!"##$%&$' %)*"&+),% -). /012&$.
34
56789:; 4
Explain how this synthesis of amino acius, staiting with natuial pioline, woiks.
Explain the steieoselectivity of each step aftei the fiist.
N
H
CO
2
H
N
CO
2
Me
R
O
O
NH
3
N
NH
O
O
H
HO R
CF
3
CO
2
H
N
NH
O
O
H
R
H
2
Pd
N
NH
O
O
H
H R
H
H
2
O
N
H
CO
2
H
HO
2
C NH
2
H R
+
5".2)%$ )- &0$ 2.)<*$=
A simple exeicise in the cieation of a new steieogenic centie via a cyclic
inteimeuiate.
!"##$%&$' %)*"&+),
Nothing exciting happens until the hyuiogenation step. The
steieoselectivity of the ieaction with ammonia is inteiesting but not of
any consequence as that steieochemistiy uisappeais in the elimination.
This gives the !-enone as expecteu since the alkene anu the caibonyl
gioup aie in the same plane.
41
! This methou was inventeu by B.
W. Bycioft anu u. R. Lee, "# %&'(#
)*+#, %&'(# %*((-.#, 197S, 988.
> Solutions Nanual to accompany 0iganic Chemistiy 2e
N
CO
2
Me
R
O
O
NH
3
N
R
O
O
NH
2
O
N
NH
O
O
H
HO R
CF
3
CO
2
H
N
NH
O
O
H
H
2
O R
N
NH
O
O
H
R H
N
NH
O
O
H
R
The new steieogenic centie is cieateu in the hyuiogenation step. The
molecule is slightly folueu anu the catalyst inteiacts best with the
outsiue (convex) face so that it auus hyuiogen fiom the same face as the
iing junction hyuiogen. All that iemains is to hyuiolyse the piouuct
without iacemization. Biu you notice that the configuiation of the new
amino aciu ()) is the same as that of the natuial amino acius.
56789:; >
This is a synthesis of the iacemic uiug tazouolene. If the enantiomeis of the
uiug aie to be evaluateu foi biological activity, they must be sepaiateu. At
which stage woulu you iecommenu sepaiating the enantiomeis anu how woulu
you uo it.
O
Ph O Ph
O O
BF
3
O
Ph
O
1.
HO NH
2
2. H
2
, catalyst
H
N OH
Ph
OH
H
HCl
H
N OH
Ph
Ph
3
PBr
2
N
Ph
5".2)%$ )- &0$ 2.)<*$=
Fiist steps in planning an asymmetiic synthesis by iesolution.
Solutions foi Chaptei 41 - Asymmetiic synthesis ?
!"##$%&$' %)*"&+),
You meeu to ask: which is the fiist chiial inteimeuiate. Can it be
conveniently iesolveu. Will the chiiality suivive subsequent steps. The
fiist inteimeuiate is chiial but it enolizes veiy ieauily anu the enol is
achiial, so that's no goou. The seconu inteimeuiate is chiial but it has
thiee chiial centies anu these aie eviuently not contiolleu. We woulu
have to sepaiate the uiasteieoisomeis befoie iesolution anu that woulu
be a waste of time anu mateiial since all of them give the next
inteimeuiate anyway.
O
Ph
O O
Ph
OH
chiral
achiral
H
N OH
Ph
OH
H
three
chiral
centres
The next inteimeuiate, the amino alcohol is iueal: it has only one
chiial centie anu that is not affecteu by the last ieaction. It has two
'hanules' foi iesolution - the amine anu the alcohol. We might make a
salt with taitaiic aciu oi an estei of the alcohol with some chiial aciu.
Alteinatively we coulu iesolve tazauolene itself: it still has an amino
gioup anu we coulu foim a salt with a suitable aciu.
56789:; ?
Bow woulu you make enantiomeiically eniicheu samples of these compounus
(eithei enantiomei).
OH OH
OH
OH
OH
OH
OH
5".2)%$ )- &0$ 2.)<*$=
Fiist steps in planning an asymmetiic synthesis.
!"##$%&$' %)*"&+),
Theie aie many possible answeis heie. What we hau in minu was some
soit of asymmetiic Biels-Aluei ieaction foi the fiist, an asymmetiic
aluol foi the seconu oi else opening an epoxiue maue by Shaipless
epoxiuation, asymmetiic uihyuioxylation foi the thiiu, anu peihaps
asymmetiic uihyuioxylation of a / alkene foi the fouith. 0f couise you
! This synthesis is fiom the
0pjohn company anu is in only the
patent liteiatuie (%&'(# 01234#,
1984, 4@@, 6S11.
3 Solutions Nanual to accompany 0iganic Chemistiy 2e
might have useu iesolution oi asymmetiic hyuiogenation, oi the chiial
pool, oi any othei stiategy fiom chaptei 41.
O N
O
O
O N
O
O
LiBH
4
OH
H
t-BuOOH
(i-PrO)
4
Ti
D-()-DET
O
Me
3
Al
OH
OH
OH OH
OH
OH
OsO
4
, K
3
Fe(CN)
6
, K
2
CO
3
DHQD ligand
OH
OH
OsO
4
, K
3
Fe(CN)
6
, K
2
CO
3
DHQD ligand
Lewis
acid
56789:; 3
In the following ieaction sequence, the steieochemistiy of manuelic
aciu is tiansmitteu to a new hyuioxy-aciu by steieochemically
contiolleu ieactions. uive mechanisms foi each ieaction anu state
whethei it is steieospecific oi steieoselective. 0ffei some
iationalization foi the cieation of new steieogenic centies in the fiist
anu last ieactions.
HO
2
C Ph
OH
(S-(+)-mandelic
acid
t-BuCHO
O
O
O
Ph
t-Bu
1. LDA
2. PrBr
O
O
O
Ph
t-Bu
H
H
2
O
HO
2
C
Ph OH
5".2)%$ )- &0$ 2.)<*$=
Youi chance to examine an ingenious methou of asymmetiic inuuction.
Solutions foi Chaptei 41 - Asymmetiic synthesis A
!"##$%&$' %)*"&+),
The fiist ieaction amounts to cyclic acetal foimation except that one of
the 'alcohols' is a caiboxylic aciu. The ieaction is steieospecific (no
change) at the oiiginal chiial centie anu steieoselective at the new one.
t-Bu H
O
HO
2
C
Ph
HO
H
HO
2
C
Ph
O
HO
t-Bu
H
HO
2
C
Ph
O
H
2
O
t-Bu
Ph
O
t-Bu
O
OH
H
O
O
O
Ph
t-Bu
The seconu ieaction cieates a lithium enolate anu alkylates it. It is
again steieospecific at the unchangeu chiial centie anu steieoselective
at the new one. Finally, acetal hyuiolysis pieseives the new quateinaiy
centie unchangeu (steieospecific) by a mechanism that is the ieveise of
the fiist step.
O
O
O
Ph
t-Bu
LDA
O
O
O
Ph
t-Bu
Li
Br
O
O
O
Ph
t-Bu
H
O
O
OH
Ph
t-Bu
etc
acetal
hydrolysis
HO
2
C
Ph OH
Now, as fai as the iationalization is conceineu, the fiist stepa takes
place thiough a sequence of ieveisible ieactions anu theiefoie unuei
theimouynamic contiol so the most stable piouuct will be foimeu. It
may seem suipiising that this shoulu be the +52 compounu, but the
confoimation of this chaii-like five-membeieu iing piefeis to have the
two substituents pseuuoequatoiial.
t-Bu H
O
HO
2
C
Ph
HO
H
O
O
O
Ph
t-Bu
O O
O
Ph
t-Bu
best approach
for electrophile
favoured
conformation
O O
LiO
Ph
t-Bu
H
enolate
The alkylation is unuei kinetic contiol anu, as a lithium enolate has
moie oi less a flat iing, the alkyl haliue appioaches the opposite face to
the 3-Bu gioup. It has to appioach oithogonally to the iing as it must
oveilap with the p oibital of the enolate.
! This is Seebach's clevei methou
of pieseiving the knowleuge of a
chiial centie while it is uestioyeu
in a ieaction. Fiist a tempoiaiy
centie (at the 3-butyl gioup) is
cieateu in a steieoselective
ieaction; the oiiginal centie is
uestioyeu by enolisation but the
tempoiaiy centie can be useu to
ie-cieate it: B. Seebach '3 67#, "# 0(#
%&'(# )*+#, 198S, 4@A, SS9u.
B Solutions Nanual to accompany 0iganic Chemistiy 2e
56789:; A
This ieaction squence can be useu to make enantiomeiically eniicheu
amino acius. Which compounu is the oiigin of the chiiality anu how is it
maue. Suggest why this paiticulai enantiomei of the piouuct amino
aciu might be foimeu. Suggest ieagents foi the last stages of the
piocess. Woulu the enatiomeiically eniicheu staiting mateiial be
iecoveieu.
H
2
N Ph
H Me
RCHO
N Ph
H Me
R
HCN
N
H
Ph
H Me
R
CN
NH
2
R
CN
5".2)%$ )- &0$ 2.)<*$=
Step-by-step uiscusssion of a simple but useful sequence.
!"##$%&$' %)*"&+),
The amine, phenylethylamine, is the oiigin of the chiiality. It is easily
maue by iesolution, foi example by ciystallising the salt of the iacemic
amine with taitaiic aciu. This means that both enantiomeis aie ieauily
available.
H
2
N Ph
H Me
HO
2
C
CO
2
H
OH
OH
crystallize
HO
2
C
CO
2
OH
OH
H
3
N Ph
H Me
+
H
2
N Ph
H Me
neutralize
This paiticulai enantiomei of the amino aciu piouuct belongs to the
natuial ()) seiies. The unnatuial (8) enantiomei woulu also be valuable
anu can be maue fiom the othei enantiomei of the staiting mateiial.
The last stages of the piocess iequiie cleavage of one C-N bonu anu
hyuiolysis of the nitiile. It will be impoitant to uo this without
iacemizing the newly cieateu centie.
N
H
Ph
H Me
R
CN
hydrolysis
reductive cleavage
NH
2
R
CN
H must not be
racemized
! Theie is a goou example of the
application of this methou by K. Q.
Bo '3 67# in 9'7:# %&5(# 0+36, 1979,
B>, 9S6.
Solutions foi Chaptei 41 - Asymmetiic synthesis C
The C-N bonu can be cleaveu ieuuctively by hyuiogenation as it is an
;-benzyl bonu. This woulu also hyuiogenate the nitiile so that must
fiist be hyuiolyseu using aciu oi base, as weak as possible. The staiting
mateiial is not iecoveieu anu the chiiality is lost as the by-piouuct is
just ethyl benzene, the nitiogen atom being tiansfeiieu to the piouuct.
N
H
Ph
H Me
R
CN
acid or base
N
H
Ph
H Me
R
HO
2
C
H
2
/Pd/C
NH R
CO
2
H
+
Me
Ph
56789:; B
Explain the steieochemistiy anu mechanism in the synthesis of the chiial
auxiliaiy 8-phenylmenthol fiom (+)-pulegone. Aftei the ieaction with Na in 5-
Pi0B, what is the minoi (1S%) component of the mixtuie.
O
R-(+)-pulegone
PhMgBr
CuBr
O
Ph
KOH
EtOH
reflux
O
Ph
55:45 mixture 87:13 mixture
with other diastereoisomer
Na
i-PrOH
toluene
OH
Ph
87:13 mixture
with another diastereoisomer
Cl
Cl
O
1.
2. crystallise
3. KOH
H
2
O, EtOH
OH
Ph
one diastereoisomer;
one enantiomer
5".2)%$ )- &0$ 2.)<*$=
A combination of confoimational analysis, steieoselective ieactions,
anu iesolution to get a single enantiomei.
!"##$%&$' %)*"&+),
The fiist ieaction is a conjugate auuition that eviuently goes without
any woithwhile steieoselectivity. The steieochemistiy is not fixeu in
the auuition but in the piotonation of the enolate in the woik-up.
Equilibiation of the mixtuie by ieveisible enolate foimation with K0B
in ethanol gives mostly the all-equatoiial compounu.
D Solutions Nanual to accompany 0iganic Chemistiy 2e
O
O
Ph
O
Ph
=
O
Ph
KOH
EtOH
reflux
O
Ph
H
Ph Cu
Reuuction by that smallest of ieagents, an election, gives the all-
equatoiial piouuct. Since the steieochemical iatio in the piouuct is the
same as in the staiting mateiials (87:1S), the ieuuction must be totally
steieoselective. The all-equatoiial ketone gives 1uu% all-equatoiial
alcohol anu the minoi isomei must give one othei uiasteieoisomei (we
cannot say which).
O
Ph Ph
OH
O
Ph
OH
Ph
Na
i-PrOH
toluene
Na
i-PrOH
toluene
The mixtuie still has to be sepaiateu anu, as it is a mixtuie of
uiasteieoisomeis, it can be sepaiateu by physical means. The
chloioacetate is just a convenient ciystalline ueiivative.
56789:; C
Suggest syntheses foi single enantiomeis of these compounus.
OMe
O t-Bu
O
OMe
O OH
HO
5".2)%$ )- &0$ 2.)<*$=
Bevising you own asymmetiic syntheses.
!"##$%&$' %)*"&+),
The fiist compounu is an estei ueiiveu fiom a cyclic seconuaiy alcohol
that coulu be maue fiom the coiiesponuing enone by asymmetiic
ieuuction.
! Two fiactional ciystallisations
actually give Su% of the iequiieu
compounu accoiuing to the uetails
givem by 0. 0it, <4=# )>.3&# %*77#,
199S, EFFF, SS2.
Solutions foi Chaptei 41 - Asymmetiic synthesis G
OMe
O t-Bu
O
OMe
CO
ester
OMe
OH
OMe
OMe
O
OMe
by asymmetric
reduction
Reuuction with Coiey's CBS ieuucing agent gave the alcohol in 9S%
ee.
OMe
O
OMe
BH
3
-THF
10% CBS
oxazaborolidine
OMe
OH
OMe
(t-BuCO)
2
O
TM
The seconu compounu coulu be maue by a Wittig ieaction with a
stabilizeu yliu anu the iequiieu uiol aluehyue ueiiveu fiom an epoxy-
alcohol anu hence an allylic alcohol by Shaipless epoxiuation.
O OH
HO
Wittig
CHO
O OH
HO
Ph
3
P
+
A B
A
CHO
O O
OH OH
Sharpless
epoxidation
The fiist pait of the synthesis gives an inteimeuiate that hau been
useu in the synthesis of the antibiotic methymycin. In piactice the
Wittig was caiiieu out on the epoxy-aluehyue anu tieatment of the last
inteimeuiate with aqueous aciu gace the taiget molecule.
OH
t-BuOOH
(i-PrO)
4
Ti
(+)-DET
O
OH
79% yield, >95% ee
[O]
CHO
O ylid B O
O
! This compounu was useu to
make a compounu fiom the gingko
tiee by E. }. Coiey anu A. v. uaval,
?'346&'@4*. A'33#, 1988, >G, S2u1.
! S. Nasamune '3 67#, "# 0(# %&'(#
)*+# 197S, GC, SS12