Triphenylphosphine-Diethyl Azodicarboxylate1


[603-35-0]  · C18H15P  · Triphenylphosphine-Diethyl Azodicarboxylate  · (MW 262.30) (DEAD)

[1972-28-7]  · C6H10N2O4  · Triphenylphosphine-Diethyl Azodicarboxylate  · (MW 174.18)

(reagent in the Mitsunobu reaction, which is a versatile, mild dehydration reaction, widely used for the synthesis of esters and ethers, for the formation of C-N, C-S, and C-halogen bonds, and for inverting the configuration of a stereogenic carbon containing an OH group1)

Physical Data: see Triphenylphosphine and Diethyl Azodicarboxylate.

Handling, Storage, and Precautions: all reagents and solvents must be anhydrous. In general, the Mitsunobu betaine (1) is generated in situ from the phosphine and the azodicarboxylate; however, in some cases it is essential to preform the betaine. The betaine is an unstable, colorless, crystalline solid, rapidly hydrolyzed on contact with moisture. It can be crystallized from dry THF or CHCl3/hexane.

The Mitsunobu Reaction.

A mixture of triphenylphosphine (TPP) and diethyl azodicarboxylate (DEAD) is generally used; however, diisopropyl azodicarboxylate (DIAD) is cheaper and works just as well. The overall reaction enables the replacement of the hydroxyl group of an alcohol by a nucleophile X (eq 1).

The phosphine accepts the oxygen (to give triphenylphosphine oxide) while the azodicarboxylate accepts the two hydrogens (to give the corresponding hydrazine derivative). The reaction occurs under mild (0-25 °C), essentially neutral conditions, can be carried out in the presence of a wide range of functional groups, and usually gives good yields (60-90%). In general, the reaction proceeds well with primary and secondary alcohols, and inversion of configuration is observed.1 Retention of configuration may result from neighboring group participation,2 or a change in mechanism if the alcohol is very hindered.3a Racemization may result if the C-O bond is prone to SN1 cleavage.4 Examples of H-X in the reaction (eq 1) include carboxylic acids, thioacids, phenols, thiols, imides, sulfonamides, hydrazoic acid, heterocyclic compounds, hydrogen halides, phosphate diesters, phosphinic acids, and certain active methylene compounds. The pKa of H-X should generally be less than 13. LiX or ZnX2 sometimes give better results than HX.1c THF is the most commonly used solvent, but other solvents such as dichloromethane, chloroform, benzene, toluene, ethyl acetate, DMF, and HMPA can also be used. The reaction is faster in nonpolar solvents; for example, formation of ethyl benzoate is about 30 times faster in CHCl3 than in MeCN.5a A problem commonly encountered with the Mitsunobu reaction is the separation of the product from triphenylphosphine oxide. This can be overcome by the use of a phosphine containing a basic group such as diphenyl(2-pyridyl)phosphine6 or (4-dimethylaminophenyl)diphenylphosphine,7 where an aqueous acid wash removes the corresponding phosphine oxide, or by using a polymer-bound phosphine.8 Similarly, dimethyl azodicarboxylate (the corresponding hydrazine is water soluble)9 and a polymer-supported azodicarboxylate10 can be used to facilitate product isolation. The reaction is best explained by assuming successive formation of the betaine (1), the protonated N-phosphonium salt (2), and the alkoxyphosphonium salt (3), which collapses in SN2 fashion (eq 2).

Without acidic components, N-alkylhydrazinedicarboxylates (4) can be formed.5b,11 NMR studies of the reaction of alcohols with DEAD and TPP in the absence of acidic components have revealed that the key intermediate is the pentavalent dialkoxyphosphorane (5).1c,5 In the presence of an acidic component, phosphorane intermediates are present in equilibrium with the oxyphosphonium salt (3).3

The combination of DEAD and TPP has been utilized most often as the condensation reaction system, but dimethyl, diisopropyl, and di-t-butyl azodicarboxylates (6) can also be used instead of DEAD; the azodicarboxamide (7) has been used as well.1,12 Triphenylphosphine can be substituted by a variety of trivalent phosphorus compounds, including substituted triarylphosphines and trialkylphosphines.1c

Order of Addition of the Reagents.

The order of addition can be crucial. The most commonly used procedure is to dissolve the alcohol (ROH), the acid (HX), and triphenylphosphine in THF, cool to 0 °C, add the DEAD (or DIAD) slowly with stirring, and then stir at room temperature for several hours. If this procedure fails to give the desired product, the betaine (TPP-DEAD adduct) should be preformed (addition of DEAD to TPP in THF at 0 °C) before addition of a mixture of the ROH and the HX,13 or addition of ROH followed by slow addition of HX or HX and a buffering salt (strong acids),14,15 or addition of HX followed by ROH (weak acids).16 The advantage of preforming the betaine is that X- is not generated in the presence of a powerful oxidant (the azodicarboxylate). Preformation of the betaine should minimize radical-induced side-reactions (radicals are produced when TPP and DEAD are mixed17).

Ester Formation.

A variety of alcohols react at room temperature with carboxylic acids in the presence of DEAD and TPP to produce the corresponding esters.1 When polyols are used, the reaction generally takes place at the less hindered hydroxyl group, as exemplified in the reaction of 1,3-butanediol (eq 3).18,19 When 1,2-propanediol or styrene glycol is used, however, the more sterically encumbered C-2 benzoate is predominantly obtained with complete inversion of the stereochemistry.19 This result has been explained by the formation of a dioxaphospholane (8) as the key intermediate (eq 4).3b,19,20a With acyclic 1,4-diols such as isomaltitol,20b five-membered cyclic ether formation takes place in preference to esterification.

Thymidine (9) reacts with aromatic carboxylic acids to give 5-O-aroylthymidines (10) (eq 5). The yield of esters increases with the acidity of the carboxylic acid, indicating the importance of the protonated N-phosphonium salt (2).21,22

The reaction of chiral secondary carbinols with carboxylic acids, DEAD, and TPP gives the corresponding esters with inverted configuration. Removal of the carboxyl group affords the enantiomer of the parent alcohol (eqs 6-9).23-27 For the purpose of inverting the stereochemistry of a secondary carbinol center, 3,5-dinitrobenzoic acid,28 p-nitrobenzoic acid,22b and chloroacetic acid29 have been recommended, because of increased yield and ease of purification and removal of the carboxyl group from the resulting esters.

With some exceptions, a primary hydroxyl group is generally more reactive than a secondary one.22a,30 Steric congestion and electronic effects sometimes retard the reaction and/or result in the formation of a complex mixture.31

The solvent also plays an important role in the success of the reaction. In general, reaction in benzene or toluene gives higher yields of inverted products.1,22b,32 Although pyridine is not suitable in the preparation of nucleotides,33a pyridine can be used for the synthesis of sucrose epoxide,33b and a mixture of dioxane-pyridine (9:1) can be utilized in the preparation of sugar carboxylates.22a Mixed solvent systems may be necessary when the acid and alcohol components have widely differing solubilities. Thus a mixture of HMPA and dichloromethane works well in the synthesis of lipophilic carbohydrate esters such as cord factor.33c

Allylic and benzylic cyanohydrins react with carboxylic acids, DEAD, and TPP to give inverted esters with 92-99% ee, while extensive racemization takes place with benzaldehyde cyanohydrins containing strongly electron-donating substituents (eq 10). Saturated aliphatic cyanohydrins afford esters in which the original configuration is retained.34

Propargylic alcohols react with carboxylic acids, DEAD, and TPP to give the corresponding inverted esters without formation of allenic alcohols.35 Similarly, in allylic alcohols where no bias exists against the normal SN2 process, clean regiospecific inversion is invariably observed or implied.1,36 In specific cases where the SN2 pathway is hindered for some reason, such as eclipsing of substituents, allylic rearrangement can occur (eqs 11-13).1,37 When compound (11) reacts with benzoic acid, DEAD, and TPP, (13) and (14a,b) (a/b = 4:1) are obtained in a ratio of 1:1. Similar treatment of (11) in the presence of PdCl2 (0.1 equiv) results in the nearly exclusive production of (14a,b) (73%; a/b = 10:1) via (12).37d

Reaction with Thiocarboxylic Acids, Phosphoric Acids, Sulfonic Acids, and their Derivatives.1

Thiocarboxylic acids,38,13 dithiocarboxylic acids,39 and dimethyldithiocarbamic acid zinc salt,40 as well as various phosphorus oxyacids41 and phosphorus thioacids,42 can also be utilized. a,o-Mercapto alcohols form cyclic thioethers whereas thiols react with both DEAD and TPP-DEAD to form disulfides.43a 2-Mercaptoazoles also react with alcohols in the presence of DEAD and TPP.43b Although arenesulfonic acids do not enter into the reaction, a combination of DEAD-TPP with methyl p-toluenesulfonate as a nucleophile carrier gives the corresponding alkyl sulfonates (eq 14).44 Alternatively, Zinc p-Toluenesulfonate reacts with a variety of secondary alcohols to produce the desired tosylates with clean inversion and in good yields, with some exceptions (eq 15).45

Reaction with Hydroxy Acids.

A study of reactions of threo-3-hydroxycarboxylic acids (15) with DEAD and TPP revealed that both hydroxyl group activation (HGA) and carboxyl group activation processes (CGA) are involved. With small R1 and R2, the zwitterion (16) is more stable than (17), so that HGA is exclusively observed, resulting in the formation of alkenes. On the other hand, the CGA process via (17) is progressively preferred as the size of R1 and R2 increases (eq 16).46a,b When the reaction is carried out in acetonitrile, CGA predominates.46c

Hydroxy acids HO-(CH2)n-CO2H with n &egt; 3 react with DEAD and TPP to afford the corresponding lactones.1 This procedure can be utilized in the preparation of macrolide antibiotics and related compounds. Macrolactonization by the use of DEAD-TPP depends on the reaction conditions and the structure of the seco acids. Thus dropwise addition of the hydroxy acid (18) over a period of 10 h to a mixture of DEAD (7.7 equiv) and TPP (7.5 equiv) affords the lactone (19) in 59% yield as well as the unwanted dilactide (20) in a yield of <1%. On the other hand, the reaction of (18) with DEAD (5.0 equiv) and TPP (5.0 equiv) at 25 °C for 18 h gives (19) and (20) in 2% and 40% yields, respectively (eq 17).47

The reaction of the seco acid (21) of colletodiol with DEAD and TPP gives the lactone (22) in 45% yield after recrystallization (eq 18),48a while the seco acid (23), which has a closely related structure to (21), affords the corresponding lactone (24) in only 4% yield (eq 19).48b,49

Reaction with Phenols and Other Oxygen Nucleophiles.

When alcohols react with phenols, DEAD, and TPP, the corresponding aryl alkyl ethers are produced. A tertiary amine may facilitate the reaction.50a In general, the reaction proceeds with clean inversion of chiral secondary carbinol centers (eq 2; AH = a phenol).50b Depending on the structure of the substrate, allylic rearrangement51,52 and neighboring group participation can be observed.2,53 Phenols having a hydroxyalkyl chain in a suitable position for cyclization afford the corresponding cyclic aryl ether.54 Silanols react with phenols and with alcohols in the presence of DEAD and TPP to afford the corresponding silyl ethers.55 Oximes56 and N-hydroxy imides57 can also be utilized as acidic components.

Reaction with Di- and Polyols.

Although intermolecular dehydration between two molecules of alcohols to afford acyclic ethers usually does not occur with the DEAD-TPP system, intramolecular cyclization of diols to produce three to seven-membered ethers is a common and high yielding reaction. Contrary to an early report,58a 1,3-propanediol does not form oxetane.5b Oxetanes can be formed, however, using the trimethyl phosphite modification of the Mitsunobu reaction.1c The reaction of (S)-1,2-propanediol and (R)-1,4-pentanediol with DEAD and TPP affords the corresponding cyclic ethers with 80-87% retention of stereochemistry at the chiral carbon, while (S)-phenyl-1,2-ethanediol affords racemic styrene oxide. In contrast to the reaction of the same 1,2-diols with benzoic acid (eq 4), oxyphosphonium salts (25a) and (25b) have been postulated as key intermediates in the present reaction (eq 20).58b,e

The reaction of cyclic trans-1,2-diols with DEAD and TPP generally gives the corresponding oxiranes via phosphoranes.1,33b,59 Cyclic cis-1,2-diols also react with DEAD/TPP to afford primarily phosphoranes (26) which decompose into final product(s) such as oxiranes (with retention of configuration) (eq 21)60 and dehydrated alcohols and/or ketones (eq 22).61

Carbon-Nitrogen Bond Formation.

Phthalimide reacts with alcohols, DEAD, and TPP to give the corresponding N-alkylphthalimides with inversion of configuration (eq 2; HA = phthalimide).1 Nitrophthalimide is more reactive than phthalimide.22a If the reaction site is hindered and an SN1 process favored, some stereochemical scrambling is observed. For example, the reaction of (27) with phthalimide in the presence of DEAD and TPP results in complete epimerization, giving (28a) and (28b) in a ratio of 1:1 (eq 23).62 Neighboring group participation is also possible in some cases.63

Alcohols having an acidic hydrogen atom adjacent to the hydroxyl group may undergo dehydration rather than substitution.1 Thus the reaction of diethyl maleate (29) with phthalimide, DEAD, and TPP gives diethyl fumarate without any detectable formation of the substituted product.64a With Hydrazoic Acid, however, (29) gives the expected azido succinate (30) in 74% yield (eq 24).44a Dehydration is regioselective in some cases.64b,c

Since azides are very useful in organic synthesis (especially for the introduction of primary amino groups and the construction of heterocyclic systems), the direct conversion of alcohols into azides has been extensively studied (eq 2; HA = HN3).1,65 Diphenyl Phosphorazidate66 and the zinc azide/bis-pyridine complex67 can be used instead of HN3. Treatment of alcohols with hydrazoic acid, DIAD, and excess TPP in THF, followed by addition of water or aqueous acid, affords amines in moderate to good yields (eq 25).68

Acyclic amides and imides with pKa < 13 can be expected to function as acidic components in the present reaction system. Thus the reaction of N-benzyloxycarbonylbenzamide with ethyl (S)-(-)-lactate gives the inverted N-alkylated product (31a) and the O-alkylated product (31b) in 19% and 48% yields, respectively (eq 26).69 This result suggests that the alkoxyphosphonium salt (3) is a hard alkylating reagent.

In the alkylation of imidodicarbonates and tosylcarbamates, the yield of alkylated product increases as the acidity of the NH acids increases. Thus imidodicarbonates and tosylcarbamates with pKa < 13 give the corresponding N-alkylated products in 83-93% yields, while lower yields are obtained with less acidic substrates.70a The combination of 1,1-(Azodicarbonyl)dipiperidine (ADDP) with Tri-n-butylphosphine appears to be superior to that of DEAD with TPP in the alkylation of amides.12 In the presence of DEAD and TPP, dibenzyl imidodicarbonate does not react with alcohols, but it does react with a-hydroxy stannanes to give the corresponding N-alkylated products (eq 27).71

The O-acylhydroxamate (32a) (pKa 6-7) reacts with benzyl alcohol, DEAD, and TPP to give N- and O-alkylated products, while the less acidic O-alkylhydroxamate (32b) (pKa 9-10) gives only the N-alkyl product (eq 28).72a

Intramolecular dehydration of 3-hydroxy carboxamides affords the corresponding b-lactams. Side reactions include elimination and formation of aziridines and oxazolidines (eq 29).72,73 The efficiency of b-lactam formation is dependent on substrate substituents (including protecting groups for the side-chain amino group) as well as on the choice of azodicarboxylate and PIII compound.1c,74-76 For example, the dipeptide (33) reacts with DEAD and TPP to give a 2:1 mixture of the b-lactams (34a) and (34b). Control of the labile C-5 stereocenter can be achieved by use of Triethyl Phosphite instead of TPP; (34a) and (34b) are obtained in a >50:1 ratio (eq 30).75 3-Hydroxy O-alkylhydroxamates can also be converted into the corresponding b-lactams (eq 31).1c,77

Purines and pyrimidines react with various alcohols in the presence of DEAD and TPP (eq 32).78 The alcohol (35) gives a carbocyclic nucleoside (36) in 65% yield along with a small amount (9%) of the 7-substituted purine derivative (eq 33).79-81

Reaction with Amino Alcohols and Related Compounds.

Both secondary and tertiary carbamates bearing a vicinal hydroxyl group react with carboxylic acids in the presence of DEAD and TPP to afford the corresponding esters with inversion of configuration (eq 34).82 Reaction of N-t-butoxycarbonylserine with methanol, DEAD, and TPP gives the corresponding methyl ester in >98% yield (eq 35).83 Without methanol, N-benzyloxycarbonyl- or N-t-butoxycarbonylserine reacts with the preformed adduct of DEAD and TPP to afford the b-lactone (eq 35).84 The N-protected serine methyl ester (37a) and threonine methyl ester (37b) react with DEAD and TPP to give the dehydrated products (38a) and (38b) (eq 36).85

In the absence of an acidic component, b-(N-carbonylamino) alcohols afford aziridines or oxazolines, depending on the structure of the substrate. Contrary to the case of (37), the N-benzyloxycarbonylamino alcohol (39), with no acidic hydrogen present at the position adjacent to the hydroxyl group, affords the aziridine (40) in 85% yield (eq 37),86,87 while the N-acylamino alcohols (41) give the oxazolines (42) in 31-68% yields (eq 38).88

Protection of the amino group by an electron-withdrawing group is not necessarily required for the cyclization. Amino alcohols of general structure HO-(C)n-NHR react with DEAD and TPP to form the corresponding cyclic amines. Thus 2-aminoethanols give aziridines in 18-90% yields.89 The reaction of the tetrafluoroborate salt of 3-(benzylamino)-1-propanol with DEAD and TPP gives the corresponding azetidine in 50% yield (eq 39).90 Five- and six-membered cyclic amines are also prepared by the reaction of amino alcohols with DEAD and TPP (eqs 40 and 41).91 Although azepines are not formed from straight-chain amino alcohols, compound (43) gives the azepines (45a) and (45b) by SN2 substitution of the intermediate phosphorane (44) (eq 42).92

O-Glycosidation with Phenols.

Monosaccharides possessing a free anomeric hydroxyl group react with phenol, DEAD, and trivalent phosphorus compounds to give phenyl glycosides. The yield is higher with trialkylphosphines (Bu3P, Pr3P).93 Coupling of phenols and 2-a-(phenylthio)- or 2-a-(phenylseleno)-a-D-pyranoses by the use of DEAD and TPP gives aryl 2-deoxy-b-D-glycosides in 70-85% yields with high stereoselectivity (inversion of anomeric center) (eq 43).94 Intramolecular phenolic glycosidation is also possible.95

O-Glycosidation with Carboxylic Acids.

Reaction of carbohydrates having a free anomeric hydroxyl group with carboxylic acids gives the corresponding glycosyl esters (eq 44).96 Intramolecular glycosidation of (46) can be accomplished by the use of the preformed Bu3P-DEAD betaine at low temperature (eq 45).97

Glycosidation with Nitrogen Nucleophiles and N-Hydroxy Compounds.

Reaction of an anomeric hydroxyl group with nitrogen nucleophiles and with N-hydroxy heterocycles affords the corresponding glycosides.1,98,99 The a-lactol (48) (a:b = ca. 8:1) reacts with N-hydroxyphthalimide, DIAD, and TPP to give the b-glycoside (49) (eq 46).100

Carbon-Carbon Bond Formation.

Direct coupling of an alcohol with a carbon acid by the use of DEAD/TPP has been limited to only a few examples because of the lack of carbon acids with pKa < 13. If enolizable carbonyl compounds are used, alkylation generally takes place on oxygen.69a,101 Thus the reaction of 1,3-cyclohexanedione with isopropanol, DEAD, and TPP affords exclusively the O-alkylated product (eq 47).101a Cyanoacetate reacts at the carbon atom, while diethyl malonate is unreactive.101a However, the reaction of diethyl malonate with alcohols in the presence of ADDP and Bu3P affords C-alkylated products in 3-56% yields (eq 48).12 Ethyl nitroacetate and nitromalonate oxidize the alcohol via an aci-nitro ester (eq 49).102 o-Nitroarylacetonitriles of general formula (50) undergo alkylation on carbon (eq 50).16,103

g-Nitro alcohols react with DEAD and TPP to afford a-nitrocyclopropanes in good to excellent yields (eq 51).104a On the other hand, nitro alcohols bearing electron-withdrawing or unsaturated substituents at the a-carbon experience exclusive intra- and intermolecular O-alkylation and furnish good to excellent yields of alkyl nitronates (eq 52). In contrast, 1-phenylsulfonyl-1-nitro-3-propanol affords the corresponding cyclopropane.104b Bis-sulfones readily undergo alkylation by alcohols.104c Novel intramolecular SN2 and SN2 type arylation occurs with certain aromatic and allylic alcohols (eqs 53 and 54).105

Miscellaneous Reactions.

Dialkyl phosphonates react with alcohols in the presence of DIAD and TPP to give trialkyl phosphites (eq 55).5a TPP-DIAD reacts with KHF2 or HF-pyridine to form difluorotriphenylphosphorane (eq 56).106

1. (a) Mitsunobu, O. S 1981, 1. (b) Castro, B. R. OR 1983, 29, 1. (c) Hughes, D. L. OR 1992, 42, 335. (d) Mitsunobu, O. COS 1991, 6, 1. (e) Mitsunobu, O. COS 1991, 6, 65.
2. Freedman, J.; Vaal, M. J.; Huber, E. W. JOC 1991, 56, 670.
3. (a) Camp, D.; Jenkins, I. D. JOC 1989, 54, 3049. (b) Camp, D.; Jenkins, I. D. JOC 1989, 54, 3045. (c) Camp, D.; Jenkins, I. D. AJC 1992, 45, 47.
4. Brown, R. F. C.; Jackson, W. R.; McCarthy, T. D. TL 1993, 34, 1195.
5. (a) Harvey, P.; Jenkins, I. D., unpublished results. (b) Von Itzstein, M.; Jenkins, I. D. JCS(P1) 1986, 437. (c) Von Itzstein, M.; Jenkins, I. D. JCS(P1) 1987, 2057. (d) Von Itzstein, M.; Jenkins, I. D. AJC 1984, 37, 2447.
6. Camp, D.; Jenkins, I. D. AJC 1988, 41, 1835.
7. Von Itzstein, M.; Mocerino, M. SC 1990, 20, 2049; Von Itzstein, M.; Jenkins, M. J.; Mocerino, M. Carbohydr. Res. 1990, 208, 287.
8. Amos, R. A.; Emblidge, R. W.; Havens, N. JOC 1983, 48, 3598.
9. Spry, D. O.; Bhala, A. R. H 1986, 24, 1653.
10. Arnold, L. D.; Assil, H. I.; Vederas, J. C. JACS 1989, 111, 3973.
11. Dialkyl phosphonates have been reported to promote this reaction: Osikawa, T.; Yamashita, M. Shizuoka Daigaku Kogakubu Kenkyu Hokoku 1984, 37 (CA 1985, 103, 142 095d).
12. Tsunoda, T.; Yamamiya, Y.; Ito, S. TL 1993, 34, 1639.
13. Volante, R. P. TL 1981, 22, 3119.
14. Varassi, M.; Walker, K. A. M.; Maddox, M. L. JOC 1987, 52, 4235.
15. Hughes, D. L.; Reamer, R. A.; Bergan, J. J.; Grabowski, E. J. J. JACS 1988, 110, 64.
16. Macor, J. E.; Wehner, J. M. H 1993, 35, 349.
17. Camp, D.; Hanson, G.; Jenkins, I. D., JOC 1995, 60, 2977.
18. Mitsunobu, O.; Kimura, J.; Iizumi, K.; Yanagida, N. BCJ 1976, 49, 510.
19. (a) Pautard, A. M.; Evans, S. A., Jr. JOC 1988, 53, 2300. (b) Pautard-Cooper, A.; Evans, S. A., Jr. JOC 1989, 54, 2485. (c) Pautard-Cooper, A.; Evans, S. A., Jr. JOC 1989, 54, 4974. (d) Pautard-Cooper, A.; Evans, S. A., Jr. T 1991, 47, 1603.
20. (a) Pawlak, J. L.; Padykura, R. E.; Kronis, J. D.; Aleksejczyk, R. A.; Berchtold, G. A. JACS 1989, 111, 3374. (b) Jenkins, I. D.; Richards, G., unpublished results.
21. Mitsunobu, O.; Kimura, K.; Fujisawa, Y. BCJ 1972, 45, 245.
22. (a) Grynkiewicz, G. Pol. J. Chem. 1979, 53, 2501. (b) Martin, S. P.; Dodge, J. A. TL 1991, 32, 3017.; Dodge, J. A.; Trujillo, J. I.; Presnell, M. JOC 1994, 59, 234.
23. Georg, G. I.; Kant, J.; Gill, H. S. JACS 1987, 109, 1129.
24. Ito, Y.; Kobayashi, Y.; Kawabata, T.; Takase, M.; Terashima, S. T 1989, 45, 5767.
25. Evans, D. A.; Gauchet-Prunet, J. A.; Carreira, E. M.; Charette, A. B. JOC 1991, 56, 741.
26. Danishefsky, S. L.; Cabal, M. P.; Chow, K. JACS 1989, 111, 3456.
27. Breslow, R.; Link, T. TL 1992, 33, 4145.
28. (a) Mori, K.; Otsuka, T.; Oda, M. T 1984, 40, 2929. (b) Mori, K.; Ikunaka, M. T 1984, 40, 3471. (c) Mori, K.; Ishikura, M. LA 1989, 1263. (d) Mori, K.; Watanabe, H. TL 1984, 25, 6025.
29. Saïah, M.; Bessodes, M.; Antonakis, K. TL 1992, 33, 4317.
30. Weinges, K.; Haremsa, S.; Maurer, W. Carbohydr. Res. 1987, 164, 453.
31. See, For example: (a) Lindhorst, T. K.; Thiem, J. LA 1990, 1237. (b) Sakamoto, S.; Tsuchiya, T.; Umezawa, S.; Umezawa, H. BCJ 1987, 60, 1481. (c) Palmer, C. F.; Parry, K. P.; Roberts, S. M.; Ski, V. JCS(P1) 1991, 2051. (d) Bartlett, P. A.; Meadows, J. D.; Ottow, E. JACS 1984, 106, 5304. (e) Jeker, N.; Tamm, C. HCA 1988, 71, 1904. See also references 1a and 1c.
32. See, for example: (a) Loibner, H.; Zbiral, E. HCA 1977, 60, 417. (b) Goya, S.; Takadate, A.; Fujino, H.; Irikura, M. YZ 1981, 101, 1064.
33. (a) Kimura, J.; Fujisawa, Y.; Yoshizawa, T.; Fukuda, K.; Mitsunobu, O. BCJ 1979, 52, 1191. (b) Guthrie, R. D.; Jenkins, I. D.; Thang, S.; Yamasaki, R. Carbohydr. Res. 1983, 121, 109; 1988, 176, 306. (c) Jenkins, I. D.; Goren, M. B. Chem. Phys. Lipids 1986, 41, 225.
34. Warmerdam, E. G. J. C.; Brussee, J.; Kruse, C. G.; van der Gen, A. T 1993, 49, 1063.
35. (a) Kang, S. H.; Kim, W. J. TL 1989, 30, 5915. (b) Jarosz, S.; Glodek, J.; Zamojski, A. Carbohydr. Res. 1987, 163, 289.
36. See, for example: (a) Grossé-Kobo, B.; Mosset, P.; Grée, R. TL 1989, 30, 4235. (b) Balan, A.; Ziffer, H. CC 1990, 175. (c) Clive, D. L. J.; Daigneault, S. JOC 1991, 56, 3801.
37. (a) Farina, V. TL 1989, 30, 6645, and references cited therein. (b) Jefford, C. W.; Moulin, M.-C. HCA 1991, 74, 336. (c) Carda, M.; Marco, J. A. T 1992, 48, 9789. (d) Lumin, S.; Falck, J. R.; Capdevila, J.; Karara, A. TL 1992, 33, 2091. (e) Charette, A. B.; Cote, B. TL 1993, 34, 6833.
38. (a) Kanematsu, K.; Yoshiyasu, T.; Yoshida, M. CPB 1990, 38, 1441. (b) Moree, W. J.; van der Marel, G. A.; Liskamp, R. M. J. TL 1992, 33, 6389. (c) Strijtveen, B.; Kellogg, R. M. RTC 1987, 106, 539. (d) Jenkins, I. D.; Thang, S. AJC 1984, 37, 1925.
39. Kpegba, K.; Metzner, P. S 1989, 137.
40. Rollin, P. TL 1986, 35, 4169.
41. (a) Mlotkowska, B.; Zwierzak, A. Pol. J. Chem. 1979, 53, 359. (b) Campbell, D. A. JOC 1992, 57, 6331.; Campbell, D. A.; Bermak, J. C. JOC 1994, 59, 658.
42. Mlotkowska, B.; Wartalowska-Graczyk, M. JPR 1987, 329, 735.
43. (a) Camp, D.; Jenkins, I. D. AJC 1990, 43, 161. (b) Dancy, I.; Laupichler, L.; Rollin, P.; Thiem, J. SL 1992, 283, and references cited therein.
44. (a) Loibner, H.; Zbiral, E. HCA 1976, 59, 2100. (b) Peterson, M. L.; Vince, R. JMC 1991, 34, 2787.
45. (a) Still, W. C.; Galynker, I. JACS 1982, 104, 1774. (b) Galynker, I.; Still, W. C. TL 1982, 23, 4461.
46. (a) Mulzer, J.; Brüntrup, G.; Chucholowski, A. AG(E) 1979, 18, 622. (b) Mulzer, J.; Lammer, O. AG 1983, Suppl., 887. (c) Adam, W.; Narita, N.; Nishizawa, Y. JACS 1984, 106, 1843.
47. Justus, K.; Steglich, W. TL 1991, 32, 5781.
48. (a) Tsutsui, H.; Mitsunobu, O. TL 1984, 25, 2163. (b) Ohta, K.; Miyagawa, O.; Tsutsui, H.; Mitsunobu, O. BCJ 1993, 66, 523.
49. For recent reports of macrolactonization, see, for example: (a) Barrett, A. G. M.; Carr, R. A. E.; Attwood, S. V.; Richardson, G.; Walshe, N. D. A. JOC 1986, 51, 4840. (b) Smith A. B., III; Noda, I.; Remiszewski, S. W.; Liverton, N. J.; Zibuck, R. JOC 1990, 55, 3977. (c) White, J. D.; Kawasaki, M. JACS 1990, 112, 4991. (d) Hanessian, S.; Chemla, P. TL 1991, 32, 2719.
50. (a) Riehter, L. S.; Gadek, T. R. TL 1994, 35, 4705. (b) See, for example: Heumann, A.; Faure, R. JOC 1993, 58, 1276, and references cited therein.
51. For alkyl aryl ether formation without allylic rearrangement, see, for example: Pirrung, M. C.; Brown, W. L.; Rege, S.; Laughton, P. JACS 1991, 113, 8561.
52. For alkyl aryl ether formation with allylic rearrangement, see, for example: Danishefsky, S.; Berman, E. M.; Ciufolini, M.; Etheredge, S. J.; Segmuller, B. E. JACS 1985, 107, 3891.
53. Walba, D. M.; Eidman, K. F.; Haltiwanger, R. C. JOC 1989, 54, 4939.
54. (a) Sugihara, H.; Mabuchi, H.; Hirata, M.; Imamoto, T.; Kawamatsu, Y. CPB 1987, 35, 1930. (b) Macor, J. E.; Ryan, K.; Newman, M. E. T 1992, 48, 1039.
55. Clive, D. L. J.; Kellner, D. TL 1991, 32, 7159.
56. See, for example: Stachulski, A. V. JCS(P1) 1991, 3065.
57. See, for example: Brown, P.; Calvert, S. H.; Chapman, P. C. A.; Cosham, S. C.; Eglington, A. J.; Elliot, R. L.; Harris, M. A.; Hinks, J. D.; Lowther, J.; Merrikin, D. J.; Pearson, M. J.; Ponsford, R. J.; Syms, J. V. JCS(P1) 1991, 881.
58. (a) Carlock, J. T.; Mack, M. P. TL 1978, 5153. (b) Robinson, P. L.; Barry, C. N.; Bass, S. W.; Jarvis, S. E.; Evans, S. A., Jr. JOC 1983, 48, 5396. (c) Bestmann, H. J.; Pecher, B.; Riemer, C. S 1991, 731.
59. (a) Mitsunobu, O.; Kudo, T.; Nishida, M.; Tsuda, N. CL 1980, 1613. (b) Brandstetter, H. H.; Zbiral, E. HCA 1980, 63, 327. (c) Mark, E.; Zbiral, E.; Brandstetter, H. H. M 1980, 111, 289. (d) Guthrie, R. D.; Jenkins, I. D.; Yamasaki, R.; Skelton, B. W.; White, A. H. JCS(P1) 1981, 2328. (e) Guthrie, R. D.; Jenkins, I. D. AJC 1981, 34, 1997. (f) Guthrie, R. D.; Jenkins, I. D.; Yamasaki, R. Carbohydr. Res. 1980, 85, C5. (g) Guthrie, R. D.; Jenkins, I. D.; Yamasaki, R.; Skelton, B. W.; White, A. H. JCS(P1) 1981, 2328. (h) McGowan, D. A.; Berchtold, G. A. JOC 1981, 46, 2381.
60. Palomino, E.; Schaap, A. P.; Heeg, M. J. TL 1989, 30, 6797.
61. Penz, G.; Zbiral, E. M 1981, 112, 1045.
62. (a) Iida, H.; Yamazaki, N.; Kibayashi, C. JOC 1987, 52, 1956. (b) Yamazaki, N.; Kibayashi, C. TL 1988, 29, 5767.
63. Audia, J. E.; Colocci, N. TL 1991, 32, 3779.
64. (a) Wada, M.; Sano, T.; Mitsunobu, O. BCJ 1973, 46, 2833. (b) Akita, H.; Yamada, H.; Matsukura, H.; Nakata, T.; Oishi, T. CPB 1990, 38, 2377. (c) Iimori, T.; Ohtsuka, Y.; Oishi, T. TL 1991, 32, 1209.
65. For an unsuccessful result, see: Roemmele, R. C.; Rapoport, H. JOC 1989, 54, 1866.
66. (a) Lal, B.; Pramanik, B. N.; Manhas, M. S.; Bose, A. K. TL 1977, 1977. (b) Pearson, W. H.; Hines, J. V. JOC 1989, 54, 4235.
67. (a) Viaud, M. C.; Rollin, P. S 1990, 130. (b) Gajda, T.; Matusiak, M. S 1992, 367. (c) Duclos, O.; Duréault, A.; Depezay, J. C. TL 1992, 33, 1059. (d) Duclos, O.; Mondange, M.; Duréault, A.; Depezay, J. C. TL 1992, 33, 8061.
68. Fabiano, E.; Golding, B. T.; Sadeghi, M. M. S 1987, 190.
69. (a) Morimoto, H.; Furukawa, T.; Miyazima, K.; Mitsunobu, O. CL 1973, 821. For C- and N-alkylation of imides and related compounds, see also: (b) Sammes, P. G.; Thetford, D. JCS(P1) 1989, 655. (c) Kim, T. H.; Rapoport, H. JOC 1990, 55, 3699.
70. (a) Koppel, I.; Koppel, J.; Degerbeck, F; Grehn, L.; Ragnarsson, U. JOC 1991, 56, 7172. See also, for example: (b) Slusarska, E.; Zwierzak, A. LA 1986, 402. (c) Tanner, D.; Birgersson, C.; Dhaliwal, H. K. TL 1990, 31, 1903. (d) Arnould, J. C.; Landier, F.; Pasquet, M. J. TL 1992, 33, 7133. (e) Macor, J. E.; Blank, D. H.; Post, R. J.; Ryan, K. TL 1992, 33, 8011. (f) Campbell, J. A.; Hart, D. J. JOC 1993, 58, 2900.
71. Chong, J. M.; Park, S. B. JOC 1992, 57, 2220.
72. (a) Miller, M. J.; Mattingly, P. G.; Morrison, M. A.; Kerwin, J. F., Jr. JACS 1980, 102, 7026. (b) Teng, M.; Miller, M. J. JACS 1993, 115, 548.
73. (a) Bose, A. K.; Sahu, D. P.; Manhas, M. S. JOC 1981, 46, 1229. (b) Bose, A. K.; Manhas, M. S.; Sahu, D. P.; Hegde, V. R. CJC 1984, 62, 2498.
74. Huang, N. Z.; Kalish, V. J.; Miller, M. J. T 1990, 46, 8067.
75. Salituro, G. M.; Townsend, C. A. JACS 1990, 112, 760, and references cited therein.
76. For the reaction of hydroxyamino acid derivatives with DEAD-TPP and related systems, see, for example: (a) Nakajima, K.; Tanaka, T.; Neya, M.; Okawa, K. BCJ 1982, 55, 3237. (b) Nakajima, K.; Sasaki, H.; Neya, M.; Morishita, M.; Sakai, S.; Okawa, K. In Peptide Chemistry 1982; Sakakibara, S., Ed.; Protein Research Foundation: Osaka, 1983; pp 19-24.
77. Lotz, B. T.; Miller, M. J. JOC 1993, 58, 618, and references cited therein.
78. Toyota, A.; Katagiri, N.; Kaneko, C. SC 1993, 23, 1295.
79. Katagiri, N.; Toyota, A.; Shiraishi, T.; Sato, H.; Kaneko, C. TL 1992, 33, 3507.
80. For related reports, see, for example: (a) Toyota, A.; Katagiri, N.; Kaneko, C. CPB 1992, 40, 1039. (b) Katagiri, N.; Sato, H.; Arai, S.; Toyota, A.; Kaneko, C. H 1992, 34, 1097. (c) Toyota, A.; Katagiri, N.; Kaneko, C. H 1993, 36, 1625. (d) Jenny, T. F.; Previsani, N.; Benner, S. A. TL 1991, 32, 7029. (e) Jenny, T. F.; Schneider, K. C.; Benner, S. A. Nucleosides Nucleosides 1992, 11, 1257. (f) Overberger, C. G.; Chang, J. Y. TL 1989, 30, 51. (g) Bestmann, H. J.; Roth, D. AG(E) 1990, 29, 99. (h) See ref. 31(b).
81. For O-alkylation of purines, see, for example: Schulz, B. S.; Pfleiderer, W. HCA 1987, 70, 210, and references cited therein.
82. (a) Lipshutz, B. H.; Miller, T. A. TL 1990, 31, 5253. For neighboring group participation in related reactions, see: (b) Campbell, J. A.; Hart, D. J. TL 1992, 33, 6247.
83. Branquet, E.; Durand, P.; Vo-Quang, L.; Le Goffic, F. SC 1993, 23, 153.
84. (a) Arnold, L. D.; Kalantar, T. H.; Vederas, J. C. JACS 1985, 107, 7105. (b) Ramer, S. E.; Moore, R. N.; Vederas, J. C. CJC 1986, 64, 706. See also: (c) Parker, W. L.; Rathnum, M. L.; Liu, W.-C. J. Antibiot. 1982, 35, 900.
85. (a) Wojciechowska, H.; Pawlowicz, R.; Andruszkiewicz, R.; Grzybowska, J. TL 1978, 4063. (b) Andruszkiewicz, R.; Grzybowska, J.; Wojciechowska, H. Pol. J. Chem. 1981, 55, 67.
86. Coleman, R. S.; Carpenter, A. J. JOC 1992, 57, 5813.
87. (a) Wipf, P.; Miller, C. P. TL 1992, 33, 6267. See also: (b) Galéotti, N.; Montagne, C.; Poncet, J.; Jouin, P. TL 1992, 33, 2807.
88. Roush, D. M.; Patel, M. M. SC 1985, 15, 675.
89. Pfister, J. R. S 1984, 969.
90. Sammes, P. G.; Smith, S. CC 1983, 682.
91. (a) Bernotas, R. C.; Cube, R. V. TL 1991, 32, 161. (b) Bernotas, R. C. TL 1990, 31, 469. (c) Holladay, M. W.; Nadzan, A. M. JOC 1991, 56, 3900.
92. Kozikowski, A. P.; Okita, M. TL 1985, 26, 4043.
93. Grynkiewicz, G. Pol. J. Chem. 1979, 53, 1571.
94. Roush, W. R.; Lin, X.-F. JOC 1991, 56, 5740.
95. Delgado, A.; Clardy, J. JOC 1993, 58, 2862.
96. (a) Smith, A. B., III; Hale, K. J.; Rivero, R. A. TL 1986, 27, 5813. (b) de Masmaeker, A.; Hoffmann, P.; Ernst, B. TL 1989, 30, 3773. (c) Smith, A. B., III; Rivero, R. A.; Hale, K. J.; Vaccaro, H. A. JACS 1991, 113, 2092. (d) Smith, A. B., III; Hale, K. J.; Vaccaro, H. A.; Rivero, R. A. JACS 1991, 113, 2112.
97. Smith, A. B., III; Sulikowski, G. A.; Sulikowski, M. M.; Fujimoto, K. JACS 1992, 114, 2567.
98. For glycosidation with HN3, see: Schörkhuber, W.; Zbiral, E. LA 1980, 1455.
99. For glycosidation with N-hydroxy heterocycles, see: Grochowski, E.; Stepowska, H. S 1988, 795, and references cited therein.
100. Nicolaou, K. C.; Groneberg, R. D. JACS 1990, 112, 4085.
101. (a) Kurihara, T.; Sugizaki, M.; Kime, I.; Wada, M.; Mitsunobu, O. BCJ 1981, 54, 2107. (b) Bajwa, J. S.; Anderson, R. C. TL 1990, 31, 6973. (c) Nakayama, E.; Watanabe, K.; Miyauchi, M.; Fujimoto, K.; Ide, J. J. Antibiot. 1990, 43, 1122. (d) Czernecki, S.; Valéry, J.-M. S 1991, 239.
102. Mitsunobu, O.; Yoshida, N. TL 1981, 22, 2295.
103. Macor, J. E.; Wehner, J. M. TL 1991, 32, 7195.
104. (a) Yu, J.; Falck, J. R.; Mioskowski, C. JOC 1992, 57, 3757. (b) Falck, J. R.; Yu, J. TL 1992, 33, 6723. (c) Yu, J.; Cho, H.-S.; Falck, J. R. JOC 1993, 58, 5892.
105. (a) Magnus, P.; Gallagher, T.; Schulz, J.; Or, Y.-S.; Ananthanarayan, T. P. JACS 1987, 109, 2706. (b) Boger, D. L.; Wysocki, R. J., Jr; Ishizaki, T. JACS 1990, 112, 5230. (c) Magnus, P.; Mugrage, B.; DeLuca, M. R.; Cain, G. A. JACS 1990, 112, 5220.
106. Harvey, P.; Jenkins, I. D. TL 1994, 35, 9775.

Ian D. Jenkins

Griffith University, Brisbane, Australia

Oyo Mitsunobu

Aoyama Gakuin University, Tokyo, Japan

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