Synthesis of α-Amino-γ-lactams through Pd-Catalzed Intramolecular Allylic Alkylation of Sarcosine Allyl Amides

Article abstract of DOI:10.1002/ejoc.201301659

N-Protected amino acid allyl amides with an allylic leaving group can be used as substrates in palladium-catalyzed allylic alkylation. Whereas intermolecular allylations proceed with excellent yields under standard conditions for enolate reactions, the intramolecular version is not a trivial issue. N-Protected glycine amides preferentially form piperidinones through N-allylation, but the corresponding sarcosine derivatives provide γ-lactams in acceptable to good yields in dichloromethane, especially when the corresponding titanium enolates are formed.

Full text of DOI:10.1002/ejoc.201301659

FULL PAPER
DOI: 10.1002/ejoc.201301659
Synthesis of α-Amino-γ-lactams through Pd-Catalzed Intramolecular Allylic
Alkylation of Sarcosine Allyl Amides
Sarah Thies[a] and Uli Kazmaier*[a]
Keywords: Allylation / Amino acids / Intramolecular reactions / Lactams / Palladium
N-Protected amino acid allyl amides with an allylic leaving
group can be used as substrates in palladium-catalyzed all-
ylic alkylation. Whereas intermolecular allylations proceed
with excellent yields under standard conditions for enolate
reactions, the intramolecular version is not a trivial issue. N-
Protected glycine amides preferentially form piperidinones
through N-allylation, but the corresponding sarcosine deriva-
tives provide γ-lactams in acceptable to good yields in di-
chloromethane, especially when the corresponding titanium
enolates are formed.
lecular allylic alkylations could be carried out with amino
acid derivatives. The analogous reactions using N-protected
amino acid amides were also investigated by Poli et al., but
with these substrates not a C-allylation but rather an N-
allylation of the deprotonated amide was observed
(Scheme 1, b).[13]
Introduction
Allylic alkylations are definitely one of the most popular
palladium-catalyzed reactions,[1] and a wide range of mech-
anistic investigations as well as synthetic applications have
been reported during the last decades.[2] In addition to
intermolecular alkylations, a variety of intramolecular pro-
tocols have also been developed that have provided access
to macrocycles,[3] polycycles,[4] or heterocycles[5] of different
ring size. In general, a stabilized carbanion (malonate, β-
keto ester, disulfone, etc.) is generated in a molecule con-
taining an allylic leaving group such as an allyl carbonate
or a vinyl epoxide. According to this protocol, Poli et al.
investigated cyclizations of functionalized malonamides in
great detail (Scheme 1, a).[6] They observed, that strongly
electron-withdrawing groups (COOR, COR, CN, SO2Ph)
gave the cyclic product in yields of 70–80%, whereas weaker
electron-withdrawing groups such as chloride failed to un-
dergo cyclization. In the latter case the formation of the
dienamide under the basic conditions was the major side
reaction.[7] The yield could be increased by transmetallation
of the carbanion to Ti[8] or by using phase-transfer condi-
tions.[9] This approach gives direct access to γ-lactams in a
highly diastereoselective fashion. Such γ-lactams are not
only interesting as synthetic building blocks, but are also
found in a number of natural products.[10] In addition, γ-
lactams can also be introduced into, for example, peptidic
drugs, optimizing the pharmacological properties of these
compounds.[11] Their incorporation, in general, results in a
rigidification of the peptide backbone, and freezing of the
active conformation can improve the biological activity.[12]
For this purpose it would be advantageous if such intramo-
Scheme 1. Intramolecular allylic alkylations of N-allylamides.
Our group is also involved in natural product synthesis
focusing on peptidic structures, and our aim is the develop-
ment of new synthetic protocols for the synthesis of unusual
and/or highly functionalized amino acids and peptides.[14]
For an efficient modification of natural products or drugs
(for SAR studies) it is important to introduce the desired
variations as late as possible in the synthesis to save both
human and financial resources. The ideal situation would
be the modification of a natural product/drug precursor in
the very last step. An early realization of this approach was
reported by Seebach et al. with the stereoselective methyl-
ation of cyclosporine in 1993.[15] During the last years we
developed several protocols for transition-metal-catalyzed
allylic alkylations of chelated amino acid ester enolates.[16]
Besides the popular Pd-catalysts, Rh-[17] and Ru com-
plexes[18] can also be applied, and the great advantage of
the chelated ester enolates results from their much higher
[a] Institute for Organic Chemistry, Saarland University,
P. O. Box 151150, 66041 Saarbrücken, Germany
E-mail: u.kazmaier@mx.uni-saarland.de
http://www.uni-saarland.de/lehrstuhl/kazmaier.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301659.
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S. Thies, U. Kazmaier
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stability and reactivity.[19] The generally used glycine ester
To investigate the reaction behavior of such allyl amides,
enolates react with π-allyl complexes at –78 °C (or even we synthesized a selection of amino acid derivatives with
lower), allowing side reactions such as isomerizations to be different N-protecting groups (Scheme 4). The yields ob-
suppressed.[20] The substrate spectrum could also be in- tained in the different reaction steps are summarized in
creased by using deprotonated peptide esters, which can be Table 1. Starting from monosilyl-protected allyl carbonate
regio- and stereoselectively allylated at a C-terminal glycine 1,[25] the amine functionality was introduced through Pd-
unit.[21] The stereochemical outcome of this process can be catalyzed N-allylation of N-trifluoroacetylated amines.[26]
controlled by the stereogenic centers of the peptide chain. This approach allowed the introduction of different N-alkyl
Very recently, we could show that peptides can also be all- groups (2a–c). Saponification of the trifluoroacetic acid
ylated at a central glycine unit, as long as it is connected to (TFA) group resulted in free secondary amines 3, which
a secondary amino acid (proline or N-alkyl amino acid), could be coupled to a range of protected amino acids. In
which allows the formation of an amide enolate general,
2-bromo-1-ethylpyridinium
tetrafluoroborate
(Scheme 2).[22]
(BEP) was used as coupling reagent, giving excellent yields
for secondary amines and N-alkylated amino acids.[27]
However, other coupling reagents such as propylphos-
phonic anhydride (T3P) could also be used with comparable
success (entry 6).[28] The carbonate functionality was intro-
duced according to standard procedures in high overall
yield.
Scheme 2. Stereo- and regioselective allylic alkylation of peptides.
Results and Discussion
We were interested to see whether the reaction conditions
developed for intramolecular allylic alkylations were also
suitable for intramolecular reactions of peptidic N-allyl
amides. This approach would allow the direct incorporation
of γ-lactams into a peptide chain. Alternatively, the N-alkyl-
ated amides may undergo a Claisen rearrangement,[23] re-
sulting in the formation of allylated peptides (Scheme 3).[24]
Scheme 4. Synthesis of several N-alkyl allylamides.
Because the TFA-protected glycine derivatives always
gave the best results in allylic alkylations, we first tried to
obtain the corresponding TFA-amide 4b by using this pro-
tocol. Unfortunately, the yields obtained were moderate
(max. 40%), probably because of competitive azlactone for-
mation. Therefore, we decided to make a detour via the
corresponding Fmoc amide 4a, which could be converted
into the TFA-derivative 4b in almost quantitative yield
(Scheme 5).
Scheme 3. Possible reaction pathways of peptidic N-allylamides.
Table 1. Preparation of allyl amides 6.
Entry
R
Yield [%]
RЈCOOH
Yield [%]
2
3
4
5
6
1
2
3
4
5
6
7
Bn
Bn
Bn
Bn
Bn
Me
2a
88
3a
99
Fmoc-Gly
TFA-Gly
Boc-Gly
Boc-β-Ala
Boc-Sar
Boc-Sar
Boc-Sar
4a
4b
4c
4d
4e
4f
76
98
84
5b
93
82
85
93
84
99
6b
6c
6d
6e
6f
96
96
94
90
85
85
5c
5d
5e
5f
85
81
2b
2c
64
95
3b
3c
91
89
99[a]
94
(CH2)2OTHP
4g
5g
6g
[a] T3P was used as coupling reagent.
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Synthesis of α-Amino-γ-lactams
membered ring, a process that is probably slower than the
six-membered ring cyclization. Unfortunately, this reaction
also failed and, although we varied a wide range of reaction
parameters (base, chelating metal salt, solvent, tempera-
ture), in all cases a more or less inseparable mixture of
products was obtained. As one of them, the dienylamide
could be detected, which was obtained through elimination
under the strong basic reactions conditions (Scheme 8).[7]
Scheme 5. Synthesis of TFA-protected glycine allylamide 4b.
With these allylamides in hand, we first undertook ex-
periments concerning the desired intramolecular allylation.
Amide 6b was subjected to the optimized reaction condi-
tions for intermolecular allylic alkylation. However, in con-
trast to these, no reaction was observed at low temperature,
and when the reaction mixture was warmed to room tem-
perature only 25% starting material could be recovered.
Clearly the long reaction time and high temperature results
in cleavage of the TFA group by the base. We made similar
observations previously during our work on peptide Claisen
rearrangements.[24] When the reaction mixture was heated
to reflux, the starting material was completely consumed
and piperidinone 7b was obtained in moderate yield
(Scheme 6). The same reaction was also carried out with
the Boc-protected derivative 6c, which was expected to be
more stable towards decomposition, and in this case the
corresponding product 7c was obtained in higher yield.
These results are consistent with the observations described
by Poli et al.[13]
Scheme 8. Formation of dienylamides.
Another option to suppress amide deprotonation/cycliza-
tion is replacement of the acidic proton by an alkyl group.
In this case the amount of base can be reduced (in theory)
to slightly more than 1 equiv. Therefore, we next examined
the use of N-methylated analogue 6e (sarcosine, Sar). As
expected, no N-allylation occurred but, interestingly, also
no elimination such as in Scheme 8 was observed
(Scheme 9). Only starting material was recovered, even
when the reaction mixture was heated to reflux overnight.
This observation made us question whether the enolate was
formed at all. To investigate this, we deprotonated 6e with
various amounts of LHMDS and quenched the reaction
mixture with D2O. Interestingly, with 1.5 equiv. of base no
D-incorporation at the α-position of the sarcosine was ob-
served. Clearly, under these conditions the enolate is not
formed, which explains the recovery of the starting material
in the previous example. Even with 2.5 equiv. base only
Scheme 6. Intramolecular N-allylation of allylamides 6.
Whereas Boc-protected derivative 6c required strong base
for deprotonation, the TFA-derivative 6b probably does
not. Based on the high acidity of the latter, it should be
deprotonated by the alcoholate formed in the π-allyl com-
plex formation step. To investigate this option, we heated
6b in the presence of the Pd-catalyst without additional
base and found that, indeed, piperidinone 7b was obtained
in quantitative yield under these completely neutral reac-
tion conditions (Scheme 7).
Scheme 9. Reactions of sarcosin allyl amides. Reagents and condi-
tions: (a) 1. LHMDS (1.5 equiv.), ZnCl2 (1.5 equiv.), [allylPdCl]2
(2 mol-%), PPh3 (4 mol-%), THF, –78 °C to room temp.; 2. THF,
55 °C, 16 h. (b) 1. LHMDS (3.5 equiv.), ZnCl2 (1.5 equiv.), [all-
ylPdCl]2 (2 mol-%), PPh3 (4 mol-%), THF, –78 °C, 3 h; 2. D2O.
(c) 1. LHMDS (3.5 equiv.), ZnCl2 (1.5 equiv.), allyl ethyl carbonate
(1.0 equiv.), [allylPdCl]2 (2 mol-%), PPh3 (4 mol-%), THF, –78 °C
to room temp., 16 h. (d) 1. TFA-Gly-OtBu (1.0 equiv.), LHMDS
(2.5 equiv.), ZnCl2 (1.5 equiv.), THF, –78 °C, 30 min; 2. 6e, [all-
ylPdCl]2 (1 mol-%), PPh3 (4.5 mol-%), THF, –78 °C to room temp.,
Scheme 7. Intramolecular N-allylation of TFA-protected allylamide
6b.
Considering that this was actually not the reaction we
were looking for, we next tried to roll back this undesired
side reaction by replacing the glycine by a β-alanine. Here,
the N-allylation should result in the formation of a seven- 16 h.
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S. Thies, U. Kazmaier
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around 50% D-incorporation occurred, but with 3.5 equiv. case the product could be obtained for the first time in pre-
LHMDS incorporation was complete (8). Clearly, a rela- paratively acceptable yield. Other titanium salts [Ti(OiPr)4,
tively large excess of base is required for complete depro- TiCl4, Cp2TiCl2] were less effective under the same reaction
tonation. However, even under these conditions the Pd-cat- conditions (26–36% yield), and many other metal salts
alyzed cyclization failed.
[CoCl2, CuBr, Bi(OTf)2 Mg(OTf)2] failed completely. A
We therefore carried out two further control experiments. comparable result was also obtained in dichloroethane (en-
We subjected 6i to an intermolecular allylation by using try 4), but considering its higher toxicity, dichloromethane
allyl ethyl carbonate. The benzoate 6i was chosen to achieve was used for the further optimizations. When the LHMDS
selective ionization of the more reactive allyl carbonate. Al- solution in dichloromethane was warmed to room tempera-
though the yield was moderate, the desired allylation prod- ture before the allyl amide was added, a slight clouding was
uct 9 was obtained without problems. Clearly, the enolate observed, probably caused by deprotonation/chlorocarbene
is sufficiently reactive to undergo allylation, and the failure formation. But this side effect could be suppressed by pre-
of the cyclization is not a problem of the enolate per se. To paring the LHMDS solution at a temperature below
investigate the reactivity of the allyl carbonate subunit, 6e –25 °C, resulting in a slightly increased yield (entry 5). It is
was reacted with a chelated enolate according to our stan- worth mentioning, that all attempts to use other bases
dard procedure for enolate allylation reactions. In this case, (LDA, LTMP) failed.
allylation product 10 was obtained almost quantitatively,
In general, in allylic alkylations of chelated enolates, a
clearly indicating that the sarcosine amide 6e is an excellent Pd/phosphine ratio of at least 1:2 is required to avoid pre-
substrate for allylic alkylations. We can therefore exclude cipitation of Pd0, but it is not clear that this ratio is also
the possibility that the allyl amide forms some enolate-Pd best for nonchelating enolates, as formed from 6e. It should
complexes that are inactive under the reaction conditions.
be mentioned that, in contrast to chelated enolates, “nor-
We next focused on variation of the reaction conditions, mal” enolates of esters and amides are critical nucleophiles
mainly by changing the solvent, the chelating metal salt, in Pd-catalyzed allylic alkylations, because they can form
and the Pd/ligand ratio (Table 2). In general, enolate chem- inactive Pd-enolates. Although, this does not seem to be the
istry is performed in ether solvents such as tetrahydrofuran case with our allylamide enolates, as established from the
(THF), diethyl ether, or dioxane. With the zinc enolate no results of the control experiments, the amount of phosphine
cyclization product could be obtained in any of these sol- might have an influence by competing with the enolate for
vents, whereas with ClTi(OiPr)3 traces of 12e could be de- the coordination sides at the Pd. Therefore, we systemati-
termined in THF. We increased the amount of catalyst to cally varied the amount of phosphine used (entries 5–10).
5% (10 mol-% Pd0) to obtain a reasonable amount of prod- Whereas the yield dropped upon reducing the Pd/PPh3 ra-
uct (entry 1). A further improvement was obtained by tio, it also increased significantly when up to a fivefold ex-
switching from THF to toluene (entry 2), and most surpris- cess of PPh3 was used. A higher excess gave no further im-
ingly to dichloromethane (entry 3). Although one may ex- provement. These results indicate that the enolate might co-
pect that the latter solvent can be (at least in part) depro- ordinate to the Pd-catalyst and that this coordination might
tonated under the rather basic reaction conditions, in this be suppressed by a large phosphine excess. If this is the case,
one might also expect the outcome of the reaction to be
influenced by the type of phosphine used. Replacing the
Table 2. Thiol addition towards allylated dipeptides 6 and 7.
PPh3 by the less electron-donating P(OPh3)3 resulted in a
slightly reduced yield (entry 11). The same result was ob-
tained with the sterically hindered XPHOS ligand (en-
try 12), whereas performing the reaction with dppe and
carbene ligands such as isopropyl-NHC failed. It should
be mentioned that other Pd sources such as Pd2(dba)3 or
Pd(PPh3)4 could also be used, but could not compete with
the optimized [AllylPdCl]2/PPh3 system.
Entry Solvent
PR3
(mol-%)
Ratio Pd/PR3 Yield
[%]
With these optimized reaction conditions in hand, we
subjected allylamides 6e–h to the same conditions (Table 3).
The yields obtained were comparable, with the THP-pro-
tected derivative 6g giving an excellent yield of 88%. To
establish whether the latter good result was influenced by
the presence of the THP group, we also investigated the
reaction of the free alcohol. In this case the yield dropped
to 50%, which might be caused by an interaction of the
alcoholate formed with the π-allyl complex, however, the
result was still in a preparatively useful range.
1
2
3
4
5
6
7
8
THF
toluene
CH2Cl2
PPh3 (22.5)
PPh3 (22.5)
PPh3 (22.5)
1:2.25
1:2.25
1:2.25
1:2.25
1:2.25
1:1.25
1:1.75
1:2.75
1:3.75
1:5.25
1:5.25
1:1.75
trace
30
45[a]
45
ClCH2CH2Cl PPh3 (22.5)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PPh3 (22.5)
PPh3 (12.5)
PPh3 (17.5)
PPh3 (27.5)
PPh3 (37.5)
PPh3 (52.5)
P(OPh)3 (52.5)
XPHOS (17.5)
51[b]
32[b]
45[b]
59[b]
67[b]
75[b]
61[b]
61[b]
9
10
11
12
In all the examples investigated, the anti-configured
product was formed preferentially (anti/syn ratio of 3–5:1),
whereas the highest selectivity was observed with the N-
[a] Base solution prepared at –20 °C and warmed to room tempera-
ture. [b] Base solution prepared at –20 °C without warming to
room temperature.
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Synthesis of α-Amino-γ-lactams
idine (5.0 mL, 61.8 mmol, 2.5 equiv.) were dissolved in dichloro-
methane (50 mL) and the solution was cooled to 0 °C before ethyl
chloroformate (2.8 mL, 29.6 mmol, 1.2 equiv.) was added. After
complete consumption of the alcohol (TLC), 1 n KHSO4 solution
was added. After separation of the layers, the aqueous layer was
extracted three times with diethyl ether. The combined organic lay-
ers were dried (Na2SO4), the solvent was removed in vacuo and the
crude product was purified by flash chromatography (hexanes/ethyl
acetate, 9:1) to give 1 (6.56 g, 24.0 mmol, 97%) as a colorless oil.
1H NMR (CDCl3): δ = 5.75 (dtt, J = 11.4, 5.8, 1.4 Hz, 1 H, 3-H),
5.60 (dtt, J = 11.3, 6.6, 1.6 Hz, 1 H, 2-H), 4.70 (dt, J = 6.6, 1.2 Hz,
2 H, 1-H), 4.29 (dt, J = 5.8, 1.6 Hz, 2 H, 4-H), 4.19 (q, J = 7.1 Hz,
2 H, 9-H), 1.31 (t, J = 7.1 Hz, C-10), 0.91 (s, 9 H, 6-H), 0.07 (s, 6
H, 7-H) ppm. 13C NMR (CDCl3): δ = 155.1 (s, C-8), 134.4 (d, C-
3), 123.7 (d, C-2), 64.0 (t, C-9), 63.6 (t, C-1), 59.6 (t, C-4), 25.9 (q,
C-6), 18.2 (s, C-5), 14.3 (q, C-10), –5.27 (q, C-7) ppm. C13H26O4Si
(274.43): calcd. C 56.90, H 9.55; found C 56.51, H 9.04.
Table 3. Thiol addition towards tetrapeptide 12 containing an allyl
glycine subunit.
Entry
6
R
12
Yield [%]
anti/syn
1
2
3
4
6e
6f
6g
6h
Bn
Me
12e
12f
12g
12h
75
69
88
50
87:13
76:24
82:18
78:22
CH2CH2OTHP
CH2CH2OH
benzylated derivative 6e used in the optimization studies.
For structure elucidation, the diastereomeric products were
separated by preparative HPLC, and NOE experiments
were carried out with the major diastereomer. No NOE was
observed between the α- and the β-proton, which is a clear
indication of their anti-orientation. For the syn isomer a
strong NOE should be expected.[29] In addition, the cou-
pling constants for these protons are in the range of 9.6 to
10.8 Hz, which is also typical for trans-oriented protons in
γ-lactams (coupling constants of 6.5–8.0 Hz are generally
observed for the cis isomers).[30]
General Procedure for the N-Allylation of Trifluoroacetamides: All-
ylpalldium chloride dimer (7.3 mg, 0.02 mmol, 2 mol-%) and tri-
phenylphosphine (23.5 mg, 0.09 mmol, 9 mol-%) were dissolved in
DMF (10 mL) and stirred at room temperature for 15 min before
carbonate 1 was added (1.0 mmol). The TFA-amide (1.3 mmol)
and sodium hydride (31 mg, 1.3 mmol) were also dissolved in DMF
(7 mL), before the catalyst/carbonate solution was added. The reac-
tion mixture was stirred at room temperature until complete con-
sumption of 1 was observed (1–3 h, TLC). In the case of N-benz-
ylamide, the reaction mixture was heated to reflux overnight. The
solvent was removed in vacuo and the crude product was purified
by flash chromatography.
Conclusions
N-Benzyl-4-[tert-butyldimethylsilyloxy-(2E)-buten-1-yl]trifluor-
acetamide (2a): Allylamide 2a (7.97 g, 20.6 mmol, 88%) was ob-
tained as a yellow oil as a mixture of rotamers according to the
general procedure for N-allylations from 1 (6.44 g, 23.4 mmol) and
N-benzyltrifluoroacetamide (6.19 g, 30.5 mmol) after flash
chromatography (hexanes/ethyl acetate, 98:2). HRMS (CI): calcd.
for C 1 9 H2 8 F3 NO2 S i [ M ]+ 3 8 7 . 1 84 8; fo un d 3 87. 1808.
C19H28F3NO2Si (387.51): calcd. C 58.89, H 7.28, N 3.61; found C
58.21, H 7.21, N 7.21.
Major Rotamer: 1H NMR (CDCl3): δ = 7.40–7.29 (m, 3 H, 1-H, 2-
H), 7.14 (m, 2 H, 3-H), 5.77–5.56 (m, 2 H, 7-H, 8-H), 4.62 (s, 2 H,
5-H), 4.20 (dd, J = 4.1, 1.5 Hz, 2 H, 9-H), 3.92 (d, J = 5.2 Hz, 2
H, 6-H), 0.92 (s, 9 H, 12-H), 0.08 (s, 6 H, 10-H) ppm. 13C NMR
(CDCl3): δ = 135.0 (d, C-4), 134.8 (d, C-8), 129.0 (d, C-3), 128.3
(d, C-2), 127.3 (d, C-1), 122.8 (d, C-7), 62.6 (t, C-9), 48.5 (t, C-5),
46.8 (t, C-6), 25.8 (q, C-12), 18.4 (s, C-11), –5.30 (q, C-10) ppm.
We have demonstrated that intramolecular allylic alkyl-
ations using functionalized amino acid allyl amides are not
trivial. The reactions do not proceed under standard condi-
tions that are generally used for reactions of enolates, but
good to high yields are obtained with the corresponding
titanium enolates in dichloromethane as solvent. Applica-
tions of this protocol for the direct introduction of γ-lact-
ams into peptides are under investigation.
Experimental Section
General Remarks: All air- and moisture-sensitive reactions were
carried out in dried glassware under a nitrogen atmosphere. THF
was distilled from sodium-benzophenone. LHMDS solutions were
prepared from freshly distilled HMDS and commercially available
n-butyllithium (1.6 m in hexane) in THF before use. The products
were purified by flash chromatography on silica gel columns (40–
63 μm). Mixtures of hexanes and ethyl acetate were generally used
as eluents. Analytical TLC was performed on precoated silica gel
plates (Macherey–Nagel, Polygram SIL G/UV254). Visualization
was accomplished with UV-light or KMnO4 solution. The dia-
stereomeric ratios were determined by HPLC with a chiral column
Minor Rotamer (selected signals): 1H NMR (CDCl3): δ = 4.61 (s, 2
H, 5-H), 4.15 (dd, J = 3.9, 1.5 Hz, 2 H, 9-H), 0.91 (s, 9 H, 12-H),
0.07 (s, 6 H, 10-H) ppm. 13C NMR (CDCl3): δ = 135.3 (d, C-4),
134.7 (d, C-8), 128.9 (d, C-3), 128.2 (d, C-2), 128.0 (d, C-1), 122.0
(d, C-7), 62.8 (t, C-9), 47.7 (t, C-5), 25.9 (q, C-12), –5.26 (q, C-
10) ppm.
4-[tert-butyldimethylsilyloxy-(2E)-buten-1-yl]-N-methyl-trifluoracet-
amide (2b): Allylamide 2a (5.98 g, 19.2 mmol, 64%) was obtained
as a pale-yellow oil as a mixture of rotamers according to the gene-
ral procedure for N-allylations from 1 (8.23 g, 30.0 mmol) and N-
methyltrifluoroacetamide (4.96 g, 39.0 mmol) after flash
chromatography (hexanes/ethyl acetate, 98:2). HRMS (CI): calcd.
for C13H25F3NO2Si [M + H]+ 312.1562; found 312.1621.
C13H24F3NO2Si (311.42): calcd. C 50.14, H 7.77, N 4.50; found C
50.14, H 7.31, N 4.70.
(Chiracel ODH). H and 13C NMR spectra were recorded with a
1
Bruker AV II-400 [400 MHz (1H) and 100 MHz (13C)] spectrometer
in CDCl3 or CD3OD. Chemical shifts are reported in ppm (δ) with
respect to TMS, and CHCl3 or CH3OH was used as the internal
standard. Mass spectra were recorded with a Finnigan MAT 95
spectrometer (quadrupole) by using the CI technique. Elemental
analyses were performed at Saarland University.
[(Z)-4-tert-Butyldimethylsilyloxy-2-butenyl] Ethyl Carbonate (1):
Monosilyl-protected (2Z)-butendiol (5.00 g, 24.7 mmol) and pyr-
Major Rotamer: 1H NMR (CDCl3): δ = 5.77 (dtt, J = 15.3, 2.9,
1.3 Hz, 1 H, 4-H), 5.64 (dtt, J = 15.3, 6.3, 1.7 Hz, 1 H, 3-H), 4.20
Eur. J. Org. Chem. 2014, 1695–1707
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1699

S. Thies, U. Kazmaier
(3.75 g, 12.0 mmol). H NMR (CDCl3): δ = 5.79–5.67 (m, 2 H, 3-
FULL PAPER
(dd, J = 2.9, 1.3 Hz, 2 H, 5-H), 4.04 (d, J = 6.2 Hz, 2 H, 2-H), 3.08
1
(q, J1,F = 1.5 Hz, 3 H, 1-H), 0.91 (s, 9 H, 8-H), 0.07 (s, 6 H, 6- H, 4-H), 4.16 (dd, J = 3.5, 1.4 Hz, 2 H, 5-H), 3.21 (d, J = 4.9 Hz,
H) ppm. 13C NMR (CDCl3): δ = 134.5 (d, C-4), 122.1 (d, C-3),
2 H, 2-H), 2.43 (s, 3 H, 1-H), 1.65 (br. s, 1 H, NH), 0.90 (s, 9 H,
62.8, 62.6 (t, C-5), 50.4 (t, C-2), 34.0 (q, C-1), 25.9 (q, C-8), 18.4 8-H), 0.07 (s, 6 H, 6-H) ppm. 13C NMR (CDCl3): δ = 131.0, 128.6
(s, C-7), –5.28 (q, C-6) ppm.
(2d, C-3, C-4), 63.5 (t, C-5), 53.3 (t, C-2), 36.0 (q, C-1), 26.0 (q, C-
8), 18.4 (s, C-7), –5.20 (q, C-6) ppm. HRMS (CI): calcd. for
C11H25NOSi [M]+ 215.1705; found 215.1697.
1
Minor Rotamer (selected signals): H NMR (CDCl3): δ = 4.00 (d,
J = 6.0 Hz, 2 H, 2-H), 2.98 (s, 3 H, 1-H) ppm. 13C NMR (CDCl3):
δ = 134.6 (d, C-4), 122.6 (d, C-3), 62.8, 62.6 (t, C-5), 25.9 (q, C-8),
18.4 (s, C-7), –5.32 (q, C-6) ppm.
[4-tert-Butyldimethylsilyloxy-(2E)-buten-1-yl][2-(tetrahydropyran-
2-yloxy)ethyl]amine (3c): Allylamine 3c (4.67 g, 14.2 mmol, 89%)
as a yellow oil was obtained according to the general procedure for
4-[tert-Butyldimethylsilyloxy-(2E)-buten-1-yl]-N-[2-(tetrahydro-
pyran-2-yloxy)ethyl]trifluoracetamide (2c): Allylamide 2c (7.31 g,
17.2 mmol, 95%) was obtained as a yellow oil as a mixture of rota-
mers according to the general procedure for N-allylations from 1
(5.00 g, 18.2 mmol) and N-[2-(tetrahydropyran-2-yloxy)ethyl]-tri-
fluoroacetamide (5.71 mg, 23.7 mmol) after flash chromatography
(hexanes/ethyl acetate, 9:1 to 8:2). HRMS (CI): calcd. for
1
TFA-cleavage from 2c (6.75 g, 15.9 mmol). H NMR (CDCl3): δ =
5.81–5.47 (m, 2 H, 9-H, 10-H), 4.59 (dd, J = 4.3, 2.9 Hz, 1 H, 5-
H), 4.17 (dd, J = 4.5, 1.0 Hz, 2 H, 11-H), 3.89–3.83 (m, 2 H, 1-Ha,
6-Ha), 3.55–3.48 (m, 2 H, 1-Hb, 6-Hb), 3.27 (d, J = 5.6 Hz, 2 H, 8-
H), 2.80 (dd, J = 4.3, 2.6 Hz, 2 H, 7-H), 1.83 (m, 1 H, 3-Ha), 1.71
(m, 1 H, 4-Ha), 1.60–1.50 (m, 5 H, 2-H, 3-Hb, 4-Hb, NH), 0.90 (s,
9 H, 14-H), 0.06 (s, 6 H, 12-H) ppm. 13C NMR (CDCl3): δ = 131.0,
128.7 (2d, C-9, C-10), 99.1 (d, C-5), 67.0 (t, C-6), 63.5 (t, C-11),
62.4 (t, C-1), 51.2 (t, C-8), 48.9 (t, C-7), 30.6 (t, C-4), 25.9 (q, C-
14), 25.4 (t, C-2), 19.6 (t, C-3), 18.4 (s, C-13), –5.20 (q, C-12) ppm.
HRMS (CI): calcd. for C17H36NO3Si [M + H]+ 330.2420; found
330.2457. C17H35NO3Si (329.55): calcd. C 61.96, H 10.70, N 4.25;
found C 61.95, H 10.68, N 4.36.
C
1 9 H3 5 F3 NO4 Si [M + H]+ 429.2243; found 426.2296.
C19H34F3NO4Si (425.56): calcd. C 53.62, H 8.05, N 3.29; found C
53.93, H 8.00, N 3.57.
1
Major Rotamer: H NMR (CDCl3): δ = 5.76 (dt, J = 15.4, 4.3 Hz,
1 H, 10-H), 5.64 (m, 1 H, 9-H), 4.58 (dd, J = 4.3, 3.6 Hz, 1 H, 5-
H), 4.18–4.15 (m, 4 H, 8-H, 11-H), 3.92 (dt, J = 10.3, 6.0 Hz, 1 H,
6-Ha), 3.79 (t, J = 8.0 Hz, 1 H, 1-Ha), 3.68–3.50 (m, 4 H, 1-Hb, 6-
Hb, 7-H), 1.79–1.70 (m, 2 H, 3-Ha, 4-Ha), 1.60–1.51 (m, 4 H, 2-H,
3-Hb, 4-Hb), 0.91 (s, 9 H, 14-H), 0.07 (s, 6 H, 12-H) ppm. 13C NMR
(CDCl3): δ = 156.8 (q, J15,F = 35.8 Hz, C-15), 134.4 (d, C-10), 123.2
(d, C-9), 116.4 (q, J16,F = 288.0 Hz, C-16), 98.9 (d, C-5), 64.7 (t,
C-6), 62.6 (t, C-11), 62.2 (t, C-1), 48.8 (t, C-8), 46.0 (t, C-7), 30.5
(t, C-4), 25.8 (q, C-14), 25.3 (t, C-2), 19.4 (t, C-3), 18.3 (s, C-13),
–5.38 (q, C-12) ppm.
Amide Coupling Using 2-Bromo-1-ethylpyridinium Tetrafluoroborate
(BEP). General Procedure: Amine 3 (1 equiv.) was dissolved in
dichloromethane (1 mL/mmol) under N2 before BEP (1.1 equiv.)
and the amino acid (1.1 equiv.) were added. The solution was co-
oled to –10 °C then diisopropylamine (2.0 equiv.) was added drop-
wise. After stirring at –10 °C for 20 min, the mixture was warmed
to room temperature overnight. The solvent was removed in vacuo
and the crude product was purified by flash chromatography.
1
Minor Rotamer (selected signals): H NMR (CDCl3): δ = 3.79 (2t,
N-Fluorenylmethoxycarbonyl-glycyl-{N-benzyl-N-[4-tert-butyldi-
methylsilyloxy-(2E)-buten-1-yl]}amide (4a): Allylamide 4a (2.33 g,
4.08 mmol, 76%) was obtained as a pale-yellow oil as a mixture of
rotamers according to the general procedure for peptide couplings
from 3a (1.56 g, 5.35 mmol), Fmoc-Gly-OH (1.75 g, 5.89 mmol),
BEP (1.61 g, 5.89 mmol), and diisopropylamine (1.38 g,
10.7 mmol) after flash chromatography (hexanes/ethyl acetate, 9:1
to 7:3). HRMS (CI): calcd. for C34H43N2O4Si [M + H]+ 571.2947;
found 571.2974. C34H42N2O4Si (570.79): calcd. C 71.54, H 7.42, N
4.91; found C 70.79, H 7.24, N 5.22.
J = 8.0 Hz, 1 H, 1-Ha), 0.90 (s, 9 H, 14-H), 0.07 (s, 6 H, 12-H) ppm.
13C NMR (CDCl3): δ = 157.0 (q, J15,F = 35.6 Hz, C-15), 134.2 (d,
C-10), 122.5 (d, C-9), 98.9 (d, C-5), 65.7 (t, C-6), 62.9 (t, C-11),
62.1 (t, C-1), 50.1 (t, C-8), 46.2 (t, C-7), 30.4 (t, C-4), 25.8 (q, C-
14), 25.2 (t, C-2), 19.2 (t, C-3), –5.33 (q, C-12) ppm.
Cleavage of the TFA-Protecting Group. General Procedure: The
TFA-protected amide 2 (1.0 equiv.) was dissolved in methanol–
water (9:1) before potassium carbonate (1.5 to 2 equiv.) was added.
After complete consumption of 2 (TLC) the solvent was removed
in vacuo and the residue was dissolved in ethyl acetate. The clear
solution was washed with water and the aqueous layer was ex-
tracted four times with ethyl acetate. The combined organic layers
were dried (Na2SO4), the solvent was removed in vacuo, and the
crude product was used without further purification.
1
Major Rotamer: H NMR (CDCl3): δ = 7.76 (d, J = 7.4 Hz, 2 H,
19-H), 7.62 (d, J = 7.0 Hz, 2 H, 22-H), 7.42–7.15 (m, 9 H, 1-H, 2-
H, 3-H, 20-H, 21-H), 5.87 (br. s, 1 H, NH), 5.65 (m, 2 H, 7-H, 8-
H), 4.65 (s, 2 H, 5-H), 4.40 (d, J = 7.4 Hz, 2 H, 16-H), 4.26 (t, J
= 7.3 Hz, 1 H, 17-H), 4.17 (m, 2 H, 9-H), 4.11 (m, 2 H, 14-H),
3.83 (d, J = 3.9 Hz, 2 H, 6-H), 0.91 (s, 9 H, 12-H), 0.07 (s, 6 H,
10-H) ppm. 13C NMR (CDCl3): δ = 168.2 (s, C-13), 156.1 (s, C-
15), 143.9 (s, C-18), 141.3 (s, C-23), 136.7 (s, C-4), 132.9 (d, C-8),
129.1, 128.7, 128.2, 127.9, 127.7, 127.0, 126.3 (5d, C-1, C-2, C-3,
C-20, C-21), 125.2 (d, C-22), 122.7 (d, C-7), 119.9 (d, C-19), 67.1
(t, C-16), 62.6 (t, C-9), 48.7 (t, C-5), 47.2, 47.1 (2t, C-6, d, C-17),
42.6 (t, C-14), 25.9 (q, C-12), 18.3 (s, C-11), –5.31 (q, C-10) ppm.
Benzyl[4-tert-butyldimethylsilyloxy-(2E)-buten-1-yl]amine (3a): Al-
lylamine 3a (5.32 g, 18.3 mmol, Ͼ99%) was obtained as a yellow
oil according to the general procedure for TFA-cleavage from 2a
1
(7.07 g, 18.3 mmol). H NMR (CDCl3): δ = 7.33–7.30 (m, 4 H, 2-
H, 3-H), 7.25 (m, 1 H, 1-H), 5.83–5.69 (m, 2 H, 7-H, 8-H), 4.17
(dd, J = 4.6, 1.3 Hz, 2 H, 9-H), 3.80 (s, 2 H, 5-H), 3.28 (dd, J =
5.7, 1.0 Hz, 2 H, 6-H), 1.47 (br. s, 1 H, NH), 0.91 (s, 9 H, 12-H),
0.07 (s, 6 H, 10-H) ppm. 13C NMR (CDCl3): δ = 140.3 (s, C-4),
131.2, 128.6 (2d, C-7, C-8), 128.4, 128.2 (2d, C-2, C-3), 126.9 (d,
C-1), 63.5 (t, C-9), 53.3 (t, C-5), 50.6 (t, C-6), 25.7 (q, C-12), 18.4
(s, C-11), –5.19 (q, C-10) ppm. HRMS (CI): calcd. for C17H30NOSi
[M + H]+ 292.2052; found 292.2100. C17H29NOSi (291.50): calcd.
C 70.04, H 10.03, N 4.80; found C 69.74, H 9.56, N 5.32.
Minor Rotamer (selected signals): 1H NMR (CDCl3): δ = 4.46 (s, 2
H, 5-H), 4.40 (d, J = 7.4 Hz, 2 H, 16-H), 4.08 (d, J = 3.8 Hz, 2 H,
6-H), 0.07 (s, 6 H, 10-H) ppm. 13C NMR (CDCl3): δ = 168.1 (s, C-
13), 135.5 (s, C-4), 133.8 (d, C-8), 129.1, 128.7, 128.2, 127.9, 127.7,
127.0, 126.3 (5d, C-1, C-2, C-3, C-20, C-21), 123.6 (d, C-7), 62.9
(t, C-9), 49.0 (t, C-5), 42.7 (t, C-14), –5.26 (q, C-10) ppm.
[4-tert-Butyldimethylsilyloxy-(2E)-buten-1-yl]methylamine (3b): All-
ylamine 3b (2.36 g, 10.9 mmol, 91%) was obtained as a yellow oil
according to the general procedure for TFA-cleavage from 2b
N-Trifluoroacetyl-glycyl-{N-benzyl-N-[4-tert-butyldimethylsilyl-
oxy-(2E)-buten-1-yl]}amide (4b): Allylamide 4b was obtained by
1700
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1695–1707

Synthesis of α-Amino-γ-lactams
treating a solution of 4a (1.28 g, 2.13 mmol) in acetonitrile (35 mL)
with diethylamine (17 mL). After stirring for 30 min at room tem-
perature all starting material was consumed (TLC). The solvent
was removed in vacuo and the residue was dissolved in methanol
(25 mL). Triethylamine (1.19 mL, 8.52 mmol) and ethyl trifluoro-
acetate (1.27 mL, 10.7 mmol) were added and the solution was
stirred at room temperature for 3 d. The clear solution was concen-
trated in vacuo and the crude product was purified by flash
chromatography (hexanes/ethyl acetate, 9:1 to 7:3) to give 4b
(931 mg, 2.09 mmol, 98%) as a colorless oil as a mixture of rota-
mers. HRMS (CI): calcd. for C17H23F3N2O3Si [M – C4H8]+
388.1430; found 388.1469. C21H31F3N2O3Si (444.56): calcd. C
56.74, H 7.03, N 6.30; found C 56.79, H 6.80, N 6.80.
to 7:3). HRMS (CI): calcd. for C25H42N2O4Si [M]+ 462.2914;
found 462.2908. C25H42N2O4Si (462.70): calcd. C 64.89, H 9.15, N
6.05; found C 64.47, H 9.53, N 6.15.
Major Rotamer: 1H NMR (CDCl3): δ = 7.38–7.30 (m, 3 H, 1-H, 2-
H), 7.24 (m, 2 H, 3-H), 5.69–5.55 (m, 2 H, 7-H, 8-H), 5.38 (br. s,
1 H, NH), 4.60 (s, 2 H, 5-H), 4.18 (m, 2 H, 9-H), 3.82 (d, J =
4.0 Hz, 2 H, 6-H), 3.46 (t, J = 5.7 Hz, 2 H, 14-H), 2.59 (t, J =
5.7 Hz, 2 H, 15-H), 1.45 (s, 9 H, 18-H), 0.93 (s, 9 H, 12-H), 0.08
(s, 6 H, 10-H) ppm. 13C NMR (CDCl3): δ = 171.9 (s, C-13), 156.0
(s, C-16), 137.3 (s, C-4), 132.3 (d, C-8), 128.6 (d, C-2), 128.1 (d, C-
3), 127.4 (d, C-1), 123.6 (d, C-7), 79.0 (s, C-17), 62.7 (t, C-9), 48.2
(t, C-5), 48.0 (t, C-6), 36.4 (t, C-14), 33.2 (t, C-15), 28.4 (q, C-18),
25.9 (q, C-12), 18.3 (s, C-11), –5.29 (q, C-10) ppm.
Major Rotamer: 1H NMR (CDCl3): δ = 7.61 (br. s, 1 H, NH), 7.40–
7.30 (m, 3 H, 1-H, 2-H), 7.26 (m, 2 H, 3-H), 5.69 (m, 2 H, 7-H, 8-
H), 4.63 (s, 2 H, 5-H), 4.18–4.15 (m, 4 H, 9-H, 14-H), 3.81 (dd, J
= 5.1, 1.4 Hz, 2 H, 6-H), 0.91 (s, 9 H, 12-H), 0.07 (s, 6 H, 10-
1
Minor Rotamer (selected signals): H NMR (CDCl3): δ = 7.15 (d,
J = 7.1 Hz, 2 H, 3-H), 4.49 (s, 2 H, 5-H), 4.02 (d, J = 3.8 Hz, 2 H,
6-H), 3.46 (t, J = 5.7 Hz, 2 H, 14-H), 2.59 (t, J = 5.7 Hz, 2 H, 15-
H), 1.44 (s, 9 H, 18-H), 0.92 (s, 9 H, 12-H), 0.08 (s, 6 H, 10-H) ppm.
13C NMR (CDCl3): δ = 136.4 (s, C-4), 133.2 (d, C-8), 128.9 (d, C-
2), 127.6 (d, C-1), 126.3 (d, C-3), 124.4 (d, C-7), 63.1 (t, C-9), 49.8
(t, C-5), 46.7 (t, C-6), 36.3 (t, C-14), 33.4 (t, C-15), 25.9 (q, C-12),
–5.23 (q, C-10) ppm.
H) ppm. 13C NMR (CDCl3): δ = 166.5 (s, C-13), 156.8 (q, J15,F
=
35.8 Hz, C-15), 136.2 (s, C-4), 133.4 (d, C-8), 128.8 (d, C-2), 128.3
(d, C-3), 127.9 (d, C-1), 122.2 (d, C-7), 115.5 (q, J16,F = 287.3 Hz,
C-16), 62.4 (t, C-9), 49.0 (t, C-5), 47.3 (t, C-6), 41.4 (t, C-14), 25.9
(q, C-12), 18.3 (s, C-11), –5.33 (q, C-10) ppm.
N-tert-Butyloxycarbonyl-sarcosyl-{N-benzyl-N-[4-tert-butyldimeth-
ylsilyloxy-(2E)-buten-1-yl]}amide (4e): Allylamide 4e (6.00 g,
13.0 mmol, 81%) was obtained as a colorless oil as a mixture of
three rotamers according to the general procedure for peptide cou-
plings from 3a (4.69 g, 16.1 mmol), Boc-Sar-OH (3.35 g,
17.7 mmol), BEP (4.85 g, 17.7 mmol) und diisopropylamine
(4.16 g, 32.0 mmol) after flash chromatography (hexanes/ethyl acet-
ate, 8:2 to 7:3). HRMS (CI): calcd. for C25H43N2O4Si [M + H]+
463.2947; found 463.2948. C25H42N2O4Si (462.70): calcd. C 64.89,
H 9.15, N 6.05; found C 64.29, H 8.85, N 6.43.
Major Rotamer: 1H NMR (CDCl3): δ = 7.37–7.29 (m, 3 H, 1-H, 2-
H), 7.24 (m, 2 H, 3-H), 7.16 (d, J = 7.3 Hz, 2 H, 3-H), 5.68–5.56
(m, 2 H, 7-H, 8-H), 4.59, 4.50, 4.45 (s, 2 H, 5-H), 4.16, 4.10, 4.07
(s, 2 H, 9-H), 4.00 (br. s, 2 H, 14-H), 3.80 (d, J = 9.8 Hz, 2 H, 6-
H), 2.95, 2.91 (s, 3 H, 18-H), 1.48, 1.43 (s, 9 H, 17-H), 0.91, 0.90
(s, 9 H, 12-H), 0.07, 0.06 (s, 6 H, 10-H) ppm. 13C NMR (CDCl3):
δ = 169.0, 168.8, 168.7 (s, C-13), 156.2, 155.7 (s, C-15), 137.2, 136.5
(s, C-4), 133.4, 132.4, 132.2 (d, C-8), 129.0, 128.9, 128.5 (d, C-2),
128.2 (d, C-3), 127.5, 127.3 (d, C-1), 126.4, 126.2 (d, C-3), 123.8,
123.6 (d, C-7), 79.8 (s, C-16), 64.5, 62.8, 62.5 (t, C-9), 50.8, 50.2,
50.0, 49.3, 49.1, 48.5, 47.5, 47.1, 47.0 (t, C-5, C-6, C-14), 35.8, 35.6
(q, C-18), 28.3 (q, C-17), 25.9 (q, C-12), 18.4 (s, C-11), –5.29, –5.25
(q, C-10) ppm.
1
Minor Rotamer (selected signals): H NMR (CDCl3): δ = 7.17 (d,
J = 7.0 Hz, 2 H, 3-H), 4.47 (s, 2 H, 5-H), 4.07 (d, J = 5.2 Hz, 2 H,
6-H), 0.90 (s, 9 H, 12-H), 0.06 (s, 6 H, 10-H) ppm. 13C NMR
(CDCl3): δ = 134.9 (s, C-4), 134.4 (d, C-8), 129.2 (d, C-2), 128.1
(d, C-1), 126.3 (d, C-3), 123.0 (d, C-7), 62.8 (t, C-9), 47.4 (t, C-6),
41.5 (t, C-14) ppm.
N-tert-Butyloxycarbonyl-glycyl-{N-benzyl-N-[4-tert-butyldimethyl-
silyloxy-(2E)-buten-1-yl]}amide (4c): Allylamide 4c (3.76 g,
8.40 mmol, 84%) was obtained as a colorless oil as a mixture of
rotamers according to the general procedure for peptide couplings
from 3a (2.92 g, 10.0 mmol), Boc-Gly-OH (1.93 g, 11.0 mmol),
BEP (3.01 g, 11.0 mmol), and diisopropylamine (2.59 g,
20.0 mmol) after flash chromatography (hexanes/ethyl acetate, 8:2
to 7:3). HRMS (CI): calcd. for C24H41N2O4Si [M + H]+ 449.2791;
found 449.2884. C24H40N2O4Si (448.67): calcd. C 64.25, H 8.99, N
6.24; found C 64.51, H 8.88, N 6.29.
Major Rotamer: 1H NMR (CDCl3): δ = 7.36–7.28 (m, 3 H, 1-H, 2-
H), 7.22 (m, 2 H, 3-H), 5.67–5.44 (m, 3 H, 7-H, 8-H, NH), 4.60 (s,
2 H, 5-H), 4.16 (m, 2 H, 9-H), 4.03 (s, 2 H, 14-H), 3.77 (d, J =
4.2 Hz, 2 H, 6-H), 1.45 (s, 9 H, 17-H), 0.90 (s, 9 H, 12-H), 0.06 (s,
6 H, 10-H) ppm. 13C NMR (CDCl3): δ = 168.6 (s, C-13), 155.7 (s,
C-15), 136.8 (s, C-4), 132.9 (d, C-8), 128.6 (d, C-2), 128.2 (d, C-3),
127.5 (d, C-1), 122.9 (d, C-7), 79.5 (s, C-16), 62.6 (t, C-9), 48.6 (t,
C-5), 47.2 (t, C-6), 42.2 (t, C-14), 28.3 (q, C-17), 25.9 (q, C-12),
18.3 (s, C-11), –5.31 (q, C-10) ppm.
N-tert-Butyloxycarbonyl-sarcosyl-{N-4-[tert-butyldimethylsilyloxy-
(2E)-buten-1-yl]-N-methyl}amide (4f): Allylamide 4f (456 mg,
1.18 mmol, Ͼ99%) was obtained as a colorless oil as a mixture of
rotamers from 3b (330 mg, 1.53 mmol) and Boc-Sar-OH (223 mg,
1.18 mmol). The reaction was carried out in ethyl acetate (2 mL),
and T3P (1.05 mL, 1.77 mmol) in combination with diisopropyl-
amine (618 μL, 3.54 mmol) was used as coupling reagent. Flash
chromatography (hexanes/ethyl acetate, 9:1 to 1:1). HRMS (CI):
calcd. for C19H39N2O4Si [M + H]+ 387.2634; found 387.2664.
C19H38N2O4Si (386.60): calcd. C 59.03, H 9.91, N 7.25; found C
59.36, H 9.70, N 7.48.
1
Minor Rotamer (selected signals): H NMR (CDCl3): δ = 7.14 (d,
J = 7.2 Hz, 2 H, 3-H), 4.44 (s, 2 H, 5-H), 4.00 (d, J = 5.2 Hz, 2 H,
6-H), 1.43 (s, 9 H, 17-H), 0.89 (s, 9 H, 12-H), 0.05 (s, 6 H, 10-
H) ppm. 13C NMR (CDCl3): δ = 135.7 (s, C-4), 133.6 (d, C-8),
129.0 (d, C-2), 127.8 (d, C-1), 126.4 (d, C-3), 123.8 (d, C-7), 62.9
(t, C-9), 49.0 (t, C-5), 47.0 (t, C-6), 42.4 (t, C-14), –5.27 (q, C-
10) ppm.
N-tert-Butyloxycarbonyl-β-alanyl-{N-benzyl-N-[4-tert-butyldimeth-
Major Rotamer: 1H NMR (CDCl3): δ = 5.70–5.55 (m, 2 H, 7-H, 8-
ylsilyloxy-(2E)-buten-1-yl]}amide (4d): Allylamide 4d (3.16 g, H), 4.16 (m, 2 H, 9-H), 4.03–3.95 (m, 4 H, 4-H, 6-H), 2.91–2.89
6.80 mmol, 85%) was obtained as a colorless oil as a mixture of
rotamers according to the general procedure for peptide couplings
from 3a (2.33 g, 8.00 mmol), Boc-β-Ala-OH (1.67 g, 8.80 mmol),
BEP (1.67 g, 8.80 mmol), and diisopropylamine (2.07 g,
16.0 mmol) after flash chromatography (hexanes/ethyl acetate, 8:2
(m, 6 H, 13-H, 14-H), 1.45 (s, 9 H, 1-H), 0.89 (s, 9 H, 12-H), 0.05
(s, 6 H, 10-H) ppm. 13C NMR (CDCl3): δ = 168.2 (s, C-5), 156.3
(s, C-3), 133.0 (d, C-8), 124.5 (d, C-7), 79.8 (s, C-2), 63.1 (t, C-9),
50.2 (t, C-6), 49.0 (t, C-4), 35.5, 33.6 (2q, C-13, C-14), 28.3 (q, C-
1), 25.9 (q, C-12), 18.3 (s, C-11), –5.31 (q, C-10) ppm.
Eur. J. Org. Chem. 2014, 1695–1707
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1701

S. Thies, U. Kazmaier
FULL PAPER
Minor Rotamer (selected signals): H NMR (CDCl3): δ = 3.85 (d,
1
group cleavage, alcohol 5c (1.50 g, 4.49 mmol, 82%) was obtained
3J6,7 = 8.4 Hz, 2 H, 6-H), 1.41 (s, 9 H, 1-H), 0.89 (s, 9 H, 12-H), from 4c (2.47 g, 5.50 mmol) after flash chromatography (hexanes/
0.05 (s, 6 H, 10-H) ppm. 13C NMR (CDCl3): δ = 168.6 (s, C-5), ethyl acetate, 3:7 to EE) as a yellow oil as a mixture of rotamers.
155.7 (s, C-3), 132.1 (d, C-8), 123.7 (d, C-7), 79.7 (s, C-2), 62.8 (t, HRMS (CI): calcd. for C18H27N2O4 [M]+ 335.1965; found
C-9), 50.4 (t, C-6), 49.2 (t, C-4), 35.6, 33.5 (2q, C-13, C-14), 25.9
(q, C-12), 18.4 (s, C-11), –5.25 (q, C-10) ppm.
335.1969.
Major Rotamer: 1H NMR (CDCl3): δ = 7.37–7.27 (m, 3 H, 1-H, 2-
H), 7.22 (d, J = 6.7 Hz, 2 H, 3-H), 5.77–5.54 (m, 3 H, 7-H, 8-H,
NH), 4.61 (s, 2 H, 5-H), 4.16 (m, 2 H, 9-H), 4.04–4.02 (m, 4 H, 6-
H, 11-H), 1.64 (s, 1 H, OH), 1.45 (s, 9 H, 14-H) ppm. 13C NMR
(CDCl3): δ = 168.8 (s, C-10), 155.9 (s, C-12), 136.7 (s, C-4), 132.5
(d, C-8), 128.6 (d, C-2), 128.2 (d, C-3), 127.6 (d, C-1), 124.6 (d, C-
7), 79.7 (s, C-13), 62.4 (t, C-9), 48.9 (t, C-5), 47.2 (t, C-6), 42.2 (t,
C-11), 28.3 (q, C-14) ppm.
N-tert-Butyloxycarbonyl-sarcosyl-{N-4-[tert-butyldimethylsilyloxy-
(2E)-buten-1-yl]-N-(2-tetrahydropyran-2-yloxyethyl)}amide (4g):
Allylamide 4g (6.59 g, 13.2 mmol, 94%) was obtained as a colorless
oil as a mixture of three rotamers according to the general pro-
cedure for peptide couplings from 3c (4.66 g, 14.1 mmol), Boc-Sar-
OH (2.94 g, 15.6 mmol), BEP (4.27 g, 15.6 mmol) and diisopropyl-
amine (4.93 mL, 28.2 mmol) after flash chromatography (hexanes/
1
1
ethyl acetate, 9:1 to 6:4). H NMR (CDCl3): δ = 5.72–5.60 (m, 2
Minor Rotamer (selected signals): H NMR (CDCl3): δ = 7.15 (d,
H, 9-H, 10-H), 4.58 (dd, J = 3.9, 3.1 Hz, 1 H, 5-H), 4.19–3.96 (m,
6 H, 8-H, 11-H, 16-H), 3.83 (m, 2 H, 6-H), 3.63 (m, 1 H, 1-Ha),
3.51–3.48 (m, 3 H, 1-Hb, 7-H), 2.93, 2.90 (s, 3 H, 20-H), 1.81–1.70
(m, 2 H, 3-Ha, 4-Ha), 1.59–1.47 (m, 13 H, 2-H, 3-Hb, 4-Hb, 19-H),
1.43 (s, 9 H, 19-H), 0.92, 0.91 (s, 9 H, 14-H), 0.08, 0.07 (s, 6 H, 12-
H) ppm. 13C NMR (CDCl3): δ = 168.9, 168.8, 168.6 (s, C-15),
156.3, 156.2 (s, C-17), 132.7, 131.9, 131.7 (d, C-10), 125.0, 124.4,
124.2 (d, C-9), 99.0, 98.9 (d, C-5), 79.7 (s, C-18), 65.9, 65.8, 65.0,
63.2, 63.1, 63.0, 62.9, 62.7, 62.4, 62.3, 62.2, 62.1 (3t, C-1, C-6, C-
11), 50.7, 50.0, 49.9, 49.7, 49.6, 47.0 (2t, C-8, C-16), 46.2, 46.1, 45.9
(t, C-7), 35.7, 35.6, 35.4 (q, C-20), 30.6, 30.4 (t, C-4), 28.4 (q, C-
19), 25.9 (q, C-14), 25.4, 25.3 (t, C-2), 19.5, 19.4, 19.3 (t, C-3),
18.4 (s, C-13), –5.24, –5.29 (q, C-12) ppm. HRMS (CI): calcd. for
C25H49N2O6Si [M + H]+ 501.3315; found 501.3338. C25H48N2O6Si
(500.74): calcd. C 59.96, H 9.66, N 5.59; found C 60.09, H 9.51, N
5.61.
J = 7.3 Hz, 2 H, 3-H), 4.61 (s, 2 H, 5-H), 3.80 (d, J = 4.4 Hz, 2 H,
6-H), 1.44 (s, 9 H, 14-H) ppm. 13C NMR (CDCl3): δ = 168.7 (s, C-
10), 155.7 (s, C-12), 135.6 (s, C-4), 132.9 (d, C-8), 129.0 (d, C-2),
127.8 (d, C-1), 126.4 (d, C-3), 125.3 (d, C-7), 79.6 (s, C-13), 62.6
(t, C-9), 49.3 (t, C-5), 47.1 (t, C-6), 42.3 (t, C-11) ppm.
N-tert-Butyloxycarbonyl-β-alanyl-{N-benzyl-N-[4-hydroxy-(2E)-
buten-1-yl]}amide (5d): According to the general procedure for silyl
group cleavage, alcohol 5d (1.48 g, 4.25 mmol, 85%) was obtained
from 4d (2.31 g, 5.00 mmol) after flash chromatography (hexanes/
ethyl acetate, 1:1 to ethyl acetate) as a yellow oil as a mixture of
rotamers. HRMS (CI): calcd. for C19H29N2O4 [M + H]+ 349.2083;
found 349.2082. C19H28N2O4 (348.44): calcd. C 65.49, H 8.10, N
8.04; found C 64.90, H 8.34, N 7.93.
Major Rotamer: 1H NMR (CDCl3): δ = 7.37–7.27 (m, 3 H, 1-H, 2-
H), 7.22 (d, J = 6.6 Hz, 2 H, 3-H), 5.75–5.55 (m, 2 H, 7-H, 8-H),
5.31 (br. s, 1 H, NH), 4.60 (s, 2 H, 5-H), 4.13 (d, J = 3.8 Hz, 2 H,
9-H), 3.83 (dd, J = 5.1, 1.1 Hz, 2 H, 6-H), 3.44 (m, 2 H, 11-H),
2.58 (m, 2 H, 12-H), 1.63 (s, 1 H, OH), 1.43, 1.42 (s, 9 H, 15-
H) ppm. 13C NMR (CDCl3): δ = 171.9 (s, C-10), 156.0 (s, C-13),
137.3 (s, C-4), 132.2 (d, C-8), 128.6 (d, C-2), 128.1 (d, C-3), 127.4
(d, C-1), 126.0 (d, C-7), 79.2 (s, C-14), 62.5 (t, C-9), 48.5 (t, C-5),
46.8 (t, C-6), 36.6 (t, C-11), 33.1 (t, C-12), 28.4 (q, C-15) ppm.
Cleavage of the Silyl Protecting Group. General Procedure: The sil-
ylated allyl amide 4 was dissolved in anhydrous THF (1 mL/mmol)
then a solution of tetrabutylammoniumfluoride (1.5 equiv.) in an-
hydrous THF (7 ml/mmol) was added. After stirring for 30 min and
complete consumption of the starting material (TLC), the solvent
was removed in vacuo and the crude product was purified by flash
chromatography.
1
Minor Rotamer (selected signals): H NMR (CDCl3): δ = 7.13 (d,
J = 7.1 Hz, 2 H, 3-H), 4.49 (s, 2 H, 5-H), 4.01 (d, J = 4.2 Hz, 2 H,
6-H), 1.43, 1.42 (s, 9 H, 15-H) ppm. 13C NMR (CDCl3): δ = 168.7
(s, C-10), 155.7 (s, C-12), 136.3 (s, C-4), 132.5 (d, C-8), 128.9 (d,
C-2), 127.7 (d, C-1), 126.3 (d, C-3), 125.4 (d, C-7), 62.8 (t, C-9),
50.1 (t, C-5), 48.2 (t, C-6), 36.3 (t, C-11), 33.4 (t, C-12) ppm.
N-Trifluoroacetyl-glycyl-{N-benzyl-N-[4-hydroxy-(2E)-buten-1-
yl]}amide (5b): According to the general procedure for silyl group
cleavage, alcohol 5b (639 mg, 1.93 mmol, 93%) was obtained from
4b (923 mg, 2.08 mmol) after flash chromatography (hexanes/ethyl
acetate, 3:7 to ethyl acetate) as a colorless oil as a mixture of rota-
mers. HRMS (CI): calcd. for C15H17F3N2O3 [M]+ 330.1191; found
330.1155. C15H17F3N2O3 (330.30): calcd. C 54.54, H 5.19, N 8.48;
found C 54.33, H 5.38, N 8.52.
N-tert-Butyloxycarbonyl-sarcosyl-{N-benzyl-N-[4-hydroxy-(2E)-
buten-1-yl]}amide (5e): According to the general procedure for silyl
group cleavage, alcohol 5e (3.30 g, 9.48 mmol, 93%) was obtained
from 4e (4.71 g, 10.2 mmol) after flash chromatography (hexanes/
ethyl acetate, 1:1 to ethyl acetate) as a yellow oil as a mixture of
Major Rotamer: 1H NMR (CDCl3): δ = 7.62 (br. s, 1 H, NH), 7.40–
7.30 (m, 3 H, 1-H, 2-H), 7.26 (m, 2 H, 3-H), 5.80–5.60 (m, 2 H, 7-
H, 8-H), 4.64 (s, 2 H, 5-H), 4.21–4.12 (m, 4 H, 9-H, 11-H), 3.83
(dd, J = 5.2, 1.3 Hz, 2 H, 6-H), 1.58 (s, 1 H, OH) ppm. 13C NMR
(CDCl3): δ = 166.5 (s, C-10), 157.0 (q, J12;F = 37.9 Hz, C-12), 136.1
(s, C -4), 132.6 (d, C-8), 128.8 (d, C-2), 128.2 (d, C-3), 127.9 (d, C-
1), 123.8 (d, C-7), 115.5 (q, J13,F = 287.0 Hz, C-13), 62.2 (t, C-9),
49.1 (t, C-5), 47.3 (t, C-6), 41.3 (t, C-11) ppm.
1
three rotamers. H NMR (CDCl3): δ = 7.37–7.29 (m, 3 H, 1-H, 2-
H), 7.25, 7.17 (m, 2 H, 3-H), 5.78–5.58 (m, 2 H, 7-H, 8-H), 4.59,
4.50, 4.46 (s, 2 H, 5-H), 4.12–3.81 (m, 6 H, 6-H, 9-H, 11-H), 2.98,
2.96, 2.94 (s, 3 H, 15-H), 1.46, 1.42 (s, 9 H, 14-H) ppm. 13C NMR
(CDCl3): δ = 169.2, 168.7, 168.5 (s, C-10), 156.2, 155.7 (s, C-12),
137.1, 136.1 (s, C-4), 132.8, 132.5, 132.0 (d, C-8), 128.9, 128.5 (d,
C-2), 128.2 (d, C-3), 127.7, 127.6, 127.4 (d, C-1), 126.4, 126.2 (d,
C-3), 125.6, 125.3, 124.9 (d, C-7), 80.0, 79.9 (s, C-13), 62.6, 62.5,
62.3 (t, C-9), 50.8, 50.7, 50.0, 49.6, 49.3, 48.9, 48.7, 47.4, 47.3, 47.2
(3t, C-5, C-6, C-11), 35.9, 35.7, 35.6 (q, C-15), 28.3 (q, C-14) ppm.
HRMS (CI): calcd. for C19H28N2O4 [M]+ 348.2049; found
348.2066. C19H28N2O4 (348.44): calcd. C 65.49, H 8.10, N 8.04;
found C 64.79, H 8.10, N 7.91.
1
Minor Rotamer (selected signals): H NMR (CDCl3): δ = 7.58 (br.
s, 1 H, NH), 7.17 (d, J = 7.1 Hz, 2 H, 3-H), 4.48 (s, 2 H, 5-H),
4.07 (d, J = 5.8 Hz, 2 H, 6-H) ppm. 13C NMR (CDCl3): δ = 156.9
(q, J12,F = 37.5 Hz, C-12), 134.8 (s, C-4), 133.4 (d, C-8), 129.2 (d,
C-2), 128.2 (d, C-1), 126.3 (d, C-3), 124.6 (d, C-7), 62.5 (t, C-9),
49.4 (t, C-5), 47.5 (t, C-6), 41.4 (t, C-11) ppm.
N-tert-Butyloxycarbonyl-glycyl{N-benzyl-N-[4-hydroxy-(2E)-
buten-1-yl]}amide (5c): According to the general procedure for silyl
N-tert-Butyloxycarbonyl-sarcosyl-{N-[4-hydroxy-(2E)-buten-1-yl]-
N-methyl}amide (5f): According to the general procedure for silyl
1702
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1695–1707

Synthesis of α-Amino-γ-lactams
group cleavage, alcohol 5f (265 mg, 0.97 mmol, 84%) was obtained
from 4f (450 mg, 1.16 mmol) after flash chromatography (hexanes/
H, 8-H), 4.63–4.58 (m, 4 H, 5-H, 9-H), 4.24–4.15 (m, 4 H, 11-H,
14-H), 3.82 (dd, J = 3.6, 3.6 Hz, 2 H, 6-H), 1.33 (t, J = 7.1 Hz, 3
ethyl acetate, 1:1 to ethyl acetate) as a yellow oil as a mixture of H, 12-H) ppm. 13C NMR (CDCl3): δ = 166.5 (s, C-13), 156.9 (q,
rotamers. HRMS (CI): calcd. for C13H24N2O4 [M]+ 272.1736; J15,F = 37.9 Hz, C-15), 154.8 (s, C-10), 136.0 (s, C-4), 128.9 (d, C-
found 272.1730.
2), 128.3 (d, C-3), 128.0 (d, C-8), 127.9 (d, C-1), 127.7 (d, C-7),
66.5 (t, C-9), 64.2 (t, C-11), 49.1 (t, C-5), 46.9 (t, C-6), 41.3 (t, C-
14), 14.2 (q, C-12), (C-16 not detected) ppm.
1
Major Rotamer: H NMR (CDCl3): δ = 5.78 (m, 1 H, 8-H), 5.65
(m, 1 H, 7-H), 4.16 (br. s, 2 H, 9-H), 4.04–3.97 (m, 4 H, 4-H, 6-
H), 2.94–2.92 (m, 6 H, 10-H, 11-H), 1.69 (t, J = 5.2 Hz, 1 H, OH),
1.45 (s, 9 H, 1-H) ppm. 13C NMR (CDCl3): δ = 168.3 (s, C-5),
156.3 (s, C-3), 132.5 (d, C-8), 125.9 (d, C-7), 79.9 (s, C-2), 62.8 (t,
C-9), 50.2 (t, C-6), 49.1 (t, C-4), 35.6, 33.8 (2q, C-10, C-11), 28.3
(q, C-1) ppm.
1
Minor Rotamer (selected signals): H NMR (CDCl3): δ = 7.55 (br.
s, 1 H, NH), 7.13 (d, J = 7.0 Hz, 2 H, 3-H), 4.46 (s, 2 H, 5-H),
4.07 (d, J = 5.5 Hz, 2 H, 6-H), 1.31 (t, J = 7.1 Hz, 3 H, 12-H) ppm.
13C NMR (CDCl3): δ = 134.7 (s, C-4), 129.3 (d, C-2), 128.4 (d, C-
8), 127.3 (d, C-7), 126.4 (d, C-1), 126.3 (d, C-3), 66.9 (t, C-9), 64.3
(t, C-11), 49.4 (t, C-5), 47.3 (t, C-6), 41.4 (t, C-14) ppm.
1
Minor Rotamer (selected signals): H NMR (CDCl3): δ = 3.87 (br.
s, 2 H, 6-H), 1.75 (br. s, 1 H, OH), 1.42 (s, 9 H, 1-H) ppm. 13C
NMR (CDCl3): δ = 156.2 (s, C-3), 131.8 (d, C-8), 125.3 (d, C-7),
62.6 (t, C-9), 50.4 (t, C-6), 50.0 (t, C-4), 35.8, 34.0 (2q, C-10, C-
11) ppm.
N-tert-Butyloxycarbonyl-glycyl-{N-benzyl-N-[4-ethoxycarbonyl-
oxy-(2E)-buten-1-yl]}amide (6c): According to the general pro-
cedure for allyl carbonate formation, 6c (1.53 g, 3.76 mmol, 96%)
was obtained from 5c (1.31 g, 3.92 mmol) after flash chromatog-
raphy (hexanes/ethyl acetate, 7:3 to 6:4) as a colorless oil as a mix-
ture of rotamers. HRMS (CI): calcd. for C21H31N2O6 [M + H]+
407.2137; found 407.2206. C21H30N2O6 (406.47): calcd. C 62.05, H
7.44, N 6.89; found C 61.93, H 7.64, N 6.95.
Major Rotamer: 1H NMR (CDCl3): δ = 7.37–7.27 (m, 3 H, 1-H, 2-
H), 7.21 (d, J = 6.6 Hz, 2 H, 3-H), 5.78–5.53 (m, 2 H, 7-H, 8-H),
5.53 (br. s, 1 H, NH), 4.60–4.58 (m, 4 H, 5-H, 9-H), 4.22 (q, J =
7.1 Hz, 2 H, 11-H), 4.04–4.00 (m, 4 H, 6-H, 14-H), 1.46 (s, 9 H,
17-H), 1.32 (t, J = 7.1 Hz, 3 H, 12-H) ppm. 13C NMR (CDCl3): δ
= 168.7 (s, C-13), 155.7 (s, C-15), 154.8 (s, C-10), 136.6 (s, C-4),
128.7 (d, C-2), 128.2 (d, C-3), 129.2, 127.9 (2d, C-1, C-8), 126.8 (d,
C-7), 79.6 (s, C-16), 66.7 (t, C-9), 64.2 (t, C-11), 48.6 (t, C-5), 46.9
(t, C-6), 42.2 (t, C-14), 28.3 (q, C-17), 14.2 (q, C-12) ppm.
N-tert-Butyloxycarbonyl-sarcosyl-{N-[4-hydroxy-(2E)-buten-1-yl]-
N-(2-tetrahydropyran-2-yloxyethyl)}amide (5g): According to the
general procedure for silyl group cleavage, alcohol 5g (3.82 g,
9.89 mmol, 99%) was obtained from 4g (5.00 g, 10.0 mmol) after
flash chromatography (hexanes/ethyl acetate, 1:1 to ethyl acetate)
as a yellow oil as a mixture of rotamers. HRMS (CI): calcd. for
C
19H35N2O6 [M + H]+ 387.2450; found 387.2425. C19H34N2O6
(386.48): calcd. C 59.05, H 8.87, N 7.25; found C 59.04, H 8.92, N
6.87.
Major Rotamer: 1H NMR (CDCl3): δ = 5.77–5.66 (m, 2 H, 9-H,
10-H), 4.55 (br. s, 1 H, 5-H), 4.15–3.95 (m, 6 H, 8-H, 11-H, 13-H),
3.82 (m, 2 H, 6-H), 3.61 (m, 1 H, 1-Ha), 3.54–3.46 (m, 3 H, 1-Hb,
7-H), 2.90 (s, 3 H, 17-H), 1.78–1.67 (m, 2 H, 3-Ha, 4-Ha), 1.53–
1.49 (m, 4 H, 2-H, 3-Hb, 4-Hb), 1.43 (s, 9 H, 16-H) ppm. 13C NMR
(CDCl3): δ = 169.1 (s, C-12), 156.3 (s, C-14), 132.1 (d, C-10), 126.2
(d, C-9), 99.0 (d, C-5), 79.8 (s, C-15), 65.9, 62.7, 62.4 (3t, C-1, C-
6, C-11), 50.7, 50.1, 49.6, 47.5 (2t, C-8, C-13), 46.4 (t, C-7), 35.7
(q, C-17), 30.4 (t, C-4), 28.3 (q, C-16), 25.3 (t, C-2), 19.6 (t, C-
3) ppm.
Minor Rotamer (selected signals): 1H NMR (CDCl3): δ = 1.41 (s, 9
H, 16-H) ppm. 13C NMR (CDCl3): δ = 168.9 (s, C-12), 156.2 (s,
C-14), 131.7 (d, C-10), 126.6 (d, C-9), 99.1 (d, C-5), 80.0 (s, C-15),
62.8, 62.6, 62.3 (3t, C-1, C-6, C-11), 50.6, 49.9, 49.8, 47.4 (2t, C-8,
C-13), 46.6 (t, C-7), 35.6 (q, C-17), 30.6 (t, C-4), 25.2 (t, C-2), 19.3
(t, C-3) ppm.
1
Minor Rotamer (selected signals): H NMR (CDCl3): δ = 7.13 (d,
J = 7.2 Hz, 2 H, 3-H), 5.50 (br. s, 1 H, NH), 4.43 (s, 2 H, 5-H),
4.20 (q, J = 7.1 Hz, 2 H, 11-H), 3.79 (br. s, 2 H, 6-H), 1.44 (s, 9 H,
17-H), 1.31 (t, J = 7.1 Hz, 3 H, 12-H) ppm. 13C NMR (CDCl3): δ
= 135.4 (s, C-4), 128.4, 127.7 (2d, C-1, C-8), 129.1 (d, C-2), 127.2
(d, C-7), 126.4 (d, C-3), 67.1 (t, C-9), 64.1 (t, C-11), 49.3 (t, C-5),
46.9 (t, C-6), 42.3 (t, C-14) ppm.
N-tert-Butyloxycarbonyl-β-alanyl-{N-benzyl-N-[4-ethoxycarbonyl-
oxy-(2E)-buten-1-yl]}amide (6d): According to the general pro-
cedure for allyl carbonate formation, 6d (1.46 g, 3.47 mmol, 94%)
was obtained from 5d (1.29 g, 3.70 mmol) after flash chromatog-
raphy (hexanes/ethyl acetate, 7:3 to 6:4) as a colorless oil as a mix-
ture of rotamers. HRMS (CI): calcd. for C22H33N2O6 [M + H]+
421.2294; found 421.2338. C22H32N2O6 (420.50): calcd. C 62.84, H
7.67, N 6.66; found C 62.78, H 8.00, N 6.72.
Major Rotamer: 1H NMR (CDCl3): δ = 7.36–7.28 (m, 3 H, 1-H, 2-
H), 7.20 (d, J = 6.8 Hz, 2 H, 3-H), 5.78–5.60 (m, 2 H, 7-H, 8-H),
5.32 (br. s, 1 H, NH), 4.60–4.58 (m, 4 H, 5-H, 9-H), 4.21 (q, J =
7.1 Hz, 2 H, 11-H), 4.01 (d, J = 5.8 Hz, 2 H, 6-H), 3.87 (br. s, 2
H, 6-H), 3.44 (t, J = 5.8 Hz, 2 H, 14-H), 2.56 (t, J = 5.5 Hz, 2 H,
15-H), 1.42 (s, 9 H, 18-H), 1.32 (t, J = 7.1 Hz, 3 H, 12-H) ppm.
13C NMR (CDCl3): δ = 172.0 (s, C-13), 156.0 (s, C-16), 154.9 (s,
C-10), 137.1 (s, C-4), 129.1 (d, C-8), 128.6 (d, C-2), 128.1 (d, C-3),
127.5 (d, C-1), 126.3 (d, C-7), 79.1 (s, C-17), 66.8 (t, C-9), 64.2 (t,
C-11), 48.2 (t, C-5), 47.8 (t, C-6), 36.3 (t, C-14), 33.4 (t, C-15), 28.4
(q, C-18), 14.2 (q, C-12) ppm.
Synthesis of Allyl Carbonates. General Procedure: A solution of
allyl alcohol 5 and pyridine (2.5 equiv.) in dichloromethane
(0.7 mL/mmol) was cooled to 0 °C before ethyl chloroformate
(1.2 equiv.) was added. The mixture was warmed to room tempera-
ture overnight, then 1 n KHSO4 (3 mL/mmol) was added and the
aqueous layer was extracted thrice with dichloromethane. The com-
bined organic layers were washed with 1M CuSO4, H2O and brine,
dried (Na2SO4), and the solvents evaporated in vacuo. The crude
product was purified by flash chromatography.
N-Trifluoroacetyl-glycyl-{N-benzyl-N-[4-ethoxycarbonyloxy-(2E)-
buten-1-yl]}amide (6b): According to the general procedure for allyl
carbonate formation, 6b (706 mg, 1.76 mmol, 96%) was obtained
from 5b (608 mg, 1.84 mmol) after flash chromatography (hexanes/
ethyl acetate, 7:3 to 6:4) as a colorless oil as a mixture of rotamers.
HRMS (CI): calcd. for C18H22F3N2O5 [M + H]+ 403.1436; found
403.1468. C18H21F3N2O5 (402.36): calcd. C 53.73, H 5.26, N 6.96;
found C 53.93, H 5.34, N 87.01.
1
Minor Rotamer (selected signals): H NMR (CDCl3): δ = 7.11 (d,
J = 7.2 Hz, 2 H, 3-H), 4.47 (s, 2 H, 5-H), 4.19 (q, J = 7.1 Hz, 2 H,
11-H), 3.44 (t, J = 5.8 Hz, 2 H, 14-H), 1.43 (s, 9 H, 18-H), 1.31 (t,
J = 7.1 Hz, 3 H, 12-H) ppm. 13C NMR (CDCl3): δ = 171.8 (s, C-
13), 154.8 (s, C-10), 136.1 (s, C-4), 129.9 (d, C-8), 129.0 (d, C-2),
Major Rotamer: 1H NMR (CDCl3): δ = 7.58 (br. s, 1 H, NH), 7.40–
7.30 (m, 3 H, 1-H, 2-H), 7.22 (m, 2 H, 3-H), 5.79–5.65 (m, 2 H, 7-
Eur. J. Org. Chem. 2014, 1695–1707
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1703

S. Thies, U. Kazmaier
FULL PAPER
127.7 (d, C-1), 126.8 (d, C-7), 126.3 (d, C-3), 67.2 (t, C-9), 64.1 (t,
C-11), 50.0 (t, C-5), 46.5 (t, C-6), 36.4 (t, C-14), 33.2 (t, C-15) ppm.
Minor Rotamer (selected signals): 1H NMR (CDCl3): δ = 2.86 (s, 3
H, 20-H), 1.39 (s, 9 H, 19-H), 1.28 (t, J = 7.1 Hz, 3 H, 14-H) ppm.
13C NMR (CDCl3): δ = 168.7 (s, C-15), 156.0 (s, C-17), 154.8 (s,
C-12), 130.0 (d, C-10), 125.8 (d, C-9), 99.0 (d, C-5), 79.8 (s, C-18),
67.0 (t, C-11), 65.9, 62.1 (2t, C-1, C-6), 64.1 (t, C-13), 50.0, 49.6
(2t, C-8, C-16), 47.1 (t, C-7), 35.5 (q, C-20), 30.4 (t, C-4), 28.4 (q,
C-19), 25.2 (t, C-2), 19.5 (t, C-3) ppm.
N-tert-Butyloxycarbonyl-sarcosyl-{N-benzyl-N-[4-ethoxycarbonyl-
oxy-(2E)-buten-1-yl]}amide (6e): According to the general pro-
cedure for allyl carbonate formation, 6e (1.14 g, 2.71 mmol, 90%)
was obtained from 5e (1.05 g, 3.00 mmol) after flash chromatog-
raphy (hexanes/ethyl acetate, 7:3 to 6:4) as a colorless oil as a mix-
1
ture of three rotamers. H NMR (CDCl3): δ = 7.37–7.30 (m, 3 H,
N-tert-Butyloxycarbonyl-sarcosyl-{N-[4-ethoxycarbonyloxy-(2E)-
buten-1-yl]-N-(2-hydroxyethyl)}amide (6h): THP-protected alcohol
6g (1.20 g, 2.61 mmol) was dissolved in methanol (20 mL), p-tolu-
enesulfonic acid (20 mg, 0.1 mmol) was added and, after stirring
for 30 min, when all 6g was consumed (TLC), solid NaHCO3
(420 mg, 5 mmol) was added. After evaporation of the solvent, the
residue was dissolved in ethyl acetate and water was added. The
aqueous layer was extracted thrice with diethyl ether, the combined
organic layers were dried (Na2SO4), the solvent was removed in
vacuo, and the crude product was purified by flash chromatography
(hexanes/ethyl acetate, 1:1 to ethyl acetate) to give 6h (835 mg,
2.23 mmol, 85%) as a colorless oil as a mixture of rotamers. HRMS
(CI): calcd. for C17H31N2O7 [M + H]+ 375.2131; found 375.2122.
3
1-H, 2-H), 7.23 (m, 2 H, 3-H), 7.15 (d, J3,2 = 7.4 Hz, 2 H, 3-H),
5.80–5.61 (m, 2 H, 7-H, 8-H), 4.60–4.44 (m, 4 H, 5-H, 9-H), 4.21,
3
4.19 (q, J11,12 = 7.1 Hz, 2 H, 11-H), 4.08–3.98 (m, 4 H, 6-H, 14-
H), 3.84, 3.80 (br. s, 2 H, 6-H), 2.92, 2.90, 2.95 (s, 3 H, 18-H), 1.42
3
(s, 9 H, 17-H), 1.32, 1.30 (t, J12,11 = 7.1 Hz, 3 H, 12-H) ppm. 13C
NMR (CDCl3): δ = 169.0 (s, C-13), 156.2 (s, C-15), 154.8 (s, C-10),
137.0, 136.1 (s, C-4), 129.7, 129.3, 128.9, 128.3, 127.7, 127.6, 127.4,
127.0, 126.4, 126.2 (5d, C-1, C-2, C-3, C-7, C-8), 79.9 (s, C-16),
67.2, 66.9 (t, C-9), 64.2, 64.1, 64.0 (t, C-11), 50.2, 50.0, 49.6 (t, C-
14), 49.3, 48.8, 48.6 (t, C-5), 47.3, 47.0, 46.9 (t, C-6), 35.6 (q, C-
18), 28.3 (q, C-17), 14.2 (q, C-12) ppm. HRMS (CI): calcd. for
C22H32N2O6 [M]+ 420.2260; found 420.2224. C22H32N2O6 (420.50):
calcd. C 62.84, H 7.67, N 6.66; found C 62.65, H 7.73, N 6.61.
C
17H30N2O7 (374.43): calcd. C 54.53, H 8.08, N 7.48; found C
54.54, H 7.99, N 7.53.
N-tert-Butyloxycarbonyl-sarcosyl-{N-methyl-N-[4-ethoxycarbonyl-
oxy-(2E)-buten-1-yl]}amide (6f): According to the general pro-
cedure for allyl carbonate formation, 6f (271 mg, 0.79 mmol, 85%)
was obtained from 5f (252 mg, 0.93 mmol) after flash chromatog-
raphy (hexanes/ethyl acetate, 9:1 to 3:7) as a colorless oil as a mix-
ture of rotamers. HRMS (CI): calcd. for C12H20N2O6 [M – tBu]+
288.1321; found 288.1285. C16H28N2O6 (344.40): calcd. C 55.80, H
8.19, N 8.13; found C 55.79, H 8.09, N 8.18.
Major Rotamer: 1H NMR (CDCl3): δ = 5.81–5.67 (m, 2 H, 4-H, 5-
H), 4.62 (d, J = 4.0 Hz, 2 H, 6-H), 4.20 (q, J = 7.1 Hz, 2 H, 8-H),
4.11–3.95 (m, 4 H, 3-H, 11-H), 3.75 (m, 2 H, 1-H), 3.51 (m, 2 H,
2-H), 3.03 (br. s, 1 H, OH), 2.91 (s, 3 H, 15-H), 1.45 (s, 9 H, 14-
H), 1.31 (t, J = 7.1 Hz, 3 H, 9-H) ppm. 13C NMR (CDCl3): δ =
170.6 (s, C-10), 156.2 (s, C-12), 154.8 (s, C-7), 130.4 (d, C-5), 126.4
(d, C-4), 80.1 (s, C-13), 67.3 (t, C-6), 64.1 (t, C-8), 61.6 (t, C-1),
50.1, 47.2 (2t, C-3, C-11), 50.0 (t, C-2), 35.6 (q, C-15), 28.3 (q, C-
14), 14.2 (q, C-9) ppm.
Major Rotamer: 1H NMR (CDCl3): δ = 5.78–5.67 (m, 2 H, 7-H, 8-
H), 4.60 (d, J = 8.4 Hz, 2 H, 9-H), 4.19 (q, J = 7.1 Hz, 2 H, 11-
H), 4.04–3.91 (m, 4 H, 4-H, 6-H), 2.92–2.90 (m, 6 H, 13-H, 14-H),
1.46 (s, 9 H, 1-H), 1.30 (t, J = 7.1 Hz, 3 H, 12-H) ppm. 13C NMR
(CDCl3): δ = 168.3 (s, C-5), 154.9, 154.8 (2s, C-3, C-10), 129.9 (d,
C-8), 126.7 (d, C-7), 79.9 (s, C-2), 67.2 (t, C-9), 64.1 (t, C-11), 50.2
(t, C-6), 48.9 (t, C-4), 35.6, 33.7 (2q, C-13, C-14), 28.3 (q, C-1),
14.2 (q, C-12) ppm.
1
Minor Rotamer (selected signals): H NMR (CDCl3): δ = 4.59 (d,
J = 5.6 Hz, 2 H, 6-H), 3.42 (m, 2 H, 2-H), 2.96 (s, 3 H, 15-H), 1.42
(s, 9 H, 14-H), 1.29 (t, J = 7.1 Hz, 3 H, 9-H) ppm. 13C NMR
(CDCl3): δ = 169.3 (s, C-10), 156.6 (s, C-12), 154.9 (s, C-7), 129.3
(d, C-5), 126.3 (d, C-4), 66.8 (t, C-6), 64.2 (t, C-8), 60.2 (t, C-1),
50.7, 49.6 (2t, C-3, C-11), 48.9 (t, C-2), 36.3 (q, C-15) ppm.
1
Minor Rotamer (selected signals): H NMR (CDCl3): δ = 4.66 (d,
N-tert-Butyloxycarbonyl-sarcosyl-{N-[4-benzoyloxy-(2E)-buten-1-
yl]-N-benzyl}amide (6i): Alcohol 5e (1.05 g, 3.00 mmol) was dis-
solved in dichloromethane (30 mL) together with pyridine (363 μL,
4.50 mmol) and the solution was cooled to 0 °C before DMAP
(37 mg, 0.30 mmol, 10 mol-%) and benzoyl chloride (519 μL,
4.50 mmol) were added. The mixture was warmed to room tem-
perature overnight, then 1N KHSO4 (10 mL) was added and the
aqueous layer was extracted thrice with dichloromethane. The com-
bined organic layers were washed with 1M CuSO4, H2O, and brine,
dried (Na2SO4), and the solvents evaporated in vacuo. The crude
product was purified by flash chromatography (hexanes/ethyl acet-
ate, 8:2 to 7:3) to give 6i (1.38 g, 2.95 mmol, 98%) as a colorless
J = 8.7 Hz, 2 H, 9-H), 4.20 (q, J = 7.1 Hz, 2 H, 11-H), 1.42 (s, 9
H, 1-H) ppm. 13C NMR (CDCl3): δ = 129.6 (d, C-8), 126.2 (d, C-
7), 66.9 (t, C-9), 64.2 (t, C-11), 50.3 (t, C-6), 50.0 (t, C-4), 35.5,
33.8 (2q, C-13, C-14) ppm.
N-tert-Butyloxycarbonyl-sarcosyl-{N-[4-ethoxycarbonyloxy-(2E)-
buten-1-yl]-N-(2-tetrahydropyran-2-yloxyethyl)}amide (6g): Accord-
ing to the general procedure for allyl carbonate formation, 6g
(3.71 g, 8.09 mmol, 86%) was obtained from 5g (3.68 g, 9.52 mmol)
after flash chromatography (hexanes/ethyl acetate, 1:1 to 3:7) as
a colorless oil as a mixture of rotamers. HRMS (CI): calcd. for
C22H38N2O8 [M]+ 458.2628; found 458.2632. C22H38N2O8 (458.55):
calcd. C 57.62, H 8.35, N 6.11; found C 57.76, H 8.34, N 6.45.
1
oil as a mixture of three rotamers. H NMR (CDCl3): δ = 8.05 (d,
J = 7.5 Hz, 2 H, 12-H), 7.57 (d, J = 7.0 Hz, 1 H, 14-H), 7.45 (m,
Major Rotamer: 1H NMR (CDCl3): δ = 5.79–5.65 (m, 2 H, 9-H,
10-H), 4.60–4.53 (m, 3 H, 5-H, 11-H), 4.20–3.90 (m, 6 H, 8-H, 13- 2 H, 13-H), 7.36–7.16 (m, 5 H, 1-H, 2-H, 3-H), 5.85–5.70 (m, 2 H,
H, 16-H), 3.79 (m, 2 H, 6-H), 3.59 (m, 1 H, 1-Ha), 3.49–3.42 (m, 7-H, 8-H), 4.80 (m, 2 H, 9-H), 4.52, 4.47, 4.61 (s, 2 H, 5-H), 4.11–
3 H, 1-Hb, 7-H), 2.89 (s, 3 H, 20-H), 1.76–1.66 (m, 2 H, 3-Ha, 4- 4.01 (m, 4 H, 6-H, 16-H), 3.88, 3.84 (br. s, 2 H, 6-H), 2.95 (s, 3 H,
Ha), 1.54–1.50 (m, 4 H, 2-H, 3-Hb, 4-Hb), 1.43 (s, 9 H, 19-H), 1.27
20-H), 1.47, 1.43, 1.41 (s, 9 H, 19-H) ppm. 13C NMR (CDCl3): δ
(t, J = 7.1 Hz, 3 H, 14-H) ppm. 13C NMR (CDCl3): δ = 169.0 (s, = 169.1, 169.0 (s, C-15), 166.2, 166.1 (s, C-10), 156.2, 155.7 (s, C-
C-15), 156.3 (s, C-17), 154.8 (s, C-12), 130.4 (d, C-10), 126.2 (d, C- 17), 137.1, 137.0, 136.2 (s, C-4), 133.2, 133.1, 133.0 (d, C-14), 130.0
9), 98.9 (d, C-5), 79.7 (s, C-18), 67.3 (t, C-11), 65.0, 62.3 (2t, C-1, (s, C-11), 129.6, 129.0, 128.9, 128.7, 128.6, 128.5, 128.4, 128.3,
C-6), 64.0 (t, C-13), 50.6, 49.9 (2t, C-8, C-16), 46.2 (t, C-7), 35.7 127.7, 127.6, 127.4, 127.0, 126.5, 126.3 (6d, C-1, C-2, C-3, C-7, C-
(q, C-20), 30.6 (t, C-4), 28.3 (q, C-19), 25.3 (t, C-2), 19.3 (t, C-3),
14.2 (q, C-14) ppm.
8, C-13), 79.9 (s, C-18), 64.4, 64.2, 64.1 (t, C-9), 50.8, 50.7, 50.2 (t,
C-16), 49.7, 49.5, 49.0, 48.8 (t, C-5), 47.5, 47.4, 47.2, 47.1 (t, C-6),
1704
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1695–1707

Synthesis of α-Amino-γ-lactams
35.8, 35.7, 35.6 (q, C-20), 28.3 (q, C-19) ppm. HRMS (CI): calcd.
for C26H32N2O5 [M]+ 452.2311; found 452.2333.
0.44 mL, 0.70 mmol) was added to hexamethyldisilazane (157 μL,
0.76 mmol) in THF (2 mL) at –78 °C. After stirring 30 min at this
temperature, carbonate 6c (84 mg, 0.20 mmol) was added in THF
(2 mL) and the reaction mixture was stirred for 3 h before D2O
(1 mL) was added. The cooling bath was removed and the mixture
was warmed to room temperature and then diluted with diethyl
ether. The aqueous layer was extracted with diethyl ether, the com-
bined organic layers were dried (Na2SO4), and the solvents evapo-
rated in vacuo to give 8 (75 mg, 0.18 mmol, 90%) as a colorless oil
1-Benzyl-4-trifluoracetyl-5-vinylpiperazin-2-one (7b): Allylpalla-
dium chloride dimer (0.7 mg, 2.0 μmol, 2 mol-%) and tri-
phenylphosphine (2.4 mg, 9.0 μmol, 9 mol-%) were dissolved in
DMF (1 mL) and the solution was stirred at room temperature for
15 min. This solution was added to a solution of allyl carbonate 6b
(40 mg, 0.10 mmol) in DMF (2 mL) and the mixture was heated to
100 °C overnight. The solvent was removed in vacuo and the crude
product was purified by flash chromatography (hexanes/ethyl acet-
ate, 8:2 to 7:3) to give 7b (34 mg, 0.10 mmol, Ͼ99%) as a colorless
oil as a mixture of three rotamers. 1H NMR (CDCl3): δ = 7.38–
7.26 (m, 5 H, 1-H, 2-H, 3-H), 5.53 (ddd, J = 15.2, 10.5, 4.2 Hz, 1
H, 8-H), 5.32 (dd, J = 15.1, 1.4 Hz, 1 H, 9-Hcis), 5.29 (dd, J = 15.0,
1.1 Hz, 1 H, 9-Hcis), 5.24, 4.72 (br. s, 1 H, 7-H), 5.09 (d, J =
10.1 Hz, 1 H, 9-Htrans), 5.05 (dd, J = 10.1, 1.1 Hz, 1 H, 9-Htrans),
4.91, 4.87 (d, J = 14.4 Hz, 1 H, 10-Ha), 4.85 (d, J = 18.9 Hz, 1 H,
5-Ha), 4.47 (d, J = 17.7 Hz, 1 H, 5-Ha), 4.35 (d, J = 13.9 Hz, 1 H,
10-Hb), 4.19 (d, J = 17.7 Hz, 1 H, 5-Hb), 3.93 (d, J = 18.8 Hz, 1
H, 5-Hb), 3.64 (dd, J = 12.8, 3.8 Hz, 1 H, 6-Ha), 3.56 (dd, J = 13.0,
4.3 Hz, 1 H, 6-Ha), 3.30 (d, J = 12.9 Hz, 1 H, 6-Hb) ppm. 13C NMR
(CDCl3): δ = 163.4, 162.8 (s, C-11), 156.9 (q, J16,F = 37.6 Hz, C-
12), 155.3 (q, J12,F = 27.9 Hz, C-12), 135.3, 135.2 (s, C-4), 131.7,
131.1 (d, C-8), 128.9, 128.7 (d, C-2), 128.2, 127.3, 126.4, 126.3 (2d,
C-1, C-3), 119.9, 119.6 (t, C-9), 116.0 (q, J13,F = 286.6 Hz, C-13),
52.7, 49.9 (d, C-7), 50.1, 49.9 (t, C-10), 48.3, 47.0 (t, C-6), 45.5,
44.5 (t, C-5) ppm. HRMS (CI): calcd. for C15H15F3N2O2 [M]+
312.1086; found 312.1086. C15H15F3N2O2 (312.29): calcd. C 57.69,
H 4.84, N 8.97; found C 57.71, H 5.11, N 8.79.
1
as a mixture of rotamers. H NMR (CDCl3): δ = 7.33–7.13 (m, 5
H, 1-H, 2-H, 3-H), 5.80–5.60 (m, 2 H, 7-H, 8-H), 4.58–4.56 (m, 4
H, 5-H, 9-H), 4.47, 4.42 (m, 2 H, 5-H), 4.19, 4.17 (q, J = 7.1 Hz,
2 H, 11-H), 4.06–3.94 (m, 3 H, 6-H, 14-H), 3.83, 3.78 (br. s, 2 H,
6-H), 2.93, 2.89 (s, 3 H, 18-H), 1.45, 1.41, 1.40 (s, 9 H, 17-H), 1.30,
1.28 (t, J = 7.1 Hz, 3 H, 12-H) ppm. 13C NMR (CDCl3): δ = 169.0,
168.9, 168.7, 168.5 (s, C-13), 156.1, 155.6 (s, C-15), 154.8 (s, C-10),
137.0, 136.9, 136.1, 135.9 (s, C-4), 129.7, 129.2, 129.0, 128.9, 128.8,
128.5, 128.2, 128.1, 127.7, 127.6, 127.5, 127.4, 126.9, 126.8, 126.4,
126.3, 126.2 (5d, C-1, C-2, C-3, C-7, C-8), 79.8 (s, C-16), 67.1, 66.8,
66.6 (t, C-9), 64.1, 64.0 (t, C-11), 49.3, 48.7, 48.5 (t, C-5), 47.2,
47.1, 46.9, 46.8 (t, C-6), 35.6, 35.7, 35.5 (q, C-18), 28.2 (q, C-17),
14.2 (q, C-12) ppm. HRMS (CI): calcd. for C22H31DN2O6 [M]+
421.2323; found 421.2329. C22H31DN2O6 (421.51): calcd. C 62.69,
H 7.89, N 6.65; found C 62.82, H 7.75, N 6.88.
General Procedure for Pd-Catalyzed Allylic Alkylations: Zinc chlor-
ide (204 mg, 1.5 mmol) was heated in a Schlenk tube with the heat
gun until dry. After cooling to room temperature, the salt was dis-
solved in THF (5 mL) before the amino acid ester or amide
(1.0 mmol) as added. In a second Schlenk tube, hexamethyldisilaz-
ane (450 mg, 0.58 mL, 2.8 mmol) was dissolved in THF (5 mL).
The the stirred solution was cooled to –78 °C before nBuLi (1.6 m
in hexane, 1.56 mL, 2.5 mmol) was added. The cooling bath was
removed for 10 min and, after cooling again to –78 °C, the glycine
ester/amide and zinc chloride solution was added at this tempera-
ture. After stirring for 30 min, a solution of allylpalladium chloride
dimer (3.66 mg, 0.01 mmol, 1 mol-%), triphenylphosphine
(11.8 mg, 0.045 mmol, 4.5 mol-%) and the corresponding allyl car-
bonate (0.5 mmol) in THF (5 mL) was added at –78 °C. The reac-
tion mixture was warmed to room temperature overnight, then di-
luted with diethyl ether (20 mL) and hydrolyzed with 1 n HCl
(10 mL). The aqueous layer was extracted thrice with diethyl ether,
the combined organic layers were dried (Na2SO4), the solvent was
removed in vacuo, and the crude product was purified by flash
chromatography.
1-Benzyl-4-tert-butyloxycarbonyl-5-vinylpiperazin-2-one (7c): A
fresh prepared LHMDS solution in THF (3 mL), obtained from
HMDS (90 mg, 0.56 mmol) and BuLi (1.6 m in hexane, 0.31 mL,
0.50 mmol) at –20 °C, was added to a solution of allyl carbonate 6c
(81 mg, 0.20 mmol) and zinc chloride (41 mg, 0.30 mmol) in THF
(3 mL) at –78 °C and the mixture was stirred at this temperature
for 30 min. A solution of allylpalladium chloride dimer (1.5 mg,
4.0 μmol, 2 mol-%) and triphenylphosphine (2.1 mg, 8.0 μmol,
4 mol-%) in THF (3 mL) was added at –78 °C and the reaction
mixture was warmed to room temperature overnight. To complete
the reaction, the mixture was subsequently heated to reflux for an-
other 7 h, before it was cooled to room temperature and hydrolyzed
with NH4OAc buffer (5 mL). The aqueous layer was separated and
extracted thrice with diethyl ether. The combined organic layers
were dried (Na2SO4), the solvent was removed in vacuo, and the
crude product was purified by flash chromatography (hexanes/ethyl
acetate, 7:3 to 6:4) to give 7c (50 mg, 0.15 mmol, 76%) as a yellow
oil as a mixture of rotamers.
Major Rotamer: 1H NMR (CDCl3): δ = 7.36–7.25 (m, 5 H, 1-H, 2-
H, 3-H), 5.53 (ddd, J = 17.3, 10.5, 4.2 Hz, 1 H, 8-H), 5.18 (dd, J
= 10.5, 1.4 Hz, 1 H, 9-Htrans), 5.02 (dd, J = 17.3, 1.4 Hz, 1 H, 9-
Htrans), 4.82–4.78 (m, 2 H, 7-H, 10-Ha), 4.42 (d, J = 14.5 Hz, 1 H,
10-Hb), 4.33 (d, J = 18.3 Hz, 1 H, 5-Ha), 3.91 (d, J = 18.3 Hz, 1
H, 5-Hb), 3.56 (dd, J = 12.5, 4.5 Hz, 1 H, 6-Ha), 3.19 (dd, J = 12.5,
1.7 Hz, 1 H, 6-Hb), 1.46 (s, 9 H, 14-H) ppm. 13C NMR (CDCl3): δ
= 165.5 (s, C-11), 153.8 (s, C-12), 135.9 (s, C-4), 133.6 (d, C-8),
128.7, 128.6 (d, C-2/C-3), 127.9 (d, C-1), 117.7 (t, C-9), 80.9 (s, C-
13), 49.9 (2d, C-7, C-10), 48.4 (t, C-6), 45.3 (t, C-5), 28.3 (q, C-
14) ppm.
N-tert-Butyloxycarbonyl-α-allyl-sarcosyl-{N-benzyl-N-[4-ethoxy-
carbonyloxy-(2E)-buten-1-yl]}amide (9): According to the general
procedure for Pd-catalyzed allylic alkylations, allylated sarcosine
derivative 9 was obtained from benzoate 6i (136 mg, 0.3 mmol) and
allyl ethyl carbonate (39 mg, 0.30 mmol) using 3.5 equiv. of
LHMDS. After purification by flash chromatography (hexanes/
ethyl acetate, 9:1 to 7:3), 9 (75 mg, 0.15 mmol, 51%) was obtained
as yellow oil as a mixture of rotamers. 1H NMR (CDCl3): δ = 8.05
(m, 2 H, 12-H), 7.57 (m, 1 H, 14-H), 7.46 (m, 2 H, 13-H), 7.36–
7.22 (m, 5 H, 1-H, 2-H, 3-H), 7.11 (d, J = 7.3 Hz, 2 H, 3-H), 5.81–
5.70 (m, 3 H, 7-H, 8-H, 22-H), 5.21 (t, J = 8.0 Hz, 1 H, 16-H),
5.15–4.78 (m, 5 H, 9-H, 16-H, 23-H), 4.54 (s, 2 H, 5-H), 4.00 (m,
2 H, 6-H), 2.80, 2.77, 2.76 (s, 3 H, 20-H), 2.55 (m, 2 H, 21-H),
1.43, 1.30, 1.29 (s, 9 H, 19-H) ppm. 13C NMR (CDCl3): δ = 170.6,
169.8 (s, C-15), 166.2, 166.1 (s, C-10), 155.6, 155.5 (s, C-17), 137.3,
137.1, 136.7 (s, C-4), 134.1, 134.0, 133.9 (d, C-22), 133.1, 133.0 (d,
C-14), 130.1, 130.0 (s, C-11), 129.6, 129.4, 129.1, 129.0, 128.9,
Minor Rotamer (selected signals): 1H NMR (CDCl3): δ = 5.56 (ddd,
J = 17.2, 10.5, 4.2 Hz, 1 H, 8-H) ppm.
N-tert-Butyloxycarbonyl-α-deuterio-sarcosyl-{N-benzyl-N-[4-ethoxy- 128.8, 128.6, 128.4, 128.3, 128.1, 127.7, 127.6, 127.4, 127.2, 127.1,
carbonyloxy-(2E)-buten-1-yl]}amide (8): nBuLi (1.6 m toluene, 126.8, 126.6, 126.3 (6d, C-1, C-2, C-3, C-7, C-8, C-13), 118.1, 117.8
Eur. J. Org. Chem. 2014, 1695–1707
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1705

S. Thies, U. Kazmaier
FULL PAPER
(t, C-23), 80.5, 80.1, 80.0 (s, C-18), 64.4, 64.1 (t, C-9), 54.0, 49.9,
49.5 (d, C-16), 48.4 (t, C-5), 47.7, 47.1, 46.6 (t, C-6), 33.7, 33.5 (q,
1
Minor Rotamer (selected signals): H NMR (CDCl3): δ = 4.32 (br.
s, 1 H, 6-H), 1.42 (s, 9 H, 9-H) ppm. 13C NMR (CDCl3): δ = 170.7
C-20), 29.4 (t, C-21), 28.4, 28.3, 28.1 (q, C-19) ppm. HRMS (CI): (s, C-5), 155.9 (s, C-7), 136.3 (d, C-2), 117.6 (t, C-1), 80.0 (s, C-8),
calcd. for C2 9 H3 6 N2 O5 [M]+ 492.2624; found 492.2600. 64.0 (d, C-6), 41.2 (d, C-3), 28.3 (q, C-9) ppm.
C
29H36N2O5 (492.61): calcd. C 70.71, H 7.37, N 5.69; found C
3-[(tert-Butyloxycarbonyl)methylamino]-1-(2-tetrahydropyran-2-yl-
oxyethyl)-4-vinylpyrrolidin-2-one (12g): According to the general
procedure for Pd-catalyzed intramolecular allylations, pyrrolidin-2-
one 12g (65 mg, 0.18 mmol, 88%) was obtained as a colorless oil
as a mixture of rotamers from allyl carbonate 6g (92 mg,
0.20 mmol) after flash chromatography (hexanes/ethyl acetate, 9:1
to 4:6). Ratio anti/syn = 82:18. HPLC (Chiracel ODH; hexane/iP-
rOH, 90:10; 1 mL/min): (anti)-12g: tR = 41.35, 59.13 min; (syn)-
12g: tR = 49.49, 52.01 min. HRMS (CI): calcd. for C19H33N2O5 [M
+ H]+ 369.2345; found 369.2380. C19H32N2O5 (368.47): calcd. C
61.93, H 8.75, N 7.60; found C 62.10, H 8.96, N 7.90.
70.53, H 6.96, N 6.26.
Pd-Catalyzed Intramolecular Allylations. General Procedure: The
LHMDS solution was prepared from HMDS (157 μL, 0.76 mmol)
and nBuLi (0.44 mL, 0.70 mmol) in dichloromethane (2 mL) at
–78 °C. After the addition of BuLi, the cooling bath was removed
and the reaction mixture was warmed to –25 °C, before it was co-
oled again to –78 °C. A solution of the corresponding allyl sub-
strate 6 (0.20 mmol) and chlorotitaniumtriisopropoxide (1 m in hex-
ane, 0.22 mL, 0.22 mmol) in THF (2 mL) was added at this tem-
perature. After stirring for 30 min, a solution of allylpalladi-
umchloride dimer (3.7 mg, 10.0 μmol, 5 mol-%) and triphenylphos-
phine (27.5 mg, 105 μmol, 52.5 mmol-%) in dichloromethane
(1 mL) was added. The reaction mixture was warmed to room tem-
perature overnight before it was hydrolyzed with a mixture of 2 n
NaOH and satd. potassium sodium tartrate solution. The solution
was stirred until the layers separated, then the aqueous layer was
separated and extracted twice with dichloromethane. The combined
organic layers were dried (Na2SO4), the solvent was removed in
vacuo, and the crude product was purified by flash chromatog-
raphy.
1
Major Rotamer: H NMR (CDCl3): δ = 5.80 (ddd, J = 17.5, 9.8,
8.2 Hz, 1 H, 2-H), 5.19–5.11 (m, 2 H, 1-H), 4.67 (d, J = 10.8 Hz,
1 H, 6-H), 4.58 (s, 1 H, 13-H), 3.90–3.80 (m, 2 H, 12-Ha, 17-Ha),
3.71–3.35 (m, 5 H, 4-Ha, 11-H, 12-Hb, 17-Hb), 3.27 (dd, J = 9.8,
9.8 Hz, 1 H, 4-Hb), 3.00 (ddd, J = 18.3, 9.1, 9.1 Hz, 1 H, 3-H), 2.84
(s, 3 H, 10-H), 1.80–1.70 (m, 2 H, 14-Ha, 15-Ha), 1.58–1.48 (m, 4 H,
14-Hb, 15-Hb, 16-H), 1.43 (s, 9 H, 9-H) ppm. 13C NMR (CDCl3): δ
= 170.5 (s, C-5), 156.0 (s, C-7), 136.4 (d, C-2), 117.9 (t, C-1), 98.9
(d, C-13), 80.3 (s, C-8), 65.4, 62.6, 62.5 (d, C-6, 2t, C-12, C-17),
49.8 (t, C-4), 43.2 (t, C-11), 42.1 (d, C-3), 30.7 (q, C-10, t, C-14),
28.3 (q, C-9), 25.4 (t, C-16), 19.6 (t, C-15) ppm.
1-Benzyl-3-[N-(tert-butyloxycarbonyl)-N-methylamino]-4-vinyl-
pyrrolidin-2-one (12e): According to the general procedure for Pd-
catalyzed intramolecular allylations, pyrrolidin-2-one 12e (48 mg,
0.25 mmol, 75 %) was obtained from allyl carbonate 6e (84 mg,
0.2 mmol) after flash chromatography (hexanes/ethyl acetate, 9:1 to
1:1) as a pale-yellow oil as a mixture of rotamers. Ratio anti/syn =
86:14. 1H NMR (CDCl3): δ = 7.33–7.28 (m, 3 H, 14-H, 15-H), 7.24
(d, J = 6.5 Hz, 2 H, 13-H), 5.69 (m, 1 H, 2-H), 5.13–5.06 (m, 2 H,
1-Ha, 1-Hb), 4.66 (d, J = 9.5 Hz, 1 H, 6-H), 4.51–4.40 (m, 3 H, 6-
H, 11-H), 3.27 (br. s, 1 H, 4-Ha), 3.14–2.95 (m, 2 H, 3-H, 4-Hb),
2.86, 2.83 (s, 3 H, 10-H), 1.45, 1.42 (s, 9 H, 9-H) ppm. 13C NMR
(CDCl3): δ = 170.5, 170.2 (s, C-5), 155.9, 155.3 (s, C-7), 136.0 (d,
C-2), 135.8 (s, C-12), 128.7 (d, C-14), 128.3, 128.1 (d, C-13), 127.7,
127.5 (d, C-15), 117.9, 117.6 (t, C-1), 80.3, 80.0 (s, C-8), 63.8, 63.0
(d, C-6), 47.7 (t, C-4), 47.1, 47.0 (t, C-11), 41.6, 41.1 (d, C-3), 31.9
(q, C-10), 28.2 (q, C-9) ppm. HPLC (Chiracel ODH; hexane/
iPrOH, 90:10; 1 mL/min): (anti)-12e: tR = 33.96, 75.48 min; (syn)-
12e: tR = 38.81, 51.68 min. HRMS (CI): calcd. for C19H26N2O3
[M]+ 330.1943; found 330.1926.
Minor Rotamer (selected signals): 1H NMR (CDCl3): δ = 3.26 (dd,
J = 9.8, 9.8 Hz, 1 H, 4-Hb), 2.80 (s, 3 H, 10-H), 1.45 (s, 9 H, 9-
H) ppm. 13C NMR (CDCl3): δ = 136.9 (d, C-2), 117.7 (t, C-1),
110.0 (d, C-13), 80.0 (s, C-8), 41.7 (d, C-3) ppm.
3-[(tert-Butyloxycarbonyl)methylamino]-1-(2-hydroxyethyl)-4-
vinylpyrrolidin-2-one (12h): According to the general procedure for
Pd-catalyzed intramolecular allylations, pyrrolidin-2-one 12h
(29 mg, 0.10 mmol, 50%) was obtained as a colorless oil as a mix-
ture of rotamers from allyl carbonate 6h (75 mg, 0.20 mmol) after
flash chromatography (hexanes/ethyl acetate, 1:1 to 1:9). Ratio
anti/syn = 78:22. HPLC (Chiracel ODH; hexane/iPrOH, 90:10;
1 mL/min): (anti)-12g: tR = 33.37, 36.04 min; (syn)-12g: tR = 36.04,
54.87 min. HRMS (CI): calcd. for C14H24N2O4 [M]+ 284.1736;
found 284.1734.
1
Major Rotamer: H NMR (CDCl3): δ = 5.77 (m, 1 H, 2-H), 5.20–
5.10 (m, 2 H, 1-H), 4.40 (d, J = 9.6 Hz, 1 H, 6-H), 3.77 (m, 2 H,
12-H), 3.56–3.45 (m, 2 H, 4-Ha, 11-Ha), 3.36 (m, 1 H, 11-Hb), 3.25
(dd, J = 9.8, 9.8 Hz, 1 H, 4-Hb), 3.07 (ddd, J = 17.8, 8.9, 8.9 Hz,
1 H, 3-H), 2.84 (s, 3 H, 10-H), 1.42 (s, 9 H, 9-H) ppm. 13C NMR
(CDCl3): δ = 171.7 (s, C-5), 155.9 (s, C-7), 136.5 (d, C-2), 118.1 (t,
C-1), 80.5 (s, C-8), 64.2 (d, C-6), 60.2 (t, C-12), 50.0 (t, C-4), 46.5
(t, C-11), 41.7 (d, C-3), 33.4 (q, C-10), 28.3 (q, C-9) ppm.
3-[(tert-Butyloxycarbonyl)methylamino]-1-methyl-4-vinylpyrrolidin-
2-one (12f): According to the general procedure for Pd-catalyzed
intramolecular allylations, pyrrolidin-2-one 12f (35 mg, 0.14 mmol,
69%) was obtained as a colorless oil as a mixture of rotamers from
allyl carbonate 6f (69 mg, 0.20 mmol) after flash chromatography
(hexanes/ethyl acetate, 1:1 to 3:7). Ratio anti/syn = 88:20. HPLC
Minor Rotamer (selected signals): 1H NMR (CDCl3): δ = 3.24 (dd,
J = 9.8, 9.8 Hz, 1 H, 4-Hb), 1.43 (s, 9 H, 9-H) ppm. 13C NMR
(CDCl3): δ = 171.9 (s, C-5), 155.3 (s, C-7), 136.1 (d, C-2), 117.6 (t,
C-1), 80.4 (s, C-8), 60.6 (t, C-12), 49.8 (t, C-4), 46.6 (t, C-11), 42.2
(d, C-3), 33.4 (q, C-10), 28.3 (q, C-9) ppm.
(Chiracel ODH; hexane/iPrOH, 90:10; 1 mL/min): (anti)-12f: tR
=
15.35, 19.20 min; (syn)-12f: tR = 12.89, 15.35 min. HRMS (CI):
calcd. for C1 3 H2 2 N2 O3 [M]+ 254.1630; found 254.1604.
C13H22N2O3 (254.33): calcd. C 61.39, H 8.72, N 11.01; found C
61.56, H 8.68, N 11.41.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of NMR spectra of all new compounds.
1
Major Rotamer: H NMR (CDCl3): δ = 5.80 (m, 1 H, 2-H), 5.18–
5.10 (m, 2 H, 1-H), 4.53 (d, J = 10.3 Hz, 1 H, 6-H), 3.38 (dd, J =
8.9, 8.9 Hz, 1 H, 4-Ha), 3.11 (dd, J = 9.3, 9.3 Hz, 1 H, 4-Hb), 3.00
(m, 1 H, 3-H), 2.88–2.75 (m, 6 H, 10-H, 11-H), 1.41 (s, 9 H, 9-
H) ppm. 13C NMR (CDCl3): δ = 170.4 (s, C-5), 155.3 (s, C-7), 136.2
(d, C-2), 117.9 (t, C-1), 80.3 (s, C-8), 63.1 (d, C-6), 50.5 (t, C-4),
41.7 (d, C-3), 30.1, 30.0 (2q, C-10, C-11), 28.2 (q, C-9) ppm.
Acknowledgments
Financial support by the Deutsche Forschungsgemeinschaft
(DFG) is gratefully acknowledged.
1706
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1695–1707

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Received: November 5, 2013
Published Online: January 14, 2014
Eur. J. Org. Chem. 2014, 1695–1707
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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