Synthesis and application of chiral bisphosphines through lithiation-conjugate addition tandem cyclization of chiral α,β,ψ,ω-unsaturated bisphosphine oxide

Article abstract of DOI:10.1039/b109269c

Upon treatment with lithium diisopropylamide achiral and chiral α,β,ψ,ω-unsaturated bisphosphine oxides underwent lithiation-conjugate addition tandem cyclization to afford the corresponding endo-α,β-unsaturated cyclic bisphosphine oxides; sequential ster

Full text of DOI:10.1039/b109269c

Synthesis and application of chiral bisphosphines through
lithiation–conjugate addition tandem cyclization of chiral
a,b,y,w-unsaturated bisphosphine oxide
Yasuo Nagaoka, Hideki Inoue, Nawal El-Koussi† and Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan.
E-mail: tomioka@pharm.kyoto-u.ac.jp
Received (in Cambridge, UK) 16th October 2001, Accepted 28th November 2001
First published as an Advance Article on the web 7th January 2002
Upon treatment with lithium diisopropylamide achiral and
chiral a,b,y,w-unsaturated bisphosphine oxides underwent
lithiation–conjugate addition tandem cyclization to afford
the corresponding endo-a,b-unsaturated cyclic bisphos-
phine oxides; sequential stereoselective reduction of the
cyclized bisphosphine oxide gave the corresponding trans-
and cis-bisphosphines that were successfully applicable in a
catalytic asymmetric hydrogenation as chiral bisphosphine
ligands.
As part of our studies aimed at a synthetic application of lithium
Fig. 1 Synthesis and cyclization of 3.
phosphonates,1 we have developed an organolithium-initiated
conjugate addition–Michael tandem cyclization of a,b,y,w-
Asymmetric cyclization was also carried out using a chiral
a,b,y,w-unsaturated phosphine oxide 7.
unsaturated bisphosphonates 3 giving the corresponding carbo-
cycles bearing two phosphonate moieties.2 If selective deproto-
nation of an a-vinylic proton of 3 is possible, intramolecular
Michael addition of the resulting a-vinyl anion 4 produces
endo-a,b-unsaturated cyclic bisphosphonates and bisphosphine
oxides 5 (Fig. 1). In contrast to the established double Michael
reaction of a,b,y,w-unsaturated biscarboxylates for an efficient
way to construct carbocycles,3 such a lithiation–cyclization
sequence is a unique feature of the unsaturated bisphosphonates
or bisphosphine oxides 3. Since phosphonates are isosteric
analogues of natural phosphates, nucleotides, amino acids and
so on,4,5 and they are also versatile synthetic precursors of
olefins6 as well as chiral phosphine ligands,7 the synthetic
methodology for 5 is desirable to be developed. We describe
herein the facile and selective synthesis of 5 through lithiation–
Michael cyclization of 3 with lithium diisopropylamide.
Unsaturated bisphosphonates and phosphine oxides 3 were
readily prepared by the Horner–Wadsworth–Emmons reaction
of methylenebisphosphonates or diethyl(diphenylphosphor-
yl)methylphosphonate 28 with the corresponding a,y-dialde-
hydes 19 (Fig. 1). Reaction of 3a (Y = OEt, n = 6) with 1.3
equivalents of LDA in THF at 278 °C for 10 min afforded the
corresponding six-membered bisphosphonate 5a (Y = OEt, n =
6) as a sole product in 82% yield. No products derived from a
conjugate addition of LDA to 1a were observed.2 Likewise, the
five-membered bisphosphonate 5b (Y = OEt, n = 5) was
obtained in 75% yield by treating 3b with LDA for 20 min at
278 °C. The seven-membered bisphosphonate 5c (Y = OEt, n
= 7) was not a suitable target and was obtained in 16% yield by
the treatment of 3c at 220 °C for 10 min.10 The cyclization of
bisphosphine oxides 3d (Y = Ph, n = 6) with LDA in THF was
also examined and was found to be quite difficult due to its
extremely low solubility in a variety of solvents.
† Visiting scientist from Faculty of Pharmacy, Assiut University, Egypt.
Fig. 2 Tandem cyclization of 7 and conversion to biphosphates 14–16.
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We extended the lithiation–Michael cyclization of 3 to an
asymmetric reaction of a chiral a,b,y,w-unsaturated bi-
ligands for asymmetric reactions is the focus of our current
study.
sphosphine oxide 7 prepared from
L-tartaric acid (Fig. 2).
This work was supported by a Grant-in-Aid for Scientific
Research on Priority Areas (A) ‘Exploitation of Multi-Element
Cyclic Molecules’ from the Ministry of Education, Culture,
Sports, Science and Technology, Japan. N. E.-K. acknowledges
financial support from the Ministry of Higher Education of
Egypt.
DIBAL-H reduction of the dimethyl ether of ethyl tartrate 611
followed by Horner–Wadsworth–Emmons reaction of die-
thyl(diphenylphosphoryl)methylphosphonate 2 (Y = Ph) gave
an unsaturated bisphosphine oxide 7 in 48% overall yield.
Reaction of 7 with LDA in THF at 278 °C for 10 min afforded
tandem cyclization products (2)-9 in 60% yield and (2)-10 in
22% yield. The newly created asymmetric centers of 9 and 10
were assigned by NMR analysis, especially NOE measurement.
Selective production of 9 as a major carbocycle was ascribable
to the favorable cyclization shown in 8a, where the vinyl anion
attacks an olefin carbon from the direction opposite to the
adjacent methoxy group. The unsaturated phosphine moiety in
8a takes a more stable conformation than that in 8b that
produces 10. Lithium aluminium hydride treatment of 9 in THF
at 0 °C underwent 1,4-reduction to afford trans-11 and cis-12 in
79% and 15% yields, respectively. Diimide reduction of 9 in
aqueous methanol, on the contrary, gave cis-12 as a major
isomer in 62% yield together with trans-11 in 30% yield. Both
reduction methods were applied to 10 and, however, gave trans-
13 as a sole product without formation of cis product, probably
due to severe steric repulsion by three contiguous cis-groups on
the five-membered ring. These phosphine oxides were readily
converted to the requisite bisphosphines by deoxygenation with
trichlorosilane in benzene at 110 °C in nearly quantitative
yields.
Chiral bisphosphines prepared as above were applicable into
catalytic asymmetric reactions. For example, catalytic asym-
metric hydrogenation of 17 under 5 atmospheres of hydrogen
gas with 0.1 mol% of 15 and rhodium(NBD)2 perchlorate12 in
methanol at 50 °C for 24 h afforded quantitatively N-acetyl
phenylalanine 18 in 90% ee (Fig. 3).13
In summary, we have developed a lithiation–cyclization
procedure of readily available chiral and achiral a,b,y,w-
unsaturated bisphosphine oxides and bisphosphonates for the
conventional synthesis of chiral bisphosphines, which were
useful as chiral ligands for catalytic asymmetric reactions.
Application of the bisphosphines obtained here into the chiral
Notes and references
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2 Y. Nagaoka and K. Tomioka, Org. Lett., 1999, 1, 1467.
3 For the double Michael cyclization of unsaturated carbonyl compounds,
see: (a) P. Perlmutter, Conjugate Addition Reactions in Organic
Synthesis, Pergamon Press, London, 1992; (b) R. A. Bunce, Tetra-
hedron, 1995, 51, 13103; (c) T. Uyehara, N. Shida and Y. Yamamoto,
J. Org. Chem., 1992, 57, 3139.
4 For reviews on alkylphosphonates, see: (a) R. L. Hilderbrand, The Role
of Phosphonates in Living Systems, CRC Press, Boca Raton, FL, 1983;
(b) R. Engel, in Handbook of Organophosphorus Chemistry, ed. R.
Engel, Marcel Dekker, New York, 1992, ch. 11; (c) R. Engel, Chem.
Rev., 1977, 77, 349; (d) G. A. Rodan, Annu. Rev. Pharmacol. Toxicol.,
1998, 38, 375.
5 Bisphosphonates were used as receptor molecules for the anomer-
selective recognition of amino sugars. T. Schrader, J. Am. Chem. Soc.,
1998, 120, 11816.
6 S. E. Kelly, in Comprehensive Organic Synthesis, ed. B. M. Trost,
Pergamon, Oxford, 1991.
7 (a) K. Tomioka, Synthesis, 1990, 541; (b) R. Noyori, Asymmetric
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8 Methylenebisphosphonate 2 (Y = OEt) is commercially available.
Diethyl(diphenylphosphoryl)methylphosphonate
2 (Y = Ph) was
prepared by the lithiation of methyl(diphenyl)phosphine oxide with
LDA and then treatment with dichlorophosphonate, see: M.-P. Teulade,
P. Savignac, E. E. Aboujaoude, S. Lietge and N. Collignon, J.
Organomet. Chem., 1986, 304, 283.
9 J. Fakstorp, D. Raleigh and L. E. Schniepp, J. Am. Chem. Soc., 1950, 72,
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10 A large amount of mixture of polymeric products was obtained.
11 D. Seebach, H.-O. Kalinowski, B. Bastani, G. Crass, H. Daum, H. Dörr,
N. P. DuPreez, V. Ehrig, W. Langer, C. Nüssler, H.-A. Oei and M.
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13 Hydrogenation with trans-14 and 16 gave quantitatively 18 in 22% ee
and 21% ee.
Fig. 3 Catalytic asymmetric hydrogenation with 15.
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