Technical Field This invention relates to chiral heterocyclic compounds useful for asymmetric synthesis and catalysis. More particularly, the invention relates to chiral heterocyclic phosphine, sulfur, and nitrogen compounds for asymmetric synthesis and catalysis in the production of enantiomerically pure products.

Background Art The biological activities of many pharmaceuticals, fragrances, food additives and agrochemicals are often associated with their absolute molecular configuration.

While one enantiomer gives a desired biological function through interactions with natural binding sites, another enantiomer usually does not have the same function and sometimes has deleterious side effects. A growing demand in pharmaceutical industries is to market a chiral drug in enantiomerically pure form.

To meet this challenge, chemists have explored many approaches for acquiring enantiomerically pure compounds ranging from optical resolution and structural modification of naturally occurring chiral substances to asymmetric catalysis using synthetic chiral catalysts and enzymes. Among these methods, asymmetric catalysis is often the most efficient because a small amount of a chiral catalyst can be used to produce a large quantity of a chiral target molecule. During the last two decades, great effort has been devoted to discovering new asymmetric catalysts and more than a half-dozen commercial industrial processes have used asymmetric catalysis as the key step in the production of enantiomerically pure compounds.

The majority of current asymmetric catalytic processes relies on transition metal catalysts bearing chiral ligands. Asymmetric phosphine ligands have played a significant role in the development of transition metal catalyzed asymmetric reactions.

While certain metal catalyzed phosphine chiral ligands have shown acceptable enantioselectivities in numerous reactions, there are a variety of reaction in which only modest enantioselectivity has been achieved with these ligands. The use of enzymes as asymmetric catalysts is limited because very few pure enzymes have been found to facilitate highly enantioselective catalytic reactions.

Given the limitations with transition metal catalysts and enzymes, the use of organic catalysts for asymmetric synthesis has attracted increasing attention.

Compared with transition metal catalysts, there are several advantages of using pure organic catalysts: recovery of organic catalysts generally is easy since the catalysts are covalently bound and relatively stable; no contamination of toxic heavy metals exists during the reaction; and pure organic catalysts, as compared to metal catalysts, are environmentally benign.

Several organic asymmetric catalysts have been discovered and used in industrial applications. For example, chiral phosphines are known to catalyze a number of organic reactions. Vedejs et al., in the Journal of Organic Chemistry ("J.

Org. Chem. '),Vol. 61, 8368 (1996), demonstrated phosphine-catalyzed enantioselective acylations of secondary alcohols. Whitesell and Felman, J: Org.

Chem., Vol. 42, 1663 (1977), used nitrogen-based chiral auxiliaries such as trans 2,5- dimethylpyrrolidine for organic synthesis.

This invention discloses several new chiral heterocyclic compounds for asymmetric synthesis and catalysis. These compounds contain rigid ring structures useful for restricting conformational flexibility of the compounds, thus enhancing chiral recognition. The invention provides chiral heterocyclic compounds which contain phosphorous, nitrogen, and sulfur atoms within the ring structure. The chiral heterocyclic compounds disclosed in the invention allow for new catalytic asymmetric processes, including reactions proceeding by a variety of methods described herein.

In such a manner, the invention provides an efficient and economical method with which to synthesize chiral drugs and agrochemicals.

Disclosure of the Invention It is an object of the invention to provide chiral heterocyclic compounds for asymmetric synthesis and catalysis.

It is also an object of the invention to provide chiral heterocyclic phosphine, sulfur, and nitrogen compounds for asymmetric synthesis and catalysis in the production of enantiomerically pure products.

It is also an object of the invention to provide chiral heterocyclic phosphine, sulfur, and nitrogen compounds for asymmetric synthesis and catalysis in organic reactions such as [3+2l cycloaddition, nucleophilic gamma addition, Baylis-Hillman, acyl transfer, aziridation of aldehydes, epoxidation, thioether-mediation, alkylation, deprotonation, and other commonly known asymmetric carbon-carbon bond formations.

It is also an object of the invention to provide a method of making chiral heterocyclic phosphine, sulfur, and nitrogen compounds for asymmetric synthesis and catalysis.

It is also an object of the invention to provide an efficient and economical method with which to synthesize chiral drugs and agrochemicals.

In accordance with the invention, there is thus provided a chiral heterocyclic phosphine compound selected from each enantiomer of the formula I or II wherein n is 1 or 2; R is selected from alkyl having 1-8 carbon atoms, aryl, and substituted aryl; R' is selected from hydrogen, alkyl having 1-8 carbon atoms, aryl, and substituted aryl; and A is selected from a carbocyclic or heterocyclic, aromatic, saturated or partially saturated, mono- or bicyclic ring, which can be further substituted with one or more alkyl or aryl groups, and can comprise one or more additional chiral centers. In one embodiment of the invention, a chiral heterocyclic phosphine compound is provided as an asymmetric catalyst or a component of an asymmetric catalyst in organic reactions selected from [3+2] cycloaddition, nucleophilic gamma addition, Baylis-Hillman, acyl transfer, and other commonly known asymmetric carbon-carbon bond formations.

In accordance with another object of the invention, there is provided a chiral heterocyclic sulfur compound selected from each enantiomer of the formula III or IV wherein n is 1 or 2; R is selected from alkyl having 1-8 carbon atoms, aryl, and substituted aryl; and A is selected from a carbocyclic or heterocyclic, aromatic, saturated or partially saturated, mono- or bicyclic ring, which can be further substituted with one or more alkyl or aryl groups, and can comprise one or more additional chiral centers. In one embodiment of the invention, a chiral heterocyclic sulfur compound is provided as an asymmetric catalyst or a component of an asymmetric catalyst in organic reactions selected from aziridation of aldehydes, epoxidation, thioether- mediation, and other commonly known asymmetric carbon- carbon bond formations.

In accordance with another object of the invention, there is provided a chiral heterocyclic nitrogen compound selected from each enantiomer of the formula V or VI wherein n is 1 or 2; R is selected from alkyl having 1-8 carbon atoms, aryl, and substituted aryl; A is selected from a carbocyclic or heterocyclic, aromatic, saturated or partially saturated, mono- or bicyclic ring, which can be further substituted with one or more alkyl or aryl groups, and can comprise one or more additional chiral centers; R" is selected from hydrogen, alkyl having 1-8 carbon atoms, aryl, substituted aryl, and a group of the formula VII or VIII wherein the chiral nitrogen heterocycle in the group is identical to the other chiral nitrogen heterocycle in formula V or VI; and R"' is a diradical selected from alkyl diradicals having 1-8 carbon atoms, aryl diradicals, or substituted aryl diradicals. In one embodiment of the invention, a chiral heterocyclic nitrogen compound is provided as an asymmetric catalyst, a component of an asymmetric catalyst, or a chiral auxiliary in organic reactions selected from Baylis-Hillman, acyl transfer, alkylation, deprotonation, and other commonly known asymmetric carbon-carbon bond formations.

Detailed Description of the Invention This invention pertains to a chiral heterocyclic phosphine, sulfur, or nitrogen compound for asymmetric synthesis and catalysis in the production of enantiomerically pure products.

A suitable aryl of the invention includes phenyl, furan, thiophene, pyridine, pyrole, napthyl and similar aromatic rings. Substituted aryl refers to an aryl substituted with one or more alkyl groups having 1-8 carbon atoms, alkoxy having 1-8 carbon atoms, alkylcarbonyl having 1-8 carbon atoms, carboxy, alkoxycarbonyl having 2-8 carbon atoms, halo (Cl, Br, F or I) amino, alkylamino or dialkylamino.

A suitable carbocyclic or heterocyclic, aromatic, saturated or partially saturated, mono- or bicyclic ring, which can be further substituted with one or more alkyl or aryl groups, and can comprise one or more additional chiral centers for use herein includes but is not limited to one derived from the parent compound furan, thiophene, pyrrole, tetrahydrofuran, tetrahydrothiopene, pyrrolidine, arsole or phosphole; or from the parent compound bipyridine, carbazole, benzofuran, indole, benzpyrazole, benzopyran, benzopyronone or benzodiazine.

Alkyls having 1-8 carbon atoms include straight or branched chain alkyls and cycloalkyls having 3 to 8 carbon atoms. Representative examples are methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl, cyclopentyl, hexyl cyclohexyl and the like. The alkyl group can be substituted with phenyl, substituted phenyl or alkoxy, carboxy, alkyoxycarbonyl, halo, amino, or alkyl amino or dialkylamino as defined above. Those skilled in the chemical art will recognize a wide variety of equivalent substituents.

A diradical is selected from alkyl diradicals having 1-8 carbon atoms, aryl diradicals, or substituted aryl diradicals. A suitable diradical includes but is not limited to -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -C6H4-, or ortho-substituted- C6H4-, and the like.

The invention encompasses a variety of asymmetric reactions utilizing catalysts of the invention, such as [3+2] cycloaddition, nucleophilic gamma addition, Baylis-Hillman, acyl transfer, aziridation of aldehydes, epoxidation, thioether- mediation, alkylation, deprotonation, and other commonly known asymmetric carbon-carbon bond formations. The catalyst of the invention provides efficient and practical methods for producing chiral drugs for antihypertensive, antihistamine, cardiovascular and central nervous system therapies. The chiral heterocyclic compounds of the invention are also important in the production of chiral agrochemicals.

CHIRAL, HETEROCYCLIC PHOSPHINE, SULFUR, AND NITROGEN COMPOUNDS The invention provides chiral heterocyclic compounds containing phosphorous, sulfur, and nitrogen atoms. Chiral heterocyclic phosphine compounds, e.g., phosphabicyclo[2.2. l]heptanes I and phosphacycle II are shown in Figure 1.

Fig. 1 Both I and II contain rigid fused bicyclo structures which restrict conformational flexibility in the chiral system, leading to high enantioselectivity for a variety of asymmetric reactions described above.

The synthesis of chiral phosphabicyclo[2.2.1]heptanes depends on the availability of enantiomerically pure cyclic 1,4-diols (Scheme 1). Halterman et al., Organometallics, Vol. 10, 3449 (1991) and Vollhardt, Journal of the American Chemical Society ("JAm. Chem. Soc. "), Vol. 109, 8105 (1987) have previously prepared chiral cyclopentadiene derivatives from chiral diols. Halterman has synthesized chiral diols 1 and 2 from the inexpensive starting materials p-xylene and p-diisopropylbenzene, respectively.

The synthesis employed Birch reduction, followed by asymmetric hydroboration and recrystallization to 100% enantiomeric excess ("ee"). Conversion of the optically R Li,EtNH2 I)lpcBH2 inEt20 OH R = Me, I MsCI. Et3N OMs R = Mc, 3 R RS (from(+)-Pinene) <0» M,Cr. E1,N~ ,OoR RR 2) H202, NaOH R=iPr,2 > 99 °Nn R . R = /Pr, 4 OH OMs BH3 R, R, I)Li2PphinTF,rtBH3 R ~ Me, 5, I)HBF4.OM%cH2 R = Me, 7, 96 % 2) BH3 . THF PhC R = Pr, 6,50% 2) NaHCO3 Ph/S R = 'per, 8, 96% 2) R NaHCO3 Scheme I pure diols to the corresponding mesylates proceeds cleanly. Nucleophilic substitution by Li2PPh on the chiral dimesylates 3 and 4 generated the corresponding bicyclic phosphines, which were trapped by BH3-THF to form the air-stable boron-protected monophosphines 5 and 6, respectively. Deprotection with a strong acid produces the desired products [7, (1R, 2S, 4R, 5S)-(+)-2, 5-dimethyl-7-phenyl-7- phosphabicyclo[2.2.1]heptane; 8, (1R, 2R, 4R, 5R)-(+)-2, 5-diisopropyl-7-phenyl-7- phosphabicyclo-[2.2.1]heptane] in high yields. The chiral phosphacycle 10 was synthesized by the route show in Scheme 2.

Scheme 2 Chiral heterocyclic sulfur compounds, thiobicyclo[2.2.1]heptanes, III, and thiocycle IV, are shown in Figure 2.

Fig. 2 Thiobicyclo[2,2,1]heptanes (e.g., III) can be made by nucleophilic addition of Na2S to the chiral dimesylates (Scheme 3).

Scheme 3 Chiral heterocyclic nitrogen compounds, e.g., azabicyclo[2,2,1]heptanes V, and azacyclo VI were made by a slightly different route (Scheme 4).

Nucleophilic addition of azide to dimesylate 3 forms intermediate 12. Reduction of 12 with H2 to an amine and intramolecular closure of the amine on to the mesylate occurs smoothly in the same operation gives the desired product 13. Further straightforward reactions lead to the other desired chiral nitrogen containing compounds 14 and 15. Scheme4 The sulfur and nitrogen chiral heterocyclic compounds of the general formula IV and VI were synthesized according to the method shown in Scheme 5. I) Asyrnrnic dmb(ni'on 2) Qxidxion by 1i°2 Mo 1)Pirsol Coupling or 2) Eiiniinxion I) LEydXation and oxidxion by *°2 2) Ch reolution or I) NtCI. Et3N Hz H 2)Ialy VI 3), . Hv 8hea \N VI MA HO H 1)O, Et3N H Ci, E 3N ( IV S: Scheme 5 ASYMMETRIC SYNTHESIS AND CATALYSIS USING CHIRAL HETEROCYLIC COMPOUNDS The invention is illustrated by using the chiral heterocyclic compounds of the invention in asymmetric synthesis and catalysis.

[3+2] CYCLOADDITIONS WITH CHIRAL HETEKOCYCLIC COMPOUNDS The identification of the prostaglandins, steroids and related natural products as important synthetic targets has stimulated the development of many diverse strategies for the synthesis of five-membered carbocycles. The efficient stereoselective synthesis of highly functionalized cyclopentane rings remains an important challenge in organic chemistry. Among the reported methods for the synthesis of five-membered ring carbocycles, [3+2] cycloadditions have the advantage of simultaneously forming multiple bonds, although issues of chemo-, regio-, diastereo- and enantioselectivity must be resolved if such a process is to achieve useful generality. Transition metal-catalyzed, anionic, cationic, and free radical mediated [3+2] cycloadditions have previously been investigated in the formation of five-member carbocycles. However, none of these methods produce the regioselectivity, enantioselectivity, and scope of application for the synthesis of cyclohexane derivatives.

Asymmetric [3+2] cycloadditions were conducted using several known chiral phosphine catalysts (16-18) to provide comparison points with [3+2] cycloadditions conducted with the chiral heterocyclic phosphine compound of the invention.

The asymmetric reactions were done by mixing ethyl 2,3-butadienoate and ethyl acrylate in benzene with 10 mol % of phosphine at room temperature. Table 1 lists the results with different chiral heterocyclic phosphine compounds. H COOR1 cat. chiral E H H phinecmpds. K2 K2 K3 E + K3 + K3 H OR, - - N2, It COOR1 COOK1 K2 Nz, rt .COOR, E A B Table 1. Phosphine-Catalyzed Asymmetric (3+2) Cycloaddition Entry Phospine E R1 R2 R3 solvent T(°C) Yield(%) A:Bb %ee of Ab Config.@ 7 7 COOEt Et H H benzene rt 66 95:5 81 (-)R 2 8 COOEt Et H H benzene rt 76 97:3 81 (-)R 3 16 COOEt Et H H benzene rt 80 80:20 56 (+)S 4 17 COOEt Et H H benzene rt 83 72:29 6 (+)S 5 18 COOEt Et H H benzene rt 33 73:27 12 (-)R 6 7 COOiB@ Et H H benzene rt 46 100:0 86 (-)R 7 7 COOiB@ Et H H benzene rt 69 95:5 89 (-)R 8 7 COOiB@ Et H H toluene 0 42 97:3 93 (-)R 9 8 COOM Et H H benzene rt 87 96:4 79 (-)R 10 8 COOiB@ Et H H benzene rt 92 100:0 88 (-)R II 8 COOiB@ Et H H toluene 0 88 100:0 93 (-)R 12 8 COOiB@ Et H H benzene rt 75 95:5 88 (-)R 13 7 COOEt tBu H H benzene rt 13 97:3 89 (-)R 14 8 COOEt tBu H H benzene rt 84 94:6 69 (-)R 15 8 COOEt El COOEt H benzene rt 49 ---.- 79 (+) 16 8 COOEt Et H COOEt benzene rt 84 -------- 36 (-) a The reaction was carried out under N, using a chiral phosphine (tO mol %), 2.3-butadienoate(100 mol %) and an electron deficientolefins (to0 mol %) b. A:B and % ee were measured by GC using and γ.DEX columns The absolute configuration was determined by comparing the optical rotation with the literature value.

Phosphabicyclo[2.2.1]heptanes 7-8 are more effective both in terms of regioselectivity (A:B ratio) and enantioselectivity (% ee of A) than known chiral phosphines 16-18. The absolute configuration of product A was assigned by correlation with (1R, 3R)-dihydroxymethyl-3-cyclopentane. In particular, the enantioselectivity with 7 (81% ee, R) is much higher than with 17 (6% ee, S), which illustrates the consequences of using a rigid bicyclic [2.2.1] structure rather than the conformationally more flexible five-membered ring phosphine.

Changing the size of ester group in the electron-deficient olefin alters the enantioselectivity. With phosphine 7, the enantioselectivity increases as the size of ester increases (entry 1, Et, 81% ee; entry 6, Bu, 86% ee; entry 7, tBu, 89% ee). A similar trend was observed with phosphine 8 (entries 2, 9-10, and 12). Upon cooling the reaction to 0 OC in toluene, up to 93 % ee of A was obtained with phosphines 7-8 with excellent regioselectivity (entries 8 and 11). Increasing the size of the ester moiety in the 2,3-butadienoates, however, has different effects on the product ee with phosphine 7 (entry 1, Et, 81% ee; entry 13, tBu, 89% ee) or 8 (entry 2 , Et, 81% ee; entry 14, tBu, 69% ee). A second major difference between catalysis by 70r 8 is in the yield of products. The conversion to the desired products with 8 is generally higher than with 7 (e.g., entries 6-8 vs entries 9-12). With diethyl maleate (entry 15) and diethyl fumarate (entry 16) as substrates, single cis- and trans-products were obtained with 8, respectively. While the % ee of the cis-product (entry 15, 79% ee) is slightly lower than the result with ethyl acrylate (entry 2, 81% ee), the trans- product has much lower optical purity (entry 16, 36% ee). As indicated by the Table 1, a [3+2] cycloaddition between 2,3-butadienoates and electron deficient olefins catalyzed by the chiral heterocyclic compounds of the invention provides cyclopentene products with excellent regioselectivity and enantioselectivity.

ASYMMETRIC NUCLEOPHILIC GAMMA ADDITION The success of chiral heterocyclic phosphine catalyzed [3+2] cycloadditions between 2,3-butadienoates and electron-deficient olefins prompted further examination of other chiral heterocyclic phosphine catalyzed reactions. One such reaction, discovered by Trost, J. Am. Chem. Soc., Vol. 116, 3167 (1994), is the phosphine catalyzed "umpolung" C-C bond formation at the y-position of 2- butynoates with malonate-type nucleophiles (Scheme 6). In this phosphine catalyzed "umpolung" C-C bond forming reaction, generation of electrophilic character at the y-carbon of 2-butynoates creates a regiochemical complement to the Michael addition.

Using chiral phosphabicyclo[2.2. l]heptanes 7 and 8 as catalysts, and under conditions similar to those cited by Trost, moderate enantioselectivities (42-68% ee, entry 1-4) have been obtained between ethyl 2-butynoate and several pronucleophiles with 7 as the catalyst (Table 2).

Scheme 6 Table 2. Phosphine-Catalyzed Asymmetric y-Addition" O o (19) COOMe ;eOOMe 1 \ Hz 80 16 76 59(-) \ OOEt 2 50 72 57 68(-) COOEt (20) 0COOEt20 3 COOEt 110 50 44 51(+) NCOOEt a: The reaction was carried out under N2 with chiral phosphine 1 (30 mol%), NaOAc (50 mol%), acetic acid (50 mol%), ethyl 2-butynoate (100 mol%) and Nu-H (100 mol%). b: % ee was measured by GC with a y-Dex column.

Under milder reaction conditions, using ethyl 2,3-butadienoate as an electrophile instead of 2-butynoate, the y-addition reaction was conducted under various conditions by changing catalysts, additives, and substrates. Table 3 lists the results of this asymmetric reaction with several chiral phosphines (7, 8, 10, 16-18). E300C*H 00 OAc+H()0 H H H I*ilFm m 0Et Table 3. Asymmetric y-Addition Catalyzed by Various Chiral Phosphinesa Entry Phosphine Time Yield (5) ee % b rotation 1 7 27h 76 74 - 2 8 27h 80 69 - 3 10 18 71 35 + 4 16 4d 58 8 - 5 17 5 d 66 20 + 6 18 >10d 46 20 + a: The reaction was carried out under N2 at rt. With chiral phosphines (1-6) (10 mol%), NaOAc (50 mol%), AcOH (50 mol%), ethyl 2,3-butadienoate (100 mol%) and 2-methoxycarbonyl cyclopentanone (100 mol%). B: % ee was measured by GC with a y-Dex column.

The new phosphines 7 and 8 (entries 1-2) are more selective and active catalysts than the previously reported chiral phosphines 16-18 (entries 4-6).

Compared to the conformationally rigid dimethyl phosphabicyclo[2.2.1]heptane 7 (entry 1, 74% ee), the corresponding five-membered ring phosphacycle 16 gives much lower enantioselectivity (entry 4, 8% ee). This result is similar to that observed in the asymmetric cyclic phosphine catalyzed [3+2] cycloaddition described above. Phosphacycle 10 produced moderate enantioselectivity (entry 3).

Other Applications of the Invention Many other asymmetric organic reactions can by facilitated by the chiral heterocyclic compounds of the invention. For example, the chiral heterocyclic nitrogen compound of general formula V or compound 15 can be used as chiral catalysts or auxiliaries for asymmetric deprotonation, enamine alkylation, cycloaddition reactions, and the Baylis-Hillman reaction. The dimer derivative of azabicyclo[2.2.1]heptane, 15, can serve as a chiral auxiliary in an asymmetric deprotonation. The fused [2.2.1] structure in V makes the nitrogen lone pair more nucleophilic than other trialkyl amines such as Et3N.

The chiral heterocyclic sulfur compounds of the invention are particularly suited for use in asymmetric epoxidation of aldehydes. Most epoxidation systems are still not very efficient for unfunctionalized trans-olefins. Direct epoxidation of carbonyl compounds using sulfur ylides formed from III and IV provides a route for the formation of chiral trans epoxides. One target is (2R, 2S)-3-(4-methoxyphenyl) glycidate, which is a key intermediates for the synthesis of diltiazem hydrochloride, a potent blocker used for the treatment of anginina pectoris and hypertension.

Like epoxides, aziridines are important chiral building blocks in organic chemistry. Aggarwal et al., J: Org. Chem., Vol. 61, 430 (1996), applied his epoxidation system for asymmetric aziridination by replacing aldehydes with imines as the substrates, with impressive selectivity results. The application of chiral heterocyclic sulfur compounds of the general formula III or IV as asymmetric catalysts should similarly provide high enantioselectivity for a variety of substrates.

EXAMPLES Unless otherwise indicated, all reactions were carried out under nitrogen.

THF and ether were freshly distilled from sodium benzophenone ketyl. Toluene and 1,4-dioxane were freshly distilled from sodium. Dichloromethane and hexane were freshly distilled from CaH2. Column chromatography was performed using EM Silica gel 60 (230-400 mesh). 1H, 13C and 31p NMR were recorded at 300 or 360 MHZ NMR spectrometers. Chemical shifts are reported in ppm downfield from TMS with the solvent resonance as the internal standard. Optical rotation was obtained on a Perkin-Elmer 241 polarimeter. MS spectra were recorded on a KRATOS mass spectrometer MS 9/50 for LR-EI and HR-EI. GC analysis were done using chiral capillary columns (Supelco y-Dex 225 or P-Dex 120).

Example 1 Compounds 1-4 (shown in Scheme 1) were prepared according to literature procedure. See, e.g., Halterman et al., Organometallic, Vol. 15, 3957 (1996); Halterman & Chen, J. Am. Chem. Soc., Vol. 114, 2276 (1992).

Example 2 (1R, 2S, 4R, 5S)-(+)-2, 5-Dimethyl-7-phenyl-7-phosphabicyclo [2,2,l]heptane borane (5). To phenylphosphine (3.0 ml, 27.3 mmol) in THF (200 mL) was added n- BuLi (34.5 mL of a 1.6 M solution in hexane, 55 mmol) via syringe at -78 OC over 20 min. Then the orange solution was warmed up to rt and stirred for one hour at room temperature. To the resulting orange-yellow suspension was added a solution of (1 S,2S,4S,5S)-2,5-dimethyl-cyclohexane- 1 ,4-diol bis(methanesulfonate) (8.25 g, 27.5 mmol) in THF (100 mL) over 15 min. After the mixture was stirred overnight at room temperature, the pale-yellow suspension was hydrolyzed with NH4Cl-saturated aqueous solution. The mixture was extracted with ether (2 x 50 mL), and the combined organic solution was dried over anhydrous sodium sulfate. After filtering, the solvents were removed under reduced pressure. The residue was taken into methylene chloride (100 mL) and treated with BH3,THF (40 mL of a 1.0 M solution in THF, 40 mmol). After being stirred overnight, it was poured into NH4Cl-saturated aqueous solution which was extracted with CH2Cl2 (3 x 50 mL). The combined organic solution was dried over anhydrous Na2SO4. After filtration, the solvent was removed on rotavapor. The residue was subjected to chromatography on silicon gel column, eluted with hexanes/CH2Cl2 (4:1). The product was isolated as a white solid, <BR> <BR> soluble in CHCl3, THF, ether and AcOEt. Yield: 1.95 g (31%). [a]25, = + 59.5" ° (c 1.07, CHCl3). H-NMR (CDCl3): 5 7.60-7.30 (m, 5 H, C6H5), 2.60-2.40 (m, 2 H, CHP(BH3)Ph), 2.15-2.05 (m, 1 H, CH), 2.04-1.80 (m, 4 H, CH2), 1.65-1.50 (m, 1 H, CH), 1.32 (d, J(NH)= 6.5 Hz, 3 H, CH3), 0. 59 (d, J(NH)= 6.7 Hz, 3 H, CH3), 1.6- 0.2 (br, BH3); 13C-NMR (CDCl3): 5 131.74 (d, 2J(PC) = 7.3 Hz, Cortho), 130.56 (d, J(PC)= 43.9 Hz, Cipso), 129.92 (d, 4J(PC)= 2.0 Hz, Cpara), 128.44 (d, J(PC)= 8.6 Hz, Cmeta), 43.07 (d, J(CP)=30.5 Hz, CHP(BH3)Ph), 40.85 (d, J(PC)=31.6 Hz, CHP(BH3=Ph), 36.27 (CH2), 36.67 (d, J(PC)=13.5 Hz, CH2), 35.91 (d, ²J(PC)=3.5 Hz, CH), 34.65 (d, 2J(PC) 9.8 Hz, CH), 20.78 (CH3) 20.53 (CH3); 31P-NMR (CDCl3); 5 36.3 (d, broad, J(PB)= 58.8 Hz). MS m/z 232 (M+, 0.42), 218 (M+-BH3, 100), 203 (7.41), 176 (14.60), 136 (9.81), 109 (16.67), 91(6.59), 77 (5.51), 65 (3.71); HRMS Calcd for C,4H22BP: 232.1552 (M+); found: 232.1578; Cl4H,9P: 218.1224 (M+-BH3); found: 218.1233.

Example 3 (1R, 2R, 4R, 5R)-(+)-2, 5-Diisopropyl-7-phenyl-7-phosphabicyclo [2,2,l]heptane borane ( 6). Using the same procedure as in the preparation of 5. Yield: 0.33 g (50%). [α]D25 = + 25.5° (c 1.02, CHCl3). H-NMR (CDCl3): 5 7.55-7.30 (m, 5 H, C6H5), 2.85-2.70 9 (m, 2 H CHP(BH3)Ph), 2.30-2.20 (m, 1 H, CH), 2.18-2.00 (m, 1 H, CH), 1.95-1.65 (m, 4 H, C112), 1.40-1.20 (m, 2 H, CH), 1.03 (d, J(PH)= 6.5 Hz, CH3), 0.87 (d, J(PH)= 6.7 Hz, CH3), 0.85 (d, 3J(PH) = 7.4 Hz, CH-3), 0.53 (s, broad, 3 H, CH3), 1.5-0.2 (broad, BH3); 13C-NMR (CDCl3); #C=131.19 (d, ²J(PC)=8.3 Hz, Cortho), 130.71 (d, J(PC)=45.2 Hz, Cipso), 129.97 (d, 4J(PC)=2.5 Hz, Cpara), 128.45 (d, 3J(PC) = 9.5 Hz, Cmeta), 50.30 (d, 2J(PC) = 2.1 Hz, CH), 48.77 (d, 2J(PC) = 9.7 Hz, CH), 38.27 (d, J(PC)= 30.5 Hz, CHP(BH3)Ph), 36.81 (CH2), 36.71 (d, 'J(PC) = 31.5 Hz, CHP(BH3)Ph), 34.73 (d, 3J(PC) = 13.7 Hz, CH2), 31.92 (CHMe2), 31.12 (CHMQ), 22.41 (CH3), 21.55 (CH3), 20.73 (CH3), 20.10 (CH3); 31P-NMR (CDCl3) 36.d (d, broad, 'J(PB) = 51.4 Hz).

Example 4 (1R, 2S, 4R, 5S)-(+)-2, 5-Dimethyl-7-phenyl-7-phosphabicyclo[2,2,1]heptane (7) To a solution of corresponding borane complex of the phosphine (1.0 g, 4.31 mmol) in CH2CI2 (22 mL) was added tetrafluoroboric acid-dimethyl ether complex (2.63 mL, 21.6 mmol) dropwise via a syringe at -5 OC. After the addition, the reaction mixture was allowed to warm up slowly, and stirred at rt. After 20 h, 3'P NMR showed the reaction was over, it was diluted by CH2C12, neutralized by saturated NaHCO3 aqueous solution. The aqueous layer was extracted with CH2Cl2. The combined organic solution was washed with brine, followed by water, and then dried over Na2SO4. Evaporation of the solvent gave a pure phosphine product, which was confirmed by NMR. Yield: 0.9 g (96%). [a]25, = +92.5° (c 2.3, toluene); 'H NMR (CDCl3, 360 MHZ) 7.38~7.34 (m, 2H), 7.26~7.21 (m, 2H), 7.19~7.16 (m, 1H), 2.60~2.54 (m, 2H), 1.89~1.62(m, 5H), 1.44~1.42(m, 1H), 1.16(d, J=6.12 Hz, 3H), 0.55 (d, J = 6.95 Hz, 3H); '3C NMR (CDCl3) 5 138.68 (d, J = 29.3 Hz), 131.42 (d, J = 13.0 Hz), 127.88 (d, J = 2.35 Hz), 126.57 (s), 47.34 (d, J = 13.5 Hz), 45.26 (d, J = 10.2 Hz), 39.21 (d, J = 6.7 Hz), 39.21 (d, J = 5.3 Hz), 38.74 (d, J = 6.7 Hz), 34.69 (d, 17.2 Hz), 22.37 (d, J = 7.8 Hz), 21.52 (s); 31P NMR(CDCl3) 5-7.29.

Example 5 (1R, 2R, 4R, 5R)-(+)-2, 5-Diisopropyl-7-phenyl-7-phosphabicyclo[2,2,1]heptane (8). Using the same procedure as in the preparation of 7. Yield: 1.0 g (95.5%). [α]D25 = +43.9° (c 1.2, toluene); lH NMR (CDCl3, 360 MHZ) 5 7.35-7.30 (m, 2H), 7.24-7.14 (m, 3H), 2.94~2.85 (m, 2H), 1.76-1.53 (m, 5H), 1.25-1.14 (m, 2H), 1.06 (d, J = 7.77 Hz, 3H), 0.95-08.0 (m, 1H), 0.87 (dd, J = 3.77 Hz, 7.89 Hz, 6 H), 0.49 (d, J = 9.30 Hz, 3H); 13C NMR (CDCl3) 138.83 (d, J = 30.49 Hz), 130.69 (d, J = 12.2 Hz), 127.71 (d, J = 2.87 Hz), 126.45 (s), 53.38 (d, J = 6.34 Hz), 48.63 (d, J = 17.06 Hz), 41.97 (d, J = 13.43 Hz), 40.51 (d, J = 9.96 Hz), 37.60 (d, J = 11.09 Hz), 37.39 (d, J = 9.74 Hz), 33.03 (d, 6.11 Hz), 31.86(s), 21.89(s), 21.78 (s), 21.23 (s), 20.40 (s); 31P NMR(CDC13) 5-7.49.

Example 6 Enantioselective [3+2] Cycloaddition: General Procedure for Asymmetric [3+2] Cycloaddition as Shown in Table 1. The procedure is exemplified by the reaction methyl 2,3-butadienoate and methyl acrylate in the presence of 8. Under the nitrogen, to a solution of ethyl 2,3-butadienoate (112 mg, 1.0 mmol) and methyl acrylate (0.9 ml, 10 mmol) in benzene (5 ml) was added chiral heterocyclic phospine compound 8 (1.0 ml of 0.1M solution in toluene, 0.1 mmol) dropwise via syringe at room temperature. After stirring the mixture for 3 hours, TLC showed the reaction was complete. The ratio of two regioisomers (A:B = 96:4) and enantiomeric excesses of the crude reaction mixture (79% ee of A and 0% of B) were measured by Capillary GC. After the reaction mixture was concentrated in vacuo, the residue was purified by chromatograpy on a silica gel column (hexanes/ethyl acetate, 15:1).

Yield: 175 mg, 87%.

Example 7 Preparation of Compound 10 (as shown in Scheme 2) (1R, 1'R)-Bicyclopentyl-(2S, 2'S)-diol Bis(methanesulfonate) (9). To a solution of (1R, 1'R)-bicyclopentyl-(2S, 2'S)-diol (0.8 g, 4.65 mmol) and triethylamine (1.68 mL, 12.09 mmol) in CH2C12 (30 mL) was added dropwise a solution of methanesulfonyl chloride (0.76 mL, 9.92 mmol) in CH2C12 (2 mL) at 0 OC. After 30 min at 0 OC, the reaction mixture was stirred for an additional 2 h at rt, then quenched by saturated aqueous ammonium chloride solution (25 mL). The aqueous layer was extracted with CH2C12 (3 x 20 mL) and the combined organic solution was dried over Na2 SO4.

After evaporation of the solvent, a white solid was obtained which was used directly for the next step. 1H NMR (CDC13, 200 MHZ) 5 5.01(m, 2H), 3.04 (s, 6 H), 2.17 (m, 2 H), 2.15-1.65 (m, 10 H), 1.43-1.52 (m, 2 H); 13C NMR 86.8, 48.2, 38.4, 32.8, 27.4, 22.5.

10-BH3. To phenylphosphine (0.39 mL, 3.55 mmol) in THF (50 mL) was added n- BuLi (4.9 mL of a 1.6 M solution in hexane, 7.8 mmol) via syringe at 0 OC over 2 min. The orange solution was warmed to rt and stirred for 1 h. To the resulting orange-yellow suspension was added a solution of (1R, 1'R)-bicyclopentyl-(2S, 2'S)- diol bis(methanesulfonate) (1.16 g, 3.55 mmol) in THF (30 mL) over 3 min. After the mixture was stirred overnight at rt, the pale-yellow suspension was hydrolyzed with saturated NH4C1 solution. The mixture was extracted with ether (2 x 50 mL), and the combined organic extract was dried over anhydrous Na2 SO4, and evaporated.

The residue was dissolved in CH2C12 (30 mL), treated with BH3,THF (10 mL of a 1.0 M solution in THF, 10 mmol) and the mixture was stirred overnight. Work up required addition of saturated NH4C1 solution and extraction with CH2Cl2 (30 mL).

The combined organic extract was dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The residue was subjected to silica gel chromatography, eluting with hexanes/CH2Cl2 (3:1) affording the product as a white solid. Yield: 0.35 g (38%). IH-NMR (CDCl3) 5 7.80-7.65 (m, 2 H), 7.55-7.35 (m, 3H), 3.00-2.10 (m, 4 H), 2.00-1.30 (m, 12 H), 1.30-0.20 (m, 3H); 13C-NMR (CDCl3)5 132.2 (d, 2J(PC) = 8.0 Hz), 130.8 (d, 4J(PC) = 2.3 Hz), 129.3 (d, 1J(PC) = 45.2 Hz), 128.6 (d, 3J(PC) = 9.2 Hz), 53.5 (d, 2J(PC) = 5.1 Hz), 52.6 (d, 2J(PC) = 6.0 Hz), 45.3 (d, J(PC) = 35.9 Hz), 41.0 (d, J(PC) = 37.1 Hz), 32.3 (d, ²J(PC) = 5.1 Hz), 32.0 (d, ²J(PC) = 6.6 Hz), 28.1 (d, J(PC) = 5.0 Hz), 27.8 (d, J(PC) = 4.8 Hz), 26.1 (d, 3J(PC) = 6.7 Hz), 25.8 (d, 3J(PC) = 6.0 Hz); 31P-NMR (CDCl3) 5 48.1 (q, br, 1J(PB) = 53 Hz).

Preparation of Compound 10. To a solution of 10-BH3 (0.293 g, 1.34 mmol) in CH2C12 (8 mL) was added tetrafluoroboric acid-dimethyl ether complex (0.69 mL, 5.69 mmol) dropwise via syringe at -5 OC. After the addition, the reaction mixture was allowed to warm slowly to rt and was stirred for 20 h. When 31P NMR showed the reaction was complete, the mixture was diluted with CH2C12, neutralized with saturated aqueous NaHCO3 solution and the aqueous layer was extracted with CH2Cl2. The combined organic solution was washed with brine, followed by water, and then dried over Na2SO4. Evaporation of the solvent gave a pure phosphine product 10. Yield: 0.256 g (92%). 1H NMR (CDCl3, 360 MHZ) 5 7.46~7.42 (m, 2H), 7.35~7.26 (m, 3H), 2.93~2.77 (m, 2 H), 2.50~2.40 (m, 2 H), 2.09~2.01 (m, 1 H), 1.87~1.42 (m, 10 H), 1.28~1.19 (m, 1 H); 13C NMR (CDCl3) # 139.46 (s), 139.20 (s), 132.28 (s), 132.09 (s), 127.91 (d, J = 5.25 Hz), 127.42 (s), 54.48 (d, J = 1.99 Hz), 53.34 (s), 44.85 (d, J = 13.40 Hz), 44.13 (d, J = 6.61 Hz), 32.49(m), 32.23 (s), 31.89 (s), 29.09 (d, J = 5.16 Hz), 26.05 (s), 25.60 (d, J = 7.88 Hz); 31P NMR (CDC13) 16.33.