Stereoselective total synthesis of cryptomoscatone E1

Article abstract of DOI:10.1016/j.tetasy.2015.07.005

Abstract The stereoselective total synthesis of cryptomoscatone E1 has been accomplished. The strategy involves Carreira's asymmetric alkynylation and olefin cross-metathesis reactions as key steps.

Full text of DOI:10.1016/j.tetasy.2015.07.005

Tetrahedron: Asymmetry xxx (2015) xxx–xxx
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective total synthesis of cryptomoscatone E1
⇑
Atla Raju, Kasa Shiva Raju, Gowravaram Sabitha
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The stereoselective total synthesis of cryptomoscatone E1 has been accomplished. The strategy involves
Carreira’s asymmetric alkynylation and olefin cross-metathesis reactions as key steps.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 4 June 2015
Accepted 10 July 2015
Available online xxxx
1
. Introduction
O
O
OH
OH
O
Cavalheiro et al. reported in 2000 the isolation of cryptomosca-
OH
OH
O
O
tone E1 1 (Fig. 1) from the branch and stem bark of Cryptocarya
1
moschata. Cryptomoscatone E1 is part of a series of related
6
-substituted 5,6-dihydroypyran-2-ones along with two hydroxyl
(+)-cryptofolione 2
cryptomoscatone E11
groups with the same stereostructure and two olefinic systems
with an (E)-configuration. Several structurally related congeners
have also been isolated and identified, and the family remains of
significant interest to the biological, medical, and synthetic com-
O
O
OH
OH
O
OH
OH
2
munities. Among the styrylpyrones isolated from Cryptocarya
(
Z)-cryptomoscatone D2 4
sp., cryptofolione, and cryptomoscatones D1 and D2, demonstrate
antiproliferative activity, whereas, Z-cryptomoscatone D2 is a G2
checkpoint inhibitor. The biological activities of strictifolione have
not been studied. As part of our continuing interest in the total syn-
(+)-strictifolione 3
O
O
OH
OH
O
OH
OH
O
3
thesis of bio-active natural products, together with the structural
features of cryptomoscatones, we were encouraged to synthesize
this natural product. In 2013, Yadav et al. disclosed the first syn-
thesis of cryptomoscatone E1. Herein we report the total synthesis
cryptomoscatone D1 5
cryptomoscatone D2 6
4
cryptomoscatone E1 1 using 1,3-propanediol as a starting material.
Figure 1. Structures of natural d-lactones 1–6.
2
. Results and discussion
the alkynylation reaction directly. Thus, Carreira’s asymmetric
alkynylation of aldehyde generated from 10 with phenyl
acetylene using (+)-N-methylephedrine gave the desired propargyl
alcohol 9 with excellent diastereomeric ratio 95:5 in 86% yield over
two steps.
6
The retrosynthetic analysis of 1 is depicted in Scheme 1. The
target molecule cryptomoscatone E1 1 can be easily accessible
from homoallyl alcohol 7 and vinyl lactone 8 by utilizing olefin
cross-metathesis reaction, whereas 7 can be prepared from known
alcohol 10 by oxidation and alkynylation reaction with phenyl
acetylene (Scheme 2).
The synthesis of cryptomoscatone E1 starts with the known pri-
mary alcohol 10 prepared from commercially available inexpen-
sive 1,3-propane diol as reported.5 Alcohol 10 was oxidized
under Swern conditions and the crude aldehyde was subjected to
The absolute configuration of the stereogenic center generated
in the reaction was confirmed in a later stage based on
Rychnovsky’s analogy. Partial reduction of triple bond was
achieved with Red-Al to furnish trans-compound 11.
Deprotection of the TBDPS group with TBAF furnished the 1,3-diol,
which was protected with 2,2-DMP in the presence of a catalytic
amount of PPTS, to furnish acetonide compound 7. At this stage,
the relative configuration of a secondary 1,3-diol was assigned
7
13
⇑
Corresponding author. Tel.: +91 40 27191629; fax: +91 40 27160512.
E-mail addresses: gowravaramsr@yahoo.com, sabitha@iict.res.in (G. Sabitha).
based on Rychnovsky method. In the C NMR spectrum of 7,
the resonance arising from the acetonide methyl groups appeared
http://dx.doi.org/10.1016/j.tetasy.2015.07.005
957-4166/Ó 2015 Elsevier Ltd. All rights reserved.
0
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A. Raju et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
O
19.8
30.1
98.7
O
O
OH
OH
O
7
cryptomoscatone E1 1
Figure 2.
O
O
O
O
4
. Experimental
+
7
8
4.1. General
Reactions were conducted under N
as CH Cl , THF, and EtOAc. All reactions were monitored by TLC
silica-coated plates and visualized under UV light). n-Hexane
(bp 60–80 °C) was used. Yields refer to chromatographically and
2
in anhydrous solvents such
OH
OTBDPS
2
2
(
9
1
13
spectroscopically ( H and C NMR) homogeneous material. Air
sensitive reagents were transferred by syringe or double-ended
needle. Evaporation of solvents was performed at reduced pressure
OTBDPS
1
13
on a Buchi rotary evaporator. H and C NMR spectra of samples in
CDCl were recorded on Varian FT-400 MHz, Varian FT-500 MHz
HO
1,3-propanediol
Scheme 1. Retrosynthetic analysis for 1.
OH
HO
3
1
0
and Bruker UXNMR FT-300 MHz (Avance) spectrometers.
Chemical shift d is reported relative to TMS (d = 0.0) as an internal
standard. Mass spectra were recorded EI conditions at 70 eV on ES-
MSD (Agilent technologies) spectrometers. Column chromatogra-
phy was performed on silica gel (60–120 mesh) supplied by
Acme Chemical Co., India. TLC was performed on Merck 60 F-254
silica gel plates. Optical rotations were measured with JASCO
DIP-370 Polarimeter.
at d = 30.1 and 19.8 ppm and that of the quaternary carbon atom at
d = 98.7 ppm, thus indicating a 1,3-syn-relationship (Fig. 2).
After confirming the stereochemistry, compound
subjected to olefin cross-metathesis reaction with a vinyl
lactone using a Grubb’s second generation catalyst (10 mol %)
to give the lactone compound 12 in 86% yield. This compound
upon hydrolysis led to the formation of target lactone,
7
was
8
2
b
4
.1.1. (3R,5R)-5-((tert-Butyldiphenylsilyl)oxy)-1-phenyloct-7-
en-1-yn-3-ol 9
A solution of oxalyl chloride (0.5 mL, 5.64 mmol) in 10 mL of
cryptomoscatone E1 (1) as
a
liquid in 90% yield. The
C, IR, HRMS) and specific rotation
D 3
[a] = +30.9 (c 0.1, CHCl ) of 1 were in complete agreement with
freshly distilled CH
DMSO (0.8 mL, 11.29 mmol) in 2 mL of CH
wise. The mixture was stirred for 15 min at À78 °C upon which
alcohol 10 (1 g, 2.82 mmol) in 2 mL CH Cl was added dropwise.
The reaction was stirred for 30 min at À78 °C then triethylamine
neat, 2.4 mL, 16.94 mmol) was added dropwise. The mixture
Cl
2 2
was cooled to À78 °C, and anhydrous
1
13
spectroscopic data ( H,
Cl was added drop-
2
2
8
2
4
31
the literature data {lit.: [
. Conclusion
In conclusion, a stereoselective total synthesis of cryptomosca-
D 3
a] = +29.4 (c 0.4, CHCl )}.
2
2
3
(
was stirred for 30 min at À78 °C then for 30 min at 0 °C, after
which it was transferred to a separatory funnel and washed with
tone E1 1 has been accomplished in 13 steps and in 24% overall
yield (lit.: 12 steps and 16.2% overall yield).
5
mL for each of H
2
O, 1 M HCl, saturated sodium bicarbonate, then
Cl
(2 Â 10 mL). The
4
brine. Each wash was back-extracted with CH
2
2
OH
OTBDPS
ref 5
OTBDPS
a
HO
,3-propanediol
OH
HO
9
1
10
O
O
OH
OTBDPS
d
c
b
O
11
7
O
O
O
O
OH
OH
O
O
O
e
1
2
cryptomoscatone E1 1
N, dryCH Cl
, À78 °C, 2 h; (ii) Phenylacetylene, Et
Scheme 2. Synthesis of cryptomoscatone E1. Reagents and conditions: (a) (i) (COCl)
methylephedrine, dry toluene, 25 °C, 20 h, 86% (over 2 steps) (dr 95:5); (b) Red-Al, THF, 0 °C, 3 h, 90%; (c) (i) TBAF, THF, 0 °C, 3 h; (ii) 2,2-DMP, PPTS, 0 °C–rt,10 h, 79% (over 2
steps); (d) Grubbs-II catalyst, CH Cl , reflux, 1 h, 86%; (e) 4 M HCl, THF, 0 °C, 1 h, 90%.
2
, DMSO, Et
3
2
2
3 2
N, Zn(OTf) , (+)-N-
2
2
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A. Raju et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
3
combined organic layers were dried over Na
centrated under reduced pressure. The crude product was passed
through a short silica plug with 100% CH Cl , concentrated under
reduced pressure, and then the crude aldehyde (0.914 g, yellow
oil) was immediately subjected to the next reaction without fur-
ther purification. A 50 mL flask was charged with zinc triflate
2
SO
4
, filtered, and con-
2 4
over Na SO . The solvent was removed under reduced pressure,
and the crude diol was subjected to the next reaction without fur-
ther purification. 2,2-Dimethoxypropane (0.35 mL, 2.75 mmol) and
catalytic PPTS (42 mg, 0.165 mmol) were added successively to a
2
2
solution of diol (0.3 g, 1.37 mmol) in CH
was stirred for 10 h at room temperature and then quenched with
solid NaHCO . The crude compound was concentrated in vacuo and
2 2
Cl (5 mL). The solution
(
1
1.038 g, 2.85 mmol) and heated to 120 °C under high vacuum for
4 h. After cooling to room temperature, 10 mL of dry toluene fol-
3
purified by column chromatography (15% Hexane/EtOAc) to afford
lowed by (+)-N-methylephedrine (0.558 g, 3.11 mmol) and triethyl
amine (0.48 mL, 3.37 mmol) were added and the resultant inhomo-
geneous mixture was stirred for 3 h at room temperature under
argon. Alkyne (0.317 g, 3.11 mmol) dissolved in 5 mL of dry
toluene was added over 5 minutes and then the reaction was
stirred for 30 min. Next, the aldehyde (0.914 g, 2.59 mmol)
the acetonide product 7 (0.327 g, 92%) as a colorless liquid.
2
8
[
a
]
D
= +20 (c 0.2, CHCl
3
). IR (neat)
m
max: 2992, 2940, 1378, 1199,
À1
1
1167, 967, 746 cm . H NMR (500 MHz, CDCl ): d 7.39–7,36 (m,
3
2H), 7.31–7.27 (m, 2H), 7.24–7.20 (m, 1H), 6.59 (d, J = 16.0 Hz,
1H), 6.17 (dd, J = 16.0, 6.2 Hz, 1H), 5.87–5.78 (m, 1H), 5.13–5.05
(m, 2H), 4.55–4.50 (m, 1H), 4.00–3.94 (m, 1H), 2.38–2.32 (m,
1H), 2.23–2.16 (m, 1H), 1.65 (td, J = 13.1, 2.5 Hz, 2H), 1.52 (s, 3H),
(
dissolved in approximately 1 mL of dry toluene) was added over
min. After 2.5 h, TLC (30% ethyl acetate/hexane) showed no
1
3
3
1.47 (s, 3H). C NMR (CDCl
3
, 75 MHz): d 136.5, 133.9, 130.6,
aldehyde remained. The reaction was diluted with ether and
quenched with a saturated aqueous ammonium chloride solution.
The aqueous phase was washed 3 more times with ether. The
organic phases were washed with brine and dried over sodium sul-
fate. After evaporation of the volatiles column chromatography
129.8, 128.4, 127.5, 127.5, 126.4, 117.2, 98.7, 70.0, 68.3, 40.7,
36.5, 30.1, 19.8. HRMS (ESI) for C17
281.1524; calcd: 281.1524.
22 2
H O
Na [M+Na]+ found:
4.1.4. (R)-6-((E)-3-((4R,6R)-2,2-Dimethyl-6-((E)-styryl)-1,3-dioxan-
4-yl)prop-1-en-1-yl)-5,6-dihydro-2H-pyran-2-one 12
(
2
CHCl
20% followed by 50% ethyl acetate/hexane) yielded (1.108 g,
28
.20 mmol) 86.48% (over 2 steps) of product. [
). IR (neat) max: 3444, 2931, 2858, 1427, 1110, 1071, 756,
H NMR (500 MHz, CDCl ): d 7.73–7.69 (m, 4H),
a
]
D
: +15.9 (c 0.36,
A solution of Grubbs II catalyst (24 mg, 0.027 mmol) in dry
3
m
CH
(120 mg, 0.465 mmol) and vinyl lactone 8 (86 mg, 0.697 mmol)
in dry CH Cl (1 mL) at rt, and the mixture was refluxed for 1 h.
2 2
Cl (1 mL) was added dropwise to a solution of compound 7
À1
1
7
7
4
2
2
1
1
2
4
40 cm
.
3
.44–7.27 (m, 11H), 5.65–5.56 (m, 1H), 4.96–4.92 (m, 1H),
.87–4.81 (m, 2H), 4.10–4.05 (m, 1H), 2.39 (d, J = 5.0 Hz, 1H),
.29–2.22 (m, 1H), 2.20–2.14 (m, 1H), 2.08–2.02 (m, 1H),
2
2
The solvent was then removed under reduced pressure and the
crude product was purified by column chromatography (40%
13
28
.00–1.94 (m, 1H), 1.07 (s, 9H). C NMR (CDCl
3
, 125 MHz): d
Hexane/EtOAc) to give liquid 12 (141 mg, 86%). [
0.15, CHCl ). IR (neat)
956, 745 cm
a
]
D
= À40.6 (c
35.8, 134.7, 134.0, 133.9, 133.3, 131.6, 129.7, 129.6, 128.2,
3
m
max: 2936, 2864, 1715, 1368, 1240, 1019,
H NMR (500 MHz, CDCl ): d 7.40–7.28 (m, 5H),
À1
1
28.1, 127.6, 127.4, 122.6, 117.5, 89.8, 85.1, 71.5, 61.2, 43.8, 41.7,
.
3
+
6.9, 19.3. HRMS (ESI) for
77.2219; calcd: 477.2225.
C
30
H
34
O
2
SiNa [M+Na] found:
7.25–7.21 (m, 1H), 6.88 (d, J = 9.6, 4.5 Hz, 1H), 6.60 (d, J = 16.0 Hz,
1H), 6.17 (dd, J = 16.0, 6.2 Hz, 1H), 6.05 (td, J = 9.9, 1.9 Hz, 1H),
5
.90–5.83 (m, 1H), 5.71–5.64 (m, 1H), 4.93–4.87 (m, 1H), 4.55–
4
1
.1.2. (3R,5R,E)-5-((tert-Butyldiphenylsilyl)oxy)-1-phenylocta-
,7-dien-3-ol 11
4.50 (m, 1H), 4.02–3.96 (m, 1H), 2.47–2.18 (m, 4H), 1.66–1.60
(m, 2H), 1.52 (s, 3H), 1.46 (s, 3H). C NMR (CDCl , 75 MHz): d
3
1
3
To a cold (0 °C) solution of propargylic alcohol 9 (1 g, 2.2 mmol)
163.9, 144.6, 136.5, 130.7, 130.1, 129.6, 129.4, 128.4, 127.6,
in THF (5 mL) was added Red-Al (1 mL, 70 wt% in toluene,
.3 mmol) dropwise. After 1 h at 0 °C, the reaction mixture was
quenched carefully by the dropwise addition of saturated aqueous
sodium sulfate (Caution: vigorous evolution of H may result).
126.4, 121.4, 98.7, 77.7, 70.0, 68.0, 60.3, 38.9, 36.4, 30.1, 19.8.
+
3
HRMS (ESI) for C22
377.1729.
H
26
O
4
Na [M+Na] found: 377.1736; calcd:
2
Next EtOAc was added and the mixture was allowed to warm to
rt. The organic layer was washed with brine and the combined
aqueous layer was extracted several times with EtOAc. The
combined organic extracts were dried over Na SO , filtered, and
2 4
concentrated under reduced pressure. The residue was
chromatographed on silica gel (30% Hexane/EtOAc) to provide
4.1.5. (R)-6-((1E,4R,6R,7E)-4,6-Dihydroxy-8-phenylocta-1,7-dien-
1-yl)-5,6-dihydro-2H-pyran-2-one (cryptomoscatone E1) 1
A 4 M aq HCl solution (0.5 mL) was added dropwise over 5 min
to a solution of 12 (20 mg, 0.056 mmol) in THF (4 mL) at 0 °C. The
mixture was stirred at 0 °C for 30 min, quenched with satd aq
NaHCO
combined organic layer was washed with brine (2 Â 10 mL), dried
(Na SO ), and concentrated. The residue was subjected to column
chromatography (60% Hexane/EtOAc) to afford a pure viscous
3
(10 mL) and then extracted with EtOAc (4 Â 10 mL). The
allylic alcohol 11 (0.903 g, 90% yield) as
a
colorless oil.
max: 3444, 2931, 2857,
H NMR (300 MHz, CDCl ): d
2
8
[
a
]
D
= +35.3 (c 0.23, CHCl
3
). IR (neat)
m
2
4
À1
1
1
7
6
427, 1110, 1070, 740, 702 cm
.
3
2
8
.76–7.68 (m, 4H), 7.48–7.20 (m, 11H), 6.45 (d, J = 15.8 Hz, 1H),
.08 (dd, J = 15.8, 6.2 Hz, 1H), 5.67–5.51 (m, 1H), 4.97–4.78
liquid 1 (16 mg, 90%). [
a]
D
= +30.9 (c 0.1, CHCl
3
). IR (neat)
m
max
À1
:
.
3409, 2924, 2854, 1712, 1384, 1251, 1053, 969, 818, 752 cm
H NMR (500 MHz, CDCl ): d 7.40–7.22 (m, 5H), 6.91–6.84 (m,
3
1
(
(
m, 2H), 4.53–4.43 (m, 1H), 4.04–3.95 (m, 1H), 2.25–2.14
13
m, 2H), 1.84–1.76 (m, 2H), 1.08 (s, 9H).
C NMR (CDCl
3
,
1H), 6.59 (d, J = 15.8 Hz, 1H), 6.21 (dd, J = 15.8, 6.5 Hz, 1H), 6.03
(d, J = 9.7 Hz, 1H), 5.92–5.84 (m, 1H), 5.69 (dd, J = 15.4, 6.4 Hz,
7
1
4
4
5 MHz): d 136.7, 135.8, 134.7, 134.0, 133.9, 133.5, 131.9, 129.8,
29.7, 129.6, 128.4, 127.6, 127.5, 127.4, 126.4, 117.5, 72.4, 70.9,
1H), 4.92–4.86 (m, 1H), 4.58–4.53 (m, 1H), 4.03–3.96 (m, 1H),
+
13
3.2, 41.9, 26.9, 19.2. HRMS (ESI) for C30
H
36
O
2
SiNa [M+Na] found:
2.45–2.40 (m, 2H), 2.32–2.27 (m, 2H), 1.75–1.68 (m, 2H).
NMR (CDCl
29.8, 128.9, 128.5, 127.6, 126.4, 121.3, 77.8, 73.2, 71.1, 42.5,
C
79.2389; calcd: 479.2382.
3
, 75 MHz): d 164.1, 144.9, 136.4, 131.5, 130.7, 130.0,
1
+
4
.1.3. (4R,6R)-4-Allyl-2,2-dimethyl-6-((E)-styryl)-1,3-dioxane 7
40.6, 29.6. HRMS (ESI) for C19
calcd: 337.1410.
22 4
H O Na [M+Na] found: 337.1414;
A 1 M solution of TBAF in THF (3.2 mL, 3.2 mmol) was added to
a solution of compound 11 (0.73 g, 1.6 mmol) in dry THF (5 mL) at
°C. The mixture was stirred at room temperature for 3 h. After
completion of the reaction, the mixture was diluted with EtOAc
10 mL). The combined organic layers were washed with brine,
and the mixture was extracted with EtOAc (3 Â 10 mL), and dried
0
Acknowledgements
(
A.R. and K.S.R. thanks to UGC, New Delhi, India for the award of
fellowship. All the authors thank CSIR, New Delhi, India for
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A. Raju et al. / Tetrahedron: Asymmetry xxx (2015) xxx–xxx
financial support as part of XII Five Year plan programme under the
title ORIGIN (CSC-0108).
3. (a) Sabitha, G.; Bhaskar, V.; Reddy, S. S. S.; Yadav, J. S. Helv. Chim. Acta 2010, 93,
29–338; (b) Sabitha, G.; Reddy, S. S. S.; Reddy, D. V.; Bhaskar, V.; Yadav, J. S.
3
Synthesis 2010, 20, 3453–3460; (c) Toneto Novaes, L. F.; Drekener, R. L.; Avila, C.
M.; Pilli, R. A. Tetrahedron 2014, 70, 6467–6473.
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