Counteranion-directed catalysis in the tsuji-trost reaction: Stereocontrolled access to 2,5-disubstituted 3-hydroxy-tetrahydrofurans

Full text of DOI:10.1002/anie.201205479

Angewandte
Chemie
DOI: 10.1002/anie.201205479
Stereoselective Catalysis
Counteranion-Directed Catalysis in the Tsuji–Trost Reaction: Stereo-
controlled Access to 2,5-Disubstituted 3-Hydroxy-Tetrahydrofurans**
Martin Arthuis, Rodolphe Beaud, Vincent Gandon,* and Emmanuel Roulland*
The concept of counteranion-directed catalysis (CDC) is
applicable to reactions in which cationic intermediates are
formed.[1] In principal, it can even be applied to transition-
metal-catalyzed reactions,[2] as demonstrated for gold catal-
ysis by Toste and co-workers,[3] and for palladium catalysis by
List and co-workers.[4] The latter group showed that the
positively charged p-allyl/PdII complex of the Tsuji–Trost
reaction[5,6] can interact with a chiral counteranion, thus
allowing an efficient direct a allylation of aldehydes by
asymmetric counteranion-directed catalysis (ACDC). In the
proposed mechanism, the chiral phosphate counteranion
establishes hydrogen bonds with the HN moiety of the
intermediate enamine as well as an ionic interaction with the
charged PdII center, thus resulting in a very organized
transition state (Scheme 1).
ylate counterion plays a prominent directing role. We propose
a mechanism that is based on DFT calculations and chemical
experiments, and which indicates that the stereocontrol may
in part be a result of the formation of an unusual noncovalent
bond between the counteranion and one of the hydrogen
atoms of the cationic p-allyl/Pd complex itself. The two
hydroxy groups are also involved in the mechanism, and the
sum of all these noncovalent interactions leads preferentially
to the highly organized chiral transition state [pR]° (see
Schemes 1 and 3), a prediction that accounts well for the
observed diastereoselectivity.
In the course of our total synthesis of (+)-oocydin A (1;
Figure 1),[7] we devised this convenient approach to 2,5-
disubstituted 3-hydroxy-tetrahydrofuran 4 from the readily
Figure 1. Examples of natural products that feature the 2,5-disubsti-
tuted 3-hydroxy-tetrahydrofuran motif.
available syn diol 3, giving 4 in a surprisingly high d.r. (trans/
cis = 96:4; Scheme 2). This high selectivity was unexpected,
considering the work of Hara et al.,[8] who observed a poor
diastereoselectivity (trans/cis = 37:63) for the cyclization of 5
to 6 (Scheme 2). This result led us to suspect a directing effect
of the b-OH group in the stereoselective cyclization of 3 to 4,
and prompted us to further explore this promising reaction.
The first confirmation of our hypothesis was the observation
that even anti diol 7 cyclized diastereoselectively, leading to
2,5-disubstituted 3-hydroxy-tetrahydrofuran 8[9] (anti/syn =
95:5, 97% yield; Scheme 2). We must emphasize that in anti
diols as well as in syn diols, the newly formed vinyl function is
selectively installed trans to the b-OH group (which does not
cyclize), while the stereogenic center that bears the g-OH
group (which cyclizes) seems to have no impact on the
stereoselectivity, which is counterintuitive.
In order to gain some insight into the mechanism of this
reaction, DFT calculations were carried out, starting with the
syn diol series (Scheme 3).[10,11] The nucleophilic attack of the
g-OH group at the p-allyl moiety was modeled (outer-sphere
mechanism).[12] The calculations showed that cyclization
transition states could not be found if the acetate counter-
anion was not taken into account. No convergence could be
Scheme 1. Rationalized examples of CDC in the Tsuji–Trost reaction.
Herein, we disclose a highly diastereoselective synthesis
of 2,5-disubstituted 3-hydroxy-tetrahydrofurans through the
formation of a p-allyl/PdII intermediate, in which the carbox-
[*] Dr. M. Arthuis, R. Beaud, Prof. Dr. V. Gandon, Dr. E. Roulland
CNRS/Institut de Chimie des Substances Naturelles (ICSN)
Centre de Recherche de Gif
Avenue de la Terrasse, 91198 Gif-sur-Yvette (France)
E-mail: emmanuel.roulland@parisdescartes.fr
Homepage: http//www.icsn.cnrs-gif.fr
Prof. Dr. V. Gandon
Universitꢀ Paris Sud, ICMMO (UMR CNRS 8182)
91405 Orsay (France)
[**] The ICSN and the CNRS are acknowledged for their financial
support. Dr. Gꢀraldine Masson (ICSN), Dr. Sylvain Aubry (ICSN),
and Dr. Yves Janin (Institut Pasteur, Paris) are warmly acknowledged
for valuable scientific discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201205479.
ꢀ
reached in the C O bond formation with the cationic “base-
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Table 1: Correlation between the pKa value of the conjugated acid of the
counteranion and the diastereomeric ratio of cyclization.
Entry Leaving group
Relative
d.r.
pKa of HX
configuration
in H2O
ꢀ
1
2
3
4
tert-BuCO2
MeCO2ꢀ
syn (13a)
anti (7a)
syn (13)
96:4 (14a/b)
95:5 (8a/b)
92:8 (14a/b)
94:6 (8a/b)
90:10 (14a/b) 4.47
90:10 (8a/b)
5.01
4.76
anti (7)
p-MeOPhCO2ꢀ
syn (13b)
anti (7b)
syn (13c)
anti (7c)
ꢀ
PhCO2
88:12 (14a/b) 4.20
86:14 (8a/b)
the one with the b-OH function is beneficial in terms of
energy.[10] The more stable starting diastereomers [pS] and
[pR] both exhibit two O···HO interactions, [pR] also shows
a weak O···Pd interaction.[15] Instead of this ion pairing, [pR]°
shows quite a strong hydrogen bond with the p-allyl system.
This interaction is not geometrically feasible in [pS]°, which
lies higher in free energy than [pR]° (DDG° = 2.1 kcalmolꢀ1).
Thus, the diastereomer derived from complex A is predicted
to prevail, which is indead observed experimentally. With this
model, which is based on noncovalent interactions, exper-
imental results can also be predicted for the anti diol series.[10]
A set of chemical experiments was performed with
substrates 7 and 13, which feature different counteranions,
the conjugated acids of which have different pKa values
(Table 1). A clear correlation could be observed between the
d.r. and the pKa value, independent of the relative config-
uration of the starting diol. Counteranions that corresponded
to weaker acids gave better diastereomeric ratios (Table 1,
entries 1 and 2), which is logical because they
Scheme 2. Synthesis of tetrahydrofurans and directing effect of b-OH
group. Reaction conditions: A) [Pd2(dba)3], P(4-MeOC6H4)3, THF,
408C; B) [Pd(dba)2], PPh3, THF, RT; C) [Pd2(dba)3], P(4-MeOPh)3,
pyridine (0.5 equiv), toluene, RT. [a] Reaction performed at 508C.
[b] Major product. [c] Relative configuration established by NOESY
experiments. [d] The relative configurations of 10a and 10b remain
undetermined. MPM=methoxyphenylmethylidene, TBDPS=tert-butyl-
diphenylsilyl.
free” system.[10] On the other hand, when the acetate was H-
bonded to the cyclizing OH group, transition states could be
located on the potential-energy surface.[13–14] While the
interaction with the cyclizing OH group is a prerequisite,
have a greater tendency to form H-bonds than
counteranions that correspond to stronger
acids (Table 1, entries 3 and 4).
We also prepared b-OH-protected sub-
strates 9 and 11 (Scheme 2), which are able to
form only one H-bond with the counteranion.
As expected, both substrates cyclized with
a slower rate, gave incomplete conversions
even at higher temperatures, and resulted in
a highly reduced diastereoselectivity, compa-
rable to substrate 5, which has no b-OH
group. Calculations that were made on sim-
plified analogues of 9 and 11 confirmed this
observation.[10]
We also carried out experiments to proof
the existence of the unusual H-bonding inter-
action involving the p-allyl/Pd species, as
suggested by DFT calculations. Expecting an
isotopic effect, we synthesized 3D, an ana-
logue of 3 in which the hydrogen atom that
Scheme 3. DFT calculations of the two pathways leading to the major (A) and the minor
(B) product (Gibbs free energy, kcalmolꢀ1).
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supposedly forms the H-bond, was replaced by a deuterium
atom.[16] Allyl acetate 3D cyclized to 4D with a d.r. of 91:9
(experiment repeated twice), instead of the d.r. of 96:4 that
was observed for 4 under the same experimental conditions. It
ꢀ
ꢀ
is known that C D···O bonding is slightly weaker than C
H···O bonding in comparison,[17] hence this small decrease of
the observed d.r. is likely due to an isotopic effect, which
confirms the existence of an H-bonding interaction involving
the p-allyl/Pd moiety.
This synthetic method is particularly valuable with regard
to its efficiency and the abundance of the tetrahydrofuran
motif in natural products.[18] Many of these have very
intriguing structures and/or interesting biological properties,
hence the existence of a great number of strategies and
methods that are aimed at their synthesis.[19] The very
encouraging results mentioned above led us to subject
complex allylacetates to this reaction in order to evaluate
the scope of this transformation with regard to the synthesis
of fragments of natural products. Thus, we synthesized 28, the
C9–C19 fragment of (+)-oocydin A (1). In the key step, triol
21 was subjected to our Pd catalysis conditions and cyclized
into tetrahydrofuran 22 in 80% yield and with a good d.r. of
90:10 (Scheme 4). Because 21 is a triol, tetrahydropyran
derivatives could have been obtained through a concurrent
pathway involving the d-OH group. This reaction fortunately
did not occur, thus showing that the title reaction is both
stereo- and chemoselective. The small decrease in diastereo-
selectivity observed here is likely due to the supplementary d-
OH function, which could disturb the formation of [pR]° by
forming a detrimental H-bond. Triol 21 was readily synthe-
sized from known bis(epoxide) 15.[20] The reaction of 15 with
a sulfur ylide[21] led to the corresponding bis(allylic alcohol)
16, and a selective monoprotection gave allylic alcohol 17.
The latter was transformed into allyl acetate 18, which was
regioselectively reduced to diene 19.[22] Allyl acetate 20 was
obtained through a selective[23] cross-metathesis reaction,[24]
which involved exclusively the less-hindered alkene function
of diene 19. Compound 20 was deprotected,[25] furnishing key
triol 21, which was then transformed to tetrahydrofuran 22.
We pursued our synthesis from 22 by using a VO(acac)2-
directed epoxidation,[26] which gave 23. Mild reaction con-
ditions[27] provided the cyclic silanyle ether 24. The racemic
CoIII–salen complex reported by Jacobsen[28] catalyzed the
mild hydrolysis of fragile epoxide 24 into diol 25 in good yield.
NaIO4-promoted oxidative cleavage of 25 furnished an
aldehyde that was immediately transformed into (E)-a,b-
unsaturated ketone 26,[29–30] and subsequently into diazo
ketone 27.[31] Compound 28, the C9–C19 fragment of
(+)-oocydin A (1), was cleanly obtained through the AgI-
catalyzed Wolff rearrangement of diazo ketone 27.[32] It is
noteworthy that in terms of number of steps, selectivity, and
mildness of conditions, the method we developed for the
synthesis of 2,5-disubstituted 3-hydroxy-tetrahydrofurans
favorably compares with the conventional method, namely
the Roush and Micalizio method.[33] The latter was used by
Hoye and Wang in their remarkably elegant total synthesis of
(+)-oocydin A (1).[34]
Scheme 4. Second generation synthesis of the C9–C19 fragment of
(+)-oocydin A (1). Reaction conditions: a) nBuLi, Me3SI, THF, 458C,
76%; b) second generation Grubbs’ catalyst, (Z)-but-2-ene-1,4-diyl
diacetate (neat), 458C, 74%; c) NaH, TBSCl, DME, 08C; d) Ac2O, 4-
DMAP, pyridine, RT, 98% (over 2 steps); e) [Pd2(dba)3], nBu3P,
HCO2H, Et3N, THF, 608C, 97%; f) TBAF, THF, RT, 98%; g) CeCl3·-
(H2O)7, oxalic acid, MeCN, reflux, 90%; h) cond. C in Scheme 2, 408C,
80% (d.r.=90:10); i) VO(acac)2, tBuO2H, PhMe, 908C, 75%;
j) (tBu)2Si(OTf)2, 2,6-lutidine, TTBP, CH2Cl2, 08C, 80%; k) rac-CoIII–
salen, H2O, THF, RT, 80%; l) NaIO4, silica gel, CH2Cl2, RT, then
PO(OEt)2CHMeCOMe, NaH, THF, 08C, 83%; m) CF3COOCH2CF3,
nBuLi, HMDS, THF, ꢀ788C, then Et3N, H2O, MsN3, MeCN, 358C,
50% (over 2 steps); n) PhCO2Ag, Et3N, MPMOH, THF, RT, 60%.
acac=acetylacetonate, DMAP=dimethylaminopyridine, DME=1,2-
dimethoxyethane, HMDS=hexamethyldisilazane, TBAF=tetrabutylam-
monium fluoride, TBS=tert-butyldimetylsilyl, TTBP=2,4,6-tri-tert-butyl-
pyrimidine.
obtusallene III (2; Figure 1).[35] The cyclization of triol 33 was
again chemo- and diastereoselective, and tetrahydrofuran 34
was obtained in good yield and d.r. Homoallylic alcohol 31
was synthesized from commercially available ester 29 through
the one-pot transformation of its ester function into the
Scheme 5. Synthesis of the C8–C15 fragment of (ꢀ)-obtusallene III (2).
Reaction conditions: a) MeNH(OMe)·HCl, LiHMDS, THF, ꢀ208C!
=
08C, then H2C CHCH2MgCl; b) K-Selectride, THF, Et2O, ꢀ788C, 61%
(over 3 steps); c) 2m HCl, H2O, vacuum, 85%; d) allyl acetate, second
generation Grubbs’ catalyst, CH2Cl2, 82%; e) cond. A in Scheme 2,
358C, 78%, d.r.=90:10.
We also used our methodology in the synthesis of
compound 34 (Scheme 5), the C8–C15 fragment of (ꢀ)-
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desired ketone via a Weinreb amide.[36] The resulting b,g-
unsaturated ketone 30 was diastereoselectively reduced to
alcohol 31 using K-Selectride. The iso-propylidene protective
group of 31 was removed, leading to triol 32, which gave the
key intermediate 33 as a mixture of E/Z isomers through
cross-metathesis with allyl acetate.[24]
[11] To the best of our knowledge, calculations on the Tsuji – Trost
ꢀ
reaction in which a carbon heteroatom bond is formed have not
been carried out so far, although such reactions have been
ꢀ
known for three decades. For recent calculations involving C C
bond formation, see: P. Meletis, M. Patil, W. Thiel, W. Frank, M.
Braun, Chem. Eur. J. 2011, 17, 11243 – 11249.
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Tenaglia, Tetrahedron Lett. 1988, 29, 2927 – 2930.
[13] For DFT calculations in which the counteranion is H-bonded to
the substrate for the sake of stereoselectivity, see: M. Barba-
zanges, M. Augꢀ, J. Moussa, H. Amouri, C. Aubert, C.
Desmarets, L. Fensterbank, V. Gandon, M. Malacria, C. Ollivier,
Chem. Eur. J. 2011, 17, 13789 – 13794.
[14] This result is consistent with experimental studies, which show
that the Tsuji – Trost allylation can be retarded when the base
forms a strong H-bond with an imidazolium moiety, making it
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[15] The formation of ion pairs may sometimes slow down the rate of
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14471 – 14473.
To conclude, a new example of counteranion-directed
catalysis of the Tsuji–Trost reaction has been described. The
method constitutes a novel diastereoselective approach
toward 2,5-disubstituted 3-hydroxy-tetrahydrofurans. The
selectivity was rationalized by DFT calculations, which
showed the prominent role of the counteranion establishing
noncovalent interactions. This mechanistic proposal is
strongly supported by a series of chemical experiments.
Classically used in more efficient and elegant strategies of
synthesis, substrate-directed chemical reactions[37–38] allow
step and atom economy and provide a pathway toward the
ideal total synthesis.[39] We have demonstrated the relevance
of our approach for the total synthesis of natural products
through our syntheses of fragments of (+)-oocydin A (1) and
(ꢀ)-obtusallene III (2). Many other natural products can be
targeted with our method, as it allows facile access to four out
of the eight possible stereoisomers of 2,5-disubstituted 3-
hydroxy-tetrahydrofuran analogues.
[16] Experiment kindly suggested by one of the referees of this
manuscript. See experimental section for the details of the
syntheses of 3D and 4D.
Received: July 11, 2012
Published online: && &&, &&&&
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Keywords: counteranion-directed catalysis · hydrogen bonds ·
natural products · palladium · tetrahydrofuran
.
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Communications
Stereoselective Catalysis
M. Arthuis, R. Beaud, V. Gandon,*
E. Roulland*
&&&& — &&&&
Counteranion-Directed Catalysis in the
Tsuji–Trost Reaction: Stereocontrolled
Access to 2,5-Disubstituted 3-Hydroxy-
Tetrahydrofurans
Hydrogen bonds can play a prominent
role in organometallic catalysis, as shown
for the title reaction, in which a counter-
anion directs the cyclization through the
formation of hydrogen bonds that likely
involve a proton of the p-allyl/palladium
species itself. The reaction allows access
to four out of the eight stereoisomers of
2,5-disubstitued 3-hydroxy-tetrahydrofur-
ans and thus fragments of complex
natural products.
6
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
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