08_chapter 1

CHAPTER I
NATURALLY OCCURRING MOLECULES BEARING CHIRAL
y-BUTY ROLACTONE RING SYSTEMS
Introduction
ptically active chiral compounds are enjoying an unprecedented renaissance
in virtually all disciplines of biology, medicine, biochemistry and chemistry.
They are finding increasing utility in food industry, material sciences, in the
synthesis of pharmaceutically important compounds and agrochemicals. Hence
chirality and asymmetric synthesis imply piytal involvement in biological
b
activity. Hence the synthesis of chiral compounds becomes a special and brutally
challenging testing ground for methods in asymmetric synthesis1.
Transformations of optically active natural products such as arninoacids,
hydroxy acids, carbohydrates etc, optical resolution of an intermediate or final
products and chemical or biochemical synthesis are few of the methods to obtain
enantiomerically pure compounds. Out of thes chemical or biochemical synthesis
3
is clearly attractive since it offers a great variation of solutions as well as challenge
for the search of new methods2.
Chemists have long been fascinated by the remarkable rate acceleration and
high regio- and stereo selectivities obtained by asymmetric synthesis.
The
successful application of chiral reagents to asymmetric synthesis requires their
ready availability. Of the available methods of obtaining various optically active
'-;
compounds of definite absolute configuration, asymmetric synthesis seems to have
the highest potential. Thus, the design of highly efficient methods for asymmetric
synthesis constitutes one of the most challenging and exciting fields in synthetic
organic chemistry .
i
d .
,,.
Asymmetric synthesis implies the $e-novo synthesis of a chiral substance
from an achiral precursor such that one enantiomer predominates over the other.
Out of the several strategies for getting enantiomerically pure compounds, the one
using readily available chiral molecules obtained from the chiral pool, as starting
point for synthesising molecules with desired stereochemistry gains promin nce3.
f
Hence during the past t w o decades there has been a great deal of interest to find
.
cheap and potential chiral molecules from chiral pool to accomplish synthetic
X.--
efforts with a high degree of asymmetric induction. Hence inexpensive naturally
X.,
occurring molecules possessing numerous functional groups and stereogenic
centres are significant.
Since the quantity of optically active compounds isolated from natural
;
-'.-.,,sources
is often less than milligram, difficulties are encountered in stereochemical
.
,
.
.
studies. The best way to circumvent this difficulty is to execute an enantioselective
synthesis of the target molecule starting from a compound of known absolute
configuration2.
The ingenious synthetic methodologies that employ members of the "chiral
carbon pool" comprise a significant portion of this technology. To the organic
chemists, the chiral pool, which is composed mainly of naturally occurring amino
J
1
acids,
teip nes,
j
sugars and
carbohydrates is
an
invaluable
source
of
stereochemically pure molecules. The majority of them are commercially available
and many are inexpensive4.
/ 4'
1%--.An effort towards this direction,
this laboratory has recently identified
(2S,3 S)-Tetrahydro-3-hydroxy-5-oxo-2,3-furmdicboxylic
acid [(-)-hydroxycitric
acid lactonels and (2S,3R)-Tetrahydr0-3-hydroxy-5-0~0-2,3
-furandicarboxy lic
acid [(+)-hydroxycitric acid lactone] as potential chirons for the synthesis of
various optical1.y active intermediates and introduced a select group of molecules
with complete physical data. As the unique structure and stereochemistry of these
molecules rnatch$Gith
the chiial y-butyralacionc moiety of a large number of
complex natural molecules, these molecules can judiciously be used for their
synthesis.
As this thesis concerns with the structural and synthetic investigations
of
chiral
(2S,3R)-Tetrahydro-3-hydroxy-5-oxo-2,3-furandicarboxylic acid
[(+)-hydroxycitric acid lactone]- a molecule with chiral y-butyrolactone skeleton,
the present review deals with the strategies for the synthesis of chiral
y-butyrolactone skeleton of naturally occurring molecules which have interesting
synthetic as well as pharmaceutical applications6. Stereochemically defined
y-butyrolactones serve as key building blocks for the synthesis of alkaloids,
macrocyclic antibiotics, pheromones, antileukemics and flavour components.
Generally appropriately functionalised y-butyrolactones are obtained from
molecules such as amino acids, hydroxy acids, carbohydrates, chiral sulphoxides
or epoxides7**. Though already few reviews2,9,10 deal with these topics, an
exhaustive inventory of chiral y-butyrolactone bearing natural products and their
general synthetic approaches are lacking. In this background an inventory o f\:
',,
naturally occurring molecules bearing chiral y-butyrolactone moiety is listed at
1
first followed by the strategies for the synthesis of chiral y-butyrolactone moiety.
I
i
,/
+-.:-A
).,
i-
? '
.
G
Inventory of naturally occurring molecules bearing
y-butyrolactone moiety
Name
Structure
No.
v,::~~,
0
1
Reference
0
acetylcholine
Analogue
of.
B$-)
C5Hll
2
O
e
a
H
3
0
4
~
~
HPh, 2
Z
0
ll
y-nonalact one
12
y -caprolactone
12,21
y-Trityloxymethyly-butyrolactone
13
Podophyllotoxin
14
r o
0
5
Me0
M&
@
++'
OMe
'
<IT
6
Me 0
'.
0~
Podorhizon
15
Annonacea acetogenin
16
Murisolin
17
OMe
OMe
7
chiral
,
llb,,
8
R
Black-tailed deer
pheromone
Japaneese
beetlepherornone
Tu berolid e
Litsenilide Cl
Litsenilide C2
Valerolactone
P-hydroxyvalerolac tone
A B ring subunit of
~reinantholideA
Actinomy cete
Epianastrephin
Anastrephin
lsostegane
OMe
Oak lactone
Isoavenaciolide
Avenaciolide
Ethisolide
31
'
.
o+oc2b
H2C
32
44
H
oe:
H25q2vw
(+)-Dihydrocanadensolide
47,5 1
Muconin
52
Cinatrin C
53
Cinatrin c3
53
Me
33
AH
0
34
35
t; \
HOW
0'
c1$25
H~~,.,.
H0
oyy&H
HZsCI
21ab11,..
H0
"'* OH
P
Calcidiol lactone
36
.lc,T
HO
37
o
Trilobacin
55
Q u ararib ea
metabolite
56
CH,
38
:W:
H ~
OWIH
N CH3
~
O p m
""H .
"''Irn3
Funebral
(+)S quamot acin
43
i
Corrossoline
0
OH
Stemolide
59
Vernolep in
Vernomenin
Precursor of CGA 8000
Paeonilactone A
54
--i3
55
-
68
Sapranthin
69
"B
56
'i.
H
57
Rosigenin
OTOY
COOH
"'CH~COOH
Intermediate of
X-14547 A
(Ionophore -antibiotic)
70
Hornocitric acid
lactone
71
(+)-Digitoxigenin
72
Ancep senolide
73
(-)-Methylenolactocin
74-78
Protolichesterinic acid
76
(-)-Phaseolinic acid
75
0
58
H0
59
H
&
I
"
p
f
Me
H
l
60
'"'COOH
61
"Q"""
"'COOH
62
[+)-Phaseolinic acid
Lissoclinolide
r-c!
Steganone
.-gym
"'"H
Frullanolide
Arbusculin
MGO
Podophyllotoxin
OMe
Picropodophyllin
(+)-Dihydroactinidiolide
Aeginetolide
Asteriscanolide
Paniculide A
Enterolactone
H0
Arctigenin
OMe
OMe
Syringolide 1
Syringolide 2
:A0
86
d
d
Hll~p~o~llb..
H0
.A0
87
H, , c . ~ c o ~ ~ ~ . . ,
Secosyrin 1
104
Secosyrin 2
104
Suributin 1
100, 104
Syributin 2
100, 104
H0
88
='\
HO
OCOC5H11
89
I
H0
0C0C7Hl5
Scobinolide
91
OH
~IIIIH
V
Lipid metabolites
106
Blastirnycinone
106
~ ~ 5 C ~ OAc
f
0
93
1.3
Synthesis of chiral y-butyrolactone ring systems of naturally
occurring molecules
It is well established that ~lhtarnicacid (96) has been extensively used as a
starting point for the synthesis of a large number of natural products (1-10) with
desired chiral y-butyrolactone moiety (Scheme I. 1)
'"l9.
Scheme 1.1
Chiral y-caprolactone (3) and black-tailed deer pheromone (10) were
obtained in high optical purity from optically active propargylic carbinols (99)
prepared by the asymmetric reduction of a- acetylinic ketones with chiral complex
[LiAlh, N-methyl ephedrine-3,5-dimethyl phenol] (Scheme I.2) 20p21.
Scheme 1.2
Reports
on
the
enantioselective
of
synthesis
(2)-5-(l-deceny1)-
oxacyclopentan-Zone (Il), the pheromone of the Japanese Beetle employing
20-23
99-101 as starting material are also available (Scheme 1.3)
.
Scheme 1.3
B. Maurer and A. Hauser have successivel
synthesis of
.--'
several lactones of Polianthes family adopting different strategies (Schemes 1.4
and 1.5) 24.
Scheme L4
Scheme 1.5
Several synthetic approaches are available on Eldanolide (g), the wing
gland pheromone of the male African sugar-cane borer using different starting
materials (Scheme 1.6) 18.25-31
CH
H 0 OH
106
107
108
OM:
H0
-OH
OH
+
f
OM
Scheme 1.6
Traditionally carbohydrates such as D-ribonolactone has been employed as
chiral synthons for the synthesis of a large number of molecules containing
y-lactone moiety (Scheme 1.7)32-34 .
Scheme 1.7
r
Readily available y-butyrolactone precursor (110) from natural sources has
0 been used by R. K. Bfeckrnan Jr. et al. for the preparation of the AA3 ring system
of eremantholide A (21) (Scheme I.
@
","
"-,
L
Scheme 1.8
L-lyxono-l,4-lactone (22), the chiral template of several aldonolactones
which are extensively used for the synthesis of enzyme inhibitors, antibiotics,
peptides and antimetabolites has been synthesised from D-gulono- l ,4-lactone
(Scheme 1.9)36 .
Scheme 1.9
Stereocontrolled aldol condensation between 6-methyl heptanal and lactone
(1 12) has lead to the synthesis of abutanolide (23), the fermentation product of an
actinomy.cete species CNB-228 (Scheme 1.1o)'~.
Scheme 1.10
Synthesis of (+)-epianastrephin (24), pheromone of Caribbean fruit fly and
its antipode (25) using different starting materials has been demonstrated (Scheme
I. l
1)38y39.
Scheme 1.11
The first successful, highly specific asymmetric synthesis of (-)-isostegane
(26), a very important antileukaemic lignan starting from a chiral butenolide (115)
$34-i "
was reported by Koga et al. (Scheme I. 1
0Mt:
Scheme 1.12
Several synthetic methodologies have been investigated to obtain 5- buty1,4methyl-tetrahydro-2-furanone (27), the ccquercus lactone" or "oak lactone"
(Scheme 1.13)30*41-44.
Scheme L13
Synthesis of (R)-enantiomer of 4-dodecanolide (28), a defensive secretion
of Rove Beetles via asymmetric reduction with immobilised Baker's yeast on
monoalkylated-3-0x0-glutarates (121) and from L-tartaric acid (122) has been
achieved (Scheme I. 14)42945.
Scheme L14
Routes for the synthesis of avenaciolide (30) and its diastereomer
isoavenaciolide (29), two naturally occurring secondary metabolites present in the
/--\
cultures of Aspergillus and Pencillium species have bee
tarting with
\
43,47-49
123-126 independently (Scheme I. 15)
Scheme 1.15
Synthesis of 30 from several other synthons were also reported. Another
natural product ( 3aS,6aS)-ethisolide (3 1) was prepared from (1 19) (Scheme
1,16)42.44,50
Scheme L16
Synthesis of (+)-dihy drocanadensolide (32) using Tungsten-K-allyl
complexes4'
involving
the
diastereoselective
rearrangement5' were reported (Scheme I. 17).
Scheme 1.17
Zwitterionic
Aza-Claissen
An acetogenin, muconin (33) a potent and selective in vitro cytotoxic agent
against
pancreatic
and
breast
tumor
cell lines
has
been
synthesised
(Scheme I. l8)'2.
Scheme 1.18
Evans and coworkers reported the asymmetric synthesis of phospholipase
A2 inhibitors, Cinatrin C, and Cj (34 & 35) employing aldol reaction of ketal1
'
4
protected tartrate ester enolates (Scheme I. l&
,'
-+
OM-
BnO
I
0
Scheme 1.19
25-Hydroxy vitamin D3 26,234actone (calcidiol lactone) (36), one of the
major metabolites of vitamin Dj has been synthesised using C-22 steroid aldehyde
and citramalic acid (Scheme I. 20)'~.
Scheme 1.20
The first total synthesis of Trilobasin (37), an excellent cytotoxic
(O/+nonaceous
acetogenin, was described by Sinha by Kennedy oxidative-
cyclisation with rhenium oxide followed by the Mltsunobu inversion of alcohols
(Scheme 1.21)@. TL
Scheme 1.21
Recently Le Quense et al. reported the synthesis of quararibea metabolite
(38), funebral (39) an
3Tunebrine
sg, r '3
activity (Scheme 1.221..
,)
(40) having a wide range of physiological
Scheme 1.22'
Synthesis of Isotelekin (41), a sesquiterpene lactone, has been reported
(Scheme 1 . 2 3 ) ~ ~ .
Scheme 1.23
The total synthesis of (+)-squamotacin (42), an Annonaceous acetogenin,
adopting Sharpless asymmetric dihydroxylation and epoxidation reactions, was
reported by Sinha (Scheme 1.24)~'.
Scheme 1.24
4
6
Corrossolin (43), yet another member of t h e p o n a c e o u s family, has been
synthesised by Yu-Lin Wu et al. recently from an aldehyde (132) obtained from
D-glucono lactone (Scheme 1.25 -/ 63
p
Scheme 1.25
The first synthetic route to Stemolide (44), a diterpenoid having potent
cytotoxic activity, is demonstrated by vanTamelen et al. (Scheme 1.26)60 . '-3
Scheme 1.26
d
Starting with (R)-lactic acid (133), (-)-yertinolide (45), a p-tetronic acid
derivative isolated from VerticiNium intertexturn, was synthesised adopting
Seebach's chiral self-reproduction method by Matsuo et al. (Scheme 1.27)'2'',
Scheme 1.27
Synthesis of natural adriadysiolide (46), a monoterpenoid from marine
sponge, starting from 3-methyl-2-cyclopenten- l -one (134) is also available
(Scheme 1 . 2 8 ) ~ ~ .
Scheme 1.28
The total synthesis of the bis-a-methylene lactonic sesquiterpenes,
vernolepin (47) and vernomenin (48), two potent tumor inhibitors were achieved
in several steps from dienone ester (135) (Scheme 1.29)".
Scheme 1.29
Yang et al. used Mn(OAc),-mediated oxidative free radical cyclization
method f o r the synthesis of (-)-triptolide (50),
(49) and
(-)-triptonide
(+)-triptophenolide (51) (Scheme 1.30 1 ~ ~ ~ ~ ~ .
v
The unchlorinated precursor of CGA 8000 (52), the internal Ciba-Geigy
code number for a new phenylamide fungicide, was synthesised enantioselectively
by two conceptionally different routes: (a) by starting from L-malic acid (138) and
(b) by the enantioselective hydrogenation of an enarnide intermediate (139), using
chiral Rh- or Ru-pho sphine-comp lexes (Scheme I. 3 1)65.
COOH
52
Scheme L31
Paeonilactone A (53), a compound having lot of pharmaceutical
applications, has been synthesised by Backvall et al. using palladium, copper
catalysed reactions of cy clohexadiene (140) (Scheme 1.32)67.
53
Scheme 1.32
A biosynthesis
h-
of yosigenin
(54),
an unusual
metabolite from
MycosphaereZZu rosigena, is reported by L. Camarda et al. (Scheme 1.33
Scheme 1.33
("\
A simple synthesis of Sapranthin (55), an alkaloid, is reported
Waterman (Scheme 1.34) 69.
Scheme L34
The synthetic intermediate (56), for ionophore antibiotic X - 14547A, was
resulted by the asymmetric alkylation of aldehydes using optically active SAMP
hydrazones (141) (Scheme 1.35) 70.
Scheme 1.35
Enantioselective syntheses of homocitric acid lactones (57a & 57b) were
described employing thermal Diels-Alder cycloaddition strategy (Scheme I.3 6 ) 71.
57b
57a
Scheme 1.36
(+)-Digitoxigenin ( S ) ,a natural cardenolide, has been synthesised by
Stork ef al. (Scheme 1.37)'~.
Scheme 1.37
Larson el al. demonstrated the application of alkylidenation reaction for the
synthesis of ancepsenolide (59), a bisbutenolide of marine origin (Scheme 1.38)'~.
Scheme 1.38
Syntheses of (-)-methylenolactocin (60), a densely functionalized and
isomerization-prone antitumor antibiotic. isolated from the Penicilliunz sp. were
.p
illustrated by a number of groups. (-) and (+)-Bhaseolinic acid (62, 63), metabolite
of a fungus Macrophomina phmeolina, have been prepared by Valentin el al. as
CO-productsof 60. Roy et al. also reported the preparation of protolichesterinic
acid (61) along with methylenolactocin (Scheme 1.39)74-77 ,
Scheme 1.39
Two independent stereoselective syntheses of lissoclinolide (64), a
secondary metaboli te from the ternicate Lissoclznum patella, have been achieved
using (148) and (149) (Scheme 1 . 4 0 ) ~ ~ ~ ' ~ .
Scheme L40
2 -/
Depezay et al. reported the synthesis of (-)-bfuricatacin
( 6 5 ) , an
annonaceous acetogenin, from D-isoascorbic acid. Another simple procedure
involving TMSOF and an aldehyde is also described (Scheme 1.41)811X2.
Scheme L41
tA novel synthesis of (+)-P'aeonolactone B (66) has been accomplished from
a tricyclic ketone (151) (Scheme 1.42)83.
Scheme 1.42
Total synthesis of (-)-Steganone (67) utilizing a samarium (11) iodide
promoted 8-endoketyl-olefine cyclization has been reported by Molander et al.
(Scheme 1.43)84.
(C0)3Cr I
OMe
Scheme 1.43
5.
.H--,
Ferraz el al. reported a short route to (-)-~:ntlactone (68)
employing
thallium triacetate mediated cyclization of (-)-isopulegol (152) (Scheme 1-44)".
Scheme 1.44
Two different routes to a-methylene-y-butyrolactones, [(-)-Frullanolide
(69) and (+)-Arbusculin B (70)], allergenic sesquiterpene lactones, have been
designed starting from a-methyl lactones (153) (Scheme 1.45)
Scheme 1.45
A stereocontrolled synthesis of (-)-picropodophyllone (71) was achieved by
the Michael addition of lithium salt of cyanohydrin to (R)-3-(2,2-dimethyl-1,3dioxolan-4-yl)-cis-2-propeonate(154) (Scheme 1.46) ".
Scheme L46
Recently Berkowitz et al. reported the synthesis of (-)-podophyllotoxin
(72) and i t s C-2 epimer, (-)-picropodophyllin (73) starting from 155 (Scheme
1.47)~~.
SENQ
SEMO
OTIPS
o
OTPS
o
sir
o
o
I
155
S EMQ
SEMQ
Scheme 1.47
h
4
Total syntheses of kkginetolide (76), (R)-dihydroactinidiolide (74) and
(R)-actinidiolide (75) have been reported involving asymmetric catalytic heteroDiels-Alder methodology (Scheme 1.48)89?90.
Scheme L48
A recent successful synthetic effort depicting (+/-)-Asteriscanolide (77), a
cyclooctane sesquiterpene lactone from Asteriscus aqualieus, employing three
independent strategies have been reported (Scheme 1.49)
Scheme 1.49
*
A total synthesis of Paniculide A (78), a'highly oxygenated sesquiterpene
lactone,
starting
from
D-glucose
and
methyl-4,6-0-benzylidine-a-D-
glucop yranoside involving Ferrier 'S car bocyclization and CIaisen rearrangement
was reported by Chida and coworkers (Scheme I. 50) 94.
D-glucose
- 0
OMe
Methyl-4,6-0benzylidine- a- 1==4
D-glucopyrano side
OMOM
Scheme '1.50
Independent enantioselective syntheses of natural dibenzylbutyrolactone
lignans like (-)-enterolactone (79), (-)-pluviatolide (80) and (+)-arctigenin (U),
having antiturnor activity, platelet-activating factor (PAF), sodium selective
diuretic properties and inhibitory effects on microsomal monooxygenases in
95-98
insects, have been reported (Scheme L 5 1)
,
OMe
162
-
79
Scheme 1.51
Syntheses
of (-)-S-methoxyhinokinin
(83)
and
(-)-hinokinin
(82),
employing conjugate addition of benzylic dithioacetals to chiral dihydrofuran
ketones as the key step followed by appropriate reduction and oxidation reactions,
are known (Scheme 1.52)96p".
Scheme L52
Non protein elicitors syringolide 1 and 2 (84 & 85), from bacterial plant
pathogen Pseuhnzonas syringaae pv. lonzalo which trigger a hypersensitive
defence response in resistant soybean plant, have been sytlthesised making use of
different synthons (Scheme I.53) 100-103
OMOM
01-1
Scheme 1.53
First total synthesis of (+)-Secosyrins 1 and 2 (86, 87) using the spiro
skeleton prepared by taking advantage of an alkyne-cobalt complex using
diisopropyl tartrate (164) were achieved by Hanaoka et al. (Scheme 1.54) Io4.
-
toys
BllO,,,,
H0
BnO
BU~
164
H0
I
Scheme L54
Syributins 1 and 2 (88 & 89) from diisopropyl tartrate using alkyne-cobalt
complex were achieved by Hanaoka et al.
Enantioselective synthesis of 88 and
89 through the Sharpless catalytic asymmetric dihydroxylation is also reported
(Scheme I.55)"'.
Scheme 1.55
Synthesis of scobinolide (go), a monoterpene lactone, was carried out by
Thaller et al. (Scheme 1.56) l"'.
Scheme 1.56
Trisubstituted butyrolactones such as lipid metabolites (91,92) and
Blastimicinone (93) were synthesised by Sibi et al. following independent
strategies (Scheme 1.57)106,107 .
~~9~:
HIII,~.
-S===
-
'.,
R'O
R
9 1 R=Ci4Hs, R' = COCH,
92 R= C1a33,
R' = CH3C0
\
Ph
NHCHO
OH
R
93
Scheme 1.57
OH
Momose ef al. achieved the synthesis of NFX-2 (94) and NFX-4 (95)
employing stereoselective intrarnolecular lactonization of homochiral N-benzyl-N methyl-3-hydroxy-4-pentenamides (165) and 0-TBDMS (Scheme 1.58)"'.
V""'"'
-
HI~,,,
TBDMSO
.H0
+*,
R
Scheme 1.58
1.4
Scope and Objective of the Present Study
Asymmetric synthesis involves the use of chiral auxiliaries - catalytically
or stoichiometrically , chiral molecules as starting points for obtaining optically
active molecules. Usage of simple chiral molecules as chiral building blocks is an
important strategy in the synthesis of naturally occurring molecules especially
when they are derived from cheap and abundantly available small molecules such
as lactic acid, tartaric acid etc. Hence inexpensive natural products possessing
numerous functional groups and stereogenic centres are of great interest to organic
chemists.
Hence there is a great deal of interest prevailing in the synthesis of
naturally occurring molecules bearing chiral y-butyrolactone ring systems which
are widely distributed. It is clear from the review that most of these molecules
have potential biological as well as pharmacological applications.
In this background it is the objective of the present study to explore the
..
possibility of using ( 2 ~ ,R)-Tetrahydro-3
3
-hydroxy-5-0x0-2,3-furandicarboxylic
acid, [(+)hydroxycitric acid lactone or hibiscus acid], a chiral molecule from the
chiral pool, as chiral synthon in the preparation of potential optically active
molecules bearing chiral y-butyrolactone moiety or their derivatives.
Garcinia acid, one of the optical isomers of hydroxycitric acid found
extensive application in the pharmacological as well as synthetic fronts. However
only very little information is available on Hibiscus acid. The potential of the
molecule is not yet explored due to the non-availability of the compound in the
market. This is due to the lack of any economically viable large-scale isolation
procedure and physical data of the compound. In spite of the ready accessibility in
the optically pure form from the chiral pool, no effort has been made towards the
use of hibiscus acid in the broad area of asymmetric synthesis. In this background,
a detailed reinvestigation on the isolation and structure of the title compound is
necessary .
The present investigation aims at the synthesis of novel chiral synthons,
ligands and catalysts starting from hibiscus acid and their application in
asymmetric synthesis. It is proposed to carry out various chemical modifications
on the acid, to obtain novel functionalised chiral synthons and ligands especially
useful for asymmetric catalysis. In general attempts will be focussed to project
!
I
,
(2S,3R)-Tetrahydro-3-hydroxy-5-oxo-2,3-fboxyli
choice for asymmetric synthesis from the chiral pool.
acid
as yet another