Large-scale synthesis of Singh's catalyst in a one-pot procedure starting from proline

Article abstract of DOI:10.1021/op200283q

A practical one-pot procedure for the preparation of Singh's catalyst from either l-/d-proline or Boc-proline is described. The coupling partner, a chiral amino alcohol, can be prepared and used directly without purification from the corresponding amino acid ester. Moreover, a procedure for tert-butoxycarbonyl (Boc) group removal using concentrated HCl in MeOH-DCM was developed and utilized for the multigram-scale synthesis of Singh's catalyst.

Full text of DOI:10.1021/op200283q

Article
pubs.acs.org/OPRD
Large-Scale Synthesis of Singh’s Catalyst in a One-Pot Procedure
Starting from Proline
Albrecht Berkessel,*,† Wacharee Harnying,† Nongnaphat Duangdee,† Jorg-M. Neudorfl,†
̈
̈
and Harald Groger‡
̈
†Department of Chemistry (Organic Chemistry), University of Cologne, Greinstrasse 4, 50939 Cologne, Germany;
‡Department of Chemistry (Organic Chemistry I), University of Bielefeld, Universitatsstr. 25, 33501 Bielefeld, Germany
̈
S
* Supporting Information
ABSTRACT: A practical one-pot procedure for the preparation of Singh’s catalyst from either L-/D-proline or Boc-proline is
described. The coupling partner, a chiral amino alcohol, can be prepared and used directly without purification from the
corresponding amino acid ester. Moreover, a procedure for tert-butoxycarbonyl (Boc) group removal using concentrated HCl in
MeOH−DCM was developed and utilized for the multigram-scale synthesis of Singh’s catalyst.
the original method reported by Singh et al.,2 a series of
catalysts of type 1 were prepared from Boc-proline (2) and the
corresponding diphenylamino alcohols 3 in a sequential two-
step method, i.e. condensation and Boc-deprotection, with
INTRODUCTION
The use of chiral organocatalysts, purely organic and metal-free
small molecules, has emerged as a highly efficient synthetic tool
for enantioselective transformations (asymmetric organocatal-
■
ysis) in a wide range of reactions.1 Small chiral organocatalysts
isolation of the intermediate from the condensation reaction,
i.e. 4 (Scheme 2). We envisioned an alternative synthesis of 1 in
are generally nontoxic, stable, and fairly easy to design and
synthesize from readily available chiral sources, such as natural
a one-pot multistep synthesis to give an economical preparative
method in which the reaction product from the initial step is
amino acids and other chiral amines. Among them, proline-
used directly without purification for the next step (Scheme 3).
based chiral organocatalysts have been developed extensively
and applied successfully in several reactions. Singh and co-
workers have designed proline amide catalysts of type 1
(Scheme 1), bearing gem-diphenyl substituents at the β-carbon,
In fact, Boc-L-proline (2) and the L-diphenylamino alcohol 3
are commercially available but rather expensive compared to
the precursor L-proline (5) and the L-leucine ester 6,
respectively. Thus, the synthesis of 1 starting from easily
which play a key role in providing high enantioselectivity in the
direct aldol reaction of ketones with aldehydes.2 The catalyst 1
accessible and cheap L-proline (5) and the L-leucine ester 6 in a
one-pot transformation would offer an improved overall
has been proven to be one of the most effective organocatalysts
economy of the process. Herein, we report a practical one-
for asymmetric direct aldol reactions of water-miscible ketones
such as acetone with various aldehydes in aqueous medium.3
pot procedure for the preparation of the Singh’s catalyst 1
directly from either Boc-proline (2) or proline (5), and leucine
Later, Groger and Berkessel et al. reported the use of this
̈
methyl ester hydrochloride (6). Novel conditions for Boc
group removal were also developed and utilized on multigram
scale in the synthesis of 1.
catalyst 1 in a modular chemoenzymatic synthesis of all four
stereoisomers of 1,3-diols through a combination of asymmetric
organocatalysis and biocatalysis in a one-pot synthesis in
aqueous reaction media (Scheme 1).4 The catalyst 1/ent-1 was
applied for the initial organocatalytic aldol reaction of acetone
with aldehydes under solvent-free conditions. The compatibility
of the organocatalyst 1 with the biocatalyst (ADH) allowed its
direct use in the subsequent enzymatic reduction without the
need for a workup step. Notably, high enantioselectivities were
obtained when low catalyst loadings were used under kinetic
control.5 Furthermore, Wang et al. have successfully identified
1 as a catalyst for the aldol reaction of acetone with α-amino
aldehydes in the synthesis of the antibiotic linezolid,6 and for
the aldol-lactonization of 2-formylbenzoic esters with ketones/
aldehydes in a three-step synthesis of the natural product (S)-
(−)-3-butylphthalide with a high level of enantioselectivity.7
As mentioned above, Singh’s catalyst 1 was used very
successfully in our work in asymmetric organocatalytic aldol
reactions, especially in water as solvent or under solvent-free
conditions.4,5 To support our study, we needed a practical and
reproducible procedure for the large-scale preparation of 1. In
Synthesis of the Catalyst 1 Starting from Boc-proline
(2). According to reported procedures,2,8 Boc-L-proline (2) was
condensed with the L-diphenylamino alcohol (S)-3 via a mixed
anhydride method using ethyl chloroformate or isobutyl
chloroformate, as shown in Scheme 2. The resulting N-Boc
proline amide (S,S)-4 was purified by recrystallization and then
subjected to Boc-deprotection by treatment with formic acid or
TFA. After neutralization, workup, and recrystallization, the
proline amide (S,S)-1 was obtained in 82−83% yield. In our
hands, the removal of the Boc group using formic acid or TFA
resulted in the formation of side products (e.g., the N-formyl
pyrrolidinyl derivative), leading to the lower yield of the desired
(S,S)-1. Thus, an alternative method was needed that would
provide 1 in high yield and high purity. We found that the use
of a solution of HCl(g) in MeOH for the Boc-deprotection step
Received: October 11, 2011
Published: December 1, 2011
© 2011 American Chemical Society
123
dx.doi.org/10.1021/op200283q | Org. ProcessRes. Dev. 2012, 16, 123−128

Organic Process Research & Development
Article
Scheme 1. Singh’s catalyst 1 and its application in combined asymmetric organo- and biocatalytic reaction sequences.4,5
Scheme 2. Synthesis of the catalyst 1 as reported by Singh et al.2
Scheme 3. Synthesis of the catalyst 1 in a one-pot multistep
synthesis starting from either Boc-proline (2) or proline (5)
Scheme 5. Attempted synthesis of (S,S)-1 via Pro-NCA (7)
successfully used in the synthesis of small peptides,9 and in the
preparation of chiral α,α-diaryl-2-pyrrolidinemethanols.10
Ideally, the anhydride 7 could provide 1 in a single operation,
by coupling with the amino alcohol 3 and concomitant
decarboxylation. As outlined in Scheme 5, L-proline (5) was
converted quantitatively to the anhydride (S)-7 by reaction
with triphosgene in THF, followed by the addition of
tributylamine to affect cyclization. The resulting homogeneous
solution of (S)-7 was used immediately for the coupling step.
Unfortunately, all attempts to condense (S)-7 and (S)-3 failed.
In all cases, we observed the polymerization of (S)-7, while (S)-
3 remained unchanged. Upon addition of (S)-7 to a (S)-3
solution at 0 °C, the evolution of gas (CO2) occurred rapidly to
afford a white solid. A trace of (S,S)-1 could be detected when
the reaction was performed at a temperature as low as −40 °C.
At lower temperature, no conversion to the desired product
occurred. It appears that (S)-3 mainly acts as a polymerization
initiator in the known base-catalyzed polymerization of Pro-
NCA (7).11 This assumption is also supported by the order of
amine nucleophilicities (determined by kinetic experiments)
according to which secondary amines are 102−103 times more
nucleophilic than typical primary alkyl amines.12
led to a clean conversion, and could be applied directly to the
reaction mixture after the completion of the initial
condensation process. As illustrated in Scheme 4, we performed
Scheme 4. Synthesis of the catalyst 1, starting from Boc-L-
proline (2)
such a combination of the coupling of (S)-2 with the pure
amino alcohol (S)-3 on a gram scale, using less expensive ethyl
chloroformate, and a subsequent removal of the Boc group was
achieved by adding a HCl(g)/MeOH solution directly to the
reaction mixture. After a final neutralization and workup step,
we were pleased to find that this procedure proceeded highly
efficiently and led to the desired proline amide (S,S)-1 in a very
good yield of 95% after recrystallization.
Synthesis of the Catalyst 1 Starting from Proline (5).
Having succeeded in performing a one-pot multistep synthesis
of 1 from 2, we further aimed at a multigram-scale synthesis of
1 starting from cheap L-proline (5), ideally without isolation of
any intermediates. The in situ generation of N-protected
proline was required for this purpose. We first attempted the
desired transformation via the reactive intermediate proline-N-
carboxyanhydride (Pro-NCA, 7, Scheme 5), which has been
Consequently, we considered suitable N-protection of
proline as the crucial factor for success in the coupling reaction
with (S)-3. We therefore focused our attention to the in situ
generation of Cbz- or Boc-protected proline, which could be
readily deprotected in the final step.13 In particular, we
examined the generation of the mixed anhydride intermediates
9 by sequentially reacting L-proline with different reagents as
124
dx.doi.org/10.1021/op200283q | Org. ProcessRes. Dev. 2012, 16, 123−128

Organic Process Research & Development
Article
Scheme 6. In situ preparation of the mixed anhydride (S)-9 (A) and the removal of the Boc group from the crude (S,S)-4 using
conc. HCl (B)
Scheme 7. Preparation of (S,S)-1 on 100 mmol scale in a one-pot procedure
outlined in Scheme 6(A). We found that the in situ generation
of Boc-protected proline, (S)-8a, using Boc2O (97% purity, 1.1
equiv) in the presence of NEt3 (3.5 equiv), followed by
treatment with ethyl chloroformate (1 equiv) resulted in the
clean formation of the mixed anhydride (S)-9a. The subsequent
coupling reaction with (S)-3 led to the N-Boc proline amide
(S,S)-4 in high purity. It is worthwhile noting that the
carboxylate group of (S)-8a does not significantly react with
Boc2O, even when it is present in an excess of 2 equiv. In
contrast, if (S)-8a was not formed quantitatively in the first
step, the remaining proline reacted with ethyl chloroformate,
leading to its undesired N-ethyl carbamate. It should also be
noted that the N-Cbz anhydride 9b could be cleanly formed
when purified Cbz-protected proline was used but not in a one-
pot procedure using Cbz-Cl. This is probably due to the
reagent Cbz-Cl, which is typically contaminated to some extent
with benzyl chloride (formed upon storage even for shorter
periods of time and at low temperatures).14
With an operationally simple and efficient coupling
procedure in hand, we then focused on the development of
novel conditions for Boc group removal, to be utilized in the
large-scale synthesis of 1. For this purpose, we envisaged the
use of commercially concentrated HCl, more practical and
convenient than the use of gaseous HCl. Gratifyingly, we found
that the Boc group of (S,S)-4 in the crude product still
containing triethylammonium chloride could be deprotected
using conc. HCl in a mixture of MeOH/DCM (2:1), as shown
in Scheme 6(B). The conversion proceeded via a slurry-to-
homogeneous transformation. It should be mentioned that the
reaction was sluggish and did not go to completion when only
MeOH was used as a single solvent. On 10 mmol scale, by
using ∼12 equiv of conc. HCl, the deprotection was complete
after stirring at rt for 15 h to give (S,S)-1·HCl in high purity
according to NMR analysis. While these results were very
encouraging, we wanted to avoid the use of a large excess of
HCl. Furthermore, the reaction did not reach completion in a
reasonable time on the larger scale. We felt that the process
needed to be more consistent if it was going to be used on
larger scale. We therefore examined the reaction on 50 mmol
scale at 50 °C. The most consistent results were obtained when
∼5 equiv of conc. HCl (20 mL) was used in a mixture of
MeOH/DCM of 80:40 mL. The deprotection was complete
within 6−7 h, yielding the protonated proline (S,S)-1·HCl in
high purity. After neutralization with 6 N NaOH and workup,
the crude product was purified by a final recrystallization to
furnish (S,S)-1.
The procedure described above was implemented on 100
mmol scale in a one-pot procedure, starting from L-proline (5)
and the crude amino alcohol (S)-3, obtained quantitatively
from the reaction of the L-leucine ester (S)-6 and PhMgBr (5
equiv).15 As illustrated in Scheme 7, L-proline (5) was first
converted to the mixed anhydride (S)-9a and then condensed
with the crude amino alcohol (S)-3. After concentration under
reduced pressure, the resulting crude (S,S)-4 was stirred in a
mixture of conc. HCl/MeOH/DCM (40:160:80 mL) at 50 °C
for 7 h to afford (S,S)-1·HCl. Subsequent neutralization,
workup, and recrystallization furnished the desired (S,S)-1 in
70% isolated yield based on the L-leucine ester (S)-6. Using the
same procedure, (R,R)-1 could be synthesized starting from D-
proline and (R)-3 instead.
We also performed the synthesis of (R,R)-1 from Boc-D-
proline on 25 mmol scale using the procedure described in
Scheme 7 starting from step 2. For this purpose, D-leucine was
first converted to the D-leucine ester (R)-6 by treatment with
125
dx.doi.org/10.1021/op200283q | Org. ProcessRes. Dev. 2012, 16, 123−128

Organic Process Research & Development
Article
Figure 1. X-ray crystal structures of (S,S)-1·HCl (left, chloride anion is omitted for clarity), and (R,R)-1 (right).
thionyl chloride in MeOH at reflux for 3 h.16 Subsequent
reaction with PhMgBr (5 equiv)17 afforded the desired (R)-3
which was used directly without purification for the
condensation with Boc-D-proline. After purification by
recystallization with EtOAc, (R,R)-1 was obtained in 72%
based on D-leucine (89% yield calculated from the crude
product by NMR analysis).
Furthermore, we were able to characterize the structure of
the catalyst 1 by X-ray crystallography in both the protonated
form as (S,S)-1·HCl, and the free proline amide form of (R,R)-
1, as depicted in Figure 1. These two crystal structures show
differences in mainly in the positioning of the proline’s
pyrrolidine ring. There is an intramolecular hydrogen bond
between the proline’s N-atom and the amide-NH in the free
proline amide (R,R)-1, whereas the protonated N-atom of
proline in the (S,S)-1·HCl salt points away from the amide-NH
bond, presumably to minimize steric hindrance.
In conclusion, we have developed an efficient and practical
one-pot procedure for the synthesis of proline amide
organocatalysts, in particular Singh’s catalyst 1, starting from
either proline or Boc-proline. This synthetic strategy can be
applied to large laboratory scale, and can potentially be
extended to technical synthesis. One of the key features is the
removal of the Boc-group using concentrated HCl in MeOH/
DCM as a clean and convenient protection method.
fractionating column at atmospheric pressure under Ar
atmosphere. Et2O was freshly distilled from Na/benzophenone.
NEt3 and CH2Cl2 were freshly distilled from CaH2.
Synthesis of (S,S)-1. Procedure A: Synthesis Starting
from L-Boc-proline. A dry, 250-mL Schlenk flask containing L-
Boc-proline (2.583 g, 12 mmol) was fitted with a mechanical
stirrer, argon inlet tube, and flushed with argon. Anhydrous
CH2Cl2 (50 mL) was added, and the solution was cooled to 0
°C, followed by the addition of Et3N (1.68 mL, 12 mmol. The
reaction mixture was then treated with ethyl chloroformate
(1.14 mL, 12 mmol) and stirred at 0 °C for 30 min, resulting in
the formation of triethylammonium hydrochloride as a white
precipitate. A solution of the pure (S)-3 (2.694 g, 10 mmol) in
anhydrous CH2Cl2 (50 mL) was added dropwise. After the
addition was complete, the reaction mixture was stirred at 0 °C
to room temperature overnight. To the resulting white slurry of
the crude N-Boc-proline amide (S,S)-4 was added a solution of
HCl(g) in MeOH (48 mL, 1.25 M, 60 mmol). A clear colorless
solution was obtained and stirred at rt overnight. The resulting
solution of the (S,S)-1·HCl salt was evaporated under reduced
pressure and diluted with EtOAc (60 mL). The mixture was
made slightly basic (pH 8−9) with 1 N KOH (∼60 mL) with
vigorous stirring to give (S,S)-1. After separation of the organic
layer, the aqueous phase was extracted with EtOAc (3 × 50
mL). The combined organic layers were washed with 1 N
KOH, H2O, and brine, dried over MgSO4, and concentrated in
vacuo, affording (S,S)-1 as a white solid in quantitative yield.
After recrystallization from EtOAc, (S,S)-1 was obtained as a
white crystalline solid [3.482 g, 95% yield based on (S)-3].
Procedure B: Synthesis Starting from L-Proline. A dry, 1-L
three-necked flask containing dry Mg turnings (12.16 g, 500
mmol), fitted with a mechanical stirrer, dried reflux condenser,
argon inlet tube, and a 250-mL pressure-equalized addition
funnel, was flushed with argon and charged with anhydrous
Et2O (100 mL). A solution of bromobenzene (79.30 g, 505
mmol) in dry Et2O (200 mL) was placed into the addition
funnel and added slowly and dropwise over a 2.0−2.5 h period.
After completion of the addition, the mixture was warmed to 40
°C and aged for 0.5 h to complete the reaction. The resulting
brown solution of PhMgBr was cooled to 0 °C in an ice bath
and a bent flask containing (S)-6 (18.026 g, 99 mmol) as dry
fine powder was fitted to a side neck of the reaction flask. By
rotation and tapping, the solid (S)-6 was gradually added to the
EXPERIMENTAL SECTION
■
1
General. H and 13C NMR spectra were measured on a
Bruker Avance 400, a Bruker DRX 500 or a Bruker Avance II
600 spectrometer at ambient temperature and are referenced to
the solvent used. IR spectra were measured on a Shimadzu
IRAffinity-1 instrument. Optical rotations were measured on a
Perkin-Elmer 343 Plus polarimeter. Melting points were
determined on a Buchi apparatus and are uncorrected.
̈
L-Proline (99%, BioChemica AppliChem), Boc-L-proline
(>99%, BACHEM Biochemica GmbH), Boc-D-proline
(>99%, NovaBiochem), L-leucine methyl ester hydrochloride
and D-leucine (99%, Alfa Aesar-Johnson Matthey Co.), Boc2O
(97%, Acros or ≥98%, Fluka) were purchased from the
suppliers indicated and used as received. Ethyl chloroformate
(99%) was purified prior to use: shaken with sat. aq. Na2CO3
(three times), aq. 50% CaCl2 (three times), and brine (twice),
then dried with Na2SO4 and redistilled using an efficient
126
dx.doi.org/10.1021/op200283q | Org. ProcessRes. Dev. 2012, 16, 123−128

Organic Process Research & Development
Article
solution under vigorous stirring. After the addition was
complete, the reaction mixture was stirred at 0 °C for 30 min
and then at rt for 15 h to give a light-yellow liquid mixed with a
white precipitate. The resulting heterogeneous mixture was
cooled to 0 °C and quenched by the slow addition of saturated
NH4Cl (300 mL), resulting in vigorous evolution of gas. The
mixture was then diluted with EtOAc (200 mL) and H2O (100
mL) and partitioned. After separation of the organic layer, the
aqueous phase (pH 7−8) was extracted with EtOAc. The
combined organic layers were washed with sat. NaHCO3, H2O,
and brine, were dried over Na2SO4 and evaporated to dryness
in vacuo. The crude product was obtained as a pale-yellow solid
(27.212 g) containing (S)-3 in quantitative yield together with
a small amount of biphenyl as a byproduct (by NMR and GC−
MS analysis), and used for the next step without further
purification.
To a suspension of L-proline (11.515 g, 100 mmol) and
Boc2O (22.961 g, 105 mmol) in dry CH2Cl2 (200 mL) was
slowly added Et3N (45.0 mL, 324 mmol) at 0 °C. The cooling
bath was removed, and the reaction mixture was stirred at rt for
1 h. During this time the mixture became homogeneous as
proline reacted with Boc2O to afford the intermediate N-Boc
proline (S)-8a. Then, the reaction mixture was cooled to 0 °C
and treated with ethyl chloroformate (9.50 mL, 100 mmol),
resulting in the formation of triethylammonium hydrochloride
as a white precipitate. Upon completion of the addition, the
resulting slurry was stirred for an additional 30 min. The crude
solid of (S)-3 (99 mmol) was then added in portions by means
of a funnel (rinsing with dry CH2Cl2). Upon completion of the
addition, the reaction mixture was stirred at 0 °C to room
temperature overnight, followed by evaporation of volatiles
under reduced pressure to provide the crude N-Boc proline
amide (S,S)-4 as a pale-yellow solid. MeOH (160 mL) and
CH2Cl2 (80 mL) were then added to the crude (S,S)-4,
followed by slow addition of conc. HCl (40 mL). The resulting
slurry was heated to 50 °C and stirred for 7 h. During this time,
the mixture became homogeneous (after ∼2.5 h). After the
reaction was complete (TLC analysis), the resulting solution of
the (S,S)-1·HCl salt was evaporated under reduced pressure
and diluted with H2O (200 mL) and EtOAc (300 mL). The
mixture was cooled to 0 °C and made slightly basic (pH 8−9)
with 6 N NaOH (∼70 mL), with vigorous stirring, to give
(S,S)-1. Since (S,S)-1 was only partially soluble in EtOAc, the
conversion of (S,S)-1·HCl to (S,S)-1 proceeded via a slurry-to-
slurry transformation. After separation of the organic layer, the
aqueous phase was extracted with EtOAc (3 × 200 mL). The
combined organic layers were washed with 1 N NaOH, H2O,
and brine and were dried over Na2SO4. The solution was
filtered through a short pad of silica and concentrated in vacuo
to afford (S,S)-1 as a pale-yellow solid. After purification by
recrystallization from EtOAc, (S,S)-1 was obtained as a white
crystalline solid [25.457 g, 70% yield based on (S)-6].
Hz, 3H, CH3), 0.85 (d, J = 6.6 Hz, 3H, CH3); 13C NMR
(CDCl3, 150 MHz): 147.2 (ArC), 144.5 (ArC), 128.4 (ArCH),
128.0 (ArCH), 126.6 (ArCH), 126.3 (ArCH), 125.8 (ArCH),
125.5 (ArCH), 79.0 (C−OH), 54.4 (CHNH2), 39.4 (CH2),
25.3 [CH(CH3)2], 24.1 (CH3), 21.3 (CH3); IR (ATR): ν 3339,
3265, 2955, 2866, 1637, 1599, 1586, 1508, 1491, 1468, 1449,
1385, 1182, 1057, 1005, 901, 743 (s), 694 (s), 638 cm−1; Anal.
Calcd for C18H23NO: C, 80.26; H, 8.61; N, 5.20. Found: C,
80.28; H, 8.50; N, 5.06.
(R)-2-Amino-4-methyl-1,1-diphenylpentan-1-ol, (R)-3.
Prepared from (R)-6 according to procedure B, and purified by
recrystallization from EtOAc to give (R)-3 as white crystals; mp
127−129 °C; [α]20 +100.0 (c 1.0, CHCl3); Anal. Calcd for
D
C18H23NO: C, 80.26; H, 8.61; N, 5.20. Found: C, 80.29; H,
8.51; N, 5.11.
(S)-N-((S)-1-Hydroxy-4-methyl-1,1-diphenylpentan-2-
yl)pyrrolidine-2-carboxamide, (S,S)-1. White crystals (re-
crystallization from EtOAc); mp 184−186 °C; [α]20D −49.7 (c
1.0, CHCl3) [lit.:2 mp 184−187 °C; [α]25 −45.9 (c 1.2,
D
CHCl3)]; 1H NMR (CDCl3, 600 MHz): δ 7.94 [d, J = 8.2 Hz,
1H, C(O)NHCH], 7.53 (t, J = 6.8 Hz, 4H, ArH), 7.28 (t, J =
7.8 Hz, 2H, ArH), 7.22 (t, J = 7.8 Hz, 2H, ArH), 7.16 (t, J = 7.3
Hz, 1H, ArH), 7.10 (t, J = 7.3 Hz, 1H, ArH), 5.41 (bs, 1H,
OH), 4.59 [t, J = 9.3 Hz, 1H, C(O)NHCHCH], 3.49 [dd, J =
9.2, 4.8 Hz, 1H, C(O)CHNH], 2.81 (dt, J = 10.1, 6.8 Hz, 1H,
NHCHH′CH2), 2.56 (dt, J = 10.3, 6.2 Hz, 1H, NHCHH′CH2),
2.03 (bs, 1H, NH), 1.91−1.80 (m, 2H, CHCH2CH), 1.59−1.50
[m, 1H, CH(CH3)2], 1.49−1.36 (m, 2H, CH2CH2CH), 1.27−
1.15 (m, 2H, CH2CH2CH2), 0.90 (d, J = 6.5 Hz, 3H, CH3),
0.84 (d, J = 6.7 Hz, 3H, CH3); 13C NMR (CDCl3, 150 MHz):
175.9 [C(O)NH], 146.6 (ArC), 145.1 (ArC), 128.2 (ArCH),
127.9 (ArCH), 126.6 (ArCH), 126.4 (ArCH), 125.7 (ArCH),
125.6 (ArCH), 80.9 (C-OH), 60.3 [C(O)NHCH], 56.9
[CHC(O)], 47.0 (NHCH2), 37.3 [CH2CHC(O)], 30.5
(CH2CH2CH), 25.7 (CH2CH2CH2), 25.4 [CH(CH3)], 23.8
(CH3), 21.5 (CH3); IR (ATR): ν 3464, 3343, 3275, 2967, 2870,
1636, 1512, 1493, 1447, 1144, 1101, 1059, 885, 745 (s), 700
(s), 640 cm−1; Anal. Calcd for C23H30N2O2: C, 75.37; H, 8.25;
N, 7.64. Found: C, 75.35; H, 8.27; N, 7.60.
(R)-N-((R)-1-Hydroxy-4-methyl-1,1-diphenylpentan-2-
yl)pyrrolidine-2-carboxamide, (R,R)-1. White crystals (re-
crystallization from EtOAc); mp 185−187 °C; [α]20 +50.9 (c
D
1.0, CHCl3); Anal. Calcd for C23H30N2O2: C, 75.37; H, 8.25;
N, 7.64. Found: C, 75.37; H, 8.25; N, 7.62.
CCDC 842976 and CCDC 842977 contain the supple-
mentary crystallographic data for this paper [compounds (S,S)-
1·HCl and (R,R)-1]. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
ASSOCIATED CONTENT
■
(S)-2-Amino-4-methyl-1,1-diphenylpentan-1-ol, (S)-3.
Prepared from (S)-6 according to procedure B and purified by
recrystallization from EtOAc to give (S)-3 as white crystals; mp
S
* Supporting Information
IR and NMR spectra of (S)-4, (S,S)-1, the intermediate (S)-9a,
and the crude products obtained in the course of the synthesis
according to procedures A and B. This material is available free
of charge via the Internet at http://pubs.acs.org.
126.5−128.5 °C; [α]20D −97.7 (c 1.0, CHCl3) [lit.:18 mp 136−
1
138 °C; [α]25 −96.6 (c 1.0, CHCl3)]; H NMR (CDCl3, 600
D
MHz): δ 7.60 (d, J = 7.5 Hz, 2H, ArH), 7.46 (d, J = 7.4 Hz, 2H,
ArH), 7.30 (t, J = 7.8 Hz, 2H, ArH), 7.26 (t, J = 7.8 Hz, 2H,
ArH), 7.24−7.13 (m, 2H, ArH), 4.24 (bs, 1H, OH), 3.97 (dd, J
= 10.2, 1.7 Hz, 1H, NCH), 1.62−1.52 [m, 1H, CH(CH3)2],
1.25 (ddd, J = 14.1, 10.3, 3.8 Hz, 1H, CHCHH′CH), 1.19 (bs,
2H, NH2), 1.10−1.02 (m, 1H, CHCHH′CH), 0.88 (d, J = 6.5
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: berkessel@uni-koeln.de. Fax: (+49) 221-4705102
127
dx.doi.org/10.1021/op200283q | Org. ProcessRes. Dev. 2012, 16, 123−128

Organic Process Research & Development
Article
ACKNOWLEDGMENTS
■
This work was supported by the Deutsche Forschungsgemein-
schaft (priority program “Organocatalysis”) and by the Fonds
der Chemischen Industrie.
REFERENCES
■
(1) For reviews on asymmetric organocatalysis, see: (a) Berkessel,
A.; Groger, H. Asymmetric Organocatalysis; Wiley-VCH: Weinheim,
̈
2005; (b) List, B.; Yang, J. W. Science 2006, 313, 1584−1586. (c)
Dalko, P. I., Ed. Enantioselective Organocatalysis; Wiley-VCH:
Weinheim, 2007; (d) Melchiorre, P.; Marigo, M.; Carlone, A.;
Bartoli, G. Angew. Chem., Int. Ed. 2008, 47, 6138−6171.
(2) Raj, M.; Vishnumaya.; Ginotra, S. K.; Singh, V. K. Org. Lett. 2006,
8, 4097−4099.
(3) (a) Maya, V.; Raj, M.; Singh, V. K. Org. Lett. 2007, 9, 2593−2595.
(b) Raj, M.; Maya, V.; Singh, V. K. J. Org. Chem. 2009, 74, 4289−4297.
(c) Review: Raj, M.; Singh, V. K. Chem. Commun. 2009, 6687−6703.
(4) Baer, K.; Kraußer, M.; Burda, E.; Hummel, W.; Berkessel, A.;
Groger, H. Angew. Chem., Int. Ed. 2009, 48, 9355−9358.
̈
(5) Rulli, G.; Duangdee, N.; Baer, K.; Hummel, W.; Berkessel, A.;
Groger, H. Angew. Chem., Int. Ed. 2011, 50, 7944−7947.
̈
(6) Song, L.; Chen, X.; Zhang, S.; Zhang, H.; Li, P.; Luo, G.; Duan,
W.; Wang, W. Org. Lett. 2008, 10, 5489−5492.
(7) Zhang, H.; Zhang, S.; Liu, L.; Luo, G.; Duan, W.; Wang, W. J.
Org. Chem. 2010, 75, 368−374.
(8) Yang, R.-Y.; Da, C.-S.; Yi, L.; Wu, F.-C.; Li, H. Lett. Org. Chem.
2009, 6, 44−49.
(9) (a) Bailey, J. L. J. Chem. Soc. 1950, 3461−3466. (b) Denkewalter,
R. G.; Schwam, H.; Strachan, R. G.; Beesley, T. E.; Veber, D. F.;
Schoenewaldt, E. F.; Barkemeyer, H.; Paleveda, W. J.; Jacob, T. A. Jr.;
Hirschmann, R. J. Am. Chem. Soc. 1966, 88, 3163−3164. (c) Berges, D.
A.; DeWolf, W. E. Jr.; Dunn, G. L.; Grappel, S. F.; Newman, D. J.;
Taggart, J. J.; Gilvarg, C. J. Med. Chem. 1986, 29, 89−95.
(10) (a) Mathre, D. J.; Jones, T. K.; Xavier, L. C.; Blacklock, T. J.;
Reamer, R. A.; Mohan, J. J.; Jones, E. T. T.; Hoogsteen, K.; Baum, M.
W.; Grabowski, E. J. J. J. Org. Chem. 1991, 56, 751−762. (b) Xavier, L.
C.; Mohan, J. J.; Mathre, D. J.; Thompson, A. S.; Carroll, J. D.; Corley,
E. G.; Desmond, R. Organic Syntheses; John Wiley & Sons: New York,
1998; Collect. Vol. 9, pp 676−687
(11) (a) Berger, A.; Kurtz, J.; Katchalski, E. J. Am. Chem. Soc. 1954,
76, 5552−5554. (b) Kurtz, J.; Fasman, G. D.; Berger, A.; Katchalski, E.
J. Am. Chem. Soc. 1958, 80, 393−397.
(12) Mayr, H.; Ofial, A. R. J. Phys. Org. Chem. 2008, 21, 584−595.
(13) (a) Wuts, P. G. M.; Greene, T. W. Protective Groups in Organic
Synthesis, 4th ed.; John Wiley & Sons, Inc.: Hoboken, NJ, 2007.
(b) Huy, P.; Schmalz, H.-G. Synthesis 2011, 954−960.
(14) Wunsch, E. Synthesis 1986, 958−960.
̈
(15) PhMgBr was first prepared by reacting Mg metal and PhBr in
Et2O, and the solid (S)-6 was then added to it. To obtain the best
results, the solid (S)-6 must be finely ground and dried in high vacuum
prior to use. By GC−MS analysis of the crude (S)-3, only a small
amount of biphenyl was observed as a byproduct. (S)-3 was obtained
quantitatively, as evidenced by 1H NMR analysis using methyl
cinnamate as external standard.
(16) Elders, N.; Schmitz, R. F.; de Kanter, F. J. J.; Ruijter, E.; Groen,
M. B.; Orru, R. V. A. J. Org. Chem. 2007, 72, 6135−6142.
(17) (R)-3 was prepared by addition of a solution of phenyl-
magnesium bromide in Et2O (2.8 M, obtained from Acros) to a
suspension of the crude solid of (R)-6 in Et2O.
(18) Zhou, Z.; Guo, Y. Synth. Commun. 2008, 38, 676−687.
128
dx.doi.org/10.1021/op200283q | Org. ProcessRes. Dev. 2012, 16, 123−128