Efficient stereoselective syntheses of constrained glutamates via Michael-induced ring closing reactions

Article abstract of DOI:10.1002/ejoc.200700965

Zn-chelated glycine ester enolates are highly efficient nucleophiles for the synthesis of conformationally constrained glutamates via domino sequences of Michael additions and subsequent ring closures (MIRC). This protocol allows the generation of 3-6-mem

Full text of DOI:10.1002/ejoc.200700965

FULL PAPER
DOI: 10.1002/ejoc.200700965
Efficient Stereoselective Syntheses of Constrained Glutamates via Michael-
Induced Ring Closing Reactions
Christian Schmidt[a] and Uli Kazmaier*[a]
Dedicated to Prof. V. Jäger on the occasion of 65th birthday
Keywords: Chelated enolates / Constrained amino acids / Glutamates / Michael addition / Michael-induced ring closure
(MIRC)
Zn-chelated glycine ester enolates are highly efficient nu-
cleophiles for the synthesis of conformationally constrained
glutamates via domino sequences of Michael additions and
subsequent ring closures (MIRC). This protocol allows the
generation of 3–6-membered ring systems in high yields and
excellent diastereoselectivities. Depending on the reaction
conditions either carbocyclic or heterocyclic ring systems are
obtained.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
tion,[8] several routes have been developed to construct the
ring units.[1a,9] Joucla et al. were the first who reported on
an approach based on the MIRC (Michael-induced ring
closure) concept[10] to the desired cyclopropylic compounds
by using lithium enolates of O’Donnell’s phenylimino gly-
cine esters[11] as nucleophiles.[12] Besides the imines, the
Schöllkopf bislactime ethers can be used for an asymmetric
approach of that kind as well.[13]
Prolineglutaminic acid (C), which can be seen as a chi-
mera of proline and glutaminic acid, is a simplified ana-
logue of kainic acid. Therefore it was the target of several
synthetic approaches. Yoo et al. described an intramolecu-
lar Michael addition which provided a diastereomeric mix-
ture of protected cis- and trans-C.[14] Correira et al. used a
[2+2]-cycloaddition as key step in their synthesis, and there-
fore they were able to obtain the cis-isomer stereoselec-
tively.[15] Enantioselective syntheses also of the cis-isomer
were described by Sabol[16] and Karoyan et al.[17] The later
ones used a zinc enolate cyclization of a chiral glycin deriva-
tive as key step (Scheme 1). The addition of zinc salts was
essential for the success of this reaction.
Introduction
Cyclic amino acids, such as (2-carboxycyclopropyl)gly-
cines A (Figure 1) or the many derivatives from the family
of the kainoids have attracted interest due to their remark-
able biological activity. These amino acids can be regarded
as conformationally fixed analogues of the natural amino
acid glutamate. It has been shown that these amino acids
can interact very strongly and selectively with the meta-
botropic glutamate receptors in the mammalian central ner-
vous systems.[1] (–)-Kainic acid (B), the parent member of
the class of marine natural products, was first isolated in
1953 from Digenea simplex.[2] This alkaloid exhibits potent
anthelmintic[3] properties but is used primarily as a neuro-
excitatory agent[4] by the neuroscience community in mod-
eling afflictions such as epilepsy,[5] Alzheimer’s disease,[6]
and Huntington’s chorea.[7]
In our group, metal-chelated glycine ester enolates also
play a dominant role in the stereoselective synthesis of α-
amino acids.[18] Therefore we tried to apply these nucleo-
philes also to domino reactions, such as conjugate additions
and subsequent cyclizations.[19]
Due to very promising results in the field of the palla-
dium-catalyzed allylic alkylations[20] we used the chelated
zinc enolate of the trifluoroacetyl-protected glycine ester 1
as a nucleophile and commercially available methyl (2E)-4-
bromo-but-2-enoate 2a as a first acceptor (Scheme 2). The
reaction gave a mixture of the desired cyclopropyl product
Figure 1. Conformationally constrained glutaminic acids.
Therefore, the interest in the stereoselective synthesis has
increased considerably in recent years. Besides approaches
to introduce the amino acid functionality via Strecker reac-
[a] Universität des Saarlandes, Institut für organische Chemie,
Im Stadtwald, Geb. C4.2, 66123 Saarbrücken
Fax: +49-681-302-2409
E-mail: u.kazmaier@mx.uni-saarland.de
Eur. J. Org. Chem. 2008, 887–894
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
887

C. Schmidt, U. Kazmaier
FULL PAPER
Results and Discussion
To prove the generality of this domino reaction, we also
synthesized the corresponding (Z)-substrates 5 with leaving
groups in homoallylic position. For these molecules two dif-
ferent pathways concerning the second reaction are pos-
sible: either C-alkylation leading to a four-membered ring
7 or N-alkylation to give a five-membered heterocyclic ring
8. (Scheme 3).[19a]
Scheme 1. Asymmetric synthesis of prolineglutaminic acid accord-
ing to Karoyan et al.
4 (with an exclusive trans orientation of the substituents at
the cyclopropyl ring) and the direct substitution product 3
in a 7:3 ratio. To avoid the direct substitution, we switched
to a weaker leaving group X, which should not react with
the glycine enolate directly, but hopefully with the ester
enolate formed in the Michael addition. And indeed, with
phosphate 2b we observed only the cyclopropyl products in
59% yield, but the α,β-diastereoselectivity was lower
Scheme 3. Reactions of chelated enolates with homologated
(anti/syn 79:21) than before. In palladium-catalyzed allylic Michael acceptors 5.
alkylations the diastereoselectivities were raised signifi-
With brominated substrate 5a we could isolate the
cantly when (Z)-configured substrates were used instead of
the (E)-isomers. A similar effect was also observed here. In
the reaction of (Z)-2b, only one diastereomer was obtained
(GC-analysis), which was identical to the major isomer in
the previous reaction.[19a]
Michael product 6a (only the anti-diastereomer detectable)
in 59% yield by quenching the reaction after 2.5 h at –78 °C
(Table 1, entry 1). When the reaction mixture was warmed
up to room temperature overnight the cyclized products
were obtained in excellent yield (entry 2). Surprisingly, cy-
clobutane 7 was formed preferentially (52%) besides pro-
lineglutaminic acid derivative 8 (39%). For both molecules
only one diastereomer could be detected by GC-analysis.
X-ray structure analysis of 7 confirmed the relative configu-
ration to be anti,trans.[19a]
Table 1. Reactions of chelated enolates with homologated Michael
acceptors 5.
Entry Substrate Reaction
conditions
%
Ratio
6/7/8
% ds
Yield[a]
1
2
3
4
(Z)-5a
(Z)-5a
(Z)-5b
(Z)-5a
THF, –78 °C, 2.5 h
THF, –78 °C to r.t.
THF, –78 °C to r.t.
1) THF, –78 °C, 2 h
2) 1.5 equiv. tBuOH,
–78 °C to r.t.
59
91
90
90
100:0:0
0:57:43
0:87:13
0:0:100
Ͼ97
Ͼ97
Ͼ97
Ͼ98
5
(E)-5a
1) THF, –78 °C, 2 h
2) 1.5 equiv. tBuOH,
–78 °C to r.t.
94
0:0:100
90
[a] Isolated yield.
Both cyclization products are interesting candidates as
glutamate analogues, and therefore it is highly attractive to
find selective protocols towards the one or the other. The
product mixture obviously arises from a competitive cycli-
zation either by the enolate formed in the addition step or
Scheme 2. Reactions of chelated enolates with functionalized
Michael acceptors.
888
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 887–894

Constrained Glutamates via Ring Closing Reactions
the deprotonated amide. One might expect that the enolate acid ester 9a (Table 2, entry 1).[21] Under the analogous re-
intermediate is more reactive than the trifluoroacetamide, action conditions as described before, addition products
and should therefore react at lower temperature. To make were obtained in 82%. The major product was the Michael
the substrate more reactive we switched to the correspond- adduct 10a, followed by the enolate cyclization product 11.
ing iodide (5b); and indeed, the yield of 7 could be increased The pipecolinic acid 12 was formed only as a side product.
to 78% and only 12% of 8 was formed (Table 1, entry 3).
On the other hand, the higher acidity of the amide func-
tionality can be used to get a clean N-cyclization. To avoid
the enolate reaction we added tBuOH to the reaction mix-
ture after 2 h at –78 °C. TLC control showed that after that
time all Michael acceptor was consumed but no cyclization
occurred. The mixture was warmed to room temperature
overnight, and the cis-proline derivative 8 was obtained ex-
clusively in 90% yield as a single diastereomer (entry 4).
In previous work we observed that (Z)-configured Michael
acceptors gave higher anti-selectivities in the addition step.
To prove the generality of this observation, and to get also
the syn-isomer for analytical purposes we also investigated
the addition towards (E)-5a. And indeed, the selectivitiy
dropped to 90% ds, although the yield was excellent (entry
5). The isomers could easily be separated by GC using the
chiral column Chirasil--Val. To confirm the cis-orientation
of the substituents at the proline ring, we compared the H
NMR coupling constants (Jα,β = 8.4 Hz) of the major iso-
Scheme 4. Reactions of chelated enolates with Michael acceptors
9.
1
mer with those from the literature (cis: Jα,β = 8.3 Hz, trans:
The 5-ring cyclization is kinetically favoured over the 6-
ring formation, and relatively fast even at low temperature.
Jα,β = 7.5 Hz).[17]
Encouraged by these nice results we were interested to Obviously a significant amount of enolate had reacted be-
see if it is possible to get also the corresponding pipecolinic fore it was quenched by the alcohol added. In contrast, cy-
acid derivatives 12 from the ε-halogenated Michael ac- clization via the amide seems to be slow. Therefore, we de-
ceptors 9 (Scheme 4). In principle three different products cided to have a closer look to the Michael addition. Already
can be expected in this case: The Michael adduct 10, the after 4 h at –78 °C nearly half of the Michael adduct under-
enolate cyclization product 11 and the N-alkylation product went cyclization (entry 2). Therefore it was relatively easy
12. In our first experiment we used the (Z)-bromohexenoic to get a clean conversion into 11 by simply warming up the
Table 2. Reactions of chelated enolates with homologated Michael acceptors 9.
Entry
Substrate
Reaction conditions
% Yield[a]
82
Ratio
10/11/12
% ds
Ͼ97
9
X
1
9a
Br
1) THF, –78 °C, 2 h
50:41:9
2) 1.5 equiv. tBuOH, –78 °C to r.t.
THF, –78 °C, 4 h
THF, –78 °C to r.t.
THF, –78 °C to –60 °C
THF, –78 °C to –60 °C
2
3
4
5
6
9a
9a
9b
9c
9b
Br
Br
95
92
87
93
81
55:45:0
0:100:0
100:0:0
100:0:0
100:0:0
Ͼ97
Ͼ97
95
97
95
OPO(OEt)2
Cl
OPO(OEt)2
1) THF, –78 °C to –55 °C
2) 1.5 equiv. tBuOH, –55 °C to r.t.
1) THF, –78 °C to –60 °C
2) 1.5 equiv. tBuOH, –60 °C to r.t.
3) 10 mol-% Bu4NI, room temp., 24 h
1) THF, –78 °C to –60 °C
2) 1.5 equiv. tBuOH, –60 °C to r.t.
3) 60 °C, 6 h
1) THF, –78 °C to –60 °C
2) 1.5 equiv. tBuOH, –60 °C to r.t.
3) HMPA, room temp., 12 h
1) THF, –78 °C to –60 °C
2) 1.5 equiv. tBuOH, –60 °C to r.t.
3) DMF, 40 °C, 12 h
7
9c
9c
9c
9c
9c
Cl
Cl
Cl
Cl
Cl
n.d.[b]
Ͼ90:Ͻ5:Ͻ5
n.d.
n.d.
n.d.
Ͼ 95
97
8
29
20:0:80
9
n.d.[b]
64
25:0:76
10
11
0:0:100
1) THF, –78 °C to –60 °C
2) 1.5 equiv. tBuOH, –60 °C to r.t.
3) DMPU, 10 mol-% Bu4NI, room temp., 24 h
73
0:0:100
[a] Isolated yield. [b] Product ration determined by NMR spectroscopy.
Eur. J. Org. Chem. 2008, 887–894
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
889

C. Schmidt, U. Kazmaier
FULL PAPER
reaction mixture to room temperature without the addition lylic position. The Michael addition in this case was very
of tBuOH (entry 3). 11 was obtained as a single stereoiso- fast, and a complete consumption of 2c was observed after
mer (as determined by GC) in 92%. While the two ste- 10 min. The Michael adduct 13 could be obtained in high
reogenic centres at the α- and β-position of the amino acid yield and excellent diastereoselectivity (98% ds) (entry 1).
result from the highly stereoselective anti-Michael addition, Again, with the corresponding (E)-isomer the selectivity
the third stereogenic centre is formed in the cyclization step. was slightly worse (89% ds) (entry 2).
The expected trans-orientation of the substituents on the
Table 3. Reactions of chelated enolates with Michael acceptors 2c
having an allylic leaving group.
five-membered ring could be confirmed by X-ray structure
analysis.
To suppress the enolate alkylation we switched to less
reactive leaving groups such as phosphate (9b) and chloride
(9c). And indeed, with both the corresponding Michael ad-
duct was obtained in high yield and selectivity, and no cycli-
zation was observed. With these leaving groups one might
have a chance to protonate the enolate and to get the pipec-
olinic acid. The optimization of the reaction conditions is
illustrated in Table 2. Unfortunately, the phosphate was a
too weak leaving group to undergo any cyclization (entry
6) and therefore the optimization focused on the chloride
9c. Even after warming up the reaction mixture to room
temperature after the addition of alcohol and Bu4NI (to
generate a better leaving group via Finkelstein reaction) no
significant improvement could be obtained (entry 7). Re-
fluxing the reaction mixture caused several side reactions
and the overall yield dropped, although the formation of
some pipecolinic acid was observed (entry 8). Because alky-
lation reactions in general proceed well in dipolar aprotic
solvents, we checked also the influence of these additives.
HMPA and DMF both were suitable to increase the
amount of cyclization product, and the best isolated yield
of 12 (97% ds) was obtained by a combination of DMPU
and Bu4NI (entry 11).
According to the results obtained with the proline deriv-
ative 8 and the cyclization product 12 one can expect a cis-
orientation of the substituents on the ring system. Never-
theless we compared the coupling constants of 12 with
those of the closely related β-benzylated pipecolinic acid de-
rivatives[22] D and E. A coupling constant of 4.7 Hz be-
tween the α- and β-proton clearly confirmed the cis-orienta-
tion (Figure 2).
Entry Substrate Reaction conditions
%
Ratio
% ds
Yield[a] 13/4/14
1
2
3
4
(Z)-2c
(E)-2c
(Z)-2c
(Z)-2c
THF, –78 °C, 30 min
THF, –78 °C, 30 min
THF, –78 °C to r.t.
1) THF, –78 °C, 30 min
2) 1.5 equiv. tBuOH,
–78 °C to r.t.
84
86
77
68
100:0:0
100:0:0
0:100:0 Ͼ97
0:100:0 Ͼ97
98
89
5
(Z)-2c
1) THF, –78 °C, 30 min
2) 2.5 equiv. HOAc,
–78 °C;
n.d.[b]
0:95 5
Ͼ97
3) 2 equiv. KOtBu,
–78 °C to r.t.
6
7
(Z)-2c
(Z)-2c
1) THF, –78 °C, 30 min
2) CF3CH2OH,
–78 °C to r.t.
1) THF, –78 °C, 30 min
2) 1.5 equiv. HOAc,
–78 °C to r.t.
n.d.[b]
75
68:32:0 n.d.
16: 3:81
90
3) DMPU, 10 mol-% Bu4NI,
r.t., 5 d
[a] Isolated yield. [b] Product ration determined by NMR spec-
troscopy.
If the reaction mixture was warmed up to room tempera-
ture, 4 was obtained in a clean reaction and good yield (en-
try 3). Attempts to quench the enolate by addition of
tBuOH were unsuccessful in this case. Here, also only the
Figure 2. Determination of configuration by NMR.
Although we knew from our previous work[19a] that cyclopropyl derivative 4 was obtained (entry 4). Obviously,
shorter Michael acceptors with the leaving group in the al- tBuOH is not acidic enough to cause a complete proton-
lylic position (2) form the cyclopropyl amino acids 4 easily, ation of the enolate, and the threering-cyclization is kinet-
we wondered, if we could not get also the corresponding ically highly favoured removing irreversibly the enolate
cis-azetidine glutaminic acids 14 under our optimized reac- from the equilibrium. To prove this assumption we
tion conditions (Table 3). Again, we chose the chloro deriv- quenched the enolate with HOAc. Subsequent addition of
ative 2c to avoid direct nucleophilic substitution at the al- KOtBu again resulted in the formation of the cyclopropyl
890
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 887–894

Constrained Glutamates via Ring Closing Reactions
added. The layers were separated, the aqueous phase was washed
twice with CH2Cl2 and the combined organic layers were dried
(Na2SO4). After evaporation of the solvent in vacuo the crude
product was purified by flash chromatography.
derivative 4 (entry 5). Therefore, because tBuOH obviously
is unsuitable, we switched to more acidic proton donors
such as trifluoroethanol (entry 6). Indeed, the amount of
4 could be reduced, but no N-alkylation was observed. A
breakthrough was the combination of HOAc (to quench the
enolate) and the addition of DMPU/Bu4NI which proved
superior in the pipecolinic acid case (entry 7). Although
the cyclization was very slow, under these conditions the
azetidine 14 could be obtained in 61% yield (90% ds). 4
was formed only in traces.
Michael Acceptors (Z)-2c and (E)-2c: According to Pihko and
Salo[24] fresh distilled α-chloroacetaldehyde (978 mg, 12.4 mmol)
was treated with methyl diphenyloxyphosphorylacetate (3.14 g,
10.3 mmol) at –90 °C. After 2 h and warming the reaction mixture
to –78 °C it was hydrolyzed with NH4Cl solution. After separation
of the layers, the aqueous phase was extracted three times with
ether. The combined organic layers were dried (Na2SO4) and the
solvent was evaporated in vacuo (40 °C, 330 mbar). After purifica-
tion by flash chromatography (pentane/Et2O, 97:3) the (Z)-isomer
(902 mg, 6.70 mmol, 65%) and (E)-isomer (81 mg, 0.6 mmol, 6%)
were obtained in pure form as colorless oils. Rf(Z)-2a = 0.57,
Rf(E)-2a = 0.43 (hexanes/EtOAc, 7:3).
Conclusions
In conclusion we could show that Michael-induced ring
closing reactions (MIRC) are excellently suited to generate
conformationally constrained glutamates. By carefully opti-
mizing the reaction conditions it is possible to get selec-
tively the one or the other product. While three- and five-
membered rings are formed easily, the selective synthesis of
four- and six-membered products is more difficult.
1
(Z)-2c: H NMR (500 MHz): δ = 3.72 (s, 3 H), 4.64 (dd, J = 6.9,
1.7 Hz, 2 H), 5.86 (dt, J = 11.4, 1.6 Hz, 1 H), 6.30 (dt, J = 11.4,
6.9 Hz, 1 H) ppm. 13C NMR (125 MHz): δ = 39.7, 51.6, 121.3,
144.2, 165.8 ppm.
1
(E)-2c: H NMR (500 MHz): δ = 3.74 (s, 3 H), 4.15 (dd, J = 6.1,
1.6 Hz, 2 H), 6.09 (dt, J = 15.4, 1.6 Hz, 1 H), 6.97 (dt, J = 15.4,
6.1 Hz, 1 H) ppm. 13C NMR (125 MHz): δ = 42.4, 51.8, 123.7,
141.9, 166.0 ppm. Based on the high volatility of 2c we were not
able to get elemental analysis and HRMS.
Experimental Section
Cyclopropyl Amino Acids 4: According to the general procedure for
Michael additions, TFA-Gly-OtBu (82 mg, 0.36 mmol) was treated
with (Z)-2c (66 mg, 0.49 mmol). The reaction mixture was warmed
to room temperature overnight before hydrolysis. Flash chromatog-
raphy (hexanes/EtOAc, 9:1) gave 4 (90 mg, 0.28 mmol, 77%) as a
General Remarks: All reactions were carried out in oven-dried
glassware (100 °C) under argon. All solvents were dried before use.
THF was distilled from LiAlH4 and stored over molecular sieves.
The products were purified by flash chromatography on silica gel.
Mixtures of EtOAc and hexanes were generally used as eluents.
TLC: commercially precoated Polygram® SIL-G/UV 254 plates. Vi-
sualization was accomplished with UV-light and KMnO4 solution.
Melting points are uncorrected. NMR spectra were recorded in
CDCl3 using a Bruker DRX 500 or a Bruker AV 400 NMR spec-
trometer. The formation of rotamers causes broad signals in some
cases and/or a second set of signals. Selected signals in the NMR
spectra for the minor isomers are extracted from the spectra
of the isomeric mixture. GC analyses were performed on a Varian
1
colorless solid, m.p. 44 °C. H NMR (500 MHz): δ = 1.06 (ddd, J
= 8.9, 5.7, 5.7 Hz, 1 H), 1.29 (ddd, J = 9.2, 5.2, 5.2 Hz, 1 H), 1.49
(s, 9 H), 1.73 (m, 1 H), 1.84 (ddd, J = 8.8, 4.6, 4.6 Hz, 1 H), 3.67
(s, 3 H), 4.10 (t, J = 7.9 Hz, 1 H), 6.98 (d, J = 7.9 Hz, 1 H) ppm.
13C NMR (125 MHz): δ = 12.7, 17.7, 23.6, 27.5, 51.8, 54.3, 83.8,
115.4 (J = 287.8 Hz), 156.6 (J = 37.6 Hz), 168.2, 173.0 ppm. GC
(Chira-Si--Val, 100 °C, 10 min; 5°/min; 180 °C, 30 min): tR(2R)
=
23.55 min, tR(2S) = 23.71 min. C13H18F3NO5 (325.28): calcd. C
48.00, H 5.58, N 4.31; found C 48.07, H 5.39, N 4.28. HRMS
calcd. for C13H19F3NO5 [M + H]+: 326.1215, found 326.1258.
3400 GC and
a chiral column Permabond Chirasil--Val
(25mϫ0.25 mm) from Macherey–Nagel. Melting points were de-
termined on a Büchi melting point apparatus and are uncorrected.
CI-MS analyses were performed using a Finnigan MAT 95. Ele-
mental analyses were carried out at the department of chemistry,
University of Saarbrücken.
Michael Acceptor (Z)-5a: According to a procedure described by
de Meijere et al.[25] methyl 5-hydroxypentynoate (3.84 g,
30.0 mmol) was dissolved in CH2Cl2 (60 mL). Tetrabromomethane
(7.86 g, 33.0 mmol) was added and after cooling to 0 °C PPh3
(7.86 g, 30.0 mmol) was added in portions. Stirring was continued
until no alcohol could be detected (4 h). PPh3O was removed by
filtration through silica using Et2O as eluent. The solvent was re-
moved in vacuo and the crude product was subjected to column
chromatography. Elution with hexane allowed the removal of CBr4
and CHBr3, before the product was eluted with CH2Cl2. The 5-
bromopentynoate (3.98 g, 20.8 mmol, 60%) was obtained as color-
less liquid. 1H NMR (500 MHz): δ = 2.90 (t, J = 7.3 Hz, 2 H), 3.44
(t, J = 7.1 Hz, 2 H), 3.75 (s, 3 H) ppm. 13C NMR (125 MHz): δ =
23.0, 27.2, 52.7, 74.2, 85.3, 153.7 ppm. C6H7BrO2 (191.02): calcd.
C 37.73, H 3.69; found C 37.56, H 3.64.
Preparation of the Michael Acceptors: The required α,β-unsaturated
esters were obtained either via Lindlar hydrogenation or via a cis-
selective Horner–Wadsworth–Emmons reaction using the Ando
protocol.[23]
General Procedure for Michael Additions: In a Schlenk flask hexa-
methyldisilazane (0.3 mL, 1.42 mmol) was dissolved in THF
(2 mL). The solution was cooled to –78 °C before n-BuLi (1.6 ,
0.78 mL, 1.25 mmol) was added. The cooling bath was removed
and the solution was warmed up for 15 min, before it was cooled
again to –78 °C. In a second Schlenk flask ZnCl2 (80 mg,
0.57 mmol) was dried with a heat gun in high vacuum, before it
was dissolved in THF (3 mL). After addition of TFA-Gly-OtBu
(115 mg, 0.5 mmol) the solution was cooled to –78 °C, before the
fresh prepared LHMDS solution was added. 15 Min later the
Michael acceptor (0.5 mmol) was added in THF (2 mL). After
complete consumption of the starting materials (TLC control) the
solution was diluted with diethyl ether before 1  KHSO4 was
This alkynoate (914 mg, 4.78 mmol) was dissolved in a mixture of
hexanes (10 mL) and tBuOH (2.5 mL). Pd/BaSO4 (5% Pd) and
quinoline (80 mg) were added and the hydrogenation was carried
out under typical Lindlar conditions. Samples were taken to con-
trol the process of the reaction (by GC). The crude product was
purified by flash chromatography (hexanes/EtOAc, 95:5) giving rise
Eur. J. Org. Chem. 2008, 887–894
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
891

C. Schmidt, U. Kazmaier
FULL PAPER
to
a
colorless liquid (725 mg, 3.76 mmol, 79%). 1H NMR
δ = 27.9, 29.9, 34.2, 36.2, 46.2 (J = 3.5 Hz), 51.9, 63.1, 82.9, 116.1 (J
(500 MHz): δ = 3.22 (dt, J = 6.8, 6.6 Hz, 2 H), 3.46 (t, J = 6.6 Hz,
= 287.1 Hz), 155.8 (J = 37.1 Hz), 168.2, 171.4 ppm. Minor rotamer
1
2 H), 3.70 (s, 3 H), 5.90 (dt, J = 11.4, 1.6 Hz, 1 H), 6.27 (dt, J = (selected signals): HNMR (500 MHz): δ = 1.42 (s, 9 H), 1.73 (m,
11.4, 7.0 Hz, 1 H) ppm. 13C NMR (125 MHz): δ = 31.7, 121.5, 1 H), 2.09 (m, 1 H), 2.89 (m, 1 H), 3.71 (s, 3 H), 3.80 (m, 1 H),
146.2, 166.4 ppm. C6H9BrO2 (193.04): calcd. C 37.33, H 4.70;
found C 37.20, H 4.47.
4.62 (d, J = 7.8 Hz, 1 H) ppm. 13C NMR (125 MHz): δ = 26.6,
27.8, 34.5, 39.3, 47.2, 51.9, 62.0 (J = 2.9 Hz), 83.3, 116.0 (J =
287.9 Hz), 155.4 (J = 37.1 Hz), 168.5, 171.3 ppm.
Michael Acceptor (Z)-5b: According to the literature[26] 5a (514 mg,
2.66 mmol) was dissolved in acetone (2.2 mL). NaI (481 mg,
3.21 mmol) was added and the mixture was refluxed for 6 h. After
cooling to room temperature CH2Cl2 (10 mL) and H2O (10 mL)
were added. After separation of the layers, the aqueous phase was
extracted twice with CH2Cl2 (10 mL). The combined organic layers
were dried (Na2SO4) and the solvent was evaporated in vacuo.
Flash chromatography (hexanes/EtOAc, 96:4) provided (Z)-5b
(225 mg, 2.05 mmol, 78%) as a clear, pale red liquid and in ad-
dition (E)-5b (52 mg, 0.22 mmol, 8%) as minor product.
1
trans-8 (selected signals): H NMR (500 MHz): δ = 1.43 (s, 9 H),
2.66 (m, 1 H), 3.70 (s, 3 H) ppm. GC (Chirasil-Val, 135 °C, iso-
thermic): tR(trans-8) = 50.99 min, tR(cis-8) = 61.31 min. C14H20F3NO5
(339.31): calcd. C 49.55, H 5.94, N 4.13; found C 49.78, H 5.93, N
4.11. HRMS calcd. for C14H21F3NO5 [M + H]+: 340.1372, found
340.1365.
Michael Acceptor 9c: According to the preparation of 2c, 9c was
obtained from γ-chlorobutyraldehyde (989 mg, 9.29 mmol) and
methyl 2-(diphenyloxyphosphoryl)acetate (4.24 g, 13.9 mmol) in
69% yield (1.04 g, 6.41 mmol, 95%). 1H NMR (500 MHz): δ = 1.91
(dt, J = 6.9 Hz, 2 H), 2.78 (tdd, J = 7.6, 6.9, 1.6 Hz, 2 H), 3.54 (t,
J = 6.9 Hz, 2 H), 3.69 (s, 3 H), 5.82 (dt, J = 11.5, 1.6 Hz, 1 H),
6.20 (dt, J = 11.5, 7.6 Hz, 1 H) ppm. 13C NMR (125 MHz): δ =
26.4, 31.9, 44.3, 51.1, 120.5, 148.2, 166.6 ppm. HRMS calcd. for
C7H11Cl35O2 [M]+: 162.0448, found 162.0418.
1
[(Z)-5a]: H NMR (500 MHz): δ = 3.20–3.28 (m, 4 H), 3.70 (s, 3
H), 5.90 (d, J = 11.7 Hz, 1 H), 6.19 (dt, J = 11.4, 6.3 Hz, 1 H)
ppm. 13C NMR (125 MHz): δ = 3.8, 32.5, 51.2, 121.2, 147.9, 166.4
ppm. C6H9IO2 (240.04): calcd. C 30.02, H 3.78; found C 30.07, H
3.76.
1
[(E)-5a]: H NMR (500 MHz): δ = 2.76 (tdd, J = 7.1, 7.1, 1.6 Hz,
2 H), 3.18 (t, J = 7.1 Hz, 2 H), 3.71 (s, 3 H), 5.87 (d, J = 15.4 Hz,
1 H), 6.82 (dt, J = 15.8, 6.8 Hz, 1 H) ppm. 13C NMR (125 MHz):
δ = 1.5, 35.7, 51.6, 122.9, 146.3, 166.4 ppm. HRMS calcd. for
C6H10IO2 [M + 1]+: 239.9726, found 240.9722.
Michael Addition Product 10a: According to the general procedure
for Michael additions TFA-Gly-OtBu (90 mg, 0.40 mmol) was
treated with methyl (Z)-6-bromo-2-hexenoate[21] (76 mg,
0.37 mmol). After 4.5 h at –78 °C the reaction was quenched with
HOAc (1 mL). Flash chromatography (hexanes/EtOAc, 9:1) pro-
vided 10a (72 mg, 0.16 mmol, 52%) and 11 (46 mg, 0.13 mmol,
Michael Addition Product 6: According to the general procedure for
Michael additions TFA-Gly-OtBu (120 mg, 0.48 mmol) was treated
with (Z)-5a (81 mg, 0.42 mmol). After 2 hours and warming the
reaction mixture to –70 °C 1  KHSO4 (5 mL) was added to
quench the reaction. Flash chromatography (hexanes/EtOAc, 1:1)
gave rise to 6 (138 mg, 0.38 mmol, 91%) as a colorless oil. 1H NMR
(500 MHz): δ = 1.47 (s, 9 H), 1.93 (m, 2 H), 2.37 (dd, J = 16.3,
5.6 Hz, 1 H), 2.45 (dd, J = 16.3, 6.2 Hz, 1 H), 2.79 (m, 1 H), 3.41–
3.52 (m, 2 H), 3.69 (s, 3 H), 4.58 (dd, J = 8.3, 4.1 Hz, 1 H), 7.79
(d, J = 8.3 Hz, 1 H) ppm. 13C NMR (125 MHz): δ = 28.0, 30.0,
33.0, 34.3, 35.6, 52.3, 54.6, 83.9, 115.7 (J = 287.7 Hz), 157.4 (J =
37.6 Hz), 168.7, 172.8 ppm. C14H21BrF3NO5 (420.22): calcd. C
40.02, H 5.04, N 3.33; found C 40.31, H 5.18, N 3.48. HRMS
calcd. for C14H22Br79F3NO5 [M]+: 420.0633, found 420.0446.
1
43%). H NMR (500 MHz): δ = 1.47 (s, 9 H), 1.53 (m, 2 H), 1.92
(m, 2 H), 2.36 (dd, J = 16.0, 5.5 Hz, 1 H), 2.44 (dd, J = 16.0,
6.5 Hz, 1 H), 2.48 (m, 1 H), 3.37 (m, 2 H), 3.69 (s, 3 H), 4.57 (dd,
J = 8.3, 4.2 Hz, 1 H), 7.76 (d, J = 8.3 Hz, 1 H) ppm. 13C NMR
(125 MHz): δ = 27.9, 29.4, 29.8, 32.8, 35.0, 36.5, 52.2, 55.1, 83.7,
115.7 (J = 288.0 Hz), 157.5 (J = 37.4 Hz), 168.9, 173.0 ppm.
HRMS (CI) calcd. for C15H24Br79F3NO5 [M + H]+: 434.0790,
found 434.0756.
Michael Addition Product 10b: According to 10a, 10b was obtained
1
in 78% yield as colorless oil. H NMR (500 MHz): δ = 1.30 (m, 6
H), 1.43 (m, 1 H), 1.45 (s, 9 H), 1.53 (m, 1 H), 1.72 (m, 2 H), 2.36
(dd, J = 15.8, 4.9 Hz, 1 H), 2.45 (dd, J = 15.8, 5.0 Hz, 1 H), 2.48
(m, 1 H), 3.67 (s, 3 H), 4.0 (dt, J = 6.3 Hz, 2 H), 4.07 (m, 4 H),
4.55 (dd, J = 8.2, 3.9 Hz, 1 H), 7.97 (d, J = 8.2 Hz, 1 H) ppm. 13C
NMR (125 MHz): δ = 16.0, 16.1, 26.8, 27.6 (J = 6.8 Hz), 27.9, 34.9,
36.5, 52.2, 55.2, 63.8 (J = 5.8 Hz), 66.7 (J = 5.8 Hz), 83.5, 115.8 (J
= 287.8 Hz), 157.5 (J = 37.5 Hz), 168.9, 173.1 ppm.
Cyclobutyl Amino Acids 7: The reaction was carried out as de-
scribed for 6. The reaction mixture was warmed to room tempera-
ture before hydrolysis. 1H NMR (500 MHz): δ = 1.43 (s, 9 H), 1.98
(m, 2 H), 2.14 (m, 2 H), 2.78 (m, 1 H), 3.03 (dt, J = 9.4 Hz), 3.66
(s, 3 H), 4.32 (dd, J = 10.1, 6.9 Hz, 1 H), 7.33 (s, 1 H) ppm. 13C
NMR (125 MHz): δ = 21.7, 22.4, 27.9, 40.7, 41.7, 52.0, 57.4, 83.1,
115.7 (J = 286.9 Hz), 157.2 (J = 37.1 Hz), 168.2, 174.6 ppm. GC
Michael Addition Product 10c: According to 10a, 10c was obtained
1
in 94% yield as a colorless oil. H NMR (500 MHz): δ = 1.47 (s, 9
(Chirasil-Val, 135 °C, isothermic): tR(R) = 37.41 min, tR(S)
=
H), 1.53 (m, 2 H), 1.84 (m, 2 H), 2.36 (dd, J = 16.0, 5.4 Hz, 1 H),
2.44 (dd, J = 16.0, 6.1 Hz, 1 H), 2.48 (m, 1 H), 3.46–3.56 (m, 2 H),
3.69 (s, 3 H), 4.57 (dd, J = 8.4, 4.2 Hz, 1 H), 7.76 (d, J = 8.4 Hz,
1 H) ppm. 13C NMR (125 MHz): δ = 27.8, 28.1, 29.7, 34.9, 36.5,
44.3, 52.2, 55.1, 83.6, 115.7 (J = 287.7 Hz), 157.4 (J = 37.6 Hz),
168.9, 173.0 ppm. HRMS calcd. for C15H24Cl35F3NO5 [M + H]+:
390.1295, found 390.1334.
38.55 min. C14H20F3NO5 (339.31): calcd. C 49.55, H 5.94, N 4.13;
found C 49.30, H 5.96, N 4.27.
Proline Derivative 8: According to the general procedure for
Michael additions TFA-Gly-OtBu (127 mg, 0.56 mmol) was treated
with (Z)-5a (100 mg, 0.52 mmol). After 2 hours tBuOH (68 mg,
0.92 mmol) was added to the reaction mixture and the solution
was warmed to room temperature over 12 h. Flash chromatography
(hexanes/EtOAc, 8:2) provided 8 (156 mg, 0.46 mmol, 90%) as a
colorless oil. Diastereomeric ratio 98:2.
Cyclopentyl Amino Acids 11: According to the general procedure
for Michael additions TFA-Gly-OtBu (108 mg, 0.48 mmol) was
treated with methyl (Z)-6-bromo-2-hexenoate (78 mg, 0.38 mmol).
The reaction mixture was warmed to room temperature overnight,
before it was hydrolyzed with 1  KHSO4. Flash chromatography
(hexanes/EtOAc, 95:5) provided 11 (138 mg, 0.39 mmol, 92%) as a
1
cis-8: Major rotamer: H NMR (500 MHz): δ = 1.44 (s, 9 H), 1.89
(m, 1 H), 2.16 (m, 1 H), 2.39 (dd, J = 17.1, 7.3 Hz, 1 H), 2.51 (dd,
J = 17.1, 7.9 Hz, 1 H), 2.80 (m, 1 H), 3.62 (m, 1 H), 3.70 (s, 3 H),
3.96 (m, 1 H), 4.53 (d, J = 8.4 Hz, 1 H) ppm. 13C NMR (125 MHz): colorless oil, which solidified on standing, m.p. 43–44 °C. 1H NMR
892
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 887–894

Constrained Glutamates via Ring Closing Reactions
(500 MHz): δ = 1.45 (s, 9 H), 1.56 (m, 1 H), 1.62–1.75 (m, 2 H),
1.82–1.90 (m, 2 H), 1.97 (m, 1 H), 2.53–2.65 (m, 2 H), 3.68 (s, 3
H), 4.26 (dd, J = 8.5 Hz, 1 H), 7.37 (d, J = 8.5 Hz, 1 H) ppm. 13C
NMR (125 MHz): δ = 25.1, 27.9, 29.9, 30.4, 45.1, 47.3, 52.2, 57.4,
6.3 Hz, 1 H), 2.66 (m, 1 H), 3.70 (s, 3 H), 4.23–4.34 (m, 3 H) ppm.
13C NMR (100 MHz): δ = 27.9, 29.2, 31.7, 52.1, 57.3, 66.5, 83.0,
168.2, 170.8 ppm. C14H20F3NO5 (325.28): calcd. C 48.00, H 5.58,
N 4.31; found C 48.07, H 5.39, N 4.28. HRMS calcd. for
83.2, 118.4 (J = 287.6 Hz), 156.9 (J = 37.8 Hz), 169.1, 176.4 ppm. C13H19F3NO5 [M + H]+: 326.1215, found 326.1193.
C15H22F3NO5 (354.15): calcd. C 50.99, H 6.28, N 3.96; found C
51.24, H 6.31, N 4.00. HRMS calcd. for C15H23F3NO5 [M + H]+:
354.1528, found 354.1503.
Acknowledgments
Pipecolinic Acid Derivative 12: According to the general procedure
This work was supported by the Deutsche Forschungsgemeinschaft
for Michael additions TFA-Gly-OtBu (86 mg, 0.38 mmol) was
(DFG) and by the Fonds der Chemischen Industrie.
treated with 9c (29 mg, 0.18 mmol). After stirring for 2 h and
warming the reaction mixture to –60 °C tBuOH (41 mg,
0.55 mmol) in THF (0.5 mL) was added. After 15 min DMPU
(2 mL) and NaI (10 mg, 0.07 mmol) were added. The reaction mix-
ture was warmed to room temperature over 24 h. Flash chromatog-
raphy (hexanes/EtOAc, first 9:1, then 8:2) gave rise to 12 (46 mg,
[1] a) K. Shimamoto, Y. Ohfune, J. Med. Chem. 1996, 39, 407–423
and references cited herein; b) K. Shimamoto, Y. Ohfune, Syn-
lett 1993, 919–920; c) P. L. Ornstein, T. J. Bleisch, M. B. Ar-
nold, R. A. Wright, B. G. Johnson, D. D. Schoepp, J. Med.
Chem. 1998, 41, 346–357; d) R. Pellicciari, G. Costantino, Curr.
Opin. Chem. Biol. 1999, 3, 433–440; e) M. G. Moloney, Nat.
Prod. Rep. 1999, 16, 485–498, and references therein.
[2] S. Murakami, T. Takemoto, Z. Shimizu, J. Pharm. Soc. Jpn.
1953, 73, 1026–1028.
1
0.13 mmol, 73%, 98% ds) as a colorless oil. H NMR (500 MHz):
δ = 1.43 (s, 9 H), 1.48–1.88 (m, 4 H), 2.26 (m, 1 H), 2.43 (dd, J =
16.8, 8.2 Hz, 1 H), 2.64 (dd, J = 16.8, 6.8 Hz, 1 H), 3.51 (ddd, J =
13.4, 13.4, 3.2 Hz, 1 H), 3.67 (s, 3 H), 3.87 (d, J = 13.4 Hz, 1 H),
5.16 (d, J = 5.2 Hz, 1 H) ppm. 13C NMR (125 MHz): δ = 25.1,
26.3, 27.9, 35.0, 37.5, 42.9 (J = 3.7 Hz), 51.7, 56.3, 82.9, 116.1 (J
= 287.1 Hz), 156.7 (J = 37.1 Hz), 167.9, 171.9 ppm. Minor rotamer
(selected signals): 1H NMR (500 MHz): δ = 1.45 (s, 9 H), 3.21 (ddd,
J = 13.4, 13.2, 2.9 Hz, 1 H), 3.68 (s, 3 H), 4.42 (d, J = 13.4 Hz, 1
H), 4.82 (d, J = 5.0 Hz, 1 H) ppm. 13C NMR (125 MHz): δ = 25.1,
26.4, 27.8, 35.8, 37.3, 40.3, 52.2, 58.2 (J = 3.1 Hz), 83.1, 167.7,
171.8 ppm. C15H22F3NO5 (354.15): calcd. C 50.99, H 6.28, N 3.96;
found C 51.40, H 6.34, N 3.56. HRMS calcd. for C15H23F3NO5
[M + H]+: 354.1528, found 354.1570.
[3] I. Nitta, H. Watase, Y. Tomiie, Nature (London) 1958, 181,
761–762.
[4] For a recent review, see: Q. Wang, S. Yu, A. Simonyi, G. Sun,
A. Sun, Mol. Neurobiol. 2005, 31, 3–16, and references therein.
[5] G. Sperk, Prog. Neurobiol. (Oxford) 1994, 42, 1–32.
[6] a) S. Goodenough, D. Schleusner, C. Pietrzik, T. Skutella, C.
Behl, Neuroscience (Oxford) 2005, 132, 581–589; b) A.
Mohmmad, R. Sultana, J. Keller, D. St. Clair, W. Markesbery,
D. Butterfield, J. Neurochem. 2006, 96, 1322–1335.
[7] a) J. T. Coyle, R. Schwarcz, Nature 1976, 263, 244–246; b) E. G.
McGeer, P. L. McGeer, Nature 1976, 263, 517–519.
[8] a) S. R. Landor, P. D. Landor, M. Kalli, J. Chem. Soc. Perkin
Trans. 1 1983, 2921–2925; b) H. Pajouhesh, J. Chen, S. H. Pa-
jouhesh, Tetrahedron: Asymmetry 2000, 11, 4537–4541.
[9] a) J. M. McIntosh, R. K. Leavitt, P. Mishra, K. C. Cassidy,
J. E. Drake, R. J. Chanda, J. Org. Chem. 1988, 53, 1947–1952;
b) R. Pellicciari, B. Natalini, M. Marinozzi, J. B. Monahan,
J. P. Snyder, Tetrahedron Lett. 1990, 31, 139–142; c) K. El Abdi-
oui, J. Martinez, P. Viallefont, Y. Vidal, Bull. Soc. Chim. Belg.
1997, 106, 425–431; d) J. Rifé, R. M. Ortuño, G. A. Lajoie, J.
Org. Chem. 1999, 64, 8958–8961; e) K. Godula, W. A. Don-
aldson, Tetrahedron Lett. 2001, 42, 153–154; f) D. K. Mohapa-
tra, J. Chem. Soc. Perkin Trans. 1 2001, 1851–1852; g) H. Pa-
jouhesh, K. Curry, H. Pajouhesh, M. H. Meresht, B. Patrick,
Tetrahedron: Asymmetry 2003, 14, 593–596.
Michael Addition Product 13: According to the general procedure
for Michael additions TFA-Gly-OtBu (136 mg, 0.60 mmol) was
treated with 2c (67 mg, 0.50 mmol) at –90 °C. After 30 min and
warming the reaction mixture to –78 °C the reaction was quenched
by 1  KHSO4 (1 mL). Flash chromatography (hexanes/EtOAc,
9:1) provided 13 (151 mg, 0.38 mmol, 84%, 98% ds) as a colorless
oil.
anti-13: 1H NMR (500 MHz): δ = 1.47 (s, 9 H), 2.85 (m, 1 H), 3.58
(dd, J = 11.5, 6.4 Hz, 1 H), 3.63 (dd, J = 11.5, 6.2 Hz, 1 H), (m, 1
H), 3.70 (s, 3 H), 4.72 (dd, J = 8.2, 4.9 Hz, 1 H), 7.62 (d, J =
8.2 Hz, 1 H) ppm. 13C NMR (125 MHz): δ = 27.9, 33.0, 39.6, 44.5,
52.3, 54.1, 84.2, 115.7 (J = 287.7 Hz), 157.4 (J = 37.6 Hz), 168.2,
172.4 ppm.
[10] a) R. D. Little, J. R. Dawson, Tetrahedron Lett. 1980, 21, 2609–
2612; b) P. Prempree, S. Radviroongit, Y. Thebtaranonth, J.
Org. Chem. 1983, 48, 3553–3556.
[11] Review: M. J. O’Donnell, Aldrichimica Acta 2001, 34, 3–15.
[12] M. Joucla, M. El Goumzili, B. Fouchet, Tetrahedron Lett.
1986, 27, 1677–1680.
syn-13: Selected signals. 1H NMR (500 MHz): δ = 1.48 (s, 9 H),
3.71 (s, 3 H), 4.76 (dd, J = 8.3, 4.7 Hz, 1 H), 7.48 (d, J = 8.3 Hz,
1 H) ppm. HRMS calcd. for C13H20ClF3NO5 [M + H]+: 362.0937,
found 362.1010.
[13] A. Mazón, C. Pedregal, W. Prowse, Tetrahedron 1999, 55,
7057–7064.
[14] S. Yoo, S. Lee, N. Kim, Tetrahedron Lett. 1988, 29, 2195–2196.
[15] M. J. S. Carpes, P. Miranda, C. R. Correira, Tetrahedron Lett.
1997, 38, 1869–1872.
[16] J. Sabol, G. Flynn, D. Friedrich, E. W. Huber, Tetrahedron Lett.
1997, 38, 3687–3690.
[17] P. Karoyan, G. Chassaing, Tetrahedron Lett. 2002, 43, 253–255.
[18] U. Kazmaier, Liebigs Ann./Recueil 1997, 285–295 and refer-
ences cited therein.
[19] a) M. Pohlman, U. Kazmaier, Org. Lett. 2003, 5, 2631–2633;
b) M. Pohlman, U. Kazmaier, T. Lindner, J. Org. Chem. 2004,
69, 6909–6912; c) B. Mendler, U. Kazmaier, V. Huch, M. Veith,
Org. Lett. 2005, 7, 2643–2646; d) B. Mendler, U. Kazmaier,
Synthesis 2005, 2239–2245.
[20] a) U. Kazmaier, F. L. Zumpe, Angew. Chem. 1999, 111, 1572–
1574; Angew. Chem. Int. Ed. 1999, 38, 1468–1470; b) U. Kaz-
Azetidine Derivative 14: According to the general procedure for
Michael additions TFA-Gly-OtBu (125 mg, 0.55 mmol) was treated
with 2c (54 mg, 0.40 mmol) at –78 °C. After 15 min HOAc (57 mg,
0.95 mmol) was added. DMPU (2 mL) and NaI (10 mg,
0.07 mmol) were added after further 15 min, and the cooling bath
was removed. After stirring for 5 d and flash chromatography (hex-
anes/EtOAc first 9:1, then 8:2) 14 (79 mg, 0.24 mmol, 61%, 90%
ds) was obtained as colorless oil. 1H NMR (400 MHz): δ = 1.46 (s,
9 H), 2.38 (dd, J = 16.9, 8.9 Hz, 1 H), 2.47 (dd, J = 16.9, 5.1 Hz,
1 H), 2.58 (m, 1 H), 3.68 (s, 3 H), 4.01 (dd, J = 4.6, 1.5 Hz, 1 H),
4.15 (ddd, J = 11.2, 5.3, 1.5 Hz, 1 H), 4.43 (dd, J = 11.2, 3.7 Hz,
1 H) ppm. 13C NMR (100 MHz): δ = 27.8, 29.7, 33.9, 52.0, 59.0,
66.8, 82.7, 116.3 (J = 287.1 Hz), 148.4 (J = 39.0 Hz), 168.9, 171.1
1
ppm. Minor rotamer (selected signals): H NMR (400 MHz): δ =
1.45 (s, 9 H), 2.22 (dd, J = 17.0, 8.5 Hz, 1 H), 2.38 (dd, J = 17.0,
Eur. J. Org. Chem. 2008, 887–894
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
893

C. Schmidt, U. Kazmaier
[23] K. Ando, J. Org. Chem. 1999, 64, 8406–8408.
[24] P. Pihko, T. Salo, Tetrahedron Lett. 2003, 44, 4361–4364.
[25] J. Zindel, A. de Meijere, Synthesis 1994, 190–194.
[26] J. Hine, R. G. Ghirardelli, J. Org. Chem. 1958, 23, 1550–1552.
Received: October 12, 2007
FULL PAPER
maier, F. L. Zumpe, Angew. Chem. 2000, 112, 805–807; Angew.
Chem. Int. Ed. 2000, 39, 802–804; c) U. Kazmaier, F. L. Zumpe,
Eur. J. Org. Chem. 2001, 4067–4076.
[21] M. Lautens, J.-F. Paquin, S. Piguel, M. Dahlmann, J. Org.
Chem. 2001, 66, 8127–8134.
[22] L. S. Hegedus, J. Am. Chem. Soc. 1990, 112, 2264–2273.
Published Online: December 7, 2007
894
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 887–894