Studies in asymmetric synthesis

187 Pages·024.853 MB·English

by  Reid, Joan A

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.
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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.