(R)- and (S)-Proline-Derived Chiral Phosphoramides as Organo catalysts for the Enantiodivergent Aldol Reaction of Isatins with Cyclohexanone in the Presence of Water

Article abstract of DOI:10.1055/s-0036-1591916

Novel organocatalysts derived from (R)- and (S)-proline and incorporating a chiral phosphoramide fragment were rationally designed and subsequently synthesized. These chiral compounds catalyze the enantioselective aldol addition reaction of cyclohexanone

Full text of DOI:10.1055/s-0036-1591916

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–N
paper
A
en
C. Cruz-Hernández et al.
Paper
Synthesis
(R)- and (S)-Proline-Derived Chiral Phosphoramides as Organo-
catalysts for the Enantiodivergent Aldol Reaction of Isatins with
Cyclohexanone in the Presence of Water
Carlos Cruz-Hernándeza
Perla E. Hernández-Gonzáleza
Eusebio Juaristi*a,b
0
0
0
0
0-
0
0
3
0-
9
3
6
7-
0
2
0
Ph
R
Ph
Me
Me
R
O
R
R
O
O
N
R
O
N
a Departamento de Química, Centro de Investigación y de
Estudios Avanzados, Avenida IPN 2508, 07360 Ciudad de
México, Mexico
b El Colegio Nacional, Luis González Obregón 23, Centro
Histórico, 06020 Ciudad de México, Mexico
juaristi@relaq.mx
R
P
S
P
N
H
N
H
N
R
N
HN
HN
R
R
Me
Me
Ph
Ph
O
O
O
O
O
O
Cat.* (10 mol%)
BzOH (10 mol%)
Cat'.* (10 mol%)
BzOH (10 mol%)
HO
OH
S
R
R
O
R
O
N
H
H2O, 3 °C, 48 h
H2O, 3 °C, 48 h
R
S
N
H
R
O
R
O
N
H
N
H
R = NO2, Br, Cl, F, H; 45–94% yield; dr up to 90:10; er up to 93:7
Received: 10.11.2017
Accepted after revision: 20.12.2017
Published online: 05.02.2018
metric aldol addition reaction as one of the most successful
strategies.9
In this regard, there is increasing interest in the devel-
opment of enantioselective organocatalyzed nucleophilic
additions to isatins, as a way to synthesize enantioenriched
3-substituted 3-hydroxyindolin-2-ones,10 which represent
a valuable fragment in many pharmacologically active com-
pounds.11 Although several reports describe the stereose-
lective aldol addition of acetone to isatins,12 the use of
cyclohexanone as nucleophilic partner has been limited to
reactions catalyzed by primary amines in chiral frame-
works presenting an additional hydroxy,13a,b amino,13c–f imi-
no,13g amide,14 sulfonamide15a or imidazole group15b (Figure
1).
DOI: 10.1055/s-0036-1591916; Art ID: ss-2017-m0730-op
Abstract Novel organocatalysts derived from (R)- and (S)-proline and
incorporating a chiral phosphoramide fragment were rationally de-
signed and subsequently synthesized. These chiral compounds catalyze
the enantioselective aldol addition reaction of cyclohexanone to
prochiral isatins in the presence of water. These observations are partic-
ularly relevant since reports of asymmetric aldol reactions between
cyclohexanone and isatins catalyzed by chiral secondary amines remain
scarce, with primary amines being the most studied and successful cat-
alysts. The present report includes a thorough evaluation of the new bi-
functional catalysts that actually give rise to either enantiomer of the
chiral product by proper selection of the configuration of the proline
moiety.
Key words asymmetric organocatalysis, dual activation, hydrophobic
interactions, Brønsted acids, Lewis bases
Ar
HO
NH
N
H2N
Ph
N
NH2
O
The use of chiral organic molecules as catalysts to accel-
erate synthetic processes with high stereoselectivity has
advanced with great impetus and success since the pio-
neering studies of Hajos and Parrish1a and Wiechert and co-
workers1b in the early 1970s, as well as the contributions
from the groups of Denmark,2 Iseki,3 Jacobsen4 and Dalko5
in the 1990s. Nevertheless, it was not until the beginning of
the 21st century that the field of asymmetric organocataly-
sis emerged formally and forcefully following the seminal
works of List and co-workers6a and MacMillan and co-
workers,6b who carried out asymmetric organocatalyzed al-
dol and Diels–Alder reactions, respectively. Since then, or-
ganocatalysis has been consolidated as a valuable method-
ology to induce stereoselectivity in a great variety of chem-
ical transformations.7 In this context, stereoselective C–C
bond-forming reactions currently play a central role in the
synthesis of drugs and natural products,8 with the asym-
NH2
Ph
V. K. Singh13c
Ar = Ph, 1-Np
S. S. Chimni13f
Y. Cheng13g
F
O
O
H
N
Mes
Ar
H2N
S
N
H
N
H
O
O
O
NH2
F
NH2
H. Nakano14c
Ar = 1-anthracenyl
H. Yang15a
K. Ishimaru14a
Figure 1 Successful organocatalysts used in the enantioselective
addition of cyclohexanone to isatins
Interestingly, secondary amines, such as proline deriva-
tives, explored as organocatalysts in this transformation af-
forded lower stereoselectivities than the primary amine an-
alogues, or even proved to be inactive.16 Figure 2 shows four
salient examples of such proline derivatives. Catalyst A13c
was efficient in aldol reactions involving aryl aldehydes as
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

B
C. Cruz-Hernández et al.
Paper
Synthesis
N
NH
SO2Mes
O
Ph
Ph
N
H
O
O
N
H
N
H
O
O
O
OH
HN
Ts
NH
H
H
H
N
N
N
NH
NH
NH
A
B
C
D
V. K. Singh13c
C. Qi16a
H. Zhao14b
C. Nájera16b
Figure 2 Secondary amines evaluated as catalysts in the aldol addition of cyclohexanone to isatin
electrophiles, but was unable to catalyze the desired nucle-
ophilic addition to isatins. By the same token, proline deriv-
ative B16a afforded good results only when reactive alde-
hydes were used as aldol acceptors. The efficiency of cata-
lyst C14b was moderate but its primary amine analogues
showed better results. So far, Nájera’s catalyst D16b is the
most successful secondary amine employed for the prepa-
ration of enantioenriched 3-substituted 3-hydroxyindolin-
2-ones; nevertheless, only two examples with cyclohexa-
none as nucleophile were reported.
As part of our continuing interest in the development of
more sustainable asymmetric organocatalysis,17 we have
recently reported the advantages of solvent-free reactions
by means of ball-milling activation,18 the convenient use of
neat reaction conditions,19 or the employment of green sol-
vents such as water20 or the use of nonvolatile ionic liq-
uids.21 Herein, we describe the design and synthesis of sev-
eral novel proline-derived organocatalysts, incorporating a
chiral phosphoramide segment, that are able to catalyze the
enantioselective aldol addition of cyclohexanone to isatins
in the presence of water. The new catalysts were designed
based on the accepted mechanism operative in enamine-
activated aldol reactions,22 and seeking to generate a chiral
C2-symmetric, helix-type conformation in the catalyst (Fig-
ure 3).23,24 These structural characteristics were anticipated
to induce efficient enantiodiscrimination, by selectively
blocking one of the enantiotopic faces of the prochiral
carbonyl group in isatin.
With these considerations in mind, molecular structure
I (Figure 3) was selected for the new catalyst since it pres-
ents four attractive characteristics: (1) It contains the pyr-
rolidine fragment necessary to perform imine–enamine ac-
tivation.25 (2) It presents a rather acidic N–H bond, adjacent
to both the carbonyl and phosphoryl groups. This Brønsted
acid is anticipated to activate electrophiles via hydrogen
bonding.26 Indeed, the phosphoramido group should pres-
ent both acidic and basic properties similarly to Terada’s27a,b
and Akiyama’s27c,d phosphoric acids. (3) The chiral cyclo-
hexane framework generates a hydrophobic environment
which could improve the interactions between catalyst and
substrates in the presence of water.28 (4) Finally, the N-α-
phenylethyl groups of same configuration (either R,R or S,S)
were anticipated to adopt the desired C2-symmetric, pro-
peller-like chiral environment in I, as consequence of A1,3
strain.29
Dual functional group:
P=O, Lewis base;
N-H, Brønsted acid
*
CH3
O
N
N
Chiral
hydrophobic
group
N
N
*
*
O
P
H3C
P
H
H
R
O
N
H
HN
*
Lewis base
imine–enamine activation
Our Expectation
I
CH3
tBu
N
N
N
N
H3C
tBu
P
H
H
O
H
H
H
O
E. Juaristi23
N. Cramer24a
Figure 3 Design of the newly developed catalyst and its comparison with known, structurally related molecules
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

C
C. Cruz-Hernández et al.
Paper
Synthesis
It is important to mention that phosphoramide deriva-
tives related to I but lacking both the N-α-phenylethyl
group and the proline segment have been reported by Li
and co-workers30 who employed them as chiral auxiliaries
in nucleophilic addition to imines, obtaining good yields
and moderate to excellent diastereoselectivity (Figure 4).
Furthermore, Li and co-workers have developed group-as-
sisted purification (GAP) chemistry with these systems
which provide a good alternative to reduce purification
steps and solvent consumption, a goal of green chemis-
try.30f–j
azide under microwave irradiation to generate chiral azides
3 in excellent yield.
The azido group in derivatives 3 was reduced by catalyt-
ic hydrogenation with Pd/C at atmospheric pressure and
ambient temperature30 to obtain the chiral phosphora-
mides 4 (Scheme 1). In order to obtain the desired catalysts
5a–e, it was convenient to perform a one-pot, two-step re-
action involving the conversion of trisphosphoramides 4
into their lithium salts with n-butyllithium, before treat-
ment with the methyl ester of (R)- or (S)-proline (Scheme
1).
At this point, it was possible to obtain suitable crystals
of
derivatives
(1R,2R,1′R,2′R)-1,32
(1S,2S,1′S,2′S)-1,33
R
ArCHO
TiCl4, DIPEA
(1R,2R,1′R,2′R)-2,34 (1S,2S,1′R,2′R)-3,35 (1R,2R,1′S,2′S)-3,36
(1S,2S,1′R,2′R)-437 and (1R,2R,1′S,2′S)-438 for X-ray diffrac-
tion analysis, which made it possible to confirm the struc-
tures of the catalysts and to determine their crystal confor-
mation and configurations, both relative and absolute.
Contrary to expectations, none of the crystallographic
structures of diazaphosphole derivatives 2, 3 and 4 presents
the anticipated helix-type conformation of the N-α-phenyl-
ethyl groups on the phosphoramide moiety; by contrast,
both phenyl rings in each compound are oriented to the
same side of the molecule, syn to the phosphoryl group and
anti to the P-substituent, be it either Cl, N3 or NH2 (Figure
5). In contrast, diamine dihydrochlorides 1 showed the an-
ticipated helix-type conformation in the solid state (Figure
5).
O
N
N
N
N
O
N
N
O
LiNu
P
R
R
R
R
P
P
CH2Cl2, r.t., 30 h
NH2
N
HN
R
*
Ar
Ar
Nu
G. Li30
R = Bn, iPr, 1-Np,
tBu, iBu
>80%
dr from 8:2 to
>99:1
Figure 4 Li’s trisphosphoramide as chiral auxiliary
The synthesis of catalysts with general structure I
(Scheme 1) began with the condensation of phosphorus
oxychloride and the corresponding diamines according to
the literature procedure.30 In this regard, enantiopure di-
amines 1 were synthesized according to the procedure de-
scribed by Juaristi and co-workers31 starting from cyclohex-
ene oxide and (R)- or (S)-α-phenylethylamine (see the Sup-
A salient characteristic in the crystal structures of deriv-
atives 3 and 4 is that they provide evidence for C–H···O non-
bonded interactions between the ortho hydrogens at the
phenyl rings and the phosphoryl oxygen atom (Figure 6).
Indeed, the average distance for one of these hydrogens is
porting
Information
for
experimental
details).
Subsequently, the bisamidophosphoryl chlorides 2 were
subjected to a nucleophilic addition reaction with sodium
Ph
Me
Ph
Me
Ph
Me
Ph
Me
O
Ph
Me
O
R
R
R
R
R
N
N
O
Cl
Cl
NH2
N
N
S
O
S
O
S
S
S
i
ii
iii
iv
P
P
P
P
S
NH2
N
Cl
N3
S
S
S
S
S
N
N
H
NH2
N
N
HN
R
R
R
R
R
Ph
Me
Ph
Me
Ph
Me
Ph
Me
Ph
Me
(1S,2S,1'R,2'R)-1
or
(1S,2S,1'R,2'R)-2
or
(1S,2S,1'R,2'R)-3
or
(1S,2S,1'R,2'R)-4
or
(1S,2S,1'R,2'R,2''S)-5a
or
(1R,2R,1'S,2'S)-1
(1R,2R,1'S,2'S)-2
(1R,2R,1'S,2'S)-3
(1R,2R,1'S,2'S)-4
(1R,2R,1'S,2'S,2''S)-5b
Ph
Me
O
Ph
Me
O
Ph
Me
Ph
Me
O
Ph
Me
O
R
R
R
R
R
N
O
Cl
N
NH2
N
N
R
R
R
R
R
iii
iv
ii
i
P
P
P
P
S
N
NH2
Cl
N3
R
R
R
R
R
N
H
N
NH2 Cl
N
N
HN
R
R
R
R
R
Ph
Me
Ph
Me
Ph
Me
Ph
Me
Ph
Me
(1R,2R,1'R,2'R,2''S)-5c
or
(1R,2R,1'R,2'R)-1
or
(1S,2S,1'S,2'S)-1
(1R,2R,1'R,2'R)-2
or
(1S,2S,1'S,2'S)-2
(1R,2R,1'R,2'R)-3
or
(1S,2S,1'S,2'S)-3
(1R,2R,1'R,2'R)-4
or
(1S,2S,1'S,2'S)-4
(1R,2R,1'R,2'R,2''R)-5d*
or
(1S,2S,1'S,2'S,2''S)-5e (ent-5d)
Scheme 1 Synthesis of the chiral phosphoramides 5a–e. Reagents and conditions: i) 1) NaOH (1 M), Et2O r.t.; 2) P(O)Cl3, Et3N, toluene, r.t. to reflux, 12
h. ii) NaN3, DMF/DMSO (9:1), MW (40 watts), 60 °C, 1 h. iii) H2, Pd/C, MeOH, r.t. 6 h. iv) 1) n-BuLi, THF, 0 °C, 20 min; 2) (S)-Pro-OMe, THF, 0 °C to r.t.,
24–36 h. * Reaction was carried out with (R)-Pro-OMe.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

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C. Cruz-Hernández et al.
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Synthesis
Figure 5 Solid-state conformations of representative derivatives prepared in this work
2.6 Å, which is the sum of the van der Waals radii. The dis-
tance between the second ortho hydrogen and the phos-
phoryl oxygen is 3.4 Å, which is larger than the sum of the
van der Waals radii; nevertheless, according to Jeffrey39
both H···O distances could be in line with the existence of
hydrogen-bonding interactions of different strength, one
moderately strong and the other weak. In contrast, deriva-
tive 2 presents longer H···O distances of 2.89 and 4.26 Å;
thus, only the first is in line with a hydrogen-bonding inter-
action. These stabilizing C–H···O interactions40 along with
crystal packing forces41 may be the factors that induce the
observed ‘U-type’ conformation, rather than the anticipated
helix-type conformation.
ure 7). While small, this energy difference is in accord with
that anticipated (see above) and suggests that a significant
amount of the propeller-like conformation Ia should be
present during the course of the reaction. On the other
hand, conformer Ic, which orients both phenyl groups anti
to the oxygen, so that no stabilizing C–H···O interaction is
operative, is estimated to be 1.8 kcal/mol higher in energy
relative to the propeller-like conformer Ia, and 1.4 kcal/mol
higher in energy than the ‘U-type’ conformer Ib (Figure 7).
In order to evaluate the catalytic performance of novel
phosphoramide derivatives 5a–e, we examined the aldol
reaction between cyclohexanone (6) and p-nitrobenzalde-
hyde
(7)
employing
chiral
phosphoramide
(1R,2R,1′R,2′R,2′′S)-5c as the organocatalyst (Table 1). The
reaction was carried out in solvents of low polarity such as
toluene, CH2Cl2 and THF, solvents of medium polarity such
as MeCN, the polar aprotic solvents DMF and DMSO, and
polar protic solvents such as MeOH, water, and brine. Fur-
thermore, the reaction was also performed under neat con-
ditions at room temperature. As can be appreciated from
Table 1, in the less polar solvents toluene, CH2Cl2 and THF,
the reaction proceeded with moderate diastereoselectivity,
poor enantioselectivity and low yields (Table 1, entries 1–
3). Furthermore, the reaction did not take place in polar
aprotic solvents (Table 1, entries 5 and 6). More promising
results in terms of yield and stereoselectivity were ob-
served with water and brine as solvents, or under neat con-
ditions (Table 1, entries 8–10).
It is well established that acid additives can enhance the
efficiency of amine-catalyzed aldol reactions. In particular,
mineral or carboxylic acids generally enhance both reaction
rate and selectivity because they tend to accelerate enam-
ine formation by activation of the electrophile. Further-
more, Brønsted acids have been proposed to stabilize the
reaction’s transition state.42 Accordingly, we evaluated sev-
eral Brønsted acids of different strength as additives in the
reaction carried out under neat conditions, anticipating
Figure 6 Nonbonded C–H···O interactions between the ortho hydro-
gens at the phenyl rings and the phosphoryl group
To gain additional insight regarding the conformational
behavior of the proposed catalysts, theoretical calculations
were carried out with compound (1R,2R,1′R,2′R,2′′S)-5c as
reference model. Calculations were performed at the DFT
level of theory with B3LYP functional and the 6-31G* basis
set, a rather successful theoretical method in the modelling
of organic molecules containing heteroatoms with lone
electron pairs. Figure 7 shows the lowest-energy conforma-
tions and their relative energies in kcal/mol. It can be ap-
preciated that the conformer orienting both phenyls syn to
each other and to the phosphoryl oxygen (‘U-type’ con-
former, Ib in Figure 7) is estimated to be 0.4 kcal/mol higher
in energy than the anticipated helix-type conformer Ia (Fig-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

E
C. Cruz-Hernández et al.
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Synthesis
Figure 7 Energy differences between the three lowest-energy conformers of catalyst (1R,2R,1′R,2′R,2′′S)-5c determined by DFT with the 6-31G* basis
set
Table 1 Optimization of the Asymmetric Aldol Reaction between Cyclohexanone and p-Nitrobenzaldehyde with Catalyst 5ca
O
O
O
OH
R
Cat.* 5c (10 mol%)
S
NO2
NO2
6
7
8
Entry
Solvent
Additive (10 mol%)
Temp (°C)
Time (h)
Yieldb (%)
drc (anti/syn)
erd (anti/syn)
1
2
toluene
CH2Cl2
THF
–
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
3
68
68
68
68
80
80
68
48
48
48
20
16
16
16
144
90
72
72
20
20
46
46
47
23
24
13
n.r.
n.r.
22
89
85
87
96
97
95
96
37
99
96
90
88
99
96
97
80:20
68:32
73:27
58:42
–
69:31/77:23
52:48/61:39
61:39/72:28
57:43/57:43
–
–
3
–
4
MeCN
DMF
–
5
–
6
DMSO
MeOH
water
brine
neat
–
–
–
7
–
66:34
63:37
66:34
72:28
68:32
75:25
77:23
71:29
80:20
78:22
75:25
78:22
77:23
77:23
85:15
74:26
57:43/61:39
55:45/66:34
59:41/69:31
63:37/70:30
63:37/69:31
70:30/69:31
68:32/65:35
66:34/64:36
66:34/79:21
50:50/62:38
59:41/69:31
63:37/72:28
73:27/72:28
71:29/75:25
82:18/74:26
88:12/68:32
8
–
9
–
10
11
12
13
14
15
16
17
18
19
20
21
22
–
neat
BzOH
neat
(R)-mandelic acid
(S)-mandelic acid
p-nitrobenzoic acid
PTSA
neat
neat
neat
neat
TFA
toluene
THF
BzOH
BzOH
water
brine
water
brine
BzOH
BzOH
BzOH
BzOH
3
a Reaction conditions: aldehyde (0.1 mmol), cyclohexanone (10 equiv), catalyst (1R,2R,1′R,2′R,2′′S)-5c (10 mol%).
b Yield of pure product (both diastereomers).
c Determined by 1H NMR spectroscopy of the crude product.
d Determined by chiral HPLC of the isolated product.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

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C. Cruz-Hernández et al.
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Synthesis
that they would accelerate the reaction and improve both
stereoselectivity and yield. In the event, the Brønsted acids
that afforded the best results in terms of reaction yield were
benzoic acid, (R)- and (S)-mandelic acid, and p-nitrobenzoic
acid (Table 1, entries 11–14). For subsequent work, it was
decided to use benzoic acid as additive in water or brine
solvents (Table 1, entries 19 and 20). Finally, in order to fur-
ther improve the stereoselectivity of the reaction, the reac-
tion temperature was lowered to 3 °C, with water as solvent
exhibiting the best performance, of 96% yield, 85:15 an-
ti/syn (unlike/like) diastereomeric ratio (dr), and 82:18 en-
antiomeric ratio (er) of the major diastereomer (Table 1, en-
try 21).
equivalents resulted in increased reaction rate and higher
diastereoselectivity (Table 2, entry 8); nevertheless, when
the amount of cyclohexanone was further increased to 10
equivalents, the diastereoselectivity falls drastically, appar-
ently because the reaction becomes too fast (Table 2, entry
9). By contrast, lower amounts of cyclohexanone (1 or 2
equivalents) result in slower or even unsuccessful reactions.
Due to inconsistences in the use of anti/syn descriptors for
this system in the reported literature, we prefer to use the
unlike/like descriptors proposed by Seebach and Prelog.43 In
this regard, we obtained the (3R,2′S)-diastereomer as the
major product, and this corresponds to the unlike diaste-
reomer.
Initially 5-nitroisatin (9a) was used as substrate in the
aldol reaction with cyclohexanone, with water or brine as
solvent, or under neat reaction conditions at room tem-
perature, and with benzoic acid as additive (Table 2, entries
1–3); the addition reaction proceeded best in water as sol-
vent, which was then selected as the medium of choice.
When the reaction temperature was lowered to 3 °C (Table
2, entry 4) the stereoselectivity was indeed improved, al-
though the reaction required significantly longer time to
reach completion. On the other hand, the process could be
accelerated by increasing catalyst and additive loadings (Ta-
ble 2, compare entries 5–7). Finally, the amount of cyclo-
hexanone (6) was increased in order to secure dissolution
of both the isatin and the catalyst in the biphasic medium.
In this regard, increasing the amount of cyclohexanone to 7
With the best reaction conditions established for
organocatalyst (1R,2R,1′R,2′R,2′′S)-5c (entry 8 in Table 2),
we proceeded to examine the effect of the catalyst’s stereo-
chemistry, and to determine whether double stereoinduc-
tion44 by the proline and phosphoramide fragments in the
catalyst is operative. In the event (Table 3), it can be appre-
ciated that the configuration of the phosphoramide frag-
ment has no significant influence on the resulting configu-
ration of the product (Table 3, entries 1 and 3–5), thus rul-
ing out a potential match/mismatch effect. On the other
hand, when proline of opposite configuration is present in
the organocatalyst, then the enantiomeric product (ent-
10a) is obtained, in almost the same yield and stereoselec-
tivity:
compare
(1R,2R,1′R,2′R,2′′S)-5c
with
(1R,2R,1′R,2′R,2′′R)-5d (Table 3, entries 3 and 4). These ob-
Table 2 Optimization of the Reaction Conditions in the Aldol Reaction between Cyclohexanone and 5-Nitroisatin Catalyzed by Chiral Phosphoramide 5ca
O
O
O
HO
S
O2N
O2N
R
O
O
N
N
H
H
6
9a
10a
Entry
Solvent
Catalyst*/BzOH additive (mol%) 6 (equiv)
Temp (°C)
Time (h)
Yieldb (%)
drc (u/l)
erd
78:22
1
2
3
4
5
6
7
8
9
neat
10
10
10
10
5
10
5
25
25
25
3
96
48
79
90
94
91
83
95
97
94
98
76:24
78:22
79:21
79:21
75:25
76:24
77:23
90:10
77:23
brine
water
water
water
water
water
water
water
80:20
89:11
94:6
97:3
92:8
94:6
92:8
93:7
5
48
5
96
5
3
168
48
15
20
10
10
5
3
5
3
36
7
3
48
36
10
3
a Reaction was carried out with catalyst (1R,2R,1′R,2′R,2′′S)-5c.
b Yield of pure product (both diastereomers).
c Determined by 1H NMR spectroscopy of the crude product.
d Determined by chiral HPLC of the isolated product.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

G
C. Cruz-Hernández et al.
Paper
Synthesis
servations are in line with those recently reported for the
asymmetric Michael addition reaction catalyzed by diaste-
reomeric pyrrolidine sulfinamides.45
Table 4 Aldol Addition Reaction of Cyclohexanone (6) to Isatins 9a–e
in the Presence of Water
O
O
O
HO
Cat.* (10 mol%)
BzOH (10 mol%)
S
Table 3 Influence of Catalyst 5a–e Configuration on the Aldol Reac-
tion between Cyclohexanone and 5-Nitroisatin
R
O
R
R
O
N
H2O, 3 °C, 48 h
H
N
H
O
6
9a–e
10a–e
O
O
HO
Cat.* (10 mol%)
BzOH (10 mol%)
S
O2N
O2N
O
Catalyst
R
Product
Yielda (%) drb (u/l)
erc
R
O
H2O, 3 °C, 48 h
N
N
H
H
5c
5d
5c
5d
5c
5d
5c
5d
5c
5d
5-NO2
5-NO2
5-Br
5-Br
5-F
10a
94
90
85
83
87
85
84
80
49
45
90:10
88:12
90:10
90:10
80:20
76:24
80:20
79:21
80:20
81:19
92:8
6
9a
10a
ent-10a
10b
93:7
Entry
Catalyst*
Yielda (%)
drb (u/l)
erc
76:24
86:14
86:14
85:15
86:14
85:15
77:23
75:25
ent-10b
10c
1
2
3
4
5
5a
5b
5c
5d
5e
89
87
94
90
90
89:11
87:13
90:10
85:15
78:22
96:4
93:7
92:8
7:93
93:7
5-F
ent-10c
10d
7-Cl
7-Cl
H
ent-10d
10e
Ph
Me
S
H
ent-10e
N
O
O
R
a Yield of pure product (both diastereomers).
Ph
Me
Ph
Me
R
R
P
S
b Determined by 1H NMR spectroscopy of the crude product.
c Determined by chiral HPLC of the isolated product.
N
R
N
H
N
O
N
O
O
P
O
S
R
HN
P
S
S
S
Ph
Me
N
N
S
R
N
H
N
H
HN
HN
substrates facilitates product isolation in the solid form,
without the need of traditional purification methods such
as chromatography.30f–j In our catalysts, the presence of the
phosphoryl segment might help in isolation of the product
by precipitation of the organocatalyst; nevertheless, similar
solubility properties of products 10a–e and organocatalysts
5c–e prevented the application of such methodology.
A plausible activation mechanism for this reaction is
presented in Figure 8. It is considered that the nucleophile
is activated by the pyrrolidinic amine via an enamine, while
the isatin substrate is activated by noncovalent interactions
with the phosphoryl group. In particular, dual activation of
the electrophile as shown in TS*-X involves hydrogen bond-
ing between the N–H bond in isatin and the phosphoryl
group of the catalyst. Simultaneously, the amide carbonyl
group in isatin participates in hydrogen bonding with the
acidic N–H bond in the catalyst. Alternatively, both carbonyl
groups in isatin could form a hydrogen bond with the acidic
N–H bond in the catalyst, as in structure TS*-Y (Figure 8).
Both transition structures are in line with the observed
configuration of the major product.
R
R
Ph
Me
Ph
Me
(1S,2S,1'R,2'R,2''S)-5a
(1R,2R,1'S,2'S,2''S)-5b
(1R,2R,1'R,2'R,2''S)-5c
Ph
Me
O
Ph
Me
O
R
S
N
O
N
O
R
S
P
P
R
S
N
N
R
S
N
H
N
H
HN
HN
R
S
Ph
Me
Ph
Me
(1R,2R,1'R,2'R,2''R)-5d
(1S,2S,1'S,2'S,2''S)-5e (ent-5d)
a Yield of pure product (both diastereomers).
b Determined by 1H NMR spectroscopy of the crude product.
c Determined by chiral HPLC of the isolated product.
The reaction scope was then examined by varying the
substitution pattern in the isatin substrate, and using the
diastereomeric
catalysts
(1R,2R,1′R,2′R,2′′S)-5c
and
(1R,2R,1′R,2′R,2′′R)-5d, which contain proline fragments of
opposite configuration, to obtain both enantiomers of prod-
ucts 10a–e (Table 4). In most cases, the diastereomeric and
enantiomeric ratios varied from moderate to good, al-
though unsubstituted isatin afforded lower enantioselectiv-
ity. The absolute configuration of aldol products was deter-
mined by comparison with the reported literature, which is
based on NMR spectroscopy12f,14a,c and optical rotation da-
ta.13d
In conclusion, novel bifunctional chiral organocatalysts
5a–e incorporating the privileged proline moiety in combi-
nation with a chiral phosphoramide segment were synthe-
sized. These catalysts promoted the diastereo- and enanti-
oselective aldol addition of cyclohexanone to various isat-
ins in the presence of water in good yield and
stereoselectivity. This is one of the rare cases where sec-
ondary amines efficiently catalyze this transformation. In
As mentioned above, Li and co-workers have developed
a technique defined as group-assisted purification where
introduction of an N-phosphoryl substituent in appropriate
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

H
C. Cruz-Hernández et al.
Paper
Synthesis
Bisamidophosphoryl Chlorides 2; General Procedure
O
H
H
O
In a round-bottom flask equipped with a magnetic stirrer, and under
inert atmosphere, was dissolved the corresponding free diamine 1 (1
equiv) in anhydrous toluene. Et3N (4 equiv) was added and the result-
ing mixture was stirred at room temperature for 30 min. Subsequent-
ly, phosphorus oxychloride (1.4 equiv) was added dropwise at ambi-
ent temperature via syringe, with vigorous agitation and under argon
atmosphere (CAUTION: the system requires a proper outlet to avoid
pressurization due to hydrogen chloride liberation). The flask was
equipped with a condenser and heated to reflux in an oil bath for 12
to 16 h, until the end of the reaction could be confirmed by TLC. The
reaction mixture was allowed to reach room temperature and then
water (2 volumes) was added. The organic layer was separated and
the aqueous layer was extracted with EtOAc. The organic layers were
combined and dried with anhydrous sodium sulfate; the solvent was
removed by vacuum distillation, and the crude product was purified
by column chromatography on silica gel (hexane–EtOAc, 100:0 to
80:20).
H
O
H
H
H
O
H
N
O
O
H
Ph
Ph
N
N
P
N
N
N
N
H
O
O
P
N
H
O
H
O
Ph
H
H
Ph
O
N
N
H
TS*- X
TS*- Y
Figure 8 Plausible transition states for the enamine-catalyzed addition
of cyclohexanone to isatin
this regard, it was established that the stereoinduction
mainly originates from the proline segment. Thus, by prop-
er selection of the configuration of the proline, either enan-
tiomer of the product can be obtained. The stereochemical
outcome of the reaction may be explained in terms of bi-
functional activation by the catalyst.
(3aS,7aS)-2-Chlorooctahydro-1,3-bis[(1R)-1-phenylethyl]-1H-
1,3,2-benzodiazaphosphole 2-Oxide [(1S,2S,1′R,2′R)-2]
General procedure was followed using 2.7 g (8.5 mmol) of free di-
amine (1S,2S,1′R,2′R)-1, 3.4 g (4.8 mL, 34.1 mmol) of Et3N and 1.8 g
(1.12 mL, 11.9 mmol) of P(O)Cl3 to obtain 3.3 g (8.2 mmol) of the de-
sired product as a white solid; 95% yield; mp 137.2 °C; [α]D25 +24.7 (c
1.13, CHCl3).
Commercially available reagents were used as received. Anhydrous
solvents were obtained by distillation under the described condi-
tions.46 Reactions activated by microwave irradiation were performed
in a single-mode Discover System reactor from CEM Corporation. Col-
umn chromatography was carried out with Merck silica gel (0.040–
0.063 mm). TLC was performed with Merck DC-F254 plates employ-
ing UV light and iodine vapor for visualization. Melting points were
measured with a Büchi B-540 apparatus, and are uncorrected. Optical
rotations were measured in an Anton Paar MCP-100 polarimeter with
reagent grade solvents. IR spectra were recorded on a Varian-640 ap-
paratus. NMR spectra were obtained with JEOL GSX-270 (270 MHz),
Bruker Advance 300 (300 MHz), JEOL Eclipse 400 (400 MHz) and JEOL
ECA-500 (500 MHz) spectrometers. High-resolution mass spectra
(HRMS) were obtained with a HPLC 1100 apparatus coupled to a
MSD-TOF Agilent Technologies HR-MSTOF 1069A system. Elemental
analyses were performed using a Thermo Finnigan Flash CHNS/O
1112 apparatus. Crystallographic data were collected with Enraf-No-
nius Kappa CCD and Enraf-Nonius CAD-4 X-ray diffractometers. Dias-
tereoselectivity and enantioselectivity were measured by chiral HPLC
on Dionex HPLC UltiMate 3000 equipment with a UV/visible detector,
diode array, at 210 and 254 nm.
IR (ATR): 3699, 3679, 3664, 2970, 2936, 2866, 2844, 1494, 1453, 1353,
1298, 1267, 1225, 1205, 1183, 1143, 1054, 1017, 930, 895, 810, 783,
733, 700, 659, 606, 565 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.54 (d, JH-H = 7.4 Hz, 2 H), 7.51 (d, JH-H
=
8.1 Hz, 2 H), 7.21–7.39 (m, 6 H), 4.84 (dq, 3JH-H = 7.6 Hz, 3JP-H = 13.6 Hz,
3
3
1 H), 4.59 (dq, JH-H = 7.1 Hz, JP-H = 17.7 Hz, 1 H), 3.04 (td, JH-H = 2.5,
10.6 Hz, 1 H), 2.85 (td, JH-H = 3.0, 10.4 Hz, 1 H), 1.85 (d, JH-H = 7.1 Hz, 3
H), 1.77 (d, JH-H = 7.1 Hz, 3 H), 1.64–1.70 (m, 1 H), 1.56–1.62 (m, 1 H),
1.45–1.55 (m, 2 H), 1.11 (qt, JH-H = 3.7, 13.4 Hz, 1 H), 0.86–1.04 (m, 2
H), 0.72 (qd, JH-H = 3.4, 12.3 Hz, 1 H).
1H{31P} NMR (500 MHz, CDCl3): δ = similar spectrum as above, except
for 4.84 (q, 3JH-H = 6.7 Hz, 1 H), 4.59 (q, 3JH-H = 6.5 Hz, 1 H).
13C NMR (125.8 MHz, CDCl3): δ = 143.1 (d, 3JP-C = 10.1 Hz), 142.7 (d,
3JP-C = 3.8 Hz), 128.6 (2 C), 128.2 (2 C), 127.3 (2 C), 127.0 (4 C), 61.3 (d,
JP-C = 11.3 Hz), 58.9 (d, JP-C = 11.3 Hz), 53.1 (d, JP-C = 3.8 Hz), 49.9 (d,
JP-C = 3.8 Hz), 30.0 (d, JP-C = 12.6 Hz), 28.9 (d, JP-C = 8.8 Hz), 24.2 (d, JP-C
1.3 Hz), 24.0 (d, JP-C = 1.3 Hz), 19.4, 14.6.
=
31P NMR (202.5 MHz, CDCl3): δ = 29.5.
HRMS (ESI-TOF): m/z [M + H]+ calcd for [C22H28ON2ClP + H]+:
403.170056; found: 403.170092 (error = 0.088366 ppm).
Liberation of Free Diamines from Their Dihydrochlorides 1
Anal. Calcd for C22H28ON2ClP (402.8973 g/mol): C, 65.58; N, 6.95; H,
7.00. Found: C, 65.57; N, 6.97; H, 7.32.
The dihydrochloride 1 (1 equiv) was suspended in Et2O in an Erlen-
meyer flask at room temperature, before the addition of 1 M aq NaOH
(4 equiv). The biphasic mixture was stirred until the complete disso-
lution of 1 (ca. 30 min). The product was extracted with Et2O, the or-
ganic layer was dried with anhydrous sodium sulfate, the solvent was
removed by distillation, and the product was dried under reduced
pressure. The product was used without further purification to syn-
thesize 2.
(3aR,7aR)-2-Chlorooctahydro-1,3-bis[(1S)-1-phenylethyl]-1H-
1,3,2-benzodiazaphosphole 2-Oxide [(1R,2R,1′S,2′S)-2]
General procedure was followed using 3.2 g (9.9 mmol) of free di-
amine (1R,2R,1′S,2′S)-1, 4.0 g (5.5 mL, 39.7 mmol) of Et3N and 2.1 g
(1.3 mL, 13.9 mmol) of P(O)Cl3 to obtain 3.8 g (9.4 mmol) of the de-
25
sired product as a white solid; 96% yield; mp 138 °C; [α]D –24.5 (c
1.29, CHCl3).
1H, 13C and 31P NMR spectra are identical to those recorded for its en-
antiomer (see the Supporting Information for the complete character-
ization).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

I
C. Cruz-Hernández et al.
Paper
Synthesis
(3aR,7aR)-2-Chlorooctahydro-1,3-bis[(1R)-1-phenylethyl]-1H-
1,3,2-benzodiazaphosphole 2-Oxide [(1R,2R,1′R,2′R)-2]
(3aS,7aS)-2-Azidooctahydro-1,3-bis[(1R)-1-phenylethyl]-1H-1,3,2-
benzodiazaphosphole 2-Oxide [(1S,2S,1′R,2′R)-3]
General procedure was followed using 3.1 g (9.6 mmol) of free di-
amine (1R,2R,1′R,2′R)-1, 3.9 g (5.4 mL, 38.5 mmol) of Et3N and 2.1 g
(1.26 mL, 13.5 mmol) of P(O)Cl3 to obtain 3.3 g (8.2 mmol) of the de-
General procedure was followed using 0.5 g (1.2 mmol) of
(1S,2S,1′R,2′R)-2, 0.16 g (2.5 mmol) of NaN3 and 10 mL of solvent mix-
ture to obtain 0.48 g (1.2 mmol) of the desired product as a crystal-
line solid; 95% yield; mp 106 °C; [α]D25 +21.8 (c 1.02, CHCl3).
25
sired product as a white solid; 85% yield; mp 123.1 °C; [α]D –9.9 (c
1.06, CHCl3).
IR (ATR): 2985, 2949, 2853, 2135, 1602, 1494, 1454, 1452, 1388, 1357,
1299, 1248, 1232, 1210, 1183, 1156, 1137, 1080, 1057, 1030, 1016,
IR (ATR): 2988, 2970, 2931, 2865, 1494, 1453, 1379, 1353, 1325, 1294,
1266, 1220, 1204, 1165, 1137, 1111, 1076, 1053, 1028, 997, 963, 926,
991, 969, 933, 898, 813, 783, 764, 745, 705, 666, 613, 576, 574 cm–1
.
869, 775, 754, 741, 702, 631, 597, 570 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.59 (d, JH-H = 7.7 Hz, 2 H), 7.49 (d, JH-H
=
1H NMR (500 MHz, CDCl3): δ = 7.52 (d, JH-H = 7.77 Hz, 2 H), 7.35–7.42
7.4 Hz, 2 H), 7.21–7.42 (m, 6 H), 4.64 (dq, 3JH-H = 7.0 Hz, 3JP-H = 14.1 Hz,
3
3
3
(m, 4 H), 7.26–7.33 (m, 3 H), 7.19–7.25 (m, 1 H), 4.90 (dq, JH-H = 7.1
1 H), 4.46 (dq, JH-H = 6.8 Hz, JP-H = 19.5 Hz, 1 H), 2.88 (td, JH-H = 2.7,
10.4 Hz, 1 H), 2.71–2.81 (m, 1 H), 1.81 (d, JH-H = 7.2 Hz, 3 H), 1.76
(d, JH-H = 7.0 Hz, 3 H), 1.69–1.75 (m, 1 H), 1.42–1.62 (m, 3 H), 0.91–
1.11 (m, 3 H), 0.72–0.86 (m, 1 H).
3
3
3
Hz, JP-H = 14.3 Hz, 1 H), 4.20 (dq, JH-H = 6.7 Hz, JP-H = 6.8 Hz, 1 H),
2.89–2.97 (m, 1 H), 2.66–2.74 (m, 1 H), 1.78 (d, JH-H = 6.7 Hz, 3 H), 1.72
(d, JH-H = 7.1 Hz, 3 H), 1.74–1.79 (m, 1 H), 1.38–1.53 (m, 3 H), 1.18 (qd,
JH-H = 3.5, 12.1 Hz, 1 H), 1.05 (qt, JH-H = 3.9, 13.4 Hz, 1 H), 0.79–0.91 (m,
1 H), 0.66 (qd, JH-H = 2.8, 12.6 Hz, 1 H).
3
13C NMR (100.5 MHz, CDCl3): δ = 143.0 (d, JP-C = 6.9 Hz), 142.7 (d,
3JP-C = 3.08 Hz), 128.7 (2 C), 128.4 (2 C), 127.3, 127.2 (2 C), 127.1, 127.0
(2 C), 60.5 (d, JP-C = 10.8 Hz), 60.4 (d, JP-C = 10.0 Hz), 53.3 (d, JP-C = 3.8
Hz), 50.9 (d, JP-C = 3.8 Hz), 50.8 (d, JP-C = 3.8 Hz), 29.5 (d, JP-C = 10.0 Hz),
28.8 (d, JP-C = 8.5 Hz), 24.1, 24.0, 19.9.
1H{31P} NMR (500 MHz, CDCl3): δ = similar spectrum as above, except
for 4.90 (q, 3JH-H = 7.1 Hz, 1 H), 4.20 (q, 3JH-H = 6.9 Hz, 1 H).
13C NMR (125.8 MHz, CDCl3): δ = 145.4 (d, 3JP-C = 10.1 Hz), 139.7 (d,
3JP-C = 3.8 Hz), 128.5 (2 C), 128.4 (2 C), 128.0 (2 C), 127.5, 127.2, 126.5
(2 C), 62.7 (d, JP-C = 11.3 Hz), 61.2 (d, JP-C = 10.1 Hz), 56.1 (d, JP-C = 3.8
Hz), 51.6 (d, JP-C = 5.0 Hz), 30.8 (d, JP-C = 7.5 Hz), 29.8 (d, JP-C = 11.3 Hz),
24.5, 23.7 (d, JP-C = 1.3 Hz), 23.2 (d, JP-C = 5.0 Hz), 19.9 (d, JP-C = 3.8 Hz).
31P NMR (161.8 MHz, CDCl3): δ = 21.0.
HRMS (ESI-TOF): m/z [M
410.210426; found: 410.210429 (error = 0.008142 ppm).
+ +
H]+ calcd for [C22H28ON5P H]+:
31P NMR (202.5 MHz, CDCl3): δ = 29.8.
HRMS (ESI-TOF): m/z [M + H]+ calcd for [C22H28ON2ClP + H]+:
(3aR,7aR)-2-Azidooctahydro-1,3-bis[(1S)-1-phenylethyl]-1H-1,3,2-
benzodiazaphosphole 2-Oxide [(1R,2R,1′S,2′S)-3]
403.170056; found: 403.170094 (error = 0.093347 ppm).
General procedure was followed using 1.5
g (3.7 mmol) of
(1R,2R,1′S,2′S)-2, 0.48 g (7.5 mmol) of NaN3 and 40 mL of solvent mix-
ture to obtain 1.4 g (3.5 mmol) of the desired product as a crystalline
solid; 94% yield; mp 105 °C; [α]D25 –22.1 (c 1.11, CHCl3).
Anal. Calcd for C22H28ON2ClP (402.8973 g/mol): C, 65.58; N, 6.95; H,
7.00. Found: C, 65.85; N, 7.02; H, 6.98.
1H, 13C and 31P NMR spectra are identical to those recorded for its en-
antiomer (see the Supporting Information for the complete character-
ization).
(3aS,7aS)-2-Chlorooctahydro-1,3-bis[(1S)-1-phenylethyl]-1H-
1,3,2-benzodiazaphosphole 2-Oxide [(1S,2S,1′S,2′S)-2]
General procedure was followed using 6.0 g (18.6 mmol) of free di-
amine (1S,2S,1′S,2′S)-1, 7.5 g (10.4 mL, 74.4 mmol) of Et3N and 3.9 g
(2.4 mL, 25.7 mmol) of P(O)Cl3 to obtain 6.7 g (16.6 mmol) of the de-
(3aR,7aR)-2-Azidooctahydro-1,3-bis[(1R)-1-phenylethyl]-1H-
1,3,2-benzodiazaphosphole 2-Oxide [(1R,2R,1′R,2′R)-3]
25
sired product as a white solid; 90% yield; mp 126 °C; [α]D +7.4 (c
0.98, CHCl3).
General procedure was followed using 0.5
g (1.2 mmol) of
1H, 13C and 31P NMR spectra are identical to those obtained for its en-
antiomer (see the Supporting Information for the complete character-
ization).
(1R,2R,1′R,2′R)-2, 0.16 g (2.5 mmol) of NaN3 and 10 mL of solvent
mixture to obtain 0.47 g (1.1 mmol) of the desired product as a vis-
cous oil; 93% yield; [α]D25 –13.0 (c 0.99, CHCl3).
IR (ATR): 3061, 3028, 2975, 2936, 2864, 2132, 1603, 1494, 1451, 1376,
1338, 1296, 1246, 1227, 1206, 1182, 1136, 1075, 1060, 1021, 964,
Bisamidophosphoryl Azides 3; General Procedure
929, 898, 814, 750, 699, 652, 611, 576 cm–1
.
Sodium azide (2 equiv) was dissolved in a mixture of DMF–DMSO
(9:1) in a microwave flask equipped with a magnetic stirrer. To the
resulting solution was added the corresponding starting chloride 2 (1
equiv). The system flask was equipped with a condenser and submit-
ted to microwave irradiation at 40 watts and 60 °C for 1 h. The reac-
tion mixture was allowed to reach room temperature and then cooled
at 3 °C in an ice bath before the addition of 3 volumes of distilled wa-
ter (exothermic process). The mixture was extracted with Et2O (3 ×).
The organic layers were combined, dried over anhydrous sodium sul-
fate and concentrated. The crude product was purified by column
chromatography on silica gel (hexane–EtOAc, 95:5).
1H NMR (500 MHz, CDCl3): δ = 7.55 (d, JH-H = 7.4 Hz, 2 H), 7.43 (d, JH-H
7.4 Hz, 2 H), 7.36–7.41 (m, 2 H), 7.20–7.35 (m, 4 H), 4.57 (dq, JH-H
=
=
3
6.9 Hz, 3JP-H = 18.7 Hz, 1 H), 4.33 (dq, 3JH-H = 6.9 Hz, 3JP-H = 10.4 Hz, 1 H),
2.74–2.92 (m, 2 H), 1.84–1.91 (m, 1 H), 1.72 (d, JH-H = 7.1 Hz, 3 H), 1.67
(d, JH-H = 6.7 Hz, 3 H), 1.57–1.63 (m, 2 H), 1.51–1.56 (m, 1 H), 1.01–
1.14 (m, 3 H), 0.80–0.92 (m, 1 H).
1H{31P} NMR (500 MHz, CDCl3): δ = similar spectrum as above, except
for 4.57 (q, 3JH-H = 6.9 Hz, 1 H), 4.33 (q, 3JH-H = 7.1 Hz, 1 H).
3
13C NMR (125.8 MHz, CDCl3): δ = 144.2 (d, JP-C = 5.0 Hz), 140.3 (d,
3JP-C = 2.5 Hz), 128.5 (2 C), 128.4 (2 C), 128.2 (2 C), 127.6, 127.2, 126.9
(2 C), 62.9 (d, JP-C = 11.3 Hz), 61.2 (d, JP-C = 10.1 Hz), 54.2 (d, JP-C = 3.8
Hz), 52.2 (d, JP-C = 3.8 Hz), 29.9 (d, JP-C = 10.1 Hz), 29.8 (d, JP-C = 8.8 Hz),
24.3 (d, JP-C = 1.3 Hz), 23.9 (d, JP-C = 1.3 Hz), 22.0 (d, JP-C = 5.0 Hz), 18.9
(d, JP-C = 2.5 Hz).
31P NMR (202.5 MHz, CDCl3): δ = 20.7.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

J
C. Cruz-Hernández et al.
Paper
Synthesis
HRMS (ESI-TOF): m/z [M
+
H]+ calcd for [C22H28ON5P
+
H]+:
(3aR,7aR)-2-Aminooctahydro-1,3-bis[(1R)-1-phenylethyl]-1H-
410.210426; found: 410.210633 (error = 0.207339 ppm).
1,3,2-benzodiazaphosphole 2-Oxide [(1R,2R,1′R,2′R)-4]
General procedure was used with 1.4 g (3.4 mmol) of (1R,2R,1′R,2′R)-
3 and 0.2 g of palladium catalyst to afford 1.25 g (3.28 mmol) of the
desired product as a white solid; 96% yield; mp 161.9 °C; [α]D25 –24.8
(c 1.07, CHCl3).
(3aS,7aS)-2-Azidooctahydro-1,3-bis[(1S)-1-phenylethyl]-1H-1,3,2-
benzodiazaphosphole 2-Oxide [(1S,2S,1′S,2′S)-3]
General procedure was followed using 4.0
g (9.9 mmol) of
(1S,2S,1′S,2′S)-2, 1.3 g (19.9 mmol) of NaN3 and 40 mL of solvent mix-
ture to obtain 3.9 g (9.6 mmol) of the desired product as a viscous oil;
96% yield; [α]D25 +12.3 (c 1.95, CHCl3).
IR (ATR): 3413, 3058, 2933, 2857, 1601, 1582, 1494, 1449, 1373, 1295,
1278, 1236, 1179, 1160, 1139, 1078, 1034, 1013, 962, 925, 889, 868,
785, 765, 732, 702, 653, 609, 566 cm–1
.
1H, 13C and 31P NMR spectra are identical to those recorded for its en-
antiomer (see the Supporting Information for the complete character-
ization).
1H NMR (500 MHz, CDCl3): δ = 7.55 (d, JH-H = 7.4 Hz, 2 H), 7.42 (d, JH-H
=
=
3
7.4 Hz, 2 H), 7.27–7.36 (m, 4 H), 7.19–7.26 (m, 2 H), 4.58 (dq, JH-H
7.1 Hz, 3JP-H = 15.9 Hz, 1 H), 4.44 (dq, 3JH-H = 7.1 Hz, 3JP-H = 9.8 Hz, 1 H),
2
2.69–2.78 (m, 1 H), 2.59–2.67 (m, 1 H), 2.41 (d, JP-H = 3.5 Hz, 2 H),
1.72–1.81 (m, 1 H), 1.68 (d, JH-H = 7.1 Hz, 3 H), 1.67 (d, JH-H = 7.1 Hz, 3
Phosphoramides 4 by Catalytic Hydrogenation of Azides 3
H), 1.59–1.65 (m, 1 H), 1.43–1.56 (m, 2 H), 0.93–1.03 (m, 4 H).
1H{31P} NMR (500 MHz, CDCl3): δ = similar spectrum as above, except
for 4.58 (q, 3JH-H = 6.9 Hz, 1 H), 4.44 (q, 3JH-H = 7.1 Hz, 1 H), 2.46 (s, 2 H).
Under argon atmosphere, the corresponding azide 3 (1 equiv) was
dissolved in MeOH in a round-bottom flask equipped with a magnetic
stirrer. 1% Pd/C (15% w/w) was added with care and the reaction flask
was charged with hydrogen gas using balloons and syringes. The re-
action mixture was stirred at room temperature for 6 h until the total
consumption of the starting material (corroborated by TLC). The mix-
ture was poured onto a Celite pad to remove the catalyst, and the fil-
trate was concentrated under reduced pressure. The product was pu-
rified by column chromatography on silica gel (CH2Cl2–MeOH, 98:2).
3
13C NMR (125.8 MHz, CDCl3): δ = 144.0 (d, JP-C = 5.0 Hz), 141.6 (d,
3JP-C = 2.5 Hz), 128.3 (2 C), 128.2 (4 C), 127.4 (2 C), 127.1, 126.8, 62.2
(d, JP-C = 11.3 Hz), 60.6 (d, JP-C = 10.1 Hz), 52.9 (d, JP-C = 3.8 Hz), 51.5 (d,
JP-C = 3.8 Hz), 30.6 (d, JP-C = 8.8 Hz), 30.2 (d, JP-C = 10.1 Hz), 24.4 (d, JP-C
1.3 Hz), 24.1 (d, JP-C = 1.3 Hz), 22.2 (d, JP-C = 3.8 Hz), 19.4 (d, JP-C = 3.8
Hz).
=
31P NMR (202.5 MHz, CDCl3): δ = 24.0.
(3aS,7aS)-2-Aminooctahydro-1,3-bis[(1R)-1-phenylethyl]-1H-
1,3,2-benzodiazaphosphole 2-Oxide [(1S,2S,1′R,2′R)-4]
HRMS (ESI-TOF): m/z [M
384.219928; found: 384.220260 (error = 0.864804 ppm).
+ +
H]+ calcd for [C22H30ON3P H]+:
General procedure was used with 1.3 g (3.2 mmol) of (1S,2S,1′R,2′R)-3
and 0.20 g of palladium catalyst to afford 1.2 g (3.1 mmol) of the de-
sired product as a crystalline solid; 98% yield; mp 191 °C; [α]D25 +60.9
(c 1.05, CHCl3).
Anal. Calcd for C22H30ON3P (383.4669 g/mol): C, 68.91; N, 10.96; H,
7.89. Found: C, 69.15; N, 11.16; H, 8.09.
(3aS,7aS)-2-Aminooctahydro-1,3-bis[(1S)-1-phenylethyl]-1H-
1,3,2-benzodiazaphosphole 2-Oxide [(1S,2S,1′S,2′S)-4]
IR (ATR): 3458, 3240, 3087, 3060, 3027, 2974, 2936, 2860, 1601, 1563,
1493, 1447, 1378, 1297, 1198, 1181, 1157, 1078, 1059, 1014, 988,
926, 910, 782, 730, 698, 664, 643, 622, 607, 567 cm–1
.
General procedure was used with 3.9 g (9.6 mmol) of (1S,2S,1′S,2′S)-3
and 0.59 g of palladium catalyst to afford 3.25 g (8.5 mmol) of the de-
sired product as a white solid; 89% yield; mp 161.2 °C; [α]D25 +24.5 (c
0.92, CHCl3).
1H, 13C and 31P NMR spectra are identical to those recorded for its en-
antiomer (see the Supporting Information for the complete character-
ization).
1H NMR (500 MHz, CDCl3): δ = 7.46–7.54 (m, 4 H), 7.26–7.34 (m, 4 H),
2
7.17–7.24 (m, 2 H), 4.54–4.67 (m, 2 H), 2.99 (d, JP-H = 4.9 Hz, 2 H),
2.84 (td, JH-H = 2.9, 10.3 Hz, 1 H), 2.77 (tq, JH-H = 2.7, 10.2 Hz, 1 H), 1.77
(d, JH-H = 7.1 Hz, 3 H), 1.66 (d, JH-H = 7.1 Hz, 3 H), 1.48–1.57 (m, 2 H),
1.40–1.47 (m, 2 H), 0.92–1.05 (m, 2 H), 0.69–0.82 (m, 2 H).
1H{31P} NMR (500 MHz, CDCl3): δ = similar spectrum as above, except
for 4.62 (q, 3JH-H = 7.6 Hz, 1 H), 4.60 (q, 3JH-H = 7.8 Hz, 1 H), 2.99 (s, 2 H).
Phosphoramide Catalysts 5; General Procedure
3
13C NMR (125.8 MHz, CDCl3): δ = 144.5 (d, JP-C = 6.3 Hz), 144.4 (d,
In a round-bottom flask equipped with a stirring bar, and under ar-
gon atmosphere, the corresponding trisphosphoramide 4 (1 equiv)
was dissolved in anhydrous THF and cooled at 3 °C before the drop-
wise addition of n-BuLi (2.8 M in hexanes; 1.2 equiv) with a syringe.
The mixture was stirred at 0 °C for 20 min before the addition of (R)-
or (S)-proline methyl ester (5 equiv) dissolved in anhydrous THF. The
reaction mixture was allowed to reach room temperature, and then
stirred for an additional 24 h. Subsequently, the reaction mixture was
poured over ice–water and extracted with EtOAc. The organic layer
was dried with sodium sulfate and filtered; the solvent was removed
by distillation, and the crude product was purified by column chro-
matography on silica gel (hexane–EtOAc, 1:1 to 0:1; or CH2Cl2–MeOH,
95:5).
3JP-C = 6.3 Hz), 128.2 (2 C), 128.0 (2 C), 127.2 (2 C), 127.1 (2 C), 126.7,
126.6, 60.0 (d, JP-C = 11.3 Hz), 59.4 (d, JP-C = 10.1 Hz), 51.3 (d, JP-C = 3.8
Hz), 49.9 (d, JP-C = 5.0 Hz), 30.3 (d, JP-C = 8.8 Hz), 30.0 (d, JP-C = 10.1 Hz),
24.3, 24.3, 18.1, 16.6.
31P NMR (202.5 MHz, CDCl3): δ = 25.0.
HRMS (ESI-TOF): m/z [M
384.219928; found: 384.219874 (error = –0.139825 ppm).
+ +
H]+ calcd for [C22H30ON3P H]+:
(3aR,7aR)-2-Aminooctahydro-1,3-bis[(1S)-1-phenylethyl]-1H-
1,3,2-benzodiazaphosphole 2-Oxide [(1R,2R,1′S,2′S)-4]
General procedure was used with 1.0 g (2.4 mmol) of (1R,2R,1′S,2′S)-3
and 0.15 g of palladium catalyst to afford 0.83 g (2.2 mmol) of the de-
sired product as a crystalline solid; 89% yield; mp 192 °C; [α]D25 –63.2
(c 1.07, CHCl3).
(1S,2S,1′R,2′R,2′′S)-5a
1H, 13C and 31P NMR spectra are identical to those recorded for its en-
antiomer (see the Supporting Information for the complete character-
ization).
General procedure was followed with 0.22
g (0.6 mmol) of
(1S,2S,1′R,2′R)-4, 0.05 g (0.26 mL, 0.7 mmol) of n-BuLi and 0.39 g (3.0
mmol) of (S)-Pro-OMe to obtain 0.18 g (0.4 mmol) of pure product as
a white foam; 65% yield; [α]D25 +41.2 (c 0.33, CHCl3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

K
C. Cruz-Hernández et al.
Paper
Synthesis
3
IR (ATR): 2936, 2867, 1697, 1493, 1447, 1420, 1300, 1210, 1182, 1154,
1081, 1058, 1019, 991, 931, 900, 849, 782, 732, 699, 675, 624, 588
H), 1.62 (d, 3JH-H = 7.1 Hz, 3 H), 1.58 (d, JH-H = 7.1 Hz, 3 H), 1.38–1.55
(m, 4 H), 1.24 (qd, JH-H = 3.7, 12.1 Hz, 1 H), 1.12 (qt, JH-H = 3.7, 13.1 Hz,
1 H), 0.91 (qt, JH-H = 3.9, 13.2 Hz, 1 H), 0.66 (qd, JH-H = 3.3, 12.3 Hz, 1 H).
cm–1
.
1H NMR (500 MHz, CDCl3): δ = 8.95 (br, 1 H), 7.52 (d, JH-H = 7.6 Hz, 2
H), 7.50 (d, JH-H = 8.1 Hz, 2 H), 7.25–7.34 (m, 4 H), 7.09–7.23 (m, 2 H),
13C NMR (100.5 MHz, CDCl3): δ = 177.2, 147.0 (d, JP-C = 4.6 Hz), 141.6
(d, JP-C = 3.0 Hz), 128.5, 128.4, 128.1, 127.1, 126.8, 126.6, 62.5 (d, JP-C
=
3
3
3
5.56 (dq, JH-H = 7.1 Hz, JP-H = 11.5 Hz, 1 H), 4.48 (dq, JH-H = 7.1 Hz,
3JP-H = 16.1 Hz, 1 H), 3.63–3.80 (m, 2 H), 2.85–3.07 (m, 2 H), 2.75–2.84
(m, 1 H), 2.24 (br, 1 H), 2.15 (dq, JH-H = 8.1, 12.9 Hz, 1 H), 1.96 (dq,
JH-H = 6.2, 12.1 Hz, 1 H), 1.68 (d, JH-H = 7.1 Hz, 3 H), 1.60–1.75 (m, 2 H),
1.57 (d, JH-H = 7.1 Hz, 3 H), 1.35–1.55 (m, 4 H), 1.06–1.18 (m, 2 H), 0.92
(qt, JH-H = 4, 13.2 Hz, 1 H), 0.65 (qd, JH-H = 3.2, 12.4 Hz, 1 H).
12.2 Hz), 62.0 (d, JP-C = 10.8 Hz), 61.5 (d, JP-C = 7.1 Hz), 52.2 (d, JP-C = 4.8
Hz), 51.9 (d, JP-C = 4.5 Hz), 47.4, 30.7, 30.4 (d, JP-C = 8.9 Hz), 30.0 (d,
JP-C = 9.5 Hz), 26.5, 24.6, 24.2, 22.7 (d, JP-C = 4.7 Hz), 19.9 (d, JP-C = 3.8
Hz).
31P NMR (161.8 MHz, CDCl3): δ = 14.3.
HRMS (ESI-TOF): m/z [M
+ +
H]+ calcd for [C27H37O2N4P H]+:
13C NMR (125.8 MHz, CDCl3): δ = 177.9 (d, JP-C = 3.3 Hz), 144.3 (d, JP-C
=
481.272691; found: 481.273094 (error = 0.836006 ppm).
36.6 Hz), 143.8 (d, JP-C = 34.7 Hz), 128.5, 128.1, 127.2, 127.1, 126.9,
126.8, 61.6 (d, JP-C = 6.8 Hz), 61.18 (d, JP-C = 11.5 Hz), 58.8 (d, JP-C = 12.3
Hz), 52.5 (d, JP-C = 4.0 Hz), 49.3 (d, JP-C = 5.7 Hz), 47.5, 31.0, 30.7 (d,
JP-C = 9.7 Hz), 29.3 (d, JP-C = 9.5 Hz), 26.4, 24.4 (d, JP-C = 0.8 Hz), 24.4 (d,
JP-C = 1.3 Hz), 19.5 (d, JP-C = 1.8 Hz), 16.0.
(1R,2R,1′R,2′R,2′′R)-5d
General procedure was followed with 1.5
g (3.9 mmol) of
(1R,2R,1′R,2′R)-4, 0.32 g (1.78 mL, 4.9 mmol) of n-BuLi and 2.65 g
(20.5 mmol) of (R)-Pro-OMe to obtain 1.3 g (2.79 mmol) of pure prod-
uct as a white foam; 68% yield; [α]D25 –46.2 (c 0.403, CHCl3).
31P NMR (202.5 MHz, CDCl3): δ = 15.6.
HRMS (ESI-TOF): m/z [M
+ +
H]+ calcd for [C27H37O2N4P H]+:
IR (ATR): 2936, 2865, 1694, 1603, 1492, 1450, 1421, 1374, 1338, 1298,
1205, 1182, 1145, 1076, 1060, 1021, 964, 930, 901, 850, 763, 732, 700,
481.272691; found: 481.272440 (error = –0.522888 ppm).
654, 618, 587 cm–1
.
(1R,2R,1′S,2′S,2′′S)-5b
1H NMR (500 MHz, CDCl3): δ = 8.35 (br, 1H), 7.49 (d, JH-H = 7.4 Hz, 2H),
7.39 (d, JH-H = 7.3 Hz, 2H), 7.24-7.32 (m, 4H), 7.11-7.23 (m, 2H), 4.39
(dq, 3JH-H = 6.8 Hz, 3JP-H = 22.3 Hz, 1H), 4.18 (dq, 3JH-H = 7.4 Hz, 3JP-H = 7.7
Hz, 1H), 3.61-3.72 (m, 1H), 1.96-2.02 (m, 1H), 1.84-1.92 (m, 1H), 1.75-
General procedure was followed with 0.17
g (0.46 mmol) of
(1R,2R,1′S,2′S)-4, 0.035 g (0.2 mL, 0.55 mmol) of n-BuLi and 0.30 g
(2.3 mmol) of (S)-Pro-OMe to obtain 0.13 g (0.29 mmol) of pure prod-
uct as a white foam; 63% yield; [α]D25 –117.2 (c 0.67, CHCl3).
3
1.82 (m, 1H), 1.64 (d, JH-H = 6.8 Hz, 3H), 1.50-1.62 (m, 5H), 1.49 (d,
IR (ATR): 2934, 2869, 1708, 1493, 1447, 1379, 1324, 1300, 1210, 1183,
3JH-H = 6.9 Hz, 3H); 1.23-1.31 (m, 1H), 1.0-1,19 (m, 4H), 0.63-0.74 (m,
1153, 1080, 1059, 1017 cm–1
.
1H).
1H NMR (400 MHz, CDCl3): δ = 7.48 (d, JH-H = 7.6 Hz, 4 H), 7.28 (q, JH-H
=
13C NMR (125.8 MHz, CDCl3): δ = 177.0, 147.0 (d, JP-C = 4.9 Hz), 141.1
7.5 Hz, 4 H), 7.15–7.28 (m, 2 H), 4.41–4.65 (m, 2 H), 3.77 (br, 1 H), 3.67
(t, JH-H = 10.4 Hz, 1 H), 2.96–3.08 (m, 1 H), 2.80–2.95 (m, 2 H), 2.08–
2.23 (m, 1 H), 1.84–1.96 (m, 1 H), 1.67 (d, JH-H = 6.8 Hz, 3 H), 1.63–1.75
(m, 1 H), 1.57 (d, JH-H = 7.1 Hz, 3 H), 1.38–1.63 (m, 4 H), 1.06–1.34 (m,
3 H), 0.60–1.05 (m, 3 H).
(d, JP-C = 1.7 Hz), 128.9, 128.4, 128.2, 126.9, 126.7, 126.6, 62.4 (d, JP-C =
12.0 Hz), 61.4 (d, JP-C = 10.5 Hz), 61.0 (d, JP-C = 7.1 Hz), 55.0 (d, JP-C = 4.7
Hz), 51.5 (d, JP-C = 4.0 Hz), 47.1, 30.4, 30.2 (d, JP-C = 8.8 Hz), 28.9 (d,
JP-C = 9.2 Hz), 26.2, 24.6, 24.2, 22.4 (d, JP-C = 4.1 Hz), 17.3.
31P NMR (202.5 MHz, CDCl3): δ = 13.5.
13C NMR (100.5 MHz, CDCl3): δ = 176.3, 143.8, 143.7, 128.5, 128.2,
HRMS (ESI-TOF): m/z [M
+ +
H]+ calcd for [C27H37O2N4P H]+:
128.1, 127.4, 127.1, 127.0, 126.9, 61.5 (d, JP-C = 7.3 Hz), 61.2 (d, JP-C
=
481.272691; found: 481.273054 (error = 0.75893 ppm).
11.5 Hz), 59.3 (d, JP-C = 12.4 Hz), 52.2 (d, JP-C = 2.9 Hz), 49.8 (d, JP-C = 5.5
Hz), 47.3, 30.6 (d, JP-C = 9.6 Hz), 30.5, 29.4 (d, JP-C = 9.6 Hz), 26.0, 24.4 (2
C), 19.3, 17.1.
31P NMR (161.8 MHz, CDCl3): δ = 14.2.
(1S,2S,1′S,2′S,2′′S)-5e
General procedure was followed with 0.39
g (1.1 mmol) of
(1S,2S,1′S,2′S)-4, 0.08 g (0.45 mL, 1.3 mmol) of n-BuLi and 0.68 g (5.3
mmol) of (S)-Pro-OMe to obtain 0.31 g (0.66 mmol) of pure product
as a white foam; 60% yield; [α]D25 +48.2 (c 0.11, CHCl3).
HRMS (ESI-TOF): m/z [M
+ +
H]+ calcd for [C27H37O2N4P H]+:
481.272691; found: 481.272083 (error = –1.264671 ppm).
IR (ATR): 2936, 2865, 1694, 1603, 1492, 1450, 1421, 1374, 1338, 1298,
1205, 1182, 1145, 1076, 1060, 1021, 964, 930, 901, 850, 763, 732, 700,
(1R,2R,1′R,2′R,2′′S)-5c
General procedure was followed with 1.2
g
(3.1 mmol) of
654, 618, 587 cm–1
.
(1R,2R,1′R,2′R)-4, 0.24 g (1.34 mL, 3.7 mmol) of n-BuLi and 2.0 g (15.5
mmol) of (S)-Pro-OMe to obtain 1.0 g (2.2 mmol) of pure product as a
white foam; 70% yield; [α]D25 –82.5 (c 1.02, CHCl3).
1H NMR (300 MHz, CDCl3): δ = 8.74 (br, 1 H), 7.48 (d, JH-H = 7.4 Hz, 2
H), 7.37 (d, JH-H = 7.2 Hz, 2 H), 6.96–7.34 (m, 6 H), 4.42 (dq, 3JH-H = 6.9
3
3
3
Hz, JP-H = 20.5 Hz, 1 H), 4.18 (dq, JH-H = 7.7 Hz, JP-H = 6.0 Hz, 1 H),
3.55–3.67 (m, 1 H), 2.55–3.22 (m, 3 H), 1.76–2.17 (m, 3 H), 1.34–1.75
(m, 5 H), 1.62 (d, 3JH-H = 6.9 Hz, 3 H), 1.50 (d, 3JH-H = 6.9 Hz, 3 H), 0.37–
1.31 (m, 6 H).
IR (ATR): 2935, 2867, 1694, 1650, 1492, 1449, 1422, 1374, 1299, 1205,
1181, 1152, 1076, 1020, 937, 930, 901, 845, 764, 732, 700, 652, 618,
588 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.52 (d, JH-H = 7.4 Hz, 2 H), 7.42 (d, JH-H
=
=
13C NMR (125.8 MHz, CDCl3): δ = 175.2, 146.7, 141.1, 128.6, 128.5,
128.3, 127.1, 126.9, 126.6, 62.4 (d, JP-C = 11.6 Hz), 61.5 (d, JP-C = 10.6
Hz), 61.0 (d, JP-C = 7.2 Hz), 55.1 (d, JP-C = 3.3 Hz), 51.5, 46.9, 30.3, 30.2,
29.2 (d, JP-C = 8.5 Hz), 25.7, 24.5, 24.2, 22.7, 18.1.
3
7.2 Hz, 2 H), 7.26–7.36 (m, 4 H), 7.15–7.26 (m, 2 H), 4.52 (dq, JH-H
7.2 Hz, 3JP-H = 14.9 Hz, 1 H), 4.24 (dq, 3JH-H = 7.2 Hz, 3JP-H = 8.4 Hz, 1 H),
3.67–3.77 (m, 1 H), 3.66 (dd, JH-H = 4.2, 18.3 Hz, 1 H), 2.99 (dt, JH-H
=
6.5, 10.3 Hz, 1 H), 2.82 (dt, JH-H = 6.5, 10.4 Hz, 1 H), 2.72–2.80 (m, 1 H),
2.08–2.22 (m, 1 H), 1.80 (dq, JH-H = 6.2, 13.0 Hz, 1 H), 1.64–1.73 (m, 3
31P NMR (202.5 MHz, CDCl3): δ = 13.8.
HRMS (ESI-TOF): m/z [M
481.272691; found: 481.273242 (error = 1.143523 ppm).
+ +
H]+ calcd for [C27H37O2N4P H]+:
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N

L
C. Cruz-Hernández et al.
Paper
Synthesis
Table 5 HPLC Data for Aldol Products 10a–e
Compound
HPLC conditions
Retention time (min)
[α]D25 (MeOH)
unlike (M)a
like (m)a
10a
Chiralpak® AD-H
hexane–i-PrOH, 8:2
0.5 mL/min, 210 nm
29.2 (m)
37.2 (M)
32.1 (M)
42.2 (m)
+37.7
–40.2
+18.4
–20.0
+44.4
–50.6
+31.0
–38.6
+18.9
–20.8
ent-10a
10b
29.2 (M)
36.9 (m)
31.8 (m)
41.9 (M)
Chiralpak® AD-H
hexane–i-PrOH, 9:1
0.5 mL/min, 210 nm
59.6 (m)
84.6 (M)
56.9 (M)
64.8 (m)
ent-10b
10c
60.1 (M)
85.7 (m)
57.6 (m)
65.4 (M)
Chiralpak® AD-H
hexane–i-PrOH, 9:1
0.5 mL/min, 210 nm
76.7 (M)
85.5 (m)
66.5 (M)
70.5 (m)
ent-10c
10d
74.8 (m)
85.7 (M)
65.3 (m)
69.2 (M)
Chiralpak® AD-H
hexane–i-PrOH, 93:7
1.0 mL/min, 210 nm
51.4 (m)
61.6 (M)
45.1 (M)
47.1 (m)
ent-10d
10e
51.5 (M)
60.9 (m)
44.9 (m)
47.1 (M)
Chiralpak® OJ
hexane–i-PrOH, 8:2
0.5 mL/min, 210 nm
34.6 (M)
46.1 (m)
26.3 (M)
30.5 (m)
ent-10e
34.8 (m)
45.0 (M)
26.2 (m)
30.1 (M)
a M denotes major; m denotes minor.
Racemic Aldol Products; General Procedure11a
Acknowledgment
In a sealed tube were mixed the corresponding isatin (0.5 mmol), cy-
clohexanone (5.0 mmol), diethylamine (1.0 mmol) and EtOH (5 mL).
The mixture was heated at 80 °C for 24 h. Then, the solvent was re-
moved by vacuum distillation and the product purified by column
chromatography on silica gel (hexane–EtOAc, 7:3 to 1:1).
We gratefully acknowledge Ma. Teresa Cortes Picasso, Luisa Rodríguez
Pérez and Víctor González Díaz for their assistance in the recording of
NMR spectra, Marco Leyva Ramírez for his assistance in the operation
of the X-ray diffractometer, Géiser Cúellar Rivera for obtaining the
high-resolution mass spectra, and Gabina Dionisio Cadena and Anto-
nio Gómez Pérez for technical support.
Asymmetric Aldol Reaction; General Procedure
In a vial equipped with a magnetic stirrer were suspended the corre-
sponding catalyst (0.02 mmol) and benzoic acid (0.02 mmol) in dis-
tilled water (1 mL), before the addition of cyclohexanone (6) (0.15 mL,
1.4 mmol). The resulting mixture was stirred at 3 °C for 20 min; then,
the corresponding isatin (0.2 mmol) was added. The reaction mixture
was left standing at 3 °C for 48 h. The product was extracted with
EtOAc (3 ×); the combined organic phase was dried over sodium sul-
fate and concentrated, and the crude product was purified by column
chromatography on silica gel (hexane–EtOAc, 8:2 to 1:1). Yields were
calculated after purification, the diastereomeric ratio was determined
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591916.
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Synthesis
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(CCDC 1589104): C22H32Cl2N2, orthorhombic, P212121; a =
12.1774(9) Å, b = 13.1283(10) Å, c = 13.9320(9) Å; α = 90°, β =
90°, γ = 90°; V = 2227.3(3) Å3; z = 4, z′ = 1; R1 = 4.07%.
(33) Crystal data for (1S,2S,1′S,2′S)-1 (CCDC 1589107): C22H32Cl2N2,
orthorhombic, P212121; a = 12.130(2) Å, b = 12.166(2) Å, c =
13.935(3) Å; α = 90°, β = 90°, γ = 90°; V = 2056.4(7) Å3; z = 4, z′ =
1; R1 = 4.23%.
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(34) Crystal data for (1R,2R,1′R,2′R)-2 (CCDC 1589128): C22H28ClN2OP,
tetragonal, P41; a = 9.337(4) Å, b = 9.337 Å, c = 24.805(15) Å; α =
90°, β = 90°, γ = 90°; V = 2162.5(13) Å3; z = 4, z′ = 1; R1 = 3.5%.
(35) Crystal data for (1S,2S,1′R,2′R)-3 (CCDC 1589095): C22H28N5OP,
orthorhombic, P212121; a = 7.5054(3) Å, b = 8.6800(4) Å, c =
34.1605(5) Å; α = 90°, β = 90°, γ = 90°; V = 2225.45(17) Å3; z = 4,
z′ = 1; R1 = 4.27%.
(36) Crystal data for (1R,2R,1′S,2′S)-3 (CCDC 1589094): C22H28N5OP,
orthorhombic, P212121; a = 7.4759(4) Å, b = 8.6939(4) Å, c =
34.2042(17) Å; α = 90°, β = 90°, γ = 90°; V = 2223.09(19) Å3; z =
4, z′ = 1; R1 = 5.56%.
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(37) Crystal data for (1S,2S,1′R,2′R)-4 (CCDC 1589105): C22H30N3OP,
monoclinic, P21;
12.6593(3) Å;
1065.11(4) Å3; z = 2, z′ = 1; R1 = 4.26%.
a
=
=
12.2137(2) Å,
b
=
7.6245(1) Å,
90°;
c
V
=
=
α
90°, 115.379(1)°,
β
=
γ
=
(38) Crystal data for (1R,2R,1′S,2′S)-4 (CCDC 1589106): C22H30N3OP,
monoclinic, P21;
12.6533(3) Å;
1064.69(4) Å3; z = 2, z′ = 1; R1 = 3.64%.
a
=
=
12.2140(2) Å,
b
=
7.6234(2) Å,
90°;
c
V
=
=
α
90°, 115.355(1)°,
β
=
γ
=
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–N