Cross-metathesis/isomerization/allylboration sequence for a diastereoselective synthesis of anti-homoallylic alcohols from allylbenzene derivatives and aldehydes

Article abstract of DOI:10.1002/chem.201403954

We describe a highly diastereoselective approach to anti-homoallylic alcohols from allylbenzene derivatives and aldehydes. The strategy is based on a cross-metathesis/isomerization/allylboration sequence catalyzed successively by ruthenium and iridium. This methodology provides another way to access this class of compounds, which leads to the preparation of hitherto-unknown homoallylic alcohols without the requirement to control the stereochemistry of the 1-alkenyl boronate intermediates. Our study towards an enantioselective version of this sequential reaction is also reported.

Full text of DOI:10.1002/chem.201403954

DOI: 10.1002/chem.201403954
Full Paper
&
Synthetic Methods
Cross-Metathesis/Isomerization/Allylboration Sequence for
a Diastereoselective Synthesis of Anti-Homoallylic Alcohols from
Allylbenzene Derivatives and Aldehydes
Rꢀmy Hemelaere, FranÅois Carreaux,* and Bertrand Carboni[a]
Abstract: We describe a highly diastereoselective approach
to anti-homoallylic alcohols from allylbenzene derivatives
and aldehydes. The strategy is based on a cross-metathesis/
isomerization/allylboration sequence catalyzed successively
by ruthenium and iridium. This methodology provides an-
other way to access this class of compounds, which leads to
the preparation of hitherto-unknown homoallylic alcohols
without the requirement to control the stereochemistry of
the 1-alkenyl boronate intermediates. Our study towards an
enantioselective version of this sequential reaction is also re-
ported.
Introduction
borabicyclo[3.3.2]decane ([10-TMS-9-BBD-H]). The Z g-substitut-
ed allylboranes generated reacted with aldehydes to give ho-
moallylic alcohols with a modest-to-high diastereoselectivity in
favor of the syn product.[7] A three-component procedure
based on the hydroboration of propargyl bromide as the first
step was also reported to give anti-homoallylic alcohols.[8] The
cross-metathesis reaction of hindered olefins with pinacol allyl
boronate followed by a subsequent allylboration led to the
anti products with high selectivity.[9] A catalytic borylation–ally-
lation approach with bis(pinacolato)diboron (B2pin2) as the bor-
onate source has also been developed with different sub-
strates.[10] For example, a “one-pot” procedure from E-allylic al-
cohols catalyzed by a palladium pincer complex was described
to produce homoallylic alcohols with high anti selectivity.[11]
Among the catalytic reactions, which can be useful to gener-
ate allylboronates as transient intermediates, the double-bond
isomerization of 1-alkenyl boronates has drawn the attention
of several groups. 3-Alkoxy-1-alkenyl boronates were the first
substrates studied with success, probably due to the presence
of the oxygen-containing functionality.[12] However, the failed
attempt of an intramolecular isomerization–allylboration se-
quence with various transition metals was described, which
compromised the idea to develop a sequential reaction from
this kind of alkenyl boronate.[13]
Allylboration of aldehydes is probably one of the most popular
and efficient methods for the preparation of functionalized ho-
moallylic alcohols.[1] One of the main reasons for this success,
besides simple implementation, is the predictable diastereo-
control of the allylation products via a six-membered transition
state depending upon the stereochemistry of the starting allyl-
boron reagent.[2] Numerous preparative methods of this struc-
tural class of reactants have been reported in the literature,
most often with strict control of the geometry of the double
bond to secure the construction of adjacent chiral centers in
a highly diastereoselective manner.[3] However, in some cases,
the low stability towards hydrolysis makes purification difficult
and the necessity arises to devise reactions by simplifying ex-
perimental implementation and improving the resource effi-
ciency (time, cost, etc.),[4] therefore other strategies have
emerged to generate g-substituted allylboron reagents in situ
(with subsequent addition to carbonyl compounds).
For instance, with acyclic derivatives the 1,4-addition of an
organometallic reagent to an alkenyl boronate with a g-acetal
group followed by an allylboration reaction stereoselectively
furnished anti-diol derivatives.[5] Aggarwal and co-workers have
developed a protocol that combines lithiated carbamates, vinyl
boronic esters, and aldehydes to provide homoallylic alcohols
with generally high diastereomeric and enantiomeric ratios.[6]
The “one-pot” procedure can also be initiated by hydrobora-
tion of allenes with nonracemic Soderquist borane 10-TMS-9-
Since then, very few works have been published that de-
scribe the generalization of this reaction for other alkenyl boro-
nates and integrate it into a sequential reaction for the synthe-
sis of functionalized homoallylic alcohols. It was shown that
a cationic rhodium(I) complex effectively catalyzed the olefin
migration of 1-alkenyl boronates in 1,2-dichloroethane at
reflux in the presence of aldehydes to give the corresponding
allylation products.[14] However, the observed diastereoselectiv-
ity in favor of the anti product depends on the double-bond
geometry of the starting materials. During the preparation of
this manuscript, the same group described a new procedure
that used a cationic iridium(I) complex under milder conditions
[a] Dr. R. Hemelaere, Dr. F. Carreaux, Dr. B. Carboni
Institut des Sciences Chimiques de Rennes 1
UMR 6626 CNRS, Universitꢀ de Rennes 1
Campus de Beaulieu, 35042 Rennes CEDEX (France)
Fax: (+33)0299236747
E-mail: francois.carreaux@univ-rennes1.fr
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403954.
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for the synthesis of anti-homoallylic alcohols.[15] In all cases, the
stereodefined 1-alkenyl boronates were prepared by conven-
tional hydroboration of the corresponding terminal al-
kynes.[14–16]
Results and Discussion
At the outset of the investigation, we initially compared the
catalytic activity of different pre-catalysts for the isomerization
of model substrate (E)-4,4,5,5-tetramethyl-2-(3-phenyl-propen-
yl)-[1,3,2]dioxaborolane (2a; Table 1). Compound 2a can be
easily prepared by esterification of the corresponding commer-
cially available boronic acid.[14] Among the ruthenium pre-cata-
lysts selected for this study, M71-SIPr was chosen for its ability
to promote alkene isomerization in a 1,4-benzoquinone-free
process.[19] With conventional heating, the desired product 3a
was only obtained when an excess of TMS vinyl ether (TMSO-
ethene) was used to generate the likely ruthenium–hydride
complex (Table 1, entries 1 and 2).[20] Although the stereoselec-
tivity is completely in favor of the E isomer in MeOH under mi-
crowave irradiation (MWI), the conversion still remained
modest (Table 1, entry 3). No improvement was obtained by
changing the ruthenium pre-catalyst (G-II in place of M71-
SIPr), but a loss of stereoselectivity was observed (Table 1,
entry 4). The use of an iridium-mediated system increased the
formation of the isomerized product. Catalyst [Ir(cod)-
(PPh2Me)2]PF6 (cod=1,5-cyclooctadiene) activated by H2 in
THF gave superior results relative to the ruthenium metathesis
pre-catalysts attempted, and the double-bond migration took
place under milder conditions with high stereoselectivity
(Table 1, entry 5).[21]
Taking into account that the accessibility of starting materi-
als is an important consideration for the development of
useful organic reactions, we envisaged the preparation of
novel homoallylic alcohols from terminal alkenes and alde-
hydes based on a cross-metathesis/isomerization/allylboration
sequence (Scheme 1). Moreover, due to the lower reactivity of
Scheme 1. Sequential reactions, including an allylboration step, for the prep-
This catalytic procedure has proven compatible with the
presence of an aldehyde in the reaction medium, which allows
“one-pot” formation of the desired homoallylic alcohol from
the alkenyl boronate 2a (Scheme 2). Addition of 4-nitrobenzal-
dehyde (1 equiv) to 2a (1 equiv) gave compound 5aa (after
purification) with an unoptimized yield of 60%. Only the anti
diastereomer was observed, which confirmed the high stereo-
selectivity of the isomerization step in favor of the E isomer.[22]
We were surprised that this high diastereoselectivity was main-
aration of acyclic homoallylic alcohols.
alkenes relative to terminal alkynes, this strategy should be
more appropriate for the multistep synthesis of multifunctional
products. Recently, we described a simple cross-metathesis
procedure for the synthesis of 3-aryl-1-propenyl boronates,
which are potentially good substrates for an isomerization re-
action given their structural characteristics.[17] In this paper, we
report our efforts devoted to the
Table 1. Optimization of the isomerization methodology with different pre-catalysts.[a]
implementation of a three-com-
ponent reaction of functional-
ized homoallylic alcohols from
allyl benzene derivatives 1, pina-
col vinyl boronic ester 4, and al-
dehydes. An activated iridium
catalyst [IrH2(thf)2(PPh2Me)2]PF6
([Ir])[18] was used for the olefin
transposition reaction, which
provides the allylboration prod-
ucts with high diastereoselectiv-
ity after the reaction with alde-
hydes. The selectivity is inde-
pendent of the stereochemistry
of the 1-alkenyl boronate precur-
sors obtained by the cross-meta-
thesis reaction. An asymmetric
version of this new sequence
that used a chiral Brønsted acid
catalysis system was also ex-
plored with interesting results.
Entry
Pre-catalyst [mol%]
Conditions
Conversion [%][b]
E/Z 3a[c]
1
2
3
4
5
M71-SIPr (10)
M71-SIPr (10)
M71-SIPr (10)
G-II (10)
MeOH, reflux, 20 h
–
–
TMSO-ethene CH2Cl2, reflux, 20 h
MeOH, MWI, 708C, 80 W, 45 min.[d]
MeOH, MWI, 708C, 80 W, 45 min.[d]
THF, rt, 2 h[e]
28
40
30
90
90:10
100:0
90:10
100:0
[Ir(cod)(PPh2Me)2]PF6 (3)
[a] All pre-catalysts were used without further treatment. [b] Conversion based on 2a. [c] Determined by analy-
sis of the 1H NMR spectra of the product mixtures. [d] Reaction was carried out in the Explorer24 CEM reactor.
[e] Hydrogen gas was gently bubbled into a solution of [Ir(cod)(PPh2Me)2]PF6 (3 mol%) in THF (0.15m) for
around 2 min prior the addition of 2a (0.20 mmol).
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Table 2. Synthesis of anti-homoallylic alcohols 5 from allylbenzene 1a.[a]
Entry
R
Product
5aa
Yield [%][b]
Anti/syn[c]
>98:2
1
2
63
60
5ab
>98:2
3
4
5
5ac
5ad
5ae
66
70
65
>98:2
>98:2
>98:2
Scheme 2. Synthesis of 5aa from 1a by a cross-metathesis/isomerization/al-
lylboration sequence with two different catalysts.
tained when the double-bond geometry of the alkenyl boro-
nate was not controlled. Indeed, the cross-metathesis reaction
between allylbenzene 1a and vinylboronic acid pinacol ester 4
in the presence of G-I led to the alkenyl boronate intermediate
as a mixture of isomers (E/Z=5.7:1).[17] After filtration of the
Grubbs first-generation catalyst, this intermediate
was used directly in the iridium-catalyzed isomeriza-
tion–allylboration sequence to afford only the anti-
homoallylic alcohol 5aa in 63% yield.[23] This result
provides real added value for the methodology rela-
tive to those previously described.[14,15]
[a] Reaction scale: 1a (0.20 mmol), 4 (2 equiv), G-I (3 mol%) in CH2Cl2
(0.2m); then RCHO (1 equiv), [Ir(cod)(PPh2Me)2]PF6 (3 mol%) in THF
(0.15m). [b] Isolated yield of pure product 5. [c] Determined by analysis of
1
the H NMR spectra of the product mixtures prior to purification.
The process also works well with aromatic and
alkyl aldehydes to afford the anti products with
yields of 60–70% (Table 2).[24]
We next explored the scope and limitations of this
new diastereoselective approach for the synthesis of
homoallylic alcohols by variation of the nature of the
allylbenzene derivatives 1 (Figure 1).[25] In all cases,
compounds 5 were synthesized with high diastereo-
selectivity (anti/syn= >98:2). The variation in the ob-
tained yields can be mainly attributed to the allylbo-
ration step because the isomerization reaction is
almost complete (>90%) in all cases.[26] The steric
hindrance of the generated allylboronates (5ca
versus 5da), as well as the electron density on the
C=O group of the aldehydes used in the allylation re-
action [electron-deficient (5 fa) versus electron-rich
system (5 fb)] have an influence on the yield of the
reaction.
Taking into account that a substantial majority of
these compounds are new, we took this opportunity
to transform some of them into the corresponding
a,b-unsaturated d-lactones, a scaffold largely present
in biologically active natural products.[27] Following
a known synthetic approach for this class of com- Figure 1. Synthesis of diversely functionalized anti-homoallylic alcohols 5.
pounds,[28] the homoallylic alcohols 5 were converted
to acrylate esters 6a–e with acryloyl chloride in pres-
ence of triethylamine. Subsequent ring-closing metathesis cat-
alyzed by M71-SIPr afforded 7a–e (Scheme 3).
We then turned our attention to an asymmetric version of
this methodology. We studied different strategies, for instance
the introduction of a chiral diol auxiliary on the boron atom.[29]
Whatever chiral boronic ester 2 was used, the stereoselective
isomerization reaction (E/Z= >98:2) was almost quantitative
after 2 h, even with hindered camphor derivative 2d.[30–31] After
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Table 4. Optimization of an enantioselective isomerization–allylboration
sequence.[a]
Entry
Solvent
T [8C]
t [h]
Yield [%][b]
ee [%][c]
Scheme 3. Synthesis of a,b-unsaturated d-lactones from 5.
1
2
3
toluene
CH2Cl2
toluene
0
0
À30
24
24
96
52
43
45
74
68
74
evaporation of the solvent, a solution of 4-nitrobenzaldehyde
in CH2Cl2 was added to the residue under typical conditions
(low temperature) described in the literature for such chiral al-
lylboronates.[32] In all cases, the allylated compound 5aa was
obtained with high diastereoselectivity (anti/syn= >98:2), the
best enantiomeric ratio, measured by chiral HPLC, was found
for the reaction with (R,R)-diisopropyl tartrate [(+)-DIPT] as
a chiral auxiliary (Table 3, entry 2).[33] A disappointing enantio-
meric excess (10% ee) was obtained with camphor-derived diol
2d, by using a scandium-catalyzed protocol that has proven
efficiency with crotylboronates (Table 3, entry 3).[34]
[a] Reaction scale: 2a (0.20 mmol), [Ir(cod)(PPh2Me)2]PF6 (3 mol%) in THF
(0.15m); then RCHO (1 equiv), (S)-TRIP-PA (5 mol%) in solvent (0.15m).
[b] Isolated yield after flash chromatography. [c] Determined by integra-
tion of the CF3 signals of the diastereomeric Mosher’s esters in the
19F NMR spectra. Absolute configuration determined by analysis of the
1H NMR spectra of the corresponding Mosher’s esters.
In our case, the crude mixture from the iridium-catalyzed
isomerization reaction of the E alkenyl boronate 2a was used
directly to optimize the allylboration reaction in the presence
of (S)-TRIP-PA (5 mol%). A solution of 4-nitrobenzaldehyde
(1 equiv) and 2a (1 equiv) was added to the residue under
a range of conditions (Table 4). From this small screening, we
found that toluene was the most suitable solvent to perform
this transformation at 08C in acceptable yield (Table 4, entry 1).
Despite high diastereoselectivity in favor of the anti isomer,
the observed enantioselectivity (74% ee) was not comparable
to that obtained from alkenyl boronates with a terminal alkyl
chain (up to 96% ee) as observed by Murakami.[15] In support
of our result, Murakami and co-workers also described the
preparation of homoallylic alcohol 5ab (88% ee) from 2a
(1 equiv) and benzaldehyde (2 equiv) catalyzed by another cat-
ionic iridium(I) complex/chiral phosphoric acid system, which
required a greater quantity of chiral TRIP (20 versus 5 mol%)
coupled with a lower reaction temperature (À158C).[37] Based
on these observations, we believe the enantioselectivity drop
for this class of compounds can be attributed to the presence
of the phenyl group which must be disturbed for preferential
interaction between the allylboronate intermediate and the
chiral phosphoric acid.[38]
Table 3. Chiral allylboronates evaluated for an isomerization–allylboration
sequence.[a]
Entry Boronate LA[b]
T [8C]
Yield e.r.
Absolute
[%][c] [%][d] configuration[e]
1
2
3
2b
2c
2d
none
none
Sc(OTf)3 À78
À78 to rt 60
50:50
16:84 (1S,2R)
55:45 (1R,2S)
–
À78
54
45
[a] Reaction scale: 2 (0.20 mmol), [Ir(cod)(PPh2Me)2]PF6 (3 mol%) in THF
(0.15m), then aldehyde (1 equiv) in CH2Cl2 (0.15m). [b] Lewis acid
(10 mol%). [c] Isolated yield after flash chromatography. [d] Enantiomeric
ratio (e.r.) measured by chiral HPLC. [e] Determined by analysis of the
1H NMR spectra of the corresponding Mosher’s esters.
Considering the good availability of the starting materials,
we finally examined the application of this enantioselective
catalytic process in a three-step sequence with a range of allyl-
benzene derivatives and aldehydes (Figure 2). After removal of
the ruthenium catalyst by filtration, the crude product of the
cross-metathesis reaction was engaged in an isomerization re-
action, followed by the catalytic enantioselective allylboration
without any purification steps. The unoptimized yields of iso-
lated products 5 are acceptable for a three-step sequential re-
action. In all cases, only one diastereomer was obtained and
enantioselectivity (54–82%) was determined from the corre-
sponding Mosher’s esters.
Despite the encouraging result obtained from the tartrate-
derived boronic ester, the air/moisture sensitivity of 2c, as well
as the low-temperature allylboration conditions, make devel-
opment of a practical and general asymmetric cross- metathe-
sis/isomerization/allylboration sequence more difficult. The
enantioselective allylboration with the catalytic system de-
scribed by Jain and Antilla seemed to be an appropriate alter-
native to alleviate the present drawbacks.[35] Indeed, the bi-
naphthyl-derived chiral phosphoric acid (TRIP-PA; Table 4) pro-
moted the allylboration reaction of pinacol-derived boronate
esters with high enantioselectivity under mild conditions (even
at room temperature) and has shown compatibility with differ-
ent transition-metal catalysts in tandem reactions.[15,36]
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(0.20 mmol, 1.00 equiv). The mixture was allowed to stir at rt for
20 h. THF was then removed under reduced pressure and the resi-
due was purified by column chromatography (cyclohexane/EtOAc)
to afford the desired homoallylic alcohol 5.
Acknowledgements
This work was supported by the University of Rennes 1 and
the Centre National de la Recherche Scientifique (CNRS). R.H.
thanks “la Rꢀgion Bretagne” for a research fellowship. We also
thank Omꢀga Cat System for the generous provision of catalyst
M71-SIPr.
Keywords: allylboration
isomerization · metathesis
· catalysis · domino reactions ·
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Figure 2. Asymmetric cross-metathesis/isomerization/allylboration sequence.
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Conclusion
We report a diastereoselective, catalytic cross-metathesis/iso-
merization/allylboration sequence for the preparation of anti-
homoallylic alcohols from allyl-substituted derivatives and alde-
hydes. The main advantages of this new three-step sequence
are the accessibility of the starting materials relative to alkynes
and the ability to obtain the homoallylic alcohols in a highly
diastereoselective manner without structurally stereo-defined
alkenyl boronates as transient intermediates. In our quest to
develop an asymmetric version of this process, we found that
the allylboration reaction catalyzed by a chiral phosphoric acid
gave the best results. The enantioselectivity measured re-
mained modest in all cases but, due to the unconventional
structure of the allylboronates generated during the process,
different conditions seem necessary to enhance it. Work under-
way in our laboratory is focused on this target.
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Experimental Section
General procedure for the cross-metathesis/isomerization/al-
lylboration sequence
Compound 4 (0.40 mmol) and catalyst G-I (3 mol%) were added
successively to a solution of 1 (0.20 mmol) in dry CH2Cl2 (0.2m)
under an argon atmosphere. The resulting mixture was heated at
reflux for 18 h. After this time, the solution was filtered through
a short pad of silica and CH2Cl2 was removed under reduced pres-
sure to afford the product 2, which was used without further pu-
rification. A flask was charged with [Ir(cod)(PPh2Me2)2]PF6 (3 mol%)
and flushed with argon. Anhydrous THF (0.15m) was added. Dihy-
drogen was gently bubbled into the solution via a needle for
around 2 min to give a light-yellow solution. The excess dihydro-
gen was then replaced with argon.
(0.20 mmol, 1.00 equiv) in dry THF (0.15 m) was immediately added
to the solution that contained the catalyst, followed by aldehyde
A solution of crude 2
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Received: June 13, 2014
Published online on && &&, 0000
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FULL PAPER
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Synthetic Methods
R. Hemelaere, F. Carreaux,* B. Carboni
&& – &&
Cross-Metathesis/Isomerization/
Allylboration Sequence for
a Diastereoselective Synthesis of Anti-
Homoallylic Alcohols from
Allylbenzene Derivatives and
Aldehydes
The ruthenium and iridium associa-
tion: A complementary and alternative
method for the synthesis of anti-homo-
allylic alcohols by a novel, highly diaste-
reoselective, catalytic, three-component
cross-metathesis/isomerization/allylbora-
tion reaction between allylbenzene de-
rivatives, a vinyl boronate, and alde-
hydes has been achieved (see scheme).
Chem. Eur. J. 2014, 20, 1 – 7
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ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
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These are not the final page numbers! ÞÞ