Pyrrolidine-Based P,O Ligands from Carbohydrates: Easily Accessible and Modular Ligands for the Ir-Catalyzed Asymmetric Hydrogenation of Minimally Functionalized Olefins

Article abstract of DOI:10.1002/cctc.201801485

The potential of P,O-iminosugar based ligands in the Ir-catalyzed asymmetric hydrogenation of minimally functionalized olefins is presented. These new ligands were prepared from easily available carbohydrates (D-mannose, D-ribose and D-arabinose). The stereochemical and polyfunctional diversity of carbohydrates allowed the modulation of the ligands, both from their electronic properties and the rigidity of their backbone. High enantioselectivities (ee’s up to 99 %) can be reached in the hydrogenation of selected tri- and disubstituted substrates.

Full text of DOI:10.1002/cctc.201801485

Accepted Article
Title: Pyrrolidine-based P,O ligands from carbohydrates: Easily
accessible and modular ligands for the Ir-catalyzed asymmetric
hydrogenation of minimally functionalized olefins
Authors: Pilar Elías-Rodríguez, Carlota Borràs, Ana T. Carmona, Jorge
Faiges, Inmaculada Robina, Oscar Pamies, and Montserrat
Diéguez
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Pyrrolidine-based P,O ligands from carbohydrates: Easily
accessible and modular ligands for the Ir-catalyzed asymmetric
hydrogenation of minimally functionalized olefins
Pilar Elías-Rodríguez,[a] Carlota Borràs,[b] Ana T. Carmona,[a] Jorge Faiges,[b] Inmaculada Robina,*[a]
Oscar Pàmies*[b] and Montserrat Diéguez*[b]
Abstract: The potential of P,O-iminosugar based ligands in the Ir-
catalyzed asymmetric hydrogenation of minimally functionalized
olefins is presented. These new ligands were prepared from easily
available carbohydrates (D-mannose, D-ribose and D-arabinose). The
stereochemical and polyfunctional diversity of carbohydrates allowed
the modulation of the ligands, both from their electronic properties and
the rigidity of their backbone. High enantioselectivities (ee’s up to
99%) can be reached in the hydrogenation of selected tri- and
disubstituted substrates.
certain olefin geometry and nature of the substrate. To overcome
these problems, recent research has focused on the possibility of
changing the N-donor atom in these heterodonor ligands by more
stable and easier to prepare S- and O-donor functionalities.[4] In
this respect, our group reported the first application of a
P,thioether ligand family in this process[4b] and further
improvements with new generations of P,tioether ligands.[4c-f] In
2011, Pfaltz and coworkers also demonstrated for the first time
that phosphine,O ligands (Figure 1), that coordinate to the metal
through the carbonyl oxygen atom and the phosphine moiety, can
also be used in the AH of minimally functionalized olefins with
results comparable to the most commonly used Ir-P-oxazoline
catalysts.[4a] However, high enantioselectivities were obtained
only for a few trisubstituted olefins and no results were reported
for the more challenging disubstituted substrates. The results also
showed that high enantioselectivities were obtained when
substituents at both the phosphine group and the O-donor moiety
were bulky. This is an important drawback because phosphines
with bulky substituents are prepared from a much more expensive
precursor, and they are much less stable than the commonly used
diphenylphosphine analogues. After this initial success, no new
developments were published with other P,O-ligands.[5] Therefore,
a systematic study of the scope of P,O-ligands for this process is
still needed.
Introduction
Asymmetric metal-based catalysis offers some of the most
efficient, sustainable and straightforward routes for synthesizing
enantiomerically pure compounds.[1] These compounds play
fundamental roles in pharmacy, agro-chemistry, fine chemistry
and natural product chemistry. Among the metal-catalysed
processes, the asymmetric hydrogenation (AH) of olefins has
dominated both industry and academia for many years, mainly
because of its high efficiency in transferring the chiral information
from the catalyst to the product, its perfect atom economy and its
operational simplicity.[1] In this field, the AH of functionalized
olefins (e.g. enamides, dehydroamino acid derivatives, …)[2] is
dominated by Rh- and Ru-diphosphine catalysts, while the
reduction of minimally functionalized olefins (those without a
highly coordinative group)[3] is mostly carried out with Ir-P-
oxazoline catalysts. Compared with the AH of functionalized
olefins, the reduction of minimally functionalized olefins is
underdeveloped and thus has a limited synthetic utility. Although
advances in catalyst design with new types of P,N-heterodonor
ligands have been made, most catalysts are still specific for a
Figure 1. Proline-based P,O-ligands used by Pfaltz and coworkers for the
asymmetric hydrogenation of minimally functionalized trisubstituted olefins.
[a]
Dr. P. Elías-Rodríguez, Dr. A. T. Carmona, Prof. Dr. I. Robina
Departamento de Química Orgánica
Universidad de Sevilla
C/ Prof. García González, 1. 41012 Sevilla. Spain
E-mail: robina@us.es
Ms. C. Borràs, Mr. J. Faiges, Dr. O. Pàmies, Prof. Dr. M. Diéguez
Departament de Química Física i Inorgànica
Universitat Rovira i Virgili
To investigate the potential of P,O-based ligands in the Ir-
catalyzed asymmetric hydrogenation of minimally functionalized
olefins, in this study we developed a modular pyrrolidine-based
phosphine/phosphite-O ligand library (L1-L10; Figure 2). The new
ligands are relevant not only because they are easily prepared in
large quantities from unexpensive carbohydrates (D-mannose, D-
ribose and D-arabinose), but also because they can be easily
modulated with well-established carbohydrate chemistry. Such
modularity allowed us to speed up the evaluation of several ligand
parameters and facilitated the iterative optimization of the most
promising candidates. They were tested in the AH of 32 alkenes,
[b]
C/ Marcel·lí Domingo, 1. 43007 Tarragona. Spain
E-mail: oscar.pamies@urv.cat and montserrat.dieguez@urv.cat
Supporting information for this article is given via a link at the end of
the document
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including challenging 1,1-disubstituted and substrates with poorly
coordinative groups whose hydrogenated derivatives can be
transformed into high-value organic compounds. These series of
ligands allowed us to study the effect on catalytic performance of
(i) the configuration of the pyrrolidine moiety (with ligands L1 and
L2), (ii) the pyrrolidine backbone rigidity (with ligands L2 and L3),
(iii) the size of the chelate ring (with ligands L1 and L4), (iv) the
type of O-donor group (carbamate, L1; amide, L6-L7; and urea,
L8-L9), (v) the replacement of the phosphine moiety by a chiral
biaryl phosphite group (ligands L10)[6]. We also studied the
replacement of the carbamate O-donor group by a thiourea
moiety (ligand L11).
configuration of the carbons bearing the isopropylidene group and
differ on the type of the O-donor group and the type of P-
functionality. Their synthesis started from pyrrolidine 1, easily
obtained from D-mannose and recently reported by our group.[7]
Tosylation of 1 followed by reaction with KPPh2 in THF at -35 °C
afforded amino-phosphine L1 in 57% yield. Its structure was
confirmed by 1H-NMR by the disappearance of the signals
corresponding to the tosyl group and the appearance of a
multiplet (δ = 7.55-7.33 ppm) for 10 H corresponding to the
diphenylphosphino group. In the 31P-NMR spectrum the signal at
-23.2 ppm is compatible with the phosphine moiety. Boc
deprotection and reaction with different acyl halides in the
presence of Et3N gave compounds L6-L9, with amide and urea
groups, in moderate-to-good yields. Their structures were also
confirmed by NMR. Therefore, 31P-NMR spectra showed the
expected one singlet in the region compatible with the phosphine
moiety, except for L7 for which the presence of two rotamers was
observed. Finally, reaction of alcohol 1 with one equivalent of the
corresponding phosphorochloridite (ClP(OR)2) formed in situ
gave access to carbamate-phosphite ligands L10a-b, with the
desired configuration of the biaryl phosphite group. The 31P-NMR
spectra showed two singlets for each compound at around 130
ppm compatible with phosphite moieties. The presence of two
rotamers for each ligand, as for L7, was confirmed by performing
the 2D-31P DOSY NMR experiment that shows that the two
isomers have the same diffusion coefficient (see Supporting
Information). Both isomers also showed the same HR-mass
spectra.
Protected pyrrolidine-phosphine L4, with
a
2,3-trans
Figure 2. Pyrrolidine-based ligands L1-L11.
configuration and which differs from ligand L1 in a longer
phosphine alkyl chain, was also prepared starting from D-
mannose (Scheme 1) through intermediate 3 that was recently
reported by us.[7] Primary alcohol protection and iodination
afforded derivative 4, which after hydrogenation and subsequent
deprotection gave alcohol 5. Mesylation and displacement with
KPPh2 in THF at -40 °C furnished protected pyrrolidine
phosphine-carbamate L4 in 69% yield. The 31P-NMR spectrum
shows the expected singlet at -15.4 ppm compatible with a
phosphine moiety.
Results and Discussion
Synthesis of ligands
Schemes 1-3 show the synthetic sequences, first for those
ligands derived from D-mannose, then for ligands derived from D-
ribose and finally for ligands derived from D-arabinose. Starting
from D-mannose (Scheme 1), the phosphine/phosphite-O ligands
L1, L4, L6-L9 and L10a-b were obtained. They have the same
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Scheme 1. Synthesis of ligands L1, L4, L6-L9 and L10a-b derived from D-mannose.
Scheme 2. Synthesis of ligands L2-L3 and L11 derived from D-ribose.
Scheme 3. Synthesis of ligand L5 derived from D-arabinose
The preparation of ligands L2, L3 and L11 with different
configuration at the carbons bearing the isopropylidene group
than L1 and L4 analogues, is shown in Scheme 2. Starting from
D-ribose, pyrrolidine phosphine 9 was prepared following our
recently reported procedure.[8] N-Boc protection of compound 6,
followed by tosylation afforded cyclic carbamate 8 as was also
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observed by us with similar 2,3-cis compounds.[9] Nucleophilic
ring opening with KPPh2 in THF gave the corresponding
pyrrolidine-phosphine 9. The phosphine moiety was ascertained
by the signal at -20.9 ppm in the 31P-NMR. Reaction with 3,5-
ditrifluoromethylisothyocyanate and Boc2O/Py gave thiourea-
phosphine ligand L11 and carbamate-phosphine ligand L2,
respectively, in moderate yields. Deprotection of cyclic carbamate
8 with THF:HCl 4M (1:1) followed by conventional benzylation
gave the benzylated carbamate 11. The nucleophilic ring opening
of 11 using KPPh2 in refluxing THF followed by N-Boc protection
afforded L3 in 55% yield.
Table 1. Ir-catalyzed hydrogenation of substrate S1 using [Ir(cod)2]BArF/L1-
L11 catalyst precursors.[a]
Entry
1
Ligand
L1
% Conv[b]
80
% ee[c]
97 (R)
68 (R)
58 (R)
nd
2
L2
35
Finally, protected pyrrolidine-phosphine L5, with a 2,3-cis
configuration and differing from L4 in the configuration of C-2 of
the pyrrolidine ligand backbone and also in the N carbamate (Cbz
vs Boc), was obtained from 13 which was prepared from D-
arabinose (Scheme 3).[10] Carbamate protection and reduction
with LiAlH4 at -10 °C gave alcohol 15 in good yield. Phosphine
moiety was introduced by the above described conventional
method giving L5 in 52% yield.
3
L3
35
4
L4
<5
5
L5
100
29
30 (S)
97 (R)
98 (R)
70 (R)
67 (R)
65 (R)
3 (S)
6
L6
7
L7
40
1
The formation of ligands was confirmed by 31P {1H}, H and
8
L8
60
13C {1H} NMR spectra and mass spectrometry. The spectra
assignments were supported by the information obtained from 1H-
1H and 1H-13C correlation measurements. See experimental
section for purification and characterization details.
9
L9
58
10
11
12
L10a
L10b
L11
50
<5
Asymmetric hydrogenation of minimally functionalized
olefins
<2
nd
The library of P,O/S ligands L1-L11 was evaluated in the Ir-
catalyzed asymmetric hydrogenation of trisubstituted minimally
functionalized olefins (S1-S16) and challenging 1,1-disubstituted
olefins (S17-S32). The catalyst was generated in situ by adding
the corresponding P,O/S-ligand to the catalyst precursor
[Ir(cod)2]BArF following the procedure reported by Pfaltz.[4a]
Initially, following the study with proline-based P,O ligands
reported by Pfaltz, we tested ligands L1-L11 in the AH of an ,-
unsaturated ester S1 (Table 1). This allowed a direct comparison
with Pfaltz's P,O catalytic systems.[4a] The results with ligands L1-
L3 indicated that activity and enantioselectivity are very sensitive
to the chirality and rigidity of the pyrrolidine moiety (entries 1-3).
The highest activity and enantioselectivity was achieved with
ligand L1 (entry 1), with an R-configuration at C-2 and 3S,4R
configuration at the pyrrolidine carbons bearing the
isopropylidene group. The results with ligands L1, L4 and L5
indicated that the chelate ring size also influences the catalytic
performance. Ligands L4-L5, that form a less stable 8-membered
chelate ring, gave lower enantioselectivities than ligands L1 and
L2 (entries 4-5 vs 1-2). This agrees with the hemilabile character
of the carbamate group upon coordination to iridium. Even ligand
L4 affected negatively its activity. The results with ligands L1 and
L6-L9 also indicated that the type of O-donor group affects
enantioselectivity considerably (entries 1, 6-9), with the highest
enantioselectivities (ee’s up to 98%) being achieved with a
carbamate (ligand L1) and an amido (ligands L6 and L7) group.
Finally, we also found that the replacement of either the
phosphine (ligand L1) by a biaryl phosphite moiety (ligands L10)
or the carbamate moiety (ligand L1) by a thiourea group (ligand
L11) had a detrimental effect on catalytic performance (entry 1 vs
10-12).
13[d]
14[d]
15[d]
65
33 (R)
98 (R)
94 (R)
>99
>99
[a]
Reactions carried out using 0.5 mmol of substrate and
2 mol% of
[Ir(cod)2]BArF, 2 mol% of corresponding ligand at 50 bar of H2 for 4 h.
[b] Conversion determined by 1H NMR. [c] Enantiomeric excesses determined by
chiral HPLC. [d] Data from ref [4a].
In summary, high enantioselectivities (up to 98% ee) were
achieved with the pyrrolidine-based phosphine-carbamate and
phosphine-amido ligands L1, L6 and L7. The best combination of
activity and enantioselectivity was obtained with ligand L1.
Compared with the results obtained with the proline-based P,O
analogues (33% ee, entry 13, ligand L12),[4a] the introduction of a
more rigid bicyclic backbone increased enantioselectivity to 97%
ee (entry 6, our ligand L6). In addition, our results are comparable
with the excellent enantioselectivities achieved with the bulkier,
less stable and more costly di-tert-butyl- or dicyclohexyl-
phosphine analogues L13 and L14 developed by Pfaltz’s group
(Table 1, entries 14 and 15).
To further assess the performance of the new P,O-ligands in
the AH of α,β-unsaturated carboxylic esters, we reduced S2-S11
(see Figure 3) with the Ir/L1 catalytic system, that had provided
the best combination of activity and enantioselectivity.
Advantageously, the ee’s were independent of the electronic
nature of the substrate phenyl ring (S1-S4) and the steric
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properties of the alkyl substituent (S1, S5-S7). High ee’s were
also attained in the reduction of the challenging Z-analogues (S8
and S9) and α-substituted carboxylic esters (S10 and S11). It is
worth noting that being able to hydrogenate such a range of ,-
unsaturated esters is highly significant since the reduced products
are found in relevant products,[11] such as natural products,
agrochemicals and fragrances.
parameters behave as described for the hydrogenation of
trisubstituted olefins. The highest enantioselectivity (74% ee at
only 1 bar of H2, entry 1) was therefore achieved with the
pyrrolidine-based carbamate-phosphine ligand L1. Ligands L6
and L7, that provided also high enantioselectivity in the reduction
of trisubstituted olefins, gave much lower enantioselectivities in
this case (entries 6 and 7).
Table 2. Ir-catalyzed hydrogenation of substrate S17 using Ir(cod)BArF/L1-
L11 catalyst precursors.[a]
Entry
1
Ligand
L1
% Conv[b]
80
% ee[c]
74 (R)
44 (R)
42 (R)
7 (R)
2
L2
25
3
L3
33
4
L4
40
5
L5
100
15
9 (S)
6
L6
50 (R)
12 (R)
45 (R)
33 (R)
29 (S)
8 (R)
7
L7
16
8
L8
75
9
L9
35
Figure 3. Minimally functionalized trisubstituted olefins and selected
asymmetric hydrogenation results. Reaction conditions: 2 mol% of catalyst
precursor, 2 mol% of ligand, CH2Cl2 as solvent, 50 bar of H2, 4 h.
10
11
12
L10a
L10b
L11
12
10
<2
nd
We next tested the P,O/S-ligands in the AH of other
representative minimally functionalized trisubstituted substrates,
namely trisubstituted alkenes S12-S16, including the widely
studied α-methylstilbenes S12-S13 and the allylic alcohol S14
(see Figure 3 and the Supporting Information for a complete set
of results). The pyrrolidine-based Ir-P,O catalytic systems were
less appropriate for the reduction of α-methylstilbenes S12-S13
and allylic alcohol S14 (ee's up to 79%) but high
enantioselectivities (up to 91% ee) were achieved for β-
substituted unsaturated ketones S15 and S16. The effective
hydrogenation of this type of ketones opens up a sustainable
route to obtain chiral β-substituted ketones.[12] These results are
comparable with those reported with the successful proline-based
P,O-ligand,[4a] with the added advantage that our pyrrolidine-
[a]
Reactions carried out using 0.5 mmol of substrate and
2 mol% of
[Ir(cod)2]BArF, 2 mol% of the corresponding ligand at 1 bar of H2 for 4 h.
[b] Conversion determined by chiral GC. [c] Enantiomeric excesses determined
by chiral GC.
Continuing with the AH of 1,1-disubstituted alkenes, we tested
the substrates shown in Figure 4 (see Supporting Information for
a complete set of results). Advantageously, we found that the
Ir/L1 system was robust against variations in the electronic and
steric nature of the substrate aryl substituent, with ee’s ranging
from 73% to 76%. Thus, terminal olefins S18-S22 were reduced
in good enantioselectivity comparable to S17. Among other
published results, we also found an important effect of the type of
the alkyl chain on enantioselectivity, with high enantioselectivities
only obtained for substrates with a tert-butyl group (i.e. 74% ee
for S17 vs <20% ee for substrates S23–S25). These results are
in accordance with the existence of a competing isomerization
process, which was confirmed by studying the degree of indirect
incorporation of deuterium due to the isomerization process in the
deuteration of S23 (Scheme 4). It was found that deuterium was
not only added to the double bond but also at the allylic position.
Accordingly, the mass spectra of the corresponding deuterated
products indicated the presence of reduced species with more
than two deuterium atoms.
based P,O-ligand contains
a more stable and cheaper
diphenylphosphine donor group.
We finally tested ligands L1-L11 in the AH of 1,1-disubstituted
olefins. Unlike trisubstituted substrates, only a few recent
catalysts have provided high enantioselectivitites in the
hydrogenation of 1,1-disubstituted olefins.[3e] In these reductions,
the catalyst must not only control the face selectivity coordination
(there are only two substituents while in trisubstituted olefins there
are three) but also avoid the isomerization of the olefins into E-
trisubstituted substrates, which are then hydrogenated giving the
opposite enantiomer. As a model substrate, we have chosen the
3,3-dimethyl-2-phenyl-1-butene S17. The results (see Table 2)
indicated that, except the nature of the O-donor group, all ligand
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Conclusions
New pyrrolidine-based phosphine/phosphite-O/S ligands have
been applied in the asymmetric hydrogenation of 32 minimally
functionalized olefins. The new ligands are relevant not only
because they are easily prepared in a large scale from
unexpensive carbohydrates (D-mannose, D-ribose and D-
arabinose), but also because they can be easily modulated with a
well-established carbohydrate chemistry. Such modularity proved
to be crucial for the search of the most efficient catalyst for each
type of substrate. High enantioselectivities (ee's up to 99%) could
be achieved in the hydrogenation of selected tri- and disubstituted
substrates. In comparison with the related successful proline-
based P,O ligands[4a], the use of a more-rigid bicyclic backbone
affected positively the enantioselectivity and extended the range
of substrates that can been reduced, including 1,1-disubstituted
allylic acetates. In addition, our ligands have a diphenyl phosphine
moiety, which improves stability compared to related proline-
based P,O ligands that contain the bulkier phosphine groups.
These results pave the way for further development of new
generations of modular and readily available sugar based-P,O-
ligands for the asymmetric hydrogenation of minimally
functionalized substrates, including the more challenging Z-tri-
and disubstituted alkenes.
Figure 4. Selected results for the asymmetric hydrogenation of 1,1-disubstituted
substrates S18-S32 using [Ir(cod)2]/L1-L11 as catalyst precursor. Reaction
conditions: 2 mol% of [Ir(cod)2]BArF, 2 mol% of ligand, CH2Cl2 as solvent, 1 bar
of H2, 4 h.
Experimental Section
General remarks
All reactions were carried out using standard Schlenk techniques under an
atmosphere of argon. Commercial chemicals were used as received.
Solvents were dried by standard procedures and stored under argon.
Phosphorochloridites were easily prepared in one step from the
corresponding biphenols.[14] Compounds 1-3,[7] 6-9[8] and 13[10c] were
prepared as previously reported. Optical rotations were measured in a 1.0
cm or 1.0 dm tube with a Jasco P-2000 spectropolarimeter. Infrared
spectra were recorded with Jasco FTIR-410 spectrometer. 1H, 13C{1H} and
31P{1H} NMR spectra were recorded using a Bruker, AV300, AV500 and
Varian Mercury-400 MHz spectrometer for solutions in CDCl3, C6D6 and
DMSO-d6 at room temperature or heating (343 K, 363 K). Chemical shifts
are relative to that of SiMe4 (1H and 13C{1H}) as internal standard or H3PO4
Scheme 4. Deuteration of substrate S23. The percentage of incorporation of
deuterium atoms is shown in brackets. The result of the indirect addition of
deuterium due to the isomerization process is shown in red.
Finally, due to the importance of AH of olefins with poorly
coordinative groups we also studied the hydrogenation of this type
of disubstituted substrates (Figure 4, see Supporting Information
for a complete set of results). We focused on the reduction of the
aryl boronic ester (S26), the alkyl boronic ester (S27), the enol
phosphinate (S28) and allylic acetates (S29–S32). Although low-
to-moderate enantioselectivities were obtained with S26 to S28,
the pyrrolidine-based P,O ligands were well suited for the
reduction of allylic acetates. Excellent enantioselectivities
(ranging from 97% to 99% ee) comparable to the best one
reported were achieved with ligand L8 for several substituted
allylic acetates (S29–S32), maintaining the mild reaction
conditions (1 bar of H2). The reduction of allylic acetates provides
a straightforward route to the synthesis of relevant products which
are used in the cosmetic industry as components of fragrance
mixtures (e.g., Pamplefleur) and also in the pharmaceutical
industry (e.g., intermediates for the synthesis of modulators of
dopamine D3 receptors).[13]
(
31P) as external standard. 1H and 13C assignments were made on the
basis of 1H-1H gCOSY and 1H-13C gHSQC experiments. Mass spectra (CI
and ESI) were recorded on Micromass AutoSpeQ and QTRAP (Applied
Biosystem) and Orbitrap Elite spectrometers. NMR and mass spectra were
registered in CITIUS (University of Seville) and in SRCiT (Universitat
Rovira i Virgili).
(2R,3S,4R)-N-terc-Butoxycarbonyl-2-diphenylphosphinomethyl-3,4-
O-isopropylidene-pyrrolidine-3,4-diol (L1).
Tosylate 2[7] (300 mg, 0.700 mmol) was disolved in dry THF (9 mL) under
Ar and was cooled to -35 °C. Then KPPh2 (1.7 mL, 0.9 mmol, 0.5 M in
THF) was slowly added and the reaction mixture was stirred for 50 min.
IRA-120H+ was added, stirred for several minutes and then filtered through
Celite, washed
with AcOEt and evaporated to dryness. Column
chromatography on silica gel (Cyclohexane → AcOEt:cyclohexane, 1:5),
gave L1 (176 mg, 0.400 mmol, 57%) as a colourless oil. 31P NMR (121.5
MHz, DMSO-d6 343 K, δ ppm) δ -23.2 (s). 1H NMR (300 MHz, DMSO-d6,
t
343 K, δ ppm, J Hz) δ 1.22 (s, 3H, CH3), 1.29 (s, 12H, CH3, Bu, NBoc,
CH3), 2.27 (m, 2H, CH2-P), 3.34 (dd, 1H, CH2-N 2JH-H= 12.9, 3JH-H = 4.5),
3.66 (m, 1H, CH2-N), 3.97 (m, 1H, CH-N), 4.73 (m, 2H, CH-O), 7.44 (m,
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10H, CH=). 13C NMR (75.4 MHz, DMSO-d6, 343 K, δ ppm) δ 24.5 (CH3),
26.4 (CH3), 27.1 (CH3, tBu, NBoc), 29.1 (CH2-P), 50.2 (CH2-N), 60.9 (CH-
N), 78.4 (CH-O), 83.7 (CH-O), 110.3 (C), 139.0-128.1 (aromatic carbons),
153.2 (C=O). αD +48.4 (c 0.56, CH2Cl2). IR νmax 2980, 2927, 1691 (C=O),
1162, 1055, 695 cm-1.
the mixture was washed with sat. aq. Na2S2O3, water and brine. The
reaction mixture was dried (Na2SO4), filtered and evaporated. Purification
by column chromatography on silica gel (cyclohexane
→
AcOEt:cyclohexane - 1:20) afforded N-tert-butoxycarbonyl-1,4,5-trideoxy-
6-O-tert-butyldimethylsilyl-1,4-imino-5-iodo-2,3-O-isopropyli-dene-D-
talitol (4) (865 mg, 77%, 2 steps) as a colorless oil, that was used
immediately in the next step. 1H NMR (300 MHz, CDCl3, δ ppm) δ 0.09 (s,
6H, CH3), 0.91 (s, 9H, CH3, tBu), 1.31 (s, 3H, CH3), 1.44 (s, 3H, CH3), 1.47
(s, 9H, CH3), 3.81 (m, 4H), 4.11 (m, 1H), 4.62 (m, 3H).
(2R,3R,4S)-N-terc-Butoxycarbonyl-2-diphenylphosphinomethyl-3,4-
O-isopropylidene-pyrrolidine-3,4-diol (L2).
To a solution of 9 (239.3 mg, 0.70 mmol) in dry pyridine (3.5 mL) Boc2O
(382 mg, 1.75 mmol) was added and the reaction mixture was stirred at r.t.
for 6.5 h. Then, the mixture was evaporated to dryness. The residue was
dissolved in EtOAc and washed with water and brine. The organic phase
was dried (Na2SO4), filtered and concentrated. Purification by column
chromatography on silica gel (AcOEt:cyclohexane - 1:8) afforded L2
(148.8 mg, 0.34 mmol, 48%) as a pale yellow oil. 31P NMR (121.5 MHz,
CDCl3, δ ppm) δ: -20.1 (s). 1H NMR (500 MHz, CDCl3, δ ppm) δ: 1.31 (s,
To a solution of 4 (705 mg, 1.34 mmol) in EtOH (14 mL), Et3N (450 μL)
and Pd/C (10%, cat.) were added and the reaction hydrogenated at 1 atm
for 4 h. The crude product was filtered through Celite and the solvent
evaporated under vacuum. The resulting residue was purified by column
chromatography on silica gel (EtOAc:cyclohexane - 1:10 → AcOEt) to give
the dehalogenated derivative (490 mg, 82%). 1 M TBAF in THF (0.49 mL,
0.49 mmol) was added to a solution of this compound (180 mg, 1.49 mmol)
in THF (6 mL) and the mixture was stirred at r.t. for 6 h and then the solvent
evaporated under vacuum. Purification by column chromatography on
silica gel (CH2Cl2:MeOH - 50:1) afforded compound 5 (128 mg, quant.) as
a colorless oil, that was used immediately in the next step. 1H NMR (300
MHz, CDCl3, δ ppm) δ 1.27 (s, 3H, CH3), 1.40 (s, 3H, CH3), 1.33 (m, 1H),
1.44 (s, 9H, CH3, tBu), 1.72 (m, 1H), 3.22 (dd, 1H, J = 13.2 Hz, J = 4.9 Hz),
3.46 (m, 3H), 3.89 (m, 1H), 4.24 (m, 1H), 4.43 (m, 1H), 4.67 (t, 1H, J = 5.3
Hz),
t
3H, CH3), 1.37 (s, 9H, CH3, Bu, NBoc), 1.44 (s, 3H, CH3), 2.43 (dd, 1H,
CH2-P, 2JH-H = 13.2 Hz, 3JH-H = 10.4 Hz), 2.87 (d, 1H, CH2-P), 3.34 (dd, 1H,
CH2-N, 2JH-H = 13.2 Hz , 3JH-H = 4.5 Hz), 3.78 (m, 1H, CH2-N), 3.98 (m, 1H,
CH-N), 4.66 (m, 1H, CH-O), 4.76 (br t, 1H, CH-O, 3JH-H = 3JH-H = 6.2 Hz),
7.32 (m, 5H, CH=), 7.45 (m, 2H, CH=), 7.55 (m, 2H, CH=). 13C NMR (125.7
t
MHz, CDCl3, δ ppm) δ: 25.4 (CH3), 27.0 (CH3), 28.6 (CH3, Bu), 29.0 (d,
CH2-P, JC,P = 15.1 Hz), 51.1 (CH2-N), 58.1 (d, CH-N, JC,P = 24.2 Hz), 77.4
(CH-O), 80.3 (d, CH-O, JC,P = 21.3 Hz), 112.8 (C), 128.6-139.6 (aromatic
carbons), 154.5 (C=O). αD +61.1 (c 0.82, CH2Cl2). ESI-HRMS m/z found
442.2134, calc. for C25H33NO4P [M+H]+: 442.2142. IR νmax 2978, 2932,
1692 (C=O), 1162, 854, 695 cm-1.
Then a solution of MsCl (55 μL, 0.71 mmol) in pyridine (1 mL) was added
dropwise to a 0 ºC solution of alcohol 5 (67.5 mg, 0.24 mmol) in CH2Cl2 (2
mL) and the mixture stirred at r.t. for 2 h. Water was then added dropwise
under stirring and the mixture evaporated to dryness. The residue was
dissolved in CH2Cl2 and washed with water and brine. The organic phase
was dried (Na2SO4), filtered and concentrated. The crude mesylate was
dissolved in anhydrous THF (2 mL) and cooled to -40 ºC. KPPh2 (565 μL,
0.28 mmol, 0.5 M in THF) was slowly added and the mixture was stirred at
-40 ºC for 15 min. IRA-120H+ resin was added and the mixture diluted with
AcOEt, filtered through Celite and washed with AcOEt and CH2Cl2.
Evaporation of the solvent and purification by column chromatography on
silica gel (AcOEt:cyclohexane - 1:10→1:5) afforded L4 (74 mg, 69%, 2
steps). 31P NMR (121.5 MHz, DMSO-d6, δ ppm, mixture of rotamers) δ -
15.4 (s), -16.1 (s). 1H-NMR (300 MHz, DMSO-d6, 363 K, δ ppm) δ 1.24 (s,
(2R,3R,4S)-N-tert-Butoxycarbonyl-3,4-di-O-benzyl-2-
diphenylphosphinomehyl-pyrrolidine-3,4-diol (L3).
To a solution of 11 (150.6 mg, 0.44 mmol) in dry THF (4 mL) cooled to 0
ºC, KPPh2 (1.8 mL, 0.89 mmol, 0.5 M in THF) was slowly added and the
mixture was heated at reflux for 1.5 h. Then, IRA-120H+ resin was added,
filtered through Celite and washed with CH2Cl2. Evaporation of the solvent
and purification by column chromatography on silica gel (CH2Cl2, 1% Et3N)
afforded pyrrolidine 12 (171.1 mg, 0.36 mmol, 80%). Boc2O (194 mg, 0.89
mmol) in dry pyridine (2 mL) was subsequently added and the reaction
mixture was stirred at r.t. for 6 h. Then, the mixture was evaporated to
dryness. The residue was dissolved in EtOAc and washed with water and
brine. The organic phase was dried (Na2SO4), filtered and concentrated.
Purification by column chromatography on silica gel (AcOEt:cyclohexane
- 1:8) afforded L3 (114 mg, 0.20 mmol, 55%) as a pale yellow oil. 31P NMR
(121.5 MHz, CDCl3, δ ppm) δ: -19.2 (s). 1H NMR (500 MHz, CDCl3, δ ppm)
δ: 1.32 (s, 9H, CH3, tBu, NBoc), 2.52 (m, 1H, CH2-P), 2.75 (m, 1H, CH2-P),
3.29 (dd, 1H, CH2-N, 2JH-H = 11.3 Hz, 3JH-H = 4.0 Hz), 3.62 (m, 1H, CH2-N),
4.07 (m, 1H, CH-N), 4.16 (m, 2H, 2xCH-O), 4.67 (m, 4H, CH2Ph), 7.37 (m,
20H, CH=). 13C NMR (125.7 MHz, CDCl3, δ ppm) δ: 27.7 (CH3, tBu, CH2-
P), 48.7 (CH2-N), 56.1 (d, CH-N, JC,P = 22.4 Hz), 71.2 (CH2Ph), 71.8
(CH2Ph), 76.6 (CH-O), 78.4 (CH-O), 78.7 (C, tBu), 126.9-138.1 (aromatic
carbons), 153.5 (C=O. αD +32.9 (c 0.78, CH2Cl2). ESI-HRMS m/z found
582.2760, calc. for C36H41NO4P [M+H]+: 582.2768. IR νmax 2976, 2923,
1688 (C=O), 1391, 1100, 695 cm-1.
t
3H, CH3), 1.34 (s, 3H, CH3), 1.36 (s, 9H, CH3, Bu), 1.53 (m, 2H, CH2-
3
CH2P), 2.08 (m, 2H, CH2-P), 3.23 (dd, 1H, CH2-N, JH-H = 4.8 Hz), 3.65
(ap.d, 1H, CH2-N, 2JH-H = 12.9 Hz), 3.98 (m, 1H, CH-N), 4.48 (m, 1H, CH-
O), 4.68 (t, 1H, CH-O, 3JH-H= 3JH-H= 5.1 Hz), 7.41 (m, 8H, CH=), 7.52 (m,
1H, CH=), 7.77 (m, 1H, CH=). 13C NMR (75.4 MHz, DMSO-d6, 363 K, δ
ppm) δ 23.0 (d, , CH2-CH2P, JC-P = 12.1 Hz), 24.5 (CH3), 26.3 (CH3), 26.8
(d, CH2-P, JC-P= 17.3 Hz), 27.6 (CH3, tBu), 50.3 (CH2-N), 63.7 (d, CH-N,
JC-P= 12.8 Hz), 78.2 (CH-O, C, tBu), 83.1 (CH-O), 110.2 (C), 138.1-127.9
(Aromatic carbons), 153.3 (C=O), αD +14.8 (c 1.3, CH2Cl2). ESI-HRMS m/z
found 456.2292, calc. for C26H35NO4P [M+H]+: 456.2298.
(2R,3S,4R)-N-Benzyloxycarbonyl-2-diphenylphosphinoethyl-3,4-O-
isopropylidene-pyrrolidine-3,4-diol (L5).
To a solution of 15 (257 mg, 0.799 mmol) in dry CH2Cl2 (5 mL) cooled to
0 °C, a solution of MsCl (187 μL, 2.39 mmol) in dry pyridine (2.5 mL) was
added. The reaction mixture was left to stand at r.t. under Ar for 2 h. Then
it is cooled to 0°C and H2O (3 mL) is added dropwise, left at r.t. for 15 min
and concentrated to dryness. The obtained residue was dissolved in
CH2Cl2 (15 mL) and washed with H2O (3 x 10 mL). The organic phase is
dried (Na2SO4), filtered and concentrated to dryness. The resulting crude
product is then dissolved in dry THF (5.8 mL) under Ar, cooled to -78 °C,
and KPPh2 (4.46 mL, 0.5 M in THF, 2.23 mmol) was added dropwise. The
reaction mixture was left to stand at that temperature for 15 min under Ar.
Then, a saturated aqueous solution of NH4Cl (3 mL) was added and the
solution allowed to reach r.t. The aqueous phase is extracted with CH2Cl2
and the combined organic phases are dried (Na2SO4), filtered and
(2S,3S,4R)-N-tert-Butoxycarbonyl-2-diphenylphosphinoethyl-3,4-O-
isopropylidene-pyrrolidine-3,4-diol (L4).
To a solution of 3[7] (650 mg, 2.14 mmol) in dry CH2Cl2 (3 mL), NEt3 (595
μL, 4.28 mmol) and TBSCl (612 mg, 2.14 mmol) were added. After stirring
at r.t overnight, the reaction was quenched with sat. aq. soln. of NH4Cl and
extracted with CH2Cl2 (3 x 10 mL). The combined organic phases were
washed with brine, dried (Na2SO4), filtered and concentrated. To a solution
of the crude product in dry toluene (18 mL), imidazole (466 mg, 6.85 mmol),
PPh3 (1.30 g, 4.92 mmol) and I2 (868 mg, 3.42 mmol) were added and the
mixture was refluxed for 2 h. After cooling to r.t. and diluting with AcOEt,
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10.1002/cctc.201801485
ChemCatChem
FULL PAPER
concentrated to dryness. Purification by column chromatography on silica
gel (AcOEt: cyclohexane - 1:5) gave L5 (201 mg, 0.42 mmol, 52%, 2 steps)
as a colorless oil. 31P NMR (121.5 MHz, CDCl3, δ ppm) δ -15.0 (s). 1H NMR
(300 MHz, CDCl3, δ ppm) δ 1.33 (s, 3H, CH3), 1.42 (s, 3H, CH3), 1.85 (m,
1H, CH2-CH2P), 2.04 (m, 2H, CH2-CH2P, CH2-P), 2.24 (m, 1H, CH2-P),
3.29 (dd, 1H, CH2-N, 2JH-H= 12.6 Hz, 3JH-H= 4.2 Hz), 3.90 (dd, 1H, CH2-N,
(2R,3S,4R)-N,N-Diisopropylcarbamoyl-2-diphenylphosphinomethyl-
3,4-O-isopropylidene-pyrrolidine-3,4-diol (L8). Compound L8 (45%
yield) was prepared according to the general procedure from L1 and N,N-
diisopropylcarbamoyl chloride, followed by column chromatography on
silica gel (AcOEt:hexane - 1:3). 31P NMR (121.5 MHz, CDCl3, δ ppm) δ -
23.4 (s). 1H NMR (300 MHz, CDCl3, δ ppm) δ 1.00 (d, 6H, CH3, iPr, 3JH-
H= 6.6 Hz), 1.22 (d, 6H, CH3, iPr, 3JH-H= 6.6 Hz), 1.28 (s, 3H, CH3, ), 1.42
(s, 3H, CH3), 2.15 (d, 2H, CH2-P, 3JH-H= 8.1 Hz), 3.38 (d, 1H, CH2-N, 2JH-
H= 12.6 Hz), 3.51 (m, 3H, CH2-N, CH, iPr), 4.18 (m, 1H, CH-N), 4.67 (m,
1H, CH-O), 4.78 (m, 1H, CH-O), 7.36 (m, 6H, CH=), 7.45 (m, 4H, CH=).
13C NMR (75.4 MHz, CDCl3, δ ppm) δ 20.6 (CH3, iPr), 22.4 (CH3, iPr), 25.0
3
2JH-H= 12.6 Hz, JH-H= 6.9 Hz), 4.07 (m, 1H, CH-N), 4.72 (m, 2H, CH-O),
5.06 (d, 1H, 2JH,H= 12.3 Hz, CH2Ph), 5.11 (d, 1H, CH2Ph, 2JH,H= 12.3 Hz),
7.31 (m, 11H, CH=), 7.43 (m, 4H, CH=). 13C NMR (75.4 MHz, CDCl3, δ
ppm) δ 24.6 (d, CH2-CH2P, JC,P= 11.5 Hz), 25.3 (CH3), 26.2 (d, CH2-CH2P
CH2-P, JC,P= 18.0 Hz), 26.6 (CH3), 50.5 (CH2-N), 60.9 (d, CH-N, JC,P= 14.9
Hz), 67.0 (CH2Ph), 77.9 (CH-O), 80.0 (CH-O), 113.1 (C), 139.2-128.0 (C-
arom.), 154.8 (C=O). αD -57.6 (c 0.78, CH2Cl2). IR νmax 2985, 2929, 1698
(C=O), 1408, 1209, 695 cm-1. ESI-HRMS m/z found 490.2134, calc. for
C29H33NO4P [M+H]+: 490.2142.
i
(CH3), 26.7 (CH3), 29.6 (d, CH2-P, JC-P= 16.3 Hz), 47.3 (CH, Pr), 53.3
(CH2-N), 62.2 (d, CH-N, JC-P = 17.9 Hz), 78.7 (CH-O), 84.2 (d, CH-O, JC-
P= 9.7 Hz), 111.5 (C), 138.1-128.6 (aromatic carbons), 161.3 (C=O). αD -
5.2 (c 1.3, CH2Cl2). ESI-HRMS m/z found 469.2610, calc. for C27H38N2O3P
[M+H]+: 469.2615. IR νmax 2988, 2932, 1685 (C=O), 1141, 1058, 695 cm-1.
General procedure for the formation of compounds L6–L9.
(2R,3S,4R)-N-Adamantan-1-carbamoyl-2-diphenylphosphinomethyl-
3,4-O-isopropylidene-pyrrolidine-3,4-diol (L9). Compound L9 (55%
yield) was prepared according to the general procedure from L1 and 1-
adamantyl isocyanate, followed by column chromatography on silica gel
(AcOEt: hexane - 1:3). 31P NMR (121.5 MHz, CDCl3, δ ppm) δ -23.8 (s).
1H NMR (300 MHz, CDCl3, δ ppm) δ 1.29 (s, 3H, CH3), 1.42 (s, 3H, CH3),
1.63 (s, 6H, CH2, ad), 1.85 (s, 6H, CH2, ad), 2.02 (s, 3H, CH, ad), 2.22 (m,
1H, CH2-P), 2.34 (m, 1H, CH2-P), 3.29 (m, 1H, CH2-N), 3.70 (d, 1H, CH2-
N, 2JH-H = 12.6 Hz), 4.00 (m, 1H, CH-N), 4.78 (br.s, 2H, CH-O), 7.41 (m,
10H, CH=). 13C NMR (75.4 MHz, CDCl3, δ ppm) δ 25.1 (CH3), 27.0 (CH3),
29.7 (CH), 30.6 (d, CH2-P, JC-P = 16.3 Hz), 36.6 (CH2), 42.4 (CH2), 51.4
(CH2-N), 61.6 (d, CH-N, JC-P = 16.7 Hz), 79.1 (CH-O), 85.0 (d, CH-O, JC-P
= 9.6 Hz), 111.9 (C), 137.8-128.7 (aromatic carbons), 155.5 (C=O). αD
+37.3 (c 0.75, CH2Cl2). ESI-HRMS m/z found 519.2766, calc. for
C31H40N2O3P [M+H]+: 519.2771. IR νmax 2905, 2845, 1643 (C=O), 1508,
1056, 696 cm-1.
TFA (20 mol%) was added dropwise at 0 °C to a solution of L1 (0.2 mmol)
in dry CH2Cl2 (3 mL) containing 4 Ǻ molecular sieves. The mixture was
stirred at r.t. for 1 h, then filtered and evaporated to dryness. The residue
was dissolved in CH2Cl2, treated with Ambersep 900 (OH-) resin, filtered
and evaporated. A solution of Et3N (2.0 eq.), the corresponding carbonyl
compound (1.3 eq.) and the deprotected amine was stirred at rt for 2-4 h.
After addition of sat. aqueous NH4Cl, the mixture was extracted with
CH2Cl2 (3x10 mL). The combined organic phases were washed with brine,
dried (Na2SO4), filtered and concentrated. Purification by column
chromatography on silica gel afforded the corresponding acylated
compound.
(2R,3S,4R)-N-Pivaloyl-2-diphenylphosphinomethyl-3,4-O-
isopropylidene-pyrrolidine-3,4-diol (L6). Compound L6 (74% yield) was
prepared according to general procedure from L1 and pivaloyl chloride,
followed by column chromatography on silica gel (AcOEt:cyclohexane -
1:5). 31P NMR (121.5 MHz, CDCl3, δ ppm) δ -24.2 (s). 1H NMR (300 MHz,
General procedure for the preparation of the pyrrolidine-phosphite
ligands L10a-b.
t
CDCl3, δ ppm) δ 1.14 (s, 9H, CH3, Bu), 1.28 (s, 3H, CH3), 1.36 (s, 3H,
CH3), 2.18 (m, 1H, CH2-P), 2.44 (m, 1H, CH2-P), 3.51 (m, 1H, CH2-N), 4.09
(m, 1H, CH2-N), 4.68 (br.s, 1H, CH-N), 4.81 (m, 2H, CH-O), 7.35 (m, 6H,
CH=), 7.43 (m, 2H, CH=), 7.53 (m, 2H, CH=). 13C NMR (75.4 MHz, CDCl3,
δ ppm) δ 25.0 (CH3), 26.7 (CH3), 27.7 (CH3, tBu), 29.7 (CH2-P), 38.7 (C),
53.0 (CH2-N), 63.0 (CH-N), 80.2 (CH-O), 82.3 (CH-O), 111.7 (C), 138.5-
128.7 (aromatic carbons), 176.4 (C=O), αD +198.4 (c 0.56, CH2Cl2). ESI-
HRMS m/z found 426.2186, calc. for C25H33NO3P [M+H]+: 426.2193. IR
νmax 2980, 2920, 1611 (C=O), 1207, 1042, 697 cm-1.
The corresponding phosphorochloridite (1.1 mmol) produced in situ was
dissolved in toluene (5 mL) and pyridine (3.8 mmol, 0.3 mL) was added.
The corresponding alcohol 1 (1 mmol) was azeotropically dried with
toluene (3x1 mL) and dissolved in toluene (5 mL) to which pyridine (3.8
mmol, 0.3 mL) was added. The solution was transferred slowly at 0 oC to
the solution of the phosphorochloridite. The reaction mixture was stirred
overnight at 80 oC, and the pyridine salts were removed by filtration.
Evaporation of the solvent gave a white foam, which was purified by flash
chromatography in alumina (toluene:triethylamine – 100:1) to produce the
corresponding ligand as a white solid.
(2R,3S,4R)-N-Benzoyl-2-diphenylphosphinomethyl-3,4-O-
isopropylidene-pyrrolidine-3,4-diol (L7). Compound L7 (72% yield) was
prepared according to the general procedure from L1 and benzoyl chloride,
followed by column chromatography on silica gel (AcOEt:hexane - 1:7). αD
+85.5 (c 0.6, CH2Cl2). ESI-HRMS m/z found 446.1873, calc. for
C27H29NO3P [M+H]+: 446.1880. IR νmax 2990, 2917, 1627 (C=O), 1208,
1058, 695 cm-1. Major rotamer (63%): 31P NMR (121.5 MHz, CDCl3, δ
ppm): -24.8 (s). 1H NMR (300 MHz, CDCl3, δ ppm): 1.28 (s, 3H, CH3), 1.40
L10a: Yield: 167.2 mg (50%). TOF-MS (ESI+): m/z: calcd for
C39H50NO7PSi2: 754.2756 [M-Na]+; found 754.2761. αD -420.5 (c 1.4,
CH2Cl2). IR νmax 2953, 1698 (C=O), 1399, 1174, 973, 831 cm-1. Major
rotamer (63%): 31P NMR (121.5 MHz, CDCl3, δ ppm), 134.2 (s). 1H NMR
(300 MHz, CDCl3, δ ppm): 0.45 (s, 9H, CH3, SiMe3), 0.52 (s, 9H, CH3,
SiMe3), 1.08 (s, 3H, CH3), 1.09 (s, 9H, CH3, tBu, NBoc), 1.28 (s, 3H, CH3),
3.24 (dd, 1H, CH2-N, 2JH-H =12.5 Hz, 3JH-H =5.2 Hz), 3.43 (m, 1H, CH), 3.55
(m, 1H, CH2-OP), 4.07 (m, 2H, CH2-N, CH-O), 4.39 (m, 1H, CH2-O), 4.73
(d, 1H, CH-O, 3JH-H =5.2 Hz), 6.83 (m, 2H, CH=), 7.07 (m, 2H, CH=,), 7.18
(m, 1H, CH=), 7.27 (m, 1H, CH=), 7.65 (m, 2H, CH=), 8.04 (m, 2H, CH=).
13C NMR (75.4 MHz, CDCl3, δ ppm): -0.6 (CH3, SiMe3), -0.1 (CH3, SiMe3),
2
(s, 3H, CH3), 2.42 (dd, 1H, CH2-P, JH-H = 14.1 Hz,2JH-H = 8.4 Hz), 2.52
(ddd, 1H, CH2-P, 2JH-H = 14.1 Hz, 3JH-H = 5.4 Hz, 4JH-H = 1.8 Hz), 3.63 (m,
2H, CH2-N), 4.88 (m, 3H, CH-N, 2x CH-O), 7.31 (m, 15H, CH=). 13C NMR
(75.4 MHz, CDCl3, δ ppm): 25.0 (CH3), 26.9 (CH3), 30.5 (d, CH2-P, JC-P
=
16.1 Hz), 54.5 (CH2-N), 61.3 (d, CH-N, JC-P = 14.9 Hz), 79.7 (CH-O), 84.2
(d, CH-O, JC-P= 9.7 Hz), 111.9 (C,), 138.2-127.3 (aromatic carbons), 170.8
(C=O). Minor rotamer (37%): 31P NMR (121.5 MHz, CDCl3, δ ppm), -24.8
(s). 1H NMR (300 MHz, CDCl3, δ ppm): 1.33 (s, 3H, CH3), 1.51 (s, 3H, CH3),
1.95 (m, 1H, CH2-P), 2.14 (m, 1H, CH2-P), 4.00 (m, 1H, CH2-N), 4.14 (m,
1H, CH-N), 4.29 (d, 1H, CH2-N, 2JH-H = 13.8 Hz), 4.74 (m, 1H, CH-O), 4.88
(m, 1H, CH-O), 7.31 (m, 15H, CH=). 13C NMR (75.4 MHz, CDCl3, δ ppm):
24.8 (CH3), 26.8 (CH3), 31.3 (d, CH2-P, JC-P = 17.4 Hz), 50.4 (CH2-N), 63.2
(d, CH-N, JC-P= 18.2 Hz), 78.4 (CH-O), 83.8 (d, CH-O, JC-P= 10.1 Hz),
111.8 (C), 138.2-127.3 (aromatic carbons), 169.9 (C=O).
t
t
21.1 (C, Bu, NBoc), 24.6 (CH3), 26.7 (CH3), 26.8 (CH3), 27.9 (CH3, Bu,
NBoc), 52.8 (CH2-N), 63.3 (CH), 64.5 (CH2-OP), 79.3 (CH-O), 82.5 (CH-
O), 111.3 (C), 122.5 – 153.6 (aromatic carbons) 153.0 (C=O). Minor
rotamer (37%): 31P NMR (121.5 MHz, CDCl3, δ ppm), 138.0 (s). 1H NMR
(300 MHz, CDCl3, δ ppm): 0.49 (s, 9H, CH3, SiMe3), 0.53 (s, 9H, CH3,
SiMe3), 1.03 (s, 3H, CH3), 1.28 (s, 3H, CH3), 1.34 (s, 9H, CH3, tBu, NBoc),
2.79 (dd, 1H, CH2-N, 2JH-H =12.3 Hz, 3JH-H =5.3 Hz), 3.55 (m, 1H, CH2-N),
4.07 (m, 3H, CH2-OP, CH), 4.23 (m, 1H, CH-O), 4.66 (d, 1H, CH-O, 3JH-H
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10.1002/cctc.201801485
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=5.3 Hz), 6.83 (m, 2H, CH=), 7.07 (m, 2H, CH=), 7.18 (m, 1H, CH=), 7.27
(m, 1H, CH=), 7.65 (m, 2H, CH=), 8.04 (m, 2H, CH=), 8.12 (s, 1H, CH=).
13C NMR (75.4 MHz, CDCl3, δ ppm): NMR (C6D6), δ: -0.4 (CH3, SiMe3), -
1.0 (CH3, SiMe3), 21.1 (C, tBu, NBoc), 24.5 (CH3), 26.7 (CH3), 26.8 (CH3),
28.0 (CH3, tBu, NBoc), 52.8 (CH2-N), 63.4 (CH), 64.0 (CH2-OP), 78.9 (CH-
O), 82.0 (CH-O), 111.3 (C), 122.5 – 153.6 (aromatic carbons), 153.3 (C=O).
(6S,7R,7aS)-6,7-O-Bis(benzyloxy)-tetrahydropyrrolo[1,2-c]oxazol-3-
one (11) .
To a mixture of 10 (36 mg, 0.23 mmol) and NaH (35 mg, 1.4 mmol) in dry
DMF (1.8 mL) at 0 °C BnBr (163 μL, 1.37 mmol) was added dropwise. The
reaction mixture was stirred at r.t. under Ar for 5.5 h, cooled to 0 °C and
then Et3N (2 mL) and MeOH (2 mL) were added. The reaction mixture is
concentrated to dryness. The residue was diluted with CH2Cl2 and washed
with H2O and brine. The organic phase was dried (Na2SO4), filtered and
concentrated to dryness. Purification by column chromatography on silica
gel (AcOEt: cyclohexane - 1:2 → 1:1) furnished 11 (70 mg, 0.21 mmol,
90%) as a white solid. 1H NMR (300 MHz, CDCl3, δ ppm) δ 3.27 (dd, 1H,
L10b: Yield: 167.2 mg (50%). TOF-MS (ESI+): m/z: calcd for
C39H50NO7PSi2: 754.2756 [M-Na]+; found 754.2759. αD 473.3 (c 2.4,
CH2Cl2). IR νmax 2956, 1696 (C=O), 1399, 1174, 955, 829 cm-1. Major
rotamer (61%): 31P NMR (121.5 MHz, CDCl3, δ ppm): 129.7 (s). 1H NMR
(300 MHz, CDCl3, δ ppm): 0.48 (m, 18H, CH3, SiMe3), 1.18 (s, 3H, CH3),
1.32 (m, 3H, CH3), 1.40 (s, 9H, CH3, tBu, NBoc), 3.53 (dd, 1H, CH2-N, 2JH-
CH2-N, JH,H = 11.4 Hz, JH,H = 5.7 Hz), 3.74 (dd, 1H, CH2-N, JH-H= 11.4
Hz, 3JH,H = 5.7 Hz), 3.95 (m, 2H, CH-O, CH-N), 4.14 (td, 1H, CH-O, 3JH-H
2
3
2
2
=11.9 Hz, JH-H =5.7 Hz), 3.76 (m, 2H, CH2-OP, CH2-N), 4.00 (m, 2H,
=
H
CH2-OP, CH), 4.54 (m, 1H, CH-O), 4.61 (m, 1H, CH-O), 6.85 (m, 2H, CH=),
7.08 (m, 2H, CH=), 7.33 (m, 2H, CH=), 7.66 (m, 2H, CH=), 8.07 (m, 2H,
CH=). 13C NMR (75.4 MHz, CDCl3, δ ppm): -0.6 (CH3, SiMe3), -0.1 (CH3,
SiMe3), 21.1 (C, tBu, NBoc), 24.6 (CH3), 28.0 (CH3, tBu, NBoc), 28.2 (CH3),
54.2 (CH2-N), 63.3 (CH), 64.6 (CH2-OP), 78.9 (CH-O), 82.4 (CH-O), 111.0
(C), 124.9 – 153.7 (aromatic carbons), 153.7 (C=O). Minor rotamer (39%):
31P NMR (121.5 MHz, CDCl3, δ ppm), 130.6 (s). 1H NMR (300 MHz, CDCl3,
δ ppm): 0.48 (m, 18H, CH3, SiMe3), 1.12 (s, 3H, CH3), 1.20 (m, 9H, CH3,
tBu, NBoc), 1.32 (m, 3H, CH3), 3.15 (m, 1H, CH2-N), 3.25 (dd, 1H, CH2-
OP, 2JH-H =12.6 Hz, 3JH-H =5.7 Hz), 4.00 (m, 3H, CH2-N, CH2-OP, CH), 4.25
(m, 1H, CH-O), 4.54 (m, 1H, CH-O), 6.85 (m, 2H, CH=), 7.08 (m, 2H, CH=),
7.21 (m, 2H, CH=), 7.66 (m, 2H, CH=), 8.07 (m, 2H, CH=). 13C NMR (75.4
3JH-H= 5.7 Hz, 3JH-H= 3.3 Hz), 4.31 (t, 1H, CH2-O,2JH-H= 3JH-H= 8.4 Hz), 4.57-
4.48 (m, 3H, CH2Ph, CH2Ph, CH2-O), 4.65 (d, 1H, CH2Ph), 4.87 (d, 1H,
CH2Ph, 2JH,H= 12.0 Hz), 7.31 (m, 10H, CH=), 13C NMR (75.4 MHz, CDCl3,
δ ppm) δ 49.0 (CH2-N), 59.2 (CH-N), 63.9 (CH2-O), 72.2 (CH2Ph), 73.2
(CH2Ph), 77.4 (CH-O), 80.2 (CH-O), 137.9-127.9 (Aromatic carbons),
162.8 (C=O), αD +36.9 (c 0.78, CH2Cl2). IR νmax 2922, 2894, 1749 (C=O),
1244, 766, 697 cm-1. ESI-HRMS m/z found 362.1353, calc. for
C20H21NO4Na [M+Na]+: 362.1363.
(2R,3S,4R)-N-Benzyloxycarbonyl-2-ethoxycarbonylethyl-yl-3,4-O-
isopropyliden-pyrrolidine-3,4-diol (14).
t
MHz, CDCl3, δ ppm): -0.5 (CH3, SiMe3), 1.0 (CH3, SiMe3), 21.1 (C, Bu,
To a solution of 13[10] (751 mg, 3.28 mmol) in EtOH:H2O (1:1) (12 mL)
NaHCO3 (276 mg, 3.28 mmol) and CbzCl (0.55 mL, 3.6 mmol) were added.
The reaction mixture was stand at r.t. for 3 h. Then saturated aqueous
solution of NaHCO3 (25 mL) was added and the aqueous phase was
extracted with AcOEt (3 x 15 mL). The combined organic phases were
dried (Na2SO4), filtered and concentrated to dryness. Purification by
column chromatography on silica gel (AcOEt: cyclohexane - 1:3) gave 14
(1.15 g, 3.16 mmol, 97%) as a colorless oil. NMR and IR data coincide with
those of its enantiomer.[10b] αD -55.2 (c 0.73, CH2Cl2). CI-HRMS m/z found
364.1756, calc. for C19H26NO6 [M+H]+: 364.1760.
NBoc), 24.6 (CH3), 26.8 (CH3, tBu, NBoc), 28.2 (CH3), 52.5 (CH2-N), 63.7
(CH), 64.0 (CH2-OP), 78.8 (CH-O), 82.6 (CH-O), 111.2 (C), 124.9 – 153.7
(aromatic carbons), 153.2 (C=O).
(2R,3R,4S)-N-(3,5-Bis
(trifluoromethyl)
phenyl)-2-
diphenylphosphinomethyl-3,4-O-isopropylidene-pyrrolidine-1-
carbothioamide-3,4-diol (L11).
To a solution of 9[8] (195 mg, 0.570 mmol) in dry CH2Cl2 (6 mL) 3,5-
bis(trifluoromethyl) phenylisothiocyanate (0.26 mL, 1.5 mmol) was added.
The reaction mixture was allowed to stand at r.t. for 3.5 h and then
concentrated to dryness. Purification by column chromatography on silica
gel (AcOEt: cyclohexane - 1:5) gave L11 (230 mg, 0.370 mmol, 66%) as a
white foam. 31P NMR (121.5 MHz, CDCl3, δ ppm) δ -20.6 (s). 1H NMR (500
MHz, CDCl3, δ ppm) δ 1.40 (s, 3H, CH3), 1.55 (s, 3H, CH3), 2.60 (ddd, 1H,
CH2-P, 2JH-H = 14.0 Hz, 2JH-H = 4.5 Hz, 3JH-H = 2.5 Hz), 2.79 (dd, 1H, CH2-
(2R,3S,4R)-N-Benzyloxycarbonyl-2-hydroxyethyl-3,4-O-
isopropiliden-pyrrolidine-3,4-diol (15).
To a suspension of LiAlH4 (35 mg, 0.91 mmol) in dry Et2O (3 mL) cooled
at -10 °C, a solution of 14 (275 mg, 0.756 mmol) in dry Et2O (5 mL) was
added dropwise under Ar. After 10 min, sat. aq. soln. of Na2SO4 (30 mL)
was added dropwise and the mixture was diluted with water and extracted
with AcOEt (3x50 mL). The combined organic phases were dried (Na2SO4),
filtered and concentrated to dryness. The resulting crude was purified by
column chromatography on silica gel (toluene: acetone - 5:1) to afford 15
(171 mg, 0.532 mmol, 70%) as a colorless oil. 1H NMR (300 MHz, CDCl3,
δ ppm) δ 1.34 (s, 3H, CH3), 1.50 (s, 3H, CH3), 1.78 (m, 1H, CH2-CH2O),
1.98 (m, 1H, CH2-CH2O ), 3.31 (dd, 1H, CH2-N, 2JH-H= 12.3 Hz, 3JH-H= 4.2
Hz), 3.63 (m, 2H, CH2O), 3.97 (dd, 1H, CH2-N, 2JH-H= 12.3 Hz, 3JH-H= 6.9
Hz), 4.24 (m, 1H, CH-N), 4.75 (m, 2H, CH-O), 5.12 (s, 2H, CH2Ph), 7.34
(m, 5H, CH=), 13C NMR (75.4 MHz, CDCl3, δ ppm) δ 25.2 (CH3), 26.4 (CH3),
32.4 (CH2-CH2O), 49.7 (CH2-N), 57.0 (CH-N), 59.3 (CH2O), 67.5 (CH2Ph),
78.3 (CH-O), 79.7 (CH-O), 113.5 (C), 136.4-128.5 (Aromatic carbons),
155.4 (C=O). αD -25.6 (c 0.78, CH2Cl2). IR νmax 3472 (OH), 2948, 1677
(C=O), 1422, 1079, 696 cm-1. ESI-HRMS m/z found 344.1466, calc. for
C17H23NO5Na [M+Na]+: 344.1468.
2
3
3
P, JH-H = 14.0 Hz, JH-H = 9.0 Hz), 3.65 (dd, 1H, CH2-N, JH-H = 4.5 Hz),
4.40 (m, 1H, CH-N), 4.55 (dd, 1H, CH2-N, 2JH-H = 13.0 Hz, 3JH-H = 7.5 Hz),
4.84 (m, 1H, CH-O), 4.94 (br t, 1H, CH-O, 3JH-H = 3JH-H = 6.5 Hz), 6.93 (br
d, 1H, NH, J = 2.5 Hz), 7.28 (m, 3H, CH=), 7.36 (m, 3H, CH=), 7.48 (m,
4H, CH=), 7.64 (m, 3H, CH=), 13C NMR (125.7 MHz, CDCl3, δ ppm) δ 25.3
(CH3), 26.6 (CH3), 28.8 (d, CH2-P, JC,P = 13.9 Hz ), 54.9 (CH2-N), 60.2 (d,
CH-N, JC,P = 23.1 Hz), 77.1 (CH-O), 79.9 (d, CH-O, JC,P = 3.0 Hz), 114.0
(C), 118.9 (c, JC,F = 3.8 Hz, CH=), 123.2 (c, JC,F = 272.6, CF3), 140.5-124.9
(Aromatic carbons), 179.3 (C=S), αD +42.4 (c 0.58, CH2Cl2). ESI-HRMS
m/z found 613.1497, calc. for C29H28F6N2O2PS [M+H]+: 613.1508. IR νmax
3238 (NH), 2993, 2927, 1371, 1275 (C=S), 1126 (C-F), 695 cm-1.
(6S,7R,7aS)-6,7-Dihydroxy-tetrahydropyrrolo
(10).
[1,2-c]-oxazol-3-one
To a solution of compound 8[8] (170 mg, 0.850 mmol) in THF (8 mL) cooled
to 0 °C, a solution of 4M HCl (8 mL) was added dropwise. After 3 h at r.t.,
the reaction mixture was concentrated to dryness and the resulting crude
was purified by column chromatography on silica gel (CH2Cl2: MeOH - 20:
1 → 10: 1) to give 10 (122 mg, 0.770 mmol, 90%) as a white solid. The
NMR data and IR are consistent with those of its enantiomer.[7] αD +28.4 (c
0.49, CH2Cl2). ESI-HRMS m/z found 182.0420, calc. for C6H9NO4Na
[M+Na]+: 182.0424.
Typical Procedure for the hydrogenation of minimally functionalized
olefins
The corresponding ligand (L1-L11) (0.01 mmol) was dissolved in CH2Cl2
(2 mL) and [Ir(cod)2]BArF (0.01 mmol, 4.0 mg) was added. Then, substrate
(0.5 mmol) was added to the solution. The mixture was introduced in a
high-pressure autoclave. The autoclave was purged four times with
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10.1002/cctc.201801485
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hydrogen and then pressurized to the desired hydrogen pressure. After the
desired reaction time, the autoclave was depressurized and the solvent
evaporated off. The residue was dissolved in Et2O (1.5 mL) and filtered
through a short Celite plug. The enantiomeric excess was determined by
chiral GC or chiral HPLC, and the conversions were determined by 1H
NMR or chiral GC (see Supporting Information for characterization and ee
determination details).
Chem. 2010, 2992–2997; d) Q. Chen, M. Kuriyama, X. Hao, T. Soeta, Y.
Yamamoto, K.-i. Yamada, K. Tomioka, Chem. Pharm. Bull. 2009, 57,
1024–1027. For examples of P,O ligands used in the reduction of
functionalized olefins, see: e) J. Cipot, R. McDonald, M. Stradiotto,
Organometallics 2006, 25, 29–31. f) K. Park, P. O. Lagaditis, A. J. Lough,
R. H. Morris, Inorg. Chem. 2013, 52, 5448–5456. g) S. Yang, W. Che,
H.-L. Wu, S.-F. Zhu, Q.-L. Zhou, Chem. Sci. 2017, 8, 1977–1980.
Our group has demonstrated the benefits of introducing biaryl phosphite
moiety in the ligands for this process, see for example: a) P. W. N. M.
van Leeuwen, P. C. J. Kamer, C. Claver, O. Pámies, M. Diéguez, Chem.
Rev. 2011, 111, 2077–2118; b) M. Magre, O. Pàmies, M. Diéguez, Chem.
Rec. 2016, 16, 1578–1590.
[6]
Acknowledgements
Financial support from the Spanish Ministry of Economy and
Competitiveness (CTQ2016-74878-P and CTQ2016-77270-R)
and European Regional Development Fund (AEI/FEDER, UE),
the Catalan Government (2014SGR670 and 2017SGR1472), and
the ICREA Foundation (ICREA Academia award to M.D) is
gratefully acknowledged. We also acknowledge the Spanish
Ministry of Education for a FPU fellowship (PER), Dr. Elena
Moreno-Clavijo for helpful discussions and CITIUS-NMR-MS
service of the University of Seville for technical assistance.
[7]
[8]
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Keywords: asymmetric hydrogenation • iridium • P,O ligands •
olefins • unfunctionalized
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Entry for the Table of Contents
FULL PAPER
Pilar Elías-Rodríguez, Carlota Borràs,
Ana T. Carmona, Jorge Faiges,
Inmaculada Robina,* Oscar Pàmies* and
Montserrat Diéguez*
Page No. – Page No.
Pyrrolidine-based P,O ligands from
carbohydrates: Easily accessible and
modular ligands for the Ir-catalyzed
The potential of P,O-iminosugar based ligands in the Ir-catalyzed asymmetric
hydrogenation of minimally functionalized olefins is presented. Improving previous
results, we have demonstrated that the use of a more-rigid bicyclic backbone not only
affected positively the enantioselectivity but also extended the range of substrates
that can be efficiently reduced.
asymmetric
hydrogenation
of
minimally functionalized olefins
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