Asymmetric synthesis of β-substituted α-methylenebutyro-lactones via trip-catalyzed allylation: Mechanistic studies and application to the synthesis of (S)-(-)-hydroxymatairesinol

Article abstract of DOI:10.1002/adsc.201300392

Asymmetric allylation of (hetero)aromatic aldehydes by a zinc(II)-allylbutyrolactone species catalyzed by a chiral BINOL-type phosphoric acid gave β-substituted α-methylenebutyrolactones in 68 to >99% ee and 52-91% isolated yield. DFT studies on the intermediate Zn ²⁺-complex - crucial for chiral induction - suggest a six-membered ring intermediate, which allows the phosphoric acid moiety to activate the aldehyde. The methodology was applied to the synthesis of the antitumour natural product (S)-(-)-hydroxymatairesinol.

Full text of DOI:10.1002/adsc.201300392

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DOI: 10.1002/adsc.201300392
Asymmetric Synthesis of b-Substituted a-Methylenebutyro-
lactones via TRIP-Catalyzed Allylation: Mechanistic Studies and
Application to the Synthesis of (S)-(À)-Hydroxymatairesinol
Michael Fuchs,a Markus Schober,a Andreas Orthaber,b,* and Kurt Fabera,*
a
Department of Chemistry, University of Graz, Heinrichstraße 28, 8010 Graz, Austria
Fax : (+43)-(0)316-380-9840; phone: (+43)-(0)316-380-5332; e-mail: Kurt.Faber@Uni-Graz.at
Department of Chemistry, ꢀngstrçm Laboratories, Uppsala University, Box 523, 75120 Uppsala, Sweden
b
Fax : (+46)-018-471-6844; phone: (+46)-018-471-6585; e-mail: andreas.orthaber@kemi.uu.se
Received: May 6, 2013; Revised: June 28, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300392.
ꢁ 2013 The Authors. Published by Wiley-VCH Verlag GmbH &Co. KGaA. This is an open access article under
the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and re-
production in any medium, provided the original work is properly cited and is not used for commercial purposes.
Abstract: Asymmetric allylation of (hetero)aromat-
ic aldehydes by a zinc(II)-allylbutyrolactone species
catalyzed by a chiral BINOL-type phosphoric acid
gave b-substituted a-methylenebutyrolactones in 68
to >99% ee and 52–91% isolated yield. DFT stud-
ies on the intermediate Zn2+-complex – crucial for
chiral induction – suggest a six-membered ring in-
termediate, which allows the phosphoric acid
moiety to activate the aldehyde. The methodology
was applied to the synthesis of the antitumour natu-
ral product (S)-(À)-hydroxymatairesinol.
aration of lactono-based allylboronates – required for
the preparation of the title compound class – is un-
known. Allyl-Sn and allyl-Si esters, another widely
used class of allylating reagents, require additional
Lewis acid activation during the allylation step,[5]
which can harm the lactone scaffold. Therefore, new
methodologies are desirable, whereby stereoselectiv-
ity is induced through reactants which show a broad
functional group tolerance including esters and lac-
tones. For racemic allylation variants, organozinc
compounds are regularly used, because they are easily
prepared from the corresponding allylic halides and
zinc dust[6] and show a high tolerance towards a varie-
ty of functional groups.[7] To date, reports on the
asymmetric Zn2+-mediated Barbier-type allylation re-
action are scarce,[8] although high diastereoselectivity
can be induced regarding the syn:anti ratio of the two
chiral centers formed during the allylation with
Keywords: asymmetric allylation; butyrolactones;
chiral phosphoric acids; hydroxymatairesinol; orga-
nozinc reagents
butyroACHTUNGTRNEUNG
lactone 4 (Scheme 1).[3] A possible explanation
Asymmetric allylation is a key transformation in or- for the lack of asymmetric protocols may be that
ganic synthesis, which has been enabled through addi- most reactions are run in highly coordinating and/or
tion of various organometallic species onto aldehydes polar solvents (such as THF, DMF, DME or even
and ketones forming up to two chiral centers in water) which is essential for metal insertion into the
a single step. A variety of methodologies has been de- carbon-halide bond. On the other hand, polar media
veloped, mainly using allylboronates or silanes in enhance the reaction rate of the uncatalyzed (achiral)
combination with stoichiometric or catalytic amounts reaction by impeding the coordination of chiral addi-
of the chiral reagent or mediator.[1] However, the tives and thus interfere with chirality transfer. Howev-
asymmetric synthesis of butyrolactone-based natural er, catalytic methods involving chiral zinc catalysts
products (e.g., lignans) via allylation of aldehydes still have been reported recently,[9] demonstrating that
remains troublesome,[2] although racemic methods chiral induction by organozinc compounds is possible.
have been recently developed.[3] Only a few catalytic
Our study was initiated by the identification of an
approaches exist.[4] Allylboronates have proven to be appropriate catalyst for our model reaction, using al-
a unique tool for asymmetric allylation, but the prep- dehyde 2, which serves as precursor for (S)-(À)-hy-
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Scheme 1. Model reaction for optimization of the asymmetric allylation.
droxymatairesinol (1) (Scheme 1).[3] Chiral phosphoric hydes with high stereoselectivities for C C bond for-
acids have emerged as a new class of organocatalysts mation.[14] Although mechanistic proposals for phos-
since the pioneering work of Akiyama[10] and phoric acid catalysis involving aldehydes are rare,[15]
Terada[11] and their tremendous potential as chiral re- we identified (S)-TRIP as being a potential catalyst
agents has sparked many investigations.[12] In this con- candidate since initial experiments indicated that rea-
text, Antilla and Jain have recently applied chiral sonable amounts of product with promising levels of
phosphoric acids, such as 3,3’-bis(2,4,6-triisopropyl- enantiomeric excess (ee 20%, syn:anti 9:91) are
phenyl)-1,1’-binaphthyl-2,2’-diyl hydrogenphosphate formed in toluene/THF at a catalyst loading of 5
(TRIP),[13] to the asymmetric allylboration of alde- mol% (Table 1, entry 1). The addition of NH4Cl for
À
Table 1. Optimization of asymmetric allylation.[a]
Entry
Solvent
R=
Conversion [%][b]
syn:anti[c]
ee [%][d]
1
2
3
4
5
6
7
8
toluene/THF 1/1
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
76
90
41
67
>99
8
22
40
57
15
20
17
72
48
17
45
76
69
79
9:91
8:92
12:88
4:96
5:95
10:90
<1:>99
9:91
12:88
11:89
14:86
9:91
8:92
3:97
7:93
<1:>99
<1:>99
<1:>99
<1:>99
20
<1
12
<1
<1
75
80
70
55
73
64
71
82
80
84
91
93
95
98
toluene/EtOH 1/1
toluene/1-decanol 1/1
toluene/NMP 1/1
toluene/DME 1/1
toluene/DME 99.5/0.5
toluene/MTBE 1/1
CH2Cl2/Et2O 1/1
9
CH2Cl2/Et2O 2/1
10
11
12
13
14[e]
15
16[f]
17[g]
18[g,h]
19[i]
CH2Cl /
N
CH2Cl2/A(n-Bu)2O 1/1
CH2Cl2/Ph2O 1/1
CH2Cl2/toluene/Et2O 1/2/1
toluene/
N
toluene/Et2O 1/1
toluene/
A
Bn
Bn
Bn
Bn
toluene/AHCUTNGTRENNUNG
toluene/iPr2O 4/1
toluene/(i-Pr)2O 4/1
AHCTUNGTRENNUNG
[a]
Reaction conditions: aldehyde 2 (entries 1–15) or 5 (entries 16–19, 40 mM), bromolactone 4 (1.5 equiv.), Zn dust
(1.75 equiv.), NH4Cl (3.5 equiv.), 48C, 720 rpm, 16 h.
Conversions were determined via HPLC-UV at 215 nm.
The syn:anti ratios were determined via HPLC-UV analysis.
The ees were determined via HPLC-UV analysis on a chiral stationary phase.
50 mol% of (S)-TRIP.
[b]
[c]
[d]
[e]
[f]
10 mol% of (S)-TRIP and 4 equiv. of NH4Cl.
[g]
[h]
[i]
10 mol% of (S)-TRIP, 8 equiv. of NH4Cl and 2 equiv. of 4.
Experiment was conducted at À308C.
20 mol% of (S)-TRIP, 8 equiv. of NH4Cl and 2 equiv. of 4.
2
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Asymmetric Synthesis of b-Substituted a-Methylenebutyrolactones via TRIP-Catalyzed Allylation
Figure 1. Favoured transition state SaxRalcS-15 (left) and disfavoured SaxSalcR-15 (right).
acidic activation of the Zn surface in allylation reac-
In summary, these observations lead us to the con-
tions[3] was essential; no product formation was ob- clusion that the catalytically active species would be
served in its absence. Noteworthy, activation accord- the protonated phosphoric acid, coordinating the zinc
ing to Knochel et al. (TMSCl+1,2-dibromoethane)[16] core via the P=O moiety (Figure 1). Since accelera-
showed positive effects on the conversion, but gave tion of the same reaction by Brønsted acids has been
racemic product. Upon addition of the potassium salt previously observed, we assume that the aldehyde is
[3a]
À
of the chiral phosphoric acid we observed declining activated via the acidic P OH.
conversion and enantioselectivity (66% conversion
Since the reaction medium was expected to be an
and 10% ee, compare with Table 1, entry 1). Changing important parameter, careful optimization studies, es-
the inserting metal to indium slowed down the unca- pecially of the polar component, were conducted. The
talyzed reaction. However, no chiral induction was most important results are summarized in Table 1 (for
found upon addition of the chiral phosphoric acid. detailed information see the Supporting Information):
Experiments using the preformed phosphoric acid salt Compared to the initial results with toluene/THF, eth-
+
(TRIPÀ NH4 ) showed reduced conversions and ste- anol gave high yields but only racemic product
reoselectivities. Alternatively, the Zn2+-TRIP species (entry 2). An extension of the alkane chain (1-dec-
(acting as a catalytically active Lewis acid) would lead anol) showed improved selectivity in combination
to a transition state intermediate via single coordina- with a decreased conversion, implying that either
tion with a long distance beween the chirality-induc- steric issues in the coordination of the transition state
ing (i-Pr)3C6H2 ligands and the lactone moiety, which intermediate or the dipole moment of the solvent
could not explain the high (dia)stereoinduction exper- were important for the stereoselectivity (entry 3). Sol-
imentally observed[20a] (see Figures S01 and S02 in the vents with higher coordination strength/dipole, such
Supporting Information).
as NMP (N-methylpyrrolidone) and DME (1,2-dime-
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Michael Fuchs et al.
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thoxyethane) completely destroyed the chiral induc-
Aliphatic aldehydes reacted with good conversion
tion due to impeded ligand exchange on the zinc (~90%) but showed low enantioselectivities, and
metal core (entries 4 and 5). However, at reduced double bond isomerization was observed for alkenyl
levels of DME (0.5%), elevated ees were observed derivatives (e.g., cinnamic aldehyde), where conver-
again going in hand with diminished activity (entry 6). sions were in the range of ~60% accompanied by iso-
Non-coordinating ethers, such as MTBE (methyl tert- merization products (~20–30%). Bulky residues (e.g.,
butyl ether) gave high selectivities, but low conver- 4-tert-butylphenyl, naphthyl, entries 7 and 8) were
sions (entry 7). In pure MTBE the ee was decreased converted in good yields with very high stereoprefer-
without an increase in conversion. Dichloromethane ence. Noteworthy, reactions performed under anhy-
proved to be an attractive alternative to toluene, as drous conditions gave the same results as batches in
conversion was almost doubled with a slight decline moist solvents under air. The absolute configuration
in stereocontrol (entries 8 and 13). Since diethyl ether of 6 was determined via asymmetric synthesis[14] (see
had emerged as a potential polar candidate, similar below), products 7–13 were elucidated by CD spec-
ethers were tested. Based on their steric properties it troscopy using 6 as reference (same Cotton effect, see
became clear that the inner coordination sphere of Supporting Information).
the zinc center seemed to have the highest influence,
In order to demonstrate the applicability of the
as ethers with higher steric hindrance had a positive method, we transformed precursor 6, obtained from
influence on the stereoinduction rather than the alkyl (R)-TRIP-catalyzed allylation, to the natural product
chain length (entries 8–12). Further increase in selec- (S)-(À)-hydroxymatairesinol (1)[17] via a short se-
tivity was achieved when toluene was added again quence depicted in Scheme 2.[3a] The latter is used in
and these ternary solvent mixtures gave the first ee clinical studies[18] as a precursor to the mammalian
above 80% at reasonable levels of conversion lignan enterolactone, which exhibits antitumour acti-
(entry 13). Since alcohols (including phenol) led to vity.[18a,19]
a dramatic decline of stereocontrol, we envisaged to
The stereochemical outcome of the asymmetric syn-
protect the phenol moiety on substrate 2 in order to thesis of 1 was opposite to that of the allylboration
exclude such negative effects by the substrateꢂs OH with the same catalyst[14] owing to the different mech-
moiety. Benzyl-protected vanilline 5, was converted anism of the latter reaction, which requires acidic ac-
with an ee of 91% (entry 16) and a reasonable yield. tivation of the boronic ester.[20] Based on the experi-
In order to further increase the conversion, we mental results (anti-configured products) and the con-
raised the amounts of reagents and used less of the siderations on the catalystꢂs nature (protonated phos-
polar solvent, which pushed stereoselectivities even phoric acid coordinated to zinc) DFT calculations
further (entries 17 and 18). The last boost to the opti- yielded only model structure 15 as energetically and
mization was accomplished by employing a higher mechanistically reasonable intermediate (Figure 1),
catalyst loading (20 mol%) giving the precursor of when stationary points were investigated using the
1 in almost perfect stereoselectivity (ee 98%, syn:anti M06 functional with a triple-z basis set (6-311G**).[21]
<1:>99) and an acceptable isolated yield (Table 1, The structure 15 consists of a double coordination of
entry 19, Table 2, entry 1). Comparison of entries 14 the P(O)OH group to the zinc-allyl-aldehyde ring
(R=H, 50 mol% catalyst, de 94%, ee 80%) and 16 system in a chair-like transition state (Zimmerman–
(R=Bn, 10 mol% catalyst, de >99%, ee 91%) clearly Traxler model). Both six-membered rings are distort-
shows that the presence of the benzyl protective ed and zinc coordinates the allylic carbon atom. How-
group was beneficial with respect to stereoselectivities ever, the distance to the adjacent C atom is in the
and catalyst loading.
order of 2.4 to 2.8 ꢀ, forecasting the C=C bond to be
Having developed a practicable protocol for the formed and causing a significant ring contraction. The
asymmetric synthesis of lactone 6, we investigated the phosphoric acid coordinates the Zn center through
À
substrate scope and the upscaling of the reaction the P=O moiety, while the P OH unit activates the
(Table 2). All further substrates tested were nicely aldehyde giving a flat six-membered ring (coordina-
converted with 1.1 equivalents of bromolactone 4 at tion of the phosphoric acid yields >200 kcalmolÀ1).[22]
reduced catalyst loadings (10 mol%). Electron-rich al- With this concept about the intermediateꢂs geometry,
dehydes showed similar conversion levels as electron- we then focused on the mode of chiral induction
deficient analogues (entries 3, 5, 6). The only limita- during alcohol formation by investigating two stereo-
tion regarding aromatic residues was found in the al- chemical situations: SaxSalcR and SaxRalcS.[23] The com-
lylation of furfural, which gave decreased syn:anti-ste- bination Sax and RalcS was favoured by 1.7 kcalmolÀ1,
reocontrol (entry 4). Since similar effects were ob- which translates to an ee of 91% (experimentally ob-
served using THF as solvent, we assume that zinc-co- served 94%). Careful analysis of the calculated struc-
ordination by oxygen atoms accelerates the reaction tures (Figure 1) did not reveal any significant steric
in a non-selective fashion.
hindrance between the phenyl substituent of the sub-
strate and the catalyst in both isomeric structures.
4
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Asymmetric Synthesis of b-Substituted a-Methylenebutyrolactones via TRIP-Catalyzed Allylation
Table 2. Substrate scope of asymmetric allylation.[a]
Entry
1[e]
Product
Conversion [%][b]
syn:anti[c]
ee [%][d]
73 (71)
<1:>99
90
73 (71)[f]
<1:>99[f]
98[f]
2
3
4
5
6
7
91 (88)
84 (79)
>99 (91)
77[h]
<1:>99
<1:>99
14:86
94
96
n.d.[g]
<1:>99
<1:>99
<1:>99
<1:>99
96
88[h]
97
95 (91)
86 (80)
>99
97
8
[a]
Reaction conditions: aldehyde (20 mM), bromolactone 4 (1.1 equiv.) Zn dust (6 equiv.), NH4Cl (8 equiv.), toluene/
4/1, 48C, 720 rpm, 16 h.
ACHTUNGTRENNUNG(i-Pr)2O
[b]
[c]
[d]
[e]
[f]
Conversions were determined via HPLC-UV at 215 nm, isolated yields are given in brackets.
1
The syn:anti ratio was determined via H NMR.
The ee was determined via HPLC-UV analysis on a chiral stationary phase.
2 equiv. of 4 were used.
(R)-TRIP (20 mol%) gave 6.
Not determined due to inseparable syn:anti-mixture.
No isolated yields are given due to inseparable minor impurities (for details see Supporting Information).
[g]
[h]
However, steric repulsion can be found between the mediate by coordination of different ethers [Me2O,
isopropyl moieties of the ligand and the lactone (4.6 Et2O, (i-Pr)2O and THF] was assessed by means of
vs. 3.2 ꢀ), which results in shorter Zn-allyl-carbon dis- continuum models (IEF-PCM). Overall, stabilization
tances in the favoured SaxRalcS structure (2.4 vs. 2.6 ꢀ; by a single solvent molecule lies within the range of
Figure 1).
ca. À13 to À15 kcalmolÀ1, with a minimum energy for
In order to comprise contributions from non-cata- THF (for details see the Supporting Information).
lyzed turnovers, stabilization of the proposed inter- Therefore, an acceleration of the non-catalyzed reac-
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Michael Fuchs et al.
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Scheme 2. Synthesis of (S)-(À)-hydroxymatairesinol (1).
tion by higher coordinating ethers can be deduced,
explaining the reduced ee value in presence of these
solvents.
provided by SNIC through Uppsala Multidisciplinary Center
for Advanced Computational Science (UPPMAX) under
Project p2011197. A. Orthaber is thankful to the Austrian
Science Fund (FWF) for an Erwin-Schrçdinger-Fellowship
(J3193-N17).
In conclusion, the catalytic asymmetric allylation of
aldehydes by allylzinc species using a chiral, BINOL-
derived phosphoric acid (TRIP) was demonstrated.
Careful choice of the reaction conditions gave high
isolated yields and almost perfect enantio- and diaste-
reoselectivities. The preparative scale applicability of
the method was demonstrated by the total synthesis
of (S)-(À)-hydroxymatairesinol (1) in 98% ee and
46% overall yield, starting from aldehyde 5 (including
its benzyl protection). Finally, a proposal for the tran-
sient species was developed by DFT calculations,
which explains the stereochemical outcome due to
steric interaction of the lactone residue with the
ligand of the TRIP-catalyst.
References
[1] a) S. E. Denmark, J. Fu, Chem. Rev. 2003, 103, 2763–
2793; b) H. Yamamoto, M. Wadamoto, Chem. Asian J.
2007, 2, 692–698; c) M. Yus, J. C. Gonzꢃlez-Gꢄmez, F.
Foubelo, Chem. Rev. 2011, 111, 7774–7854; d) H. La-
chance, D. G. Hall, Org. React. 2008, 73, 1–573.
[2] T. Elford, D. Hall, Synthesis 2010, 893–907.
[3] a) D. M. Hodgson, E. P. A. Talbot, B. P. Clark, Org.
Lett. 2011, 13, 2594–2597; b) Y. Z. Gao, X. Wang, L. D.
Sun, L. G. Xie, X. H. Xu, Org. Biomol. Chem. 2012, 10,
3991; c) for the syn-diastereomer see: F. Zhang, Y.
Yang, L. Xie, X. Xu, Chem. Commun. 2013, 49, 4697–
4699.
Experimental Section
[4] V. Rauniyar, D. G. Hall, J. Org. Chem. 2009, 74, 4236–
4241; T. P. Montgomery, A. Hassan, B. Y. Park, M. J.
Krische, J. Am. Chem. Soc. 2012, 134, 11100–11103.
[5] a) J. E. Baldwin, R. M. Adlington, J. B. Sweeney, Tetra-
hedron Lett. 1986, 27, 5423–5424; b) A. Hosomi, H. Ha-
shimoto, H. Sakurai, Tetrahedron Lett. 1980, 21, 951–
954; c) Y. Masuyama, Y. Nimura, Y. Kurusu, Tetrahe-
dron Lett. 1991, 32, 225–228; d) K. Tanaka, H. Yoda, Y.
Isobe, A. Kaji, J. Org. Chem. 1986, 51, 1856–1866.
[6] R. Finding, U. Schmidt, Angew. Chem. 1970, 82, 482–
482; Angew. Chem. Int. Ed. Engl. 1970, 9, 456–457.
[7] a) H. Ding, C. Zhang, X. Wu, C. Yang, X. Zhang, J.
Ding, Y. Xie, Bioorg. Med. Chem. Lett. 2005, 15, 4799–
4802; b) F. Lambert, B. Kirschleger, J. Villiꢅras, J. Or-
ganomet. Chem. 1991, 406, 71–86; c) A. S.-Y. Lee, Y.-T.
Chang, S.-H. Wang, S.-F. Chu, Tetrahedron Lett. 2002,
43, 8489–8492; d) H. Mattes, C. Benezra, Tetrahedron
Lett. 1985, 26, 5697–5698.
General Procedure for the Asymmetric Allylation
A 50-mL round-bottom flask, equipped with a magnetic stir
bar, was charged with zinc dust (109 mg, 1.67 mmol), NH4Cl
(130 mg, 2.4 mmol) and (S)-TRIP (22 mg, 0.029 mmol). Tol-
uene (12 mL, precooled to 48C), (i-Pr)2O (3 mL, precooled
to 48C), the corresponding aldehyde (0.29 mmol) and bro-
molactone 4 (35 mL, 58 mg, 0.33 mmol) were added, the
flask was closed with a stopper equipped with a Teflon ring
and parafilm to avoid water condensation and stirred at 48C
in a fridge for 16 h. The slurry was concentrated under re-
duced pressure to about 4 mL, which were directly applied
to column chromatography on silica gel with toluene/THF
8/1 as eluent except where stated otherwise.
[8] a) H. R. Appelt, J. B. Limberger, M. Weber, O. E. D.
Rodrigues, J. S. Oliveira, D. S. Lꢆdtke, A. L. Braga, Tet-
rahedron Lett. 2008, 49, 4956–4957; b) B.-C. Hong, J.-H.
Hong, Y.-C. Tsai, Angew. Chem. 1998, 110, 482–484;
Angew. Chem. Int. Ed. 1998, 37, 468–470; c) R. P. A.
Melo, J. A. Vale, G. Zeni, P. H. Menezes, Tetrahedron
Lett. 2006, 47, 1829–1831.
Acknowledgements
We would like to thank Klaus Zangger and Bernd Werner
for recording NMR spectra and Gerald Rechberger for high
resolution mass spectra. Walter Keller and Kerstin Fauland
are acknowledged for assistance with CD spectra. Wolfgang
Kroutil is thanked for much good advice and inspiring dis-
cussions. The computations were performed on resources
[9] a) T. Hamada, K. Manabe, S. Kobayashi, Angew.
Chem. 2003, 115, 4057–4060; Angew. Chem. Int. Ed.
6
asc.wiley-vch.de
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ÝÝ
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Asymmetric Synthesis of b-Substituted a-Methylenebutyrolactones via TRIP-Catalyzed Allylation
2003, 42, 3927–3930; T. Hamada, K. Manabe, S. Ko-
bayashi, Angew. Chem. 2003, 115, 4714; Angew. Chem.
Int. Ed. 2003, 42, 4565; b) M. Fujita, T. Nagano, U.
Schneider, T. Hamada, C. Ogawa, S. Kobayashi, J. Am.
Chem. Soc. 2008, 130, 2914–2915; c) S. Kobayashi, T.
Endo, U. Masaharu, Angew. Chem. 2011, 123, 12470–
12473; Angew. Chem. Int. Ed. 2011, 50, 12262–12265;
d) K. Takeuchi, T. Takeda, T. Fujimoto, I. Yamamoto,
Tetrahedron 2007, 63, 5319–5322.
[16] A. Krasovskiy, V. Malakhov, A. Gavryushin, P. Kno-
chel, Angew. Chem. 2006, 118, 6186–6190; Angew.
Chem. Int. Ed. 2006, 45, 6040–6044.
[17] a) J. Fischer, A. J. Reynolds, L. A. Sharp, M. S. Sher-
burn, Org. Lett. 2004, 6, 1345–1348; b) B. Raffaelli, K.
Wahala, T. Hase, Org. Biomol. Chem. 2006, 4, 331–341.
[18] a) N. M. Saarinen, R. Huovinen, A. Warri, S. I. Makela,
L. Valentin-Blasini, L. Needham, C. Eckerman, Y. U.
Collan, R. Santti, Nutr. Cancer 2001, 41, 82–90;
b) N. M. Saarinen, A. Warri, S. I. Makela, C. Eckerman,
M. Reunanen, M. Ahotupa, S. M. Salmi, A. A. Franke,
L. Kangas, R. Santti, Nutr. Cancer 2000, 36, 207–216.
[19] a) D. Ingram, D. Sanders, M. Kolybaba, D. Lopez,
Lancet 1997, 350, 990–994; b) N. M. Saarinen, R. Huo-
vinen, A. Wꢇrri, S. I. Mꢇkelꢇ, L. Valentꢈn-Blasini, R.
Sjçholm, J. ꢉmmꢇlꢇ, R. Lehtilꢇ, C. Eckerman, Y. U.
Collan, R. S. Santti, Mol. Cancer Ther. 2002, 1, 869–
876.
[10] a) T. Akiyama, J. Itoh, K. Yokota, K. Fuchibe, Angew.
Chem. 2004, 116, 1592–1594; Angew. Chem. Int. Ed.
2004, 43, 1566–1568; b) T. Akiyama, H. Morita, J. Itoh,
K. Fuchibe, Org. Lett. 2005, 7, 2583–2585.
[11] a) D. Uraguchi, K. Sorimachi, M. Terada, J. Am. Chem.
Soc. 2004, 126, 11804–11805; b) D. Uraguchi, K. Sori-
machi, M. Terada, J. Am. Chem. Soc. 2005, 127, 9360–
9361; c) D. Uraguchi, M. Terada, J. Am. Chem. Soc.
2004, 126, 5356–5357.
[12] a) T. Akiyama, Chem. Rev. 2007, 107, 5744–5758;
b) A. G. Doyle, E. N. Jacobsen, Chem. Rev. 2007, 107,
5713–5743; c) M. Terada, Synthesis 2010, 1929–1982;
d) M. Terada, Chem. Commun. 2008, 4097–4112; e) J.
Yu, F. Shi, L.-Z. Gong, Acc. Chem. Res. 2011, 44, 1156–
1171; f) A. Zamfir, S. Schenker, M. Freund, S. B. Tso-
goeva, Org. Biomol. Chem. 2010, 8, 5262–5276.
[13] S. Hoffmann, A. M. Seayad, B. List, Angew. Chem.
2005, 117, 7590–7593; Angew. Chem. Int. Ed. 2005, 44,
7424–7427.
[20] a) M. N. Grayson, S. C. Pellegrinet, J. M. Goodman, J.
Am. Chem. Soc. 2012, 134, 2716–2722; b) H. Wang, P.
Jain, J. C. Antilla, K. N. Houk, J. Org. Chem. 2013, 78,
1208–1215.
[21] a) G. Ercolani, L. Schiaffino, J. Org. Chem. 2011, 76,
2619–2626; b) Y. Zhao, D. G. Truhlar, Acc. Chem. Res.
2008, 41, 157–167; the method is known to accurately
describe main group elements, but was recently also
successfully used for Zn-mediated reactions.
[22] The splitting into the two parts results in two charged
subunits, which probably leads to overestimated stabili-
zation energies due to the lack of dissipation of charge
in the surroundings. However, the high energy indicates
that the uncoordinated species is significantly less
stable.
[14] P. Jain, J. C. Antilla, J. Am. Chem. Soc. 2010, 132,
11884–11886.
[15] a) N. Momiyama, H. Tabuse, M. Terada, J. Am. Chem.
Soc. 2009, 131, 12882–12883; b) F.-L. Sun, M. Zeng, Q.
Gu, S.-L. You, Chem. Eur. J. 2009, 15, 8709–8712; c) M.
Terada, K. Soga, N. Momiyama, Angew. Chem. 2008,
120, 4190–4193; Angew. Chem. Int. Ed. 2008, 47, 4122–
4125.
[23] SaxRalcS refers to: Sax =axial chirality of catalyst is (S);
R
alc =alcohol is (R)-configured, S=configuration at the
chiral center formed in the lactone ring.
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ÞÞ
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COMMUNICATIONS
8 Asymmetric Synthesis of b-Substituted a-Methylenebutyro-
lactones via TRIP-Catalyzed Allylation: Mechanistic
Studies and Application to the Synthesis of (S)-(À)-
Hydroxymatairesinol
Adv. Synth. Catal. 2013, 355, 1 – 8
Michael Fuchs, Markus Schober, Andreas Orthaber,*
Kurt Faber*
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