(penmacric acid -...
TRANSCRIPT
-
PARTB
Chapter 3
Jlpproach towards the synthesis of (Penmacric acid
-
Approach towards the synthesis of Penmacric acid Chapter 3
3.1. Introduction
Unnatural and non-proteinogenic amino acids have become very important and
attractive synthetic targets due to their intrinsic biological activities and applications as
conformational modifiers for physiologically active peptides. Pyroglutamic acid (1), due
to its unique structural features, is utilized as a versatile chiral building block for the
synthesis of several natural products such as pyrrolidine alkaloids/ kainoids,2 (-)-
bulgecinine,3 (-)-domic acid,4 enantiomerically pure proline derivatives5 and a wide
variety of non-proteinogenic amino acids.6 Derived from glutamic acid, derivatives of
pyroglutamic acids are an inexpensive source of chirality and have been used as chiral
auxiliaries in Diels-Aider reactions7, alkylation and aldol reactions8 of chiral enolates,
kinetic resolution of amino acids and Michael addition processes (Fig. 1).
Rl, __ ,R2
~R3 H
Amino acid derivatives Pyrrolidines & Kainoids
Peptidomimetics ¢::== ===:> Chiral Auxiliaries
'"Q"' ~ln
Pyrrolizidines & lndolizidines N-bridged bicyclic compounds
Figure 1. Applications of pyrogluatamic acid {1}
In the area of amino acids, differently substituted prolines9 as well as y-amino
acid derivatives10 have been synthesized from pyroglutamic acid (1). Chiral saturated
heterocyclic compounds such as pyrrolidines11, (+)-adalinine12, indolizidines13 and fused
lactams14 have also been prepared. Alkaloids such as (-)-stemoamide15 and (+)-
ipalbidine16, (+)-lentiginosine17, PKC modulators18, ACE and esterase inhibitors19 and
119
-
Approach towards the synthesis of Penmacric acid Chapter 3
gastro protective substances such as Al-77-820 are representative compounds
synthesized using pyroglutamic acid derivatives. Other significant natural products such
as dihydro-kikumycin 82\ anthelvencin22, heliotridane23, several alexines24, swainsonine
derivative25
, manzamine alkaloids26, calyculins27, bulgainine28 and carzinophin A29 are
representative examples which have been synthesized employing pyroglutamic acid as
the source of chirality.
In the recent years, C-C bond forming reactions at various positions of
pyroglutamates have attracted attention from a number of research groups and
considerable thought has been paid on the stereochemical outcome of such reactions,
and consequently in recent years, a number of total syntheses of several complex
natural products and bioactives have been reported (Fig. 2).
HO H
HO"d) 90 CIH. H2N ', C02H
( + )-Lentiginosine TL, 2001, 2509
0
0
e~02H
Ar'',· l_;NH
HO
Chlorpheg TL, 2003, 5271
(-) Stemoamide JACS, 2000, 4295
N
( + )-lpalbidine TL, 2003, 3035
~ 0 N C02Me H
D eoxydysibetaine TL, 2003, 5961
Mona tin TL, 2001, 6793
(+) & (-) Aza-muricatacin TA, 2001, 1503
0~C11H23 H OH
Figure 2. Natural products synthesized using pyroglutamate template
120
-
Approach towards the synthesis of Penmacric acid Chapter 3
The advantage of pyroglutamic acid in asymmetric synthesis lies in a rigid five-
membered skeleton with strong stereo-electronic influence of two different carbonyl
entities in the molecule which can be differentially functionalized. Thus, due to their
importance of substituted pyroglutamates have been the favored targets of many
groups and need of more simpler and safe route is still to exist {Fig. 3).
C-4 Functionalisation C-3 Functionalisation
'- I
I I
Functionalisation ____ .. O~CO H of lactam carbonyl 1 N '
2
I H ', I '
I
~----· Functionalisation of Carboxylic acid
N-Functionalisation C-2 Functionalisation
Figure 3. Possible sites of functionalisation on pyroglutamate skeleton
3.2. Basis of work
H, NH2
H02C~ ~~ 0 N C02H
H
2
Figure 4. Penmacric acid (2)
Penmacric acid {2) {Fig. 4) is an unusual amino acid isolated in 1975 independently by
Welter et al. 31 and Mbadiwe32 from the seeds of the leguminous tree Pentaclethra
macrophyl/a, commonly known as "pauco nuts" or "owala seeds" in less than 0.5% w/w
of the dry bean endosperm; these legumes are indigenous to the humid lowlands of
West Africa, the seeds of which are used both as staple food in the local diet, and also
find application for their medicinal value as anti-inflammatories.33'34 The absolute
configuration of penmacric acid was initially assigned from 1H NMR studies in
association with CD measurements and this was later supported by a single crystal X-ray
121
-
Approach towards the synthesis of Penmacric acid Chapter 3
structure.35 A number of chemical studies were carried out on penmacric acid by the
Belgian workers who originally reported its isolation;36 thus, the lactam of penmacric
acid is hydrolysed under a variety of acidic conditions to the substituted adipic acid 3
which recloses in dilute acid solution to give either of two possible substituted pipecolic
acids 4 and 5 (Scheme 1). Despite detailed chemical studies nothing is known about the
biological origin or role of penmacric acid.
3
aC02H+ NH3 H02C',· N 0
/ ; +
HOzC::aNH3 H02C' N 0
H
5
Scheme 1. Chemical studies on penmacric acid
The impressive biological properties, low natural abundance, and the distinctive
architecture have made penmacric acid and its analogs attractive target for the
synthetic efforts. From a structural perspective, assembling the glycine motif at beta
position of C-4 of pyroglutamate poses a significant synthetic challenge, and to date,
only three research groups have documented strategies to address the synthetically
demanding C-4 stereocenter in the context of its synthesis.
Moloney's approach (2003)37
The first synthetic approach for 2 was attempted by Moloney and co-workers in 2003
(Scheme 2). They have utilized the bicyclic lactams 6a and 6b which is derived from
pyroglutaminol following a simultaneous protection of the hydroxyl and amide
functionalities by a single benzylidene protecting group.38'39 Lithium enolate of bicyclic
lactam 6a react with various aldehydes gave a diastereomeric mixture of exo and endo
products (7a:7a'=2:1, PhCHO; 1:2.7, chloral). With this outcome, they anticipated that
122
-
Approach towards the synthesis of Penmacric acid Chapter 3
H NHTs
Rl~-~ ArCH=NTs
o~NAO
LDA, -78 °C
OH OH
LDA, -78 °C, THF Ph-
-
Approach towards the synthesis of Penmacric acid Chapter 3
material and 22% of the elimination product 9b'. Compound 9b was then converted to
ester 10 in low yield. Deprotection (TFA, 45%) was followed by the usual oxidation-
protection sequence, gave lactam 12 in 8% yield over the three steps, a compound with
the correct relative configuration for penmacric acid (2).
Naito's approach (2007t0
H2N~02H
i) CbzCI, NaHC03 ii) H2S04, MeOH
iii) Mel, DEAD, PPh3
H NHBoc
3M HCI, Me02C~. AcOEt
1
£)._ 0 N C02Me
I
3M HCI, AcOEt
Boc
18a
H, C02Me
i) DBU, PhMe ii) mCPBA
iii) Mgl2, PhMe
H NHOBn
Me02c~ ___ .PH 4steps C)...
N C02Me I Cbz
17a
H, C02 Me
BnOHN~ L pH
"'In 0 N C02H BocHN~
---- 0 N C02Me I
4steps C)... N C02Me
H Boc I Cbz
(1'-epi)-2 18b 17b
Scheme 3. Naito's approach to 2
In 2007, Naito and co-workers described the first total synthesis of 2 in 12 steps (5.4%
overall yield) as well as the synthesis of the {1'-epi)-2 (3.0% overall yield). The key step
of Naitos approach involves the Et3B-induced radical reaction of oxime ether 16 and
iodoproline 15 via an iodine atom-transfer process (Scheme 3}. 3-hydroxy-4-iodoproline
(15) required for the Et3B-induced radical reaction was prepared by a Mitsunobu
reaction on protected trans-4-hydroxy-L-proline (13) to convert hydroxyl group to iodide
124
-
Approach towards the synthesis of Penmacric acid Chapter 3
to give 1441 following the elimination of HI using DBU to obtain 3A-dehydroproline
which was epoxidated with mCPBA in the presence of 4A'-thiobis(6-t-butyl-o-cresol) as
a radical scavenger, the epoxide ring of which was regioselectively opened with
magnesium iodide to afford the expected 3-hydroxy-4-iodoproline (15) via nucleophilic
attack of the iodide ion on less hindered carbon of the epoxy ring.42.43 Radical addition
of hydroxyproline 15 to oxime ether 16 using Et3B as the radical indicator gave
inseparable 1:1 diastereomers, 17a and 17b which was converted into separable fully
protected penmacric acid 18 a and epi-penmacric acid 18b via number of steps involving
removal of Cbz group, introduction of Boc group, removal of hydroxyl group using
Barton-McCombie radical deoxygenation and oxidation of the corresponding pyrrolidine
into separable pyrrolidinone. Finally, deprotection of two Boc groups and hydrolysis of
two methyl esters 18a and 18b gave penmacric (2) and (1'-ep1}2 acid respectively.
Pelloux-Leon & Minassian approach (2009}44
Penmacric acid (2) has also been synthesized by Minassian and co-workers starting from
N-triisopropylsilylpyrrole (19) (Scheme 4). The key-steps of the Minassians route are the
addition of the pyrrole nucleus onto a chiral nitrone and the formation of the
pyroglutamic acid moiety by reductive hydrogenation of the pyrrole followed by
oxidation of the corresponding pyrrolidine into pyrrolidinone. The chiral glycinyl
substituent was introduced by the addition of 1945 onto the cyclic chiral nitrone (S}-2046
followed by methanolysis to give intermediate 21, which on treatment with palladium
black as catalyst in formic acid gave amino ester, the free amino group of which was
then protected with Boc followed by the removal of bulky silyl group using TBAF/acetic
acid to give 22. The carbmethoxy group at the a-position was introduced by subsequent
trichloroacetylation and treatment of the crude mixture with sodium methoxide to give
corresponding methyl ester and protection of nitrogen of the pyrrole nucleus with Boc
following typical procedures gave 23.47 The later was hydrogenated using Rh/Ab03 as
catalyst at 60 bars pressure in methanol to give {1:1) mixture of inseparable pyrrolidines
125
-
Approach towards the synthesis of Penmacric acid Chapter 3
24a & 24b which on subsequent oxidation with ruthenium tetraoxide was converted
into fully protected separable diastereomers 18a and 25, which were finally deprotected
in two step sequence to give free 2 and (S-ep1}2.
0 e o,w~o
N + I ,.~0 TIPS Ph'
19 20
24a,b
l RuCI3.3H20/Nal04 (dr = 1:1)
18a
i) TFA, CH2CI2
HCI, CH2CI2
then MeOH
23
2
TIPS-N::x~~ 0 OMe OH
21
i) Pd/MeOH/HC02H j ii) Boc20, NEt3 iii) TBAF, AcOH
NHBoc
Meo2c-\ i) CI3CCOCI 0
ii) MeONa/MeOH N iii) Boc protection ~
22
+ NHBoc Meo,c-::6 ii) liOH, THF/H20 (3/1) NH2 Ho2c-
-
Approach towards the synthesis of Penmacric acid Chapter 3
products, with 4a- adduct predominating due to facial preference induced by the
carboalkoxy group.49 Titanium enolates, however, give almost exclusively the 4a- aldol
adducts.50 Similar facial preferences have been reported by Moloney and co-workers37
for the aldol reaction of bicyclic lactam (Fig. 5). Extension of this strategy to penmacric
acid synthesis using N-Tosyl benzaldimine51 however proved unsuccessful as only 4a-
products were obtained.37 These results were in consonance with an earlier report that
the reaction of pyroglutamate derived enolates with N-Tosyl benzaldimine provides only
two diastereomeric 4a- products in 4:1 ratio.52 We hypothesized that exclusive
formation of 4a- adducts in the reaction might be due to steric bulk of N-Tosyl group
and its replacement with N-Boc might reduce this facial selectivity to provide direct
access to penmacric acid (Fig 5).
Moloney's approach
H NHTs
Ph~.
0~ La
{
several steps
Penmacric acid (2) ====:> A 0 N C02Me + I Boc
Figure 5. Retrosynthetic analysis
3.4. Results and discussion
R
Penmacric acid
_..Boc N
)I
We initiated our efforts with the preparation of N-Boc benzaldimine (27)53 by reacting
benzaldehyde, benzenesulfinic acid sodium salt and t-butyl carbamate in presence of
formic acid resulted in a-amido benzenesufone 26 as white solid which was filtered,
127
-
Approach towards the synthesis of Penmacric acid Chapter 3
dried and then treated with K2C03 in THF under refluxing condition to give benzaldimine
27 in 90% yield for two steps (Scheme 5). Imine 27 was fully characterized by
comparison of its spectral data with that of the reported data. The MS spectrum of 27
~CHO v BocNH2, PhS02Na HCOOH, CH 30H, Hp
rt, 3 days
HN_..Boc
~so2Ph 26
THF, reflux
Scheme 5. Synthesis of N-Boc benzaldimine {27)
showed M+1 peak at m/z 198. TheIR spectrum of 27 showed characteristic absorptions
at 1717 (s, C=O), 1633 (m, C=N) cm-1 whereas the 1H-NMR showed characteristic peaks
at l5 7.48-7.94 (SH, m, ArH), 8.88 (1H, s, CH=N), 1.61 (9H, s, C(CH3h) (Fig. 6).
~ I
1H-NMR, 300 MHz, CDCI3
9.0 8_'\ 8.0 !.5 7,0 (i.S f>.O 55 5.0 4.;'\ 4.0 3.5 3J) 2.5 2.0 15 1.0 05 0.0 ppm
r§1 ~~~ (:1~ hi
Figure 6. 1H-NMR of compound 27
128
-
Approach towards the synthesis of Penmacric acid Chapter 3
The common methodology used for the functionalisation of pyroglutamate at C-
4 position is the regioselective deprotonation at C-4 of N-carbamate protected
pyroglutamate using LiHMDS followed by quenching with electrophiles. The
deprotonation at C-4 is facilitated by the urethane protecting group at nitrogen as the
ring carboxyl becomes imidic in nature thus facilitating the deprotonation at C-4. In
addition, the carbamate group may also stabilize the resulting enolate by coordinating
with the lithium (Fig. 7).
Figure 7. C-4 lithium eno/ate
Thus, Methyl N-Boc pyroglutamate (28},54 prepared from glutamic acid following
literature procedures, on treatment with LiHMDS at -78 oc afforded the ester enolate which reacted with N-Boc benzaldimine (27) at same temperature to give a
diastereomeric mixture of three products (29, 30 and 31) in 5:2:3 ratio as judged by the
integration of signals in the 1H-NMR spectrum (Scheme 6}.
YNHBoc Yh H~-Ph J\ ,< -------Ph 6~R'-._45
25
Boc+HN 65JY..'-._45
25
BocH+N GR 4R 25
~ ~ i) LiHM DS, THF, -78 oc 0 N C02Me
I ii) 27, 2 h, -78 oc 0 N C02Me 0 N C02 Me 0 N C02Me Boc 1 I I
28 Boc Boc Boc 29 30 31
(87%, 29-30-31 ratio 5:2:3)
Scheme 6. Reaction of imine 27 with Li enolate of 28
129
-
Approach towards the synthesis of Penmacric acid Chapter 3
A mixture of two compounds 29 and 30 (83:17) could be separated from the
third 31 by flash column chromatography. Repeated recrystallisations of the mixture of
29 and 30 from diethyl ether gave a pure sample of 29 as distinct crystalline white solid
(29%) and 31 as clear viscous oil (7.0%). All the three diastereomers were fully
characterized by their spectral data ie MS, IR and NMR (Table 1).
Table 1. Spectral data of compounds 29, 30 and 31
1 H NMR {CDCI3)
Compound IR
No. -1 H-35,
em ArH NH H-6 H-2 C02 Me H-4 Boc1 Boc2 H-3R
0 7.30 5.65 9.78 4.47 3.75 3.17 2.2, 2.06 1.48 1.39
Multi- 1791 m d dd d s m m,m s s
29 plicity 1753
1717 1NH,6 16,NH 7.2 1 {Hz) - h3S 8.6 - - -- - -
7.2 16,4 4.9
0 7.30 6.64 4.84 4.10 3.74 3.21 2.09, 1.95 1.45 1.39
Multi- 1787 m br dd d s m m,m s s
plicity 1751 30
1710 16,NH 4.8 1 {Hz) - - 12,35 8.6 - - -- - -
16,4 9.1
0 7.29 6.50 4.94 4.2 3.57 3.16 2.41,1.65. 1.46 1.38
Multi- 1788 m br dd ddb s m m, brm s s
31 plicity 1751
1709 18.8 1 {Hz) - - - - - -- - -
14.9
•H-35 and H-3R were not assigned; bunresolved dd
With all the isomers in hand after chromatography and crystallisation, a series of
two dimensional NMR experiments were performed in order to assign the relative
stereochemistry at C-4 and C-6 The stereochemistry at C-4 of the major isomer 29 was
judged to be trans with respect to C-2 ie (45) using NOE experiments in CDCI3 (Fig. 8).
130
-
Approach towards the synthesis of Penmacric acid Chapter 3
First we irradiated the hydrogen at C-2 in order to determine the spatial orientation of
the hydrogens at C-3. The proton at 2.2 ppm was assigned as H-35 by its enhancement
of 6.7% on irradiating the signal for H-2 at 4.47 ppm, and irradiation of H-4 at 2.83 ppm
gave an enhancement of 5.1% to H-3R at 2.06 ppm.
29, NOE, 300 MHz, CDCI3
H-2
5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5
5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 ppm
Figure B. Key NOESY correlations for compound 29
131
-
Approach towards the synthesis of Penmacric acid Chapter 3
The isomer 30 was deemed to have the same (45) stereochemistry as the
transfer of magnetization was observed between H-2 proton and H-35 and H-4 and H-3R
in its NOESY spectrum (Fig. 9). Thus both isomers exhibited trans stereochemistry at C-4
with respect to C-2.
H·3R~
H·3S~
H-4~
H-2~
30
30, NOESY, 400 MHz, CDCI3
+ &; a a
Q ) ·~@ • 0 " ~
-
Approach towards the synthesis of Penmacric acid Chapter 3
Careful crystallization of 29 enabled the isolation of crystals suitable for single-
crystal X-ray analysis and confirmed its (6R) stereochemistry at C-6 (Fig. 10). Hence 30, the
other 4a.- product, was assigned 25,45,65 configuration.
Figure 10. X-ray structure of compound 29.
The stereochemistry at C-4 of 31 was thus deductively assigned as (4R). In order
to establish its relative stereochemistry at C-4 and C-6, phenyl group in 31 was
oxidatively transformed using in situ generated Ru04 from RuCI3fNai04 to carboxylic
H NHBoc H Ph H Ph
Ph~. BocHN~. BocHN~
O~C02Me O.J:')....C02Me 0 N C02Me I I I Boc Boc Boc
29 30 31
H NHBoc
Me02C~, 45 O~C02Me
I Boc
(4,6-epi-) 33 (36.2%)
BocHN~~~:Me BocHN,; O~C02Me 0 N C02Me
I I Boc Boc
(4-epi-) 34 (23%) (6-epi-) 32 (35.6%)
Scheme 7. Synthesis of epimers of penmacric acid
133
-
a
Approach towards the synthesis of Penmacric acid Chapter 3
function and esterified to 32 using diazomethane in overall 35.6% yield (Scheme 7). 32
was found to be C6-epimer of penmacric acid ester having spectral data identical with
that of methyl ester of epi-penmacric acid reported by Takeaki Naito et a/.40 Similarly,
4,6-epi-, and 4-epi-penmacric acids (33 and 34) were prepared from 29 and 30
respectively following the same protocol. All the three epimers of penmacric acid were
fully characterized by their spectral data ie MS, IR and NMR. The C-4 trans relationship
of compound 33 and 34 was reconfirmed by NOE experiments in deuterobenzene (Fig.
11 and 13) and the absolute configuration [(25,45,6R}-33 and {25,45,65)-34] was later
supported by single crystal X-ray structure of compound 33 (Fig. 12).
Table 2. Spectral data of compounds 32, 33 and 34
2H NMR"
Compound IR ester ester H-35, Boc Boc
No. cm·1 NH H-6 H-2 H-4 1 2 H-3R 1 2
8 1789 5.67 4.5 3.80 3.77 3.08 2.56,2.08° 1.50 1.45
32 Multi- 1750 br m s s m m,brm s s
plicity 1717
8 5.38 4.61 4.28 3.29 3.22 3.44 2.02,1.65 1.36 1.34
Multi- 1790 d dd dd s s m m,m s s
plicity 1750 33
J (Hz) 1717 JNH,6 J6,NH 8.9 J2,35 10.8 - - - - - -
8.9 J6,4 2.6 J2,3R 2.6
8 5.76 4.67 4.43 3.26 3.20 2.97 2.07,1.69 1.38 1.35
Multi-1789 br dd dd s s m m,ddd s s
plicity 34 1749
1718 )6,4 9.4 J2,35 9.8 J3R,35 10.5
J (Hz) - - - - J3R,4 9.2 - -J6,NH 4.2 J2,3R 1.4
J3R,2 1.4
- b, Internal standard for 32 (CDCI3), 33 (C6D6) and 34 (C6D6), H-35 and H-3R were not ass1gned
6-epi, 4-epi, 4,6-epi corresponds to l'-epi, 3-epi, 3,1'-epimers of penmacric acid (2) respectively according to usual
pyroglutamate numbering.
134
-
Approach towards the synthesis of Penmacric acid
H-2
l. ______ ____
l~~ .5 4.0 3.5 . 3.0
H-4
1.5 4.0 3.5 3.0
2.5
2.5
N I Boc
33
2.0
2.0
2.2%
H-35
i
Chapter 3
33, NOE, 400 MHz, C.D6 H-3R
1.5 1.0 0.5 ppm
H-3R
i
r 1.5 1.0 0.5 ppm
S-40
Figure 11. Key NOESY correlations for compound 33
Figure 12. X-ray structure of compound 33
135
-
Approach towards the synthesis of Penmacric acid Chapter 3
H-35 34, NOE, 400 MHz, C60 6
H-2 t J,
1 I~( 1=1 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
H-4 H-3R
t i--r r~l I~( I~(
5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
H-2
t H-3R H-35 t t
1~r I~( I~( 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 ppm
Figure 13. Key NOESY correlations for compound 34
As titanium enolates are known to enhance the diastereoselectivity in aldol
reactions,50'55 addition of chlorotitanium enolate of 28 with imine 27 was also studied.
Thus, pyroglutamate derived titaniumtrichloro enolate, prepared by dropwise addition
of TiCI4 (1M in CH2CI 2) to a solution of 28 in CH2CI2 at -78 oc followed by slow addition of DIPEA after 5 min resulted in deep violet enolate solution, reacted with N-Boc
136
-
Approach towards the synthesis of Penmacric acid Chapter 3
benzaldimine (27) at same temperature for 2 h. In contrast to the results obtained with
lithium enolate, only a single diastereomer 29 was obtained in excellent yield (Scheme
8).
O~C02Me I Boc
28
i) TiCI4, CH2CI2, Dl PEA, -78 ·c iil 21, 2 h, -78 ·c
H NHBoc
Ph~-.4s
O~C02Me I Boc
29 (72%)
Scheme 8. Reaction of imine 27 with Ti enolate of 28
Since the structure of penmacric acid consists of pyroglutamic acid residue with
glycine motif at C-4 and also carboxylate group is expected to be sterically less hindered
than phenyl group, in order to achieve one step synthesis of penmacric acid we next
studied the reaction of lithium enolate of 28 with Methyl N-Boc-a-iminoacetate {37)56
(Scheme 9) prepared in situ from Methyl N-Boc-2-bromoglycinate (36).
35
NBS, CCI4
hv (500 W) 10-30 °C
NHBoc
~ Me02C Br
36
TEA, THF
-78 ·c Me02C
Scheme 9. Synthesis of Methyl N-Boc-a-iminoacetate {37)
NBoc
)
37
2-bromoglycine ester 36 required for the synthesis was prepared by irradiating a
solution of Methyl N-Boc-glycinate (35)57 and N-bromosuccinimide {NBS) in CCI4,
keeping the reaction mixture between 10-30 oc using a water bath. Subsequent elimination with TEA was achieved at -78 oc and the cold crude imine 37 was rapidly filtered and transferred into a pre-prepared lithium enolate solution of 28, prepared
with 1.2 equiv of LiHMDS in THF at -78 oc for 30 minutes. No aldol product was obtained and the starting pyroglutamate 28 was recovered unchanged. This may be due to
inefficiency of the transfer and filtration procedure which allowed the sensitive imine 37
137
-
Approach towards the synthesis of Penmacric acid Chapter 3
to warm considerably above -78 oc. To overcome this problem, the cold lithium enolate solution of pyroglutamate 28 was rapidly transferred via cannula to the crude imine 37
solution at -78 oc without isolating the later. This method gave a mixture of two
diastereomeric products, 33 and 34 (Scheme 10) in 71% yield in a ratio of 7:3 as judged
by integration of signals in the 1H NMR spectrum.
O~C02Me I Boc
28
i) LiHMDS, THF, -78 oc ii) 37, 2 h, -78 oc
i) TiCI4, CH2CI 21 DIPEA, -78 oC
ii) 37, 2 h, -78 oc
(4-epi-) 34 (62.3%)
H NHBoc
Me02C~ .. 45 J:X. 0 N C02Me
I Boc
(4,6-epi-) 33 (41.3%)
+
H C02Me
BocHN~ .. 45 J:X. 0 N C02Me
I Boc
(4-epi-) 34 (18%)
(11%, 10-11 ratio 7:3)
Scheme 10. Reaction of imine 37 with Li & Ti enol ate of 28
High stereoselectivity (exclusive 65) was also observed in reaction of titanium
enolate of 28 with imine 37, where 34 was obtained as the sole product (Scheme 10).
The attack of Ti-enolate to the si-face of imine in reaction could be rationalized through
a more chelated intermediate (Fig. 14).
Figure. 14. Proposed transition state model
In an effort to establish our proposed chelated transition state assembly, we
next investigated the reaction of Ti-enolate of 28 with activated N-tosyl benzaldimine
(38) derived from benzaldehyde (absence of chelation due to carbmethoxy group). 138
-
Approach towards the synthesis of Penmacric acid
PhCHO + TsNH2 + TEA
,....Ts N
ci 38(72%)
Scheme 12. Synthesis of N-tosyl benzaldimine (38)
Chapter 3
N-tosyl benzaldimine (38)51 was prepared following the method reported in
literature by treating TiCI4 to a ice-cooled solution of benzaldehyde, tosylamide and TEA
in CH2CI2 for 30 min to give 38 in 72% yield. Imine 38 was fully characterized by
comparison of its melting point and spectral data with that of the reported data. The MS
spectrum of 38 showed M+l peak at m/z 260 whereas its 1H-NMR showed characteristic
peaks at o 7.33-7.94 (9H, m, ArH), 9.03 (lH, s, CH=N), 2.44 (3H, s, PhCH3) (Fig. 15).
1H-NMR, 300 MHz, CDCI3
~ 1'
9.0 8.5 8.0 'l.S 1.0 65 b.O 5'..5 .S.O 4 . .S 4.0 3 .. '\ J.O ::!.5 Z.O I . .S 1.0 0.5 ppm
~ ~~~ ~
Figure 15. 1H-NMR of compound 38
139
-
Approach towards the synthesis of Penmacric acid Chapter 3
It is pertinent to note that in absence of such chelation in N-Tosyl imine 38, its
reaction with titanium enolate of 28 afforded a diastereomeric mixture of 4a-products
{39 and 40) in a ratio of 65:35 (by 1H-NMR) similar to the results observed in case of Li-
enolate as reported by Young eta/52 (Scheme 12).
O~C02Me I Boc
28
ii) 38, 2 h, -78 oc
H NHTs
Ph~, 45 ~ 0 N C02Me
I Boc
39 (23%)
H Ph
TsHN~
+ O~C02Me I Boc 40
(85%, 39-40 ratio 65:35)
Scheme 12. Reaction of imine 38 with Ti enolate of 28
The structure and stereochemisty of both the diastereomers 39 and 40 were
assigned by comparison of their delta and coupling values with the reported analogues
(41a and 41b).52 Chromatography and recrystallisation gave the pure major isomer 39 in
23% yield and impure 40 but the spectrum of minor isomer was obtained by subtraction
(Table 3 and 4).
Type of proton
NH
H-2
H NHTs
Ph~-.45 ~ 0 N C02CH2Ph
I Boc
41a
H Ph
TsHN~_- 45 O~C02CH2Ph
I Boc 41b
Table 3. Comparison of 1H-NMR data b/w 41a and 39
reported (40a) observed (39)
() multiplicity 1 (Hz) () multiplicity
6.37 d 1NH,6= 4.0 6.46 d
4.46 dd 12,35 = 9.6
4.42 d 12,3R = 1.2
140
1 (Hz)
1NH,6= 4.0
12,35 = 9.5
-
Approach towards the synthesis of Penmacric acid Chapter 3
J6.4=7.1 dd
)6,4 = 6.9 H-6 4.26 dd 4.34
J6,NH = 4.0 J6,NH = 4.0
H-4 3.02 m - 3.05 m -
H-35 2.05 ddd - 2.06 m -
H-3R 1.78 ddd - 1.81 m -
Table 4. Comparison of 1H-NMR data b/w 41b and 40
reported {41b) observed {40) Type of proton
0 multiplicity J (Hz) 0 multiplicity J (Hz)
NH 6.78 d JNH,6= 9 6.76 d JNH,6= 9.1
H-2 4.17 dd J2,35 = 9.6
4.15 dd J2,35 = 9.1
h_3R = 2.2 J2,3R = 2.3
dd )6,4 = 4.7
dd )6.4 = 4.8
H-6 4.61 4.65 J6,NH = 9.0 J6,NH: 9.1
H-4 3.21 m - 3.2 m -
H-35 1.90 m - 1.79- -m
H-3R 2.05 m - 2.12
The high exo-stereoselectivity observed in the reaction of imine 37 with lithium
enolate of 28 is indeed surprising and hence it appeared interesting to study the
condensation of unsubstituted N-Boc imine 43 (Scheme 13) with lithium enolate of 28.
K2C03 THF, reflux
X ..
HN_...Boc NaH _...Boc
H BocNH2, PhS02Na N
)=o H~S02Ph /'\ )l
H HCOOH, CH30H, Hp H H
rt, 3 days 42 (86%) LiHMDS 43 X ..
Scheme 13. Unsuccessful efforts to tert-butyl methylenecarbamate {43)
141
-
Approach towards the synthesis of Penmacric acid Chapter 3
We attempted to prepare the N-Boc imine 43 employing the same strategy as
described for N-Boc benzaldimine (27) ie synthesis of sulfone corresponds to
formaldehyde followed by its elimination with base (Scheme 13). Treatment of 30% aq.
formaldehyde solution with benzene sulfinic acid sodium salt , tert-butyl carbamate in
the presence of formic acid for 3 d gave sulfone 42 as white solid in 86.4% yield which
was fully characterized by MS, NMR and IR. The MS spectrum of 42 showed [M+NH4t peak at m/z 298 whereas 1H-NMR showed characteristic peaks at 5 7.53-7.94 (5H, m,
ArH), 5.42 (lH, br, NH), 1.26 (9H, s, C(CH3h) (Fig. 16).
~~~~~~!§ ~ a~ .,., \\\\IP \1
1H NMR, 300 MHz, CDCI3
t;~:Ph 42
Figure 16. 1H-NMR of compound 42
~
" 1i I
-~~-~~ :-~=
-
Approach towards the synthesis of Penmacric acid Chapter 3
attempts to isolate the imine 43 were unsuccessful. Intrigued by the instability of 43 it
was decided to generate the imine 43 in situ from the sulfone 42 with UHMDS. The
addition of Lithium enolate of pyroglutame 28, generated by treatment with 2.3 equiv
of UHMDS at -78 oc with the sufone 42 (1.1 equiv) at same temperature, expectedly
found to be non-stereoselective, giving an almost 1:1 ratio of 4a- and 4~-products 44
and 45, respectively (Scheme 14) as judged by integration of signals in the 1H-NMR
spectrum.
O~C02Me I Boc
28
i) LiHMDS, THF, -78 "C
ii) 42, 2 h, -78 ·c
BocHN-,,
~ 0 N C02Me I Boc
44 (35%)
BocHNn 4R
2
0 N C02Me I Boc
45 (33.2%)
{74%, 44-45 ratio 52:48)
Scheme 14. Reaction of sulfone 42 with Li enol ate of 28
Both the diastereomers were fully characterized by their spectral data ie MS, IR and
NMR (Table 5).
Table 5. Spectral data of compound 44 and 45
lH NMR (CDCI 3)
compound IR mp
No. . ·1 H-35/
em ·c NH H-2 C02 Me H-6 X 2 H-4 Bocl Boc2 H-3R
3.49/ 0 5.15 4.58 3.78 2.81 2.14 1.50 1.42
3.33 1772
multi 44 1707 96 br dd s m/m m m s s
plicity
J (Hz) 12,35 8.9
- - - - - - -J2,3R 1. 7
3.49/ 0 1786 5.17 4.5 3.77 2.75 2.51/1.79 1.49 1.42
3.34 1784 106
45 multi 1710 br dd3 s m/m m m,m s s
plicity
"unresolved dd
143
-
Approach towards the synthesis of Penmacric acid Chapter 3
With both the isomers in hand after chromatographic separation, 4-~
stereochemistry of the isomer 45 was assigned using NOE experiments in CDCI3, by the
irradiation of H-2, H-3 and H-4 (Fig. 17). This experiment was similar to the one on
intermediate 29. First we determined the spatial orientation of hydrogens at C-3. The
3.5%
~~'Hs BocHN nd:_ -~H 5.s%
0 N C02Me I
Boc 45
H-35 H-2 t 45, NOE, 300 MHz, CDCI3 l
1 1~1 l~l 1~r 45 4.0 35 3.0 2.5 2.0 1.5 1.0 05 ppm
H-2 H-35
i H-4 t l
!~( l l~l 45 4.0 35 3.0 2.5 2.0 15 1.0 0.5 ppm
S-43
Figure 17. Key NOE5Y correlations for compound 45
proton at 2.51 ppm was assigned as H-35 by its enhancement of 5.8% on irradiating the
signal for H-2 at 4.5 ppm, and irradiation of H-4 at 2. 75 ppm gave an enhancement of
3.5% to H-35 at ppm. Also, an 2.3% enhancement of H-4 was also observed on
144
-
Approach towards the synthesis of Penmacric acid Chapter 3
irradiation of H-2. All these results indicated that N-Boc aminomethyl moiety and ~
oriented H-3R have a cis-relationship.
In contrast to the results obtained with Li enolate, reaction of chlorotitanium
enolate of 28 with imine 42 gave predominantly 4a-isomer 44 in 67% yield {Scheme 15).
Incidentally, this also constitutes a one step synthesis of 44 and 45 as intermediates for
{45) and {4R) 4-aminomethyl glutamic acid respectively serving as glutamate transport
inhibitors which were otherwise have been synthesized in multisteps.58
o¥co2Me I Boc
28
i) TiCI4, CH2CI2, DIPEA, -7s•c
ii) 42, 2 h, -78 ·c
BocHN-,, '.45
O~C02Me I Boc
44(67%)
Scheme 15. Reaction of sulfone 42 with Ti enolate of 28
3.5. Conclusion
In conclusion, we have accomplished a short formal synthesis of three epimers of
penmacric acid, and have shown dependency of the stereochemical outcome in the
reaction of imines with Li enolates of pyrogluatmate, to the steric bulk of substituents.
On the other hand, chelation seems to be predominant factor in reaction with titanium
enolates.
145
-
Approach towards the synthesis of Penmacric acid Chapter 3
3.6. Experimental
3.6.1. General methods
All enolate reactions were done using flame-dried glassware under nitrogen
atmosphere. THF was distilled from sodium/benzophenone ketyl immidiately before
use. Triethylamine, N,N-diisopropylethylamine and dichloromethane were distilled
over calcium hydride. N-bromosuccinimide was recrystallised from water prior to
use. Reactions were monitored by thin layer chromatography (TLC) using 0.25 mm E.
Merck pre-coated (Merch 60 F254) silica gel plates using ninhydrine as visualizing
agent. Purification was performed by flash chromatography using silica gel {230-400
mesh}. NMR spectra were recorded either on a Bruker Advance-300 or Advance-400
spectrometers. Chemical shifts are reported as ppm {delta) relative to TMS as
internal standard. Mass spectra were recorded on LCQ Advantage MAX (ESI}, JOEL
JMS-600H (EI/HRMS) and Accu. TOF JMS T100 LC (DART/HRMS) mass spectrometer.
IR spectra were recorded on a Perkin-Elmer FT-IR RXI spectrometer. Optical rotations
were determined on an Autopol Ill polarimeter. Unit cell determination and intensity
data collection (29 = 50°} was performed on a Bruker Smart Apex diffractometer with CCD area detector at 293 K. Structure solutions by direct methods and refinements
by full-matrix least-squares methods on F2. XSCANS [Siemens Analytical X-ray
Instrument Inc.: Madison, Wisconsin, USA 1996] was used for data collection and
reduction. SHELXTL-NT [Bruker AXS Inc.: Madison, Wisconsin, USA 1997] was used
for structure refinement.
3.6.2. Experimental details
Two-step preparation of N-tert-butoxycarbonyl benzaldimine {27)
Step 1: tert-Butyl carbamate (2.93 g, 25 mmol) and benzenesulfinic acid sodium salt (8.2
g, 50 mmol) were taken into a 250 ml round bottom flask and dissolved in a mixture of
methanol (25 ml) and water (50 ml). Benzaldehyde (50 mmol) was then added, followed
146
-
Approach towards the synthesis of Penmacric acid Chapter 3
by formic acid {1.9 ml) and the reaction mixture was stirred for 3 days at room
temperature. The resulting white solid was filtered off and washed with water and
ether, redissolved in dichloromethane, dried over Na2S04, and concentrated under
reduced pressure to afford the respective a-ami do benzenesulphone {26} as white solid.
Step 2: An oven dried round bottom flask was charged with anhydrous potassium
carbonate (16 g) and dry THF {10 ml/mmol) under nitrogen atmosphere. Then, the a.-
amido benzenesulphone 26 {19.4 mmol) was added and the mixture was heated to
reflux with stirring under a nitrogen atmosphere for 17 h. The mixture was then cooled
to room temperature, filtered through a short pad of celite and concentrated under
reduced pressure. The residue was redissolved in dichloromethane, dried over Na2504,
filtered and concentrated under reduced pressure to afford the corresponding N-Boc
aldimine 27 in 90% yield (for two steps) which was kept under high vacuum at rt for
several hours before use.
Colorless oil; IR (thin film, cm-1) 2983, 1713, 1627, 1263, 1217, 1157;
1H NMR {300 MHz, CDCI3) o 8.88 {1H, s, CH=N), 7.91-7.94 (2H, m, ArH), 7.54-7_57 {1H, m, ArH), T48-7.50 {2H, m, ArH), 1.61{9H, s,
{CH3hCO); 13C NMR (75 MHz, CDCI3) o 169.8, 162.7, 134.1, 133.6,
130.3, 128.9, 82.4, 28.0; MS (ESI): m/z 205, found 205[M+Ht, 106[M-C2H80 2t,
Methyi{2S,4RS)-N-tert-butoxycarbonyi-4-[{6RS)-N-tert-
butoxycarbonylamidobenzyl)pyroglutamate {29, 30, 31}
Lithium enolate
Under nitrogen atmosphere and at -78 °(, LiHMDS {1.0 M in THF, 7.63 ml, 7.64 mmol)
was added slowly to the magnetically stirred solution of Methyl (25)-N-tert-
butoxycarbonypyroglutamate 28 {1.54 g, 6.36 mmol) in freshly distilled THF {30 ml), and
the reaction mixture was stirred for 1 hat -78 oc. A solution of N-Boc aldimine 27 (1.69 g, 8.27 mmol) in tetrahydrofuran {20 ml) was added dropwise to the reaction mixture
and stirring was continued for additional 2 h at -78 oc . The reaction mixture was 147
-
Approach towards the synthesis of Penmacric acid Chapter 3
quenched with saturated aqueous ammonium chloride {15 ml), allowed to warm to
room temperature, diluted with water (25 ml), and extracted with ethyl acetate {3 x 25
ml). The combined organic layer was washed with brine (25 ml), dried (Na2S04), and
concentrated in vacuo to give a mixture of three diastereoisomers 29, 30 and 31 (2.48 g,
87%) as white foam which was flash chromatograped on a silica gel column using ethyl
acetate-hexane {30:70) as eluant to give a mixture of 29, 30 (83:17) and pure 31 as clear
viscous oil {0.68g, 23.8%}. Repeated recrystallisations of the mixture of 29 & 30 from
diethyl ether gave a pure sample of 29 as distinct crystalline white solid (0.82 g, 29%)
and 30 as clear viscous oil {0.19 g, 7.0%}.
Titanium enolate
A solution of TiCI4 {1.0 M in CH2Cb, 1.16 ml, 1.16 mmol,) was added dropwise to a
stirred solution of 28 (0.26 g, 1.07 mmol) in anhydrous CH2CI2 {10 ml) at -78 oc under nitrogen, giving a yellow slurry. After 5 minutes, N,N-diisopropylethylamine (0.37 ml,
2.14 mmol) was added slowly over a period of 15 min. The resulting violet colored
solution was stirred at -78 oc under nitrogen for 1.5 h, a solution of N-Boc aldimine 27
{0.26 g, 1.28 mmol) in CH2CI2 (5 ml) was added to it over a period of 10 mins, and the
stirring was continued at -78 oc for 2 h. The reaction was quenched by addition of saturated aqueous ammonium chloride (5 ml), allowed to warm to room temperature,
diluted with water (15 ml), and extracted with CH2CI2 (3 x 10 ml). The combined organic
extracts were washed with brine {2x10 ml), dried (Na2S04) and concentrated in vacuo to
give a white foam which was purified using flash chromatography over a silica gel
column using ethyl acetate-hexane as eluant (30:70) to give pure 29 as white crystalline
solid {0.34 g, 72%).
H NHBoc
Ph~
h 0 N C02 Me I Boc
29
Methyi(2S,4S)-N-tert-butoxycarbonyi-4-[(6R)-N-tert-
butoxycarbonylamidobenzyl)pyroglutamate (29)
Colorless crystalline solid; mp 172-175 oc; [found: C, 61.51; H, 7.12; N, 6.32. C23H32N201 requires C, 61.59; H, 7.19; N, 6.25%];
148
-
Approach towards the synthesis of Penmacric acid Chapter 3
Rt (30% EtOAc/hexane) 0.35;1H NMR {300 MHz, CDC13) b 7.26-7.35 (5H, m, ArH), 5.64-
5.67 {1H, d, JNH,6 7.2 Hz, NH), 4.87-4.91 {1H, dd, J 6,NH 7.2 Hz, J6,4 4.9, H-6), 4.46-4.49 {1H,
d, h,35 8.6 Hz, H-2), 3.75 {3H, s, C02CH3), 3.13-3.21 (1H, m, H-4), 2.14-2.26 (1H, m, H-35),
2.03-2.10 {1H, m, H-3R), 1.48 {9H, s, {CH3}3CO), 1.39 {9H, s, {CH3}3CO); 13C NMR (75 MHz,
CDCI3) b 172.6, 171.6, 155.7, 149.1, 140.3, 128.7, 127.6, 127.0, 84.0, 80.0, 56.9, 54.9,
52.7, 46.9, 28.3, 27.9, 26.1; IR(thin film, cm-1) 2980, 1791, 1753, 1717, 1500, 1456, 1370,
1314, 1156, 1047; M5 (E51): m/z 448, found 471 [M+Nat; HRM5 (DART): m/z calcd. for
C23H33N201 [M+Ht: 449.2287; found: 449.2271; [a]28o= -10.3 (c 0.81, CHCI3).
H Ph BocHN~
h 0 N C02Me I Boc
30
Methyi{2S,45)-N-tert-butoxycarbonyi-4-[{65)-N-tert-
butoxycarbonylamidobenzyl]pyroglutamate {30)
Clear viscous oil; R1(30% EtOAc/hexane) 0.35/H NMR {400
MHz, CDCI3) b 7.27-7.34 (5H, m, ArH), 6.64 (1H, br, NH),
4.85-4.88 {1H, dd, J6,4 9.1 Hz, J6,NH 4.8 Hz, H-6), 4.09-4.12
{1H, d, h,3s 8.4 Hz, H-2), 3.74 {3H, s, C02CH3), 3.18-3.24 (1H, m, H-4), 2.06-2.12 {1H, m,
H-3R), 1.91-2.00 (1H, m, H-35), 1.45 (9H, s, (CH3)3CO), 1.39 {9H, s, (CH3)3CO); 13C NMR
(75 MHz, CDCI3) & 173.8, 171.4, 155.0, 148.8, 138.3, 128.7, 128.0, 127.9, 83.9, 79.7, 57.0,
54.6, 52.7, 46.1, 28.3, 27.8, 25.1; IR (thin film, cm-1) 3021, 2366, 1787, 1751, 1710, 1492,
1370, 1313, 1217, 1157; M5 (E51): m/z 448, found 471[M+Nat; HRM5 (DART): m/z calcd.
for C23H33N201 [M+Ht: 449.2287; found: 449.2288; [a]28o= -47.7 (c 0.84 CHCI3).
H Ph
BocHN~--6 4 2
Methyi{2S,4R)-N-tert-butoxycarbonyl-4-[ ( 6R)-N-tert-
butoxycarbonylamidobenzyl] pyroglutamate {31)
Clear viscous oil; [found: C, 61.45; H, 7.26; N, 6.22.
C23H32N201 requires C, 61.59; H, 7.19; N, 6.25%]; R1 {30%
EtOAc/hexane) 0.31;1H NMR {300 MHz, CDCI3) b 7.26-7.32
(5H, m, ArH), 6.50 (1H, br, NH), 4.92-4.97 (1H, dd, J 8.8, 4.9 Hz, H-6), 4.39-4.45 (1H, dd
0 N C02 Me I Boc
31
(unresolved), H-2), 3.57 {3H, s, C02CH3), 3.12-3.20 (1H, m, H-4), 2.36-2.47 (1H, m, H-3), 149
-
Approach towards the synthesis of Penmacric acid Chapter 3
1.64-1.67 (1H, b m, H-3), 1.46 (9H, s, (CH3}3CO), 1.38 (9H, s, (CH3)3CO); 13C NMR (75 MHz,
CDCI3) 8 173.4, 171.1, 155.1, 148.8, 138.4, 128.7, 127.9, 127.0, 84.1, 79.7, 57.0, 54.6,
52.5, 46.9, 28.3, 27.9, 24.0; IR (thin film, cm-1) 2923, 1788, 1751, 1709, 1497, 1455,
1370, 1313, 1217, 1157, 1028; MS (ESI}: m/z 448, found 471 [M+Nat; HRMS (ESI): m/z
calcd. for C23H33N20 7 [M+Ht: 449.2287; found: 449.2315; [a]29o= +22.5 (c 0.88, CHCI3).
General procedure for Methyl (25,4RS)-N-tert-butoxycarbonyi-4-[(6RS)-
methoxycarbonyi-N-tert-butoxycarbonylaminomethyl]pyroglutamate (32, 33, 34)
To a stirred solution of 31 (0.22 g, 0.51 mmol) in a mixture of CH3CN (4 ml) and CCI4 (4
ml) was added a solution of Nal04 (1.14 g, 5.34 mmol) in water (7 ml) and the stirring
was continued for additional 15 min. RuCI3.3H20 (10 mg, cat.) was added to it and the
reaction mixture was vigorously stirred for 12 h. CH2CI2 (15 ml) was added and the
aqueous layer was extracted with CH2CI2 (3 x 10 ml) and dried (Na2S04). The residue
obtained after concentration was redissolved in THF (5 ml) to which a solution of
diazomethane in ether was added with swirling. Water (15 ml) was added to it and
extracted with ethyl acetate (3 x 15 ml). The combined organic phases were dried
(Na2S04) and concentrated in vacuo to give a colorless oil (0.094 g, 43%); purified by
flash column chromatography on silica gel using ethyl acetate-hexane as eluant (45:65)
to give 32 as viscous oil (0.078 g, 35.6%) which was crystallised from diethyl ether to
white solid after standing overnight.
Methyi(25,4R)-N-tert-butoxycarbonyi-4-[(6R)methoxycarbonyi-N-tert-
butoxycarbonylaminomethyl] pyroglutamate (32}
H, C02Me BocHNh 0 N C02 Me
I Boc
32
White solid; mp 122-125 oc; [found: C, 53.11; H, 7.09; N,
6.57. C19H3oN209 requires C, 53.02; H, 7.02; N, 6.51%]; Rt
(50% EtOAc/hexane) 0.4/H NMR {300 MHz, CDCI3) 8 5.67
(1H, br, NH), 4.50-4.61 (2H, m, H-6+H-2}, 3.80 (3H, s,
C02CH3), 3.77 {3H, s, C02CH3), 3.04-3.12 (1H, m, H-4), 2.51-
150
-
Approach towards the synthesis of Penmacric acid Chapter 3
2.61 {1H, m, H-3), 2.04-2.13 (1H, b m, H-3), 1.50 {9H, s, (CH3hCO), 1.45 (9H, s, (CH3hCO);
Be NMR {100 MHz, CDCI3) o 171.1, 170.3, 169.5, 154.2, 147.9, 83.0, 79.3, 56.0, 51.9, 51.6, 51.5, 44.4, 27.1, 26.7, 23.0; IR (thin film, cm-1) 2960, 2923, 1789, 1750, 1717, 1501,
1457, 1396, 1259, 11S6, 1027; M5 (E51}: m/z 430, found 4S3 [M+Nat; HRM5 (DART):
m/z calcd. for C9H15N20 5 [M-C10H1504t: 231.0981; found : 231.1008; [a]30
0= -7.7 (c 0.31 CHCI3).
Methyi(2S,4S}-N-tert-butoxycarbonyi-4-[(6R} methoxycarbonyl
-N-tert-butoxycarbonylaminomethyl] pyroglutamate {33}
H NHBoc
Meo2c_:;( .. 4 J:'X. 0 N C02 Me
I Boc
Colorless crystalline solid; 36.2%; mp 137-139 °C; [found:
C, S3.09; H, 7.12; N, 6.48. C19H3oNz09 requires C, S3.02; H,
7.02; N, 6.S1%]; Rt {SO% EtOAc/hexane) 0.62;1H NMR (400
MHz, C6D6} o S.37-S.39 (1H, d, JNH,6 8.9 Hz, NH), 4.6S-4.S7 33
(1H, dd, J6,NH 8.9 Hz, )6,4 2.6 Hz, H-6), 4.27-4.30 (1H, dd, Jz,3s
10.8 Hz, h,3R 2.6, H-2), 3.41-3.47 (lH, m, H-4), 3.29 (3H, s, C02CH3), 3.22 {3H, s, C02CH3),
1.98-2.07 {1H, m, H-35}, 1.63-1.68 (1H, m, H-3R); 1.36 {9H, s, (CH3hCO}, 1.34 {9H, s,
(CH3hCO); Be NMR {100 MHz, C6D6) o 171.5, 171.3, 170.7, 1S6.7, 1S0.2, 83.3, 80.0, S6.9, S2.6, S2.3, S1.9, 4S.6, 28.2, 27.8, 2S.O; IR (thin film, cm-1) 3021, 2981, 1790, 17SO, 1717,
1S01, 1370, 1316, 1216, 11S4; M5 (E51}: m/z 430, found 4S3[M+Nat; HRM5 (EI): m/z
calcd. for C19H3oNz09[Mt: 430.19S1; found: 430.1977; [a]29
0= -6S.O (c 0.32 CHCh).
Methyi(2S,4S}-N-tert-butoxycarbonyl-4-[(65}-methoxycarbonyi-N-tert-
butoxycarbonylaminomethyl] pyroglutamate {34}
H C02Me
BocHN~
h 0 N C02 Me I Boc
34
White foam; 23%; Rt (SO% EtOAc/hexane) O.S3;1H NMR
(400 MHz, C6D6) o S. 78 (1H, br, NH), 4.6S-4.69 (1H, dd, J6,4 9.4 Hz, J6,NH 4.2 Hz, H-6), 4.42-4.4S (1H, dd, Jz,3s 9.8 Hz,
h,3R 1.4 Hz, H-2), 3.26 (3H, s, COzCH3), 3.20 (3H, s, C02CH3),
2.9S-2.99 (1H, m, H-4), 2.03-2.11 (1H, m, H-35}, 1.66-1.72
151
-
Approach towards the synthesis of Penmacric acid Chapter 3
(1H, ddd, hR,3s 10.5 Hz, hRA 9.2 Hz, J 3R,2 1.4 Hz, H-3R); 13C NMR {100 MHz, C6D6) 0 172.1,
171.6, 171.1, 155.4, 150.3, 83.2, 79.8, 57.1, 53.3, 52.08, 52.05, 45.3, 28.3, 27.9, 25.0; IR
(thin film, cm-1) 3020, 2979, 1789, 1749, 1718, 1501, 1370, 1316, 1216, 1154; MS (ESI):
m/z 430, found 453 [M+Nat; HRMS (EI): m/z calcd. for C19H3oN209 [Mt: 430.1951;
found: 430.1984; [a)27 0= +3.3 (c 0.56, CHCI3).
Methyi(25,45)-N-tert-butoxycarbonyi-4-[(6RS)-methoxycarbonyi-N-tert-
butoxycarbonylaminomethyl] pyroglutamate (33 and 34) [Scheme 10]
Lithium enolate
N-bromosuccinimide (0.56 g, 3.16 mmol) was added to a stirred solution of Methyl N-
tert-butoxycarbonylglycinate (35)27 {0.57 g, 3.02 mmol) in CCI4 (10 ml) under nitrogen
atmosphere. The stirred solution was illuminated with 500 W lamp for 1 h, keeping the
reaction mixture between 10-30 oc using a water bath. The resulting orange reaction mixture was then filtered and the filtrate was concentrated in vacuo to afford the crude
Methyl 2-Bromo-N-tert-blitoxycarbonylglycinate {36) as yellow oil. To the crude
bromide 36 in THF (6 ml) at -78 oc under nitrogen was added anhydrous triethylamine (0.46 ml, 3.30 mmol) with stirring and the reaction mixture was stirred for 45 min at -78
oc to afford a crude imine 3725 solution. Meanwhile to a stirred solution of pyroglutamate 28 {0.67 g, 2.75 mmol) in THF {12 ml) was slowly added LiHMDS {1.0 Min
THF, 3.44 ml, 3.44 mmol) at -78 oc and the reaction mixture was stirred for 1 h. The cold crude enolate solution was then quickly added to crude imine solution via cannula and
stirred for another 2 h at -78 oc. Saturated aqueous ammonium chloride (6 ml) was added and the reaction mixture was allowed to warm to room temperature; water (15
ml) was added and was extracted with ethyl acetate (3 x 15 ml). The combined organic
extracts were washed with brine (15 ml), dried (Na2S04) and concentrated in vacuo to
give a mixture of two diasteroisomers {33 and 34} as yellow foam (0.84 g, 71%) which
was purified by flash column chromatography on silica gel, using ethyl acetate-hexane
152
-
Approach towards the synthesis of Penmacric acid Chapter 3
(40:60} as eluant to afford 33 (0.48 g, 41.3%} as viscous oil (crystallised further from
diethyl ether to a crystalline solid}, and 34 as white foam (0.21 g, 18%}.
Titanium enolate
28 (0.29 g, 1.21 mmol) was dissolved in anhydrous CH2Ch (10 ml) under nitrogen with
stirring, cooled to -78 oc and TiCI4 (1.0 M in CH2CI2, 1.32 ml, 1.32mmol} was added dropwise followed by slow addition of DIPEA (0.25ml, 1.46 mmol) after 5 min, and the
resultant deep violet enol ate solution was stirred for 1.5 h at -78 oc. Meanwhile a fresh imine 37 solution (-78°C} was prepared in anhydrous CH2Ch (6ml) as described above,
quickly added to enolate solution via cannula and the reaction mixture was stirred for
another 2 h at -78°C. The reaction mixture was then quenched with saturated aqueous
ammonium chloride (10 ml), allowed to warm to room temperature, diluted with water
(15 ml) and extracted with dichloromethane (3 x 15 ml). The combined organic extracts
were washed with brine (15 ml), dried (Na2S04), and concentrated in vacuo to give the
crude product as yellowish foam (0.37 g, 71.7%) which was purified by flash column
chromatography on silica using ethyl acetate-hexane as eluant (40:60} to give 34 as a
white foamy solid (0.32g, 62.3%} .
N-tert-para-toluenesulonylamidobenzyl benzaldimine {38)
A solution of TiCI4 (1.0 M in CH2Ch, 9.48 ml, 9.5 mmol,) was added dropwise to a stirred,
ice cooled solution of benzaldehyde (1.92 ml, 19 mmol), p-toluenesulfonamide (3.25 g,
19 mmol) and triethylamine (7.94 ml, 57 mmol) in anhydrous CH2Cb (40 ml) and the
mixture was stirred for 30 min. The titanium dioxide was removed by suction filtration
through celite and washed with CH2CI2 (20 ml). Evaporation of the solvent under
reduced pressure afforded a white solid which was broken up by refluxing in anhydrous
diethyl ether (75 ml) for 15 min. The residual triethylamine hydrochloride salt was
removed by filtration and the filtrate was concentrated under reduced pressure to
afford the crude imine. Purification by crystallization (hexane/ CH2CI2) afforded 38 as
white solid (1.76 g, 72%}.
153
-
Approach towards the synthesis of Penmacric acid Chapter 3
White solid, mp 110 ·c; 1H NMR (300 MHz, CDCI3) S 9.03 (1H, s,
CH=N}, 7.87-7.94 (4H, m, ArH), 7.59-7.64 (1H, t, J = 7.5, ArH), 7.46-
7.51 (2H, t, J = 7.3, ArH}, 7.33-7.36 (2H, d, J = 8.2, ArH), 2.44 (3H, s,
PhCH3); 13C NMR (75 MHz, CDCI3) S 170.2, 144.7, 135.0, 131.3, 129.8,
129.2, 128.1, 21.7; IR (thin film, cm-1) 1602, 1320, 1158, 1088; MS (ESI}: m/z 259, found
260[M+Ht.
Methyi(25,4S}-N-tert-butoxycarbonyl-4-[ ( GRS)-N-para-
toluenesulonylamidobenzyl]pyroglutamate (39 and 40)
Compounds 39 and 40 were obtained following the general procedure for 29, 30 & 31.
Titanium enolate
Purification by flash column chromatography on silica gel, using ethyl acetate-hexane
(40:60) as eluant separated mixture of 39 and 40 (0.526 g, 85%) together with unreacted
tosylamide. The major diastereoisomer 39 was separated and purified by repeated
recrystallisation from diethyl ether which provided distinct crystalline white solid 39
(0.142 g, 23%). The minor isomer 40 could not be obtained pure but the spectrum was
obtained by subtraction from the mixture.
H NHTs
Ph~ 6 -. 4
~ 0 N C02Me I
Methyi(25,4S)-N-tert-butoxycarbonyi-4-[(6R)-N-para-
toluenesulonylamidobenzyl]pyroglutamate (39)
White crystalline solid; mp 171-175 oc; [found: C, 59.70; H,
39
Boc 5.99; N, 5.61. C2sH3oN207S requires C, 59.75; H, 6.02; N,
5.57%]; Rt (40% EtOAc/hexane) 0.32; 1H NMR (300 MHz,
CDCI3) S 7.46-7.49 (2H, d, J 8.1 Hz, ArH), 7.09-7.17 (7H, m, ArH), 6.45-6.47 (1H, d, JNH.G
4.0 Hz, NH}, 4.40-4.44 (1H, d, h,3s 9.5 Hz, H-2), 4.33-4.36 (1H, dd, J6,NH 4.0 Hz, J6,4 6.9 Hz,
H-6), 3.71 (3H, s, C02CH3 ), 3.01-3.10 (1H, m, H-4), 2.35 (3H, s, ArCH3), 2.00-2.12 (1H, m,
H-35), 1.78-1.85 (1H, m, H-3R), 1.74 (9H, s, (CH3)3CO}; 13C NMR (75 MHz, CDCI3) S 173.0,
171.3, 148.8, 143.2, 137.2, 136.8, 129.3, 128.5, 128.1, 127.7, 127.4, 84.2, 59.0, 56.7,
154
-
Approach towards the synthesis of Penmacric acid Chapter 3
52.7, 46.7, 27.9, 25.6, 21.5; IR (thin film, cm-1) 2993, 1749, 1720, 1457, 1328, 1215,
1157, 1092; MS (ESI): m/z 502, found 525 [M+Nat; HRMS (DART): m/z calcd. for
C2oH23N20sS1 [M-CsH1002t: 403.1327; found: 403.1281; [af8o= +77.5 (c 0.6, CHCI3).
H NHTs
Ph~
h 0 N C02Me I Boc
39+40
Methyi(2S,4S)-N-tert-butoxycarbonyi-4-[(6S)-N-para-
toluenesulonylamidobenzyl]pyroglutamate (40 from 39+40)
Rt (40% EtOAc/hexane) 0.32; 1H NMR (300 MHz, CDC13) o 7.42-7.45 (2H, d, J 8.2 Hz, ArH), 7.00-7.17 (7H, m, ArH), 6.75-6.78
(1H, d, JNH.G 9.1 Hz, NH), 4.63-4.68 (1H, dd, J6,NH 9.1 Hz, J6,4 4.8
Hz, H-6), 4.13-4.17 (1H, dd, h,3s 9.1 Hz, J2,3R 2.3 Hz, H-2), 3.73 (3H, s, C02CH3), 3.16-3.24
(1H, m, H-4), 2.30 (3H, s, ArCH3), 1.79-2.12 (2H, m, H-3S+H-3R), 1.43 (9H, s, (CH3hCO);
13C NMR (75MHz, CDCI3) o 173.6, 171.2, 148.6, 142.9, 137.7, 136.4, 129.2, 128.6, 128.0, 127.9, 126.9, 84.1, 57.7, 57.0, 46.5, 27.8, 24.7, 21.4; IR (thin film, cm-1) 2933, 1749,
1720, 1457, 1327, 1263, 1214, 1156, 1092; MS (ESI): m/z 502, found 525 [M+Nat.
tert-butyl phenylsulfonylmethylcarbamate (42)
A mixture of tert-butyl carbamate (1.5 g, 12.8 mmol) and benzenesulfinic acid sodium
salt ( 4.20 g, 25.6 mmol) were suspended in a solution of methanol in water (1:2, 45 ml}
followed by the addition of 30% aqueous formalin (2.56 ml, 25.6 mmol) and formic acid
(98%, 1.5 ml). The reaction was allowed to stir for 3 days at room temperature during
which time the product precipitated as a white solid. The crystalline sulfone 42 was
filtered off with suction, washed with water and diethyl ether, redissolved in
dichloromethane, dried over Na2S04, and concentrated under reduced pressure to
afford the sulfone 42 (3.0 g, 86.4%).
White solid; mp 155-157 oc; 1H NMR (300 MHz, CDCI3) o 7.91-7.94 (1H, d, J 7.4 Hz, ArH), 7.53-7.68 (3H, m, ArH), 5.42 (1H, br, NH), 4.52-4.54
(2H, d, J 7.0 Hz, CH2), 1.26 (9H, s, (CH3hCO); 13C NMR (75 MHz, CDCI3) ()
154.0, 137.0, 134.2, 129.3, 129.1, 81.2, 62.2, 28.1; IR (thin film, cm-1)
155
-
Approach towards the synthesis of Penmacric acid Chapter 3
1703, 1477, 1448, 1421, 1364, 1291, 1142, 1087, 1007; MS (ESI): m/z 271, found 289
[M+NH4t,
Methyl (2S,4RS)-N-tert-butoxycarbonyi-4-(N-tert-
butoxycarbonylaminomethyl)pyroglutamate (44 and 45}
Lithium enolate
UHMDS (1.0 M in THF, 6.14 ml, 6.14 mmol) was added dropwise to a solution of 28 {0.65
g, 2.672 mmol) in anhydrous THF (15 ml) at -78 oc under nitrogen atmosphere with stirring. The reaction mixture was stirred for 1.2 h, a solution of sulfone 42 (0. 79g, 2.93
mmol) in THF (15 ml) was added to it, and the stirring was continued for a further 2 h at
-78 oc. The reaction was quenched with aqueous saturated ammmonium chloride solution (15 ml), allowed to warm to room temperature, diluted with water (25 ml), and
extracted with ethyl acetate (3 x 25 ml). The combined organic extracts were washed
with brine {15 ml) and dried (Na2S04). Removal of the solvent in vacuo gave the product
as a pale yellow foam (0.73 g, 74%) which was purified by flash column chromatography
on silica gel using ethyl acetate-hexane (45:65) as eluant to give 44 (0.34 g, 35%) and 45
(0.33 g, 33.2%) as viscous oils which crystallised to white solid on standing overnight.
Titanium enolate
TiCI4 {1.0 M in CH2CI 2, 3.3 ml, 3.3 mmol) was added dropwise to a solution of 28 (0.35g,
1.43 mmol) in anhydrous CH2CI 2 (10 ml) at -78 oc under nitrogen atmosphere with stirring followed after 5 mins by dropwise addition of DIPEA (0.62 ml, 3.59 mmol)
resulting into a deep violet colored solution. The reaction mixture was stirred for 1.5 h
at -78 oc and a solution of sulfone 42 (0.42 g, 1.58 mmol) in CH2CI2 (10 ml) was added (warm to dissolve). After stirring for 2 h at the same temperature, the reaction was
quenched with aqueous saturated ammonium chloride solution (12 ml) and the mixture
was allowed to warm to room temperature. Water {15 ml) was added and the product
was extracted with dichloromethane (3 x 20 ml). The combined organic extracts were
156
-
Approach towards the synthesis of Penmacric acid Chapter 3
washed with brine (10 ml), dried (Na2504) and concentrated in vacuo to yield the crude
product 44 (0.43 g, 82%) which was purified by flash column chromatography on silica
gel, using ethyl acetate-hexane (45:65) as eluant to give 44 (0.358 g, 67%) as clear oil
which crystallised on standing overnight.
6 BocHN-,,
J:'x. 0 N C02Me I Boc
44
Methyl (25,45)-N-tert-butoxycarbonyi-4-(N-tert-
butoxycarbonylaminomethyl)pyroglutamate (44)
White solid; mp 95-97 OC; [found: C, 54.88; H, 7.45; N, 7.61.
C23H32N201 requires C, 54.83; H, 7.58; N, 7.52%]; Rt (70%
EtOAc/hexane) 0.5;1H NMR {300 MHz, CDCI3) o 5.15 (1H, br, NH), 4.56-4.60 (1H, dd, h,35 8.9 Hz, h,3R 1.7 Hz, H-2), 3.78 (3H, s, C02CH3 ), 3.46-3.52
(1H, m, H-6), 3.30-3.36 (1H, m, H-6), 2. 77-2.85 (1H, m, H-4), 2.06-2.23 (2H, m, H-3R+H-
35), 1.50 {9H, s, (CH3)3CO), 1.42 (9H, s, (CH3)3CO); 13C NMR (75 MHz, CDCI3) 8 174.4,
171.6, 156.3, 83.9, 79.5, 57.0, 52.7, 42.7, 39.5, 28.3, 27.9, 25.6; IR (thin film, cm-1) 2928,
1772, 1707, 1520, 1459, 1374, 1313, 1258, 1217, 1158; MS (ESI): m/z 372, found 395
[M+Nat; HRMS (DART): m/z calcd. for C17H29N20 7 [M+Ht: 373.1974; found: 373.2010;
[a] 220= -40.2 (c 0.28, CHCI3).
6
BocHN~
0 N C~Me I
Methyl (2S,4R)-N-tert-butoxycarbonyi-4-(N-tert-
butoxycarbonylaminomethyl)pyroglutamate (45)
White solid; mp 105-107 OC; [found: C, 54.91; H, 7.53; N,
7.49. C23H32N201 requires C, 54.83; H, 7.58; N, 7.52%]; Rt
(70% EtOAc/hexane) 0.43; 1H NMR {300 MHz, CDCb) o 5.17 (1H, br, NH), 4.47-4.53 (1H, dd (unresolved), H-2}, 3.77 (3H, s, C02CH3 ), 3.46-3.52 (1H,
m, H-6), 3.30-3.38 (1H, m, H-6), 2.70-2.80 (1H, m, H-4), 2.46-2.56 (1H, m, H-3$), 1.74-
Boc
45
1.84 (1H, m, H-3R), 1.49 (9H, s, (CH3)3CO), 1.42 (9H, s, (CH3)3CO); 13C NMR (75 MHz,
CDCI3) o 174.2, 171.7, 156.3, 149.2, 84.1, 79.6, 57.4, 52.6, 43.4, 40.3, 28.4, 27.9, 25.2; IR(thin film, cm-
1) 3020, 1786, 1748, 1710, 1511, 1369, 1308, 1216, 1156; MS (ESI): m/z
372, found 395 [M+Naf; HRMS (DART): m/z calcd. for C11H29N207 [M+Ht: 373.1974;
found: 373.1982; [a] 23 o= -44.1 (c 0.2, CHCI3).
157
I
-
Approach towards the synthesis of Penmacric acid
3.7. Spectral data
J 7.5 7.0
1H NMR, 300 MHz, CD03
yHBoc
Ph:{}.
o ~ C02Me Boc 29
6.5 (d) :')5
~ ~~~§S~~B ~~~~§~~g~~
~~·~vP
5,0 4.5 -tO 3.5 3.0 :15 2.0 1.5
'l~( )~( l:i Is( '~' ):( l§n:l 11:!:1'!!"1 :;:, '-"
:!!'! !OE
\I ~ ~
13C NMR, 75 MHz, CD03
H NHBoc Ph~.
~ 0 ~ C02Me Boc
29
Figure 18. 1H-NMR of compound 29
g$~ :!33
\II
I I I I I 135 130 125 120 ll5
I I I I I I I I I U m B W U M D ~ G
Figure 19. 13C-NMR of compound 29 158
Chapter 3
?!•J,::qn:Jiti~r1' l~~~-~4( t> ,:;u;t il.~•m! ~" A~ l,&:tn~~.,.., \'l': >.!1 m V.Hc!
-
Approach towards the synthesis of Penmacric acid
~~E~~i@
~~
1.5
r~1
"' X ~
I 1 H NMR, 400 MHz, CDCI,
H Ph BocHNh o 1;-1 C02Me
Bee __;jj)
5.5 .:.s 40 .L~ .lO
I~( (~I lsl 2JJ
!:\lsi
Figure 20. 1H-NMR of compound 30
~~ s " 9!:0::: E~ ~ :! I I
"'c NMR, 75 MHz, CDCI3
BocHNh 0 1;-1 C02Me
Bee 30
., ~s~ ..,
®
~£!5 M
\V
Chapter 3
C'~trJ>:l~ ~~tt l'HUtttn :O..'a! lllll?V~,;:-~;~LNAn~.). ~~!() •
~i'!X!~
f: · lrl:1f:ll.l!~UO!': ~ta~ttnr i!f~- m:.~t.tl Oint t~.~l !ttSlr'..M ~'-"'~t ~ ~ !fa Ml ~~;;,.
;;!re'G ~~~i~ SOIJ
-
Approach towards the synthesis of Penmacric acid
I
~ I
1H NMR. 300 MHz. CDCI3
H. Ph
BocHN_:~A 0 N C02Me
I
Bee 31
;% S£$;~~ ~¥~~~~
f \~P ~1?
Chapter 3
\I\
f;.~,:,."'1~m:n'.t!t $( J.:it.t !::(" ~~- ·~~.:l';:; ~~
~ "'
J __) '-----" '------~
'--------1' ''"-----'! Ll r {
II
i.S 7.0 6.5 6.0 5.S S.O 4.5 4.0 .l5 3.0 2.5 2.0 !.5 1.0 0.5 wm
l~l I;( \§1 lsi I~( Is( l§( is( ~1~
I I \1/
13c NMR, 75 MHz, CDCI3
~h BocHN,h
0 N C02Me I
Bee 31
Figure 22. 1H-NMR of compound 31
175 170 16." !flO 15.5 150 l-t-5 '140 135 1~ 11:5 120 11.5 110 105 too 95 90 85 80 75 70 65 60 .55 50 45 .;o ~5 30 25 20 15 10 o prm
Figure 23. 13C-NMR of compound 31
160
-
Approach towards the synthesis of Penmacric acid
7.5
""
1H NMR, 300 MHz, CDCI3
Hh.co,Me BocHN 6 4
2
0 ~ C02 Me
Boc __3_2
'1.0 (..5 6.0 5.5
~~~ 5.0 3.0 2.5 2.1)
Is( 1:1 1:1
Figure 24. 1H-NMR of compound 32
\I/
170
1'c NMR, 100 MHz, CDCI3 H CO,Me
BocHNh
o ~ co2Me
Boc '----~3.2. ___ ~
I j 160 ISO 140 1:10
1 J 120 110 100 90 70 (I!
Figure 25. 13C-NMR of compound 32 161
40
1.0
1 20
Chapter 3
~l-!:t~! ftt.O ~H~~;J 'fl!:!(. :un·F~ ~~ m w~ l
t' • A::t;::.$i;i~ ~H-"~tUlt r-~u_ x~•~l~ r~ :,_:! i::S.lli"l! lft':(~t P~!ID 1~~wu ra.~ t;l~
·~ ~}!]~ s.:t~m ~l
n m t1 l ~ mt.;a~ r;w,s. MHGJ!:: lil t.:'t.Hlt.'1rt;: ~ .lJJ tl ~-£1-.~ ~ ~-~:!let" 1! ){(;.~ t ;;1 l.tw:~~.o/.:m Be l
- ... ::1W#t: ,. l.m:ut,..
: ~~i.~ ~ :
-
Approach towards the synthesis of Penmacric acid
ISO
1H NMR, 400 MHz, C6 D,;
YHBoc Meo,ch
0 J;'l C02 Me
Boc 33
7.0 (!.0 5.5 5.0 -t5 -1.!1 ]5 3.0 2.5 2.0 1.5 1.0
~~~ f:: " 5::~~ ~ ~
~~
13C N MR, 100 MHz, C60 6
H NHBoc
Me02Ch 0 N C02 Me
I
Boc 33
l:l !:l l:l 1:¥;1~1 l:l ~~~ ~~~
Figure 26. 1H-NMR of compound 33
170 160 1:«> 1.:0 no 120 110 100 90 80 70 60
Figure 27. 13C-NMR of compound 33
162
Chapter 3
'' .~; f~··
} ~:~YJ;~ ::::.: t,.~~~
~$~~~ ~.0.~ ~~
i*6.UH2t t.i.~J:~!
-
Approach towards the synthesis of Penmacric acid
7.0
\1/
1H NMR, 400 MHz, C6 D6
H co,Me
SocHW~t~
6S
o N/ co,Me I
Soc __3i
I
6.0 5.:-
ls(
I I
13C NMR, 100 MHz, ~6 tyC02Me
SocHN 'h 0 ~ C02 Me
Soc
'------~34--~
§~~§~~~gg,¥~§~~
·~~
I I I
:S.O 4.5 4.0 3.5 .J.O 2.~ ~.0 15 1.0
1~1 1~1 ~~~lsi lsi lsi ~~~
Figure 28. 1H-NMR of compound 34
~ ~ II
~~~ \
1 I I I
Chapter 3
f:· ~ J.::l(:HH~(,~ Nz#'R.Hf
""'~ i:~*:a t>M~ i~.;'
~>;:;~ s~t·~ l'!PY>:ii: :t~* n:: ~m' >e:;>;;::;';' ~
~ ;:~ ~ ~!f.Ulll'.: n:at$ ~.m~Pfl II< ~.~!l'l:J) M< . " ~ ,~.me~ ::a u~ ~~#';; ;1 ?.H'-~l u~~~~;; :.: l"Z'~
0.5
l'l.S l'iO IIi. 125 120 115 Ito lOS lt~ 9!1 I'J
-
Approach towards the synthesis of Penmacric acid
~~Ej~~;E~
\\~r;P
1H NMR, 300 MHz, CDCI3
'1.5 1.0
1~1 hsl
yHTs Phh 0 t;J C02Me
Boc 39
6.0
~~~~~~ ~
5.0 -1.5 4.0 3.5
lsl~l 1~1
~ft~~~~~~~z~~
~V!l)JJ)
:!..5 20 1.5
1~1 ~~~ lsi 1~1
Figure 30. 1H-NMR of compound 39
\I I IV\~
13C NMR, 75 MHz, CDCI3
H NHTs Phh 0 t;J C02Me
Bee
39
q~ ~ ~ " ~.~ " 'C j
fO-$:?) !
e-~ .. :·•~t.:f.lltltl (lt:t .. ' 11.:~.11:: !l'lt ;}.;! !:mill :¥,..,~ W:HO .5~
~i::;~ ~ :i'X! ti !Hl! !'::~"M ~~~li
tl "
~ itt! . .;;;~: r.:at c.~~~m i; fli }.~~}~It: il: ~.S cr t~.!$ :::w~: ~ t$,:-wt ':t m.~l Ci t.~l,t( ~ I
..,..-. .. ~!;, ....... ,.. JtZ:l i3: p; H.~~..: fll .;..re.e f'Cl 3::1).1;;~}.!.1~
fl" • 1:'-£.;.;: '>'u.w!ta S! .• )!1R. 'it ~,!~:!.lf"...::.u~-..,.,. .. ,~ U..",.'>c-T• t: ---••• r:;r~ ..s::r:~B wr: :s IOH II'.~~ nl ·•-~=-rut ~·-:3-}
~f · ~r.t 140 13~ 130 125 120 115 110 105 100 9~ 90 35 SO 75 70 (.._c; 60 55 50 45 40 .'5 ,lO 2.5 20 !;'> 10 ppm
Figure 31. 13C-NMR of compound 39 164
-
Approach towards the synthesis of Penmacric acid
§~~E~E~§~~~i~~~
~~7!JP?P
1H NMR, 300 MHz, CDCI3
yHTs Ph'h 0 1)1 C02Me
Boc
39+40
1.•.0 S.5 50 2.5 2.0 1.~
(~i~ 1~n:l ~~~~)
Figure 32. 1H-NMR of compound 39+40
\IV
1'c NMR, 75 MH2, CDC!3
H NHTs
Phh 0 1)1 C02Me
Boc
39+40
1.0
Chapter 3
..,.,..,.,..1.,.,.;.,. »> ~..-
-
Approach towards the synthesis of Penmacric acid
DEPT 135, 75 MHz, CDCI3
H NHTs Phh 0 f:' C02Me
Boc 39+40
Chapter 3
::::::, ~.,.,..).,,.;\""' 0•-N< ..... ,,...,.,.
:;~¥ ""'g·~
.~· .. ~..:rill if....
-
Approach towards the synthesis of Penmacric acid
~& ~.....;
~!:::
l I ~ . .., co -
I I
70 60 50
Figure 36. 13C-NMR of compound 44
1H NMR, 300 MHz, CDCI3
BocHNb
0 t;J C02Me Boc 45
-c ~~ ,... V"> ..... j o\
""· I I
r---r--f"'iO"'C ~r-.:·n o:'lC'IC'l
\II
Chapter 3
•t:>«>Y"'1:1"""\th J:"t
H.
-
Approach towards the synthesis of Penmacric acid Chapter 3
~ ~, c "' ~\ ,.I-t •r• ,.., :: 3 ~ 0 "' '"" .... ""1:~~ ,... ~ ::! ~o' ,... ~ «:r--v-; "' ..... "' "' ("J -:-~ ':'l I I I I I I I \II
1'c NMR, 75 MHz, CDCI3
6
Boci-IN~
0 N C02Me I
Boc 45
180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 ppm
Figure 38. 13C-NMR of compound 45
168
-
Approach towards the synthesis of Penmacric acid Chapter 3
3.8. References
1. (a) lkota N. Tetrahedron Lett. 1992, 33, 2553; (b) Rosset S.; Celerier J. P.; Lhommet
G. Tetrahedron Lett. 1991, 51, 7521.
2. (a) Baldwin J. E.; Pritchard G. J.; Williamson D. S. Tetrahedron 2000, 57, 7991; (b)
Campbell A. D.; Raynham T. M.; Taylor R. J. K. J. Chern. Soc. Perkin Trans. 1. 2000,
3194; (c) A. Rubio; J. Ezquerra and A. Escribano, Tetrahedron Lett., 1998, 39, 2171.
3. Ohta T.; Hosoi A.; Nozoe S. Tetrahedron Lett. 1988, 29, 329.
4. Ohfune Y.; Tomita M. J. J. Am. Chern. Soc. 1982, 104, 3511.
5. (a) Van Betsbrugge J.; Van Den Nest W.; Verheyden P.; Tourwe D. Tetrahedron
1998, 54, 1753; (b) Li H.; Sakamoto T.; Kikugawa Y. Tetrahedron Lett. 1997, 38,
6677.
6. Hanessian S.; McNaughton-Smith G.; Lombart H.; Lubell W. Tetrahedron 1997, 53,
12789
7. Menezes, R. F.; Zazza, C. A.; Sheu, J. and Smith, M. B. Tet. Lett. 1989, 30, 3295.
8. (a) Davies, S. G.; Doisneau, G. J. M.; Prodger, J. C. and Sanganee, H. J. Tet. Lett.
1994, 35, 2369 (b) Davies, S. G.; Doisneau, G. J. M.; Prodger, J. C. and Sanganee,
H. J. Tet. Lett. 1994, 35, 2373.
9. (a) li, H.; Sakamoto, T. and Kikugawa, Y. Tet. Lett. 1997, 38, 6677 (b) Escribano, A.;
Carreno, M. C. and Rciano, J. L. G. Tet. Lett. 1994, 53, 2053 (c) Herdeis, C.;
Hubmann, H. P. and Potter, H. Tet. Asymm. 1994, 5, 119 (d) Herdeis, C.;
Hubmann, H. P. and Potter, H. Tet Asymm. 1994, 5, 351 (e) Moody, C. M. and
Young, D. W. J. Chern. Soc. (PT-1} 1997, 3519 (f) Moody, C. M. and Young, D. W.
Tet. Lett. 1994, 35, 7277 (g) Panday, S. K.; Brunet, D. G. and Langlois, N. Tet. Lett.
1994, 35, 6673 (h) Collado, 1.; Ezquerra, J. and Pedregal, C. J. Org. Chern. 1995, 60,
5011.
10. Zhang, X.; Schmitt, A. C.; Jiang, W. Tet. Lett. 2001, 42, 5335.
11. Rosset, S.; Celerier, J. P. and lhommet, G. Tet. Lett. 1992, 51, 7521
12. Honda, T. and Kimura, M. Org. Lett. 2000, 2, 3925.
169
-
Approach towards the synthesis of Penmacric acid Chapter 3
13. (a) Marchalin, S.; Szemes, F.; Bar, N. and Decroix, B. Heterocycles 1999, 110, 8696
(b) Smith, A. l.; Williams, S. F. and Holmes, A. B. J. Am. Chern. Soc. 1988, 110,
8696 (c) Saliou, C.; Fleurant, A.; Celerier, J. P. and Lhommet, G. Tet. Lett. 1991, 32,
3365.
14. Colombo, l.; Giacomo, M. D.; Vinci, V.; Colombo, M.; Manzoni, l.; Scolastico, C.
Terahedron 2003, 59, 4501.
15. Kinoshita, A. and Mori, A. J. Org. Chern. 1996, 61, 8356.
16. Honda, T.; Namiki, H.; Nagase, H. and Mizutanu, H. Tet. Lett. 2003, 44, 3035.
17. Yoda, H.; Katoh, H.; Ugihara, Y. and Takabe, K. Tet. Lett. 2001, 42, 2509.
18. Qiao, l.; Wang, S.; George, C.; Lewin, N. E.; Blumberg, P. M. Kazikowski, A. P. J.
Am. Chern. Soc. 1998, 120, 6629.
19. Fang, F. G.; Bato, M.; Kim, G. and Danishefsky, S. Tet. Lett. 1989, 30, 3625.
20. Shimojima, Y.; Hayashi, H.; Ooka, T.; Shibukawa, M.; litaka, Y. Tet. Lett. 1982, 23,
5435.
21. Lee, M. and Lown, J. W. J. Org. Chern. 1987, 52, 5717.
22. Lee, M.; Coulter, D. M. and Lown, J. W. J. Org. Chern 1988, 53, 1855.
23. (a) Kwon, T. W.; Keusenkothen, P. F.; Smith, M. B. J. Org. Chern. 1992, 57, 6169 (b)
Keusenkothen, P. F.; Smith, M. B. J. Chern. Soc. Perkin Trans. 11994, 2485.
24. (a) lkota, N. Tet. Lett. 1992, 33, 2533 (b) lkota, N.; Nakagawa, H.; Ohno, 5.;
Noguchi, K.; Okuyama, K. Tetrahedron 1998, 54, 8985.
25. (a) lkota, N. and Hanaki, A. Chern. Pharm. Bull. 1990, 38, 2712 (b) Jkota, N. Chern.
Pharm. Bull. 1993, 41, 1717.
26. Martin, S. F.; Humphrey. J. M.; Ali, A.; Hillier, M. C. J. Am. Chern. Soc. 1999, 121,
866.
27. Hamada, Y.; Tanada, Y.; Yokokawa, F. and Shioiri, T. Tet. Lett. 1991, 32, 5983.
28. Ohta, T.; Hosoi, A. and Nozae, S. Tetra. Lett. 1998, 29, 329.
29. Hamada, Y.; Tanada, Y.; Yokokawa, F. an~ Shioiri, T. Tet. Lett. 1991, 32, 5983.
30. For a review, see: (a) Najera C.; Yus M.; Tetrahedron: Asymmetry 1999, 10, 2245;
(b) Panday S. K.; Prasad J.; Dikshit D. K. Tetrahedron: Asymmetry 2009, 1581.
170
-
Approach towards the synthesis of Penmacric acid Chapter 3
31. Welter A.; Jadot J.; Dardenne G.; Marlier M.; Casimir J. Phytochemistry 1975, 14,
1347.
32. Mbadiwe E. I. Phytochemistry 1975, 14, 1351.
33. lsichei M. 0.; Achinewhu S. C. Food Chern. 1988, 30, 83.
34. Akah P. A.; Nwambie A. I. J. Ethnopharmaco/. 1994,42, 179.
35. Dupont, L.; Dideberg, 0.; Welter, A. Acta Crystallogr., Sect. B: Struct. Sci., 1975,
31, 1018.
36. Welter, A.; Jadot, J.; Dardenne, G.; Marlier, M.; Casimir, J. Bull. Soc. Chim. Be/g.,
1975, 84, 453.
37. Anwar, M.; Bailey, J. H.; Dickinson, L. C.; Edwards, H. J.; Goswami, R.; Moloney,
M.G. Org. Biomol. Chern. 2003, 1, 2364 and references cited therein.
38. Thottathil, J. K.; Przybyla, C.; Malley, M.; Gougoutas, J. Z. Tetrahedron Lett., 1986,
27, 1533.
39. Thottathil, J. K.; Moniot, J. M.; Mueller, R. H.; Wong, M. K. Y.; Kissick, T. P. J. Org.
Chern., 1986, 51, 3140.
40. Ueda, M.; Ono, A.; Nakao, D.; Miyata, 0.; Naito, T. Tetrahedron Lett. 2007, 48,
841.
41. {a) Donohoe, T. J.; Sintim, H. 0.; Sisangia, L.; Harling, J. D. Angew. Chern., Int. Ed.
2004, 43, 2293; {b) Schumacher, K. K.; Jiang, J.; Joullie', M. M. Tetrahedron:
Asymmetry 1998, 9, 47; {c) Dormoy, J. R. Synthesis 1982, 753.
42. {a) Robinson, J. K.; Lee, V.; Claridge, T. D. W.; Baldwin, J. E.; Schofield, C. J.
Tetrahedron 1998, 54, 981; {b) Kishi, Y.; Aratani, M.; Tanino, H.; Fukuyama, T.;
Goto, T. Chern. Commun. 1972, 64.
43. Bonini, C.; Righi, G. Tetrahedron 1992, 48, 1531.
44. Berini, C.; Pelloux-Leon, N.; Minassian, F.; Denis, J. Org. Biomol. Chern. 2009, 7,
4512.
45. Bray, B. L.; Mathies, P. H.; Naef, R.; Solas, D. R.; Tidwell, T. T.; Artis, D. R.;
Muchowski, J. M. J. Org. Chern., 1990, 55, 6317-6328.
171
-
Approach towards the synthesis of Penmacric acid Chapter 3
46. Tamura, 0.; Gotanda, K.; Yoshino, J.; Morita, Y.; Terashima, R.; Kikuchi, M.;
Miyawaki, T.; Mita, N.; Yamashita, M.; Ishibashi, H.; Sakamoto, M. J. Org. Chern.,
2000, 65, 8544-8551.
47. Ganske, J. A.; Pandey, R. K.; Postich, M. J.; Smith, K. M. J. Org. Chern., 1989, 54,
4801-4807.
48. For a review, see: (a) Najera, C.; Yus, M. Tetrahedron: Asymmetry 1999, 10, 2245;
(b) Panday, S. K.; Prasad, J.; Dikshit, D. K. Tetrahedron: Asymmetry 2009, 1581.
49. Dikshit, D. K.; Panday, S. K. J. Org. Chern. 1992, 57, 1920.
50. Dikshit, D. K.; Bajpai, S. N. Tetrahedron Lett. 1995, 36, 3231.
51. Jennings, W. B.; Lovely, C. J. Tetrahedron 1991, 47, 5561.
52. Bowler, A. N.; Doyle, P. M.; Hitchcock, P. B.; Young, D. W. Tetrahedron 1997, 53,
10545.
53. Kanazawa, A. M.; Denis, J. N.; Greene, A. E. J. Org. Chern. 1994, 59, 1238.
54. Katoh, T.; Nagata, Y.; Kobayashi, Y.; Arai, K.; Minami, J.; Terashima, S. Tetrahedron
1994, 50, 6221.
55. (a) Heathcock, C. H. Aldrichimica Acta 1990, 23, 99; (b) Evans, D. A.; Howard, P.
N.; Clark, J. S.; Rieger, D. L. Tetrahedron 1992, 48, 2127; (c) Siegel, C.; Thornton, E.
R. J. Am. Chem. Soc. 1989, 111, 5722.
56. Armstrong, A.; Edmonds, I. D.; Swarbrick, M. E.; Treweeke, N. R. Tetrahedron
2005, 61, 8423.
57. Biagini, S.C. G.; Gibson, S. E.; Keen, S. P. J. Chern. Soc. Perkin Trans. 11998, 2485.
58. Wehbe, J.; Rolland, V.; Fruchier, A.; Roumestant, M. L.; Martinez, J. Tetrahedron:
Asymmetry 2004, 15, 851.
172