Double dearomatization of bis(diphenviphosphinamides) through anionic cyclization. A facile route of accessing multifunctional systems with antitumor properties

Article abstract of DOI:10.1021/jo070276q

(Chemical Equation Presented) The sequential one-pot double dearomatization of bis(N-benzyl-P,P-diphenylphosphinamides) via anionic cyclization is described for the first time. Protonation and alkylation of the dearomatized dianions provide bis(tetrahydro

Full text of DOI:10.1021/jo070276q

Double Dearomatization of Bis(diphenylphosphinamides) through
Anionic Cyclization. A Facile Route of Accessing Multifunctional
Systems with Antitumor Properties
Gloria Ruiz-Go´mez,† Mar´ıa Jose´ Iglesias,† Manuel Serrano-Ruiz,‡ Santiago Garc´ıa-Granda,§
Andre´s Francesch,| Fernando Lo´pez-Ortiz,*,† and Carmen Cuevas|
AÄ rea de Qu´ımica Orga´nica, UniVersidad de Almer´ıa, Carretera de Sacramento, 04120 Almer´ıa, Spain,
AÄ rea de Qu´ımica Inorga´nica, UniVersidad de Almer´ıa, Carretera de Sacramento, 04120 Almer´ıa, Spain,
Departamento de Qu´ımica F´ısica y Anal´ıtica, UniVersidad de OViedo, AVda. Julia´n ClaVer´ıa 8,
33006 OViedo, Spain, and PharmaMar S.A. AV. de los Reyes, 1, P.I. La Mina,
28770 Colmenar Viejo, Madrid, Spain
flortiz@ual.es
ReceiVed February 8, 2007
The sequential one-pot double dearomatization of bis(N-benzyl-P,P-diphenylphosphinamides) via anionic
cyclization is described for the first time. Protonation and alkylation of the dearomatized dianions provide
bis(tetrahydro-2,1-benzazaphospholes) in good yield and with very high regio- and stereocontrol. Acid-
catalyzed methanolysis of the bisheterocycles affords bis(methyl γ-aminophosphinates) stereospecifically.
The doubly phosphorylated systems proved to be active against a series of cancer cell lines.
Introduction
pounds containing the P(O)OH fragment, γ-aminophosphinic
acids and their derivatives represent an important subclass of
therapeutic agents.4 They are phosphorus analogues of γ-ami-
nobutyric acid, GABA, the major inhibitory neurotransmitter
in the mammalian central nervous system. This structural
The tetrahedral phosphinic acid moiety plays a central role
in the biological activity of a wide range of natural products
and synthetic compounds.1 The properties of this structural motif
as a pharmacophore arise mainly from the capability of
mimicking the transition state of enzymatic amide formation
or hydrolysis2 and of interacting with the metal present in the
active site of some metalloenzymes.1e,3 It has been shown that
acyclic and cyclic phosphinamides bearing a hydroxamic acid
functional group are potent antitumor agents acting as inhibitors
of matrix metalloproteinases.3a,d Among the family of com-
(3) (a) Pikul, S.; Dunham, K. L. M.; Almstead, N. G.; De, B.; Natchus,
M. G.; Anastasio, M. V.; McPhail, S. J.; Snider, C. E.; Taiwo, Y. O.; Chen,
L.; Dunaway, C. M.; Gu, F.; Mieling, G. E. J. Med. Chem. 1999, 42, 87.
(b) Dive, V.; Cotton, J.; Yiotakis, A.; Michaud, A.; Vassiliou, S.; Jiracek,
J.; Vazeux, G.; Sechauvet, M.-T.; Cuniasse, P.; Corvol, P. Proc. Natl. Acad.
Sci. U.S.A. 1999, 96, 4330. (c) Grembecka, J.; Mucha, A.; Cierpicki, T.;
Kafarski, P. J. Med. Chem. 2003, 46, 2641. (d) Sørensen, M. D.; Blæhr, L.
K. A.; Christensen, M. K.; Høyer, T.; Latini, S.; Hjarnaa, P.-J. V.; Bjo¨rkling,
F. Bioorg. Med. Chem. 2003, 11, 5461. (e) Mallari, J. P.; Choy, C. J.; Hu,
Y.; Mart´ınez, A. R.; Hosaka, M.; Toriyabe, Y.; Maung, J.; Blecha, J. E.;
Pavkovic, S. F.; Berkman, C. E. Bioorg. Med. Chem. 2004, 12, 6011. (f)
Dive, V.; Georgiadis, D.; Matziari, M.; Makaritis, A.; Beau, F.; Cuniasse,
P.; Yiotakis, A. Cell. Mol. Life Sci. 2004, 61, 2010. (g) Engel, C. K.; Pirard,
B.; Schimanski, S.; Kirsch, R.; Habermann, J.; Klinger, O.; Schlotte, V.;
Weithmann, K. U.; Wendt, K. U. Chem. Biol. 2005, 12, 181. (h) Bianchini,
G.; Aschi, M.; Cavicchio, G.; Crucianelli, M.; Preziuso, S.; Gallina, C.;
Nastari, A.; Gavuzzod, E.; Mazza, F. Bioorg. Med. Chem. 2005, 13, 4740.
(i) Devel, L.; Rogakos, V.; David, A.; Makaritis, A.; Beau, F.; Cuniasse,
P.; Yiotakis, A.; Dive, V. J. Biol. Chem. 2006, 281, 11152.
* Corresponding author. Telephone: +34 950 015478. Fax: +34 950 015481.
† AÄ rea de Qu´ımica Orga´nica, Universidad de Almer´ıa.
‡ AÄ rea de Qu´ımica Inorga´nica, Universidad de Almer´ıa.
§ Universidad de Oviedo.
| PharmaMar S.A.
(1) (a) Murdoch, D.; McTavish, D. Drugs 1992, 43, 123. (b) Zeiss, H.-
J. Pestic. Sci. 1994, 41, 269. (c) Seto, H.; Kuzuyama, T. Nat. Prod. Rep.
1999, 16, 589. (d) McGuire, J. J.; Haile, W. H.; Valiaeva, N.; Bartley, D.;
Guo, J.; Coward, J. K. Biochem. Pharmacol. 2003, 65, 315. (e) Yiotakis,
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10.1021/jo070276q CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/18/2007
3790
J. Org. Chem. 2007, 72, 3790-3799

Double Dearomatization of Bis(diphenylphosphinamides)
CHART 1
SCHEME 1. Anionic Cyclization-Electrophilic Trapping of
Diphenylphosphinamides
similarity led to the identification of TPMPA (Chart 1) as the
most potent GABAC receptor antagonist known to date.5 The
γ-aminophosphinic acid substructure is also present in phos-
phinothricin, a phosphoglutamic acid analogue in which the
CO2H group distal to the amino moiety has been replaced by a
P(O)(OH)CH3 fragment. Phosphinothricin is a component of
the natural tripeptide bialaphos and is being currently used as
a nonselective herbicide.6 Some phosphinothricin analogues have
been found to be inhibitors of glutamine synthase7 and showed
herbicidal activity as well.8 The pseudopeptide 1 is a key
component of a potent inhibitor of human folylpoly-γ-glutamate
synthetase, FPGS.9
triazenes14 and tosylaziridines15 were also dearomatized via
anionic cyclization after treatment with an organolithium base.
We have previously reported that the lithiation of diphe-
s
nylphosphinamides 2 with an excess of BuLi in THF at
-90 °C in the presence of HMPA or DMPU leads to the
formation of N-CR anions16 that undergo anionic cyclization
by attack at the ortho position of a P-phenyl ring. Electrophilic
trapping of the dearomatized species afforded tetrahydro-2,1-
benzazaphospholes 3 and 4 and 2,1-benzazaphosphepine 5 with
high regio- and stereocontrol (Scheme 1).16b,17 These hetero-
cycles may be converted into γ-aminophosphinic acids and
esters (e.g., 6) through acid solvolysis of the phosphinamide
linkage.10,17a,18
We have shown that γ-aminophosphinic acid and esters are
accessible via a methodology based on nucleophilic dearoma-
tizing reactions (NDAr) of tertiary diphenylphosphinamides.10
NDAr reactions followed by electrophilic trapping allow for
exploitation of the latent functionalization represented by the
conjugated π system of benzenoid rings to prepare more
elaborate molecules.11 In the case of dearomatizing anionic
cyclization (DAC) processes, the loss of aromaticity is con-
comitant with the formation of a carbo- or heterocyclic ring.
The first examples of DAC reactions were reported 40 years
ago.12 However, the utility of this strategy for constructing
complex molecules has been demonstrated only recently.
Clayden et al. showed that DAC reactions of lithiated tertiary
benzamides provide the key intermediates for the synthesis of
a series of natural products and non-natural derivatives.13 Phenyl
In these transformations, the N-R1 substituent generally acts
as a passive spectator. Only the bulkiest group exerted some
influence on the reaction course due to steric effects.18 Prelimi-
nary antitumor assays on some of the dearomatized compounds
synthesized showed promising growth cell inhibition parameters.
We thought that the utility of this methodology could be further
extended by connecting two N-benzyldiphenylphosphinamide
moieties through a methylene chain and performing the double
dearomatization on the resulting bisphosphinamides via the one-
pot sequential anionic cyclization-electrophilic quench. The bis-
(azaphosphaheterocyclic) system thus formed may exhibit
enhanced biological activity as compared to the mono-
heterocycles.18a The results of this study together with the
evaluation of the cytotoxicity of some selected products are
presented in this paper.
(5) (a) Chebib, M.; Mewett, K. N.; Johnston, G. A. R. Eur. J. Pharmacol.
1998, 357, 227. (b) Chebib, M.; Johnston, G. A. R. J. Med. Chem. 2000,
43, 1427.
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Koenig, W. A.; Zaehner, J. HelV. Chim. Acta 1972, 55, 224.
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Bioorg. Chem. 1990, 18, 154. (b) Logusch, E. W.; Walker, D. M.;
McDonald, J. F.; Franz, J. E.; Villafranca, J. J.; Dilanni, C. L.; Colanduoni,
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Physiol. 1991, 95, 1057.
Results and Discussion
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6757.
(10) Ferna´ndez, I.; Lo´pez-Ortiz, F.; Tejerina, B.; Garc´ıa-Granda, S. Org.
Lett. 2001, 3, 1339.
The required bisphosphinamides 8a-c have been prepared
in high yield by treating the corresponding N,N′-dibenzylamine
7 with chlorodiphenylphosphine (2.1 equiv) in toluene in the
(11) (a) Pape, A. R.; Kaliappan, K. P.; Ku¨ndig, E. P. Chem. ReV. 2000,
100, 2917. (b) Smith, P. L.; Chordia, M. D.; Harman, W. D. Tetrahedron
2001, 57, 8203. (c) Mealy, M. J.; Bailey, W. F. J. Organomet. Chem. 2002,
646, 59. (d) Keane, J. M.; Harman, W. D. Organometallics 2005, 24, 1786.
(12) (a) Drozd, V. N. Dokl. Akad. Nauk SSSR 1966, 169, 107; Chem.
Abstr. 1966, 65, 73314. (b) Drozd, V. N. Int. J. Sulfur Chem. 1973, 8, 443.
(c) Kaupp, G.; Gru¨ter, H.-W.; Teufel, E. Chem. Ber. 1982, 115, 3208. (d)
Truce, W. E.; Madaj, E. J., Jr. Sulfur Rep. 1983, 3, 259. (e) Dashan, L.;
Trippett, S. Tetrahedron Lett. 1983, 24, 2039. (f) Crandall, J. K.; Ayers, T.
A. J. Org. Chem. 1992, 57, 2993. (g) Padwa, A.; Filipkowski, M. A.; Kline,
D. N.; Murphree, S.; Yeske, P. E. J. Org. Chem. 1993, 58, 2061.
(13) For reviews, see: (a) Clayden, J. Organolithiums: SelectiVity for
Synthesis; Pergamon: Amsterdam, 2002. (b) Clayden, J.; Kenworthy, M.
N. Synthesis 2004, 1721. (c) Clayden, J.; Read, B.; Hebditch, K. R.
Tetrahedron 2005, 61, 5713. For some recent work, see also: (d) Clayden,
J.; Knowles, F. E.; Menet, C. J. J. Am. Chem. Soc. 2003, 125, 9278. (e)
Clayden, J.; Knowles, F. E.; Baldwin, I. R. J. Am. Chem. Soc. 2005, 127,
2412.
(14) (a) Nishiwaki, K.; Ogawa, T.; Matsuo, K. Angew. Chem., Int. Ed.
2002, 41, 484. (b) Nishiwaki, K.; Ogawa, T.; Tagami, K.-I.; Tanabe, G.;
Muraoka, O.; Matsuoa, K. Tetrahedron 2006, 62, 10854.
(15) (a) Breternitz, H. J.; Schaumann, E.; Adiwidjaja, G. Tetrahedron
Lett. 1991, 32, 1299. (b) Aggarwal, V. K.; Ferrara, M. Org. Lett. 2000, 2,
4107. (c) Aggarwal, V. K.; Alonso, E.; Ferrara, M.; Spey, S. E. J. Org.
Chem. 2002, 67, 2335. (d) Luisi, R.; Capriati, V.; Florio, S.; Ranaldo, R.
Tetrahedron Lett. 2003, 44, 2677.
(16) (a) Ferna´ndez, I.; Gonza´lez, J.; Lo´pez-Ortiz, F. J. Am. Chem. Soc.
2004, 126, 12551. (b) Ramallal, A.; Ferna´ndez, I.; Lo´pez-Ortiz, F.; Gonza´lez,
J. Chem.-Eur. J. 2005, 11, 3022.
(17) (a) Ferna´ndez, I.; Ruiz-Go´mez, G.; Iglesias, M. J.; Lo´pez-Ortiz, F.;
AÄ lvarez-Manzaneda, R. ArkiVoc 2005, 375. (b) Ferna´ndez, I.; Ruiz-Go´mez,
G.; Alfonso, I.; Iglesias, M. J.; Lo´pez-Ortiz, F. Chem. Commun. 2005, 5408.
(18) (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.
J. Org. Chem, Vol. 72, No. 10, 2007 3791

Ruiz-Go´mez et al.
SCHEME 2. Synthesis of Bisphosphinamides 8
SCHEME 3. Synthesis of Bis(tetrahydro-2,1-benzazaphospholes) 11 and 12a
s
s
a Reaction conditions: (a) (i) BuLi (5 equiv), THF, -90 °C, HMPA (10 equiv), t1 (min); (ii) ROH (8 equiv), -90 °C, 30 min; (b) (i) BuLi (5 equiv),
THF, -90 °C, HMPA (10 equiv), t1 (min); (ii) TBDMSCl (5 equiv), -90 °C, 30 min; (iii) MeOH, -90 °C, 30 min.
presence of triethylamine (5 equiv) at -80 °C for 30 min,19
followed by in situ oxidation with m-CPBA (Scheme 2). N,N′-
Dibenzylethylenediamine 7a is commercially available. Di-
amines 7b,c were synthesized according to the methods
described in the literature as shown in Scheme 2.20
methanol or 2,6-di(tert-butyl)-4-methylphenol (DTBMP) and
stirring the reaction mixture for 30 min (Scheme 3). By analogy
with the reactions of monophosphinamides,18a it was expected
that the use of MeOH would favor the formation of heterocycles
containing a [1,3]-cyclohexadiene system with a cis fusion (i.e.,
compounds 11), whereas [1,4]-cyclohexadiene derivatives would
be the major products of the trapping reaction with the bulky
phenol (compounds 12). The metalation time was optimized
for each substrate and protonating agent, and the results are
shown in Table 1. As a rule, longer times were needed for
achieving the metalation of 8c. Gratifyingly, the double DAC-
MeOH reaction afforded the bis(tetrahydro-2,1-benzazaphosp-
holes) 11 in good yields as a mixture of meso:rac stereoisomers.
Small amounts (18-24%) of doubly dearomatized products
protonated at the γ position with respect to the phosphorus (i.e.,
compounds 12 as mixtures of meso:rac stereoisomers), as well
as monodearomatized products protonated at the R (13, 6%)
and γ (14, 6-28%) positions, were also formed. Compounds
13a and 14a (n ) 1) were synthesized in high yield (g85%)
and with excellent regio- and stereoselectivities by treatment
of 8a with sBuLi (1.2 equiv) at -90 °C in THF in the absence
of HMPA for 30 min and subsequent addition of an excess of
MeOH or DTBMP at the same temperature. For compounds
11, the diastereoselectivity increased in the series 11a < 11c <
The double anionic cyclization of bisphosphinamides 8 might
lead to a complex mixture of products: meso and chiral
(racemic) compounds in which the dearomatized heterocyclic
system may contain three or four stereogenic centers and the
carbon-carbon double bonds can be distributed in a variety of
positions. Using the DAC-protonation sequence of reactions of
phosphinamides 2 as reference,18 the dearomatization of 8a-c
was performed by lithiating the bisphosphinamides with 5 equiv
s
of BuLi at -90 °C in THF in the presence of an excess of
HMPA. The dearomatized species were neutralized by adding
(19) This is a slight variation of the method described for the synthesis
of N,N′-dibenzyl-N,N′-(diphenylphosphinyl)ethylenediamine. (a) Rodr´ıguez,
I.; Zubiri, M.; Milton, H. L.; Cole-Hamilton, D. J.; Slawin, A. M. Z.;
Woollins, J. D. Polyhedron 2004, 23, 693. (b) Zijp, E. J.; van der Vlugt, J.
I.; Spek, A. L.; Vogt, D. Dalton Trans. 2005, 512.
(20) Reaction conditions for preparation of diimines 8a,b: Blatt, H.
Organic Synthesis; John Wiley & Sons, Inc.: New York, 1943; Collective
Vol. I, pp 80-81. Reaction conditions for reduction of 8a,b: (a) Tietze, L.
F.; Eicher, Th. Reactions and Syntheses in the Organic Chemistry
Laboratory; University Science Books: Mill Valley, CA, 1989. (b) Khan,
M. S.; Gupa, M. Pharmazie 2002, 57, 377.
3792 J. Org. Chem., Vol. 72, No. 10, 2007

Double Dearomatization of Bis(diphenylphosphinamides)
TABLE 1. Optimized Reaction Conditions for the Synthesis of 2,1-Bisazaphospholes 11 and 12 and Distribution of Products
11
12
reaction
conditions
yield (%)
(meso:rac)
yield (%)
(meso:rac)
ratio
11:12
entry
t1 (min)
ROH
1
2
3
4
5
6
7
8
9
a
b
a
b
a
30
30
30
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
DTMBP
DTMBP
DTMBP
DTMBP
DTMBP
a, 59 (63:37)a,b
a, 75 (64:36)a
b, 58 (86:14)a
b, 65 (57:43)a
c, 54 (73:27)
c, 94 (100:0)
a, 19 (68:32)a
a, 14 (87:13)a
b, 18 (67:33)a
b, 5 (73:27)a
c, 24 (80:20)a
3.1:1
5.4:1
3.2:1
13:1
30
120
120
60
60
60
2.2:1
b
a
99:<1
<1:99
<1:99
<1:99
<1:99
<1:99
a, 75 (61:39)
a, 75 (70:30)
a, 97 (67:33)
b, 73 (67:33)
c, 83 (83:17)
ac
ad
a
10
11
60
120
a
a Concentration of the reaction 7-10 mM. b Also formed 4% of Ph2P(O)Bus. c Concentration of the reaction 1 mM. d Solvent anhydrous and deoxygenated.
11b (entries 1, 3, 5), while for derivatives 12 the ratio of meso:
rac stereoisomers is almost identical for 12a,b and increases
slightly for the bisazaphosphole with the longest methylene
chain, 12c (entries 7-11).
in the reaction of the Grignard reagent of 1,8-bis(chloromethyl)-
naphthalene with 9-trimethylsilylanthracene.23 However, to the
best of our knowledge, this is the first time that a double DAC
reaction has been described.
We have previously shown that quenching the dearomatized
anions formed in the DAC reactions of phosphinamides 2 with
methanol can be achieved in high yield and with total R
regioselectivity, provided that the anion is allowed to react with
tert-butyldimethylchlorosilane (TBDMSCl) prior to the addition
of the protonating agent.17a To our delight, the application of
this modified method to the dearomatization-methanol trapping
of bisphosphinamides 8 [Scheme 3, reaction conditions (b)]
resulted in a significant improvement of both the yield of 11
and the ratio 11:12 (cf., entries 1, 3, 5 with the corresponding
2, 4, 6). The preference for the protonation at the R position
increased with the increment of the methylene groups of the
linker (entries 2, 4, 6). In this sense, the reaction of 8c is singular
for it affords 11c exclusively and in almost quantitative yield.
This fact suggests that in the reaction mediated by TBDMSCl,
the system behaves as two isolated mono-phosphinamides when
the doubly dearomatized species are separated by four meth-
ylenic groups.
The DAC-protonation reaction with the bulky phenol was
remarkable. The process furnished bisazaphospholes 12 almost
exclusively. This means that starting on achiral substrates,
products containing six chiral centers are formed in good yield.
The heterocycles were obtained as mixtures of meso:rac isomers.
The diastereoselectivity increased steadily with increasing the
length of the methylene bridge.
Products formally involving double NDAr reactions have been
reported. The anions resulting either through borohydride
reduction or enolate addition to nitroarenes have been trapped
via Mannich reaction with formaldehyde and primary diamines
to give bis(3-azabicyclo[3.3.1]nonanes) linked through a me-
thylene bridge, generally in low yields.21 Genuine examples of
double NDAr reactions are the coupling of 9-anthracenediazo-
nium salts with the amine precursors22 and the bis-adduct formed
We next extended the potential of the double DAC reaction
of bisphosphinamides 8 by introducing a functionalization into
the dearomatized systems. Previous studies on N-alkyl-N-
benzyldiphenylphosphinamides 2 indicated that an arylhy-
droxymethyl fragment could be installed very efficiently at the
position γ to the phosphorus by trapping the dearomatized
anions formed in the anionic cyclization with aldehydes.17b,18b
Thus, we explored the reactivity of dilithiated bisphosphinamide
8c toward benzaldehyde. After some experimentation, we found
the optimized reaction conditions shown in Scheme 4. The
reaction affords quantitatively the expected γ-functionalized bis-
(tetrahydro-2,1-benzazaphospholes) 15 as a mixture of 15_meso
and 15_rac stereoisomers in a ratio 89:11, which in turn are
obtained as mixtures of epimers at the hydroxylic carbon (ratio
of 15a_meso:15b_meso of 85:15; ratio of 15a_rac:15b_rac of
64:36). Bisazaphosphole 15a_meso could be isolated through
flash-column chromatography (eluent AcOEt:MeOH 25:1). The
isomers 15b_meso, 15a_rac, and 15b_rac could not be separated
and were identified from a mixture of the compounds in a
relative ratio of 37:40:23. As observed for the analogous reaction
of phosphinamides 2, the major product obtained arose from
the addition of the prochiral electrophile with like topicity (see
below for structural assignment).
DAC reactions of diarylphosphinamides provide an entry to
conformationally restricted γ-aminophosphinic acids and esters
by solvolysis of the P-N bond of the azaphosphole ring.17,18,24
The bisheterocycles prepared here also successfully undergo this
solvolysis. For instance, the treatment of 12a_meso with a
diluted methanolic solution of HCl at room temperature for ca.
1 h produced quantitatively the methanolysis of the phosphi-
namide linkage affording the bis(methyl γ-aminophosphinate)
16 stereospecifically (Scheme 5). As in the monocyclic series,17a
inversion of the configuration at the phosphorus center is
assumed.25
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(23) Harvey, S.; Junk, P. C.; Raston, C. L.; Salem, G. J. Org. Chem.
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(24) Ruiz Go´mez, G.; Lo´pez Ortiz, F. Synlett 2002, 781.
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1294.
J. Org. Chem, Vol. 72, No. 10, 2007 3793

Ruiz-Go´mez et al.
SCHEME 4. Synthesis of Functionalized Bis(tetrahydro-2,1-benzazaphospholes) 15
the absence of 31P,1H coupling between the phosphorus nucleus
and the proton of the methine carbon bonded to the nitrogen
atom. Selected NOEs observed for compounds 11, 12, and 15a
are shown in Figure 1 (see also Supporting Information). The
NOE correlations detected for the PhCHOH moiety in the
diastereoisomers 15a_meso and 15b_meso indicate that
attack like of the dearomatized carbanion to the carbonyl group
leading to 15a_meso takes place preferentially, in agreement
with the analogous reaction of the corresponding mono-
phosphinamide 2.10
SCHEME 5. Synthesis of Bis(methyl γ-aminophosphinate)
16
The meso/rac pairs of stereoisomers could be unequivocally
identified for 11a, 12a, and 11c by means of X-ray diffraction
analysis. Single crystals of 11a_meso and 11c_meso were
obtained by slow evaporation of their dichloromethane-
chloroform solutions,27 whereas 12a_meso crystallized from a
dichloromethane solution. All crystal structures showed the
existence of an inversion center. The spacer connecting the
heterocycles adopts a staggered conformation in which the
bisbenzazaphosphole fragments are arranged antiperiplanar, thus
minimizing the steric interactions between the bulkiest groups
(see Supporting Information). The PdO bonds are oriented in
opposite directions, which contributes to minimize dipole
interactions.
In all other cases, the assignment of the meso/rac isomers
was realized through chiral HPLC.28 The chromatogram of rac
derivatives showed two well-separated peaks corresponding to
the two enantiomers present in the racemate. Under the same
experimental conditions, the chromatogram of the meso isomers
exhibited a single peak with a retention time clearly different
from that of the rac stereoisomers (Figure S22). The results of
the stereochemical analysis indicate that the meso compounds
were preferentially formed in all cases.
Structural Characterization. Pure compounds 11, 12, and
15a_meso could be readily isolated.26 The structural assignment
was based on the analysis of the APCI-MS, 1D (1H, 13C, 31P,
and DEPT), and 2D (gCOSY45, gHMQC, gHMBC, and
gNOESY) spectra. The [1,3]- and [1,4]-cyclohexadiene
systems can be easily distinguished on the basis of their NMR
data (e.g., the sp3/sp2-hybridized carbon R to the phosphorus,
see Supporting Information), the most characteristic being the
specific region of the 31P NMR spectrum in which each
regioisomer appears (Table 2, Figure S1). Products of proto-
nation at the R position, 11, appear at δ(31P) ≈ 48 ppm, whereas
compounds 12 and 15 are identified by δ(31P) values of about
28 ppm. The presence of the phenylhydroxymethyl fragment
in compounds 15a_meso is evidenced in the 13C{1H} spectrum
by a singlet signal at δ 74.31 ppm for the methine carbon. The
CH-OH group shows two signals in the 1H NMR spectrum at
δ 5.25 and 6.34 ppm for the methine and hydroxy protons,
respectively. The relative configuration of the benzazaphosphole
In Vitro Cytotoxicity Studies. Representative dearomatized
compounds were submitted to in vitro cytotoxicity assays to
evaluate their properties as possible antitumor agents. For
completeness, the bisphosphinamides 8a and 8c were included
in the bioactivity study as well. A preliminary screening was
carried out for the activity of bisphosphinamides 8a and 8c and
benzazaphospholes 11a-c_meso, 14a, and 15a_meso on HT29
(colon), LoVo-Dox (colon), and A549 (NSCL) cells at concen-
3
fragments was deduced from the magnitude of the J(nX1H)
1
(X ) H, 31P)18 and was confirmed through the respective
NOESY spectra (Supporting Information). Thus, the cis fusion
of the rings in compounds 11 is deduced from the large
magnitude of the vicinal coupling between the bridgehead
methine protons [3J(1H1H) > 10 Hz]. The syn arrangement of
the phenyl rings in the azaphosphole fragment is consistent with
(26) Compound 11a_meso was recrystallized from a mixture of di-
choloromethane-chloroform. The bisazaphospholes 12a_meso and 12c_me-
so precipitated from diethyl ether. All other compounds were purified
through column chromatography on silica gel or silica gel containing a 5%
of triethyl amine or neutral Al2O3 using mixtures of AcOEt:MeOH as eluent.
Heterocycles 12a-c_rac were obtained as mixtures of 12a-c_rac:12a-
c_meso in ratios of 70:30, 21:79, and 52:48, respectively.
(27) Although the analysis of the X-ray data of 11a_meso provided a
clear identification of the structure (Supporting Information), the poor quality
of the crystal did not allow a complete structural analysis.
(28) The stationary phase consisted of a Chiralcel OD-H column, and
eluent mixtures of hexane:isopropanol were used at a constant flux of 0.5
mL/min operating in isocratic mode.
3794 J. Org. Chem., Vol. 72, No. 10, 2007

Double Dearomatization of Bis(diphenylphosphinamides)
TABLE 2. 31P NMR Data (δ, ppm) of 2,1-Bisazaphospholes 11, 12, and 15a
δ(31P)
11a
11b
11c
12a
12b
12c
15a
15b
meso
rac
47.63
49.17
48.83
49.48
28.07
28.67
28.76
28.67
29.01
49.22b
49.30b
29.21c
28.45c
28.84c
28.92d
29.19d
a For comparison, the δ(31P) values of 3a (E ) H, R2 ) Me) and 4 are 30.81 and 52.01 ppm, respectively.17a b Chemical shift measured from the crude
reaction. c Chemical shift measured from a mixture of rac and meso structures.26 d The relative configuration of the carbon bearing the OH group could not
be unequivocally established.
FIGURE 1. Selected NOEs measured in the 2D NOESY spectra of (a) 11, (b) 12, and (c) 15a_meso.
TABLE 3. In Vitro GI50 (µM) Results for Phosphinamide 8c and a Series of Benzazaphosphole Compounds
prostate
LN-caP
ovary
breast
melanoma
SKMEL28
NSCL
A549
leukemia
K562
pancreas
PANC1
colon
LOVO
cervix
HELA
compound
IGROV
SK-BR3
HT29
LOVO-DOX
8c
1.53
1.89
6.56
3.98
1.16
2.71
3.39
7.97
0.37
1.29
>15.0
>11.4
0.43
2.00
2.52
>15.0
>11.4
1.53
2.54
3.04
>15.0
>11.4
2.45
3.92
4.43
9.58
5.90
2.23
3.10
3.73
13.8
11.4
2.56
2.90
3.96
>15.0
>11.4
3.39
2.75
3.07
>15.0
>11.4
2.83
0.82
1.92
15.0
3.10
2.92
>15.0
>11.4
3.14
11b_meso
11c_meso
15a_meso
14a
>11.4
>11.4
2.79
0.68
trations of 50, 15, and 5 µg/mL. Gratifyingly, good tumor
growth inhibition, less than 0% of viability for concentrations
of 50 and 15 µg/mL, was observed for 8c and bisbenzazaphos-
pholes 11b,c_meso, and 15a_meso (see Supporting Information).
By contrast, compounds 8a and 11a_meso proved to be inactive.
Interestingly, monodearomatized compound 14a showed also
a remarkable biological activity (see Supporting Information).
These results indicate that bis-benzazaphosphole derivatives, as
well as non-dearomatized bisphosphinamides, show relevant in
vitro cytotoxicity activity provided that the phosphinamide
moieties are separated by an aliphatic chain of three or four
carbon atoms. For mono-benzazaphosphole systems, remarkable
activity is observed even for phosphinamide moieties separated
by a methylene chain of two carbons.
A panel of 11 human tumor cell lines was subsequently used
to evaluate the cytotoxic potential of compounds 8c, 11b_meso,
11c_meso, 14a, and 15a_meso: prostate carcinoma tumor cells
(LN-caP), ovarian cells sensitive (IGROV), SK-BR3 breast
adenocarcinoma, MEL28 malignant melanoma, A-49 lung
carcinoma NSCL, K562 chronic myelogenous leukemia, PANC1
pancreatic epitheloid carcinoma, HT29 colon carcinoma cells,
LoVo lymph node metastasis cells and the corresponding LoVo-
Dox cells resistant to Doxorubicin, and cervix epitheloid
carcinoma (HeLa). A conventional colorimetric assay29 was set
up to estimate GI50 values, that is, the drug concentration that
causes 50% cell growth inhibition after 72 h continuous
exposure to the test molecules. The results are summarized in
Table 3.30
from the data collected in Table 3. The comparison between
11b_meso and 11c_meso indicates that antitumor efficacy
diminishes on increasing from three to four methylene groups
the chain length of the linker connecting the two dearomatized
moieties. For most cell lines, the installation of a polar group
at the γ-position with respect to the phosphorus, cf., 11c_meso
and 15a_meso, produces a slight improvement of the tumor
growth inhibition. Curiously, the doubly dearomatized com-
pounds proved to be less efficient than bisphosphinamide 8c
for inhibiting the tumor growth. Nevertheless, the best results
were obtained for 14a containing a mono-dearomatized fragment
linked to an intact diphenylphosphinamide moiety. Overall, the
in vitro data suggest that the dearomatization of a single Ph2P-
(O) unit of bisphosphinamides 8 is beneficial for the antitumor
activity and that the effect of the second phosphinamide group
may contribute to improve the hydrophobicity of the molecule.
The bioassays performed do not provide information about the
mode of action of the new phosphinamide derivatives. Phos-
phinamides bearing a hydroxamic acid substituent linked at the
nitrogenatomactaspotentmatrixmetalloproteinaseinhibitors.3a,d,31
On the basis of structural similarities of these inhibitors with
the compounds here described, one may expect that the later
most probably interact with the same targets.
In summary, we have demonstrated the feasibility of in situ
double anionic cyclization dearomatization-electrophilic trapping
reactions of bisdiphenylphosphinamides. The methodology
developed allows the conversion of easily available achiral
starting materials into multifunctional compounds containing
6-10 stereocenters in a single reaction step in moderate to good
yield and with very high regio- and stereocontrol. Antitumor
assays on some benzazaphospholes synthesized showed promis-
ing results that may be useful for further SAR work. The P-N
Although the number of compounds tested is small, some
trends in structure-activity relationships (SAR) can be deduced
(29) Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, J.;
Vistica, D.; Warren, J. T.; Bokesch, H.; Kenney, S.; Boyd, M. R. J. Natl.
Cancer Inst. 1990, 82, 1107.
(30) Ruiz Go´mez, G.; Ferna´ndez, I.; Lo´pez Ortiz, F. Patent to PharmaMar
S.A., P200601793. Es 2006.
(31) Chen, L.; Rydel, T. J.; Gu, F.; Dunaway, M.; Pikul, S.; Dunham,
K. M.; Barnett, B. L. J. Mol. Biol. 1999, 293, 545.
J. Org. Chem, Vol. 72, No. 10, 2007 3795

Ruiz-Go´mez et al.
CHART 2. Scheme Numbering Used for the NMR Assignments of (N-Benzyl-P,P-diphenylphosphinamides) 8a-c
669 (M + 1, 100). Anal. Calcd (%) for C42H42N2O2P2: C, 75.43;
linkage of the dearomatized bisheterocycles obtained can be
smoothly solvolyzed to give bis(γ-aminophosphinic esters). This
simple transformation makes it possible to conceive further
applications of bisbenzazaphospholes 11 and 12 as building
blocks for the construction of macromolecules containing
unusual functionalizations. This chemistry is being currently
explored.
H, 6.33; N, 4.19. Found: C, 75.42; H, 6.22; N, 4.36.
General Procedure for the Dearomatizing Anionic Cycliza-
tion of Bis(N-benzyl-P,P-diphenylphosphinamides) 8a-c. To a
solution of 8a-c (2.99 × 10-4 mol) and HMPA (0.52 mL,
2.99 × 10-3 mol) in THF (30 mL) was added a solution of
sBuLi (1.15 mL, of a 1.3 M solution in cyclohexane, 1.50 ×
10-3 mol) at -90 °C. After 30 min of metalation was added MeOH
(2 mL) or 2,6-di-tert-butyl-4-methylphenol (DTBMP) (532.4 mg,
2.39 × 10-3 mol). The reaction mixture was stirred at -90 °C for
30-120 min (see Table 1). Next, the reaction mixture was
poured into ice water and extracted with ethyl acetate (3 × 15 mL).
The organic layers were dried over Na2SO4 and concentrated in
Experimental Section
For general experimental details, see the Supporting Information.
General Procedure for the Preparation of Bis(N-benzyl-P,P-
diphenylphosphinamides) 8a-c. To a solution of the appropriate
N,N′-dibenzylalkylendiamine (8.6 mmol) and triethylamine (6.0 mL,
43.0 mmol) in toluene (120 mL) was added chlorodiphenylphos-
phine (3.24 mL, 18.06 mmol) at -80 °C. After 30 min of stirring,
the solvent was distilled. Next, a solution of m-CPBA (77%)
(3.85 g, 17.2 mmol) in CH2Cl2 (30 mL) was added at -40 °C.
Once oxidation was complete (30 min), the reaction was poured
into ice water and extracted with ethyl acetate (3 × 15 mL) and
washed with 1 N NaOH (2 × 15 mL) and water (1 × 15 mL). The
organic layers were dried over Na2SO4 and concentrated in vacuo.
Precipitation from AcOEt and Et2O afforded 8a and 8b,c, respec-
tively, as white solids with a purity higher than 97% (NMR)
(Chart 2).
1
1
vacuo. H, H{31P}, and 31P{1H} NMR spectra of the crude reac-
tion were measured to determine the regio- and stereoselectivity
of the process. The reaction mixture was then purified by recrys-
tallization from a mixture of dicholoromethane-chloroform, pre-
cipitation from diethyl ether, or by flash column chromatography
(silica gel, silica gel containing a 5% of triethyl amine, or neutral
alumina) using different mixtures of ethyl acetate:methanol as
eluent.
(1RP*,3R*,3aS*,7aS*)-2-{2-[(1SP*,3S*,3aR*,7aR*)-1,3-Diphe-
nyl-1-oxide-2,3,3a,7a-tetrahydro-1H-2,1-benzazaphosphol-2-yl]-
ethyl]}-1,3-diphenyl-2,3,3a,7a-tetrahydro-1H-2,1-benzazaphos-
phol 1-Oxide (11a_meso). Yield after recrystallization from
CH2Cl2/CHCl3 35% (67 mg) (Chart 3). Mp 230-1 °C. 1H NMR δ
2.58 (m, 2H, H-8), 2.81 (m, 2H, H-8′), 2.89 (m, 2H, H-3a),
3.06 (tt, 2H, 3JHH 11.4 Hz, 3JHH 3.0 Hz, 2JPH 11.4 Hz, H-7a), 4.12
(d, 2H, 3JHH 9.3 Hz, H-3), 5.29 (ddt, 2H, 3JHH 9.5 Hz, 3JHH 5.5 Hz,
N,N′-Ethane-1,2-diylbis[N-benzyl-P,P-diphenyl(phosphinic
amide)] (8a). Isolated yield 83% (4.57 g). Mp 171 °C. 1H NMR δ
3
3
3.10 (m, 4H, JPH 10.6 Hz, H-4), 3.83 (d, 4H, JPH 9.9 Hz, H-3),
4JHH 0.8 Hz, H-4), 5.85 (dddt, 2H, JHH 9.5 Hz, JHH 3.0 Hz, JHH
3
3
3
4
7.02 (m, 4H, ArH), 7.18-7.60 (m, 18H, ArH), 7.74 (m, 8H, JPH
12.1 Hz, H-6). 13C NMR δ 44.02 (C-4), 49.73 (d, JPC 3.7 Hz,
0.8 Hz, 3JPH 9.5 Hz, H-7), 5.92 (ddc, 2H, 3JHH 9.5 Hz, 3JHH 5.5 Hz,
2
2
5
4
C-3), 127.12 (C-12), 127.75 (C-10), 128.41 (d, JPC 6.0 Hz, C-6),
4JHH 0.8 Hz, JPH 0.8 Hz, H-5), 6.04 (m, 2H, JPH 2.4 Hz, H-6),
1
4
128.62 (C-11), 130.31 (d, JPC 128.6 Hz, C-5), 131.85 (d, JPC
1.8 Hz, C-8), 132.20 (d, 3JPC 9.6 Hz, C-7), 137.27 (d, 3JPC 4.0 Hz,
C-9). 31P NMR δ 31.00. MS (m/z) 641 (M + 1, 100). Anal. Calcd
(%) for C40H38N2O2P2: C, 74.99; H, 5.98; N, 4.37. Found: C, 75.08;
H, 6.03; N, 4.36.
7.09 (m, 4H, H-14), 7.31-7.55 (m, 12H, ArH), 7.62 (m, 4H, 3JPH
12.2 Hz, H-10). 13C{1H} NMR δ 37.49 (d, JPC 84.1 Hz, C-7a),
1
2
2
40.77 (d, JPC 2.4 Hz, C-8), 43.44 (C-3a), 68.35 (d, JPC 21.6 Hz,
C-3), 119.40 (d, 2JPC 8.4 Hz, C-7), 123.38 (d, 3JPC 11.4, C-4), 124.27
(d, 3JPC 5.4 Hz, C-6), 124.36 (d, 4JPC 1.2 Hz, C-5), 127.54 (C-14),
3
128.23 (C-16), 128.42 (d, JPC 12.7 Hz, C-11), 128.71 (C-15),
N,N′-Propane-1,3-diylbis[N-benzyl-P,P-diphenyl(phosphin-
ic amide)] (8b). Isolated yield 73% (4.11 g). Mp 118 °C. 1H NMR
δ 1.72 (m, 2H, H-5), 2.53 (m, 4H, 3JHH 7.9 Hz, 3JPH 10.4 Hz, H-4),
4.03 (d, 4H, 3JPH 9.7 Hz, H-3), 7.28 (m, 10H, H-11, H-12, H-13),
131.49 (d, 2JPC 9.9 Hz, C-10), 131.61 (d, 4JPC 2.9 Hz, C-12), 133.33
(d, 1JPC 12.5 Hz, C-9), 138.91 (d, 3JPC 9.6 Hz, C-13). 31P{1H} NMR
δ 47.63. MS (m/z) 641 (M + 1, 100). Anal. Calcd (%) for
C40H38N2O2P2: C, 74.99; H, 5.98; N, 4.37. Found: C, 75.10; H,
6.05; N, 4.33.
3
7.39-7.52 (m, 6H, H-8, H-9), 7.83 (m, 4H, JPH 11.5 Hz, H-7).
13C NMR δ 25.67 (t, 3JPC 3.3 Hz, C-5), 42.45 (d, 2JPC 3.0 Hz, C-4),
2
49.05 (d, JPC 3.0 Hz, C-3), 127.31 (C-13), 128. 43 (C-12, C-13),
(1RP*,3R*,3aS*,7aS*)-2,2′-Ethane-1,2-diylbis(1,3-diphenyl-
2,3,3a,7a-tetrahydro-1H-2,1-benzazaphosphol)1,1′-Dioxide(11a_rac).
Yield after chromatography (AcOEt/MeOH, 25:1) 20% (38 mg).
Oil. 1H NMR δ 2.67-2.94 (m, 6H, H-3a, H-8), 3.06 (m, 2H, 2JPH
128.51 (d, 3JPC 13.2 Hz, C-8), 131.75 (d, 1JPC 129.2 Hz, C-6), 131.75
(d, 4JPC 3.0 Hz, C-9), 132.31 (d, 2JPC 9.0 Hz, C-7), 136.98 (d, 3JPC
4.2 Hz, C-10). 31P NMR δ 30.83. MS (m/z) 655 (M + 1, 100).
Anal. Calcd (%) for C41H40N2O2P2: C, 75.21; H, 6.16; N, 4.28.
Found: C, 75.26; H, 6.17; N, 4.31.
3
11.7 Hz, H-7a), 4.07 (d, 2H, JHH 9.2 Hz, H-3), 5.29 (ddc, 2H,
3
3
3JHH 9.5 Hz, JHH 5.4 Hz, H-4), 5.87 (m, 2H, JPH 9.5 Hz, H-7),
3
3
5
5.94 (ddc, 2H, JHH 9.5 Hz, JHH 5.4 Hz, JHH 0.8 Hz, H-5), 6.06
(m, 2H, H-6), 7.00 (m, 4H, H-14), 7.19-7.40 (m, 6H, H-15, H-16),
7.40-7.59 (m, 6H, H-11, H-12), 7.72 (m, 4H, 3JPH 12.4 Hz, H-10).
13C{1H} NMR δ 37.26 (d, 1JPC 84.1 Hz, C-7a), 40.33 (C-8), 43.39
(C-3a), 67.85 (d, 2JPC 21.0 Hz, C-3), 119.43 (d, 2JPC 8.4 Hz, C-7),
N,N′-Butane-1,4-diylbis[N-benzyl-P,P-diphenyl(phosphinic
amide)] (8c). Isolated yield 81% (4.65 g). Mp 158 °C. 1H NMR δ
3
3
1.16 (m, 4H, H-5), 2.61 (m, 4H, JHH 7.0 Hz, JPH 10.5 Hz, H-4),
4.08 (d, 4H, 3JPH 9.8 Hz, H-3), 7.28 (m, 10H, H-11, H-12, H-13),
3
7.39-7.52 (m, 12H, H-8, H-9), 7.84 (m, 8H, JPH 11.7 Hz, H-7).
3
3
3
2
13C NMR δ 25.14 (d, JPC 3.3 Hz, C-5), 42.90 (d, JPC 3.0 Hz,
123.31 (d, JPC 11.4 Hz, C-4), 124.36 (C-5), 124.44 (d, JPC 5.4
Hz, C-6), 127.70 (C-14), 128.36 (C-16), 128.44 (d, JPC 13.2 Hz,
3
2
C-4), 49.24 (d, JPC 3.6 Hz, C-3), 127.23 (C-13), 128.24 (C-11),
128. 36 (C-12), 128.44 (d, JPC 12.9 Hz, C-8), 131.70 (d, JPC 2.7
3
4
2
C-11), 128.61 (C-15), 131.39 (d, JPC 10.2 Hz, C-10), 131.61 (d,
1
2
Hz, C-9), 131.91 (d, JPC 128.9 Hz, C-6), 132.30 (d, JPC 9.3 Hz,
4JPC 2.5 Hz, C-12), 133.25 (d, 1JPC 126.2 Hz, C-9), 139.24 (d, 3JPC
9.6 Hz, C-13). 31P{1H} NMR δ 49.17. MS (m/z) 641 (M + 1, 100).
C-7), 137.37 (d, JPC 4.8 Hz, C-10). 31P NMR δ 30.92. MS (m/z)
3
3796 J. Org. Chem., Vol. 72, No. 10, 2007

Double Dearomatization of Bis(diphenylphosphinamides)
CHART 3. Scheme Numbering Used for the NMR Assignments of Bis(benzazaphospholes) 11-15
Anal. Calcd (%) for C40H38N2O2P2: C, 74.99; H, 5.98; N, 4.37.
Found: C, 74.78; H, 5.84; N, 4.27.
diphenyl-2,3,3a,6-tetrahydro-1H-2,1-benzazaphosphol 1-Oxide
(12a_meso). Yield after precipitation from Et2O 50% (96 mg). Mp
1
219-20 °C. H NMR δ 2.64-2.87 (m, 8H, H-6, H-8), 3.12 (m,
(1RP*,3R*,3aS*,7aS*)-2-{3-[(1SP*,3S*,3aR*,7aR*)-1,3-Diphe-
nyl-1-oxide-2,3,3a,7a-tetrahydro-1H-2,1-benzazaphosphol-2-yl]-
propyl}-1,3-diphenyl-2,3,3a,7a-tetrahydro-1H-2,1-benzazaphos-
phol 1-Oxide (11b_meso). Yield after chromatography on silica
2H, H-3a), 3.96 (d, 2H, 3JHH 9.3 Hz, H-3), 5.43 (m, 2H, H-4), 5.69
(m, 2H, H-5), 6.59 (m, 2H, 3JPH 16.6 Hz, H-7), 7.19 (m, 4H, H-14),
7.36-7.51 (m, 12H, ArH), 7.68 (m, 4H, 3JPH 11.6 Hz, H-10). 13C-
3
2
{1H} NMR δ 27.63 (d, JPC 12.6 Hz, C-6), 40.64 (d, JPC 2.4 Hz,
1
gel (AcOEt/MeOH, 60:1 to 30:1) 47% (92 mg). Oil. H NMR δ
2
2
C-8), 46.62 (d, JPC 13.8 Hz, C-3a), 67.19 (d, JPC 12.0 Hz, C-3),
122.82 (d, 3JPC 6.6 Hz, C-4), 124.98 (d, 4JPC 1.2 Hz, C-5), 127.90
(C-14), 128.28 (d, 3JPC 13.2 Hz, C-11), 128.49 (C-16), 128.85 (C-
15), 131.39 (d, 4JPC 3.0 Hz, C-12), 131.53 (d, 2JPC 10.8 Hz, C-10),
1.50 (m, 2H, H-9), 2.59-2.86 (m, 6H, H-3a, H-8), 3.01 (m, 2H,
2JPH 11.4 Hz, H-7a), 4.10 (d, 2H, 3JHH 9.2 Hz, H-3), 5.32 (m, 2H,
3
4
3
H-4), 5.91 (m, 2H, JHH 9.5 Hz, JHH 2.6 Hz, JPH 9.5 Hz, H-7),
3
3
5.99 (dd, 2H, JHH 9.5 Hz, JHH 5.3 Hz, H-5), 6.09 (m, 2H, H-6),
1
1
3
4
133.04 (d, JPC 120.7 Hz, C-7a), 133.53 (d, JPC 132.8 Hz, C-9),
H-5), 6.09 (m, 2H, H-6), 7.23 (dd, 4H, JHH 7.8 Hz, JHH 2.8 Hz,
135.36 (d, JPC 9.6 Hz, C-7), 138.19 (d, JPC 8.4 Hz, C-13). 31P-
{1H} NMR δ 28.07. MS (m/z) 641 (M + 1, 100). Anal. Calcd (%)
for C40H38N2O2P2: C, 74.99; H, 5.98; N, 4.37. Found: C, 74.82;
H, 6.04; N, 4.38.
2
3
H-15), 7.33-7.56 (m, 12H, ArH), 7.84 (ddd, 4H, 3JHH 7.3 Hz, 4JHH
1.8 Hz, JPH 12.7 Hz, H-10). 13C{1H} NMR δ 25.99 (C-9), 37.52
3
(d, 1JPC 84.7 Hz, C-7a), 39.63 (d, 2JPC 3.0 Hz, C-8), 43.26 (C-3a),
66.58 (d, 2JPC 21.6 Hz, C-3), 119.36 (d, 2JPC 8.1 Hz, C-7), 123.39
3
4
(d, JPC 11.4 Hz, C-4), 124.46 (d, JPC 3.0 Hz, C-5), 124.54 (d,
(1RP*,3S*,3aR*)-2-{3-[(1SP*,3R*,3aS*)-1′,3′-Diphenyl-1′-oxide-
2′,3′,3a′,6′-tetrahydro-1′H-2′,1′-benzazaphosphol-2-yl]propyl}-
1,3-diphenyl-2,3,3a,6-tetrahydro-1H-2,1-benzazaphosphol 1-Ox-
ide (12b_meso). Yield after chromatography on silica gel-Et3N (5%)
3JPC 9.6 Hz, C-6), 127.59 (C-15), 128.06 (C-17), 128.46 (d, JPC
3
12.3 Hz, C-12), 128.65 (C-16), 131.58 (d, 2JPC 9.9 Hz, C-11), 131.66
(d, 4JPC 2.4 Hz, C-13), 133.90 (d, 1JPC 126.1 Hz, C-10), 139.32 (d,
3JPC 9.6 Hz, C-14). 31P{1H} NMR δ 48.83. MS (m/z) 655 (M + 1,
100). Anal. Calcd (%) for C41H40N2O2P2: C, 75.21; H, 6.16; N,
4.28. Found: C, 75.28; H, 6.07; N, 4.32.
1
(AcOEt/MeOH, 40:1) 46% (90 mg). Oil. H NMR δ 1.40-1.74
(m, 2H, H-9), 2.43 (m, 2H, H-8), 2.71-2.95 (m, 6H, H-6, H-8′),
3
3.15 (m, 2H, H-3a), 4.18 (d, 2H, JHH 9.4 Hz, H-3), 5.57 (m, 2H,
3
H-4), 5.79 (m, 2H, H-5), 6.65 (m, 2H, JPH 16.0 Hz, H-7), 7.30-
(1RP*,3R*,3aS*,7aS*)-2-{4-[(1SP*3S*,3aR*,7aR*)-1,3-Diphe-
nyl-1-oxide-2,3,3a,7a-tetrahydro-1H-2,1-benzazaphosphol-2yl]-
butyl}-1,3-diphenyl-2,3,3a,7a-tetrahydro-1H-2,1-benzazaphos-
phol 1-Oxide (11c_meso). Yield after chromatography (AcOEt/
3
7.55 (m, 16H, ArH), 7.86 (m, 4H, JPH 13.1 Hz, H-10). 13C{1H}
3
2
NMR δ 26.23 (C-9), 27.66 (d, JPC 12.6 Hz, C-6), 39.01 (d, JPC
2
2
3.0 Hz, C-8), 46.34 (d, JPC 14.4 Hz, C-3a), 66.00 (d, JPC
12.0 Hz, C-3), 123.08 (d, JPC 6.6 Hz, C-4), 124.90 (d, JPC
1.2 Hz, C-5), 127.97 (C-15), 128.12 (C-17), 128.39 (d, JPC 13.1
Hz, C-12), 128.80 (C-16), 131.46 (d, JPC 3.0 Hz, C-13), 131.60
3
4
1
MeOH, 49:1) 37% (74 mg). Oil. H NMR δ 1.03-1.18 (m, 4H,
3
H-9), 2.45-2.64 (m, 4H, H-8), 2.84 (dddd, 1H, 3JHH 10.7 Hz, 3JHH
4
3
3
3
9.7 Hz, JHH 5.9 Hz, JPH 2.9 Hz, H-3a), 3.04 (m, 1H, JHH 10.7
2
1
3
4
2
(d, JPC 10.2 Hz, C-11), 133.04 (d, JPC 121.3 Hz, C-7a), 133.91
Hz, JHH 3.7 Hz, JHH 2.9 Hz, JPH 10.7 Hz, H-7a), 4.26 (d, 1H,
1
2
3JHH 9.7 Hz, H-3), 5.34 (ddddd, 1H, 3JHH 9.5 Hz, 3JHH 5.9 Hz, 4JHH
(d, JPC 133.3 Hz, C-10), 134.94 (d, JPC 9.6 Hz, C-7), 138.75 (d,
3JPC 8.4 Hz, C-14). 31P{1H} NMR δ 28.67. MS (m/z) 655 (M + 1,
100). Anal. Calcd (%) for C41H40N2O2P2: C, 75.21; H, 6.16; N,
4.28. Found: C, 75.34; H, 6.24; N, 4.30.
4
4
2.9 Hz, JHH 0.9 Hz, JPH 2.3 Hz, H-4), 5.92-6.01 (m, 2H, H-5,
H-7), 6.11 (ddddd, 1H, 3JHH 9.5 Hz, 3JHH 5.3 Hz, 4JHH 2.9 Hz, 4JHH
4
0.9 Hz, JPH 0.9 Hz, H-6), 7.21-7.55 (m, 16H, ArH), 7.88 (ddd,
4H, 3JHH 7.7 Hz, 4JHH 1.7 Hz, 3JPH 12.3 Hz, H-11). 13C{1H} NMR
(1RP*,3S*,3aR*)-2-{4-[(1SP*,3R*,3aS*)-1′,3′-Diphenyl-1′-oxide-
2′,3′,3a′,6′-tetrahydro-1′H-2′,1′-benzazaphospholyl]butyl}-1,3-
diphenyl-2,3,3a,6-tetrahydro-1H-2,1-benzazaphosphol 1-Oxide
(12c_meso). Yield after precipitation from Et2O 65% (130 mg).
1H NMR δ 1.12 (m, 4H, H-9), 2.38-2.58 (m, 4H, H-8), 2.72-
1
2
δ 25.84 (C-9), 33.77 (d, JPC 84.7 Hz, C-7a), 41.85 (d, JPC 2.4
2
Hz, C-8), 43.06 (C-3a), 67.32 (d, JPC 20.1 Hz, C-3), 119.51 (d,
2JPC 8.3 Hz, C-7), 123.50 (d, JPC 11.4 Hz, C-4), 124.40 (d, JPC
3
4
3.0 Hz, C-5), 124.51 (d, 3JPC 10.2 Hz, C-6), 127.55 (C-15), 128.11-
2
4
3
128.66 (3CHAr), 131.62, (d, JPC 9.6 Hz, C-11), 131.74 (d, JPC
2.94 (m, 4H, H-6), 3.14 (m, 2H, H-3a), 4.05 (d, 2H, JHH 9.5 Hz,
1
3
3
2.4 Hz, C-13), 134.01 (d, JPC 126.2 Hz, C-10), 139.37 (d, JPC
10.2 Hz, C-14). 31P{1H} NMR δ 49.48. MS (m/z) 669 (M + 1,
100). Anal. Calcd (%) for C42H42N2O2P2: C, 75.43; H, 6.33; N,
4.19. Found: C, 75.51; H, 6.42; N, 4.23.
H-3), 5.50 (m, 2H, H-4), 5.74 (m, 2H, H-5), 6.66 (m, 2H, JPH
16.2 Hz, H-7), 7.26-7.39 (m, 10H, ArH), 7.46-7.53 (m, 6H, H-12,
3
H-13), 7.91 (m, 4H, JPH 12.8 Hz, H-10). 13C{1H} NMR δ 25.76
3
2
(C-9), 27.65 (d, JPC 12.6 Hz, C-6), 41.70 (d, JPC 2.4 Hz, C-8),
46.25 (d, 2JPC 13.8 Hz, C-3a), 66.72 (d, 2JPC 12.0 Hz, C-3), 122.86
(d, 3JPC 6.0 Hz, C-4), 125.03 (C-5), 127.83 (C-15), 128.26 (C-17),
(1RP*,3S*,3aR*)-2-{2-[(1SP*,3R*,3aS*)-(1′,3′-Diphenyl-1-oxide-
2′,3′,3a′,6′-tetrahydro-1′H-2′,1′-benzazaphosphol-2-yl]ethyl}-1,3-
J. Org. Chem, Vol. 72, No. 10, 2007 3797

Ruiz-Go´mez et al.
3
4
3
3
4
4
128.46 (d, JPC 13.2 Hz, C-12), 128.80 (C-16), 131.57 (d, JPC
(ddddt, 1H, JHH 9.4 Hz, JHH 5.3 Hz, JHH 2.9 Hz, JHH 0.9 Hz,
2
1
3
4
4
2.4 Hz, C-13), 131.75 (d, JPC 10.8 Hz, C-11), 133.32 (d, JPC
4JPH 0.9 Hz, H-6), 6.99 (ddd, 2H, JHH 7.7 Hz, JHH 1.3 Hz, JHH
1.3 Hz, H-20), 7.09-7.19 (m, 5H, ArH), 7.23-7.55 (m, 12H, ArH),
7.65 (ddd, 2H, 3JHH 7.0 Hz, 4JHH 1.1 Hz, 3JPH 12.5 Hz, H-12), 7.70
(ddd, 2H, 3JHH 7.0 Hz, 4JHH 1.5 Hz, 3JPH 12.8 Hz, H-16), 7.75 (ddd,
2H, 3JHH 6.8 Hz, 4JHH 1.3 Hz, 3JPH 11.9 Hz, H-16′). 13C{1H} NMR
1
2
120.7 Hz, C-7a), 133.85 (d, JPC 133.4 Hz, C-10), 134.88 (d, JPC
9.6 Hz, C-7), 138.65 (d, 3JPC 9.0 Hz, C-14). 31P{1H} NMR δ 28.76.
MS (m/z) 669 (M + 1, 100). Anal. Calcd (%) for C42H42N2O2P2:
C, 75.43; H, 6.33; N, 4.19. Found: C, 75.02; H, 6.42; N, 3.94.
(1R*,3S*,3aR*)-2,2′-Butene-1,4-diylbis(1,3-diphenyl-2,3,3a,6-
tetrahydro-1H-2,1-benzazaphosphol) 1,1′-Dioxide (12c_rac). Yield
after chromatography on neutral alumina (AcOEt/MeOH, 30:1) 14%
(28 mg). Identified from a mixture of 9c_rac:9c_meso (52:48). 1H
NMR δ 1.14 (m, 4H, H-9), 2.37-2.57 (m, 4H, H-8), 2.73-2.95
(m, 4H, H-6), 3.15 (m, 2H, H-3a), 4.05 (d, 2H, 3JHH 9.3 Hz, H-3),
5.50 (m, 2H, H-4), 5.75 (m, 2H, H-5), 6.66 (m, 2H, 3JPH 16.5 Hz,
H-7), 7.25-7.40 (m, 10H, ArH), 7.47-7.52 (m, 6H, H-12, H-13),
1
2
3
δ 37.60 (d, JPC 84.1 Hz, C-7a), 40.14 (dd, JPC 2.4 Hz, JPC 4.2
Hz, C-8), 43.46 (C-3a), 44.49 (d, 2JPC 3.0 Hz, C-9), 49.82 (d, 2JPC
2
2
3.0 Hz, C-10), 68.25 (d, JPC 21.0 Hz, C-3), 119.32 (d, JPC 8.4
3
4
Hz, C-7), 123.24 (d, JPC 11.4 Hz, C-4), 124.42 (d, JPC 3.6 Hz,
C-5), 124.51 (d, 3JPC 10.2 Hz, C-6), 127.01 (C-24), 127.40 (C-20),
3
3
128.30 (d, JPC 11.4 Hz, CHAr), 128.37 (d, JPC 9.6 Hz, CHAr),
2
128.25-128.61 (5CHAr), 131.43 (d, JPC 10.2 Hz, C-12), 131.48
(d, 1JPC 135.8 Hz, C-15), 131.55 (d, 1JPC 131.6 Hz, C-15′), 131.61
(d, 4JPC 2.4 Hz, CHAr), 131.65 (d, 4JPC 3.0 Hz, CHAr), 131.80 (d,
4JPC 3.0 Hz, CHAr), 132.23 (d, 2JPC 9.0 Hz, C-16), 132.25 (d, 2JPC
7.88 (m, 4H, JPH 12.8 Hz, H-10). 13C{1H} NMR δ 25.68 (C-9),
3
27.64 (d, 3JPC 12.0 Hz, C-6), 41.91 (d, 2JPC 2.4 Hz, C-8), 46.16 (d,
2JPC 13.8 Hz, C-3a), 67.11 (d, JPC 12.0 Hz, C-3), 122.83 (d, JPC
2
3
1
3
9.0 Hz, C-16′), 133.25 (d, JPC 125.5 Hz, C-11), 137.50 (d, JPC
4
4.2 Hz, C-23), 139.05 (d, JPC 10.2 Hz, C-19). 31P{1H} NMR δ
3
6.6 Hz, C-4), 125.07 (d, JPC 1.2 Hz, C-5), 127.84 (C-15), 128.26
3
(C-17), 128.44 (d, JPC 13.2 Hz, C-12), 128.77 (C-16), 131.54 (d,
30.92, 49.19. MS (m/z) 641 (M + 1, 100). Anal. Calcd (%) for
C40H38N2O2P2: C, 74.99; H, 5.98; N, 4.37. Found: C, 74.82; H,
6.10; N, 4.38.
4JPC 3.0 Hz, C-13), 131.65 (d, 2JPC 10.2 Hz, C-11), 133.33 (d, 1JPC
1
2
120.7 Hz, C-7a), 133.99 (d, JPC 134.0 Hz, C-10), 134.88 (d, JPC
9.6 Hz, C-7), 138.75 (d, 3JPC 9.0 Hz, C-14). 31P{1H} NMR δ 28.84.
MS (m/z) 669 (M + 1, 100). Anal. Calcd (%) for C42H42N2O2P2:
C, 75.43; H, 6.33; N, 4.19. Found: C, 75.32; H, 6.12; N, 4.34.
(1RP*,3S*,3aR*,6R*,10S*))-2-{4-[(1SP*,3R*,3aS*)-1′,3′-Diphen-
yl-6′-hydroxyphenylmethyl-1′-oxide-2′,3′,3a′,6′-tetrahydro-1′H-
2′,1′-benzazaphospholyl]butyl}-1,3-diphenyl-6-hydroxyphenyl-
methyl-2,3,3a,6-tetrahydro-1H-2,1-benzazaphosphol 1-Oxide
(15a_meso). Yield after chromatography (AcOEt/MeOH, 15:1) 70%
N-{2-[(1RP*,3S*,3aR*)-1,3-Diphenyl-1-oxido-1,3,3a,6-tetrahy-
dro-2H-2,1-benzazaphosphol-2-yl]ethyl}-N-benzyl-P,P-diphen-
ylphosphinic Amide (14a). Yield after chromatography (AcOEt/
1
MeOH, 15:1) 85% (163 mg). Oil. H NMR δ 2.63-3.14 (m, 7H,
2
3
H-3a, H-6, H-8, H-9), 3.88 (dd, 1H, JHH 15.3 Hz, JPH 7.4 Hz,
H-10), 3.88 (d, 1H, 3JHH 9.3 Hz, H-3), 4.09 (dd, 1H, 2JHH 15.3 Hz,
3JPH 10.0 Hz, H-10′), 5.41 (m, 1H, H-4), 5.72 (m, 1H, H-5), 6.64
(m, 1H, H-7), 7.05 (m, 2H, H-20), 7.13 (m, 2H, H-24), 7.20 (m,
3H, ArH), 7.27-7.55 (m, 12H, ArH), 7.65-7.81 (m, 6H, H-12,
H-16, H-16′). 13C{1H} NMR δ 27.65 (d, 3JPC 12.8 Hz, C-6), 39.92
1
3
(184 mg). Oil. H NMR δ 1.14 (m, 4H, H-9), 2.49 (m, 2H, JPH
14.1 Hz, H-8), 3.00 (m, 2H, H-8′), 3.17-3.28 (m, 4H, H-3a, H-6),
3.15 (m, 2H, H-3a), 4.30 (d, 2H, 3JHH 8.5 Hz, H-3), 5.25 (sa, H-10),
5.53 (m, 2H, 3JHH 10.6 Hz, H-5), 5.72 (dd, 2H, 3JHH 10.6 Hz, 4JPH
4.0 Hz, H-4), 6.34 (sa, 1H, H-11, OH), 6.85 (m, 2H, 3JPH 17.3 Hz,
H-7), 7.19-7.58 (m, 26H, ArH), 7.99 (ddd, 4H, 3JHH 7.6 Hz, 4JHH
2
3
2
(dd, JPC 2.8 Hz, JPC 4.0 Hz, C-8), 44.52 (d, JPC 3.0 Hz, C-9),
46.60 (C-3a), 49.68 (d, 2JPC 3.3 Hz, C-10), 67.26 (d, 2JPC 12.0 Hz,
3
4
C-3), 122.60 (d, JPC 6.6 Hz, C-4), 125.10 (d, JPC 1.5 Hz, C-5),
127.03 (C-24), 127.67 (CHAr), 128.34 (CHAr), 128.35 (CHAr),
128.45 (d, JPC 9.3 Hz, CHAr), 128.48 (d, JPC 11.9 Hz, CHAr),
128.92 (CHAr), 131.46 (CHAr), 131.53 (d, JPC 127.7 Hz, CAr),
131.61 (d, JPC 1.7 Hz, CHAr), 131.65 (d, JPC 2.0 Hz, CHAr),
131.63 (d, JPC 128.4 Hz, CAr), 132.26 (d, JPC 9.0 Hz, CHAr),
132.29 (d, JPC 9.3 Hz, CHAr), 132.87 (d, JPC 120.6 Hz, CAr),
133.23 (d, 1JPC 132.6 Hz, CAr), 135.42 (d, 2JPC 9.6 Hz, C-7), 137.63
(d, 3JPC 4.4 Hz, C-23), 138.34 (d, 3JPC 8.4 Hz, C-19). 31P{1H} NMR
δ 28.52, 30.89. MS (m/z) 641 (M + 1, 100). Anal. Calcd (%) for
C40H38N2O2P2: C, 74.99; H, 5.98; N, 4.37. Found: C, 74.92; H,
6.08; N, 4.32.
1.8 Hz, JPH 12.9 Hz, H-13). 13C{1H} NMR δ 24.50 (C-9), 40.74
3
3
3
(C-8), 45.74 (d, 3JPC 12.0 Hz, C-6), 46.99 (d, 2JPC 14.4 Hz, C-3a),
65.82 (d, 2JPC 12.0 Hz, C-3), 74.31 (C-10), 124.37 (d, 3JPC 7.2 Hz,
C-4), 124.68 (C-5), 125.87 (C-21), 126.59 (C-23), 127.92 (C-22),
128.11-128.78 (CHAr), 131.88 (d, 4JPC 3.6 Hz, C-15), 131.92 (d,
1
4
4
1
2
2
1
2JPC 10.2 Hz, C-13), 133.02 (d, JPC 116.7 Hz, C-12), 133.78 (d,
1
1JPC 119.5 Hz, C-7a), 138.44 (d, JPC 8.4 Hz, C-16), 139.64 (d,
3
2JPC 8.4 Hz, C-7), 142.83 (C-20). 31P{1H} NMR δ 28.67. MS (m/
z) 881 (M + 1, 100). Anal. Calcd (%) for C56H54N2O4P2: C, 76.35;
H, 6.18; N, 3.18. Found: C, 76.28; H, 6.14; N, 3.25.
General Procedure for the Optimized Conditions for Mono-
dearomatizing Anionic Cyclization of Bis(N-benzyl-P,P-diphen-
ylphosphinamides) 8a. To a solution of 8a (2.99 × 10-4 mol) in
THF (30 mL) was added a solution of sBuLi (0.28 mL, of a 1.3 M
solution in cyclohexane, 3.56 × 10-4 mol) at -90 °C. After
30 min of metalation was added MeOH (1 mL) or 2,6-di-tert-butyl-
4-methylphenol (DTBMP) (199.6 mg, 8.97 × 10-4 mol). The
reaction mixture was stirred at -90 °C for 30 min. Next, the
reaction mixture was poured into ice water and extracted with ethyl
acetate (3 × 15 mL). The organic layers were dried over Na2SO4
and concentrated in vacuo. 1H, 1H{31P}, and 31P{1H} NMR spectra
of the crude reaction were measured to determine the regio- and
stereoselectivity of the process. The reaction mixture was then
purified via flash column chromatography using a mixture of ethyl
acetate:methanol, 15:1, as eluent.
N-{3-[(1RP*,3S*,3aR*)-1,3-Diphenyl-1-oxido-1,3,3a,6-tetrahy-
dro-2H-2,1-benzazaphosphol-2-yl]propyl}-N-benzyl-P,P-diphen-
ylphosphinic Amide (14b). Yield after chromatography on silica
1
gel-Et3N (5%) (AcOEt/MeOH, 40:1) 22% (43 mg). Oil. H NMR
δ 2.33-2.98 (m, 8H, H-6, H-8, H-9, H-10), 3.18 (m, 1H, H-3a),
2
3
3.97 (dd, 1H, JHH 15.3 Hz, JPH 11.3 Hz, H-11), 4.04 (dd, 1H,
2JHH 15.3 Hz, 3JPH 10.9 Hz, H-10′), 4.06 (d, 1H, 3JHH 9.3 Hz, H-3),
5.53 (m, 1H, H-4), 5.79 (m, 1H, H-5), 6.70 (m, 1H, H-7), 7.15-
7.62 (m, 19H, ArH), 7.71-7.95 (m, 6H, H-13, H-17, H-17′). 13C-
3
3
{1H} NMR δ 26.25 (d, JPC 3.6 Hz, C-9), 27.71 (d, JPC 12.6 Hz,
2
2
C-6), 39.48 (d, JPC 3.0 Hz, C-8), 42.26 (d, JPC 3.6 Hz, C-10),
46.43 (d, JPC 13.2 Hz, C-3a), 48.82 (d, JPC 3.0 Hz, C-11), 66.55
(d, JPC 12.0 Hz, C-3), 122.78 (d, JPC 6.0 Hz, C-4), 125.16 (d,
4JPC 1.2 Hz, C-5), 127.11 (CHAr), 127.94 (CHAr), 128.33 (CHAr),
128. 39 (CHAr), 128.49 (CHAr), 128.51 (d, 3JPC 10.8 Hz, CHAr),
2
2
2
3
N-{2-[-(1RP*,3R*,3aS*,7aS*)-1,3-Diphenyl-1-oxido-1,3,3a,7a-
tetrahydro-2H-2,1-benzazaphosphol-2-yl]ethyl}-N-benzyl-P,P-
diphenylphosphinic Amide (13a). Yield after chromatography
3
128.55, (d, JPC 9.0 Hz, CHAr), 128.58 (CHAr), 128.91 (CHAr),
131.56 (d, 4JPC 2.4 Hz, CHAr), 131.58 (d, 4JPC 1.8 Hz, CAr), 131.65
2
2
1
(d, JPC 10.8 Hz, CHAr), 131.75 (d, JPC 10.2 Hz, CHAr), 131.93
(AcOEt/MeOH, 15:1) 60% (115 mg). Oil. H NMR δ 2.72-2.97
1
1
(m, 5H, H-3a, H-8, H-9), 3.04 (m, 1H, 3JHH 11.0 Hz, 4JHH 2.9 Hz,
2JPH 11.0 Hz, H-7a), 3.86 (dd, 1H, 2JHH 15.4 Hz, 3JPH 9.8 Hz, H-10),
(d, JPC 129.2 Hz, CAr), 131.99 (d, JPC 129.2 Hz, CAr), 132.30
(d, 2JPC 9.0 Hz, CHAr), 132.40 (d, 2JPC 9.0 Hz, CHAr), 132.91 (d,
1JPC 120.2 Hz, CAr), 133.68 (d, JPC 133.4 Hz, CAr), 135.24 (d,
1
2
3
4.07 (dd, 1H, JHH 15.4 Hz, JPH 10.3 Hz, H-10′), 4.10 (d, 1H,
3
3
3JHH 10.3 Hz, H-3), 5.27 (dddt, 1H, 3JHH 9.5 Hz, 3JHH 5.5 Hz, 4JHH
1.1 Hz, JPH 2.5 Hz, H-4), 5.88-5.98 (m, 2H, H-5, H-7), 6.09
2JPC 9.6 Hz, C-7), 137.04 (d, JPC 3.6 Hz, C-23), 138.50 (d, JPC
4
8.4 Hz, C-19). 31P{1H} NMR δ 28.66, 31.27. MS (m/z) 655 (M +
3798 J. Org. Chem., Vol. 72, No. 10, 2007

Double Dearomatization of Bis(diphenylphosphinamides)
3
3
CHART 4. Scheme Numbering Used for the NMR
Assignments of Phenylphosphinate 16
H-7), 5.69 (dd, 2H, JHH 3.6 Hz, JHH 8.6 Hz, H-4), 5.90 (m, 2H,
H-5), 6.54 (dd, 2H, 3JHH 4.9 Hz, 3JPH 19.8 Hz, H-2), 7.17 (s, 10H,
H-16, H-17, H-18), 7.46-7.58 (m, 6H, H-13, H-14), 7.84 (m, 4H,
H-12). 13C{1H} NMR δ 27.23 (d, JPC 13.8 Hz, C-3), 41.58 (d,
3
2JPC 12.0 Hz, C-6), 47.42 (C-9), 51.29 (d, 2JPC 6.0 Hz, C-10), 65.55
(C-7), 125.30 (d, 3JPC 9.6 Hz, C-5), 126.43 (C-18), 126.81 (C-17),
127.00 (d, 4JPC 1.2 Hz, C-4), 128.59 (d, 3JPC 13.2 Hz, C-12), 129.15
1
2
(C-16), 130.21 (d, JPC 131.6 Hz, C-1), 132.06 (d, JPC 9.6 Hz,
4
C-12), 132.22 (d, JPC 3.0 Hz, C-14), 139.65 (C-15), 143.49 (d,
2JPC 8.4 Hz, C-2). 31P{1H} NMR δ 34.89. MS (m/z) 705 (M + 1,
100). Anal. Calcd (%) for C42H46N2O4P2: C, 71.58; H, 6.58; N,
3.97. Found: C, 72.23; H, 7.05; N, 4.32.
1, 100). Anal. Calcd (%) for C41H40N2O2P2: C, 75.21; H, 6.16; N,
4.28. Found: C, 75.24; H, 6.14; N, 4.30.
Acknowledgment. This paper is dedicated to Professor
Miguel Yus on the occasion of his 60th birthday. Financial
support through Ministerio de Educacio´n, Cultura y Deporte
(Project CTQ2005-01792), is gratefully acknowledged. G.R.-
G. thanks Ministerio de Ciencia y Tecnolog´ıa for a doctoral
fellowship.
Synthesis of (RP*) Methyl {(6S*)-6-[(R*)-({2-[(S*)-({(1R*)-
2-[(SP′*)-Methoxy(phenyl)phosphoryl]cyclohexa-2,5-dien-1-yl}-
benzyl)amino]ethyl}amino)benzyl]cyclohexane-1,4-dien-1-yl}-
Phenylphosphinate (16). To a solution of 12a_meso (0.16 × 10-3
mol, 0.100 g) in 6 mL of dry methanol was added 4 mL of a
solution of 1 M HCl(g) in diethyl ether at room temperature, and
the mixture was stirred for 50 min. Next, the pH was set to neutral
by adding 1 N NaOH, and the reaction was extracted with ethyl
acetate (3 × 15 mL). The organic layers were dried over Na2SO4
and concentrated in vacuo, affording an oil 0.113 g (>97%) (Chart
4).
Supporting Information Available: 13C, DEPT135, and 2D
gNOESY spectra of 11a-c_meso, 11a_rac, 12a-c_meso, 12c_rac,
13a, 14a, and 15a_meso, molecular view of 11a_meso, and X-ray
data of 11c_meso and 12a_meso. This material is available free of
charge via the Internet at http://pubs.acs.org.
3
3
1H NMR δ 1.38 (m, 2H, H-3), 2.32 (ddd, JHH 5.5 Hz, JHH
2
8.6 Hz, JHH 23.4 Hz, 2H, H-3′), 2.48 (m, 4H, H-9), 3.51 (m, 2H,
3
3
H-6), 3.72 (d, JPH 11.0 Hz, 6H, H-10), 4.11 (d, 2H, JHH 4.2 Hz,
JO070276Q
J. Org. Chem, Vol. 72, No. 10, 2007 3799