Synthesis of glycidol- and sugar-derived bicyclic β- and γ/δ-amino acids for peptidomimetic design

Article abstract of DOI:10.1002/ejoc.200500386

Constrained bicyclic β- and γ/δ-amino acids using glycidol and sugar derivatives were developed. The synthetic strategies involved epoxide ring opening of a glycidol derivative, and subsequent coupling with sugar-derived amines, leading to di- or trisubst

Full text of DOI:10.1002/ejoc.200500386

FULL PAPER
Synthesis of Glycidol- and Sugar-Derived Bicyclic β- and γ/δ-Amino Acids for
Peptidomimetic Design
Elisa Danieli,[a] Andrea Trabocchi,[a] Gloria Menchi,[a] and Antonio Guarna*[a]
Keywords: Scaffold / Peptidomimetics / Ring opening / Peptides / Amino acids / Solid-phase synthesis
Constrained bicyclic β- and γ/δ-amino acids using glycidol
and sugar derivatives were developed. The synthetic strate-
gies involved epoxide ring opening of a glycidol derivative,
and subsequent coupling with sugar-derived amines, leading
to di- or trisubstitued bicyclic scaffolds after cyclisation with
trifluoroacetic acid. Achievement of β- or γ/δ-amino acids
was accomplished by changing the protecting group strategy
of the starting materials. Compatibility of the scaffold with
solid-phase peptide synthesis was assessed by preparing
model peptidomimetics using acid- and base-labile resins,
thus giving a new tool for peptidomimetic design.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
logical properties as single compounds.[8] Many synthetic
approaches to the creation of β-amino acids have been pub-
lished, giving a great variety of β-amino acids as a tool for
medicinal chemistry,[9] and some examples include bicyclic
β-amino acids, which are thought to mimic a rigidified β-
proline.[10] In particular, (3S)-carboxypyrrolidine,[11] and β2-
and β3-homoprolines[12] have been reported as β-proline an-
alogues, and it has been demonstrated that the correspond-
ing oligomers are capable of forming rigid secondary struc-
tures. During the last years we have been developing new
bicyclic amino acids based on the 6,8-dioxa-3-azabicy-
clo[3.2.1]octane skeleton, which derives from the combina-
tion of amino acids and tartaric acid or sugar derivatives,[13]
and selected compounds were applied as peptidomimetics
and reverse-turn inducers.[14] The synthetic strategy fol-
lowed a general concept consisting in two basic reactions,
namely coupling and cyclisation by a trans-acetalisation
process, involving a diol species carrying an electrophile and
an amino carbonyl derivative having both nucleophilic and
electrophilic moieties. Coupling reaction occurs in the first
step, followed by acetalisation of the diol species on the
carbonyl moiety. Following the concept of formal COOH
Introduction
The development of new therapeutics based on bioactive
peptides is a valid tool for drug discovery, but it has been
generally limited due to several pharmacological problems,
including poor absorption, rapid metabolism and low oral
bioavailability. Thus, considerable attention has been dedi-
cated to the generation of peptidomimetics,[1] which are able
to preserve peptide-like activity and to enhance resistance
towards proteases. In the context of this research area, un-
natural amino acids are of great interest in drug discovery,
and their use as new building blocks for the development
of peptidomimetics with high diversity level and possessing
high-ordered structures is of special interest. In particular,
medicinal chemistry has taken advantage of the use of
amino acid homologues to introduce elements of diversity
for the generation of new molecules as drug candidates. β-
Amino acids gathered interest in the so-called “peptidomi-
metic approach”, where a peptide lead is processed into a
new non-peptide molecule in a hierarchical approach.[2]
They also proved to be of great interest in the field of folda-
mers, as the corresponding β-peptides demonstrated excep-
tional capabilities to generate stable secondary structures
such as β-turns, β-sheets and α-helices,[3] as well as showing
great stability towards proteolysis.[4] Recently, γ- and δ-
amino acids gathered the same interest. In particular, the
folding properties of γ-[5] and δ-peptides[6] have been investi-
gated, as they proved to generate stable secondary struc-
tures. β-Amino acids are found in many naturally occurring
peptides as key components,[7] and also exhibit pharmaco-
[a] Dipartimento di Chimica Organica “Ugo Schiff”, Università
degli Studi di Firenze, Polo Scientifico di Sesto Fiorentino,
Via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy
Fax: +39-055-4573569
E-mail: antonio.guarna@unifi.it
Figure 1. Formal COOH shift of BTAa scaffolds.
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200500386
Eur. J. Org. Chem. 2005, 4372–4381

Bicyclic β- and γ/δ-Amino Acids for Peptidomimetic Design
FULL PAPER
shift (Figure 1), we planned to design and synthesise a new
scaffold having the carboxylic function in position 5, in or-
der to generate a β-amino acid, which would be isomeric to
α-amino acid BGS (Bicycle from Glyceraldehyde and Ser-
ine),[14b] and γ/δ-amino acid BTG (Bicycle from Tartaric
acid and Glycine) compounds.[13a,14a]
Results and Discussion
The new bicyclic β-amino acid was specifically designed
to be introduced into peptides as a β-proline analogue by
means of solid-phase peptide synthesis according to the
Scheme 2.
Fmoc protocol. The retrosynthetic approach for
1
tuted β-amino acid, starting from a sugar of the tetrose fam-
ily. Thus, protected l-threose derivative 11 was prepared as
reported[21] and used as sugar component, providing a hy-
droxymethyl functionality in 7-exo position of the scaffold.
(Scheme 1) considered the combination of glyceraldehyde
and 3-amino-1,2-propanediol derivatives to obtain the key
adduct for the preparation of the title scaffold, in analogy
with the synthesis of BGS compounds.[14b] In particular, ra-
cemic 3 was chosen as starting material for the synthetic
route, and reactions with either protected glyceraldehyde
4
[15] by reductive amination, or with isopropylidene-glycerol
triflate 5[16] by SN2 reaction were taken into account. More-
over, a second synthetic strategy involved epoxide ring
opening of 8 by (2,2-dimethyl-1,3-dioxolan-4-yl)methanam-
ines 6 and 7 deriving from sugars (Scheme 1).
Scheme 3.
Scheme 1.
Compound 3 was obtained with excellent purity and
yield after a two-step procedure involving reaction of ben-
zylamine with 8[17] in anhydrous CH2Cl2 for 16 h, and sub-
sequent hydrogenation of the benzylic group (Scheme 2).
LiNTf2 was used as Lewis acid promoter for ring opening
of 8, as described by Cossy et al.[18]
Reaction of 3 with isopropylidene-glycerol triflate 5 af-
forded a diastereomeric mixture of 10 in 71% yield and
with good purity to be used as crude material for the next
step. As an alternative coupling method, attempted re-
ductive amination of isopropylidene-glyceraldehyde 4 with
3 and NaBH(OAc)3 failed.[19]
Furthermore, sugar component 6, obtained from amin-
ation of protected sugar derivative 4, was taken into account
to accomplish the epoxide ring opening of 8 (Scheme 3),[20]
and, in order to expand the possibility of generating scaffolds
with higher molecular diversity, it was developed a trisubsti- Scheme 4.
Eur. J. Org. Chem. 2005, 4372–4381
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E. Danieli, A. Trabocchi, G. Menchi, A. Guarna
FULL PAPER
Reductive amination with benzylamine produced the amine β-amino acids 1 and 2 were obtained with good purity in 89%
13 (Scheme 3), which after catalytic hydrogenolysis afforded and 70% yields, and showed higher chemical stability with re-
free amine 7 in quantitative yield and in almost pure form. spect to scaffolds 19 and 20.
Subsequent reaction of 6 and 7 with 8 and LiNTF2, in anal-
The inversion of the protecting group strategy with re-
ogy with the previous procedure (see Scheme 2), gave the ad- spect to the sugar and glycidol components allowed to gen-
ducts 10 and 14, respectively, in good yield and purity, which erate a γ/δ-amino acid (Scheme 5). Specifically, the acid-la-
were further manipulated to give the corresponding bicyclic bile TBDMS protecting group on the glycidol hydroxy
scaffolds. The amine function was thus protected to facilitate function was replaced with an O-benzyl moiety, and a si-
subsequent ring closure, and Fmoc-urethane was taken into lylated sugar component was used instead of the O-benzyl-
account, giving 15 (75%) and 16 (78%) after purification ated sugar derivative 11, thus giving a free hydroxymethyl
(Scheme 4). Oxidation of the secondary alcohol was achieved group at C-7 after acid cyclisation.
by Swern reaction to obtain 17 and 18 as single stereoisomers,
The hydroxy group of erythrose derivative 22, prepared
due to the loss of the stereogenic center at the carbon atom as reported,[14a] was protected with the acid-labile TBDMS
bearing the hydroxy group. The cyclisation step was initially group, and successively the resulting amino alcohol was de-
carried out in methanol with TFA (4 equiv.), according to re- benzylated. Compound 24 was allowed to react with O-ben-
ported procedures for the synthesis of sialic analogues bear- zyl glycidyl ether to give the adduct 25, which showed the
ing a bicyclic acetal,[22] but a complex mixture of compounds protection scheme totally reversed with respect to 14. Fur-
was obtained, probably related with monocyclic species. On ther amine protection with the Fmoc group, Swern oxi-
the contrary, cyclisation with 95% TFA, in analogy with dation of the secondary alcohol, and acid cyclisation pro-
other bicyclic compounds yet developed by our duced the bicyclic compound 28, which upon oxidation
group,[13c,14a–14b] afforded the desired products 19 and 20 in gave access to γ/δ-amino acid 29, having a protected hy-
Ͼ90% yield and with good purity, and having the hy- droxymethyl group in position 5 of the scaffold. It is worth
droxymethyl moiety at C-5 deprotected from the acid-labile noting that such compound, having the COOH group in 7-
TBDMS group. Although showing complete compatibility endo configuration, is suitable for generating reverse-turn
with aqueous acid/base treatments, compounds 19 and 20 peptides, and moreover such structure may act as a new
displayed marked instability during chromatographic purifi- bicyclic Ser–Xaa dipeptide isoster.[13b]
cation on silica gel, giving pure products in poor yields.[23]
Finally, the bicyclic β-amino acid 1 was anchored to the
Consequently, it was required to use the scaffolds as crude base-labile HMBA resin with the aim of evaluating the
material for subsequent transformations. Bicyclic amino compatibility of this new compound with solid-phase pep-
alcohols 19 and 20 showed full compatibility with Jones’ tide synthesis.
method for alcohol oxidation to the carboxylic function, in
The ester linkage was achieved by DIC/HOBt-mediated
contrast to BTKa (Bicycles from Tartaric acid and Keto coupling, and after Fmoc deprotection with 30% piperidine
amine) scaffolds bearing a phenyl ring on C-5.[13c] Thus, final in DMF, the amine was acetylated by acetic anhydride. The
Scheme 5.
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Eur. J. Org. Chem. 2005, 4372–4381

Bicyclic β- and γ/δ-Amino Acids for Peptidomimetic Design
FULL PAPER
Scheme 6.
resulting peptidomimetic compound 31 was cleaved off the Moreover, change of the protecting group strategy on both
resin as ethylamide by treatment with excess of ethylamine glycidol and sugar derivatives allowed to generate Fmoc-
in water/THF at room temperature and for 18 h to give 32 protected γ/δ-amino acids using the same reaction pathway.
in 70% overall yield (Scheme 6). The NMR spectra of 32 Finally, the compatibility with solid-phase peptide chemis-
showed a mixture of two rotamers due to cis/trans isomeris- try was demonstrated using both acid- and base-labile res-
ation at the tertiary amide bond, in a 1:3 ratio. Successively, ins, thus giving a new tool for peptidomimetic design of
a tripeptidomimetic containing l-Phe and l-Leu at the constrained peptide sequences. Further applications of
amino and carboxy termini of the scaffold, respectively, was these bicyclic β-amino acids as peptidomimetic scaffolds in
prepared using the acid-labile Rink-amide-MBHA resin, reverse-turn and cyclic peptides will be reported in due
with the aim to assess full compatibility with common acid- course.
labile resins (Scheme 6). Peptide couplings on both func-
tionalities of the bicyclic amino acid proved to be slow, and
complete conversion was achieved after repeated coupling
cycles. Cleavage of the peptidomimetic from the resin using
95% TFA gave the title compound 35 in 41% overall yield,
showing complete stability of the bicyclic acetal moiety un-
der strong acid conditions. NMR analysis of 35 in [D6]
DMSO as solvent showed a mixture of cis/trans-amides in
a 1:4 ratio, still due to slow interconversion at the C–N
formed in oven-dried glassware. All the solid-phase reactions were
amide bond of the scaffold. NOESY analysis assessed the
Experimental Section
General Remarks: Chromatographic separations were performed on
silica gel using flash-column techniques; Rf values refer to TLC
carried out on 25 mm silica gel plates (Merck F254) with the same
eluent indicated for column chromatography. CH2Cl2 was distilled
from CaH2. All reactions requiring anhydrous conditions were per-
carried out on a shaker, using solvents of HPLC quality. Peptide
major rotamer as the trans-amide, as evinced from the
strong NOESY peak between Phe H-α and H-2exo of the
scaffold (Scheme 6).
35 was purified with an HPLC system equipped with a semiprepar-
1
ative C18 10 μm, 250×4.6 mm, reverse-phase column. H and 13C
NMR spectra were recorded with NMR instruments operating at
200 MHz and 400 MHz for 1H and 50.33 and 100.66 for 13C,
respectively, and using CDCl3 solutions unless otherwise stated. EI
mass spectra were carried out at 70 eV ionizing voltage. Peptide 35
was characterised by 2D NMR, HPLC and ESI-MS. FT-IR spectra
Conclusions
In conclusion, we have developed new Fmoc-protected were recorded in CHCl3 solutions.
bicyclic amino acids starting from glycidol and sugar deriv-
(R/S)-1-Benzylamino-3-(tert-butyldimethylsilyloxy)propan-2-ol (9):
atives, using a simple and efficient synthetic route. In par-
ticular, two convergent synthetic methods were taken into
account for the β-amino acid, thus enabling the generation
To a solution of tert-butyldimethylsilyl glycidyl ether (8) (1 g,
5.31 mmol) and benzylamine (597 μL, 5.47 mmol) in anhydrous
CH2Cl2 (2 mL) was added LiNTf2 (762 mg, 2.65 mmol). The reac-
of a more general class of trisubstituted bicyclic scaffolds. tion mixture was stirred under nitrogen and at room temperature
Eur. J. Org. Chem. 2005, 4372–4381
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E. Danieli, A. Trabocchi, G. Menchi, A. Guarna
FULL PAPER
for 12 h, then the mixture was diluted with diethyl ether (60 mL),
(2R/2S)-1-(tert-Butyldimethylsilyloxy)-3-[{[(4S)-2,2-dimethyl-1,3-di-
oxolan-4-yl]methyl}(fluoren-9-ylmethoxycarbonyl)amino]propan-2-ol
(15): To a solution of 10 (1.10 g, 3.44 mmol), in dioxane (22 mL)
was added at 0 °C a solution of Na2CO3·H2O (364 mg, 3.44 mmol)
in H2O (22 mL), and then Fmoc-O-Su (1.17 g, 3.47 mmol). The
mixture was stirred at room temperature overnight, then the or-
quenched with
a saturated aqueous solution of NaHCO3
(3×30 mL) and extracted with CH2Cl2 (2×40 mL). The combined
organic layers were dried with Na2SO4 and concentrated in vacuo
to give 9 (1.44 g, 99%) as a yellow oil. 1H NMR (400 MHz,
CDCl3): δ = 7.39–7.26 (m, 5 H), 4.28–4.11 (m, 2 H), 3.80 (s, 2 H),
3.51 (m, 1 H), 2.85 [d, 1 H, 3J(H,H) = 12 Hz], 2.79 (dd, 1 H, 3JH,H ganic solvent was evaporated in vacuo, the aqueous layer was satu-
= 12, 12 Hz), 0.82 (s, 9 H), 0.04 (s, 6 H) ppm. 13C NMR (CDCl3): rated with NaCl and extracted with CH2Cl2 (3×20 mL). The com-
δ = 133.4 (s, 1 C), 128.8 (d, 2 C), 128.7 (d, 2 C), 128.5 (d, 1 C),
bined organic layers were dried with anhydrous Na2SO4 to give a
68.0 (d, 1 C), 64.8 (t, 1 C), 52.3 (t, 1 C), 50.2 (t, 1 C), 25.5 (q, 3 crude oil, which was purified by flash chromatography (EtOAc/
C), 17.9 (s, 1 C), –5.8 (q, 2 C) ppm. MS: m/z (%) = 295 (0.5) [M+],
petroleum ether, 1:3; Rf = 0.21), thus affording compound 15
238 (7), 204 (1), 91 (100). IR (CHCl ): ν = 3523, 2937, 1603,
(1.40 g, 75 %) as a mixture of diastereomers (colorless oil). 1H
˜
3
1463 cm–1.
NMR (400 MHz, CDCl3): δ = 7.72 (d, 2 H, JH,H = 7.6 Hz), 7.53
3
(m, 2 H), 7.36 (m, 2 H), 7.29 (m, 2 H), 4.60 (m, 1 H, diast. A),
4.51 (m, 1 H, diast. B), 4.18 (s, 2 H), 3.98 (m, 1 H), 3.78–3.30 (m,
5 H), 3.27–2.80 (m, 4 H), 1.90 (br. s, 1 H), 1.36 (s, 3 H), 1.20 (s, 3
H), 0.91 (s, 9 H), 0.01 (s, 6 H) ppm. 13C NMR (CDCl3): δ = 158.0
(s, 1 C, diast. A), 156.9 (s, 1 C, diast. B), 143.5 (s, 2 C), 141.2 (s, 2
C), 127.6 (d, 2 C), 126.9 (d, 2 C), 124.3 (d, 2 C), 119.9 (d, 2 C),
109.1 (s, 1 C), 74.8 (d, 1 C), 71.0 (d, 1 C, diast. A), 70.3 (d, 1 C,
diast. B), 66.9 (t, 1 C, diast. A), 66.3 (t, 1 C, diast. B), 64.6 (t, 1 C,
diast. A), 64.0 (t, 1 C, diast. B), 60.3 (t, 1 C), 52.3 (t, 1 C, diast.
A), 51.8 (t, 1 C, diast. B), 51.4 (t, 1 C, diast. A), 51.3 (t, 1 C, diast.
B), 47.0 (d, 1 C), 26.5 (q, 1 C), 25.7 (q, 3 C), 25.1 (q, 1 C), 18.0 (s,
1 C), –5.7 (q, 2 C) ppm. MS: m/z (%) = 288 (4) [M+ – Fmoc –
(R/S)-1-Amino-3-(tert-butyldimethylsilyloxy)propan-2-ol (3): Com-
pound 9 (1.7 g, 5.75 mmol) was dissolved in MeOH (190 mL), and
20% Pd(OH)2/C (430 mg) was added; the resulting suspension was
stirred under hydrogen and at room temperature overnight. The
catalyst was then removed by careful filtration through Celite,
washed with MeOH, and the resulting solution was passed through
a column filled with Amberlyst A-21 resin to give after solvent
evaporation pure 3 (1.17 g, 99%) as a yellow oil. 1H NMR
(200 MHz, CDCl3): δ = 4.60 (br. s, 2 H), 3.74–3.71 (m, 1 H), 3.58–
3.40 (m, 2 H), 2.92–2.79 (m, 2 H), 2.46 (br. s, 2 H), 0.86 (s, 9 H),
0.04 (s, 6 H) ppm. 13C NMR (CDCl3): δ = 68.2 (t, 1 C), 64.9 (d, 1
C), 43.1 (t, 1 C), 25.7 (q, 3 C), 18.2 (s, 1 C), –5.7 (q, 2 C) ppm.
(CH ) ], 248 (17), 178 (100). IR (CHCl ): ν = 3447, 2955, 2857,
˜
3 2
3
MS: m/z (%) = 205 (7) [M+], 175 (11), 131 (13). IR (CHCl ): ν =
1698 cm–1. C30H43NO6Si (541.7): calcd. C 66.51, H 8.00, N 2.59;
˜
3
3308, 2931, 1586 cm–1. C9H23NO2Si (205.4): calcd. C 52.63, H
found C 66.07, H 7.82, N 2.30.
11.29, N 6.82; found C 52.60, H 11.21, N 6.87.
1-(tert-Butyldimethylsilyloxy)-3-[{[(4S)-2,2-dimethyl-1,3-dioxolan-4-
yl]methyl}(fluoren-9-ylmethoxycarbonyl)amino]propan-2-one (17): A
solution of (COCl)2 (506 μL, 5.98 mmol) in dry CH2Cl2 (16 mL)
under nitrogen was cooled to –60 °C, then anhydrous DMSO
(990 μL, 13.96 mmol) in dry CH2Cl2 (7 mL) was slowly added in
order to keep the temperature constant. After 10 min, a solution
of 15 (2.7 g, 4.99 mmol) in CH2Cl2 (12 mL) was added dropwise,
still maintaining the temperature at –60 °C. The mixture was stirred
for 30 min, then DIPEA (4.2 mL, 24.9 mmol) was added and, after
10 min, the reaction mixture was left to warm to room temperature,
and to react for an additional 1.5 h. Successively, 5 % KHSO4
(40 mL) and Et2O (60 mL) were added, the organic phase was sepa-
rated and washed with a saturated aqueous solution of NaHCO3
(2R/2S)-1-(tert-Butyldimethylsilyloxy)-3-{[(4S)-2,2-dimethyl-1,3-di-
oxolan-4-ylmethyl]amino}propan-2-ol (10): To a solution of 3 (1.4 g,
6.85 mmol) and diisopropylethylamine (2.02 mL, 11.83 mmol) in
anhydrous CH2Cl2 (15 mL) was added dropwise, at 0 °C and under
nitrogen, a solution of d-1,2-O-isopropylidene-glycerol triflate 5
(1.65 g, 6.22 mmol) in CH2Cl2 (20 mL). The reaction mixture was
stirred at 0 °C for 30 min, and then at room temperature for 16 h.
The mixture was then quenched with 5 % NaHCO3 solution
(15 mL), and the organic layer was separated, washed with H2O
(3×10 mL) and dried with Na2SO4 to give after solvent evapora-
tion compound 10 as an oil (1.41 g, 71%), sufficiently pure for the
next step. Alternatively, compound 10 was obtained starting from
(tert-butyldimethylsilyl)glycidyl ether (8) (1.40 g, 7.4 mmol) and (3 ×60 mL), H2O (3 ×60 mL), brine (3 ×60 mL), and dried with
(4S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (6) (1.16 g,
7.7 mmol). To a solution of these reagents in anhydrous CH2Cl2
(2.5 mL), LiNTf2 (1.07 g, 7.4 mmol) was added. The reaction mix-
ture was stirred under nitrogen and at room temperature for 12 h,
then it was diluted with diethyl ether (75 mL), washed with a satu-
rated aqueous solution of NaHCO3 (3×35 mL) and the aqueous
phase extracted with CH2Cl2 (2×50 mL). The combined organic
layers were dried with Na2SO4 and concentrated in vacuo to afford
10 (2.03 g, 86%) as a colorless oil and as a 1:1 mixture of two
diastereomers, sufficiently pure for the next step. 1H NMR
Na2SO4. Solvent evaporation afforded a crude yellow oil which was
purified by flash chromatography (EtOAc/petroleum ether, 1:4; Rf
= 0.30) to give 17 (1.62 g, 60%) as a yellow oil. [α]2D2 = +2.0 (c =
0.5, CHCl3). 1H NMR (400 MHz, CDCl3; 1.2:1 mixture of two
3
rotamers): δ = 7.76 (d, 2 H, JH,H = 7.6 Hz, rot. A), 7.74 (d, 2 H,
3
3JH,H = 7.8 Hz, rot. B), 7.57 (d, 2 H, JH,H = 7.4 Hz, rot. A), 7.51
(d, 2 H, 3JH,H = 7.4 Hz, rot. B), 7.39 (m, 2 H), 7.32 (m, 2 H), 4.57
(AB system, 2 H, rot. A), 4.47 (AB system, 2 H, rot. B), 4.39 (d, 2
3
3
H, JH,H = 9.6 Hz, rot. A), 4.30 (d, 2 H, JH,H = 4.0 Hz, rot. B),
4.24 (m, 1 H, rot A), 4.20 (m, 2 H, rot A), 4.20–4.16 (m, 1 H) 4.02
(400 MHz, CDCl3): δ = 4.62 (br. s, 2 H), 4.29 (m, 1 H), 4.05 (m, 2 (dd, 1 H, 3JH,H = 8.4, 6.4 Hz, rot. A), 3.99 (s, 2 H, rot B), 3.81 (m,
3
H), 3.87 (m, 1 H), 3.58 (m, 2 H), 3.03 (m, 2 H), 2.92 (m, 1 H), 2.83
1 H, rot. B), 3.72 (dd, 1 H, JH,H = 14.8, 3.6 Hz, rot. A), 3.68 (dd,
(m, 1 H), 1.37 (s, 3 H), 1.28 (s, 3 H), 0.83 (s, 9 H), 0.00 (s, 6 H) 1 H, 3JH,H = 8.4, 6.4 Hz, rot. B), 3.56 (dd, 1 H, 3JH,H = 8.4, 7.2 Hz,
ppm. 13C NMR (CDCl3): δ = 111.0 (s, 1 C), 73.1 (t, diast. A, 1 C),
72.8 (t, diast. B, 1 C), 68.5 (t, diast. A, 1 C), 68.4 (t, diast. B, 1 C),
67.6 (t, 1 C), 66.2 (t, diast. A, 1 C), 65.8 (t, diast. B, 1 C), 52.7 (d,
1 C), 52.4 (d, diast. A, 1 C), 52.1 (d, diast. B, 1 C), 27.4 (q, 1 C),
26.4 (q, 3 C), 25.7 (q, 1 C), 18.9 (s, 1 C), –4.9 (s, 2 C) ppm. MS:
rot. A), 3.35 (dd, 1 H, JH,H = 14.8, 3.6 Hz, rot. B), 3.28 (dd, 1 H,
3
3
3JH,H = 8.4, 7.2 Hz, rot. B), 3.12 (dd, 1 H, JH,H = 14.8, 6.8 Hz,
3
rot. A), 2.94 (dd, 1 H, JH,H = 14.8, 6.4 Hz, rot. B), 1.36 (s, 3 H,
rot. A), 1.32 (s, 3 H, rot. B), 1.30 (s, 3 H, rot. A), 1.26 (s, 3 H, rot.
B), 0.93 (s, 9 H, rot. A), 0.91 (s, 9 H, rot. B), 0.08 (s, 6 H) ppm.
m/z (%) = 319 (0.3) [M+], 304 (2), 218 (7), 204 (8), 69 (100). IR 13C NMR (CDCl3): δ = 206.3 (s, 1 C, rot. A), 206.0 (s, 1 C, rot.
(CHCl ): ν = 2930, 2248, 1710 cm–1. C H NO Si (319.5): calcd.
B), 156.3 (s, 1 C, rot. A), 156.0 (s, 1 C, rot. B), 143.7 (s, 2 C), 141.4
(s, 2 C), 127.7 (d, 2 C), 127.2 (d, 2 C), 124.7 (d, 2 C), 120.0 (d, 2
˜
3
15 33
4
C 56.39, H 10.41, N 4.38; found C 56.31, H 10.35, N 4.29.
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Bicyclic β- and γ/δ-Amino Acids for Peptidomimetic Design
C), 109.2 (s, 1 C), 75.3 (d, 1 C, rot. A), 74.9 (d, 1 C, rot. B), 68.4 C, rot. B), 68.7 (t, 1 C), 68.2 (t, 1 C, rot. A), 67.5 (t, 1 C, rot. B),
FULL PAPER
(t, 1 C, rot. A), 68.0 (t, 1 C, rot. B), 67.1 (t, 1 C, rot. A), 66.9 (t, 1
C), 66.6 (t, 1 C, rot. B), 55.4 (t, 1 C, rot. A), 55.3 (t, 1 C, rot. B),
48.7 (t, 1 C, rot. A), 48.4 (t, 1 C, rot. B), 47.0 (d, 1 C), 46.6 (t, 1
C, rot. A), 46.4 (t, 1 C, rot. B) ppm. MS: m/z (%) = 381 (0.14)
50.7 (t, 1 C, rot. A), 50.0 (t, 1 C, rot. B), 47.2 (d, 1 C), 26.9 (q, 1 [M+], 336 (1), 178 (100). IR (CHCl ): ν = 3440, 3028, 1703 cm–1.
˜
3
C), 25.7 (q, 3 C), 25.4 (q, 1 C), 18.0 (s, 1 C), –5.7 (q, 2 C) ppm.
C21H19NO6 (381.4): calcd. C 66.13, H 5.02, N 3.67; found C 65.96,
H 5.07, N 3.37.
MS: m/z (%) = 482 (75) [M+ – tBu], 424 (88), 394 (6), 366 (4), 246
(100), 178 (30). IR (CHCl ): ν = 2932, 2858, 1738, 1702, 1452 cm–1.
˜
3
Benzyl{[(4S,5S)-5-(benzyloxymethyl)-2,2-dimethyl-1,3-dioxolan-4-
yl]methyl}amine (13): Benzylamine (0.961 mL, 8.8 mmol) was
added to a solution of 11 (2 g, 8 mmol) in THF (40 mL), under
nitrogen, and then NaBH(OAc)3 (2.54 g, 12 mmol) portionwise and
at 0 °C. The mixture was stirred at room temperature overnight,
then saturated NaHCO3 was added, and organic products were ex-
tracted with EtOAc (3×40 mL). The organic phase was dried with
Na2SO4, filtered and concentrated under reduced pressure. The res-
idue was purified by silica gel chromatography (EtOAc/petroleum
ether, 1:1; Rf = 0.6) to give 13 (1.70 g, 62%) as a colorless oil.
C
30H41NO6Si (539.7): calcd. C 66.76,H 7.66, N 2.60; found C
66.56, H 7.59, N 2.47.
(1S,5S)-3-(Fluoren-9-ylmethoxycarbonyl)-5-(hydroxymethyl)-6,8-di-
oxa-3-azabicyclo[3.2.1]octane (19): Compound 17 (1.3 g,
2.41 mmol) was dissolved in trifluoroacetic acid (5 mL) and MeOH
(50 μL), and was stirred overnight at room temperature. After TFA
evaporation, the crude oil was dissolved in EtOAc, washed with
saturated NaHCO3, brine, and dried with anhydrous Na2SO4. Af-
ter solvent evaporation, compound 19 was obtained as a pale yel-
low foam (880 mg, 91%). An analytical sample of 19 was obtained
by flash chromatography (EtOAc/petroleum ether, 1:2; Rf = 0.57)
in 35% yield after purification on silica gel. [α]2D2 = –1.3 (c = 0.5,
CHCl3). 1H NMR (400 MHz, CDCl3; 1:1.5 mixture of two rota-
1
[α]2D1 = –12.7 (c = 0.58, CHCl3). H NMR (200 MHz, CDCl3): δ =
7.33 (m, 5 H), 7.31 (m, 5 H), 4.58 (s, 2 H), 4.02 (m, 2 H), 3.82 (s,
2 H), 3.61 (AB system, 2 H), 2.82 (AB system, 2 H), 1.88 (br. s, 1
H), 1.43 (s, 6 H) ppm. 13C NMR (CDCl3): δ = 140.0 (s, 1 C), 137.8
(s, 1 C), 128.2 (d, 3 C), 127.9 (d, 2 C), 127.5 (d, 3 C), 126.8 (d, 2
C), 109.0 (s, 1 C), 78.2 (d, 1 C), 78.0 (d, 1 C), 73.4 (t, 1 C), 70.6 (t,
1 C), 53.9 (t, 1 C), 51.1 (t, 1 C), 27.2 (q, 1 C), 26.9 (q, 1 C) ppm.
MS: m/z (%) = 342 (0.45) [M+ + H], 327 (1), 250 (4), 234 (4),
3
mers): δ = 7.77 (d, 2 H, JH,H = 7.5 Hz), 7.53 (m, 2 H), 7.41–7.25
(m, 4 H), 4.78 (m, 1 H, rot. A), 4.58–4.49 (m, 1 H), 4.48 (s, 2 H),
4.38 (m, 1 H, rot. A), 4.24 (m, 1 H), 3.99–3.76 (m, 3 H), 3.73 (s, 2
3
H), 3.60 (m, 1 H, rot. A), 3.24 (m, 1 H, rot. B), 3.07 (d, 1 H, JH,H
= 12.6 Hz, rot. A), 2.98 (m, 1 H, rot. B), 1.74 (br. s, 1 H) ppm. 13
C
120 (74), 91 (100). IR (CHCl ): ν = 3012, 2867, 1603, 1454, 1372,
˜
3
1229 cm–1. C21H27NO3 (341.4): calcd. C 73.87, H 7.97, N 4.10;
NMR (CDCl3): δ = 155.9 (s, 1 C), 143.7 (s, 2 C), 141.3 (s, 2 C),
127.7 (d, 2 C), 127.0 (d, 2 C), 124.8 (d, 2 C), 120.0 (d, 2 C), 102.2
(s, 1 C), 73.5 (d, 1 C, rot. A), 73.0 (d, 1 C, rot. B), 68.6 (t, 1 C),
67.7 (t, 1 C, rot. A), 67.3 (t, 1 C, rot. B), 66.4 (t, 1 C), 48.5 (t, 1 C,
rot. A), 48.2 (t, 1 C, rot. B), 47.2 (d, 1 C), 46.8 (t, 1 C, rot. A), 46.5
(t, 1 C, rot. B) ppm. MS: m/z (%) = 367 (1) [M+], 178 (100). IR
found C 73.67, H 8.07, N 4.00.
{[(4S,5S)-5-(Benzyloxymethyl)-2,2-dimethyl-1,3-dioxolan-4-
yl]methyl}amine (7): To a suspension of 20% Pd(OH)2/C (150 mg)
in absolute ethanol (10 mL) under hydrogen was added a solution
of 13 (612 mg, 1.79 mmol) in absolute ethanol (8 mL). The reaction
mixture was vigorously stirred at room temperature overnight, then
it was filtered through Celite, and the solvent evaporated in vacuo
to give 7 (450 mg, 99%) as a pure yellow oil. [α]2D1 = –14.0 (c =
0.53, CHCl3). 1H NMR (200 MHz, CDCl3): δ = 7.29 (m, 5 H),
4.54 (s, 2 H), 3.96–3.70 (m, 2 H), 3.55 (AB system, 2 H), 2.89 (dd,
(CHCl ): ν = 2930, 2880, 2248, 1792, 1451 cm–1. C21H21NO5
(367.4): calcd. C 68.65, H 5.76, N 3.81; found C 68.61, H 5.57, N
3.72.
˜
3
(1S,5S)-3-(Fluoren-9-ylmethoxycarbonyl)-6,8-dioxa-3-azabicyclo-
[3.2.1]octane-5-carboxylic Acid (1): To a solution of 19 (505 mg,
1.37 mmol) in acetone (27 mL) was added Jones’ reagent at 0 °C
[preparated by slow addition of H2SO4 (1 mL) to a solution of
CrO3 (549 mg, 5.49 mmol) in H2O (6 mL) at 0 °C] and the mixture
was stirred at room temperature overnight. 2-Propanol was then
added until the color of the solution turned deep green/blue, then
the mixture was filtered through Celite and the solvents were evap-
orated. The crude product was dissolved in EtOAc (20 mL), and
treated twice with 5% Na2CO3 solution (2×15 mL). The organic
products were extracted with diethyl ether, then the aqueous phase
was acidified to pH = 1 with concd. HCl, and extracted with
3
3
1 H, JH,H = 13.2, 3.7 Hz), 2.76 (dd, 1 H, JH,H = 13.2, 5.8 Hz),
2.00 (br. s, 2 H), 1.37 (s, 6 H) ppm. 13C NMR (CDCl3): δ = 137.6
(s, 1 C), 128.1 (d, 2 C), 127.4 (d, 3 C), 108.9 (s, 1 C), 80.2 (d, 1 C),
77.1 (d, 1 C), 73.4 (t, 1 C), 70.5 (t, 1 C), 43.9 (t, 1 C), 27.1 (q, 1
C), 26.8 (q, 1 C) ppm. MS: m/z (%) = 251 (2) [M+], 237 (1), 221
(1), 143 (2), 121 (13), 91 (100). IR (CHCl ): ν = 3387, 2990, 2868,
˜
3
1601, 1372 cm–1.
(R/S)-1-({[(4S,5S)-5-(Benzyloxymethyl)-2,2-dimethyl-1,3-dioxolan-
4-yl]methyl}amino)-3-(tert-butyldimethylsilyloxy)propan-2-ol (14):
EtOAc (3 × 15 mL). The organic phase was washed with brine, Compound 14 was obtained according to the same procedure as
dried with anhydrous Na2SO4, filtered, and concentrated to give 1
(469 mg, 89%) as a pale yellow solid. An analytical sample of 1
(192 mg, 41%) was obtained by flash chromatography (EtOAc/pe-
troleum ether, 2:1 with 0.1% TFA; Rf = 0.28). [α]2D5 = +6.2 (c =
0.5, CHCl3). 1H NMR (400 MHz, CDCl3; 1:1 mixture of two rota-
for 10, starting from 7 (686 mg, 2.73 mmol) and tert-butyldimethyl-
silyl-glycidyl ether 8 (499 mg, 2.65 mmol), to afford a yellow oil
(1.12 g, 96%), sufficiently pure for the next step. An analytical sam-
ple of compound 14 was obtained by flash chromatography
(EtOAc/petroleum ether, 1:1; Rf = 0.3). 1H NMR (200 MHz,
CDCl3; mixture of two diastereomers): δ = 7.33 (m, 5 H) 4.65 (br.
3
mers): δ = 8.10 (br. s, 1 H), 7.79 (d, 2 H, JH,H = 7.4 Hz), 7.76 (m,
2 H), 7.74–7.30 (m, 4 H), 4.77 (m, 1 H, rot. A), 4.62 (m, 1 H, rot. s, 2 H), 4.56 (s, 2 H), 4.12–4.03 (m, 1 H), 3.94–3.84 (m, 2 H), 3.75–
B), 4.58–4.38 (m, 2 H), 4.27 (m, 1 H), 4.17 (m, 2 H, rot. A), 4.09
(m, 2 H, rot. A), 4.03 (m, 1 H, rot. A), 3.90 (m, 1 H, rot. B), 3.76
(m, 1 H, rot. B), 3.55 (d, 1 H, JH,H = 13.6 Hz, rot. A), 3.35 (d, 1
3.48 (m, 4 H), 3.18–2.97 (m, 4 H), 1.40 (s, 3 H), 1.38 (s, 3 H), 0.89
(s, 9 H), 0.08 (s, 6 H) ppm. 13C NMR (CDCl3): δ = 137.0 (s, 1 C),
128.5 (d, 2 C), 128.2 (d, 3 C), 110.6 (s, 1 C), 78.0 (d, 1 C, diast. A),
77.9 (d, 1 C, diast. B), 75.8 (d, 1 C, diast. A), 75.6 (d, 1 C, diast.
B) 73.9 (t, 1 C) 69.8 (t, 1 C, diast. A), 69.6 (t, 1 C, diast. B), 67.4
3
3
3
H, JH,H = 13.2 Hz, rot. B), 3.32 (d, 1 H, JH,H = 9.2 Hz, rot. B),
3.25 (d, 1 H, 3JH,H = 13.2 Hz, rot. B), 3.19 (d, 1 H, 3JH,H = 12.8 Hz,
rot. B) ppm. 13C NMR (CDCl3): δ = 168.0 (s, 1 C), 156.2 (s, 1 C, (t, 1 C, diast. A), 67.3 (d, 1 C, diast. B), 65.5 (t, 1 C, diast. A), 65.0
rot. A), 156.1 (s, 1 C, rot. B), 143.6 (s, 2 C), 141.3 (s, 2 C), 127.8
(d, 2 C), 127.1 (d, 2 C), 124.9 (d, 2 C), 120.0 (d, 2 C), 101.2 (d, 1 (t, 1 C), 26.7 (q, 1 C), 26.6 (q, 1 C), 25.7 (q, 3 C), 18.2 (s, 1 C), –
C, rot. A), 100.7 (d, 1 C, rot. B), 73.8 (d, 1 C, rot. A), 73.2 (d, 1
5.7 (q, 2 C) ppm. MS: m/z (%) = 440 (1) [M+ + H], 424 (1), 382
(t, 1 C, diast. B), 51.8 (t, 1 C, diast. A), 51.6 (t, 1 C, diast. B), 50.7
Eur. J. Org. Chem. 2005, 4372–4381
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4377

E. Danieli, A. Trabocchi, G. Menchi, A. Guarna
(3), 362 (1), 348 (1), 332 (2), 318 (2), 294 (1), 264 (5), 250 (1), 218 mers): δ = 7.68 (m, 2 H), 7.47 (m, 2 H), 7.34–7.22 (m, 9 H), 4.45
FULL PAPER
(5), 91 (100). IR (CHCl ): ν = 3543, 2930, 1732 cm–1. C H NO Si
(439.7): calcd. C 62.83, H 9.40, N 3.19; found C 62.76, H 9.33, N
3.12.
(m, 2 H), 4.48–4.31 (m, 3 H), 4.17 (m, 1 H), 4.16 (m, 1 H, rot. A),
˜
3
23 41
5
3
4.00 (m, 1 H, rot. B), 3.90 (d, 1 H, JH,H = 13.2 Hz, rot. A), 3.81
3
(d, 1 H, JH,H = 13.2 Hz, rot. A), 3.76–3.70 (m, 1 H, rot. A), 3.65
(m, 2 H), 3.59–3.54 (m, 1 H), 3.39–3.31 (m, 2 H, rot. A), 3.26– 3.19
(m, 2 H, rot. B), 3.16 (m, 1 H, rot. B), 2.97 (d, 1 H, 3JH,H = 12.4 Hz,
rot. B), 2.88 (m, 1 H, rot. B), 2.30 (br. s, 1 H) ppm. 13C NMR
(CDCl3): δ = 155.9 (s, 1 C), 143.7 (s, 2 C), 141.3 (s, 2 C), 137.6 (s,
1 C), 128.5 (d, 2 C), 127.8 (d, 5 C), 127.1 (d, 2 C), 124.8 (d, 2 C),
120.0 (d, 2 C), 103.2 (s, 1 C), 77.7 (d, 1 C, rot. A), 77.0 (d, 1 C,
rot. B), 75.4 (d, 1 C, rot. A), 74.9 (d, 1 C, rot. B), 73.5 (t, 1 C),
70.1 (t, 1 C), 67.7 (t, 1 C), 66.0 (t, 1 C), 48.2 (t, 1 C, rot. A), 47.9
(t, 1 C, rot. B), 47.2 (d, 1 C), 46.5 (t, 1 C, rot. A), 46.1 (t, 1 C, rot.
(R/S)-1-[{[(4S,5S)-5-(Benzyloxymethyl)-2,2-dimethyl-1,3-dioxolan-
4-yl]methyl}(fluoren-9-ylmethoxycarbonyl)amino]-3-(tert-butyldi-
methylsilyloxy)propan-2-ol (16): Compound 16 was obtained ac-
cording to the same procedure as for 15, starting from 14 (554 mg,
1.26 mmol), to afford a colorless oil (660 mg, 78%) after purifica-
tion by flash column chromatography (EtOAc/petroleum ether, 1:4;
Rf = 0.15). 1H NMR (200 MHz, CDCl3; 1:1 mixture of two dia-
stereomers): δ = 7.74 (m, 2 H) 7.56 (m, 2 H), 7.35 (m, 4 H), 7.25
(s, 5 H), 4.58–4.48 (m, 4 H), 4.25–4.12 (m, 1 H), 3.83–3.23 (m, 11
H), 1.40 (s, 3 H), 1.37 (s, 3 H), 0.91 (s, 9 H), 0.07 (s, 6 H) ppm.
13C NMR (CDCl3): δ = 156.0 (s, 1 C), 143.6 (s, 2 C), 141.0 (s, 2
C), 137.6 (s, 1 C), 128.0 (d, 2 C), 127.4 (d, 5 C), 126.8 (d, 2C),
124.4 (d, 2 C), 119.6 (d, 2 C), 109.2 (s, 1 C, diast. A), 109.1 (s, 1
C, diast. B), 77.9 (d, 1 C), 76.8 (d, 1 C), 73.2 (t, 1 C), 71.2 (d, 1 C,
diast. A), 70.5 (d, 1 C, diast. B), 69.9 (t, 1 C), 66.7 (t, 1 C), 64.7 (t,
1 C, diast. A), 64.2 (t, 1 C, diast. B), 52.2 (t, 1 C, diast. A), 51.9
(t, 1 C, diast. B), 51.2 (t, 1 C, diast. A), 50.6 (t, 1 C, diast. B), 47.1
(d, 1 C), 26.8 (q, 2 C, diast A), 26.7 (q, 2 C, diast. B), 25.6 (q, 3
B) ppm. MS: m/z (%) = 487 (3) [M+], 57 (100). IR (CHCl ): ν =
˜
3
2928, 2871, 2248, 1792, 1702, 1451, 1227 cm–1. C29H29NO6 (487.5):
calcd. C 71.44, H 6.00, N 2.87; found C 71.36, H 5.87, N 2.83.
(1S,5R,7S)-7-exo-(Benzyloxymethyl)-3-(fluoren-9-ylmethoxycarbon-
yl)-6,8-dioxa-3-azabicyclo[3.2.1]octane-5-carboxylic Acid (2): Com-
pound 2 was obtained according to the same procedure as for 1
starting from 20 (67 mg, 0.137 mmol) and using a different workup:
the crude product was dissolved in EtOAc (5 mL) and washed with
a saturated aqueous solution of NaHCO3 (2×5 mL); the aqueous
phase was then acidified to pH = 1 with HCl and extracted with
EtOAc (3×5 mL). The organic phase was then dried with anhy-
drous Na2SO4, filtered and concentrated to give 2 (48 mg, 70%).
An analytical sample was obtained by flash chromatography
(EtOAc/petroleum ether, 2:5; Rf = 0.65) to give pure 2 as a pale
yellow oil. [α]2D5 = +3.2 (c = 0.25, CHCl3). 1H NMR (200 MHz,
CDCl3; 3:2 mixture of two rotamers): δ = 7.76 (m, 2 H), 7.59 (m,
2 H), 7.40–7.26 (m, 9 H), 4.60–4.47 (m, 1 H), 4.55 (s, 2 H), 4.44–
C), 18.0 (q, 3 C), –5.6 (q, 2 C) ppm. MS: m/z (%) = 604 (1)[M+
–
tBu], 546 (1), 408 (1), 368 (4), 234 (1), 178 (49), 91 (100). IR
(CHCl ): ν = 3450, 2930, 2858, 2248, 1694 cm–1. C38H51NO7Si
˜
3
(661.9): calcd. C 68.95, H 7.77, N 2.12; found C 68.59, H 7.37, N
1.90.
1-[{[(4S,5S)-5-(Benzyloxymethyl)-2,2-dimethyl-1,3-dioxolan-4-
yl]methyl}(fluoren-9-ylmethoxycarbonyl)amino]-3-(tert-butyldimeth-
ylsilyloxy)propan-2-one (18): Compound 18 was obtained accord-
ing to the same procedure as for 17, starting from 16 (660 mg,
1.00 mmol), to afford a colorless oil (332 mg, 50%) after purifica-
tion by flash column chromatography (EtOAc/petroleum ether, 1:6;
3
4.23 (m, 2 H), 4.14–4.07 (m, 2 H), 4.01 (d, 1 H, JH,H = 13.2 Hz,
3
rot. A), 3.66 (d, 1 H, JH,H = 13.9 Hz, rot. B), 3.52 (m, 2 H), 3.41
3
(m, 1 H), 3.28 (d, 1 H, JH,H = 12.4 Hz), 3.13 (m, 1 H) ppm. 13C
NMR (CDCl3): δ = 171.2 (s, 1 C), 156.0 (s, 1 C), 143.8 (s, 1 C),
141.3 (s, 1 C), 137.8 (s, 1 C), 128.4 (d, 2 C), 127.7 (d, 5 C), 127.1
(d, 2 C), 125.0 (d, 2 C), 120.0 (d, 2 C), 101.5 (s, 1 C, rot. A), 102.0
(s, 1 C, rot. B), 77.8 (d, 1 C), 75.5 (d, 1 C, rot. A), 75.0 (d, 1 C,
rot. B), 73.5 (t, 1 C), 70.4 (d, 1 C, rot. A), 70.0 (d, 1 C, rot. B),
67.8 (t, 1 C, rot. A), 67.4 (t, 1 C, rot. B), 48.7 (t, 1 C, rot. A), 48.3
(t, 1 C, rot. B), 47.1 (d, 1 C), 46.3 (t, 1 C, rot. A), 46.0 (t, 1 C, rot.
Rf = 0.27). [α]2D5 = –6.0 (c = 0.4, CHCl3). 1H NMR (400 MHz,
3
CDCl3; 1:1 mixture of two rotamers): δ = 7.78 (d, 2 H, JH,H
=
3
7.6 Hz, rot. A), 7.77 (d, 2 H, JH,H = 7.2 Hz, rot. B), 7.58 (d, 2 H,
3JH,H = 7.6 Hz, rot. A), 7.54 (d, 2 H, 3JH,H = 7.6 Hz, rot. B), 7.44–
7.25 (m, 9 H), 4.62 (s, 2 H, rot. A), 4.51 (s, 2 H), 4.56–4.38 (m, 2
H), 4.35 (s, 2 H, rot. A), 4.26 (s, 2 H, rot. B), 4.21 (m, 1 H), 4.03
(s, 2 H, rot. B), 3.99 (m, 1 H), 3.89–3.85 (m, 1 H), 3.81–3.77 (m, 1
B) ppm. MS: m/z (%) = 501 (1) [M+], 178 (100). IR (CHCl ): ν =
˜
3
3
3440, 2928, 2871, 2248, 10706, 1451 cm–1. C29H27NO7 (501.5):
H), 3.70–3.62 (m, 1 H), 3.48 (dd, 1 H, JH,H = 10.4, 5.6 Hz, rot.
3
A), 3.42 (dd, 1 H, JH,H = 10.4, 4.0 Hz, rot. A), 3.26 (dd, 1 H,
calcd. C 69.45, H 5.43, N 2.79; found C 69.32, H 5.37, N 2.48.
3JH,H = 15.2, 6.4 Hz, rot. B), 3.20 (dd, 1 H, JH,H = 15.2, 7.2 Hz,
3
Benzyl({(4S,5R)-5-[(tert-butyldimethylsilyloxy)methyl]-2,2-dimeth-
yl-1,3-dioxolan-4-yl}methyl)amine (23): To a solution of 22 (1.23 g,
5.04 mmol), prepared as reported,[14a] in dry CH2Cl2 (4 mL) was
added at 0°, under nitrogen, imidazole (300 mg, 4.54 mmol) and
tert-butyldimethylsilyl chloride (660 mg, 4.54 mmol). The mixture
was stirred at 0 °C for 1 h, and at room temperature for 1.5 h. The
solvent was evaporated, and the crude product was dissolved in
EtOAc (20 mL) and washed with 1 n HCl, a saturated solution of
NaHCO3 and brine. The organic phase was then dried with anhy-
drous Na2SO4, filtered, and concentrated to give a crude oil that
was purified by flash column chromatography (EtOAc/petroleum
ether, 1:1; Rf = 0.60), to afford 23 as a colourless oil (1.33 g, 72%).
[α]2D5 = –3.2 (c = 1, CHCl3). 1H NMR (200 MHz, CDCl3): δ = 7.31
(m, 5 H), 4.41–4.32 (m, 1 H), 4.18–4.08 (m, 1 H), 3.83 (s, 2 H),
rot. B), 1.38 (s, 6 H), 0.96 (s, 9 H), 0.10 (s, 6 H, rot. A), 0.09 (s, 6
H, rot. B) ppm. 13C NMR (CDCl3): δ = 205.9 (s, 1 C), 156.4 (s, 1
C), 143.9 (s, 2 C), 141.3 (s, 2 C), 137.6 (s, 1 C), 128.3 (d, 2 C), 127.7
(d, 5 C), 127.1 (d, 2 C), 124.8 (d, 2 C), 119.9 (d, 2 C), 109.2 (s, 1
C), 77.9 (d, 1 C), 77.7 (d, 1 C), 73.5 (t, 1 C), 70.1 (t, 1 C, rot. A),
69.9 (t, 1 C, rot. B), 68.5 (t, 1 C, rot. A), 68.2 (t, 1 C, rot. B), 67.5
(t, 1 C, rot. A), 67.2 (t, 1 C, rot. B), 55.2 (t, 1 C), 49.5 (t, 1 C), 47.3
(d, 1 C), 27.1 (q, 1 C), 26.8 (q, 1 C), 25.7 (q, 3 C), 18.0 (s, 1 C), –
5.6 (q, 2 C) ppm. MS: m/z (%) = 539 (1) [M+ – CH2OBn], 480 (1),
424 (1), 395 (1), 178 (12). IR (CHCl ): ν = 2931, 2858, 1700 cm–1.
˜
3
C38H49NO7Si (659.9): calcd. C 69.16, H 7.48, N 2.12; found C
68.96, H 7.24, N 2.02.
(1S,5R,7S)-7-exo-(Benzyloxymethyl)-3-(fluoren-9-ylmethoxycarbon-
yl)-5-(hydroxymethyl)-6,8-dioxa-3-azabicyclo[3.2.1]octane (20): 3.65–3.60 (m, 2 H), 2.92–2.73 (m, 2 H), 2.17 (br. s, 1 H), 1.39 (s, 3
Crude 20 (248 mg, 99%) was obtained according to the same pro-
H), 1.34 (s, 3 H), 0.85 (s, 9 H), 0.03 (s, 6 H) ppm. 13C NMR
cedure as for 19, starting from 18 (332 mg, 0.5 mmol). Purification (CDCl3): δ = 139.7 (s, 1 C), 128.0 (d, 2 C), 127.8 (d, 2 C), 126.6
by flash chromatography (EtOAc/petroleum ether, 1:3; Rf = 0.43)
gave pure 20 (90 mg, 37%) as a pale yellow oil. [α]2D5 = –5.2 (c =
0.5, CHCl3). 1H NMR (400 MHz, CDCl3; 1:1 mixture of two rota-
(d, 1 C), 107.8 (s, 1 C), 77.3 (d, 1 C), 76.9 (d, 1 C), 61.5 (t, 1 C),
54.0 (t, 1 C) 48.2 (d, 1 C), 27.9 (q, 1 C), 25.7 (q, 3 C), 25.3 (q, 1
C), 18.1 (s, 1 C), –5.5 (q, 2 C) ppm. MS: m/z (%) = 365 (6) [M+],
4378
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 4372–4381

Bicyclic β- and γ/δ-Amino Acids for Peptidomimetic Design
FULL PAPER
350 (21), 274 (5), 120 (100), 106 (20), 91 (91). IR (CDCl ): ν =
3-(Benzyloxy)-1-[({(4S,5R)-5-[(tert-butyldimethylsilyloxy)methyl]-
2,2-dimethyl-1,3-dioxolan-4-yl}methyl)(fluoren-9-ylmethoxycarbon-
yl)amino]propan-2-one (27): Compound 27 was obtained according
to the same procedure as for 17, starting from 26 (950 mg,
1.44 mmol), to afford a colorless oil (654 mg, 64%) after purifica-
tion by flash column chromatography (EtOAc/petroleum ether, 1:6;
Rf = 0.38). [α]2D4 = –3.5 (c = 0.3, CHCl3). 1H NMR (200 MHz,
CDCl3; 1:1 mixture of two rotamers): δ = 7.74 (m, 2 H), 7.64–7.49
(m, 2 H), 7.34 (m, 9 H), 4.58–4.40 (m, 4 H), 4.27–4.14 (m, 3 H),
4.10 (s, 2 H), 3.87 (s, 2 H), 3.87–3.80 (m, 1 H), 3.61–3.56 (m, 1 H),
3.47–3.41 (m, 1 H), 2.98–2.86 (m, 1 H), 1.35 (s, 3 H, rot A), 1.33
(s, 3 H, rot B), 1.24 (s, 3 H, rot A), 1.21 (s, 3 H, rot B), 0.88 (s, 9
H, rot A), 0.85 (s, 3 H, rot B), 0.05 (s, 6 H, rot A), 0.02 (s, 6 H,
rot B) ppm. 13C NMR (CDCl3): δ = 203.2 (s, 1 C), 155.7 (s, 1 C),
143.6 (s, 2 C), 140.9 (s, 2 C), 136.8 (s, 1 C), 128.2 (d, 2 C), 127.4
(d, 5 C), 126.7 (d, 2 C), 124.4 (d, 2 C), 119.5 (d, 2 C), 108.0 (s, 1
C), 76.7 (d, 1 C), 76.4 (d, 1 C), 73.7 (t, 1 C, rot A), 73.2 (t, 1 C,
rot B), 66.8 (t, 1 C), 61.3 (t, 1 C, rot A), 61.1 (t, 1 C, rot B), 55.3
(t, 1 C, rot A), 55.0 (t, 1 C, rot B), 48.2 (t, 1 C, rot A), 47.9 (t, 1
C, rot B), 47.0 (d, 1 C), 27.5 (q, 1 C), 25.6 (q, 3 C), 24.9 (q, 1 C),
20.6 (s, 1 C), –5.6 (q, 2 C) ppm. MS: m/z (%) = 659 (14) [M+], 553
˜
3
3318, 2930, 2857, 2247, 1462, 1372, 1095 cm–1. C20H35NO3Si
(365.6): calcd. C 65.71, H 9.65, N 3.83; found C 64.30, H 9.01, N
3.62.
({(4S,5R)-5-[(tert-butyldimethylsilyloxy)methyl]-2,2-dimethyl-1,3-di-
oxolan-4-yl}methyl)amine (24): Compound 24 was obtained accord-
ing to the same procedure as for 7, starting from 23 (1.28 g,
3.49 mmol), to afford a colourless oil (847 mg, 88%), sufficiently
pure for the next step. [α]2D0 = –2.2 (c = 0.25, CHCl3). 1H NMR
(200 MHz, CDCl3): δ = 4.17–4.12 (m, 2 H), 3.67–3.60 (m, 2 H),
2.92–2.87 (m, 2 H), 1.44 (br. s, 2 H), 1.40 (s, 3 H), 1.34 (s, 3 H),
0.88 (s, 9 H), 0.06 (s, 6 H) ppm. 13C NMR (CDCl3): δ = 107.7 (s,
1 C), 79.4 (d, 1 C), 77.0 (d, 1 C), 61.4 (t, 1 C), 41.3 (t, 1 C), 28.0
(q, 1 C), 25.8 (q, 3 C), 25.4 (q, 1 C), 18.1 (s, 1 C), –5.5 (q, 2 C)
ppm. MS: m/z (%) = 275 (1)[M+], 260 (5), 218 (16), 160 (18), 131
(38). IR (CDCl ): ν = 3685, 2930, 2858, 2247, 1471, 1382, 1253,
˜
3
1095 cm–1. C13H29NO3Si (275.5): calcd. C 56.68, H 10.61, N 5.08;
found C 56.52, H 10.45, N 4.91.
1-(Benzyloxy)-3-({[5-[(tert-butyldimethylsilyloxy)methyl]-2,2-di-
methyl-1,3-dioxolan-4-yl}methyl)amino}propan-2-ol (25): Com-
pound 25 was obtained according toh the same procedure as for
10, starting from 24 (827 mg, 3.02 mmol) and benzyl-glycidyl ether
(446 μL, 2.93 mmol), to afford 1.29 g of a yellow oil, sufficiently
pure for the next step. An analytical sample of compound 25 was
obtained by flash chromatography (EtOAc/petroleum ether, 1:2; Rf
= 0.1). 1H NMR (200 MHz, CDCl3; mixture of two diastereomers):
δ = 7.32 (s, 5 H), 4.55 (s, 2 H), 4.31 (m, 1), 4.12 (m, 1 H), 3.88 (m,
1 H), 3.65–3.60 (m, 2 H), 3.50–3.46 (m, 2 H), 2.85–2.78 (m, 2 H),
2.74–2.63 (m, 2 H), 1.40 (s, 3 H), 1.33 (s, 3 H), 0.87 (s, 9 H), 0.05
(s, 6 H) ppm. 13C NMR (CDCl3): δ = 138.5 (s, 1 C), 128.8 (d, 2
C), 128.1 (d, 3 C), 108.6 (s, 1 C), 77.4 (d, 1 C), 76.9 (d, 1 C), 74.0
(t, 1 C), 73.3 (t, 1 C), 69.1 (d, 1 C), 62.2 (t, 1 C), 52.9 (t, 1 C), 49.6
(t, 1 C), 28.7 (q, 1 C), 26.5 (q, 3 C), 26.1 (q, 1 C), 18.9 (s, 1 C), –
4.7 (q, 2 C) ppm. MS: m/z (%) = 439 (1) [M+], 424 (9), 382 (12),
348 (1), 324 (7), 318 (5), 288 (48), 194 (71), 91 (100). IR (CDCl3):
(3), 245 (12), 178 (21), 91 (37), 57 (100). IR (CDCl ): ν = 2931,
˜
3
2858, 2248, 1739, 1697, 1452, 1246, 1105 cm–1. C38H49NO7Si
(659.9): calcd. C 69.16, H 7.48, N 2.12; found C 68.77, H 7.31, N
2.16.
(1S,5R,7R)-5-(Benzyloxymethyl)-3-(fluoren-9-ylmethoxycarbonyl)-
7-endo-(hydroxymethyl)-6,8-dioxa-3-azabicyclo[3.2.1]octane (28):
Crude 28 was obtained according to the same procedure as for 1,
starting from 27 (300 mg, 0.455 mmol), to afford a pale yellow oil
(210 mg, 94%) after purification by flash chromatography (EtOAc/
petroleum ether, 1:4; Rf = 0.41). [α]2D5 = –2.8 (c = 0.70, CHCl3). 1H
NMR (400 MHz, CDCl3; 1:1 mixture of two rotamers): δ = 7.86
(m, 2 H), 7.48 (m, 2 H), 7.31–7.21 (m, 9 H), 4.56–4.51 (m, 2 H),
4.40–4.26 (m, 3 H), 4.21–4.15 (m, 2 H), 3.91–3.87 (m, 1 H), 3.74
(s, 2 H), 3.58–3.52 (m, 1 H), 3.40–3.37 (m, 1 H), 3.19–3.13 (m, 1
H), 3.05–2.99 (m, 1 H) ppm. 13C NMR (CDCl3): δ = 155.4 (s, 1
C), 143.7 (s, 2 C), 141.2 (s, 2 C), 137.4 (s, 1 C), 128.4 (d, 2 C), 127.7
(d, 5 C), 127.6 (d, 2 C), 124.8 (d, 2 C), 119.9 (d, 2 C), 114.0 (s, 1
C), 78.7 (d, 1 C), 76.4 (d, 1 C), 73.9 (t, 1 C), 71.5 (t, 1 C, rot A),
71.1 (t, 1 C, rot B), 67.8 (t, 1 C, rot A), 66.9 (t, 1 C, rot B), 61.2
(t, 1 C), 53.0 (d, 1 C), 48.7 (t, 1 C), 42.8 (d, 1 C) ppm. MS: m/z
ν = 2930, 2858, 2247, 1471, 1257, 1097 cm–1. C H NO Si (439.7):
˜
23 41
5
calcd. C 62.83, H 9.40, N 3.19; found C 62.02, H 9.12, N 3.12.
(R/S)-3-(Benzyloxy)-1-[({(4S,5R)-5-[(tert-butyldimethylsilyloxy)
methyl]-2,2-dimethyl-1,3-dioxolan-4-yl}methyl)(fluoren-9-ylmeth-
oxycarbonyl)amino]propan-2-ol (26): Compound 26 was obtained
according to the same procedure as for 15, starting from 25 (1.29 g,
2.93 mmol), to afford a colorless oil (967 mg, 50% over two steps)
after purification by flash column chromatography (EtOAc/petro-
(%) = 487 (1) [M+], 178 (100), 91 (67). IR (CDCl ): ν = 3065, 2955,
˜
3
2265, 1750, 1698, 1451, 1246 cm–1. C29H29NO6 (487.5): calcd. C
1
leum ether, 1:4; Rf = 0.29). H NMR (200 MHz, CDCl3; 1:1 mix-
71.44, H 6.00, N 2.87; found C 70.45, H 5.61, N 2.70.
ture of two diastereomers): δ = 7.74 (m, 2 H), 7.57 (m, 2 H), 7.31
(m, 9 H), 4.65 (m, 1 H), 4.54 (m, 3 H), 4.24–4.00 (m, 3 H), 3.79– (1S,5R,7S)-5-(Benzyloxymethyl)-3-(fluoren-9-ylmethoxycarbonyl)-
3.61 (m, 3 H), 3.49–3.43 (m, 3 H), 3.36–3.14 (m, 2 H), 3.08–2.93 6,8-dioxa-3-azabicyclo[3.2.1]octane-7-endo-carboxylic Acid (29):
(m, 1 H), 1.42 (s, 3 H, diast.A), 1.35 (s, 3 H, diast. B), 1.32 (s, 3 Compound 29 was obtained according to the same procedure as
H, diast. A), 1.17 (s, 3 H, diast B), 0.88 (s, 9 H, diast A), 0.85 (s,
9 H, diast. B), 0.05 (s, 6 H, diast. A), 0.02 (s, 6 H, diast. B) ppm.
13C NMR (CDCl3): δ = 156.8 (s, 1 C), 143.9 (s, 2 C), 141.3 (s, 2
for 19, starting from 28 (165 mg, 0.34 mmol), to afford a pale yel-
low oil (36 mg, 21%) after flash chromatography (EtOAc/petro-
leum ether, 2:7, TFA 0.1%; Rf = 0.1). [α]2D4 = –4.1 (c = 0.27, CHCl3).
C), 138.1 (s, 1 C), 128.3 (d, 2 C), 127.7 (d, 5 C), 127.1 (d, 2 C), 1H NMR (400 MHz, CDCl3; 1:1 mixture of two rotamers): δ =
124.7 (d, 2 C), 119.1 (d, 1 C), 108.4 (s, 1 C), 76.6 (d, 1 C), 76.1 (d,
1 C), 73.5 (t, 1 C, diast A), 73.4 (t, 1 C, diast B), 72.2 (t, 1 C), 70.3
(t, 1 C, diast A), 70.1 (t, 1 C, diast B), 67.0 (t, 1 C, diast A), 66.6
(t, 1 C, diast B), 61.6 (t, 1 C, diast A), 61.4 (t, 1 C, diast B), 54.5
(t, 1 C), 49.6 (t, 1 C, diast A), 49.0 (t, 1 C, diast B), 47.4 (d, 1 C),
27.8 (q, 1 C, diast A), 27.4 (q, 1 C, diast B), 26.0 (q, 3 C), 25.5 (q,
1 C, diast A), 25.3 (q, 1 C, diast B), 18.4 (s, 1 C), –5.2 (q, 2 C)
7.65 (m, 2 H), 7.46 (m, 2 H), 7.27 (m, 9 H), 6.21 (br. s, 1 H), 4.73–
4.67 (m, 1 H), 4.57–4.45 (m, 3 H), 4.33 (m, 1 H), 4.12–4.02 (m, 3
H), 3.95–3.83 (m, 1 H), 3.64–3.58 (m, 2 H), 3.19–3.06 (m, 2 H)
ppm. 13C NMR (CDCl3): δ = 170.7 (s, 1 C), 155.9 (s, 1 C), 141.1
(s, 2 C), 137.1 (s, 2 C), 130.1 (s, 1 C), 128.4 (d, 2 C), 127.8 (d, 5
C), 127.6 (d, 2 C), 124.9 (d, 2 C), 119.9 (d, 2 C), 106.0 (s, 1 C),
76.7 (d, 1 C), 75.5 (d, 1 C), 73.9 (t, 1 C), 70.8 (t, 1 C), 68.3 (t, 1
ppm. MS: m/z (%) = 661 (1) [M+], 604 (1), 546 (1), 408 (8), 178 C), 48.6 (t, 1 C), 47.0 (d, 1 C), 43.8 (t, 1 C) ppm. MS: m/z (%) =
(79), 91 (100). IR (CDCl ): ν = 3442, 2930, 2858, 2247, 1694, 1451,
501 (9) [M+], 393 (3), 279 (20). IR (CDCl ): ν = 3689, 2930, 2359,
˜
˜
3
3
1251, 1103 cm–1. C38H51NO7Si (661.9): calcd. C 68.95, H 7.77, N
1722, 1696, 1451, 1215 cm–1. C29H27NO7 (501.5): calcd. C 69.45,
2.12; found C 68.02, H 7.46, N 2.08.
H 5.43, N 2.79; found C 68.74, H 5.48, N 2.50.
Eur. J. Org. Chem. 2005, 4372–4381
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4379

E. Danieli, A. Trabocchi, G. Menchi, A. Guarna
FULL PAPER
Ac-BGG-NHEt (32): HMBA-AM resin (100 mg, 0.08 mmol) was
used as starting reagent. Coupling of 1 was performed using a
threefold amino acid excess (91 mg, 0.24 mmol), a mixture of HOBt
(54 mg, 0.40 mmol) and DIC (62 μL, 0.40 mmol) as coupling rea-
gents, and catalytic DMAP (1 mg) as base, in DMF as solvent
(2 mL), shaking the mixture for 12 h. Fmoc deprotection was per-
formed twice with 30% piperidine in DMF for 10 min, followed by
resin washing with DMF. After Fmoc deprotection, the resin-
bound compound was treated with Ac2O (76 μL, 0.8 mmol), and
DMAP (1 mg) overnight. After resin washings with DMF and
CH2Cl2, compound 32 was cleaved off the resin with a solution of
70% EtNH2 in H2O (1 mL) and THF (1 mL), and the mixture was
stirred at room temperature for 12 h, then the solution was filtered
and the solvents were evaporated. The resulting crude oil was puri-
fied by semi-preparative HPLC using 0–10% CH3CN for 5 min,
then 10–90% CH3CN for 25 min as gradient (tR = 13.9 min) to
give a pure compound (14 mg, 70%) as a 3:1 mixture of two rota-
mers (white solid). 1H NMR (400 MHz, CDCl3; major rotamer): δ
[1]
a) V. J. Hruby, G. Li, C. Haskell-Luevano, M. Shenderovich,
Biopolymers 1997, 43, 219–266; b) J. Gante, Angew. Chem. Int.
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gew. Chem. Int. Ed. Engl. 1993, 32, 1244–1267; e) W. M. Kaz-
mierski (Ed.), Methods in Molecular Medicine, Peptidomimetics
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[2] D. L. Steer, P. Perlmutter, A. I. Smith, M.-I. Aguilar, Curr.
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[3] a) S. H. Gellman, Acc. Chem. Res. 1998, 31, 173–180; b) B. L.
Iverson, Nature 1997, 385, 113–115; c) D. Seebach, J. L. Mat-
thews, Chem. Commun. 1997, 2015–2022.
[4] For a review on β-peptides, see: R. P. Cheng, S. H. Gellman,
W. F. DeGrado, Chem. Rev. 2001, 101, 3219–3232.
[5] a) S. Hanessian, X. Luo, R. Schaum, S. Michnick, J. Am.
Chem. Soc. 1998, 120, 8569–8570; b) T. Hintermann, K. Gade-
mann, B. Jaun, D. Seebach, Helv. Chim. Acta 1998, 81, 983–
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[6] L. Szabo, B. L. Smith, K. D. McReynolds, A. L. Parrill, E. R.
Morris, J. Gervay, J. Org. Chem. 1998, 63, 1074–1078.
[7] a) Enantioselective Synthesis of β-Amino Acids (Ed.: E. Juari-
sti), Wiley-VCH, New York, 1997; b) G. Cardillo, C. Tomasini,
Chem. Soc. Rev. 1996, 25, 117–131.
3
= 6.62 (br. s, 1 H), 4.75 (m, 1 H), 4.41 (d, 1 H, JH,H = 13.8 Hz),
3
3
4.04 (d, 1 H, JH,H = 10.1 Hz), 3.94 (m, 1 H), 3.84 (d, 1 H, JH,H
3
= 13.0 Hz), 3.56 (d, 1 H, JH,H = 13.0 Hz), 3.38 (m, 2 H), 3.10 (d,
1 H, 3JH,H = 13.8 Hz), 2.75 (s, 3 H, rot. A), 1.11 (t, 3 H) ppm. ESI-
MS: m/z = 229 [M+ + H], 251 [M+ + Na].
[8] See, for example: a) S. G. Davies, G. D. Smyth, A. M. Chippin-
dale, J. Chem. Soc. Perkin Trans. 1 1999, 3089–3092; b) H.
Sone, T. Nemoto, H. Ishiwata, M. Ojika, K. Yamada, Tetrahe-
dron Lett. 1993, 34, 8449–8452; c) G. Casiraghi, L. Colombo,
G. Rassu, P. Spanu, J. Org. Chem. 1991, 56, 6523–6527; d) J. N.
Denis, A. Correa, A. E. Greene, J. Org. Chem. 1990, 55, 1957–
1959; e) S. Shinagawa, T. Kanamaru, S. Harada, M. Asai, H.
Okazaki, J. Med. Chem. 1987, 30, 1458–1467.
Ac-Phe-BGG-Leu-NH2 (35): Rink-HMBA resin (200 mg,
0.13 mmol) was used as starting reagent. Fmoc deprotections were
performed twice with 30% piperidine in DMF for 10 min, followed
by resin washing with DMF. Coupling of leucine was performed
using a fourfold Fmoc-amino acid excess (0.53 mmol), a mixture of
HOBt (72 mg, 0.53 mmol) and DIC (83 μL, 0.53 mmol) as coupling
reagents and DMAP (1 mg, 0.05 mmol) as base, in DMF (2 mL)
as solvent, shaking the mixture for 12 h. After Fmoc deprotection,
compound 1 was mounted on peptide resin using a twofold amino
acid excess (99 mg, 0.26 mmol) and a mixture of HOBt (72 mg,
0.53 mmol) and DIC (83 μL, 0.53 mmol) in DMF (2 mL) for 16 h.
After Fmoc deprotection, peptide bound to resin 33 was treated
with an activating mixture containing HOBt (72 mg, 0.53 mmol),
DIC (83 μL, 0.53 mmol) and Fmoc-Phe-OH (204 mg, 0.53 mmol)
in DMF (2 mL), to obtain peptide 34, that, after Fmoc deprotec-
tion, was treated with Ac2O (145 μL, 1.32 mmol), and DMAP
(1 mg, 0.01 mmol) overnight. After resin washing with DMF and
CH2Cl2, the peptide was cleaved off the resin with a solution of
95% TFA/2.5% TIS/2.5% H2O (2 mL, 1×5 min, 1×2 h) and then
the solutions were filtered, combined and concentrated in vacuo to
give crude peptide 35. Semi-preparative HPLC using 0–10%
CH3CN for 5 min, then 10–90% CH3CN for 25 min as gradient
(tR = 11.2 min) gave pure 35 (25 mg, 41%), as a white solid. 1H
NMR (400 MHz, [D6]DMSO; mixture of two rotamers, 4:1; major
[9]
a) A. F. Abdel-Magid, J. H. Cohen, C. A. Maryanoff, Curr.
Med. Chem. 1999, 6, 955–969; b) E. Juaristi, H. Lopez-Ruiz,
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ids 1996, 11, 397–408; d) D. C. Cole, Tetrahedron 1994, 50,
9517–9582; e) M. Liu, M. P. Sibi, Tetrahedron 2002, 58, 7991–
8035.
[10]
[11]
[12]
[13]
Y. J. Kim, D. A. Kaiser, T. D. Pollard, Y. Ichikawa, Bioorg.
Med. Chem. Lett. 2000, 10, 2417–2419.
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1, 1717–1720.
S. Abele, K. Vögtli, D. Seebach, Helv. Chim. Acta 1999, 82,
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a) A. Guarna, A. Guidi, F. Machetti, G. Menchi, E. G. Occhi-
ato, D. Scarpi, S. Sisi, A. Trabocchi, J. Org. Chem. 1999, 64,
7347–7364; b) N. Cini, F. Machetti, G. Menchi, E. G. Occhiato,
A. Guarna, Eur. J. Org. Chem. 2002, 873–880; c) A. Guarna,
I. Bucelli, F. Machetti, G. Menchi, E. G. Occhiato, D. Scarpi,
A. Trabocchi, Tetrahedron 2002, 58, 9865–9870.
a) A. Trabocchi, G. Menchi, M. Rolla, F. Machetti, I. Bucelli,
A. Guarna, Tetrahedron 2003, 59, 5251–5258; b) A. Trabocchi,
N. Cini, G. Menchi, A. Guarna, Tetrahedron Lett. 2003, 44,
3489–3492; c) D. Scarpi, E. G. Occhiato, A. Trabocchi, R. J.
Leatherbarrow, A. B. E. Brauer, N. Nievo, A. Guarna, Bioorg.
Med. Chem. 2001, 9, 1625–1632; d) A. Trabocchi, E. G. Occhi-
ato, D. Potenza, A. Guarna, J. Org. Chem. 2002, 67, 7483–
7492; e) A. Trabocchi, D. Potenza, A. Guarna, Eur. J. Org.
Chem. 2004, 4621–4627.
[14]
3
rotamer): δ = 8.41 (d, 1 H, JH,H = 8.3 Hz), 7.89 (m, 1 H,), 7.48
(m, 1 H), 7.33 (m, 5 H), 7.17 (m, 1 H), 4.96 (m, 1 H), 4.86 (m, 1
3
H), 4.34 (m, 1 H), 4.17 (d, 1 H, JH,H = 13.7 Hz), 3.91 (d, 1 H,
3JH,H = 12.8 Hz), 3.70 (m, 1 H), 3.40 (m, 1 H), 3.01 (d, J = 12.8 Hz,
3
1 H), 2.98–2.77 (m, 2 H), 2.89 (d, 1 H, JH,H = 14 Hz), 1.83 (s, 3
H), 1.62–1.43 (m, 3 H), 0.93 (m, 6 H) ppm. ESI-MS: m/z = 461
[M+ + H], 483 [M+ + Na].
[15]
[16]
[17]
[18]
[19]
M. J. Earle, A. Abdur-Rashid, N. D. Priestley, J. Org. Chem.
1996, 61, 5697–5700.
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2471–2476.
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Interestingly, the N-benzylated compound 9 showed opposite
reactivity, as SN2 reaction with 5 failed probably due to steric
Acknowledgments
The authors would like to thank COFIN 2004–2005, FIRB 2001
(RBNE01RZH4_004) and Università degli Studi di Firenze for fin-
ancial support. Ente Cassa di Risparmio di Firenze is gratefully
acknowledged for the purchase of a 400 MHz NMR instrument.
Ms. Brunella Innocenti and Mr. Maurizio Passaponti are acknowl-
edged for technical support.
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 4372–4381

Bicyclic β- and γ/δ-Amino Acids for Peptidomimetic Design
FULL PAPER
hindrance, while reductive amination of 4 furnished the corre-
sponding N-benzylated adduct, although in 46% yield.
[20] Protected 3-amino-1,2-propanediol 6 was obtained by LiAlH4
reduction of the oxime derived from 4, or by reduction of the
azide derived from d-1,2-O-isopropylideneglycerol. See: K.
Danielmeier, E. Steckhan, Tetrahedron: Asymmetry 1995, 6,
1181–1190; F. S. Gibson, M. S. Park, H. Rapoport, J. Org.
Chem. 1994, 59, 7503–7507, respectively.
[21] Z.-J. Yao, Y.-L. Wu, J. Org. Chem. 1995, 60, 1170–1176.
[22] K.-G. Liu, H.-B. Zhou, Y.-L. Wu, Z.-J. Yao, J. Org. Chem.
2003, 68, 9528–9531.
[23] Partial degradation to monocyclic derivatives was also ob-
served after prolonged storage.
Received: May 30, 2005
Published Online: September 1, 2005
Eur. J. Org. Chem. 2005, 4372–4381
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4381