless of the electronic nature of the aryl
substitutent of 1in the series investigated, and adducts 13gꢀk
were all prepared in high yields.
Having demonstrated the general reactivity of DAAE 1
as a Michael acceptor, the utility of this transformation as
a template for preparing a variety of important natural
product-like ring systems became the next focus (Schemes 3
and 4). Thus, Michael adducts 13aꢀk were studied in diazo
decomposition reactions using dirhodium(II) catalysis.
Treatment of the Mukaiyama-Michael adducts 13a,b and
Attempted addition reactions of 1a with carbamates as
amino nucleophiles did not occur, but primary benzyl
amines served as good nucleophiles for this reaction.
However, benzyl amine addition products were found to
be prone to elimination, reverting to the starting enone 1a,
and were therefore difficulttoisolate. Thus, p-methoxyani-
line (12f) proved to be the ideal amino nucleophile and
(13) (a) The reaction of 13a (as with 13b,gꢀk) with Rh2(OAc)4 gave
predominately the cycloheptatriene intermediate, which produced the
desired tetralone upon in situ treatment with TFA:
(b) McKervey, M. A.; Tuladhar, S. M.; Twohig, M. F. J. Chem. Soc.,
Perkin Trans. 1 1990, 1047–1054.
(12) The addition reaction with N-methylpyrrole was accompanied
by ∼20% of alkylation at the C(3)-position of pyrrole.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Synthesis of Natural Product-like Tetralones
Scheme 4. Synthesis of Natural Product-like Heterocycles
13gꢀk with catalytic Rh2(pfb)4 in CH2Cl2 at 40 °C provided
β-tetralones 14aꢀg in 80ꢀ90% yield (Scheme 3). The use
of Rh2(OAc)4 was effective as a catalyst; however, trifluor-
oacetic acid was necessary to convert the intermediate
cycloheptatrienes to the thermodynamically more stable
tetralones.13 The considerably more Lewis acidic perfluo-
robutyrate (pfb) catalyst, however, was sufficient as a cata-
lyst for both carbene formation and isomerization, and
therefore proved superior as a catalyst. Furthermore, a
series of electron-withdrawing and electron-donating groups
were tolerated in both the para and meta-positions in these
reactions. Another intriguing product was that produced
from the reaction of butenolide 13c with Rh2(pfb)4 (1mol%)
in hot CH2Cl2, which provided the tetralone-butenolide
conjugate 15 as a single diastereomer in 89% yield.14 No
competitive reaction of the intermediate metal carbene with
the butenolide ring was observed in this case.
The catalytic diazo decomposition reactions of hetero-
cyclic addition products 13dꢀf were next investigated
(Scheme 4). With the indole addition product 13d, the
reaction with Rh2(Oct)4 (2 mol %) at 40 °C in CH2Cl2
provided the dihydrocarbazole product 16 in 75% yield. In
this case <10% of the product mixture resulted from
reaction of the metal carbene with the phenyl ring instead
of with indole. Similarly, the reaction of the pyrrole addition
product 13e with Rh2(Oct)4 provided the intermediate dihy-
droindole product 17 in 73% yield. In this case, no reaction
with the phenyl ring was observed. Finally, the aza-Michael
product 13f was subjected to Rh2(OAc)4 in refluxing toluene,
and the reaction provided the pyrrolidinone 18 as a mixture
(∼2.5:1) of diastereomers. To simplify characterization,
pyrrolidinone 18 was aromatized with catalytic Pd/C to
afford the pyrrole product 19 in 76% overall yield.
In conclusion, we have synthesized a series of novel diazo-
acetoacetate enones 1, and utilized their reactivity as general
Michael acceptors with a variety of different nucleophiles to
prepare a diverse library of valuable complex diazoaceto-
acetates 13. Furthermore, by applying 13 in a series of
selective dirhodium(II)-catalyzed ring forming reactions,
we have demonstrated that the 1,4-additions of DAAEs 1
provide a versatile template for the construction of impor-
tant carbocyclic and heterocyclic ring systems such as
dihydroindoles, dihydrocarbazoles, β-tetralones, and pyrro-
lidinones.15 As was demonstrated with pyrrolidinone 18
(Scheme 4), Pd/C catalyzed dehydrogenative aromatization
reactions of 14ꢀ17 could similarly be used to synthesize the
corresponding aromatic 5-hydroxyindoles, 2-hydroxycarba-
zoles, and 2-hydroxynapthols.16 The general synthetic strat-
egy outlined offers advantages over traditional synthetic
techniques to prepare similar natural product-like ring
systems because natural product-like compounds 14ꢀ19
can be made in only three steps from commercial materials
with great functional diversity utilizing a common approach.
Furthermore, the iterative metal-catalyzed steps result in an
economical and environmentally friendly process due to
limited regent quantities and waste generation.
Acknowledgment. Support for this research from the
National Institutes of Health (GM 46503) and the Na-
tional Science Foundation (CHE 1212446) is gratefully
acknowledged.
(14) Kitajima, H.; Ito, K.; Katsuki, T. Tetrahedron 1997, 53, 17015–
17028.
(15) For reviews regarding these ring systems as well as the corre-
sponding aromatic systems, see: (a) Inman, M.; Moody, C. J. Chem. Sci.
€
2013, 4, 29–41. (b) Schmidt, A. W.; Reddy, K. R.; Knolker, H. Chem.
Supporting Information Available. Experimental proce-
dures, characterization data, and copies of 1H and 13C NMR
spectra for compounds 1, 13, and 14ꢀ19. This material is
available free of charge via the Internet at http://pubs.acs.org.
Rev. 2012, 112, 3193–3328. (c) Flores-Gaspar, A.; Martin, R. Synthesis
2013, 45, 563–580. (d) Young, I. S.; Thornton, P. D.; Thompson, A. Nat.
Prod. Rep. 2010, 27, 1801–1839.
(16) For Pd/C-catalyzed dehydrogenative aromatizations of hetero-
cycles, see: (a) Karmakar, A. C.; Kar, G. K.; Ray, J. K. J. Chem. Soc.,
Perkin Trans. 1 1991, 8, 1997–2002. (b) Camacho-Davila, A.; Herndon,
J. W. J. Org. Chem. 2006, 71, 6682–6685.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX