Stereoselective Synthesis of Aryl Cyclopentene Scaffolds by Heck-Matsuda Desymmetrization of 3-Cyclopentenol

Article abstract of DOI:10.1002/chem.201404159

A new enantioselective Heck-Matsuda desymmetrization reaction was accomplished by using 3-cyclopentenol to produce chiral five-membered 4-aryl cyclopentenol scaffolds in good yields and high ee's, together with some 3-aryl-cyclopentanones as minor products. Mechanistically, the hydroxyl group of 3-cyclopentenol acts as a directing group and is responsible for the cisarrangement in the formation of the 4-aryl-cyclopentenols.

Full text of DOI:10.1002/chem.201404159

DOI: 10.1002/chem.201404159
Communication
&
Synthetic Methods
Stereoselective Synthesis of Aryl Cyclopentene Scaffolds by
Heck–Matsuda Desymmetrization of 3-Cyclopentenol
Ricardo A. Angnes, Juliana M. Oliveira, Caio C. Oliveira, Nelson C. Martins, and
Carlos Roque D. Correia*[a]
We describe herein our results on the enantioselective syn-
Abstract: A new enantioselective Heck–Matsuda desym-
metrization reaction was accomplished by using 3-cyclo-
thesis of cis-aryl-cyclopentenols 8, with the aryl cyclopenta-
nones 9 as a minor product (Scheme 1). Equally important is
pentenol to produce chiral five-membered 4-aryl cyclo-
the practical way by which these reactions can be carried out
pentenol scaffolds in good yields and high ee’s, together
and the mechanistic insights they provide.
with some 3-aryl-cyclopentanones as minor products.
We began our studies by evaluating the enantioselective
Mechanistically, the hydroxyl group of 3-cyclopentenol
Heck arylation of the commercially available cyclopentenol 7
acts as a directing group and is responsible for the cis-
using bisoxazoline L1 as a ligand, applying a protocol previ-
arrangement in the formation of the 4-aryl-cyclopente-
ously reported by us.[4] The reaction was completed in 30 min
nols.
at 608C, and, contrary to our initial expectations, we obtained
two products which were readily isolated and purified by flash
chromatography in a combined yield of 63%. The products
Desymmetrizations are powerful strategies in organic synthesis
for the construction of enantioenriched molecules from prochi-
ral starting materials.[1] Chiral transition metal catalysis has
been instrumental in the development of the desymmetriza-
tion strategy.[2] Advances within this strategy have also brought
enormous benefits to the field of enantioselective catalysis,
mainly when associated with organic synthesis.[1,2] The enantio-
selective Heck reaction has been a pivotal tool in organic syn-
thesis, with new versions bringing significant advances to the
field. This is certainly the case for the Heck–Matsuda reaction,
which involves the arylation of olefins using arenediazonium
salts.[3]
were identified as the novel cis-(1S,4R)-4-(4-methoxyphenyl)-
cyclopent-2-enol (8a) and (S)-3-(4-methoxyphenyl)cyclopenta-
none (9a) as the minor product. Aryl cyclopentenol 8a was
identified by spectroscopic and spectrometric analysis and by
comparison to its known trans analogue.[7] Aryl-cyclopenta-
none 9a is a well-known compound and its specific rotation
provided the basis for the assignment of its absolute stereo-
chemistry as S. This absolute stereochemistry was also con-
firmed by the straightforward transformation of 8a into aryl-
cyclopentanone 9a by double bond hydrogenation followed
by Jones oxidation (Scheme 2).
In 2012, we reported the first example of an enantioselective
Heck–Matsuda reaction: the desymmetrization of unactivated
olefin 2 employing the chiral bisoxazoline ligand L1.[4] Later on,
this enantioselective arylation was applied to both butene-diol
isomers 4 on route to the synthesis of valuable aryl-lactones 6,
as shown in Scheme 1.[5a] Aiming at expanding the usefulness
and synthetic potential of this strategy, we envisioned its appli-
cation with the symmetrical cyclopentenol 7 for the construc-
tion of important arylated five-membered carbocycles scaffolds
in a straightforward and efficient manner. Substituted cyclo-
pentenes are structural motifs of many natural products and
bioactive compounds.[6]
Scheme 1. Heck–Matsuda-based enantioselective desymmetrizations.
[a] R. A. Angnes, Dr. J. M. Oliveira, C. C. Oliveira, Dr. N. C. Martins,
Prof. Dr. C. R. D. Correia
The Heck products shown above are valuable and useful in-
termediates for organic synthesis. In particular, formation of
aryl cyclopentenol 8a is mechanistically intriguing, because de-
symmetrization led to the formation of a highly functionalized
compound bearing two stereogenic centers in an unprece-
dented cis arrangement.[8]
Institute of Chemistry
State University of Campinas- Unicamp
C.P. 6154, CEP. 13083-970, Campinas, S¼o Paulo (Brazil)
E-mail: roque@iqm.unicamp.br
Homepage: www.correia-group.com
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404159.
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Scheme 2. Enantioselective arylation of 7 using L1.
Scheme 4. Scope of the reaction regarding formation of aryl-cyclopentenols
8.
Scheme 3. Ligand screening for the enantioselective arylation of 7.
Further optimization, using palladium(II) trifluoroacetate,
(Pd(TFA)2, 2.5 mol%), lower temperature (408C), and 1 equiv of
DTBMP as base, gave 8a in 64% yield and 92% ee (Scheme 4).
Next, to access its synthetic potential, the reaction scope was
evaluated with several diazonium salts containing electron do-
nating (ED) or electron withdrawing (EW) groups in different
substitution patterns.
Several N,N-ligands were then screened to evaluate the in-
fluence of the ligand and also to optimize the Heck reaction.
Some illustrative results are presented in Scheme 3. Following
the trend observed for the bisoxazoline L1, ligand L2 provided
a slight increase in the yield of the Heck products 8a/9a
(71%) with a decreased product ratio of about 2:1 and ee’s of
61% for 8a and 28% for 9a. Unexpectedly, the PyBOX ligand
L3 exclusively produced aryl cyclopentenol 8a with a 56%
yield, albeit in only 25% ee. Higher yields and enantiomeric ex-
cesses were observed with PyOX ligands L4 and L5. With
ligand L5, the Heck products were obtained in a combined
yield of 88% in a ratio of 2.5:1 producing the major product
(1S,4R)-aryl cyclopentenol 8a in a good 82% ee, and, surpris-
ingly, aryl-cyclopentanone 9a of inverted configuration (ent-
9a; 3R) in only 16% ee. Similar results were obtained with
PyOX ligand L4, which also provided the cyclopentenol 8a
(72% ee) and the ent-9a (21% ee) in a combined yield of 72%.
In another surprising event, QUINOX ligand L6 produced
almost exclusively the aryl-cyclopentanone ent-9a with an ex-
cellent 84% yield and an ee of 46%.
Gratifyingly, the enantioselective Heck–Matsuda reaction
demonstrates good scope, as arylations can be carried out
with arenediazonium salts bearing ED and EW substituents.[9]
More importantly, the ee’s of the major product aryl-cyclopen-
tenols 8a-o were excellent in all cases, ranging from 85% up
to 99%. Surprisingly, the o-phenol-cyclopentenol 8 f was ob-
tained as the exclusive Heck product in 92% ee. Aryl-cyclopen-
tenol 8 f is a particularly interesting compound and its struc-
ture was further confirmed by its conversion to o-OMe aryl-
cyclopentenol 8b (Scheme 4).
Notably, electron deficient arenediazonium salts produced
aryl-cyclopentenols 8h–o in uniformly higher ee’s (93–99%).
The electronically borderline benzenediazonium tetrafluorobo-
rate gave the aryl-cyclopentenol 8g in a low to moderate 44%
yield with an excellent 95% ee. Regardless of electronic bias,
the ortho-substituted arenediazonium salts provided lower
yields of the arylated products, indicating some steric influence
in the arylation process, although this does not constitute
a general trend, as can be seen for compounds 8b and 8 f. As-
signment of the absolute stereochemistry for compounds in
Scheme 4 was confirmed by the X-ray diffraction of 8h
(Figure 1).
The inversion of configuration for the aryl-cyclopentanone
9a when using ligands L4–L6 was a striking observation. Al-
though not clear at this stage, we speculate that kinetic resolu-
tion might be operating in the case of L4 and L5 with elec-
tron-rich diazonium salts leading to the conversion of aryl cy-
clopentenol ent-8a into aryl-cyclopentanone ent-9a by means
of some free chiral Pd hydride complex (for a possible ration-
ale, see supporting information).
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In all cases examined, the aryl-cyclopentanones were ob-
tained as a minor component of the reaction, and only cyclo-
pentanones isolated in yields higher than 8% are shown in
Scheme 7. The aryl-cyclopentenol 8 to aryl-cyclopentanone 9
ratio varied from 2.2:1 up to >20:1 depending on the aryldia-
zonium salt used. It should be highlighted that both com-
pounds are readily separated by column chromatography.
Somewhat unexpectedly, aryl-cyclopentanones 9a, 9c, and 9e
derived from ED-substituted aryldiazonium salts have an R con-
figuration with ee’s varying from 17 to 22%. The reasons for
such stereochemical inversion are not clear at present, but, as
mentioned before, we hypothesize that kinetic resolution
might be involved in the formation of those compounds (see
supporting information for a rationale). On the other hand,
phenyl- and halogen-substituted aryldiazonium salts provided
aryl-cyclopentanones 9g, 9h, and 9i with the expected S con-
figuration in low to moderate ee’s (18–58%), whereas EW-sub-
stituted diazonium salts furnished, in general, aryl cyclopenta-
nones 9j and 9l in good to high ee’s (88 and 93%, respective-
ly), with the surprising exception of 9m. Interestingly, 3-aryl-cy-
clopentanones derived from meta-substituted diazonium salts
displayed lower ee’s, regardless of their electronic nature (com-
pounds 9c, 9k, and 9n, Scheme 7). Despite effective alterna-
tives available in the literature,[13] from the synthetic stand-
point, aryl cyclopentanones 9 can also be obtained in good
yields and high ee’s from aryl-cyclopentenols 8, as indicated in
Scheme 2, thus further demonstrating the potential of the
enantioselective Heck–Matsuda reaction to produce distinct
and synthetically useful intermediates.
Figure 1. ORTEP diagram for the compound 8h. Displacement ellipsoids are
drawn at the 50% probability level. Hydrogen atoms are shown as small
spheres of arbitrary radius.
Although the mechanistic details of this enantioselective
Heck–Matsuda arylation are still under investigation, a catalytic
cycle for the formation of the aryl-cyclopentenols 8 is pro-
posed using the PyOX ligand L5 (Scheme 5).10] Formation of
In conclusion, the enantioselective Heck–Matsuda arylation
of the symmetrical cyclopent-3-enol (7) using PyOX ligand L5
provides two Heck products with good to excellent selectivi-
ties (2.2 up to >20:1). The major products, the cis-4-arylcyclo-
pent-2-enols 8 can be obtained in moderate to good yields in
ee’s varying from 85 to 99% and constitute novel and highly
functionalized five-membered scaffolds that open up new syn-
thetic opportunities.[6,8] Moreover, the minor and mechanisti-
cally relevant 3-aryl-cyclopentanones 9 were obtained in ee’s
varying from 17 up to 93%. A rationale is provided for the for-
mation of those Heck products featuring an intriguing direct-
ing effect of the hydroxyl group of the symmetrical cycloalke-
nol in the catalytic cycle. Formation of the 3-aryl-cyclopenta-
nones 9 features an interesting syn Pd walking ending up in
a Wacker-type oxidation. As a synthetically oriented method,
these Heck arylations are operationally simple to carry out.
They are clean, fast, and do not require any special technique
in the laboratory.
Scheme 5. Proposed catalytic cycle for the enantioselective arylation of 7.
cis-aryl-cyclopentenols 8 can be rationalized by a somewhat in-
triguing endo orientation of the hydroxyl group in the enantio-
determining step as indicated by transition state D. We hy-
pothesize that a weak Lewis acid–base interaction of the endo-
oriented hydroxyl group towards the cationic PdII (D) is the
major driving force favoring this transition state and formation
of the (1S,4R)-4-(phenyl)cyclopent-2-enol Heck product.[11]
Formation of the majority of the aryl-cyclopentanones 9 ob-
served in this study probably involves a transition state similar
to the one proposed in Scheme 5, but in which the hydroxyl
group of cyclopentenol 7 assumes an exo orientation in the
carbopalladation step (transition state G, Scheme 6). As carbo-
palladation occurs on the opposite face of the hydroxyl group,
an interesting palladium syn chain walking then leads to the
carbinol–Pd complex L, which, by a terminal Wacker-type oxi-
dation, probably with the participation of the solvent metha-
nol, forms the aryl-cyclopentanones 9.[12]
Experimental Section
A 15 mL vessel containing a magnetic stir bar was charged with
Pd(TFA)2 (2.5 mol%), ligand L5 (5.0 mol%) and methanol (5.3 mL,
0.075m). The resulting light-orange solution was then stirred for
10 min at 408C. At this point, we added DTBMP (2,6-di-tert-butyl-4-
methylpyridine) (1 equiv), olefin 7 (2 equiv), followed by the addi-
tion of the appropriate arenediazonium salt 1 (1 equiv). The reac-
tion was monitored by TLC until complete consumption of the di-
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Scheme 6. Proposed catalytic cycle for the enantioselective synthesis of cyclopentanones 9 involving a Pd syn chain walking and a Wacker-type oxidation.
remove the polar components. The resulting solution was concen-
trated under vacuum and the crude products purified by flash
chromatography using EtOAc/hexanes 30% as eluent to obtain the
major Heck products aryl-cyclopentenols 8a–o and the minor aryl-
cyclopentanones 9a–n.
Acknowledgements
Financial support was provided by the S¼o Paulo Research
Foundation - Fapesp (2011/23832-6; 2013/07600-3). We are
also grateful to Dr. Cristiane Schwalm for her help with the
X-ray diffraction.
Keywords: aryldiazonium salts
·
chiral N,N ligands
·
desymmetrization · Heck reaction · palladium
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Received: June 28, 2014
Published online on August 26, 2014
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