Chiron approach for the total synthesis of (+)-synargentolide B

Article abstract of DOI:10.1016/j.tet.2017.09.041

A concise and efficient chiron approach for the total synthesis of natural product synargentolide B was achieved in 10 steps with overall yields of 11.3% from D-mannitol and L-ethyl lactate. The key reactions included anti-Barbier allylation, cross-metathesis, and an intramolecular Yamaguchi esterification.

Full text of DOI:10.1016/j.tet.2017.09.041

Accepted Manuscript
Chiron approach for the total synthesis of (+)-synargentolide B
Jun Liu, Yangguang Gao, Linlin Wang, Yuguo Du
PII:
S0040-4020(17)30977-8
10.1016/j.tet.2017.09.041
TET 28992
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 27 July 2017
Revised Date: 19 September 2017
Accepted Date: 22 September 2017
Please cite this article as: Liu J, Gao Y, Wang L, Du Y, Chiron approach for the total synthesis of (+)-
synargentolide B, Tetrahedron (2017), doi: 10.1016/j.tet.2017.09.041.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Chiron approach for the total synthesis of (+)-synargentolide B
Jun Liu,1,* Yangguang Gao,2 Linlin Wang,1 Yuguo Du 1,2
1State Key Laboratory of Environmental Chemistry and Eco-toxicology, Research Center for
Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; 1School of
Chemistry and Chemical Engineering, University of Chinese Academy of Sciences, Beijing
100049, China
Corresponding Author: *E-mail: junliu@rcees.ac.cn;
A concise and efficient chiron approach for the total synthesis of natural product
synargentolide B was achieved in 10 steps with overall yields of 11.3% from
D-mannitol and L-ethyl lactate. The key reactions included anti-Barbier allylation,
cross-metathesis, and an intramolecular Yamaguchi esterification.
1. Introduction
5,6-Dihydro-α-pyrone moiety is an ubiquitous heterocyclic unit found in a
number of biologically active natural products, such as synargentolide B (1)
1, synargentolide A (2), anamarine (3),2 synrotolide (4),3 which have displayed a
variety of biological properties, including cytotoxic,4 antifungal and antibacterial
activity5. (Figure 1)
O
O
O
OAc OAc
O
OAc
OH
O
OAc OAc
O
H3C
H3C
H3C
OAc OAc
Anamarine (3)
OAc
OH
OAc
(+)-Synargentolide B (1)
(+)-Synargentolide A (2)
OAc
OAc OAc
H3C
O
H3C
OAc
OAc OAc
O
O
O
O
Synrotolide (4)
4-deacetoxy-10- -olguine (5)
epi
Figure 1. Chemical structures of natural products containing 5,6-Dihydro-α-pyrone
Synargentolide A & B are naturally occurring products consisting of a 5,
6-Dihydro-α-pyrone, free or acetylated 1,2-polyols as well as an unsaturated bond and
were first isolated from South African genus Syncolostemon argenteus by Rivett et. al
in 1998.1 Initially, the structure of synargentolide B was indecisively established
based on
extensive spectroscopic analysis.1 Almost at the same time, the
determination of the absolute stereochemistry of synargentolide B was completed by
two groups in 2013.8a,8b Until now, four total syntheses were reported for
8
(+)-synargentolide B and one synthesis for its analogue9 in the literature. Prasad et.
al8a has accomplished the total syntheses of compound 1 and its diastereomers starting
from (S)-lactic acid and the two enantiomers of tartaric acid using Wittig-Horner
1

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reaction and ring-closing metathesis as their key steps. Meanwhile, Sabitha’s work 8b
commenced with D-ribose, D-mannitol, and (+)/(–)-DET to synthesize synargentolide
B and its diastereomers through a tandem ring-closing/cross-metathesis reaction.
Herein, we report the synthesis of natural (+)-synargentolide B beginning with
D-mannitol and L-ethyl lactate as chiral templates.
2. Results and discussion
Our approach for the synthesis of (+)-synargentolide B (1) is depicted in Scheme 1.
As shown in Scheme 1, the disconnection process began with two double bonds at
C1-C2 and C3’-C4’, each of which could be realized by a cross-metathesis reaction
and an intramolecular Yamaguchi esterification,10 respectively. The building block 6
was readily derived from L-ethyl lactate, and the intermediate 7 which contains three
contiguous chiral centers could be obtained from commercially available D-mannitol.
Scheme 1. Retrosynthetic analysis of (+)-synargentolide B (1)
The synthesis of fragment 6 was accessible from L-ethyl lactate over 4 steps as shown
in Scheme 2. Protection of L-ethyl lactate as its silyl ether with TBSCl, imidazole in
DCM afforded compound 10 in a high yield (96%). Reduction of compound 10 by
DIBAL-H in DCM at –78 °C furnished the corresponding aldehyde. Subsequent
treatment of the aldehyde generated in situ with vinylmagnesium chloride furnished
the desired anti product 8 as a 5.8:1 mixture of diastereoisomers.11 Unfortunately, the
attempted separation of the two disasteromers of 8 via flash chromatography proved
2

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problematic. Deprotection of compound 8 by TBAF in THF followed by
peracetylization with acetic anhydride in pyridine provided the building block 6 in 72%
yield as a 7:1 separable mixture of C5’-diastereomers.
Scheme 2. Synthesis of compound 6.
Reagents and conditions: (a) TBSCl, imidazole, DCM, rt, 96%; (b) DIBAL-H, DCM, -78 °C-rt,
then vinylmagnesium chloride, Et2O, -98 °C-rt; (c) TBAF, THF, then Ac2O, pyridine, 72% for 4
steps.
As depicted in Scheme 3, our synthesis of compound 7 commenced with D-mannitol,
which was converted to 12 in 3 steps in excellent yield according to a modified
reported procedure.12 Selective hydrolysis of primary acetonide and oxidative
cleavage of resulting diol occurred simultaneously with H5IO6 resulted in 11 in almost
quantitative yield. Allylation of the aldehyde 11 under the zinc-mediated Barbier
reaction gave homoallyl alcohol 13 as an inseparable anomeric mixture (81%,
1
anti:syn=4:1, determined by H-NMR). When aldehyde 11 was subjected to the
Grignard reaction with allylmagnesium bromide in dry ether, homoallyl alcohol 13
was obtained only in 55% yield as diastereomeric mixture (65:35).
Scheme 3. Synthesis of compound 7.
Reagents and conditions: (d) ref 12, 69% for 3 steps; (e) H5IO6, MeOH, RT; (f) Allyl
bromide, excess Zn dust, saturated NH4Cl, THF, 0-5oC, 72% for 2 steps; (g) methyl
acrylate (10 eq), Grubbs’ 2nd generation catalyst (0.03eq), DCM, RT,18h, 56%; (h)
LiOH, THF, H2O, RT; (i) 2,4,6-trichlorobenzoyl chloride, pyridine, DCM, 0oC to RT,
83% for 2 steps;
In the next step, we planned to subject diene 13 to mono-cross-metathesis with methyl
methacrylate. To ensure selective mono-cross-metathesis of diene, the sterically
protecting group acetonide is necessary to be present (Scheme 3). In the case of
acetonide protected diene 13, best results were obtained with 3 mol % of Grubbs’ 2nd
3

ACCEPTED MANUSCRIPT
generation catalyst in DCM at ambient temperature, 5 equiv of methyl acrylate
present from the outset, and slow addition of further 5 equiv over 12h, and the
trans-α,β-unsaturated ester 9 was obtained in 56% yield with 9% bis-cross-metathesis
byproduct 14.13 Treatment of ester 9 with LiOH in THF/H2O afforded the
corresponding acid in almost quantitative yield. 10b Intramolecular esterification of
acid 15 under modified Yamaguchi conditions10 afforded cis-α,β-unsaturated lactone
7 in 83% yield as an 8:1 mixture of readily separable diastereomers. The
δ-lactonization of 7 could be explained through activation of carboxylic acid with
2,4,6-trichlorobenzoyl and subsequent pyridine assisted addition-elimination.10b
Scheme 4. Synthesis of (+)-synargentolide B (1).
Reagents and conditions: (j) Grubbs’ 2nd generation catalyst (0.05eq), DCM, reflux,
4h, 63%; (k) PPTS, MeOH, reflux, 6h, 78%.
With these two key fragments in hand, we set out to prepare natural
(+)-synargentolide B (1) through the planned cross-metathesis (Scheme 4). We are
pleased to find that cross-metathesis between side chain 6 and core 7 was successfully
carried out by treatment with Grubbs II catalyst in reflux DCM to provide compound
16 in 63% yield with 11% dimer 17. Finally, removal of the acetonide group in
compound 16 by PPTS in MeOH proceeded smoothly to afford (+)-synargentolide B
(1) in 78% yield.8 The physical and spectroscopic data (1H and 13C NMR) of our
synthetic sample 1 were in good agreement with natural product synargentolide B.1
3. Conclusions
In summary, natural (+)-synargentolide B was successfully accomplished by using
D-mannitol and L-ethyl lactate as chiral template. Key features of our strategy toward
practical total synthesis of (+)-synargentolide B are the efficient combination of a
anti-Barbier allylation, cross-metathesis, and an intramolecular Yamaguchi
esterification. Our convergent and effective strategy provides a candidate for the
synthesis of other related synargentolide analogs taking advantage of the inherent
chiral centers from natural carbohydrates.
4.Experimental section
4.1 General Experimental
Unless noted otherwise, commercially available materials were used without further
4

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purification. Yields refer to chromatographically and spectroscopically (1H NMR)
homogeneous materials. All solvents were dried according to the established
procedures ahead of use. Flash chromatography (FC) was performed using silica gel
(200-300 meshes) according to the standard protocol. All reactions under standard
conditions were monitored by thin-layer chromatography (TLC) on gel F254 plates.
Optical rotations were measured using a polarimeter with a thermally jacketed 5 cm
cell at approximately 25 oC. High-resolution mass spectrometry data (HRMS) were
1
acquired using a Q-TOF analyzer in acetone or methanol as solvent. H NMR, 13C
NMR were measured on 400 MHz or 100 MHz spectrometers (NMR in CDCl3 with
TMS as an internal standard). Chemical shifts (δ) are given in ppm relative to residual
1
solvent (usually chloroform; δ 7.26 for H NMR or 77.0 for proton decoupled 13C
NMR), and coupling constants (J) in Hz. Multiplicity is tabulated as s for singlet, d
for doublet, t for triplet, q for quadruplet, and m for multiplet and br when the signal
in question is broadened.
4.2. Experimental Procedures
Synthesis of compound 8:
To a solution of TBS protected lactate 10(1.78 g, 7.6 mmol) in DCM (30 mL) was
added DIBAL-H (1.2M in toluene, 11.4 mmol) via syringe at -98oC under N2
protection. After 10 min, vinyl magnesium chloride (21.5mL, 15 mmol) was added
into the mixture. The solution was then warmed to room temperature and stirred at
room temperature overnight. The reaction was quenched by the addition of saturated
K/Na tartrate. The aqueous layer was extracted with DCM. The combined organic
phase was washed with brine, dried over Na2SO4 and concentrated under vacuum.
The crude allylic alcohol could be used for next step without any purification. A small
sample was purified by flash column chromatography (Hexanes/EtOAc 15:1) to get
the physical data of 8 as a 5.8:1 mixture of diastereoisomers: [α]D25 = +27.6 (c 0.45,
CHCl3); 1H NMR (400 MHz, CDCl3): δ = 5.81 (ddd, J = 16.8, 10.8, 6.4 Hz, 1H), 5.28
(dt, J = 17.2, 1.6 Hz, 1H), 5.20 (dd, J = 10.4, 1.6 Hz, 1H), 4.02 (q, J = 2.0 Hz, 1H),
3.86–3.82 (m, 1H), 2.29 (d, J = 4.0 Hz, 1H), 1.07 (d, J = 6.4 Hz, 3H), 0.89 (s, 9H),
0.08 (s, 6H) ppm. 13C NMR (100 MHz, CDCl3): δ = 136.6, 116.5, 71.3, 25.8, 18.1,
17.6, -4.4, -4.9 ppm; HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C11H24O2SiNa [M +
Na]+ , 239.1443; found 239.1461.
Synthesis of compound 6:
To a stirred solution of crude 8 (0.85 g, 0.39 mmol) in dry THF (15 mL) was added
TBAF (1.31 g, 5 mmol) at room temperature. After completion of the reaction
(monitored by TLC), the solution was concentrated under vacuum. The crude diol was
used in the next step without further purification. To a vigorously stirred solution of
the crude diol in pyridine (8 mL) was added acetic anhydride (1 mL). The resulting
mixture was stirred at room temperature for 2 h. The reaction was quenched by the
addition of MeOH (10 mL) and concentrated with toluene. The residue was poured
into saturated aqueous CuSO4 (10 mL) and extracted with DCM (3 × 20 mL). The
combined organic phase was washed with brine, dried over Na2SO4 and concentrated
5

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under vacuum. The crude was purified by flash column chromatography
25
(Hexanes/EtOAc 6:1) to give compound 6 as a colorless oil. [α]D = -37 (c 0.42,
1
CHCl3); H NMR (400 MHz, CDCl3): δ = 5.82-5.71 (m, 1H), 5.33-5.27 (m, 3H),
5.08-5.01 (m, 1H), 2.07 (s, 3H), 2.02 (s, 3H), 1.18 (d, J = 6.4 Hz, 3H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 170.4, 170.1, 132.0, 119.4, 75.6, 70.4, 21.1, 21.0, 14.9 ppm;
HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for C9H14O4Na [M + Na]+ , 209.0790; found
209.0773.
Synthesis of compound 13:
To a solution of the diacetonide 12 (150 mg, 0.66 mmol) in EtOAc (10 mL) was
added orthoperiodic acid (300 mg, 1.3 mmol) at room temperature and stirred for 30
min. The reaction was quenched by aqueous saturated NaHCO3 (20 mL) and filtered
through celite. The aqueous layer was extracted with EtOAc (3 x 20 mL). The
combined organic solution was concentrated to give the crude aldehyde 11 as
colorless oil. (Caution: The aldehyde 11 was highly unstable and decomposed rapidly
on flash column or in CDCl3 at room temperature.) The crude aldehyde obtained
could be used in the next step without further purification. To a mixture of crude 11
(ca. 0.66 mmol), Zn dust (86 mg, 1.32 mmol) and allyl bromide (0.114 mL, 13.2
mmol) in THF (8 mL) was added a saturated solution of NH4Cl (1 mL) by two
portions at 0oC. After 15min, the solution was warmed to rt and stirred for further
15min. The mixture was filtered and washed with brine (20 mL). The aqueous layer
was extracted with EtOAc (2 x 20 mL). The combined organic phase was washed
with brine, dried over Na2SO4 and concentrated under vacuum. The crude was
purified by flash column chromatography (Hexanes/EtOAc 8:1) to give compound 13
(95 mg, 72% over 2 steps) as a mixture of two diastereomers (anti:syn=4:1,
1
1
determined by crude H-NMR). [α]D25= +97 (c 0.6, CHCl3); H NMR (400 MHz,
CDCl3): δ = 5.91-5.76 (m, 2H), 5.42 (d, J = 17.2 Hz, 1 H), 5.24 (d, J = 10.0 Hz, 1H),
5.15-5.10 (m,2H), 4.44 (t, J = 7.2 Hz, 1H), 3.86-3.83 (m, 1H), 3.73 (dd, J = 8.0,4.4 Hz,
1H), 2.32-2.17 (m, 3H), 1.42 (s, 3H), 1.40 (s, 3H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 136.3,134.0, 118.6, 118.2, 108.9, 82.4, 78.1, 70.3, 37.2, 26.89, 26.86 ppm. HRMS
(ESI-TOF) m/z: [M+Na]+ Calcd for C11H18O3Na[M + Na]+ 221.1153; found
221.1178.
Synthesis of compound 9:
Grubbs 2nd catalyst (15 mg, 0.018 mmol) was added to the mixture of 13 (120 mg,
0.6 mmol) and methyl acrlyate (0.271ml, 3.0 mmol) in dry DCM (15 mL). The
reaction was stirred at rt and another 5 equiv of methyl acrylate (0.271ml, 3.0 mmol)
was slow added to the solution over 12h. After completion of the reaction (monitored
by TLC), the solution was concentrated and purified by flash column chromatography
25
(Hexanes/EtOAc 3:1) to give compound 9 as a yellowish oil (87 mg, 56%). [α]D
=
+74 (c 2.6, CHCl3); 1H NMR (400 MHz, CDCl3): δ = 7.03-6.91 (m, 1H), 5.94-5.77 (m,
2H), 5.43 (d, J = 17.2 Hz, 1H), 5.27 (d, J = 10.0 Hz, 1H), 4.43 (t, J = 7.6 Hz, 1H),
3.98-3.94 (m, 1H), 3.74-3.64 (m, 4H), 2.45-2.31 (m, 2 H), 2.26 (br s, 1H), 1.43 (s,
3H), 1.41 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 166.6, 144.7, 136.2, 123.7,
6

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119.8, 109.2, 82.4, 78.2, 70.0, 51.5, 35.7, 27.1, 26.9 ppm. HRMS (ESI-TOF) m/z:
[M+Na]+ Calcd for C13H20O5Na[M + Na]+ 279.1208; found 279.1243.
Synthesis of compound 7:
To a solution of 9 (44 mg, 0.17 mmol) in THF (5 mL) was added 2M aqueous LiOH
(3mL) dropwise and the reaction was stirred for 2 h at room temperature. Amberlite
IR-120 (H+) was then added to neutralize the solution and the mixture was poured into
water (10 mL) and extracted with DCM (3 × 10 mL). The combined organic solution
was concentrated to give 15 as colorless oil. The crude acid was used in the next step
without further purification. To a solution of crude 15 in pyridine (3 mL) was added a
solution of 2,4,6-trichlorobenzoyl chloride (53mg, 0.20 mmol) in dry DCM (1 mL) at
0oC and the reaction mixture was warmed to room temperature. After completion of
the reaction (monitored by TLC), the solution was concentrated under vacuum. The
residue was poured into saturated aqueous CuSO4 (10 mL) and extracted with DCM
(2 × 10 mL). The combined organic phase was washed with brine, dried over Na2SO4
and concentrated under vacuum. The crude was purified by flash column
chromatography (Hexanes/EtOAc 2:1) to give compound 7 as a colorless oil (32 mg,
25
1
83% for two steps). [α]D = +8.1 (c 0.7, CHCl3); H NMR (400 MHz, CDCl3): δ =
6.92 (ddd, J = 8.8, 5.2, 3.2 Hz, 1 H), 6.03 (dt, J = 10.0, 0.4 Hz, 1 H), 5.94 (ddd, J =
17.2, 10.4, 6.4 Hz, 1 H), 5.45 (d, J = 16.8 Hz, 1 H), 5.28 (d, J = 10.4 Hz, 1 H),
4.51-4.20 (m, 2 H), 3.92 (t, J = 7.2 Hz, 1 H), 2.58-2.53 (m,2 H), 1.45 (s, 3 H), 1.43 (s,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 162.9, 144.6, 135.3, 121.4, 118.4, 110.0,
80.8, 80.1, 77.8, 27.0, 26.9, 25.9 ppm. HRMS (ESI-TOF) m/z: [M+Na]+ Calcd for
C12H16O4Na[M + Na]+ 247.0946; found 247.0911.
Synthesis of compound 16 and 17:
To a stirred solution of lactone 7 (72 mg, 0.32mmol) and diacetate 6 (241 mg, 0.072
mmol) in dry CH2Cl2 (15 mL) was added Grubbs 2nd catalyst (13 mg, 0.016 mmol) at
room temperature. After being stirred under reflux for 4 h, the brown solution was
concentrated and purified by flash column chromatography (Hexanes/EtOAc 2:1) to
give compound 16 as a colorless oil (77 mg, 63%) and dimer 17 (14 mg, 11%).
compound 16: [α]D25 = +37.8 (c 1.1, CHCl3); 1H NMR (400 MHz): δ 6.93 (dt, J = 9.6,
4.0 Hz, 1 H), 6.05 (dt, J = 9.8, 2.0 Hz, 1 H), 5.88-5.60 (m, 2 H), 5.42 (dd, J = 5.2, 4.0
Hz, 1 H), 5.08 (dq, J = 6.8, 3.6 Hz, 1 H), 4.43- 4.53 (m, 2 H), 3.90 (t, J = 7.2 Hz, 1 H),
2.54-2.57 (m, 2 H), 2.10 (s, 3 H), 2.06 (s, 3 H), 1.45 (s, 6 H), 1.23 (d, J = 6.8 Hz, 3 H);
13C NMR (100 MHz) δ 170.4, 169.9, 162.6, 144.6, 132.4, 127.3, 121.4, 110.4, 80.9,
79.1, 77.9, 74.5, 70.6, 26.9, 26.2, 21.1, 21.0, 15.0; HRMS (ESI-TOF) m/z: [M+Na]+
Calcd for C19H26O8Na: 405.1525, Found 405.1582
25
1
compound 17: [α]D -15.8 (c 0.3, CHCl3); H NMR (400 MHz): δ 6.90 (dt, J = 9.6,
4.4 Hz, 2 H), 5.97-6.01(m, 4 H), 4.44-4.50 (m, 4H), 3.94(t, J = 7.2Hz, 2 H), 2.54-
2.56 (m, 4 H), 1.45 (s, 6H), 1.42 (s, 6H); 13C NMR (100 MHz) δ 162.8, 144.7, 131.2,
121.3, 110.1, 80.5, 79.3, 77.9, 27.0, 26.9, 26.1; HRMS (ESI-TOF) m/z: [M+Na]+
Calcd for C22H28O8Na: 443.1682, Found: 443.1742
7

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Synthesis of (+)-synargentolide B (1):
To a solution of 16 (22 mg, 0.058 mmol) in MeOH (5 mL) was added PTSA.H2O (4
mg, 0.02 mmol) at room temperature. The mixture was stirred under reflux for 6 h and
concentrated under vacuum. The crude was purified by flash column chromatography
(Hexanes/EtOAc 1:2) to give synargentolide
B
(1) (15.4 mg, 78%).
24
(+)-Synargentolide B: [α]D25= +39 (c 0.45, CHCl3); [α]D +25.8 (c 1.2, MeOH);
24
7a 1
[α]D +23.3 (c 1.2, MeOH) ; H NMR (400 MHz, CDCl3): δ = 6.95 (ddd, J = 9.2,
4.8, 3.6 Hz, 1H), 6.04 (d, J = 9.2 Hz, 1H), 5.89 (dd, J = 15.6, 4.8 Hz, 1H), 5.81 (dd, J
= 15.6, 6.0 Hz, 1H), 5.31-5.34 (m, 1H), 5.06 (dq, J = 6.8, 3.6, 1H), 4.48-4.54 (m, 2H),
3.71-3.73 (m, 1H), 2.75(br s, 2H), 2.55-2.57 (m, 2H), 2.09 (s, 3H), 2.05 (s, 3H), 1.21
(d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ = 170.5, 170.2, 163.5, 145.6,
134.1, 127.0, 121.0, 76.8, 75.0, 74.4, 70.6, 69.5, 25.7, 21.3, 21.2, 15.2 ppm. HRMS
(ESI): calcd. for C16H22O8Na [M+Na]+ , 365.1212; found 365.1248.
Acknowledgments
This work was supported by the National Basic Research Program of China (Grant
2015CB931903), the National Key Research and Development Program of China
(2016YFA0203102) , the Strategic Priority Research Program of Chinese Academy of
Sciences (Grant XDB14040201) and NNSF of China (Projects 21372254 and
21321004). We thank Dr. Wei Liu and Qi Yu for HRMS measurements.
Supporting Information
Supplementary data related to this article can be found at
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