Flexible and modular syntheses of enantiopure 5-cis-substituted prolinamines from l-pyroglutamic acid

Article abstract of DOI:10.1055/s-0034-1379457

A wide range (25 examples) of 5-cis-substituted prolinamines is prepared in five to ten steps starting from cheap l-pyroglutamic acid. Three routes, differing mainly in the order of introduction of the substituents at the 5-cis position, the pyrrolidine nitrogen atom, and the exocyclic amino function, are successfully developed.

Full text of DOI:10.1055/s-0034-1379457

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 575–586
paper
575
F. Prause et al.
Paper
Synthesis
Flexible and Modular Syntheses of Enantiopure 5-cis-Substituted
Prolinamines from L-Pyroglutamic Acid
Felix Prause
Johannes Kaldun
OH
H
NR3R4
NR3R4
R1 MgX O
R1
Benjamin Arensmeyer1
Benedikt Wennemann2
Benjamin Fröhlich1
Dagmar Scharnagel
Matthias Breuning*
N
N
O
R2
H
(X)
R2
25 examples
5–10 steps, up to 64% yield
Organic Chemistry Laboratory, University of Bayreuth,
Universitätsstraße 30, 95447 Bayreuth, Germany
matthias.breuning@uni-bayreuth.de
Received: 12.09.2014
Accepted after revision: 23.10.2014
Published online: 27.11.2014
Ph
Ph
Ar
Ar
Ph
Ph
N
N
N
Me
H
OH
DOI: 10.1055/s-0034-1379457; Art ID: ss-2014-t0562-op
OTMS
B
O
Me
1
2 Ar = 3,5-(CF3)2C6H3
3
Abstract A wide range (25 examples) of 5-cis-substituted prolin-
amines is prepared in five to ten steps starting from cheap L-pyroglu-
tamic acid. Three routes, differing mainly in the order of introduction of
the substituents at the 5-cis position, the pyrrolidine nitrogen atom,
and the exocyclic amino function, are successfully developed.
Me
Me
N
R1
Me
H
N
HN
R2
NR3R4
4
5
Figure 1 The privileged proline derived ligands 1–43–6 and the new 5-
cis-substituted prolinamines 5
Key words amines, ligands, stereoselective synthesis, pyrrolidines,
prolinamines
we tested these compounds in copper(II)-catalyzed Henry
reactions.8,9 Indeed, the simple diamine 5a, which possesses
a 5-cis-phenyl group, proved to be an excellent chiral ligand
(Scheme 1).10 Extremely high asymmetric inductions of 99%
ee were obtained with a wide range of aromatic, heteroaro-
matic, vinylic, and aliphatic aldehydes (36 examples), thus
making diamine 5a superior to all the other chiral ligands
examined so far in this type of reaction. Encouraged by this
success, we decided to study in more detail this interesting,
but almost unknown class11 of diamines 5, and therefore we
had to develop efficient and modular routes for their prepa-
ration.
Proline-derived amino alcohols and diamines have
found manifold applications in asymmetric catalysis. Some
prominent examples are Corey’s bicyclic CBS catalyst 1 (Fig-
ure 1), nowadays routinely used in enantioselective ketone
reductions,3 Jørgensen’s diarylprolinol silyl ether 2, a stan-
dard chiral organocatalyst,4 Soai’s tertiary amino alcohol 3,
one of the first chiral ligands for enantioselective additions
of diorganozinc reagents to aldehydes,5 and Gong’s iso-
borneol-substituted diamine 4, which gives excellent enan-
tioselectivities in copper-catalyzed Henry reactions.6 All
these compounds gain their high stereodiscriminating abil-
ities from the rigid bi- or oligocyclic nature of the interme-
diately formed reactive species, which, in return, is defined
by the privileged prolinol or prolinamine skeleton. Surpris-
ingly, no attention in asymmetric catalysis has as yet been
paid to proline derivatives possessing an additional substit-
uent at the 5-cis position, although such a substituent
might further enhance the level of chirality transfer.
Ph
N
Me
NHMe
5a (cat.)
CuCl2 or CuBr2 (cat.)
O
OH
*
+ MeNO2
NO2
R
H
Et3N, THF, –25 °C
R
>90%, 99% ee
(36 examples)
In the course of our studies on conformationally rigid li-
gands,7 we became interested in prolinamines of general
structure 5 and their performance in enantioselective catal-
ysis. Due to their close structural relationship to diamine 4,
R = aryl, hetaryl, 1-alkenyl, alkyl
Scheme 1 Enantioselective Henry reactions catalyzed by the prolin-
amine–copper(II) complexes [CuX2·5a] (X = Cl, Br)10
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 575–586

576
F. Prause et al.
Paper
Synthesis
Synthetic Routes
der to keep the system as simple as possible (Scheme 3 and
Table 1). The required precursor, the N-tert-butoxycarbon-
yl-protected dimethyl amide 7, was prepared in two steps
and in a good 81% yield by esterification of L-pyroglutamic
acid (6) with methanol, in situ amidation with dimethyl-
amine, and N-tert-butoxycarbonyl protection. Four differ-
ent aryl substituents R1 were introduced in analogy to
known sequences on pyroglutamic esters.12,13 Treatment of
7 with a slight excess of the respective Grignard reagent
(R1MgX) afforded the amino ketones 8a–d in acceptable to
good yields (43–76%). The subsequent three-step cycliza-
tions of 8a–d (N-Boc deprotection with concomitant imine
formation, reduction of the intermediate Δ1-pyrrolidine,
and reintroduction of the N-Boc protection) were accom-
plished in one pot without isolation of the intermediates,
giving the prolinamides 9a–c14 in good yields (76–90%). The
cis selectivities in the reductive cyclization step were pleas-
ing (dr ≥85:15),15 even with cheap sodium borohydride as
the reductant.16 Solely for the 1-naphthyl derivative 9d, the
cis selectivity dropped to 70:30,15 which explains the low
56% yield of the isolated product. The tert-butoxycarbonyl
group was reattached to the pyrrolidine nitrogen atom for
two reasons: (1) it facilitates significantly the chromato-
graphic purification, and (2) it serves as the precursor for
an N-methyl group. The final reduction of compounds
9a,b,d with lithium aluminum hydride at reflux tempera-
ture delivered the desired diamines 5b,c,e in excellent ≥85%
yields. In the case of 9c, however, partial defluorination of
the aryl trifluoromethyl groups occurred, leading to an in-
separable mixture.
An important precondition for our planned synthesis of
various prolinamines 5 was the elaboration of effective
strategies (Scheme 2), which permit a flexible screening of
the substituent R1 at the 5-cis position, R2 at the pyrrolidine
nitrogen atom, and R3R4 at the exocyclic amino function.
Based on literature protocols on the conversion of carba-
mate-protected pyroglutamic esters into 5-cis-substituted
proline esters,12,13 we focused on three major routes (I–III)
that all start from cheap L-pyroglutamic acid (6), but differ
in the order of the introduction of the R1–R4 moieties. Route
I is characterized by an early-stage installment of the NR3R4
group via an amide (6 → B), an intermediate attachment of
R1 (B → A), and a final incorporation of R2 (A → 5). In route
II, by contrast, R1 is introduced first (6 → D), then R2 (D → C),
and NR3R4 last by hydroxyl–amine exchange (C → 5). Route
III also proceeds via the ester D, but the NR3R4 moiety is in-
stalled via amidation (D → E) before R2 (E → 5). All three
routes offer distinct advantages with respect to the substit-
uent to be varied. While the synthetic work is minimized in
route I for a screening of R1 and R2, route II seems to be well
suited for a broad variation of the amino function NR3R4
since it can be introduced in the very last step. Route III pro-
vides a welcome alternative to route II, in particular if the
NR3R4 moiety cannot be introduced last due to compatibili-
ty reasons.
R1
N
R2
NR3R4
5
1. MeOH, H+;
O
O
R2
R2
R1MgX
route I
R1
NR3R4
route II
route III
Me2NH
O
6
R1
NMe2
NHBoc
O
2. Boc2O
81%
N
Boc
NMe2
O
O
R1
R'O2C
7
8a–d
R1
N
N
N
R2
NR3R4
NR3R4
R'O2C
OH
1. TFA
2. NaBH4
LAH
A
C
E
O
R1
R1
3. Boc2O
N
N
Boc
R1
R2
NR3R4
Me
NMe2
NMe2
9a–d
5b–e
O
O
Scheme 3 Route I: three-step cyclization
R1
O
N
R'O2C
N
NR3R4
R'O2C
OR
B
D
Table 1 Yields of Compounds 8, 9 and 5 Prepared According to
Scheme 3
R1
NR3R4
O
O
Entry R1
Yield of 8 (%) Yield of 9 (%)a Yield of 5 (%)
N
H
6
OH
1
2
3
4
Ph
72 (8a)
55 (8b)
76 (8c)
43 (8d)
76 (9a)
90 (9b)
85 (9c)
56 (9d)
85 (5b)
97 (5c)
Scheme 2 Envisioned synthetic routes I–III
4-MeOC6H4
3,5-(F3C)2C6H3
1-naphthyl
–
b (5d)
Route I
87 (5e)
a Yield of isolated pure cis diastereomer.
b Inseparable mixture of 5d and partially defluorinated derivatives.
Our initial investigations were aimed at a fast screening
of the 5-cis substituent R1, for which route I was envisaged,
and methyl groups were chosen as the R2–R4 groups in or-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 575–586

577
F. Prause et al.
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Synthesis
In order to prevent the unwanted fluoride–hydride ex-
change, we elaborated a milder, stepwise route for the con-
version of 9c into 5d (Scheme 4). After N-deprotection of 9c
with trifluoroacetic acid and methylation of the pyrrolidine
nitrogen atom, the amide function was reduced with bo-
rane–tetrahydrofuran complex in refluxing tetrahydrofu-
ran. This sequence provided the diamine 5d in an overall
60% yield without the formation of any defluorinated by-
products.
lithium hexamethyldisilazide and subsequent trapping
with ethyl chloroformate, which delivered amide 11 in an
overall yield of 79% from 6. Addition of phenylmagnesium
bromide in the presence of N,N,N′,N′-tetramethylethylene-
diamine (TMEDA),20 which is required to suppress compet-
ing attack on the carbamate group,18 afforded the ring-
opened ketone 12 in 60% yield. The following reductive
one-step cyclization with triphenylsilane–boron trifluo-
ride–diethyl ether complex (Ph3SiH–BF3·OEt2) provided the
pyrrolidine amide 13 with excellent cis selectivity (initial dr
>95:5).15 Final global reduction with lithium aluminum hy-
dride delivered the desired diamine 5b in overall just five
steps and 36% yield from 6. Compared to the synthesis of 5b
using the three-step cyclization (cf. Scheme 3 and Table 1,
entry 1: seven steps, 38% overall yield), this route is shorter
by two steps, but the requisite ethoxycarbonyl protecting
group makes the synthesis more laborious (anhydrous con-
ditions for ethyl chloroformate attachment, Grignard–
TMEDA adducts for addition)20 and restricts the chemical
flexibility (harsher conditions for carbamate cleavage).21
1. TFA
2. MeI
F3C
3. BH3•THF
9c
N
Me
60%
NMe2
F3C
5d
Scheme 4 Preparation of diamine 5d from 9c
The possibility of a last-step variation of the substituent
R2 at the pyrrolidine nitrogen was demonstrated on the 5-
phenyl derivative 9a (Scheme 5). N-Deprotection with tri-
fluoroacetic acid afforded amide 10a, which was reduced
with lithium aluminum hydride to give diamine 5f14 in 87%
yield over two steps. Reductive amination of 5f with benz-
1. MeOH, H+;
PhMgBr
TMEDA
O
O
Me2NH
O
6
O
2. LiHMDS;
ClCO2Et
Ph
NMe2
NHCO2Et
N
60%
EtO2C
NMe2
79%
11
12
aldehyde–sodium
triacetoxyborohydride
[PhCHO–
NaBH(OAc)3] provided the N-benzyl derivative 5h in a good
90% yield, while the analogous ethylation failed to give suf-
ficient product formation. With the reagent combination
acetic acid–sodium borohydride,17 however, the N-ethylat-
ed prolinamine 5g was obtained in a high 95% yield.
Ph3SiH
BF3•OEt2
LAH
O
Ph
Ph
N
N
83%
92%
Me
EtO2C
NMe2
NMe2
13
5b
Scheme 6 Route I: one-step cyclization
TFA
95%
LAH
92%
O
9a
Ph
Ph
N
H
N
H
Route II
NMe2
NMe2
10a
5f
In route II, prolinols of general type C (see Scheme 2) are
required as the precursors for the last-step variation of the
exocyclic amino group NR3R4 by hydroxyl–amine exchange.
The two 5-cis-aryl derivatives 17a and 17b were prepared
as outlined in Scheme 7, starting from L-pyroglutamic acid
(6), which was converted in a high 92% yield into the known
pyroglutamate 1422 by esterification and subsequent N-
tert-butoxycarbonyl protection. Applying the four-step se-
quence12,13,16 that had already been successfully used in
route I, delivered the prolines 16a10 and 16b23 in 51% and
26% overall yields, albeit with a lower cis preference in the
cyclization step (dr = 70:30 and 50:50, respectively),15 com-
pared to the analogous reaction on the corresponding di-
methyl amides 7 (dr = 85:15 and 70:30, respectively, cf.
Scheme 3). Interestingly, a partial diastereomer-differenti-
ating N-tert-butoxycarbonyl protection was observed for
the phenyl-substituted intermediate. With just a slight ex-
cess of di-tert-butyl dicarbonate, the cis/trans ratio in-
creased from 70:30 to 85:15 in 16a, presumably since the
pyrrolidine nitrogen atom in the cis isomer is more freely
accessible than in the trans isomer. Global reduction of
→ 5g: AcOH, NaBH4
→ 5h: PhCHO, NaBH(OAc)3
5g R2 = Et: 95%
5h R2 = Bn: 90%
Ph
N
R2
NMe2
Scheme 5 Route I: variation of R2
It was envisaged that a further shortening of this ap-
proach to diamines 5 might be possible by using a variant of
Martin’s procedure,18 in which a two-step protocol is de-
scribed for the introduction of 5-cis substituents to N-
ethoxycarbonyl-protected pyroglutamic esters. We ex-
plored this route for the synthesis of diamine 5b (Scheme
6). The preparation of the required amide 11 was first met
with some difficulties. After conversion of L-pyroglutamic
acid (6) into the corresponding dimethyl amide, all at-
tempts to attach the ethoxycarbonyl group to the lactam
function under standard conditions (ethyl chloroformate,
weak base such as Et3N)19 failed to give acceptable yields of
11, due to fast decomposition of the chloroformate.19a This
problem was overcome by quantitative deprotonation with
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 575–586

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F. Prause et al.
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Synthesis
NaBH(OAc)3, TFA
Ph3SiH, B(C6F5)3
Ph3SiH, BF3·OEt2
16a,b with lithium aluminum hydride in refluxing tetrahy-
drofuran afforded the 5-cis-aryl-substituted prolinols 17a,b
in good yields (82–96%), and in diastereomerically pure
form after purification.
no reaction
O
O
no reaction
Ph
X
NHBoc
8a X = NMe2
15a X = OMe
N-deprotection
1. MeOH, H+
2. Boc2O
O
O
R1MgX
O
6
OSiEt3
O
a R1
OMe
O
92%
N
Boc
O
+
15a: 92%
15b: 59%
Ph
OMe
NHBoc
Ph
X
N
Boc
Et3SiH
B(C6F5)3
15a,b
14
X
1. TFA
NHBoc
2. NaBH4
3. Boc2O
9a X = NMe2: 32%
16a X = OMe : 0%
18 X = NMe2: 17%
19 X = OMe: 79%
LAH
O
R1
R1
17a: 96%a
17b: 82%
16a: 60%a
16b: 47%
N
N
Boc
Scheme 8 Studies on the one-step cyclizations of the N-Boc-protected
γ-amino phenylketones 8a and 15a26
Me
OH
OMe
16a,b
15–17: a: R1 = Ph; b: R1 = 1-naphthyl
17a,b
ditions).24 The resulting N-tert-butoxycarbonyl-protected
pyrrolidines 16c–e23,28,29 were isolated in good 82–88%
yields and with pleasing cis selectivities (initial dr
>85:15).15 Thus, this reagent combination permits the effi-
cient synthesis of 5-cis-alkyl prolines without the need of
any N-deprotection–reprotection steps. Final reduction of
pyrrolidines 16c–e delivered the prolinols 17c–e in 77–94%
yields.
Scheme 7 Route II: synthesis of the prolinol precursors 17a,b.23 a Data
taken from ref. 10.
At this point we focused on bypassing the uneconomic
N-tert-butoxycarbonyl removal and reattachment steps,
which was a necessary part of the standard three-step cy-
clizations12,13 of N-tert-butoxycarbonyl-protected α-amino
δ-oxo esters. Literature protocols describing more efficient
one-step reductive cyclizations are rare; there is a single re-
port from McDermott et al. on the triacetoxyborohydride–
trifluoroacetic acid [NaBH(OAc)3–TFA] mediated ring clo-
sure of an alkynyl derivative of 15,24 and there are two re-
ports on triphenylsilane–tris(pentafluorophenyl)borane
[Ph3SiH–B(C6F5)3] induced cyclizations of alkyl derivatives
of 15.25 We applied these two sets of conditions to the phe-
nyl-substituted model substrates 8a and 15a (Scheme 8),
but no reaction was observed. The reactivity of the latter
phenyl ketones is apparently significantly reduced com-
pared to the alkyl and alkynyl examples. The attempted re-
ductive cyclizations of 8a and 15a with triphenylsilane in
the presence of boron trifluoride–diethyl ether complex as
a stronger Lewis acid resulted, as expected, in a quantitative
loss of the N-tert-butoxycarbonyl group. Some success was
achieved with the less bulky silane, triethylsilane. Treat-
ment of the amide 8a with triethylsilane–tris(pentafluoro-
phenyl)borane [Et3SiH–B(C6F5)3] afforded a 2:1 mixture of
the desired prolinamide 9a (32% yield) and the non-cy-
clized, silylated alcohol 18 (17% yield).26 In the case of ester
15a, however, no corresponding product 16a was detected;
only the carbonyl hydrosilylation product 19 was formed in
79% yield.26
O
O
R1MgX
NaBH(OAc)3, TFA
14
R1
OMe
15c: 94%
15d: 63%
15e: 54%
16c: 86%
16d: 82%
16e: 88%
NHBoc
15c–e
LAH
O
R1
R1
N
N
17c: 80%
17d: 77%
17e: 94%
Me
OH
Boc
OMe
16c–e
17c–e
15–17: c: R1 = Me; d: R1 = i-Pr; e: R1 = Bn
Scheme 9 Route II: synthesis of the prolinol precursors 17c–e23
Variation of the substituent R2 on the pyrrolidine nitro-
gen atom was accomplished using the 5-phenyl-substituted
ester 16a (Scheme 10). N-Deprotection with trifluoroacetic
acid followed by reductive amination with acetic acid–sodi-
um borohydride, acetone–sodium triacetoxyborohydride,
and, respectively, benzaldehyde–sodium triacetoxyborohy-
dride delivered the N-ethyl, N-isopropyl and N-benzyl pyr-
rolidine esters 20a–c in excellent 91–98% yields over two
steps. Reduction with lithium aluminum hydride provided
the prolinols 17f–h in ≥94% yield.
The final hydroxyl–amine exchange on the prolinols
17a–h was put into practice by activation of the alcohol
function as a mesylate, and subsequent treatment of the
crude intermediate with an excess of the respective amine
(Table 2).30 A set of 18 5-cis-substituted prolinamines 5 was
thus prepared by amination with ammonia (→ 5i–m),
methylamine (→ 5a,10 5n–p), dimethylamine (→ 5b,e,q–s),
and other secondary amines such as diethylamine, pyrroli-
dine, piperidine, and methyl benzylamine (→ 5t–w). The
product formation in this two-step sequence was generally
While all attempts on single-step cyclizations of aryl
substituted N-tert-butoxycarbonyl α-amino δ-oxo esters
and amides failed, we were successful in developing such a
procedure for aliphatic derivatives (Scheme 9). The amino
ketone precursors 15c–e (R1 = Me,27 i-Pr, Bn), which were
prepared in acceptable to high yields by treatment of com-
pound 14 with the respective Grignard reagents at –40 °C,
readily cyclized upon treatment with triacetoxyborohy-
dride–trifluoroacetic acid in ethyl acetate (McDermott con-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 575–586

579
F. Prause et al.
Paper
Synthesis
1. TFA
2. → 17f:
Route III
AcOH, NaBH4
→ 17g,h: acetone or PhCHO,
NaBH(OAc)3
Route III also proceeded via the N-tert-butoxycarbonyl-
protected methyl esters 16, but the NR3R4 substituents
were introduced by amidation and the reductions to give
the amines were performed as the last step (Table 3). After
saponification of 16a (R1 = Ph), 16c (R1 = Me), and 16d (R1 =
i-Pr) with lithium hydroxide (LiOH) in ethanol, the resulting
crude acids were activated with pivaloyl chloride (PvCl) to
give unsymmetric anhydrides, which were trapped in situ
with the respective amines (methylamine, dimethylamine,
pyrrolidine, and methyl benzylamine) to give the corre-
sponding amides 9a and 21a–e31 in high yields of 82–95%.
Reductions with lithium aluminum hydride were unevent-
ful and delivered the amines 5a,b,q,u,w,x as the major
products in 74–98% yields. Smaller amounts of by-products,
which were formed in the reductions of the secondary am-
ides 21a,b, were easily removed by column chromatogra-
phy. This provided a distinct advantage over route II, where
the removal of the excess amine, as required for the hydrox-
yl–amine exchange, from the polar diamines 5 was more la-
borious. In the cases of the prolinamines 5q and 5u, which
were also prepared via route II from the esters 16c and 16a
in low 14% and 50% overall yields (see Schemes 7 and 9 and
Table 2), the overall yields could be significantly increased
to 86% and 80%, respectively, by using route III.
O
16a
Ph
20a: 91%
20b: 98%
20c: 95%
N
R2
OMe
20a–c
LAH
Ph
17f, 20a: R2 = Et
17g, 20b: R2 = i-Pr
17h, 20c: R2 = Bn
17f: 98%
17g: 94%
17h: 94%
N
R2
OH
17f–h
Scheme 10 Route II: variation of the substituent R2
high, irrespective of the attached substituents R1 and R2,
but the high polarity of the resulting products made their
purification difficult, which explains the mediocre isolated
yields of some of the products. In the case of the 5-methyl
and 5-isopropyl derivatives 5k,l,q,r, additional problems
arose due to their high volatility.
Table 2 Route II: Variation of the Exocyclic Amino Group NR3R4
MsCl,
then HNR3R4
R1
R1
N
N
R2
R2
OH
NR3R4
17a–h
5a,b,e,i–w
Entry 17
R1
R2
Me
5
NR3R4
Yield (%)a
Table 3 Route III: Introduction of the NR3R4 Group via Amides
1
a
b
c
Ph
i
NH2
85
49
24
48
32
75b
84
77
77
65
54
18
23
44
40
52
51
73
2
1-naphthyl
Me
Me
Me
Me
Me
Et
j
NH2
1. LiOH
2. PvCl;
HNR3R4
16a
16c
16d
3
Me
i-Pr
Bn
k
l
NH2
LAH
O
R1
R1
4
d
e
a
f
NH2
N
Boc
N
NR3R4
NR3R4
Me
5
m
a
n
o
p
b
e
q
r
NH2
9a, 21a–e
5a,b,q,u,w,x
6
Ph
NHMe
NHMe
NHMe
NHMe
NMe2
NMe2
NMe2
NMe2
NMe2
NEt2
R1
NR3R4
Yield of
21, 9a (%)
Yield of
5 (%)
7
Ph
Entry 16
8
g
h
a
b
c
Ph
i-Pr
Bn
1
2
3
4
5
6
a
d
a
c
Ph
NHMe
86 (21a)
82 (21b)
92 (9a)
82 (5a)
74 (5x)
85 (5b)a
98 (5q)
98 (5u)
84 (5w)
9
Ph
i-Pr
Ph
NHMe
10
11
12
13
14
15
16
17
18
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
NMe2
1-naphthyl
Me
i-Pr
Bn
Me
Ph
NMe2
88 (21c)
82 (21d)
95 (21e)
a
a
pyrrolidinyl
NMeBn
d
e
a
a
a
a
Ph
s
a Identical to Table 1, entry 1.
Ph
t
Ph
u
v
w
pyrrolidinyl
piperidinyl
NMeBn
The preparation of the diamine 5y, in which the pyrroli-
dine nitrogen atom is unsubstituted, is shown in Scheme
11. N-Deprotection of the amide 21a with trifluoroacetic
acid and reduction of the resulting product 10b with lithi-
um aluminum hydride afforded 5y in 60% overall yield. It
should be noted that this compound would presumably not
be accessible via route II since the secondary NH function
would prohibit the required selective mesylation of the al-
cohol (cf. Table 2, R2 would be H).
Ph
Ph
a Yields not optimized.
b Data taken from ref. 10.
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580
F. Prause et al.
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Synthesis
cation of the polar final products. Furthermore, due to the
introduction of NR3R4 as an amide, this approach also per-
mits the synthesis of derivatives that are not accessible by
route II, without the use of additional protecting groups.
In addition, it was shown for the first time that aliphat-
ic, N-tert-butoxycarbonyl-protected α-amino δ-oxo esters
can be cyclized directly into the corresponding 5-cis-alkyl
prolines by using triacetoxyborohydride–trifluoroacetic
acid. Thus, N-tert-butoxycarbonyl removal and reattach-
ment steps, which are required under the standard cycliza-
tion conditions, are made redundant.
In summary, we have developed three routes (I–III) to-
ward the novel and interesting class of 5-cis-substituted
prolinamines 5. Starting from L-pyroglutamic acid (6), the
diamines 5 were prepared in five to ten steps, depending on
the route and the substitution pattern chosen, and in up to
64% yield (diamine 5q). The practicality, applicability and
modular nature of the approaches have been demonstrated
by the synthesis of 25 different diamines 5, which possess a
wide variety of different substituents R1–R4. The now possi-
ble rapid access to tailor-made derivatives will permit fur-
ther investigations on the potential of the diamines 5 as chi-
ral ligands in asymmetric catalysis.
TFA
LAH
O
21a
Ph
Ph
N
H
N
H
97%
62%
NHMe
NHMe
5y
10b
Scheme 11 Synthesis of the secondary diamine 5y
Variations of the substituent R2 were carried out on the
secondary amide 10a (Scheme 12), which was prepared
from 9a according to Scheme 5. Reductive aminations deliv-
ered the amides 10c and 10d, which were reduced to give
the corresponding amines 5g and 5h in 85–88% yields over
two steps. This sequence provides a welcome alternative to
that shown in Scheme 5, in which the reduction step pre-
cedes the reductive amination.
→ 10c: AcOH, NaBH4
→ 10d: PhCHO, NaBH(OAc)3
O
10a
Ph
10c: 93%
10d: 95%
N
R2
NMe2
10c,d
LAH
10c, 5g: R2 = Et
10d, 5h: R2 = Bn
Ph
5g: 95%
5h: 89%
N
R2
NMe2
5g,h
Scheme 12 Route III: variation of the substituent R2
All reactions with moisture-sensitive reagents were carried out under
an argon atmosphere in anhydrous solvents, which were prepared us-
ing standard procedures.32 Petroleum ether (PE) refers to the fraction
boiling in the 60–80 °C range. Commercially available reagents (high-
est quality available) were used as received. Reactions were moni-
tored by thin-layer chromatography on precoated silica gel (Mache-
rey-Nagel, Alugram SIL G/UV254). Spots were made visual under UV
light (254 nm) or by staining with aqueous KMnO4, vanillin, or ceric
ammonium molybdate. Silica gel (Macherey-Nagel, particle size 40–
63 μm) was used for column chromatography. Melting points were
measured on a Stuart SMP10 digital or a Büchi M-565 melting point
apparatus and are uncorrected. Optical rotations were recorded on a
Jasco P-1020 polarimeter (10 cm cell). Infrared spectra were recorded
on a Jasco FT-IR-410 or a PerkinElmer Spectrum 100 FT-IR spectrome-
ter. NMR spectra were obtained using a Bruker Avance 300, a Bruker
Avance 400, or a Bruker Avance III HD 500 instrument, and were cali-
brated using the residual non-deuterated solvent as an internal refer-
ence. The peak assignments in the 1H and 13C NMR spectra were made
on the basis of 2D NMR methods (COSY, HSQC, HMBC). High-resolu-
tion mass spectrometry was performed on a Bruker Daltonics micrO-
TOF focus mass spectrometer using ESI (electrospray ionization).
Conclusions
Each of the discussed approaches to 5-cis-substituted
prolinamines of general type 5 includes three key sequenc-
es, the installment of the 5-cis substituent R1 via a Grignard
addition–recyclization protocol, the introduction of R2 by
direct reduction of the protecting group (R2 = Me) or by N-
deprotection–reductive amination, and the attachment of
the exocyclic NR3R4 group, either by amidation or by ami-
nation. The major difference is the order of introduction,
which directly couples the usefulness of a route with the
envisioned substituent pattern.
Route I (order of substituent introduction: NR3R4 first,
then R1, and R2 last) is well suited for a rapid screening of R1
and R2 substituents under the premise of a given NR3R4
group. Moreover, the short nature of this approach (seven
to nine steps, or in just five steps by using Martin’s one-step
cyclization) in combination with the good diastereoselec-
tivities in the cyclization step makes this route particularly
attractive for the large-scale synthesis of a given target pro-
linamine 5. Route II (order of substituent introduction: R1
first, then R2, and NR3R4 last) offers the advantage of varia-
tion of the NR3R4 substituent in the final step. With the vast
number of commercially available amines, this approach
provides a simple access to a plethora of derivatives. In
route III (order of substituent introduction: R1 first, then
NR3R4, and R2 last), an amide reduction is performed as the
last step, which normally delivers the diamine 5 with high
purity, thus avoiding the need for a time-consuming purifi-
The syntheses of compounds 5b, 5f, and 5h according to route I, 5l
and 5n according to route II, and of 5u according to route III are de-
scribed here as representative examples. See the Supporting Informa-
tion for the syntheses of all other compounds.
(S)-tert-Butyl 2-(Dimethylcarbamoyl)-5-oxopyrrolidine-1-carbox-
ylate (7)
A solution of (S)-pyroglutamic acid (6) (15.0 g, 116 mmol) and
TsOH·H2O (663 mg, 3.49 mmol) in anhydrous MeOH (150 mL) was
heated at reflux temperature for 24 h. Gaseous Me2NH was bubbled
through the solution at r.t. for 6 h (the volume of the solution in-
creased by ca. 25 mL) and the stoppered flask was stirred at r.t. for 48
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581
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Synthesis
h. The solvent and excess Me2NH were carefully removed under re-
duced pressure to give the crude amide (17.4 g) as yellowish oil that
solidified upon standing. This material was dissolved in anhydrous
CH2Cl2 (200 mL) and Boc2O (30.3 g, 139 mmol), Et3N (19.3 mL, 15.3 g,
151 mmol) and DMAP (709 mg, 5.80 mmol) were added at r.t. After
stirring for 24 h, the reaction mixture was quenched with sat. aq
NH4Cl (200 mL) and the layers were separated. The aq layer was ex-
tracted with CH2Cl2 (3 × 200 mL) and the combined organic layers
washed with brine (200 mL), dried over MgSO4, and evaporated. Flash
chromatography (silica gel, CH2Cl2–MeOH, 100:0 → 95:5) delivered
the product 7 (24.0 g, 93.6 mmol, 81%) as a yellowish resin, which
crystallized upon standing to give a slightly yellow solid.
tion of the residue in MeOH (80 mL). The solvent was removed after
stirring overnight at r.t. The resulting orange oil was diluted four
times with MeOH (35 mL) and evaporated again. The residue was sus-
pended in anhydrous CH2Cl2 (100 mL) and Et3N (1.03 mL, 747 mg,
7.38 mmol), Boc2O (1.61 g, 7.38 mmol) and DMAP (30.1 mg, 246
μmol) were added at r.t. After stirring for 1 d, sat. aq NH4Cl (100 mL)
was added and the layers were separated. The aq layer was extracted
with CH2Cl2 (3 × 50 mL) and the combined organic layers were
washed with brine (50 mL) and dried over MgSO4. Removal of the sol-
vent and column chromatography (silica gel, PE–EtOAc, 2:1 → 1:2) af-
forded the pyrrolidine amide 9a14 (1.19 g, 3.74 mmol, 76%) as a slight-
ly yellowish oil.
21
Mp 86–89 °C; [α]D –35.8 (c 1.04, MeOH); Rf = 0.34 (CH2Cl2–MeOH,
[α]D21 +35.8 (c 0.60, CH2Cl2); Rf = 0.50 (EtOAc).
95:5).
IR (ATR): 2974, 1689, 1655, 1389, 1362, 1155, 729, 700 cm–1
.
IR (ATR): 2977, 2937, 1771, 1648, 1365, 1305, 1285, 1251, 1146, 1021,
1H NMR (400 MHz, CDCl3): δ (70:30 mixture of rotamers) = 1.10 [s,
6.4 H, C(CH3)3], 1.39 [s, 2.6 H, C(CH3)3], 1.97 (m, 1.3 H, 3-HH, 4-HH),
2.14 (m, 1.7 H, 3-HH, 4-HH), 2.28 (m, 1 H, 3-HH), 3.04 (s, 3 H, NCH3),
3.12 (s, 0.9 H, NCH3), 3.15 (s, 2.1 H, NCH3), 4.68 (m, 1 H, 2-H, 5-H),
4.80 (m, 0.7 H, 2-H), 4.95 (m, 0.3 H, 5-H), 7.19 (t, J = 7.3 Hz, 1 H, Ph-H),
7.31 (t, J = 7.5 Hz, 2 H, Ph-H), 7.74 (d, J = 7.3 Hz, 2 H, Ph-H).
840 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.46 [s, 9 H, C(CH3)3], 1.87 (m, 1 H, 3-
HH), 2.22 (m, 1 H, 3-HH), 2.42 (ddd, J = 17.4, 9.5, 3.0 Hz, 1 H, 4-HH),
2.70 (ddd, J = 17.4, 10.3, 9.8 Hz, 1 H, 4-HH), 2.98 (s, 3 H, NCH3), 3.08 (s,
3 H, NCH3), 4.92 (dd, J = 9.2, 2.4 Hz, 1 H, 2-H).
13C NMR (100 MHz, CDCl3): δ = 21.4 (C-3), 28.0 [C(CH3)3], 31.4 (C-4),
36.0 (NCH3), 36.8 (NCH3), 56.4 (C-2), 83.1 [C(CH3)3], 149.8 (1-CO2),
170.7 (2-CON), 173.8 (C-5).
HRMS (ESI): m/z [M + Na]+ calcd for C12H20N2O4Na: 279.1315; found:
279.1316.
13C NMR (100 MHz, CDCl3): δ (mixture of rotamers) = 28.2, 28.4
[C(CH3)3], 28.7, 28.9 (C-3), 34.8, 35.9 (C-4), 36.3, 37.2 [N(CH3)2], 58.0,
62.5 (C-5), 63.6 (C-2), 79.8 [C(CH3)3], 126.6, 127.0, 128.1, 128.4 (CH-
Ph), 144.6 (Cq-Ph), 154.8 (1-CO2), 172.6 (2-CON).
HRMS (ESI): m/z [M + H]+ calcd for C18H27N2O3: 319.2016; found:
319.2018.
(S)-2-(tert-Butoxycarbonylamino)-N,N-dimethyl-5-oxo-5-phenyl-
pentanamide (8a)
(2S,5R)-2-(Dimethylaminomethyl)-1-methyl-5-phenylpyrrolidine
(5b)
PhMgBr (12.1 mL, 1.0 M in THF, 12.1 mmol) was added at –20 °C to a
solution of the 5-oxopyrrolidine 7 (3.00 g, 11.7 mmol) in anhydrous
THF (80 mL) and the mixture was allowed to warm to r.t. overnight.
Sat. aq NH4Cl (50 mL) was added and the layers were separated. The
aq layer was extracted with EtOAc (3 × 50 mL), and the combined or-
ganic layers were washed with brine (50 mL) and dried over MgSO4.
Removal of the solvent under reduced pressure and column chroma-
tography (silica gel, PE–EtOAc, 1:2 → 0:1) afforded the amino ketone
8a (2.82 g, 8.42 mmol, 72%) as a colorless solid.
LAH (3.84 mL, 2.0 M in THF, 7.69 mmol) was added at 0 °C to a solu-
tion of amide 9a (408 mg, 1.28 mmol) in anhydrous THF (18 mL). Af-
ter 1 h, the reaction mixture was heated at reflux temperature over-
night. The solution was diluted with Et2O (25 mL) and treated with
sat. aq Na2SO4 until H2 evolution ceased. The resulting mixture was
filtered through a pad of Celite® and the filter cake was washed thor-
oughly (CH2Cl2–MeOH, 9:1, 300 mL). Evaporation of the solvent and
column chromatography (silica gel, CH2Cl2–MeOH, 90:10) delivered
diamine 5b (238 mg, 1.09 mmol, 85%) as a slightly yellowish oil.
Mp 74–77 °C; [α]D22 +0.3 (c 1.00, MeOH); Rf = 0.31 (Et2O).
[α]D29 +20.1 (c 1.00, MeOH); Rf = 0.26 (CH2Cl2–MeOH, 9:1).
IR (ATR): 2943, 2765, 1454, 1155, 1032, 850, 754, 698 cm–1
.
IR (ATR): 3349, 2974, 2931, 1702, 1678, 1645, 1492, 1365, 1163, 1050,
688 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.37 [s, 9 H, C(CH3)3], 1.82 (m, 1 H, 3-
HH), 2.22 (m, 1 H, 3-HH), 2.95 (s, 3 H, NCH3), 2.96 (m, 1 H, 4-HH), 3.19
(s, 3 H, NCH3), 3.20 (m, 1 H, 4-HH), 4.71 (m, 1 H, 2-H), 5.53 (d, J = 8.0
Hz, 1 H, NH), 7.43 (t, J = 7.6 Hz, 2 H, Ph-H), 7.54 (t, J = 7.4 Hz, 1 H, Ph-
H), 7.94 (d, J = 7.4 Hz, 2 H, Ph-H).
13C NMR (100 MHz, CDCl3): δ = 27.4 (C-3), 28.4 [C(CH3)3], 33.8 (C-4),
35.8 (NCH3), 37.2 (NCH3), 49.7 (C-2), 79.6 [C(CH3)3], 128.1, 128.6,
133.1 (CH-Ph), 137.1 (Cq-Ph), 155.8 (NCO2), 172.0 (C-1), 199.4 (C-5).
1H NMR (400 MHz, CDCl3): δ = 1.70 (m, 2 H, 3-HH, 4-HH), 2.04 (m, 2
H, 3-HH, 4-HH), 2.18 (s, 3 H, 1-CH3), 2.30 [s, 6 H, N(CH3)2], 2.37 (dd, J =
12.0, 8.2 Hz, 1 H, 2-H), 2.52 (m, 2 H, 2-CH2), 3.24 (m, 1 H, 5-H), 7.22
(m, 1 H, Ph-H), 7.30 (m, 2 H, Ph-H), 7.35 (m, 2 H, Ph-H).
13C NMR (100 MHz, CDCl3): δ = 29.5 (C-3), 34.0 (C-4), 39.7 (1-CH3),
46.6 [N(CH3)2], 64.7 (C-2), 65.3 (2-CH2), 72.7 (C-5), 127.0, 127.5, 128.4
(CH-Ph), 143.9 (Cq-Ph).
HRMS (ESI): m/z [M + H]+ calcd for C14H23N2: 219.1856; found:
219.1858.
HRMS (ESI): m/z [M + Na]+ calcd for C18H26N2O4Na: 357.1785; found:
357.1786.
(2S,5R)-N,N-Dimethyl-5-phenylpyrrolidine-2-carboxamide (10a)
(2S,5R)-tert-Butyl 2-(Dimethylcarbamoyl)-5-phenylpyrrolidine-1-
carboxylate (9a)
A solution of amide 9a (1.21 g, 3.80 mmol) in CH2Cl2 (38 mL) was
treated with TFA (5.86 mL, 8.67 g, 76.0 mmol) and stirred overnight at
r.t. The solvent was removed under reduced pressure and the result-
ing oil was diluted five times with CH2Cl2 (20 mL) and evaporated
again, in order to remove excess TFA. The residue was filtered through
a pad of basic alumina [activity I, CH2Cl2–MeOH–NH3 (aq, 25%),
90:9:1] to give amide 10a (790 mg, 3.62 mmol, 95%) as a yellowish
solid.
A solution of the amino ketone 8a (1.64 g, 4.92 mmol) in anhydrous
CH2Cl2 (50 mL) was treated at r.t. with TFA (7.50 mL, 11.1 g, 97.4
mmol) and stirred overnight. The solvent was removed under re-
duced pressure and the resulting orange oil was diluted five times
with CH2Cl2 (30 mL) and evaporated again, in order to remove excess
TFA. NaBH4 (279 mg, 7.38 mmol) was slowly added at 0 °C to a solu-
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Synthesis
Mp 106–109 °C; [α]D22 –37.7 (c 0.50, MeOH); Rf = 0.48 (CH2Cl2–MeOH,
9:1).
13C NMR (125 MHz, CDCl3): δ = 29.6 (C-3), 34.9 (C-4), 46.3 [N(CH3)2],
57.0 (1-CH2), 60.8 (C-2), 65.9 (2-CH2), 69.8 (C-5), 126.9, 127.0, 127.6,
128.0, 128.4, 129.8 (CH-Ph), 139.1, 144.4 (Cq-Ph).
HRMS (ESI): m/z [M + H]+ calcd for C20H27N2: 295.2169; found:
295.2170.
IR (ATR): 3288, 2952, 2924, 1629, 1397, 1091, 870, 760, 704 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.70 (m, 1 H, 4-HH), 1.92 (m, 1 H, 3-
HH), 2.20 (m, 2 H, 3-HH, 4-HH), 2.89 (br s, 1 H, NH), 3.01 (s, 3 H,
NCH3), 3.05 (s, 3 H, NCH3), 4.10 (m, 2 H, 2-H, 5-H), 7.25 (m, 1 H, Ph-H),
7.33 (m, 2 H, Ph-H), 7.47 (m, 2 H, Ph-H).
(S)-Methyl 2-[(tert-Butoxycarbonyl)amino]-6-methyl-5-oxohepta-
noate (15d)
13C NMR (100 MHz, CDCl3): δ = 31.4 (C-3), 34.8 (C-4), 36.0, 36.6
[N(CH3)2], 58.6 (C-2), 64.5 (C-5), 127.0, 127.3, 128.6 (CH-Ph), 142.8
(Cq-Ph), 174.1 (2-CON).
i-PrMgBr (5.33 mL, 2.9 M in 2-methyltetrahydrofuran, 15.5 mmol)
was added at –40 °C to a solution of the 5-oxopyrrolidine 1422 (2.51 g,
10.3 mmol) in anhydrous THF (30 mL). After 2 h at –40 °C, sat. aq
NH4Cl (100 mL) was added. The aq layer was extracted with CH2Cl2
(3 × 200 mL) and the combined organic layers were dried over MgSO4.
Removal of the solvent under reduced pressure and column chroma-
tography (silica gel, PE–EtOAc, 4:1 → 1:1) delivered 15d (1.86 g, 6.47
mmol, 63%) as a colorless oil.
HRMS (ESI): m/z [M + H]+ calcd for C13H19N2O: 219.1492; found:
219.1493.
(2S,5R)-2-(Dimethylaminomethyl)-5-phenylpyrrolidine (5f)
Amide 10a (960 mg, 4.40 mmol) was dissolved in THF (70 mL) and
LAH (13.2 mL, 1.0 M in THF, 13.2 mmol) was added at 0 °C. After 1 h,
the mixture was heated at reflux temperature overnight. The solution
was diluted with Et2O (30 mL) and treated with sat. aq Na2SO4 until H2
evolution had ceased. The resulting mixture was filtered through a
pad of Celite® and the filter cake was rinsed with CH2Cl2–MeOH (9:1,
300 mL). Evaporation of the solvent and filtration through a pad of ba-
sic alumina (activity I, PE–Et2O, 1:0 → 0:1) provided diamine 5f14 (825
mg, 4.04 mmol, 92%) as a yellowish oil.
[α]D25 +40.4 (c 0.48, CHCl3); Rf = 0.52 (PE–EtOAc, 4:1).
IR (ATR): 3500–3250, 2973, 1744, 1707, 1389, 1364, 1200, 1161,
1025, 1013, 757 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 1.04 [d, J = 6.9 Hz, 3 H, CH(CH3)2], 1.05
[d, J = 6.9 Hz, 3 H, CH(CH3)2], 1.39 [s, 9 H, C(CH3)3], 1.85 (m, 1 H, 3-
HH), 2.06 (m, 1 H, 3-HH), 2.40–2.63 (m, 3 H, 4-H2, 6-H), 3.69 (s, 3 H,
OCH3), 4.22 (m, 1 H, 2-H), 5.09 (d, J = 7.4 Hz, 1 H, NH).
[α]D21 +13.4 (c 1.00, MeOH); Rf = 0.21 (CH2Cl2–MeOH–Et3N, 90:10:1).
13C NMR (75 MHz, CDCl3): δ = 18.27, 18.29 (C-7, 6-CH3), 26.5 (C-3),
28.3 [C(CH3)3], 36.1 (C-6), 41.0 (C-4), 52.4 (OCH3), 53.1 (C-2), 80.0
[C(CH3)3], 155.5 (NCO2), 173.0 (C-1), 213.5 (C-5).
HRMS (ESI): m/z [M + H]+ calcd for C14H26NO5: 288.1806; found:
288.1803.
IR (ATR): 3500–3100, 2942, 2765, 1454, 1263, 1098, 1038, 845, 754,
698 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.59 (m, 1 H, 3-HH), 1.73 (m, 1 H, 4-
HH), 2.02 (m, 1 H, 3-HH), 2.17 (m, 1 H, 4-HH), 2.32 [s, 6 H, N(CH3)2],
2.38 (dd, J = 12.1, 5.4 Hz, 1 H, 2-CHH), 2.47 (dd, J = 12.1, 8.3 Hz, 1 H, 2-
CHH), 3.49 (m, 1 H, 2-H), 3.57 (br s, 1 H, NH), 4.25 (dd, J = 8.8, 7.1 Hz, 1
H, 5-H), 7.22 (m, 1 H, Ph-H), 7.30 (m, 2 H, Ph-H), 7.38 (m, 2 H, Ph-H).
(2S,5R)-1-tert-Butyl 2-Methyl 5-Isopropylpyrrolidine-1,2-dicar-
boxylate (16d)
13C NMR (100 MHz, CDCl3): δ = 30.0 (C-3), 33.5 (C-4), 46.0 [N(CH3)2],
56.4 (C-2), 62.6 (C-5), 65.7 (2-CH2), 126.8, 127.1, 128.5 (CH-Ph), 143.9
(Cq-Ph).
HRMS (ESI): m/z [M + H]+ calcd for C13H21N2: 205.1699; found:
205.1700.
NaBH(OAc)3 (1.83 g, 8.64 mmol) was added at 0 °C to a solution of the
amino ketone 15d (1.90 g, 6.61 mmol) in EtOAc (35 mL). After 10 min,
TFA (2.20 mL, 3.26 g, 28.6 mmol) was added dropwise over a period of
40 min. The mixture was stirred for 2 h at 0 °C and then overnight at
r.t. Sat. aq NaHCO3 (100 mL) was added and most of the organic sol-
vent was removed under reduced pressure. CH2Cl2 (100 mL) was add-
ed, the layers were separated and the organic layer was washed with
sat. aq NaHCO3 (2 × 100 mL). The combined aq layers were re-extract-
ed with CH2Cl2 (2 × 200 mL) and the combined organic layers were
washed with brine (100 mL) and dried over MgSO4. Evaporation of the
solvent and column chromatography (silica gel, PE–EtOAc, 6:1) pro-
vided 16d (1.47 g, 5.42 mmol, 82%) as a colorless oil.
(2S,5R)-1-Benzyl-2-(dimethylaminomethyl)-5-phenylpyrrolidine
(5h)
Benzaldehyde (39.8 μL, 41.8 mg, 394 μmol) and AcOH (30.0 μL, 31.6
mg, 524 μmol) were added at r.t. to a solution of the amine 5f (53.6
mg, 262 μmol) in DCE (0.5 mL). NaBH(OAc)3 (88.8 mg, 420 μmol) was
added after 10 min and the solution was stirred for 4 h. The mixture
was quenched with sat. aq NaHCO3 (4 mL). The aq layer was extracted
with CH2Cl2 (4 × 3 mL) and the combined organic layers were dried
over MgSO4. Evaporation of the solvent and column chromatography
[silica gel, CH2Cl2–MeOH–NH3 (aq, 25%), 190:9:1] provided diamine
5h (69.2 mg, 235 μmol, 90%) as a colorless oil.
[α]D30 +40.4 (c 1.00, CHCl3); Rf = 0.70 (PE–EtOAc, 4:1).
IR (ATR): 2959, 2874, 1754, 1692, 1381, 1364, 1194, 1162, 1103, 929,
769 cm–1
.
1H NMR (300 MHz, CDCl3): δ (60:40 mixture of rotamers) = 0.87 [d, J =
6.7 Hz, 3 H, CH(CH3)2], 0.94 [d, J = 6.8 Hz, 3 H, CH(CH3)2], 1.37 [br s, 5.4
H, C(CH3)3], 1.41 [br s, 3.6 H, C(CH3)3], 1.70–2.08 [m, 4 H, 3-HH, 4-H2,
CH(CH3)2], 2.14 (m, 1 H, 3-HH), 3.59 (m, 0.4 H, 5-H), 3.67 (m, 0.6 H, 5-
H), 3.68 (s, 3 H, OCH3), 4.17 (m, 0.6 H, 2-H), 4.28 (m, 0.4 H, 2-H).
[α]D28 +20.3 (c 1.00, MeOH); Rf = 0.15 (EtOAc).
IR (ATR): 3030, 2937, 2815, 2769, 1491, 1452, 1033, 754, 700 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.67 (m, 1 H, 4-HH), 1.78 (m, 1 H, 3-
HH), 1.98 (m, 3 H, 3-HH, 4-HH, 2-CHH), 2.11 [s, 6 H, N(CH3)2], 2.24 (t,
J = 11.1 Hz, 1 H, 2-CHH), 2.96 (m, 1 H, 2-H), 3.45 (d, J = 13.4 Hz, 1 H, 1-
CHH), 3.69 (dd, J = 9.8, 5.6 Hz, 1 H, 5-H), 3.83 (d, J = 13.4 Hz, 1 H, 1-
CHH), 7.23 (m, 6 H, Ph-H), 7.33 (t, J = 7.6 Hz, 2 H, Ph-H), 7.46 (d, J = 7.3
Hz, 2 H, Ph-H).
13C NMR (75 MHz, CDCl3): δ (mixture of rotamers) = 18.2, 18.6
[CH(CH3)2], 19.9, 20.1 [CH(CH3)2], 26.5, 27.5 (C-4), 28.3 [C(CH3)3], 29.2
(C-3), 31.3, 31.4 [CH(CH3)2], 51.8, 52.0 (OCH3), 60.0, 60.5 (C-2), 64.1,
64.4 (C-5), 79.8 [C(CH3)3], 154.6 (1-CO2), 173.8, 174.0 (2-CO2).
HRMS (ESI): m/z [M + Na]+ calcd for C14H25NO4Na: 294.1676; found:
294.1673.
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(2S,5S)-2-(Hydroxymethyl)-5-isopropyl-1-methylpyrrolidine (17d)
NaBH4 (292 mg, 7.72 mmol) was added portionwise at 0 °C to a solu-
tion of this ester (336 mg, 1.64 mmol) in AcOH (3 mL). After gas evolu-
tion had ceased, the solution was heated at 60 °C for 2 h. Sat. aq
NaHCO3 (4 mL) was slowly added and the mixture was made basic by
the addition of solid Na2CO3. The aq layer was extracted with CH2Cl2
(3 × 25 mL) and the combined organic layers dried over MgSO4. Evap-
oration of the solvent and column chromatography (silica gel, PE–
EtOAc, 10:1) afforded the ester 20a (352 mg, 1.51 mmol, 92%) as a col-
orless oil.
LAH (1.23 g, 32.5 mmol) was added at 0 °C to a solution of ester 16d
(1.47 g, 5.42 mmol) in anhydrous THF (30 mL). The reaction mixture
was heated under reflux for 16 h. Aq NaOH (10%, 6 mL) was added at
0 °C and the mixture was stirred for 30 min at r.t. The solids that
formed were removed by filtration through a pad of Celite® and the
filter cake was rinsed with Et2O (200 mL). Evaporation of the solvent
delivered amino alcohol 17d (654 mg, 4.16 mmol, 77%) as a slightly
yellowish oil.
[α]D27 +53.0 (c 1.00, MeOH); Rf = 0.43 (PE–EtOAc, 9:1).
25
[α]D +47.0 (c 2.00, CHCl3); Rf = 0.70 [CH2Cl2–MeOH–NH3 (aq, 25%),
IR (ATR): 2967, 2951, 1749, 1732, 1192, 1163, 1074, 756, 701 cm–1
.
80:18:2].
1H NMR (500 MHz, CDCl3): δ = 0.91 (t, J = 7.2 Hz, 3 H, 1-CH2CH3), 1.85
(m, 1 H, 4-HH), 2.01 (m, 1 H, 3-HH), 2.12 (m, 2 H, 3-HH, 4-HH), 2.51
(dq, J = 12.9, 7.1 Hz, 1H, 1-CHH), 2.69 (dq, J = 13.0, 7.3 Hz, 1H, 1-CHH),
3.47 (dd, J = 9.1, 4.8 Hz, 1 H, 2-H), 3.71 (dd, J = 9.4, 5.9 Hz, 1 H, 5-H),
3.76 (s, 3 H, OCH3), 7.23 (m, 1 H, Ph-H), 7.32 (m, 2 H, Ph-H), 7.48 (m, 2
H, Ph-H).
13C NMR (125 MHz, CDCl3): δ = 12.6 (1-CH2CH3), 29.4 (C-3), 35.7 (C-4),
47.0 (1-CH2CH3), 51.9 (OCH3), 65.0 (C-2), 69.2 (C-5), 127.1, 127.4,
128.3 (CH-Ph), 144.3 (Cq-Ph), 176.3 (2-CO2).
IR (ATR): 3600–3100, 2955, 2871, 2783, 1465, 1385, 1367, 1209,
1032, 963, 755 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 0.76 [d, J = 6.8 Hz, 3 H, CH(CH3)2], 0.83
[d, J = 6.9 Hz, 3 H, CH(CH3)2], 1.35–1.85 [m, 5 H, 3-H2, 4-H2, CH(CH3)2],
2.19 (s, 3 H, 1-CH3), 2.30 (m, 1 H, 5-H), 2.48 (m, 1 H, 2-H), 2.94 (br s, 1
H, OH), 3.31 (dd, J = 10.5, 1.9 Hz, 1 H, 2-CHH), 3.58 (dd, J = 10.6, 3.6 Hz,
1 H, 2-CHH).
13C NMR (75 MHz, CDCl3): δ = 15.3 [CH(CH3)2], 20.2 [CH(CH3]2, 23.8
(C-4), 26.0 (C-3), 29.0 [CH(CH3)2], 39.0 (1-CH3), 61.2 (2-CH2), 67.1 (C-
2), 71.9 (C-5).
HRMS (ESI): m/z [M + H]+ calcd for C14H20NO2: 234.1487; found:
HRMS (ESI): m/z [M + H]+ calcd for C9H20NO: 158.1539; found:
234.1489.
158.1542.
(2S,5R)-1-Ethyl-2-(hydroxymethyl)-5-phenylpyrrolidine (17f)
(2S,5R)-2-(Aminomethyl)-5-isopropyl-1-methylpyrrolidine (5l)
To a solution of ester 20a (310 mg, 1.33 mmol) in anhydrous THF (15
mL), LAH (106 mg, 2.79 mmol) was added at 0 °C and the mixture was
stirred at r.t. overnight. The solution was diluted with Et2O (15 mL)
and treated with sat. aq Na2SO4 until H2 evolution had ceased. The re-
sulting mixture was filtered through a pad of Celite® and the filter
cake was rinsed with CH2Cl2–MeOH (9:1, 100 mL). Evaporation of the
solvent and column chromatography (silica gel, CH2Cl2–MeOH, 95:5)
provided amino alcohol 17f (268 mg, 1.31 mmol, 98%) as a colorless
oil.
K2CO3 (100 mg, 725 μmol) was added to a solution of the alcohol 17d
(76.0 mg, 483 μmol) in CH2Cl2 (3 mL). The resulting suspension was
treated with MsCl (46.8 μL, 69.2 mg, 604 μmol) and stirred overnight.
Aq NH3 (25%, 3 mL, 44.0 mmol) and MeOH (3 mL) were added and the
mixture was stirred overnight. Evaporation of the solvent and column
chromatography [silica gel, CH2Cl2–MeOH–NH3 (aq, 25%), 90:9:1]
provided the prolinamine 5l (36.0 mg, 230 μmol, 48%) as a yellowish
oil.
[α]D28 +70.2 (c 1.00, MeOH); Rf = 0.36 (CH2Cl2–MeOH, 95:5).
25
[α]D +30.6 (c 1.00, CHCl3); Rf = 0.30 [CH2Cl2–MeOH–NH3 (aq, 25%),
IR (ATR): 3500–3100, 2963, 2873, 1452, 1193, 1028, 756, 699 cm–1
.
90:8:2].
1H NMR (500 MHz, CDCl3): δ = 0.92 (t, J = 7.2 Hz, 3 H, 1-CH2CH3), 1.71
(m, 1 H, 4-HH), 1.88 (m, 1 H, 3-HH), 1.99 (m, 1 H, 3-HH), 2.78 (m, 1 H,
4-HH), 2.64 (m, 2 H, 1-CH2), 3.00 (br s, 1 H, OH), 3.04 (m, 1 H, 2-H),
3.48 (dd, J = 10.5, 2.7 Hz, 1 H, 2-CHH), 3.70 (dd, J = 10.5, 4.1 Hz, 1 H, 2-
CHH), 3.76 (dd, J = 9.7, 6.5 Hz, 1 H, 5-H), 7.24 (m, 1 H, Ph-H), 7.32 (m,
2 H, Ph-H), 7.36 (m, 2 H, Ph-H).
13C NMR (125 MHz, CDCl3): δ =12.3 (1-CH2CH3), 27.9 (C-3), 35.4 (C-4),
45.9 (1-CH2CH3), 63.1 (C-2), 63.6 (2-CH2), 69.2 (C-5), 127.2, 128.5
(CH-Ph), 144.3 (Cq-Ph).
IR (ATR): 3600–2400, 2955, 2871, 2781, 1462, 1320, 1150, 985, 766
cm–1
.
1H NMR (300 MHz, CDCl3): δ = 0.78 [d, J = 6.8 Hz, 3 H, CH(CH3)2], 0.84
[d, J = 6.9 Hz, 3 H, CH(CH3)2], 1.36–1.60 (m, 3 H, 3-HH, 4-H2), 1.67 (br
s, 2 H, NH2), 1.61–1.85 [m, 2 H, 3-HH, CH(CH3)2], 2.19 (s, 3 H, 1-CH3),
2.22 (m, 1 H, 5-H), 2.34 (m, 1 H, 2-H), 2.61 (dd, J = 12.9, 3.1 Hz, 1 H, 2-
CHH), 2.71 (dd, J = 12.9, 5.1 Hz, 1 H, 2-CHH).
13C NMR (75 MHz, CDCl3): δ = 15.4 [CH(CH3)2], 20.3 [CH(CH3)2], 23.5
(C-4), 26.4 (C-3), 29.1 [CH(CH3)2], 39.6 (1-CH3), 43.8 (2-CH2), 68.2 (C-
2), 72.2 (C-5).
HRMS (ESI): m/z [M + H]+ calcd for C13H20NO: 206.1539; found:
HRMS (ESI): m/z [M + H]+ calcd for C9H21N2: 157.1699; found:
206.1540.
157.1702.
(2S,5R)-1-Ethyl-2-(methylaminomethyl)-5-phenylpyrrolidine (5n)
(2S,5R)-Methyl 1-Ethyl-5-phenylpyrrolidin-2-carboxylate (20a)
Et3N (272 μL, 197 mg, 1.95 mmol) and MsCl (102 μL, 152 mg, 1.32
mmol) were added at 0 °C to a solution of the alcohol 17f (160 mg,
779 μmol) in CH2Cl2 (6 mL). After stirring overnight at r.t., aq NH2Me
(40%, 2.12 mL, 23.3 mmol), Et3N (108 μL, 78.8 mg, 779 μmol) and
MeOH (6 mL) were added and the reaction mixture was stirred over-
night. Evaporation of the solvent and column chromatography (silica
gel, CH2Cl2) provided the prolinamine 5n (142 mg, 654 μmol, 84%) as
a colorless wax.
A solution of the ester 16a10 (3.20 g, 10.5 mmol) in CH2Cl2 (120 mL)
was treated with TFA (16.1 mL, 23.9 g, 210 mmol) and stirred over-
night at r.t. The solvent was removed under reduced pressure and the
resulting oil was diluted five times with CH2Cl2 (80 mL) and evaporat-
ed again, in order to remove excess TFA. The residue was filtered
through a pad of basic alumina [activity I, CH2Cl2–MeOH–NH3 (aq,
25%), 95:4.5:0.5] to give the known33 ester, (2S,5R)-methyl 5-phen-
ylpyrrolidine-2-carboxylate (2.13 g, 10.4 mmol, 99%) as a colorless oil.
Rf = 0.39 (CH2Cl2–MeOH, 95:5).
26
[α]D +59.7 (c 1.00, MeOH); Rf = 0.29 [CH2Cl2–MeOH–NH3 (aq, 25%),
90:9:1].
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Synthesis
IR (ATR): 2964, 2790, 1452, 1372, 1190, 1135, 1028, 755, 699 cm–1
.
[α]D21 2.0 (c 0.5, MeOH); Rf = 0.20 (CH2Cl2–MeOH, 9:1).
1H NMR (500 MHz, CDCl3): δ = 0.89 (t, J = 7.2 Hz, 3 H, 1-CH2CH3), 1.67
(m, 1 H, 4-HH), 1.79 (m, 1 H, 3-HH), 1.95 (m, 1 H, 3-HH), 2.05 (m, 1 H,
4-HH), 2.52 (s, 3 H, NCH3), 2.63 (m, 4 H, 1-CH2, 2-CHH, NH), 2.71 (dd,
J = 11.4, 4.5 Hz, 1 H, 2-CHH), 3.00 (m, 1 H, 2-H), 3.69 (dd, J = 9.2, 6.6
Hz, 1 H, 5-H), 7.21 (m, 1 H, Ph-H), 7.29 (m, 2 H, Ph-H), 7.37 (m, 2 H,
Ph-H).
13C NMR (125 MHz, CDCl3): δ = 12.4 (1-CH2CH3), 28.9 (C-3), 35.3 (C-4),
37.0 (NCH3), 46.4 (1-CH2CH3), 57.0 (2-CH2), 62.1 (C-2), 69.0 (C-5),
126.8, 127.2, 128.2 (CH-Ph), 145.3 (Cq-Ph).
IR (ATR): 2954, 2925, 2777, 1453, 1073, 880, 755, 699 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 1.64–1.84 [m, 6 H, 3-HH, 4-HH,
N(CH2CH2)2], 2.05 (m, 2 H, 3-HH, 4-HH), 2.20 (s, 3 H, 1-CH3), 2.54 [m,
6 H, 5-H, 5-CHH, N(CH2CH2)2], 2.73 (dd, J = 11.1, 3.1 Hz, 1 H, 5-CHH),
3.24 (m, 1 H, 2-H), 7.22 (m, 1 H, Ph-H), 7.32 (m, 4 H, Ph-H).
13C NMR (100 MHz, CDCl3): δ = 23.6 [N(CH2CH2)2], 29.6 (C-4), 34.0 (C-
3), 39.8 (1-CH3), 55.1 [N(CH2CH2)2], 62.0 (5-CH2), 65.8 (C-5), 72.6 (C-
2), 126.9, 127.5, 128.3 (CH-Ph), 144.0 (Cq-Ph).
HRMS (ESI): m/z [M + H]+ calcd for C16H25N2: 245.2012; found:
245.2010.
HRMS (ESI): m/z [M + H]+ calcd for C14H23N2: 219.1856; found:
219.1857.
(2R,5S)-tert-Butyl 2-Phenyl-5-(pyrrolidine-1-carbonyl)pyrroli-
dine-1-carboxylate (21d)
Acknowledgment
The financial support of the German research foundation (DFG) is
gratefully acknowledged.
LiOH·H2O (49.7 mg, 1.18 mmol) was added to a solution of the ester
16a10 (213 mg, 697 μmol) in EtOH (3 mL). After stirring for 16 h, HCl
(1 M, 15 mL) was added and the aq layer was extracted with EtOAc
(4 × 10 mL). The combined organic layers were dried over MgSO4 and
evaporated to give the crude acid (200 mg), which was dissolved in
anhydrous THF (7 mL). Et3N (195 μL, 142 mg, 1.40 mmol) and PvCl
(135 μL, 133 mg, 1.10 mmol) were added at r.t. and the resulting sus-
pension was stirred for 2.5 h. Pyrrolidine (165 μL, 147 mg, 2.06
mmol) was added and stirring was continued for 16 h. The mixture
was evaporated and sat. aq NaHCO3 (50 mL) was added. The aq layer
was extracted with CH2Cl2 (3 × 50 mL) and the combined organic lay-
ers were dried over MgSO4 and evaporated. Column chromatography
(silica gel, PE–EtOAc, 3:1 → 0:1) afforded the amide 21d (197 mg, 572
μmol, 82%) as a colorless resin.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379457.
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References
(1) New address: Institute of Organic Chemistry, University of
Würzburg, Am Hubland, 97074 Würzburg, Germany.
(2) New address: Institute of Inorganic Chemistry, University of
Würzburg, Am Hubland, 97074 Würzburg, Germany.
(3) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 5551. (b) Corey, E. J.; Shibata, S.; Bakshi, R. K. J. Org. Chem.
1988, 53, 2861. (c) Corey, E. J.; Helal, C. J. Angew. Chem. Int. Ed.
1998, 37, 1986.
(4) (a) Franzén, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.;
Kjærsgaard, A.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127,
18296. (b) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew.
Chem. Int. Ed. 2005, 44, 4212. (c) Jensen, K. L.; Dickmeiss, G.;
Jiang, H.; Albrecht, L.; Jørgensen, K. A. Acc. Chem. Res. 2012, 45,
248.
(5) (a) Soai, K.; Ookawa, A.; Ogawa, K.; Kaba, T. J. Chem. Soc., Chem.
Commun. 1987, 467. (b) Soai, K.; Ookawa, A.; Kaba, T.; Ogawa, K.
J. Am. Chem. Soc. 1987, 109, 7111.
(6) (a) Zhou, Y.; Dong, J.; Zhang, F.; Gong, Y. J. Org. Chem. 2011, 76,
588. (b) Zhou, Y.; Gong, Y. Eur. J. Org. Chem. 2011, 6092.
(c) Zhou, Y.; Zhu, Y.; Yan, S.; Gong, Y. Angew. Chem. Int. Ed. 2013,
52, 10265.
[α]D25 32.8 (c 1.00, MeOH); Rf = 0.34 (PE–EtOAc, 1:1).
IR (ATR): 2973, 2873, 1687, 1651, 1389, 1363, 1153, 1118, 760, 733,
701 cm–1
.
1H NMR (500 MHz, CDCl3): δ (66:34 mixture of rotamers) = 1.08 [s, 6
H, C(CH3)3], 1.37 [s, 3 H, C(CH3)3], 1.78–2.21 [m, 7 H, 3-HH, 4-H2,
N(CH2CH2)2], 2.26 (m, 1 H, 3-HH), 3.46 [m, 2 H, N(CH2CH2)2], 3.62 [m,
1.34 H, N(CH2CH2)2], 3.76 [m, 0.66 H, N(CH2CH2)2], 4.45 (m, 0.34 H, 5-
H), 4.60 (m, 0.66 H, 5-H), 4.66 (t, J = 7.2 Hz, 0.66 H, 2-H), 4.94 (dd, J =
7.9, 2.9 Hz, 0.34 H, 2-H), 7.19 (m, 1 H, Ph-H), 7.29 (m, 2 H, Ph-H), 7.75
(m, 2 H, Ph-H).
13C NMR (125 MHz, CDCl3): δ (mixture of rotamers) = 24.15, 24.24,
26.3, 26.4 [N(CH2CH2)2], 28.1, 28.35 [C(CH3)3], 28.43, 28.7 (C-4), 34.7,
35.8 (C-3), 46.10, 46.16, 46.18, 46.3 [N(CH2CH2)2], 59.3, 59.6 (C-5),
62.2, 63.4 (C-2), 79.7, 79.9 [C(CH3)3], 126.5, 126.6, 126.9, 128.0, 128.3
(CH-Ph), 143.6, 144.6 (Cq-Ph), 153.8, 154.6 (1-CO2), 171.2 (5-CON).
HRMS (ESI): m/z [M + 2 H – Boc]+ calcd for C15H21N2O: 245.1648;
found: 245.1650.
(7) (a) Breuning, M.; Steiner, M. Synthesis 2008, 2841. (b) Breuning,
M.; Hein, D.; Steiner, M.; Gessner, V. H.; Strohmann, C. Chem.
Eur. J. 2009, 15, 12764. (c) Breuning, M.; Steiner, M.; Mehler, C.;
Paasche, A.; Hein, D. J. Org. Chem. 2009, 74, 1407. (d) Breuning,
M.; Steiner, M.; Hein, D.; Hörl, C.; Maier, P. Synlett 2009, 2749.
(e) Breuning, M.; Hein, D. Eur. J. Org. Chem. 2013, 7575.
(8) Reviews: (a) Boruwa, J.; Gogoi, N.; Saikia, P. P.; Barua, N. C. Tet-
rahedron: Asymmetry 2006, 17, 3315. (b) Palomo, C.; Oiarbide,
M.; Laso, A. Eur. J. Org. Chem. 2007, 2561. (c) Blay, G.;
Hernández-Olmos, V.; Pedro, J. R. Synlett 2011, 1195.
(d) Chelucci, G. Coord. Chem. Rev. 2013, 257, 1887. (e) Ananthi,
N.; Velmathi, S. Indian J. Chem., Sect. B: Org. Chem. Incl. Med.
Chem. 2013, 52, 87.
(2R,5S)-1-Methyl-2-phenyl-5-(pyrrolidin-1-ylmethyl)pyrrolidine
(5u)
LAH (95.8 mg, 2.53 mmol) was added at 0 °C to a solution of ester 21d
(145 mg, 421 μmol) in anhydrous THF (10 mL). After 1 h at 0 °C, the
reaction mixture was heated at reflux temperature for 18 h. The solu-
tion was diluted with Et2O (20 mL) and treated with sat. aq Na2SO4
until H2 evolution had ceased. The resulting mixture was filtered
through a pad of Celite® and the filter cake was rinsed with CH2Cl2–
MeOH (9:1, 200 mL). Evaporation of the solvent and column chroma-
tography [silica gel, CH2Cl2–MeOH–NH3 (aq, 25%), 97:3:0
85:13.5:1.5] provided diamine 5u (101 mg, 413 μmol, 98%) as a
slightly brownish oil.
→
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 575–586

585
F. Prause et al.
Paper
Synthesis
(9) For selected recent examples, see: (a) Yao, L.; Wei, Y.; Wang, P.;
He, W.; Zhang, S. Tetrahedron 2012, 68, 9119. (b) Qin, D.-D.; Lai,
W.-H.; Hu, D.; Chen, Z.; Wu, A.-A.; Ruan, Y.-P.; Zhou, Z.-H.; Chen,
H.-B. Chem. Eur. J. 2012, 18, 10515. (c) Xu, K.; Lai, G.; Zha, Z.;
Pan, S.; Chen, H.; Wang, Z. Chem. Eur. J. 2012, 18, 12357.
(d) Leighty, M. W.; Shen, B.; Johnston, J. N. J. Am. Chem. Soc.
2012, 134, 15233. (e) White, J. D.; Shaw, S. Org. Lett. 2012, 14,
6270. (f) Dai, Q.; Rana, N. K.; Zhao, J. C.-G. Org. Lett. 2013, 15,
2922. (g) Qin, D.-D.; Yu, W.; Zhou, J.-D.; Zhang, Y.-C.; Ruan, Y.-P.;
Zhou, Z.-H.; Chen, H.-B. Chem. Eur. J. 2013, 19, 16541. (h) Das,
A.; Kureshy, R. I.; Prathap, K. J.; Choudhary, M. K.; Rao, G. V. S.;
Khan, N. H.; Abdi, S. H. R.; Bajaj, H. C. Appl. Catal. A 2013, 459,
97. (i) Deng, T.; Cai, C. J. Fluorine Chem. 2013, 156, 183. (j) Ćwiek,
R.; Niedziejko, P.; Kałuża, Z. J. Org. Chem. 2014, 79, 1222.
(10) Scharnagel, D.; Prause, F.; Kaldun, J.; Haase, R. G.; Breuning, M.
Chem. Commun. 2014, 50, 6623.
(11) Besides 5a (see ref. 10), there are only two further diamines of
type 5 known, namely 5f and a 5-cis, N′-diaryl derivative, see:
(a) Castro, A. C.; Depew, K. M.; Grogan, M. J.; Holson, E. B.;
Hopkins, B. T.; Johannes, C. W.; Keaney, G. F.; Koney, N. O.; Liu,
T.; Mann, D. A.; Nevalainen, M.; Peluso, S.; Perez, L. B.; Snyder, D.
A.; Tibbitts, T. T. WO 2008024337 A2, 2008; Chem. Abstr. 2008,
148, 308502. (b) Hutchison, A.; Peterson, J.; Doller, D.;
Gustavson, L. E.; Caldwell, T.; Yoon, T.; Pringle, W.;
Bakthavatchalam, R.; Shen, Y.; Steenstra, C.; Yin, H.; De Simone,
R.; He, X.-S. WO 2002094799 A2, 2002; Chem. Abstr. 2002, 138,
4617.
(12) For selected examples, see: (a) Fournie-Zaluski, M.-C.; Coric, P.;
Thery, V.; Gonzalez, W.; Meudal, H.; Turcaud, S.; Michel, J.-B.;
Roques, B. P. J. Med. Chem. 1996, 39, 2594. (b) Xu, Y.; Choi, J.;
Calaza, M. I.; Turner, S.; Rapoport, H. J. Org. Chem. 1999, 64,
4069. (c) Baldwin, J. J.; McDonald, E.; Moriarty, K. J.; Sarko, C. R.;
Machinaga, N.; Nakayama, A.; Chiba, J.; Shin, I.; Yoneda, Y. WO
2001000206 A1, 2001; Chem. Abstr. 2001, 134, 86149. (d) Pei, Z.;
Li, X.; Longenecker, K.; von Geldern, T. W.; Wiedeman, P. E.;
Lubben, T. H.; Zinker, B. A.; Stewart, K.; Ballaron, S. J.; Stashko,
M. A.; Mika, A. K.; Beno, D. W. A.; Long, M.; Wells, H.; Kempf-
Grote, A. J.; Madar, D. J.; McDermott, T. S.; Bhagavatula, L.;
Fickes, M. G.; Pireh, D.; Solomon, L. R.; Lake, M. R.; Edalji, R.; Fry,
E. H.; Sham, H. L.; Trevillyan, J. M. J. Med. Chem. 2006, 49, 3520.
(e) Kimura, T.; Kawano, K.; Doi, E.; Kitazawa, N.; Takaishi, M.;
Ito, K.; Kaneko, T.; Sasaki, T.; Miyagawa, T.; Hagiwara, H.;
Yoshida, Y. US 20070117839 A1, 2007; Chem. Abstr. 2007, 147,
31141. (f) Alvaro, G.; Bergauer, M.; Giovannini, R.; Profeta, R.
WO 2007042239 A1, 2007; Chem. Abstr. 2007, 146, 422302.
(g) See also references 11b, 13b and 27.
sequence to be performed as a one-pot, three-step procedure,
with comparable overall yields. To the best of our knowledge,
there is just one example in which NaBH4 has been used; see
ref. 12e.
(17) Gribble, G. W.; Jasinski, J. M.; Pellicone, J. T.; Panetta, J. A. Syn-
thesis 1978, 766.
(18) (a) Rudolph, A. C.; Machauer, R.; Martin, S. F. Tetrahedron Lett.
2004, 45, 4895. (b) Brenneman, J. B.; Machauer, R.; Martin, S. F.
Tetrahedron 2004, 60, 7301.
(19) Such protocols work well for the corresponding esters, see:
(a) Rigo, B.; Lespagnol, C.; Pauly, M. J. Heterocycl. Chem. 1988,
25, 49. (b) Jain, R. Org. Prep. Proced. Int. 2001, 33, 405.
(20) In further studies we found that Grignard reagents containing
lithium salts, as formed by transmetalation of organolithiums,
are not suited for addition. The reaction of compound 11 with
PhMgBr–LiCl–TMEDA (1.5:1.9:1.5), for example, provided 12 in
just 5% yield.
(21) According to ref. 18a, the ethoxycarbonyl group can be removed
with TMSI in refluxing MeCN.
(22) Pyroglutamate 14 is also commercially available. For selected
procedures on the preparation of 14 from 6 or of ent-14 from
ent-6, see: (a) Coudert, E.; Acher, F.; Azerad, R. Synthesis 1997,
863. (b) Aggarwal, V. K.; Astle, C. J.; Iding, H.; Wirz, B.; Rogers-
Evans, M. Tetrahedron Lett. 2005, 46, 945. (c) Reilly, M. WO
2007110835 A2, 2007; Chem. Abstr. 2007, 147, 406709.
(d) Vaswani, R. G.; Chamberlin, A. R. J. Org. Chem. 2008, 73,
1661. (e) Anelli, P. L.; Brocchetta, M.; Lattuada, L.; Manfredi, G.;
Morosini, P.; Murru, M.; Palano, D.; Sipioni, M.; Visigalli, M. Org.
Process Res. Dev. 2009, 13, 739. (f) Hsu, M.-C.; King, C.-H. R.;
Yuan, J.; Chen, W.-C.; Chou, S.-Y.; Shi, B. WO 2010009014 A2,
2010; Chem. Abstr. 2010, 152, 168816.
(23) In the cases of 16b and 16c, the minor diastereomers could not
be fully removed during this stage and the mixtures were
carried on to the next step, where separation by column chro-
matography was successful.
(24) McDermott, T. S.; Bhagavatula, L.; Borchardt, T. B.; Engstrom, K.
M.; Gandarilla, J.; Kotecki, B. J.; Kruger, A. W.; Rozema, M. J.;
Sheikh, A. Y.; Wagaw, S. H.; Wittenberger, S. J. Org. Process Res.
Dev. 2009, 13, 1145.
(25) (a) Lin, G.-J.; Huang, P.-Q. Org. Biomol. Chem. 2009, 7, 4491.
(b) Aebi, J.; Binggeli, A.; Green, L.; Hartmann, G.; Maerki, H. P.;
Mattei, P. US 20110082294 A1, 2011; Chem. Abstr. 2011, 154,
410031. (c) For related cyclizations of γ-amino ketones, see:
Abels, F.; Lindemann, C.; Schneider, C. Chem. Eur. J. 2014, 20,
1964.
(26) The silyl ethers 18 and 19 were isolated as single diastereomers
with unknown absolute configurations.
(13) For selected examples, see: (a) Momotake, A.; Togo, H.;
Yokoyama, M. J. Chem. Soc., Perkin Trans.
(b) Hoveyda, H.; Schils, D.; Zoute, L.; Parcq, J. WO 2011073376
A1, 2011; Chem. Abstr. 2011, 155, 123247.
1
1999, 1193.
(27) Amino ketone 15c is a known compound, but was not charac-
terized; see: Ayesa, S.; Belda, O.; Björklund, C.; Nilsson, M.;
Russo, F.; Sahlberg, C.; Wiktelius, D. WO 2013095275 A1, 2013;
Chem. Abstr. 2013, 159, 166189.
(28) (a) Mohite, A. R.; Bhat, R. G. J. Org. Chem. 2012, 77, 5423.
(b) Belema, M.; Hewawasam, P. US 20110237636 A1, 2011;
Chem. Abstr. 2011, 155, 484481.
(14) Amide 9a and diamine 5f are known, but were not previously
characterized; see ref. 11a.
(15) The cis/trans ratios were determined from the H NMR spectra
1
of the crude reaction mixtures after reductive cyclization. The
determination of the exact values was difficult for the N-Boc-
protected pyrrolidines since both diastereomers existed as mix-
tures of rotamers.
(29) For other approaches to 16c, see ref. 28a and: Wei, L.; Lubell, W.
D. Can. J. Chem. 2001, 79, 94.
(30) The structures of the products 5, prepared by hydroxy–amine
exchange, were unambiguously confirmed by 2D NMR experi-
ments and, for 5a (see ref. 10) and 5b, by comparison with
material obtained via route III. Rearrangements of 17 into β-
amino piperidines via the sequence of mesylation–aziridinium
formation–nucleophilic attack at C-2 with ring enlargement
were not observed. It has been shown that such rearrangements
(16) In most literature protocols, hydrogenations (see ref. 12) or
modified borohydrides (see ref. 13) are used for the reduction of
the intermediate Δ1-pyrrolidines. Even though the use of these
reagents often results in better cis selectivities, we chose cheap
NaBH4 for the reductions, because this reagent allows the N-
deprotection, reductive cyclization, and N-reprotection
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 575–586

586
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Paper
Synthesis
do not occur under mild mesylation conditions and with
amines as the nucleophiles, see: (a) Pargo, D. G.; Cossy, J. Chem.
Eur. J. 2014, 20, 4516. See also: (b) Reitsema, R. H. J. Am. Chem.
Soc. 1949, 71, 2041. (c) Biel, J. H.; Hoya, W. K.; Leiser, H. A. J. Am.
Chem. Soc. 1959, 81, 2527. (d) Hammer, C. F.; Heller, S. R.; Craig,
J. H. Tetrahedron 1972, 28, 239.
(32) Purification of Laboratory Chemicals; Armarego, W. L. F.; Perrin,
D. D., Eds.; Butterworth-Heinemann: Oxford, 2000, 4th ed.
(33) (a) Haddad, M.; Imogai, H.; Larchevêque, M. J. Org. Chem. 1998,
63, 5680. (b) Severino, E. A.; Costenaro, E. R.; Garcia, A. L. L.;
Correia, C. R. D. Org. Lett. 2003, 5, 305. (c) van Esseveldt, B. C. J.;
Vervoort, P. W. H.; van Delft, F. L.; Rutjes, F. P. J. T. J. Org. Chem.
2005, 70, 1791. (d) Stead, D.; O’Brien, P.; Sanderson, A. Org. Lett.
2008, 10, 1409.
(31) Amide 21c is a known, but only partially characterized com-
pound, see: Miyazaki, M.; Naito, H.; Sugimoto, Y.; Yoshida, K.;
Kawato, H.; Okayama, T.; Shimizu, H.; Miyazaki, M.; Kitagawa,
M.; Seki, T.; Fukutake, S.; Shiose, Y.; Aonuma, M.; Soga, T. Bioorg.
Med. Chem. 2013, 21, 4319.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 575–586