4630
`4630
`
`J. Am. Chern. Soc. 1984, 106, 4630-4632
`J. Am. Chern. Soc. 1984, 106, 4630-4632
`
`Table II. TFA-Catalyzed Erythro-Selective Ketone Reduction with
`Table II. TFA-Catalyzed Erythro-Selective Ketone Reduction with
`PhMe2SiHQ
`PhMe2SiHQ
`
`run
`run
`
`ketone
`ketone
`
`time, h
`time, h
`
`0
`0
`
`Jly0Bl
`Jly0Bl
`Pr
`Pr
`
`Me
`Me
`
`c
`c
`JlyNHS02 PC'
`JlyNHS02 PC'
`pr
`pr
`
`Me
`Me
`
`0
`
`°
`
`JlyNHCOOEt
`JlyNHCOOEt
`Po
`Po
`
`Me
`Me
`
`6
`6
`
`20
`20
`
`2.5
`2.5
`
`CMe 0
`CMe 0
`
`0.25
`0.25
`
`2
`
`3
`
`4
`4
`
`product
`product
`(% yield)b
`(% yield)h
`
`OH
`OH
`
`Jy 0H
`Jy0H
`Pc
`Pc
`
`Me
`Me
`
`OH
`OH
`JyNHS02 PC'
`JyNHS02 PC'
`Ph
`Ph
`
`Me
`Me
`
`OH
`OH
`
`JyNHCOOEt
`JyNHCOOEt
`Ph
`Ph
`
`threo:
`threo:
`erythroC
`erythroC
`7:93
`7:93
`
`(72)
`(72)
`
`2:98
`2:98
`
`(66)d
`(66)d
`
`<1:99
`<1:99
`
`(87)
`(87)
`
`Me
`Me
`2
`2
`OMe OH
`OMe OH
`
`<1:99
`<1:99
`
`r¢tr:""WO"
`~"w'" ~'~OO"
`~"""'O". (84)
`o
`
`(84)
`
`M.
`Me
`
`fl.
`
`O'y~e
`O'v~e
`
`OMe
`OMe
`
`3
`3
`4
`4
`a Typically 1.1-1.2 mmol of PhMe2SiH and I mmol of a ketone were
`a Typically 1.1-1.2 mmol of PhMe2SiH and I mmol of a ketone were
`allowed to react in 1-2 mL of TFA at 0 °C. b The benzoyl protecting
`allowed to react in 1-2 mL of TFA at 0 °C. b The benzoyl protecting
`group was removed under basic (I M KOH/MeOH, r.t.) condition,
`group was removed under basic (I M KOH/MeOH, r.t.) condition,
`and the total yield is given. The isolated major product is illustrated.
`and the total yield is given. The isolated major product is illustrated.
`CDetermined by lH NMR analysis. The amino alcohol 2 gave a peak
`CDetermined by lH NMR analysis. The amino alcohol 2 gave a peak
`at 0 4.83 (d, J = 3 Hz, CH-OH) and 4 at 0 5.03 (d, J = 4 Hz). dThis
`at 0 4.83 (d, J = 3 Hz, CH-OH) and 4 at 0 5.03 (d, J = 4 Hz). dThis
`amino alcohol gave a peak at 0 4.78 (d, J = 3 Hz, CH-OH).
`amino alcohol gave a peak at 0 4.78 (d, J = 3 Hz, CH-OH).
`
`[R3SiHFnn-Bu4Nj+ species which attacks the ketone carbonyl
`[R3SiHFnn-Bu4Nj+ species which attacks the ketone carbonyl
`carbon according to the Felkin transition-state model. 12 Par(cid:173)
`carbon according to the Felkin transition-state model. 12 Par(cid:173)
`ticularly noteworthy is that no metal cations are involved in the
`ticularly noteworthy is that no metal cations are involved in the
`reaction. Thus, coordination effects by a metal cation are com(cid:173)
`reaction. Thus, coordination effects by a metal cation are com(cid:173)
`pletely eliminated, and only the bulkiness of the reagent accounts
`pletely eliminated, and only the bulkiness of the reagent accounts
`for the stereose1ectivity. In this sense, the reagent is characterized
`for the stereose1ectivity. In this sense, the reagent is characterized
`as a "bulky naked hydride". 13
`as a "bulky naked hydride". 13
`In striking contrast to the TBAF-catalyzed threo-directed re(cid:173)
`In striking contrast to the TBAF-catalyzed threo-directed re(cid:173)
`duction, erythro-se1ective reduction was achieved by using the same
`duction, erythro-se1ective reduction was achieved by using the same
`hydrosilanes under acidic conditions. 14
`hydrosilanes under acidic conditions. 14
`For example, di(cid:173)
`For example, di(cid:173)
`methylphenylsilane (1.2 mmol) was added to a trifluoroacetic acid
`methylphenylsilane (1.2 mmol) was added to a trifluoroacetic acid
`(TFA) (I mL) solution of 2-(benzoyloxy)-I-phenyl-l-propanone
`(TFA) (I mL) solution of 2-(benzoyloxy)-I-phenyl-l-propanone
`at 0 °C. After being stirred for 6 h, the solution was neutralized
`at 0 °C. After being stirred for 6 h, the solution was neutralized
`with aqueous NaHC03 solution and worked up. Alkaline hy(cid:173)
`with aqueous NaHC03 solution and worked up. Alkaline hy(cid:173)
`drolysis followed by silica gel filtration gave a 7:93 mixture of
`drolysis followed by silica gel filtration gave a 7:93 mixture of
`threo- and erythro-l-phenyl-l ,2-propanediol in 72% yield. The
`threo- and erythro-l-phenyl-l ,2-propanediol in 72% yield. The
`reduction of N-protected a-amino ketones showed remarkable
`reduction of N-protected a-amino ketones showed remarkable
`erythro selectivity as shown in Table II.
`erythro selectivity as shown in Table II.
`The contrastive selectivity under TBAF vs. TF A catalysis is
`The contrastive selectivity under TBAF vs. TF A catalysis is
`noticeable. Whereas the TBAF-catalyzed reduction is explained
`noticeable. Whereas the TBAF-catalyzed reduction is explained
`by the Felkin model, the TF A catalysis may be rationalized by
`by the Felkin model, the TF A catalysis may be rationalized by
`the proton-bridged Cram's cyclic model. 15
`the proton-bridged Cram's cyclic model. 15
`The usefulness of the stereocontrolled reduction is demonstrated
`The usefulness of the stereocontrolled reduction is demonstrated
`by the chiral syntheses of useful drugs. Reduction of 14.16 ([aJ23o
`by the chiral syntheses of useful drugs. Reduction of 14.16 ([aJ23o
`-5.12° (c 5, CH2CI2» and 317 ([aJ2oo -33.1 ° (c 1, CHCI3» with
`-5.12° (c 5, CH2CI2» and 317 ([aJ2oo -33.1 ° (c 1, CHCI3» with
`dimethylphenylsilane in TFA gave 2 ([aJ2oo -41 ° (c 0.2, CHCI3»
`dimethylphenylsilane in TFA gave 2 ([aJ2oo -41 ° (c 0.2, CHCI3»
`and 4 ([aj2oo -31.7° (c I, CHCI 3», respectively (Table II).
`and 4 ([aj2oo -31.7° (c I, CHCI3», respectively (Table II).
`
`(12) (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
`(12) (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
`2199. (b) Anh, N. T.; Eisenstein, O. Nouv. J. Chirn. 1977, 1, 61.
`2199. (b) Anh, N. T.; Eisenstein, O. Nouv. J. Chirn. 1977, 1, 61.
`(13) Metal hydrides with
`tetrabutylammonium gegen cations,
`(13) Metal hydrides with
`tetrabutylammonium gegen cations,
`BU4NBH3CN: Hutchins, R. 0.; Kandasamy, D. J. Arn. Chern. Soc. 1973,
`BU4NBH3CN: Hutchins, R. 0.; Kandasamy, D. J. Arn. Chern. Soc. 1973,
`95,6131. BU4NBH4: Brandstrom, A.; Junggren, U.; Lamm, B. Tetrahedron
`95,6131. BU4NBH4: Brandstrom, A.; Junggren, U.; Lamm, B. Tetrahedron
`Lett. 1972, 3173. Raber, D. J.; Guida, W. C. J. Org. Chern. 1976,41,690.
`Lett. 1972, 3173. Raber, D. J.; Guida, W. C. J. Org. Chern. 1976,41,690.
`Sorrell, T. N.; Pearlman, P. S. Tetrahedron Lett. 1980,21,3963.
`Sorrell, T. N.; Pearlman, P. S. Tetrahedron Lett. 1980,21,3963.
`(14) So-called "Ionic Hydrogenation" conditions. Kursanov, D. N.; Parnes,
`(14) So-called "Ionic Hydrogenation" conditions. Kursanov, D. N.; Parnes,
`Z. N.; Loim, N. M. Synthesis 1974, 633.
`Z. N.; Loim, N. M. Synthesis 1974, 633.
`(15) Cram, D. J.; Wilson, D. R. J. Arn. Chern. Soc. 1963, 85, 1245.
`(15) Cram, D. J.; Wilson, D. R. J. Arn. Chern. Soc. 1963, 85, 1245.
`(16) Although the reported value for 1 is [a]23D-5.9° (c 5, CH2CI2) (ref
`(16) Although the reported value for 1 is [a]23D-5.9° (c 5, CH2CI2) (ref
`4), our sample was found to be optically pure, as repeated recrystallization
`4), our sample was found to be optically pure, as repeated recrystallization
`did not change the [alD value.
`did not change the [alD value.
`(17) Prepared from (S)-alanine by (i) methoxycarbonylation (MeOCOCI,
`(17) Prepared from (S)-alanine by (i) methoxycarbonylation (MeOCOCI,
`OW), (ii) acid chloride formation (SOCI2), (iii) N,N-dimethylamide forma(cid:173)
`OW), (ii) acid chloride formation (SOCI2), (iii) N,N-dimethylamide forma(cid:173)
`tion (HNMe2)' and (iv) ketone synthesis (2,5-(MeOhC6H3Li) in 66% overall
`tion (HNMe2)' and (iv) ketone synthesis (2,5-(MeOhC6H3Li) in 66% overall
`yield in optically pure form.
`yield in optically pure form.
`
`Lithium aluminum hydride reduction (THF, 60°C) of 2 gave
`Lithium aluminum hydride reduction (THF, 60°C) of 2 gave
`l-ephedrinel8 in 80% yield, while alkaline hydrolysis (KOH,
`l-ephedrinel8 in 80% yield, while alkaline hydrolysis (KOH,
`MeOH-H20 (3:1), reflux) of 4 gave l-methoxamine,2o an adre-
`MeOH-H20 (3:1), reflux) of 4 gave l-methoxamine,2o an adre-
`nergic vasopressor, in 83% yield.
`nergic vasopressor, in 83% yield.
`
`OH
`OH
`
`OMe OH
`OMe OH
`
`©r1:M
`©fe"' ~.
`• ~M'
`o
`:
`o
`:
`o
`:
`o
`:
`
`NHMe
`NHMe
`{-ephedrine
`I-ephedrine
`
`NHz
`NHz
`
`OMe
`OMe
`{-methoxamine
`I-methoxamine
`
`(18) The sam fIe was converted to the hydrochloride, [a]25D-33.5° (c I,
`(18) The sam fIe was converted to the hydrochloride, [a]25D-33.5° (c I,
`HP); !it. 19 [a]2 D-33 to -35.5 0 (c 5, H2O).
`HP); !it. 19 [a]2 D-33 to -35.5 0 (c 5, H2O).
`(19) "The Merck Index", 10th ed.; Merck & Co.: Rahway, NJ, 1983; No.
`(19) "The Merck Index", 10th ed.; Merck & Co.: Rahway, NJ, 1983; No.
`3558, p 520.
`3558, p 520.
`(20) The sam fIe was converted to the hydrochloride, [a]25D-27.9° (c 3,
`(20) The sam fIe was converted to the hydrochloride, [a]25D-27.9° (c 3,
`H20); !it.2l [a]2 D-28.5° (c 4, H2O).
`H20); !it.2l [a]2 D-28.5° (c 4, H2O).
`(21) Baltzly, R.; Mehta, N. B. J. Med. Chern. 1968, 11, 833.
`(21) Baltzly, R.; Mehta, N. B. J. Med. Chern. 1968, 11, 833.
`
`Palladium-Catalyzed Coupling of Vinyl Triflates with
`Palladium-Catalyzed Coupling of Vinyl Triflates with
`Organostannanes. A Short Synthesis of Pleraplysillin-l
`Organostannanes. A Short Synthesis of Pleraplysillin-l
`
`William 1. Scott, G. T. Crisp, and 1. K. Stille'"
`William 1. Scott, G. T. Crisp, and 1. K. Stille'"
`
`Department of Chemistry, Colorado State University
`Department of Chemistry, Colorado State University
`Ft. Collins, Colorado 80523
`Ft. Collins, Colorado 80523
`Received April 2, 1984
`Received April 2, 1984
`Revised Manuscript Received June 18, 1984
`Revised Manuscript Received June 18, 1984
`
`Although a variety of allylic compounds are capable of acting
`Although a variety of allylic compounds are capable of acting
`as electrophiles in palladium-catalyzed coupling reactions,1 vinylic
`as electrophiles in palladium-catalyzed coupling reactions,1 vinylic
`compounds that act as electrophiles are limited almost solely to
`compounds that act as electrophiles are limited almost solely to
`vinyl halides. I- 3 Allylic sulfonates, for example, readily undergo
`vinyl halides. I- 3 Allylic sulfonates, for example, readily undergo
`palladium-catalyzed coupling reactions,4 but there is no docu(cid:173)
`palladium-catalyzed coupling reactions,4 but there is no docu(cid:173)
`mented example for the insertion of a transition metal into the
`mented example for the insertion of a transition metal into the
`carbon-oxygen bond of a vinyl sulfonate. This is somewhat
`carbon-oxygen bond of a vinyl sulfonate. This is somewhat
`surprising since bromide, iodide, and tosylate all show similar
`surprising since bromide, iodide, and tosylate all show similar
`leaving group tendencies5 and similar allylic reactivities in pal(cid:173)
`leaving group tendencies5 and similar allylic reactivities in pal(cid:173)
`ladium-catalyzed transformations.4 In an effort to understand
`ladium-catalyzed transformations.4 In an effort to understand
`this apparent anomaly and to add to the functional groups on vinyl
`this apparent anomaly and to add to the functional groups on vinyl
`carbons that will undergo catalytic and stoichiometric insertion
`carbons that will undergo catalytic and stoichiometric insertion
`reactions with the group VIII transition metals, the palladium(cid:173)
`reactions with the group VIII transition metals, the palladium(cid:173)
`catalyzed reactions of vinyl sulfonates were explored. In particular,
`catalyzed reactions of vinyl sulfonates were explored. In particular,
`the reaction of vinyl triflates6 with organostannanes7 was un(cid:173)
`the reaction of vinyl triflates6 with organostannanes7 was un(cid:173)
`dertaken.
`dertaken.
`Upon addition of 4-tert-butylcyclohexenyl triflate (1) to a 2
`Upon addition of 4-tert-butylcyclohexenyl triflate (1) to a 2
`mol% solution of tetrakis(triphenylphosphine)palladium(O) in
`mol% solution of tetrakis(triphenylphosphine)palladium(O) in
`tetrahydrofuran (THF) at room temperature, a reaction occurred
`tetrahydrofuran (THF) at room temperature, a reaction occurred
`immediately as observed by 31p NMR.8 However, addition of
`immediately as observed by 31p NMR.8 However, addition of
`
`(1) For a general review, see: Tsuji, J. "Organic Synthesis with Palladium
`(1) For a general review, see: Tsuji, J. "Organic Synthesis with Palladium
`Compounds"; Springer-Verlag: Berlin, 1980. Trost, B. M.; Verhoeven, T.
`Compounds"; Springer-Verlag: Berlin, 1980. Trost, B. M.; Verhoeven, T.
`R. In "Comprehensive Organometallic Chemistry"; Wilkinson, G., Stone, F.
`R. In "Comprehensive Organometallic Chemistry"; Wilkinson, G., Stone, F.
`G. A., Abel, E. W., Eds.; Pergamon: Oxford, 1982; Vol. 8, Chapter 57.
`G. A., Abel, E. W., Eds.; Pergamon: Oxford, 1982; Vol. 8, Chapter 57.
`(2) (a) For the palladium-catalyzed coupling of alanes with enol phos(cid:173)
`(2) (a) For the palladium-catalyzed coupling of alanes with enol phos(cid:173)
`phates, see: Takai, K.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1980, 21,
`phates, see: Takai, K.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1980, 21,
`2531-2534. (b) For some examples of the palladium-catalyzed coupling of
`2531-2534. (b) For some examples of the palladium-catalyzed coupling of
`vinyl halides, see: Heck, R. F. Ace. Chern. Res. 1979, 12, 146-151. Negishi,
`vinyl halides, see: Heck, R. F. Acc. Chern. Res. 1979, 12, 146-151. Negishi,
`E. ibid. 1982, 15, 340-345.
`E. ibid. 1982, 15, 340-345.
`(3) (a) For the nickel-catalyzed coupling of Grignard reagents with methyl
`(3) (a) For the nickel-catalyzed coupling of Grignard reagents with methyl
`vinyl ethers, see: Wenkert, E.; Michelotti, E. L.; Swindell, C. S. J. Arn. Chern.
`vinyl ethers, see: Wenkert, E.; Michelotti, E. L.; Swindell, C. S. J. Am. Chern.
`Soc. 1979, 101, 2246-2247. (b) For the nickel-catalyzed coupling of Grignard
`Soc. 1979, 101, 2246-2247. (b) For the nickel-catalyzed coupling of Grignard
`reagents with silyl enol ethers, see: Hayashi, T.; Katsura, Y.; Kamuda, M.
`reagents with silyl enol ethers, see: Hayashi, T.; Katsura, Y.; Kamuda, M.
`Tetrahedron Lett. 1980, 21, 3915-3918.
`Tetrahedron Lett. 1980, 21, 3915-3918.
`(4) For example, see: Trost, B. M.; Chan, D. M. T. J. Arn. Chern. Soc.
`(4) For example, see: Trost, B. M.; Chan, D. M. T. J. Arn. Chern. Soc.
`1983,105,2315-2325. Matsushita, H.; Negishi, E. J. Org. Chern. 1982,47,
`1983,105,2315-2325. Matsushita, H.; Negishi, E. J. Org. Chern. 1982,47,
`4161-4165. Semmelhack, M. F.; Brickner, S. J. J. Arn. Chern. Soc. 1981,
`4161-4165. Semmelhack, M. F.; Brickner, S. J. J. Arn. Chern. Soc. 1981,
`103, 3945-3947.
`103, 3945-3947.
`(5) McMurry, J. "Organic Chemistry"; Brooks/Cole: Monterey, CA,
`(5) McMurry, J. "Organic Chemistry"; Brooks/Cole: Monterey, CA,
`1984; P 301-302.
`1984; P 301-302.
`(6) McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1980,21,4313-4316.
`(6) McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1980, 21, 4313-4316.
`(7) For an example of the palladium-catalyzed reaction of vinyl halides
`(7) For an example of the palladium-catalyzed reaction of vinyl halides
`with organostannanes, see: Kosugi, M.; Hagiwara, 1.; Migita, T. Chern. Letl.
`with organostannanes, see: Kosugi, M.; Hagiwara, 1.; Migita, T. Chern. Letl.
`1983, 839-840.
`1983, 839-840.
`
`0002-7863/84/1506-4630$01.50/0
`0002-7863/84/1506-4630$01.50/0
`
`© 1984 American Chemical Society
`© 1984 American Chemical Society
`
`NPC02231219
`
`NOVARTIS EXHIBIT 2125
`Par v Novartis, IPR 2016-00084
`Page 1 of 3
`
`

`
`Communications to the Editor
`Communications to the Editor
`
`J. Am. Chern. Soc., Vol. 106, No. 16, 1984 4631
`J. Am. Chern. Soc., Vol. 106, No. 16, 1984 4631
`
`Table I. Palladium-Catalyzed Coupling of Vinyl Triflates with
`Table I. Palladium-Catalyzed Coupling of Vinyl Triflates with
`Organotins
`Organotins
`
`Scheme I
`Scheme I
`
`a.LDA
`8.LDA
`b. Tf2NPh
`
`91%
`91%
`
`II
`
`OT!
`
`-...;:::
`
`5
`5
`
`95: 5
`95: 5
`
`Me3Sn~SiMes
`
`100%
`
`/
`
`o
`0
`
`a.II·PrI2NMgB,
`•. II-PTI2NMgBr
`b. Tf2NPh
`
`63%
`63%
`
`OT!
`
`M~Sn~SiMe3
`
`90%
`
`97:3
`97:3
`
`t5'~
`
`"
`
`6
`
`95: 5
`95:5
`
`&
`
`98:2
`98:2
`
`"
`
`~ TRIFLATE
`TRIFLATE
`EXAMPLE
`
`ORGANOTIN
`ORGANOTIN
`
`ISOLATED
`REACTION
`ISOLATED
`REACTION
`.!.l!lUhl ~ lillQl!L
`.!.l!lUhl ~ lillQl!L
`
`POT' ..... n ......
`POT' .... Sn ......
`17 ff
`17 ff 01
`., ~ 80
`..... n ~ ao
`0.' P"
`0.' P"
`31 ~ o.
`B~Sn~ ~ g.
`
`.... Sn
`
`8u;3SnH
`8u;3SnH
`
`B~Sn~
`
`78
`78
`
`M",nC=C"~
`M",nC=C"~
`
`41
`
`~.'~3
`~SI~3
`I
`I
`
`90
`00
`
`Scheme II
`Scheme II
`
`b. T!2NPh D PdIPPh3i4 /LiCI
`~OTf
`r---------..
`/
`~ 4
`~ 4
`b. Tf2NPh Cr PdIPPh3i4/LiCI
`0Q
`0Q
`n Br
`G.B
`
`DC' ~"n~l~ 3. ~ .. ~
`DC' ~"n~l~ 3. ~ .. ~
`t(Y 80
`t(Y 80
`L
`L
`
`I
`I
`
`100
`100
`
`00
`90
`
`QJ.,M.3
`Q JS IM .3
`I
`I
`
`100
`100
`
`Bu .. n~
`Bu .. n~
`
`133
`133
`
`OT,
`
`OT,
`~ M.~~SiMe.a
`~ M.~~SiMe.a
`
`17
`17
`
`100
`
`~SI~ 90
`~.,~
`
`90
`
`(rOT'
`(rOT'
`OoT!
`OOT'
`
`10
`10
`
`vinyltributylstannane (2) to the resulting dark brown solution did
`vinyltributylstannane (2) to the resulting dark brown solution did
`not lead to the coupled product (3).
`not lead to the coupled product (3).
`When 1 was added to a mixture of 2 equiv of lithium chloride
`When 1 was added to a mixture of 2 equiv of lithium chloride
`and 2 mol% of palladium(O) in THF at room temperature, a
`and 2 mol% of palladium(O) in THF at room temperature, a
`reaction again occurred immediately, as observed by 31p NMR,
`reaction again occurred immediately, as observed by 31p NMR,
`and now a colorless solution was generated. Addition of 2 to this
`and now a colorless solution was generated. Addition of 2 to this
`mixture (70°C, 17 h) led to a quantitative conversion of 1 to 3,
`mixture (70°C, 17 h) led to a quantitative conversion of 1 to 3,
`as indicated by GC analysis.
`as indicated by GC analysis.
`Assuming that the oxidative addition of triflate (1) to palladium
`Assuming that the oxidative addition of triflate (1) to palladium
`takes place, the resulting vinylpalladium(II) triflate appears in(cid:173)
`takes place, the resulting vinylpalladium(II) triflate appears in(cid:173)
`capable of entering a catalytic cyc1e.8•9 In the presence of lithium
`capable of entering a catalytic cyc1e.8•9 In the presence of lithium
`chloride, apparently a vinylpalladium(II) chloride complex was
`chloride, apparently a vinylpalladium(II) chloride complex was
`generated, which was then capable of undergoing further reaction
`generated, which was then capable of undergoing further reaction
`with 2 to afford coupled products and generate a palladium(O)
`with 2 to afford coupled products and generate a palladium(O)
`species.
`species.
`
`('Ir0Tf
`('Ir0Tf
`
`~ + PdL4
`~ + PdL4
`
`----.~ [ +OPdILlnOTf ]
`- - - -... ~ [ +OPdILlnOT!]
`
`1
`1
`
`3
`As shown in Table I, the coupling of vinyl triflates with or(cid:173)
`As shown in Table I, the coupling of vinyl triflates with or(cid:173)
`ganotin compounds has been found to be general. 10. 11 The re-
`ganotin compounds has been found to be general. 10. 11 The re-
`
`-N
`"N 3
`
`(8) The stoichiometric reaction of 1 with palladium(O) complexes both in
`(8) The stoichiometric reaction of 1 with palladium(O) complexes both in
`the presence and in the absence of lithium chloride is currently under inves(cid:173)
`the presence and in the absence of lithium chloride is currently under inves(cid:173)
`tigation.
`tigation.
`(9) Labadie. J. W.; Stille. J. K. J. Am. Chern. Soc. 1983,105,6129-6137.
`(9) Labadie, J. W.; Stille, J. K. J. Am. Chern. Soc. 1983,105,6129-6137.
`(10) Details of the scope of this reaction will be reported in due course.
`(10) Details of the scope of this reaction will be reported in due course.
`
`[(0) 9
`o
`9
`
`'
`
`12
`12
`
`93%
`93%
`
`a. L-Select'ide(!lJ
`•. L-SelectrideQ!)
`
`b. T!2NPh
`
`nOQ
`
`13
`13
`
`73%
`73%
`
`SnBu3
`;=I
`
`LiCu
`
`~ 10
`
`10
`
`~snBU3
`~snBU3
`o
`o
`
`11
`11
`
`75% PdlPPhai4
`75% PdIPP~i4
`LiCI
`LiCI
`
`~ 14
`~ 14
`
`duction of 1 proceeded in good yield, as shown by example 3. The
`duction of 1 proceeded in good yield, as shown by example 3. The
`coupling reaction seems suited to alkylation at sterically hindered
`coupling reaction seems suited to alkylation at sterically hindered
`centers, as shown in examples 6 and 7. Finally, the reaction allows
`centers, as shown in examples 6 and 7. Finally, the reaction allows
`the facile stereoselective formation of 1,3-dienes under mild
`the facile stereoselective formation of 1,3-dienes under mild
`conditions (examples 1 and 6-10).
`conditions (examples 1 and 6-10).
`The ability to regioselectively form vinyl triflates by utilizing
`The ability to regioselectively form vinyl triflates by utilizing
`well-known enolate chemistry I2.13 and then to convert them into
`well-known enolate chemistry I2.13 and then to convert them into
`olefins is illustrated in Scheme I. Thus, 2-methylcyclohexanone
`olefins is illustrated in Scheme I. Thus, 2-methyJcyclohexanone
`could be converted into the 6-methyl triflate 5 (5:7 = 95:5) or
`could be converted into the 6-methyl triflate 5 (5:7 = 95:5) or
`the 2-methyl triflate 7 (7:5 = 97:3), and these could then be
`the 2-methyl triflate 7 (7:5 = 97:3), and these could then be
`coupled to afford 6 and 8, respectively.
`coupled to afford 6 and 8, respectively.
`The following procedure is illustrative. To a mixture of 0.56
`The following procedure is illustrative. To a mixture of 0.56
`g (13 mmol) of lithium chloride and 0.032 g (0.028 mmol, 1.6
`g (13 mmol) of lithium chloride and 0.032 g (0.028 mmol, 1.6
`
`(11) Satisfactory JR, lH NMR, and 13C NMR spectra and either HRMS
`(11) Satisfactory JR, lH NMR, and 13C NMR spectra and either HRMS
`or combustion analyses were obtained for all new compounds.
`or combustion analyses were obtained for all new compounds.
`(12) McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983,24,979-982.
`(12) McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983,24,979-982.
`(l3) Kraft, M. E.; Holton, R. A. Tetrahedron Lett. 1983, 24,1345-1348.
`(l3) Kraft, M. E.; Holton, R. A. Tetrahedron Lett. 1983, 24,1345-1348.
`(14) (a) Cimino, G.; DeStefano, S.; Minale, L. Tetrahedron 1972, 28,
`(14) (a) Cimino, G.; DeStefano, S.; Minale, L. Tetrahedron 1972, 28,
`4761-4767. (b) Cimino, G.; DeStefano, S.; Minale, L. Experirnentia 1974,
`4761-4767. (b) Cimino, G.; DeStefano, S.; Minale, L. Experirnentia 1974,
`30,864. (c) Thompson, J. E.; Walker, R. P.; Wratten, S. J.; Faulkner, D.
`30,864. (c) Thompson, J. E.; Walker, R. P.; Wratten, S. J.; Faulkner, D.
`J. Tetrahedron Lett. 1982, 23, 1865-1873.
`J. Tetrahedron Lett. 1982, 23, 1865-1873.
`
`NPC02231220
`
`NOVARTIS EXHIBIT 2125
`Par v Novartis, IPR 2016-00084
`Page 2 of 3
`
`

`
`4632
`4632
`
`J. Am. Chem. Soc. 1984, 106, 4632-4633
`J. Am. Chem. Soc. 1984, 106, 4632-4633
`
`mol %) of tetrakis(triphenylphosphine)palladium(O) under argon
`mol %) of tetrakis(triphenylphosphine)palladium(O) under argon
`was added 10 mL of dry THF followed by a solution of 0.51 g
`was added 10 mL of dry THF followed by a solution of 0.51 g
`(1.8 mmol) of vinyl triflate 1 and 0.62 g (1.8 mmol) of tetra(cid:173)
`(1.8 mmol) of vinyl triflate 1 and 0.62 g (1.8 mmol) of tetra(cid:173)
`butyl tin in 10 mL of THF. This slurry was heated to reflux for
`butyl tin in 10 mL of THF. This slurry was heated to reflux for
`17 h, cooled to room temperature, and diluted with 60 mL of
`17 h, cooled to room temperature, and diluted with 60 mL of
`pentane. After washing with a 10% ammonium hydroxide solution
`pentane. After washing with a 10% ammonium hydroxide solution
`(3 X 25 mL) and drying (MgS04), the resulting solution was
`(3 X 25 mL) and drying (MgS04), the resulting solution was
`filtered through a short pad of silica gel and concentrated under
`filtered through a short pad of silica gel and concentrated under
`reduced pressure to give 0.28 g (80%) of l-butyl-4-tert-butyl(cid:173)
`reduced pressure to give 0.28 g (80%) of l-butyl-4-tert-butyl(cid:173)
`cyclohexene6 (example 2) as a colorless oil.
`cyclohexene6 (example 2) as a colorless oil.
`This methodology was applied to the synthesis of pleraplysillin-I
`This methodology was applied to the synthesis of pleraplysillin-I
`(14),14 as shown in Scheme II.
`(E)-Vinyltin 11 was formed by
`(14),14 as shown in Scheme II.
`(E)-Vinyltin 11 was formed by
`addition of the lithium (E)-vinyltin cuprate 1015 to 3-furfuryl
`addition of the lithium (E)-vinyltin cuprate 1015 to 3-furfuryl
`bromide16 (73% yield). Triflate 13 was prepared as one regioi(cid:173)
`bromide16 (73% yield). Triflate 13 was prepared as one regioi(cid:173)
`somer from 5,5-dimethyl-2-cyclohexenoneI7 by conjugate reduc(cid:173)
`somer from 5,5-dimethyl-2-cyclohexenoneI7 by conjugate reduc(cid:173)
`tion 18 followed by enolate trapping with N-phenyltriflimide. 12
`tion 18 followed by enolate trapping with N-phenyltriflimide. 12
`Palladium-catalyzed coupling of 11 with 13 afforded pleraply(cid:173)
`Palladium-catalyzed coupling of 11 with 13 afforded pleraply(cid:173)
`sillin-I (14) in 75% yield. 19,2o No other isomers were observed.
`sillin-I (14) in 75% yield. 19,2o No other isomers were observed.
`Thus, vinyl triflates couple with organostannanes in the presence
`Thus, vinyl triflates couple with organostannanes in the presence
`of lithium chloride and palladium(O) catalysts to give a variety
`of lithium chloride and palladium(O) catalysts to give a variety
`of olefin-substituted products. This reaction represents the first
`of olefin-substituted products. This reaction represents the first
`case of a transition-metal-catalyzed reaction of a vinyl sulfonate.
`case of a transition-metal-catalyzed reaction of a vinyl sulfonate.
`In effect, this allows the conversion of the oxygen of regioselectively
`In effect, this allows the conversion of the oxygen of regioselectively
`formed enolates into a leaving group for palladium-catalyzed
`formed enolates into a leaving group for palladium-catalyzed
`reactions.
`reactions.
`
`Acknowledgment. We gratefully acknowledge support for this
`Acknowledgment. We gratefully acknowledge support for this
`research through Grant CHE-8305468 from the National Science
`research through Grant CHE-8305468 from the National Science
`Foundation. Palladium chloride was generously loaned by
`Foundation. Palladium chloride was generously loaned by
`Johnson-Matthey Inc. through the Johnson-Matthey Metal Loan
`Johnson-Matthey Inc. through the Johnson-Matthey Metal Loan
`Program.
`Program.
`
`(15) Corey, E. J.; Wollenberg, R. H. Tetrahedron Lett. 1975, 16,
`(15) Corey, E. J.; Wollenberg, R. H. Tetrahedron Lett. 1975, 16,
`2225-2226.
`2225-2226.
`(16) Parker, K. A.; Johnson, W. S. Tetrahedron Lett. 1969, 10,
`(16) Parker, K. A.; Johnson, W. S. Tetrahedron Lett. 1969, 10,
`1329-1332.
`1329-1332.
`(17) Hiegel, G. A.; Burk, P. J. Org. Chern. 1973, 38, 3637-3639.
`(17) Hiegel, G. A.; Burk, P. J. Org. Chern. 1973, 38, 3637-3639.
`(18) (a) Ganem, B. J. Org. Chern. 1975,40, 146-147. (b) Fortunato, J.
`(18) (a) Ganem, B. J. Org. Chern. 1975,40, 146-147. (b) Fortunato, J.
`M.; Ganem, B. Ibid. 1976,41,2194-2200.
`M.; Ganem, B. Ibid. 1976,41,2194-2200.
`(19) For a prior synthesis of 14, see: Masaki, Y.; Hashimoto, K.; Serizawa,
`(19) For a prior synthe&is of 14, see: Masaki, Y.; Hashimoto, K.; Serizawa,
`Y.; Kaji, K. Chern. Lett. 1982, 1879-1880.
`Y.; Kaji, K. Chern. Lett. 1982, 1879-1880.
`(20) NMR and IR spectra of 14 were identical with spectra of authentic
`(20) NMR and IR spectra of 14 were identical with spectra of authentic
`material. The authors thank Professors Faulkner, Masaki, and Minale for
`material. The authors thank Professors Faulkner, Masaki, and Minale for
`copies of the spectra of 14.
`copies of the spectra of 14.
`
`Reversible Protonation of the Oxo Bridge in a
`Reversible Protonation of the Oxo Bridge in a
`Hemerythrin Model Compound. Synthesis, Structure,
`Hemerythrin Model Compound. Synthesis, Structure,
`and Properties of (j.L-Hydroxo)bis(wacetato)(cid:173)
`and Properties of (j.L-Hydroxo)bis(wacetato)(cid:173)
`bis[hydrotris( I-pyrazolyl)borato ]diiron(III),
`bis[hydrotris( 1-pyrazolyl)borato ]diiron(III),
`[(HB(pzh)Fe(OH) (02CCH3hFe(HB(pz)3)]+
`[(HB(pzh)Fe(OH) (02CCH3hFe(HB(pz)3)]+
`
`William H. Armstrong and Stephen J. Lippard*
`William H. Armstrong and Stephen J. Lippard*
`
`Department of Chemistry
`Department of Chemistry
`Massachusetts Institute of Technology
`Massachusetts Institute of Technology
`Cambridge, Massachusetts 02139
`Cambridge, Massachusetts 02139
`Received April 3, 1984
`Received April 3, 1984
`
`Recently the synthesis and properties of binuclear iron com(cid:173)
`Recently the synthesis and properties of binuclear iron com(cid:173)
`plexes that serve as structural, spectroscopic, and chemical models
`plexes that serve as structural, spectroscopic, and chemical models
`for the (woxo)bis(wcarboxylato)diiron(III) core of the met forms
`for the (woxo)bis(wcarboxylato)diiron(III) core of the met forms
`of marine invertebrate respiratory proteins hemerythrin (Hr) and
`of marine invertebrate respiratory proteins hemerythrin (Hr) and
`myohemerythrin (myoHr)I.2 were described.3,4 Oxo-bridged
`myohemerythrin (myoHr)I.2 were described.3,4 Oxo-bridged
`
`(I) (a) Stenkamp, R. E.; Sieker, L. C.; Jensen, L. H. J. Arn. Chern. Soc.
`(I) (a) Stenkamp, R. E.; Sieker, L. C.; Jensen, L. H. J. Arn. Chern. Soc.
`1984, 106,618-622. (b) Sanders-Loehr, J.; Loehr, T. M. Adv. Inorg. BiD(cid:173)
`1984, 106,618-622. (b) Sanders-Loehr, J.; Loehr, T. M. Adv. Inorg. BiD(cid:173)
`chern. 1979, 1, 235-252. (c) Wilkins, R. G.; Harrington, P. C. Ibid. 1983,
`chern. 1979, 1, 235-252. (c) Wilkins, R. G.; Harrington, P. C. Ibid. 1983,
`5,51-85. (d) Klotz, I. M.; Kurtz, D. M., Jr. Acc. Chern. Res. 1984, 17, 16-22.
`5,51-85. (d) Klotz, 1. M.; Kurtz, D. M., Jr. Acc. Chern. Res. 1984,17, 16-22.
`(2) (a) Hendrickson, W. A. In "Invertebrate Oxygen-Binding Proteins:
`(2) (a) Hendrickson, W. A. In "Invertebrate Oxygen-Binding Proteins:
`Structure, Active Site, and Function"; Lamy, J., Lamy, J., Eds.; Marcel
`Structure, Active Site, and Function"; Lamy, J., Lamy, J., Eds.; Marcel
`Dekker: New York, 1981; pp 503-515. (b) Sheriff, S.; Hendrickson, W. A.;
`Dekker: New York, 1981; pp 503-515. (b) Sheriff, S.; Hendrickson, W. A.;
`Smith, J. L. Life Chern. Rep. 1983, Suppl. 1, 305-308.
`Smith, J. L. Life Chern. Rep. 1983, Suppl. 1, 305-308.
`
`Figure 1. Structure of the (IL-hydroxo )bis(IL-acetato) bis [hydrotris(l(cid:173)
`Figure 1. Structure of the (lL-hydroxo)bis(lL-acetato)bis[hydrotris(1-
`pyrazolyl)boratoldiiron(III) cation (1) showing the 40% probability
`pyrazolyl)boratoldiiron(III) cation (1) showing the 40% probability
`thermal ellipsoids and atom labeling scheme. The hydrogen atom bound
`thermal ellipsoids and atom labeling scheme. The hydrogen atom bound
`to atom 0 is depicted at its refined position with an arbitrary B value of
`to atom 0 is depicted at its refined position with an arbitrary B value of
`1.0 A2. The remaining hydrogen atoms are omitted for clarity.
`1.0 A2. The remaining hydrogen atoms are omitted for clarity.
`
`Table I. Comparison of Structural Features of
`Table I. Comparison of Structural Features of
`[FeiOH)(02CCHlMHB(pzhhl+ (l)a and
`[FeiOH)(02CCHlMHB(pzhhl+ (l)a and
`[Fe20(02CCHlMHB(pzhhl (2)b
`[Fe20(02CCHlMHB(pzhhl (2)b
`bond length, A
`bond length, A
`or angle, deg C
`or angle, deg C
`Fe(I)· .. Fe(2)
`Fe(I)· .. Fe(2)
`Fe-Obridge
`Fe-Obridge
`Fe(l)-O-Fe(2)
`Fe(1)-O-Fe(2)
`Fe-N
`Fe-N
`
`3.439 (I)
`3.1457 (6)
`3.1457 (6)
`3.439 (1)
`1.960 (4), 1.952 (4)e
`1.960 (4), 1.952 (4)e
`1.780 (2), 1.788 (2)
`1.780 (2), 1.788 (2)
`123.6(1)
`123.1 (2)
`123.1 (2)
`123.6(1)
`2.148 (3)-2.200 (3)
`2.087 (4)-2.110 (5)
`2.148 (3)-2.200 (3)
`2.087 (4)-2.110 (5)
`mean 2.102
`mean 2.102
`mean 2.165
`mean 2.165
`2,040 (2)-2.050 (3)
`1.994 (4)-2.001 (4)
`1.994 (4)-2.001 (4)
`2,040 (2)-2.050 (3)
`mean 1.999
`mean 1.999
`mean 2.043
`mean 2.043
`C Atoms are labeled for both com(cid:173)
`aThis work. bReference 3b.
`aThis work. bReference 3b.
`C Atoms are labeled for both com(cid:173)
`pounds as shown in Figure I. dNumbers in parentheses are estimated
`pounds as shown in Figure 1. dNumbers in parentheses are estimated
`standard deviations in the last digit. eThe H atom was first located on
`standard deviations in the last digit. eThe H atom was first located on
`a difference Fourier map at 0.94 A from the 0 atom; the refined O-H
`a difference Fourier map at 0.94 A from the 0 atom; the refined O-H
`distance is 0.70 (6) A.
`distance is 0.70 (6) A.
`
`Fe-Oacetat,
`Fe-Oacetat,
`
`binuclear iron centers are also believed to occur in ribonucleotide
`binuclear iron centers are also believed to occur in ribonucleotide
`reductase from Escherichia coliS and in some purple acid phos(cid:173)
`reductase from Escherichia coliS and in some purple acid phos(cid:173)
`phatases. 6 Here we report that, from the reaction mixture used
`phatases. 6 Here we report that, from the reaction mixture used
`by us to produce binuclear iron model compounds for metHr and
`by us to produce binuclear iron model compound