Phosphoramidite Ligands Based on Simple 1,2-Diols: Synthesis, Use in Copper-Catalyzed Asymmetric Additions, and Achirotopic Stereogenic Phosphorus Centres

Article abstract of DOI:10.1002/adsc.201600368

Phosphoramidite ligands are widely used in catalysis and normally constructed from large C₂-symmetrical diols such as BINOL or TADDOL. We report here on new ligands based on a set of simple diols that had been previously overlooked. Ligands based on (S,S)-trans-cyclohexanediol and (R,R)-(+)-1,2-diphenyl-1,2-ethanediol, in combination with both chiral and achiral amines, were tested in 3 different copper-catalyzed asymmetric reactions and up to 89% ee was observed. A different ligand gave the best results in each reaction examined. Using meso-cis-cyclohexanediol and meso-cis-diphenyl-1,2-ethanediol with a chiral non-racemic amine gave diastereomeric ligands bearing achirotopic stereogenic phosphorus atoms which were characterized with the assistance of X-ray crystallography and variable temperature NMR studies. This work provides a new set of ligands that may be useful in some asymmetric reactions when phosphoramidites based on BINOL and TADDOL are ineffective. We also identify a novel stereochemical feature of phosphoramidites that may be useful in asymmetric catalysis and ligand design. (Figure presented.).

Full text of DOI:10.1002/adsc.201600368

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DOI: 10.1002/adsc.201600368
Phosphoramidite Ligands Based on Simple 1,2-Diols: Synthesis,
Use in Copper-Catalyzed Asymmetric Additions, and Achirotopic
Stereogenic Phosphorus Centres
Nisha Mistrya and Stephen P. Fletchera,*
a
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA,
U.K.
E-mail: stephen.fletcher@chem.ox.ac.uk
Received: April 6, 2016; Revised: June 21, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600368.
Abstract: Phosphoramidite ligands are widely used phosphorus atoms which were characterized with the
in catalysis and normally constructed from large C2- assistance of X-ray crystallography and variable tem-
symmetrical diols such as BINOL or TADDOL. We perature NMR studies. This work provides a new set
report here on new ligands based on a set of simple of ligands that may be useful in some asymmetric re-
diols that had been previously overlooked. Ligands actions when phosphoramidites based on BINOL
based on (S,S)-trans-cyclohexanediol and (R,R)- and TADDOL are ineffective. We also identify
(+)-1,2-diphenyl-1,2-ethanediol, in combination with a novel stereochemical feature of phosphoramidites
both chiral and achiral amines, were tested in 3 dif- that may be useful in asymmetric catalysis and ligand
ferent copper-catalyzed asymmetric reactions and up design.
to 89% ee was observed. A different ligand gave the
best results in each reaction examined. Using meso-
cis-cyclohexanediol and meso-cis-diphenyl-1,2-etha- Keywords: achirotopic stereogenic centres; asymmet-
nediol with a chiral non-racemic amine gave diaste- ric catalysis; copper catalysis; ligands; phosphorami-
reomeric ligands bearing achirotopic stereogenic dites; phosphorus stereochemistry
Introduction
many modified BINOLs, such as 3,3-disubstituted
[13] and hydrogenated F[14] versions have been report-
Phosphoramidite ligands are commonly used as the ed (Figure 1).
E
source of asymmetry in enantioselective catalysis.
We note that phosphoramidite ligands based on
They have proven effective in combination with simple diol backbones are almost unreported. To the
a broad range of metals including Ir, Rh, Pd, Ag, Au, best of our knowledge, the only relevant use of
Ni and Cu,[1] and are particularly popular in asymmet- simple diols was by Gavrilov and co-workers who de-
ric conjugate addition,[2] allylic substitution[3–6] and hy- scribed combining chiral 1,2-diols with achiral amines
drogenation reactions.[7,8] The modular nature of phos- to give ligands such as G, H, and I (Figure 2).[15,16]
phoramidites, which are constructed from a diol-back-
Here, we describe a set of phosphoramidite ligands
bone and an amine, allows libraries that may be finely based on simple 1,2-diols and test these ligands in
tuned for enantioselectivity in specific reactions, and copper-catalyzed asymmetric addition reactions. We
has contributed to the extensive use of these ligands first examined chiral (S,S)-trans-cyclohexanediol and
in modern chemistry.
In terms of the diol-backbone, most phosphorami- with bis(1-phenylethyl)amines to give J–M, where J+
dites use BINOL[9] (A) or
ꢀspiroꢁ (B) or K (and L+M) are diastereomers.
TADDOL[10] (C) diol which are powerful sources of
To obtain N and O, we used (S,S)-trans-cyclohexa-
(R,R)-(+)-1,2-diphenyl-1,2-ethanediol in combination
a
asymmetry.[1] More flexible diols, such as the bis- nediol and (R,R)-(+)-1,2-diphenyl-1,2-ethanediol in
phenol moiety seen in ligand D, where backbone combination with an achiral amine.[17] Finally, using
asymmetry is induced by the amido-unit, are also ef- meso cis-cyclohexanediol and meso cis-diphenyl-1,2-
fective in certain reactions.[11,12] Generally, BINOL- ethanediol with a chiral non-racemic amine gave dia-
based phosphoramidites are the most widely used and stereomeric ligands P+Q and R+S, respectively,
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Table 1. 1,4-Conjugate addition of alkylzirconium reagents.
Entry
Ligand
Yield [%][a]
ee [%][b]
1
2
3
4
5
6
7
8
9
A
J
K
L
M
N
O
P+Q
Q
47
57
65
40
18
39
36
64
30
36
27
91
<M->56
ꢀ3
ꢀ37
9
ꢀ20
ꢀ27
ꢀ19
ꢀ14
ꢀ12
ꢀ15
10
11
P
R+S
[a]
Isolated yield.
[b]
Determined by HPLC on a chiral non-racemic stationary
phase. Negative sign indicates opposite absolute stereo-
chemistry shown in 3.
Figure 1. Commonly used phosphoramidite ligands: based
on BINOL (A), ꢀspiroꢁ (B), TADDOL (C), ꢀflexibleꢁ (D)
and modified BINOL (E and F) backbones.
Figure 2. Previously reported phosphoramidites based on
simple 1,2-diols.
which bear achirotopic[18] stereogenic phosphorus
atoms (vida infra).
Results and Discussion
We decided to test the new ligands in copper-cata-
lyzed asymmetric addition reactions and first exam-
ined a hydrometallation–conjugate addition reac-
tion.[19] Compound 3 was obtained in 91% ee using
prototypical phosphoramidite A (Table 1, entry 1),
which is far superior to all of the results obtained
with ligands shown in Figure 3, where J gave the best
result (56% ee, entry 2).
The copper-catalyzed desymmetrization of bicyclic
4 with Me3Al, was then examined (Table 2).[20] Sim-
plePhos ligands (such as T) first described in 2007,
are not phosphoramidites, but have obvious similari-
ties – phosphinamines have aryl groups directly at-
tached to the P-atom.[21] Using T, compound 5 can be
obtained in 91% ee, but we were only able to achieve
83% ee (Table 2, entry 1) using T prepared in our lab-
oratory.
Figure 3. a) Generic phosphoramidite ligand made from
a simple diol. b) New ligands reported here.
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Table 2. Desymmetrization of oxabenzonorbornadienes.
Table 3. Asymmetric conjugate addition to form all carbon
quaternary centres.
Yield[a] [%]
ee [%][b]
Entry
Ligand
Yield[a] [%]
anti:syn[b]
ee [%][c]
Entry
Ligand
1
2
3
4
5
6
7
8
T
J
K
L
M
N
O
P+Q
Q
P
96
79
93
93
(84)
(98)
75
93
98
66
99
58
97:3
99:1
98:2
99:1
97:3
97:3
97:3
99:1
99:1
97:3
98:2
90:10
83
17
1
2
3
4
5
6
7
8
9
U
J
K
L
M
O
41
9
92
ꢀ52
ꢀ7
29
27
21
27
85
23
32
83
48
86
ꢀ40
81
33
79
ꢀ8
P+Q[c]
Q
73
89
ꢀ19
ꢀ18
7
racemic
45
ꢀ74
ꢀ48
ꢀ64
9
R+S
S
10
11
12
10
R+S
S
[a]
Isolated yield, the product is highly volatile.
Determined by GC on a chiral non-racemic stationary
phase.
The opposite enantiomer of the ligand mixture, derived
from the R,R-amine, was used in this example.
[b]
[a]
Isolated yield of anti alcohols, Conversion (in parenthe-
ses) determined by 1H NMR spectroscopy.
[c]
[b]
[c]
1
Determined by H NMR spectroscopy on the crude reac-
tion mixture.
Determined by HPLC on a chiral non-racemic stationary
phase. Negative sign indicates opposite absolute stereo-
chemistry to that shown in 5.
amine portion of the ligand appears to determine the
absolute stereochemistry. The idea that the amine
controls the absolute configuration is supported by
comparing diastereomeric phosphoramidites J and K
Pleasingly, all of the new ligands examined showed (Table 3, entries 2 and 3), and the lack of fixed stereo-
high conversion and excellent anti:syn ratios. Using li- chemistry in the backbone of U.
gands L and M, (entries 4 and 5) which bear a diphen-
Forming all-carbon quaternary centres via asym-
yl backbone, we obtained comparable enantioselectiv- metric catalysis is important because of their presence
ity to using SimplePhos, with 86% ee and 79% ee ob- in natural products.[22,23,26] A prominent example is the
served. Ligand O, also bearing the diphenyl backbone, asymmetric addition of Me3Al to enone 8 which sets
but with an achiral amine, gave the highest observed the absolute stereochemistry in the synthesis of taxa-
enantioselectivity (89% ee, entry 7).
diene by Baran and co-workers.[27,28] We examined the
The final reaction investigated was a 1,4-additon addition to 8 without variation of Alexakisꢁs condi-
with Me3Al to form quaternary centres. The synthesis tions, but using ligand M (Figure 4). We observed
of enantioenriched all carbon quaternary centres is 46% yield and a respectable 72% ee and note this
still considered a synthetic challenge[22] and asymmet- would likely improve if reaction optimization took
ric conjugate addition can be highly effective in form- place.
ing these motifs.[23]
Phosphoramidites based on meso cis-1,2-cyclohexa-
Alexakis and co-workers developed the asymmetric nediol (P and Q) and meso 1,2-diphenyl-1,2-ethane-
addition of AlMe3 to 6.[24,25] Ligand U (94% ee) gave diol (R and S) deserve detailed discussion. The vast
the best-reported results, and similar enantioselectivi- majority of phosphoramidite ligands do not possess
ty was observed in our hands (92% ee, Table 3,
entry 1). Isolated yields here are generally low be-
cause the product is highly volatile. The use of the
phosphoramidites in Figure 3 was generally detrimen-
tal to enantioselectivity, with the notable exception of
M (Table 3, entry 5, 81% ee). Matched/mismatched
amine and diol stereochemistry is important here.
While M gave 81% ee, diastereomeric L gave ꢀ40%
Figure 4. Quaternary centre formation from Baranꢁs trisub-
ee (in favour of the opposite enantiomer), so that the stituted enone 8.
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stereochemistry about the phosphorus atom, although
P-chiral phosphoramidites with tetrahedral asymme-
try have been synthesized from non-C2-symmetrical
diols.[15,29,30] To the best of our knowledge, there are
no reports of phosphoramidites with achirotopic ste-
reogenic P-atoms.
Ligand synthesis from meso-cis-cyclohexanediol
and a chiral non-racemic amine gave a mixture of two
diastereomeric ligands as readily observed by
31P NMR spectroscopy on material purified by flash
column chromatography. The diastereoisomers can be
separated by HPLC using a chiral non-racemic sta-
tionary phase (Figure 6a). Semi-preparative condi-
tions
[Chiralpakꢃ
IC;
hexane:i-PrOH
99:1;
1 mL.minꢀ1, l=210 nm, tR =4.29 min (P, minor), tR =
5.96 min (Q, major)] allowed us to isolate 104 mg of
Q and 46 mg of P over about 9 h. Heating either P or
Q at >708C, or any other conditions we examined,
does not interconvert P and Q.
X-ray crystallographic structure analysis revealed
that P and Q differ in their phosphorus stereochemis-
try, where the amine group is either in a position that
could be described as ꢀequatorialꢁ or ꢀexoꢁ in P, or
more ꢀaxialꢁ or ꢀendoꢁ as in Q (Figure 5b). In minor
isomer P, which has an ꢀequatorialꢁ amine, the phos-
phorous lone pair is in an axial-like position, and
vice-versa.
In each of the X-ray crystallographic structures ob-
tained, only a single cyclohexane conformer was ob-
served, so that the phosphorus has 4 unique substitu-
ents and the P-atoms appear to be tetrahedral asym-
metric. Presumably, these 3D structures correspond to
the lowest energy conformation for each ligand, but
packing forces may favour different conformations in
the solid state than in solution.[31]
1
Figure 5. a) HPLC [Chiralpakꢃ IC; hexane:i-PrOH 99:1;
1 mL.minꢀ1, l=210 nm, tR =4.29 min (minor), tR =5.96 min
(major)] trace showing separation of P and Q. b) X-ray crys-
tallographic structures of P and Q. CCDC 1472705 and
CCDC 1472706 contain the supplementary crystallographic
data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
In solution, as observed by H NMR spectroscopy,
in both the ꢀaxialꢁ (Q) and ꢀequatorialꢁ (P) com-
pounds, two additional isomers are present. Based on
the VT NMR studies described below (Figure 6), we
attribute these isomers to two chair conformations
(Figure 7a) that rapidly interconvert in solution at
room temperature. The isomers are present in roughly
equal ratios, so that one conformer does not appear
favoured over the other.
Upon cooling ꢀaxialꢁ Q, extensive broadening of
1H NMR spectroscopy signals for the 2 protons at package have been previously estimated to have
~3.4 ppm (Figure 6a) is observed. Variable tempera- a 10% error.[32] These rate constants, k, were used to
¼
ture NMR experiments allowed us to quantify the construct an Eyring plot (Figure 6c), from which DH
energy associated with the isomerization of Q, and it (61.2 kJmolꢀ1) and DS (62.5 kJꢀ1 molꢀ1) were ob-
¼
¼
is roughly consistent with a cyclohexane ring flip.
tained. We note that this DS value is relatively high
Spectra were recorded on a Bruker AVIII HD for a conformational process;[33] the discrepancy may
500 MHz spectrometer equipped with a VT probe, be due to our VT NMR which has an error of ꢁ28C.
with a temperature range of ꢀ608C to 258C, using d2- Nevertheless, these values support chair isomeriza-
¼
¼
dichloromethane as solvent. Using the gNMR model- tion, and inserting the values for DH and DS into
¼
¼
¼
ling package to simulate the spectra (see Figure 6b) the Gibbs free energy equation (DG =DH ꢀTDS )
¼
allowed us to estimate rate constants (k) for exchange enabled the barrier to isomerization (DG =
at each temperature. k values obtained by the gNMR 42.6 kJmolꢀ1) to be calculated at room temperature
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Figure 7. a) The two chair conformations of Q rapidly inter-
convert in solution at room temperature. b) NOSEY NMR
experiments carried out at 213 K show that Ha and He still
interconvert on the NMR timescale at this temperature.
(298 K), consistent with the modelled isomerization
rate of ~600,000 sꢀ1.
The P-stereochemistry of Q is fixed in the solid
state so that the P-atom has tetrahedral asymmetry
and a single isomer is observed. In solution, at room
temperature, the two oxygen substituents appear to
rapidly interconvert by a cyclohexane ring flip (see
Figure 7a) at ~6ꢄ105 Sꢀ1. EXSY NMR shows rapid
exchange on the NMR timescale even at 213 K (Fig-
ure 7b). A consequence of these solution dynamics is
that the P-atoms stereochemistry rapidly inverts from
r- to s-. Atropisomers are often defined as conformers
that have a half life of >1000 seconds at room tem-
perature[34,35] providing guidance as to how to deal
with rapidly equilibrating isomers, and suggesting
these phosphorus atoms should not be considered chi-
rotopic.
The relative stereochemistry of P and Q needs to
be addressed. The P and Q isomeric pair differ ac-
cording to P-stereochemistry, similar to the stereo-
chemical features of double bonds (cis-trans), cyclo-
hexane ring substituents (axial-equatorial) or bridged
Figure 6. a) Variable temperature NMR experiments on
1
ligand Q. Upon cooling to 213 K, the H NMR spectroscopy
signals associated with Ha and He are well resolved. b) Si-
mulated spectra using gNMR. c) Eyring plot to determine
¼
¼
¼
DH , DS and DG .
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gands. In a 1,4-conjugate addition reaction, best ac-
complished using BINOL-based phosphoramidites,
the new ligands were ineffective. However, good re-
sults were obtained in two different reactions that re-
quire less sterically demanding monodentate P-li-
gands. Comparable ees with those previously reported
(up to 89%) for the addition of Me3Al in ring opening
desymmetrization were achieved. We anticipate that
the ligands reported here might be useful in asymmet-
ric reactions where BINOL- and TADDOL-based
phosphoramidites are unable to provide high levels of
asymmetry.
Experimental Section
General Procedure for the Synthesis of Ligands J–S
Freshly distilled PCl3 (1.0 equiv.) was added dropwise over
about 1 min to a stirred and cooled (08C) solution of Et3N
(8.0 equiv.) in CH2Cl2 under an argon atmosphere. (S)-
Bis[(S)-1-phenylethyl]amine {or (R)-bis[(R)-1-phenylethyl]-
AHCTUNGTREaNGNUN mine, according to Figure 3} (1.0 equiv.) in CH2Cl2 was
added to the cooled reaction mixture before stirring was
continued for 2 h at room temperature. The reaction mix-
ture was then cooled to 08C and the diol (1.0 equiv.) was
added and stirring was then continued at room temperature
overnight. The reaction mixture was concentrated under
vacuum. The crude product was taken up in toluene and fil-
tered over a short pad of alumina, washing with more tolu-
ene. The filtrate was concentrated under vacuum and the
residue purified by flash column chromatography (alumina,
100% toluene) to give the pure ligand.
(3aS,7aS)-N,N-Bis[(S)-1-phenylethyl]hexahydrobenzo[d]
[1,3,2]dioxaphosphol-2-amine (J): White solid; yield: 17%;
1H NMR (400 MHz, CDCl3): d=7.15–7.04 (m, 10H), 4.55–
4.46 (m, 2H), 3.64 (ddd, J=12.0, 9.0, 3.8, 1H), 3.45 (ddd,
J=12.0, 9.0, 3.8 Hz, 1H), 2.24 (ddt, J=12.3, 9.0, 3.4 Hz,
2H), 1.86–1.76 (m, 2H), 1.67 (d, J=7.1 Hz, 6H), 1.62–1.53
(m, 1H), 1.44–1.23 (m, 3H); 13C NMR (101 MHz, CDCl3):
d=143.4, 143.4, 128.0, 128.0, 127.9, 126.6, 80.7, 78.9, 53.8,
53.7, 30.9 (d, J=6.2 Hz), 30.2 (d, J=5.0 Hz), 24.2 (d, J=
Figure 8. a) HPLC [Chiralpakꢃ IA; hexane:i-PrOH 99:1;
1 mL.minꢀ1, l=210 nm, tR =6.07 min (major), tR =9.99 min
(minor)] showing separation of S and R. b) X-ray crystallo-
graphic structure of R. CCDC 1472707 contains the supple-
mentary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
16.6 Hz), 22.7 (d, J=10.0 Hz); 31P NMR (162 MHz, CDCl3):
25
589
d=144.70; [a] : ꢀ193.6 (c=1.0 in CHCl3); HR-MS (CI
with ammonia as the reagent gas): m/z=370.1950, calcd. for
C22H29NO2P [M+H]+: 370.1930; IR (ATR, CHCl3): n=696,
766, 1029, 1097, 2943, 3025 cmꢀ1.
systems (endo-exo). As the P-atoms differ in stereo-
chemistry but are not (in solution) chirotopic, the cen-
tres are best described as achirotopic stereogenic.[36]
(3aS,7aS)-N,N-Bis[(R)-1-phenylethyl]hexahydrobenzo[d]
As the best descriptors for the isomeric pairs seen [1,3,2]dioxaphosphol-2-amine (K): White crystalline solid;
1
yield: 17%; H NMR (400 MHz, CDCl3): d=7.16–7.03 (m,
10H), 4.65–4.54 (m, 2H), 3.54–3.37 (m, 2H), 2.31–2.19 (m,
2H), 1.87–1.78 (m, 2H), 1.71 (d, J=7.2 Hz, 6H), 1.68–1.59
(m, 1H), 1.49–1.27 (m, 3H); 13C NMR (101 MHz, CDCl3):
d=143.3, 127.9, 127.9, 127.9, 126.6, 81.1, 78.5, 78.4, 52.8,
52.7, 30.9 (d, J=5.5 Hz), 30.1 (d, J=4.7 Hz), 24.3, 24.1, 22.5
here has not yet been established, we suggest (arbitra-
rily), ꢀaxialꢁ and ꢀequatorialꢁ (Figure 8)
Conclusions
(d, J=11.3 Hz); 31P NMR (162 MHz, CDCl3): d=142.66;
25
589
We have described a set of phosphoramidite ligands
based on simple diols and tested them in catalytic
[a] : +220.0 (c=1.0 in CHCl3); HR-MS (CI with methane
as the reagent gas): m/z=370.1934, calcd. for C22H29NO2P
[M+H]+: 370.1930; IR (ATR, CHCl3): n=696, 765, 1030,
ꢀ
asymmetric C C bond forming reactions. In the case
of meso-diols we obtained mixtures of P-isomeric li- 1449, 2938, 3028 cmꢀ1.
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(4R,5R)-4,5-Diphenyl-N,N-bis[(S)-1-phenylethyl]-1,3,2-di-
oxaphospholan-2-amine (L): Foamy white solid; yield: 62%;
1H NMR (400 MHz, CDCl3): d=7.3 (s, 1H), 7.2–7.1 (m,
11H), 7.1–7.0 (m, 13H), 4.8 (s, 2H), 4.7 (t, J=8.3 Hz, 2H),
1.7 (d, J=7.1, 6H); 13C NMR (101 MHz, CDCl3): d=143.0,
137.8 (d, J=8.0 Hz), 136.1 (d, J=8.0 Hz), 128.5 (d, J=
6.1 Hz), 127.8, 127.2, 126.7 (d, J=16.0 Hz), 84.9, 82.6 (d, J=
Minor Isomer (P): White solid; yield: 6% yield);
1H NMR (400 MHz, CDCl3): d=7.15–7.01 (m, 10H), 4.56–
4.43 (m, 3H), 4.37 (dt, J=4.8, 2.4 Hz, 1H), 2.04–1.94 (m,
1H), 1.93–1.70 (m, 3H), 1.67 (d, J=7.2 Hz, 6H), 1.63–1.56
(m, 1H), 1.55–1.47 (m, 1H), 1.35 (ddt, J=10.7, 7.1, 3.7 Hz,
1H), 1.28–1.17 (m, 2H); 13C NMR (101 MHz, CDCl3): d=
143.4, 127.9, 127.9, 127.9, 126.5, 74.7 (d, J=6.9 Hz), 73.6 (d,
J=7.1 Hz), 52.9, 52.8, 29.7 (d, J=3.7 Hz), 29.4 (d, J=
5.8 Hz), 52.6, 52.5, 22.6; 31P NMR (162 MHz, CDCl3): d=
5.3 Hz), 22.6, 22.5, 21.6, 20.6; 31P NMR (162 MHz, CDCl3):
25
589
148.4. [a] : ꢀ188.6 (c=1.0 in CHCl3); HR-MS (ESI): m/z=
25
589
468.2088, calcd. for C30H31NO2P [M+H]+: 468.2087; IR
(ATR, CHCl3): n=697, 782, 996, 1124, 1204, 1451, 1495,
2971, 3030 cmꢀ1.
d=143.82; [a] : ꢀ139.0 (c=1.0 in CHCl3); HR-MS (GC-
MS with ammonia as the reagent gas): m/z=370.1934, calcd.
for C22H28NO2P [M+H]+: 370.1930; IR (ATR, CHCl3): n=
698, 755, 986, 1125, 1449, 2935 cmꢀ1
.
(4R,5R)-4,5-Diphenyl-N,N-bis[(R)-1-phenylethyl]-1,3,2-
dioxaphospholan-2-amine (M): Foamy white solid; yield:
Major Isomer (Q): White solid; yield: 104 mg (13%);
1H NMR (400 MHz, chloroform-d): d=7.16–7.03 (m, 10H),
4.72 (s, 2H), 4.20–4.07 (m, 2H), 1.95 (dt, J=21.2, 5.1 Hz,
2H), 1.86 (dq, J=11.8, 4.3 Hz, 2H), 1.70 (d, J=7.2 Hz, 6H),
1.63–1.51 (m, 2H), 1.42–1.29 (m, 2H); 13C NMR (101 MHz,
chloroform-d): d=143.4, 128.0, 128.0, 127.9, 126.6, 71.9,
71.8, 52.1, 52.0, 30.1 (d, J=2.2 Hz), 30.1 (d, J=3.1 Hz), 22.5,
1
36%; H NMR (400 MHz, CDCl3): d=7.4–7.3 (m, 6H), 7.2
(ddt, J=7.3, 5.3, 2.6 Hz, 4H), 7.2–7.1 (m, 10H), 5.0 (d, J=
8.7 Hz, 1H), 4.9 (d, J=8.7 Hz, 1H), 4.8–4.7 (m, 2H), 1.8 (d,
J=7.1 Hz, 6H); 13C NMR (101 MHz, CDCl3): d=143.0,
138.1 (d, J=8.0 Hz), 136.5 (d, J=5.0 Hz), 128.5 (d, J=
7.3 Hz), 128.4, 128.0–127.7 (m), 127.4, 126.6, 126.4, 84.6 (d,
21.8, 21.4; 31P NMR (162 MHz, chloroform-d): d=150.25;
J=4.1 Hz), 82.9 (d, J=6.3 Hz), 53.1, 53.0, 22.7; 31P NMR
25
589
[a] : ꢀ234.5 (c=1.0 in CHCl3); HR-MS (CI with methane
25
589
(162 MHz, CDCl3): d=149.4; [a]
: +191.1 (c=1.0 in
as the reagent gas): m/z=370.1940, calcd. for C22H28NO2P
[M+H]+: 370.1930; IR (ATR, CHCl3): n=698, 770, 989,
1126, 1450, 2935 cmꢀ1.
CHCl3); HR-MS (CI with methane as the reagent gas): m/
z=468.2093, calcd. for C30H31NO2P [M+H]+: 468.2087; IR
(ATR, CHCl3): n=697, 1008, 1205, 1305, 2841, 3030 cmꢀ1.
(3aS,7aS)-N-Benzhydryl-N-isopropylhexahydrobenzo[d]
[1,3,2]dioxaphosphol-2-amine (N): White crystalline solid;
yield: 14%; 1H NMR (400 MHz, CDCl3): d=7.4–7.3 (m,
8H), 7.3–7.2 (m, 2H), 5.8 (d, J=12.2 Hz, 1H), 3.8 (hept, J=
6.7 Hz, 1H), 3.5–3.4 (m, 1H), 3.4–3.3 (m, 1H), 2.3–2.2 (m,
1H), 2.2–2.1 (m, 1H), 1.9–1.7 (m, 2H), 1.7–1.5 (m, 1H), 1.4–
1.3 (m, 3H), 1.2 (d, J=6.8 Hz, 3H), 1.0 (d, J=6.8 Hz, 3H);
13C NMR (101 MHz, CDCl3): d=129.3, 129.2, 129.0, 129.0,
128.3, 126.9, 126.9, 81.0 (d, J=2.5 Hz), 78.5 (d, J=6.3 H),
61.0 (d, J=16.2 Hz), 47.1 (d, J=5.4 Hz), 30.8, 30.8, 30.1,
30.1, 24.2, 24.1, 24.1, 24.1, 24.0, 24.0; 31P NMR (162 MHz,
CDCl3): d=145.05; [a]25859: +13.3 (c=1.0 in CHCl3); HR-MS
(CI with methane as the reagent gas): m/z=370.1939, calcd.
for C22H29NO2P [M+H]+: 370.1930; IR (ATR, CHCl3): n=
698, 775, 1018, 1200, 1307, 2937, 3027 cmꢀ1.
(4S,5R)-4,5-Diphenyl-N,N-bis[(S)-1-phenylethyl]-1,3,2-di-
oxaphospholan-2-amine (R+S): The two isomers were sepa-
rated by chiral preparative HPLC [Chiralpakꢃ IA; hexa-
ne:i-PrOH 99:1; 1 mL.minꢀ1, l=210 nm]: tR =6.07 min
(major), tR =9.99 min (minor).
Minor Isomer (R): White solid; yield: 2%; 1H NMR
(400 MHz, CDCl3): d=7.21–7.07 (m, 12H), 7.09–7.00 (m,
8H), 5.57–5.48 (m, 2H), 4.85 (s, 2H), 1.77 (d, J=7.1 Hz,
6H); 13C NMR (101 MHz, CDCl3): d=138.6, 138.6, 138.1,
138.1, 128.0, 128.0, 127.9, 127.7, 127.5, 127.5, 127.3, 127.2,
126.7, 77.7 (d, J=5.3 Hz), 77.4, 52.0, 51.9, 22.8, 22.7;
31P NMR (162 MHz, CDCl3): d=149.02; [a]25859: ꢀ292.8 (c=
1.0 in CHCl3); HR-MS (CI with ammonia as the reagent
gas): m/z=468.2091, calcd. for C30H30NO2P [M+H]+:
468.2087; IR (ATR, CHCl3): n=697, 783, 1010, 1451, 2971,
3029 cmꢀ1.
Major Isomer (S): White solid; yield: 8%; 1H NMR
(400 MHz, CDCl3): d=7.19–7.09 (m, 10H), 7.09–7.03 (m,
6H), 6.99–6.90 (m, 4H), 5.83 (dd, J=6.5, 4.0 Hz, 1H), 5.63
(dd, J=6.5, 1.8 Hz, 1H), 4.66 (dq, J=9.5, 7.2 Hz, 2H), 1.78
(d, J=7.1 Hz, 6H); 13C NMR (101 MHz, CDCl3): d=143.3–
143.1 (m), 128.0, 128.0, 127.8, 127.8, 127.5–127.5 (m), 127.1,
127.0, 127.0–126.9 (m), 126.7, 82.8 (d, J=8.7 Hz), 81.8 (d,
J=8.3 Hz), 53.4, 53.3, 22.7, 22.6; 31P NMR (162 MHz,
CDCl3): d=145.81; [a]25 : ꢀ152.1 (c=1.0 in CHCl3); HR-
MS (CI with ammonia 5a89s the reagent gas): m/z=468.2078,
calcd. for C30H30NO2P [M+H]+: 468.2087; IR (ATR,
CHCl3): n=698, 778, 1008, 1452, 2971, 3030 cmꢀ1.
(4R,5R)-N-Benzhydryl-N-isopropyl-4,5-diphenyl-1,3,2-di-
oxaphospholan-2-amine (O): White crystalline solid; yield:
54%; 1H NMR (400 MHz, CDCl3): d=7.4–7.3 (m, 12H),
7.3–7.2 (m, 5H), 7.2–7.2 (m, 3H), 7.1–7.0 (m, 2H), 5.9 (d,
J=13.3, 1H), 4.9–4.8 (m, 2H), 4.1 (h, J=6.6 Hz, 1H), 1.4
(d, J=6.7 Hz, 3H), 1.2 (d, J=6.7 Hz, 3H); 13C NMR
(101 MHz, CDCl3): d=143.4 (d, J=4.3 Hz), 143.2 (d, J=
3.6 Hz), 138.1 (d, J=8.0 Hz), 136.7 (d, J=4.5 Hz), 129.1 (d,
J=3.1 Hz), 128.8 (d, J=3.4 Hz), 128.4 (d, J=4.8 Hz), 128.4,
128.3 (d, J=4.8 Hz), 128.2, 127.4, 126.9 (d, J=8.7 Hz), 126.3,
84.6 (d, J=4.6 Hz), 83.1 (d, J=6.3 Hz), 60.6 (d, J=17.5 Hz),
46.8 (d, J=3.5 Hz), 23.8; 31P NMR (162 MHz, CDCl3): d=
Full experimental procedures and spectra can be found in
the Supporting Information.
25
589
151.5; [a] : ꢀ5.0 (c=1.0 in CHCl3); HR-MS (ESI): m/z=
468.2085, calcd. for C30H31NO2P [M+H]+: 468.2087; IR
(ATR, CHCl3): n=698, 790, 1001, 1159, 1453, 2969,
3030 cmꢀ1.
(3aR,7aS)N,N-Bis[(S)-1-phenylethyl]hexahydrobenzo[d]
[1,3,2]dioxaphosphol-2-amine (P+Q): The two isomers
were separated by chiral preparative HPLC [Chiralpakꢃ
IC; hexane:i-PrOH 99:1; 1 mL.minꢀ1, l=210 nm]: tR =
4.29 min (minor), tR =5.96 min (major).
Acknowledgements
This work was financially supported by the EPSRC (EP/
H003711/1). We acknowledge Dr. Barbara Odell for her help
with the NMR studies and Lukas Pfeifer for determining the
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7
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asc.wiley-vch.de
crystal structures. Thanks to Patricia Fernandez Rodriguez
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Phosphoramidite Ligands Based on Simple 1,2-Diols:
Synthesis, Use in Copper-Catalyzed Asymmetric Additions,
and Achirotopic Stereogenic Phosphorus Centres
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Adv. Synth. Catal. 2016, 358, 1 – 9
Nisha Mistry, Stephen P. Fletcher*
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