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Asymmetric and DoublyAsymmetric 1,3-DipolarCycloadditons in theSynthesis of EnantiopureOrganophosphorusCompoundsK. Michaz Pietrusiewicz , WieszawaHozody , Marek Koprowski , StefanoCicchi , Andrea Goti & Alberto Brandia Department of Organic Chemistry , M.Curie-Sklodowska University , Gliniana33, 20-031 Lublin, Polandb Department of Organic Chemistry , M.Curie-Sklodowska University , Gliniana33, 20-031 Lublin, Polandc Centre of Molecular andMacromolecular Studies, P.A.S ,Sienkiewicza 112, Lódź, Polandd Dipartimento di Chimica Organica ,Universita di Firenze , via Capponi 9,50121 Firenze, Italy

e Dipartimento di Chimica Organica ,Universita di Firenze , via Capponi 9,50121 Firenze, Italyf Dipartimento di Chimica Organica ,Universita di Firenze , via Capponi 9,50121 Firenze, ItalyPublished online: 17 Mar 2008.

To cite this article: K. Michaz Pietrusiewicz , Wieszawa Hozody ,Marek Koprowski , Stefano Cicchi , Andrea Goti & Alberto Brandi (1999)Asymmetric and Doubly Asymmetric 1,3-Dipolar Cycloadditons in theSynthesis of Enantiopure Organophosphorus Compounds, Phosphorus,Sulfur, and Silicon and the Related Elements, 144:1, 389-392, DOI:10.1080/10426509908546263

To link to this article: http://dx.doi.org/10.1080/10426509908546263

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Phosphorus. Sulfur and Silicon, 1999, Vol. 144-146. pp. 389-392 © 1999 OPA (Overseas Publishers Association) N.V.Reprims available directly from the publisher Published by license under thePhotocopying permitted by license only Gordon and Breach Science Publishers imprint.

Primed in Malaysia

Asymmetric and Doubly Asymmetric 1,3-DipolarCycloadditons in the Synthesis of Enantiopure

Organophosphorus Compounds

K. MICHAL PIETRUSIEWICZa, WIESLAWA HOLODYa,MAREK KOPROWSKIb, STEFANO CICCHIC, ANDREA GOTIC and

ALBERTO BRANDIC

^Department of Organic Chemistry, M. Curie-Skfodowska University, Gliniana 33,20-031 Lublin, Poland, Centre of Molecular and Macromolecular Studies,

P.A.S, Sienkiewicza 112, Lodz, Poland, and cDipartimento di Chimica Organica,Universita di Firenze, via Capponi 9, 50121 Firenze, Italy

Enantiopure five-membered ring nitrones derived from L-tartaric acid and from Z--malic acidundergo highly regio- and stereoselective cycloaddition reactions with an excess of racemic2,3-dihydro-l-phenyl-l//-phospholes producing two readily separable tricyclic cycloadductsand concomitantly effecting kinetic resolution of the dihydrophosphole derivative. Stereo-chemistry of the cycloaddition process and scope of the kinetic resolution process have beenestablished in details and adjusted to produce dihydrophosphole derivatives in good yieldsand in very high optical purity. To effect syntheses of single cycloadducts of 100% ee thetechniques of doubly asymmetric synthesis and parallel kinetic resolutions have beenemployed. The resulting tricyclic cycloadducts feature 2,2-connection of pyrrolidine andphospholane rings and five to seven contiguous stereogenic centers of which three have beeninduced and one or two kinetically resolved during the cycloaddition process.

During our ongoing research'15' on the use of 1,3-dipolar cycloadditions for

stereoselective construction of functionalized P-chiral systems we have found recently161

that reaction of racemic 1-phenyl dihydrophosphole oxide (1) with enantiopure nitrone

derived from P-glyceraldehyde gave a 1.7:1 mixture of only two stereoisomeric products

i ?

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390 K. MICHAL PIETRUS1EWICZ et al.

originating from the (/<)-l and the (.V)-l, respectively,1'1 and left the unreacted portion of

1 enriched accordingly in the .V enantiomer. Further research in the same vein and

judicious use of five-membered ring nitrones derived from /.- or /)-tartaric acid'89' and /.-

or /)-malic acid1'"1 in combination with various dihydrophosphole derivatives resulted in

the development of a general and highly enantioselective 1,3-dipolar cydoaddition

procedure which offers ready access to both the enantiopure P-chiral tricyclic

cycloadducts and the resolved P-chiral dihydrophosphole derivatives of very high

enantiomeric purity. The procedure is exemplified below with a reaction of the /.-tartaric

Bu'O OBi/ Bu'O OButJ

P

\ /

benzene

60°C.38h

1.5 eq 91%

acid derived nitrone with a 50% excess of racemic

1 which yielded selectively only two readily

separable enantiopure cycloadducts and left

nearly entire excess of 1 almost completely

resolved.'"' The analysis of the stereochemical

OBut

(-YK>96%ee

27%

Ph

i > O

-o \ //

Ph

major

course of this cydoaddition has been facilitated by the X-ray structures of the two

cycloadducts and pointed out to the two plausible TS constructs which are delineated

above. As it follows, 1 has been approached by the nitrone exclusively from the face

bearing the smaller P=O substituent and exclusively in the exo mode. The enantiomers of

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ENANTIOPURE ORGANOPHOSPHORUS COMPOUNDS 391

1 have thus been discriminated by the proximal (C3) OBu' group in the nitrone which

could effectively hinder the approach in the minor path but apparently could not exert

such an effect in the major path. This clear-cut enantiodiscriminating pattern has then

been exploited in the equally facile and efficient kinetic resolutions utilizing the same /.-

tartaric acid derived nitrone and a series of 1-phenyl dihydrophosphole chalcogenides

possessing similarly well differentiated faces of the dihydrophosphole ring. The resolved

1-phenyl dihydrophosphole chalcogenides were obtained in ca 31% yield and were found

0 Ph Ph Se Ph O OEt

6(-ysP

to be of 98-100% optical purity. They are listed above in their absolute configurations

together with the 1-ethoxy derivative which was analogously resolved with the aid of the

/.-malic acid derived nitrone, albeit somewhat less cleanly and less efficiently.

The cycloadducts formed in these kinetic resolution experiments are also highly

valuable as they feature five to seven contiguous stereogenic centers of the unique

configuration and can serve as immediate precursors to a family of enantiopure amino

alcohols and amino phosphines incorporating the 2,2'-coup!ed pyrrolidino-phospholane

ring system in their structure. They are usually easily isolated from the reaction mixtures

° * .>Ph

\ /'

ButO,OBut

benzene

60°C.12h100%

' \ //f\ benzene ^? * \ / 60°C,12h+ \S 1 9 0 %

O- " H

by chromatography or prompt crystallization but they can be also conveniently obtained

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392 K.MICHAL PIETRUSIEWICZ era/.

by means of the doubly asymmetric cydoadditions which, with the appropriate pairing of

substrate enantiomers as exemplified above, afford enantiopure cycloadducts of the

desired absolute stereochemistry as the single products. Alternatively, use of a racemic

dihydrophosphole derivative and the technique of parallel kinetic resolution'12'leads to

OBut s ^ n .Phbenzene

60°C,22 h

OBu1

the highly selective production of two distinct easily separable cycloadducts, each

derived from a different nitrone and a different dihvdronhosnhole enantiomer.

References

[ I ] A. Brandi, P. Cannavo', K.M. Pietrusiewicz, M. Zabfocka, and M. Wieczorek, J. Org.Chem. 54,3073 (1989).

[ 2] A. Brandi, S. Cicchi, A. Goti, K.M. Pietrusiewicz, and W. Wisniewski, Tetrahedron 46,7093(1990).

[ 3] A. Brandi, S. Cicchi, A. Goti, K.M. Pietrusiewicz, M. Zabiocka, and VV. Wisniewski,J.Org. Chem. 56,4383 (1991).

[4] K.M. Pietrusiewicz, I. Salamonczyk, W. Wieczorek, A. Brandi, S. Cicchi, and A. Goti,Tetrahedron 47,9083 (1991).

[ 5] A. Brandi, S. Cicchi, A. Goti, K.M. Pietrusiewicz, Tetrahedron: Asymmetry 2, 1063(1991).

[ 6] A. Goti, S. Cicchi, A. Brandi, and K.M. Pietrusiewicz, Tetrahedron: Asymmetry 2,1371(1991).

[ 7] K.M. Pietrusiewicz, W. Wieczorek, A. Goti, and A. Brandi. Phosphorus, Sulfur andSilicon 10, 131 (1992).

[ 8] R. Ballini, E. Mercantoni, and M. Petrini, J. Org. Chem. 57, 1316 (1992).

[ 9] S. Cicchi, I. Hold, and A. Brandi, J. Org. Chem. 58,5274 (1993).

[10] S. Cicchi, A. Goti, and A. Brandi, J. Org. Chem. 60,4743 (1995).

[II] S. Cicchi, A. Goti, M. Koprowski, and K.M. Pietrusiewicz, / . Org. Chem. 59, 1315(1994).

[12] E. Vedejs, and X. Chen, J. Am. Chem. Soc. 119,2584 (1997).

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