First synthesis of P-chirogenic prophosphatranes

Article abstract of DOI:10.1016/j.tetlet.2011.01.041

Syntheses are reported for the novel P-chirogenic bicyclic prophosphatranes P(RNCH₂CH₂)₂N(OCH₂CH₂) - (8) in which the two R groups [i.e., 1-methylenenaphthyl and 1,2-methoxybenzyl (8)] and in its corresponding phosphine oxide (9) are different. Also synthesized was the transannulated protonated phosphatrane cation in the salt [HP(RNCH₂CH₂)₃N]Cl in which the three R groups [i.e., 1-methylenenaphthyl, 1,2-methoxybenzyl, and (S)-1-phenethyl (14)] are different, and also in its corresponding deprotonated prophosphatrane form P(RNCH₂CH₂)₃N (15). Good analytical resolution of racemic 9 is reported, whereas only partial resolution was achieved for diastereomeric 14.

Full text of DOI:10.1016/j.tetlet.2011.01.041

Tetrahedron Letters 52 (2011) 1545–1548
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
First synthesis of P-chirogenic prophosphatranes
Yibo Zhou a, Daniel W. Armstrong b, Ying Zhang b, John G. Verkade a,
⇑
a Department of Chemistry, Iowa State University, Ames, IA 50011-3111, United States
b Department of Chemistry and Biochemistry, University of Texas at Arlington, 700 Planetarium Place, Arlington, TX 76019-0065, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Syntheses are reported for the novel P-chirogenic bicyclic prophosphatranes P(RNCH2CH2)2N(OCH2CH2)—
(8) in which the two R groups [i.e., 1-methylenenaphthyl and 1,2-methoxybenzyl (8)] and in its
corresponding phosphine oxide (9) are different. Also synthesized was the transannulated protonated
phosphatrane cation in the salt [HP(RNCH2CH2)3N]Cl in which the three R groups [i.e., 1-methylenenaph-
thyl, 1,2-methoxybenzyl, and (S)-1-phenethyl (14)] are different, and also in its corresponding deproto-
nated prophosphatrane form P(RNCH2CH2)3N (15). Good analytical resolution of racemic 9 is reported,
whereas only partial resolution was achieved for diastereomeric 14.
Received 13 November 2010
Revised 4 January 2011
Accepted 10 January 2011
Available online 18 January 2011
Keywords:
Prophosphatrane
P-Chirogenic
Resolution
Ó 2011 Elsevier Ltd. All rights reserved.
Enantiomeric
Catalyze
Nucleophilic organophosphorus catalysts enjoy wide use in or-
ganic reactions,1 and many phosphine ligands are exceedingly
effective in metal-assisted cross couplings.2 Such transformations
are of increasing interest in the synthesis of pharmaceuticals,2 fine
chemicals,3 and compounds of biological interest.4 Bulky electron-
rich phosphines can be particularly useful for aryl chloride5 and
also for aromatic and heteroaromatic silanoate6 substrates in cross
coupling reactions. Prochiral olefins have been hydrogenated
enantioselectively using chiral phosphites in the presence of a rho-
dium catalyst.7 Allylation catalyzed by palladium/chiral phosphine
ligand systems appears to be of considerable utility8 and such a li-
gand has also been reported to efficiently facilitate an asymmetric
Heck8e,9 as well as other Heck-type reactions.9b
Chiral organophosphorus compounds catalyze a wide variety of
useful enantiomeric transformations as organocatalysts.10 Chiral
phosphines catalyze the enantioselective acylation of alcohols to
effect their kinetic resolution10a,11 as well as desymmetrization of
meso diols via acylation.10a Chiral phosphines also catalyze reac-
tions of prochiral substrates as in MBH10a,12 and aza-MBH reac-
tions,10a formation of asymmetric quaternary carbon centers in
variety of important organic reactions13 and to function as excel-
lent ligands for palladium-catalyzed transformations.14 Because a
significant number of such reactions are carried out with prochiral
substrates, it would be of interest to investigate the efficacy of
P-chirogenic prophosphatranes in such reactions. P-chirogenic
compounds15 form a sizeable sub-class of chiral phosphines, but
no examples of P-chirogenic prophosphatranes have been reported
until now.
Prophosphatrane structures of types A and B, for example,
feature a P-chiral ‘pocket’ for substrate activation by the nucleo-
philic phosphorus. Such a pocket in A and/or B may be anticipated
to favor high product ee values since the R groups are held quite
rigidly in place by the bicyclic framework and by the planarity of
all four nitrogens.1,2 This rigidity would be reasonably maintained
by any changes in the N?P transannular distance that could
potentially occur during the catalytic cycle.
Here we report initial results for the synthesis of chiral 8 and 9
in Scheme 1, and chiral 14 and 15 in Scheme 2.
The synthesis of racemic 8 was achieved by monoprotection of
an NH2 group in 2 with BOC to provide intermediate 3, which was
the addition of nucleophiles to the c-position of ethyl butynoate
and ethyl 2,3-butadineate,10a and also in Steglich rearrange-
ments.10a Cycloadditions of the [4 + 2] type are catalyzed by chiral
phosphines as well as such reactions of the relatively rare [3 + 2]
variety.10a
R'
R"
R'
R
R
P
P
N
N
N
O
N
N
Non-chiral prophosphatranes of type A (with two or three iden-
tical R groups) in Figure 1 have been reported to catalyze a wide
N
N
A
B
⇑
Corresponding author. Tel.: +1 515 294 5023; fax: +1 515 294 0105.
E-mail address: jverkade@iastate.edu (J.G. Verkade).
Figure 1. Prophosphatranes.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.041

1546
Y. Zhou et al. / Tetrahedron Letters 52 (2011) 1545–1548
O
CH2CH2NH H2SO4 1. 1 equiv
CH2CH2NH2
CH2CH2OH
CH2CH2NH2
(BOC)2O
85%
HN
N
N
2. NaOH
55%
CH2CH2NH H2SO4
1
2
CHO
CH2CH2NHBOC
CH2CH2OH
CH2CH2NHBOC
CH2CH2OH
1.
N
2. NaBH4
92%
CH2CH2NHCH2(1-naphthyl)
CH2CH2NH2
4
3
CHO
OMe
CH2CH2NH2
CH2CH2OH
1.
HCl
MeOH
85%
N
2. NaBH4
88%
CH2CH2NHCH2(1-naphthyl)
5
CH2CH2NHCH2(2-MeOC6H4)
CH2CH2OH
HMPT/PCl3
N
CH3CN
87%
CH2CH2NHCH2(1-naphthyl)
6
MeO
tBuOK
H
N
THF
87%
N
P
O
Cl
N
+
7
MeO
MeO
(Me3SiO)2
O
P
N
O
Toluene
50 o
80%
P
N
O
N
N
C
N
9
N
8
Scheme 1. Synthesis of prophosphatrane 8 and its oxide 9.
then followed by reductive amination of the second NH2 group
with -naphthaldehyde, BOC deprotection, and reductive
BOC deprotection of 12, 13 was afforded in very good overall yield
(66% from 6 through four steps) and in 21% overall yield from 1
through nine steps. This represents the first synthesis of a tetra-
amine of type 13 with three different R groups on the terminal
NH groups. Our methodology is amenable to scale-up and easy
purification of the products of each step via column chromatogra-
phy. Analogously to the synthesis of non-chiral prophosphatranes
of type of A,16 diastereomeric 15 was obtained by reaction of 13
with ClP((NMe)2)2, which was prepared in situ via the reaction of
HMPT {P(NMe2)3} with PCl3, to form the salt 14 which was then
deprotonated with tBuOK in THF. The 31P NMR spectrum of 15
showed two peaks [d 127.89 (s), 127.83 (s)] consistent with the
presence of two diastereomers.
Results of chiral HPLC separation experiments with 9 and 14 are
shown in Figures 2 and 3, respectively. Racemic prophosphatrane
oxide 9 was successfully resolved into a pair of enantiomers on a
Chiralpak IA column with a mobile phase of methyl t-butyl
ether/methanol/acetic acid/triethylamine (85:15:0.3:0.2). The dia-
stereomeric phosphatrane salt 14 was partially separated to a pair
of diastereomers on a Chiralpak IC column with a mobile phase of
a
amination with ortho-benzaldehyde to afford compound 6 bearing
different R groups attached to the two terminal NH groups. Under
similar conditions for the synthesis of non-chiral prophosphatr-
anes of type A,16 compound 6 was converted into the oxa-prophos-
phatrane salt 7, which was then deprotonated to afford
oxa-prophosphatrane 8. The overall yield of 8 through seven steps
from 1 is 28%. This is the first report of the synthesis of a prophos-
phatrane featuring two different heteroatoms on the phosphorus.
For purification and optical resolution of an air- and moisture-
stable derivative of 8, this type B product was converted into its
corresponding oxide 9 in 80% yield via CH3SiOOSiCH3 oxidation.
Our synthesis of a P-chirogenic prophosphatrane of type A with
three different R groups on the P–N nitrogens relied on the suc-
cessful synthesis of the intermediate tetraamine 13 in Scheme 2.
Starting with 6, which was synthesized from 1 as shown in Scheme
1, the two terminal NH groups were protected by BOC, followed by
protection of the OH group as the mesylate 11, which was allowed
to react with (s)-1-methyl benzylamine to provide 12. Following

Y. Zhou et al. / Tetrahedron Letters 52 (2011) 1545–1548
1547
BOC
CH2CH2NCH2(o-MeO)C6H4
(BOC)2O
95%
MsCl, Et3N
CH2Cl2
92%
6
N
CH2CH2OH
CH2CH2NCH2-(1-naphthyl)
BOC
10
BOC
BOC
Ph NH2
Me
CH3CN, reflux
(s)-
CH2CH2NCH2(o-MeO)C6H4
CH2CH2NCH2(o-MeO)C6H4
CH2CH2NHCHPhMe-(s)
CH2CH2NCH2-(1-naphthyl)
N
CH2CH2OMs
N
CH2CH2NCH2-(1-naphthyl)
BOC
BOC
11
12
CH2CH2NHCH2(o-MeO)C6H4
CH2CH2NHCHPhMe-(s)
HMPT/PCl3
CH3CN
85%
HCl
N
MeOH
CH2CH2NHCH2-(1-naphthyl)
76% yield
from 11
13
OMe
OMe
H
P
K-t-OBu
CH3
*
CH3
*
N
P
N
N
(s)
Cl
N
(s)
N
N
THF
92%
N
+
14
N
15
2 diastereomers
2 diastereomers
Scheme 2. Synthesis of diastereomeric prophosphatrane 15.
sets the stage for further enantiomeric resolution and subsequent
evaluation of compounds of the title type in inducing enantioselec-
tivity in organic reactions.
Acknowledgments
J.G.V. is grateful to the NSF for a grant (0750463) in support of
this research. D.W.A. gratefully acknowledges the Robert A. Welch
Foundation (Y-0026) for partial support of this work.
Figure 2. Enantiomeric separation of 9 on a Chiralpak IA column (15 cm).
Supplementary data
Supplementary data (experimental details and characteriza-
tional data [NMR spectral (1H, 13C, 31P) HRM spectral and HPLC
conditions]) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2011.01.041.
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