Total synthesis of (R,R,R)-α-tocopherol through asymmetric cu-catalyzed 1,4-addition

Article abstract of DOI:10.1002/chem.201404379

By introducing a disposable activating substituent at C-3, the asymmetric 1,4-addition to a notoriously unreactive 2-substituted chromenone was achieved with high levels of (2R)-stereoselectivity in the presence of a chiral Cu^I-phosphoramidite

Full text of DOI:10.1002/chem.201404379

DOI: 10.1002/chem.201404379
Communication
&
Vitamin E Synthesis
Total Synthesis of (R,R,R)-a-Tocopherol Through Asymmetric Cu-
Catalyzed 1,4-Addition
Andreas Ole Termath,[a] Hanna Sebode,[a] Waldemar Schlundt,[a] Renꢀ T. Stemmler,[b]
Thomas Netscher,[b] Werner Bonrath,[b] and Hans-Gꢁnther Schmalz*[a]
efficient overall total synthesis of 1 still remains an open chal-
lenge.
Abstract: By introducing a disposable activating substitu-
ent at C-3, the asymmetric 1,4-addition to a notoriously
Building on our interests in enantioselective 1,4-addition
chemistry[6] we recently devised a novel strategy towards a-to-
unreactive 2-substituted chromenone was achieved with
high levels of (2R)-stereoselectivity in the presence of
copherol (1) which involves the addition of a methyl-anion re-
a chiral CuI-phosphoramidite complex as a catalyst. This
agent to a chromenone precursor as the key stereogenic step
paved the way for an efficient and conceptually novel syn-
(Scheme 1).[7] Employing substrates of type 3, we achieved the
Ni-catalyzed conjugate addition of AlMe3 to afford the chroma-
thesis of (R,R,R)-a-tocopherol from readily available start-
ing materials.
none products of type 2 in high yield, however, only as a 1:1
mixture of the 2R and 2S stereoisomers. Remarkably, all at-
tempts to perform the Ni-catalyzed reaction in an asymmetric
Due to its physiological importance and powerful antioxidant
properties a-tocopherol (1), which is the most prominent
member of the vitamin E family of compounds, represents an
essential food constituent of
fashion in the presence of chiral ligands remained completely
unsuccessful, presumably because of a radical mechanism in-
volved.[7]
high commercial value.[1] Note-
worthy, (all-rac)-1 is produced in-
dustrially on a multi 10.000 tons
per year scale and mainly used
in animal nutrition.[2] While all
eight individual stereoisomers
within this equimolar mixture
are biologically active, the natu-
Scheme 1. Retrosynthetic analysis of 1 based on an asymmetric 1,4-addition to a chromenone precursor.
ral (R,R,R)-isomer (1) clearly ex-
hibits the highest activity.[3] As
the growing demand of isomeri-
cally pure 1 cannot be satisfied from the limited natural sour-
ces, the development of stereoselective (and scalable) synthe-
ses of (R,R,R)-1 represents a very important task. Pfaltz et al.
have demonstrated that the side chain stereocenters can be
established with impressive levels of selectivity through Ir-cata-
lyzed asymmetric hydrogenation.[4] While several 2R-selective
approaches towards 1 have been published,[5] for instance ex-
ploiting an organocatalytic chroman synthesis[5d] or a chiral
sulfoxide-directed allylation step,[5b] the stereocontrolled set-up
of the (R)-configured quaternary center C-2 in the frame of an
While 2-substituted chromenones of type 3 were found not
to react with AlMe3 or MeMgBr in the presence of CuI catalysts
under various conditions, we reasoned that an additional (dis-
posable) electron-withdrawing group at C-3 (e.g., as in 4)
should enhance the reactivity of the substrates allowing to ex-
ploit a Cu-catalyzed asymmetric 1,4-addition[8] to generate the
quaternary center stereoselectively. We here report the suc-
cessful realization of this concept and its application as the key
step in an efficient total synthesis of (R,R,R)-a-tocopherol (1).
At first, a suitable methodology for the preparation of acti-
vated substrates of type 4 had to be developed. Known proto-
cols[9] for the synthesis of 2-alkyl-substituted chromenones
bearing an ester group at C-3 could not be applied in our case
due to the facile formation of the thermodynamically more
stable 3-acylcoumarins. Also, various attempts to introduce an
ester functionality by alkoxycarbonylation[10] of chromenones
of type 3 or their 3-bromo derivatives failed. Nevertheless, the
synthesis of the key substrate 4a was finally achieved via vinyl
ether formation and subsequent Friedel–Crafts acylation as
shown in Scheme 2.
[a] Dr. A. O. Termath, B. Sc. H. Sebode, M. Sc. W. Schlundt,
Prof. Dr. H.-G. Schmalz
Universitꢀt zu Kçln, Department fꢁr Chemie
Greinstrasse 4, 50939 Kçln (Germany)
E-mail: schmalz@uni-koeln.de
[b] Dr. R. T. Stemmler, Dr. T. Netscher, Priv.-Doz. Dr. W. Bonrath
DSM Nutritional Products, Research and Development
P.O. Box 2676, 4002 Basel (Switzerland)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201404379.
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Communication
in the absence of a CuI catalyst
at ꢀ788C and testing some
chiral CuI complexes did not
result in any chiral induction.
Therefore, the study was contin-
ued employing AlMe3 as a less
reactive reagent. Because the
stereochemical analysis was too
difficult at the stage of the b-ke-
toesters of type 13 (mixture of
diastereomers), the 1,4-addition
products 13 were further con-
verted into the chromanones of
type 2 by demethoxycarbonyla-
tion under Krapcho condi-
tions.[17] It was found that an
excess (typically 35 equiv) of
water is recommended, especial-
ly on a multi-mmol scale, to sup-
press a partial racemization of
2b under the conditions of the
Krapcho demethoxycarbonyla-
Scheme 2. Synthesis of the activated chromenone 4a: a) CO(OMe)2, NaH/KH, THF, reflux, 4 h; b) ClCOOMe, MgCl2,
pyridine, CH2Cl2, RT, 3 d; c) i) Tf2O, NEt3, 3 h, ii) 9, Et3N, CH2Cl2, RT, 5 d; d) Eaton’s reagent, 558C, 1 h. Eaton’s reagent
= 7.7 wt% P4O10 in MeSO3H; Tf2O = trifluoromethanesulfonic anhydride.
Starting from (R,R)-hexahydrofarnesyl acetone (5)[11] the b-ke-
toester 6 was prepared by reaction with dimethyl carbonate in
the presence of KH/NaH.[12] While the conversion of 6 into the
2-acyl-malonate 7 could not be achieved with DBU-CO2/MeI[13]
we succeeded to perform this second methoxycarbonylation
step in excellent yield by treatment of 6 with methyl
chloroformate in the presence of MgCl2 (as a coordi-
nating agent) and pyridine as a base.[14] After in situ
activation of the malonate 7 by O-sulfonylation and
reaction of the resulting enol triflate 8 with the aro-
matic building block 9[7] the aryl vinyl ether 10 was
obtained as a mixture of double bond isomers.[15] The
Friedel–Crafts-type cyclization of 10 to the activated
chromenone 4a was then achieved using Eaton’s re-
agent (P4O10 in MeSO3H).[16]
tion (LiCl, DMSO, 1508C, 4 h) by securing a rapid protonation
of the initially formed enolate.
We then tested various chiral ligands in the CuI-catalyzed re-
action of the achiral substrate 4b with AlMe3 under standard
conditions A (THF, ꢀ308C, dropwise addition of the chrome-
For the optimization of the key 1,4-addition step
we also prepared compound 4b with an unbranched
Scheme 4. a) Cu-catalyzed 1,4-addition of AlMe3 to activated chromenones of type 4
with b) subsequent demethoxycarbonylation. For selectivities and yields, see Table 1.
side chain as an achiral model substrate (Scheme 3).
In this case, commercial palmitoyl chloride (11) was
reacted with dimethyl malonate in the presence of
NaH to afford the ketodiester 12 in excellent yield.
The conversion of 12 into 4b was then performed following
the protocols used before in the preparation of 4a.
With the chromenones 4a and 4b in our hands we next in-
vestigated the key 1,4-addition (Scheme 4). Initial experiments
with MeMgBr revealed that the 1,4-addition takes place even
none 4b to the mixture of catalyst and AlMe3)[18] using copper
thiophenecarboxylate (CuTC) as the CuI source. The enantio-
meric ratio of the product (2b/ent-2b) was determined by
means of HPLC[19] after demethoxycarbonylation of intermedi-
ate 13. Initially, various chiral P,P-ligands which had been suc-
cessfully used in Cu-catalyzed
asymmetric
1,4-additions[6,20]
(e.g., ferrocene-based Tania-
phos,[21] or Josiphos,[22] and
Taddol-derived phosphine-phos-
phites[23]) were tested, however,
no significant levels of conver-
sion or enantioselectivity were
observed. Likewise, the chiral
Scheme 3. Synthesis of the model substrate 4b: a) NaH, dimethyl malonate, THF, RT, 5 h; b) Tf2O, NEt3, CH2Cl2, RT,
3 h, then 9, Et3N, RT, 2 d, 64%; c) Eaton’s reagent, 558C, 3 h, 50%.
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Communication
carbene ligand SIMes-leucinol[24] only afforded the racemic
product (rac-2b; ꢁ2% ee). Next, we tested chiral phosphor-
amidite ligands, introduced by Alexakis for the enantioselective
generation of quaternary stereocenters through 1,4-addition
using aluminum reagents.[25] While a rapid conversion (TLC)
but only a racemic product was observed with ligand L1
(Table 1; entry 1) we obtained 2b with a significant level of
enantioselectivity (40% ee) for the first time using the BINOL-
derived MonoPhos ligand L2.[26] The enantioselectivity was
then optimized by systematic variation of the ligand structure,
especially with respect to the substituents R1 and R2 at the ni-
trogen atom. Out of 35 MonoPhos-type phosphoramidites
tested, the (commercially available)[27] N-methyl-N-benzyl-sub-
stituted ligand L5 gave rise to the highest enantioselectivity
(entry 3). With only 12 mol% of ligand at ꢀ508C (conditions B)
the 1,4-addition proceeded with an improved yield and with-
out loss of selectivity (entry 4). The subtle dependence of the
reaction outcome on the ligand structure is exemplified by the
drop of selectivity associated with the introduction of a single
methyl group at the benzyl substituent (L7, entry 5).
To our surprise, the substrate
matched/mismatched effect with respect to the configuration
of the side chain stereocenters could be excluded (entries 6
and 7). Further experiments employing the stereochemically
undefined substrate 4a’ (mixture of four diastereomers) re-
vealed that the selectivity could not be improved just by
ligand variation. Eventually, it was found that a greatly im-
proved stereoselectivity could be achieved by changing the
copper source from CuTC to (CuOTf)2·benzene[18,28] and the sol-
vent from THF to Et2O (conditions C). Much to our satisfaction,
the reaction of 4a proceeded smoothly under the optimized
conditions (using ligand L5) even on a gram scale affording
the desired chromanone 2a in 83% isolated yield after deme-
thoxycarbonylation with a stereoselectivity of 97:3 (2R/2S). The
(2R)-configuration of the main diastereomer (2a) was con-
firmed by means of an authentic sample prepared independ-
ently from natural (R,R,R)-a-tocopherol (1) by O-methylation
(! 14)[29] followed by PCC oxidation[30] (Scheme 5).
Finally, completion of the synthesis was achieved by Pd-cata-
lyzed hydrogenolysis of the keto function of chromanone 2a,
affording O-methyl-a-tocopherol in 97% yield, which had been
with the “natural”, branched side
chain (4a) yielded the product
with a much lower degree of se-
lectivity under the developed re-
action conditions (entry 6). As
a comparable (opposite) selectiv-
ity was found with the enantio-
Scheme 5. Preparation of an authentic sample of the (2R)-configured 1,4-addition product 2a for characterization
meric ligand ent-L5 a significant
purposes. a) PCC, CH2Cl2, reflux, 3 d, 53%.
previously converted to a-toco-
Table 1. Performance of various phosphoramidite ligands in the Cu-catalyzed 1,4-addition of AlMe3 to chrome-
pherol (1) by Lewis acid-induced
cleavage of the methyl ether
functionality[5d] (Scheme 6).
none substrates according to Scheme 4.
In conclusion, we have suc-
cessfully developed a conceptual-
ly novel (2R)-selective total syn-
thesis of a-tocopherol (1) by ex-
ploiting a catalytic and stereose-
lective 1,4-addition as a key step
(4a ! 2a). The synthesis re-
quires only eight steps (33%
overall yield) starting from (R,R)-
hexahydrofarnesyl acetone (5) as
an industrially accessible com-
pound. Moreover, we could
demonstrate that Cu-catalyzed
1,4-additions to particularly un-
reactive 2-substituted chrome-
nones can be achieved with
high levels of catalyst-directed
stereocontrol by introduction of
Entry
Conditions[a]
Substrate
Ligand
2R/2S[b]
Yield [%][c]
1
2
3
4
5
6
7
8
A
A
A
B
A
A
A
A
A
A
C
C
C
4b
4b
4b
4b
4b
4a
4a
4a’
4a’
4a’
4a’
4a’
4a
L1
L2
L5
L5
L7
L5
ent-L5
L5
L4
L6
L3
L5
L5
50:50
70:30
97:3
98:2
89:11
79:21
22:78
80:20
no conversion
no conversion
89:11
95:5
97:3
n.d.
n.d
76
94
n.d.
n.d.
n.d.
n.d.
9
10
11
12
13
n.d.
n.d.
83
a
removable activating ester
[a] A: CuTC (10 mol%), ligand (20 mol%), AlMe3 (2 equiv), THF, ꢀ308C, overnight; B: CuTC (10 mol%), ligand
(12 mol%), AlMe3 (2 equiv), THF, ꢀ508C, overnight; C: (CuOTf)2·benzene (5 mol%), ligand (12 mol%), AlMe3
(2 equiv), Et2O, ꢀ508C, overnight. [b] Determined by means of HPLC (after demethoxycarbonylation). [c] Isolat-
ed yield of chromanone 2 over 2 steps.
substituent at C-3.
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Communication
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Keywords: asymmetric conjugate addition · copper catalysis ·
chiral ligands · chromenones · vitamin E
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[28] R. M. Maksymowicz, P. M. C. Roth, S. P. Fletcher, Nat. Chem. 2012, 4,
649–654.
Received: July 13, 2014
[29] For the synthesis of compound 14, see: A. Wang, R. P. A. Fraga, E. Hçr-
mann, A. Pfaltz, Chem. Asian J. 2011, 6, 599–606.
Published online on August 1, 2014
Chem. Eur. J. 2014, 20, 12051 – 12055
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