SN1-type substitution reactions of N-protected β-hydroxytyrosine esters: Stereoselective synthesis of β-Aryl and β-alkyltyrosines

Article abstract of DOI:10.1002/asia.201101016

The title compounds were prepared by aldol reaction of anisaldehyde and the respective N,N-dibenzyl glycinates. Deprotection of the nitrogen atom with Pearlman's catalyst delivered the unprotected β-hydroxytyrosine esters, which were further N-protected as N,N-phthaloyl (Phth) and N- fluorenylmethylcarbonyloxy (Fmoc) derivatives. The Friedel-Crafts reaction with various arenes was studied employing these alcohols as electrophiles. It turned out that the facial diastereoselectivitiy depends on the nitrogen protecting group and on the ester group. The unprotected substrates (NH₂) gave preferentially syn-products but the anti-selectivity increased when going from NHFmoc over NPhth to NBn₂. If the ester substituent was varied the syn-preference increased in the order Me A model is suggested to explain the facial diastereoselectivity based on a conformationally locked benzylic cation intermediate. The reactions are preparatively useful for the N-unprotected isopropyl ester, which gave Friedel-Crafts alkylation products with good syn-selectivity (anti/syn=21:79 to 7:93), and for the N,N-dibenzyl-protected methyl ester, which led preferentially to anti-products (anti/syn=80:20 to >95:5). Upon acetylation of the latter compound to the respective acetate, Bi(OTf)₃-catalyzed alkylation reactions became possible, in which silyl enol ethers served as nucleophiles. The respective alkylation products were obtained in high yield and with excellent anti-selectivitiy (anti/syn≥95:5). Copyright

Full text of DOI:10.1002/asia.201101016

DOI: 10.1002/asia.201101016
SN1-Type Substitution Reactions of N-Protected b-Hydroxytyrosine Esters:
Stereoselective Synthesis of b-Aryl and b-Alkyltyrosines
David Wilcke, Eberhardt Herdtweck, and Thorsten Bach*[a]
Dedicated to the 150th anniversary of German-Japanese relations
Abstract: The title compounds were
prepared by aldol reaction of anisalde-
hyde and the respective N,N-dibenzyl
glycinates. Deprotection of the nitro-
gen atom with Pearlmanꢀs catalyst de-
livered the unprotected b-hydroxytyro-
sine esters, which were further N-pro-
tected as N,N-phthaloyl (Phth) and N-
but the anti-selectivity increased when
going from NHFmoc over NPhth to
NBn2. If the ester substituent was
varied the syn-preference increased in
the order Me <Et <iPr. The reactions
were shown to be fully stereoconver-
gent and proceeded under kinetic
product control. A model is suggested
to explain the facial diastereoselectivity
based on a conformationally locked
benzylic cation intermediate. The reac-
tions are preparatively useful for the
N-unprotected isopropyl ester, which
gave Friedel–Crafts alkylation products
with good syn-selectivity (anti/syn=
21:79 to 7:93), and for the N,N-diben-
zyl-protected methyl ester, which led
preferentially to anti-products (anti/
syn=80:20 to >95:5). Upon acetyla-
tion of the latter compound to the re-
fluorenylmethylcarbonyloxy
(Fmoc)
spective acetate, BiACTHUNGRETNNU(G OTf)3-catalyzed al-
derivatives. The Friedel–Crafts reaction
with various arenes was studied em-
ploying these alcohols as electrophiles.
It turned out that the facial diastereo-
selectivitiy depends on the nitrogen
protecting group and on the ester
group. The unprotected substrates
(NH2) gave preferentially syn-products
kylation reactions became possible, in
which silyl enol ethers served as nucle-
ophiles. The respective alkylation prod-
ucts were obtained in high yield and
with excellent anti-selectivitiy (anti/
synꢀ95:5).
Keywords: alkylation · amino acids ·
aromatic substitution
· carboca-
tions · diastereoselectivity
Introduction
derivatives A (R=H, Ac) was more closely examined
(Scheme 1). In this case the putative cation intermediate
would be flanked by an a-substituent that carries a hydrogen
atom, a substituted amino group (PG=protecting group),
and an ester group (COOR1).
In recent years, reactions at chiral benzylic cations have re-
ceived increased attention by synthetic organic chemists[1]
and have been shown to occur with significant acyclic ste-
reocontrol.[2] Common precursors of these cations are the
respective alcohols or acetates, which undergo an intermo-
lecular[3] nucleophilic displacement under acidic conditions
with a variety of nucleophiles, for example, with arenes[4] in
a Friedel–Crafts-type alkylation,[5] with silyl enol ethers,[6] or
with nitriles[7] in a Ritter reaction.[8] NMR spectroscopic
studies of the respective cations have supported the hypoth-
esis that a preferred conformation exists in which the three
substituents at the stereogenic center in a-position to the
cationic carbon atom are responsible for the reaction out-
come.[9] So far, the substitution pattern at this stereogenic
center has been restricted to a hydrogen atom, a methyl
group, and an additional functional group, which has been
widely varied. In the present study, the reaction of tyrosine
Scheme 1. Nucleophilic substitution reactions at title compounds A to
provide b-aryl and b-alkyltyrosines of general structure B.
Products B resulting from a nucleophilic displacement are
b-branched tyrosine derivatives, which belong to the class of
b,b-diarylalanines. Compounds of this type attracted syn-
thetic interest in the past because of their biological impor-
tance as modified amino acids.[10] Aziridines were identified
as suitable starting materials and—following up on earlier
work by Styngach et al.[11]—Zwanenburg et al. showed that
3-arylaziridine-2-carboxylates 1 react with arene nucleo-
philes at the benzylic position (Scheme 2) to give b,b-di
arylalanines.[12] Indole was employed as a representative nu-
cleophile (2 equiv) and BF3·OEt2 (1.5 equiv) served as the
[a] D. Wilcke, Dr. E. Herdtweck, Prof. Dr. T. Bach
Department Chemie and Catalysis Research Center (CRC)
Technische Universitꢁt Mꢂnchen
Lichtenbergstraße 4, 85747 Garching (Germany)
Fax : (+49)89-289-13315
E-mail: thorsten.bach@ch.tum.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201101016.
Chem. Asian J. 2012, 00, 0 – 0
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
&
&
&
These are not the final page numbers! ÞÞ

FULL PAPERS
acted unselectively. It was postulated that different confor-
mations are involved in the formation of the intermediate
secondary alkyl cations and that the threonine-derived
cation reacts selectively due to a hindered rotation around
the bond to the adjacent stereogenic center. For the allo-
threonine-derived cation the rotation is unrestricted and
there is no facial diastereoselectivity.
To our knowledge, no precedence for the reaction of sub-
strates A in SN1-type displacement reactions with arene and
silyl enol ethers exists. Our studies reported herein provide
evidence that these substrates react under acidic conditions
via a benzylic cation intermediate. The facial diastereoselec-
tivity upon nucleophilic attack at the chiral cation inter-
mediate depends strongly on the protecting group at the ni-
trogen atom and, to a lesser extent, on the alkyl ester group.
It was possible to achieve a high diastereoselectivity in favor
of either the syn- or anti-product by judicious selection of
the substitution pattern in the b-hydroxytyrosine substrate.
Scheme 2. Synthesis of b-aryltryptophane esters 2 from aziridines 1 ac-
cording to Zwanenburg et al.[12] (An=para-methoxyphenyl).
Lewis acid. The phenylsubstituted aziridine 1a reacted ste-
reospecifically to provide exclusively the SN2-type substitu-
tion product anti-2a. The anisyl-substituted aziridine 1b,
however, yielded a mixture of diastereomeric products anti-
2b and syn-2b (d.r.=anti/syn=55:45). The formation of
a diastereomeric mixture was ascribed to the presence of an
intermediate benzylic cation along a SN1-type pathway. As it
was prepared from racemic substrate 1a, product anti-2a in
the experiments by Zwanenburg and co-workers was race-
mic. A related enantiomerically pure b-phenyltryptophane
ester was obtained by Hruby et al. from an enantiomerically
pure aziridine.[13] An enantioselective synthesis of b,b-diary-
lalanines was recently described by Leighton et al. employ-
ing a Rh-catalyzed aza-Darzens reaction and a subsequent
stereospecific aziridine ring opening.[14]
Aziridine ring opening reactions of 3-arylaziridine-2-car-
boxylates were also achieved with InCl3 as Lewis acidic cat-
alyst.[15] Ishikawa et al. observed a stereospecific reaction
course in the reaction of trans-aziridine 3 with indole to
product 4 (Scheme 3). Other arene nucleophiles (furan, pyr-
role, 1,3-dimethoxybenzene, and N,N-dimethylaniline) re-
sulted in diastereomeric product mixtures, in which the anti-
product prevailed (d.r.=91:9 to 66:34).
Results and Discussion
Preparation of Starting Materials
The reaction of N,N-dibenzylglycinates with anisaldehyde[18]
was employed as a synthetic entry to the respective anti-b-
hydroxytyrosine esters 5–7 (Scheme 4), which were isolated
in diastereomerically pure form after column chromatogra-
phy. The observed simple diastereoselectivity is presumably
a consequence of the almost exclusive formation of the (O)-
E-enolate, which adds to the aldehyde in a Zimmerman–
Traxler transition state.[18c,19]
Scheme 4. Preparation of products anti-5–7 by aldol reaction of a glycine-
derived enolate and para-methoxybenzaldehyde. Yields and d.r. refer to
the isolated material obtained after column chromatography.
Despite the prevalence of the anti-diastereoisomer in the
latter reactions it was possible to isolate from the reaction
mixture also the syn-diastereoisomer in significant amounts.
When the aldol reaction was performed at higher tempera-
ture (ꢁ558C) and upon fractional crystallization, ester syn-5
could be obtained (Figure 1), which served as substrate for
Scheme 3. Synthesis of b,b-diarylalanine ester 4 by stereospecific ring
opening of aziridine 3 according to Ishikawa et al.[15]
Additional examples for a non-stereospecific aziridine
ring opening by arenes were recently reported by Shi et al.
in work related to gold(I)-catalyzed substitution reactions at
the aziridine ring.[16] The Friedel–Crafts alkylation of ben-
zene with threonine and allothreonine trifluoromethansulfo-
nates was studied by Effenberger et al.[17] Employing rela-
tively harsh conditions (CF3SO3H, 808C), a high diastereose-
lectivity was observed for the displacement of the trifluoro-
methanesulfonate in the N,N-phthaloyl
threonine ester. The diastereomeric allothreonine ester re-
ACHTUNGTREN(NUGN Phth)-protected
Figure 1. Structure of syn-aldol product syn-5 and of b-hydroxytyrosine
esters 8–10.
&
&
&2
&
www.chemasianj.org
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!

Stereoselective Synthesis of b-Aryl and b-Alkyltyrosines
the synthesis of the respective syn-b-hydroxytyrosine esters.
A facile hydrogenolysis of N,N-dibenzylamines 5–7 was ach-
ieved upon treatment with hydrogen in the presence of
Pearlmanꢀs catalyst, Pd(OH)2/C.[20] From anti-5 and syn-5
the respective methyl esters anti-8[21a] (97%, d.r.ꢀ95:5) and
syn-8[21] (98%, d.r.=27:73) were readily available. The anti-
b-hydroxytyrosine esters 6 and 7 delivered the free amino
esters anti-9 (95%, d.r.=97:3) and anti-10 (quant., d.r.ꢀ
95:5).
Diastereoselective Reactions with 1,3-Dimethoxybenzene as
Substrate – Influence of the Nitrogen Protecting Groups
A hallmark of SN1-type substitution reaction is their lack of
stereospecifity.[24] The intermediacy of a benyzlic cation in
the reaction of substrate 8 with 1,3-dimethoxybenzene in the
presence of HBF4 (3 equiv) became apparent by the obser-
vation that the relative configuration of the starting material
was inconsequential for the diastereoselectivity of the substi-
tution reaction (stereoconvergent reaction course). Both
anti- and syn-8 delivered predominantly the product syn-15
(Scheme 6).
Methyl ester 5 served also as starting material for the
preparation of the N,N-Phth- and the N-Fmoc(fluorenylme-
thyloxycarbonyl)-protected products 13 and 14 (Scheme 5).
Scheme 6. Diastereoselective, stereoconvergent Friedel–Crafts alkylation
of 1,3-dimethoxybenzene with both diastereoisomers of alcohol 8.
The reaction was performed by dissolving the substrate
and the arene in CH2Cl2 at ꢁ788C. Addition of the acid
with a syringe led to an immediate color change from color-
less to yellow. Upon warming to room temperature, the
color intensified and the orange-colored reaction mixture
was quenched with aqueous NaHCO3 once room tempera-
ture was reached. The diastereomeric ratio was determined
Scheme 5. Preparation of the Phth- and Fmoc-protected b-hydroxytyro-
sine methyl esters anti-13 and anti-14. The respective syn-diastereoiso-
mers were prepared in an analogous fashion starting from syn-5.
1
Temporary silyl protection was required to avoid excessive
retro aldol reaction. As exemplified for anti-product anti-5
(d.r.ꢀ95:5), the respective silyl ether anti-11 was obtained
as the intermediate, which gave upon hydrogenolysis the
free amino ester anti-12 (93% over two steps, d.r.ꢀ95:5).
N-Protection and subsequent desilylation were performed
without the isolation of the intermediate silyl ethers. Reac-
tion of amine anti-12 with phthalic anhydride[22] and immedi-
ate desilylation with HCl produced anti-product anti-13
(55%, d.r.=85:15). Analogously, the Fmoc-protected b-hy-
droxytyrosine ester anti-14 (d.r.ꢀ95/5) was obtained in
close to quantitative yield by treatment of amine anti-12
with FmocCl under Schotten–Baumann conditions[23] and
acidic O-silyl deprotection.
from the crude product mixture by H NMR spectroscopy.
The major diastereoisomeric product syn-15 turned out to
be a crystalline solid and its relative configuration was
proven by single-crystal X-ray crystallography (Figure 2).
The same reaction sequence could be performed in a com-
pletely analogous fashion starting from syn-diastereoisomer
syn-5 (d.r.=80:20) and delivered the corresponding Fmoc-
derivative syn-14 (d.r.=38:62). As already seen in the
phthaloyl protection of anti-diastereoisomer anti-12, the re-
action leads to partial epimerization. It was therefore not
possible to obtain syn-13 from syn-12. Instead, the reaction
delivered an anti/syn-mixture (d.r.=62:38).
Figure 2. Crystal structure of diastereomerically pure product syn-15.
Chem. Asian J. 2012, 00, 0 – 0
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
3
&
&
&
These are not the final page numbers! ÞÞ

Thorsten Bach et al.
FULL PAPERS
Although the crystal structure suggests a synclinal relation-
To rule out that any equilibrium effects influence the ste-
reoselectivity, the amino acids 15, which were obtained by
deprotection and which had different product diastereo-
meric ratios, were subjected to the typical reaction condi-
tions of a Friedel–Crafts alkylation reaction (Scheme 6; 1,3-
dimethoxybenzene, HBF4·OEt2 in CH2Cl2). No equilibration
was observed and thermodynamic product control can be
ruled out.
ꢁ
ship for the two C H bonds at the adjacent stereogenic cen-
ters, H NMR data indicate that the preferred conformation
1
in solution is—as in related products[4c]—a conformation in
which the dihedral angle is closer to 1808 (antiperiplanar)
than to 608. The vicinal coupling constant (3JHH) between
the two protons is 9.1 Hz. If the steric bulk of the substitu-
ents is increased, the coupling constant increases even fur-
ther (see below).
When the other methyl esters 5, 13, and 14, in which the
tyrosine nitrogen atom is protected, were subjected to a Frie-
del–Crafts reaction with 1,3-dimethoxybenzene, a significant
variation of the diastereoselectivitiy was observed. The N,N-
dibenzyl derivative 5 delivered anti-product anti-16 as the
major diastereoisomer (d.r.=88:12) as did the phthaloyl-
protected b-hydroxytyrosine 13. In the latter case, however,
the diastereomeric ratio of arylated product 17 was signifi-
cantly lower (d.r.=79:21). In contrast to the doubly nitro-
gen-protected substrates, the N-Fmoc derivative 14 pro-
duced a mixture of products with an excess of syn-diastereo-
isomer syn-18. All stereochemical results depicted in
Scheme 7 were shown to be completely independent from
the substrate configuration. The reactions proceeded stereo-
convergently, and the relative product configuration was ex-
clusively determined by the protecting group at the nitrogen
atom but not by the diastereomeric ratio of the starting ma-
terial.
Influence of the Size of the Ester Group and a Mechanistic
Model
The diastereoselectivity in the reaction of b-hydroxytyrosine
methyl ester (8) with 1,3-dimethoxybenzene was already
high (d.r.=10:90, Scheme 6) and despite the fact that an im-
proved selectivity was observed with the respective ethyl
ester (9, d.r.=7:93) and isopropyl ester (10, d.r.=7:93) the
improvement was not very significant in terms of absolute
numbers. The less selective reaction with 2-methylthiophene
(Scheme 8) enabled a better picture on the influence of the
Scheme 8. Diastereoselectivity in the Friedel–Crafts reaction of 2-methyl-
thiophene with different b-hydroxytyrosine esters 8–10.
ester group on the diastereoselectivity. Methyl ester 8 under-
went, under acidic conditions, a diastereoselective reaction
in which the major product was formed with only moderate
selectivity (d.r.=25:75). With ethyl ester 9 as substrate the
selectivity improved (product 20, d.r.=20:80) and was best
with isopropyl ester 10 (product 21, d.r.=17:83).
Scheme 7. Diastereoselectivity in the Friedel–Crafts reaction of 1,3-dime-
thoxybenzene with different N-protected b-hydroxytyrosine methyl esters
5, 13, and 14.
Although the relative configuration of the major product
was in this case not proven by crystallography, the assign-
ment can be safely made based on analogy. It is further sup-
ported by NMR data. Most notably, the shielding effect of
the anisyl group on synclinal substituents—as observed pre-
viously for related products[4c]—is significant. In the case of
products 19–21, the respective protons at CH3 (in 19),
CH2Me (in 20), and CHMe2 (in 21) in the ester part are
clearly influenced. In the major syn-diastereoisomers, in
which the ester groups adopt a synclinal position to the
anisyl group, they are shielded relative to the minor anti-dia-
stereoisomer, in which the ester groups are antiperiplanar to
the anisyl group (see below).
The relative configuration of products 16–18 was deter-
mined by deprotection at the nitrogen atom and conversion
into the free amino acid esters 15, the relative configuration
of which had been previously established (see above). Hy-
drogenolysis was the preferred method for removal of the
benzyl groups (H2, Pd(OH)2/C in MeOH; quant.).[20] Depro-
tection of the phthaloyl group was achieved by hydrazonoly-
sis (N2H4 in MeOH; 51%)[25] and the Fmoc group was re-
moved by treatment with piperidine in CH2Cl2 (quant.).[23]
The diastereomeric ratio remained unchanged in the depro-
tection step. Still, the values given in Scheme 7 relate to the
values determined by integration of appropriate 1H NMR
signals of the crude product mixture.
In earlier work we had postulated that stereoselective in-
termolecular reactions of benzylic cations with a prostereo-
&
&
&4
&
www.chemasianj.org
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!

Stereoselective Synthesis of b-Aryl and b-Alkyltyrosines
genic center adjacent to a stereogenic center occur from
a preferred conformation that is dictated by 1,3-allylic
strain.[4] This hypothesis was substantiated by extensive
NMR studies on chiral cations of this type in superacidic
media.[9] If applied to the respective cations C formed from
substrates with the general structure A (Figure 1), it can be
inferred that a favored conformation as depicted in Figure 3
either diastereomeric form upon appropriate tuning[28] of
the protective group. A high syn-selectivity is achieved with
the isopropyl ester 10, in which the amino group of b-hy-
droxytyrosine is unprotected. Reactions of this type with
other arene nucleophiles are summarized in Table 1. Quite
clearly the model presented above allows only a coarse eval-
uation of the diastereoselectivity but cannot be used to ex-
plain minor deviations in selectivity. The electronic and
steric parameters of the individual arenes must be taken
into account to fully appreciate the observed chemo- and
diastereoselectivies.
Table 1. Diastereoselective Friedel–Crafts alkylation of arenes ArH with
aminoalcohol 10 to provide syn-products syn-22.
Figure 3. Preferred conformation of cations C and approach of the aryl
nucelophile ArH from the more accessible face. For PG1 =PG2 =H (sub-
strates 8–10) or Bn (substrates 5–7), the nitrogen atom is likely to be pro-
tonated.
Entry[a]
ArH
Product
Yield [%][b]
d.r. (anti/syn)[c]
exists. A similar conformation has been previously suggested
by Ohfune et al. to explain the diastereoselectivity in the
formation of cyclic carbamates by oxidation of N-Boc-pro-
tected tyrosine esters.[26] In our case, protonation of the alco-
hol leads to homolytic cleavage and formation of cations C.
Basic amino groups are likely to be protonated under these
conditions and do not exert a neighboring group assistance.
The attack of the nucleophile is rather governed by steric
factors. Small protecting groups (PG1 =H, Fmoc; PG2 =H)
at the amino group invite an attack from the same face, and
syn-products result. The selectivity further increases if the
steric bulk of the ester group increases (Scheme 8). Large
protecting groups (PG1 =PG2 =Phth, Bn) direct the attack
of the nucleophile to the opposite face and favor formation
of the respective anti-products.
It appears likely that the non-stereospecific ring opening
reactions of aziridines observed by Zwanenburg et al. and
by Ishikawa et al. also follow, at least partly, a pathway via
cations of type C. Since the reactions are promoted by
Lewis acids, it is reasonable to assume that the acids coordi-
nate to the amine making it bulkier than the respective
ester group, thus generating preferentially the anti-products.
This model also accommodates earlier results, for example,
concerning the diastereoselectivity observed in the hydroly-
sis of N-phthaloyl-protected b-bromoarylalanine derivatives
to b-hydroxyarylalanine derivatives[27] or in the hydrolysis of
3-aryl-1-benzylaziridine-2-carboxylates[15] (with H2O as nu-
cleophile).
1
22a
99
7:93
2
22b
90
21:79
3
4
22c
22d
97
94
11:89
15:85
[a] All reactions were conducted at a substrate concentration of 100 mm
with 3.00 equivalents of HBF4·OEt2 as Brønsted acid and 4.00 equivalents
of ArH as the nucleophile. [b] Yield of isolated product. [c] The diaste-
reomeric ratio (d.r.) of the crude product was determined by 1H NMR
spectroscopy.
The reactions summarized in Table 1 follow the diastereo-
selectivity trend observed for the Friedel–Crafts alkylation
of 2-methylthiophene (10!21, Scheme 8, d.r.=17:83). Most
diastereoselectivities are even higher (entries 1, 3, and 4),
which is in line with the previous observation[4c] that the
sterically least congested arene nucleophile 2-methylthio-
phene provides a lower diastereoface discrimination than
1,3-dimethoxybenzene
(entry 1)
and
N-tosylpyrrole
(entry 4). The influence of the 4-bromo substituent in 4-
bromo-1,3-dimethoxybenzene is minor (entry 2) while the
influence of the 2-methoxy substituent in 1,2,3-trimethoxy-
benzene is significant. It appears as if the latter arene would
encounter a slightly increased repulsion with the amino
Diastereoselective Synthesis of either syn- or anti-b-
Aryltyrosines
From a preparative point of view a key result of this study is
the observation that b-aryltyrosines can be obtained in
Chem. Asian J. 2012, 00, 0 – 0
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
5
&
&
&
These are not the final page numbers! ÞÞ

Thorsten Bach et al.
FULL PAPERS
group in a cation of type C as compared to the other arenes,
which would be in line with the higher selectivity the same
arene encounters in the reaction with the N,N-dibenzylated
substrate 5 (Scheme 7, Table 2, 5!16, 23).
Table 2. Diastereoselective Friedel–Crafts alkylation of arenes ArH with
aminoalcohol 5 to provide anti-products anti-23.
Figure 4. Preferred conformation (sawhorse projection) of products anti-
23c and syn-23c in solution and deshielding effect of the anisyl substitu-
ent.
In this conformation, the shielding effect of the anisyl sub-
stituent on the synclinal methyl ester group is apparent in
the minor diastereoisomer. The protons resonate at d=
3.75 ppm in the major product (anti-23c) and at d=
3.67 ppm in the minor product (syn-23c). This result is in
full agreement with the data obtained for products 19–21
(Scheme 8), where the major products showed the shielding
effect (see above).
Entry[a]
ArH
Product
Yield [%][b]
d.r. (anti/syn)[c]
>95:5
1
23a
53
2
23b
58
80:20
Diastereoselective Synthesis of anti-b-Alkyltyrosines
Despite significant recent improvements in direct, catalytic
nucleophilic SN1-type reactions of alcohols,[29] previous ex-
periments in our group[6a] with related substrates suggested
that the BiACHTNUTRGNENG(U OTf)3-catalyzed (Tf=trifluoromethanesulfonyl)
substitution of the respective acetates is the preferred way
to achieve alkylation reactions. Silyl enol ethers were em-
3
4
23c
23d
82
30
89:11
>95:5
ployed as nucleophiles to achieve a Bi
ACHTUNGRTEN(NUGN OTf)3-catalyzed, dia-
[a] All reactions were conducted at a substrate concentration of 125 mm
with 3.00 equivalents of HBF4·OEt2 as Brønsted acid and 4.00 equivalents
of ArH as the nucleophile. [b] Yield of isolated product. [c] The diaste-
reomeric ratio (d.r.) of the crude product was determined by 1H NMR
spectroscopy.
stereoselective SN1-type alkylation reaction (Table 3).[30]
Table 3. Bi
ACHTUNGTREN(UNGN OTf)3-catalyzed, diastereoselective SN1-type alkylation of
silyl enol ethers with acetate 24 to provide anti-products anti-25.
Indeed, in these reactions, which led predominantly to the
anti-products, 1,2,3-trimethoxybenzene (Table 2, entry 1) re-
acted with the highest selectivity. The other arenes, includ-
ing 1,3-dimethoxybenzene (Scheme 7, product 16), showed
a diastereoselectivity that is lower (entries 2, 3) but still
preparatively useful. Side reactions occurred (entries 1, 2,
and 4), however, and diminished the yields, most severely in
the case of N-tosylpyrrole (entry 4). Intramolecular Friedel–
Crafts reactions of one of the benzyl groups at the nitrogen
atom with the intermediate benzylic cations were not ob-
served; rather it appears as if elimination and debenzylation
reactions had taken place.
Entry[a]
R
R1
Product
Yield [%][b]
d.r. (anti/syn)[c]
1
2
3
H
H
Me
Ph
Me
OMe
25a
25b
25c
90
78
quant.
>95:5
>95:5
>95:5
[a] All reactions were conducted at a substrate concentration of 125 mm
with 10 mol% of Bi(OTf)3 as the Lewis acid and 4.00 equivalents of ArH
AHCTUNGTRENNUNG
as the nucleophile. [b] Yield of isolated product. [c] The diastereomeric
ratio (d.r.) of the crude product was determined by 1H NMR spectrosco-
py.
The products of the 2-methylthiophene reaction, com-
1
pounds anti-23c and syn-23c, showed H NMR spectra that
nicely illustrate the aforementioned configuration assign-
ment. The vicinal coupling constant (3JHH) between the two
protons at the stereogenic centers is large (11.8 Hz for both
anti-23c and syn-23c), suggesting an antiperiplanar relation-
ship of these protons in the preferred solution conformation
(Figure 4).
While the selective O-acetylation of substrates 8–10 is not
feasible based on literature reports,[31] it was possible to con-
vert alcohols 5, 13, and 14 into the respective acetates. How-
ever, only acetate 24, derived from alcohol 5, showed the
desired reactivity in the attempted BiACTHNUTRGENUN(G OTf)3-catalyzed sub-
&
&
&6
&
www.chemasianj.org
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!

Stereoselective Synthesis of b-Aryl and b-Alkyltyrosines
stitution reactions (Table 3). The reactions resulted in single
products, to which — based on analogy with the Friedel–
Crafts reactions (Table 2) — the anti-configuration was as-
signed. Further support for the configuration assignment
was obtained from a single-crystal X-ray analysis of the
major product anti-25a (Figure 5).
Scheme 9. BiACTHNUGTRENUNG(OTf)3-catalyzed, diastereoselective SN1-type alkylation of 2-
(trimethylsilyloxy)propene with acetate 26.
and with perfect diastereoselectivity to afford the product
anti-27.
The anti-relationship established in products such as 25
and 27 is found in many natural products, for example, in
the amaryllidaceae alkaloids narciclasine[33] and lycorici-
dine.[34] The importance of b,b-diarylalanines has been previ-
ously mentioned (vide supra) and it is expected that the de-
scribed arylation method will turn out to be useful for the
stereoselective synthesis of these compounds.
Experimental Section
Figure 5. Crystal structure of diastereomerically pure product anti-25a.
General Materials and Methods
All reactions involving moisture-sensitive chemicals were carried out in
flame-dried glassware in dried solvents with magnetic stirring under
argon atmosphere. Tetrahydrofuran (THF), diethyl ether (Et2O), and di-
chloromethane (CH2Cl2) were purified by using a SPS-800 solvent purifi-
cation system (M. Braun). Diisopropylamine was distilled over calcium
hydride. All other chemicals were used as received. TLC was performed
on silica-coated glass plates (silica gel 60 F254) with detection under UV
(254 nm) light or by ceric ammonium molybdate (CAM) with subsequent
heating. Flash chromatography was performed on silica gel 60 (Merck,
230–400 mesh) with the indicated eluent. All solvents used for chroma-
tography were distilled prior to use. Compounds 6 and 8 were prepared
according to literature procedures.[18e,21] The preparation and analytical
data of compounds 5, 7–14, 24, and 26 are reported in the Supporting In-
formation. IR spectra were recorded on a JASCO IR-4100 spectrometer
(ATR). MS/HRMS measurements were performed on a Finnigan MAT
8200 (EI), a Finnigan MAT 95S (HR-EI), a Finnigan LCQ classic (ESI),
and a Thermo Finnigan LTQ FT (HRMS-ESI) instrument. 1H- and
13C NMR spectra were recorded in CDCl3 at 303 K either on a Bruker
AV-360 or a Bruker AV-500 spectrometer. The chemical shifts are report-
ed relative to CHCl3 (d=7.26 ppm). Apparent multiplets that occur as
a result of the accidental equality of coupling constants to those of mag-
netically nonequivalent protons are marked as virtual (virt). If clearly
visible, virtual doublets in para-substituted arenes were also assigned and
marked as virtual (virt). The multiplicities of 13C NMR signals were de-
termined by DEPT experiments, and assignments were made based on
COSY, HMBC, and HMQC experiments. Melting points were measured
on a Koffler Thermopan and are uncorrected. Elemental analyses were
carried out on an Elementar Vario EL at the Department Chemie at the
Technische Universitꢁt Mꢂnchen.
The alkylation reaction was proven to be stereoconver-
gent as were all previous reactions under acidic conditions.
Irrespective of whether substrate 24 was employed as anti-
(anti/synꢀ95:5) or as syn-diastereoisomer (anti/syn=35:65),
the same product anti-25b was obtained in the reaction with
2-(trimethylsilyloxy)propene. Although the anti-selectivity
observed for substrate 24 is in line with the model depicted
in Figure 3, it cannot be ruled out that a neighboring group
participation occurs in the Lewis acid-catalyzed reactions.
The N,N-dibenzylamino group could, in the absence of stoi-
chiometric acid sources, induce the stereoconvergent forma-
tion of a quarternary trans-aziridinium ion intermediate,
which is known to be attacked stereospecifically by a nucleo-
phile, with inversion of configuration.[32]
Conclusions
In summary, we have found a useful method for the deriva-
tization of b-hydroxytyrosine esters by SN1-type nucleophilic
displacement reactions. The method is useful for the prepa-
ration of both anti- and syn-b-aryl derivatives. In addition, it
is possible to access anti-alkylation products via the respec-
tive N,N-dibenzyl substituted acetates. The substrate scope
was not probed regarding related b-hydroxyarylalanine com-
pounds; however, it is expected that they react in a similar
fashion as long as cation formation is feasible. In general,
one strong electron-donating substituent is required within
the aryl group to provide sufficient reactivity.[4c] Scheme 9
shows the reaction of acetate 26, which is derived from pi-
peronal, with a silyl enol ether. In analogy to the transfor-
mation of 24 into 25b, the reaction proceeded in good yield
Single Crystal X-Ray Structure Determinations of Compounds syn-15 and
anti-25a
The data were collected on an X-ray single-crystal diffractometer
equipped with a CCD detector (APEX II, k-CCD), a rotating anode
(Bruker AXS, FR591) with MoKa radiation (l=0.71073 ꢄ), and a graph-
ite monochromator by using the SMART software package.[35] The meas-
urements were performed on single crystals coated with perfluorinated
ether. The crystals were fixed on the top of a glass fiber and transferred
to the diffractometer. Crystals from syn-15 (CCDC 857982) and anti-25a
(CCDC 857981) were frozen under a stream of cold nitrogen. A matrix
Chem. Asian J. 2012, 00, 0 – 0
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
7
&
&
&
These are not the final page numbers! ÞÞ

Thorsten Bach et al.
FULL PAPERS
scan using three short runs was used to determine the initial lattice pa-
rameters. Reflections were merged and corrected for Lorenz and polari-
zation effects, scan speed, and background using SAINT.[36] Absorption
corrections, including odd and even ordered spherical harmonics were
performed using SADABS.[36] Space group assignments were based upon
systematic absences, E statistics, and successful refinement of the struc-
tures. Structures were solved by direct methods with the aid of successive
difference Fourier maps, and were refined against all data using
WinGX[37] based on SIR-92.[38] Hydrogen atoms could be located in the
difference Fourier maps and were allowed to refine freely. If not men-
tioned otherwise, non-hydrogen atoms were refined with anisotropic dis-
(m), 1032 (s), 917 (m), 721 cmꢁ1 (s); 1H NMR (500 MHz, CDCl3): d=
3.57 (s, 3H), 3.60 (s, 3H), 3.77 (s, 3H), 3.84 (s, 3H), 5.50 (d, 3J=12.1 Hz,
1H), 5.89 (d, 3J=12.1 Hz, 1H), 6.43 (d, 4J=2.4 Hz, 1H), 6.48 (dd, 3J=
8.4 Hz, 4J=2.4 Hz, 1H), 6.68–6.61 (m, 2H), 7.17–7.20 (m, 2H), 7.36 (d,
3J=8.4 Hz, 1H), 7.63 (dd, J=5.5 Hz, J=3.0 Hz, 2H), 7.73 ppm (dd, J=
5.5 Hz, 4J=3.0 Hz, 2H); 13C NMR (90.6 MHz, CDCl3): d=42.9 (d), 52.4
(q), 54.1 (d), 55.0 (q), 55.2 (q), 55.5 (q), 99.1 (d), 104.2 (d), 113.5 (d),
122.9 (s), 123.3 (d), 127.8 (d), 129.3 (d), 131.4 (s), 132.7 (s), 133.9 (d),
157.9 (2C, 2xs), 159.4 (s), 167.3 (s), 169.0 ppm (s); MS (ESI): m/z (%)=
476 (87) [(M+H)+], 368 (34), 338 (100) [(M-C8H9O2)+], 306 (36), 278
(17); HRMS (ESI): C27H26NO7 [(M+H)+]: calcd: 476.1704; found:
476.1723; elemental analysis: calcd. (%) for C27H25NO7: C: 68.20, H:
5.30, N: 2.95; found: C: 68.28, H: 5.58, N: 2.69.
3
4
3
placement parameters. Full-matrix least-squares refinements were carried
2
out by minimizing Sw
N
scheme. Neutral atom scattering factors for all atoms and anomalous dis-
persion corrections for the non-hydrogen atoms were taken from the In-
ternational Tables for Crystallography.[40] Images of the crystal structures
were generated by PLATON.[41]
18: Reaction of alcohol 14 (89.5 mg, 200 mmol) with HBF4·OEt2 (82.3 mL,
600 mmol) and 1,3-dimethoxybenzene (105 mL, 800 mmol) yielded, after
flash chromatography (eluent: pentane/diethylether=2:1!1:2), 18
(86 mg, 152 mmol, 76%) as a colorless solid [d.r. (anti/syn)=32:68]; Rf =
0.17 (pentane/diethylether=1:1); m.p.: 64–658C; IR (ATR): n˜ =3337 (w),
3005 (w), 2925 (m), 2837 (m), 1722 (vs), 1609 (s), 1505 (vs), 1450 (m),
1247 (s), 1208 (s), 1032 (vs), 739 cmꢁ1 (s); 1H NMR (500 MHz, CDCl3):
d=3.54 (s, 3H), 3.75 (s, 3H), 3.76 (s, 3H), 3.77 (s, 3H), 4.16–4.25 (m,
2H), 4.33–4.38 (m, 1H), 4.76 (d, 3J=9.2 Hz, 1H), 5.04 (virt. t, 3J
General Procedure for the Friedel–Crafts Alkylation Reactions
A flame-dried Schlenk flask was purged with argon and charged with the
benzylic alcohol and the respective arene nucleophile in dry CH2Cl2
(2.00 mL). The solution was cooled to ꢁ788C and HBF4·OEt2 was added
via a syringe. The resulting mixture was warmed to ambient temperature
over a period of 3 h. The reaction was quenched with sat. aqueous
NaHCO3 (6 mL) and diluted with CH2Cl2 (6 mL). The layers were sepa-
rated and the aqueous layer was extracted with CH2Cl2 (2ꢅ10 mL). The
combined organic layers were dried over Na2SO4, filtered, and concen-
trated in vacuo. The crude product was purified by flash chromatography
to give the respective Friedel–Crafts product.
3
ffi 8.9 Hz, 1H), 5.40 (d, J=8.7 Hz, 1H), 6.42–6.46 (m, 2H), 6.80–6.83 (m,
2H), 7.09 (d, 3J=9.0 Hz, 1H), 7.19–7.21 (m, 2H), 7.28–7.29 (m, 2H),
7.37–7.41 (m, 2H), 7.49–7.51 (m, 2H), 7.75 ppm (d, 3J=7.3 Hz, 2H);
13C NMR (90.6 MHz, CDCl3): d=45.1 (d), 47.0 (d), 52.0 (q), 55.2 (q),
55.3 (q), 55.5 (q), 57.2 (d), 67.0 (t), 98.9 (d), 104.6 (d), 113.7 (d), 119.9
(2C, 2xd), 120.5 (s), 125.0 (d), 125.1 (d), 127.0 (2C, 2xd), 127.6 (2C, 2xd),
129.4 (d), 129.6 (d), 132.2 (s), 141.2 (2C, 2xs), 143.8 (2C, 2xs), 155.8 (s),
158.0 (s), 158.3 (s), 159.9 (s), 172.8 ppm (s); MS (ESI): m/z (%)=568
(100) [(M+H)+], 499 (14), 360 (21), 282 (38); HRMS (ESI): C34H34NO7
[(M+H)+]: calcd: 568.2330; found: 568.2323.
15: Reaction of
8 (45.0 mg, 200 mmol) with HBF4·OEt2 (82.3 mL,
600 mmol) and 1,3-dimethoxybenzene (105 mL, 800 mmol) yielded, after
flash chromatography (eluent: CH2Cl2 (100%)!CH2Cl2/MeOH=95:5),
15 (53 mg, 153 mmol, 77%) as a colorless solid [d.r. (anti/syn)=10:90];
Rf =0.32 (CH2Cl2/MeOH=95:5); m.p.: 1138C; IR (ATR): n˜ =3408 (w),
2952 (m,), 2832 (m,), 1736 (vs), 1609 (s), 1498 (s), 1465 (m), 1242 (vs),
1173 (vs), 1030 (vs), 830 cmꢁ1 (s); 1H NMR (360 MHz, CDCl3): d=1.49
(bs, 2H), 3.52 (s, 3H), 3.75 (s, 3H), 3.76 (s, 3H), 3.77 (s, 3H), 4.17 (d,
3J=9.1 Hz, 1H), 4.59 (d, 3J=9.1 Hz, 1H), 6.43 (d, 4J=2.4 Hz, 1H), 6.47
(dd, 3J=8.4 Hz, 4J=2.4 Hz,1H), 6.78 (virt. d, J=8.5 Hz, 2H), 7.16 (d,
3J=8.4 Hz, 1H), 7.22 ppm (virt. d, J=8.7 Hz, 2H); 13C NMR (90.6 MHz,
CDCl3): d=47.8 (d), 51.7 (q), 55.1 (q,) 55.3 (q), 55.4 (q), 58.3 (d), 98.8
(d), 104.3 (d), 113.5 (d), 121.5 (s), 129.1 (d), 129.2 (d), 133.9 (s), 158.0 (s),
158.4 (s), 159.5 (s), 175.4 ppm (s). MS (ESI): m/z (%)=346 (100,
[(M+H)+]), 208 (7); HRMS (ESI): C19H24NO5 [(M+H)+]: calcd:
346.1649; found: 346.1655.
19: Reaction of alcohol 8 (45.0 mg, 200 mmol) with HBF4·OEt2 (82.3 mL,
600 mmol) and 2-methylthiophene (77.4 mL, 800 mmol) yielded, after flash
chromatography [eluent: CH2Cl2 (100%)!CH2Cl2/MeOH=98:2], 19
(57 mg, 187 mmol, 93%) as a yellow oil [d.r. (anti/syn)=25:75]; Rf =0.41
(CH2Cl2/MeOH=95:5); IR (ATR): n˜ =2948 (w), 2837 (m), 1736 (vs),
1610 (m), 1510 (vs), 1437 (m), 1246 (vs), 1178 (s), 1033 (s), 801 (m),
729 cmꢁ1 (m); 1H NMR (360 MHz, CDCl3): d=1.59 (bs, 2H), 2.41 (d,
4J=0.9 Hz, 3H), 3.54 (s, 3H), 3.77 (s, 3H), 4.00 (d, 3J=7.7 Hz, 1H), 4.41
(d, 3J=7.7 Hz, 1H), 6.57–6.58 (m, 1H), 6.71 (d, 3J=3.4 Hz, 1H), 6.81–
6.85 (m, 2H), 7.26–7.30 ppm (m, 2H); 13C NMR (90.6 MHz, CDCl3): d=
15.3 (q), 51.3 (d), 51.9 (q), 55.2 (q), 60.2 (d), 113.8 (d), 124.7 (d), 125.7
(d), 129.1 (d), 133.1 (s), 139.2 (s), 141.2 (s), 158.5 (s), 174.3 ppm (s); MS
(ESI): m/z (%)=306 (100) [(M+H)+]; HRMS (ESI): C16H20NO3S
[(M+H)+]: calcd: 306.1158; found: 306.1154.
16: Reaction of alcohol 5 (101 mg, 250 mmol) with HBF4·OEt2 (103 mL,
750 mmol) and 1,3-dimethoxybenzene (132 mL, 1.00 mmol) yielded, after
flash chromatography (eluent: pentane/diethylether=9:1!1:2), 16
(129 mg, 245 mmol, 98%) as a colorless solid [d.r. (anti/syn)=88:12]; Rf =
0.53 (pentane/diethylether=1:1). m.p.: 72–748C; IR (ATR): n˜ =3023 (w),
2946 (m), 2837 (m), 1725 (vs), 1505 (vs), 1435 (s), 1207 (s), 1131 (vs),
698 cmꢁ1 (vs); 1H NMR (500 MHz, CDCl3): d=3.30 (d, 2J=13.7 Hz,
2H), 3.61 (s, 3H), 3.71 (s, 6H), 3.82 (s, 3H), 4.04 (d, 2J=13.7 Hz, 2H),
4.26 (d, 3J=12.3 Hz, 1H), 4.89 (d, 3J=12.3 Hz, 1H), 6.31–6.34 (m, 2H),
20: Reaction of alcohol 9 (47.9 mg, 200 mmol) with HBF4·OEt2 (82.3 mL,
600 mmol) and 2-methylthiophene (77.4 mL, 800 mmol) yielded, after flash
chromatography [eluent: CH2Cl2 (100%)!CH2Cl2/MeOH=98:2], 20
(65 mg, 200 mmol, quant.) as a yellow oil [d.r. (anti/syn)=20:80]; Rf =0.62
(CH2Cl2/MeOH=95:5); IR (ATR): n˜ =3365 (w), 3059 (w), 2935 (w),
2833 (w), 1729 (vs), 1610 (m), 1510 (vs), 1463 (m), 1248 (vs), 1180 (s),
1080 (m), 1028 (vs), 793 cmꢁ1 (s); 1H NMR (360 MHz, CDCl3): d=1.04
(t, 3J=7.1 Hz, 3H), 1.60 (bs, 2H), 2.41 (d, 4J=1.0 Hz, 3H), 3.77 (s, 3H),
3.98 (d, 3J=8.0 Hz, 1H), 3.99 (q, 3J=7.1 Hz, 2H), 4.38 (d, 3J=8.0 Hz,
1H), 6.56–6.58 (m, 1H), 6.71 (d, 3J=3.5 Hz, 1H), 6.81–6.84 (m, 2H),
7.27–7.30 ppm (m, 2H); 13C NMR (90.6 MHz, CDCl3): d=13.9 (q), 15.2
(q), 51.5 (d), 55.2 (q), 60.2 (d), 60.8 (t), 113.8 (d), 124.6 (d), 125.6 (d),
129.2 (d), 133.2 (s), 139.1 (s), 141.4 (s), 158.5 (s), 173.8 ppm (s); MS
(ESI): m/z (%)=320 (100) [(M+H)+]; HRMS (ESI): C17H22NO3S
[(M+H)+]: calcd: 320.1315; found: 320.1313.
3
6.73–6.76 (m, 2H), 6.92–6.95 (m, 2H), 6.97 (d, J=9.1 Hz, 1H), 7.00–7.02
(m, 4H), 7.22–7.26 ppm (m, 6H); 13C NMR (90.6 MHz, CDCl3): d=41.9
(d), 50.7 (q), 54.5 (t), 55.2 (q), 55.3 (q), 55.5 (q), 63.5 (d), 99.0 (d), 104.2
(d), 113.2 (d), 123.1 (s), 126.9 (d), 127.6 (d), 127.9 (d), 129.4 (d), 130.1
(d), 133.9 (s), 139.0 (s), 157.9 (2C, 2xs), 159.2 (s), 171.3 ppm (s); MS (EI,
70 eV): m/z (%)=466 (3) [(M-C2H3O2)+], 268 (33), 257 (100) [(M-
C17H18O2N)+], 138 (42), 91 (93); HRMS (EI): C31H32NO3 [(M-C2H3O2)+
]: calcd: 466.2377; found: 466.2380.
21: Reaction of alcohol 10 (50.6 mg, 200 mmol) with HBF4·OEt2 (82.3 mL,
600 mmol) and 2-methylthiophene (77.4 mL, 800 mmol) yielded, after flash
chromatography [eluent: CH2Cl2 (100%)!CH2Cl2/MeOH=95:5], 21
(66 mg, 198 mmol, 99%.) as a yellow oil [d.r. (anti/syn)=17:83]; Rf =0.53
(CH2Cl2/MeOH=95:5); IR (ATR): n˜ =3387 (w), 3056 (w), 2981 (m),
2837 (w), 1727 (s), 1610 (m), 1510 (vs), 1464 (m), 1245 (vs), 1178 (s),
1105 (s), 1031 (s), 798 cmꢁ1 (s); 1H NMR (500 MHz, CDCl3): d=0.91 (d,
17: Reaction of alcohol 13 (71.1 mg, 200 mmol) with HBF4·OEt2 (82.3 mL,
600 mmol) and 1,3-dimethoxybenzene (105 mL, 800 mmol) yielded, after
flash chromatography (eluent: pentane/diethylether=4:1!2:1), 17
(84 mg, 177 mmol, 88%) as a colorless, highly viscous oil [d.r. (anti/syn)=
79:21]; Rf =0.30 (pentane/diethylether=1/2); IR (ATR): n˜ =2933 (m),
2832 (w), 1713 (vs), 1609 (m), 1509 (s), 1466 (m), 1386 (s), 1250 (s), 1124
&
&
&8
&
www.chemasianj.org
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!

Stereoselective Synthesis of b-Aryl and b-Alkyltyrosines
3J=6.3 Hz, 3H), 1.12 (d, 3J=6.3 Hz, 3H), 1.61 (bs, 2H), 2.41 (bs, 3H),
3.76 (s, 3H), 3.94 (d, 3J=8.2 Hz, 1H), 4.34 (d, 3J=8.2 Hz, 1H), 4.83
(sept., 3J=6.3 Hz, 1H), 6.56–6.58 (m, 1H), 6.71 (d, 3J=3.3 Hz, 1H), 6.82
(virt. d, J=8.7 Hz, 2H), 7.28 ppm (virt. d, J=8.7 Hz, 2H); 13C NMR
(90.6 MHz, CDCl3): d=15.3 (q), 21.3 (q), 21.6 (q), 51.7 (d), 55.2 (q), 60.2
(d), 68.3 (d), 113.7 (d), 124.6 (d), 125.6 (d), 129.2 (d), 133.2 (s), 139.1 (s),
141.6 (s), 158.6 (s), 173.3 ppm (s); MS (ESI): m/z (%)=334 (100)
[(M+H)+], 306 (8); HRMS (ESI): C18H24NO3S [(M+H)+]: calcd:
334.1471; found: 334.1470.
(dd, 3J=3.4 Hz, 4J=1.6 Hz, 1H), 6.62–6.65 (m, 2H), 6.94–6.97 (m, 2H),
7.05 (virt. d, J=8.1 Hz, 2H), 7.32–7.35 ppm (m, 3H); 13C NMR
(90.6 MHz, CDCl3): d=21.1 (q), 21.5 (q), 21.6 (q), 47.5 (d), 55.2 (q), 60.7
(d), 68.4 (d), 111.4 (d), 112.8 (d), 113.5 (d), 123.1 (d), 126.7 (d), 129.5 (d),
129.7 (d), 130.8 (s), 134.7 (s), 136.2 (s), 144.4 (s), 158.5 (s), 172.8 ppm (s);
MS (ESI): m/z (%)=457 (100) [(M+H)+], 429 (8), 298 (3); HRMS
(ESI): C24H29O5N2S [(M+H)+]: calcd: 457.1792; found: 457.1786.
23a: Reaction of alcohol 5 (101 mg, 250 mmol) with HBF4·OEt2 (103 mL,
750 mmol) and 1,2,3-trimethoxybenzene (168 mg, 1.00 mmol) yielded,
after flash chromatography (eluent: pentane/diethylether=6:1!1:3), 23a
(73 mg, 131 mmol, 53%) as a colorless oil [d.r. (anti/syn)= >95:5]; Rf =
0.37 (pentane/diethylether=1:1); IR (ATR): n˜ =3030 (w), 2948 (m), 2831
(m), 1730 (s), 1493 (s), 1244 (s), 1095 (vs), 732 (vs), 698 cmꢁ1 (vs);
1H NMR (500 MHz, CDCl3): d=3.30 (d, 2J=13.7 Hz, 2H), 3.61 (s, 3H),
3.76 (s, 3H), 3.77 (s, 3H), 3.78 (s, 3H), 3.82 (s, 3H), 4.05 (d, 2J=13.7 Hz,
2H), 4.17 (d, 3J=12.4 Hz, 1H), 4.89 (d, 3J=12.4 Hz, 1H), 6.45 (d, 3J=
8.7 Hz, 1H), 6.73 (d, 3J=8.7 Hz, 1H), 6.74–6.77 (m, 2H), 6.92–6.95 (m,
2H), 7.00–7.02 (m, 4H), 7.22–7.25 ppm (m, 6H); 13C NMR (90.6 MHz,
CDCl3): d=42.0 (d), 50.8 (q), 54.4 (t), 55.3 (q), 55.8 (q), 60.5 (q), 60.6
(q), 64.0 (d), 107.0 (d), 113.4 (d), 121.1 (d), 126.9 (d), 128.0 (d), 128.4 (s),
129.3 (d), 129.7 (d), 134.0 (s), 139.0 (s), 142.2 (s), 151.6 (s), 152.2 (s),
158.0 (s), 171.1 ppm (s); MS (ESI): m/z (%)=556 (100) [(M+H)+], 496
(12) [(M-C2H3O2)+]; HRMS (ESI): C34H38NO6 [(M+H)+]: calcd:
556.2694; found: 556.2686.
22a: Reaction of alcohol 10 (50.6 mg, 200 mmol) with HBF4·OEt2
(82.3 mL, 600 mmol) and 1,3-dimethoxybenzene (105 mL, 800 mmol) yield-
ed, after flash chromatography [eluent: CH2Cl2 (100%)!CH2Cl2/
MeOH=95:5], 22a (74 mg, 198 mmol, 99%.) as a colorless oil [d.r. (anti/
syn)=7:93]; Rf =0.32 (CH2Cl2/MeOH=95:5); IR (ATR): n˜ =3387 (w),
2933 (m), 2837 (m), 1726 (s), 1608 (s), 1505 (vs), 1462 (s), 1243 (s), 1207
(s), 1176 (m), 1106 (s), 1031 (vs), 820 cmꢁ1 (s); 1H NMR (500 MHz,
CDCl3): d=0.86 (d, 3J=6.3 Hz, 3H), 1.12 (d, 3J=6.3 Hz, 3H), 1.56 (bs,
2H), 3.74 (s, 3H), 3.76 (s, 3H), 3.77 (s, 3H), 4.13 (d, 3J=9.8 Hz, 1H),
3
3
4
4.52 (d, J=9.8 Hz, 1H), 4.81 (sept., J=6.3 Hz, 1H), 6.43 (d, J=2.4 Hz,
1H), 6.48 (dd, 3J=8.4 Hz, 4J=2.4 Hz, 1H), 6.74–6.78 (m, 2H), 7.21–
7.26 ppm (m, 3H); 13C NMR (90.6 MHz, CDCl3): d=21.2 (q), 21.6 (q),
48.3 (d), 55.2 (q), 55.3 (q), 55.4 (q), 58.5 (d), 67.9 (d), 98.9 (d, C-c), 104.4
(d), 113.5 (d), 122.0 (s), 128.6 (d), 129.5 (d), 133.8 (s), 158.1 (s), 158.5 (s),
159.5 (s), 174.4 ppm (s); MS (ESI): m/z (%)=374 (100) [(M+H)+], 346
(5); HRMS (ESI): C21H28NO5 [(M+H)+]: calcd: 374.1962; found:
374.1956.
23b: Reaction of alcohol 5 (101 mg, 250 mmol) with HBF4·OEt2 (103 mL,
750 mmol) and 1-bromo-2,4-dimethoxybenzene (144 mL, 1.00 mmol) yield-
ed, after flash chromatography (eluent: pentane/diethylether=6:1!1:1),
23b (87 mg, 144 mmol, 58%) as a colorless solid [d.r. (anti/syn)=80:20];
Rf =0.26 (anti)/0.31 (syn) (pentane/diethylether=1:1); m.p.: 1068C; IR
(ATR): n˜ =3034 (w), 2938 (m), 2837 (m), 1729 (s), 1510 (s), 1453 (s),
1206 (vs), 1144 (s), 1028 (s), 748 (s), 699 cmꢁ1 (s); 1H NMR (500 MHz,
CDCl3): d=3.31 (d, 2J=13.7 Hz, 2H), 3.65 (s, 3H), 3.73 (s, 3H), 3.81 (s,
3H), 3.83 (s, 3H), 4.02 (d, 2J=13.7 Hz, 2H), 4.23 (d, 3J=12.3 Hz, 1H),
22b: Reaction of alcohol 10 (50.6 mg, 200 mmol) with HBF4·OEt2
(82.3 mL, 600 mmol) and 1,2,3-trimethoxybenzene (135 mg, 800 mmol)
yielded after flash chromatography [eluent: CH2Cl2 (100%)!CH2Cl2/
MeOH=95:5] 22b (73 mg, 181 mmol, 90%.) as a colorless oil [d.r. (anti/
syn)=21:79]; Rf =0.40 (CH2Cl2/MeOH=95:5); IR (ATR): n˜ =3387 (w),
2938 (m), 2832 (m), 1726 (s), 1492 (m), 1415 (m), 1243 (s), 1092 (vs),
799 cmꢁ1 (m); 1H NMR (360 MHz, CDCl3): d=0.84 (d, 3J=6.3 Hz, 3H),
3
3
1.13 (d, J=6.3 Hz, 3H), 1.67 (bs, 2H), 3.69 (s, 3H), 3.74 (s, 3H), 3.83 (s,
4.82 (d, J=12.3 Hz, 1H), 6.35 (s, 1H), 6.75 (virt. d, J=8.7 Hz, 2H), 6.92
6H), 4.09 (d, 3J=9.9 Hz, 1H), 4.50 (d, 3J=9.9 Hz, 1H), 4.81 (sept., 3J=
6.3 Hz, 1H), 6.68 (d, 3J=8.7 Hz, 1H), 6.76–6.79 (m, 2H), 7.10 (d, 3J=
8.7 Hz, 1H), 7.19–7.22 ppm (m, 2H); 13C NMR (90.6 MHz, CDCl3): d=
21.2 (q), 21.7 (q), 48.6 (d), 55.2 (q), 55.9 (q), 58.8 (d), 60.6 (q), 60.8 (q),
68.1 (d), 107.3 (d), 113.6 (d), 122.0 (d), 127.4 (s), 129.5 (d), 133.6 (s),
142.5 (s), 152.4 (s), 152.5 (s), 158.2 (s), 174.0 ppm (s); MS (ESI): m/z
(%)=426 (18) [(M+Na)+], 404 (100) [(M+H)+], 376 (6), 236 (8);
HRMS (ESI): C22H30NO6 [(M+H)+]: calcd: 404.2068; found: 404.2064.
(virt. d, J=8.7 Hz, 2H), 7.00–7.02 (m, 4H), 7.18 (s, 1H), 7.22–7.25 ppm
(m, 6H); 13C NMR (90.6 MHz, CDCl3): d=42.2 (d), 50.8 (q), 54.4 (t),
55.3 (q), 55.8 (q), 56.2 (q), 63.3 (d), 97.1 (d), 101.7 (s), 113.3 (d), 124.5
(s), 126.9 (d), 128.0 (d), 129.2 (d), 130.1 (d), 131.1 (d), 133.2 (s), 138.9 (s),
155.0 (s), 157.3 (s), 158.1 (s), 171.2 ppm (s); MS (ESI): m/z (%)=606
(100) {[MACTHNUTRGENNGU ACHTUNGTRENNUGN
(81Br)+H]+}, 604 (99) {[M(79Br)+H]+}; HRMS (ESI):
C33H3579BrNO5 [(M+H)+]: calcd: 604.1693; found: 604.1696.
23c: Reaction of alcohol 5 (101 mg, 250 mmol) with HBF4·OEt2 (103 mL,
750 mmol) and 2-methylthiophene (96.8 mL, 1.00 mmol) yielded, after
flash chromatography (eluent: pentane/diethylether=9:1!1:1), 23c
(100 mg, 206 mmol, 82%) as a colorless solid [d.r. (anti/syn)=89:11]; Rf =
0.39 (anti)/0.31 (syn) (pentane/diethylether=4:1); m.p.: 119–1208C; IR
(ATR): n˜ =3028 (w), 2951 (w), 2837 (m), 1725 (vs), 1512 (vs), 1263 (vs),
1037 (s), 748 (vs), 698 cmꢁ1 (vs); 1H NMR (500 MHz, CDCl3): d=2.31
(d, 4J=1.0 Hz, 3H), 3.25 (d, 2J=13.6 Hz, 2H), 3.75 (s, 3H), 3.85 (s, 3H),
22c: Reaction of alcohol 10 (50.6 mg, 200 mmol) with HBF4·OEt2
(82.3 mL, 600 mmol) and 1-bromo-2,4-dimethoxybenzene (115 mL,
800 mmol) yielded, after flash chromatography [eluent: CH2Cl2 (100%)!
CH2Cl2/MeOH=95:5], 22c (88 mg, 195 mmol, 97%.) as a pale yellow oil
[d.r. (anti/syn)=11:89]; Rf =0.45 (CH2Cl2/MeOH=95:5); IR (ATR): n˜ =
3383 (w), 2938 (m), 2837 (m), 1725 (s), 1598 (m), 1509 (s), 1462 (m), 1204
(vs), 1027 (vs), 820 (s), 729 cmꢁ1 (s); 1H NMR (500 MHz, CDCl3): d=
0.85 (d, 3J=6.3 Hz, 3H), 1.11 (d, 3J=6.3 Hz, 3H), 1.57 (bs, 2H), 3.74 (s,
3H), 3.80 (s, 3H), 3.86 (s, 3H), 4.10 (d, 3J=9.8 Hz, 1H), 4.49 (d, 3J=
2
3
3
3.91 (d, J=13.6 Hz, 2H), 3.98 (d, J=11.8 Hz, 1H), 4.68 (d, J=11.8 Hz,
1H), 6.42 (dd, 3J=3.4 Hz, 4J=1.0 Hz, 1H), 6.51 (d, 3J=3.4 Hz, 1H),
6.80–6.83 (m, 2H), 6.88–6.90 (m, 2H), 6.93–6.95 (m, 4H), 7.22–7.25 ppm
(m, 6H); 13C NMR (90.6 MHz, CDCl3): d=15.2 (q), 45.7 (d), 51.0 (q),
54.2 (t), 55.4 (q), 65.4 (d), 113.6 (d), 123.9 (d), 124.5(d), 127.0 (d), 128.0
(d), 129.3 (d), 129.8 (d), 133.1 (s), 138.6 (2C, 2xs), 143.3 (s), 158.5 (s),
171.1 ppm (s); MS (ESI): m/z (%)=486 (100) [(M+H)+], 388 (57) [(M-
C5H5S)+], 298 (12); HRMS (ESI): C30H32NO3S [(M+H)+]: calcd:
486.2097; found: 486.2090.
3
9.8 Hz, 1H), 4.81 (sept., J=6.3 Hz, 1H), 6.44 (s, 1H), 6.76–6.80 (m, 2H),
7.19–7.22 (m, 2H), 7.48 ppm (s, 1H); 13C NMR (90.6 MHz, CDCl3): d=
21.2 (q), 21.6 (q), 47.9 (d), 55.2 (q), 55.8 (q), 56.3 (q), 58.4 (d), 68.0 (d),
96.9 (d), 102.1 (s), 113.6 (d), 123.5 (s), 129.5 (d), 132.2 (d), 133.1 (s), 155.3
(s), 157.8 (s), 158.3 (s), 174.3 ppm (s); MS (ESI): m/z (%)=454 (100)
{[MACHTUNGTRENNUNG ACHTUNGTRENNUGN
(81Br)+H]+}, 452 (99) {[M(79Br)+H]+}, 426 (6), 424 (6), 236 (11)
[(M-C7H8BrO2)+]; HRMS (ESI): C21H2779BrO5N [(M+H)+]: calcd:
452.1067; found: 452.1065.
23d: Reaction of alcohol 5 (101 mg, 250 mmol) with HBF4·OEt2 (103 mL,
750 mmol) and N-tosylpyrrole (221 mg, 1.00 mmol) yielded, after flash
chromatography (eluent: pentane/diethylether=9:1!1:2), 23d (46 mg,
75.6 mmol, 30%) as a colorless solid [d.r. (anti/syn)= >95:5]; Rf =0.50
(pentane/diethylether=1:1); m.p.: 658C; IR (ATR): n˜ =3030 (w), 2952
(w), 2841 (w), 1732 (s), 1510 (s), 1370 (vs), 1251 (vs), 1135 (vs), 1030 (m),
22d: Reaction of alcohol 10 (50.6 mg, 200 mmol) with HBF4·OEt2
(82.3 mL, 600 mmol) and N-tosylpyrrole (177 mg, 800 mmol) yielded, after
flash chromatography [eluent: CH2Cl2 (100%)!CH2Cl2/MeOH=95:5],
22d (86 mg, 188 mmol, 94%.) as a yellow oil [d.r. (anti/syn)=15:85]; Rf =
0.49 (CH2Cl2/MeOH=95:5); IR (ATR): n˜ =2981 (w), 2837 (w), 1728 (s),
1510 (s), 1247 (s), 1173 (vs), 1032 (m), 811 cmꢁ1 (s); 1H NMR (360 MHz,
CDCl3): d=0.78 (d, 3J=6.3 Hz, 3H), 1.13 (d, 3J=6.3 Hz, 3H), 1.55 (bs,
2H), 2.32 (s, 3H), 3.73 (s, 3H), 3.83 (d, 3J=9.0 Hz, 1H), 4.77 (sept., 3J=
1
673 cmꢁ1 (vs); H NMR (500 MHz, CDCl3): d=2.32 (s, 3H), 3.27 (d, 2J=
14.0 Hz, 2H), 3.57 (s, 3H), 3.81 (d, 3J=12.0 Hz, 1H), 3.84 (s, 3H), 4.01
2
3
3
4
(d, J=14.0 Hz, 2H), 5.17 (d, J=12.0 Hz, 1H), 6.03 (dd, J=3.3 Hz, J=
1.5 Hz, 1H), 6.12 (virt. t, 3J ffi 3.4 Hz, 1H), 6.65–6.68 (m, 2H), 6.82–6.84
6.3 Hz, 1H), 4.82 (d, 3J=9.0 Hz, 1H), 6.31 (virt. t, J ffi 3.4 Hz, 1H), 6.48
3
Chem. Asian J. 2012, 00, 0 – 0
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
9
&
&
&
These are not the final page numbers! ÞÞ

Thorsten Bach et al.
FULL PAPERS
(m, 2H), 6.97–6.99 (m, 4H), 7.03–7.05 (virt. d, J=8.1 Hz, 2H), 7.13 (dd,
3J=3.4 Hz, 4J=1.5 Hz,1H), 7.18–7.20 (m, 6H), 7.29 ppm (virt. d, J=
8.1 Hz, 2H); 13C NMR (90.6 MHz, CDCl3): d=21.5 (q), 40.7 (d), 50.9
(q), 54.5 (t), 55.3 (q), 65.8 (d), 11.3 (d), 11.4 (d), 113.0 (d), 123.2 (d),
126.6 (d), 126.8 (d), 128.0 (d), 128.8 (d), 129.4 (d), 130.7 (d), 131.5 (s),
136.2 (s), 136.6 (s), 138.6 (s), 144.0 (s), 158.3 (s), 170.2 ppm (s); MS
(ESI): m/z (%)=609 (100) [(M+H)+], 282 (8); HRMS (ESI):
C36H37N2O5S [(M+H)+]: calcd: 609.2418; found: 609.2412.
elemental analysis: calcd. (%) for (C30H35NO5): C: 73.59, H: 7.21, N:
2.86; found: C: 73.28 , H: 7.24, N: 2.79.
27: Reaction of acetate 26 (553 mg, 1.16 mmol) with BiACTHUNRGTNEUNG(OTf)3 (76.3 mg,
116 mmol) and 2-trimethylsilyloxy-propene (767 mL, 4.65 mmol) in nitro-
methane (9.28 mL) yielded, after flash chromatography (eluent: pentane/
diethylether=6:1!1:1), 27 (394 mg, 832 mmol, 72%) as a yellow oil [d.r.
(anti/syn)= >95:5]; Rf =0.25 (pentane/diethylether=2:1); IR (ATR): n˜ =
3024 (w), 2928 (w), 2894 (w), 2841 (w), 1717 (vs), 1490 (s), 1443 (m),
1243 (vs), 1173 (s), 1025 (s), 926 (m), 746 (s), 698 cmꢁ1 (vs); 1H NMR
(360 MHz, CDCl3): d=1.43 (t, 3J=7.1 Hz, 3H), 1.91 (s, 3H), 2.45 (dd,
General Procedure for the Diastereoselective SN1-type Alkylations of Silyl
Enol Ethers
3
2
3
2J=16.0 Hz, J=4.3 Hz, 1H), 2.53 (dd, J=16.0 Hz, J=9.3 Hz, 1H), 3.27
(d, 2J=13.7 Hz, 2H), 3.48 (d, 3J=11.5 Hz, 1H), 3.75 (ddd, 3J=4.3 Hz,
3J=9.3 Hz, 3J=11.5 Hz, 1H), 3.89 (d, 2J=13.7 Hz, 2H), 4.28 (dq, 2J=
A flame-dried Schlenk flask was purged with argon and charged with the
benzylic acetate in dry nitromethane. The respective silyl enol ether and
3
2
3
Bi
N
10.8 Hz, J=7.1 Hz, 1H), 4.38 (dq, J=10.8 Hz, J=7.1 Hz, 1H), 5.95 (m,
1H), 6.02 (m, 1H), 6.29 (d, 4J=1.7 Hz, 1H), 6.47 (dd, 3J=7.9 Hz, 4J=
1.7 Hz, 1H), 6.70 (d, 3J=7.9 Hz, 1H), 6.93–6.97 (m, 4H), 7.20–7.25 ppm
(m, 6H); 13C NMR (90.6 MHz, CDCl3): d=14.8 (q), 30.4 (q), 40.3 (d),
48.5 (t), 54.2 (t), 60.4 (t), 64.8 (d), 100.8 (t), 107.8 (d), 108.2 (d), 122.5 (d),
127.0 (d), 128.0 (d), 129.1 (d), 134.3 (s), 138.7 (s), 146.2 (s), 147.4 (s),
171.1 (s), 206.0 ppm (s); MS (ESI): m/z (%)=474 (100) [(M+H)+], 366
(4); HRMS (ESI): C29H32NO5 [(M+H)+]: calcd: 474.2275; found:
474.2276.
at ambient temperature for 3 h. The reaction was quenched with sat.
aqueous NaHCO3 (6 mL) and diluted with CH2Cl2 (6 mL) The layers
were separated and the aqueous layer was extracted with CH2Cl2 (2ꢅ
10 mL). The combined organic layers were dried over Na2SO4, filtered,
and concentrated in vacuo. The crude product was purified by flash chro-
matography to give the respective product.
25a: Reaction of acetate 24 (81.0 mg, 181 mmol) with BiACTHUNRGTNEUNG(OTf)3 (11.8 mg,
18.1 mmol) and 1-phenyl-1-(trimethylsilyloxy)ethylene (148 mL, 724 mmol)
in nitromethane (1.45 mL) yielded, after flash chromatography (eluent:
pentane/diethylether=4:1!2:1), 25a (82 mg, 162 mmol, 90%) as a color-
less solid [d.r. (anti/syn)ꢀ95:5]; Rf =0.13 (pentane/diethylether=4:1);
m.p.: 1128C; IR (ATR): n˜ =2939 (w), 2835 (w), 1689 (vs), 1512 (vs), 1451
(m), 1244 (s), 1220 (s), 1029 (m), 746 cmꢁ1 (vs); 1H NMR (360 MHz,
Acknowledgements
2
3
2
CDCl3): d=3.00 (dd, J=16.4 Hz, J=4.0 Hz, 1H), 3.11 (dd, J=16.4 Hz,
3J=9.2 Hz, 1H), 3.27 (d, 2J=13.7 Hz, 2H), 3.63 (d, 3J=11.6 Hz, 1H),
3.82 (s, 3H), 3.83 (s, 3H), 3.91 (d, 2J=13.7 Hz, 2H), 4.01 (ddd, 3J=
4.0 Hz, 3J=9.2 Hz, 3J=11.6 Hz, 1H), 6.77 (virt. d, J ffi 8.7 Hz, 2H), 6.85
(virt. d, J=8.7 Hz, 2H), 6.91 (dd, 3J=6.6 Hz, 4J=2.7 Hz, 4H), 7.18–7.23
This project was supported by the Deutsche Forschungsgemeinschaft (Ba
1372-12), by the graduate college NanoCat (scholarship to D. W.), and by
the TUM Graduate School. The help of Andrea Schmidt (undergraduate
research participant) and of Takuya Ishikawa (exchange student) is grate-
fully acknowledged.
3
(m, 6H), 7.37 (virt. t, J ffi 7.6 Hz, 2H), 7.45–7.51 (m, 1H), 7.77 ppm (dd,
3J=8.3 Hz, 4J=1.2 Hz, 2H); 13C NMR (90.6 MHz, CDCl3): d=39.9 (d),
43.9 (t), 51.2 (q), 54.2 (t), 55.3 (q), 65.1 (d), 113.5 (d), 126.9 (d), 127.9 (d),
128.0 (d), 128.4 (d), 129.1 (d), 129.9 (d), 132.7 (s), 132.9 (d), 136.8 (s),
138.8 (s), 158.3 (s), 172.0 (s), 197.6 ppm (s); MS (ESI): m/z (%)=508
(100) [(M+H)+], 406 (10), 282 (7); HRMS (ESI): C33H34NO4 [(M+H)+]:
calcd: 508.2482; found: 508.2467.
[1] Review: P. G. Cozzi, F. Benfatti, Angew. Chem. 2010, 122, 264–267;
Angew. Chem. Int. Ed. 2010, 49, 256–259.
[2] For intermolecular reactions at chiral benzylic cations that are part
of a ring system, see: a) W. L. Bencze, L. I. Barsky, R. W. J. Carey,
A. A. Renzi, G. DeStevens, J. Med. Chem. 1967, 10, 138–144; b) R.
Alonso, L. Castedo, D. Dominguez, J. Org. Chem. 1989, 54, 424–
428; c) K. Suzuki, T. Tatsuoka, T. Shihara, T. Ohno, K. Aisaka, R.
Ogino, M. Kuroki, F. Satoh, S. Miyano, K. Sumoto, Chem. Pharm.
Bull. 1996, 44, 132–138; d) S. Brandꢁnge, J.-E. Bꢁckvall, H. Leijon-
marck, J. Chem. Soc. Perkin Trans. 1 2001, 2051–2054; e) M. Da-
voust, J. A. Kitching, M. J. Fleming, M. Lautens, Chem. Eur. J. 2010,
16, 50–54; f) J. Guin, C. Besnard, P. Pattison, J. Lacour, Chem. Sci.
2011, 2, 425–428.
[3] For diastereoselective cyclization reactions via chiral benzylic cat-
ions, see: a) D. Lednicer, D. E. Emmert, S. C. Lyster, G. W. Duncan,
J. Med. Chem. 1969, 12, 881–885; b) A. A. Khalaf, R. M. Roberts, J.
Org. Chem. 1972, 37, 4227–4235; c) F. E. Ziegler, J. A. Schwartz, J.
Org. Chem. 1978, 43, 985–991; d) E. Brown, M. Loriot, J.-P. Robin,
Tetrahedron Lett. 1979, 20, 1389–1392; e) P. A. Ganeshpure, R. Ste-
venson, Chem. Soc. Perkin Trans. 1 1981, 1681–1684; f) S. R. Angle,
M. S. Louie, J. Org. Chem. 1991, 56, 2853–2866; g) M. Medarde,
A. C. Ramos, E. Caballero, J. L. Lꢆpez, R. Pelꢇez-Lamamiꢈ de
Clairac, A. San Feliciano, Tetrahedron Lett. 1998, 39, 2001–2004;
h) J. A. Elings, R. S. Downing, R. A. Sheldon, Eur. J. Org. Chem.
1999, 837–846; i) S. Nagumo, I. Miyoshi, H. Akita, N. Kawahara,
Tetrahedron Lett. 2002, 43, 2223–2226; j) F. Mꢂhlthau, T. Bach, Syn-
thesis 2005, 3428–3436; k) S. J. Coote, S. G. Davies, A. M. Fletcher,
P. M. Roberts, J. E. Thomson, Chem. Asian J. 2010, 5, 589–604; l) C.
Liꢈbert, M. K. Brinks, A. G. Capacci, M. J. Fleming, M. Lautens,
Org. Lett. 2011, 13, 3000–3003.
25b: Reaction of acetate 24 (112 mg, 250 mmol) with BiACTHUNRGTNEUNG(OTf)3 (16.4 mg,
25.0 mmol) and 2-trimethylsilyloxy-propene (165 mL, 1.00 mmol) in nitro-
methane (2.00 mL) yielded, after flash chromatography (eluent: pentane/
diethylether=6:1!1:1), 25b (87 mg, 195 mmol, 78%) as a yellow oil [d.r.
(anti/syn)ꢀ95:5]; Rf =0.39 (pentane/diethylether=1:1); IR (ATR): n˜ =
3058 (w), 2950 (m), 2835 (m), 1724 (vs), 1513 (vs), 1453 (s), 1358 (s),
1247 (vs), 1029 (m), 1029 (m), 829 (s), 746 cmꢁ1 (vs); 1H NMR
(360 MHz, CDCl3): d=1.88 (s, 3H), 2.48 (dd, 2J=15.9 Hz, 3J=4.3 Hz,
1H), 2.56 (dd, 2J=15.9 Hz, 3J=9.1 Hz, 1H), 3.25 (d, 2J=13.8 Hz, 2H),
3.51 (d, 3J=11.4 Hz, 1H), 3.78 (ddd, 3J=4.3 Hz, 3J=9.1 Hz, 3J=11.4 Hz,
2
1H), 3.85 (s, 6H), 3.88 (d, J=13.8 Hz, 2H), 6.78–6.85 (m, 4H), 6.89–6.92
(m, 4H), 7.17–7.21 ppm (m, 6H); 13C NMR (90.6 MHz, CDCl3): d=30.5
(q), 39.8 (d), 48.6 (t), 51.2 (q), 54.3 (t), 55.4 (q), 65.0 (d), 113.6 (d), 127.0
(d), 127.9 (d), 129.2 (d), 129.8 (d), 132.6 (s), 138.6 (s), 158.5 (s), 171.8 (s),
206.2 ppm (s); MS (ESI): m/z (%)=446 (100) [(M+H)+]; HRMS (ESI):
C28H32NO4 [(M+H)+]: calcd: 446.2326; found: 446.2324.
25c: Reaction of acetate 24 (112 mg, 250 mmol) with BiACTHUNRGTNEUNG(OTf)3 (16.4 mg,
25.0 mmol) and 1-methoxy-2-methyl-1-trimethylsiloxy-1-propene (203 mL,
1.00 mmol) in nitromethane (2.00 mL) yielded, after flash chromatogra-
phy (eluent: pentane/diethylether=4:1), 25c (122 mg, 249 mmol, quant.)
as a colorless solid [d.r. (anti/syn)ꢀ95:5]; Rf =0.16 (pentane/diethyl-
ether=4:1); m.p.: 768C; IR (ATR): n˜ =2974 (m), 2950 (m), 2838 (m),
1728 (vs), 1513 (s), 1250 (s), 1133(s), 1028 (m), 833 (m), 751 (s), 700 cmꢁ1
(m); 1H NMR (500 MHz, CDCl3): d=0.89 (s, 3H), 1.03 (s, 3H), 3.11 (d,
2J=13.5 Hz, 2H), 3.53 (s, 3H), 3.68–3.78 (m, 3H), 3.85 (s, 6H), 3.91 (d,
3J=11.4 Hz, 1H), 6.74–7.00 (m, 8H), 7.15–7.25 ppm (m, 6H); MS (ESI):
m/z (%)=512 (12) [(M+Na)+], 490 (100) [(M+H)+], 430 (17), 233 (26);
HRMS (ESI): C30H36NO5 [(M+H)+]: calcd: 490.2588; found: 490.2566;
[4] a) F. Mꢂhlthau, O. Schuster, T. Bach, J. Am. Chem. Soc. 2005, 127,
9348–9349; b) D. Stadler, F. Mꢂhlthau, P. Rubenbauer, E. Herdt-
weck, T. Bach, Synlett 2006, 2573–2576; c) D. Stadler, T. Bach,
Chem. Asian J. 2008, 3, 272–284; d) J. Y. L. Chung, D. Mancheno,
&
&
&10
&
www.chemasianj.org
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!

Stereoselective Synthesis of b-Aryl and b-Alkyltyrosines
P. G. Dormer, N. Variankaval, R. G. Ball, N. N. Tsou, Org. Lett.
2008, 10, 3037–3040; e) D. Stadler, T. Bach, Angew. Chem. 2008,
120, 7668–7670; Angew. Chem. Int. Ed. 2008, 47, 7557–7559.
[5] Recent review on Friedel–Crafts alkylation reactions: M. Rueping,
B. J. Nachtsheim, Beilstein J. Org. Chem. 2010, 6, No. 6.
[6] a) P. Rubenbauer, T. Bach, Tetrahedron Lett. 2008, 49, 1305–1309;
b) P. Rubenbauer, Adv. Synth. Catal. 2008, 350, 1125–1130.
[7] P. Rubenbauer, T. Bach, Chem. Commun. 2009, 2130–2132.
[8] Reviews on Ritter reactions: a) L. I. Krimen, D. J. Cota, Org. React.
1969, 17, 213–325; b) R. Bishop in Comprehensive Organic Synthe-
sis, Vol. 6 (Eds.: B. M. Trost, I. Fleming, E. Winterfeldt), Pergamon,
Oxford, 1991, 261–300; c) A. Guꢈrinot, S. Reymond, J. Cossy, Eur.
J. Org. Chem. DOI: 10.1002/ejoc.201101018.
[9] a) F. Mꢂhlthau, D. Stadler, A. Goeppert, G. A. Olah, G. K. S. Pra-
kash, T. Bach, J. Am. Chem. Soc. 2006, 128, 9668–9675; b) D. Sta-
dler, A. Goeppert, G. Rasul, G. A. Olah, G. K. S. Prakash, T. Bach,
J. Org. Chem. 2009, 74, 312–318.
[10] J. Lin, S. Liao, V. J. Hruby, J. Pept. Res. 2005, 65, 105–112 and refer-
ences therein.
[20] K. Yoshida, S. Nakajima, T. Wakamatsu, Y. Ban, M. Shibasaki, Het-
erocycles 1988, 27, 1167–1168.
[21] a) F. A. Davis, H. Liu, P. Zhou, T. Fang, G. V. Reddy, Y. Zhang, J.
Org. Chem. 1999, 64, 7559–7567; b) U. Schçllkopf, T. Beulshausen,
Liebigs Ann. Chem. 1989, 223–225.
[22] T. Sasaki, K. Minamoto, H. Itoh, J. Org. Chem. 1978, 43, 2320–2325.
[23] a) L. A. Carpino, G. Y. Han, J. Org. Chem. 1972, 37, 3404–3409;
b) L. A. Carpino, Acc. Chem. Res. 1987, 20, 401–407.
[24] a) J. Clayden, N. Greeves, S. Warren, P. Wothers, Organic Chemistry,
Oxford University Press, Oxford, 2001, pp. 422–423; b) J. E.
McMurry, Organic Chemistry, 8th ed., Cengage Learning Emea,
Andover, 2011, pp. 385–389.
[25] M. N. Khan, J. Org. Chem. 1995, 60, 4536–4541.
[26] K. Shimamoto, Y. Ohfune, Tetrahedron Lett. 1988, 29, 5177–5180.
[27] C. A. Hutton, Tetrahedron Lett. 1997, 38, 5899–5902.
[28] M. T. Reetz, Pure Appl. Chem. 1992, 64, 351–359.
[29] Review: E. Emer, R. Sinisi, M. G. Capdevila, D. Petruzziello, F. De
Vincentiis, P. G. Cozzi, Eur. J. Org. Chem. 2011, 647–666.
[30] a) I. Paterson, Tetrahedron Lett. 1979, 20, 1519–1520; b) M. T.
Reetz, S. Hꢂttenhain, P. Walz, U. Lçwe, Tetrahedron Lett. 1979, 20,
4971–4974; c) M. T. Reetz, F. Hꢂbner, S. H. Hꢂttenhain, H. Heim-
bach, K. Schwellnus, P. Walz, Chem. Ber. 1984, 117, 322–335; d) T.
Mukaiyama, S. Matsui, K. Homma, S. Kobayashi, Bull. Chem. Soc.
Jpn. 1990, 63, 2687–2690; e) P. A. Grieco, S. T. Handy, Tetrahedron
Lett. 1997, 38, 2645–2648.
[11] E. P. Styngach, K. I. Kuchkova, T. M. Efremova, A. A. Semenov,
Chem. Heterocycl. Compd. 1973, 9, 1378–1382.
[12] J. Legters, L. Thijs, B. Zwanenburg, Recl. Trav. Chim. Pays-Bas
1992, 111, 16–21.
[13] C. Xiong, W. Wang, C. Cai, V. J. Hruby, J. Org. Chem. 2002, 67,
1399–1402.
[14] S. Corey Valdez, J. L. Leighton, J. Am. Chem. Soc. 2009, 131,
14638–14639.
[31] a) W. S. Fones, J. Org. Chem. 1952, 17, 1534–1539; b) W. A. Bolhof-
er, J. Am. Chem. Soc. 1952, 74, 5459–5461.
[15] a) T. Manaka, S.-I. Nagayama, W. Desadee, N. Yajima, T. Kumamo-
to, T. Watanabe, T. Ishikawa, M. Kawahata, K. Yamaguchi, Helv.
Chim. Acta 2007, 90, 128–142; b) see also: Y. Hayashi, T. Kumamo-
to, M. Kawahata, K. Yamaguchi, T. Ishikawa, Tetrahedron 2010, 66,
3836–3841.
[32] a) R. M. Allen, G. W. Kirby, J. Chem. Soc. Perkin Trans. 1 1973,
363–368; b) A. Gayet, P. G. Anderson, Adv. Synth. Catal. 2005, 347,
1242–1246; c) Y. Kim, H.-J. Ha, S. Y. Yun, W. K. Lee, Chem.
Commun. 2008, 4363–4365 and references therein.
[33] G. Ceriotti, Nature 1967, 213, 595–596.
[16] Z. Zhang, M. Shi, Chem. Eur. J. 2010, 16, 7725–7729.
[17] F. Effenberger, T. Weber, Angew. Chem. 1987, 99, 146–147; Angew.
Chem. Int. Ed. Engl. 1987, 26, 142–143.
[34] T. Okamoto, Y. Torii, Y. Isogai, Chem. Pharm. Bull. 1968, 16, 1860–
1864.
[35] APEX suite of crystallographic software. APEX 2 Version 2008.4.,
Bruker AXS Inc., Madison, 2008.
[36] SAINT, Version 7.56a and SADABS Version 2008/1. Bruker AXS
Inc., Madison, 2008.
[37] L. J. Farrugia, J. Appl. Crystallogr. 1999, 32, 837–838.
[38] A. Altomare, M. C. Burla, M. Camalli, G. L. Cascarano, C. Giaco-
vazzo, A. Guagliardi, A. G. G. Moliterni, G. Polidori, R. Spagna, J.
Appl. Crystallogr. 1999, 32, 115–119.
[39] G. M. Sheldrick, “SHELXL-97”, University of Gçttingen, 1998.
[40] International Tables for Crystallography, Vol. C, Tables 6.1.1.4
(pp. 500–502), 4.2.6.8 (pp. 219–222), and 4.2.4.2 (pp. 193–199) (Ed.:
A. J. C. Wilson), Kluwer Academic Publishers, Dordrecht, 1992.
[41] A. L. Spek, “PLATON”, A Multipurpose Crystallographic Tool,
Utrecht University, 2010.
[18] a) G. Guanti, L. Banfi, E. Narisano, C. Scolastico, Tetrahedron Lett.
1984, 25, 4693–4696; b) C. D. Gray, P. W. Jeffs, J. Chem. Soc. Chem.
Commun. 1987, 1329–1330; c) G. Guanti, L. Banfi, E. Narisano, C.
Scolastico, Tetrahedron 1988, 44, 3671–3684; d) T. Elder, L. C.
Gregory, A. Orozco, J. L. Pflug, P. S. Wiens, T. J. Wilkinson, Synth.
Commun. 1989, 19, 763–767; e) H. J. G. Broxterman, R. M. J. Lis-
kamp, Recl. Trav. Chim. Pays-Bas 1991, 110, 46–52; f) A. Negro,
M. J. Garzꢆn, J. F. Martꢉn, A. El Marini, M. L. Roumestant, R.
Lꢇzaro, Synth. Commun. 1991, 21, 359–369; g) T. Hense, D. Hoppe,
Synthesis 1997, 1394–1398; h) A. Yamashita, E. B. Norton, R. T.
Williamson, D. M. Ho, S. Sinishtaj, T. S. Mansour, Org. Lett. 2003, 5,
3305–3308.
[19] a) H. E. Zimmerman, M. D. Traxler, J. Am. Chem. Soc. 1957, 79,
1920–1923; b) C. H. Heathcock, C. T. Buse, W. A. Kleschick, M. C.
Pirrung, J. E. Sohn, J. Lampe, J. Org. Chem. 1980, 45, 1066–1081;
c) D. A. Evans, J. V. Nelson, T. R. Taber, Top. Stereochem. 1982, 13,
1–115.
Received: January 20, 2012
Published online: && &&, 0000
Chem. Asian J. 2012, 00, 0 – 0
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
11
&
&
&
These are not the final page numbers! ÞÞ

FULL PAPERS
Nucleophilic Substitution Reactions
The choice of protecting groups
decides about the stereochemical fate
of the intermediate benzylic carbocat-
ion formed in the reactions of sub-
strates 1. If the ester group is signifi-
cantly bulkier than the amino group,
syn-products (syn-2) prevail. If the size
of the amino group is increased by
dibenzylation and the ester group is
small, the respective anti-products
(anti-3) are formed with significant
diastereoselectivity.
David Wilcke, Eberhardt Herdtweck,
Thorsten Bach*
&&&& — &&&&
SN1-Type Substitution Reactions of N-
Protected b-Hydroxytyrosine Esters:
Stereoselective Synthesis of b-Aryl and
b-Alkyltyrosines
&
&
&12
&
www.chemasianj.org
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!