Use of ketene dithioacetal as a latent carboxylic acid in the macrolactonization applicable to the synthesis of dilactonic pyrrolizidine alkaloids

Article abstract of DOI:10.1021/jo951363y

Acid 5a (or 5b) bearing the ketene dithioacetal moiety functioned as an equivalent of a dicarboxylic acid. Use of the ketene dithioacetal in the formation of 11-membered dilactones is demonstrated. Compound 5a (or 5b) was converted to an acid imidazolide which reacted regioselectively with retronecine at the allylic position. Mild acidic hydrolysis of the ketene dithioacetal moiety led to a thioester, which underwent macrocyclization with the secondary hydroxyl group mediated by silver(I) trifluoroacetate to give derivatives of the pyrrolizidine alkaloids.

Full text of DOI:10.1021/jo951363y

J . Org. Chem. 1996, 61, 1473-1477
1473
Use of Keten e Dith ioa ceta l a s a La ten t Ca r boxylic Acid in th e
Ma cr ola cton iza tion Ap p lica ble to th e Syn th esis of Dila cton ic
P yr r olizid in e Alk a loid s
Wen-Chih Chou and J im-Min Fang*
Department of Chemistry, National Taiwan University, Taipei 106, Taiwan, Republic of China
Received J uly 26, 1995X
Acid 5a (or 5b) bearing the ketene dithioacetal moiety functioned as an equivalent of a dicarboxylic
acid. Use of the ketene dithioacetal in the formation of 11-membered dilactones is demonstrated.
Compound 5a (or 5b) was converted to an acid imidazolide which reacted regioselectively with
retronecine at the allylic position. Mild acidic hydrolysis of the ketene dithioacetal moiety led to
a thioester, which underwent macrocyclization with the secondary hydroxyl group mediated by
silver(I) trifluoroacetate to give derivatives of the pyrrolizidine alkaloids.
In tr od u ction
Resu lts a n d Discu ssion
In order to avoid formation of γ-lactones such as
crobarbatic acid derivatives 3, the tertiary hydroxyl group
of ketene dithioacetal 2 was protected as an ether.
Alcohol 2 was treated with NaH and PhCH2Br in reflux-
ing THF to give, in 95% yield, benzyl ether 4a , which
was saponified to the acid 5a . After activation to
imidazolide 6a , regioselective esterification with (+)-
retronecine was carried out to give ester 7a in a 93%
yield. The side product imidazole was readily removed
on stirring with IR-120 resin (acidic form). No esterifi-
cation with the secondary alcohol of retronecine was
observed. The ratio of the two diastereomers in 7a was
deduced to be 1:1 on the basis of analysis of 9a /10a (see
below).
Ketene dithioacetals are usually difficult to hydrolyze
but readily form spiro orthodithioesters by assistance of
a neighboring hydroxyl group.3,8 The first transformation
of a ketene dithioacetal to a thioester was demonstrated
by the conversion of 7a to 8a . On treatment with
concentrated hydrochloric acid for a short period, ketene
dithioacetals 7a were smoothly converted to thioesters
8a (88%) bearing an activated carboxyl group suitable
for the formation of macrocyclic lactones. Hydrolysis
with organic acid catalysts such as AcOH, TFA, and
TsOH required prolonged periods and gave lower yields.
The diastereomeric mixture of 8a was treated with silver-
(I) trifluoroacetate and 4-DMAP in refluxing THF to give
9a and 10a (1:1) in 55% yield. In the absence of 4-DMAP,
the yield was lower (22%).9a The reaction did not occur
in hot toluene presumably due to poor solubility of the
substrates. Treatment of 8a with copper(I) trifluo-
romethanesulfonate in refluxing benzene failed to pro-
duce the macrocycle.9b
Ketene dithioacetals are frequently used as latent
carboxylic acids in addition to other applications.1 We
previously carried out a stereoselective synthesis of
ketene dithioacetal 2 via the reaction of ethyl pyruvate
with the 2-propenyl-1,3-dithian-2-ylzinc reagent derived
from dithiane 1 (Scheme 1).2 The stereochemistry in 2
results from the strong chelating ability of the zinc cation
and oxygen atoms of pyruvate. As a masked form of
2-hydroxy-2,3-dimethylglutaric acid, ester 2 is readily
converted to crobarbatic acid ethyl ester 3 on hydrolysis
with HgCl2 catalysis.3 Crobarbatic acid has been shown
to bear two trans-methyl groups;3,4 however, its absolute
configuration is still unknown. Ester 2 has the potential
for regioselective elaboration to an 11-membered dilac-
tonic pyrrolizidine alkaloid, crobarbatine (9d or 10d ),5
by esterification of retronecine at the allylic hydroxyl
group and macrocyclization subsequent to hydrolysis of
the ketene dithioacetal moiety. We report herein the
results of this investigation. In the present case, the
ketene dithioacetal not only functions as a masked
carboxylic acid at an early stage of the synthesis but also
was readily transformed to an activated thioester for the
ultimate formation of the macrocyclic lactone. It is well
documented6 that ω-hydroxy acids are generally activated
as the corresponding ω-hydroxy thioesters, which un-
dergo macrolactonization by catalysis with thiophilic
metal ions such as Ag(I), Cu(I), Hg(II), and Tl(I). The
use of ω-hydroxy thioesters in the synthesis of pyrrolizi-
dine alkaloids has been reported.4a,7
X Abstract published in Advance ACS Abstracts, February 1, 1996.
(1) (a) Kolb, M. Synthesis 1990, 171. (b) Lee, T.-J .; Holtz, W. J .;
Smith, R. L. J . Org. Chem. 1982, 47, 4750. (c) Chamberlin, A. R.;
Chung, J . Y. L. J . Org. Chem. 1985, 50, 4425.
(2) (a) Fang, J .-M.; Hong, B.-C. J . Org. Chem, 1987, 52, 3162. (b)
Chen, M.-Y.; Fang, J .-M. J . Org. Chem. 1992, 57, 2937.
(3) (a) Fang, J .-M.; Liao, L.-F.; Hong, B.-C. J . Org. Chem. 1986, 51,
2828. (b) Fang, J .-M.; Hong, B.-C.; Liao, L.-F. J . Org. Chem. 1987, 52,
855.
(4) (a) Huang, J .; Meinwald, J . J . Am. Chem. Soc. 1981, 103, 861.
(b) Adams, R.; Rogers, E. F. J . Am. Chem. Soc. 1939, 61, 2815.
(5) (a) Puri, S. C.; Sawhney, R. S.; Atal, C. K. Experientia 1973, 29,
390. (b) For a recent review of pyrrolizidine alkaloids, see: Robins, D.
J . Nat. Prod. Rep. 1989, 221.
(6) For reviews of macrolide syntheses, see: (a) Masamune, S.;
Bates, G. S.; Corcoran, J . W. Angew. Chem., Int. Ed. Engl. 1977, 16,
585. (b) Nicolaou, K. C. Tetrahedron 1977, 33, 683. (c) Back, T. G.
Terahedron 1977, 33, 3041.
The diastereomers 9a and 10a were separated by
HPLC, and their structures were assigned by comparison
of their polarity and NMR data with those of analogs 9c
and 10c (Table 1).4a In addition to other signals, the H-8
and C-8 resonances of 10a appeared at higher fields (δΗ
5.08-5.14 and δC 76.79) than those of 9a (at δΗ 5.59 and
δC 78.64). Alcohol 2 was similarly alkylated with 4-meth-
(8) Lee, T.-J .; Holtz, W. J .; Smith, R. L. J . Org. Chem. 1982, 47,
4750.
(9) Use of 4-DMAP to facilitate macrolactonization: (a) Niwa, H.;
Okamoto, O.; Yamada, K. Tetrahedron Lett. 1988, 29, 5139. The use
of Ag(I) is superior to other metal ions in the transformation of
thioesters to esters; see: (b) Gerlach, H.; Thalmann, A. Helv. Chim.
Acta 1974, 57, 293.
(7) Brown, K.; Delvin, J . A.; Robins, D. J . J . Chem. Soc., Perkin
Trans. 1 1983, 1819.
0022-3263/96/1961-1473$12.00/0 © 1996 American Chemical Society

1474 J . Org. Chem., Vol. 61, No. 4, 1996
Chou and Fang
Ta ble 1. Som e P er tin en t 1H a n d 13C NMR Da ta of
Cr oba r ba tin e Der iva tives 9a -10c (CDCl3, δ Va lu es)
Sch em e 1a
compda
H-2
H-8
Me-2′
C-2
C-7
C-8
C-2′
9a
10a
9b
10b
9cb
10cb
5.88
5.59
1.53 134.94 72.54 78.64 80.83
6.00
5.91
5.98
5.08-5.14 1.49 133.88 74.56 76.79 79.49
5.58 1.50 134.86 72.47 78.74 80.70
5.07-5.11 1.46 133.68 74.43 76.89 79.39
5.96-6.06 5.34-5.39 1.56 134.90 73.24 78.23 82.17
5.96-6.02 5.08-5.24 1.51 134.41 74.37 76.98 81.74
a
Compound 9a (or 9b or 9c) was less polar on silica gel than
b
the corresponding isomer 10a (or 10b or 10c). Data are adapted
from ref 4a.
compound 10a (or 10b) was tentatively assigned to have
the (2′R,3′S,7R,8R) configuration by analogy to 10c.4a
Attempts to remove the benzyl protecting groups in
10a or 10b failed. Hydrogenation of 10a over 5% Pd/C
saturated the double bond of the retronecine moiety
without cleavage at the benzyl group. Treatment of 10a
with Me3SiI10 in CH2Cl2 gave a product 11a ,11 which was
considered to be the C-8 epimer of 10a as it showed all
the characteristic proton and carbon resonances, except
the chemical shifts on the retronecine ring were distinct
from those of 10a . Treatment of 10a with dissolving
metal (Li/NH3),12 of 10b with DDQ13 or CAN,14 or
photolysis (λ ) 300 nm) sensitized with 1,4-dicyano-
naphthalene15 all caused rupture of the macrolides and
led to intractable products. (Methylthio)methyl ether
4c,16 prepared by treating (()-2 with Me2SO-Ac2O,17 was
unsuitable for the total synthesis. The (methylthio)-
methyl protecting group decomposed upon saponification
of 4c followed by acidification with aqueous HCl.
In summary, we have demonstrated a route for the
synthesis of dilactones in a regioselective manner. As
an example, ketene dithioacetal 2 functioned as an
equivalent of 2-hydroxy-2,3-dimethylglutaric acid, so that
esterification with retronecine occurred regioselectively
at the desired allylic position. Upon acid-catalyzed
hydrolysis, the ketene dithioacetal moiety was readily
converted to a thioester suitable for the subsequent
(10) (a) J ung, M. E.; Lyster, M. A. J . Org. Chem. 1977, 42, 3761. (b)
Olah, G. A.; Narang, S. C. Tetrahedron 1982, 38, 2225.
(11) Compound 11a : 1H NMR (CDCl3) δ 1.07 (d, J ) 6.9 Hz, 3 H),
1.52 (s, 3 H), 2.29 (dd, J ) 3.6, 15.6 Hz, 1 H), 2.46-2.52 (m, 4 H), 2.77
(dd, J ) 15.6, 11.1 Hz, 1 H), 3.00-3.12 (m, 1 H), 3.68 (d, J ) 16.4 Hz,
1 H), 4.10-4.20 (m, 1 H), 4.42, 4.68 (AB quartet, J ) 11.0 Hz, 2 H),
4.70-4.80 (m, 1 H), 4.48, 5.16 (AB quartet, J ) 12.3 Hz, 2 H), 5.33 (br
s, 1 H), 6.10 (s, 1 H), 7.27-7.42 (m, 5 H); 13C NMR (CDCl3) δ 15.31 (q),
20.65 (q), 33.68 (t), 37.55 (t), 38.25 (d), 54.35 (t), 56.10 (t), 59.99 (t),
66.45 (t), 72.00 (d), 78.20 (d), 79.44 (s), 127.37 (d, 3 C), 128.25 (d, 2 C),
129.70 (d), 131.77 (s), 138.64 (s), 169.64 (s), 173.58 (s).
(12) Philips, K. D.; Zemlicka, J .; Horowitz, J . P. Carbohydr. Res.
1973, 30, 281.
(13) Trost, B. M.; Chung, J . Y. L. J . Am. Chem. Soc. 1985, 107, 4586.
(14) J ohansson, R. ; Samuelsson, B. J . Chem. Soc., Perkin Trans. 1
1984, 2371.
a
Reagents and conditions: (i) BuLi, THF, -30 °C; ZnCl2 (3
equiv), -100 °C; 85% (92% de); (ii) aqueous EtOH, HgCl2; 86%;
(iii) for 4a , NaH, PhCH2Br, THF, reflux, 4 h; 95%; for 4b, NaH,
p-MeOC6H4CH2I, THF, reflux, 16 h; 75%; (iv) t-BuOK (8 equiv),
H2O (2 equiv), THF, 26 °C, 0.5 h; then HCl; 5a , 100%; 5b, 96%;
(v) N,N′-carbonyldiimidazole (1.1 equiv), THF, 26 °C, 4 h; 6a , 95%;
6b, 98%; (vi) NaH (0.2 equiv), retronecine (1 equiv), THF, 26 °C,
2 h; then NH4Cl (aq); 7a , 93%; 7b, 100%; (vii) HCl, CH2Cl2, 26
°C, 0.5 h; 8a , 88%; 8b, 53%. (viii) silver trifluroacetate (6 equiv),
DMAP (12 equiv), THF, reflux, 40 h; 9a /10a (1:1), 55%; 9b/10b
(1:1), 67%.
(15) Pandey, G.; Krishna, A. Synth. Commun. 1988, 18, 2309.
(16) Compound 4c: 1H NMR (CDCl3) δ 0.99 (d, J ) 6.9 Hz, 3 H),
1.27 (t, J ) 7.2 Hz, 3 H), 1.41 (s, 3 H), 2.08-2.15 (m, 2 H), 2.20 (s, 3
H), 2.78-2.87 (m, 4 H), 3.11-3.20 (m, 1 H), 4.13 (q, J ) 7.2 Hz, 2 H),
4.48, 4.62 (AB quartet, J ) 10.4 Hz, 2 H), 5.94 (d, J ) 10.0 Hz, 1 H).
(17) Pojer, P. M.; Angyal, S. J . Aust. J . Chem. 1978, 31, 1031.
oxybenzyl iodide to give 4b, which was subsequently
transformed into the macrolides 9b and 10b (1:1). These
two isomers also showed characteristic resonances in
1
their H and 13C NMR spectra (Table 1). The more polar

Synthesis of Dilactonic Pyrrolizidine Alkaloids
J . Org. Chem., Vol. 61, No. 4, 1996 1475
293 (4), 232 (12), 187 (1), 159 (100), 132 (18), 91 (23); 1H NMR
(CDCl3) δ 0.99 (d, J ) 6.6 Hz, 3 H), 1.38 (s, 3 H), 2.00-2.12
(m, 2 H), 2.70-2.85 (m, 4 H), 3.24 (dq, J ) 10.1, 6.6 Hz, 1 H),
4.42, 4.51 (AB quartet, J ) 11.6 Hz, 2 H), 6.09 (d, J ) 10.1
Hz, 1 H), 7.17-7.34 (m, 5 H), 9.52 (br s, 1 H); 13C NMR (CDCl3)
δ 15.05 (q), 19.07 (q), 25.17 (t), 29.67 (t), 30.29 (t), 41.16 (d),
65.70 (t), 83.12 (s), 126.53 (s), 126.94 (d, 3 C), 128.16 (d, 2 C),
135.61 (d), 139.05 (s), 178.06 (s); HRMS for C17H22O3S2 calcd
338.1010, found 338.0983.
2,3-Dim eth yl-4-(1,3-d ith ia n ylid en e)-2-[(4-m eth oxyben -
zyl)oxy]bu ta n oic Acid (5b). Ester (()-4b (0.89 g) was
saponified by a procedure similar to that for 5a to give acid
(()-5b (0.80 g, 96%): oil; Rf 0.28 (EtOAc/hexane (1:1)); IR
(neat) 3500-2400 , 1708, 1505, 1245 cm-1; MS m/ z (rel
intensity) 368 (4, M+), 323 (0.5), 159 (100), 132 (30), 121 (46);
1H NMR (CDCl3) δ 1.03 (d, J ) 6.9 Hz, 3 H), 1.47 (s, 3 H),
1.98-2.11 (m, 2 H), 2.76-2.84 (m, 4 H), 3.26 (dq, J ) 10.1,
6.9 Hz, 1 H), 3.75 (s, 3 H), 4.41, 4.48 (AB quartet, J ) 10.6
Hz, 2 H), 6.03 (d, J ) 10.1 Hz, 1 H), 6.82 (d, J ) 8.5 Hz, 2 H),
7.26 (d, J ) 8.5 Hz, 2 H), 9.30 (br s, 1 H); 13C NMR (CDCl3) δ
14.56 (q), 19.08 (q), 25.00 (t), 25.59 (t), 30.17 (t), 41.40 (d), 55.13
(q), 65.97 (t), 82.24 (s),, 113.60 (d, 2 C), 127.75 (s), 128.90 (d,
2 C), 130.27 (s), 134.00 (d), 158.94 (s), 177.71 (s); HRMS for
C18H24O4S2 calcd 368.1116, found 368.1119.
macrolactonization. This is the first report that a ketene
dithioacetal can be hydrolyzed to a thioester and used
in the synthesis of pyrrolizidine alkaloids.
Exp er im en ta l Section
Mass spectra were recorded at an ionizing voltage 70 or 20
eV. A quartz cuvette (length 10 cm) was used for optical
rotation measurements. Merck silica gel 60F sheets were used
for analytical TLC. Column chromatography was conducted
on silica gel 60 (Merck, 70-230 mesh ASTM). A µ-Porasil
column (25 cm × 7.8 mm i.d.) was used for HPLC; the flow
rate of indicated eluent was 5 mL/min. Retronecine, [R]26
)
D
+50.1° (c 1.2, ethanol), was prepared by hydrolysis of mono-
crotaline according to the literature procedure.4 Preparation
of (()-2 was reported.2
Eth yl 2-(Ben zyloxy)-2,3-dim eth yl-4-(1,3-dith ian yliden e)-
bu ta n oa te (4a ). Under an atmosphere of argon, a suspension
of NaH (0.45 g of 60% oil dispersion, 11.3 mmol) in anhydrous
THF (20 mL) was placed in a 50 mL round-bottomed flask
equipped with a refluxing condenser and capped with a
septum. A solution of alcohol (()-2 (1.57 g, 5.7 mmol) in THF
o
(5 mL) was added dropwise at 25 C. The evolution of H2 was
apparent. The mixture was stirred for 10 min to give a turbid
solution, after which PhCH2Br (0.5 mL, 5 mmol) in THF (5
mL) was added dropwise. The mixture was heated at reflux
for 4 h and cooled, and saturated NH4Cl aqueous solution (5
mL) was added. THF was removed by rotary evaporation, and
the residue was extracted with EtOAc (2 × 30 mL). The
organic phase was washed with brine, dried (Na2SO4), and
filtered, and the filtrate was concentrated by rotary evapora-
tion. The residue was chromatographed on a silica gel column
by elution with EtOAc/hexane (1:9) to give benzyl ether (()-
4a (1.98 g, 95%): oil; Rf 0.35 (EtOAc/hexane (1:9)); IR (neat)
1725, 697 cm-1; MS m/ z (rel intensity) 366 (0.5, M+), 293 (3),
2-(Ben zyloxy)-2,3-d im et h yl-4-(1,3-d it h ia n ylid en e)b u -
ta n oyl Im id a zolid e (6a ). Under argon atmosphere, a solu-
tion of acid (()-5a (258 mg, 0.76 mmol) in THF (5 mL) was
added to a solution of 1,1′-carbonyldiimidazole (136 mg, 0.84
mmol) in THF (5 mL). The mixture was stirred at 25 °C for
4 h, after which it was concentrated by rotary evaporation.
The residue was partitioned between CH2Cl2 and water, and
the aqueous layer was extracted with Et2O (2 × 30 mL). The
combined organic extracts were dried (Na2SO4) and concen-
trated by rotary evaporation to yield the corresponding imid-
azolide (()-6a (282 mg, 95%). Further purification was
conducted by chromatography on a silica gel column with
elution of EtOAc/hexane (1:1): oil; Rf 0.43 (EtOAc/hexane (1:
1)); IR (neat) 1715, 1462, 1284, 1234 cm-1; MS m/ z (rel
intensity) 388 (4, M+), 297 (4), 293 (14), 159 (100), 91 (12); 1H
NMR (CDCl3) δ 0.96 (d, J ) 6.9 Hz, 3 H), 1.55 (s, 3 H), 2.10-
2.16 (m, 2 H), 2.61-2.70 (m, 1 H), 2.79-2.88 (m, 3 H), 3.53
(dq, J ) 9.9, 6.9 Hz, 1 H), 4.25, 4.55 (AB quartet, J ) 11.4 Hz,
2 H), 5.89 (d, J ) 9.9 Hz, 1 H), 7.03 (s, 1 H), 7.23-7.35 (m, 5
H), 7.81 (s, 1 H), 8.70 (s, 1 H); 13C NMR (CDCl3) δ 15.03 (q),
16.25 (q), 24.58 (t), 29.27 (t), 29.74 (t), 41.24 (d), 66.50 (t), 85.92
(s), 117.21 (d), 126.86 (d, 2 C), 127.29 (d), 127.97 (d, 2 C), 129.54
(d), 130.31 (s), 131.44 (d), 136.80 (s), 137.95 (d), 171.88 (s);
HRMS for C20H24N2O2S2 calcd 388.1279, found 388.1277.
2,3-Dim eth yl-4-(1,3-d ith ia n ylid en e)-2-[(4-m eth oxyben -
zyl)oxy]bu ta n oyl Im id a zolid e (6b). Acid (()-5b (194 mg)
was treated with 1,1′-carbonyldiimidazole by a procedure
similar to that for 6a to give imidazolide (()-6b (215 mg,
98%): oil; Rf 0.30 (EtOAc/hexane (35:65)); IR (neat) 3142, 1714,
1508, 1246 cm-1; MS m/ z (rel intensity) 418 (0.5, M+), 323
1
159 (100) , 132 (14), 91 (27); H NMR (CDCl3) δ 1.05 (d, J )
6.9 Hz, 3 H), 1.29 (t, J ) 7.2 Hz, 3 H), 1.47 (s, 3 H), 2.04-2.19
(m, 2 H), 2.78-2.87 (m, 4 H), 3.24 (dq, J ) 10.1, 6.9 Hz, 1 H),
4.19 (q, J ) 7.2 Hz, 2 H), 4.45, 4.57 (AB quartet, J ) 11.3 Hz,
2 H), 6.45 (d, J ) 10.1 Hz, 1 H), 7.21-7.42 (m, 5 H); 13C NMR
(CDCl3) δ 14.04 (q), 14.33 (q), 18.82 (q), 24.83 (t), 29.36 (t),
29.96 (t), 42.06 (d), 60.53 (t), 66.16 (t), 81.85 (s), 126.77 (s),
126.87 (d, 3 C), 127.81 (d, 2 C), 134.17 (d), 138.80 (s), 173.06
(s); HRMS for C19H26O3S2 calcd 366.1323, found 366.1329.
Eth yl 2,3-Dim eth yl-4-(1,3-d ith ia n ylid en e)-2-[(4-m eth -
oxyben zyl)oxy]bu ta n oa te (4b). p-Methoxybenzyl iodide
was prepared from p-methoxybenzyl bromide and NaI in Me2-
CO. Alcohol 2 (0.83 g) was treated with NaH and p-methoxy-
benzyl iodide by a procedure similar to that for 4a to give
p-methoxybenzyl ether (()-4b (0.89 g, 75%): oil; Rf 0.22
(MeOH/CH2Cl2 (1:9)); IR (neat) 1726 cm-1; MS m/ z (rel
intensity) 396 (12, M+), 323 (4), 289 (1), 260 (35), 159 (100),
132 (148), 121 (78), 91 (8); 1H NMR (CDCl3) δ 1.01 (d, J ) 6.9
Hz, 3 H), 1.28 (t, J ) 7.3 Hz, 3 H), 1.44 (s, 3 H), 2.05-2.17 (m,
2 H), 2.75-2.85 (m, 4 H), 3.20 (dq, J ) 10.1, 6.9 Hz, 1 H), 3.78
(s, 3 H), 4.17 (q, J ) 7.3 Hz, 2 H), 4.35, 4.46 (AB quartet, J )
10.7 Hz, 2 H), 6.01 (d, J ) 10.1 Hz, 1 H), 6.84 (d, J ) 8.5 Hz,
2 H), 7.29 (d, J ) 8.5 Hz, 2 H); 13C NMR (CDCl3) δ 14.29 (q),
14.57 (q), 19.09 (q), 25.13 (t), 29.64 (t), 30.27 (t), 42.30 (d), 55.21
(q), 60.78 (t), 66.16 (t), 82.08 (s), 113.53 (d, 2 C), 126.83 (s),
128.70 (d, 2 C), 131.21 (s), 134.71 (d), 158.81 (s), 173.50 (s);
HRMS for C20H28O4S2 calcd 396.1429, found 396.1430.
1
(2), 159 (100), 132 (38), 121 (36), 68 (35); H NMR (CDCl3) δ
0.91 (d, J ) 6.8 Hz, 3 H), 1.50 (s, 3 H), 2.03-2.11 (m, 2 H),
2.58-2.65 (m, 1H), 2.77-2.83 (m, 3 H), 3.46 (dq, J ) 9.9, 6.8
Hz, 1 H), 3.75 (s, 3 H), 4.13, 4.45 (AB quartet, J ) 10.7 Hz, 2
H), 5.84 (d, J ) 9.9 Hz, 1 H), 6.78 (d, J ) 8.5 Hz, 2 H), 6.98 (s,
1 H), 7.11 (d, J ) 8.5 Hz, 2 H), 7.75 (s, 1 H), 8.64 (s, 1 H); 13
C
NMR (CDCl3) δ 15.30 (q), 16.66 (q), 24.91 (t), 29.61 (t), 30.13
(t), 41.53 (d), 55.15 (q), 66.63 (t), 86.03 (s), 113.67 (d, 2 C),
117.55 (d), 128.91 (d, 2 C), 129.05 (s), 130.40 (s), 130.40 (d),
132.05 (d), 138.37 (d), 159.11 (s), 172.39 (s); HRMS for
C21H26N2O3S2 calcd 418.1385, found 418.1390.
2-(Ben zyloxy)-2,3-d im et h yl-4-(1,3-d it h ia n ylid en e)b u -
ta n oic Acid (5a ). To a solution of ester (()-4a (280 mg, 0.76
mmol) and H2O (27 mg, 1.53 mmol) in THF (10 mL) was added
t-BuOK (0.68 g, 6.1 mmol) at 0 °C. The orange solution was
stirred at 25 °C for 0.5 h, HCl (0.55 mL of 12 N solution) was
added, and the solution was concentrated by rotary evapora-
tion. The residue was extracted with EtOAc (2 × 30 mL), the
combined extracts were washed with brine, dried (Na2SO4),
and filtered, and the filtrate was concentrated by rotary
evaporation. The residue was chromatographed on a silica gel
column by elution with EtOAc to give acid (()-5a (795 mg,
96%): oil; Rf 0.55 (EtOAc); IR (neat) 3500-2400 , 1705, 1277,
697 cm-1; MS m/ z (rel intensity) 339 (7, M+ + 1), 338 (5, M+)
Retr on ecin e Ester of 2-(Ben zyloxy)-2,3-d im eth yl-4-
(1,3-d ith ia n ylid en e)bu ta n oic Acid (7a ). To a suspension
of NaH (5 mg of 80% oil dispersion, 0.17 mmol) in anhydrous
THF (10 mL) was added (+)-retronecine (124 mg, 0.80 mmol)
at 25 °C under argon atmosphere. The suspension was stirred
at 25 °C for 5 min, and evolution of H2 ceased, after which a
solution of (()-6a (311 mg, 0.80 mmol) in THF (10 mL) was
added dropwise over a period of 1 min. The reaction mixture
was stirred for 2 h, and aqueous NH4Cl (9 mg in 0.1 mL of
water, 0.17 mmol) was added, after which the mixture was
stirred for 5 min. The solution was concentrated by rotary

1476 J . Org. Chem., Vol. 61, No. 4, 1996
Chou and Fang
evaporation, and the residue was chromatographed on a silica
gel column by elution with MeOH/CH2Cl2 (1:9) to give crude
ester 7a contaminated with imidazole. The crude ester was
dissolved in CH2Cl2 (20 mL), IR-120 resin (acidic form) was
added, and the resulting mixture was stirred for 1 h. The
mixture was filtered, and the filtrate was concentrated to give
pure 7a (351 mg, 93%): oil; Rf 0.26 (MeOH/CH2Cl2 (1:9)); IR
(neat) 3200, 1730, 1063 cm-1; MS m/ z (rel intensity) 476 (10,
M+ + 1), 475 (1, M+), 339 (5), 159 (100), 138 (20), 106 (10), 91
(t), 33.47 (t), 35.95 (t), 38.05 (d), 45.84 (t), 53.91 (t), 55.23 (q),
61.83 (t), 62.43 (t), 66.33 (t), 70.70 (d), 78.54 (d), 82.24 (s),
113.66 (d, 2 C), 128.80 (d, 2 C), 128.95 (d), 130.22 (s), 132.75
(s), 159.03 (s), 173.44 (s), 198.60 (s); HRMS for C26H37NO6S2
calcd 523.2062, found 523.2060.
Cr oba r ba tin e Der iva tives 9a a n d 10a . Under an argon
atmosphere, a solution of thioester 8a (56 mg, 0.11 mmol) in
anhydrous THF (10 mL) was added dropwise over a period of
2 h to a refluxing THF (30 mL) solution containing 4-(di-
methylamino)pyridine (166 mg, 1.36 mmol) and silver(I)
trifluoroacetate (145 mg, 0.68 mmol). The resulting green
solution was heated at reflux for an additional 40 h, cooled,
and stirred at room temperature for 2 h. The mixture was
bubbled with H2S (prepared from FeS and dilute H2SO4) until
no more black precipitate appeared. The black precipitate was
filtered, the filtrate was concentrated and chromatographed
on a silica gel column by elution with MeOH/CH2Cl2 (1:9), Rf
0.37, to give dilactones 9a and 10a (24 mg, 55%, 1:1 ratio).
Two isomers were separated by HPLC. 9a : oil; tR 7.83 min
(MeOH/CH2Cl2 (2:8)); [R]26D ) +32.3° (c 1.12, CHCl3); IR (neat)
1731, 699 cm-1; MS m/ z (rel intensity) 385 (6, M+), 279 (32),
251 (35), 220 (23), 135 (52), 119 (100), 91 (28); 1H NMR (CDCl3)
1
(36); H NMR (CDCl3) δ 1.06 (d, J ) 6.8 Hz, 3 H), 1.51 (s, 3
H), 2.00-2.17 (m, 4 H), 2.76-2.97 (m, 5 H), 3.21-3.30 (m, 1
H), 3.43-3.58 (m, 2 H), 4.10 (br d, J ) 15.3 Hz, 1 H), 4.37-
4.44 (m, 2 H), 4.50-4.52 (m, 2 H), 4.65-4.90 (m, 2 H), 5.82
(br s, 1 H), 6.01 (d, J ) 10.1 Hz, 1 H), 7.22-7.38 (m, 5 H); 13
C
NMR (CDCl3) δ 14.28 (q), 18.87 (q), 24.71 (t), 29.30 (t), 29.86
(t), 35.71 (t), 41.93 (d), 53.26 (t), 61.36 (t), 61.72 (t), 66.10 (t),
70.10 (d), 77.96 (d), 82.09 (s), 126.74 (d, 3 C), 126.79 (d), 127.42
(s), 127.84 (d, 2 C), 132.84 (s), 133.40 (d), 138.42 (s), 172.85
(s); HRMS for C25H33NO4S2 calcd 475.1851, found 475.1842.
Retr on ecin e Ester of 2,3-Dim eth yl-4-(1,3-d ith ia n yl-
iden e)-2-[(4-m eth oxyben zyl)oxy]bu tan oic Acid (7b). Treat-
ment of imidazolide (()-6b (401 mg) with (+)-retronecine by
a procedure similar to that for 7a , after removal of residual
imidazole with IR-120 resin, gave ester 7b (484 mg, 100%):
1.10 (d, J ) 7.1 Hz, 3 H), 1.53 (s, 3 H), 1.92-2.15 (m, 2 H),
δ
2.02 (dd, J ) 16.6, 1.6 Hz, 1 H), 2.45 (ddq, J ) 10.1, 7.1, 1.6
Hz, 1 H), 2.72-2.79 (m, 1H), 3.03 (dd, J ) 16.6, 10.7 Hz, 1 H),
3.28 (ddd, J ) 8.9, 6.9, 2.0 Hz, 1 H), 3.50 (dd, J ) 20.3, 5.5
Hz, 1 H), 3.94 (dd, J ) 20.3, 1.9 Hz, 1 H), 4.34, 4.46 (AB
quartet, J ) 11.3 Hz, 2 H), 4.45-4.47 (m, 1 H), 4.43, 4.55 (AB
quartet, J ) 11.6 Hz, 2 H), 5.59 (ddd, J ) 5.2, 5.2, 1.8 Hz, 1
H), 5.88 (br d, J ) 1.9 Hz, 1H), 7.25-7.41 (m, 5 H); 13C NMR
(CDCl3) δ 16.10 (q), 20.37 (q), 33.17 (t), 37.24 (t), 38.75 (d),
54.18 (t), 59.27 (t), 61.13 (t), 66.97 (t), 72.54 (d), 78.64 (d), 80.83
(s), 127.36 (d, 3 C), 128.10 (d, 2 C), 132.40 (s), 134.94 (d), 138.89
(s), 173.08 (s), 174.19 (s); HRMS for C22H27NO2 calcd 385.1890,
found 385.1895. 10a : oil, tR 9.83 min (MeOH/CH2Cl2 (2:8));
oil; Rf 0.24 (MeOH/CH2Cl2 (1:9)); IR (neat) 3200, 1730 cm-1
;
MS m/ z (rel intensity) 506 (1, M+ + 1), 505 (0.1, M+), 367 (2),
1
232 (2), 159 (60), 132 (15), 121 (21); H NMR (CDCl3) δ 1.00
(d, J ) 6.7 Hz, 3 H), 1.46 (s, 3 H), 1.89-2.00 (m, 2 H), 2.05-
2.13 (m, 2 H), 2.71-2.90 (m, 5 H), 3.14-3.25 (m, 1 H), 3.42-
3.53 (m, 2 H), 3.76 (s, 3 H), 4.10 (br d, J ) 15.6 Hz, 1 H), 4.28-
4.35 (m, 2 H), 4.37-4.50 (m, 2 H), 4.65-4.85 (m, 2 H), 5.78
(br s, 1 H), 5.94 (d, J ) 10.1 Hz, 1 H), 6.86 (d, J ) 8.7 Hz, 2
H), 7.24 (d, J ) 8.7 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ
14.53 (q), 19.24 (q), 24.97 (t), 29.58 (t), 30.12 (t), 35.67 (t), 42.07
(d), 53.95 (t), 55.21 (q), 61.45 (t), 61.91 (t), 66.07 (t), 70.39 (d),
78.70 (d), 82.31 (s), 113.59 (d, 2 C), 127.35 (d), 127.65 (s), 128.76
(d, 2 C), 130.47 (s), 132.55 (s), 133.70 (d), 158.93 (s), 173.18
(s); HRMS for C26H35NO5S2 calcd 505.1957, found 505.1955.
[R]26 ) -41.5° (c 0.53, CHCl3); IR (neat) 1738, 699 cm-1; MS
D
m/ z (rel intensity) 385 (0.1, M+), 279 (8), 251 (35), 220 (10),
136 (40), 119 (60), 91 (28); 1H NMR (CDCl3) δ 1.03 (d, J ) 6.9
Hz, 3 H), 1.49 (s, 3 H), 2.00-2.11 (m, 2 H), 2.19 (dd, J ) 15.7,
3.2 Hz, 1 H), 2.45-2.65 (m, 2 H), 2.79 (dd, J ) 15.7, 11.1 Hz,
1 H), 3.19-3.30 (m, 1 H), 3.46 (dd, J ) 16.4, 5.6 Hz, 1 H), 3.97
(br d, J ) 16.4 Hz, 1 H), 4.38-4.44 (m, 1 H), 4.39, 5.11 (AB
quartet, J ) 11.4 Hz, 2 H), 4.40, 4.73 (AB quartet, J ) 11.1
Hz, 2 H), 5.08-5.14 (m, 1 H), 6.00 (br d, J ) 1.9 Hz, 1 H),
7.25-7.46 (m, 5 H); 13C NMR (CDCl3) δ 15.43 (q), 20.81 (q),
33.70 (t), 37.36 (t), 38.65 (d), 53.79 (t), 57.52 (t), 61.51 (t), 66.28
(t), 74.56 (d), 76.79 (d), 79.49 (s), 127.14 (d, 3 C), 128.16 (d, 2
C), 133.58 (s), 133.88 (d), 139.15 (s), 170.64 (s), 173.50 (s);
HRMS for C22H27NO2 calcd 385.1890, found 385.1895.
Retr on ecin e Ester of 2-(Ben zyloxy)-2,3-d im eth yl-4-
[[(3-m er ca p t op r op yl)su lfa n yl]ca r b on yl]b u t a n oic Acid
(8a ). To a stirring solution of 7a (321 mg, 0.68 mmol) in CH2-
Cl2 (20 mL) was added HCl (37%, 0.25 mL) at 25 °C; the
solution turned pink immediately. After 0.5 h, the solution
was concentrated by rotary evaporation, and the residue was
chromatographed on a silica gel column by elution with MeOH/
CH2Cl2 (1:9) to give thioester 8a (294 mg, 88%): oil; Rf 0.26
(MeOH/CH2Cl2 (1:9)); IR (neat) 3341, 1726 (ester), 1682
(thioester), 699 cm-1; MS (20 eV) m/ z (rel intensity) 493 (4,
M+), 386 (4), 369 (4), 278 (10), 200 (21), 138 (100), 113 (97);
1H NMR (CDCl3) δ 0.97 (d, J ) 6.5 Hz, 3 H), 1.46 (s, 3 H),
1.85 (quin, J ) 7.0 Hz, 2 H), 2.01-2.10 (m, 2 H), 2.40-2.70
(m, 2 H), 2.55 (t, J ) 7.0 Hz, 2 H), 2.79-2.99 (m, 2 H), 2.96 (t,
J ) 7.0 Hz, 2 H), 3.50-3.70 (m, 2 H), 4.21 (br d, J ) 15.4 Hz,
1 H), 4.50-4.62 (m, 4 H), 4.70, 4.81 (AB quartet, J ) 13.8 Hz,
2 H), 5.78 (br s, 1 H), 7.26-7.35 (m, 5 H); 13C NMR (CDCl3) δ
14.42 (q), 17.21 (q), 23.27 (t), 27.27 (t), 33.39 (t), 35.83 (t), 38.10
(d), 45.86 (t), 53.93 (t), 61.27 (t), 61.40 (t), 66.57 (t), 70.21 (d),
78.53 (d), 82.44 (s), 126.73 (d, 3 C), 127.13 (d), 128.26 (d, 2 C),
Cr oba r ba tin e Der iva tives 9b a n d 10b. Thioester 8b (73
mg) was treated with silver trifluoroacetate and 4-(dimethyl-
amino)pyridine by a procedure similar to that for 9a /10a to
give dilactones 9b and 10b (1:1; 39 mg, 67%). 9b: tR 14.5 min
(MeOH/CH2Cl2 (1:9)); [R]23D ) +39.0° (c 0.20, CHCl3); IR (neat)
1735, 1247 cm-1; MS m/ z (rel intensity) 416 (8, M+ + 1), 415
(1, M+), 294 (4), 279 (19), 250 (41), 220 (23), 136 (47), 121 (100);
1H NMR (CDCl3) δ 1.06 (d, J ) 7.0 Hz, 3 H), 1.50 (s, 3 H),
1.93-2.07 (m, 2 H), 1.97 (dd, J ) 16.5, 1.2 Hz, 1 H), 2.42 (ddq,
10.9, 7.0, 1.2 Hz, 1 H), 2.65-2.80 (m, 1 H), 2.99 (dd, J ) 10.5,
16.5 Hz, 1 H), 3.25 (ddd, J ) 8.8, 6.7, 2.2 Hz, 1 H), 3.49 (dd, J
) 16.6, 4.3 Hz, 1 H), 3.78 (s, 3 H), 3.93 (br d, J ) 16.6 Hz, 1
H), 4.24, 4.36 (AB quartet, J ) 10.7 Hz, 2 H), 4.34-4.45 (m, 1
H), 4.46, 4.62 (AB quqrtet, J ) 11.7 Hz, 2 H), 5.58 (ddd, J )
5.3, 5.3, 1.9 Hz, 1 H), 5.91 (br d, J ) 1.8 Hz, 1 H), 6.84 (d, J )
8.7 Hz, 2 H), 7.30 (d, J ) 8.7 Hz, 2 H); 13C NMR (CDCl3) δ
16.11 (q), 20.43 (q), 33.20 (t), 37.20 (t), 38.72 (d), 54.24 (t), 55.30
(q), 59.27 (t), 61.13 (t), 66.70 (t), 72.47 (d), 78.74 (d), 80.70 (s),
113.53 (d, 2 C), 128.90 (d, 2 C), 130.97 (s), 132.51 (s), 134.86
(d), 159.03 (s), 173.13 (s), 174.33 (s); HRMS for C23H29NO6 calcd
415.1995, found 415.2020. 10b: tR 16.3 min (MeOH/CH2Cl2
132.80 (s), 138.10 (s), 173.18 (s), 198.64 (s); HRMS for C25H35
NO5S2 calcd 493.1957, found 493.1968.
-
Retr on ecin e Ester of 2,3-Dim eth yl-4-[[(3-m er ca p to-
p r op yl)su lfa n yl]ca r bon yl]-2-[(4-m eth oxyben zyl)oxy]bu -
ta n oic Acid (8b). Ester 7b (784 mg) was treated with concd
HCl by a procedure similar to that for 8a to give thioester 8b
(432 mg, 53%): oil; IR (neat) 3358, 1723 (ester), 1675 (thioester)
cm-1; MS m/ z (rel intensity) 524 (2, M+ + 1), 523 (0.3, M+),
1
369 (1), 278 (2), 249 (3), 228 (4), 137 (25), 121 (100); H NMR
(300 MHz, CDCl3) δ 0.92 (d, J ) 6.7 Hz, 3 H), 1.41 (s, 3 H),
1.81 (quin, J ) 7.0 Hz, 2 H), 1.93-2.00 (m, 2 H), 2.38-2.60
(m, 2 H), 2.52 (t, J ) 7.0 Hz, 2 H), 2.76-2.85 (m, 2 H), 2.92 (t,
J ) 7.0 Hz, 2 H), 3.35-3.46 (m, 2 H), 3.76 (s, 3 H), 4.01 (br d,
J ) 15.6 Hz, 1 H), 4.25-4.40 (m, 4 H), 4.62-4.80 (m, 2 H),
5.81 (br s, 1 H), 6.83 (d, J ) 8.6 Hz, 2 H), 7.23 (d, J ) 8.6 Hz,
2 H); 13C NMR (CDCl3) δ 14.39 (q), 17.17 (q), 23.96 (t), 27.26
(1:9)); [R]23D -46.8° (c 0.47, CHCl3); IR (neat) 1735, 1246 cm-1
;
MS m/ z (rel intensity) 416 (5, M+ + 1), 415 (1, M+), 294 (2),
279 (10), 250 (27), 220 (13), 136 (29), 121 (100); 1H NMR
(CDCl3) δ 0.99 (d, J ) 7.0 Hz, 3 H), 1.46 (s, 3 H), 2.00-2.09

Synthesis of Dilactonic Pyrrolizidine Alkaloids
J . Org. Chem., Vol. 61, No. 4, 1996 1477
(m, 2 H), 2.15 (dd, J ) 15.8, 3.2 Hz, 1 H), 2.42-2.68 (m, 2 H),
2.73 (dd, J ) 11.2, 15.8 Hz, 1 H), 3.25-3.31 (m, 1 H), 3.46 (dd,
J ) 16.0, 5.3 Hz, 1 H), 3.78 (s, 3 H), 3.98 (br d, J ) 16.0 Hz,
1 H), 4.40-4.48 (m, 1 H), 4.30, 4.61 (AB quartet, J ) 10.5 Hz,
2 H), 4.37, 5.09 (AB quartet, J ) 11.6 Hz, 2 H), 5.07- 5.11 (m,
1 H), 5.98 (br s, 1 H), 6.87 (d, J ) 8.5 Hz, 2 H), 7.34 (d, J ) 8.5
Hz, 2 H); 13C NMR (CDCl3) δ 15.40 (q), 20.82 (q), 33.70 (t),
37.33 (t), 38.61 (d), 53.81 (t), 55.27 (q), 57.42 (t), 61.41 (t), 66.01
(t), 74.43 (d), 76.89 (d), 79.39 (s), 113.64 (d, 2 C), 128.73 (d, 2
C), 131.26 (s), 133.54 (s), 133.68 (d), 158.87 (s), 170.64 (s),
173.60 (s); HRMS for C23H29NO6 calcd 415.1995, found 415.2002.
Ack n ow led gm en t. We thank the National Science
Council of the Republic of China for financial support
(Grant NSC84-2113-M002-010).
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of new
compounds (30 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O951363Y