Efficient Syntheses of Traumatic Lactone and Rhizobialide

Article abstract of DOI:10.1002/chem.201901210

Herein, we report the total synthesis of traumatic lactone and rhizobialide by utilizing allenoic acid to construct the lactone ring. The key starting materials, allenoic acids, could be prepared by the ATA (allenation of terminal alkynes) of a terminal alkyne with an aldehyde that contained a protected hydroxyl group followed by hydrolysis. Importantly, the asymmetric synthesis could be realized just by replacing racemic diphenylprinol with (R)- or (S)-diphenylprinol to deliver the optically active allenoate.

Full text of DOI:10.1002/chem.201901210

A Journal of
Accepted Article
Title: Efficient Syntheses of Traumatic Lactone and Rhizobialide
Authors: Jing Zhou, Shihua Song, Feng Jiang, Chunling Fu, and
Shengming Ma
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Efficient Syntheses of Traumatic Lactone and Rhizobialide
Jing Zhou[a], Shihua Song[a], Feng Jiang[a], Chunling Fu[a], Shengming Ma*[a]
Dedication ((optional))
Abstract: Herein, we reported the total syntheses of traumatic
lactone and rhizobialide via the strategy of utilizing allenoic acid to
construct the lactone ring. The key starting materials, allenoic acids,
could be prepared by the ATA (allenation of terminal alkynes) of a
terminal alkyne with an aldehyde bearing a protected hydroxyl group
followed by hydrolysis. Importantly, the asymmetric syntheses could
be realized just by replacing racemic diphenylprinol with (R)- or (S)-
diphenylprinol to deliver the optically active allenoate.
resource, traumatic lactone 1 was prepared in 1951 from 9-
hydroxyoctadec-12-enoic acid 5, which was isolated from the
seed oil of sarmentosus by Gunstone, by its treatment with
[10b]
K2CO3.
Sayre et al. mimicked the formation of traumatic
lactone in nature.[11] It’s obvious that these methods suffer from
unavailable starting materials, strong acid, and high temperature.
It’s only lately that we reported the racemic and asymmetric
syntheses of traumatic lactone[12] by Pd-catalyzed allene-
asymmerization of 2,3-allenyl carbonates to produce the key
allene moiety with 91% ee, and the additional recrystallization
work-up was necessary to obtain excellent ee values. So there
is still a need for the development of new efficient approaches to
traumatic lactone, especially the asymmetric versions.
1. Introduction
Recently, ATA (allenation of terminal alkynes)[13] reactions
have emerged as a powerful method to prepare functionalized
allenes. On the other hand, we have developed the strategy
utilizing allenoic acid to construct lactone ring based on Au-
catalysis[14,15] to modulate the control of axial-to-central chirality
transfer efficiency and Z/E selectivity-the stereoselective
cyclization of allenoic acid.[14b] We envisage such a strategy by
combination ATA reaction with Au-catalysis could be exploited
for the synthesis of traumatic lactone. The retrosynthetic
analysis of traumatic lactone is shown in Scheme 1.
Molecules containing γ-butyrolactone moiety extensively occur
in nature and many of them have potentials as lead drug
compounds [1-6] or fine chemicals releasing unique fragrance [7]
.
Traumatic lactone 1, γ-(7-carboxyheptyl) γ-butyrolactone, was
isolated by Masamune from phaseolus vulgaris, beni-kintoki.[8]
Structurally very related lactone, rhizobialide 2, was isolated
from glycyrrhiza uralensis, and showed anti-bacterial activity
against Staphylococcus aureus CMCCB26001 and Escherichia
coli CMCCB44102.[3,9] In this paper, we wish to report our recent
efforts towards the syntheses of these two naturally occurring
lactones (Fig. 1).
Previous works:
O
H2SO4
55%
O
HOOC
OH
O
OH
traumatic acid 3
O
traumatic lactone 1
molten
p-TsOH, I2
200 oC, 6 h
O
HCl
K2CO3
O
OMe
acetone
then rt, MeOH, 16 h
O
- n-C5H11COOH
4
OH
O
H3C
OH
7
5
Fig. 1 The structures of traumatic lactone (R)/(S)-1 and rhizobialide (S)-2
Retrosynthetic analysis:
HO
2. Results and Discussion
HO
O
O
O
O
rac-12
rac-11
O
O
O
rac-traumatic lactone
2.1. Synthesis of rac-traumatic lactone
BnO
BnO
7
diphenylprinol
Nayak et al. prepared traumatic lactone 1 from traumatic acid
3.[10a] Interestingly, even before the isolation from natural
ATA reaction
O
+
Au-cyclosiomerization
BnO
HO
4
CO2Et
4
6
8
rac-9 (R = Et)
rac-10 (R = H)
CO2R
OH
5
heptane-1,7-diol
[a]
J. Zhou, S. Song, F. Jiang, C. Fu, S. Ma
Department Laboratory of Molecular Recognition and Synthesis,
Department of Chemistry, Zhejiang University, 310027 Hangzhou
city, Zhejiang, People’s Republic of China.
Scheme 1. The previous works and retrosynthetic analysis for traumatic
lactone
E-mail: masm@sioc.ac.cn
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Thus, 1,7-heptandiol was treated with BnBr in the presence of
NaH to afford the monoetherification product, benzoxyheptanol,
in 61% yield, which was subsequently oxidized to aldehyde 6
with oxygen as the oxidant under the catalysis of
Fe(NO3)3·9H2O, TEMPO, and NaCl[16a] (Scheme 2). ATA
reaction of ethyl 4-pentynoate 8 and aldehyde 6 in the presence
of diphenylprinol afforded allenoate rac-9,[13] which was
hydrolyzed to afford allenoic acid rac-10. Its AuCl(LB-Phos)-
catalyzed cyclziation[14b] afford E-alkenyl lactone (E)-11 with a
E/Z selectivity of 96:4. The C=C bond and benzyl ether unit in
this product were hydrogenated and cleaved simultaneously to
afford lactone rac-12 with a terminal primary alcohol unit. Under
the catalysis of 5 mol% Pd/C, the reaction of (E)-10 in ethyl
acetate with 25 atm H2 for 36 h would led to the formation
lactone ring opening product, therefore, the reaction time was
shortened to 30 h to afford rac-12 in 94% NMR yield exclusively.
Subsequent aerobic oxidation with KCl[16b,c] afforded the racemic
traumatic acid 1.
Scheme 3. The synthesis of (Ra)-9 and (Ra)-10.
After hydrolysis, the cycloiosmerization of optically active
allenioc acid (Ra)-10 was optimized to ensure the efficiency of
chirality transfer and a high E/Z selectivity (Table 1). The optimal
o
cyclization reaction conditions at -20 C led to the formation of
(S,E)-11 in 96% ee with a E/Z selectivity of 98:2.
Table 1. Optimization of the reaction conditions for the
cyclization of (Ra)‐10[a]
.
11
Recovery
Entry
T/oC
t/h
2
of
(Ra)-
10/%[b]
Yield/% [b]
100
(S,E)/(R,Z) [b]
96:4
ee%[c]
96
1
2
3
4
25
0
0
11 100
12 100
36 75
97:3
95
0
-20
-40
98:2
96
0
98:2
-
23
Scheme 2. The synthesis of (±) traumatic lactone
[a] AgOTs (0.01 mmol), AuCl(LB-Phos) (0.01 mmol), and CHCl3 (2 mL) were
stirred at room temperature for 15 min under nitrogen atmosphere; then 0.2
mmol of (Ra)-10 and CHCl3 (1 mL) were added. [b] Determined by 1H NMR of
crude product using 1,3,5-trimethylbenzene as internal standard. [c] ee % of
(S,E)-11; Determined by chiral high-performance liquid chromatography (HPLC)
analysis.
2.2. Synthesis of (R)- and (S)-traumatic lactones
With a synthetic route being developed for racemic traumatic
lactone 1, the enantioselective synthesis of (R)-traumatic lactone
was conducted just by replacing racemic diphenylprinol with (S)-
diphenylprinol 7 to deliver the optically active allenoate (Ra)-9,
which was hydrolyzed to afford allenoic acid (Ra)-10 (Scheme 3).
However, owing to the existence of free carboxylic acid group,
the direct analysis of (Ra)-10 by HPLC analysis is difficult but not
obligatory. The following results witnessed the hydrolysis by
LiOH·H2O had no damage on the ee value.
Finally, after hydrogenation and subsequent aerobic
oxidation, the (R)-traumatic acid (R)-1 was afforded in 33%
combined yield. Upon converting it to its benzyl ester (R)-13, the
ee value of (R)-traumatic lactone was identified as 92%
(Scheme 4).
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Scheme 6. The synthesis of rac-rhizobialide 2 from rac-traumatic lactone
1.
Scheme 4. The asymmetric synthesis of (R)-traumatic lactone.
In order to have a highly selective synthesis, we considered to
use alcohol 12 as the starting point. We conducted the aerobic
oxidation of primary alcohol rac-12 to aldehyde rac-16. The
reaction of rac-16 with n-C6H13MgBr afforded secondary alcohol
rac-17, which was oxidized with oxygen to afford rac-rhizobialide
2[16] (Scheme 7).
In addition, we also synthesized (S)-traumatic lactone with a
similar efficiency and ee by replacing amino alcohol (S)-7 with
(R)-7 (Scheme 5).
Scheme 7. The synthesis of rac-rhizobialide 2 from primary alcohol.
2.3.2. Synthesis of (S)-rhizobialide
Under the catalysis of 10 mol% Fe(NO3)3∙9H2O, 10 mol%
TEMPO, and 10 mol% NaCl, the aerobic oxidation reaction of
(S)-12 in 1,2-dichloroethane afforded aldehyde (S)-16 in 69%
NMR yield; the NMR yield of (S)-16 was improved to 72% when
the reaction was conducted in CH2Cl2 (eq. 2).
Scheme 5. The asymmetric synthesis of (S)-traumatic lactone.
2.3. Synthesis of rhizobialide
2.3.1. Synthesis of rac-rhizobialide
TEMPO (10 mol%)
HO
NaCl (10 mol%)
(2)
7
Fe(NO3)3•9H2O (10 mol%)
2 (balloon), solvent, rt, 8.5 h
O
O
O
There is only one report on its synthesis from glutamic acid
with 8 steps.[17] Due to the similarity of rhizobialide as compared
to traumatic lactone, we tried to prepare rhizobialide from
O
O
O
(S)-12
(S)-16
DCE: 69% NMR yield;
DCM: 72% NMR yield
o
traumatic lactone. At 0 C, the solution of rac-traumatic lactone
in CH2Cl2 was treated with 10 mol% anhydrous DMF and 1.5
equiv of freshly distilled (COCl)2. After 17 h at rt, the free
carboxylic acid group was converted to the corresponding acyl
chloride 14, which was subsequently treated with n-C6H13MgBr
The reaction of aldehyde (S)-16 with n-C6H13MgBr afforded
secondary (S)-17, which was further oxidized with oxygen to
afford 65% yield of rhizobialide (S)-2: the whole synthesis took 7
20
steps from aldehyde 6 to afford the target in 19.4%: [a]D = -
o
in THF at -10 C for 8 h[18] to afford 22% isolated yield of rac-
20
24.4 (c = 0.54, CHCl3) (ref.: [a]D = -19.7 (c = 0.55, CHCl3)
rhizobialide 2 together with 22% lactonyl ester 15 as an
inseparable mixture. Moreover, rac-Traumatic lactone was
recovered in 43% yield (Scheme 6).
(Scheme 8).
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mixture was warmed up to rt gradually and reacted for another 1.5 h and
then at 35 oC for 1 h. The resulting mixture was cooled with an ice-water
bath for 5 minutes and BnBr (14.3 mL, d = 1.44 g/mL, 20.592 g, 120
mmol) was added dropwise within 15 minutes. Subsequently, the flask
was warmed up to rt gradually. The reaction was complete after being
stirred at rt for 7 h as monitored by TLC and quenched with H2O (100
mL). After stirring for 10 minutes, the reaction mixture was extracted with
ethyl acetate (40 mL × 5). The combined organic layer was washed with
water, brine and dried over anhydrous Na2SO4. After filtration and
evaporation, the residue was purified by chromatography on silica gel
[eluent: petroleum ether (60-90 oC)/ethyl acetate = 100/1 (500 mL) to
50/1 (1000 mL) to 30/1 (1000 mL) to 20/1 (500 mL) to 10/1 (500 mL) to
8/1 (500 mL) to 5/1 (600 mL) to 1/1 (600 mL)] on silica gel to afford 7-
(benzyloxy)heptan-1-ol[19] (13.5661 g, 61%) as a liquid: 1H NMR (300
MHz, CDCl3) δ 7.38-7.23 (m, 5H, ArH), 4.49 (s, 2H, OCH2), 3.58 (t, J =
6.5 Hz, , 2H, OCH2), 3.46 (t, J = 6.5 Hz, 2H, OCH2), 1.94 (s, 1H, OH),
1.67-1.46 (m, H, CH2 × 2), 1.44-1.27 (m, 6H, CH2 × 3); 13C NMR (75 MHz,
CDCl3) δ 138.5, 128.2, 127.5, 127.4, 72.7, 70.3, 62.7, 32.5, 29.6, 29.1,
26.0, 25.6.
Scheme 8. The asymmetric synthesis of rhizobialide (S)-2.
3. Conclusion
In conclusion, allenylation of terminal alkynoate with 7-
benzoxyheptanal in the presence of (S)- or (R)-diphenylprinol,
AuCl(LB-Phos)-catalyzed
highly
stereoselective
cycloisomerization of allenoic acid and Fe(NO3)3∙9H2O
/TEMPO/MCl-catalyzed aerobic oxidation have been applied as
the key technology for efficient (enantioselective) syntheses of
the naturally occurring traumatic lactone and rhizobialide.
Further synthetic application of these reactions is being pursued
in our laboratory.
4.2.1.2. Synthesis of 7-(benzyloxy)heptanal 6 (zj-9-063)
Typical Procedure Ⅰ :[16] To
a three-necked flask were added
4. Experimental Section
4.1. General
Fe(NO3)3∙9H2O (1.7105 g, purity = 98%, 4.2 mmol), NaCl (0.2437 g, 4.2
mmol), TEMPO (0.6688 g, purity = 98%, 4.2 mmol), and DCE (320 mL)
sequentially. An oxygen balloon was equipped followed by dropwise
addition of a solution of 7-(benzyloxy)heptan-1-ol in 100 mL of DCE at
room temperature within 0.5 h in oxygen atmosphere from the balloon.
The resulting mixture was stirred for 9.5 h until the reaction was complete
as monitored by TLC. After transfer to a separation funnel, the organic
phase was washed with 3 M HCl (aq., 30 mL × 3), a saturated solution of
NaHCO3 (30 mL), brine sequentially, and dried over anhydrous Na2SO4.
After filtration and evaporation, the residue was purified by
chromatography on silica gel [eluent: petroleum ether (60-90 oC)/ethyl
acetate = 50/1 (500 mL) to 30/1 (480 mL) to 20/1 (500 mL) to 10/1 (1040
mL) to 5/1 (300 mL) to afford 7-(benzyloxy)heptanal 6[19] (7.1345 g, 68%)
as a liquid: 1H NMR (300 MHz, CDCl3) 9.75 (t, J = 1.8 Hz, 1H, CHO),
7.38-7.23 (m, 5H, ArH), 4.50 (s, 2H, OCH2), 3.46 (t, 2H, J = 6.5 Hz,
OCH2), 2.41 (td, J1 = 7.3 Hz, J2 = 1.7 Hz, 2H, CH2), 1.68-1.55 (m, 4H,
CH2 × 2), 1.46-1.27 (m, 4H, CH2 × 2); 13C NMR (75 MHz, CDCl3) δ 202.7,
138.5, 128.3, 127.5, 127.4, 72.8, 70.1, 43.7, 29.5, 28.9, 25.9, 21.9.
1H and 13C nuclear magnetic resonance spectra were recorded with an
instrument operated at 300 MHz for 1H NMR spectra and 75 MHz for 13
C
NMR spectra. CDCl3 was used as solvent in all NMR experiments.
Chemical shifts (δ) are given in parts per million (ppm). Infrared spectra
were recorded from the films of pure samples on sodium chloride plates
on a FT-IR spectrometer. Mass and HRMS spectra were carried out in EI
mode. Flash column chromatography was performed on silica gel.
Dioxane and THF were refluxed over sodium wire using diphenyl ketone
as indicator and distilled right before use. CuBr2 was purchased from J &
K. (S)-α,α-diphenylprolinol and (R)-α,α-diphenylprolinol were purchased
from Shanghai Darui Fine Chemicals. AgOTs was purchased from Alfa
Aesar. Other commercially available reagents were purchased and used
without further purification.
4.2. Synthesis of traumatic lactones
4.2.1.3. Synthesis of ethyl 12-(benzyloxy)dodeca-4,5-dienoate rac-9 (zj-
8-085, jf-1-009)
4.2.1. Synthesis of rac-traumatic lactone
4.2.1.1. Synthesis of 7-(benzyloxy)heptan-1-ol (zj-8-127)
BnO
6
Ph
CuBr2 (20 mol%)
dioxane, 130 oC, 17 h
OBn
6
Ph
OH
+
+
O
CO2Et
N
H
CO2Et
rac-7
rac-9
8
6
58%
1.5 equiv.
1.5 equiv.
Typical Procedure Ⅱ : To
a flame-dried Schlenk tube with a
polytetrafluoroethylene plug were added CuBr2 (0.1353 g, 0.6 mmol,
99%), rac-2-(diphenylhydroxymethyl)pyrrolidine rac-7 (0.7744 g, 3.0
mmol, 98%), ethyl pent-4-ynoate 8 (0.5678 g, 4.5 mmol)/dioxane (2.5
mL), and 7-(benzyloxy)heptanal 6 (0.9902 g, 4.5 mmol)/dioxane (2.5 mL)
sequentially under nitrogen atmosphere. The Schlenk tube was then
sealed by screwing the polytetrafluoroethylene plug tightly. The reaction
To a flame-dried three-necked flask with an addition funnel were added
NaH (4.4174 g, purity = 60% in mineral oil, 110 mmol) and DMF (150 mL)
sequentially at rt under nitrogen atmosphere. Then the resulting mixture
was cooled to -10 oC and a solution of heptane-1,7-diol (13.8975 g, purity
= 95%, 100 mmol) in DMF (50 mL) was added quickly. The resulting
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was complete after being stirred in an oil bath preheated at 130 oC for 17
h as monitored by TLC. The resulting mixture was cooled to room
temperature, diluted with Et2O (30 mL), and washed with an aqueous
solution of hydrochloric acid (10 mL, 3 M). The organic layer was
separated and the aqueous layer was extracted with Et2O (10 mL). The
combined organic layer was washed with brine and dried over anhydrous
Na2SO4. After filtration and evaporation, the residue was purified by
chromatography on silica gel [eluent: petroleum ether (60-90 oC)/ethyl
acetate = 100/1 (500 mL) to 50/1 (500 mL) to 30/1 (500 mL)] to afford
rac-9[13] (0.5930 g, 58%) as a liquid: 1H NMR (300 MHz, CDCl3) δ 1H
NMR (300 MHz, CDCl3) δ 7.40-7.20 (m, 5H, ArH), 5.19-5.06 (m, 2H, =CH
× 2), 4.49 (s, 2H, ArCH2), 4.12 (q, J = 7.0 Hz, 2H, CH2), 3.46 (t, J = 6.6
Hz, 2H, CH2), 2.44-2.35 (m, 2H, CH2), 2.34-2.23 (m, 2H, CH2), 2.02-1.89
(m, 2H, CH2), 1.67-1.54 (m, 2H, CH2), 1.45-1.27 (m, 6H, CH2 × 3), 1.24 (t,
J = 7.1 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3) δ 203.5, 172.8, 138.5,
128.1, 127.3, 127.2, 92.2, 89.4, 72.6, 70.2, 60.0, 33.2, 29.5, 28.8, 28.7,
28.6, 25.8, 23.7, 14.0; IR (neat) ν (cm-1) 3092, 3064, 3030, 2976, 2931,
2855, 2791, 1962, 1732, 1496, 1454, 1371, 1301, 1250, 1158, 1100,
1028; MS (70 ev, EI) m/z (%) 331 (M++1, 5.01), 330 (M+, 7.89), 91 (100);
HRMS calcd for C21H30O3 [M+]: 330.2195, Found: 330.2199.
(0.0358 g, 0.06 mmol), and CHCl3 (6 mL) under nitrogen atmosphere
sequentially. After stirring for 15 min, rac-10 (0.3616 g, 1.2 mmol) and
CHCl3 (6 mL) were added. The reaction mixture was then continuously
stirred at 25 oC for 3 h and complete as monitored by TLC. Filtration
through a short column of silica gel [eluent: Et2O (20 mL × 3)] and
evaporation afforded a crude mixture of (E)-11 and (Z)-11 (E/Z = 96/4, as
determined by 1H NMR analysis). Column chromatography on silica gel
afforded (E)-11 (0.3479 g, 96%, E/Z = 96/4 as determined by 1H NMR
analysis) [eluent: petroleum ether (60-90 oC)/ethyl acetate = 15/1 (480
mL) to 10/1 (550 mL) to 7/1 (400 mL)] as an oil: 1H NMR (300 MHz,
CDCl3) δ 7.38-7.20 (m, 5H, ArH), 5.78 (dtd, J1 = 15.3 Hz, J2 = 6.9 Hz, J3
= 0.9 Hz, 1H, =CH), 5.47 (ddt, J1 = 15.3 Hz, J2 = 7.2 Hz, J3 = 1.4 Hz, 1H,
=CH), 4.85 (q, J = 7.1 Hz, 1H, CH), 4.49 (s, 2H, CH2), 3.46 (t, J = 6.5 Hz,
2H, CH2), 2.53-2.45 (m, 2H, CH2), 2.39-2.26 (m, 1H, one proton from
CH2), 2.05 (q, J = 6.7 Hz, 2H, CH2 ), 2.00-1.85 (m, 1H, one proton from
CH2), 1.66-1.53 (m, 2H, CH2), 1.45-1.23 (m, 6H, CH2 × 3); the following
signals are discernible for (Z)-6: δ 5.69-5.59 (m, 1H, =CH), 5.26-5.16 (m,
1H, CH); 13C NMR (75 MHz, CDCl3) δ 176.9, 138.5, 135.3, 128.1, 127.4,
127.3, 127.2, 80.9, 72.6, 70.2, 31.8, 29.4, 28.7, 28.6, 28.5, 25.8; IR
(neat) ν (cm−1) 3087, 3061, 3030, 2930, 2855, 2792, 1770, 1673, 1496,
1455, 1362, 1327, 1216, 1175, 1102, 1008; GC-MS (GC condition:
injector: 280 oC; column: DB5 column 30 m × 0.25 mm, temperature
programming: 60 oC (2 min), 20 oC/min to 280 oC, 280 oC (30 min);
detector: 280 oC) (70 ev, EI) m/z (%) for (E)-11: tR (major) = 9.36 min:
302 (M+, 0.38), 193 [(M - C7H9O)+, 14.03], 91 (100); for (Z)-11: tR (minor)
= 9.14 min: 302 (M+, 0.12), 193 [(M - C7H9O)+, 8.64], 91 (100); Elemental
analysis calcd (%) for C19H26O3: C, 75.46; H, 8.67; Found: C, 75.11; H,
8.63.
4.2.1.4. Synthesis of 12-(benzyloxy)dodeca-4,5-dienoic acid rac-10 (zj-8-
086, jf-1-010)
4.2.1.6. Synthesis of rac-traumatic lactone (zj-8-095, zj-8-097)
Typical Procedure Ⅲ: To a round-bottom flask were added rac-9
(0.5331 g, 1.62 mmol), EtOH/H2O = 1:1 by volume (pre-mixed by using 8
mL of H2O and 8 mL of EtOH), and LiOH∙H2O (0.1075 g, 2.43 mmol,
95%) sequentially. After continuous stirring for 3 h under reflux at 90 oC,
the reaction was complete as monitored by TLC. Then the mixture was
cooled to room temperature. After evaporation to remove EtOH, the
resulting mixture was acidified with an aqueous solution of hydrochloric
acid (aq., 3.0 M) until pH = 1 and then extracted with Et2O (15 mL × 3).
The combined organic layer was washed with brine, dried over
anhydrous Na2SO4, filtration, evaporation, and column chromatography
on silica gel to give rac-10 (0.4671 g, 96%) [eluent: petroleum ether (60-
90 oC)/ ethyl acetate = 10/1 (550 mL) to 5:1 (600 mL) to 3:1 (240 mL)] as
an oil: 1H NMR (300 MHz, CDCl3) δ 11.28 (bs, 1H, COOH), 7.43-7.22 (m,
5H, ArH), 5.22-5.09 (m, 2H, =CH × 2), 4.51 (s, 2H, ArCH2), 3.46 (t, J =
6.6 Hz, 2H, CH2), 2.52-2.41 (m, 2H, CH2), 2.35-2.22 (m, 2H, CH2), 2.02-
1.89 (m, 2H, CH2), 1.68-1.55 (m, 2H, CH2), 1.46-1.24 (m, 6H, CH2 × 3);
13C NMR (75 MHz, CDCl3) δ 203.7, 178.7, 138.5, 128.3, 127.7, 127.5,
92.8, 89.4, 72.8, 70.4, 33.0, 29.6, 28.9, 28.8, 28.7, 25.9, 23.5; IR (neat) ν
(cm-1) 3686-2142 (COOH), 1963, 1714, 1496, 1455, 1361, 1251, 1208,
1160, 1100, 1028; MS (70 ev, EI) m/z (%) 303 (M++1, 37.01), 302 (M+,
3.92), 91 (100); HRMS calcd for C19H26O3 [M+]: 302.1882, Found:
302.1882.
Typical Procedure Ⅴ: To a round-bottom flask were added (E)-11
(E/Z = 96/4) (0.3021 g, 1.0 mmol), EtOAc (6 mL), and Pd/C (10% on C,
dry, 0.0533 g, 0.05 mmol) sequentially. Then the flask was placed in an
autoclave. The mixture was stirred under H2 (25 atm) at rt for 30 h and
then filtered through a short column of silica gel eluted with EtOAc (15
mL × 4). After evaporation, crude rac-12[20] (94% NMR yield, determined
by 1H NMR of crude product using 1,3,5-trimethylbenzene as internal
standard) was afforded, which was then submitted to next step without
purification.
Following Typical Procedure Ⅰ:[16] To a three-necked flask were added
Fe(NO3)3∙9H2O (0.0406 g, 0.1 mmol, 98%), KCl (0.0075 g, 0.1 mmol),
TEMPO (0.0239 g, 0.15 mmol, 98%), alcohol rac-12 (prepared above),
and DCE (5 mL) sequentially. The resulting mixture was stirred at rt for
17 h until the reaction was complete as monitored by TLC. After filtration
through a short column of silica gel [eluent: DCM (10 mL × 4)] and
evaporation, the residue was purified by chromatography on silica gel
[eluent: petroleum ether (60-90 oC)/ethyl acetate = 5/1 (600 mL) to 3/1
(600 mL) to 2/1 (800 mL)] to afford rac-traumatic lactone (0.1471 g, 65%,
2 steps) as a white solid: m. p. 53.9-55.1 oC (n-hexane/dichloromethane)
(Lit.[8] m. p. 48.5-50 oC (isopropyl ether/n-hexane)); 1H NMR (300 MHz,
CDCl3) δ 11.03 (bs, 1H, COOH), 4.51 (quintet, J = 7.2 Hz, 1H, OCH),
2.62-2.48 (m, 2H, CH2), 2.43-2.25 (m, 3H, CH2 + one proton from CH2),
1.96-1.53 (m, 5H, CH2 × 2 + one proton from CH2), 1.53-1.22 (m, 8H,
CH2 × 4); 13C NMR (75 MHz, CDCl3) δ 179.3, 177.5, 80.9, 35.1, 33.7,
28.72, 28.68, 28.6, 28.5, 27.6, 24.8, 24.2; IR (neat) ν (cm−1) 3716-2218
4.2.1.5. Synthesis of (E)-5-(8-(benzyloxy)oct-1-en-1-yl)dihydro-2(3H)-
furanone (E)-11 (zj-8-089)
Typical Procedure Ⅳ:[14b] To a dried Schlenk tube were added AgOTs
(0.0171 g, 0.06 mmol, weighed in a glove box, 98%), AuCl(LB-Phos)
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(COOH), 1771, 1711, 1461, 1420, 1356, 1284, 1186, 1017; MS (70 ev,
EI) m/z (%) 229 (M+ + 1, 19.74), 228 (M+, 1.81), 211 (100), 85 (100).
1496, 1454, 1363, 1250, 1207, 1160, 1101, 1028; MS (70 ev, EI) m/z (%)
303 (M++1, 10.72), 302 (M+, 2.49), 91 (100); HRMS calcd for C19H26O3
[M+]: 302.1882, Found: 302.1885.
4.2.2. Total synthesis of (R)-traumatic lactone
4.2.2.3. Synthesis of (S,E)-5-(8-(benzyloxy)oct-1-en-1-yl)dihydro-2(3H)-
furanone (S,E)-11 (zj-8-096)
4.2.2.1. Synthesis of ethyl (Ra)-12-(benzyloxy)dodeca-4,5-dienoate (Ra)-9
(zj-8-088, jf-1-012)
Typical Procedure Ⅶ: To a dry Schlenk tube were added AgOTs
(0.0214 g, 0.075 mmol, weighed in a glove box, 98%), Au(LB-Phos)Cl
(0.0448 g, 0.075 mmol), and CHCl3 (15 mL) under nitrogen atmosphere
sequentially. After stirring at room temperature for 15 min, the reaction
was cooled down to -20 oC and then (Ra)-10 (0.9063 g, 3.0 mmol) and
CHCl3 (15 mL) were added. The reaction mixture was then continuously
stirred at -20 oC for 15.5 h as monitored by TLC. The reaction was then
warmed up to room temperature, filtration through a short column of silica
gel [eluent: Et2O (30 mL × 3)], and evaporation to afford a crude mixture
of (S,E)-11 and (R,Z)-11 ((S,E)/(R,Z) = 98/2 determined by 1H NMR of
crude product). Column chromatography on silica gel [eluent: petroleum
ether (60-90 oC)/ethyl acetate = 15/1 (480 mL) to 10/1 (550 mL) to 8/1
(540 mL) to 7/1 (640 mL)] afforded (S,E)-11 (0.8647 g, 95%, (S,E)/(R,Z)
= 98/2 determined by 1H NMR) as an oil: 96% ee (HPLC conditions:
Chiralcel PA-2 column, n-hexane/i-PrOH = 90:10, 1.0 mL/min, λ = 214
nm, tR (major) = 34.3 min, tR (minor) = 52.3 min; [α]D20 = +21.2 (c = 1.045,
CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.38-7.20 (m, 5H, ArH), 5.84-5.71
(m, 1H, =CH), 5.46 (ddt, J1 = 15.5 Hz, J2 = 7.2 Hz, J3 = 1.4 Hz, 1H, =CH),
4.84 (q, J = 7.1 Hz, 1H, CH), 4.48 (s, 2H, OCH2), 3.45 (t, J = 6.6 Hz, 2H,
CH2), 2.54-2.44 (m, 2H, CH2), 2.39-2.24 (m, 1H, one proton from CH2),
2.05 (q, J = 6.7 Hz, 2H, CH2), 2.00-1.83 (m, 1H, one proton from CH2),
1.67-1.53 (m, 2H, CH2), 1.45-1.22 (m, 6H, CH2 × 3); the following signals
are discernible for (R,Z)-11: δ 5.68-5.58 (m, 1H, =CH), 5.26-5.15 (m, 1H,
CH); 13C NMR (75 MHz, CDCl3) δ 176.8, 138.4, 135.2, 128.1, 127.32,
127.28, 127.2, 80.8, 72.6, 70.1, 31.7, 29.4, 28.6, 28.5, 28.4, 25.7; IR
(neat) ν (cm−1) 3087, 3062, 3030, 2929, 2853, 2791, 1774, 1671, 1496,
1453, 1364, 1327, 1175, 1101; GC-MS (GC condition: injector: 280 oC;
column: DB5 column 30 m × 0.25 mm, temperature programming: 60 oC
(2 min), 20 oC/min to 280 oC, 280 oC (30 min); detector: 280 oC) (70 ev,
EI) m/z (%) for (S,E)-11: tR (major) = 9.30 min: 302 (M+, 0.15), 193 [(M -
C7H9O)+, 7.81], 91 (100); for (R,Z)-11: tR (minor) = 9.11 min: 193 [(M -
C7H9O)+, 7.33], 91 (100); Elemental analysis calcd (%) for C19H26O3: C,
75.46; H, 8.67; Found: C, 75.19; H, 8.53.
Typical Procedure Ⅵ: To a dry Schlenk flask were added CuBr2
(0.4958 g, 2.2 mmol, 99%), (S)-7 (2.8396 g, 11 mmol, 98%), 8 (2.0787 g,
16.5 mmol)/dioxane (20 mL), and 6 (3.6311 g, 16.5 mmol)/dioxane (13
mL) sequentially under nitrogen atmosphere. After continuous stirring for
17 h under reflux at 120 oC, the reaction was complete as monitored by
TLC. The resulting mixture was cooled to room temperature. The mixture
was diluted with ether (90 mL) and then washed with an aqueous
solution of hydrochloric acid (3 M, 15 mL × 3). The organic layer was
separated and the aqueous layer was extracted with Et2O (20 mL). The
combined organic layer was washed with brine and dried over anhydrous
Na2SO4. After filtration and evaporation, the residue was purified by
chromatography on silica gel [eluent: petroleum ether (60-90 oC)/ethyl
acetate = 100/1 (300 mL) to 50:1 (300 mL) to 30:1 (500 mL) to 20:1 (500
mL) to 10:1 (500 mL)] to afford (Ra)-9 (1.8645 g, 51%) as an liquid: 95%
ee (HPLC conditions: Chiralcel AS-H column, n-hexane/i-PrOH = 100:1,
1.0 mL/min, λ = 214 nm, tR (major) = 17.2 min, tR (minor) = 18.8 min;
[α]D = -49.2 (c = 1.005, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1H NMR
20
(300 MHz, CDCl3) δ 7.42-7.21 (m, 5H, ArH), 5.19-5.07 (m, 2H, =CH × 2),
4.49 (s, 2H, ArCH2), 4.11 (q, J = 7.1 Hz, 2H, CH2), 3.45 (t, J = 6.5 Hz, 2H,
CH2), 2.44-2.35 (m, 2H, CH2), 2.34-2.22 (m, 2H, CH2), 2.01-1.89 (m, 2H,
CH2), 1.67-1.55 (m, 2H, CH2), 1.45-1.28 (m, 6H, CH2 × 3), 1.24 (t, J = 7.2
Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3) δ 203.5, 172.9, 138.5, 128.2,
127.4, 127.3, 92.2, 89.4, 72.7, 70.2, 60.1, 33.3, 29.6, 28.9, 28.8, 28.6,
25.9, 23.7, 14.1; IR (neat) ν (cm-1) 3088, 3067, 3028, 2972, 2932, 2855,
2787, 1962, 1738, 1496, 1454, 1371, 1300, 1253, 1203, 1159, 1100,
1028; MS (70 ev, EI) m/z (%) 331 (M++1, 2.40), 330 (M+, 5.77), 91 (100);
HRMS calcd for C21H30O3 [M+]: 330.2195, Found: 330.2193.
4.2.2.2. Synthesis of (Ra)-12-(benzyloxy)dodeca-4,5-dienoic acid (Ra)-10
(zj-8-090, jf-1-013)
4.2.2.4. Synthesis of (R)-traumatic lactone (zj-8-098, zj-8-099)
Following Typical Procedure Ⅲ, the reaction of (Ra)-9 (1.7655 g, 5.35
mmol), EtOH/H2O = 1:1 by volume (pre-mixed by using 27 mL of H2O
and 27 mL of EtOH), and LiOH·H2O (0.3550 g, 8.025 mmol, 95%) for 4 h
afforded (Ra)-10 (1.5523 g, 96%) [(eluent: petroleum ether (60-90
oC)/ethyl acetate = 15/1 (300 mL) to 10/1 (550 mL) to 5/1 (600 mL)] as an
Following Typical Procedure Ⅴ, the reaction of (S,E)-11 ((S,E)/(R,Z) =
98/2) (0.7242 g, 2.4 mmol)/EtOAc (14.5 mL) and Pd/C (10% on C, dry,
0.1277 g, 0.12 mmol) for 30 h afforded crude (R)-12 (96% NMR yield,
determined by 1H NMR of crude product using 1,3,5-trimethylbenzene as
internal standard), which was submitted to next step without further
characterization.
oil: [α]D = -35.5 (c = 1.005, CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.47
20
(bs, 1H, COOH), 7.40-7.23 (m, 5H, ArH), 5.19-5.09 (m, 2H, =CH × 2),
4.51 (s, 2H, ArCH2), 3.46 (t, J = 6.6 Hz, 2H, CH2), 2.46 (t, J = 7.1 Hz, 2H,
CH2), 2.34-2.23 (m, 2H, CH2), 2.02-1.90 (m, 2H, CH2), 1.67-1.55 (m, 2H,
CH2), 1.45-1.24 (m, 6H, CH2 × 3); 13C NMR (75 MHz, CDCl3) δ 203.6,
178.9, 138.5, 128.3, 127.6, 127.5, 92.7, 89.3, 72.8, 70.4, 33.0, 29.5, 28.9,
28.8, 28.7, 25.9, 23.5; IR (neat) ν (cm-1) 3699-2268 (COOH), 1963, 1710,
Following Typical Procedure Ⅰ, the reaction of Fe(NO3)3∙9H2O (0.0980
g, 0.24 mmol, 98%), KCl (0.0179 g, 0.24 mmol), TEMPO (0.0573 g, 0.36
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mmol, 98%), DCE (5 mL), and (R)-12 (prepared above)/DCE (7 mL) for
24 h afforded (R)-traumatic lactone (0.3881 g, 71%) [eluent: petroleum
ether (60-90 oC)/ethyl acetate = 5/1 (600 mL) to 4/1 (500 mL) to 3/1 (540
mL) to 30/1 (500 mL) to 20/1 (400 mL)] as a liquid: 96% ee (HPLC
conditions: Chiralcel AS-H column, n-hexane/i-PrOH = 100:1, 1.0 mL/min,
λ = 214 nm, tR (major) = 21.2 min, tR (minor) = 18.4 min); [α]D20 = +49.3 (c
= 1.00, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.42-7.18 (m, 5H, ArH),
5.18-5.06 (m, 2H, =CH × 2), 4.49 (s, 2H, ArCH2), 4.12 (q, J = 7.1 Hz, 2H,
CH2), 3.46 (t, J = 6.8 Hz, 2H, CH2), 2.45-2.35 (m, 2H, CH2), 2.34-2.22 (m,
2H, CH2), 2.01-1.89 (m, 2H, CH2), 1.67-1.53 (m, 2H, CH2), 1.47-1.28 (m,
6H, CH2 × 3), 1.24 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3) δ
203.6, 173.0, 138.6, 128.2, 127.5, 127.4, 92.3, 89.5, 72.8, 70.3, 60.2,
33.4, 29.6, 29.0, 28.9, 28.7, 25.9, 23.8, 14.1; IR (neat) ν (cm−1) 3084,
3063, 3030, 2978, 2931, 2855, 2789, 1962, 1737, 1496, 1454, 1372,
1301, 1251, 1196, 1180, 1158, 1132, 1099, 1076, 1028; MS (70 ev, EI)
m/z (%) 331 (M+ + 1, 11.01), 330 (M+, 9.50), 91 (100); HRMS calcd for
C21H30O3 [M+]: 330.2195, found: 330.2192.
mL) to 2/1 (900 mL)] as
a
white solid: m. p. 63.6-65.4 oC (n-
hexane/dichloromethane); [α]D = +31.4 (c = 1.025, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 10.88 (bs, 1H, COOH), 4.50 (quintet, J = 6.8 Hz, 1H,
CH), 2.55 (dd, J1 = 9.4 Hz, J2 = 6.9 Hz, 2H, CH2), 2.41-2.26 (m, 3H, CH2
+ one proton from CH2), 1.95-1.52 (m, 5H, CH2 × 2 + one proton from
CH2), 1.52-1.24 (m, 8H, CH2 × 4); 13C NMR (75 MHz, CDCl3) δ 179.3,
177.5, 80.9, 35.1, 33.7, 28.73, 28.69, 28.6, 28.5, 27.6, 24.8, 24.2; IR
(neat) ν (cm−1) 3728-2284 (COOH), 1770, 1708, 1462, 1420, 1356, 1185,
1017; MS (70 ev, EI) m/z (%) 229 (M+ + 1, 13.81), 228 (M+, 0.63), 221
[(M - OH)+, 88.79], 85 (100); Elemental analysis calcd (%) for C12H20O4:
C, 63.14; H, 8.83; Found: C, 63.07; H, 8.64.
20
4.2.2.5. Esterification for determination of the ee value of (R)-traumatic
lactone: synthesis of (R)-13 (zj-8-121)
4.2.3.2. Synthesis of (Sa)-12-(benzyloxy)dodeca-4,5-dienoic acid (Sa)-10
(zj-8-114)
Following Typical Procedure Ⅲ, the reaction of (Sa)-9 (1.7107 g, 5.2
mmol), EtOH/H2O = 1:1 by volume (pre-mixed by using 26 mL of H2O
and 26 mL of EtOH), and LiOH·H2O (0.3451 g, 7.8 mmol, 95%) for 3.5 h
afforded (Sa)-10 (1.5518 g, 99%) [(eluent: petroleum ether (60-90
oC)/ethyl acetate = 15/1 (300 mL) to 10/1 (550 mL) to 5/1 (600 mL) to 3/1
(400 mL)] as an oil: [α]D20 = +35.8 (c = 0.965, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 11.05 (bs, 1H, COOH), 7.40-7.21 (m, 5H, ArH), 5.19-5.09 (m,
2H, =CH × 2), 4.51 (s, 2H, ArCH2), 3.46 (t, J = 6.6 Hz, 2H, CH2), 2.50-
2.40 (m, 2H, CH2), 2.35-2.22 (m, 2H, CH2), 2.02-1.89 (m, 2H, CH2), 1.68-
1.53 (m, 2H, CH2), 1.46-1.24 (m, 6H, CH2 × 3); 13C NMR (75 MHz,
CDCl3) δ 203.6, 179.1, 138.5, 128.3, 127.6, 127.4, 92.7, 89.3, 72.7, 70.3,
33.0, 29.5, 28.9, 28.8, 28.6, 25.9, 23.5; IR (neat) ν (cm−1) 3708-2219
(COOH), 1963, 1711, 1496, 1454, 1411, 1362, 1250, 1207, 1160, 1101,
1076, 1028; MS (70 ev, EI) m/z (%) 303 (M+ + 1, 12.67), 302 (M+, 3.15),
91 (100); HRMS calcd for C19H26O3 [M+]: 302.1882, found: 302.1884.
Typical Procedure Ⅷ: To a Schlenk tube were added (Ra)-traumatic
lactone (0.0682 g, 0.3 mmol), DMF (5 mL), K2CO3 (0.1243 g, 0.9 mmol),
and BnBr (42.8 μl, d = 1.44 g/mL, 0.0617 g, 0.36 mmol). After continuous
stirring for 19 h at rt, the reaction was complete as monitored by TLC.
The mixture was diluted with water (20 mL) and stirred at rt for 10 min
and then extracted with ethyl acetate (20 mL × 4). The combined organic
layer was washed with brine and dried over anhydrous Na2SO4. After
filtration and evaporation, the residue was purified by chromatography on
silica gel [(eluent: petroleum ether (60-90 oC)/ethyl acetate = 5/1 (600
mL) to 3/1 (400 mL)] to afford (R)-13 (0.0917 g, 96%) as an oil: 92% ee
(HPLC conditions: Chiralcel AS-H column, n-hexane/i-PrOH = 90:10, 1.0
20
mL/min, λ = 214 nm, tR (major) = 51.0 min, tR (minor) = 42.0 min); [α]D
=
+22.2 (c = 1.01, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.41-7.26 (m, 5H,
ArH), 5.11 (s, 2H, ArCH2), 4.47 (quintet, J = 7.1 Hz, 1H, OCH), 2.56-2.47
(m, 2H, CH2), 2.39-2.24 (m, 3H, CH2 + one proton from CH2), 1.91-1.51
(m, 5H, CH2 × 2 + one proton from CH2), 1.50-1.20 (m, 8H, CH2 × 4); 13
C
4.2.3.3. Synthesis of (R,E)-5-(8-(benzyloxy)oct-1-en-1-yl)dihydro-2(3H)-
furanone (R,E)-11 (zj-8-123)
NMR (75 MHz, CDCl3) δ 177.2, 173.5, 136.0, 128.4, 128.0, 80.8, 65.9,
35.4, 34.1, 28.93, 28.88, 28.8, 28.7, 27.8, 25.0, 24.7; IR (neat) ν (cm−1
)
3087, 3061, 3033, 2929, 2856, 1771, 1732, 1498, 1456, 1419, 1383,
1351, 1260, 1195, 1180, 1143, 1132, 1076, 1021; MS (70 ev, EI) m/z (%)
319 (M+ + 1, 22.16), 318 (M+, 1.53), 211 (100); HRMS calcd for C19H26O4
[M+]: 318.1831, found: 318.1836.
4.2.3. Total synthesis of (S)-traumatic lactone
Following Typical Procedure Ⅶ, the reaction of AgOTs (0.0319 g,
0.1125 mmol, 98%), Au(LB-Phos)Cl (0.0672 g, 0.1125 mmol), CHCl3 (25
mL), and (Sa)-10 (1.3588 g, 4.5 mmol)/CHCl3 (20 mL) for 15.5 h afforded
(R,E)-11 (1.3266 g, 98%, (R,E)/(S,Z) = 98/2 determined by 1H NMR)
[eluent: petroleum ether (60-90 oC)/ethyl acetate = 15/1 (450 mL) to 10/1
(500 mL) to 7/1 (880 mL)] ((R,E)/(S,Z) = 98/2 determined by 1H NMR of
crude product) as an oil: 97% ee (HPLC conditions: Chiralcel PA-2
column, n-hexane/i-PrOH = 90:10, 1.0 mL/min, λ = 214 nm, tR (major) =
50.9 min, tR (minor) = 44.1 min; [α]D20 = -21.4 (c = 0.98, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 7.40-7.21 (m, 5H, ArH), 5.78 (dtd, J1 = 15.3 Hz, J2 =
4.2.3.1. Synthesis of ethyl (Sa)-12-(benzyloxy)dodeca-4,5-dienoate (Sa)-4
(zj-8-112)
Following Typical Procedure Ⅵ, the reaction of CuBr2 (0.6759 g, 3.0
mmol, 99%), (R)-7 (3.8781 g, 15 mmol, 98%), 8 (2.8362 g, 22.5
mmol)/dioxane (25 mL), and 6 (4.9559 g, 22.5 mmol)/dioxane (20 mL) for
14.5 h afforded product (Sa)-9 (1.8805 g, 38%) [(eluent: petroleum ether
(60-90 oC)/ethyl acetate = 100/1 (500 mL) to 80/1 (500 mL) to 50/1 (500
6.8 Hz, J3 = 0.8 Hz, 1H, =CH), 5.47 (ddt, J1 = 15.3 Hz, J2 = 7.2 Hz, J3
=
1.4 Hz, 1H, =CH), 4.86 (q, J = 7.2 Hz, 1H, CH), 4.49 (s, 2H, CH2), 3.46 (t,
J = 6.5 Hz, 2H, CH2), 2.57-2.44 (m, 2H, CH2), 2.39-2.26 (m, 1H, one
proton from CH2), 2.05 (q, J = 6.7 Hz, 2H, CH2), 2.01-1.85 (m, 1H, one
proton from CH2), 1.66-1.55 (m, 2H, CH2), 1.45-1.23 (m, 6H, CH2 × 3);
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the following signals are discernible for (S,Z)-11: δ 5.69-5.59 (m, 1H,
=CH), 5.26-5.17 (m, 1H, CH); 13C NMR (75 MHz, CDCl3) δ 176.9, 138.5,
135.3, 128.1, 127.4, 127.30, 127.28, 80.9, 72.6, 70.2, 31.8, 29.5, 28.7,
28.6, 28.52, 25.50, 25.8; IR (neat) ν (cm−1) 3088, 3062, 3029, 2927, 2854,
2790, 1771, 1673, 1496, 1455, 1422, 1362, 1327, 1196, 1180, 1142,
1132, 1076, 1009; GC-MS (70 ev, EI) m/z (%) for (R,E)-11: tR (major) =
9.12 min: 302 (M+, 0.07), 193 [(M - C7H9O)+, 7.58], 91 (100); for (S,Z)-11:
tR (minor) = 8.95 min: 193 [(M - C7H9O)+, 7.35], 91 (100); Elemental
analysis calcd (%) for C19H26O3: C, 75.46; H, 8.67; Found: C, 75.10; H,
8.57.
NMR (75 MHz, CDCl3) δ 177.0, 173.2, 135.8, 128.2, 127.8, 80.7, 65.7,
35.2, 33.9, 28.8, 28.7, 28.6, 28.5, 27.7, 24.8, 24.5; IR (neat) ν (cm−1
)
3088, 3064, 3033, 2926, 2855, 1771, 1731, 1498, 1456, 1418, 1384,
1353, 1195, 1180, 1142, 1132, 1076, 1021; MS (70 ev, EI) m/z (%) 319
(M+ + 1, 7.92), 318 (M+, 1.21), 211 (100); HRMS calcd for C19H26O4 [M+]:
318.1831, found: 318.1836.
4.3. Synthesis of rhizobialide
4.3.1 Synthesis of rac-rhizobialide
4.2.3.4. Synthesis of (S)-traumatic lactone (zj-8-124, zj-8-132)
4.3.1.1 Synthesis of rac-rhizobialide 2 from rac-traumatic lactone 1 (zj-8-
125, zj-8-130)
Following Typical Procedure Ⅴ, the reaction of (R,E)-11 ((R,E)/(S,Z) =
98/2) (1.2082 g, 4 mmol)/EtOAc (24 mL) and Pd/C (10% on C, dry,
0.2128 g, 0.2 mmol) for 30 h afforded crude (S)-12 (96% NMR yield,
determined by 1H NMR of crude product using 1,3,5-trimethylbenzene as
internal standard), which was then submitted to next step without further
characterization.
To a flame-dried Schlenk flask were added rac-traumatic lactone 1
(114.2 mg, 0.5 mmol), and DCM (1.5 mL) sequentially at rt under
nitrogen atmosphere. Then the resulting mixture was cooled by ice-water
and DMF (3.9 μl, d = 0.948 g/mL, 3.7 mg, 0.05 mmol) was added. After
that, (COCl)2 (63.5 μl, d = 1.5 g/mL, 95.3 mg, 0.75 mmol) was added by
syringe within 5 min. Subsequently, the ice-water was removed and the
reaction mixture was warmed up to rt gradually and reacted for another
17 h. The resulting mixture was evaporated to give a residue 14, which
was used directly without further purification in the next step.
Following Typical Procedure Ⅰ, the reaction of Fe(NO3)3∙9H2O (0.1648
g, 0.4 mmol, 98%), KCl (0.0299 g, 0.4 mmol), TEMPO (0.0956 g, 0.6
mmol, 98%), DCE (10 mL) and (S)-12 (prepared above)/DCE (12 mL) for
26 h afforded (S)-traumatic lactone (0.6231 g, 68%, 2 steps) [eluent:
petroleum ether (60-90 oC)/ethyl acetate = 5/1 (600 mL) to 3/1 (600 mL)
to 2/1 (600 mL) to 1/1 (400 mL)] as a white solid: m. p. 62.9-64.3 oC (n-
hexane/dichloromethane); [α]D = -31.7 (c = 1.04, CHCl3); 1H NMR (300
20
MHz, CDCl3) δ 11.25 (bs, 1H, COOH), 4.50 (quintet, J = 6.8 Hz, 1H,
OCH), 2.55 (dd, J1 = 9.6 Hz, J2 = 6.9 Hz, 2H, CH2), 2.42-2.27 (m, 3H,
CH2 + one proton from CH2), 1.94-1.53 (m, 5H, CH2 × 2 + one proton
from CH2), 1.52-1.20 (m, 8H, CH2 × 4); 13C NMR (75 MHz, CDCl3) δ
179.5, 177.5, 80.9, 35.2, 33.7, 28.8, 28.7, 28.60, 28.55, 27.7, 24.8, 24.3;
IR (neat) ν (cm−1) 3729-2228 (COOH), 1770, 1709, 1462, 1418, 1356,
1284, 1192, 1180, 1143, 1132, 1076, 1019; MS (70 ev, EI) m/z (%) 229
(M+ + 1, 54.05), 228 (M+, 2.19), 211 (100), 85 (100); Elemental analysis
calcd (%) for C12H20O4: C, 63.14; H, 8.83; Found: C, 63.09; H, 8.67.
To another flame-dried Schlenk flask were added n-C6H13MgBr (0.52
mL, c = 1.0 M, 0.52 mmol), and THF (0.5 mL) sequentially at rt under
nitrogen atmosphere. The reaction was cooled down to -10 oC and then 14
(prepared above) in THF (1.5 mL) was added within 5min. After being
stirred at -10 oC for 8 h, the reaction was quenched with HCl (2 mL, ω =
10%). The flask was removed from the cryogenic reactor and warmed up
to rt gradually. The reaction mixture was extracted with DCM (10 mL × 3).
The combined organic layer was washed with brine and dried over
anhydrous Na2SO4. After filtration and evaporation, the residue was
purified by chromatography on silica gel [eluent: petroleum ether (60-90
oC)/ethyl acetate = 10/1 (550 mL) to 8/1 (450 mL) to 5/1 (600 mL) to 3/1
(480 mL) to 1/1 (600 mL)] on silica gel to afford a mixture of 2 and 15
(66.4 mg, 1:1 (determined by 1H NMR analysis), 22% (2), 22% (15)), as
well as rac-traumatic lactone 1 (49.0 mg, 43%).
4.2.3.5. Esterification for determination of the ee value of (S)-traumatic
lactone: synthesis of (S)-13 (zj-8-135)
Following Typical Procedure Ⅷ, the reaction of (S)-traumatic lactone
(0.0685 g, 0.3 mmol), DMF (5 mL), K2CO3 (0.1243 g, 0.9 mmol), and
BnBr (43 uL, d = 1.44 g/mL, 0.0619 g, 0.36 mmol) for 8 h afforded
product (S)-13 (0.0894 g, 94%) [(eluent: petroleum ether (60-90 oC)/ethyl
acetate = 10/1 (550 mL) to 5/1 (700 mL)] as an oil: 93% ee (HPLC
conditions: Chiralcel AS-H column, n-hexane/i-PrOH = 90:10, 1.0 mL/min,
λ = 214 nm, tR (major) = 37.6 min, tR (minor) = 48.5 min); [α]D20 = -22.4 (c
= 1.00, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.47-7.24 (m, 5H, ArH),
5.10 (s, 2H, ArCH2), 4.48 (quintet, J = 6.8 Hz, 1H, OCH), 2.56-2.45 (m,
2H, CH2), 2.40-2.21 (m, 3H, CH2 + one proton from CH2), 1.90-1.50 (m,
5H, CH2 × 2 + one proton from CH2), 1.50-1.19 (m, 8H, CH2 × 4); 13C
4.3.1.2 Synthesis of 5-(8-hydroxyoctyl)dihydro-2(3H)-furanone rac-12 (zj-
8-143)
Following Typical Procedure Ⅴ, the reaction of rac-11 (0.4532 g, 1.5
mmol)/EtOAc (9 mL), and Pd/C (10% on C, dry, 0.0799 g, 0.075 mmol)
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for 30 h afforded rac-12[20] (0.2929 g, 91%) [eluent: petroleum ether (60-
CH2), 2.46-2.24 (m, 5H, CH2 × 2 + one proton from CH2), 1.95-1.15 (m,
90 oC)/ethyl acetate = 8/1 (270 mL) to 5/1 (360 mL) to 3/1 (400 mL) to
21H, CH2 × 10 + one proton from CH2), 0.88 (t, J = 6.6 Hz, 3H, CH3); 13
C
1.5/1 (500 mL)] as
a
white solid: m. p. 59.1-60.1 oC (n-
NMR (75 MHz, CDCl3) δ 211.3, 177.1, 80.8, 42.6, 42.5, 35.4, 31.4, 29.0,
28.92, 28.88, 28.72, 28.65, 27.8, 25.0, 23.6, 23.5, 22.3, 13.8; IR (neat) ν
(cm−1) 2953, 2930, 2849, 1778, 1710, 1471, 1462, 1417, 1377, 1265,
1225, 1193, 1127, 1077; MS (70 ev, EI) m/z (%) 297 (M+ + 1, 100);
Elemental analysis calcd (%) for C18H32O3: C, 72.93; H, 10.88; Found: C,
72.92; H, 10.60.
hexane/dichloromethane); 1H NMR (300 MHz, CDCl3) δ 4.50 (quintet, J =
6.8 Hz, 1H, OCH), 3.61 (t, J = 6.6 Hz, 2H, OCH2), 2.54 (dd, J1 = 9.6 Hz,
J2 = 6.9 Hz, 2H, CH2), 2.40-2.27 (m, 2H, one proton from CH2 + OH),
1.93-1.23 (m, 15H, CH2 × 7 + one proton from CH2); 13C NMR (75 MHz,
CDCl3) δ 177.4, 81.0, 62.5, 35.3, 32.5, 29.2, 29.1, 29.0, 28.7, 27.8, 25.5,
25.0; IR (neat) ν (cm−1) 3406, 3342, 2988, 2935, 2853, 1755, 1470, 1356,
1234, 1197, 1181, 1127, 1058, 1026, 1009; MS (70 ev, EI) m/z (%) 215
(M+ + 1, 14.09), 214 (M+, 0.27), 85 (100).
4.3.2. Synthesis of optically active rhizobialide
4.3.2.1. Synthesis of ethyl (Sa)-12-(benzyloxy)dodeca-4,5-dienoate (Sa)-4
(zj-8-133)
4.3.1.3. Synthesis of 5-(8-oxooctyl)dihydro-2(3H)-furanone rac-16 (zj-8-
148)
Following Typical Procedure Ⅵ, the reaction of CuBr2 (0.6759 g, 3.0
mmol, 99%), (R)-7 (3.8711 g, 15 mmol, 98%), 8 (2.8341 g, 22.5
mmol)/dioxane (25 mL), and 6 (4.9505 g, 22.5 mmol)/dioxane (20 mL) for
17 h afforded product (Sa)-9 (2.3622 g, 48%) [(eluent: petroleum ether
(60-90 oC)/ethyl acetate = 100/1 (300 mL) to 50/1 (500 mL × 2) to 30/1
(500 mL) to 20/1 (500 mL) to 10/1 (220 mL)] as a liquid: 96% ee (HPLC
conditions: Chiralcel AS-H column, n-hexane/i-PrOH = 100:1, 1.0 mL/min,
λ = 214 nm, tR (major) = 9.1 min, tR (minor) = 7.8 min); [α]D20 = +49.4 (c =
1.00, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.37-7.20 (m, 5H, ArH), 5.18-
5.06 (m, 2H, =CH × 2), 4.48 (s, 2H, CH2), 4.11 (q, J = 7.2 Hz, 2H, CH2),
3.45 (t, J = 6.6 Hz, 2H, CH2), 2.44-2.34 (m, 2H, CH2), 2.33-2.21 (m, 2H,
CH2), 2.02-1.88 (m, 2H, CH2), 1.68-1.53 (m, 2H, CH2), 1.47-1.28 (m, 6H,
CH2 × 3), 1.23 (t, J = 7.2 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3) δ
203.6, 172.9, 138.6, 128.2, 127.4, 127.3, 92.3, 89.5, 72.7, 70.3, 60.1,
33.3, 29.6, 28.9, 28.8, 28.7, 25.9, 23.8, 14.1.
Following Typical Procedure Ⅰ, the reaction of Fe(NO3)3∙9H2O (0.0489
g, 0.12 mmol, 99%), NaCl (0.0071 g, 0.12 mmol), TEMPO (0.0191 g,
0.12 mmol, 98%), DCM (3 mL), and rac-12 (0.2570 g, 1.2 mmol)/DCE (3
mL) at room temperature afforded rac-16[16a] (0.1848 g, 73%) [eluent:
petroleum ether (60-90 oC)/ethyl acetate = 8/1 (360 mL) to 5/1 (600 mL ×
2)] as an oil: 1H NMR (300 MHz, CDCl3) δ 9.76 (s, 1H, CHO), 4.50
(quintet, J = 6.8 Hz, 1H, CH), 2.59-2.48 (m, 2H, CH2), 2.48-2.39 (m, 2H,
CH2), 2.39-2.26 (m, 1H, one proton from CH2), 1.96-1.53 (m, 5H, CH2 × 2
+ one proton from CH2), 1.53-1.21 (m, 8H, CH2 × 4); 13C NMR (75 MHz,
CDCl3) δ 202.5, 177.0, 80.6, 43.3, 35.0, 28.7, 28.6, 28.5, 28.4, 27.5, 24.7,
21.5; IR (neat) ν (cm−1) 2931, 2857, 2723, 1774, 1723, 1462, 1421, 1390,
1354, 1284, 1219, 1180, 1121, 1018; MS (70 ev, EI) m/z (%) 213 (M+ + 1,
10.52), 212 (M+, 0.27), 85 (100); HRMS calcd for C12H20O3 [M+]:
212.1412, found: 212.1416.
4.3.2.2. Synthesis of (Sa)-12-(benzyloxy)dodeca-4,5-dienoic acid (Sa)-10
(zj-8-136)
4.3.1.4. Synthesis of rac-rhizobialide (zj-8-150, zj-8-153)
Typical Procedure Ⅸ :[21] To a dry Schlenk tube were added n-
C6H13MgBr (1.05 mL, 1.05 mmol, 1.0 M in THF), and THF (3 mL) under
nitrogen atmosphere. The solution was cooled to -10 oC, and a solution
of rac-16 (0.1480 g, 0.7 mmol) in 4 mL of THF was added dropwise at
this temperature within 2 min. The resulting mixture was then stirred at 0
oC for 20 h until the reaction was complete as monitored by TLC. The
resulting mixture was quenched with a 1.0 M aqueous solution of HCl
(1.5 mL) at 0 oC, warmed up to room temperature, and extracted with
ethyl acetate (10 mL × 3). The combined organic layer was washed with
brine and dried over anhydrous Na2SO4. After filtration and evaporation,
the crude product rac-17 was then used in the next step.
Following Typical Procedure Ⅲ, the reaction of product (Sa)-9 (2.2454
g, 6.8 mmol), EtOH/H2O = 1:1 by volume (pre-mixed by using 34 mL of
H2O and 34 mL of EtOH), and LiOH·H2O (0.4510 g, 10.2 mmol, 98%) for
3 h afforded (Sa)-10 (2.0205 g, 98%) [(eluent: petroleum ether (60-90
oC)/ethyl acetate = 15/1 (300 mL) to 10/1 (550 mL) to 5/1 (300 mL)] as an
oil: [α]D = +35.7 (c = 1.00, CHCl3); 1H NMR (300 MHz, CDCl3) δ 11.38
20
(bs, 1H, COOH), 7.38-7.21 (m, 5H, ArH), 5.20-5.08 (m, 2H, =CH × 2),
4.50 (s, 2H, CH2), 3.46 (t, J = 6.6 Hz, 2H, CH2), 2.50-2.39 (m, 2H, CH2),
2.34-2.22 (m, 2H, CH2), 2.02-1.89 (m, 2H, CH2), 1.67-1.54 (m, 2H, CH2),
1.46-1.24 (m, 6H, CH2 × 3); 13C NMR (75 MHz, CDCl3) δ 203.6, 179.1,
138.4, 128.3, 127.6, 127.4, 92.7, 89.3, 72.7, 70.3, 33.0, 29.5, 28.9, 28.8,
28.6, 25.9, 23.4.
Following Typical Procedure Ⅰ, the reaction of Fe(NO3)3∙9H2O (0.0286
g, 0.07 mmol, 99%), NaCl (0.0041 g, 0.07 mmol), TEMPO (0.0111 g,
0.07 mmol, 98%), DCE (1.5 mL), and rac-17 (0.7 mmol, prepared
4.3.2.3. Synthesis of (R,E)-5-(8-(benzyloxy)oct-1-en-1-yl)dihydro-2(3H)-
furanone (R,E)-11 (zj-8-137)
above)/DCE (2 mL) at room temperature for 16
h afforded rac-
rhizobialide (0.1221 g, 59%, 2 steps) [eluent: petroleum ether (60-90
oC)/ethyl acetate = 8/1 (360 mL) to 5/1 (600 mL)] as a white solid: m. p.
56.2-57.3 oC (n-hexane/dichloromethane); 1H NMR (300 MHz, CDCl3) δ
4.49 (quintet, J =6.5 Hz, 1H, OCH), 2.53 (dd, J1 = 9.2 Hz, J2 = 7.1 Hz, 2H,
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0.35 mmol, 98%), DCM (8 mL), and (S)-12 (0.7487 g, 3.5 mmol)/DCM
(9.5 mL) at room temperature afforded (S)-16 (0.5311 g, 72%) [eluent:
petroleum ether (60-90 oC)/ethyl acetate = 8/1 (360 mL) to 6/1 (560 mL)
to 4/1 (800 mL)] as an oil: [α]D20 = -34.2 (c = 1.02, CHCl3); 1H NMR (300
MHz, CDCl3) δ 9.77 (s, 1H, CHO), 4.50 (quintet, J = 6.8 Hz, 1H, OCH),
2.58-2.48 (m, 2H, CH2), 2.48-2.28 (m, 3H, CH2 + one proton from CH2),
1.94-1.79 (m, 1H, one proton from CH2), 1.79-1.53 (m, 4H, CH2 × 2),
1.52-1.23 (m, 8H, CH2 × 4); 13C NMR (75 MHz, CDCl3) δ 202.5, 177.0,
80.6, 43.4, 35.1, 28.8, 28.7, 28.6, 28.5, 27.6, 24.8, 21.6; IR (neat) ν
(cm−1) 2932, 2857, 2722, 1770, 1723, 1462, 1421, 1390, 1353, 1284,
1219, 1180, 1121, 1017; MS (70 ev, EI) m/z (%) 213 (M+ + 1, 56.61), 212
(M+, 1.43), 85 (100); HRMS calcd for C12H20O3 [M+]: 212.1412, found:
212.1409.
Following Typical Procedure Ⅶ, the reaction of AgOTs (0.0462 g,
0.1625 mmol, 98%), Au(LB-Phos)Cl (0.0970 g, 0.1625 mmol), CHCl3 (35
mL), and (Sa)-10 (1.9627 g, 6.5 mmol)/CHCl3 (20 mL) for 15.5 h afforded
(R,E)-11 (1.9293 g, 98%, (R,E)/(S,Z) = 98/2 determined by 1H NMR)
[eluent: petroleum ether (60-90 oC)/ethyl acetate = 15/1 (480 mL) to 10/1
(550 mL) to 7/1 (560 mL × 3)] ((R,E)/(S,Z) = 98/2 determined by 1H NMR
of crude product) as an oil: 97% ee (HPLC conditions: Chiralcel PA-2
column, n-hexane/i-PrOH = 90:10, 1.0 mL/min, λ = 214 nm, tR (major) =
50.2 min, tR (minor) = 43.9 min; [α]D20 = -21.0 (c = 1.01, CHCl3); 1H NMR
4.3.2.6. Synthesis of (S)-rhizobialide (zj-8-154, zj-8-156)
(300 MHz, CDCl3) δ 7.40-7.20 (m, 5H, ArH), 5.78 (dt, J1 = 15.3 Hz, J2
=
7.2 Hz, 1H, =CH), 5.47 (dd, J1 = 15.3 Hz, J2 = 6.9 Hz, 1H, =CH), 4.85 (q,
J = 7.1 Hz, 1H, CH), 4.49 (s, 2H, CH2), 3.46 (t, J = 6.8 Hz, 2H, CH2), 2.49
(dd, J1 = 9.5 Hz, J2 = 6.5 Hz, 2H, CH2), 2.38-2.25 (m, 1H, one proton
from CH2), 2.05 (q, J = 6.7 Hz, 2H, CH2), 2.00-1.85 (m, 1H, one proton
from CH2), 1.66-1.54 (m, 2H, CH2), 1.44-1.22 (m, 6H, CH2 × 3); the
following signals are discernible for (S,Z)-11: δ 5.67-5.58 (m, 1H, =CH),
5.26-5.16 (m, 1H, CH); 13C NMR (75 MHz, CDCl3) δ 176.9, 138.5, 135.2,
128.1, 127.34, 127.28, 127.2, 80.9, 72.6, 70.1, 31.7, 29.4, 28.7, 28.6,
28.5, 25.4, 25.7.
Following Typical Procedure Ⅸ, the reaction of n-C6H13MgBr (2.7 mL,
2.7 mmol, 1.0 M in THF), THF (7.5 mL), and (S)-16 (0.3811 g, 1.8
mmol)/THF (10.5 mL) at 0 oC for 17 h afforded the crude product (S)-17,
which was then used in the next step.
4.3.2.4. Synthesis of (S)-5-(8-hydroxyoctyl)dihydro-2(3H)-furanone (S)-12
(zj-8-138)
Following Typical Procedure Ⅰ, the reaction of Fe(NO3)3∙9H2O (0.0732
g, 0.18 mmol, 98%), NaCl (0.0104 g, 0. 18 mmol), TEMPO (0.0288 g, 0.
18 mmol, 98%), DCE (3 mL), and (S)-17 (1.8 mmol, prepared
above)/DCE (6 mL) at room temperature for 14.5 h afforded (S)-
rhizobialide (0.3433 g, 65%, 2 steps) [eluent: petroleum ether (60-90
oC)/ethyl acetate = 8/1 (360 mL) to 5/1 (900 mL)] as a white solid: m. p.
61.3-62.6 oC (n-hexane/dichloromethane) (Lit. [17] m. p. 54-55 oC); [α]D
=
20
-24.4 (c = 0.54, CHCl3); (Lit.[17] [α]D26 = -19.7 (c = 0.55, CHCl3)); 1H NMR
(300 MHz, CDCl3) δ 4.49 (quintet, J = 6.8 Hz, 1H, OCH), 2.59-2.46 (m,
2H, CH2), 2.46-2.26 (m, 5H, CH2 × 2 + one proton from CH2), 1.95-1.16
(m, 21H, CH2 × 10 + one proton from CH2), 0.88 (t, J = 6.8 Hz, 3H, CH3);
13C NMR (75 MHz, CDCl3) δ 210.8, 176.7, 80.4, 42.2, 42.1, 35.0, 31.1,
28.7, 28.6, 28.5, 28.4, 28.3, 27.5, 24.7, 23.25, 23.17, 22.0, 13.5; IR
(neat) ν (cm−1) 2978, 2955, 2931, 2849, 1778, 1710, 1470, 1463, 1419,
1378, 1312, 1226, 1193, 1175, 1128, 1078, 1010; MS (70 ev, EI) m/z (%)
298 (M+ + 2, 100), 297 (M+ + 1, 100).
Following Typical Procedure Ⅴ, the reaction of (R,E)-11 ((R,E)/(S,Z) =
98/2) (1.8116 g, 6 mmol)/EtOAc (30 mL), and Pd/C (10% on C, dry,
0.3190 g, 0.3 mmol) for 29.5 h afforded (S)-12 (1.1505 g, 90%) [eluent:
petroleum ether (60-90 oC)/ethyl acetate = 10/1 (330 mL) to 7/1 (350 mL)
to 5/1 (600 mL) to 3/1 (600 mL) to 2/1 (600 mL) to 1.5/1 (500 mL) to 1/1
(600 mL)] as
a
white solid: m. p. 72.1-73.3 oC (n-
hexane/dichloromethane); [α]D = -34.5 (c = 0.99, CHCl3); 1H NMR (300
MHz, CDCl3) δ 4.50 (quintet, J = 6.8 Hz, 1H, CH), 3.62 (t, J = 6.6 Hz, 2H,
OCH2), 2.54 (dd, J1 = 9.2 Hz, J2 = 7.1 Hz, 2H, CH2), 2.41-2.26 (m, 1H,
one proton from CH2), 2.15 (s, 1H, OH), 1.94-1.19 (m, 15H, CH2 × 7 +
one proton from CH2); 13C NMR (75 MHz, CDCl3) δ 177.4, 81.0, 62.7,
20
Acknowledgements ((optional))
35.4, 32.5, 29.2, 29.10, 29.07, 28.7, 27.8, 25.5, 25.0; IR (neat) ν (cm−1
)
3406, 3335, 2986, 2925, 2853, 1755, 1470, 1430, 1356, 1233, 1196,
1181, 1142, 1132, 1076, 1058, 1026, 1009; MS (70 ev, EI) m/z (%) 215
(M+ + 1, 36.12), 214 (M+, 0.60), 85 (100); Elemental analysis calcd (%)
for C12H22O3: C, 67.26; H, 10.35; Found: C, 67.20; H, 10.29.
Financial support from National Basic Research Program
(21690063 and 21572202) is greatly appreciated.
Keywords: EATA reaction • Gold-catalyzed cyclziation •
Asymmetric Total synthesis • Traumatic lactone • Rhizobialide
4.3.2.5. Synthesis of (R)-5-(8-oxooctyl)dihydro-2(3H)-furanone (S)-16 (zj-
8-151)
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FULL PAPER
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10.1002/chem.201901210
Chemistry - A European Journal
FULL PAPER
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Jing Zhou, Shihua Song, Chunling Fu,
Shengming Ma*
Page No. – Page No.
Efficient Syntheses of Traumatic
Lactone and Rhizobialide
The racemic and enantioselective synthesis of Traumatic lactone and Rhizobialide
are reported from available starting materials. Excelletnt enantioselectivities were
realized by combination EATA reaction with AuCl(LB-Phos)-catalyzed highly
stereoselective cycloisomerization.
This article is protected by copyright. All rights reserved.