Molecular diversity of tonghaosu: Synthesis of lactam-containing tonghaosu analogs

Article abstract of DOI:10.1055/s-2003-41042

A new type of tonghaosu analogs containing spiroketal and lactam functionality was synthesized from methyl 2-furoate and amino alcohols. The stereoselective control of spiroketal chirality was also explored.

Full text of DOI:10.1055/s-2003-41042

PAPER
1995
Molecular Diversity of Tonghaosu: Synthesis of Lactam-Containing
Tonghaosu Analogs
S
ynthesis of Lact
i
am-C
o
a
ntaining To
o
nghaosu
A
na
-
logs Lin Yin, Zheng-Min Yang, Tai-Shan Hu, Yu-Lin Wu*
State Key Laboratory of Bio-organic & Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, P. R. China
E-mail: ylwu@mail.sioc.ac.cn
Received 13 May 2003; revised 19 June 2003
of lactam-containing tonghaosu analogs is outlined in
Scheme 2. Keto esters 3, readily prepared by Friedel–
Crafts reaction of methyl 2-furoate with corresponding
acyl chlorides,6 were reduced selectively with NaBH4 to
form furanyl alcohols 4 in good yields. Compounds 4 re-
acted with 2-ethylaminoethanol in refluxing methanol to
give amides 5, which were treated with camphorsulfonic
acid (CSA) to afford smoothly lactam-containing tongha-
osu analogs 6. Similarly, compound 10 was prepared
starting from acyl chloride 7 and 2-ethylaminophenol (8)
(Scheme 3). Unlike other kinds of tonghaosu analogs,
amide containing tonghaosu analogs were found to be
more stable and could be kept at room temperature for
long time, which would facilitate further research.
Abstract: A new type of tonghaosu analogs containing spiroketal
and lactam functionality was synthesized from methyl 2-furoate and
amino alcohols. The stereoselective control of spiroketal chirality
was also explored.
Key words: tonghaosu analogs, antifeedant, lactam, spiroketaliza-
tion, diastereoselective
Tonghaosu, 2-(2,4-hexadiynylidene)-1,6-dioxaspiro-[4.4]-
non-3-ene (1) is an antifeedant component of a vegetable
called tonghao (Chrysanthemum sgetum L. or C. Coro-
narium L.) in China and was also found in other plants of
the tribe Athemdeae.1,2 The first synthesis of tonghaosu
was reported in early 1960s by Bohlmann and co-workers,
however, in quite low overall yield.3 Recently, we devel-
oped a general and concise synthetic methodology for
tonghaosu and its spiroketal enol ether characterized ana-
logs, which employed acid-catalyzed dehydration-
spiroketalization as the key step (Scheme 1).4,5 Up to now
a diversity of tonghaosu analogs 2 with varied unsaturated
groups and B-rings have been prepared and most of them
showed antifeeding activity comparable to that of tongha-
osu. Herein, we would like to report our further efforts to-
wards the synthesis of both racemic and enantiopure
lactam-containing tonghaosu analogs.
O
OH
O
O
a
O
O
OMe
Ar
OMe
Ar
4
3
3a, Ar = phenyl
3b, Ar = p-Cl-phenyl
3c, Ar = p-MeO-phenyl
3d, Ar = 5-chloro-3-methyl
4a 95%
4b 97%
4c 91%
4d 93%
-1-phenyl-1H-pyrazole-4-yl
O
OH
OH
b
O
c
O
O
N
N
Ar
O
O
Ar
A
B
O
5
6
1 (Tonghaosu)
6a 79% 6b 80%
6c 75% 6d 83%
X
O
( )n
acid
Unsat
A
Unsat
B
( )n
O
O
Scheme 2 Synthesis of lactams 6. Reagents and conditions: (a)
NaBH4, MeOH; (b) 2-ethylaminoethanol, Et3N, MeOH, reflux; (c)
CSA, CH2Cl2, r.t.
HO
X
HO
Unsat = Ar, heteroaromatic rings
2
X = CH2, n = 0 or 1 ;
X = O, n = 1
Our previous findings demonstrated that compounds re-
sulting from selective reduction of endo-cyclic double
bond of tonghaosu analogs were more effective insect an-
tifeedant.7 With these new compounds in hand, we also
carried out the reduction reaction. Compounds 6 and 10
Scheme 1
In view of the important roles that amide-containing com-
pounds play in agrochemicals, we anticipated that intro-
duction of an amide functionality into tonghaosu analog
might give rise to better biological activity. The synthesis
8
were treated with NaBH4/NiCl2 in methanol with DME
as a co-solvent to give 11 and 12 respectively. The reac-
tions were complete in several minutes giving the prod-
ucts in high yields (Scheme 4).
Synthesis 2003, No. 13, Print: 18 09 2003. Web: 28 08 2003.
Art Id.1437-210X,E;2003,0,13,1995,2000,ftx,en;F04203SS.pdf.
DOI: 10.1055/s-2003-41042
© Georg Thieme Verlag Stuttgart · New York

1996
B.-L. Yin et al.
PAPER
Et
HO
OH
O
M/L
O
HN
O
a
O
+
O
*
O
Cl
N
Ph
HO
7
8
M = Ti(OiPr)4
O
L = (R)-(+) BINOL, L-(+)DET etc.
O
O
b
O
Scheme 5 Chiral Lewis acid catalyzed spiroketalization
Ph
O
N
Ph
HO
O
13, which was treated with CuSO4 for 24 hours in reflux-
ing toluene (Condition A) to give a mixture of 14 and 15
in moderate selectivity (Scheme 6). However, under a
milder condition with camphorsulfonic acid as the pro-
moter in dichloromethane at room temperature (Condition
B), the spiroketalization was effected in a highly dia-
stereoselective manner with 14 as the predominant prod-
uct. Results from two cyclization methods are shown in
Table 1. The absolute configuration of 14a was deter-
mined unambiguously by X-ray structure (Figure 1). The
stereochemistry of 14b, 14c and 14e was assigned as
shown in Scheme 5 in analogy with 14a.
9
10
Scheme 3 Synthesis of lactam 10. Reagents and conditions: (a)
Et3N, CH2Cl2, 89%; (b) i. NaBH4, MeOH; ii. CSA, CH2Cl2, r.t., 5 h,
84%
O
O
a
O
O
N
N
O
O
Ar
Ar
6a Ar = phenyl
6b Ar = p-Cl-phenyl
11a 85%
11b 80%
HO
a
Ar
O
O
OMe
a
O
Ar
N
O
N
O
O
OH
O
O
N
O
Ph
Ph
4
OH
O
13
4a Ar = phenyl
10
12
84%
4b Ar = p-Cl-phenyl
4c Ar = p-MeO-phenyl
4e Ar = naphthalen-1-yl
Scheme 4 Selective reduction of 6 and 10. Reagents and conditions:
a) NaBH4/NiCl2, DME/MeOH, 0 °C to r.t.
O
O
b
O
+
O
Tonghaosu analogs so far obtained are all recemic com-
pounds. In order to better understand the structure-activity
relationships of tonghaosu analogs and to find more effec-
tive green agrochemicals, efforts towards the synthesis of
enantiopure tonghaosu analogs are urgently needed. Al-
though a variety of methods are available for synthesis of
spiroketal containing compounds, no method can be relied
on for construction of the stereochemistry of spiroketal
carbon.9
N
N
Ar
Ar
O
O
14
15
Scheme 6 Synthesis of optical tonghaosu analogs 14 and 15.
Reagents and Conditions: (a) (S)-prolinol, Et3N, MeOH, reflux; (b)
Condition A: CuSO4·5H2O, toluene, reflux, 24 h; Condition B: CSA,
CH2Cl2, r.t., 24 h
In summary, a series of lactam-containing tonghaosu ana-
logs were prepared in a concise and effective way. Proli-
nol-derived furan amides afforded lactams 14 and 15 in
high diastereoselectivity with 14 as the major product.
As mentioned above, acid-catalyzed dehydration
spiroketalization was the key step in the synthesis of ton-
ghaosu analogs, and both Brønsted and Lewis acids, such
as CuSO4·5H2O, and ZnCl2, were effective promoters. We
envisioned that enantioselective spiroketalization might
be effected in the presence of a chiral Lewis acid. Our ini-
tial investigation was to use titanium(IV) as the Lewis
acid and screen a series of chiral ligands. Unfortunately,
the preliminary results were unsatisfactory and the best ee
value was only up to 20% (Scheme 5), presumably due to
the reversibility of spiroketalization under acid condi-
tions, thus eroding the established chirality.
Table 1 Spiroketalization of 13 Under Two Different Conditionsa
Substrate
Condition A
Condition B
Ratio of
14:15
Yield (%)
Ratio of Yield (%)
14:15
13a
13b
13c
13e
2.5:1
2.3:1
–
74
70
–
8.4:1
–
82
–
We then turned our attention to substrate-controlled meth-
od to construct spiroketal center. Instead of an achiral
amino alcohol, for example, 2-ethylaminoethanol, a chiral
one was used to prepare spiroketalization precursor. (S)-
Prolinol reacted with furan ester 4 to afford furan amide
8.8:1
8.1:1
85
87
3.5:1
84
a Condition A: CuSO4·5H2O, toluene, reflux, 24 h; Condition B:
CSA, CH2Cl2, r.t., 24 h.
Synthesis 2003, No. 13, 1995–2000 © Thieme Stuttgart · New York

PAPER
Synthesis of Lactam-Containing Tonghaosu Analogs
1997
1H NMR (300 MHz, CDCl3): d = 7.34 (4 H, m), 7.06 (1 H, d, J = 3.9
Hz), 6.20 (1 H, d, J = 3.9 Hz), 5.81 (1 H, s), 3.81 (3 H, s).
MS: m/z = 266 (M+, 32.6), 249 (19.5), 235 (8.9), 231 (21.3), 208
(12.7), 207 (100.0).
HRMS: m/z calcd for C13H11ClO4: 266.0346; found: 266.0319.
4c
Oil; yield: 2.37 g (91%).
IR (film): 3419, 2957, 1840, 1733, 1612, 1514, 1439, 1307, 1251,
1141, 1041, 1033, 763 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.36 (2 H, dd, J = 7.7, 1.8 Hz),
7.13 (1 H, d, J = 3.5 Hz), 7.58 (2 H, dd, J = 6.8, 2.0 Hz), 6.18 (1 H,
dd, J = 3.2, 0.5 Hz), 5.81 (1 H, s), 3.87 (3 H, s), 3.83 (3 H, s).
MS: m/z = 262 (M+, 23.6), 245 (27.9), 148 (55.7), 131 (41.6), 99
(26.3), 58 (100.0).
Anal. Calcd for C14H14O5: C, 64.12, H, 5.38. Found: C, 64.33, H,
5.16.
Figure 1 X-ray crystal structure of 14a
4d
Colorless solid; yield: 3.35 g (93%); mp 92–93 °C.
This new type of tonghaosu analogs was more stable than
other tonghaosu products including natural ones, and
showed obvious antifeedant activity in preliminary bio-
logical tests. Compound 14e also showed good pesticidal
activity.
IR (film): 3358, 2937, 1720, 1595, 1553, 1502, 1304, 1211, 1139,
1015, 761 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.46 (5 H, m), 7.11 (1 H, d, J = 3.7
Hz), 6.35 (1 H, dd, J = 3.5, 0.9 Hz), 5.85 (1 H, s), 3.84 (3 H, s), 2.22
(3 H, s).
MS: m/z = 346 (M+, 35.0), 286 (50.5), 153 (100.0).
IR spectra were recorded on Perkin-Elmer 983 or Shimadzu IR-440
1
spectrometer. H and 13C NMR were recorded in CDCl3 on an
HRMS: m/z calcd for C18H19ClN2O4: 346.0720; found: 346.0738.
AMX-300, DPX-300 or DRX-400 spectrometer with TMS as the
internal standard. Mass spectra were taken on a Mariner (PE, for
ESI), HP5973N or HP5989A instrument. HRMS (EI) spectra were
obtained on a Kratos CONCEPT 1H mass spectrometer. Optical ro-
tations were measured on a Perkin-Elmer 241 MC polarimeter at
20°C. Elemental analyses were carried out at the Microanalytic
Laboratory of Shanghai Institute of Organic Chemistry. Flash col-
umn chromatography was performed on silica gel H (10–40 mm)
with petroleum ether (bp 60–90°C)–EtOAc or EtOAc–EtOH sys-
tem as eluent.
4e
Syrup; yield: 2.48 g (88%).
IR (KBr): 3347, 2944, 1723, 1587, 1206, 843 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.96 (1 H, d, J = 6.6 Hz), 7.85 (2
H, dd, J = 9.0, 2.1 Hz), 7.68 (1 H, d, J = 7.0 Hz), 7.44 (3 H, m), 7.08
(1 H, d, J = 3.6 Hz), 6.21 (1 H, d, J = 3.3 Hz), 5.81 (1 H, s), 3.84 (3
H, s).
MS: m/z 346 (M+, 74.3), 329 (21.7), 245 (63.1.5), 171 (100.0).
Anal. Calcd for C17H14O4: C, 72.33, H, 5.00. Found: C, 72.47, H,
5.24.
Furanols 4; General Procedure
To a solution of 3 (10 mmol) in absolute MeOH (20 mL) at 0 °C was
added NaBH4 (0.19 g, 5 mmol) in portions. The reaction mixture
was stirred overnight, and then distilled H2O (10 mL) was added.
The organic solvent was removed under reduced pressure. The res-
idue was extracted with EtOAc (3 × 15 mL). The combined organic
extracts were washed with brine and dried (Na2SO4). Removal of
solvents and purification by chromatography afforded 4.
Lactams 6; General Procedure
To a solution of furan ester 4 (10 mmol) in anhyd MeOH (20 mL)
under N2 were added 2-ethylaminoethanol (0.89 g, 10 mmol) and
Et3N (10 mL). The mixture was refluxed for 24 h, cooled to r.t., and
concentrated under reduced pressure. The residue obtained was dis-
solved in CH2Cl2 (20 mL), and to the solution was added a catalytic
amount of CSA (20 mg, 0.86 mmol). The resulting mixture was
stirred at r.t. for 24 h, and then quenched with sat. aq NaHCO3 so-
lution. The separated aqueous phase was extracted with CH2Cl2,
and the combined organic layers were washed with brine and dried
(Na2SO4). After removal of the solvent, the residue was chromato-
graphed to afford lactam 6.
4a
Oil; yield: 2.20 g (95%).
IR (film): 3441, 3032, 2954, 1718, 1142, 1020, 762, 701 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.28–7.41 (5 H, m), 7.06 (1 H, d,
J = 3.9 Hz), 6.20 (1 H, d, J = 3.9 Hz), 5.81 (1 H, s), 3.81 (3 H, s).
MS: m/z = 232 (M+, 32.1), 173 (100.0), 127 (51.0), 123 (17.9), 117
(27.5), 115 (22.2), 105 (18.4).
6a
White solid; yield: 2.14 g (79%); mp 165–166 °C.
Anal. Calcd for C13H12O4: C, 67.23, H, 5.21. Found: C, 67.01, H,
5.14.
IR (KBr): 3084, 2978, 2889, 1649, 1493, 1448, 1355, 939, 828, 693
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.63–7.13 (5 H, m), 6.53 (1 H, d,
J = 5.7 Hz), 6.09 (1 H, d, J = 6.0 Hz), 5.55 (1 H, s), 4.51 (1 H, td,
J = 11.7, 3.3 Hz), 4.02 (1 H, ddd, J = 11.7, 4.5, 0.9 Hz), 3.78 (1 H,
td, J = 12.0, 4.5 Hz), 3.59 (1 H, m), 3.47 (1 H, m), 3.28 (1 H, dd,
J = 3.0, 0.9 Hz), 1.23 (3 H, td, J = 6.9, 3.0 Hz).
4b
Oil; yield: 2.59 g (97%).
IR (film): 3419, 1695, 1593, 1536, 1492, 1440, 1410, 1321, 1211,
1140, 983, 771, 760 cm–1.
Synthesis 2003, No. 13, 1995–2000 © Thieme Stuttgart · New York

1998
B.-L. Yin et al.
PAPER
MS: m/z = 271 (M+, 47.0), 227 (26.0), 215 (26.0), 172 (100.0), 144
MS: m/z = 335 (M+, 15.0), 230 (73.0), 202 (28.7), 199 (55.8), 136
(31.5), 116 (32.5), 115 (49.1).
(80.5).
Anal. Calcd for C16H17NO3: C, 70.83; H, 6.32; N, 5.16. Found: C,
70.33; H, 6.25; N, 5.00.
HRMS: m/z calcd for C20H17NO4: 335.1158. found: 335.1121.
Lactam 10
6b
To a solution of 9 (3.36 g, 5 mmol) in MeOH (20 mL) was added
NaBH4 (0.39 g, 5 mmol) in portions at 0 °C. The resulting mixture
was stirred for 4 h at r.t. and distilled H2O (10 mL) was added to
quench the reaction. The solvent was removed under reduced pres-
sure. The aqueous phase was extracted with EtOAc and the com-
bined organic layers were washed with brine and dried (Na2SO4).
The solvents were evaporated and the obtained residue was dis-
solved in CH2Cl2 (20 mL). To this solution was added a catalytic
amount of CSA (20 mg, 0.86 mmol) and the resulting mixture was
stirred at r.t. for 24 h, and then quenched with sat. aq NaHCO3 so-
lution. The aqueous phase was separated and extracted with
CH2Cl2, and the combined organic layers were washed with brine
and dried (Na2SO4). After removal of the solvent, the residue was
chromatographed to afford 10; amorphous solid; yield: 2.68 g
(84%).
White solid; yield: 2.44 g (80%); mp 116–117 °C.
IR (KBr): 3088, 2933, 2881, 1652, 1489, 1347, 1197, 937, 846, 718,
512 cm–1.
1H NMR (300M Hz, CDCl3): d = 7.53 (2 H, dd, J = 6.2, 2.1 Hz),
7.24 (2 H, dd, J = 3.9, 1.9 Hz), 6.53 (1 H, d, J = 5.7 Hz), 6.11 (1 H,
d, J = 5.6 Hz), 5.50 (1 H, s), 4.46 (1 H, td, J = 11.9, 3.6 Hz), 4.01 (1
H, ddd, J = 11.9, 4.2, 1.6 Hz), 3.76 (1 H, td, J = 11.9, 4.5 Hz), 3.59
(1 H, m), 3.44 (1 H, m), 3.29 (1 H, ddd, J = 12.7, 3.5, 1.5 Hz), 1.21
(3 H, t, J = 7.2 Hz).
MS: m/z = 305 (32.8, M+), 206 (100.0), 115 (63.7), 233 (39.1), 208
(33.8).
HRMS: m/z calcd for C16H16ClNO3: 305.0819; found: 305.0841.
IR (KBr): 3105, 1684, 1501, 1413, 1360, 1244, 1099, 989, 924
cm–1.
6c
White solid; yield: 2.26 g (75%); mp 122–123 °C.
1H NMR (300 MHz, CDCl3): d = 7.38–7.07 (9 H, m), 6.65 (1 H, d,
J = 5.7 Hz), 6.37 (1 H, d, J = 5.7 Hz), 5.60 (1 H, s), 4.10 (2 H, m),
1.33 (3 H, t, J = 7.2 Hz).
MS: m/z = 319 (M+, 55.3), 291 (48.1), 274 (10.5), 263 (100.0), 234
(18.8), 128 (100.0).
IR (film): 3092, 2941, 1650, 1510, 1254, 1199, 1179, 1008, 985,
939, 846 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.56 (2 H, dd, J = 6.8, 2.2 Hz),
6.85 (2 H, dd, J = 6.9, 2.0 Hz), 6.51 (1 H, d, J = 5.3 Hz), 6.03 (1 H,
dd, J = 5.5, 0.6 Hz), 5.50 (1 H, s), 4.49 (1 H, td, J = 12.0, 3.5 Hz),
4.00 (1 H, ddd, J = 12.1, 4.6, 1.4 Hz), 3.80 (3 H, s), 3.76 (1 H, dd,
J = 8.0, 4.5 Hz), 3.60 (1 H, m), 3.44 (1 H, m) 3.28 (1 H, ddd,
J = 12.4, 3.0, 1.4 Hz), 1.19 (3 H, t, J = 7.6 Hz).
HRMS: m/z calcd for C20H17NO3: 319.1208. found: 319.1234.
NaBH4/NiCl2 Reduction of 6a,b and 10; 9-Ethyl-2-[(Z)-phenyl-
methylidene]-1,6-dioxa-9-azaspiro[4.5]decan-10-one (11a);
Typical procedure
MS: m/z = 301 (77.2, M+), 245 (33.5), 230 (41.1), 229 (31.6), 202
(100.0), 153 (84.7), 131 (30.5).
To a solution of compound 6a (1 mmol) in DME (5 mL) and anhyd
MeOH was added NaBH4 (190 mg, 5 mmol) at 0 °C, and then NiCl2
(20 mg) in portions. The mixture was stirred at r.t. for 1 h until the
material disappeared according to TLC. Sat. aq NaHCO3 was then
added until pH 8, the mixture was extracted with Et2O and the com-
bined organic layers were washed with brine and dried (Na2SO4).
Removal of solvents yielded the crude product, which was purified
by chromatography to afford 11a; syrup; yield: 116 mg (85%).
Anal. Calcd for C17H19NO4: C, 67.76; H, 6.36; N, 4.65. Found: C,
67.85; H, 6.39, N, 4.60.
6d
Syrup; yield: 3.34 g (83%).
IR (KBr): 2984, 1659, 1502, 1378, 1213, 1008, 942, 769 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.53–7.31 (5 H, m), 6.55 (1 H, d,
J = 5.8 Hz), 6.07 (1 H, d, J = 5.8 Hz), 5.31 (1 H, s), 4.39 (1 H, td,
J = 12.1, 3.3 Hz), 3.95 (1 H, dd, J = 11.7, 4.1Hz), 3.69 (1 H, td,
J = 12.3, 4.6 Hz), 3.46 (2 H, m), 3.21 (1 H, dd, J = 12.8, 2.3 Hz),
2.37 (3 H, s), 1.16 (3 H, t, J = 7.0 Hz).
IR (film): 2959, 2934, 1675, 1653, 1490, 1449, 1355, 1187, 1040,
987, 921 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.53 (2 H, m), 7.23 (2 H, m), 7.08
(1 H, m), 5.31 (1 H, s), 4.33 (1 H, td, J = 8.0, 3.3 Hz), 3.87 (1 H, dd,
J = 12, 4.2 Hz), 3.76–3.54 (2 H,m), 3.47–3.38 (1 H, m), 3.21 (1 H,
dd, J = 12.0, 3.3 Hz), 2.91 (2 H, m), 2.72 (1 H, m), 1.99 (1 H, m),
1.20 (3 H, m).
MS: m/z = 385 (M+, 55.0), 286 (50.5), 153(100.0).
HRMS: m/z calcd for C21H24ClN3O3: 401.1506; found: 401.1539.
MS: m/z = 273 (M+, 71.4), 182 (72.3), 155 (100.0), 154 (35.9), 128
Amide 9
To a solution of 2-ethylaminophenol (0.69 g, 5 mmol) in anhyd
THF (20 mL) under N2 was added the acid chloride 7 (1.17 g, 5
mmol) slowly at 0 °C. The mixture was stirred for 2 h at the same
temperature, then for additional 3 h at r.t. Distilled H2O (10 mL)
was added to quench the reaction. The separated aqueous phase was
extracted with EtOAc and the combined organic layers were
washed with brine and dried (Na2SO4). After removal of the sol-
vents, the residue was chromatographed to afford 9; syrup; yield:
1.49 g (89%).
(22.9), 126 (29.5).
Anal. Calcd for C16H19O3N: C, 70.33; H, 6.96; N, 5.13. Found: C,
70.06; H, 6.53; N, 4.89.
11b
This compound was prepared from 6b according to the procedure
similar to 11a; white solid; yield: 122 mg (80%); mp 84–86 °C.
IR (film): 2978, 2937, 1668, 1490, 1357, 1303, 1203, 1089, 988,
843 cm–1.
IR (KBr): 3213, 2983, 1648, 1628, 1591, 1538, 1419, 1278 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.42 (2 H, d, J = 8.4 Hz), 7.21 (2
H, d, J = 8.4 Hz), 5.26 (1 H, s), 4.29 (1 H, td, J = 12.0, 3.3 Hz), 3.88
(1 H, dd, J = 12.0, 4.5 Hz,), 3.70 (1 H, td, J = 11.7, 4.5 Hz,), 3.83 (1
H, m), 3.43 (1 H, m), 3.20 (1 H, dd, J = 12.8, 3.3 Hz), 2.91 (2 H, m),
2.70 (1 H, m), 2.04–1.95 (1 H, m), 1.21 (3 H, t, J = 7.5 Hz).
1H NMR (300 MHz, CDCl3): d = 8.15 (1 H, s), 7.88 (2 H, d, J = 6.9
Hz), 7.55 (1 H, t, J = 7.5 Hz), 7.43 (2 H, t, J = 7.5 Hz), 7.24–7.18 (1
H, m), 7.04–6.98 (2 H, m), 6.94 (1 H, d, J = 3.3 Hz), 6.84 (1 H, t,
J = 7.2 Hz), 5.99 (1 H, d, J = 3.0 Hz), 4.15–4.08 (1 H, m), 3.56–
3.49 (1 H, m), 1.33–1.15 (3 H, m).
Synthesis 2003, No. 13, 1995–2000 © Thieme Stuttgart · New York

PAPER
Synthesis of Lactam-Containing Tonghaosu Analogs
1999
MS: m/z = 307 (M+, 30.6), 182 (100.0), 155 (94.4), 152 (62.5), 126
(42.8).
Anal. Calcd for C17H17NO3: C, 72.07; H, 6.05; N, 4.94. Found: C,
71.85; H, 6.09; N, 4.90.
HRMS: m/z calcd for C17H18ClNO3: 307.0975; found: 307.0961.
14b
White solid; Method A: 1.54 g; (49%); mp 204–206 °C;
[a]D +169.0 (c = 1.0, CHCl3).
12
This compound was prepared from 10 according to the procedure
similar to 11a; syrup; yield: 130 mg (81%).
IR (KBr): 2975, 1686, 1503, 1417, 1316, 1271, 958, 918 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.25–6.97 (9 H, m), 5.32 (1 H, s),
4.12–4.03 (2 H, m), 3.12–2.94 (3 H, m), 2.32–2.28 (1 H, m), 1.34–
1.25 (3 H, m).
IR (KBr): 2982, 2888, 1671, 1582, 1488, 1456, 1253, 1083, 933,
851, 738 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.52 (2 H, dt, J = 2.4, 9.1Hz), 7.23
(2 H, dt, J = 6.8, 2.0 Hz,), 6.53 (1 H, d, J = 5.6 Hz), 6.09 (1 H, d,
J = 5.6 Hz), 5.49 (1 H, s), 4.17 (1 H, dd, J = 10.5, 3.0 Hz), 3.97 (1
H, t, J = 10.4 Hz), 3.89 (1 H, m), 3.75 (1 H, m), 3.51 (1 H, td,
J = 10.5, 1.8 Hz), 2.12 (2 H, m), 1.89 (1 H, m), 1.57 (1 H, m).
MS: m/z = 317 (27.1, M+), 273 (75.2), 261 (34.0), 206 (100.0), 208
(34.2), 115 (73.2).
MS: m/z = 322 (M+ + 1, 22.6), 321 (M+, 100.0), 276 (11.9), 232
(11.2), 230 (16.0), 203 (98.0), 202 (31.4).
Anal. Calcd for C20H19NO3: C, 74.75; H, 5.96; N, 4.35. Found: C,
74.66; H, 5.81; N, 4.55.
HRMS: m/z calcd for C17H16ClNO3: 317.0819; found: 317.0835.
Optical Tonghaosu Analogs 14 and 15; General Procedure
Method A: To a solution of furan ester 4 (10 mmol) in anhyd MeOH
(20 mL) under N2 was added (S)-prolinol (1.01 g, 10 mmol) and
Et3N (10 mL). The mixture was refluxed for 24 h, cooled to r.t., and
concentrated under reduced pressure. The obtained residue was
treated with CuSO4⋅5H2O (2.5 g, 10 mmol) in refluxing toluene (20
mL) until the material disappeared according to TLC. After removal
of the solvent, the residue was chromatographed to afford 14 and
15.
15b
White solid; Method A: 0.67 g (21%); mp 162–163 °C; [a]D- 232.0
(c = 1.0, CHCl3).
IR (KBr): 2983, 2875, 1671, 1488, 1327, 1253, 1084, 925, 850, 737,
62 5 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.49 (2 H, dd, J = 9.3, 3.3 Hz),
7.28 (2 H, dd, J = 9.3, 3.3 Hz), 6.47 (1 H, d, J = 5.4 Hz), 6.26 (1 H,
d, J = 5.7 Hz), 5.48 (1 H, s), 4.33 (1 H, dd, J = 9.9, 4.5 Hz), 4.22 (1
H, m), 3.62 (3 H, m), 2.27 (1 H, m), 2.04 (2 H, m), 1.60 (1 H, m).
Method B: To a solution of furan ester 4 (10 mmol) in anhyd MeOH
(20 mL) under N2 was added prolinol (1.01 g, 10mmol) and Et3N
(10 mL). The mixture was refluxed for 24 h, cooled to r.t., and con-
centrated under reduced pressure. The obtained residue was dis-
solved in CH2Cl2 (20 mL), and to the solution was added a catalytic
amount of CSA (20 mg, 0.86 mmol). The resulting mixture was
stirred at r.t. for 24 h, and then quenched with sat. aq NaHCO3 so-
lution. The separated aqueous phase was extracted with CH2Cl2,
and the combined organic layers were washed with brine and dried
(Na2SO4). After removal of the solvent, the residue was chromato-
graphed to afford 14 and 15.
MS: m/z = 317 (16.3, M+), 273 (47.8), 261 (22.7).
HRMS: m/z calcd for C17H16ClNO3: 317.0819; found: 317.0829.
14c
Syrup; Method B: 239 mg (76%); [a]D +116.0 (c = 1.0, CHCl3).
IR (KBr): 2942, 2876, 1671, 1450, 1300, 1250, 1179, 928, 852, 737
cm–1.
1H NMR (300 MHz, CDCl3): d = 7.52 (2 H, d, J = 8.8 Hz), 6.85 (2
H, d, J = 8.8 Hz), 6.48 (1 H, d, J = 5.6 Hz), 6.19 (1 H, d, J = 5.7 Hz),
5.49 (1 H, s), 4.31 (2 H,m), 3.81 (3 H, s), 3.63 (3 H, m), 2.27 (1 H,
m), 2.02 (2 H, m), 1.60 (1 H, m).
14a
White solid; Method A: yield: 1.60 g (50%); Method B: 2.71 g
(73%); mp 204–206 °C; [a]D +99.6 (c = 1.0, CHCl3).
MS: m/z = 313 (M+, 100.0), 269 (46.6), 257 (34.8), 242 (25.0): 202
(96.4), 174 (32.9), 165 (73.7), 131 (26.2).
IR (KBr): 3092, 3019, 2960, 2882, 1668, 1595, 1489, 1349, 1137,
1096, 938, 812, 692 cm–1. 1H NMR (300 MHz, CDCl3): d = 7.58 (2
H, d, J = 7.5 Hz), 7.31 (2 H, m), 7.17 (1 H, d, J = 7.4 Hz), 6.49 (1
H, d, J = 5.8 Hz), 6.24 (1 H, d, J = 5.6 Hz), 5.53 (1 H, s), 4.36–4.23
(2 H, m), 3.70–3.58 (3 H, m), 2.29–2.22 (1 H, m), 2.07–1.94 (2 H,
m), 1.64–1.43 (1 H, m).
Anal. Calcd for C18H19NO4: C, 68.99; H, 6.11; N, 4.47. Found: C,
68.88; H, 6.25; N, 4.42.
15c
Syrup; Method B: 27.2 mg (9%); [a]D –208.6 (c = 1.0, CHCl3).
MS: m/z = 283 (58.6, M+), 239 (100.0), 227 (38.6), 172 (77.6), 144
(51.5), 116 (46.6), 115 (57.6).
IR (KBr): 2942, 2876,1671, 1606, 1584, 1509, 1450, 1300, 1250,
1179, 928, 852, 817, 737 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.55 (2 H, d, J = 8.7 Hz), 6.84 (2
H, dd, J = 7.5, 2.1 Hz), 6.45 (1 H, dd, J = 5.7, 1.5 Hz), 6.01 (1 H,
dd, J = 6.0, 0.9 Hz), 5.50 (1 H, s), 4.16 (1 H, dd, J = 11.1, 3.9 Hz),
4.00 (1 H, t, J = 11.8 Hz), 3.86 (1 H, m), 3.79 (3 H, s), 3.75 (1 H,
m), 3.51 (1 H, t, J = 11.4 Hz), 2.07 (2 H, m), 1.89 (1 H, m), 1.55 (1
H, m).
HRMS: m/z calcd for C17H17NO3: 283.1208; found: 283.1196.
15a
White solid; Method A: 0.60 g (25%); Method B: 0.29 g (9%); mp
162–163 °C; [a]D –275.3 (c = 1.0, CHCl3).
IR (KBr): 3082, 2977, 2889, 1663, 1489, 1458, 1348, 1335, 1241,
994, 947, 815, 691 cm–1.
MS: m/z = 313 (M+, 100.0), 269 (45.8), 257 (35.3), 202 (85.9), 174
(29.8), 165 (51.6), 131 (25.6).
1H NMR (300 MHz, CDCl3): d = 7.61 (2 H, d, J = 7.9 Hz), 7.29 (2
H, m), 7.15 (1 H,, J = 7.8 Hz), 6.56 (1 H, d, J = 5.9 Hz), 6.06 (1 H,
d, J = 5.8 Hz), 5.55 (1 H, s), 4.15 (1 H, dt, J = 11.3, 1.9 Hz), 3.99 (1
H, m), 3.86 (1 H, m), 3.71 (1 H, m), 3.83 (1 H, m), 2.06 (2 H, m),
1.87 (1 H, m), 1.52 (1 H, m).
Anal. Calcd for C18H19NO4: C, 68.99; H, 6.11; N, 4.47. Found: C,
68.77; H, 5.98; N, 4.36.
14e
Syrup; Method A: 217.6 mg (65%); Method B: 257.9 mg (77%);
[a]D +145.3 (c = 1.0, CHCl3).
MS: m/z = 283 (3.6, M+), 239 (44.4), 172 (54.0), 144 (50.0), 116
(68.1), 115 (100.0).
Synthesis 2003, No. 13, 1995–2000 © Thieme Stuttgart · New York

2000
B.-L. Yin et al.
PAPER
IR (KBr): 2961, 2881, 1666, 1456, 1269, 1235, 1035, 930, 777
cm–1.
References
(1) Partial result has been published: Wu, Z.-H.; Wang, J.; Li, J.-
C.; Xu, Y.-Z.; Yu, A.-L.; Feng, Z.-R.; Shen, J.; Wu, Y.-L.;
Guo, P.-F.; Wang, Y.-N. Nat. Prod. R & D [China] 1994, 6,
1; Chem. Abstr. 121, 101920.
1H NMR (300 MHz, CDCl3): d = 8.14 (1 H, m), 7.84 (1 H, d, J = 6.9
Hz), 7.72 (1 H, d, J = 8. 3 Hz), 7.53–7.42 (4 H, m), 6.66 (1 H, d,
J = 5. 5 Hz), 6.33 (1 H, d, J = 5.7 Hz), 6.24 (1 H, s), 4.34 (1 H, dd,
J = 4.3, 9.8 Hz), 4.21 (1 H, m), 3.70–3.60 (3 H, m), 2.25–2.19 (1 H,
m), 2.06–1.95 (2 H, m), 1.62–1.55 (1 H, m).
MS: m/z = 334 (M+ + 1, 97.8), 333 (M+, 31.0), 288 (12.3), 276
(15.1), 260 (7.0), 205 (13.9), 194 (24.8), 165 (100.0).
(2) (a) Hegnauer, R. In Chemotaxonomie der Pflanzen, Vol. 3;
Birkhauser Verlag: Basel, 1964, 447. (b) Bohlmann, F.;
Burkhardt, T.; Zdero, C. Naturally Occurring Acetylenes;
Academic Press: London, 1973. (c) Greger, H. In The
Biology and Chemistry of Compositae; Heywood, V. H.;
Harborne, J. B.; Turner, B. L., Eds.; Academic Press:
London, 1977, Chap. 32. (d) Bohlmann, F. In Chemistry
and Biology of Naturally Occurring Acetylenes and Related
Compounds; Lam, J.; Bretler, H.; Anason, T.; Hansen, L.,
Eds.; Elsvier: Amsterdam, 1988, 1. (e) Zdero, C.;
Bohlmann, F. Plant Syst. Evol. 1990, 171, 1.
Anal. Calcd for C21H19NO3: C, 75.66; H, 5.74; N, 4.20. Found: C,
75.84, H, 5.91; N, 4.33.
15e
Amorphous solid; Method A: 62.2 mg (19%); Method B: 31.8 mg
(10%); [a]D –192.7 (c = 1.0, CHCl3).
IR (KBr): 2925, 2887, 1663, 1456, 1335, 1197, 994, 779 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.07 (1 H, m), 7.82 (1 H, m), 7.74
(1 H, m), 7.49 (4 H, m), 6.80 (1 H, d, J = 5.7 Hz), 6.26 (1 H, s), 6.13
(1 H, d, J = 5.7 Hz), 4.03 (1 H, m), 3.91 (1 H, m), 3.75 (2 H, m),
3.54 (1 H, m), 2.27–2.20 (1 H, m), 2.05–1.94 (2 H, m), 1.63–1.53 (1
H, m).
MS: m/z = 334 (M+ + 1, 14.0), 333 (M+, 58.4), 289 (10.5), 277
(18.1), 222 (48.6), 194 (23.8), 165 (100.0).
(3) (a) Bohlmann, F.; Jastrow, H.; Ertringshausen, G.; Kramer,
D. Chem. Ber. 1964, 97, 801. (b) Bohlmann, F.; Florentz,
G. Chem. Ber. 1966, 99, 990.
(4) (a) Gao, Y.; Wu, W.-L.; Ye, B.; Zhou, R.; Wu, Y.-L.
Tetrahedron Lett. 1996, 37, 893. (b) Gao, Y.; Wu, W.-L.;
Wu, Y.-L.; Ye, B.; Zhou, R. Tetrahedron 1998, 54, 12523.
(5) (a) Fan, J.-F.; Zhang, Y.-F.; Wu, Y.; Wu, Y.-L. Chinese J.
Chem. 2001, 19, 1254; Chem. Abstr. 136, 263012. (b) Fan,
J.-F.; Yin, B.-L.; Zhang, Y.-F.; Wu, Y.-L.; Wu, Y. Huaxue
Xuebao 2001, 59, 1756; Chem. Abstr. 136, 083647.
(6) Blanchette, J. A.; Brown, E. V. J. Am. Chem. Soc. 1952, 74,
2098.
Anal. Calcd for C21H19NO3: C, 75.66; H, 5.74; N, 4.20. Found: C,
76.04, H, 5.81; N, 4.17.
(7) Fan, J.-F. Ph. D. Thesis; Shanghai Institute of Organic
Chemistry: China, 2000.
Acknowledgments
(8) Yin, B.-L.; Fan, J.-F.; Gao, Y.; Wu, Y.-L. Synlett 2003, 399.
(9) Reviews: (a) Brimble, M. A.; Fares, F. A. Tetrahedron 1999,
55, 7661. (b) Mead, K. T.; Brewer, B. N. Curr. Org. Chem.
2003, 7, 227; and references cited therein.
This work was supported by the National Natural Science Founda-
tion of China (grant No. 29672083, 20072043), the Chinese Acade-
my of Sciences, the State Ministry of Science and Technology
(G2000077502) and the Shanghai Committee of Science and Tech-
nology.
Synthesis 2003, No. 13, 1995–2000 © Thieme Stuttgart · New York