An efficient synthesis of synargentolide A from D-mannitol

Article abstract of DOI:10.1016/j.tetasy.2010.10.001

An efficient synthesis of synargentolide A is described by using d-mannitol and d-malic acid. The key features of the synthetic strategy include Wittig olefination, ring closing-metathesis reaction and cross-metathesis reaction for the formation of synarg

Full text of DOI:10.1016/j.tetasy.2010.10.001

Tetrahedron: Asymmetry 21 (2010) 2517–2523
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Tetrahedron: Asymmetry
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An efficient synthesis of synargentolide A from D-mannitol
⇑
Ahmed Kamal , Moku Balakrishna, Papagari Venkat Reddy, Shaikh Faazil
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of synargentolide A is described by using D-mannitol and D-malic acid. The key fea-
tures of the synthetic strategy include Wittig olefination, ring closing-metathesis reaction and cross-
metathesis reaction for the formation of synargentolide A.
Received 2 September 2010
Accepted 29 September 2010
Available online 26 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
D-malic acid 16 as well as (S)-2,3-O-isopropylidene glyceraldehyde
24.
The d-lactone ring system is found in a number of natural prod-
ucts and is also featured in many intermediates that are required
for the synthesis of biologically important compounds.1 In particu-
Olefin triacetate fragment 15 was prepared from
which is commercially available, as depicted in Scheme 2. Accord-
ingly, 1,2:3,4:5,6-tri-O-isopropylidene- -mannitol, was treated
D-mannitol,
D
lar,
a
,b-unsaturated lactones have been shown to exhibit a wide
with H5IO6 according to the reported procedure11 to afford alde-
hyde 8 via acid hydrolysis of a terminal acetonide and the cleavage
of the thus formed diol, which without further purification was
taken up for a Wittig olefination with MeTPPBr and t-BuOK in
dry THF to furnish the olefin 9 in 55% yield. Selective hydrobora-
tion of olefin 9 was achieved with dicyclohexylborane [(Cy)2BH]
followed by oxidative work-up12 to provide the desired regioisom-
er of homologated primary alcohol 10 (75% yield) as the major
product (primary alcohol/secondary alcohol 3:1). Primary alcohol
10 was oxidized under Swern oxidation conditions to give the cor-
responding aldehyde, which without further purification (as a
crude) on Wittig olefination with MeTPPBr and n-BuLi in dry THF
gave olefin 11. The 1,2-O-isopropylidene group of compound 11
was selectively cleaved by using CuCl2ꢀ2H2O in CH3CN to afford
diol 12 in 88% yield.13 Diol 12 on monotosylation14 (TsCl/Bu2SnO/
Et3N/CH2Cl2) followed by treatment with LiAlH4 provided alcohol
13 in good yield. Deprotection of the acetonide group in 13 was
achieved with (PTSA/MeOH/rt) to afford triol 14 in 75% yield,
which was acetylated with Ac2O in the presence of Et3N/DMAP
to afford triacetate 15 in 81% yield.
range of biological activities.2 Spicegerolide 3,3 synrotolide 4,4
hyptolide 5,5 and anamarine 66 belong to this class of conjugated
d-lactones, and it is believed that the presence of a Michael accep-
tor moiety in their skeleton is responsible for their biological activ-
ity (cytotoxic properties). Synargentolide A,7 an
a,b-unsaturated
polyoxygenated lactone, was isolated in 1998 from the extracts
of Syncolostemon argenteus. The structure of synargentolide A
was proposed to be 1 by Davies-Coleman and Rivett based on spec-
troscopic and chemical methods.7 Marco et al.8 synthesized and
reported the structure of synargentolide A 1, and found that the
spectroscopic data of the synthetic product did not match with
those of the reported one for the natural product. Hence it was
mentioned that the proposed structure for the synargentolide A 1
differs from that of the actual one. Recently this proposed structure
of synargentolide A 1 was revised9 and was shown to be 2 (Fig. 1).
2. Results and discussion
As part of our studies directed toward the synthesis of lactones
and other biologically active molecules,10 we herein report an effi-
cient approach for the synthesis of synargentolide A 2 by employ-
Vinyl lactone fragment 23 was prepared from
D-malic acid. The
primary alcohol 17 was prepared from -malic acid according to a
D
literature procedure.15 Primary alcohol 17 was oxidized under
Swern oxidation conditions to afford the corresponding aldehyde,
which without further purification (as a crude) on Wittig olefin-
ation with MeTPPBr and t-BuOK in dry THF gave olefin 18 in 60%
yield. The PMB group of olefin 18 was deprotected by using DDQ
to furnish alcohol compound 19. Esterification of the 19 using
acryloyl chloride and triethylamine in CH2Cl2 furnished acryl ester
20 in high yield, which upon ring-closing metathesis (RCM) with
ing
D-mannitol, a cost-effective and readily available starting
material. Our initial retrosynthetic plan is outlined in Scheme 1.
Retrosynthetically, synargentolide A could be obtained via an ole-
fin cross-metathesis reaction of olefin triacetate 15 and vinyl lac-
tone 23. Olefin triacetate 15 can be prepared from
D-mannitol
after several manipulations; vinyl lactone 23 can be prepared from
⇑
Grubbs’ 1st generation catalyst gave
Deprotection of the TBDPS group of 21 with TBAF afforded alcohol
a,b-unsaturated lactone 21.
Corresponding author. Tel.: +91 40 27193157; fax: +91 40 27193189.
E-mail address: ahmedkamal@iict.res.in (A. Kamal).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.10.001

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A. Kamal et al. / Tetrahedron: Asymmetry 21 (2010) 2517–2523
OAc
OAc
OAc OAc
O
O
O
OAc
O
OAc OAc
OAc
OAc OAc
O
O
O
Revised structure of
spicegerolide
Isolated structure of
synargentolide A
synargentolide A
1
2
3
OAc OAc
OAc OAc
OAc OAc
O
O
O
OAc
OAc
O
OAc
OAc OAc
O
hyptolide
anamarine
synrotolide
4
5
6
Figure 1. Chemical structures of some polyoxygenated a,b-unsaturated d-lactones.
HO
O
OAc
O
O
O
D-mannitol
OAc
O
OAc OAc
O
15
13
11
7
+
OAc OAc
O
O
O
OPMB
2
O
O
D-malic acid
TBDPSO
TBDPSO
OH
O
23
20
17
16
O
O
O
O
(S)-2,3-O-isopropylidine glyceraldehyde
24
O
OH
O
27
25
Scheme 1. Retrosynthetic analysis of synargentolide A.
22. Finally the vinyl lactone was obtained from the compound 22
in two steps. Accordingly, compound 22 was subjected to Swern
oxidation conditions to give the corresponding aldehyde, which
upon Wittig olefination with MeTPPBr and t-BuOK in THF gave
the vinyl lactone fragment 23 in 39% yield (Scheme 3).16
generation G-II catalyst9 to give synargentolide A 2. The spectro-
scopic and analytical data were comparable to the revised struc-
ture of synargentolide A 2.9b
3. Conclusion
The vinyl lactone fragment 23 was also prepared from (S)-2,3-
O-isopropylidene glyceraldehyde as depicted in Scheme 4. The
Zn-mediated stereoselective allylation of (S)-2,3-O-isopropylidene
glyceraldehyde afforded anti-homoallylic alcohol 25 as the major
isomer (anti/syn = 95:5)17 in 80% yield, which was separated from
the minor isomer by silica gel chromatography. Esterification of
homoallylic alcohol 25 using acryloyl chloride and triethylamine
in CH2Cl2 furnished acryl ester 26 in 82% yield, which upon ring-
closing metathesis (RCM) with Grubbs’ 1st generation catalyst
In conclusion, we have developed a practical and enantioselec-
tive total synthesis of synargentolide A 2, a naturally occurring lac-
tone possessing four stereogenic centers; this was achieved
starting from readily available D-mannitol and (S)-2,3-O-isopropyl-
idine glyceraldehyde. The key steps include Wittig olefination, ring
closing metathesis and cross metathesis. The syntheses of related
compounds of this family are underway in our laboratory.
gave a,b-unsaturated lactone 27. Treatment of 27 with H5IO6 fur-
4. Experimental
4.1. General
nished the aldehyde, which upon Wittig olefination with MeTPPBr
and t-BuOK in dry THF gave the vinyl lactone fragment 23 in 40%
yield. Finally coupling of both the fragments, that is, triacetate
fragment 15 and the vinyl lactone fragment 23 was achieved via
an olefin cross-metathesis reaction by using Grubb’s second
Reagents and chemicals were purchased from Aldrich. All sol-
vents and reagents were purified by standard techniques. THF

A. Kamal et al. / Tetrahedron: Asymmetry 21 (2010) 2517–2523
2519
O
O
O
O
O
O
(a)
O
(b)
(c)
O
O
O
D-Mannitol
O
OH
7
O
O
O
8
9
10
OH
O
OH
O
O
(f)
(e)
(d)
O
HO
O
O
O
12
13
11
OAc OAc
OH OH
(g)
(h)
OAc
OH
14
15
Scheme 2. Reagents and conditions: (a) Ref. 10; (b) MeTPPBr, t-BuOK, THF, 0 °C to rt, 6 h, 55%; (c) (Cy)2BH, THF, 0 °C to rt, 12 h, then H2O2, NaOH, 0 °C to rt, 2 h, 75%; (d) (i)
(COCl)2, DMSO, Et3N, CH2Cl2, ꢃ78 °C, 1.5 h; (ii) MeTPPBr, n-BuLi, THF, ꢃ78 °C, 2 h, 48% over two steps; (e) CuCl2ꢀ2H2O, CH3CN, 0 °C, 30 min, 88%; (f) (i) TsCl, Bu2SnO, Et3N,
CH2Cl2, 2 h; (ii) LAH, THF, 3 h, reflux, 73%; (g) PTSA, MeOH, 4 h, 75%; (h) Ac2O, TEA, DMAP, CH2Cl2, 0 °C to rt, 3 h, 81%.
was freshly distilled from LiAlH4. Crude products were purified by
column chromatography on 60–120 silica gel. IR spectra were re-
corded on Perkin–Elmer 683 spectrometer. Optical rotations were
obtained on a Horiba 360 digital polarimeter. 1H and 13CNMR spec-
tra were recorded in CDCl3 solution on Varian Gemini200, Brucker
Avance 300. Chemical shifts are reported in parts per million with
respect to the internal TMS. Mass spectra were recorded on VG
micromass-7070H (70 Ev).
was washed with ether (50 mL). Next, THF was evaporated and then
extracted with EtOAc (3 ꢁ 50 mL). The combined organic layers
were dried over anhydrous Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography using silica gel,
60–120 mesh by eluting EtOAc–hexane5:95 to afford the compound
9 (2.73 g, 55%) as a colorless liquid. ½a D26
¼ ꢃ3:1 (c 1, CHCl3); IR
ꢂ
(neat): cmax
:
2988, 2883, 1375, 1216, 1065, 847; 1H NMR
(300 MHz, CDCl3): d 1.31 (s, 3H), 1.36 (s, 3H), 1.38 (br s, 6H), 3.60
(t, J = 7.36 Hz, 1H), 3.85–3.93 (m, 1H), 4.01–4.13 (m, 2H), 4.31 (t,
J = 7.36 Hz, 1H), 5.17 (d, J = 10.57 Hz, 1H), 5.38 (d, J = 17.18 Hz,
1H), 5.89 (m, 1H); 13C NMR (75 MHz, CDCl3): 25.16, 26.59, 26.85
(two carbons), 66.91, 76.61, 80.35, 81.06, 109.3, 109.53, 117.05,
135.83; MS–ESIMS: m/z 251 (M+Na)+.
4.2. (4S,40R,5R)-2,2,20,20-Tetramethyl-5-vinyl-4,40-bi(1,3-
dioxolane) 9
To methyltriphenylphosphonium bromide (15.52 g, 43.47
mmol) in dry THF (200 mL) under a nitrogen atmosphere at 0 °C
was added t-BuOK (3.65 g, 32.61 mmol) and then stirred for 4 h at
the same temperature. To this orange yellow ylide solution, the
above crude aldehyde 8 (5 g, 21.73 mmol) in dry THF (20 mL) was
added and stirred at the same temperature for 2 h. The reaction
mixture was quenched with saturated aqueous NH4Cl solution
(30 mL). The mixture was filtered over a Celite pad and the residue
4.3. 2-((4S,40R,5R)-2,2,20,20-Tetramethyl-4,40-bi(1,3-dioxolan)-5-
yl)ethanol 10
To a stirred solution of alkene 9 (2.65 g, 11.62 mmol) in dry THF
(50 mL) at 0 °C dicyclohexylborane (46.49 mL, 23.24 mmol, 0.5 M
in THF) was slowly added. The mixture was stirred at room
OPMB
OPMB
(a)
(b)
O
(c)
TBDPSO
(e)
TBDPSO
D-malic acid
OH
16
18
17
O
OH
19
O
O
O
(d)
TBDPSO
TBDPSO
TBDPSO
PCY3
20
21
O
O
Ph
Cl
Cl
O
Ru
(f)
(g)
HO
PCY3
22
23
Gr-I
Scheme 3. Reagents and conditions: (a) Ref. 14; (b) (i) (COCl)2, DMSO, Et3N, CH2Cl2, ꢃ78 °C, 1.5 h; (ii) MeTPPBr, t-BuOK, THF, 0 °C to rt, 6 h, 60% over two steps; (c) DDQ,
H2O:CH2Cl2 (1:19), 0 °C to rt, 1 h, 82%; (d) acryloyl chloride, Et3N, DMAP, CH2Cl2, 0 °C to rt, 2 h, 80%; (e) Gr-I, CH2Cl2, 35 °C, 48 h, 80%; (f) TBAF, THF, 0 °C to rt, 30 min, 85%; (g)
(i) Dess–Martin periodinate, CH2Cl2, 0 °C to rt, 1 h; (ii) MeTPPBr, t-BuOK, THF, 0 °C to rt, 6 h, 39% over two steps.

2520
A. Kamal et al. / Tetrahedron: Asymmetry 21 (2010) 2517–2523
O
O
O
O
O
O
O
(a)
(b)
(c)
O
H
O
O
OH
O
O
27
O
25
26
24
O
OAc
PCY3
N
N
Ph
O
Cl
Cl
Ar
Ar
(e)
(d)
Ru
Cl
Cl
O
OAc OAc
PCY3
2
O
23
Ph
PCY3
Gr-I
Gr-II
Scheme 4. Reagents and conditions: (a) Zn, allyl bromide, THF, satd NH4Cl, 0 °C to rt, 4 h, 90%; (b) acryloyl chloride, Et3N, CH2Cl2, DMAP, 0 °C to rt, 2 h, 82%; (c) Gr-I, CH2Cl2,
35 °C, 48 h, 78%; (d) (i) H5IO6, EtOAc, 2 h; (ii) MeTPPBr, t-BuOK, THF, 0 °C to rt, 6 h, 40% over two steps; (e) Gr-II, 15, anhydrous CH2Cl2, reflux, 60%.
temperature for 12 h. Then it was cooled to 0 °C and treated with
aqueous NaOH (7.5 mL, 3 M aqueous solution) followed by H2O2
(3 mL, 50% aqueous solution). The reaction mixture was stirred
for 2 h at room temperature. After completion of the reaction,
the reaction mixture was quenched with aqueous NH4Cl (30 mL)
and the reaction mixture extracted with EtOAc (3 ꢁ 40 mL). The
combined organic layers were dried over anhydrous Na2SO4 and
concentrated in vacuo. The residue was purified by column chro-
matography using silica gel, 60–120 mesh, by eluting EtOAc–hex-
ane 30:70 to afford the compound 10 (2.15 g, 75%) as a colorless
residue was purified by column chromatography using silica gel,
60–120 mesh, by eluting EtOAc–hexane 5:95 to afford compound
11 (1 g, 48% from two steps) as a colorless liquid. ½a D26
ꢂ
¼ þ4:3 (c
1, CHCl3); IR (neat): c ;
max: 2987, 1375, 1217, 1064 cmꢃ1 1H NMR
(300 MHz, CDCl3): d 1.33 (s, 3H), 1.34 (s, 3H), 1.37 (s, 3H), 1.39
(s, 3H), 2.25–2.35 (m, 1H), 2.52–2.60 (m, 1H), 3.54 (t, J = 7.5 Hz,
1H), 3.89–4.03 (m, 3H), 4.1 (dd, J = 7.5, 13.5 Hz, 1H), 5.05–5.15
(m, 2H), 5.81–5.96 (m, 1H); 13C NMR (75 MHz, CDCl3): 25.20,
26.0, 26.94, 27.2, 37.38, 67.58, 77.07, 79.51, 80.32, 108.92,
109.54, 117.30, 134.07; MS–ESIMS: m/z 265 (M+Na)+. HR ESIMS:
m/z calcd for C13H22O4Na: 265.1415; found: 265.1418
liquid. ½a 2D6
ꢂ
¼ þ10:2 (c 1, CHCl3); IR (neat):
cmax: 3451, 2986,
2935, 2882, 1372, 1215, 1068, 847; 1H NMR (300 MHz, CDCl3): d
1.31 (s, 3H), 1.34 (s, 3H), 1.37 (br s, 6H), 1.76–1.87 (m, 1H), 1.95–
2.05 (m, 1H), 2.4 (br s, 1H), 3.56 (t, J = 7.5 Hz, 1H), 3.77 (t,
J = 6.79 Hz, 2H), 3.87–4.12 (m, 4H); 13C NMR (75 MHz, CDCl3):
13C NMR (75 MHz, CDCl3): 25.15, 26.54, 26.81, 27.13, 35.89,
4.5. (R)-1-((4R,5R)-5-Allyl-2,2-dimethyl-1,3-dioxolan-4-
yl)ethane-1,2-diol 12
To a stirred solution of alkene 11 (0.95 g, 3.92 mmol) in aceto-
nitrile (15 mL) at 0 °C was added CuCl2ꢀ2H2O (0.66 g, 3.92 mmol)
and then stirred for 30 min at the same temperature. After comple-
tion of the reaction the reaction mixture was quenched with satu-
rated aq NaHCO3 solution (10 mL). Then the reaction mixture was
extracted with EtOAc (3 ꢁ 20 mL). The combined organic layers
were dried over anhydrous Na2SO4 and concentrated in vacuo.
The residue was purified by column chromatography using silica
gel, 60–120 mesh, by eluting EtOAc–hexane 50:50 to afford com-
60.53, 67.8, 77.09, 79.59, 81.12, 109.10, 109.67; IR (neat): cmax
:
3451, 2986, 2935, 2882, 1372, 1215, 1068; MS–ESIMS: m/z 269
(M+Na)+. HR ESIMS: m/z calcd for C12H22O5Na: 269.1364; found:
269.1371.
4.4. (4S,40R,5R)-5-Allyl-2,2,20,20-tetramethyl-4,40-bi(1,3-
dioxolane) 11
To a stirred solution of oxalyl chloride (1.08 mL, 12.8 mmol), in
dry CH2Cl2 (40 mL), DMSO (1.81 mL, 25.6 mmol) was added at
ꢃ78 °C and stirred at the same temperature for 30 min. Compound
10 (2.1 g, 8.53 mmol) in dry CH2Cl2 (10 mL) was added at ꢃ78 °C to
the reaction mixture and stirred for 1 h at the same temperature.
Then Et3N (3.56 mL, 25.6 mmol) was added at ꢃ78 °C, and the
reaction mixture was allowed to warm to room temperature for
30 min. The reaction mixture was diluted with water (30 mL)
and extracted with CHCl3 (3 ꢁ 40 mL). The combined organic lay-
ers were washed with brine (40 mL), dried over anhydrous Na2SO4,
and concentrated in vacuo to afford the crude aldehyde as a yellow
sirup. To methyltriphenylphosphonium bromide (6.08 g, 17.04
mmol) in dry THF (50 mL) at ꢃ78 °C, n-BuLi (8.52 mL, 12.78 mmol,
1.5 M in hexane) was added and stirred for 1 h at 0 °C. Then to the
orange yellow ylide, the above crude aldehyde in dry THF (10 mL)
was added slowly at ꢃ78 °C and the reaction mixture allowed to
stir at 0 °C for 1 h. After completion, the reaction mixture was
quenched with saturated aqueous NH4Cl solution (20 mL) and ex-
tracted with ether (3 ꢁ 20 mL). The combined organic layers were
dried over anhydrous Na2SO4 and concentrated in vacuo. The
pound 12 (0.7 g, 88%) as a colorless liquid. ½a D26
ꢂ
¼ þ10:9 (c 0.1,
MeOH); IR (neat): c ;
max: 3371, 2934, 1375, 1075 cmꢃ1 1H NMR
(300 MHz, CDCl3): d 1.36 (s, 3H), 1.38 (s, 3H), 2.30–2.37 (m, 1H),
2.49–2.54 (m, 1H), 3.63–3.7 (m, 3H), 3.74–3.80 (m, 1H), 4.01–
4.13 (m, 1H), 5.03–5.19 (m, 2H), 5.78–5.91 (m, 1H); 13C NMR
(75 MHz, CDCl3): 26.66, 26.99, 37.44, 67.64, 77.12, 79.54, 80.27,
108.93, 117.35, 134.14; MS–ESIMS: m/z 225 (M+Na)+. HR ESIMS:
m/z calcd for C10H18O4Na: 225.1102; found: 225.1116.
4.6. (R)-1-((4R,5R)-5-Allyl-2,2-dimethyl-1,3-dioxolan-4-
yl)ethanol 13
To a stirred solution of diol 12 (0.63 g, 3.11 mmol) in CH2Cl2
(15 mL), were added Bu2SnO (catalytic amount), and Et3N
(0.52 mL, 3.74 mmol) at 0 °C and then stirred for 1 h. Then, tosyl
chloride (0.592 g, 3.11 mmol) was added and stirred for a further
5 h at room temperature. Next, the reaction mixture was diluted
with CH2Cl2 (5 mL), washed with water (5 mL), brine (5 mL), dried
over Na2SO4, and concentrated in vacuo. The crude residue was
used in the next step without purification. To a stirred solution

A. Kamal et al. / Tetrahedron: Asymmetry 21 (2010) 2517–2523
2521
of lithium aluminum hydride (0.11 g, 3.09 mmol) in dry THF
(20 mL), the above compound dissolved in dry THF (5 mL) was
added at 0 °C, the reaction mixture was heated at reflux and stirred
for 3 h, then quenched with satd aq Na2SO4 solution and filtered
through a pad of Celite, dried over Na2SO4, and concentrated in va-
cuo. The crude residue was purified by column chromatography
using silica gel, 60–120 mesh, by eluting EtOAc–hexane, 2:8 to af-
reaction mixture was allowed to warm to room temperature for
30 min. The reaction mixture was diluted with water (20 mL)
and extracted with CHCl3 (3 ꢁ 50 mL). The combined organic lay-
ers were washed with brine (20 mL), dried over anhydrous Na2SO4,
and concentrated under vacuum to afford crude aldehyde as a yel-
low sirup. To methyltriphenylphosphonium bromide (5.77 g,
16.16 mmol) in dry THF (75 mL) under a nitrogen atmosphere at
0 °C was added t-BuOK (1.45 g, 12.93 mmol) and stirred for 4 h at
the same temperature. To this orange yellow ylide solution, the
above crude aldehyde in dry THF (10 mL) was added and stirred
at the same temperature for 2 h. After completion of the reaction,
the mixture was quenched with saturated aqueous NH4Cl solution
(30 mL). The mixture was filtered over a Celite pad and the residue
was washed with ether (30 mL). Next, THF was evaporated and ex-
tracted with EtOAc (3 ꢁ 50 mL). The combined organic layers were
dried over anhydrous Na2SO4 and concentrated in vacuo. The res-
idue was purified by column chromatography using silica gel,
60–120 mesh, by eluting EtOAc–hexane 5:95 to afford the com-
ford 13 (0.42 g, 73% from 12) as a light yellow sirup. ½a D26
ꢂ
¼ þ5:2 (c
1, CHCl3); IR (neat): c ;
max: 3448, 2985, 2933, 1375, 1061 cmꢃ1 1H
NMR (300 MHz, CDCl3): d 1.2 (d, J = 6.79 Hz, 3H), 1.37 (s, 6H),
1.74 (br s, 1H), 2.24–2.34 (m, 1H), 2.41–2.49 (m, 1H), 3.55 (dd,
J = 7.55, 12.08 Hz, 1H), 3.82–3.91 (m, 1H), 3.95–4.05 (m, 1H),
5.06–5.12 (m, 2H), 5.79–5.93 (m, 1H); 13C NMR (75 MHz, CDCl3):
18.56, 26.99, 27.21, 38.41, 67.09, 76.37, 83.38, 108.44, 117.36,
134.04; MS–ESIMS: m/z 209 (M+Na)+. HR ESIMS: m/z calcd for
C10H18O3Na: 209.1153; found: 209.1165.
4.7. (2R,3R,4R)-Hept-6-ene-2,3,4-triol 14
pound 18 (2.97 g, 60%) as a colorless liquid. ½a D26
¼ þ11:6 (c 1,
ꢂ
To a stirred solution of 13 (0.35 g, 1.88 mmol) in MeOH (5 mL),
PTSA (catalytic amount) was added at 0 °C and stirred for 4 h at
room temperature. After completion of reaction, the reaction mix-
ture was quenched with saturated aq NaHCO3 solution (3 mL), ex-
tracted with EtOAc (5 ꢁ 10 mL), and the combined organic layers
were washed with brine (10 mL), dried over Na2SO4, and concen-
trated in vacuo. The crude residue was purified by column chroma-
tography using silica gel, 60–120 mesh, by eluting EtOAc–hexane,
CHCl3); IR (neat): c ;
max: 2931, 2859, 1513, 1247, 1110, 703 cmꢃ1
1H NMR (300 MHz, CDCl3): d 0.99 (s, 9H), 2.18–2.37 (m, 2H), 3.46
(m, 1H), 3.60 (dq, J = 6.04, 10.57 Hz, 2H), 3.72 (s, 3H), 4.39 (d,
J = 11.33 Hz, 1H), 4.46 (d, J = 11.33 Hz, 1H), 4.9–5.02 (m, 2H),
5.64–5.80 (m, 1H), 6.76 (d, J = 9.0 Hz, 2H), 7.14 (d, J = 9.0 Hz, 2H),
7.32 (m, 6H), 7.61 (m, 4H); 13C NMR (75 MHz, CDCl3): 19.19,
26.81, 36.03, 55.22, 65.54, 71.55, 79.03, 113.64, 116.85, 127.62,
129.22, 129.59, 130.92, 133.54, 134.89, 135.60, 159.01; MS–ESIMS:
m/z 483 (M+Na)+. HR ESIMS: m/z calcd for C29H36O3NaSi:
483.2331; found: 483.2309.
8:2 to afford 14 (0.206 g, 75%) as a colorless sirup. ½a D26
ꢂ
¼ ꢃ10:3
(c 1, CHCl3); IR (neat):
c
max: 3377, 2926, 1068 cmꢃ1
;
1H NMR
(300 MHz, CDCl3): d 1.23 (d, J = 6.42 Hz, 3H), 2.26–2.37 (m, 2H),
3.29 (br s, 1H), 3.83–3.94 (m, 2H), 3.95–4.03 (br s, 1H), 5.07–5.15
(m, 2H), 5.74–5.89 (m, 1H); 13C NMR (75 MHz, CDCl3): 18.73,
37.98, 69.62, 70.01, 75.24, 117.84, 134.34: MS–ESIMS: m/z 164.2
(M+NH4)+.
4.10. (R)-1-(2,2-Dimethyl-1,1-diphenylpropoxy)pent-4-en-2-ol 19
To a solution of 18 (2.8 g, 6.087 mmol) in H2O/CH2Cl2 (1:19)
(30 mL) was added dichlorodicyanoquinone (DDQ) (1.52 g,
6.696 mmol) at 0 °C. The solution was stirred for 1 h. After comple-
tion of the reaction, the reaction mixture was quenched with so-
dium bicarbonate solution (10 mL) and the solution was filtered
through a pad of Celite. The combined filtrate was dried over anhy-
drous Na2SO4 and concentrated in vacuo, and then purified by col-
umn chromatography using silica gel, 60–120 mesh, by eluting
EtOAc–hexane 10:90 to afford compound 19 (1.7 g, 82%) as a color-
4.8. (2R,3R,4R)-Hept-6-ene-2,3,4-triyl triacetate 15
To a solution of the triol (0.1 g, 0.68 mmol) in dry CH2Cl2 (5 mL)
Et3N (0.381 mL, 2.74 mmol), acetic anhydride (0.258 mL,
2.74 mmol) and DMAP (catalytic) were added slowly. The mixture
was then stirred for 3 h at room temperature. After completion of
the reaction, the reaction mixture was quenched with aqueous
NH4Cl (5 mL) and the reaction mixture was extracted with EtOAc
(3 ꢁ 5 mL). The combined organic layers were dried over anhy-
drous Na2SO4 and concentrated in vacuo. The residue was purified
by column chromatography using silica gel 60–120 mesh, by elut-
ing with EtOAc–hexane 5:95 to furnish 15 (0.15 g, 81%), which
showed physical and spectroscopic properties identical to those
less liquid. ½a 2D6
ꢂ
¼ þ4:2 (c 1, CHCl3); IR (neat):
cmax: 3408, 2931,
2859, 1110, 702 cmꢃ1
;
1H NMR (300 MHz, CDCl3): d 1.07 (s, 9H),
2,24 (t, J = 6.79, 13.4 Hz, 2H), 3.54 (dd, J = 6.98, 10.19 Hz, 1H), 3.68
(dd, J = 6.42, 10.19 Hz, 1H), 3.78 (m, 1H), 5.04–5.11 (m, 2H), 5.72–
5.86 (m, 1H), 7.36–7.47 (m, 6H), 7.65 (m, 4H); 13C NMR (75 MHz,
CDCl3): 19.21, 26.81, 37.53, 67.29, 71.20, 117.38, 127.72, 129.76,
133.09, 134.31, 135.48; MS–ESIMS: m/z 363 (M+Na)+. HR ESIMS:
m/z calcd for C21H28O2NaSi: 363.1756; found: 363.1768.
published.9b
½
a 2D6
ꢂ
¼ þ23:8 (c 1, CHCl3); IR (neat):
cmax: 1744,
1372, 1222, 1063, 1026 cmꢃ1
;
1H NMR (300 MHz, CDCl3): d 1.13
(d, J = 6.23 Hz, 3H), 1.95 (s, 3H), 1.97 (s, 3H), 2.07 (s, 3H), 2.20
(m, 2H), 4.93 (m, 1H), 5.05–5.10 (m, 3H), 5.15 (m, 1H), 5.62–5.71
(m, 1H); 13C NMR (75 MHz, CDCl3): 16.11, 20.74, 20.81, 21.03,
35.52, 67.39, 69.86, 73.83, 118.60, 132.34, 170.01, 170.08,
170.20; MS–ESIMS: m/z 295 (M+Na)+. HR-ESIMS: m/z calcd for
4.11. (R)-1-(2,2-Dimethyl-1,1-diphenylpropoxy)pent-4-en-2-yl
acrylate 20
To a stirred solution of compound 19 (1.6 g, 4.706 mmol) in dry
CH2Cl2 (20 mL), acryloyl chloride (0.422 mL, 5.17 mmol), triethyl-
amine (1.30 mL, 9.412 mmol) and DMAP (cat) were added succes-
sively at 0 °C for 2 h. After completion of the reaction, the reaction
mixture was taken into CH2Cl2 (10 mL), washed with brine
(20 mL), dried over anhydrous Na2SO4, and concentrated in vacuo.
The crude residue was purified by column chromatography using
silica gel, 60–120 mesh, by eluting with EtOAc–hexane 5:95 to af-
C13H20O6Na: 295.1157; found: 295.1169.
4.9. (R)-1-((1-(2,2-Dimethyl-1,1-diphenylpropoxy)pent-4-en-2-
yloxy)methyl)-4 methoxybenzene 18
To a stirred solution of oxalyl chloride (1.36 mL, 16.16 mmol), in
dry CH2Cl2 (100 mL), DMSO (2.29 mL, 32.32 mmol) was added at
ꢃ78 °C and stirred at the same temperature for 30 min. Compound
17 (5 g, 10.77 mmol) in dry CH2Cl2 (15 mL) was added at ꢃ78 °C to
the reaction mixture and stirred for 1 h at the same temperature.
Then Et3N (4.49 mL, 32.32 mmol) was added at ꢃ78 °C, and the
ford product 20 (1.49 g, 80%) as a liquid. ½a D26
ꢂ
¼ þ8:3 (c 1, CHCl3);
IR (neat): c ;
max: 2932, 2859, 1726, 1192, 1112, 703 cmꢃ1 1H NMR
(300 MHz, CDCl3):
d 0.97 (s, 9H), 2.38 (m, 2H), 3.67 (d,
J = 4.72 Hz, 2H), 4.94–5.08 (m, 3H), 5.6–5.79 (m, 2H), 5.99–6.08
(m, 1H), 6.32 (dd, 1H), 7.26–7.40 (m, 6H), 7.57 (m, 4H); 13C NMR

2522
A. Kamal et al. / Tetrahedron: Asymmetry 21 (2010) 2517–2523
(75 MHz, CDCl3): 19.21, 26.76, 35.00, 64.32, 73.66, 116.65, 117.90,
127.65, 128.67, 129.57, 130.55, 133.26, 135.52, 165.61; MS–ESIMS:
m/z 395 (M+H)+. HR ESIMS: m/z calcd for C24H30O3NaSi: 417.1861;
found: 417.1853.
1H NMR (CDCl3, 300 MHz): d 2.47–2.42 (m, 2H), 4.98–4.88 (m,
1H), 5.31–5.27 (dd, 1H, J = 10.76 Hz), 5.43–5.37 (dd, 1H,
J = 17.34 Hz), 6.06–5.88 (m, 2H), 6.89–6.83 (m, 1H): 13C NMR
(CDCl3, 75 MHz): d 29.3, 77.7, 117.8, 121.6, 134.8, 144.3, 163.7.
MS–EIMS: m/z 125 (M+H)+.
4.12. (R)-6-((2,2-Dimethyl-1,1-diphenylpropoxy)methyl)-5,6-
dihydropyran-2-one 21
4.15. (1R,2R,4E)-2-(Acetyloxy)-1-[(1R)-1-(acetyloxy)ethyl]-5-
[(2R)-6-oxo-3,6-dihydro-2H-2-pyranyl]-4-pentenyl acetate 2
(synargentolide A)
To a stirred solution of compound 20 (0.4 g, 1.015 mmol) in dry
CH2Cl2 (800 mL), Grubbs’ 1st generation catalyst I (10 mol %) was
added at reflux for 48 h. After completion of the reaction, the reac-
tion mixture was directly adsorbed on silica gel and purified by
column chromatography by eluting EtOAc–hexane 30:70 to afford
To a solution of compound 15 (0.038 g, 0.14 mmol) and com-
pound 23 (0.07 g, 0.56 mmol) in dry CH2Cl2 (100 mL) under nitro-
gen conditions, Grubbs-II catalyst (0.071 g, 0.08 mmol) was added.
The resulting mixture was refluxed for 4 h. After completion of the
reaction, the solvent was evaporated and the crude residue was
purified by column chromatography using silica gel, 60–120 mesh,
by eluting EtOAc–hexane 20:80 to afford product 2 (0.028 g, 55%).
compound 21 (0.297 g, 80%) as a liquid. ½a D26
ꢂ
¼ þ47:8 (c 1, CHCl3);
IR (neat):
c ;
max: 2932, 2858, 1729, 1108, 703 cmꢃ1 1H NMR
(300 MHz, CDCl3): d 1.06 (s, 9H), 2.35–2.61 (m, 2H), 3.82 (d,
J = 4.91 Hz, 2H), 4.46 (m, 1H), 5.98 (dd, J = 1.5, 8.3 Hz, 1H), 6.80–
6.87 (m, 1H), 7.33–7.41 (m, 6H), 7.62 (m, 4H); 13C NMR (75 MHz,
CDCl3): 19.22, 25.88, 26.74, 64.71, 77.53, 121.16, 127.76, 129.85,
132.74, 132.89, 135.48, 135.54, 144.83, 163.74; MS–ESIMS: m/z
389 (M+Na)+. HR ESIMS: m/z calcd for C22H26O3NaSi: 389.1548;
found: 389.1538.
½
a 2D6
ꢂ
¼ þ36:5 (c 1, CHCl3); IR (neat):
c ;
max: 1738, 1374, 1024 cmꢃ1
1H NMR (300 MHz, CDCl3): d 1.18 (d, J = 6.4 Hz, 3H), 2.0 (s, 3H),
2.04 (s, 3H), 2.13 (s, 3H), 2.28 (m, 2H), 2.39 (m, 2H), 4.86 (m,
1H), 4.98 (m, 1H), 5.08 (dt, J = 7.2, 4.0 Hz, 1H), 5.15 (m, 1H),
5.67–5.79 (m, 2H), 6.03 (dt, J = 10.4, 2.4 Hz, 1H), 6.84 (ddd,
J = 8.8, 4.0, 2.4 Hz, 1H); 13C NMR (75 MHz, CDCl3): 16.0, 20.6,
20.8, 21.0, 29.4, 34.3, 67.5, 69.8, 73.7, 77.2, 121.5, 128.3, 130.9,
144.5, 163.8, 170.0, 170.1, 170.2. MS–ESIMS: m/z 391 (M+Na)+.
HR ESIMS: m/z calcd for C18H24O8Na: 391.1368; found: 391.1376.
4.13. (R)-6-(Hydroxymethyl)-5,6-dihydropyran-2-one 22
To a stirred solution of compound 21 (0.9 g, 2.46 mmol) in dry
THF (10 mL) was added tetrabutylammoniumfluoride (TBAF)
(2.46 mL, 2.46 mmol, 1 M in toluene) at 0 °C for 30 min. After com-
pletion of the reaction, the reaction mixture was quenched with
satd aq NH4Cl (5 mL), then THF was evaporated and extracted with
EtOAc (3 ꢁ 10 mL) and organic layers were washed with brine,
dried over anhydrous Na2SO4, and concentrated in vacuo. The
crude product was purified by column chromatography using silica
gel, 60–120 mesh, by eluting with EtOAc–hexane 7:3 to afford
Acknowledgment
The authors M.B.K, P.V.R., and S.F. wish to thank UGC, New Delhi
for the award of research fellowships.
References
compound 22 (0.267 g, 85%) as a colorless oil. ½a D26
¼ þ120:9 (c
ꢂ
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0.1, CHCl3); IR (neat): cmax
: 3400, 2929, 1713, 1260, 1039,
816 cmꢃ1 1H NMR (300 MHz, CDCl3): d 2.28–2.38 (m, 1H), 2.54–
;
2.66 (m, 1H), 3.48 (br s, 1H), 3.71 (dd, J = 12.27 Hz, 1H), 3.87 (m,
J = 12.27 Hz, 1H), 4.47–4.57 (m, 1H), 5.98 (dd, J = 2.26, 9.82 Hz,
1H), 6.91–6.97 (m, 1H); 13C NMR (75 MHz, CDCl3): 25.17, 63.55,
78.41, 120.71. 145.57, 164.14; MS–EIMS: m/z 129 (M+H)+.
4.14. (R)-6-Vinyl-5,6-dihydropyran-2-one 23
To a stirred solution of compound 22 (0.2 g, 1.56 mmol) in
CH2Cl2 (5 mL), Dess–Martin periodinate (0.728 g, 1.71 mmol) was
added at 0 °C for 1 h. After completion of the reaction, the reaction
mixture was quenched with saturated sodium thiosulfate solution
(5 mL) and saturated aqueous sodium bicarbonate solution (5 mL).
The reaction mixture was extracted with dichloromethane (3 ꢁ
5 mL), dried over anhydrous Na2SO4 and concentrated at 30 °C in
vacuo to afford the aldehyde. This was used directly in the next
step without further purification. To methyltriphenylphosphonium
bromide (0.78 g, 1.562 mmol) in dry THF (12 mL) under a nitrogen
atmosphere at 0 °C was added t-BuOK (0.21 g, 1.87 mmol) and stir-
red for 4 h at the same temperature. To this orange yellow ylide
solution, the above crude aldehyde in dry THF (3 mL) was added
and stirred at the same temperature for 2 h. The reaction mixture
was quenched with saturated aqueous NH4Cl solution (5 mL).
The mixture was filtered over a Celite pad and the residue was
washed with ether (5 mL). Next, THF was evaporated, and then ex-
tracted with EtOAc (3 ꢁ 10 mL). The combined organic layers were
dried over anhydrous Na2SO4 and concentrated in vacuo. The res-
idue was purified by column chromatography using silica gel,
60–120 mesh, EtOAc–hexane 20:80 to afford the compound 23
(0.075 g, 39%) as a colorless liquid. ½a D26
¼ þ94:3 (c 0.1, CHCl3);
ꢂ

A. Kamal et al. / Tetrahedron: Asymmetry 21 (2010) 2517–2523
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