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Studies in asymmetric synthesis PDF

187 Pages·024.853 MB·English
by  ReidJoan A
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STUDISS m A8YMM3TEIC 8YMTH2SI8 (Abstract of thesis submitted by J.A. Reid for degree of Ph. D. ) It has been shown by McKenzie and his school that when optically active esters of a-keto-acids (R.00,002#*) and a Orignard reagent (R*MgX) interact the diastereo- isomerides [R.OR *(0MgX).C02#*3 are produced in unequal amounts. The substituted glycollic acids, obtained by hydrolysis, were optically active, although not optically pure. The analogous reactions using optically active esters of y -, ^-, £ - .......... keto-acids had v irtu a lly not been studied. In the present investigation the interaction of ( - ) -menthyl esters of u>-acetyl fa tty acids [CH^.CO. C02C^qH^ and phenyl magnesium bromide has been studied with a viev/to obtaining asymmetric synthesis and to relating this to the length of the chain in ter­ vening between the carbonyl and carbomenthoxy groups. The investigation has entailed the preparation of the above type of esters when n = 0, 2, 3, 4 and 8, and th eir treatment with phenyl magnesium bromide. The hydroxy-acids or (with n = 2 and 3) lactones, obtained after hydrolysis of the resulting esters, were optically active, except in the case of n = 8. With n = 2 or 3, the degree of asymmetric synthesis was dependent on reaction conditions. The addition of a Grignard reagent to a carbonyl group has previously been found to occur asymmetrically only when the carbonyl group is in a molecule containing a "fixed centre of asymmetry". It has now been found that an asymmetric reaction occurs when an optically active organo-metallic compound adds to a ketone. This type of reaction has been studied using (-)-m enthyl ^ bromoacetate, acetophenone and zinc. The -hydroxy acid obtained on hydrolysis was optically active. The extent of the asymmetric synthesis was found to be remarkably constant, irrespective of a wide variation in reaction con­ ditions. Theories of asymmetric synthesis are discussed and a theory involving energy differences of two transition states is proposed as an explanation of the results obtained in this investigation. ^-Hydroxy- V -phenyl-n-valeric acid (n = 2) has been prepared and resolved. STUDIES IN ASYMŒTRIC SYITTHSSIS Joan A. Reid, B. Sc. (London) Thesis submitted to the U niversity of London fo r the Degree of Doctor of Philosophy Chemistry Department Bedford College fo r Women, (U niversity of London), London, N.W. 1. February, 1950. ProQuest Number: 10097961 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest 10097961 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 CONTSms Page AQKNOUliEDGSMSNTS ............................................................................... vi GENERAL NOTES.............................................................................................. v ii I. INTRODUCTION ............................................................................... 1 ^ la . D e fin itio n of asymmetric synthesis . . . IL. Total asymmetric synthesis . . . 2 Ic . Asymmetric syntheses involving Grignard re agent s . . . . . . . . . ..# ... ... 3 Id, Present in v e s tig a tio n ...........................................15 n . PREPARATION OF ( - ) -MENTHYL ESTERS................................... 1? I la. ( - ) -Menthyl p y ru v a te . . . 17 IIL . (-)-M enthyl laevulate ...............................................1 8 lie . (-)-M enthyl -acetyl-n -L u tyrate, [(-)-menfchyl 4-keto-pentan-i-carLoxylate ] . . . 18 Ild . (-)-M entliyl ^ - ace ty l-n -v a le rate [ (-)- menthyl 5-ket o-he% an4-carLoxylate]........................... 2i lie . ( - ) -Menthyl w -ace t yip e l arg ona te [(-)-menthyl 9-keto-decan-1 -carhoxyl ate j ........................... 26 I l f . Note on physical properties of ( - ) -menthyl u -acetyl fa tty acid esters in relatio n to structure . . . . . . . . . . . . . . . . . . 28 Ilg . ( - ) -Menthyl "bromoacetate . . . . . . . . . 30 I I I . INTERACTION OF PHENYL MAGNESIUM BROMIDE AND ( - ) -MENTHYL Ü -ACETYL FATTY ACID ESTERS . . . 32 Ilia . Introductxon . . . . . . . . . . . . . . . 32 IIIL . Preparation of phenyl magnesium Bromide ... 33 i l IIIc . Method of estim ation of diphenyl .................... 33 Illd . Conditions employed for the Grignard reaction, and is o la tio n of the products . . . 34 Ille . O utline of Grignard reactions studied . .. 35 I l l f . Interaction of (-)-m enthyl pyruvate and phenyl magnesium bromide . . . 36 Illg . In teractio n of ( - ) -menthyl laevulate and phenyl magnesium bromide . . . 37 ( i) Reaction co n d itio n s . . . 37 ( ii) Iso latio n of y -hydroxy-y-phenylvaleric acid and its lactone (y-phenyl-y-valero- 1a c t o ne) ... . . . . . . . . . ... ... 3^ ( i i i ) Conversion of y-h^^droxy-^-phenylvaleric acid in to its lactone .................................. 40 (iv ) Reconversion of y-phenyl-y-valerolactone i nt o t he a ci d . . . . . . . . . . #. ... 4-i (v) Relationship between reaction conditions and yi eld . . . • .. ••• ».. ... 4-2 (v i) Relationship between reaction conditions and degree of asymmetric synthesis (i.e . specific rotation of product). ... 4-5 (v ii) Further observations,from large scale experiments, on the relationship between reaction conditions and results . . . ... 4-6 ( v iii) O ptical examination of y -hydroxy-y-phenyl- v a le ric acid precipitated from alkaline solution • .. • .• . . . . . . . . . 55 (ix ) Neutral products obtained ... 59 Illh . Interaction of ( - ) menthyl f^-acetyl-n- butyrate and phenyl magnesium bromide . . . 60 I l l j . Interactio n of (-)-m enthyl ^ -acetyl-n - valerate and phenyl magnesium bromide . .. 64- Illk . In teractio n of ( - ) -menthyl ^ -a c e ty l- pelargonate and phenyl magnesium bromide 67 IV. INTERACTION OF ACETOPHENONE, ( - ) -MENTHYL BROMO- ACBTATB AND Z IN C .............................................................................. 68 V. CORRELATION OF RESULTS................................................................ 77 iii Page V I. DISCUSSION OP CONCLUSIONS IN RELATION TO THEORIES OP ASYMMETRIC SYNTHESIS ..................... 92 V ia. Previous work ................................................. 92 VIU. Present investigation . . . . . . ... 102 V II. PREPARATION AND RESOLUTION OP (±)-y-HYDRCXY- y-PHBNYIiV.ALSRIC ACID (3-HYDROXY-3-PHBNYL- BUTAN-1 -CARBOXYL IC AC ID )............................................. i 1 3 V ila . Introduction ................................................. 115 V IIL . Preparation ( - ) -y-hydroxy-y-phenyl- valeric acid ................................................. 115 V IIc . Resolution - prelim inary experiments 11 6 V lld . Conditions fo r iso latio n of y-hydroxy- y-phenylvaleric acid and y-phenyl-y- valerolactone from the "brucine salt of the acxd . . . . . . . . . . . . . . . 117 V ile . Resolution using brucine in aqueous me di um . . . . . . . . . . . . . . . 117 V III. EXPERIMENTAL ................................................................ 1 20 V illa . Preparation of (-)-manthyl pyruvate 120 V IILb. Preparation of ( - ) -menthyl laevulate 121 V IIIc . Preparation of ( - ) -menthyl ^ -a c e ty l- n-Lutyrate . . . ........................................... 122 V llld . Preparation, of ( - ) -menthyl O -acetyl- n—V aler ate . . . . . . . . . . . . 123 V llle . Preparation of (-)-m enthyl -a c e ty l- pelargonate ................................................. 127 V lllf . Preparation of (-)-m enthyl "bromoacetate 131 iv Page V lllg . Grignard r e a c tio n s .............................................. 132 ( i) Phenyl magnesium bromide solution (containing 0*125 g- mol. PhIvîgBr) ... 132 De term ination of amount of diphenyl formed ............................................ 133 ( ii) P a rtia l asymmetric synthesis of a tro la c tin ic acid ................................. 134 ( i i i ) P a rtia l asymmetric synthesis of y-hydroxy-y-phenylvaleric acid and y-phenyl-y-valerolactone ... ... 136 P recip itatio n of y-hydroxy-y-phenyl- v aleric acid, from an alkaline solution, w ith 5N-sulphuric acid ... 139 (iv ) P a rtia l asymmetric synthesis of r-phenyl-g-caprolactone ................... 140 (v) In teractio n of ( - ) -menthyl -a c e ty l- n-valerate and phenyl magnesium bromide . . . . . . . . . . . . ... 145 (v i) In teractio n of ( - ) -menthyl ^C-acetyl- pelargonate and phenyl magnesium b r omi de . . . . .. . . . . . . ... 146 V lllh . Reformatsky reactions ... 149 (i) P a rtia l asymmetric synthesis of p-hydroxy-p-phenylbutyric acid . . . 149 ( ii) Preparation of (_±)-P-hydroxy- P-phenylbutyric a c i d .................... . . . 152 ( i i i ) Preparation of 2-hydroxy-2-isobutyl 4-methyl-hexanoic acid . . . . . . 152 VIIIj. (+)-y-hydroxy-y-phenylvaleric acid ... 153 (i) Preparation ..................... 153 ( 1X) Re8olu tXon . . . . . . . . . ... 154 Page IX. 8UMMAEY ..................... ................................................................1 58 X. REPSRaNCBS ...............................................................................160 vi I express my sincere thanks to Professor B.jS. Turner, P.Pw.S., fo r his in terest and advice in connection w ith th is investigation. I am indebted to Mr. P. Robinson fo r photographing the diagram of the Grignard reaction Apparatus. The work was carried out during the tenure of an assistant ship, which was made available to Professor Turner by the Department of S c ie n tific and In d u strial Research. I am g ratefu l to them fo r permission to incorporate this work in a Ph. D. Thesis. P rior to holding the assistant- ship I received a train in g grant,from H ertfordshire County Council, which I g ra te fu lly acknowledge.

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