Cyclopentannulation of Conjugated Enones Using a Vinyldiazomethane-Based Reagent

Article abstract of DOI:10.1021/ja4054866

Herein, we describe a two-step method for the cyclopentannulation of conjugated enones using methyl 3-(tert-butyldimethylsilyloxy)-2-diazo-3- butenoate (1) as a bifunctional reagent. The enol silane and stabilized diazoalkane functionalities are exploited independently in sequential Mukaiyama-Michael and diastereoselective α,α′-diketone coupling. Di-, tri-, and tetrasubstituted enones are amenable to annulation under this protocol. Overall, this chemistry is an effective surrogate for a substituted acetone 1,3-dipole .

Full text of DOI:10.1021/ja4054866

Communication
pubs.acs.org/JACS
Cyclopentannulation of Conjugated Enones Using a
Vinyldiazomethane-Based Reagent
Matthew Del Bel, Alexander Rovira, and Carlos A. Guerrero*
Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0358,
United States
S
* Supporting Information
dures have been developed, and in some instances, general
ABSTRACT: Herein, we describe a two-step method for
the cyclopentannulation of conjugated enones using
methyl 3-(tert-butyldimethylsilyloxy)-2-diazo-3-butenoate
(1) as a bifunctional reagent. The enol silane and
stabilized diazoalkane functionalities are exploited inde-
pendently in sequential Mukaiyama−Michael and diaster-
eoselective α,α′-diketone coupling. Di-, tri-, and tetrasub-
stituted enones are amenable to annulation under this
protocol. Overall, this chemistry is an effective surrogate
for a substituted “acetone 1,3-dipole”.
reagent classes have been devised for the synthesis of
cyclopentanoids.1 Here, we describe the use of methyl 3-(tert-
butyldimethylsiloxy)-2-diazo-3-butenoate,2 represented by for-
mula 1 in Scheme 1B, as a bifunctional reagent for two-step
a
Scheme 1. Annulation in Detail
he stereo- and regiocontrolled synthesis of substituted
T
cyclopentanones is an enduring research problem,
especially in connection with natural product synthesis1 (see
Figure 1A for a small selection of cyclopentanoid natural
a
Conditions and notes: (a) (CuOTf)2·PhH (10 mol %), ligand 6 (22
mol %), toluene, 55 °C, 2 h; (b) [Rh(OAc)2]2 (2 mol %), CH2Cl2, rt,
1.5 h.
annulation, wherein the enol silane bonds first to the
electrophilic β-carbon of a conjugated enone3 and then the
diazo group participates in Cu(I)-catalyzed formal α,α′-
diketone coupling. Though this approach requires two separate
steps, it (i) can be applied to various conjugated enones, (ii)
gives ready access to structures where an acetone unit has been
added in a 1,2-fashion across an electron deficient alkene
(equivalent to an “acetone-1,3-dipole”), and (iii) provides
annulation products not easily obtained by established
methods.
Figure 1. (A) Cyclopentanone-bearing natural products; (B) concept
for two-step cyclopentannulation.
products). A variety of creative methods for both cyclization
and annulations have been developed. 3C + 2C annulations,
wherein an electron-deficient alkene serves as a 2C component,
have been particularly popular as the requisite conjugated
enone-containing starting materials are readily obtained and are
versatile synthetic intermediates. Single and multistep proce-
Some of the best studied, single step methods for 3C + 2C
annulation of enones include Trost’s Pd-catalyzed trimethylene-
Received: June 1, 2013
© XXXX American Chemical Society
A
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Journal of the American Chemical Society
Communication
methane (TMM) cycloaddition,4 Danheiser’s Lewis acid
mediated allenylsilane cycloaddition,5 Boger’s thermally
induced cyclopropene ketal cycloaddition,6 Lu’s phosphine-
catalyzed union of electron-deficient alkenes with 2,3-
butadienoates or 2-butynoates,7 and low valent transition
metal-catalyzed processes.1c Despite the existence of these
powerful methodologies, alternative approaches, many requir-
ing more than one step, continue to appear in the chemical
literature.8
a
Table 1. Reaction Scope (h,i,j)
As part of a recent study, we needed a method that would
formally append acetone across a conjugated enone. We further
required that if a substituted, unsymmetrical acetone fragment
were used, the extra group would be proximal to the former
enone α-carbon rather than the β-carbon (as occurs with
several of the aforementioned methods). Conceptually, these
requirements could be met using methyl 3-(tert-butyldimethyl-
siloxy)-2-diazo-3-butenoate (1). Recently, Doyle reported that
reagent 1 undergoes Mukaiyama−Michael addition reactions to
conjugated enones under Zn(II)-catalysis, producing function-
alized diazoacetates.3 However, the interaction of the resultant
enol silane and stabilized diazoalkane functionalities was not
explored.9 We questioned whether an intermediate like 2
(potentially derived from Mukaiyama−Michael addition of 1 to
(R)-carvone; see Scheme 1A) might undergo intramolecular,
chemo-, and regioselective cyclopropanation, to generate
general structure 3, prior to deliberate fluoride-induced
fragmentation of the electronically biased oxycyclopropane,10
ultimately giving β-ketoester 4. After initial experimentation
and optimization, we found that compound 2 was converted
directly to unsaturated ester 5 when treated with 10 mol %
(CuOTf)2·PhH and 22 mol % bis(oxazoline) 6 (see Scheme
1B; an isolated yield for 5 was not recorded, see below).11 The
use of ligated Cu(I) is essential since without 6 complex
reaction mixtures result arising from other reaction pathways.
For example, as shown in Scheme 1C, conjugate addition
product 7, derived from cyclohexenone and 1, underwent an
internal hydrogen transfer when treated with otherwise “ligand-
free” Cu(I) or Rh(OAc)2.12
In performing the first step of the overall annulation, we
replaced the Zn(OTf)2 catalyst that Doyle employed with tert-
butyldimethylsilyl trifluoromethanesulfonate (TBSOTf).13 In
addition to slightly improving convenience (especially since the
preparation of 1 requires TBSOTf), this change permitted the
use substrates bearing suitably protected heteroatom function-
ality (see entries 6, 10, and 11 in Table 1). Moreover,
conjugated enones with sterically demanding γ- and δ-
substitution (see entires 3, 5, and 8−11) underwent addition.
For these experiments, the observed diastereoselectivity ranged
from 5:1 to >19:1.
a
Conditions and notes: (a) 1 (1.2 equiv), TBSOTf (20 mol %), 0 °C;
(b) (i) (CuOTf)2·PhH (12.5 mol %), ligand 6 (27.5 mol %), toluene,
55 °C; n-Bu4NF (1.3 equiv), 0 °C; (ii) MOMCl (3 equiv), i-Pr2EtN (5
equiv), CH2Cl2, rt; (c) 1 (1.1 equiv) used; (d) 1 (2.0 equiv) used; (e)
1 (1.4 equiv) used; (f) TBSOTf (10 mol %) used; (g) (CuOTf)2·PhH
(10 mol %), ligand 6 (22 mol %) used; (h) for all cyclic enones, only
the cis ring fusion was observed after annulation; (i) Mukaiyama−
Michael reaction times vary from 30 min to 20 h, specific values given
in Supporting Information; (j) annulation reaction times vary from 25
min to 6 h, specific values given in Supporting Information.
During preliminary studies of the annulation, we observed
that the crude reaction mixtures contained β-siloxy-α,β-
unsaturated esters (similar to 5), yet these proved unstable to
common chromatographic methods, including the use of
Florisil.14 This complicated characterization efforts as multiple
species, all bearing the desired constitution, were present after
the loss of the trialkylsilyl group. Thus, the silyl ethers were
deliberately cleaved upon workup using n-Bu4NF and the
resulting crude material was treated with excess chloromethyl
methyl ether and excess di-iso-propylethylamine to generate
stable methoxymethyl ethers. We highlight that this measure
was taken solely to aid in characterization, and that the
annulation certainly does not require this process. Also, we note
that yields for the second step of this process comprise the
deprotection/reprotection events, indicating that the yields
listed are minimums for annulation and are likely higher than
indicated.
The second step of annulation proceeds unremarkably.
Generally, substrates that are competent Michael acceptors in
the first step are well suited for the Cu(I)-catalyzed cyclization.
One type of exception noted is that substrates bearing an aryl
group at either the α- or β-carbon of the conjugated enone are
not amenable to the second step of the annulation, ostensibly
because the intermediate Cu(I)-carbenoid may react with the
arene though Buchner-type cyclopropanation and/or related
processes.15 Cyclic 5- and 6-membered enones furnish no
detectable levels of the trans-diastereomer, while acyclic 1,2-
disubstituted enones give trans-3,4-disubstituted cyclopenta-
B
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Journal of the American Chemical Society
Communication
nones. Entry 12 is noteworthy in that it demonstrates that
vicinal, all-carbon quaternary stereocenters may be created by this
process.16 Finally, it is worth mentioning that the second step
scales well as entry 9 may be conducted on a gram scale with
only slight decrease in yield (61%; see Supporting Information
for details).
Experiments were conducted to clarify the nature of the
cyclization process. For instance, purely thermal treatment of
(+)-2 (toluene, reflux, 40 h) in an attempt to induce a dipolar
cycloaddition of the diazoacetate fragment with the enol silyl
ether does not furnish compound 5, the observed immediate
product of annulation prior to deprotection/protection
(Scheme 2).17 Also, treatment of compound (+)-2 with BF3·
decarboxylation mechanism.19 Again, the observed yields are
those of the sequences beginning with the purified
Mukaiyama−Michael addition adducts. Such a sequence
complements other annulations yet does not require oxidative
cleavage of an alkene to give a carbonyl, a fact that could prove
useful in the synthesis of polyfunctional molecules containing
multiple alkenes or other easily oxidized functional groups.20
In conclusion, we have devised and developed a cyclo-
pentannulation sequence dependent on the bifunctional
reactivity of reagent 1. The two-step process is applicable to
differentially substituted α,β-unsaturated enones, which are
readily obtained and are very common synthetic intermediates.
Additionally, products not easily obtained by other means are
made available using this approach, and optional methox-
ycarbonyl group removal gives products of a formal cyclo-
addition of acetone. Given the sheer number of cyclopentanoid
natural products, the use of reagent 1 in complex molecule
synthesis endeavors seems promising. Such studies are
currently underway in our laboratory.
a
Scheme 2. Selected Control Experiments
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
a
AUTHOR INFORMATION
Corresponding Author
guerrero@ucsd.edu
Conditions and notes: (a) Toluene, reflux, 40 h; (b) BF3·OEt2,
■
CH3NO2, −10 to 0 °C, 21 h.
OEt2 in nitromethane, conditions reported by Mander18 to be
effective for cyclizing γ,δ-unsaturated α-diazoketones, provided
only silyl ether hydrolysis product (−)-21, casting uncertainty
over a Lewis acid catalyzed process.
Finally, we note that removal of the methoxycarbonyl group
gives facile access to products of formal dipolar cycloaddition of
a molecule of acetone across a conjugated enone. As shown in
Table 2, diverting the crude reaction mixtures of the Cu(I)-
catalyzed annulation to heating in wet DMSO or DMF instead
of deprotection-protection brought about removal of the ester
group altogether via an acyl ketene-based hydrolysis−
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the University of California
and the American Chemical Society Petroleum Research Fund
(PRF# 52871-DNI1). We thank the Figueroa Laboratory
(UCSD) for advice on and use of gloveboxes and the
Dorrestein Laboratory (UCSD) for use of mass spectrometers.
NMR spectrometers used throughout our investigations were
acquired through NSF grants to the UC San Diego Department
of Chemistry and Biochemistry (CHE-9709183 and CHE-
0741968). We thank Jesus C. Pascual for early technical
assistance.
a
Table 2. Decarboxylative Annulation with 1
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D
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