Synthesis of 4-(Arylmethyl)proline Derivatives

Article abstract of DOI:10.1055/s-0037-1611672

A synthesis of 4 - (arylmethyl)proline by using Suzuki cross-couplings was developed. The route permits access to a variety of 4-substituted proline derivatives bearing various aryl moieties that expand the toolbox of proline analogues for studies in chemistry and biology.

Full text of DOI:10.1055/s-0037-1611672

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
Georg Thie-
me Verlag
Stuttgart ·
New York
2019, 30,
A
A
–
C
S. Loosli et al.
Letter
Synlett
Synthesis of 4-(Arylmethyl)proline Derivatives
Simon Loosli◊
Ar
Ar
Carlotta Foletti◊
6 examples
*
N
*
N
3 examples
74–89%
Marcus Papmeyer
CO2tBu
CO2tBu
CO2H
N
60–83%
Helma Wennemers*
0
0
0
0-0
0
0
2-
3
0
7
5-5
7
4
1
Boc
Boc
Fmoc
R
ETH Zürich, Laboratory for Organic Chemistry, D-CHAB,
Vladimir-Prelog-Weg 3, 8093 Zürich, Switzerland
Helma.Wennemers@org.chem.ethz.ch
◊ These authors contributed equally.
Ar =
Published as part of the 30 Years SYNLETT – Pearl Anniversary
Issue
Received: 20.12.2018
Accepted after revision: 16.01.2019
Published online: 25.01.2019
in transferring these reaction conditions, which rely on
Wittig reactions of 4-oxoproline followed by hydrogena-
tion, to larger aryl moieties (Scheme 1, top).
DOI: 10.1055/s-0037-1611672; Art ID: st-2018-b0822-l
We therefore sought an alternative route and we envi-
sioned Suzuki reactions between an organoborane–proline
derivative and aryl halides as a strategy that might provide
access to proline derivatives with various aryl groups
(Scheme 1, bottom). Here, we report a general synthetic
route to arylmethyl proline derivatives that permits the in-
troduction of a broad range of aryl moieties at C.
License terms:
Abstract A synthesis of 4-(arylmethyl)proline by using Suzuki cross-
couplings was developed. The route permits access to a variety of 4-
substituted proline derivatives bearing various aryl moieties that ex-
pand the toolbox of proline analogues for studies in chemistry and
biology.
Our synthetic route relies on the hydroboration of the
Boc/tBu-protected 4-methyleneproline 5, which was ob-
tained from (2S,4R)-4-hydroxyproline (1) by slight modifi-
cation of a previously published procedure (Scheme 2).10
This four-step synthesis started with Boc-protection of 1,
followed by oxidation to ketone 3, protection of the carbox-
Key words arylmethylprolines, prolines, hydroboration, Suzuki cross-
coupling
Proline is the only proteogenic amino acid with a cyclic
backbone, which confers to this residue a uniquely restrict-
ed conformation. Nature and scientists have used proline
and its derivatives to regulate numerous processes, ranging
from ion-gating and the structural integrity of skin to
asymmetric catalysis.1–4 The development of proline ana-
logues and their incorporation into peptides and other
compounds is therefore of great interest. Proline derivatives
with different substituents at C are the most common, due
to their natural occurrence and the ease of functionaliza-
tion of (2S,4R)-4-hydroxyproline.1,5 Examples include deriv-
atives with heteroatoms at C, e.g., F, Cl, N3, NH2, or alkyl
groups, e.g., Me and tBu.1,6 In contrast, derivatives with aryl-
methyl substituents at C are less commonly utilized, possi-
bly due to a lack of a straightforward synthetic route.
t
ylic acid as the Bu ester in 4, and introduction of an exo-
cyclic methylene group by a Wittig reaction.11
Previous route using Wittig reaction and hydrogenation:
O
R
R
*
OTBS
OTBS
CO2H
N
N
N
Boc
Boc
Boc
R = e.g. Ph, C6H4(4-OMe), C6H4(3-F), (Boc)indol
Herein, route using Suzuki reaction:
9-BBN
*
R
*
We became interested in proline derivatives bearing
naphthyl moieties, for their value in the molecular recogni-
tion of RNA.7 Synthetic routes have been reported for the
functionalization of proline at C with benzylic or indolyl-
methyl substituents.6a,8,9 However, we had limited success
CO2tBu
CO2tBu
CO2H
N
N
N
Boc
Boc
Fmoc
Scheme 1 Synthetic routes to 4-(arylmethyl)proline derivatives
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–C

B
S. Loosli et al.
Letter
Synlett
Reassuringly, this route also permitted the synthesis of
proline derivatives bearing substituted naphthyl moieties
(7b and 7c) as well as phenyl (7d), 9-anthryl (7e), or pyren-
1-yl (7f) substituents in good overall yields (60–83%;
Scheme 3).15 All derivatives were obtained with a diastereo-
selectivity of ~3:2 in favor of the syn-product, as deter-
mined by analysis of 1H NMR NOE spectroscopy.11
HO
HO
O
TCCA
TEMPO
Boc2O
CO2H
CO2H
CO2H
N
H
N
N
1,4-dioxane/H2O
CH2Cl2
90%
Boc
Boc
90%
1
2
3
O
DCC, tBuOH
DMAP
CH3P(Ph)3Br
tBuOK
CO2tBu
CO2tBu
Because peptide syntheses typically require Fmoc-pro-
tected amino acids, we converted 7a–c into the respective
N
N
dry THF
CH2Cl2
Boc
87% (over two steps)
Boc
4
5
t
Fmoc-amino acids 8a–c. Simultaneous removal of the Bu
TCCA = trichloroisocyanuric acid
protecting groups in 6 M HCl in 1,4-dioxane, and subse-
quent Fmoc-protection afforded 8a–c in yields of 74–89%
(Scheme 4). The diastereoisomers were separated by pre-
parative reverse-phase HPLC to obtain enantiomerically
pure amino acids at a scale of up to 2.5 g.15,16
Scheme 2 Synthesis of the common precursor tert-butyl N-(tert-
butoxycarbonyl)-4-methyleneprolinate (5)
Hydroboration of the 4-methyleneproline 5 with 9-BBN
provided the organoborane 6, which was used for the Suzu-
ki reaction without further purification (Scheme 3, top).
For the Suzuki reaction, various catalysts and conditions
were explored by using 2-bromonaphthalene as a model
aryl bromide. We focused in particular on catalysts that had
proven valuable for cross-couplings with other amino acid
derivatives (Scheme 3, bottom).12 Among the tested palladi-
um-based catalysts, reactions with PEPPSI13 showed the
highest conversion of 5 and 2-bromonaphthalene into the
Suzuki reaction product 7a. Under optimized conditions [5
M aq KOH, ArBr (1.3 equiv), PEPPSI(3% mol)], the 4-(2-
naphthylmethyl)proline derivative 7a was obtained in a
yield of 83%. Note that 3 mol% of PEPPSI was enough to ob-
tain these results. Because PEPPSI is more air-stable than
other palladium catalysts,14 this catalyst was used for all
further experiments.
Ar
Ar
1. 6 M HCl, 1,4-dioxane/H2O
2. 1.1 equiv. Fmoc-Cl, NaHCO3
H2O–1,4-dioxane
*
*
CO2tBu
CO2H
N
N
Boc
Fmoc
8a–c
7a–c
Ar =
OCH3
CO2CH3
8a, 85%
8b, 74%
8c, 89%
Scheme 4 Synthesis of Fmoc-protected amino acids 8a–c
In conclusion, we have introduced a synthetic route to
access proline derivatives bearing a variety of arylmethyl
substituents at the -position. The products were obtained
in good yields for every tested aromatic moiety. The dia-
stereoselectivity of the hydroboration step was modest, but
the diastereoisomeric products could be separated on a
gram scale. Installation of a Fmoc-protecting group was
straightforward. Thus, the route provides access to proline
derivatives with a variety of arylmethyl moieties at C that
are suitably protected for solid-phase peptide synthesis.
We envision these derivatives as being valuable additions to
the toolkit of proline analogues for applications in chemis-
try and chemical biology.
Ar
9-BBN
1. 2 equiv. KOH
2. 1.3 equiv. Ar-Br,
3 mol% PEPPSI
dr ~ 3:2
syn/anti
*
1.1 equiv. 9-BBN
*
5
CO2tBu
THF, RT, 16 h
THF, 60°C
6 h
CO2tBu
N
N
Boc
Boc
7a–f
6
CO2CH3
OCH3
Ar =
7c, 81%
7b, 60%
7a, 83%
7d, 76%
Funding Information
The authors gratefully acknowledge financial support by the Swiss
National Science Foundation (grant 200020_178805).
S
w
i
s
N
ati
o
n
a
lS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
(2
0
0
0
2
0
_
1
7
8
8
0
5)
7e, 63%
7f, 68%
Supporting Information
iPr
Ph
iPr
P
Ph
N
N
Supporting information for this article is available online at
PCy2
OMe
https://doi.org/10.1055/s-0037-1611672.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
iPr
iPr
Fe
PdCl2
MeO
Cl Pd Cl
N
P
Ph
Ph
References and Notes
Cl
PEPPSI
PdCl2(dppf)
SPhos Pd(OAc)2
(1) Shoulders, M. D.; Raines, R. T. Annu. Rev. Biochem. 2009, 78, 929.
(2) For examples, see: (a) Arnold, U.; Hinderaker, M. P.; Köditz, J.;
Golbik, R.; Ulbrich-Hofmann, R.; Raines, R. T. J. Am. Chem. Soc.
2003, 125, 7500. (b) Lummis, S. C.; Beene, D. L.; Lee, L. W.;
Scheme 3 Top: Suzuki cross-coupling reaction to yield various 4-(aryl-
methyl)proline derivatives 7a–f. Bottom: Catalysts tested in the Suzuki
cross-coupling reaction.
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–C

C
S. Loosli et al.
Letter
Synlett
Lester, H. A.; Broadhurst, R. W.; Dougherty, D. A. Nature 2005,
438, 248. (c) Lieblich, S. A.; Fang, K. Y.; Cahn, J. K. B.; Rawson, J.;
LeBon, J.; Ku, H. T.; Tirrell, D. A. J. Am. Chem. Soc. 2017, 139,
8384. (d) Metrano, A. J.; Abascal, N. C.; Mercado, B. Q.; Paulson,
E. K.; Hurtley, A. E.; Miller, S. J. J. Am. Chem. Soc. 2017, 139, 492.
(3) Liu, J.; Wang, L. Synthesis 2017, 49, 960.
NMR (126 MHz, C2Cl4D2, 60 °C):  = 172.2, 172.0, 153.6, 137.6,
137.4, 133.5, 133.5, 132.1, 128.1, 128.1, 127.6, 127.5, 127.4,
127.2, 127.1, 126.8, 126.8, 126.1, 125.4, 80.9, 80.8, 79.6, 79.5,
59.8, 59.7, 52.1, 51.6, 39.3, 39.2, 37.7, 36.7, 36.4, 28.4, 28.0, 28.0.
HRMS (ESI+): m/z [M + H]+ calcd C25H34NO4: 412.2482; found:
412.2485.
(4) Lewandowski, B.; Wennemers, H. Curr. Opin. Chem. Biol. 2014,
22, 40.
(4S)- and (4R)-1-[(9H-Fluoren-9-ylmethoxy)carbonyl]-4-(2-
naphthylmethyl)-L-proline (8a); Typical Procedure
(5) (a) Remuzon, P. Tetrahedron 1996, 52, 13803. (b) Pandey, A. K.;
Naduthambi, D.; Thomas, K. M.; Zondlo, N. J. J. Am. Chem. Soc.
2013, 135, 4333.
Prolinate 7a (4.8 g, 11.7 mmol, 1 equiv) was dissolved in a 6 M
soln of HCl in 1,4-dioxane (110 mL), and the mixture was
stirred for 3 h at r.t. The pH was adjusted to 8–9 with sat. aq
NaHCO3, then a soln of FmocCl (3.6 g, 14.0 mmol, 1.2 equiv) in
1,4-dioxane (50 mL) was added, and the mixture was stirred at
r.t. for 2 h. Low-boiling volatiles were removed under reduced
pressure, and EtOAc (50 mL) was added. The solution was acidi-
fied to pH 2–3 with 1 M HCl, and the organic phase was sepa-
rated and extracted with EtOAc (3 × 100 mL). The combined
organic layers were washed with brine, dried (MgSO4), and fil-
tered. All volatiles were removed under reduced pressure, and
the product was purified by column chromatography (silica gel,
0–5% MeOH in CH2Cl2 with 0.1% HCO2H) to give a white
powder: yield: 4.7 g (84%). The diastereoisomers were subse-
quently separated by reverse-phase semipreparative HPLC
[Reprosil-Gold 120 C18, 10 m; 250 × 30 mm column, MeCN
and H2O–MeCN–TFA (100:1:0.1)].
(6) (a) Del Valle, J. R.; Goodman, M. J. Org. Chem. 2003, 68, 3923.
(b) Koskinen, A. M. P.; Helaja, J.; Kumpulainen, E. T. T.; Koivisto,
J.; Mansikkamäki, H.; Rissanen, K. J. Org. Chem. 2005, 70, 6447.
(7) Foletti, C.; Kramer, R. A.; Mauser, H.; Jenal, U.; Bleicher, K. H.;
Wennemers, H. Angew. Chem. Int. Ed. 2018, 57, 7729.
(8) (a) Ezquerra, J.; Pedregal, C.; Yruretagoyena, B.; Rubio, A.;
Carreño, M. C.; Escribano, A.; García Ruano, J. L. J. Org. Chem.
1995, 60, 2925. (b) Rawson, D. J.; Brugier, D.; Harrison, A.;
Hough, J.; Newman, J.; Otterburn, J.; Maw, G. N.; Price, J.;
Thompson, L. R.; Turnpenny, P.; Warren, A. N. Bioorg. Med.
Chem. Lett. 2011, 21, 3771.
(9) Krapcho, J.; Turk, C.; Cushman, D. W.; Powell, J. R.; DeForrest, J.
M.; Spitzmiller, E. R.; Karanewsky, D. S.; Duggan, M.; Rovnyak,
G.; Schwartz, J.; Natarajan, S.; Godfrey, J. D.; Ryono, D. E.;
Neubeck, R.; Atwal, K. S.; Petrillo, E. W. Jr. J. Med. Chem. 1988, 31,
1148.
(4S)-Diastereomer
[]D –40.7 ± 0.5 (c 0.2, MeOH). TLC (silica gel, 2% MeOH in CH2-
Cl2): Rf = 0.56. FTIR (neat): 3051, 2923, 1701, 1421, 1352, 1247,
(10) (a) Herdewijn, P.; Claes, P. J.; Vanderhaeghe, H. Can. J. Chem.
1982, 60, 2903. (b) De Luca, L.; Giacomelli, G.; Porcheddu, A.
Org. Lett. 2001, 3, 3041.
1176, 1122, 1006, 972, 843, 739 cm–1
.
1H NMR (500 MHz, C2Cl4D2, 60 °C):  = 7.92–7.79 (m, 3 H; Ar),
7.77–7.60 (m, 3 H; Ar), 7.59–7.44 (m, 4 H; Ar), 7.43–7.21 (m, 5
H; Ar), 4.55–4.41 (m, 2 H; CH2–Fmoc), 4.41–4.28 (m, 1 H; H),
4.28–4.18 (m, 1 H; CH–Fmoc), 3.77–3.52 (m, 1 H; H), 3.25–
3.16 (m, 1 H; H), 3.01–2.79 (m, 2 H; CH2-Naph), 2.57 (hept,
J = 7.7 Hz, 1 H; H), 2.50–2.36 (m, 1 H; H), 2.12–1.93 (m, 1 H;
H). 13C NMR (500 MHz, C2Cl4D2, 60 °C):  = 173.2 (CO2H), 156.4
(C=OFmoc), 143.5 (Ar), 141.1 (Ar), 137.0 (Ar), 133.4 (Ar), 132.1
(Ar), 128.2 (Ar), 127.6 (Ar), 127.5 (Ar), 127.4 (Ar), 127.0 (Ar),
126.9 (Ar), 126.7 (Ar), 126.1 (Ar), 125.5 (Ar), 124.8 (Ar), 119.8
(Ar), 67.9 (CH2–Fmoc), 59.4 (C), 52.2 (C), 47.1 (CH–Fmoc),
39.7 (C), 38.8 (CH2–Naph), 34.4 (C). HRMS (ESI+): m/z [M +
H]+ calcd for C31H28NO4: 478.2013; found: 478.2003.
(11) For details, see the Supporting Information.
(12) For the use of the Suzuki reaction to prepare amino acids, see:
(a) Campbell, A. D.; Raynham, T. M.; Taylor, R. J. K. Tetrahedron
Lett. 1999, 40, 5263. (b) Sabat, M.; Johnson, C. R. Org. Lett. 2000,
2, 1089. (c) Lu, X.; Xiao, B.; Shang, R.; Liu, L. Chin. Chem. Lett.
2016, 27, 305.
(13) O’Brien, C. J.; Kantchev, E. A. B.; Valente, C.; Hadei, N.; Chass, G.
A.; Lough, A.; Hopkinson, A. C.; Organ, M. G. Chem. Eur. J. 2006,
12, 4743.
(14) Ray, L.; Shaikh, M. M.; Ghosh, P. Dalton Trans 2007, 4546.
(15) tert-Butyl (4S/4R)-N-(tert-Butoxycarbonyl)-4-(2-naphthyl-
methyl)-L-prolinate (7a); Typical Procedure
An oven-dried Schlenk flask was charged with methylene deriv-
ative 5 (4.0 g, 14.1 mmol, 1 equiv) under N2. A 0.5 M soln of 9-
BBN in THF (31.0 mL, 15.5 mmol, 1.1 equiv) was added in one
portion, and the solution was stirred vigorously at 60 °C for 6 h.
The mixture was then allowed to cool to r.t. and 5 M aq. KOH
(5.6 mL, 5 M, 28.0 mmol, 2 equiv) was added. The mixture was
stirred for 20 min, then 2-bromonaphthalene (7a; 3.8 g, 18.36
mmol, 1.3 equiv) was added together with PEPPSI (287.7 mg,
423 mol, 0.03 equiv). The mixture was stirred for a further
16 h at r.t., then H2O (120 mL) and EtOAc (120 mL) were added
and the phases were separated. The aqueous phase was
extracted with EtOAc (3 × 120 mL), and the organic layers were
combined, washed with brine, dried (MgSO4), and concentrated.
The resulting yellow–brown oil (9.9 g) was purified by column
chromatography (silica gel, 0–25% EtOAc–hexane) to give a col-
orless oil; yield: 4.8 g (83%).
(4R)-Diastereomer
[]D –10.8 ± 0.3 (c 0.2, MeOH). TLC (silica gel, 2% MeOH in CH2-
Cl2): Rf = 0.56. FTIR (neat): 3045, 2966, 1700, 1661, 1417, 1351,
1241, 1282, 1122, 1002, 947, 887, 737 cm–1
.
1H NMR (500 MHz, C2Cl4D2, 60 °C):  = 7.91–7.80 (m, 3 H; Ar),
7.73 (dd, J = 7.6, 2.9 Hz, 2 H; Ar), 7.62 (s, 1 H; Ar), 7.59–7.48 (m,
4 H; Ar), 7.39 (tt, J = 7.6, 1.4 Hz, 2 H; Ar), 7.35–7.27 (m, 3 H; Ar),
4.56–4.36 (m, 3 H; H, CH2–Fmoc), 4.32–4.19 (m, 1 H; CH–
Fmoc), 3.74–3.49 (m, 1 H; H), 3.31–3.10 (m, 1 H; H), 2.97–
2.80 (m, 2 H; CH2–Naph), 2.80–2.65 (m, 1 H; H), 2.47–1.88 (m,
2 H; H). 13C NMR (500 MHz, C2Cl4D2, 60 °C):  = 173.8 (CO2H),
156.1 (C=OFmoc), 143.5 (Ar), 141.1 (Ar), 136.8 (Ar), 133.4 (Ar),
132.1 (Ar), 128.2 (Ar), 127.6 (Ar), 127.5 (Ar), 127.4 (Ar), 127.0
(Ar), 127.0 (Ar), 126.8 (Ar), 126.1 (Ar), 125.5 (Ar), 124.8 (Ar),
119.82 (Ar), 67.9 (CH2–Fmoc), 59.2 (C), 51.7 (C), 47.1 (CH–
Fmoc), 38.9 (CH2–Naph, C), 34.3 (C). HRMS (ESI+): m/z [M +
H]+ calcd C31H28NO4: 478.2013; found: 478.2003.
1H NMR (500 MHz, C2Cl4D2, 60 °C):  = 7.82–7.71 (m, 3 H), 7.59–
7.52 (m, 1 H), 7.48–7.37 (m, 2 H), 7.27 (dd, J = 8.4, 1.7 Hz, 1 H),
4.26–4.02 (m, 1 H), 3.75–3.55 (m, 1 H), 3.14 (dd, J = 10.6, 9.0 Hz,
1 H), 2.89–2.76 (m, 2 H), 2.72–2.44 (m, 1 H), 2.42–1.88 (m, 1 H),
1.63 (ddd, J = 12.8, 9.5, 7.9 Hz, 1 H), 1.51–1.33 (m, 18 H). 13C
(16) Note that the Suzuki reaction is not compatible with the use of
Fmoc-protected amines. The stereochemistry at the stereogenic
centers was retained during the synthesis.
Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–C