Novel results obtained by freezing berry pseudorotation of phosphoranes (10-P-5)

Article abstract of DOI:10.1002/hc.10072

By freezing Berry pseudorotation of spirophosphoranes with recourse to the rigidity of the Martin bidentate ligand, we successfully prepared configurationally stable enantiomeric pairs of optically active phosphoranes, and could isolate anti-apicophilic C-apical O-equatorial (O-cis) phosphoranes. The effect of σ* _P-O orbital of the O-cis phosphorane was investigated both experimentally and theoretically, O-cis phosphoranes were revealed to be much more electrophilic at the phosphorus atom than O-trans isomers by experimental studies. The acidity of the α-proton of an O-cis benzylphosphorane was found to be higher than that of the corresponding O-trans isomer. By the reaction of the α-carbanion of an O-cis benzylphosphorane with PhCHO, we succeeded in the first isolation and full structural characterization of a 12-P-6 phosphate bearing an oxaphosphetane ring, the intermediate in the Wittig type reaction using a 10-P-5 phosphorane.

Full text of DOI:10.1002/hc.10072

Heteroatom Chemistry
Volume 13, Number 5, 2002
Novel Results Obtained by Freezing Berry
Pseudorotation of Phosphoranes (10-P-5)
Kin-ya Akiba,1 Shiro Matsukawa,2 Kazumasa Kajiyama,2 Masaaki
Nakamoto,2 Satoshi Kojima,2 and Yohsuke Yamamoto2
1Advanced Research Center for Science and Engineering, Waseda University, 3-4-1 Ohkubo,
Shinjuku-ku, Tokyo 169-8555, Japan
2Department of Chemistry, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama,
Higashi-Hiroshima 739-8526, Japan
Received 23 June 2001; revised 22 March 2002
processes involving phosphoryl transfer, and re-
ABSTRACT: By freezing Berry pseudorotation of
cently, artificial phosphorus compounds have been
spirophosphoranes with recourse to the rigidity of
used in herbicides, insecticides, and medicines [1].
the Martin bidentate ligand, we successfully pre-
Thus, the mechanism of reaction involving phos-
pared configurationally stable enantiomeric pairs
phorus compounds has been a topic of interest for
of optically active phosphoranes, and could isolate
quite some time. Through the pioneering work of
“anti-apicophilic” C-apical O-equatorial (O-cis) phos-
Westheimer and others [2], it is now widely ac-
phoranes. The effect of
orbital of the O-cis phos-
P
O
cepted that the reaction process involves a pentava-
lent phosphorus intermediate (or transition state)
formed by nucleophilic attack upon the tetraco-
ordinate phosphorus atom, and that the stability
and stereochemistry (both steric and electronic ef-
fects combined) of the transient species (or tran-
sition state) greatly influence the outcome of the
process. Therefore, to deduce a basic understand-
ing of the process, much attention has been fo-
cused on the stereochemistry by using various
model compounds, and, through these studies, it
has been found that the permutation of the inter-
mediate is an important factor [3]. The permutation
is usually interpreted in terms of the Berry pseu-
dorotation [4]. Since the process requires only si-
multaneous bending of bonds, the energy barrier
is generally very small. However, by utilizing the
rigidity of the Martin bidentate ligand, we could
successfully freeze Berry pseudorotation. Here we
describe our recent results on the preparation of
configurationally stable enantiomeric pairs of op-
tically active phosphoranes [5], on the first isola-
tion and full characterization of an “anti-apicophilic”
(O-cis) phosphorane [6], on the reactivities of O-cis
phorane was investigated both experimentally and
theoretically. O-cis phosphoranes were revealed to be
much more electrophilic at the phosphorus atom than
O-trans isomers by experimental studies. The acidity
of the ␣-proton of an O-cis benzylphosphorane was
found to be higher than that of the corresponding O-
trans isomer. By the reaction of the -carbanion of an
O-cis benzylphosphorane with PhCHO, we succeeded
in the first isolation and full structural characteriza-
tion of a 12-P-6 phosphate bearing an oxaphosphetane
ring, the intermediate in the Wittig type reaction us-
C
ing a 10-P-5 phosphorane.
2002 Wiley Periodicals,
Inc. Heteroatom Chem 13:390–396, 2002; Published on-
line in Wiley Interscience (www.interscience.wiley.com).
DOI 10.1002/hc.10072
INTRODUCTION
Phosphorus compounds are of significance due
to their important role in numerous biological
Correspondence to: Kin-ya Akiba; e-mail: akibaky@waseda.jp
2002 Wiley Periodicals, Inc.
c
390

Novel Results Obtained by Freezing Berry Pseudorotation of Phosphoranes (10-P-5) 391
SCHEME 1
phosphoranes (S. Matsukawa, K. Kajiyama, M.
Nakamoto, Y. Yamamoto, S. Kojima, and K.-y.
Akiba, unpublished results), which were found to
be largely different from those of regular (O-trans)
phosphoranes, and on the stabilization of hexa-
coordinated anions derived from the reactions of
␣-anions from O-cis phosphoranes, including the
first X-ray analysis of a 12-P-6 phosphate bearing
an oxaphosphetane ring system (S. Matsukawa, K.
Kajiyama, M. Nakamoto, Y. Yamamoto, S. Kojima,
and K.-y. Akiba, unpublished results).
rigid optically active phosphoranes with asymme-
try only at phosphorus. In order to assure the high
enantiomeric purity of the chiral alcohols, the alco-
hols 3 were converted to their (R)-(+)-Mosher es-
ters (4-RP and 4-SP) as described in Scheme 2, using
the acid chloride derived from (R)-(+)-2-methoxy-
2-(trifluoromethyl)phenylacetic acid. A comparison
of the 31P NMR charts of the diastereomeric mix-
tures, the Mosher ester 4-SP derived from 3-SP, and
the Mosher ester 4-RP derived from 3-RP, clearly
shows that the crude samples of neither 4-SP nor
4-RP showed the presence of the opposing diastere-
omers. This implies that epimerization had not oc-
curred either during the two consecutive transfor-
mations of esters 2-RP and 2-SP to 4-RP and 4-SP,
respectively, or during the purification procedures.
Thus, we could confirm the high enantiomeric pu-
rity of the alcohols 3-RP and 3-SP.
RESULTS AND DISCUSSIONS
Freezing Berry Pseudorotation and Isolation
of Optically Active 10-P-5 Spirophosphoranes
(1 and 3) with Asymmetry Only at Phosphorus
By utilizing Martin’s phosphorane 1, we have suc-
ceeded in preparing and characterizing the first con-
figurationally stable enantiomeric pairs of optically
active phosphoranes 3-RP and 3-SP, and 1-RP and
1-SP, which bear asymmetry only at phosphorus.
Compounds 3-RP and 3-SP were obtained from a di-
astereomeric pair of (o-OC(CF3)2C6H4)2P CH2CO2(-)
menthyl (2-RP and 2-SP) which could be separated in
relatively large quantities by fractional crystalliza-
tion by using MeOH-H2O as solvent. The removal
of the chiral menthyl moiety was achieved by treat-
ing the diastereomers with an excess amount of
LiAlH4 in refluxed Et2O, as depicted in Scheme 1,
thereby generating the first enantiomeric pair of
Furthermore, the first optically active
pair of enantiomeric P H phosphoranes (o-
OC(CF3)2C6H4)2P H (1-RP and 1-SP) with asymmetry
only at the pentacoordinate phosphorus atom could
be obtained from diastereomeric phosphoranes
(o-OC(CF3)2C6H4)2P CH2NHC H(CH3)Ph (5-RP and
5-SP), of which the absolute stereochemistry was
also determined, by treatment with MeLi (Scheme 3
and 4). The high enantiomeric purities of the P H
SCHEME 2
SCHEME 3

392 Akiba et al.
SCHEME 4
phosphoranes were confirmed by converting each of
them to their corresponding (-)-menthyl esters 2-RP
and 2-SP (Scheme 5). Racemization between 1-RP
and 1-SP did not take place at room temperature [5].
O-cis 6, which involves the oxidation of in situ gen-
erated dianion 9.
The new protocol provided 6a and 6b exclu-
sively at low temperatures in high yields, and aryl
derivative 6f could also be synthesized for the first
time by these procedures [10]. The possible reaction
mechanism is shown in Scheme 6: (i) Reaction of
P H(equatorial) phosphorane 1 with more than two
equivalents of RLi provides the dianion 9, where one
equivalent of RLi works as a base and the other as a
nucleophile. (ii) In the resulting dianion 9, the lone
pair electrons on the phosphorus occupy an equato-
rial position because of its extreme electron-donicity.
Oxidant I2 reacts with the dianion 9 to produce
P I (equatorial) phosphorane A, and the remaining
alkoxide anion rapidly cyclizes with simultaneous
elimination of I to form O-cis spirophosphorane 6,
exclusively.
Isolation and Synthesis of Novel
Anti-Apicophilic C-Apical O-Equatorial
(O-cis) Spirophosphorane 6
It is well established that trigonal bipyramidal 10-
P-5 phosphoranes prefer to have the more electron-
withdrawing groups of the five substituents at the
apical positions on the basis of the concept of api-
cophilicity [7]. The only exceptions to this gener-
ality had been the case where some sort of steric
constraints disallowed such configurations [8]. How-
ever, we have recently succeeded in the first isola-
tion and full characterization of an “anti-apicophilic”
phosphorane (O-cis 6b) in which an oxygen atom
occupies an equatorial position and a carbon atom
occupies an apical position in a five-membered ring
without applying restrictions that would not permit
the formation of the more stable stereoisomer (O-
trans 7b) [6]. In the presence of pyridine, O-cis 6b
was formed as a major product via a unique thermal
cyclization reaction of P H (apical) phosphorane
8b with concomitant H2 elimination whereas 8a–c
gave O-trans 7a–c in toluene and o-dichlorobenzene
(Scheme 6) [9]. One disadvantage of this proce-
dure is that it is not suitable for the preparation
of anti-apicophilic phosphoranes that may undergo
stereomutation around these temperatures. There-
fore we developed mild and highly selective proce-
dures for preparing anti-apicophilic phosphoranes
Enhanced Electrophilicity of O-cis Phosphorane
6: Effect of ␴
Orbital in the Equatorial Plane
P O
O-cis phosphorane 6 has one of the two P O bonds
on the equatorial plane, and therefore has a ␴
P
O
orbital on the same plane. On the other hand, O-trans
phosphorane 7 has only the corresponding P C
bonds on the equatorial plane, hence has only a
␴
of ␴
C, accordingly (Fig. 1). Since the energy level
should be significantly lower than that of
P
P
O
␴
C, there should be an apparent effect of ␴
P
P O
to show the difference in the reactivity between 6
and 7 toward nucleophiles (electrophilicity of phos-
phoranes) and in the stability of carbanions ␣ to the
phosphorus atom. Now we describe the effects of the
SCHEME 5

Novel Results Obtained by Freezing Berry Pseudorotation of Phosphoranes (10-P-5) 393
SCHEME 7
conditions (5 equiv. of MeLi at rt for 6 h), 7b slowly
reacted with MeLi to give 11. These results clearly
show that the electrophilicity of O-cis 6 is higher
than that of O-trans 7. This is in agreement with the
SCHEME 6
rationale that the lower-lying ␴
orbital in
P
O(equatorial)
O-cis 6 should be able to accept an electrophile much
␴
orbital of 6 from both experimental and theo-
P
O
more easily than the higher-lying ␴ C(equatorial) orbital
P
retical viewpoints.
in O-trans 7.
Reactions of O-cis 6b and O-trans 7b with nu-
cleophiles were examined. Using TBAF (tetrabuty-
lammonium fluoride; (n-Bu)4N+F ) as a nucleophile,
the reaction of 6b readily afforded a hexacoordinate
Stabilization of Lone Pair Electrons Adjacent
to the Phosphorus of O-cis 6: Effect of the
Orbital in the Equatorial Plane
P
O
phosphate bearing a P F bond 10 (1 JP = 706 Hz)
F
while 7b did not react at all. The configuration of
phosphate 10 could not be determined with certainty
because of rapid decomposition by trace amounts of
H2O. However we have already characterized the cor-
responding hexacoordinate fluoroantimonate with
two Martin ligands by X-ray analysis [11] and there-
fore, in phosphate 10, the fluorine atom is also likely
to be located anti to the oxygen because of the trans
influence of the fluorophosphate. These can be ex-
plained by the attack of the fluoride anti at the P O
or Sb O (equatorial) bond of the O-cis isomer. Sim-
ilarly, O-cis 6b reacted with 1 equiv. of MeLi at 0 C
for 90 min to give the corresponding adduct 11 (82%
yield) after hydrolysis, while O-trans 7b did not react
under similar conditions (Scheme 7). Under forcing
Deprotonation of O-cis 6h with KHMDS (potas-
sium hexamethyldisilazide; (Me3Si)2N K+) occurred
in THF at 0 C for 30 min and gave the ␣-deuterated
product (40% deuterated) after treating the mixture
with D2O. On the other hand, O-trans 7h could not
be deprotonated under the same conditions. There-
fore, the results clearly show that the acidity of the
␣-proton of O-cis 6h is higher than that of O-trans
7h. Moreover, the benzyl anion (12h) of 6h was
much more stable stereochemically than the neutral
molecule of 6h. In THF, O-cis 6h was totally con-
verted to the O-trans 7h at 60 C over 5 h. Under the
same conditions, the benzyl anion (12h) remained
almost unchanged.
Theoretical Study on
Orbitals of O-cis and
O-trans Phosphoranes in the Equatorial Plane
In order to evaluate the difference in energy between
the ␴
orbital of O-cis phosphorane and the ␴
P
O
P C
orbital of the O-trans isomer, theoretical calculations
for 6a and 7a were carried out (B3PW91/6-31G(d)).
As shown in Fig. 2, the energy of ␴
(LUMO + 4) is lower than that of ␴
of 6a
of 7a
P
O
P
C
FIGURE 1 Expected enhanced electrophilicity of O-cis 6
due to a low-lying
orbital.
(LUMO + 5) by 18.7 kcal/mol. Other LUMOs below
P
O

394 Akiba et al.
SCHEME 8
and the corresponding ␣-anion of O-trans (13a) is
much smaller (4.7 kcal/mol) than the difference
between 6a and 7a (14.1 kcal/mol) (Fig. 3). The re-
sults indicate that the equilibrium between 6a and
12a should be shifted much more toward the anion
(12a) in comparison with the corresponding equilib-
rium between 7a and 13a. That is, the CH3 protons
of the O-cis phosphorane (6a) are much more acidic
than the corresponding CH3 protons of the O-trans
phosphorane (7a). This is consistent with the experi-
mental observation of enhanced acidity of the benzyl
protons in O-cis 6h in comparison with O-trans 7h
as shown in Scheme 8. Theoretical calculations were
carried out by Professor Shigeru Nagase of the In-
stitute for Molecular Science, and will be published
later [12].
FIGURE 2 Energies of molecular orbitals for ␴
of O-cis
O
P
6a and ␴
of O-trans 7a.
P
O
␴
(X = O or C) were distributed on the aromatic
P
X
rings of the Martin ligands. Therefore the orbitals re-
sponsible for nucleophilicity and stabilization of the
␣-carbanion should be the ␴ X. This large differ-
P
ence in the energy between ␴
and ␴
orbitals
P
O
P C
provides theoretical evidence for the enhanced re-
activity of O-cis spirophosphorane 6 compared with
the O-trans isomer 7 as shown in Scheme 7.
In addition, theoretical calculations show that
the energy difference between ␣-anion of O-cis (12a)
FIGURE 3 Decrease in energy difference between the anionic pair of O-cis 12a and O-trans 13a compared with the corre-
sponding neutral pair of O-cis 6a and O-trans 7a attributable to nC → ␴ stabilization.
P
O

Novel Results Obtained by Freezing Berry Pseudorotation of Phosphoranes (10-P-5) 395
Stabilization of Hexacoordinated Anions
Derived from the Reactions of ␣-Anions from
O-cis 6: Trans Influence of the P O Bond
Reaction of the ␣-anion of O-trans benzylphospho-
rane 7h with PhCHO proceeded smoothly to afford
stilbenes and 13 in high yields (Scheme 9). Z-stilbene
was formed preferentially (Z/E was 59:41) in the re-
action with n-BuLi, and the Z/E ratio was up to 80:20
using KH as a base in the presence of 18-crown-
6 ether. The Z-selectivity was lower than that of a
spirophosphorane bearing an ethoxycarbonylmethyl
group [13]. In contrast to the smooth formation of
stilbenes from O-trans benzylphosphorane 7h, the
reaction of the corresponding anion of O-cis 6h with
PhCHO gave only the adduct, i.e., two diastereomers
of 14 without the formation of stilbenes (Scheme 9).
These two diastereomers (14A and 14B) could
not be separated by TLC, however, a prolonged re-
action time (>24 h) using n-BuLi as the base pro-
vided only 14B, whose structure was confirmed by
X-ray analysis to have the relative configuration of
RP S S . We have already reported on the rapid
one-step pseudorotation at the phosphorus of O-
cis spirophosphoranes [6], similarly 14B existed as
a rapidly equilibrating mixture of RP S S and
SP S S , which showed distinct 31P NMR signals
at low temperatures.
Scheme 10 illustrates the possible mechanism of
the reaction of the O-cis benzyl anion 12h–M with
PhCHO. Kinetically, the addition of PhCHO to the
anion proceeds in a manner in which both phenyl
groups avoid each other at the aldol condensation
stage, and the resulting phosphate Int-A, where the
two phenyl groups become overlapped by forming
the oxaphosphetane ring, is the predominant inter-
mediate. Int-A gives 14A by treating it with a proton
source. However, Int-A is expected to be unstable
because of steric repulsion between the two phenyl
groups on the four-membered ring, and therefore
SCHEME 10
retro-aldol cleavage takes place from Int-A to re-
produce 12h–M. On the other hand, when the addi-
tion proceeds in an opposite manner, i.e., two phenyl
groups are overlapped with each other at the aldol
condensation stage, intermediates Int-B are gener-
ated. Both the Int-B are sterically less hindered,
and should be more stable intermediates than Int-
A. After equilibrium is established, only Int-B were
observed in the reaction solution, and 14B was ob-
tained as the sole adduct after hydrolysis in this
system.
When the thermodynamic product 14B was de-
protonated by KH in THF to form hexacoordinate
phosphate, three 31P NMR signals were observed in
the solution at the initial stage. But finally, only a sig-
nal at 110 ppm was observed after equilibration,
and the most stable phosphate 15B–K(18-crown-6)
could be isolated as single crystals by recrystalliza-
tion from n-hexane-CH2Cl2 under Ar (Scheme 11).
Surprisingly, these crystals were stable toward ato-
mospheric moisture at room temperature for several
months. The X-ray structure of 15B–K(18-crown-6)
is shown in Fig. 4. This became the first X-ray analy-
sis of a 12-P-6 phosphate bearing an oxaphosphetane
ring system. The structure is a slightly distorted oc-
tahedral one, and the two phenyl groups on the
SCHEME 9
SCHEME 11

396 Akiba et al.
[3] (a) Holmes, R. R. Pentacoordinated Phosphorus, ACS
Monograph 175 and 176; American Chemical Soci-
ety: Washington, DC, 1980; Vols. 1 and 2; (b) Akiba,
K.-y. (Ed.). Chemistry of Hypervalent Compounds;
Wiley-VCH: New York, 1999.
[4] Berry, R. S. J Chem Phys 1960, 32, 933–938.
[5] (a) Kojima, S.; Kajiyama, K.; Akiba, K.-y. Tetrahedron
Lett 1994, 35, 7037–7040; (b) Kojima, S.; Kajiyama,
K.; Akiba, K.-y. Bull Chem Soc Jpn 1995, 68, 1785–
1797.
[6] Kojima, S.; Kajiyama, K.; Nakamoto, M.; Akiba, K.-y.
J Am Chem Soc 1996, 118, 12866–12867.
[7] (a) Trippett, S. Phosphorus Sulfur 1976, 1, 89–98;
(b) Holmes, R. R. J Am Chem Soc 1978, 100, 433–
446; (c) Eisenhut, M.; Mitchell, H. L.; Traficante, D.
D.; Kaufman, R. J.; Deutsch, J. M.; Whitesides, G. M.
J Am Chem Soc 1974, 96, 5385–5397; (d) Moreland,
C. G.; Doak, G. O.; Littlefield, L. B.; Walker, N. S.;
Gilje, J. W.; Braun, R. W.; Cowley, A. H. J Am Chem
Soc 1976, 98, 2161–2165; (e) Buono, G.; Llinas, J. R.
J Am Chem Soc 1981, 103, 4532–4540; (f) Griend,
L. V.; Cavell, R. G. Inorg Chem 1983, 22, 1817–1820;
(g) McDowell, R. S.; Streitwieser, Jr. A. J Am Chem
Soc 1985, 107, 5849–5855; (h) Wang, P.; Zhang,
Y.; Glaser, R.; Reed, A. E.; Schleyer, P. von R.;
Streitwieser, A. J Am Chem Soc 1991, 113, 55–64;
(i) Wasada, H.; Hirao, K. J Am Chem Soc 1992,
114, 16–27; (j) Thatcher, G. R. J.; Campbell, A. S. J
Org Chem 1993, 58, 2272–2281; (k) Nakamoto, M.;
Kojima, S.; Matsukawa, S.; Yamamoto, Y.; Akiba,
K.-y. J Organomet Chem 2002, 643–644, 441–452.
[8] (a) Timosheva, N. V.; Prakasha, T. K.;
Chandrasekaran, A.; Day, R. O.; Holmes, R. R.
Inorg Chem 1995, 34, 4525–4526; (b) Timosheva,
N. V.; Chandrasekaran, A.; Prakasha, T. K.; Day, R.
O.; Holmes, R. R. Inorg Chem 1996, 35, 6552–6560;
(c) Vollbrecht, S.; Vollbrecht, A.; Jeske, J.; Jones, P. G.;
Schmutzler, R.; du Mont, W.-W. Chem Ber/Recueil
1997, 130, 819–822.
FIGURE 4 Crystal structure (30% thermal ellipsoids) of
15B–K(18-crown-6).
four-membered ring are located with a trans rela-
tionship to each other. The most important finding
is that the structure has a configuration which could
be assumed to have been formed by the attack of the
alkoxide anion to the ␴
orbital of a O-cis phos-
P
O
phorane 14B. This is consistent with the highly elec-
trophilic nature of the ␴ O orbital and stabilization
P
of the subsequent hexacoordinate state by the trans
influence of the P O bond.
[9] Kajiyama, K.; Kojima, S.; Akiba, K.-y. Tetrahedron
Lett 1996, 37, 8409–8412.
[10] Kajiyama, K.; Yoshimune, M.; Nakamoto, M.;
Matsukawa, S.; Kojima, S.; Akiba, K.-y. Org Lett 2001,
3, 1873–1875.
[11] Kojima, S.; Doi, Y.; Okuda, M.; Akiba, K.-y.
Organometallics 1995, 14, 1928–1937.
[12] Nagase, S. The Institute for Molecular Science,
Okazaki, Japan.
[13] Kojima, S.; Takagi, R.; Akiba, K.-y. J Am Chem Soc
1997, 119, 5970–5971.
REFERENCES
[1] Engel, R. (Ed.). Handbook of Organophosphorus
Chemistry; Marcel Dekker: New York, 1992.
[2] (a) Westheimer, F. H. Acc Chem Res 1968, 1, 70–78;
(b) Thatcher, G. R. J.; Kluger, R. Adv Phys Org Chem
1989, 25, 99–265.