Synthesis of highly substituted pyroglutamates via a domino Michael addition-Claisen rearrangement-lactamisation approach

Article abstract of DOI:10.1039/b811382c

Chelated enolates are versatile nucleophiles for Michael additions to α,β-unsaturated allylic esters. By quenching the reaction with TMSCl and heating a subsequent Ireland-Claisen rearrangement can occur. Direct cyclisation of the rearrangement product gives rise to highly substituted pyroglutamic acid derivatives.

Full text of DOI:10.1039/b811382c

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of highly substituted pyroglutamates via a domino Michael
addition–Claisen rearrangement–lactamisation approach
Christian Schmidt and Uli Kazmaier*
Received 4th July 2008, Accepted 20th August 2008
First published as an Advance Article on the web 28th October 2008
DOI: 10.1039/b811382c
Chelated enolates are versatile nucleophiles for Michael additions to a,b-unsaturated allylic esters. By
quenching the reaction with TMSCl and heating a subsequent Ireland–Claisen rearrangement can
occur. Direct cyclisation of the rearrangement product gives rise to highly substituted pyroglutamic
acid derivatives.
was formed as a 2 : 1 (syn : anti) diastereoisomeric mixture,
Introduction
indicating a moderate E/Z-selectivity in the enolate formation
Pyroglutamic acid can be looked upon as an internally protected
step. Yamazaki and Kitazume investigated the addition of lithium
enolates to fluorinated allylic acrylates.24 They obtained good
selectivities but moderate yields. Unfortunately, this reaction was
limited to unsubstituted allyl esters.
glutamic acid. It can be found as the N-terminal end group in
many natural products such as gonadotropin-1 and thyrotropin-
releasing2 hormones, depsipeptides like the didemnines3 as well as
many others.4 Pyroglutamic acid is also a valuable chiral building
block for natural product synthesis,5 such as for domoic6 and
kainic acid.7 In addition it serves as a starting material for the
synthesis of chiral auxiliaries, such as RAMP.8
Results and discussion
To investigate such a domino sequence with chelated enolates, we
synthesised several (2Z)-configured unsaturated allylic esters 1, be-
cause of their better selectivities in the Michael addition step.18 Sur-
prisingly, this was not as easy as expected. Attempts to introduce
the cis double bond via Lindlar hydrogenation were unsuccessful,
because especially with terminal allylic esters the double bond was
also hydrogenated, and we were not able to separate the allylic
esters from the saturated ones. Coupling of (2Z)-hexenoic acid
with several allylic alcohols under Steglich conditions25 resulted
in the formation of an E/Z-mixture. Probably, the DMAP used
as a catalyst undergoes 1,4-addition–elimination on the a,b-
unsaturated ester, resulting in an isomerisation. Therefore, we
decided to deprotonate the alcohol with BuLi, and add the lithium
alcoholate obtained to the acyl halide at -40 ◦C (Scheme 1). Under
these mild conditions, the allylic esters 1 could be obtained in good
yield and without isomerisation (Table 1).
Substituted pyroglutamates can easily be obtained by lactami-
sation of the corresponding glutamates, which themselves are
accessible via Michael addition of suitably protected glycine eno-
lates. Very popular in this respect are the enolates of O’Donnell’s
phenylimino glycine esters,9 which also allow the preparation of
an asymmetric version using chiral alcohols in the ester moieties10
or chiral phase transfer catalysts.11 Also frequently used are the
“chiral glycine enolates” described by Scho¨llkopf et al.12 and
Seebach and Suzuki.13 These enolates can also be applied in
Michael-induced ring closures (MIRC),14 if Michael acceptors
bearing a leaving group are used.15
Our group is also involved in amino acid synthesis, investigating
reactions of chelated ester enolates.16 These enolates were found
to be excellent nucleophiles in a wide range of reactions, including
Michael additions to nitroalkenes17 and a,b-unsaturated esters.18
In reactions of unsaturated esters containing a leaving group
in a suitable position, cyclic products could be obtained via a
subsequent ring closure (MIRC).19 Interestingly, the selectivities
in the Michael addition step are significantly better with the (Z)-
a,b-unsaturated esters, compared with the (E)-isomers.
Based on our long term research on Claisen rearrangements,20
especially for the synthesis of unsaturated amino acids and
peptides,21 we were interested to see if it was also possible
to combine the Michael addition with a subsequent Claisen
rearrangement, preferentially under Ireland conditions.22 A first
example of such a domino process was described by Kuwajima
and Aoki.23 They reported on Cu-catalysed additions of Grignard
reagents to a,b-unsaturated allylic esters in the presence of
TMSCl. Subsequent heating initiated a Claisen rearrangement of
the in situ formed silylketenacetal. The carboxylic acid obtained
Scheme 1 Preparation of a,b-unsaturated allylic esters 1
To get an impression of the selectivity in the Michael addition
step we first investigated this part of our planned domino process
Table 1 Preparation of a,b-unsaturated allylic esters 1
Entry
R¢
R¢¢
R¢¢¢
Yield (%)
Ester
1
2
3
4
5
H
H
Ph
H
iPr
H
Me
H
H
H
H
H
H
Ph
H
73
82
89
78
88
1a
1b
1c
1d
1e
Institut fu¨r Organische Chemie, Universita¨t des Saarlandes, D-66123
Saarbru¨cken, Germany. E-mail: u.kazmaier@mx.uni-saarland.de; Fax: +49
681 302 2409; Tel: +49 681 302 3409
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Table 2 Michael additions to a,b-unsaturated allylic esters 1
Entry
Ester
R¢
R¢¢¢
Product
Yield (%)
anti : syn
1a
2
3
1a
1a
1c
1d
H
H
Ph
H
H
H
H
Ph
2a
2a
2c
2d
86
91
90
73
>99 : 1
98 : 2
98 : 2
97 : 3
Scheme 3 Domino Michael addition–Claisen rearrangement–lactam-
4
isations.
a Reaction in the presence of ZnCl2.
Michael addition, these two stereoisomers have to be formed in
the rearrangement step, probably via an E/Z-enolate mixture.
This would be in good agreement with the results described by
Kuwajima and Aoki.23
The determination of the relative configuration was relatively
easily possible with these products by NOESY NMR experiments.
The major cis-product showed interactions between 9-H and 2-H
as well as 6-H, whereas the minor trans-isomer showed interactions
between 9-H and the ring protons at C-2 and C-4 (Fig. 1).
(Scheme 2). Esters 1 were found to be much less reactive than
the esters investigated before, having a leaving group at the g-
position.19 The reactions with zinc-chelated glycine ester enolates
had to be warmed to room temperature for complete conversion
(Table 2, entry 1). But even under these conditions the selectivity
was excellent. Interestingly, the corresponding lithium enolate
reacted at -78 ◦C and gave comparable yield and selectivity,
independent of the allylic ester used (entries 2–4).
Scheme 2 Michael additions to a,b-unsaturated allylic esters 1.
Fig. 1 Determination of configuration of 3a.
To prove the generality of this reaction sequence we also inves-
tigated the rearrangements of the other substrates 1b–1e (Table 3,
entries 3–6). All substrates underwent Claisen rearrangement,
although not always completely. This was especially the case with
the phenyl-substituted derivatives 1c and 1d, where a significant
amount of Michael product was obtained. With the cinnamyl
substrate 1d 4 stereogenic centres were formed in one step. While
the configuration of C-2/C-3 is controlled by the Michael addition
step (which is highly selective) the stereogenic centres at C-4 and
C-6 are the result of the Claisen rearrangement. No induced
diastereoselectivity (C-3/C-4) was observed, and the moderately
simple diastereoselectivity (C-4/C-6), which provides information
about the enolate geometry, indicates that probably a low E/Z-
enolate selectivity is responsible for this observation.
With these results in hand we next focused on the combination of
Michael addition and Ireland–Claisen rearrangement. Attempts
to trap the zinc enolate with TMSCl and to initiate the rearrange-
ment by heating were unsuccessful (Table 3, entry 1). Only the
Michael adduct 2 could be obtained, albeit in high yield. Probably
the zinc enolate formed in situ is either too stable or a Reformatsky
type C-enolate, which can not undergo Claisen rearrangement.
Therefore, we repeated the reaction with the lithium enolate.
◦
TMSCl was added at -78 C after all the Michael acceptor was
consumed, and the mixture was warmed to room temperature
and refluxed for 12 h. A clean conversion was observed (only
7% Michael adduct 2) but interestingly it was not the acyclic
rearrangement product that was obtained but the pyroglutamic
acid derivative 3a (Scheme 3).
Obviously, under these reaction conditions the deprotonated
amide attacks the silylester formed in the rearrangement step, and
under the workup conditions (1 M KHSO4) the TFA-protecting
group is directly cleaved. Interestingly, 3a was formed as a nearly
1 : 1 diastereoisomeric mixture. With respect to the highly selective
Conclusion
In conclusion we can show that the combination of a Michael
addition of chelated enolates with the Ireland–Claisen rearrange-
ment is a straightforward protocol towards highly substituted
pyroglutaminic acid derivatives. Up to four stereogenic centres
can be generated in one step.
Table 3 Domino Michael addition–Claisen rearrangement–lactamisa-
tions
Further investigations, especially concerning the control of
stereoselectivity and the absolute configuration are in progress.
Yield (%)
d.r.
d.r.
Entry
Ester
2
3
(C-3 : C-4)
(C-4 : C-6)
Experimental Section
1a
2
3
4
5
6
1a
1a
1b
1c
1d
1e
88
7
21
26
29
10
—
89
71
52
58
81
—
43 : 57
42 : 58
44 : 56
31 : 69
48 : 52
—
—
—
Allyl (2Z)-hexenoate (1a)
(2Z)-Hexenoic acid (2.79 g, 24.47 mmol) was dissolved in acetoni-
trile (20 mL) before ethyldiisopropylamine (4.70 mL, 27.45 mmol)
was added at 0 ◦C. Allyl bromide (3.46 mL, 40 mmol) was
added and the mixture was allowed to warm to room temperature
overnight. The solvent was removed in vacuo and the residue was
—
83 : 17
—
a Reaction in the presence of ZnCl2.
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dissolved in ether. The solution was washed with 1 N KHSO4 and
the aqueous layer was extracted twice with CH2Cl2. The combined
organic layers were dried (Na2SO4) and after evaporation of the
solvent the crude product was purified by flash chromatography
(hexanes : EtOAc 95 : 5) giving rise to 1a (2.77 g, 18.00 mmol, 73%)
as a colourless oil. 1H NMR (500 MHz, CDCl3): d = 0.93 (t, J =
7.4 Hz, 3H), 1.46 (tq, J = 7.4, 7.4 Hz, 2H), 2.62 (ddt, J = 7.5, 7.4,
1.7 Hz, 2H), 4.60 (ddd, J = 5.7, 1.4, 1.4 Hz, 2H), 5.22 (ddt, J =
10.4, 1.4, 1.4 Hz, 1H), 5.31 (ddt, J = 17.2, 1.4, 1.4 Hz, 1H), 5.79
(dt, J = 11.5, 1.7 Hz, 1H), 5.93 (ddt, J = 17.2, 10.4, 5.7 Hz, 1H),
6.23 (td, J = 11.5, 7.5 Hz, 1H). 13C NMR (125 MHz): d = 13.7
(q), 22.3 (t), 31.0 (t), 64.5 (t), 118.0 (d), 119.4 (d), 132.4 (t), 151.9
(d), 166.0 (s). HRMS (CI) calcd for C9H15O2 [M + H]+: 155.1072.
Found: 155.1080.
Cinnamyl (2Z)-hexenoate (1d)
According to the general procedure for the preparation of the
unsaturated allyl esters, 1d was obtained from (2Z)-hexenoic acid
(811 mg, 7.11 mmol) and cinnamylalcohol (451 mg, 3.37 mmol)
1
in 78% yield (573 mg, 2.63 mmol) as a colourless oil. H NMR
(500 MHz): d = 0.93 (t, J = 7.4 Hz, 3H), 1.46 (tq, J = 7.4, 7.4 Hz,
2H), 2.63 (ddt, J = 7.5, 7.5, 1.7 Hz, 2H), 4.75 (dd, J = 6.4, 1.3 Hz,
2H), 5.80 (dt, J = 11.5, 1.5 Hz, 1H), 6.21–6.32 (m, 2H), 6.64 (d,
J = 15.9 Hz, 1H), 7.23 (m, 1H), 7.29, 7.37 (2 m, 4H). 13C NMR
(125 MHz): d = 13.7 (q), 22.3 (t), 31.0 (t), 64.4 (t), 119.5 (d), 123.5
(d), 126.6 (d), 128.6 (d), 128.0 (d), 133.9 (d), 136.3 (s), 151.0 (d),
166.1 (s). HRMS (CI) calcd for C15H18O2 [M]+: 230.1307. Found:
230.1301.
1-Isopropylallyl (2Z)-hexenoate (1e)
Preparation of the unsaturated allylic esters 1
According to the general procedure for the preparation of the
unsaturated allyl esters, 1e was obtained from (2Z)-hexenoic
acid (798 mg, 7.00 mmol) and 1-isopropylallylalcohol (338 mg,
3.38 mmol) in 88% yield (547 mg, 2.97 mmol) as a colourless oil.
1H NMR (500 MHz): d = 0.90–0.94 (m, 9H), 1.45 (m, 2H), 1.88
(m, 1H), 2.61 (ddt, J = 7.5, 7.5, 1.7 Hz, 2H), 5.08 (m, 1H), 5.17–
5.23 (m, 2H), 5.73– 5.80 (m, 2H), 6.20 (dt, J = 11.5, 7.5 Hz, 1H).
13C NMR (125 MHz): d = 13.7 (q), 17.9 (q), 18.0 (q), 22.3 (t),
31.0 (t), 31.9 (d), 78.8 (d), 117.3 (t), 120.0 (d), 134.9 (d), 150.3 (d),
165.8 (s). HRMS (CI) calcd for C12H20O2 [M]+: 196.1463. Found:
196.1457.
(2Z)-Hexenoic acid chloride was freshly prepared by the addition
of oxalyl chloride (4 mmol) to hexenoic acid26 (2 mmol) at room
temperature. After stirring for 20 min, the excess of oxalyl chloride
was removed in vacuo (40 ◦C, 200 mbar). The crude acyl chloride
was used without further purification.
The corresponding allylic alcohol (1 mmol) was dissolved in
THF (5 mL) and cooled to -40 ◦C before n-BuLi (1.1 mmol) was
added. After stirring for 10 min the crude acyl halide (2 mmol) was
added and the mixture was allowed to warm to room temperature.
After 2 h 1 N KHSO4 was added and after the usual workup the
esters 5 were purified by flash chromatography (hexanes : EtOAc
~ 95 : 5).
Michael addition of chelated enolates to allylic esters 1
In a Schlenk flask hexamethyldisilazane (0.3 mL, 1.42 mmol) was
dissolved in THF (2 mL). The solution was cooled to -78 ◦C before
n-BuLi (1.6 M, 0.78 mL, 1.25 mmol) was added. The cooling bath
was removed and the solution was allowed to warm up for 15 min,
2-Methylallyl (2Z)-hexenoate (1b)
According to the general procedure for the preparation of the
unsaturated allyl esters, 1b was obtained from (2Z)-hexenoic acid
(804 mg, 7.05 mmol) and methylallylalcohol (240 mg, 3.33 mmol)
◦
before it was cooled again to -78 C. In a second Schlenk flask
1
in 82% yield (426 mg, 2.73 mmol) as a colourless oil. H NMR
ZnCl2 (80 mg, 0.57 mmol) was dried with a heat gun under 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 freshly 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 ether before 1 N
KHSO4 was 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.
(500 MHz): d = 0.93 (t, J = 7.4 Hz, 3H), 1.46 (tq, J = 7.4, 7.4 Hz,
2H), 1.75 (s, 3H), 2.62 (ddt, J = 7.5, 7.5, 1.7 Hz, 2H), 4.52 (s, 2H),
4.91 (s, 1H), 4.97 (s, 1H), 5.80 (dt, J = 11.5, 1.6 Hz, 1H), 6.22 (td,
J = 11.5, 7.5 Hz, 1H). 13C NMR (125 MHz): d = 13.7 (q), 19.5
(q), 22.3 (t), 31.0 (t), 67.2 (t), 112,8 (t), 119.5 (d), 140,2 (t), 150.9
(d), 166.0 (s). HRMS (CI) calcd for C10H17O2 [M + H]+: 169.1229.
Found: 169.1227.
1-Phenylallyl (2Z)-hexenoate (1c)
According to the general procedure for the preparation of the
unsaturated allyl esters, 1c was obtained from (2Z)-hexenoic
acid (854 mg, 7.49 mmol) and 1-phenylallylalcohol (502 mg,
3.75 mmol) in 89% yield (767 mg, 3.34 mmol) as a colourless
oil. 1H NMR (500 MHz): d = 0.91 (t, J = 7.4 Hz, 3H), 1.45 (m,
2H), 2.62 (ddt, J = 7.4, 3.2, 1.7 Hz, 2H), 5.23 (dt, J = 10.4, 1.3,
1.3 Hz, 1H), 5.29 (dt, J = 17.1, 1.3, 1.3 Hz, 1H), 5.84 (dt, J =
11.5, 1.7 Hz, 1H), 6.02 (ddt, J = 17.1, 10.4, 5.9 Hz, 1H), 6.24 (dt,
J = 11.5, 7.5 Hz, 1H), 6.29 (d, J = 5.9 Hz, 1H), 7.28 (m, 1H),
7.32–7.37 (m, 4H). 13C NMR (125 MHz): d = 13.7 (q), 22.3 (t),
31.0 (t), 75.7 (t), 116.8 (d), 119.6 (d), 127.1 (d), 128.5 (d), 128.0
(d), 136.5 (d), 139.1 (s), 151.2 (d), 165.3 (s). HRMS (CI) calcd for
C15H18O2 [M]+: 230.1307. Found: 230.1318.
5-Allyl 1-tert-butyl 3-propyl-2-(trifluoroacetylamino)-
pentanedioate (2a)
According to the general procedure for the Michael additions, 2a
was obtained from TFA-Gly-OtBu (475 mg, 2.09 mmol) and allyl
ester 1a (293 mg, 1.90 mmol) in 91% yield (660 mg, 1.73 mmol)
as a colourless oil. 1H NMR (500 MHz): d = 0.87 (t, J = 6.9 Hz,
3H), 1.27–1.40 (m, 4H), 1.44 (s, 9H), 2.33–2.48 (m, 3H), 4.51–4.60
(m, 3H), 5.28 (ddt, J = 10.4, 2.4, 1.2 Hz, 1H), 5.28 (ddt, J = 17.2,
1.5, 1.2 Hz, 1H), 5.86 (ddt, J = 17.2, 10.4, 5.9 Hz, 1H), 7.85 (d,
J = 8.0 Hz, 1H). 13C NMR (100 MHz): d = 13.8 (q), 19.9 (t), 27.8
(q), 32.8 (t), 35.0 (t), 36.6 (d), 55.3 (d), 65.7 (t), 83.2 (s), 115.8 (q,
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J = 287 Hz), 118.8 (t), 131.6 (d), 157.1 (q, J = 37 Hz), 169.2 (s),
172.8 (s). Anal. calcd for C17H26F3NO5 (381.39): C 53.54; H 6.87;
N 3.67. Found: C 53.65; H 6.62; N 3.88.
(0.8 mmol). After complete consumption of 1 (~ 30 min) freshly
dist. TMSCl (4 mmol) was added at -78 ◦C. The cooling bath
was removed and the reaction mixture was allowed to warm to
rt. After refluxing for 12–14 h the reaction mixture was cooled to
rt before ether and 1 N KHSO4 were added. The aqueous layer
was washed twice with CH2Cl2, the combined organic layers were
dried (Na2SO4) and the solvent was evaporated in vacuo. The crude
product was purified by flash chromatography.
1-tert-Butyl 5-(2-methylallyl) 3-propyl-2-(trifluoroacetylamino)-
pentanedioate (2b)
According to the general procedure for the Michael additions,
2b was obtained from TFA-Gly-OtBu (110 mg, 0.48 mmol) and
allyl ester 1b (73 mg, 0.43 mmol) as the minor product (besides
pyroglutamate 3b) in 21% yield (36 mg, 0.09 mmol) as a colourles
tert-Butyl 4-allyl-3-propyl-pyroglutamate (3a)
1
According to the general procedure for the domino reactions, 3a
was obtained from TFA-Gly-OtBu (128 mg, 0.50 mmol) and allyl
ester 1a (79 mg, 0.51 mmol) in 89% yield (122 mg, 0.46 mmol) as a
diastereoisomeric mixture. Ratio of (3,4-cis)-3a : (3,4-trans)-3a =
oil. H MR (500 MHz): d = 0.89 (t, J = 7.0 Hz, 3H), 1.29–1.41
(m, 4H), 1.46 (s, 9H), 1.73 (s, 3H), 2.38–2.48 (m, 3H), 4.48 (d, J =
13.0 Hz, 1H), 4.52 (d, J = 13.0 Hz, 1H), 4.58 (dd, J = 8.3, 4.0 Hz,
1H), 4.93 (s, 1H), 4.96 (s, 1H), 7.86 (d, J = 8.3 Hz, 1H). 13C NMR
(125 MHz): d = 13.8 (q), 19.4 (q), 20.0 (t), 27.9 (q), 32.9 (t),
35.1 (t), 36.7 (d), 55.4 (d), 68.4 (t), 83.3 (s), 113.5 (t), 115.8 (q, J =
288 Hz), 139.4 (s), 157.1 (q, J = 37 Hz), 169.2 (s), 172.7 (s). HRMS
calcd for C18H29F3NO5 [M + H]+: 396.1999. Found: 396.2005.
1
57 : 43. (3,4-cis)-3a: Rf: 0.27 (hexanes : EtOAc 9 : 1). H NMR
(500 MHz): d = 0.90 (t, J = 7.0 Hz, 3H), 1.3–1.22 (m, 4H), 1.43 (s,
9H), 2.16 (m, 1H), 2.44–2.49 (m, 2H), 2.59 (m, 1H), 3.74 (d, J =
3.4 Hz, 1H), 5.02 (dd, J = 10.2, 1.0 Hz, 1H), 5.07 (dd, J = 17.1,
1.0 Hz, 1H), 5.81 (m, 1H), 6.65 (bs, 1H). 13C NMR (125 MHz): d =
13.7 (q), 20.3 (t), 27.9 (q), 29.5 (t), 29.8 (t), 41.9 (d), 42.9 (d), 59.1
(d), 82.2 (s), 116.3 (t), 135.8 (d), 171.1 (s), 179.1 (s). (3,4-trans)-3a:
5-(1-Phenylallyl) 1-tert-butyl 3-propyl-2-(trifluoroacetylamino)-
pentanedioate (2c)
1
Rf: 0.17 (hexanes : EtOAc 9 : 1). H NMR (500 MHz): d = 0.90
According to the general procedure for the Michael additions, 2c
was obtained from TFA-Gly-OtBu (120 mg, 0.53 mmol) and allyl
ester 1c (107 mg, 0.46 mmol) in 90% yield (192 mg, 0.42 mmol)
(t, J = 7.3 Hz, 3H), 1.36 (dqd, J = 7.5, 7.5, 7.3 Hz, 2H), 1.43 (s,
9H), 1.52 (m, 2H), 2.15 (m, 1H), 2.21 (m, 1H), 2.29 (m, 1H), 2.41
(m, 1H), 3.67 (d, J = 4.7 Hz, 1H), 5.03 (m, 2H), 5.70 (m, 1H),
6.58 (bs, 1H). 13C NMR (125 MHz): d = 13.9 (q), 19.8 (t), 27.9
(q), 35.2 (t), 37.5 (t), 42.2 (d), 46.9 (d), 60.1 (d), 82.1 (s), 117.5 (t),
135.0 (d), 171.3 (s), 178.8 (s). Anal. calcd for C15H25NO3 (267.36):
C 67.38; H 9.42; N 5.24. Found: C 67.20; H 8.99; N 5.01. HRMS
calcd for C15H26NO3 [M + H]+: 268.1913. Found: 268.1895.
1
as a 1 : 1 diastereoisomeric mixture. H NMR (500 MHz): d =
0.81, 0.86 (2t, J = 7.1, 7.0 Hz, 3H), 1.19–1.38 (m, 4H), 1.42, 1.44
(2s, 9H), 2.24–2.51 (m, 3H), 4.54–4.59 (m, 1H), 5.24–5.30 (m, 2H),
5.95–6.03 (m, 1H), 6.25–6.27 (m, 1H), 7.27–7.36 (m, 5H), 7.74–
7.78 (m, 1H). 13C NMR (125 MHz): d = 13.78, 13.83 (2q), 19.95,
19.99 (2t), 27.89, 27.90 (2q), 32.73, 32.87, 35.25, 35.35 (4t), 36.79,
36.80 (2d), 55.37, 55.43 (2d), 77.07 (d), 83.29 (s), 117.46, 117.53
(2t), 127.20 (d), 127.22 (d), 128.57 (d), 128.60 (d), 128.4 (d), 135.68,
135.73 (2d), 138.31, 138.35 (2 s), 169.23, 171.99 (2 s), signals for
TFA-group not observed. HRMS calcd for C23H30F3NO5 [M +
H]+: 457.2076. Found: 457.2066.
tert-Butyl 4-(2-methylallyl)-3-propyl-pyroglutamate (3b)
According to the general procedure for the domino reactions, 3b
was obtained from TFA-Gly-OtBu (110 mg, 0.48 mmol) and allyl
ester 1b (73 mg, 0.43 mmol) as the major product (besides Michael
adduct 2b) in 71% yield (82 mg, 0.31 mmol) as a colourless oil.
Ratio (3,4-cis)-3b : (3,4-trans)-3b = 58 : 42. (3,4-cis)-3b: Rf: 0.26
5-Cinnamyl 1-tert-butyl 3-propyl-2-(trifluoroacetylamino)-
pentanedioate (2d)
1
(hexanes : EtOAc 9 : 1). H NMR (500 MHz): d = 0.90 (t, J =
6.9 Hz, 3H), 1.18–1.31 (m, 3H), 1.42 (m, 1H), 1.44 (s, 9H), 1.73
According to the general procedure for the Michael additions
(without ZnCl2), 2d was obtained from TFA-Gly-OtBu (111 mg,
0.49 mmol) and allyl ester 1d (105 mg, 0.46 mmol) in 73% yield
(153 mg, 0.36 mmol) as a colourless oil. 1H NMR (500 MHz): d =
0.90 (t, J = 6.9 Hz, 3H), 1.31–1.42 (m, 4H), 1.46 (s, 9H), 2.37–2.51
(m, 3H), 4.35 (dd, J = 8.4, 4.0 Hz, 1H), 4.74 (d, J = 6.6 Hz, 2H),
6.25 (dt, J = 15.9, 6.6 Hz, 1H), 6.65 (d, J = 15.9 Hz, 1H), 7.26
(m, 1H), 7.29–7.37 (m, 4H), 7.87 (d, J = 8.4 Hz, 1H). 13C NMR
(125 MHz): d = 13.9 (q), 20.0 (t), 27.9 (q), 32.9 (t), 35.2 (t), 36.7
(d), 55.4 (d), 65.8 (t), 83.3 (s), 115.6 (q, J = 288 Hz), 122.4 (d),
126.6 (d), 128.6 (d), 128.2 (d), 134.9 (d), 136.0 (s), 157.1 (q, J = 37
Hz), 169.2 (s), 172.8 (s). HRMS calcd for C23H30F3NO5 [M + H]+:
457.2076. Found: 457.2089.
(s, 3H), 2.05 (d, J = 16.4, 11.4 Hz, 1H), 2.46–2.53 (m, 2H), 2.75
(m, 1H), 3.74 (s, 1H), 4.68 (s, 1H), 4.78 (s, 1H), 6.31 (bs, 1H). 13
C
NMR (125 MHz): d = 13.6 (q), 20.2 (t), 22.7 (q), 29.7 (d), 32.6
(d), 40.9 (d), 41.8 (d), 58.6 (d), 82.1 (s), 110.6 (t), 143.3 (d), 171.4
1
(s), 179.0 (s). (3,4-trans)-3b: Rf: 0.16 (hexanes : EtOAc 9 : 1). H
NMR (500 MHz): d = 0.90 (t, J = 6.9 Hz, 3H), 1.36 (m, 2H), 1.45
(s, 9H), 1.52 (m, 2H), 1.69 (s, 3H), 2.10–2.25 (m, 3H), 2.48 (dd,
J = 13.5, 3.3 Hz, 1H), 3.69 (d, J = 3.4 Hz, 1H), 4.68 (s, 1H), 4.78
(s, 1H), 6.25 (bs, 1H). 13C NMR (125 MHz): d = 13.9 (q), 29.7
(t), 21.8 (q), 37.8 (d), 39.8 (d), 42.4 (d), 45.4 (d), 60.0 (d), 82.1 (s),
113.2 (t), 142.8 (d), 171.7 (s), 179.3 (s). Anal. calcd for C16H27NO3
(281.40): C 68.29; H 9.67; N 4.98. Found: C 68.12; H 9.45; N 5.10.
tert-Butyl 4-(3-phenylallyl)-3-propyl-pyroglutamate (3c)
Domino Michael addition–Ireland–Claisen
rearrangement–lactamisation
According to the general procedure for the domino reactions, 3c
was obtained from TFA-Gly-OtBu (126 mg, 0.55 mmol) and allyl
ester 1c (112 mg, 0.49 mmol) as the major product (besides Michael
adduct 2c) in 52% yield (88 mg, 0.26 mmol) as a colourless oil.
According to the general procedure for the Michael addi-
tions, TFA-Gly-OtBu (1 mmol) was reacted with allylic ester 1
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Ratio (3,4-cis)-3c : (3,4-trans)-3c = 56 : 44. (3,4-cis)-3c: Rf: 0.26
(s), 177.2 (s). HRMS calcd for C21H29NO3 [M]+: 343.2147. Found:
343.2138.
1
(hexanes : EtOAc 9 : 1). H NMR (500 MHz): d = 0.93 (t, J =
7.1 Hz, 3H), 1.32–1.48 (m, 3H), 1.45 (s, 9H), 1.57 (m, 1H), 2.36
(m, 1H), 2.53 (m, 1H), 2.62–2.69 (m, 2H), 3.75 (d, J = 3.6 Hz,
1H), 6.22 (ddd, J = 15.7, 7.4, 6.1 Hz, 1H), 6.22 (bs, 1H), 6.46 (d,
J = 15.7 Hz, 1H), 7.19 (m, 1H), 7.26–7.33 (m, 4H). 13C NMR
(125 MHz): d = 13.8 (q), 20.4 (t), 28.0 (q), 29.5 (t), 30.0 (t), 42.0
(d), 43.4 (d), 59.1 (d), 82.3 (s), 126.1 (d), 128.5 (d), 127.2 (d), 127.5
(d), 131.8 (d), 137.3 (s), 171.1 (s), 178.6 (s), signals for TFA-group
not observed. (3,4-trans)-3c: Rf: 0.17 (hexanes : EtOAc 9 : 1). 1H
NMR (500 MHz): d = 0.93 (t, J = 7.3 Hz, 3H), 1.42 (s, 9H),
1.43–1.65 (m, 4H), 2.27–2.38 (m, 2H), 2.52 (m, 1H), 2.61 (m, 1H),
3.73 (d, J = 4.4 Hz, 1H), 6.14 (ddd, J = 15.7, 7.3 Hz, 7.3 Hz, 1H),
6.43 (d, J = 15.7 Hz, 1H), 6.58 (bs, 1H), 7.20 (m, 1H), 7.26–7.35
(m, 4H). 13C NMR (125 MHz): d = 13.9 (q), 19.8 (t), 27.8 (q),
34.4 (t), 37.5 (t), 42.2 (d), 47.1 (d), 60.1 (d), 82.0 (s), 126.0 (d),
128.3 (d), 126.6 (d), 127.1 (d), 132.7 (d), 137.1 (s), 171.3 (s), 178.5
(s). Anal. calcd for C21H29NO3 (343.46): C 73.44; H 8.51; N 4.08.
Found: C 72.93; H 8.63; N 4.11. HRMS calcd for C21H29NO3 [M]+:
343.2147. Found: 343.2157.
tert-Butyl 4-(4-methyl-2-pentenyl)-3-propyl-pyroglutamate (3e)
According to the general procedure for the domino reactions, 3e
was obtained from TFA-Gly-OtBu (101 mg, 0.45 mmol) and allyl
ester 1e (82 mg, 0.42 mmol) as the major product (besides Michael
adduct 2e) in 81% yield (105 mg, 0.34 mmol) as a colourless oil.
Ratio (3,4-cis)-3e : (3,4-trans)-3e = 52 : 48. (3,4-cis)-3e: 1H NMR
(500 MHz): d = 0.90–0.95 (m, 9H), 1.29–1.43 (m, 3H), 1.45 (s,
9H), 1.54 (m, 1H), 2.11 (m, 1H), 2.23 (ddd, J = 13.2, 6.6, 6.6 Hz,
1H), 2.38–2.56 (m, 3H), 3.71 (dd, J = 3.7, 0.8 Hz, 1H), 5.34 (m,
1H), 5.45 (dd, J = 15.4, 6.6 Hz, 1H), 5.93 (bs, 1H). 13C NMR
(100 MHz): d = 13.8 (q), 20.4 (t), 22.48 (q), 22.51 (q), 28.0 (q),
28.5 (t), 29.8 (t), 31.1 (d), 42.0 (d), 43.3 (d), 59.1 (d), 82.2 (s),
123.8 (d), 139.9 (d), 171.2 (s), 178.7 (s), signals for TFA-group not
observed. (3,4-trans)-3e: 1H NMR (500 MHz): d = 0.89–0.95 (m,
9H), 1.36 (tdd, J = 7.5, 7.4, 7.4 Hz, 2H), 1.45 (s, 9H), 1.46–1.63 (m,
2H), 2.11 (m, 1H), 2.16–2.27 (m, 2H), 2.38 (m, 1H), 3.66 (dd, J =
5.1 Hz, 1H), 5.25 (m, 1H), 5.42 (dd, J = 15.3, 6.6 Hz, 1H), 5.99 (bs,
1H). 13C NMR (100 MHz): d = 14.0 (q), 19.9 (t), 22.5 (q), 22.6 (q),
28.0 (q), 31.0 (t), 33.9 (t), 37.5 (d), 42.0 (d), 47.2 (d), 60.0 (d), 82.1
(s), 123.2 (d), 141.1 (d), 171.4 (s), 178.5 (s), signals for TFA-group
not observed. HRMS calcd for C18H31O3 [M]+: 309.2304. Found:
309.2292.
tert-Butyl 4-(1-phenylallyl)-3-propyl-pyroglutamate (3d)
According to the general procedure for the domino reactions, 3d
was obtained from TFA-Gly-OtBu (106 mg, 0.47 mmol) and allyl
ester 1d (97 mg, 0.42 mmol) as the major product (besides Michael
adduct 2d) in 58% yield (85 mg, 0.25 mmol) as a mixture of
diastereomers. Ratio (3,4-cis)-3d : (3,4-trans)-3d = 69 : 31. (3,4-
Acknowledgements
1
cis)-3d (major diastereomer): H NMR (500 MHz): d = 0.75 (t,
Financial support by the Deutsche Forschungsgemeinschaft as
well as the Fonds der Chemischen Industrie is gratefully acknowl-
edged.
J = 7.3 Hz, 3H), 1.26–1.48 (m, 4H), 1.51 (s, 9H), 2.43 (m, 1H),
3.10 (dd, J = 8.0, 8.0 Hz, 1H), 3.65 (dd, J = 8.0, 7.9 Hz, 1H),
3.77 (d, J = 3.8 Hz, 1H), 4.96 (ddd, J = 17.1, 1.3, 1.3 Hz, 1H),
5.10 (ddd, J = 10.3, 1.3, 1.3 Hz, 1H), 6.38 (bs, 1H), 6.42 (ddd, J =
17.1, 10.3, 7.9 Hz, 1H), 7.24 (m, 1H), 7.27–7.36 (m, 4H). 13C NMR
(125 MHz): d = 13.7 (q), 20.2 (t), 27.9 (q), 29.2 (t), 43.0 (d), 46.2
(d), 46.9 (d), 58.5 (d), 82.1 (s), 115.7 (t), 126.5 (d), 128.0 (d), 128.5
(d), 140.4 (d), 142.2 (s), 171.0 (s), 177.7 (s), signals for TFA-group
not observed. (3,4-cis)-3d (minor diastereomer, selected signals):
1H NMR (500 MHz): d = 0.93 (t, J = 7.3 Hz, 3H), 1.48 (s, 9H),
2.60 (m, 1H), 3.04 (dd, J = 8.0, 6.3 Hz, 1H), 3.34 (d, J = 6.0 Hz,
1H), 3.73 (dd, J = 6.7, 6.7 Hz, 1H), 6.19 (bs, 1H), 6.27 (ddd,
J = 16.8, 10.4, 8.3 Hz, 1H). 13C NMR (125 MHz): d = 13.9 (q),
20.8 (t), 27.9 (q), 29.4 (t), 43.4 (d), 47.4 (d), 48.3 (d), 59.1 (d),
82.2 (s), 115.4 (t), 140.1 (d), 141.3 (s), 170.7 (s), 177.2 (s). (3,4-
trans)-3d (major diastereomer): 1H NMR (500 MHz): d = 0.75 (t,
J = 7.3 Hz, 3H), 1.16–1.18 (m, 4H), 1.42 (s, 9H), 2.17 (m, 1H),
2.46 (dd, J = 8.0, 4.1 Hz, 1H), 3.56 (dd, J = 8.2, 8.1 Hz, 1H),
3.61 (dd, J = 3.4 Hz, 1H), 5.01 (ddd, J = 17.0, 1.2, 1.2 Hz,
1H), 5.10 (ddd, J = 10.1, 0.9, 0.9 Hz, 1H), 6.25 (ddd, J = 17.0,
10.1, 8.2 Hz, 1H), 6.32 (bs, 1H), 7.17–7.28 (m, 5H). 13C NMR
(125 MHz): d = 13.6 (q), 19.4 (t), 27.9 (q), 38.0 (t), 41.6 (d),
51.7 (d), 52.2 (d), 59.8 (d), 82.0 (s), 116.1 (t), 126.6 (d), 128.3 (d),
128.5 (d), 138.9 (d), 141.5 (s), 171.3 (s), 177.4 (s), signals for TFA-
group not observed. (3,4-trans)-3d (minor diastereomer, selected
signals): 1H NMR (500 MHz): d = 0.77 (t, J = 7.3 Hz, 3H), 1.44
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