Naplephos through the looking-glass: Chiral bis(phosphanylamides) based on β-1,2-D-glucodiamine and their application in enantioselective allylic substitutions

Article abstract of DOI:10.1002/ejoc.201100960

The straightforward design of a new library of chiral ligands (elpanphos) based on β-1,2-D-glucodiamine is described, which represents the enantiomeric counterpart of the naplephos library. In this guise, two representative ligands have been successfully

Full text of DOI:10.1002/ejoc.201100960

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100960
Naplephos through the Looking-Glass: Chiral Bis(phosphanylamides) Based on
β-1,2-D
-Glucodiamine and Their Application in Enantioselective Allylic
Substitutions
Vincenzo Benessere,[a] Antonella De Roma,[b] Raffaella Del Litto,[a] Matteo Lega,[a,c] and
Francesco Ruffo*[a,c]
Keywords: Asymmetric catalysis / Carbohydrates / Phosphanes / Palladium
The straightforward design of a new library of chiral ligands
(elpanphos) based on β-1,2- -glucodiamine is described,
which represents the enantiomeric counterpart of the na-
plephos library. In this guise, two representative ligands have
been successfully applied in the Pd-catalyzed desymmetriz-
ation of meso-cyclopent-2-ene-1,4-diol, which leads to the
expected enantiomer within short times and with high ees in
both traditional and unconventional solvents.
D
ducing defined steric hindrance or additional coordinating
functions next to the metal centre. Positions 4 and 6 are
instead useful for phase-tagging the ligands.
Introduction
Homogeneous enantioselective catalysis is central for the
production of fine chemicals.[1] In this field, innovative
metal catalysts can be rationally prepared by selecting
building blocks from the chiral pool.
Accordingly, the ligands were tested[5] in a number of
asymmetric reactions in both traditional solvents and ionic
liquids, and afford, in several cases, the chiral products in
high ees (Scheme 1 shows naplephos-a, one of the best per-
forming ligands, and the corresponding catalysis).
Within this frame, we recently[2] prepared a library of
ligands (naplephos) based on d-glucose[3] (Figure 1). The
multifunctional nature of the carbohydrate scaffold is fully
employed for a precise tailoring of the ligands: position 2
displays a rigid diphenylphosphanylamide arm, an essential
coordination motif of Trost’s privileged ligands based on
trans-cyclohexanediamine.[4] Position 3 is suitable for intro-
Scheme 1. The desymmetrization of meso-cyclopent-2-ene-1,4-diol
promoted by naplephos-a.
Figure 1. General formula of the naplephos library of ligands.
In order to fully employ the versatility of this strategy,
we have rationally designed the related library of ligands
(elpanphos),[6] which shows a specular stereochemistry of
coordination. This action aims to furnish a complete sce-
nario, in order to perform the same catalytic processes but
with the production of the chiral products in opposite con-
figuration.
On the basis of the relative orientations of positions 2
and 3 in the naplephos ligands, this approach has been pur-
sued by introducing the same essential coordinating motifs
[a] Dipartimento di Chimica “Paolo Corradini”,
Università di Napoli “Federico II”,
Complesso Universitario di Monte S.Angelo,
Via Cintia, 80126 Napoli, Italy
Fax: +39-081-674090
E-mail: ruffo@unina.it
[b] Istituto Zooprofilattico Sperimentale del Mezzogiorno,
Dipartimento di Sanità Animale,
Via Salute 2, 80055 Portici, Italy
[c] Consorzio Interuniversitario di Reattività Chimica e Catalisi,
via Celso Ulpiani 27, 80127 Bari, Italy
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100960.
Eur. J. Org. Chem. 2011, 5779–5782
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5779

V. Benessere, A. De Roma, R. Del Litto, M. Lega, F. Ruffo
SHORT COMMUNICATION
in positions 1 and 2, which clearly provide a pseudo-enan- alcohols and in the most common ionic liquids, a feature
tiomeric coordination environment (compare Figures 1 and particularly attractive as it allows the performing of bi-
2).
phasic asymmetric catalysis[8] (see below).
Both elpanphos ligands represent the specular counter-
part of naplephos-a (see Scheme 1), and, therefore, they
were examined in the asymmetric desymmetrization of 1 for
useful comparison. This intramolecular allylic substitution
affords the key precursors of mannostatines and is also a
standard test for the assessment of the stereo-orienting
properties of new ligands.[9]
Within this preliminary investigation, the influence of
temperature and additives on the performance of the cata-
lysts was assessed (Table 1).
Table 1. Catalytic conversion of 1 to 2.[a]
Ligand
T
[K]
Solvent
Time Conversion ee {+(S,R)-2}
[min] [%][b]
[%][c]
Figure 2. General formula of the elpanphos library of ligands.
1
2
3
4
5
6
7
8
9
elpanphos-a 298 THF[d]
elpanphos-a 273 THF[d]
elpanphos-a 258 THF[d]
elpanphos-a 298 THF
elpanphos-a 273 THF
elpanphos-a 258 THF
elpanphos-aЈ 298 THF[d]
elpanphos-aЈ 298 bmpyBF4
elpanphos-aЈ 298 bmpyBF4
I recycle
5
Ͼ99
Ͼ99
92
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
95
95
96
84
86
86
96
94
89
In this report, we communicate that this strategy prom-
ises to be plainly successful, as newly synthesized elpanphos
ligands were applied with full accomplishment of the expec-
tations.
15
30
30
30
30
5
[e]
[e]
30
30
Results and Discussion
[e]
10 elpanphos-aЈ 298 bmpyBF4
30
Ͼ99
79
The very simple synthesis of the ligands (elpanphos-a
and -aЈ) is reported in Scheme 2.
II recycle
[e]
11 elpanphos-aЈ 298 bmimBF4
12 elpanphos-aЈ 298 bmimBF4
I recycle
30
30
Ͼ99
Ͼ99
90
81
[e]
[e]
13 elpanphos-aЈ 298 bmimBF4
30
Ͼ99
77
II recycle
[a] Catalyst:substrate 1:20. [b] Determined by NMR spectra of the
crude reaction mixtures. [c] Determined by HPLC on Chiracel OD-
H, by using 2-propanol/hexane, 1:10, 1.0 mL/min, UV (254 nm).
[d] Triethylamine as additive. [e] Catalyst:substrate 1:10. Triethyl-
amine as additive.
The following should be observed: (i) in THF (Entries 1–
7), the reaction proceeded in high yield within short reac-
tion times; (ii) as desired, the elpanphos ligands produced
preferential formation of the opposite enantiomer with re-
spect to the naplephos ligands, +(S,R)-2 vs. -(R,S)-2; (iii) the
marked beneficial influence of an added base was demon-
strated:[9e] the ee of the reaction increased in the presence
of triethylamine (Entry 1 vs. 4, 2 vs. 5, or 3 vs. 6); (iv) lower-
ing the temperature from 298 to 258 K poorly influenced
the enantioselectivity, with a small favourable effect. Thus,
the optimal reaction conditions were found at 298 K in the
presence of triethylamine, which allowed the attainment of
Scheme 2. Synthesis of elpanphos ligands.
This involves the ready attainment of the known key in- the product in only 5 min with a 95–96% ee for both li-
termediate 3,4,6-tri-O-acetyl-1,2-β-glucodiamine 3[7] start- gands (Entries 1 and 7). This also demonstrates that the
ing from inexpensive glucosamine hydrochloride. Its con- presence of diverse phase-tags has no effect on the stereo-
densation with two equivalents of diphenylphosphanylben- chemistry of the reaction.
zoic acid (DPPBA) affords elpanphos-a, which is highly sol-
The stereochemical outcome of the reaction can clearly
uble in common organic solvents, such as dichloromethane, be explained on the basis of the mechanism proposed by
THF and methanol. Treatment of the ligand with meth- Trost for this reaction.[9a,10] In our case, his cartoon models
anolic ammonia completely deprotects the acetyl groups, can be translated as shown in Scheme 3, where, of the sugar
and the corresponding polar form of the ligand (elpanphos- moiety, only the chair has been reported for the sake of
aЈ) could be obtained. This latter molecule is soluble in clarity.
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Chiral Bis(phosphanylamides) Based on β-1,2-d-Glucodiamine
the ligand, which is likely more sensitive at position 1. After
the second recycle, the catalytic solution was left aside, and
24 h later, fresh substrate was added to the resting catalyst.
Notably, the product was again obtained in quantitative
yield and with significant ee (55%).
A similar general behaviour was observed in bmimBF4,
where the values for the ee were between 90 and 77%.
Conclusions
This work substantiates the strategy aimed at preparing
effective ligands in a simple way from the chiral pool. Thus,
the elpanphos library was designed by starting from conve-
nient glucosamine hydrochloride, proving to be much more
viable compared to species otherwise accessible only from
the expensive l series.
Furthermore, the natural presence of polar phase-tags in
the multifunctional[15] sugar structure allows the per-
forming of the same asymmetric process in ionic liquids and
with unprecedented enantioselectivity.
Experimental Section
General Considerations: NMR spectra were recorded in CDCl3
(CHCl3, δ = 7.26 ppm, and 13CDCl3 δ = 77 ppm, as internal stan-
dards) with a 200 MHz (Varian Model Gemini) and a 400 MHz
(Bruker DRX-400). 31P NMR experiments were carried out by
using aqueous 85% phosphoric acid as external reference (δ =
0 ppm). Specific optical rotatory powers [α] were measured with
a Perkin–Elmer Polarimeter (model 141) at 298 K and 589 nm in
chloroform or in methanol (c = 1.0 g/100 mL). THF was distilled
from LiAlH4, dichloromethane from CaH2, diethyl ether from Na.
Scheme 3. Model for the enantioselectivity.
The rate-limiting step is the activation of one carbam-
mate in I to give a π-allyl intermediate (II or IIЈ). Activation
of the “left” carbammate function (step i) leads to the at-
tainment of II, which then results in –(R,S)-2, while acti-
vation of the “right” function (step ii) preludes the achieve-
ment of +(S,R)-2. Both reactions occur with simultaneous
rotation of the five-membered ring, which is clearly in-
hibited by steric contacts only in the case of the clockwise
rotation (i) that accompanies formation of II.
Finally, it also should be noted that, according to our
assumption, the presence of free hydroxy groups in el-
panphos-aЈ allowed the catalytic study in ionic liquids,[11,12]
where the original Trost ligand based on trans-cyclohexane-
diamine does not show appreciable solubility.
The reactions were performed by adding the substrate
and triethylamine to a solution of the catalyst at 298 K.
After 30 min, the organic product was extracted with di-
ethyl ether and analyzed. The catalyst phase was recycled
for further runs. In bmpyBF4, the first run quantitatively
afforded the chiral product in high ee (94%, Entry 8), which
is the highest value reported so far[2a,5a] for this reaction
under unconventional conditions. In subsequent recycles,
the conversion was still complete (Entries 9 and 10), while
the enantioselectivity only slightly decreased, as rarely ob-
served[13] in ionic solvents for AAA.[14] The observed re-
duction of enantioselectivity and the simultaneous persist-
Preparation of 3,4,6-Tri-O-acetyl-β-1,2-D-diamineglucose (3): This
compound was obtained by adapting a known procedure[7] in order
to avoid use of AgN3: a solution of 1-bromo-3,4,6-tri-O-acetyl-α-
d-glucosamine hydrobromide[7] (0.90 g, 2.0 mmol) in acetonitrile
(10 mL) was treated with TMSN3 (0.24 g, 2.0 mmol) and a 1.0 m
solution of TBAF (2 mL, 2.0 mmol) in THF. After stirring for 1 h,
the solvent was removed under vacuum, and the residue was dis-
solved in chloroform (10 mL). The resulting solution was shaken
with 2 m aqueous KOH (4 mL), and then washed with water
(4 mL). After drying the solution over sodium sulfate, the solvent
was evaporated under vacuum, and the residue filtered through a
column of silica gel (eluent: ethyl acetate) to afford 1-azido-3,4,6-
tri-O-acetyl-β-d-glucosamine (0.45 g, 68%). The compound was
dissolved in ethyl acetate (10 mL) in the presence of 10% Pd/C
(0.18 g) and treated with H2 (1 atm) for 1.5 h. After filtration, the
solvent was removed under vacuum to afford pure 3,4,6-tri-O-
acetyl-β-1,2-d-diamineglucose in quantitative yield.
Preparation of Elpanphos-a: A solution of 3,4,6-tri-O-acetyl-β-1,2-
d-diamineglucose (0.61 g, 2.0 mmol), diphenylphosphanylbenzoic
acid (1.2 g, 2.0 mmol), 4-dimethylaminopyridine (0.49 g, 4.0 mmol)
and 1,3-dicyclohexylcarbodiimide (0.82 g, 4.0 mmol) in dry dichlo-
romethane (10 mL) was stirred for 18 h at room temperature under
inert atmosphere to afford a suspension. The residue was removed
by filtration. The resulting solution was evaporated under vacuum,
and the residue was chromatographed on silica gel (2:1 ethyl acet-
ate:hexane) to afford the pure product as a white solid (1.2 g, 72%).
ence of activity may be due to a gradual anomerization of C50H46N2O9P2 (880.87): calcd. C 68.18, H 5.26, N 3.18; found C
Eur. J. Org. Chem. 2011, 5779–5782
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5781

V. Benessere, A. De Roma, R. Del Litto, M. Lega, F. Ruffo
SHORT COMMUNICATION
68.72, H 5.34, N 3.35. [α] = 3.5 (c 1.0, CHCl3). 1H NMR: δH
=
Acknowledgments
7.85 (m, 1 H), 7.58 (d, 3JNH-H1 = 9.0 Hz, 1 H, NH), 7.47 (m, 1 H),
3
7.36–6.97 (m, 26 H), 6.37 (d, JNH-H2 = 8.5 Hz, 1 H, NH), 5.29 (t,
The authors thank the CIMCF (Università di Napoli “Federico
II”) for NMR facilities.
3
3
3
3JH1-NH = JH1-H2, 1 H, 1-H), 5.18 (t, JH4-H3 = JH4-H5 = 9.5 Hz,
3
3
1 H, 4-H), 5.02 (t, JH2-H3 = JH3-H4, 1 H, 3-H), 4.47 (q, 1 H, 2-
H), 4.17 (dd, JH6-H5 = 4.11, JH6-H6Ј = 12.4 Hz, 1 H, 6-H), 3.94
3
2
[1] H. U. Blaser, E. Schmidt (Eds.), Asymmetric Catalysis on Indus-
trial Scale, Wiley-VCH, Weinheim, 2004.
3
(dd, JH6Ј-H5 = 1.86 Hz, 1 H, 6Ј-H), 3.63 (m, 1 H, 5-H), 1.99 (s, 3
H, AcO), 1.96 (s, 3 H, AcO), 1.93 (s, 3 H, AcO) ppm. 13C NMR: [2] a) V. Benessere, F. Ruffo, Tetrahedron: Asymmetry 2010, 21,
171; b) V. Benessere, M. Lega, F. Ruffo, A. Silipo, Tetrahedron
2011, 67, 4826.
δC = 172.3, 171.2, 170.8, 169.7, 168.8, 141–127 (aromatics), 80.8,
73.8, 73.3, 68.14, 62.2, 53.9, 21.4, 21.2, 21.0 ppm. 13P NMR: δ =
–8.0, –12.0 ppm.
[3] Other groups are also active within this field of research. For
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4283; b) M. Diéguez, O. Pàmies, A. Ruiz, Y. Diàz, S. Castillón,
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guez, O. Pàmies, Chem. Eur. J. 2008, 14, 944; h) V. Benessere,
A. De Roma, R. Del Litto, F. Ruffo, Coord. Chem. Rev. 2010,
254, 390; i) M. Diéguez, O. Pàmies, S. Woodward, Coord.
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[4] a) B. M. Trost, D. L. Van Vranken, C. Bingel, J. Am. Chem.
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2003, 299, 1691; c) Q. L. Zhou (Ed.), Privileged Chiral Ligands
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[5] a) V. Benessere, A. De Roma, F. Ruffo, ChemSusChem 2008, 1,
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Preparation of Elpanphos-aЈ: A solution of elpanphos-a (0.44 g,
0.50 mmol) in methanol (5 mL) was saturated with gaseous ammo-
nia. After a few hours, addition of diethyl ether (50 mL) caused
precipitation of the product as a white solid, which was filtered,
washed with diethyl ether and dried under vacuum (0.30 g, 80%).
C44H40N2O6P2 (754.76): calcd. C 70.02, H 5.34, N 3.71; found C
1
69.77, H 5.41, N 3.59. [α] = 10.5 (c 1.0, MeOH). H NMR: δH
=
=
3
7.85 (m, 1 H), 7.70 (m, 1 H), 7.5–6.9 (m, 26 H), 5.09 (d, JH1-H2
3
9.7 Hz, 1 H, 1-H), 4.05 (t, JH3-H2 = 9.9 Hz, 1 H, 2-H), 3.87 (d,
2Jgem = 12.5 Hz, 1 H, 6-H), 3.71 (dd, JH6Ј-H5 = 4.9 Hz, 1 H, 6Ј-
3
H), 3.65–3.30 (m, 3 H, 3-H, 4-H, 5-H) ppm. 13C NMR: δC = 174.6,
172.6, 145–130 (aromatics), 82.8, 81.0, 77.6, 73.2, 64.1, 58.0 ppm.
13P NMR: δP = –7.0, –10.5 ppm.
Desymmetrization of meso-2-Cyclopenten-1,4-diol-isocyanate in
THF
[6] The name elpanphos was constructed by reversing the letters
of the term naple.
[7] A. Bertho, A. Révész, Justus Liebigs Ann. Chem. 1953, 581, 11.
[8] B. Cornils, W. A. Herrmann, I. T. Horvarth, W. Leitner, S.
Mecking, H. Olivier-Borbigou, D. Vogt (Eds.), Multiphase
Homogeneous Catalysis, Wiley-VCH, Weinheim, 2005.
[9] a) B. M. Trost, D. L. Van Vranken, Angew. Chem. Int. Ed. Engl.
1992, 31, 228; b) B. M. Trost, D. L. Van Vranken, J. Am. Chem.
Soc. 1993, 115, 444; c) B. M. Trost, B. Breit, Tetrahedron Lett.
1994, 35, 5817; d) B. M. Trost, B. Breit, S. Peukert, J. Zam-
brano, J. W. Ziller, Angew. Chem. Int. Ed. Engl. 1995, 34, 2386;
e) B. M. Trost, D. E. Patterson, J. Org. Chem. 1998, 63, 1339;
f) S. Lee, C. W. Lim, C. E. Song, K. M. Kim, C. H. Jun, J. Org.
Chem. 1999, 64, 4445; g) C. W. Lim, S. Lee, Tetrahedron 2000,
56, 5135; h) B. M. Trost, J. L. Zambrano, W. Ritcher, Synlett
2001, 907; i) N. Buschmann, A. Rueckert, S. Blechert, J. Org.
Chem. 2002, 67, 4325; j) C. E. Song, J. W. Yang, E. J. Roh, S. G.
Lee, J. H. Ahn, H. Han, Angew. Chem. Int. Ed. 2002, 41, 3852;
k) B. M. Trost, Z. Pan, J. Zambrano, G. Kujat, Angew. Chem.
Int. Ed. 2002, 41, 4691; l) A. Agarkov, E. W. Uffman, S. R.
Gibeltson, Org. Lett. 2003, 5, 2091; m) D. Zhao, Z. Wang, K.
Ding, Synlett 2005, 2067.
Without NEt3: meso-2-cyclopenten-1,4-diol-isocyanate (0.10 g,
0.20 mmol), [Pd2(dba)3]·CHCl3 (0.005 g, 0.005 mmol) and the li-
gand (0.015 mmol) were dissolved in dry THF (1 mL). The mixture
was stirred at the desired temperature, and, after the required reac-
tion time, the solvent was removed under vacuum. Column
chromatography on silica gel (1:2 ethyl acetate/hexane) gave the
desired product as a white solid in 80–85% yield.
With NEt3: meso-2-cyclopenten-1,4-diol-isocyanate (0.10 g,
0.20 mmol), [Pd2(dba)3]·CHCl3 (0.005 g, 0.005 mmol) and the li-
gand (0.015 mmol) were dissolved in dry THF (1 mL) containing
triethylamine (0.030 g, 0.30 mmol). The mixture was stirred at the
desired temperature, and, after the required reaction time, the sol-
vent was removed under vacuum. Column chromatography on sil-
ica gel (1:2 ethyl acetate/hexane) gave the desired product as a white
solid in 80–85% yield.
In
RTIL:
meso-2-cyclopenten-1,4-diol-isocyanate
(0.050 g,
0.10 mmol), [Pd2(dba)3]·CHCl3 (0.005 g, 0.005 mmol) and el-
panphos-aЈ (0.012 g, 0.015 mmol) were vigorously stirred in RTIL
(1 mL) under an inert atmosphere. After 30 min, the product was
extracted with dry diethyl ether (3ϫ15 mL) in 70–80% yield and
analyzed. Recycling was carried out by adding fresh substrate and
triethylamine to the active catalytic solution.
[10] B. M. Trost, M. Machacek, A. Aponick, Acc. Chem. Res. 2006,
39, 747.
[11] J. P. Hallett, T. Welton, Chem. Rev. 2011, 111, 3508.
[12] Two convenient ionic liquids were used: 1-butyl-3-methylimida-
zolium tetrafluoroborate (bmimBF4) and 1-butyl-4-methylpyr-
idinium tetrafluoroborate (bmpyBF4).
[13] See, for example: M. R. Castillo, S. Castillón, C. Claver, J. M.
Fraile, A. Gual, M. Martín, J. A. Mayoral, E. Sola, Tetrahedron
2011, 67, 5402.
The enantiomeric excesses were determined by chiral HPLC, Chira-
cel OD-H, 1:10 2-propanol/hexane, UV 254 nm, retention times:
–(R,S)-2: 22–24 min; +(S,R)-2: 30–32 min. The absolute configura-
tion was obtained by comparison with a sample of known chirality.
[14] AAA is the acronym for asymmetric allylic alkylation, a palla-
dium-catalyzed substitution reaction of a nucleophile with a
substrate containing a leaving group in an allylic position.
[15] R. H. Crabtree, New J. Chem. 2011, 35, 18.
Supporting Information (see footnote on the first page of this arti-
Received: July 1, 2011
cle): Relevant proton and carbon NMR spectra are presented.
Published Online: August 25, 2011
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Eur. J. Org. Chem. 2011, 5779–5782