Modular and highly stereoselective approach to all-carbon tetrasubstituted alkenes

Article abstract of DOI:10.1021/ol503624v

A modular and completely stereoselective approach for the construction of all-carbon tetrasubstituted alkenes is described. It is based on the three-fold, sequential metal-catalyzed, cross-coupling functionalization of simple enolphosphate dibromide templates with carbon nucleophiles, affording tetrasubstituted alkenes as single isomers.

Full text of DOI:10.1021/ol503624v

Letter
pubs.acs.org/OrgLett
Modular and Highly Stereoselective Approach to All-Carbon
Tetrasubstituted Alkenes
†
‡
Tobrman*,†
Vladislav Kotek, Hana Dvora
†
̌
k
́
ova,
‡
́
and Tomas
́
̌
Department of Organic Chemistry and Laboratory of NMR Spectroscopy, University of Chemistry and Technology, Prague,
5, 166 28 Prague 6, Czech Republic
Technicka
́
*
S Supporting Information
ABSTRACT: A modular and completely stereoselective
approach for the construction of all-carbon tetrasubstituted
alkenes is described. It is based on the three-fold, sequential
metal-catalyzed, cross-coupling functionalization of simple
enolphosphate dibromide templates with carbon nucleophiles,
affording tetrasubstituted alkenes as single isomers.
etrasubstituted alkene is a simple, yet important motif
Scheme 1. Electrophilic Templates in the Stereoselective
Synthesis of Tetrasubstituted Alkenes
T
occurring in many substances, including pharmaceuticals
1
−3
and bioactive natural products.
In addition, all-carbon
tetrasubstituted alkenes possess extraordinary structural, elec-
tronic, and chemical properties and are also key substrates in
various asymmetric processes (hydrogenations, epoxidations,
4
−6
etc.), generating highly congested vicinal stereogenic centers.
Efficient synthesis of noncyclic, single-isomer tetrasubstituted
alkenes represents a daunting challenge for organic chemists.
Among many routes to tetrasubstituted alkenes, direct
carbometalation of internal alkynes is by far the most frequently7
utilized strategy, and remarkable achievements have been made.
However, to achieve both regio- and stereocontrolled synthesis,
the structure of the starting alkyne must fulfill certain steric
conditions or require the presence of a suitable directing group.
The most successful and selective approaches utilize regiose-
lective carbometalation to generate multimetalated templates,
which serve as formal doubly or triply nucleophilic synthons
amenable to further elaboration. This ultimately creates an
the regio- and stereochemical outcome of the overall process.
The presence of the activated C−O bond allows the
discrimination of geminal halogen atoms with subsequent
formation of two carbon−carbon bonds. At the same time, it
serves as a latent leaving group for the formation of a third C−C
bond.
8
elementometalation/functionalization nexus. Transition-metal-
9
10
catalyzed cascade reactions, oxidative Heck reaction, meta-
1
1
12a,b
Therefore, several types of halogenated enolesters 1a−f were
thesis reaction, or protocols based on chemistry of ynolates
or ketenes can be mentioned as other frequently used methods
for the synthesis of tetrasubstituted alkenes.
16
1
2c
prepared, sulfonates, carboxylate, or phosphate esters, and
conditions for their selective monoarylation were screened
(
Table 1). After the exhaustive optimization, Negishi reaction of
Surprisingly, significantly less attention has been paid to the
use of solely electrophilic templates (Scheme 1). Thus, the two-
fold cross-coupling reactions of tetrasubstituted double bonds
chlorinated phosphate 1a with p-tolylzinc chloride in the
presence of PdCl (dppp) afforded alkene (Z)-3a in 84% yield
2
1
3
14
(Table 1, entry 1). On the contrary, reaction of phenylzinc
chloride or phenylmagnesium chloride with the brominated
analogue afforded only the product of the elimination (Table 1,
entry 2). Switching to phenylboronic acid restored the
stereospecific coupling and gave the product (Z)-3b in 89%
yield (Table 1, entry 3), indicating that the fine-tuning of the
reaction conditions is necessary for obtaining the desired
product. It was important to use optimized conditions for the
cross-coupling reaction; otherwise, the reaction failed to give the
bearing vicinal or geminal substituents have been reported,
but the most versatile (and challenging at the same time)
approaches would take advantage of three consecutive cross-
coupling reactions of the olefin template. Only one example of
such an approach utilizing CF -substituted alkenes has been
3
reported so far, but separation of isomers was required in this
1
5
case.
As a part of our ongoing project for the development of new
bioactive compounds, we envisioned the cross-coupling
functionalization of simple halogenated enol-type templates as
an amenable route to tetrasubstituted olefins. The structure of
the proposed template plays a crucial role in terms of controlling
Received: December 16, 2014
Published: January 14, 2015
©
2015 American Chemical Society
608
DOI: 10.1021/ol503624v
Org. Lett. 2015, 17, 608−611

Organic Letters
Letter
Table 1. Optimization of Stereo- and Regioselective Cross-
Coupling Reaction of Enolesters 1a−f with Phenylboronic
Acid and Phenylzinc Chloride
Scheme 2. Stereoselective Cross-Coupling of Enolphosphates
1b and 4a−c with Arylboronic Acid
,
ab
a
entry
1
2
catalyst
product (%)
b
1
2
3
4
5
6
7
1a
1b
1b
1c
1d
1e
1f
2c
2c
2a
2a
2a
2b
2a
PdCl (dppp)
(Z)-3a, 84
2
PdCl (dppp)
c
2
b
Pd(OAc) , PPh
(Z)-3b, 89
2
3
3
3
d
e
Pd(OAc) , PPh
40, 5:1
2
d
e
Pd(OAc) , PPh
100, 3:1
2
PdCl (dppp)
f
2
d
Pd(OAc) , PPh
<10
2
3
a
b
c
Isolated yield. Isolated product was >98% Z. Formation of 1-
d
phenyl-1-hexyne was observed. Conversion of starting compound.
e
f
Z/E ratio. No cross-coupling reaction was observed.
expected alkenes (Z)-3a,b, and side reactions including
elimination occurred. In case of tosylates 1c,d, the Suzuki
reaction with phenylboronic acid proceeded smoothly; however,
a mixture of (Z)- and (E)-alkenes was formed (Table 1, entries 4
and 5). Pivalates 1e,f failed to give the expected alkenes, and
unreacted starting compounds were detected in the crude
reaction mixture. These observations indicate that the rate of
oxidation addition of enolphosphates 1a,b is responsible for the
a
b
Isolated yield. Alkenes were isolated as a single stereoisomer (>98%
c
d
Z). Starting compound. Reaction was carried out at 60 °C.
reagents, alkylzinc halides, or trialkylaluminums were not
successful. Only products of elimination and/or reduction
were obtained. The only exception was the methylation with
(CH ) In, which gave the corresponding methyl derivative (Z)-
17
chemo- and stereoselectivity outcome of the reaction.
3
3
After establishing the optimized reaction condition for
selective arylation, we applied the Suzuki reaction of enol
phosphates 1a−c with boronic acid to the reaction of phosphates
6f in 88% yield (Scheme 3). Developed methodology enabled
introduction of a hetaryl substituent, as demonstrated in the
reaction of phosphate (Z)-3b with 2-thienylboronic acid, where
the expected product (Z)-5g was prepared in 86% yield (Scheme
3).
4
a−d with various boronic acids. Thus, boronic acids bearing
fluorine atoms or electron-donating groups were successfully
coupled with phosphate substituted with a simple alkyl group
With the series of stereodefined phosphates in hand,
introduction of the third carbon group was required to complete
the stereoselective synthesis of tetrasubstituted alkenes. The Pd-
catalyzed reaction with boronic acids led to low conversion and/
or decomposition, while Ni catalysts, which are particularly
useful for the activation of unreactive C−O bonds, afforded a
mixture of geometrical isomers. Therefore, we turned our
(
Scheme 2). The presence of a functionality in the structure of
starting phosphates 4c,d was well-tolerated, as shown in the
preparation of functionalized phosphate (Z)-5f.
In the next step, we again took advantage of the different
reactivity of C−Br and C−O bonds to install the second carbon
group. To this end, Suzuki reaction was chosen again; however,
an undesired erosion of the double bond geometry was observed
with the majority of tested catalytic systems. Only the use of a
RuPhos supported Pd catalyst allowed the functionalization of
the starting material without any isomerization of the double
bond. As shown in Scheme 3, boronic acids coupled with
enolphosphates (Z)-3b and (Z)-5b,d,e afforded the expected
stereoisomers (Z)-6a,b and (E)-6a,b in high yields. The structure
and isomeric purity of the stereoisomers (Z)-6a,b and (E)-6a,b
18
attention to the Kumada coupling. It was necessary to use
DMAEE-complexed Grignard reagents and PdCl (XantPhos) as
2
the catalyst in THF to prevent the formation of undesired
1
9
byproducts and to achieve stereospecific coupling. Under these
conditions, no trace of alkene geometry erosion was observed.
Thus, p-tolyl, phenyl, and benzylmagnesium chlorides afforded
the corresponding tetrasubstituted alkenes in high yields as single
isomers, which was confirmed by the preparation of each E and Z
isomer of compound (Z)-7a,b and (E)-7a,b (Scheme 4). In
contrast, the results with simple alkyl (ethyl, allyl) Grignard
reagents were unsatisfactory. Therefore, cross-coupling with
trialkylaluminums was used instead to install methyl, allyl, and
benzyl groups on substrates (E)-7d and (Z)-7e,f. In addition,
application of trialkylaluminums opens a route to stereoselective
functionalization of enolphosphate 6 under mild conditions.
1
3
were determined by comparison of C NMR spectra and NOE
experiment. The Negishi reaction of (Z)-5f with 3-
CF C H ZnCl·LiCl also proceeded successfully (Scheme 3).
3
6
4
The functionalized neopentylglycol boronate and styrenylbor-
onic acid were used as starting compounds for the production of
the expected products (E)-6d and (Z)-6e in uniformly high
yields. All attempts to introduce alkyl groups using alkylboron
6
09
DOI: 10.1021/ol503624v
Org. Lett. 2015, 17, 608−611

Organic Letters
Letter
Scheme 3. Preparation of Stereodefined Trisubstituted
Scheme 4. Preparation of Tetrasubstituted Alkenes via Cross-
Coupling Reaction of Enolphosphate 6 with Grignard or
Organoaluminum Reagents
Enolphosphate 6 by the Cross-Coupling Reaction of
,
ab
,
a b
Phosphates 5
a
b
Isolated yield. Alkenes were isolated as the single stereoisomer
c
(>98% Z or E). The compound was prepared by cross-coupling
4
d e
reaction with Grignard reagent R MgX. Starting compound. The
compound was prepared by cross-coupling reaction with R Al.
4
3
a
b
Isolated yield. Alkenes were isolated as a single stereoisomers (>98%
methodology for the synthesis of functionalized and more
complex molecules as well as bioactive substances is underway in
our laboratory.
c
d
Z or E). Starting compound. Cross-coupling reaction of (Z)-5f with
-CF C H ZnCl catalyzed by PdCl MeCN ; RuPhos was used.
3
3
6
4
2
2
e
Cross-coupling reaction of (Z)-3b with (CH ) In catalyzed by
3
3
PdCl (CH CN) ; RuPhos was used.
2
3
2
ASSOCIATED CONTENT
Supporting Information
■
*
S
In summary, we have developed a new approach for the
completely stereoselective synthesis of tetrasubstituted alkenes,
allowing modular access to a wide variety of alkenes. The
methodology is based on three consecutive cross-coupling
reactions of enolphosphate templates with carbon nuclephiles,
where the following features can be emphasized: First, chemo-
and stereoselective cross-coupling reactions of enolphosphate
dibromide with boronic acids proceeds at the terminal carbon at
the trans position relative to the phosphate moiety under mild
reaction conditions with complete selectivity. Second, RuPhos-
derived Pd catalysts enabled substitution of the second bromine
atom by reaction with organozinc reagents or boronic acids.
Third, the cross-coupling reaction of trisubstituted enolphos-
phate with arylmagnesium halides catalyzed with
Detailed experimental procedures, characterization of all
1
13
compounds, and copies of H and C NMR and selected
NOE spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: tomas.tobrman@vscht.cz.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from specific university research (MSMT No.
21/2012 and No. 20/2013).
■
PdCl (XantPhos) accomplished the stereoselective synthesis of
2
tetrasubstituted alkenes. Further extension of the developed
6
10
DOI: 10.1021/ol503624v
Org. Lett. 2015, 17, 608−611

Organic Letters
Letter
(
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DOI: 10.1021/ol503624v
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