Unprecedented asymmetric induction through configurationally stable lithium N-(α-methylbenzyl)phosphinamides. A new entry to enantiomerically pure γ-aminophosphinic acids and esters

Article abstract of DOI:10.1039/b510685k

The first examples of configurationally stable N-benzyl-N-phosphinoyl carbanions are described. Their applications to the synthesis of homochiral γ-aminophosphinic acids and esters via highly enantioselective dearomatising reactions are shown. The Royal S

Full text of DOI:10.1039/b510685k

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Unprecedented asymmetric induction through configurationally stable
lithium N-(a-methylbenzyl)phosphinamides. A new entry to
enantiomerically pure c-aminophosphinic acids and esters{{
Ignacio Ferna´ndez,a Gloria Ruiz Go´mez,a Ignacio Alfonso,b Mar´ıa J. Iglesiasa and Fernando Lo´pez Ortiz*a
Received (in Cambridge, UK) 27th July 2005, Accepted 9th September 2005
First published as an Advance Article on the web 30th September 2005
DOI: 10.1039/b510685k
The first examples of configurationally stable N-benzyl-
N-phosphinoyl carbanions are described. Their applications
to the synthesis of homochiral c-aminophosphinic acids and
esters via highly enantioselective dearomatising reactions are
shown.
Scheme 1 Dearomatising cyclisation of N-benzylphosphinamides 1.
Reagents: (i) t-BuLi, Et2O, 290 uC; (ii) THF, DMPU (6 equiv.),
Chiral, nonracemic, configurationally stable organolithium species
290 uC, then E+; (iii), H3O+.
are valuable reagents in asymmetric synthesis owing to their ability
to form carbon–carbon bonds, often with a high degree of
c-amino phosphinic acid and ester derivatives. The later being
enantioselectivity. Many dipole-stabilised N-benzyl and N-allyl
carbanions showing these characteristics are known.1 Generally,
interesting building blocks for c-peptide chemistry.
Racemic-, (S)-, and (R)-phosphinamides 5 were readily prepared
the stabilisation is provided by a carbonyl group linked to the
nitrogen atom.2 The phosphoramide group is also very efficient in
in high yield by reaction of the corresponding a-methylbenzyl-
amine with Ph2P(O)Cl in toluene in the presence of triethylamine,
promoting the metalation at a N-benzylic position and the
synthetic utility of these anions has been extensively studied.3
followed by deprotonation of the resulting phosphinamide with
NaH in THF and methylation with MeI.
However, the applications of chiral anions of N-benzylphosphoric
Under optimised reaction conditions the lithiation of (S)-5 with
triamides have been limited to the alkylation and stannylation
t-BuLi in THF at 290 uC in the presence of 6 equivalents of
HMPA and subsequent anionic cyclisation was complete in about
of derivatives containing rac-trans-1,2-cyclohexanediamine as a
chiral auxiliary.4
1 min. The instantaneous trapping reaction of the dearomatised
We have previously reported that the lithiation of N-benzyl-
N-methyldiphenylphosphinamide (1a, R1 5 Me) in Et2O solution
species with benzaldehyde furnished a mixture of two azaphos-
pholes 6a and 7a (ratio 90:10) epimers in the hydroxylic carbon in
gives rise to a mixture of monomeric and dimeric benzylic
anions 2.5 In THF as solvent, these anions evolve through a
a yield of 93% (Scheme 2, see Table S1 in ESI). Increasing the
dearomatising cyclisation reaction6 leading after electrophilic
quenching time to 1 min produced the almost quantitative
quench to tetrahydrobenzoazaphospholes 3.7 These heterocycles
conversion of (S)-5 with a slight decrease in the diastereomeric
ratio (Table 1, entry 7).
were smoothly transformed into c-amino phosphinic acids 4 and
esters,8 a class of compounds showing promising antitumor
The reactions with furfural and isobutyraldehyde as electro-
philes proceed in the same manner, although with slightly lower
activity and potential scaffolds for the synthesis of c-phosphapep-
yields and diastereoselectivities (Table 1, entries 8, 9). In the
tides (Scheme 1). Support for the feasibility of asymmetric
induction in this process is provided by the work of Clayden
and co-workers on the analogous anionic dearomatisation of
N-(a-methylbenzyl)benzamides.9
In this paper we describe the application of the dearomatising
anionic cyclisation–alkylation sequence to chiral phosphinamides
5. The process affords homochiral tetrahydrobenzoazaphospholes
in which the P–N linkage could be easily solvolysed to give
a
´
Area de Qu´ımica Orga´nica, Universidad de Almer´ıa, Carretera de
Sacramento, 04120, Almer´ıa, Spain. E-mail: flortiz@ual.es
bDepartamento de Qu´ımica Inorga´nica y Orga´nica, Universidad Jaume
I, Castello´n, Spain
{ Dedicated to Professor Joaqu´ın Plumet on the occasion of his 60th
birthday.
{ Electronic supplementary information (ESI) available: optimisation
study of the dearomatising cyclisation reaction, synthetic procedures, and
NMR characterisation of 6a–c, 10, 11, and 12. HPLC chromatograms of
rac-6b, 8 ,9, and 6b, 8, 9. 2D gNOESY spectra and selected rows of 10, 11.
Scheme 2 Dearomatising cyclisation of (S)-5. Reagents: (i) t-BuLi, THF,
HMPA (6 equiv.), 290 uC, 1 min; (ii) E+ 5 R1CHO (R1 5 Ph, Furyl, iPr),
2,6-di-tert-butyl-4-methylphenol, BnBr, 1 min; (iii) MeOH–H2O.
1
1H, H{31P} NMR spectra of 12 and 13. See DOI: 10.1039/b510685k
5408 | Chem. Commun., 2005, 5408–5410
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center. It implies that the open chain benzylic carbanion is
configurationally stable on the timescale of the cyclisation and
very efficiently transmits the chiral information to four new
stereogenic centers, two of them notably apart from the origin of
chirality. It is also remarkable the fact that the asymmetric
induction process involves the exclusive attack to one of the two
diastereotopic P-phenyl rings.
Table 1 Distribution of products in the dearomatising anionic
cyclisation–alkylation of chiral N-a-methylbenzylphosphinamidesa
Yield
Product (%)b 6 : 7c
ee
Entry Reagent E+
(%)d
1
2
3
4
5
6
7
8
9
rac-5
rac-5
rac-5
rac-5
Rac-5
rac-5
(S)-5
(S)-5
(S)-5
(R)-5
(S)-5
(R)-5
(S)-5
(R)-5
PhCHO
PhCHO
C4H3OCHO
(CH3)2CHCHO rac-6c/7c 78
ArOH
BrCH2Ph
PhCHO
C4H3OCHO
rac-6a/7a 98
rac-6a/7a 6e
rac-6b/7b 91
88 : 12
81 : 19
69 : 31
The dearomatisation–alkylation sequence of phosphinamides 5
was extended to include 2,6-di-tert-butyl-4-methylphenol and
benzylbromide as electrophiles. The protonation with the hindered
phenol proceeded in good yield to give azaphospholes 8 (Table 1,
entries 5, 11, 12). The alkylation with BnBr required some
optimisation. High yields of rac-9 and enantiopure compounds 9
and ent-9 were obtained when DMPU was used as cosolvent and
the times for metalation and quenching were increased to 12 h
and 30 min, respectively (Table 1, entries 6, 13, 14). In both cases a
minor diastereoisomeric (,8%) epimer in the phosphorus atom
was also formed. Column chromatography allowed the isolation
of the major pure compounds. NOE measurements of the new
products showed that the stereochemical course of the process was
the same observed for azaphospholes 6.
rac-8
rac-9
6a/7a
6b/7b
77
84e,f
98
88 : 12 .99
81 : 19 .99
68 : 32
89 : 11 .99
.99
.99
91
78
(CH3)2CHCHO 6c/7c
95
10
11
12
13
14
a
PhCHO
ArOH
ArOH
BrCH2Ph
BrCH2Ph
ent-6a/7a 97
8
74
ent-8
9
ent-9
73
84e,f
80e,f
.99
.99
All reactions were carried on a 20 mM scale using 1 min. of
lithiation and 1 min. with E+. Crude yield. Ratio of (S) : (R)
epimers in the exocyclic methine. Separated by column chromato-
b
c
d
graphy except 6b, which precipitated from ether. Ee determined by
e
chiral HPLC. For further details see ESI. DMPU was used as
cosolvent. 12 h of lithiation and 30 min reacting with the E+. A
minor diastereoisomer (,8%) epimer in the phosphorus atom was
also isolated.
f
We have previously shown that tetrahydrobenzoazaphospholes
can be converted quantitatively into c-aminophosphinic acids and
esters by solvolysis of the P–N bond.8 Such compounds and their
derivatives are important bioactive targets as inhibitors analogues
of 4-aminobutyric acid (GABA) and glutamic acid.10 However,
only few syntheses, and generally non stereoselective, of this type
of compounds have been described.11
reaction with isobutyraldehyde small amounts (,4%) of a
compound epimer of 6c in the phosphorus atom were also
formed. As expected, the analogous reactions of phosphinamides
(R)-5 and rac-5 provided ent-6–7 and racemic 6–7, respectively
(Table 1). Surprisingly, the reaction practically failed when DMPU
was used as cosolvent under otherwise the same reaction
conditions (Table 1, entry 2).
Treating 6b with HCl in dry methanol produced the stereo-
specific formation of the aminophosphinic ester 12 in almost
quantitative yield. Attack of methanol to the phosphorus center of
the phosphinamide linkage is assumed to proceed with inversion of
the configuration as described in the literature (Scheme 3).8a,12 The
corresponding acid 13 was obtained by performing the hydrolysis
of 6b with diluted hydrochloric acid in acetone.
All the tetrahydrobenzoazaphospholes 6–7 were conveniently
isolated by column chromatography except 6b, which precipitated
from Et2O. The enantiomer ratios of 6–7 were determined using
chiral HPLC. In all cases very high enantiomeric excesses were
found (Table 1).
In summary, the sequential dearomatisation–alkylation reported
here is a highly diastereo- and enantioselective and high yield
procedure, which allows the synthesis of enantiomerically pure
functionalized [1,4]-cyclohexadiene derivatives, and constitutes the
first example of a configurationally stable tertiary lithiated benzylic
carbanion dipolarly stabilised by a phophinamide group. This
carbanion undergoes cascade reactions which proceed with a large
degree of both retention and transmission of the chiral informa-
tion, even to remote centers of the system. Furthermore, simply
solvolysis of the dearomatised products gives access to the
preparation of enantiomerically pure c-N-methylamino phosphinic
acids and esters in high yields, which represents an easy entry to
phosphorus-containing c-peptide mimetics. This chemistry and
their applications as antitumour agents is under exploration.
All new compounds were fully characterised based on their 1D
and 2D NMR data. Attack of the electrophile at the c position to
the phosphorus is evidenced by the large deshielding and couplings
to the phosphorus observed for the CHLCP(O)N moiety in the
3
1H and 13C NMR spectra (dH y 6.6 ppm, JPH y 17 Hz, dCy
133 ppm, 1JPC y 120 Hz).§ Additionally, the magnitude of the 31
P
chemical shifts of heterocycles 6–7 about 30 ppm is typical of
c-alkylated tetrahydrobenzoazaphospholes.8 The absolute con-
figuration was deduced by the analysis of the 2D NOESY spectra
of the esters 10 and 11 derived from the reaction of 6b and ent-6b
with the (R)-Mosher reagent, respectively (Fig. 1). The NOEs
observed indicate that the lithiation–cyclisation sequence went with
complete retention of the configuration of the original chiral
Scheme 3 Stereospecific synthesis of an enantiomerically pure
c
Fig. 1 Selected NOEs observed for (1RP,3S,4R,7R,10S,15R)-10 and
(1SP,3R,4S,7S,10R,15R)-11.
aminophosphinic acid and ester. Reagents: for (1RP,3S,4R,7R,10S)-12 (i)
2N HCl, acetone; for (3S,4R,7R,10S)-13 (ii) 0.6 N HCl, dry methanol.
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3 (a) P. Savignac and Y. Leroux, J. Organomet. Chem., 1973, 57, C47; (b)
P. Savignac and M. Dreux, Tetrahedron Lett., 1976, 17, 2025; (c)
D. Seebach and M. Yoshifuji, Helv. Chim. Acta, 1981, 64, 643; (d)
C. Grison, A. Thomas, F. Coutrot and P. Coutrot, Tetrahedron, 2003,
59, 2101.
Financial support by the Ministerio de Educacio´n y Ciencia
(Project CTQ2004-21931-E) is gratefully acknowledged. I.F.
thanks Junta de Andaluc´ıa for a doctoral fellowship. I.A. is
thankful to MEC for a Ramo´n y Cajal research contract.
4 (a) J. F. K. Mu¨ller, B. Spingler and M. Zehnder, Synlett, 1997, 1059; (b)
B. Spingler, J. F. K. Mu¨ller, M. Neuburger and M. Zehnder,
J. Organomet. Chem., 1998, 570, 293; (c) J. F. K. Mu¨ller, M. Zehnder,
F. Barbosa and B. Spingler, Helv. Chim. Acta, 1999, 82, 1486.
5 I. Ferna´ndez and F. Lo´pez-Ortiz, Chem. Commun., 2004, 1142.
6 I. Ferna´ndez, J. Gonza´lez and F. Lo´pez-Ortiz, J. Am. Chem. Soc., 2004,
126, 12551.
Notes and references
§ NMR data of 6a (25 uC, CDCl3): 1H NMR (300.13 MHz): d 1.41 (s,
3
3
5
H-11), 2.27 (d, 3H, JPH 9.2 Hz, H-12), 2.98 (ddddd, 1H, JPH 2.2, JHH
11.4 3JHH 4.0, 3JHH 3.9, 4JHH 1.8 Hz, H-7), 3.40 (ddd, 1H, 5JHH 11.4, 4JHH
3
3
4.4, JHH 2.2 Hz, H-4), 3.84 (bs, OH, H-13), 4.98 (d, 1H, JHH 3.9 Hz,
H-10), 5.49 (ddt, 1H, 4JPH 4.4, 3JHH 10.4, 3JHH 2.2 Hz, H-5), 5.75 (m, 1H,
3JHH 10.4, 4JHH 4.0, 3JHH 2.2 Hz, H-6), 6.79 (ddd, 1H, 3JPH 17.2, 3JHH 4.0,
4JHH 1.8 Hz, H-8), 7.63-7.22 (m, 8H, ArH), 7.92 (m, 2H, H-15). 13C NMR
7 I. Ferna´ndez, A. Force´n-Acebal, F. Lo´pez-Ortiz and S. Garc´ıa-Granda,
J. Org. Chem., 2003, 68, 4472.
8 (a) I. Ferna´ndez, F. Lo´pez-Ortiz, B. Tejerina and S. Garc´ıa-Granda,
Org. Lett., 2001, 3, 1339; (b) I. Ferna´ndez, F. Lo´pez-Ortiz, A. Mene´ndez-
Vela´zquez and S. Garc´ıa-Granda, J. Org. Chem., 2002, 67, 3852.
9 (a) J. Clayden, F. E. Knowles and C. J. Menet, Tetrahedron Lett., 2003,
44, 3397; (b) J. Clayden, F. E. Knowles and C. J. Menet, Synlett, 2003,
1701; (c) J. Clayden, F. E. Knowles and C. J. Menet, J. Am. Chem. Soc.,
2003, 125, 9278.
10 (a) J. Hiratake and J. Oda, Biosci., Biotechnol., Biochem., 1997, 61, 211;
(b) M. Chebib and G. A. R. Johnston, J. Med. Chem., 2000, 43, 1427;
(c) Aminophosphonic and Aminophosphinic Acids. Chemistry and Bio-
logical Activity, ed. V. P. Kukhar and H. R. Hudson, John Wiley,
New York, 2000.
11 (a) S. C. Fields, Tetrahedron, 1999, 55, 12237; (b) J. Kehler, B. Ebert,
O. Dahl and P. Krogsgaard-Larsen, Tetrahedron, 1999, 55, 771.
12 (a) D. A. Tyssee, L. P. Bausher and P. Haake, J. Am. Chem. Soc.,
1973, 95, 8066; (b) M. J. P. Harger, J. Chem. Soc., Chem. Commun.,
1976, 520; (c) M. J. P. Harger, J. Chem. Soc., Perkin Trans. 1, 1979,
1294.
2
3
(75.47 MHz): d 18.35 (C-11), 25.26 (d, JPC 3.0 Hz, C-12), 44.75 (d, JPC
12.0 Hz, C-7), 52.46 (d, JPC 13.8 Hz, C-4), 66.84 (d, JPC 10.2 Hz, C-3),
2
2
3
75.70 (C-10), 123.41 (d, JPC 6.6 Hz, C-5), 126.51 (d, JPC 1.8 Hz, C-6),
4
4
2
128.61–126.48 (12CAr), 131.71 (d, JPC 3.0 Hz, C-17), 131.83 (d, JPC
10.2 Hz, C-15), 132.88 (d, 1JPC 134.6 Hz, C-14), 134.49 (d, 1JPC 120.1 Hz,
2
3
C-9), 137.53 (d, JPC 9.6 Hz, C-8), 141.65 (C-18), 142.83 (d, JPC 8.4 Hz,
C-22). 31P NMR (121.50 MHz): d 29.12. MS (APCI): m/z 442 (M + 1,
100%).
1 A. Basu and S. Thayumanavan, Angew. Chem., Int. Ed., 2002, 41, 716.
2 (a) D. Hoppe and T. Hense, Angew. Chem., Int. Ed. Engl., 1997, 36,
2283; (b) K. M. Bertini-Gross and P. Beak, J. Am. Chem. Soc., 2001,
123, 315; (c) T. A. Johnson, D. O. Jang, B. W. Slafer, M. D. Curtis and
P. Beak, J. Am. Chem. Soc., 2002, 124, 11689; (d) N. J. Ashweek,
P. Brandt, I. Coldham, S. Dufour, R. E. Gawley, F. Haeffner, R. Klein
and G. Sanchez-Jimenez, J. Am. Chem. Soc., 2005, 127, 449.
5410 | Chem. Commun., 2005, 5408–5410
This journal is ß The Royal Society of Chemistry 2005