The 2-(triphenylsilyl)ethoxycarbonyl-("Tpseoc"-) group: A new silicon-based, fluoride cleavable oxycarbonyl protecting group highly orthogonal to the Boc-, Fmoc- and Cbz-groups

Article abstract of DOI:10.3390/molecules16064695

Starting from 2-(triphenylsilyl)ethanol a new oxycarbonyl protecting group cleavable by fluoride ion induced Peterson-elimination has been developed. Known 2-(triphenylsilyl)ethanol has been prepared from commercially available triphenylvinylsilane by a hydroboration-oxidation sequence using the sterically hindered borane reagent 9-BBN. The silyl alcohol was subsequently transformed into its chloroformate, imidazolylcarboxylic acid ester and p-nitrophenyl carbonate and used in standard protocols for the formation of carbamates and carbonates. The Tpseoc group proved to be highly resistant against acidic conditions applied in removal of tert-butyl esters and the t-Boc-group. It also withstood catalytic hydrogenation, treatment with morpholine, methylhydrazine and Pd-reagents/allyl-scavanger combinations, conditions required to cleave Cbz-, Fmoc-, phthalimide- and Alloc-groups. The Tpseoc-group is cleaved upon treatment with TBAF/CsF at 0 °C or r.t. with cleavage times reaching from <10 min. to 24 h. Its orthogonality, ease of cleavage and UV-detectability makes the Tpseoc-group a promising alternative to other widely used silicon based amine protecting groups like the Teoc- and SES-groups.

Full text of DOI:10.3390/molecules16064695

Molecules 2011, 16, 4695-4718; doi:10.3390/molecules16064695
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
The 2-(Triphenylsilyl)ethoxycarbonyl-(“Tpseoc”-) Group:
A New Silicon-Based, Fluoride Cleavable Oxycarbonyl Protecting
Group Highly Orthogonal to the Boc-, Fmoc- and Cbz-Groups
Martin Golkowski and Thomas Ziegler *
Institute of Organic Chemistry, University of Tübingen, Auf der Morgenstelle 18, 72076 Tübingen,
Germany
* Author to whom correspondence should be addressed; E-Mail: Thomas.Ziegler@uni-tuebingen.de;
Tel.: +49-(0)7071-29-78763; Fax: +49-(0)7071-29-5244.
Received: 29 April 2011; in revised form: 30 May 2011 / Accepted: 31 May 2011 /
Published: 7 June 2011
Abstract: Starting from 2-(triphenylsilyl)ethanol a new oxycarbonyl protecting group
cleavable by fluoride ion induced Peterson-elimination has been developed. Known
2-(triphenylsilyl)ethanol has been prepared from commercially available triphenylvinyl-
silane by a hydroboration-oxidation sequence using the sterically hindered borane reagent
9-BBN. The silyl alcohol was subsequently transformed into its chloroformate,
imidazolylcarboxylic acid ester and p-nitrophenyl carbonate and used in standard protocols
for the formation of carbamates and carbonates. The Tpseoc group proved to be highly
resistant against acidic conditions applied in removal of tert-butyl esters and the
t-Boc-group. It also withstood catalytic hydrogenation, treatment with morpholine,
methylhydrazine and Pd-reagents/allyl-scavanger combinations, conditions required to
cleave Cbz-, Fmoc-, phthalimide- and Alloc-groups. The Tpseoc-group is cleaved upon
treatment with TBAF/CsF at 0 °C or r.t. with cleavage times reaching from <10 min. to
24 h. Its orthogonality, ease of cleavage and UV-detectability makes the Tpseoc-group a
promising alternative to other widely used silicon based amine protecting groups like the
Teoc- and SES-groups.
Keywords: Peterson-elimination; protecting group; silicon; fluoride ion; acid stable

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1. Introduction
Masking potentially reactive sites of a polyfunctionalized organic molecule with appropriate
protecting groups is a fundamental process in modern synthetic organic chemistry. Regardless of
whether the target of a synthesis is a complex secondary metabolite, a protein, oligonucleotide or
saccharide, they all contain functional groups like carbonyl moieties, carboxylic acid groups, alcohols,
amines, among others, which might interfere with a process that converts another functional group in
the desired manner. In order to navigate through the networks of reactivity in complex organic
molecules a tremendous variety of protecting groups has been developed in the past and the reports of
an ongoing search for more elaborated protecting strategies fill the pages of ever growing
comprehensive works on the topic [1]. The field of peptide synthesis delivers illuminating insight into
protecting group chemistry, as most of the functional groups mentioned above appear in this substance
class. Especially protection of the amine moiety in amino acids underwent a constant evolution from
simple amides to more sophisticated carbamates finally resulting in the triumvirate of amine protecting
groups consisting of the Boc- [2], Cbz- [3] and Fmoc-group [4]. Those three justify their superiority by
the ease of installation, mild cleavage conditions, the excellent orthogonality among each other and not
the least, the vast experience gained by the community of synthetic organic chemists since their
introduction in the 1930s and 70s. During our investigation of the synthesis of glycopeptide mimetics
we were prospecting for an amine protecting group which should be specifically cleavable by fluoride
ions under mild conditions, but at the same time resistant enough to survive the acidic conditions
applied to cleave the Boc-group. Thorough examination of the literature revealed that there are only
few silicon based amine protecting groups cleavable by fluoride ions with almost none of them
matching our demands. By far the most popular among them is the Teoc-group [5], based on the
2-(trimethylsilyl)ethyl-(Tmse-) moiety first described in the context of a protecting-strategy for peptide
synthesis by Sieber [6]. The Teoc-group is unfortunately prone to acidolysis and is not orthogonal to
the Boc-group. Another frequently used amine protecting group is the sulfonamide based SES-group
[7] which in turn suffers from the necessity of somewhat harsh cleavage conditions. Two at first glance
very useful protecting groups appeared to be the diphenylsilyldiethylene-(DPside-) group [8] and
the triisopropylsilyloxycarbonyl-(Tsoc-) group [9]. The former is introduced into molecules bearing
an amine moiety via a nucleophilic substitution reaction of bis[2-(p-toluenesulfonyloxy)ethyl]-
diphenylsilane resulting in the formation of a 1-aza-4-silacyclohexane-derivative. Although possessing
advantageous orthogonality to a variety of other amine protecting groups, the fact that it retains the
basic character of the amine moiety and its limitation to sterically unhindered primary amines limit the
applicability of the DPside-group. The above mentioned Tsoc-group seems so far to be the most
attractive option, as it can be attached to relatively electron poor and sterically hindered primary and
secondary amines. It is orthogonal to the Fmoc-, Cbz- and Boc-group and cleavage kinetics are very
promising. One flaw might be that Tsoc-group can’t be attached to very electron poor amines or
alcohols. In addition the procedure involved in the installation of the Tsoc-group turns out to be
somewhat laborious compared to the Teoc- and SES-group, where storable activated formate reagents
are used in standard protocols for their introduction. In the course of our investigations we finally
stumbled across 2-(triphenylsilyl)ethanol, which was used previously as a phosphate-ester protecting
group in oligonucleotide synthesis [10]. The increased electronegativity of the triphenylsilyl-moiety

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lead to the assumption that the silicons β-effect might be sufficiently diminished to prevent the
alcohol and its derivatives from undergoing acid induced Peterson-elimination [11] as observed in
Teoc-derivatives. At the same time we expected superior liability to elimination induced by attack of a
nucleophilic species like fluoride or hydroxyl ions at silicon due to its increased electrophilicity.
Despite the estimated favorable properties of the 2-(triphenylsilyl)ethyl moiety mentioned, we found
no further evidence in the literature of its use in any kind of protecting strategy, leading to the opinion
that an investigation of an amine protecting group based on the oxycarbonyl derivative of
2-(triphenylsilyl)ethanol might turn out as a promising endeavor.
2. Results and Discussion
2-(Triphenylsilyl)ethanol (2) was previously synthesized in only moderate yields (25-30%) by
hydrosilylation of vinyl acetate with triphenylsilane employing dichlorodirhodium tetracarbonyl as the
catalyst [10] or, much more efficiently, by treatment of ethylene oxide with triphenylsilyl lithium [12].
Starting from commercially available triphenylvinylsilane (1) we chose instead to use a straight-
forward hydroboration-oxidation sequence to synthesize silyl alcohol 2 employing sterically hindered
borane 9-BBN and, in regard to the expected susceptibility to elimination, the mild oxidant
NaBO3•4H2O yielding alcohol 2 in an excellent yield of 88%. Borane-THF complex was also tested in
the hydroboration step resulting in formation of a mixture of regioisomeric 1-(triphenylsilyl)ethanol
and 2 in a ratio of 2:3 (unpublished results). This finding does not differ significantly from the
regioisomer distribution observed in the hydroboration/oxidation of trimethylvinylsilane with
BH3•THF and 9-BBN reported by Brown et al. [13]. Treatment of β-silyl alcohol 2 with p-nitrophenyl
chloroformate, carbonyldiimidazole (CDI) [14] or phosgene [15], respectively resulted in a
clean conversion of 2 to the corresponding p-nitrophenyl-2-(triphenylsilyl)ethyl carbonate (3),
1H-imidazole-1-carboxylic acid 2-(triphenylsilyl)ethyl ester (4) and 2-(triphenylsilyl)ethyl
chloroformate (5) in yields of 88%, 88% and 94%, respectively (Scheme 1).
Scheme 1. Preparation of Tpseoc-reagents.
O
O
Ph3Si
O
NO2
N
ii, 88%
iii, 88%
iv, 94%
3
i, 88%
OH
Ph3Si
O
N
Ph3Si
Ph3Si
O
2
1
4
O
Cl
Ph3Si
O
5
Reagents and conditions. i: 9-BBN, THF, 0°C-reflux, 3 h then NaBO3*4H2O, water, 45°C, 3 h;
ii: pNPOCOCl, Py, DCM, 24 h, r.t.; iii: CDI, benzene, 2 h, r.t.; iv: COCl2, toluene, K2CO3, 0°C-
r.t., 4 h.

Molecules 2011, 16
4698
The two former compounds 3 and 4 are crystalline, shelf stable solids and showed no sign of
decomposition, as indicated by TLC, even after several weeks of storage at room temperature.
Chloroformate 5 was obtained as crystalline solid by crystallization from dry n-hexane and retained its
reactivity over a period of at least two months of storage in the refrigerator at −20 °C under an
atmosphere of nitrogen. With the appropriate tools in hand the next step in our investigations was
planned to be the Tpseoc-protection of a series of different L-leucine esters and L-proline tert-butyl
ester, derivatives 11-15 (Scheme 2), and a series of variably protected 1,6-diaminohexane-derivatives,
compounds 21-25 (Scheme 3). The Tpseoc-derivatives were synthesized according to general
procedure A by reacting the corresponding ammonium derivatives of the amino acids 6-10 (Scheme 2)
and diamines 16-20 (Scheme 3) with p-nitrophenyl-2-(triphenylsilyl)ethyl carbonate 3 in presence of
triethylamin and DMF as solvent for 24 h at room temperature.
Scheme 2. Synthesis and testing of Tpseoc-derivatives of L-leucine- and L-proline esters.
O
O
A-
RO
O
O
O
H
RO
NH
Ph3Si
N
Ph3Si
O
N
H
O
+
NH3
O
O
6, 8, 9,10
11, 13, 14, 15
33
6
9
14
11
33
14
33
i, 98%
i, 98%
ii, vi,71%
i, 87%
i, 88%
iv, vi, 90%
v, vi, 88%
vii, 95%
11
8
13
10
15
13
33
15
33
iii, vi, 83%
O
O
6: R = tBu, A-= Cl-
H
11: R = tBu
13: R = Bn
14: R = All
15: R = Me
N
8: R = Bn, A-= pTosO-
9: R = All, A-= pTosO-
10: R = Me, A-= Cl-
H2N
O
37
O
O
O
O
O
O
vii, 89%
ii, vi, 69%
O
i, 95%
N
N
H
O
N
H
N
N
O
NH
O
H
O
O
Ph3Si
O
SiPh3
O
38
7
34
12
Reagents and conditions. i: TpseocOpNP, DMF, Et3N, 24 h, r.t.; ii: TFA/DCM 1:1, 1,3-dimethoxybenzene, 4 h,
0°C; iii: Pd/C (10%), H2, EtOAc, 4 h; iv: Pd(PPh3)4, morpholine, THF, 2 h, r.t.; v: 1M-NaOH, MeOH/THF, 1h,
r.t.; vi: L-leucine-tBu-ester*HCl, HBTU, HOBt, DIPEA, DMF, 0°C-r.t., 16 h, vii: TBAF*3H2O, CsF, THF, r.t..
The yields of Tpseoc-protected amino acid esters 11-15 and bisprotected diamines 21-24 obtained
by this method were in the range of 99-87% (Table 1). Due to its base-sensitive nature, the
Fmoc-protected diamine 25 was synthesized by treatment of the TFA-salt of Fmoc-1,6-diaminohexane
20 with chloroformate 5 and Hünig`s base in DCM for 3 h in a yield of 83%. On the next stage of our
investigations, compounds 11-15 and 21-25 were designated to be tested for the stability of the
Tpseoc-group under conditions necessary to cleave the ester function or the second amino protecting

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group in a competitive manner. First the Tpseoc-protected leucine and proline tert-butyl esters 11 and
12 were treated with 50% TFA in DCM, conditions usually applied to cleave tert-butyl esters [1], in
the presence of 1,3-dimethoxybenzene as a cation-scavanger [16].
Scheme 3. Synthesis and testing of Tpseoc-protected diamines.
R1
N
R1
N
H
H
N
6
H
O
N
NH2*TFA
N
O
Ph3Si
NHBoc
R2
R2
SiPh3
6
6
O
O
O
21, 22, 23, 24, 25
16, 17, 18, 19, 20
35
16
21
19
24
20
25
21
35
24
35
25
35
i, 99%
ii, vii, 85%
i, 97%
v, vii, 80%
vi, vii, 90%
vii, 91%
17
22
22
35
i, 83%
i, 94%
i, 99%
iii, vii, 81%
iv, vii, 85%
18
23
23
35
H
H2N
N
6
NHBoc
O
16, 21: R1= H, R2=Boc
17, 22: R1= H, R2=Alloc
13, 23: R1= H, R2=Cbz
14, 24: R1= R2= Pht
15, 25: R1= H, R2=Fmoc
39
Reagents and conditions. i: TpseocOpNP, DMF, Et3N, 24 h, r.t.; ii: TFA/DCM 1:4, 1,3-dimethoxybenzene,
45 min., 0°C; iii: Pd(PPh3)4, Me2NH*BH3, DCM, 2 h, r.t.; iv: Pd/C (10%), H2, THF, 8 h, r.t.; v: MeNHNH2,
toluene, 36 h, 80°C; vi: DMF/morpholine 1:1, 1 h, r.t; vii: N-Boc-L-alanine, HBTU, HOBt, DIPEA, DMF,
0°C-r.t., 16 h; viii: TBAF*3H2O, CsF, THF, 24 h, r.t..
Table 1. Yields of protection and cleavage steps.
Tpseoc-
protection
Tpseoc-cleavage
Competitive
cleavage/coupling
Substrate
TBAF/CsF in THF
H-Leu-OtBu•HCl 6
H-Pro-OtBu 7
11 (98%)
12 (95%)
13 (98%)
14 (87%) a
15 (88%) a
21 (99%)
22 (94%)
23 (99%)
24 (97%)
25 (83%)
27 (66%)
29 (91%)
31 (86%) b
33 (71%)
34 (69%)
33 (83%)
33 (90%)
33 (88%)
35 (85%)
35 (81%)
35 (85%)
35 (80%)
35 (90%)
-
37 (95%) c
38 (89%) d
H-Leu-OBn•TosOH 8
H-Leu-OAll•TosOH 9
H-Leu-OMe•HCl 10
BocNH(CH2)6NH2•TFA 16
AllocNH(CH2)6NH2•TFA 17
CbzNH(CH2)6NH2•TFA 18
PhtN(CH2)6NH2•TFA 19
FmocNH(CH2)6NH2•TFA 20
Prasterone 26
-
-
-
39 (91%) e
-
-
-
-
Prasterone 26 (88%) f
Boc-Trp(H)-OMe 28 (91%) f
36 (92%) c
Boc-Trp(H)-OMe 28
Phe 30
-
32 (98%)
a: purified by crystallization; b: crude yield; c: 6 h, r.t.; d: 1.5 h, r.t.; e: 24 h, r.t.; f: 10 min., 0 °C.
In both cases TLC indicated complete consumption of the starting material after 4 h at 0 °C with
obviously no significant formation of side products. When we tried to obtain an analytical sample of
the amorphous free acid of Tpseoc-protected L-leucine by silica gel column chromatography eluting
the product with a n-hexane/ethyl acetate mixture containing 1% acetic acid or formic acid, we

Molecules 2011, 16
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observed formation of a non-polar side product after passing the material through the column, as
indicated by TLC. Changing the column material to acidic or neutral alumina with the same eluent or
RP-8 silica gel eluting the free acid with a methanol/water mixture didn’t change the outcome of the
purification step. Since in all other cases of ester cleavage in 11-15 and in the competetive deprotection
of the amino protecting groups in 21-25 similar problems with the purification of the free acids and
amines were encountered, we chose to couple the crude products of the deprotection step in a standard
peptide coupling protocol with either L-leucine tert-butyl ester for free acids or N-Boc-L-alanine for
free amines. By comparing the yields of the resulting peptides 33, 34 and 35 we expected to achieve an
indirect but nonetheless authentic feedback of the stability of the Tpseoc-group under the cleavage
conditions examined. For the coupling step we chose to employ HBTU [17] as coupling agent, since it
allows performing the coupling step in a one-pot manner and reliably leads to very high yields.
When this strategy was applied for tert-butyl esters 11 and 12 the dipeptides 33 and 34 were
obtained in yields of 71% and 69% respectively. In contrast, benzyl ester derivative 13, deprotected by
hydrogenation with Pd/C (10%) in ethyl acetate, allyl ester derivative 14, cleaved by treatment with
Pd(PPh3)4/morpholine in THF [18], and methyl ester derivative 15, saponified with 1M-NaOH in
THF/MeOH, yielded the same dipeptide 33 in 83%, 90% and 88% respectively. The yields obtained,
together with the observation that methyl ester 15 decomposed slowly when treated with DCM/TFA
1:1 at room temperature, as indicated by TLC (half-life ca. 12 h, unpublished results), lead to the
conclusion that the Tpseoc-group could very well be termed orthogonal to tert-butyl esters and the
t-Boc-group, but exhibits limited stability under prolonged exposure to strong acid. Noteworthy seems
the outcome of methyl ester cleavage with 1M-NaOH in ester 15 which proceeded very cleanly, as
judged by TLC analysis, and lead to high yields of dipeptide 33, suggesting that the Tpseoc-group is
not as prone to hydroxyl-ion induced elimination as initially expected [10]. Examination of the
competitive cleavage of a second amino-protecting group in mono Tpseoc-protected diamines 21-25
(Scheme 3) drew a quite similar picture. When N-Tpseoc-N´-Boc-protected 1,6-diaminohexane 21 was
treated with 20% TFA in DCM in presence of 1,3-dimethoxybenzene complete Boc-cleavage was
observed after 45 min. at 0 °C. As expected, due to the shorter duration of the exposure to acid, the
yield of 85% of peptide 35 obtained in the subsequent coupling step turned out to be significantly
higher compared to tert-butyl ester cleavage/coupling sequence applied for 11 and 12. Cleavage of the
Alloc-group in diamino-derivative 22 was achieved by treatment with tetrakis(triphenylphosphine)
palladium(0) in DCM and BH3•Me2NH as allyl-scavenger [19], furnishing peptide 35 after the
coupling step in 81% yield.
Cbz-derivative 23 was hydrogenated with Pd/C (10%) in dry THF as solvent instead of ethyl
acetate used in deprotection of 12 (no reaction). Subsequent coupling to N-Boc-L-alanine yielded 85%
of peptide 35. The best results for phthalimide-cleavage in diamino-derivative 24 were obtained by
using methylhydrazine in toluene under anhydrous conditions.

Molecules 2011, 16
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Scheme 4. Synthesis and testing of Tpseoc-protected alcohols, electron poor amines and amino-acids.
Heating the reaction mixture to 80 °C lead to complete cleavage of the phthalimide moiety after
36 h and subsequent peptide coupling yielded 80% of peptide 35. Treatment of Fmoc-protected
diamine 25 with morpholine/DMF under anhydrous conditions followed by peptide coupling resulted
in 90% recovery of peptide 35. To further explore the scope of the Tpseoc-group we desired to protect
an alcohol function as the corresponding carbonate and an electron poor amine, like the indole-
nitrogen found in tryptophan. The capability of the Teoc-group as an alcohol protecting group was
investigated earlier by Chattopadhyaya et al. and some favorable properties, especially very fast
cleavage under exposure to an fluoride ion source were described [20]. In an analogical approach,
prasterone 26 was transformed into its Tpseoc-carbonate with TpseocCl 5 in DCM and pyridine as the
base. The reaction proceeded only slowly unless a catalytic amount of DMAP was added. After 24 h
no further progression of the reaction could be observed, even upon addition of excess TpseocCl.
Workup and chromatographic purification yielded moderate 66% of Tpseoc-protected prasterone 27
(Scheme 4), but the process for carbonate formation might be optimized by use of TMEDA as the base
[21]. As electron poor amine N-Boc-L-tryptophan methyl ester 28 was chosen as a model compound
and treatment with TpseocIm 4 in pyridine at 80 °C for 36 h resulted in formation of Tpseoc-protected
tryptophan derivative 29 in satisfactory 91% yield (Scheme 4). Additionally chloroformate 5 was
tested in a standard protection protocol widely used for installation of carbamate protecting groups in

Molecules 2011, 16
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peptide chemistry, in which a free amino acid is treated with a chloroformate in water or water/dioxane
(THF) in presence of a base like NaOH, carbonates or hydrogencarbonates [1]. To this end,
L-phenylalanine 30 was reacted with TpseocCl 5 in water/dioxane and NaHCO3 as the base.
Unfortunately the obtained crude Tpseoc-L-phenylalanine 31 suffered from the same problems as
Tpseoc-L-leucine described above, but coupling to leucine tert-butyl ester using the HBTU-technique
resulted in formation of dipeptide 32 in an excellent yield of 98%. (Scheme 4)
A so far unanswered question was the behavior of the Tpseoc-group under exposure to a fluoride
ion source. Consequently the peptides 32, 33, 34 and 35 as well as the prasterone-carbonate 27 and
tryptophan derivative 29 were treated with either 3 mol equivalents of TBAF•3H2O or a mixture of
2 mol eq. TBAF•3H2O/2 mol eq. CsF [8] with THF as the solvent at 0 °C or room temperature.
Generally cleavage times were significantly reduced by use of TBAF•3H2O/CsF mixtures resulting in
relatively slow Tpseoc-cleavage from the primary amine of peptide 35 (24 h, r.t.) and much faster
cleavage from the primary amine of dipeptide 32 and 33 (both 6 h, r.t.) and the secondary amine in
peptide 34 (90 min., r.t.). The tendency of accelerated cleavage rates going from primary amines to
amines attached to sec. carbon and sec. amines might account for the release of strain induced into the
molecules due to steric bulkiness of the Tpseoc-group. Both, the carbonate 27 and electron poor
N-Tpseoc-derivative 29, were cleaved very fast with the reaction completed after 10 minutes at 0 °C.
Accordingly the observed cleavage kinetics are significantly enhanced compared to those reported for
the detachment of the Teoc- and SES-group, but at the same time much slower than those described for
more fluoride sensitive silicon based amino protecting groups like the Psoc-group introduced by
Wagner et al. [22]. This suggests that the Tpseoc-group could be applied orthogonally in combination
with the Psoc-group or the closely related fluoride-cleavable PTMSEL-linker, which was designed for
solid-phase synthesis and possesses advantageous properties with respect to its superior fluoride
sensitivity [23,24]. Concerning the occurrence of racemisation in Tpseoc-protected amino acids during
the deprotection step it should be mentioned that none of the Tpseoc-derivatives deprotected according
to the procedure above did show any alteration of optical rotation compared to authentic samples. Also
the NMR-spectra of the free amines and alcohols lacked signals caused by isomeric products, giving
rise to the assumption that under given conditions no significant racemisation of the material took
place. Furthermore it should be noted that generally compounds bearing the Tpseoc-moiety exhibit a
very good solubility in commonly used organic solvents and almost half of the compounds were
obtained as crystalline solids making them very convenient to handle.
3. Experimental
3.1. General
Chemicals were purchased from Sigma-Aldrich (triphenylvinylsilane, HOBt, morpholine, Pd/C
(10%)), Merck (DIPEA, TFA, NaBO3•4H2O), Acros Organics (9-BBN soln., Me2NH•BH3), TCI
(HBTU), Fluka (phosgene soln. 20% in toluene, TBAF•3H2O, Pd(PPh3)4), Bachem (amino acids), Alfa
Aesar (CsF) and were of the highest purity available. DCM and DMF were distilled from phosphorous
pentoxide. THF, benzene, toluene and hexane were distilled from sodium/benzophenone. Pyridine,
Et3N and DIPEA were distilled from CaH2. All solvents were stored over molecular sieves 3 Å under

Molecules 2011, 16
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an atmosphere of nitrogen until used. NMR-spectra were recorded on either a Bruker Avance 400 or a
Bruker ACX 250 spectrometer and calibrated on TMS-peak or solvent-signal peak (1H-CDCl3:
13
1
13
7.26 ppm; C-CDCl3: 77.16 ppm; H-MeOH-D4: 3.31 ppm; C-MeOH-D4: 49.00 ppm). FT-ICR-MS
spectra were recorded on a Bruker Apex II FT-ICR-MS (FAB) spectrometer. Optical rotations were
determined with a Perkin-Elmer Model 341 Polarimeter, melting points with a Büchi Melting Point
M-560. Elemental analysis was performed on a HEKAtech Euro EA Analyzer. L-Leucine benzyl ester
hydro-p-tosylate (8) and L-leucine allyl ester hydro-p–tosylate (9) were prepared following the
procedures described in [25] and [26]. N-Boc-1,6-diaminohexane (16) was prepared following the
procedure in [27]. N-Alloc-1,6-diaminohexane•TFA (17), N-Cbz-1,6-diaminohexane•TFA (18),
N-Phth-1,6-diaminohexane•TFA (19) and Fmoc-1,6-diaminohexane•TFA (20) were prepared from
N-Boc-1,6-diaminohexane (16) via introduction of the Alloc-, Cbz-, phthaloyl- and Fmoc-groups
according to standard protocols, subsequent cleavage of the Boc-group with 20% TFA/DCM and were
used for the syntheses without further purification. All yields given below are isolated yields
determined after purification of the product either by silica gel column chromatography or
crystallization and were not optimized unless noted otherwise.
3.2. Preparation of the Reagents for Introduction of the Tpseoc-group
2-(Triphenylsilyl)ethanol (2) [8],[28]. A 250 mL round-bottom flask equipped with gas inlet and a
stirring bar was charged with triphenylvinylsilane (1, 1.02 g, 3.56 mmol) dissolved in dry THF
(20 mL) under an atmosphere of nitrogen. At 0 °C a 0.5 M 9-BBN soln. in THF (14.2 mL, 7.12 mmol,
2 eq.) was added dropwise to the mixture, which was afterwards refluxed for 3 h, then the solution was
again cooled to 0 °C and water (15 mL) was added very carefully (gas evolution!), followed by
NaBO3•4H2O (3.29 g, 21.4 mmol, 6 eq.). During oxidation the temperature rose slightly to ca. 45 °C
and was kept at this temperature until TLC showed complete oxidation of the borane (3 h). The
mixture was then diluted with Et2O (200 mL) and transferred to a separatory funnel. The aqueous layer
was separated and the organic layer washed twice with sat. NaHCO3 soln., once with brine, dried over
Na2SO4 and the solvent evaporated under vacuum. Column chromatography on silica gel with the
eluent mixture light petroleum ether/ethyl acetate 7:3 yielded pure title compound 2 (953 mg,
3.13 mmol, 88%) as a colorless crystalline solid. An analytical sample of alcohol 2 was obtained by
crystallization from cyclohexane/n-hexane. m.p.: 98.5-99.5 °C (lit. [13]: 97-98.5 °C). 1H-NMR (400 MHz,
CDCl3): δ 7.58-7.53 (m, 6H, aryl-Si), 7.47-7.36 (m, 9H, aryl-Si), 3.93-3.86 (m, 2H, CH2OH),
1.89-1.83 (m, 2H, SiCH2), 1.46 (t, J = 4.4Hz, 1H, OH). 13C-NMR (100.6 MHz, CDCl3): δ 135.7 (aryl,
meta), 134.5 (aryl, ipso), 129.8 (aryl, para), 128.1 (aryl, ortho), 59.9 (CH2OH), 18.9 (SiCH2).
4-Nitrophenyl-2-(triphenylsilyl)ethyl carbonate (3). In a 100 mL round-bottom flask equipped with gas
inlet and a stirring bar silyl alcohol 2 (1.95 g, 6.41 mmol) was dissolved in dry DCM (30 mL) under a
nitrogen atmosphere. The solution was cooled to 0 °C, pyridine (2.6 mL, 32.05 mmol, 5 eq.) and
4-nitrophenyl chloroformate (1.61 g, 8.01 mmol, 1.25 eq.) were added and the mixture stirred for 24 h
at r.t.. Thereafter the solution was transferred to a separatory funnel, diluted with DCM (150 mL),
washed twice with 1M-NaHSO4 soln., once each with sat. NaHCO3 soln. and brine, dried over Na2SO4
and the solvent removed under vacuum. The residual viscous oil was subjected to silica gel column

Molecules 2011, 16
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chromatography with the eluent mixture n-hexane/ethyl acetate 4:1 yielding mixed carbonate 3
(2.63 g, 5.61 mmol, 88%) as a pale yellow crystalline solid. An analytical sample was obtained by
crystallization from cyclohexane/n-hexane. m.p.: 105.5-106 °C. FT-ICR-MS: m/z [M+Na]+ calcd for
C27H23NO5SiNa: 492.1238, found: 492.1234. Anal. calcd for C27H23NO5Si: N, 2.98; C, 69.06; H, 4.94;
1
found: N, 2.88; C, 68.98; H, 4.95. H-NMR (400 MHz, CDCl3): δ 8.30-8.24 (m, 2H, aryl-pNP),
7.61-7.54 (m, 6H, aryl-Si), 7.5-7.38 (m, 9H, aryl-Si), 7.36-7.3 (m, 2H, aryl- pNP), 4.54-4.48 (m, 2H,
13
CH2OH), 2.09-2.02 (m, 2H, SiCH2); C-NMR (100.6 MHz, CDCl3): δ 155.7, 152.5, 145.4, 135.6,
133.5, 130.1, 128.3, 125.4, 121.9, 67.8, 14.9.
1H-Imidazole-1-carboxylic acid 2-(triphenylsilyl)ethyl ester (4) [15]. In a 25 mL round-bottom flask
equipped with gas inlet and a stirring bar alcohol 2 (1.0 g, 3.28 mmol) was dissolved in dry benzene
(6 mL) under a nitrogen atmosphere. Then CDI (639 mg, 3.94 mmol, 1.2 eq.) was added and the
mixture stirred for 2 h at rt. Thereafter the solution was diluted with DCM (60 mL), transferred to a
separatory funnel, washed twice with 1M-NaHSO4 soln., once each with sat. NaHCO3 soln. and brine.
After evaporation of the solvent under vacuum a white solid was obtained, which was crystallized
from cyclohexane/n-hexane to yield imidazolide 4 (1.16 g, 2.9 mmol, 88%) as colorless platelets. m.p.:
91.5-93.5 °C. FT-ICR-MS: m/z [M+Na]+ calcd for C24H22N2O2SiNa: 421.1343, found: 421.1342.
Anal. calcd for C24H22N2O2Si: N, 7.03; C, 72.33; H, 5.56; found: N, 6.67; C, 72.44; H, 5.68. 1H-NMR
(400 MHz, CDCl3): δ 7.92 (s, 1H, Im), 7.60-7.54 (m, 6H, aryl-Si), 7.49-7.37 (m, 9H, aryl-Si), 7.28-7.24
13
(m, 1H, Im), 7.03-7.00 (m, 1H, Im), 4.68-4.61 (m, 2H, CH2OH), 2.08-2.02 (m, 2H, SiCH2); C-NMR
(100.6 MHz, CDCl3): δ 148.7, 137.1 (Im), 135.5, 133.5, 130.5 (Im), 130.1, 128.3, 117.1 (Im), 66.7, 14.6.
2-(Triphenylsilyl)ethyl chloroformate (5) [16]. In a 25 mL round-bottom flask equipped with gas inlet
and a stirring bar silyl alcohol 2 (1 g, 3.28 mmol) was dissolved in dry toluene (5 mL) under a nitrogen
atmosphere. After addition of freshly dried K2CO3 (453 mg, 3.28 mmol, 1 eq.) the solution was cooled
to 0 °C and a 20% phosgene soln. in toluene (2.42 mL, 4.59 mmol, 1.4 eq.) added dropwise over a
period of 20 min. After complete addition the mixture was stirred for an additional 4 h at r.t.. Excess
phosgene was then blown off in a stream of nitrogen, the residual toluene solution filtered and the
solvent evaporated under vacuum. The raw chloroformate solidified after some time under vacuum and
was crystallized from dry n-hexane to yield pure title compound 5 (1.13 g, 3.08 mmol, 94%) as
colorless needles. m.p.: 79.5-80.0 °C; Anal. calcd for C21H19ClO2Si: C, 68.74; H, 5.22; found: C,
68.75; H, 5.29. 1H-NMR (400 MHz, CDCl3): δ 7.57-7.51 (m, 6H, aryl-Si), 7.49-7.37 (m, 9H, aryl-Si),
4.55-4.48 (m, 2H, CH2OH), 2.05-1.98 (m, 2H, SiCH2). 13C-NMR (100.6 MHz, CDCl3): δ 150.6,
135.6, 133.3, 130.2, 128.4, 70.8, 14.8.
3.3. General Procedure for the Tpseoc-protection of Aliphatic Primary and Secondary Amines A
General Procedure A: In a 25 mL round-bottom flask equipped with gas inlet and a stirring bar mixed
carbonate 3 (400 mg, 0.85 mmol) was dissolved in dry DMF (5 mL) under a nitrogen atmosphere. To
the solution was added the corresponding amino acid ester ammonium derivative (0.94 mmol, 1.1 eq.)
and Et3N (356 μl, 2.56 mmol, 3 eq.) and the resulting shiny yellow solution stirred for 24 h at r.t.. After
completion of the reaction (TLC) the mixture was diluted with ethyl acetate (100 mL) and transferred

Molecules 2011, 16
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to a separatory funnel, washed twice each with water and 1M-NaHSO4-soln., three times with
5%-Na2CO3-soln. and once with brine. The organic layer was dried over Na2SO4 and the solvent
removed in vacuum. The residual crude Tpseoc-protected amino acid was then purified either by silica
gel column chromatography or crystallization.
N-2-(Triphenylsilyl)ethoxycarbonyl-L-leucine tert-butyl ester (11). The protected leucine derivative 11
was prepared following the general procedure A from L-leucine tert-butyl ester (210 mg, 0.94 mmol,
1.1 eq.). The crude product was subjected to silica gel column chromatography with the eluent mixture
n-hexane/ethyl acetate 8.5:1.5 yielding the protected amino acid 11 (430 mg, 0.83 mmol, 98%) as
20
colorless gum. RF: 0.42 (n-hexane/EA 4:1). [α]D = −7.1° (c = 1.0, CHCl3). FT-ICR-MS: m/z
[M+Na]+ calcd for C31H39NO4SiNa: 540.2541, found: 540.2542. Anal. calcd for C31H39NO4Si: N, 2.71;
C, 71.92; H, 7.59; found: N, 2.77; C, 71.75; H, 8.04. 1H-NMR (400 MHz, CDCl3): δ 7.65-7.55 (m, 6H,
aryl-Si), 7.49-7.36 (m, 9H, aryl-Si), 5.16 (d, 1H, J = 9.1 Hz, NH), 4.41-4.26 (m, 3H, CH2O/α-CH),
2.0-1.9 (m, 2H, SiCH2), 1.81-1.69 (m, 1H, γ-CH), 1.69-1.58 (m, 1H, β-CH2), 1.57-1.47 (m, 1H, β-CH2),
1.52 (s, 9H, t-Bu), 1.05-0.95 (m, 6H, δ-CH3). 13C-NMR (100.6 MHz, CDCl3): δ 172.5, 156.1, 135.5, 134.1,
129.7, 128.0, 81.6 (tBu), 62.7 (CH2O), 52.9 (α-CH), 42.0 (β-CH2), 28.0 (tBu), 24.8, 22.8, 22.0, 14.8.
N-2-(Triphenylsilyl)ethoxycarbonyl-L-proline tert-butyl ester (12). The protected proline derivative 12
was prepared following general procedure A from L-proline tert-butyl ester (160 mg, 0.94 mmol,
1.1 eq.). The crude product was purified by silca gel column chromatography with the eluent mixture
n-hexane/ethyl acetate 4:1 yielding protected amino acid 12 (405 mg, 0.81 mmol, 95%) as a colorless
gum. RF: 0.36 (n-hexane/EA 4:1). [α]D20 = −27.5° (c = 1.0, CHCl3). FT-ICR-MS: m/z [M+Na]+ calcd
for C30H35NO4SiNa: 524.2228, found: 524.2225. Anal. calcd for C30H35NO4Si: N, 2.79; C, 71.82; H,
1
7.03; found: N, 2.86; C, 71.71; H, 7.42. H-NMR from the mixture of isomers (400 MHz, CDCl3):
δ 7.60-7.54 (m, 6H, aryl-Si), 7.46-7.34 (m, 9H, aryl-Si), 4.50-4.21/4.0-3.94 (m, 3H, CH2O/α-CH),
3.63-3.55/ 3.51-3.43/3.41-3.34 (m, 2H, δ-CH2N), 2.19-1.71 (m, 6H, SiCH2-/β-CH2/ γ-CH2), 1.49/1.48
13
(s, 9H, t-Bu). C-NMR of the mixture of isomers (100.6 MHz, CDCl3): δ 172.0/171.9, 154.9/154.6,
135.5/135.5, 134.2/134.1, 129.6/129.6, 128.0/128.0, 81.0/80.9 (t-Bu), 62.7 (CH2O), 59.7/59.4 (α-CH),
46.6/46.1 (γ-CH2), 30.8/29.8 (β-CH2), 28.0/27.9 (t-Bu), 24.1/23.3, 15/14.9.
N-2-(Triphenylsilyl)ethoxycarbonyl-L-leucine benzyl ester (13). The protected leucine derivative 13
was prepared following general procedure A from L-leucine benzyl ester hydro-p-tosylate [25]
(369 mg, 0.94 mmol, 1.1 eq.). The crude product was purified by silca gel column chromatography
with the eluent mixture n-hexane/ethyl acetate 8.25:1.75 yielding protected amino acid 13 (456 mg,
0.83 mmol, 98%) as a colorless gum. RF: 0.4 (n-hexane/EA 4:1). [α]D20 = −7.7° (c = 1.0, CHCl3). FT-
ICR-MS: m/z [M+Na]+ calcd for C34H37NO4SiNa: 574.2384, found: 574.23799. Anal. calcd for
1
C34H37NO4Si: N, 2.54; C, 74.01; H, 6.76; found: N, 2.57; C, 74.14; H, 7.09. H-NMR (400 MHz,
CDCl3): δ 7.57-7.51 (m, 6H, aryl-Si), 7.46-7.29 (m, 14H, aryl-Si/Bn), 5.21-5.12 (m, 2H, Bn-CH2),
4.89 (d, 1H, J = 8.6 Hz, NH), 4.43-4.35 (m, 3H, SiCH2CH2O/α-CH), 1.90-1.83 (m, 2H, SiCH2CH2O),
1.70-1.56 (m, 2H, β-CH2), 1.53-1.44 (m, 1H, γ-CH), 0.96-0.89 (m, 6H, δ-CH3); 13C-NMR (101 MHz,
CDCl3): δ 172.5, 156.1, 135.7, 135.5, 134.2, 129.8, 128.7, 128.5, 128.3, 128.1, 67.1 (Bn-CHH2), 63.0
(SiCH2CH2O), 52.5 (α-CH), 41.8 (β-CH2), 24.8, 22.9, 21.9, 21.2, 14.8.

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N-2-(Triphenylsilyl)ethoxycarbonyl-L-leucine allyl ester (14). The protected leucine derivative 14 was
prepared following the general procedure A from L-leucine allyl ester hydro-p-tosylate [26] (322 mg,
0.94 mmol, 1.1 eq.). The crude product was purified by crystallization from cyclohexane/n-hexane
yielding protected amino acid 14 (372 mg 0.74 mmol, 87%) as colorless needles. RF: 0.42
(n-hexane/EA 4:1). MP: 95-96 °C. [α]D20 = −10.2° (c = 1.0, CHCl3). FT-ICR-MS: m/z [M+Na]+ calcd
for C30H35NO4SiNa: 524.2228, found: 524.2225. Anal. calcd for C30H35NO4Si: N, 2.79; C, 71.82; H,
1
7.03; found: N, 2.88; C, 71.95; H, 7.50. H-NMR (400 MHz, CDCl3): δ 7.57-7.52 (m, 6H, aryl-Si),
7.46-7.35 (m, 9H, aryl-Si), 5.97-5.86 (m, 1H, vinyl-CH), 5.37-5.23 (m, 2H, vinyl-CH2), 4.89 (d, 1H,
J = 8.7 Hz, NH), 4.65-4.61 (m, 2H, allyl-CH2O), 4.41-4.26 (m, 3H, SiCH2CH2O/α-CH), 1.92-1.84 (m,
2H, SiCH2CH2O), 1.75-1.57 (m, 2H, β-CH2), 1.55-1.45 (m, 1H, γ-CH), 0.98-0.91 (m, 6H, δ-CH3).
13C-NMR (100.6 MHz, CDCl3): δ 173.0, 156.2, 135.6, 134.2, 131.8 (vinyl-CH), 129.8, 128.1, 118.8
(vinyl-CH2), 65.9 (allyl-CH2O), 63.0 (SiCH2CH2O), 52.5 (α-CH), 41.9 (β-CH2), 24.8, 23.0, 21.9, 14.9.
N-2-(Triphenylsilyl)ethoxycarbonyl-L-leucine methyl ester (15). The protected leucine derivative 15
was prepared following the general procedure A from L-leucine methyl ester hydrochloride (170 mg,
0.94 mmol, 1.1 eq.). The crude product was purified by crystallization from cyclohexane/hexane
yielding protected amino acid 15 (355 mg, 0.75 mmol, 88%) as colorless needles. RF: 0.37
20
(n-hexane/EA 4:1). MP: 112.5-113 °C. [α]D = −7.7° (c = 1.0, CHCl3). FT-ICR-MS: m/z [M+Na]+
calcd for C28H33NO4SiNa: 498.2071, found: 492.2068. Anal. calcd for C28H33NO4Si: N, 2.94; C,
1
70.70; H, 6.99; found: N, 2.65; C, 70.93; H, 7.02. H-NMR (400 MHz, CDCl3): δ 7.57-7.52 (m, 6H,
aryl-Si), 7.46-7.38 (m, 9H, aryl-Si), 4.89 (d, 1H, J = 8.7 Hz, NH), 4.39-4.27 (m, 3H, SiCH2CH2O/α-CH),
3.73 (s, 3H, OCH3), 1.91-1.85 (m, 2H, SiCH2CH2O), 1.73-1.44 (m, 3H, β-CH2/γ-CH), 0.98-0.91
13
(m, 6H, δ-CH3). C-NMR (100.6 MHz, CDCl3): δ 173.8, 156.2, 135.6, 134.2, 131.8, 129.8, 128.1,
63.0 (SiCH2CH2O), 52.4 (α-CH/OCH3), 41.9 (β-CH2), 24.8, 22.9, 21.9, 14.9.
N-2-(Triphenylsilyl)ethoxycarbonyl-N`-tert-butoxycarbonyl-1,6-diaminohexane (21). The 1,6-diamino-
hexane derivative 21 was prepared following the general procedure A from N-Boc-1,6-diaminohexane
16 (237 mg, 0.94 mmol, 1.1 eq.). The crude product was purified by silica gel column chromatography
with the eluent mixture n-hexane/ethyl acetate 7:3 yielding bisprotected diamine 21 (457 mg,
0.84 mmol, 99%) as colorless gum. RF: 0.35 (n-hexane/EA 7:3). FT-ICR-MS: m/z [M+Na]+ calcd for
C32H42N2O4SiNa: 569.2806, found: 569.2802. Anal. calcd for C32H42N2O4Si: N, 5.12; C, 70.29; H,
1
7.74; found: N, 5.15; C, 70.24; H, 8.15. H-NMR (400 MHz, CDCl3): δ 7.57-7.56 (m, 6H, aryl-Si),
7.45-7.33 (m, 9H, aryl-Si), 4.60-4.44 (m, 2H, NH), 4.34-4.24 (m, 2H, SiCH2CH2O), 3.15-3.04 (m, 4H,
NHCH2), 1.92-1.82 (m, 2H, SiCH2CH2O), 1.51-1.38 (m, 4H, chain-CH2), 1.45 (s, 9H, tBu), 1.36-1.24
(m, 4H, chain-CH2). 13C-NMR (100.6 MHz, CDCl3): δ 156.7, 156.1, 135.6, 134.3, 129.8, 128.1, 79.2,
62.4, (SiCH2CH2O), 40.8/40.5 (NHCH2), 30.1, 30.0, 28.5 (t-Bu), 26.4, 26.4, 15.0.
N-2-(Triphenylsilyl)ethoxycarbonyl-N`-allyloxycarbonyl-1,6-diaminohexane (22). The 1,6-diamino-
hexane derivative 22 was prepared following the general procedure A from N-Alloc-1,6-
diaminohexane hydrotrifluoroacetate 17 (295 mg, 0.94 mmol, 1.1 eq.). The crude product was purified
by silica gel column chromatography with the eluent mixture n-hexane/ethyl acetate 6.25:3.75 yielding
bisprotected diamine 22 (424 mg 0.80 mmol, 94%) as colorless gum. RF: 0.20 (n-hexane/EA 7:3).

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FT-ICR-MS: m/z [M+Na]+ calcd for C31H38N2O4SiNa: 553.2493, found: 553.2496. Anal. calcd for
1
C31H38N2O4Si: N, 5.28; C, 70.15; H, 7.22; found: N, 5.21; C, 69.70; H, 7.50. H-NMR (400 MHz,
CDCl3): δ 7.57-7.51 (m, 6H, aryl-Si), 7.45-7.34 (m, 9H, aryl-Si), 5.98-5.86 (m, 1H, vinyl-CH),
5.34-5.18 (m, 2H, vinyl-CH2), 4.79 (s, broad, 1H, -NH), 4.56 (d, 2H, J = 4.9 Hz, allyl-CH2O), 4.48
(s, broad, 1H, NH), 4.33-4.25 (m, 2H, SiCH2CH2O), 3.21-3.04 (m, 4H, NHCH2), 1.91-1.82 (m, 2H,
13
SiCH2CH2O), 1.54-1.38 (m, 4H, chain-CH2), 1.37-1.26 (m, 4H, chain-CH2); C-NMR (100.6 MHz,
CDCl3): δ 156.7, 156.4, 135.6, 134.3, 133.1, 129.8, 128.1, 117.7, 65.5 (allyl-CH2O), 62.4
(SiCH2CH2O), 40.9/40.8 (NHCH2), 30.0, 26.3, 15.0.
N-2-(Triphenylsilyl)ethoxycarbonyl-N`-benzyloxycarbonyl-1,6-diaminohexane (23). The 1,6-diamino-
hexane derivative 23 was prepared following the general procedure A from N-Cbz-1,6-diaminohexane
hydrotrifluoroacetate 18 (341 mg 0.94 mmol, 1.1 eq.). The crude product was purified by silica gel
column chromatography with the eluent mixture n-hexane/ethyl acetate 6.5:3.5 yielding bisprotected
diamine 23 (487 mg 0.84 mmol, 98%) as colorless gum. RF: 0.23 (n-hexane/EA 7:3); FT-ICR-MS:
m/z [M+Na]+ calcd for C35H40N2O4SiNa: 603.2650, found: 603.2653. Anal. calcd for C35H40N2O4Si:
N, 4.82; C, 72.38; H, 6.94; found: N, 4.70; C, 71.95; H, 7.19. 1H-NMR (400 MHz, CDCl3): δ 7.58-7.52
(m, 6H, aryl-Si), 7.46-7.29 (m, 15H, aryl-Si/Bn), 5.11 (s, 2H, Bn-CH2O), 4.84 (s, broad, 1H, NH),
4.51 (s, broad, 1H, NH), 4.35-4.26 (m, 2H, SiCH2/CH2O), 3.23-3.04 (m, 4H, NHCH2), 1.92-1.82 (m,
2H, SiCH2CH2O), 1.55-1.38 (m, 4H, chain-CH2), 1.36-1.24 (m, 4H, chain-CH2); 13C-NMR
(100.6 MHz, CDCl3): δ 156.7, 156.5, 136.7, 135.6, 134.3, 129.7, 128.6, 128.2, 128.1, 66.7 (Bn-CH2O),
62.4 (SiCH2CH2O), 41.0/40.8 (NHCH2), 30.0, 26.3, 15.0.
N-2-(Triphenylsilyl)ethoxycarbonyl-N′-phthaloyl-1,6-diaminohexane (24). The 1,6-diaminohexane
derivative 24 was prepared following the general procedure A from N-phthaloyl-1,6-diaminohexane
hydrotrifluoroacetate 19 (338 mg, 0.94 mmol, 1.1 eq.). The crude product was purified by silica gel
column chromatography with the eluent mixture n-hexane/ethyl acetate 6.5:3.5 yielding bisprotected
diamine 25 (472 mg, 0.82 mmol, 97%) as colorless gum. RF: 0.28 (n-hexane/EA 7:3). FT-ICR-MS:
m/z [M+Na]+ calcd for C35H36N2O4SiNa: 599.2337, found: 599.2333. Anal: calcd for C35H36N2O4Si:
N, 4.86; C, 72.89; H, 6.29; found: N, 4.76; C, 72.70; H, 6.62. 1H-NMR (400 MHz, CDCl3): δ 7.87-7.80
(m, 2H, Pht), 7.73-7.67 (m, 2H, Pht), 7.57-7.50 (m, 6H, aryl-Si), 7.44-7.33 (m, 9H, aryl-Si), 4.47
(s, broad, 1H, NH), 4.35-4.23 (m, 2H, SiCH2CH2O), 3.68 (t, 2H, J = 7.1 Hz, PhtNCH2), 3.14-3.05
(m, 2H, NHCH2), 1.91-1.81 (m, 2H, SiCH2CH2O), 1.73-1.63 (m, 2H, chain-CH2), 1.49-1.27 (m, 6H,
chain-CH2). 13C-NMR (100.6 MHz, CDCl3): δ 168.6 (Pht-CON), 156.6 (OCONH), 135.6, 134.3,
134.0, 132.2, 129.7, 128.1, 123.3, 62.4 (SiCH2CH2O), 40.8 (NHCH2), 37.9, 29.9, 28.6, 26.5,
26.3, 15.0.
3.4. Preparation of Tpseoc-protected Amines and Alcohols with Various Methods
N-2-(Triphenylsilyl)ethoxycarbonyl-N`-(9-fluorenyl)methoxycarbonyl-1,6-diaminohexane (25). In a
25 mL round-bottom flask equipped with gas inlet and a stirring bar N-Fmoc-1,6-diaminohexane
hydrotrifluoroacetate 20 (443 mg, 0.98 mmol) was dissolved in dry DCM (5 mL) together with
Hünig`s base (380 µL, 2.18 mmol, 2.22 eq) under a nitrogen atmosphere. At 0 °C was then slowly

Molecules 2011, 16
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added a solution of chloroformate 5 (400 mg, 1.09 mmol, 1.1 eq.) dissolved in dry DCM (5 mL). The
mixture was stirred an additional 1 h at 0 °C and another 2 h at r.t.. After completion of the reaction the
solution was diluted with diethyl ether and transferred to a separatory funnel. The organic layer was
washed twice each with 1M-NaHSO4 soln., sat. NaHCO3 soln. and once with brine, dried over Na2SO4
and the solvent evaporated under vacuum. The crude product was then subjected to silica gel column
chromatography with the eluent mixture toluene/acetone 9.25:0.75 yielding title compound 25 (540 mg
0.81 mmol, 83%) as colorless solid. An analytical sample of colorless crystals was obtained by
crystallization from cyclohexane/chloroform. RF: 0.35 (toluene/acetone 9.25:0.75). MP: 147.5-148.0 °C.
1
FT-ICR-MS: m/z [M+Na]+ calcd for C42H44N2O4SiNa: 691.2963, found: 691.2965. H-NMR
(400 MHz, CDCl3): δ 7.78 (d, 2H, J = 7.4 Hz, Fmoc), 7.61 (d, 2H, J = 7.4 Hz, Fmoc), 7.59-7.52 (m,
6H, aryl-Si), 7.46-7.29 (m, 13H, aryl-Si/ Fmoc), 4.85 (s, broad, 1H, NH), 4.49 (s, broad, 1H, NH),
4.42 (d, 2H, J = 6.6 Hz, Fmoc-OCH2), 4.36-4.20 (m, 3H, SiCH2CH2O/Fmoc-CH2CH), 3.25-3.04 (m,
4H, NHCH2), 1.96-1.83 (m, 2H, SiCH2CH2O), 1.58-1.21 (m, 8H, chain-CH2). 13C-NMR (100.6 MHz,
CDCl3): δ 156.7, 156.6, 144.1, 141.4, 135.6, 134.3, 129.8, 128.6, 128.1, 127.8, 127.1, 125.1, 120.1,
66.6 (Fmoc-OCH2), 62.4 (SiCH2CH2O), 47.4 (Fmoc-CH2CH), 40.9/40.8 (NHCH2), 30.0, 27.0,
26.3, 15.0.
3β-[2-(Triphenylsilyl)ethoxycarbonyloxy]androst-5-en-17-one (27). In a 5 mL Schlenk-tube equipped
with a stirring bar prasterone 26 (143 mg, 0.50 mmol) was dissolved in dry DCM (2 mL) under a
nitrogen atmosphere. To the solution of the steroid was added at 0 °C chloroformate 5 (200 mg, 0.55
mmol, 1.1 eq.) followed by pyridine (134 μL, 1.65 mmol, 3 eq.) and DMAP (6.7 mg, 50 μmol, 0.1
eq.). The resulting mixture was then stirred at 0 °C for 2 h and additional 24 h at r.t.. Thereafter the
mixture was diluted with EtOAc, transferred to a separatory funnel, washed twice with 1M-NaHSO4
soln., once with sat. NaHCO3 soln., once with brine and dried over Na2SO4. After removal of the
solvent in vacuum the residue was subjected to silica gel column chromatography with the eluent
mixture n-hexane/ethyl acetate 3:1 yielding protected steroid 27 (207 mg, 0.33 mmol, 66%) as a
20
colorless foam. RF: 0.41 (n-hexane/EA 3:1). [α]D = +1.2° (c = 1.0, CHCl3); FT-ICR-MS: m/z
1
[M+Na]+ calcd for C40H46O4SiNa: 641.3058, found: 641.3063. H-NMR (400 MHz, CDCl3):
δ 7.56-7.50 (m, 6H, aryl-Si), 7.46-7.35 (m, 9H, aryl-Si), 5.44- 5.40 (m, 1H, C6-H), 4.49-4.4 (m, 1H,
C3-H) 4.36-4.29 (m, 2H, SiCH2CH2O), 2.52-2.30 (m, 3H, scaffold), 2.16-2.04 (m, 2H, scaffold),
1.99-1.82 (m, 6H, SiCH2CH2O, scaffold), 1.72-1.43 (m, 6H, scaffold), 1.34-1.24 (m, 2H, scaffold),
1.20-1.09 (m, 1H, scaffold), 1.07-1.00 (m, 1H, scaffold), 1.04 (s, 3H, CH3), 0.89 (s, 3H, CH3).
13C-NMR (100.6 MHz, CDCl3): δ 221.0 (C17), 154.6 (OCOO), 139.8 (C5), 135.6, 133.8, 129.9,
128.2, 122.2 (C6), 77.4, 65.7 (SiCH2CH2O), 51.8, 50.2, 47.6, 38.1, 36.9, 36.8, 36.0, 31.6, 31.5, 30.9,
27.8, 22.0, 20.5, 19.4, 14.8, 13.7.
N-tert-Butoxycarbonyl-1-[2-(triphenylsilyl)ethoxycarbonyl]-L-tryptophan methyl ester (29). In a
25 mL round-bottom flask equipped with gas inlet and a stirring bar N-Boc-L-tryptophan methyl ester
(200 mg, 0.63 mmol) was dissolved in dry pyridine (5 mL) under a nitrogen atmosphere. After
addition of TpseocIm 4 (375 mg, 0.94 mmol, 1.5 eq.) the mixture was heated to 80 °C for 36 h, diluted
with ethyl acetate and transferred to a separatory funnel. The organic layer was washed twice with
1N-HCl soln., once with sat. NaHCO3 soln. and once with brine, dried over Na2SO4 and the solvent

Molecules 2011, 16
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evaporated under vacuum. The residual crude product was subjected to silica gel column
chromatography with the eluent mixture n-hexane/ethyl acetate 4:1 yielding title compound 29
(370 mg, 0.57 mmol, 91%) as colorless foam. RF: 0.3 (n-hexan/EtOAc 4:1). [α]D20 = +22.4° (c = 1.0,
1
CHCl3). FT-ICR-MS: m/z [M+Na]+ calcd for C38H40N2O6SiNa: 671.2548, found: 671.2549. H-NMR
(400 MHz, CDCl3): δ 8.13 (d, broad, 1H, J = 6.2 Hz, Trp), 7.61-7.54 (m, 6H, aryl-Si), 7.51-7.35 (m,
10H, aryl-Si/Trp), 7.31 (t, broad, 1H, J = 7.4 Hz, Trp), 7.24 (t, broad, 1H, J = 7.3 Hz, Trp), 7.19 (s,
broad, 1H, Trp), 5.01 (d, 1H, J = 7.8 Hz, Boc-NH), 4.67-4.71 (m, 3H, SiCH2CH2O/α-CH), 3.68 (s, 3H,
OCH3), 3.25-3.07 (m, 2H, β-CH2), 2.12-2.03 (m, 2H, SiCH2CH2O), 1.42/1.29 (s, broad, 9H, t-BuH);
13C-NMR (100.6 MHz, CDCl3): δ 172.4 (COO), 155.2 (OCONH), 150.8, 135.6, 133.7, 130.5, 130.4,
128.3, 124.8, 123.7, 122.9, 119.0, 115.8, 115.4, 80.1 (t-Bu), 65.3 (SiCH2CH2O), 53.7 (α-CH), 52.5
(OCH3), 28.4 (t-Bu), 27.9, 14.8.
N-2-(Triphenylsilyl)ethoxycarbonyl-L-phenylalanine (31). In a 50 mL round-bottom flask equipped
with a stirring bar L-phenylalanine 30 (205 mg, 1.24 mmol) and NaHCO3 (229 mg, 2.73 mmol,
2.2 eq.) were dissolved in water (10 mL). The mixture was cooled to 0 °C and a solution of TpseocCl 5
(500 mg, 1.36 mmol, 1.1 eq.) in dioxane (10 mL) was added dropwise. The resulting slurry was then
stirred for 1 h at 0 °C and 4 h at r.t., dioxane removed under vacuum and the residual aqueous phase
acidified with solid NaHSO4. After being transferred to a separatory funnel the aqueous phase was
extracted three times with EtOAc, the combined organic phases washed once each with 1M-NaHSO4-
soln., water and brine and dried over Na2SO4. After removal of the solvent under vacuum the title
compound 31 (529 mg 1.07 mmol, 86%) was obtained as a colorless foam in high purity. The crude
Tpseoc-protected free acid was used in the synthesis of 32 without further purification. FT-ICR-MS:
m/z [M+Na]+ calcd for C30H29NO4SiNa: 518.1758, found: 518.1756. 1H-NMR (400 MHz, MeOH-D4):
δ 7.51-7.44 (m, 6H, aryl-Si), 7.42-7.30 (m, 9H, aryl-Si), 7.26-7.07 (m, 5H, aryl-Phe), 4.39 (dd, 1H,
J = 8.9 Hz/5 Hz, α-CH), 4.18-4.09 (m, 2H, SiCH2CH2O), 3.15 (dd, 1H, J = 13.9 Hz/5 Hz, β-CH), 2.90
(dd, 1H, J = 13.9 Hz/9 Hz, β-CH), 1.83-1.81 (m, 2H, SiCH2CH2O). 13C-NMR (100.6 MHz,
MeOH-D4): δ 175.1 (COOH), 158.4 (OCONH), 138.4, 136.5, 135.3, 130.8, 130.3, 129.4, 129.1, 127.7,
63.8 (SiCH2CH2O), 56.5 (α-CH), 38.7 (β-CH2), 15.8.
N-2-(Triphenylsilyl)ethoxycarbonyl-L-phenylalanyl-L-leucine tert-butyl ester (32): In a 25 mL round
bottom flask equipped with gas inlet and a stirring bar the crude Tpseoc-protected L-phenylalanine 31
(300 mg, 0.61 mmol, 1.2 eq.) was dissolved in dry DMF (5 mL) together with leucine tert-butyl ester
hydrochloride (113 mg, 0.50 mmol) and HOBt (103 mg, 0.76 mmol, 1.5 eq.) under a nitrogen
atmosphere. After cooling the solution to 0 °C Hünig`s base (263 μL, 1.51 mmol, 3 eq.) and HBTU
(288 mg, 0.76 mmol, 1.5 eq.) were added, the mixture stirred for 2 h at 0 °C and for additional 14 h at
r.t.. Thereafter the mixture was diluted with EtOAc, transferred to a separatory funnel, washed twice
each with 1N-NaHSO4-soln. and sat. NaHCO3-soln., once with brine and dried over Na2SO4. After
removal of the solvent under vacuum the residual white solid was subjected to silica gel column
chromatography with the eluent mixture n-hexane/ethyl acetate 7.75: 2.25 yielding the dipeptide 32
(323 mg, 0.49 mmol, 98%) as a colorless crystalline solid. An analytical sample of colorless needles
was obtained by crystallization from cyclohexane/n-hexane. RF: 0.41 (n-hexane/EA 3:1). m.p.:
131-132 °C. [α]D20 = −7.4° (c = 1.0, CHCl3). FT-ICR-MS: m/z [M+Na]+ calcd for C40H48N2O5SiNa:

Molecules 2011, 16
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687.3225, found: 687.3228. Anal. calcd for C40H48N2O5Si: N, 4.21; C, 72.26; H, 7.28; found: N, 4.32;
1
C, 72.41; H, 7.61. H-NMR (400 MHz, CDCl3): δ 7.55-7.49 (m, 6H, aryl-Si), 7.44-7.32 (m, 9H,
aryl-Si), 7.29-7.13 (m, 5H, aryl-Phe), 6.19 (d, 1H, J = 7.9 Hz, CONH), 5.02 (s, 1H, OCONH),
4.46-4.34 (m, 2H, α-CH), 4.29-4.21 (m, 2H, SiCH2CH2O), 3.11-2.98 (m, 2H, β-CHH2-Phe), 1.86-1.78
(m, 2H, SiCH2CH2O), 1.59-1.49 (m, 2H, β-CH2-Leu), 1.48-1.37 (m, 1H, γ-CH), 1.42 (s, 9H, t-Bu),
0.92-0.84 (m, 6H, δ-CH3). 13C-NMR (100.6 MHz, CDCl3): δ 171.6, 170.5, 156.1, 136.4, 135.6, 134.1,
129.8, 129.5, 128.8, 128.2, 128.2, 127.1, 82.0 (t-Bu), 63.2 (SiCH2CH2O), 56.0, 51.5, 42.0, 38.4, 28.1
(t-Bu), 24.9, 22.8, 22.2, 14.8.
3.5. Competitive protecting group cleavage in N-Tpseoc-L-leucine esters 11, 13, 14, 15, N-Tpseoc-L-
proline ester 12 and subsequent amide coupling with L-leucine tert-butyl ester. Competitive cleavage
of the amino protecting groups in N-Tpseoc-1,6-diaminohexane derivatives 21, 22, 23, 24, and 25 and
subsequent amide coupling with N-Boc-L-alanine
General procedure B for the coupling of crude Tpseoc-protected proline and leucine free acids
obtained from ester cleavage in 11, 12, 13, 14, 15 with L-leucine tert-butyl ester and of the crude
N-Tpseoc-protected 1,6-diaminohexane free bases obtained from protecting group cleavage in 21, 22,
23, 24 and 25 with N-Boc-L-alanine: In a 25 mL round-bottom flask equipped with gas inlet and a
stirring bar the crude Tpseoc-protected amino acid/N-Tpseoc-protected 1,6-diaminohexane, obtained
following the deprotection protocol given below, was dissolved in dry DMF (5 mL) together with
leucine tert-butyl ester hydrochloride/N-Boc-L-alanine (1.25 eq.) and HOBt (1.5 eq.) under a nitrogen
atmosphere. After cooling the solution to 0 °C Hünig`s base (1.5 eq./3 eq.) and HBTU (1.5 eq.) were
added, the mixture stirred for 2 h at 0 °C and for additional 14 h at r.t.. Thereafter the mixture was
diluted with EtOAc, transferred to a separatory funnel, washed twice each with 1M-NaHSO4-soln. and
sat. NaHCO3-soln., once with brine and dried over Na2SO4. After removal of the solvent under vacuum
the residual crude Tpseoc-protected peptides were subjected to silica gel column chromatography.
N-2-(Triphenylsilyl)ethoxycarbonyl-L-leucyl-L-leucine tert-butyl ester (33). Pure N-Tpseoc-L-leucyl-L-
leucine tert-butyl ester 33 was obtained by chromatography with the eluent mixture n-hexane/ethyl
acetate 8.25:1.75 as a crystalline solid. An analytical sample was obtained by crystallization from
20
cyclohexane/n-hexane. RF: 0.38 (n-hexane/EA 4:1). MP: 118.5 °C. [α]D = −24.8° (c = 1.0, CHCl3).
1
FT-ICR-MS: m/z [M+Na]+ calcd for C37H50N2O5SiNa: 653.3381, found: 653.3383. H-NMR
(400 MHz, CDCl3): δ 7.57-7.50 (m, 6H, aryl-Si), 7.45-7.34 (m, 9H, aryl-Si), 6.19 (d, broad, 1H, J =
8.1 Hz, CONH), 5.04 (d, broad, 1H, J = 7.8 Hz, OCONH), 4.52-4.44 (m, 1H, α-CH), 4.34-4.25 (m,
2H, SiCH2CH2O), 4.20-4.11 (m, 1H, α-CH), 1.93-1.83 (m, 2H, SiCH2), 1.72-1.57 (m, 4H, β-CH2),
1.56-1.38 (m, 2H, γ-CH), 1.45 (s, 9H, t-Bu), 0.96-0.89 (m, 6H, δ-CH3). 13C-NMR (100.6 MHz,
CDCl3): δ 172, 171.9, 156.4, 135.6, 134.1, 129.8, 128.1, 81.9 (t-Bu), 63.1 (SiCH2CH2O), 53.4 (α-CH),
51.5 (α-CH), 41.8 (β-CH2), 41.5 (β-CH2), 28.0 (t-Bu), 24.9, 24.7, 23.1, 22.9, 22.2, 22.1, 14.9.
N-2-(Triphenylsilyl)ethoxycarbonyl-L-prolyl-L-leucine tert-butyl ester (34). Pure N-Tpseoc-L-prolyl-L-
leucine tert-butyl ester 34 was obtained by chromatography with the eluent mixture n-hexane/ethyl
acetate 7:3 as a colorless gum. RF: 0.47 (n-hexane/EA 3:2). [α]D20 = −50.8° (c = 1.0, CHCl3). FT-ICR-

Molecules 2011, 16
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1
MS: m/z [M+Na]+ calcd for C36H46N2O5SiNa: 637.3069, found: 637.3067. H-NMR from the mixture
of isomers (400 MHz, CDCl3): δ 7.59-7.51 (m, 6H, aryl-Si), 7.45-7.32 (m, 9H, aryl-Si), 7.05/6.39 (s,
broad, 1H, CONH), 4.50/4.43 (s, broad, 1H, α-CH), 4.40-4.25/4.13-4.03 (m, 3H, SiCH2CH2O/α-CH),
3.50 (s, broad, 1H, δ-CH), 3.25/3.09 (s, broad, 1H, δ-CH), 2.36-1.74 (m, 6H, SiCH2/β-CH2), 1.70-1.32
(m, 12H, γ-CH2/t-Bu), 0.90 (d, broad, 6H, J = 6.2 Hz, δ-CH3). 13C-NMR from the mixture of isomers
(100.6 MHz, CDCl3): δ 171.8, 171.4, 156.3/155.5, 135.6, 134.1, 129.1, 128.1, 81.7 (t-Bu), 63.4
(SiCH2CH2O), 60.7 (α-CH-Pro), 51.7/51.1 (α-CH-Leu), 47.3/ 46.7(β-CH2-Pro), 41.7 (β-CH2-Leu),
30.9, 28.2, 28.0 (t-Bu), 25.0, 24.6, 23.7, 22.9, 22.2, 14.9.
N-2-(Triphenylsilyl)ethoxycarbonyl-N`(N-tert-butoxycarbonyl)-L-alanyl-1,6-diaminohexane (35). Pure
N-Boc-L-alanyl-N`-Tpseoc-1,6-diaminohexane 35 was obtained by chromatography with the eluent
20
mixture n-hexane/ethyl acetate 2:3 as a colorless foam. RF: 0.34 (hexane/EA 2:3). [α]D = −2.6°
(c = 1.0, CHCl3). FT-ICR-MS: m/z [M+Na]+ calcd for C35H47N3O5SiNa: 640.3177, found: 640.3177.
1H-NMR (400 MHz, CDCl3): δ 7.56-7.50 (m, 6H, aryl-Si), 7.44-7.32 (m, 9H, aryl-Si), 6.51 (s, broad,
1H, amide-NH), 5.24 (d, broad, 1H, J = 5.7 Hz, OCONH), 4.61 (s, broad, 1H, OCONH), 4.35-4.23
(m, 2H, SiCH2CH2O), 4.15-4.01 (m, 1H, α-CH), 3.27-3.18 (m, 2H, CONHCH2), 3.13-3.03 (m, 2H,
CONHCH2), 1.91-1.82 (m, 2H, SiCH2), 1.52-1.39 (m, 4H, chain-CH2), 1.43 (s, 9H, t-Bu), 1.30 (d, 3H,
13
J = 7 Hz, β-CH3), 1.32-1.25 (m, 4H, chain-CH2). C-NMR (100.6 MHz, CDCl3): δ 172.9 (CONH),
156.7, 155.7, 135.6, 134.2, 129.7, 128.1, 80.0 (t-Bu), 62.4 (SiCH2CH2O), 50.2 (α-CH-Ala), 40.6, 39.3,
29.4, 28.4 (t-Bu), 26.3, 26.2, 18.6, 14.9.
tert-Butyl ester cleavage in N-2-(triphenylsilyl)ethoxycarbonyl-L-leucine tert-butyl ester (11) [16]. In a
Schlenk-tube equipped with a stirring bar protected amino acid 11 (127 mg, 0.249 mmol) was
dissolved in dry DCM (1 mL) under a nitrogen atmosphere. To the solution were added
1,3-dimethoxybenzene (163 μL, 1.25 mmol, 5 eq.) and TFA (1 mL) and the mixture stirred at 0 °C
until TLC showed complete cleavage of the ester (4 h). The solution was then evaporated to dryness
and the residual crude Tpseoc-protected amino acid coupled with L-leucine tert-butyl ester following
the general procedure B using L-leucine tert-butyl ester (70 mg, 0.311 mmol), HBTU (142 mg,
0.374 mmol), HOBt (51 mg, 0.374 mmol) and Hünig`s base (130 µl, 0.747 mmol, 3 eq.) yielding
Tpseoc-protected dipeptide 33 (112 mg, 0.178 mmol, 71%).
tert-Butyl ester cleavage in N-2-(triphenylsilyl)ethoxycarbonyl-L-proline tert-butyl ester (12) [16]. In
a Schlenk-tube equipped with a stirring bar protected amino acid 12 (150 mg, 0.299 mmol) was
dissolved in dry DCM (1 mL) under a nitrogen atmosphere. To the solution were added
1,3-dimethoxybenzene (196 μL, 1.50 mmol, 5 eq.) and TFA (1 mL) and the mixture stirred at 0 °C
until TLC showed complete cleavage of the ester (4 h). The solution was then evaporated to dryness
and the residual crude Tpseoc-protected amino acid coupled with L-leucine tert-butyl ester following
general procedure B using L-leucine tert-butyl ester (84 mg, 0.374 mmol), HBTU (170 mg,
0.449 mmol), HOBt (61 mg, 0.449 mmol) and Hünig`s base (156 µL, 0.897 mmol, 3 eq.) yielding
Tpseoc-protected dipeptide 34 (127 mg, 0.207 mmol, 69%).
Benzyl ester cleavage in N-2-(triphenylsilyl)ethoxycarbonyl-L-leucine benzyl ester (13). In a 25 mL
round-bottom flask equipped with gas inlet a stirring bar benzyl ester 13 (189 mg, 0.343 mmol) was

Molecules 2011, 16
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dissolved in EtOAc (5 mL). A spatula tip of Pd/C (10%) was added and the mixture stirred under an
atmosphere on hydrogen until TLC indicated complete consumption of the starting material (4 h).
Then the solution was filtered through a pad of Celite and the solvent evaporated under vacuum. The
residual crude Tpseoc-protected amino acid was then coupled with L-leucine tert-butyl ester (96 mg,
0.429 mmol) following general procedure B using HBTU (195 mg, 0.515 mmol), HOBt (70 mg,
0.515 mmol) and Hünig`s base (179 µL 1.03 mmol, 3 eq.) yielding of Tpseoc-protected dipeptide 33
(181 mg, 0.284 mmol, 83%).
Allyl ester cleavage in N-2-(triphenylsilyl)ethoxycarbonyl-L-leucine allyl ester (14) [18]. In a Schlenk-
tube equipped with a stirring bar allyl ester 14 (100 mg, 0.199 mmol) was dissolved in dry THF (1 mL)
under a nitrogen atmosphere. To the solution were added Pd(PPh3)4 (23 mg, 20 μmol, 0.1 eq.) and
morpholine (173 μL, 1.99 mmol, 10 eq.) and the mixture stirred at room temperature until TLC
showed complete consumption of the starting material (2 h). Then the mixture was diluted with
EtOAc, transferred to a separatory funnel, washed twice with 1M-NaHSO4 soln., once with water and
once with brine, the organic layer dried over Na2SO4 and the solvent evaporated under vacuum. The
residual crude Tpseoc-protected amino acid was then coupled with L-leucine tert-butyl ester following
the general procedure B using L-leucine tert-butyl ester (56 mg, 0.249 mmol), HBTU (113 mg
0.299 mmol), HOBt (40 mg, 0.299 mmol) and Hünig`s base (104 µL, 0.597 mmol, 3 eq.) yielding
Tpseoc-protected dipeptide 33 (113 mg, 0.180 mmol, 90%).
Methyl ester cleavage in N-2-(triphenylsilyl)ethoxycarbonyl-L-leucine methyl ester (15). In a 25 mL
round bottom-flask equipped with a stirring bar methyl ester 15 (100 mg, 0.210 mmol) was dissolved
in MeOH/ THF 3:2 (3 mL). Then a 1M-NaOH soln. (630 μL, 0.63 mmol, 3 eq.) was added and the
mixture stirred at r.t. until TLC showed complete consumption of the starting material (1 h). The
mixture was then diluted with 1M-NaHSO4 soln. (25 mL), transferred to a separatory funnel and
extracted three times with DCM. The combined organic phases were washed once with water and
brine, dried over Na2SO4 and the solvent evaporated under vacuum. The residual crude Tpseoc-
protected amino acid was then coupled with L-leucine tert-butyl ester (59 mg, 0.263 mmol) following
the general procedure B using HBTU (119 mg, 0.315 mmol), HOBt (43 mg, 0.315 mmol) and Hünig`s
base (110 µL, 0.630 mmol, 3 eq.) yielding Tpseoc-protected dipeptide 33 (117 mg, 0.185 mmol, 88%).
Boc-cleavage in N-2-(triphenylsilyl)ethoxycarbonyl-N′-tert-butoxycarbonyl-1,6-diaminohexane (21)
[16]. In a Schlenk-tube equipped with a stirring bar diamine 21 (100 mg, 0.183 mmol) was dissolved
in dry DCM (1.6 mL) under a nitrogen atmosphere. To the solution were added 1,3-dimethoxybenzene
(119 μL, 0.915 mmol, 5 eq.) and TFA (400 μL) and the solution stirred at 0 °C until TLC indicated
complete consumption of the starting material (45 min.). The mixture was then evaporated to dryness
and the residual crude Tpseoc-protected diamine coupled with N-Boc-L-alanine (43 mg, 0.229 mmol)
following the general procedure B using HBTU (104 mg, 0.274 mmol), HOBt (37 mg, 0.274 mmol)
and Hünig`s base (96 µL, 0.630 mmol, 3 eq.) yielding Tpseoc-protected peptide 35 (96 mg,
0.155 mmol, 85%).
Alloc-cleavage in N-2-(triphenylsilyl)ethoxycarbonyl-N′-allyloxycarbonyl-1,6-diaminohexane (22) [19].
In a Schlenk-tube equipped with a stirring bar diamine 22 (108 mg, 0.203 mmol) was dissolved in dry

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DCM (2.5 mL) under a nitrogen atmosphere. To the solution were added Pd(PPh3)4 (12 mg,
10.2 µmol, 0.05 eq.) and Me2NH•BH3 (24 mg, 0.406 mmol, 2 eq.) and the resulting yellow solution
stirred at r.t. until TLC indicated complete consumption of the starting material (2 h). Then methanol
(0.5 mL) was added and the mixture stirred for additional 30 min.. Subsequently the solvent was
removed under vacuum, the residue taken up in EtOAc and transferred to a separatory funnel. The
organic layer was washed twice with sat. NaHCO3 soln., once with brine, dried over Na2SO4 and the
solvent removed under vacuum. The residual crude Tpseoc-protected diamine was then coupled
with N-Boc-L-alanine (48 mg, 0.254 mmol) following general procedure B using HBTU (116 mg,
0.305 mmol), HOBt (31 mg, 0.305 mmol) and Hünig`s base (53 µL, 0.305 mmol, 1.5 eq.) yielding
Tpseoc-protected peptide 35 (102 mg, 0.165 mmol, 81%).
Cbz-cleavage in N-2-(triphenylsilyl)ethoxycarbonyl-N′-benzyloxycarbonyl-1,6-diaminohexane (23). In
a 25 mL round-bottom flask equipped with gas inlet and a stirring bar diamine 23 (82 mg,
0.141 mmol) was dissolved in dry THF (5 mL). A spatula tip of Pd/C (10%) was added and the
mixture placed under an atmosphere of hydrogen and stirred until TLC showed complete consumption
of the staring material (8 h). Then the solution was filtered through a pad of Celite and the solvent
evaporated under vacuum. The residual crude Tpseoc-protected diamine was then coupled with N-Boc-
L-alanine (33 mg, 0.176 mmol) following the general procedure B using HBTU (80 mg, 0.212 mmol),
HOBt (29 mg, 0.212 mmol) and Hünig`s base (37 µL, 0.212 mmol, 1.5 eq.) yielding Tpseoc-protected
peptide 35 (74 mg, 0.120 mmol, 85%).
Phthalimide cleavage in N-2-(triphenylsilyl)ethoxycarbonyl-N′-phthaloyl-1,6-diaminohexane (24) [29].
In a Schlenk-tube equipped with a stirring bar diamine 24 (100 mg, 0.173 mmol) was dissolved in dry
toluene (5 mL) under a nitrogen atmosphere. To the solution was added methylhydrazine (182 μL,
3.46 mmol, 20 eq.) and the resulting mixture stirred at 80 °C until TLC indicated complete
consumption of the starting material (24 h). Then the solvent was removed under vacuum and the
residual crude Tpseoc-protected diamine coupled with N-Boc-L-alanine (41 mg, 0.216 mmol)
following general procedure B using HBTU (99 mg, 0.260 mmol), HOBt (35.1 mg, 0.260 mmol) and
Hünig`s base (45 µL, 0.260 mmol, 1.5 eq.) yielding Tpseoc-protected peptide 35 (86 mg, 0.139 mmol,
80%).
Fmoc-cleavage in N-2-(triphenylsilyl)ethoxycarbonyl-N′-(9-fluorenyl)methoxycarbonyl-1,6-diamino-
hexane (25) [1]. In a Schlenk-tube equipped with a stirring bar diamine 25 (150 mg, 0.224 mmol) was
dissolved in dry DMF (1 mL) under a nitrogen atmosphere. To the solution was added morpholine
(1 mL) and the resulting mixture stirred at r.t. for 1 h. Then the solvent was removed under vacuum
and the residual crude Tpseoc-protected diamine coupled with N-Boc-L-alanine (53 mg, 0.280 mmol)
following the general procedure B using HBTU (127 mg, 0.336 mmol), HOBt (45 mg, 0.336 mmol)
and Hünig`s base (60 µL, 0.336 mmol, 1.5 eq.) yielding Tpseoc-protected peptide 35 (125 mg,
0.202 mmol, 90%).

Molecules 2011, 16
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3.6. Fluoride-ion induced Tpseoc-cleavage in 27, 29, 32, 33, 34 and 35:
General procedure C for the Tpseoc-deprotection of aliphatic primary and secondary amines and
alcohols [8]: In a round bottom flask equipped with gas inlet and a stirring bar the corresponding
Tpseoc-protected amine or alcohol was dissolved in dry THF under an atmosphere of nitrogen. To the
solution were added 2 mol eq. TBAF•3H2O and 2 mol eq. CsF at the temperature noted below and
stirred at this temperature until completion of Tpseoc-cleavage was indicated by TLC. Then the
mixture was acidified by adding 1M-NaHSO4 soln. and stirred another 10 min. at rt. For deprotection
of basic amines the solution was then diluted with additional water, transferred to a separatory funnel
and extracted three times with EtOAc. The aqueous phase was then made alkaline by addition of
1N-NaOH and again extracted three times with EtOAc. Afterwards the combined organic layers were
washed once each with water and brine, dried over Na2SO4 and the solvent removed in vacuum,
leaving the free amine in high purity. An analytical sample could be obtained by silica gel column
chromatography with CHCl3/MeOH/Et3N mixtures as eluent. For non-basic amines and alcohols the
mixture was neutralized by addition of sat. NaHCO3-soln and extracted three times with EtOAc. The
combined organic layers were washed with water and brine and the residual crude product purified by
silica gel column chromatography.
Deprotection of 3β-[2-(Triphenylsilyl)ethoxycarbonyloxy]androst-5-en-17-one (27). According to
general procedure C Tpseoc-prasterone 27 (100 mg, 0.162 mmol) was dissolved in dry THF (2 mL)
and treated with TBAF•H2O (102 mg, 0.323 mmol) and CsF (49 mg, 0.323 mmol) at 0 °C. TLC
showed complete cleavage of the Tpseoc-group after 10 min. and chromatographic purification with
the eluent mixture light petroleum ether/ethyl acetate 3:2 yielded prasterone (41 mg, 0.142 mmol,
88%) as a white solid. The material proofed to be identical to an authentic sample of prasterone as
indicated by NMR-spectra and optical rotation [30].
Deprotection of N-tert-butoxycarbonyl-1-[2-(triphenylsilyl)ethoxycarbonyl]-L-tryptophan methyl ester
(29). According to general procedure C Tpseoc-protected thryptophan derivative 29 (100 mg,
0.154 mmol) was dissolved in dry THF (2 mL) and treated with TBAF•3H2O (97 mg 0.303 mmol) and
CsF (47 mg, 0.303 mmol) at 0 °C. TLC showed complete cleavage of the Tpseoc-group after 10 min.
and chromatographic purification with the eluent mixture light petroleum ether/ethyl acetate 3:2
yielded N-Boc-tryptophan methyl ester (45 mg, 0.140 mmol, 91%) as colorless crystals. The material
proofed to be identical to an authentic sample of N-Boc-tryptophan methyl ester as indicated by
NMR-spectra and optical rotation [31].
Deprotection of N-2-(triphenylsilyl)ethoxycarbonyl-L-phenylalanyl-L-leucine tert-butyl ester (32) to
L-phenylalanyl-L-leucine tert-butyl ester (36). According to the general procedure C Tpseoc-protected
dipeptide 32 (100 mg, 0.15 mmol) was dissolved in dry THF (2 mL) and treated with TBAF•3H2O
(95 mg, 0.30 mmol) and CsF (46 mg, 0.30 mmol) at r.t.. TLC showed complete cleavage of the
Tpseoc-group after 6 h and aqueous workup yielded L-phenylalanyl-L-leucine tert-butyl ester 36
(46 mg, 0.138 mmol, 92%) as a colorless gum. An analytical sample was obtained by chromatography
eluting with CHCl3 containing 2.5% MeOH and 1% Et3N. The material showed NMR-spectra lacking

Molecules 2011, 16
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signals from isomeric dipeptides and optical rotation in agreement with data published before [32]
indicating that no racemisation took place during deprotection of the Tpseoc-group. RF: 0.31 (CHCl3
20
1
+2.5% MeOH). [α]D = −35.4° (c = 1.0, DMF), lit.: -35.2° (c = 1, DMF) [32]. H-NMR (400 MHz,
CDCl3): δ 7.66 (d, broad, 1H, J = 8.5 Hz, CONH), 7.35-7.20 (m, 5H, Phe), 4.50 (dt, 1H, J = 8.7 Hz/5
Hz, α-CH-Leu), 3.65 (dd, 1H, J = 9.2 Hz/4 Hz, α-CH-Phe), 3.24 (dd, 1H, J = 13.7 Hz/4 Hz, β-CH-
Phe), 2.73 (dd, 1H, J = 13.7 Hz/ 9.2 Hz, β-CH-Phe) 1.66-1.43 (m, 5H, β/γ-CH-Leu, NH2), 1.46 (s, 9H,
13
t-Bu), 0.97-0.92 (m, 6H, δ-CH3-Leu). C-NMR (100.6 MHz, CDCl3): δ 174.0, 172.3, 137.8, 129.8,
128.8, 126.9, 81.8 (t-Bu), 56.4, 51.0, 41.9, 40.9, 28.1 (t-Bu), 25.0, 23.0, 22.1.
Deprotection of N-2-(triphenylsilyl)ethoxycarbonyl-L-leucyl-L-leucine tert-butyl ester (33) to L-leucyl-
L-leucine tert-butyl ester (37). According to the general procedure C Tpseoc-protected dipeptide 33
(179 mg, 0.284 mmol) was dissolved in dry THF (3 mL) and treated with TBAF•3H2O (179 mg,
0.568 mmol) and CsF (86 mg, 0.568 mmol) at r.t.. TLC showed complete cleavage of the Tpseoc-
group after 6 h and aqueous workup yielded L-leucyl-L-leucine tert-butyl ester 37 (81 mg, 0.270 mmol,
95%) as a colorless gum. An analytical sample was obtained by chromatographic purification eluting
with CHCl3 containing 1% MeOH and 1% Et3N. The material showed NMR-spectra lacking signals
from isomeric dipeptides. [α]D20 = −21.5° (c = 1.0, CHCl3). FAB-MS calcd for C16H32N2O3: m/z 301.3
[M+H]+, 245.2 [M-tBu+H]+. FT-ICR-MS: m/z [M+Na]+ calcd for C16H32N2O3: 301,2486 found:
1
301.2486. H-NMR (400 MHz, CDCl3): δ 7.58 (d, broad, 1H, J = 8.5 Hz, CONH), 4.46 (dt, 1H,
J = 8.7 Hz/5.1 Hz, α-CH-Leu-ester), 3.40 (dd, 1H, J = 8.2 Hz/3.6 Hz, α-CH-Leu), 1.76-1.22 (m, 8H,
13
β/γ-CH-Leu, NH2), 1.44 (s, 9H, t-BuH), 0.97-0.89 (m, 12H, δ-CH3). C-NMR (100.6 MHz, CDCl3):
δ 175.5, 172.6, 81.8 (t-BuH), 53.8, 51.1, 44.3, 42.0, 28.2 (t-Bu), 25.2, 25.1, 23.6, 23.1, 22.3, 21.6.
Deprotection of N-2-(triphenylsilyl)ethoxycarbonyl-L-prolyl-L-leucine tert-butyl ester (34) to L-prolyl-
L-leucine tert-butyl ester (38) [33,34]. According to the general procedure C Tpseoc-dipeptide 34
(112 mg, 0.182 mmol) was dissolved in dry THF (2 mL) and treated with TBAF•3H2O (115 mg,
0.364 mmol) and CsF (55 mg, 0.364 mmol) at rt. TLC showed complete cleavage of the Tpseoc-group
after 90 min. and aqueous workup yielded L-prolyl-L-leucine tert-butyl ester 38 (45 mg, 0.162 mmol,
89%) as colorless crystals. An analytical sample was obtained by chromatographic purification eluting
with CHCl3 containing 1% MeOH and 1% Et3N. The material showed NMR-spectra lacking signals
from isomeric dipeptides. [α]D20 = −14.6° (c = 1.0, CHCl3). FAB-MS calcd for C15H28N2O3: m/z 285.2
1
[M+H]+, 229.2 [M-tBu+H]+. H-NMR (400 MHz, CDCl3): δ 7.93 (d, broad, 1H, J = 8.6 Hz, CONH),
4.40 (dt, 1H, J = 8.8 Hz/5 Hz, α-CH-leu), 3.74 (dd, 1H, J = 9.2 Hz/5.3 Hz, α-CH-Pro), 3.0 (dt, 1H,
J = 10.0 Hz/6.9 Hz, δ-CH2-Pro), 2.90 (dt, 1H, J = 10.2 Hz/6.2 Hz, δ-CH2-Pro), 2.43 (s, broad, 1H,
NH), 2.18-2.06 (m, 1H, β-CH-Pro), 1.92-1.82 (m, 1H, β-CH-Pro), 1.73-1.47 (m, 5H, β/γ-CH-Leu,
γ-CH-Pro), 1.44 (s, 9H, t-Bu), 0.96-0.87 (m, 6H, δ-CH-Leu). 13C-NMR (100.6 MHz, CDCl3): δ 174.9,
172.5, 81.7 (t-Bu), 60.6, 50.9, 47.4, 41.8, 31.0, 28.1 (t-Bu), 26.3, 25.2, 23.0, 22.2.
Deprotection of N-2-(triphenylsilyl)ethoxycarbonyl-N′-(N-tert-butoxycarbonyl)-L-alanyl-1,6-diamino-
hexane (35) to N-(N′-tert-butoxycarbonyl-L-alanyl)-1,6-diaminohexane (39): According to general
procedure C Tpseoc-peptide 35 (125 mg 0.202 mmol) was dissolved in dry THF (2 mL) and treated
with TBAF•3H2O (128 mg, 0.404 mmol) and CsF (61 mg, 0.404 mmol) at r.t.. TLC showed complete

Molecules 2011, 16
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cleavage of the Tpseoc-group after 24 h and aqueous workup yielded N-(N′-Boc-L-alanyl)-1,6-
diaminohexane 39 (53 mg, 0.202 mmol, 91%) as a colorless gum. An analytical sample was obtained
by chromatography with the eluent mixture chloroform/methanol 9:1-8:2 containing 1% Et3N.
20
[α]D = −25.5° (c = 1.0, CHCl3). FAB-MS calcd for C14H29N2O3: m/z 288.2 [M+H]+, 188.2
[M-BOC+H]+. FT-ICR-MS: m/z [M+Na]+ calcd for C14H29N3O3: 288,2282 found: 288,2284. 1H-NMR
(400 MHz, CDCl3): δ 6.69 (s, broad, 1H, -CONH), 5.37 (d, broad, 1H, J = 7.1 Hz, OCONH), 4.19-4.07
(m, 1H, α-CH), 3.97-3.82 (m, 2H, CH2NHCO), 3.25-3.15 (m, 2H, chain-CH2), 2.75-2.66 (m, 2H,
chain-CH2), 1.53-1.43 (m, 4H, chain-CH2), 1.42 (s, 9H, t-Bu), 1.35-1.27 (m, 7H, chain-CH2/β-CH3).
13C-NMR (100.6 MHz, CDCl3): δ 172.9, 155.8, 80.0 (t-BuH), 51.1 (α-CH), 41.2, 39.4, 31.8, 29.4, 28.4
(t-Bu), 26.5, 26.3, 18.7 (β-CH3).
4. Conclusions
In summary a new fluoride ion cleavable amino/alcohol protecting group based on the 2-(triphenyl-
silyl)ethoxycarbonyl- (“Tpseoc”-) moiety was developed and installed into a series of amino acids and
peptides and a steroid alcohol. The protected derivatives were synthesized via a short and efficient
route starting from commercially available triphenylvinylsilane. Contrary to the Teoc-group, the
Tpseoc-group proved to be highly resistant to acidic conditions necessary to cleave tert-butyl esters
and the Boc-group. The Tpseoc-group was found to be compatible with a wide range of conditions,
e.g., basic conditions needed to cleave methyl-esters and the Fmoc-group, catalytic hydrogenation with
Pd/C in various solvents, treatment with Pd-catalysts in presence of an allyl-scavenger as applied in
cleavage of allyl-based protecting groups and methylhydrazine, used in deprotection of phthaloyl-
groups. Cleavage of the Tpseoc-group was achieved by treatment with TBAF•3H2O and CsF with
cleavage times ranging from 10 minutes to 24 hours. The observed cleavage kinetics are significantly
enhanced compared to those reported for of Teoc- and SES-group [1]. Its general applicability as
carbamate or carbonate protecting group and the fact that it can be introduced via standard methods
employing a stable crystalline chloroformate reagent together with its UV-detectability make the
Tpseoc-group a promising candidate for being adopted into the pool of protecting groups used more
frequently in organic synthesis. Especially the very fast cleavage from electron poor amines and
alcohols and its orthogonality to acid and fluoride labile linkers should make the Tpseoc-group an
interesting choice as protecting group in automated solid-phase synthesis of oligonucleotides, peptides
and saccharides. Adjustment of the Tpseoc-groups reactivity pattern could be established by
introduction of electron releasing or electron withdrawing residues on the phenyl groups of the
triphenylsilyl-moiety.
Acknowledgements
We wish to thank Dorothee Wistuba for the measurement of the high resolution mass spectra, the
members of the NMR-division of the Institute of Organic Chemistry and Gregor Lemansky for
numerous discussions on the topic.

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