Stereoselective formal synthesis of (+)-allokainic acid via thiol-mediated acyl radical cyclization

Article abstract of DOI:10.1248/cpb.58.1511

Stereoselective formal synthesis of (+)-allokainic acid was accomplished starting from L-glutamate by using a thiol-mediated acyl radical cyclization as a key step. The cyclization of a formylalkenoate proceeded in a highly diastereoselective manner to gi

Full text of DOI:10.1248/cpb.58.1511

November 2010
Regular Article
Chem. Pharm. Bull. 58(11) 1511—1516 (2010)
1511
Stereoselective Formal Synthesis of (؉)-Allokainic Acid via
Thiol-Mediated Acyl Radical Cyclization
Ken-ichi YAMADA, ,a Tomohiro SATO,a Masaki HOSOI,a Yasutomo YAMAMOTO,b and
*
,b
*
Kiyoshi TOMIOKA
a Graduate School of Pharmaceutical Sciences, Kyoto University; Yoshida, Sakyo-ku, Kyoto 606–8501, Japan: and
b Faculty of Pharmaceutical Sciences, Doshisha Women’s College of Liberal Arts; Kodo, Kyotanabe, Kyoto 610–0395,
Japan. Received August 2, 2010; accepted August 20, 2010; published online August 30, 2010
Stereoselective formal synthesis of (؉)-allokainic acid was accomplished starting from L-glutamate by using
a thiol-mediated acyl radical cyclization as a key step. The cyclization of a formylalkenoate proceeded in a highly
diastereoselective manner to give trans-4,5-disubstituted pyrrolidin-3-one without the production of the cis-iso-
mer. The pyrrolidinone was then converted into the established synthetic intermediate of (؉)-allokainic acid via
the iron-catalyzed coupling reaction with an isopropenyl Grignard reagent.
Key words (ϩ)-allokainic acid; acyl radical cyclization; thiol; stereoselective synthesis
Construction of heterocyclic motifs is of great importance oxidation–Wittig olefination sequence. Removal of the tri-
in synthetic organic chemistry because most of biologically ethylsilyl (TES) group and the oxidation of the resulting al-
significant molecules are heterocycles.1) Among those, pyrro- cohol afforded 6. The acyl radical cyclization of 6, however,
lidine rings are abundantly found in bioactive alkaloids, such only gave a complex mixture, including no desired cyclized
as nicotine, cocaine, and kainic acid. We have already re- product, with a complete consumption of starting 6. We
ported the thiol-catalyzed acyl radical cyclization reaction of speculated that the conformer C required for the cyclization
alkenals.2) In this reaction, acyl radicals are directly gener- would be unfavorable because of the steric repulsion between
ated from aldehydes through hydrogen abstraction by an in the N-benzyl and the siloxymethyl moiety (Chart 3). We,
situ generated thiyl radical, and undergo addition to an olefin therefore, plan to fix the conformation by N,O-protection as
moiety of the same molecule to give a-substituted cycloalka- cyclic carbamate 1.
nones in high yield. The usefulness of this reaction was high-
Cyclic formylalkenoate 1 was prepared from known ester
lighted in the total synthesis of marine diterpenoid (Ϫ)-cyan- 7 (Chart 4).38,39) N-Alkylation of 7 was successful when
thiwigin F.3) Herein, we report the acyl radical cyclization for potassium tert-butoxide was used as a base with 18-crown-6
the stereoselective pyrrolidine ring construction and its appli- to give 8 in 87% yield.38) For the deprotonation of 7, it was
cation to the synthesis of (ϩ)-allokainic acid (3).4—27) We ex- important to add a pre-mixed solution of the alkoxide and the
pected that the construction of N-containing heterocycles crown ether to a solution of 7 cooled in an ice-water bath be-
would be realized by utilizing this cyclization reaction (Chart fore the addition of the bromide. When the deprotonation
1).28—36) The acyl radical cyclization of N-containing cyclic was carried out at room temperature, not only 8 (67%) but
formylalkenoate 1 would proceed via conformer A with the also a significant amount of the tert-butyl ester analog of 8
minimum 1,3-allylic strain to preferentially give trans-2, was obtained (13%). When the alkoxide was added to a solu-
rather than via conformer B that gives cis-2.
Results and Discussion
First, the acyl radical cyclization of 6 was tested. Formyl-
alkenoate 6 was prepared starting from known alcohol 4
(Chart 2).37,38) After N-alkylation with 1-bromo-2-(triethyl-
siloxy)ethane, an alkenoate moiety was installed by a Swern
Chart 2. Preparation of 6 and Its Attempted Acyl Radical Cyclization
Chart 1. Acyl Radical Cyclization of 1 via Conformer A to Give trans-2, a
Potential Intermediate for (ϩ)-Allokainic Acid (3), and Conformer B to Chart 3. Conformers of Acyl Radical Generated from 6: Conformer C
Give cis-2
Required for the Cyclization and Undesired Conformer D
∗ To whom correspondence should be addressed. e-mail: yamak@pharm.kyoto-u.ac.jp; tomioka@pharm.kyoto-u.ac.jp © 2010 Pharmaceutical Society of Japan

1512
Vol. 58, No. 11
tion of the crown ether and 7, the yield of 8 was dramatically whose hydrogen abstraction from thiol affords trans-2. We
decreased to 40%. The alkylation using sodium hydride or hence expected that lower temperature should decelerate the
silver oxide was sluggish and not clean, resulting in low yield entropy-increasing decarbonylation process. Thus, the reac-
of 8 (14—25%) with partial recovery of 7 (0—53%).
tion was performed at 70 °C using an excess amount of the
Alkanoate 8 was dehydrogenated to alkenoate 9 by initiator and the thiol (entry 4). Although a longer reaction
Ito–Saegusa oxidation in 69% yield. The same transforma- time was required for the complete consumption of 1, the
tion was also achieved by selenylation–oxidative elimination yield of trans-2 was increased to 38% while the production
sequence using lithium hexamethyldisilazide and phenylsel- of 10 was decreased to 7%.
enyl chloride, and then sodium periodate to give a desilylated
In order to complete a formal synthesis of (ϩ)-allokainic
analog of 9 in slightly lower yield (45%). Acidic removal of acid, introduction of an isopropenyl group was required. Ini-
the TES group from 9 followed by Dess–Martin periodinane tially, a nucleophilic substitution reaction under Anderson’s
(DMP) oxidation afforded 1 in 62% yield.
condition was attempted.40) The mixture of trans-2 and 10
First, the acyl radical cyclization of 1 was performed was treated with LiAlH(Ot-Bu)3 to give trans-alcohol 11 in
under our standard conditions: in refluxing benzene with 33% yield along with lactone 12 (1%), which was probably
0.3 eq of tert-dodecanethiol and 2,2Ј-azobisisobutyronitrile produced by spontaneous cyclization of the cis-isomer of 11
(AIBN) (Table 1, entry 1).2) Although the yield was quite low (Chart 6). At the same time, deformylation product 10 was
(3%), desired cyclized product trans-2 was obtained as a sole converted into the corresponding saturated ester and removed
diastereomer along with quantitative recovery of starting 1 at this stage by silica gel column chromatography. Using
(95%). The relative configuration of trans-2 was confirmed NaBH4 as a reducing agent in ethanol, the yield and the di-
by nuclear Overhauser effect spectroscopy (NOESY) cross astereoselectivity were less satisfactory to give 11 and 12 in
peaks observed between the angular hydrogen and the a-pro-
ton of the ester moiety (see Experimental).
The yield of trans-2 was increased when more than stoi-
chiometric amounts of the thiol and the radical initiator were
used; trans-2 was obtained in 21% and 26% yield at 110 °C
and 130 °C, respectively (entry 2, 3). The yield of deformyl-
ated 10 was, however, also increased to 9% at 110 °C (entry
2) and 15% at 130 °C (entry 3). The production of 10 could
be explained by the decarbonylation of acyl radical E gener-
ated from 1 (Chart 5). Cyclization of E gives intermediate F,
Chart 5. Formation of trans-2 and 10 in Acyl Radical Cyclization of 1
Chart 6. Conversion of trans-2 to Tosylate 13 and Bromide 16
Table 1. Acyl Radical Cyclization of Cyclic Formylalkenoate 1 to Give trans-2 and 10
Chart 4. Preparation of 1 from Known Ester 7
Initiator
(eq)
t-C12H25SH
Temp.
(°C)
Time
(h)
trans-2
(%)
10
(%)
1
(%)
Entry
Solvent
(eq)
1
AIBN (0.3)
V-40 (1.5)
V-40 (3)
0.3
3
4.5
10
C6H6
PhMe
PhCl
80
110
130
70
19
16
46
86
3
21
26
38
2
9
15
7
95
10
0
2
3a)
4b)
AIBN (4)
PhMe
0
a) The reaction was started with V-40 (1.5 eq) and the thiol (3 eq), and 1.5 eq each of these were added to the reaction mixture after 34 h. b) The reaction was started with
AIBN (1 eq) and the thiol (10 eq), and AIBN was portionwise (1 eq each) added to the reaction mixture after 12, 36, and 60 h.

November 2010
1513
mide to give 17, Hanessian’s intermediate19) of (ϩ)-allo-
kainic acid in 36% yield along with the cis-isomer in 6%
yield (Chart 8). The production of byproduct 18 suggests that
the moderate yield of the coupling reaction is probably due
to b-elimination of alkyl–iron intermediate H. The coupling
reaction with trans-16 would also give 17 in similar effi-
ciency because it was indicated that a radical process should
be involved in the formation of an alkyl–iron intermediate
from an alkyl bromide.42)
Conclusion
We have tested the acyl radical cyclization of the N-con-
taining formylalkenoates. Although the yield was not satis-
factory, trans-4,5-disubstituted pyrrolidin-3-one was pro-
duced in a perfectly stereoselective manner. The product was
converted into the known intermediate of (ϩ)-allokainic acid
(3) in 4 steps.
Chart 7. Unexpected Formation of Cyclopropanes 14 and 15 by the Reac-
tion of Tosylate 13 with Cuprates
Experimental
General All melting points are uncorrected. IR spectra were expressed
1
in cmϪ1. H-NMR (500 MHz) and 13C-NMR (125 MHz) spectra were meas-
ured in CDCl3 unless otherwise mentioned. Chemical shifts and coupling
constants are presented in ppm d and Hz respectively. 13C peak multiplicity
assignments were made based on distortionless enhancement by polarization
transfer (DEPT) data. Abbreviations are as follows: s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet; br, broad. The wavenumbers of maximum
absorption peaks of IR spectroscopy were presented in cmϪ1. All the reac-
tions were conducted under argon atmosphere, except for reactions in aque-
ous media. Column chromatography was carried out with silica gel.
Chart 8. Formal Synthesis of (ϩ)-Allokainic Acid (3)
12% and 5% yield, respectively. Tosylation of 11 under Tan-
abe’s condition41) proceeded smoothly to give 13, which was
separated from 12 at this stage.
(2-Bromoethoxy)triethylsilane TESCl (128 g, 0.85 mol) was added
dropwise over 10 min at 0 °C to a stirred solution of 2-bromoethanol (50 ml,
0.71 mol) and imidazole (121 g, 1.78 mol) in dry N,N-dimethylformamide
(DMF) (710 ml). After the addition was completed, the mixture was stirred
for 0.5 h at 0 °C. After addition of satd NaHCO3 (400 ml), the mixture was
extracted with AcOEt (300 mlϫ3). The combined organic layers were
washed with water (300 mlϫ3) and brine (100 ml), and dried over Na2SO4.
Concentration and column chromatography (hexane, then hexane/AcOEtϭ
19/1) gave the titled compound (127 g, 75%) as colorless oil of bp
110 °C/22 mmHg: Rf 0.5 (hexane/AcOEtϭ19/1). 1H-NMR: 0.63 (6H, q,
Jϭ8.0), 0.97 (9H, t, Jϭ8.0), 3.40 (2H, t, Jϭ6.7), 3.89 (2H, t, Jϭ6.7). 13C-
NMR: 4.6 (CH2), 6.8 (CH3), 33.3 (CH2), 63.5 (CH2). IR (neat): 1095. Elec-
tron impact (EI)-MS m/z: 211 (Mϩ2ϪEt), 209 (MϩϪEt). Anal. Calcd for
C8H19BrOSi: C, 40.17; H, 8.01. Found: C, 40.12; H, 8.18.
Then, the isopropenylation with higher order cuprate was
attempted using Anderson’s condition (Chart 7). The ex-
pected substitution, however, failed to proceed, and unex-
pected cyclopropane 14 was obtained in 32% yield at room
temperature. The reaction did not proceed at Ϫ60 °C, and at
Ϫ50 °C, cyclopropanecarboxylate 15 was produced in 32%
yield along with 37% recovery of tosylate 13. These results
show that the deprotonation at the a-position of the ester
moiety is faster than the desired substitution and gives the
enolate of 13, which then undergoes 3-exo-tet cyclization to
give 15. At room temperature, ester 15 further reacts with
two equiv of the cuprate to form 14 through 1,2-addition fol-
lowed by 1,4-addition of the resulting intermediate a,b-un-
saturated ketone. The use of the Gilman-type lithium iodide
complex was unbeneficial and gave 15 in 16% yield. The
stereochemistry of the ring fusion in 14 and 15 was assigned
according to that of the parent molecule 13, and the stereo- (9H, t, Jϭ7.8), 1.05 (9H, s), 2.65 (1H, dt, Jϭ14.0, 4.3), 2.91 (1H, ddd,
chemistry at the 6-positions was determined based on the
small coupling constant (4.0 Hz) between the protons at the
position and the adjacent protons. The relative configuration
of the side chain in 14 was not determined, though only one
of the diastereomers was obtained.
Finally, the isopropenyl group was introduced by the iron-
catalyzed coupling reaction under Cossy’s condition.42) Tosyl-
ate 13 was treated with lithium bromide to give 16 and the
trans-isomer in 55% and 27% yield, respectively (Chart 6).
The relative configuration of the products was determined by
nOe experiments (see Experimental). The formation of the
trans-isomer would be due to a re-substitution reaction of 16
with lithium bromide. The major isomer 16 was subjected to
the iron-catalyzed reaction with isopropenylmagnesium bro-
(S)-2-(Benzyl(2-(triethylsiloxy)ethyl)amino)-3-(tert-butyldiphenyl-
siloxy)propan-1-ol A mixture of alcohol 437,38) (54 mg, 0.13 mmol), the
above bromide (0.09 ml, 0.4 mmol), and NaHCO3 (22 mg, 0.26 mmol) in
DMF (0.4 ml) was stirred for 21 h at 100 °C. After addition of satd NH4Cl
(2 ml), the mixture was extracted with AcOEt (10 mlϩ5 mlϫ2). The com-
bined organic layers were dried over Na2SO4. Concentration and column
chromatography (hexane/AcOEtϭ19/1) gave the titled compound (47 mg,
61%) as pale yellow oil: Rf 0.5 (hexane/AcOEtϭ19/1, developed three
1
times). [a]D25 Ϫ30.5 (cϭ1.33, CHCl3). H-NMR: 0.55 (6H, q, Jϭ7.8), 0.92
Jϭ6.1, 8.0, 14.0), 3.08 (1H, m), 3.43—3.51 (3H, m), 3.57 (1H, dd, Jϭ4.9,
11.0), 3.63 (1H, dd, Jϭ6.1, 10.7), 3.75 (1H, d, Jϭ14.0), 3.78 (1H, dd,
Jϭ5.8, 10.7), 3.88 (1H, d, Jϭ14.0), 7.23 (1H, m), 7.28—7.29 (4H, m),
7.35—7.46 (6H, m) 7.65—7.66 (4H, m). 13C-NMR: 4.2 (CH2), 6.6 (CH3),
19.0 (C), 26.8 (CH3), 51.8 (CH2), 56.0 (CH2), 60.0 (CH2), 61.41 (CH2),
61.48 (CH2), 62.6 (CH), 127.0 (CH), 127.8 (CH), 128.3 (CH), 128.7 (CH),
129.81 (CH), 129.84 (CH), 133.26 (C), 133.30 (C), 135.55 (CH), 135.59
(CH), 140.3 (C). IR (neat): 3448. FAB-MS m/z: 578 (MϩHϩ). High resolu-
tion (HR)-MS-FAB (m/z): [MϩH]ϩ Calcd for C34H52NO3Si2, 578.3486.
Found: 578.3492.
Ethyl (S,E)-4-(Benzyl(2-(triethylsiloxy)ethyl)amino)-5-(tert-butyl-
diphenylsiloxy)pent-2-enoate (5) Oxalyl chloride (0.13 ml, 1.5 mmol)
was added to a solution of dimethyl sulfoxide (DMSO) (0.18 ml, 2.6 mmol)
in CH2Cl2 (7.0 ml) at Ϫ78 °C. After 5 min, a solution of the above alcohol
(567 mg, 0.98 mmol) in CH2Cl2 (1.2 ml) was added over 5 min, and the mix-
ture was stirred for another 20 min. Then, Et3N (0.68 ml, 4.9 mmol) was
added, and the mixture was warmed to Ϫ15 °C over 15 min. A solution of

1514
Vol. 58, No. 11
Calcd for C15H30NO5Si, 332.1893. Found: 332.1878.
Ph3PϭCHCO2Et (975 mg, 2.8 mmol) in CH2Cl2 (5.8 ml) was added to the
mixture, which was then allowed to warm up to room temperature over 1 h.
The mixture was poured into brine (10 ml). The two layers were separated
and the aqueous layer was extracted with AcOEt (20 mlϫ3). The combined
organic layers were dried over Na2SO4. Concentration and column chro-
matography (hexane/Et2Oϭ19/1) gave alkenoate 5 (443 mg, 70%) as pale
yellow oil: Rf 0.3 (hexane/Et2Oϭ19/1, developed three times). [a]D25 ϩ19.0
Methyl (S,E)-2-Oxo-3-(2-(triethylsiloxy)ethyl)oxazolidine-4-acrylate
(9) To a solution of 8 (13.6 g, 41 mmol) in THF (260 ml) was added freshly
distilled TMSCl (10 ml, 82 mmol) and a 1.0 M solution of NaHMDS in THF
(82 ml, 82 mmol) at Ϫ78 °C. The mixture was stirred for 1 h at 0 °C and
transferred via cannula into a suspension of Pd(OAc)2 (11 g, 49 mmol) in
CH3CN (180 ml) at room temperature. After 3 h, the reaction was quenched
by addition of satd. NH4Cl (100 ml). The resulting salts were removed by fil-
tration through a celite pad. The filtrate was extracted with AcOEt
(200 mlϫ3). The combined organic layers were washed with brine (100 ml)
and dried over Na2SO4. Concentration and column chromatography (hexane/
AcOEtϭ3/1) gave 9 (9.3 g, 69%) as pale yellow oil: Rf 0.5 (hexane/
1
(cϭ1.00, CHCl3). H-NMR: 0.51 (6H, q, Jϭ7.9), 0.89 (9H, t, Jϭ7.9), 1.03
(9H, s), 1.30 (3H, t, Jϭ7.4), 2.65—2.77 (2H, m), 3.47—3.55 (3H, m), 3.69
(1H, d, Jϭ14.4), 3.75 (1H, dd, Jϭ6.4, 10.2), 3.80 (1H, d, Jϭ14.4), 3.86 (1H,
dd, Jϭ6.4, 10.2), 4.21 (2H, q, Jϭ7.4), 6.02 (1H, dd, Jϭ1.5, 15.9), 6.97 (1H,
dd, Jϭ6.7, 15.9), 7.20—7.44 (11H, m), 7.61—7.63 (4H, m). 13C-NMR: 4.2
(CH2), 6.6 (CH3), 14.2 (CH3), 19.1 (C), 26.7 (CH3), 52.9 (CH2), 56.5 (CH2),
60.2 (CH2), 62.3 (CH2), 62.9 (CH), 64.0 (CH2), 123.7 (CH), 126.9 (CH),
127.7 (CH), 128.2 (CH), 128.4 (CH), 129.7 (CH), 133.3 (C), 135.6 (CH),
140.2 (C), 146.2 (CH), 166.4 (C). IR (neat): 1720, 1651. FAB-MS m/z: 646
(MϩHϩ). HR-MS-FAB (m/z): [MϩH]ϩ Calcd for C38H56NO4Si2, 646.3748.
Found: 646.3742.
Ethyl (S,E)-4-(Benzyl(2-hydroxyethyl)amino)-5-(tert-butyldiphenyl-
siloxy)pent-2-enoate A solution of 5 (50 mg, 0.080 mmol) in AcOH/
tetrahydrofuran (THF)/H2O (1/1/3, 0.4 ml) was stirred for 16 h at room tem-
perature. After satd NaHCO3 (5 ml) was added, the mixture was extracted
with CHCl3 (5 mlϫ3). The combined organic layers were dried over Na2SO4.
Concentration and column chromatography (hexane/AcOEtϭ5/1) gave the
titled alcohol (42 mg, 99%) as colorless oil: Rf 0.6 (hexane/AcOEtϭ5/1, de-
veloped three times). [a]D25 ϩ61.3 (cϭ1.64, CHCl3). 1H-NMR: 1.04 (9H, s),
1.29 (3H, t, Jϭ7.2), 2.65 (1H, dt, Jϭ13.5, 3.4), 2.94 (1H, ddd, Jϭ4.3, 9.2,
13.5), 3.42 (1H, m), 3.51 (1H, m), 3.55—3.62 (3H, m), 3.81—3.85 (2H, m),
4.19 (2H, q, Jϭ7.2), 5.77 (1H, d, Jϭ15.9), 6.80 (1H, dd, Jϭ7.9, 15.9),
7.27—7.43 (11H, m), 7.52—7.53 (2H, m), 7.59—7.61 (2H, m). 13C-NMR:
14.1 (CH3), 19.0 (C), 26.7 (CH3), 51.2 (CH2), 55.7 (CH2), 59.2 (CH2), 60.5
(CH2), 61.6 (CH), 63.5 (CH2), 124.8 (CH), 127.3 (CH), 127.7 (CH), 127.8
(CH), 128.6 (CH), 128.9 (CH), 129.8 (CH), 129.9 (CH), 132.9 (C), 133.0
(C), 135.59 (CH), 135.65 (CH), 139.1 (C), 143.5 (CH), 165.9 (C). IR (neat):
3456, 1720, 1651. FAB-MS m/z: 532 (MϩHϩ). HR-MS-FAB (m/z):
[MϩH]ϩ Calcd for C32H42NO4Si, 532.2883. Found: 532.2879.
AcOEtϭ3/1). [a]D25 ϩ5.1 (cϭ1.88, CHCl3). H-NMR: 0.60 (6H, q, Jϭ8.1),
1
0.95 (9H, t, Jϭ8.1), 3.09 (1H, ddd, Jϭ4.0, 8.5, 14.5), 3.52 (1H, ddd, Jϭ3.5,
4.5, 14.5), 3.72 (1H, ddd, Jϭ4.0, 4.5, 10.5), 3.78 (3H, s), 3.81 (1H, ddd,
Jϭ3.5, 8.5, 10.5), 4.01 (1H, dd, Jϭ6.5, 8.5), 4.45 (1H, t, Jϭ8.5), 4.65 (1H,
dt, Jϭ6.5, 8.5), 6.04 (1H, d, Jϭ15.5), 6.76 (1H, dd, Jϭ8.5, 15.5). 13C-NMR:
4.2 (CH2), 6.7 (CH3), 44.5 (CH2), 51.9 (CH3), 58.1 (CH), 61.2 (CH2), 66.4
(CH2), 125.7 (CH), 143.1 (CH), 157.6 (C), 165.5 (C). IR (neat): 1759, 1658.
FAB-MS m/z: 330 (MϩHϩ). HR-MS-FAB (m/z): [MϩH]ϩ Calcd for
C15H28NO5Si, 330.1737. Found: 330.1754.
Methyl (S,E)-3-(2-Hydroxyethyl)-2-oxooxazolidine-4-acrylate A so-
lution of 9 (23.9 g, 71 mmol) in AcOH/THF/H2O (2/5/15, 390 ml) was
stirred for 6 h at room temperature. After addition of satd NaHCO3 (250 ml),
the mixture was saturated with NaCl and extracted with CHCl3 (200 mlϫ
18). The combined organic layers were dried over Na2SO4. Concentration
and column chromatography (hexane/AcOEtϭ3/1, then AcOEt) gave the ti-
tled alcohol (14.1 g, 92%) as colorless solids of mp 70—72 °C: Rf 0.5
(AcOEt). [a]D25 ϩ6.1 (cϭ1.0, CHCl3). H-NMR: 3.19 (1H, ddd, Jϭ4.0, 7.1,
1
15.0), 3.53 (1H, ddd, Jϭ3.7, 5.8, 15.0), 3.76—3.85 (2H, m), 3.78 (3H, s),
4.06 (1H, dd, Jϭ6.6, 8.7), 4.51 (1H, dd, Jϭ8.5, 8.7), 4.58 (1H, dt, Jϭ6.6,
8.5), 6.09 (1H, d, Jϭ15.8), 6.78 (1H, dd, Jϭ8.5, 15.8). 13C-NMR: 45.1
(CH2), 52.1 (CH3), 58.1 (CH), 61.0 (CH2), 66.7 (CH2), 126.3 (CH), 142.9
(CH), 158.7 (C), 165.6 (C). IR (KBr): 3417, 1728, 1659. FAB-MS m/z: 216
(MϩHϩ). HR-MS-FAB (m/z): [MϩH]ϩ Calcd for C9H14NO5, 216.0872.
Found: 216.0858.
Methyl (S,E)-2-Oxo-3-(2-oxoethyl)oxazolidine-4-acrylate (1) To a so-
lution of the above alcohol (5.4 g, 25 mmol) in CH2Cl2 (180 ml) was added
Dess–Martin periodinane (12.7 g, 30 mmol). After 1 h, i-PrOH (11 ml) was
added, and the resulting suspension was stirred for 1 h at room temperature.
The solid material was filtered off through a celite pad. Concentration of the
filtrate and column chromatography (hexane/AcOEtϭ1/2) twice gave alde-
hyde 1 (4.4 g, 75%) as colorless oil: Rf 0.35 (hexane/AcOEtϭ1/4, developed
three times). [a]D25 ϩ38.9 (cϭ2.05, CHCl3). 1H-NMR: 3.78 (3H, s), 3.85
(1H, d, Jϭ19.3), 4.11 (1H, m), 4.35 (1H, d, Jϭ19.3), 4.56—4.62 (2H, m),
6.04 (1H, d, Jϭ15.6), 6.73 (1H, m), 9.59 (1H, s). 13C-NMR: 51.8 (CH3),
52.0 (CH2), 57.3 (CH), 66.8 (CH2), 126.6 (CH), 141.7 (CH), 157.9 (C),
165.2 (C), 195.5 (CH). IR (neat): 1728, 1658. FAB-MS m/z: 214 (MϩHϩ).
HR-MS-FAB (m/z): [MϩH]ϩ Calcd for C9H12NO5, 214.0715. Found:
214.0714.
Methyl (7R,7aS)-3,6-Dioxohexahydropyrrolo[1,2-c]oxazole-7-acetate
(trans-2) and Methyl (S,E)-3-Methyl-2-oxooxazolidine-4-acrylate (10)
(Table 1, Entry 4) A solution of aldehyde 1 (3.5 g, 17 mmol), AIBN
(2.7 g, 17 mmol), and tert-dodecanethiol (38 ml, 170 mmol) in toluene (1.1 l)
was heated at 70 °C for 86 h. During that period, additional portions
of AIBN (2.7 g, 17 mmol each) were added after 12, 36, and 60 h. Con-
centration of the reaction mixture and column chromatography (hexane/
AcOEtϭ1/1) of the resulting crude material gave a 10 : 1 mixture of trans-2
and 10 (1.56 g, 38% and 4%, respectively) as yellow oil and 10 (84 mg, 3%)
as yellow oil. The ratio of trans-2 and 10 was determined based on the
integration area of 1H-NMR signals at 3.58 (the a-CH2 of the ketone moiety
of trans-2 in CDCl3) and 2.87 ppm (NCH3 of 10). The mixture of trans-2
and 10 was further purified by another column chromatography (hexane/
AcOEtϭ1/1) to give trans-2, which was characterized as below.
Ethyl (S,E)-4-(Benzyl(2-oxoethyl)amino)-5-(tert-butyldiphenylsiloxy)-
pent-2-enoate (6) Oxalyl chloride (0.03 ml, 0.3 mmol) was added to a so-
lution of DMSO (0.04 ml, 0.6 mmol) in CH2Cl2 (1.1 ml) at Ϫ78 °C. After
5 min, a solution of the above alcohol (110 mg, 0.21 mmol) in CH2Cl2
(1.2 ml) was added over 2 min, and the mixture was stirring for another
20 min at Ϫ78 °C. Then, Et3N (0.15 ml, 1.1 mmol) was added, and the mix-
ture was warmed to room temperature over 20 min. The reaction was
quenched by addition of water (5 ml) and the solution was extracted with
CHCl3 (10 mlϫ3). The combined organic layers were washed with brine
(5 ml) and dried over Na2SO4. Concentration and column chromatography
(hexane/AcOEtϭ19/1) gave aldehyde 6 (91 mg, 86%) as pale yellow oil: Rf
0.2 (hexane/AcOEtϭ19/1, developed three times). [a]D25 ϩ10.7 (cϭ1.43,
1
CHCl3). H-NMR: 1.05 (9H, s), 1.30 (3H, t, Jϭ7.0), 3.29 (1H, dd, Jϭ1.9,
17.7), 3.45 (1H, dd, Jϭ1.9, 17.7), 3.51 (1H, m), 3.73 (1H, d, Jϭ13.6),
3.79—3.87 (3H, m), 4.21 (2H, q, Jϭ7.0), 6.00 (1H, dd, Jϭ1.2, 15.9), 6.92
(1H, dd, Jϭ6.7, 15.9), 7.28—7.47 (11H, m), 7.62—7.65 (4H, m), 9.50 (1H,
dd, Jϭ1.9, 1.9). 13C-NMR: 14.1 (CH3), 19.1 (C), 26.8 (CH3), 57.0 (CH2),
60.5 (CH2), 60.9 (CH2), 63.2 (CH), 64.2 (CH2), 124.3 (CH), 127.7 (CH),
127.9 (CH), 128.6 (CH), 128.9 (CH), 129.9 (CH), 132.9 (C), 133.0 (C),
135.6 (CH), 135.7 (CH), 138.4 (C), 144.8 (CH), 166.1 (C), 202.6 (CH). IR
(neat): 1720, 1651. FAB-MS m/z: 530 (MϩHϩ). HR-MS-FAB (m/z):
[MϩH]ϩ Calcd for C32H40NO4Si, 530.2727. Found: 530.2721.
Methyl (S)-2-Oxo-3-(2-(triethylsiloxy)ethyl)oxazolidine-4-acrylate (8)
To a solution of 738,39) (9.8 g, 57 mmol) in THF (110 ml) was added a mix-
ture of 18-crown-6 (1.5 g, 5.7 mmol) and a 1.0 M solution of t-BuOK in THF
(68 ml, 68 mmol) at 0 °C. After 30 min, (2-bromoethoxy)triethylsilane
(16 ml, 69 mmol) was added to the mixture, which was then warmed up to
room temperature. After 17 h, the reaction was quenched by addition of satd.
NH4Cl (200 ml). The mixture was extracted with AcOEt (100 mlϫ5). The
combined organic layers were washed with brine (50 ml) and dried over
Na2SO4. Concentration and column chromatography (hexane/AcOEtϭ2/1)
gave 8 (16.6 g, 87%) as pale brown oil: Rf 0.2 (hexane/AcOEtϭ1/1). [a]D25
Ϫ3.7 (cϭ1.08, CHCl3). 1H-NMR: 0.60 (6H, q, Jϭ8.0), 0.95 (9H, t, Jϭ8.0),
1.92 (1H, m), 2.11 (1H, m), 2.31, (2H, m), 3.17 (1H, m), 3.55 (1H, m), 3.70
(3H, s), 3.78 (2H, m), 3.96 (1H, dd, Jϭ6.2, 8.5), 4.06 (1H, m), 4.36 (1H, dd,
Jϭ8.5, 8.5). 13C-NMR: 3.8 (CH2), 6.3 (CH3), 26.4 (CH2), 28.2 (CH2), 44.0
(CH2), 51.5 (CH3), 55.1 (CH), 60.9 (CH2), 66.5 (CH2), 157.8 (C), 172.5 (C).
IR (neat): 1747. FAB-MS m/z: 332 (MϩHϩ). HR-MS-FAB (m/z): [MϩH]ϩ
trans-2: Rf 0.37 (hexane/AcOEtϭ1/1, developed three times). [a]D25
Ϫ106.3 (cϭ2.1, CHCl3). 1H-NMR (CD2Cl2): 2.57 (1H, dd, Jϭ8.0, 17.0),
2.64 (1H, ddd, Jϭ3.0, 8.0, 9.0), 2.87 (1H, dd, Jϭ3.0, 17.0), 3.56 (1H, d,
Jϭ18.5), 3.68 (3H, s), 4.11 (1H, d, Jϭ18.5), 4.16 (1H, ddd, Jϭ3.5, 7.5, 9.0),
4.52 (1H, dd, Jϭ3.5, 9.5), 4.71 (1H, dd, Jϭ7.5, 9.5). 13C-NMR: 31.2 (CH2),
48.9 (CH), 52.2 (CH3), 52.4 (CH2), 61.0 (CH), 68.1 (CH2), 160.2 (C), 171.5
(C), 210.5 (C). IR (neat): 1761, 1734. FAB-MS m/z: 214 (MϩHϩ). HR-MS-
FAB (m/z): [MϩH]ϩ Calcd for C9H12NO5, 214.0715. Found: 214.0710. The
relative configuration was determined to be as drown by NOESY cross
peaks observed between the angular NCH (4.16 ppm) and one of the a-CH2

November 2010
1515
of the ester moiety (2.57 ppm).
bath was removed. After 0.5 h, the reaction was quenched by the addition of
1 N HCl (10 ml), and the mixture was diluted with water (20 ml) and ex-
10: Rf 0.33 (hexane/AcOEtϭ1/1, developed three times). [a]D25 Ϫ8.3
1
(cϭ0.4, CHCl3). H-NMR: 2.82 (3H, s), 3.79 (3H, s), 4.01 (1H, dd, Jϭ6.7, tracted with AcOEt (30 mlϫ3). The combined organic layers were washed
8.9), 4.25—4.30 (1H, m), 4.48 (1H, dd, Jϭ8.9, 8.9), 6.09 (1H, d, Jϭ15.6), with brine (15 ml) and dried over Na2SO4. Concentration and column chro-
6.77 (1H, dd, Jϭ8.6, 15.6). 13C-NMR: 29.6 (CH3), 52.1 (CH3), 58.9 (CH),
matography (hexane/AcOEtϭ2/1) gave 14 (16 mg, 32%, a single diastere-
omer) as colorless oil: Rf 0.6 (hexane/AcOEtϭ1/1, developed three times).
66.2 (CH2), 126.0 (CH), 142.4 (CH), 158.2 (C), 165.5 (C). IR (neat): 1759,
1720, 1666. FAB-MS m/z: 186 (MϩHϩ). HR-MS-FAB (m/z): [MϩH]ϩ [a]D25 ϩ28.3 (cϭ0.55, CHCl3). 1H-NMR: 1.12 (3H, dd, Jϭ2.5, 8.5), 1.73
Calcd for C8H12NO4, 186.0766. Found: 186.0764.
(3H, s), 1.99 (1H, dd, Jϭ4.0, 4.0), 2.04 (1H, dd, Jϭ10.0, 18.0), 2.21 (1H,
Methyl (6S,7R,7aS)-6-Hydroxy-3-oxohexahydropyrrolo[1,2-c]oxazole- m), 2.38—2.45 (2H, m), 2.89 (1H, ddq, Jϭ9.0, 10.0, 8.5), 3.11 (1H, dd,
7-acetate (11), (3aR,3bS,8aR)-Hexahydro-2H-furo[3؅,2؅:3,4]pyrrolo[1,2- Jϭ2.5, 15.5), 4.02 (1H, m), 4.09 (1H, dd, Jϭ7.5, 15.5), 4.24 (1H, dd, Jϭ8.0,
c][1,3]oxazole-2,6-dione (12), and Methyl (S)-3-Methyl-2-oxooxazolidine- 11.5), 4.56 (1H, dd, Jϭ11.0, 11.5), 4.69 (1H, d, Jϭ1.5), 4.80 (1H, d, Jϭ1.5).
4-propionate To an ice-cooled and stirred suspension of LiAlH(Ot-Bu)3 13C-NMR: 15.8 (CH3), 22.3 (CH3), 33.7 (CH), 35.9 (CH), 38.6 (CH), 40.8
(890 mg, 3.5 mmol) in THF (8 ml), a solution of the 10 : 1 mixture of trans-2
(CH2), 45.2 (CH), 51.5 (CH2), 62.6 (CH), 68.0 (CH2), 112.5 (CH2), 142.6
and 10 (543 mg, 2.35 and 0.23 mmol, respectively) in THF (2 ml) was added. (C), 161.7 (C), 209.6 (C). IR (neat): 1743, 1690, 1643. FAB-MS m/z: 250
After 30 min, the reaction mixture was poured into water (20 ml). After addi- (MϩHϩ). HR-MS-FAB (m/z): [MϩH]ϩ Calcd for C14H20NO3, 250.1443.
tion of 10% HCl (10 ml), the aqueous layer was saturated with NaCl, and the Found: 250.1445. The relative configuration of the tricyclic core was deter-
1
mixture was extracted with CHCl3 (30 mlϫ26). The combined organic lay- mined based on coupling constants of H-NMR (see the text). The stereo-
ers were dried over Na2SO4. Concentration and column chromatography chemistry of the side chain was not determined.
(hexane/AcOEtϭ1/3) gave a 33 : 1 mixture of 11 and 12 (168 mg, 33% and
1%, respectively) as yellow oil with [a]D25 Ϫ5.02 (cϭ1.00, CHCl3) and the
titled propionate (19 mg, 43%) as yellow oil. The ratio of 11 and 12 was de-
termined based on the integration area of 1H-NMR signals at 3.40—
3.46 ppm (the overlapping a-CH2 of the ester moieties of 11 and 12) and
5.11 ppm (the OCH of 12).
Methyl (5aS,6R,6aR,6bS)-3-Oxohexahydrocyclopropa[c]pyrrolo[1,2-
c]oxazole-6-carboxylate (15). Method A To a solution of 2-bromo-
propene (0.14 ml, 1.6 mmol) in THF (8 ml) at Ϫ78 °C, was added 1.76 M t-
BuLi in pentane (1.8 ml, 3.2 mmol) dropwise. After 1 h, the mixture was
transferred rapidly by cannula (1.0 ml THF wash) into a stirred suspension
of CuCN (88 mg, 0.96 mmol, dried by a heat-gun in vacuo) in THF (1.0 ml)
at Ϫ78 °C. After 5 min, the cooling bath was removed. After complete disso-
1
11: Rf 0.3 (hexane/AcOEtϭ1/3, developed three times). H-NMR: 2.25
(1H, m), 2.43 (1H, dd, Jϭ8.3, 16.8), 2.63 (1H, dd, Jϭ6.8, 16.8), 2.76 (1H, lution of the CuCN was observed, the reaction mixture was re-cooled to
br s), d: 3.42 (1H, dd, Jϭ6.1, 12.3), 3.65 (1H, dd, Jϭ3.9, 12.3), 3.68—3.75 Ϫ78 °C and rapidly added by cannula to a solution of tosylate 13 (74 mg,
(4H, m), 4.24 (1H, m), 4.34 (1H, dd, Jϭ4.2, 8.9), 4.56 (1H, ddϭ8.9, 8.9). 0.2 mmol) in THF (3.0 ml) cooled at Ϫ78 °C. After 5 min, the reaction was
13C-NMR: 34.9 (CH2), 49.0 (CH), 52.1 (CH3), 53.4 (CH2), 63.1 (CH), 68.5 stirred for 15 h at Ϫ60 °C and then for further 24 h at Ϫ50 °C. The reaction
(CH2), 77.9 (CH), 161.8 (C), 172.6 (C). IR (neat): 3425, 1736. FAB-MS m/z:
216 (MϩHϩ). HR-MS-FAB (m/z): [MϩH]ϩ Calcd for C9H14NO5, 216.0872. diluted with water (20 ml) and extracted with AcOEt (20 mlϫ3). The com-
Found: 216.0894. bined organic layers were washed with brine (10 ml) and dried over Na2SO4.
was quenched by the addition of 1 N HCl (10 ml). The reaction mixture was
1
12: H-NMR: 2.50 (1H, dd, Jϭ17.8), 2.71 (1H, m), 2.84 (1H, dd, Jϭ8.3, Concentration and column chromatography (hexane/AcOEtϭ2/1) gave cy-
17.8), 3.45 (1H, dd, Jϭ2.2, 13.9), 3.75 (1H, m), 4.26—4.31 (2H, m), 4.61 clopropanecarboxylate 15 (16 mg, 32%) as white solids of mp 131—133 °C
(1H, dd, Jϭ7.6, 9.3), 5.11 (1H, ddd, Jϭ2.4, 6.8, 6.8). 13C-NMR: 31.6 (CH2), and recovered tosylate 13 (22 mg, 37%). The relative configuration was de-
44.4 (CH), 52.5 (CH2), 63.5 (CH), 66.3 (CH2), 83.8 (CH), 160.3 (C), 174.1 termined based on coupling constants of 1H-NMR (see the text).
(C). IR (KBr): 1743. FAB-MS m/z: 184 (MϩHϩ). HR-MS-FAB (m/z):
[MϩH]ϩ Calcd for C8H10NO4, 184.0610. Found: 184.0619.
15: Rf 0.4 (hexane/AcOEtϭ1/1, developed three times). [a]D25 ϩ5.6
(cϭ0.016, CHCl3). 1H-NMR: 1.69 (1H, dd, Jϭ4.0, 4.0), 2.25 (1H, ddd,
The propionate: Rf 0.5 (hexane/AcOEtϭ1/3, developed three times). [a]D25 Jϭ1.5, 4.0, 11.5), 2.49 (1H, m), 3.09 (1H, dd, Jϭ2.5, 15.5), 3.69 (3H, s),
1
ϩ23.7 (cϭ0.36, CHCl3). H-NMR: 1.88 (1H, m), 2.10 (1H, dddd, Jϭ3.4,
3.99 (1H, m), 4.10 (1H, dd, Jϭ8.0, 15.5), 4.26 (1H, dd, Jϭ7.5, 11.5), 4.56
7.0, 8.8, 12.5), 2.32—2.36 (2H, m), 2.86 (3H, s), 3.78—3.69 (4H, m), 3.94 (1H, dd, Jϭ10.5, 11.5). 13C-NMR: 31.4 (CH), 32.3 (CH), 34.1 (CH), 51.3
(1H, dd, Jϭ6.7, 8.9), 4.38 (1H, Jϭ8.9, 8.9). 13C-NMR: 26.7 (CH2), 28.3 (CH2), 52.1 (CH3), 62.4 (CH2), 67.8 (CH), 161.7 (C), 171.1 (C). IR (KBr):
(CH2), 29.1 (CH3), 52.0 (CH3), 56.3 (CH), 66.5 (CH2), 166.9 (C), 172.8 (C).
1751, 1728. FAB-MS m/z: 198 (MϩHϩ). HR-MS-FAB (m/z): [MϩH]ϩ
IR (neat): 1744. FAB-MS m/z: 200 (MϩHϩ). HR-MS-FAB (m/z): [MϩH]ϩ Calcd for C9H12NO4, 198.0766. Found: 198.0767.
Calcd for C8H14O4N, 188.0923. Found: 188.0928.
Methyl (6S,7R,7aS)-3-Oxo-6-(tosyloxy)hexahydropyrrolo[1,2-c]oxazole-
Method B To a solution of 2-bromopropene (0.17 ml, 1.9 mmol) in THF
(9 ml) at 0 °C, was added 1.76 M t-BuLi in pentane (2.2 ml, 3.9 mmol) drop-
7-acetate (13) To a solution of a 13 : 1 mixture of 11 and 12 (135 mg, 0.59 wise. After 1 h, the mixture was transferred rapidly by cannula into a stirred
and 0.047 mmol, respectively) in CH3CN (1.3 ml), was added Me3N·
HCl (60 mg, 0.63 mmol), Et3N (0.22 ml, 1.6 mmol), and TsCl (181 mg,
0.95 mmol) at 0 °C, and the mixture was stirred for 1 h at room temperature.
After addition of water (5 ml), the mixture was extracted with CHCl3
(10 mlϫ3), and the combined organic layers were dried over Na2SO4. Con-
centration and column chromatography (CHCl3/AcOEtϭ9/1) gave tosylate
13 (201 mg, 92%) as colorless columns of mp 143—144 °C and recovered
12 (5 mg, 58% recovery) as white solids.
suspension of CuI (217 mg, 1.14 mmol, dried by a heat-gun in vacuo) in
THF (1.0 ml) at 0 °C. After 30 min, the mixture was cooled to Ϫ78 °C and
then rapidly added by cannula to a solution of tosylate 13 (71 mg,
0.19 mmol) in THF (4.0 ml) cooled at Ϫ78 °C. After 30 min, the cooling
bath was removed, and the mixture was stirred for further 30 min. The reac-
tion was quenched by the addition of 1 N HCl. The aqueous layer was ex-
tracted with AcOEt (30 mlϫ3). The combined organic layers were washed
with brine (20 ml) and dried over Na2SO4. Concentration and column chro-
13: Rf 0.3 (CHCl3/AcOEtϭ9/1). [a]D25 Ϫ39.0 (cϭ1.00, CHCl3). 1H-NMR: matography (hexane/AcOEtϭ1/1) gave 15 (6 mg, 16%) as white solids.
2.40—2.55 (5H, m), 2.46 (1H, dd, Jϭ8.6, 16.6), 3.30 (1H, dd, Jϭ6.1, 13.2), Methyl (6R,7R,7aS)-6-Bromo-3-oxohexahydropyrrolo[1,2-c]oxazole-7-
3.64—3.78 (5H, m), 4.36 (1H, dd, Jϭ4.2, 9.5), 4.54 (1H, dd, Jϭ8.3, 9.5), acetate (16) and Methyl (6S,7R,7aS)-6-Bromo-3-oxohexahydropyrrolo-
4.91 (1H, m), 7.37 (2H, d, Jϭ8.3), 7.78 (2H, d, Jϭ8.3). 13C-NMR: 21.7
[1,2-c]oxazole-7-acetate (trans-16) Tosylate 13 (128 mg, 0.35 mmol) was
(CH3), 33.8 (CH2), 47.5 (CH), 50.7 (CH2), 52.1 (CH3), 62.3 (CH), 68.2 dissolved in dry THF (3.5 ml), and LiBr (304 mg, 3.5 mmol) was added to
(CH2), 84.4 (CH), 127.8 (CH), 130.1 (CH), 132.9 (C), 145.6 (C), 160.4 (C), the solution. The mixture was heated under reflux for 2.5 h. After addition of
171.4 (C). IR (KBr): 1751, 1728, 1365, 1173. EI-MS m/z: 369 (Mϩ). Anal. water (5 ml), the mixture was extracted with AcOEt (10ϫ3 ml). The com-
Calcd for C16H19NO7S: C, 52.02; H, 5.18; N, 3.79. Found: C, 51.74; H, 5.12; bined organic layers were washed with brine (5 ml) and dried over Na2SO4.
N, 3.78.
Concentration and column chromatography (hexane/AcOEtϭ2/1) gave bro-
(5aS,6R,6aR,6bS)-6-(2,4-Dimethylpent-4-enoyl)hexahydrocyclopropa- mide 16 (54 mg, 55%) as colorless solids of mp 77—78 °C and trans-16
[c]pyrrolo[1,2-c]oxazol-3-one (14) To a solution of 2-bromopropene
(0.18 ml, 2.0 mmol) in THF (10 ml) at Ϫ78 °C, was added 1.76 M t-BuLi in
pentane (2.3 ml, 4.0 mmol) dropwise. After 1 h, the mixture was transferred
(26 mg, 27%) as yellow solids of mp 65—67 °C.
16: Rf 0.50 (hexane/AcOEtϭ1/1, developed three times). [a]D25 ϩ48.5
1
(cϭ1.00, CHCl3). H-NMR: 2.19 (1H, m), 2.56 (1H, dd, Jϭ6.3, 16.9), 2.74
rapidly by cannula (1.0 ml THF wash) into a stirred suspension of CuCN (1H, dd, Jϭ7.8, 16.9), 3.72 (3H, s), 3.81 (1H, dd, Jϭ1.5, 13.5), 3.98 (1H,
(89 mg, 1.0 mmol, dried by a heat-gun in vacuo) in THF (1.0 ml) at Ϫ78 °C. ddd, Jϭ3.5, 8.0, 10.0), 4.32 (1H, dd, Jϭ3.5, 9.5), 4.36 (1H, dd, Jϭ6.1,
After 5 min, the cooling bath was removed. After complete dissolution of the 13.5), 4.56 (1H, dd, Jϭ8.0, 9.5), 4.86 (1H, m). 13C-NMR: 33.6 (CH2), 44.8
CuCN was observed, the reaction mixture was re-cooled to Ϫ78 °C, and a (CH), 52.1 (CH3), 54.9 (CH), 57.0 (CH2), 61.5 (CH), 66.1 (CH2), 161.8 (C),
solution of tosylate 13 (74 mg, 1.0 mmol) in THF (2.0 ml) cooled to Ϫ78 °C
171.4 (C). IR (KBr): 1744. FAB-MS m/z: 280 (Mϩ2ϩHϩ), 278 (MϩHϩ).
was rapidly added by cannula (0.5 ml THF wash). After 5 min, the cooling HR-MS-FAB (m/z): [MϩH]ϩ Calcd for C9H13BrNO4, 278.0028. Found:

1516
Vol. 58, No. 11
278.0031. The relative configuration was determined by stronger nOe (3%,
see below) observed between the BrCH and b-CH of the bromine atom at
4.86 and 2.19 ppm, respectively, and the absence of that between the BrCH
and the a-CH2 of the ester moiety.
7) Oppolzer W., Robbiani C., Bättig K., Helv. Chim. Acta, 63, 2015—
2018 (1980).
8) Kraus G. A., Nagy J. O., Tetrahedron Lett., 24, 3427—3430 (1983).
9) DeShong P., Kell D. A., Tetrahedron Lett., 27, 3979—3982 (1986).
trans-16: Rf 0.46 (hexane/AcOEtϭ1/1, developed three times). [a]D25 10) Baldwin J. E., Li C.-S., J. Chem. Soc., Chem. Commun., 1987, 166—
1
Ϫ28.8 (cϭ1.00, CHCl3). H-NMR: 2.37 (1H, dd, Jϭ9.9, 16.6), 2.53 (1H,
168 (1987).
dddd, Jϭ4.0, 8.3, 8.3, 9.9), 2.85 (1H, dd, Jϭ4.0, 16.6), 3.72 (3H, s), 3.78 11) Barcoa A., Benettia S., Casolarib A., Pollinib G. P., Spallutoa G.,
(1H, dd, Jϭ7.8, 12.6), 3.81 (1H, ddd, Jϭ4.9, 8.3, 8.3), 3.90 (1H, dd, Jϭ6.3, Tetrahedron Lett., 31, 4917—4920 (1990).
12.6), 4.07 (1H, m), 4.46 (1H, dd, Jϭ4.9, 9.5), 4.58 (1H, dd, Jϭ8.3, 9.5). 12) Yoo S.-E., Lee S.-H., Yi K.-Y., Jeong N., Tetrahedron Lett., 31,
13C-NMR: 34.3 (CH2), 48.5 (CH), 50.4 (CH), 52.1 (CH3), 54.0 (CH2), 62.9
6877—6880 (1990).
(CH), 68.1 (CH2), 160.5 (C), 171.3 (C). IR (KBr): 1736. FAB-MS m/z: 13) Mooiweer H. H., Hiemstra H., Speckamp W. N., Tetrahedron, 47,
280 (Mϩ2ϩHϩ), 278 (MϩHϩ). HR-MS-FAB (m/z): [MϩH]ϩ Calcd for
3451—3462 (1991).
C9H13BrNO4, 278.0028. Found: 278.0031. The relative configuration was 14) Yoo S.-E., Yi K.-Y., Lee S.-H., Kim N.-J., Bull. Korean Chem. Soc.,
determined by weaker nOe (1%, see above) observed between the BrCH and 13, 94—96 (1992).
b-CH of the bromine atom at 4.07 and 2.53 ppm, respectively, and that ob- 15) Barco A., Benetti S., Spalluto G., J. Org. Chem., 57, 6279—6286
served between the BrCH and the a-CH2 of the ester moiety at 2.37 ppm
(3%).
Methyl (6R,7S,7aS)-3-Oxo-6-(prop-1-en-2-yl)hexahydropyrrolo[1,2-c]-
(1992).
16) Hatakeyama S., Sugawara K., Takano S., J. Chem. Soc., Chem. Com-
mun., 1993, 125—127 (1993).
oxazole-7-acetate (17), Methyl (6S,7S,7aS)-3-Oxo-6-(prop-1-en-2-yl)- 17) Yoo S.-E., Suh J.-H., Yi K.-Y., Bull. Korean Chem. Soc., 14, 166—168
hexahydropyrrolo[1,2-c]oxazole-7-acetate, and Methyl (S)-3-((S)-2-Oxo-
oxazolidin-4-yl)pent-4-enoate (18) A mixture of a 0.5 M solution of iso-
(1993).
18) Agami C., Cases M., Couty F., J. Org. Chem., 59, 7937—7940 (1994).
propenylmagnesium bromide in THF (52 ml, 0.52 mmol) and TMEDA 19) Hanessian S., Ninkovic S., J. Org. Chem., 61, 5418—5424 (1996).
(0.04 ml, 0.2 mmol) was added dropwise over 7 min to a solution of bromide 20) Hanessian S., Ninkovic S., Reinhold U., Tetrahedron Lett., 37, 8971—
16 (46 mg, 0.17 mmol) and FeCl3 (3 mg, 0.02 mmol) in THF (0.2 ml) at 0 °C.
8974 (1996).
After 30 min, the reaction was quenched by addition of satd NH4Cl (2 ml). 21) Miyata O., Ozawa Y., Ninomiya I., Aoe K., Hiramatsu H., Naito T.,
The mixture was extracted with AcOEt (10 mlϫ3). The combined organic
layers were washed with brine (5 ml) and dried over Na2SO4. Concentration
and column chromatography (hexane/AcOEtϭ1/1) gave a 71 : 11 : 18 mix-
Heterocycles, 46, 321—333 (1997).
22) Chevliakov M. V., Montgomery J., Angew. Chem., Int. Ed., 37, 3144—
3146 (1998).
ture of 17, cis-isomer, and 16 (21 mg, 36%, 6%, and 8%, respectively) as 23) Anada M., Sugimoto T., Watanabe N., Nakajima M., Hashimoto S.,
white solids of mp 77—78 °C with [a]D25 ϩ10.1 (cϭ0.525, CHCl3), and 18
Heterocycles, 50, 969—980 (1999).
(17 mg, 50%) as colorless oil. 1H- and 13C-NMR, and IR were in good 24) Chevliakov M. V., Montgomery J., J. Am. Chem. Soc., 121, 11139—
agreement with those reported for 17 and the cis-isomer.19) The ratio of 17,
11143 (1999).
cis-isomer, and 16 was determined based on the integration area of 1H-NMR 25) Ma D., Wu W., Deng P., Tetrahedron Lett., 42, 6929—6931 (2001).
signals at 4.45—4.58 (the overlapping OCH2 of the three compounds), 4.24
(the other OCH2 of the cis-isomer), and 3.98 ppm (the NCH of 16).
17: Rf 0.6 (hexane/AcOEtϭ1/1, developed three times). lit.19) [a]D ϩ4.0
(cϭ1.0, CHCl3). FAB-MS m/z: 240 (MϩHϩ). HR-MS-FAB (m/z): [MϩH]ϩ
Calcd for C12H18NO4, 240.1236. Found: 240.1241.
26) Cook G. R., Sun L., Org. Lett., 6, 2481—2484 (2004).
27) Jung Y. C., Yoon C. H., Turos E., Yoo K. S., Jung K. W., J. Org.
Chem., 72, 10114—10122 (2007).
28) “Radicals in Organic Synthesis,” ed. by Renaud P., Sibi M. P., Wiley-
VCH, Weinhem, 2001.
18: Rf 0.1 (hexane/AcOEtϭ1/1, developed three times). [a]D25 Ϫ8.6
(cϭ0.40, CHCl3). 1H-NMR: 2.39 (1H, dd, Jϭ7.8, 15.5), 2.44 (1H, dd,
Jϭ6.3, 15.5), 2.69 (1H, m), 3.69 (3H, s), 3.93 (1H, m), 4.16 (1H, dd, Jϭ6.0,
8.9), 4.47 (1H, dd, Jϭ8.9, 8.9), 5.13 (1H, br s), 5.25 (1H, d, Jϭ17.2), 5.28
(1H, d, Jϭ10.2), 5.67 (1H, ddd, Jϭ8.6, 10.2, 17.2). 13C-NMR: 35.3 (CH2),
44.3 (CH), 51.9 (CH3), 54.5 (CH), 67.8 (CH2), 119.9 (CH2), 134.4 (CH),
159.4 (C), 171.8 (C). IR (KBr): 1766, 1728, 1643. FAB-MS m/z: 200
(MϩHϩ). HR-MS-FAB (m/z): [MϩH]ϩ Calcd for C9H14NO4, 200.0923.
Found: 200.0927.
29) Crich D., Eustace K. A., Ritchie T. J., Heterocycles, 28, 67—70
(1989).
30) Ryu I., Matsu K., Minakata S., Komatsu M., J. Am. Chem. Soc., 120,
5838—5839 (1998).
31) Allin S. M., Barton W. R. S., Bowman W. R., McInally T., Tetrahedron
Lett., 42, 7887—7890 (2001).
32) Benati L., Leardine R., Minozzi M., Nanni D., Spagnolo P., Org. Lett.,
4, 3079—3081 (2002).
33) Taaning R. H., Thim L., Karaffa J., Campana A. G., Hansen A. M.,
Skrydstrup T., Tetrahedron, 64, 11884—11895 (2008).
Acknowledgements This research was partially supported by a Grant- 34) Baldwin J. K., Moloney M. G., Parsons A. F., Tetrahedron, 48, 9373—
in-Aid for Young Scientist (B) and a Grant-in-Aid for Scientific Research 9384 (1992).
(A) from the Japan Society for the Promotion of Science (JSPS), and Tar- 35) Gandon L A, Russell A. G., Snaith J. S., Org. Biomol. Chem., 2004,
geted Protein Research Program from Japan Science and Technology
Agency.
2270—2271 (2004).
36) Bennett N. J., Prodger J. C., Pattenden G., Tetrahedron, 63, 6216—
6231 (2007).
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