Tandem wittig - Ene reaction approach to kainic acid

Article abstract of DOI:10.1021/jo900196t

The first example of a tandem Wittig - intramolecular ene reaction approach and its application toward the synthesis of kainic acid is reported. The synthetic pathway involves conversion of prenyl bromide into phosphorane 3, followed by one-pot Wittig ole

Full text of DOI:10.1021/jo900196t

study of neurological disorders such as epilepsy,4 Alzheimer’s
disease,5 Huntington’s chorea,6 and so forth.
Tandem Wittig-Ene Reaction Approach to
Kainic Acid
Kainic acid is an amino acid with three contiguous stereogenic
centers in the pyrrolidine ring. Among these, the C-2, C-3
arrangement is trans while the C-3, C-4 substituents are in a
thermodynamically less favorable cis configuration, a factor
implicated in its interesting biological properties.7 The increasing
worldwide8 demand and the challenging cis-3,4 stereochemistry
of this molecule have led to the development of several synthetic
strategies9 including the first asymmetric synthesis by Oppolzer
and Thirring10 using a stereocontrolled intramolecular ene
reaction.
Mahesh S. Majik,† Peruninakulath S. Parameswaran,‡ and
Santosh G. Tilve*,†
Department of Chemistry, Goa UniVersity, Taleigao Plateau,
Goa 403 206, India, and National Institute of Oceanography,
Dona Paula, Goa 403 004, India
stilVe@unigoa.ac.in
Continuing our interest in the synthesis of marine natural
products and other biologically active compounds,11 we herein
report a facile synthesis of pyrrolidone 2, a key intermediate in
the total synthesis12 of (-)-R-kainic acid 1. The preparation of
compound 2, which has substituents at the C-3 and C-4 positions
in the desired cis geometry, has been achieved using our newly
developed tandem Wittig-intramolecular ene reaction.
In our retrosynthetic analysis, compound 2 was envisioned
to result from phosphorane 3 via a tandem Wittig-ene reaction.
The phosphorane 3, in turn, could be obtained from prenyl
bromide (Scheme 1).
ReceiVed January 29, 2009
Thus, N-alkylation of benzylamine with prenyl bromide in
the presence of K2CO3 followed by treatment of monoalkylated
benzylamine with bromoacetyl bromide yielded N,N-disubsti-
tuted bromoacetamide 5a. Reaction of 5a with PPh3 afforded
the corresponding Wittig salt, which on deprotonation using
NaOH provided the required phosphorane 3a in good yield
(Scheme 2). With a sufficient amount of phosphorane 3a in
hand, our next plan was to prepare the pyrrolidine skeleton.
Toward this end, phosphorane 3a was refluxed with glyoxalic
acid in different solvents. As expected, two reactions, that is,
the Wittig reaction and the intramolecular ene reaction, took
place in a tandem fashion, yielding the desired product 6a along
with its thermodynamically more stable, trans analogue 7a in
varying proportions (Scheme 3 and Table 1).
The first example of a tandem Wittig-intramolecular ene
reaction approach and its application toward the synthesis
of kainic acid is reported. The synthetic pathway involves
conversion of prenyl bromide into phosphorane 3, followed
by one-pot Wittig olefination and an ene reaction with
glyoxalic acid to give the cis fused pyrrolidine skeleton of
kainic acid.
(4) Sperk, G. Prog. Neurobiol. (Oxford, U.K.) 1994, 42, 1.
(5) (a) Mohmmad, A.; Sultana, R.; Keller, J.; St. Clair, D.; Markesbery, W.;
Butterfield, D. J. Neurochem. 2006, 96, 1322. (b) Goodenough, S.; Schleusner,
D.; Pietrzik, C.; Skutella, T.; Behl, C. Neuroscience 2005, 132, 581.
(6) (a) Coyle, J. T.; Schwarcz, R. Nature (London, U.K.) 1976, 263, 244.
(b) McGeer, E. G.; McGeer, P. L. Nature (London, U.K.) 1976, 263, 517.
(7) (a) Horikawa, M.; Shima, Y.; Hashimoto, K.; Shirahama, H. Heterocycles
1995, 40, 1009. (b) Hashimoto, K.; Horikawa, M.; Ishida, M.; Shinozaki, H.;
Shirahama, H. Bioorg. Med. Chem. Lett. 1992, 2, 743. (c) Shirahama, H. In
Organic Synthesis in Japan Past, Present and Future; Noyori, R., Ed.; Tokyo
Kagaku Dozin Co. Ltd.: Tokyo, 1992; p 373.
The kainoid group of nonproteinogenic pyrrolidine dicar-
boxylic acids has attracted considerable interest from synthetic
chemists because of its varied neuropharmacological properties
as well as its unique and challenging structural features.1 (-)-
R-Kainic acid 1, isolated from Digenea simplex2 and several
other red algae,3 displays potent neuroexcitatory activity in the
mammalian central nervous system and is widely used in the
(8) (a) Tremblay, J.-F. Chem. Eng. News 2001, 29, 19. (b) Tremblay, J.-F.
Chem. Eng. News 2000, 6, 131. (c) Tremblay, J.-F. Chem. Eng. News 2000, 3,
14.
(9) For very recent syntheses, see: (a) Tomooka, K.; Akiyama, T.; Man, P.;
Suzuki, M. Tetrahedron Lett. 2008, 49, 6327. (b) Sakaguchi, H.; Tokuyama,
H.; Fukuyama, T. Org. Lett. 2008, 10, 1711. (c) Jung, Y. C.; Yoon, C. H.; Turos,
E.; Soo Yoo, K.; Jung, K. W. J. Org. Chem. 2007, 72, 10114. (d) Thuong, M.;
Sottocornola, S.; Prestat, G.; Broggini, G.; Madec, D.; Poli, G. Synlett 2007,
1521. (e) Sakaguchi, H.; Tokuyama, H.; Fukuyama, T. Org. Lett. 2007, 10, 1635.
(10) Oppolzer, W.; Thirring, K. J. Am. Chem. Soc. 1982, 104, 4978.
(11) (a) Patre, R.; Gawas, S.; Sen, S.; Parameswaran, P. S.; Tilve, S. G.
Tetrahedron Lett. 2007, 48, 3517. (b) Parvatkar, P.; Parameswaran, P. S.; Tilve,
S. G. Tetrahedron Lett. 2007, 48, 7870. (c) Majik, M. S.; Shet, J. B.; Tilve,
S. G.; Parameswaran, P. S. Synthesis 2007, 663. (d) Shet, J.; Desai, V.; Tilve,
S. G. Synthesis 2004, 1859.
† Goa University.
‡ National Institute of Oceanography.
(1) (a) Moloney, M. G. Nat. Prod. Rep. 2002, 19, 597. (b) Parsons, A. F.
Tetrahedron 1996, 52, 4149. (c) Hollmann, M.; Heinemann, S. Annu. ReV.
Neurosci. 1994, 17, 31. (d) MacGeer, E. G.; Olney, J. W.; MacGeer, P. L. Kainic
Acid as a Tool in Neurobiology; Raven: New York, 1978.
(2) Murakami, S.; Takemoto, T.; Shimizu, Z. J. Pharm. Soc. Jpn. 1953, 73,
1026.
(3) Impellizzeri, G.; Mangiafico, S.; Oriente, G.; Piateli, M.; Sciuto, S.;
Fattorusso, E.; Magno, S.; Santacrore, C.; Sica, D. Phytochemistry (ElseVier)
1975, 14, 1549.
(12) Xia, Q.; Ganem, B. Org. Lett. 2001, 3, 485.
10.1021/jo900196t CCC: $40.75
Published on Web 04/07/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 3591–3594 3591

TABLE 1. Tandem Wittig-Intramolecular Ene Reaction
SCHEME 1. Retrosynthetic Analysis Depicting the Tandem
Wittig-Intramolecular Ene Reaction
entry substrate (R)
conditions
products ratioa (% yield)
1.
2.
3.
4.
H
H
H
OMe
250 °C, PhOPh, 4 h
6a:7a
1:7 (40)
20:1 (60)
20:1 (58)
5:1 (65)
110 °C, toluene, 24 h 6a:7a
140 °C, xylene, 24 h 6a:7a
110 °C, toluene, 24 h 6b:7b
a The ratio of diastereomers was calculated on the basis of the 1H
NMR.
SCHEME 4. Synthesis of Pyrrolidone
SCHEME 2. Synthesis of Phosphorane
propenyl methyl peaks of cis and trans isomers (6a and 7a)
appear at δ 1.46 (s) and 1.70 (s), respectively, in their 1H NMR
spectra. Additional proof is provided by the observation that
one of the C-3 side chain methylene protons appears signifi-
cantly upfield (δ 2.43) in the cis as compared (δ 2.60) to the
trans isomer.13 When the reaction was carried out in refluxing
toluene or xylene (24 h), the cis/trans ratio was found to be
1
20:1, as indicated by H NMR spectra of the crude products
(entries 2 and 3, respectively). These results indicated a possible
cis to trans thermally induced isomerization in diphenyl ether
(bp 250 °C).
To complete the formal synthesis of the kainic acid, removal
of the benzyl group in 6a was necessary. However, debenzy-
lation using the reported method14 failed in our hands to provide
the desired amide 2. Subsequently, the modified phosphorane
3b was prepared (Scheme 2), which, upon treatment with
glyoxalic acid in refluxing toluene, provided 6b (entry 4). CAN
oxidation of 6b resulted in simultaneous deprotection of the
PMB group and esterification of the carboxylic acid, giving
methyl ester 2a in good yield (95%). The Ganem’s intermediate,
ethyl ester 2b, was obtained in 68% yield (Scheme 4). The
spectral data of 2b were identical to those reported in literature.12
The above one-pot deprotection and esterification did not affect
the stereochemistry of C-3, C-4.
SCHEME 3. Tandem Wittig-Intramolecular Ene Reaction
The synthesis of pyrrolidone 2b constitutes a formal synthesis
of kainic acid. The overall yield of the five-step synthesis of
pyrrolidone 2b from prenyl bromide is 25% and is comparable
with the literature procedure, that is, 10% in seven steps9d from
chlorosulfone and 39% in four steps12 from prenylamine.
In conclusion, the present work demonstrates the feasibility
and synthetic utility of a tandem Wittig-ene sequence for the
assembly of cis fused 3,4-disubstituted pyrrolidone 6. The
conversion of 6b to Ganem’s advanced intermediate 2b
constitutes a formal synthesis of (()-kainic acid.
(13) Baldwin, J. E.; Fryer, A. M.; Pritchard, G. J. J. Org. Chem. 2001, 66,
2597.
(14) Bull, S. D.; Davies, S. G.; Fenton, G.; Mulvaney, A. W.; Prasad, R. S.;
Smith, D. A. Chem. Commun. 2000, 337.
With diphenyl ether as the refluxing solvent (4 h) the products
6a and 7a were obtained in the ratio 1:7. The stereochemical
assignments were facilitated by the observation that the iso-
3592 J. Org. Chem. Vol. 74, No. 9, 2009

3.91 [4.16] (d, J ) 6.9 Hz, 2H), 4.38 [4.81] (s, 2H), 4.97 [5.05] (t,
J ) 6.6 Hz, 1H), 6.76 [6.82] (d, J ) 8.4 Hz, 2H), 6.94 [7.11] (d,
J ) 8.4 Hz, 2H), 7.60-7.85 (m, 15H). 13C NMR (CDCl3, 75 MHz):
δ 18.0 [17.8], 25.7 [25.6], 32.6, 44.1 [46.6], 48.2 [50.4], 55.3, 113.9
[114.2], 118.5 [119.0], 119.1, 119.3, 120.2 [120.3] 127.9 [129.2],
128.6 [128.5], 129.8, 129.9, 130.0, 133.6, 133.7, 133.8, 134.4, 137.3
[137.4], 158.9, 164.0 [164.2]. HRMS: m/z [M + H]+ calcd for
C33H35NO2P, 508.2405; found, 508.2401.
General Procedure for Preparation of N-Protected 2-Pyrroli-
done (6): To a solution of 1.2 equiv of phosphorane 3 in dry toluene
(30 mL) was added 1 equiv of glyoxalic acid (50% aq soln), and
the mixture was stirred at room temperature for 30 min. The reaction
mixture was refluxed in a Dean-stark equipped flask for 24 h. After
the reaction was over, it was cooled to room temperature, NaHCO3
(20 mL) was added, and then the mixture was washed with Et2O
(3 × 20 mL). The aqueous layer was neutralized with 2 N HCl (30
mL) and extracted with Et2O (3 × 20 mL). A combined organic
phase was dried over anhyd Na2SO4 and concentrated under reduced
pressure, and recrystallizaton using hexanes/EtOAc (7:3) afforded
the desired product 6.
Experimental Section
General Remarks: Column chromatography was performed by
using Merck silica gel 60/120 mesh size. H (300 MHz) and 13C
1
(75 MHz) NMR spectra were recorded on a Bruker 300 instrument.
Chemical shifts are expressed in δ relative to tetramethylsilane
(TMS), and the coupling constant J is given in Hz. Chemical shifts
within square brackets give the values of the amide torsion isomer.
General Procedure for Preparation of N,N-Disubstituted Bro-
moacetamide (5): To a stirred solution of benzylamine or p-methoxy
benzylamine (3 equiv) and K2CO3 (1 equiv) in anhyd CH3CN (10
mL) was added a solution of prenyl bromide (1 equiv) in CH3CN
(2 mL) over a period of 10 min in an ice cold water bath. The
reaction mixture was stirred for 1 h at room temperature and then
concentrated under reduced pressure. Purification of residue by
column chromatography on silica gel (hexanes/EtOAc ) 7:3)
afforded N-prenyl benzylamine (the yield of product was calculated
on the basis of the recovery of starting benzylamine). To a stirred
solution of N-prenyl benzylamine (1 equiv) and K2CO3 (2 equiv)
in CHCl3 (20 mL) was added a solution of bromoacetyl bromide
(1.2 equiv) in CHCl3 (1 mL) at 0 °C over a period of 10 min. The
reaction mixture was then stirred for 1 h at room temperature and
diluted with water (20 mL), and product was extracted with CHCl3
(3 × 20 mL). The organic phase was washed with H2O (2 × 20
mL), followed by NaHCO3 (2 × 30 mL), dried over anhyd Na2SO4,
filtered, and concentrated in vacuum. Purification of residue by
column chromatography on silica gel (hexanes/EtOAc ) 7:3)
afforded the desired product 5.
N-Benzyl-N-prenyl-2-bromoacetamide (5a): Yield 65% (2 steps);
light yellow thick oily compound. IR (ν max): 1647 cm-1. 1H NMR
(CDCl3, 300 MHz): δ 1.60 [1.53] (s, 3H), 1.73 [1.71] (s, 3H), 3.87
[4.01] (d, J ) 6.6 Hz, 2H), 3.91 [3.84] (s, 2H), 4.58 [4.55] (s, 2H),
5.11-5.16 (m, 1H), 7.16-7.39 (m, 5H). 13C NMR (CDCl3, 75
MHz): δ 17.8, 25.6, 26.3 [26.5], 45.7 [43.5], 48.3 [50.8], 119.3
[118.5], 126.3 [127.3], 127.7 [127.9], 128.5 [128.9], 136.8 [136.2],
137.2, 166.8. HRMS: m/z [M + Na]+ calcd for C14H18NOBrNa,
318.0469; found, 318.0474.
N-Benzyl-2-pyrrolidone (6a): Yield 60%; white crystalline solid,
1
mp 113-114 °C. IR (ν max): 3485-2289, 1739, 1639 cm-1. H
NMR (CDCl3, 300 MHz): δ 1.48 (s, 3H), 2.47 (dd, J ) 4.5 Hz,
16.2 Hz, 1H), 2.71 (dd, J ) 8.7 Hz, 16.2 Hz, 1H), 3.10-3.22 (m,
3H), 3.51-3.56 (m, 1H), 4.50 (s, 2H), 4.75 (s, 1H), 4.85 (s, 1H),
7.29-7.38 (m, 5H). 13C NMR (CDCl3, 75 MHz): δ 19.7, 31.8, 41.1,
42.3, 47.2, 49.6, 115.6, 128.0, 128.7, 128.8, 135.3, 142.2, 175.0,
175.4. HRMS: m/z [M + Na]+ calcd for C16H19NO3Na, 296.1263;
found, 296.1253.
N-(p-Methoxy)benzyl-2-pyrrolidone (6b): Yield 65%; white
crystalline solid, mp 103-104 °C. IR (ν max): 3600-2245, 1722,
1645 cm-1. 1H NMR (CDCl3, 300 MHz): δ 1.46 (s, 3H), 2.39 (dd,
J ) 6.6 Hz, 17.1 Hz, 1H), 2.79 (dd, J ) 5.4 Hz, 17.4 Hz, 1H),
3.09-3.14 (m, 3H), 3.45-3.48 (m, 1H), 3.80 (s, 3H), 4.37 (d, J )
14.4 Hz, 1H), 4.45 (d, J ) 14.1 Hz, 1H), 4.72 (s, 1H), 4.81 (s,
1H), 6.87 (d, J ) 8.4 Hz, 2H), 7.19 (d, J ) 8.4 Hz, 2H). 13C NMR
(CDCl3, 75 MHz): δ 19.7, 31.5, 41.2, 42.2, 46.5, 49.4, 55.2, 114.2,
115.5, 127.4, 130.0, 142.3, 159.3, 175.1, 175.5. HRMS: m/z [M +
Na]+ calcd for C17H21NO4Na, 326.1368; found, 326.1365.
Preparation of N-Benzyl-2-pyrrolidone (7a): To a solution of
phosphorane (0.332 g, 0.87 mmol) 3a in dry diphenyl ether (20
mL) was added glyoxalic acid (0.128 g, 0.87 mmol, 50% aq soln),
and the mixture was stirred at room temperature for 30 min. The
reaction mixture was refluxed for 4 h. After the reaction was over,
it was cooled to room temperature, NaHCO3 (20 mL) was added,
and then the mixture was washed with Et2O (3 × 20 mL). The
aqueous layer was neutralized with 2 N HCl (30 mL) and extracted
with Et2O (3 × 20 mL). The combined organic phases were dried
over anhyd Na2SO4 and concentrated under reduced pressure to
give light yellow color thick liquid 7a (0.095 g, 40%). IR (ν max):
3485-2289, 1739, 1639 cm-1. 1H NMR (CDCl3, 300 MHz): δ 1.70
(s, 3H), 2.64 (dd, J ) 4.8 Hz, 16.2 Hz, 2H), 2.74-2.83 (m, 1H),
2.89-2.93 (m, 1H), 3.10-3.16 (m, 1H), 3.30-3.36 (m, 1H), 4.42
(d, J ) 14.7 Hz, 1H), 4.57 (d, J ) 14.7 Hz, 1H), 4.85 (s, 1H), 4.87
(s, 1H), 7.24-7.36 (m, 5H). 13C NMR (CDCl3, 75 MHz): δ 19.2,
34.7, 41.7, 46.4, 47.0, 49.5, 114.0, 127.9, 128.1, 128.7, 128.8, 128.9,
135.5, 142.4, 174.3, 175.7. HRMS: m/z [M + Na]+ calcd for
C16H20NO3NNa, 296.1263; found, 296.1260.
N-(p-Methoxy)benzyl-N-prenyl-2-bromoacetamide (5b): Yield
66% (2 steps); light yellow thick oily compound. IR (ν max): 1647
1
cm-1. H NMR (CDCl3, 300 MHz): δ 1.62 [1.56] (s, 3H), 1.75
[1.73] (s, 3H), 3.80 [3.82] (s, 3H), 3.91 [3.88] (s, 2H), 3.87 [3.99]
(d, J ) 6.9 Hz, 2H), 4.52 [4.49] (s, 2H), 5.05-5.20 (m, 1H), 6.86
[6.89] (d, J ) 8.4 Hz, 2H), 7.18 [7.13] (d, J ) 8.4 Hz, 2H). 13C
NMR (CDCl3, 75 MHz): δ 17.9, 25.7, 26.5, 45.5 [43.3], 47.8 [50.3],
55.2, 114.0 [114.3], 119.5 [118.6], 127.7 [129.4], 128.9 [128.0],
136.7 [137.1], 159.0 [159.2], 166.8. HRMS: m/z [M + Na]+ calcd
for C15H20NO2BrNa, 348.0575; found, 348.0566.
General Procedure for Preparation of Phosphorane (3): To a
stirred solution of PPh3 (1.1 equiv) in dry benzene (20 mL) was
added N,N-disubstituted bromoacetamide 5 (1 equiv), and the
solution was stirred at room temperature for 8 h. Water (40 mL)
was added to the reaction mixture, and the mixture was washed
with benzene (3 × 30 mL). Benzene (50 mL) was added to aqueous
layer followed by 2 N NaOH with constant shaking to the
phenolphthalein end point. The benzene layer was dried over anhyd
Na2SO4 and concentrated to give a thick liquid 3.
N-Prenyl-N-benzyl-2-[triphenylphosphoranylidene] Acetamide
(3a): Yield 85%; yellow color thick liquid. IR (ν max): 1640 cm-1
.
1H NMR (CDCl3, 300 MHz): δ 1.52 [1.48] (s, 3H), 1.66 [1.65] (s,
3H), 2.09 (d, J ) 12.6 Hz, 1H), 3.77 [3.99] (d, J ) 6.6 Hz, 2H),
4.50 [4.41] (s, 2H), 5.05-5.09 [5.10-5.15] (m, 1H), 7.10-7.51
(m, 20H). 13C NMR (CDCl3, 75 MHz): δ 17.8, 25.6, 29.6, 45.6
[42.6], 50.8 [47.7], 119.6, 126.2, 128.3, 128.5, 131.8, 132.0, 132.8,
137.5, 170.5. HRMS: m/z [M + H]+ calcd for C32H33NOP,
478.2300; found, 478.2313.
General Procedure for the Preparation of 2-Pyrrolidone (2):
To an ice cooled solution of N-protected 2-pyrrolidone 6 (1 equiv)
in alcohol (5 mL) was added ceric ammonium nitrate (4 equiv),
and the mixture was stirred for 1 h at 0 °C. This mixture was further
stirred for 12 h at room temperature. The reaction mixture was
neutralized with aqueous NaHCO3, extracted with EtOAc (3 × 20
mL), and dried over anhyd Na2SO4, and solvent was removed in
vacuum to afford a crude oil. Further purification was done on silica
gel (hexanes/EtOAc ) 6: 4) to afford the desired product 2 as a
white crystalline solid.
N-Prenyl-N-(p-methoxy)benzyl-2-[triphenylphosphoran-
ylidene] Acetamide (3b): Yield 86%; yellow color thick liquid. IR
1
(ν max): 1647 cm-1. H NMR (CDCl3, 300 MHz): δ 1.59 [1.48]
(s, 3H), 1.67 [1.65] (s, 3H), 2.01 (br s, 1H), 3.78 [3.77] (s, 3H);
J. Org. Chem. Vol. 74, No. 9, 2009 3593

2-Pyrrolidone (2a): Yield 95%; mp 89-90 °C. IR (ν max):
NMR (CDCl3, 75 MHz): δ 14.1, 20.2, 30.6, 40.4, 44.6, 44.7, 60.6,
114.8, 143.0, 172.3, 178.0. HRMS: m/z [M + Na]+ calcd for
C11H17NO3Na, 234.1106; found, 234.1101.
1
3203, 1732, 1693 cm-1. H NMR (CDCl3, 300 MHz): δ 1.67 (s,
3H), 2.31 (dd, J ) 9.9 Hz, 17.4 Hz, 1H), 2.80 (dd, J ) 4.5 Hz,
17.4 Hz, 1H), 3.09 (ddd, J ) 4.2 Hz, 4.5 Hz, 9.6 Hz, 1H),
3.26-3.32 (m, 2H), 3.59 (dd, J ) 6.6 Hz, 9.9 Hz, 1H), 3.70 (s,
3H), 4.78 (s, 1H), 4.87 (s, 1H), 6.01 (br s, 1H). 13C NMR (CDCl3,
75 MHz): δ 20.1, 30.3, 40.4, 44.5, 44.7, 51.7, 114.9, 142.9, 172.8,
178.2. HRMS: m/z [M + Na]+ calcd for C10H15NO3Na, 220.0950;
found, 220.0947.
Acknowledgment. We thank IISc, Bangalore, for the HRMS
facility, and DST, CSIR New Delhi, for financial support.
M.S.M. is thankful to CSIR for the award of the Senior Research
Fellowship.
Supporting Information Available: Copies of 1H NMR, 13
C
Ganem’s Intermediate (2b): Yield 68%; mp 104-105 °C. IR
1
(ν max): 3205; 1730; 1696 cm-1. H NMR (CDCl3, 300 MHz): δ
NMR of all the compounds, and DEPT spectra of 5a, 6a, 7a,
and 2b. This material is available free of charge via the Internet
at http://pubs.acs.org.
1.26 (t, J ) 7.2 Hz, 3H), 1.67 (s, 3H), 2.28 (dd, J ) 9.9 Hz, 17.4
Hz, 1H), 2.78 (dd, J ) 4.5 Hz, 17.4 Hz, 1H), 3.07 (m, 1H),
3.55-3.60 (m, 2H), 3.57 (dd, J ) 6.6 Hz, 9.9 Hz, 1H), 4.15 (q, J
) 7.2 Hz, 2H), 4.78 (s, 1H), 4.86 (s, 1H), 6.37 (br s, 1H). 13C
JO900196T
3594 J. Org. Chem. Vol. 74, No. 9, 2009