Parallel synthesis of novel heteroaromatic acromelic acid analogues from kainic acid

Article abstract of DOI:10.1021/jo000846l

A range of new C-4 heteroaromatic acromelic acid analogues has been synthesized in a parallel fashion from (-)-α-kainic acid 1. Protection of the amine and carboxylate groups of 1 followed by ozonolysis gave methyl ketone 8. A silyl enol ether 9, generated regiospecifically from the methyl ketone 8 using "kinetic" conditions, was brominated in situ with phenyltrimethylammonium perbromide to give the key α-bromo ketone 10. Parallel cyclization reactions of bromo ketone 10 with thioamides and thioureas were then performed. The aromatic heterocyclic derivatives 11a-d and 19 produced were deprotected to give the new kainoid amino acids 6a-d and 25 in excellent yield. Compounds 6a and 6c show strong binding to the kainate receptor. Reaction of 10 with alternative condensing agents was also briefly investigated.

Full text of DOI:10.1021/jo000846l

2588
J . Org. Chem. 2001, 66, 2588-2596
P a r a llel Syn th esis of Novel Heter oa r om a tic Acr om elic Acid
An a logu es fr om Ka in ic Acid
J ack E. Baldwin,* Andrew M. Fryer, and Gareth J . Pritchard†
The Dyson Perrins Laboratory, South Parks Road, Oxford OX1 3QY, U.K.
jack.baldwin@chem.ox.ac.uk
Received J une 1, 2000
A range of new C-4 heteroaromatic acromelic acid analogues has been synthesized in a parallel
fashion from (-)-R-kainic acid 1. Protection of the amine and carboxylate groups of 1 followed by
ozonolysis gave methyl ketone 8. A silyl enol ether 9, generated regiospecifically from the methyl
ketone 8 using “kinetic” conditions, was brominated in situ with phenyltrimethylammonium
perbromide to give the key R-bromo ketone 10. Parallel cyclization reactions of bromo ketone 10
with thioamides and thioureas were then performed. The aromatic heterocyclic derivatives 11a -d
and 19 produced were deprotected to give the new kainoid amino acids 6a -d and 25 in excellent
yield. Compounds 6a and 6c show strong binding to the kainate receptor. Reaction of 10 with
alternative condensing agents was also briefly investigated.
In tr od u ction
The kainoid family of nonproteinogenic amino acids
includes (-)-R-kainic acid (1), (-)-domoic acid (2), and
the acromelic acids A (3) and B (4) among its members
(Figure 1).1 This interesting class of compounds displays
potent biological activity, namely insecticidal,2 anthelm-
intic,3 and most significantly, potent neuroexcitatory
activity.1,4 They act as conformationally restricted ana-
logues of the neurotransmitter L-glutamic acid, the
primary excitatory neurotransmitter in the mammalian
central nervous system (CNS), which acts at a number
of different receptors.5 Kainoids show predominant activ-
ity at the kainate subclass of ionotropic glutamate
receptors and new ligands that behave selectively as
agonists or antagonists are highly sought after as tools
for neuropharmacological research into the functioning
of these receptors in the CNS.6
Several concise syntheses of the naturally occurring
kainoids and ‘unnatural’ C-4 analogues (e.g., 5a -d ) have
been carried out by others1,7 and by us.8 We have recently
reported in preliminary form a rapid route to C-4 thiazole
and aminothiazole acromelic acid analogues starting from
† Present address: Department of Chemistry, Loughborough Uni-
versity, Loughborough, Leicestershire LE11 3TU, U.K.
(1) For a comprehensive review, see: Parsons, A. F. Tetrahedron
1996, 52, 4149.
(2) Maeda, M.; Kodama, T.; Tanaka, T.; Yoshizumi, H.; Takemoto,
T.; Nomoto, K.; Fujita, T. Chem. Pharm. Bull. 1986, 34, 4892.
(3) (a) Watase, H.; Tomiie, Y.; Nitta, I. Nature (London) 1958, 181,
761. (b) Daigo, K. J . Pharm. Soc. J pn. 1959, 79, 350.
(4) (a) Meldrum, B.; Garthwaite, J . Trends Pharmacol. Sci. 1990,
11, 379. (b) Konno, K.; Shirahama, H.; Matsumoto, T. Tetrahedron Lett.
1983, 24, 939. (c) Konno, K.; Hashimoto, K.; Ohfune, Y.; Shirahama,
H.; Matsumoto, T. J . Am. Chem. Soc. 1988, 110, 4807. (d) Shirahama,
H. In Organic Synthesis in J apan Past, Present and Future; Noyori,
R., Ed.; Tokyo Kagaku Dozin Co. Ltd.: Tokyo, 1992; p 373.
(5) (a) Cantrell, B. E.; Zimmerman, D. M.; Monn, J . A.; Kamboj, R.
K.; Hoo, K. H.; Tizzano, J . P.; Pullar, I. A.; Farrell, L. N.; Bleakman,
D. J . Med. Chem. 1996, 39, 3617 and references cited therein.
(6) (a) Mayer, M. Nature 1997, 389, 542. (b) Clarke, V. R. J .; Ballyk,
B. A.; Hoo, K. H.; Mandelzys, A.; Pellizzari, A.; Bath, C. P.; Thomas,
J .; Sharpe, E. F.; Davies, C. H.; Ornstein, P. L.; Schoepp, D. D.; Kamboj,
R. K.; Collingridge, G. L.; Lodge, D.; Bleakman, D. Nature 1997, 389,
599.
F igu r e 1. Kainoid family and analogues.
commercially available (-)-R-kainic acid (1).9 Herein, we
wish to report in detail the parallel synthesis of het-
eroaromatic kainoid analogues 6a -d and approaches to
other C-4 aromatic heterocyclic kainoids.
(8) (a) Baldwin, J . E.; Bamford, S. J .; Fryer, A. M.; Rudolph, M. P.
W.; Wood, M. E. Tetrahedron 1997, 53, 5233. (b) Baldwin, J . E.;
Bamford, S. J .; Fryer, A. M.; Rudolph, M. P. W.; Wood, M. E.
Tetrahedron 1997, 53, 5255. (c) Baldwin, J . E.; Fryer, A. M.; Spyvee,
M. R.; Whitehead, R. C.; Wood, M. E. Tetrahedron 1997, 53, 5273. (d)
Baldwin, J . E.; Fryer, A. M.; Pritchard, G. J .; Spyvee, M. R.; Whitehead,
R. C.; Wood, M. E. Tetrahedron Lett. 1997, 39, 707. (e) Baldwin, J . E.;
Fryer, A. M.; Pritchard, G. J .; Spyvee, M. R.; Whitehead, R. C.; Wood,
M. E. Tetrahedron 1998, 54, 7465.
(9) Baldwin, J . E.; Fryer, A. M.; Pritchard, G. J . Bioorg. Med. Chem.
Lett. 2000, 10, 309.
(7) Maeda, H.; Kraus, G. A. J . Org. Chem. 1997, 62, 2314.
10.1021/jo000846l CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/28/2001

Acromelic Acid Analogues from Kainic Acid
J . Org. Chem., Vol. 66, No. 8, 2001 2589
Ta ble 1. P r ep a r a tion a n d Dep r otection Rea ction s of C-3
Sch em e 1. Syn th esis of Br om o Keton e 10
C-4 cis-Acr om elic Acid An a logu es
cyclized
product
deprotected
kainoid
R
yield (%)
yield (%)
Me
11a
11b
11c
11d
99
91
100
100
6a
6b
6c
6d
100
100
97
Ph
NH2
NHMe
100
unsymmetrical ketone can therefore be achieved via the
bromination of a requisite silyl enol ether.11 Treatment
of 8 with lithium hexamethyldisilylamide in tetrahydro-
furan at -78 °C in the presence of excess trimethylsilyl
chloride gave the silyl enol ether 9, which was not
isolated but treated directly with the brominating agent.
The use of NBS as brominating agent led to a mixture of
brominated products from which 10 was obtained in 42%
yield. It was gratifying, however, to find that treatment
of 9 with phenyltrimethylammonium perbromide (PTAB)
produced much better results, giving the desired bromo
ketone 10 as a single isomer in 93% yield after purifica-
tion by silica gel chromatography.
Resu lts a n d Discu ssion
Our synthetic route uses 1 as a starting material, and
our overall aim has been to convert the C-4 isopropylidine
substituent into a number of different reactive groups
from which libraries of substituted aromatic heterocycles
can be produced by standard cyclization reactions. Typi-
cal reactive groups include 1,2-dicarbonyl, 1,3-dicarbonyl,
acetylenic ketone, and R-bromo ketone functionalities
that would each undergo different cyclization reactions,
forming diverse families of C-4 heteroaromatic acromelic
acid analogues. In the present study, an R-bromo ketone
was chosen as the reactive unit for the C-4 position.
Preliminary investigation of protecting group strategies
revealed that subsequent chemistry was problematic with
methyl esters protecting the carboxylic acids. In addition,
protection of the amine as the tert-butyloxy carbamate
was found not to fully withstand the later cyclization
reactions. The more sterically hindered tert-butyl esters
were therefore chosen to protect the carboxylic acids and
the less acid-labile benzoyl group was used to protect the
amine. In a one-pot procedure 1 was esterified with
isobutylene and concentrated sulfuric acid in 1,4-dioxane,
basified with aqueous sodium hydroxide and acylated on
nitrogen using benzoyl chloride (Scheme 1). Olefin 7 was
obtained in good yield and was then treated with ozone
in methanol and dichloromethane at -78 °C. A reductive
workup using triphenylphosphine gave a high yield of
methyl ketone 8.
Bromination of methyl ketone 8 under acidic conditions
led to mixtures of brominated products and epimerization
of the C-4 stereocenter. The bromination of 8 therefore
had to be carried out using basic conditions under kinetic
control so that bromination took place on the methyl
group rather than at the C-4 ring position. Initial studies
focused on generating a kinetic enolate from 8 by treat-
ment with LiHMDS in tetrahydrofuran at -78 °C. This
enolate was then quenched at -78 °C with molecular
bromine or NBS giving disappointing yields of the bromo
ketone 10. Silyl enol ethers can be generated regioselec-
tively from unsymmetrical ketones with the appropriate
choice of conditions.10 Regiospecific bromination of an
With 10 now readily available, parallel cyclization
reactions were investigated. Our initial target C-4 het-
erocycles were thiazole and aminothiazoles, which could
be accessed by reacting 10 with thioamides and thioureas
(Hantzsch synthesis).12 Typical thioamides and thioureas
were chosen to demonstrate the feasibility of this route.
The cyclization procedure involved heating 10 with 1
equiv of the condensing agent and 1 equiv of sodium
bicarbonate in ethanol under reflux (Table 1). Cyclized
products 11a -d were obtained in excellent yield with
little or no purification necessary. Deprotection of 11a -d
was achieved by heating under reflux in 6 M hydrochloric
acid, and purification by ion-exchange chromatography
using Dowex 50WX8 removed liberated benzoic acid,
giving the free kainoid amino acids 6a -d in excellent
yields. Initially, problems were encountered with the
deprotection of the aminothiazole derivative 11d . If the
deprotection was left on for extended periods, some epim-
erization at C-4 was observed, but provided the reaction
time was approximately 5 h, hydrolysis of the benzamide
was complete before epimerization took place. This
epimerization raised concerns that the other compounds
6a -c could have epimerized during the deprotection step.
We therefore sought means of confirming that the C-4
stereochemistry was still correct and that epimerization
had not taken place to give the more thermodynamically
1
stable C-3, C-4 trans compounds. H NMR NOE experi-
ments with the deprotected compounds 6a and 6b
indicated that the stereochemistry around the pyrrolidine
ring was the desired 4S configuration (Figure 2).
Unfortunately, 6a -d could not be recrystallized suc-
cessfully for X-ray crystallographic analysis and so final
(11) Blanco, L.; Amice, P.; Conia, J . M. Synthesis 1976, 194.
(12) (a) Dickey, J . B.; Byers, J . R. Organic Syntheses; Wiley: New
York, 1943; Collect. Vol. II, p 31. (b) Metzger, J . V. In Comprehnsive
Heterocyclic Chemistry, 1st ed.; Katritzky, A. R., Rees, C. W., Eds.;
1984; Vol. 6, p 294.
(10) Corey, E. J .; Gross, A. W. Tetrahedron Lett. 1984, 25, 495.

2590 J . Org. Chem., Vol. 66, No. 8, 2001
Baldwin et al.
Ta ble 2. P r ep a r a tion a n d Dep r otection Rea ction s of C-3,
C-4 tr a n s-Acr om elic Acid An a logu es
cyclized
product
deprotected
kainoid
R
yield (%)
yield (%)
Me
16a
16b
16c
55%
97%
93%
17a
17b
17c
99%
95%
96%
NH2
NHMe
F igu r e 2. NOE experiments for 6a and 6b.
Sch em e 2. Syn th esis of Br om o Keton e 15
sets of C-4 epimers 6a , 6c, and 6d and 17a -c indicated
that the C-4 stereochemistry of 6a , 6c, and 6d was indeed
correct. We have recently noted an empirical rule for
assigning C-4 stereochemistry to both protected and
unprotected kainoid amino acids.13 When both C-4 epimers
1
are available, the rule states that in the H NMR spectra
for the pair of C-4 epimers one of the methylene protons
on the C-3 side chain of the correct 4S isomer appears at
lower chemical shift than the corresponding proton for
the undesired 4R isomer. In addition, the rule states that
the difference in chemical shift between the two indi-
vidual methylene protons for the 4S isomer is signifi-
cantly greater than the corresponding difference for the
4R isomer. This rule was in full agreement with the pairs
of epimers 6a and 17a , 6c and 17b, and 6d and 17c.
Shirahama has also reported an empirical rule concern-
ing the relative positions of the C-4 protons in pairs of
unprotected C-4 epimers, and this rule also holds for
these pairs of epimers.14
It was our aim to prepare other heterocycles from
bromo ketone 10 in addition to thiazoles and aminothia-
zoles. Cyclization reactions of 10 with benzamidine,
2-aminopyridine, and 1,2-phenylenediamine were thus
investigated (Scheme 3). Unfortunately, benzamidine
cyclized significantly more slowly with 10 than the
reactions involving thioamides and thioureas and proved
to be too basic (pKa 11.6 in water at 20 °C).15 This caused
epimerization at C-4, giving the imidazole derivative 18
in 65% yield. The cyclization with 2-aminopyridine (pKa
6.82 in water at 20 °C)15 was more promising, producing
the [1,2-a]imidazopyridine 19 in 24% yield. Some C-4
epimerization also occurred, however, and the undesired
epimer 20 was isolated in 38% yield, although supris-
ingly, this epimer was unstable and suffered decomposi-
tion before it could be fully characterized. Finally,
cyclization of 10 with 1,2-phenylenediamine (pKa 4.47 in
water at 20 °C)15 proceeded as planned, giving the
dihydroquinoxaline derivative 21 without any epimer-
confirmation of stereochemistry was obtained by synthe-
sising their C-4 epimers possessing the undesired 4R
configuration. Methyl ketone 13 was in hand from our
earlier protecting group investigations and was deliber-
ately epimerized at C-4 with DBU in toluene at room
temperature (Scheme 2). Complete epimerization could
not be facilitated even after the reaction mixture was
heated under reflux for 16 h. A 5:1 mixture of C-4 epimers
was obtained in favor of the isomer with the 4R config-
uration (Note: major isomer only shown in Scheme 2 and
reported in the Experimental Section). Separation of the
two epimers was difficult, and so the 5:1 mixture was
brominated using the same procedure as described above.
The epimeric bromides produced were more readily
separated by column chromatography, and bromo ketone
15 was obtained as a single isomer in a yield of 58% (two
steps). Cyclization reactions of 15 with thioacetamide,
thiourea, and N-methylthiourea were performed to give
the thiazole derivatives 16a-c. Deprotection was achieved
as before by refluxing 16a -c in 6 M hydrochloric acid,
and ion-exchange chromatography using Dowex 50WX8
gave the amino acids 17a -c with the 4R configuration
(13) Baldwin, J . E.; Fryer, A. M.; Pritchard, G. J . J . Org. Chem.
2001, 66, 2597.
(14) Hashimoto, K.; Konno, K.; Shirahama, H. J . Org. Chem. 1996,
61, 4685.
(15) Perrin, D. D. In Dissociation Constants of Organic Bases in
Aqueous Solution; Butterworth: London, 1965.
1
(Table 2). Comparison of the H NMR data for the two

Acromelic Acid Analogues from Kainic Acid
J . Org. Chem., Vol. 66, No. 8, 2001 2591
Sch em e 3. Rea ction s of 10 w ith Dia m in es
Sch em e 4. Dep r otection of Nitr ogen
Heter ocyclicsa
a
Reagents: (1) 6 M HCl (aq), ∆; (2) Dowex 50WX8 ion-exchange.
Ta ble 3. Ki Va lu es in µM for Com p ou n d s 6a -d a n d 5a -d
compd
Ki (µM)
compd
Ki (µM)
6a
6b
6c
6d
0.006
0.29
0.005
0.016
5a
5b
5c
5d
0.1
0.01
0.04
1.3
ization at C-4. Oxidation to the desired quinoxaline 22
did not occur under the reaction conditions but was
achieved by an aerial oxidation using 10% palladium on
carbon in refluxing ethanol. The oxidation process did,
however, cause epimerization at C-4, and the undesired
quinoxaline epimer 23 was also obtained.
Deprotection of 18, 19, 22, and 23 was carried out as
before followed by ion-exchange chromatography on
Dowex 50WX8 (Scheme 4). The C-4 imidazole derivative
24 with the undesired 4R isomer was obtained quanti-
tatively from 18, and its structure was confirmed by
X-ray crystallography.16 [1,2-a]Imidazopyridine kainoid
analogue 25 was produced in 98% yield, but deprotection
of the pair of quinoxalines 22 and 23 gave the same 6:1
ratio of C-4 epimers 26, 27 in each case (in favor of the
undesired 4R isomer). The epimerization in this particu-
lar deprotection reaction was presumably taking place
as a consequence of the inherent weak basicity of the
quinoxaline substituent (the pKa of quinoxaline itself is
0.7 in water at 20 °C).15
ment was undertaken. Compounds 6a -d were screened
against the kainate receptor for Ki values, and com-
pounds 5a -d were also screened for comparison. The
results are summarized in Table 3.
It can be seen that compounds 6a , 6c, and 6d all show
strong binding to the kainate receptor. Compounds 6a
and 6d show a stronger binding than 5b, which was
previously reported as the most active compound. The
route, reported in this paper, thus allows chemists and
neuropharmacologists to access a range of very active
acromelic acid analogues easily.
Su m m a r y
A parallel synthesis of new C-4 heteroaromatic kainoid
amino acids has been investigated. The route focused on
a key bromo ketone 10, which was efficiently synthesized
in three steps from commercially available (-)-R-kainic
acid 1. New C-4 thiazole and aminothiazole acromelic
acid analogues 6a -d were produced by standard cycliza-
tion reactions of thioamides and thioureas with 10
followed by deprotection. This process should allow the
rapid preparation of a number of related thiazole and
aminothiazole kainoid amino acids, which will be valu-
able as neuropharmacological probes. New kainoids
6a -d are currently undergoing further biological evalu-
ation, and initial results have shown that compounds 6a
and 6c are twice as active as 5b and are thus the most
Biologica l Da ta
With our target C-4 thiazole and aminothiazole ac-
romelic acid analogues in hand, initial biological assess-
(16) Full structure refinement was not carried out; a copy of the
structure is given in the Supporting Information.

2592 J . Org. Chem., Vol. 66, No. 8, 2001
Baldwin et al.
ethyl acetate (9:1 v/v) to give 8 (660 mg, 99%) as a white
potent neuroexcitatory kainoids known. Synthesis of
other C-4 heterocycles from bromo ketone 10 was also
investigated but problems with epimerization at C-4 were
encountered due to the basicity of the condensing agents
employed. The new [1,2-a]imidazopyridine kainoid ana-
logue 25 was synthesized by this route but not as
efficiently as the thiazoles and aminothiazoles. Further
work toward synthesising other reactive units at C-4 from
which other heterocycles can be produced is currently in
progress. We are also studying the use of alternative
protecting groups in the system so that milder deprotec-
tion conditions can be employed to obtain the kainoid
amino acids without C-4 epimerization. The results of
these studies will be reported in due course.
crystalline solid: mp 135-137 °C; [R]22 -12.6 (c 1.9, CHCl3);
D
IR (CHCl3) νmax 1720s, 1634s; 1H NMR (200 MHz; CDCl3)
mixture of rotamers; δ 1.28, 1.39, 1.46, 1.52 (18H, 4 × s), 2.15,
2.25 (3H, 2 × s), 2.21-2.57 (2H, complex), 2.78-3.02 (1H, m),
3.45-3.65 (1H, m), 3.67-4.13 (2H, complex), 4.22, 4.40 (1H, 2
× d, J ) 5, 5 Hz), 7.29-7.60 (5H, complex); 13C NMR (50.3
MHz; CDCl3) mixture of rotamers; δ 27.58, 27.90, 30.46, 30.72,
34.50, 34.76, 40.85, 42.97, 46.78, 49.82, 50.06, 51.65, 64.90,
66.54, 81.37, 81.47, 82.04, 82.45, 127.06, 127.35, 128.53,
130.12, 130.49, 135.91, 136.39, 170.09, 170.62, 170.96; MS
(APCI+) m/z 432 (MH+, 100).
(2S,3S,4S)-N-Ben zoyl-4-(b r om oa cet yl)-2-ter t-b u t oxy-
ca r bon yl-3-ter t-bu toxyca r bon ylm eth ylp yr r olid in e (10).
To a 1 M solution of lithium hexamethyldisilylamide (365 µL,
0.37 mmol) at -78 °C under an argon atmosphere was added
chlorotrimethylsilane (320 µL, 2.44 mmol) dropwise. A cold
(-78 °C) solution of 8 (105 mg, 0.24 mmol) in tetrahydrofuran
(1.2 mL) was then added dropwise. After being stirred for 25
min at -78 °C, the reaction mixture was warmed to 0 °C and
phenyltrimethylammonium tribromide (93 mg, 0.25 mmol) was
added. The reaction was stirred at 0 °C for 30 min and then
concentrated in vacuo. The residue was taken up into ethyl
acetate, and the organics were washed with water and sat-
urated brine. After drying (MgSO4) and removal of the solvent
in vacuo, the residue was purified by flash chromatography
on silica gel eluting with dichloromethane/ethyl acetate (9:1
v/v) to give 10 (115 mg, 93%) as a white crystalline solid: mp
159-160 °C; [R]22D +23.2 (c 1.0, CHCl3); IR (CHCl3) νmax 1732s,
1638s; 1H NMR (200 MHz; CDCl3) mixture of rotamers δ 1.29,
1.40, 1.44, 1.52 (18H, 4 × s), 2.30-2.56 (2H, complex), 2.82-
3.04 (1H, m), 3.71-4.26 (5H, complex), 4.42, 4.43 (1H, 2 × d,
J ) 5, 5 Hz), 7.30-7.61 (5H, complex); 13C NMR (50.3 MHz;
CDCl3) mixture of rotamers δ 27.64, 27.95, 34.63, 34.80, 41.18,
43.35, 47.75, 47.92, 48.19, 48.63, 50.17, 50.52, 65.16, 66.75,
81.65, 82.14, 82.55, 126.90, 127.09, 128.34, 129.98, 130.35,
135.50, 136.00, 169.66, 170.01, 170.62, 170.88, 200.21, 200.80;
MS (APCI+) m/z 512, 510 (MH+, 19 and 34); HRMS m/z calcd
for C24H3381BrNO6 (MH+) 512.1471, obsd 512.1471; HRMS m/z
calcd for C24H3379BrNO6 (MH+) 510.1491, obsd 510.1491.
(2S,3S,4S)-N-Ben zoyl-2-ter t-bu toxyca r bon yl-3-ter t-bu -
t oxyca r b on ylm et h yl-4-(2′-m et h ylt h ia zol-4′-yl)p yr r oli-
d in e (11a ). To a stirred solution of 10 (19.0 mg, 0.037 mmol)
in ethanol (1 mL) were added thioacetamide (2.8 mg, 0.037
mmol) and sodium bicarbonate (3.1 mg, 0.037 mmol). The
reaction was heated under reflux for 2 h and then concentrated
in vacuo. The residue was taken up into ethyl acetate, and
the organics were washed with saturated aqueous sodium
bicarbonate. The aqueous phase was extracted with ethyl
acetate, and the combined organics were washed with water
and saturated brine. After drying (MgSO4) and removal of the
solvent in vacuo, the residue was purified by flash chroma-
tography on silica gel eluting with dichloromethane/ethyl
acetate (9:1 v/v) to give 11a (18.0 mg, 99%) as a white
Exp er im en ta l Section
Gen er a l Meth od s. All solvents and reagents were purified
by standard techniques reported in Purification of Laboratory
Chemicals (Perrin, D. D.; Armarego, W. L. F. Purification of
Laboratory Chemicals, 3rd ed.; Pergamon Press: Oxford, 1988)
or used as supplied from commercial sources as appropriate.
Solvents were removed under reduced pressure using a water
or dry ice condenser as necessary. Flash chromatography was
carried out using Sorbsil C60 (40-63 mm, 230-40 mesh) silica
gel as stationary phase. Thin-layer chromatography was
carried out on aluminum plates precoated with Merck silica
gel 60 F254 which were visualized by quenching of UV fluo-
rescence or by staining with 10% w/v ammonium molybdate
in 2 M sulfuric acid (followed by heat) as appropriate. Other
general experimental information and spectroscopic instru-
mentation used have been described in ref 8e. 13C NMR in D2O
are referenced internally to 1,4-dioxane.
(2S,3S,4S)-N-Ben zoyl-2-ter t-bu toxyca r bon yl-3-ter t-bu -
t oxyca r b on ylm et h yl-4-isop r op ylid en ylp yr r olid in e (7).
To a solution of 1 monohydrate (300 mg, 1.29 mmol) in 1,4-
dioxane (3 mL) at 0 °C with stirring was added concentrated
sulfuric acid (0.612 mL) dropwise. Isobutylene (4.5 mL (excess))
was added, and the reaction was sealed and allowed to warm
to room temperature for 62 h. After being cooled to 0 °C, the
reaction vessel was opened and a solution of sodium hydroxide
(785 mg, 19.6 mmol) in water (4 mL) was added dropwise with
vigorous stirring. Benzoyl chloride (302 µL, 2.60 mmol) was
added, and stirring continued for 22 h at room temperature.
After removal of the solvent in vacuo, the residue was taken
up into chloroform and the organics were washed with water.
The aqueous phase was extracted with chloroform, and the
combined organics were washed with saturated brine. The
organics were dried (MgSO4) and concentrated in vacuo, and
the residue was purified by flash chromatography on silica gel
eluting with dichloromethane/ethyl acetate (9:1 v/v) to give 7
(455 mg, 82%) as a white crystalline solid: mp 114-116 °C;
1
[R]22 -39.0 (c 1.5, CHCl3); IR (CHCl3) νmax 1728s, 1630s; H
D
NMR (200 MHz; CDCl3) mixture of rotamers; δ 1.35, 1.37, 1.47,
1.52 (18H, 4 × s), 1.65, 1.77 (3H, 2 × s), 1.93-2.51 (2H,
complex), 2.69-3.17 (2H, complex), 3.43-3.96 (2H, complex),
4.21, 4.32 (1H, 2 × d, J ) 6, 3 Hz), 4.55-5.02 (2H, complex),
7.29-7.63 (5H, complex); 13C NMR (50.3 MHz; CDCl3) mixture
of rotamers; δ 21.92, 22.61, 27.64, 27.78, 27.93, 28.29, 34.20,
34.45, 41.29, 43.03, 44.56, 46.72, 47.03, 52.34, 64.25, 66.58,
81.00, 81.75, 82.16, 113.39, 114.15, 126.86, 127.28, 128.53,
129.94, 130.42, 136.24, 136.79, 140.69, 142.17, 169.84, 170.78,
171.32, 171.44; MS (APCI+) m/z 430 (MH+, 100). Anal. Calcd
for C25H35NO5: C, 69.89; H, 8.22; N, 3.26. Found: C, 69.54; H,
8.24; N, 3.12.
crystalline solid: mp 163-165 °C; [R]22 -36.9 (c 1.1, CHCl3);
D
IR (CHCl3) νmax 1732s, 1630s; 1H NMR (200 MHz; CDCl3)
mixture of rotamers δ 1.29, 1.35, 1.44, 1.52 (18H, 4 × s), 1.90-
2.57 (2H, complex), 2.64, 2.71 (3H, 2 × s), 2.90-3.09 (1H, m),
3.63-4.12 (3H, complex), 4.33, 4.36 (1H, 2 × d, J 5, 9 Hz),
6.64, 6.85 (1H, 2 × s), 7.31-7.62 (5H, complex); 13C NMR
(100.6 MHz; CDCl3) mixture of rotamers δ 19.28, 19.33, 27.74,
27.91, 28.06, 34.63, 34.85, 40.69, 42.55, 42.75, 44.72, 49.78,
54.20, 63.81, 66.19, 80.72, 80.81, 81.63, 82.09, 114.32, 114.63,
126.88, 127.24, 128.24, 128.29, 129.70, 130.10, 136.20, 153.22,
153.61, 165.90, 169.84, 170.61, 170.75, 170.85, 171.01; MS
(APCI+) m/z 487 (MH+, 100); HRMS m/z calcd for C26H35SN2O5
(MH+) 487.2267, obsd 487.2267.
(2S,3S,4S)-Acetyl-N-ben zoyl-2-ter t-bu toxyca r bon yl-3-
ter t-bu toxyca r bon ylm eth yl-4-p yr r olid in e (8). A solution
of 7 (666 mg, 1.55 mmol) in methanol (15 mL) and dichlo-
romethane (10 mL) was cooled to -78 °C, and ozone was
bubbled through this solution for 45 min. Triphenylphosphine
(447 mg, 1.71 mmol) was added, and the reaction was warmed
to room temperature and stirred for 1 h. The reaction was
concentrated in vacuo, and the residue was purified by flash
chromatography on silica gel eluting with dichloromethane/
(2S,3S,4S)-N-Ben zoyl-2-ter t-bu toxyca r bon yl-3-ter t-bu -
t oxyca r b on ylm et h yl-4-(2′-p h en ylt h ia zol-4′-yl)p yr r oli-
d in e (11b). To a stirred solution of 10 (37.0 mg, 0.073 mmol)
in ethanol (2 mL) were added thiobenzamide (10.0 mg, 0.073
mmol) and sodium bicarbonate (6.1 mg, 0.073 mmol). The
reaction was heated under reflux for 4 h and then concentrated
in vacuo. The residue was taken up into ethyl acetate, and
the organics were washed with saturated aqueous sodium

Acromelic Acid Analogues from Kainic Acid
J . Org. Chem., Vol. 66, No. 8, 2001 2593
bicarbonate. The aqueous phase was extracted with ethyl
acetate, and the combined organics were washed with water
and saturated brine. After drying (MgSO4) and removal of the
solvent in vacuo, the residue was purified by flash chroma-
tography on silica gel eluting with dichloromethane/ethyl
acetate (19:1 v/v) to give 11b (36.0 mg, 91%) as a white
the solid residue was dissolved in water (10 mL) and loaded
onto a preactivated column of ion-exchange resin (Dowex 50W-
X8 (H+ form)). After the column was flushed with water (100
mL), the compound was eluted with 2 M ammonia solution
(50 mL) and the resulting solution was evaporated in vacuo
to give 6a (10 mg, 100%) as a white waxy solid. Free amino
crystalline solid: mp 110-112 °C; [R]22 -80.0 (c 1.2, CHCl3);
acid; [R]25 +44.7 (c 0.6, H2O); IR (KBr disk) νmax 3600-
D
D
1
1
IR (CHCl3) νmax 1732brs, 1631s; H NMR (200 MHz; CDCl3)
2450brs, 1700brs, 1652brs; H NMR (500 MHz; D2O) δ 1.89
mixture of rotamers, major rotamer only assigned δ 1.43, 1.54
(2 × 9H, 2 × s), 2.05 (1H, ca. dd, J ) 17, 11 Hz), 2.62 (1H, ca.
dd, J ) 17, 8 Hz), 2.93-3.13 (1H, m), 3.72-3.91 (2H, complex),
4.06-4.15 (1H, m), 4.51 (1H, d, J ) 10 Hz), 6.84 (1H, s), 7.32-
7.63 (8H, complex), 7.92-7.99 (2H, complex); 13C NMR (100.6
MHz; CDCl3) mixture of rotamers, major rotamer assigned
only; δ 27.94, 28.07, 34.68, 42.70, 42.96, 54.67, 63.73, 80.72,
81.62, 114.92, 126.44, 127.37, 128.22, 128.93, 130.11, 133.36,
136.27, 155.05, 168.46, 169.91, 170.92, 171.17; MS (APCI+)
m/z 549 (MH+, 27); HRMS m/z calcd for C31H37SN2O5 (MH+)
549.2423, obsd 549.2423.
(1H, dd, J ) 16, 10 Hz), 2.48 (1H, dd, J ) 16, 5 Hz), 2.58 (3H,
s), 2.93-2.99 (1H, m), 3.55, 3.57 (1H, dd, J ) 12, 6 Hz), 3.71,
3.74 (1H, dd, J ) 12, 7 Hz), 3.86 (1H, dd, J ) 14, 7 Hz), 3.96
(1H, d, J ) 8 Hz), 7.02 (1H, s); 13C NMR (125.8 MHz; D2O) δ
18.32, 35.66, 41.95, 43.73, 49.03, 65.06, 117.21, 150.88, 169.23,
173.77, 177.52; MS (electrospray, positive ion) m/z 271 (MH+,
100).
(2S,3S,4S)-3-Meth ylen eca r boxy-4-(2′-p h en ylth ia zol-4′-
yl)p yr r olid in e-2-ca r boxylic Acid (6b). To 11b (32.0 mg,
0.058 mmol) was added 6 M hydrochloric acid (2 mL), and the
reaction was heated under reflux for 8 h. The solution was
cooled to room temperature and concentrated in vacuo, and
the solid residue was dissolved in water (10 mL) and loaded
onto a preactivated column of ion-exchange resin (Dowex 50W-
X8 (H+ form)). After the column was flushed with water (100
mL), the compound was eluted with 2 M ammonia solution
(50 mL), and the resulting solution was evaporated in vacuo
to give 6b (19.5 mg, 100%) as a white solid. Free amino acid:
(2S,3S,4S)-4-(2′-Am in ot h ia zol-4′-yl)-N-b en zoyl-2-ter t-
b u t oxyca r b on yl-3-ter t-b u t oxyca r b on ylm et h ylp yr r oli-
d in e (11c). To a stirred solution of 10 (50.0 mg, 0.098 mmol)
in ethanol (2.5 mL) was added thiourea (7.5 mg, 0.098 mmol)
and sodium bicarbonate (8.2 mg, 0.098 mmol). The reaction
was heated under reflux for 1 h and then concentrated in
vacuo. The residue was taken up into ethyl acetate, and the
organics were washed with saturated aqueous sodium bicar-
bonate. The aqueous phase was extracted with ethyl acetate,
and the combined organics were washed with water and
saturated brine. After drying (MgSO4), the solvent was re-
moved in vacuo to give 11c (56.0 mg, 100%) as a colorless
mp 161-165 °C; [R]25 -9.9 (c 0.4, 1 M HCl (aq)); IR (KBr
D
disk) νmax 3700-2000brs, 1721m, 1704s, 1652s; 1H NMR (200
MHz; D2O) δ 1.73 (1H, dd, J ) 17, 10 Hz), 2.46 (1H, dd, J )
17, 5 Hz), 2.79-2.95 (1H, m), 3.49, 3.55 (1H, dd, J ) 12, 4
Hz), 3.64, 3.70 (1H, dd, J ) 12, 7 Hz), 3.79-3.89 (1H, m), 4.00
(1H, d, J ) 9 Hz), 7.10 (1H, s), 7.31-7.37 (3H, complex), 7.73-
7.78 (2H, complex); 13C NMR (125.8 MHz; D2O) δ 35.67, 42.77,
44.09, 49.96, 65.35, 118.37, 127.27, 129.95, 131.35, 133.46,
153.43, 170.32, 173.92, 177.37; MS (electrospray, positive ion)
m/z 333 (MH+, 100).
gum: [R]22 -30.7 (c 1.3, CHCl3); IR (CHCl3) νmax 1732brs,
D
1626brs; 1H NMR (200 MHz; CDCl3) mixture of rotamers δ
1.29, 1.36, 1.44, 1.52 (18H, 4 × s), 2.05-2.19 (1H, m), 2.53
(1H, ca. dd, J ) 17, 5 Hz), 2.82-3.02 (1H, m), 3.53-3.73, 3.93-
4.05 (3H, complex), 4.32, 4.40 (1H, 2 × d, J ) 3, 9 Hz), 5.09,
5.12 (2H, 2 × brs), 6.03, 6.22 (1H, 2 × s), 7.35-7.60 (5H,
complex); 13C NMR (100.6 MHz; CDCl3) mixture of rotamers
δ 27.73, 27.91, 28.06, 34.51, 40.65, 42.49, 42.70, 44.57, 48.51,
53.98, 64.10, 66.22, 80.68, 81.58, 104.58, 126.86, 127.24,
128.25, 129.74, 130.11, 136.14, 149.91, 167.85, 170.01, 170.77,
171.18; MS (APCI+) m/z 488 (MH+, 100); HRMS m/z calcd for
(2S,3S,4S)-4-(2′-Am in ot h ia zol-4′-yl)-3-m et h ylen eca r -
boxyp yr r olid in e-2-ca r boxylic Acid (6c). To 11c (26 mg,
0.046 mmol) was added 6 M hydrochloric acid (2 mL), and the
reaction was heated under reflux for 12h. The solution was
cooled to room temperature and concentrated in vacuo, and
the solid residue was dissolved in water (10 mL) and loaded
onto a preactivated column of ion-exchange resin (Dowex 50W-
X8 (H+ form)). After the column was flushed with water (100
mL), the compound was eluted with 2 M ammonia solution
(50 mL) and the resulting solution was evaporated in vacuo
to give 6c (14 mg, 97%) as a beige waxy solid. Free amino
acid: [R]25D +9.5 (c 0.4, H2O); IR (KBr disk) νmax 3700-2400brs,
C
25H34SN3O5 (MH+) 488.2219, obsd 488.2219.
(2S,3S,4S)-N-Ben zoyl-2-ter t-bu toxyca r bon yl-3-ter t-bu -
t oxyca r b on ylm et h yl-4-(2′-(m et h yla m in o)t h ia zol-4′-yl)-
p yr r olid in e (11d ). To a stirred solution of 10 (51.0 mg, 0.10
mmol) in ethanol (1.5 mL) were added N-methylthiourea (9.0
mg, 0.10 mmol) and sodium bicarbonate (8.4 mg, 0.10 mmol).
The reaction was heated under reflux for 0.5 h and then
concentrated in vacuo. The residue was taken up into ethyl
acetate, and the organics were washed with saturated aqueous
sodium bicarbonate. The aqueous phase was extracted with
ethyl acetate and the combined organics washed with water
and saturated brine. After drying (MgSO4) and removal of the
solvent in vacuo, the residue was purified by flash chroma-
tography on silica gel eluting with dichloromethane/ethyl
acetate (1:1 v/v) to give 11d (50.0 mg, 100%) as a white
1
1634brs; H NMR (200 MHz; D2O) δ 1.75 (1H, dd, J ) 17, 10
Hz), 2.35 (1H, dd, J ) 17, 5 Hz), 2.64-2.82 (1H, m), 3.31-
3.48 (1H, m), 3.49-3.61 (2H, complex), 3.84 (1H, d, J 8 Hz),
6.22 (1H, s); 13C NMR (125.8 MHz; D2O) δ 36.77, 42.07, 44.20,
48.92, 65.54, 106.64, 145.31, 170.90, 174.23, 179.00; MS
(electrospray, positive ion) m/z 272 (MH+, 100).
(2S,3S,4S)-4-(2′-(Meth yla m in o)th ia zol-4′-yl)-3-m eth yl-
en eca r boxyp yr r olid in e-2-ca r boxylic Acid (6d ). To 11d (37
mg, 0.074 mmol) was added 6 M hydrochloric acid (2 mL), and
the reaction was heated under reflux for 5 h. The solution was
cooled to room temperature and concentrated in vacuo, and
the solid residue was dissolved in water (10 mL) and loaded
onto a preactivated column of ion-exchange resin (Dowex 50W-
X8 (H+ form)). After the column was flushed with water (100
mL), the compound was eluted with 2 M ammonia solution
(50 mL), and the resulting solution was evaporated in vacuo
to give 6d (21 mg, 100%) as a white waxy solid. Free amino
crystalline solid: mp 203-204 °C; [R]22 -39.9 (c 1.3, CHCl3);
D
IR (CHCl3) νmax 1732brm, 1626m; 1H NMR (200 MHz; CDCl3)
mixture of rotamers δ 1.27, 1.36, 1.44, 1.51 (18H, 4 × s), 2.04-
2.18 (1H, m), 2.53 (1H, ca.. dd, J 17, 5 Hz), 2.83-2.99 (1H,
m), 2.91, 2.93 (3H, 2 × s), 3.54-3.71 (2H, complex), 3.93-4.05
(1H, m), 4.32, 4.41 (1H, 2 × d, J ) 5, 9 Hz), 5.09, 5.29 (1H, m),
5.99, 6.20 (1H, 2 × s), 7.31-7.61 (5H, complex); 13C NMR
(100.6 MHz; CDCl3) mixture of rotamers δ 27.73, 27.94, 28.07,
31.94, 32.14, 34.58, 40.85, 42.62, 42.79, 44.64, 54.24, 64.02,
66.28, 80.59, 81.47, 102.49, 126.92, 127.33, 128.20, 128.28,
129.71, 130.06, 136.30, 150.45, 169.84, 170.51, 170.98, 171.28;
acid: [R]25 -30.6 (c 0.6, H2O); IR (KBr disk) νmax 3700-
D
2100brs, 1726m, 1708m; 1H NMR (500 MHz; D2O) δ 2.07 (1H,
dd, J 16, 10 Hz), 2.51 (1H, dd, J 16, 5 Hz), 2.93 (3H, s), 2.95-
3.04 (1H, m), 3.59, 3.62 (1H, dd, J 11, 5 Hz), 3.70-3.79 (2H,
complex), 4.04 (1H, d, J 7 Hz), 6.47 (1H, s); 13C NMR (125.8
MHz; D2O) δ 32.18, 36.94, 41.98, 44.27, 48.75, 65.63, 104.89,
144.60, 172.56, 174.15, 179.17; MS (electrospray, positive ion)
m/z 286 (MH+, 100).
MS (APCI+) m/z 502 (MH+, 40); HRMS m/z calcd for C26H36
-
SN3O5 (MH+) 502.2376, obsd 502.2376.
(2S,3S,4S)-3-Meth ylen eca r boxy-4-(2′-m eth ylth ia zol-4′-
yl)p yr r olid in e-2-ca r boxylic Acid (6a ). To 11a (18 mg, 0.037
mmol) was added 6 M hydrochloric acid (2 mL), and the
reaction was heated under reflux for 16 h. The solution was
cooled to room temperature and concentrated in vacuo, and
(2S,3S,4S)-N-ter t-Bu toxyca r bon yl-2-m eth oxyca r bon yl-
3-m e t h oxyca r b on ylm e t h yl-4-isop r op ylid e n ylp yr r oli-

2594 J . Org. Chem., Vol. 66, No. 8, 2001
Baldwin et al.
d in e (12). To methanol (5 mL) at 0 °C was added thionyl
chloride (0.63 mmol, 8.66 mmol) dropwise. After the addition
was complete, 1 monohydrate (500 mg, 2.16 mmol) was added,
and the reaction was heated at 60 °C for 16 h. After removal
of the solvent in vacuo, the white solid was recrystallized from
chloroform/diethyl ether to give (2S,3S,4S)-2-methoxycarbonyl-
3-methoxycarbonylmethyl-4-isopropylidenylpyrrolidine hydro-
chloride as a white crystalline solid. To a solution of (2S,3S,4S)-
2 -m e t h ox y ca r b on y l -3 -m e t h ox y ca r b on y l m e t h y l -4 -
isopropylidenylpyrrolidine hydrochloride (950 mg, 3.41 mmol)
in dichloromethane (6 mL) was added triethylamine (804 µL,
5.76 mmol) at room temperature under an atmosphere of
argon. A solution of di-tert-butyl dicarbonate (990 mg, 4.54
mmol) in dichloromethane (6 mL) was then added dropwise,
and the reaction was stirred at room temperature for 3 h.
4-(Dimethylamino)pyridine (10 mg) was then added, and
stirring was continued for 1 h. After removal of the solvent in
vacuo, the residue was taken up into dichloromethane and the
organics were washed with 1 M aqueous citric acid, saturated
aqueous sodium bicarbonate, and saturated brine. The organ-
ics were dried (MgSO4) and concentrated in vacuo, and the
residue was purified by flash chromatography on silica gel
eluting with dichloromethane/ethyl acetate (12:1 v/v) to give
CDCl3) mixture of rotamers δ 1.36, 1.44 (9H, 2 × s), 2.18 (3H,
s), 2.38-2.70 (2H, complex), 2.90-3.13 (2H, complex), 3.18-
3.52 (1H, m), 3.59-3.76 (1H, m), 3.65, 3.71 (2 × 3H, 2 × s),
3.93-4.02 (1H, m); 13C NMR (50.3 MHz; CDCl3) mixture of
rotamers δ 28.02, 28.17, 29.13, 30.31, 36.01, 36.48, 40.74,
41.54, 47.98, 51.76, 52.13, 52.30, 54.06, 55.07, 63.39, 63.71,
80.52, 80.66, 153.46, 171.68, 172.08, 172.31, 172.42; MS (Probe
CI (NH3)) m/z 344 (MH+, 2); HRMS m/z calcd for C16H26NO7
(MH+) 344.1709, obsd 344.1709.
(2S,3S,4R)-N-ter t-Bu toxyca r bon yl-2-m eth oxyca r bon yl-
3-m et h oxyca r b on ylm et h yl-4-(b r om oa cet yl)p yr r olid in e
(15). To a 1 M solution of lithium hexamethyldisilylamide (1.75
mL, 1.75 mmol) at -78 °C under an argon atmosphere was
added chlorotrimethylsilane (1.53 mL, 11.66 mmol) dropwise.
A cold (-78 °C) solution of 14 (400 mg, 1.17 mmol) in
tetrahydrofuran (4.4 mL) was then added dropwise. After
being stirred for 25 min at -78 °C, the reaction was warmed
to 0 °C, and then phenyltrimethylammonium perbromide (461
mg, 1.23 mmol) was added. After being stirred at 0 °C for 0.5
h, the reaction was concentrated in vacuo. The residue was
taken up into ethyl acetate, and the organics were washed with
water and saturated brine. After drying (MgSO4) and removal
of the solvent in vacuo, the residue was purified by flash
chromatography on silica gel eluting with dichloromethane/
ethyl acetate (12:1 v/v) to give 15 (285 mg, 58%) as a colorless
syrup: [R]23D -30.0 (c 1.5, CHCl3); IR (thin film) νmax 1734brs,
1694brs; 1H NMR (200 MHz; CDCl3) mixture of rotamers δ
1.39, 1.41, 1.45 (9H, 3 × s), 2.42-2.78 (2H, complex), 2.94-
3.12 (1H, m), 3.33-3.55 (2H, complex), 3.66, 3.74 (2 × 3H, 2
× s), 3.88-4.10 (3H, complex), 4.15 (1H, d, J 3 Hz); 13C NMR
(50.3 MHz; CDCl3) mixture of rotamers δ 28.02, 28.13, 34.03,
36.01, 36.45, 41.99, 42.49, 42.79, 48.02, 48.81, 49.40, 50.78,
51.12, 51.70, 51.92, 52.24, 52.39, 63.38, 63.75, 80.79, 153.26,
171.77, 171.90, 172.24, 199.87; MS (probe CI (NH3)) m/z 424,
422 (MH+, 23, 23); HRMS m/z calcd for C16H2581BrNO7 (MH+)
424.0794, obsd 424.0794; HRMS m/z calcd for C16H2579BrNO7
(MH+) 422.0814, obsd 422.0814.
(2S,3S,4R)-N-ter t-Bu toxyca r bon yl-2-m eth oxyca r bon yl-
3-m eth oxyca r bon ylm eth yl-4-(2′-m eth ylth ia zol-4′-yl)p yr -
r olid in e (16a ). To a stirred solution of 15 (48.0 mg, 0.11 mmol)
in ethanol (1.5 mL) were added thioacetamide (8.5 mg, 0.11
mmol) and sodium bicarbonate (9.6 mg, 0.11 mmol). The
reaction was heated under reflux for 4 h and then concentrated
in vacuo. The residue was taken up into ethyl acetate, and
the organics were washed with saturated aqueous sodium
bicarbonate. The aqueous phase was extracted with ethyl
acetate, and the combined organics were washed with water
and saturated brine. After drying (MgSO4), the solvent was
removed in vacuo to give a residue which was purified by flash
chromatography on silica gel (eluting with 4:1 v/v dichlo-
romethane/ethyl acetate) to give 16a (25 mg, 55%) as a pale
yellow gum: [R]23D -21.4 (c 0.7, CHCl3); IR (CHCl3) νmax 1737s,
1691s; 1H NMR (400 MHz; CDCl3) mixture of rotamers δ 1.41,
1.45 (9H, 2 × s), 2.52-2.69 (2H, complex), 2.67 (3H, s), 2.93-
2.98 (1H, m), 3.24-3.32 (1H, m), 3.57 (3H, s), 3.63-3.77 (1H,
m), 3.73, 3.75 (3H, 2 × s), 3.91-4.00 (1H, m), 4.05, 4.11 (1H,
2 × d, J 9, 9 Hz), 6.88 (1H, s); 13C NMR (100.6 MHz; CDCl3)
mixture of rotamers δ 19.16, 28.20, 28.32, 35.33, 35.57, 44.74,
44.99, 45.59, 45.99, 50.99, 51.72, 51.60, 52.02, 52.21, 63.92,
64.35, 80.33, 114.41, 114.53, 152.78, 153.02, 153.56, 166.11,
171.48, 172.54; MS (APCI+) m/z 421 (M + Na+, 32), 399 (MH+,
20); HRMS m/z calcd for C18H27SN2O6 (MH+) 399.1590, obsd
399.1590.
12 (0.671 g, 91%) as a colorless syrup: [R]23 -17.8 (c 1.2,
D
CHCl3); (lit.17 [R]25 -12.7 (c 2.1, CHCl3)); IR (CHCl3) νmax
D
1737s, 1690s; 1H NMR (300 MHz; CDCl3) mixture of rotamers
δ 1.38, 1.45 (9H, 2 × s), 1.67 (3H, s), 2.18-2.38 (2H, complex),
2.74-2.87 (1H, m), 2.93-3.03 (1H, m), 3.35-3.48 (1H, m),
3.60-3.72 (1H, m), 3.68, 3.74 (2 × 3H, 2 × s), 4.04, 4.14 (1H,
2 × d, J ) 4, 3 Hz), 4.67, 4.90 (2 × 1H, 2 × s); 13C NMR (50.3
MHz; CDCl3) mixture of rotamers δ 22.07, 22.17, 27.82, 28.05,
28.22, 32.77, 40.74, 41.72, 45.10, 45.84, 47.45, 47.71, 51.72,
52.00, 52.13, 52.27, 63.58, 63.92, 80.18, 113.28, 113.53, 141.42,
141.55, 153.86, 154.51, 172.54, 172.65, 172.93; MS (APCI+)
m/z 364 (M + Na+, 88); HRMS m/z calcd for C17H31N2O6
(MNH4+) 359.2182, obsd 359.2182.
(2S,3S,4S)-N-ter t-Bu toxyca r bon yl-2-m eth oxyca r bon yl-
3-m eth oxyca r bon ylm eth yl-4-a cetylp yr r olid in e (13). A
solution of 12 (1.200 g, 3.52 mmol) in methanol (20 mL) and
dichloromethane (10 mL) was cooled to -78 °C and ozone was
bubbled through the solution for 30 min. Triphenylphosphine
(0.93 g, 3.52 mmol) was then added, and the reaction was
warmed to room temperature and stirred for 1.5 h. The
reaction was concentrated in vacuo, and the residue was
purified by flash chromatography on silica gel eluting with
dichloromethane/ethyl acetate (9:1 v/v) to give 13 (1.208 g,
100%) as a colorless syrup: [R]23 +6.42 (c 1.1, CHCl3); IR
D
(CHCl3) νmax 1740s, 1710s, 1694s; 1H NMR (300 MHz; CDCl3)
mixture of rotamers δ 1.37, 1.43 (9H, 2 × s), 2.18 (3H, s), 2.45-
2.68 (2H, complex), 2.78-2.87 (1H, m), 2.89-2.99 (1H, m),
3.41-3.52 (1H, m), 3.58-3.77 (1H, m), 3.67, 3.73 (2 × 3H, 2 ×
s), 4.13, 4.21 (1H, 2 × d, J 6, 4 Hz); 13C NMR (50.3 MHz;
CDCl3) mixture of rotamers δ 27.86, 28.03, 28.18, 30.34, 32.56,
33.07, 40.68, 41.94, 46.34, 46.99, 50.34, 51.43, 51.43, 52.20,
52.46, 63.84, 80.55, 153.72, 154.40, 172.15, 172.35, 172.53,
172.89; MS (APCI+) m/z 366 (M + Na+, 100); HRMS m/z calcd
for C16H29N2O7 (MNH4+) 361.1975, obsd 361.1975.
(2S,3S,4R)-N-ter t-Bu toxyca r bon yl-2-m eth oxyca r bon yl-
3-m eth oxyca r bon ylm eth yl-4-a cetylp yr r olid in e (14). To a
solution of 13 (412 mg, 1.20 mmol) in toluene (7.5 mL) was
added DBU (270 µL, 1.80 mmol), and the reaction was stirred
under an atmosphere of argon for 14 h. A further portion of
DBU (270 µL, 1.80 mmol) was then added, and the reaction
was heated under reflux for 1.5 h. The solvent was removed
in vacuo, and the residue was taken up into ethyl acetate. The
organics were washed sequentially with saturated aqueous
sodium bicarbonate, water, and saturated brine and dried
(MgSO4), and the solvent was removed in vacuo to give a 5:1
mixture of 14 and 13 (403 mg, 98%) as a colorless syrup which
was used in the next reaction without further purification.
Limited spectroscopic data obtained for the major isomer 14:
IR (thin film) νmax 1746brs, 1698brs; 1H NMR (200 MHz;
(2S,3S,4R)-4-(2′-Am in oth ia zol-4′-yl)-N-ter t-bu toxyca r -
bon yl-2-m eth oxycar bon yl-3-m eth oxycar bon ylm eth ylpyr -
r olid in e (16b). To a stirred solution of 15 (49.0 mg, 0.12
mmol) in ethanol (1.5 mL) were added thiourea (8.8 mg, 0.12
mmol) and sodium bicarbonate (9.8 mg, 0.12 mmol). The
reaction was heated under reflux for 1 h and then concentrated
in vacuo. The residue was taken up into ethyl acetate, and
the organics were washed with saturated aqueous sodium
bicarbonate. The aqueous phase was extracted with ethyl
acetate, and the combined organics were washed with water
and saturated brine. After drying (MgSO4), the solvent was
removed in vacuo to give 16b (45.0 mg, 97%) as a colorless
(17) Papaioannou, D.; Sivas, M.; Kouvelas, E.; Francis, G. W.;
Aksnes, D. W. Acta Chem. Scand. 1994, 48, 831.

Acromelic Acid Analogues from Kainic Acid
J . Org. Chem., Vol. 66, No. 8, 2001 2595
gum: [R]23 -26.1 (c 1.3, CHCl3); IR (CHCl3) νmax 3496w,
and the reaction was heated under reflux for 16 h. The solution
was cooled to room temperature and concentrated in vacuo,
and the solid residue was dissolved in water (10 mL) and
loaded onto a preactivated column of ion-exchange resin
(Dowex 50W-X8 (H+ form)). After the column was flushed with
water (100 mL), the compound was eluted with 2 M ammonia
solution (50 mL) and the resulting solution was evaporated
in vacuo to give 17c (31 mg, 96%) as a beige waxy solid. Free
amino acid: [R]23D -48.9 (c 1.1, H2O); IR (KBr disk) υmax 3700-
2000brs, 1651s; 1H NMR (200 MHz; D2O) δ 2.26 (1H, ca.dd, J
15, 8 Hz), 2.48 (1H, ca.dd, J 15, 4 Hz), 2.57-2.73 (1H, m), 2.70
(3H, s), 3.13-3.38 (2H, complex), 3.47, 3.53 (1H, ca.dd, J 11,
8 Hz), 3.79 (1H, d, J 8 Hz), 6.28 (1H, s); 13C NMR (125.8 MHz;
D2O) δ 32.13, 39.97, 45.33, 45.62, 49.57, 65.63, 104.25, 146.69
and 146.86, 173.21 and173.27, 173.99, 179.45;18 MS (APCI+)
m/z 286 (MH+, 100).
D
1
3397w, 1734s, 1690brs; H NMR (200 MHz; CDCl3) mixture
of rotamers δ 1.41, 1.44 (9H, 2 × s), 2.38-2.63 (2H, complex),
2.72-2.93 (1H, m), 2.93-3.12 (1H, m), 3.54-3.93 (2H, com-
plex), 3.59, 3.60, 3.74, 3.76 (2 × 3H, 4 × s), 3.93-4.06 (1H,
m), 6.04 (1H, brs), 6.19, 6.20 (1H, 2 × s), 6.24 (1H, brs); 13C
NMR (50.3 MHz; CDCl3) mixture of rotamers δ 28.14, 28.24,
35.28, 35.45, 44.67, 45.06, 45.47, 45.90, 50.73, 51.40, 51.67,
52.13, 52.39, 63.85, 64.20, 80.37, 80.44, 104.16, 104.29, 148.52,
153.42, 154.15, 169.36, 169.58, 171.87, 173.73; MS (APCI+)
m/z 400 (MH+, 33); HRMS m/z calcd for C17H26SN3O6 (MH+)
400.1542, obsd 400.1542.
(2S,3S,4R)-N-ter t-Bu toxyca r bon yl-2-m eth oxyca r bon yl-
3-m eth oxyca r bon ylm eth yl-4-(2′-(N-m eth yla m in o)th ia zol-
4′-yl)p yr r olid in e (16c). To a stirred solution of 15 (53.0 mg,
0.13 mmol) in ethanol (1.5 mL) were added N-methylthiourea
(11.3 mg, 0.13 mmol) and sodium bicarbonate (10.6 mg, 0.13
mmol). The reaction was heated under reflux for 30 min and
then concentrated in vacuo. The residue was taken up into
ethyl acetate, and the organics were washed with saturated
aqueous sodium bicarbonate. The aqueous phase was extracted
with ethyl acetate, and the combined organics were washed
with water and saturated brine. After drying (MgSO4), the
solvent was removed in vacuo to give 16c (48.0 mg, 93%) as a
(2S,3S,4R)-N-Ben zoyl-2-ter t-bu toxyca r bon yl-3-ter t-bu -
t oxyca r b on ylm et h yl-4-(2′-p h en ylim id a zol-4′-yl)p yr r oli-
d in e (18). To a stirred solution of 10 (37.0 mg, 0.073 mmol)
in ethanol (2.5 mL) were added benzamidine hydrochloride
(11.4 mg, 0.073 mmol) and sodium bicarbonate (12.2 mg, 0.145
mmol). The reaction was heated under reflux for 24 h and then
concentrated in vacuo. The residue was taken up into ethyl
acetate, and the organics were washed with saturated aqueous
sodium bicarbonate. The aqueous phase was extracted with
ethyl acetate, and the combined organics were washed with
water and saturated brine. After drying (MgSO4) and removal
of the solvent in vacuo, the residue was purified by flash
chromatography on silica gel eluting with dichloromethane/
ethyl acetate (2:1 v/v) to give 18 (25.0 mg, 65%) as a white
colorless gum: [R]23 -22.2 (c 1.3, CHCl3); IR (CHCl3) νmax
D
1
3432w, 1738s, 1690s; H NMR (200 MHz; CDCl3) mixture of
rotamers δ 1.40, 1.42, 1.44, 1.46 (9H, 4 × s), 2.41-2.72 (2H,
complex), 2.78-3.13 (2H, 2 × m), 2.94 (3H, d, J 5 Hz), 3.52-
3.96 (2H, complex), 3.59, 3.67, 3.72, 3.73 (2 × 3H, 4 × s), 4.01
(1H, d, J 9 Hz), 5.49 (1H, brs), 6.22 (1H, s); 13C NMR (50.3
MHz; CDCl3) mixture of rotamers δ 28.12, 28.24, 32.06, 35.24,
35.46, 44.54, 45.04, 45.50, 45.89, 50.64, 51.37, 51.61, 51.98,
52.18, 64.00, 64.43, 80.20, 80.34, 102.64, 149.64, 153.50,
154.12, 171.55, 171.95, 172.82, 173.07; MS (APCI+) m/z 414
(MH+, 63); HRMS m/z calcd for C18H28SN3O6 (MH+) 414.1699,
obsd 414.1699.
crystalline solid: mp 89-91 °C; [R]22 -17.2 (c 0.8, CHCl3);
D
IR (CHCl3) νmax 3691w, 3462w, 1728brs, 1631s; 1H NMR (200
MHz; CDCl3) δ 1.39, 1.51 (2 × 9H, 2 × s), 2.51-2.73 (2H,
complex), 2.81-3.04 (1H, m), 3.20-3.41 (1H, m), 3.75-4.01
(2H, complex), 4.43 (1H, d, J ) 9 Hz), 6.88 (1H, s), 7.27-7.63
(8H, complex), 7.79-7.84 (2H, complex); 13C NMR (100.6 MHz;
CDCl3) δ 28.00, 29.65, 36.37, 42.60, 44.27, 55.17, 64.63, 81.11,
81.95, 125.35, 127.42, 128.30, 128.85, 130.45, 135.40, 146.59,
169.43, 170.75; MS (APCI+) m/z 532 (MH+, 53), 476 (100);
HRMS m/z calcd for C31H38N3O5 (MH+) 532.2811, obsd 532.2861.
(2S,3S,4R)-3-Meth ylen eca r boxy-4-(2′-m eth ylth ia zol-4′-
yl)p yr r olid in e-2-ca r boxylic Acid (17a ). To 16a (20 mg,
0.048 mmol) was added 2 M hydrochloric acid (3 mL), and the
reaction was heated under reflux for 14 h. The solution was
cooled to room temperature and concentrated in vacuo, and
the solid residue was dissolved in water (10 mL) and loaded
onto a preactivated column of ion-exchange resin (Dowex 50W-
X8 (H+ form)). After the column was flushed with water (100
mL), the compound was eluted with 2 M ammonia solution
(50 mL) and the resulting solution was evaporated in vacuo
to give 17a (13 mg, 99%) as a beige waxy solid. Free amino
(2S,3S,4S)-N-Ben zoyl-2-ter t-bu toxyca r bon yl-3-ter t-bu -
toxyca r bon ylm eth yl-4-(im id a zo[1′,2′-a ]p yr id -2′-yl)p yr r o-
lid in e (19). To a stirred solution of 10 (72.0 mg, 0.073 mmol)
in ethanol (2.5 mL) were added 2-aminopyridine (13.3 mg,
0.141 mmol) and sodium bicarbonate (11.9 mg, 0.141 mmol).
The reaction was heated under reflux for 5.5 h and then
concentrated in vacuo. The residue was taken up into ethyl
acetate, and the organics were washed with saturated aqueous
sodium bicarbonate. The aqueous phase was extracted with
ethyl acetate, and the combined organics were washed with
water and saturated brine. After drying (MgSO4) and removal
of the solvent in vacuo, the residue was purified by flash
chromatography on silica gel eluting with dichloromethane/
ethyl acetate (1:1 v/v) to give 19 (17.0 mg, 24%) as a beige
acid: [R]23 -29.3 (c 0.5, H2O); IR (KBr disk) νmax 3700-
D
2200brs, 1724m; 1H NMR (500 MHz; D2O) δ 2.44 (1H, dd, J )
16, 8 Hz), 2.54 (3H, s), 2.68 (1H, dd, J ) 16, 5 Hz), 2.71-2.77
(1H, m), 3.42-3.49 (2H, complex), 3.61-3.66 (1H, m), 3.89 (1H,
d, J ) 10 Hz), 7.10 (1H, s); 13C NMR (125.8 MHz; D2O) δ 18.47,
38.43, 45.82, 46.09, 49.91, 65.45, 117.36, 151.01, 169.85,
173.82, 177.98; MS (APCI+) m/z 271 (MH+, 100).
(2S,3S,4R)-4-(2′-Am in ot h ia zol-4′-yl)-3-m et h ylen eca r -
boxyp yr r olid in e-2-ca r boxylic Acid (17b). To 16b (44.0 mg,
0.11 mmol) was added 2 M hydrochloric acid (3 mL), and the
reaction was heated under reflux for 14 h. The solution was
cooled to room temperature and concentrated in vacuo, and
the solid residue was dissolved in water (10 mL) and loaded
onto a preactivated column of ion-exchange resin (Dowex 50W-
X8 (H+ form)). After the column was flushed with water (100
mL), the compound was eluted with 2 M ammonia solution
(50 mL) and the resulting solution was evaporated in vacuo
to give 17b (28.5 mg, 95%) as a beige waxy solid. Free amino
crystalline solid: mp 203 °C; [R]25 -50.0 (c 0.7, CHCl3); IR
D
(CHCl3) νmax 1728s; 1H NMR (400 MHz; CDCl3) mixture of
rotamers δ 1.32, 1.35, 1.43, 1.53 (2 × 9H, 4 × s), 2.03-2.46
(2H, complex), 3.02-3.17 (1H, m), 3.81-4.22 (3H, complex),
4.37, 4.44 (1H, 2 × d, J ) 7, 3 Hz), 6.73-6.80 (1H, m), 7.12-
7.20 (1H, m), 7.25-7.64 (7H, complex), 8.01, 8.08 (1H, 2 × d,
J ) 7, 7 Hz); 13C NMR (100.6 MHz; CDCl3) mixture of rotamers
δ 27.80, 27.86, 28.06, 35.02, 38.66, 40.88, 42.78, 44.51, 48.89,
53.89, 64.24, 66.50, 80.70, 81.69, 82.15, 109.48, 110.02, 112.27,
117.26, 117.36, 124.48, 124.78, 125.38, 125.59, 126.84, 127.29,
128.29, 129.72, 130.17, 136.10, 136.80, 144.31, 144.93, 169.92,
170.69, 170.98; MS (APCI+) m/z 506 (MH+, 100); HRMS m/z
calcd for C29H36N3O5 (MH+) 506.2655, obsd 506.2655.
acid: [R]23 -46.7 (c 0.8, H2O); IR (KBr disk) νmax 3600-
D
2300brs, 3427s, 3191s, 1700s; 1H NMR (200 MHz; D2O) δ 2.29
(1H, ca. dd, J 16, 8 Hz), 2.52 (1H, ca.dd, J 16, 4 Hz), 2.59-
2.73 (1H, m), 3.13-3.41 (2H, complex), 3.50, 3.57 (1H, ca. dd,
J 12, 8 Hz), 3.84 (1H, d, J 9 Hz), 6.34 (1H, s); 13C NMR (125.8
MHz; D2O) δ 39.85, 45.42, 45.86, 49.66, 65.55, 106.31, 146.82,
171.19, 174.08, 179.44; MS (APCI+) m/z 272 (MH+, 100).
(2S,3S,4R)-3-Met h ylen eca r b oxy-4-(2′-(m et h yla m in o)-
th ia zol-4′-yl)p yr r olid in e-2-ca r boxylic Acid (17c). To 16c
(47 mg, 0.11 mmol) was added 2 M hydrochloric acid (3 mL),
(2S,3S,4S)-3-Met h ylen eca r boxy-4-(im id a zo[1′,2′-a ]p y-
r id -2′-yl)p yr r olid in e-2-ca r boxylic Acid (25). To 19 (16.0
mg, 0.032 mmol) was added 6 M hydrochloric acid (3 mL), and
the reaction was heated under reflux for 7 h. The solution was
(18) Two carbon signals seen for C-2 and C-4, of 2-methylaminothia-
zole group, due to restricted rotation.

2596 J . Org. Chem., Vol. 66, No. 8, 2001
Baldwin et al.
cooled to room temperature and concentrated in vacuo, and
the solid residue was dissolved in water (10 mL) and loaded
onto a preactivated column of ion-exchange resin (Dowex 50W-
X8 (H+ form)). After the column was flushed with water (100
mL), the compound was eluted with 2 M ammonia solution
(50 mL) and the resulting solution was evaporated in vacuo
to give 25 (9.0 mg, 98%) as a beige gum. Free amino acid:
145.36, 154.53, 170.07, 170.66, 170.80; MS (APCI+) m/z 518
(MH+, 91), 406 (100); HRMS m/z calcd for C30H36N3O5 (MH+)
518.2655, obsd 518.2655.
(2S,3S,4R)-3-Meth ylen eca r boxy-4-(2′-p h en ylim id a zol-
4′-yl)p yr r olid in e-2-ca r boxylic Acid (24). To 18 (16.0 mg,
0.030 mmol) was added 6 M hydrochloric acid (2 mL), and the
reaction was heated under reflux for 9 h. The solution was
cooled to room temperature and concentrated in vacuo, and
the solid residue was dissolved in water (10 mL) and loaded
onto a preactivated column of ion-exchange resin (Dowex 50W-
X8 (H+ form)). After the column was flushed with water (100
mL), the compound was eluted with 2 M ammonia solution
(50 mL), and the resulting solution was evaporated in vacuo
to give 24 (9.5 mg, 100%) as a white solid. Free amino acid:
[R]25 +39.4 (c 0.3, H2O); IR (KBr disk) νmax 3700-2100brs,
D
1
1738m, 1716m, 1694s; H NMR (500 MHz; D2O) δ 2.03, 2.06
(1H, dd, J 15, 9 Hz), 2.41, 2.45 (1H, dd, J 15, 6 Hz), 3.16-3.22
(1H, m), 3.73, 3.77 (1H, m), 3.97, 4.00 (1H, dd, J 12, 8 Hz),
4.04-4.07 (1H, m), 4.09 (1H, d, J 6 Hz), 7.19-7.22 (1H, m),
7.65-7.71 (2H, complex), 7.87 (1H, s), 8.48 (1H, d, J 7 Hz);
13C NMR (125.8 MHz; D2O) δ 37.26, 38.76, 44.35, 48.20, 66.10,
113.51, 114.12, 116.14, 128.60, 131.58, 136.73, 143.15, 173.70,
179.21; MS (electrospray, positive ion) m/z 290 (MH+, 100).
(2S,3S,4S)-N-Ben zoyl-2-ter t-bu toxyca r bon yl-3-ter t-bu -
toxycar bon ylm eth yl-4-(qu in oxal-2′-yl)pyr r olidin e (22) an d
(2S,3S,4R)-N-Ben zoyl-2-ter t-b u t oxyca r b on yl-3-ter t-b u -
t oxyca r b on ylm et h yl-4-(q u in oxa l-2′-yl)p yr r olid in e (23).
To a stirred solution of 10 (51.0 mg, 0.073 mmol) in ethanol
(2.5 mL) were added phenylenediamine (10.8 mg, 0.10 mmol)
and sodium bicarbonate (8.4 mg, 0.10 mmol). The reaction was
heated under reflux for 7 h and then concentrated in vacuo.
The residue was taken up into ethyl acetate, and the organics
were washed with saturated aqueous sodium bicarbonate. The
aqueous phase was extracted with ethyl acetate, and the
combined organics were washed with water and saturated
brine. After drying (MgSO4) and removal of the solvent in
vacuo, the residue was redissolved in ethanol (3 mL) and 10%
palladium on charcoal (30 mg) was added. The reaction was
heated under reflux for 3 h, and the catalyst was then filtered
off and the solvent removed in vacuo. Purification by flash
chromatography on silica gel eluting with dichloromethane/
ethyl acetate (1:1 v/v) gave two close running fractions.
Fraction 1 contained 22 (26.0 mg, 50%) as a white crystalline
solid: mp 195-197 °C; [R]25D -46.3 (c 0.9, CHCl3); IR (CHCl3)
mp 240 °C dec; [R]25 -30.0 (c 0.2, 1 M HCl (aq)); IR (KBr
D
1
disk) νmax 3650-2400brs, 1652brs; H NMR (200 MHz; D2O)
δ 2.35, 2.43 (1H, dd, J 15, 8 Hz), 2.59, 2.67 (1H, dd, J 15, 4
Hz), 2.72-2.92 (1H, m), 3.40-3.58 (2H, complex), 3.65-3.80
(1H, m), 3.95 (1H, d, J 8 Hz), 7.14 (1H, s), 7.41-7.44 (3H,
complex), 7.62-7.65 (2H, complex); 13C NMR (125.8 MHz; D2O)
δ 38.85, 40.22, 45.18, 49.00, 65.02, 117.51, 123.49, 126.80,
129.73, 131.54, 132.25, 145.73, 172.78, 177.89; MS (electro-
spray, positive ion) m/z 316 (MH+, 100).
(2S,3S,4R)-3-Meth ylen eca r boxy-4-(qu in oxa l-2′-yl)p yr -
r olid in e-2-ca r boxylic Acid (26). To 22 (19 mg, 0.037 mmol)
was added 6 M hydrochloric acid (2 mL), and the reaction was
heated under reflux for 5 h. The solution was cooled to room
temperature and concentrated in vacuo, and the solid residue
was dissolved in water (10 mL) and loaded onto a preactivated
column of ion-exchange resin (Dowex 50W-X8 (H+ form)). After
the column was flushed with water (100 mL), the compound
was eluted with 2 M ammonia solution (50 mL) and the
resulting solution was evaporated in vacuo to give a 6:1
mixture of 26 and 27 (11 mg, 99%) as a beige gum. Limited
spectroscopic data was obtained for the major isomer 26: IR
(KBr disk) νmax 3700-2100brs, 1738m, 1716m, 1694s; 1H NMR
(200 MHz; D2O) δ 2.62 (1H, dd, J 15, 9 Hz), 2.84 (1H, dd, J
15, 4 Hz), 2.97-3.15 (1H, m), 3.83-3.93 (3H, complex), 4.09
(1H, d, J 9 Hz), 7.72-7.90 (2H, complex), 7.90-8.09 (2H,
complex), 8.78 (1H, s); 13C NMR (50.3 MHz; D2O) δ 36.42,
45.56, 48.77, 50.18, 64.26, 128.42, 128.85, 131.73, 132.05,
140.96, 142.11, 145.15, 154.20, 171.60, 175.42; MS (APCI+)
m/z 302 (MH+, 37), 208 (100).
1
νmax 1728s; H NMR (400 MHz; CDCl3) mixture of rotamers,
major rotamer assigned only δ 1.35, 1.54 (2 × 9H, 2 × s), 2.04
(1H, ca. dd, J ) 16, 4 Hz), 2.27 (1H, ca. dd, J ) 16, 4 Hz),
3.15-3.21 (1H, m), 3.95-4.00, 4.11-4.16 (3H, complex), 4.55
(1H, d, J ) 9 Hz), 7.34-8.12 (9H, complex), 8.61 (1H, s); 13C
NMR (100.6 MHz; CDCl3) δ 27.89, 28.06, 34.45, 43.26, 45.28,
53.85, 64.22, 81.19, 81.90, 127.23, 128.28, 128.38, 129.30,
129.53, 129.75, 130.22, 136.15, 141.52, 142.13, 145.36, 154.53,
170.07, 170.66, 170.80; MS (APCI+) m/z 518 (MH+, 91), 406
(100); HRMS m/z calcd for C30H36N3O5 (MH+) 518.2655, obsd
518.2655. Fraction 2 contained 23 (23.0 mg, 44%) as a pale
Ack n ow led gm en t. We would like to thank the
EPSRC for a studentship to A.M.F., the EPSRC mass
spectrometry service (Swansea) for high-resolution mass
spectra, and Miss Heidi Vollmer (Oxford) for X-ray
crystallographic work. We would also thank L. Hoffman-
La Roche for biological testing.
yellow gum: [R]25 +13.2 (c 1.125, CHCl3); IR (CHCl3) νmax
D
1725brs; 1H NMR (400 MHz; CDCl3) mixture of rotamers,
major rotamer assigned only δ 1.23, 1.55 (2 × 9H, 2 × s), 2.54-
2.59 (1H, m), 2.63-2.68 (1H, m), 3.23-3.31 (1H, m), 3.71-
3.79 (1H, m), 3.92-3.96 (1H, m), 4.23 (1H, t, J ) 11 Hz), 4.56
(1H, d, J ) 10 Hz), 7.36-7.44 (3H, complex), 7.63-7.65 (2H,
complex), 7.72-7.80 (2H, complex), 8.06-8.09 (2H, complex),
8.73 (1H, s); 13C NMR (100.6 MHz; CDCl3) δ 27.89, 28.06,
34.45, 43.26, 45.28, 53.85, 64.22, 81.19, 81.90, 127.23, 128.28,
128.38, 129.30, 129.53, 129.75, 130.22, 136.15, 141.52, 142.13,
Su p p or t in g In for m a t ion Ava ila b le: Copies of the
1HNMR or 13CNMR spectra for compounds 12, 13, 8, 10, 11a -
d , 6a -d , 15, 16a -c, 17a -c, 18, 24, 25, 22, 23, 19, and 26/27,
as well as an X-ray structure for 18. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O000846L