Studies towards the Total Synthesis of Kadcotrione B

Article abstract of DOI:10.1055/s-0039-1691494

A convergent and efficient approach towards the total synthesis of Kadcotrione B is described. For this purpose, the syntheses of two fragments, 6/6/5-fused tricyclic ring and C-9 side chain, were accomplished. The salient features of these syntheses are

Full text of DOI:10.1055/s-0039-1691494

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–I
paper
A
en
J. S. Reddy et al.
Paper
Synthesis
Studies towards the Total Synthesis of Kadcotrione B
Julakanti Satyanarayana Reddy*a,1
O
H
O
Kadsura coccinea
rich source of Kadcotrione B
Marri Gangababua
Patel Manimalaa
Aluru Rammohana,b
Jillu Singh Yadava
HWE olefination
HOOC
O
Intramolecular
aldol condensation
O
BnO
H
Evans aldol
2-methylcyclohexane-
1,3-dione
+
OBn
O
Michael addition
HO
OH
H
a Division of Natural Products Chemistry, CSIR-Indian
Institute of Chemical Technology, Hyderabad
500007, Telangana, India
sjsnreddy@gmail.com
b Department of Chemistry, Sri Venkateswara
University, Tirupati 517502, Andhra Pradesh, India
1,5-pentanediol
O
O
H
Kadcotrione B
Used in Chinese
traditional medicine
Robinson Annulation
Reported as
Anti HIV active
HOOC
Received: 08.09.2019
Accepted after revision: 05.11.2019
Published online: 21.11.2019
DOI: 10.1055/s-0039-1691494; Art ID: ss-2019-z0513-op
O
O
H
O
O
Abstract A convergent and efficient approach towards the total syn-
thesis of Kadcotrione B is described. For this purpose, the syntheses of
two fragments, 6/6/5-fused tricyclic ring and C-9 side chain, were ac-
complished. The salient features of these syntheses are the utilization of
aldol condensation, Evans aldol reaction, Horner–Wadsworth–Emmons
olefination, Michael addition, Robinson annulation, and Wacker oxida-
tion.
C
C
B
B
A
A
H
O
O
COOH
H
H
Kadcotrione C (2)
Kadcotrione B (1)
Figure 1 Structures of Kadcotrione B and C
Key words aldol condensation, diastereoselectivity, Hagiwara–
Weiland–Miescher ketone, Horner–Wadsworth–Emmons reaction,
Kadcotrione, Michael addition
terparts.3,9 The unprecedented lanostane triterpenoids con-
tain the tricyclic core with four stereocenters and two
consecutive centers on ring-C in an unusual position.
Hence, synthesis of these architecturally complex and bio-
logically active yet naturally scarce anti-HIV compounds
have urged interest in the synthetic chemistry community.
Considering the growing importance of this family of
molecules and our continuing efforts in the synthesis of
complex natural products with promising biological activi-
ties,10 herein we describe the synthesis of 6/6/5 fused tricy-
clic ring 3 and the C-9 side-chain 4 of Kadcotrione B, by an
efficient approach involving Michael addition, Wacker oxi-
dation, Robinson annulation, Evans aldol reaction, and
Horner–Wadsworth–Emmons olefination utilizing easily
accessible starting materials 2-methylcyclohexane-1,3-di-
one and 1,5-pentanediol.
The retrosynthetic analysis of Kadcotrione B, as shown
in Scheme 1, is envisaged from fragments 3 and 4 through
Michael addition. The fragment 3 could be obtained via in-
tramolecular aldol condensation followed by methylation
from the diketone 5. The compound 5 is obtained from 6 via
allylation followed by Wacker oxidation. We hypothesized
that ketone 6, could be derived from commercially available
2-methylcyclohexane-1,3-dione (7) through sequential
transformations including Birch reduction, and Michael ad-
dition followed by Robinson annulation. The compound 4,
The novel Kadcotrione B and Kadcotrione C (Figure 1)
are uniquely rearranged lanostane triterpenoids and were
isolated from the stems of Kadsuracoccinea by Sun and co-
workers in 2013, exhibiting anti-HIV-1 activities with EC50
values of 30.29 and 54.81 M respectively.2 However, they
belong to climbing plants of the Schisandraceae family, con-
taining two genera Schisandra and Kadsura. There are about
50 plant species of this kind around the world, mainly dis-
tributed Southeast Asia and North America.3 So far they
have been used in folk medicines for many years in China
and known as ‘wu weizi’ and ‘nan wu Wei zi’.4 The lanos-
tane and cycloartane type triterpenoids from Schisandrace-
ae family show tremendous biological activities including
antihepatitis,5 antitumor,6 and anti-HIV-1.2,7 Moreover,
some species of this family are used as an essential material
in the food and beverage industries such as wine, juice, jelly,
etc., for maintaining good health.8
Structurally, Kadcotrione B and C are composed of a
6/6/5-fused tricyclic ring system and a C-9 side chain. Their
structures were elucidated by NMR and electronic circular
dichroism spectroscopic methods.2 Those results unexpect-
edly revealed a considerable structural diversity among la-
nostane type triterpenoids when compared to other coun-
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–I
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
J. S. Reddy et al.
Paper
Synthesis
was envisaged from amide 8, via a Weinreb amide forma-
tion followed by vinyl Grignard addition. Further, com-
pound 8 could be accessed from 1,5-pentanediol (9) follow-
ing general procedures.
triketone 10 was catalyzed by L-phenylalanine and D-cam-
phorsulfonic acid (D-CSA) to give the Hagiwara–Weiland–
Miescher ketone 11 in 83% yield with 95% ee. Regioselective
ketal protection of 11 was achieved with ethylene glycol
and a catalytic amount of p-toluenesulfonic acid (PTSA) us-
ing the Dean–Stark apparatus in benzene solvent to obtain
the ketal 12 in 90% yield. Birch reduction (reductive methyl-
ation) of compound 12 with Li, liquid NH3, and an excess
amount of methyl iodide (10 equiv) at lower temperatures
led to ,-dimethyl trans-decalone 13 in 65% yield.11 Com-
pound 13 was subjected to LiAlH4 to furnish the sec-alcohol
14 as a single isomer in 88% yield.12 Subsequently, the pro-
tection of sec-alcohol in 14 as its benzyl ether was achieved
by using optimal reaction conditions (NaH, BnBr) in a 94%
yield.13 The compound 15 underwent acid hydrolysis with 4
N HCl/THF (1:4) resulting in the ketone 6 in excellent yield.
HOOC
Intramolecular
aldol condensation
OBn
O
H
O
H
O
+
BnO
O
H
Michael addition
O
4
3
H
Wacker oxidation
Kadcotrione B (1)
HWE olefination
O
O
O
H
N
O
O
BnO
OBn
Ph
8
5
Evans aldol
Synthesis of 6/6/5-Fused Tricyclic Ring 3
O
O
After successful completion of decalone 6, we proceeded
towards the synthesis of the 6/6/5-tricyclic ring ketone 3
with the requisite stereochemistry. Thus, we initially fol-
lowed the protocol developed by Smith,14 a four-step syn-
thetic sequence in which the compound 6 reacted with
trimethylsilyl chloride and LDA in THF solvent to give the
corresponding enol ether. Further, the reaction with allyl
bromide and benzyltrimethylammonium fluoride (BTAF)
delivered the monoallyl ketone as a 1:1 epimeric mixture.
Then, treatment with K2CO3 in MeOH led to a more stable
equatorial isomer, finally undergoing Wacker oxidation in
the presence of CuCl and PdCl2 in oxygen atmosphere fur-
nishing the diketone 5 in 61% yield (4 steps).15 Subsequent-
ly, compound 5 underwent an internal aldol condensation
with NaH to afford tricyclic enone 16 in 75% yield.16 Then,
the installation of the methyl group at the -position to the
keto group of compound 16 with the opposite stereocenter
was done presenting the existing stereochemistry at ring
junction. Thus, compound 16 was reacted with LiHMDS and
methyl iodide to afford the desired compound 3 as a single
isomer in a stereoselective manner in 74% yield, which was
further structurally identified by X-ray crystallographic
analysis17 (Scheme 3).
BnO
HO
OH
O
7
9
6
Robinson annulation
Scheme 1 Retrosynthetic analysis of the 6/6/5-tricyclic fragment 3
and the C-9 aliphatic fragment 4 of Kadcotrione B
Synthesis of Decalone 6
Our initial synthetic strategy followed for the prepara-
tion of compound 6 is outlined in Scheme 2. Ethyl vinyl ke-
tone underwent Michael addition with commercially avail-
able diketone 7 in the presence of organic base triethyl-
amine to give the triketone 10 in 92% yield. Subsequently,
the construction of trans-decalone 11, was achieved by
adopting the method developed by Hagiwara.11 Thus, the
O
O
O
O
a
b
O
O
O
11
7
10
O
O
O
O
c
d
e
Synthesis of C-9 Side-Chain 4
O
O
The synthesis of aliphatic fragment 4, as shown in
Scheme 4, was pursued with commercially available 1,5-
pentanediol (9). Selective silyl protection on 1,5-pentanedi-
ol (9) gave the corresponding monosilyl ether. Further, ap-
plication of Swern oxidation furnished the aldehyde 17.
Then, the Z-isomer 19a was synthesized instead of its cor-
responding E-isomer 19b.18 Thus initially, we prepared the
Still–Gennari phosphonate 1819 and then, attempted the
Horner–Wadsworth–Emmons reaction of 17 with 18 to
give a separable mixture of ,-unsaturated ester 19a and
19b in 74% yield with excellent stereoselectivity (Z:E ~ 20:1,
determined by 1H NMR spectroscopy).20 The resultant
13
12
O
O
O
O
O
f
g
BnO
BnO
HO
14
6
15
Scheme 2 Synthesis of compound 6. Reagents and conditions: (a) ethyl
vinyl ketone, Et3N, EtOAc, 70 °C, 10 h, 92%; (b) L-phenylalanine, D-CSA,
DMF, 30 to 70 °C, 7 days, 83% (95% ee); (c) ethylene glycol, PTSA, ben-
zene, reflux, 12 h, 90%; (d) Li/liquid NH3, MeI, THF, –78 to –33 °C, 3 h,
65%; (e) LiAlH4, Et2O, –78 °C to rt, 24 h, 88%; (f) benzyl bromide, NaH,
DMF, 0 °C to rt, 12 h, 94%; (g) 4 N HCl/THF (1:4), 0 °C to rt, 6 h, 95%.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–I

C
J. S. Reddy et al.
Paper
Synthesis
,-unsaturated ester 19a underwent reduction with di-
isobutylaluminum hydride to afford the primary alcohol 20
in excellent yield. Compound 20 was then protected as its
benzyl ether using NaH and BnBr in THF. Further, it was
subjected to TBAF in THF to cleave the silyl group affording
21 in 77% yield (2 steps).
Subsequently, compound 21 was oxidized to aldehyde
under Swern oxidation conditions. Further, it was converted
into carboxylic acid 22 using NaH2PO4, NaClO2, and 2-meth-
yl-2-butene in the solvent mixture of tert-butyl alcohol and
water by adopting the method developed by Pinnick et al.21
Compound 22 was coupled with (R)-4-benzyloxazoli-
din-2-one (23) through mixed anhydride at –20 °C using
pivaloyl chloride (Piv-Cl), Et3N, and LiCl to provide the im-
ide 24 in a 87% yield. Diastereoselective methylation of 24
according to Evans protocol with LiHMDS and MeI afforded
the compound 8 in 80% yield as a 9:1 mixture of isomers
and later separated by column chromatography.22 Thereaf-
ter, removal of the chiral auxiliary by using LiOH and H2O2
was accomplished to give the corresponding acid in excel-
lent yield, which in turn was reacted with N,O-dimethylhy-
droxylamine to produce a Weinreb amide. Finally, this was
treated with vinylmagnesium bromide to obtain the desired
compound 4 in 62% yield (3 steps, Scheme 4).23
O
O
O
H
H
a,b,c,d
e
6
BnO
BnO
5
16
O
H
f
BnO
H
3
X-ray structure of 3
Attempted Synthesis of Compound 25
Scheme 3 Synthesis of compound 3. Reagents and conditions: (a) LDA,
TMSCl, THF, 0 °C → rt, 1 h; (b) BTAF, allyl bromide, THF, rt, 3 h;
(c) K2CO3, MeOH, rt, 3 h; (d) CuCl, PdCl2, O2, 12 h, DMF/H2O (9:1), 61%
(4 steps); (e) NaH, THF, 25 °C, 5 h; then, reflux 2 h, 75%; (f) LiHMDS,
HMPA, MeI, THF, –40 °C to 0 °C, 3.5 h, 74% [LDA: lithium diisopropyl-
amide; LiHMDS: lithium bis(trimethylsilyl)amide; HMPA: hexamethyl-
phosphoramide].
With the key fragments 3 and 4 in hand, we proceeded
to unite them through Michael addition and further elabo-
ration into Kadcotrione B (1) via a two-step sequence in-
cluding the deprotection of benzyl group, and oxidation of
primary and secondary alcohols in a single step. Thus ini-
tially, we attempted the coupling reaction of 3 and 4, ac-
cording to Michael addition with NaOEt as a base, which
unfortunately resulted in the decomposition of 4 (Scheme
5). Several other conditions were also investigated, but the
results are not fruitful yet (Table 1).16b,24 However, we
thought that the reason for the unsuccessful results of the
ref. 15
a
HO
OH
TBSO
O
9
17
TBSO
b
TBSO
O
O
OH
OBn
OBn
19a
20
Table 1 Attempted Reactions for the Michael Addition of 3 and 4
O
e, f
c, d
HO
HO
Entry
Reagent and conditions
Observations
OBn
21
22
1
2
3
4
5
6
NaOEt, THF, –30 to 0 °C, 12 h
t-BuOK, THF, –30 to 0 °C, 12 h
LDA, THF, –33 °C to rt, 10 h
KHMDS, THF, –78 to 0 °C, 6 h
NaHMDS, THF, –78 °C, 6 h
LiHMDS, THF, –78 °C, 6 h
decomposition of 4
O
O
O
O
–
–
–
–
–
h
g
N
N
O
O
OBn
8
Ph
24
Ph
O
O
O
O
O
F3CH2CO
i, j, k
NH
Ph
P
O
F3CH2CO
OBn
23
18
4
Scheme 4 Synthesis of compound 4; (a) 18, KHMDS, [18]-crown-6,
THF, –78 °C, 2 h, 74% (95:5); (b) DIBAL-H, CH2Cl2, 0 °C, 2 h, 96%; (c)
BnBr, NaH, THF, 0 °C → rt, 12 h, 90%; (d) TBAF, THF, 0 °C → rt, 6 h, 85%;
(e) (COCl)2, DMSO, Et3N, CH2Cl2, –78 °C, 2.5 h, 83%; (f) NaH2PO4, NaClO2,
2-methyl-2-butene, tert-butyl alcohol, 0 °C → rt, 12 h, 90%; (g) 23,
Et3N, Piv-Cl, LiCl, 0 °C, 4 h, 87%; (h) LiHMDS, MeI, –78 °C, 3.5 h, 80%
(95:5); (i) LiOH·H2O, H2O2, THF/H2O (4:1), 0 °C, 20 h, 97%; (j) N-meth-
ylpiperidine, isobutyl chloroformate, MeNH(OMe)·HCl, CH2Cl2, –15 °C,
22.5 h, 75%; (k) vinyl bromide, Mg, THF, 0 °C, 1 h, 85% [KHMDS: potassi-
um bis(trimethylsilyl)amide; DIBAL: diisobutyaluminum hydride; TBAF:
tetrabutylammonium fluoride].
BnO
for conditions
see Table 1
Kadcotrione B (1)
3
+ 4
O
H
O
BnO
H
25
Scheme 5 Attempted synthesis of compound 25
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–I

D
J. S. Reddy et al.
Paper
Synthesis
coupling reaction of 3 and 4 was due to steric crowding
posed by fused A, B rings of fragment 3. Further efforts to-
wards completion of the total synthesis of Kadcotrione B
are under investigation in our laboratory.
In conclusion, we have developed an efficient synthetic
route for the preparation of fused 6/6/5 tricyclic ring 3 and
C9-side chain 4 of Kadcotrione B using inexpensive starting
materials. The method is suitable for the synthesis of such
class of bioactive natural products in further research
works. In spite of our current best efforts, the Michael addi-
tion was not successful. Presently, completion of the total
synthesis of Kadcotrione B using this route is actively being
pursued in our laboratory.
warmed to 30 °C and stirred for 24 h and then warmed to 10 °C for
every 24 h intervals up to 4 days. After cooling to rt, the mixture was
poured into cold aq NaHCO3, and extracted with EtOAc (3 × 100 mL).
The combined extracts were washed with brine, dried (Na2SO4), and
concentrated under reduced pressure. The resulting residue was puri-
fied by column chromatography on silica gel eluting with EtOAc/hex-
ane (1:3) to afford the chiral enone 11 as a yellow oil; yield: 2.27 g
25
(83%); 95% ee; Rf = 0.46 (35% Et2O in hexane); []D +127.44 (c 1.64,
benzene).
IR (neat): 2949, 1710, 1666, 1610, 1452, 1310 cm–1
.
1H NMR (400 MHz, CDCl3):  = 2.87 (dtd, J = 16.0, 5.2, 1.2 Hz, 1 H),
2.72–2.64 (m, 1 H), 2.55–2.40 (m, 4 H), 2.18–2.04 (m, 3 H), 1.81–1.73
(m, 4 H), 1.42 (s, 3 H).
13C NMR (75 MHz, CDCl3):  = 211.9, 197.5, 158.1, 130.5, 50.4, 37.1,
33.1, 29.4, 27.0, 23.1, 21.3, 11.1.
ESI-MS: m/z = 215 [M + Na]+.
All moisture or oxygen-sensitive reactions were carried out under N2
atmosphere in oven-dried flasks. The reagents were purchased from
Sigma-Aldrich chemicals and solvents were used purified by distilla-
tion over the indicated drying agents: THF (Na), CH2Cl2 (CaH2), ace-
tone (CaSO4), benzene (Na), MeOH (Mg), and were transformed under
N2. Technical grade EtOAc and hexane were used for column chroma-
tography and distilled before use. All reactions were monitored by
TLC using silica gel F254 plates. The products were purified by col-
umn chromatography on silica gel (60–120 mesh and 100–200 mesh)
packed in a glass column. Optical rotations of chiral compounds were
measured with a digital polarimeter using 1 mL cell of 1 dm path
length. FT-IR spectra were recorded on KBr disc or neat. The 1H and
13C NMR spectra were recorded in CDCl3 and CD3OD on a Bruker 300,
400, and 500 MHz instruments at ambient temperature. Mass spectra
were recorded on Micro mass VG 7070H mass spectrometer for EI, VG
Autospec mass spectrometer for FABMS, and micromass Quatro LC-
triple quadrupole mass spectrometer for ESI analysis.
(S)-5,8a-Dimethyl-3,4,8,8a-tetrahydro-2H-spiro[naphthalene-1,2′-
[1,3]dioxolan]-6(7H)-one (12)
To a stirred solution of enone 11 (1.05 g, 5.46 mmol) in benzene (20
mL) were sequentially added PTSA (94 mg, 0.546 mmol) and ethylene
glycol (0.36 mL, 6.55 mmol) at rt. The resulting mixture was stirred
vigorously overnight at 110 °C using a Dean–Stark apparatus. After
cooling, the resulting solution was poured into aq NaHCO3 at 0 °C. The
organic phase was separated, and the aqueous layer was extracted
with Et2O (3 × 50 mL). The combined extracts were washed with
brine, dried (MgSO4), and concentrated under reduced pressure. The
resulting residue was purified by flash column chromatography, elut-
ing with EtOAc/hexane (2:8) to afford 12 as a white solid; yield: 1.16 g
(90%); mp 51–53 °C; Rf = 0.57 (35% Et2O in hexane); []D25 +103.38 (c
0.46, CHCl3).
IR (neat): 2951, 1665, 1337, 1163, 1092, 1029, 920 cm–1
.
1H NMR (500 MHz, CDCl3):  = 4.00–3.89 (m, 4 H), 2.74–2.70 (m, 1 H),
2.49–2.35 (m, 2 H), 2.23 (td, J = 13.0, 8.0, 5.5 Hz, 1 H), 2.18–2.10 (m, 1
H) 1.88 (td, J = 13.5, 8.5, 5.0 Hz, 2 H), 1.83–1.77 (m, 4 H), 1.72–1.57 (m,
4 H), 1.32 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 198.3, 159.9, 129.8, 112.5, 65.1, 64.8,
45.0, 33.4, 29.4, 26.3, 26.2, 21.2, 20.6, 11.2.
2-Methyl-2-(3-oxopentyl)cyclohexane-1,3-dione (10)
To a stirred solution of 2-methyl-1,3-cyclohexadione (7; 5.0 g, 39.63
mmol) in EtOAc (200 mL) were added Et3N (6.62 mL, 47.55 mmol) and
ethyl vinyl ketone (4.51 mL, 45.57 mmol) at rt. The resulting mixture
was heated at 70 °C for 10 h. Then, the mixture was cooled to rt, dilut-
ed with H2O (100 mL), and stirred for 15 min. The organic layer was
separated, and the aqueous layer was extracted with EtOAc (3 × 100
mL). The combined organic layers were washed with brine, dried
(Na2SO4), and concentrated under reduced pressure. The resulting
residue was purified by column chromatography on silica gel eluting
with EtOAc/hexane (1:3) to afford 10 as a colorless oil; yield: 7.66 g
(92%).
1H NMR (500 MHz, CDCl3):  = 2.76–2.70 (m, 2 H), 2.62 (ddd, J = 16.0,
7.0, 5.0 Hz, 2 H), 2.38 (q, J = 14.5, 7.0 Hz, 2 H), 2.31 (t, J = 7.0 Hz, 2 H),
2.08–2.00 (m, 3 H), 1.93–1.85 (m, 1 H), 1.23 (s, 3 H), 1.02 (t, J = 7.5 Hz,
3 H).
13C NMR (125 MHz, CDCl3):  = 210.1, 209.9, 64.3, 37.6, 36.9, 35.8,
29.7, 19.8, 17.5, 7.6.
ESI-MS: m/z = 237 [M + H]+.
(8aS)-5,5,8a-Trimethylhexahydro-2H-spiro[naphthalene-1,2′-
[1,3]dioxolan]-6(5H)-one (13)
To a stirred refluxing solution of Li (519 mg, 74.8 mmol, 4.31 equiv) in
liquid ammonia (100 mL) and THF (20 mL) at –40 °C was added a
solution of 12 (4.09 g, 17.32 mmol) in anhyd THF (50 mL). The result-
ing solution was stirred at the same temperature for 1 h and MeI
(10.78 mL, 173.2 mmol, 10.0 equiv) was added as rapidly as possible.
After stirring for 1.5 h, the reaction was quenched with solid NH4Cl
(10 g) and allowed to reach rt until most of all ammonia was evapo-
rated. The mixture was then poured into H2O (20 mL) and extracted
with Et2O (3 × 50 mL). The combined organic extracts were washed
with brine, dried (MgSO4), and concentrated in vacuo. The residue
was purified by column chromatography on silica gel eluting with
EtOAc/hexane (1:5) to afford 13 as a yellow solid; yield: 2.84 g (65%);
mp 67–69 °C; Rf = 0.48 (25% EtOAc in hexane); []D25 –32.61 (c 1.308,
CHCl3).
(S)-5,8a-Dimethyl-3,4,8,8a-tetrahydronaphthalene-1,6(2H,7H)-di-
one (11)
To a stirred solution of 10 (3 g, 14.26 mmol) in DMF (210 mL) was se-
quentially added L--phenylalanine (2.35 g, 14.26 mmol) and D-CSA
(1.65 g, 7.13 mmol) at rt under N2 atmosphere. The resulting mixture
was stirred at the same temperature for 24 h. Then, the mixture was
IR (neat): 2927, 2856, 1700, 1600, 1457, 1178, 1070, 753 cm–1
.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–I

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J. S. Reddy et al.
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Synthesis
1H NMR (500 MHz, CDCl3):  = 43.96–3.83 (m, 4 H), 2.61 (ddd, J = 15.5,
14.0, 6.5 Hz, 1 H), 2.33 (ddd, J = 11.5, 6.0, 5.5 Hz, 1 H), 1.94 (td, J = 13.5,
5.0 Hz, 1 H), 1.85 (dd, J = 12.0, 3.5 Hz, 1 H), 1.74–1.64 (m, 3 H), 1.56–
1.43 (m, 4 H), 1.23 (s, 3 H), 1.07 (3 H), 1.03 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 216.5, 112.8, 65.1, 64.7, 49.0, 47.6,
42.6, 34.4, 30.1, 29.7, 25.3, 22.8, 21.7, 21.5, 15.9.
(6S,8aS)-6-(Benzyloxy)-5,5,8a-trimethyloctahydronaphthalen-
1(2H)-one (6)
To a stirred solution of ketal 15 (1.3 g, 3.77 mmol) in THF (10 mL) was
added aq 3 N HCl (5 mL) at rt. The resulting mixture was stirred at the
same temperature for 10 h and then partitioned between H2O (20 mL)
and Et2O (20 mL). The organic phase was separated, and the aqueous
layer was extracted with Et2O (3 × 30 mL). The combined organic lay-
ers were washed with sat. aq NaHCO3, brine, dried (MgSO4), and con-
centrated in vacuo. The residue was purified by column chromatogra-
phy on silica gel using EtOAc/hexane (1:10) as eluent to afford 6 as a
white solid; yield: 1.07 g (95%); mp 54–56 °C; Rf = 0.4 (10% EtOAc in
hexane); []D25 +14.80 (c 0.40, CHCl3).
ESI-MS: m/z = 275 [M + Na]+.
(6S,8aS)-5,5,8a-Trimethyloctahydro-2H-spiro[naphthalene-1,2′-
[1,3]dioxolan]-6-ol (14)
To a stirred solution of LiAlH4 (258 mg, 6.53 mmol) in Et2O (20 mL)
was added dropwise a solution of 13 (1.5 g, 5.94 mmol) in Et2O (20
mL) at –10 °C under N2. The resulting mixture was allowed to reach rt
and stirred for 24 h. Then the mixture was cooled to 0 °C and the ex-
cess of LiAlH4 was quenched with a minimum amount of sat. aq NH4-
Cl. The mixture was filtered through a pad of Celite and washed with
Et2O several times. The combined organic layers was washed with
brine, dried (MgSO4), and concentrated in vacuo. The residue was pu-
rified by column chromatography on silica gel eluting with EtOAc/
hexane (1:9) to afford 14 (1.33 g, 88%) as a white solid; mp 83–85 °C;
Rf = 0.40 (25% EtOAc in hexane); []D25 –16.66 (c 0.44, CHCl3).
IR (neat): 2941, 2867, 1706, 1456, 1113, 772 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.32–7.27 (m, 4 H), 7.24–7.7.20 (m, 1
H), 4.64 (d, J = 12.0 Hz, 1 H), 4.39 (d, J = 12.0 Hz, 1 H), 2.88–2.85 (m, 1
H), 2.54 (td, J = 14.0, 7.5 Hz, 1 H), 2.18–2.14 (m, 1 H), 2.07–2.01 (m, 1
H), 1.93–1.89 (m, 1 H), 1.75–1.63 (m, 3 H), 1.57–1.44 (m, 3 H), 1.13 (s,
3 H), 1.09 (dd, J = 11.5, 3.0 Hz, 1 H), 0.98 (s, 3 H), 0.92 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 215.3, 139.1, 128.1, 127.4, 127.2, 85.4,
71.3, 53.0, 48.6, 39.7, 37.4, 31.0, 28.0, 26.2, 22.3, 20.6, 18.5, 16.7.
ESI-HRMS: m/z calcd for C20H28O2Na [M + Na]+: 323.1987; found:
323.2000.
IR (neat): 3440, 2944, 2873, 1458, 1107, 1042, 951 cm–1
.
1H NMR (500 MHz, CDCl3):  = 3.95–3.88 (m, 3 H), 3.85–3.80 (m, 1 H),
3.24 (dd, J = 10.0, 4.5 Hz, 1 H), 1.70–1.29 (m, 11 H), 1.04 (s, 3 H), 0.98
(s, 3 H), 0.79 (s, 3 H).
(2S,6S,8aS)-6-(Benzyloxy)-5,5,8a-trimethyl-2-(2-oxopropyl)octa-
hydronaphthalen-1(2H)-one (5)
13C NMR (125 MHz, CDCl3):  = 113.2, 78.6, 65.1, 64.7, 48.1, 43.0, 38.8,
30.3, 28.6, 27.9, 27.0, 23.0, 20.5, 16.4, 15.3.
ESI-HRMS: m/z calcd for C15H27O3 [M + H]+: 255.1960; found:
255.1968.
To a stirred solution of ketone 6 (1.3 g, 4.32 mmol) in THF (15 mL) was
added LDA (5.19 mL, 5.19 mmol, 1.2 equiv, 1.0 M in THF) at 0 °C. The
resulting mixture was stirred for 15 min at the same temperature. Af-
ter that, a solution of Me3SiCl (0.65 mL, 5.19 mmol, 1.2 equiv) and
Et3N (0.72 mL, 5.19 mmol, 1.2 equiv) in THF (5 mL) were added at the
same temperature. The resulting mixture was stirred at the same
temperature for 1 h. The mixture was diluted with hexane (20 mL),
sat. aq sodium potassium tartrate (20 mL) was added, and stirred vig-
orously for 1 h at rt. The organic phase was separated, and the aque-
ous layer was extracted with Et2O (2 × 20 mL). The combined organic
layers were washed with brine, dried (MgSO4), and concentrated in
vacuo to give the corresponding silyl enol ether (1.3 g, 3.48 mmol),
which was directly used in the next step without purification.
(6S,8aS)-6-(Benzyloxy)-5,5,8a-trimethyloctahydro-2H-
spiro[naphthalene-1,2′-[1,3]dioxolane] (15)
To a flame-dried two-necked flask equipped with a stir bar and NaH
(98 mg, 60% dispersion in mineral oil, 4.11 mmol) in DMF (4 mL) was
added dropwise a solution of 14 (350 mg, 1.37 mmol) in DMF (2 mL)
at 0 °C. The resulting mixture was stirred for 1 h at rt and treated with
benzyl bromide (0.24 mL, 2.05 mmol) at the same temperature. The
resulting mixture was allowed to reach rt and stirred for 24 h. After
completion of the reaction, the mixture was cooled to 0 °C, quenched
with ice, and partitioned between H2O (10 mL) and EtOAc (10 mL).
The organic phase was separated, and the aqueous layer was extract-
ed with EtOAc (3 × 20 mL). The combined organic layers were washed
with brine, dried (Na2SO4), and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel us-
ing eluent EtOAc/hexane (2:98) to afford 15 as a colorless oil; yield:
444 mg (94%); Rf = 0.40 (10% EtOAc in hexane); []D25 +19.03 (c 0.60,
CHCl3).
To a stirred solution of the above crude silyl enol ether (1.3 g, 3.48
mmol) in THF (15 mL) containing 4Å molecular sieves at 0 °C was
added allyl bromide (1.50 mL, 17.44 mmol, 5.0 equiv) and a suspen-
sion of BTAF (977 mg, 5.22 mmol, 1.5 equiv) in THF (2 mL). The result-
ing mixture was stirred for 3 h at rt. After completion of the reaction,
the mixture was filtered and the filtrate was concentrated in vacuo.
The residue was purified by column chromatography to obtain the al-
lylated compound (1.01 g) as a 1:1 mixture of epimers. Then it was
dissolved in MeOH, treated with K2CO3 (0. 5 g), and allowed to stir at
rt for 3 h. CH2Cl2 was added to the mixture and filtered through a pad
of Celite. Concentration of the filtrate in vacuo afforded the allyl com-
pound as a colorless liquid and as a single isomer (0.9 g, 60%), which
was used directly in the next step without purification.
IR (neat) : 2944, 2872, 1455, 1109, 1066, 949 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.36–7.23 (m, 5 H), 4.66 (d, J = 12.0 Hz,
1 H), 4.42 (d, J = 12.0 Hz, 1 H), 3.96–3.88 (m, 3 H), 3.86–3.79 (m, 1 H),
2.96 (dd, J = 10.0, 5.0 Hz, 1 H), 1.89–1.82 (m, 1 H), 1.69–1.65 (m, 1 H),
1.63–1.57 (m, 1 H), 1.53–1.23 (m, 8 H), 1.06 (s, 3 H), 0.99 (s, 3 H), 0.85
(s, 3 H).
13C NMR (125 MHz, CDCl3):  = 139.4, 128.0, 127.3, 127.1, 113.3, 86.1,
71.2, 65.1, 64.6, 48.6, 43.0, 38.8, 30.3, 28.5, 28.1, 23.1, 22.5, 20.4, 16.5,
16.3.
To a stirred solution of the above allyl compound (900 mg, 2.64
mmol) in DMF/H2O (9:1, 12 mL) was sequentially added PdCl2 (70 mg,
0.39 mmol) and CuCl (261 mg, 2.64 mmol). The resulting dark brown
solution was stirred at rt and under O2 at atmospheric pressure for 8
h. After completion of the reaction (as indicated by TLC analysis), H2O
(5 mL) and EtOAc (20 mL) were added. The organic phase was separat-
ed, and the aqueous phase was extracted with EtOAc (2 × 50 mL). The
combined organic layers were washed with H2O (3 × 15 mL) and
brine, dried (Na2SO4), and concentrated under reduced pressure. The
ESI-MS: m/z = 367 [M + Na]+.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–I

F
J. S. Reddy et al.
Paper
Synthesis
residue was purified by column chromatography on silica gel using
EtOAc/hexane (1:5) as eluent to afford 1,4-diketone 5 as a colorless
oil; yield: 756 mg (61% over 4 steps); Rf = 0.4 (20% EtOAc in hexane);
[]D25 +8.31 (c 0.16, CHCl3).
1H NMR (500 MHz, CDCl3):  = 7.36–7.33 (m, 4 H), 7.28–7.24 (m, 1 H),
5.66 (d, J = 1.0 Hz, 1 H), 4.68 (d, J = 11.5 Hz, 1 H), 4.44 (d, J = 11.5 Hz, 1
H), 2.95 (dd, J = 11.5, 4.0 Hz, 1 H), 2.46–2.42 (m, 1 H), 2.33–2.28 (m, 1
H), 2.01–1.96 (m, 1 H), 1.94–1.89 (m, 1 H), 1.82 (dt, J = 12.5, 3.0 Hz, 1
H), 1.78–1.73 (m, 1 H), 1.67–1.53 (m, 3 H), 1.71 (s, 3 H), 1.15 (d, J = 7.5
Hz, 3 H), 1.12–1.03 (m, 2 H), 0.94 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 211.8, 191.5, 139.0, 128.2, 127.4,
127.3, 121.0, 85.7, 71.5, 52.8, 48.0, 47.0, 39.7, 39.4, 34.8, 34.4, 28.3,
22.7, 20.9, 19.6, 16.6, 14.8.
IR (neat): 2937, 1705, 1455, 1359, 1102, 772 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.35–7.30 (m, 4 H), 7.28–7.24 (m, 1 H)
4.67 (d, J = 12.0 Hz, 1 H), 4.41 (d, J = 12.0 Hz, 1 H), 3.28–3.21 (m, 1 H),
2.91–2.86 (m, 2 H), 2.19 (s, 3 H), 2.12–2.06 (m, 2 H), 1.96–1.92 (m, 1
H), 1.83–1.74 (m, 2 H), 1.62–1.49 (m, 3 H), 1.25–1.16 (m, 5 H), 1.07
(dd, J = 12.0, 3.5 Hz, 1 H), 0.99 (s, 3 H), 0.95 (s, 3 H).
ESI-HRMS: m/z calcd for C24H32O2Na [M + Na]+: 353.2471; found :
353.2473.
13C NMR (75 MHz, CDCl3):  = 214.5, 207.4, 139.1, 128.1, 127.5, 127.3
127.2, 85.4, 71.3, 53.8, 48.3, 43.3, 41.5, 39.8, 33.0, 33.0, 31.0, 30.4,
27.9, 22.3, 20.8, 18.4, 16.6.
Ethyl (Z)-7-[(tert-Butyldimethylsilyl)oxy]-2-methylhept-2-enoate
(19a)
ESI-HRMS: m/z calcd for C23H32O3Na [M + Na]+: 357.2430; found:
To a stirred solution of phosphonate 18 (347 mg, 1.0 mmol) in THF (8
mL) was added 18-crown-6 (275 mg, 1.04 mmol) in MeCN and
KHMDS (1.0 mL, 1.0 mmol, 1.0 M solution in THF) at –78 °C over a
period of 5 min. After stirring at the same temperature for 20 min, al-
dehyde 17 (216 mg, 1.0 mmol) was added and stirred for 1.5 h at the
same temperature. The reaction was quenched with sat. aq NH4Cl (10
mL). The organic phase was separated, and the aqueous phase was ex-
tracted with Et2O (2 × 15 mL). The combined extracts were washed
with H2O and brine, dried (Na2SO4), and concentrated in vacuo. The
resulting residue was purified by column chromatography on silica
gel eluting with EtOAc/hexane (1:20) to furnish the Z-isomer 19a as
pale yellow oil; yield: 222 mg (74%); Rf = 0.5 (5% EtOAc in hexane).
357.2443.
(3aS,7S,9aS)-7-(Benzyloxy)-6,6,9a-trimethyl-3,3a,4,5,5a,6,7,8,9,9a-
decahydro-2H-cyclopenta[a]naphthalen-2-one (16)
To a stirred solution of diketone 5 (750 mg, 2.10 mmol) in anhyd THF
(20 mL) was added NaH (60% in mineral oil; 252 mg, 10.51 mmol) at
0 °C. The resulting mixture was allowed to reach rt and stirred for 5 h.
Then the mixture was refluxed for 2 h and then cooled to 0 °C and
quenched with H2O (5 mL). The organic phase was separated, and the
aqueous layer was extracted with Et2O (2 × 15 mL). The combined or-
ganic phases were washed with brine, dried (Na2SO4), and concen-
trated in vacuo. The crude material was purified by column chroma-
tography on silica gel column eluting with EtOAc/hexane to afford the
tricyclic enone 16 as a white solid; yield: 534 mg (75%); mp 91–93 °C;
Rf = 0.35 (10% EtOAc in hexane); []D25 –67.23 (c 0.3, CHCl3).
(Z)-7-[(tert-Butyldimethylsilyl)oxy]-2-methylhept-2-en-1-ol (20)
To a stirred solution of 19a (346 mg, 1.15 mmol) in CH2Cl2 (8 mL) was
added DIBALH (4.6 mL, 4.6 mmol, 1 M in hexane) at 0 °C. After stir-
ring at the same temperature for 20 min, the mixture was allowed to
warm to rt and stirred for 2 h. After the reaction mixture was
quenched with 10% aq Rochelle salt (10 mL) at 0 °C, the mixture was
warmed to rt and stirred for 1 h. The organic phase was separated and
the aqueous phase was extracted with CH2Cl2 (3 × 15 mL). The com-
bined organic extracts were washed with H2O and brine, dried
(Na2SO4), and concentrated in vacuo. The resulting residue was puri-
fied by column chromatography on silica gel eluting with EtOAc/hex-
ane (1:9) to furnish 20 as a colorless oil; yield: 285 mg (96%); Rf = 0.3
(10% EtOAc in hexane).
IR (neat): 2939, 2866, 1710, 1455, 1216, 1103 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.31–7.32 (m, 4 H), 7.29–7.26 (m, 1 H),
5.68 (d, J = 1.0 Hz, 1 H), 4.69 (d, J = 12.0 Hz, 1 H), 4.44 (d, J = 11.5 Hz, 1
H), 2.96 (dd, J = 11.0, 4.0 Hz, 1 H), 2.94–2.88 (m, 1 H), 2.55 (dd, J =
19.0, 6.5 Hz, 1H), 2.28–2.23 (m, 1 H), 2.01–1.96 (m, 1 H), 1.94 (dd, J =
18.5, 2.0 Hz, 1 H), 1.82–1.55 (m, 4 H), 1.19 (s, 3 H), 1.07 (dd, J = 9.5, 4.0
Hz, 1 H), 1.03–0.88 (m, 8 H).
13C NMR (75 MHz, CDCl3):  = 209.5, 193.8, 138.9, 128.1, 127.3, 127.3,
122.1, 85.6, 71.4, 53.0, 42.2, 39.6, 39.5, 38.2, 35.4, 34.7, 28.2, 22.6,
20.9, 19.3, 16.5.
1H NMR (300 MHz, CDCl3):  = 5.29 (t, J = 7.5 Hz, 1 H), 4.12 (s, 2 H),
3.60 (t, J = 6.3 Hz, 2 H), 2.06 (q, J = 14.7, 7.5 Hz, 2 H), 1.79 (s, 3 H),
1.55–1.46 (m, 2 H), 1.42–1.33 (m, 2 H), 0.89 (s, 9 H), 0.04 (s, 6 H).
13C NMR (75 MHz, CDCl3):  = 134.4, 128.3, 63.0, 61.4, 32.3, 27.2, 26.2,
25.9, 21.1, 18.3, -5.3.
ESI-MS: m/z = 339 [M + H]+.
(3S,3aS,5aR,7S,9aS)-7-(Benzyloxy)-3,6,6,9a-tetramethyl-
3,3a,4,5,5a,6,7,8,9,9a-decahydro-2H-cyclopenta[a]naphthalen-2-
one (3)
ESI-MS: m/z = 259 [M + H]+.
To a stirred solution of enone 16 (520 mg, 1.53 mmol) in THF (8 mL)
was added LiHMDS (1.68 mL, 1.68 mmol, 1 M in THF) at 0 °C, over a
period of 5 min. The resulting pale yellow solution was stirred at 0 °C
for 1 h, then cooled to –40 °C, and was sequentially treated with
HMPA (0.5 mL) and MeI (0.10 mL, 1.68 mmol). The reaction mixture
was allowed to warm to 0 °C and stirred for 1 h, and then quenched
with H2O (10 mL). The organic phase was separated, and the aqueous
phase was extracted with Et2O (2 × 15 mL). The combined extracts
were washed with H2O and brine, dried (Na2SO4), and concentrated in
vacuo. The resulting residue was purified by silica gel column chro-
matography on silica gel eluting with EtOAc/hexane (3:7) to furnish
the methylated enone 3 as a white solid; yield: 399 mg (74%); mp 87–
89 °C; Rf = 0.4 (20% EtOAc in hexane); []D25 –92.17 (c 0.34, CHCl3).
(Z)-7-(Benzyloxy)-6-methylhept-5-en-1-ol (21)
To a flame-dried round-bottomed flask (100 mL) charged with a mag-
net stir bar and NaH (60% in mineral oil; 69 mg, 2.90 mmol) was add-
ed THF (10 mL) and the mixture was stirred at 0 °C. After stirring the
mixture at the same temperature for 10 min, a solution of alcohol 20
(250 mg, 0.96 mmol) in THF (5 mL) and benzyl bromide (0.17 mL,
1.44 mmol) were sequentially added. After that, the reaction mixture
allowed to warm to rt and stirred for 12 h. The mixture was quenched
with H2O (10 mL) at 0 °C. The mixture was warmed to rt and vigor-
ously stirred for 10 min. The organic phase was separated, and the
aqueous phase was extracted with EtOAc (3 × 15 mL). The combined
extracts were washed with H2O and brine, dried (Na2SO4), and con-
centrated in vacuo. The resulting residue was purified by column
IR (neat): 3447, 2945, 2877, 1706, 1464, 1135, 769 cm–1
.
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–I

G
J. S. Reddy et al.
Paper
Synthesis
chromatography on silica gel eluting with EtOAc/hexane (1:19) to fur-
nish the benzyl ether as a colorless oil; yield: 301 mg (90%); Rf = 0.5
(10% EtOAc in hexane).
ESI-HRMS: m/z calcd for C15H20O3Na [M + Na]+: 271.1310; found:
271.1325.
(R,Z)-4-Benzyl-3-[7-(benzyloxy)-6-methylhept-5-enoyl]oxazoli-
din-2-one (24)
The above compound (300 mg, 0.86 mmol) in THF (10 mL) was stirred
at 0 °C for 10 min and treated with TBAF (1.29 mL, 1.29 mmol, 1 M in
THF). After that, the mixture was allowed to warm to rt and the stir-
ring was continued for 6 h. The mixture was quenched with H2O (10
mL) at rt and vigorously stirred for 30 min. The organic phase was
separated, and the aqueous phase was extracted with EtOAc (3 × 15
mL). The combined organic extracts were washed with H2O and brine,
dried (Na2SO4), and concentrated in vacuo. The resulting residue was
purified by column chromatography on silica gel eluting with EtOAc/
hexane (1:5) to furnish the 21 as a colorless oil; yield: 171 mg (85%);
Rf = 0.6 (30% EtOAc in hexane).
To a stirred solution of 22 (1.0 g, 4.02 mmol) in THF (15 mL) at –20 °C
was added Et3N (1.40 mL, 10.06 mmol) and Piv-Cl (0.49 mL, 4.02
mmol). After stirring at –20 °C for 1 h, LiCl (256 mg, 6.04 mmol) fol-
lowed by (R)-4-benzyloxazolidin-2-one (23; 712 mg, 4.02 mmol)
were added at the same temperature. The resulting mixture was
stirred at –20 °C for 1 h and then at 0 °C for 2 h. The mixture was
quenched with sat. aq NH4Cl. The organic phase was separated, and
the aqueous phase was extracted with EtOAc (3 × 20 mL). The com-
bined extracts were washed with H2O, sat. aq Na2CO3 and brine, dried
(Na2SO4), and concentrated in vacuo. The resulting residue was puri-
fied by column chromatography on silica gel eluting with EtOAc/hex-
ane (1:6) to afford 24 as a colorless oil; yield: 1.42 g (87%); Rf = 0.6
(20% EtOAc in hexane); []D25 –35.56 (c 0.88, CHCl3).
IR (neat): 3450, 2932, 2873, 1458, 1219, 1067, 772 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.35–7.27 (m, 5 H), 5.38 (t, J = 7.2 Hz, 1
H), 4.46 (s, 2 H), 4.00 (s, 2 H), 3.61 (t, J = 6.3 Hz, 2 H), 2.04 (q, J = 14.7,
7.5 Hz, 2 H), 1.79 (s, 3 H), 1.62–1.51 (m, 2 H), 1.44–1.36 (m, 3 H).
13C NMR (75 MHz, CDCl3):  = 138.3, 132.0, 129.4, 128.2, 127.6, 127.4,
76.1, 71.5, 68.3, 62.4, 32.0, 27.2, 25.9, 21.0.
IR (neat): 2930, 1782, 1700, 1386, 1214, 1087, 771 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.37–7.18 (m, 10 H), 5.40 (t, J = 7.2 Hz,
1 H), 4.70–4.60 (m, 1 H), 4.46 (s, 2 H), 4.19–4.10 (m, 2 H), 4.02 (s, 2 H),
3.28 (dd, J = 13.2, 3.0 Hz, 1 H), 2.98–2.85 (m, 2 H), 2.73 (dd, J = 13.2,
9.6 Hz, 1 H), 2.13 (q, J = 15.6, 8.1 Hz, 2 H), 1.80–1.69 (m, 5 H).
ESI-HRMS: m/z calcd for C16H32O3SiNa [M + Na]+: 257.1517; found:
257.1505.
13C NMR (75 MHz, CDCl3):  = 172.9, 153.3, 138.4, 135.1, 133.0, 129.3,
128.8, 128.4, 128.2, 127.5, 127.4, 127.2, 71.5, 68.3, 66.0, 55.0, 37.7,
34.8, 26.8, 24.2, 21.5.
(Z)-7-(Benzyloxy)-6-methylhept-5-enoic Acid (22)
To a stirred solution of the oxalyl chloride (0.73 mL, 8.53 mmol) in
CH2Cl2 (10 mL) was added dropwise DMSO (1.21 mL, 17.04 mmol) at
–78 °C. After stirring at the same temperature for 15 min, a solution
of 21 (1.0 g, 4.26 mmol) in CH2Cl2 (5 mL) was added. The resulting
mixture was stirred for another 30 min at the same temperature.
Then, Et3N (2.0 mL, 2.0 mmol) was added and the stirring was contin-
ued for another 10 min at –78 °C. The reaction mixture was warmed
to rt and H2O (10 mL) was added. The organic phase was separated,
and the aqueous phase was extracted with CH2Cl2 (3 × 20 mL). The
combined organic extracts were washed with H2O, sat. aq Na2CO3 and
brine, dried (Na2SO4), and concentrated in vacuo. The resulting resi-
due was purified by column chromatography on silica gel eluting with
EtOAc/hexane (1:6) to furnish the intermediate aldehyde as a color-
less oil; yield: 821 mg (83%); Rf = 0.4 (20% EtOAc in hexane).
ESI-MS: m/z = 430 [M + Na]+.
(R)-4-Benzyl-3-[(R,Z)-7-(benzyloxy)-2,6-dimethylhept-5-
enoyl]oxazolidin-2-one (8)
To a stirred solution of 24 (950 mg, 2.33 mmol) in anhyd THF (10 mL)
at –78 °C was added LiHMDS (4.66 mL, 2.0 mmol, 1 M solution in
THF) dropwise under N2 atmosphere. After stirring at –78 °C for 30
min, MeI (0.43 mL, 6.99 mmol) was added to the reaction mixture.
The resulting mixture was stirred for another 3 h at –78 °C. The mix-
ture was quenched with sat. aq NH4Cl and warmed to rt. The organic
phase was separated, and the aqueous phase was extracted with EtOAc
(3 × 20 mL). The combined extracts were washed with H2O, sat. aq
Na2CO3 and brine, dried (Na2SO4), and concentrated in vacuo. The re-
sulting residue was purified by column chromatography on silica gel
eluting with EtOAc/hexane (1:9) to afford 8 as a colorless oil; yield:
To a stirred solution of the above aldehyde (800 mg, 3.44 mmol) in t-
BuOH/2-methyl-2-butene (20 mL, 2:1) at rt was added a mixture of
NaClO2 (622 mg, 6.88 mmol) and NaH2PO4 (825 mg, 6.88 mmol) dis-
solved in minimum amount of H2O at the same temperature. The re-
sulting yellow colored mixture was warmed to rt and stirred for 2 h.
The volatile solvents were removed under reduced pressure, H2O (20
mL) was added, and the aqueous layer was acidified to pH 3 using aq 1
N HCl. The organic phase was separated and the aqueous phase was
extracted with EtOAc (3 × 20 mL). The combined organic extracts
were washed with H2O, sat. aq Na2CO3 and brine, dried (Na2SO4), and
concentrated in vacuo. The resulting residue was purified by silica gel
column chromatography on silica gel eluting with EtOAc/hexane (1:3)
to afford 22 as a pale yellow oil; yield: 768 mg (90%); Rf = 0.4 (30%
EtOAc in hexane).
25
785 mg (80%); Rf = 0.4 (10% EtOAc in hexane); []D –46.0 (c 0.3,
CHCl3).
IR (neat): 2930, 1779, 1698, 1454, 1387, 1214, 771 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.36–7.18 (m, 10 H), 5.35 (t, J = 7.2 Hz,
1 H), 4.64–4.56 (m, 1 H), 4.45 (s, 2 H), 4.11 (d, J = 4.8 Hz, 2 H), 3.98 (s,
2 H), 3.74–3.63 (m, 1 H), 3.24 (dd, J = 13.2, 3.3 Hz, 1 H), 2.75 (dd, J =
13.2, 9.3 Hz, 1 H), 2.05 (q, J = 16.5, 7.5 Hz, 2 H), 1.88–1.77 (m, 4 H),
1.50–1.39 (m, 1 H), 1.20 (d, J = 6.9 Hz, 3 H).
13C NMR (75 MHz, CDCl3):  = 176.8, 152.9, 138.4, 135.2, 132.6, 129.3,
128.8, 128.6, 128.2, 127.6, 127.4, 127.2, 71.7, 68.3, 65.8, 55.2, 37.7,
37.2, 33.2, 25.4, 21.5, 17.4.
IR (neat): 2938, 1708, 1453, 1247, 1071, 939 cm–1
.
ESI-HRMS: m/z calcd for C26H31NO4Na [M + Na]+: 444.2151; found:
444.2169.
1H NMR (300 MHz, CDCl3):  = 7.35–7.27 (m, 5 H), 5.35 (t, J = 7.5 Hz, 1
H), 4.45 (s, 2 H), 3.99 (s, 2 H), 2.32 (t, J = 7.5 Hz, 2 H), 2.13–2.03 (m, 2
H), 1.79 (s, 3 H), 1.74–1.62 (m, 2 H).
13C NMR (75 MHz, CDCl3):  = 179.6, 138.2, 133.1, 128.2, 127.5, 127.4,
71.58, 68.1, 33.2, 26.7, 24.6, 21.5.
(R,Z)-9-(Benzyloxy)-4,8-dimethylnona-1,7-dien-3-one (4)
To a stirred solution of 8 (750 mg, 1.77 mmol) in THF/H2O (5:1, v/v, 12
mL) at 0 °C was added a mixture of 30% H2O2 (0.32 mL, 10.67 mmol)
and LiOH (105 mg, 4.42 mmol) prepared at 0 °C. After stirring at the
© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–I

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J. S. Reddy et al.
Paper
Synthesis
same temperature for 1.5 h, the reaction mixture was warmed to rt
and stirred for another 1.5 h. Then, the mixture was cooled to 0 °C
and quenched with sat. aq Na2SO3 and acidified with aq 1 N HCl to pH
5. The organic phase was separated, and the aqueous phase was ex-
tracted with EtOAc (3 × 20 mL). The combined extracts were washed
with H2O, sat. aq Na2CO3, and brine, dried (Na2SO4), and concentrated
in vacuo. The resulting residue was purified by column chromatogra-
phy on silica gel eluting with EtOAc/hexane (1:6) to afford the inter-
mediate carboxylic acid as a colorless oil; yield: 450 mg (97%); Rf = 0.4
(30% EtOAc in hexane).
References
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To a stirred solution of the above acid (450 mg, 1.71 mmol) in CH2Cl2
(12 mL) at –15 °C were added N-methylpiperidine (0.62 mL, 5.14
mmol) and isobutyl chloroformate (0.33 mL, 2.56 mmol) and the re-
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EtOAc/hexane (1:1) to afford the intermediate Weinreb amide as a
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mmol) in THF (4 mL) at 0 °C was added vinylmagnesium bromide
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was stirred for 2 h at the same temperature. The reaction mixture was
quenched with sat. aq NH4Cl (20 mL), the organic phase was separat-
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combined organic extracts were washed with H2O and brine, dried
(Na2SO4), and concentrated in vacuo. The resulting residue was puri-
fied by column chromatography on silica gel eluting with EtOAc/hex-
ane (1:9) to afford 4 as a colorless oil; yield: 226 mg (85%); Rf = 0.4
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IR (neat): 2930, 1779, 1698, 1454, 1387, 1214, 771 cm–1
.
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1H NMR (300 MHz, CDCl3):  = 7.34–7.25 (m, 5 H), 6.40 (dd, J = 17.4,
10.5 Hz, 1 H), 6.23 (dd, J = 17.4, 1.5 Hz, 1 H), 5.74 (dd, J = 10.2, 1.5 Hz,
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13C NMR (75 MHz, CDCl3):  = 203.6, 138.4, 135.0, 132.7, 128.6, 128.2,
127.9, 127.5, 127.4, 71.7, 68.3, 42.7, 32.9, 25.2, 21.6, 16.3.
ESI-MS: m/z = 273 [M + H]+.
Acknowledgment
J.S.R. and M.G.B. thank UGC, New Delhi for financial support. P. Mani-
mala and A. Rammohan thank JSY for support. JSY thanks CSIR and
DST for Bhatnagar and JC Bose fellowships.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1691494.
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© 2019. Thieme. All rights reserved. Synthesis 2019, 51, A–I