Photochemically induced electron transfer (PET) catalyzed radical cyclization: A practical method for inducing structural changes in peptides by formation of cyclic amino acid derivatives

Article abstract of DOI:10.1021/jo010144b

A new radical cyclization reaction of unsaturated amino acid derivatives is presented. The reaction is induced by photoelectron transfer (PET) catalysis and proceeds, in comparison to commonly applied methods, under mild, nonoxidizing, and nontoxic conditions in neutral medium. This type of radical cyclization reaction can be used in peptide chemistry for inducing structural changes in peptides.

Full text of DOI:10.1021/jo010144b

6896
J . Org. Chem. 2001, 66, 6896-6904
P h otoch em ica lly In d u ced Electr on Tr a n sfer (P ET) Ca ta lyzed
Ra d ica l Cycliza tion : A P r a ctica l Meth od for In d u cin g Str u ctu r a l
Ch a n ges in P ep tid es by F or m a tion of Cyclic Am in o Acid
Der iva tives
Marco J onas,† Siegfried Blechert,*,† and Eberhard Steckhan‡,§
Institut fu¨r Chemie, Technische Universita¨t Berlin, Strasse des 17. J uni 135, D-10623 Berlin, Germany,
and Kekule´-Institut fu¨r Organische Chemie und Biochemie, Universita¨t Bonn, Gerhard-Domagk-Strasse
1, D-53121 Bonn, Germany
blechert@chem.tu-berlin.de
Received February 6, 2001
A new radical cyclization reaction of unsaturated amino acid derivatives is presented. The reaction
is induced by photoelectron transfer (PET) catalysis and proceeds, in comparison to commonly
applied methods, under mild, nonoxidizing, and nontoxic conditions in neutral medium. This type
of radical cyclization reaction can be used in peptide chemistry for inducing structural changes in
peptides.
In tr od u ction
which readily undergo fragmentation by loss of the
trimethylsilyl group, leading to free R-aminomethyl
radicals. These radicals can act as reactive intermediates
in many different types of reactions, for example radical
cyclization reactions5 leading to piperidine or pyrrolidine
structures.6 In contrast to other methods,7 the generation
of R-aminomethyl radicals by PET can be performed
under mild, nonoxidative, and nontoxic conditions.
The lifetime of the intermediate R-silylmethylamino
radical cation is decisive for the success of these reactions.
Recently, we investigated the PET-catalyzed intermo-
lecular addition of R-silylmethyl carbamates to acceptor-
substituted olefins, which is possible only by prolongation
of the lifetime of the intermediate radical cation using a
co-sensitization protocol.8
Here, we report PET-catalyzed radical cyclization
reactions of unsaturated N-trimethylsilylmethyl amino
acid derivatives and their application in peptide chem-
istry.9 Besides carrying the trimethylsilylmethyl group,
the nitrogen function of the amino acid derivative has to
be acylated by a protecting group, another amino acid,
or a peptide to achieve an oxidation potential in the range
1.4-1.6 V (vs Ag/AgCl).10 It is not necessary to activate
Over the last 15 years, the activation of molecules by
single electron transfer (SET) has proved to be an
important concept in developing new reactions. Many
useful applications in selective synthesis even for complex
compounds have been found.1 In our investigations, we
are interested in developing new SET-catalyzed reactions
of synthetic importance.2
Besides the light-induced formation of radical cations
as intermediates in cycloaddition reactions,3 the genera-
tion of radicals under nonoxidative, nontoxic, and mild
conditions via photoinduced electron transfer (PET) is of
great value.4 By one-electron oxidation an intermediate
radical cation is formed, which subsequently fragments
into an electrophilic leaving group and a neutral radical.
On the basis of this principle, R-silylmethylamino
derivatives can act as starting materials for R-amino-
methyl radicals. Upon irradiation of R-silylmethylamino
derivatives with UV/vis light in the presence of a
sensitizer, R-silylmethylamino radical cations are formed,
† Technische Universita¨t Berlin.
‡ Universita¨t Bonn.
§ Deceased February 10, 2000.
(1) Schmittel, M.; Burghart, A. Angew. Chem. 1997, 109, 2658-2682.
Schmittel, M.; Burghart, A. Angew. Chem., Int. Ed. Engl. 1997, 36,
2551-2589.
(5) (a) Giese, B. In Radicals in Organic Synthesis: Formation of
Carbon-Carbon Bonds; Organic Chemical Series, Vol. 5; Baldwin, J .
E., Ed.; Pergamon Press: Oxford, 1986. (b) Surzer, J .-M. In Reactive
Intermediates; Abramovitch, A. R., Ed.; Plenum Press: New York,
1980; Vol. 1.
(6) (a) Khim, S.-K.; Cederstrom, E.; Ferri, D. C.; Mariano, P. S.
Tetrahedron 1996, 52, 3195-3222, and references therein. (b) Pandey,
G.; Reddy, G. D.; Chakrabartie, D. J . Chem. Soc, Perkin Trans. 1 1996,
219-224, and references therein.
(7) (a) Ikeda, M.; Kugo, Y.; Sato, T. J . Chem. Soc., Perkin Trans. 1
1996, 1819-1824. (b) Esch, P. M.; Hiemstra, H.; Speckamp, W. N.
Tetrahedron Lett. 1990, 31, 759-762. (c) Kano, S.; Yuasa, Y.; Asami,
K.; Shibuya, S. Heterocycles 1988, 27, 1437-1443. (d) Burnett, D. A.;
Choi, J .-K.; Hart, D. J .; Tsai, Y.-M. J . Am. Chem. Soc. 1984, 106, 8201-
8209. (e) Hart, D. J .; Tsai, Y.-M. J . Am. Chem. Soc. 1984, 106, 8209-
8217.
(8) Meggers, E.; Steckhan, E.; Blechert, S. Angew. Chem. 1995, 107,
2317-2319; Angew. Chem., Int. Ed. Engl. 1995, 34, 2137-2139.
(9) In part from: J onas, M. Ph.D. Thesis, Technische Universita¨t
Berlin, 1999.
(2) (a) Gieseler, A.; Steckhan, E.; Wiest, O.; Knoch, F. J . Org. Chem.
1991, 56, 1405-1411. (b) Gu¨rtler, C. F.; Steckhan, E.; Blechert, S.
Synlett 1994, 141-142. (c) Gu¨rtler, C. F.; Steckhan, E.; Blechert, S.
Angew. Chem. 1995, 107, 2025-2026; Angew. Chem., Int. Ed. Engl.
1995, 34, 1900-1901. (d) Gu¨rtler, C. F.; Steckhan, E.; Blechert, S. J .
Org. Chem. 1996, 61, 4136-4143. (e) Gu¨rtler, C. F.; Steckhan, E.;
Blechert, S. Chem. Eur. J . 1997, 3, 447-452. (f) Peglow, T.; Blechert,
S.; Steckhan, E. Chem. Eur. J . 1998, 4, 107-112.
(3) (a) Botzem, J .; Haberl, U.; Steckhan, E.; Blechert, S. Acta Chem.
Scand. 1998, 52, 175-193. (b) Peglow, T.; Blechert, S.; Steckhan, E.
J . Chem. Soc., Chem. Commun. 1999, 433-434.
(4) (a) See review on PET: Mattay, J . Angew. Chem. 1987, 99, 849-
869; Angew. Chem., Int. Ed. Engl. 1987, 26, 825-845. Mattay, J .
Synthesis 1989, 233-252. (b) Gutenberger, G.; Steckhan, E.; Blechert,
S. Angew. Chem. 1998, 110, 679-681; Angew. Chem., Int. Ed. 1998,
37, 660-662. (c) Gutenberger, G.; Steckhan, E.; Blechert, S. Tetrahe-
dron Lett. 2000, 41, 461-464. (d) J ahn, U.; Mueller, M.; Aussieker, S.
J . Am. Chem. Soc. 2000, 122, 5212-5213. (e) J ahn, U.; Aussieker, S.
Org. Lett. 1999, 1, 849-852.
(10) For oxidation potential of R-silylcarbamate see: Yoshida, J .-I.;
Isoe, S. Tetrahedron Lett. 1987, 28, 6621-6624.
10.1021/jo010144b CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/15/2001

Formation of Cyclic Amino Acid Derivatives
J . Org. Chem., Vol. 66, No. 21, 2001 6897
Ta ble 1. Resu lts of th e P ET-Ca ta lyzed Ra d ica l
Cycliza tion of 3, 4a ,b, 5, 8a ,b, a n d 10
Sch em e 1. Syn th esis of P ET P r ecu r sor s 3, 4a ,b, 5,
8a -c, a n d 10a
amino acid
product
yield (%)
ratio cis/trans
3
4a
4b
8a
8b
10
5
11
51
34
45
54
30
65
45
<1:99
1:2
1:2
1:5
1:5
1:6
>99:1
12a
12b
14a
14ba
16
13
a
The product contains 15 (12%).
Sch em e 2. P ET Rea ction s of 3, 4a ,b, 5, 8a ,b, a n d
10a
a
Reagents and conditions: (a) TMSCH2Cl, KI, Na2CO3, MeCN,
83 °C, 12 h, 55-60%. (b) ClCO2Me, NaOH (0.8 N), MTBE, 0 °C,
0.5 h 98%. (c) NaBH4, MeOH, THF, 98%. (d) Ph3CCl, Py, 7d, 28%.
(e) (1) NaBH4, MeOH, THF, 94%. (2) ClCH2COCl, toluene, NEt3,
0 °C, 2 h, then KOH (50%), Bu4NI, 10 h, 64%. (f) Boc2O, NEt3,
MeOH, 65 °C, 99%. (g) TsCl, NEt3, CH2Cl2, 12 h, 65%. (h)
AcOCH2CHdCHCH2OAc, Cl2(PCy3)2RudCHPh 5 mol %, CH2Cl2,
40 °C,12 h. (i) (1) KCN, MeOH. (2) MnO2, pentane/CH2Cl2 (1:1).
(3) MnO2, NaCN, HOAc, MeOH, 12 h, 75% (4 steps).
a
the double bond acting as radical acceptor with an
electron-withdrawing group. Photoexcited 9,10-anthracene
dicarbonitrile (ADC) and biphenyl (BP) as co-sensitizer
were used to induce the reaction.
Reagents and conditions: 20 mol % BP, 30 mol % ADC, MeOH/
MeCN (2:3), irradiation λ > 345 nm. BP: biphenyl, ADC: 9,10-
anthracenedicarbonitrile.
The irreversible oxidation potentials of compounds
3-5, 8a ,b, and 10 are close to 1.4 V (vs Ag/AgCl) except
for 8c, for which no discrete oxidation potential was
measurable. In all cases except for 8c the corresponding
pyrrolidines 11-13 or piperidines 14a ,b and 16 were
formed on radiation (UV/vis) in the presence of ADC (20
mol %) and BP (30 mol %) (Scheme 2, Table 1).
The cyclization products 11-14 and 16 were obtained
in moderate to good yield, but 8c did not react.14 The ring
size strictly depends on the length of the side chain. The
diastereoselectivity is moderate to good, except for 11 and
13, where the diastereoselectivity is excellent.15 The
major diastereomer has trans configuration (see Table
1), except for 13, which is cis configurated. The relative
Resu lts a n d Discu ssion
As model compounds, the amino acid derivatives 3-5
were synthesized as shown in Scheme 1 starting from
racemic allylglycine methyl ester 1. After N-alkylation
(f 2), the nitrogen atom was acylated to give the N-Moc
derivative 3. Reduction of ester 3 led to 4a , which was
tritylated to give 4b. Morpholinone 5 was obtained from
2 by ester reduction, subsequent treatment with chloro-
acetyl chloride, and cyclization. Additionally, the model
compounds 8a -c and 10 were synthesized starting from
homoallylglycinol trityl ether 6.11 In the same manner
as above, after N-alkylation (f 7), the nitrogen atom was
acylated to give the N-Moc, N-Boc, or N-Ts derivatives
8a -c. 10 was generated from 8a via cross olefin meta-
thesis12 (f 9) followed by deprotection and oxidation13
of the allyl alcohol (Scheme 1).
(12) (a) For a review see: Blechert, S.; Schuster, M. Angew. Chem.
1997, 109, 2124-2144; Angew. Chem., Int. Ed. Chem. 1997, 36, 2037-
2056. (b) Schwap, P.; Grubbs, R. H.; Ziller, J . W. J . Am. Chem. Soc.
1996, 118, 100-110, and references therein.
(13) Corey, E. J .; Gilman, N. W.; Ganem, B. E. J . Am. Chem. Soc.
1968, 90, 5616-5617.
(14) The high oxidation potential might be the reason 8c did not
cyclize.
(11) Pernerstorfer, J .; Schuster, M.; Blechert, S. Synthesis 1999,
138-144.

6898 J . Org. Chem., Vol. 66, No. 21, 2001
J onas et al.
Sch em e 3. Mech a n ism of th e P ET Rea ction
Sch em e 4. Syn th esis of 17a ,b, 18a -d , 19, a n d 20
a n d Th eir P ET Rea ction a
configuration of the compounds shown in Table 1 was
confirmed by NOE experiments. The size of the N-
protecting group does not influence the diastereoselec-
tivity but the reaction rate of the cyclization. Bulky
protecting groups such as Boc in 8b favor the open chain
product 15.16 An acceptor-substituted double bond im-
proves the yield as well as the diastereoselectivity. The
PET-catalyzed radical cyclization is completed within an
hour. In the case of 13, however, an extremely long
reaction time (12 h) is observed due to the decrease in
the fragmentation reaction rate. This observation was
supported by our results with similar cyclic compounds
such as morpholinediones, piperazinediones, and oxazol-
idinones.17
On the basis of our results and previous studies,4c we
propose a mechanism starting with a SET process
between the primary electron donor BP (Eox ) 1.98 V vs.
SCE) and the photoexcited ADC (Ered(S1) ) 2.0 V vs SCE)
(Scheme 3).18 In a subsequent SET reaction, the BP-
radical cation oxidizes the R-silymethylcarbamate (e.g.,
3) or the R-silylmethylamide (e.g., 19), leading to the
desired radical cation (Scheme 3). After R-desilylation,19
supported by the attack of methanol, the neutral radical
is intramolecularly captured by the double bond. Finally,
the reduction of the secondary radical by the ADC radical
anion followed by protonation completes the reaction.
Because of the mild conditions for the formation of
proline derivatives (e.g., 11), it was our aim to apply this
PET-catalyzed cyclization to influence the secondary
structure of peptides by the in situ formation of a proline
residue. Proline influences the peptide structure20 by
acting as a â-sheet breaker, an R-helix breaker, or a weak
R-helix former depending on its position in the peptide.21
It is also frequently found in â-turns.22 Therefore, we
expected structural changes in the peptide backbone (of
a
Reagents and conditions: for details see text.
proteins or oligopeptides) upon the PET-catalyzed cy-
clization reaction of oligopeptides containing the ap-
propriate proline precursors.
For these investigations we synthesized di- and oligo-
peptides starting from the enantiomerically pure unsat-
urated N-silylmethyl amino acid (-)-2 derived from
enantiomerically pure (-)-1.23 The peptides 17-20 are
readily accessible by means of a peptide coupling reaction
and, in the case of 19 and 20, by further saponification24
of the ester followed by another peptide formation
(Scheme 4).
The oxidation pontentials of 17-20 are close to +1.6
V (vs Ag/AgCl). As shown in Scheme 4 and Table 2, the
PET-catalyzed cyclization was successful for all peptides.
The 4-methylproline-containing peptides were obtained
in 24-86% yield. No exceptions were found, even though
it is known that Z-protecting groups act as quenchers of
the PET reaction.25 The stereochemistry of the com-
(15) (a) Damm, W.; Hoffmann, U.; Macko, L.; Neuburger, M.;
Zehnder, M.; Giese, B. Tetrahedron 1994, 50, 7029-7048. (b) Schubert,
S.; Renaud, P.; Carrupt, P.-A.; Schenk, K. Helv. Chim. Acta 1993, 76,
2473-2489. (c) For a review on stereoselectivity in radical reactions
see: Beckwith, A. L. J . Tetrahedron 1981, 37, 3073-3100.
(16) The open chain product 15 can be explained by further oxidation
of the intermediate radical.
(17) J onas, M.; Blechert, S.; Steckhan, E. Unpublished results.
(18) Gould, I. R.; Ege, D.; Moser, J . E.; Farid, S. J . Am. Chem. Soc.
1990, 112, 4290-4301.
(21) (a) Anfinsen, C. B.; Scheraga, H. A. Adv. Protein Chem. 1975,
29, 205. (b) Robson, B.; Suzuki, E. J . Mol. Biol. 1976, 107, 327-356.
(c) Richardson, J . S.; Richardson, D. C. Science 1988, 240, 1648-1652.
(d) Sankararamakrishnan, R.; Vishveshwara, S. Biopolymers 1990, 30,
187-205.
(22) (a) Ananthanarayanan, V. S.; Shyamasundar, N. Biochem.
Biophys. Res. Commun. 1981, 102, 295-301. (b) Smith, J . A.; Pease,
L. G. Crit. Rev. Biochem. 1980, 8, 315-399
(19) Zhang, X.; Yeh, S.-R.; Hong, S.; Freccero, M.; Albini, A.; Falvey,
D. E.; Mariano, P. S. J . Am. Chem. Soc. 1994, 116, 4211-4220.
(20) Schulz, G. E. Principles of Protein Structure; Springer: Berlin,
1979.
(23) Except for 17a ,b.
(24) Qabar, M. N.; Urban, J .; Kahn, M. Tetrahedron 1997, 53,
11171-11178.
(25) J onas, M.; Blechert, S.; Steckhan, E. Unpublished results.

Formation of Cyclic Amino Acid Derivatives
J . Org. Chem., Vol. 66, No. 21, 2001 6899
Ta ble 2. Resu lts of th e P ET-Ca ta lyzed Cycliza tion of th e
at the N-terminus, N-methylamide at the C-terminus)
were chosen because of the availability of high-quality
force field parameters. For each of the three compounds,
∼20 000 conformations were generated.
P ep tid es 17-20
peptide
product
R
yield (%)
ratio cis/trans
17a
18a
18b
18c
18d
17b
19
21a
22a
22b
22c
22d
21b
23
PhCO
H
Me
Bn
i-Bu
FMOC-Gly
24
33
57
51
70
55
86
64
1:3
1:2
1:2
2:3
1:2
1:2
1:3
2:1
An analysis of the low-energy conformations found in
these calculations shows that all three compounds behave
similarly. All the low-energy conformations display a
hydrogen bond (NH‚‚‚O distance <200 pm) between the
amino group of Leu(2) and the carbonyl group of Leu(5),
which is characteristic for a â-turn. This clearly demon-
strates that there is no special effect of the methyl group.
20
24
pounds shown in Table 2 was confirmed by NOE and two-
dimensional NMR experiments.
Con clu sion
Obviously, the observed diastereoselectivity is not
influenced by the side chain of neighboring amino acids.
However, it reflects the approach of the intermediate
radical toward the double bond which is determined by
the predominant conformation of the peptide chain (e.g.,
20).
The PET-catalyzed radical cyclization reaction is easily
carried out under nonoxidative, nontoxic, and mild condi-
tions. This reaction is applicable to peptides. The proline-
containing peptides resulting from this cyclization reac-
tion are of potential interest with respect to the photo-
chemically induced structural changes in their secondary
structure. In a simple example, we were able to demon-
strate this effect on the relative amount of R-helix in the
secondary structure during the transformation of 20 to
24 by the PET-catalyzed reaction. Therefore, we expect
that this PET-catalyzed cyclization is also applicable to
the formation of â-turn mimetics.
The influence of a proline moiety on the conformation
of oligoleucines has already been reported.26 Therefore,
we were able to show structural changes during the
transformation of 20 to 24 by CD spectroscopy. Due to
the specific absorptions of peptides, one can distinguish
between R-helix (two maxima at 190 and 215 nm, two
minima at 205 and 225 nm), â-sheet (one maximum at
195 nm, one minimum at 202 nm), and random chain
conformation (one maximum at 220 nm, one minimum
at 195 nm). It is also possible to calculate the relative
amount of each conformation in mixed spectra.27 Because
of the limited chain length of 20 and 24, we observed for
these peptides only spectra of the mixed type. The CD
spectrum of 20 shows two maxima at 185 and 213 nm
and two minima at 200 and 237 nm, which changes after
the reaction giving 24, showing one maximum at 190 nm,
one minimum at 203 nm, and a shoulder at 230 nm.
Therefore, we can conclude a change in the secondary
structure during the transformation of 20 to 24 caused
by the PET-catalyzed cyclization reaction.28
While the conformational consequences of a proline
residue within an oligopeptide chain are well known, we
considered whether an additional methyl group at postion
4 of the proline changes this situation. Therefore, we
performed a conformational search using the molecular
mechanics software TINKER29 with the CHARMM2230
force field, which is especially designed to perform protein
simulations. Calculations on three individual compounds
have been performed, namely, on AcO-Leu(1)-Leu(2)-
Leu(3)-Pro(4)-Leu(5)-NHMe and the two 4-methyl proline
derivatives (methyl group cis or trans to the backbone).
The terminating groups used in the calculation (acetyl
Exp er im en ta l Section
Gen er a l Meth od s. 1H NMR spectra were recorded at 200,
400, or 500 MHz. (Bruker), and 13C NMR spectra were
recorded at 50.3 MHz. Optical rotations were measured on a
digital polarimeter (Perkin-Elmer) at room temperature. Thin-
layer chromatography (TLC) was performed on Merck 60F254
(0.2 mm) sheets which were developed with ethanolic molyb-
dophosphoric acid, a solution of KMnO4 in water, or UV light.
Flash chromatography (FC) was performed on Merck (0.04-
0.063 mm) silica. All chemicals were of the highest commercial
available purity and were used without further purification.
Solvents used for chromatography were distilled before use.
Photolyses were performed with a light source system consist-
ing of a Hanovia 976C1010 1000 W xenon arc lamp, a Mu¨ller-
Elektronik LAX 1000 lamp housing, and a Schott WG345 long-
pass filter. The system was designed for use with wavelengths
(λ) greater than 345 nm.
Gen er a l P r oced u r e for P h otolysis (P r oced u r e P ). The
unsaturated amino acid derivatives {0.1-0.4 mmol/L in MeOH/
MeCN (2:3, 50 mL)}, 20 mol % of ADC (9,10-anthracenedicar-
bonitrile), and 30 mol % of BP (biphenyl) were vigorously
mixed in a 100 mL Schlenk tube. Before the reaction is started,
the solution was evacuated until gas evolution stopped and
purged for 10 min with Ar to free it from O2. Then the solution
was irradiated for 60-80 min under Ar with a 1000 W xenon
arc lamp (λ > 345 nm), while being monitored by TLC. After
the reaction was finished, the products were purified by FC.
ADC and BP were reisolated nearly quantitatively.
(26) Narita, M.; Isokawa, S.; Doi, M.; Wakita, R. Bull. Chem. Soc.
J pn. 1986, 59, 3547-3552.
Gen er a l P r oced u r e for P ep tid e F or m a tion (P r oced u r e
F ). One equivalent of the C-protected amino acid, 1.2 equiv of
the N-protected amino acid, and 1.2 equiv of HABT (1-hydroxy-
7-azabenzotriazole) were dissolved in a minimum amount of
absolute MeCN. At 0 °C 1.2 equiv of DIC (diisopropyl carbo-
diimide) followed by 1.2 equiv of DIEA (diisopropylethylamine)
were added to the mixture. After 0.5 h the mixture was allowed
to warm to room temperature. During the reaction a precipi-
tate was formed. After the reaction was finished, the mixture
was dissolved in 50-100 mL of MTBE (methyl tert-butyl ether)
and was subsequently washed twice with 10% citric acid, twice
with saturated Na2CO3 solution, and with saturated NaCl
solution. The organic layer was dried over MgSO4, and the
solvent was evaporated. Separation of the products was
effected by FC unless otherwise stated.
(27) Greenfield, N.; Fasman, G. D. Biochemistry 1969, 8, 4108-4116.
(28) Furthermore the CD spectra, NMR spectra, and the dramatic
change in the solubility during the formation of 24 are hints for the
change in the secondary structure. 24 is less soluble in MeOH, CDCl3,
and CH2Cl2 than 20. The 1H NMR signals of 24 are broadened, whereas
the NMR signals of 20 are sharp.
(29) TINKER (Version 3.8) is
a modular program package for
molecular mechanics-based potential energy calculations, molecular
dynamics simulation, distance geometry, and structural analysis
written by Ponder, J . W., and co-workers.
(30) MacKerell, A. D., J r.; Bashford, D.; Bellott, M.; Dunbrack, R.
L., J r.; Evanseck, J . D.; Field, M. J .; Fischer, S.; Gao, J .; Guo, H.; Ha,
S.; J oseph-McCarthy, D.; Kuchnir, L.; Kuczera, K.; Lau, F. T. K.;
Mattos, C.; Michnick, S.; Ngo, T.; Nguyen, D. T.; Prodhom, B.; Reiher,
W. E., III; Roux, B.; Schlenkrich, M.; Smith, J . C.; Stote, R.; Straub,
J .; Watanabe, M.; Wiorkiewicz-Kuczera, J .; Yin, D.; Karplus, M. J .
Phys. Chem. B 1998, 102, 3586-3616.

6900 J . Org. Chem., Vol. 66, No. 21, 2001
J onas et al.
L-2-(Tr im et h ylsila n ylm et h yla m in o)-p en t -4-en e Ca r -
b oxylic Acid Met h yl E st er (H -(N-Tr im et h ylsila n yl-
m eth yl-2-a llyl)-Gly-OMe) (-)-(2). L-allylglycine methyl ester
(-)-(1) (600 mg, 4.6 mmol), chloromethyltrimethylsilane (0.71
mL, 5.1 mmol), KI (846 mg, 5.1 mmol), and Na2CO3 (540 mg,
5.1 mmol) were dissolved in absolute MeCN (20 mL). After 12
h at 83 °C the solvent was evaporated and the residue was
dissolved in MTBE. After filtration the solvent was evaporated.
FC with MTBE/hexane (1:5, Rf ) 0.42) afforded (-)-2 (544 mg,
methylsilanyl)methylamino)-pent-4-enol was obtained as a
colorless oil (yield 94%). H NMR (200 MHz, CDCl3): δ 5.74
1
(ddt, J ) 18, 10, 7 Hz, 4-H), 5.07 (mc, 5-H2), 3.63 (dd, J ) 10,
4 Hz, 1-H), 3.57 (dd, J ) 10, 6 Hz, 1-H′), 2.58 (mc, 2-H), 2.20
(ddbr, J ) 12, 7 Hz, 3-H). CH2TMS: 2.01 (s), 0.02 (s). 13C NMR
(CDCl3): δ 135.0 (d, C-4), 117.6 (t, C-5), 62.0 (t, C-1), 61.2 (d,
C-2), 36.3 (t, C-3). CH2TMS: 35.5 (t), -2.8 (q). HRMS: calcd
for C8H18NSi (M+ - OMe) 156.1209, found 156.1209; calcd for
C6H16NOSi (M+ - C3H5) 146.1001, found 146.0997.
1
55%) as an oil. H NMR (200 MHz, CDCl3): δ 5.77 (dtd, J )
F or m a tion of th e Mor p h olin on e r a c-5. At 0 °C a solution
of chloroacetyl chloride (203 mg, 1.8 mmol) in toluene (5 mL)
was added to a solution of the amino alcohol (336 mg, 1.8
mmol) and NEt3 (5 mL) in toluene (20 mL). After 2 h at room
temperature a catalytic amount of Bu4NI and 20 mL of a KOH
solution (50%) were added. After 10 h the organic layer was
separated, and the aqueous layer was extracted with MTBE
(3 × 20 mL). Purification by FC with MTBE/hexane (1:1, Rf )
18, 8, 8 Hz, 4-H), 5.08 (dd, J ) 18, 3 Hz, 5-H), 5.06 (dd, J ) 8,
3 Hz, 5-H′), 3.71 (s, CO2Me), 3.26 (t, J ) 6 Hz, 2-H), 2.40 (dd,
J ) 8, 6 Hz, 3-H2); CH2TMS: 2.03, 1.98 (2 d, J ) 14 Hz), 0.04
(s). 13C NMR (CDCl3): δ 175.2 (s, C-1), 133.8 (d, C-4), 117.5 (t,
C-5), 64.7 (d, C-2), 51.4 (q, CO2Me), 38.0 (t, C-3); CH2TMS 37.2
(t), -2.7 (q). HRMS calcd for C9H18NO2 (M+ - Me) 200.1107,
found 200.1101. [R]DRT -39° (c ) 0.38, MTBE). Racemic 2 was
prepared analogously from racemic 1.
1
0.35) afforded rac-5 (260 mg, 64%) as a colorless oil. H NMR
2-(Meth oxyca r bon yl(tr im eth ylsila n yl)m eth yla m in o)-
p en t-4-en e Ca r boxylic Acid Meth yl Ester (r a c-3). Methyl
chloroformate (125 µL, 1.6 mmol) was added slowly under
stirring at 0 °C to a suspension of rac-2 (320 mg, 1.5 mmol) in
MTBE (10 mL) and water (10 mL). Afterward a 0.8 N NaOH
solution (2 mL) was added. After 0.5 h, MTBE (20 mL) was
added and the organic layer was separated. The aqueous layer
was extracted with MTBE (3 × 20 mL). Removal of the solvent
afforded rac-3 (405 mg, 98%) as a colorless oil. No further
purification was necessary. 1H NMR (200 MHz, CDCl3): δ 5.74
(mc, 4-H), 5.12 (dd, J ) 16, 3 Hz, 5-H), 5.08 (dd, J ) 8, 3 Hz,
5-H′), 4.7-4.3 (m, 2-H), 3.69 (s, CO2Me), 3.66 (s, CO2Me), 2.8-
2.4 (m, 3-H2, CH2TMS), 0.04 (s, TMS). 13C NMR (CDCl3): δ
171.3 (s, C-1), 157.1 (s, CO2Me), 133.8 (d, C-4), 117.9 (t, C-5),
60.7 (d, C-2), 52.3 (q, CO2Me), 51.9 (q, CO2Me), 36.6 (t, C-3).
CH2TMS: 33.6 (t), -1.4 (q). HRMS: calcd for C12H23NO4Si
(M+) 273.1396, found 273.1397.
(200 MHz, CDCl3): δ, 4.14, 4.04 (2d, J ) 16 Hz, 2-H2), 3.82
(dd, J ) 12, 2 Hz, 6-H), 3.64 (dd, J ) 12, 3 Hz, 6-H′), 3.09 (mc,
5-H); 5-allyl: 5.69 (ddt, J ) 17, 10, 6 Hz), 5.12 (d, J ) 17 Hz),
5.10 (d, J ) 10 Hz), 2.44 (t br, J ) 6 Hz); CH2TMS: 3.35, 2.23
(2d, J ) 15 Hz), 0.05 (s). 13C NMR (CDCl3): δ 165.6 (s, C-3),
67.7 (t, C-2), 65.5 (t, C-6), 57.6 (d, C-5); 5-allyl: 133.4 (d), 118.8
(t), 34.5 (t); CH2TMS: 37.2 (t), -1.3 (q). HRMS: calcd for
C
11H21NO2Si (M+ - H) 227.1342, found 227.1345.
2-((Tr im et h ylsila n yl)m et h yla m in o)h ex-5-en yl Tr it yl
Eth er (r a c-7). The same procedure as for the preparation of
rac-2 was used. 2-Aminohex-5-enyl trityl ether (rac-6)31 (1.2
g, 5 mmol), chloromethyltrimethylsilane (0.69 mL, 5 mmol),
KI (0.83 g, 5 mmol), and Na2CO3 (0.53 g, 5 mmol) afforded
rac-7 (1.3 g, 60%) as a colorless oil. Purification was achieved
by FC with MTBE/hexane (1:5, Rf ) 0.37). 1H NMR (400 MHz,
CDCl3): δ 5.76 (ddt, J ) 16, 10, 6 Hz, 5-H), 4.94 (dd, J ) 16,
2 Hz, 6-H), 4.91 (dd, J ) 10, 2 Hz, 6-H′), 3.18 (dd, J ) 9, 4 Hz,
1-H), 3.00 (dd, J ) 9, 6 Hz, 1-H), 2.60 (m, 2-H), 1.97 (mc, 4-H),
1.56 (dt, J ) 14, 6 Hz, 3-H), 1.43 (dt, J ) 14, 7 Hz, 3-H); Tr:
(1-Hyd r oxym eth ylbu t-3-en yl)tr im eth ylsila n ylm eth yl-
ca r ba m ic Acid Meth yl Ester (r a c-4a ). MeOH (2 mL) was
slowly added under stirring to a suspension of rac-3 (190 mg,
0.7 mmol) and NaBH4 (133 mg, 3.5 mmol) in THF (10 mL).
After complete reduction MeOH (10 mL) was added. After the
evolution of H2 had ceased, the solvent was evaporated. The
crude product was suspended in MTBE (20 mL), and a
saturated solution of NH4Cl (30 mL) was added. The organic
layer was separated, and the aqueous layer was extracted with
MTBE (3 × 20 mL). Removal of the solvent afforded rac-4a
(168 mg, 98%) as a colorless oil. No further purification was
7.5-7.2 (m); CH2TMS: 1.94, 1.84 (2d, J ) 12 Hz), 0.04 (s). 13
C
NMR (CDCl3): δ 138.9 (d, C-5), 114.3 (t, C-6), 64.1 (t, C-1),
60.9 (d, C-2), 30.3 (t, C-4), 26.9 (t, C-3); Tr: 144.3 (s), 128.7,
127.7, 126.9 (3d), 86.2 (s); CH2TMS: 36.4 (t), -2.6 (q).
HRMS: calcd for C29H38NOSi (M+ + H) 444.2773, found
444.2727.
Tr im eth ylsilan ylm eth yl(1-tr ityloxym eth ylpen t-4-en yl)-
ca r ba m ic Acid Meth yl Ester (r a c-8a ). The same procedure
as for rac-3 was used. rac-7 (226 mg, 0.5 mmol), methyl
chloroformate (42 µL, 0.55 mmol), and 1 N NaOH (1 mL)
afforded rac-8a (240 mg, 96%) as a colorless oil, which was
1
necessary. H NMR (400 MHz, 55 °C, CDCl3): δ 5.78 (ddt, J
) 17, 10, 7 Hz, 3-H), 5.11 (ddd, J ) 17, 3, 2 Hz, 4-H), 5.06 (d,
J ) 10 Hz, 4-H′), 3.85 (br, CH2OH), 3.7-3.6 (m, 1-H, CH2-
OH), 3.69 (s, CO2Me), 2.68, 2.54 (2d, J ) 15 Hz, CH2TMS),
2.36 (t, J ) 7 Hz, 2-H2), 0.08 (s, TMS). 13C NMR (CDCl3): δ
157.9 (s, CO2Me), 134.6 (d, C-3), 117.5 (t, C-4), 63.7 (t, CH2-
OH), 52.4 (q, CO2Me). CH2TMS: 33.2 (t), -1.4 (q), C-2 and
C-1 were not detected. HRMS: calcd for C11H23NO3Si (M+)
245.1447, found 245.1450.
1
purified by FC with MTBE/hexane (1:10, Rf ) 0.48). H NMR
(200 MHz, C6D6, 80 °C): δ 5.83 (ddt, J ) 16, 10, 7 Hz, 4-H),
5.06 (ddd, J ) 16, 4, 2 Hz, 5-H), 5.00 (ddd, J ) 10, 4, 2 Hz,
5-H), 4.33 (mc, 1-H), 3.73 (s, CO2Me), 3.21 (d, J ) 8 Hz,
-OCH2), 2.08 (mc, 3-H2), 1.62 (mc, 2-H2); Tr: 7.5-7.2 (m); CH2-
TMS: 2.51, 2.41 (2d, J ) 14 Hz), 0.05 (s, TMS). 13C NMR
(CDCl3, 55 °C): δ 157.6 (s, CO2Me), 137.9 (d, C-4), 114.8 (t,
C-5), 64.3 (t, -OCH2), 57.1 (d, C-1), 52.0 (q, CO2Me), 30.5 (t,
C-3), 27.0 (t, C-2); Tr: 144.1 (s), 128.8, 127.7, 126.9 (3d), 86.9
(s). CH2TMS: 34.6 (t), -1.0 (q). HRMS: calcd for C31H39NO3-
Si (M+) 501.2699, found 501.2687.
Tr im eth ylsila n ylm eth yl(1-tr ityloxym eth ylbu t-3-en yl)-
ca r ba m ic Acid Meth yl Ester (r a c-4b). At 80 °C rac-4a (180
mg, 0.73 mmol) and triphenylchloromethane (245 mg, 0.88
mmol) were stirred in pyridine (5 mL). After 7 days MTBE
(50 mL) was added and the mixture was washed with 10%
citric acid (3 × 20 mL). Drying over MgSO4, removal of the
solvent, and purification by FC with MTBE/hexane (1:1, Rf )
0.28) afforded rac-4b (100 mg, 28%) as a colorless oil. 1H NMR
(200 MHz, 55 °C, CDCl3): δ 7.5-7.2 (m, Tr), 5.73 (ddt, J )
17, 10, 7 Hz, 3-H), 5.09 (ddd, J ) 17, 3, 2 Hz, 4-H), 5.02 (d, J
) 10 Hz, 4-H′), 4.32 (br, 1-H), 3.71 (s, CO2Me), 3.22 (d, J ) 7
Hz, CH2OR), 2.32 (mc, 2-H2). CH2TMS: 2.42 (s), 0.13 (s). 13C
NMR (55 °C, CDCl3): δ 157.4 (s, CO2Me), 144.1 (s, Tr), 135.0
(d, C-3), 128.8, 127.7, 127.0 (3d, Tr), 116.8 (t, C-4), 86.9 (s,
Tr), 64.0 (t, CH2OR), 57.6 (d, C-1), 52.0 (q, CO2Me), 34.4 (t,
Tr im eth ylsilan ylm eth yl(1-tr ityloxym eth ylpen t-4-en yl)-
ca r ba m ic Acid ter t-Bu tyl Ester (r a c-8b). rac-7 (150 mg,
0.34 mmol), Boc2O (148 mg, 0.67 mmol), and NEt3 (0.5 mL)
were heated to reflux. After the reaction was finished, removal
of the solvent and residual reagents under reduced pressure
afforded rac-8b (184 mg, 99%) as a colorless oil. No further
1
purification was necessary. H NMR (200 MHz, C6D6, 55 °C):
δ 5.84 (ddt, J ) 18, 10, 7 Hz, 4-H), 5.03 (ddd, J ) 18, 4, 2 Hz,
5-H), 5.03 (ddd, J ) 10, 4, 2 Hz, 5-H′), 4.22 (mc, 1-H), 3.14 (d,
J ) 7 Hz, -OCH2), 2.05 (mc, 3-H2), 1.59 (mc, 2-H2), 1.49 (s,
Boc); Tr: 7.5-7.2 (m); CH2TMS: 2.51, 2.39 (2d, J ) 14 Hz),
0.08 (s). 13C NMR (CDCl3, 55 °C): δ 156.1 (s, Boc), 138.1 (d,
C-4), 114.8 (t, C-5), 79.1 (s, Boc), 64.7 (t, -OCH2), 57.0 (d, C-1),
30.5 (t, C-3), 29.6 (t, C-2), 28.6 (q, Boc); Tr: 144.2 (s, Tr), 128.8,
127.7, 126.9 (3d), 86.8 (s); CH2TMS: 34.9 (t), -0.8 (q).
HRMS: calcd for C34H46NO3Si (M+) 544.3247, found 544.3245.
C-2); CH2TMS: 35.3 (t), -1.1 (q). HRMS: calcd for C30H37
-
NO3Si (M+) 487.2543, found 487.2544.
5-Allyl-4-tr im eth ylsila n ylm eth ylm or p h olin -3-on e (r a c-
5). Red u ction of r a c-2 w ith Na BH4. The same procedure
as for rac-4a was used. Without further purification 2-((tri-

Formation of Cyclic Amino Acid Derivatives
J . Org. Chem., Vol. 66, No. 21, 2001 6901
4-Meth yl-N-tr im eth ylsilan ylm eth yl-N-(1-tr ityloxym eth -
ylp en t-4-en yl)ben zen e Su lfon a m id e (r a c-8c). rac-7 (100
mg, 0.23 mmol), tosyl chloride (47 mg, 0.25 mmol), NEt3 (0.5
mL), and CH2Cl2 (10 mL) were stirred for 12 h. The crude
mixture was added to a saturated solution of NaCl (20 mL).
The aqueous layer was extracted with CH2Cl2 (3 × 20 mL).
Purification by FC with MTBE/hexane (1:10, Rf ) 0.48)
(2,4-tr a n s)-4-Meth ylp yr r olid in e-1,2-d ica r boxylic Acid
Dim eth yl Ester (r a c-11). Following the procedure P, rac-3
(0.5 mmol, 136 mg), BP (23 mg) and ADC (22 mg) yielded after
purification by FC with MTBE/hexane (1:1, Rf ) 0.23) rac-11
(52 mg, 51%, 1:1 mixture of rotamers) as a colorless oil. 1H
NMR (400 MHz, CDCl3): δ 4.41/4.34 (dd, J ) 8, 3 Hz, 2-H),
3.8-3.6 (m, 4-H, 5-H), 3.72, 3.68 (2s, 2 × CO2Me), 3.03/2.95
(dd, J ) 11, 9 Hz, 5-H′), 2.39 (mc, 4-H′), 2.09 (ddd, J ) 9, 6, 3
Hz, 3-H), 1.84 (mc, 3-H′), 1.05/1.03 (d, J ) 7 Hz, 4-Me). 13C
NMR (CDCl3): δ 173.2/173.1 (s, 2-CO2Me), 155.4/154.9 (s,
1-CO2Me), 59.3/59.0 (d, C-2), 53.6/53.2 (t, C-5), 52.5, 52.2 (q,
1-, 2-CO2Me), 38.6/37.5 (t, C-3), 32.1/31.1 (d, C-4), 17.3 (q,
4-Me). HRMS: calcd for C8H15NO4 (M+) 201.1001, found
201.1000.
2-H yd r oxym et h yl-4-m et h ylp yr r olid in e-1-ca r b oxylic
Acid Meth yl Ester (r a c-12a ). Following the procedure P, rac-
4a (24 mg, 0.1 mmol), BP (5 mg), and ADC (5 mg) yielded after
purification by FC with EtOAc/CH2Cl2 rac,cis- and trans-12a
(34%). rac,cis-12a (Rf ) 0.25, 2 mg) was eluted first as an oil,
followed by rac,trans-12a (Rf ) 0.21, 4 mg) as the second
fraction.
1
afforded rac-8c (90 mg, 65%) as a colorless oil. H NMR (200
MHz, C6D6, 55 °C): δ 7.65 (d, J ) 8 Hz, Ts), 7.4-7.1 (m, Ts,
Tr), 5.76 (ddt, J ) 18, 10, 6 Hz, 4-H), 5.0-4.9 (m, 5-H), 3.98
(mc, 1-H), 3.03 (d, J ) 6 Hz, -OCH2), 2.41 (s, Ts), 2.0-1.4 (m,
2-H2, 3-H2); CH2TMS: 2.53, 2.40 (2d, J ) 16 Hz), 0.07 (s). 13C
NMR (CDCl3, 55 °C): δ 142.6 (s, Ts), 137.8 (d, C-4), 136.9 (s,
Ts), 129.4 (d, Ts), 127.3 (d, Ts), 114.9 (t, C-5), 63.8 (t, -OCH2),
58.6 (d, C-1), 30.6 (t, C-3), 29.7 (t, C-2), 21.5 (q, Ts); Tr: 143.5
(s), 128.6, 127.7, 126.9 (3d), 86.9 (s); CH2TMS: 35.3 (t), -1.1
(q). HRMS: calcd for C35H40NO3SSi (M+ - Me) 582.2498, found
582.2497.
P r ep a r a tion of r a c-10: Acetic Acid 6-(Meth oxyca r bo-
n yl(t r im et h ylsila n yl)m et h yla m in o)-7-t r it yloxym et h yl-
h ep t-2-en yl Ester (r a c-9). Cr oss Meta th esis. rac-8a (158
mg, 0.36 mmol), but-2-ene-1,4-diol diacetate (115 mg, 0.72
mmol), and [Ru]32 (44 mg, 5 mol %) were dissolved in CH2Cl2
(5 mL) and heated for 12 h at 40 °C. Purification by FC with
MTBE/hexane (1:4, Rf ) 0.22) afforded rac-9 (180 mg, 87%).
1H NMR (200 MHz, 55 °C, CDCl3): δ 7.5-7.2 (m, Tr), 5.79
(dt, J ) 16, 6 Hz, 2-H), 5.54 (dt, J ) 16, 6 Hz, 3-H), 4.51 (d, J
) 6 Hz, 1-H2), 4.22 (mc, 6-H), 3.69 (s, CO2Me), 3.16 (d, J ) 7
Hz, 7-H2), 2.04 (s, Ac), 2.02 (mc, 4-H2), 1.67 (mc, 5-H2); CH2-
TMS: 2.44, 2.35 (2d, J ) 14 Hz), 0.00 (s). 13C NMR (55 °C,
CDCl3): δ 170.4 (s, Ac), 157.5 (s, CO2Me), 134.9 (d, C-2), 124.9
(d, C-3), 64.8 (t, C-1), 64.4 (t, C-7), 57.2 (d, C-6), 52.0 (q,
CO2Me), 29.2 (t, C-4), 29.0 (t, C-5), 20.7 (q, Ac); Tr: 144.1 (s),
128.9, 127.7, 127.0 (3d), 87.0 (s); CH2TMS: 34.9 (t), -1.0 (q).
HRMS: calcd for C34H43NO5Si (M+) 573.2911, found 573.2923.
6-(Meth oxyca r bon yl(tr im eth ylsila n yl)m eth yla m in o)-
7-tr ityloxyh ept-2-en oic Acid Meth yl Ester (r a c-10). Tr an s-
ester ifica tion of th e Aceta te Gr ou p . The allyl acetate rac-9
(180 mg, 0.3 mmol) was stirred with KCN (10 mg) in absolute
MeOH (50 mL). After complete transesterification the solvent
was evaporated. MTBE (20 mL) was added to the crude
mixture. Filtration over Celite afforded (6-hydroxy-1-trityl-
oxymethylhex-4-enyl)(trimethylsilanyl)methylcarbamic acid
methyl ester (160 mg, 96%). 1H NMR (200 MHz, CDCl3): δ
7.5-7.2 (m, Tr), 5.63 (mc, 4-H, 5-H2), 4.26 (mc, 1-H), 4.05 (d, J
) 4 Hz, 6-H2), 3.69 (s, CO2Me), 3.16 (d, J ) 7 Hz, -CH2OR),
2.03 (mc, 3-H2), 1.58 (mc, 2-H2); CH2TMS: 2.44, 2.34 (2d, J )
14 Hz), 0.00 (s). 13C NMR (CDCl3): δ 157.5 (s, CO2Me), 131.7
(d, C-5), 130.2 (d, C-4), 64.4 (t, CH2OR), 63.4 (t, C-6), 57.1 (d,
C-1), 52.0 (q, CO2Me), 29.3 (t, C-3), 29.0 (t, C-2); Tr: 144.1 (s),
128.8, 127.7, 127.0 (3d), 87.1 (s); CH2TMS: 34.7 (t), -1.1 (q).
HRMS: calcd for C32H41NO4Si (M+) 531.2805, found 531.2811.
Oxid a tion of th e Allyl Alcoh ol. Allyl alcohol (160 mg, 0.3
mmol) and MnO2 (524 mg, 6 mmol) were stirred in pentane/
CH2Cl2 (1:1, 10 mL) overnight. The crude oily aldehyde (150
mg) obtained after filtration was used without purification for
the next step. MnO2 (524 mg, 6 mmol), NaCN (40 mg, 0.8
mmol), HOAc (13 µL), and the aldehyde (150 mg) were stirred
in absolute MeOH (10 mL). After complete reaction and
removal of the solvent, MTBE was added. Filtration over Celite
afforded rac-10 (141 mg) as a colorless oil. No further purifica-
tion was necessary. Overall yield starting from rac-8a : 75%.
1H NMR (400 MHz, CDCl3): δ 7.4-7.2 (m, Tr), 6.91 (dt, J )
16, 7 Hz, 3-H), 5.80 (d, J ) 16 Hz, 2-H), 4.22 (mc, 6-H), 3.73
(s, CO2Me), 3.69 (s, CO2Me), 3.15 (mc, 7-H2), 2.15 (td, J ) 8, 7
Hz, 4-H2), 1.7-1.5 (m, 5-H2); CH2TMS: 2.40, 2.34 (2d, J ) 14
Hz), -0.02 (s). 13C NMR (CDCl3): δ 166.7 (s, C-1), 157.4 (s,
CO2Me), 148.0 (d, C-3), 121.5 (d, C-2), 64.2 (t, C-7), 56.9 (d,
C-6), 52.1 (q, CO2Me), 51.1 (q, CO2Me), 28.9 (t, C-4), 28.2 (t,
C-5); Tr: 143.9 (s), 128.7, 127.7, 127.0 (3d), 87.0 (s); CH2TMS:
34.7 (t), -1.1 (q). HRMS: calcd for C32H38NO5Si (M+ - Me)
544.2519, found 544.2519.
(2,4-cis)-4-Meth ylp r olin ol (r a c,cis-12a ). 1H NMR (400
MHz, CDCl3): δ 3.97 (mc, 2-H), 3.8-3.7 (m, 5-H, CH2OH), 3.72
(s, CO2Me), 3.60 (dd, J ) 12, 7 Hz, CH2OH), 2.80 (t, J ) 10
Hz, 5-H′), 2.2-2.1 (m, 3-H, 4-H), 1.26 (mc, 3-H′), 1.02 (d, J )
6 Hz, 4-Me). 13C NMR (CDCl3): δ 67.4 (t, CH2OH), 61.9 (d,
C-2), 54.2 (t, C-5), 52.6 (q, CO2Me), 37.1 (t, C-3), 32.1 (d, C-4),
16.7 (q, 4-Me), carbonyl C was not detected. HRMS: calcd for
C7H12NO2 (M+ - CH2OH) 142.0868, found 142.0863.
(2,4-tr a n s)-4-Meth ylp r olin ol (r a c,tr a n s-12a ). 1H NMR
(400 MHz, CDCl3): δ 4.08 (mc, 2-H), 3.72 (s, CO2Me), 3.64 (mc,
CH2OH), 3.52 (dd, J ) 10, 7 Hz, 5-H), 3.01 (dd, J ) 10, 8 Hz,
5-H′), 2.30 (mc, 4-H), 1.8-1.5 (m, 3-H2), 1.02 (d, J ) 7 Hz,
4-Me). 13C NMR (CDCl3): δ 67.7 (t, CH2OH), 60.2 (d, C-2), 54.2
(t, C-5), 52.7 (q, CO2Me), 36.4 (t, C-3), 31.8 (d, C-4), 17.9 (q,
4-Me), carbonyl C was not detected. HRMS: calcd for C7H12
-
NO2 (M+ - CH2OH) 142.0868, found 142.0863.
4-Met h yl-2-t r it yloxym et h ylp yr r olid in e-1-ca r b oxylic
Acid Meth yl Ester (r a c-12b). Following the procedure P, rac-
4b (73 mg, 0.15 mmol), BP (7 mg), and ADC (7 mg) yielded
after purification by FC with MTBE/hexane (1:4, Rf ) 0.30) a
1:2 mixture of rac,cis- and trans-12b (28 mg, 45%) as a
colorless oil. HRMS: calcd for C27H28NO3 (M+ - H) 414.2069,
found 414.2066. rac,trans-12b: 1H NMR (400 MHz, 58 °C,
CDCl3): δ 7.6-7.1 (m, Tr), 4.0-3.8 (m, 2-H), 3.40 (s, CO2Me),
3.52 (dd, J ) 10, 7 Hz, CH2OR), 3.3-3.1 (m, 5-H, CH2OR),
2.95 (mc, 5-H′), 2.4-2.1 (m, 3-H, 4-H), 1.7-1.5 (m, 3-H′), 1.02
(d, J ) 7 Hz, 4-Me). 13C NMR (CDCl3): δ 155.6 (s, CO2Me),
64.5 (t, CH2OR), 57.7 (d, C-2), 54.0 (t, C-5), 52.0 (q, CO2Me),
18.0 (q, 4-Me); Tr: 144.4 (s), 128.8, 127.9, 127.0 (3d), 86.8 (s);
(C-3 and C-4 were not detected). rac,cis-12b: 1H NMR (400
MHz, 58 °C, CDCl3): δ 7.6-7.1 (m, Tr), 4.0-3.8 (m, 2-H), 3.40
(sbr, CO2Me), 3.3-3.1 (m, 5-H, CH2OR), 2.85 (t, J ) 10 Hz,
5-H′), 2.4-2.1 (m, 3-H, 4-H), 1.7-1.5 (m, 3-H′), 1.06 (d, J ) 7
Hz, 4-Me).
5-Meth yl-2-tr ityloxym eth ylpiper idin e-1-car boxylic Acid
Meth yl Ester (r a c-14a ). Following the procedure P, rac-8a
(86 mg, 0.17 mmol), BP (9 mg), and ADC (9 mg) yielded after
purification by FC with MTBE/hexane (10:1, Rf ) 0.17) a 1:5
mixture of rac,cis- and trans-14a (52 mg, 51%) as a colorless
oil. rac,trans-14a : 1H NMR (500 MHz, CDCl3): δ 7.4-7.1 (m,
Tr), 4.42 (mc, 2-H), 3.7-3.6 (m, 6-H), 3.65 (s, CO2Me), 3.17 (dd,
J ) 10, 8 Hz, CH2OR), 3.00 (dd, J ) 8, 6 Hz, CH2OR), 2.72
(dd, J ) 13, 3 Hz, 6-H′), 1.70 (mc, 3-H, 5-H), 1.40 (mc, 3-H′,
4-H), 1.14 (mc, 4-H′), 0.88 (d, J ) 7 Hz, 5-Me). 13C NMR
(CDCl3): δ 157.3 (s, CO2Me), 61.5 (t, CH2OR), 52.4 (q, CO2Me),
50.8 (d, C-2), 44.8 (t, C-6), 27.3 (d, C-5), 25.4 (t, C-4), 20.4 (t,
C-3), 16.6 (q, 5-Me); Tr: 144.1 (s), 128.7, 127.7, 127.0 (3d), 86.5
(s). HRMS: calcd for C28H30NO3 (M+ - H) 428.2226, found
428.2227.
5-Meth yl-2-tr ityloxym eth ylpiper idin e-1-car boxylic Acid
ter t-Bu tyl Ester (r a c-14b). Following the procedure P, rac-
8b (105 mg, 0.19 mmol), BP (9 mg), and ADC (9 mg) yielded
after purification by FC with MTBE/pentane (1:3) a 1:5
mixture of rac,cis- and trans-14b and 15. rac-14b (Rf ) 0.29,
(31) Compound 6 was prepared according to ref 11.
(32) [Ru]: Cl2(PCy3)RudCHPh, Cy ) cyclohexyl, see also refs 12a,b.

6902 J . Org. Chem., Vol. 66, No. 21, 2001
J onas et al.
26 mg, 30%) was eluted first as an oil and rac-15 (oily, Rf )
0.19, 11 mg, 12%) as a second fraction. rac,trans-14b: 1H NMR
(400 MHz, 55 °C, CDCl3): δ 7.5-7.0 (m, Tr), 4.46 (dddd, J )
7, 7, 5, 3 Hz, 2-H), 3.64 (d, J ) 14 Hz, 6-H), 3.21 (dd, J ) 9, 7
Hz, CH2OR), 3.10 (dd, J ) 9, 7 Hz, CH2OR), 2.81 (dd, J ) 14,
4 Hz, 6-H′), 1.84 (mc, 3-H), 1.74 (mc, 5-H), 1.6-1.4 (m, 3-H′,
4-H), 1.49 (s, Boc), 1.22 (mc, 4-H′), 0.97 (d, J ) 7 Hz, 5-Me).
13C NMR (CDCl3): δ 61.6 (t, -CH2O), 50.5 (d, C-2), 44.6 (t, C-6),
27.5 (d, C-5), 25.6 (t, C-4), 20.6 (t, C-3), 16.6 (q, 5-Me); Tr: 144.1
(s), 128.7, 127.7, 126.9 (3d), 86.3 (s); Boc: 155.8 (s), 79.0 (s),
28.6 (q). MS (EI, 200 °C): m/z (%) 410 (2), 368 (1), 341 (4), 243
(Tr+, 90), 228 (M+ - Tr, 10), 198 (78), 183 (35), 165 (50), 142
(94), 105 (32), 98 (93), 81 (86), 69 (100), 57 (92). HRMS: calcd
Hz), 4.18 (dd, J ) 12, 4 Hz). 13C NMR (CDCl3): δ 170.2/169.8
(s, CO2Me), 62.3/59.3 (d, C-2), 52.5/52.2 (q, CO2Me); 2-allyl:
134.0/132.0 (d), 119.7/118.4 (t), 33.4/33.2 (t); CH2TMS: 40.7/
35.6 (t), -0.7/-1.9 (q); benzoyl-Gly-:167.9/167.4 (s), 167.2/167.0
(s), 133.8/133.7 (s), 131.6, 128.5/128.4, 127.0 (3d), 42.1/41.9 (t).
HRMS: calcd for C19H28N2O4Si (M+) 376.1818, found 376.1819.
F MOC-Gly-(N -t r im e t h ylsila n ylm e t h yl-2-a llyl)-Gly-
OMe (18a ). Following the procedure F, (-)-2 (108 mg, 0.5
mmol), FMOC-Gly-OH (178 mg, 0.6 mmol), HABT (82.6 mg),
DIC (0.093 mL), DIEA (0.102 mL), and MeCN (10 mL) were
used in the coupling reaction. Purification was achieved by
dissolving the crude product in a minimum amount of MTBE
and filtering off the urea. 18a (244 mg, 99%, 1:1 mixture of
for C19H15 (Tr+) 243.1173, found 243.1178; calcd for C12H22
-
rotamers) was obtained as a colorless oil. H NMR (400 MHz,
1
NO3 (M+ - Tr) 228.1600, found 228.1602.
CDCl3): δ 4.3-3.8 (m, 2-H), 3.74 (s, CO2Me); 2-allyl: 5.9-5.6
(m), 5.15 (mc), 2.9-2.5 (m); CH2TMS: 2.96, 2.70 (2d, J ) 16
Hz), 0.17/0.08 (s, TMS); FMOC-Gly-: 7.76 (d, J ) 8 Hz), 7.62
(mc), 7.40, 7.31 (2t, J ) 8 Hz), 4.38 (mc), 4.3-3.8 (m). 13C NMR
(CDCl3): δ 170.2/169.8 (s), 167.7/167.2 (s) 156.0 (s), 143.8 (s),
141.2 (s), 134.0/132.0 (d), 127.6 (d), 126.9 (d), 125.1 (d), 119.8
(d), 119.6/118.2 (t), 67.0 (t), 62.1/59.2 (d), 52.4/52.1 (q), 47.0
(d), 42.9/42.7 (t), 40.4 (t), 33.3/33.2 (t); CH2TMS: 35.6 (t)
-0.7/-1.9 (q). HRMS: calcd for C27H34N2O5Si (M+) 494.2237,
found 494.2232.
F or m yl(1-t r it yloxym et h ylp en t -4-en yl)ca r b a m ic Acid
ter t-Bu tyl Ester (r a c-15). 1H NMR (400 MHz, CDCl3): δ 7.4-
7.2 (m, Tr), 5.73 (ddt, J ) 16, 10, 6 Hz, 4-H), 4.97 (dd, J ) 16,
2 Hz, 5-H), 4.94 (dd, J ) 10, 2 Hz, 5-H′), 4.80 (mc, 1-H), 3.39
(mc, CH2OR), 3.20 (dd, J ) 8, 5 Hz, CH2OR), 1.97 (mc, 3-H2),
1.83 (mc, 2-H), 1.59 (mc, 2-H′), 1.43 (s, Boc). 13C NMR (CDCl3):
δ 163.9 (d, formyl), 137.5 (d, C-5), 115.2 (t, C-6), 63.5 (t, C-1),
30.4 (t, C-4), 28.4 (t, C-3); Tr: 143.9 (s), 128.6, 127.9, 126.9
(3d), 86.4 (s); Boc: 152.9 (s), 83.8 (s), 28.0 (q). HRMS: calcd
for C31H34NO4 (M+ - H) 484.2488, found 484.2488.
5-Meth oxycar bon ylm eth yl-2-tr ityloxym eth ylpiper idin e-
1-ca r boxylic Acid Meth yl Ester (r a c-16). Following the
procedure P, rac-10 (90 mg, 0.16 mmol), BP (7 mg), and ADC
(7 mg) yielded after purification by FC with MTBE/hexane (1:
3, Rf ) 0.23) a 1:6 mixture of rac,cis- and trans-16 (51 mg,
65%) as a colorless oil. rac,trans-16: 1H NMR (500 MHz,
CDCl3): δ 7.5-7.3 (m, Tr), 4.54 (mc, 2-H), 3.86 (d br, J ) 14
Hz, 6-H), 3.75 (s, CO2Me), 3.66 (s, CO2Me), 3.28 (dd, J ) 8, 7
Hz, CH2OR), 3.14 (dd, J ) 8, 6 Hz, CH2OR), 2.84 (dd, J ) 14,
3 Hz, 6-H′), 2.50 (dd, J ) 14, 8 Hz, 5-CH2R), 2.37 (dd, J ) 14,
7 Hz, 5-CH2R), 2.18 (mc, 5-H), 1.80 (mc, 3-H), 1.58 (ddd, J )
14, 8, 3 Hz, 3-H′), 1.52 (ddt, J ) 14, 8, 4 Hz, 4-H), 1.36 (dbr,
J ) 14 Hz, 4-H′). 13C NMR (CDCl3): δ 173.2 (s, CO2Me), 157.0
(s, CO2Me), 61.2 (t, CH2OR), 52.5 (q, CO2Me), 51.5 (q, CO2Me),
50.7 (d, C-2), 43.0 (t, C-6), 35.1 (t, 5-CH2R), 29.6 (d, C-5), 23.5
(t, C-4), 20.6 (t, C-3); Tr: 144.0 (s), 128.6, 127.8, 127.0 (3d),
86.5 (s). HRMS: calcd for C30H34NO3 (M+ + H) 488.2437, found
488.2433.
7-Met h ylt et r a h yd r op yr r olo[2,1-c][1,4]oxa zin e-4-on e
(r a c-13). Following the procedure P (but irradiation time 12
h), rac-5 (80 mg, 0.35 mmol), BP (16 mg), and ADC (16 mg)
yielded after purification by chromatography on SEPHADEX
LH-20 with CH2Cl2/MeOH gradient (50:1 f 1:1) rac-13 (4 mg,
7%, GC yield 45%) as a colorless oil. 1H NMR (500 MHz,
CDCl3): δ 4.24 (d, J ) 16 Hz, 3-H), 4.14 (dd, J ) 12, 4 Hz,
1-H), 4.02 (d, J ) 16 Hz, 3-H′), 3.80 (mc, 9-H), 3.65 (dd, J )
11, 9 Hz, 6-H), 3.24 (t, J ) 12 Hz, 1-H′), 3.19 (d, J ) 11 Hz,
6-H′), 2.32 (mc, 7-H), 2.07 (dt, J ) 12, 6 Hz, 8-H), 1.14 (d, J )
7 Hz, 7-Me), 1.10 (dt, J ) 16, 12 Hz, 8-H′). 13C NMR (CDCl3):
δ 69.0 (t, C-1), 67.0 (t, C-3), 57.9 (d, C-9), 51.9 (t, C-6), 37.3 (t,
C-8), 31.7 (d, C-7), 17.9 (q, 7-Me) (C-4 was not detected).
HRMS: calcd for C8H13NO2 155.0946, found 155.0943. Anal.
Calcd for C8H13NO2: C, 61.91; H, 8.45; N, 9.03. Found: C,
61.23; H, 8.36; N, 8.93.
Ben zoyl-Gly-(N-Tr im et h ylsila n ylm et h yl-2-a llyl)-Gly-
OMe (r a c-17a ).33 Following the procedure F, rac-2 (108 mg,
0.5 mmol), hippuric acid (116 mg, 0.6 mmol), HABT (82.6 mg),
DIC (0.093 mL), DIEA (0.102 mL), and MeCN (10 mL) were
used in the coupling reaction. Purification by FC with MTBE/
hexane (1:1, Rf ) 0.23) afforded rac-17a (85 mg, 45%, 1:1
mixture of rotamers) as a colorless oil. 1H NMR (200 MHz,
CDCl3): δ 4.38/3.81 (dd, J ) 9, 6 Hz, 2-H), 3.73/3.72 (s, CO2-
Me); 2-allyl: 5.9-5.6 (m), 5.3-5.0 (m), 2.9-2.5 (m); CH2TMS:
3.03 (d, J ) 16 Hz), 2.9-2.5 (m), 0.17/0.06 (s); benzoyl-Gly-:
7.83 (dd, J ) 8, 1 Hz), 7.5-7.3 (m, N-H, Ph), 4.28 (t, J ) 4
F MOC-Ala -(N -t r im e t h ylsila n ylm e t h yl-2-a llyl)-Gly-
OMe (18b). Following the procedure F, (-)-2 (108 mg, 0.5
mmol), FMOC-Ala-OH (186 mg, 0.6 mmol), HABT (82.6 mg),
DIC (0.093 mL), DIEA (0.102 mL), and MeCN (10 mL) were
used in the coupling reaction. Purification by FC with MTBE/
hexane (1:3, Rf ) 0.28) afforded 18b (90 mg, 35%, 1:1 mixture
1
of rotamers) as a colorless oil. H NMR (400 MHz, CDCl3): δ
4.45 (mc)/3.63 (dd, J ) 9, 8 Hz, 2-H), 3.74/3.68 (s, CO2Me);
2-allyl: 5.75 (mc), 5.15 (mc), 2.9-2.5 (m); CH2TMS: 3.09, 2.67
(2d, J ) 16 Hz)/2.63, 2.50 (2d, J ) 15 Hz), 0.16/0.07 (s, TMS);
FMOC-Ala-: 7.76, 7.60 (2d, J ) 8 Hz), 7.40, 7.31 (2t, J ) 8
Hz), 4.74 (q, J ) 7 Hz), 4.35 (mc), 4.21 (mc), 1.35/1.33 (d, J )
7 Hz). 13C NMR (CDCl3): δ 170.1 (s, CO2Me), 143.9/143.8 (s),
141.3 (s), 134.1/132.6 (d), 127.6 (d), 127.0 (d), 125.2 (d), 119.6
(d), 119.4/118.5 (t), 67.0/66.8 (t), 62.6/60.0 (d), 52.5/52.1 (q),
47.2/46.7 (d), 42.3 (t), 35.8 (t), 34.1/33.2 (t), 19.7/19.3 (q), -0.7/-
2.1 (q, TMS), (-CONR2 and -NCOOR were not detected).
HRMS: calcd for C28H36N2O5Si (M+) 508.2393, found 508.2389.
F MOC-P h e -(N -t r im e t h ylsila n ylm e t h yl-2-a llyl)-Gly-
OMe (18c). Following the procedure F, (-)-2 (108 mg, 0.5
mmol), FMOC-Phe-OH (232 mg, 0.6 mmol), HABT (82.6 mg),
DIC (0.093 mL), DIEA (0.102 mL), and MeCN (10 mL) were
used in the coupling reaction. Purification by FC with MTBE/
hexane (1:4, Rf ) 0.26) afforded 18c (220 mg, 75%, 1:1 mixture
1
of rotamers) as a colorless oil. H NMR (200 MHz, CDCl3): δ
7.76 (d, J ) 8 Hz, FMOC), 7.57 (dbr, J ) 8 Hz, FMOC), 7.40
(t, J ) 8 Hz, FMOC), 7.3-7.2 (m, FMOC, Phe), 5.9-5.6 (m,
NH, allyl), 5.43 (ddt, J ) 17, 10, 7 Hz, allyl), 5.2-5.0 (m, allyl,
Phe), 4.84 (q, J ) 7 Hz, Phe), 4.63 (tbr, J ) 8 Hz, 2-H), 4.4-
4.1 (m, 3H, FMOC), 3.70 (mc, 2-H), 3.73/3.61 (s, CO2Me), 3.2-
2.4 (m, allyl, CH2TMS, Phe), 2.15 (mc, allyl), 0.19/0.09 (s, TMS).
13C NMR (CDCl3): δ 171.3 (s), 170.2/169.9 (s), 155.3/155.1 (s),
143.7/143.6 (s), 141.1/141.0 (s), 136.3/136.0 (s), 134.4/132.5 (d),
129.4/129.3 (d), 128.4/128.3 (d), 127.5/126.9 (d), 125.0/124.9 (d),
119.8 (d), 118.9/117.5 (t), 67.0/66.7 (t), 62.5/60.0 (d), 52.2/51.8
(q), 51.6 (d), 47.0/46.9 (d), 41.4 (t), 39.9/39.6 (t), 35.8 (t), 33.7/
33.2 (t), -0.7/-2.3 (q, TMS). HRMS: calcd for C34H40N2O5Si
(M+) 584.2707, found 584.2707.
F MOC-Le u -(N -t r im e t h ylsila n ylm e t h yl-2-a llyl)-Gly-
OMe [(-)-18d ]. Following the procedure F, (-)-2 (285 mg, 1.3
mmol), FMOC-Leu-OH (561 mg, 1.6 mmol), HABT (216 mg),
DIC (0.252 mL), DIEA (0.270 mL), and MeCN (10 mL) were
used in the coupling reaction. Purification by FC with MTBE/
hexane (1:4, Rf ) 0.29) afforded (-)-18d (420 mg, 76%, 1:1
mixture of rotamers) as a colorless oil. 1H NMR (400 MHz,
CDCl3): δ 7.76 (d, J ) 8 Hz, FMOC), 7.60 (d, J ) 8 Hz, FMOC),
7.40 (t, J ) 8 Hz, FMOC), 7.31 (t, J ) 8 Hz, FMOC), 5.75 (mc,
allyl), 5.63/5.45 (d, J ) 9 Hz, NH), 5.15 (mc, allyl), 4.79 (ddd,
J ) 9, 9, 4 Hz, Leu), 4.6 (mc, 2-H, Leu), 4.35 (mc, FMOC), 4.16
(mc, FMOC), 3.67 (mc, 2-H), 3.70 (s, CO2Me), 3.10, 2.67 (2 d, J
) 16 Hz, CH2TMS), 2.63 (d, J ) 15 Hz, CH2TMS), 2.85-2.45
(33) For simplification the following abbreviations for the amino
acids are used: 2-(trimethylsilanylamino)pent-4-enoic acid: H-(N-
trimethylsilanylmethyl-2-allyl)-Gly-OH; 4-methylpyrrolidine-2-carbox-
ylic acid (4-methylprolin): H-Mpr-OH.

Formation of Cyclic Amino Acid Derivatives
J . Org. Chem., Vol. 66, No. 21, 2001 6903
(m, allyl, CH2TMS), 1.75-1.3 (m, Leu), 1.1-0.9 (m, Leu), 0.16/
0.07 (s, TMS). 13C NMR (CDCl3): δ 172.5/171.4 (s), 170.1/170.0
(s), 155.8/155.7 (s), 143.9/143.8 (s), 143.6 (s), 141.1 (s), 134.2/
132.7 (d), 127.5 (d), 126.9 (d), 125.0 (d), 119.8 (d), 119.3/118.2
(t), 66.9/66.6 (t), 62.4/60.0 (d), 52.3/51.9 (q), 49.5/48.7 (d), 47.0
(d), 43.4/42.8 (t), 41.8 (t), 35.6 (t), 33.9/33.2 (t), 24.3 (d), 23.5/
23.4 (d), 21.7/21.3 (q), -0.8/-2.3 (q, TMS). HRMS: calcd for
C31H42N2O5Si (M+) 550.2863, found 550.2864. [R]D -69° (c 1.4,
CHCl3).
trimethylsilanylmethyl-2-allyl)-Gly-OH (250 mg. 0.47 mmol),
H-Leu-Leu-Leu-Leu-NH2*CF3CO2H (247 mg, 0.42 mmol), HABT
(64 mg), DIC (0.073 mL), DIEA (0.100 mL), and MeCN (10
mL) were used in the coupling reaction. Purification by
crystallization (MeOH, Et2O) afforded 20 (512 mg, 81%, 1:2
mixture of rotamers) as a colorless powder. 1H NMR (400 MHz,
D3COD): δ 7.8 (mc, FMOC), 7.6 (mc, 6 H, FMOC), 7.4 (mc, 6
H, FMOC), 7.3 (mc, 6 H, FMOC), 5.9 (mc, 1 H, 2-H), 5.7 (mc, 2
H), 5.2-5.0 (m, 6 H), 4.7-4.55 (m, 3 H), 4.4-4.0 (m, 12 H),
3.00 (d, J ) 16 Hz, 1 H), 2.6-2.45 (m, 11 H), 1.8-1.45 (m, 45
H), 1.0-0.8 (m, 90 H), 0.16 (s, 9 H, TMS), 0.07 (s, 18 H, TMS).
IR (ATR, cm-1): ν 3355 (m), 1526 (s), 1350 (s), 803 (m), 731
F MOC-Gly-Gly-(N-tr im eth ylsila n ylm eth yl-2-a llyl)-Gly-
OMe (r a c-17b). Following the procedure F, rac-2 (350 mg,
1.6 mmol), FMOC-Gly-Gly-OH (691 mg, 1.9 mmol), HABT (265
mg), DIC (0.302 mL), DIEA (0.332 mL), and MeCN (10 mL)
were used in the coupling reaction. Purification by FC with
CH2Cl2/MeOH (50:1, Rf ) 0.14) afforded rac-17b (880 mg, 98%,
1:1 mixture of rotamers) as a colorless oil. 1H NMR (400 MHz,
CDCl3): δ 7.77, 7.61 (2d, J ) 8 Hz, FMOC), 7.40, 7.31 (2t, J )
8 Hz, FMOC), 6.96 (d br, J ) 16 Hz, NH), 5.81 (ddt, J ) 18,
10, 7 Hz, allyl)/5.70 (ddt, J ) 17, 10, 7 Hz, allyl), 5.47 (mc,
NH), 5.25-5.1 (m, allyl), 4.41 (mc, FMOC), 4.29/3.83 (dd, J )
10, 6 Hz, 2-H), 4.24 (t br, J ) 7 Hz, FMOC), 4.2-3.9 (m, 2 ×
Gly), 3.74/3.72 (s, CO2Me), 2.96 (d, J ) 16 Hz, CH2TMS), 2.85-
2.55 (m, allyl, CH2TMS), 0.16/0.05 (s, TMS). 13C NMR
(CDCl3): δ 170.1/169.7 (s, CO2Me), 62.1/59.2 (d, C-2), 52.4/52.1
(q, CO2Me); FMOC: 156.4, 143.7, 141.1 (3 s), 127.5, 126.9,
125.0, 119.8 (4d), 67.1 (t), 46.9 (d); 2-allyl: 133.9/132.0 (d),
119.6/118.2 (t), 33.3/33.1 (t); Gly: 168.8 (s), 167.5/167.0 (s), 44.1
(t), 41.4/41.2 (t); CH2TMS: 40.5/35.5 (t), -0.8/-1.9 (q).
HRMS: calcd for C29H37N3O6Si (M+) 551.2452, found 551.2439.
F MOC-Gly-Gly-(N-tr im eth ylsila n ylm eth yl-2-a llyl)-Gly-
Gly-Gly-NH2 (r a c-19). Sa p on ifica tion of th e Meth yl Ester
r a c-17b. A solution of LiOH (0.3 N, 16 mL) was added to a
solution of rac-17b (880 mg, 1.6 mmol) in THF (20 mL) at 0
°C. After 30 min at 0 °C the reaction mixture was added to
HCl (0.3 N, 50 mL) and EtOAc (50 mL). The organic layer was
separated, and the aqueous layer was extracted with EtOAc
(3 × 20 mL). The colorless solid (704 mg) obtained after
evaporation of the solvent was used without purification for
the next step. Peptide coupling: 150 mg (0.28 mmol) of the
solid, HABT (41 mg, 0.28 mmol), DIC (0.048 mL, 0.28 mmol),
and DIEA (0.047 mL, 0.28 mmol) were dissolved in DMF (5
mL). After 30 min a suspension of H-Gly-Gly-NH2*HCl (94 mg,
0.56 mmol) and DIEA (0.031 mL, 0.18 mmol,) in DMF (2 mL)
was added. After 2 h the reaction mixture was added to Et2O
(10 mL), and the crude product was obtained by filtration.
Purification by FC with CH2Cl2/MeOH (50:1 f 1:1) afforded
rac-19 (105 mg, 57%, 5:1 mixture of rotamers) as a colorless
(m). MS (FAB, m-nitrobenzyl alcohol): m/z (%) 1011 (M+
+
Na, 12), 989 (M+ + H, 30), 973 (M+ - Me, 100). CD (c ) 0.76
mM in TFE) λmax [nm] (mol. ellip.): 186 (210681), 200
(-47663), 213 (39469), 237 (-42408).
Ben zoyl-Gly-Mp r -OMe (r a c-21a ). Following the proce-
dure P, rac-17a (82 mg, 0.22 mmol), BP (10 mg), and ADC (10
mg) yielded after purification by FC with CHCl3/EtOAc (2:1,
Rf ) 0.29) a 1:3 mixture of rac,cis- and trans-21a (14 mg, 24%)
as a colorless oil. HRMS: calcd for C16H20N2O4 (M+) 304.1423,
found 304.1424. rac,trans-21a : 1H NMR (500 MHz, CDCl3):
δ 7.83 (d, J ) 8 Hz, Ph), 7.54, 7.47 (2 t, J ) 8 Hz, Ph), 7.24 (s
br, NH), 4.66 (dd, J ) 10, 2 Hz, 2-H), 4.4-4.2 (m, Gly), 3.85
(mc, 5-H), 3.77 (s, CO2Me), 3.13 (dd, J ) 9, 9 Hz, 5-H′), 2.6
(mc, 4-H), 2.20 (ddd, J ) 13, 6, 2 Hz, 3-H), 1.91 (dt, J ) 13, 10
Hz, 3-H′), 1.16 (d, J ) 7 Hz, 4-Me). 13C NMR (CDCl3): δ 172.2
(s, CO2Me), 167.2 (s, Gly), 133.8 (s, Ph), 133.6, 128.5, 127.1
(3d, Ph), 59.1 (d, C-2), 52.8 (t, C-5), 52.3 (q, CO2Me), 42.4 (t,
Gly), 36.7 (t, C-3), 32.5 (d, C-4), 17.2 (q, 4-Me). Differing values
of rac,cis-21a : 1H NMR: δ 4.49 (dd, J ) 10, 10 Hz, 2-H), 3.78
(s, CO2Me), 3.22 (dd, J ) 10, 10 Hz, 5-H′), 2.5 (mc, 3-H), 2.45
(mc, 4-H), 1.65 (dt, J ) 12, 10 Hz, 3-H′), 1.19 (d, J ) 7 Hz,
4-Me). 13C NMR: δ 172.4 (s, CO2Me), 59.6 (d, C-2), 53.1 (t,
C-5), 52.4 (q, CO2Me), 37.1 (t, C-3), 33.8 (d, C-4), 16.8 (q, 4-Me).
F MOC-Gly-Mp r -OMe (22a ). Following the procedure P,
18a (88 mg, 0.18 mmol), BP (10 mg), and ADC (10 mg) yielded
after purification by FC with MTBE/hexane (3:1, Rf ) 0.33) a
1:2 mixture of cis- and trans-22a (25 mg, 33%) as a colorless
oil. HRMS: calcd for C24H26N2O5 (M+) 422.1842, found 422.1845.
trans-22a : 1H NMR (500 MHz, CDCl3): δ 7.81, 7.65 (2d, J )
8 Hz, FMOC), 7.44, 7.35 (2t, J ) 8 Hz, FMOC), 5.80 (mc, NH),
4.64 (dd, J ) 10, 2 Hz, 2-H), 4.41 (d, J ) 8 Hz, FMOC), 4.27
(t br, J ) 8 Hz, FMOC), 4.1 (mc, Gly), 3.9-3.7 (m, 5-H), 3.75
(s, CO2Me,), 3.07 (dd, J ) 9, 9 Hz, 5-H′), 2.45 (mc, 4-H), 2.18
(ddd, J ) 13, 6, 2 Hz, 3-H), 1.88 (dt, J ) 13, 10 Hz, 3-H′), 1.14
(d, J ) 7 Hz, 4-Me). 13C NMR (CDCl3): δ 172.2 (s, CO2Me),
58.9 (d, C-2), 52.6 (t, C-5), 52.2 (q, CO2Me), 36.6 (t, C-3), 32.3
(d, C-4), 17.0 (q, 4-Me); FMOC: 156.1, 143.7, 141.1 (3 s), 127.5,
127.0, 125.0, 119.8 (4d), 67.0 (t), 46.9 (d); Gly: 166.9 (s), 43.2
(t br). Differing values of cis-22a : 1H NMR: δ 4.46 (dd, J ) 9,
9 Hz, 2-H), 3.9-3.7 (m, 5-H), 3.76 (s, CO2Me,), 3.15 (mc, 5-H′),
2.6-2.3 (m, 3-H, 4-H), 1.62 (dt, J ) 12, 10 Hz, 3-H′), 1.17 (d,
J ) 7 Hz, 4-Me). 13C NMR: δ 172.2 (s, CO2Me), 59.4 (d, C-2),
52.8 (t, C-5), 52.7 (q, CO2Me), 36.8 (t, C-3), 33.7 (d, C-4), 16.7
(q, 4-Me).
F MOC-Ala -Mp r -OMe (22b). Following the procedure P,
18b (60 mg, 0.12 mmol), BP (5 mg), and ADC (5 mg) yielded
after purification by FC with MTBE/hexane (3:2, Rf ) 0.13) a
1:2 mixture of cis- and trans-22b (30 mg, 57%) as a colorless
oil. HRMS: calcd for C25H28N2O5 (M+) 436.1998, found 436.2001.
trans-22b: 1H NMR (500 MHz, CDCl3): δ 7.81, 7.64 (2d, J )
8 Hz, FMOC), 7.44, 7.31 (2t, J ) 8 Hz, FMOC), 5.75 (d br, J
) 8 Hz, NH), 4.66 (dd, J ) 9, 3 Hz, 2-H), 4.6 (mc, Ala), 4.38 (d
br, J ) 7 Hz, FMOC), 4.26 (t br, J ) 7 Hz, FMOC), 3.82 (dd,
J ) 9, 8 Hz, 5-H), 3.78 (s, CO2Me), 3.27 (dd, J ) 9, 9 Hz, 5-H′),
2.55 (mc, 4-H), 2.16 (ddd, J ) 12, 6, 3 Hz, 3-H), 1.89 (dt, J )
12, 9 Hz, 3-H′), 1.45 (mc, Ala), 1.13 (d, J ) 7 Hz, 4-Me). 13C
NMR (CDCl3): δ 172.3 (s, CO2Me), 58.7 (d, C-2), 53.5 (t, C-5),
52.2 (q, CO2Me), 36.4 (t, C-3), 32.6 (d, C-4), 17.2 (q, 4-Me);
FMOC: 155.6, 143.8, 141.3 (3 s), 127.7, 127.0, 125.1, 119.9 (4
d), 67.0 (t), 47.1 (d); Ala: 171.3 (s), 48.2 (d), 18.4 (q). Differing
values for cis-22b: 1H NMR: δ 5.81 (d br, J ) 8 Hz, NH),
4.49 (dd, J ) 8, 8 Hz, 2-H), 3.94 (dd, J ) 10, 8 Hz, 5-H), 3.79
(s, CO2Me), 3.18 (dd, J ) 10, 10 Hz, 5-H′), 2.5 (mc, 3-H), 2.4
1
powder. H NMR (500 MHz, CDCl3): δ 7.84 (s br, NH), 7.75
(d, J ) 8 Hz, FMOC), 7.6 (mc, FMOC), 7.38, 7.29 (2t br, J ) 8
Hz, FMOC), 6.98, 6.56 (2s br, NH), 5.8-5.6 (m, allyl), 5.15 (mc,
allyl), 4.54 (dd, J ) 10, 6 Hz, 2-H), 4.4 (mc, FMOC), 4.25-3.6
(m, FMOC, 4 × Gly, CH2TMS, 2-H), 3.01, 2.80 (2 d, J ) 16
Hz, CH2TMS), 2.9-2.45 (m, CH2TMS, allyl), 0.18/0.01 (s,
TMS). 13C NMR (CDCl3): δ 173.0/172.5 (s, CO2Me), 63.5/60.2
(d, C-2); FMOC: 156.9, 143.7, 141.2 (3 s), 127.7, 127.0, 125.1,
119.9 (4 d), 67.1 (t), 47.0 (d); 2-allyl: 133.8/133.1 (d), 119.4/
118.2 (t), 33.0/32.7 (t); CH2TMS: 41.2/35.7 (t), -0.6/-1.6 (q,
TMS); Gly: 170.7, 170.2, 169.3, 168.0 (4s), 44.1, 43.5, 42.6,
41.7 (4t). MS (FAB, m-nitrobenzyl alcohol): m/z (%) 673 (M+
+ Na, 10), 651 (M+ + H, 20), 520 (M+ - [NH-Gly-Gly-NH2],
30).
FMOC-Leu -(N-tr im eth ylsilan ylm eth yl-2-allyl)-Gly-Leu -
Leu -Leu -Leu -NH2 (20). Sa p on ifica t ion of t h e Met h yl
Ester (-)-18d . A solution of LiOH (4 N, 5 mL) was added to
a solution of (-)-18d (590 mg, 1.1 mmol) in THF (10 mL) and
water (5 mL). After 5 h HCl (6 N, 3 mL) was added, followed
by a saturated Na2CO3 solution (5 mL) and a solution of
FMOC-Cl (312 mg) in THF (5 mL). After 3 h the reaction
mixture was acidified (pH ) 2) and extracted with EtOAc (10
× 20 mL). Purification by FC with CH2Cl2/MeOH (gradient,
50:1 f 1:1) afforded FMOC-Leu-(N-trimethylsilanylmethyl-
2-allyl)-Gly-OH (424 mg, 72%) as a colorless solid. IR (ATR,
cm-1): ν 3307 (w), 1718 (s), 1640 (m), 1599 (m), 759 (m), 740
(s). HRMS: calcd for C30H40N2O5Si 536.2707, found 536.2707.
Peptide coupling: Following the procedure F, FMOC-Leu-(N-

6904 J . Org. Chem., Vol. 66, No. 21, 2001
J onas et al.
(mc, 4-H), 1.6 (mc, 3-H′), 1.16 (d, J ) 7 Hz, 4-Me). 13C NMR:
δ 172.3 (s, CO2Me), 59.5 (d, C-2), 54.0 (t, C-5), 52.3 (q, CO2Me),
37.0 (t, C-3), 34.0 (d, C-4), 16.6 (q, 4-Me).
10, 3 Hz, 2-H), 4.45 (mc, FMOC), 4.42 (d, J ) 7 Hz, FMOC),
4.2-3.6 (m, 5 H, 5-H, 2 × Gly), 3.75 (s, CO2Me), 3.01 (dd, J )
9, 9 Hz, 5-H′), 2.5 (mc, 4-H), 2.21 (ddd, J ) 13, 6, 3 Hz, 3-H),
1.80 (ddd, J ) 13, 10, 10 Hz, 3-H′), 1.08 (d, J ) 7 Hz, 4-Me).
13C NMR (CDCl3): δ 172.1 (s, CO2Me), 59.1 (d, C-2), 52.8 (t,
C-5), 52.4 (q, CO2Me), 36.6 (t, C-3), 32.4 (d, C-4), 17.1 (q, 4-Me);
FMOC: 156.4, 143.8, 141.3 (3 s), 127.7, 127.1, 125.1, 120.0 (4
d), 67.0 (t), 47.1 (d); Gly: 168.9, 166.7 (2 s), 44.2, 41.8 (2 t br).
Differing values for rac,cis-21b: 1H NMR: δ 3.76 (s, CO2Me),
3.12 (mc, 5-H′), 2.5-2.3 (m, 3-H, 4-H), 1.56 (ddd, J ) 12, 10,
10 Hz, 3-H′), 1.11 (d, J ) 7 Hz, 4-Me). 13C NMR: δ 172.3 (s,
CO2Me), 59.5 (d, C-2), 53.2 (t, C-5), 53.0 (q, CO2Me), 37.0 (t,
C-3), 33.7 (d, C-4), 16.8 (q, 4-Me).
F MOC-Gly-Gly-Mp r -Gly-Gly-NH2 (r a c-23). Following the
procedure P, rac-19 (80 mg, 0.12 mmol), BP (6 mg), and ADC
(6 mg) yielded after purification by crystallization (Et2O/
MeOH) a 1:3 mixture of rac,cis- and trans-23 (60 mg, 86%) as
a colorless powder. MS (FAB, m-nitrobenzyl alcohol): m/z (%)
601 (M+ + Na, 100). rac,trans-23: 1H NMR (500 MHz, CD3-
OD/CDCl3): δ 7.69 (d, J ) 8 Hz, FMOC), 7.55 (mc, FMOC),
7.33, 7.24 (2t br, J ) 8 Hz, FMOC), 4.4-4.3 (m, 2-H, FMOC),
4.16 (t, J ) 7 Hz, FMOC), 4.1-3.6 (m, 5-H, 4 × Gly), 3.02 (dd,
J ) 9, 9 Hz, 5-H′), 2.5 (mc, 4-H), 2.09 (ddd, J ) 13, 6, 4 Hz,
3-H), 1.78 (ddd, J ) 13, 9, 9 Hz, 3-H′), 1.03 (d, J ) 7 Hz, 4-Me).
13C NMR (CDCl3): δ 170.0 (s, CONR), 60.8 (d, C-2), 53.1 (t,
C-5), 36.2 (t, C-3), 32.5 (d, C-4), 16.8 (q, 4-Me); FMOC: 157.1,
143.5, 141.0 (3 s), 127.5, 126.8, 124.7, 119.7 (4 d), 66.7 (t), 47.1
(d); Gly: 168.5 (s), 43.6, 42.6, 41.7, 41.4 (4 t). Differing values
for cis-23: 1H NMR: δ 4.2 (mc, 2-H), 3.10 (dd, J ) 10, 10 Hz,
5-H′), 2.35 (mc, 3-H, 4-H), 1.6-1.4 (m, 3-H′), 1.08 (d, J ) 7 Hz,
4-Me). 13C NMR: δ 61.7 (d, C-2), 53.3 (t, C-5), 36.9 (t, C-3),
33.5 (d, C-4) 16.1 (q, 4-Me).
F MOC-P h e-Mp r -OMe (22c). Following the procedure P,
18c (97 mg, 0.17 mmol), BP (8 mg), and ADC (8 mg) yielded
after purification by FC with MTBE/hexane (1:1 Rf ) 0.16) a
2:3 mixture of cis- and trans-22c (30 mg, 51% yield on 70%
conversion) as a colorless oil. HRMS: calcd for C31H32N2O5
(M+) 512.2311, found 512.2312. trans-22c: 1H NMR (500 MHz,
CDCl3): δ 7.80 (d, J ) 8 Hz, FMOC), 7.6-7.25 (m, FMOC,
Phe), 5.8-5.6 (m, NH), 4.79/4.75 (q, J ) 8 Hz, Phe), 4.63 (dd,
J ) 9, 3 Hz, 2-H), 4.5-4.2 (m, 3 H, FMOC), 3.78 (s, CO2Me),
3.40 (t br, J ) 8 Hz, 5-H), 3.2-3.1 (m, 5-H, Phe), 3.05 (mc,
Phe), 2.5-2.3 (m, 4-H), 2.12 (ddd, J ) 12, 6, 3 Hz, 3-H), 1.83
(dt, J ) 12, 9 Hz, 3-H′), 1.15 (d, J ) 7 Hz, 4-Me). 13C NMR
(CDCl3): δ 172.2 (s, CO2Me), 58.9 (d, C-2), 53.6 (t, C-5), 52.1
(q, CO2Me), 36.5 (t, C-3), 32.6 (d, C-4), 17.0 (q, 4-Me); FMOC:
155.6, 143.8, 141.2 (3 s), 127.6, 127.0, 125.1, 119.9 (4 d), 67.1
(t), 47.1 (d); Phe: 170.3, 136.0 (2 s), 129.8, 129.7, 128.4 (3 d),
53.8 (d), 39.0 (t). Differing values for cis-22c: 1H NMR: δ 3.86
(ddbr, J ) 9, 8 Hz, 5-H), 3.79 (s, CO2Me), 2.68 (dd, J ) 9, 9
Hz, 5-H′), 2.5-2.3 (m, 3-H, 4-H′), 1.54 (ddd br, J ) 9, 9, 9 Hz,
3-H′), 1.15 (d, J ) 7 Hz, 4-Me). 13C NMR: δ 172.2 (s, CO2Me),
59.8 (d, C-2), 52.6 (t, C-5), 52.2 (q, CO2Me), 37.0 (t, C-3), 33.7
(d, C-4), 17.3 (q, 4-Me).
F MOC-Leu -Mp r -OMe (22d ). Following the procedure P,
(-)-18d (100 mg, 0.18 mmol), BP (8 mg), and ADC (8 mg)
yielded after purification by FC with MTBE/hexane (1:1, Rf )
0.23) a 1:2 mixture of cis- and trans-22d (60 mg, 70%) as a
colorless oil. HRMS: calcd for C25H28N2O5 (M+) 478.2468, found
478.2468. trans-22d : 1H NMR (500 MHz, CDCl3): δ 7.76, 7.59
(2d, J ) 8 Hz, FMOC), 7.39, 7.30 (2 t, J ) 8 Hz, FMOC), 5.46
(d br, J ) 9 Hz, NH), 4.61 (dd, J ) 9, 3 Hz, 2-H), 4.53 (ddd, J
) 14, 9, 5 Hz, Leu), 4.5-4.3 (m, FMOC), 4.21 (tbr, J ) 8 Hz,
FMOC), 3.77 (dd, J ) 9, 8 Hz, 5-H), 3.73 (s, CO2Me), 3.29 (dd,
J ) 9, 9 Hz, 5-H′), 2.5 (mc, 4-H), 2.11 (ddd, J ) 12, 6, 3 Hz,
3-H), 1.9-1.7 (m, 3-H′, Leu), 1.55 (mc, Leu), 1.09 (d, J ) 7 Hz,
4-Me), 1.03/0.98 (d, J ) 6 Hz, Leu). 13C NMR (CDCl3): δ 172.4
(s, CO2Me), 58.8 (d, C-2), 53.5 (t, C-5), 52.2 (q, CO2Me), 36.6
(t, C-3), 32.7 (d, C-4), 17.3 (q, 4-Me); FMOC: 155.3, 143.9, 141.3
(3 s), 127.7, 127.1, 125.2, 120.0 (4 d), 67.1 (t), 47.2 (d); Leu:
171.6 (s), 50.8 (d), 42.0 (t, C-8), 24.6 (q), 22.0 (d). Differing
values for cis-22d : 1H NMR: δ 4.43 (dd, J ) 9, 9 Hz, 2-H),
3.98 (dd, J ) 9, 7 Hz, 5-H), 3.74 (s, CO2Me), 3.12 (dd, J ) 10,
9 Hz, 5-H′), 2.4 (mc, 3-H), 2.35 (mc, 4-H), 1.12 (d, J ) 7 Hz,
4-Me). 13C NMR: δ 172.5 (s, CO2Me), 59.5 (d, C-2), 54.1 (t,
C-5), 52.3 (q, CO2Me), 37.2 (t, C-3), 34.1 (d, C-4), 16.7 (q, 4-Me).
F MOC-Gly-Gly-Mp r -OMe (r a c-21b). Following the pro-
cedure P, rac-17b (60 mg, 0.11 mmol), BP (5 mg), and ADC (5
mg) yielded after purification by FC with CH2Cl2/MeOH (50:1
f 10:1) a 1:2 mixture of rac,cis- and trans-21b (25 mg, 55%)
as a colorless oil. HRMS: calcd for C26H29N3O6 (M+) 479.2056,
found 479.2055. rac,trans-21b: 1H NMR (500 MHz, CDCl3):
δ 7.75 (d, J ) 8 Hz, FMOC), 7.6 (mc, FMOC), 7.38, 7.30 (2t br,
J ) 8 Hz, FMOC), 6.9 (mc, NH), 5.6 (mc, NH), 4.56 (dd br, J )
F MOC-Leu -Mp r -Leu -Leu -Leu -Leu -NH2 (24). Following
the procedure P, 20 (95 mg, 0.1 mmol), BP (4 mg), and ADC
(4 mg) yielded after purification by crystallization (MeOH/
water) a 2:1 mixture of cis- and trans-24 (56 mg, 64%) as a
colorless powder. No NMR spectra were obtained. Qualitative
amino acid analysis (22d and a mixture of Pro and Leu was
used as reference): L-Leu (tR ) 7.276, greatest peak), trans-
L-4-methylprolin (tR ) 12.933), cis-L-4-methylprolin (tR
)
)
13.675, double area of trans isomer). IR (CH2Cl2): ν (cm-1
3272 (m), 1632 (s), 1533 (m), 1450 (m). MS (FAB, m-nitrobenzyl
alcohol): m/z (%) 939 (M+ + Na). CD (c ) 0.23 mM in TFE)
λmax [nm] (mol. ellip.): 190 (114567), 203 (-94283), 230 (sh,
-27275).
Ack n ow led gm en t. Financial support by the Volks-
wagen-Stiftung (I/71748) and the Fonds der Chemischen
Industrie is gratefully acknowledged. Our sincere thanks
are to Prof. Dr. Christoph van Wu¨llen, Technische
Universita¨t Berlin, for the performance of the protein
simulations. We are thankful to Berlin Chemie for the
amino acid analysis.
J O010144B