Stereoselective Total Synthesis of Cryptomoscatone F1

Article abstract of DOI:10.1055/s-0035-1561394

A concise stereoselective total synthesis of cryptomoscatone F1 has been accomplished by utilization of asymmetric acetate aldol reaction, Brown's asymmetric allylation, and olefin cross-metathesis as key transformations.

Full text of DOI:10.1055/s-0035-1561394

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–G
paper
A
E. Srinivas et al.
Paper
Synthesis
Stereoselective Total Synthesis of Cryptomoscatone F1
Eedubilli Srinivasa,b
acetate aldol reaction
Palash Duttaa,b
Bogonda Gangannaa,b
Ahmad Alkhazim Alghamdic
Jhillu Singh Yadav*a
Still–Gennari
reaction
O
O
OH OH OH
OH OH OH
O
O
+
Brown's allylation
cross-metathesis
a Natural Products Chemistry Division, CSIR Indian
Institute of Chemical Technology, Tarnaka,
Hyderabad 500007, TS, India
O
S
O
OH
b Academy of Scientific and Innovative Research,
New Delhi, India
N
+
H
OTBS
S
c Engineer Abdullah Baqshan for Bee Research,
King Saudi University, Saudi Arabia
yadavpub@gmail.com
Bn
Received: 23.12.2015
Accepted after revision: 12.02.2016
Published online: 07.03.2016
Our retrosynthetic strategy is outlined in Scheme 1. Ini-
tial disconnection was made at the 11–21 trans-olefinic
double bond of cryptomoscatone F1 (1) and the reconnec-
tion was planned via cross-metathesis11 between the two
key intermediates 7 and vinyl lactone 8. While the key in-
termediate 7 could be synthesized from commercially
available trans-cinnamaldehyde (11) by employing iterative
acetate aldol reactions with (4S)-3-acetyl-4-benzylthiazoli-
dine-2-thione (12) for the creation of two stereocenters fol-
DOI: 10.1055/s-0035-1561394; Art ID: ss-2015-z0736-op
Abstract A concise stereoselective total synthesis of cryptomoscatone
F1 has been accomplished by utilization of asymmetric acetate aldol re-
action, Brown’s asymmetric allylation, and olefin cross-metathesis as
key transformations.
Key words cryptomoscatone F1, acetate aldol reaction, Brown’s
asymmetric allylation, olefin cross-metathesis
acetate aldol
reaction
Naturally occurring 6-substituted 5,6-dihydro-α-py-
rones have been observed in several botanical families and
fungi species. Among them 6-(ω-arylalkenyl)-5,6-dihydro-
α-pyrones bearing no substituent at C4 are characteristic of
Cryptocarya species (Lauraceae).1,2 These α-pyrones are
structurally characterized by 5,6-dihydro-α-pyrone, 1,3-
diol or 1,3,5-triol, and trans-styryl skeletons. Cryptomos-
catone F1 (1, Figure 1), a class of 6-(ω-arylalkenyl)-5,6-di-
hydro-α-pyrones, has been isolated from branch and stem
bark of Cryptocarya species such as Cryptocarya mandio-
canna,3 and C. moschata Lauraceae. Lactones isolated from
these species have been shown to exhibit several biological
activities such as anti-inflammatory,4 antiproliferative ac-
tivity,5 and inhibition of the growth of breast-cancer cell
lines.6
Thus, the interesting biological features and our ongoing
research on the synthesis of biologically active lactone-con-
taining natural products,7,8 prompted us to explore the syn-
thesis of cryptomoscatone F1 (1). Earlier we reported the
synthesis of cryptomoscatone D2 (4), cryptomoscatone E1
(2), and (+)-cryptofolione (5).8 Sabitha and Raju reported
the first total synthesis of cryptomoscatone F1 (1)9 and
Ramesh et al. have also accomplished the synthesis of cryp-
tomoscatone F1.10 Herein we disclose a concise convergent
strategy for the synthesis of cryptomoscatone F1.
Brown's allylation
Still–Gennari
reaction
O
2
1
O
3
OH OH OH
21
101
51
71
81
4
61
41
6
11
31
91
5
1
cross-metathesis
O
TBSO
OTBS OH
O
+
7
8
TBSO
OH
O
OTBS
S
N
OH
S
9
10
Bn
O
S
O
N
OTBS
+
H
S
Bn
11
13
12
Scheme 1 Retrosynthetic analysis of cryptomoscatone F1
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

B
E. Srinivas et al.
Paper
Synthesis
O
O
O
OH OH
O
OH OH
O
OH OH
O
cryptomoscatone E1 (2)
cryptomoscatone D1 (3)
cryptomoscatone D2 (4)
O
O
O
OH OH
O
OH OH OH
OH OH
O
O
(+)-cryptofolione (5)
(+)-strictifolione (6)
cryptomoscatone F1 (1)
Figure 1 Natural products containing styrylpyrones
lowed by Brown’s asymmetric allylation for the creation of
an additional stereogenic center. Vinyl lactone 8 could be
obtained from the known TBS ether12 13 of homoallyl alco-
hol using key reactions such as Jacobsen’s kinetic resolu-
tion,13 Still–Gennari olefination,14 and finally lactonization.
Our forward synthesis towards the total synthesis of
cryptomoscatone F1 (1), started with titanium-mediated
asymmetric acetate aldol15b–e addition reaction between
trans-cinnamaldehyde (11) and (4S)-3-acetyl-4-benzylthi-
azolidine-2-thione (12)15a that produced column chromato-
graphically separable diastereomers 14a and 14b in a 9:1
ratio (Scheme 2), the acetate aldol product 14a was ob-
tained in 84% isolated yield with high diastereoselectivity.
Protection of the secondary hydroxy group in 14a as its cor-
responding TBS ether was accomplished by the treatment
with TBSOTf and 2,6-lutidine in dichloromethane at 0 °C to
afford 15 in 86% yield. Reductive cleavage of the chiral aux-
iliary in compound 15 was achieved using DIBAL-H at –78 °C
in dichloromethane to give an intermediate aldehyde that
was used directly in the next step without further purifica-
tion. Iteration of the acetate aldol reaction with aldehyde,
obtained in the previous step, was carried out with auxilia-
ry 12 in a similar way to afford 9a as the major diastereo-
mer (9a/9b 9:1 after chromatographic separation) in 78%
yield over two steps. The secondary hydroxy group in com-
pound 9a was protected as its TBS ether to obtain 16 in 88%
yield. Reductive removal of chiral auxiliary with DIBAL-H
furnished aldehyde 17 in 90% yield, and the aldehyde was
OH
O
OH
O
S
S
TiCI4, DIPEA
CH2Cl2, 12
N
N
+
11
S
S
0 °C to –78 °C
10 min, 93%
dr 9:1
14b
anti (9%)
14a
syn (84%)
Bn
Bn
2,6-lutidine
TBS–OTf
CH2Cl2, 0 °C to r.t.
10 min, 86%
OTBS O
S
O
S
TBSO
OH
O
S
1. DIBAL-H, CH2Cl2
–78 °C,15 min
N
N
S
N
S
S
2. 12, TiCI4, DIPEA
CH2Cl2, 0 °C to –78 °C
10 min, 78% (2 steps)
9a
syn:anti = 9:1
Bn
Bn
15
12
Bn
+ 9b
2,6-lutidine
TBS–OTf
CH2Cl2, 0 °C to r.t.
10 min, 88%
TBSO
OTBS O
TBSO
OTBS O
S
(–)-Ipc2B(allyl)
Et2O, –100 °C, 1 h, 88%
DIBAL-H, CH2Cl2
7
H
N
S
–78 °C,15 min, 90%
17
16
Bn
Scheme 2 Synthesis of key intermediate 7
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

C
E. Srinivas et al.
Paper
Synthesis
TBSCl, imidazole
CH2Cl2, 0 °C to r.t.
OH
OTBS
HF•Py, THF
0 °C to r.t., 8 h
OTBS
OTBS
2 h, 92%
82%
18
19
O
OTBS
1. DMP, CH2Cl2
OTBS
0 °C to r.t., 1 h
O
PTSA, benzene
r.t., 6 h, 75%
OH
2. NaH, THF
MeO
20
O
(CF3CH2O)2POCH2CO2Me
–78 °C, 1 h, 80%
8
10
Scheme 3 Synthesis of vinyl lactone
O
O
OTBS OTBS OH
O
OH OH OH
O
2 M HCl, THF
r.t., 1 h, 84%
Grubbs II
7
8
+
CH2Cl2, reflux
4 h, 76%
21
1
Scheme 4 Synthesis of cryptomoscatone F1
subjected to Brown’s asymmetric allylation16 with (–)-B-
allyldiisopinocampheylborane [(–)-Ipc2B(allyl)] in Et2O at
–100 °C to give the desired key intermediate 7 in 88% yield
as a single diastereomer.
tion, and olefin cross-metathesis as key steps with an over-
all yield of 25%.
Vinyl lactone 8, the cross-metathesis partner of 7, was
synthesized from the known chiral allyl alcohol 1812
(Scheme 3). Compound 18 was protected as its TBS ether
using TBSCl and imidazole in CH2Cl2 to give disilylated com-
pound 19 in 92% yield. The selective deprotection17 of pri-
mary TBS ether was carried out with HF·Py in THF to afford
primary alcohol 10 in 82% yield. Dess–Martin periodinane
(DMP) oxidation of alcohol 10 gave the corresponding alde-
hyde, which was directly subjected to Still–Gennari reac-
tion with methyl P,P-bis(2,2,2-trifluoroethyl) phosphono-
acetate and NaH to furnish cis-olefinic ester 20 in 80% yield
over two steps. Cyclization of the ester 20 was carried out
with PTSA in benzene to afford vinyl lactone 8 in 75%
yield.18
Unless otherwise mentioned, all reactions were carried out under an
inert atmosphere of argon or N2 using standard syringe, septa, and
cannula techniques. Commercial reagents were used without further
purification. All solvents were purified by standard techniques. IR
spectra were recorded with a Perkin-Elmer 683 spectrophotometer
with NaCl optics and the spectra were calibrated against the polysty-
rene absorption at 1610 cm–1. Samples were scanned neat, as KBr wa-
fers, or as a thin film in CHCl3. Optical rotations were obtained with a
Jasco DIP-360 digital polarimeter. NMR spectra were recorded in
CDCl3 with a Bruker 300, Varian Unity 500 NMR spectrometer. Col-
umn chromatographic separations were carried out on silica gel (60–
120 mesh). Mass spectra were obtained on a Finnigan MAT1020B or
micro mass VG 70-70H spectrometer operating at 70 eV using a direct
inlet system.
(4S)-4-Benzyl-3-[(3R,4E)-3-hydroxy-5-phenylpent-4-enoyl]thiazo-
With the two key fragments 7 and 8 in hand, the next
concern was to couple them by olefin cross-metathesis re-
action (Scheme 4). Thus, the cross-metathesis reaction be-
tween olefins 7 and 8 (1:4) ratio in the presence of Grubbs
II catalyst in CH2Cl2 at reflux for 4 hours gave the desired
α,β-unsaturated δ-lactone 21 in 76% yield. Finally, the silyl
groups in lactone 21 were deprotected upon treatment
with 2 M HCl in THF to afford cryptomoscatone F1 (1) in
84% yield. The 1H NMR and 13C NMR spectra and optical ro-
tation were found to be identical with the data from the lit-
erature.9,10
lidine-2-thione (14a)
To a stirred solution of (4S)-3-acetyl-4-benzylthiazolidine-2-thione
(12, 3.0 g, 11.95 mmol) in CH2Cl2 (40 mL) at 0 °C was added TiCl4 (1.57
mL, 14.34 mmol) dropwise. The yellow thick suspension was stirred
for 10 min, and then DIPEA (2.4 mL, 14.34 mmol) was added drop-
wise at 0 °C. The mixture was stirred for 10 min at 0 °C, then cooled to
–78 °C followed by the addition of freshly distilled trans-cinnamalde-
hyde (11, 1.6 mL, 11.95 mmol) in CH2Cl2 (15 mL). The mixture was
stirred for 10 min, quenched with sat. NH4Cl and warmed to r.t. The
layers were separated and the aqueous layer was extracted with
CH2Cl2 (2 × 30 mL). The combined organic layers were dried (anhyd
Na2SO4), filtered, and concentrated under reduced pressure. The
crude product was purified by flash column chromatography (silica
gel, 5% EtOAc–hexane) to furnish aldol product 14a (3.87 g, 84%) as a
yellow liquid and 14b (0.39 g, 9%) as a yellow liquid; [α]D25 +128.2 (c
1.34, CHCl3).
In conclusion, we have achieved a short and convergent
synthesis of cryptomoscatone F1 in 9 steps involving asym-
metric acetate aldol reactions, Brown’s asymmetric allyla-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

D
E. Srinivas et al.
Paper
Synthesis
IR (neat): 3391, 3026, 1688, 1344, 1162, 749, 698 cm–1
.
tered, and concentrated under reduced pressure. The crude product
was purified by column chromatography (silica gel, 5% EtOAc–hex-
ane) to give 9a as yellow solid (2.2 g, 78%, 2 steps); mp 92–93 °C; the
diastereomer 9b was also obtained (0.2 g, 7%, two steps); [α]D25 –10.6
(c 0.48, CHCl3).
1H NMR (500 MHz, CDCl3): δ = 7.37–7.14 (m, 10 H), 6.65 (d, J = 15.4
Hz, 1 H), 6.24 (dd, J = 5.8, 15.4 Hz, 1 H), 5.36 (m, 1 H), 4.83 (br m, 1 H),
3.69 (dd, J = 17.3, 2.9 Hz, 1 H), 3.34–3.44 (m, 2 H), 3.24 (dd, J = 3.8,
12.5 Hz, 1 H), 3.04 (dd, J = 1.9, 10.6 Hz, 1 H), 2.88 (d, J = 11.5 Hz, 1 H).
IR (KBr): 3486, 2953, 2930, 2856, 1689, 1258, 1161, 835, 751 cm–1
.
13C NMR (75 MHz, CDCl3): δ = 201.3, 172.4, 136.4, 136.3, 130.6, 129.8,
129.4, 129.0, 128.5, 127.8, 127.3, 126.5, 68.6, 68.3, 45.7, 36.8, 32.1.
MS (ESI): m/z = 406 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C21H21NO2S2Na: 406.0911; found:
406.0906.
1H NMR (300 MHz, CDCl3): δ = 7.48–7.15 (m, 10 H), 6.54 (d, J = 15.9
Hz, 1 H), 6.17 (dd, J = 15.9, 7.3 Hz, 1 H), 5.39 (ddd, J = 10.6, 7.1, 3.9 Hz,
1 H), 4.59 (dd, J = 13.2, 7.0 Hz, 1 H), 4.43 (dd, J = 17.4, 9.6 Hz, 1 H),
3.71–3.14 (m, 5 H), 3.13–2.95 (m, 1 H), 2.88 (d, J = 11.6 Hz, 1 H), 1.99–
1.83 (m, 1 H), 1.75 (ddd, J = 14.0, 5.5, 3.2 Hz, 1 H), 0.92 (s, 9 H), 0.10
(m, 6 H).
13C NMR (75 MHz, CDCl3 ): δ = 201.2, 172.4, 136.5, 136.4, 132.0, 130.1,
129.4, 128.8, 128.5, 127.6, 127.2, 126.4, 73.3, 68.3, 66.4, 46.1, 44.2,
40.1, 36.7, 32.0, 25.8, 18.0, –3.9, –4.8.
(4S)-4-Benzyl-3-[(3R,4E)-3-(tert-butyldimethylsiloxy)-5-phenyl-
pent-4-enoyl]thiazolidine-2-thione (15)
2,6-Lutidine (1.3 mL, 11.2 mmol) was added to a solution of alcohol
14a (3.3 g, 8.62 mmol) in anhyd CH2Cl2 (35 mL) at 0 °C. After 5 min,
TBSOTf (3.0 mL, 12.92 mmol) was added dropwise and the mixture
was stirred at 0 °C for 5 min. The mixture was quenched with sat.
NaHCO3 solution. The layers were separated and the aqueous layer
was extracted with CH2Cl2 (2 × 30 mL). The combined organic layers
were washed with brine solution, dried (anhyd Na2SO4), filtered, and
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, 2% EtOAc–hexane) to give 15 (3.7
g, 86%) as a yellow solid; mp 78–79 °C; [α]D25 +165.2 (c 1.28, CHCl3).
MS (ESI): m/z = 564 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C29H39NO3S2SiNa: 564.2038; found:
564.2034.
(3S,5R,E)-1-[(S)-4-Benzyl-2-thioxothiazolidin-3-yl]-3,5-bis(tert-
butyldimethylsiloxy)-7-phenylhept-6-en-1-one (16)
2,6-Lutidine (0.28 mL, 2.41 mmol) was added to a solution of alcohol
9a (1 g, 1.85 mmol) in anhyd CH2Cl2 (10 mL) at 0 °C. After 15 min,
TBSOTf (0.64 mL, 2.78 mmol) was added dropwise and the mixture
was stirred at 0 °C for 5 min. The mixture was quenched by the addi-
tion of sat. NaHCO3 solution. The layers were separated and the aque-
ous layer was extracted with CH2Cl2 (2 × 30 mL). The combined organ-
ic layers were washed with brine solution, dried (anhyd Na2SO4), fil-
tered, and concentrated under reduced pressure. The residue was
purified by column chromatography (silica gel, 2% EtOAc–hexane) to
give 16 (1.07 g, 88%) as a yellow liquid; [α]D25 +116.4 (c 0.44, CHCl3).
IR (KBr): 3453, 2953, 2929, 2855, 1697, 1255, 1161, 834 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.38–7.16 (m, 10 H), 6.56 (d, J = 15.8
Hz, 1 H), 6.21 (dd, J = 6.8, 15.8 Hz, 1 H), 5.21 (m, 1 H), 4.97–4.86 (m, 1
H), 3.80–3.69 (m, 1 H), 3.36–3.16 (m, 3 H), 3.02 (dd, J = 2.3, 10.6 Hz, 1
H), 2.86 (d, J = 11.3 Hz, 1 H), 0.89 (s, 9 H), 0.11 (s, 3 H), 0.08 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 201.1, 171.3, 136.5, 131.7, 129.8, 129.3,
128.8, 128.5, 127.5, 127.1, 126.4, 70.5, 68.6, 46.7, 36.5, 32.1, 25.7,
18.0, –4.2, –4.9.
IR (KBr): 2955, 2928, 2854, 1703, 1364, 1255, 1157, 1070, 834 cm–1
.
MS (ESI): m/z = 520 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C27H35NO2S2SiNa: 520.1776; found:
1H NMR (300 MHz, CDCl3): δ = 7.44–7.19 (m, 10 H), 6.54 (d, J = 15.9
Hz, 1 H), 6.19 (dd, J = 15.9, 6.7 Hz, 1 H), 5.24 (ddd, J = 10.6, 6.9, 3.8 Hz,
1 H), 4.55–4.44 (m, 1 H), 4.39 (dd, J = 12.8, 6.4 Hz, 1 H), 3.69–3.53 (m,
1 H), 3.38–3.19 (m, 3 H), 3.03 (dd, J = 13.0, 10.8 Hz, 1 H), 2.86 (d, J =
11.5 Hz, 1 H), 1.92 (td, J = 13.4, 6.7 Hz, 1 H), 1.82–1.69 (m, 1 H), 0.92
(d, J = 2.9 Hz, 9 H), 0.86 (s, 9 H), 0.11 (m, 6 H), 0.06 (m, 6 H).
520.1779.
(3S,5R,E)-1-[(S)-4-Benzyl-2-thioxothiazolidin-3-yl]-5-(tert-butyl-
dimethylsiloxy)-3-hydroxy-7-phenylhept-6-en-1-one (9a)
To a stirred solution of 15 (2.7 g, 5.42 mmol) in anhyd CH2Cl2 (35 mL)
at –78 °C was added a 25 wt% solution of DIBAL-H in toluene (7.3 mL,
10.84 mmol) dropwise over 10 min and the mixture was stirred at
–78 °C for 10 min. The mixture was quenched with sat. aq sodium po-
tassium tartrate solution (10 mL) and the mixture was stirred vigor-
ously at r.t. for a further 1 h. The layers were separated and the aque-
ous layer was extracted with CH2Cl2 (2 × 30 mL). The combined or-
ganic layers were washed with brine solution, dried (anhyd Na2SO4),
filtered, and concentrated under reduced pressure to give the crude
aldehyde, which was used in the next step without further purifica-
tion.
13C NMR (75 MHz, CDCl3): δ = 201.0, 172.0, 136.9, 136.6, 132.7, 129.6,
129.4, 128.9, 128.5, 127.4, 127.2, 126.4, 70.8, 68.7, 66.7, 46.4, 46.2,
36.5, 32.2, 25.9, 25.8, 18.2, 18.0, –4.1, –4.3, –4.5, –4.7.
MS (ESI): m/z = 679 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C35H53NO3S2Si2Na: 678.2903; found:
678.2891.
(4S,6R,8R,E)-6,8-Bis(tert-butyldimethylsiloxy)-10-phenyldeca-1,9-
dien-4-ol (7)
A 25% solution of DIBAL-H in toluene (1.6 mL, 2.38 mmol) was slowly
added over 5 min to a stirred solution of 16 (0.78 g, 1.19 mmol) in
anhyd CH2Cl2 (10 mL) at –78 °C, and the mixture was stirred at –78 °C
for 10 min. After completion of the reaction, sat. aq potassium sodium
tartrate solution (5 mL) was added and the mixture was stirred vigor-
ously at r.t. for additional 1 h. The mixture was then extracted with
CH2Cl2 (2 × 15 mL) and the combined organic layers were washed
with brine solution (20 mL), dried (Na2SO4), and concentrated under
reduced pressure. The crude product was purified by flash column
chromatography (silica gel, 3% EtOAc–hexane) to give 17 (0.48 g, 90%)
as a clear liquid.
To a stirred solution of (4S)-3-acetyl-4-benzylthiazolidine-2-thione
(12, 1.45 g, 5.78 mmol) in CH2Cl2 (25 mL) at 0 °C was added TiCl4 (0.7
mL, 6.35 mmol) dropwise. The thick yellow suspension was stirred for
10 min and then DIPEA (1.1 mL, 6.35 mmol) was added dropwise at
0 °C. The dark red solution was stirred for 10 min at 0 °C and then
cooled to –78 °C. To the mixture was added a solution of the aldehyde
(1.5 g, 5.78 mmol) in CH2Cl2 (15 mL). The mixture was stirred for 15
min and then it was quenched with sat. aq NH4Cl solution. The layers
were separated and the aqueous layer was extracted with CH2Cl2 (3 ×
30 mL). The combined organic layers were dried (anhyd Na2SO4), fil-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

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E. Srinivas et al.
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Synthesis
To a stirred solution of 1.0 M solution of (–)-Ipc2B(allyl) in pentane
(0.6 mL, 0.62 mmol) and anhyd Et2O (3 mL) at –100 °C was added a
solution of the aldehyde 17 (0.250 g, 0.56 mmol) in Et2O (5 mL) drop-
wise. The mixture was stirred at –100 °C for 1 h and then warmed to
0 °C. The mixture was quenched by dropwise addition of 30% aq H2O2
(1 mL) and 1 M aq NaOH (1 mL). The layers were separated and the
aqueous layer was extracted with EtOAc (2 × 10 mL) and the com-
bined organic layers were washed with brine solution (6 mL), dried
(Na2SO4), filtered, and concentrated under vacuum. The crude prod-
uct was purified by column chromatography (silica gel, 5% EtOAc–
13C NMR (75 MHz, CDCl3): δ = 140.5, 114.3, 73.2, 60.0, 39.1, 25.8, –4.4,
–5.0.
MS (ESI): m/z = 217 [M + H]+.
HRMS: m/z [M + H]+ calcd for C11H25O2Si: 217.1618; found: 217.1613.
Methyl (Z,R)-5-(tert-Butyldimethylsiloxy)hepta-2,6-dienoate (20)
To a stirred solution of alcohol 10 (0.24 g, 1.11 mmol) in dry CH2Cl2 (4
mL) was added Dess–Martin periodinane (0.710 g, 1.66 mmol) at 0 °C,
and the mixture was stirred for 1 h at r.t. The mixture was quenched
with sat. Na2S2O3 and NaHCO3 solns (1:1 mixture, 5 mL) and extract-
ed with CH2Cl2 (2 × 5 mL). The combined organic layers were washed
with H2O (10.0 mL) and brine (10.0 mL), dried (Na2SO4), and concen-
trated to furnish the corresponding aldehyde as a yellow liquid, which
was directly used in the next reaction.
25
hexane) to give 7 (0.24 g, 88%) as a clear liquid; [α]D +18.6 (c 0.46,
CHCl3).
IR (KBr): 3453, 2953, 2931, 2857, 1070, 834, 773 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.42–7.18 (m, 5 H), 6.48 (d, J = 15.9 Hz,
1 H), 6.13 (dd, J = 15.9, 6.9 Hz, 1 H), 5.83 (ddt, J = 17.2, 10.2, 7.1 Hz, 1
H), 5.11 (ddd, J = 9.9, 2.6, 1.5 Hz, 2 H), 4.37–4.27 (m, 1 H), 4.18–4.08
(m, 1 H), 3.89–3.79 (m, 1 H), 3.35 (s, 1 H), 2.33–2.17 (m, 2 H), 1.94–
1.82 (m, 2 H), 1.65 (ddd, J = 14.7, 9.2, 4.7 Hz, 1 H), 1.52 (dt, J = 14.3, 9.2
Hz, 1 H), 0.91 (s, 9 H), 0.90 (s, 9 H), 0.13 (s, 6 H), 0.06 (s, 3 H), 0.03 (m,
3 H).
13C NMR (75 MHz, CDCl3): δ = 136.7, 134.9, 132.8, 129.5, 128.5, 127.5,
126.3, 117.2, 71.0, 68.8, 67.7, 44.5, 42.3, 40.2, 25.8, 25.7, 18.1, 17.9, –3.9,
–4.6, –4.8, –4.9.
To a stirred solution of (CF3CH2O)2POCH2CO2Me (0.5 mL, 2.21 mmol)
in anhyd THF (3 mL) was added NaH (66 mg, 1.66 mmol) at –78 °C.
The temperature was raised to 0 °C and the mixture was stirred for
0.5 h. To the mixture, the aldehyde (0.237 g, 1.11 mmol) dissolved in
THF (3 mL) was added at –78 °C. The mixture was stirred for 1 h,
quenched with sat. NH4Cl solution (5 mL), and extracted with EtOAc
(2 × 8 mL). The combined organic layers were washed with brine (10
mL), dried (Na2SO4), concentrated, and purified by column chroma-
tography (silica gel, 5% EtOAc–hexane) to give 20 (0.24 g, 80% over 2
steps) as a yellow syrup; [α]D25 –9.6 (c 1.5, CHCl3).
MS (ESI): m/z = 513 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C28H50O3Si2Na: 513.3196; found:
513.3178.
1H NMR (500 MHz, CDCl3): δ = 6.34 (dt, J = 7.1, 4.4 Hz, 1 H), 5.88–5.76
(m, 2 H), 5.20 (dt, J = 3.2, 1.5 Hz, 1 H), 5.07 (dt, J = 3.0, 1.5 Hz, 1 H),
4.29–4.19 (m, 1 H), 3.71 (s, 3 H), 2.90–2.84 (m, 2 H), 0.89 (s, 9 H), 0.05
(s, 3 H), 0.04 (s, 3 H).
(R)-1,3-Bis(tert-butyldimethylsiloxy)pent-4-ene (19)
To a stirred solution of alcohol 18 (1.2 g, 5.55 mmol) in CH2Cl2 (12 mL)
at 0 °C, imidazole (0.75 g, 11.11 mmol) and TBSCl (0.91 g, 6.11 mmol)
were added and the mixture was stirred for 2 h at r.t. The mixture
was diluted with CH2Cl2 and washed with water (20 mL), brine solu-
tion (15 mL), dried (Na2SO4), and concentrated under reduced pres-
sure. The crude residue was purified by column chromatography (sil-
ica gel, 4% EtOAc–hexane) to furnish bis(silyl ether) 19 (1.68 g, 92%) as
a colorless liquid; [α]D25 –2.5 (c 1, CHCl3).
1H NMR (500 MHz, CDCl3): δ = 5.86–5.76 (m, 1 H), 5.18–4.99 (m, 2 H),
4.27 (q, J = 6.1 Hz, 1 H), 3.72–3.60 (m, 2 H), 1.76–1.60 (m, 2 H), 0.89 (s,
18 H), 0.07–0.02 (m, 12 H).
13C NMR (125 MHz, CDCl3): δ = 141.6, 113.5, 70.7, 59.4, 41.1, 29.7,
25.9, 25.8, –4.4, –4.9, –5.3.
MS (ESI): m/z = 331 [M + H]+.
HRMS: m/z [M + H]+ calcd for C17H39O2Si2: 331.2488; found: 331.2475.
13C NMR (75 MHz, CDCl3): δ = 166.7, 146.3, 140.7, 120.5, 114.2, 72.5,
50.9, 37.1, 29.6, 25.7, –4.5, –4.9.
MS (ESI): m/z = 271 [M + H]+.
HRMS: m/z [M + H]+ calcd for C14H27O3Si: 271.1729; found: 271.1718.
(R)-6-Vinyl-5,6-dihydro-2H-pyran-2-one (8)
To a stirred solution of 20 (0.25 g, 0.925 mmol) in distilled benzene
was added a catalytic amount of PTSA and the mixture was stirred at
r.t. for 6 h. Solid NaHCO3 (0.02 g) was added to quench the PTSA and
the mixture was extracted with EtOAc (2 × 10 mL). The combined or-
ganic layers were dried (Na2SO4), concentrated, and purified by col-
umn chromatography (silica gel, 20% EtOAc–hexane) to afford vinyl
lactone 8 (0.086 g, 75%) as a yellow liquid; [α]D25 +91.3 (c 0.3, CHCl3).
IR (neat): 1726, 1463, 1284, 1214 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 6.92–6.86 (m, 1 H), 6.08–6.04 (m, 1 H),
6.0–5.92 (m, 1 H), 5.41 (m, 1 H), 5.30 (m, 1 H), 4.97–4.90 (m, 1 H),
2.50–2.42 (m, 2 H).
(R)-3-(tert-Butyldimethylsiloxy)pent-4-en-1-ol (10)
To a stirred solution of 19 (1.5 g, 4.53 mmol) in THF (15 mL) at 0 °C
was added HF·Py in THF (0.68 mL, 4.53 mmol) and the mixture was
stirred for 8 h at r.t. The mixture was quenched with sat. NaHCO3
solution (15 mL). The layers were separated and the aqueous layer
was extracted with EtOAc (2 × 10 mL). The organic extract was
washed with brine solution (10 mL), dried (Na2SO4), concentrated,
and purified by column chromatography (silica gel, 6% EtOAc–hex-
13C NMR (75 MHz, CDCl3): δ = 163.7, 144.3, 134.8, 121.6, 117.8, 77.7,
29.3.
MS (ESI): m/z = 125 [M + H]+.
HRMS: m/z [M + H]+ calcd for C7H9O2: 125.0602; found: 125.0595.
(R)-6-[(1E,4S,6R,8R,9E)-6,8-Bis(tert-butyldimethylsiloxy)-4-hy-
droxy-10-phenyldeca-1,9-dien-1-yl]-5,6-dihydro-2H-pyran-2-one
(21)
25
ane) to afford 10 (0.8 g, 82%) as a colorless liquid; [α]D +5.6 (c 0.5,
CHCl3).
1H NMR (300 MHz, CDCl3): δ = 5.91–5.78 (m, 1 H), 5.26–5.10 (m, 2 H),
4.45–4.39 (m, 1 H), 3.87–3.78 (m, 1 H), 3.76–3.68 (m, 1 H), 2.49 (br s,
1 H), 1.90–1.80 (m, 1 H), 1.76–1.68 (m, 1 H), 0.90 (s, 9 H), 0.10 (s, 3 H),
0.06 (s, 3 H).
To a stirred solution of homoallylic alcohol 7 (0.04 g, 0.082 mmol) and
vinyl lactone 8 (0.04 g, 0.326 mmol) in dry CH2Cl2 under argon atmo-
sphere, Grubbs II catalyst (7 mg, 10 mol%) was added. The resulting
mixture was stirred at reflux for 4 h. After completion of the reaction,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

F
E. Srinivas et al.
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Synthesis
the solvent was evaporated and the crude residue was purified by col-
umn chromatography (silica gel, 15% EtOAc–hexane) to afford 21
(0.036 g, 76%) as a dark brown oil; [α]D25 +56.2 (c 2.0, CHCl3).
References
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IR (KBr): 3486, 2953, 2930, 2856, 1689, 1258, 1161, 835, 751 cm–1
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1H NMR (300 MHz, CDCl3): δ = 7.45–7.19 (m, 5 H), 6.93–6.82 (m, 1 H),
6.49 (d, J = 15.9 Hz, 1 H), 6.20–6.00 (m, 2 H), 5.97–5.82 (m, 1 H), 5.69
(dd, J = 15.5, 6.6 Hz, 1 H), 4.88 (dd, J = 14.5, 7.3 Hz, 1 H), 4.35–4.16 (m,
2 H), 4.05 (s, 1 H), 3.70 (dd, J = 13.8, 6.1 Hz, 1 H), 2.44 (dd, J = 8.1, 3.7
Hz, 2 H), 2.37–2.19 (m, 3 H), 2.02–1.75 (m, 3 H), 0.90 (d, J = 1.2 Hz, 18
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129.3, 128.6, 127.6, 126.4, 121.6, 78.0, 71.0, 69.0, 67.8, 44.4, 40.8,
40.5, 29.7, 25.9, 25.8, 18.1, 17.9, –3.9, –4.6, –4.7, –4.8.
MS (ESI): m/z = 609 [M + Na]+.
HRMS: m/z [M + Na]+ calcd for C33H54O5Si2Na: 609.3427; found:
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Cryptomoscatone F1 (1)
To a stirred solution of lactone 21 (15 mg, 0.026 mmol) in THF (1 mL)
at 0 °C was added a few drops of 2 M HCl. The mixture was warmed to
r.t. and then stirred for 1 h. The reaction was then quenched with sat.
NaHCO3 solution and layers were separated. The aqueous layer was
extracted with EtOAc (2 × 5 mL) and the combined organic layers
were washed with brine solution, dried (Na2SO4), filtered, concentrat-
ed under reduced pressure, and the residue was purified by column
chromatography (silica gel, 75% EtOAc–hexane) to give 1 (7 mg, 84%)
as a brown liquid; [α]D25 +31.4 (c 0.64, CHCl3) {Lit.9 [α]D25 +35.0 (c 1.0,
CHCl3)}.
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IR (neat): 3402, 2930, 2856, 1713, 1384, 1258, 1054, 751 cm–1
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1H NMR (300 MHz, CDCl3): δ = 7.43–7.21 (m, 5 H), 6.89 (ddd, J = 13.8,
9.6, 4.2 Hz, 1 H), 6.61 (d, J = 15.9 Hz, 1 H), 6.23 (dd, J = 15.9, 6.5 Hz, 1
H), 6.07–6.02 (m, 1 H), 5.93–5.85 (m, 1 H), 5.70 (dd, J = 15.4, 6.4 Hz, 1
H), 4.91 (dd, J = 14.9, 6.5 Hz, 1 H), 4.60 (t, J = 7.0 Hz, 1 H), 4.34–4.27
(m, 1 H), 4.05 (dd, J = 14.4, 9.4 Hz, 1 H), 2.47–2.41 (m, 2 H), 2.30 (dd,
J = 15.2, 7.9 Hz, 2 H), 1.87 (dt, J = 14.4, 10.1 Hz, 1 H), 1.74–1.65 (m, 3
H).
13C NMR (75 MHz, CDCl3): δ = 164.0, 144.7, 136.5, 131.6, 131.1, 130.3,
129.9, 128.6, 127.8, 126.5, 121.6, 77.8, 73.8, 70.0, 68.1, 42.9, 42.3,
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MS (ESI): m/z = 358 [M + H]+.
HRMS: m/z [M + H]+ calcd for C21H26O5: 358.2014; found: 358.2007.
Acknowledgement
E.S. thanks the University Grants Commission (UGC), New Delhi and
P.D. and B.G. thank the Council of Scientific and Industrial Research
(CSIR), New Delhi for the award of fellowships. J.S.Y. thanks CSIR and
Department of Science and Technology (DST), New Delhi for the Bhat-
nagar and J. C. Bose Fellowships, respectively.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-16561394.
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Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G