Chemoselective synthesis of N-protected alkoxyprolines under specific solvation conditions

Article abstract of DOI:10.1002/ejoc.201402429

N-Protected hydroxyprolines (Hyp) were transformed chemoselectively into alkoxyproline derivatives by direct O-alkylation. The starting Hyp was transformed into the corresponding dianion in a mixture of dimethyl sulfoxide and tetrahydrofuran (1:16 v/v) as solvent. Under these conditions, the carboxy-anion showed reduced nucleophilicity because it was specifically solvated, and the more reactive oxy-anion was selectively alkylated. N-Protected trans-4-alkoxy-, cis-4-alkoxy- and trans-3-alkoxyprolines were thus obtained in a single step in very high overall yields and with complete stability of the stereogenic center configuration. Copyright

Full text of DOI:10.1002/ejoc.201402429

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FULL PAPER
DOI: 10.1002/ejoc.201402429
Chemoselective Synthesis of N-Protected Alkoxyprolines under Specific
Solvation Conditions
Voichita Mihali,[a][‡] Francesca Foschi,[a] Michele Penso,*[a] and Gianluca Pozzi*[a]
Keywords: Synthetic methods / Alkylation / Chemoselectivity / Amino acids / Solvent effects / Ion pairs
N-Protected hydroxyprolines (Hyp) were transformed
chemoselectively into alkoxyproline derivatives by direct O-
it was specifically solvated, and the more reactive oxy-anion
was selectively alkylated. N-Protected trans-4-alkoxy-, cis-4-
alkylation. The starting Hyp was transformed into the corre- alkoxy- and trans-3-alkoxyprolines were thus obtained in a
sponding dianion in a mixture of dimethyl sulfoxide and
tetrahydrofuran (1:16 v/v) as solvent. Under these conditions,
the carboxy-anion showed reduced nucleophilicity because
single step in very high overall yields and with complete sta-
bility of the stereogenic center configuration.
sulfoxide (DMSO), diglyme, etc.), which specifically sol-
vated the cation-oxido-anion ion pair, decreasing its nucleo-
philicity,[8] thus increasing the N-chemoselectivity of the re-
action.
Introduction
Chemoselectivity[1] is still a formidable challenge in cur-
rent organic synthesis, even though several strategies for the
selective transformation of molecules containing different
nucleophilic groups of similar reactivity has been made
available in the last years.[2] These strategies can be summa-
rized in three broad categories: (a) Protection of one spe-
cific functional group, (b) simultaneous transformation of
all reactive centers, then restoration of one of the centers,
or (c) activation of the target group and/or deactivation of
groups that should remain unaltered.[2a] Previously, we ap-
plied the activation/deactivation approach to the N-alkyl-
ation of substrates that contain nucleophilic N,O-centers
such as 2-hydroxycarbazole,[3] tyrosine,[4,5] serine and
threonine (2-nitrobenzene)sulfonamido esters.[6] Under the
reaction conditions applied, both functions were deproton-
ated by an inorganic base, with formation of the corre-
sponding dianion. Following the empirical principle that
“the anion derived from the weaker acid is the stronger nu-
cleophile”,[3,7] the aza-anion was expected to preferentially
react with the alkylating agent; actually, in most cases, a
complex mixture of N-mono-, O-mono-, and N,O-bis-alkyl-
ated products was formed. The chemoselectivity of the pro-
cess was increased by carrying out the reactions in the pres-
ence of a coordinating non-hydrogen-bond donor (non-
HBD) solvent (N,N-dimethylformamide (DMF), dimethyl
Proline and proline chimeras have peculiar dynamic and
structural roles in protein folding[9] due to their ability to
stabilize peptide secondary structures such as β-turns or
polyproline helices. Furthermore, proline derivatives and
peptides have been widely used as catalysts in stereoselective
organic synthesis.[10] In this context, 3- and 4-hydroxypro-
lines (3-Hyp, 4-Hyp) hold a prominent role in view of their
distinctive catalytic features[10d,11] and because they can be
converted into more sophisticated molecules by transforma-
tion of the hydroxy function. Procedures of O-alkylation
and O-acylation lead not only to catalytic active proline
ethers[12] and esters,[13] respectively, but also to starting
materials for the preparation of pyrrolidinyl PNA,[14] to
proline-containing polymers,[15] dendrimers,[16] silica-
grafted prolines,[17] and O-glycosylated-Hyp,[18] with the lat-
ter compounds being major structural components of sev-
eral plant glycoproteins.[19]
Despite the clear interest aroused by modified Hyp, it
appears that the selective O-alkylation of the hydroxy func-
tion of such compounds is not trivial. The most general
approaches rely on the treatment of N-protected Hyp with
a large excess of alkylating agent in the presence of a strong
inorganic base, typically NaH, in the aprotic dipolar
DMF.[20] Under these conditions, an alkoxyproline ester is
formed, which is isolated and then hydrolyzed to give the
desired product. Unfortunately, this lengthy, two-step pro-
cedure often leads to low final yields. Some authors have
reported examples of selective O-alkylation of N-protected
3-Hyp by using NaH in tetrahydrofuran (THF)[21] com-
bined, if necessary, with a catalytic amount of crown
ether;[15f,17a,22] however, these approaches have limited
scope with respect to the alkylating agent. Some O-alkyl-
[a] CNR – Institute of Molecular Science and Technologies
(ISTM),
Via Golgi 19, 20133 Milano, Italy
E-mail: michele.penso@istm.cnr.it
gianluca.pozzi@istm.cnr.it
http://www.istm.cnr.it/
[‡] Present address: Dipartimento di Chimica, Università degli
Studi,
Via Golgi 19, 20133 Milano, Italy
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402429.
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V. Mihali, F. Foschi, M. Penso, G. Pozzi
FULL PAPER
ation reactions have been reported to occur in the presence tio of the solvents. The best results were obtained by using
of KOH as a base in a water/dioxane mixture[20a] or in the DMSO/THF solvent system in volumetric ratio v/v =
DMSO.[23] Following our interest in the use of non-natural 1:16 (entry 7). Under these conditions, 2a was obtained in
α-amino acids for peptidomimetic synthesis,[24] we have re- almost quantitative yields, whereas in the DMF/THF cou-
cently attempted the O-alkylation reaction of N-protected ple and/or in more concentrated solutions (v/v = 1:8) the O-
Hyp with various alkyl halides under reported conditions. alkylation process was less efficient (entries 4–6). The ra-
This groundwork exploration indicated that with most tionale behind the drastic chemoselectivity variation found
alkylating agents only the corresponding Hyp ester was upon changing the reaction media is the generation under
formed when the base employed was not strong enough to strongly basic conditions of an oxy-carboxy dianion, which
deprotonate the hydroxy group (e.g., KOH). On the other in the less coordinating solvent THF forms tight, relatively
hand, the use of stronger bases (e.g., NaH) associated with low-reactive ion-pairs. As a consequence, only the more nu-
a stoichiometric amount of alkylating agent led to mixtures cleophilic oxy-anion is alkylated, albeit in low yields. In
of the three possible products (alkoxyproline ester, Hyp es- strongly coordinating solvents (DMF and DMSO) the di-
ter, and O-alkoxyproline), whereas with an excess of alkylat- anion forms solvent-separated ion pairs in which the two
ing agent the alkoxyproline ester was usually obtained as nucleophilic centers exhibit similar reactivity toward the al-
the major or exclusive product.[25]
kylating agent. Under the reaction conditions we used, the
The disappointing findings on the O-alkylation of N-pro- carboxy-anion is specifically solvated by DMSO and par-
tected Hyp described above, in contrast to the excellent re- ticipates in a less reactive solvent-shared ion pair,[8] while
sults previously obtained in the case of N-alkylation reac- the unsolvated oxyanion is more reactive and is selectively
tions, prompted us to explore the use of specific solvation alkylated.
conditions. As a result, a general one-step, high-yielding
procedure for the chemoselective O-alkylation of N-pro-
tected Hyp allowing straightforward access to a broad
range of alkoxyproline derivatives has been developed.
Results and Discussion
The seemingly undemanding selective O-alkylation of
trans-1-[(benzyloxy)carbonyl]-4-hydroxy-l-proline (trans-
Cbz-4-Hyp, 1a) with n-hexyl iodide to give trans-[(benz-
yloxy)carbonyl]-4-hexyloxy-l-proline (trans-1-Cbz-4-hex-
yloxy-l-proline, 2a) was chosen as a model reaction to ana-
lyze the effect of the solvent on product distribution.
Scheme 1. Two-step preparation and deprotection of trans-O-hexyl-
Cbz-4-Hyp 2a.
Table 1. Solvent screening for the O-alkylation of trans-Cbz-4-Hyp
1a.[a]
Among various standard literature methods tested, a
two-step sequence (Scheme 1) based on the use of NaH as
base and DMF as solvent had initially given the best result
in terms of reaction yields.[19] The product was isolated in
modest yields after direct hydrolysis of the intermediate alk-
oxyproline ester 3a carried out under basic conditions
(Table 1, entry 1). The model reaction was then performed
in different media using NaH as base and an excess of n-
hexyl iodide. In strongly coordinating non-HBD solvents,
such as DMF and DMSO (entries 1 and 2), both the
hydroxy and carboxylic acid functions of 1a reacted with n-
hexyl iodide to give alkoxyproline ester 3a. Base-mediated
hydrolysis of the latter afforded O-alkoxyproline 2a. A dif-
ferent reaction outcome was observed in THF (entry 3), in
Entry
Solvent
t [h]
2a [%][b]
3a [%][b]
1
2
3
4
5
6
7
DMF[c]
24
24
24
48
48
24
24
36[d]
34[d]
20
40
51
37
38
–
–
–
–
–
DMSO[c]
THF[c]
DMF/THF (1:8)[e],[f]
DMF/THF (1:16)[c],[f]
DMSO/THF (1:8)[e],[f]
DMSO/THF (1:16)[c],[f]
70
94
[a] Reaction conditions: 1a (1 mmol), n-hexyl iodide (2.5 mmol),
NaH (2.5 mmol), –20 to 25 °C (see Exp. Sect.). [b] Isolated yield.
[c] At 25 °C. Solvent volume: 3.4 mL. [d] Overall yield upon hydrol-
ysis of 3a. [e] Solvent volume: 1.8 mL. [f] v/v ratio in parentheses.
The stability of the stereogenic centers of proline under
which the target product 2a was formed in low yield as the the optimized reaction conditions represents an additional
sole detectable product. This solvent was thus selected as attractive feature of our approach. Actually, the proximity
the major component of specific solvating mixtures as illus- of the carboxy anion should prevent attack of the base on
trated in our preceding reports.[3,4] The model reaction was the α-hydrogen atom, by both electrostatic repulsion and
operated in THF containing molar amounts of either DMF inductive effects. To confirm this hypothesis, the obtained
(2.6 mol DMF per mol 1a) or DMSO (2.8 mol DMSO per compound 2a was quantitatively N-deprotected by
mol 1a) (entries 4–7). Complete chemoselectivity towards hydrogenolysis of the Cbz group[26] to give the known
the hydroxy function was achieved with all the mixtures amino acid 4a (Scheme 1) and the optical rotatory power
tested, but the reactivity of the system depended greatly on of the material obtained was compared with reported
the concentration of the reagents and on the volumetric ra- data.[27] It is worth noting that N-protected and N-unpro-
2
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Synthesis of N-Protected Alkoxyprolines
tected proline derivatives form aggregates in solution, the Table 3. Chemoselective O-alkylation of N-protected cis-4-Hyp 1c
and 1d.[a]
stability of which depends both on the nature of the solvent
and on the concentration. In particular, α-amino acid 4a in
CHCl3 solution (c 0.94) forms a clearly visible suspension
and its [α]2D0 value decreases with time from –78 (t0) to –65
(t5min), reaching a stable value of –40 at t30min. The same
solution was then diluted (c 0.19) and the stable value –34.1
was measured (ref.[27] –35.1, c 0.5, CHCl3). In contrast, the
rotatory optical power of 4a in MeOH does not fluctuate
with either time (c 1, [α]2D0 = –43.0 at t0 and t30min) or di-
lution (c 0.2, [α]2D0 = –42.5 at t0 and t30min).
The scope of the present method was further explored
by reacting trans-Cbz-4-Hyp 1a and trans-1-(tert-butoxy-
carbonyl)-4-hydroxy-l-proline (trans-Boc-4-Hyp, 1b) with a
representative series of alkylating agents (Table 2). The ex-
amined reactions were completely chemoselective in the
case of both activated (entries 3, 4, and 9–13) and nonacti-
vated alkyl halides, and the corresponding 4-alkoxyprolines
Entry
Y
RX
Cbz C6H13I
CH2=CHCH2Br
Boc C6H13I
CH2=CHCH2Br
t [h]
5
Yield [%][b]
1
2
3
4
24
24
24
24
5a
5b
5c
5d
88
91
90
100
[a] Reaction conditions: see Table 1. [b] Isolated yield.
base and were obtained in substantially lower yields (3–
63%) than in the present case.
2 were isolated in very high yields (91–100%). Furthermore, Table 4. Chemoselective O-alkylation of N-protected cis-3-Hyp 1e
and 1f.[a]
Cbz-derivative 1a was found to be less reactive than Boc-
proline 1b toward allyl or benzyl bromide (compare entries
3 and 9, and entries 4 and 10), most likely because of unfa-
vorable π-π interactions between the carbobenzyloxy moi-
ety on the proline and the unsaturated alkyl halide. The
reaction was then extended to cis-4-Hyp derivatives 1c and
1d, and similar positive results were obtained with both
nonactivated and activated alkylating agents (Table 3).
Entry
Y
RX
Cbz C6H13I
CH2=CHCH2Br
Boc C6H13I
CH2=CHCH2Br
t [h]
6
Yield [%][b]
Table 2. Chemoselective O-alkylation of N-protected trans-4-Hyp
1a and 1b.[a]
1
2
3
4
24
24
20
24
6a
6b
6c
6d
79
95
71
84
[a] Reaction conditions: see Table 1. [b] Isolated yield.
The immobilization of catalytically active prolines onto
various supports has been pursued in an attempt to simplify
their separation and recycling.[29] Phase-tagging strategies,
including functionalization of l-proline derivatives with
Entry
Y
RX
t [h]
2
Yield [%][b]
1
2
3
4
5
6
7
8
Cbz C6H13
I
24
26
24
24
24
28
24
24
6
2a
2b
2c
2d
2e
2f
2g
2h
2i
94
95
100
98
91
92
94
96
100
100
96
C3H7I
Table 5. Chemoselective O-alkylation of N-protected trans-4-Hyp
1a and 1b with fluorous alkyl halides.[a]
CH2=CHCH2Br
PhCH2Br
MeI
C
10H21
I
Boc C6H13
I
C3H7I
CH2=CHCH2Br
PhCH2Br
4-CH2=CHC6H4CH2Br
HCϵCCH2Br
EtCϵCCH2Br
9
10
11
12
13
6
24
3
2j
2k
2l
96
93
24
2m
[a] Reaction conditions: see Table 1. [b] Isolated yield.
Complete chemoselectivity and good yields were also
reached in the synthesis of 3-alkoxyproline derivatives 6a–d
(Table 4) by O-alkylation of trans-3-Hyp derivatives 1e and
1f with n-hexyl iodide and allyl bromide. These 3-alkoxy-
prolines were recently incorporated into peptide chains for
the study of caspase-2 mediated neuronal cell death.[28] To
this end, the 3-alkoxyprolines were prepared by hydrolysis
Entry
Y
RX
t [h]
8
Yield [%][b]
1
2
3
4
Cbz
7a
7b
7a
7b
28
36
48
30
8a
8b
8c
8d
55
58
43
44
Boc
[a] Reaction conditions: 1 (1 mmol), 7 (1.5 mmol), NaH (3 mmol),
of the corresponding esters in the presence of Ag2O as a –20 to 25 °C (see Exp. Sect.). [b] Isolated yield.
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V. Mihali, F. Foschi, M. Penso, G. Pozzi
FULL PAPER
fluorous ponytails have also been explored.[30] Thus, as a
further valuable application of our chemoselective synthetic
protocol, proline derivatives 8a–d, containing polyfluorin-
ated alkoxy chains, were prepared by direct O-alkylation of
1a and 1b with suitable fluorous alkyl halides 7a[31] and
7b[32] (Table 5). In this case, a molar ratio 7/1 of 1.5 was
used instead of the usual 2.5. Due to the adopted stoichio-
metry and to the deactivating effect of the fluorine atoms,
somewhat decreased reaction rates and product yields were
observed compared with those achieved with standard alkyl
halides (Table 2). Nevertheless, our method proved to be
superior to any other reported approach to the synthesis of
similar fluorous-functionalized 4-Hyp. As an example, the
Cbz protective group of 8b was easily removed by
hydrogenolysis to give the corresponding free amino acid in
56% overall yield with respect to 1a. The same product had
been previously prepared from 1a by a four-step synthetic
route in 26% overall yield.[33]
1 mL), and the crude material was extracted with EtOAc (5ϫ
3 mL). The organic layer was washed with brine (3ϫ 2 mL), dried
with MgSO4, and the solvent was distilled under vacuum (RV).
The product was isolated by flash chromatography (monitoring the
elution by TLC, with spots developed by spraying the TLC plate
with a Ninhydrin solution and heating to 110 °C). Analytical and
spectroscopic data for two new compounds, 2a and 6d, are re-
ported.
(2S,4R)-1-[(Benzyloxy)carbonyl]-4-(hexyloxy)pyrrolidine-2-carbox-
ylic Acid (2a): Reaction time 24 h. Purified by FCC (EtOAc/
MeOH, 4:1); yield 328 mg (94%); oil; [α]2D0 = –37.5 (c 5, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 7.34–7.28 (m, 5 H), 5.16–5.11
(m, 2 H), 4.48–4.44 (m, 1 H), 4.06 (m, 1 H), 3.67–3.59 (m, 2 H),
3.38–3.37 (m, 2 H), 2.45–2.13 (m, 2 H), 1.52–1.50 (m, 2 H), 1.27–
1.25 (m, 6 H), 0.88–0.86 (m, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ (two rotamers) = 177.3 and 175.8, 155.7 and 154.6,
136.1, 128.3–127.4 (5CAr), 76.5 and 76.1, 69.3, 67.4 and 66.1, 59.0
and 58.5, 51.8 and 51.6, 36.6 and 35.0, 31.4, 29.5, 25.6, 22.4,
13.8 ppm. IR (neat): ν = 2960, 1740, 1645, 1189, 1010 cm–1
.
˜
C19H27NO5 (349.42): calcd. C 65.31, H 7.79, N 4.01; found C
65.42, H 7.88, N 3.89.
Conclusions
(2S,3S)-3-(Allyloxy)-1-(tert-butoxycarbonyl)pyrrolidine-2-carbox-
ylic Acid (6d): Reaction time 24 h. Purified by FCC (EtOAc/
MeOH, 7:3); yield 228 mg (84%); clear wax; [α]2D0 = –9.8 (c 0.5,
CHCl3). 1H NMR (300 MHz, CDCl3): δ = 5.97–5.85 (m, 1 H),
5.38–5.20 (m, 2 H), 4.68–4.63 (m, 2 H), 4.10–4.03 (m, 2 H), 3.67–
3.51 (m, 2 H), 2.17–2.04 (m, 2 H), 1.50–1.42 (m, 9 H) ppm. 13C
NMR (75 MHz, CDCl3): δ (two rotamers) = 172.3 and 170.9,
153.9, 133.9, 117.6, 81.9 and 80.9, 80.2, 65.7, 65.3 and 64.9, 44.9
A straightforward, direct synthetic route to alkoxypro-
lines has been developed. The advantages of this method
compared with reported approaches are the lower number
of steps, the excellent yields, the complete chemoselectivity,
the reduced amounts of alkylating agent employed, and the
preservation of the stereogenic centers.
and 44.6, 30.4, 28.3 (3CH ) ppm. IR (neat): ν = 3035, 2931, 1750,
˜
3
1639, 1619, 1205, 1003 cm–1. C13H21NO5 (271.31): calcd. C 57.55,
Experimental Section
H 7.80, N 5.16; found C 57.70, H 7.98, N 5.01.
Materials and Methods: All reactions were carried out in flame-
dried glassware equipped with a magnetic stirring bar. Isolated
yields refer to homogeneous materials (TLC, NMR). Reagent-
grade commercially available reagents and solvents were used; an-
hydrous solvents were used as purchased. TLC was performed
using 0.25 mm silica-gel precoated plates and visualized by UV-254
light, CAM or Ninhydrin (0.2 g in 100 mL of EtOH) staining. Sil-
ica-gel (particle size 0.040–0.063 mm) was used for flash column
chromatography (FCC). Melting points are corrected. IR spectra
are reported in frequency of absorption (cm–1). Optical rotation
[α]D values were measured at 589 nm, using a 10 cm ϫ 5 mL cell, c
is in g/100 mL. NMR spectra were recorded at 300.13 MHz for 1H,
(2S,4R)-4-(Hexyloxy)pyrrolidine-2-carboxylic Acid (4a): To a solu-
tion of 2a (69 mg, 0.20 mmol) in anhydrous EtOH (3 mL) was
added Pd/C (10% Pd, 83 mg) and the reaction mixture was stirred
at room temp. under H2 (1 atm) for 4 h, then the reaction mixture
was filtered through a Celite pad and the filtrate was concentrated
under vacuum to afford 4a (36 mg, 0.17 mmol, 85%) as colorless
crystals; m.p. 174–175.1 °C (ref.[27] 173–174 °C); [α]2D0 = –34.2 (c
0.5, CHCl3) [ref.[27] [α]2D0 = –35.1 (c = 0.5, CHCl3)]. Spectroscopic
data are in accordance with the literature.[27]
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures, analytical and spectro-
75.00 MHz for 13C, and 282.407 MHz for 19F. TMS was used as scopic data, and copies of 1H, 13C, and 19F NMR spectra for all
external reference; δ are given in ppm and J values are given in Hz.
new compounds.
General Procedure for the O-Alkylation of N-Cbz- and N-Boc-Pro-
tected Hydroxyprolines (1): NaH (55% in mineral oil, 109 mg,
2.5 mmol) was placed in a flame-dried, two-necked round-bot-
tomed flask, equipped with a stirring bar, nitrogen inlet, and rubber
septum; the oil was removed by rinsing the hydride with anhydrous
pentane (3ϫ 5 mL); the resulting white solid was gently flushed
with nitrogen until complete dryness. After cooling the flask at
–20 °C under nitrogen, a solution of N-protected hydroxyproline 1
(1 mmol) in a mixture of anhydrous THF (1 mL) and DMSO
(0.1 mL) was slowly added by using a syringe. The temperature was
then raised to 0 °C and the heterogeneous mixture was stirred for
30 min. The temperature was reduced again to –20 °C and a solu-
tion of the alkyl halide (2.5 mmol) in THF (0.6 mL) was added by
using a syringe. Finally, the temperature was set at 25 °C and the
reaction mixture was stirred until the starting material was com-
pletely consumed (TLC analysis). The reaction was then quenched
by adjusting the pH 4 with 10% aqueous solution of KHSO4 (ca.
Acknowledgments
This research was supported by the National Research Council
(CNR), Italy and carried out within the framework of the Project
“SusChem Lombardia: Prodotti e processi chimici sostenibili per
l’industria lombarda”.
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4
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Synthesis of N-Protected Alkoxyprolines
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Received: April 16, 2014
Published Online: ᭿
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5

Job/Unit: O42429
/KAP1
Date: 14-07-14 18:30:08
Pages: 6
V. Mihali, F. Foschi, M. Penso, G. Pozzi
FULL PAPER
Chemoselective Alkylation
Several N-protected hydroxyprolines (trans-
4-Hyp, cis-4-Hyp, trans-3-Hyp) were O-
alkylated with activated, nonactivated, and
polyfluorinated alkyl halides by using a
THF/DMSO mixture as solvent. The reac-
tion proceeds through the formation of the
oxy-carboxy dianion and is completely
chemoselective owing to specific solvation
of the carboxyanion function.
V. Mihali, F. Foschi, M. Penso,*
G. Pozzi* .......................................... 1–7
Chemoselective Synthesis of N-Protected
Alkoxyprolines under Specific Solvation
Conditions
Keywords: Synthetic methods / Alkylation /
Chemoselectivity / Amino acids / Solvent
effects / Ion pairs
6
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Eur. J. Org. Chem. 0000, 0–0