Synthesis of 4-hydroxy-β3-homoprolines and their insertion in α/β/α-tripeptides

Article abstract of DOI:10.1007/s00726-012-1401-0

The stereoselective syntheses of 2-cyclopropyl- and (2S)-2-hydroxymethyl- (3R,4S)-4-hydroxy-β³-homoproline are described. The reported amino acids were constructed through 1,3-dipolar cycloaddition of strained alkylidenecyclopropanes with enant

Full text of DOI:10.1007/s00726-012-1401-0

Amino Acids (2013) 44:769–780
DOI 10.1007/s00726-012-1401-0
ORIGINAL ARTICLE
Synthesis of 4-hydroxy-b3-homoprolines and their insertion
in a/b/a-tripeptides
•
Franca M. Cordero Carolina Vurchio
•
•
Marco Lumini Alberto Brandi
Received: 26 July 2012 / Accepted: 7 September 2012 / Published online: 28 September 2012
Ó Springer-Verlag 2012
´
Abstract The stereoselective syntheses of 2-cyclopropyl-
and (2S)-2-hydroxymethyl-(3R,4S)-4-hydroxy-b3-homopro-
linearedescribed. Thereported aminoacidswere constructed
through 1,3-dipolar cycloaddition of strained alkylidenecy-
clopropanes with enantiopure pyrroline N-oxides derived
from malic acid followed by thermal rearrangement of the
adducts in the presence of trifluoroacetic acid. The two-step
sequence afforded the homoprolines suitably protected to be
directly used as building blocks in peptidomimetic synthesis
as proved by the synthesis of the two model mixed a/b/a
tripeptides Phe-b3-HPro-Val.
2005; Steer et al. 2002; Juaristi and Lopez-Ruiz 1999).
More recently, the use of b-amino acids as organocatalysts
was also reported (Terakado et al. 2005; Mitsumori et al.
2006; Limbach 2006; Davies et al. 2007; Gruttadauria et al.
2008; Tsandi et al. 2009; Hiraga et al. 2011; Yang and
Wong 2011).
b3-Homoproline (pyrrolidine-2-acetic acid, b3-HPro, 1)
(Fig. 1) is of particular interest. For example, this b-amino
acid has been used in place of proline to produce biological
´
active mimics that are not degraded by peptidases (Bala-
spiri et al. 1975; Ondetti and Engel 1975; Szirtes et al.
´
1986; Aguilar et al. 2007; Katarzynska et al. 2008). In
Keywords Cycloaddition ꢀ Rearrangement ꢀ
addition, a variety of derivatives of both (3S)- and (3R)-b3-
HPro show biological and pharmacological activities
(Deutsch et al. 2001; Davies et al. 2004; Fu¨lep et al. 2006;
Zhu et al. 2009; Andries et al. 2011) and were used as
synthetic intermediates of various aza-heterocycles (Luly
and Rapoport 1983; Rabiczko et al. 2002; Ranatunga et al.
2010). Finally, the conformational behavior of b3-HPro
Peptidomimetics ꢀ Heterocycles ꢀ Small ring systems
Introduction
b-Amino acids are a class of interesting compounds fre-
quently found in biologically active products (for example,
b-alanine, b-tyrosine, and a-hydroxy-b-phenylalanine are
components of the vitamin pantothenic acid, the antibiotic
edenine A, and the anticancer TaxolÒ, respectively) and
commonly used as synthetic intermediates and building
blocks of peptidomimetics in general and b-peptides in
particular (for a selection of recent reviews on b-amino
´
(Gobi et al. 2010) and the secondary structure of its olig-
omers were investigated (Abele et al. 1999). Thus, the
synthesis and study of these b-amino acids in enantiopure
form is an important area within organic chemistry, and
new approaches to C-2-substituted derivatives of 1,
unavailable by simple homologation of proline, are highly
desirable (for some examples of optically active 2-substi-
tuted b3-homoprolines, see: Yi et al. 2003; Davies et al.
2004; Saavedra et al. 2009; Ranatunga et al. 2010; Benz
et al. 2011). We have previously shown that adducts of
pyrroline N-oxides 3 with methylenecyclopropane (MCP)
and bicyclopropylidene (BCP) such as 4 and 5 undergo a
thermal rearrangement with fragmentation in the presence of
trifluoroacetic acid (TFA) to N-trifluoroacetyl b3-homopro-
lines 6 and 7, respectively (Fig. 2) (Cordero et al. 2004a,
2009).
¨
acids, see: Szakonyi and Fu¨lop 2011; Weiner et al. 2010;
¨
Kiss and Fu¨lop 2010; Seebach et al. 2009; Horne and
Gellman 2008; Liljeblad and Kanerva 2006; Kuhl et al.
F. M. Cordero (&) ꢀ C. Vurchio ꢀ M. Lumini ꢀ A. Brandi
`
Dipartimento di Chimica ‘‘Ugo Schiff’’, Universita degli Studi di
Firenze, Via della Lastruccia 13,
50019 Sesto Fiorentino, FI, Italy
e-mail: franca.cordero@unifi.it
123

770
F. M. Cordero et al.
OR
H
O-tert-butyl- and O-benzyl-protected nitrones used in the
synthesis of homoprolines 2 were prepared following pre-
viously reported procedures (Cicchi et al. 1995, 2001; Wu
et al. 2009) except for the benzylation step. In particular,
treatment of diethyl malic ester with benzyl trichloroace-
timidate (for benzylation of dimethyl malic ester under
similar conditions, see: Keck et al. 1991; Christoffers and
H
4
CO2H
CO2H
R2
6
N
N
H
2
R1
H
1
2
3-HPro
β
Fig. 1 Structures of b3-homoproline (1) and 4-hydroxy derivatives 2
¨
Rossler 2000; Bertus et al. 2003; Brimble et al. 2011) in the
R
R
TFA
R
CO2H
3a'
presence of triflic acid afforded the corresponding benzyl
ether 8 in 98 % yield (Scheme 1).
2'
6'
N
N
N
O
O
F3C
The 1,3-DC of nitrone 9 with BCP afforded exclusively
isoxazolidine 10 derived from the addition of the sym-
metric dipolarophile to the nitrone Re face (Scheme 2).
The observed diastereoselectivity proves that the 4-OBn
group hinders the Si face of the pyrroline N-oxide with the
same efficiency of the bulkier 4-OtBu group when BCP is
used as dipolarophile (Zorn et al. 1999). The cycloaddition
was carried out at 60 °C to avoid the alternative thermal
rearrangement of 5-spirocyclopropaneisoxazolidines that
takes place under neutral conditions, affording 4-tetrahy-
dropyridones (Zorn et al. 1999; Brandi et al. 2003; Cordero
et al. 2004b). The conversion of nitrone 9 was monitored
by TLC and was complete after 2 days.
O
4
3
6
R
CO2H
R
TFA
N
N
O
F3C
O
5
7
Fig. 2 Synthesis of N-trifluoroacetyl b3-homoprolines by 1,3-
DC/ATR
Here, we present the application of this two-step
sequence 1,3-dipolar cycloaddition (1,3-DC)/acidic ther-
mal rearrangement (ATR) to the synthesis of 4-hydroxy-
b3-homoprolines 2 (Fig. 1) having a cyclopropane ring
(R1–R2 = CH2–CH2) and a 2-hydroxyethyl chain on C-2
(R1 = H, R2 = CH2-CH2OH) and their incorporation in a
a/b/a tripeptide.
Isoxazolidine 10 smoothly underwent ATR in the pres-
ence of a slight excess (1.5 equiv) of TFA giving homo-
proline 11 in high yield. The use of the OBn instead of the
OtBu protection was found to be highly beneficial, because
the yield of ATR increased from 73 to 92 % (Cordero et al.
2009). The cyclopropane ring spirofused at C-30 is found
intact on the C-2 carbon of 11 after the rearrangement. In
fact, this method is a general access to 2-cyclopropyl-b3-
homoprolines, compounds not easily available by other
synthetic approaches but particularly interesting because of
the well-known key role played by the cyclopropyl ring on
reactivity, conformational freedom, and biological activity
of various compounds including amino acids (Gnad and
Reiser 2003; Brackmann and de Meijere 2007a, b). Finally,
as a result of the anti TS in the cycloaddition step,
4-hydroxyl group on the pyrrolidine ring of 11 is trans
oriented with respect to the substituent on C-2 analogously
to HYP (Persikov et al. 2000; Berisio et al. 2002;
Schumacher et al. 2006; Krane 2008; Gorres and Raines
2010).
Results and discussion
The use of an enantiopure 4-hydroxy pyrroline N-oxide as
building block in the synthesis of b3-homoprolines offers
valuable opportunities. The presence of a bulky group on
nitrone C-4 such as OtBu group can force the dipolarophile
to add only on the less hindered nitrone diastereoface (Zorn
et al. 1999). As a consequence, complete control of con-
figuration of the isoxazolidine C-3a0 and, therefore, of the
homoproline C-3 stereocenter could be achieved. More-
over, the presence of the hydroxy group can confer
important properties to the final homoproline. In this
regard, we just recall the most common posttranslational
modification of proline (Pro) into 4-hydroxyproline (HYP)
that is an essential stabilizer of collagen structure (Persikov
et al. 2000; Berisio et al. 2002; Schumacher et al. 2006;
Krane 2008; Gorres and Raines 2010).
Summing up (3R, 4S)-4-hydroxy-2-cyclopropyl-b3-
homoproline 11 was obtained through the two-step
NH
OBn
OBn
Protected 4-hydroxy pyrroline N-oxides can be conve-
niently prepared in enantiopure form from malic acid, a
common chiral pool compound available in both the
enantiomeric forms (Cicchi et al. 1995; Goti et al. 1997,
1999, 2000; Ohtake et al. 1999; Cordero et al. 2002;
Merino et al. 2003; Wu et al. 2009; Delso et al. 2010). The
OH
(Wu et al.
2009)
CCl3
BnO
EtO2C
EtO2C
diethyl
N
O
CF3SO3H
Et2O, rt
98%
CO2Et
CO2Et
8
9
L
-malic ester
Scheme 1 Synthesis of O-benzyl nitrone 9
123

Synthesis of 4-hydroxy-b3-homoprolines
771
OBn
reactive site caused by the valine residue. This result
suggests a reduced flexibility of 16 that could adopt a
U-shaped conformation induced by the presence of the
cyclopropyl group.
BnO
H
(a)
(b)
O
9
N
CO2H
N
H
N
78%
92%
O
OBn
O
CF3
11
Having established that 2-cyclopropyl-b3-homoproline 2
(R = Bn, R1–R2 = CH2CH2, Fig. 1) is a suitable building
block for peptidomimetic synthesis, we sought to test the
versatility of the 1,3-DC/ATR approach to 4-hydroxy-b3-
homoprolines by synthesizing a 2-mono-substituted deriv-
ative. The introduction of a 2-hydroxyethyl chain, that is,
the lateral chain of Ser, appeared particularly interesting as
the amino acid 2 (R1 = H, R2 = CH2-CH2OH, Fig. 1) can
be considered as a mimetic of the dipeptide Pro-Ser
deprived of the amide moiety and, moreover, the primary
hydroxyl group could be used to introduce different sub-
stituents on C-2.
anti
10
Scheme 2 Synthesis of b-homoproline 11 by 1,3-DC/ATR sequence.
Reaction conditions: (a) BCP, toluene, 60 °C, 2 days; (b) TFA (1.5
equiv), CH3CN, 70 °C (MW), 15 min
sequence 1,3-DC/ATR in 72 % overall yield and with total
stereoselectivity.
In principle, the amino acid 11 could be directly used in
peptidomimetic synthesis having a free carboxylic group
and the nitrogen atom and the 4-OH function orthogonally
protected. Actually, it is known that some synthetic amino
acids react poorly or do not react at all with natural amino
acids under standard reaction conditions. In this regard, a
more substituted analog of 11 such as the 4,5-bis(benzyl-
oxy)-6-(benzyloxymethy)-2-cyclopropyl-b3 homoproline
does not undergo intermolecular coupling at the pyrrolidine
nitrogen atom. In that case, the lack of reactivity was
overcome by reversing the common order of coupling in
the synthesis of a mixed a/b/a tripeptide and by performing
the N-acylation intramolecularly (Cordero et al. 2009).
Fortunately, the less substituted 4-benzyloxy-2-cyclopro-
pyl-b3-homoproline showed a regular reactivity of the
nitrogen atom as proved by the synthesis of the a/b
dipeptide 14 (Scheme 3). In particular, acid 11 was ester-
ified with a bulky alcohol such as tert-butanol, and after
N-deprotection was coupled with N-Fmoc valine under
standard conditions to give 14 in 66 % yield.
Alkoxycarbonyl-methylenecyclopropanes such as 19 are
highly regioselective dipolarophiles in nitrone 1,3-DC
reactions affording the required 4-alkoxycarbonyl-5-spir-
ocyclopropanoisoxazolidines (Brandi et al. 1988, 1992;
Cordero et al. 1993; Mauduit et al. 1998). A mixture of
nitrone 18 and 19 gave the diastereomeric adducts 20a and
20b in 6:1 ratio and 81 % overall yield by heating at 30 °C
overnight (Scheme 5) (see also Pisaneschi et al. 2006a).
By heating in the presence of TFA, the main adduct 20a
was converted into the malic acid derivative 21 that
spontaneously undergoes decarboxylation under the reac-
tion conditions affording the 2-unsubstituted b3-homopro-
line 22 in low yield (Scheme 6).
To avoid decarboxylation, the ester group in 20a was
selectively reduced with DIBAL (Scheme 7), and the
4-hydroxymethyl-isoxazolidine 23 and the corresponding
acetate 24 were subjected to the ATR process. By heating
in the presence of TFA, isoxazolidine 23 gave the expected
homoproline 25 along with the N-deprotected amino acid
Accordingly, the synthesis of an a/b/a tripeptide was
studied following a standard approach (Scheme 4). Acid 11
smoothly reacted with Val-OMe to give dipeptide 15 in
83 % yield. Reductive removal of the trifluoroacetyl group
afforded 16 that was coupled with Boc-Phe to get tripeptide
17 in 31 % yield. The reactivity of dipeptide 16 was poorer
compared to ester 13, likely due to the hindrance of the
1
26 (Scheme 7). H NMR analysis of the crude mixtures
obtained under similar reaction conditions (70 °C, 5 min,
CH3CN) except for the amount of TFA showed that the
OBn
OBn
OBn
OBn
(a)
(b)
(a)
27%
(b)
CO2H
N
N
CO2 H
CO2tBu
H
H
O
NH
N
83%
82%
N
quant.
H
H
O
CO2Me
OBn
CF3
O
CF3
O
CF3
O
CF3
11
15
12
11
OBn
OBn
OBn
H
N
N
(c)
N
(c)
66%
H
CO2t Bu
H
O
NH
FmocHN
N
BocHN
Ph
H
CO2Me
CO
2 tBu
N
H
H
H
CO2Me
31%
O
O
O
14
13
16
17
Scheme 3 Synthesis of the dipeptide 14. Reaction conditions:
(a) AcOtBu, HClO4; (b) NaBH4, MeOH, rt; (c) Fmoc-Val, DIPEA,
PyBrop, DMAP, CH3CN
Scheme 4 Synthesis of the a/b/c tripeptide 17. Reaction conditions:
(a) Val-OMe, EDCI, HOBt, CH2Cl2; (b) NaBH4, MeOH, rt, 1.5 h;
(c) Boc-Phe, DIPEA, PyBrop, DMAP, CH3CN
123

772
F. M. Cordero et al.
tBuO
CO2Et
It is worth to be noted that the cycloaddition of pyrroline
N-oxides with 2,3-unsubstituted acrylic acid derivatives
affords cycloadducts with the opposite regiochemistry,
compared to 20, leading to 2-hydroxy-3-(pyrrolidin-2-
yl)propanoic acid derivatives after reduction of the N–O
bond (Argyropoulos et al. 2007; Pisaneschi et al. 2006b;
tBuO
CO2Et tBuO
EtO2C
H
H
30 °C
+
+
N
N
toluene
N
O
O
O
69%
12%
18
19
20a
20b
Scheme 5 1,3-DC of nitrone 18 with dipolarophile 19
´
Salvati et al. 2005; Cordero et al. 2005; Sar et al. 2005,
2003). Only in one case, the formation of a little amount of
a 2-(2-hydroxyethyl)-b3-homoproline was reported (Mao
et al. 2010).
OtBu
OtBu
CO2Et
CO2
CO2Et
TFA(1.5 eq)
20a
CO2H
N
N
CH3CN
80 °C, 1.5h
H
The new homoproline 27 could be coupled at both the
N- and C-terminus with a-amino acids without problems as
showed in Scheme 8. Interestingly, N-acylation of dipep-
tide 29 occurred with a higher yield compared to the analog
reaction on 16 (Schemes 4, 8), validating the constraint
effect on the dipeptide conformation exerted by the
cyclopropyl ring on C-2 of the b3-homoproline.
F3C
O
F3C
O
22
21
Scheme 6 ATR of isoxazolidine 20a
25/26 ratio decreases by increasing TFA. The overall yield
of 25 and 26 after chromatography was good (92–94 %)
and did not change with the quantity of the acid used sug-
gesting that a partial hydrolysis of 25 occurs under the ATR
reaction conditions. The greater instability of the trifluoro-
acetamide group in 25 compared with other analog N-tri-
fluoroacetyl-homoprolinescanbe rationalizedconsideringan
anchimeric assistance of the primary hydroxyl group. At the
temperature necessary to induce the ATR process, 25 can
undergo an intramolecular 6-exo-trig trans-acylation with the
formation of an easily hydrolysable trifluoroacetyl ester. The
complete transformation of 25 into 26 by simple heating at
60 °C in MeOH confirmed this hypothesis (Scheme 7).
ATR of isoxazolidine 24, having the acetylated
hydroxymethyl group, occurred smoothly and with no
surprises under standard conditions. Protected b3-homo-
proline 27 was obtained in 90 % yield by heating a solution
of protonated 24 at 70 °C for 2 min in a microwave oven
(Scheme 7). The two-step 1,3-DC/ATR sequence allowed
to obtain 27 in 62 % overall yield with control of the
absolute configuration of the two new stereocenters C-2
and C-3.
Conclusions
The two-step sequence 1,3-DC/ATR applied to enantiopure
pyrroline N-oxides easily derived from malic acid was
proved to be a reliable and versatile approach to the
interesting class of C-2-substituted 4-hydroxy-b3-homo-
proline. The two synthesized homoprolines 11 and 27
could be directly inserted in mixed a/b/a tripeptides
showing an acceptable reactivity at both the N- and
C-terminus. The pyrrolidine nitrogen atom turned out to be
particularly sensible to steric hindrance exerted by vicinal
groups especially in the case of 2-cyclopropyl derivatives.
These nitrogen reactivity properties indirectly suggest a
good propensity of 2-cyclopropyl-homoprolines to induce
reverse turns when inserted in peptides, whereas the
2-hydroxymethyl-homoproline can be regarded as a new
non-hydrolysable Pro-Ser mimetic.
OH
OAc
OtBu
tBuO
tBuO
H
OAc
CO2H
27
H
N
OtBu
OtBu
(d)
(b)
(a)
OAc
OAc
NH
20a
(b)
(a)
N
N
H
88%
90%
92%
O
O
N
CO2H
N
H
82%
23
24
H
70%
O
CF3
O
O
CO2Me
OtBu
CF3
(c)
O
CF3
92-94%
OtBu
OtBu
H
TFA 25 : 26[a]
27
28
OH
OH
equiv ratio
OtBu
+
3.6 : 1
3.3 : 1
1.7 : 1
1.1
1.5
2.0
OAc
OAc
NH
CO2H
CO2H
N
O
N
H
(c)
H
H
N
N
26
25
H
CF3
N
H
CbzHN
Ph
54%
H
CO2Me
MeOH, 60 °C
O
CO2Me
O
O
Scheme 7 Synthesis and ATR of isoxazolidines 23 and 24. [a] Deter-
mined by 1H NMR analysis of the crude mixture. Reaction
conditions: (a) DIBAL; (b) Ac2O, DMAP (cat); (c) TFA (1.1, 1.5
or 2 equiv), CH3CN, 70 °C (MW), 5 min; (d) TFA (1.5 equiv),
CH3CN, 70 °C (MW), 2 min
29
30
Scheme 8 Synthesis of the a/b/a tripeptide 30. Reaction conditions:
(a) Val-OMe, EDCI, HOBt, CH2Cl2; (b) NaBH4, MeOH, rt, 1 h;
(d) Cbz-Phe, DIPEA, PyBrop, DMAP, CH3CN
123

Synthesis of 4-hydroxy-b3-homoprolines
773
aq. Na2CO3 solution. The organic solution was dried over
Na2SO4, filtered, and concentrated. Purification of the
residue by chromatography (petroleum ether/AcOEt = 10/
1) afforded 8 (1.088 g, 98 %) as a colorless oil. 8:
The possibility of getting these b-amino acids through
the process described above constitutes an important first
step toward their potential applications in the peptidomi-
metic field and the study of the secondary structure of
amino acid sequences containing them. Studies for the
evaluation of biological and organocatalytic activity of the
synthesized 4-hydroxy-b3-homoprolines and peptides are
in progress.
23
Rf = 0.31 (petroleum ether/AcOEt = 10/1). ½aꢁD = –59.9
(c = 6.8, CHCl3). 1H-NMR (400 MHz): d = 7.38–7.27
(m, 5H, Ar–H), 4.77 (d, J = 11.4 Hz, 1H, CH2Ph), 4.55 (d,
J = 11.4 Hz, 1H, CH2Ph), 4.39 (dd, J = 7.7, 5.2 Hz, 1H,
CHOBn), 4.27–4.10 (m, 4H, CH3CH2O), 2.82 (A part of an
ABX system, J = 16.0, 5.2 Hz, 1H, OCHCHH), 2.76 (B
part of an ABX system, J = 16.0, 7.7 Hz, 1H, OCHCHH),
1.30 (t, J = 7.1 Hz, 3H, CH3) 1.24 (t, J = 7.1 Hz, 3H,
CH3). 13C-NMR (50 MHz): d = 171.3 (s, CO), 169.9.0 (s,
CO), 137.2 (s, Ar), 128.3 (d, 2C, Ar), 128.0 (d, 2C, Ar),
127.8 (d, Ar), 74.6 (d, COCH), 73.0 (t, CH2Ph), 61.2 (t,
CH2CH3), 60.9 (t, CH2CH3), 38.1 (t, COCH2CH), 14.21 (q,
CH3), 14.16 (q, CH3). IR (CDCl3): m = 3,031, 2,984,
1,733, 1,376, 1,275, 1,179, 1,114, 1,028 cm-1. C15H20O5
(280.32): calcd. C 64.27, H 7.19; found C 64.04, H 7.25.
Experimental
General
Chemicals were purchased from Sigma-Aldrich and Alfa
Aesar. BCP was synthesized as previously reported (de
Meijere et al. 2002). Reactions anhydrous conditions were
carried out under an atmosphere of nitrogen and the sol-
vents were appropriately dried before use. Chromato-
graphic purifications were performed on silica gel 60
(0.040–0.063 mm, 230–400 mesh ASTM, Merk) using
flash-column technique; Rf values refer to TLC carried out
on 0.25-mm silica gel plates with the same eluant indicated
for column chromatography unless otherwise stated. All
evaporations were carried out at reduced pressure. NMR
spectra were recorded on Varian GEMINI 200, GEMINI
300, MERCURY 400, and INOVA 400 spectrometers
using CDCl3 solutions, unless otherwise stated, and were
referenced internally to solvent reference frequencies.
(3a0R,40S)-40-(Benzyloxy)tetrahydrodispiro[cyclopropane-
1,20-pyrrolo[1,2-b]isoxazole-30,100-cyclopropane] (10)
A
mixture of nitrone 9 (152 mg, 0.795 mmol) and BCP
(140 mg, 1.75 mmol) in toluene (0.8 mL) was heated at
60 °C in a Sovirel tube for 2 days. The solvent was
evaporated and the crude product was purified by chro-
matography (petroleum ether/AcOEt = 3/1) to give 10
(168 mg, 78 %) as a pale yellow oil. 10: Rf = 0.30
23
(petroleum ether/AcOEt = 3/1). ½aꢁD = ?26.7 (c = 0.8,
1
Assignments were made on the basis of H–1H COSY,
CHCl3). 1H-NMR (400 MHz): d = 7.37–7.27 (m, 5H, Ar–
H), 4.51 (A part of an AB system, J = 11.8 Hz, 1H,
CHHPh), 4.42 (B part of an AB system, J = 11.8 Hz, 1H,
CHHPh), 4.04 (pseudo dt, J = 5.9, 3.0 Hz, 1H, 40-H), 3.56
(d, J = 2.8 Hz, 1H, 3a0-H), 3.46–3.40 (m, 2H, 60-H), 2.25
(dddd, J = 13.3, 8.9, 7.7, 5.9 Hz, 1H, 50-Ha), 1.91 (dddd,
J = 13.3, 5.9, 4.9, 3.2 Hz, 1H, 50-Hb), 0.86–0.68 (m, 4H, c-
Pr), 0.66–0.60 (m, 1H, c-Pr), 0.48–0.37 (m, 1H, c-Pr),
0.25–0.13 (m, 2H, c-Pr) ppm. 13C-NMR (100 MHz):
d = 138.0 (s, Ar), 128.4 (d, 2C, Ar), 127.7 (d, Ar), 127.6
(d, 2C, Ar), 83.8 (d, C-40), 78.4 (d, C-3a0), 71.1 (t, CH2Ph),
66.3 (s, C-20), 56.3 (t, C-60), 30.9 (s, C-30), 30.9 (t; C-50),
11.4 (t, c-Pr), 10.1 (t, c-Pr), 4.63 (t, c-Pr), 4.59 (t, c-Pr)
ppm. IR (CDCl3): m = 3,080, 3,032, 3,002, 2,946, 1,454,
1,357, 1,179, 1,071, 1,027 cm-1. MS (EI): m/z (%) = 271
(1) [M?], 256 (1), 242 (1), 180 (15), 166 (2), 152 (13), 108
(6), 91 (100), 69 (14), 41 (25). C17H21NO2 (271.35): calcd.
C 75.25, H 7.80, N 5.16; found C 75.37, H 8.15, N 4.89.
HMQC, HSQC, and HMBC experiments. Mass spectra:
MS (EI) were recorded on a QP5050 Shimadzu spec-
trometer with a GC (70-eV ionizing voltage); MS (ESI)
were recorded on a LCQ Fleet Ion Trap Mass Spectrometer
with Surveyor Plus LC System (Thermo Scientific) oper-
ating in positive (?ESI) and negative (-ESI) ion mode by
direct infusion of a methanolic solution of the sample.
Melting points (mp) were determined on an electrothermal
apparatus and are not corrected. Polarimetric measure-
ments were taken on a JASCO DIP-370. IR spectra were
recorded with a PerkinElmer Spectrum BX FT-IR System
spectrophotometer. Elemental analyses were performed
with a PerkinElmer 2400 analyzer. Microwave-assisted
reactions were carried out in a CEM DiscoverTM single-
mode microwave reactor with IR temperature sensor using
an irradiation power of 150 W with simultaneous cooling.
Diethyl (2S)-2-(benzyloxy)succinate (8) Triflic acid
(0.415 mL, 4.75 mmol) was added to a mixture of diethyl
malate (753 mg, 3.96 mmol), benzyl trichloroacetimidate
1-[(2R,3S)-3-(Benzyloxy)-1-(trifluoroacetyl)pyrrolidin-2-yl]
cyclopropanecarboxylic acid (11) A mixture of 10
(126 mg, 0.464 mmol) and TFA (55 L, 0.7 mmol) in
CH3CN (11.8 mL) was heated in the microwave reactor at
70 °C for 15 min. The reaction mixture was concentrated
˚
(2.0 g, 7.92 mmol), and 3 A molecular sieves in anhydrous
Et2O (33 mL) under nitrogen atmosphere. The mixture was
stirred for 15 h at rt, filtered, and washed with a saturated
123

774
F. M. Cordero et al.
and purified by chromatography (hexane/Et2O = 1/1) to
give 11 (153 mg, 92 %) as a pale yellow oil. 11: Rf = 0.32
23
J = 11.8 Hz, 1H, OCHHPh), 4.49 (B part of an AB sys-
tem, J = 11.8 Hz, 1H, OCHHPh), 3.92 (pseudo dt,
J = 4.9, 4.3 Hz, 1H, 3-H), 3.12–2.88 (m, 3H, 2-H, 5-Ha, 5-
Hb), 2.34 (br s, NH), 1.96–1.82 (m, 2H, 4-H), 1.40 [s, 9H,
C(CH3)3], 1.20–1.00 (m, 2H, c-Pr), 0.99–0.76 (m, 2H, c-Pr)
ppm. MS (?ESI) m/z = 318.04 [M ? H]?, 340.12
[M ? Na]?}. 0PyBroP (70 mg, 0.150 mmol), DIPEA (26
L, 0.150 mmoli) and DMAP (4.6 mg, 0.038 mmol) were
added to a mixture of 13 (25 mg, 0.075 mmol) and Fmoc-
Val (51 mg, 0.150 mmol) in CH3CN (0.4 mL) cooled at
0 °C. The reaction mixture was stirred at rt for 4 days and
then concentrated. Purification by chromatography (hex-
ane/AcOEt = 7/3) gave 14 (31.5 mg, 66 %) as a white
waxy solid. 14: Rf = 0.2 (hexane/AcOEt = 4/1).
(hexane/Et2O = 1/1). ½aꢁD = ?28.2 (c = 0.8, CHCl3).
1H-NMR (400 MHz): d = 7.38–7.27 (m, 5H, Ar–H), 4.65
(A part of an AB system, J = 12.0 Hz, 1H, CHHPh), 4.59
(B part of an AB system, J = 12.0 Hz, 1H, CHHPh), 4.35–
4.32 (m, 1H, 2-H), 4.29–4.25 (m, 1H, 3-H), 3.96–3.86 (m,
1H, 5-Ha), 3.81–3.73 (m, 1H; 5-Hb), 2.28 (pseudo ddt,
J = 13.3, 5.4, 8.2 Hz, 1H, 4-Ha), 2.10–2.00 (m, 1H, 4-Hb),
1.48 (ddd, J = 9.8; 7.4; 4.5 Hz, 1H, c-Pr), 1.31 (ddd,
J = 9.7; 7.4; 4.5 Hz, 1H, c-Pr), 1.14 (ddd, J = 9.8; 7.4;
4.5 Hz, 1H, c-Pr), 0.96 (ddd, J = 9.7; 7.4; 4.5 Hz, 1H,
c-Pr) ppm. 13C-NMR (100 MHz): d = 179.5 (s, CO2H),
156.8 (q, JCF = 36.7 Hz, COCF3), 137.8 (s, Ar), 128.5 (d,
2C, Ar), 127.8 (d, Ar), 127.6 (d, 2C, Ar), 116.3 (q,
JCF = 288.0 Hz, CF3), 81.0 (d, C-3), 71.0 (t, CH2Ph), 65.7
(d, C-2), 46.3 (tq, JCF = 3.8 Hz, C-5), 31.0 (t, C-4), 23.9
(s, c-Pr), 15.9 (t, c-Pr), 14.7 (t, c-Pr) ppm. 19F-NMR
(188 MHz): d = -77.2 (s, 3F, CF3) ppm. IR (CDCl3):
23
½aꢁD = -6.5 (c = 0.5, CHCl3). Mixture of conformers [A
major, B minor (detectable signals)]: 1H-NMR (400 MHz):
d = 7.80–7.71 (m, 2H, Ar–H), 7.64–7.57 (m, 2H, Ar–H),
7.43–7.35 (m, 2H, Ar–H), 7.35–7.21 (m, 7H, Ar–H), 5.61
(br d, J = 9.1 Hz, NH, A), 4.87 (s, 1H, 2-H, B), 4.73 (A
part of an AB system, J = 12.0 Hz, 2H, OCHHPh, B), 4.65
(B part of an AB system, J = 12.0 Hz, 2H, OCHHPh, B),
4.62 (A part of an AB system, J = 11.8 Hz, 1H, OCHHPh,
A), 4.58 (B part of an AB system, J = 11.8 Hz, 1H,
OCHHPh, A), 4.47–4.11 (m, 5H, 3-H, CH-iPr, OCH2Fmoc,
CHFmoc), 4.33 (br s, 1H, 2-H, A) 3.94–3.83 (m, 1H, 5-Ha,
A), 3.77–3.60 (m, 1H, 5-Hb, A and 5-Ha, B), 3.45–3.36 (m,
1H, 5-Hb, B), 2.35–2.22 (m, 1H, 4-Ha), 2.10–1.93 (m, 2H,
CHMe2, 4-Hb), 1.46 [s, 9H, C(CH3)3, B], 1.40 [s, 9H,
C(CH3)3, A], 1.34–1.19 (m, 2H, c-Pr), 0.99 (d, J = 6.7 Hz,
3H, CH3), 0.90 (d, J = 6.7 Hz, 3H, CH3), 0.95–0.79 (m,
2H, c-Pr, A), 0.77–0.66 (m, 1H, c-Pr, B), 0.46–0.37 (m, 1H,
c-Pr, B) ppm. 13C-NMR (50 MHz): d = 172.3 (s, CO, A),
172.0 (s, CO, B), 171.9 (s, CO, B), 171.8 (s, CO, A), 156.3
(s, OCONH, A), 155.8 (s, OCONH, B), 143.9 (s, Ar), 143.8
(s, Ar), 141.2 (s, 2C, Ar), 138.1 (s, Ar), 128.3 (d, 2C, Ar),
127.5 (d, 5C, Ar), 127.0 (d, 2C, Ar),125.1 (d, 2C, Ar),
119.8 (d, 2C, Ar), 83.0 (d, C-3, B), 81.7 (d, C-3, A), 81.4 (s,
CMe3, B), 80.7 (s, CMe3, A), 70.8 (t, OCH2Ph, A), 70.5 (t,
OCH2Ph, B), 67.0 (t, OCH2Fmoc, A), 66.8 (t, OCH2Fmoc,
B), 64.5 (d, C-2, A), 61.1 (d, C-2, B), 57.5 (d, CH-iPr, B),
57.2 (d, CH-iPr, A), 47.2 (t, C-5, A), 47.0 (d, CHFmoc),
46.0 (t, C-5, B), 32.2 (d, CHMe2, B), 31.6 (d, CHMe2, A),
30.8 (t, C-4), 28.1 [q, 3C, C(CH3)3], 25.7 (s, c-Pr, B), 25.2
(s, c-Pr, A), 19.8 (q, CHCH3), 17.1 (q, CHCH3) 13.8 (t, c-
Pr, A), 13.2 (t, c-Pr, A), 12.2 (t, c-Pr, B), 09.2 (t, c-Pr, B)
ppm. IR (CDCl3): m = 3427, 3068, 2970, 1715, 1643,
1507, 1143 cm-1. MS (?ESI) m/z = 661.39 [M ? Na]?.
C39H46N2O6 (638.79): calcd. C, 73.33; H, 7.26; N, 4.39; O,
15.03; found C, 72.99; H, 7.30; N, 4.08; O, 15.63.
m = 3,067, 2,912, 1,693, 1,454, 1,431, 1,205, 1,152 cm-1
.
MS (?ESI) m/z = 380.2 [M ? Na]?. MS (-ESI)
m/z = 356.3 [M - H]-. C17H8F3NO4 (357.32): calcd. C
57.14, H 5.08, N 3.92; found C 57.41; H 5.17; N 4.23.
tert-Butyl 1-((2R,3S)-3-(benzyloxy)-1-{N-[(9H-fluoren-9-
ylmethoxy)carbonyl]-L-valyl}pyrrolidin-2-yl)cyclopropan-
ecarboxylate (14) A mixture of b-homoproline 11
(100 mg, 0.28 mmol) and HClO4 (60 %, 11 lL, 0.1 mmol)
in AcOtBu (0.56 mL) was stirred at rt for 20 h, cooled at
0 °C, and treated dropwise with a saturated aq. NaHCO3
solution (2.5 mL). After 10 min, the mixture was extracted
with CH2Cl2 (4 9 3 mL). The combined organic phases
were washed with H2O and brine, dried over Na2SO4, fil-
tered, and concentrated. Filtration through silica gel (hex-
ane/Et2O = 15/1) gave tert-butyl ester 12 (31 mg, 27 %)
1
as a yellow oil. {Rf = 0.34 (n-hexane/Et2O = 15/1). H-
NMR (200 MHz): d = 7.39–7.28 (m, 5H, Ar–H), 4.67 (A
part of an AB system, J = 11.8 Hz, 1H, OCHHPh), 4.59
(B part of an AB system, J = 11.8 Hz, 1H, OCHHPh),
4.41 (br s, 1H, 2-H), 4.29–4.22 (m, 1H, 3-H), 4.01–3.68 (m,
2H, 5-H), 2.42–2.20 (m, 1H, 4-Ha), 2.16–1.95 (m, 1H, 4-
Hb), 1.41 [s, 9H, C(CH3)3], 1.38–1.23 (m, 1H, c-Pr), 1.13–
1.00 (m, 1H, c-Pr), 0.99–0.84 (m, 1H, c-Pr), 0.84–0.70 (m,
1H, c-Pr) ppm. MS (?ESI) m/z = 436.16 [M ? Na]?}.
NaBH4 (5.7 mg, 0.15 mmol) was added to a solution of 12
(31 mg, 0.075 mmol) in MeOH (1.5 mL) at 0 °C. The
reaction mixture was stirred at rt for 6 h, treated with wet
Na2SO4, stirred for further 20 min, and then filtered on
CeliteÒ. The solution was dried over Na2SO4, filtered, and
concentrated to give pyrrolidine 13 (25 mg) as a yellow oil
which was used without further purification. {Rf = 0.12
(hexane/Et2O = 1/1). 1H-NMR (200 MHz): d = 7.40–
7.22 (m, 5H, Ar–H), 4.59 (A part of an AB system,
Methyl
pyrrolidin-2-yl]cyclopropyl}carbonyl)-L-valinate (15)
mixture of b-homoproline 11 (65 mg, 0.182 mmol), N-(3-
N-({1-[(2R,3S)-3-(benzyloxy)-1-(trifluoroacetyl)
A
123

Synthesis of 4-hydroxy-b3-homoprolines
775
dimethylaminopropyl)-N’-ethylcarbodiimide hydrochlo-
ride (EDCI, 70 mg, 0.364 mmol), and 1-hydroxybenzotri-
azole (HOBt, 49 mg, 0.364 mmol) in dry CH2Cl2
(0.750 mL) was stirred at 0 °C for 20 min. In a separate
flask, a mixture of Val-OMe HCl (55 mg, 0.328 mmol) and
Et3N (0.037 mL, 0.364 mmol) in CH2Cl2 (0.650 mL) was
stirred for 15 min and then added to the activated
b-homoproline. The reaction mixture was stirred at rt for
23 h and then filtered through a short pad of silica gel
(CH2Cl2/MeOH = 60/1) to give 15 (71 mg, 83 %) as a
yellow oil. 15: Rf = 0.33 (CH2Cl2/MeOH = 60/1). 1H-
NMR (400 MHz): d = 7.37–7.25 (m, 5H, Ar–H), 6.43 (br
d, J = 8.4 Hz, NH), 4.60 (A part of an AB system,
J = 11.7 Hz, 1H, OCHHPh), 4.52 (B part of an AB sys-
tem, J = 11.7 Hz, 1H, OCHHPh), 4.45–4.40 (m, 1H, 3-H),
4.44 (dd, J = 8.4, 4.9 Hz, 1H, CH-iPr), 4.11 (br s, 1H, 2-
H), 3.91–3.82 (m, 1H, 5-Ha), 3.72 (s, 3H, OCH3), 3.79–
3.68 (m, 1H, 5-Hb), 2.27 (pseudo ddt, J = 13.7, 5.2,
8.5 Hz, 1H, 4-Ha), 2.13 (d septet, J = 4.9, 6.9 Hz, 1H,
CHMe2), 2.10–1.99 (m, 1H, 4-Hb), 1.29–1.20 (m, 1H,
c-Pr), 1.10–0.99 (m, 1H, c-Pr), 0.77 (m, 1H, c-Pr), 0.91 (d,
J = 6.9 Hz, 3H, CH3), 0.88 (d, J = 6.9 Hz, 3H, CH3), 0.77
(ddd, J = 9.7; 6.8; 5.3 Hz, 1H, c-Pr) ppm. 13C-NMR
(50 MHz): d = 172.2 (s, CO), 172.0 (s, CO), 156.8 (q,
JCF = 36.8 Hz, COCF3), 137.7 (s, Ar), 128.4 (d, 2C, Ar),
127.8 (d, Ar), 127.7 (d, 2C, Ar), 116.2 (q, JCF = 287.7 Hz,
CF3), 81.6 (d, CH-iPr), 71.2 (t, OCH2Ph), 68.7 (d, C-2),
57.3 (d, C-3), 52.1 (q, OCH3), 46.3 (dt, JCF = 3.6 Hz,
C-5), 30.9 (d, CHMe2), 30.7 (t, C-4), 27.4 (s, c-Pr), 18.8 (q,
CHCH3), 17.7 (q, CHCH3) 13.0 (t, c-Pr), 11.1 (t, c-Pr)
ppm. 19F-NMR (188 MHz): d = -72.3 (s, 3F, CF3) ppm.
IR (CDCl3): m = 3438, 3032 2968, 1738, 1690, 1511,
1438, 1207, 1153 cm-1. MS (?ESI) m/z = 493.3 [M ?
Na]?. MS (-ESI) m/z = 469.5 [M - H]-.
(m, 1H, 4-Ha), 1.94–1.81 (m, 1H, 4-Hb), 1.47 (ddd,
J = 9.5, 6.6, 3.9 Hz, 1H, c-Pr), 0.96 (ddd, J = 9.5, 6.6,
3.7 Hz, 1H, c-Pr), 0.89 (d, J = 7.2 Hz, 3H, CHCH3), 0.87
(d, J = 7.4 Hz, 3H, CHCH3), 0.80 (ddd, J = 9.3, 6.6,
3.9 Hz, 1H, c-Pr), 0.60 (ddd, J = 9.3, 6.6, 3.7 Hz, 1H, c-
Pr), ppm. 13C-NMR (100 MHz): d = 173.6 (s, CO), 172.8
(s, CO), 138.1 (s, Ar), 128.4 (d, 2C, Ar), 127.7 (d, Ar), 127.6
(d, 2C, Ar), 81.7 (d, C-3), 72.0 (t, OCH2Ph), 70.4 (d, C-2),
57.4 (d, CH-iPr), 51.8 (q, OCH3), 44.4 (t, C-5), 31.3 (t, C-4),
30.8 (d, CHMe2), 23.7 (s, c-Pr), 19.4 (q, CHCH3), 18.0 (q,
CHCH3), 15.0 (t, c-Pr), 09.9 (t, c-Pr) ppm. IR (CDCl3):
m = 3,348, 3,174, 3,031, 2,967, 1,738, 1,653, 1,541, 1,437,
1,259, 1,211, 1,095 cm-1. MS (?ESI) m/z = 375.22
[M ? H]?, 397.28 [M ? Na]?. MS (-ESI) m/z = 373.61
[M - H]-.
Methyl N-[(1-{(2R,3S)-3-(benzyloxy)-1-[N-(tert-butoxycar-
bonyl)-L-phenylalanyl]pyrrolidin-2-yl}cyclopropyl)carbon-
yl]-L-valinate (17) Following the same procedure as for
14, tripeptide17 (23 mg, 31 %) wasobtained as a white waxy
solid starting from 16 (46 mg, 0.122 mmol) and Boc-Phe
(49 mg, 0.183 mmol) (reaction time, 5 days). 17: Rf = 0.44
(CH2Cl2/CH3CN = 15/1). Mixture of conformers [A major,
B minor (detectable signals)]: 1H-NMR (400 MHz):
d = 7.37–7.01 (m, 10H, Ar–H), 7.15 (br d, J = 7.6 Hz, Val-
NHCO, A), 7.09 (br d, J = 7.3 Hz, Val-NHCO, B), 5.31 (br
d, J = 9.5 Hz, Phe-NHCO, B), 5.26 (br d, J = 8.8 Hz, Phe-
NHCO, A), 4.91–4.81 (m, 1H, CHCH2Ph, B), 4.80–4.70 (m,
1H, CHCH2Ph, A), 4.67 (br s, 1H, 2-H, A), 4.59 (d,
J = 11.7 Hz, 1H, OCHHPh), 4.53–4.32 (m, 2HA ? 3HB,
OCHHPh, CH-iPr, A ? B and 3-H, B), 4.22 (br s, 1H, 2-H,
B), 4.15–4.08 (m, 1H, 3-H, A), 3.86–3.76 (m, 1H, 5-Ha, A),
3.73 (s, 3H, OCH3, B), 3.69 (s, 3H, OCH3, A), 3.69–3.59 (m,
1H, 5-Ha, B), 3.38–3.27 (m, 1H, 5-Hb, B), 3.24–3.13 (m, 1H,
5-Hb, A), 3.05–2.80 (m, 2H, CHCH2Ph), 2.19–1.83 (m, 3H,
CHMe2, 4-H), 1.38[s, 9H, C(CH3)3, A], 1.35[s, 9H, C(CH3)3,
B], 1.19–1.08 (m, 1H, c-Pr, A), 0.92 (d, J = 6.8 Hz, 3H,
CH3), 0.91 (d, J = 6.8 Hz, 3H, CH3), 0.80–0.73 (m, 1H, c-Pr,
A), 0.58–0.46 (m, 1H, c-Pr, B), 0.46–0.28 (m, 2H, c-Pr, A)
ppm. 13C-NMR (100 MHz): d = 172.9 (s, C = O), 172.5 (s,
C = O), 172.2 (s, C = O), 154.9 (s, OCONH), 138.0 (s, Ar),
136.4 (s, Ar), 129.4 (d, 2C, Ar), 128.5 (d, 2C, Ar), 128.3 (d,
2C, Ar), 127.7 (d, Ar), 127.6 (d, 2C, Ar), 126.9 (d, 1C, Ar),
83.5 (d, C-3, B), 81.9 (d, C-3, A), 79.7 (s, CMe3), 70.7 (t,
OCH2Ph), 60.0 (d, C-2), 57.6 (d, CH-iPr), 53.1 (d,
CHCH2Ph), 52.0 (q, OCH3), 46.4 (t, C-5, A), 45.6 (t, C-5, B),
39.9 (t, OCH2Ph), 30.9 (d, CHMe2), 30.5 (t, C-4), 28.3 [q, 3C,
C(CH3)3], 27.3 (s, c-Pr), 19.0 (q, CHCH3), 18.0 (q, CHCH3),
12.5 (t, c-Pr, A), 10.1(t, c-Pr, A), 09.8(t, c-Pr, B), 08.7(t, c-Pr,
B) ppm. IR (CDCl3): m = 3,435, 3,318, 3,031, 2,970, 1,739,
1,703, 1,647, 1,498, 1,437, 1,368, 1,166 cm-1. MS (?ESI)
m/z = 644.32 [M ? Na]?. MS (-ESI) m/z = 620.55
[M - H]-.
Methyl N-({1-[(2R,3S)-3-(benzyloxy)pyrrolidin-2-yl]cyclo-
propyl}carbonyl)-L-valinate
(16) NaBH4
(10.5 mg,
0.276 mmol) was added at 0 °C to a solution of dipeptide
15 (65 mg, 0.138 mmol) in MeOH (2.8 mL). The reaction
mixture was stirred at rt for 1.5 h, treated with wet Na2SO4,
stirred for further 20 min, and then filtered on CeliteÒ. The
solution was dried over Na2SO4, filtered, and concentrated
to give 16 (47 mg, 82 %) as a yellow oil which was used in
the next step without further purification. 16: Rf = 0.47
1
(CH2Cl2/MeOH = 25/1). H-NMR (400 MHz): d = 9.77
(br d, J = 8.2 Hz, NHCO), 7.37–7.23 (m, 5H, Ar–H), 4.54
(A part of an AB system, J = 11.6 Hz, 1H, OCHHPh),
4.47 (dd, J = 8.2, 4.6 Hz, 1H, CH-iPr), 4.46 (B part of an
AB system, J = 11.6 Hz, 1H, OCHHPh), 4.06 (ddd,
J = 7.8, 5.7, 3.0 Hz, 1H, 3-H), 3.69 (s, 3H, CH3O), 3.15
(pseudo dt, J = 2.3, 9.5 Hz, 1H, 5-Ha), 3.01 (pseudo dt,
J = 7.6, 9.5 Hz, 1H, 5-Hb), 2.57 (d, J = 5.7 Hz, 1H, 2-H),
2.12 (dqq, J = 4.6, 7.4, 7.2 Hz, 1H, CHMe2), 2.08–1.96
123

776
F. M. Cordero et al.
Ethyl [(2R,3S)-3-tert-butoxy-1-(trifluoroacetyl)pyrrolidin-
2-yl]acetate (22)
68 (23), 57 (100). C13H23NO3 (241.33): calcd. C 64.70, H
9.61, N 5.80; found C 64.98, H 9.66, N 5.68.
A
mixture of 20a (50.4 mg,
0.178 mmol) and TFA (21 lL, 0.27 mmol) in CH3CN
(5.9 mL) was heated at 80 °C for 1.5 h. The reaction
mixture was concentrated and purified by chromatography
(CH2Cl2/MeOH = 20/1) to give 22 (15 mg, 26 %). 22:
Rf = 0.22 (AcOEt). 1H-NMR (400 MHz): d = 4.15 (q,
J = 7.1 Hz, 2H, CH2Me), 3.88 (pseudo q, J = 6.4 Hz, 1H,
3-H), 3.39 (ddd, J = 8.7, 6.4, 4.5 Hz, 1H, 2-H), 3.33–3.18
(m, 2H, 5-H), 2.74 (A part of an ABX system, J = 16.7,
4.5 Hz, 1H, 6-Ha), 2.67 (B part of an ABX system,
J = 16.7, 8.7 Hz, 1H, 6-Hb), 2.19–2.10 (m, 1H, 4-Ha),
1.82–1.73 (m, 1H, 4-Hb), 1.26 (t, J = 7.1 Hz, 3H,
CH2CH3), 1.18 [s, 9H, C(CH3)3] ppm. IR (CDCl3):
m = 2,978, 2,934, 1,728, 1,681, 1,392, 1,367, 1,192,
[(30S,3a0R,40S)-40-tert-Butoxytetrahydro-30H-spiro[cyclo-
propane-1,20-pyrrolo[1,2-b]isoxazol]-30-yl]methyl ace-
tate (24) Acetic anhydride (3.4 mL, 38.5 mmol) was
added to a solution of crude isoxazolidine 23 (470 mg) and
a catalytic amount of DMAP in pyridine (9.5 mL) under
nitrogen atmosphere at 0 °C. The reaction mixture was
stirred at rt overnight, treated with MeOH (5 mL) at 0 °C
for 30 min, and then concentrated. The crude product was
dissolved in CH2Cl2 (10 mL) and washed with 5 % aq.
NaHCO3 solution (10 mL). The aqueous solution was
extracted with CH2Cl2 (3 9 15 mL) and the combined
organic phases were dried over Na2SO4, filtered, and
concentrated. Purification by chromatography (Et2O/hex-
ane = 4/1) gave 24 (486 mg, 88 %) as colorless oil. 24:
1,145 cm-1
.
[(30S,3a0R,40S)-40-tert-Butoxytetrahydro-30H-spiro[cyclo-
propane-1,20-pyrrolo[1,2-b]isoxazol]-30-yl]methanol
(23) A 1 M solution of DIBAL-H in hexane (3.2 mL,
3.2 mmol) was added dropwise to a solution of the adduct
20a (261 mg, 0.92 mmol) in CH2Cl2 (3.1 mL) under
nitrogen atmosphere at 0 °C. The reaction mixture was
stirred at 0 °C for 1 h and then treated in sequence with
MeOH and a saturated aq. sodium and potassium tartrate
solution. The aqueous phase was extracted with CH2Cl2
and the organic extracts were dried over Na2SO4. Evapo-
ration of the solvent and purification by chromatography
gave crude 23 (222 mg) which was used in the next step
without further purification. Purification of a small amount
of the crude compound (50 mg) by chromatography (Et2O/
petroleum ether = 10/1) afforded analytically pure 23
(46 mg, 92 %) as a white solid. 23: Rf = 0.30 (Et2O/
23
Rf = 0.30 (Et2O/n-hexane = 4/1). ½aꢁD = -20.5 (c = 0.8,
1
CHCl3). H-NMR (400 MHz): d = 4.26–4.21 (m, 1H, 40-
H), 4.23 (dd, J = 11.3, 6.7 Hz, 1H, CHH-OAc), 4.06 (dd,
J = 11.3, 7.6 Hz, 1H, CHH-OAc), 3.77 (dd, J = 8.0,
4.2 Hz, 1H, 3a0-H), 3.38–3.23 (m, 2H, 60-H), 3.10 (pseudo
q, J = 7.5 Hz, 1H, 30-H), 2.18 (dddd, J = 12.8, 9.0, 7.4,
6.4 Hz, 1H, 50-Ha), 2.05 (s, 3H, CH3C = O), 1.73 (dddd,
J = 12.8, 6.9, 4.5, 3.8 Hz, 1H, 50-Hb), 1.20 [s, 9H,
C(CH3)3], 0.97–0.91 (m, 1H, c-Pr), 0.82–0.77 (m, 2H,
c-Pr), 0.59–0.53 (m, 1H, c-Pr) ppm. 13C-NMR (50 MHz):
d = 170.5 (s, COMe), 76.2 (d, C-3a0), 73.9 (s, CMe3), 72.2
(d, C-40), 64.0 (s, C-20), 62.7 (t, CH2-OAc), 55.2 (t, C-60),
45.7 (d, C-30), 34.6 (t, C-50), 28.6 [q, 3C, C(CH3)3], 20.8 (q,
COCH3), 9.3 (t, c-Pr), 6.8 (t, c-Pr) ppm. IR (CDCl3):
m = 2,979, 1,738, 1,366, 1,243, 1,235, 1,217, 1,214, 1,210,
1,036 cm-1. MS (EI): m/z (%) = 283 (0.8) [M?], 226 (1),
210 (0.3), 198 (0.3), 166 (18), 156 (7), 112 (16), 110 (10),
82 (10), 68 (20), 57 (100). C15H25NO4 (283.36): calcd. C
63.58, H 8.89, N 4.94; found C 63.21, H 8.82, N 4.62.
24
petroleum ether = 10/1). ½aꢁD ¼ ꢂ47:3 (c = 0.6, CHCl3).
mp 80–81 °C. 1H-NMR (400 MHz): d = 4.52 (q,
J = 7.2 Hz, 1H, 40-H), 3.82 (pseudo dt, J = 2.0, 10.6 Hz,
1H, CHH-OH), 3.72 (t, J = 7.4 Hz, 1H, 3a0-H), 3.49 (ddd,
J = 13.7, 8.9, 4.9 Hz, 1H, 60-Ha), 3.46 (pseudo dt, J = 5.5,
10.4 Hz, 1H, CHH-OH), 3.24 (dt, J = 13.7, 7.6 Hz, 1H, 60-
Hb), 3.19 (ddd, J = 10.4, 7.4, 5.5 Hz, 1H, 30-H), 2.86 (dd,
J = 10.4, 2.4 Hz, 1H, OH), 2.32 (dddd, J = 12.5, 7.6, 7.2,
4.9, 1H, 50-Ha), 1.78 (ddt, J = 12.5, 8.9, 7.6 Hz, 1H, 50-
Hb), 1.27 [s, 9H, C(CH3)3], 0.92 (ddd, J = 11.4, 6.7,
5.5 Hz, 1 H, c-Pr), 0.77 (ddd, J = 11.4, 7.2, 6.1 Hz, 1H, c-
Pr), 0.70–0.64 (m, 1 H; c-Pr), 0.48 (ddd, J = 10.5, 7.2,
5.5 Hz, 1H, c-Pr) ppm. 13C-NMR (50 MHz): d = 75.2 (d,
C-3a0), 75.0 (s, CMe3), 72.6 (d, C-40), 62.7 (s, C-20), 60.8 (t,
CH2OH), 54.7 (t, C-60), 48.9 (d, C-30), 34.0 (t, C-50), 28.7
[q, 3C, C(CH3)3], 9.2 (t, c-Pr), 6.9 (t, c-Pr) ppm. IR (KBr):
m = 3,158, 2,968, 2,930, 1,367, 1,358, 1,196, 1,172, 1,062,
1,035, 1,021, 805 cm-1. MS (EI): m/z (%) = 241 (2.4)
[M?], 184 (4), 154 (9), 126 (11), 112 (17), 98 (9), 82 (12),
(2S)-2-[(2R,3S)-3-tert-Butoxy-1-(trifluoroacetyl)pyrroli-
din-2-yl]-3-hydroxypropanoic acid (25) and (2S)-2-
[(2R,3S)-3-tert-butoxypyrrolidin-2-yl]-3-hydroxypropanoic
acid (26) A mixture of 23 (31 mg, 0.128 mmol) and TFA
(15 lL, 0.26 mmol) in CH3CN (4.3 mL) was heated in the
microwave reactor at 70 °C for 5 min. The reaction mix-
ture was concentrated and purified by chromatography
(AcOEt/MeOH from 10/1 to 5/1) to give 25 (23.3 mg,
56 %) and 26 (11.4 mg, 38 %). 25: Rf = 0.30 (AcOEt/
MeOH = 10/1). 1H-NMR (400 MHz, CD3OD): d = 4.33–
4.29 (m, 2H, 2-H, 3-H), 3.87–3.70 (m, 3H, 7-Ha, 5-H), 3.65
(dd, J = 11.0, 4.7 Hz, 1H, 7-Hb), 2.78–2.73 (m, 1H, 6-H),
2.30 (ddt, J = 13.6, 4.5, 9.5 Hz, 1H, 4-Ha), 1.98–1.90 (m,
1H, 4-Hb), 1.21 [s, 9H, C(CH3)3] ppm. 13C-NMR (50 MHz,
CD3OD): d = 176.1 (s, CO2H), 158.3 (q, JCF = 36.4 Hz,
COCF3), 117.7 (q, JCF = 285.0 Hz, CF3), 76.0 (s, CMe3),
123

Synthesis of 4-hydroxy-b3-homoprolines
777
73.1 (d, C-3), 67.5 (d, C-2), 62.2 (t, C-7), 49.0 (d, C-6),
46.2 (q, JCF = 4.6 Hz, C-5), 33.4 (t, C-4), 28.7 [q, 3C,
C(CH3)3] ppm. 19F-NMR (188 MHz, CD3OD): d =
-76.9 ppm. MS (EI): m/z (%) = 327 (0.2) [M?], 271 (4),
253 (10), 236 (11), 218 (5), 202 (3), 182 (11), 178 (7), 166
(10), 140 (5), 126 (5), 96 (6), 69 (21), 57 (100). 26:
Rf = 0.19 (AcOEt/MeOH = 10/1). 1H-NMR (400 MHz,
CD3OD): d = 4.34 (pseudo dt, J = 5.6, 3.6 Hz, 1H, 3-H),
4.00 (A part of an ABX system, J = 11.0, 4.7 Hz, 1H, 7-
Ha), 3.91 (B part of an ABX system, J = 11.0, 6.9 Hz, 1H,
7-Hb), 3.72 (dd, J = 5.6, 4.1 1H, 2-H), 3.42–3.29 (m, 2H,
5-H), 2.63–2.55 (m, 1H; 6-H), 2.20 (pseudo ddt, J = 13.7,
5.6, 8.3 Hz, 1H, 4-Ha), 1.96–1.83 (m, 1H, 4-Hb), 1.22 [s,
9H, C(CH3)3] ppm. 13C-NMR (200 MHz, CD3OD):
d = 177.6 (s, CO2H), 76.2 (s, CMe3), 73.4 (d, C-3), 68.2
(d, C-2), 62.8 (t, C-7), 49.0 (d, C-6), 44.7 (t, C-5), 34.3 (t,
C-4), 28.9 [s, 3C, C(CH3)3] ppm. MS (?ESI) m/z = 254.12
[M ? Na]?. MS (-ESI) m/z = 230.27 [M - H]-.
Methyl
N-{(2S)-3-(acetyloxy)-2-[(2R,3S)-3-tert-butoxy-
1-(trifluoroacetyl)pyrrolidin-2-yl]propanoyl}-L-valinate
(28) Following the same procedure as for 15, dipeptide
28 (60 mg, 70 %) was obtained as a white waxy solid
starting from b-homoproline 27 (60 mg, 0.162 mmol). 28:
Rf = 0.48 (CH2Cl2/MeOH = 5/1). 1H-NMR (400 MHz):
d = 6.30 (br d, J = 8,6 Hz, NH), 4.62–4.57 (m, 1H, 3-H),
4.46 (dd, J = 8.6, 4.9 Hz, 1H, CH-iPr), 4.36 (dd, J = 11.1,
9.0 Hz, 1H 7-Ha), 4.24 (dd, J = 11.1, 5.6 Hz, 1H, 7-Hb),
4.17 (dd, J = 5.6, 2.6 Hz, 1H, 2-H), 3.87–3.78 (m, 1H, 5-
Ha), 3.72 (s, 3H, OCH3), 3.59 (ddd, J = 10.6, 7.9, 5.6 Hz,
1H, 5-Hb), 3.38 (pseudo dt, J = 9.0, 5.6 Hz, 1H, 6-H), 2.04
(s, 3H, CH3C = O) 2.19 (pseudo ddt, J = 13.0, 5.1,
7.9 Hz, 1H, 4-Ha), 2.11 (dseptet, J = 5.0, 6.9 Hz, 1H,
CHMe2), 1.87–1.77 (m, 1H, 4-Hb), 1.19 [s, 9H, C(CH3)3],
0.90 (d, J = 6.9 Hz, 3H, CH3), 0.87 (d, J = 6.9 Hz, 3H,
CH3) ppm. 13C-NMR (50 MHz): d = 171.7 (s, CO2Me),
170.7 (s, CONH), 170.4 (s, CH3CO), 156.3 (q,
JCF = 36.8 Hz, COCF3), 116.1 (q, JCF = 287.4 Hz, CF3),
74.8 (s, CMe3), 70.8 (d, C-3), 66.2 (d, C-2), 63.0 (t, C-7),
57.4 (d, CH-iPr), 52.2 (q, OCH3), 46.4 (d, C-6), 46.0 (dt,
JCF = 3.4 Hz, C-5), 33.5 (t, C-4), 30.9 (d, CHMe2), 28.5
[q, 3C, C(CH3)3], 20.7 (q, CH3CO), 18.8 (q, CHCH3), 17.7
(q, CHCH3) ppm. 19F-NMR (188 MHz): d = -72.1 (s, 3F,
CF3) ppm. IR (CDCl3): m = 3,420, 2,973, 1,740, 1,687,
1,511, 1,438, 1,365, 1,245, 1,206, 1,152 cm-1. MS (EI):
m/z (%) = 483 (0.4) [M?], 125 (11), 111 (19), 97 (33), 71
(50), 57 (100), 43 (95), 41 (46). MS (?ESI) m/z = 483.1
[M ? H]?.
(2S)-3-(Acetyloxy)-2-[(2R,3S)-3-tert-butoxy-1-(trifluoroace-
tyl)pyrrolidin-2-yl]propanoic acid (27) A mixture of 24
(79 mg, 0.279 mmol) and TFA (32 lL, 0.42 mmol) in
CH3CN (9.2 mL) was heated in the microwave reactor at
70 °C for 2 min. The reaction mixture was concentrated and
purified by chromatography (CH2Cl2/MeOH = 20/1) to
give 27 (92.2 mg, 90 %). 27: Rf = 0.29 (CH2Cl2/MeOH =
23
20/1). ½aꢁD = -10.6 (c = 0.8, CHCl3). 1H-NMR
(400 MHz, CD3OD): d = 4.36–4.31 (m, 2H, 2-H, 3-H), 4.35
(dd, J = 11.2, 8.0 Hz, 1H, 7-Ha), 4.15 (dd, J = 11.2, 5.9 Hz,
1H, 7-Hb), 3.89–3.81 (m, 1H, 5-Ha), 3.78–3.69 (m, 1H, 5-
Hb), 3.03 (pseudo dt, J = 5.9, 8.0 Hz, 1H, 6-H), 2.29
(pseudo ddt, J = 13.6, 4.7, 9.2 Hz, 1H, 4-Ha), 2.01 (s, 3H,
COCH3), 1.99–1.92 (m, 1H, 4-Hb), 1.21 [s, 9H, C(CH3)3]
ppm. 1H-NMR (400 MHz): d = 4.42 (dd, J = 11.3, 7.9 Hz,
1H, 7-Ha), 4.37–4.32 (m, 1H, 2-H), 4.24–4.21 (m, 1H, 3-H),
4.19 (dd, J = 11.3, 6.2 Hz, 1H, 7-Hb), 3.91–3.82 (m, 1H; 5-
Ha), 3.67 (ddd, J = 10.5, 8.8, 4.6 Hz, 1H, 5-Hb), 3.24–3.19
(m, 1H, 6-H), 2.23–2.14 (m, 1H, 4-Ha), 2.05 (s, 3H, COCH3),
1.96–1.87 (m, 1H, 4-Hb), 1.19 [s, 9H, C(CH3)3] ppm. 13C-
NMR (50 MHz): d = 175.0 (s, CO2H), 170.6 (s, COCH3),
156.4 (q, JCF = 37.0 Hz, COCF3), 116.1 (q,
JCF = 287.5 Hz, CF3), 74.9 (s, CMe3), 71.3 (d, C-3), 65.6 (d,
C-2), 62.0 (t, C-7), 45.5 (q, JCF = 3.7 Hz, C-5), 45.4 (t, C-6),
33.0 (t, C-4), 28.3 [q, 3C, C(CH3)3], 20.7(q, COCH3) ppm.
19F-NMR (188 MHz, CD3OD): d = -73.7 ppm. IR
(CDCl3): m = 3,492, 2,977, 2,935, 1,741, 1,714, 1,689,
1,449, 1,392, 1,366, 1,243, 1,154 cm-1. MS (EI): m/z
(%) = 314 (0.9), 295 (1), 254 (10), 235 (21), 218 (15), 203
(11), 184 (7), 175 (7), 161 (15), 57 (100). MS (?ESI)
m/z = 392.25 [M ? Na]?. MS (-ESI) m/z = 368.21 [M -
H]-. C15H22F3NO6 (369.33): calcd. C 48.78, H 6.00, N 3.79;
found C 49.12, H 6.33, N 3.73.
Methyl N-{(2S)-3-(acetyloxy)-2-[(2R,3S)-3-tert-butoxypyrr-
olidin-2-yl]propanoyl}-L-valinate (29) NaBH4 (11.2 mg,
0.295 mmol) was added to a solution of 28 (71.2 mg,
0.147 mmol), in MeOH (2.9 mL) at 0 °C. The reaction
mixture was stirred at rt for 1 h, concentrated, cooled at 0 °C,
diluted with H2O (5 mL), and extracted with AcOEt
(4 9 5 mL). The combined organic phases were washed
with brine, dried over Na2SO4, filtered, and concentrated.
Filtration through a short pad of silica gel (AcOEt) afforded
29 (47 mg, 82 %) as a waxy solid. 29: Rf = 0.32 (AcOEt).
1H-NMR (400 MHz): d = 8.34 (br d, J = 9.0 Hz, NHCO),
5.85–5.74 (m, 1H, NH), 4.55 (dd, J = 9.0, 5.5 Hz, 1H, CH-
iPr), 4.41 (d, J = 3.9 Hz, 1H, 3-H), 4.20 (d, J = 11.8 Hz,
1H, 2-H), 3.78–3.61 (m, 2H, 7-Ha, 5-Ha), 3.68 (s, 3H, CH3O),
3.55 (dm, J = 12.7 Hz, 1H, 7-Hb), 3.45 (pseudo t,
J = 9.6 Hz, 1H, 5-Hb), 2.29–2.08 (m, 2H, 4-Ha, CHMe2),
2.15 (s, 3H, CH3C = O), 1.95–1.81 (m, 2H, 6-H, 4-Hb), 1.08
[s, 9H, C(CH3)3], 0.94 (d, J = 7.0 Hz, 3H, CHCH3), 0.93 (d,
J = 7.09 Hz, 3H, CHCH3) ppm. 13C-NMR (50 MHz):
d = 173.0 (s, COMe), 172.5 (s, CONH), 171.6 (s, CO2Me),
74.5 (s, CMe3), 72.0 (d, C-3), 63.8 (d, C-2), 58.9 (t, C-7), 57.0
(d, CH-iPr), 51.9 (q, OCH3), 51.5 (d, C-6), 46.8 (t, C-5), 31.8
123

778
F. M. Cordero et al.
Aguilar M-I, Purcell AW, Devi R, Lew R, Rossjohn J, Smith AI,
Perlmutter P (2007) b-Amino acid-containing hybrid peptides—
new opportunities in peptidomimetics. Org Biomol Chem
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poulou C (2007) Asymmetric nitrone cycloadditions and their
application to the synthesis of enantiopure pyrrolidine and
pyrrolizidine derivatives. Tetrahedron 63:321–330
(t, C-4), 31.6 (d, CHMe2), 28.1 [q, 3C, C(CH3)3], 22.5 (q,
COCH3), 19.1 (q, CHCH3), 17.8 (q, CHCH3) ppm. IR
(CDCl3): m = 3,309, 2,969, 2,891, 1,741, 1,659, 1,619,
1,534, 1,462, 1,437, 1,392, 1,366, 1,259, 1,205, 1,190,
1,096 cm-1. MS (?ESI) m/z = 387.21 [M ? H]?, 409.45
[M ? Na]?.
Methyl N-[(2S)-3-(acetyloxy)-2-((2R,3S)-1-{N-[(benzyloxy)
carbonyl]phenylalanyl}-3-tert-butoxypyrrolidin-2-yl)prop-
anoyl]-L-valinate (30) Following the same procedure as for
14, tripeptide 30 (39 mg, 54 %) was obtained as a white
waxy solid starting from 29 (42 mg, 0.109 mmol) and N-
Cbz-Phe (49 mg, 0.163 mmol) (reaction time: overnight).
´
´
Balaspiri L, Penke B, Papp Gy, Dombi Gy, Kovacs K (1975) Rationelle
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23
30: Rf = 0.32 (CH2Cl2/CH3CN = 2/1). ½aꢁD = -13.9
Berisio R, Vitagliano L, Mazzarella L, Zagari A (2002) Crystal
structure of the collagen triple helix model [(Pro–Pro–Gly)10]3.
Protein Sci 11:262–270
1
(c = 0.74, CHCl3). H-NMR (400 MHz): d = 7.37–7.18
(m, 10H, Ar–H), 7.13–7.07 (m, 2H, Ar–H), 6.82 (br d,
J = 8.7 Hz, Val-NHCO), 5.32 (br d, J = 8.2 Hz, Phe-
NHCO), 5.07 (A part of an AB system, J = 12.3 Hz, 1H,
OCHHPh), 5.03 (B part of an AB system, J = 12.3 Hz, 1H,
OCHHPh), 4.68–4.59 (m, 1H, CHCH2Ph), 4.45 (dd, J = 8.7,
5.3 Hz, 1H, CH-iPr), 4.39 (dd, J = 10.7, 4.7 Hz, 1H, 7-Ha),
4.36–4.27 (m, 2H, 3-H, 7-Hb) 4.13 (d, J = 5.5 Hz, 1H 2-H),
3.65–3.51 (m, 1H, 5-Ha), 3.55 (s, 3H, CH3O), 3.45–3.33 (m,
1H, 5-Hb), 3.24–3.15 (m, 1H, 6-H), 3.19 (X part of an AXY
system, J = 13.8, 5.3 Hz, 1H, CHCHHPh), 3.00 (Y part of
an AXY system, J = 13.8, 6.8 Hz, 1H, CHCHHPh),
2.20–2.02 (m, 2H, 4-Ha, CHMe2), 2.07 (s, 3H, CH3C = O),
1.84–1.71 (m, 1H, 4-Hb), 1.73 [s, 9H, C(CH3)3], 0.93 (d,
J = 6.8 Hz, 3H, CHCH3), 0.93 (d, J = 6.8 Hz, 3H, CHCH3)
ppm. 13C-NMR (100 MHz): d = 172.1 (s, CO2Me), 171.7
(s, Val-CONH), 171.1 (s, Phe-CONH), 170.9 (s, COMe),
155.8 (s, OCONH) 136.2 (s, Ar), 135.7 (s, Ar), 129.3 (d, 2C,
Ar), 128.6 (d, 2C, Ar), 128.4 (d, 2C, Ar), 128.1 (d, 2C, Ar),
128.0 (d, 2C, Ar), 127.0 (d, 2C, Ar), 74.6 (s, CMe3), 72.6 (d,
C-3), 66.9 (t, CHCH2Ph), 64.4 (d, C-2), 64.4 (t, C-7), 57.4 (d,
CH-iPr), 54.9 (d, CHCH2Ph), 52.0 (q, OCH3), 48.4 (d, C-6),
46.7 (t, C-5), 37.7 (t, OCH2Ph), 32.8 (t, C-4), 30.5 (d,
CHMe2), 28.4 [q, 3C, C(CH3)3], 22.7 (q, COCH3), 19.1 (q,
CHCH3), 17.9 (q, CHCH3) ppm. IR (CDCl3): m = 3,427,
3,065, 3,032, 2,969, 2,935, 1,738, 1,720, 1,674, 1,633, 1,509,
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1,437, 1,417, 1,391, 1,347, 1,256, 1,193, 1,081, 1,057, cm-1
.
MS (?ESI) m/z = 690.46 [M ? Na]?. C36H49N3O9
(667.79): calcd. C, 64.75; H, 7.40; N, 6.29; O, 21.56; found
C, 64.48; H, 7.03; N, 6.31; O, 22.63.
Acknowledgments Authors thank Ministry of University and
support
Research (MIUR
(PRIN2008BRXNTY).
Rome-Italy)
for
financial
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