Practical one-pot double functionalizations of proline

Article abstract of DOI:10.1055/s-0030-1258428

Solubilization of proline as the triethylammonium salt allows N-protection (as the Boc, Cbz or Moc derivative) and subsequent esterification or amidation of the carboxy terminus to be performed in an efficient one-pot fashion. Based on this concept, highly practical protocols were developed to prepare a series of proline derivatives (including Pro-Ser dipetides, Weinreb amides and N-protected proline esters), which are important intermediates, for instance, for the synthesis of proline-derived peptides, chiral reagents and catalysts for asymmetric synthesis. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258428

954
PAPER
Practical One-Pot Double Functionalizations of Proline
Practical
One-
e
Pot
D
ouble
t
Functi
e
onalization
r
s
of
P
roline Huy, Hans-Günther Schmalz*
Department für Chemie, Universität zu Köln, Greinstr. 4, 50939 Köln, Germany
Fax +49(221)4703064; E-mail: schmalz@uni-koeln.de
Received 23 December 2010; revised 8 January 2011
route, i.e. through N-Boc-protection of 1 (under Schotten–
Baumann conditions)8 and subsequent esterification9 of
the carbamate 5 (Scheme 2). While this two-step protocol
afforded the products in high yield, we asked ourselves
Abstract: Solubilization of proline as the triethylammonium salt
allows N-protection (as the Boc, Cbz or Moc derivative) and subse-
quent esterification or amidation of the carboxy terminus to be per-
formed in an efficient one-pot fashion. Based on this concept,
highly practical protocols were developed to prepare a series of pro- whether the overall effort could be reduced by omitting
line derivatives (including Pro-Ser dipetides, Weinreb amides and
N-protected proline esters), which are important intermediates, for
the interim workup and isolation of 5. A key challenge in
this context was to manage the low solubility of proline in
instance, for the synthesis of proline-derived peptides, chiral re-
most organic solvents.10
agents and catalysts for asymmetric synthesis.
Key words: proline derivatives, peptides, carbamates, N-protect-
ing groups, solvent effects, coupling reagents
a
b
CO2H
CO2H
CO2R
quant.
82–99%
N
N
N
H
Boc
5 (crude)
Boc
1
2a R = Me
2b R = t-Bu
Among the common proteinogenic amino acids, only pro-
line (1) represents a secondary amine and accordingly Scheme 2 ‘Classical’ two-step synthesis of the proline esters 2a/2b:
(a) Boc2O, NaHCO3, H2O, THF; (b) (ROC=O)2O, DMAP (cat.),
THF, 82% (R = Me), 99% (R = t-Bu); Boc = tert-butoxycarbonyl.
plays a special role in protein chemistry and biology. In
addition, proline is of significant importance in organic
chemistry as a chiral starting material for the synthesis of
peptide mimetics,1 alkaloids of the general structure 3,2 As the result of extensive experimentation, we herein de-
certain peptoid natural products,3 and chiral molecules of scribe practical one-step procedures for the synthesis of
type 4 (Scheme 1), which are used in asymmetric synthe- double-functionalized proline derivatives of type 2.11 Our
sis and catalysis. Examples are oxazaborolidine catalysts methodology is centrally based on the dissolution of pro-
for Corey–Bakshi–Shibata (CBS) reductions4 or Diels– line as the triethylammonium salt. This allows the N-pro-
Alder reactions.5 Compounds of type 4 have recently also tection to be performed in an aprotic organic solvent (such
found many applications in organocatalysis.6
as CHCl3, CH2Cl2 or THF), which is needed for the sub-
sequent esterification or amidation step.12 In such sol-
vents, the reaction of 1 with Boc2O (or other related
reagents) does not take place in the absence of triethyl-
amine; however, on addition of (already substoichiomet-
ric amounts of) triethylamine a clear solution forms after
one to three hours, which indicates a full conversion of 1
into 7a. We assume an equilibration between the nearly
undissolved, zwitterionic form of proline (1) and the at
least partly dissolved ammonium carboxylate 6, which re-
acts with Boc2O to give the soluble carbamate 7a
(Scheme 3). The addition of Moc2O (or Boc2O) and 4-
(dimethylamino)pyridine (DMAP)9a then results in the
formation of 2a or 2b, respectively, in comparable yields
(81–97%) to the ‘classical’ two-step procedure (Table 1,
entries 1 and 2). In the preparation of 2b, it is sufficient to
simply add DMAP (0.1 equiv) after three hours to the re-
action mixture, if two equivalents of Boc2O were used in
the beginning.13
The synthesis of such compounds usually involves dou-
ble-protected intermediates of type 2 which are prepared
from 1 in two steps (N-protection as a carbamate, and es-
ter or amide formation).
R
N
YR
3
PG-X;
H-YR
CO2H
O
N
N
PG
R
R
H
2
1
OH
N
H
4
Scheme 1 Proline derivatives of type 2 as synthetic intermediates
for 32 and 43–5
In the course of our recent work concerning the synthesis
of proline-derived peptide mimetics,7 we initially pre-
pared proline esters 2a and 2b following the classical
As Table 1 shows, the Weinreb amide 2c was obtained in
83% yield, even on a 175-mmol scale using technical
grade solvents and no protecting gas atmosphere (entry 3).
The Pro-Ser dipeptide 2d was prepared in 80% yield
(Table 1, entry 4). In both cases, N,N¢-dicyclohexylcarbo-
diimide (DCC) served as a coupling reagent in combina-
tion with DMAP1b,d,14 or 1-hydroxybenzotriazole
SYNTHESIS 2011, No. 6, pp 0954–0960
x
x
.
x
x
.2
0
1
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Advanced online publication: 10.02.2011
DOI: 10.1055/s-0030-1258428; Art ID: T56010SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Practical One-Pot Double Functionalizations of Proline
955
Table 1 One-Pot Synthesis of the Boc-Protected Proline Derivatives 2a–e
–
Cl
HO
YR
–
O
Cl
reagents
Boc2O
–
Bn
Me
H2N
CO2H
CO2
N
+
+
Et3N
HYR
0 °C to r.t.
overnight
+
O
O
H
N
N
H3N
OMe
Et3NH
N
solvent
H
Boc
CO2Me
Boc
r.t., 1–3 h
1
8
9
10
2a–e
7a
Entry
Solvent
Boc2O (equiv) Et3N (equiv) Reagents (equiv)
H-YR
Product
2a
Yield (%)
1
2
3
4
5
THF
THF
1.0
2.4
1.05
1.0
1.0
0.6
0.3
1.3
2.3
3.3
Moc2O (2.0), DMAP (0.1)
DMAP (0.1)
H-OMe
81
97
83a
80
72
H-Ot-Bu
2b
CHCl3
CH2Cl2
THF
8 (1.2), DMAP (0.2), DCC (1.1)
9 (1.1), HOBt (1.0), DCC (1.1)
H-NMeOMe
2c
H-NH-Ser-OMe
2d
1. PivCl (2.0); 2. LiCl (1.7), 10 (1.1)
Evans auxiliary 10
2e
a 2c was synthesized on a 175-mmol scale (20 g of proline → 37 g of 2c). Because of the large reaction scale, the mixture was already cooled
in an ice bath during the addition of Et3N.
(HOBt)1a,3a,15 as the nucleophilic catalyst. For the attach- carbonyl (Cbz), methoxycarbonyl (Moc), 9-fluorenyl-
ment of the much less nucleophilic carbamate 10 (i.e., the methoxycarbonyl (Fmoc)] as N-protecting reagents in
Evans auxiliary), the carboxylate 7a was best activated as such one-pot protocols. First, we examined the synthesis
a mixed anhydride by primary reaction with pivaloyl chlo- of the N-Cbz-protected proline methyl ester 2f (Table 2,
ride (PivCl).16 Subsequent addition of carbamate 10 and entries 1–4). This compound was obtained by successive
lithium chloride17 then afforded 2e in 72% yield (Table 1, treatment of proline (1) with CbzCl (1.05 equiv) and Moc-
entry 5).
Cl (2 equiv) in the presence of triethylamine and DMAP.18
The yield of 2f proved to be strongly solvent-dependent:
best results were obtained in methanol (without DMAP to
avoid methanolysis of CbzCl) or chloroform (74–76%),
while the yield dropped to 63% in dichloromethane and to
10% in tetrahydrofuran. Therefore, all further transforma-
tions were performed in chloroform (as a nucleophilic sol-
vent, methanol is not suitable for these reactions). The
Cbz-protected proline derivatives 2g,9a 2h1d and 2i14 were
obtained in 70% to 77% yield by treatment of proline (1)
with CbzCl and triethylamine in chloroform, and succes-
sive addition of a coupling reagent, a nucleophilic catalyst
and an appropriate nucleophile (Table 2, entries 5–7). Us-
ing MocCl as a more reactive N-protecting reagent, the
methyl ester 2j19 was obtained in 81% using methanol as
As indicated in Scheme 4, two equivalents of pivaloyl
chloride are required to ensure a good (72%) yield of 2e;
with only one equivalent of pivaloyl chloride, the yield
dropped to 30%. This can be understood by considering
that tert-butyl alcohol is produced during the Boc-protec-
tion step (1 to 7a) and consumes one equivalent of piv-
aloyl chloride to form the tert-butyl ester 12. If not
trapped by pivaloyl chloride, tert-butyl alcohol may also
compete with carbamate 10 in the reaction with the mixed
anhydride 11 to give 2b (isolated as a side product when
only 1 equiv of PivCl was used).
Having succeeded in preparing a series of N-Boc-L-pro-
line derivatives, we next investigated the possibility of
also employing chloroformates [PG-Cl; PG = benzyloxy-
YR
–
Et3N
–
reagents
HYR
Boc2O
–
CO2
CO2
CO2
O
+
+
N
N
N
N
+
Et3NH
Et3NH
Boc
H2
H
Boc
1
6
7a
2a–e
partly soluble
fully soluble
insoluble in
organic solvents
Scheme 3 Proposed mechanism for the one-pot functionalizations
O
Bn
N
OPiv
O
N
O
O
Boc2O
Et3N
PivCl
7a
+ t-BuOH
LiCl
10
1
(2.0 equiv)
N
Boc
11
+ t-BuO-Piv (12)
Boc
2e
72%
Scheme 4 One-pot synthesis of the proline derivative 2e using two equivalents of pivaloyl chloride as a coupling reagent
Synthesis 2011, No. 6, 954–960 © Thieme Stuttgart · New York

956
P. Huy, H.-G. Schmalz
PAPER
Table 2 One-Pot Synthesis of the Cbz-, Moc- and Fmoc-Protected Proline Derivatives 2f–l
YR
–
PG-Cl
Et3N
solvent
–20 °C to r.t.
0.5–1 h
reagents
CO2H
CO2
O
HYR
0 °C to r.t.
overnight
+
N
N
N
Et3NH
H
PG
PG
1
2f–l
7b PG = Cbz
7c PG = Moc
7d PG = Fmoc
Entry
Solvent
PG-Cl (equiv)
Et3N (equiv) Reagents (equiv)
H-YR
Product Yield (%)
1
2
MeOH
CHCl3
CH2Cl2
THF
CbzCl (1.05)
CbzCl (1.05)
CbzCl (1.05)
CbzCl (1.05)
CbzCl (1.05)
CbzCl (1.05)
CbzCl (1.05)
MocCl (2.8)
MocCl (1.05)
FmocCl (1.05)
3.3
3.3
3.3
3.3
1.3
2.3
3.3
3.0
1.3
3.3a
MocCl (2.0)
H-OMe
2f
2f
2f
2f
2g
2h
2i
76
74
63
10
77
76
70
81
69
83
MocCl (2.0), DMAP (0.3)
MocCl (2.0), DMAP (0.3)
MocCl (2.0), DMAP (0.3)
Boc2O (1.3), DMAP (0.3)
8 (1.3), DMAP (0.3), DCC (1.1)
9 (1.2), HOBt (1.0), DCC (1.1)
–
H-OMe
3
H-OMe
4
H-OMe
5
CHCl3
CHCl3
CHCl3
MeOH
CHCl3
CHCl3
H-Ot-Bu
6
H-NMeOMe
H-NH-Ser-OMe
H-OMe
7
8
2j
2k
2l
9
Boc2O (1.3), DMAP (0.3)
9 (1.1), HOBt (1.0), DCC (1.05)
H-Ot-Bu
10
H-NH-Ser-OMe
a DIPEA instead of Et3N was used as a base.
a solvent (Table 2, entry 8). Also, using MocCl, the syn- nucleophile HYR (in the presence of a suitable coupling
thesis of the tert-butyl ester 2k was achieved (69% yield) reagent) would lead to the desired product of type 2, inter-
in chloroform after treatment of the primary intermediate mediate 13 would presumably give rise to undesired side
7c with Boc2O and DMAP9a (Table 2, entry 9). Using products (such as proline oligomers).
Hünig’s base (DIPEA) instead of triethylamine, the less
The strong solvent effect observed in the synthesis of 2f
may be explained by assuming that more polar solvents
(such as MeOH or CHCl3) ‘protect’ the carboxylate func-
tion by forming a stronger solvent cage. Because of the
small reactivity difference of the two nucleophilic sites, it
is crucial to add the chloroformate (PG-Cl) slowly as a di-
reactive reagent FmocCl was found to convert 1 into the
carbamate intermediate 7d, from which the dipeptide 2l1a
was obtained in 83% yield by reaction with methyl serin-
ate 9 in the presence of DCC and HOBt (Table 2, entry
10).
The results summarized in Table 2 deserve some addition- lute solution (in CHCl3) at –20 °C.20
al comments. From a mechanistic point of view, the reac-
Interestingly, when pyridine instead of triethylamine was
tion is interesting because the (at least partly) soluble and
used as a base, only complex mixtures were formed which
therefore reacting prolinate 6 represents an ambident nu-
did not contain significant amounts of the desired product
cleophile which, in principle, can react with the chlorofor-
mate (PG-Cl) in two different ways (Scheme 5).
Accordingly, either a N-protected carboxylate of type 7 or
an activated, O-acylated intermediate of type 13 (mixed
anhydride) could result. While further reaction of 7 with a
(as shown in the case of 2f). We assume that pyridine (like
DMAP)18 acts as a nucleophilic catalyst to activate the
chloroformate which in turn leads to a lower chemoselec-
tivity.21 A comparison of the different chloroformates also
YR
solvent
cage
HYR
–
CO2
O
N
N
+
PG
PG
2
Et3NH
Et3N
–
CO2
1
PG-Cl
7
N
H
+
OPG
O
Et3NH
side
products
6
N
H
13
Scheme 5 ‘One-pot’ double functionalization of proline (1) using chloroformate reagents
Synthesis 2011, No. 6, 954–960 © Thieme Stuttgart · New York

PAPER
Practical One-Pot Double Functionalizations of Proline
957
der to remove the remaining urea, the residue was dissolved in
MTBE (100 mL), and the solution was filtered and again concen-
trated under reduced pressure. Column chromatographic purifica-
tion of the crude product (49.3 g, dissolved in a little CHCl3 under
warming) on silica gel (700 g) with EtOAc–cyclohexane (2:3 → 1:1
→ 3:2) afforded the amide 2c as a pale yellow oil; yield: 37.3 g
(144 mmol, 83%).
suggests that FmocCl as the least reactive PG-Cl reagent
reacts most selectively, as indicated by the high yield of
dipeptide 2l (Table 2).
Finally, we would like to emphasize that the one-pot pro-
tocols described here cannot simply be used for the de-
rivatization of other amino acids. For example, using
valine as a substrate, neither the N-Boc tert-butyl ester nor
the N-Cbz methyl ester could be obtained, possibly be-
cause of the negligible solubility of valine (and other
amino acids) in most organic solvents.10
[a]D20 –16.9 (c 1.46, CHCl3) [Lit.3b [a]D26 –13.1 (c 1.1, CHCl3)].
IR (ATR): 2971, 2933, 1692, 1670, 1449, 1385, 1349, 1253, 1158,
1117, 1083 (s) cm–1.
1H NMR (300 MHz, CDCl3): d = 4.64/4.54 (2 × d, J = 7.9, 8.2 Hz,
1 H, NCH), 3.72/3.66 (2 × d, J = 3.0, 2.9 Hz, 3 H, OCH3), 3.52–
3.33 (m, 2 H, NCH2), 3.14 (d, J = 3.0 Hz, 3 H, NCH3), 2.17–2.04
(m, 1 H, NCHCHH), 1.92–1.79 (m, 3 H, NCHCHHCH2), 1.40–1.34
[m, 9 H, C(CH3)3].
13C NMR (75 MHz, CDCl3): d = 173.7/173.2 [CH(CO)], 154.4/
153.8 [N(CO)], 79.4 [C(CH3)3], 61.2/61.1 (OCH3), 56.7/56.4
(NCH), 46.8/46.5 (NCH2), 32.3/32.2 (NCH3), 30.4/29.5
(NCHCH2), 28.4/28.3 [C(CH3)3], 24.0/23.3 (NCH2CH2).
In summary, we have developed efficient, practical and
scalable one-pot procedures for the direct conversion of
proline (1) into N-protected proline esters and amides of
type 2. Because of the shorter overall reaction time and
the avoidance of workup/isolation at the stage of the pri-
mary N-protected intermediates of type 5 (or 7), we are
optimistic that our protocols will find application in the
future, especially for large-scale preparations.
LRMS (EI): m/z (%) = 185 (10), 170 (20), 114 (85), 70 (100), 57
(90).
1H and 13C NMR spectra were recorded at r.t. in CDCl3 on Bruker
instruments (Avance DPX 300 or Avance DRX 500). Chemical
shifts (d) are reported in parts per million (ppm) from tetramethyl-
silane using the residual solvent resonance as the internal standard
(CDCl3: 7.24 ppm for 1H NMR, 77.0 ppm for 13C NMR). Multiplic-
ities are abbreviated as follows: s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet). IR spectra were recorded on a Perkin-
Elmer Paragon 1000 FT IR spectrometer in ATR mode at r.t. Mass
spectra were recorded on Finnigan instruments [MAT Inocs 50 Gal-
axy system (for EI) and MAT 900 (for ESI)]. Optical rotations were
determined on a Perkin-Elmer 343 polarimeter. Melting points (un-
corrected) were determined on a Büchi B-545 instrument. Analyti-
cal TLC was carried out using precoated silica gel plates (Merck
TLC plates, silica gel 60 F254). Flash column chromatography was
performed using Merck silica gel 60 (0.040–0.063 mm). All water-
sensitive reactions were carried out in flame-dried glassware under
an argon atmosphere. Chemicals were purchased from Merck,
Sigma-Aldrich, Fluka, Acros, Lancaster or Strem and used without
further purification. Solvents were dried as follows: THF was dis-
tilled from sodium/benzophenone under argon atmosphere; CH2Cl2
was refluxed and distilled from CaH2 under argon.
N-Boc-Protected Proline Derivatives 2a, 2b and 2d; General
Procedure
The solvent and the reagents (including equivalents) are given in
Table 1 (the reagents are written in the order they were added). In
general, a suspension of L-proline (1; 2–9 mmol, 1 equiv) in an ap-
propriate solvent ([1] = 0.3 mol/L) was treated with Boc2O and
Et3N at r.t. and the mixture was stirred for 1–3 h; full conversion
into 7a was monitored through the formation of a clear solution.
Then, the reaction mixture was cooled to 0 °C, treated with addi-
tional reagents (see Table 1, ‘Reagents’ column) and stirred at r.t.
overnight (except for 2a: 2 h). For workup, the reaction mixture was
either filtered with EtOAc–cyclohexane (1:1) through a layer of sil-
ica gel or diluted with MTBE (and filtered, when DCC was used),
washed with 1 M HCl, sat. NaHCO3 soln and brine, dried over
MgSO4 and concentrated under reduced pressure. All products were
purified by column chromatography on silica gel (EtOAc–cyclo-
hexane).
Methyl N-(tert-Butoxycarbonyl)-L-prolinate (2a)
20
Yield: 352 mg (81%); colorless oil; [a]D –56.2 (c 1.685, CHCl3)
[Lit.22 [a]D20 –56.5 (c 4.2, CHCl3)].
IR (ATR): 2972, 2930, 1749, 1692, 1403, 1365, 1201, 1086 cm–1.
Large-Scale Synthesis of the N-Boc-L-proline-Derived Weinreb
Amide 2c [tert-Butyl (S)-2-{[Methoxy(methyl)amino]carbon-
yl}pyrrolidine-1-carboxylate]
1H NMR (300 MHz, CDCl3): d = 4.25/4.15 (2 × dd, J = 8.1, 2.3,
8.3, 3.8 Hz, 1 H, NCH), 3.65 (s, 3 H, OCH3), 3.52–3.27 (m, 2 H,
NCH2), 2.22–2.04 (m, 1 H, NCH2CHH), 1.95–1.73 (m, 3 H,
NCH2CHHCH2), 1.39/1.34 [2 × s, 9 H, C(CH3)3].
13C NMR (75 MHz, CDCl3): d = 173.6/173.3 [CH(CO)], 154.3/
153.6 [N(CO)], 79.6 [C(CH3)3], 59.0/58.6 (NCH), 51.9/51.7
(OCH3), 46.4/46.2 (NCH2), 30.7/29.8 (NCHCH2), 28.3/28.1
[C(CH3)3], 24.2/23.5 (NCH2CH2).
A suspension of L-proline (1; 20.0 g, 174 mmol, 1.0 equiv) and
Boc2O (39.0 mL, 182 mmol, 1.05 equiv) in CHCl3 (350 mL) was
cooled to 0 °C and treated within 10 min with Et3N (31.4 mL,
226 mmol, 1.3 equiv). The cooling bath was removed and the mix-
ture was stirred at r.t. for 1.5 h, at which time a clear solution had
formed. The mixture was cooled again in an ice bath before hydrox-
ylamine 8 (20.33 g, 208 mmol, 1.2 equiv) was added. Then, the
mixture was stirred for a further 30 min in order to quench the ex-
cess Boc2O, and treated successively with DMAP (4.25 g, 34.7
mmol, 0.2 equiv) and dropwise with a soln of DCC (39.4 g,
191 mmol, 1.1 equiv) in CHCl3 (150 mL). The cooling bath was re-
moved and the mixture was stirred at r.t. for 20 h. To quench the re-
maining DCC, 1 M HCl (150 mL) was added to the reaction mixture
(cooled to 0 °C) and stirring was continued for a further 15 min.
Then, the mixture was filtered, the residue (N,N¢-dicyclohexylurea)
was washed with CHCl3 (3 × 50 mL) and the combined organic
phases were washed with 1 M HCl (150 mL), NaHCO3 soln (150
mL) and half-saturated NaCl soln (150 mL). The organic phase was
dried over MgSO4, then concentrated under reduced pressure. In or-
LRMS (EI): m/z (%) = 128 (10), 114 (15), 70 (25), 56 (50), 41
(100).
tert-Butyl N-(tert-Butoxycarbonyl)-L-prolinate (2b)
20
Yield: 2.28 g (97%); colorless oil; [a]D –52.2 (c 1.245, CHCl3)
[Lit.23 [a]D25 –50.5 (c 3.4, CHCl3)].
IR (ATR): 2970, 1738, 1692, 1545, 1391, 1363, 1254, 1162, 1117,
1086 cm–1.
1H NMR (500 MHz, CDCl3): d = 4.13/4.05 (2 × dd, J = 8.4, 3.0,
8.9, 3.0 Hz, 1 H, NCH), 3.49–3.28 (m, 2 H, NCH2), 2.17–2.04 (m,
Synthesis 2011, No. 6, 954–960 © Thieme Stuttgart · New York

958
P. Huy, H.-G. Schmalz
PAPER
1 H, NCH2CHH), 1.90–1.82 (m, 2 H, NCH2CHHCHH), 1.81–1.73
(m, 1 H, NCH2CH2CHH), 1.40–1.37 [m, 18 H, 2 × C(CH3)3].
HRMS (ESI): m/z calcd for C20H26N2O5Na: 397.1740; found:
397.174.
13C NMR (125 MHz, CDCl3): d = 172.2 [CH(CO)], 154.2/153.8
[N(CO)], 80.7/79.5/79.3 [C(CH3)3], 59.6/59.5 (NCH), 46.4/46.2
(NCH2), 30.8/29.8 (NCHCH2), 28.3/28.2/27.9/27.8 [C(CH3)3],
24.1/23.3 (NCH2CH2).
N-Cbz-, N-Moc- and N-Fmoc-Protected Proline Derivatives
2f–i, 2k and 2l; General Procedure
The solvent and the reagents (including equivalents and the order of
addition) are given in Table 2. In general, a suspension of L-proline
(1; 9–11 mmol, 1 equiv) and Et3N (or DIPEA in the case of 2l) in
CHCl3 ([1] = 0.3 mol/L) was cooled to –20 °C and treated very
slowly with a soln of PG-Cl (PG = Cbz, Moc, Fmoc) in CHCl3
([PG-Cl] = 2 mol/L). The cooling bath was removed and the mix-
ture was stirred at r.t. for 0.5–1 h; full conversion into 7b–d was in-
dicated by formation of a clear solution. Then, the reaction mixture
was cooled to 0 °C, treated with additional reagents (see Table 2,
‘Reagents’ column) and stirred at r.t. overnight. For workup, the re-
action mixture was either filtered with EtOAc–cyclohexane (1:1)
through a layer of silica gel or diluted with MTBE (and filtered,
when DCC was used), washed with 1 M HCl, sat. NaHCO3 soln and
brine, dried over MgSO4 and concentrated under reduced pressure.
All products were purified by column chromatography on silica gel
(EtOAc–cyclohexane; for 2l: MeOH–EtOAc, 1:50).
LRMS (EI): m/z (%) = 170 (5), 114 (15), 70 (20), 56 (50), 41 (100).
Methyl N-(tert-Butoxycarbonyl)-L-prolyl-L-serinate (2d)
Yield: 503 mg (80%); pale yellow oil; [a]D20 –18.1 (c 2.56, CHCl3).
IR (ATR): 3347, 2971, 1741, 1684, 1651, 1539, 1395, 1206 (s),
1160, 1085 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.10–6.79 (m, 1 H, NH), 4.53 (s,
1 H, NHCH), 4.16 (pseudo-t, J = 6.0 Hz, 1 H, BocNCH), 3.93–3.68
(m, 6 H, CH2OH, OCH3), 3.41–3.32 (m, 2 H, NCH2), 2.06–1.71 (m,
4 H, NCH2CH2CH2), 1.36 [s, 9 H, C(CH3)3].
13C NMR (75 MHz, CDCl3): d = 173.0/172.5 [(CO)NH], 170.6
[(CO)OCH3], 155.0/154.4 [N(CO)O], 80.4 [C(CH3)3], 62.8/62.5/
62.2 (CH2OH), 60.7/60.5/60.0 (BocNCH), 54.9/54.6/54.3 (NHCH),
52.4 (OCH3), 47.0 (NCH2), 30.9/29.4/29.3 (NCH2CH2CH2), 28.1/
27.7 [C(CH3)3], 24.4/23.6 (NCH2CH2).
Methyl N-(Benzyloxycarbonyl)-L-prolinate (2f; Table 2, Entry
1)
LRMS (EI): m/z (%) = 316 (<1) [M+], 243 (5), 170 (15), 114 (90),
70 (100), 57 (55), 41 (30).
20
Yield: 1.75 g (76%); pale yellow oil; [a]D –59.3 (c 1.34, CHCl3)
[Lit.1f [a]D20 –54.6 (c 0.48, CHCl3)].
HRMS (ESI): m/z calcd for C14H24N2O6Na: 339.1532; found:
339.154.
IR (ATR): 3030, 2976, 1744, 1698, 1606, 1445, 1406, 1349 (vs),
1198, 1166, 1116, 1086, 1000 (s) cm–1.
1H NMR (300 MHz, CDCl3): d = 7.34–7.26 (m, 5 H, C6H5), 5.18–
4.99 (m, 2 H, CH2Ph), 4.37/4.32 (2 × dd, J = 8.8, 3.1, 8.9, 3.5 Hz, 1
H, NCH), 3.71–3.41 (m, 5 H, NCH2, OCH3), 2.27–2.11 (m, 1 H,
NCHCHH), 2.03–1.80 (m, 3 H, NCHCHHCH2).
13C NMR (75 MHz, CDCl3): d = 173.2/173.0 [CH(CO)], 154.8/
154.2 [N(CO)], 136.6/136.5 (CH2CPh), 128.3/127.8/127.7
(5 × CHPh), 66.9/66.8 (OCH2), 59.0/58.7 (OCH3), 52.1/52.0 (NCH),
46.8/46.3 (NCH2), 30.8/29.8 (NCHCH2), 24.2/23.4 (NCH2CH2).
tert-Butyl (S)-2-[(S)-4-Benzyl-2-oxo-1,3-oxazolidin-3-ylcarbon-
yl]pyrrolidine-1-carboxylate (2e)
To a suspension of L-proline (1; 1.04 g, 9.05 mmol, 1.0 equiv) in
anhyd THF (45 mL) cooled to 0 °C ([1] = 0.2 mol/L) were added
under argon atmosphere Boc2O (1.94 mL, 9.05 mmol, 1.0 equiv)
and Et3N (4.2 mL, 29.9 mmol, 3.3 equiv) and stirring was continued
at r.t. for 5 h to form a clear solution. Then, the mixture was cooled
in an ice bath before PvCl (2.23 mL, 18.10 mmol, 2.0 equiv) was
very slowly added. The cooling bath was removed and the mixture
was stirred at r.t. for 2.5 h, then cooled again to 0 °C before anhyd
LiCl (650 mg, 15.5 mmol, 1.7 equiv) and the Evans auxiliary 10
(1.764 g, 9.96 mmol, 1.1 equiv) were added, and this mixture was
stirred at r.t. for another 14 h. The suspension was diluted with 1 M
HCl (10 mL) and MTBE (45 mL). The organic phase was separated
and washed with 1 M HCl (10 mL), sat. aq NaHCO3 (10 mL) and
brine (10 mL), dried over MgSO4 and concentrated under reduced
pressure. Purification of the residue by column chromatography on
silica gel (EtOAc–cyclohexane, 1:2 to 1:1) delivered 2e as a color-
less oil; yield: 2.45 g (6.53 mmol, 72%).
LRMS (EI): m/z (%) = 263 (1) [M+], 204 (25), 160 (25), 91 (100).
tert-Butyl N-(Benzyloxycarbonyl)-L-prolinate (2g)
Yield: 2.69 g (77%); colorless solid; mp 43–44 °C (Lit.24 44–
20
25
45 °C); [a]D –50.3 (c 1.985, CHCl3) [Lit.24 [a]D –52.5 (c 2.2,
CHCl3)].
IR (ATR): 3032, 2972, 2877, 1735, 1699, 1586, 1408, 1219, 1146,
1115, 1085 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.35–7.25 (m, 5 H, C6H5), 5.17–
5.03 (m, 2 H, CH2Ph), 4.27/4.22 (2 × dd, J = 9.2, 2.8, 8.8, 3.5 Hz, 1
H, NCH), 3.62–3.38 (m, 2 H, NCH2), 2.24–2.07 (m, 1 H, NCH-
CHH), 1.99–1.78 (m, 3 H, NCHCHHCH2), 1.42/1.32 [2 × s, 9 H,
C(CH3)3].
[a]D20 –23.2 (c 1.36, CHCl3).
IR (ATR): 3060, 2973, 1774, 1683, 1600, 1476, 1384, 1243, 1203,
1162, 1107 cm–1.
13C NMR (75 MHz, CDCl3): d = 171.8/171.7 [CH(CO)], 154.6/
154.3 [N(CO)], 136.8/136.6 (CH2CPh), 128.4/128.3/128.2/127.9/
127.9/127.7/127.6 (5 × CHPh), 81.0 [C(CH3)3], 66.7 (CH2Ph), 59.8/
59.4 (NCH), 46.8/46.3 (NCH2), 30.8/29.8 (NCHCH2), 27.8/27.7
[C(CH3)3], 24.1/23.3 (NCH2CH2).
1H NMR (500 MHz, CDCl3): d = 7.29–7.20 (m, 5 H, C6H5), 5.38–
5.35 (m, 1 H, BocNCH), 4.59–4.55 (m, 1 H, NCHCH2Ph), 4.16–
4.09 (m, 2 H, CH2O), 3.57–3.51 (m, 1 H, NCHH), 3.45–3.29 (m, 2
H, NCHH, CHHPh), 2.75/2.55 (2 × dd, J = 9.8, 3.5, 10.8, 1.7 Hz, 1
H, CHHPh), 2.34–2.24 (m, 1 H, BocNCHCHH), 1.84 (s, 3 H,
BocNCHCHHCH2), 1.39/1.35 [2 × s, 9 H, C(CH3)3].
LRMS (EI): m/z (%) = 204 (5), 160 (10), 91 (65), 57 (100), 41 (55),
13C NMR (125 MHz, CDCl3): d = 173.3/173.0 [CH(CO)], 154.2/
153.6 [(CO)OC(CH3)3], 153.1 [(CO)N(CO)O], 135.4/135.2
(CH2CPh), 129.4/129.3/129.0/128.8/127.4/127.1 (5 × CHPh), 79.7/
79.6 [OC(CH3)3], 66.5 (CH2O), 59.0 (BocNCH), 55.6/55.2
(CHCH2Ph), 46.8/46.6 (NCH2), 38.1/37.6 (CH2Ph), 30.8/29.7
(BocNCHCH2), 28.4 [C(CH3)3], 24.1/23.0 (NCH2CH2).
39 (20).
N-Cbz-L-proline-Derived Weinreb Amide 2h [Benzyl (S)-2-
{[Methoxy(methyl)amino]carbonyl}pyrrolidine-1-carboxylate]
Yield: 2.03 g (76%); pale yellow oil; [a]D20 –2.5 (c 2.445, CHCl3).
IR (ATR): 3028, 2970, 2939, 2879, 1702, 1668, 1607, 1443, 1405,
1352, 1318, 1207, 1171, 1116, 1082 cm–1.
LRMS (EI): m/z (%) = 318 (5), 207 (20), 178 (25), 114 (60), 91
(55), 70 (100), 57 (55), 41 (100).
Synthesis 2011, No. 6, 954–960 © Thieme Stuttgart · New York

PAPER
Practical One-Pot Double Functionalizations of Proline
959
1H NMR (300 MHz, CDCl3): d = 7.32–7.27 (m, 5 H, C6H5), 5.17–
4.98 (m, 2 H, CH2Ph), 4.73/4.62 (2 × dd, J = 8.2, 3.4, 8.3, 3.7 Hz, 1
H, NCH), 3.76 (s, 3 H, OCH3, one rotamer), 3.68–3.57 (m, 1 H,
NCHH), 3.55–3.44 (m, 1 H, NCHH), 3.36 (s, 3 H, OCH3, second
rotamer), 3.18 (s, 3 H, NCH3, one rotamer), 3.06 (s, 3 H, NCH3, sec-
ond rotamer), 2.24–2.10 (m, 1 H, NCHCHH), 2.07–1.95 (m, 1 H,
NCH2CHH), 1.94–1.78 (m, 2 H, NCHCHH, NCH2CHH).
13C NMR (75 MHz, CDCl3): d = 172.1 [(CO)NH], 170.8
[(CO)OCH3], 155.6 [N(CO)O], 143.9/143.6 (CHCCCH), 141.2
(CCHC), 127.7/127.0/125.1/125.0/119.9 (ArH), 67.8 [CH2O(CO)],
62.3 (NHCH), 60.7 (CH2OH), 55.1 (NCH), 52.6 (OCH3), 47.5
[CHCH2O(CO)], 47.1 (NCH2), 29.3 (NCHCH2), 24.6 (NCH2CH2).
Methyl N-(Methoxycarbonyl)-L-prolinate (2j)
A soln of L-proline (1; 2.16 g, 18.8 mmol, 1.0 equiv) in MeOH
(40 mL) was cooled to 0 °C and treated with Et3N (7.9 mL,
56.4 mmol, 3.0 equiv) before MocCl (4.1 mL, 52.6 mmol,
2.8 equiv) was added dropwise. The mixture was stirred at r.t. for
21 h, then MeOH was removed under reduced pressure and the res-
idue was dissolved in 1 M HCl (40 mL). After extraction with
MTBE (3 × 40 mL), the combined organic phases were dried over
MgSO4 and concentrated under reduced pressure to give 2j as a col-
orless oil; yield: 2.852 g (15.2 mmol, 81%).
13C NMR (75 MHz, CDCl3): d = 172.8 [CH(CO)], 154.9/154.2
[N(CO)], 136.7/136.6 (CH2CPh), 128.4/128.3/128.2/127.9/127.8/
127.7 (5 × CHPh), 67.1/66.8 (CH2Ph), 61.3/60.8 (OCH3), 56.9/56.5
(NCH), 47.2/46.7 (NCH2), 32.1 (NCH3), 30.5/29.6 (NCHCH2),
24.2/23.4 (NCH2CH2).
LRMS (EI): m/z (%) = 232 (5), 204 (25), 160 (25), 91 (100), 65
(10).
Methyl N-(Benzyloxycarbonyl)-L-prolyl-L-serinate (2i)
[a]D20 –71.2 (c 2.815, CHCl3) [Lit.25 [a]D20 –78.6 (c 1.3, MeOH)].
Yield: 2.28 g (70%); colorless solid; mp 106 °C (Lit.1g 103–
20
25
107 °C); [a]D –24.4 (c 1.53, CHCl3) [Lit.1g [a]D –29.0 (c 2,
IR (ATR): 2981, 2952, 1748, 1717, 1683, 1389, 1200, 1117, 1089
CHCl3)].
cm–1.
IR (ATR): 3317, 3065, 2952, 1745, 1668, 1538, 1531, 1454, 1416,
1355, 1205, 1119 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.31/4.25 (2 × dd, J = 5.0, 3.5,
8.4, 3.3 Hz, 1 H, NCH), 3.67–3.60 (m, 6 H, 2 × OCH3), 3.58–3.33
(m, 2 H, NCH2), 2.24–2.07 (m, 1 H, NCHCHH), 2.00–1.77 (m, 3 H,
NCHCHHCH2).
13C NMR (75 MHz, CDCl3): d = 173.1/173.0 [CH(CO)], 155.3/
154.8 [N(CO)], 59.0/58.6 (2 × OCH3), 52.4/52.0 (NCH), 46.7/46.2
(NCH2), 30.8/29.7 (NCHCH2), 24.2/23.3 (NCH2CH2).
1H NMR (300 MHz, CDCl3): d = 7.30–7.24 (m, 5 H, C6H5), 7.19/
6.91 (2 × d, J = 7.9, 4.5 Hz, 1 H, NH), 5.14–5.02 (m, 2 H, CH2Ph),
4.58–4.56 (m, 1 H, NHCH), 4.26–4.24 (m, 1 H, CbzNCH), 3.89–
3.29 (m, 8 H, NCH2, CH2OH, OCH3), 2.12–1.76 (m, 4 H,
NCH2CH2CH2).
13C NMR (75 MHz, CDCl3): d = 172.6/172.1 [(CO)NH], 170.7
[(CO)OCH3], 155.4 [N(CO)O], 136.2 (CH2CPh), 128.3/127.9/127.7
(5 × CHPh), 67.2 (CH2Ph), 62.8/62.2 (CH2OH), 60.4 (CbzNCH),
54.9/54.4 (NHCH), 52.5 (OCH3), 46.9 (NCH2), 29.4 (NCHCH2),
24.4 (NCH2CH2).
LRMS (EI): m/z (%) = 187 (5) [M+], 128 (100), 82 (10), 59 (5), 42
(15).
Acknowledgment
LRMS (EI): m/z (%) = 350 (<1) [M+], 215 (5), 160 (40), 114 (5), 91
(100), 70 (25).
For financial support we thank the DFG (FO 806) and the Fonds der
Chemischen Industrie (Doctoral Fellowship to P.H.).
HRMS (EI): m/z calcd for C17H22N2O6: 350.1477; found: 350.148.
References
tert-Butyl N-(Methoxycarbonyl)-L-prolinate (2k)
Yield: 1.59 g (69%); colorless liquid; [a]D20 –52.2 (c 1.275, CHCl3).
(1) Selected references: (a) Gentilucci, L.; Cerisoli, L.;
De Marco, R.; Tolomelli, A. Tetrahedron Lett. 2010, 51,
2576. (b) Dai, N.; Etzkorn, F. A. J. Am. Chem. Soc. 2009,
131, 13728. (c) Chiba, K.; Sugihara, M.; Yoshida, K.;
Mikami, Y.; Kim, S. Tetrahedron 2009, 65, 8014.
(d) Heiser, U.; Niestroj, A. J.; Schulz, I. WO Patent 007415
A2, 2009. (e) Sun, H.; Martin, C.; Kesselring, D.; Keller, R.;
Moeller, K. D. J. Am. Chem. Soc. 2006, 128, 13761.
(f) Pfeifer, M. E.; Linden, A.; Robinson, J. A. Helv. Chim.
Acta 1997, 80, 1513. (g) Falorni, M.; Porcheddu, A.;
Giacomelli, G. Tetrahedron: Asymmetry 1996, 7, 1999.
(2) Selected references: (a) Woodin, K. S.; Jamison, T. F.
J. Org. Chem. 2007, 72, 7451. (b) Ni, Y.; Zhao, G.; Ding, Y.
J. Chem. Soc., Perkin Trans. 1 2000, 3264. (c) Sibi, M.;
Christensen, J. J. Org. Chem. 1999, 64, 6434. (d)Céliméne,
C.; Dhimane, H.; Lhommet, G. Tetrahedron 1998, 54,
10457.
(3) See, for example: (a) Chena, Z.; Ye, T. New J. Chem. 2006,
30, 518. (b) Yokokawa, F.; Sameshima, H.; In, Y.; Minoura,
K.; Ishida, T.; Shioiri, T. Tetrahedron 2002, 58, 8127.
(4) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc.
1987, 109, 5551. (b) Corey, E. J.; Helal, C. J. Angew. Chem.
Int. Ed. 1998, 37, 1986. (c) Stemmler, R. T. Synlett 2007,
997.
IR (ATR): 3088, 2975, 2953, 1738, 1699, 1446, 1385, 1152, 1119,
1089 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.18/4.08 (2 × dd, J = 8.2, 2.8,
8.3, 3.4 Hz, 1 H, NCH), 3.64/3.60 (2 × s, 3 H, OCH3), 3.55–3.30 (m,
2 H, NCH2), 2.21–2.03 (m, 1 H, NCHCHH), 1.96–1.72 (m, 3 H,
NCHCHHCH2), 1.40/1.38 [2 × s, 9 H, C(CH3)3].
13C NMR (75 MHz, CDCl3): d = 171.9/171.7 [CH(CO)], 155.3/
154.9 [N(CO)], 81.0 [C(CH3)3], 59.7/59.5 (NCH), 52.3/52.2
(OCH3), 46.8/46.2 (NCH2), 30.7/29.8 (NCHCH2), 27.8 [C(CH3)3],
24.1/23.3 (NCH2CH2).
LRMS (EI): m/z (%) = 128 (100), 114 (5), 82 (10), 57 (10), 41 (20).
Methyl N-(9-Fluorenylmethoxycarbonyl)-L-prolyl-L-serinate
(2l)
20
Yield: 630 mg (83%); colorless solid; mp 118 °C; [a]D –6.7 (c
1.06, CHCl3).
IR (ATR): 3320, 2950, 1743, 1664, 1419, 1203, 1120, 1086 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.74 (d, J = 7.4 Hz, 2 H, ArH),
7.59–7.55 (m, 2 H, ArH), 7.40–7.35 (m, 2 H, ArH), 7.31–7.26 (m,
2 H, ArH), 7.10–6.84 (m, 1 H, NH; thereunder at 7.09, d,
J = 7.4 Hz), 4.59–4.56 (m, 1 H, NHCH), 4.41–4.19 [m, 4 H, NCH,
CHCH2O(CO)], 3.99–3.86 (m, 2 H, CH2OH), 3.85–3.73 (m, 4 H,
OCH3, NCHH), 3.56–3.50 (m, 1 H, NCHH), 3.17 (s, 1 H, OH),
(5) Corey, E. J. Angew. Chem. Int. Ed. 2002, 41, 1650.
(6) For recent reviews, see: (a) Bertelsen, S.; Jørgensen, K. A.
Chem. Soc. Rev. 2009, 38, 2178. (b) MacMillan, D. W. C.
Nature (London) 2008, 455, 304. (c) Dondoni, A.; Massi,
A. Angew. Chem. Int. Ed. 2008, 47, 4638.
2.20–2.02 (m,
3 H, NCHCH2CHH), 1.94–1.84 (m, 1 H,
NCHCH2CHH).
Synthesis 2011, No. 6, 954–960 © Thieme Stuttgart · New York

960
P. Huy, H.-G. Schmalz
PAPER
(14) Zhou, Z. H.; Tang, Y. L.; Li, K. Y.; Liu, B.; Tang, C. C.
(7) Zaminer, J.; Brockmann, C.; Huy, P.; Opitz, R.; Reuter, C.;
Beyermann, M.; Freund, C.; Müller, M.; Oschkinat, H.;
Kühne, R.; Schmalz, H.-G. Angew. Chem. Int. Ed. 2010, 49,
7111.
(8) (a) Anderson, G. W.; McGregor, A. C. J. Am. Chem. Soc.
1957, 79, 6180. (b) Kaname, M.; Mashige, H.; Yoshifuji, S.
Chem. Pharm. Bull. 2001, 49, 531.
(9) (a) Takeda, K.; Akiyama, A.; Nakamura, H.; Takizawa, Y.;
Mizuno, Y.; Takayanagi, H.; Harigaya, Y. Synthesis 1994,
1063. (b) Held, I.; Von Den Hoff, P.; Stephenson, D. S.;
Zipse, H. Adv. Synth. Catal. 2008, 350, 1891.
Heteroat. Chem. 2003, 14, 603.
(15) (a) König, W.; Geiger, R. Chem. Ber. 1970, 103, 788.
(b) Deng, S.; Taunton, J. Org. Lett. 2005, 7, 299.
(16) DCC-mediated coupling of 10 in the presence of DMAP led
to the isolation of 2e in only 48% yield, along with 21% of
the tert-butyl ester 2b resulting from the reaction of 7a with
tert-butyl alcohol.
(17) (a) Ho, G.-J.; Mathre, D. J. J. Org. Chem. 1995, 60, 2271.
(b) Soloshonok, V. A.; Ueki, H.; Jiang, C.; Cai, C.; Hruby,
V. J. Helv. Chim. Acta 2002, 85, 3616.
(10) Hayashi, Y.; Matsuzawa, M.; Yamaguchi, J.; Yonehara, S.;
Matsumoto, Y.; Shoji, M.; Hashizume, D.; Koshino, H.
Angew. Chem. Int. Ed. 2006, 45, 4593.
(11) To the best of our knowledge, the only one-step protocols for
the synthesis of compounds of type 2 described so far lead to
N-Moc (or N-Eoc)-protected proline esters; see: (a) Kanth,
J. V. B.; Perlasamy, M. Synth. Commun. 1995, 25, 1523.
(b) Oliveira, D. F.; Miranda, P. C. M. L.; Correia Carlos, R.
D. J. Org. Chem. 1999, 64, 6646.
(18) Kim, S.; Lee, J. I.; Kim, Y. C. J. Org. Chem. 1985, 50, 560.
(19) Methyl ester 2j was synthesized in 93% yield with K2CO3
instead of Et3N.11b
(20) For example, the yield of tert-butyl ester 2k (Table 2, entry
9) dropped to 42% when MocCl was added undiluted.
(21) Mayr, H.; Ofial, A. R. Angew. Chem. Int. Ed. 2006, 45,
1844; and references cited therein.
(22) Beckett, R. P.; Davies, S. G.; Mortlock, A. A. Tetrahedron:
Asymmetry 1992, 3, 123.
(12) Protic solvents such as water or alcohols are rival
(23) Gibson, F. S.; Bergmeier, S. C.; Rapoport, H. J. Org. Chem.
1994, 59, 3216.
nucleophiles.
(13) The esterification step requires DMAP as a nucleophilic
catalyst, which activates both Boc2O (to react with the
carboxylate) and the resulting mixed anhydride (to react
with t-BuOH); see ref. 9a.
(24) Anderson, G. W.; Callahan, F. M. J. Am. Chem. Soc. 1960,
82, 3359.
(25) Irie, K.; Ishida, A.; Nakamura, T.; Oh-ishi, T. Chem. Pharm.
Bull. 1984, 32, 2126.
Synthesis 2011, No. 6, 954–960 © Thieme Stuttgart · New York