Phosphinamide-directed benzylic lithiation. application to the synthesis of peptide building blocks

Article abstract of DOI:10.1021/ol7028096

N-Benzyldiphenylphosphinamides are deprotonated at the NC_α position diastereospecifically upon treatment with f-BuLi in diethyl ether at low temperature. The reaction of the anions with alkyl, acyl, and tin halides, aliphatic and aromatic aldehydes, and Michael acceptors allowed installation of a variety of functional groups into the benzylic arm in excellent yields. Cleavage of the P-N linkage affords 1,2-amino alcohols and α-, β-, and γ-amino acids.

Full text of DOI:10.1021/ol7028096

ORGANIC
LETTERS
2008
Vol. 10, No. 4
537-540
Phosphinamide-Directed Benzylic
Lithiation. Application to the Synthesis
of Peptide Building Blocks
Pascual On˜a Burgos,† Ignacio Ferna´ndez,† Mar´ıa Jose´ Iglesias,†
Santiago Garc´ıa-Granda,‡ and Fernando Lo´pez Ortiz*,†
AÄ rea de Qu´ımica Orga´nica, UniVersidad de Almer´ıa, Carretera de Sacramento s/n,
04120 Almer´ıa, Spain, and Departamento de Qu´ımica F´ısica y Anal´ıtica, UniVersidad
de OViedo, C/Julia´n ClaVer´ıa 8, 33006 OViedo, Spain
flortiz@ual.es
Received November 20, 2007
ABSTRACT
N-Benzyldiphenylphosphinamides are deprotonated at the NC position diastereospecifically upon treatment with t-BuLi in diethyl ether at low
r
temperature. The reaction of the anions with alkyl, acyl, and tin halides, aliphatic and aromatic aldehydes, and Michael acceptors allowed
installation of a variety of functional groups into the benzylic arm in excellent yields. Cleavage of the P−N linkage affords 1,2-amino alcohols
and -, -, and -amino acids.
r
â
γ
Dipole-stabilized carbanions adjacent to the nitrogen atom
of amides and carbamates have been studied in great detail
due to the utility of these synthons in organic synthesis.1
For instance, they have been used for the stereoselective
synthesis of N/C-protected R-, â-, and γ-amino acids.2 In
contrast, R-aminoalkyl organolithiums stabilized by phos-
phorus-based functional groups have received much less
attention. Savignac et al. described the first N-benzylic
deprotonation assisted by a PdO group on N-benzylphos-
phoramides and subsequent electrophilic trapping.3 Although
some additional examples have been reported,4 the scope of
this synthetic methodology remains largely unexplored.
Further, the attempted NCR lithiation of N-benzyl-N-meth-
yldiphenylthiophosphinamide with s-BuLi or t-BuLi led after
electrophilic quench to products of ortho attack exclusively.5
We have shown that N-benzyldiphenylphosphinamides can
be deprotonated in THF at either the benzylic6 or ortho7
position (Scheme 1) with excellent regiocontrol. The NCR
(3) (a) Savignac, P.; Leroux, Y. J. Organomet. Chem. 1973, 57, C47.
(b) Savignac, P.; Dreux, M.; Leroux, Y. Tetrahedron Lett. 1974, 15, 2651.
(c) Savignac, P.; Leroux, Y.; Normant, H. Tetrahedron 1975, 31, 877. (d)
Savignac, P.; Dreux, M. Tetrahedron Lett. 1976, 17, 2025.
(4) Phosphoramides: (a) Seebach, D.; Yoshifuji, M. HelV. Chim. Acta
1981, 64, 643. (b) Seebach, D.; Lohmann, J. J.; Syfrig, M. A.; Yoshifuji,
M. Tetrahedron 1983, 39, 1963. (c) Mu¨ller, J. F. K.; Zehnder, M.; Barbosa,
F.; Spingler, B. HelV. Chim. Acta 1999, 82, 1486 and references cited
therein. (d) Hammerschmidt, F.; Hanbauer, M. J. Org. Chem. 2000, 65,
6121. Phosphonamides: (e) Afarinkia, K.; Jones, C. L.; Yu, H.-W. Synlett
2003, 509. R. Synlett 2004, 1300. (f) Lo´pez, B.; Maestro, A.; Pedrosa, R.
Synthesis 2006, 817 and references cited therein.
† Universidad de Almer´ıa.
‡ Universidad de Oviedo.
(1) Reviews: (a) Basu, A.; Thayumanavan, S. Angew. Chem., Int. Ed.
2002, 41, 716. (b) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P.
Angew. Chem., Int. Ed. 2004, 43, 2206. (c) Chinchilla, R.; Na´jera, C.; Yus,
M. Tetrahedron 2005, 61, 3139. (d) Wu, G.; Huang, M. Chem. ReV. 2006,
106, 2596.
(2) (a) Park, Y. S.; Beak, P. J. Org. Chem. 1997, 62, 1574. (b) Barberis,
C.; Voyer, N.; Roby, J.; Che´nard, S.; Tremblay, M.; Labrie, P. Tetrahedron
2001, 57, 2965. (c) Bragg, R. A.; Clayden, J.; Menet, C. J. Tetrahedron
Lett. 2002, 43, 1955.
(5) Yoshifuji, M.; Ishizuka, T.; Choi, Y, J.; Inamoto, N. Tetrahedron
Lett. 1984, 25, 553.
10.1021/ol7028096 CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/19/2008

Scheme 1
anions undergo dearomatization through anionic cyclization
quantitatively.8 The benzylic anions proved to be stable in
diethyl ether and were characterized through NMR.9
These results indicate that the deprotonation of N-
benzylphosphinamides can be tuned by selecting the ap-
propriate reaction conditions. Here we wish to report on the
regio- and stereocontrolled NCR lithiation of N-benzyldiphe-
nylphosphinamides and their reactivity toward a broad
selection of electrophiles. Dephosphorylation of the new
functionalized phosphinamides provides access to important
building blocks for organic synthesis such as 1,2-amino
alcohols and R-, â-, and γ-amino acids.
Figure 1. Structural diversity achieved for N-Pop derivatives.
all cases the major compound corresponded to the u
configuration. The diastereoselectivity is sterically controlled
since the ratio of epimers increases notably when the alkyl
group attached to the nitrogen is the more sterically demand-
ing benzyl group. The formation of a single stereosiomer
6b in the reaction of lithiated 1b with pivalaldehyde supports
this conclusion (entry 5, Table 1).
Acroleine undergoes [1,2] addition exclusively furnishing
7, whereas methyl vinyl ketone and methyl acrylate react in
a [1,4] manner with total chemoselectivity leading to 8 and
9, respectively (entries 7 and 8).
Phosphinamides 1 are smoothly deprotonated by the action
of t-BuLi in Et2O at -90 °C to give the NCR lithiated species
1Li. Electrophilic quench of the anions affords products
2-12 in good to excellent yields (Table 1). Wide structural
The conjugate addition to methyl acrylate represents a
facile entry to N- and C-protected γ4-amino acids (Figure
1).10 The R and â10 homologues 10 and 11 also can be
prepared in good yields by the respective addition of methyl
chloroformiate and methyl bromoacetate to 1Li (entries 9
and 10, Table 1).11 In addition, tin may be readily installed
at the benzylic position by treating 1Li with Me3SnCl (entry
11, Table 1). The stannanes 12a,b thus obtained are
interesting reagents for transmetalation and/or cross coupling
reactions.12 The structure of 2-12 was assigned based on
their spectroscopic data (see the Supporting Information).
The relative configuration of 4-7 is supported by the
magnitude of 3JXY (X ) 31P, 1H; Y ) 13C, 1H) for the amino
alcohol moiety. Compounds 4 were identified previously as
byproducts in the dearoamatizing anionic cyclization of 1a
and the same structural motif is present in two ortho-
substituted derivatives of u-4 characterized through X-ray
diffraction.8b Additionally, the X-ray crystal structure of
Table 1. NCR Lithiation of 1 and Electrophilic Quench of 1Li
1a,
1b,
entry
E
product yield [%]a,b yield [%]a,b
1
2
Me
Bn
2
3
71
82
63
60
3
4
5
6
7
8
9
10
11
PhCHOH
4
5
6
7
8
9
10
11
12
96 (3:1)
95 (2.6:1)
83 (1.8:1)
90 (5:1)
70
78
72
63
70
89 (8:1)
97 (3.8:1)
76 (>99)
98 (6.5:1)
68
84
76
25
86
Ph(CH2)2CHOH
t-BuCHOH
CH2dCHCHOH
CH2CH2COMe
CH2CH2CO2Me
CO2CH3
(8) (a) Ferna´ndez, I.; Lo´pez Ortiz, F.; Mene´ndez Vela´zquez, A.; Garc´ıa
Granda, S. J. Org. Chem. 2002, 67, 3852. (b) Ferna´ndez, I.; Force´n-Acebal,
A.; Lo´pez-Ortiz, F.; Garc´ıa-Granda, S. J. Org. Chem. 2003, 68, 4472. (c)
Mora´n-Ramallal, A.; Lo´pez-Ortiz, F.; Gonza´lez, J. Org. Lett. 2004, 6, 2141.
(d) Lo´pez-Ortiz, F.; Iglesias, M. J.; Ferna´ndez, I.; Andu´jar-Sha´nchez, C. M.;
Ruiz-Go´mez, G. Chem. ReV. 2007, 107, 611. (e) Ruiz-Go´mez, G.; Iglesias,
M. J.; Serrano-Ruiz, M.; Garc´ıa-Granda, S.; Francesch, A.; Lo´pez-Ortiz,
F.; Cuevas, C. J. Org. Chem. 2007, 72, 3790.
CH2CO2CH3
SnMe3
a Isolated yields. b The diastereomeric ratio u:l is shown in parentheses.
(9) Ferna´ndez, I.; Lo´pez-Ortiz, F. Chem. Commun. 2004, 1142.
(10) â- and γ-amino acids are important building blocks for peptide
mimetic chemistry. (a) Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem.
BiodiVersity 2004, 1, 1111. (b) Chatterjee, S.; Roy, R. S.; Balaram, P. J. R.
Soc. Interface 2007, 4, 587.
(11) N-Phosphoryl amino acids are considered to play an important role
for biomolecular origins. Cheng, C. M.; Liu, X. H.; Li, Y. M.; Ma, Y.;
Tan, B.; Wan, R.; Zhao, Y. F. Origins Life EVol. Biosphere 2004, 34, 455.
(12) Directed metalation combined with transition metal catalyzed cross
coupling reactions is a valuable synthetic strategy: (a) Macklin, T. K.;
Snieckus, V. Org. Lett. 2005, 7, 2519. (b) MacNeil, S. L.; Wilson, B. J.;
Snieckus, V. Org. Lett. 2006, 8, 1133.
diversity is achieved through reaction with alkyl halides,
aliphatic and aromatic aldehydes, acyl halides, and Michael
acceptors (Figure 1). The reaction with aldehydes takes place
with moderate to excellent face selectivity (entries 3-6). In
(6) (a) Ferna´ndez, I.; Lo´pez-Ortiz, F.; Tejerina, B.; Garc´ıa-Granda, S.
Org. Lett. 2001, 3, 1339. (b) Ferna´ndez, I.; Gonza´lez, J.; Lo´pez-Ortiz, F. J.
Am. Chem. Soc. 2004, 126, 12551.
(7) Ferna´ndez, I.; On˜a-Burgos, P.; Ruiz-Go´mez, G.; Bled, C.; Garc´ıa-
Granda, S.; Lo´pez-Ortiz, F. Synlett 2007, 611.
538
Org. Lett., Vol. 10, No. 4, 2008

amino alcohol 6b (Supporting Information) confirmed the
assignments of relative configuration made.
configuration of 14-17. Slow evaporation at room temper-
ature of a saturated solution of 15 in ethyl acetate provided
X-ray quality crystals. The X-ray structure of 15 confirms
the assignment made (Supporting Information). The absolute
configuration of γ-amino ester 19 has been established
through correlation with the corresponding amino acid (see
bellow). We assume that the reaction yielding 18 follows
the same stereochemical sense.2b,15
The origin of the stereoselectivity in the deprotonation-
electrophilic quench sequence could be unraveled by syn-
thesizing 15 through an indirect route involving lithium-
tin exchange steps. The reaction of the benzylic anion of
(S)-1c with Me3SnCl (Scheme 2) furnished a 1:1 mixture of
Once the synthesis of R-functionalized phosphinamides
2-12 was available, we envisaged to enhance the scope of
the process by introducing asymmetry. For that purpose we
employed the (S)-R-methylbenzylphosphinamide, (S)-1c,
which contains a readily accessible chiral auxiliary. We have
previously shown that the lithiation of the N-methyl analogue
of (S)-1c by t-BuLi in THF occurs selectively at the chiral
carbon.13 The benzylic anion formed undergoes anionic
cyclization to give enantiomerically pure dearomatized
products (Scheme 1, route a). To our delight, treatment of
(S)-1c with t-BuLi in Et2O at -90 °C followed by quenching
with the electrophiles shown in Table 2 provides enantio-
Scheme 2. Diastereospecific Lithiation of Phosphinamide
(S)-1c
Table 2. Reactions of Lithiated (S)-1c with Electrophilesa
the two possible diasteroisomeric stannanes 20 and 21. After
chromatographic separation, successive treatment of com-
pound 20 with s-BuLi and pivalaldehyde gave (1R,2S,3S)-
15 as a single stereoisomer (Scheme 2).
entry electrophile (E+)
product
yield [%]a ratio u:l
1
2
3
4
5
6
7
MeI
PhCHO
t-BuCHO
Ph(CH2)2CHO
CH2dCHCHO
ClCO2Me
(1R,2S)-13
71
The formation of epimers 20 and 21 may be explained
through two conflicting pathways: stannilation of a con-
figurationally unstable carbanion or a benzylic anion con-
figurationally stable which undergo addition to Me3SnCl both
with inversion and retention of configuration. The stereospe-
cific transformation of (S)-1c into 15 via 20 supports the
second assertion.13 Moreover, assuming that tin-lithium
exchange proceeds with retention of configuration,15 these
results also reveal that both the deprotonation and electro-
philic quench proceed diastereospecifically, the pro-R proton
is exclusively removed, and the reactions with carbon-
centered electrophiles shown in Table 2 take place with
retention of configuration.16 The diastereospecificity of the
lithiation-alkylation of (S)-1c is a distinguishing feature with
respect to the carboxamide analogues.2c
(1R,2S,3S)-14b
(1R,2S,3S)-15b
(1R,2S,3S)-16b
(1R,2S,3S)-17b
(2S,3S)-18
76 (88)
95 (96)
81 (97)
78 (89)
60
91:9c
>99c
88:12c
92:8c
CH2dCH2CO2Me (4R,5S)-19
74
a Isolated yields, numbers in parentheses indicate conversion. b Absolute
configuration of the major compound 14a-17a isolated. c Diastereomeric
ratio calculated from 31P NMR data.
merically pure compounds 13-19, substituted exclusively
at the secondary NCR-center. Product ratios and isolated
yields are given in Table 2.
Alkylation with MeI affords the meso phosphinamide
(1R,2S)-13 (Table 2, entry 1).14 The benzylic anion attacks
the CO group of aliphatic and aromatic aldehydes with high
preference for the re face (entries 2-5). In the case of
pivalaldehyde, the reaction proceeds diastereospecifically to
give (1R,2S,3S)-15 (entry 3). The use of methyl chloroformi-
ate and methyl acrylate leads to the respective N-phosphoryl
R- and γ-amino esters (2S,3S)-18 and (4R,5S)-19 (entries 6
and 7).
The products of benzylic alkylation and acylation of
phosphinamides 1 shown so far can be viewed as function-
alized amino compounds protected at the nitrogen by a Pop
group.17 Although a number of methods may be used for
cleavage of the P-N linkage of tertiary phosphinamides,18
the efficiency of the deprotection depends on the structure
(15) Acylation of NCR-lithiated N-benzylarylcarboxamides and carbam-
ates proceeds in a similar manner. Faibish, N. C.; Park, Y. S.; Lee, S.;
Beak, P. J. Am. Chem. Soc. 1997, 119, 11561. See also ref 2c.
(16) N-Boc anilino benzylic anions react with Me3SnCl with inversion,
while tin-lithium exchange occurs with retention of configuration. Park,
Y. S.; Boys, M. L.; Beak, P. J. Am. Chem. Soc. 1996, 118, 3757. See also
ref 15.
3
Similar to the achiral series, the magnitude of JXY (X )
1
1
31P, H; Y ) 13C, H) allowed for establishing the absolute
(13) Ferna´ndez, I.; Ruiz-Go´mez, G.; Alfonso, I.; Iglesias, M. J.; Lo´pez-
Ortiz, F. Chem. Commun. 2005, 5408.
(14) Structure confirmed through alternative synthesis via phosphorylation
of the appropriate amine.
(17) We suggest the use of Pop as an abbreviation for P(O)Ph2 by
similarity with Boc stabilized benzyllithium anions.
Org. Lett., Vol. 10, No. 4, 2008
539

Scheme 3. Synthesis of 1,2-Amino Alcohols and R-, â-, and γ-Amino Acids through Ephosphinylation of NCR-Functionalized
Phosphinamidesa
a The enantiomeric purity of 25 and 27 was >99, determined by chiral HPLC.
of the substrate. After some experimentation we found that
the Ph2PO group of 2b, 10a, 11a, and (4R,5S)-19 can be
successfully removed with concentrated HCl in THF at room
temperature (Scheme 3, route A). Neutralization with diluted
NaOH furnishes the respective secondary amine 22, and
amino acids 23 (R), 24 (â), and 25 (γ). Under these reaction
conditions the phosphorus-containing byproduct formed is
recovered as Ph2P(O)Cl, which can be recycled for the
synthesis of the starting phosphinamide. Surprisingly, de-
phosphorylation of (4R,5S)-19 affords unprotected (R)-26
directly.19 Very few stereoselective syntheses of the N/C-
protected biologically relevant10 γ4-amino acid 26 are
available.2a,20 Moreover, attemps to generate the free amino
acid led to the formation of the corresponding γ-lactone.21
The two-step route that converts (S)-1c into (R)-26 exempli-
fies nicely the synthetic utility of the methodology described
here.
N-Deprotection of 6b and 15 to give 1,2-amino alcohols
27 and 28, respectively, is best achieved by LiAlH4 in THF
at low temperature (Scheme 3, route B). Interestingly, the
treatment of 6b with n-BuLi in THF at -78 °C and
subsequent warming to -10 °C promoted the quantitative
nitrogen-to-oxygen rearrangement of the Ph2P(O) group to
give 29 (Scheme 3, route C).22 This lithiation procedure
offers the possibility of accessing enantiomerically pure 1,2-
amino alcohols selectively protected at the O or N, which
are important synthons in organic chemistry.
In summary, we have shown that diphenylphosphinamides
are very convenient starting materials for the synthesis of
functionalized amines via amino-substituted benzyllithiums.
Compared with carboxamides the Pop group provides
excellent control of the absolute configuration along the
deprotonation-substitution pathway. Lithiation of chiral
phosphinamides leads to configurationally stable N-benzylic
carbanions diastereospecifically, which react with a series
of electrophiles to give NCR-functionalized phosphorus-based
compounds diastereospecifically in high yields. Excellent
[1,2] vs [1,4] additions have been observed for Michael
acceptors. The Pop group can be efficiently removed under
a variety of reaction conditions. The potential of N-Pop based
chemistry has been demonstrated by the synthesis of 1,2-
amino alcohols and R-, â-, or γ-amino acids. Additional work
on enantioselective deprotonations directed by the Pop group
is in progress.
Acknowledgment. This research was supported by the
Ministerio de Educacio´n y Ciencia (MEC) (projects CTQ2005-
1792BQU and 05093BQU to S.G.G.). I.F. thanks the Ramo´n
y Cajal program for financial support.
(18) (a) Koizumi, T.; Haake, P. J. Am. Chem. Soc. 1973, 95, 8073. (b)
Zwierzak, A.; Podstawczyn˜ska, I. Angew. Chem., Int. Ed. Engl. 1977, 16,
702. (c) Zidani, A.; Carrie´, R.; Vaultier, M. Bull Soc. Chim. Fr. 1992, 129,
71. (d) Ramsden, J. A.; Brown, J. M. Tetrahedron: Asymmetry 1994, 5,
2033. (e) Kingsley, S.; Vij, A.; Chandrasekhar, V. Inorg. Chem. 2001, 40,
6057. (f) Denmark, S. E.; Dorow, R. L. Chirality 2002, 14, 241. (g) Wyatt,
P.; Eley, H.; Charmant, J.; Daniel, B. J.; Kantacha, A. Eur. J. Org. Chem.
2003, 4216. (h) Hartung, C. G.; Fecher, A.; Chapell, B.; Snieckus, V. Org.
Lett. 2003, 5, 1899.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds and
tables of crystallographic data for 6b and 15. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL7028096
(19) Absolute configuration assigned by comparison of optical rotation
of (R)-26‚HCl with published data. Morlacchi, F.; Losaco, V.; Tortorella,
V. Gazz. Chim. Ital. 1975, 105, 349.
(20) Ramachandran, P. V.; Biswas, D. Org. Lett. 2007, 9, 3025.
(21) (a) Ramachandran, P. V.; Burghardt, T. E. Chem. Eur J. 2005, 11,
4387. (b) Cheemala, M. N.; Knochel, P. Org. Lett. 2007, 9, 3089.
(22) For N to O migration of phosphoramidates see: (a) Plapinger, R.
E.; Wagner-Jauregg, T. J. Am. Chem. Soc. 1953, 75, 5757. (b) Xue, C.-B.;
Yin, Y.-W.; Zhao, Y.-F. Tetrahedron Lett. 1988, 29, 1145. (c) Ora, M.;
Mattila, K.; Lo¨nnberg, T.; Oivanen, M.; Lo¨nnberg, H. J. Am. Chem. Soc.
2002, 124, 14364.
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Org. Lett., Vol. 10, No. 4, 2008